ANTI-HYPERLIPIDEMIC EFFECT OF HRIDAYARNAVA RASA
– A RANDOMIZED DOUBLE BLIND CLINICAL STUDY
ChaudhariSwapnil1 ,Galib R, Patgiri BJ3 , Prajapati PK4
- Central Ayurveda Research Institute for Drug Development, Kolkata 70009.
- Dept of Rasashastra and bhaishajyakalpana, All Indian Institute of Ayurveda, New Delhi, India 110076.
- Dept of Rasashastra and BhaishajyaKalpana, IPGT&RA, Gujarat Ayurved University, Jamnagar, Gujarat
Background: Hyperlipidemia is modifiable risk factor for cardiovascular diseases, and its prevalence is alarmingly increasing in India. Though different treatment modalities are effectively used in the conventional system, they have certain limitations including certain adverse effects. Ayurvedic metallic and herbo-mineral formulations are safely practiced in Indian subcontinent without any evident side effects. Hridayarnava Rasa is one such Ayurvedic herbo-metalo-mineral formulation containing Tamra Bhasma(incinerated copper) that is being successfully prescribed in the management of lipid disorders.
Aims and Objectives: To evaluate anti-hyperlipidemic effect of two samples of Hridayarnava Rasaprepared by using Tamra Bhasma processed in Surana Kanda (HRTBS) and Panchamrita during Amritikarana (HRTBP).
Materials and methods: Total 126 patients of hyperlipidemiafulfilling inclusion criteria were randomly grouped into two. Patients registered in one group (n= 62) were administered with 125 mg of HRTBP (Hridayarnava Rasa prepared by using Tamra Bhasma processed in Panchamrita for Amritikarana) and another Group (n =64) with HRTBS (Hridayarnava Rasa prepared by using Tamra Bhasma processed in Suranakanda for Amritikarana) twice daily for 8 weeks along with honey as an adjuvant in both groups.
Results and Conclusion: Both the drugs have shown significant effect in reducing lipid parameters but the difference in between the groups is statistically insignificant. On comparison, HRTBP showed better results than HRTBS.
KEY WORDS: Copper, Hridayarnava Rasa, Hyperlipidemia, Tamra
Address for correspondence:
Dr R Galib, Dept of Rasashastra and bhaishajyakalpana, All Indian Institute of Ayurveda, New Delhi, India 110076 Email: galib14.yahoo.co.in
Financial support: NIL, Conflict of interest : None
|How to cite this article: Chaudhari S ,GalibR,PatgiriBJ,PrajapatiPK.Anti-hyperlipidemic effect of Hridayavarana Rasa -A randomized double blind clinical study.Indian JAyurveda Res 2018;1:4-10|
Prevalence of cardiovascular diseases are emerging as global threat and estimated to account for 26% mortality due to non-communicable diseases in India.Raised lipid levels are well reported as major predictive risk factors for cardiovascular diseases and atherosclerosis.[2,3]About 79% of the general adult Indian population has abnormalities in not less than one of the lipid parameters with no urban, rural differences. Statins and fibrates are most commonly prescribed medications as hypolipidemic agents.[5,6] Though, there is extensive evidence about their safety and efficacy but use of these synthetic drugs has certain adverse effects. Myalgia, hepatopathy, renal failure, increased risk of diabetes and rhabdomyolysis are the most common side effects from statin use.[7,8,9,10]
Considering wide magnitude of lipid disorders in Indian subcontinent and absence of promising therapy with safety in conventional systems; suffering population is turning towards certain other alternatives for safe and effective remedies.
Hridayarnava Rasa, one such herbometalo-mineral compound formulation explained in Ayurveda classics containing Tamra Bhasma (incinerated copper) as an integral component is indicated in the treatment of abnormal lipid levels. Previous studies reported safety of both Tamra Bhasma and Hridayarnava Rasa in experimental animals up to genotoxic levels.[11,12,13]Tamra Bhasma (copper) is claimed to possess Medopaha (reducing fats/lipids) and Lekhana (scraps excessive fat) activities. [14,15] Diet rich in copper has a beneficial effect on blood cholesterol.Such evidences substantiate the role of copper as a lipid lowering agent. Tamra Bhasma is also reported to have anti-hyperlipidemic action through experimental studies. As no clinical evidences are available on copper based formulation, Hridayarnava Rasa; the present study is planned to evaluate therapeutic effect of the same in hyperlipidemia.
MATERIALS AND METHODS
An interventional, randomized double blind clinical trial. Registered patients were grouped into two by using computer generated randomization sequence.
Subjects presentingwith increased levels of any of the serum lipids such as S. cholesterol (>200 mg/dL), S. triglycerides (>150 mg/dL), S. LDL (>130 mg/dL), S. VLDL (>40 mg/dL) were selected from outpatient department of Institute for Post Graduate Teaching and Research in Ayurveda, Jamnagar, Gujarat between June 2015 to September 2016 after obtaining informed consent from them. Ethical clearance was obtained from Institutional Ethics Committee vide Lr No. (PGT/7A/2014-2015/2652 dated 19/12/2014). Study was registered in Clinical Trial Registry of India (CTRI/2015/08/006127 dated 20/08/2015). Each patient was examined in detail with relevant pathological and biochemical investigations before and after treatment.(Chart No.1)
Patients of either sex aged between 20 to 60 years with increased levels of any of the serum lipids were included in the study.
Patients with pathologies of liver, heart, kidney, lungs and other organs were excluded from the study. Poorly controlled hypertension (≥200/120mm Hg), uncontrolled diabetes mellitus type II (Fasting blood sugar>250mg/dl), impaired renal function (serum creatinine ≥1.2 mg/dl), pregnancy and lactation were also excluded from study.
A total of 180 patients were screened for hyperlipidemia. Among them 126 patients satisfying inclusion criteria were enrolled into the study and grouped into two groups
Hridayarnava Rasa was prepared by triturating equal proportions of Kajjali (black sulphide of mercury) and Tamra Bhasma (incinerated copper) with the decoction of Triphala (three myrobalans) and juice of Solanumnigrum Linn. Copper scraps with 99.89% pure copper was procured from local industrial area, Jamnagar, India was used in Tamra Bahsma preparation. In current study, Hridayarnava Rasa was prepared by using Tamra Bhasma processed in SuranaKanda (HRTBS) and Panchamrita during Amritikarana(HRTBP).Trial drugs were prepared at department of Rasashastra and Bhaishajya Kalpana, IPGT and RA, Gujarat Ayurveda University, Jamnagar.
Both the trial drugs were administered at a dose of 125mg twice a day with honey as Anupana (adjuvant) for eight weeks. As, current study type was randomized double blind, selected patients were randomly divided into two groups viz; group A and B using computer generated randomization sequence.Patients of Group A were administered with Hridayarnava Rasa prepared by using Tamra Bhasma processed in Panchamrita for Amritikarana (HRTBP) while the patients of Group B with Hridayarnava Rasa prepared by using Tamra Bhasma processed in Surana Kanda for Amritikarana(HRTBS).
The assessment of the signs and symptoms were done on day 0 and 56. Severity was assessed by grading 0 to 3 (absence to severe) for symptoms described for Medoroga like Kshudra Shwasa (exertional dyspnoea), Trishna (increased thirst), Swedadhikya (excessive sweating), Nidradhikya (excessive sleep), Atikshudha (increased appetite), Sada (fatigue) and Daurgandhya (bad odour).  Score adopted for the main signs and symptoms was based on WHO – guidelines for clinical research methodology in Ayurveda. 
Assessments was done based on changes observed in lipid parameters like S. cholesterol, S. triglycerides, S. LDL, S. VLDL before and after treatment in terms of percentage relief.
Haematological parameters like total leucocytes count (TLC), red blood cells (RBC), haemoglobin (Hb), white blood cells (WBC), erythrocyte sedimentation rate (ESR) and biochemical investigations like lipid profile, Blood urea, RBS, S. Creatinine, SGOT, SGPT, Alk. Phosphatase etc. were carried out to assess the condition of disease and to exclude any underlying pathology
Chart I: Assessment for eligibility
Wilcoxon signed Rank Test was applied to evaluate effect of therapy in individual group for Subjective criteria. Paired ‘t’ test was applied to evaluate effect of therapy on Haematological, Biochemical parameters. Coefficient of variation (CV) was applied to the statistical data to evaluate the differences in the effect of two therapies in Lipid profile. Overall effect of therapy on each scale was calculated with reference to percentage improvement in all inclusion criteria. A p < 0.05 was used to test the significance. Statistical analysis was performed using Sigma Stat 3.1 software.
In the present study 126 patients were registered, of which 103 participants completed the study. The socio demographic data of the participants shows that 51.59% (65) were female and the rest 48.41% (61) were males. The age groups of 41-50, 51-60 years consisted of 43.65% (55), 33.3% (42) participants respectively. The major Participants (96.03%, 121) of the study belonged to the Hindu religion. The family history of the participants revealed that 50.79% (64) had positive family history for DM followed by 29.37% (37) for hypertension, 20.63% (26) for obesity and 9.52% (12) for hyperlipidaemia. Out of the registered patients in the trial; 95.24% (120) were consuming tea or coffee on daily basis whereas 10.32% (13) of patients were having tobacco chewing as addiction. Maximum 51.59% (65) patients were under psychological stress, while 32.54% (41) patients were sentimental. 65.08% (82) of patients were doing routine work, while 18.25% (23) patients do exercise regularly. Irregularity in exercise was found in 16.67% (21) patients. Sleep pattern showed that maximum 87.3% (110) of patients have habit of day sleep. Fifteen (11.9%) patients have type-2 diabetes and 4.76% (06) have Hypertension. Prakriti (genetic phenotype) of the majority of enrolled patients was KaphaVataja (60, 47.62%), while 23.02% (29) patients were of KaphaPittaja.
Chief complaints reported were KshudraShwasa among 21.36% (22), Trisha 25.24% (26), Nidradhikya 14.56% (15), Sada 47.57% (49), Kshudhadhikya 12.62% (13), Swedadhikya 51.46% (53) and Daurgandhya 21.36% (22). Within the group, (Wilcoxon signed ranks test) statistical significance (p<0.05) on signs and symptoms of hyperlidemia was found for both Hridayarnava Rasa interventions except on Kshudhadhikya. HRTBP exhibitedinsignificant decrease (P> 0.05) in Daurgandhya. (Table 1) On the lipid profile, HRTBP exhibited better results in reducing S. Cholesterol 2.05%, S. Triglyceride 14.39% and VLDL level 14.00%, whereas in HRTBS reduction was found 0.61% in S. Cholesterol, 4.25% in S. Triglyceride and 2.67% in VLDL level. Comparative efficacy of both the test drugs on subjective and lipid parameters have been assessed and results are shown in Table 2 and 3. Overall effect of therapy is also assessed in percentage involvement. (Table 4)
SAFETY AND TOLERABILITY
All haematological and biochemical variables were within normal limits in both the treatment groups at the baseline. (Table 5 and 6) Twenty-three patients were dropped out from the study. Six patients of group A and five patients of group B were irregular in further visits during treatment course. Five patients of group A and four patients of group B have discontinued treatment due to their service related hectic schedules. Three patients of group B have left the city due to other reasons. No adverse reactions were reported during the clinical trial indicating safety of Hridayarnava Rasa when administered along with honey as adjuvant at a dose of 250mg/day for eight weeks.
Table 1: Effect of Hridayarnava Rasa on signs and symptoms of hyperlipidemia (BT and AT) – test statistics within group (Wilcoxon signed ranks test)
|Signs and symptoms||HRTBS||HRTBP|
|Mean ± SEM||P||Mean ± SEM||P|
Table – 2: Effect of test drugs on chief complaints in comparison to HRTBP and HRTBS
|Chief complaints||No||Mean||SD||CV||Better group|
Table – 3: Comparative effect of test drugs on lipid profile
|S. Cholesterol (mg/dl)||51||52||3.76||1.19||34.12||44.43||906.39||3726.88||HRTBP|
|S. Triglycerides (mg/dl)||51||52||27.90||8.73||108.94||103.43||390.46||1184.66||HRTBP|
|Serum HDL (mg/dl)||51||52||1.33||1.65||10.96||10.31||822.35||623.77||HRTBS|
|Serum LDL (mg/dl)||51||52||0.84||0.90||33.91||37.68||4022.11||4168.95||HRTBP|
|Serum VLDL (mg/dl)||51||52||5.43||1.09||22.18||20.59||408.47||1878.87||HRTBP|
Table No. 4: Overall effect of therapy
Table 5: Effect of Hridayarnava Rasa on hematological investigations (BT and AT) – paired sample test (paired t test)
|Mean difference||SD||t||P||Mean difference||SD||t||P|
|T WBC(103 /dl)||132.69||1624.41||0.58||>0.05||486.27||1345.21||2.58||<0.05|
|RBC (106 /dl)||0.009||0.28||0.25||>0.05||0.12||0.455||1.070||>0.05|
|Platelet (103 /dl)||10.25||41.68||1.77||>0.05||0.05||65.90||0.006||>0.05|
Table 6: Effect of Hridayarnava Rasa on biochemical investigations (BT and AT) – paired sample test (paired t test)
|Blood sugar (mg/dl)||0.01||28.72||0.004||>0.05||0.37||21.13||0.126||>0.05|
|Blood urea (mg/dl)||3.01||11.44||1.90||>0.05||0.54||6.47||0.605||>0.05|
|S. creatinine (mg/dl)||0.04||0.17||1.74||>0.05||0.003||0.17||0.161||>0.05|
|Total protein (g/dl)||0.08||0.72||0.81||>0.05||0.03||0.62||0.44||>0.05|
|Alkaline phosphate (IU/L)||3.08||17.84||1.24||>0.05||5.39||21.70||1.77||>0.05|
|Uric acid (mg/dl)||0.49||1.25||2.820||<0.01||0.45||0.91||3.52||>0.05|
|S calcium (mg/dl)||0.025||0.942||0.19||>0.05||0.49||19.24||0.18||>0.05|
Oxidative stress, diet rich in cholesterol and hypercholesterolemia increases LDL resulting higher risk for development of atherosclerosis. The first line defensive enzymes against the free radical produced during the oxidative stress are the antioxidant enzymes, mainly superoxide dismutase (SOD) and catalase. Copper is one of vital trace element of body required for normal physiological functions. Deficiency of copper leads to nervous weakness, anemia, connective tissue weakness and the hypo activity of cytochrome C oxidase, lysyl oxidase and SOD etc. Published reports provided scientific evidences for linkage between cholesterol metabolism and copper utilization.[26,27] Copper deficiency leads to hypercholesterolemia in several species as reported in different laboratories. Tamra Bhasma possess rich source of copper. Earlier studies report that, Tamra Bhasma inhibits lipid peroxidation and induces the activity of SOD; providing scientific evidence for its anti-oxidant agent.[29,30] Tamra Bhasma is prepared with two different Amritikarana methods which helps in elimination of blemishes from the end product and increases its therapeutic efficacy. Hence, Hridayarnava Rasa was prepared by using Tamra Bhasma processed in SuranaKanda and Panchamrita during Amritikarana and evaluated for anti-hyperlipidemic activity
Ingredients of Triphala are reported with different pharmacological actions. Haritaki (Terminalia chebula) is reported to have anti-oxidant, cardio-protective actions.[31,32] Bibhitaki (Terminalia belerica) has been reported to have antioxidant, hepato-protective activities. Amalaki (Embelica officinalis) has anti-oxidant, cardio-protective and hepato-protective actions.[34,35,36] Kakamachi (Solanum nigrumL.) has anti-hyperlipidemic, hepato-protective and anti-oxidant activities.[37,38,39] Observed anti-hyperlipidemic activity of both the samples of Hridayarnava Rasa may be attributed to involvement of one or more mechanisms mentioned above.
Both the trial drugs provided significant results in reducing level of lipid parameters. The difference in between the groups is statistically insignificant. On comparison, HRTBP has shown better results than HRTBS. Considering the encouraging results, it can be said that both the drugs can be successfully used in cases of hyperlipidemia. However, the observations can be revalidated through clinical trials involving larger sample size.
ACKNOWLEDGEMENT: Authors acknowledge the support received from Institute for Post Graduate Teaching and Research in Ayurveda, Gujarat Ayurved University, Jamnagar – 361 008, Gujarat, India.
- World Health Organization. Non communicable diseases country profiles, 2014, 1-210.
- Sanchez-Inigo L, Navarro-Gonzalez D, Fernandez-Montero A, Pastrana-Delgado JandMartinez J. The TyG index may predict the development of cardiovascular events. Eur J Clin Invest 2016; 46(2): 189-197.
- Gong Z, Qi Y, Zhao F, Liu J, Wang WandLiu J, et al., Association between very low density lipoprotein cholesterol and cholesterol absorption/synthesis markers in patients with moderate and high risk of coronary heart disease, ZhonghuaXinXue Guan Bing ZaZhi 2015; 43(11): 936-942.
- Joshi SR, Anjana RM, Deepa M, Pradeepa R, Bhansali A, Dhandania VK, et al., Prevalence of dyslipidemia in urban and rural India: The ICMR–INDIAB Study, PLoS ONE 2014; 9(5): e96808.
- Singh RS, Chaudhary DK, Mohan A, Kumar P, Chaturvedi CP, Ecelbarger CM, et al. Greater efficacy of atorvastatin versus a non-statin lipid-lowering agent against renal injury: potential role as a histone deacetylase inhibitor, Sci Rep 2016; 6: 38034.
- Shah CP, Shah BP, Dani SI, Channa BB, Lakshmanan SS, Krishnamani NC, et al., Efficacy and safety of the intensive dose of rosuvastatin 40mg/day in patients with acute coronary syndrome and at high risk of cardiovascular disease-ROSUVEES-2. Indian Heart J 2016; 68(6): 766-771.
- Ramkumar S, Raghunath A, Raghunath S. Statin therapy: Review of safety and potential side effects. ActaCardiol Sin 2016; 32: 631-639.
- Khan A, Maki KC, Ito MK, et al. Statin associated muscle symptoms: characteristics of patients and recommendations by providers. J ClinLipidol. 2015; 9(3):460.
- Benes LB, Bassi NS and Davidson NH, The risk of hepatotoxicity, new onset diabetes and rhabdomyolysis in the era of high-intensity statin therapy: does statin type matter?,ProgCardiovasc Dis 2016; 59(2):145-152.
- Ambapkar SN, Shetty N andDwivedy A. Statin induced rhabdomyolosis. J Assoc Physicians India 2016; 64(7): 93-94.
- Chaudhari SY, Jagtap C, Thakkar J, Galib R, Prajapati PK, Assessment of genotoxic potential of TamraBhasma(incinerated copper). Int J Green Pharm 2015; 9: 175-179.
- Jagtap CY, Chaudhari SY, Thakkar JH, Galib R, Prajapati PK. Assessment of genotoxic potential of Hridayarnava Rasa (a herbo-mineralo-metallic ayurvedic formulation) using chromosomal aberration and sperm abnormality assays. ToxicolInt2014; 21: 242-247.
- Chaudhari SY, Nariya M, Galib R, Prajapati PK, Acute and sub-chronic toxicity of TamraBhasma (incinerated copper) prepared with and without Amritikarana, JAIM 2016; 7: 23-29.
- Somdeva, Mishra SN. RasendraChudamani, 14/69, Varanasi, Uttar Pradesh, India, ChaukhambhaOrientalia; 2004.
- Bhairava, Mishra SN, Anandakanda, KriyakaranaVishranti4/62, Varanasi, Uttar Pradesh, India, ChaukhambaOrientalia; 2008.
- Klevay LM. Trace element and mineral nutrition in disease: ischemic heart disease, In: Clinical Nutrition of the Essential Trace Elements and Minerals: The Guide for Health Professionals, edited by Bogden, JD andKlevay LM, (The Humana Press Inc, Totowa), 2000.
- Jagtap CY, Ashok BK, Patgiri BJ, Prajapati PK, Ravishankar B. Evaluation of antihyperlipidemic activity of TamraBhasma prepared from Shodhita (purified) and Ashodhita (unpurified) Tamra. Indian J Nat Prod Resour 2013; 4(2): 205-211.
- Gopala Krishna, Rasendrasarasamgraha, HridrogaChikitsa 2/1-3, ‘Rasavidyotini’ Hindi commentary by IndradevTripathi, Varanasi, Uttar Pradesh, India, Chaukhambaorientalia; 2008; pg- 380
- Madhava, Shastri N. MadhavaNidana, Hindi Commentary, Uttarardha 34/1, Delhi, MotilalBanarasidas; 2005; pg.32
- Baghel MS, Rajgopala S, WHO – guidelines for clinical research methodology in Ayurveda. WHO sponsored project, Institute for Post Graduate teaching and Research in Ayurveda, Gujarat Ayurved University Publications-2011.
- Joseph M Hilbe, Sigma Stat: A second look, The American Statistician, vol 59 (2), 2005;187-191
- Wornholtz A, Mollnau H, Oelze M, Wendt M andMunzel T. Antioxidant and endothelial dysfunction in Hyperlipidemia. CurrHypertens Rep 2001; 53(3): 60.
- Parthasarathy S, Santanam N, Ramchandran S, andMeihac O. Oxidant and antioxidants in atherogenesis: An appraisal. J Lipid Res 1999; 40: 2143-57.
- Soetan K, Olaiya C, Oyewole O. The importance of mineral elements for humans, domestic animals and plants: A review. African Journal of Food Science 2010; 4(5): 200-222.
- Cunningham I J. Some biochemical and physiological aspects of copper in animal nutrition. Biochem J 1931; 25: 1267.
- Klevay L M. Hypercholesterolemia in rats produced by an increase in the ratio of zinc to copper ingested. Am J ClinNutr 1973; 26: 1060–1068.
- Hooper P L, Visconti L, Garry P J and Johnson G E. Zinc lowers high-density lipoprotein-cholesterol levels. JAMA 1980; 244: 1960–1961.
- Klevay L M. Trace element and mineral nutrition in disease: ischemic heart disease. In Clinical Nutrition of the Essential Trace Elements and Minerals: The Guide for Health Professionals, edited by Bogden, J D andKlevay L M (The Humana Press Inc., Totowa, NJ), 2000.
- Tripathi YB, Singh VP. Role of Tamrabhasma an Ayurvedic preparation in the management of lipid peroxidation in liver of albino rats. Ind J ExpBiol 1996; 34: 66-70.
- Tripathi YB, Singh VP. Toxicology and free radical scavenging property of TamraBhasma. Ind J ClinBiochem 2003; 18(2): 181-189.
- Suchalatha S, Devi CS. Antioxidant activity of ethanolic extract of Terminaliachebula fruit against isoproterenol – induced oxidative stress in rats. Indian Journal of Biochemistry and Biophysics 2005; 42: 246-249.
- Suchalatha S, Devi CS. Protective effect of Terminaliachebula against lysosomal enzyme alterations in isoproterenolinduced cardiac damage in rats. Experimental clnical cardiology 2005; 10(2): 91-95.
- Shukla S, Jadon A, Bhadauria M. Protective effect of TerminaliabelericaRoxb, and gallic acid agaistcarbontetra chloride induced damage in albino rats, Journal of Ethanopharmacology 2006; 109: 214-218.
- Poltanov EA, Shikov AN, Dorman HJ, Pozharitskaya ON, Makarov VG, Tikhonov VP, et al. Chemical and antioxidant evaluation of Indian gooseberry (Emblicaofficinalis, syn. PhyllanthusemblicaL.) supplements. Phytother Res 2009; 23: 1309-15
- Sultana S, Ahmad S, Khan N, Jahangir T. Effect of Emblicaofficinalis(Gaertn) on CCl4 induced hepatic toxicity and DNA synthesis in Wistar rats. Indian J ExpBiol 2005; 43:430-436.
- Bhattacharya SK, Bhattacharya A, Sairam K, Ghosal S. Effect of bioactive tannoid principles of Emblicaofficinalis on ischemia reperfusion induced oxidative stress in rat heart, Phytomedicine 2002; 9(2): 171-174.
- Mohamed Saleem TS, Chetty CM, Ramkanth S, Alagusundaram M, Gnanaprakash K, ThiruvengadaRajan VS, Angalaparameswari S. Solanumnigrum– A review. Phcog Rev 2009; 3: 342-45.
- Jani DK, Ahir KB. Review: Kakmachi (Solanumnigrum Linn.) – A prominent herb in Ayurveda. Life science leaflets. 2010; 9: 234-40.
- Jain R, Sharma A, Gupta S, Sarethy I, Gabrani R. Solanumnigrum: Current Perspectives on Therapeutic Properties. Alternative Medicine Review 2011; 16(1): 78-85.