Standard Ribavirin Research Articles

Cytotoxic and antiviral activities of Jatropha variegata and Jatropha spinosa in relation to their metabolite profile

Jatropha variegata and Jatropha spinosa (family: Euphorbiaceae) are utilized in Yemeni traditional medicine to treat respiratory tract infection and in different skin conditions such as wound healing, as antibacterial and hemostatic. In this study, we evaluated the cytotoxicity and the antiviral activities of the methanolic J. variegata (leaves: Ext-1, stems: Ext-2, and roots: Ext-3), and J. spinosa extracts (aerial parts: Ext-4 and roots: Ext-5), in addition to their methylene chloride fractions of roots extracts (F-6 and F-7, respectively). All samples were tested against three human cancer cell lines in vitro (MCF-7, HepG2, and A549) and two viruses (HSV-2 and H1N1). Both plants showed significant cytotoxicity, among them, the methylene chloride fractions of roots of J. variegata (F-6) and J. spinosa roots (F-7) showed the highest activity on MCF-7 (IC50 = 1.4 and 1 μg/mL), HepG2 (IC50 = 0.64 and 0.24 μg/mL), and A549 (IC50 = 0.7 and 0.5 μg/mL), respectively, whereas the IC50 values of the standard doxorubicin were (3.83, 4.73, and 4.57 μg/mL) against MCF-7, HepG2, and A549, respectively. These results revealed that the roots of both plants are potential targets for cytotoxic activities. The in vitro results revealed potential antiviral activity for each of Ext-3, Ext-5, F-6, and F-7 against HVS-2 with IC50 of 101.23, 68.83, 4.88, 3.24 μg/mL and against H1N1 with IC50 of 51.29, 27.92, 4.24, and 3.06 μg/mL respectively, whereas the IC50 value of the standard acyclovir against HVS-2 was 83.19 μg/mL and IC50 value of the standard ribavirin against H1N1 was 52.40 μg/mL .The methanol extracts of the roots (Ext-3 and Ext-5) of both plants were characterized using UPLC/MS. A total of 73 metabolites were annotated, including fourteen diterpenoids, eleven flavonoids, ten phenolic acid conjugates, twelve fatty acids and their conjugates, five triterpenes and steroids, two sesquiterpenes, and six coumarins. The cytotoxicity and antiviral activities determined in the present work are explained by the existence of flavonoids, coumarins and diterpenes with commonly known cytotoxicity and antiviral activities.

Quinolone-N-acylhydrazone hybrids as potent Zika and Chikungunya virus inhibitors

This work reports the synthesis of quinolone-N-acylhydrazone hybrids, namely 6-R-N'-(2-hydxoxybenzylidene)-4-oxo-1,4-dihydroquinoline-3-carbohydrazide (R = H: 5a, F: 5b, Cl: 5c and Br: 5d), which exhibited excellent activity against arbovirus Zika (ZIKV) and Chikungunya (CHIKV). In vitro screening towards ZIKV and CHIKV inhibition revealed that all substances have significant antiviral activity, most of them being more potent than standard Ribavirin (5a-d: EC50 = 0.75–0.81 μM, Ribavirin: EC50 = 3.95 μM for ZIKV and 5a-d: 1.16–2.85 μM, Ribavirin: EC50 = 2.42 μM for CHIKV). The quinolone-N-acylhydrazone hybrids were non-toxic against Vero cells, in which compounds 5c and 5d showed the best selectivities (SI = 1410 and 630 against ZIKV and CHIKV, respectively). Antiviral activity was identified by inhibition of viral RNA production in a dose-dependent manner. In the evaluation of the time of addition of the compounds, we observed that 5b and 5c remain with strong effect even in the addition for 12 h after infection. The above results indicate that quinolone-N-acylhydrazones represent a new and promising class to be further investigated as anti-ZIKV and anti-CHIKV agents.

Impact of ribavirin dose reduction on the efficacy of pegylated interferon plus ribavirin combination therapy for elderly patients infected with genotype 1b and high viral loads

To examine the impact of ribavirin dose reduction on the efficacy of pegylated interferon (PEG IFN) plus ribavirin combination therapy for elderly patients infected with genotype 1b and high viral loads. A total of 72 patients, over 65 years old, were recruited for this study. Patients were divided into groups receiving either 600-800 mg of ribavirin according to bodyweight (Group 1, n = 36) or 400 mg of ribavirin (Group 2, n = 36) plus 1.5 µg/kg (range: 1.3-2.0 µg/kg) of PEG IFN-α-2b for 48 weeks. Total ribavirin doses were administrated at 9.80 ± 2.39 mg/kg per day (3.29 ± 0.80 g/kg) for Group 1 and 5.87 ± 1.82 mg/kg per day (1.97 ± 0.61 g/kg) for Group 2 (P < 0.001). According to the total clearance (CL/F) of ribavirin, 34 of 36 patients in Group 1 received over-doses of ribavirin. In contrast, numbers of those receiving equivalent doses of ribavirin were two of 36 patients in Group 1 and 36 of 36 patients in Group 2, respectively (P < 0.001). End-of-treatment response (ETR) rates were observed in 23 of 36 patients (63.9%) in the standard ribavirin dose protocol and in 23 of 36 patients (63.9%) in the reduction ribavirin dose protocol (NS). Sustained virological response (SVR) rates were observed in 11 of 36 patients (30.6%) in the standard ribavirin dose protocol, and in 13 of 36 patients (36.1%) in the reduced ribavirin dose protocol (NS). Reduction of ribavirin doses for elderly patients did not affect the outcome for the 48-week combination therapy.

Rapid virological response to peginterferon and ribavirin for hepatitis C genotype 1: The role of weight-based ribavirin exposure

We read with great interest the report by Mangia et al. in a recent issue of HEPATOLOGY.1 They assigned 696 patients with hepatitis C virus genotype 1 (HCV-1) to peginterferon plus ribavirin 1000–1200 mg/day for 48 weeks (standard, n = 237) or for 24, 48, or 72 weeks if patients were HCV-RNA–negative at weeks 4, 8, or 12, respectively (variable, n = 459). The sustained virological response (SVR) was comparable between the standard group (45.1%) and the variable group (48.8%). Patients with rapid virological response (RVR; HCV-RNA–negative at weeks 4) achieved a high SVR rate with either standard 48-week (87.0%) or abbreviated 24-week (77.2%) treatment, respectively. However, only 26.7% of patients attained an RVR, indicating the urgency of increasing RVR rate to ensure treatment efficacy. Although the RVR rate in the study by Mangia et al. was substantially higher than those in previous reports from Europe and the United States (10%–22.6%),2-5 it was considerably lower than that of our recent study in Taiwan (43.5%).6 Similarly, the RVR rate of patients with HCV-2 was noticeably higher in Taiwanese patients (86.7%)7 than in whites (71.1%).8 Several factors have been predictors of an RVR for HCV-1, such as lower viremia,1, 5, 6 young age,1, 5, 9 and HCV-1b.2 However, these factors are unchangeable. Recently, ribavirin dose,2 low body weight,9 and the first 4 weeks of weight-based ribavirin exposure with a cut-off point of 13 mg/kg/day5 have been associated with the achievement of an RVR. These findings suggest the role of weight-based ribavirin exposure, an adjustable factor, in achieving an RVR. Table 1 summarizes the relationship among ribavirin dose, body weight, and RVR rate in patients with HCV-1 in recent large clinical trials. A regimen with the standard dose of ribavirin (1000–12000 mg/day) had a considerably higher rate of RVR (22.6%–43.5%) than that with a lower dose of ribavirin (800 mg/day, 10%–21.6%). Moreover, a negative linear trend was observed between the body weight and the chance of attaining an RVR in either the lower or standard ribavirin groups. A study by Loustaud-Ratti et al. demonstrated that plasma concentration of ribavirin after the first dose, expressed by ribavirin area under the concentration-time curves (AUC0–12h), was associated with RVR.10 These observations highlight the potential role of weight-based ribavirin exposure during the first 4 weeks of combination therapy on the achievement of an RVR. Because RVR is the most important single predictor of an SVR, further prospective studies are encouraged to explore the crucial dose of weight-based ribavirin exposure during first 4 weeks for achieving an RVR to maximize the treatment efficacy. Ming-Lung Yu* , Chia-Yen Dai* , Jee-Fu Huang , Wan-Long Chuang* , * Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan.

Management and therapy of chronic hepatitis C in HIV

Chronic hepatitis C is currently one of the leading causes of hospitalization and death in HIV+ persons. Treatment is particularly challenging in coinfected patients due to lower efficacy and more side effects. The combination of pegylated interferon plus ribavirin is the current treatment of choice. In the absence of contraindications, treatment should be provided with no restrictions up front (e.g., asking unnecessarily for a liver biopsy) and revisited at weeks 4 and 12. Treatment should only be continued in early virological responders. The use of standard ribavirin doses (1000-1200 mg/day) and for at least 12 months is crucial to maximize the effect of therapy. In patients with rapid virological response (undetectable viraemia at week 4), shorter periods of therapy (24 weeks) may be advisable for hepatitis C virus genotypes 2 and 3. Patients with low CD4 percentages should defer treatment and prioritize highly active antiretroviral therapy. Didanosine should never be co-administered with ribavirin due to potential life-threatening complications. When possible, zidovudine, stavudine and abacavir should be replaced by other agents having no deleterious interactions with ribavirin. The treatment of chronic hepatitis C has become a priority in hepatitis C virus/HIV-coinfected patients, and the best results are obtained by tailoring therapy to the individual patient's characteristics.

Cost-effectiveness of hematologic growth factors for anemia occurring during hepatitis C combination therapy

In hepatitis C virus (HCV)-infected patients who develop anemia during combination therapy, erythropoietic growth factors maintain higher drug treatment levels compared to ribavirin dose reduction, which may lead to an increase in treatment response rates. This study estimated the cost-effectiveness of growth factor therapy in maintaining anemic HCV-infected patients on target drug levels during combination therapy. A decision analysis using a Markov model was developed with 7 health states: Sustained viral response, chronic HCV, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, liver transplantation, and death. Data sources included population-based studies of growth factor therapy, previously published estimates of costs and natural history of hepatitis C, and recent prospective studies. Our reference case was a 45-year-old Caucasian man with HCV infection (genotype 1, 2, or 3) who developed anemia while undergoing combination therapy with ribavirin and pegylated interferon. We compared growth factor injections (darbepoetin alpha or epoetin alpha) during combination therapy with standard ribavirin dose reduction. Compared to a ribavirin dose reduction strategy, the cost of darbepoetin per additional quality-adjusted life-year was 34,793 dollars for genotype 1 and 33,832 dollars for genotypes 2 or 3 versus 60,600 dollars and 64,311 dollars for epoetin. For all genotypes, the results were sensitive to changes in the cure rates of HCV therapy, the utility of chronic HCV, the costs of growth factors, and the age at which therapy is begun. In conclusion, use of erythropoietic growth factors, specifically darbepoetin, for patients with anemia occurring during HCV combination therapy appears to be cost-effective for genotypes 1, 2, or 3.

High-dose, short-duration ribavirin aerosol therapy compared with standard ribavirin therapy in children with suspected respiratory syncytial virus infection

Children with suspected respiratory syncytial virus infection were examined prospectively in a randomized evaluation of standard ribavirin aerosol therapy (6 gm/300 ml water for 18 hours daily) compared with high-dose, short-duration ribavirin aerosol therapy (6 gm/100 ml water given for a period of 2 hours three times a day) by means of an oxygen hood (n = 20) or a ventilator (n = 12). Viral shedding was quantitated daily; clinical observations were recorded daily by 2 physicians aware and one unaware of treatment assignments. Study characteristics evaluated at entry were not significantly different in the high-dose and the standard-dose groups. Viral titers and clinical scores decreased similarly in both groups during the study; pulmonary function test results were also similar at discharge in children not receiving mechanical ventilation. Potential complications related to aerosol therapy were noted in three patients (one hood patient who was receiving standard therapy; two patients with an endotracheal tube in place who were receiving high-dose therapy); substantial crystallization was noted in the tubing of the patients undergoing intubation and receiving high-dose therapy. Environmental sampling revealed that ribavirin was nearly undetectable near patients supported by mechanical ventilation who were receiving either form of therapy, and was significantly decreased on a daily basis in patients without an endotracheal tube who were receiving high-dose therapy compared with those receiving standard therapy. The effects of high-dose, short-duration aerosol ribavirin therapy were similar to those of standard-dose therapy in our study patients and resulted in a decreased release of ribavirin into the room of patients receiving therapy by means of an oxygen hood. (J P EDIATR 1994;125:635-41)