- Journal of SOPI
Transcription
- Journal of SOPI
F E NC A MACOVIG R A IL H P (INDIA) JOURNAL OF PHARMACOVIGILANCE & DRUG SAFETY • VOLUME 9 • NUMBER 1 • SOCIETY O JANUARY - MARCH, 2010 NUMBER 1 VOLUME 7 JANUARY - MARCH, 2010 • PAGES 1-52 Journal of Pharmacovigilance & Drug Safety (Official Publication of Society of Pharmacovigilance, India) Volume 7, No 1, 2010 Society of Pharmacovigilance (India) Patron: Prof. K.C. Singhal Treasurer: Dr. Govind Mohan President: Prof. R.K.Goyal Vice President Prof. Meera Desai Secy. International Affairs Co-ordinator Asia Pacific Dr. S. Ziaur Rahman Prof. J.F. Knight Secretary: Dr. Sandeep Agarwal Editor - in - Chief Dr. Anurag Tomar Executive Committee Dr. R.N. Acharya (Jamnagar) Dr. Priti Baijal (Delhi) Dr. Pramod Mediratta (Delhi) Dr. G.P. Rauniar (Nepal) Dr. Surendra K. Goyal (Sirsa) Dr. Arunabha Ray (Delhi) Dr. Y.P. Singla (Sirsa) Prof. D.D. Santani (Ahmedabad) Organizing Secretary Immediate Past President Dr. H.S. Rehan (Delhi) Dr. K.K. Sharma (Delhi) Editorial Board Editor-in-Chief Dr. Anurag Tomar Dr. B.R. Madan (Jaipur) Dr. R.K. Goyal (Vadodara) Dr. M.C. Sharma (Jaipur) Dr. Sandhya Kamat (Mumbai) Dr. S.K. Tripathi (Kolkata) Dr. Urmila Thatte (Mumbai) Dr. V.N. Sharma (Jaipur) Dr. Shobha Kulshresthra (Jaipur) Dr. Pramil Tiwari (SAS Nagar) Dr. Sagun Desai (Karamsad) Dr. Naresh Khanna (Delhi) Dr. R. Balaraman (Vadodara) International Advisory Board Dr. Dr. Dr. Dr. Ralph Edwards (Sweden) G.P. Velo (Italy) P. Subish, (Nepal) John Autian (USA) Dr. Dr. Dr. Dr. Sten Olsson (Sweden) R.H.B. Meyboon (Sweden) Chris J.VanBoxtel (Holland) Abha Agarwal (U.S.A.) Journal of Pharmacovigilance & Drug Safety (ISSN 0972-8899) is published by the Society of Pharmacovigilance, India (SOPI). Journal is provided free of charge to Life members. For institutional library annual subscription is Rs. 2000/- and for individuals Rs. 500/- per annum. Loose issues will not be sold. Manuscripts and illustration for publication should be sent to Dr. Anurag Tomar, Editor-in Chief, Journal of Pharmacovigilance & Drug Safety, NIMS City Centre, 4 Govind Marg, Jaipur - 302004 India. Email [email protected] Please refer to instruction for Authors, for additional information concerning preparation of manuscripts for publication. FOR YOUR KIND ATTENTION ? The Views expressed by the authors do not necessarily reflect those of the sponsor or publisher. Although every care has been taken to ensure technical accuracy, no responsibility is accepted for errors of omissions. ? The claims of the manufacturers and efficacy of the products advertised in the journal are the responsibility of the advertiser. The journal does not own any responsibility for the guarantee of the products advertised Journal of Pharmacovigilance & Drug Safety January - March, 2010 Volume 7 : Number 1 Particulars Page From the Desk of the Editor Contents..... John Autian Oration-2009 1-6 BRUCE HUGMAN Pharmacogenomics: The Future of Pharmacovigilance 7-8 SANTANU K. TRIPATHI Cholesterol Lowering Potential Of Seabuckthorn 9-13 IMRAN ZAFAR, M. FAHIM Off Label Drug Treatment and Related Problem in Children 14-17 CHETAN MEHNDIRATTA, SYED ZIAUR RAHMAN, PIPASHA BISWAS Nanobiotechnology Today: Focus on Nanoparticles 18-26 ANSHUL KUMAR, IMRAN ZAFAR A Retrospective Comparison of Buprenorphine & Pentazocine as an Analgesic in AMI at Pravara Rural Hospital. 27-31 RAHUL KUNKULOL, PRONOB K SANYAL, KAILAS R. GADEKAR, Y GRIDHAR REDDY Biosafety Issues In Laboratories: A Review 32-37 AMIT JAIN, ZAHRA HASHEMI Pharmacovigilance of Homeopathy - Questioning its Efficacy 38-42 DINESH K. JAIN, RAJ K. ARYA Risks and Recall of Medicines Pharmacovigilance Perspective ADITI NIGAM, ETHIRAJ DHANARAJ, PRAMIL TIWARI Events NEWS & CONFERENCE ANNOUNCEMENTS 43-52 In the modern era of clinical application of knowledge of pharmacology, it is a big dilemma in choosing between the good and the best drug. In making a decision for treatment planning clinician must consider the additional features of local and systemic issues, patient's economic status as well as potential adverse effect of the drug. There are large number of drug trial going on world wide to observe the effect of a particular drug or a molecule. However, the scenario has changed drastically in last 20 years. What it was with the western/ developed world is now shifting over to developing world. India is set to grab clinical trial business, making the subcontinent world's preferred destination for clinical trials. The big reason being low cost of trial along with friendly drug control system with competent work force and patient availability. Indian investigators and clinical trial research professionals have already demonstrated their medical and scientific skills in various global clinical trials. It is time now to capitalize on this opportunity. Indian investigators and research professionals can prove their ability and show to the world and register their presence now as well as for future. Clinical trials can provide answers related to the use or not to use a therapeutic agent that can benefit millions of patients in India and worldwide contributing to global drug research and development programme. It takes a huge amount of money to bring one drug to market through a series of procedure, but the success rate is variable. Therefore, we clinicians, researchers, pharmacologists and all the people related should have drug safety as our primary concern. And that concern can only be translated to human welfare if we are documenting the good as well adverse effect of a particular drug, whether new or old. The journal here provides a platform to document all the drug related events. With the request to all the members and readers to kindly document and submit their articles in the journal. I thank the members of editorial board in helping me to come out with another issue of the esteemed journal. Dr. Anurag Tomar MBBS, MD (Pediatrics) Editor in Chief J Pharmcovig Drug Safety 2010 (January-March) Volume : 7 Issue : 1 (Page 1-6) John Autian Oration-2009 BRUCE HUGMAN PO. Box 246 Amphur Muang, Chiang, Rai Thailand 57000 The Front Line he didn't. What did the pharmacist say? Take one tablet three times a day after meals. I have been to that hospital. It is inundated with patients: the wards are overflowing and the corridors are heaving with queues of people waiting for attention. Everyone on the staff is doing their best, but the odds against the delivery of universally effective healthcare are depressingly large. Lives are saved, bodies are repaired, wounds are stitched, disease is treated but, I suspect, it is a lottery, the risks of which the wealthy and educated would never tolerate. Today, I am not concerned with the political, economic and financial issues of healthcare, urgent and enormous though those are; no, I want to remind us that this is life as it is experienced at the front line, as it is for so many people, in so many countries, where there are healthcare services at all. I want to take you on a journey to the front line, the front line where patients are sick or at risk and where doctors and nurses, pharmacists and traditional healers are struggling to make people well; the front line where, like in a battle or the aftermath of a natural disaster, the priorities and needs are urgent and vivid. I want to see what we can learn from the messy and dramatic reality of the front line, and how what we learn there might influence our thinking and practice in pharmacovigilance and patient safety. Signposts For The Journey On this journey to the front line, I shall pause to consider a number of questions, including: F Why treatment often fails to be as safe as it should be, and what can be done F Why status differentials compromise many aspects of patient safety F Why HCPs are less committed than we would wish to reporting ADRs F Why we should pay attention to Honda worldwide and to Mrs Gupta and the millions of street traders in India F Why listening at the front line is critical for success F Why we in PV need to be well-known and trusted Neglected At Hospital Well Documented Problems I started with an anecdote which raises deep concerns for me, but that is not a good enough basis on which to develop a serious professional argument. I must at least refer to the research which tells us that there really are widespread problems at the front line. You know it already: the prevalence of adverse reactions and the morbidity and mortality associated with them; the frequency of medical and medication errors; staggeringly low levels of patient compliance around the world (WHO estimates that 50% may be near the mark in many places); dangerously irrational prescribing of antibiotics; the incursion of substandard and counterfeit medicines, among the major headline issues. All of this is extensively and dramatically documented in the literature: at the heart of healthcare there are radical, dangerous problems and deficiencies, which have proved extremely difficult to moderate or remedy. Many of these fall within our areas of interest and responsibility. Let us start with a very low-level anecdote. I am the guardian of a lovely piece of land in the north of Thailand. I am not the owner, because foreigners are not allowed to own land in Thailand, but I care for it as if it were my own, and have replanted what was a bare hillside with thousands of trees. For many years now, the serious daily work has been done by farmworker, Mr Tom, originally from a poor hill-tribe village on the border with Burma. He is neither clever nor literate, but he is loyal and hard-working. Recently he had some trouble with his left leg swelling and went to the busy government hospital in the local market town. When he returned I asked him what had happened. The doctor had given him some pills, he told me, showing me a small plastic bag with his name on it. What was the problem? I asked. The doctor didn't say. What will the pills do? The doctor didn't say. Did he ask to see you again? No How, then, do our concerns about PV and patient safety relate to the front line, this place of human drama and frequent failure? What Went Wrong? Let me return to the story of my farmworker, Mr Tom. The problems and failures are illuminating. First, the characteristics of the actors 1 John Autian Oration-2009 The doctor was under extreme pressure of time 8F The doctor did not feel any need to explain anything to 8F the patient, and so The doctor dealt with the patient as an object on a rapidly moving production line The patient was deferential and undemanding 8F The pharmacist dispensed the pills and nothing 8F more What were the risks of a consultation of this kind? Under such pressure of time, both diagnostic and 8F medication errors are more likely The patient had no understanding of the cause of the 8F symptoms and therefore how to remedy or prevent them with or without drugs in the future The patient did not know what drugs he was 8F prescribed, how they worked, what effects they would have nor what risks they carried There was no secondary patient information about the 8F medicine, which was dispensed in a plastic bag from bulk supplies. (Even if there had been printed material this patient could not have read it in any case.) The patient left the consultation essentially untouched 8F personally, emotionally, intellectually, and with no new knowledge about his body, the disease or about medicines What are the chances of an ADR experienced by this patient being recognised and reported by anyone? What are the chances of this patient becoming a more intelligent, critical and rational user of medicines? Before I am finished, I shall make some suggestions as to how we can begin to address some of these problems, but first I want to take our analysis a bit further. The Social And Professional Context What are some of the social and professional characteristics which support and intensify some of the problems we've identified? India, like many Asian countries, has what the sociologists call a High Power Distance Indicator. This describes the distance, and the differences in personal freedom to act between the powerful, wealthy and educated from those who are relatively powerless, poor and educated to only basic levels, if at all. Though things are changing, status remains an important dimension of social identity, and deference to those of higher status an almost instinctive response for many. As India's great democracy progresses, these influences may diminish further, but they are embedded in the culture (and in religion), as they are in China and my homeland, Thailand, and many other places. They are by no means absent in developed countries. These values have a profound influence on every aspect of life, including bureaucracy, education and healthcare. Even in relatively egalitarian societies, there is a tendency for bureaucrats, educators and healthcare professionals to assume that they know best and that they do not need to consult their constituents about their wishes, needs and priorities. It's evident, for example, in classrooms and lecture halls round the world where the fruitless and boring transmission of information masquerades under the label of education. True education is the development of dynamic and critical minds, where there is no fear of debate, questioning, or critical argument even if the target is the most distinguished professor in the entire universe. Some of India's dramatic economic and social development has come from the liberating effect of this process the creation of dynamic, entrepreneurial, risk-taking modern thinkers. But this has, as yet, affected only a minority, mostly from the privileged middle classes, and there are also many sectors which lag far behind and not just here. Status arrogance and paternalism, as well as authoritarianism, of course, corrupt systems and communications in many parts of the world by hi-jacking them for their own purposes and professional protectionism is a good example of the process. The maintenance of disabling power differentials compromises the growth and maturity of those who are kept in dependence; it is a very real form of oppression. Inequality and injustice are also rooted in differentials in knowledge and access to information. Knowledge IS power, and it may be exercised generously or oppressively. Patients who know little about disease and therapeutics are gravely disadvantaged when faced with the decisions or opinions of status superiors. We can all experience this when we are reliant on experts to solve even our domestic problems plumbers, electricians, mechanics, relationships with whom can be very complex when it comes to issues a good deal less important than life and death (though I have to say that life and death are real issues with the work of some of the electricians I have had the misfortune to employ). As long as doctors assume that they have all the answers, and patients adopt attitudes of uncritical deference, we shall never have safe and effective healthcare. As long as bureaucratic systems are developed at the centre and imposed on the rest of the world by people who believe they know best, the systems will never deliver the fruits of their good intentions. J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 2 John Autian Oration-2009 who believe they know best, the systems will never deliver the fruits of their good intentions. Long And Complex Forms: What Use Are They? I take as a very simple example of this ADR report forms in many parts of the world. Why do so many systems fail to deliver frequent and useful information about the risks of drugs, in some kind of credible ratio to the actual use of drugs? If we revisit the front line we observed earlier, here are the some of the reasons we can extrapolate for low levels of response to ADR reporting: F No time F No commitment or knowledge No motivation F How can we address these profound obstacles? and patient safety concerns. Does Honda's Greenwing brand really deserve so much more attention, creativity, energy and marketing talent than the health and welfare of the people of India or any other country? Yet, as you know, our vital work gets a millionth part of the exposure of the most modest commercial product. (There are exceptions, and the Indian oral contraceptive campaign is one of the but they are rare.) Walking down the streets of any town, I am unlikely pass a patient safety shop and if I did, its windows would be shuttered, its doors would be closed, and there might be a very small notice by the door saying something incomprehensible like, 'Pharmacovigilance Centre'. Gosh! Can't you just see the population queuing to get some? Before this excursion into retail marketing, my question was, What can we do to overcome some of the enormous obstacles of ignorance, low motivation and lack of enthusiasm for what we do? Tripping Over Honda Vivid Presence And High Profile Rather early one morning recently (well, rather early for me), I was walking through the centre of the market town where I live in northern Thailand, at a time when the shops were opening up and the business of the day was getting going. I had to step off the sidewalk to avoid a bunch of new motorcycles parked where I should have been able to walk. I looked up, and on the broad terrace in front of the shop, workers were hauling out great elevated display stands, inclined platforms and big, colourful posters on stands; others were wheeling out more motorbikes to join the herd on the sidewalk. The terraces was being swept and washed, and the waiting bikes being buffed and polished till they sparkled in the sun. We first have to ensure that pharmacovigilance and patient safety are vividly on the map in every healthcare curriculum, on the agendas of every hospital and clinic, in the minds of every healthcare professional and every journalist, citizen and patient. That's a great project for every medical, nursing and pharmacy school for the education of the nation's children and for the public relations departments which every PV centre should have. OK, that's a radical, long-term goal, but we need to be actively engaged in pursuing it now, everywhere remembering that scientists, bureaucrats and academics are not always the best people to do it. There's a lot to be learnt from street stalls and traders whose colourful creativity is evident everywhere in India: if we had some of Mrs Gupta's marketing skills, there wouldn't be a passing citizen who didn't end up going home with something useful from our shop which they didn't set out to acquire, but which they are pleased to have. Everyday life in the world of business, in this case of Honda: they were putting their goods on display to the best possible advantage, to catch the attention of as many potential customers as possible. The Great Marketing Enterprise Now this is a very low-level anecdote from a sleepy old man in a provincial town: BUT what I observed there, and have reported to you, is one small example of a vast, universal human enterprise happening every day in every part of the world in every great city and every tiny community: people with something to sell, or a message to promote, are actively and creatively and ingeniously finding ways to get noticed. Of course, it's a vast human enterprise which, generally speaking, does not include much in the way of healthcare offers and messages, and even fewer pharmacovigilance Ask And Listen Or Go Extinct But for the other problems? The answer is simple: we must ask the people we want to involve, and listen to what they say. That is the core practice of every successful commercial enterprise in the world: they constantly research the tastes, needs, wants, attitudes and behaviour of their customers and potential customers; they ask and they listen. They are successful because what they manufacture, print or broadcast is tailored accurately to the known needs and tastes of the market. They can bring J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 3 John Autian Oration-2009 innovations to market (which the public didn't realise it wanted) because they know so much about the tastes and habits of the market that they can anticipate what will be acceptable and popular. Companies who don't have this knowledge of their market simply disappear. Bureaucracies don't disappear, however blind they are to the tastes, habits and behaviour of their audiences. They just tend to plough on doing what they've always done because that's what they're paid to do. No matter that the outcomes are poor and the customers are disillusioned. To those officials who say to me (as they often do) that patient safety and the serious business of healthcare has nothing to learn from the bustling and vulgar world of commerce, I say: think again; are traders not communicating messages and trying to influence people's behaviour, just as we should be trying to do? Do they not have a genius for getting noticed, just as we should be? We're talking about provoking change, and that needs energy and imagination and a willingness to take risks. What Can We Do To Help You Report ADRs? If we want healthcare professionals to report ADRs, we have to ask them (after we've convinced then that PV is important): what is the maximum effort you are prepared to make to tell us about ADRs in your practice? Some will say, 'No time. Can't do.' Others might say: 'I'm willing to put a date and a patient reference on a pre-printed, pre-paid, addressed postcard which takes me no more than twenty seconds. You can then follow that up and do the work.' Now, we're getting somewhere! Yes, more work for the PV centre following up initial contact, but what is preferable more work or no reports? The system has to be resourced to do the job as it is specified at the front line. Instead of a long, complicated, demanding form (and I've seen many which are an insult to a busy professional) this postcard solution offers us a very efficient, quick mechanism where the barrier to co-operation is very low. (There might be a comparable electronic solution as well, of course.) I'm not saying this is the best or only answer, but it is an answer, and it's a great deal better than much of what currently passes for a credible system in many places. Stodge From The Centre Most ADR forms are devised at the centre, by scientists and officials who know what they want in elaborate and comprehensive detail, but without any serious thought (if any thought) about the effect it will have at the front line let alone asking for the opinion of the people at the front line. What we should be trying to do in co-opting the help of busy professionals, is finding the overlap between the maximum they are willing to do and the absolute minimum we require to operate the system. Reciprocity This principle of engagement and reciprocal communication applies across the board in all our immediate concerns, and across the whole of healthcare. Without it, patient safety is at risk at every point along the way. Transmission only, the method of centralised bureaucracies, top-down institutions and unhelpful professionals, doesn't work. Patients who are dealt with as bundles of symptoms to be medicated will not enjoy the quality of life and health of those who are seen as whole people in the complex context of family and social life; patients who learn nothing about their disease and their medication can never become mature citizens, taking responsibility for their own bodies and health and those of their children, families and communities; patients who are uncritical and undemanding in the face of professional confidence, or assertiveness or arrogance will remain helpless and dependent; patients who are not given full and intelligible information about their medicines, may not take them, may not take them properly, may be seriously harmed by them. We only have to know that there is one patient in the world swallowing their suppositories (as there certainly is), and one nurse giving an intra-thecal injection of an intravenous fluid (as there certainly is), to know that communication of all kinds is central to safe and effective therapy. Compassion And Support But there are much bigger issues too. Health is not just about an absence of disease or of troubling symptoms, nor is it about the medication of every element of discomfort that we poor human beings are subject to. It has a far wider role in the creation of a dynamic and healthy society. Healthcare is the front line where we see the suffering of human beings, caused by disease, accidents, impossible work conditions, insanitary living conditions, hunger, poverty, domestic abuse, addiction, irresponsible behaviour, ignorance and criminal activity too. We cannot respond to these vast and intractable problems in any radical way, but we have a duty to treat those who suffer from them with empathy and attention, and to make sure that what we do is not just short-term patching up for return to the battle front. When our patients leave us, they should J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 4 John Autian Oration-2009 have not only their pills, but a small measure of confidence, optimism and belief in themselves. They should feel that they have been taken seriously and that even the experts may be able to learn from them. They should feel a little better able to cope with their burdens in one way or another. They should feel a similar sense of familiarity and confidence in relation to us, the pharmacovigilance and patient safety professionals and, more to the point, should feel able to trust us and our commitment to the best possible solutions for everyone. Remember Honda? Think of the public profile and accessibility of most regulatory and pharmacovigilance authorities! Invisible! What Should We Be Doing? What Do Patients Want? So, where does all this high-flown stuff leave us? What's the relevance to pharmacovigilance and patient safety? It is this: beyond the science- the data management, the signal detection, the causality assessment, the risk management before all of that, we must be out at the front line seeing, experiencing and understanding what exactly is going on, what is driving people, what their beliefs and behaviour are. We must be out and about asking people what they want, how they could collaborate with us, what their problems are, how WE can help THEM. Research shows us that in the list of patient priorities, effective treatment is always at the top, but very close, wherever the question has been investigated, come effective explanation and communication. And in those countries where healthcare is at increasing risk of challenge in the courts, it is the healthcare professionals and institutions which do not communicate with their patients, which do not seem to care about them, which are most likely to be sued. Patients do not sue doctors they like. Attention Heals And if we are talking about effectiveness, we must at least acknowledge in passing the immense amount of research there has been on placebo: patients, in many disease categories, respond positively to attention, concern and kindness, with and without medicines. If we are blind to the psychological and spiritual dimensions of therapy, or our systems ensure that they are neglected, we are missing out on a very powerful resource. And, in terms of public feelings about a regulatory authority, especially in a crisis, we know that reactions will be more rational and moderate if the authority is known and trusted and seen to be positively committed to communication and the interests of the people. We need to be talking to patients about their attitudes and behaviour; teaching them about drug safety and rational use; identifying and reducing the most common risks - interactions, counterefeit medicines, noncompliance; sharing of medicines; poor storage conditions and so on; finding effective ways of discovering information about the real, front line situation and planning our response. And it is the doctors, nurses, pharmacists, pharmacist assistants and technicians, and traditional healers, who need to be our committed eyes and ears, seeded throughout the nation. They need to be the ones who are driving our work, shaping our policies and systems, telling us what needs to be done at the front line. What Are The Priorities In Pharmacovigilance? Healthcare, in all its modern and traditional manifestations is a remarkable if variably successful enterprise, with some great, enduring achievements to its credit. The success of pharmacovigilance is less easy to assess, with its object as the prevention of harm, which is difficult to measure, though the absence of major disasters like thalidomide might suggest a measure of success. But there are those who are inclined to judge PV by such crude measures as the number of drug withdrawals prompted by ADR reporting systems. This, it can certainly be argued, seems more like a measure of failure in many cases, when useful drugs are taken off the market because their risks cannot be satisfactorily managed. Here we enter the complex area of risk communication and a further area of challenges for us. Some of the principles we have already discussed will be pertinent here too. Over the years, there has been no shortage of communications about the risks of particular drugs in the form of label changes, boxed warnings, email alerts, bulletins, Dear Doctor letters and many other methods. What has become clear in some dramatic cases is that these communications have had little or no influence on rescribing behaviour. (This has also been the case in relation to antibiotic prescribing.) Why Is Risk Communication Currently So Unsatisfactory? What, then, have been the failures here? The high level answer is simple: regulatory authorities in many parts of the world have simply not found effective ways of communicating urgent and important messages to their healthcare professionals in ways which influence their behaviour. Now I have no panacea solutions to this. J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 5 John Autian Oration-2009 Various communications activities have differential effects in the Tome country and in different parts of the world, but we have very little direct evidence of what works well, how and why. Our evidence of failure is rather unsatisfactory, too, because it usually comes from prescribing or dispensing statistics which, inevitably, follow a long time behind the mistakes. What we do know is that communications become more effective, for any audience at all, the nearer they approach the one-to-one end of the spectrum: the more personal and individual the contact, the greater the impact will be. Ineffective Routines Dear Doctor letters are an elaborate, time-consuming and expensive mechanism for communicating new information about risk to a mass audience, but there is little evidence that they have much effect. Yet, regulatory authorities require companies to produce them, year after year. Many of them are lengthy, complex documents which, I suspect, busy healthcare professionals don't get round to reading, or won't remember if they do. What we have to do is to ask them what would be useful and effective for them, and then seek feedback and test the results time and time again. A similar kind of empty, administrative routine has driven the production of some patient information leaflets in countries where these have been mandatory. The PIL for Viagra, one of the most successful and popular drugs in the history of the world, is a ridiculous document (here it is) printed in tiny, condensed type on a very odd shape of paper, full of complex and obscure information. I ask you: in the heat of the moment, on the way to the bedroom, WHO IS GOING TO READ THIS? That is a perfect symbol of the failure of imagination of those who sit and make decisions a million miles from the front line. Did the regulators who approved this PIL think, for a moment, of the situation of the patient who has just been prescribed or just bought Viagra? We know, only too well, that doctors and pharmacists are often not reliable communicators of thoughtful risk and safety information, so does the regulator assume that the PIL is an effective fallback resource for all kinds and conditions of patients? Does the regulator imagine that, as the patient lights the candles and turns on the soft music that he'll be sitting down reading this impenetrable document? I doubt that such a regulator and the company which produces the document think about anything at all except technical and legal matters which are important to them in their dimly lit offices. They have no empathy for the end-user, no concept at all of what things look like at the front line. These kinds of narrow-minded bureaucrats are the enemy within: they are as dangerous to patient safety as defective drugs. Against them and their obstructionism and shortsightedness we must be ever vigilant, ready to sweep them away when we have opportunity. Do not ever imagine that bureaucratic or administrative routines are ever the real answer to front line social problems. So What's Better? Having raised the issue with such strength, I shall at least offer you some thoughts about remedies, but only briefly, because this takes us away from the main theme of the material. Verbal or printed information about risk and safe use must focus on the top few priorities: IF YOU READ NOTHING ELSE, READ THIS. Great progress has been made in improving patient information in some countries by talking to patients and to patient groups about what information they want and is useful to them. They have also generated good ideas about various forms in which patients need the information and can make use of it as opposed to the one size fits all philosophy of regulation. If we remember that up to half the population in even advanced countries may not be able to read or make sense of printed health information, we have some measure of the huge challenge, and of the absurdity of over-reliance on printed information. My message then, evident, I hope, throughout this journey, is this: we must not only look outwards to the real, complex world, but must be out in the midst of the real world, gathering reliable evidence about what people are thinking, saying and doing; communicating, engaging, listening. It is the doctors, nurses, pharmacists, pharmacist assistants and technicians, and traditional healers, who need to be our committed eyes and ears, seeded throughout the nation. They, along with citizens and patients, need to be the ones who are driving our work, shaping our policies and systems, telling us what needs to be done at the front line, and how our work can have the maximum positive impact on the health of the nation. Whatever we are doing, we must think about the front line; and after we've thought about it, we must go out and find out what is happening there, ask and observe, question and investigate. Then we can hope to be told about and to find solutions which fit with reality and will change how people think and behave. It's the revolution of shifting from top-down to bottom-up, from transmission to interaction, from the centre to the front line, and it can change our world for the better, beyond recognition. J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 6 J Pharmcovig Drug Safety 2010 (January-March) Volume : 7 Issue : 1 (Page 7-8) ORIGINAL ARTICLE Pharmacogenomics - The Future of Pharmacovigilance SANTANU K TRIPATHI Department of Pharmacology, Burdwan Medical College, Burdwan 713104 Ethical Concerns Drugs are the indispensable companion of human life. Drugs prolong life, protect and promote health, prevent diseases but they also hurt and harm. Adverse drug reactions (ADRs) are the unfortunate legacy of pharmacotherapy. PGx studies however pose some unique ethical dilemma. How to ensure that PGx information / data of a given patient will not be misused or used for purposes other than optimizing treatment for the given patient? Should a PGx study require prior ethics committee approval? Should informed consent be obtained for PGx testing? Labeling as 'non-responder' or 'ADR-prone' may lead to insurance and workplace discrimination that ADRs are mainly of two types: Type A that are augmented pharmacological effects, and Type B that are bizarre. The Type B or idiosyncratic ADRs have hitherto been considered non-preventable. Recent developments in molecular genetics revealed that many of the Type B ADRs could be predicted and hence avoided through individualizing drug therapy based on genetic information. may result in erosion of self-image and vulnerability to psychological instability. How to ensure maintenance of patient privacy and confidentiality? How to deal with unfavorable polymorphism association with some ethnic minority? - Pharmacological apartheid! Drug responses, desired or adverse, are in general considered as a gene-by-environment phenotype. Traditionally, severe uncommon ADRs triggered exploration of pharmacogenetic phenotypes, using a forward genetic, phenotype-to-genotype approach (Pharmacogenetics). With successful sequencing of the entire human genome by The Human Genome Project and associated phenomenal technological advances in genomics, a reverse genetic, genotype-to-phenotype approach, has been feasible (Pharmacogenomics). This makes the ADR risk anticipation more precise. Safer treatment strategies can be planned through a tailored approach. Pharmacogenomics (PGx) aims at developing rational means to optimize drug therapy, with respect to the patients' genotype, and thus ensuring maximum efficacy with minimal adverse effects. Such approaches promise the advent of personalized medicine in which drugs and drug combinations are optimized for each individual's unique genetic makeup. Through in-depth genome-wide analysis of the determinants of drug responses PGx holds the promise for being exploited as a pharmacovigilance tool for riskstratification. Direct-to-Consumer (DTC) Advertising and PGx Tests DTC advertising for PGx tests is likely to affect the demand for genetic technologies in clinical practice. Genelex advertises testing for three important drug metabolizing enzymes (CYP2D6, CYP2C19, and CYP2C9) at $250/each or $650 for all three. (www.healthanddna.com, accessed July 31, 2003). Regulators need to pay particular attention to DTC advertising for PGx based tests since there is widespread debate over the wisdom of such marketing strategy. Regulatory Challenges Regulatory processes should be able to guide the development and approval of PGx-based drugs and diagnostics that will be safe and effective for public use as well as “least burdensome” to industry sponsors. Labeling is one way to encourage providers to use PGx-based tests. The FDA criteria for PGx drug label include safety (the seriousness of the adverse event), effectiveness (the consequences of not responding), incidence of clinical outcome, variability in the clearance of the drug, how well adverse events can be managed, need to educate providers and third-party payers, and feasibility of accessing and using the test. Application of PGx-based therapies in clinical settings will typically require the availability to the provider, through the drug label, of the information about genetic variation and of an accurate and valid genotyping test. FDA's gatekeeping function specifies if the test is required or suggested. FDA advocated the use of PGx to increase post-marketing safety, and approved trastuzumab Pre-Prescription Genotyping and PGx Testing Technologies Conventional PGx tests involving techniques like Southern blot, polymerase chain reaction (PCR) or restriction frequent length polymorphism (RELP) analysis are run on one-gene / one-test basis. This means for the 70 variant alleles of the CYP2D6 locus, 70 genetic tests are to be performed. The newer technology DNA chip microarray permits simultaneous testing of all or as many alleles as wished. 7 Tripathi : Pharmacogenomics The Future of Pharmacovigilance (Herceptin®) and the associated tests for HER2/neu overexpression in breast cancer (the first PGx prescription) in a bid to regulate PGx-based drugs and diagnostics in combination. Only women with HER2/neu over-expressing breast tumors, as confirmed by a genetic test, may benefit from use of Herceptin. Accordingly, Herceptin labeling specifies the tests that are approved for guiding prescribing decisions. In contrast, the label for Atomoxetine (Strattera®), used to treat ADHD, notes that a test for genetic mutations is available but it does not specify that the test is required, it is only suggested or recommended. Off- Label Use of PGx Drugs Testing for thiopurine methyltransferase (TPMT) enzyme mutations prior to prescribing 6-mercaptopurine (6MP) for patients with ALL is one of the most evolved and best understood applications of PGx, but 6MP, approved for oncology, is increasingly being used off-label for other disease areas. It has been particularly challenging for FDA to regulate offlabel use. PGx-Guided Drug Rescue Drugs withdrawn from the market because of serious adverse events (SAEs) might be rescued by identifying genetic associations that accurately predict the occurrence of the ADR and that could be tested for before prescribing. Practical barriers to drug rescue include lack of real examples difficulties with retrospective analysis fears of litigation expired or near-expired drug patents the possibility that providers would still not use the drug in clinical practice because of worries about safety based on the initial drug indication. Industry Concerns The industry has been worried about premature regulatory constraints and desires clear guidelines and transparency from regulators. An economic disincentive for industry in developing PGx based drugs and diagnostics is the decreased likelihood for blockbuster drugs. Physicians Inform Thyself The physician's checklist for applying PGx in reducing ADRs include the following: F Check if the intended drug is metabolized by a polymorphic drug metabolizing enzyme. F Study if the prevalence of a deficient variant is high in the patient population being treated. F Consider alternative drugs that are not subject to polymorphic drug metabolizing enzymes. F If no alternative, prescribe but counsel patient to carefully monitor for possible ADRs. F Remember ADR problems are compounded if multiple drugs metabolized by the same polymorphic drug metabolizing enzymes are used. F Circumstances permitting, consider genotyping beforehand to reduce possibility of ADR, or afterwards to ascertain if genetic variance is indeed the cause of the ADR. More Cost-Effectiveness Analysis Needed A review of the literature revealed that only 11 costeffectiveness of PGx tests had been published as of July 2004. To make such analyses useful they need to be conducted prior to widespread implementation of PGx tests, but the catch-22 is that the data to evaluate them are often lacking or proprietary. Implications for public health programmes Elucidation of population and cross-ethnic differences in pharmacogenetics traits will pave the path for more successful disease control, containment and eradication programmes with drugs and vaccines. Appropriate policy decisions can be arrived at national level towards reducing some ADRs known to occur more frequently and / or more seriously in a given population. Epilogue ADRs have a multigenic and multifactorial aetiology, akin to that observed with complex diseases. Genetic factors may play a major role in the pathogenesis of many ADRs, and pre-prescription testing may allow us to prevent or at least minimise the ADRs, as has been shown for abacavir hypersensitivity. PGx has been one of the most immediate and important applications of the Human Genome Project. PGx advocates for prescribing decisions based on genetic test results besides optimizing success in drug development (DD). Interest in PGx and personalized medicine is accelerating because of ongoing concerns about ADRs and the high failure rates in DD. The future prospect of personalised medicine in the context of PGx and pharmacovigilance seems to be bright and encouraging, yet highly challenging. It is the need of the hour that all the stake holders e.g., industry, regulators, care providers and the people at large, analyze the opportunities and challenges in achieving efficient, science-based risk management in the area of PGx. Demonstration of the clinical utility of PGxbased tests is going to be crucial before they can be recommended for use in clinical practice. Large multicentre studies are urgently needed to identify and collect samples from well phenotyped patients with ADRs, which will serve as a resource to establish individual susceptibility to the ADRs. With the advances in technologies (genotyping, proteomic, metabonomic, informatics and statistical), PGx, in the wider context of a systems biology approach has the potential to help in predicting the toxicity of drugs and through this bring us closer to the concept of personalised medicine. J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 8 J Pharmcovig Drug Safety 2010 (January-March) Volume : 7 Issue : 1 (Page 9-13) Cholesterol lowering potential of Seabuckthorn ORIGINAL ARTICLE IMRAN ZAFAR, M. FAHIM1, Institute of Pharmacy, NIMS University Rajasthan, Jaipur - 303 121 1 V.P.Chest Institute, University of Delhi, Delhi - 110 007 ABSTRACT The present study was designed to investigate the effect of Seabuckthorn on lipid profile, its antioxidant potency and its effect on haemodynamic changes and baroreceptor mediated blood pressure regulatory mechanism in hypercholesterolemic rats. For induction of hypercholesterolemia rats were fed with fructose in drinking water and in vivo experiment had done to investigate the heamodynamic as well as biochemical profile of seabuckthorn.it is a natural product and investigations carried out so far do not report any apparent toxic effect. Based upon the results of the present study, it is recommended that seabuckthorn pulp oil may be supplemented with normal diet for providing protection against hypercholesterolemia. The fall in blood pressure of animals having a normal lipid profile suggests that it may have a hypotensive effect. Hence, its use as a lipid lowering agent needs to be carefully monitored especially in people with cardiac problems. Conclusive evidence shows that baroreceptor modulation of heart rate is impaired in animals and patients with atherosclerosis. It has been suggested that oxygen free radicals produced in atherosclerosis may contribute to baroreceptor dysfunction.Seabuckthorn prevented development of hypertension and reduced insulin resistance in chronically fructose fed rats and reduced vascular superoxide anion production through lowering the NAD (P) H oxidase activity in hypertensive rats. Key words- Hypercholestrolemia, Hypertension, Atherosclerosis, Baroreceptor Dysfunction, Free Radicals Introduction including carotenoids, tocopherols, sterols, flavonoids, lipids, ascorbic acid, tannins, etc.; many of them possess biological and therapeutic activity. Flavanoids such as leucocyanidin, catechin, flavonol and flavones lower cholesterol, prevent inflammation and vitamin C degradation and probably control formation of atherosclerotic plaques6. In addition, the sterols and stanols present in seabuckthorn reduce the absorption of cholesterol. Together, these effects may be beneficial in hypercholesterolemia and ultimately atherosclerosis. 7,8.To the best of our knowledge, no study has reported the effect of Seabuckthorn pulp oil on lipid profile and baroreflexes in hypercholesterolemia. Hence, the present study was planned to investigate the effect of SBT on serum lipid profile and baroreflex sensitivity in experimentally induced hypercholesterolemia in rats. Cardiovascular disease (CVD) encompasses a number of different diseases including coronary heart disease, stroke and peripheral vascular disease. However, the underlying pathology for all of these disorders is atherosclerosis1. A number of risk factors for CVD have been described, such as hypercholesterolemia (HC)2. hypertension3, smoking, diabetes and obesity4. Till date, there have been many studies on mechanisms by which high levels of LDLcholesterol affect biology of blood vessels and cause atherosclerotic lesion formation. Arterial baroreceptors are known to regulate absolute blood pressure and ultimately help in maintaining adequate circulation to brain and other organs. Baroreflex contributes importantly to neural circulatory control. Abnormalities in arterial baroreflex function have been linked to adverse cardiovascular outcomes5. Functional (neural) mechanisms, in addition to structural vascular changes, contribute importantly to altered baroreflex responses in normal and pathophysiological states. Presently available lipid lowering agents are mainly synthetic drugs, which have many side effects. Natural compounds with fewer side effects are being looked into as an alternative therapy. Seabuckthorn contains a series of chemical compounds Methods Healthy male Wistar albino rats, weighing between 250300 g, were obtained from the animal house of VPCI. They were housed in cages in groups of four rats per cage and were kept in room temperature maintained at 25±2°C with a 12-h light/dark cycle. Experiments were performed according to the guidelines of the Committee for the Purpose of Control and Supervision of Experiments on 9 Imran Zafar : Cholesterol lowering potential of Seabuckthorn Animals (CPCSEA), India. The Institutional Animal Ethical Committee, Vallabhbhai Patel Chest Institute (VPCI), University of Delhi, New Delhi, India, approved this study. Preparation of Seabuckthorn Pulp Oil We procured SBT pulp oil from DIPAS (Defense Institute of Physiological and Allied Sciences). Fruits of seabuckthorn were collected from hilly regions of western Himalayas, India and dried J Pharmcovig Drug Safety 2009 (April June) 6(1) : 3-7under shade. The extraction was carried out using fruit by deseeding and crushing the berries. The pulp was centrifuged to obtain SBT pulp oil. Plan of Study Hypercholesterolemia was induced by feeding rats with 10% fructose for 3 weeks in drinking water. SBT pulp oil was given in a dose of 2ml/kg body weight orally. Study was conducted in 20 rats, which were randomly divided into following groups. Control Group(I) -Rats fed with normal pellet diet: Rats of this group were maintained on normal balanced diet and water for 3 weeks. Hypercholestrolemic Group(II)- Rats fed with 10% fructose: For induction of hypercholesterolemia, rats were maintained on normal pellet and 10% fructose in drinking water for 3 weeks. Fructose+Seabuckthorn Group(III)- Rats given 10% fructose and seabuckthorn pulp oil: rats of this group were maintained on normal pellet and 10% fructose in drinking water and seabuckthorn pulp oil for 3 weeks. Seabuckthorn pulp oil (2ml/kg/day) is administered through oral route with the help of oral feeding needle. Seabuckthorn Group (IV)-Rats fed with normal pellet diet along with seabuckthorn: In order to study the effect of seabuckthorn on normal rats, seabuckthorn was administered in the dose of 2ml/kg/day, orally with the help of oral feeding needle for 3 weeks. Biochemical Determinations After completion of experiment, under deep anesthesia blood samples were collected by direct heart puncture after opening the chest of the animal. Blood was allowed to clot and then centrifuged for 10 min at 5000 rpm, to obtain the serum. Serum sample was transferred into dry and clean vials and stored at -20°C for biochemical analysis at a later date and determined by commercially available spectrophotometric assay kits (Monozymes, India), as per the manufacturer procedure given. Arterial Blood Pressure and Heart Rate Rat was anesthetized with urethane dissolved in distilled water and injected intraperitoneally (i.p.) at a dose of 1gm/kg body weight. Disappearance of pedal reflexes indicated adequate anesthesia. Rat was placed on a small table and secured by tying the limbs. A middle incision was given in the neck region; retracting the pretracheal muscle exposed trachea and a transverse incision was given in between two rings. A cannula was introduced into the opening to allow free breathing without obstruction. Body temperature of the rat was maintained at 37-38 oC. Femoral artery of one side was exposed and a polyethylene catheter filled with heparin solution (500 IU/ml, v/v) was inserted in the artery through a small incision for recording arterial blood pressure (ABP). The catheter was attached to 23gauge needle connected via three-way stopcock to a pressure transducer (Statham-P23D). Femoral vein of the other limb was cannulated for injecting drugs (Ashraf et al., 2005). Prior to recording ABP, catheter was flushed with heparinized saline solution (500 IU/ml, v/v) to prevent formation of any blood clot, which might interfere with normal recording of ABP. The pressure recording system was calibrated with the help of a mercury manometer before each experiment. Arterial blood pressure was measured after 20 min of stabilization period. Systolic, diastolic, mean arterial pressures and heart rate were displayed and recorded on Power Lab data-acquisition system (4SP, AD Instruments, Australia) with a computerized analysis programme. Measurement Of Baroreflex Sensitivity (BRS) BRS was measured by administering 20µg/ml/kg phenylephrine (vasoconstrictor) and sodium nitroprusside (vasodilator) through venous catheter. The resultant changes in heart rate at corresponding rise or fall in SBP were measured at different time intervals (every 2 sec). The relationship between increase in SBP evoked by phenylephrine and associated bradycardia or decrease in SBP evoked by sodium nitroprusside and associated tachycardia was assessed by regression analysis for individual animal. The regression coefficient (slope of regression line), expressed as beats per minute per mm of mercury (beats/min/mmHg) was taken as an index of baroreflex sensitivity. Statistical Analysis The data are presented as mean ± SEM. Statistical analysis was done by analysis of variance (ANOVA) followed by J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 10 Imran Zafar : Cholesterol lowering potential of Seabuckthorn tukeys multiple comparison method. P value for statistical significance was set at 5% i.e., p< 0.05. Results No significant difference in the diet intake and body weight was observed among the various groups. Haemodynamic Profile Effect of seabuckthorn on arterial blood pressure and heart rate along with fructose in drinking water showed significant (P<0.05) fall in total cholesterol, triglycerides, LDL-C and significant (P<0.05) increase in HDL-C level compared with hypercholesterolemic group. Following treatment of rats with seabuckthorn on normal diet for 3 weeks, hypercholesterolemic rats showed significant (P<0.05) decrease in total cholesterol, triglycerides, LDC-L, and significantly (P<0.05) increased HDL-C level compared with hypercholesterolemic group. These are followings data shown in Table-2 Rats fed with fructose showed rise in systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate compared with control rats. Treatment of rats with seabuckthorn along with fructose prevented the rise in systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate compared with hypercholesterolemic rats. Treatment of rats with seabuckthorn on normal diet for 3 weeks prevented the rise in systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate compared with hypercholesterolemic rats. These are followings data shown in Table-1. Effect of seabuckthorn on the arterial baroreceptor mediated blood pressure regulatory mechanism Baroreflex sensitivity was measured as a ratio of bradycardia response to rise in arterial pressure by phenylephrine or as a ratio of tachycardia response to fall in arterial pressure by sodium nitroprusside. Rats given fructose showed significant (P<0.05) decrease in Lipid Profile baroreflex sensitivity compared to the control rats. Treatment with seabuckthorn along with the fructose showed significant (P<0.05) restoration of baroreflex sensitivity compared with hypercholesterolemic group. Rats treated with seabuckthorn and maintained on normal diet did not show any change in baroreflex sensitivity compared with control group. These are followings data shown in Table-3. Effect of Seabuckthorn on serum lipid profile Rats given fructose (10%) in drinking water developed hypercholesterolemia marked by significant (P<0.05) increase in total cholesterol, triglycerides, LDL-C, and a significant (P<0.05) decrease in the level of HDL-C compared with control rats. Treatment with seabuckthorn J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 11 Imran Zafar : Cholesterol lowering potential of Seabuckthorn Lipid profile Discussion Hypercholesterolemia, which is characterized by high levels of lipoprotein containing cholesterol in blood, is generally accepted as a major risk factor for the development of atherosclerosis and subsequent myocardial ischemia 9 .Wistar rat as a model of hypercholesterolemia has been chosen for the present study as it shows increase in serum cholesterol due to feeding of fructose rich diet. Rats can develop hypercholesterolemia after feeding the fructose rich diet for a long period of time. But rats have shown functional changes in vascular responsiveness even with a relatively small elevation of plasma cholesterol levels10. So, it has been suggested that, rat may be a good model for studying vascular functions during hypercholesterolemia prior to the development of atherosclerotic lesions 11 . In the present study, fructose rich diet feeding for 3 weeks caused a significant increase in serum TC, LDL-C, TG with a significant decrease in HDL-C in rats. Seabuckthorn treatment along with fructose diet in rats (preventive effect) showed significant reduction in serum TC, LDL-C, TG with a significant increase in HDL-C compared with hypercholesterolemic rats. After treatment with Seabuckthorn along with normal diet for 3 weeks in hypercholesterolemic rats (therapeutic effect) showed further reduction in serum TC, LDL-C, TG with a significant increase in HDL-C compared with hypercholesterolemic rats. Haemodynamic profile In this study, hypercholesterolemic rats show significant rise in SBP, DBP, MAP and HR. Another important finding is that Seabuckthorn treatment along with fructose feeding in rats (preventive) completely prevented the rise J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 12 Imran Zafar : Cholesterol lowering potential of Seabuckthorn in SBP, DBP, MAP and HR compared with hypercholesterolemic group. However, hypotensive effect was observed in rats treated with Seabuckthorn and fed with normal diet. Taken together, the present data suggest that Seabuckthorn attenuated the development of hypertension in hypercholesterolemic rats probably through its antioxidative properties. Baroreflex sensitivity Results of the present study showed that the bradycardia response to phenylephrine (PE) and the tachycardia response to sodium nitroprusside (SNP) were attenuated in hypercholesterolemic animals. The linear regression analysis of the reflex changes in HR in response to changes in SBP indicated a decreased baroreflex sensitivity in hypercholesterolemic rats compared with normal rats. The present work have shown that Seabuckthorn treatment along with fructose feeding in rats improved the baroreflex sensitivity to depressor and pressor responses to SNP and PE, respectively. Further, rats treated with Seabuckthorn and maintained on normal diet did not show any change in baroreflex sensitivity. Seabuckthorn has shown antioxidant activity in our study as well as in other studies11. This may explain its beneficial effect on the baroreflex sensitivity in hypercholesterolemic rats as decreased baroreflex sensitivity has been correlated with oxidative stress 12 . References 1. Naseem, K.M., The role of nitric oxide in cardiovascular diseases .2005 Mol Aspects Med., 26, 33-65. 2. Creager, M.A., Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest.1990, 86,1, 228-234. 3. Panza JA, Quyyumi AA, Brush JE Jr and Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med. 1990 323,1, 22-27. 4. Jousilahti P, Vartiainen E, Tuomilehto J and Puska P. Sex, age, cardiovascular risk factors, coronary heart disease: a prospective follow-up study of 14786 middle-aged men, women in Finland. Circulation 1999, 99,9, 1165-1172. 5. La Rovere MT, Bigger JT Jr, Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet.1998. 14;351,9101,478-84. 6. Ross R. The pathogenesis of atherosclerosisan update. N Engl J Med.1986, 314:,488 500. 7. Vallance P, Collier J and Moncanda S. Effect of endothelium derived nitric oxide on peripheral arteriolar tone in man. Lancet.1989, 344; 997-1000. 8. Davis, P.F.. Vascular cell interaction with special reference to the pathogenesis of atherosclerosis. Lab invest. 1986, 55, 2-24. 9. Saini HK, Arneja AS and Dhalla NS. Role of cholesterol in cardiovascular dysfunction. Can J Cardiol. 2004. 1: 20,3, 333-346. 10. O' Rourke and Docherty JR. Effects of a highcholesterol diet on vascular and endothelial function in rat aorta. Pharmacology 1998, 56,1-6. 11. S. Geetha, M. Sai ram, Virendra singh, G. Ilavazhagon and R.C. Sawhney. Effect of seabuckthorn on sodium nitroprusside induced cytotoxicity in Murine Macrophages. Biomed pharcother, 2002, 56 , 463-467 12. Girouard, H., Denault, C., Chulak, C. and Champlain, J.D. Treatment by N-acetylcysteine and melatonin increases cardiac baroreflex and improves antioxidant reserve. Am J Hypertens. 2004, 17, 947-954 J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 13 J Pharmcovig Drug Safety 2010 (January-March) Volume : 7 Issue : 1 (Page 14-17) Off Label Drug Treatment and Related Problem in Children ORIGINAL ARTICLE CHETAN MEHNDIRATTA, SYED ZIAUR RAHMAN, PIPASHA BISWAS1 Department of Pharmacology, Jawaharlal Nehru Medical College, AMU, Aligarh - 202002, 1 Symogen UK Marlow, Buckinghamshire SL7 1JW, United Kingdom. Introduction Special Characteristics of Paediatric Pharmacovigilance In pediatrics, majority of medications are off label because of the scarcity of pediatric cases in clinical trials. The routine procedure for determining the dosage, indications, route and contraindications depends on the adult clinical trials. Because of the difference in drug pharmacokinetics and pharmacodynamics in the pediatric and adult population the above mentioned method for pediatric prescription is very inadequate and incomplete. This has caused a lot of disasters in the past e.g. solvent, which was used to make sulfanilamide palatable caused renal failure, grey baby syndrome by chloramphenicol and thalidomide disaster. The role of pharmacovigilance and pharmacoepidemiology lies in the fact that post marketing studies are the single most evidence based method to substantiate the safety signals in pediatric population. The benefit-risk ratio of a given drug has to be assessed and the decisions should be based on sound knowledge and observations. Ideally the drugs, which have pediatric labeling information should be prescribed and in medications which do not have any details in pediatric population the use should be judged by the seriousness of the condition and other available treatment modalities. When a drug or medical device is used to treat a disease or condition not listed on its label, or used in such a way that's not outlined in the label, it's said to be used off-label. This off-label use is also sometimes referred to as extra-label use, nonapproved use or unapproved use. A response which is noxious, and unintended and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease as for the modification of physiological function excluding failure to accomplish the intended purpose (WHO Technical Report Series, 498, 1972), while, Edwards IR, et al defined ADR as “An appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, alteration of dosage regimen, or withdrawal of the product. The conduct of pharmacovigilance for medicines for paediatric use requires special attention. Childhood diseases and disorders may be qualitatively and quantitatively different from their adult equivalents. Chronic conditions may require chronic treatment and hence the susceptibility to adverse drug reactions (ADRs) may change throughout the patient's life-time according to age and the stage of growth and development. Irrespective of the duration of treatment, growth and development during childhood reflect many underlying processes which may result in ADRs not seen in the adult population. Also, the associated rapid changes in body mass present additional challenges in identifying and selecting the optimal dosing regimen. Particular problems associated with the lack of reliable data in paediatric populations include: F Lack of clinical trials in the paediatric population limits the safety data available; F Lack of kinetics data or dose-finding studies may lead to under or over-dosing in some age groups; F Under-dosing may result in lack of benefit or development of resistance; F Over-dosing may result in an increase of Type A reactions; F Lack of appropriate formulations may lead to incorrect dosing, use of products of less controlled quality or inappropriately high local concentrations leading to local adverse reactions; F Routinely available safety data may not adequately capture events arising in the paediatric population. F Safety data in the paediatric population cannot necessarily be extrapolated from data in adults because certain ADRs may only be seen in the paediatric population depending on the maturation of organ systems (e.g. kidney, liver, blood-brain-barrier), metabolism, growth and development. In particular: F The pharmacokinetics and pharmacodynamics of a 14 Chetan Mehndiratta: Off Label Drug Treatment and Related Problem in Children compound may be different in the paediatric population compared with adults and the former may be particularly vulnerable to adverse drug reactions (ADRs) or have different drug interaction profiles; F The paediatric population may be more susceptible to ADRs from specific excipients; F Different adverse events may be relevant for different paediatric age groups and specific F Pharmacovigilance tailored accordingly. In utero exposure may represent an additional risk factor; F Due to maturation, growth and development the paediatric population may be susceptible to drug induced growth and developmental disorders, as well as to delayed ADRs not seen in adults. Long term follow-up data may be necessary to detect such effects; F Drug-induced “programming” may occur i.e. permanent effects may result from a drug exposure at a sensitive point in development ('critical window'), often in fetal or neonatal life; F Certain ADRs may only be seen in the paediatric population, irrespective of effects on growth and development. The problems are accentuated when the drugs involved are not authorized for paediatric use F Unlicensed medicines or medicines used 'off-label' may have inadequate product information to support safe paediatric use; F Underreporting of adverse reactions occurs in relation to unlicensed or 'off-label' use. F In addition, children may be unable to communicate adverse events clearly to their carers/ health care professionals or may not be aware of the adverse events as such. F Premature babies may be at a much higher risk (for example due to slow elimination of xenobiotics, distribution barriers, physiological regulatory functions and “imprinting”) and therefore need enhanced pharmacovigilance. Background The paediatric population is defined in the European Union as those persons aged between 0 and 16 years. Many medicines are prescribed to the paediatric population on an unlicensed or 'off-label' basis, because they have not been adequately tested and/or formulated and authorized for use in appropriate paediatric age groups. Rather they have been tested and formulated for adults. This varies according to the setting in which the medicines are prescribed. Whereas only 10-20% of medicines prescribed for children by general practitioners have not been licensed for use in children, this number rises to about 45% of medicines used in general paediatric wards and over 90% of those used in neonatal intensive care. Doctors prescribing such medicines for children have to take responsibility for this unlicensed (off-label) use. They may prescribe adult formulations, or use licensed medicines in an unlicensed way (for example crushed in drinks to enable children to take them). Because a child's body does not behave like that of a small adult, it is not possible to make a simple extrapolation from the adult data. For some medicines, this lack of information or appropriate formulations may expose children to side effects, over-dosing or under-dosing (lack of efficacy). Why are so few medicines specifically licensed for use in children? Until 10-15 years ago there was widespread reluctance to conduct studies of medicines on children due to ethical reasons. However, there has been a significant shift in opinion in recent years, such that the lack of trials and the dearth of information is now seen as the chief ethical concern. There are also practical difficulties that may make clinical studies on children more complex and expensive than those on adults. Finally, the pharmaceutical industry chooses what medicines to develop, test and market. The potential return often is not sufficient to justify investment in R&D of medicines specifically for children. Concerns over children's medicines surfaced in the UK in the late 1990s. In 2000 the Council of Health Ministers decided that the European Commission would address this issue. The resulting new EU Regulation on Medicinal Products for Paediatric Use should enter into force in the UK before the end of 2006. Age Classification Children are a heterogonous group. Within the paediatric population, (0 to 18), there are different sub-groups and international guidelines separate them into five groups: 1. 2. 3. 4. 5. Preterm newborn infants; Term newborn infants 0-27 days; Infants 28 days 23 months; Children 2 - 11 years and; Adolescents between 12 and 16/18 years. J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 15 Chetan Mehndiratta : Off Label Drug Treatment and Related Problem in Children Aim and Objectives 1. To study the use of drugs (mostly Antibiotics) in pediatric patients. 2. Effect of off label drug use in the vulnerable population group with particular reference to pediatric off label use. 3. To see how the pediatric age group patients are treated in a well equipped urban settings hospital. 4. To identify the safety risk in pediatric population from off label drug use. 5. To see the awareness among the practicing physicians about pediatric use of drugs. Methods In the present cohort study, prescriptions of paediatric patients were reviewed and examined in a Out patient Department, Child Welfare Clinic, Maternity Home, Defense Colony, New Delhi. All prescriptions were audited for any off-label drug prescriptions as per available evidence based information. Results In the following clinical setup, off-label paediatric prescriptions were monitored. Out patient Department, Child Welfare Clinic, Maternity Home, Defense Colony, New Delhi Patient profile: Middle class Delhi population living in Pucca housing with proper sanitation facilities. Drugs and ADR reported for the month of October & November 2008 from patients reporting to OPD of the health care set up. Drug used: Cotrimoxazole Pediatric tablets 100mg sulfomethoxazole + 20mg trimethoprim SS [single strength] 200mg sulfomethoxazole + 40mg trimethoprim. Total no of patients treated with this combination in month of October & November 2008 were 75. - - - - - - J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 16 Chetan Mehndiratta : Off Label Drug Treatment and Related Problem in Children - - - - - Discussion The harm from off label and unlicensed medicines use in children is scarce. There is however sufficient evidence that harm actually occurs and is underreported.This supports measures to improve information on medicines used in children. This also supports setting up prospective monitoring of ADR's in children, including for children in the community, in order to obtain an objective picture of the risks and benefits of paediatric medicines. FPaediatric clinical trials remain challenging for physicians, clinical pharmacologists, regulators and industry due to numerous specifics of this highly vulnerable population. FNew measures to avoid or minimise pain and distress in the paediatric population during clinical trials have to be developed. FNew methodological approaches for clinical trials in the paediatric exist, but have to be further explored. FPharmacovigilance in the paediatric population requires specific tools and considerations to appropriately detect adverse reactions and in particular address long-term safety risks. Note: The study is a part of a project report for the partial approval of Certificate Course in Pharmacovigilance and Pharmacoepidemiology, during (September December, 2008), Symogen India Pvt. Ltd., New Delhi, References 1.PDCO opinions on PIPs and waivers are transforme into EMEA decisions within the timeframe laid down by the Paediatric Regulation (Regulation (EC) No 1901/2006, as ``amended). The decions can be found on the EME A website:http/www.emea.europa.eu/htms/human/paeditri cs/decisins.html 2. The document on procedural advice for validation of new Marketing authorization applications forextensions /variations and compliance check with an agreed PIP is published in the Medicines for children section of the EMEA website. 3. More information about the PDCO and the Paediatric Regulation is available in the 'Medicines for children' section of the EMEA website. 4. This press release, together with other information on the work of the EMEA, can be found on the EMEA website: http://www.emea.europa.eu 5. Conroy S, Choonara I, Impicciatore P, et al. Survey of unlicensed and off-label drug use in paediatric wards in European countries. BMJ 2000;320:7982. 6. Turner S, Nunn AJ, Fielding K, Choonara I. Adverse reactions to unlicensed and off-label drugs on paediatric wards. Acta Paediatr 1999;88:9658 7. Straand J, Rokstad K, Heggedal U. Drug prescribing for children in general practice. A report from More & Romsdal Prescription Study. Acta Paediatr 1998;87: 21824. 8. Rylance G,Woods C, Cullen R, Rylance M. Use of drugs by children. BMJ 1988;297:4457. 9. Bonati M, Choonara I, Hoppu K, Pons G, Seyberth H.Closing the gap in drug therapy. Lancet 1999;353: 1625. 10.Van den Anker J, Choonara I. ENDIC European Network for Drug Investigation in Children. Pediatric and Perinatal Drug Therapy 1999;3:1516. 11.Wikipedia,the free encyclopedia:Off Label Use in Pediatric, can be found on Website: http//en. wikipedia.org /off label use. b J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 17 J Pharmcovig Drug Safety 2010 (January-March) Volume : 7 Issue : 1 (Page 18-26) Nanobiotechnology Today: Focus on Nanoparticles ANSHUL KUMAR, IMRAN ZAFAR Institute of Pharmacy NIMS University Rajasthan , Jaipur - 303 121 ABSTRACT Nanobiotechnology is the branch of nanotechnology with biological and biochemical applications or uses. Nanobiotechnology often studies existing elements of nature in order to fabricate new devices These include bottom-up and molecular self-assembly, biological effects of naked nanoparticles and nano-safety, drug encapsulation and nanotherapeutics, and novel nanoparticles for use in microscopy, imaging and diagnostics. This review highlights recent nanoparticle research is currently an area of intense scientific research, due to a wide variety of potential applications in biomedical, optical, and electronic fields. History pottery. The object was then placed to a kiln and heated to about 600°C in a reducing atmosphere. Although generally nanoparticles are considered an invention of modern science, they actually have a very long history. Specifically, nanoparticles were used by artisans as far back as in the 9th century Mesopotamia for generating a glittering effect on the surface of pot. Lustre technique shows that craftsmen had a rather sophisticated empirical knowledge of materials. The technique originates in the Islamic world. As Muslims were not allowed to use gold in artistic representations, they had to find a way to create a similar effect without using real gold. The solution they found was using lustre. Even these days pottery from the Middle Ages and Renaissance often retain a distinct gold or copper colored metallic glitter. This so called lustre is caused by a metallic film that was applied to the transparent surface of a glazing. The lustre can still be visible if the film has resisted atmospheric oxidation and other weathering. Michael Faraday provided the first description, in scientific terms, of the optical properties of nanometerscale metals in his classic 1857 paper "Experimental relations of gold (and other metals) to light." Much of the modern day studies of these objects have been conducted at the ESRF laboratory. Several techniques were used to characterizes the chemical and physical properties of these lustre, such as Rutherford Backscattering Spectrometry (RBS), optical absorption in the visible-ultraviolet region, electron microscopy (TEM and SEM) The lustre originates within the film itself, which contains silver and copper nanoparticles, dispersed homogeneously in the glassy matrix of the ceramic glaze. These nanoparticles were created by the artisans by adding copper and silver salts and oxides together with vinegar, ochre, and clay, on the surface of previously-glazed Figure 1 : Silicon nanopowder Nanodiamonds, TEM Image 18 Kumar A : Nanobiotechnology today: focus on Nanoparticles Properties Classification Nanoparticles are of great scientific interest as they are effectively a bridge between bulk materials and atomic or molecular structures. A bulk material should have constant physical properties regardless of its size, but at the nanoscale this is often not the case. Size-dependent properties are observed such as quantum confinement in semiconductor particles, surface plasmon resonance in some metal particles and superparamagnetism in magnetic materials. The properties of materials change as their size approaches the nanoscale and as the percentage of atoms at the surface of a material becomes significant. For bulk materials larger than one micrometre the percentage of atoms at the surface is minuscule relative to the total number of atoms of the material. The interesting and sometimes unexpected properties of nanoparticles are partly due to the aspects of the surface of the material dominating the properties in lieu of the bulk properties. Nanoparticles exhibit a number of special properties relative to bulk material. For example, the bending of bulk copper (wire, ribbon, etc.) occurs with movement of copper atoms/clusters at about the 50 nm scale. Copper nanoparticles smaller than 50 nm are considered super hard materials that do not exhibit the same malleability and ductility as bulk copper. The change in properties is not always desirable. Ferroelectric materials smaller than 10 nm can switch their magnetisation direction using room temperature thermal energy, thus making them useless for memory storage. Suspensions of nanoparticles are possible because the interaction of the particle surface with the solvent is strong enough to overcome differences in density, which usually result in a material either sinking or floating in a liquid. Nanoparticles often have unexpected visible properties because they are small enough to confine their electrons and produce quantum effects. For example gold nanoparticles appear deep red to black in solution. The large surface area to volume ratio also reduces the incipient melting temperature of nanoparticles. Moreover nanoparticles have been found to impart some extra properties to various day to day products. Like the presence of titanium dioxide nanoparticles impart what we call as the self-cleaning effect, and the size being nanorange, the particles can't be seen. Nano Zinc Oxide particles have been found to have superior UV blocking properties compared to its bulk substitute. This is one of the reasons why it is often used in the sunscreen lotions. These nanoparticles are hard, and impart their properties to the polymer (plastic). Nanoparticles have also been attached to textile fibers in At the small end of the size range, nanoparticles are often referred to as clusters. Nanospheres, nanorods, and nanocups are just a few of the shapes that have been grown. Metal, dielectric, and semiconductor nanoparticles have been formed, as well as hybrid structures (e.g., core-shell nanoparticles). Nanoparticles made of semiconducting material may also be labeled quantum dots if they are small enough (typically sub 10 nm) that quantization of electronic energy levels occurs. Such nanoscale particles are used in biomedical applications as drug carriers or imaging agents. Semi-solid and soft nanoparticles have been manufactured. A prototype nanoparticle of semi-solid nature is the liposome. Various types of liposome nanoparticles are currently used clinically as delivery systems for anticancer drugs and vaccines. Characterization Nanoparticle characterization is necessary to establish understanding and control of nanoparticle synthesis and applications. Characterization is done by using a variety of different techniques, mainly drawn from materials science. Common techniques are electron microscopy [TEM, SEM], atomic force microscopy [AFM], dynamic light scattering [DLS], x-ray photoelectron spectroscopy [XPS], powder x-ray diffractometry [XRD], Fourier transform infrared spectroscopy [FTIR], Matrix-Assisted LaserDesorption Time-of-flight mass spectrometry [MALDITOF], and Ultraviolet-visible spectroscopy. Whilst the theory has been known for over a century (see Robert Brown), the technology for Nanoparticle tracking analysis (NTA) allows direct tracking of the Brownian motion and this method therefore allows the sizing of individual nanoparticles in solution. Fabrication of Nanoparticles There are several methods for creating nanoparticles; attrition and pyrolysis are common methods. In attrition, macro or micro scale particles are ground in a ball mill, a planetary ball mill, or other size reducing mechanism. The resulting particles are air classified to recover nanoparticles. In pyrolysis, a vaporous precursor (liquid or gas) is forced through an orifice at high pressure and burned. The resulting solid (a version of soot) is air classified to recover oxide particles from by-product gases. Pyrolysis often results in aggregates and agglomerates rather than J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 19 Kumar A : Nanobiotechnology today: focus on Nanoparticles singleton primary particles. A thermal plasma can also deliver the energy necessary to cause evaporation of small micrometre size particles. The thermal plasma temperatures are in the order of 10000 K, so that solid powder easily evaporates. Nanoparticles are formed upon cooling while exiting the plasma region. The main types of the thermal plasmas torches used to produce nanoparticles are dc plasma jet, dc arc plasma and radio frequency (RF) induction plasmas. In the arc plasma reactors, the energy necessary for evaporation and reaction is provided by an electric arc which forms between the anode and the cathode. For example, silica sand can be vaporized with an arc plasma at atmospheric pressure. The resulting mixture of plasma gas and silica vapour can be rapidly cooled by quenching with oxygen, thus ensuring the quality of the fumed silica produced. The working frequency is typically between 200 kHz and 40 MHz. Laboratory units run at power levels in the order of 30-50 kW while the large scale industrial units have been tested at power levels up to 1 MW. As the residence time of the injected feed droplets in the plasma is very short it is important that the droplet sizes are small enough in order to obtain complete evaporation. The RF plasma method has been used to synthesize different nanoparticle materials, for example synthesis of various ceramic nanoparticles such as oxides, carbours/carbides and nitrides of Ti and Si. Inert-gas aggregation is frequently used to make nanoparticles from metals with low melting points. The metal is vaporized in a vacuum chamber and then super cooled with an inert gas stream. The super cooled metal vapor condenses in to nanometer-sized particles, which can be entrained in the inert gas stream and deposited on a substrate or studied in situ. Nanoparticle Morphology Nanostars of Vanadium (IV) oxide Scientists have taken to naming their particles after the real world shapes that they might represent. Nanospheres, nanoreefs, nanoboxes and more have appeared in the literature. These morphologies sometimes arise spontaneously as an effect of a templating or directing agent present in the synthesis such as micellular emulsions or anodized alumina pores, or from the innate crystallographic growth patterns of the materials themselves. Some of these morphologies may serve a purpose, such as long carbon nanotubes being used to bridge an electrical junction, or just a scientific curiosity like the stars shown at left. J Pharmcovig Drug Safety 2010 (January-March) Volume : 7 (1) 20 Cluster Physics In physics, the term clusters(Physics) denotes small, multiatom particles. As a rule of thumb, any particle of somewhere between 3 and 3*10^7 atoms is considered a cluster. Two-atom particles are sometimes considered clusters as well. The term can also refer to the organization of protons and neutrons within nuclei. Cluster science was born in the 1980s. One purpose of the research was to study the gradual development of collective phenomena which characterize a bulk solid. These are for example the color of a body, its electrical conductivity, its ability to absorb or reflect light, and magnetic phenomena such as Ferro-, ferri-, or antiferromagnetism. These are typical collective phenomena which only develop in an aggregate of a large number of atoms. It was found that collective phenomena break down for very small cluster sizes. It turned out, for example, that small clusters of a ferromagnetic material are superparamagnetic rather than ferromagnetic. Paramagnetism is not a collective phenomenon, which means that the ferromagnetism of the macrostate was not conserved by going into the nanostate. The question then was asked for example “How many atoms do we need in order to obtain the collective metallic or magnetic properties of a solid”? Soon after the first cluster sources had been developed in 1980, an ever larger community of cluster scientists was involved in such studies. This development led to the discovery of fullerenes in 1986 and carbon nanotubes a few years later. Powder (Substance) A powder is a dry, bulk solid composed of a large number of very fine particles that may flow freely when shaken or tilted. Powders are a special sub-class of granular materials, although the terms powder and granular are sometimes used to distinguish separate classes of material. In particular, powders refer to those granular materials that have the finer grain sizes, and that therefore have a greater tendency to form clumps when flowing. Granulars refers to the coarser granular materials that do not tend to form clumps except when wet. Mechanical properties Typically, a powder can be compacted or loosened into a vastly larger range of bulk densities than can a coarser granular material. When deposited by sprinkling, a powder may be very light and fluffy. When vibrated or compressed Kumar A : Nanobiotechnology today: focus on Nanoparticles it may become very dense and even lose its ability to flow. The bulk density of coarse sand, on the other hand, does not vary over an appreciable range. The clumping behavior of a powder arises because of the molecular Van der Waals force that causes individual grains to cling to one another. Only when the grains are very small and lightweight does the Van der Waals force become predominant, causing the material clump like a powder. Many other powder behaviors are common to all granular materials. These include segregation, stratification, jamming and unjamming, fragility, loss of kinetic energy, frictional shearing, compaction and Reynolds' dilatancy. Nanocrystal Fahlman, B. D. has described a nanocrystal as any nanomaterial with at least one dimension ¡ 100nm and that is single crystalline. More properly, any material with a dimension of less than 1 micrometre, i.e., 1000 nanometers, should be referred to as a nanoparticle, not a nanocrystal. For example, any particle which exhibits regions of crystallinity should be termed nanoparticle or nanocluster based on dimensions. These materials are of huge technological interest since many of their electrical and thermodynamic properties show strong size dependence and can therefore be controlled through careful manufacturing processes. Crystalline nanoparticles are also of interest because they often provide single-domain crystalline systems that can be studied to provide information that can help explain the behaviour of macroscopic samples of similar materials, without the complicating presence of grain boundaries and other defects. Semiconductor nanocrystals in the sub10nm size range are often referred to as quantum dots. Crystalline nanoparticles made with zeolite are used as a filter to turn crude oil onto diesel fuel at an ExxonMobil oil refinery in Louisiana, a method cheaper than the conventional way. A layer of crystalline nanoparticles is used in a new type of solar panel named SolarPly made by Nanosolar. It is cheaper than other solar panels, more flexible, and claims 12% efficiency. The term NanoCrystal is a registered trademark of Elan Pharma International Limited (Ireland) used in relation to Elan's proprietary milling process and nanoparticulate drug formulations. Nanoparticle photovoltaic cell Generally, solar cells on the market today do not produce much electricity from ultraviolet light, instead it is either filtered out or absorbed by the cell, heating the cell. That heat is wasted energy and J Pharmcovig Drug Safety 2010 (January-March) Volume : 7 (1) 21 could even lead to damage to the cell. By diluting particles of silicon in alcohol, covering a solar cell with it and letting the alcohol evaporate to leave the nanoparticles of silicon on the cell has been increased the cell power output by 67% in the ultraviolet range and about 10% in the visible range . On the other hand, titanium dioxide and zinc oxide become transparent at the nanoscale, however are able to absorb and reflect UV light. Safety Issues Nanoparticles present possible dangers, both medically and environmentally. Most of these are due to the high surface to volume ratio, which can make the particles very reactive or catalytic. Hey are also able to pass through cell membranes in organisms, and their interactions with biological systems are relatively unknown. However, free nanoparticles in the environment quickly tend to agglomerate and thus leave the nano-regime, and nature itself presents many nanoparticles to which organisms on earth may have evolved immunity (such as salt particulates from ocean aerosols, terpenes from plants, or dust from volcanic eruptions). A fuller analysis is provided in the article on nanotechnology. According to the San Francisco Chronicle, "Animal studies have shown that some nanoparticles can penetrate cells and tissues, move through the body and brain and cause biochemical damage they also have shown to cause a risk factor in men for testicular cancer. But whether cosmetics and sunscreens containing nanomaterials pose health risks remains largely unknown, pending completion of long-range studies recently begun by the FDA and other agencies." Diesel nanoparticles have been found to damage the cardiovascular system in a mouse model. Uses of Nanobiotechnology Since its inception, Strem Chemicals has focused on offering unique organometallic compounds for both academic and industrial research purposes. Close relationships with leading researchers in the field have enabled Strem to stay abreast of the latest scientific advances in and regularly add novel chemicals to our product portfolio. Most recently, Strem has embraced the emerging area of nanotechnology and formed collaboration with the Max-Planck-Institut fuer Kohlenforschung. A series of nanomaterials, including metal nanoclusters, metal nanocolloids (organosols and hydrosols), metal nanopowders, metal nanoparticles, and magnetic fluids are now available from Strem. Below is a discussion of potential applications of these nanomaterials in the medical/pharmaceutical market. Kumar A : Nanobiotechnology today: focus on Nanoparticles Biosensors and Biolabels Using Biosensors and biolabels to understand living cells Nanotechnology has the potential to increase our ability to understand the fundamental working of living cells. Many potential applications for metal nanomaterials as biosensors and biolabels are under investigation. They have found use in cellular studies, enhanced spectroscopic techniques, biochips, and protein and enzyme analysis. Using Fluorescent Nanoparticles for Cell Labeling and Magnetic Nanoparticles as Sensors. Multi-calor labeling of both fixed and living cells with fluorescent nanoparticles conjugated with biological ligands that specifically bind against certain cellular targets enables the recording of diffusion pathways in receptor cells. Uptake of nanoparticles into the vesicular compartments around the nucleus of cells can be used to label the cells so that their pathway and fate can be followed. The nanoparticles exhibit reduced photobleaching as compared to traditional dyes and are passed on to daughter cells during cell division, therefore allowing for much longer term observation. Magnetic nanoparticles can also act as sensors for assessing how external stresses affect changes in intracellular biochemistry and gene expression. How Colloidal Gold Nanoparticles and Colloidal Gold Biofunctionalized Nanomodules Are Used to Monitor Cells Colloidal gold nanoparticles have been found to strongly enhance the native signals of chemical constituents in cells. Surface Enhanced Raman Spectroscopy (SERS) relies on this signal magnification and serves as a tool for ultra-sensitive monitoring of the intracellular distribution of these chemicals. Colloidal gold biofunctionalized nanomodules also have potential for use in enzyme multi-sensors. Gold nanoparticles coated with proteins have been used to detect conformation changes in the attached proteins via observation of calor changes in the solution. Overview Medical use of nanomaterials Nanomedicine seeks to deliver a valuable set of research tools and clinically helpful devices in the near future. The National Nanotechnology Initiative expects new commercial applications in the pharmaceutical industry that may include advanced drug delivery systems, new therapies, and in vivo imaging. Neuro-electronic interfaces and other nanoelectronics-based sensors are another active goal of research. Further down the line, the speculative field of molecular nanotechnology believes that cell repair machines could revolutionize medicine and the medical field. Nanomedicine is a large industry, with nanomedicine sales reaching 6.8 billion dollars in 2004, and with over 200 companies and 38 products worldwide, a minimum of 3.8 billion dollars in nanotechnology R&D is being invested every year. As the nanomedicine industry continues to grow, it is expected to have a significant impact on the economy. Antigen Detection Linkers Protective Layer Fluorescent signaling Biocompatibility Shape recognition Figure 2. Diagram showing how nanotechnology methods can improve our understanding of living cells. J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 22 Kumar A : Nanobiotechnology today: focus on Nanoparticles Medical Use of Nanomaterials Drug Delivery Nanomedical approaches to drug delivery center on developing nanoscale particles or molecules to improve the bioavailability of a drug. Bioavailability refers to the presence of drug molecules where they are needed in the body and where they will do the most good In vivo imaging is another area where tools and devices are being developed. Using nanoparticle contrast agents, images such as ultrasound and MRI have a favorable distribution and improved contrast. The new methods of nanoengineered materials that are being developed might be effective in treating illnesses and diseases such as cancer. Drug delivery systems, lipid- or polymer-based nanoparticles, can be designed to improve the pharmacological and therapeutic properties of drugs. The strength of drug delivery systems is their ability to alter the pharmacokinetics and biodistribution of the drug. Nanoparticles have unusual properties that can be used to improve drug delivery. Where larger particles would have been cleared from the body, cells take up these nanoparticles because of their size. Complex drug delivery mechanisms are being developed, including the ability to get drugs through cell membranes and into cell cytoplasm. If a drug is cleared too quickly from the body, this could force a patient to use high doses, but with drug delivery systems clearance can be reduced by altering the pharmacokinetics of the drug. Cancer The small size of nanoparticles endows them with properties that can be very useful in oncology, particularly in imaging. Quantum dots (nanoparticles with quantum confinement properties, such as size-tunable light emission), when used in conjunction with MRI (magnetic resonance imaging), can produce exceptional images of tumor sites. These nanoparticles are much brighter than organic dyes and only need one light source for excitation. This means that the use of fluorescent quantum dots could produce a higher contrast image and at a lower cost than todays organic dyes used as contrast media. The downside, however, is that quantum dots are usually made of quite toxic elements. Another nanoproperty, high surface area to volume ratio, allows many functional groups to be attached to a nanoparticle, which can seek out and bind to certain tumor cells. Additionally, the small size of nanoparticles (10 to 100 nanometers), allows them to preferentially accumulate at tumor sites (because tumors lack an effective lymphatic drainage system). A very exciting research question is how to make these imaging nanoparticles do more things for cancer. For instance, is it possible to manufacture multifunctional nanoparticles that would detect, image, and then proceed to treat a tumor? This question is under vigorous investigation; the answer to which could shape the future of cancer treatment. A promising new cancer treatment that may one day replace radiation and chemotherapy is edging closer to human trials. Kanzius RF therapy attaches microscopic nanoparticles to cancer cells and then "cooks" tumors inside the body with radio waves that heat only the nanoparticles and the adjacent (cancerous) cells. Sensor test chips containing thousands of nanowires, able to detect proteins and other biomarkers left behind by cancer cells, could enable the detection and diagnosis of cancer in the early stages from a few drops of a patient's blood. Nanoparticles of cadmium selenide (quantum dots) glow Molecular Imaging & Therapy Improved Imaging Localized Therapy Cancer Diagnosed Targeting Medication Homing on Tumor Killing Cancer Cells Figure 3. A schematic illustration showing how nanoparticles or other cancer drugs might be used to treat cancer. J Pharmcovig Drug Safety 2010 (January-March) Volume : 7 (1) 23 Kumar A : Nanobiotechnology today: focus on Nanoparticles when exposed to ultraviolet light. When injected, they seep into cancer tumors. The surgeon can see the glowing tumor, and use it as a guide for more accurate tumor removal. In photodynamic therapy, a particle is placed within the body and is illuminated with light from the outside. The light gets absorbed by the particle and if the particle is metal, energy from the light will heat the particle and surrounding tissue. Light may also be used to produce high energy oxygen molecules which will chemically react with and destroy most organic molecules that are next to them (like tumors). This therapy is appealing for many reasons. It does not leave a “toxic trail” of reactive molecules throughout the body (chemotherapy) because it is directed where only the light is shined and the particles exist. Photodynamic therapy has potential for a noninvasive procedure for dealing with diseases, growths, and tumors. Surgery At Rice University, a flesh welder is used to fuse two pieces of chicken meat into a single piece. The two pieces of chicken are placed together touching. A greenish liquid containing gold-coated nanoshells is dribbled along the seam. An infrared laser is traced along the seam, causing the two sides to weld together. This could solve the difficulties and blood leaks caused when the surgeon tries to restitch the arteries he/she has cut during a kidney or heart transplant. The flesh welder could meld the artery into a perfect seal. Visualization Tracking movement can help determine how well drugs are being distributed or how substances are metabolized. It is difficult to track a small group of cells throughout the body so scientists used to dye the cells. These dyes needed to be excited by light of a certain wavelength in order for them to light up. While different color dyes absorb different frequencies of light, there was a need for as many light sources as cells. A way around this problem is with luminescent tags. These tags are quantum dots attached to proteins that penetrate cell walls. The dots can be random in size, can be made of bioinert material, and they demonstrate the nanoscale property that color is size-dependent. As a result, sizes are selected so that the frequency of light used to make a group of quantum dots fluoresce is an even multiple of the frequency required to make another group incandesce. Then both groups can be lit with a single light source. Nanoparticle Targeting It is greatly observed that nanoparticles are promising tools for the advancement of drug delivery, medical imaging, and as diagnostic sensors. However, the biodistribution of these nanoparticles is mostly unknown due to the difficulty in targeting specific organs in the body. Current research in the excretory systems of mice, however, shows the ability of gold composites to h selectively target certain organs based on their size and charge. These composites are encapsulated by a dendrimer and assigned a specific charge and size. Positively-charged gold nanoparticles were found to enter the kidneys while negatively-charged gold nanoparticles remained in the liver and spleen. It is suggested that the positive surface charge of the nanoparticle decreases the rate of osponization of nanoparticles in the liver, thus affecting the excretory pathway. Even at a relatively small size of 5nm, though, these particles can become compartmentalized in the peripheral tissues, and will therefore accumulate in the body over time. While advancement of research proves that targeting and distribution can be augmented by nanoparticles, the dangers of nanotoxicity become an important next step in further understanding of their medical uses. Diagnostics How Nanotechnology Methods Can Improve Medical Diagnostics Early detection of disease remains a primary goal of the medical community. Nanotechnology holds great promise for enabling the achievement of this goal. Nanoparticles in particular have exhibited tremendous potential for detecting fragments of viruses, pre-cancerous cells, disease markers, and indicators of radiation damage. Gold coatings have made it possible to use toxic cobalt nanoparticles for biomedical applications. Gold coated ferromagnetic nanoparticles tagged with HIV antibodies may be able to detect virus particles left after completion of conventional drug therapy. Metal nanoparticles in the form of dendrimers have also been functionalized with different biomolecules to detect specific proteins, antibodies, and other disease indicators. Fluorescent markers can also be attached to the dendrimers. Early Cancer Detection Using Superparamagnetic Iron Oxide (USPIO) Particles and Magnetic Resonance Imaging (MRI) Biomolecule coated ultra small superparamagnetic iron oxide (USPIO) particles injected in the blood stream recognize target molecular markers J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 24 Kumar A : Nanobiotechnology today: focus on Nanoparticles Figure 4. Diagram showing how nanoparticles can be used to detect diseased cells present inside cells and induce a specific signal for detection by magnetic resonance imaging (MRI). This technology may allow for detection of individual cancer cells months or years earlier than traditional diagnostic tools, which require the presence of hundreds of cancer cells. How Biobarcode Amplification Assays (BCA) Use Nanoparticles in Disease Detection. A nanoparticle-based biobarcode amplification assay (BCA) utilizes gold nanoparticles and magnetic microparticles attached to large numbers of DNA strands and antibodies for a specific disease marker. The marker binds to the nano- and microparticles forming a complex that is separated from the sample using a magnetic field. Heating the complexes releases the DNA barcodes, which emit an amplified signal due to their large numbers. This BCA technology has been applied to the detection of markers forAlzheimer's disease and is being investigated for numerous others.Targeted Drug DeliveryHow Nanotechnology Can Improve Targeted Drug Delivery Methods Targeted drug delivery systems can convey drugs more effectively and/or more conveniently, increase patient compliance, extend the product life cycle, provide product differentiation, and reduce health care costs. Drug delivery systems that rely on nanomaterials also allow for targeted delivery of compounds characterized by low oral bioavailability due to poor water solubility, permeability and/or instability and provide for longer sustained and controlled release profiles. These technologies can increase the potency of traditional small molecule drugs in addition to potentially providing a mechanism for treating previously incurable diseases. Using Magnetic Nanoparticles Targeted Drug Delivery - What This 'Tag and Drag' Process Involves. The use of magnetic nanoparticles in targeted drug delivery systems is under investigation by several research groups. Therapeutic drug molecules have been immobilized on the surface of magnetic nanoparticles or nanocrystals and directed to a specific target tissue using a magnetic field gradient. The drug is released by applying a radio frequency (RF) pulse. Gold coated iron, nickel and cobalt ferromagnetic nanoparticles have been employed in this “tag and drag” approach. In hypothermal treatment, magnetic nanoparticles are directed to diseased tissue containing heat sensitive tumors. An AC magnetic field is applied such that the nanoparticles become heated, causing destruction of the cancerous cells. More effective radiation therapy for tumor treatment can also be expected using metallic nanoparticles instead of, for example, magnetite. The nanoparticles allow the application of higher dosages of radiation at the tumor while sparing normal tissue. Other Applications for Nanomaterials in the Medical and Pharmaceutical Sector. Numerous other potential applications exist in the medical and pharmaceutical field for nanomaterials from Strem. Areas currently under investigation include gene therapy, antibacterial/ antimicrobial agents for burn and wound dressings, repair of damaged retinas, artificial tissues, prosthetics, enhancing signals for magnetic resonance imaging examinations, and as radio frequency controlled switching of complex biochemical processes. List of Nanomaterials that Strem Can Supply to All Types of Industry: A listing of specific metal nanoclusters, metal nanocolloids (organosols and hydrosols), metal nanopowders, metal nanoparticles, and magnetic fluids offered by Strem is available upon request or via our website. Application sheets discussing the potential use of these products in the medical and pharmaceutical, defense and security, chemical, automotive, and energy fields, and as magnetic fluids, can also be obtained from Strem. More information is also available in the form of a reference sheet listing literature source materials. J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 25 Kumar A : Nanobiotechnology today: focus on Nanoparticles Result and Decision: In nanotechnology, a particle is defined as a small object that behaves as a whole unit in terms of its transport and properties. It is further classified according to size: In terms of diameter, fine particles cover a range between 100 and 2500 nanometers, while ultrafine particles, on the other hand, are sized between 1 and 100 nanometers. Similarly to ultrafine particles, nanoparticles are sized between 1 and 100 nanometers, though the size limitation can be restricted to two dimensions. Nanoparticles may or may not exhibit sizerelated intensive properties that differ significantly from those observed in fine particles or bulk materials. Nanoclusters have at least one dimension between 1 and 10 nanometers and a narrow size distribution. Nanopowders are agglomerates of ultrafine particles, nanoparticles, or nanoclusters. Nanometer sized single crystals, or singledomain ultrafine particles, are often referred to as nanocrystals. References 1. Fahlman, B. D. Materials Chemistry; Springer: Mount Pleasant, MI, 2007; 1, 282-283. 2. See for example US TM Reg. Nos. 2386089 / 2492925 and EU CTM Reg. No. 000885079 3. Faraday, Michael (1857). "Experimental relations of gold (and other metals) to light". Phil. Trans. Roy. Soc. London 147:145181. doi:10.1098/rstl.1857 4. Buffat, Ph.; Burrel, J.-P. (1976), "Size effect on the melting temperature of gold particles", Physical ReviewA13(6):22872298,doi:10.1103/PhysRevA.13.2 287,http://link.aps.org/abstract/PRA/v13/p2287 5. Yugang Sun and Younan XI a Science 298 (2002) 2176. doi:10.1126/science.1077229 6. Catherine Murphy, Science 298 (2002) 2139.doi: 10.1126/science.1080007 7. Anisa Mnyusiwalla, Abdallah S Daar and Peter A Singer 2003 Nanotechnology 14 R9-R13 doi:10.1088/0957-4484/14/3/201 8. Ying, Jackie. Nanostructure Materials. New York: Academic Press, 2001. 9. Keya Davidson. "FDA urged to limit nanoparticle use in cosmetics and sun screens Francisco Chronicle.20 April 2007. 10. http://www.bloomberg.com/apps/news?pid= Washington story&sid=aBt.yLf.Yf Oo study -Pollution Particles Lead to Higher Heart Attack Risk (Update1) 11. http://www.autobloggreen.com/2007/08/21/siliconnanoparticle -film-can-increase-solar-cell performance/ 12. http://www.nano.dtu.dk/upload/centre/nanodtu/nano eknologiske_horisonter / supplerende% 20 under visningsmateriale /kap1/ nanoscience % 20and % 20 nanotechnologies % 20 opportunities % 20 and % 20 uncertainties.pdf J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 26 J Pharmcovig Drug Safety 2010 (January-March) Volume : 7 Issue : 1 (Page 27-31) A Retrospective Comparison of Buprenorphine & Pentazocine as an Analgesic in AMI at Pravara Rural Hospital. ORIGINAL ARTICLE RAHUL KUNKULOL, PRONOB K SANYAL, KAILAS R. GADEKAR, Y GRIDHAR REDDY1 Department of Pharmacology, Prosthodontics and Biochemistry YCMM and RDF'S, Ahmednagar, Pin: 414 003. Dept. of Orthodontics, NIMS University Rajasthan, Jaipur 303121 1 ABSTRACT The study aimed to compare Pentazocine and Buprenorphine as an analgesic in the treatment of acute myocardial infarction in terms of morbidity, mortality, and outcome and to find out differences if any in the ultimate prognosis. This was a retrospective study. For the study, patients suffering from AMI admitted in ICCU of Pravara Rural Hospital from 1999 2009were chosen. Pentazocine was used in the treatment of AMI from 1999 2002 in this institution (n-117). From 2003 2009Buprenorphine was used instead of Pentazocine for the treatment of pain of AMI (n-123). Patients were grouped as 1) Pentazocine treated 2) Buprenorphine treated and following parameters were studied, ECG, Morbidity and mortality, infract size and clinical status at discharge.ECG parameters, regression of infract went in favor of Buprenorphine, The morbidity profile in terms of arrhythmias, CCF and shock was significantly less in Buprenorphine treated group. Mortality in Pentazocine treated group was significantly higher as well as extension of infract was notable in this group. All in all in the present study Buprenorphine unequivocally came out as the better drug in the emergency treatment of AMI. Key words: AMI, ECG, Pentazocine, Buprenorphine Introduction choice. Due to unavailability of Morphine, as Morphine comes under restricted drugs and has narcotic code other analgesics preferred are Pentazocine, Buprenorphine, Meperidine. Pentazocine acts as a weak antagonist or a partial agonist at mu receptor while it is agonist at Kappa. Buprenorphine is described as mixed agonist antagonist acting mainly as partial agonist at mu receptors with some antagonistic activity at Kappa. Buprenorphine is 25-50 times more potent than Morphine. In the emergency department, the goals for the management of patient with suspected AMI include control of cardiac pain. Parenterally administrated narcotic analgesics are a critically important part of therapy to control cardiac pain for the patients with acute myocardial ischemic syndromes. These agents are very effective and when used with appropriate caution and monitoring are also generally safe. They not only relieve sensation of pain but also relieve the effective and physiologic reaction to pain and thus reduce patient anxiety. The haemodynamic effects of these agents are quite different in patients with active pain during the period of acute ischemia or in patients that are haemodynamically unstable. Haemodynamic studies during these acute setting however are extremely difficult to perform because the patients acute distress mandates rapid administration of analgesic agent prior to the institution of invasive monitoring. With these cautions relating to data interpretation in mind, it is still possible to make certain recommendations regarding the use of analgesic therapy in AMI. Although a wide verity of analgesics has been used in the treatment of pain associated with AMI including Meperidine, Pentazocine, Buprenorphine and Morphine, the last remained the drug of In view of the aforementioned pharmacological actions of Buprenorphine and Pentazocine more particularly so in the setting of acute myocardial infarction, it was thought Prudent to evaluate the use of Pentazocine and Buprenorphine in the treatment of acute myocardial infarction. Aims and Objective To study and compare the outcome of use of Pentazocine and Buprenorphine in patients suffering from AMI.To evaluate results in terms of various parameters of AMI in patients treated with Pentazocine and Buprenorphine.To find out differences if any in the ultimate prognosis of acute myocardial infarction in terms of morbidity and mortality in patients treated with Pentazocine and Buprenorphine. 27 Kunkulol et al: A Retrospective Comparison Of Buprenorphine & Pentazocine As An Analgesic In AMI At Pravara Rural Hospital Methods This was a retrospective study. Patients suffering from AMI admitted in ICCU of Pravara Rural Hospital from 1999 2005 were chosen. Pentazocine was used in the treatment of AMI from 1999, 2002 in this institution (N117). From 2002-2005 Buprenorphine was used instead of Pentazocine for the treatment of pain of AMI (N-123). The patients who have suffered from acute attack of myocardial infarction and are on same other concomitant therapy were grouped as under: 1. Pentazocine treated 2. Buprenorphine treated 4. Mortality-Mortality was recorded in numbers i) ii) iii) iv) Within 24 hrs 24-48 hrs 48-72 hrs 72 hrs and beyond after administration of opioid 5. Clinical status at the time of discharge from the hospital were noted which includes; 1) Normal 2) Poor 3) Death Statistical analysis was done by using ‘Z’ test. p<0.05 was considered to be statistically significant. Following parameters were studied, 1. ECG parameters recorded after administration of opioid-ECG changes during the course of treatment were recorded at 6 hrs, 12 hrs, and 24 hrs after administration of opioid and at discharge as persistent, extension and regression of infract and were compared between both the groups. 2. Serum enzymes studies after administration of opioids included LDH, CPK, and GOT. 3. Morbidity - i.e. important complications / treatment complications in pentazocine and Buprenorphine treated patients of AMI were noted a. Arrhythmias b. Congestive heart failure c. Cardiogenic shock Results All the patients included in the study received the same other concomitant therapy and the only difference in the therapy for the two groups was the use of either Pentazocine or Buprenorphine, the results obtained in this study can very well be attributed to the use of two opioid. Comparison of ECG parameters in Pentazocine and Buprenorphine treated patients of acute myocardial infarction (values recorded within 24 hrs of administration of Opioid) and ST elevation or depression pattern showed highly significant difference (P < 0.01) in favor of Buprenorphine treated patients than that of Pentazocine treated patients. (Table no. 1&2) Table 1: Comparison of ECG parameters in Pentazocine and Buprenorphine treated patients of acute myocardial infarction (values recorded within 24 hrs of administration of Opioids). J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 28 Kunkulol et al: A Retrospective Comparison Of Buprenorphine & Pentazocine As An Analgesic In AMI At Pravara Rural Hospital Table 2:- ST elevation or depression pattern in Pentazocine and Buprenorphine treated patients of acute myocardial infarction (values recorded within 24 hrs of administration of Opioids). Figure 1:- Comparison of ECG changes in Pentazocine and Buprenorphine treated patients of acute myocardial infarction Pentazocine (n = 117) Buprenorphine (n=123) For all the above three graphs after applying the 'Z' test of difference between two proportions there was a significant difference in favour of Buprenorphine in comparison with Pentazocine. Table 3:- Complication/s/treatment complication/s in Pentazocine and Buprenorphine treated patients of acute myocardial infarction Figure 2:-Comparison of mortality in Pentazocine and Buprenorphine treated patients of AMI J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 29 Kunkulol et al: A Retrospective Comparison Of Buprenorphine & Pentazocine As An Analgesic In AMI At Pravara Rural Hospital Figure 3. Clinical status at discharge in Pentazocine and Buprenorphine treated patients of AMI Pentazocine (n = 117) Buprenorphine (n=123) Note: - For the above table after applying the 'Z' test of difference between two proportions, there was a significant difference in favor of Buprenorphine in all complications in both the groups i.e. in between Pentazocine and Buprenorphine for Table no.5,6,7. Discussion On comparison of ECG changes in Buprenorphine treated and Pentazocine treated patients at 6 hours, 12 hours, 24 hours and at discharge, the observations reveled persistent ECG changes, extension of infract, and regression patterns which were statistically highly significant (P< 0.01) in favor of Buprenorphine treated patients as compare to Pentazocine treated patients at 6 hours, 12 hours, 24 hours and at discharge (Figure 1 Graph 3a, 3b, 3c). The complication/s/ treatment complication/s were observed in 40(34.18%) Pentazocine treated patients while in 17 (13.82%) Buprenorphine treated patients (Table no. 3). On comparison of mortality in Pentazocine and Buprenorphine treated patients, mortality count was 24 (20.52%) in Pentazocine treated patients out of which 09 died within 24 hours, and remaining 15 patients died in 24 48 hours. The mortality count with Buprenorphine treated patients was 05 (4.08%) and the death of all these 05 patients occurred after 72 hours of administration of these drugs. The mortality with Pentazocine treated patients was statically highly significant (P < 0.01) as compared to the Buprenorphine treated patients (Figure 2). The study of clinical status of patients at discharge revealed that 77% of Buprenorphine treated patients and only 39.31% of Pentazocine treated patients became normal, while the clinical status of 40.17% of Pentazocine treated patients and 18.69% of Buprenorphine treated patients was poor at discharge. This study revealed that the clinical status at discharge was statically highly significant (P < 0.01) in favor of Buprenorphine treated patients (Figure 3).The various parameters which we studied yielded statistically significant or highly significant results in favor of Buprenorphine over Pentazocine. Most of the deleterious changes with Pentazocine which either resulted into morbidity and or mortality or heralded the onset of the same occurred during the first 24 hours of administration of Pentazocine. The unequivocal results in favor of Buprenorphine implicitly points towards Pentazocine as the not unlikely cause for the harmful events in the patients of AMI. Furthermore most of the events or the significant changes in the parameter studied were in the first 24 hours after administration of Pentazocine, where as the occurrence of the same, the same time frame with Buprenorphine was minimal and insignificant. For those who critically evaluate, we have some additional advantages of Buprenorphine which would definitely satisfy them, these are provided by the studies of Keith J et al on opioids receptors and myocardial protection which reported : FThe recent studies of Schultz et al which suggested that delta opioid receptors in the intact rat heart mediate cardio protective effects of ischemic preconditioning and opioids. FThe reduction in binding affinity of kappa receptor was correlated with reduction in vulnerability of ventricles to fibrillate and incidence of ventricular fibrillation. FPentazocine binds to kappa receptors and acts as an agonist at kappa sites. It stimulates K3 receptor and causes sedation and supraspinal analgesia, while K1 stimulation causes spinal analgesia thus the binding to kappa receptor is increased. FThese data allowed speculation that the cardioprotective effects of both ischemic preconditioning and opioids was in some way related to activity of delta receptors and in versely to activity of kappa receptor. J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 30 Kunkulol et al: A retrospective comparison of Buprenorphine & Pentazocine as an analgesic in AMI at Pravara Rural Hospital F Additionally Xia and coworkers proposed that activation of kappa receptors may be a contributing factors for arrhythmia induced by myocardial ischemia and reperfusion. F In an in vivo rat model of AMI, opioid receptor stimulation has been observed to result in a reduction in infarct size similar to ischemic preconditioning and was due to involvement of myocardial ATP Sensitive potassium channel (KATP). Further it was suggested that opening of KATP channel may be an endogenous protective mechanism in humans also. F Opening of KATP channel is differentially involved in antinociceptive effects of some opioids including Buprenorphine, Morphine as Pentazocine, Fentanyl or Levorphanol. F On the basis of analysis of these in vivo data, it was speculated that and Methadone but not in others such Buprenorphine posses previously unrecognized beneficial cardioprotective effects in patients including those undergoing by pass surgery and those experiencing an AMI. F Importantly data from antinociceptive studies indicated that differences have existed between opioids for antinociception with Buprenorphine having greatest cardioprotective potential while in contrast Pentazocine having least or no cardioprotective potential. F Further it has been reported that Buprenorphine at doses that induce antinociception also provides protection against myocardial ischemia. With such a plethora of advantages of Buprenorphine over Pentazocine it can be safely argued and concluded that the observations of the present study singling out unequivocally Buprenorphine as by far the better drug between the two studied for used in AMI can not be perchance. Conclusion All in all in the present study Buprenorphine Unequi vocally came out as the better drug in the emergency treatment of AMI. In view of these results Buprenorphine is recommended for the treatment of pain in all types of AMI and especially in those with compromised cardiac functions. J Pharmcovig Drug Safety 2010 (January-March) Volume : 7 (1) 31 References 1. Avery GS: Drug treatment: 2nd edition: 325 - 6, 1213: 1980. 2. Carl P and Crawford ME: Long term treatment with epidural opioids: Anaesthesia:1986, 41: 32. 3. Buprenex package insert (Norwich Eaton Resolution, 1985/6. US), 4. Elimauer S, Different opioids in patients at cardiovascular risk, Anaesthesist, 1994, 43(11), 7439. 5. Elliot M, “Harrison's Principles of Internal Medicine”, 243. Acute myocardial infarction, 2001, 15th edition. 6. Kaplan JA, editor cardiac anaesthesia, Cardiovascular Pharmacology, 1983, 2, 65 69. 7. Martindales, The complete drug references, 1999, 32nd Ed.,P22. 8. Lee's Synopsis of anaesthesia, 1999, 12th edition: ch.26. 9. Keith J, Opioid receptors and myocardial protection, Clin. Drug. Invest. 1998. 15 (5), 445 54. 10. Mitaka C, Comparison of Haemodynamic effects of Morphine, Buprenorphine and Pentazocine on ICU patients, Bull Tokyo Med Dent. Univ., 1985, 32 (2); 31- 9. 11. Oranto Joseph, Cardiovascular emergencies, 1986, 9, 145. 12. Rabinov M, A double blind comparison of the relative efficacy, side effects, and cost of Buprenorphine in Patients after cardiac surgery: Aust N Z J Surgery: 57 (4): 227- 31. 13. Richard C, 39 Acute myocardial infarction, Braunwald E, Heart diseases, 1988, 1215 - 25, 4th Ed. 14. Terry R and Pasternek G: Opioid analgesics and antagonists, Goodman Gilman's The Pharmacological basis of Therapeutics, 1996, 9th ed., 546- 48. J Pharmcovig Drug Safety 2010 (January-March) Volume : 7 Issue : 1 (Page 32-37) Biosafety Issues In Laboratories: A Review REVIEW ARTICLE AMIT JAIN, ZAHRA HASHEMI1 Nidaan Diagnostic and Research Center, Aligarh-202001 Centre for Safety & Rational Use of Indian Systems of Medicine, Ibn Sînâ Academy, Aligarh-202001 1 In spite of vigorous awareness campaigns about the transmission of various infections by blood or parentral routes, there seems to be little or negligible change in the perception not only among the laymen but also the healthcare workers and paramedical staff. Since the advent of AIDS epidemic extra ordinary efforts had gained momentum regarding the biosafety and prevention of laboratory acquired infections all over the world but now they seem to be again vaining .The lack of proper infrastructure, low levels of awareness and certain degree of complacency among laboratory staff all seem to be contributing factors. Biosafety infractions are common, including inadequate laboratory location, lack of biosafety protocols, and dangerous disposal practices. In one of the studies Ninety-four percent of respondents stated that continuing education regarding biosafety in laboratory safety would be useful 1.This article is an effort to quickly refresh all the facts that a healthcare personnel already had read or know regarding the biosafety in laboratories. potentially infected materials must be aware of potential hazards, and must be trained and proficient in the practices and techniques required to handle such material safely. Each laboratory should develop or adopt a biosafety or operations manual that identifies the hazards that will or may be encountered, and that specifies practices and procedures designed to minimize or eliminate exposures to these hazards. Laboratory personnel, safety practices, and techniques must be supplemented by appropriate facility design and engineering features, safety equipment, and management practices Safety Equipment (Primary Barriers) Safety equipment includes biological safety cabinets (BSCs), enclosed containers, and other engineering controls designed to remove or minimize exposures to hazardous biological materials. The biological safety cabinet (BSC) is the principal device used to provide containment of infectious splashes or aerosols generated by many microbiological procedures 3, 4. Three types of biological safety cabinets (Class I, II, III) used in microbiological laboratories. Open-fronted Class I and Class II biological safety cabinets are primary barriers which offer significant levels of protection to laboratory personnel and to the environment when used with good microbiological techniques. The Class II biological safety cabinet also provides protection from external contamination of the materials (e.g., cell cultures, microbiological stocks) being manipulated inside the cabinet. The gas-tight Class III biological safety cabinet provides the highest attainable level of protection to personnel and the environment. An example of another primary barrier is the safety centrifuge cup, an enclosed container designed to prevent aerosols from being released during centrifugation. It must be used when handling infectious agents that can be transmitted through the aerosol route of exposure. Safety equipment also may include items for personal protection, such as gloves, coats, gowns, shoe covers, boots, respirators, face shields, safety glasses, or goggles. Personal protective equipment is often used in combination with biological safety cabinets, however in some situations in which it is impractical Biosafety in a laboratory set up may be considered under following three heads: - Universal work precautions -- Guidelines in relation to blood, body fluids etc. Effective use of disinfection and sterilization Safe disposal of hospital waste. I. Universal Work Precautions: Universal precautions refer to precautions consistently applied to all patients regardless of their blood borne infection status 2. Blood and body fluids of all the patients are taken to be positive for HIV, HBV, and HCV and other blood borne pathogens. All instruments and equipment that have come in contact with blood are considered to be potentially contaminated and must be properly handled, cleaned sterilized and safely disposed off. Universal precautions took the place of and eliminated the need for the isolation category "Blood and Body Fluid Precautions" in the 1983 CDC Guidelines for Isolation Precautions in Hospitals. The most important element of it is strict adherence to standard microbiological practices and techniques. Persons working with infectious agents or 32 Jain A: Biosafety Issues in Laboratories: A Review to work in biological safety cabinets, personal protective equipment may form the primary barrier between personnel and the infectious materials. Secondary barriers such as hand washing sinks and waste decontamination facilities must be available to reduce potential environmental contamination. Biosafety Levels: Four biosafety levels (BSLs) are described, which consist of combinations of laboratory practices and techniques, safety equipment, and laboratory facilities. Each combination is specifically appropriate for the operations performed, the documented or suspected routes of transmission of the infectious agents, and the laboratory function or activity. Biosafety Level 3 practices, safety equipment, and facility design and construction are applicable to clinical, diagnostic, teaching, research, or production facilities in which work is done with indigenous or exotic agents with a potential for respiratory transmission, and which may cause serious and potentially lethal infection, Mycobacterium tuberculosis, St. Louis encephalitis virus, and Coxiella burnetii are representative of the microorganisms assigned to this level. Primary hazards to personnel working with these agents relate to auto inoculation, ingestion, and exposure to infectious aerosols. Biosafety Level 1 practices, safety equipment, and facility design and construction are appropriate for undergraduate and secondary educational training and teaching laboratories, and for other laboratories in which work is done with defined and characterized strains of viable microorganisms not known to consistently cause disease in healthy adult humans. Biosafety Level 1 represents a basic level of containment that relies on standard microbiological practices with no special primary or secondary barriers recommended, other than a sink for hand washing. Biosafety Level 2 practices, equipment, and facility design and construction are applicable to clinical, diagnostic, teaching, and other laboratories in which work is done with the broad spectrum of indigenous moderate-risk agents that are present in the community and associated with human disease of varying severity. With good microbiological techniques, these agents can be used safely in activities conducted on the open bench, provided the potential for producing splashes or aerosols is low. Hepatitis B virus, HIV, the salmonellae, and Toxoplasma spp. and recent H1N1 influenza virus, are representative of microorganisms assigned to this containment level. For those performing rapid immunoassay tests for influenza, splash protection is required. For those performing more complex procedures (e.g., direct or indirect fluorescent antibody tests [DFA, IFA], culture, molecular assays), a Class II biosafety cabinet (BSC) in a biosafety level-2 (BSL-2) laboratory is required. .Biosafety level-3 (BSL-3) practices are no longer required for H1N1 viral isolation5 Biosafety Level 2 is appropriate when work is done with any human-derived blood, body fluids, tissues, or primary human cell lines where the presence of an infectious agent may be unknown. (Laboratory personnel working with human-derived materials should refer to the OSHA Blood borne Pathogen Standard 6 for specific required precautions.) Biosafety Level 4 practices, safety equipment, and facility design and construction are applicable for work with dangerous and exotic agents that pose a high individual risk of life-threatening disease, which may be transmitted via the aerosol route and for which there is no available vaccine or therapy. Viruses such as Marburg or CongoCrimean hemorrhagic fever are manipulated at Biosafety Level 4. The laboratory worker's complete isolation from aerosolized infectious materials is accomplished primarily by working in a Class III BSC or in a full-body, air-supplied positive-pressure personnel suit. The Biosafety Level 4 facility itself is generally a separate building or completely isolated zone with complex, specialized ventilation requirements and waste management systems to prevent release of viable agents to the environment. Except in extraordinary circumstances (e.g., suspected hemorrhagic fever), the initial processing of clinical specimens and serological identification of isolates can be done safely at Biosafety Level 2, the recommended level for work with blood borne pathogens such as hepatitis B virus and HIV. The containment elements described in Biosafety Level 2 are consistent with the OSHA standard, "Occupational Exposure to Blood borne Pathogens" 7, 8 from the Occupational Safety and Health Administration. This requires the use of specific precautions with all clinical specimens of blood or other potentially infectious material (Universal or Standard Precautions).9 Additionally, other recommendations specific for clinical laboratories may be obtained from the National Committee for Clinical 10 Laboratory Standards. Biosafety Level 2 focuses on the prevention of percutaneous and mucous membrane exposures to clinical material. Primary barriers such as biological safety J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 33 Jain A: Biosafety Issues in Laboratories: A Review cabinets (Class I or II) should be used when performing procedures that might cause splashing, spraying, or splattering of droplets. Biological safety cabinets also should be used for the initial processing of clinical specimens when the nature of the test requested or other information suggests the likely presence of an agent readily transmissible by infectious aerosols I. General Bio-Safety Guidelines For Laboratory Workers 1) Access to laboratory should be limited at the discretion of laboratory- in charge when experiments are in progress. The door should have a symbol of 'BIOHAZARD - NO ADMITANCE'. Laboratories should be well ventilated so as to ensure that the personnel do not breathe in contaminated air. 2) Eating, drinking, smoking and application of cosmetics are prohibited in the laboratory Sandals and open style shoes do not afford proper foot protection and are not to be used. Contact lenses especially the soft ones should not be worn. 3) Laboratory and work tables should be scrupulously cleaned with liquid detergents and disinfectants. Laboratory work surface should be decontaminated once a day after completion of day's activity and immediately after spill of viable material with disinfectant. .4) Biological safety cabinets and other primary containment devices e.g. centrifuge safety caps should be used whenever handing hazardous specimens and when it is likely to produce aerosols or infectious droplets. 5) Blood and other specimen containers should be labeled with a warning sign. The outside of the specimen container should be cleaned with sodium hypochlorite solution in case of visible contamination. 6) Gloves should be worn while dealing with blood specimens, blood-soiled items, body fluids, excretions, secretions, surface materials and objects exposed to them. 7) Gowns/laboratory coats must be worn while working with potentially infective materials and removed before leaving the laboratory. 8) Hands should be washed immediately after contact with blood and before leaving the laboratory. 9) Mechanical pipetting devices should be used. Mouth should be followed to minimize the creation of aerosols. 10) Accidental wounds from sharp instruments should be avoided. Extreme caution is warranted when handing needles and sharps to avoid auto inoculation. Needles should be promptly placed in a puncture resistant container immediately after decontamination. 11) Paper work should not be done on potentially contaminated surface. 12) All potentially contaminated materials and wastes from the laboratory should be disposed after decontamination preferably by autoclaving. A label with a globally accepted biological hazard sign should be applied. 13) Effective use of sterilization and disinfection. II. Effective Use of Sterilization and Disinfection: Disinfection is a process which reduces the number of pathogenic microorganisms, but not necessarily bacterial spores from inanimate objects or skin, to a level which is not harmful to health. Sterilization is a process which destroys all micro-organisms including bacterial spores. The level of decontamination should be such that there is not risk for infection when using the equipment. Classification of infection risk from equipment or environment into three categories and suggested levels of decontamination. Low Risk: Items in contact with normal and intact skin, or the inanimate environment not in contact with the patient (e.g. walls, floors, ceilings, furniture, sinks and drains). Cleaning and drying is usually adequate except when there is spill of blood/body fluids. Intermediate Risk: Equipment which does not penetrate the skin or enter sterile areas of the body but is in contact with mucous membranes or non-intact skin, or other items contaminated with virulent or transmissible organisms (e.g. respiratory equipment gastro-intestinal endoscopes, vaginal instruments, thermometers). High level disinfection is usually adequate. High Risk: Items penetrating sterile tissues, including body cavities and the vascular system (e.g. surgical instruments, intra-uterine devices, vascular catheters, syringes and needles etc.) Decontamination followed by cleaning and sterilization is required. High level disinfection may sometimes be appropriate if sterilization is not possible. J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 34 Jain A: Biosafety Issues in Laboratories: A Review Environmental Cleaning: Floors, surfaces, sinks and drains should be cleaned with warm water and detergent Routine use of disinfectants is unnecessary. If there is spillage of blood, body fluids or sputum, disinfection before cleaning is recommended in high risk areas or following spillage from a known infected patient the surface is cleaned using freshly prepared 0.5 - 1% sodium hypo chlorite solution 11 Gloves should be worn. Release of chlorine gas from disinfection of large spillage can be hazardous to staff. If spillage is immediately removed general disinfection of the room is not necessary though cleaning will suffice. Disinfection: Most of the disinfectants used in health care settings in this country, if used in proper concentration and for suitable period of time are effective against HIV. Either thermal or chemical processes are used for disinfection. Thermal disinfection is preferred whenever possible12. It is generally more reliable, leaves no residue, is more easily controlled and is non-toxic. Organic matter (serum, blood pus or faecal matter) interferes with the antimicrobial efficiency of either method. The larger the number of microbes present the longer it takes to disinfect. Boiling (100oC) for 20-30 minutes (holding time) is a very simple and reliable method for the inactivation of all microorganisms including hepatitis B, HIV and mycobacterium. Carefully done, it is a high-level disinfection procedure .The main use of chemical disinfectants is for heat labile equipments where single use is not cost effective. III. Safe Disposal of Laboratory Wastes : Laboratory wastes are potential hazards. Infectious waste can transmit numerous diseases in the community and put those who handle waste and live on its proximity, at risk. Besides, the increasing use of disposables in health care is also posing an additional burden on the waste management facility. It is extremely important that the recycling of these items is prevented. Only a small percentage (<10%) of the waste generated in health care settings are infectious while another 5% is non-infectious but hazardous. The most practical approach to the management of biomedical waste is to identify and segregate infectious waste, for which some special precautions appear prudent. This will drastically reduce the cost of the disposal methods in health care settings. Setting up of Biomedical Waste Facility. Every hospital, nursing home, veterinary institution , animal-house, blood banks, research institutes generating J Pharmcovig Drug Safety 2010 (January-March) Volume : 7 (1) 35 biomedical wastes should install an appropriate biomedical waste facility in the premises or should set up a common facility in accordance with the directions given by the appropriate authority. Every hospital should have a waste management programme. It helps in determining both the type and quantity of waste being generated in the hospital including the laboratory and determines the feasible methods of disposal. Containing Waste at Generation Point At the generation point i.e. the laboratory waste is managed in the following was F Collection F Segregation and weighing F Storage Waste segregation is the key to any waste management scheme. It consists of placing different types of waste in different containers or colour-coded bags at the site of generation. This helps in reducing the bulk of infectious waste and contains spread of infection to general waste. Proper segregation should identify waste according to source and type of disposal / disinfection. Waste should be segregated into different categories at the site of generation i.e. in the laboratory and weighed separately at the time the waste is being disposed. Solid Non infectious waste is collected in black bags and disposed as household waste. Infectious waste must be separated at the point of generation itself and should be decontaminated prior to its storage, transport and disposal. Solid infectious waste is disposed as follows: Sharps a) Needles and syringe nozzle-shredded in needledestroyer (if available): if not available decontaminated as in b) b) Scalpel blades / lancets / broken glass-should be put in separate container with bleach, transferred to plastic/cardboard boxes, sealed to prevent spillage and transported to incinerator. Glass wares should be disinfected, cleaned and sterilized. Culture plates with viable culture should be autoclaved in plastic autoclave bags, media are removed and collected in yellow bags and disposed of by incineration/ microwaving/hot air oven. The plates can be reused after sterilization. Swabs should be chemically disinfected followed by incineration. Disposable items include single Jain A: Biosafety Issues in Laboratories: A Review are often recycled and have the risk of being reused illegally, these should be disinfected by dipping in freshly prepared 1% Sodium hypochlorite for 30 minutes to 1 hour. Bins which can be used for this purpose are a set of twin bins, one inside the otherwise the inner one being perforated and easily extractable. This minimizes contact when the contents are being removed. Disposable items like to gloves, syringes etc. should be shredded cut or mutilated before disposal followed by deep burial or properly accounted before disposal. Extreme care should be taken while handing the needles. Packing, Storage and Transport All segregated and disinfected waste should be packed in proper containers and color-coded bags (Table1), with red labels mentioning details of biomedical waste and biohazard signs. All containers used for storage of such waste shall be provided with a properly covered lid. Such containers should be inaccessible to scavengers and protected against insects, birds, animals and rain. There should not be any spillage during handing and transit of such waste. The waste sharps, after pre-treatment should be broken before packing in the container. The waste should-be transported in vehicles authorized for this purpose only. No such waste should be stored in the place where it is generated for a period of more than two days. Treatment and Disposal Disposal methods: Disposal may be done by Municipal Corporation and or Sanitary landfill. If incinerator is not available, deep burial in controlled landfill sites is recommended. Decontamination should be carried out before burial. Incineration (Temprature = 750oC): Incinerator burns / reduces the infectious waste to ashes and therefore favoured by hospitals. It may be of two types-common or individual. There are some disadvantages like pollution/incomplete melting of needle. Hospitals with more than 30 beds or 1000 patients per month should have an incinerator. Plastics cannot be incinerated. J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 36 Jain A: Biosafety Issues in Laboratories: A Review Guidelines for Waste Disposal 13 All biomedical wastes should be treated and disposed of strictly in accordance with the options mentioned in the Table 1. Waste which cannot be incinerated, (plastics) should be pretreated by disinfectant and disposed of in an environmentally sound manner. Waste should not be dumped discharged or disposed in any place other than a site identified for the purpose. All precautions and personal safety measures should be taken (including provision of protective clothing, masks, gloves, gumboots, goggles, etc. as may be necessary). Hepatitis B vaccine is recommended for affording protection to all personnel engaged in handling biomedical waste, or being exposed to such wastes against infection from handing or exposure. References 1. Assessment of laboratory and biosafety practices associated with bacterial culture in veterinary clinics J. Scott Weese, DVM, DVSc, DACVIM; John F. Prescott, VetMB, PhD. Journal of the American Veterinary Medical Association. 1, 2009,234, No. 3,352-358. 10.2460/javma.234.3.352 2. CDC update: Universal precautions for preventing transmission of human immunodeficiency virus, hepatitis B virus and other blood borne pathogens in health care settings. MMWR 1988; 377-388. 3. Centers for Disease Control and Prevention. Primary containment for biohazards: selection, installation and use of biological safety cabinets. Washington, DC: U.S. Government Printing Office, 2000. All treatment and disposal facilities should be located at specified area away from the general service area of the hospital, public places and residential areas. When the treatment option is burial, the pits should be located at sites away from agricultural land, residential areas, ground-and sale water sources. There should be no leakage from the pits in to surrounding areas. All plastics should be disinfected, shredded and disposed o in an environmentally friendly manner. Recycling of disposables e.g. syringes, needles, gloves, transfusion bags etc. should be prevented. All liquid waste should be disinfected and flushed in the sinks at the point of generation. 5. Interim Biosafety Guidance for All Individuals handling Clinical Specimens or Isolates containing 2009-H1N1 Influenza A Virus (Novel H1N1), including Vaccine Strains. www.cdc.gov/h1n1flu/specimencollection.htmn Biomedical waste should not be disposed of on open land and municipal dustbins. Untreated liquid waste should not be let into sewers. 7. U.S. Department of Labor, Occupational Safety and Health Administration. 1991. (2) Maintenance of Records. Separate records for classification of waste and their regular disposal should be maintained in the laboratory. The waste disposal programme should be supervised and monitored regularly. IV. Implementation of Bio-Safety Practices in Lab Although guidelines regarding universal precautions and other bio-safety practices are available since long, strict implementation is not in practice in healthcare settings in India even in the capital city. With increase in the prevalence of HIV infection, there is a definite need that the health care workers take bio-safety practices seriously. For effective compliance, the laboratory managers should ensure adequate supply of personal protective equipments, availability of materials for hand washing, disinfectants and set up an effective waste disposal programme for disposal of biomedical wastes. Training regarding need of and national guidelines of bio-safety practices is extremely important and should be provided at regular intervals for different levels of health care workers. Guidelines for bio-safety should be provided which may be modified from time to time according to requirement 4. Kruse, R.H., Puckett, W.H., and Richardson, J.H. Biological safety cabinetry. Clin Microbiol Rev 1991; 4:207-41. 6. U.S. Department of Labor, Occupational Safety and Health Administration. 1991. Occupational Exposure to Blood borne Pathogens, Final Rule. Fed. Register 56:6417564182. 8. Richmond, J.Y. 1994. "HIV Biosafety: Guidelines and Regulations." In (G. Schochetman, J. R. George, Eds.), AIDS Testing, Edition 2 (pp. 346-360). Springer-Verlag New York, Inc. 9. Centers for Disease Control. 1988. Update: Universal Precautions for Prevention of Transmission of Human Immunodeficiency Virus, Hepatitis B Virus and Other Blood borne Pathogens in Healthcare Settings. MMWR, 37:377-382, 387, 388. 10. National Committee for Clinical Laboratory Standards (NCCLS). 1997. Protection of laboratory workers from instrument biohazards and infectious disease transmitted by blood, body fluids, and tissue. Approved guideline. 1977, NCCLS Doc. M29-A (ISBN1-56238-339-6. 11. WHO Biosafety manual 2nd edition, 1993 World health organization. 12. Interim Biosafety Guidance for All Individuals handling Clinical Specimens or Isolates containing 2009-H1N1 Influenza A Virus (Novel H1N1), including Vaccine Strains CDC 2009. www.cdc.gov/h1n1flu/guidelines_labworkers 13. WHO managing Medical Waste in developing countries. 1994 World health organization, Geneva. J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 37 J Pharmcovig Drug Safety 2010 (January-March) Volume : 7 Issue : 1 (Page 38-42) Pharmacovigilance of Homeopathy Questioning its Efficacy ORIGINAL ARTICLE DINESH K. JAIN, RAJ K. ARYA Department of Pharmacology, G.R. Medical College, Gwalior -474001 ABSTRACT Creation of knowledge is a continuous process in the history of mankind. In primitive period treatment was associated with appeasing the sprits. The idea of a God or Gods was later conceived to intervene and protect him from the evil spirits. Before the advent of science based approaches, repeated attempts were made to construct systems of therapeutics. One of these was allopathy. The favoured remedies include blood letting, emetics and purgative which was responsible for death of many patients. Hahnemann introduced the practice of Homeopathy in the early 19th century in reaction against allopathy. After review of all Homeopathic principles on the basis of present medical knowledge, it has been found that they are illogical, irrational and not in accordance with the knowledge of available criteria's of scientific therapeutic system. Government of India is ready to prohibit use of such drugs which are therapeutically ineffective, then it is the duty of pharmacologists to inform to government about ineffectiveness of Homeopathic drugs. (Key Words: Hahnemann, Homeopathy, Adverse Effects, Therapeutically Ineffective, Drugs And Cosmetics Act.) Creation of Knowledge is a Continuous Process the context of present knowledge. If we follow the concepts that developed knowledge opposes, it is quite irrational. "Medicineman, primitive healers, has no connection with the knowledge of medicine, pharmacy, or even surgery. It is associated with appeasing the spirits. When the medicineman amputates a finger, trephines a skull, cauterizes a scalp, cuts the prepuce from a male child, sucks the blood or pus from a wound, or opens a vein for blood letting, he does so without any intention of counteracting a pathological condition on a rational basis. His purpose is to permit the egress of an evil spirit from the body, and for this purpose alone he employs a surgical procedure. The idea that disease is a punitive measure dispensed by the gods for violation of religious principles was a later conception. Man's concept of spirits antedated his belief in benevolent deities or gods. The idea of a God or Gods was later conceived to intervene and protect him from the evil spirits."1 "The great Greek physician Hippocrates (460-377 BC) has been called the father of modern medicine. He denied the intervention of deities and demons in the development of disease."3 Before Hippocrates it was presumed that all diseases are due to supernatural influences. It was Hippocrates who first of all opposed supernatural influences in the development of diseases. He presented revolutionary concept which made him father of modern medical science. "Before the advent of science based approaches, repeated attempts were made to construct systems of therapeutics many of which produced even worse results than pure empiricism. One of these was allopathy, espoused by James Gregory (1735-1821). The favoured remedies include blood letting, emetics and purgatives, which were used until the dominant symptoms of the disease were suppressed. Many patients died from such treatment and it was in reaction against it that Hahnemann introduced the practice of Homeopathy in the early 19th Century."4 "Superstition and development of knowledge are two contradictory concepts in a society. The concepts and beliefs that are prevalent in society, if genuine, based on logic and reason, need no reformation and thus would continue to be practiced. But this does not hold true. On the basis of evolved knowledge, change in the society is a normal practice of healthy community"2 Present Status of Homeopathy Creation of knowledge is a continuous process. The history of knowledge is closely associated with the history of human being. Beliefs, traditions and concepts of our forefathers should be changed if they are found unsuitable in Samuel Hahnemann of Germany (1755-1843) developed a new system of therapeutics - Homeopathy. It entered India during 1810-1839 and now it has become a part of Indian culture. 38 Jain D: Pharmacovigilance of Homeopathy - Questioning its Efficacy India has the highest number of Homeopaths. "Homeopathy reached its peak of popularity in the early nineteenth century. Today there is a resurgence of the popularity of this old medical practice. There are about 3000 recognized practitioners in the U.S. who practice Homeopathy. In the US there are at least five schools and training centers for Homeopathy. In France, 16 percent of the population uses Homeopathic drug products on a regular basis. In England, 45 percent of conventional physicians refer patients to Homeopathic practitioners. In Russia, at least 20 percent of the medical care is Homeopathic. Homeopathy has a strong following in Belgium, Germany, Netherlands, Italy and South America. Homeopathy traditionally has had a strong following in poorer countries. India has 100,000 prescribers of Homeopathic medicine."5 This indicates Homeopathy is becoming popular throughout the world. What is Homeopathy ? "The guiding principles of Homeopathy are like cures like and activity can be enhanced by dilution."6 "Like cures like" means symptoms of disease can be reproduced in a healthy body by a drug then this drug is effective in that disease. Similar symptoms in the remedy remove similar symptoms in the disease. The second important principle of Homeopathy is "dilution potentiates the potency." According to Hahnemann, effect of drugs is potentiated by dilution even to the extent that an effective dose may not contain a single molecule of drug. Hahnemann recommended 30th potency dilution in which one molecule of drug would be in a volume of a sphere of literally astronomical circumference. Other important principles of Homeopathy are"7,8,9,10 (1) Knowledge regarding etiology, pathology and nature of disease is not important. (2) Name and diagnosis of disease are not necessary. (3) Removal of symptoms means total cure, no symptoms indicate no disease. (4) Bacteria or other microbial agents, and any other external factors are not responsible for development of disease. According to Homeopathy, dirty food and dirty water cannot be held responsible for any disease. (5) Hahnemann rejected the examination of blood, urine and other investigations for diagnosis and treatment of diseases. (6) If symptoms of disease are changed then drug should be changed (7) Medicines can show nothing curative besides their tendency for produce morbid symptoms in healthy persons. (8) Jealousy, lack of love, disturbed piece, selfishness, unfairness, unjustified attitude, non religious thought are the causative factors in the development of psora which is the basis of all diseases. (9) Homeopathy opposes external application of lotion and ointment in skin diseases (10) It opposes injections & vaccinations. (11) To know study of effectiveness of a drug, it should not be given to patients. (12) Homeopathy condemns the principle of removal of external manifestations of disease by an external means whatsoever (13) Parts of body or organs from the body can be removed and yet man will exist. (14) This pathy says "God warned that he should be followed otherwise men will suffer from tuberculosis and fever". (15) When the treatment of infant is concerned, Hahmenn advised drug administration to the nursing mother. Pharmacovigilance & Duty of Pharmacologist "World Health Organization defines pharmacovigilance is the science & activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug related problems. Recently its concerns have been widened to include herbals, traditional & complementary medicines, blood products, biological medical devices & vaccines (W.H.O. 2002). Appreciating the importance and benefits of pharmacovigilance, Central Drugs Standards Control Organization (CDSCO), Ministry of Health and Family Welfare, Govt. of India launched the National Pharmacovigilance Programme (NPP) in November 2004"11 Safety and efficacy are two major concerns about any drug. Pharmacokinetic, pharmacodynamic and efficacy study of drugs of modern medical science are possible because drugs of modern medical science are known single chemical molecules. Whereas these studies of substances of alternative and complementary medicines are not possible because effective single chemical molecules are not known. Unfortunately, when this term pharmacovigilance is mentioned, there is still a confusion on this topic. Pharmacologists and other medical specialists think that pharmacovigilance is concerned only with side effects, untoward effects and toxic effects. It is absolutely wrong. Efficacy should be the first step of pharmacovigilance. When alternative and complementary medicines are included in pharmacovigilance, evaluation of efficacy should be the first concern because efficacy of these systems are doubtful. It is rightly mentioned in the most standard text book of medicine "Complementary and alternative medical (CAM) practices include Acupuncture, Ayurvedic Medicine, Dance Therapy, Massage, Meditation, Naturopathy, Siddha Medicine, Unani J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 39 Jain D: Pharmacovigilance of Homeopathy - Questioning its Efficacy Medicine, Yoga, Homeopathy etc. None the less, over the past few decades thousands of studies have been performed of various CAM approaches including hundreds of trials involving herbal, Acupuncture, or Homeopathy. To date however, no single approach has been proven effective in convincing way. (If they had, the practice would no longer be considered CAM. Several factors contribute to the lack of convincing evidence. The vast majority of CAM studies have been seriously flawed by lack of appropriate controls, bias on the part of the investigators, small sample sizes, reliance on highly subjective and non-validated measures of benefit, and by in appropriate statistical tests."12 Actually efficacy is included in adverse reactions but pharmacologists are ignoring this fact. Analysis of efficacy of drugs is a part of study of adverse reaction. "An adverse drug reaction is defined as any response to a drug that is noxious and unintended and that occurs at doses used in man for the prophylaxis, diagnosis or therapy of disease or for modification of physiological function (WHO)"13 Unintended action of drug means that action of drug which is not planned or not intended to happen. If a drug has no therapeutic effect then therapeutic dose can not be determined and such action will be unintended. Therefore absence of efficacy is also a type of adverse reaction of drug. A substance is being given to a patient for treatment and if this substance has no therapeutic effect then absence of such effect becomes part of adverse reaction because absence of therapeutic effect is harmful to patient and such absence is unintended action of drug. Study of efficacy is a part of study of adverse reaction as described in this definition. "Adverse drug reaction or an adverse reaction means a response to a medicine in the humans or animals, which is noxious and unintended, including lack of efficacy, and which occurs at any dosage and can also result from an overdose, misuse or abuse of a medicine."14 Therefore it is the duty of pharmacologists to study and discuss efficacy of substances used in alternative and complementary systems of medicine first. Pharmacologists are talking of side effects and toxic effects of substances of CAM without discussing efficacy. "Review articles of pharmacovigilance of ayurvedic and unani medicines are being publishing in journals without raising questions on efficacy of these systems.15.16 It is giving wrong massage to medical scientists, society and government that substances of CAM are therapeutically effective. Analysis of Homeopathic Principles Drug is a substance used in the prevention, diagnosis, treatment or cure of disease in man or animal. Criteria of a drug in all type of therapeutic systems should be the same. Estimation of therapeutic utility of drugs in modern medical science or in alternative and complementary systems of medicine is based on common principles of medical science. Modern medical science is based on logical, controlled clinical trials, accurate experimentation with full knowledge of pathogenesis of disease and pharmacokinetic and pharmacodynamic study of drugs. Samuel Hahnemann (1755-1843), a German physician, formulated Homeopathy's basic principles in the late eighteenth century. In those days modern scientific medicine was in infancy, that's why Hahnemann had limitations due to lack of medical knowledge at that time. Today we have vast and developed medical knowledge. Hahnemann's principles of Homeopathy can be analysed on its basis. "Hahnemann had two erroneous principles. Firstly, that like cures like; and secondly that the actions of drugs are potentiated by dilution. "Hahnemann's first principle was a sweeping generalization based on the fact that a large dose of cinchona bark induced in him a malarial paroxysm; the reason for this occurrence being that he had previously suffered from malaria and the gastric irritation excited the paroxysm."17 The main constituent of cinchona bark is quinine. "Oral administration of quinine often results in nausea, vomiting and epigastric pain."18 Relapse of malaria may occur by acute gastrointestinal problem or any intercurrent malady. Hahnemann had taken cinchona after symptomatic cure of malaria. Gastrointestinal problem created by cinchona could be responsible for recurrence of malarial paroxysm. If first principle of Homeopathy is true then quinine should produce rigors in healthy body but "the effect of quinine on normal body temperature is negligible."19 It shows first principle of Hahnemann was wrong. "His second principle was based on the fact that trituration of mercury increased its pharmacological actions. This effect was due to oxidation of the mercury first to mercurous and, later, to mercuric oxide."20 Hahnemann wrongly thought that potentiated effect was due to dilute mercury. He did not understand that after trituration & dilution mercury modified in to other compounds. Actually "elemental mercury can not react with biologically J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 40 Jain D: Pharmacovigilance of Homeopathy - Questioning its Efficacy important molecules."21 "Cases are recorded where individuals have swallowed a pound or two of the liquid metal (perfectly pure) without any harmful effect."22 Now it is clear that it was not dilution and trituration which increased potency of mercury. It was actually conversion of mercury in to mercuric oxide which was responsible for increased potency. "For therapeutic effect, plasma concentration of lithium in mania should range from .9 to 1.4 mEq/L. Concentration higher than 1.5 mEq/L is associated with an increased incidence of side effects, while those about 2 mEq/AL may result in serious toxicity."23 Increased concentration of lithium causes more potent effect on body which also proves that second principle of Homeopathy, dilution increases potency was wrong. "After review of all Homeopathic principles on the basis of present medical knowledge, it has been found that they are illogical, irrational and not in accordance with the knowledge of available criterias of scientific therapeutic system."24 This fact can be understood very easily when we analyse principles of Homeopathy. Opinion of Standard Medical Text Books & Journals "Hahnemann's system of Homeopathy rapidly drifted in to absurdities. From 1829 onward he recommended the administration of all drugs at the thirtieth potency which corresponds to a concentration of 1 pat in 1060 parts".25 "The claims of Homeopathy are, however difficult to understand in the light of present concept of diseases, nor can they be substantiated by various scientific methods applied to the study of modern medicine."26 "Pharmacologists generally feel that in the absence of conclusive evidence from empirical studies that Homeopathic medicines can reproducibly be shown to differ from placebo in clinical studies conducted according to modern scientific standards, there is no point in discussing the hypotheses of Homeopathy."27 "Homeopathy so far as it follows the principles of its founder, has no place for medical sciences such as chemistry, anatomy, physiology, pathology. Attempts have been made by many scientists to interpret such result in terms of modern science of physiology but they have not been convincing. The patients of Homeopath died of the 28 disease" 29 "Medical Journal Lancet declares that Homeopathic drug are not better than a placebo. Swiss scientists compared the result of more than 100 trials of Homeopathic medicines with the same number of trials of conventional medicines in a range of conditions. They found that Homeopathy had no more than placebo effect. An editorial written in the Lancet titled "The end of Homeopathy" demands that doctors recognize the absence of real curative powers in Homeopathic medicine. The editorial also says. "It is more surprising that the debate continue after 150 years of unfavorable finding." "World Health Organization (WHO) said that do not depend on Homeopathy for the treatment of HIV, TB and malaria. Research scholars of young science network from U.K. and Africa wrote to WHO to prevent Homeopathic treatment in TB, diarrhea, influenza, malaria, HIV. They also said, there is no evidence that Homeopathy is effective in these ailments and when Homeopathy is used in place of modern medical science, for these diseases, death is certain. They also said that world should understand danger of Homeopathic treatment."30 Conclusion Rules of Homeopathy and the concepts of modern medical science are contradictory to each other. Either modern medical science is correct or Homeopathy is accurate. Both Homeopathy and modern medical science can not be correct. Either modern medical science should be banned or Homeopathy should be discarded. If we are saying that both are correct, this indicates our inefficiency and in capabilities to reach a definite conclusion. If we are accepting contradictions in the field of knowledge then it is the crime against humanity and science. Actually Hahnemann concluded wrong conclusions on the basis of wrong analysis due to lack of knowledge. There were no knowledge of human physiology, pathology, pathogenesis of diseases, investigations, biochemistry, pharmaceutical chemistry, genetics, physics, clinical trials, diagnosis of diseases at the time of Hahnemann, that's why he had limitations. He formulated unscientific and illogical hypothesis which can be proved wrong today. Homeopathic drugs do not have any effect on human body, neither therapeutic effect nor any side effect because it is used in such dilutions which contain no any drug molecule. The main drawback of Homeopathy is that it interferes application of modern medical science which makes curable disease incurable and fatal. J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 41 Jain D: Pharmacovigilance of Homeopathy - Questioning its Efficacy These are the facts which I am putting in front of the scientific fraternity to take further action regarding applicability of Homeopathy. Govt. is ready to ban all drugs which have no therapeutic utility. Then it is our duty to take appropriate steps to peruse Government of India to prohibit use of Homeopathic drugs which have no therapeutic utility. "According to drug and cosmetics act 1940, section26A, if the Central Government is satisfied that any drug does not have the therapeutic value claimed or purported to be claimed for it, then, that Government may, by notification in the official Gazatte, prohibit the manufacture, sale or distribution of such drug or cosmetic."31 References 1. Gordon BL.Medicine throughout antiquity. Philadelphia : F.A. Davis Company; 1949: 110-111. 2. Jain D.K. :Homeopathy an Illusion Delhi : Peacock Books; 2009, p. IX,X 3. Coleman J. Abnormal Psychology and modern life. Bombay : Taraporewala and Sons; 1976, 27. 4. Rang HP, Dale MM, Ritter JM, Moore PK. Pharmacology. Sthed. New York : Churchil Livingstone; 2003, 3. 5. Jain D.K. Homeopathy an Illusion Delhi : Peacock Books; 2009, p. IX,X. 6. Rang HP, Dale MM, Ritter JM, Moore PK. Pharmacology. Sthed. New York : Churchil Livingstone; 2003, 3. 7. Hahnemann S. Organon of medicine (English). 6th ed. New Delhi : B Jain Publishers (P) Ltd., 1993. 8. Hahnemann S. Organon of medicine (Hindi). New Delhi : B. Jain Publishers (P) Ltd.; 1996. 9. Kent JT. Lectures on Homeopathic Philosophy. New Delhi : B Jain Publishers (P) Ltd.; 1993. 11. Adithan C. National Pharmacovigilance programme. Indian J. Pharmacol 2005; 37: 347. 12. Strauss SE. Complementary and alternative Medicine. In : Kasper LD, Braun Wald E, Fauci SA, Hauser SL, Longo DL, Jameson JL, editors. Harrison's principles of internal medicine. 16th ed. New York : McGraw Hill; 2005; Vol. 1, 66-69. 13. Satoskar RS, Bhandarkar SD, Ainapure SS. Pharmacology & Pharmacotherapeutic. 18th ed. Mumbai : Popular Prakashan; 2003, 36. 14. Yadav S. Status of adverse drug reaction monitoring and pharmacovigilance in selected countries. Indian J. Pharmacol. 2008; 40: Supplement: 54. 15. Thatte V, Bhalerao S. Pharmacovigilance of ayurvedic medicines in India. Indian J. Pharmacol. 2008; 40: Supplement. : 510. 16. Rahman SZ, Khan RA, Latif A. Importance of Pharmacovigilance in Unani system of medicine. Indian J. Pharmacol 2008; 40: Supplement : 517. 17. Satoskar RS, Bhandarkar SD, Ainapure SS. Pharmacology & Pharmacotherapeutic. 18th ed. Mumbai : Popular Prakashan; 2003, p. 655. 18. Krantz CJ, Carr CJ. The pharmacological principles of medical practice. 6th ed. Baltimore : Williams and Wilkins; 1965: 158. 19. Modell W, Schield H, Wilson A. Applied pharmacology. American editon. Toronto : W.B. Saunders Company; 1976, 9. 20. Klaassen CD. Heavy metals and heavy metal antagonists. In Gilman AG, Goodman L, Gilman A, editors. Goodman & Gilman's pharmacological basis of therapeutics. 6th ed. Newyork : Macmillan; 1980; 1623. 21. Modi NJ. Textbook of medical jursiprudence and toxicology. 9th ed. Bombay : N.M. Tripathi Publishers; 1975 : 551. 22. Colasanti BK. Antidepressant therapy. In Craig C, Stitzel R, editors. Modern pharmacology. 2nd ed. USA : Little Brown; 1986, 544. 23. Jain DK. Homeopathy an illusion, Delhi : Peacock Books; 2009. 24. Laurence DR, Bennett PN, Brown MJ. Clinical pharmacology. 8th ed. New York : Churchill Livingstone; 1997: 13-14. 25. Paranjpe AS. A history of pharmacology. Poona : Maharastra Medical Journal; 1962; 679-681. 26. Boseley S. Some questions about Homeopathy. The Hindu. Delhi, 27.8.05, p. 20. 27. Raj Express Gwalior 25.8.2009. 28. The Drugs and Cosmetic Act 1940, Govt. of India. J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 42 J Pharmcovig Drug Safety 2010 (January-March) Volume : 7 Issue : 1 (Page 43-52) Risks and Recall of Medicines Pharmacovigilance Perspective REVIEW ARTICLE ADITI NIGAM, ETHIRAJ DHANARAJ, PRAMIL TIWARI Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research, SAS Nagar-16006 ABSTRACT Adverse drug reactions (ADRs) are a significant cause of morbidity and mortality. Rare ADRs can easily go undetected in clinical trials and thereby pose a major threat to the patient population. Pharmacovigilance assumes a potentially important role in identifying ADRs, leading to generation of drug alerts. When the risks outweigh the benefits, the medicine in question is recalled from the market. Delay in withdrawal may occur due to inability to establish cause and effect relationship between the drug and the ADR. This may be attributed to confounding by indication (Rosigltazone) and also drug versus class effect (COX-II inhibitors). The removal of a medicine from the market upon establishment of safety risks looks plausible enough, but requires careful thought over the huge magnitude of patients already exposed to its harms. The safety based medicine recalls do not follow a uniform pattern all over the world. This can be partly attributed to the heterogeneity of treatment effects in which a few segments of the population are more susceptible to adverse effects due to genetic predisposition or metabolic factors. The safety profile noted in Introduction drug behavior in more diverse populations. As soon as it is established that risks outweigh the benefit, the concerned medicines are removed from the market. That sounds plausible enough but is a serious issue considering the effects on the huge number of patients on the particular medicine therapy prior to withdrawal. For example Dexfenfluramine was withdrawn owing to cardiopulmonary toxicity; the patients exposed in clinical trial were 1200. However, the estimated patients exposed prior to withdrawal were 23,000,000 [1]. Drug recalls may occur as a consequence of risks reported with their use. The following examples illustrate this: 1) Cerivastatin was first approved by US-FDA as a lipid-lowering drug in June 1997 and withdrawn in August 2001. By the year 2000, a total of 549 cases of rhabdomyolysis associated with cerivastatin use had been reported to WHO-Uppsala Monitoring Centre. Consequently, a safety alert was issued regarding an association between cerivastatin, myopathy and rhabdomyolysis. In August 2001, the manufacturer voluntarily withdrew cerivastatin from the market on the grounds of an increased risk of rhabdomyolysis [2]. 2) Nomifensine (an antidepressant) had been available in Germany since 1976 and had been prescribed to an estimated ten million patients prior to its marketing in the U.S. in July, 1985. Initial labeling for the product reflected a variety of long-recognized hypersensitivity reactions, including fever, liver injury, hemolytic anemia and eosinophilia, that were apparently all readily reversible. At the time of marketing approval, US-FDA was aware of Adverse drug reactions (ADRs) are a significant cause of morbidity and mortality. Before a medicine is marketed, the experience on its safety and efficacy is limited to its use in clinical trials. The conditions under which patients were studied during the clinical trials do not necessarily reflect the way the medicines are used in the hospital or in general practice. The information about rare but serious ADRs, chronic toxicity, use in special groups (e.g. pregnant and lactating women, children, elderly etc.,) and drug interactions are often incomplete or not available initially. No drug which is pharmacologically active is entirely without hazard. The hazard may be insignificant or may be acceptable in relation to the drugs therapeutic action. Furthermore, not all hazards can be known before a drug is marketed. Pharmacovigilance is, therefore, an important post-marketing tool in ensuring the safety of medicines. This review focuses on risks and safety based medicine recalls. Risks Involved in Using Medicines The profiling of a new drug is incomplete at the time of approval, especially with respect to its safety data. Safety signals for drugs may arise at different stages of drug development including clinical trials. Nevertheless, these trials being relatively short, with small sample sizes designed to prove efficacy rather than detect safety, and studied in selected populations, often do not reflect the 43 Nigam et al: Risks and Recall of Medicines - Pharmacovigilance Perspective US-FDA was aware of reports of less than twenty hemolytic anemia cases, all non-fatal; however, in 1985, when other country adverse reaction reports showed the hemolytic anemia might be fatal, labeling was revised to reflect the potential seriousness of the reaction. Due to an increase in serious hemolytic anemia cases seen in Europe, marketing of nomifensine was reconsidered by the manufacturer, who announced a worldwide withdrawal of the drug in January 1986 [3]. Some medicines continue to remain in the market despite reported adverse effects. This is understandable because: 1) they may be the only available options for a few sets of the patients for example, felbamate (anti-epileptic). 2) Drug remains on the market until better options become available in terms of safety and efficacy. For example, terfenadine (approved in 1985) was found to cause cardiac arrhythmias but it continued to be on the market till the arrival of the newer analogue fexofenadine in 1997. 3) Drugs do not pose much of a safety risk on their own but the same is magnified upon combination with other drugs which may turn out to be dangerous as in the case of mibefradil. 4) Improper use of a drug may also lead to its withdrawal as in the case of the bromfenac. 5) Withdrawal may also become the last option to choose if all other risk management techniques fail as was observed in the case of the heartburn treatment cisapride. Its label was changed several times in 1998, but the US-FDA found that the percentage of patients inappropriately exposed to the drug was unchanged. Delay in Withdrawal Pergolide was approved in 1988 in US as an adjunctive therapy with levodopa in Parkinson's disease, and finally was withdrawn from the market in 2007 because of valvular heart disease. It appears that there was a delay in the recognition of the role of pergolide in producing valvular heart disease. The first step in reporting a safety issue is the diagnosis of medical event. This was not accomplished easily in this case as cardiac monitoring generally was not indicated with pergolide. Even when a cardiac abnormality became clinically apparent, the diagnosis of the specific abnormality was still difficult. Finally, after the abnormality is diagnosed and to be reported to the regulatory as a drug related adverse event, the physicians must have a suspicion that the event was secondary to exposure to a drug. In this case, the diagnosis of the valvular heart disease and attribution to pergolide were problematic. Pergolide (an antiparkinson drug) was withdrawn in US and Canada but is still used in UK, Europe and Singapore with safety alerts in place. Confounding by Indication Rosiglitazone, an antidiabetic agent, was approved in May 1999 in US but was found to cause or exacerbate congestive heart failure in some patients. As diabetes mellitus is a well known risk factor for cardiovascular disease, and the patient received the drug for glycemic control; so it is difficult to determine whether the ADR was caused by rosiglitazone, or was an expected manifestation of the patient's underlying disease. The question to be answered in evaluating the reports is whether there is something being experienced by the patients using the drug that is out of line with what is expected, not only with the drug, but with the underlying disease. To attribute an ADR to a drug, establishing the causal relationship between the drug and the symptoms experienced needs to be established. US-FDA urging led to revised labels of the influenza drugs, Tamiflu (Oseltamivir, Roche) and Zanamivir (Relenza, GSK). Both Roche and GSK revised the warnings and precautions section of Tamiflu and Relenza labels to inform doctors of certain “neuropsychiatric events” associated with the use of the drugs “in patients with influenza”, that “in some cases resulted in label outcomes” [4,5]. The safety alert issued by US-FDA, as well as the revised labels, acknowledged that the contribution of the drugs to the neuropsychiatric events “has not been established”. The impetus for the requested labeling changes was studies of patients in Japan who took Ta m i f l u a n d r e p o r t e d e x p e r i e n c i n g c e r t a i n neuropsychiatric events, such as delirium, delusions and hallucinations. US-FDA regulators conceded, however, delirium and other such neuropsychiatric events can be complications of influenza itself. Drug Effect versus Class Effect Rofecoxib was approved in May 1999 in US as an antiinflammatory drug but withdrawn due to increased risk of myocardial infarction or stroke. Another drug of the same class Valdecoxib approved in November 2001 was withdrawn due to risk of toxic epidermal necrolysis. Interestingly, other drugs of the same class Etoricoxib and Celecoxib continue to remain in the market. Statins is another class of drugs which shows varied responses. Cerivastatin approved in June 1997 as a lipid lowering drug was withdrawn in August 2001 due to increased risk of rhabdomyolysis. However, Simvastatin approved in December 1991 and Atorvastatin approved in December 1996 continue to be widely used. It is difficult to determine whether the events are directly related to the use of the drugs, J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 44 Nigam et al: Risks and Recall of Medicines - Pharmacovigilance Perspective an underlying medical condition, or other risk factors, a combination of these factors or other unexplored factors. Safety Based Medicine Recall Pattern between Countries Drugs withdrawn from market in various countries on account of safety are shown in Table 1. Comparing the drug withdrawal and availability pattern between countries shows drugs withdrawn in one country to be in use at other places. For example, 1) Aprotinin (an antihaemorrhagic) is withdrawn in UK and Europe, subject to restricted use in USA, Canada, Australia and Singapore, and freely available in India; 2) Tegaserod (indicated for irritable bowel syndrome) is withdrawn in US but is available in India; 3) Nefazodone (an antidepressant) is withdrawn in Canada and Singapore, but is in use in Europe and USA along with safety alert. The difference in medicine withdrawal pattern among various countries can be partly attributed to the heterogeneity of treatment effects and differences in indication approval policies by the regulatory agencies. For example Pappas et. al. studied 13 antimicrobial compounds approved by both the US-FDA and EMEA and found significant differences in the indications for most antimicrobial agents [14]. For example, Linezolid has a US indication for vancomycin resistant Enterococcus faecium infections, but no similar indication in Europe and Micafungin is indicated for pediatric use in Europe but not in the US. This may be due to the altered performance of a medicine in relation to the racial, genetic or other environmental factors in a population. For example, patients who have no thiopurineS-methyltransferase (TPMT) activity, a normal dose of mercaptopurine results in an accumulation of the active compound, placing the patient at increased risk for the myelosuppressive effects [15]. More recently, the relationship of warfarin dose requirements with the CYP450, 2C9 and VKORC1 gene polymorphisms have led to a consideration in a labeling change by the US-FDA [16]. There are differences among countries in the occurrence of ADRs and other drug-related problems. This may be due to differences in diseases and prescribing practices, genetics, diet, traditions of the people, drugs manufacturing processes used which influence pharmaceutical quality and composition, drug distribution and use including indications, dose and availability. Drug Safety Reviews and Signal Generation Pharmacovigilance networks have been developed by the drug regulatory agencies to monitor any adverse drug reactions. Labelling changes are made quicker in order to respond to new or emerging safety information of an approved drug. Examining the appearance of labelling changes, black box warning and withdrawals is a reasonable way to seek-out the most important new ADRs. Signals can arise from post-marketing data and other sources, such as preclinical data and events associated with other products in the same pharmacologic class. At the time of approval, clinical data are available on limited number of patients treated for relatively short periods. Once a product is marketed, large number of patients may be exposed, including patients with co-morbid illnesses, patients using concomitant medications, and patients with chronic exposure. Such signals assist the development of alerts by pooling the data. The country-wise current drug safety reviews are shown in Table 2. Some selected examples are discussed. Tumor Necrosis Factor-Alfa Antagonists: Serious Skin Reactions Tumor Necrosis Factor-alfa (TNF-á) antagonists infliximab (approved in 1998), etanercept (approved in 2000) and adalimumab (approved in 2002) are indicated for rheumatoid arthritis. The reported ADRs are erythema multiforme, Stevens Johnson syndrome and toxic epidermal necrosis. Among the three drugs, Infliximab accounted for a greater number of serious dermatological reactions [19]. A total of 3821 ADRs to Infliximab were reported to MHRA during the period July 1963 to August 2009, out of which, 491 were fatal ADRs [20]. Epoetin Alfa: Increased Risk of Death in Cancer Patients Erythropoiesis-stimulating agent (ESA) Epoetin alfa was approved (1999) by US-FDA to treat anemia caused by chemotherapy in cancer patients. The potential risks identified were thromboembolic disease, promotion of tumor growth and decreased survival in these patients. The new labelling by US-FDA now stipulates that epoetin alfa should not be used in patients receiving potentially curative treatments and removed the indication for ESA in breast cancer or head and neck cancer patient. ESA is approved for use only after a patient's hemoglobin levels fall below 10 g/dL. ESA labeling in the US contrasts starkly with that in Europe where the European regulatory agency recommends blood transfusions instead of ESA use [21,22]. J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 45 Nigam et al: Risks and Recall of Medicines - Pharmacovigilance Perspective Conclusion There is nothing as an absolutely 'safe' drug. Although the benefits of a drug to a significant proportion of the intended patients may be clear, a major crisis can arise when a few dozen people out of perhaps hundreds of thousands receiving the drug suffer or die as a result of taking it. Thus, even when a drug is known to provide significant benefits to a substantial portion of the treated population, a relatively infrequent occurrence of harm may give rise to demands for drug to be restricted in use or withdrawn completely. The drug control authorities make judgments on behalf of populations rather than individuals, usually on the basis of uncertain and incomplete information. Such action may leave individuals or groups of individuals significantly disadvantaged. Despite stringent regulatory norms, harmful drugs pave their way into the market, compromising public health. Hence, measures to check this must be rigorously adhered. Additionally, regular and systematic reporting of adverse effects by healthcare professionals should be encouraged. The safety warnings issued should be incorporated into prescribing practices. The public needs to be informed regarding the prudent use of medicines and the available information regarding both the benefits and the risks should be disseminated to communicate the safety concerns that arise from time to time. Medicine information should be pooled between various nations to gain a better perspective of the medicine's profile. All the available evidence should be impartially evaluated and appropriate medicine safety measures should be formulated. Assessment of risks and benefits should be done without any bias as the generated evidence forms the basis of the next decisive action. Thus, continuous medicine safety monitoring through pharmacovigilance is essential to safeguard against the adverse effects of medicines. Table 1: Drugs Withdrawn from Market in Various Countries (2000 onwards) Country / Drug Year Withdrawn Indication Reason for Withdrawal USA [6,7] Efalizumab Chronic plaque psoriasis 2009 Progressive multifocal leukoencephalopathy Tegaserod Irritable Bowel Syndrome 2007 Cardiovascular Risk Pergolide Anti-Parkinson 2007 Valvular Disease Valdecoxib Analgesic 2005 Cardiovascular Risk and Adverse skin effects Rofecoxib Analgesic 2004 Myocardial Infarction or stroke Levomethadyl Opiate dependence 2003 Fatal Arrhythmia Europe [8] Sibutramine Anti-obesity 2010 Increased risk of cardiovascular events Efalizumab Chronic plaque psoriasis 2009 Progressive multifocal leukoencephalopathy Rimonabant Anti-obesity 2009 Psychiatric Disorders Lumiracoxib Analgesic 2007 Hepatotoxicity Aprotinin Reducing peri-operative blood loss 2007 Increased Mortality Carisoprodol Acute lower back pain 2007 Psychomotor Impairment Clobutinol Cough Suppressant 2007 QT Prolongation J Pharmcovig & Drug Safety (January-March)2010 Volume : 7 Issue : 1 46 Nigam et al: Risks and Recall of Medicines - Pharmacovigilance Perspective Country / Drug Year Withdrawn 2007 2005 Indication Reason for Withdrawal Veralipride Valdecoxib Hot flushes a/w menopuase Analgesic Parecoxib Rofecoxib Analgesic Analgesic Efalizumab United Kingdom [9] Chronic plaque psoriasis 2009 Rimonabant Lumiracoxib Aprotinin Valdecoxib Anti-obesity Analgesic Reducing peri-operative blood loss Analgesic 2008 2007 2007 2005 Rofecoxib Analgesic 2004 Progressive multifocal leukoencephalopathy Psychiatric Disorders Hepatotoxicity Increased Mortality Serious skin rash and thromboembolic events Increased thromboembolic events 2007 2004 Hepatotoxicity Increased thromboembolic events Progressive multifocal leukoencephalopathy Valvular Disease Hepatotoxicity Serious skin rash and thromboembolic events Increased thromboembolic events Increased risk of suicidal behaviour 2005 2004 Depression & Tardive dyskinesia Serious skin rash and thromboembolic events Increased ThromboembolicEvents Increased Thromboembolic Events Australia [10] Lumiracoxib Rofecoxib Analgesic Analgesic Canada [11] Efalizumab Chronic plaque psoriasis 2009 Pergolide Lumiracoxib Valdecoxib Anti-Parkinson Analgesic Analgesic 2007 2007 2005 Rofecoxib Nefazodone Analgesic Antidepressant 2004 2003 Singapore [12] Efalizumab Chronic plaque psoriasis 2009 Nimesulide Valdecoxib Analgesic Analgesic 2007 2005 Rofecoxib Analgesic 2004 Nefazodone Cerivastatin Phenylpropanola mine Cisapride Antidepressant Lipid-lowering Decongestant and Appetite suppressant Gastroesophageal Reflux 2004 2001 2000 Progressive multifocal leukoencephalopathy Hepatotoxicity Serious skin rash and thromboembolic events Increased thromboembolic Events Hepatic Failure Rhabdomyolysis Risk of Hemorrhagic Stroke 2000 QT Prolongation Serious skin rash and thromboembolic events Increased thromboembolic events Lactic Acidosis Cardiac Arrhythmias Cardiac Arrhythmias India [13] Valdecoxib Analgesic 2005 Rofecoxib Phenformin Terfenadine Astemizole Analgesic Antihyperglycemic Antihistaminic Antihistaminic 2004 2003 2003 2003 J Pharmcovig Drug Safety 2010 (January-March) Volume : 7 (1) 47 Nigam et al: Risks and Recall of Medicines - Pharmacovigilance Perspective Table 2: Country-Wise Current Drug Safety Reviews Date Drug Aug 13, 2008 Natalizumab Indication Europe [8] Relapsing-remitting multiple sclerosis Acute bacterial sinusitis, acute exacerbation of chronic bronchitis and communityacquired pneumonia Acute or chronic complicated pyelonephritis Jul 24, 2008 Moxifloxacin Jul 24, 2008 Norfloxacin Jul 1, 2008 Erythropoietin Chronic renal failure and Anaemia with non-myeloid tumours Jun 26, 2008 Etoricoxib Rheumatoid arthritis and ankylosing spondylitis Jun 26, 2008 Ergot derived Dopamine agonists (Cabergoline, Pergolide, Bromocriptine, Lisuride) Jun 17,2008 Inhaled Insulin T1 or T 2 Diabetes mellitus (Exubera) Combination therapy for HIV Apr 4, 2008 Abacavir infection Mar 20, 2008 Bortezomib Multiple Myeloma Parkinson’s disease Feb 14, 2008 Telbivudine Chronic Hepatitis B Jan 24, 2008 T2 Diabetes mellitus Rosiglitazone Jun 2, 2009 Mycophenolate mofetil May 26, 2009 Erlotinib Feb 9, 2009 Bevacizumab Feb 2, 2009 Toremifene United Kingdom [9] Prophylaxis of acute transplant rejection Non small cell lung cancer Off-label intravitreal use (CAN WE REMOVE?) Hormone dependent metastatic breast cancer in postmenopausal women J Pharmcovig Drug Safety 2010 (January-March) Volume : 7 (1) 48 Safety Issue Progressive multifocal leukoencephalopathy Fatal Liver Injury Greater risks than benefits in urinary infections and pyelonephritis Increased risk of tumour progression, venous thromboembolism and shorter overall survival in cancer patients Cardiovascular side effects Risk of Fibrosis, particularly Cardiac fibrosis Lung Cancer Heart Attack Cardiac and Pulmonary Side effects Risk of peripheral Neuropathy Increased cardiovascular risk in patients with ischemic heart disease and/or peripheral arterial disease Pure red cell aplasia GI perforation Severe eye inflammation and sterile endophthalmitis Dose related prolongation of the QTc interval Nigam et al: Risks and Recall of Medicines - Pharmacovigilance Perspective Date Jan 6, 2009 Drug Temsirolimus Indication Advanced renal-cell carcinoma Nov 7, 2008 Rituximab Non-Hodgkin’s lymphoma and Rheumatoid Arthritis Oct 2, 2008 Etoricoxib Sep 9, 2008 Cabergoline Rheumatoid arthritis and ankylosing spondylitis Parkinson’s disease Sep 5, 2008 Methylnaltrexone Opioid induced constipation Aug 15, 2008 Natalizumab Multiple Sclerosis Aug 5, 2008 Lenalidomide Jul 21, 2008 Pergolide Transfusion dependent anemia due to myelodysplastic syndromes (MDS) Parkinson’s disease Jul 16, 2008 Adalimumab Jul 10, 2008 Deferasirox Jun 18, 2008 Inhaled Insulin (Exubera) Apr 30, 2008 Tenofovir Feb 20, 2008 Modafinil Feb 18, 2008 Mycophenolate mofetil Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease and psoriasis Transfusional he mosiderosis T1 or T2 Diabetes mellitus Glioblastoma multiforme Obstructive sleep apnea/hypopnea syndrome (OSAHS), and shift work sleep disorder (SWSD) Prophylaxis of acute transplant rejection Feb 15, 2008 Telbivudine Chronic Hepatitis B Feb 11, 2008 Alemtuzumab Remission consolidation in B-Cell Chronic Lymphocytic Leukemia Acute bacterial sinusitis, acute exacerbation of chronic bronchitis and communityacquired pneumonia Dermatophytosis, chronic mucocutaneous, cutaneous, and oropharyngeal candidosis Feb 11, 2008 Moxifloxacin Feb 1, 2008 Ketoconazole J Pharmcovig Drug Safety 2010 (January-March) Volume : 7 (1) 49 Safety Issue Severe hypersensitivity reactions during infusion Progressive multifocal leukoencephalopathy Not to be used if BP over 140/90 Fibrotic Cardiac Valvulopathy Use when response to usual laxative treatment not sufficient Progressive multifocal leukoencephalopathy Teratogenicity Fibrotic Cardiac Valvulopathy Hepatosplenic T-cell lymphoma Liver failure,GI haemorrhage and ulceration, and renal tubulopathy Primary lung malignancy Impaired renal function Serious skin rash and psychiatric symptoms Progressive multifocal leukoencephalopathy Risk of Peripheral Neuropathy Fatal infectious complications Serious hepatic reactions and bullous skin reactions Risk of hepatotoxicity Nigam et al: Risks and Recall of Medicines - Pharmacovigilance Perspective Date Drug Indication Safety Issue USA [17,18] Oct 16, 2009 Iron Dextran injection Sep 25, 2009 Sitagliptin Sep 25, 2009 Deferasirox Iron deficient state not amenable to oral iron therapy Anaphylactic-type reactions including fatalities T2 Diabetes mellitus Acute pancreatitis Transfusional he mosiderosis Increased adverse events including acute renal failure, GI haemorrhages and death Sep 16, 2009 Natalizumab Relapsing-remitting multiple sclerosis Progressive multifocal leukoencephalopathy Sep 3, 2009 Prophylaxis of organ rejection Pure red cell aplasia Mycophenolate mofetil Aug 31, 2009 Tumour Necrosis Factor Juvenile idiopathic arthritis, (TNF) Blockers rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, Crohn’s disease, and ankylosing spondylitis Increased risk of lymphoma, leukaemia and new-onset psoriasis Aug 28, 2009 Leukotriene inhibitors (Montelukast, Zafirlukast and Zileuton) Prophylaxis and chronic treatment of asthma Neuropsychiatric events Aug 27, 2009 Etravirine HIV-1 strains resistant to nonSevere skin reactions like nucleoside reverse transcriptase Stevens-Johnson syndrome, inhibitor) and other antiretrovirals toxic epidermal necrolysis and erythema multiforme Aug 24, 2009 Orlistat Obesity management Serious liver injury including liver failure Jul 1, 2009 Insulin Glargine Diabetes Mellitus Possible risk for cancer in patients with diabetes Jun 4, 2009 Proplythiouracil Hyperthyroidism due to Graves’ disease Serious liver injury, including liver failure and death Erlotinib Non small GI perforation May 8, 2009 cell lung cancer Mar 24, 2009 Mycophenolate mofetil Prophylaxis of organ rejection Increased susceptibility to infection and possible development of lymphoma and other neoplasms Feb 26, 2009 Metoclopramide GI disorders Tardive dyskinesia on long term or high dose J Pharmcovig Drug Safety 2010 (January-March) Volume : 7 (1) 50 Nigam et al: Risks and Recall of Medicines - Pharmacovigilance Perspective Date Drug Indication Safety Issue Feb 23, 2009 Zonisamide Partial seizures Metabolic Acidosis Feb 4, 2009 Reduction of mortality Serious bleeding events and mortality in patients with sepsis Drotrecogin in severe sepsis Jan 16, 2009 Local anaesthetics Relieving pain from mammography and other medical tests Cardiac arrhythmias and Fatal strokes Jan 15, 2009 Atomoxetine Attention-Deficit Hyperactivity Disorder Hepatotoxicity Jan 2, 2009 Varenicli ne and Buproprion Smoking Cessation Aids Suicidal Ideation and Behaviour Nov 24, 2008 Phenytoin and Fosphenytoin Sodium Tonic-clonic (grand mal) and complex-partial seizures Serious skin reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis) Nov 12, 2008 Bisphosphonates Osteoporosis, Paget’s disease and bone metastases Serious atrial fibrillation events Oct 7, 2008 Bronchospasm associated with chronic obstructive pulmonary disease Increased risk of stroke Sep 26, 2008 Epoetin Alpha Anemia in chronic renal failure patients,zidovudine-treated HIVinfected patients and cancer patients Increased mortality in patients after acute ischemic stroke Sep 23, 2008 Duloxetine Major depressive disorder and Diabetic peripheral neuropathic pain Urinary retention Tiotropium Bromide Sep 4, 2008 Tumour Necrosis Factor Juvenile idiopathic arthritis (JIA), (TNF) Blockers rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, Crohn’s disease, and ankylosing spondylitis Jul 7, 2008 SSRI and SNRI antidepressants Major depressive Disorder Birth defects (Persistent pulmonary hypertension of the newborn) Jun 23, 2008 Minocycline Adult periodontitis Thyroid disorders J Pharmcovig Drug Safety 2010 (January-March) Volume : 7 (1) 51 Risk of Histoplasmosis and other invasive fungal infections Nigam et al: Risks and Recall of Medicines - 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[cited 2010 Mar 15]; Available from: 22. US FDA Early Communication about an Ongoing URL:http://www.tga.gov.au/recalls/index.htm Safety Review: Epoetin alfa. [Online]. 2008 [cited 11. Health Canada: Advisories, Warnings and Recalls for 2009 Mar 15]; Available from:URL: http://www. Health Professionals. [Online]. [cited 2010 Mar 15]; Fda.gov/cder/drug/e arly_comm/epoetin_alfa.html Available from: URL:http://www.hc-sc.gc.ca/dhpmps/medeff/ advisories-avis/prof/index-eng.php 12. Singapore Government Health Sciences Authority: Product Safety Alerts (for healthcare professionals). J Pharmcovig Drug Safety 2010 (January-March) Volume : 7 (1) 52 JOURNAL OF PHARMACOVIGILANCE & DRUG SAFETY Annual Subscription Form JOURNAL OFFICE : For Office Use Dr. Anurag Tomar, Editor in Chief, Journal of Pharmacovigilance & Drug Safety NIMS City Center, 4, Govind Marg, Jaipur-302004, India Email : [email protected] [email protected] Ref: No. Cash/Cheque/ DD for Rs. 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Organization as author: The Cardiac Society of Australia and New Zealand. Clinical exercise stress testing. Safety and performance guidelines. Med J Aust 1996;164:284-4. Books and other Monographs:Personal author(s): Ringsven MK, Bond D. Gerontology and leadership skills for nurses. 2nd ed. Albany (NY): Delmar Publishers; 1996 Chapter in a book: Philips SJ, Whisnant JP. Hypertension and stroke. In: Laragh JH, renner BM, editors. Hypertension: Pathophysiology, diagnosis and management. 2nd ed. New York: Raven Press; 1995.p. Tables and Figure: These should be given in the end after references section consecutively, and provided with caption. Footnotes should be identified by lower case lettrs and cited in the tables as italicized superscripts. All tables should be cited in the text. Figure should be kept to the inimum, colored figure, halftone figure will be charged @ Rs 200 per figure. 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Tel: 011-23741723, 011-23408151 Mob: 09811694040, 09999903031 E-mail: [email protected], [email protected] Website: www.isrpt.co.in 43rd Annual Conference of Indian Pharmacological Society Date : From 13th to 16th December, 2010 Venue : Hyderabad Theme : Pharmacology & Translational Research Conference Secretariat: Dr. B. Dinesh Kumar, Organizing Secretary - IPS - 2010 Food and Drug Toxicology Research Center (FDTRC) National Institute of Nutrition ( ICMR), Tarnaka, Hyderabad- 500 007 Tel: +91(40) 2719 7322 Email : [email protected], [email protected] 5th Federation of Asian and Oceanian Neuroscience Societies (FAONS) Congress - 2010 XXVIII Annual Meeting of Indian Academy of Neurosciences Date : From 25th to 28th November, 2010 Venue : Lucknow Theme : Emerging Trends in Basic and Clinical Neuroscience Conference Secretariat: Dr. Vinay K. Khanna, Organizing Secretary - IAN 2010 Dr. Prahlad K. 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