(R)-Carvedilol

The chemical warfare agent sulfur mustard and its structural analog nitrogen mustard (NM) cause severe vesicating skin injuries. The pathologic mechanisms for the skin injury following mustard exposure are poorly understood; therefore, no effective countermeasure is available. Previous reports demonstrated the protective activity of carvedilol, a US Food and Drug Administration (FDA)-approved β-blocker, against UV radiation-induced skin damage. Thus, the current study evaluated the effects of carvedilol on NM-induced skin injuries in vitro and in vivo. In the murine epidermal cell line JB6 Cl 41-5a, β-blockers with different receptor subtype selectivity were examined. Carvedilol and both of its enantiomers, R- and S-carvedilol, were the only tested ligands statistically reducing NM-induced cytotoxicity. Carvedilol also reduced NM-induced apoptosis and p53 expression. In SKH-1 mice, NM increased epidermal thickness, damaged skin architecture, and induced nuclear factor κB (NF-κB)-related proinflammatory genes as assessed by RT² Profiler PCR (polymerase chain reaction) Arrays. To model chemical warfare scenario, 30 minutes after exposure to NM, 10 μM carvedilol was applied topically. Twenty-four hours after NM exposure, carvedilol attenuated NM-induced epidermal thickening, Ki-67 expression, a marker of cellular proliferation, and multiple proinflammatory genes. Supporting the in vitro data, the non-β-blocking R-enantiomer of carvedilol had similar effects as racemic carvedilol, and there was no difference between carvedilol and R-carvedilol in the PCR array data, suggesting that the skin protective effects are independent of the β-adrenergic receptors. These data suggest that the β-blocker carvedilol and its enantiomers can be repurposed as countermeasures against mustard-induced skin injuries. SIGNIFICANCE STATEMENT: The chemical warfare agent sulfur mustard and its structural analog nitrogen mustard cause severe vesicating skin injuries for which no effective countermeasure is available. This study evaluated the effects of US Food and Drug Administration (FDA)-approved β-blocker carvedilol on nitrogen mustard-induced skin injuries to repurpose this cardiovascular drug as a medical countermeasure.

Roux‐en‐Y gastric bypass is one of the most common surgical treatments for obesity due to the effective long‐term weight loss and remission of associated comorbidities. Carvedilol, a third‐generation β‐blocker, is prescribed to treat cardiovascular diseases. This drug is a weak base with low and pH‐dependent solubility and dissolution and high permeability. As the changes in the gastrointestinal tract anatomy and physiology after roux‐en‐Y gastric bypass can potentially affect drug pharmacokinetics, this study aimed to assess the effect of roux‐en‐Y gastric bypass on the pharmacokinetics of carvedilol enantiomers. Nonobese (n = 15, body mass index < 25 kg/m2), obese (n = 19, body mass index ≥ 30), and post‐roux‐en‐Y gastric bypass subjects submitted to surgery for at least 6 months (n = 19) were investigated. All subjects were administered a single oral dose of 25‐mg racemic carvedilol, and blood was sampled for up to 24 hours. Plasma concentrations of (R)‐ and (S)‐carvedilol were determined by liquid chromatography–tandem mass spectrometry. The maximum plasma concentration (Cmax) and the area under the plasma concentration‐time curve (AUC) of (R)‐carvedilol were 2‐ to 3‐fold higher than (S)‐carvedilol in all groups. Obese subjects have shown reduced Cmax of (R)‐ and (S)‐carvedilol without changing the AUC. Post‐roux‐en‐Y gastric bypass subjects presented a 3.5‐fold reduction in the Cmax of the active (S)‐carvedilol and a 1.9 reduction in the AUC from time 0 to infinity compared to nonobese subjects. The time to reach Cmax of (S)‐carvedilol increased 2.5‐fold in post‐roux‐en‐Y gastric bypass subjects compared to obese or nonobese. Although the β‐blockade response was not assessed, the reduced exposure to carvedilol in subjects post‐roux‐en‐Y gastric bypass may be clinically relevant and require dose adjustment.