The Veterans Affairs Continuous Positive Airway Pressure Use and Diabetic Retinopathy Study.

Significance: Obstructive sleep apnea has been linked to the development and progression of diabetic retinopathy. In this study, diabetic patients compliant with continuous positive airway pressure therapy (CPAP) for sleep apnea were less likely to have retinopathy, emphasizing the benefits and potential therapeutic role of CPAP in individuals with both conditions.

Purpose: The aim of this study was to compare the prevalence of diabetic retinopathy in type 2 diabetic patients with obstructive sleep apnea who were compliant with CPAP therapy with those who were not compliant with CPAP therapy.

Open-Label Single-Dose Study to Assess the Effect of Mild and Moderate Hepatic Impairment on the Pharmacokinetics of Mirogabalin.

Background And Objectives: Mirogabalin is an αδ ligand being developed to treat neuropathic pain. A small fraction of mirogabalin is metabolized by the liver, where hepatic impairment may affect exposure. The objective of this phase I, open-label single-dose study was to determine if mild or moderate hepatic impairment alters the pharmacokinetics of mirogabalin.

An Open-Label Crossover Study of the Pharmacokinetics of the 60-mg Edoxaban Tablet Crushed and Administered Either by a Nasogastric Tube or in Apple Puree in Healthy Adults.

Background: Edoxaban is an orally active, direct factor Xa inhibitor indicated to reduce the risk of stroke and systemic embolism in non-valvular atrial fibrillation and for the treatment of venous thromboembolism.

Objectives: This study assessed the pharmacokinetics, safety, and tolerability of the edoxaban 60-mg tablet crushed and administered via a nasogastric tube in a water suspension or orally mixed in apple puree.

Methods: This phase 1, open-label, crossover study randomized 30 healthy adults to receive three edoxaban treatment regimens (oral 60-mg edoxaban tablet, or 60-mg edoxaban tablet crushed and administered via a nasogastric tube or orally in apple puree) in one of six treatment sequences.

Teleretinal imaging for detection of referable macular degeneration.

Purpose: The purpose of this study was to determine the sensitivity and specificity for detection of referable age-related macular degeneration (AMD) using an existing nonmydriatic telemedicine pathway for diabetic retinopathy screening with comparison to same-day face-to-face examination by a retina specialist.

Methods: Subjects in this study underwent nonmydriatic and mydriatic digital retinal imaging on the same day as stereoscopic dilated examination of the macula by a retina specialist and the level of AMD was recorded for each eye. Images were graded by two trained readers as nonreferable or referable (AREDS [Age-Related Eye Disease Study] grading of level 3 or greater).

Clinical safety, tolerability and efficacy of combination tolterodine/pilocarpine in patients with overactive bladder.

Aims: The purpose of this study was to assess the safety, tolerability and impact on overactive bladder (OAB) symptoms of a novel combination of tolterodine immediate-release (IR) 2 mg and delayed-release pilocarpine 9 mg in patients with OAB.

Methods: Eligible patients with OAB were randomised to each of three treatments [tolterodine/pilocarpine (2/9 mg), tolterodine IR 2 mg or placebo] twice daily for 4 weeks in a double-blind, crossover fashion. At the end of the 12-week, double-blind treatment period, patients could enter an open-label extension during which they were re-randomised to either tolterodine/pilocarpine (3/13.

Tissue penetration of telavancin after intravenous administration in healthy subjects.

The pharmacokinetic disposition of telavancin administered 7.5 mg/kg of body weight every 24 h was determined in plasma and skin blister fluid. The mean penetration of telavancin into blister fluid was 40%.

Pharmacokinetics of oral cyclosporin A when co-administered to enhance the oral absorption of paclitaxel.

The objective of this study was to evaluate the pharmacokinetics of oral cyclosporin A (CsA) when co-administered to enhance the oral absorption of paclitaxel. Patients received oral paclitaxel in doses of 60-360 mg/m(2) in combination with a dose of oral CsA of 15 mg/kg. Dose escalation of paclitaxel from 60 to 300 mg/m(2) resulted in a significant decrease in the area under the concentration-time curve (AUC) of CsA from 24.

A phase I and pharmacokinetic study of bi-daily dosing of oral paclitaxel in combination with cyclosporin A.

Purpose: To investigate dose escalation of bi-daily (b.i.d.

The effect of different doses of cyclosporin A on the systemic exposure of orally administered paclitaxel.

The objective of this study was to define the minimally effective dose of cyclosporin A (CsA) that would result in a maximal increase of the systemic exposure to oral paclitaxel. Six evaluable patients participated in this randomized cross-over study in which they received at two occasions two doses of 90 mg/m(2) oral paclitaxel 7 h apart in combination with 10 or 5 mg/kg CsA. Dose reduction of CsA from 10 to 5 mg/kg resulted in a statistically significant decrease in the area under the plasma concentration-time curve (AUC) and time above the threshold concentrations of 0.

Metabolism and excretion of paclitaxel after oral administration in combination with cyclosporin A and after i.v. administration.

The objective of this study was to compare the quantitative excretion of paclitaxel and metabolites after i.v. and oral drug administration.

Oral paclitaxel and concurrent cyclosporin A: targeting clinically relevant systemic exposure to paclitaxel.

Oral paclitaxel is not inherently bioavailable because of the overexpression of P-glycoprotein by intestinal cells and the significant first-pass extraction by cytochrome P450-dependent processes. This study sought to simulate the toxicological and pharmacological profile of a clinically relevant schedule of paclitaxel administered on clinically relevant i.v.

Phase I and pharmacokinetic study of oral paclitaxel.

Purpose: To investigate dose escalation of oral paclitaxel in combination with dose increment and scheduling of cyclosporine (CsA) to improve the systemic exposure to paclitaxel and to explore the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT).

Patients And Methods: A total of 53 patients received, on one occasion, oral paclitaxel in combination with CsA, coadministered to enhance the absorption of paclitaxel, and, on another occasion, intravenous paclitaxel at a dose of 175 mg/m(2) as a 3-hour infusion.

Results: The main toxicities observed after oral intake of paclitaxel were acute nausea and vomiting, which reached DLT at the dose level of 360 mg/m(2).

Phase I trial of orally administered pentosan polysulfate in patients with advanced cancer.

Tumor angiogenesis is critically important to tumor growth and metastasis. We have shown that pentosan polysulfate (PPS) is an effective inhibitor of heparin-binding growth factors in vitro and can effectively inhibit the establishment and growth of tumors in nude mice. Following completion of our Phase I trial of s.

Comparative metabolism of the antiviral dimer 3'-azido-3'-deoxythymidine-P-2',3'-dideoxyinosine and the monomers zidovudine and didanosine by rat, monkey, and human hepatocytes.

AZT-P-ddI is an antiviral heterodimer composed of one molecule of 3'-azido-3'-deoxythymidine (AZT) and one molecule of 2',3'-dideoxyinosine (ddI) linked through their 5' positions by a phosphate bond. The metabolic fate of the dimer was studied with isolated rat, monkey, and human hepatocytes and was compared with that of its component monomers AZT and ddI. Upon incubation of double-labeled [14C]AZT-P-[3H]ddI in freshly isolated rat hepatocytes in suspension at a final concentration of 10 microM, the dimer was taken up intact by cells and then rapidly cleaved to AZT, AZT monophosphate, ddI, and ddI monophosphate.

Phase I dose-escalation pharmacokinetics of AZT-P-ddI (IVX-E-59) in patients with human immunodeficiency virus.

3'-Azido-3'-deoxythymidilyl-(5',5')-2',3'-dideoxy-5'-inosinic acid (AZT-P-ddI, IVX-E-59, Scriptene) is a heterodimer composed of one molecule of 3'-azido-3'-deoxythymidine (zidovudine or AZT) and one molecule of 2',3'-dideoxyinosine (didanosine or ddI) linked through their 5' positions by a phosphate bond. AZT-P-ddI exhibits enhanced antiviral activity and selectivity in vitro compared with AZT and ddI alone. The pharmacokinetics of AZT-P-ddI were studied in 12 patients with human immunodeficiency virus (HIV) who had CD4+ cell counts higher than 200 cells/mm3.

Bioequivalence of a highly variable drug: an experience with nadolol.

Purpose: To assess the bioequivalence of nadolol 40mg and 160mg tablets (Zenith-Goldline Pharmaceuticals) using Corgard 40mg and 160mg tablets (Bristol-Meyers Squibb) as reference products, to estimate the effect of food in the gastrointestinal tract on nadolol bioavailability, and to evaluate the effectiveness of standard pharmacokinetic metrics AUCt, AUC infinity, and Cmax in bioequivalence determinations.

Methods: Four bioequivalence studies were conducted as described in the FDA Guidance. Four additional studies of varying designs were conducted to establish bioequivalence of the 40mg tablet in terms of Cmax.

Anti-hypertensive effects of intravenous compared with oral captopril.

Twenty mild to moderate hypertensive subjects (11 men, 9 women, mean age 54.3 years, range 39-65 years) were studied to determine whether an intravenous form of captopril could be as safe and efficacious as an oral form and to estimate the time course of anti-hypertensive action over a wide dose range (100-fold) of i.v.

The pharmacokinetics and pharmacodynamics of fosinopril in haemodialysis patients.

The pharmacokinetics and pharmacodynamics of fosinoprilat, the diacid of fosinopril sodium (a new angiotensin-converting enzyme (ACE) inhibitor), were investigated in six haemodialysis patients. Intravenous 14C-fosinoprilat (7.5 mg), oral 14C-fosinopril sodium (10 mg) and oral fosinopril sodium (10 mg) were administered in an open-label, randomized study.

Once-daily fosinopril in the treatment of hypertension.

This multicenter, dose-ranging study evaluated the antihypertensive effectiveness of once-daily administration of fosinopril sodium in 220 patients with supine diastolic blood pressure of 95-115 mm Hg. After a 4-week placebo period, patients were randomly assigned to double-blind therapy with either placebo or 10, 40, or 80 mg fosinopril once daily for 4 weeks. If treatment goals were not met, chlorthalidone 25 mg/day was added for weeks 5 to 8.

Pharmacokinetics of fosinopril in patients with various degrees of renal function.

Single-dose kinetics of fosinopril, a new phosphorus-containing angiotensin-converting enzyme inhibitor and its active diacid, fosinoprilat, were investigated in patients with mild, moderate, or severe renal impairment and in those with normal renal function. After an intravenous dose of 14C-fosinoprilat (7.5 mg), total body clearance of fosinoprilat was significantly greater (p less than 0.

Fosinopril pharmacokinetics and pharmacodynamics in chronic ambulatory peritoneal dialysis patients.

The pharmacokinetics and pharmacodynamics of fosinoprilat, the diacid of fosinopril sodium, a new angiotensin-converting enzyme (ACE) inhibitor, were investigated after the oral administration of 10 mg of fosinopril sodium to 6 chronic ambulatory peritoneal dialysis (CAPD) patients. The results from 1 patient are reported separately because of the presence of concomitant liver dysfunction. The mean t1/2, Cmax, tmax, and AUC values for 5 of the CAPD patients were 19.

Pharmacokinetics, safety, and pharmacologic effects of fosinopril sodium, an angiotensin-converting enzyme inhibitor in healthy subjects.

The pharmacokinetics, pharmacodynamics, and safety of fosinopril sodium (SQ 28,555), a new orally active angiotensin-converting enzyme (ACE) inhibitor, was evaluated in 73 healthy men in two separate studies. In study I, doses ranging from 10 to 640 mg were administered once daily for 3 days to seven groups of five subjects each. Serum aldosterone levels, ACE activity, and sitting blood pressure were determined, as were pharmacokinetic parameters of fosinoprilat, the active diacid of fosinopril.

Pharmacokinetics of captopril in healthy subjects and in patients with cardiovascular diseases.

Captopril, the first orally active inhibitor of angiotensin-converting enzyme, is used widely in the treatment of hypertension and congestive heart failure. The pharmacokinetics of this agent have been studied extensively in healthy subjects and in patients with hypertension, congestive heart failure, and chronic renal failure. Captopril contains a sulphydryl group and binds readily to albumin and other plasma proteins.