Population pharmacokinetics and safety of AZD1446, a neuronal nicotinic receptor agonist, administered in healthy volunteers.

AZD1446 is a highly selective agonist of central α4β2 and α2β2 neuronal nicotinic receptors. The compound has been shown to improve cognition in preclinical studies and thus has potential for treatment of cognitive disorders, including Alzheimer's disease (AD). This report presents the pharmacokinetics of AZD1446 based on a pooled population pharmacokinetic analysis of five studies in Caucasian and Japanese healthy volunteers.

AZD5213: a novel histamine H3 receptor antagonist permitting high daytime and low nocturnal H3 receptor occupancy, a PET study in human subjects.

The histamine H3 receptor represents an appealing central nervous system drug target due to its important role in the neurobiology of cognition and wake-sleep regulation. The therapeutic benefit of H3 antagonists/inverse agonists may be hampered by disruption of sleep that has been observed in humans with prolonged high H3 receptor occupancy (H3RO), extending into night-time. AZD5213 is a highly selective H3 antagonist (in vitro inverse agonist) developed to achieve a pharmacokinetic profile permitting circadian fluctuations of H3RO.

Evaluation of the effects of AZD3480 on cardiac repolarization: a thorough QT/QTc study using moxifloxacin as a positive control.

In order to evaluate their potential effects on cardiac repolarization, all new drugs must undergo clinical electrocardiographic evaluation in a thorough QT/QTc (TQT) study. AZD3480, a central nervous system-selective, neuronal nicotinic receptor (NNR) agonist, is predominantly metabolized by cytochrome P450 2D6 (CYP2D6). Employing an innovative design, this TQT study assessed the effects of supratherapeutic doses of AZD3480, relative to those of placebo, on cardiac repolarization in healthy male volunteers genotyped as either poor metabolizers (PMs) or extensive metabolizers (EMs) of CYP2D6 substrates.

Pharmacokinetics in renally impaired subjects of NXY-059, a nitrone-based, free-radical trapping agent developed for the treatment of acute stroke.

Objective: NXY-059 is a nitrone-based, free-radical trapping agent being developed for the treatment of acute ischaemic stroke. Elimination of NXY-059 is primarily renal. The objective of the study was to investigate the pharmacokinetics of NXY-059 in subjects with renal impairment.

Influence of food intake on electrocardiograms of healthy male volunteers.

Objective: To study the influence of food intake on electrocardiogram (ECG) variables (heart rate, QT-, QTc-, PR-intervals, QRS-time) and morphological alterations of the T-waves in 12 healthy male volunteers.

Methods: The study was of open, three-period crossover design. On each occasion, all subjects fasted from midnight.

The protective action of chlormethiazole against ischaemia-induced neurodegeneration in gerbils when infused at doses having little sedative or anticonvulsant activity.

1. The effect of chlormethiazole administration on delayed neuronal death in gerbil hippocampus following transient global ischaemia has been examined. Chlormethiazole was administered either intraperitoneally or by intravenous infusion with either the dose or the time of infusion varied.

A study of the psychometric effects of chlormethiazole in healthy young and elderly subjects.

The pharmacokinetics and effects of chlormethiazole (91 mg intravenously together with 356 mg orally) on psychomotor performance were studied in 10 young (mean age 29 years) and 10 older (mean age 66.2 years) volunteers using an open design. Chlormethiazole affected psychomotor function and decreased subjective arousal in both age groups.

Selective dopamine D2 antagonist and prolactin response in acute schizophrenia--results from remoxipride studies. The Canadian Remoxipride Study Group.

1. In a double-blind dose finding study prolactin was assessed at baseline and end of treatment in three groups of acute schizophrenics receiving low, intermediate and high doses of remoxipride as compared to a controlled group that received haloperidol. 2.

Plasma concentration of remoxipride in relation to antipsychotic effect and adverse symptoms. The Canadian Remoxipride Study Group.

The possible relationship between plasma concentration of remoxipride and antipsychotic effect/adverse symptoms has been evaluated in a 6-week double-blind dose-finding study in schizophrenic patients. The study comprised 3 parallel groups with fixed daily doses of 30-90 mg, 120-240 mg or 300-600 mg, divided in order to be given three times a day. A total of 79 patients from the three groups, who were treated with the maximum dose for 4 weeks or more, were included in the analysis.

Clinical pharmacokinetics of remoxipride.

The clinical pharmacokinetics of remoxipride, a pure enantiomer, have been studied in healthy volunteers and patients. After oral administration the drug is rapidly and almost completely absorbed with a bioavailability above 90%. Thus remoxipride is a low clearance drug, with a systemic plasma clearance of about 120 ml/min, and without any first-pass metabolism.

The bioavailability and pharmacodynamics of chlormethiazole in healthy young and elderly volunteers: preliminary findings.

A preliminary analysis of a study of the bioavailability and pharmacodynamics of chlormethiazole in healthy young and elderly volunteers has been performed. The bioavailability assessed by a stable isotope method and the pharmacodynamic effects assessed by psychometric tests were found not to differ between the two age groups.

Alaproclate: a pharmacokinetic and biochemical study in patients with dementia of Alzheimer type.

Alaproclate, a specific inhibitor of neuronal serotonin re-uptake, was given to 12 patients with dementia of Alzheimer type. The drug was rapidly absorbed and an elimination half-life of 7.1 +/- 0.

Chlormethiazole (Heminevrin), pethidine and nitrous oxide as compared to halothane for general anesthesia.

The anaesthetic and postanaesthetic course in a group of gynaecological patients anaesthetized with chlormethiazole (Heminevrin) was investigated and the results compared to a similar group of patients anaesthetized with halothane. Both drugs were used as the main anaesthetic agent in the respective regimes, supplemented by nitrous oxide/oxygen and muscle relaxants. Because chlormethiazole is devoid of analgetic effects, the importance of using pethidine in combination with chlormethiazole is emphasized.

A double-blind study of zimelidine, a serotonin uptake inhibitor, and desipramine, a noradrenaline uptake inhibitor, in endogenous depression. II. Biochemical findings.

In a comparative evaluation of zimelidine, a potent serotonin (5-HT) uptake inhibitor, and desipramine, a potent noradrenaline (NA) uptake inhibitor, 65 hospitalized patients with endogenous depression were evaluated for the following biochemical variables: 5-HT uptake in platelets, 5-HT concentration in whole blood, inhibition of the 5-HT and NA accumulation in rat hypothalamic synaptosomes incubated in the patients' plasma, the excretion of 4-hydroxy-3-methoxyphenyl glycol (HMPG) in urine and the pretreatment levels of the amine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and HMPG in cerebrospinal fluid (CSF). results of the biochemical studies confirmed that zimelidine and desipramine have different profiles with respect to monoamine uptake. Thus zimelidine caused more marked inhibition of 5-HT uptake than desipramine, especially in rat brain synaptosomes incubated in the patient's plasma.

Zimelidine and norzimelidine protein binding measured by equilibrium dialysis and cerebrospinal fluid.

Steady-state concentrations of a new antidepressant, zimelidine (ZIM), and its active metabolite, norzimelidine (NZIM), were measured in plasma and cerebrospinal fluid (CSF) in eight depressed patients. Free drug, as calculated from the ratio of CSF to plasma concentration, of ZIM was 8.4 +/- 1.

Excretion of paracetamol in human breast milk.

Breast milk and plasma levels of paracetamol were monitored in 3 lactating women after ingestion of a single 500 mg dose of paracetamol. The paracetamol concentrations were consistently lower in milk, with a mean milk/plasma AUC ratio of 0.76.

Effects of zimelidine and desipramine on serotonin and noradrenaline uptake mechanisms in relation to plasma concentrations and to therapeutic effects during treatment of depression.

The selective inhibitors of neuronal 5-hydroxytryptamine (5-HT) and noradrenaline (NA) uptake, zimelidine and desipramine, were compared in a double blind crossover study of 40 inpatients with endogenous depression. The clinical effects of these two drugs and some biochemical variables related to the monoamine systems were studied during 4 weeks' treatment. Patients with a low pretreatment level of 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) (less than 20 ng/ml) responded significantly better to zimelidine treatment than those with a high pretreatment level (greater than 20 ng/ml).

Prolonged infusion of chlormethiazole in intensive care.

Chlormethiazole has proved useful for prolonged sedation in patients receiving artificial ventilation of the lungs during intensive care. In short-term infusions sedation and unconsciousness can be produced quickly and reversal is rapid on stopping the administration. After prolonged infusion, however, recovery is much slower because of accumulation of the drug.

Chlormethiazole treatment and breast feeding.

Four mothers receiving chlormethiazole for pre-eclampsia and their babies were the subjects of the investigation. Blood samples at delivery and blood and breast milk samples in the postpartum period were analysed for chlormethiazole. Concentrations ranged from 1.

Pharmacokinetics of clomethiazole in healthy adults.

The systemic availability of clomethiazole was assessed by comparing blood levels after intravenous and oral administration. Clomethiazole was rapidly absorbed after oral administration to volunteers, particularly when administered as syrup. The fraction of the given dose that reached the systemic circulation after 1 capsule of clomethiazole (192 mg clomethiazole) was 0.

Kinetics of chlormethiazole in patients with alcohol withdrawal manifestations.

Chlormethiazole administered orally to patients in mild degrees of alcohol withdrawal was generally rapidly absorbed, showed a rapid distributive phase, and had an elimination phase 1 1/2 of 2.6 to 4.7 hr.