Abstract
Viscum album, an infrequently used antihypertensive in homeopathy, is evaluated by 1-group pretest–posttest model in primary hypertension. The drug was administered for 12 weeks at a dosage of 10 drops 3 times a day. Using paired t test, a significant drop in blood pressure (P < .0001) and serum triglyceride (P < .0001) was observed in the treatment group. This dual effect of Viscum album shows promise in optimizing therapy for primary hypertension.
Introduction
Hypertension has a multifactorial etiology that leads to systemic vascular damage that has a propensity to induce cardiovascular as well as noncardiovascular complications. Hypertension follows an insidious onset, at times only noted in routine check-up, which prevents early diagnosis. 1 The ever-increasing global morbidity and mortality is pegged down to hypertension. Epidemiological studies have established a strong association between hypertension and fatal and nonfatal events. The long-standing cardiovascular complications of hypertension include atherosclerosis, angina, myocardial infarction, and congestive cardiac failure. 2 As hypertension is a chronic illness, drug therapy needs to be taken for a long period (even lifelong). Despite the multitude of antihypertensive drugs available, only 17% to 27% of hypertensives achieve optimal blood pressure. 3 The aim of therapy in hypertension is to lower the blood pressure to near-normalcy without incidental fluctuation. Although the modern system of medicine has a wide array of drugs for treating hypertension, it is confounded by persistently annoying adverse drug reaction. Lowering blood pressure is the main target to reach in the attempt to reduce cardiovascular complications in hypertensive patients. 4 Moreover resistant hypertension is not uncommon and is associated with an elevated risk of hypertensive complications. Importantly, the prevalence of multiple disease conditions has been increasing during the past years, suggesting a future increase in the frequency of resistant hypertension. 5 In this scenario the search for a novel drug from the alternative system of medicine would be promising and imperative. Homeopathic preparation does offer antihypertensive options of which Viscum album 6 has been used for over 2 centuries.
The crude mistletoe extract prevents changes in erythrocytes, packed cell volume of erythrocytes, plasma protein levels, and erythrocyte sedimentation rate, which indicates that the extract prevents changes in blood viscosity—a major determinant of arterial blood pressure. 7 Moreover, an animal trial of Viscum album aqueous extract on albino Wistar rats has shown antihypertensive effect without any change in heart rate. 8 Lack of scientific validation by a clinical trial made this drug the choice for this study. Hence, our research initiative is to clinically validate the effect of Viscum album on hypertension by undertaking a simple methodology involving a few laboratory parameters.
The experimental model of “1-group pretest–posttest study” design was taken up due to ethical and administrative reasons. The parameters used in this study to prove the efficacy of the drug are systolic blood pressure, diastolic blood pressure, serum cholesterol, and serum triglycerides. These biochemical parameters were included to find the probable domains of the drug and antecedent beneficial effects. Serum lactate dehydrogenase, serum urea, and serum creatine phosphokinase myocardial band would indicate potential adverse effects.
Materials and Methods
Approval of the Institutional Ethics Committee of Father Muller Charitable Institution was obtained before the initiation of the project, and the procedures followed were in accordance with the ethical guidelines for biomedical research provided by the Indian Council of Medical research, New Delhi. Informed consent was obtained from each individual before the screening study.
Patients attending the outpatient department of Fr Muller Homeopathic Hospital, Fr Muller Homeopathic Hospital extension in St Antony’s ashram were chosen for the study. Approximately 50 to 100 patients were screened to ensure enrollment of a minimum of 30 patients in the trial. The selected patients were newly diagnosed and have not yet taken any medication for hypertension. They were not given any other drug during the period of study. Individuals who do not respond to the intervention and have worsening symptoms would be excluded from the study. See Table 1 for inclusion and exclusion criteria.
Inclusion and Exclusion Criteria.
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CHD, coronary heart disease.
Purposive sampling was followed in this study. Patients met the inclusion criteria were included in the study and were subjected to the following biochemical tests: serum cholesterol, serum triglycerides, serum lactate dehydrogenase, serum urea, and serum creatine phosphokinase myocardial band. The blood samples were drawn from the patients at the beginning as well as at the end of the study for biochemical tests. Only serum creatine phosphokinase myocardial band test was repeated 2 months after the study to confirm the cardiotoxicity of the drug. The biochemical tests were done using the following methodology (see Table 2).
Methodology Used to Conduct the Biochemical Tests.
Abbreviation: LHD, lactate dehydrogenase; CKMB, creatine phosphokinase myocardial band.
A research team comprising 2 doctors who were pursuing internship was formulated to measure blood pressure. This team was supervised by the principal investigator. Each patient’s blood pressure was measured 3 times in a span of 2 to 3 weeks at forenoon in supine position to elicit the mean baseline blood pressure. Blood pressures were measured by using an apparatus with mercury manometer. The instrument was certified by the Bureau of Indian Standards.
After eliciting 3 blood pressure readings from each patient, they were treated for 12 consecutive weeks with Viscum album mother tincture, which was procured from Fr Muller Homeopathic Pharmaceutical Division. The drug was prepared according to the standards of the Homeopathic Pharmacopoeia of India. The dosage was 10 drops in 30 mL of distilled water, which was repeated 3 times in a day, morning, afternoon, and night for 12 consecutive weeks. The drug was taken half an hour after food. All the patients were provided medicine bottles with droppers. There were 2 follow-ups in a week, which were conducted by the research team. At each attendance the patient’s blood pressure was recorded and they were inquired of nasal congestion, tiredness, depression, and appetite.
Hence a total of 27 blood pressure recordings were recorded from each patient during the period of the study, that is, 3 for mean baseline recording and 12 weeks × 2 follow-ups = 24 during intervention.
Research Methodology and Statistics
Criteria for deciding the efficacy of homeopathic drug was based on following parameters:
Change in systolic blood pressure
Change in diastolic blood pressure
Change in biochemical parameters
Data from the sample were subjected to paired t test to determine the significance of the efficacy of the drug. This statistical tool was used because the sample size was small and each subject provided 2 observations: blood pressure before medication and blood pressure at the end of 12 weeks of medication.
The statistical test was executed by using open source software, OpenOffice.org Calc by Oracle (OOo 3) for Ubuntu Linux 10.04 (Lucid Lynx).
Results and Observation
The data of 41 patients were statistically analyzed for the efficacy of the drug (N = 41).
As per the JNC 7 categorization for hypertension, it was observed that 7% of the treated patients belong to prehypertensive group, 59% in stage 1 and 33% in stage 2. There was a statistically significant drop in systolic (P < .001) as well as diastolic pressure (P = .0017) in the sample group at the end of 12 weeks of medicine. The mean value of systolic blood pressure of the sample dropped from 155.74 mm Hg to 141.45 mm Hg after 3 months of medication. The drop in the mean value of diastolic pressure is from 84.42 mm Hg to 79.55 mm Hg (see Table 3).
Mean Value of Blood Pressure: Pre- and Posttreatment With P Value.
Abbreviation: SD, standard deviation.
The changes in the biochemical parameters are shown in Table 4.
Biochemical Values: Pre- and Posttreatment With P Values.
Abbreviation: SD, standard deviation; LHD, lactate dehydrogenase; CKMB, creatine phosphokinase myocardial band.
There was no statistically significant change in serum cholesterol (P = .142). The reduction in serum triglyceride was highly significant (P < .0001). The mean value of the sample dropped from 170.8 to 113.3 mg/dL.
The drug caused a spurt in the serum creatine phosphokinase myocardial band values. The mean value of this cardiac marker rose from 14 to 21 U/L at the end of 12 weeks of medication. Although the mean value of the sample is within the normal range, 11 patients showed values above normal (>24 U/L). None of the patients had any signs of cardiac or musculoskeletal discomforts. After 2 months of washout period, the blood samples of all the individuals were drawn to estimate this enzyme marker. The result showed a statistically significant drop in the value (P < .001). The serum creatine phosphokinase myocardial band value of the 11 patients who had a high value due to Viscum album administration showed a marked drop. This observation verifies that the increase was due to the drug administered.
Serum lactate dehydrogenase (P = .006) as well as serum urea (P = .01) of the patients rose significantly at the end of 12 weeks of medication but neither the mean value of the sample nor the individual value of each subject rose above the normal level.
Discussion
Viscum album, a bi-perennial shrub distributed widely in tropical and subtropical region of Africa, Asia, and Europe, 9 is one of the main medicinal plants used in African folk medicines to treat arterial hypertension. 10 The drug showed a significant reduction in the mean value of systolic as well diastolic blood pressure, which could be attributed to a mechanism involving nitric oxide synthase-2 and nitric oxide synthase-3 overexpression and thereby a correlated increase in nitric oxide and cyclic guanosine monophosphate production. 11 The aforementioned biochemical process may activate a nonspecific noncompetitive inhibition of calcium (2+) influx as well as Ca (2+) mobilization from intracellular stores. 12 The result is vasorelaxation.
The evaluation of biochemical parameters, namely, serum urea, serum lactate dehydrogenase, serum cholesterol, and serum triglycerides, may not give a firm understanding of the pharmacological activity but will definitely give its propensity.
The mean value of serum urea increased from 24.6 to 28.5 mg/dL (P = .01). Although it is a significant increase, none of the individuals of the treatment group had value above normal (normal = 50 mg/dL). This shows that the drug might be safe and may be administered to patients having renal impairment. The above-mentioned observation is further strengthened by the antioxidant studies on liver, kidney, and heart tissues of streptozotocin-induced diabetic rats. This study concludes by stating that Viscum album has a potent antioxidant activity. 13 But the study on tolerability of mistletoe among immune-compromised individuals showed an increased serum urea nitrogen and serum creatinine levels. 14 Therefore, the observation of a statistically significant increase of serum urea within the normal limits has to be viewed cautiously.
The lipid profile of the treatment group showed statistically significant reduction in triglycerides (P < .0001) and no change in serum cholesterol (P = .142). This observation does not give a clear impression of the antilipidemic property of the drug when viewed in light of research studies conducted by Avci et al 15 and Ben et al. 16 The study of Avci et al noted reduction in lipid profile of Viscum album–treated mice rats, whereas the study of Ben et al reported increased serum cholesterol in Viscum album–treated male wistar rats. This uncertainty in the antilipidemic property of the drug is further strengthened due to lack of complete lipid profile analysis in the study. This area requires a detailed and a thorough inquiry.
The extract, which is considered to be safe as per preclinical study 17 and systematic review of clinical and animal experiments, 18 increased levels of serum lactate dehydrogenase and creatine phosphokinase myocardial band in the treatment group. These 2 markers depict the integrity of cardiac muscle. Although the mean value of serum lactate dehydrogenase of the sample rose significantly (P = .006), it was within the normal range, and none of the individuals showed any adverse clinical signs or symptoms. This observation becomes relevant due to the increase of the mean value of creatine phosphokinase myocardial band in which 11 individuals had values above normal limits. The aforementioned parallel rise in cardiac markers gives a strong leaning toward the cardiotoxic capability of the drug, which may be attributed to the presence of viscotoxins 19 and lectins 20 in the extract.
Hypertension is often associated with dyslipidemia, and therapy with Viscum album will definitely be doubly beneficial for those who are suffering from hypertension and hypertriglyceridemia. This 2-pronged effect of Viscum album would be ideal in treating preeclampsic states where there is hypertension and raised triglycerides. 21
Conclusion
Viscum album can be considered as a good choice to regulate blood pressure as well as to lower serum triglyceride levels. The usual pharmacotherapy of hypertension is affected through sympatholytic, vasodilatory, and diuretic effects. The chemical characterization of Viscum album is different from those drugs used in the modern system of medicines and it putatively acts through calcium channels, which could be modulated by other drugs that could lead to synergism. The authors would recommend further comparative clinical studies of Viscum album with other standard pharmacotherapeutic agents.
The increased serum creatine phosphokinase myocardial band level is the only detriment to Viscum album therapy from our study, which has to be validated by toxicology studies on cell lines of cardiac muscles.
We can look forward to promising use of Viscum album therapy per se and in conjunction with drugs of modern system of medicines.
Footnotes
Acknowledgements
We would like to acknowledge Rajiv Gandhi University of Health Sciences, Bangalore, for providing financial assistance and Father Muller Charitable Institutions, Mangalore, for providing logistics support for the project.
Author Contributions
KJP: Principal investigator of the project, data analysis and interpretation, manuscript preparation. PLP: Co-investigator of the project, data analysis, manuscript preparation (discussion part). MSB: mentor and data analysis. SS: Data analysis.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This work was financially supported by the Rajiv Gandhi University of Health Sciences, Bangalore, Karnataka, India (Grant Number: RGUHS/R&D/Research Grants/P01/2011-12).
Ethical Approval
Approval of Institutional Ethics Committee of Father Muller Charitable Institution was obtained before the initiation of the project, and the procedures followed were in accordance with the ethical standards provided by Indian Council of Medical research, New Delhi. Informed consent was obtained from each individual before the screening study. The clinical trial is registered in the Clinicaltrials.gov protocol registration system (Registration Number: NCT01527760).