Evaluation of Antipyretic Effect of a Traditional Polyherbal Preparation

[Full title: Evaluation of Antipyretic Effect of a Traditional Polyherbal Preparation: A Double-Blind, Randomized Clinical Trial]

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Life International Journal of Pharmacology ISSN 1811-7775 Life science alert ansinet Asian Network for Scientific Information

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International Journal of Pharmacology 4 (3): 190-195, 2008 ISSN 1811-7775 2008 Asian Network for Scientific Information Evaluation of Antipyretic Effect of a Traditional Polyherbal Preparation: A Double-Blind, Randomized Clinical Trial M. Gupta, 'B.P. Shaw and A. Mukherjee 'Department of Dravyaguna, Institute of Post Graduate Ayurvedic Education and Research. 294/3/1, A.P.C. Road, Kolkata-700009, India Division of Pharmaceutical Technology, Department of Chemical Technology, Calcutta University, 92, A.P.C. Road, Kolkata-700009, India Abstract: The ancient. Ayurvedic text. Charak samhita of Indian medicine prescribes a specific group of ten plants having antipyretic properties with minimal side-effects. The aqueous extract of polyherbal ayurvedic preparation PD-10 (from the roots of Hemidesmus indicus R. Br. (Asclepiadaccac), Rubia cordifolia ... (Rubiaceae), Cissampelos pareira L. (Menispermaceae), fruits of Terminalia chebula Retz. (Combretaceae). Emblica officinalis Gaertn. (Euphorbiaceae), Terminalia bellirica Roxb. (Combretaceae), Vitis vinifera L. (Vitaccac), Grewia asiatica .. (Tiliaceae), Salvadora persica L. (Salvadoraccac) and granules of Saccharum officinarum L. (Poaceae)) exhibited significant antipyretic-analgesic properties during rodent experiments while exhibiting low toxicity and ulcerogenicity. The presence of flavonoids, tannins and polyphenols in this extract prompted this double-blind, randomized clinical trial on 60 patients using Aspirin (60 mg kg 'body weight per day) as the standard drug for comparison. The primary outcome measured was reduction in body temperature, while the secondary outcomes measured were prevalence of associated symptoms of fever and routine blood and urine parameters. A representative sample of patients was also studied for reduction in the level of Prostaglandin (PGE). The clinical trial showed that fever was rapidly and substantially reduced after oral administration of PD-10 and this antipyretic effect was more sustained and highly significant (p<0.001) when compared to Aspirin. Many associated symptoms of fever also exhibited significant reductions when PD-10 was administered as compared to Aspirin. Prostaglandin levels also registered a substantial decrease during treatment with the test drug. Key words: Polyherbal preparation, antipyretic, clinical trial, prostaglandin INTRODUCTION Fever is an elevation in the body temperature of warm-blooded animals caused by abnormal functioning of the thermoregulatory mechanism in the central nervous system (l'auci et al., 1998). The conventional treatment of fever using non-steroidal synthetic antipyretics has been usually associated with gastro-toxicity, nephro-loxicily. hepato-loxicity, central TICTVOUS system anl dermatological effects (Suleyman et al., 2007). However, traditional Indian systems of medicine like Ayurveda are based on comprehensive treatment of ailments relying only on natural herbal drugs which lead to fewer sideeffects. Ayurvedic literatures like Charak Sambila provide a rich text for common herbal drugs that have been in traditional usage for centuries for treatment of many diseases. According to Ayurveda, pyrexia originates from a combination of indigestion, seasonal variations and significant alterations in daily routine (Sharma and Dash, 1998). Charak Samhita has classified the medicinal plants into 50 Mahakashays on the basis of their actions, each Mahakashay having en plants (Sharma and Dash, 1999). The group of antipyretic drugs called Jwarhar Mahakashay consists of Sariva (Hemide smus indicus R. Br.). Manjistha (Rubia cordifolia L.), Patha (Cissampelos pareira L.), Haritaki (Terminalia chebula Retz), Amala (Emblica officinalis Gaertn.), Fibhitak (Terminalia bellirica Roxb.), Draksha (Vitis vinifera L.), Parushak (Grewia asiatica L.), Peelu (Salvadora persica L.) and Sharkara (Saccharum officinarum L.) plants, which have been ascribed with antipyretic action (Sharma and Dash, 1999). Some of these medicinal plants have been reported to exhibit pharmacological actions such as anti-inflammatory, analgesic, hepato-protective, anti-microbial and antiulcer Corresponding Author: Dr. Mradu Gupta, Department of Dravyaguna, Institute of Post Graduate Ayurvedic Education and Research, 294/3/1, A.P.C. Road, Kolkata-700009, India Tel: 91-33-24614461, 91-9433665125 190

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Int. J. Pharmacol., 4 (3): 190-195, 2008 properties (Gupta et al., 2008). Besides various sugars, these plants were reported having triterpenoids. flavonoids, flavonidic glycosides and polyphenolic compounds (Sharma et al., 2001; Kirtikar and Basu, 1984; Baltenweck-Guyot et al., 2000; Foo et al., 1998; Kundu and Mahato, 1993). Flavonoids and polyphenolic compounds are known for biological effects that include anti-inflammatory, anti-microbial, anti-hepatotoxic and anti-ulcer activities (Narayana et al., 2001; Owcycle et al.. 2005). Preliminary phytochemical analysis of the aqueous extract of a homogenous mixture of these ten plants revealed the presence of tannins, flavonoids, glycosides and salicyclates (Gupta et al., 2008). Experimental studies on rodents indicated very low toxicity (LD),>>8000 mg kg) and low ulcerogenicity of this polyherbal preparation as compared to aspirin. The antipyretic-analgesic effect of this polyherbal preparation mentioned in standard Ayurvedic texts was evaluated during experimental trials on rats and mice and found to be very significant (Gupta et al., 2008). However, there were no scientific evaluations based on clinical trials about The antipyretic efficacy of this medicinal preparation. This research effort was aimed at the clinical evaluation for antipyretic efficacy of a traditional combined formulation of Jwarhar mahakashay drugs of Charak Samhita by direct measurement of body temperature, assessment of secondary symptoms and appropriate supportive laboratory investigations. MATERIALS AND METHODS This clinical trial was a double-blind, randomized, placebo-controlled, parallel-group study involving a total of 60 patients having fever. The study was carried out al the Tristitute of Post Graduate Ayurvedic Education and Research al S.V.S.P. Hospital, Kolkata and the Department of Chemical Technology, Calcutta University, Kolkata. Preparation of research drug and its administration: The roots of Sariva (Hemidesmus indicus R. Br.), Manjistha (Rubia cordifolia L.) and Patha (Cissampelos pareira L.). fruits of Haritaki (Terminalia chebula Retz.), Amala (Emblica officinalis Gaertn.), Vibhitak (Terminalia bellirica Roxb.), Draksha (Vitis vinifera L.), Parushak (Grewia asiatica L.) and Peelu (Salvadora persica L.) and Sharkara granules (Saccharum officinarum L.) were obtained from the Apothecary Department of the Institute of Post Graduate Ayurvedic Education and Research Kolkata during May 2006. These were authenticated and identified by the Department of Ethnobotany, Botanical Survey of India, Shibpur, Howrah and a voucher specimen 191 was deposited in the herbarium before their utilization. All plant parts were dried in shade and coarsely powdered up to 40 mesh size. Equal portions by weight of all ingredients were homogenously mixed and subjected to soxhlet extraction in refluxing distilled water. The extraction was continued for 48 h using distilled water four times by weight of the crude drug mixture. The aqueous extract was filtered through calico cloth and was further concentrated to solid under reduced pressure over water bath in a rotary evaporator. The extract yield from 300 g of plant powder mixture was 75 g. This Jwarhar Mahakashay preparation was termed PD-10 for all systematic evaluation studies and used for the clinical trials during 2006-07. Patients: Patients were selected after general examination from the Outdoor Patients Department of the Institute of Post Graduate Ayurvedic Education and Research (S.V.S.P. Hospital), Kolkata using the following inclusion criteria: (1) Age: 15-60 years; (ii) Sex: both male and female; and (iii) History of fever: duration of fever up to 7 days. Patients were excluded if they reported any history of Iraiona, malignancy, severe systemic and organ disorders. major surgery and chronic fever. Pregnant and lactating females were excluded from the study (Sen 1994). Ethical aspects: All patients were given verbal and written information about the potential risks and benefits of participation in the study. Written consent was required before randomization. The institutional clinical research committee of the participating center approved the study protocol Treatment allocation and blinding: Initially 75 patients were selected for the purpose of this study, out of which 60 patients were finally followed up for this study. These patients were randomly allocated to one of the three equal-sized treatment groups and received the treatment dose of 60 mg kg body weight per day. The treatmentgroups included: Group A (standard group): the drug Aspirin (60) mg kg body weight per day), Group D (test drug group): the test drug PD-10 Group C (control group): rice powder as placebo. Treatment consisted of oral ingestion of the treatment drug 3 times daily for 5 days. All patients were advised light diet, plenty of water and rest. The study medication was provided in white paper boxes, mumbered consecutively with a medication number. The treatment allocation schedule was based on computer-generated random numbers. The treatment. codes resided with the principal investigator and the local investigators were not aware of treatment assignments. No treatment code was broken before the last follow-up visit was completed.

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Int. J. Pharmacol., 4 (3): 190-195, 2008 The body temperature was measured orally by means of a standard doctor's thermometer in °F at the start of the treatment and on hourly basis during the first 4 h. It was taken at 4 h intervals during the next 8 h. at 6 h intervals during the subsequent 12 h and a 12 h intervals for the next 2 days. In addition to the temperature measurements done al the Quickor Patients Department, the patients and their attendants were given elaborate instructions to measure the patients' body temperature and record the same in a diary. Follow-up visits were continued for five days after the treatment period to record if there was any relapse of fever. Outcome measures: The primary outcome measure in this study was the reduction in body temperature after treatment. This was initially measured and compared on hourly basis and later at progressively larger intervals. The secondary outcome measure was the prevalence of secondary symptoms commonly associated with fever among the patients. These symptoms included bodyache, headache, running nose. nausca, indigestion. weakness and anorexia (Sharma and Dash, 1998). As a tertiary outcome measure, the hematological examinations of blood (TC, DC, Hb%, ESR, malaria parasite) and urine (colour, appearance, protein, sugar. urobilinogen, phosphates, RBC, pus cells, parasites, yeast cells, etc.) were done for all the patients before and after treatment. Prostaglandin E, (PGE) is a very polent. Dever producing autacoids metabolite from arachidonic acid (Fauci et al., 1998; Bennett and Pluni, 1996). Most nonsteroidal antipyretics such as Aspirin and Ibuprofen inhibit fever by blocking the biosynthesis of Prostaglandins within the endotheliumi of the hypothalamic vasculature. These findings suggest that the antipyretic effect of the research drug can also be estimated by measuring its impact on the prostaglandin levels during treatment. Therefore, a representative sample of 18 patients, six cach belonging to the three treatment groups, was taken up for measurement of Prostaglandin E (PGE). The estimation of PGE; level was done following HPLC method (Galli et al., 1995) at the pathological laboratory of Rama Krishna Mission Seva Pratisthan Hospital, Kolkata, a reputed medical institution having facilities for this specialized test. The objective of this limited study was to confirm and corroborate the overall findings of antipyretic effect assessed during the detailed study as described earlier. Statistical analysis: The results obtained were presented as mean±SEM. Analysis of variance was performed by ANOVA procedures (Pipkin and Livingstone, 1984). Values of p<0.05 were considered statistically significant, p<0.01 were considered very significant and values of p<0.001 were taken as highly significant. RESULTS General information: A total of 60 patients (36 female and 24 male) were randomized and received trial medication after providing written agreement of their participation in the trial. The patients were of an average age of 36.67 years. Sevenly seven percent of the patients belonged to the minority Muslim community, while 72% resided in an urban or semi-urban area. There was no significant group difference with regard to distribution of sex, age, community, habitat or occupation. A total of 15 patients who did not participate in the entire trial or did not turn up for regular follow-up visits were excluded from the study. Evaluation of antipyretic effect: The mean degrees of fever, defined as the average body temperature in F in excess of 98.6°F, recorded in respect of the various groups over the study duration is shown in Table 1. During the clinical study, there was no appreciable change in the level of fever in the control group (group C) during the first 18 h, since the degrees of fever ranged between 1.96 to 2.66°F. Even after 72 h, there was a persistent and substantial level of fever (1.34°F). In case of the test drug group (group D), the level of fever decreased rapidly and substantially within 2 h of the administration of the first drug dose. The subjects had practically no fever until very close to the time of the second dose and this trend continued for the subsequent doses as well. The periodic peaking of fever levels just before the drug administration also showed a clear frend of sharp decrease as compared to the initial fever level. Thus, the average degrees of fever were 2.77°F at 0 h. 1.61 F at 8 h, 0.85°F at 24 h and 0.1°F at 36 h, the level of fever subsequently remaining al zero level. In the standard group (group A), the level of fever decreased substantially within 3 h of the administration of the first drug dose. Thereafter, the subjects had almost no fever until very close to the time of the second dose and this trend continued for the subsequent doses as well. Table 1: Mean Time (h) degrees of fever during clinical study FIL Group C Group D Group A 2.41±0.19 2.77=0.19 2.79±0.19* 2.42±0.14 0.82=0.22" 1.19±0.21* 2.60±0.12 0.19=0.09 0.38±0.00* 2.61±0.12 0.08±0.04* 2.GG±0.15 2.22±0.14 1.61-0.15 1.75±0.16* 2.21±0.10 0.48±0.10° 2.2016 0.05±0.04* 24 h 1.9±0.15 0.85 0.10 0.92±0.09" 36 h 2.02±0.11 0.1=0.00 0.18±0.07* 48 h 2.07±0.11 0.07±0.04* 60 h 1.77±0.08 0.08±0.03* 72 h 1.34±0.10 0.03±0.02" Significance related to control; "p<0.001, *p<0.01, *p<0.1, (ANOVA test); Values expressed are Mean±SEM (n = 20) 192

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Int. J. Pharmacol., 4 (3): 190-195, 2008 Table 2: Decrease in incidence of associated secondary symptoms during clinical study 83.317.60 Group A (%) 75.013.80 Symptom Group C (%) Group D (%) Body ache 222-64 75.08.30 ITeadache 28.6-5.9 80.0 16.90 Running nose 20.0-6.6 77.8±11.8 75.0±7.20 Nausea 0.0=0.0 100.0±0.00 33.3±8.10 Indigestion 37.5-9.7 83.3+2.40 60.0+10.5 Weakness 40.0-8.9 83.3+3.40 66.7+7.70 Anorexia -33.3=8.0 75.0±4.80 66.7±9.40 Total 24.5-6.6 80.9±3.50 66.7±7.80 Values expressed are Mean+SEM (n-20) Table 3: Increase in routine hematological parameters during clinical study Parameters Group D (%) Group A (%) 7.36±0.58 Group C(%) Mean g (%) of hemoglobin Erythrocyte (mill'cu mm) 5.52±1.09 7.12-1.35 2.81±0.55 2.15-0.13 Leucocytes (mill/cu mm) -3.10±0.77 -1.61-0.85 Neutrophil (cu mu Lymphocyte (cu mm) 2.23±0.30 -12.03+1.57 Monocyte (cu mm) -13.04+2.51 Eosinophil (cu mm) -46.701.97 Basophil (cu mm) ESR (num h Malarial parasite 0.000.00 -16.89±2.86 0.00±0.00 Values expressed are Mean LSTM (n = 20) 6.15=0.92 -15.57-2.08 -23.81-1.86 -56.36-2.53 0.00 0.00 -17.61=1.72 0.00 0.00 1.118±1.06 3.20+1.21 -0.32±0.18 -15.98+1.67 -36.00+3.06 -50.00 6.28 0.00 10.00 -11.67±0.59 0.00±0.00 Table 4: Prostaglandin E2 (PGE2) levels in patients during clinical shidy Groups C D A Decrease (%) 2.35-0.76 13.19-2.11 11.32-2.58 Significance related to control; p<0.001; p<0.01; p<0.1 (ANOVA test); Values given are Mean+SEM (n = 6) The periodic peaking of fever levels just before the drug administration also showed a clear decreasing trend as compared to the initial fever level. For example, the degrees of fever were 2.79°F al 0 h, 1.75°F al 8 h. 0.92°F al. 21 h and 0.18°F at 36 h, the level of fever subsequently remaining al negligible levels. The results obtained were found to be highly significant (p<0.001) during ANOVA analysis. Evaluation of associated secondary symptoms: All the patients were assessed for the presence of each of the seven pre-determined associated secondary symptoms. namely body ache, headache, running nose, nausea, indigestion, weakness and anorexia before and after treatment. The decrease in the incidence of each of these secondary symptoms in the three groups is presented in Table 2. The overall incidence of secondary symptoms in patients showed a decrease of 24.5% in terms of number of symptom-patients in case of Group C during the treatment period, while the decrease was 80.9% in case of Group D and 66.7% in case of Group A patients. Highly appreciable relief from the associated secondary symptoms of nausea, indigestion, anorexia, body ache, running nose and headache was observed in case of the test drug group (Group D) as compared to the control group (Group C). Laboratory investigations regarding secondary parameters: The increase in the values of different hematological parameters during the treatment is shown in Table 3. The routine hematological examination of all the patients suggested that none of the patients were suffering from malaria. No other substantial difference among the groups was noticed in respect of the other hematological parameters studied. The routine pathological examination of urine samples of patients revealed no appreciable changes in the colour, appearance, pII, protein, sugar, ketones, bile salts, bile pigments, urobilinogen, phosphates, occult blood, R.B.C., yeast cells and parasites during the treatment period. The level of epithelial cells and pus cells reduced by 20-25% in case of both Group D and Group A. while no appreciable changes were noticed in case of Group C. Estimation of prostaglandin levels: The decrease in the Prostaglandin E, (PGE) levels in the representative sample of patients belonging to the three groups during treatment as estimated by IIPLC method is detailed in Table 4. The overall Prostaglandin E2 (PGE,) level registered a decrease of 13.19% in case of the test drug group and 11.32% in case of the standard drug group, while in case of the control group, the decrease was only 2.35%. DISCUSSION The clinical study showed that fever was rapidly and substantially reduced in case of patients who were administered the test drug. The antipyretic effect of the research drug was also more sustained in nature when compared to the standard drug, Aspirin. ANOVA tests conducted to establish the statistical significance of the clinical findings showed that the results were highly significant (p<0.001). The secondary symptoms, especially body ache, rumming nose, anorexia and headache also exhibited a drastic reduction when the test drug (PD-10) was administered as compared to Aspirin. Laboratory investigations in the form of routine blood examination, malarial testing and routine urine tests did not show significant difference in the impact on these parameters between various groups. However, the overall Prostaglandin E (PGE) level in case of the representative sample registered a substantial decrease during treatment. 193

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Int. J. Pharmacol., 4 (3): 190-195, 2008 with PD-10, which is consistent with and corroborates the overall findings regarding the antipyretic efficacy of PD-10 during clinical study. As per the modem palho-physiology concept, fever is produced due to exogenous purogens that act on the host cells and produce endogenous pyrogens in the form of cytokines, which are regulatory polypeptides. The endothelial cells of anterior hypothalamus release arachidonic acid metabolites when exposed to these endogenous pyrogenic cytokines (Leon, 2002). One of the arachidonic acid metabolite prostaglandin E (PGE) is a very potent fever producing aulacoid that affects the hypothalamus receptors, raising the thermo-regulatory set point and causing hyperthermia (Fauci et al., 1998; Bermell and Plum, 1996). In such an event, management. of symptomatic fever ailments was undertaken with nonsteroidal anti-inflammatory and antipyretic chemicals in modern medicine that associate significant risk from gastro-toxicity to hepato-toxicity to nephro-toxicity (Suleyman et al., 2007). Traditional Ayurvedic text Charak Samhita describes a specific group of 10 drugs (called warhar mahakashay) that possess antipyretic properties. Polyherbal formulations have been commonly used in this Indian system of medicine with the objective of holistic treatment of the disease and its associated symptoms using synergic effect of the constituent medicinal plants. The aqueous extract of homogenous mixture of the dried parts of these ten plants mixed in equal quantities by weight was termed PD-10 for analysis. Flavonoids and flavonidic glycosides were reported in most of these plants and were observed present in spot test with PD-10 preparation (Baltenweck-Guyot et al., 2000; Foo et al., 1998; Kundu and Mahato, 1993) Flavonoids have been known to exhibit strong antipyretic properties as well as anti-oxidant properties (Narayana et al., 2001; Nijveldi et al., 2001). Most of these medicinal plants have been reported to exhibit pharmacological actions such as anti-inflammatory, analgesic, hepato-protective, anti-microbial and anti-ulcer properties (Gupta et al., 2008). Preliminary phytochemical screening of the extract. indicated the presence of tamins, reducing sugars, flavonoids, glycosides and salicyclates (Gupta et al., 2008). Flavonoids are well known for their ability to inhibit pain perception (Sawadogo et al., 2006) and to exhibit anti-inflammatory properties due to their inhibitory effects on enzymes involved in the production of the chemical mediator of inflammation (Oweyele et al., 2005). Flavonoids and its related compounds also exhibit inhibition of arachidonic acid peroxidation, which results in reduction of prostaglandin levels thus reducing the fever (Baumann et al., 1980). Since flavonoids exhibit several biological effects such as anti-inflammatory, antimicrobial, anti-hepato-toxic and anti-ulcer activities (Narayana et al., 2001; Nijveldt et al., 2001), it is likely that the antipyretic action of PD-10 preparation is primarily related to the presence of flavonoids. Evaluation of the antipyretic action of PD-10 during clinical trials indicates that this polyherbal preparation from a mixture of the ten Jwarhar Mahakashay drugs exhibits significant antipyretic efficacy that is substantial and sustained in nature and comparable in strength to some of the existing chemical antipyretics such as Aspirin. The antipyretic effect of the test drug was validated and found to be significant following statistical analysis. The use of PD-10 also led to a substantial reduction in the incidence of associated secondary physical parameters of fever. The antipyretic action was also confirmed by a definite lowering of the Prostaglandin levels in the representative sample. The antipyretic properties of Jwarhar Mahakashay drugs as described in the traditional Ayurvedic text. (Charak samhita) were evaluated and assessed using modern scientific techniques in this clinical study. The overall research findings corroborate and validate the antipyretic efficacy of these drugs, which has been traditionally ascribed to them. REFERENCES Ballenweck-Guyol, R., J.M. Trendel P. Albrecht and A. Chaeffer, 2000. Glycosides and phenylpropanoid glycerol in Vitis vinifera cv. Gewürztraminer wine. J. Agric. Food Chem., 48: 6178-6182. Bauman, L., F. Von Bruechan Sen and G. Wunn, 1980. Flavonoids and related compounds as inhibition of arachidonic acid peroxidation. Prostaglandins, 20: 627-639. Bennett, JC and F. Plum, 1996. CECIL Textbook of Medicine. Prism Indian Edition. 20th Ed., Saunders (W.B.) Co. Ltd., ISBN: 0-7216-3573-3, pp: 1532-1535. Fauci, A.S., E. Braunwald, K.J. Isselbacker, J.D. Wilson. and I.B. Martin et al., 1998. Harrison's Principles of Internal Medicine. 14th Edhi, McGraw-Hill, New York, ISBN-10: 0070202915, pp: 84-86. Foo, L. Y., Y. Lu and II. Wong, 1998. Biphenyl-linked biflavanoids from grape promace. Phytochemistry. 47: 1137-1140. Gatti, R., R. Gotti, V. 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Int. J. Pharmacol., 4 (3): 190-195, 2008 Gupta, M., B.P. Shaw and A. Mukherjee, 2008. Studies on antipyretic-analgesic and ulcerogenic activity of polyherbal preparation in rats and mice. Int. J. Pharmacol., 4: 88-94. Kirtikar, K.R. and B.D. Basu, 1984. Indian Medicinal Plant. 1-4th Edn, Lalit Mohan Basu M.B., Allahabad, India, ISBN: 81 70892791 pp: 1: 95, 388, 607; 2: 1020,1303. 1537; 3: 1596, 2221; 1: 2661. Kundu, A.K. and S.B. Mahato, 1993. Triterpenoids and their glycosides from Terminalia chebula. Phytochemistry, 32: 999-1002. Leon, L..R., 2002. Cytokine regulation of fever: studies using gene knockout mice. J. Applied Physiol. 92: 2648-2655. Narayana, K.R., M.S. Reddy, M.R. Chaluvadi and D.R. Krishna, 2001. Bioflavonoids classification, pharmacological, biochemical effects and therapeutic potential. Ind. J. Pharmacol., 33: 2-16. Nijveldt, R.J., E. Van Nood, D.E. Von IIoorn, P.G. Boelens, K. Van Norren and P.A.M. Van Leeuwen, 2001. Flavonoids: A review of probable mechanisms of action and potential applications. Am. J. Clin. Nutr.. 74: 418-425. Oweyele, V.B., Y.Y. Oloriegbe, E.A. Balogun and A.O. Soladoye. 2005. Analgesic and antiinflammatory properties of Nelsonia canescens leaf extract. J. Ethnopharmacol., 99: 153-156. Pipkin, F.B. and C. Livingstone, 1984. Medical Statistics Made Easy. 1st Edn., Churchil Livingstone, Edinburgh, New York, ISBN: 0113028885, pp: 70-75. Sawadogo, W.R.. A. Meda, C.E. Lamien M. Kiendrebeogo, IP. Guissou and O.G. Nacoulma 2006. Phenolic content and antioxidant activity of six acanthaccac from Burkina Faso. J. Biol. Sci.. 6: 219-252. Sen, S.K., 1994. Essentials of Clinical Diagnosis. 7th Edn., Standard Book House, Calcutta, pp: 34-36. Sharma, P.C., M.B. Yelne and T.J. Dennis, 2001. Database on Medicinal Plants used in Ayurveda. Central Council for Research in Ayurveda and Siddha. 1st Edn, 3rd Edn, 5th Edn., Department of Indian System of Medicine, Govt. of India, New Delhi, pp: 1: 396; 3: 11, 158, 282; 5: 413, 172, 263. Sharma, R.K. and B. Dash, 1998. Charak Samhita (Chikitsa Sthanam). 3rd Edn., Chaukhamba Sanskrit Series, Varanasi, India, ISBN: 81-7080-014-5, PP: 114-116. Sharma, R.K. and B. Dash, 1999. Charak Samhita (Sutra Sthanam). 6th Edn., Chaukhamba Sanskrit Series, Varanasi, India, ISBN: 81-7080-012-9, pp: 98. Suleyman, II., B. Demircan and Y. Karagoz, 2007. Antiinflammatory and side effects of cyclooxygenase inhibitors. Pharmacol. Reports, 59: 217-258. 195

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Ayurveda, Fever, Medicinal plant, Flavonoid, Traditional usage, Modern medicine, Central nervous system, Body temperature, Statistical analysis, Control group, Patient, Treatment group, Clinical trial, Charak Samhita, Clinical evaluation, Polyherbal formulation, Anti-inflammatory, Laboratory investigation, Aqueous extract, Pharmacological action, Prostaglandin levels, Standard group, Experimental trial, Body weight, Antipyretic effect, Polyherbal preparation, Herbal drug, Urine sample, Antipyretic properties, Analgesic, Antipyretic drug, Traditional Ayurvedic Text, Ethical aspect, Antipyretic action, Traditional Indian systems of medicine, Polyphenolic compound, Treatment allocation, Prostaglandin E2, Traditional Indian system, Natural herbal drugs, Research drug, Treatment dose, Outcome measure, Hematological parameter, Secondary symptoms.