Long-term efficacy and safety of adjunctive extended-release oxcarbazepine (Oxtellar XR ) in adults with partial-onset seizures.

Objective: To evaluate long-term outcomes of adjunctive therapy with SPN-804 (Oxtellar XR , Supernus Pharmaceuticals), an extended-release tablet formulation of oxcarbazepine (OXC), in adults with refractory partial-onset seizures.

Methods: After completing a 16-week double-blind, placebo-controlled trial of SPN-804 at fixed dosages (1200 or 2400 mg QD), patients entering this open-label extension study were converted in blinded fashion to 1200 mg QD SPN-804 as a target starting dose for long-term treatment. Patients were followed for 1 year, during which SPN-804 dosages could be adjusted up to 2400 mg/day according to clinical response.

Clinical assessment of drug-drug interactions of tasimelteon, a novel dual melatonin receptor agonist.

Tasimelteon ([1R-trans]-N-[(2-[2,3-dihydro-4-benzofuranyl] cyclopropyl) methyl] propanamide), a novel dual melatonin receptor agonist that demonstrates specificity and high affinity for melatonin receptor types 1 and 2 (MT1 and MT2 receptors), is the first treatment approved by the US Food and Drug Administration for Non-24-Hour Sleep-Wake Disorder. Tasimelteon is rapidly absorbed, with a mean absolute bioavailability of approximately 38%, and is extensively metabolized primarily by oxidation at multiple sites, mainly by cytochrome P450 (CYP) 1A2 and CYP3A4/5, as initially demonstrated by in vitro studies and confirmed by the results of clinical drug-drug interactions presented here. The effects of strong inhibitors and moderate or strong inducers of CYP1A2 and CYP3A4/5 on the pharmacokinetics of tasimelteon were evaluated in humans.

Absolute Bioavailability of Tasimelteon.

Tasimelteon is a novel dual melatonin receptor agonist and is the first treatment approved by the US Food and Drug Administration for Non-24-Hour Sleep-Wake Disorder. This study was conducted to assess the absolute bioavailability of tasimelteon and to further assess the single-dose pharmacokinetics, safety, and tolerability of oral and intravenous (IV) routes of administration of the drug. This study was an open-label, single-dose, randomized, 2-period, 2-treatment, 2-sequence, crossover study in which 14 healthy volunteers were randomly administered tasimelteon as either a 20-mg capsule or IV administration of 2 mg infused over 30 minutes.

Pharmacokinetics of the dual melatonin receptor agonist tasimelteon in subjects with hepatic or renal impairment.

Tasimelteon is a circadian regulator that resets the master clock in the suprachiasmatic nuclei of the hypothalamus by binding to both melatonin MT1 and MT2 receptors making it a dual melatonin receptor agonist. Tasimelteon has been approved by the United States Food and Drug Administration for the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24). Two prospective, single-center, open-label studies evaluated the pharmacokinetics of tasimelteon and its main metabolites after a single 20 mg dose administered to subjects with mild or moderate hepatic impairment or severe renal impairment, including subjects on dialysis compared to healthy controls.

Efficacy and safety of extended-release oxcarbazepine (Oxtellar XR™) as adjunctive therapy in patients with refractory partial-onset seizures: a randomized controlled trial.

Objective: To evaluate the efficacy, tolerability, and safety of once-daily 1200 mg and 2400 mg SPN-804 (Oxtellar XR™, Supernus Pharmaceuticals), an extended-release tablet formulation of oxcarbazepine (OXC), added to 1-3 concomitant antiepileptic drugs (AEDs) in adults with refractory partial-onset seizures, with or without secondary generalization.

Methods: The Prospective, Randomized Study of OXC XR in Subjects with Partial Epilepsy Refractory (PROSPER) study was a multinational, randomized, double-blind, parallel-group Phase 3 study. The primary efficacy endpoint was median percent reduction from baseline in monthly (28-day) seizure frequency for the 16-week double-blind treatment period in the intent-to-treat (ITT) population with analyzable seizure data.

A phase 2a randomized, parallel group, dose-ranging study of molindone in children with attention-deficit/hyperactivity disorder and persistent, serious conduct problems.

Objective: To evaluate safety and tolerability of four doses of immediate-release molindone hydrochloride in children with attention-deficit/hyperactivity disorder (ADHD) and serious conduct problems.

Methods: This open-label, parallel-group, dose-ranging, multicenter trial randomized children, aged 6-12 years, with ADHD and persistent, serious conduct problems to receive oral molindone thrice daily for 9-12 weeks in four treatment groups: Group 1-10 mg (5 mg if weight <30 kg), group 2-20 mg (10 mg if <30 kg), group 3-30 mg (15 mg if <30 kg), and group 4-40 mg (20 mg if <30 kg). The primary outcome measure was to evaluate safety and tolerability of molindone in children with ADHD and serious conduct problems.

Effects of oral and intravenous terazosin and head-up tilt on blood pressure responses in patients with hypertension.

Terazosin is a selective alpha1-adrenoceptor antagonist. A double-blind, randomized, placebo-controlled, two-period study evaluated the effects of posture and of oral and intravenous administration of terazosin on blood pressure and heart rate in patients with hypertension. At least one week after withdrawal of all antihypertensive medications, 31 patients with sitting diastolic blood pressure of 95 to 114 mmHg were enrolled in the study.

Pharmacokinetic interactions between two human immunodeficiency virus protease inhibitors, ritonavir and saquinavir.

Objective: To assess the pharmacokinetic interaction between ritonavir and saquinavir.

Methods: Ritonavir and saquinavir were administered in single doses to six groups of healthy volunteers in a two-way (saquinavir alone and ritonavir plus saquinavir for groups I through V) and a three-way (ritonavir alone, saquinavir alone, and ritonavir plus saquinavir for group VI) crossover manner with the following doses: group I, 200 mg saquinavir and 300 mg ritonavir; group II, 200 mg saquinavir and 600 mg ritonavir; group III, 400 mg saquinavir and 300 mg ritonavir; group IV, 400 mg saquinavir and 600 mg ritonavir; group V; 600 mg saquinavir and 200 mg ritonavir; group VI, 600 mg saquinavir and 600 mg ritonavir.

Results: Coadministration of ritonavir markedly increased the area under the plasma concentration-time curve (AUC) and peak concentration of saquinavir (> 50-fold and 22-fold, respectively).

Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir.

Coadministration with the human immunodeficiency virus (HIV) protease inhibitor ritonavir was investigated as a method for enhancing the levels of other peptidomimetic HIV protease inhibitors in plasma. In rat and human liver microsomes, ritonavir potently inhibited the cytochrome P450 (CYP)-mediated metabolism of saquinavir, indinavir, nelfinavir, and VX-478. The structural features of ritonavir responsible for CYP binding and inhibition were examined.

Evaluation of personality as a component of the healthy condition of volunteers participating in phase I studies.

Objective: The present study was conceived in order to recommend use of the Minnesota Multiphasic Personality Inventory for the evaluation of the personality of volunteers participating in Phase I clinical trials. The study was intended to describe personality profiles as objectively as possible, attempting to identify any common traits or tendencies, and to evaluate whether age or cultural background can be associated with significant differences in volunteer personality profiles.

Subjects: 358 subjects were evaluated (290 males and 68 females; mean age 30 y, range 18-78 y).

A study of plasma disposition kinetics of lacidipine after single oral ascending doses.

This study was designed to assess the plasma disposition kinetics of single oral 4-, 6-, and 8-mg doses of lacidipine, a new once-daily calcium-entry blocker. Seventeen healthy volunteers attended the study. In almost all cases, detectable levels were found up to 24 h after the drug administration, using a new HPLC-RIA assay.

Relief of pain following intravesical capsaicin in patients with hypersensitive disorders of the lower urinary tract.

We have extended our earlier observations on pain relief produced by intravesical instillation of capsaicin (10 microM in saline) in patients with hypersensitive disorders of the lower urinary tract. Patients in group A (n = 15) received intravesical capsaicin on days 0, 14 and 28: on each occasion the drug produced a warm or burning sensation, reduction in bladder capacity and a delayed, transient improvement or disappearance of symptoms. Patients in group B (n = 5) received intravesical capsaicin (10 microM at cystometry) 3 times on day 0.

Autoradiographic localization of octylonium bromide binding sites in the rat gastrointestinal tract.

The anatomical localization of the binding sites of the spasmolytic drug octylonium bromide (OB) in the rat gastrointestinal tract was analyzed by use of light microscope autoradiography. The drug was visualized after in vitro incubation of frozen sections of the gastrointestinal tract with a 10 nM concentration of 14C-OB and after in vivo injection into the ascending, transverse, descending and sigmoidal portions of the colon. In vitro experiments demonstrated the specific accumulation of 14C-OB within the colonic and rectal smooth muscle.

Venous blood platelets decrease during allergen-induced asthmatic reactions.

To determine whether circulating platelets alter during asthmatic reactions induced by allergens, we studied nine subjects previously shown to develop an early or dual asthmatic reaction after inhalation challenge with extracts of house dust mite or grass pollen. In each subject, FEV1, circulating platelets and leucocytes were measured before, 15, 30 and 60 min, and 2, 4, 6 and 8 hr after inhalation of allergen and diluent control administered in a single-blind, randomized fashion. The same procedure was repeated in six of the nine subjects after bronchoconstriction induced by methacholine.

Immunoblockade by a specific tachykinin antiserum of the non-cholinergic contractile responses in the guinea-pig isolated bronchus.

1. In the guinea-pig isolated bronchus, capsaicin produced a concentration-dependent contraction which was tetrodotoxin- (1 microM) resistant but abolished by previous exposure to capsaicin. 2.

Octylonium bromide interacts competitively with the PAF receptor.

To clarify the nature of the interaction of octylonium bromide with the PAF receptor, saturation studies of 3H-PAF binding were made in the presence of increasing concentrations of the radioligand (from 0.06 to 7.4 nM) and of octylonium bromide (1 X 10(-8), 5 X 10(-8) and 1 X 10(-7) M) or of a potent PAF antagonist L 652,731 (2.

Prolactin-lowering effect of acute and once weekly repetitive oral administration of cabergoline at two dose levels in hyperprolactinemic patients.

To further evaluate the potency and time course of the PRL-lowering effect of single oral doses of cabergoline, two doses of the drug were given to 51 hyperprolactinemic patients who also received 2.5 mg bromocriptine according to a randomized cross-over design. One group (n = 26) received 0.

Inhibition of basal and metoclopramide-induced prolactin release by cabergoline, an extremely long-acting dopaminergic drug.

The aim of this study was to evaluate the effectiveness of the ergoline derivative cabergoline in inhibiting the serum PRL response to metoclopramide (MCP; 5 mg, iv) and the duration of this effect. Seven normal men received cabergoline (600 micrograms, orally) on day 0 and underwent a MCP test on days -1, 1, 4, 8, 15, and 28. Fasting serum PRL levels were significantly depressed from days 1-14; the nadir value occurred on day 4.

Dose-related prolactin inhibitory effect of the new long-acting dopamine receptor agonist cabergoline in normal cycling, puerperal, and hyperprolactinemic women.

Two different single doses (400 and 600 micrograms) of the new long-acting dopamine agonist cabergoline (CBG) were given to 12 normal cycling women, 17 puerperal women, and 24 hyperprolactinemic women (12 with idiopathic hyperprolactinemia and 12 with pituitary adenoma). Plasma PRL was determined in blood samples collected before and at frequent intervals for 5 days after CBG administration. Both CBG doses induced marked inhibition of PRL secretion in all women.