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| ORIGINAL ARTICLE |
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| Year : 2020 | Volume
: 41
| Issue : 2 | Page : 87-97 |
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Effect of Opuntia elatior Mill. (Nagaphani) in the management of Pandu Roga w. s. r to iron deficiency anemia; an open labeled randomized standard controlled clinical trial
Shashikant M Prajapati1, Sharada Anand2, Rabinarayan Acharya2, Mandip Goyal3
1 Department of Dravyaguna, Akhandanand Ayurved College, Ahmedabad, Gujarat, India
2 Department of Dravyaguna, Institute for Post Graduate Teaching and Research in Ayurveda, Gujarat Ayurved University, Jamnagar, Gujarat, India
3 Department of Kayachikitsa, Institute for Post Graduate Teaching and Research in Ayurveda, Gujarat Ayurved University, Jamnagar, Gujarat, India
| Date of Submission | 16-Feb-2018 |
| Date of Decision | 02-Jun-2018 |
| Date of Acceptance | 23-Jul-2021 |
| Date of Web Publication | 23-Oct-2021 |
Correspondence Address:
Rabinarayan Acharya
Department of Dravyaguna, IPGT and RA, Gujarat Ayurved University, Jamnagar, Gujarat
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ayu.AYU_31_18
 Abstract | | |
Background: Pandu Roga described in Ayurveda bears resemblance to the clinical features of anemia. The fruits of Nagaphani (Opuntia elatior Mill.) of family cactaceae, are consumed by the inhabitants of Gujarat as a hematinic agent to treat general debility and anemia. Aim and objective: To evaluate the efficacy of the O. elatior fruit juice in Pandu Roga with special reference to iron deficiency anemia. Materials and method: Present clinical study was an open labeled, randomized trial, in which 105 patients of Pandu Roga (iron deficiency anemia), were divided into two groups using the coin method of randomization. Group A received Opuntia elatior fruit juice, 20 ml twice a day with lukewarm water before meal. Group B received Punarnava Mandura (standard control), well accepted after this a herbo-mineral fromulation, two tablets of 500 mg each, twice a day with Takra (butter milk) before meal. Duration of intervention was 2 months in both groups and a follow-up of 1 month. The assessment was done based on the clinical signs and symptoms and hematological parameters such as Hb% (hemoglobin %), total red blood cell (TRBC), serum iron, serum ferritin and total iron-binding capacity (TIBC), before and after completion of the treatment. The data were subjected to statistical tests (Wilcoxon signed-rank test and paired t-tests, co-efficient of variance (CV)), and analyzed. Results: Both trial drug and the standard drug produced a statistically significant increase in Hb%, TRBC and serum Iron. The standard drug provided statistically significant increase (P < 0.05) in TIBC, whereas a statistically insignificant (P > 0.05) effect was observed in the trial group. Both trial and standard drug provided statistically significant (P < 0.001) relief in Panduta (pallor), Daurbalya (general weakness), Akshikutashotha (periorbital edema) and Pindikodveshthana (calf muscle cramps). When compared between the groups, the standard drug was found to be more effective than the trial drug. Conclusion: Fruit juice of Opuntia elatior is effective in iron deficiency anemia as it increases the hemoglobin, TRBC levels in blood along with providing relief in Panduta (pallor), Daurbalya (general weakness) Akshikutashotha (periorbital edema).
Keywords: Anemia, cactus pear, hathlo-thore, Nagaphani, opuntia elatior, panduroga, prickly pears, Punarnava Mandura
How to cite this article:
Prajapati SM, Anand S, Acharya R, Goyal M. Effect of Opuntia elatior Mill. (Nagaphani) in the management of Pandu Roga w. s. r to iron deficiency anemia; an open labeled randomized standard controlled clinical trial. AYU 2020;41:87-97 |
How to cite this URL:
Prajapati SM, Anand S, Acharya R, Goyal M. Effect of Opuntia elatior Mill. (Nagaphani) in the management of Pandu Roga w. s. r to iron deficiency anemia; an open labeled randomized standard controlled clinical trial. AYU [serial online] 2020 [cited 2023 Jun 6];41:87-97. Available from: https://www.ayujournal.org/text.asp?2020/41/2/87/329124 |
| Introduction | |  |
The World Health Organization estimates that 1.62 billion people globally are affected with anemia which corresponds to 24.8% of the world population.[1] In India, anemia affects an estimated 50% of the population.[1] Ayurveda delineates Pandu Roga as a disease entity developing due to depletion of Rasadhatu (plasma), which in turn results in deficient production of Raktadhatu (blood tissue). Pandu Roga may occur as a prime disease or as a complication of other disease or as a sign of a disease.[2] It has resemblance with the clinical picture of anemia.[3] It is the most predominant blood cell deficiency disorder and a global public health problem affecting both developing and developed countries with major consequences for human health as well as social and economic development.[4] According to the WHO, anemia is the condition in which the hemoglobin content of blood is lower than normal as a result of deficiency of one or more essential nutrients.[5] In the conventional system of medicine, iron and folic acid supplements are used in the treatment of anemia, which usually produces gastritis and other side effects such as nausea, constipation, and diarrhoea which further deteriorates the health of the patient.[6] There is an urgent need to find out herbal drugs which are easily available, effective, and low in cost to manage this disease condition. Ayurveda describes both single as well as compound formulations for the management of Pandu Roga. Punarnava Mandura,[7] one of the most regularly prescribed drugs for the management of Pandu Roga, has been established through various research works,[8],[9],[10] for its effectiveness in managing the clinical conditions of Pandu Roga.
Opuntia elatior Mill.(cactaceae), a folklore plant known as Nagaphani or Hathlo-thore is available in many parts of India and widely prevalent in the state of Gujarat.[11] Fruits of Opuntia elatior are being used by the local people of Gujarat, to combat anemia and general debility, irrespective of age. The drug has been found safe through acute and chronic toxicity studies,[12] and effective in managing anemia through experimental studies on animals.[13],[14] Further the drug has also been found effective in managing Pandu Roga (anemia) in the geriatric population.[15] It is pivotal to validate this traditional practice, scientifically, to treat Pandu Roga. In the present clinical research, Opuntia elatior fruit juice has been assessed for its efficacy in the management of Pandu Roga (iron deficiency anemia) in comparison to Punarnava Mandura, the standard control drug.
[TAG:2]Materials and methods [/TAG:2]
The study, conducted from Feb 2015 to March 2016, got approved by Institutional Ethics Committee (No. PGT/7/-A/ethics/2014-15/2652; dated December 19, 2014) and was registered in the Clinical Trials Registry of India (CTRI/2015/02/005547; dated February 16, 2015). Patients visiting the outpatient department and inpatient department, Institute for Post-Graduate Teaching and Research in Ayurveda (IPGT and RA), Jamnagar, were thoroughly examined for clinical signs and symptoms of Pandu Roga along with the necessary hematological and biochemical investigations. Subjects were enrolled for the study considering the criteria of inclusion, after getting their full consent. The registered patients were allocated into two groups, using the coin method of randomization.[16] Group A received Opuntia elatior fruit juice, group B received Punarnava Mandura tablets for 2 months. Follow-up was done for a period of 1 month. Patients were advised to stop other ongoing medications which were prescribed for the treatment of iron deficiency anemia and informed to reduce intake of food which are sour, salty, Vidahi (which causes burning sensation), Vishthambhi (which causes constipation), and Abhishyandikara Ahara (which blocks the channels). Assessment of clinical signs and symptoms was done before, during, and after treatment, and after follow-up period of 2 months. Hematological, biochemical, and routine urine examinations were repeated after the completion of 2 months' intervention.
Diagnostic criteria
Patients were diagnosed based on clinical signs and symptoms of Pandu Roga and levels of hematological parameters like Hb% (<12 g% in females and <13 g% in males), TRBC (<4.2 mill/c. mm), serum iron (<37 μg/dL), serum ferritin (>73 μg/dL), and total iron-binding capacity (TIBC) (>250 μg/dL).
Inclusion criteria
Patients between the age of 18–60 years, irrespective of gender having Hb% below 12 g (for females) and below 13 g (for males) or decreased RBC count (<4.2 mill/c. mm), serum iron (<37 μg/dL), serum ferritin (>73 μg/dL), and TIBC (>250 μg/dL) were included for the present study.
Exclusion criteria
Patients with age <18 years and more than 60 years, other types of anemia like hemolytic anemia, aplastic anemia, thalassemia, pregnant or lactating women, severe renal, hepatic and cardiac disease, cancer and other life-threatening diseases, any continuing blood loss, for example, hematemesis, melena, bleeding piles, etc., were excluded from the present study.
Posology
Juice of O elatior (Nagaphani Swarasa) preserved using sodium benzoate (1 g/kg) was given in a dose of 20 ml with lukewarm water to group A and group B received Punarnava Mandura [Table 1], two tablets of 500 mg each, with Takra (butter milk). Both the drugs were administered twice daily, before meal for a duration of 2 months.
Investigations
Blood parameters included total WBC, neutrophil percentage, lymphocyte percentage, eosinophil percentage, monocyte percentage, hemoglobin content, packed cell volume (PCV), TRBC, platelet count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and MCH concentration (MCHC).
Parameters like serum ferritin, serum iron, total iron-binding capacity, serum urea, serum creatinine, serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase were also estimated. The tests were carried out before and after treatment. Among these, serum ferritin, serum iron, total iron-binding capacity were assessed to monitor the iron stores in the body. Other tests were carried out to rule out the adverse effects on vital organs, as the drug is new.
Collection and preparation of drug
Fruits of Opuntia elatior were collected from its natural habitat in its fully ripened state, from the surrounding area of Jamnagar, Gujarat, following good collection practices guidelines. Freshly collected fruits were thoroughly washed with the adequate amount of tap water and the bunch of thorns over the fruits were neatly plucked using forceps. Following this, the outer skin of fruits was removed and the pulp was macerated and the resultant juice obtained was passed through the sieve and filtered. The filtered juice was then preserved by the addition of 1 g sodium benzoate per one liter of juice and stored in properly sealed food-grade plastic bottles of 500 ml capacity [Figure 1],[Figure 2],[Figure 3],[Figure 4],[Figure 5],[Figure 6],[Figure 7],[Figure 8]. Punarnava Mandura, the standard control drug, containing many herbo-mineral ingredients [Table 1], was prepared by the Pharmacy of GAU (Gujarat Ayurved University), following recommended procedures mentioned in AFI[17] and was dispensed to the patients in airtight food grade plastic boxes. | Figure 2: Bunch of thorns over the fruits neatly plucked by using forceps
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Criteria for assessment
The assessment was done in accordance with the Clinical Research Pro forma of Pandu Roga developed by CCRAS,[18] with slight modifications considering the study requirement. Cardinal symptoms of Pandu Roga like Panduta (pallor), Daurbalya (general weakness), Akshikutashotha (periorbital edema), Hritspandana (palpitation), Bhrama (vertigo), Shiroruja and Shotha (headache and edema), Anna-Aruchi (loss of appetite), Pindikodweshthana (calf muscle cramp), Shrama (fatigue), Ayasena Shwasa (exertional dyspnoea) were graded from 0 to 4, Hematological parameters such as Hb%, total RBC serum iron, and serum ferritine were also considered before and after treatment.
Statistical analysis
The data obtained from the study were subjected to statistical tests and analyzed for the percentage of improvement in each parameter in both the trial group and standard control group. Wilcoxon signed-Rank Test was applied to evaluate the effect of therapy in the individual group for subjective criteria. Paired “t” test was applied to evaluate the effect of therapy on hematological and biochemical investigations. Tests were performed using Sigma Stat 3.1 software 2005 by Jandel scientific software, San Jose, California).[19] The results were interpreted as; for “t” test (“P” value) Insignificant >0.05, Significant ≤0.05 ≤0.01 ≤0.001. For Wilcoxon Signed Rank (“P” value) Insignificant >0.05, Significant ≤0.05 ≤0.02 ≤0.001. Coefficient of variation (CV) was applied to the statistical data for evaluating the differences of effect in between groups for clinical, hematological and biochemical parameters.
Observations
Registered 105 patients were randomly divided into two groups for evaluation of the efficacy of the Opuntia elatior fruit juice (Nagaphani Swarasa) and Punarnava Mandura tablet. Total 96 patients completed the intervention and the rest 9 patients (8.57%) dropped out due to various personal reasons. [Figure 9] Demographic data show, among the registered patients, maximum (62.58%) belonged to the age group of 31–50 years, in both groups. [Table 2] The scrutiny of gender revealed the incidence of Pandu was higher in females (78.90%), in comparison to males in both groups [Table 2]. About 33.33% of patients were housewives as the female population was more in the study conducted, followed by 36.19% having office job as occupation and 30.47% of the registered population were from labor class [Table 3]. About 35.23% of registered patients belonged to the middle class followed by 24.76% in the lower middle class, 8.57% in upper-middle-class and 30.47% in the poor category [Table 4].
At baseline, 97.14% of patients had Panduta (pallor), while 99.04% had Daurbalya (general weakness). Akshikutashotha (periorbital edema) was found in 36.19%. Other complains were Shrama (fatigue) (98.09%), Pindikodwesthana (calf muscle cramp), (92.38%) and Shiroruja (headache) (74.28%) [Table 5]. At baseline, Hb% was noted to be 9.24 ± 0.18 and 9.44 ± 0.17 in trial and standard group, respectively. TRBC was reported to be 4.30 ± 0.13 in the trial group and 4.40 ± 0.13 in the standard group. Serum iron was 50.56 ± 7.04 in the trial group and 49.80 ± 5.40 in the standard group. Serum ferritin was 21.08 ± 5.81 in trial group and 13.98 ± 3.62 in the standard group. TIBC was found to be 369.13 ± 7.82 and 380.87 ± 9.40 in trial group and standard group, respectively. Maximum patients were taking Pittaprakopaka Ahara (food which vitiates Pitta) like; Atiushna Ahara (food which is very hot in potency) (85.71%) Katurasayukta Ahara (spicy food) (80.95%), Atitikshana Ahara (food articles which are sharp in nature) (77.14%), Ati Amla Ahara (sour food) (60.95%), Vidahibhojana (food which causes burning sensation) (89.52%), and Pramitabhojana (eating less) (67.71%). Vegavidharana (suppression of urges of urination, defecation or hunger) was found in 90.47% and Ratrijagarana (being awake in the night) in 84.76% of patients while indulging in day sleep was reported in 50.47% of the patients. Chinta (worries) was found in the majority of patients (62.85%). Krodha (anger) and Shoka (grief) were found in 54.28% and 37.14% of patients, respectively.
| Results | | |
The effectiveness of the treatment was assessed on the basis of improvement in clinical signs and symptoms and various hematological factors pertaining to anemia, based on before and after completion of the treatment.
Both trial and standard drugs provided significant results (P < 0.001) in pacifying the cardinal symptoms of Pandu Roga [Table 6]. Both trial and standard drugs produced a statistically significant increase in Hb% (<0.001), total red blood cell (TRBC) count (<0.05). The effect of both the drugs was not significant on total whit blood cell count, MCV, MCH, MCHC, and platelet count. On PCV, the standard drug produced a statistically significant increase (P<0.001) while the effect of the trial drug was statistically insignificant (P>0.05) [Table 7]. There was a statistically significant increase in serum iron level in both the groups but the increase level was high in standard (26.10%) than trial group (17.85%). Both provided significant increase in serum ferritin level, but the level of increase was much higher in standard (82.68%) than trial drug (14.32%. In TIBC level, statistically significant decrease (P < 0.05) in trial drug (1.14%) and statistically insignificant decrease (P > 0.05) in standard drug (6.01%) was observed. [Table 8] Both the drugs provided insignificant (P > 0.05) changes in serum creatinine, blood urea, SGPT, SGOT, and blood sugar level [Table 9]. There was no significant difference (P > 0.05) in the comparative effect of therapies between trial and standard drug in clinical signs and symptoms, Daurbalya (general weakness), Panduta (pallor), Akshikutashotha (periorbital edema), Hritspandana (palpitation), Bhrama (dizziness), Aruchi (tastelessness), Pindikodweshthana (calf muscle cramps), Shrama (fatigue), Ayasaja Shwasa (dyspnea on exersion) [Table 10] as well as hematological [Table 11] and biochemical parameters [Table 12]. | Table 6: Effect of therapies on cardinal symptoms (48 patients in each group)
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 | Table 7: Effect of therapies on hematological parameters (48 patients in each group)
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 | Table 8: Effect of therapy on anemia profile (48 patients in each group)
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 | Table 9: Effect of trial drugs on biological parameters (48 patients in each group)
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| Discussion | | |
The study drug Opuntia elatior has been reported to be safe[12] and a potent hematinic, through various animal experiments.[13],[14] Clinical efficacy of the drug in anemia, has been reported on the geriatric population.[15] Punarnava Mandura, was considered as the standard control, based on its classical claims and being re-established for its hematinic activity, through various animal and clinical experiments. In this study, an attempt had been made to evaluate the clinical efficacy of Nagaphani (O. elatior) fruit juice on the general population of anemia.
According to the demographic data, most of the registered patients belonged to the middle class, lower middle class and poor class. More incidence of anemia was seen in the female population, aged between 31 and 50 [Table 2] and [Table 3]. This may be due to a lack of nutrition owing to their economic status and nature of work.
The better percentage of improvement and significant results in both groups with regards to increase in hemoglobin might be due to the direct availability of iron element in its most acceptable form to the human body, which aided in quicker response in hematological parameters.
The presence of iron and ascorbic acid (Vitamin C) in trial drug[20] which reduces ferric iron to ferrous iron and remains soluble even at neutral pH and is better absorbed. Even when the diet is poor in iron, Vitamin C supplements with each meal enhances iron absorption. Vitamin C taken in divided doses with each meal increase iron absorption to a greater extent.[21] Thus, Opuntia elatior (trial drug) possesses a promising role in the management of anemia, especially iron-deficiency anemia. Its mode of action in modern parlance correlates with the Raktavardhaka (hematinic) property in Ayurveda probably by enhancing the normal physiological functions of Pitta Dosha and promoting the normal formation of Raktadhatu by Ranjana (coloration) of Rasadhatu.
There was no significant difference (P > 0.05) in the comparative effect of therapies between trial and standard drug on Hb% and RBC count. Both the drugs contain iron and Vitamin C, so it can produce improvement in Hb%.
Both trial and standard drugs were significant in increasing serum iron and ferritin. However, the standard drug was more significant in increasing serum iron (<0.001) and serum ferritin (>0.05) when compared to the trial drug.
In the management of Panduta, the results in both groups were statistically significant (P < 0.001). There was no significant difference (P > 0.05) in the comparative effect of therapies between trial drugs and standard drugs. Madhura Rasa (sweet taste) and Snigdhaguna (unctuous nature)[22] of trial drug may have worked in the pacification of Rukshata of Vata (dryness produced by Vata) and Tikshnata of Pitta (sharp nature of Pitta). This might have helped in the correction of the physiological function of Ranjaka Pitta which would have normalized Raktadhatu formation.
Trial drug was found to be statistically more significant (P < 0.001) in relieving Daurbalya (63.33%). This may be due to Madhura Rasa (sweet taste) which reduces Pitta and replenishes Rasadhatu, hence does Poshana of Uttarottara Dhatu (progressive nourishment of body tissues), in turn, results in relief of Daurbalya (general weakness). This can also be attributed to macronutrients like; protein (1.98%w/w), carbohydrate (7.54%w/w), total sugar (13.73% w/w), Vitamin C (1.29% w/w), and fat (0.25%w/w).[23] present in O. elatior fruit (trial drug). Punarnava Mandura which is a herbo-mineral compound is having herbal drugs like Shunthi, Pippali, Maricha, Chitraka which are having appetizer, digestive, and carminative properties.[24] Hence, it improves digestive power and ultimately absorption of nutrients and drug.
In relieving Hritspandana (palpitation) and Bhrama (giddiness), both trial and standard drug provided significant (P < 0.001) results. This can be substantiated through the pacification of Vata and Pitta because of Madhura Rasa and Snigdha Guṇa of trial drug. Standard drug contains Mandura which is Raktavardhaka (hematinic) so helps to increase oxygen-carrying capacity thus workload on the heart decreases. Hence, it might be the reason in decreasing Hridspandana.
Vatanulomaka (facilitating the downward movement of Vata) and Srotoshodhaka (clearing the channels) properties of standard drug helps in proper circulation in the brain, so relief was found in Bhrama (giddiness).
Vatapittahara (pacifying Vata and Pitta) property of the trial drug, may have improved digestion and thus, managed to treat Aruchi (tastelessness). Standard drug has Kapha Shamaka (pacifying Kapha), Dipana (carminant), Amapachana effect, which might have facilitated to decrease Aruchi.
Vatahara (pacifying Vata) property of the trial drug, may have contributed to relieve Pindikodweshtana (calf muscle pain). In standard drugs, this can be attributed to its Vata-Kapha Shamaka property.
Increase in Rasa and Uttarottara Dhatu (subsequent tissues) by trial drug gives proper nutrition to muscles and tissues which might be the cause of relief in Shrama (fatigue). Standard drug, due to its Dipana (carminant), Pachana (digestive) and Rasayana (rejuvenating) properties may provide nourishment and strength to tissues and thus may relieve fatigue.
Trial drug improves the quality of Rasa and Rakta as explained earlier might reduce the load on the heart and improves the circulation, thus relief of Ayasena Shwasa (dyspnea on exertion). Mandura Bhasma in Punarnava Mandura increases oxygen-carrying capacity of RBCs may facilitate the heart in its functions, which in turn helps reducing Shwasa. By virtue of Rasa (taste) and Guna (properties), pacifies aggravated Pitta (bile) and maintains normalcy, improves digestion and metabolism. The ferric and ferrous fractions of Mandura provide sufficient amount of iron, which is needed for normal erythropoiesis.
Other drugs present in Punarnava Mandura[25] like Haridra (Curcuma longa Linn.), Amalaki (Phylanthus embelica Linn.), Pippali (Piper longum Linn.), Punarnava (Boerhavia diffusa Linn.), and Trivrut (Operculina terpethum Linn.) are Pandughna in nature.[24] Drugs like Amalaki (Phylanthus embelica Linn.)[26], Danti (Baliospermum momtanum Muell. Arg.),[27] Pippali (Piper longum Linn.),[28] Punarnava (Boerhavia diffusa Linn.),[29] Kushtha (Sausurea lappa)[30] and Daruharidra (Berberis aristate DC.)[31] are documented as drugs which are having immunomodulator and antioxidant properties. Hence, they may have the potential to confer beneficial health effects due to their antioxidant activity and thus useful in anemia. Amalaki possesses antioxidant activity and could be an important dietary source of Vitamin C, which is a powerful water-soluble anti-oxidant[32] and helps in increasing iron absorption from the gut. In addition, Pippali is said to be bioavailability enhancer of the drug,[33] which further helps in easy assimilation of the drug components. Cow urine is reported to have anti-anemic action due to its erythropoietin stimulating factor.[34] Buttermilk used as Anupana (vehicle) has Dipana-Pachana (carminative and digestive), Pandughna[35] properties and rich source of minerals and Vitamin B12.[36]
The trial drug showed equally significant results in many of the factors analyzed, as compared to the standard group. Although the study revealed that the standard drug is more effective when compared with the trial drug, considering few factors regarding the trial drug like, it is used as a single drug, it is mineral-free, nontoxic, easily available, palatable, nutritive, cost-effective, it can be a drug of choice in iron deficiency anaemia.
| Conclusion | | |
Nagaphani (Opuntia elatior Mill.) fruit juice and Punarnava Mandura were found effective in the management of Pandu Roga by significantly relieving the cardinal symptoms of Pandu Roga. Both the drugs produced a statistically significant increase in Hb%, TRBC and serum iron. Trial drug showed a statistically significant reduction of total iron-binding capacity, while Punarnava Mandura produced a statistically insignificant reduction. When the effect was compared in between the groups, standard drug, Punarnava Mandura was seen to be more effective than the trial drug, Nagaphani (O. elatior) fruit juice. No adverse reactions were reported during the clinical trial indicating the safety of Nagaphani fruit juice. These results support the folklore use of O. elatior fruits in the treatment of anemia. Further large-scale studies may be carried out to establish O. elatior as the choice of drug for the management of Pandu Roga (iron deficiency anaemia).
Acknowledgement
The authors are thankful to The Director, IPGT and RA for providing the facilities to conduct this clinical study.
Financial support and sponsorship
Complete support for the conduct of the trial was by Ministry of AYUSH, Govt of India.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11], [Table 12]
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