Plasma levels of thioridazine and metabolites are influenced by the debrisoquin hydroxylation phenotype.

The pharmacokinetics of thioridazine and its metabolites were studied in 19 healthy male subjects: 6 slow and 13 rapid hydroxylators of debrisoquin. The subjects received a single 25 mg oral dose of thioridazine, and blood samples were collected during 48 hours. Concentrations of thioridazine and metabolites in serum were measured by HPLC. Slow hydroxylators of debrisoquin obtained higher serum levels of thioridazine with a 2.4-fold higher Cmax and a 4.5-fold larger AUC(0-infinity) associated with a twofold longer half-life compared with that of rapid hydroxylators. The side-chain sulphoxide (mesoridazine) and sulphone (sulphoridazine), which are active metabolites, appeared more slowly in serum and had lower Cmax values, but comparable AUC. The thioridazine ring-sulphoxide attained higher Cmax and 3.3-fold higher AUC in slow hydroxylators than in rapid hydroxylators of debrisoquin. Thus the formation of mesoridazine from thioridazine and the 4-hydroxylation of debrisoquin seem to be catalyzed by the same enzyme, whereas the formation of thioridazine ring-sulphoxide is probably formed mainly by another enzyme.

Neuroendocrine responses to single oral doses of remoxipride and sulpiride in healthy female and male volunteers.

Six female and six male healthy volunteers received 100 mg remoxipride, 200 mg sulpiride and placebo as single oral doses in a double blind trial with a randomized crossover design. The main objective was to compare the effect of the two drugs on serum prolactin levels, but effects on other hormones were also investigated. Remoxipride and sulpiride increased the serum levels of prolactin to similar peak levels. This effect was larger in female than in male subjects. Sulpiride increased prolactin levels at much lower plasma concentrations than remoxipride, and sulpiride's effect on prolactin lasted for considerably longer than remoxipride's. No consistent effects on serum levels of LH, FSH, GH, oestradiol, progesterone, testosterone or cortisol could be detected after remoxipride and sulpiride compared to placebo. No drug-related effects on plasma homovanillic acid (HVA) were found.

Pharmacokinetics of remoxipride controlled release and immediate release capsules in schizophrenic patients.

Single dose and steady-state pharmacokinetics of remoxipride, a new antipsychotic drug, were compared after administration of a controlled release capsule (CR) and an immediate release capsule (IR), both 200 mg and administered b.i.d. Thirteen patients with chronic schizophrenia entered the double-blind 6-week crossover study. Seven were evaluable for investigation of steady-state pharmacokinetics. Fluctuations in plasma remoxipride concentrations decreased considerably after remoxipride CR compared with the IR formulation. The plasma peak concentrations were significantly decreased and the trough values were increased after the CR formulation, although the average concentrations at steady-state were similar. The two formulations were bioequivalent regarding the amount of remoxipride absorbed after repeated dosing. Five out of 13 patients withdrew prematurely from the study because of ineffectiveness or refusal of treatment. Both formulations were well tolerated.

Steady-state pharmacokinetics of controlled release and immediate release formulations of remoxipride in patients with chronic schizophrenia.

Twenty-four stable, chronic schizophrenic inpatients were entered in a double-blind crossover study designed to compare single dose and steady state pharmacokinetic profiles of an immediate release formulation (IR) 200 mg BID and a controlled release formulation (CR) of remoxipride 400 mg once daily. The rate of absorption of remoxipride CR was significantly lower than the IR formulation and tmax was prolonged from 1.3 to 7.9 h after a single dose and from 2.2 to 6.0 h after repeated dosing. Although the single dose of remoxipride CR was twice as large as the single dose of the IR, the Cmax was similar for both formulations after a single dose. However, the Cmax at steady state was slightly lower for CR. There was significantly less fluctuation in plasma concentrations at steady state with the CR formulation, although the average plasma concentration of remoxipride IR and CR was similar. The mean relative bioavailability with regard to the amount of remoxipride absorbed after remoxipride CR 400 mg once daily compared to IR 200 mg BID was 97%. It was concluded that the CR formulation is suitable for a once-daily administration from a pharmacokinetic point of view.

Pharmacokinetics of remoxipride in elderly psychotic patients.

The pharmacokinetics of remoxipride when given as single doses of 50 mg and repeated doses of 50 mg, 100 mg, and 200 mg twice daily to 10 elderly psychotic patients (71-89 years) were compared with the findings of two other studies to reveal any age-related differences. The three studies comprised a total of 38 patients in three distinct age groups: elderly (71-89 years), middle-aged (46-69 years) and young (19-36 years). AUC, Cmax and Cmin of both total and unbound remoxipride increased with increasing age. The unbound fraction was similar in the three age groups. The half-life was prolonged in the elderly, most probably caused by a decrease in intrinsic clearance. A two-fold increase in AUC of both total and unbound concentrations was observed in the elderly group compared to the young, suggesting that patients over 70 years in general require half the dose needed by young adult patients. In general, the pharmacokinetics of remoxipride in the elderly are linear.

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.

Pharmacokinetics of an oral controlled release formulation of remoxipride: a double-blind, crossover comparison with conventional formulation in chronic schizophrenics.

Twenty-four stable, chronic schizophrenic inpatients were entered in a double-blind, crossover study designed to compare single-dose and steady-state pharmacokinetics of remoxipride immediate release (IR) 200 mg twice daily and controlled release (CR) 400 mg once daily. The CR formulation showed a significantly delayed absorption of remoxipride from the gastrointestinal tract. At steady state there was significantly less fluctuation in plasma concentrations. The other pharmacokinetic variables studied showed no difference. The mean relative bioavailability with regard to the amount of remoxipride absorbed after administration in CR form as compared with the IR form was 97%. Both formulations were well tolerated and there was no difference in either the incidence or the severity of adverse events. It was concluded that, from a pharmacokinetic point of view, the CR formulation of remoxipride was suitable for a once daily dosage schedule.

Pharmacokinetics of foscarnet and distribution to cerebrospinal fluid after intravenous infusion in patients with human immunodeficiency virus infection.

To investigate the pharmacokinetics and effects of intravenous foscarnet, 13 relatively healthy male patients with human immunodeficiency virus infection and a mean CD4+ lymphocyte value of 0.45 x 10(-9) cells per liter were given a continuous intravenous infusion of foscarnet (0.14 to 0.19 mg/kg per min) for 8 to 21 days. Blood and urine samples were taken during and after drug administration to monitor foscarnet concentrations. Lumbar puncture was performed during the infusion in five patients. The concentrations in plasma showed large variations both within and between patients. The disposition of foscarnet could be explained by a triexponential equation (t1/2 lambda 1, 0.40 to 2.52 h; t1/2 lambda 2, 3.20 to 16.7 h; t1/2 lambda 3, 36 to 196 h). Renal clearance accounted for most of the plasma clearance, the difference probably reflecting the passage of foscarnet into bone. Up to 20% of the cumulative dose may have been deposited in bone 7 days postinfusion. Foscarnet was distributed to the cerebrospinal fluid in a concentration varying from 13 to 68% of the simultaneous concentration in plasma. Polyuria and polydipsia were recorded in all patients. There appears to be an association between the degree of malaise, including symptoms such as nausea, vomiting, fatigue, and headache, and concentrations in plasma above 350 mumol/liter.

Clinical evaluation of rectally administered ampicillin in acute otitis media.

An ampicillin suppository was compared with amoxycillin suspension in the treatment of acute otitis media in children. Both antibiotics were given three times daily for 5 days in a daily dose of 25-50 mg/kg body weight. Safety was evaluated in 454 patients in the group given suppository and in 229 given the suspension, and 421 and 229 patients, respectively, were evaluable for efficacy. Ampicillin was rapidly absorbed and produced plasma concentrations well above the minimum inhibitory concentration for common respiratory pathogens. The overall clinical outcome was satisfactory (cured plus improved) in 89% of the patients given the suppository and in 86% given the suspension. Gastro-intestinal disturbances occurred in 28.4% of the patients given the suppository compared with 14.4% of those given the suspension. Perianal irritation was recorded in 12.1% of the patients given the suppository and in 5.2% of those given the suspension. Treatment was interrupted in 9.8% of patients given the suppository and in 0.9% of those given the suspension. In spite of these discomforts rectally administered ampicillin is considered to be a good alternative in children when oral medication is not feasible.

Impact of cefixime on the normal intestinal microflora.

The ecological effects on the normal intestinal microflora after cefixime tablets in doses of 200 mg twice daily for 7 days were studied in 10 healthy volunteers. Stool specimens were collected before and 2, 4, 7, 14 and 21 days after start of treatment. Plasma samples were collected during 12 h after the first dose on day 1 and 1 sample was taken on day 7 for bioassay of cefixime concentration. Peak plasma concentration of cefixime occurred after about 4 h with a mean of 3.0 mg/l. The mean AUC0----oc after a single dose was estimated at 21.9 mg x h/l and the mean elimination half-life was 3.9 h. The mean plasma concentration of cefixime 3 h after the morning dose on day 7 was 2.0 mg/l. The concentrations of cefixime in faeces increased during treatment. One subject had detectable concentrations in faeces on day 2, three subjects on day 4 and 8 subjects on day 7 in the order of 237-912 mg/kg faeces. There was a marked decrease in the numbers of streptococci and Escherichia coli and an increase in the numbers of enterococci during the administration of cefixime. In the anaerobic microflora, the numbers of cocci, clostridia and bacteroides were suppressed while there were minor changes in the numbers of bifidobacteria. Clostridium difficile was isolated in 5 subjects on day 7 but cytotoxin was only detected in one subject. The intestinal microflora was normalized within 2 weeks after treatment had stopped. Slightly soft stools were reported by 7 subjects. One subject had abdominal pain and diarrhoea 1 week after treatment followed by anal irritation and itching.(ABSTRACT TRUNCATED AT 250 WORDS)

A micromethod for determination of antimicrobial agents in bone.

A microtechnique, requiring very small amounts of tissue material, was developed for assay of antimicrobial agents in bone. Without previous homogenization or extraction, small bone pieces (mean weight 0.014 g) from human subjects and pigs were placed into wells in agar plates preinoculated with the test strain. Round and distinct zones of inhibition were formed around the pieces. Standards for ampicillin and flucloxacillin were prepared from freeze-dried bone pieces from human subjects and pigs with known amounts of antibiotics as well as in human plasma and phosphate-buffered saline (PBS). Curves obtained from these standards were linear. Bone pieces from human and pig maxilla gave superimposable curves, but differed from curves obtained in plasma or PBS. The method was used in a pharmacokinetic study of bacampicillin in human maxillary bone and plasma. Bacampicillin tablets (2 X 400 mg) were given to patients before oral surgery. Standardized bone pieces and plasma samples were obtained at different times during surgery. The peak ampicillin concentrations estimated from the population curves were 8.0 mg/l in plasma and 1.1 mg/l in maxillary bone. The elimination half-life of ampicillin was similar in plasma and maxillary bone.