CLINICAL SAFETY AND EFFICACY OF DHATRI LAUHA (A

Transcription

CLINICAL SAFETY AND EFFICACY OF
DHATRI LAUHA (A CLASSICAL AYURVEDIC
FORMULATION) IN IRON DEFICIENCY
ANAEMIA (PANDU ROGA)
CENTRAL COUNCIL FOR RESEARCH IN AYURVEDA AND SIDDHA
Department of AYUSH, Ministry of Health & Family Welfare, Government of India
J.L.N.B.C.E.H.Anusandhan Bhavan, 61-65, Institutional Area,
Opp. D-Block, Janakpuri, New Delhi – 110 058
Publisher :
Central Council for Research in Ayurveda and Siddha
Department of AYUSH, Ministry of Health & Family Welfare, Government of India
J.L.N.B.C.E.H.Anusandhan Bhavan, 61-65, Institutional Area
Opp. D-Block, Janakpuri, New Delhi - 110 058
E-mail : [email protected], Website : www.ccras.nic.in
© Central Council for Research in Ayurveda and Siddha, New Delhi
2010
ISBN : 978-81-907420-2-3
Cover Page design:
Dr. N. Srikanth, Assistant Director (Ayurveda)
Dr. M.M. Sharma, Research Officer (Ayurveda)
Cover Page Photo:
Amalaki, Guduchi, Madhuyashti
Printed at : Pearl Offset Press Pvt. Ltd., 5/33, Kirti Nagar Industrial Area, New Delhi-110 015.
Ph. : 25159312, 9899822992
CONTRIBUTORS
CHIEF EDITOR
Prof. G. S. LAVEKAR
Director General
CCRAS, Department of AYUSH
Ministry of Health and Family Welfare
Government of India
New Delhi
EDITOR
Dr. M. M. Padhi
Deputy Director (Technical)
Government of India
New Delhi
PROJECT COORDINATOR
Dr. N.Srikanth
Assistant Director (Ayurveda)
Government of India
New Delhi
EXPERT REVIEWERS
Dr. Manoranjan Mahapatra
Associate Professor
Department of Hematology
All India Institute of Medical Sciences
New Delhi
Prof. A.K.Sharma
Head of Department
Department of Kaya Chikitsa
National Institute of Ayurveda
Jaipur
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CENTRAL CLINICAL STUDY MONITORING &
COORDINATION
Sh. R.K. SINGHAL
Ex. Statistical Officer
Government of India
New Delhi
Dr. GURUCHARAN BHUYAN
Research Officer (Ayurveda)
Government of India
New Delhi
Dr. BANAMALI DAS
Government of India
New Delhi
Dr. B. VENKATESHWARLU
Government of India
New Delhi
Dr. M.M. SHARMA
Government of India
New Delhi
Dr. B.S. SHARMA
Government of India
New Delhi
Dr. S.K. MEHER
Government of India
New Delhi
Dr. GALIB
Ex. Research Officer (Ayurveda)
Government of India
New Delhi
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CENTRAL MONITORING & COORDINATION
OF
PRE CLINICAL SAFETY AND STANDARDIZATION STUDIES
Dr. S.N.GAIDHANI
Assistant Director (Pharmacology)
CCRAS, Department of AYUSH,
New Delhi
Mr. ARJUN SINGH
Assistant Research Officer (Chemistry)
CCRAS, Department of AYUSH,
New Delhi
Miss. SUMAN KUMARI
Senior Research Fellow (Chemistry)
CCRAS, New Delhi
TECHNICAL SUPPORT AND COMPILATION
Dr. DEEPA MAKHIJA
Central Research Institute (Ayurveda)
New Delhi
Dr. SYED HISSAR
Research Officer (Medicine)
CCRAS, New Delhi
EDITORIAL SUPPORT
Dr. M.M. Rao
Ex. Assistant Director (Ayurveda)
CCRAS, New Delhi
Dr. Sobaran Singh
CCRAS, New Delhi
Dr. Sulochana Bhat
CCRAS, New Delhi
Dr. Sarada Ota
CCRAS, New Delhi
Dr. Prameela Devi
CCRAS, New Delhi
Dr. S.K. Vedi
CCRAS, New Delhi
Dr. Shruti Khanduri
CCRAS, New Delhi
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STATISTICAL SUPPORT
Mr. RAKESH RANA
Statistical Assistant
CCRAS, New Delhi
Dr. RICHA SINGHAL
Senior Research Fellow (Statistics)
CCRAS, New Delhi
PROJECT SENIOR RESEARCH FELLOWS
Dr. SUPRABHAT BHARADWAJ
Senior Research Fellow (Ayurveda),
CCRAS, New Delhi
Dr. BABITA YADAV
Senior Research Fellow (Ayurveda),
CCRAS, New Delhi
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TASK FORCE GROUP
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Task force Group for developing the protocol of Multicentric clinical trial on
Iron deficiency Anaemia
Expert from modern Institute:
1. Dr. Praveen Aggarwal, Addl. Prof. Medicine, AIIMS
2. Dr. M.Mahapatra, Asstt. Prof. Heamatology, AIIMS
Expert from Ayurveda:
1. Dr. S.K.Mishra, Ex. Advisor (Ay.), Deptt. of AYUSH
Expert from CCRAS:
1. Dr. K.D.Sharma, Ex. Deputy Director (Tech.)
2. Dr. D.K.Mishra, Director, Ex. CRI (Ay.) New Delhi
3. Dr. V.K.Lal, Ex. Deputy Director (Pharmacognosy)
4. Dr. R.M.Anand, Ex. A.D. (Ay.)
5. Dr. S.Venu gopal Rao, Ex. A.D. (P.)
6. Dr. N.Srikanth, A.D. (Ay.)
7. Dr. Sobaran Singh, A.D. (Ay.)
8. Dr. A.C.Kar, A.D. (Ay.)
9. Dr. Sulochana, A.D. (Ay.)
10. Sh. R.K.Singal, Ex. S.O
11. Dr. M.K.Jha, Ex. R.O. (Medicine)
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DATA AND SAFETY MONITORING
BOARD
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Data and Safety Monitoring Board (DSMB) for Multicentric clinical trial on
Iron deficiency Anaemia
1. Dr. Y.K. Gupta
Prof. of Pharmacology
All India Institute of Medical Sciences,
Ansari Nagar,
New Delhi- 110029
Chairman
2. Dr. R.N. Gupta
Ex Scientist Emeritus (ICMR)
DG II/287 B, DDA Flats,
Vikas Puri, New Delhi- 110018
Member
3. Dr. S.K. Mishra
Ex Advisor (Ayurveda)
A-604, Tower Apartments,
Swasthya Vihar
Delhi-110092
Member
4. Dr. S.K. Sharma
Advisor (Ayurveda)
Deptt. Of AYUSH
Govt. Of India
Member
5. Mrs. Indira Kambo
Former Dy. Director (ICMR)
Sector, 23A, 4056, HUDA,
Gurgaon
Member
6. Dr. M.M.Padh
Deputy Director (Technical)
CCRAS, New Delhi
Member Secretary
7. Dr. Monoranjan Mahapatra
Associate Professor
Department of Hematology
AIIMS, Ansari Nagar,
New Delhi – 110 029
Special Invite
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PARTICIPATED INSTITUTES
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PARTICIPATED INSTITUTES/ CENTERS/ UNITS
1. Central Research Institute Panchakarma (Ay.) Cheruthuruthy
2. Central Research Institute (Ay.), New Delhi
3. Central Research Institute (Ay.), Bhubneshwar
4. Central Research Institute (Ay.), Lucknow
5. Central Research Institute (Ay.), Jaipur
6. Central Research Institute (Ay.), Gwalior
7. Regional Research Institute (Ay.), Banglore
8. Regional Research Institute (Ay.), Patna
9. Regional Research Institute (Ay.), Gangtok
10. Regional Research Institute (Ay.), Jammu
11. Regional Research Institute (Ay.), Mandi
12. Mahatma Gandhi Institute of Medical Sciences, Wardha
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INVESTIGATORS
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INVESTIGATORS
A. CLINICAL RESEARCH
Dr. P. Madhavikutty
Dr. Ramji Singh
Mr. Tamizh Selvam
Dr. K.K. Pandey
Dr. V.C. Deep
Dr. K.K. Rai
Dr. G. Venkateshwarlu
Dr. S.K. Singh
Dr. Mahadeo Prasad
Dr. Sri Prakash
Dr. Bharati
Dr. Alok Kumar Srivastava
Dr. Rakhee Mehra
Dr. Subhash Singh
Dr. Renu Makhija
Dr. H.M.L. Meena
Dr. D. Sehrawat
Dr. B.R. Meena
Dr. P. Makhija
Dr. Anu Bhatnagar
Dr. Deepa Makhija
Dr. B.N. Sridhar
Dr. P. Srinivas
Dr. H. Pushplatha
Dr. B. Das
Dr. M.K. Chaturvedi
Dr. S.K. Giri
Dr. K.K. Singh
Dr. D.P. Sahu
Dr. Ashok Kumar Panda
Dr. G. Babu
Dr. Krishna Kumari
Dr. L.K. Sharma
Dr. Sunita
Dr. Om Prakash
Dr. Shashidhar H. Doodamni
Dr. (Smt.) M.D. Gupta
Dr. Om Raj Sharma
Dr. U.R. Shekhar Namburi
Dr. D.Ramesh Babu
B. STANDARDISATION
C. PHARMACOLOGY
Dr. Surva Mndal
Dr. S.N. Upadhyaya
Dr. Kalyan Hazra
Dr. Prameela Pant
Dr. Manosi Das
Miss. Suman Kumari
Dr. Maduram V.
Dr. R K Singh
Mrs. Pappa Veerapandian
Dr. Pallavi Deshmukh
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SUPPORTING LABORATORY STAFF
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SUPPORTING LABORATORY STAFF
Mrs. V.N. Saraswathy
Sh. R.P. Singh
Mrs. P.T. Pankajavally
Sh. K.P. Singh
Sh. T.N. Venugopalan
Sh. B.M. Meena
Mrs. E.A. Valsakumari
Sh. Ashok Kumar Malik
Mrs. P.B. Kayarunnisa
Sh. N.V. Asthana
Mrs. Deepa Sharma
Sh. Ravi Chandra
Sh. S.M. Sharma
Sh. Pradeep Kumar
Sh. Shambhu Prasad
Sh. Rajesh Sharma
Sh. Nempal Singh
Sh. B.K. Meena
Sh. Dharamvir Dahiya
Sh. Deshraj
Sh. B.K. Swain
Sh. A.V.N. Sinha
Sh. Dasarathi Das
Sh. R.P. Tiwary
Sh. H.K. Maharana
Mr. K.K. Rakshit
Sh. N.C. Das
Mr. J.J. Singh
Sh. N.K. Rout
Mr. Y.P. Sharma
Mr. Vivek Kaul
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PREFACE
Iron Deficiency Anaemia (which is described under the disease Panduroga in
Ayurveda) is a worldwide problem with the highest prevalence in developing countries.
According to WHO, the prevalence of Anaemia in pregnancy in South East Asia is
around 56%. In India incidence of anaemia in pregnancy has been noted as high as
40-80%. 15%- 22% of maternal mortality has been estimated due to Anaemia during
pregnancy (Source: Health Information of India-2004)
In Ayurveda, detailed description concerning the etiology, pathogenesis, classification
and management of Anaemia (Panduroga) is available .It is observed that the
symptoms found in anaemia are similar with the symptoms that occur in Pandu Roga.
It is also observed that the classical treatments administered in such conditions,
alleviate the symptoms of anaemia without any side effect. The conventional iron
therapy for anaemia is only palliative and associated with side effects on long term use,
leaving a scope for research on alternative modalities.
This monograph is based on the data of multicentric open clinical trial of selected
Ayurvedic drug in iron deficiency anaemia conducted at12 peripheral research institutes
of the Council during 2007 to 2009. The scientific research studies were focussed on
establishing the clinical safety and efficacy of Dhatri Lauha.
The publication of this monograph could be possible with the active involvement,
cooperation and sincere efforts of the Incharges, Investigators and technical/non
technical staff of the participating institutes. I appreciate the efforts made by the officers
and staff of the involved institutes in bringing out this monograph.
The untiring efforts made by Mr. D.G. Nimje (Stenographer) and Mr. Prasanto (DEO)
in bringing out this publication in attractive shape are worth mentioning.
I hope this monograph would receive the attention of academicians, scientists,
physicians, research scholars and students for sustainable utilisation of benefits of
research findings.
(Dr. G S. Lavekar)
Director General
CCRAS
Date
New Delhi
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CONTENTS
Contents
Page No.
Abbreviations
3
Executive summary
5
Hindi
7
English
8
1. Introduction
11
1.1
Background
13
1.2
Demographic Trends
14
1.3
Anaemia-Modern view
15
1.4
Contemporary Trends of Diagnosis and Management
23
1.5
Anaemia – A classical view
24
1.6
Some important Ayurvedic formulations
32
2. Clinical Study
35
2.1
Objectives
37
2.2
Material and methods
37
2.2.1
Criteria for Inclusion
37
2.2.2
Criteria for Exclusion
38
2.2.3
Criteria for Withdrawal
38
2.2.4
Criteria for Assessment
38
2.2.5
Details of recruitment & follow up
38
2.2.6
Trial monitoring and data analysis
39
2.2.7
Laboratory investigations
39
2.2.8
Trial Drug dosage and duration
39
XXXIII
3. Drug Review
41
3.1
Composition of drug
44
3.2
Method of preparation
44
3.3
Important therapeutic uses
44
3.4
Ingredient profile
44
4. Preclinical study
47
4.1
Standardization
49
4.2
Raw ingredients information
58
4.3
Safety/ Toxicity study
67
5. Observation and Results
79
6. Discussion and Conclusion
103
Bibliography
109
List of Tables
113
Annexure I Case Record Forms
117
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ABBREVIATIONS
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ABBREVIATIONS
p-fp-& pjd lafgrk fpfdRlk LFkku
lq-lw-& lqJqr lafgrk lw=k LFkku
lq-m-& lqJqr lafgrk mÙkjrU=k
vk;q- iz-& vk;qosZnizdk'k
WHO – World Health Organization
IDA – Iron deficiency anaemia
Hb - Hemoglobin
RBC – Red Blood Corpuscles/cells
WBC – White Blood Corpuscles /Cells
DLC – Differential Leucocytic Count
PCV – Packed Cell Volume
TC/TLC – Total Leucocytic Count
P- Polymorphs, L – Lymphocyte
E- Eosinophils
M- Monocytes
B- Basophils
ESR – Erythrocyte Sedimentation Rate
Hct- Haematocrit
MCV – Mean Corpuscular Volume
MCH - Mean Corpuscular Hemoglobin
MCHC - Mean Corpuscular Hemoglobin Concentration
RDW –Red Blood Cell Distribution Width
3
TIBC – Total Iron Binding Capacity
SGOT- Serum Glutamic Oxaloacetic Transaminase
SGPT- Serum Glutamic Pyruvic Transaminase
RE – Reticulo Endothelial
IEC – Institutional Ethical Committee
DSMB – Data and Safety Monitoring Board
TLC –Thin Layer Chromatography
HPTLC – High Performance Thin Layer Chromatography
4
EXECUTIVE SUMMARY
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7
EXECUTIVE SUMMARY
The present work consists of the data of multicentric clinical study conducted on Iron
Deficiency Anaemia (Pandu Roga) with an Ayurvedic formulation, Dhatri Lauha. The
objective of current study was to assess the clinical safety and efficacy of Dhatri Lauha
in the patients of Iron Deficiency Anaemia through measurable objective parameters.
This multicentric study was conducted in 12 peripheral research institutes of Central
Council for Research in Ayurveda and Siddha to evaluate the safety and efficacy of
Dhatri Lauha with 45 days of treatment. Prior to clinical study, preclinical studies were
conducted for Dhatri Lauha. The formulation has been standardized by following the
Standard Operating Procedures and evaluated for its safety use / toxicity studies. No
abnormality was seen in any vital organs after administration of Dhatri Lauha at
therapeutic dose level. No significant changes were observed in any of the biochemical
and haematological parameters at therapeutic dose level when compared with controls.
Since no toxic effects were observed in preclinical studies, Council initiated the clinical
trial with Dhatri Lauha.
Total 458 Patients were enrolled in this study out of which 400 patients had
successfully completed the study. It was observed that the prevalence of anaemia was
significantly higher in females than males and maximum patients (57.2%) were either
illiterate or under matriculation. Anaemia was more prevalent in people belonging to
lower socio-economic group (58.25%). Maximum numbers of patients (53.2 %) were
housewives and about 58% patients were non-vegetarian. In females (though having
regular & normal menstrual history) Iron Deficiency Anaemia was more common. In
this study, anaemia was more prevalent in the patients of Vata Pittaja (48.7%) & Pitta
Kaphaja (30.1%) Prakriti.
Clinical study with Dhatri Lauha in the dose of 500mg twice daily after food with
warm water revealed significant improvement in weakness, fatigue, palpitation,
breathlessness and swollen feet at all the subsequent assessment stages, when
compared to baseline. Overall clinical improvement was significantly seen in 77.25%
patients and feeling of well being was observed in 79.75% patients at the end of the
study.
This therapy showed significant effect (p<0.05) in improving the Haemoglobin
percentage, Mean Corpuscular Volume (MCV), Mean Corpuscular Haemoglobin
8
Concentration (MCHC), serum iron and stored iron (Serum Ferritin).
With the administration of Dhatri Lauha, no adverse consequences were observed in
the liver and kidney functions during the study. The drug was well tolerated by the
majority of the patients.
Thus, this study revealed that Dhatri Lauha is safe and significantly increases the
Haemoglobin percentage, Serum Iron and Serum Ferritin along with improved quality
of life in subjects with Iron Deficiency Anaemia
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INTRODUCTION
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CHAPTER-1
INTRODUCTION
1.1 BACKGROUND
Anaemia is a global public health setback affecting both developing and developed
countries with major consequences for human health as well as social and economic
development1. According to WHO regions of Africa and South-East Asia have the
highest risk, where about two thirds of preschool-age children and half of all women
are affected. In numbers, the main burden is concentrated in South-East Asia. Levels
of anaemia are substantial in every state of India, the lowest prevalence of anaemia is
found in Kerala (23 percent) and it is particularly striking in the Eastern Region and in
many of the states of Northeastern Region2. Anaemia is an indicator of both poor
nutrition and poor health1. It occurs at all stages of the life cycle, but is more prevalent
in pregnant women and young children1. Globally, the most significant contributor to
the onset of anaemia is iron deficiency1.
Iron deficiency anaemia (IDA) is the most common nutritional deficiency worldwide.
Iron deficiency can arise either due to inadequate intake or poor bioavailability of
dietary iron or due to excessive loss of iron from the body. The poor bioavailability
of dietary iron is considered to be major reason for widespread iron deficiency.
Women lose a considerable amount of iron in menstruation. Some other factors
leading to anaemia are intestinal parasites (hookworm etc.) and malaria.
Iron deficiency anaemia can cause reduced work capacity in adults and impact motor
and mental development in children and adolescents. There is some evidence that iron
deficiency anaemia affects cognition in adolescent girls and causes fatigue in adult
women. Iron deficiency anaemia may affect visual and auditory functioning and is
weakly associated with poor cognitive development in children.
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According to Ayurveda, Pandu is considered as a specific disease characterized by
pallor of body which strikingly resembles with ‘Anaemia’ of modern science. Detailed
description concerning the etiology, pathogenesis, classification and management of
anaemia (Panduroga) is available in classical literatures of Ayurveda. Correcting
anaemia often requires an integrated approach due to multifactorial nature of this
disease, in order to effectively combat it, the contributing factors must be identified and
addressed. In settings where iron deficiency is the most frequent cause, additional iron
intake is usually provided through iron supplements1. There are many age-old remedies
for the treatment of this condition in Ayurveda.
Current Medical therapy –Prospects
In conventional medicine, various forms of iron viz. Ferrous sulfate, ferrous fumerate,
etc. are commonly prescribed, but these therapies have their noted adverse effects e.g.
nausea, vomiting, abdominal pain, diarrhoea /constipation.
Owing to the gravity of the situation, need is felt for search of safe and effective
Ayurvedic oral preparations to improve the haemoglobin level in iron deficiency
anaemia. Keeping the gravity of the situation and the public health need in view,
Council has initiated scientific studies on Dhatri Lauha, a promising formulation that is
being successfully prescribed by Ayurvedic physicians without any side effects since
centuries.
1.2 DEMOGRAPHIC TRENDS
Anaemia is one of the important public health problems not only in India but also in
most of the south East Asian countries. About 4-16% of maternal death is due to
anaemia. It also increases the maternal morbidity, foetal and neonatal mortality and
morbidity significantly. Anaemia is the most common nutritional problem in the world
and mainly affects women of child-bearing age (especially during pregnancy and
lactation) and young children. Globally 30% of the total world population is anaemic
and half of them are suffering from Iron Deficiency Anaemia. Anaemia in pregnancy is
present in very high percentage in India. Nearly half of the pregnant women in the
1
www.whqlibdoc.who.int
2
www.nfhsindia.org
14
world are estimated to be anaemic: 52% in Non- Industrialized as compared with
23% in industrialized countries. However, according to WHO, the prevalence of
anaemia in pregnancy in south East Asia is around 56%. In India incidence of anaemia
in pregnancy has been noted as high as 40-80%. 15%- 22% of maternal mortality
has been estimated due to anaemia during pregnancy (Source: Health Information of
India-2004)3.
Table 1. Estimated Prevalence of anaemia* (% of total affected population)
Age group
Industrialized
Countries
Non-Industrialized
Countries
Children (0-4 yrs)
20.1%
39.0%
Children (5-14 yrs)
5.9%
48.1%
Pregnant women
22.7%
52.0%
All women (15-59 yrs)
10.3%
42.3%
Men (15-59 yrs)
4.3%
30.0%
Elderly (+ 60 yrs)
12.0%
45.2%
* Iron deficiency Anaemia Assessment, Prevention and Control- A guide for
programme managers, WHO Publication.
1.3 ANAEMIA - MODERN VIEW
Definition
The general definition of anaemia is decrease in normal number of red blood cells
(RBCs) or less than the normal quantity of hemoglobin in the blood . More specifically,
it is the decrease in the concentration of hemoglobin, red blood cell volume, or red
blood cell number.
3
www.who.int/nutrition/publications
15
Signs and Symptoms5
Since hemoglobin normally carries oxygen from the lungs to the tissues, anaemia leads
to hypoxia in organs. Since all human cells depend on oxygen for survival, varying
degrees of anaemia can have a wide range of clinical consequences.
Anaemia goes undetected in many people, and symptoms can be small and vague.
The signs and symptoms can be related to the anaemia itself, or the underlying cause.
Most commonly, people with anaemia report non-specific symptoms of a feeling of
weakness and sometimes poor concentration. They may also report shortness of
breath on exertion. In very severe anaemia, the body may compensate for the lack of
oxygen carrying capability of the blood by increasing cardiac output. The patient may
have symptoms related to this, such as palpitations, angina (if preexisting heart disease
is present), intermittent claudication of the legs, and symptoms of heart failure.
On examination, the signs exhibited may include pallor but this is not a reliable sign.
There may be signs of specific causes of anaemia, eg koilonychia (in iron deficiency),
jaundice (in haemolytic anaemia), bone deformities (in thalassaemia major) or leg ulcers
(in sickle cell disease).
In severe anaemia, there may be signs of a hyperdynamic circulation: tachycardia, flow
murmurs, and cardiac enlargement. There may be signs of heart failure.
Pica, the consumption of non-food based items such as dirt, paper, wax, grass, ice,
and hair, may be a symptom of iron deficiency, although it occurs often in those who
have normal levels of hemoglobin. Restless legs syndrome is more common in those
with iron deficiency anaemia. Chronic anaemia may result in behavioral disturbances in
children as a direct result of impaired neurological development in infants, and reduced
scholastic performance in children of school age.
Less common symptoms may include swelling of the legs, arms, chronic heartburn,
vague bruises, vomiting, increased sweating, and blood in stool.
4
www.medterms.com
5
www.answers.com/topic/anaemia
16
Classification
There are two major approaches: the "kinetic" approach which involves evaluating
production, destruction and loss, and the "morphologic" approach which groups
anaemia by red blood cell size.
Production Versus Destruction or Loss
In the kinetic approach, anaemia is classified into three categories viz. Excessive
blood loss (acutely such as a hemorrhage or chronically through low-volume loss),
excessive blood cell destruction (hemolysis) or deficient red blood cell production
(ineffective hematopoiesis) .
Red Blood Cell Size
In the morphological approach, anaemia is classified by the size of red blood cells.
The size is reflected in the mean corpuscular volume (MCV). If the cells are smaller
than normal (under 80 fl), the anaemia is said to be microcytic; if they are normal size
(80-100 fl), normocytic; and if they are larger than normal (over 100 fl), the anaemia
is classified as macrocytic6.
1. MICROCYTIC ANAEMIA
Microcytic anaemia is primarily a result of hemoglobin synthesis failure/insufficiency. Iron
deficiency anaemia is the most common cause of microcytic anaemia. RBCs often
appear hypochromic and microcytic when viewed with a microscope6.
IRON DEFICIENCY ANAEMIA
History
A disease believed to be iron deficiency anaemia is described in about 1500 B.C. in
the Egyptian Ebers papyrus. It was termed chlorosis or green sickness in Medieval
Europe, and iron salts were used for treatment in France by the mid-17th century.
Thomas Sydenham recommended iron salts as treatment for chlorosis, but treatment
with iron was controversial until the 20th century, when its mechanism of action was
more fully elucidated7.
6
7
http://en.wikipedia.org/wiki/Anaemia
17
The iron cycle in humans8
Iron absorbed from the diet or released from stores circulates in the plasma bound to
transferrin, the iron transport protein. The turnover (half-clearance time) of transferrinbound iron is very rapid - typically 60 - 90 min. Because almost all of the iron
transported by transferrin is delivered to the erythroid marrow, the clearance time of
transferrin-bound iron from the circulation is affected most by the plasma iron level
and the erythroid marrow activity. When erythropoiesis is markedly stimulated, the
pool of erythroid cells requiring iron increases and the clearance time of iron from the
circulation decreases. The half-clearance time of iron in the presence of iron deficiency
is as short as 10 - 15 min. With suppression of erythropoiesis, the plasma iron level
typically increases and the half - clearance time may be prolonged to several hours.
Normally, the iron bound to transferrin turns over 10 - 20 times per day. Assuming a
normal plasma iron level of 80 - 100 μg/dL, the amount of iron passing through the
transferrin pool is 20 - 24 mg/d.
The iron-transferrin complex circulates in the plasma until it interacts with specific
transferrin receptors on the surface of marrow erythroid cells. While transferrin
receptors are found on cells in many tissues within the body - and all cells at some
time during development will display transferrin receptors - the cell having the greatest
number of receptors ( 300,000 to 400,000/cell) is the developing erythroblast.
Once the iron - bearing transferrin interacts with its receptors, the complex is
internalized via clathrin - coated pits and transported to an acidic endosome, where the
iron is released at the low pH. The iron is then made available for heme synthesis
while the transferrin receptor complex is recycled to the surface of the cell, where the
bulk of the transferrin is released back into circulation and the transferrin receptor
reanchors into the cell membrane. At this point, certain amount of the transferrin
receptor protein may be released into circulation and can be measured as soluble
transferrin receptor protein. Within the erythroid cell, iron in excess of the amount
needed for hemoglobin synthesis binds to a storage protein, apoferritin, forming ferritin.
This mechanism of iron exchange also takes place in other cells of the body
expressing transferrin receptor, especially liver parenchymal cells where the iron can be
8
Harrison’s Principles of Medicine, page 628-629
18
incorporated into heme-containing enzymes or stored. The iron incorporated into
hemoglobin subsequently enters the circulation as new red cells are released from the
bone marrow. The iron is then part of the red cell mass and will not become available
for reutilization until the red cell dies.
In a normal individual, the average red cell life span is 120 days. Thus, 0.8 - 1.0% of
red cells turn over each day. At the end of its life span, the red cell is recognized as
senescent by the cell of the reticuloendothelial (RE) system, and the cell undergoes
phagocytosis. Once within the RE cell, the hemoglobin from the ingested red cell is
broken down, the globin and other proteins are returned to the amino acid pool, and
the iron is shuttled back to the surface of the RE cell, where it is presented to
circulating transferrin. It is the efficient and highly conserved recycling of iron from
senescent red cells that supports steady state (and even mildly accelerated)
erythropoiesis.
Since each millimeter of red cells contains 1 mg of elemental iron, the amount of iron
needed to replace those red cells lost through senescence amounts to 16 - 20 mg/d
(assuming an adult with a red cell mass of 2 L). Any additional iron required for daily
red cell production come from the diet. Normally, an adult male will need to absorb at
least 1 mg of elemental iron daily to meet needs, while females in the childbearing
years will need to absorb an average of 1.4 mg/d. However, to achieve a maximum
proliferative erythroid marrow response to anaemia, additional iron must be made
available. With markedly stimulated erythropoiesis, demands for iron are increased by
as much as six toeight fold. With extravascular hemolytic anaemia, the rate of red cells
destruction is increased, but the iron recovered from the red cell is efficiently reutilized
for hemoglobin synthesis. In contrast, with intravascular hemolysis or blood loss
anaemia, the rate of red cell production is limited by the iron that can be mobilized
from body storage. Typically, the rate of mobilization under these circumstances will not
support red cell production more than 2.5 times normal. If the delivery of iron to the
stimulated marrow is suboptimal, the marrow's proliferative response is blunted, and
hemoglobin synthesis is impaired, which results in hypoproliferative marrow
accompanied by microcytic, hypochromic anaemia.
9
Food, Nutrition and Diet, page 839
19
During blood loss or hemolysis, the demand on iron supply increases and pathways
associated with inflammation interfere with iron release from stores, which results in
depletion of serum iron.
Aetiology9
There are many possible causes of iron deficiency anaemia. The condition can arise
from:
•
Inadequate iron intake secondary to a poor diet
•
Inadequate absorption resulting from gastrointestinal tract diseases
•
Inadequate utilization secondary to chronic gastrointestinal disturbances
•
Increased iron requirement for growth or blood volume, which occurs during
infancy, adolescence, pregnancy, and lactation
•
Increased blood loss due to excessive menstrual bleeding, hemorrhage, etc.
•
Defects in release from stores
Stages of Iron Deficiency10
Stage1: Moderate depletion of iron stores. No dysfunction.
Stage 2: Severe depletion of iron stores. No dysfunction.
Stage 3: Iron deficiency.
Stage 4: Iron deficiency (dysfunction and anaemia)
Clinical Findings10
Because anaemia is the last manifestation of chronic, long-term iron deficiency, the
symptoms reflect a malfunction of a variety of body systems. Inadequate muscle
function is reflected in decreased work performance and exercise tolerance. Neurologic
involvement manifested by behavioral changes, such as fatigue, anorexia, and pica,
especially pagophagia (ice eating). Abnormal cognitive development in children suggests
9
Food, Nutrition and Diet page 839
10
Food, Nutrition and Diet page 839-842
20
the presence of iron deficiency before it has developed into overt anaemia. Growth
abnormalities, epithelial disorders, and a reduction in gastric acidity are common. A
possible sign of early iron deficiency is reduced immunocompetence, particularly
defects in cell-mediated immunity and the phagocytic activity of neutrophils, which may
lead to an increased propensity for infection. Hair loss and lightheadedness can also be
associated with iron deficiency anaemia.
As iron deficiency anaemia becomes more severe, defects arise in the structure and
function of the epithelial tissues, especially of the tongue, nails, mouth, and stomach.
The skin may appear pale, and the inside of the lower eyelid may be light pink instead
of red. Fingernails can become thin and flat, and eventually koilonychia (spoon-shaped
nails) may be noted. Mouth changes include atrophy of the lingual papillae, burning,
redness, and, in severe cases, a completely smooth, waxy, and glistening appearance
to the tongue (glossitis). Angular stomatitis may also occur, as may a form of dysphagia
(difficulty in swallowing). Gastritis occurs frequently and may result in achlorhydria.
Progressive, untreated anaemia results in cardiovascular and respiratory changes that
can eventually lead to cardiac failure.
Some behavioral symptoms of iron deficiency seem to respond to iron therapy before
the anaemia is cured, suggesting they may be the result of tissue depletion of ironcontaining enzymes rather than the result of a decreased level of hemoglobin.
Other symptoms include Constipation, sleepiness, tinnitus, palpitation, hair loss,
lightheadedness, fainting or feeling faint, depression, breathlessness, muscle twitching,
tingling, numbness, or burning sensation, sleep apnea, missed menstrual cycle, heavy
menstrual period, slow social development, poor appetite, pruritus.
2. MACROCYTIC ANAEMIA
Megaloblastic Anaemia, the most common cause of macrocytic anaemia, is due to a
deficiency of either vitamin B-12 or folic acid (or both). Deficiency in folate and/or
vitamin B-12 can be due either to inadequate intake or insufficient absorption. Folate
deficiency normally does not produce neurological symptoms, while vitamin B-12
deficiency does11.
11
21
Pernicious Anaemia is caused by a lack of intrinsic factor. Intrinsic factor is required to
absorb vitamin B-12 from food. A lack of intrinsic factor may arise from an
autoimmune condition targeting the parietal cells (atrophic gastritis) that produce intrinsic
factor or against intrinsic factor itself. These lead to poor absorption of vitamin B-1211.
3. NORMOCYTIC ANAEMIA
Normocytic anaemia occurs when the overall hemoglobin levels are always decreased,
but the red blood cell size (Mean Corpuscular Volume) remains normal. Causes
include acute blood loss, anaemia due to chronic disease, aplastic anaemia (bone
marrow failure) and hemolytic anaemia11.
4. DIMORPHIC ANAEMIA
The diamorphic anaemia is caused by two causes simultaneously, e.g., macrocytic
hypochromic, due to hookworm infestation leading to deficiency of both iron and
vitamin B-12 or folic acid11.
SPECIFIC ANAEMIA
Aplastic Anaemia, is a condition generally unresponsive to anti-anaemia therapies,
sometimes curable by bone marrow transplant, but potentially fatal. Aplastic anaemia is
characterized by decreased production of red blood cells, white blood cells and
platelets. This disorder may be inherited or acquired as a result of: recent severe illness,
long-term exposure to industrial chemicals, use of anticancer drugs and certain other
medications11.
Sickle-cell Anaemia, a hereditary disorder, is a chronic, incurable condition that causes
the body to produce defective hemoglobin, which forces red blood cells to assume an
abnormal crescent shape. Unlike normal oval cells, fragile sickle cells can't hold enough
hemoglobin and oxygen to nourish body tissues. The deformed shape makes it hard
for sickle cells to pass through narrow blood vessels. When capillaries become
obstructed, a life-threatening condition called sickle cell crisis is likely to occur11.
Anaemia of Chronic Disease
Cancer, chronic infection or inflammation, and kidney and liver disease often cause mild or
moderate anaemia. Chronic liver failure generally produces the most severe symptoms12.
12
22
1.4 CONTEMPORARY TRENDS OF DIAGNOSIS AND MANAGEMENT13
Complete blood counts are done for diagnosis of an anaemia. Apart from reporting the
number of red blood cells and the hemoglobin level, the automatic counters also
measure the size of the red blood cells by flow cytometry, which is an important tool
in distinguishing between the causes of anaemia. Peripheral blood smear also be
helpful. Now a days four parameters i.e. RBC count, hemoglobin concentration, MCV
and RDW are measured, allowing other investigations such as hematocrit, MCH and
MCHC to be calculated, and compared to values adjusted for age and sex. Some
counters estimate hematocrit from direct measurements.
Kinetic approach to anaemia is reticulocyte count, which is a quantitative measure of
the bone marrow's production of new red blood cells. The reticulocyte production
index is a calculation of the ratio between the level of anaemia and the extent to which
the reticulocyte count has risen in response. If the degree of anaemia is significant,
even a "normal" reticulocyte count actually may reflect an inadequate response. If an
automated count is not available; a reticulocyte count can be done manually by
examination of blood film under a microscope. Newly formed RBCs are usually slightly
larger than older RBCs and show polychromasia. Even where the source of blood
loss is obvious, evaluation of erythropoiesis can help to assess whether the bone
marrow will be able to compensate for the loss,
Some other tests: ESR, ferritin, serum iron, transferrin, RBC count, folate level, serum
vitamin B-12, hemoglobin electrophoresis and renal function tests. Bone marrow
examination allows direct examination of the precursors to red cells when the diagnosis
remains difficult.
The management depends on severity and the cause of anaemia. Mild to moderate
iron deficiency anaemia is treated by iron supplementation with ferrous sulfate or
ferrous gluconate along with vitamin C which aid in the body's ability to absorb iron.
Vitamin supplements given orally e.g folic acid or vitamin B-12 will replace specific
deficiencies.
In anaemia of chronic disease, anaemia associated with chemotherapy, or renal disease
can be treated according to cause. In severe cases of anaemia, or with ongoing blood
loss, a blood transfusion may be necessary.
13
23
1.5 ANAEMIA - A CLASSICAL VIEW
In Ayurveda, "Pandu" is considered as a specific disease characterized by pallor of
body which strikingly resembles with 'Anaemia' of modern science14. Rakta has been
considered as a key factor for the Jeevana (life), Varna Prasadana (complexion),
mamsapushti (nourishment of muscle tissue)15. The humors (dosha) in a person due to
excessive physical exercise, constant intake of sour substances, salt, pungent (dietary)
articles, wine, earth cakes, (regular) day sleeping vitiate the blood which lead to pallor
of the skin16.
Types17
Anaemic disorders have been described to be of five types
•
Vataja Pandu
•
Pittaja Pandu
•
Kaphaja Pandu
•
Sannipataja Pandu (vitiation of all three dosha)
•
Mridbhaksanajanya Pandu (due to eating of clay)
Aetiology (Nidana)
Related to diet
•
Excessive intake of alkaline, sour, saline, corrosive and hot food
•
Consumption of mutually contradictory (incompatible) and unwholesome food
•
Excessive intake of nispava (a type of simba), masa, pinyaka (oil cake) and
sesame oil
14
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•
Excessive consumption of wine, fish
•
Eating of clay/ mud18
Related to Regime18
•
Sleeping during day time,
•
Excessive exercise
•
Excessive sexual intercourse
•
Improperly performing Pancakarma therapies
•
Transgression of prescribed seasonal regimens (rtu-vaisamya)
•
Suppression of natural urges.
Mental factor
•
Passion, worry, fear, anger and grief18
Due to other diseases19
Pallor is also found in other diseases as a premonitory sign, symptom or as a
complication
•
Raktarsa (Haemorrhagic piles)
Sotha (Oedema)
•
Raktapitta (Bleeding disorders)
Udara ( Ascites)
•
Udara Krimi (Worm infestation)
Grahani (Sprue)
•
Visamajwara (Malaria)
Jirnajwara (Chronic fever)
•
Rakta Pradara (DUB)
Kamala (Jaundice)
18
19
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Kayachikitsa by Prof. Ajay Kumar Sharma, Vol – 2, Page – 511
25
Pathogenesis (Samprapti)20,21
Aetiological factors
↓
Vitiation of all three Dosha (predominantly Pitta)
↓
Located between the skin and the muscle tissue (Sthana Samsraya)
↓
Aggravated Dosha vitiates dhatu
Esp. blood (asrik), skin and muscle
→
Loss of complexion, Strength,
unctousness and other quality of Oja
↓
Blood deficiency, laxity of dhatu (tissues) & sense organs
Different types of coloration of skin (Pallor)
20
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26
Prodromal symptoms (Purvarupa)22,23
•
Palpitation
•
Dryness of skin
•
Loss of sweating
•
Fatigue
•
Cracks in the skin
•
Excessive salivation
•
Malaise
•
Desire of eating clay
•
Peri-orbital edema
•
Yellow discolouration of faeces and urine
•
Indigestion
General Symptoms (Samanya Rupa)24 :
•
Pallor of the skin
•
Scanty blood
22
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27
•
Fat/marrow deficiency
•
Loss of glow
•
Sensory blunting
•
Tinnitus
•
Suppression of digestion
•
Weakness
•
Fatigue
•
Anorexia
•
Vertigo
•
Body ache
•
Fever
•
Exertional dyspnoea
•
Heaviness
•
Pre orbital edema
•
Fall of hair
•
Anger
•
Aversion to cold
•
Excessive sleep
•
Excessive salivation
•
Feeble speech
•
Calf muscle cramps
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SÉ.ÉÊSÉ.16/13-16
Table 1. Specific symptoms of Pandu Roga according to humours25
Vataja Pandu
Pittaja Pandu
Kaphaja
Pandu
Black and pale- Yellow or green Heaviness
yellow
Complexion
complexion
Sannipataja
Pandu
(vitiation of
all three
dosha)
Mridabhaksanajanya Pandu
(eating of clay
aggravates one
of the three
dosa)
All the three loss of strength,
types of
complexion and
pandu are
digestive capacity
simultaneously
manifested.
Dryness of skin Fever
Drowsiness
Periorbital edema
Reddishness of
the body
Burning
sensation
Vomiting
Oedema of feet
and umbilical
region
Malaise
Fainting
Whitish
complexion
Worm infestation
Bodyache
Excessive thirst
Salivation
Loose motion
associated with
blood and mucus
discharge
Pricking pain
Yellow coloured Horripilation
urine and stool
Tremor
Desire of cold
things
Prostration
Pain in the
sides of the
chest
Perspiration
Fainting
29
Headache
Anorexia
Giddiness
Dryness of
faces
Pungent taste
of mouth
Mental
fatigue
Distaste in the
mouth
Intolerance of hot Dyspnoea
and sour things
Swelling
Sour eructation
Cough
Weakness.
Foul smell of
mouth
Laziness
Loose motions
Anorexia
weakness
White
appearance
of urine,
eyes and
faces;
Desire of
pungent,
ununctuous
and hot
things
Oedema
25
Charaka Chikitsa 16/17-25
30
Principle of Treatment
Sodhana Therapy (Purificatory measures)26
•
Snehana (Oleation therapy) with Panchagavya ghrta/ Maha-tikta ghrta
Kalyanaka ghrta/ Dadima ghrta/ Katukadya ghrta, etc. especially in Vataja
Pandu
•
Vamana (emesis)/ Virechana (purgation) with Tiksna (sharp) drugs - especially in
Pittaja/ Kaphaja Pandu
Samana Therapy27
Vataja Pandu
-
Snehana (Internal oleation)
Pittaja Pandu
-
Tikta rasa (bitter taste) and Sita Virya (cold
potency) drugs
Kaphaja Pandu
-
Katu,Tikta and Usna Virya (pungent,bitter and
hot) drugs
Sannipataja Pandu
(Vitiation of all three dosha)
-
Treat all three vitiated Dosha
Mridabhaksana janya Pandu (Anaemia due to eating of clay)
26
27
Avoid causative factor, Antihelminthic treatment,
Ghee processed with strength promoting drugs
iÉjÉ {ÉÉhbÂ´ÉÉàÉªÉÉÒ ÉÎºxÉMvÉºiÉÉÒFhÉè°ôv´ÉÉÇxÉÖãÉÉäÉÊàÉBÉEè&*
ºÉÆ¶ÉÉävªÉÉä àÉßnÖÉÊ£ÉÉÎºiÉ´ÉiÉè& BÉEÉàÉãÉÉÒ iÉÖ ÉÊ´É®äSÉxÉè&**
SÉ.ÉÊSÉ.16/40
{É\SÉMÉBªÉÆ àÉcÉÉÊiÉBÉDiÉÆ BÉEãªÉÉhÉBÉEàÉlÉÉÉÊ{É ´ÉÉ *
ºxÉäcxÉÉlÉÈ PÉßiÉÆ ntÉÉiÉÂ BÉEÉàÉãÉÉ{ÉÉhbÖ®ÉäÉÊMÉhÉä **
SÉ.ÉÊSÉ.16/4
´ÉÉÉÊiÉBÉEä ºxÉäc£ÉÚÉÊªÉ-~Æ, {ÉèÉÊkÉBÉEä ÉÊiÉBÉDiÉ¶ÉÉÒiÉãÉàÉÂ **
`ãÉèÉÎ-àÉBÉEä BÉE]ÖÉÊiÉBÉDiÉÉä-hÉÆ, ÉÊ´ÉÉÊàÉgÉÆ ºÉÉÉÊzö{ÉÉÉÊiÉBÉEä*
SÉ.ÉÊSÉ.16/116-117
31
Pathya (Diet)28
Old sali (type of rice), barley, wheat, yusa (vegetable soup) of mudga (green gram),
adhaki (pigeon pea) and masura (red lentil), and Jangal mamsa rasa (meat soup of
wild animals) are beneficial.
1.6 SOME IMPORTANT AYURVEDIC FORMULATIONS
Some Single drugs:
•
Punarnava (Boerhavia diffusa) juice with honey 15 ml BD for 3 months
•
Dadima (Punica granatum) juice with honey 15 ml BD for 3 months
•
Bhringaraja (Eclipta alba) juice with honey 15 ml BD for 3 months
•
Draksha (Vitis vinifera) churna 5 gr. BD with honey for 3 months
•
Amalaki (Emblica officinalis) churna 5 gr. BD with honey for 3 months
Some Compound Formulations:
Rasa kalpas (Herbo-mineral preparations)
•
Navayasa lauha 250mg twice a day with honey for 3 months
•
Vidangadilauha 250 mg twice a day with honey for 3 months
•
Datrilauha 500 mg twice a day with luke warm water for 3 months
•
Kasisa bhasma, 125 mg twice a day with honey for 2 months
•
Lauha bhasma 125 mg twice a day with honey for 2 months
•
Mandura bhasma 125 mg twice a day with honey for 2 months
Vati (Tablets)
•
Punarnava mandura tab. 500 mg. twice a day with honey for 2 months
•
Mandura vataka. 500 mg. twice a day with honey
28
iÉÉ£ªÉÉÆ ºÉÆ¶ÉÖrBÉEÉä-~É£ªÉÉÆ {ÉlªÉÉxªÉxxÉÉÉÊxÉ nÉ{ÉªÉäiÉÂ*
¶ÉÉãÉÉÒxÉÂ ºÉªÉ´ÉMÉÉävÉÚàÉÉxÉÂ {ÉÖ®ÉhÉÉxÉÂ ªÉÚ-ÉºÉÆÉÊciÉÉxÉÂ **
32
SÉ.ÉÊSÉ.16/41
Ghee (Medicated clarified butter)
•
Dadimadya ghrita 5 gm. twice a day with warm water for 3 months
•
Vyosadya ghritam 5 gm. twice a day with warm water for 3 months
Lehyam (Confectioneries)
•
Amalaki rasayana 5 gm. twice a day with
•
Dhatryavaleha 5 gm. twice a day for 3 months
water for 3 months
Asava and Arista
•
Bijakarista 30 ml twice a day with water for 3 months
•
Gaudarista 30 ml twice a day with water for 3 months
•
Dhatryarista 30 ml twice a day with water for 3 months
•
Lohasava 30 ml twice a day with water for 3 months
•
Kumaryasava 30 ml twice a day with water for 3 months
•
Bhringarajasava 30 ml twice a day with water for 3 months
•
Punarnavarista 30 ml twice a day with water for 3 months
•
Rohitakarista 30 ml twice a day with water for 3 months
33
Blank
34
CLINICAL STUDY
35
Blank
36
CHAPTER-2
CLINICAL STUDY
2.1 OBJECTIVES
The objective of current study is to assess clinical safety and efficacy through
measurable objective parameters.
1. Observe the effect of Dhatri lauha on haematological parameters viz. Hb%,
MCV, MCHC, TIBC, Serum iron content and Serum ferritin in Iron Deficiency
Anaemia subjects.
2. Observe the clinical safety of Dhatri lauha in Iron Deficiency Anaemia subjects.
2.2 MATERIAL AND METHODS
Study Design
:
Open labelled trial
Sample Size
:
40 subjects per centre
Level of Study
:
OPD
Study Period
:
1 year (recruitment of subjects till the end of
6th month, continuation of trial therapy till end
of 8th month, last 4 months for compilation
and statistical analysis of data)
2.2.1. Criteria for Inclusion
1. Age between 15 to 60 years
2. Haemoglobin level between 6 to 10 gm /dl.
3. Serum iron content < 50 ìg /L
37
4. S. Ferritin < 30 ìg /L
5. MCHC < 34 g/dl
6. MCV < 80fL.
7. Peripheral smear of blood shows hypochromic / microcytic anaemia
2.2.2 Criteria for Exclusion
1. Age less than 15 years and more than 60 years.
2. Pregnancy and lactation
3. Severe Renal / Hepatic/ Cardiac disease
4. Any continuing blood loss e.g. Haematemesis, Melena, bleeding piles etc.
5. Dimorphic anaemia
2.2.3 Criteria for Withdrawal
During the course of the trial treatment, if any serious condition or any serious adverse
events which requires urgent treatment or if patients himself want to withdraw from the
study, such subjects withdrawn from the trial.
2.2.4 Criteria for Assessment
Changes in haemoglobin % (Cyanomethamoglobin method), MCV (Mean Corpuscular
Volume), MCHC (Mean Corpuscular Haemoglobin Concentration), Serum Iron and
Serum Ferritin levels were considered for assessing the outcome of the treatment on
0,15th, 30th, and 45th day. The safety parameters (liver and kidney function) were
assessed at 0 and 45th day.
2.2.5 Details of Recruitment and Follow-up
Ethical Review
A. Institutional Ethics Committee (IEC): The proposal was placed before
Institutional Ethics Committee of trial center for getting clearance certificate before the
project is initiated. Patient’s information sheet and informed consent form were
submitted along with project proposal for approval by IEC. Both were maintained in
duplicate with one copy given to the patient at the time of entry to the trial.
38
B. Data and Safety Monitoring Board (DSMB): A Data and safety monitoring board
at CCRAS Hqrs had carefully monitored the data and side effects during the period
of study and put in a place where by prompt reporting of adverse events occur. The
data was reviewed as every 20 participants entered the study and administered the
trial drugs.
Training to Investigators
Short-term twodays training was provided to all the investigators and laboratory
personnel involved in the multicentric trial at CCRAS Hqrs. and Central Research
Institute (Ay.), New Delhi. The investigators and technicians were briefed about the
clinical trial conduct and laboratory procedures involved in order to maintain the rigor
and uniformity.
2.2.6. Trial monitoring and data analysis
CCRAS, Hqrs, New Delhi had undertaken the monitoring of trial progress and data
analysis. Data on clinical symptoms and laboratory tests before and after the treatment
was tabulated and analyzed by using Statistical Package for Social Sciences (SPSS)
version 15.0. A p-value less than 0.05 was considered to be statistically significant.
2.2.7. Laboratory Investigations
The Laboratory Investigations (Pathological/Biochemical, etc.), which were not available
at research institutes were conducted at identified reputed labs / other Government
institutes.
2.2.8. Trial Drug /Dosage /Duration
Dhatri Lauha 500 mg. (one capsule) twice daily after meal for forty five days with
warm water.
In the pre-treatment phase de-worming was done with the prescription of one
chewable Albendazole tablet of 400 mg stat., 7 days before the treatment phase to all
cases included in the trial.
Source of Drug: National Research Institute for Ayurvedic Drug Development
(NRIADD), Kolkata.
39
Blank
40
DRUG REVIEW
41
Blank
42
CHAPTER-3
DRUG REVIEW
DHËTRÌ LAUHA
(BhaiÀajyaratn¡val¢, á£larog¡dhik¡ra : 142-147)
vÉÉjÉÒSÉÚhÉÇºªÉÉ¹]õÉè {É±ÉÉÊxÉ SÉi´ÉÉÊ®ú ±ÉÉè½þSÉÚhÉÇºªÉ *
ªÉ¹]õÒ¨ÉvÉÖEò®úVÉ¶SÉ Êuù{É±ÉÆ nùtÉiÉÂ {É]äõ PÉÞ¹]õ¨ÉÂ **142**
+¨ÉÞiÉÉC´ÉÉlÉäxÉèiÉSSÉÚhÉÈ ¦ÉÉ´ªÉ\SÉ ºÉ{iÉÉ½þ¨ÉÂ *
SÉhb÷ÉiÉ{Éä¹ÉÖ ¶ÉÖ¹EÆò ¦ÉÚªÉ: Ê{É¹]Âõ´ÉÉ xÉ´Éä PÉ]äõ ºlÉÉ{ªÉ¨ÉÂ **143**
PÉÞiÉ¨ÉvÉÖxÉÉ ºÉÆªÉÖHòÆ ¦ÉHòÉnùÉè ¨ÉvªÉiÉºiÉlÉÉxiÉä SÉ *
jÉÒxÉÊ{É ´ÉÉ®úÉxÉÂ JÉÉnäùiÉÂ {ÉlªÉÆ nùÉ¹ä ÉÉxÉÖ£ÉxvÉäxÉ **144**
¦ÉÖHòºªÉÉnùÉè ¶É¨ÉªÉÊiÉ ®úÉMä ÉÉxÉÂ Ê{ÉkÉÉÊxÉ±ÉÉänùÂ¦ÉÚiÉÉxÉÂ*
¨ÉvªÉä%zÉä Ê´É¹]õ¨¦ÉÆ VÉªÉÊiÉ xÉÞhÉÉÆ Ê´ÉnùÁiÉä xÉÉzÉ¨ÉÂ **145**
{ÉÉxÉÉzÉEÞòiÉÉxÉÂ nùÉ¹ä ÉÉxÉÂ ¦ÉHòÉxiÉä ¶ÉÒÊ±ÉiÉÆ VÉªÉÊiÉ*
B´ÉÆ VÉÒªÉÇÊiÉ SÉÉzÉÆ ¶ÉÚ±ÉÆ xÉÞhÉÉÆ ºÉÖEò¹]õ¨ÉÊ{É **146**
½þ®úÊiÉ SÉ ºÉ½þºÉÉ ªÉÖHòÉä ªÉÉäMÉ¶SÉÉªÉÆ VÉ®úÎi{ÉkÉ¨ÉÂ*
SÉIÉÖ¹ªÉ: {ÉÊ±ÉiÉPxÉ: Eò¡òÊ{ÉkÉºÉ¨ÉÖnùÂ¦É´ÉÉxÉÂ VÉªÉäpùÉMä ÉÉxÉÂ**
|ÉºÉÉnùªÉiªÉÊ{É ®úHòÆ {ÉÉhbÖ÷i´ÉÆ EòÉ¨É±ÉÉÆ VÉªÉÊiÉ **147**
(¦Éè¹ÉVªÉ®úixÉÉ´É±ÉÒ, ¶ÉÚ±É®úÉäMÉÉÊvÉEòÉ®ú; 142-147)
43
3.1 Composition of Drug
1. Dh¡tr¢ (Ëmalak¢)
Pericarp
384 g
2. Lauha c£r¸a
bhasma
192 g
3. YaÀ¶imadhu raja (YaÀ¶¢)
Root
96 g
4. Am£t¡ (Gu·£c¢) kv¡tha
Stem
Quantity Sufficient for
bhavana
3.2 Method of Preparation
Drugs 1 to 3 are powdered separately and mixed together and put in Am£t¡
KaÀ¡ya for Bh¡van¡. After seven days it is taken and dried under sunlight. It is
then mixed well.
Dose: 1/2 to 1 g
Anupana: Ghee, honey.
3.3 Important Therapeutic Uses
á£laroga (Gastric ulcer/ Duodenal ulcer/ Colic), P¡¸·u (Anaemia), K¡mal¡
(Jaundice), Amlapitta (Hyperacidity), Netraroga (Eye disorder), Palita (Graying of
hair), ViÀ¶ambha (Constipation), Ën¡ha (Distension of abdomen due to obstruction
to passage of urine and stools), Mand¡gni (Impaired digestive fire), Raktapitta
(Bleeding disorder)
3.4 Ingredient Profile
Table 3. Ingredient profile of Dhatri Lauha
Amlaki29
Lauha Bhashma30
Yashtimadhu31 Guduchi32
Latin Name
Emblica
officinalis
Gaertn.
Glycyrrhiza
glabra Linn,
Tinospora
cordifolia
(Willd.) Miers.
Family
Euphorbiaceae
Leguminosae
Menispermaceae
44
Rasa
Amla,
Madhura,
Tikta, Katu,
Kasaya
Madhura
Tikta,
Kasaya
Guna
Laghu, Ruksa
Guru, Snigdha
Laghu
Virya
Sita
Sita
Usna
Vipaka
Madhura
Madhura
Madhura
Karma
Rasayana,
Vrsya,
Caksusya,
Tridosajit
Balya,
Caksusya,
Vrsya, Varnya,
Vatapittajit,
Raktaprasadana
Tridosasamaka,
Sangrahi,
Balya,
Dipana,
Rasayana,
Raktasodhaka,
Jvaraghna
Therapeutic
uses
Bleeding
disorder;
Hyperacidity;
Increased
frequency and
turbidity of
urine; burning
micturation
Mild laxative,
haemostatic,
anaemia, menometrorrhagia,
intrinsic
haemorrhage
Pain,
haemorroids,
asthma,
weakness,
cardiac
disorder,
increased
frequency
and turbidity
of urine
Diarrhoea; Pain;
Hyperacidity;
Abdominal
disorders; Jaundice;
Anaemia; Worm
infestation; Urinary
disorder; Splenic
disease; Oedema;
Dyspnoea/Asthma;
Diseases of skin.
29
Ayurvedic Pharmacopoeia of India, Part-I, Vol-I, P-5,6
30
Ayurvedic Formulary of India, Part-I, 18:14, P-241,242
31
32
45
Blank
46
PRECLINICAL STUDIES
47
Blank
48
CHAPTER-4
PRECLINICAL
STUDIES
4.1 STANDARDISATION
Table 1. Composition of Dhatri Lauha
S. No. Ingredients
Botanical / English
Name
Part used
Ratio
1.
Dhatri (Amalaki)
Emblica officinalis
Fruit pericarp
4 parts
2.
Lauha bhasma
Calcined Iron
-
2 parts
3.
Yastimadhu
Glycyrrhiza glabra
Root
1 part
4.
Amrta (Guduchi)
Kvatha
Tinospora cordifolia Stem
Quantity
Sufficient
PREPARATION OF DHATRI LAUHA
Ingredients of formulation
1. Dhatri (Amalaki - Emblica officinalis)
Pericarp
-
384 gm
2. Lauha bhasma
(Calcined iron) -
192 gm
3. Yastimadhu (Yasti - Glycyrrhiza glabra) Root
-
96 gm
4. Guduchi (Amrta -Tinospora cordifolia)
-
Quantity
Sufficient
(For bhavana)
49
Stem
Method of preparation
1. Take all the ingredients of pharmacopoeial quality.
2. Wash and dry the ingredients (S.No.1 and 3) separately and pass through sieve
no. 85.
3. Wash and dry Ingredient S.No. 4 (kvath drvya) of the formulation compositon
powder and pass through sieve no. 44 to obtain coarse powder.
4. Add specified amount of water to the kvath dravya, soaked for four hours, heat,
reduce to one fourth and filter through muslin cloth.
5. Mix the powdered ingredients (S.No. 1 & 3) and lauha bhasma at S.No. 2
thoroughly. Levigate (bhavana for 7 days) with Guduchi kvath and dry the
mixture.
6. The dried mixture ground to powder of 40# and packed in closed container to
protect from light and moisture.
Table 5. Physico-Chemical Standards and Quality Parameters of Dhatri Lauha
S. No.
Test
1.
Description
Results
Colour
Black
Odour
Smell of amla
2.
Identification
Characteristics of Iron
3.
Loss on drying
2.215%
4.
Total -ash
32.68%
5.
Acid- insoluble ash
1.30%
6.
Water- soluble ash
0.34%
7.
pH
3.92
8.
Assay of element Total Iron content
20.38%
50
9.
Heavy/ Toxic metals
Mercury
Below Detection Limit
(<0.001ppm)
(<0.005ppm)
(<0.001ppm)
Cadmium
Arsenic
10.
11.
12.
Microbial contamination
Total aerobic count (IS : 5402 - 2002)
Total Enterobacteriaceae (IS/ ISO:7402)
Total fungal count (IS : 5403 - 1999)
Specific Pathogen
E .coli (IS : 5887 (Part I)- 1976)
Salmonella spp. (IS : 5887
(Part III)- 1976)
S.aureus (IS : 5887 (Part II)- 1976)
Pseudomonas aeruginosa (IS : 13428
(PartII)
TLC of (90 % ethanolic extract of
Dhatri lauha and its ingredients)
51
31 cfu
Absent
Absent
Absent
Absent
Absent
Absent
Enclosed herewith
52
In Iodine vapour
Under white light
Under UV 254 nm
Under UV 366 nm
Observations
1
2
1. Dhatri Lauha
0.57
0.53
0.40,
0.59,
1
2
3
4
In Iodine vapour under
white light
Rf Values
Amalaki (3)
Yastimadhu (4)
0.13, 0.27, 0.46, 0.50 0.12, 0.26, 0.38, 0.49, 0.51
0.08, 0.14, 0.16,
0.04, 0.08, 0.12, 0.15,
0.27, 0.42, 0.51
0.18, 0.23, 0.25, 0.38,
0.46, 0.49, 0.51, 0.56
0.14, 0.27
0.11, 0.25, 0.32, 0.46,
0.49, 0.51
2
3
4
4. Yastimadhu
Under UV 366 nm
Guduchi (2)
0.18, 0.33, 0.49
0.05, 0.22,
0.37, 0.43,
0.49, 0.87
0.49, 0.56
1
3. Amalaki
Dhatri Lauha (1)
0.11, 0.27, 0.41,
0.11, 0.19, 0.27,
0.49, 0.52, 0.54,
0.63, 0.87
0.12, 0.28, 0.52,
3
4
2. Guduchi
Under UV 254 nm
TLC OF DHATRI LAUHA WITH ITS INGREDIENTS
Take 2 gm each of Dhatri Lauha and its ingredients and soak in 20 ml of 90 % ethanol separately with constant
stirring for 6 hrs and keep for next 18 hrs. Next day filter the samples, dry the filtrate and prepare 10% solutions of
residue separately. Apply 7μl each of the test solutions of 10mm band on aluminum plate (size 10x10cm) pre-coated
with silica gel 60 F254 of 0.2mm thickness and develop the plate in Toluene : Chloroform : Methanol (2.0 : 6.0 : 2.0)
as mobile phase. After development dry the plate and visualize under UV 254 & 366 nm. Place the plates in Iodine
chamber till the colour of the spots appear and calculate the Rf values.
HPTLC Methodology:
Take 4 gm Dhatri Lauha powder in 40 ml of alcohol and keep overnight. Boil the
solution for 10 minutes and filter. Concentrate the filtrate and makeup to 10 ml in
standard volumetric flask. Dissolve accurately weighed 10 mg each of authentic
markers (Gallic acid and 18 â-glycyrrhitinic acid) in alcohol and make up to 10 ml in
standard flask separately. Apply 5μl each of the test solution and markers of 10mm
band on aluminium plate (size 10x10cm) pre coated with silica gel 60 F254 of 0.2 mm
thickness and develop the plates in Toluene: Ethyl acetate: Formic acid (5.0:5.0:0.5) as
mobile phase. After development dry the plate, scan at UV 254 nm using HPTLC
scanner provided with Wincats software and take chromatograph.
Track 1, ID: Dhatri Lauha 5 μl
Track 1, ID : Dhatri Lauha 5 μl
Peak Start
Start
Max
Max
Max
Position Height Position Height %
End
End
Area
Position Height
Area
%
1.
0.01 Rf
0.0 AU
0.02 Rf
287.7 AU 27.82 % 0.06 Rf
0.2 AU 3901.2 AU 12.09 %
2.
0.06 Rf
0.2 AU
0.07 Rf
13.4 AU 1.30 % 0.11 Rf
0.8 AU 269.8 AU 0.84 %
3.
0.31 Rf
2.3 AU
0.39 Rf
544.5 AU 52.64 % 0.44 Rf
5.5 AU 20038.4 AU 62.12 %
4.
0.45 Rf
7.4 AU
0.48 Rf
43.8 AU 4.23 %
0.50 Rf
16.6 AU 1128.4 AU 3.50 %
5.
0.55 Rf
22.4 AU 0.60 Rf
92.4 AU 8.94 %
0.67 Rf
27.7 AU 4115.6 AU 12.76 %
6.
0.67 Rf
28.1 AU 0.72 Rf
52.5 AU 5.08 %
0.76 Rf
26.1 AU 2802.8 AU 8.69 %
53
Track 3, ID: Gallic acid 5 μl
Track 3, ID : Gallic acid 5 μl
Peak Start
Start
Max
Max
Max
End
End
Area
Position Height
Area
%
1.
0.01 Rf
0.9 AU
0.02 Rf
119.2 AU 14.23 % 0.04 Rf
9.9 AU 1275.8 AU 2.91 %
2.
0.24 Rf
18.2 AU 0.40 Rf
687.4 AU 82.06 % 0.46 Rf
1.1 AU 41565.3 AU 94.92 %
3.
0.56 Rf
10.4 AU 0.61 Rf
31.1 AU 3.71 %
22.6 AU 947.9 AU
54
0.62 Rf
2.16 %
Track 4, ID : 18 beta glycyrrhitinic acid 10 μl
Track 4, ID : 18 beta glycyrrhitinic acid 10 μl
Peak Start
Start
Max
Max
Max
End
End
Area
Position Height
Area
%
0.05 Rf
1.94 %
1.
0.01 Rf
17.9 AU 0.02 Rf
23.2 AU 3.10 %
2.
0.43 Rf
3.8 AU
0.44 Rf
10.5 AU 1.40 % 0.47 Rf
0.8 AU 190.9 AU 1.28 %
3.
0.50 Rf
3.3 AU
0.53 Rf
15.6 AU 2.08 %
10.2 AU 323.6 AU
4.
0.57 Rf
14.6 AU 0.61 Rf
643.1 AU 85.97 % 0.64 Rf
11.1 AU 12831.0 AU 86.33 %
5.
0.68 Rf
14.8 AU 0.70 Rf
26.9 AU 3.59 %
18.5 AU 617.6 AU
6.
0.79 Rf
14.4 AU 0.80 Rf
15.1 AU 2.02 % 0.84 Rf
6.0 AU 451.5 AU 3.04 %
7.
0.95 Rf
0.0 AU
13.8 AU 1.84 %
11.5 AU 161.0 AU
0.97 Rf
55
0.54 Rf
0.72 Rf
0.97 Rf
0.1 AU 287.6 AU
2.18 %
4.16 %
1.08 %
All tracks @ 254 nm
3D view of Dhatri Lauha with Gallic acid and 18ß-glycyrrhitinic acid
1. Dhatri lauha 5 μl
(Red line)
2. Dhatri lauha 10 μl
(Violet line)
3. Gallic acid 5 μl
(Green line)
4. 18ß-Glycyrrhitinic acid 5 μl
(Yellow line)
56
Under UV 254 nm
Under UV 366 nm
After derivatization with Vanillin-sulphuric acid
TLC profile of ethanolic extract of Dhatri Lauha
Solvent system : Toluene : Ethyl acetate : Formic acid (5:5:0.5)
Track 1. Dhatri lauha 5 μl
Track 2. Dhatri lauha 10 μl
Track 3. Gallic acid 5 μl
Track 4. 18ß-Glycyrrhitinic acid 5 μl
57
4.2 RAW INGREDIENTS INFORMATION
Pharmacognosy / GENERAL REFERENCES of Ingredients
1. Phyllanthus emblica L.
(Syn.: Emblica officinalis Gaertn.)
Amalaki
Plant
Fruit & Fruit pericarp
Taxonomical description
Plantae
Phanerogams
Angiosperms
Dicotyledons
Apetalae
Euphorbiaceae
Phyllanthus
P. emblica L.
58
Botanical description of plant
A small or medium sized, deciduous tree. Leaves subsessile, closely set along the
branchlets, distichous, narrowly linear, obtuse, having appearance of pinnate leaves.
Flowers greenish-yellow, in axillary fascicles on the leaf bearing branchlets, often on the
naked portion below the leaves. Fruits fleshy, globose, with obscure vertical furrow,
pale yellow. Seeds 6, trigonous.
Part used for the formulation:
Fruit pericarp
Pharmacognostic description:
Fig. Transverse section of fruit epicarp of Amalaki
Macroscopical characteristic: Drug consists of curled pieces of pericarp of dried
fruit occuring either as separated single segment; 1-2 cm long or united as 3 or 4
segments; bulk colour grey to black, pieces showing, a broad, highly shrivelled and
wrinkled external convex surface to somewhat concave, transversely wrinkled lateral
surface, external surface shows a few whitish specks, occasionally some pieces show
a portion of stony testa (which should be removed before processing); texture rough,
cartilaginous, tough; taste, sour and astringent.
59
Microscopical characteristic: Transverse section of fruit shows epicarp consisting of
a single layered epidermis cell appearing tabular and polygonal in surface view; cuticle
present; mesocarp cells tangentially elongated parenchymatous and crushed
differentiated roughly into peripheral 8 or 9 layers of tangentially elongated smaller cells,
rest consisting of mostly 7 isodiametric larger cells with walls showing irregular
thickenings; ramified vascular elements occasionally present; stone cells present either
isolated or in small groups towards endocarp ; pitted vascular fibres, walls appearing
serrated due to the pit canals, leading into lumen.
2. Tinospora cordifolia (Willd.) Hook. f. & Thomson - Guduchi
Plant
Stem
Plantae
Phanerogams
Angiosperm
Dicotyledonae
Polypetalae
Thalamiflorae
Ranales
Menispermaceae
Tinospora
T. cordifolia
60
Botanical description of plant:
Large, glabrous, deciduous, climbing shrubs. Leaves broadly ovate, cordate, long
petiolate. Flowers small, yellow or greenish-yellow, appearing when the plant is
leafless, in axillary and terminal racemes or racemose panicles; male flowers clustered,
females usually solitary. Drupes ovoid or subglobose, glossy, red, pea-sized. Seeds
white, bean shaped, warty.
Part used for the formulation:
Stem
Fig. Transverse section of stem of Guduchi
Macroscopical characteristic: Stem terete, sparcely lenticellate. Young stem green
with smooth surfaces and swelling at nodes, older ones show a light brown surface
marked with protuberance due to circular lenticels.
Microscopic characteristic: Transverse section of stem shows 2-3 rows of cork
cells. Cork broken at some places due to opening of lanticels followed by 2-3 layers
of collenchymatous cortex and 4-6 layers of Parechymatous cortex, consisting of
circular to isodiamatric type of cells. Just below the lenticels, groups of sclereids
present in secondary cortex. Cortical cells are filled with plenty of starch grains which
61
are simple, ovoid or irregularly ovoid elliptical. Vascular zone is composed of 10-12 or
more wedge shaped strips of xylem, externally surrounded by semi-circular strips of
phloem, alternating with wide medullar rays. Phloem consists of sieve tube, companion
cells and phloem parenchyma, some of which contain calcium oxalate crystals. Vessels
cylindrical with boarded pits on walls. Largevessels posses several tyloses with
transverse septa. Medullary rays 15-20 or more cells wide containing rounded,
hemispherical, oblong, ovoid, starch grain and with faintly marked strains and central
helium. Pith composed of large, thin walled cells with starch grains.
3. Glycyrrhiza glabra Linn.
–
Yastimadhu
Plant
Root
Plantae
Phanerogams
Angiosperm
Dicotyledonae
Polypetalae
Calyciflorae
Rosales
62
Fabaceae
Glycyrrhiza
G. glabra L.
Botanical description of plant:
A hardy herb or under shrub, attaining a height of 1.8m. Roots thick, having many
branches with red or lemon-colour outside aand yellowish or pale –yellow inside.
Leaves imparipinnate, leaflets in 4-7 pairs, ovate –lanceolate, smooth. Flowers borne
in axillary spikes, papilionaceous, lavender to violet in colour. Pods compressed.
Seeds 2-5 reniform, flat, deep grey.
Part used for the formulation
:
Root
Fig. Transverse section of root of Yastimadhu
Macroscopical characteristic: Stolon is yellowish brown or dark brown,
longitudinally wrinkled externally, cut surface shows a cambium ring and a small pith rut
is similar but without pith.
63
Microscopical characteristic: Transverse section of root shows outer cork of tabular
cells, outer layers with reddish brown, amorphous contents. Cells of secondary cortex
contain isolated prisms of calcium oxalate. Phloem fibers are in readily arranged groups
of 10-15 surrounded by sheath of parenchyma cells usually continuing prisms of
calcium oxalate. Medulla is absent, Xylem tetrach, usually is principal medullary rays at
right angles to each other all parenchymatous tissue containing abundant, simple, oval
or rounded starch grains.
Table 6. STANDARDS OF RAW INGREDIENTS
(As per Ayurvedic Pharmacopoeia of India)
Emblica officinalis Gaertn.
(Amalaki)
TESTS
RESULTS
Total Ash
Not more than 7 per cent
Acid-insoluble ash
Alcohol-soluble extractive
Not less than 40 per cent
Water-soluble extractive
Tinospora cordifolia (Willd.) Hook. f. & Thomson
(Guduchi)
TESTS
RESULTS
Total Ash
Acid-insoluble ash
64
Glycyrrhiza glabra Linn.
(Yastimadhu)
TESTS
RESULTS
Total Ash
Acid-insoluble ash
Not more than 2.5 per cent
STANDARD OPERATING PROCEDURE (SOP)
Lauha Bhasma : Lauha bhasma is the product in powder form prepared with
following formulation (Rasatarangini 20/32-39, 52).
1. Shuddha Lauha
:
1 part
2. Triphala Kvath
:
1/2 part
Haritaki ( Terminalia chebula)
-
equal part
Bibhitaki (Terminalia chebula)
-
equal part
Amalaki (Emblica officinalis)
-
equal part
Water for decoction
-
16 parts
Prepared from
Method of Preparation
Prepare Triphala kvatha (as per API method) and triturate Shuddha Lauha with it to
form a bolus. Prepare chakrikas and place them in a sharav after drying. Cover each
Sharava by placing another Sharava on it mouth to mouth and seal it with clay
smeared cloth. The assembly is called as ‘Sharava Samputa’. Heat Sharava Samputas
in Gajaputa. Repeat Triphala Kvath Bhavana followed with Gajaputa till the Bhasma
obtained is Nishchumbak i.e. non magnetic. It requires about 100 Gajaputas. In
order to remove the ‘Shlishta Doshas’ (remaining drawbacks, if any) induced in the
Bhasma due to strong heating in Gajaputa, process Lauha Bhasma for Amrutikaran.
Pack the fine powdered Lauha Bhasma in air tight container.
65
Physico-chemical & Ayurvedic Parameters
Description: Reddish brown to dark brown fine powder, tasteless, odourless.
I. Loss on Ignition
:
Not more than 1% w/w
II. Assay : Iron (Fe)
:
65-75% w/w
III. Varitaratwa
:
Varitara
IV. Nirdhoomatwa
:
Nirdhooma
V. Rekhapoornatwa
:
Rekhapoorna
VI. Chumbak Pariksha
:
Nishchumbak
Lauha Bhasma
Iron (Lauha)
Common Name - Lauha
Eng. Name- Iron
Hindi Name - Lauha
Iron is the most widely distributed of all the heavy metals in the Earth’s crust.
Lauha, Shastra, Teekshna, Ayas and Krishna lauha are the synonyms of lauha.
Varieties: Munda, Teekshna and Kanta are the three varieties of lauha.
Tikshna lauha is better than Munda, and Kanta is further better than Teekshna lauha.
For medicinal purposes either use of Tikshna lauha or best variety of Kanta lauha.
Property of Kanta Lauha
ªÉi{ÉÉjÉä xÉ |ÉºÉ®ÉÊiÉ VÉãÉè iÉèãÉÉË´ÉnÖ& |ÉiÉ{iÉä *
MÉxvÉÆ ÉËcMÉÖ iªÉVÉÉÊiÉ SÉ ÉÊxÉVÉÆ ÉÊiÉBÉDiÉÉÆ ÉÊxÉà£ÉBÉEãBÉE& *
iÉ{iÉÆ nÖMvÉÆ £É´ÉÉÊiÉ ÉÊ¶ÉJÉ®ÉBÉEÉ®BÉEÆ xÉèÉÊiÉ £ÉÚÉËàÉ *
BÉßE-hÉÉÆMÉ& ºªÉÉiÉºÉVÉãÉSÉhÉBÉE& BÉEÉxiÉãÉÉäcÆ iÉnÖBÉEkÉàÉ ** (+ÉÉªÉÖ.|É.3/217)
Kanta lauha is of such a nature that a drop of oil thrown into water contained in a pot
of these iron does not spread over the surface of the water, neither does the oil stick
to the inner surface of the pot. Hingu (as asfoetida) loses its odour; paste of nimba
loses its bitterness when put in such a pot. If milk is boiled in this pot, it goes up in
66
the form of a shikhara (pyramid) but does not fall down. Chanakamla becomes black
when kept in this pot.
Kanta lauha is softer than silver and black in colour.
BÉEÉxiÉÆ àÉßnÖiÉ®Æ iÉÉ®Én °ôFÉÉiàÉ ÉÊiÉÉÊàÉ®ÉBÉE®àÉ * (®ºÉVÉãÉÉÊxÉÉÊvÉ 1/2)
Properties of Tikshna Lauha
=VVÉ´ÉãÉÆ ãÉÉäc{ÉEãÉBÉEÆ vÉÉjÉÉÒ BÉEÉ¶ÉÉÒºÉãÉäÉÊ{ÉiÉàÉÂ *
ÉÊMÉÉÊ®gÉßÆMÉÉÆÉÊBÉEiÉÆ ªÉiºªÉÉkÉÉÒFãÉÉäcÆ iÉnÖkÉàÉàÉÂ ** (®ºÉiÉ®ÆÉÊMÉhÉÉÒ 20/8)
The surface of Tikshna lauha, if smeared with paste of Amla and Kasisa give rise to
hard and fine figures having the appearance of mountain perks.
Modern View:
Lauha is a silver white metal chemically known as ferrum. It is a heavy metal of
specific gravity 7.86. This is very ductile. It appears ferro-magnetic at ordinary
temperature i.e. becomes strongly magnetized in the magnetic field. At 768 0C it uses
this property and this temperature is called Curie point of the iron. Iron becomes soft
at red-heat and fuses with difficulty at 1520C. Pure metal melts at 1539 0C and boils
at 2450 0C.
The physical and chemical properties of iron are greatly modified by the presence of
small amounts of carbon and other impurities in the metal. This is hard on account of
the presence of carbon in it. It can absorb a maximum of 5% carbon. On the basis of
this carbon content, iron is obtained in the following three types;
1. Cast Iron: It can’t be hammered.
2. Wrought Iron: Can be hammered out.
3. Steel Iron
4.3 TOXICITY STUDIES
ACUTE TOXICITY OF DHATRI LAUHA
Methodology
Seventy albino mice (Swiss) weighing 20-40 g were divided into 7 groups. The
67
equal male and female mice (5 male + 5 female) were given graded doses of dhatri
lauha (10, 100, 200, 500, 1000 & 2000 mg/Kg, p.o.). Group I received double
distilled water as control. Animals were kept on fasting for 18 hours before
experimentation. The animals were kept in observation for 96 hours for any gross
behavioural changes and mortality.
Result
The animal treated with 2000 & 1000 mg/kg, p.o. showed dull, writhing and 10%
mortality recorded within 96 h. The other groups showed no mortality.
SUB-ACUTE TOXICITY OF DHATRI LAUHA
Animal & drug profile
Animal species
:
Albino rat (Wistar strain)
Sex
:
6 M+6F
Body wt
:
110-360 gm
Age
:
> 6-8 weeks
No. of animals
:
48 ( 4 groups)
Dose level
:
500, 250, 50 mg/kg + control
Duration
:
28 days
Regulatory guidelines
:
OECD
Frequency of administration
:
Daily
Route of administration
:
Oral
Methodology
Forty eight albino rats (Wistar strain) weighing 110-360 g were divided into 4 groups.
The equal male and female (6 M + 6F) was treated with Dhatri Lauha at the dose
level of 500, 250 and 50 mg/kg. Group I received double distilled water in same ratio
reserved as control (vehicle). The mortality rate, behavioural changes, if any was
recorded during the experimentation. The body weights of animals were recorded
weekly till the completion of the experiment (Table1). Measured food and water has
68
been supplied to the experimental animals as well as control for 28 days. Investigation
of all animals in each group of the blood haematology (RBC, Hb, prothrombin time,
WBC, TLC, DLC, MCV, MCH, MCHC (Table 2) and blood biochemistry (blood
glucose, SGOT, SGPT, serum creatinine) (Table 3) on 14th day and 28th day during
the experimentation (Table 4 & 5). All animals in each group have been sacrificed on
30th day for investigation of reversibility of toxicity of the drugs, if any. The vital
organs viz., liver, kidney, lungs, spleen, ovaries, tests, stomach and intestine were
separated, weighed and kept for histopathology.
Observation
Dhatri Lauha shows no significant effect in the blood haematology (RBC, Hb,
prothrombin time, WBC, TLC, DLC, MCV, MCHC), blood biochemistry (blood
glucose, SGOT, SGPT, serum creatinine) and body weight in comparison to control
Dhatri Lauha 500 mg/kg showed dull, writhings and 33% mortality recorded within 28
days.
Table 7. Sub acute toxicity: The body weight of animals (in gm) treated with
Dhatri Lauha (values are mean + SE)
69
Table 8. Sub acute toxicity: Investigation of blood hematology of rat treated
with Dhatri Lauha after 14 days (values are mean + SE)
Table 9. Sub acute toxicity: Investigation of serum biochemistry of rat treated
70
Table 10. Sub acute toxicity : Investigation of blood hematology of rat blood
treated with Dhatri Lauha after 28 days (values are mean + SE)
Table 11. Sub acute toxicity: Investigation of serum biochemistry of rat treated
71
HISTOPATHOLOGY
The histological studies were carried out in different tissues (viz., liver, spleen, kidney,
lung, testis, ovary, stomach and intestine). The histological studies were carried out on
vital organs of rat after 15 days of drug treatment. Small pieces of tissues were
collected & fixed in Boutin’s fixative or in 10% formal saline. They were processed
mechanically and embedded in paraffin to prepare block. Sections were cut 5 to 7 μ
in thickness on a rotary microtome. The slides were stained with haematoxylin and
eosin (H/E) and mounted in DPX. The slides were studied under light microscope for
histological observation.
The report of histological findings is done only at higher dose treated group and
compared with control group of animal.
72
Liver: it is almost solid organ consisting of several lobes. Under light microscope
hepatic cells shows as usual polygonal shape radiating from centre as in case in the
normal tissues. Normal arrangement of hepatocytes with clearly brought out nuclei,
blood vessels are clear and no abnormalities are marked.
(treated with 500 mg/kg)
73
Kidney: The cell membrane is intact and normal. The cortex and medullary portion of
the kidney shows normal structure and well defined. No abnormalities are seen.
74
Spleen: Spleen is the largest lymphoid tissue in the body. The histological study reveals
the normal feature as in case of normal control animal. Outer peritoneum enclosed the
splenic pulp, blood vessels and reticular mesh work as in case of normal slide.
75
Ovary: It shows histological variations with the age. The outer covering which is
made up of single layer of cuboidal cells called germinal epithelium, mature corpus
luteum is present in stroma and blood vessels are also present in sections. The slide
shows normal features in comparison to control.
76
Testis: Each testis is covered by a thin layer of connective tissue called tunica
albuginea. The sections show numerous sominiferous tubules. Spermatogenesis takes
place in this tubule and mature spermatozoa released and all the character resembles
normal character.
77
Stomach: The outer serous coat, thick muscular layer and sub – mucosal layer is well
–defined. Mucosal layer thrown into broad folds called rugae. Mucosal membranes
shows round shaped gland which produces mucous, parietal or oxyntic cell are also
present. The surface lining is made up of columnar cells globlet cells area also
prominent. There is no abnormality in the section.
78
OBSERVATIONS AND RESULTS
79
Blank
80
CHAPTER-5
OBSERVATIONS
AND RESULTS
Multicentric study was conducted in 11 Peripheral Research Institutes of Central
Council for Research in Ayurveda and Siddha and MGIMS, Wardha to evaluate the
safety and efficacy of Dhatri Lauha in the management of Iron Deficiency Anaemia.
Total 458 Patients were enrolled in this study out of which 400 patients have
successfully completed the study. The data on various aspects is provided hereunder.
Table 12. Centre wise patients enrolled and completed
S.No
Centre Name
No. of Subjects
Enrolled
No. of Completed
Cases
Dropouts
1
CRIP, Cheruthuruthy
45
40
5
2
RRI, Bangalore
28
24
4
3
CRI, Delhi
18
17
1
4
CRI, Bhubaneshwar
12
8
4
5
CRI, Lucknow
43
38
5
6
CRI, Jaipur
43
40
3
7
CRI, Gwalior
50
46
4
8
RRI, Patna
46
40
6
81
9
RRI, Gangtok
46
41
5
10
RRI, Jammu
38
26
12
11
RRI, Mandi
42
39
3
12
MGIMS, Wardha
47
41
6
Total
458
400
58
Table 13. Distribution of patients according to age and sex *
Male
Female
Total
Age group No. of Percen
patients tage
No. of
Patients
Percen
tage
No. of
Patients
Percen
tage
15-20
2
5.41
73
20.11
75
18.75
21-30
3
8.11
87
23.97
90
22.50
31-40
10
27.03
105
28.93
115
28.75
41-50
10
27.03
76
20.94
86
21.50
51-60
12
32.43
22
6.06
34
8.50
Total
37
100.0
363
100.0
400
100.0
The prevalence of anaemia is significantly higher in females than males, which is due to
the higher requirement of iron in females of reproductive age group.
* The distribution of gender is purely based on the recruited cases in the trial. This
may not represent the available published literature.
Table 14. Distribution of patients according to educational status
Educational status
No. of patients
Percentage
Not able to read / write
106
26.5
Under matriculate
123
30.7
82
Matriculate
93
23.3
Graduate
54
13.5
PG & Above
24
6.0
Total
400
100.0
Out of 400 patients of anaemia, maximum patients (57.2%) were illiterate or under
matriculate. It may be due to lack of awareness about nutritious diet in less educated
group.
Table 15. Distribution of patients according to socio-economical status
Income Group
No. of patients
Percentage
Less than 60,000/ annum
233
58.25
60,000/ annum and above
167
41.75
Total
400
100.00
Anaemia is more prevalent in people belonging to lower socio-economic group. It may
be due to inadequate availability of the resources for taking nutritious diet.
Table 16. Distribution of patients according to occupation
Occupation
No. of patients
Percentage
Desk work
32
8.0
Field work
44
11.0
Housewife
213
53.2
Student
74
18.5
Others
37
9.3
Total
400
100.0
The maximum number of patients (53.2 %) were housewives followed by students
83
(18.5%).This may be due to irregular food habits, and adequate care is not given for
taking nutritious diet.
Table 17. Distribution of patients according to addictions
Alcohol
Tea / Coffee
Tobacco
Age group No. of Percen
patients tage
No. of
Patients
Percen
tage
No. of
Patients
Percen
tage
No
390
97.5
317
79.2
375
93.8
Yes
10
2.5
83
20.8
25
6.2
Total
400
100.0
400
100.0
400
100.0
The table above shows that 20.8% cases were having addiction of tea/coffee and that
might have induced anaemia.
Table 18. Distribution of patients according to diet
Diet
No. of patients
Percentage
Vegetarian
168
42.0
Non-vegetarian
232
58.0
Total
400
100.0
Maximum number of anaemia cases in Non-vegetarians could be explained due to
high percentage of patients belonging to lower socio-economic group, whose resources
do not meet for taking nutritious diet.
Table 19. Distribution of patients according to menstrual history
Menstrual history
No. of patients
Percentage
Regular
298
82.09
Irregular
42
11.57
Menopause
23
6.34
Total
363
100
84
Table 20. Distribution of patients according to quantity of menstruation
Quantity
No. of patients
Percentage
Normal
302
76.0
Abnormal
38
9.5
Menopause
23
5.8
Not applicable
37
8.7
Total
400
100.0
In females (though having regular & normal menstrual history) Iron Deficiency Anaemia
is more common as the amount of iron required to replace the loss is not fulfilled
adequately.
Table 21. Distribution of patients according to sharirika prakriti
Sharirika prakriti
No. of patients
Percentage
Vataja
18
4.5
Pittaja
21
5.3
Kaphaja
9
2.3
Vata kaphaja
36
9.1
Vata pittaja
197
48.7
Pitta kaphaja
119
30.1
Total
400
100.0
In this study, anaemia is more prevalent in the patients of Vata Pittaja & Pitta Kaphaja
Prakriti. It may be because of Pitta Dosha vitiation is the main factor in etiopathogenesis
of Pandu.
85
Table 22. Distribution of patients according to physical & systemic examination
Absent
Present
No. of
patients
Percen
tage
No. of
patients
Percen
tage
Pallor
78
19.5
322
80.5
Koilonychia
382
95.5
18
4.5
Lymphadenopathy
395
98.8
5
1.3
Normal
Abnormal
No. of
patients
Percen
tage
No. of
patients
Percen
tage
CVS
398
99.5
2
0.5
CNS
400
100.0
0
0.0
Digestive system
352
88.0
48
12.0
Uro-genital system
393
98.3
7
1.7
Respiratory system
384
96.0
16
4.0
Not Palpable
Palpable
No. of
patients
Percen
tage
No. of
patients
Percen
tage
Liver
394
98.5
6
1.5
Spleen
396
99.0
4
1.0
80.5% of patients had significant pallor, which is a main sign of anaemia. However, on
examination very few patients had hepato-spleenomegaly.
86
Table 23. Distribution of patients according to complaints
Assessment stage
Complaints
0 day
No. of
Patients
Weakness
15th day
%
No. of
Patients
%
30th day
No. of
Patients
%
45th day
No. of
Patients
%
No
3
0.75
32
8.00
77
19.25 145
36.25
Yes
397
99.25
368
92.00
323
80.75 255
63.75
No
8
2.00
46
11.50
109
27.25 194
48.50
Yes
392
98.00
354
88.50
291
72.75 206
51.50
Palpitation No
160
40.00
209
52.25
275
68.75 323
80.75
Yes
240
60.00
191
47.75
125
31.25 77
19.25
No
173
43.25
215
53.75
291
72.75 345
86.25
intolerance Yes
227
56.75
185
46.25
109
27.25 55
13.75
Breathless No
199
49.75
262
65.50
317
79.25 358
89.50
ness
Yes
201
50.25
138
34.50
83
20.75 42
10.50
Swollen
No
351
87.75
375
93.75
385
96.25 392
98.00
feet
Yes
49
12.25
25
6.25
15
3.75
2.00
Fatigue
Effort
8
The above table shows that there was significant improvement in all the signs/
symptoms of anaemia like weakness, fatigue, palpitation, breathlessness and swollen
feet at all the subsequent assessment stages, when compared to 0 day.
87
Fig. 1. Distribution of patients according to sharirika prakriti
Fig. 2. Distribution of patients according to complaints
88
Table 24. Distribution of patients according to suspected adverse reactions
Suspected adverse reactions
Assessment stage
Burning sensation
Nausea
Diarrhea
Skin rashes
15th day 30th day
45th day
Absent
367
366
367
Present
33
34
33
Absent
382
386
388
Present
18
14
12
Absent
395
392
393
Present
5
8
7
Absent
392
390
391
Present
8
10
9
From the above table it is evident that the drug was well tolerated by the majority of
the patients. However in few cases adverse reactions like burning sensation and nausea
were observed
Table 25. Distribution of patients according to overall clinical assessment &
overall impression of well being
Assessment stage
Status
15th day
30th day
45th day
No. of Percen No. of Percen No. of Percen
patients tage
patients tage
patients tage
Overall
clinical
assessment
Improved
221
55.25
275
68.75
309
77.25
No change
179
44.75
125
31.25
85
21.25
0.0
0
0.0
6
1.50
(Physician’s Deteriorated 0
assessment)
89
Overall
Improved
impression
of well being No change
222
55.50
281
70.25
319
79.75
178
44.50
119
29.75
77
19.25
0.0
0
0.0
4
1.0
(Patient’s
Deteriorated 0
assessment)
Overall clinical improvement was significantly seen in 77.25 % and feeling of well
being was observed in 79.75 % patients at the end of the study.
Table 26. Distribution of patients according to findings of urine examination
(Routine)
Urine
Examination
(Routine)
Status
Assessment stage
0 day
Sugar
Albumin
Bile salts
Bile Pigments
45th day
No. of
patients
Percentage No. of
patients
Percentage
Absent
398
99.50
398
99.50
Present
2
0.50
2
0.50
Absent
396
99.00
395
98.75
Present
4
1.00
5
1.25
Absent
399
99.75
400
100.00
Present
1
0.25
0
0.00
Absent
399
99.75
400
100.00
Present
1
0.25
0
0.00
The table shows that in almost all patients the parameters of routine urine examination
were unaltered after administration of Dhatri Lauha.
90
Table 27. Distribution of patients according to findings of urine examination
(Microscopic)
Urine
Examination
(Routine)
Status
Assessment stage
0 day
RBC
Pus cells
Epithelial cell
45th day
No. of
patients
Percentage No. of
patients
Percentage
Absent
327
81.75
322
80.50
Present
73
18.25
78
19.50
Absent
273
68.25
259
64.75
Present
127
31.75
141
35.25
Absent
276
69.00
275
68.75
Present
124
31.00
125
31.25
Table 28. Distribution of patients according to findings of stool examination
Stool
Examination
Status
Assessment stage
0 day
Occult blood
Ova / cyst
45th day
No. of
patients
Percentage No. of
patients
Percentage
Absent
400
100.00
399
99.75
Present
0
0.00
1
0.25
Absent
378
94.50
393
98.25
Present
22
5.50
7
1.75
91
On stool examination, occult blood was noticed in one case at the end of treatment.
However Ova/Cyst was present in 5.5% and 1.75 % cases before and after treatment
respectively even after de-worming of the patients.
Table 29. Analysis of data on lab investigations at 0 day & 45th day (Number
of observations – 400)
Lab
Assessment
Parameters Stage
Mean
Std.
Devia
tion
95%Confidence t-value p-value
Interval of the
difference
Lower Upper
Bound Bound
TLC
P%
L%
E%
M%
B%
0 day
6869.38
45th day
6796.02 1920.435
0 day
59.30
8.949
45th day
59.84
8.597
0 day
35.17
8.829
45th day
35.39
8.349
0 day
3.67
4.641
45th day
3.02
4.382
0 day
1.72
2.062
45th day
1.61
2.142
0 day
0.04
0.330
45th day
0.02
0.141
25.38
23.50
18.596 0.114
19.328
ESR (mm/ 0 day
1st hr)
45th day
1874.439 -109.988 256.698
0.787
>0.05
-1.486 .411
1.114
>0.05
-1.124 .695
0.464
>0.05
0.284
3.476
<0.05
-0.059 .272
1.261
>0.05
-0.015 .055
1.132
>0.05
2.093
<0.05
1.025
3.655
After intake of Dhatri Lauha, Total Leukocyte Count (TLC) and Differential
Leukocyte Count (except Eosinophil count) changes were statistically insignificant.
92
Table 30. Analysis of data on assessment parameters at 0 day & 45th day
(Number of observations – 400)
Lab
Assessment
Parameters Stage
Mean
Std.
Devia
tion
Interval of the
difference
Lower Upper
Bound Bound
MCHC
0 day
29.48
2.928
(g/dl)
45th day
30.63
3.192
71.97
8.469
45th day
76.39
10.794
0 day
31.08
11.286
Iron (μg/dl) 45th day
46.58
29.665
*Serum
11.47
8.35
ferritin (μg/L) 45th day
17.76
18.51
Hb (g/dl)
0 day
8.46
1.144
45th day
9.18
1.614
28.46
3.963
45th day
30.50
5.283
45th day
361.81 271.344
MCV (fL) 0 day
Serum
0 day
PCV (%) 0 day
-1.544 -0.7733 5.910
<0.05
-5.4119 -3.4305 8.774
<0.05
-18.097 -12.906 11.740
<0.05
-7.832 -4.7492 8.023
<0.05
-0.8412 -0.6026 11.894
<0.05
-2.443 -1.648
<0.05
10.119
The therapy provided significant effect (p<0.05) in improving the Haemoglobin %,
serum iron, serum ferritin, Mean Corpuscular Haemoglobin Concentration (MCHC),
Mean Corpuscular Volume (MCV) and Packed Cell Volume (PCV) as all these
parameters where found statistically significant.
* Five patients (1.25%) were excluded for the analysis of serum ferritin as their values
were found on very higher side. The serum ferritin values of excluded cases were
13.4, 8.21, 16.32, 26.7, 28.6 μg/dl on 0 day and 295.3, 250.7, 148.6, 157, 136 μg/
dl on 45th day.
93
94
Fig. 3. Effect of the therapy on Mean Corpuscular Hemoglobin Concentration (MCHC)
95
Fig. 4. Effect of the therapy on Mean Corpuscular Volume (MCV)
96
Fig.5. Effect of the therapy on Serum Iron level
97
Fig.6. Effect of the therapy on Serum Ferritin level
98
Fig.7. Effect of the therapy on Haemoglobin (Hb) level
Table 31. Analysis of data on liver function tests at 0 day & 45th day (Number
of observations – 400) (Fig.8 & 9)
Lab
Assessment
Parameters Stage
Mean
Std.
Devia
tion
Interval of the
difference
Lower Upper
Bound Bound
Serium
0 day
0.62
0.299
Bilirubin
45th day
Total (mg/dl)
0.60
0.221
Serium
0.21
0.143
Bilirubin
45th day
Direct (mg/dl)
0.20
0.146
SGPT(IU/L) 0 day
19.65
11.534
45th day
19.36
9.505
SGOT
0 day
21.39
8.586
(IU/L)
45th day
20.83
7.377
0 day
S.Alkaline 0 day
112.56 67.607
Phasphatase 45th day
(U/L)
110.43 67.288
S.Protein
7.07
3.515
(Total) (g/dl) 45th day
7.11
3.197
Albumin
0 day
4.07
1.297
(g/dl)
45th day
4.08
0.528
Globulin
0 day
2.96
1.328
(g/dl)
45th day
2.87
0.625
0 day
-0.0084 0.0561
1.450
>0.05
-0.0077 0.0206
0.895
>0.05
-0.834 1.423
0.513
>0.05
-0.244 1.366
1.370
>0.05
-1.534 5.795
1.143
>0.05
-0.5076 0.4206
0.184
>0.05
-0.1424 0.1144
0.214
>0.05
-0.0485 0.2208
1.258
>0.05
All the safety parameters were found within the normal range which reflects that Dhatri
Lauha has no adverse consequences over liver function parameters.
99
Fig. 8. Effect of the therapy on Serum bilirubin levels (Total & Direct)
Fig. 9. Effect of the therapy on SGPT & SGOT levels
100
Table 32. Analysis of data on renal function tests at 0 day & 45th day
(Number of observations – 400) (Fig.10.)
Lab
Assessment
Parameters Stage
Mean
Std.
Devia
tion
Interval of the
difference
Lower Upper
Bound Bound
Blood Urea 0 day
22.91
7.169
(mg/dl)
22.44
6.244
0.87
0.180
0.89
0.210
45th day
S.creatinine 0 day
(mg/dl)
45th day
-0.193 1.139
1.395
>0.05
-0.0357 0.0068
1.340
>0.05
The values of renal function test after treatment were found within the normal range this
shows that clinically and statistically, there is no significant effect of Dhatri Lauha on
the safety parameters.
**p-value <0.05 was considered to be statistically significant.
Fig.10. Effect of the therapy on blood urea & serum creatinine levels
101
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102
DISCUSSION AND CONCLUSION
103
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104
CHAPTER-6
DISCUSSION AND
CONCLUSION
DISCUSSION
Over one third of the world’s population suffers from anaemia and almost half of them
suffering from iron deficiency anaemia. India is one of the countries with very high
prevalence. National Family Health Survey (NFHS-3) reveals the prevalence of
anaemia to be 70-80% in children, 70% in pregnant women and 24% in adult men. In
India the prevalence of anaemia is high because of low dietary intake, poor availability
of iron and chronic blood loss due to hook worm infestation and malaria. The true
toll of iron deficiency anaemia lies in the ill-effects on maternal health and fetal
development. Poor nutritional status and anaemia in pregnancy have consequences that
may extend over generations. In order to tackle this pressing public health problem, a
multi-pronged 12 x 12 initiative has been launched in the country. The initiative is
targeted at all adolescents across the country with the aim for achieving hemoglobin
level of 12 gm% by the age of 12 years by 2012 (www.whoindia.org)
Anaemia is called Pandu roga (pallor disease) in Ayurveda. In this disease, the body
turns pale and lusterless due to deficiency of blood in quality or quantity and this could
happen due to a number of reasons.
As the strength of body, and the functioning of sense organs, mind and digestive fire
(agni) depends upon the blood, its deficiency (anaemia) causes overall reduced work
capacity and it could affect the motor and mental development in children and
adolescents. It may also be responsible for improper visual and auditory functioning
105
along with poor cognitive development in children.
Keeping the gravity of the situation and the public health needs in view, the council
has initiated scientific validation of Dhatri Lauha, a promising Ayurvedic formulation that
is being successfully practised by physicians since centuries. The formulation has been
standardized by following the Standard Operating Procedures and evaluated for its
safety use / toxicity studies. No abnormality was noted in any vital organs after
administration of Dhatri Lauha at therapeutic dose level. No significant changes were
observed in any of the biochemical and haematological parameters at therapeutic dose
level when compared with controls. Since no toxic effects were observed in preclinical
studies, Council has initiated multicentric clinical trial with Dhatri Lauha.
Pandu roga is caused by vitiation of all the three Dosha predominantly pitta. It in turn
vitiates all the tissues (Dhatus) mainly blood and meda (sarakta medas-red marrow).
There is loss of complexion, strength, unctuousness and other qualities of Ojas since
Ojas is the essence of tissues (Dhatus). Hence the drug having the qualities like - 1)
cold in potency (Seeta veerya), 2) pacifying all three doshas mainly pitta, 3) providing
nourishment to all tissues i.e. having Rasayana action, 4) Promoting qualities of ojas, 5)
Promoting quantity and quality of blood – are necessary. The drug Dhatri Lauha has
all the above mentioned qualities.
The objective of current study was to assess clinical safety and efficacy of Dhatri
Lauha through measurable objective parameters. Multicentric study was conducted in
12 centers to evaluate the safety and efficacy of Dhatri Lauha in 45 days. Total 458
Patients were enrolled in this study out of which 400 patients have successfully
completed the study.
It was observed that the prevalence of anaemia was significantly higher in females than
males, which is due to the higher requirement of iron in reproductive age group. Out
of 400 patients of anaemia, maximum patients (57.2%) were illiterate and under
matriculate. It may be due to lack of awareness of nutritious diet in less educated
group. Anaemia was more prevalent in people belonging to lower socio-economic
group. It may be due to inadequate availability of the resources for taking nutritious
diet. The maximum numbers of patients (53.2 %) were housewives followed by
students (18.5%). This may be explained due to irregular food habits, and adequate
care is not given for taking nutritious diet. 20.8% cases were having addiction of tea/
coffee and addiction to tea/coffee might have induced anaemia. Diet- wise distribution
106
of the patients shows maximum patients (58%) were non-vegetarian versus 42% of
vegetarian. Maximum number of anaemia cases in non-vegetarians could be explained
due to high percentage of patients belonging to lower socio-economic group, whose
resources do not meet for taking nutritious diet.
In females (though having regular & normal menstrual history) Iron Deficiency Anaemia
was more common as the amount of iron required to replace the loss is not fulfilled
adequately. In this study, anaemia was more prevalent in the patients of Vata Pittaja
(48.7%) & Pitta Kaphaja (30.1%) Prakriti, it may be due to vitiation of Pitta Dosha
which plays main role in etiopathogenesis of Pandu. 80.5% of patients had significant
pallor, which is a main sign of anaemia. However, on examination very few patients
had hepato-spleenomegaly.
The therapy provided significant improvement in weakness, fatigue, palpitation,
breathlessness and swollen feet at all the subsequent assessment stages, when
compared to baseline.
The drug was well tolerated by the majority of the patients. However in few cases
adverse reactions like burning sensation and nausea were observed. Overall clinical
improvement was significantly seen in 77.25% and feeling of well being was observed
in 79.75% patients at the end of the study. The parameters of routine urine
examination were unaltered after administration of Dhatri Lauha. RBC in Microscopic
urine examination was found in some cases before and after treatment, which could be
due to contamination with menstrual blood. On stool examination, occult blood was
noticed in one case at the end of treatment.
After intake of Dhatri Lauha, Total Leukocyte Count (TLC) and Differential
Leukocyte Count (DLC) changes were statistically insignificant. The increased ESR at
baseline was significantly approaching towards the normal limits after treating with
Dhatri Lauha.
The safety parameters show that Dhatri Lauha has no adverse consequences over liver
and kidney functions during the study.
The therapy provided significant effect (p<0.05) in improving the hemoglobin
percentage. Mean Corpuscular Volume (MCV) and Mean Corpuscular Hemoglobin
Concentration (MCHC) were increased due to increased hemoglobin concentration.
After completion of therapy serum iron and stored iron (serum ferritin) were increased
107
significantly (p<0.05).
This multicentric clinical trial shows that the Dhatri Lauha is safe and effective in
patients of Iron Deficiency Anaemia.
CONCLUSION
The Dhatri Lauha is safe and significantly increases the hemoglobin percentage, Serum
Iron and Serum Ferritin in subjects with Iron Deficiency Anaemia and subsequently
improves the quality of life of the subjects.
108
BIBLIOGRAPHY
109
Blank
110
BIBLIOGRAPHY
1.
Harrison’s Principles of Internal Medicine by Fauci et;al Vol -I, 17th Edition
2008 Mc Graw Hill
2.
Krause’s Food, Nutrition and diet therapy, by L. Kathleen Mahan, Sylvia
Escott stump, 11th Edition 2000: SAUNDERS.
3.
Guyton textbook of Medical Physiology, 8th edition, 1991: A Prism Saunders.
4.
Charak Samhita with the Ayurveda–Dipika Commentary (of Chakrapani Datta)
edited by Acharya Yadavji Trikamji,3rd Edition 1941 : Satyabhamabai
Pandurang, Bombay.
5.
Sushruta Samhita with Commentory of Atrideva, 3rd edition, 1960 : Motilal
Banarasidas, Varanasi
6.
Kashinath shastri (1969) : Rasatarangini, 8th edition, published by Motilal
Banarasi Das, New Delhi.
7.
Rasa Jala Nidhi compiled in Sanskrit by Bhudeb Mookerjee Vol – III,, 2nd
Edition, 1984 : Srigoukul Mudranalaya, Varanasi.
8.
Ayurveda Prakash by Upadhyaya Madhav, Arthavidyotini and Arthaprakasini
commentaries (of Vaidya Gulrajsharma Mishra) 2nd Edition 2019: Chaukhamba
Vidya Bhavan, Varanasi.
9.
Kayachikitsa by Prof. Ajay Kumar Sharma, Vol–2, 1 st Edition 2006:
Chaukhambha Orientalia, Delhi.
10.
Ayurvedic Pharmacopoeia of India, Part-I, Vol-I, Anonymous, Govt. of India,
Ministry of Health and Family Welfare, Dept. of AYUSH., New Delhi.
11.
Ayurvedic Formulary of India, Part-I, 18:14, Anonymous, 2nd edition 2003 :
Govt. of India Ministry of Health and Family Welfare, Dept. of I.S.M.H.,
New Delhi.
12.
A.I. Vogel (1961): The textbook of quantitative inorganic analysis, 3rd edition.
13.
Anonymus (1990): Phytochemical Investigations of Certain Medicinal Plants
used in Ayurveda, 1st Ed., Central Council for research in Ayurveda and
Siddha, Ministry of Health and family Welfare, Govt. of India. Published by
111
CCRAS.
14.
Compendium of Indian Medicinal Plant : Ram P. Rastogi and B. N. Mehrotra,
1993, Central Drug Research Institute, Lucknow.
15.
Kulkarni SK. Handbook of Experimental Pharmacology, Ed. 3rd. Vallabh
Prakashan, New Delhi, 1999.
16.
Quality control methods for medicinal plant materials, WHO, Geneva, 1998.
17.
Stahl, E. (2007); Thin Layer Chromatography (A laboratory Handbook), 2nd
Ed., Fully revised and expended 2nd reprint, Translated by M.R. P. Ashworth.
Publisher by Springer (India) Pvt. Ltd.
18.
Chaterjee A. & Pakrashi, S. C. (2006) : The treatise on Indian Medicinal
plants, NISCAIR, New Delhi, Vol. 2 (Revised).
19.
Paget and Barnes, Evaluation of Drug Activities: Pharmacometrics eds,
Laurance and Bacharach, Vol.I. Academic Press, New York. 1964.
112
LIST OF TABLES
113
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114
LIST OF TABLES
Table 1.
Estimated prevalence of anaemia (% of total affected population)
Table 2.
Specific symptoms of Pandu Roga according to humours
Table 3.
Ingredient Profile of Dhatri Lauha
Table 4.
Composition of Dhatri Lauha
Table 5.
Physico-Chemical Standards and Quality Parameters Of Dhatri Lauha
Table 6.
Standards of Raw Ingredients
Table 7.
Sub acute toxicity : The body weight of animals (in gm) treated with
Dhatri Lauha
Table 8.
Sub acute toxicity : Investigation of blood hematology of rat treated
with Dhatri Lauha after 14 days
Table 9.
Sub acute toxicity : Investigation of serum biochemistry of rat treated
Table 10.
Sub acute toxicity : Investigation of blood hematology of rat blood
treated with Dhatri Lauha after 28 days
Table 11.
Sub acute toxicity : Investigation of serum biochemistry of rat treated
Table 12.
Centre wise patients enrolled and completed
Table 13.
Distribution of patients according to age and sex
Table 14.
Distribution of patients according to educational status
Table 15.
Distribution of patients according to socio-economical status
Table 16.
Distribution of patients according to occupation
Table 17.
Distribution of patients according to addictions
Table 18.
Distribution of patients according to diet
Table 19.
Distribution of patients according to menstrual history
115
Table 20.
Distribution of patients according to quantity of menstruation
Table 21.
Distribution of patients according to sharirika prakriti
Table 22.
Distribution of patients according to physical & systemic examination
Table 23.
Distribution of patients according to complaints
Table 24.
Distribution of patients according to suspected adverse reactions
Table 25.
Distribution of patients according to overall clinical assessment &
overall impression of well being
Table 26.
Distribution of patients according to findings of urine examination
(Routine)
Table 27.
Distribution of patients according to findings of urine examination
(Microscopic)
Table 28.
Distribution of patients according to findings of stool examination
Table 29.
Analysis of data on lab investigations at 0 day & 45th day
Table 30.
Analysis of data on assessment parameters at 0 day & 45th day
Table 31.
Analysis of data on liver function tests at 0 day & 45th day
Table 32.
Analysis of data on renal function tests at 0 day & 45 day
116
ANNEXURE
CASE RECORD FORM
117
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118
MULTICENTRIC OPEN CLINICAL TRIAL OF
DHATRI LAUHA IN IRON DEFICIENCY ANAEMIA
STUDY CODE: 01
TRIAL CENTRE:
Name of the Investigator (s)
Subject`as Name
in BLOCK Letter
Sl. No. of the Subject
DATE OF ENROLLMENT
DATE OF Visit
0-Day
15th Day
30th Day
STATUS :
45th Day
Signature of the Director / In Charge
Completed :
Discontinued :
[Dept. of AYUSH, Ministry of Health & Family Welfare, Govt. of India]
119
CONTENTS:
1. Check list of Activities
2. Patients information Sheet
3. Consent by Subject
4. Case Record Form I – Screening
5. Case Record Form II – History
6. Case Record Form IIA – Determination of Prakriti
7. Case Record Form III – Periodical Observation and Clinical Assessment
8. Case Record Form IV (A, B, C, D) – Periodical Observation and Laboratory
Assessment
9. Case Record Form V – Consolidated Data on Periodical Observations
10. Drug Compliance Reports 1 to 3
11. Receipts
GENERAL INSTRUCTIONS:
1. Please follow all the instructions provided in the trial manual.
2. Reporting the data of each subject to monitoring center (CCRAS Hqrs):
The data on subject should be sent to the Hqrs. immediately after completion of
each visit in MS Excel form along with the photocopy of all case record forms
and the drug compliance report. Besides the regular fortnight report in MS Excel,
Covering letter for completed case record forms, Patient’s log – sheet and other
Details are to be sent to the Council at the end of every month.
3. Maintenance of records:
Checklist of activities, Drug Compliance reports, Case record forms.
Patient’s log – sheet and other details should be maintained in triplicate.
4. Use Patient Information Sheet and Consent Form printed in local languages.
5. Corrigendum:
Changes made in Inclusion / Exclusion Criteria should be noted for necessary
compliance.
120
CHECK LIST OF ACTIVITIES
Phase
Activity
Status Please
put mark
where ever
applicable
Yes
PRE
Issue of patient information
sheet
RECRUIT
Counseling-I
MENT
Signing of consent form
Referring for laboratory
screening
De- worming
Laboratory Screening &
Instructions for next visit
(Minimum 7 days after
de-worming)
Filling up of CRF I
(Screening) (0day)
RECRUIT
MENT0 DAY
POSTRECRUIT
MENT –
0 DAY
Recruitment of the subject
(If suitable) on 0 day
Filling up of CRF II
(History) (0day)
Filling up of CRF III
(Clinical Assessment) (0day)
Filling up of CRF IV-A
(Laboratory Investigations)
(0day)
121
No
Remarks if
any
Drug dispensing on 0 day,
issue of Drug Compliance
Report-I and instruction for
next follow up 1 on15th day
Payment of 1st remuneration
of Rs.100 to recruited subject
Reporting the data of each
subject to monitoring center
(CCRAS Hqrs) in MS Excel
Issue of reminders by phone/
fax/ e-mail/post card before
next follow up
POSTRECRUIT
MENT – 15
TH DAY
Follow up visit on 15th day
Collection & coding of sample
for laboratory investigations
Clinical assessment
Filling up of CRF III (Clinical
Assessment) (15th day)
Filling up of CRF IV- B
(15th day)
Drug dispensing on 15th day,
receiving of Drug Compliance
Report-I & issue of Drug
Compliance Report-II and
instruction for next follow up
2 on 30th day
Payment of 2nd remuneration
122
and notifying the adverse
reaction
next follow up
POST-
RECRUIT
for laboratory investigation
MENT–
Clinical assessment
30th DAY
Filling up of CRF IV- C
(30th day)
Report-II & issue of Drug
Compliance Report-III and
3 on 45th day
Payment of 3rd remuneration
and Notifying the adverse
reaction
next follow up
POST-
123
RECRUIT
MENT–
45th DAY
for laboratory investigation
Clinical assessment
Filling up of CRF IV- D
(45th day)
Payment of 4th remuneration
reaction
Report-IV & issue of Drug
Compliance Report-V and
5 on 75th day
Payment of 5th remuneration
reaction
Reporting the consolidated
data after the fulfillment of
study target
124
PATIENT INFORMATION SHEET
CENTRAL COUNCIL FOR RESEARCH IN AYURVEDAAND SIDDHA
MULTI CENTRIC OPEN CLINICAL TRIAL OF SELECTED DRUGS IN
IRON DEFICIENCYANAEMIA.
What is the study about?
Iron Deficiency Anaemia is commonest form of anaemia in developing countries. It is
mainly caused by Iron, Vitamin-B12 and Folate deficiency and worm infestation. It occurs
in both sexes especially in growing children and pregnant and lactating women.
In conventional medicine various forms of iron viz. Ferrous sulfate, ferrous fumerate etc.
are commonly prescribed, but these therapies have their noted adverse effects e.g. nausea,
vomitting, abdominal pain, diarrhoea/constipation.
Owing to the gravity of the situation, need is felt for search of safe /effective Siddha oral
dosage forms to improve the haemoglobin level in iron deficiency anaemia. Keeping the
gravity of the situation and the public health needs in view, the council has initiated scientific
studies on Annabhedi Chendooram, a promising formulation that is being successfully
prescribed by Siddha physicians without any side effects since centuries. The formulation
has been standardized after formulating SOPs besides safety / toxicity evaluation.
The formulation is found safe and biological activity studies revealed significant haematenic
effect. (Unpublished data of CCRAS).The objective of current study is to assess clinical
safety and efficacy through measurable objective parameters.
What will you have to do?
Your doctor will explain clearly what you have to do. It is important that you follow the
instructions scrupulously. The study will take approximately one and a half month (45
days). During treatment period, you are expected to visit the hospital seven times i.e. on
0,15th, 30th and 45th day for clinical and physiological assessment.
Before you start treatment, during the first visit to the clinic, you will undergo a complete
physical examination, required objective tests and laboratory investigations will also be
done.
125
If you are found eligible, you would be put on trial treatment for 45 days.
At each visit, you will be supplied with sufficient quantities of drugs to last until your next
visit. If any adverse reactions like skin allergy, nausea, vomiting and palpitation/tremor
etc., noticed during the treatment period, this should be noticed to the Principle Investigator.
Translated into regional language
126
WRITTEN INFORMED CONSENT FORM
CERTIFICATE BY INVESTIGATOR
I certify that I have disclosed all details about the study in the terms easily understood by
the patient.
Date: ___________
Signature of the Investigator ________________
Name _______________________________
CONSENT BY SUBJECT
I have been informed to my satisfaction, by the attending physician, the purpose of the
clinical trial and the nature of drug treatment and follow-up, including the laboratory
investigations to be performed to monitor and safeguard my body functions.
I am also aware of my right to opt out of the trial at any time during the course of the trial
without having to give the reasons for doing so. I am willing to undergo any risk for inclusion
in this study.
I, exercising my free power of choice, hereby give my consent to be included as a subject
in the clinical trial on “Multi centric open Clinical trial of selected (Dhatri Lauha)
drugs in Iron deficiency Anaemia.”
Date: ________________
Name of subject________________________
Signature or Thumb impression______________
Name: _______________
Date: ________________
Name of witness: _______________________
Signature or Thumb impression: _____________
Relationship: ___________________________
Translated into regional language
127
MULTICENTRIC OPEN CLINICAL TRIAL OF SELECTED DRUGS IN
CASE RECORD FORM I – SCREENING
BEFORE TREATMENT
1.
Centre: ..................................................................................................................
2.
Code No. (of clinical trial) :
3.
Subject Name : .....................................................................................................
4.
Sex :
5.
Date of Birth :
Male (1)
D D
Female (2)
M M
Y
Y
Y
Y
6.
Age in years :
7.
Address : ..............................................................................................................
CRITERIA FOR INCLUSION
Yes (1)
8.
Age between 15 to 60 years
9.
Hemoglobin level between 6 to 10 gm / dl
10.
Serum iron content < 50 μg /dl
11.
S. Ferritin < 30 μg /L
12.
MCHC < 34 g/dl
13.
MCV<80 fl
128
No (0)
14.
Peripheral smear for blood shows
Hypochromic & Microcytic anaemia
CRITERIA FOR EXCLUSION
15.
Age less than 15 years and more than 60 years.
16.
Pregnant / lactating woman
17.
Severe Renal/Hepatic/Cardiac disease*
18.
Any continuing blood loss e.g. hematemesis,
Yes (1)
No (0)
YES
NO
melena and bleeding piles etc.
19.
Dimorphic anaemia
20.
History of Chronic Infections
Whether the subject is suitable for enrollment?
(A subject is suitable for enrollment in the trial, if points 8 to 14 are YES and points 15 to
20 are NO)
If enrolled:
Subject SI. No.: Date: ___________
No. of strips issued _______________
Date: ______________
Signature of the Investigator: _______________
Name of the Investigator: __________________
129
* Normal range of values for SI. No. 17
Liver function tests
a. S. Bilirubin
i.
Total
0.3 — 1.0 mg/dl
ii.
Direct
0.1 – 0.3 mg/dl
b. SGPT
0 – 35 IU/L
c. SGOT
0 – 35 IU/L
d. S. Alkaline phosphatase
30 – 120 IU/L
e. S. Proteins (Total)
5.5 — 8.0 g/dI
i.
Albumin
3.5 – 5.5 g/dl
ii.
Globulin
2.0 — 3.5 g/dl
Renal function tests
f. Blood urea
15 – 40 mg/dI
g. S. Creatinine
< 1.5 mg/dl
130
CASE RECORD FORM II – HISTORY
1.
Centre: ..................................................................................................................
2.
3.
Sl. No. of the subject: .............................................................................................
4.
Subject Name : .....................................................................................................
5.
Sex :
6.
Date of Birth :
Male (1)
D D
Female (2)
M M
Y
Y
Y
Y
7.
Age in years :
8.
Address : ..............................................................................................................
9.
Educational status:
Illiterate (1)
Under (2)
Matriculation
Matriculation (3)
10.
Annual Income of the family Rs.
11.
Total number of members sharing the income
12.
Occupation:
Graduate (4)
PG (5)
and
above
Desk work (1)
Field work (2)
House Wife (3)
Student (4)
Others (specify)_______________(5)
If Field work, indicate nature of work: _____________________
131
HISTORY OF PRESENT ILLNESS:
Chief complaints with duration (in days)
13.
Weakness
14.
Fatigue
15.
Palpitation
16.
Effort intolerance
17.
Breathlessness
18.
Swollen feet
19.
Asymptomatic
20.
Onset of disease
Acute (1)
21.
Previous episodes
Yes (1)
22.
Duration of disease (in days)
Yes (1)
No (0)
Duration
(in days)
Insidious (2)
No (0)
PERSONAL HISTORY:
Addictions:
Yes (1)
23.
Alcohol:
24.
Tea / Coffee more than 4 times a day
25.
Tobacco
26.
If Yes,
Chewing (1)
No (0)
Smoking (2)
Both (3)
27.
Diet
Vegetarian (1)
Non Vegetarian (2)
Menstrual history:
28.
Regular
(1)
Irregular (2)
29.
If irregular, Specify_______________________________________________
132
30.
Duration of menstruation
Up to 5 days (1)
31.
5-7 days (2)
More than 7 days (3)
Quantity
Normal (1)
Abnormal (2)
If abnormal, Specify______________________________________________
32.
Sharirik Prakriti:
Vataj (1)
Pittaj (2)
Kaphaj (3)
Vata Kaphaj (4)
Vata pittaj (5)
Pitta kaphaj (6)
Heavy (3)
PHYSICAL EXAMINATION:
33.
Built
Lean (1)
Medium (2)
34.
Gait
Normal (0)
Abnormal (1)
35.
Body weight (Kg.) __________
36.
Height (cm)_________
37.
Body temperature (oF)____________
Blood pressure (in sitting posture of right upper limb) –
38.
Systolic_______mm/Hg
39.
Diastolic _______mm/Hg
40.
Pulse rate__________/min. (Radial pulse of right upper limb)
41.
Respiration rate _________/min.
42.
Pallor
Present (1)
Absent (0)
43.
Koilonychia
Present (1)
Absent (0)
44.
Lymphadenopathy
Present (1)
Absent (0)
133
SYSTEMIC EXAMINATION:
45.
CVS with chest
Normal (0)
Abnormal (1)
If Abnormal, specify abnormalities____________________________________
46.
CNS
Normal (0)
Abnormal (1)
If abnormal, specify abnormalities____________________________________
47.
Digestive system
Normal (0)
Abnormal (1)
Abdomen
48.
Liver
49.
Spleen
50.
Uro-genital system
Palpable (1)
Not palpable (0)
Normal (0)
Abnormal (1)
51.
Respiratory system
Normal (0)
Abnormal (1)
SAMPRAPTI (PATHOGENESIS)
52.
Anubandhya dosha
Vata (1)
Pitta (2)
Kapha (3)
53.
Anubandh dosha
Vata (1)
Pitta (2)
Kapha (3)
54.
Avraka dosha
Vata (1)
Pitta (2)
Kapha (3)
55.
Ksheena dosha
Vata (1)
Pitta (2)
Kapha (3)
56.
Ksheena dhatu
Rasa (1)
Rakta (2)
Mamsa (3)
Meda (4)
Asthi (5)
Majja (6)
Shukra (7)
Oja (8)
Rasa (1)
Rakta (2)
Mamsa (3)
Meda (4)
Asthi (5)
Majja (6)
57.
Dusya
134
Shukra (7)
Date: ______________
Oja (8)
Signature of the Investigator: _______________
Name of the Investigator: __________________
135
CASE RECORD FORM IIA
(Enter a in the appropriate box)
DETERMINATION OF PRAKRUTI
1. PHYSIOLOGICAL STATUS (PHS)
1.01 Status of Appetite: (AD)
a. Good appetite
b. Stable appetite with usually moderate desire to eat
c. Variable appetite
1.02 Dietary/Eating habits (DH)
a. Enjoys eating, ready to eat mostly & hates to miss food
b. Regular food habits, but can spend hours without food
c. Desirous to take food, eats less at a time, needs mid-meals snacks
1.03 Bowel Habits (BH)
a. Regular, once-a-day, stool well formed, if constipated it is mild
(Respond to medium strength laxative)
b. Regular & frequent, stool semisolid or loose, rarely constipated.
(Respond to mild laxatives sometimes even milk, fig., raisins etc.)
c. Variation seen, mostly constipated (strong purgatives are needed)
136
1.04 Sleeping Pattern (SH)
a. Sleeps easily but light
b. Sleeps easily and sound (heavily)
c. Trouble to get sleep, light sleeper / Variable sleep pattern
1.05 Morning feelings, after leaving the bed(MF)
a. Don’t fel fresh
b. Feel fresh. Feel well even with less sleep.
c. Feel fresh but not good when have less hours of sleep.
1.06 Dreams (DM)
a. Cool and peaceful dreams, not bothers to remember
b. Passionate dreams, sees heat, light & remembers well
c. Plenty of dreams, mostly related to motion, usually forgets
1.07 Physical working capacity/physical strength
a. Starts with speed & gets exhausted easily
b. Loves hard work, has moderate capacity
c. Good stamina but slow and not interested for physical work.
1.08 Performance of activities
a. Quickly with a lot of initiative
b. Moderately with medium initiative
c. Slow, steady and balance activities
137
1.09 Talking
a. Very fast missing words
b. Sharp, provocative and clear-cut
c. Slow, clear and stable
1.10 Walking
a. Very quick with swift movement
b. Normal and rhythm
c. Slow and steady
1.11 Associated movements of body while working
a. Excessive and frequent, difficult to tolerate
b. Less thirst, easy to tolerate
c. Moderate perspiration, consistent to climate, with pleasant smell.
1.12 Nature of Thirst (TN)
a. Excessive and frequent, difficult to tolerate
b. Less thirst, easy to tolerate
c. Moderate and variable thirst
1.13 Status of Perspiration (SP)
a. Scanty even in hot climate but odourless
b. Profuse with strong odour
c. Moderate perspiration, consistent to climate, with pleasant smell.
138
1.14 Sexual qualities (SQ)
a. Variable, strong desire, overindulgence, & gets exhausted
b. Moderate with dominating behavior
c. Usually low and steady desire, with good stamina
1.15 Quantity of seminal discharge
a. Scanty and comparatively thin in consistency
b. Moderate and normal
c. Plenty and thick
1.16 Fertility or productivity
a. Comparatively lesser
b. Less
c. Capable of producing good no. of off springs
1.17 Longevity or average age
a. Short life span
b. Moderate life span
c. Long life span
1.18 Resistance to diseases (RD)
a. Usually poor. Frequently fall ill.
b. Medium
c. Good. Able to tolerate seasonal variation, food etc. well
139
1.19 Climatic Preferences (CP)
a. Prefers warm, avoids cold climate
b. Likes cold, but intolerant to warm/hot
c. Likes normal climate & prefers warm in comparison to cold
2. MENTAL/PSYCHOLOGICAL STATUS:
2.01 Mental Reactions (MR)/Personality Traits:
a. Very sensitive, reacts quickly
b. Gets Irritated easily & sustains it.
c. Cool, calm, avoids confrontations
2.02 Memory Status (MS)
a. Remembers easily & tends to forget easily
b. Takes time to grasp, but retains for long
c. Remembers easily and tends to retain
2.03 Leadership quality(LQ)
a. Don’t like to lead and happy as a follower.
b. Requires commanding status.
c. Avoid leading.
2.04 Decision making capacity(DMC)
a. Takes immediate decision without thinking much.
b. Takes decision after properly analyzing the facts.
140
c. Avoid taking decision. Usually keeps them pending.
2.05 Concentration Power (CP)
a. Very easy to concentrate on a work, but not for long duration
b. Difficult to concentrate on a work
c. Retains concentration for a long period
2.06 Attitude towards problems or difficulties
Lot of worrying, instability in reaction
Angry, over awed, easily provoked and highly irritable
Peaceful, slow, steady and balance
2.07 Nature
a. Easily irritable, irritating to others, exaggerating, anxious
materialistic liking
b. Polite but hot-tempered, proudy, brave, bold, less but
good friendship
c. Polite, decent, not greedy, appreciating, have good and long
lasting friendship
2.08 Liking about taste (TL)
a. Sweet, salt & sour
b. Sweet, bitter & astringent
c. Pungent, astringent & bitter
141
3. PHYSICAL FEATURES: (PF)
3.01 Body frame (BF)
a. Thin body frame, unusually long/short
b. Medium frame
c. Broad, Large frame
3.02 Body weight (BW)
a. Moderate/Average weight
b. Underweight or Tendency of fluctuation
c. Over weight or with a tendency to gain weight
3.03 Distribution of body fat (DBF)
a. Unequal/on specific areas
b. Evenly distribution
c. Scanty deposition of body fat.
3.04 Nature/Texture of skin
a. Delicate, Irritable skin, gets wrinkles easily
b. Dry, rough, cracked, or having a tendency of cracking
c. Smooth, firm, soft, clear with good lusture, not prone to disorders
3.05 Complexion/skin color (SC)
a. Extremely fair / pinkish
b. Fair, reddish, burns easily
142
c. Comparatively dull or darkish, tans easily
3.06 Body Hair (BH)
a. Dry, rough, coarse, lustureless & curly
b. Soft, scanty, straight, fine textured
c. Thick, shiny, moderate
3.07 Forehead (FH)
a. Large
b. Medium
c. Small
3.08 Eyes (EF)
a. Rolling, restless, small, dull & lusterless
b. Sharp, medium sized with sclera of reddish tinge
c. Large calm stable eyes with milky white sclera
3.09 Teeth (TE)
a. Teeth are of average size, yellowish, prone to cavities
b. Dry, cracked, irregular dull white
c. Large, even, gleaming white
3.10 Tongue (TO)
a. Thin tongue, with blackish spots, often coated with thin adherent coating
b. Medium, Reddish, occasionally coated with yellow or red coating
143
c. Thick usually clear, rarely coated, coating is usually thick white
3.11 Lips (LP)
a. Soft, moist & reddish
b. Dry, thin & blackish
c. Thick & glossy
3.12 Blood Vessels (BV)
a. Prominent
b. Less prominent
c. Not visible
3.13 Scalp Hair (SH)
a. Dark in Shade, coarse, rough, easily prone to dandruff and
split ends.
b. Thin, delicate, straight, light coloured, turn grey at an early age
c. Strong, thick, dark, slightly wavy with good lusture, oiliness is
usually one of the chief complaints
3.14 Joints (JT)
a. Crackling joints, hyper mobile in nature
b. Comparatively normal but have soft and loose ligaments
c. Well lubricated, strongly built joints which are well organized,
well covered
144
3.15 Voice (VR)
a. Rough, unclear voice, which turns hoarse or cracks on strain
b. Concise, sharp voice, intense in nature & high pitched
c. Deep, pleasant, resonant voice which is melodious, resonating,
but lower in pitch and intensity
3.16 Nail (NL)
a. Hard, brittle, rough & differ in size from one another, bluish/
grayish in contour
b. Soft, Strong, well formed, Lustrous, pink in colour
c. Strong, large, thick symmetrical & somewhat pale in colour
3.17 Body temperature
a. Feels slightly cold on touch
b. Feels slightly warm on touch
c. Normal
3.18 Shape of Palms and feet
a. Short and broad
b. Medium and slim
c. Long and broad
3.19 Face
a. Small and broad with uneven features
b. Medium & oval with sharply defined features
145
c. Round, babbly and attractive with balance features
4 Social or economical status
4.01 Economy
a. Getting less outcome with hard work
b. Getting good outcome with moderate efforts
c. Enjoys lavishly and royal life
146
SCORE SHEET FOR DETERMINATION OF PRAKRUTI
Sl. no. of the subject.___________________________________________________
S.No.
Observation
Code
Options
a
b
Identified Area (V/P/K)
1.
1.01
PK
V
2.
1.02
P
K
V
3.
1.03
K
P
V
4.
1.04
P
K
V
5.
1.05
V
P
K
6.
1.06
K
P
V
7.
1.07
V
P
K
8.
1.08
V
P
K
9.
1.09
V
P
K
10.
1.10
V
P
K
11.
1.11
V
P
K
12.
1.12
P
K
V
13.
1.13
V
P
K
14.
1.14
V
P
K
15.
1.15
V
P
K
16.
1.16
V
P
K
17.
1.17
V
P
K
18.
1.18
V
P
K
19.
1.19
V
P
K
20.
2.01
V
P
K
21.
2.02
V
K
P
22.
2.03
K
P
V
23.
2.04
V
P
K
c
147
24.
2.05
P
V
K
25.
2.06
V
P
K
26.
2.07
V
P
K
27.
2.08
V
P
K
28.
3.01
V
P
K
29.
3.02
P
V
K
30.
3.03
K
P
V
31.
3.04
P
V
K
32.
3.05
K
P
V
33.
3.06
V
P
K
34.
3.07
K
P
V
35.
3.08
V
P
K
36.
3.09
P
V
K
37.
3.10
V
P
K
38.
3.11
P
V
K
39.
3.12
V
P
K
40.
3.13
V
P
K
41.
3.14
V
P
K
42.
3.15
V
P
K
43.
3.16
V
P
K
44.
3.17
V
P
K
45.
3.18
V
P
K
46.
3.19
V
P
K
47.
4.01
V
P
K
INDIVIDUAL SCORE OF VPK
V
P
K
PERCENTAGE OF VPK
V=
P=
K=
TYPE OF PRAKRUTI
Abbreviations-V-Vata, P-Pitta, K-Kapha
148
IRON DEFICIENCYANAEMIA
CASE RECORD FORM – III
PERIODICAL OBSERVATION AND CLINICALASSESSMENT
(On 0 Day)
1.
Centre: ..................................................................................................................
2.
3.
4.
Subject Name : .....................................................................................................
5.
Age in years :
6.
Sex :
7.
Date of Assessment :
Male (1)
D D
Female (2)
M M
8.
Weakness
9.
Fatigue
10.
Palpitation
11.
Effort intolerance
12.
Breathlessness
13.
Swollen feet
14.
Asymptomatic
149
Y
Yes (1)
Y
Y
Y
No (0)
Duration
(in days)
15.
Other Associated Symptoms
If Yes, Please Specify
____________________________________________________________
____________________________________________________________
____________________________________________________________
Date: ____________________________
Signature of Investigator ______________
Name of Investigator ________________
150
(On 15th Day)
1.
Centre: ..................................................................................................................
2.
3.
4.
Subject Name : .....................................................................................................
5.
Age in years :
6.
Sex :
7.
Male (1)
D D
Female (2)
M M
8.
Weakness
9.
Fatigue
10.
Palpitation
11.
Effort intolerance
12.
Breathlessness
13.
Swollen feet
14.
Asymptomatic
151
Y
Yes (1)
Y
Y
Y
No (0)
Duration
(in days)
15.
____________________________________________________________
____________________________________________________________
____________________________________________________________
Date: ____________________________
Adverse reactions:
Present (1)
Absent (0)
Duration
(in days)
16.
Burning sensation in abdomen
17.
Nausea
18.
Diarrhoea
19.
Skin rashes
20.
Any other adverse complaints / observations specify_______________________
21.
Overall clinical assessment:
Improved (1)
22.
Deteriorated (3)
Overall impression of well being by the Subject:
Improved (1)
23.
No change (2)
No change (2)
Deteriorated (3)
Status of the subject:
Continuing (1)
Drop out (2)
Reason: ______________________________
152
Death(3)
24.
Cause: _______________________________
If continuing Number of blisters issued: _________________________________
Date: ______________________
Signature of Investigator __________________
Name of Investigator ____________________
153
(On 30th Day)
1.
Centre: ..................................................................................................................
2.
3.
4.
Subject Name : .....................................................................................................
5.
Age in years :
6.
Sex :
7.
Male (1)
D D
Female (2)
M M
8.
Weakness
9.
Fatigue
10.
Palpitation
11.
Effort intolerance
12.
Breathlessness
13.
Swollen feet
14.
Asymptomatic
154
Y
Yes (1)
Y
Y
Y
No (0)
Duration
(in days)
15.
____________________________________________________________
____________________________________________________________
____________________________________________________________
Date: ____________________________
Adverse reactions:
Present (1)
Absent (0)
Duration
(in days)
16.
17.
Nausea
18.
Diarrhoea
19.
Skin rashes
20.
21.
Improved (1)
22.
Deteriorated (3)
Improved (1)
23.
No change (2)
No change (2)
Deteriorated (3)
Continuing (1)
Drop out (2)
Reason: ______________________________
155
Death(3)
24.
Cause: _______________________________
If continuing Number of blisters issued: _________________________________
Date: ______________________
156
(On 45th Day)
1.
Centre: ..................................................................................................................
2.
3.
4.
Subject Name : .....................................................................................................
5.
Age in years :
6.
Sex :
7.
Male (1)
D D
Female (2)
M M
8.
Weakness
9.
Fatigue
10.
Palpitation
11.
Effort intolerance
12.
Breathlessness
13.
Swollen feet
14.
Asymptomatic
157
Y
Yes (1)
Y
Y
Y
No (0)
Duration
(in days)
15.
____________________________________________________________
____________________________________________________________
____________________________________________________________
Adverse reactions:
Present (1)
Absent (0)
Duration
(in days)
16.
17.
Nausea
18.
Diarrhoea
19.
Skin rashes
20.
21.
Improved (1)
22.
Deteriorated (3)
Improved (1)
23.
No change (2)
No change (2)
Deteriorated (3)
Drop out (2)
Reason: ______________________________
Death (3)
Cause: _______________________________
Date: ______________________
158
(On 0 Day)
CASE RECORD FORM IV
PERIODICAL OBSERVATION AND LABORATORYASSESSMENT
FORM IV-A – LABORATORY INVESTIGATIONS
1.
Centre: ..................................................................................................................
2.
3.
4.
Subject Name : .....................................................................................................
5.
Age in years :
6.
Sex :
7.
Male (1)
D D
Female (2)
M M
Y
Y
Y
Urine Examination
Routine
8.
Sugar
Absent (0)
Present (1)
9.
Albumin
Absent (0)
Present (1)
10.
Bile Salts
Absent (0)
Present (1)
11.
Bile Pigments
Absent (0)
Present (1)
Absent (0)
Present (1)
Microscopic
12.
RBC
159
Y
13.
Pus Cells
Absent (0)
Present (1)
14.
Epithelial Cells
Absent (0)
Present (1)
15.
Any others ____________________________________________________
Stool examination
Routine
16.
Occult Blood
Absent (0)
Present (1)
Absent (0)
Present (1)
Microscopic
17.
Ova/Cyst
Blood
18.
TC (Cells/Cu. mm.) _______________
DC
19.
P _____ (%)
20. L _____ (%)
21. E ______ (%)
22.
M _____ (%) 23. B ______(%)
24.
ESR (mm / 1st hour.) __________
25.
M.C.H.C. (g/dl)________________
26.
M.C.V. (fl)______________________
27.
Serum iron (ìg/dl)_____________________
28.
Serum ferritin (ìg/L) __________________
29.
Hb (g/dl) (Cyanomethamoglobin method) ____________________
30.
PCV (%) ___________
31.
TIBC (ìg/dl) ___________
32.
General Blood Picture for morphology of RBC __________________________
Normocytic Normochromic (1)
Normocytic Hypochromic (2)
Macrocytic Normochromic (3)
Macrocytic Hypochromic (4)
Microcytic Hypochromic (5)
160
Serum Bilirubin
33.
Total
(mg/dl) ________
34.
Direct (mg/dl) _________
35.
SGPT (IU/L) ________
36.
SGOT (IU/L) ________
37.
S. Alkaline phosphatase (U/L) ________
38.
S. Proteins (Total) (g/dl) _____________
39.
Albumin (g/dl) ________
40.
Globulin (g/dl) ________
41.
Blood urea (mg/dl) ________
42.
S. Creatinine (mg/dl) ________
Date: ______________________
161
(On 15th Day)
CASE RECORD FORM - IV
FORM IV-B – LABORATORY INVESTIGATIONS
1.
Centre: ..................................................................................................................
2.
3.
Code No. of sample :
4.
5.
Subject Name : .....................................................................................................
6.
Age in years :
7.
Sex :
8.
Male (1)
D D
Female (2)
M M
Y
Y
9.
M.C.H.C. (g/dl)____________________
10.
M.C.V. (fl)________________________
11.
Serum iron (ìg/dl)___________________
12.
Serum ferritin (ìg/L) _________________
13.
Hb (g/dl) (Cyanomethamoglobin method) _______
14.
PCV (%) _______________
162
Y
Y
15.
TIBC (ìg/dl) ___________
16.
General Blood Picture for morphology of RBC ____________________
Date: ______________________
163
(On 30th Day)
CASE RECORD FORM - IV
FORM IV – C – LABORATORY INVESTIGATIONS
1.
Centre: ..................................................................................................................
2.
3.
4.
5.
Subject Name : .....................................................................................................
6.
Age in years :
7.
Sex :
8.
Male (1)
D D
Female (2)
M M
Y
Y
9.
M.C.H.C. (g/dl)____________________
10.
M.C.V. (fl)________________________
11.
Serum iron (ìg/dl)___________________
12.
Serum ferritin (ìg/L) _________________
13.
Hb (g/dl) (Cyanomethamoglobin method) _______
14.
PCV (%) _______________
164
Y
Y
15.
TIBC (ìg/dl) ___________
16.
General Blood Picture for morphology of RBC ____________________
Date: ______________________
165
(On 45th Day)
CASE RECORD FORM IV
FORM IV-D – LABORATORY INVESTIGATIONS
1.
Centre: ..................................................................................................................
2.
3.
4.
5.
Subject Name : .....................................................................................................
6.
Age in years :
7.
Sex :
8.
Male (1)
D D
Female (2)
M M
Y
Y
Y
Urine Examination
Routine
9.
Sugar
Absent (0)
Present (1)
10.
Albumin
Absent (0)
Present (1)
11.
Bile Salts
Absent (0)
Present (1)
12.
Bile Pigments
Absent (0)
Present (1)
166
Y
Microscopic
13.
RBC
Absent (0)
Present (1)
14.
Pus Cells
Absent (0)
Present (1)
15.
Epithelial Cells
Absent (0)
Present (1)
16.
Any others _____________________________________________________
Stool examination
Routine
17.
Occult Blood
Absent (0)
Present (1)
Absent (0)
Present (1)
Microscopic
18.
Ova/Cyst
Blood
19.
TC (Cells/Cu. mm.) _______________
DC
20.
P _____ (%)
21.L _____ (%)
23.
M _____ (%)
24. B ______(%)
25.
ESR (mm / 1st hour.) __________
26.
M.C.H.C. (g/dl)________________
27.
M.C.V. (fl)______________________
28.
Serum iron (ìg/dl)_____________________
29.
Serum ferritin (ìg/L) __________________
30.
Hb (g/dl) (Cyanomethamoglobin method) ____________________
31.
PCV (%) ___________
32.
TIBC (ìg/dl) ___________
33.
General Blood Picture for morphology of RBC _________________________
167
22. E ______ (%)
Serum Bilirubin
34.
Total
(mg/dl) ________
35.
Direct (mg/dl) _________
36.
SGPT (IU/L) ________
37.
SGOT (IU/L) ________
38.
S. Alkaline phosphatase (U/L) ________
39.
S. Proteins (Total) (g/dl) __________
40.
Albumin (g/dl) ________
41.
Globulin (g/dl) ________
42.
Blood urea (mg/dl) ________
43.
S. Creatinine (mg/dl) ________
Date: ______________________
168
IRON DEFICIENCY ANAEMIA.
CASE RECORD FORM V
CONSOLIDATED DATA ON PERIODICAL OBSERVATIONS
1.
Centre: ..................................................................................................................
2.
3.
4.
Subject Name : .....................................................................................................
5.
Age in years :
6.
Sex :
Sl
Subjective/
objective
Parameters
1.
Weakness
2.
Fatigue
3.
Palpitation
4.
Effort intolerance
5.
Breathlessness
6.
Swollen feet
Male (1)
Female (2)
0 day/BT
Dt.
15th day
Dt.
30th day
Dt.
45thday/AT
Dt.
Yes
(1)
Yes
(1)
Yes
(1)
Yes
(1)
No
(0)
169
No
(0)
No
(0)
No
(0)
7.
Other Associated Symptoms if Any [Specify]
Adverse reactions
8.
Burning sensation
in abdomen
Not
applicable
9.
Nausea
Not
applicable
10. Diarrhoea
Not
applicable
11. Skin rashes
Not
applicable
12
TC (Cells/Cu. mm.)
DC (%)LLLL
18
ESR (mm /1st hour.)
19
M.C.H.C. (g/dl)
20
M.C.V. (fl)
21
Serum iron (ìg/dl)
22
Serum ferritin (ìg/L)
23
Hb (g/dl) (Cyanomet
hamoglobin method)
13. P
14. L
15. E
16. M
17. B
Not
applicable
Not
applicable
Not
applicable
Not
applicable
170
13. P
14. L
15. E
16. M
17. B
24
PCV (%)
25
TIBC (ìg/dl)
26
General Blood
Picture for
morphology of RBC
S. Bilirubin
27. Total (mg/dl)
Not
Not
28. Direct (mg/dl)
applicable
applicable
29. SGPT (IU/L)
Not
Not
30. SGOT (IU/L)
applicable
applicable
31. S. Alkaline pho
sphatase (U/L)
Not
Not
32. S. Proteins (Total)
(g/dl)
applicable
applicable
33. Albumin (g/dl)
Not
Not
34. Globulin (g/dl)
applicable
applicable
35. Blood urea (mg/dl)
Not
Not
36. S. Creatinine (mg/dl)
applicable
applicable
37. Albumin (g/dl)
Not
Not
38. Globulin (g/dl)
applicable
applicable
Urine Examination
Routine
171
Microscopic
39. RBC
40. Pus Cells
Not
Not
41. Epithelial Cells
applicable
applicable
42. Occult Blood
Not
applicable
Not
applicable
43. Ova/Cyst
Not
applicable
Not
applicable
Stool Examination
44.
Overall clinical assessment
Improved (1)
45.
Deteriorated (3)
Improved (1)
46.
No change (2)
No change (2)
Deteriorated (3)
Drop out (1)
Reason: ____________________________________
Died
Cause: _____________________________________
(2)
Date: ______________________
172
DRUG COMPLIANCE REPORT FORM – I
Sl. No. of participant ____________ Name of participant _____________________
(To be translated into local language)
(To be filled by the trial participant)
(To be issued on 1st visit – 0 day and taken back on 2nd visit –15th day)
Please come for next visit on ________________ (Date and time is to be filled by the
Investigator)
Instructions to trial participant
•
Please take one capsule twice a day after food with a glass of Luke warm water
(approx. 250 ml.) maintaining 12 hours gap in between.
•
Please return the empty strip after taking medicine along with the compliance report
duly filled.
•
Please come with empty stomach and bring breakfast along with you during next visit.
Day
Date
Morning dose (Around 9 AM)
Evening dose (Around 9 PM)
Please put mark after
taking the
medicine
Please put Please enter
mark after
the time
taking the
medicine
Please enter
the time
1.
2.
3.
4.
173
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Name of participant __________________________________________________
Date:_____________
Signature or Thumb impression of the participant _______________________________
Signature of the Investigator with date _______________________________________
174
DRUG COMPLIANCE REPORT FORM – II
(To be issued on 2nd visit –15th day and taken back on 3rd visit –30th day)
Investigator)
•
•
duly filled.
•
Day
Date
taking the
medicine
mark after
the time
taking the
medicine
Please enter
the time
16.
17.
18.
19.
175
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
Date:_____________
176
DRUG COMPLIANCE REPORT FORM – III
(To be issued on 3rd visit – 30th day and taken back on 4th visit –45th day)
Investigator)
•
•
duly filled.
•
Day
Date
taking the
medicine
mark after
the time
taking the
medicine
Please enter
the time
31.
32.
33.
34.
177
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
Date:_____________
178
RECEIPT
MULTIVENTRIC OPEN CLINICAL TRIAL OF SELECTED DRUGS IN
Received an amount Rs. 100 (Rupees one hundred only) from ________________ (name)
Institute/ unit/ center _________________ (station) on _____________________ (date)
for visit no. ___________________________________________________________
Name of participant & Sl. No. _____________________________________________
Date: ______________
Signature or Thumb impression _____________
Signature of the Investigator with date _____________________________________
Signature of Account’s Personnel/
Office Personnel
Signature of the Director/ In charge
179

CLINICAL SAFETY AND EFFICACY OF DHATRI LAUHA (A

Transcription

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