Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral neuropathy.

Peripheral neuropathy is a major dose-limiting side effect of paclitaxel and cisplatin chemotherapy. In the current study, we tested the involvement of a novel class of neurotoxic sphingolipids, the 1-deoxysphingolipids. 1-Deoxysphingolipids are produced when the enzyme serine palmitoyltransferase uses l-alanine instead of l-serine as its amino acid substrate.

Lack of a pharmacokinetic drug-drug interaction between lithium and valproate when co-administered with aripiprazole.

What Is Known And Objective: The antipsychotic, aripiprazole, plus lithium or valproate demonstrates rapid and significant improvement in manic symptoms that is sustained over the long term. A previous report showed that therapeutic doses of either lithium or valproate had no clinically significant effects on the pharmacokinetics of aripiprazole. We aimed to determine the effects of co-administration of aripiprazole on the steady-state pharmacokinetics of lithium or valproate in healthy subjects.

Heidelberg-Kyoto partnership bridges life and materials sciences, strengthens bilateral ties.

Coinciding with the 150(th) anniversary of German-Japanese friendship, Kyoto University and Heidelberg University, two universities replete with history and tradition strengthened their close ties at a joint meeting in Heidelberg, Germany, forming the core of a broad collaborative effort between the two countries. This forum article provides a background and overview of the collaborations.

Two-way pharmacokinetic interaction studies between saxagliptin and cytochrome P450 substrates or inhibitors: simvastatin, diltiazem extended-release, and ketoconazole.

Background: Many medicines, including several cholesterol-lowering agents (eg, lovastatin, simvastatin), antihypertensives (eg, diltiazem, nifedipine, verapamil), and antifungals (eg, ketoconazole) are metabolized by and/or inhibit the cytochrome P450 (CYP) 3A4 metabolic pathway. These types of medicines are commonly coprescribed to treat comorbidities in patients with type 2 diabetes mellitus (T2DM) and the potential for drug-drug interactions of these medicines with new medicines for T2DM must be carefully evaluated.

Objective: To investigate the effects of CYP3A4 substrates or inhibitors, simvastatin (substrate), diltiazem (moderate inhibitor), and ketoconazole (strong inhibitor) on the pharmacokinetics and safety of saxagliptin, a CYP3A4/5 substrate; and the effects of saxagliptin on these agents in three separate studies.

Influence of renal or hepatic impairment on the pharmacokinetics of saxagliptin.

Background And Objective: Patients with type 2 diabetes mellitus often have impaired renal function or may have impaired hepatic function, which can pose significant safety and tolerability issues for antihyperglycaemic pharmacotherapies. Therefore, the pharmacokinetics and tolerability of saxagliptin and its pharmacologically active metabolite, 5-hydroxy saxagliptin, in nondiabetic subjects with mild, moderate or severe renal or hepatic impairment, or end-stage renal disease (ESRD) were compared with saxagliptin and metabolite pharmacokinetics and tolerability in healthy adult subjects.

Methods: Two open-label, parallel-group, single-dose studies were conducted.

Saxagliptin, a potent, selective inhibitor of DPP-4, does not alter the pharmacokinetics of three oral antidiabetic drugs (metformin, glyburide or pioglitazone) in healthy subjects.

Aim: To evaluate the pharmacokinetic interactions of the potent, selective, dipeptidyl peptidase-4 inhibitor, saxagliptin, in combination with metformin, glyburide or pioglitazone.

Methods: To assess the effect of co-administration of saxagliptin with oral antidiabetic drugs (OADs) on the pharmacokinetics and tolerability of saxagliptin, 5-hydroxy saxagliptin, metformin, glyburide, pioglitazone and hydroxy-pioglitazone, analyses of variance were performed on maximum (peak) plasma drug concentration (C(max)), area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) [saxagliptin + metformin (study 1) and saxagliptin + glyburide (study 2)] and area under the concentration-time curve from time 0 to time t (AUC) [saxagliptin + pioglitazone (study 3)] for each analyte in the respective studies. Studies 1 and 2 were open-label, randomized, three-period, three-treatment, crossover studies, and study 3 was an open-label, non-randomized, sequential study in healthy subjects.

An open-label study of aripiprazole: pharmacokinetics, tolerability, and effectiveness in children and adolescents with conduct disorder.

Objectives: This study evaluated flexible-dose pharmacokinetics, safety, and effectiveness of aripiprazole in children and adolescents with conduct disorder (CD).

Methods: This open-label, 15-day, three-center study with an optional 36-month extension enrolled a total of 23 patients: 12 children (6-12 years) and 11 adolescents (13-17 years) with CD and a score of 2-3 on the Rating of Aggression Against People and/or Property (RAAPP). Initially, the protocol used the following dosing: subjects <25 kg, 2 mg/day; subjects 25-50 kg, 5 mg/day; subjects >50-70 kg, 10 mg/day; and subjects >70 kg, 15 mg/day.

Dapagliflozin, a novel, selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 diabetes mellitus.

Dapagliflozin, administered to patients in once-daily oral doses, is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that blocks the reabsorption of glucose from urine into the blood. This 14-day study randomized patients with type 2 diabetes mellitus (T2DM) to four treatment groups receiving daily oral doses of 5-, 25-, or 100-mg doses of dapagliflozin or placebo, in order to evaluate glucosuria and glycemic parameters. Significant reductions in fasting serum glucose (FSG) were observed on day 2 with 100 mg dapagliflozin (-9.

Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects.

Dapagliflozin selectively inhibits renal glucose reabsorption by inhibiting sodium-glucose cotransporter-2 (SGLT2). It was developed as an insulin-independent treatment approach for type 2 diabetes mellitus (T2DM). The safety, tolerability, pharmacokinetics, and pharmacodynamics of the drug were evaluated in single-ascending-dose (SAD; 2.

Effects of the glycoprotein IIb/IIIa antagonist Roxifiban on P-selectin expression, fibrinogen binding, and microaggregate formation in a phase I dose-finding study: no evidence for platelet activation during treatment with a glycoprotein IIb/IIIa antagonist.

The hypothesis that glycoprotein (GP) IIb/IIIa antagonists stimulate platelets is controversial. Here, we report the results of flow cytometric measurements of platelet activation markers in a phase I dose optimization study of Roxifiban, an orally active GP IIb/IIIa antagonist. Whole blood was collected at pre-dose and during the dosing interval directly into citrate fixative so that circulating levels of platelet activation could be assessed.

Integrated pharmacokinetic/pharmacodynamic model of XV459, a potent and specific GPIIb/IIIa inhibitor, in healthy male volunteers.

Roxifiban is an oral prodrug of XV459, a potent and specific inhibitor of the glycoprotein (GP) IIb/IIIa receptor previously under investigation for the treatment of peripheral arterial disease and acute coronary care syndrome. The objective of the present analysis was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model that would be used to guide dose selection in Phase 2. This was a randomized, sequential, rising multiple-dose study in 41 healthy male volunteers given doses of 0.

Hepatic but not intestinal CYP3A4 displays dose-dependent induction by efavirenz in humans.

Objective: The capacity of the non-nucleoside reverse transcriptase inhibitor efavirenz to induce either liver CYP3A4 or intestinal CYP3A4, or both, as well as intestinal P-glycoprotein, was evaluated in healthy volunteers during and after a 10-day treatment course with two different daily doses.

Methods: Cohorts of 12 healthy subjects were randomized (2:1) to receive either efavirenz or placebo orally for 10 days. The first cohort received 200 mg efavirenz and the second cohort received 400 mg efavirenz daily.

Safety, tolerability, pharmacokinetics, and time course of pharmacologic response of the active metabolite of roxifiban, XV459, a glycoprotein IIb/IIIa antagonist, following oral administration in healthy volunteers.

Roxifiban is an esterprodrug that is hydrolyzed, after oral administration, to the active glycoprotein (GP) IIb/IIIa antagonist, XV459. The objectives of the study were to investigate the safety, tolerability, pharmacokinetics, and the time course of the pharmacologic response of XV459 in escalating doses of roxifiban and to assess the effect of age, loading dose of roxifiban, and aspirin pretreatment on XV459 pharmacokinetics, pharmacologic response, and safety profile in a five-part double-blind, placebo-controlled study. Healthy male volunteers (ages 18-46 years) received 7 (0.

Anticoagulant pharmacodynamics of tinzaparin following 175 iu/kg subcutaneous administration to healthy volunteers.

Tinzaparin, a sodium salt of a low-molecular-weight heparin (LMWH) produced via heparinase digestion, is used for the treatment of deep vein thrombosis (DVT) and pulmonary embolism in conjunction with warfarin for the prevention of DVT in patients undergoing hip or knee replacement surgery, and as an anticoagulant in hemodialysis circuits. Its average molecular weight ranges between 5500 and 7500 daltons (Da); the percentage of chains with molecular weight lower than 2000 Da is not more than 10% in the marketed tinzaparin formulation. While this fraction is generally considered pharmacologically inactive, this has never been evaluated in vivo.

Combination therapy with efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors in children infected with human immunodeficiency virus type 1. Pediatric AIDS Clinical Trials Group 382 Team.

Background: Consistent long-term viral suppression has been difficult to achieve in children with human immunodeficiency virus type 1 (HIV-1) infection. We tested the safety and antiviral efficacy of a novel combination consisting of efavirenz, nelfinavir, and one or more nucleoside reverse-transcriptase inhibitors in 57 children previously treated with only nucleoside reverse-transcriptase inhibitors.

Methods: The children were monitored for 48 weeks after the initiation of therapy.

The effect of increasing gastric pH upon the bioavailability of orally-administered foscarnet.

For systemic use, the anti-cytomegalovirus (CMV) agent foscarnet must be given intravenously because oral administration results in unmeasurable or barely measurable plasma levels. At low pH, foscarnet decomposes via an acid-catalyzed decarboxylation; therefore, poor oral bioavailability might be due to decomposition of foscarnet in gastric acid. We evaluated whether increasing gastric pH with ranitidine would enhance the absorption of oral foscarnet in six asymptomatic HIV-infected individuals.

Pharmacodynamics and pharmacokinetics of DMP 728, a platelet GPIIb/IIIa antagonist, in healthy subjects.

DMP 728 showed a dose-dependent inhibition of platelet aggregation at doses of 0.05 to 0.9 mg per subject, with a maximal inhibition (> 90%) of platelet aggregation at doses of 0.

Phase I safety and pharmacokinetic studies of brequinar sodium after single ascending oral doses in stable renal, hepatic, and cardiac allograft recipients.

Brequinar sodium (BQR), a substituted 4-quinoline carboxylic acid, was in clinical development in combination with cyclosporine (CsA) as a potentially effective therapy for the treatment and prophylaxis of rejection in organ transplant patients. This phase I study was performed in stable renal, hepatic, and cardiac transplant patients receiving CsA and prednisone maintenance therapy for immunosuppression. The pharmacokinetic objectives of this study were to characterize the pharmacokinetics of (a) single oral 0.

Cyclic HIV protease inhibitors: synthesis, conformational analysis, P2/P2' structure-activity relationship, and molecular recognition of cyclic ureas.

High-resolution X-ray structures of the complexes of HIV-1 protease (HIV-1PR) with peptidomimetic inhibitors reveal the presence of a structural water molecule which is hydrogen bonded to both the mobile flaps of the enzyme and the two carbonyls flanking the transition-state mimic of the inhibitors. Using the structure-activity relationships of C2-symmetric diol inhibitors, computed-aided drug design tools, and first principles, we designed and synthesized a novel class of cyclic ureas that incorporates this structural water and preorganizes the side chain residues into optimum binding conformations. Conformational analysis suggested a preference for pseudodiaxial benzylic and pseudodiequatorial hydroxyl substituents and an enantiomeric preference for the RSSR stereochemistry.

Variability in the pharmacokinetics and pharmacodynamics of low dose aspirin in healthy male volunteers.

Data describing the pharmacokinetics and pharmacodynamics of low dose aspirin (acetylsalicylic acid; ASA) are limited. This single-center study was designed to determine the rate and extent of oral absorption of 80-mg ASA tablets in healthy, young male subjects and to assess the intra- and inter-subject variability of ASA pharmacokinetics and platelet aggregation effects. Ten subjects each received a single, open-label, oral 80-mg ASA dose on three separate days.

Bromide pharmacokinetics in cystic fibrosis.

Objective: Individuals with cystic fibrosis (CF) have altered kinetics for a number of drugs, most often an increased volume of distribution (Vd) per body weight and increased clearance per body weight. To further evaluate those differences, we studied bromide kinetics (Vd, elimination rate constant, and clearance) and body mass index in eight adults with mild-to-moderate forms of CF, 21 obligate carriers of the CF gene, and 21 healthy controls. Bromide distribution approximates the extracellular fluid volume and bromide is excreted unchanged by the kidney.

Drug prescribing for patients with changing renal function.

The prevalence and course of renal dysfunction in hospitalized patients and the prescribing of renally eliminated drugs in these patients were studied. All adult inpatients at a large teaching hospital who had a serum creatinine concentration assay performed were screened for renal dysfunction (an estimated creatinine clearance of < 40 mL/min). Renally compromised patients were monitored for changes in renal function.

Intracellular zidovudine (ZDV) and ZDV phosphates as measured by a validated combined high-pressure liquid chromatography-radioimmunoassay procedure.

In vitro studies of zidovudine (ZDV) phosphorylation may not accurately reflect the in vivo dose-response relationship, which is crucial to determining the relationship between ZDV exposure, efficacy, and toxicity. However, measurement of ZDV phosphorylated anabolites in peripheral blood mononuclear cells (PBMCs) from ZDV-treated human immunodeficiency virus (HIV)-infected patients would be extremely useful in the more appropriate utilization of ZDV in the treatment of HIV infection. We developed a specific and sensitive combined high-pressure liquid chromatography (HPLC)-radioimmunoassay (RIA) procedure for the determination of ZDV, ZDV-monophosphate, ZDV-diphosphate, and ZDV-triphosphate in PBMCs taken from ZDV-treated HIV-infected patients.

Thermospray liquid chromatographic-mass spectrometric analysis of anti-AIDS nucleosides: quantification of 2',3'-dideoxycytidine in plasma samples.

Thermospray liquid chromatography-mass spectrometry was investigated as a method for quantification of 2',3'-dideoxycytidine (DDC) from human plasma. A stable isotope analog of DDC ([15N2,2H2]DDC) was used as an internal standard. Selected ion monitoring of the protonated molecular ions for DDC and the internal standard was used to record mass chromatograms.

Pharmacokinetics, toxicity, and activity of intravenous dextran sulfate in human immunodeficiency virus infection.

Polysulfated polysaccharides are attractive candidates for antiviral drug development because of their potent in vitro activities against human immunodeficiency virus (HIV), herpesviruses, and other enveloped viruses. To determine the potential anti-HIV activity of a prototypical polysulfated polysaccharide, we administered the maximally tolerated dose of dextran sulfate by continuous intravenous infusion to 10 subjects with symptomatic HIV infection for up to 14 days. Since parenteral dextran sulfate is an anticoagulant, the infusion was adjusted to produce the greatest acceptable increase in activated partial thromboplastin time.