Phentolamine 1mg/0.35ml / Aviptadil 25micrograms/0.35ml solution for injection ampoules

Objectives: Multidrug-resistant (MDR) Gram-negative bacterial infections have limited treatment options due to the impermeability of the outer membrane. New therapeutic strategies or agents are urgently needed, and combination therapies using existing antibiotics are a potentially effective means to treat these infections. In this study, we examined whether phentolamine can enhance the antibacterial activity of macrolide antibiotics against Gram-negative bacteria and investigated its mechanism of action. Methods: Synergistic effects between phentolamine and macrolide antibiotics were evaluated by checkerboard and time–kill assays and in vivo using a Galleria mellonella infection model. We utilized a combination of biochemical tests (outer membrane permeability, ATP synthesis, ΔpH gradient measurements, and EtBr accumulation assays) with scanning electron microscopy to clarify the mechanism of phentolamine enhancement of macrolide antibacterial activity against Escherichia coli. Results: In vitro tests of phentolamine combined with the macrolide antibiotics erythromycin, clarithromycin, and azithromycin indicated a synergistic action against E. coli test strains. The fractional concentration inhibitory indices (FICI) of 0.375 and 0.5 indicated a synergic effect that was consistent with kinetic time–kill assays. This synergy was also seen for Salmonella typhimurium, Klebsiella pneumoniae, and Actinobacter baumannii but not Pseudomonas aeruginosa. Similarly, a phentolamine/erythromycin combination displayed significant synergistic effects in vivo in the G. mellonella model. Phentolamine added singly to bacterial cells also resulted in direct outer membrane damage and was able to dissipate and uncouple membrane proton motive force from ATP synthesis that, resulted in enhanced cytoplasmic antibiotic accumulation via reduced efflux pump activity. Conclusions: Phentolamine potentiates macrolide antibiotic activity via reducing efflux pump activity and direct damage to the outer membrane leaflet of Gram-negative bacteria both in vitro and in vivo.

Abstract licence: CC BY

OBJECTIVE: We are still in search of new therapeutic options for COVID-19 to prevent new infections, enable fast recovery, and reduce the long-lasting symptoms or sequelae. This study aimed to investigate the short- and long-term effects of inhaled aviptadil on hospitalized, adult COVID-19 patients. METHODS: A multicenter, prospective, placebo-controlled, comparative, randomized, double-blind clinical trial was conducted. Patients were randomized 1:1 to either inhaled aviptadil or placebo, in addition to the standard care. The primary endpoint is the time from hospitalization to discharge within 30 days of treatment. The secondary endpoints are clinical and radiological score improvements. RESULTS: The study involved 80 patients enrolled from 9 clinical centers. The mean age was 55.8 ± 18.5 years, and 27 of them (33.8%) were female. The average time to discharge was 7.8 ± 4.0 days in aviptadil group and 10 ± 5.0 days in placebo (p = 0.049). Modified Borg scales were not statistically different on day 3 (p = 0.090), but significantly lower in the aviptadil group on day 7 (p = 0.033). The CT lung damage score was not different on day 1 for both groups (p = 0.962); improvement on day 28 was significantly greater in the aviptadil group (p = 0.028). The death rate was also lower in the aviptadil group (5.1%) when compared to the placebo (12.2%). There was no drop-out due to side effects. CONCLUSION: Study shows that inhaled aviptadil is well tolerated and can be used as a supplementary intervention to fasten the recovery of respiratory manifestations in hospitalized patients for COVID-19 pneumonia. OBJECTIVE: We are still in search of new therapeutic options for COVID-19 to prevent new infections, enable fast recovery, and reduce the long-lasting symptoms or sequelae. This study aimed to investigate the short- and long-term effects of inhaled aviptadil on hospitalized, adult COVID-19 patients. METHODS: A multicenter, prospective, placebo-controlled, comparative, randomized, double-blind clinical trial was conducted. Patients were randomized 1:1 to either inhaled aviptadil or placebo, in addition to the standard care. The primary endpoint is the time from hospitalization to discharge within 30 days of treatment. The secondary endpoints are clinical and radiological score improvements. RESULTS: The study involved 80 patients enrolled from 9 clinical centers. The mean age was 55.8 ± 18.5 years, and 27 of them (33.8%) were female. The average time to discharge was 7.8 ± 4.0 days in aviptadil group and 10 ± 5.0 days in placebo (p = 0.049). Modified Borg scales were not statistically different on day 3 (p = 0.090), but significantly lower in the aviptadil group on day 7 (p = 0.033). The CT lung damage score was not different on day 1 for both groups (p = 0.962); improvement on day 28 was significantly greater in the aviptadil group (p = 0.028). The death rate was also lower in the aviptadil group (5.1%) when compared to the placebo (12.2%). There was no drop-out due to side effects. CONCLUSION: Study shows that inhaled aviptadil is well tolerated and can be used as a supplementary intervention to fasten the recovery of respiratory manifestations in hospitalized patients for COVID-19 pneumonia.

Abstract licence: CC BY-NC