A clinical study to assess the comparative effect of darvyadi lauha and dhatri lauha in garbhini pandu -An open labelled randomized clinical trial

RESEARCH QUESTION

Is there any significant difference in effect of Darvyadi Lauha and Dhatri Lauha in the management of garbhini pandu in second trimester of pregnancy?

NULL HYPOTHSIS

There is no any significant difference between effectiveness of Darvyadi lauha and Dhatri lauha in the management of garbhini pandu in second trimester of pregnancy.

ALTERNATIVE HYPOTHESIS

There is significant difference between effectiveness of Darvyadi lauha and Dhatri lauha in management of garbhini Pandu in second trimester of pregnancy

INTRODUCTION

Pregnancy and child birth are natures gift. Everyone wishes to have healthy baby. Health of baby in mother womb is totally depend upon the mother health. Acharya Kashyap has described that ahara rasa is divided into 3 parts. First part nourishes her own body, second part nourishes the garbha and third is utilized for the nourishment of stana[i]. so, mother needs a better and more nourishing diet to fulfil these demands. But due to improper dietary habits, mother body unable to fulfil the nutrients, which leads certain deficiencies in mother’s body.

Anemia is the most common nutritional deficiency disorder in the world. WHO has estimated that prevalence of anemia in pregnant women is 14% in developed and 51% in developing countries and among them, 65–75% are in India[ii]. The prevalence of anemia in all the age groups is higher in India as compared to other developing countries. India contributes to about 80% of the maternal deaths due to anemia in South asia [iii]. The high prevalence of anemia in pregnancy and serious adverse consequences in both mother and baby, the management of anemia in pregnancy was recorded a very high priority both in obstetric and public health practice. According to standard laid down by WHO in 1972, A pregnant women with hemoglobin level below 11gm% should be considered anemic while in developing countries such as India, the level is bought down up to hemoglobin level 10gm% at any time during pregnancy is considered as anemia. The centers for disease control and prevention (CDC) defines anemia as hemoglobin concentration of <11g/dl in first or third trimester or hemoglobin concentration of <10.5gm/dl in the second trimester. however, during pregnancy plasma volume expands resulting in hemoglobin dilution for this reason, hemoglobin level below 10gm% at any time pregnancy is considered anemia (WHO ,1993; CDC,1990)[iv].

India is one of the countries with high prevalence of anemia during pregnancy. Anemia in pregnancy is multifactorial. Iron deficiency anemia is the most common conditions in a pregnant woman. As per ayurvedic classics, this condition occurs due to improper Rasa Dhatu in mother and continuously increasing foetal demands and is considered as Rasa Pradoshajavikara.

First line means pregnant women become weak and white in complexion which indicate severity of anaemia. In Harita Samhita vivarnatvam is included as one of eight diseases supposed to occur during pregnancy term vivarnatvam is a clear indication of pallor colour which is the main sign of Pandu. In garbhini masanumasiklakshana acharya Charaka mentioned following symptoms in 5th, 6th and 7th month. In symptoms of fifth month feeling of weakness.[vi] In symptoms of sixth month, there is feeling of weakness with loss of complexion.[vii]

In symptoms of seventh month, Chakarapani mentioned.[viii] means reduction in concentration of haemoglobin. All these symptoms are present in second trimester of pregnancy, so these symptoms indirectly indicate Garbhini Pandu. During pregnancy, a women’s body undergoes many changes in order to provide needs of her growing baby. Some of these physical changes are very obvious, such as change in the body shape and size while some changes are much less apparent, change in the mother’s blood is one of these less noticeable but important changes.

Physiological anaemia occurs during pregnancy. There is disproportionate increase in plasma volume, RBC volume and haemoglobin mass during pregnancy which leads to physiological anaemia. There is always remaining physiological iron deficiency state during pregnancy. If a pregnant lady does not take extra iron her Hb level falls below 10gm/dl & pathological iron deficiency anaemia develop. The clinical feature of anaemia depends up on the degree of anaemia, Iron deficiency impairs cell growth & proliferation especially of the RBCs.

REVIEW OF LITRATURE

Classical

Acharya Harita has described vaivarnatva as out of eight Garbhopadravas in chapter no 51 of chikitsasthan. Vaivarnatva may be taken as Pandu. Acharaya kashyapa has described pandu as symptom of garbhini when he explains Rakta gulma

[ix]

Sushruta has described four fundamental factors for conception i.e. Ritu, Kshetra, Ambu and Beeja. [x]

Sushruta has given Ambu for nourishing factors among them. The nourishment is provided through the medium of food. In this regard it is important to note that right from the moment of a fertilized ovum, it establishes contact with the mother’s nutrient medium first through osmosis and then placental circulation flow. It is the same process which Sushruta has explained while describing the mode of nourishment of fetus

 Charaka is very precise in standing the three fundamental roles of Rasa, they areS

Nourishment of her own body

Lactation

Growth of foetus

Acharya Kashyap has described that Ahara Rasa of mother is divided into 3 parts. First part nourishes her own body,second part nourishes the Garbha and the third part is utilised for the nourishment of Stana.[xii]

It is clear that Garbhavasthajanya Pandu occurs due to the foetal demands & improper functioning of the Rasa Dhatu leading to malnourishment of the body. Acharya Charaka has also described ―Pandutva‖ as a Rasa Pradoshaja Vikara [xiii] and it is a Santarpanotha Vikara. (Ch.Su.-28/10) According to Acharya Charaka and Kashyapa[xiv]  5 th month onwards Garbhini becomes emaciated, suffers from Balavarnahani. It is due to lack of nourishment of maternal Dhatus as the Rasa is driven to nourish more and more the flesh and blood of fetus.

The Rasa Nadi are situated around Nabhi. These are compressed by the growing foetus. Due to this compression Rasa does not flow freely in the body resulting in Pandu in the Garbhini. There may be no difference between Pandu and Garbhavasthajanya Pandu. When Pandu occurs during pregnancy, is known as Garbhavasthajanya Pandu. Thus, the difference between these two is only due to Avasthavishesha or specific condition, which is Garbhavastha, so the factors of Nidana Panchaka may be same in both. On describing the ‗Avasthavishesha’ we can see that the foetus is on nourished by the maternal Rasa and Rakta.[xv]

Contemporary

Anemia in pregnancy is commonly defined as a condition where the hemoglobin (Hb) concentration in a pregnant woman’s blood is below the threshold considered normal for her stage of pregnancy.

Maternal plasma volume increases by about 40-50%. RBC volume increases by 20%. There is relative fall in the level of hemoglobin and hematocrit during pregnancy. All these values return to normal by 6 weeks postpartum. In addition, there is marked demand of extra iron during pregnancy especially in the second. Even an adequate diet cannot provide extra demand of iron. Thus, there is always remains a physiological iron deficiency state during pregnancy. As a result, there is not only a fall in hemoglobin concentration in second half of pregnancy but there is also associated low serum iron, increased iron binding capacity and increased rate of iron absorption as found in iron deficiency anemia.

NEED OF STUDY

1.     To improve health status of a pregnant women in pregnancy so as to give benefit to progeny.

2.     To support the health of women and health of baby by improving haemoglobin level through ayurvedic medicine.

3.     To reduce risk to mother and baby.

4.     To ensure outcome of intrapartum state of pregnant women.

PREVIOUS

In Lauhasarvasva granth acharya Sureshwar explained this yoga

Darvyadi lauha is polyherbal formulation containing Darvi, Haritaki, Bibhitaki,Amalaka ,Shunthi,Marich, Pippali, Vidang, lauha Bhasma,madhu ,ghrita are drugs having effect raktavardhan, dipana , snehan .

Formulation composition of Darvyadi Lauha:

Name of drug

Botanical/English name

Family

Part used

Part

|Darvi

Berberis aristate Dc.

Berberidaceae

Bark

1

|Haritaki

Terminalia chebula Retz.

Combrataceae

Fruit pericarp

1

|Bibhitaki

Terminalia bellirica Roxb.

Combrataceae

Fruit pericarp

1

|Amalaki

Emblica officinalis Linn.

Euphorbiaceae

Fruit pericarp

1

|Shunthi

Zingiber officinale Rosc.

Zingiberaceae

Rhizome

1

|Marich

Piper nigrum Linn.

Piperaceae

Fruit

1

|Pippali

Piper longum Linn.

Piperaceae

Fruit

1

|Vidanga

Embelia ribes Burm.

Myrsineceae

Fruit

1

|Lauha Bhasma

Incinerated iron

1

Formulation composition of Dhatri Lauha;

Name of drug

Botanical/ English name

Family

Part used

Part

|Dhatri

Emblica officinalis Linn.

Euphorbiaceae

Fruit pericarp

4

|Lauha Bhasma

Incinerated iron

2

|Yastimadhu

Glycyrrhiza glabra Linn.

Fabaceae

Root

1

|Amruta

Tinospora cordifolia Willd.

Meninspermiaceae

Stem

QS For 07 Bhavana

METHODOLOGY

1.     Step 1 – the detailed study of garbhini pandu .

2.     Step 2 – detailed review of drug.

Procured drug - the drug will be procured from GMP certified company or it will prepare in RSBK department of AIIA, Sarita Vihar new Delhi.

Authentication and standardisation- authentication and standardisation of formulation will be done as per standardised norms.

3.     Step 3- In - silico study

4.     Step 4 – clinical study

PLAN OF STUDY

Patients attending the opd of striroga evam prasuti tantra, AIIA Sarita Vihar fulfilling the criteria for selection will be included in the study irrespective of caste, religion.

Selection of research subjects -who will be willing to give their consent to take part in research work.

A written and informed consent will be taken from patient before the beginning of the treatment.

A suitable case record form (CRF) will be prepared and filled for specific assessment.

A) IN- SILICO STUDY

In silico pharmacology / computational pharmacology is a rapidly growing area that globally

covers the development of techniques for using software to capture, analyze and integrate

biological and medical data from many diverse sources.

TYPE OF IN-SILICO STUDY

Network pharmacology; molecular docking and molecular dynamic.

AIM

HRLCMS based phytoconstituent identification of Darvyadi lauha and their computational

correlation of Gene-target-disease against Garbhini pandu.

OBJECTIVES:

HR-LCMS based phytoconstituent identification.

Searching interaction between phytoconstituent /bioactive and target proteins Garbhini pandu.

Molecular docking and Molecular dynamics of selected phytoconstituent for receptors/

protein of Garbhini pandu

                      SOFTWARE

Cytoscape, Schodinger -Prime, glide, Desmond or any other required software.

ASSESMENT CRITERIA

Gene -target-disease prediction in relation to Garbhini pandu.

Binding energy values/dock scores, Stability, pharmacokinetics and drug-likeness properties.

PRIMARY OBJECTIVE

To evaluate the effect of Darvyadi lauha in the management of garbhinipandu..

SECONDARY OBJECTIVE

To assess the change in signs and symptoms of garbha pandu i.e.panduta  (Pallor) , Aruchi  (Anorexia ), shrama (Fatigue) , etc.

To compare the effectiveness of Darvyadi Lauha & Dhatri Lauha Vati in Garbhini Pandu.

 STUDY DESIGN -

Study type

Randomised clinical trial

|Purpose

Treatment and nourishment

|Masking

Open labelled

|Timing

Prospective

|End point

Improvement in maternal health.

|Sample size

36 in each group

|No. of groups

Patients are randomly allocated into 2 groups.

SAMPLE SIZE CALCULATION –

Study aims to compare the effect of Darvyadi lauha with Dhatri lauha it is assumed that in70% of cases the qualitative improvement would be better in proposed arm assuming equal allocation (1:1) power of test 80% level of significance 5% two sided test calculated sample size is 32per group assuming 10% dropout will included 36 patient of garbhini pandu to monitor changes in respective parameters.

Non Parametric Two Group Wilcoxon Mann Whitney U-Test

Assumptions:

• The observations are independent.

• The variable under study is continuous or ordinal.

Formula: n   =        (zα/2 + zβ)2

12c (1-c) (pn-0.5)2

Where, Pn= Probability that a score from X is larger than a score from Y is larger than 1/2.

C =1/(1+k) where k Allocation ratio

 CRITERIA FOR SELECTION AND METHOD OF DATA COLLECTION –

DIAGNOSTIC CRITERIA -

·       Patients having symptomssuch as Panduta ( Pallor) ,Daurbalya (Generalised weakness),Shrama (fatigue) ,Bhrama  (dizziness), Aruchi (Anorexia), Gatrashula (bodyache ),Shwas(breathlessness), Avipak (indigestion),Shotha(oedema) as per ayurvedic classics .

·       Patients having haemoglobin level below 10gm% [xvii].

INCLUSION CRITERIA -

Pregnant females of age group of 18-35 years of life.

Pregnant females in 2nd trimester of pregnancy. (14 wks. to 28 wks.)

Patients fulfilling diagnostic criteria.

Patients willing to participate in the trial.

  EXCLUSION CRITERIA -

PARAMETERS FOR ASSESMENT AND DIAGNOSIS-

Patients suffering from pregnancy related complications like PIH, hyperemesis gravidarum,pre-eclampsia etc.

1st & 3 rd. trimester of pregnancy.

Patients of high-risk group of pregnancy4.

Patients having Hb% count less than 8gm% & more than 10%

Patients having haemoglobinopathies (such as haemophilia ,β thalassemia ,etc.)

Pregnancy associated with medical disorders and obstetrics complications

Criteria for assessment-

Change in Hb% if any.

Change in signs & symptoms of the garbhini pandu if any.

Changes in level  Sr. Ferritin, Sr. Iron if any.

INVESTIGATIONS -

To assess the effect of given treatment in 2nd trimester (14 -28 wks.) in garbhini pandu.

Investigations

Before

Treatment

1st month of treatment

2nd month of treatment

After treatment

|CBC with ESR

✔

✔

✔

✔

|Sr. ferratin

✔

✔

|Sr. Iron

✔

✔

|Hb electrophoresis

✔

 USG (level 2), Urine routine and microscopy, Quadruple marker, Oral glucose tolerance test, TIBC, LFT ,KFT (Additional Investigation will be done as routine ANC checkup in second trimester of pregnancy (14 -28 wks)).

GROUPING AND DRUG DELIVERY REGIMEN-

SN

Group

No. of patients

Intervention /medication

Dose and duration

|1

A

36

Oral administration of Darvyadi Lauha vati

500 mg 2 vati twice a day for 60 days with Madhu Sarpi

|2

B

36

Oral administration of Dhatri Lauha vati

250 mg 1 vati thrice a day with lukewarmwater for 60 days

Standard operating procedure of Darvyadi lauha formation-

                                  | | | --- | |

PREPARATION OF FINE POWDER OF RAW DRUGS SUCH AS DARVI, HARITAKI, BIBHITAKI, AMALAKI, SHUNTHI, MARICH, PIPPALI, VIDANG

MIXING OF POWDERED DRUGS WITH LAUHA BHASMA

ADDITION OF BINDING AGENT

DARVYADI LAUHA

WASHOUT PERIOD

In the case where a potential participant has had oral or IV iron and folic acid , prior to study, a 1-2 days wait will be required before enrolment in the trial (giving a 1-2 days washout period).

DURATION OF TREATMENT –

Trial is conducted for a period of 60 days.

 FOLLOW UP-

Total 2 follow ups

1st follow up -15 days after completion of treatment.

2nd follow up-15 days after 1st follow up.

CONTINUITY OF CARE

Provision for continued care after the study period

After trial, patient will be handed over to primary consultant and regular OPD medication and assessment will be followed.

 CRITERIA OF WITHDRAWL-

Patient will be withdrawal from the study if any serious complication develops which requires urgent treatments. If the condition of patient deteriorates during the trial she will be excluded from the study.

MANAGEMENT OF ADVERSE CASES-

If there is any occasion of adverse effect, additional pharmacological drugs will be prescribed in consultation with the contemporary medical practitioners or other ayurvedic drugs will be administered in consultation with the experts in the field.

If any adverse drug reaction observed by doctor or patient, it will be recorded and reported to pharmacovigilance centre, AIIA, New Delhi

RESCUE****MEDICATION-

Rescue medication related to the associated problems that arise during treatment protocol will be given as per indication.

 ANALYSIS OF RESULTS –

 The frequency distribution of baseline characteristics between two groups will be compared using chi square test .mean ,median ,SD, percentiles etc will be calculated as per need . Test of normality would be done and if passed then BT ,AT analysis would be performed using paired t test and between group comparison using unpaired T test , otherwise non parametric test like Wilcoxson sign ranked test, Mann Whitney U test. Repeated measure Anova with Post hoc test  would be used when data is collected more than two times.significance would be tested at P <0.05 .

END POINT –

Primary end point: Relief in sign and symptoms of garbhini pandu(30-40% approx.).

Secondary end point: Increase in Hb level of patient(2-3gm% approx.).

 ETHICS COMMITTEE CLEARANCE

The study will start after getting clearance from the institutional ethics committee. The objectives and methodology of the study will be clearly stated to the committee. Reporting of ADR (Adverse drug reaction), if any observed by a doctor/patient will be reported to the specific authority. The study will be registered in CTRI.

The written informed consent of the patient will be taken before her inclusion in the study.

  CO-OPERATION REQUIRED

Identification of the raw drug from Department of Dravyaguna and Rasashastra

Pathology lab, AIIA hospital

Library, AIIA hospital

Pharmacy AIIA hospital

Preparation of medicines from the department of Rasa Shastra AIIA

OPD and IPD AIIA Hospital

If needed help will be taken from other departments of AIIA with due permission from concern authority in during the course of study.

FINANCIAL SUPPORT

This study will be completed within the prescribed financial limit for the work. However, if more finance is required the request will be made for due permission and approval of extra budget to the concerned authority AIIA, in due course of research work.

 

Purchasing of Drugs

25000/-

|Preparation packaging of Darvyadi lauha

10000/-

|Packaging of Darvyadi lauha and other expences

10000/-

|Investigation

20000/-

|Total (approximate)

65000/-

 

---

[i]Sharma H. Vrudhajivak. Kashyap Samhita, Khila sthana, Yoni vyapad chikitsa adhyaya. Varanasi: Chaukhamba Sambharati Prakashan; 2014:260:19.

[ii] De Mayer EM, Tegmen A. Prevalence of anemia in the world. World Health Organ Qlty. 1998;38:302-16.

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[iii] Ezzati M, Lopez AD, Rodgers A, Vander Hoorn S, Murray CJ. Selected major risk factors and global and regional burden of disease. Lancet. 2002;360:1347-60.

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[iv]D.C. Dutta ,Hiralal konar ,textbook of obstetrics ,medical and surgical illness complicating  pregnancy ,new central book agency ,2004;260:19.

[v] Vriddhajivaka. Khilasthana 10/160. In: PV Tiwari (eds.) Kashyap Samhita. 1st ed. Varanasi Chaukhamba Vishwabharti; 2002;7

[vi] Charak Samhita , ayurved Dipika commentary by sri chakrapanidatta ,published by chaukhamba vishwabharti, Varanasi,2010 published by chaukhamba surbhartiprakash ,Varanasi ,2011 sharirasthana Mahati Garbhavakranti Adhyaya 4/21.

[vii]Charak Samhita , ayurved Dipika commentary by sri chakrapanidatta ,published by chaukhamba vishwabharti, Varanasi,2010 published by chaukhamba surbhartiprakash ,Varanasi ,2011 sharirasthana Mahati Garbhavakranti Adhyaya 4/22.

[viii] Charak Samhita , ayurved Dipika commentary by sri chakrapanidatta ,published by chaukhamba vishwabharti, Varanasi,2010 published by chaukhamba surbhartiprakash ,Varanasi ,2011 sharirasthana Mahati Garbhavakranti Adhyaya 4/23

[ix] Harita Samhita sanskritmula and Nirmala hindi commentary edited and translated by Jaimini pandey , published by chaukhamba vishwabharti ,Varanasi ,2010 ,tritiyasthan 51/1.

[x] Sushrut Samhita, Sharira Sthana, Shukrashonitashudhisharira aadhyaya  , 2/35 Ayurveda Tatva Sandipika, Ambikadatta Shastri, Chaukhamba Prakashna, Varanasi, 2008;41.

[xi] Sushrut Samhita, Sharira Sthana, Sharira Garbhavkranti  Adhyay, 3/26 Ayurveda Tatva Sandipika, Ambikadatta Shastri, Chaukhamba Prakashna, Varanasi, 2008;41.

[xii] Kashyapa, Kashyapa Samhita, Pt. Hemraja Sharma, Vidyotini Hindi commentary, Chaukhamba Sanskrit Sansthan, Varanasi (2009) Kashyapa Sh su lehadhyaya

[xiii] Charak Samhita , ayurved Dipika commentary by sri chakrapanidatta ,published by chaukhamba vishwabharti, Varanasi,2010 published by chaukhamba surbhartiprakash ,Varanasi ,2011 sharirasthana Cha. Su. 28/10;57

[xiv] Kashyapa, Kashyapa Samhita, Pt. Hemraja Sharma, Vidyotini Hindi commentary, Chaukhamba Sanskrit Sansthan, Varanasi (2009) Kashyapa Sharira Sthana Ashamangotriya Adhyaya

[xv]Kashyapa, Kashyapa Samhita, Khila Sthana, 9/46-49, Pt. Hemraja Sharma, Vidyotini Hindi commentary, Chaukhamba Sanskrit Sansthana, Varanasi, 2009;289

[xvi]  .Vaidya U, Sastry PS.lauhasarvaswam. Chowkhambha Sanskrit Series Office; 2005:Shloka 201.

[xvii]D.C. Dutta ,Hiralal konar ,textbook of obstetrics ,medical and surgical illness complicating  pregnancy ,new central book agency ,2004;260:19.