|Year : 2015 | Volume
| Issue : 1 | Page : 72-79
Safety and efficacy of Qurse-e-istisqua in chronic hepatitis C Infection: An exploratory study
Harmeet Singh Rehan1, Deepti Chopra2, Madhur Yadav3, Neeta Wardhan4, Seema Manak1, KM Siddiqui5, Mohd Aslam6
1 Department of Pharmacology, Lady Hardinge Medical College, New Delhi, India
2 Department of Pharmacology, HIMSR, Jamia Hamdard, New Delhi, India
3 Department of Medicine, Lady Hardinge Medical College, New Delhi, India
4 Department of Pharmacology, University College of Medical Sciences, New Delhi, India
5 Central Council for Research in Unani Medicines, AYUSH, Ministry of Health and Family Welfare, Janak Puri, New Delhi, India
6 Department Pharmacology Ilmul Advia, faculty of Unani Medicine, Hamdard University, New Delhi, India
|Date of Submission||11-Sep-2013|
|Date of Decision||24-Nov-2014|
|Date of Acceptance||30-Dec-2014|
|Date of Web Publication||30-Jan-2015|
Dr. Harmeet Singh Rehan
Department of Pharmacology, Lady Hardinge Medical College, New Delhi
Source of Support: None, Conflict of Interest: None
Background: Qurse-e-istisqua (Q-e-I), an Unani medicine commonly prescribed to treat liver disorders.
Objectives: To study efficacy and safety of Q-e-I in hepatitis C virus (HCV) infection.
Methods : In this randomized double-blind exploratory study, 60 naive patients of HCV infection were assigned to receive either interferonα2a (IFNα2a) (3 mIU, subcutaneous, thrice weekly), ribavirin (RBV) (1000 mg, orally, twice daily in divided doses) and placebo (n = 30) or IFNα2a, RBV and Q-e-I (5 g, orally, thrice daily in divided doses) (n = 30). HCV RNA levels, serum hyaluronic acid (SHA), ultrasound image scoring for fibrosis, liver and renal function test, prothrombin time, were done at the baseline and thereafter periodically.
Results: Early virologic response (EVR), end of treatment response (ETR) and sustained virologic response (SVR) were 90%, 96.6% and 90% in the control group and 86.6%, 90.0% and 83.3% in the treatment group. SHA level was lower in the treatment group at the end of the treatment as compared to the control group. Mean end of follow-up ultrasound image scoring for fibrosis in the control and the treatment group was 1.37 ± 0.07 and 1.22 ± 0.06 respectively. Aspartate aminotransferase (AST) levels were significantly lower in the treatment group than the control group at 1-month. Commonly observed adverse drug reactions included fever, hair fall, fatigue, anemia, and diarrhea.
Conclusion: Q-e-I was well tolerated and showed anti-fibrotic activity. EVR, ETR and SVR suggested that Q-e-I do not have any anti-HCV activity. Early recovery in AST and inhibition of progress of fibrosis in Q-e-I group was probably due to the anti-inflammatory and antioxidant activity of its ingredients.
Keywords: Fibrosis, hepatitis C, interferon, Qurse-e-istisqua, ribavirin
|How to cite this article:|
Rehan HS, Chopra D, Yadav M, Wardhan N, Manak S, Siddiqui K, Aslam M. Safety and efficacy of Qurse-e-istisqua in chronic hepatitis C Infection: An exploratory study. Indian J Pharmacol 2015;47:72-9
|How to cite this URL:|
Rehan HS, Chopra D, Yadav M, Wardhan N, Manak S, Siddiqui K, Aslam M. Safety and efficacy of Qurse-e-istisqua in chronic hepatitis C Infection: An exploratory study. Indian J Pharmacol [serial online] 2015 [cited 2020 Jan 28];47:72-9. Available from: http://www.ijp-online.com/text.asp?2015/47/1/72/150347
| » Introduction|| |
Hepatitis C is an escalating health burden worldwide. Global prevalence of hepatitis C virus (HCV) infection is around 2%, with 170 million persons chronically infected with the virus.  In India, seroprevalence in the community has been reported to be 0.87% whereas it is 1.8-2.5% among the blood donor population.  Majority (50-80%) of those infected with acute infection with HCV develop chronic infection that rarely resolves spontaneously. Chronic hepatitis C infection is associated with multiple complications such as hepatic fibrosis, cirrhosis and hepatocellular carcinoma. 
The currently recommended treatment options for the hepatitis C infection include interferon (INF) in combination with ribavirin that is associated with limitations like adverse effects, high cost, and inconvenience in administering injections. Complementary alternative medicines (CAM) viz. silymarin, glycyrrhizin are popular amongst patients with liver disorders as hepatoprotective agents , and have shown biochemical and immunological benefits. ,
Qurse-e-istisqua (Q-e-I) is a polyherbal formulation of Unani system of medicine containing Nardostachys jatamansi,Cucumis sativus,Portulacea olenlcea,Cuscuta reflexa roxb, Apium graveolens, Pistacia lentiscus, Berry, Rheum emodi, Rosa damascena, Berberis aristata, Intibus satibus and Solanum nigrum, which has been approved for hepatitis diseases.  In experimental studies, some of the constituents of Q-e-I viz N. jatamansi, A. graveolens linn, R. emodi, B. aristata and S. nigrum linn have shown antioxidant, antifibrotic and hepatoprotective activity. ,,,, There is no clinical evidence for the use of Q-e-I in literature; hence the present clinical study was designed to evaluate the efficacy and safety of Q-e-I in hepatitis C patients as an adjuvant to the conventional therapy.
| » Materials and Methods|| |
This prospective, randomized, double-blind exploratory study was conducted in the Department of Pharmacology and Department of Medicine, Lady Hardinge Medical College and associated SSK Hospital, New Delhi. HCV-RNA positive patients aged 18-60 years, of either sex, were included in the study. The exclusion criteria were; History of treatment with conventional INF, pegylated INF or ribavirin (RBV) less than 6 months prior to enrolment, creatinine levels above 150 μmol/l, hemoglobin levels below 10 g/dl, white blood cell count below 3 × 10 9 /l, platelet count below 1 × 10 11 /l; history of varices, ascites, encephalopathy, decompensated liver disease, active co-infection with HBV, history of any systemic anticancer or immune modulatory treatment 6 months prior to enrolment. Patients who used alcohol, any other anti-viral medication during the trial, pregnant women, lactating women, having history of hepatic, renal, or other major organ transplantation were also excluded from the study.
Study protocol was approved by the Institutional Ethics Committee. Informed consent was taken from all the patients. A physician of Unani system of medicine was designated as co-principal investigator. Enrolled patients were randomly assigned to receive either conventional INFα2a (3 MIU, subcutaneously, thrice weekly), RBV (1000 mg, orally, daily, in two divided doses) and placebo (in three divided doses) (control group) or conventional INFα2a, RBV and Q-e-I (5 g, orally, daily, in three divided doses) (test group). Duration of treatment for HCV infection with genotype 1 and 4 was 48 weeks and with genotype 2 and 3 was 24 weeks. For mixed HCV infections, duration of treatment was in accordance to the genotype requiring treatment for longer duration. After completion of treatment, patients were followed for a period of 24 weeks. Computer generated allocation sequence was used for randomization of subjects. Investigator and patients were masked to the treatment assignment. Placebo was made identical to the test drug in terms of shape, size, color and weight.
Complete blood count (CBC), liver function test, renal function test, prothrombin time (PT) and partial prothrombin time (PTTK) were done at baseline and at 4, 12, 24 and 48wks (for genotype 1 and 4). CBC was also carried out at 2 weeks. Baseline Anti HCV antibody, HCV RNA level, HCV genotype and HBs Ag were determined. HCV RNA levels were repeated at 12 weeks, 24 weeks (genotype 2 and 3), 48 weeks (genotype 1 and 4) and 6 months after completion of treatment in both the groups.
To evaluate the extent of fibrosis of liver serum hyaluronic acid was determined using ELISA at baseline and at the end of the therapy,  and ultrasound imaging of liver was done at baseline 4, 8, 12, 16 weeks, end of the treatment and end of the follow-up. 
Efficacy of treatment was determined by estimating the early virologic response (EVR), End-of-treatment response (ETR) and Sustained virologic response (SVR). EVR was defined as >2 log reduction in HCV RNA level as compared to the baseline by 12 weeks (partial EVR) or HCV RNA not detectable at treatment week 12 (complete EVR). ETR was considered when HCV RNA was not detected in the blood at the end of treatment, which is 48 weeks for genotype 1 and 24 weeks for other genotypes. SVR was considered when HCV RNA remained negative for 24 weeks after the cessation of treatment. 
Causality assessment of adverse drug reactions was performed using Naranjo probability scale. 
Student's t-test (paired and unpaired) was used to analyze the data, and Chi-square test was used for comparing the proportions. P < 0.05 was considered statistically significant.
| » Results|| |
A total of one hundred and two patients were screened, out of which seventy-six patients were enrolled in the study. Eight patients in the control group and 8 patients in the test group dropped out from a study on their own without giving reasons. Sixty patients completed the study [Figure 1]. Majority of patients were men 25 (83.3%) in the control group and 24 (80%) in the test group. Mean age of the patients in both the groups was comparable that is, 31.0 ± 1.29 years in the control and 36.9 ± 2.0 years in the test group. Body weight of the patients in both the groups was also similar that is, 64 ± 8.3 kg in the control and 62 ± 10.4 kg in the test group [Table 1].
Overall EVR was achieved by 53 of 60 patients; 27 (90%) in the control group and 26 (86.6%) in the test group. This was statistically insignificant (difference 3.4%; 95% confidence interval [CI], −0.12 to −0.19; P = 0.68) [Table 2]. Overall, the majority of the patients obtained a complete EVR while the number of those obtained a partial EVR was 3 of 60 patients (05%) with the no difference between the two groups [Table 2].
Overall EVR in sum total of genotype 1 and 4 was observed in 11 of 16 patients; 5 of 7 patients (71.4%) in the control group and 6 of 9 patients (66.6%) in the test group. The difference was statistically insignificant (difference, 4.8%; 95% CI, −0.41 to −0.50; P = 0.83) [Table 2].
Overall, EVR in genotype 3 was observed in 39 of 41 patients; 21 of 22 patients in (95.45%) in the control group and 18 of 19 patients (94.5%) in the test group. There was no patient with genotype 2. The difference was statistically insignificant (difference, 0.9%; 95% CI, −0.125 to −0.144; P = 0.91) [Table 2].
Overall, ETR was obtained in 56 patients (93.3%); 29 of 30 patients (96.6%) in control group and 27 of 30 patients (90.0%) in test group (difference, 3.3%; 95% CI, −0.59 to −0.191; P = 0.60) [Table 2].
Overall ETR in sum total of genotype 1 and 4 was observed in 14 of 16 patients; 7 of 7 patients in (100%) in the control group and 7 of 9 patients (77.7%) in the test group. The difference was statistically insignificant (difference, 22.3%; 95% CI, −0.048 to −0.49; P = 0.5) [Table 2].
Overall ETR in genotype 3 was observed in 39 of 41 patients; 21 of 22 patients in (95.45%) in the control group and 18 of 19 patients (94.5%) in the test group. The difference was statistically insignificant (Difference 0.9%; 95% CI, −0.125 to −0.144; P = 0.9) [Table 2].
Overall, a SVR was obtained in 52 of 60 patients (86.6%); 27 of 30 (90%) in control group and 25 of 30 (83.3%) in the test group (difference, 6.7%; 95% CI, −0.104 to −0.238; P = 0.70) [Table 2].
SVR in sum total of genotype 1 and 4 was obtained in 13 of the 16 patients (81.25%); 6 of 7 patients (85.7%) in control group and 7 of the 9 patients (77.7%) in test group. The difference between the two groups was statistically insignificant (difference, 4.5%, 95% CI, −0.29 to −0.455; P = 0.68) [Table 2].
SVR in genotype 3 was obtained in 36 of the 41 patients (87.8%); 20 of 22 patients (90.9%) in control group and 16 of the 19 patients (84.2%) in test group. The difference between the two groups was statistically insignificant (difference, 6.7%; 95% CI, −0.28 to − 0.13; P = 0.86) [Table 2].
A total of 3 of 41 (7.3%) patients with genotype 2 or 3 experienced a relapse during follow-up; including 1 of 22 (4.5%) patients in the control group and 2 of 19 (10.5%) in the test group.(Difference, 6%; 95% CI, −0.09 to − 0.25; P = 0.8). One of the 16 (6.25%) patients with genotype 1 and 4 experienced a relapse during follow-up [Table 2].
Mean baseline ultrasound image scoring for fibrosis in control and test group was 1.3 ± 0.08 and 1.37 ± 0.49 respectively. In the control group, fibrotic score remained unchanged throughout the treatment while in the test group, fibrotic score reduced significantly at 4 month (P < 0.05) and thereafter remained lower than the baseline at the end of the treatment and follow-up [Figure 2].
|Figure 2: Ultrasound image scoring for liver fibrosis (mean ± standard error mean) at baseline 1, 2, 3, 4 months, end of treatment and at the end of follow-up. *P < 0.05 - comparison within the groups|
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Mean baseline hyaluronic acid in control and test group was 103.1 ± 4.38 ng/ml and 111.8 ± 5.35 ng/ml respectively. In the control group, it increased significantly to 134.0 ± 6.9 ng/ml (P < 0.001) at the end of the treatment, whereas it remained unchanged in the test group. On comparing the two groups, the hyaluronic acid levels were significantly lower in the test group [Figure 3].
|Figure 3: Serum hyaluronic acid levels (mean ± standard error mean) at baseline and at the end of treatment. ***P< 0.001 comparison within the groups, ††P < 0.01 - comparison in between the groups|
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Hematological and biochemical response
At the end of the treatment, mean hemoglobin level in the test group was to 11.78 ± 0.22 g/dl as compared to 11.74 ± 0.28 g/dl in the control group. Significant fall in hemoglobin level in both the groups was seen throughout the treatment and end of the follow-up, but this fall in hemoglobin level was insignificantly less in the test group [Table 3].
On starting the treatment in both the groups TLC reduced, though it remained within normal limits. Reduction in TLC was significant (P < 0.001) at 3 months and end of the treatment in the control group while the rate of fall of TLC was lesser in the test group.
Within the groups significant improvement in aspartate aminotransferase (AST) (P < 0.01) and alanine aminotransferase (ALT) (P < 0.001) was observed at 1-month and till the end of the follow-up (P < 0.001) in the test group while in the control group significant improvement in AST [Figure 4] and ALT [Figure 5] levels was seen at 3 months (P < 0.001) and till the end of the follow-up. On comparing the two groups, the AST levels at end of 1-month were significantly lower in the test group. But ALT levels in the test group were insignificantly different from the control group. Significant improvement in alkaline phosphatase (ALP) [Figure 6] levels was seen in both the groups at the end of the treatment and also at the end of the follow-up. No significant difference was seen in the total bilirubin levels in both the groups [Figure 7].
|Figure 4: Serum alkaline phosphatase levels (mean ± standard error mean) at baseline, 1-month, 3 months, end of treatment and at end of follow-up. **P < 0.01, ***P < 0.001 comparison within the groups|
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|Figure 5: Serum aspartate aminotransferase levels (mean ± standard error mean) baseline, 1 month, 3 month, end of treatment and at the end of follow-up. ** P < 0.01, ***P < 0.001 comparison within the groups ,†††P< 0.001 comparison in between the groups|
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|Figure 6: Serum alanine aminotransferase levels (mean ± standard error mean) baseline, 1-month, 3 months, end of treatment and at the end of follow-up. ***P<0.001 comparison within the groups, †P<0.05 comparison in between the groups|
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|Figure 7: Prothrombin time (mean ± standard error mean) baseline, 1-month, 3 months, end of treatment and at the end of followup. *P<0.05, ***P<0.001 comparison within the groups, †P<0.05, †††P< 0.001 comparison in between the groups|
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In the control group, mean baseline PT [Figure 8] was 12.33 ± 0.13 s. It rose significantly at 1-month (P < 0.001) and then reduced significantly at 3 months (P < 0.001) and then increased beyond normal limit to 16.23 ± 1.57 s (P < 0.05) at the end of the treatment. Rise in PT was higher in the control as compared to the test group. In the test group, mean baseline PT was 12.96 ± 0.32 s. PT remained similar throughout the treatment and at the end of the treatment. Intergroup comparison also suggested significantly lower PT value (12.7 ± 0.23 s) at the end of 1-month and at the end of the treatment (12.86 ± 0.52 s).
|Figure 8: Partial thromboplastin time (mean ± standard error mean) baseline, 1-month, 3 months, end of treatment and at the end of follow-up. *P < 0.05, ***P<0.001 comparison within the groups|
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Mean baseline PTTK [Figure 9] in both the groups was within the normal limits. In control group after 3 months of the treatment PTTK value increased significantly (P < 0.05), whereas in the test group PTTK values remained similar throughout the treatment.
|Figure 9: Total bilirubin levels (mean ± standard error mean) baseline, 1-month, 3 months, end of treatment and at the end of follow-up|
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Safety and tolerability
Of the reported 174 adverse events, 91 were in the control group and 83 in the test group. Causality assessment of the adverse reactions was possible or probable to INF and RBV. Hair fall was significantly (P < 0.02) lower in the test group [Table 4]. Reduction in hemoglobin levels was observed in all the patients in both the groups but episode of significant anemia (hemoglobin level <10 g% or symptomatic anemia) occurred in 10 of the 30 patients (33%) in control group and 7 of the 30 patients (23.3%) in the test group [Table 3]. None of the patient required blood transfusion. One patient was prescribed erythropoietin for severe anemia. Serious adverse events observed during the study were hypothyroidism with pericardial effusion, diminished vision and severe depression with suicidal ideation [Table 4].
| » Discussion|| |
Complementary and alternative medicines like silymarin, glycyrrhizin and St. John's wart are commonly used in patients with chronic liver disease.  Some of these CAM may have a beneficial effect on liver enzymes, but there is no firm evidence of their efficacy on HCV infection.  A double-blind study demonstrated SVR in hepatitis C patients receiving the silymarin.  Adding to this Wagoner et al. also reported that purified flavonolignans of silymarin blocked the entry and transmission of HCV in HCV cell culture. 
In the present study, EVR, ETR and SVR were similar in patients of genotype 1, 4 and 3 in both the groups and the majority of the patients obtained a complete EVR. This suggested no additional antiviral effect of Q-e-I over standard treatment that is, IFN + RBV. There is no clinical study of Q-e-I available in the literature to compare these findings, but emodin one of the ingredients of Q-e-I, in experimental studies has shown to inhibit HBV DNA replication in HepG2.2.15 in-vitro cell culture,  though its effect needs to be studied against HCV.
In this study, Q-e-I prevented the progression of fibrosis, it was evident by the reduction in the ultrasound fibrotic score and unchanged levels of hyaluronic acid at the end of the treatment in the test group [Figure 2] and [Figure 3]. This effect could be because of the antifibrotic effect of some of the ingredients of Q-e-I viz Nardostchys jatamansi, R. emodi, B. aristata and S. nigrum linn. ,,,,
Liver enzymes are usually raised in HCV patients. Q-e-I in combination with INF and RBV, significantly reduced the raised levels of ALT (P < 0.01), AST (P < 0.001) and ALP within the group at the end of 1-month treatment as compared to standard treatment that is, placebo, INF and RBV. Comparing the groups, significant reduction in the AST levels was seen at the 1-month of the treatment. This suggested that the supplementation of Q-e-I can help in early recovery of liver enzymes. The ingredients of Q-e-I in animal studies has shown favorable effects on liver enzymes. ,,,, Other CAMs have also shown the beneficial effect on liver enzymes. Glycyrrhizin given intravenously in patients with chronic HCV infection lowered ALT levels (26% vs. 6% with placebo) within 4 weeks of treatment.  Vailati et al. reported significant decrease in ALT and AST in viral hepatitis patient treated with silymarin. 
Interferon-alpha and RBV are known to cause significant side effects and the common ones are flu-like symptoms 41%, anemia, leucopenia 13%, depression 10%, discontinuation of therapy 5% and thyroid abnormality 2%.  In the present study, 33.3% and 23.3% of the chronic hepatitis C patients had a significant fall in the hemoglobin levels in the control and test group respectively. It occurred probably due to the fact that RBV accumulates in erythrocytes and INF-α causes myelosuppression. , Fall in hemoglobin was transient, and no dose modification was required except one patient who required injection erythropoietin in the Q-e-I group. One patient developed depression with suicidal tendency in the test group, causality assessment of which was probable to INF. This required discontinuation of treatment with INF, RBV and Q-e-I. For this patient fluoxetine (20 mg, PO) was prescribed and showed improvement in the symptoms was within 4 weeks of the treatment and INF and RBV therapy was restarted along with the fluoxetine. Similar case of depression with suicidal tendency has been reported with INF by other workers.  Though INF do not cross blood brain barrier, it may reach circumventricular organs and exert its effect on central nervous system, which could be the reason for suicidal tendency. ,
| » Limitation of the Study|| |
Fibroscan could have done been a better investigation to evaluate and assess the extent of the fibrosis of the liver. Ultrasound imaging of liver was done due to the nonavailability of the fibroscan facility at the time of conduct of this study.
| » Conclusion|| |
Data suggest that Q-e-I is unlikely to benefit HCV-RNA levels in chronic hepatitis C patients, but it has therapeutic beneficial effect in preventing the progression of fibrosis and early recovery in liver enzymes. Q-e-I is safe and well-tolerated by the patients.
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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]