Cocculus hirsutus-Derived Phytopharmaceutical Drug Has Potent Anti-dengue Activity

Abstract

Dengue is a serious public health concern worldwide, with ∼3 billion people at risk of contracting dengue virus (DENV) infections, with some suffering severe consequences of disease and leading to death. Currently, there is no broad use vaccine or drug available for the prevention or treatment of dengue, which leaves only anti-mosquito strategies to combat the dengue menace. The present study is an extension of our earlier study aimed at determining the in vitro and in vivo protective effects of a plant-derived phytopharmaceutical drug for the treatment of dengue. In our previous report, we had identified a methanolic extract of aerial parts of Cissampelos pareira to exhibit in vitro and in vivo anti-dengue activity against all the four DENV serotypes. The dried aerial parts of C. pareira supplied by local vendors were often found to be mixed with aerial parts of another plant of the same Menispermaceae family, Cocculus hirsutus, which shares common homology with C. pareira. In the current study, we have found C. hirsutus to have more potent anti-dengue activity as compared with C. pareira. The stem part of C. hirsutus was found to be more potent (∼25 times) than the aerial part (stem and leaf) irrespective of the extraction solvent used, viz., denatured spirit, hydro-alcohol (50:50), and aqueous. Moreover, the anti-dengue activity of stem extract in all the solvents was comparable. Hence, an aqueous extract of the stem of C. hirsutus (AQCH) was selected due to greater regulatory compliance. Five chemical markers, viz., Sinococuline, 20-Hydroxyecdysone, Makisterone-A, Magnoflorine, and Coniferyl alcohol, were identified in fingerprinting analysis. In a test of primary dengue infection in the AG129 mice model, AQCH extract at 25 mg/kg body weight exhibited protection when administered four and three times a day. The AQCH was also protective in the secondary DENV-infected AG129 mice model at 25 mg/kg/dose when administered four and three times a day. Additionally, the AQCH extract reduced serum viremia and small intestinal pathologies, viz., viral load, pro-inflammatory cytokines, and vascular leakage. Based on these findings, we have undertaken the potential preclinical development of C. hirsutus-based phytopharmaceutical, which could be studied further for its clinical development for treating dengue.

Efficacy and Safety of a Phytopharmaceutical Drug Derived from Cocculus hirsutus in Adults with Moderate COVID-19: a Phase 2, Open-label, Multicenter, Randomized Controlled Trial

“…The evolving global understanding of the natural course of the disease during the first wave of the pandemic resulted in assumptions being made during selection of the primary endpoint that later became redundant. Interestingly, this has also been identified as a limitation in the DisCoVeRy study (a large randomized controlled trial of remdesivir in patients with severe COVID- 19), in which the use of a fixed-time endpoint may have been responsible for the failure in primary outcome [22]. RT-PCR testing was not performed on each study day because, at that time, expert opinion was that daily testing should be avoided, given the limited availability of testing kits in India during the first wave of the pandemic.…”

“…This dose was selected based on phase 1 pharmacokinetic data available at the time of protocol development, which indicated safety and tolerability of AQCH in heathy volunteers and a linear increase in peak plasma concentration (C max ) and area under the concentration-time curve (AUC), with ascending doses of up to 400 mg three times a day. The preparation, standardization, and stability of AQCH tablets have been described previously [19].…”

“…Coronavirus disease 2019 (COVID- 19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has overwhelmed healthcare systems around the world. Although most people with COVID-19 are asymptomatic or experience only mild disease, a significant proportion of patients require hospitalization and may become critically ill [1,2].…”

“…AQCH is in clinical development as an antiviral drug and has undergone comprehensive preclinical studies, including acute and repeated dose toxicity studies of oral AQCH in rodent and non-rodent species, as well as a phase 1 clinical trial (manuscripts submitted). AQCH demonstrated robust antiviral activity in in vitro studies and in an animal model of dengue [19]. Five chemical compounds have been characterized in AQCH, of which only sinococuline has potent pan-anti-dengue activity [19].…”

“…AQCH demonstrated robust antiviral activity in in vitro studies and in an animal model of dengue [19]. Five chemical compounds have been characterized in AQCH, of which only sinococuline has potent pan-anti-dengue activity [19]. In vitro mechanism-of-action studies indicate that AQCH interferes in the early stages of viral replication, and has inhibitory activity against SARS-CoV-2 with a half-maximal inhibitory concentration (IC 50 ) of 6.8 lg/mL (manuscript in preparation).…”