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. Supratherapeutic doses of AZD3480-resulting in ~10- and ~50-fold higher exposures (PMs and EMs, respectively) than achieved with a 20-mg dose-had no pharmacologic effect on cardiac repolarization relative to placebo. Likewise, no safety/tolerability concerns were observed after either supratherapeutic or 20-mg dosing to either population. No clinically relevant treatment-related changes or trends were observed in laboratory parameters, vital signs, or electrocardiogram (ECG). This study demonstrated that AZD3480 does not prolong QT/QTc interval.

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. During two of the study periods, the subjects were given a standardised meal at 1.5 h and 5.5 h after the baseline assessments, respectively, whereas, during the third period, they remained fasting for the entire study period of about 9 h. ECG and blood pressure were recorded at baseline and thereafter every hour for 8 h. RESULTS: No ECG changes were observed following the fasting condition, whereas a clear change in ECG and an increased heart rate were recorded in response to the meal intake during the other two periods. The most prominent ECG effect was the change in the size and shape of the T-waves, which were described as flattened to biphasic and, occasionally, negative. These alterations were most pronounced in the precordial leads V4 to V6 in the ECG recording immediately following the meal intake, with a gradual return to baseline conditions over 4-5 h. Moreover, a transient increase of supine systolic blood pressure was also recorded in response to the meal intake. CONCLUSIONS: The intake of a meal can cause clear and consistent ECG changes in healthy male subjects, comprising increases in heart rate as well as alterations in the size and shape of the T-waves (flattened to biphasic and, occasionally, negative). Also, a post-meal increase in the supine systolic blood pressure was recorded.

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. 2. Chlormethiazole (600 mumol kg-1, i.p.) given 60 min after ischaemia produced substantial (> 60%) neuroprotection when damage was assessed 5, 14 or 21 days later, indicating the drug does not merely delay cell death. 3. Infusion protocols were developed which would result in sustained and defined plasma concentrations. Chlormethiazole (930 mumol kg-1) was then infused intravenously for 30 min, 76.5 min or 110 min in ways resulting in sustained plasma concentrations of 200, 100 and 50 nmol ml-1 respectively. When treatment was initiated 30 min after the ischaemic episode all protocols provided effective neuroprotection. There was a dose-dependent decline in protection when plasma chlormethiazole concentrations of 50, 30 and 10 nmol ml-1 were sustained for 110 min with no protection observed at 10 nmol ml-1. 4. In contrast, when a plasma concentration of 10 nmol ml-1 was sustained by infusion for 24 h, almost total neuroprotection against the ischaemic damage was achieved. This plasma concentration produced no sedative or anticonvulsant activity. 5. These data suggest that neuroprotection depends on both dose and duration of chlormethiazole administration and that excellent neuroprotection is possible in the absence of the sedative and anticonvulsant effects of the drug.

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. The peak effect was found at approximately 30 min, i.e. at the end of the infusion, and performance returned to normal by 3 h. There was no evidence of increased sensitivity of the older subjects to the psychomotor or subjective effects of chlormethiazole. The incidence and type of reported symptoms was also similar in the two age groups. The volume of distribution of chlormethiazole was greater in the old than in the young subjects as was the elimination half-life after intravenous administration. Other pharmacokinetic variables showed no significant differences between young and old subjects.

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. Remoxipride only in high doses (300-600 mg daily) has produced a modest increase in prolactin levels at endpoint as compared to the much higher increase in prolactin secretion that accompanied haloperidol treatment. 3. The weak effects on prolactin as well as the previously reported low incidence of extrapyramidal side effects confirm the profile of remoxipride as a selective dopamine D2 antagonist with preferential effects on the mesolimbic and mesocortical tracts. 4. Male responders to either remoxipride or haloperidol treatment had significantly higher baseline prolactin levels regardless of dose and drug used. In females, there was no difference in baseline prolactin between responders and nonresponders.

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 apparent volume of distribution is 0.7 1/kg, about 80% being bound to plasma proteins (mainly alpha 1-acid glycoprotein). Remoxipride has a plasma half-life in the range of 4-7 h and is eliminated by both hepatic metabolism and renal excretion. Slightly more than 70% of the dose is recovered as urinary metabolites and about 25% is excreted unchanged. Steady-state plasma levels are reached within 2 days, and they increase linearly with doses up to 600 mg daily. There is no evidence that active metabolites of remoxipride are present in the blood. Decreased renal function is associated with increased levels of remoxipride, whereas moderate cirrhosis of the liver only slightly affects elimination. There are no pharmacokinetic interactions between remoxipride and diazepam, ethanol, biperiden, or warfarin.

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. All patients had reached steady-state at week 2 and the intra-individual trough remoxipride plasma levels remained stable over the study period. The mean steady-state trough concentrations were found to be linearly related to the dose. Responders to remoxipride treatment were observed over the total concentration range of 0.24-13.50 mumols/l. Reductions of dose or discontinuations of treatment due to adverse symptoms were not associated with elevated remoxipride concentrations. In conclusion, no obvious relationship between plasma concentration of remoxipride and its antipsychotic effect or adverse symptoms was established.

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 +/- 0.9 h (+/- SD, n = 8) was calculated. Plasma protein binding for alaproclate was 82 +/- 1%. Two weeks of repeated administration produced plasma concentrations of alaproclate similar to those predicted from a single dose. The pharmacological effect of the drug was demonstrated by an inhibition of serotonin uptake in the patients' platelets and a reduction of the serotonin concentration in blood. Global rating of clinical efficacy showed a positive effect of alaproclate in five of the patients, mainly regarding emotional functions.

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. An advantage of using chlormethiazole is that it can serve as both an induction and maintenance agent. The plasma concentrations of chlormethiazole were studied in seven patients. For induction, the mean concentration was 4.5 micrograms/ml. The mean concentration on waking at the termination of operation was 1.3 micrograms/ml. No serious side effects were encountered in either treatment. The results suggested that chlormethiazole in combination with an analgetic drug and nitrous oxide could be suitable in elderly patients, although occasionally less effective in the young.

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. Desipramine plasma was much more effective than zimelidine plasma in inhibiting NA uptake in the same preparation. The urinary excretion of HMPG decreased significantly during desipramine treatment but remained unchanged during zimelidine treatment. The combined clinical and biochemical results indicated that patients with low pretreatment levels of 5-HIAA and HVA in CSF responded significantly better to zimelidine than patients with high levels of 5-HIAA and HVA. On the other hand, patients with high levels of 5-HIAA and HVA. On the other hand, patients with high levels of HMPG in CSF tended to respond better to desipramine than those with low levels of this NA metabolite.

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 +/- 1.8% and of NZIM was 18.3 +/- 2.8%. Equilibrium dialysis (ED) of plasma from the same patients on placebo yielded free fractions of 8.6 +/- 2.2% and 28.1 +/- 3.4% for the two compounds. alpha 1-Acid glycoprotein (alpha a-AG) was also measured in the same samples. Variation in free drug using either method was not great, but did modestly correlate with alpha 1-AG concentration in six of the eight patients in whom simultaneous placebo measures were available. Our results indicate that measurements in plasma or of free drug dependent on ED lead to erroneous conclusions regarding the proportion of free NZIM to ZIM. Considering the different potencies of the parent compound and active metabolite, this is an unusual problem.

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. This value was in close agreement with the milk/plasma partition ratio of 0.81 found in vitro, and could be related to quantitative binding differences between the two fluids. The half-lives of paracetamol in plasma and breast milk were almost identical, with an overall mean of 2.7 h. As less than 0.1% of the maternal dose would be present in 100 ml milk, breast feeding need not be discontinued due to paracetamol treatment in conventional dosage.

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). In the group treated with desipramine no difference in therapeutic outcome was obtained between patients with low and high pretreatments levels of 5-HIAA in the CSF. Attempts to correlate the steady state plasma concentrations of zimelidine, norzimelidine and desipramine with the therapeutic effect were unsuccessful. The plasma concentration of norzimelidine demonstrated a significant (P less than 0.05) positive correlation with age. The mean value of the uptake of 14C-5-HT in the patient's platelets, when measured before the treatment, was significantly (P less than 0.05) lower than found in a control group. Zimelidine, mainly via its metabolite norzimelidine, caused a pronounced inhibition of uptake of 14C-5-HT in platelets, decrease in whole blood 5-HT and inhibition of accumulation of 14C-5-HT in rat hypothalamic synaptosomes incubated in the patients plasma. Desipramine produced a slight inhibition of accumulation of 14C-5-HT in rat synaptosomes, but a marked inhibition of uptake of 14C-5-HT in the patient's platelets and a decrease in whole blood 5-HT. The accumulation of 3H-NA in rat synaptosomes incubated in the patient's plasma was strongly inhibited by desipramine treatment but only slightly affected by zimelidine.

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. The pharmacokinetics of chlormethiazole in both short and prolonged infusions were studied in four patients. Following brief administrations the drug disappeared very quickly from the blood as a result of re-distribution and the patients wakened after a few minutes. Unconsciousness was associated with plasma concentrations in the range of 3--5 micrograms ml-1. After 48 h administration, recovery was much slower, the elimination half-life varying from 3.5 to 12.1 h.

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 1.340 to 1.640 micrograms/g of sample of umbilical artery blood at birth, and fell to 0.010 to 0.153 micrograms/g in capillary blood 20 to 26 hours later. After the start of breast feeding, chlormethiazole in the babies was detectable in only 3 out of 27 serial blood samples and was 0.018, 0.009 and 0.006 micrograms/g. The highest calculated amount of chlormethiazole ingested at a breast feed was 37.2 micrograms. It is suggested that breast feeding should not be delayed solely on account of chlormethiazole therapy.

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 0.25 +/- 0.18, after 2 capsules (384 mg clomethiazole) 0.38 +/- 0.18, and after 15 ml syrup (480 mg clomethiazole) 0.42 +/- 0.20. The time-blood concentration profiles were consistent with a two-compartment open model and the mean elimination half-lives of 3.6--5.0 hrs. were found for the different formulations and administration routes. Elimination half-lives showed little variation and a mean systemic clearance of 49 ml/min./kg was found for clomethiazole after intravenous administration. Clomethiazole is bound to human plasma proteins (63.4 +/- 1.6%, 37 degrees), a binding which is not affected by Vacutainer sample tubes. The blood/plasma distribution of clomethiazole was 0.76 +/- 0.02 at 37 degrees. A sensitive mass fragmentographic assay for the determination of clomethiazole in blood/plasma down to levels of 1 ng/ml (6.2 nmol/l) is described.

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. The plasma concentrations of drug attained following higher oral doses were greater than is usually the case with augmentation of dose. Intravenously infused chlormethiazole in similar patients produced relatively high plasma concentrations of the drug, with distributive and eliminative 1 1/2 similar to those of oral doses. These pharmacokinetic patterns in alcoholic patients more closely resemble those previously reported for normal young subjects than they do for normal aged subjects.