Effect of valproate on plasma levels of interleukin-6 in healthy male humans

Valproate exerts many biochemical and physiological effects and may have a modulating effect on the immune system. The present study aimed to determine whether there is a treatment effect of valproate on plasma levels of the pro-inflammatory cytokine, interleukin (IL)-6, in healthy male humans. Plasma levels of IL-6 were measured in 10 healthy male humans before and after 7 days of treatment with 1000 mg per day of valproate (i.e. 500 mg in the morning and 500 mg in the evening). All the healthy subjects had no past or current psychiatric disorder. They reported to the outpatient clinic at 09.00 h for baseline sampling. Subsequently, they were commenced on valproate 1000 mg per day for 7 days. They took the last dose of valproate at 22.00 h on the day 7, and post-treatment blood sampling for plasma levels of IL-6 was carried out on day 8. An additional blood sample was also taken from each subject at the same time to measure plasma levels of valproic acid for drug compliance. We found a significant increase in plasma levels of IL-6 after the 7 days of valproate treatment in healthy male subjects. Furthermore, there was a significant positive correlation between the changes in plasma IL-6 and blood levels of valproic acid. The findings of this study are consistent with previous studies on subjects with epilepsy, suggesting a modulating effect of valproate on the pro-inflammatory cytokine IL-6 in humans. However, studies with a larger number of participants and employing a double-blind, placebo-control group are required to confirm the findings, and also the levels of other cytokines should be measured to generalize the effect to the immune system.     

Development of tolerance to the anticonvulsant effect of vigabatrin in amygdala-kindled rats.

The anticonvulsant, adverse and biochemical effects of the novel antiepileptic drug vigabatrin (gamma-vinyl GABA), which increases GABA (gamma-aminobutyric acid) levels by inhibition of the GABA degrading enzyme GABA aminotransferase, were examined in amygdala-kindled rats after acute and chronic administration. Vigabatrin proved to be a potent anticonvulsant drug at acute doses (100-200 mg/kg), but during chronic administration, the anticonvulsant activity of the treatment was lost already in the second week of treatment. Tolerance also developed to the adverse effects, i.e. hypothermia, sedation and motor impairment. Determination of vigabatrin in plasma indicated that tolerance was not due to declining drug levels. Furthermore, determination of endogenous amino acids in plasma showed that GABA levels were highly elevated throughout the period of treatment, although the extent of GABA accumulation decreased in the second week. After cessation of chronic treatment with vigabatrin, there was no clear indication of withdrawal symptoms, except a prolonged seizure or afterdischarge duration in experiments with 100 mg/kg per day. The data suggest that chronic treatment with vigabatrin may be associated with a loss of anticonvulsant efficacy, at least when the drug is given as monotherapy.     

Inhibition of the enzyme, GABA-aminotransferase in human platelets by vigabatrin, a potential antiepileptic drug.

1. The effect of the new antiepileptic drug, vigabatrin (gamma-vinyl GABA), on the platelet enzyme, GABA-aminotransferase (GABA-T) was investigated in volunteers and patients. Platelets GABA-T activity was assayed using a radioenzymic method. 2. Three single oral doses of vigabatrin (1 g, 2 g and 4 g) were given to six healthy male volunteers in an open randomised cross over study and compared with a baseline period preceding the three treatments. 3. Significant inhibition of the platelet GABA-T was produced by treatment with all three doses and a dose-response relationship was demonstrated. The minimum enzyme activities after 1 g, 2 g and 4 g doses were 43%, 30% and 21% respectively compared with the control values. 4. A significant depression of enzyme activity occurred at 30 min after drug administration and the values remained below control values for 72 h post-dose, outlasting the presence of the drug itself in the plasma. 5. Eight patients with chronic refractory epilepsy were treated with vigabatrin for 6 weeks. After taking the 2 g daily dose for 1 week there was a marked reduction in platelet enzyme activity in all subjects but the enzyme inhibition produced by the 3 g dose was not significantly different from that produced by the 2 g dose, even after 4 weeks treatment with the larger dose. The mean enzyme activity was approximately 30% throughout the active treatment period. One week after stopping vigabatrin, the enzyme levels were not significantly different from the baseline values.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma atrial natriuretic peptide and the renin-aldosterone system during long-term administration of the diuretic xipamide in man

Summary We have studied the effect of xipamide on plasma α-atrial natriuretic peptide and the reninaldosterone-kallikrein system in twelve healthy men, using a double-blind cross-over design. After a run-in period on placebo for 1 week the subjects were treated with either placebo (n=6) or xipamide 20 mg once daily (n=6) for 16 weeks and were then switched to the alternative medication for another 16 weeks. The plasma concentration of α-atrial natriuretic peptide fell after 1 week of xipamide administration and increased during prolonged xipamide administration but remained suppressed. The changes in plasma α-ANP observed after 1 week of xipamide were negatively correlated with the changes in haematocrit and haemoglobin. Plasma renin activity (PRA), aldosterone concentration (PAC), and urinary excretion of aldosterone and kallikrein increased after 1 week of xipamide administration, levelled off during the second and fourth weeks, but remained elevated during further prolonged xipamide administration for 16 weeks. The xipamide-induced changes in PRA and PAC were positively correlated with the changes in the haematocrit and haemoglobin. Our data suggest that the changes in plasma renin, aldosterone, and α-atrial natriuretic peptide during xipamide administration may be related to diuretic-induced volume contraction.     

Plasma GABA in mood disorders

Plasma levels of gamma-aminobutyric acid (GABA) were determined in 68 healthy controls and in 133 patients with mood disorder. Plasma GABA levels were significantly lower in the patients with mood disorder compared to controls. Levels of plasma GABA were similar among diagnostic groups (primary unipolar depression, bipolar depression, mania, and secondary depression). No differences in plasma GABA were found in patients classified according to family history, nor were any correlations found between plasma GABA levels and severity of depression as determined by the 17-item Hamilton Rating Scale for Depression. These findings support the notion that low plasma GABA may represent a biological marker for mood disorder.     

Resistance exercise training reduces plasma endothelin-1 concentration in healthy young humans

Endothelin-1 (ET-1), which is produced by vascular endothelial cells, has potent vasoconstrictor and proliferative activity in vascular smooth muscle cells, and therefore has been implicated in regulation of vascular tonus and progression of atherosclerosis. We recently demonstrated that the plasma ET-1 concentration was significantly decreased by aerobic exercise training in healthy young humans and healthy older humans. However, it is unclear whether the production of ET-1 is altered by resistance exercise training. We measured the plasma ET-1 concentration before and after resistance exercise training in healthy young humans. Six healthy young men (26 +/- 1 years old) performed 8 weeks of resistance exercise training (3 days/week). There were no significant differences in body composition, blood pressure, heart rate, and maximal oxygen consumption before and after resistance exercise training. The girths of the arm and thigh significantly increased after resistance exercise training. The maximal muscle powers in the arm and leg increased after resistance exercise training. After resistance exercise training, the plasma concentration of ET-1 significantly decreased. The present study suggested that resistance exercise training, as well as aerobic exercise training, reduces the plasma ET-1 concentration in healthy young humans, and that this reduction in plasma ET-1 concentration may have beneficial effects on the cardiovascular system.     

Impaired growth hormone response to sodium valproate in normal aging

Evidence has been provided for impaired neurotransmitter functioning in the brain of elderly subjects. In order to assess central GABAergic transmission, the activity of the hypothalamic GABA system may be investigated by basal growth hormone (GH) response to the GABAergic drug sodium valproate (SV). For this purpose 15 healthy men (aged 19–81 years) received orally 800 mg SV or placebo tablets on two different occasions, 1 week apart. Blood samples were collected before and after drug administration for determining GH and SV plasma levels. A clearcut increase in plasma GH was observed following SV (P<0.001 in young persons,P<0.005 in old subjects), but in the aged subjects this rise was statistically lower than in the young men (P<0.001 at t=90 min). No difference was observed in basal GH levels and in SV plasma concentrations between elderly and young subjects. GH (= maximum post-SV GH level minus baseline GH value) was significantly inversely related to age (r=-0.90,P<0.001). These results may suggest an impaired hypothalamic-pituitary responsiveness to a pharmacological challenge enhancing endogenous GABA tone in the elderly.     

Effect of orally administered misoprostol and cimetidine on the steady state pharmacokinetics of diazepam and nordiazepam in human volunteers.

The effects of misoprostol and cimetidine on diazepam pharmacokinetics were evaluated in order to determine whether the kinetic variables for diazepam and nordiazepam alone differ with the repeated oral administration of misoprostol and cimetidine to healthy adult volunteers. The trial was conducted as an open crossover study in 12 normal subjects, divided into two groups with all subjects receiving both regimens. Total study duration was 5 weeks. An initial clinical assessment, including blood biochemistry and assessment of subject oxidation status was carried out on study day 1. On this day, subjects began taking diazepam (10 mg) orally for one week, with pharmacokinetic studies performed at day 8, when steady state levels of diazepam were reached. This was followed by one week with active drug, misoprostol to Group I and cimetidine to Group II, with pharmacokinetic studies performed at the end of a 1-week treatment. After a 2-week wash-out period, both groups took for one week, the alternate drug, i.e. cimetidine plus diazepam to Group I and misoprostol plus diazepam to Group II. On days 8, 15 and 36, subjects were admitted to the hospital for 12 h, during which time a clinical examination was carried out and blood samples were taken at time zero and at 4, 8, 12, 24, and 36 h post-dosing for the measurement of serum diazepam and nordiazepam. The main parameters measured and evaluated were diazepam and nordiazepam pharmacokinetics at steady state (days 8, 15 and 36). These were areas under the curve in the dose intervals (AUC0-24h), maximum plasma concentrations (Cmax), time to peak concentrations (Tmax), elimination half-life (t1/2), elimination constant (Kel), distribution volume (Vd), total body clearance (ClB) and clearance after oral administration (Cloral). The results demonstrated that plasma diazepam and nordiazepam concentrations had a significant increase after steady states have been reached with the simultaneous administration of 800 mg of cimetidine daily for one week. The simultaneous administration of 800 micrograms of misoprostol did not cause any significant change in diazepam and nordiazepam plasma levels after steady states had been reached. Comparing the pharmacokinetic parameters of Groups A and B as well as within groups on days 8, 15 and 36, a significant increase in plasma diazepam and nordiazepam levels was detected. This was due to a cimetidine-induced impairment in microsomal oxidation of diazepam and nordiazepam, which caused a decrease in total metabolic clearance and increased mean steady state plasma concentrations. A more prolonged half-life was observed for both groups taking cimetidine as well as an increase of mean maximum plasma concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)     

The effect of midazolam (Hypnovel) administration on antipyrine pharmacokinetics in humans

1. Twelve healthy volunteers were given a standard regimen of oral midazolam (Hypnovel®) (15mg nightly) for 10 consecutive nights.

2. Antipyrine pharmacokinetics were studied immediately before midazolam administration was started, after the dosage schedule had been completed and one week after dosing had been discontinued.

3. No statistically significant changes were seen in the disposition of antipyrine as assessed by the plasma half-lives, areas under the curve and plasma clearances. Therefore, although previous studies have demonstrated that high doses of midazolam induced the drug-metabolising enzymes in laboratory animals, such effects are unlikely to occur in humans being treated with therapeutic doses.     

Plasma angiotensin-(1-8) octapeptide measurement to assess acute angiotensin-converting enzyme inhibition with captopril administered parenterally to normal subjects

The blood pressure (BP), heart rate (HR), and humoral effects of single intravenous (i.v.) doses of the angiotensin-converting enzyme (ACE) inhibitor captopril was investigated in five normotensive healthy volunteers. Each subject received at 1-week intervals a bolus dose of either captopril (1, 5, and 25 mg) or its vehicle. The study was conducted in a single-blind fashion, and the order of treatment phases was randomized. The different doses of captopril had no acute effect on BP and HR. They induced a dose-dependent decrease in plasma ACE activity and plasma angiotensin II levels. The angiotensin-(1-8) octapeptide was isolated by solid-phase extraction and high-performance liquid chromatography (HPLC) prior to radioimmunoassay (RIA). All three doses of captopril reduced circulating angiotensin II levels within 15 min of drug administration. Only with the 25-mg dose was the angiotensin II concentration below the detection limit at 15 min and still significantly reduced 90 min after drug administration. Simultaneous and progressive decreases in plasma aldosterone levels were observed both with ACE inhibition and during vehicle injection, but the relative fall was more pronounced after captopril administration. No adverse reaction was noticed. These results demonstrate that captopril given parenterally blocks the renin-angiotensin system in a dose-dependent manner. Only with the dose of 25 mg was the inhibition of plasma-converting enzyme activity and the reduction of plasma angiotensin II sustained for at least 1 1/2 h.     

Chronic lithium administration enhances noradrenergic responses to intravenous administration of the alpha2 antagonist idazoxan in healthy volunteers

The acute and chronic effects of lithium carbonate administration at therapeutic blood levels on peripheral noradrenergic activity and sympathetic responses to alpha2 adrenoceptor blockade were examined in 10 medically and psychiatrically healthy volunteers. Supine resting levels of plasma norepinephrine and the increases in norepinephrine following intravenous infusion of 200 microg/kg of idazoxan, a selective alpha2 adrenoceptor antagonist, were determined before lithium (Li+) administration and after 5 days and after 4 weeks of daily Li+ treatment. Chronic Li+ treatment significantly increased mean resting plasma norepinephrine levels by 53.6%. The noradrenergic responses to infusions of idazoxan were slightly enhanced after 5 days of Li+ administration and significantly increased following 4 weeks of Li+ treatment. The possibility that Li+ produces functional alpha2 subsensitivity causing enhanced peripheral noradrenergic activity in humans is supported by the findings of increased mean resting plasma norepinephrine and increased response to idazoxan following chronic Li+ administration. Alteration of regulatory mechanisms in the noradrenergic system may be relevant to understanding the clinical effects of Li+ in manic-depressive illness.     

Changes in carbamazepine plasma concentrations in psychiatric patients during treatment.

Plasma concentrations of carbamazepine (CBZ) were studied in 24 psychiatric patients who were given 400 mg of CBZ every 12 h. The assays were performed on the 1st, 3rd, 8th, 15th, 22th and 29th day of the therapy. The highest minimum 12h plasma CBZ concentrations occurred on the 3rd day of therapy, then decreased up to the 15th day and remained stable thereafter. The CBZ half-time values also diminished up to the 15th day of therapy and then stabilized. This may suggest that the enzymatic autoinduction of CBZ is completed within the first 1-2 weeks of therapy. CBZ plasma levels were slightly but insignificantly higher in patients taking CBZ alone than in patients in which CBZ was added to other psychotropic drugs. A significant correlation was found between the minimum CBZ plasma concentration after the first dose and that at steady state. A dosing schedule for CBZ administration has been proposed with administration of 75% of the maintenance dose during the first week and the full CBZ maintenance dose from the beginning of the second week of CBZ therapy.     

Behavior of chlorpheniramine in vivo after administration of d- and l-chlorpheniramine maleate

A high performance liquid chromatographic (HPLC) method was developed for the determination of chlorpheniramine (I) in the plasma. By this method, 1 ng of I could be measured. Plasma levels of I were determined by the HPLC method after oral administration of d-chlorpheniramine maleate (II) or l-chlorpheniramine maleate (III) to healthy subjects and dogs. Plasma levels of I brought about by oral administration of II were evidently higher than those by III both in humans and dogs. On the other hand, there was no difference in plasma levels of I when II or III was injected intravenously into dogs. Therefore, it was considered that the discrepancy in plasma levels of I after oral administration of II and III to dogs was neither due to a difference in elimination rate nor a distribution volume but rather in first-pass effect in absorption process. The result observed in the human study could be also explained in the same way as that in dogs.     

A double stopcock technique for repeated sampling of venous blood.

Repeated sampling for measurement of venous blood levels of hemoglobin, hematocrit, plasma hemoglobin, potassium and ibuprofen with a novel method of phlebotomy, the double stopcock technique (DST), was compared to heparin lock (HPL), Angiocath with obturator (AOB) and direct venipuncture (DVP) techniques. There were 12 normal subjects in this randomized, three-way crossover trial. During each portion of the crossover, simultaneous samples for hemoglobin, hematocrit, plasma hemoglobin, potassium and ibuprofen were taken from each phlebotomy site prior to and after oral dosing with 400 mg ibuprofen. The DST was the best acceptable method based on the assessment of comfort by the subjects, followed by the AOB, HPL and DVP techniques. The least amount of blood waste was with the DST. The degree of hemolysis (as shown by plasma hemoglobin and potassium) was comparable across all techniques. Across all of the techniques, measurement of hemoglobin, hematocrit and ibuprofen levels using DST, HPL and AOB yielded lower levels than DVP. These changes were small and were not clinically significant, although statistically significant in some cases. The authors conclude that when there is need for frequent, rapid and repetitive venous blood sampling with minimal blood wastage and patient discomfort, the DST should be considered.     

Mefloquine pharmacokinetics in healthy subjects and in peptic ulcer patients after cimetidine administration.

The pharmacokinetics of orally administered mefloquine were determined in six healthy male subjects and in six ulcer patients before and after a 3-day course of cimetidine (400 mg morning and evening). Peak plasma concentrations Cmax and AUC0-infinity were similarly and significantly (P < 0.05) increased after cimetidine pretreatement in both healthy subjects and peptic ulcer patients Cmax was increased by 42.4% and 20.5% while AUC0-infinity was increased by 37.5% in healthy and peptic ulcer subjects respectively. The values of t1/2ab absorption and t1/2 beta elimination, total crearance CLT/F and volume of distribution were altered to varying levels after cimetidine treatment but the changes were not statistically significant in both healthy and peptic ulcer subjects. The established long t1/2 beta and this apparent interaction between mefloquine and cimetidine which resulted in increased mefloquine plasma concentration might be of clinical significant in patients with neurological/psychiatric history.     

Comparison of intranasal administration of haloperidol with intravenous and intramuscular administration: a pilot pharmacokinetic study

STUDY OBJECTIVE: To evaluate the pharmacokinetics of haloperidol after intranasal administration compared with intravenous and intramuscular administration, and to evaluate systemic and local tolerance of intranasal administration. DESIGN: Randomized, open-label, three-way crossover study. SETTING: Academic medical center. SUBJECTS: Four healthy volunteers (two men, two women; aged 24-37 yrs). INTERVENTION: Each subject received in a randomized order the following three treatments, with a 2-week washout period between treatments: intravenous haloperidol 2.5 mg (0.5 ml of 5.0 mg/ml) infused over 15 minutes, intramuscular haloperidol 2.5 mg (0.5 ml of 5.0 mg/ml), and intranasal haloperidol 2.5 mg (2.5 mg/0.1-ml spray into a single naris). MEASUREMENTS AND MAIN RESULTS: Blood samples were obtained serially and plasma levels determined. Noncompartmental analysis was used to estimate pharmacokinetic parameters. Physical and nasal examinations and adverse-effect profiles were obtained to assess tolerance. Mean (percent coefficient of variation) haloperidol bioavailability after intranasal administration was 63.8% (24.4%) compared with intravenous administration and 48.6% (29.4%) compared with intramuscular administration. Intranasal administration achieved higher peak levels that occurred more quickly compared with intramuscular administration. Median time to maximum concentration was 15 minutes after the intranasal dose compared with 37.5 and 15 minutes after the intramuscular and intravenous doses, respectively. Subjects had mild-to-moderate systemic adverse effects, all related to an extension of haloperidol's pharmacologic actions. Two of the four subjects complained of mild-tomoderate nasal irritation after the intranasal doses. CONCLUSION: Our results suggest that additional research studies are warranted for further evaluation of intranasal administration of haloperidol. The product provides rapid therapeutic plasma levels and sedation, with only minor and short-lived nasal irritation. These data suggest that intranasal administration of haloperidol, or other antipsychotics with similar potency, could play a role in treating psychiatric emergencies.     

Comparative beta-adrenoceptor blocking effects and pharmacokinetics of penbutolol and propranolol in man.

1 The beta-adrenoceptor blocking effects of penbutolol were compared with those of propranolol and a placebo in a double-blind trial involving six healthy volunteers. 2 Heart rate (HR), systolic blood pressure (SBP) and peak expiratory flow rate (PEFR) were measured at rest and during vigorous exercise before and at intervals up to 7 h after oral administration of the drugs. In addition, plasma renin activity (PRA) at rest and plasma levels of penbutolol and propranolol were determined. 3 Penbutolol proved to be a non-cardioselective beta-adrenoceptor blocking drug, antagonizing exercise-induced tachycardia, reducing exercise-induced increase in PEFR and decreasing PRA. The beta-adrenolytic potency of penbutolol was shown to be four-fold that of propranolol but the duration of its effect was similar. 4 The peak plasma level of penbutolol was reached 1 h after administration and its half-life was 4.5 h. 5 Comparison of plasma levels and biological activity of penbutolol revealed that after oral administration this drug is transformed into an active metabolite in man.     

Vigabatrin decreases cholecystokinin-tetrapeptide (CCK-4) induced panic in healthy volunteers.

Vigabatrin increases gamma aminobutyric acid (GABA) levels by irreversible inhibition of the GABA-catabolizing enzyme GABA-transaminase (GABA-T). Preclinical studies suggest anxiolytic effects in vigabatrin treated rats. Anxiolytic effects in patients with panic disorder (PD) could therefore be expected. To evaluate putative anxiolytic properties of vigabatrin in humans, CCK-4-induced panic symptoms were studied in healthy volunteers before and after vigabatrin treatment. After placebo-controlled administration of 50 microg CCK-4, ten healthy volunteers received vigabatrin for seven days with a daily dosage of 2 g. The treatment period was followed by a second CCK-4 challenge. Panic and anxiety were assessed using the Acute Panic Inventory (API) score and a DSM-IV derived panic-symptom-scale (PSS). ACTH and cortisol plasma levels were determined during the CCK-4 challenge. All subjects reported a marked reduction of CCK-4-induced panic symptoms and anxiety after seven days of vigabatrin treatment both in the API- and PSS-scores. Moreover, there was a significant attenuation of CCK-induced elevation of ACTH and cortisol levels following vigabatrin treatment. In conclusion, our data show that GABA-transaminase inhibitors exert anxiolytic effects in CCK-4-induced panic in healthy volunteers and suggest that GABA transaminase inhibitors might be useful in ameliorating panic symptoms also in patients with PD.     

Clinical evaluation of a naltrexone sustained-release preparation

A clinical evaluation of the naltrexone bead, a biodegradable sustained-release dosage form of 3.0 mg in weight containing 70% naltrexone in a copolymer of lactic and glycolic acids, was carried out in 4 healthy normal males. Subjects were given an intravenous dose of 10 mg naltrexone and approx. 1 week later a 63-mg dose of naltrexone by subcutaneous administration of the beads. Challenge doses of 15 mg morphine were given to each subject during the study for the assessment of narcotic blockade effects of naltrexone. For a 2-4-week period after bead administration, relatively constant plasma levels were maintained at 0.30-0.46 ng/ml for naltrexone and were 0.64-1.07 ng/ml for naltrexol. Urine levels for unchanged and conjugated naltrexone were 79-215 ng/ml and for naltrexol were 315-500 ng/ml. From kinetic analysis, an average of 2.4-2.7% of implanted dose was absorbed each day from the administration of the beads. Opiate effects of morphine challenges were mitigated during the 2-4-week period after administration of naltrexone beads.     

Effects of acute and continuous pentobarbital administration on the gamma-aminobutyric acid system

Effects of acute anesthetic doses and chronic administration of pentobarbital on γ-aminobutyric acid (GABA) and glutamic acid levels in mouse brain have been investigated. Acute administration of pentobarbital caused an increase in the brain level of GABA which was associated with pentobarbital-induced narcosis. This was further substantiated by the finding that pentobarbital-induced sleeping time was prolonged when brain GABA level was elevated by the administration of either amino-oxyacetic acid (AOAA), an inhibitor of GABA-2-oxoglutarate aminotransferase (GABA-T), or glutamate, the precursor of GABA. In addition, the activity of l-glutamate-1-carboxylase (GAD) measured during pentobarbital-induced narcosis was higher than that of the control group. On the other hand, chronic administration of pentobarbital resulted in a decrease of both GABA and glutamate levels. There was a concomitant 30 per cent decrease in the activity of GAD. This was confirmed by the finding that the rate of brain GABA accumulation induced by AOAA administration in tolerant mice was slower than that of the non-tolerant animals. Brain GABA remained at significantly lower levels after an abrupt withdrawal from pentobarbital; however, brain glutamate levels showed no significant difference as compared to the control group. It appears that the GABA system in the central nervous system may be involved in barbiturate narcosis and further linked with the development of tolerance to barbiturate.