The pharmacokinetics and effects of a long-acting preparation of superoxide dismutase (PC-SOD) in man.

AIM: To study the pharmacokinetics (PK), safety and tolerability of single rising doses up to 80 mg of superoxide dismutase covalently linked to lecithin (PC-SOD) in healthy White volunteers. METHODS: This double-blind, placebo-controlled, four-period cross-over study was performed in eight healthy volunteers (four male/four female). Three doses of PC-SOD (20, 40 and 80 mg) and placebo were administered intravenously in randomized order. Serum and urinary PC-SOD concentrations were measured predose and up to 96 h after dosing. In addition to standard safety measurements, the urinary excretion of N-acetyl-beta-glucosaminidase, alpha-glutathione S-transferase (alpha-GST) and pi-GST was measured to evaluate renal function. The PK of PC-SOD was analysed using noncompartmental and compartmental methods. RESULTS: All treatments were well tolerated, and no obvious relationship between adverse events and treatment was observed. No effects of PC-SOD on renal function could be detected. Dose normalized C(max) and AUC were not different between the different dosages, indicating linearity of plasma concentrations with dose. Estimated PC-SOD clearance was 2.54 ml min(-1)[95% confidence interval (CI) 2.07, 2.83]. The terminal half-life was estimated to be 1.54 days (95% CI 0.93, 2.15). SOD activity was elevated above baseline for 19 +/- 6 h after the 80-mg dose. CONCLUSIONS: Single intravenous administrations of PC-SOD in doses up to 80 mg were well tolerated in healthy White male and female volunteers. With the doses used, SOD activity was linearly related to the dose; after the 80-mg dose it was present for an appreciable period. These findings suggest that it is worthwhile to investigate PC-SOD in clinical conditions characterized by a high radical overload.

The effect of motilin on the rectum in healthy volunteers.

AIMS: The role of motilin in the regulation of upper gastrointestinal (GI) motility is well defined. However, little is known about the effects on the distal GI tract. To investigate the effect of exogenous motilin on rectal function, barostat measurements in the rectum were performed and lower abdominal symptoms were scored. METHODS: Eight fasted, healthy volunteers were infused intravenously with synthetic motilin or placebo over 90 min in a double-blind, randomized, cross-over design. Rectum volume was measured with a barostat device during constant pressure and during isobaric distensions. Lower abdominal symptoms were scored by visual analogue scales. Plasma motilin concentrations were measured by radioimmunoassay. RESULTS: Baseline rectum volumes were similar between treatments: 185 +/- 62 mL (motilin) and 136 +/- 41 mL (placebo). During the constant pressure procedure, motilin increased rectum volume [area under the effect curve (AUEC)] by 6%[95% confidence interval (CI) -3, 16] of baseline, compared with placebo. During isobaric distensions motilin increased rectum volume (AUEC) by 43 mL (95% CI 0.4, 85; P < 0.05) and compliance by 10 mL mmHg-1 (95% CI 0.3, 20; P < 0.05) relative to placebo. Motilin did not induce changes in the sensation of rectal feelings. CONCLUSION: Exogenous motilin increased rectal compliance in healthy volunteers, without affecting rectal sensations.

Dose-related effects of motilin on proximal gastrointestinal motility.

AIM: To assess non-invasively the dose-response relations for the effects of exogenous motilin on antrum contraction frequency, gall-bladder volume and gastric myoelectrical activity. METHODS: In a double-blind, randomized, placebo-controlled, five-way crossover study, 10 fasted healthy volunteers were infused intravenously with synthetic human motilin (0.5, 1, 2 and 4 pmol x min/kg) or placebo for 60 min. Gall-bladder volume and antrum contractions were assessed by ultrasonography and gastric myoelectrical activity by electrogastrography. Motilin concentrations were measured using a radioimmunoassay. RESULTS: Baseline plasma motilin levels (60 pmol/L) were similar for all treatments. Motilin levels increased upon the start of infusion and rapidly returned to baseline after cessation of the infusion. At motilin doses of 2 and 4 pmol.min/kg, the antrum contraction frequency was significantly augmented, with maximum differences of two contractions per 2-min interval compared to placebo, while no changes in gastric myoelectrical activity were observed. Changes in gall-bladder volume were not significantly different for any of the motilin doses compared to placebo. CONCLUSIONS: Motilin increased antrum contraction frequency, whereas no effect on gastric myoelectrical activity was observed. Antrum contraction frequency appears to be a useful biomarker for motilin efficacy, and motilin doses of 2 and 4 pmol x min/kg were equally effective.

The gastrointestinal passage and release of beclomethasone dipropionate from oral delivery systems in ileostomy volunteers.

AIMS: To study the delivery of 15 mg beclomethasone 17,21-dipropionate (BDP) to the distal part of the small bowel for three oral sustained-release formulations (I-III) and a reference capsule in volunteer ileostomists, and to compare these findings with the in vitro dissolution profiles. METHODS: Two groups of nine ileostomy volunteers (aged 20-61 years), who were otherwise healthy, were enrolled in the study. The recovery of BDP and its metabolite beclomethasone 17-monopropionate (B17P) in ileostomy effluent was investigated in a cross-over study after administration of formulations I or II or a reference capsule containing micronised BDP, and in a second open study after administration of formulation III. Radio-opaque granules were coadministered for evaluation of gastrointestinal passage. Ileostomy effluents were collected hourly for 10-12 h following drug intake. After marker beads had been counted on X-rays, ileostomy collections were analysed for BDP and its metabolites. Cumulative recovery, lag-time and mean transit time were determined for drug and marker beads. RESULTS: Gastrointestinal passage characteristics were similar for all treatments. Total drug recovery was approximately three times higher for the sustained-release formulations than for the reference capsule. Recovery of B17P from stoma fluid samples was significantly lower for formulation III than for formulations I and II. CONCLUSIONS: The novel oral formulations delivered substantial amounts of steroid drug at the distal small bowel/proximal colon, which may warrant further studies to evaluate clinical applicability.

The effects of clonazepam and vigabatrin in hyperekplexia.

Hyperekplexia is an autosomal dominant disorder caused by a point mutation in the alpha1 subunit of the glycine receptor, characterized by excessive startle responses followed by temporary generalized stiffness. Clonazepam, effective in open case studies, potentiates, through unknown mechanisms, the neurotransmitter gamma-aminobutyric acid (GABA). Vigabatrin increases GABA by inhibition of the GABA catabolic enzyme GABA-transaminase. Effects of clonazepam (1 mg for 1 day) and vigabatrin (1000 mg per day for 5 days) were investigated in a double-blind placebo-controlled cross-over study in 4 patients with hyperekplexia. The pharmacodynamic parameters were startle reflexes, studied 3 times during the day. At each time, 2 trains of 10 auditive stimuli (113 dB) were given at intervals of 10 and 60 s. Startle movements were quantified with summed areas of EMG-bursts of the orbicularis oculi, sternocleidomastoid, biceps and thenar muscles. The degrees of stiffness and drowsiness were quantified with visual analogue scores (VAS) 10 times during the day, by both the patient and the observer. Clonazepam, but not vigabatrin, reduced startle activity significantly in both paradigms. The degree of stiffness and drowsiness was not significantly influenced by either drug.

Assessment of changes in liver blood flow after food intake--comparison of ICG clearance and echo-Doppler.

Echo-Doppler measurements of portal venous blood flow in intrahepatic branches and indocyanine green (ICG) clearance after continuous i.v. infusion as measure for liver blood flow were compared to evaluate the increase in splanchnic blood flow after food intake. It was shown that both methods assessed the changes in flow in a similar manner. Changes in blood flow in intrahepatic portal vein branches measured with echo-Doppler adequately predicted the change in ICG concentrations. Hence, echo-Doppler measurements of hepatic portal blood flow in intrahepatic branches can be used to estimate changes in total liver blood flow.

Specific stimulation of brain serotonin mediated neurotransmission by dexfenfluramine does not restore growth hormone responsiveness in obese women.

OBJECTIVE: Growth hormone release in response to all known stimuli of GH secretion is blunted in obese subjects. Several studies, using d,l-fenfluramine (d,l-FF) as a serotoninergic tool, suggest that brain serotonin plays a role in the pathogenesis of this phenomenon. However, the effect of d,l-FF appears to be dependent on the stimulus used to induce GH release. Furthermore, d,l-FF has catecholamingergic properties apart from its capacity to stimulate serotonin release and to block its re-uptake. In this study, we investigated whether subchronic treatment with the highly selective serotoninergic drug dexfenfluramine (d-FF) affects the GH response to galanin or GHRH in obese subjects. DESIGN: The study had a randomized, cross-over, placebo controlled design. d-FF was administered in a dose of 15 mg twice daily during 6 days. On days 5 and 6 of treatment (with either d-FF or placebo) an i.v. bolus injection of 100 micrograms hGHRH(1-44) or a continuous infusion of p-galanin (40 pmol/kg/min over 40 minutes) were administered in randomized order. All tests were performed in the follicular phase of two consecutive menstrual cycles. PATIENTS: Eight obese women (body mass index (BMI) 34.5 +/- 3.6 kg/m2); 7 normal weight (BMI 21.9 +/- 1.9 kg/m2) age-matched control women. All women had a regular menstrual cycle. None used oral contraceptive drugs. MEASUREMENTS: GH response to either stimulus was measured both during treatment with d-FF and during treatment with placebo. RESULTS: The GH response to galanin and the response to GHRH were significantly smaller in obese subjects. d-FF significantly reduced the galanin induced GH secretion in obese subjects, but not in normal weight controls. It did not significantly affect GH release in response to GHRH in either group. CONCLUSION: This study confirms that GH secretion in response to stimuli with varying mechanisms of action is blunted in obese subjects. A decrease of central serotonin mediated neurotransmission does not appear to play a role in the pathogenesis of this phenomenon.

Plasma amino acid ratios related to brain serotonin synthesis in response to food intake in bulimia nervosa.

Fifteen bulimic women (BN) and 19 healthy female controls (CO) were studied. The subjects were cross-over treated with either fluoxetine (FXT) or placebo during 4 days. They received, in randomized order, a breakfast containing pure carbohydrate (CHO) or a protein-rich (PROT) breakfast following day 3 and 4 of each treatment period. Twenty-nine different food items were offered for lunch. The fasting serum glucose and insulin concentrations and the fasting plasma tryptophan (Trp)/large neutral amino acid (LNAA) ratio were slightly higher in BN. The changes of these metabolic parameters in response to a CHO or PROT breakfast were similar in both groups. Across breakfast type, the plasma (Trp)/(LNAA) ratio at 120 min after breakfast was higher in BN. Total caloric intake at lunchtime was less in BN. In CO, less carbohydrate was selected at lunchtime following the CHO breakfast, an effect that was abolished by FXT. Breakfast type or FXT did not have any apparent effect on food intake at lunchtime in BN. This might indicate that bulimic subjects are less sensitive to serotoninergic stimuli than control subjects.

The Neurotoxicity Scale: the validity of a patient-based scale, assessing neurotoxicity.

The validity of a patient-based scale, presumably measuring adverse effects of drugs on cognitive function, was examined in a normal volunteer study. Thirty subjects were randomly assigned to placebo or one of two doses of a benzodiazepine, temazepam (10 mg and 20 mg), in a double-blind placebo-controlled parallel group design. Plasma samples were taken before the scale was completed and up to 8 hours post-dose. After administration of the medication the subjects were asked to maintain their normal daily routine as much as possible (reading, studying, conversations). The inventory was administered twice, at 50 minutes and 2 hours post-dose (peak level). The overall score was different between the three groups, only for the second assessment, 2 h post-dose (ANOVA, P < 0.02). Multiple t-testing between the three groups revealed statistically significant differences between placebo and the 10 mg temazepam group (P = 0.02) and between placebo and the 20 mg temazepam group (P = 0.006). No significant difference was found between the two temazepam groups. Analysis of the separate questions showed least sensitivity for questions related to the domain of 'hyperexcitability' and most sensitivity for 'fatigue' and 'slowing.' The overall score appeared to be sensitive already for the lower toxicity range suggesting an 'all or nothing effect'. The subjective reports, collected by using this scale, may therefore be used for the detection of gross overall changes in cognitive functioning.

Influence of 1-desamino-8-D-vasopressin on endogenous fibrinolysis, haemodynamics and liver blood flow in healthy subjects.

1. Endogenous fibrinolytic capacity increases after administration of 1-desamino-8-D-vasopressin. This increase is commonly attributed to an increase in release of tissue-type plasminogen activator from the endothelium. However, the possibility that 1-desamino-8-D-vasopressin influences liver blood flow, which is a major determinant of tissue-type plasminogen activator clearance, cannot be ruled out. 2. The influence of 1-desamino-8-D-vasopressin on haemodynamics, liver blood flow and fibrinolytic parameters was investigated in a randomized double-blind cross-over study in nine healthy male subjects (age 20-26 years). 3. 1-Desamino-8-D-vasopressin exerted significant haemodynamic effects: mean arterial pressure decreased maximally 12 (95% confidence interval 8-15) mmHg and heart rate increased maximally 21 (95%) confidence interval 15-27) beats/min. 4. Endogenous fibrinolytic parameters increased after administration of 1-desamino-8-D-vasopressin. Both tissue-type plasminogen activator antigen and tissue-type plasminogen activator activity were elevated and showed the maximal response shortly after drug administration was completed. 5. 1-Desamino-8-D-vasopressin increased portal venous blood flow as measured with echo-Doppler. The maximal increase in mean blood flow of 55 (95% confidence interval 19-92)% was observed at the end of the 1-desamino-8-D-vasopressin infusion and coincided with the maximal changes in systemic haemodynamics and fibrinolytic parameters. The increase in portal blood flow was not reflected in significant changes in Indocyanine Green clearance. It appears that the Indocyanine Green method is relatively insensitive to increases in liver blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of intravenous temazepam. II. A study of the long-term reproducibility of pharmacokinetics, pharmacodynamics, and concentration-effect parameters.

OBJECTIVE: To evaluate the long-term reproducibility of pharmacokinetic, pharmacodynamic, and concentration-effect parameters after intravenous administration of temazepam. METHODS: Nine healthy volunteers were studied. Temazepam, 0.4 mg/kg, was infused intravenously for 30 minutes on two occasions 6 months apart. Venous plasma concentrations of temazepam were measured by HPLC in samples obtained between 0 and 24 hours. Pharmacodynamic effects were evaluated up to 8 hours for saccadic peak velocity and electroencephalogram (EEG) beta amplitudes. Subjects' state and trait anxiety were assessed by use of the Spielberger anxiety inventory. RESULTS: Significant correlations between occasions were found for area under the plasma concentration-time curve (AUC) values (r = 0.91; p < 0.01) but not for maximum concentration and half-life. Significant correlations were also found for area under the effect-time curve (AUEC) values of peak velocity (r = 0.88; p < 0.01) but not for peak velocity (r = 0.48; p > 0.05). Significant differences between the slopes of concentration effect plots on different occasions were observed in two subjects for EEG beta and in three subjects for peak velocity, with one subject showing a similar change for both parameters. Trait anxiety scores were higher on the first occasion (33 +/- 7) than on the second occasion (29 +/- 7; p < 0.01). A negative correlation was found between trait anxiety scores and the slopes of concentration-effect plots for peak velocity (r = -0.63; p < 0.01). CONCLUSIONS: For AUC and AUEC values the results indicate a reasonable long-term reproducibility of differences between subjects in the pharmacokinetics and pharmacodynamics of temazepam. However, there were limitations to the predictive value of derived concentration-effect parameters.

Effects of intravenous temazepam. I. Saccadic eye movements and electroencephalogram after fast and slow infusion to pseudo steady state.

OBJECTIVE: To study the pharmacodynamic effects of intravenous temazepam after different infusion rates to pseudo steady-state concentrations. METHODS: This was a randomized, double-blind, placebo-controlled crossover study in an academic department of clinical pharmacology. Subjects were nine healthy volunteers. A computerized infusion pump was used to obtain target plasma concentrations of temazepam after 30 or 120 minutes and to maintain these levels for 2 hours. A vehicle infusion, similar to the 30-minute (fast) infusion was used as a placebo control. Infusion schedules were based on data obtained from individual subjects after infusion of 0.4 mg/kg temazepam in 30 minutes. Target plasma concentrations were chosen to induce subhypnotic effects and averaged (+/- SD) 597 +/- 123 ng/ml. Venous plasma concentrations of temazepam were measured by HPLC. Free fractions of temazepam were assessed at the start of the pseudo steady-state concentration intervals. Electroencephalogram alpha and beta amplitudes, saccadic peak velocity, and saccadic latency were used as pharmacodynamic parameters. RESULTS: The rate of change of plasma concentrations averaged 21 +/- 4 ng/ml.min-1 during fast infusion and 5 +/- 1 ng/ml.min-1 during slow infusion of temazepam. Average pseudo steady-state concentrations were 639 +/- 132 ng/ml after fast infusion and 629 +/- 133 ng/ml after slow infusion. At the onset of pseudo steady-state concentration intervals the average free fractions of temazepam were 44% (95% confidence interval, 19% to 61%) lower for slow than for fast infusions. Compared with the slow infusion, electroencephalogram beta amplitudes were significantly larger during the first 30 minutes of pseudo steady-state concentration after fast infusion of temazepam. No significant differences were found for the other parameters. There was a slight decline of temazepam effects during the pseudo steady-state concentration intervals for all parameters after the fast infusion and for saccadic peak velocity and saccadic latency after the slow infusion. CONCLUSIONS: The pharmacodynamic effects of intravenous temazepam may depend partly on the rate of administration. Differences in pharmacodynamic effects after fast and slow infusions could be caused by changes in protein binding over time.

Effect of isotretinoin on endogenous tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) in humans.

The effect of isotretinoin on fibrinolysis was investigated in 10 healthy, male volunteers in a randomized, double-blind, crossover-designed study. Isotretinoin (40 mg) was administered in the morning and in the evening for 5 days. t-PA, u-PA and PAI-1 antigen and activity in plasma were measured every morning at 9 a.m. on days 1 to 4 and every 3 hours over 24 hours on day 5. Isotretinoin treatment had no significant stimulatory effect on endogenous t-PA antigen and activity in morning plasma samples nor on their circadian variation. Also, u-PA antigen levels did not change after isotretinoin treatment. Mean PAI-1 antigen and PAI activity in 9 a.m. plasma samples were non-significantly higher during isotretinoin than during placebo treatment. After treatment with isotretinoin a significant rise of fasting triglyceride plasma levels was observed as compared to placebo. The study shows that isotretinoin has no clinically significant effect on endogenous fibrinolysis.

Evidence for brain serotonin-mediated control of carbohydrate consumption in normal weight and obese humans.

A plasma insulin and amino acid-mediated mechanism is thought to modulate brain serotonin concentration, thereby regulating carbohydrate consumption on a meal to meal basis. It has been suggested that obesity is associated with a defect in the appetite control system. Furthermore, post-absorptive plasma levels of several amino acids are increased in obese subjects, which is ascribed to obesity-associated insulin resistance and/or hyperinsulinemia. We studied breakfast-induced changes in plasma ratios of tryptophan to other large neutral amino acids and associated differences in macro-nutrient composition of lunch food in normal weight and obese human subjects. The study was randomized, double blind and cross-over with a 2 x 2 factorial design with drug/placebo and type of breakfast as factors. Nineteen healthy, non-obese (body mass index (BMI) 22.5 +/- 1.9 kg/m2, mean +/- s.d.) and 19 obese (BMI 34.7 +/- 6.2 kg/m2) female volunteers were treated with either 60 mg fluoxetine (FXT), a serotonin re-uptake blocker specifically acting in the brain, or placebo for four days with a wash-out period between treatments of four weeks. The subjects received either a carbohydrate (CHO) breakfast (80 g maltodextrin, 300 kcal) or a protein-rich (PROT) breakfast (60% milk protein and 40% CHO, 300 kcal) on two consecutive days (days 4 and 5 of each treatment period). Plasma glucose, insulin and amino acids were measured at several time points after breakfast. Three hours after breakfast, subjects were able to choose from 29 different food items. Total energy content and weight of lunch food and energy percentage of each macronutrient were calculated.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of the concentration-effect relationships of midazolam for EEG-derived parameters and saccadic peak velocity.

1. Concentration-effect relationships of midazolam were assessed in an open study in six healthy volunteers. Saccadic eye movements and EEG parameters derived by fast Fourier transform (FFT) and aperiodic analysis (AP) were used to quantify drug effects. 2. Midazolam was infused at a rate of 0.6 mg kg-1 h-1 for a maximum of 15 min. Hypnotic effects were avoided by terminating infusions when subjects could no longer perform the eye movement test properly. 3. Wake-sleep transitions could be recognized through frequent observation of eye movements. The dose needed to reach maximum conscious sedation averaged 0.10 mg kg-1, ranging from 0.06 to 0.13 mg kg-1. 4. Sigmoidal concentration-effect relationships were found for EEG beta-amplitudes in five of six subjects, with average EC50 values (+/- s.d.) of 120 +/- 54 ng ml-1 for FFT and 104 +/- 40 ng ml-1 for AP. For the 'total number of waves' in the beta frequency range (AP) an average (n = 6) EC50 of 63 +/- 37 ng ml-1 was found. Changes in EEG alpha-amplitudes were found in three subjects, resulting in an average EC50 value of 55 +/- 32 ng ml-1. 5. For saccadic peak velocity (PV) concentration-effect relationships were linear in five subjects and sigmoidal in one. The maximal measured decrease in PV averaged -44 +/- 9%. 6. The differences in concentration-effect relationships for various effect parameters call for further studies with emphasis on the external validity and reproducibility of data. In such studies the dose needed to reach wake-sleep transition may be used as a relevant clinical end-point.

Interaction study between nifedipine and recombinant tissue-type plasminogen activator in healthy subjects.

1. In a previous study it was demonstrated that a decrease in liver blood flow produced a decrease in clearance of recombinant human tissue-type plasminogen activator (rt-PA). 2. The purpose of this randomized, double-blind, placebo-controlled, three-way, cross-over investigation was to determine the effect of nifedipine (20 mg orally), a compound that increases liver blood flow, on plasma concentrations of steady state endogenous and recombinant tissue-type plasminogen activator (t-PA and rt-PA) (35 mg of rt-PA over 2 h) in nine healthy male volunteers. 3. Nifedipine increased liver blood flow by 95% (42-167%) (mean (95% confidence interval)) as assessed by indocyanine green (ICG, 0.5 mg kg-1 i.v. bolus injection) clearance. 4. Nifedipine did not influence the plasma concentrations of total rt-PA antigen and activity as evaluated by the areas under the rt-PA curves from 30 min (time at which nifedipine was ingested) to 90 min during the rt-PA infusion (P > 0.05) and by analysis of a possible treatment x time interaction (P > 0.05). In addition, the plasma concentrations of endogenous t-PA remained unchanged when nifedipine was given alone. 5. In conclusion, by using nifedipine as a model compound it was demonstrated that the combination of rt-PA and a compound which increases liver blood flow probably does not lead to substantial changes in plasma concentrations of rt-PA.

Pharmaco-dynamics of human menopausal gonadotrophin (HMG) and follicle-stimulating hormone (FSH). The importance of the FSH concentration in initiating follicular growth in polycystic ovary-like disease.

Using a randomized double-blind cross-over design, the pharmaco-dynamic and pharmaco-kinetic properties of 'pure' follicle-stimulating hormone (FSH) (Metrodin) and human menopausal gonadotrophin (HMG) (Pergonal) were studied in 24 women with polycystic ovary-like disease (PCOD) during induction of ovulation. Fifty-six cycles were stimulated with FSH and 60 cycles with HMG, according to a standard protocol. Gonadotrophins were administered i.v. in a pulsatile fashion using pulse frequencies of either 30 or 120 min. The cycles stimulated with either 30 or 120 min pulse intervals showed no differences among themselves. During the stimulation phase, the FSH and HMG stimulated cycles showed equal and dose dependent FSH concentrations (mean +/- SD). The luteinizing hormone (LH) concentrations (mean +/- SD) were also equal but unchanged compared to the mean basal concentration. The LH, FSH, total urinary oestrogen excretion, and testosterone profiles (mean +/- SD) obtained from cycle days -10 to 0 as well as the pregnanediol profiles obtained from cycle days 0 to +14 showed no differences either. The occurrence of an endogenous preovulatory LH surge was significantly more frequent in the cycles stimulated with a pulse interval of 30 min compared to the cycles stimulated with a pulse interval of 120 min. The addition of LH as provided in HMG did not influence the FSH threshold concentration above which initiation of follicular growth occurred, since no differences were found in the FSH 'stable' concentrations between FSH and HMG stimulated cycles. However, intra- and inter-individual variation in the FSH 'stable' concentration at which follicular growth was initiated became obvious.(ABSTRACT TRUNCATED AT 250 WORDS)

Cimetidine does not influence the metabolism of the H1-receptor antagonist ebastine to its active metabolite carebastine.

Ebastine is an H1-receptor antagonist with a relative lack of sedating properties. It is almost completely converted to carebastine, and it is this metabolite which is responsible for the antihistaminic effect. Twelve healthy subjects received a single 20 mg dose of ebastine on day 2 of a multiple oral dosing regimen of either cimetidine (400 mg three times daily and 800 mg in the evening on the day preceding ebastine administration and 400 mg four times daily on the 2 following days) or placebo in a randomised cross-over design. Significant plasma concentrations of ebastine were not detected after either treatment. The AUC of carebastine was not affected by cimetidine coadministration (4049 +/- 985 ng ml-1 h after cimetidine vs 3795 +/- 959 ng ml-1 h after placebo; 95% confidence interval of the difference: -412 to 919). Cimetidine coadministration did not induce any effect of ebastine on blood pressure and heart rate or cause sedation.

CNS-related performance and haemodynamics of metoprolol-Oros and propranolol after single and 3 days dosing in healthy volunteers.

1. The effects of metoprolol-Oros 14/190 once daily, propranolol 80 mg twice daily and temazepam 10 mg once daily on central nervous system (CNS) related performance and haemodynamic variables were evaluated in a double-blind, randomized, placebo controlled, crossover study in 12 healthy volunteers. Drugs were administered for 3 consecutive days except for temazepam, which was administered on days 1 and 3 only. Treatment effects were evaluated at 0, 2, 5 and 8 h on days 1 and 3. 2. Neither beta-adrenoceptor blocker had significant effects in a battery of tests after single or 3 days dosing. Temazepam caused a decrease in saccadic peak velocity of 37.4 degrees s-1 (95% CI: 6.0, 68.9) at 2 h and an increase of auditory reaction times of 11.5 ms (0.2, 22.8) at 8 h on day 1. No significant effects of temazepam were detected on day 3. 3. Both beta-adrenoceptor blockers reduced exercise heart rate. Peak effects were measured at 2 h 40 min after propranolol but not metoprolol-Oros (difference, day 1:20 (11, 29) beats min-1, day 3:13 (8, 19) beats min-1). Both beta-adrenoceptor blockers significantly reduced baseline exercise heart rate on day 3. Compared with day 1, metoprolol-Oros caused larger reductions of exercise heart rate at all times on day 3. 4. Metoprolol-Oros and propranolol caused similar reductions of systolic- and diastolic blood pressure on days 1 and 3. Temazepam caused a small reduction in diastolic blood pressure at 5 h 40 min on day 1 but was otherwise devoid of haemodynamic effects.(ABSTRACT TRUNCATED AT 250 WORDS)

The bioavailability of digoxin from three oral formulations measured by a specific h.p.l.c. assay.

1. We have studied the absolute bioavailability of three oral formulations of digoxin, 1.0 mg, in 12 young healthy volunteers in a four way randomised cross-over study using an intravenous control. 2. Digoxin tablets (250 micrograms), liquid filled digoxin capsules (100 micrograms) and an experimental enteric-coated capsule (100 micrograms) were evaluated. In vitro dissolution at pH 1 demonstrated extensive hydrolytic breakdown of digoxin from the tablets and capsules but not from the enteric-coated capsules. 3. Serum 'digoxin' concentrations were measured by fluorescence polarization immunoassay (FPI). The systemic availability (+/- s.d.) of the capsules was 70.5 +/- 11.3%, and that of the tablets 71.5 +/- 8.6%. Drug was less available from the enteric-coated capsules (62.1 +/- 10.3%) measured with FPI. These results were reflected in the urinary drug recoveries measured by FPI. 4. By contrast, there were no differences in urinary recovery of unchanged digoxin between any of the oral treatments, when this was measured by h.p.l.c. The cross-reactivity of immunoassays for metabolites of digoxin may produce artefactual results and the optimal pharmaceutical formulation for digoxin remains to be determined.