Background Nirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (M pro ) inhibitor with potent pan–human-coronavirus activity in vitro. Methods We conducted a phase 2–3 double-blind, randomized, controlled trial in which symptomatic, unvaccinated, nonhospitalized adults at high risk for progression to severe coronavirus disease 2019 (Covid-19) were assigned in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir (a pharmacokinetic enhancer) or placebo every 12 hours for 5 days. Covid-19–related hospitalization or death from any cause through day 28, viral load, and safety were evaluated. Results A total of 2246 patients underwent randomization; 1120 patients received nirmatrelvir plus ritonavir (nirmatrelvir group) and 1126 received placebo (placebo group). In the planned interim analysis of patients treated within 3 days after symptom onset (modified intention-to treat population, comprising 774 of the 1361 patients in the full analysis population), the incidence of Covid-19–related hospitalization or death by day 28 was lower in the nirmatrelvir group than in the placebo group by 6.32 percentage points (95% confidence interval [CI], −9.04 to −3.59; P<0.001; relative risk reduction, 89.1%); the incidence was 0.77% (3 of 389 patients) in the nirmatrelvir group, with 0 deaths, as compared with 7.01% (27 of 385 patients) in the placebo group, with 7 deaths. Efficacy was maintained in the final analysis involving the 1379 patients in the modified intention-to-treat population, with a difference of −5.81 percentage points (95% CI, −7.78 to −3.84; P<0.001; relative risk reduction, 88.9%). All 13 deaths occurred in the placebo group. The viral load was lower with nirmaltrelvir plus ritonavir than with placebo at day 5 of treatment, with an adjusted mean difference of −0.868 log 10 copies per milliliter when treatment was initiated within 3 days after the onset of symptoms. The incidence of adverse events that emerged during the treatment period was similar in the two groups (any adverse event, 22.6% with nirmatrelvir plus ritonavir vs. 23.9% with placebo; serious adverse events, 1.6% vs. 6.6%; and adverse events leading to discontinuation of the drugs or placebo, 2.1% vs. 4.2%). Dysgeusia (5.6% vs. 0.3%) and diarrhea (3.1% vs. 1.6%) occurred more frequently with nirmatrelvir plus ritonavir than with placebo. Conclusions Treatment of symptomatic Covid-19 with nirmatrelvir plus ritonavir resulted in a risk of progression to severe Covid-19 that was 89% lower than the risk with placebo, without evident safety concerns. (Supported by Pfizer; ClinicalTrials.gov number, NCT04960202 .)

Enalapril-related angioedema is uncommon. Although it is most likely to occur early after initiation of therapy, it may occur at any time. It is more likely to occur in black patients, those older than 65 years, and those with a history of drug rash or seasonal allergies. Fatal angioedema or angioedema requiring airway protection did not occur in this study.

Metallothioneins (MTs) are major intracellular, zinc-binding proteins with antioxidant properties. Mouse embryonic cells null for MT due to loss of functional MT I and II genes (MT-/-) were more susceptible to apoptotic death after exposure to tert-butyl hydroperoxide or the anti-cancer agents cytosine arabinoside, bleomycin, melphalan, and cis-dichlorodiammineplatinum(II) compared with wild-type mouse embryonic cells (MT+/+). We measured basal levels of the tumor suppressor protein p53 and the death effector protein Bax and found the basal levels of both proteins were higher in MT null cells compared with MT+/+ cells. After treatment with the DNA-damaging agent cis-dichlorodiammineplatinum(II), p53 protein levels were induced in both MT+/+ and MT-/- cells with MT null cells always maintaining the highest p53 levels. The elevated sensitivity to apoptosis was not restricted to embryonic cells. Primary pulmonary fibroblasts were isolated from distinct litters of MT null, heterozygous, and wild-type mice, and all had undetectable basal MT levels. Zinc exposure increased MT levels in the wild-type and heterozygous fibroblasts but not in the MT null fibroblasts. Consistent with the induced MT levels, we found MT+/+ and MT+/- embryonic cells were less sensitive to cis-dichlorodiammineplatinum(II)-induced apoptosis compared with MT-/- cells. Our results implicate MT as a stress-responsive factor that can regulate apoptotic engagement.

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Ertugliflozin (1-25 mg/day) improved glycaemic control, body weight and blood pressure in patients with T2DM suboptimally controlled on metformin, and was well tolerated.

This study compared the blood pressure-lowering effect of ertugliflozin (1, 5, 25 mg), hydrochlorothiazide (HCTZ; 12.5 mg) and placebo in 194 patients with type 2 diabetes mellitus and hypertension for 4 weeks using ambulatory blood pressure monitoring. Endpoints (change from baseline to week 4) were: 24-h mean systolic blood pressure (SBP; primary); daytime, night-time, seated predose SBP, 24-h, daytime, night-time, seated predose diastolic blood pressure, 24-h urinary glucose excretion and fasting plasma glucose (FPG; secondary). Safety and tolerability were monitored. Significant decreases in placebo-corrected 24-h mean SBP (-3.0 to -4.0 mmHg) were recorded for all doses of ertugliflozin (for HCTZ, this was -3.2 mmHg). Daytime, but not night-time SBP was consistently reduced. Ertugliflozin produced dose-dependent significant decreases in FPG and increases in urinary glucose excretion. No notable changes in plasma renin activity or urinary aldosterone were seen. The most common adverse events were urinary tract infection, genital fungal infection, upper respiratory tract infection and musculoskeletal pain.

We recently reported that lipopolysaccharide (LPS) induces apoptosis in cultured sheep pulmonary artery endothelial cells (SPAEC). Information about survival signals against this and other stimuli for endothelial cell apoptosis is limited to factors in the extracellular space. In other cell types, apoptosis is also affected by intracellular gene products. The heat-shock response is a highly conserved cellular stress response affording cytoprotection against a variety of cytotoxic conditions. Accordingly, we tested the hypothesis that prior induction of the heat-shock response would affect apoptosis in cultured SPAEC. Exposure of SPAEC to either heat (43 degrees C, 90 min) or sodium arsenite (100 microM, 90 min) induced expression of heat-shock protein-70 (HSP-70). LPS (0.1 microg/ml) treatment of SPAEC induced apoptotic morphology, cell detachment, high molecular weight (> 30 kb) DNA fragmentation, and internucleosomal DNA fragmentation. Prior induction of the heat-shock response attenuated LPS-mediated apoptosis, a protective event associated with a concomitant attenuation of rapid (within minutes) LPS-stimulated superoxide anion (O2.-) generation. Subsequent experiments involving transient overexpression of HSP-70, by direct gene transfer, suggest a direct role for HSP-70 in the attenuation of LPS-mediated apoptosis. We conclude that the heat-shock response is an intracellular survival signal against LPS-mediated apoptosis, and that the protective mechanism may involve HSP-70 directly, as well as inhibition of LPS-mediated O2.- generation.

Tyrosine phosphatases (PTPases) dephosphorylate phosphotyrosines while dual-specificity phosphatases (DSPases) dephosphorylate contiguous and semicontiguous phosphothreonine and phosphotyrosine on cyclin dependent kinases and mitogen-activated protein kinases. Consequently, PTPases and DSPases have a central role controlling signal transduction and cell cycle progression. Currently, there are few readily available potent inhibitors of PTPases or DSPases other than vanadate. Using a pharmacophore modeled on natural product inhibitors of phosphothreonine phosphatases, we generated a refined library of novel, phosphate-free, small-molecule compounds synthesized by a parallel, solid-phase combinatorial-based approach. Among the initial 18 members of this targeted diversity library, we identified several inhibitors of DSPases: Cdc25A, -B, and -C and the PTPase PTP1B. These compounds at 100 microM did not significantly inhibit the protein serine/threonine phosphatases PP1 and PP2A. Kinetic studies with two members of this library indicated competitive inhibition for Cdc25 DSPases and noncompetitive inhibition for PTP1B. Compound AC-alphaalpha69 had a Ki of approximately 10 microM for recombinant human Cdc25A, -B, and -C, and a Ki of 0.85 microM for the PTP1B. The marked differences in Cdc25 inhibition as compared to PTP1B inhibition seen with relatively modest chemical modifications in the modular side chains demonstrate the structurally demanding nature of the DSPase catalytic site distinct from the PTPase catalytic site. These results represent the first fundamental advance toward a readily modifiable pharmacophore for synthetic PTPase and DSPase inhibitors and illustrate the significant potential of a combinatorial-based strategy that supplements the rational design of a core structure by a randomized variation of peripheral substituents.