the clinical researcher - Clinical Research Board

Transcription

April 2010; Volume 2; Number 1
ISSN 0975-4075
THE
CLINICAL
RESEARCHER
An official journal of Clinical Research Board
www.crboard.org
The Clinical Researcher
The official publication of the Clinical Research Board
Contents
REVIEW ARTICLES
Clinical Aspects of Targeting Activated Oncogenes: Blocking Src kinases for cancer treatment
Goyal Seema, Goyal Nadish, Pramod John, Dutta Abhilasha
1
Certolizumab: A Novel Anti TNF-α Monoclonal Antibody
Patel S Devang, Mehta R Hiren, Deshpande S Shrikalp, Patel B Bhavin, Patel B Paresh
6
ORIGINAL RESEARCH ARTICLES
Effectiveness of Duloxetine with Amitriptyline in Diabetic Neuropathic Pain
Kumar Narendra, Dixit Rakesh K, Saksena AK, Sachan AK, Nath R, Verma R
12
Oxidative Stress in Type 2 Diabetes Mellitus Patients: Effect of Metformin Alone and in Combination with α-lipoic Acid
Vasant SR, Dixit Rakesh K, Saksena AK, Sachan AK, Nath R, Siddique KU
16
INNOVATIONS IN RESEARCH & MEDICAL EDUCATION
Training Postgraduate Pharmacology Students in a Medical College in Western Nepal
Shankar Ravi P
22
Letrozole – Infertility an Indication
Matreja SP
28
INFORMATION FOR AUTHORS
31
NEWS
39
Scope of journal
Editor
Dr. Dinesh Badyal
Professor & Head,
Department of Pharmacology
Christian Medical College & Hospital,
Ludhiana 141008, India
Tel: +91-161-5010921 Extn: 5910
Mobile: +91-9815333776
Fax: +91-161- 5058776
Email : [email protected]
[email protected]
Joint Editor
HI Abdul Razack
Project Director
Pharmascope Foundation
Plot No. 95, PTR Nagar, Jawaharpuram
West Madurai, Tamilnadu, India
Mobile: +91 9391 8181 09
Email: [email protected]
The Clinical Researcher (TCR) is envisioned to publish high-quality, peerreviewed research that will serve to raise the understanding of clinical research
in the society and to promote clinical research. The journal covers all therapy
areas and includes initial to advanced clinical studies and latest happenings in
the field of clinical research. Articles are assessed based on topic suitability,
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cogency of argument. There are no restrictions on the background or
specialization of the authors, as long as the articles reflect high scientific
standards.
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December.
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Executive council
Dr Wang Li MD, PhD
Professor & Chairman
Academic Committee of TDMCT Centre Perking University,
China
Dr K D Tripathi MD
Ex Director Professor & Head of Pharmacology
Maulana Azad Medical College & associated G B Pant
Hospital, New Delhi
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CEO, Acunova Life Sciences, NJ, USA
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Johnson & Johnson Pharmaceutical Research &
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Professor & Head
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Secretary (Clinical Pharmacology) Indian Pharmacological
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National Agency for Medicines
Helsinki, FINLAND
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Faraz Health Care Pvt. Ltd, New Delhi
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Fortis Clinical Research Ltd, Faridabad
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Fortis Clinical Research Ltd, Faridabad
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Faculty Clinical Research
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Gr Noida,
Director, KPS Clinical Services Pvt. Ltd
Academic council
Dr Stuart MacLeod, MD, PhD, FRCPC
Professor
University of British Columbia, Vancouver, Canada
Dr Y K Gupta MD
Professor & Head
All India Institute of Medical Sciences, New Delhi
Ankush Pandey MSc (Clinical Research)
CDSCO, Directorate General of Health Services
Ministry of Health and Family Welfare, Government of India
Dr Bikash Medhi MD(AIIMS)
Associate Professor
Postgraduate Institute of Medical Education & Research,
Chandigarh
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Asst. Professor Department of Pharmacology
SGRR Institute of Medical Sciences Dehradun
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Editorial Board
Editor
Dr. Dinesh Badyal
Professor & Head,
Christian Medical College & Hospital,
Ludhiana 141008, India
Tel: +91-161-5026999 Extn: 5910
Mobile: +91-9815333776
Fax: +91-161- 5058776
Email : [email protected]
[email protected]
Joint Editor
HI Abdul Razack
Project Director
Pharmascope Foundation
Plot No. 95, PTR Nagar, Jawaharpuram
West Madurai, Tamilnadu, India
Mobile: +91 9391 8181 09
Email: [email protected]
National Advisory Board
Dr. Nirmal Rege, KEM, Mumbai
Dr. MC Gupta, PGIMS, Rohtak
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Dr. Vikas Modgil, Ranbaxy, New Delhi
Dr. Paramjit Singh, Nicholas Piramil, Mumbai
Dr. Debasish Hota, PGI, Chandigarh
Dr. Syed Ziaur Rahman, Aligarh Muslim University, Aligarh
Dr. RS Deswal, CMC, Ludhiana
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Dr. Jayeraj Pandian, CMC, Ludhiana
Dr. Hem Lata, DMC, Ludhiana
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Dr. Emillio J. Sanz Spain
Submit an article
Refer to information for authors at our
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April 2010, Volume 2; Number 1
Review article
Clinical Aspects of Targeting Activated Oncogenes: Blocking Src kinases for
Cancer Treatment
Goyal Seema1 , Goyal Nadish2, Pramod John1, Dutta Abhilasha1.
1
Department of Physiology, Christian Medical College, Ludhiana, Punjab, India.
2
SEAS, University of Pennsylvania, Philadelphia, USA
Abstract
Receptor and non receptor protein tyrosine kinase activation has long been understood as a known
mechanism for triggering of oncogenic processes within the normal cells having tumorogenic potential,
expedition of proliferative process and spread of metastasis. Efforts have, therefore, been in targeting
these tyrosine kinase receptors and c-Src oncogenes in order to specifically block the proliferation of
the malignant cells. Various knockdown strategies have been evolved and tried for this purpose
including those involving anti sense oligo nucleotide (ODNA), small interfering RNA (siRNA),
neutralising the growth factor driven signaling, induction of down regulation of receptors by
monoclonal antibodies as well as targeting receptor tyrosine kinases on epidermal growth factor
receptors (EGFR), vascular endothelial growth factor receptors (VEGFR), platelet derived growth
factor receptors (PDGFR), Insulin-like growth factor I receptor (IGF – 1 R), fibroblast growth factor
receptors (FGFR) and hepatocyte growth factor receptors (HGFR). The development of targeted
inhibitors of a specific nature is a major step in breakthrough in overall understanding of the mechanism
of various cancer formations within the body and development of specific therapeutic agents which are
customised to inhibit a defined step to halt the otherwise uncontrolled proliferation of the malignant
cells. The present article reviews the relevant studies on targeting Src kinases and its therapeutic uses in
cancer treatment.
Key words: Oncogenic mechanisms, Src, Non receptor tyrosine kinases, Targeted inhibitors
Cancer, one of the biggest enigmas of the modern
medical science, has been a focus of attention in
scientific research. As new light is shed on the
understanding of causative agents and mechanisms of
damage caused by cancer, it becomes easier to
therapeutically conquer the disease. Locating and
pinpointing a specific step in oncogenesis, helps the
medical and scientific fraternity to develop devices
and mechanisms to target those specific areas to either
stop the disease or arrest its further growth.
Cells of the body, under normal physiological
conditions, have the ability to divide at a regulated rate
and then they die or undergo apoptosis but when this
regulatory mechanism goes unchecked as is the case
of defective gene expression, that state of growth of
cells is referred to as cancer. Changes in the genetic
material constitute the basis for the development of all
Corresponding author: Pramod John; Physiology
cancer. Generally there are several consecutive such
changes which influence different steps in the cellular
signal chains .Therefore, one should not expect to find
one single clue to the mechanism of origin of cancer.
However, application of the expanding knowledge in
the oncogenesis field allows us to start comprehending
the disharmonic orchestration behind abnormal
cellular growth.
Cancer is not a contagious disease. However,
infectious agents like viruses can contribute to the
origin of cancer. Thus, it is by use of retroviruses that
most oncogenes were identified, the starting materials
in such investigations often being highly specialized,
experimentally derived tumors. It seems likely that
retroviruses play a relatively limited role for the
development of cancer under natural conditions. Two
principally different forms of activation of oncogenes
email: [email protected]
1
can be distinguished. Firstly, the normal cellular
oncogene is hyperactive, and secondly the oncogene
product is altered so that it can no longer be regulated
in a normal way. There are several examples of these
types of activation of oncogenes.
anti-cancer drug design
cell division, inhibit cell differentiation, and halt cell
death. All of these processes are important for normal
human development and for the maintenance of
tissues and organs. Oncogenes, however, typically
exhibit increased production of these proteins, thus
leading to increased cell division, decreased cell
differentiation, and inhibition of cell death; taken
together, these phenotypes define cancer cells. Thus,
oncogenes are currently a major molecular target for
Conversely, c-src activation occurs with removal of
the C-terminal phosphotyrosine, which opens the c-src
molecular structure. In the active conformation,
tyrosine 419 in the kinase domain can be
autophosphorylated and thereby activates src
completely. The main structural difference between csrc and v-src is in this C-terminal domain. V-src,
unlike c-src, is constitutively active because of its lack
of the C-terminal negative-regulatory region .Other
Non-cancer-forming retroviruses contain three genes,
called gag, pol, and env. Some tumor-inducing
retroviruses (such as RSV), however, also contain a
gene called v-src (viral-sarcoma). It was found that the
The discovery of oncogenes was originally made by v-src gene in RSV is required for the formation of
the use of retroviruses. This infers that genetic control cancer and that the other genes have no role in
elements in the virus itself can be responsible for the oncogenesis.5
abnormal expression of the oncogene. However, in
Role of Src and Non receptor protein kinases in
many cases it was found that alterations of the
malignant processes
transferred oncogene contributed to its accentuated
Src and proteins of the Src family are non-receptor
expression. 1, 2
protein tyrosine kinases that play key roles in cell
Genetic basis of viral aetiology of oncogenesis and differentiation, motility, proliferation, and survival.6
proliferation of cancer cells
Src activates focal adhesion kinase (FAK) and signal
Retrovirus-associated DNA sequences (src) originally transducers and activators of transcription 3 (STAT-3)
isolated from the Rous sarcoma virus (RSV). The and their linked activities act to control cell migration
proto-oncogene src (c-src) codes for a protein that is a through the turnover of focal adhesions and the
member of the tyrosine kinase family and was the first suppression of cell-cell contacts.7–9 Also, Src is an
proto-oncogene identified in the human genome. The important mediator of many downstream effects of
human c-src gene is located at 20q12-13 on the long receptor tyrosine kinases including the epidermal
growth factor receptor family.10 Src is a key element
arm of chromosome 20.
in growth factor receptor signaling transduction and
This gene is similar to the v-src gene of Rous sarcoma
cytoskeleton arrangement, although its effects extend
virus. This proto-oncogene may play a role in the
to many tumorigenesis-related processes including
regulation of embryonic development and cell growth.
metastasis, invasion, adhesion, migration, survival,
The protein encoded by this gene is a tyrosine-protein
angiogenesis, and differentiation11,12.They are
kinase whose activity can be inhibited by
characterized by two protein binding domains, SH2
phosphorylation by c-SRC kinase. Mutations in this
and SH3, and one kinase domain, SH1. Proteins in the
gene could be involved in the malignant progression
Src family are regulated by phosphorylation at two
of colon cancer. Two transcript variants encoding the
tyrosine residues (Tyr 530 and Tyr 419).
3
same protein have been found for this gene.
Proto-oncogenes are a group of genes that cause Inactivation of human c-src occurs when its Cterminal Tyr 530 is phosphorylated and it binds back
normal cells to become cancerous when they are
mutated.4 Mutations in proto-oncogenes are typically to the SH2 domain. This interaction and an interaction
between the SH3 domain and the kinase domain result
dominant in nature, and the mutated version of a proto
-oncogene is called an oncogene. Often, proto- in a closed, inactive conformation so the access of
oncogenes encode proteins that function to stimulate substrates to the kinase domain is diminished .
Goyal et al
Blocking Src kinases for cancer treatment
2
functions of the SH2 and SH3 domains include
interactions with protein substrates and protein
localization in the cell such as myristylation at glycine
to increase binding to the cell membrane.13
Angiogenesis is also affected by Src activity.
Establishment of colon cancer cell lines with siRNA
to Src demonstrated a decrease in VEGF mRNA
expression proportional to the decrease in Src kinase
activity.25 The cancer cells treated with Src si-RNA
Evidence of cancers caused by increased expression
had a less than 2 fold increase in the VEGF expression
of Src gene
under hypoxic conditions compared to a greater than
Src kinases are over expressed in many common 50 fold increase in the VEGF expression in the
tumor types, including colon, lung, ovarian, prostate parental cell line.26
and pancreatic cancers. Dysregulation of Src function
has been strongly linked to the pathogenesis of human Synergistic effects of over expression of Src in
oncogenic processes
cancers.14-21
Over expression of Src was shown to increase DNA
More recently, the discovery of an activating Src
synthesis in response to EGF.27 Conversely, EGFmutation in a small subset of advanced colon tumors
induced DNA synthesis can be inhibited by the overhas been reported. In addition, elevated Src
expression of an inactivated form of Src.28, 29 Over
transcription has been identified as yet another
expression of Src and EGFR led to increased EGFmechanism contributing significantly to c-Src
dependent tumor formation in nude mice30. It could
activation in a subset of human colon cancer cell
be summarized that EGFR and Src may potentiate
lines.22
receptor-mediated tumorigenesis, suggesting a role
Therapeutic measures in targeting
Src for for individual or combined inhibition of these targets.
treatment of cancers and controlling metastasis
In a series of in vitro experiments, it was shown that a
The prevalence of activated Src in cancer indicates monoclonal antibody to EGFR combined with an Src
that this protein may play a significant role in the tyrosine kinase inhibitor results in synergistic 31effects
progression of many cancers, and thus, is a likely in cell growth and colony formation assays. This
target for drug discovery. Src activation has been synergistic effect appears to be mediated through an
shown to increase growth rates and invasion increase in apoptosis.
characteristics of tumors, and to decrease apoptosis in Therapeutic uses of inhibition of SRc in treatment
tumor cells. Reduced expression of any of these of cancers
properties would potentially induce retarded tumor
Src inhibition plays a therapeutic role in combination
growth and reduction of metastatic tendencies. The
recent use of Src inhibitors or antisense therapy in with chemotherapy. Silencing RNA to Src reduced
total Src levels in vitro and resulted in an increased
nude mouse studies, pancreatic cell growth, and
leukemia cells supports the validity of this hypothesis. sensitivity to Oxaliplatin. In a murine colon cancer
model, treatment with oxaliplatin and an Src inhibitor
Inhibition of the MAPK pathway by Src has been
demonstrated. The contribution of Src in pancreatic was able to reduce tumor volume and weight more
than that achieved with either of them alone.
tumor progression has been firmly established in an
orthotopic implantation model done using human Oxaliplatin treatment also led to a more than 3-fold
increase in activated Src levels in these murine
pancreatic tumor cells, in which Src expression was
down-regulated by siRNA, resulting in a significant tumors. Treatment with an Src inhibitor decreased
activated Src, and this low level of Src activation was
reduction in the incidence of metastases.23Treatment
32
with small interfering si-RNA to Src resulted in maintained even after Oxaliplatin treatment. This
effect appears to be specific for Oxaliplatin as there
decreased phosphorylation of MAPK in vitro and in
pancreatic murine models with the reduction in tumor was no apparent interaction between Src inhibition
and treatment with SN-38, the active form of
growth 24.
Irinotecan.33
Goyal et al
3
Recognition of the importance of Src in colorectal 3. Dehm SM and Bonham K. SRC gene expression in
human cancer: The role of transcriptional activation.
cancer has led to several trials with Src tyrosine kinase
Biochem Cell Biol 2004;82:263-74.
inhibitors. Src tyrosine kinase inhibitors in clinical
development or approved for other indications include 4. Adamson, E.D. Oncogenes in development.
AZD0530, Imatinib, Dasatinib, and SKI-606..34
Development 1987; 99: 449–71.
Interestingly, histone deacetylase (HDAC) inhibitors, 5. Stehelin D, Fujita DJ, Padgett T, Varmus HE, Bishop
JM. "Detection and enumeration of transformationagents with well-documented anti-cancer activity,
defective strains of avian sarcoma virus with molecular
repress SRC transcription in a wide variety of human
hybridization". Virology 1977; 76:675-84.
cancer cell lines. Analysis of the mechanisms behind
HDAC inhibitor mediated repression could be utilized 6. Frame MC.
Src in cancer: deregulation and
consequences for cell behaviour. Biochem Biophys
in the future to specifically inhibit
Src gene
Acta 2002;1602:114-30.
expression in human cancer.
7. Avizienyte E, Frame MC. Src and FAK signaling
controls adhesion fate and the epithelial-toSrc activation is an epigenetic event marking onset of
mesenchymal transition. Curr Opin Cell Biol
proliferation, differentiation, migration, invasion,
2005;17:542-7.
Summary
angiogenesis and alteration of apoptosis. It has been
implicated in many signal transduction pathways
involved in oncogenesis. Challenge lies ahead in
identifying patients and variants of myriad forms of
cancers which are likely to be benefited by inhibition
of Src. Even after three decades of its discovery Src
remains a novel target for anticancer therapy research.
There exists a logical possibility of achieving
synergistic effects with Src inhibitors along with other
agents which act on receptor protein kinases.
However, there have been many limiting factors in
successful development of targeted therapeutic agents
to combat oncogenic process. These have been
identified as lack of reliable predictive markers for
response to any new agents in most cancers except in
case of breast cancers. An effective development of
molecularly targeted agents requires assessment of
optimal clinical exposure and regime for advanced
trials using available and newly developed biomarkers
in combination with efficacy and safety profiles
defined in research protocols. The possibilities to
develop a “designer” inhibitor specifically targeting a
defined site or step in oncogenesis are endless even in
the face of certain limitations which are likely to be
overcome in this age of expanding knowledge and
interest in this field.
8. Hiscox S, Jordan NJ, Morgan L, Green TP, Nicholson
RI. Src kinase promotes adhesion-independent
activation of FAK and enhances cellular migration in
tamoxifen- resistant breast cancer cells. Clin Exp
Metastasis 2007;24:157-67.
9. Yu CL, Meyer DJ, Campbell GS, et al. Enhanced DNAbinding activity of a Stat3-related protein in cells
transformed by the Src oncoprotein. Science 1995;
269:81-3.
10. Scaltriti M, Baselga J. The epidermal growth factor
receptor pathway : a model for targeted therapy. Clin
Cancer Res 2006;12: 5268-72.
11. Summy JM, Gallick GE: Src family kinases in tumor
progression and metastasis. Cancer Metastasis Rev
2003; 22:337–358
12. Summy JM, Gallick GE: Treatment for advanced
tumors: SRC reclaims center stage. Clin Cancer Res
2006; 12:1398–1401.
13. Yeatman TJ; “A Renaissance for Src”. Nature Rev
2004; 4: 470-480.
14. Windham TC, Parikh NU, Siwak DR, Summy JM,
McConkey DJ, Kraker AJ, Gallick GE Src activation
regulates anoikis in human colon tumor cell lines.
Oncogene 2002; 21:7797–7807.
15. Haier J, Gallick GE, Nicolson GL. Src protein kinase
pp60c-src influences adhesion stabilization of HT-29
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1. J.M. Bishop: Oncogenes. Sci Amer 1982; 246: 68-78.
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2. T. Hunter: The Proteins of Oncogenes. Sci Amer 1984;
J Exp Ther Oncol 2002; 2:237–45.
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16. Mazurenko NN, Kogan EA, Zborovskaya IB, Kisseljov
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5
Review article
Certolizumab: A Novel Anti TNF-α Monoclonal Antibody
Patel S Devang1, Mehta R Hiren1, Deshpande S Shrikalp2, Patel B Bhavin3, Patel B Paresh4,
1
Torrent Pharmaceuticals Limited, Torrent Research Centre, Village Bhat, District Gandhinagar–382428,
Gujarat, India; 2 K. B. Institute of Pharmaceutical Education and Research, GH/6, Sector-23, Gandhinagar382023 Gujarat, India; 3 Shri Sarvajanik Pharmacy College, Nr. Arvind Baug, B/H Bus-Station, Mehsana384001, Gujarat, India; 4 A. R. College of Pharmacy, Vallabh Vidyanagar-388120. District Anand, Gujarat,
India
Abstract
Crohn’s disease is an inflammatory disorder that may affect any portion of the gastrointestinal tract,
from the mouth to the rectum but large bowel and small bowel are more prone and RA is a chronic,
progressive, systemic inflammatory disease that targets primarily the synovial tissues, resulting in
destruction of cartilage and ultimately bone. TNF- α is synthesized and secreted by macrophages,
lymphocytes, neutrophils, and structural cells including fibroblasts, smooth muscle cells, astrocytes, and
microglia. TNF antagonists can induce reverse signaling through the membrane-anchored ligand and
trigger cell activation, and cytokine suppression or apoptosis. Certolizumab Pegol is used effectively in
Crohn’s disease and Rheumatoid arthritis where conventional therapy is not responded. Certolizumab
pegol is monoclonal antibodies binds to TNF-α and prevents its interaction with specific receptors. It
exhibited a linear pharmacokinetic profile after administration of a single subcutaneous injection. The
half-life is longer due to conjugation with two molecules of PEG, in-vivo half-lives in rats to 45.8
hours, while in humans the elimination half-life is 192 hours. The reported case of a 22-year-old woman
with a 4-year history of colonic Crohn’s disease who was successfully treated with certolizumab during
the first and third trimesters. It marks an era of a new biological therapy directed towards the inhibition
of TNF- α in patients with crohn’s disease and rheumatoid arthritis. It proves to be having beneficial
effect. It was well tolerated in patients with moderate-to-severe active Crohn’s disease in phases II and
III studies and clinical efficacy and good tolerability in patients with RA. But still further safety
Key words: Certolizumab, anti-TNF-α, Crohn's Disease, Rheumatoid arthritis
Crohn’s disease (CD) is an inflammatory disorder that
may affect any portion of the gastrointestinal tract,
from the mouth to the rectum but large bowel and
small bowel are more prone.1 The major costs (about
50–60% of overall costs) coming from hospitalisations
and surgery and a total economic burden of CD of
about 10.9–15.5 billion dollars in U.S. and 2.1–16.7
billion Euro in Western countries2.
The rate of occurrence of CD is slightly higher (0%10%) in females compared to males. The incidence of
CD was primarily more in people in their 20s or 30s
and secondarily in people in their 50s and 60s. CD
occurs due to the combination of genetic
Corresponding author: Patel Devang
predisposition, environmental factors, and immune
system defects1.
The common symptoms present in patients with CD
are diarrhea (sometimes bloody), abdominal pain,
fever, and weight loss. The common clinical signs of
CD include Cachexia, pallor, abscesses, and fistulas3.
Some complications of CD include malabsorption
syndromes, intestinal obstruction, gastrointestinal
carcinomas, and lymphomas. CD is diagnosed based
on endoscopic findings with biopsy combined with
clinical signs and symptoms. Radiologic assessment is
recommended in some cases but usually is not useful
as the sole diagnostic tool. Alternative causes of
email; [email protected]
6
intestinal inflammation, such as infectious, ischemic,
or other inflammatory bowel diseases, should be ruled
out. Several antibody tests may be useful for the
diagnosis of CD in conjunction with other diagnostic
tools. These tests include antineutrophil cytoplasmic
antibodies and anti-Saccharomyces cereuisiae
antibodies1.
that current therapy changes the natural history or
outcome of disease, although some preliminary
evidence that early intervention with anti-TNF therapy
reduces steroid exposure reduces hospitalization of
surgery in the short term, and promotes mucosal
healing9.
Tumor necrosis factor alpha and Antagonist
Rheumatoid arthritis (RA) is a chronic, progressive,
systemic inflammatory disease that targets primarily
the synovial tissues, resulting in destruction of
cartilage and ultimately bone. Delayed treatment often
leads to substantial disability, functional declines,
economic losses, work disability, and premature
mortality4. Onset typically occurs between 30 and 50
years of age5. The prevalence of RA ranges from 0.5%
to 1.0% and it occurs twice as often in women as in
men6. There is a significant economic burden caused
by the disease which affects society as well the
individual7.
TNF-α is a 157 amino acid pro-inflammatory cytokine
that was identified in 1975 as the factor in serum
isolated from endotoxin treated mice that induced
necrosis of a methylcholanthrene induced murine
sarcoma. TNF- α is synthesized and secreted by
macrophages, lymphocytes, neutrophils, and structural
cells including fibroblasts, smooth muscle cells,
astrocytes, and microglia. The synthesis and secretion
of TNF-α is increased in response to injury, infection,
and inflammatory stimuli as in case of CD and RA.
TNF-α is initially released from cells as a soluble
cytokine after being enzymatically cleaved from its
Established therapies for RA have limitations related cell surface-bound precursor10.
to safety, cost or efficacy which limits their long term
TNF antagonists can induce reverse signaling through
use and tolerability. The most common side effects
the membrane-anchored ligand and trigger cell
include the possibility of nausea, anemia, neutropenia,
activation, and cytokine suppression or apoptosis10.
increased risk of bruising, vomiting and diarrhoea.
Regular liver function tests are also required to detect Certolizumab pegol a monoclonal antibody to TNF-α,
any liver toxicity and prevent liver cirrhosis. Although pegylated (human) as a biologics indicated for the
tumour necrosis factor (TNF) inhibitors have treatment of RA and CD was approved in USA in
11,12
improved treatment outcomes for many patients. The May 2009 and April 2008 respectively .
emerging trend in care for RA is early initiation of Basis of discovery
biologic disease-modifying antirheumatic drug
(DMARD) therapy to prevent the damaging structural Various lines of evidence suggest that CD is the result
progression of the disease. TNF-inhibitor have shown of an exaggerated response against13constituents of the
promising results for their early use through their mucosal microflora by T cells , leading to the
production of pro-inflammatory cytokines such as
impressive clinical trial data5.
TNF-α. Such evidence together with studies showing
So tumour necrosis factor-α (TNF-α) inhibitors the anti-inflammatory effects of anti-TNF-α antibodies
represent a major advance in (RA) treatment and are in animal models and the efficacy of anti-TNF-α
the first choice in biological therapy for patients antibodies in RA stimulated the evaluation of
following an inadequate response to non-biological infliximab in patients with treatment-resistant CD14.
(DMARDs)8.
Chemistry
Current Treatment and Alternative
Certolizumab Pegol immunoglobulin, anti-(human
Since surgery will generally only be performed for tumor necrosis factor α) Fab' fragment (humanized
severe disease not responding to medical therapy, the monoclonal CDP870 heavy chain), disulfide with
proportion of patients potentially treated with biologic humanized monoclonal CDP870 light chain, pegylated
therapy in the future is likely to be much higher. at Cys-22115,16. It does not possess a fragment
Alternative treatments are also needed for those who crystallizable (Fc) region. Therefore, it does not
develop immunogenicity on in. There is little evidence mediate immune cell death by complement-dependent
Patel et al
Certolizumab and monoclonal antibody
7
cytotoxicity
(CDC)
or
antibody-dependent
cytotoxicity (ADCC). It is PEGylated; polyethylene
glycol (PEG) has been added to the Fab structure to
extend the half-life of the molecule17.
Mechanism of action and pharmacokinetics
Certolizumab pegol binds to TNFα and prevents its
interaction with specific receptors. It is derived from a
monoclonal antibody; CZP does not bind lymphotoxin
(TNFβ). Certolizumab has also been shown to be the
only anti-TNF agent that does not kill activated
lymphocytes and monocytes by apoptosis or increase
levels of degranulation and necrosis of granulocytes in
vitro18.
Following administration of single subcutaneous 20,
60, or 200mg dose in healthy volunteer, it exhibits a
linear pharmacokinetic profile.It is having high
bioavailability (estimated to be 100%), the apparent
volume of distribution was 45 mL/kg, and clearance
was 0.17 mL/h per kg. Owing to conjugation with two
molecules of PEG, it is having a longer half-life, invivo half-lives in rats 45.8 hours, while in humans the
elimination half-life is 192 hours 19.
Clinical Study
A randomized, double-blind, placebo-controlled
multicenter study evaluated the use of certolizumab in
patients with moderate to severe CD. Certolizumab
400 mg S.C. showed a significant benefit in clinical
response when compared with placebo at weeks 2
(p=0.01), 4 (p≤0.01), 8 (p≤0.01), and 10 (p=0.006),
The percentage of patients achieving remission with
certolizumab 400 mg s.c. was significantly higher than
those given placebo at weeks 4 (p≤0.05) and 8
(p≤0.01), but not at week 12. Post-hoc analysis
stratifying patients with serum CRP≥10 (n=119) or
<10 (n=171) resulted in statistically significant benefit
of certolizumab 400 mg S.C. over placebo in terms of
both clinical response and remission at all time
point20.
In another randomized, double-blind, placebocontrolled trial, for evaluated the efficacy of CZP in
662 adults with moderate-to-severe Crohn’s disease.
Patients were stratified according to baseline levels of
C-reactive protein (CRP) and were randomly assigned
to receive either 400 mg of CTZ or placebo
subcutaneously at weeks 0, 2, and 4 and then every 4
weeks. Primary end points were the induction of a
Patel et al
response at week 6 and a response at both weeks 6 and
26. Among patients with a baseline CRP level of at
least 10 mg/Ltr. In the overall population, response
rates at week 6 were 35% in the certolizumab group
and 27% in the placebo group (P = 0.02); at both
weeks 6 and 26, the response rates were 23% and
16%, respectively (P = 0.02). Serious adverse events
were reported in 10% of patients in the certolizumab
group and 7% of those in the placebo group; serious
infections were reported in 2% and less than 1%,
respectively. So induction and maintenance therapy
with CTZ in moderate to severe crohn’s disease was
associated with a modest improvement in response
rates, as compared with placebo16.
Certolizumab Pegol was further assessed in a doubleblind, placebo controlled, 24 week study enrolling 220
patients who had adult onset active rheumatoid
arthritis of at least 6 months duration and for whom
therapy with at least 1 DMARD regimen had failed.
Patients received CTZ 400 mg or placebo
subcutaneously every 4 weeks. Therapy with NSAIDs
and/or prednisone (or prednisone equivalent) at doses
of 10 mg/day or less could be continued. The primary
study end point was the ACR20 response rate at week
24. Patients who withdrew from the study for any
reason were considered nonresponders. Mean patient
age was 53.8 years; 83.6% of patients were female.
The ACR20 response rate at week 24 was 45.5% in
the certolizumab group compared with 9.3% in the
placebo group (P < 0.001). Differences in ACR20
response rate were observed as early as week 1
(36.7% vs. 6.6%; P < 0.001). At week 24, ACR50
response rate was 22.7% in the certolizumab group
compared with 3.7% in the placebo group (P 0.001).
ACR70 response rate was 5.5% in the certolizumab
group compared with 0% in the placebo group (P =
0.013). Patients treated with certolizumab also were
observed as having improved physical function,
reduced pain, improved health-related quality of life
scores, reduced fatigue, and improved work
productivity compared with those receiving placebo21.
An international, multicentre, phase 3, randomised,
double-blind, placebo-controlled study in active adultonset RA. Patients (n=619) were randomized 2:2:1 to
subcutaneous CZP 400 mg at weeks 0, 2 and 4
followed by 200 mg or 400 mg plus MTX, or placebo
plus MTX, every 2 weeks for 24 weeks.
Significantly more patients in the CZP 200 mg and
8
400 mg groups achieved an ACR20 response versus
placebo; rates were 57.3%, 57.6% and 8.7%,
respectively. CZP treated patients reported rapid and
significant improvements in physical function versus
placebo; mean changes from baseline in HAQ-DI at
week 24 were 20.50 and 20.50, respectively, versus
20.14 for placebo. Most adverse events were mild or
moderate, with low incidence of withdrawals due to
adverse events. Five patients developed tuberculosis.
CZP plus MTX was more efficacious than placebo
plus MTX, rapidly and significantly improving signs
and symptoms of RA and physical function22.
Immunogenicity
Fab fragments are generally less immunogenic than
whole antibodies, but the concept of immunogenicity
needs to be understood, since it is different from
antigenicity. Antigenicity simply refers to the process
by which an antigen binds to a specific receptor and
provokes an immune response that may be either
immunogenic or tolerogenic. It is the immunogenic
response (immunogenicity) that is potentially harmful
to the recipient. Humanization of an antibody
promotes homology with human proteins, which
reduces their antigenic profile, but even human
proteins can be immunogenic in humans.
Immunogenicity depends not only on the molecular
conformation of the protein, but also on dose,
delivery, frequency, concomitant therapy, and
individual. The ability of PEG to reduce the
immunogenicity of foreign proteins has been under
investigation, with a view to the production of
engineered monoclonal antibodies that are effective
but less immunogenic9.
Adverse Events
CZP exhibits the same spectrum of adverse events as
currently available TNF-α inhibitors23. The most
common adverse events included headache,
exacerbation of CD, urinary tract infection,
unspecified abdominal pain, fever, and nausea,
nasopharyngitis. Others included dizziness, arthralgia,
and pharyngolaryngeal pain. The following serious
adverse events were reported, in decreasing order of
frequency: worsening CD, rectal hemorrhage,
abdominal mass, reduced visual acuity, pyrexia,
vomiting and paralytic ileus, breast hyperplasia, ankle
ulcer, thrombocytopenia, and perianal abscess.
Schreiber and colleagues reported a higher incidence
Patel et al
of injection-site adverse events including burning,
erythema, inflammation, pain, or rash. The most
common reaction was burning at injection site
occurring within 30 min of administration19.
Certolizumab use in pregnancy
The Fc region of whole IgG antibodies binds with
neonatal Fc receptors to cross into the placenta.
Placental transfer of murinized IgG1 and PEGylated
Fab versions of hamster antimurine TNF antibody
TN3 was studied in pregnant rats. In addition, the
levels of each molecule in milk were assessed. Very
low levels of PEGylated Fab were detected in two of
five fetuses of rats that had been injected with antiTNF PEGylated Fab fragment during their
pregnancies. Comparatively high levels of fetal IgG1
were found in rats that received TN3 IgG1.These
results indicate a potential role for certolizumab in the
treatment of women.17 The safety and efficacy of
certolizumab during pregnancy are unknown. The
reported case of a 22-year-old woman with a 4-year
history of colonic CD who was successfully treated
with certolizumab during the first and third
trimesters24.
Safety
In the study of 216 patients serious adverse events
occurred in 6% and 7% in the certolizumab group and
placebo group respectively. Serious infection occurred
in 3% and 1% in the certolizumab group and placebo
group respectively. No deaths, solid-organ or
hematologic cancers, demyelinating diseases, or lupus
occurred during the maintenance phase. One or more
local reactions to injection occurred in 3% and 15% of
patients in the certolizumab group and placebo group
respectively25. It administered subcutaneously
demonstrated efficacy and was well tolerated in
patients with moderate-to-severe active Crohn’s
disease in phases II and III studies and clinical
efficacy and good tolerability in patients with RA26.
Dosage, administration, and formulations
CZP was delivered by subcutaneous injection
(lyophilized) as a 200 mg vial for single use in a 5 mL
vial reconstituted with water for injection. The
maximum volume that can be given by S.C. injection
at a single injection site is 1 mL. The dosage of CZP
that has demonstrated the better efficacy in clinical
trials is 400 mg administered subcutaneously; suitable
9
areas for injection are the lateral abdominal wall or
market. Nature Rev Drug Discov 2009; 8: 693 - 4
upper outer thigh. The scheduled regimen was
7. Kay J, Rahman MU. Golimumab: A novel human
administration at week 0, 2, and 4 (induction phase)
anti-TNF-α monoclonal antibody for the treatment
and then every 4 weeks from week 6 (maintenance
of rheumatoid arthritis, ankylosing spondylitis, and
phase) 19.
psoriatic arthritis. Core Evidence 2009; 4: 159–70
Conclusion
8. Fleischmann R. The clinical efficacy and safety of
CZP is a novel tumor necrosis factor alpha (TNF-α)
certolizumab pegol (CZP) in the treatment of
antagonist drug that can be used effectively in CD and
rheumatoid arthritis: focus on long-term use,
RA where conventional therapy is not responded. It
patient considerations and the impact on quality of
marks an era of a new biological therapy directed
life. Rheumatology: Research and Reviews 2009;
towards the inhibition of TNF- α in patients with
1: 95–106
crohn’s disease and rheumatoid arthritis. It proves to
9. Fleischmann R, Vencovsky J, Vollenhoven RF,
be beneficial effect.
Borenstein D, Box J, Coteur G, et al.. Efficacy and
CZP as a 400-mg S.C. injection, initially every 2
safety of certolizumab pegol monotherapy every 4
weeks for the first 3 doses and subsequently every 4
weeks in patients with rheumatoid arthritis failing
weeks for maintenance has been shown to be well
previous disease-modifying antirheumatic therapy:
tolerated and effective. Cost will also be a
the FAST4WARD study. Ann Rheum Dis 2009;
consideration and self-administration has yet to be
68: 805-11
established. Further safety on larger population will be
10. Dinesen L, Travis S. Targeting nanomedicines in
established.
the treatment of Crohn's disease: focus on
college committed to promoting rational use of drugs
certolizumab pegol (CDP870). Int J Nanomedicine
for the betterment of patient health. In order to fulfill
2007; 2: 39-47
this commitment, KISTMC has established MIS as a
11. Soczynska JK, Kennedy SH, Goldstein BI,
pilot project with an objective to provide unbiased and
Lachowski A, Woldeyohannes HO, McIntyre RS.
authentic drug information leading to the practice of
The effect of tumor necrosis factor antagonists on
evidence-based medicine that increase quality of
mood and mental health-associated quality of life:
patient health.
novel hypothesis-driven treatments for bipolar
depression? Neurotoxicology 2009; 30: 497-521
References:
1. Rivkin A. Certolizumab pegol for the management of 12. Drugs@FDA. FDA approved drug products.
Crohn's disease in adults. Clin Ther 2009;31:1158-76
Available on http://www.accessdata.fda.Gov/
scripts/cder/drugsatfda/index.cfm.Accessed
2. Caprilli R, Angelucci E, Clemente V. Recent advances
October 27, 2009.
in the management of Crohn's disease. Dig Liver Dis
2008; 40: 709-16
13. Efimova GA, Kruglov AA, Tillib SV, Kuprash
3. Behm BW, Bickston SJ. Tumor necrosis factoralpha antibody for maintenance of remission in
Crohn’s disease. The Cochrane Library 2009; 4
DV, Nedospasov SA. Tumor Necrosis Factor and
the consequences of its ablation in vivo. Mole
Immunol 2009 [ In Press].
4. Behm BW, Bickston SJ. Tumor necrosis factor- 14. Shao LM, Chen MY, Cai JT. Meta-analysis: the
efficacy and safety of certolizumab pegol in
alpha antibody for maintenance of remission in
Crohn's disease. Aliment Pharmacol Ther 2009;
Crohn's disease. Cochrane Database Syst Rev
29: 605-14.
2008; 1: 6893
5. Lin J, Ziring D, Desai S, Kim S, Wong M, Korin 15. Melmed GY, Targan SR, Yasothan U, Hanicq D,
Kirkpatrick P. Certolizumab pegol. Nat Rev Drug
Y et al. TNFalpha blockade in human diseases: an
overview of efficacy and safety. Clin Immunol
Discov 2008; 7: 641-2.
2008; 126: 13-30
16. WHO drug information 2004; 18:3: 248-249
6. Stoll JG, Yasothan U. Rheumatoid arthritis
Patel et al
10
17. Sandborn WJ, Feagan BG, Stoinov S, Honiball PJ,
Rutgeerts P, Mason D et al. Certolizumab pegol
for the treatment of Crohn's disease. N Engl J Med
2007; 19: 228-38
18. New Developments in Rheumatic Diseases 2006;
4.
19. Barnes T, Moots R. Targeting nanomedicines in
the treatment of rheumatoid arthritis: focus on
certolizumab pegol. Int J Nanomedicine 2007; 2:37
20. Cassinotti A, Ardizzone S, Porro GB.
Certolizumab pegol: an evidence-based review of
its place in the treatment of Crohn’s disease. Core
Evidence 2007; 2: 209-24.
21. Wong M, Ziring D, Korin Y, Desai S, Kim S, Lin
J et al. TNFalpha blockade in human diseases:
mechanisms and future directions. Clin Immunol
2008; 126: 121-36
22. Cada DJ, Levien TL, Baker DE. Certolizumab
Pegol. Hospital Pharmacy 2008; 12: 998–1007
23. Smolen J, Landewe RB, Mease P, Brzezicki J,
Mason D, Luijtens K et al.. Efficacy and safety of
certolizumab pegol plus methotrexate in active
rheumatoid arthritis: the RAPID 2 study. A
randomised controlled trial. Ann Rheum Dis 2009;
68: 797-804
24. Senolt L, Vencovský J, Pavelka K, Ospelt C, Gay
S. Prospective new biological therapies for
rheumatoid arthritis. Autoimmun Rev 2009; 9: 102
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25. Oussalah A, Bigard MA, Peyrin-Biroulet
Certolizumab use in pregnancy. Gut 2009; 58: 608
L.
26. Schreiber S, Khaliq-Kareemi M, Lawrance IC,
Thomsen OO, Hanauer SB, McColm J et
al.Maintenance therapy with certolizumab pegol for
Crohn's disease. N Engl J Med 2007; 357: 239-50.
Patel et al
11
Original Research Article
Effectiveness of Duloxetine with Amitriptyline in Diabetic Neuropathic Pain
Kumar Narendra 1, Dixit Rakesh K1, Saksena AK1, Sachan AK1, Nath R1, Verma R2
Department of Pharmacology and Therapeutics, 2 Neurology, CSM Medical University Lucknow, India
1
Abstract
Background: Diabetic neuropathy is often associated with pain unresponsive to conventional first line
analgesics. Numbers of adjuvant analgesics have been tried in treating in this type of pain, some of
them belong to antiepileptics, opioid analgesics, and antidepressants. Amitriptyline has been tried in
treating this type of pain but limitations are met because of its high degree of adverse effect profile.
Present study has been done to evaluate the effectiveness of duloxetine in treating diabetic neuropathic
pain and its comparison with amitriptyline.
Methods: This was a prospective randomized study design for a period of one month Patients 18 years
or above of age having inclusion criteria were enrolled after diagnosing as patients of diabetic
neuropathy. Their assessment on visual analogue scale and nerve conduction velocity study were done
on the first day of including in study. Randomly the patients were either given Duloxetine or
amitriptyline and asked for follow-up after one month. Same procedures were repeated after one month.
Data were presented as mean ± SE and compared by student t test (unpaired). P value less than 0.05 was
considered as statistically significant.
Results and conclusions: There was significant reduction in pain as assessed by VAS scale in both
groups (P<0.05). Reduction by duloxetine was comparable with that produced by amitriptyline. NCV in
both groups had not been changed significantly.
Key words: Duloxetine, Amitriptyline, Diabetes mellitus, Neuropathic pain, Visual analogue scale
Neuropathic pain is related to abnormal
somatosensory processing in central or peripheral
nervous system1. Diabetic neuropathy has been
defined as disorder which may be clinical or sub
clinical occurs in patients having long term diabetes. It
may include somatic as well autonomic nervous
system2. Painful diabetic peripheral neuropathy is a
significant cause of distress in patients with diabetes
mellitus3. It affects both type 1 and type 2 diabetes
mellitus. Overall incidence is 20-24% and prevalence
increases as the disease progresses4,5.
inhibition of norepinephrine (NE) and serotonin (5HT) reuptake at synapses. However, their use can be
limited by intolerable adverse effects. Anticholinergic
side-effects are blurring of vision, dryness of mouth,
urinary retention, constipation, orthostatic hypotension
& prolonged QT syndrome etc8,9. There are some
studies regarding the selective serotonin reuptake
inhibitors (SSRIs) and selective serotonin
norepinephrine reuptake inhibitors (SNRIs,) in the
treatment of diabetic Neuropathic pain and indicated
their effectiveness to some extent10.
The most common presentations of diabetic peripheral
neuropathic pain are burning, shooting or stabbing,
more commonly involving lower limbs. It is worse at
night and overall has negative effect on quality of
life6. Antidepressants have often, been used in
treatment of chronic pain syndrome. Out of all
antidepressants tricyclic antidepressants (TCAs) have
been most widely studied7. TCAs’ effects are due to
There is need of an agent which exerts efficacy equal
to or better than achieved by TCAs, but with more
favorable side effect profile.
Duloxetine, an
antidepressant, with dual selective inhibition of NA
and 5- HT, with less dangerous side effects than TCAs
has been studied for various types of pain syndromes
including painful polyneuropathy, fibromyalgia,
cancer pain, postherpetic neuralgia11,12,13. Very few
Corresponding author: Dixit Rakesh, Pharmacology; email: [email protected]
12
studies have been done regarding its efficacy in
peripheral diabetic neuropathic pain. Moreover no
study has been done to compare its efficacy with
amitriptyline. Keeping these things in mind, present
study has been designed to know the effectiveness of
duloxetine in diabetic peripheral neuropathic pain and
its comparison with amitriptyline.
Materials and Methods
Study was prospective and randomized which was
carried out in patients coming to the department of
Neurology, C.S. M. Medical University Lucknow.
Study was approved from institutional research
committee and it was according to the Helsinki
declaration of 1975. Patients were included in the
study after fulfilling following inclusion and exclusion
criteria and after obtaining written informed consent.
Inclusion criteria:
•
patients more than 18 years of age
•
Both male and female patient with diabetic
neuropathic pain
were asked for follow up after one month period.
Patients were suggested not to take any medication
other than prescribed antidiabetic drugs and the drugs
under study. In case of unbearable pain patients were
allowed to take paracetamol (500mg) or ibuprofen
(400mg) as rescue medicines.
Patients were divided randomly using random table
into following two groups:
Group A received tab amitriptyline 25 mg/day
Group B received Cap duloxetine 60mg/day
Both drugs were given for a period of one month.
VAS and NCV were again done after one month.
Comparisons were made in the same the group and in
between groups. Base line data of same group was
compared with data after one month. In between
groups comparison between base line data and results
after one month of therapy were compared. Values are
expressed as mean ± SE. Statistical analysis was done
by student‘t’ test and p less than 0.05 was considered
statistically significant.
Patients having symptoms for at least 6 months Results
In patients of group A (amitriptyline treated group
• Visual analogue scale more than 4
n=22) mean pain level was 6.09 ± 0.27during the
Exclusion criteria:
inclusion time after one month it became 3.91 ± 0.21
which was showing significant improvement. (Fig.1)
• Pregnant or lactating women
•
•
Hypersensitivity
amitriptyline
to
duloxetine,
•
Patients with unstable
psychiatric disorders
personality
or In group B (duloxetine treated n=22) VAS was 6.05 ±
0.42 during the time of inclusion and 3.59 ± 0.12 after
one month of therapy (Fig 1.) which also suggest
and significant improvement.
Regarding comparison between group A and group B
Patients with skin conditions in area affected in base line readings and after one month of therapy
by neuropathy
there was no statistically difference. Regarding the
• Patients already on antidepressant or anti results of NCV in Right common peroneal nerve there
was no significant difference in amitriptyline and
epileptic therapies
duloxetine treated groups when compared in pre and
• Patients with Hb A1c levels more than 11%
post treatment values (Fig. 2)
After a standardized initial evaluation, which included
Discussion and conclusion
a complete clinical history/examination,
investigations, written informed consent was taken for Neuropathic pain is a complex condition that might
inclusion in trial. Assessment of pain on visual involve multiple neurotransmitters and mechanisms.
analogue scale (VAS) and nerve conduction velocity There may lead to disregulation of neuropeptides and
(NCV) of right common peroneal nerve was done neurotransmitters and changes that occur at
(machine Neuro Perfect Medic Aid Syst)14. Patients supraspinal sites and result in facilitation of pain
transmission15.
•
Kumar et al
Duloxetine in diabetic neuropathic pain
13
Figure1. Pre and post treatment pain score in both groups
Vas Score (mean ± SE)
8
7
6
5
*
4
*
3
Amitriptyline (n=18)
2
Duloxetine (n=16)
*p<0.05
1
0
Predrug
Post drug
treatment
Figure 2. Pre and post treatment nerve conduction (NCV) velocity in both groups
NCV in m/s (mean ± SE)
50
45
40
35
Amitriptyline (n=18)
30
Duloxetine (n=16)
25
20
*p<0.05
15
10
5
0
Predrug
Post drug treatment
Peripheral diabetic neuropathy is a common and
difficult complication of diabetes. Several agents
belonging to antidepressants, antiepileptic, and opioid
groups have been tried with variable results.
Amitriptyline has been shown to be effective in
various clinical studies. Present study also favors the
effectiveness of amitriptyline in treatment of diabetic
neuropathic pain. Duloxetine belonging to newer
group SNRI and provides balanced norepinephrine
and serotonin reuptake inhibition. Duloxetine is
generally well tolerated and adverse effects are mild
like gastrointestinal upsets, appetite suppression,
insomnia, and dry mouth16,17. In present study efficacy
of duloxetine is almost equal to amitriptyline which is
Kumar et al
shown by reduction in VAS. NCV which is one of the
parameters of peripheral neuropathy did not altered by
both the drugs. Regarding the possible mechanism in
case of amitriptyline and duloxetine are their abilities
to increase the noradrenalin and serotonin activities in
CNS18,19. However in addition to noradrenalin and
serotonin amitriptyline might also affect
histaminergic, cho linergic, glutaminergic
transmissions and sodium channel which may result in
wide range of adverse effect and make this drug
unfavorable for treatment11 Duloxetine on other hand
more selective, balanced SNRI having almost equal
efficacy in reducing pain as compared to amitriptyline
but its adverse effect profile is very less in comparison
14
to amitriptyline. On the basis of present study 12. Dworkin R.H. Prevention of postherpetic neuralgia.
Lancet 1999; 353:1636-1637.
duloxetine can be a better drug for the treatment of
diabetic neuropathic pain. However more studies on 13. Arnold LM, Lu Y, Crofford LJ, et al. A double blind,
larger number of patients are required for any
multicenter trial comparing Duloxetine with placebo in
conclusive result.
treatment of fibromyalgia patient with or without major
depressive disorder. Arthritis Rheum 2004; 50:2974Acknowledgement Authors acknowledge the help,
2984.
support and encouragement by Prof. K. K. Pant. Head
of department pharmacology and therapeutics C. S. 14. Wewers M.E and Lowe N.K. A critical review of
visual analogue scales in the measurement of clinical
M. Medical University Lucknow.
phenomena. Res Nurs Health 1990; 13:227-236.
References
1. Woolf C.J. Mannion R. J. Neuropathic pain. Etiology
symptoms, mechanisms and management. Lancet
1999; 353:1959-1964.
2. Consensus statement: report and recommendations of
San Antonio conference on diabetic neuropathic,
diabetes Care 11:592-597,1988.
3. Backonja MM, Serra J. pharmacologic management
part 1: better studied neuropathic pain diseases. Pain
Med 2004; 5: S1:S28-S47.
15. Chen H, Lamer TJ, Rho RH et al. Contemporary
management of neuropathic pain for the primary care
physician. Mayo Clin Pro 2004; 79:1533-1545.
16. Shara A, Goldberg MJ, Cerimele BJ. Pharmacokinetics
and safety of duloxetine a serotonin and NE reuptake
inhibitor. J Clin Pharmacol2000; 40:161-167
17. Westanmo AD, Gayken J, Haight R. Duloxetine: a
balanced and selective norepinephrine and serotonin
reuptake inhibitor. Am J Health Syst Pharm 2005;
62:2481-2490.
4. Schnader KE, Epidemiology & impact on quality of 18. Ansari A. The efficacy of newer antidepressants in the
life of postherpetic neuralgia & painful diabetic
treatment of chronic pain: a review of current literature.
neuropathy. Clin J Pain 2002; 18: 350-4.
Harv Rev Psychiatry 2000; 7:257-277.
5. Pirart J. Diabetes Mellitus & its degenerative 19. Reisner L. Antidepressants for chronic neuropathic
complications: a prospective study of 44000 patients
pain. Curr Pain Headache Rep 2003; 7:24-33.
observed between 1947 & 1973. Diabetes Care 1978;
1:168-88.
6. Benbow SJ, Wally Mahmed ME, Macfarlane IA,
Diabetic peripheral neuropathy & quality of life. QJM
1998; 91; 733-737.
7. Magni G, The use of antidepressants in the treatment of
chronic pain; a review of the current evidence. Drugs
1991; 42:730-48.
8. Preskorn SH, Irwin HA, Toxicity of tricyclic
antidepressants–kinetics, mechanism, intervention; a
review. J Clin Psychiatry 1982; 43: 151-156.
9. Glassman AH, Bigger JT Jr. cardiovascular effects of
therapeutic doses of TCAs; a review. Arch Gen
Psychiatry 1981; 38: 815-820.
10. Finnerup NB, Otto M, Mc Quay HJ, Jensen TS,
Sindnup SH; Algorithm for neuropathic pain treatment:
an evidence based proposal. Pain 118:289-305, 2005.
11. Guay DR. Adjunctive agents in the management of
chronic pain. Pharmacotherapy 2001; 21:1070-1081.
Kumar et al
15
Original Research Article
Oxidative Stress in Type 2 Diabetes Mellitus Patients: Effect of Metformin
Alone and in Combination with α-lipoic Acid
Vasant SR1, Dixit1 Rakesh K, Saksena1 AK, Sachan AK1, Nath R1, Siddique KU2
Department of Pharmacology, 2Medicine, C.S.M. Medical University Lucknow , India
1
Abstract
Background: Oxidative stress in diabetes patients plays major role in development of significant
complications therefore addition of α-lipoic may be beneficial in reducing the long term complications
of diabetes mellitus. The effects of metformin alone and with combination with α-lipoic acid on
oxidative stress in type 2 diabetes mellitus patients were studied in this study..
Methods: Study was prospective, randomized, single blind type, conducted on type 2 DM patients
attending OPD of Medicine.. After fulfilling inclusion/ exclusion criteria, written informed consent was
taken. Study was according to declaration of Helsinki and approved by research committee. Patients
were randomized to metformin alone or metformin with α-lipoic treatment groups. Therapy was given
for a total duration of 3 months. Blood glucose levels, reduced glutathione levels, Lipid peroxide level,
and total antioxidant activities in blood were measured on day 0, and after 4,8 and 12 weeks,. Statistical
analysis was done using ANOVA followed by Newmann Keuls post Hoc test and P<0.05 was
considered to be statistically significant.
Results: Reduced glutathione levels and total antioxidant activity increased with time both the groups.
Lipid peroxide level and Blood glucose level (fasting) also decreased when compared to base line
values. All these effects were more in metformin with α-lipoic treated patients as compared to metformin
alone.
Conclusion: Results of the present study indicate that addition of α-lipoic with the antidiabetic drugs
may enhance the ant oxidative stress property of drugs. t patients.
Key words: Oxidative stress, Diabetes mellitus, Metformin, α-lipoic acid
Diabetes mellitus (DM) comprises of group of
metabolic disorders having hyperglycemia. It is
emerging as a pandemic. By the year 2025, three
quarters of the world’s 300 million adults with
diabetes will be in non-industrialized countries and
almost one third in India and China alone.1,2.
Prevalence of type 2 DM is rising much more rapidly
because of altered life style and obesity3,4. Macro and
micro vascular pathognomic changes are main cause
of mortality and morbidity in patients of DM 5.
Evidences have accumulated indicating that
generation of reactive oxygen species (oxidative
stress) may play an important role in etiology of
DM6,7. Many biochemical pathways strictly associated
with hyperglycemia (glucose auto-oxidation, polyol
pathway, prostanoid synthesis, protein glycation) can
increase the production of free radicals. An increased
oxidative stress resulted from enhanced generation of
ROS like superoxide anion (O2-), hydroxyl radical
(OH), H2O2, nitric oxide (NO) and /or depletion of
antioxidants such as superoxide dismutase, catalase,
glutathione peroxidase and reduced glutathione
( GSH) have been implicated in the etiology of the
diseases and associated complications8-11. A common
end point of hyperglycemia dependent cellular
changes is the generation of reactive oxygen
intermediates (ROIs) and the presence of elevated
oxidative stress.
Formation of advanced glycation end products
(AGEs) due to elevated nonenzymatic glycation of
proteins, lipids and nucleic acid is accompanied by
Corresponding author: Dixit Rakesh, Pharmacology; email: [email protected]
16
under hyperglycemic conditions.
•
Pregnant and breast feeding women.
It has been suggested that diabetic subjects with
vascular complications may have a defective cellular
antioxidant response against the oxidative stresses
generated by hyperglycemia. Metformin an older drug
is one of the most commonly prescribed oral
antidiabetic drugs in the world. It is effective in
decreasing insulin resistance.12
•
Patients hypersensitive to metformin or α-lipoic
acid.
Study was prospective randomized single blind in
patients of type 2 DM attending the OPD of medicine
department at C.S.M.M.U, Lucknow. Study was
according to Helsinki’s declaration & approved by
research committee. After fulfilling inclusion and
exclusion criteria, patients were asked for a written
informed consent.
Results
After standardized initial evaluation which includes
complete clinical history, examination, fasting & PP
plasma glucose levels, serum creatinine & lipid profile
patients were randomly divided into four groups and
prescribed treatment according to group for a total
Alpha-lipoic acid (ALA) also known as thioctic acid is duration of 3 months
a natural substance found in certain foods and also Group I- Metformin ( Tab. Glyciphage 500mg twice
produced in the human body. It is a unique vitamin
daily)
like antioxidant which functions both in reduced and
oxidized forms. It is able to scavenge reactive oxygen Group II-Metformin with ALA ( Tab ALA-100)
species13-15.
Blood samples were collected on day 0, and at the end
Some studies have also shown that ALA can improve of 4,8 and 12 weeks for the estimation of blood
insulin sensitivity in type 2 DM patients. However glucose (fasting), reduced glutathione level, total
16-19
.
there are no studies regarding the effects of Metformin antioxidant activity and lipid peroxide levels
on the oxidative stress. And more ever there is no Readings were taken separately at various time
study of ALA in combinations with Metformin. intervals ( 0day, and at the end 4,8 and 12 weeks) as
Therefore present study has been planned to know the mean ± SE and comparisons of individual value
effect of Metformin, alone as well as in combination within the group as well as in between the groups was
with α-lipoic acid on redox status in patients of type 2 done using ANOVA followed by Newmann Keuls
DM.
post Hoc test. P<0.05 was considered to be
statistically significant.
Material and Methods
Inclusion criteria
•
•
•
Type 2 DM patients between 20-60 years of age
Figure 1 shows GSH (reduced glutathione level) in µ
mol/lit in patients. As seen there is no statistically
difference between base line values (day 0) of
metformin alone, and metformin combined with ALA
at 4week. At 8 weeks and 12 weeks duration increase
was significant with metformin with ALA group. The
increase with metformin alone was not significantly
altered at any time intervals.
Figure 2 shows total antioxidant activity. Metformin
Fasting plasma glucose levels between 126-200 alone did not significantly alterted the TAO. Where as
mg/dl
metformin combined with metformin significantly
Post prandial glucose level between 200-300 mg/ increased the anti oxidant activity at 8 week and 12
dl.
week intervals.
Figure 3 shows lipid peroxide levels at various time
intervals. In case of metformin with ALA treated
Patients with clinically significant hepatic, cardiac,
group it was significantly reduced only at 8 and 12
renal disorders.
weeks intervals. Whereas metformin alone was not
Patients with clinically significant diabetic able in reducing LPO levels at any time intervals.
complications.
Exclusion Criteria
•
•
Vasant et al
Oxidative stress in diabetes and metformin
17
oxidative, radical generating reactions and thus represents a major source of oxygen free radicals
Figure 1. GSH (µmol/L) in both groups
1.4
*P<0.05
GSH ( µmol/ l) mean ± SE
1.2
*
*
1
MET
*
0.8
MET + ALA
0.6
0.4
0.2
0
* P,0.05
0 weeks
4 WEEKS
8 WEEKS
12 WEEKS
Duration
Figure 2. TAO (mmoles/ml) in both groups
2.5
TAO ( m moles/ ml) mean ±SE
*P<0.05
2
*
*
1.5
MET
MET + ALA
1
0.5
0
* p,0.05
Vasant et al
0 weeks
4 WEEKS
8 WEEKS
12 WEEKS
Duration
18
Figure 3. LPE (mmol MDA/ml) in both groups
*
*P<0.05
12 WEEKS
*
Duration
8 WEEKS
MET + ALA
*
4 WEEKS
MET
0 weeks
0
*p<0.05
1
2
3
4
5
6
7
8
LPO ( n moles MDA / ml) Mean ±SE
Figure 4. Fasting plasma glucose (mg/dl) in both groups
180
*P<0.05
160
140
120
*
100
MET
Plasma glucose F (mg/dl)
80
MET + ALA
60
40
20
0
0 weeks
4 WEEKS
8 WEEKS
12 WEEKS
Duration
Vasant et al
19
Fig 4 shows plasma glucose levels (fasting). This
shows significant reduction in blood glucose levels in
both groups at each interval. There is significant more
reduction in combination therapy when compared to
the monotherapy at 12 weeks intervals.
we found that in comparison to monotherapy
combination therapy with ALA was more effective in
increasing the reduced glutathione level, total
antioxidant activity and in decreasing the lipid
peroxide levels. It can be confirmed that ALA which
is well known antioxidant has beneficial effects in
Discussion
diabetes mellitus where hyperglycemia is an oxidative
DM comprises of group of common metabolic stress generating condition.
disorders characterized by variable degree of impaired
insulin secretion and insulin resistance. Oral Conclusion
antidiabetic agents like metformin has been widely Present study there fore suggests that ALA despite of
used in clinical practice for decreasing hyperglycemia being an antioxidant has additive in vivo action in
lowering plasma glucose when combined with
in type 2 diabetes mellitus.
There is increasing evidence that in certain pathologic antidiabetic drugs. Combination therapy of
antidiabetic drug and ALA is better than antidiabetic
states especially chronic diseases like diabetes
mellitus oxidative stress due to the increased drug alone in glucose lowering as well as relieving
oxidative stress. In future ALA may have adjuvant
production and /or ineffective scavenging of reactive
oxygen species may play a critical role in role in pharmacological management of diabetes
complications. High reactivity of ROS determines mellitus.
chemical changes in virtually all cellular components, References
leading to enhanced lipid per oxidation of membranes
1. Ramachandran A. Epidemiology of diabetes in
and oxidative injury to proteins, nucleic acids and
India. Three decades of research. J Assoc
other biomolecules 20. It has been suggested that in
Physicians India 2005;53:34-38
diabetes enhanced production of free radicals and
2. Mohan V. Why are Indians more prone to
oxidative stress is the central event to the development
diabetes? J Assoc Physicians India 2004;52:468-74
of complications 21. This raises the concept that an
3. WHO. Obesity. Preventing and managing the
antioxidant therapy along with lowering of the raised
global epidemic; WHO Technical Report Series
blood glucose levels may be of great interest in these
N
o. 894. Geneva: World Health
patients. Moreover, it has been recently suggested that
Organization;2000.
diabetic subjects with complications have a defective
4. Mc Keigue PM, Shah B, Marmot MG. Relation of
cellular antioxidant response against the oxidative
central obesity and insulin resistance with high
stress generated by hyperglycemia, which can
22, 23
diabetes prevalence and cardiovascular risk in
.
predispose the patient to organ failure
Thus this study was planned to determine and
compare the effect of metformin and metformin with α
-lipoic acid on redox status. Regarding blood glucose
lowering effect there is no significant difference
between metformin alone and metformin with α-lipoic
acid treated groups. Both drugs act by two dissimilar
mechanisms which are different from release of
insulin. When combination therapy of metformin with
ALA was compared with monotherapy of metformin
combination therapy reduced blood sugar level more.
These results suggest that addition of ALA strengthens
the hypoglycemic action of antidiabetic drugs. The
effect may be due to effect of ALA on GLUT4
transporters on cell membrane.
In addition redox parameters were also monitored and
Vasant et al
South Asian. Lancet 1991;337:382-6
5. Claudia RL, Gil F., Macro and micro vascular
complications are determinants of increased
mortality, in Brazilian type –II diabetes mellitus
patients. Diab Res clin Pract 2007; 75: 51-58.
6. D Giugliano, A Ceriello and G Paolisso , Oxidative
stress and diabetic vascular complications.
Diabetes Care 2000;14 123-124.
7. Matthew J. Sheetz, George L. King. Molecular
understanding of hyperglycemia's adverse effects
for diabetic complications. JAMA 2002; 288:25792588.
8. S P Wolff, Free radicals, transition metals and
oxidative stress in the etiology of diabetes mellitus
and complications. British Medical Bulletin1993:
49:642-652 .
20
9. David V. Godin ,Saleh A. Wohaieb,Maureen E. Ga
rnett, A. D. Goumeniouk, Antioxidant enzyme
alterations in experimental and clinical diabetes.
Molecular and cellular Biochemistry 1988;84:223231.
10. Baynes J.W. Role of oxidative stress in
development of complications in diabetes. Diabetes
1991; 40:405-412.
11. Antonio C, Sudhesh kumar, Ludovica P, Katerine
E., Dario G, Simultaneous control of
hyperglycemia and oxidative stress normalizes
21. Caimi G, Carollo C and Presti RL. Diabetes
mellitus: Oxidative stress. Curr Med Res
Opinion 2003;19:581-86
22. Baynes J. W and Thorpe S.R. Role of
oxidative stress in diabetic complications: a
new perspective on an old paradigm; Diabetes
1999;48:1-9
23. Brownlee M. Biochemistry and molecular cell
biology of diabetic complications. Nature
2001;414:813-820
endothelial function in Diabetes. Diabetes care
2007; 30: 649-654
12. D.Kirpichnikov,SI McFarlane,JR Sowers,
Metformin for Patients with Type 2 Diabetes
Mellitus. Ann Inter Med 2002;137:1-50
13. Joseph L. Evans, Ira D Goldfine. ά – Lipoic
acid: A multifunctional antioxidant that
improves insulin sensitivity in patients with
type 2 diabetes. Diab Tech Thera 2000;2(3):
14. Packer L, Witt EH, and Tritschler HJ, AlphaLipoic acid as a biological antioxidant. Free
Radic Biol Med 1995; 19: 227-250
15. Biewenga GP Haenen GRMM Bast A, The
pharmacology of the antioxidant lipoic acid.
Gen Pharmacol 1997;29: 315-331
16. Trinder P, Determination of glucose in blood
using glucose oxidase with alternative oxygen
acuptor. Ann clin Biochem1996;6:12-15.
17. Kazuo Asaoka and Kenji Takahashi. An
enzymatic assay of reduced glutathione using
glutathione S-Aryltransferase with Odinitrobenzene as a substrate. J Biochem
1981;90:1237-42
18. Koracevic D, Koracevic G, Djordjevic V,
Andrejevic S, Cosic V. Method for
measurement of antioxidant activity in human
fluids. J clin. Pahol, 2001;54: 356-61.
19. Ali B, Walford RL and Imamura T. Influence
of aging and ploy IC treatment on xenobiotic
metabolism in mice. Life Sciences 1985;37:
1387-93
20. Betteridge DJ. What is the oxidative stress?
Metabolism 2000;49 (suppl1):13-18
Vasant et al
21
Innovations
Training Postgraduate Pharmacology Students in a Medical College in
Western Nepal
Shankar Ravi P
Department of Pharmacology, Manipal College of Medical Sciences, Pokhara, Nepal
Abstract
The Manipal College of Medical Sciences, Pokhara, Nepal is affiliated to the Kathmandu University for
the undergraduate medical course. Since 2004, the college is also admitting students to the Master’s
course in various basic science subjects. The MSc Medical Pharmacology course is of two years duration
and emphasizes self-learning by the students. Postgraduate (PG) seminars are regularly conducted.
The PGs act as facilitators during the undergraduate problem stimulated learning (PSL) sessions. The
PGs also work in the drug information and pharmacovigilance center and the medication counseling
center run by the department in the teaching hospital. They play the role of simulated patients during
communication skills learning and assessment.
Microteaching sessions for lectures and PSL sessions are conducted. Both formative and summative
evaluation is carried out. In the University examination there are three theory papers with multiple
choice questions and short answer questions. Various exercises are carried out during the three day
practical examination. Simulated animal experiments are carried out. The PG theses are carried out in
the topic of Pharmacoepidemiology and Drug Safety. The department has been successful in training
PGs to be effective teachers of Pharmacology in a Nepalese setting.
Key words: Evaluation, Nepal, Pharmacology, Postgraduates, Simulated patients
Nepal is a small, mountainous developing country in
South Asia sandwiched between two Asian giants,
China and India. Nepal measures around 500 km in
breadth and 200 km in length and is famous as the
land of the Buddha and of Mt. Everest, the highest
mountain on Earth. Recently a number of medical
schools have been opened in the private sector. The
Nepalese pharmaceutical industry is also growing and
there are more than 38 Nepalese manufacturers and
they together meet around 34% of the domestic
demand for drugs.1
The MSc medical pharmacology course at
MCOMS: The course is of two years duration and
aims to produce teachers for medical colleges. Three
students have completed the course so far. The
students had joined the course after completing their
BPharm degree. A problem noted was that the
students did not have adequate knowledge of other
basic science subjects when they joined the course. To
overcome this lacuna, the University has started has
started a Bachelor’s course in Human Biology at its
campus in Dhulikhel. Students will henceforth be
Manipal College of Medical Sciences, the first admitted to the MSc course only after completing the
medical college in the private sector in Nepal was Human Biology course.
started in 1994.2 In 2005, there were a total of twelve Learning and activities during the course
medical schools in Nepal.2 The college admits 150
The postgraduate (PG) course emphasizes selfstudents to the undergraduate medical (MBBS) course
learning by the students. Various topics in General and
in two batches of 75 students each in February and
Systemic Pharmacology are covered in the form of PG
August.
seminars. A partial list of topics covered during the
Corresponding author: Ravi Shankar, Pharmacology; email: [email protected]
22
seminars is shown in Table 1. The seminar is of one
hour duration and is followed by a discussion. The
PGs can use overhead projector, LCD projector and
the blackboard as aids during the seminar. The faculty
members of the department attend the seminar and
evaluate the PG presenter. The criteria followed
during the evaluation are organization of the
presentation, the delivery, quality of the audiovisual
material used, coverage of the topic, mentioning
relevant references and further reading at the end of
the presentation and suggesting areas for further
research.
The PGs act as facilitators during the undergraduate
problem stimulated learning (PSL) sessions. The PGs
thus become familiar with organizing and facilitating
the PSL sessions. Communication skills, Personal or P
-drug
selection,
calculating
World
Health
Organization (WHO)/International Network for
Rational Use of Drugs (INRUD) drug use indicators,
studying common drug use problems in Nepal and
constructing a problem-analysis diagram are some of
the sessions carried out for the MBBS students. In
addition, we in the department teach critical analysis
of drug advertisements and disease mongering to the
undergraduates. The students are taught about
spontaneous adverse drug reaction (ADR) reporting
and have to design a spontaneous ADR reporting form
as a group activity.3 Student learning takes place in
small groups during the pharmacology practical
sessions.4 In addition to acting as facilitators the PGs
are taught how to assess the undergraduates (formative
assessment) during the sessions.
The department runs a drug information center (DIC),
a regional pharmacovigilance center and a medication
counseling center (MCC) in the teaching hospital and
the PGs are actively involved in these activities. The
PGs learn to answer drug queries using the various
information resources available in the DIC. They also
learn to record spontaneous ADR reports by health
personnel and also visit the wards and the medical
records department to obtain further patient
information. They play an active role in the
pharmacovigilance programme5 and are learning to
report ADRs using Vigiflow, the WHO database.
Recently, the postgraduate students are playing the
role of simulated patients during communication skills
learning and assessment.6 They have gained
Shankar
experience of assessing student communication skills
using a structured checklist.
The PGs are posted for three months in various
specialties in the teaching hospital as recommended by
the Kathmandu University.7 They are expected to
know the common diseases prevalent and their
management. This knowledge will be important in
their future career as medical teachers. The PGs are
posted for fifteen days in Medicine, Surgery,
Obstetrics and Gynecology and Pediatrics and for a
week
in
Anesthesia,
Ophthalmology,
Otorhinolaryngology and Dermatology.
Microteaching sessions during the course
The PGs conduct four lectures and facilitate two PSL
sessions during the course. The faculty members
assess the PGs during these sessions. The assessment
criteria used are shown in Table 2.
Formative evaluation
Table 3 shows the various activities carried out by the
postgraduate students. Formative evaluation is based
on performance during the various activities. PGs
maintain a log book. This assessment provides proper
feedback to the students regarding their performance.
The grading system recommended by the Kathmandu
University (KU) is as follows: Grade A- Excellent,
Grade B- good, Grade C- satisfactory, Grade D-poor
and Grade E- very poor. Grade C and above is
required for appearing for the University examination.
Summative evaluation
Both the theory and the practical sections of the
examination carry 300 marks each. The student must
get 60% of marks separately in theory and practical to
pass the examination. There are three theory papers.
Paper I deals with general pharmacology and basic
and applied sciences. Paper II concerns itself with
experimental pharmacology and biometrics while
paper III deals with systemic pharmacology and recent
advances. Each paper has two sections. Section A
consists of 50 single response multiple choice
questions (MCQs) while section B has ten short
answer questions. The time allotted for section A is
one hour while for section B the student gets two
hours.
Postgraduate pharmacology training
23
Table 1. Selection of topics covered during the postgraduate seminars in pharmacology
Central nervous system:
Antipsychotics
Antidepressant and antimanic drugs
Drugs used to treat Parkinson’s disease
History of pharmacology:
History of Classical pharmacology
Foundations of experimental pharmacology
Pharmacology in the twentieth century
Autonomic pharmacology:
The therapeutic implications of the autonomic nervous system part I
The therapeutic implications of the autonomic nervous system part II
Autacoids
Antimicrobials:
Beta lactam antibiotics
Aminoglycosides and macrolides
Drugs used for mycobacterial infections
Antiretroviral drugs
Anticancer drugs:
Opioids
NSAIDs (Non Steroidal Anti Inflammatory Drugs)
Treatment of diarrhea and dysentery
Treatment of type 1 diabetes
Treatment of type 2 diabetes
Cardiovascular system:
Nitric oxide
Antiarrythmic drugs
Management of hypertension
Other topics:
Essential medicines
Problem based learning of pharmacology
Drug discovery and development
Access to medicines in Nepal
Shankar
24
Table 2. Assessment criteria followed for the microteaching sessions
Criteria
Organization & planning
Presentation
Selection of problems
Quality of audiovisual material
Facilitating group dynamics
Coverage of topic
Ensuring student participation
Sticking to the time frame
Giving references and suggestions for
further reading
Adding to the student presentations
Question answer sessions
Total marks
Session
Lecture (marks allotted) PSL (marks allotted)
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
40
5
40
PSL- Problem Stimulated Learning
Table 3. Various activities carried out by the postgraduate pharmacology students
1.
2.
3.
4.
Attending clinical postings in the various clinical departments
Presenting and attending postgraduate seminars
Microteaching sessions (lectures and Problem Stimulated Learning sessions)
Playing the role of facilitators during Problem Stimulated Learning sessions for
the MBBS students
5. Working and answering queries in the drug information center
6. Being involved in the activities of the pharmacovigilance center
7. Playing the role of simulated patients during communication skills learning and
assessment
8. Helping with the smooth conduct of the undergraduate examinations
9. Conducting research projects with the help of the faculty members
10. Contributing articles to the Drug information bulletin and other journals
11. Carrying out activities related to the thesis
12. Carrying out simulated experiments using the computer aided learning software
package
Shankar
25
Table 4. Various activities carried out by the postgraduate pharmacology students
Topics
Personal drug (P-drug)
P-drug selection for a condition
Verifying suitability of selected P-drug for a given patient
Writing the prescription
Microteaching sessions
Lecture
PSL
Critical analysis of a published clinical trial
Critical analysis of drug promotional material
Calculating WHO/INRUD drug use indicators
Constructing a problem-analysis diagram
Practical exercises using CAL CD-ROM (two exercises)
Spotters
Clinical problems (two problems)
Role play on drug promotion
Assessing the quality of health information on the internet
Analyzing rationality of a given prescription
Total
Marks allotted
30
15
7.5
7.5
30
15
15
15
15
20
20
30
20
20
15
15
10
240
PSL- Problem Stimulated Learning, WHO- World Health Organization, INRUD- International Network for
Rational Use of Drugs,
safety. Satisfactory completion of the thesis is
necessary before the students can appear for the
Personal drug selection, microteaching sessions,
critical analysis of a published clinical trial and of examination.
drug promotional material and calculating drug use The PGs have also been involved in other research
indicators are some of the exercises carried out. The studies. They have written review articles on
practical examination carries 240 marks and the list of medicines and have published papers in both national
exercises with their marks distribution is shown in and international journals. They frequently contribute
Table 4. Sixty marks of the theory viva-voce are articles to the quarterly Drug Information Bulletin
added to the practicals. The University practical published by the department.
examination is carried out over a period of three days.
Animal experiments
Postgraduate thesis
The students had attended a month long training
University practical examination
The postgraduate students have done their theses on
‘Adverse drug reactions caused by antitubercular
drugs in a DOTS clinic’, ‘Utilization of injectable
preparations among hospital inpatients’ and ‘An
educational intervention to reduce drug-drug
interactions in the internal medicine ward’. Keeping in
mind, the focus of the department to promote the more
rational use of medicines, the topics selected were
concerned with pharmacoepidemiology and drug
Shankar
session on animal experiments in Pharmacology at the
Kasturba Medical College in Manipal, India. They
maintained a practical record book during the course.
In the University examination, the PGs have to carry
out simulated animal experiments on the computer
using the software developed by Dr. Raveendran and
others at the Jawaharlal Institute of Postgraduate
Medical Education and Research (JIPMER),
Pondicherry, India.
26
Overview of the training
The course in pharmacology for medical
undergraduates should equip the students with the skill
necessary to use essential medicines rationally.8
Pharmacologists have an important role in teaching
rational therapeutics. The department at MCOMS has
been successful in familiarizing PGs with the concept
of rational use of medicines. The PGs have become
capable of conducting small group, PSL sessions and
have obtained knowledge of common drug use
problems in Nepal.
8. Shankar PR. Pharmacology –A central
department in South Asian medical schools?
Pharmacology online Newsletter 2006; 1: 1-5.
Thus the department has been reasonably successful in
training postgraduate students to be successful
teachers of pharmacology in a Nepalese setting. The
training programme should be continued and
strengthened.
References:
1. Dixit H. Nepal’s quest for health. Third
edition. Educational publishing house,
Kathmandu: 2005.
2. Shankar PR, Mishra P, Dubey AK. Modern
medical education in Nepal. Clin Teacher
2006;3: 65-8.
3. Shankar PR, Subish P. Designing a
spontaneous adverse drug reaction reporting
form: An exercise for medical students. Int J
Risk Saf Med 2006; 18: 115-9.
4. Shankar PR, Dubey AK, Mishra P, Upadhyay
D, Subish P, Deshpande VY. Student feedback
on problem stimulated learning in
pharmacology-a questionnaire based study.
Pharmacy Edu 2004; 4: 51-6.
5. Shankar PR, Subish P, Mishra P, Dubey AK.
Teaching pharmacovigilance to medical
students and doctors. Indian J Pharmacol 2006;
38: 316-9.
6. Shankar PR, Subish P, Dubey AK, Mishra P.
Postgraduate students as simulated patients in
communication skills learning and assessment.
Pharmacy Education 2006 ;6: 157-9.
7. Curriculum Master of Sciences in
Pharmacology MSc Pharmacology (Medical)
Kathmandu University, Dhulikhel: 2002.
Shankar
27
Innovations
Letrozole – Infertility an Indication
Matreja S Prithpal
Department of Pharmacology, Gain Sagar Medical College, Ramnagar, District Patiala, Punjab 140601, India
Abstract
Letrozole, an aromatase inhibitor has been approved for the treatment of breast cancer either as an
adjuvant or advanced cases. Letrozole has given encouraging result in ovulation. Letrozole has given a
comparable result like clomiphene for induction of ovulation in patient of infertility. Letrozole has
also been found to induce ovulation in patient who do not respond to clomiphene citrate. In near future
Letrozole might be one more option for induction of ovulation
Key words: Swine flu, Oseltamivir, Children
Letrozole is a third generation, oral, non-steroidal
potent and highly specific aromatase inhibitor.
Letrozole inhibits the aromatase enzyme by
completely binding competitively & reversibly to
the heme of the cytochrome P450 subunit of the
enzyme, resulting in the reduction of estrogen
biosynthesis in all tissues.1 Letrozole is indicated
for adjuvant treatment of postmenopausal women
with hormone receptor-positive invasive early
breast cancer, treatment of early invasive breast
cancer in postmenopausal women who have
received prior standard adjuvant tamoxifen therapy,
first-line treatment in postmenopausal women with
advanced breast cancer, treatment of Advanced
breast cancer in postmenopausal women in whom
tamoxifen and other anti-estrogen therapy has
failed2.
aromatase inhibitor in the early follicular phase, the
negative feedback of estrogen is removed and
gonadotropin secretion is indirectly increased from
the pituitary, thus successfully stimulating follicular
growth3. By reducing circulating estradiol levels,
aromatase inhibitors have been used to treat
endometriosis,
estrogen
responsive
cancers,
leiomyomata uteri, as well as to induce ovulation.
Primate studies have demonstrated that administration
of aromatase inhibitors during the follicular phase
results in the development of mature follicles which,
when coupled with hCG could be shown to ovulate 4.
It is hypothesized that letrozole administration in the
early part of the menstrual cycle would release the
pituitary/ hypothalamic axis from estrogenic
feedback3 and improves in vitro fertilization outcome
in low responder patients1.This effect is quite similar
to clomiphene citrate but depletion of endometrial
Letrozole for Ovulation
and cervical mucus is not seen with Letrozole. The
Aromatase is good target for selective inhibition estradiol level during ovarian induction is
because estrogen production is the terminal step in significantly lower with other protocols3.
biosynthetic sequence. Aromatase inhibitors, in the
The use of letrozole during pregnancy has been
ovary, increase follicular sensitivity to Follicular
shown to cause birth defects in animal studies,
Stimulating Hormone (FSH). The conversion of
prompting the Food and Drug Administration
androgen substrate to estrogen is blocked, resulting in
warnings.4 Novartis reviewed its safety database and
accumulation of intraovarian androgens. This
found 13 reports of pregnant women receiving the
stimulates insulin like growth factor – I (IGF-I),
drug worldwide, contrary to its warning label. Of
which along with other endocrine and paracrine
those 13, at least two had miscarriages and two had
factor, synergises with FSH to promote
children with birth defects, Fox said. It was not clear
folliculogenesis. By a short-term administration of
how many of these women were given the drug to
Corresponding author: Matreja, Assistant Professor, Pharmacology; e-mail: [email protected]
28
increase their fertility as opposed to some other
reason. Health Canada, the country's health care
agency, issued the warning jointly with Novartis to
fertility specialists, gynaecologists and obstetricians “it is aware that Femara is being used to stimulate
ovulation in women who are infertile, or unable to
become pregnant, as a treatment to increase their
chances of becoming pregnant". The drug "should not
be used in women who may become pregnant, during
pregnancy and/or while breast-feeding, because there
is a potential risk of harm to the mother and the fetus,
including risk of fetal malformations", the company
said2.
Since that initial report, however, several full-length
studies have not shown an increased risk for
congenital malformations following the use of
letrozole to induce ovulation. A study examined
babies born to mothers who had used letrozole to
conceive, and compared them with babies born to
mothers who had conceived using clomiphene citrate.
There were no increased rates of major and minor
malformations beyond what would be expected in the
general population. Additionally, the number of
cardiac anomalies in the letrozole group was slightly
lower than that of the general population1,4 Recently,
another study was conducted comparing pregnancy
outcomes among women using letrozole to induce
ovulation to age- and disease-matched controls.
Pregnancy outcomes of women who used letrozole or
clomiphene citrate to become pregnant and women
who conceived spontaneously were examined. There
were no differences in the rates of major
malformations among the 3 groups. Moreover, no
major malformations were observed in the offspring
born to mothers who had conceived using letrozole.
Other pregnancy outcomes, including gestational age
at birth, birth weight, and maternal age at birth, were
not substantially different among the groups. When
birth weight centiles were examined, babies born to
mothers who had conceived using clomiphene citrate
were found to be of lower birth weight than would be
expected for their gestational age4
Recent studies used this rationale to compare letrozole
with Clomiphene Citrate in patients who failed to
ovulate with Clomiphene Citrate alone or ovulated
with Clomiphene Citrate but had inadequate
Matreja
endometrial development 4.
Furthermore, there tends to be an enhanced uterine
environment with the use of letrozole , which may be
relevant especially in those that have not been able to
conceive with Clomiphene Citrate. Adding to our
experience, yet another group demonstrated that when
coupled with human menopausal gonadotropins,
letrozole decreased the requirement of human
menopausal gonadotropins to achieve follicular
maturity3,5.
Letrozole is a drug which could be used to Induce
ovulation in patients who do not respond to
Clomiphene citrate, this could be a new indication for
use of Letrozole as all the studies conducted to date
have shown that the chances of birth defect is less as
compared to Clomiphene & may be even lower then
normal pregnancy. Even the number of follicles
maturing is less as compared to Clomiphene. So, it can
be said that there is hope for infertile population.
Letrozole when used for patients with endometrial
cancer had lower Estrogen surge and is used for these
young women to preserve their fertility5 .Letrozole has
also been successfully used to induce ovulation in
women who do not respond to Clomiphene citrate,
Letrozole has high pregnancy rate as compared to
Clomiphene1,6
Chronic anovulation with estrogen presence can occur
in women with Polycystic Ovarian Disease (PCOD)
and other functional abnormalities, including those
with
Cushing
syndrome,
hyperthyroidism,
hypothyroidism, late –onset adrenal hyperplasia
resulting from 21-hydroxylase deficiency, 11-alphahydroxylase deficiency, or 3-beta-hydroxysteroid
dehydrogenase deficiency1.
Other uses: Superovulation and Intra Uterine
Insemination (IUI) with letrozole and clomiphene
citrate are associated with similar pregnancy rates, but
the miscarriage rate is higher with Clomiphene
Citrate.
It can be combined with FSH and reduces the dose of
gonadotropin required for controlled ovarian
hyperstimulation. It also appears to constitute a good
alternative to Clomiphene Citrate in patients with
unexplained infertility undergoing gonadotropinstimulated COH cycles combined with IUI therapy.
Letrozole in ovulattion
29
Oral administration of the aromatase inhibitor
letrozole is effective for ovulation induction in
anovulatory infertility and for increased follicle
recruitment in ovulatory infertility. Letrozole appears
to avoid the unfavorable effects on the endometrium
frequently seen with antiestrogen use for ovulation
induction. In clomiphene-resistant PCOD patients, the
combination of letrozole and metformin leads to
higher full-term pregnancies. A letrozole –FSH
combination could be an effective ovarian stimulation
protocol in IUI cycles. Such a protocol may be more
cost-effective than FSH alone because of the
difference of FSH dose and cost1.
Studies have shown that letrozole appears to be a good
alternative for those patients who do not respond to
Clomiphene citrate; it has shown good result in
PCOD. The fetal outcome with letrozole in terms of
congenital malformation is like that of normal
pregnancy. To summarize it can be said that letrozole
is one of the drugs of choice for ovulation induction
References:
1. Sharma JB. Role of Letrozole in Ovulation
Induction. AOGD Bulletin 2007; 7:8.
2. Novartis Pharmaceuticals UK Ltd. Femara.
Summary of Product characteristics, 2005
3. Selvaraj K, Selvaraj P. Comparison of Clomiphene
citrate and letrozole for ovulation induction and
resultant pregnancy outcome. J Obstet Gynecol Ind
2004: 54 ; 579-82
4. Gill SK, Moretti M, Koren G. Is the use of letrozole to
induce ovulation teratogenic? Le Médecin de famille
Canadian 2008; 54: 353-4
5. Azim A, Oktay K. Letrozole for ovulation induction
and fertility preservation by embryo cryopreservation
in young women with endometrial carcinoma. Fertil
Steril 2007;88:657-64.
6. Quintero RB, Urban R, Lathi RB, Westphal LM,
Dahan MH. A comparison of Letrozole to
Gonadotropins for ovulation induction, in subjects who
failed to conceive with Clomiphene citrate. Fertil Steril
2007;88:879-85.
Matreja
Letrozole in ovulattion
30
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Annexure I
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“_________________________________________________________________________” here by
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journal or magazine for private or public circulation. We are fully aware of what plagiarism is.
No part of this manuscript (referenced or otherwise) has been copied verbatim from any source.
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this work is significant enough to qualify for authorship.
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Author's Name
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Attach a scanned copy when submitting manuscript. Email to: [email protected],
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Send the original by post to:
Dr. Dinesh Badyal
Editor, The Clinical Researcher
Professor & Head, Department of Pharmacology
Christian Medical College, Ludhiana-141008 (Punjab)
35
Annexure II
EXAMPLES OF REFERENCES
Articles in Journals
1. Standard journal article
Less than six authors: List all authors
Halpern SD, Ubel PA, Caplan AL. Solid-organ
transplantation in HIV-infected patients. N Engl J Med
2002 Jul 25;347:284-7.
More than six authors: List the first six authors followed by
et al.
Rose ME, Huerbin MB, Melick J, Marion DW, Palmer
AM, Schiding JK, et al. Regulation of interstitial excitatory
amino acid concentrations after cortical contusion injury.
Brain Res 2002;935:40-6.
Optional addition of a database's unique identifier for the
citation:
Halpern SD, Ubel PA, Caplan AL. Solid-organ
transplantation in HIV-infected patients. N Engl J Med
2002 Jul 25;347:284-7. PubMed PMID: 12140307.
Forooghian F, Yeh S, Faia LJ, Nussenblatt RB. Uveitic
foveal atrophy: clinical features and associations. Arch
Ophthalmol 2009 Feb;127:179-86. PubMed PMID:
19204236; PubMed Central PMCID: PMC2653214.
Optional addition of a clinical trial registration number:
Trachtenberg F, Maserejian NN, Soncini JA, Hayes C,
Tavares M. Does fluoride in compomers prevent future
caries in children? J Dent Res 2009 Mar;88:276-9. PubMed
PMID: 19329464. ClinicalTrials.gov registration number:
NCT00065988.
2. Organization as author
Diabetes Prevention Program Research Group.
Hypertension, insulin, and proinsulin in participants with
impaired glucose tolerance. Hypertension 2002;40:679-86.
3. Both personal authors and organization as author (List
all as they appear in the byline.)
Vallancien G, Emberton M, Harving N, van Moorselaar RJ;
Alf-One Study Group. Sexual dysfunction in 1,274
European men suffering from lower urinary tract
symptoms. J Urol 2003;169:2257-61.
Margulies EH, Blanchette M; NISC Comparative
Sequencing Program, Haussler D, Green ED. Identification
and characterization of multi-species conserved sequences.
Genome Res 2003 Dec;13:2507-18.
4. No author given
21st century heart solution may have a sting in the tail.
BMJ 2002;325:184.
5. Article not in English
Ellingsen AE, Wilhelmsen I. Sykdomsangst blant medisinog jusstudenter. Tidsskr Nor Laegeforen 2002;122:785-7.
Norwegian.
Optional translation of article title (MEDLINE/PubMed
practice):
Ellingsen AE, Wilhelmsen I. [Disease anxiety among
medical students and law students]. Tidsskr Nor
Laegeforen 2002 Mar 20;122:785-7. Norwegian.
6. Volume with supplement
Geraud G, Spierings EL, Keywood C. Tolerability and
safety of frovatriptan with short- and long-term use for
treatment of migraine and in comparison with sumatriptan.
Headache 2002;42 Suppl 2:S93-9.
7. Issue with supplement
Glauser TA. Integrating clinical trial data into clinical
practice. Neurology 2002;58(12 Suppl 7):S6-12.
8. Volume with part
Abend SM, Kulish N. The psychoanalytic method from an
epistemological viewpoint. Int J Psychoanal 2002;83(Pt
2):491-5.
9. Issue with part
Ahrar K, Madoff DC, Gupta S, Wallace MJ, Price RE,
Wright KC. Development of a large animal model for lung
tumors. J Vasc Interv Radiol 2002;13(9 Pt 1):923-8.
10. Issue with no volume
Banit DM, Kaufer H, Hartford JM. Intraoperative frozen
section analysis in revision total joint arthroplasty. Clin
Orthop 2002;(401):230-8.
11. No volume or issue
Outreach: bringing HIV-positive individuals into care.
HRSA Careaction. 2002 Jun:1-6.
12. Pagination in roman numerals
Chadwick R, Schuklenk U. The politics of ethical
consensus finding. Bioethics. 2002;16:iii-v.
13. Type of article indicated as needed
Tor M, Turker H. International approaches to the
prescription of long-term oxygen therapy [letter]. Eur
Respir J 2002;20:242.
Lofwall MR, Strain EC, Brooner RK, Kindbom KA,
Bigelow GE. Characteristics of older methadone
maintenance (MM) patients [abstract]. Drug Alcohol
Depend 2002;66 Suppl 1:S105.
14. Article containing retraction
Feifel D, Moutier CY, Perry W. Safety and tolerability of a
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38
News
ANNUAL CONFERENCE OF CLINICAL RESEARCH BOARD
6-7th November 2010 New Delhi
EMERGING TRENDS AND CHALLENGES
IN
CLINICAL RESEARCH
WHO SHOULD ATTEND:
Participants having affiliation to hospitals, medical, pharmacy, biotechnology institutions
contract research organizations, site management organizations, independent clinical
research firms, pharmaceutics and biotechnology companies, clinical research education &
training centres.
•Clinical research investigators
•Clinical research coordinators
•Clinical research associates
•Clinical research project managers
•Clinical research administrators
•Clinical research consultants
•Clinical research educators
•Clinical research students
•Post graduate students in Medicine, Pharmacology, Pharmacy and life sciences looking for a
career in clinical research
Pre conference workshop
5th November 2010 NEW DELHI
Clinical Research Methodology & Management
This workshop has been developed to provide overview of clinical research process with a
comprehensive review of ICH GCP, Site Management, Ethical concerns, USFDA, Schedule Y and the
elements involved in coordinating a Clinical Research.
Who Should Attend?
• Graduates & Post Graduates in Pharmaceutical, Medical, Dental and Life science looking for a
career in clinical research
• Relevant working professional in the field of clinical research industry
For Registration & Information Please Contact: [email protected]
39
News
MCRB (Membership Clinical Research Board)
Criteria for membership
•
•
•
•
•
Post graduates in Health sciences MD,MS, PhD or equivalents with relevant thesis/research work in
clinical research/clinical trials
Graduate in Health sciences (MBBS/BDS/BAMS/BHMS/BUMS/BVSc) or equivalents with one year
experience in clinical research/clinical trials
Post Graduate in Pharmacy (MPharm) or equivalents with one year experience in clinical research/
clinical trials
Graduate in allied health sciences (BPharm/BMLT/BScMLT/BPT/BMIT/BScMIT/BHIA/BScHIA/BSc
Pathology/BSc Radiology) or equivalents with two year experience in clinical research/clinical trials
Graduate in life Sciences BSc (Biotechnology/Botany/Zoology/Microbiology/Chemistry/Nursing/Home
Science/Food & Nutrition with five year experience in clinical research/clinical trials
Note: The decision of membership scrutiny council Clinical Research Board shall be final and abiding for granting the
MCRB status
Benefits of membership Clinical Research Board
• Certificate of Membership of Clinical Research Board (Data base of MCRB is searchable & updated
monthly)
• Membership of Clinical connects you to other members through participation in clinical research
education & training activities via various workshops, conferences, E-learning programs, seminars and
symposia
• Life time online full-text access to ‘The Clinical Researcher’ the official journal of CRB
• Reduced registration fees for CRB meetings, workshops, seminars and conferences
• Clinical research resources : submit a wide variety of documents and resources useful for clinical research
community
Clinical Research Networking: e-Forums discuss topics of your interest with other members in shared
interest areas of clinical research
Membership fee (life)
Indian Nationals US $ 25(1200 INR)
Others
US $ 100
Mode of payment
The cheques/demand drafts/money orders should be in favour of Clinical Research Board, payable at New
Delhi. Send completed membership forms, updated CV (curriculum vitae) and testimonials/credentials via post
at CRB haed office New Delhi
CRB address:
Head office Clinical Research Board
D-61/3, Second Floor Near Samsung Plaza
Laxmi Nagar Metro Station Laxmi Nagar New Delhi
www.crboard.org mail: [email protected]
40
News
CMCL-FAIMER REGIONAL INSTITUTE,
CHRISTIAN MEDICAL COLLEGE, LUDHIANA
MEDICAL EDUCATION FELLOWSHIPS-2011
A joint venture of Christian Medical College, Ludhiana, India &
Foundation for Advancement of International Medical Education and Research, Philadelphia, USA
The CMCL-FAIMER regional Institute's Fellowship is a two-year fellowship
program designed for Indian medical school faculties who have the potential to
play a key role in improving medical education at their institutes. The program is
uniquely designed to teach education methods and leadership skills, as well as
to develop strong professional bonds with other medical educators. The
fellowship is now running in its sixth year. Twenty fellowships are on offer for the
year 2011. Limited funding is available to support fellows’ travel, local expenses
and course fee.
The application process is online at https://faimeronline2.ecfmg.org/
For details, please visit our websites:
http://cmcl.faimerfri.org/
Important dates
Application open: June 1, 2010
Applications close: September 1, 2010
First session of 2011 fellowship: February 1-7, 2011
Dr. Tejinder Singh
Program Director
Dr. Dinesh Badyal
Secretary
41
Head Office
Clinical Research Board D-61/3 2nd Floor
Near Laxmi Nagar Metro Station & Samsung Plaza, Delhi– 110092
Regional office
58 Windsor Drive, Pine Brook, NJ, 07058, USA
www.crboard.org
mail:[email protected]

the clinical researcher - Clinical Research Board

Transcription

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