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Background: Few antiviral therapies have been studied in patients with coronavirus disease 2019 (COVID-19) and kidney impairment. Herein, the efficacy, safety, and pharmacokinetics of remdesivir, its metabolites, and sulfobutylether-β-cyclodextrin excipient were evaluated in hospitalized patients with COVID-19 and severe kidney impairment., Methods: In REDPINE, a phase 3, randomized, double-blind, placebo-controlled study, participants aged ≥12 years hospitalized for COVID-19 pneumonia with acute kidney injury, chronic kidney disease, or kidney failure were randomized 2:1 to receive intravenous remdesivir (200 mg on day 1; 100 mg daily up to day 5) or placebo (enrollment from March 2021 to March 2022). The primary efficacy end point was the composite of the all-cause mortality rate or invasive mechanical ventilation rate through day 29. Safety was evaluated through day 60., Results: Although enrollment concluded early, 243 participants were enrolled and treated (remdesivir, n = 163; placebo, n = 80). At baseline, 90 participants (37.0%) had acute kidney injury (remdesivir, n = 60; placebo, n = 30), 64 (26.3%) had chronic kidney disease (remdesivir, n = 44; placebo, n = 20), and 89 (36.6%) had kidney failure (remdesivir, n = 59; placebo, n = 30); and 31 (12.8%) were vaccinated against COVID-19. Composite all-cause mortality or invasive mechanical ventilation rates through day 29 were 29.4% and 32.5% in the remdesivir and placebo group, respectively (P = .61). Treatment-emergent adverse events were reported in 80.4% for remdesivir versus 77.5% for placebo, and serious adverse events in 50.3% versus 50.0%, respectively. Pharmacokinetic plasma exposure to remdesivir was not affected by kidney function., Conclusions: Although the study was underpowered, no significant difference in efficacy was observed between treatment groups. REDPINE demonstrated that remdesivir is safe in patients with COVID-19 and severe kidney impairment., Clinical Trials Registration: EudraCT 2020-005416-22; Clinical Trials.gov NCT04745351., Competing Interests: Potential conflicts of interest . M. E. S. received research funding from Gilead Sciences, EMD Serono, AbbVie, Angion, Novartis, Merck, Cabaletta Bio, and Otsuka; served as a scientific advisory board member for Travere, Novartis, Vera Therapeutics, Calliditas, and Mallinckrodt; and served as a data and safety monitoring board member for Alpine Immunoscience. J. R. S. received research funding, consulting fees, and lecture sponsorships from and served on advisory boards for Gilead Sciences, GSK, Janssen-Cilag, Bristol Myers Squibb, ViiV Healthcare, and Merck Sharp & Dohme (MSD). J. D. G. consulted for Gilead Sciences, Eli Lilly, GSK, and Karius; received research support or grants from Gilead Sciences, Eli Lilly, Regeneron, and MSD (Biomedical Advanced Research and Development Authority); and received nonfinancial support from Adaptive Biotechnologies, Monogram Biosciences, and Labcorp (outside the current study). J. P. T. is a consultant for Outset Medical and owns stock and/or stock options in Novo Nordisk A/S. Y. K., J. L., S. R., Y. Z., H. H., R. H. H., A. O., and H. W. are stockholders and employees of Gilead Sciences. R. H. is a former employee and stockholder of Gilead Sciences. H. N. H. received consulting fees from Gilead Sciences. R. L. G. served as a consultant for AbbVie, AstraZeneca, Eli Lilly, GSK, Gilead Sciences, Johnson & Johnson, Roivant Sciences, and Roche Pharmaceuticals; served as a national coordinating primary investigator for Johnson & Johnson; served on an academic steering committee for Roivant Sciences; received from Gilead Sciences a gift in kind to Baylor Scott & White Research Institute to facilitate NCT03383419; owns de minimis stock in AbCellera Biologics; and served as a speaker for Pfizer, outside the scope of coronavirus disease 2019 (COVID-19). D. N. F. served on a Gilead Sciences advisory board, outside the scope of COVID-19, and served as a site primary investigator for clinical trials with Gilead Sciences, Regeneron, and MetroBiotech. R. B. served on a scientific advisory board for AstraZeneca, Bayer, Boehringer Ingelheim, MSD, and Mundipharma; and served as a speaker for AstraZeneca, Bayer, MSD, Mundipharma, and Gilead Sciences, outside the scope of COVID-19. C. B. S. has received research support from Gilead Sciences, MSD, GSK, Takeda, Shire, Janssen, AbbVie, and ViiV Healthcare. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Isoproterenol (ISO) and forskolin, agents that increase adenosine 3',5'-cyclic monophosphate (cAMP) via adenylyl cyclase activation, reverse lung injury associated with increased microvascular permeability. We studied the role of rolipram, a relatively isozyme-selective cAMP phosphodiesterase (PDE) inhibitor, in reversing increased capillary permeability due to ischemia-reperfusion (I/R), a form of oxidant injury in the lung, by using the isolated perfused rat lung model. Rolipram (2 microM) administered after 45 min of ischemia and 45 min of reperfusion reduced I/R-increased permeability as measured by the capillary filtration coefficient to control lung values. Computer image analysis of air space edema and perivascular cuffing, as well as wet-to-dry weight ratios, confirms the permeability reversal by rolipram administration. Rolipram inhibition of cAMP PDE in the lung was assessed by using [3H]adenine prelabeling adapted for the whole lung and perfusate [3H]cAMP accumulation. Rolipram failed to increase perfusate cAMP alone but dramatically increased perfusate cAMP above ISO alone. Dose-response relationships of ISO or rolipram show a close correlation of the half-maximal effective dose (ED50) for injury reversal and perfusate cAMP production. The combination of rolipram and ISO produced synergistic reversal of I/R injury. We conclude that reversal of I/R-induced increased microvascular permeability can be achieved with rolipram and that the mechanism of action of rolipram is probably through PDE isozyme-selective inhibition. The similarity of the ED50 values for cAMP efflux and reversal of permeability increases also supports a close coupling between cAMP accumulation and endothelial cell permeability.

Microvascular lung injury caused by ischemia-reperfusion (IR) may occur via leukocyte-dependent and leukocyte-independent pathways. Leukocyte-endothelial adhesion may be a rate-limiting step in IR lung injury. Leukocyte adhesion to microvascular endothelium occurs when the attractant forces between leukocyte and endothelium are greater than the kinetic energy of the leukocyte and the vascular wall shear rate. We hypothesized (1) that isolated, buffer-perfused rat lungs are not free of endogenous leukocytes, (2) that endogenous leukocytes contribute to IR-induced microvascular injury as measured by the capillary filtration coefficient (Kfc), and (3) that a reduction of perfusate flow rate would potentiate leukocyte-dependent IR injury. Sixty lungs were divided into four groups: (1) low-flow controls, (2) high-flow controls, (3) low-flow IR, and (4) high-flow IR. Microvascular injury was linearly related to baseline perfusate leukocyte concentrations at both low (r = 0.78) and high (r = 0.82) flow rates. Kfc in the high-flow IR group (0.58 +/- 0.03 ml/min/cm H2O/100 g) was less (p < 0.05) than Kfc in the low-flow IR group (0.82 +/- 0.07), and in both groups Kfc values were significantly greater than low-flow (0.34 +/- 0.03) and high-flow (0.31 +/- 0.01) control Kfc values after 75 min. Retention of leukocytes in the lung, evaluated by a tissue myeloperoxidase assay, was greatest in the low-flow IR group. We conclude (1) that isolated, buffer-perfused rat lungs contain significant quantities of leukocytes and that these leukocytes contribute to IR lung injury, and (2) that IR-induced microvascular injury is potentiated by low flow.

This study evaluated the physiological effects of compounds that increase adenosine 3',5'-cyclic monophosphate (cAMP) on changes in pulmonary capillary permeability and vascular resistance induced by ischemia-reperfusion (I-R) in isolated blood-perfused rabbit lungs. cAMP was elevated by 1) beta-adrenergic stimulation with isoproterenol (ISO, 10(-5) M), 2) post-beta-receptor stimulation of adenylate cyclase with forskolin (FSK, 10(-5) M), 3) and dibutyryl cAMP (DBcAMP, 1 mM), a cAMP analogue. Vascular permeability was assessed by determining the capillary filtration coefficient (Kf,c), and capillary pressure was measured using the double occlusion technique. The total, arterial, and venous vascular resistances were calculated from measured pulmonary arterial, venous, and capillary pressures and blood flow. Reperfusion after 2 h of ischemia significantly (P less than 0.05) increased Kf,c (from 0.115 +/- 0.028 to 0.224 +/- 0.040 ml.min-1.cmH2O-1.100 g-1). These I-R-induced changes in capillary permeability were prevented when ISO, FSK, or DBcAMP was added to the perfusate at reperfusion (0.110 +/- 0.022 and 0.103 +/- 0.021, 0.123 +/- 0.029 and 0.164 +/- 0.024, and 0.153 +/- 0.030 and 0.170 +/- 0.027 ml.min-1.cmH2O-1.100 g-1, respectively). I-R significantly increased total, arterial, and venous vascular resistances. These increases in vascular resistance were also blocked by ISO, FSK, and DBcAMP. These data suggest that beta-adrenergic stimulation, post-beta-receptor activation of adenylate cyclase, and DBcAMP prevent the changes in pulmonary vascular permeability and vascular resistances caused by I-R in isolated rabbit lungs through a mechanism involving an increase in intracellular levels of cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)

Ischemia-reperfusion (IR) is a form of oxidant injury known to increase microvascular permeability in the lung. Agents that increase adenosine 3',5'-cyclic monophosphate (cAMP) levels have been shown to have beneficial effects in several models of oxidant lung injury associated with increased microvascular permeability. We investigated the role of adenylate cyclase activation with isoproterenol (ISO) or forskolin (FSK) in reversing the increased microvascular permeability associated with IR. ISO or FSK administered after 45 min of ischemia and 46 min of reperfusion caused a reduction in the capillary filtration coefficient (Kfc) from 1.25 +/- 0.13 to 0.53 +/- 0.08 and 0.55 +/- 0.10 ml.min-1.cmH2O-1.100 g tissue-1, respectively, at 90 min of reperfusion. This reduction in Kfc was accompanied by a rise in perfusate cAMP levels from 16.5 +/- 4.9 and 31.2 +/- 11.9 pmol/ml at 45 min of reperfusion to 444.2 +/- 147.8 and 276.1 +/- 91.0 pmol/ml at 105 min of reperfusion in lungs treated with ISO or FSK, respectively, at 46 min of reperfusion. Dibutyryl cAMP (DBcAMP), a membrane-permeable cAMP analogue, mimicked the permeability effect by reducing Kfc to 0.67 +/- 0.15 at 90 min of reperfusion. Significant hemodynamic changes occurred but were small and cannot explain the observed effect on Kfc. Photomicrographs from lungs treated with ISO or FSK revealed a reversal of the morphological manifestations of increased microvascular permeability. We conclude that the increased microvascular permeability associated with IR can be reversed by ISO, FSK, and DBcAMP and that cAMP produced by the lung contributes to the observed reversal.

Isolated perfused rat lungs were subjected to oxidant injury induced by tert-butyl hydroperoxide (t-buOOH), which caused a significant increase in capillary permeability as assessed by the change in the capillary filtration coefficient. t-buOOH caused an increase in the change in the capillary filtration coefficient (delta Kfc) of 0.27 +/- 0.05 ml.min.cmH2O-1.100 g lung tissue-1 (mean +/- SE) that was accompanied by an increase in thiobarbituric acid reactive products of lipid peroxidation in the lung perfusate. The addition of hemoglobin to the perfusate potentiated t-buOOH-induced lung injury as evidenced by a significantly greater (P = 0.007) delta Kfc of 0.43 +/- 0.05. t-buOOH also caused hemoglobin to release large quantities of free iron in vitro. The potentiation of t-buOOH-induced lung injury by hemoglobin was prevented by apotransferrin as evidenced by a significant reduction (P = 0.001) in delta Kfc to 0.13 +/- 0.02. No statistically significant (P greater than 0.05) changes in segmental resistances or pulmonary vascular pressures occurred in any of the lungs injured with t-buOOH when compared with time controls. These results demonstrate that t-buOOH causes an oxidant injury in isolated rat lungs that can be potentiated by free iron released from hemoglobin.

We reviewed the records of 1,738 cases of tuberculosis seen during the period from 1968 to 1988 in Mobile, Alabama. Seventy cases of tuberculous pleural effusion were identified and constituted 4.9 percent of all disease due to Mycobacterium tuberculosis during this period. Tuberculous pleural effusion was diagnosed if the patient had M tuberculosis cultured from sputum, pleura, or pleural fluid and had a roentgenographic pleural effusion without an alternative explanation for the presence of the effusion. The diagnosis of tuberculous pleural effusion was made in the absence of a positive culture if the patient had an undiagnosed lymphocytic exudative pleural effusion and all clinical and roentgenographic abnormalities resolved on antimycobacterial chemotherapy. The mean age of all patients was 47 +/- 18.4 years. The 70 cases were evenly divided between 35 that were accompanied by roentgenographic pulmonary parenchymal infiltrates and 35 that occurred in the absence of parenchymal infiltrates. We conclude that cultures of all potentially diagnostic specimens (sputum, pleural fluid, and pleura) and an intermediate-strength skin test, are sensitive tests for the diagnosis of tuberculous pleural effusion. In addition, the age of patients with tuberculous pleural effusion appears to be increasing.

Cardiac asthma has been used as a synonym for episodes of cough, dyspnea, and wheezing caused by left ventricular dysfunction. The similarity of the terms bronchial asthma and cardiac asthma, and the observed symptoms of each disease implies a common pathophysiology. Bronchial asthma is characterized pathologically by airway narrowing, inflammation, edema, and obstruction by mucus. Bronchial asthma is defined as increased responsiveness of the tracheobronchial tree, which is manifested clinically as reversible expiratory airflow obstruction. The classic symptoms of bronchial asthma are cough, dyspnea, and wheezing. Cardiac asthma produces the same symptoms, but the pathophysiology producing these symptoms is not well described. We describe two patients with cardiac asthma who failed to demonstrate airway hyperresponsiveness to nonspecific bronchoprovocation testing and we postulate that these patients' symptoms were produced exclusively by left ventricular failure.