Safety and Effectiveness of Molnupiravir in Japanese Patients with COVID-19: Final Report of Post-marketing Surveillance in Japan.

INTRODUCTION: Molnupiravir is an orally available prodrug of N-hydroxycytidine that received special approval for emergency treatment of coronavirus disease 2019 (COVID-19) in Japan in December 2021 and full approval in April 2023. To assess the real-world safety and effectiveness of molnupiravir in Japanese patients with COVID-19, we conducted nationwide post-marketing surveillance to collect data at registered institutions in Japan. METHODS: The surveillance data were collected from December 27, 2021, to May 2, 2023. All reported adverse events were collected for safety analysis. Adverse drug reactions (ADRs) were assessed by the treating physicians. Effectiveness was assessed by the composite of hospitalization or all-cause death in outpatients and the composite of oxygen/mechanical ventilation initiation or all-cause death in inpatients. The observation period was from molnupiravir initiation through day 29. RESULTS: Of 3214 patients enrolled in the survey, 3179 were analyzed for safety. At baseline, 52.31% (1663/3179) of patients were male, the median (range) age was 69.0 (18-107) years, 82.38% (2619/3179) received COVID-19 vaccines, and 95.72% (3043/3179) had risk factors for severe COVID-19 illness. COVID-19 severity at baseline was mild in 86.44% (2748/3179) and moderate I in 10.22% (325/3179). A total of 205 ADRs occurred in 5.50% (175/3179) of patients; ADRs that occurred in > 0.5% of patients were diarrhea (1.86% [59/3179]) and rash (0.69% [22/3179]). Seven serious ADRs were reported in seven patients. In the effectiveness analysis population, the incidence of all-cause death through day 29 was 1.14% (34/2988), and the incidence of death through day 29 related to COVID-19 was 0.40% (12/2988). The cumulative incidence of the composite endpoint was 2.34% (47/2006) in outpatients and 4.60% (38/826) in inpatients. CONCLUSIONS: This large-scale survey showed that molnupiravir was safe and effective in real-world settings in highly vaccinated Japanese patients with COVID-19, including older patients and those with comorbidities.

Safety and Effectiveness of Molnupiravir (LAGEVRIO®) Capsules in Japanese Patients with COVID-19: Interim Report of Post-marketing Surveillance in Japan.

INTRODUCTION: Molnupiravir is an oral antiviral drug that received special approval for emergency use in Japan on December 24 2021 for infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This post-marketing surveillance (PMS) is underway to investigate the safety and effectiveness of molnupiravir in daily clinical practice in Japan. The interim PMS data collected from December 27 2021 to June 15 2022 are reported in this publication. METHODS: This survey included adult Japanese patients treated with molnupiravir. For safety, adverse drug reactions (ADR) were assessed by physicians. Effectiveness was assessed by the composite endpoint of (1) hospitalization or (2) death in outpatients and by the composite endpoint of (3) death or (4) initiation of oxygen administration/mechanical ventilation in inpatients hospitalized for any reasons and without oxygen administration at the start of molnupiravir administration. The observation period was through 29 days from the start of molnupiravir administration. RESULTS: Of the 1031 patients in the safety analysis set, 68 (6.60%) patients reported ADRs and four (0.39%) patients reported serious ADRs. The main ADRs observed were diarrhoea [26 patients (2.52%)], rash [six patients (0.58%)], dizziness [five patients (0.48%)], and faeces soft [four patients (0.39%)]. In the effectiveness analysis from the start date of molnupiravir administration to day 29, there were 16/612 (2.61%) hospitalizations and no deaths. Oxygen administration was newly initiated in 9/199 (4.52%) inpatients after the initiation of molnupiravir administration; 2/199 (1.01%) inpatients died. CONCLUSION: This interim analysis of molnupiravir in daily clinical practice use in Japan supports the safety and effectiveness profile of molnupiravir under pandemic conditions in which Omicron was the dominant SARS-CoV-2 variant. The results of this PMS will provide valuable information for daily clinical practice use.

Production of matrix metalloproteinases in human cultured mast cells: involvement of protein kinase C-mitogen activated protein kinase kinase-extracellular signal-regulated kinase pathway.

BACKGROUND: Matrix metalloproteinases (MMPs) have been reported to play crucial roles in the migration of inflammatory cells through basement membrane components. To confirm the role of mast cells as a source of MMPs, we investigated the production of MMP and its pathway in human cultured mast cells (HCMC). We also investigated the production of tissue inhibitors of metalloproteinase (TIMPs). METHODS: HCMC was stimulated with phorbor 12-miristate 13-acetate (PMA) and/or calcium ionophore A23187 (A23187), and the resulting MMP production was evaluated by gelatin zymography and western blotting. Expression of MMP and TIMP mRNA was also examined. Granulocyte macrophage-colony stimulating factor (GM-CSF) was measured by ELISA and activation of extracellular signal-regulated kinase (ERK) was evaluated by western blotting. RESULTS: We detected the de novo synthesis of MMP-9 in HCMC after stimulation with PMA and found that the synthesis was mediated through protein kinase C-mitogen activated protein kinase kinase (MEK)-ERK pathway. The MMP-9 production induced by PMA was suppressed by simultaneous treatment with A23187, whereas GM-CSF production was potentiated. We also detected the expression of mRNA for membrane-type 1 (MT1)-MMP, TIMP-1 and TIMP-2 after stimulation with PMA. Glucocorticoids and flavonoids inhibited MMP-9 production, and TIMPs and MMP inhibitors inhibited the gelatinolytic activity of mast cell-derived MMP-9. Furthermore, phenylmethylsulfonyl fluoride, a protease inhibitor, inhibited the conversion from proMMP-9 to active MMP-9. CONCLUSIONS: These results suggest that the human mast cell is a leading member of MMP production, and the production, activation and activity are controllable by pharmacological agents.

Inhibition of syk activity and degranulation of human mast cells by flavonoids.

To investigate the effect of flavonoids on the activation of p72(syk) (Syk) protein tyrosine kinase which plays a pivotal role in the high affinity IgE receptor-mediated degranulation of mast cells, we picked out 10 flavonoids, classified them into 4 series, and examined their effects on the activation of Syk and on the degranulation of human mast cells. Flavones and flavonols showed clear inhibition, whereas flavanones and isoflavones had either weak or no effect on Syk enzymatic activity induced by amino acid peptide corresponding to the activation loop domain and on IgE-dependent degranulation of human cultured mast cells (HCMC). On the basis of calculated logP (ClogP) values as a prediction of compound lipophilicity, some flavonoids were speculated to have low lipophilicity, the reason for poor cell permeability. A significant relationship was observed between the inhibition of Syk activity and HCMC degranulation attributable to flavonoids when the ClogP values of the compounds were taken into account (r(2)=0.89). These results suggested that the impairment of mast cell degranulation by several flavonoids classified into flavones and flavonols might be mediated via inhibition of the intracellular activation of Syk.

Differential effects of beta2-adrenoceptor desensitization on the IgE-dependent release of chemical mediators from cultured human mast cells.

In the present study, we examined the inhibitory effects of the beta2-adrenoceptor agonists isoproterenol, salbutamol, fenoterol, and clenbuterol, on the release of chemical mediators from cultured human mast cells after prolonged treatment with the agonists. Although preincubation of sensitized mast cells for 10 min with beta2-adrenoceptor agonists potently inhibited mediator release, prolongation of the preincubation period up to 240 min attenuated the inhibition. The attenuation of histamine release inhibition was potent when compared with that of prostaglandin D2 (PGD2) and cysteinyl leukotriene (LT) release inhibition. In contrast, forskolin inhibited mediator release and the inhibition increased gradually in proportion to the preincubation period. The reduced inhibition by the beta2-adrenoceptor agonists was compensated for by simultaneous treatment with cholera toxin. The beta2-adrenoceptor agonists elevated intracellular cAMP levels after 10-min incubation and the elevated levels were almost comparable to those after 240-min incubation. Forskolin elevated the intracellular cAMP levels more potently after incubation for 240 min than after 10 min. When mast cells were incubated for 3 d with the beta2-adrenoceptor agonists, similar attenuation of mediator release inhibition was observed. Elevation of intracellular cAMP levels was also attenuated, although beta2-adrenoceptor mRNA expression was potentiated. The present results collectively indicate that the attenuation of mediator release inhibition by beta2-adrenoceptor agonists under the present experimental conditions involves uncoupling between beta2-adrenoceptors and Gs proteins. Furthermore, the beta2-adrenoceptor desensitization causes differential attenuating effects on the inhibition of histamine, PGD2, and LT release, suggesting that downstream events involved in each inhibitory pathway have different sensitivity to receptor desensitization.