The role of inhibin and activin in the initiation of follicular development, growth, and atresia was examined. Human recombinant inhibin (1 microgram) was unilaterally injected into the ovarian intrabursal space of 25-day-old rats. The contralateral ovary served as a control. Recruited growing follicles (350-500 microns) were observed 24 h after injection. The accumulation of follicles was greater in the inhibin-treated ovaries than in contralateral control ovaries. Moreover, the size distribution of the follicles was similar to the distribution of follicles recruited by systemic exogenous PMSG treatment. The effect of inhibin plus PMSG on follicular development was not different from that of PMSG treatment alone. Injection of human recombinant activin (1 microgram) into the ovarian bursa caused follicular atresia. Activin therapy blocked the follicular development caused by PMSG treatment. The effect of inhibin and activin on follicular development was further characterized by measuring the incorporation of [3H]thymidine into dividing cells. Inhibin enhanced follicular thymidine incorporation, while activin decreased granulosa cell proliferation. Furthermore, receptors for inhibin-A (6.4 x 10(3) receptors/cell) and activin-A (2.3 X 10(4) receptors/cell) were identified on granulosa cells. The evidence suggests that inhibin and activin act in a paracrine manner to regulate follicular development, inhibin as a follicular growth signal and activin as an atretagenic signal.

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Objectives AGILE is a Phase Ib/IIa platform for rapidly evaluating COVID-19 treatments. In this trial (NCT04746183) we evaluated the safety and optimal dose of molnupiravir in participants with early symptomatic infection. Methods We undertook a dose-escalating, open-label, randomized-controlled (standard-of-care) Bayesian adaptive Phase I trial at the Royal Liverpool and Broadgreen Clinical Research Facility. Participants (adult outpatients with PCR-confirmed SARS-CoV-2 infection within 5 days of symptom onset) were randomized 2:1 in groups of 6 participants to 300, 600 and 800 mg doses of molnupiravir orally, twice daily for 5 days or control. A dose was judged unsafe if the probability of 30% or greater dose-limiting toxicity (the primary outcome) over controls was 25% or greater. Secondary outcomes included safety, clinical progression, pharmacokinetics and virological responses. Results Of 103 participants screened, 18 participants were enrolled between 17 July and 30 October 2020. Molnupiravir was well tolerated at 300, 600 and 800 mg doses with no serious or severe adverse events. Overall, 4 of 4 (100%), 4 of 4 (100%) and 1 of 4 (25%) of the participants receiving 300, 600 and 800 mg molnupiravir, respectively, and 5 of 6 (83%) controls, had at least one adverse event, all of which were mild (≤grade 2). The probability of ≥30% excess toxicity over controls at 800 mg was estimated at 0.9%. Conclusions Molnupiravir was safe and well tolerated; a dose of 800 mg twice daily for 5 days was recommended for Phase II evaluation.

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Molnupiravir is an antiviral, currently approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for treating at-risk COVID-19 patients, that induces lethal error catastrophe in SARS-CoV-2. How this drug-induced mechanism of action might impact the emergence of resistance mutations is unclear. To investigate this, we used samples from the AGILE Candidate Specific Trial (CST)−2 (clinical trial number NCT04746183). The primary outcomes of AGILE CST-2 were to measure the drug safety and antiviral efficacy of molnupiravir in humans (180 participants randomised 1:1 with placebo). Here, we describe the pre-specified exploratory virological endpoint of CST-2, which was to determine the possible genomic changes in SARS-CoV-2 induced by molnupiravir treatment. We use high-throughput amplicon sequencing and minor variant analysis to characterise viral genomics in each participant whose longitudinal samples (days 1, 3 and 5 post-randomisation) pass the viral genomic quality criteria (n = 59 for molnupiravir and n = 65 for placebo). Over the course of treatment, no specific mutations were associated with molnupiravir treatment. We find that molnupiravir significantly increased the transition:transversion mutation ratio in SARS-CoV-2, consistent with the model of lethal error catastrophe. This study highlights the utility of examining intra-host virus populations to strengthen the prediction, and surveillance, of potential treatment-emergent adaptations.