First-in-Human Phase 1 Randomized Trial with the Anti-CD40 Monoclonal Antibody KPL-404: Safety, Tolerability, Receptor Occupancy, and Suppression of T-Cell-Dependent Antibody Response.

Blockade of the cluster of differentiation 40 (CD40)-CD40L interaction has potential for treating autoimmune diseases and preventing graft rejection. This first-in-human, randomized, double-blind, placebo-controlled study (NCT04497662) evaluated safety, pharmacokinetics, receptor occupancy, and pharmacodynamics of the humanized anti-CD40 monoclonal antibody KPL-404. Healthy volunteers were randomized to one of two single-ascending-dose groups: single intravenous KPL-404 dose 0.

The neuroprotective potential of low-dose methamphetamine in preclinical models of stroke and traumatic brain injury.

Methamphetamine is a psychostimulant that was initially synthesized in 1920. Since then it has been used to treat attention deficit hyperactive disorder (ADHD), obesity and narcolepsy. However, methamphetamine has also become a major drug of abuse worldwide.

Pharmacokinetics and absolute bioavailability of selegiline following treatment of healthy subjects with the selegiline transdermal system (6 mg/24 h): a comparison with oral selegiline capsules.

The selegiline transdermal system is a monoamine oxidase inhibitor that was recently approved by the US Food and Drug Administration for the treatment of major depressive disorder. The current study was conducted during the selegiline transdermal system development program to characterize the single-dose pharmacokinetics and absolute bioavailability of selegiline administered by the 6-mg/24-h selegiline transdermal system in healthy volunteers. Selegiline transdermal system results were compared with those obtained after a single 10-mg oral dose of selegiline HCl.

Evaluation of the potential for pharmacodynamic and pharmacokinetic drug interactions between selegiline transdermal system and two sympathomimetic agents (pseudoephedrine and phenylpropanolamine) in healthy volunteers.

Selegiline transdermal system is a recently approved monoamine oxidase inhibitor antidepressant. Medications that inhibit monoamine oxidase type A can augment the pressor effects of sympathomimetic amines, increasing the potential for hypertensive crisis. This study examined the potential for drug-drug interactions during treatment with selegiline transdermal system and pseudoephedrine or phenylpropanolamine.

Selegiline transdermal system: an examination of the potential for CYP450-dependent pharmacokinetic interactions with 3 psychotropic medications.

Selegiline transdermal system (STS) is a recently approved monoamine oxidase inhibitor antidepressant. This article reports results from 3 studies examining the potential for cytochrome P450-dependent pharmacokinetic interactions between STS and 3 psychotropic medications that might be coadministered. Three open-label, randomized, Latin square, 3-sequence crossover design studies were conducted with healthy volunteers to determine the pharmacokinetic parameters of STS 6 mg/24 h and test drug (alprazolam, olanzapine, or risperidone) when administered alone and concomitantly.

Potent inhibitory activities of hydrophobic aci-reductones (2-hydroxytetronic acid analogs) against membrane and human low-density lipoprotein oxidation.

The effects of selected aci-reductones, which are hydrophobic ascorbate-related analogs including 4-chlorophenyl-2-hydroxytetronic acid (Cpd A), 4-(1,1'-biphenyl)-2-hydroxytetronic acid (Cpd B), and 4-(4'-chloro-1,1'-biphenyl)-2-hydroxytetronic acid (Cpd C), on membrane and low density lipoprotein (LDL) oxidation were assessed. Hepatic microsomal lipid peroxidation was induced by the ascorbate + Fe(II) chemical system. All three agents inhibited membrane lipid peroxidation in a concentration-dependent manner with the order of potency: Trolox (vitamin E) < or = Cpd A << Cpd B < Cpd C; based on the EC50 values, Cpd B and Cpd C were 11- and 19-fold, respectively, more potent than Trolox.

Design, synthesis, and biological evaluation of conformationally constrained aci-reductone mimics of arachidonic acid.

An efficient and convergent synthesis has been developed for the production of 3,4-dihydroxy-5-[4-(2-((2Z)-hexenyl)phenyl)-3-(1Z)-but enyl]-2 (5H)-furanone (12d). This hydrophobic antioxidant is a stable conformationally constrained mimic of arachidonic acid (AA) (1) and its respective aci-reductone analogue (2). Pd(0)-catalyzed cross-coupling of 5-(3-butynyl)-3,4-dihydroxy-2(5H)-furanone (7) with 2-((2Z)-hexenyl)iodobenzene (8d) followed by Lindlar catalyzed hydrogenation produces 12d.

Comparative Pharmacokinetics and Bioavailability of Dilacor XR and Cardizem CD in Healthy Volunteers.

The objective of this investigation was to compare the single-dose and steady-state pharmacokinetic profiles of Dilacor XR to Cardizem CD. The study enrolled 24 healthy males and was divided into three parts: a single intravenous 25-mg bolus dose of diltiazem HCl (Cardizem Injectable) followed by a two-way crossover comparison of single and multiple once-daily 240-mg oral doses of Dilacor XR and Cardizem CD. Plasma samples were analyzed for diltiazem using a specific and sensitive HPLC assay.

The Pharmacokinetics of Once-Daily Diltiazem SR (Sustained-Release) in Young Versus Elderly Hypertensive Patients.

The objective of this open-label, outpatient, parallel-group investigation was to compare the single-dose and steady-state pharmacokinetic profiles of young (n = 12; x = 41 ± 6 years) and elderly (n = 12; X = 69 ± 4 years) hypertensive patients following administration of a once-daily formulation of diltiazem. The study was comprised of two phases. The first phase was a lead-in phase used to establish hypertensive status.

Nasal mucosal inflammation has no effect on the absorption of intranasal triamcinolone acetonide.

The potential for enhanced systemic absorption of intranasal triamcinolone acetonide was explored in patients with inflamed nasal mucosa. Twelve allergic rhinitis patients with documented nasal inflammation, and 12 healthy volunteers, each received a single, therapeutic, 400-micrograms dose of triamcinolone acetonide in each nostril. Blood was obtained at fixed time points after the dose, and plasma concentrations of triamcinolone acetonide were determined by radioimmunoassay.

The contribution of intestinal secretion to the dose-dependent absorption of celiprolol.

The contribution of the intestine to the nonlinear absorption of celiprolol in the rat was studied. After intravenous administration of 14C-celiprolol to bile duct-cannulated rats, approximately 9% of the dose was found to be associated with intestinal tissue and its contents. Microhistoautoradiography of frozen intestinal sections showed a time-dependent secretion of celiprolol from the blood into the lumen of the rat intestine.

Dispositional characteristics of a tyrosine kinase inhibitor (RG 14620) in rats and rabbits following intravenous administration or dermal application.

Based on its epidermal growth factor receptor-mediated tyrosine kinase inhibitory activity, (Z)-alpha-[(3,5-dichlorophenyl)methylene]-3- pyridylacetonitrile (RG 14620) is undergoing evaluation as a topical drug for psoriasis. Disposition studies were conducted in rats and rabbits, using [14C]RG 14620, primarily to investigate percutaneous absorption. Plasma radioactivity and the unchanged drug along with material balance were determined following intravenous administration (2.

Transport of celiprolol across human intestinal epithelial (Caco-2) cells: mediation of secretion by multiple transporters including P-glycoprotein.

1. The transepithelial transport of the beta-adrenoceptor blocking drug, celiprolol, was investigated in monolayers of the well differentiated human intestinal epithelial cell line, Caco-2. 2.

Inhaled corticosteroids in asthma: a dose-proportionality study with triamcinolone acetonide aerosol.

The systemic exposure to triamcinolone acetonide (TAA) after inhalation of aerosolized drug has not been examined previously. This study evaluates the plasma concentrations, pharmacokinetics and dose proportionality of TAA after single oral inhalations at doses of 400, 800, and 1600 mcg. Nine moderately asthmatic male patients received each of the doses in a randomized crossover manner using a 1-week washout period between dosing.

Steady-state dose proportionality of a once-a-day sustained-release diltiazem hydrochloride formulation in healthy subjects.

In this open-label, randomized, cross-over study, 12 healthy subjects received four doses of a new sustained-release formulation of diltiazem hydrochloride for six consecutive days. Blood samples were drawn on days 5 and 6 for determination of plasma diltiazem and desacetyldiltiazem levels. The peak concentrations after 120, 240, 360, and 480 mg of diltiazem were 48.

Multicenter evaluation of the efficacy and safety of sustained-release diltiazem hydrochloride for the treatment of hypertension.

In a double-blind study, patients with mild-to-moderate hypertension were randomly assigned to receive placebo or increasing daily doses of a new sustained-release formulation of diltiazem: 180 mg, 360 mg, and 540 mg, each once daily for two weeks. The numbers of evaluable patients were 26 in the placebo group and 81 in the diltiazem group at week 2, 24 and 75 at week 4, and 23 and 65 at week 6. Changes from baseline in mean supine trough (before drug administration) systolic/diastolic blood pressures were +1.

A retrospective analysis of fenoldopam renal excretion in 65 subjects: evidence for possible intrarenal formation of fenoldopam from its metabolites.

Clinical studies have suggested that the dopamine DA1 agonist, fenoldopam, may exhibit nonlinear renal excretion in humans. A retrospective population pharmacokinetic analysis of the renal excretion of fenoldopam and one of its major metabolites, fenoldopam-8-sulfate, was conducted in 65 healthy volunteers to examine this phenomenon. Fenoldopam-8-sulfate exhibited a mean (+/- SE) renal plasma clearance of 129 +/- 4 ml/min, which was independent of its AUC.

Simplified procedures for the determination of fenoldopam and its metabolites in human plasma by high-performance liquid chromatography with electrochemical detection: comparison of manual and robotic sample preparation methods.

Quantitative analytical methods, based on high-performance liquid chromatography with electrochemical detection, were developed for fenoldopam and its metabolites in human plasma. Two extraction methods, a liquid-liquid extraction method for fenoldopam and its methoxy metabolites and a liquid-solid extraction procedure for the sulfate and glucuronide conjugates of fenoldopam were developed. The extractions can either be performed manually or by robot.

Immobilized sulfatase:beta-glucuronidase enzymes for the qualitative and quantitative analysis of drug conjugates.

The enzymes sulfatase and beta-glucuronidase from Helix pomatia were simultaneously immobilized on aminopropyl control pore glass. Once immobilized, these enzymes retained activity under varied conditions of pH, organic solvent, and temperature. To hydrolyze the sulfate and glucuronide conjugates of xenobiotics, the immobilized enzymes were either added directly to incubation mixtures for qualitative in vitro studies or packed in a short stainless steel column and placed in an HPLC system for quantitative studies.

Continuous intragastric delivery of fenoldopam: relationship between plasma concentration and effects on renal function.

1. The pharmacodynamics of the dopamine DA1 agonist fenoldopam were examined in six healthy male volunteers after constant intragastric infusions of fenoldopam at dosages of 0, 10, 25, 50 and 75 mg h-1 for 6 h. 2.

Pharmacokinetic and pharmacodynamic properties of intravenous fenoldopam, a dopamine1-receptor agonist, in hypertensive patients.

1 The pharmacokinetic properties of intravenous fenoldopam, a selective dopamine1-receptor agonist, were studied in 10 patients with essential hypertension. 2 Reduction in blood pressure was linearly related to the log fenoldopam plasma concentration (r = 0.69) and the log fenoldopam infusion rate (r = 0.

Cimetidine pharmacokinetics in patients with Zollinger-Ellison syndrome.

Although most patients with Zollinger-Ellison syndrome can be effectively treated with histamine H2-receptor antagonists, many patients require large doses of drug to inhibit gastric acid secretion adequately. The purpose of the present study was to compare the pharmacokinetics of a 1200-mg oral dose of cimetidine in 9 patients with Zollinger-Ellison syndrome requiring more than 2.4 g/day of cimetidine with 5 age-matched normal volunteers receiving intravenous pentagastrin infusions.

The effect of fenoldopam, a dopaminergic agonist, on renal hemodynamics.

Fenoldopam, a dopaminergic agonist, was administered intravenously to 18 healthy male subjects in doses ranging from 0.025 to 1.0 microgram/kg/min for 2 hours.

The effect of acetaminophen on the disposition of fenoldopam: competition for sulfation.

Both fenoldopam and acetaminophen undergo conjugation with sulfate in humans. The present study was undertaken to determine if a metabolic interaction exists between these two compounds in humans. Twelve healthy male volunteers participated in a single-dose crossover study with 100 mg fenoldopam (capsule) alone or in combination with 1000 mg acetaminophen.

Effect of concomitant food intake on absorption kinetics of fenoldopam (SK&F 82526) in healthy volunteers.

Eight healthy volunteers participated in an open crossover study to assess the effect of a standardised meal on the systemic availability of a single oral dose of fenoldopam mesylate 100 mg. Subjects were studied on four separate occasions, twice fasting and twice fed in randomised, balanced order. Plasma and urine samples were obtained before and at regular intervals up to 25 h post dose.