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A Randomized Controlled Clinical Trial Of Efficacy Of Dhatrilauha On Serum Ferritin Levels In Garbhini Pandu With Special Reference To Iron Deficiency Anemia In Pregnancy.

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INTRODUCTION

    Anemia in pregnancy is a serious global health concern. Anemia is a condition in which the number of red blood cells or their oxygen-carrying capacity is insufficient to meet physiologic needs, which vary by age, sex, altitude, smoking, and pregnancy status^[1]. It is one of the most commonly encountered medical disorders during pregnancy. It is responsible for many adverse obstetric outcome^[2]. According to WHO world health organization report, about 32.4 million pregnant women are anemic worldwide, among 0.8 millions are severely anemic. Moreover, 50% cases are attributable to Iron Deficiency Anemia^[3].

     The average daily intake during second trimester   pregnancy increases by 4-6mg/day to 10mg/day in last 6-8weeks of pregnancy. In healthy, iron-sufficient women, basic iron storage depletes rapidly during pregnancy to accommodate the increasing maternal blood volume and the iron needs of the fetus.

    The size of iron storage can be calculated by histological examination i.e. reticuloendothelium of bone marrow, tranferrins levels & haematocrit.  In Iron Deficiency Anemia initially no clinical manifestation of depletion of iron storage present, in  second stage of for iron storage exhausted and tranferrins levels falls from normal values 30% to 15%. The third stage of overt iron deficiency anemia, is reached when the impaired hemoglobin synthesis resulting in a measurable decrease in hemoglobin concentration of circulating haemoglobin^[4].

     Although the haematocrit is an index of Iron Deficiency Anemia but if anemia is less sever there is overlapping the value of impaired iron status. Histological examinations bone marrow or liver biopsy and studies of iron storage provides good indices of size of iron storage but cannot be applied on wide scale results, on the other hand  measurement of the percentage saturation of tranferrin, which reflects the adequacy of iron supply to the bone marrow, it is liable method and less specific index^[2].

     The first stage of iron deficiency Anemia is characterized by decreased storage without any detectable abnormality. Therefore, sensitive method to assess iron storage is immunoradiometric test i.e. serum ferritin, several studies suggest that such estimation may provide a sensitive index of storage iron status^[5,6].

       Innumerable iron containing allopathic preparations are available to treat Iron Deficiency Anemia. They contains various iron salts like ferrous sulfate, ferrous fumarate, ferrous glycin sulfate, ferric hydroxide polymaltose complex, ferric ammonium  nitrate, iron dextran, iron choline citrate, iron sorbital citrate, ferrous calcium citrate, ferrous gluconate, colloidal iron hydroxide, ferrous succinate and ferric hydroxide^[7].

         Despite the availability of the large number of iron salts and preparations to treat anemia, the need of better preparation has been always felt. The long term treatment with iron salt is associated with several side effects like heart burn, constipation, nausea, upper gastric discomfort, diarrhoea and it may produces damaging radicals in the intestine^[8].

   National Family Health Survey (3) showed that IFA coverage as only 57.60% of all pregnant women with 32% in. Lack of effective implementation mechanisms and poor compliance due to ignorance or side-effects are the main factors in effectiveness of iron supplementation during pregnancy.

      In Ayurveda Iron deficiency anemia in pregnancy has not been referred clearly, but while discussing Garbhayapad Kashyapa stated that if a pregnant woman become weak and white complexioned, her fetus gets troubled^[9]. This condition may simulate to anemia in pregnancy and its complication. In general, under Pandu Roga the features of anemia are described. The disease Pandu Roga is called so because of the prominence of pallor in skin. It has been clearly described with etiopathogenesis, clinical features, management, etc., in the ancient texts^[10,11].

     The Pitta predominant Dosha is vitiated in Dhatus and as a result of morbidity of Dosha and Dushya (those affected by Dosha), complexion, strength, unctuousness, and other properties of Ojas (Rakta, i.e. blood or Ojas, i.e. immunity itself get diminished).Thus, it is affected with Alparakta (deficiency of blood), Alpamedas (deficiency of fat), Nihsara (diminished Ojas), Shithilendriya (looseness of body parts) and Vaivarnya (abnormality of complexion) or vitiation of Rakta leads to paleness of skinV^[9,10,11]. Hridya-Spandana (palpitation), Raukshya (dryness of skin), Sweda-Abhawa (absence of sweat) and Shrama (exhaustion) are cardinal clinical presentations. The ancient Acharyas said that though Pitta and Rakta are similar in nature, aggravation of the Pitta does not lead to increase of Rakta, rather it is decreased because of depletion of the nutrient Rasa by Pitta^{[12,13,14,15]}. Pitta is responsible for complexion that causes abnormal skin color when get vitiated^[16,17].

        Iron balance depends upon three factors-the iron requirement for production of haemoglobin, the iron losses from physical and pathological processes and the amount of iron ingested and absorbed by the intestines. The amount of iron absorption depends upon the amount of iron ingested and its absorbability.   

        Dhartiloha is effective to increase Hemoglobin percentage when given in iron deficiency anemia, therefore objective this study to evaluate precisely effect of Dhatrilauha on iron deficiency anemia in pregnancy along with iron storage by measuring Serum Ferritin levels.            

Primary Research Question

Is Dhatrilauha effective to increase serum ferritin levels in  Garbhini Pandu i.e. iron deficiency anemia in pregnancy.

Secondary Research Question1

Is Dhatrilauha effective to increase Total Iron Binding Capacity TIBC in Garbhini Pandu i.e. iron deficiency anemia in pregnancy.

Secondary Research Question1

Is Dhatrilauha is effective to enhance serum iron levels in   Garbhini Pandu i.e. iron deficiency anemia in pregnancy.

Primary Hypothesis: H¹

Dhatrilauha Vati is useful to increase serum ferritin levels Garbhini Pandu in iron deficiency anemia of pregnancy when it is given orally 500mg two times per day for 100 days.

Alternate Hypothesis: H²

Dhatrilauha Vati is useful increase Total Iron Binding (TIBC) levels in Garbhini Pandu i.e. iron deficiency anemia of pregnancy when it is given orally two times per day for 100days.

Null Hypothesis: H⁰

Dhatrilauha Vati is not useful to increase serum ferritin levels in Garbhini Pandu i.e. pregnancies Iron Deficiency Anemia when it is given orally 500mg two times per day for 100days.

Review of literature:

 Drug Review:

आमलकी-

    हन्ति वातं तदम्लत्वात्‍ पित्तं माधुर्यशैत्यत: ।

    कफं रूक्षकषायत्वात्‍ फलं धाञ्यास्ञिदोषाजित् ॥

    हरीतकीसमं धाञीफलं किन्तु विशेषत: ।

    रक्तपित्तप्रमेहघ्नं परं वृष्यं रसायनमं ॥ भा.प्र.

    विघ्यादामलके सर्वान् रसान् लवणवर्जितान्‍ । च.सु.२७

    तान्‍ गुणास्तानि कर्माणि विघ्यादामलकीष्वपी ।

    यान्युक्तानि हरीतक्या वीर्यस्य तु विपर्यय: ॥ च. चि. ३

    अम्लं समधुरं तिक्तं कषायं कटुकं सरम्‍ ।

    चक्षुष्यं सर्वदोषघ्नं वृष्यमामलकीफलम् ।

    हन्ति वातं तदम्लत्वात्पित्तं माधुर्यशैत्यत: ।

    कफं रूक्षकषायत्वात्फलेभ्योअभ्यधिकंचतत्  ॥ सु ४६

    कटुमधुरकषायं किंकचदम्लं कफघ्नम् रूचिकरमतिशीतं हन्ति पित्तस्त्रतापम्‍ ।

    श्रमदमनविबन्धाध्मानविष्टम्भदोषप्रशमनममृताभं चामलक्या: फलंस्यात्‍॥रा.नि.

     Family- Euphorbiaceae.

     Latin name -Emblica officinalis.

     Guna- Laghu, Ruksha, Sheet.

     Rasa-  Panchrasa, Lawan rasawarjit.

     Vipak- Madhur.

     Virya- Sheet.

      It is popularly known as Indian gooseberry, is commonly known as “Amla” in India and is used in Ayurveda as “rejuvenating herb” since ancient times. E. officinalis extract contains several antioxidants such as emblicanin A and B, gallic acid, ellagic acid, ascorbic acid (AA) (Vitamin C), which are used to treat several medical conditions.It also possesses several attributes like antipyretic, analgesic, antimicrobial, antifungal, antitussive, chemopreventive, immunostimulatory, hepatoprotective, cardioprotective, radioprotective, and potential to increase hemoglobin^[18].

गुडूची:

    गुडूची कटुका तिक्ता स्वादुपाकी रसायनी ।

    संग्राहिणी कषायोष्णा लघ्वी बल्याग्निदीपनी ॥

    दोषत्रयामतृड्दाहमेहकासाश्र्च पाण्डुताम्‍ ।

    कामलाकुष्ठवातास्त्रज्वरकृमिवमीहरेत्‍  ॥ भा.प्र.

    à¤…मृता संग्राहिका वातहर दीपनीय श्लेष्मशोणितविबन्धप्रशमनानाम्‍ । च.सु. २५

    ज्ञेया गुडूची गुरूरूष्णवीर्या तिक्ता कषाया ज्वरनाशिनी च ।

    दाहार्त्तितृष्णावमिरक्तवातप्रमेहपाण्डुभ्रमहारिणी च ॥ रा.नि.

    कन्दोद्धवा गुडूची च कटुष्णा संनिपातहा ।

    विषघ्नी ज्वरभूतघ्नी वलीपलितनाशिनी ॥ ध.नि.

      Family- Meni- Spermaceae.

      Latin name- Tinospora cordifolia.

      Guna- Laghu, Snigdha.

      Rasa- Tikta, Kashaya.

      Vipak- Madhur.

      Virya- Ushna.

      Prabhav- Vishaghna.

      The plant mainly contains alkaloids, glycosides, steroids, sesquiterpenoids, aliphatic compounds, essential oils, mixture of fatty acids and polysaccchrides. The alkaloids include berberine, bitter gilonin, non-glycoside gilonin gilosterol. It has immunomodulating activity. It produces leucocytosis and protects the animals from experimental infection. Petroleum ether extract showed good protection against leucopenia, protection is best in neutrophill count. It also has antiendotoxic effect in an experimental model of endotoxic shock. It claimed to reduce bone marrow toxicity of anticancer agents.

    The major phytoconstituent in Tinospora cordifolia include tinosporine, tinosporide, tinosporaside, cordifolide, cordifol, heptacosanol, clerodane furano diterpene, diterpenoid furano lactone, tinosporidine, columbin, b-sitosterol. Berberine, palmatine, tembertarine, magniflorine, choline and tinosporin are reported from the stem of the plant^[19.20].

यष्टीमधु:

    यष्टीमधु तथा यष्टीमधुकं क्लीतकं तथा ।

    अन्यत्‍  à¤•à¥à¤²à¥€à¤¤à¤¨à¤•à¤‚ तत्तु भवेत्तोयमधुलिका ।

    यष्ट‍ि हिमा गुरू: स्वाद्धी चक्षुष्या बलवर्णकृत ।

    सुस्त्रिग्धा शुक्ला केश्या स्वर्या पित्तानिलास्त्रजित्‍ ॥

    व्रणशोथविषच्छर्दितृष्णाम्लानिक्षयापहा ॥ भा.प्र.

       Family- Leguminoceae.

       Latin name- Glycyrrhiza glabra.

       Guna- Guru, Snigdha.

       Rasa- Madhur.

       Vipak- Madhur.

       Virya- Sheet.

        Moreover, studies conducted on modern scientific parameters have proved the healing, anti-ulcer, anti-inflammatory and skin regeneration activity of Yashtimadhu. The use of this plant extract in peptic ulcer is highly recommended by clinicians all over the world.  Sodium, glycyrrhizate possessed anti ulcer activity and stimulation of regeneration of skin^[21,22].

लौह भस्म:-

    लौहं रूक्षं सुमधुरतलं पाकतऋचाथ तिक्त वीर्ये

    शीतं गुरू च तुवरं लेखनञ्चातिनेञ्यम ।

    बल्यं वृष्यं जठरगदनुत्‍ श्लेष्मपित्तामयघ्नं वर्ण्य

    मेध्यं खलु किमधिकं हन्ति नानामयघ्नम ॥ ९३ ॥ रसतरंगिणी

    लौहं दीपनमुत्तमं क्षयहरं कुष्ठामयध्वंसकं

    गुल्मप्लीहविधूननं क्रिमीहरं पाण्ड्वामयघ्नं परम् ।

    मेदोमेहनिवर्हणां गदहरं दुर्नामरोगान्तकृत्

    छर्दिश्ववसहरं त्वलंबहुगिरा योगेन नानार्तिनुत् ॥ ९४ ॥ रसतरंगिणी

    विसर्पकरिकेशरी प्रबलशूलनिर्मुलन: क्षयक्ष्यकर: परं चिरजशोथ ड्कोचन: ।

    यकृद्गदविधूननो गुदमहागदेभाड्कुश: परं

    विजयतेतरां विधिहतस्तु लौहौ क्षयम् ॥९५॥ रसतरंगिणी

Disease Review:

    पाण्डुरोगा: स्मृता: पंत्र्च: वातपित्तकफैस्त्रय: ।

    चतुर्थ सन्नितातेन पंत्र्च: भक्षणान्मृद: ॥ च.चि. १६/३

    क्षाराम्ललवणात्युष्णविरूद्धासात्म्यभोजनात्‍ ।

    निष्पावमाषपिण्याकतिलतैलनिषेवणात्‍ ।

    विदग्धेdन्ने दिवास्वप्नाद्व्यायामान्मैथुनात्तथा ।

    प्रतिकर्मर्तुवैषम्याव्देगानां च विधारणात ।

    कामचिंताभयक्रोधशोकोपहतचेतस: ॥  à¤š.चि. १६/७९

    समुर्दीण यदा पित्ते ह्दये समवस्थितम्‍ ।

    वायुना बलिना क्षिप्तं संप्राप्य धमनीर्दश ॥

    प्रपन्नं केवलं देहं त्वड्मांसान्तरमा‍श्रितम्‍ ।

    प्रदुष्य कफवातासृक्त्वमासांनि करोति तत्‍ ।।

    पाण्डुहारिद्रहरितान्‍ वर्णान्बहुविधांस्त्वपि ।

    स पाण्डुरोग इत्युक्त: ॥ सु.उ. ४४/५

    त्वकस्फोटनं ष्ठीवनगात्रसादौ मृद्भभक्षणं प्रेक्षणकुटशोथ ।

    विण्मूत्रपीतत्वमथाविपाको भविष्यतस्तस्य पुर:सराणि ॥ सु.उ. ४४/५

    संभुतेdस्मिन्‍ भवेत सर्वे कर्णश्वडी हतानल: ।

    दुर्बल: सदनोdन्नद्धिद् श्रमभ्रमतिपीडित: ।।

    गात्रशुलज्वरश्वासगौरवास्चिमान्नर: ।

    मृदितैरिव गायैश्च पीडितोन्मथितैरिव ॥

    शुनाक्षिकुटो हरित: शीर्णलोमा हतप्रभ: ।

    कोपन: शिशिरव्देषी निद्रालु:ष्ठीवनोdल्पवाक् ॥

    पिण्डिकोव्देष्टकरचूरूपादरूकसदननननि च ।

    भवन्त्यारोहणायासैर्विशेषक्ष्चास्य वक्षते ॥ च.चि. १/१६

    Anemia may antedate conception; it is often aggravated by pregnancy, and the accidents of labour may perpetuate it. It is one of the prime concerns of antenatal care to forestall nothing of future health, in very large measure depend upon the state of the patient’s blood.

     To diagnose and treat anemia, yet there can be no more important aspect of antenatal care.

Physiology-

      Near term blood volume increases about 40-45% above their non pregnant levels. Pregnancy causes a state of hydraemic plethora; in other words, the total volume of the blood is increased partly by dilution, and the haemoglobin is reduced to the varying extent. Pregnancy induced hypervolemia serves to meet the demands of the enlarged uterus with greatly hypertrophied vascular system; to protect the mother and fetus against deleterious effects of impaired venous return in supine and erect position and very importantly, to safe guard the mother against adverse effects of blood loss associated with parturition. Whole blood viscosity decreases.

IDA is defined as a reduction of Hb below a certain threshold, due to ineffective erythropoiesis resulting from ID. Various threshold levels have been suggested for different situations. During a normal pregnancy, due to the expansion of plasma volume exceeding the increased production of erythrocytes up to the second trimester, the Hb starts decreasing in the first trimester, reaching its lowest point in the second trimester (up to a maximum decrease of approximately 0.5g/dl), and begins to rise again in the third trimester. Therefore some recommend an allowance for this reduction, in the diagnosis of anemia during pregnancy.

     Total iron store in female is 300mg and total iron content is 2 to 2.5gms. Total iron requirement during is 1gm, out of it  300mg to placenta, erythrocyte increases to 450ml and each ml of erythrocyte contains 1.1mg iron i.e. 450-500mg of iron and 200mg iron excreted. Practically all the iron needed in later half of pregnancy, therefore the iron requirement becomes quite large during second trimester.

   Average iron requirement is 6-7mg/day but this amount is not available from body stores so erythrocyte volume and haemoglobin mass will not develop unless exogenous iron is made available in adequate amount. In the absence of exogenous iron, the haemoglobin and haematocrit fall apparently as maternal blood volume increases.

   Haematoblast—Erythroblast—Pronormoblast—(no haemoglobin)--Basophilic Normoblst—Iron addition—Polychromatic Normoblast—Pyknotic Normoblast—Reticulocyte—Mature Erythrocyte.

      The formation of red cells in active bone marrow requires not only iron and identical traces of copper for haemoglobin formation but also folinic acid, Vit-B₁₂, Vit-C, nucleoprotein. The Vit-C is to assist the conversion of folic acid into folinic acid which is necessary for the synthesis of pyrines and pyrimidines which ultimately take part with Vit-B₁₂ ni the synthesis of nucleic acid and hence of nucleoproteins. Haemoglobin itself is a conjugated protein with a molecular weight of about 68 thousand, which contains a globin fraction bound to four heam molecules. In normal adult blood polypeptide chains are alpha, beta, gamma and delta. Hb-A(<₂β2)- This chain present in 90% adults.

Hb-A₂(<₂δ₂)- This chain present in 3% adults.

Hb-F(<₂Â¥₂)- This chain present in cord blood and replaced to fetal haemoglobin in first year.

     In bone marrow moderate erythroid hyperplasia and reticulucyte count. In spite of augmented erythropoises, the concentration of the haemoglobin and erythrocyte and heamatocrit decrease slightly.

        Practically all the complications of pregnancy are aggerevated quantitatively by anemia.the treatment consist in making good the iron which the patient lacks and the method will depend upon the time available before treatment.

    In Ayurveda, Garbhini-Pandu (anemia in pregnancy) has not been referred so far, but at one place Kashyapa stated that if a pregnant woman become weak and white complexioned, her fetus gets troubled^[5]. This condition may simulate to anemia in pregnancy and its complication. In general, under Pandu Roga the features of anemia may be kept. The disease Pandu Roga is called so because of the prominence of pallor in skin. It has been vividly described with etiopathogenesis, clinical features, management, etc., in the ancient text^[23,24].

1.World Health Organization Technical Series Report. Control of Nutritional Anemia With Special Reference To Iron Deficiency. Geneva 1975; No-540.

2.Dr. Alka Kriplani, Dr. Aparna Sharma, Dr. A.G.Radhika et al. FOGSI General and Clinical Practice Recommendations Management Of Iron Deficiency Anemia In Pregnancy.

3.World Health Organization, Global Database Of Anemia- India, 30.01.2006.

4.P.R.P Verma, Prasad et al. Standardization And Bioavailability of Ayurvedic Drug Lauha Bhasma Part-1 Physcical And Chemical Evaluation. Ancient Science of Life. 1995; Vol No. XV2 : 129-136.

5.World Health Organization, Global Nutrition Target 2025 Anemia Policy Brief.

6. Dr. Yewala G., Dr. Dalvi P. et al. A Pilot Study To Evaluate The Efficacy, Safety And Tolerability Of Ayurvedic Drug SC₃ And AYUSH RP In Sickle Cell Anemia Patients. 2011; Dept of Ayush, Ministry of Health & Family planning, Govt. of India, New Delhi.

7.Dinesh C. Sharma, Deepa Chandiramani, Manminder Riyat et al. Scientific Evaluation Of Some Ayurvedic Preparation For Correction Of Iron Deficiency Anemia. Indian Journal Of Clinical Biochemistry. 2007;22(2) 123-128.

8. G Ramadevi, S. Jonath et al. A Clinical Study On The Effect Of Dhatrilauha In Garbhini Pandu (Iron Deficiency Anemia). International Of Research In Ayurvedic Pharma. 2014; 708-712.

9.A. Keshri,P.R.P Verma, Prasad et al. Further Studies On Chemical Evaluation Lauha Bhasma Part-3. Ancient Science of Life. 1996; Vol. No. XV2 :26-30

10.Neeta Singh, K.R.C. Reddy. Pharmaceutical Study of Lauha Bhasma. AYU.2010; Vol. No.-31:387-390.

6

Primary Objectives:

To study the efficacy of Dhatrilauha Vati on serum ferritin levels in Garbhini Pandu i.e. iron deficiency anemia in pregnancy.

Other Objectives 1:

Does Dhatrilauha is effective to normalize Total Iron Binding Capacity TIBC in Garbhini Pandu i.e. iron deficiency anemia in pregnancy.

Other Objectives 2:

Does Dhatrilauha is effective to enhance serum iron levels Garbhini Pandu i.e. iron deficiency anemia in pregnancy. 

7

Methodology:

Study design-Randomized-Controlled–Open labeled-Clinical trial.

           100 females of  pregnancy Iron Deficiency Anemia.

                Initial assessment & selection of patients

        Group Allocation & Randomization by lottery method

          Group-A (n=50)                           Group-B(n=50)

      Tab-Dhatrilauha 500mg        Cap- ferrous fumarate+Folic acid+Vit-c+Vit B₁₂

          Two Times Daily for                  Two Times Daily for

                    100 days                                  100 days

  Assessment on 50^th&100^th day     Assessment on 50^th&100^th day

                                       Obsrvation

                    Classification & Presentation of Data

                                  Statistical Analysis

                                         conclusion

Study Setting- OPD/IPD of Phd research institute.

Study population- Pregnancies with Gestational Age14-20weeks coming for antenatal check up at Phd research institute.

Sample size

Sample size calculated by Danial sample size formula as per prevalence rate of Anemia is 19.6%-58.1% National Family Health Survey 2015-2016(NFHS) out of this percentage of iron deficiency anemia in urban population in all pregnancies is 50%^[4].

Sample size – Dannial formula

Prevalence rate of Anemia in pregnancy is 19.6%-58.1% (mean =38.85%) (NFHS) out of it 50%(19.42%) pregnant females are of Iron Deficiency Anemia. For this clinical trial Mild to Moderate degree Iron Deficiency Anemic pregnant females will be subjected but prevalence of this clinical entity is not expressed clearly so 50%(9.71%) prevalence is considered .

                      N=Z²p(1-p)/d²

                      Z=1.96 p=.097 d=.01

                      N=33+ dropout- 20% of 6=33+6=39=40

                      N=40 patients in each group

Sampling method : Randomization done by lottery method.

Criteria for Inclusion:

1.Pregnant women between 14^th-20^th weeks of pregnancy with a clinical diagnosis and laboratory confirmation of Iron Deficiency Anemia with serum ferritin levels below 30mg/dl.

2. Pregnant women Hb level is between 7-10gm/dl.

3. Primi and second Gravida.

4. Age-20-30year.

5.Peripheral smear for RBC showing microcytic, normocytic, and hypochromic type of erythrocytes.

Criteria for Rejection:

1.Patients having Serum Ferritin level less than 10mg/dl.

2.Patients with a history of anemia due to any bleeding conditions as bleeding piles, menorrhagia gastric ulcers etc

3.Patients having bleeding disorders as coagulation defects, thalassemia, etc

4.Presence of any other morbid disease such as renal insufficiency, coronary heart disease, hypertension, tuberculosis, diabetes mellitus, etc.

Criteria for Withdraw:

1.In any follow up Hemoglobin% become below 7gm/dl.

2.During study period Vaginal Bleeding at any stage of pregnancy.

3.During study period Spontaneous Abortion at any stage of pregnancy.

Study End point:

1.   On first follow up in more than 80% females if increased value of haemoglobin is less than 0.5gm/dl or decreased progressively.

Interventions:

1.   Administration of parentral iron supplementations to correct  deprived iron storage immediately.   

Inj-Iron Sucrose 200mg in I.V.-NS 500ml^[25].

Drug preparation:

    Dhatrilauha will be prepared from GMP certified pharmacy.

    Drug standardization will be done from our research institute.

Tests- Loss of dryness, Total ash, Percentage of iron, Ash value, Acid in soluble Ash, Water in soluble Ash, Microbial load test, test for heavy metals.

Procedure:

     After randomization as per given method 100 Pregnant females between Gestational Ages 14-20weeks with diagnosed Iron Deficiency Anemia will be selected from OPD of Strirog-Prasutitantra department of PhD institute and divided into two group i.e. Trial Group(Group-A)(n=50) & Control Group(Group-B) (n=50).

    In both groups follow ups will be taken on every 30 days to assess clinical improvement and haemoglobin concentration.

    In both groups after completion of study period i.e. after 100days if Dhatrilauha is found statistically more effective than control drug than Dhatrilauha will be continued till delivery of recruited individuals.

If Dhatrilauha is found statistically equally effective then patients will shifted on Ferrous Fumerate+ Folic Acid+VitC+VitB₁₂ combination.  

Drug: GROUP A

Dose: Tab-Dhatrilauha 500mg Two Times Daily

Duration:100days

Anupana: Water

Drug: GROUP B

Dose: Cap- Ferrous Fumerate+ Folic Acid+VitC+VitB₁₂ Two Times Daily.

Duration: 100days

      The therapeutic dose in this study was calculated to Tab- Dhatrilauha 500 mg in two divided doses after food with normal potable water will be given for 100 days with two follow-ups, each of 50 days intervals. Final assessment will be done after completion of 100 days and results will be statistically analyzed.

Diet:

     A diet containing adequate amount of bioavailable iron will be advised to both groups^[26].

Investigation

    Complete blood count.

    General blood picture for RBC morphology.

    Serum iron.

    Total iron binding capacity (TIBC).

    Serum ferritin.

Assessment of  criteria:

     The patient will be assessed on each follow-up of the following parameters:

Objective Parameters:-

1. Hb%, MCV, MCH.

2.Serum Frritin.

3.Serum Iron.

4.Total Iron Binding Capacity.

5. RBC for other Abnormalites.

Subjective Parameters:-

1. Pallar.

2. Weakness.

3. Fatigue.

4. Breathlessness

Scoring pattern on the sign and symptoms in  Garbhini Pandu i.e. Iron Deficiency Anemia

I. Pallor - Skin, face, sclera, nails (Pandu Varna Twak etc.)

Pallor absent in all these region - 0

Pallor present in any two region - 1

Pallor present in any three region - 2

Pallor present in these entire region - 3

II. Weakness (Daurbalya)

No feeling of weakness during the daily activity - 0

Sometimes feeling of weakness, but performs daily activity - 1

Often feels weakness, but hampers daily activity - 2

Always feels weakness, unable to perform daily activity even routine postural movements - 3

III. Fatigue (Shrama)

No fatigue except hard work - 0

Fatigue after moderate work for a certain period of time - 1

Fatigue after light work for a certain period of time - 2

Fatigue after routine work for a certain period of time - 3

(Hard work - weight lifting, excess work at the workplace or at home without rest, etc.; Moderate work - washing clothes and utensils, brooming, climbing stairs, cooking, etc.; Light work - walking, bathing, feeding, etc.)

IV. Breathlessness (Shwasa)

No breathlessness - 0

Breathlessness after heavy work, relieved soon, tolerable - 1

Breathlessness after moderate work, relieved later, tolerable - 2

Breathlessness after light work, relieved later, intolerable - 3

Overall assessment of result

Overall effect on the sign - symptoms and objective parameters will be calculated after the completion of 100 days therapy by the percentage of relief as shown below.

Clinical Assessment Criteria :

Good Improvement -Increase in Serum Ferritin Level by 10mg/dl.

Modarate Improvement -Increase in Serum Ferritin Level by ≥5mg/dl.

Mild Improvement -Increase in Serum Ferritin Level by <5mg/dl

Good improvement Hb percentage ≥ 1 g% gain.

Mild improvement Hb percentage ≥ 0.5–<1 g% gain.

No improvement Hb percentage ≤0.5 g% gain.

Subjective Parameters-

Complete remission of sign - symptoms: 100% relief

1.Marked improvement in sign - symptoms: ≥75–<100% relief

2.Moderate improvement in sign - symptoms: ≥50–<75% relief

3.Mild improvement in sign - symptoms: ≥25–<50% relief

4.No improvement in sign - symptoms: <25% relief.

Statistical Analysis:

Before treatment both groups will be applied F Ratio test for quantities data and Chi Square test for Qualitative data.

Effect of treatment in each group will be analyzed with Z test for quantities data and Wilcoxon test for Qualitative data.

Both groups will be analyzed with Z test for quantities data and Mannwhitneys test for Qualitative data.

Level of significance will be kept 5% i.e. p=0.05.

8

REFERENCES

1. New Delhi: ICMR, Govt. of India; 1989. ICMR. Task Force Study, Evaluation of the National Nutritional Anaemia Prophylaxis Programme.

2. Trivedi SS, Puri M. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2010. Anaemia in Pregnancy: Magnitude of Problem, Pharmaceutical; pp. 5–6. Reprint ed.

3. WHO Global Prevalance of Anemia in Geniva 2011: World Health Organization; 2016.

4.Stevens G, FinucaneM, De-Regil L, Paciorek C, Flaxman S, Branca F et al; Nutrition Impact Model Study Group (Anemia). Global, regional, and nutritional trends in hemoglobin concentration and prevalence of total and severe anemia in children and pregnant and non-pregnant women for 1995-2011: a systemic analysis of population-representative data. Lancet Glob Health. 2013;e16-e25.doi:10.1016/S2214-109X(13)7001-9.

5.Haskins, D.et al Iron metabolisam: iron stores in man measured by phlebotomy.J.cli.invest.,31: 543-547(1952)

6. Walters, G.O. et al. Serum ferreitin concentration and iron store in normal subjects. J.clin. Pathol.,26:770-772(1973)

7.Singhal M. Iron Formulations 2001; Drug index 4: 325-330

8.Hillman RS “Hematopoietic Agents : Growth Factors Minerals and Vitamines” Goodmal and Gilman’s. The Pharmacological Basis of Therapeutics. Hardman, J.G. and Limbird, L.E.(eds.) McGraw-Hill, New York., 10^th ed., 2003; pp. 1487-1517.76

9.Varanasi: Chaukhamba Surbharati Prakashan; 2000. Chakrapanidutta, Commnetator. Charaka Samhita, Chikitsa Sthana, Pandu Roga Chikitsa Adhyaya, 16/1. Reprint ed. 526.

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11. Varanasi: Chaukhamba Surbharati Prakashan; 2000. Chakrapanidutta, Commnetator. Charaka Samhita, Chikitsa Sthana, Pandu Roga Chikitsa Adhyaya, 16/12, Reprint ed. 527.

12. Ibidem. Chakrapanidutta, Commnetator. Charaka Samhita, Chikitsa Sthana, Pandu-roga Chikitsa Adhyaya, 16/4-6; 526

13. Vaidya Jadavji Trikamji Aacharya., editor. Varanasi: Chaukhamba Surbharati Prakashan; 2000. Agnivesha, Charaka, Dridhabala, Charaka Samhita, Sharira Sthana, Shariravichaya Sharira Adhyaya, 6/23. Reprint ed. 334.

14. Tiwari KP, editor. 1st ed. Varanasi: Chaukhambha Visvabharati; 1996. Vriddha Jivaka, Kashyapa Samhita, Sutra Sthana, Lehyadhyaya, 18/6.7. 3.

15. 1st ed. Varanasi: Chaukhambha Orientalia; 1994. Gangadhara, commentator. Charaka Samhita (critical notes), Vol.- IV, Chikitsa Sthana, Pandu Roga Chikitsa, 16/4-6. 165.

16. Vaidya Jadavji Trikamji Aacharya., editor. Varanasi: Chaukhamba Surbharati Prakashan; 2000. Agnivesha, Charaka, Dridhabala, Charaka Samhita, Sharira Sthana, Avakshirasiyamindriya Adhyaya 8/22. Reprint ed. 344.

17. Vaidya Jadavji Trikamji Acharya., editor. Varanasi: Chaukhamba Surbharati Prakashan; 2000. Sushruta, Sushruta Samhita, Sharira Sthana, Garbhinivyakarana Sharira Adhyaya, 10/67. Reprint ed. 395.

18. Shastri RD, editor. 13th ed. Varanasi: Chaumkambha Sanskrit Sansthan; 1999. Govindadas, Bhaishajya Ratnawali, Pittaroga Chikitsa, 9-12. 851.

19. Sharma PV. II. Varanasi: Chaukhambha Bharati Academy; 2001. Dravyaguna Vigyana; pp. 758–60. Reprint ed.

20. Sharma PV. Varanasi: Chaukhambha Bharati Academy; 2001. Dravyaguna Vigyana; pp. 761–2. Reprint ed.

21. Varanasi: Chaukhamba Surbharati Prakashan; 2000. Chakrapanidutta, Commentator. Charaka Samhita, Chikitsa Sthana, Pandu Roga Chikitsa Adhyaya, 16/70, 82, 97-99, Reprint ed; pp. 530–1.

22. Kulkarni AD, editor. commentary. 3rd ed. New Delhi: Meharchand Lachhmandas Publication; 1982. Vagbhata, Rasaratna Samuchhya-I Part, Athaha Lohani, 5/136-138. 120.

23. Gowria BS, Patelb K, Prakash J, Srinivasan K. Influence of amla fruits (Emblica officinalis) on the bio-availability of Iron from staple cereals and pulses. [Last accessed on 2013 Mar 15];Nutr Res. 2001 12:1483–92. Available from:

24. Sarkar PK, Prajapati PK, Choudhary AK, Shukla VJ, Ravishankar B. Haematinic evaluation of Lauha-bhasma and Mandur-bhasma on HgCl2-induced anaemia in rats. Indian J Pharm Sci. 2007;69:791–5.

25. World Health Organization: WHO guidelines on nutrition in (http://www.who.int/publications/guidelines/nutrition.en, accessed on 18.01.2018)

26.Shi Q, Leng W, Wazir R, et al. Intravenous Iron Sucrose Verses Oral Iron in The Treatment of Pregnancy with Iron Deficiency Anemia: A Systemic Review. Gynecol Obstet Invest. 2015;80:170-8.

9

Gantt chart

Attached

10

Annexures

Attached

11

Knowledge Gap

Despite availability of the large number of iron salts and preparations for correction of anemia and iron deficiency, the need of better iron preparation has always been felt. The haematocrit is an index of Iron Deficiency Anemia but if anemia is less sever there is overlapping the value of impaired iron status. Iron balance and its assessment techniques to evaluate its absorption. The amount of iron absorption depends on the amount of iron ingested and its absorbability. 

12

Generation of new knowledge

     Dhatrilauha is useful in treating Iron Deficiency Anemia, but maximum previous studies were based on only evaluation of hemoglobin percentage and symptomatic relief. Objectivity and preciseness were less in those studies. To overcome this problem and bring objectivity advanced and sensitive blood tests are selected for this study design. These blood test are useful to measure iron storage accurate.