A comparison of the neuro-endocrinological and temperature effects of DU 29894, flesinoxan, sulpiride and haloperidol in normal volunteers.

1. Nineteen healthy male volunteers participated in a double-blind, six-way, crossover study. With a separation of 1 week between sessions, volunteers received randomly one oral dose of each of the following compounds: 3 or 10 mg of the dopamine (DA2) receptor antagonist and serotonin (5HT1A) agonist DU 29894, 1 mg flesinoxan, 400 mg sulpiride, 3 mg haloperidol or placebo. 2. To assess the dopamine (DA2) antagonistic activity of the different compounds, plasma levels of prolactin were assessed at pre-dose, 0.5, 1, 2, 3, 4, 6 and 24 h post-dose. To assess the serotonin (5HT1A) agonistic activity, plasma levels of ACTH, cortisol and growth hormone were assessed at the same time-points as well as body temperature; the latter was also assessed 8 h post-dose. Plasma levels of DU 29894 were assessed at pre-dose and 2, 3, 4 and 24 h post-dose. 3. Sulpiride, haloperidol and both doses of 3 mg and 10 mg DU 29894 produced statistically significant increases in prolactin levels. The increase produced by 3 mg was roughly equivalent to that produced by 3 mg haloperidol whereas the increase produced by 10 mg DU 29894 was significantly larger. 4. Only 10 mg DU 29894 and 1 mg flesinoxan produced statistically significant increases in ACTH, cortisol and growth hormone. All compounds either showed a significant attenuation of the normal day time increase of body temperature (3 mg DU 29894, haloperidol and sulpiride) or a true significant decrease in body temperature (10 mg DU 29894 and flesinoxan).(ABSTRACT TRUNCATED AT 250 WORDS)

Eltoprazine in aggressive mentally handicapped patients: a double-blind, placebo- and baseline-controlled multi-centre study. The Eltoprazine Aggression Research Group.

The efficacy of eltoprazine, a mixed 5-HT1 agonist, in treating aggressive behaviour in mentally handicapped patients was evaluated in a double-blind, placebo- and baseline-controlled study. In the total sample of 160 patients who entered the 8 week double-blind treatment phase, efficacy was not demonstrated. Also in a 28 week double-blind follow-up study, efficacy could not be demonstrated. Post-hoc exploratory analyses suggested eltoprazine was significantly better than placebo in reducing aggression scores of a subgroup of severely aggressive patients. There was no evident relationship between the plasma level of eltoprazine and therapeutic effect or safety and tolerance. The overall safety and tolerance of chronic eltoprazine treatment was good. In the discussion, several issues and pitfalls of aggression research are dealt with.

Pharmacokinetics of fluvoxamine maleate after increasing single oral doses in healthy subjects.

The pharmacokinetics of fluvoxamine after single oral administration of 25, 50, and 100 mg fluvoxamine maleate was studied in a three-way cross-over study in 12 healthy male subjects. Fluvoxamine was administered orally in a solution. For dose-proportionality, AUC, and Cmax-dose relationships were evaluated by linear regression. Plasma concentrations increased in a linear dose-dependent manner in the dose range between 25 and 100 mg; t1/2 and Tmax showed no significant differences among treatments. Fluvoxamine was well tolerated.

Pharmacokinetics of fluvoxamine maleate in patients with liver cirrhosis after single-dose oral administration.

The pharmacokinetics of fluvoxamine maleate were investigated in 13 patients with biopsy-proven liver cirrhosis. They received a single oral 100mg dose as an enteric-coated tablet, and plasma samples were collected up to 168h after administration. Geometric mean values for peak plasma concentrations and area under the plasma concentration-time curves (AUC) were 39 micrograms/L and 1338 micrograms.h/L, respectively. Mean (+/- SD) elimination half-life (t1/2) was 25 +/- 11h, and increased with higher plasma bilirubin levels, although no relationship between bilirubin and AUC was observed. AUC was about 50% higher in patients than in healthy volunteers from another similar study. This was mainly because of a longer t1/2. Although there is a great overlap between AUC values of fluvoxamine in patients and healthy volunteers, it is nevertheless concluded that in patients with signs of active liver disease, e.g. raised bilirubin, it is wise to lower the initial daily dose and to carefully monitor the patient during subsequent upward dose adjustments.

Single and multiple oral dose fluvoxamine kinetics in young and elderly subjects.

The pharmacokinetics of fluvoxamine maleate was studied in two separate studies in healthy young and elderly subjects. In a single and multiple oral dose administration study, six healthy young subjects received an initial 50 mg oral dose followed by 50 mg tablets every 12 h for 28 days. In a second study, 13 elderly subjects received 50 mg tablets every 12 h for 28 days. Fluvoxamine peak plasma concentrations were reached in approximately 5-6 h following oral administration of single and multiple 50 mg doses to healthy young and elderly volunteers. The area under the curve (AUC) of fluvoxamine tended to be larger following multiple (873 ng.h/ml) as compared to single-dose administration (652 ng.h/ml). Also the terminal half-life after chronic dosing (22 +/- 6 h) tended to be longer than after single dosing. Steady-state plasma levels were obtained within 10 days' administration. The pharmacokinetics of fluvoxamine in elderly healthy subjects were no different from those recorded in young subjects. These results suggest that it is not necessary to adjust the dosage of fluvoxamine in elderly depressed patients, on the basis of pharmacokinetic arguments. Independent of the age group, approximately 3% of a dose was recovered as unchanged drug in the urine.

Decarboxylation of L-dopa in the rat isolated vascularly perfused small intestine: contribution to systemic elimination and dose-dependent first pass effect.

The contribution of the rat small intestine to systemic and presystemic elimination of L-dopa was studied. When L-dopa was administered into the vascular perfusate, a systemic extraction ratio of 0.38 was found, the major part being decarboxylated to dopamine. The intestinal L-dopa clearance was estimated to be 17.1 mL min-1 kg-1. Thus, L-dopa intestinal clearance in rat represents up to at least 20% of the total body clearance. After luminal administration of L-dopa 83-88% of the administered dose was absorbed within 60 min. The total amount of L-dopa appearing in the vascular perfusate increased more than proportionally to the increase in the dose. In contrast, the amount of dopamine increased less than proportionally to the dose. As a result, the intestinal first pass appeared to be strongly dose-dependent. Since the total percentage absorbed from the lumen was independent of the administered dose and the total amount that appeared in the vascular perfusate increased linearly with the dose, the dose dependency was probably due to saturation of intestinal L-dopa decarboxylation.

Dose-proportionality of eltoprazine. Pharmacokinetics of single oral doses in healthy subjects.

Eltoprazine. HCl belongs to a new class of psychotropic drug, the serenics. The dose-proportionality and pharmacokinetics of eltoprazine HCl has been investigated after single oral doses of 5, 10, 20 mg (18 subjects) and 30 mg (12 subjects) in a partly randomized, cross-over design. Eltoprazine was well tolerated and there were no relevant changes in safety parameters. All subjects showed irregular plasma-concentration-time profiles, some subjects demonstrating secondary peaks. The mean half-life was calculated to be about 6.5 h. The renal excretion of eltoprazine was characterized by net tubular secretion. AUC, peak plasma concentrations and the amount excreted unchanged in the urine were linearly related to the dose. Renal clearance and t1/2 were independent of dose. Thus, eltoprazine HCl was well tolerated orally and exhibited a linear pharmacokinetic profile.

Kinetics of idaverine in healthy male subjects after single dose oral and intravenous administration.

The kinetics of idaverine was studied in an open, cross-over, partially randomized design after single oral (2 mg) and intravenous (1 and 2 mg doses to 12 healthy male subjects. In the first session, the volunteers were administered 1 mg idaverine by constant intravenous infusion during 45 min. The treatments in the second and third sessions were given according to a cross-over design, randomized in blocks of six for each session (2 mg either orally or by intravenous infusion during 45 min). The washout period between the sessions was at least 1 week. Plasma, urine and faeces were analysed for idaverine and its pharmacologically active metabolite N-desmethylidaverine by gas chromatography with nitrogen flame ionisation detection. After intravenous administration, the MRT was on average 2 hours and the mean CLS was about 900 ml.min-1. CLR is about twice the glomerular filtration rate, suggesting net tubular secretion of idaverine. The AUC and the cumulative urinary and faecal excretion values gave no indication of dose-disproportionality within the range of 1 and 2 mg administered intravenously. Maximum plasma levels of 1-3 ng.ml-1 were reached between 0.5 hours and 3 hours after oral dosing. The MRT was 4.4 hours. Systemic availability was about 29%. N-desmethylidaverine was barely detectable in plasma after all doses. Idaverine was well tolerated, only a small increase in heart rate was observed.

Hepatic, intestinal and renal transport of 1-naphthol-beta-D-glucuronide in mutant rats with hereditary-conjugated hyperbilirubinemia.

Recently, a mutant rat strain was described with a genetic defect for the biliary excretion of organic anions (TR-rats). To determine the possible heterogeneity of the transport systems in liver, intestine and kidney we investigated the transport of the anion 1-naphthol-beta-D-glucuronide (1-NG) in isolated vascularly perfused organ preparations of the rat liver, intestine and kidney of both Wistar rats and TR- rats. 1-NG was administered as such (liver and kidney experiments) or formed intracellularly from 1-naphthol (1-N) (liver and gut experiments). Independent of the type of exposure to 1-NG, the biliary excretion was considerably impaired in TR- rats. In the intestine the total appearance and the vascular/luminal distribution pattern of 1-NG were not significantly different from the values in control rats. Furthermore, no significant disturbance was found with respect to the renal clearance of 1-NG in the TR- rat when compared with the Wistar rat. Thus, the genetic defect in the TR- rat is restricted to an impaired hepatobiliary excretion of 1-NG and does not affect the excretory systems of the intestine and kidney. These results suggest that the excretion of 1-NG by the liver, intestine and kidney involves distinct organ-specific transport systems.

Absorption and presystemic glucuronidation of 1-naphthol in the vasculary fluorocarbon emulsion perfused rat small intestine: the influence of the luminal flow rate and intraluminal binding.

Using an isolated vasculary perfused rat small intestine we studied the role of luminal flow rate and intraluminal binding on the absorption of 1-naphthol (1-N) and the intestinal metabolism of 1-N to 1-naphthol-beta-D-glucuronide (1-NG). Raising the luminal perfusion rate resulted in a decrease in the luminal 1-N extraction ratio and an increase in the luminal 1-N clearance Cllum. The dependency of Cllum on flow rate appeared to conform to a convective diffusion model. A differential susceptibility of 1-N absorption and the total 1-NG appearance to the luminal flow rate resulted in a flow-dependent first-pass effect of 1-N. Next, the effect of intraluminal binding on 1-N disposition was studied in experiments in which albumin was added to the luminal perfusion fluid. The unbound concentration, as the driving force for the uptake of 1-N, seems not to be rate-limiting for the appearance of 1-NG. The total appearance of 1-NG in the presence of albumin was greater than would be anticipated from the free concentration of 1-N. As a result the extent of presystemic extraction increased with increasing albumin concentration. The precise mechanisms responsible for the phenomenona are not entirely clear. Consideration of the heterogeneity in the glucuronidation capacity along the rat small intestine and along the crypt-villus axis can help to explain the obtained results.

Systemic intestinal metabolism of 1-naphthol. A study in the isolated vascularly perfused rat small intestine.

Using a vascularly and luminally perfused rat small intestine, we studied the systemic intestinal metabolism of the model substrate 1-naphthol (1-N) to 1-naphthol-beta-D-glucuronide (1-NG). An intestinal extraction ratio of 0.30 +/- 0.02 was found for 1-N. This implies that intestinal metabolism represents up to 14% of the total plasma clearance of 1-N in the rat in vivo. The formed 1-NG was preferentially released into the vascular perfusate, suggesting specialized transport carriers for 1-NG in brushborder and basolateral membrane. When the vascular flow rate was decreased from 10 to 0.5 ml/min, the clearance of 1-N appeared to be completely flow dependent. The apparent conflict between a low extraction ratio (0.30 +/- 0.02 at all flows investigated) and a flow rate-limited 1-N clearance can be explained by the presence of an intestinal vascular bed with a high extraction ratio. We suggest that 1-N is completely extracted from the mucosal blood flow. This view was confirmed by the results of experiments in which the capillary flow of the intestinal mucosa was decreased by infusion of noradrenaline. As a result a temporary decrease in the 1-N extraction ratio was observed. The contribution of the intestine to the total clearance can be masked by the hepatic clearance, because the blood supply to the intestine and liver is coupled in series. An equation was derived to describe the relative contribution of the intestine to the mesenteric clearance of the intestine-liver system. It appears that the effective contribution of the intestine to the mesenteric clearance is of little interest for high extraction drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption and presystemic glucuronidation of 1-naphthol in the vascularly fluorocarbon emulsion perfused rat small intestine. The influence of 1-naphthol concentration, perfusate flow and noradrenaline.

Using the isolated vascularly fluorocarbon emulsion perfused rat small intestine some factors which determine the extent of the intestinal glucuronidation of 1-naphthol to 1-naphthol-beta-D-glucuronide were studied. Increasing the luminal 1-naphthol concentration resulted in a concomitant increase in the 1-naphthol appearance in the vascular perfusate. In contrast, the total appearance of 1-naphthol-beta-D-glucuronide increased less than proportional to the increase in the luminal 1-naphthol concentration. About 88% of the total amount of 1-naphthol-beta-D-glucuronide excreted was released into the vascular perfusate. The capacity-limited intestinal glucuronide efflux is most likely due to saturation of the excretory mechanism for 1-naphthol-beta-D-glucuronide. Decreasing the vascular flow rate influenced both the appearance of 1-naphthol and 1-naphthol-beta-D-glucuronide in the vascular perfusate, whereas the appearance of 1-naphthol-beta-D-glucuronide in the luminal perfusate was essentially flow-independent. A noradrenaline-induced change in the haemodynamic state of the vascular bed (with the total flow kept constant) resulted in a marked decrease in the naphthol vascular concentration. The vascular 1-naphthol-beta-D-glucuronide concentration was only slightly affected. These results indicate that changes in blood flow and blood flow distribution within the intestinal wall can affect the extent of presystemic intestinal metabolism by interfering with the absorption of the parent compound and the efflux of formed conjugates. These parameters can be of paramount importance for causing variable intestinal first-pass effects of drugs in vivo.

Pharmacokinetic modelling of the effect of activated charcoal on the intestinal secretion of theophylline, using the isolated vascularly perfused rat small intestine.

The effect of activated charcoal administration on the secretion of theophylline from the blood into the intestinal lumen has been examined by use of the rat isolated vascularly perfused small intestine. A closed two compartment model was used to analyse the vascular and luminal concentration-time curves obtained. An equation was derived to calculate the time-dependent intestinal clearance. From control experiments it was concluded that theophylline is secreted by a diffusional transport system through the intestinal wall. The intestinal clearance declined rapidly with time as a result of the concomitant increase in luminal theophylline concentration. After 120 min a steady state between the vascular and luminal perfusate was established. Administration of activated charcoal in the lumen had a profound effect on the kinetics of the drug. The vascular steady state concentration was depressed dramatically. The theophylline clearance remained nearly constant with time, because the blood to lumen concentration gradient was maximized. The maximal value for the intestinal theophylline clearance was estimated to be 0.88 mL min-1 and it equalled the value for the intestinal blood flow at the absorptive site. By use of the concept of absorptive site blood flow, the maximal effect of charcoal on systemic theophylline clearance could be adequately predicted for rats, dogs and man. Activated charcoal administration is only useful to enhance the systemic clearance of drugs or toxicants if that clearance is of the same order of magnitude as the absorptive site blood flow or lower.

A ready-to-use activated charcoal mixture. Adsorption studies in vitro and in dogs: its influence on the intestinal secretion of theophylline in a rat model.

A practical, ready-to-use preparation of activated charcoal (AZU mixture) for application in toxicology has been formulated. To establish its efficacy, the formulation was tested in vitro and in dogs. The in vitro adsorption capacity was compared to that of freshly prepared charcoal suspension in water (CW) and to Carbomix. Langmuir adsorption coefficients demonstrated small but clinically insignificant differences in adsorption capacity between the preparations. The laxative sodium sulfate did not reduce the adsorption capacity of charcoal in vitro. Dogs were given 60 mg of paracetamol per kg as an oral solution followed by 5 g of activated charcoal preparation. The area under the plasma concentration versus time curve (control 2955 +/- 353 mg.min-1.l-1) was significantly reduced following CW (921 +/- 453) and AZU (786 +/- 270). The premixed AZU charcoal formulation is efficacious, inexpensive and overcomes the problems of bed-side preparation. An isolated vascularly perfused rat small intestine can be used to describe the effect of activated charcoal on the intestinal secretion of theophylline.

Maculopapular rash due to coumarin derivatives.

The case history is presented of a patient who developed a maculopapular rash following treatment with 3 different coumarin derivatives. Apparently cross-sensitivity between coumarin derivatives may occur.

Allergic contact dermatitis due to rubber chemicals in haemodialysis equipment.

6 of 80 haemodialysed patients developed a sub-acute eczematous dermatitis of the area surrounding the arteriovenous shunt in the forearm. Patch tests were positive to rubber chemicals: 6 patients reacted to the thiuram group, 4 of them also to carba compounds. Since the equipment contained only small pieces of rubber, the cause of the allergy remains obscure. It is possible that allergy was caused by short and intermittent contact of the skin with the rubber gloves used by the nursing personnel.

Secretion of the organic anion harmol sulfate from liver into blood. Evidence for a carrier-mediated mechanism.

In the liver, drugs with phenolic groups can be converted to sulfate or glucuronide conjugates and are then transported into bile or back into the bloodstream. The mechanism for transport of drugs and drug conjugates from the hepatocytes into the blood at the sinusoidal side of the cell are not well defined. In the case of carrier-mediated transport of these strongly polar conjugates, saturability of transport and mutual competition between structurally related compounds would be anticipated. This competitive aspect was investigated by using two organic anions, dibromosulfophthalein (DBSP) and harmol sulfate. The latter compound was generated by the hepatocytes from harmol, which was continuously infused into the rat in vivo and in isolated perfused rat livers. In addition we loaded the perfused rat livers with preformed harmol sulfate and studied its efflux rate to the perfusate as influenced by DBSP. In steady state, about 80% of harmol was sulfated and 20% was glucuronidated. Harmol sulfate was mainly excreted in the urine, the glucuronide was equally excreted in urine and bile. DBSP lowered the urinary excretion of harmol sulfate by about 30% which was due to a decrease in plasma concentration. However, renal clearance of harmol sulfate (3.2 +/- 0.2 ml/min) was unchanged. At the same time DBSP doubled the biliary clearance of harmol sulfate (1.0 +/- 0.1 and 2.2 +/- 0.2 ml/min in controls and DBSP studies respectively). DBSP decreased glucuronide excretion both in urine and bile. The increase in biliary output and decrease in urinary excretion of harmol sulfate is explained by competitive interaction between the organic anion DBSP and harmol sulfate at the sinusoidal level. Efflux experiments in single pass perfused isolated livers showed a clear decrease of harmol sulfate transport from liver into plasma by DBSP and provided evidence for such an inhibitory phenomenon (t 1/2 of efflux was 3.58 +/- 0.21 compared with 2.46 +/- 0.07 min for controls). These results indicate that organic anion transport from the hepatocyte into the blood stream is very likely carrier-mediated. A decrease in renal output of drug conjugates therefore may not only be due to a decrease in the conjugation process but also to a lower liver to blood transport rate which at the same time may produce a higher biliary output.