Pharmacokinetics and pharmacodynamics of cisapride in patients undergoing hemodialysis.

Twenty-two patients who were receiving hemodialysis were studied in three groups of eight subjects each to assess the pharmacokinetics during the dialysis-free interval and during hemodialysis treatment and to assess the pharmacodynamics of cisapride. Cisapride and its metabolite norcisapride were measured by use of HPLC and gas chromatography, respectively. The pharmacodynamic effect of cisapride was measured by means of radionuclide gastric emptying. After a single oral dose of 20 mg the terminal half-life of cisapride was 9.6 +/- 3.3 hours, the volume of distribution was 4.8 +/- 3.3 L/kg, the total oral plasma clearance was 380 +/- 161 ml/min, the area under the curve was 1024 +/- 447 ng.hr/ml (mean +/- SD). Norcisapride only could be detected in the dialysate (0.36 +/- 0.067 mg) and was eliminated by a hemodialysis clearance of 34.7 +/- 7.9 ml/min. Cisapride reduced gastric retention from 77.6% +/- 21.1% to 43.7% +/- 18.2% of maximum filling (40 minutes after meals) and normalized the abnormal gastric emptying time in patients receiving dialysis. Cisapride dosage adjustment or substitution after hemodialysis is not necessary.

The pharmacokinetics of metoprolol and its metabolites in dialysis patients.

The kinetics of tritiated metoprolol and its metabolites have been determined after intravenous and oral administration in dialysis patients. The kinetic behaviour of metoprolol in these patients does not differ from that in healthy volunteers, since its elimination depends on hepatic metabolism. The pharmacologically less active metabolite alpha-hydroxymetoprolol is formed to an individually varying degree and its half-life is prolonged. The concentration of the total radioactivity, which represents the sum of all metabolites, does not decline in the dialysis interval. During haemodialysis, however, its concentration decreases with a half-life of 5h. It might be assumed, that dialysis of these polar compounds is rather nonspecific and that it depends essentially on the dialysis technique.

Incidence and clinical relevance of QT prolongation caused by the new selective serotonin antagonist ketanserin.

Efficacy and safety of ketanserin were studied prospectively in a randomized, double-blind trial involving 221 patients treated for hypertension or coronary artery disease, or both. Since ketanserin has been suggested to cause QTc prolongation, the incidence and severity of this effect were investigated, as was the incidence of malignant ventricular arrhythmias during Holter monitoring. After a 1-week run-in period, all patients were examined: blood pressure was measured and electrocardiograms and 24-hour Holter electrocardiograms were obtained. Two thirds of the patients (n = 147) were then randomized to receive ketanserin for 1 week (20 mg twice daily) followed by 3 weeks of 40 mg twice daily; one third of the patients (n = 74) received placebo (twice daily) for 4 weeks. After 4 weeks of treatment, blood pressure, electrocardiograms and 24-hour Holter electrocardiograms were repeated. In hypertensive patients, ketanserin significantly reduced systolic (mean reduction 17 +/- 2 mm Hg, p less than 0.0001) and diastolic blood pressure (12 +/- 1 mm Hg, p less than 0.0001) compared to baseline, and to the placebo group (p less than 0.005 for systolic and diastolic blood pressure). The QTc interval was prolonged with ketanserin (mean 400 to 418 ms, p less than 0.01) but not with placebo (399 vs 402 ms). In the ketanserin group 30% of patients and in the placebo group 8% of patients had QTc prolongation greater than 30 ms (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma concentration, uptake by liver, and biliary excretion of tritiated cardiac glycosides in the isolated perfused guinea-pig liver.

1. Investigations were carried out on isolated perfused guinea-pig livers. Different doses of tritiated ouabain, digoxin, and digitoxin were added to the perfusion medium and the subsequent plasma elimination, hepatic uptake, and biliary excretion quantitatively measured. After the perfusion, extracts of liver, bile and plasma were subjected to thin layer chromatography in order to detect the radioactively labelled glycosides and their metabolites.2. The ouabain concentration in the plasma approached the equilibrium stage within 45 minutes. At this time 40% of the administered dose had been taken up by the liver, and no further elimination occurred. The elimination curve for ouabain followed a simple exponential function. After 1 h the tissue medium (T/M) ratio was approximately 3. In bile hardly any radioactivity could be detected. Ouabain was therefore not excreted by the liver.3. Up to 80% of the digitoxin was eliminated from the plasma within 4 hours. The elimination of radioactive material for the dose range studied could be described by a hyperbolic function. The T/M ratio in the liver varied with time. At the beginning it was as high as 10 and after 4 h reduced to approximately 3. After 45-60 min the concentration of radioactive material in the bile was 500 times as high as that in the plasma. Almost 70% of the administered radioactivity was excreted with the bile within 4 hours. At the end of the perfusion almost all the identifiable substances in plasma and bile were polar metabolites, as shown by thin layer radiochromatography.4. Digoxin behaved similarly to digitoxin.5. The findings led to the following hypothesis: uptake of cardiac glycosides into the liver cells occurs by a passive diffusion process and is related to their lipid solubility. On the other hand excretion in the bile occurs in general if polar metabolites are formed in the liver cells.

Tilidine does not affect human sphincter of Oddi motility--a randomized, controlled study.

AIM: To investigate the effects of intravenous pentazocine and tilidine on sphincter of Oddi motility. METHODS: Twenty patients with suspected sphincter of Oddi dysfunction were enrolled in a prospective, double-blind study. Sphincter of Oddi motility was assessed by means of endoscopic manometry after injection of 0.9% saline, as well as after randomized dosing with either 30 mg pentazocine i.v. (n = 10) or 50 mg tilidine i.v. (n = 10). RESULTS: Pentazocine significantly increased the sphincter of Oddi baseline pressure from 32 +/- 21 mmHg (saline) to 41 +/- 19 mmHg (P = 0.002), whereas tilidine did not alter the sphincter baseline pressure (34 +/- 15 mmHg saline vs. 36 +/- 16 mmHg tilidine, P = 0.16). Furthermore, pentazocine increased the phasic sphincter contraction amplitude (108 +/- 16 mmHg saline vs. 121 +/- 18 mmHg pentazocine, P = 0.004), but tilidine was without any effect (125 +/- 24 mmHg saline vs. 125 +/- 21 mmHg tilidine, P = 0.93). The phasic sphincter of Oddi contraction frequency and duration were not influenced either by pentazocine or by tilidine. CONCLUSION: In contrast to 30 mg of pentazocine, 50 mg of tilidine does not affect sphincter of Oddi motility. Therefore, tilidine can be used during endoscopic manometry and for analgesia in pancreatobiliary disease.

Pharmacokinetics of tilidine in terminal renal failure.

The aim of the present study was to investigate the pharmacokinetics of tilidine and its metabolites during the dialysis procedure and in the dialysis-free interval. Tilidine is a prodrug that is metabolized presystemically into the active metabolite nortilidine. Nortilidine is degraded thereafter to bisnortilidine and several polar metabolites. Nine patients with a creatinine clearance < 5 ml/min were treated in a crossover design with single oral doses of 1.5 mg/kg on the day of dialysis (dialysis performed from 3 to 6 hours after drug administration) and on a day in the dialysis-free interval. Blood samples were taken frequently and analyzed for tilidine, nortilidine, and bisnortilidine. Drug and metabolite concentrations were also measured in aliquots of dialysate collected during dialysis. Only negligible amounts of tilidine, nortilidine, and bisnortilidine (about 0.9% of the dose) were recovered from the dialysate. The pharmacokinetics of nortilidine and its inactive metabolite bisnortilidine was not affected by dialysis. The presystemic apparent clearance of the prodrug tilidine was decreased significantly during the dialysis-free interval. A significant decrease of the rate of elimination and an increase of the AUC of bisnortilidine were observed if these parameters were compared with data obtained from healthy volunteers. The plasma concentrations of nortilidine were comparable in patients and normal volunteers. Thus, a reduction of the dose of tilidine in patients with severely impaired kidney function seems not to be required. Tilidine and its metabolites cannot be removed from the body by dialysis.

Effect of concomitantly administered cimetidine or ranitidine on the pharmacokinetics of the 5-HT2-receptor antagonist ritanserin.

The effects of concurrent administration of either cimetidine 800 mg once daily or ranitidine 300 mg once daily on the single-dose pharmacokinetics of ritanserin 10 mg were investigated in an open, randomized three-way cross-over, controlled investigation in 9 healthy volunteers. Concurrent administration of cimetidine had no significant effect on the area under the plasma concentration-time curve of ritanserin compared with control experiments. The maximum plasma concentration of ritanserin was decreased significantly (105.0 +/- 9.2 versus 125.0 +/- 13.8 ng/mL; P = .0039), whereas time to reach maximal concentration (tmax) of ritanserin was only slightly but not significantly increased, if the subjects were pretreated with cimetidine. After concurrent ingestion of ranitidine, only a trend to a decrease in the maximum plasma concentration of ritanserin was observed. Time to achieve the maximum plasma concentration, terminal half-life of elimination, and the total area under the plasma concentration-time curve of ritanserin were not altered in comparison with control experiments. The results of the study show that concurrent treatment with cimetidine 800 mg once daily or ranitidine 300 mg once daily has no apparent effect on the systemically available amount of ritanserin after a single oral dose of 10 mg. Both H2-antagonists cause a significant (cimetidine) or borderline significant (ranitidine) decrease of the maximum plasma concentration of ritanserin and a slight but not significant increase in tmax (cimetidine). These effects are of minor clinical importance and seem most likely be due to a decrease of the rate of absorption of ritanserin during concurrent administration of cimetidine/ranitidine.

Drug-induced phospholipidosis. II. Alterations in the phospholipid pattern of organs from mice, rats and guinea-pigs after chronic treatment with chlorphentermine.

In three species chronic treatment with the anorectic drug chlorphentermine causes a profound alteration of the phospholipid/lipid metabolism in the organism, resulting in an increase of the fractions of phospholipids and lipids, e.g. in lungs, livers and adrenals. The results are interpreted as drug-induced generalized phospholipidosis, which is caused by amphiphilic drugs, like chlorphentermine and others. Its extent depends on several factors, like content, pattern and turnover rate of phospholipids in different organs, and on the species.

[Pharmacokinetics of gold after administration of aurokeratinate (author's transl)]. / Das pharmakokinetische Verhalten von Gold nach Gabe von Aurokeratinat.

Aurokeratinate (Auro-Detoxin) was administered intramuscularly to patients with chronic rheumatoid arthritis, using two different dosage schedules and measuring serum gold concentration. (1) Using slowly rising doses (as generally practised) the gold level gradually rose to 3.2 microgram/ml after four weeks (before the ninth injection), without reaching cumulation equilibrium. Elimination from serum occurred during this phase, with a half-life of 3-5 days. When treatment was continued at about 25 mg gold twice weekly, the cumulation equilibrium was reached with a minimal value at 3.5 microgram/ml and a maximal one of 6 microgram/ml, elimination half-life then being increased to nine days. During the subsequent maintenance treatment with 65 mg gold once a month the serum-gold concentration fell to about 1 microgram/ml, maximal values being about 6 microgram/ml, with an elimination half-life of 11 days. (2) With a constant dose of about 25 mg gold twice weekly, cumulation equilibrium was reached after two weeks (3.4 microgram/ml before the fifth injection), while on 50 mg gold every 14 days as maintenance dose the serum concentration was between 2 microgram/ml minimally and 6 microgram/ml maximally. At the modified dosage the drug was well tolerated.

[Studies on the competition of several antibiotics for binding sites to serum protein (author's transl)]. / Untersuchungen zur Konkurrenz verschiedener Antibiotika um ihre Bindungsstellen an Serumeiweissen.

Protein binding of benzylpenicillin, acidocillin, ampicillin, oxacillin, tetracycline and clindamycin was determined in vitro by equilibrium dialysis with and without combination. Concentrations of labelled drugs were measured by scintigraphy, of non-labelled drugs by agar diffusion technique using a test strain resistant against the second antibiotic of the combination. Percentage of protein binding of the different penicillins decreased somewhat in higher concentrations, whereas with tetracycline there was found a significant increase of protein binding in higher concentrations. There was no inhibition of protein binding when combining two penicillins or tetracycline with clindamycin at lower concentrations. If very high concentrations of oxacillin of flucloxacillin were used in combination with benzylpenicillin protein binding of benzylpenicillin was reduced by about 20%.

Pharmacokinetics of nortilidine and naloxone after administration of tilidine/naloxone solution or tilidine/naloxone sustained release tablets.

Valoron N is a compound which consists of the prodrug tilidine (CAS 20380-58-9), from which the active metabolite nortilidine is formed by demethylation in the liver, and the opiate antagonist naloxone (CAS 465-65-6), which prevents the abuse of the analgesic by opiate dependents. The pharmacokinetics of nortilidine and naloxone were studied in 18 male healthy subjects after oral application of tilidine/naloxone solution or tilidine/naloxone retard tablets, respectively. The following report gives the results on investigations of a) dose linearity after application of 25 mg, 50 mg and 100 mg Valoron N solution, b) dose equivalence of Valoron N solution (4 x 50 mg tilidine) and Valoron N retard tablets (2 x 100 mg tilidine) under steady state conditions, and c) the equivalence of different dose strengths of Valoron N retard tablets (50 mg, 100 mg, 200 mg tilidine/tablet). The results obtained in these studies demonstrate a dose linear kinetic for nortilidine after the application of 25 mg to 100 mg tilidine. Furthermore, there is dose equivalence between the tilidine/naloxone solution and tilidine/naloxone retard tablets, which permits the replacing of the solution with the retard tablets. Because of the equivalence of different dose strengths of Valoron N tablets, patients are able to exchange low dosed Valoron N retard tablets for higher-dosed ones (50 mg, 100 mg and 200 mg tilidine/tablet), if necessary. With their constant release of tilidine and the possibility for individual dosage, the retard tablets are efficient analgesics that improve pain therapy considerably for patients with chronic pain.

[Modification-possibility of the enterohepatic circulation of digitoxin in man]. / Uber die Beeinflussbarkeit des enterohepatischen Kreislaufs von Digitoxin beim Menschen.

Tritiated digitoxin (0.25 mg) was i.v. administered to a control group of 5 patients as well as to 5 patients with a T-tube quantitatively draining the bile fluid. During the initial 24 h after injection, 10% of the dose administered, on the second and third days 5 and 3,5%, respectively, were biliarily excreted. The amount biliarily excreted did not influence the course of the blood level as compared to the controls. Also charcoal given perorally in a sufficient amount (50 g) did not affect the blood level of radioactive digitoxin and/or its metabolites. As obtained from in vitro experiments the absorptive potency of cholestipole and cholestyramine for digitoxin and its metabolites in human bile fluid is similar to that of charcoal.

[Chloroquine keratopathy as an example of drug-induced phospholipidosis (contribution to the pathogenesis of cornea verticillata) (author's transl)]. / Die Chloroquinkeratopathie als Beispiel einer arzneimittelinduzierten Phospholipidosis (Zugleich ein Beitrag zur Pathogenese der Cornea verticillata)

Chronic treatment with certain drugs induces morphological alterations in the eye which are histologically and electron microscopically identical with those found in hereditary lipidoses (cornea verticillata, e.g. in M. Fabry). Hereditary storage diseases are the consequence of enzyme defects, the mechanism underlying the side effect of certain drugs, however, is quite different. "Amphiphilic" drugs from completely different pharmacological groups, like chloroquine, amiodarone, chlorpromazine form complexes with cellular phospholipids which cannot be metabolised by lysosomal phospholipases. Thus in all tissues with high phospholipid content or turnover typical intracellular deposites with lamellary or crystalloid structure may occur (myelin figures). Such deposites were observed in different parts of the eye and are known e.g. from the cornea as "cornea verticillata".

On the role of serotonin in the pathogenesis of pulmonary hypertension induced by anorectic drugs; an experimental study in the isolated perfused rat lung, II. Fenfluramine, mazindol, mefenorex, phentermine and R 800.

1. The influence of the anorectic drugs fenfluramine, mazindol, mefenorex, phentermine and R 800, an experimental compound, on pulmonary vascular resistance has been studied in the isolated, perfused rat lung. 2. R 800 caused a strong vasoconstriction, which was not antagonized by methysergide of phentolamine; the other drugs listed did not alter vascular resistance. 3. Mazindol and phentermine significantly prolonged the vasoconstrictive effect of serotonin due to inhibition of its metabolic breakdown. 4. Although fenfluramine inhibited serotonin metabolism it also prevented the vasoconstrictive effect of serotonin, due to its ability to act as a serotonin antagonist. 5. Mefenorex did not affect pulmonary vascular resistance, either directly or indirectly via a serotoninergic mechanism.