Phenytoin and carbamazepine decreased oral bioavailability of praziquantel.

Antiepileptic drugs, especially carbamazepine and phenytoin, are potent liver enzyme inducers. Since praziquantel, the drug used to treat neurocysticercosis, undergoes extensive liver first-pass metabolism, we carried out a prospective study to verify whether there was a decrease in oral bioavailability induced by carbamazepine and phenytoin. Carbamazepine and phenytoin significantly decreased concentrations of praziquantel, due to increased clearance secondary to induction of first pass-liver metabolism. The magnitude of the decrease is surprisingly high and may be responsible for failures of treatment.

Haemodynamic profile of the potassium channel activator EMD 52692 in anaesthetized pigs.

1. The systemic and regional haemodynamic effects of the potassium channel activator EMD 52692 or its solvent were investigated after intravenous and after intracoronary administration in anaesthetized pigs. 2. Consecutive intravenous 10 min infusions of EMD 52692 (0.15, 0.30, 0.60, 1.20 micrograms kg-1 min-1; n = 7) dose-dependently decreased mean arterial blood pressure by up to 50%. This was entirely due to peripheral vasodilatation, since cardiac output did not change. Heart rate increased by up to 50%, while left ventricular end diastolic pressure decreased dose-dependently from 6 +/- 1 mmHg to 3 +/- 1 mmHg (P less than 0.05), and stroke volume decreased from 30 +/- 2 ml to 21 +/- 2 ml (P less than 0.05). Left ventricular dP/dtmax was not affected. 3. Although cardiac output did not change, EMD 52692 caused a redistribution of blood flow from the arteriovenous anastomoses to the capillary channels. Blood flow to the adrenals, small intestine, stomach, bladder, spleen and brain increased, while renal blood flow decreased and blood flow to several muscle groups and skin were not altered. Vascular conductance was increased dose-dependently in all organs, except for the kidneys, where after the initial increase, vascular conductance returned to baseline with the highest dose. Particularly striking were the effects on the vasculature of the brain. With the highest dose of EMD 52692 blood flow more than doubled, while vascular conductance increased four fold. 4. Transmural myocardial blood flow increased slightly, which was entirely due to an increase in subepicardial blood flow. Myocardial O2-consumption and segment length shortening were not significantly affected. 5. After consecutive 10 min intracoronary infusions (0.0095, 0.019, 0.0375 and 0.075 microgram kg-1 min-1; n = 7) into the left anterior descending coronary artery (LADCA), mean arterial blood pressure was maintained with the lowest two doses, but decreased by up to 15% with the higher doses, whereas heart rate increased by up to 24%. Blood flow to the LADCA-perfused myocardium doubled with the highest dose, the subepicardium benefitting the most. Coronary venous O2-saturation increased dose-dependently from 23 +/- 2% to 60 +/- 4%, while myocardial O2-consumption of the LADCA-perfused myocardium was not affected by the drug. 6. It is concluded that EMD 52692 is a potent vasodilator, with particularly pronounced effects on vasculature of the brain. Its selectivity for vascular smooth muscle cells exceeds that for the myocytes, since with doses that are much higher than those of potential clinical interest no negative inotropic effects were observed. The compound primarily dilates arteries but some venodilatation may also occur.

Inhibitory effects of cimetidine ketoconazole and miconazole on the metabolism of praziquantel.

In order to find ways to increase the usually very low bioavailability of praziquantel, the effect of cytochrome P-450 inhibitors on the metabolism of praziquantel was investigated in rats. Cimetidine, ketoconazole, and miconazole yielded a 90% inhibition of the metabolism of praziquantel in liver microsome preparations from phenobarbital-pretreated rats at concentrations of 2.0, 0.03, and 0.01 mM, respectively. In rats in vivo ketoconazole and miconazole increased the bioavailability of praziquantel by a factor of 2 and 4, respectively in doses of 25 mg/kg. In phenytoin-pretreated rats ketoconazole increased the bioavailability of praziquantel by a factor of 1.4, whereas miconazole yielded a 5-fold increase of the bioavailability. Cimetidine was an effective inhibitor at a dose of 200 mg/kg. These results suggest that the inhibitors tested may suppress the metabolism of praziquantel in humans and consequently increase the bioavailability and blood levels at doses common in human therapy.

Penetration of praziquantel into cerebrospinal fluid and cysticerci in human cysticercosis.

Two patients with cysticercosis received praziquantel (PZQ) 75 mg/kg/day orally together with 30 mg prednisone daily for 3 weeks. The first patient presented with grand-mal seizures, a pyramidal tract syndrome and subcutaneous cysticerci, and the other had internal hydrocephalus necessitating drainage. Serial plasma samples were taken after the first dose of PZQ. Lumbar CSF was obtained from the first patient and ventricular CSF from the second. Subcutaneous cysticerci were removed from the first patient. PZQ in the specimens was assayed by GLC. For distribution between plasma and CSF a rate constant of 4.9 h-1 for free PZQ, corresponding to a t1/2 of 8 min or less for the non-protein bound fraction was calculated for Patient 1. In the second patient the distribution was so rapid that the rate constant could not be calculated. The difference in distribution rate might have been due to use of different sampling times or to a time lag in the entry of PZQ between the ventricles and the lumbar sac. The rate constant for distribution of the drug between plasma and parasites was 1.4 h-1, corresponding to a t1/2 of 30 min or less. Thus PZQ penetrates rapidly into the CSF. It enters the parasite more slowly, although still more rapidly than the plasma half-life of PZQ (1-1 1/2 h).

Mechanism of the plasma cholesterol lowering effect of tazasubrate in rats: accelerated plasma cholesterol transport with increased liver lipoprotein receptor activity.

Tazasubrate (30 mg/kg/day) a new lipid lowering agent, chemically unrelated to fibrates, reduces plasma cholesterol in rats within 2-3 days to 50% of controls. During the early rapid decrease of plasma cholesterol, increased liver cholesterol concentrations are observed. These return to normal, once the new steady state of plasma cholesterol (at 50% of controls) has been reached. Radiotracer studies with 3H-cholesterol labelled plasma very low density lipoproteins are consistent with an accelerated plasma cholesterol turnover. Analysis of the binding to liver membranes of 125I labelled cholesterol rich very low density lipoproteins (beta-VLDL) shows a marked increase in the total binding (Bmax rising from 106 ng/mg of protein 378 ng/mg), without significant alterations in the receptor affinity.

Pharmacological profile of tazasubrate, a new cholesterol-lowering agent.

The properties of tazasubrate (2-phenyl-2-[(6-ethoxy-2-benzothiazolyl)thio]propionic acid), a potent hypocholesterolemic agent, were studied in rats. Tazasubrate was found to be a reliable and highly effective hypocholesterolemic agent. There was a marked and reproducible reduction of serum cholesterol in various rat models differing in age, sex and diet, an improvement of the pathological lipoprotein pattern, slight but variable effects on serum triglycerides and phospholipids, no accumulation of intermediates of cholesterol biosynthesis, no inhibition of phospholipid metabolism (i.e. no induction of phospholipidosis), no interaction with the thyroid gland, and in contrast to fibrates, only minimal induction of peroxisomes in hepatocytes.

Praziquantel in the cerebrospinal fluid in neurocysticercosis.

In 10 patients with neurocysticercosis (NC), an assessment was made of the praziquantel (PZQ) concentration in the cerebrospinal fluid (CSF), in non-deproteinized serum and in protein-free serum: before administration of the drug and the 1st., 7th. and 21st. days of oral administration (50mg/kg/day during 21 days). Samples of CSF and blood were collected three hours after the last administration of the daily total dosage, on the 1st. and 21st. days; and from 2 to 6 hours after drug administration on the 7th. day. The total daily dosage was distributed into three equal parts of 1/3 each, with a 4 hours' interval between intakes, except in the last 5 cases, who on the 21st. day only were given the total daily dosage on a single administration. Results have shown dispersion in serum concentrations, which are similar to those seen in normal subjects as recorded in literature. There is a correlation between PZQ levels in the CSF and in the serum, the latter being very close to those found in protein-free serum fraction. The statistical treatment of results allowed the following considerations: PZQ concentrations in the CSF and in the protein free serum are in balance from the pharmacodynamic standpoint on the first day; this balance is maintained up to the 21st. day although at different levels from those seen on the 7th. day; on the 21st. day PZQ contents in CSF goes back to its similar values as recorded on the 1st. day, and this suggests that the participation of drug interaction factors has been reduced to non-significant levels. However, several factors can influence PZQ concentration in CSF, as absorption rate, liver first-pass effect and blood-brain barrier changes, and individual dose should be established for each patient based on drug concentration monitoring in the serum and/or in the CSF.

Treatment with praziquantel in a patient with schistosomiasis and chronic renal failure.

The pharmacokinetics of praziquantel in a uraemic patient, infected with Schistosoma haematobium, undergoing haemodialysis, was studied by repeated analyses of serum, urine and dialysis fluid. The results indicate the possibility of treating advanced cases of infection with S. haematobium with the normally recommended doses.

[Thin layer and high pressure liquid chromatography investigations with cefaclor in urine and serum (author's transl)]. / Dünnschicht- und Hochdruck-Flüssigkeitschromatographie mit Cefaclor in Urin und Serum.

After oral administration of 500 mg cefaclor, antibacterially active metabolites could not be detected in human urine using thin layer chromatography followed by bioautography. Degradation products of cefaclor could also not be detected in the serum of human volunteers (n = 10) using high pressure liquid chromatography with a reversed phase system. Cefaclor was eluated as a single and homogenous peak with a retention period of 2.9 min. High pressure liquid chromatography for the measurement of cefaclor serum levels and a technique for preparation of serum samples are described. After administration of 500 mg cefaclor to volunteers (n = 10), the average peak serum concentration of 9.8 mg/l, determined by high pressure liquid chromatography, was observed after one hour. Four hours later the serum level was 0.3 mg/l. Using microbiological methods no statistically significant difference was obtained in comparison with the chromatography results. Some of the sera stored at -75 degrees C for four weeks showed a substantial loss of activity of cefaclor.

Quantitative determination of praziquantel in body fluids by gas liquid chromatography.

Praziquantel was determined in body fluids by gas liquid chromatography as follows: A known amount of an internal standard and 0.1 N sodium hydroxide solution was added to the sample to be analyzed. After extraction with methyl acetate/diisopropyl ether = 30/70, the organic extract was evaporated, the residue taken up in methylacetate and an aliquot injected for glc analysis. Separation was accomplished on a OV3 silicon oil phase, and for detection and quantitation, a thermoionic FID sensitized for nitrogen-containing compounds was used. The determination limit in serum is about 0.01 micrograms/ml. The relative standard deviation for serum concentrations of 0.1 micrograms/ml was found to be 4.5%.

Clinical pharmacology in normal volunteers of praziquantel, a new drug against schistosomes and cestodes. An example of a complex study covering both tolerance and pharmacokinetics.

The tolerance of Praziquantel (2-cyclohexylcarbonyl-1, 3, 4, 6, 7, 11b-hexahydro-2H-pyrazino-[2, 1-a]isoquinoline-4-one) in oral doses of 1 X 20 mg/kg, 1 X 50 mg/kg, 3 X 10 mg/kg and 3 X 25 mg/kg body weight (tau = 4 h) was tested in a complex study involving 36 healthy volunteers. In addition to the usual assessment of clinical chemistry, haematology, coagulation physiology, urinalysis, clinico-physiological examination including EEG, and medical examination, clinico-psychological parameters were also recorded and special neurological investigations were performed. No clinically relevant changes were found in any of the laboratory parameters, nor in the medical-neurological or clinico-physiological examinations. Based on a few clinico-psychological parameters and subjective comments, the largest daily dose tested (3 X 25 mg/kg = 75 mg/kg) produced a slight, transient disturbance in general well-being, which was barely detectable on objective clinical examination. The pharmacokinetic behaviour was dominated by rapid metabolism and pronounced first-pass metabolism of praziquantel, which greatly limits the value of results obtained by GC analysis of unchanged drug in serum. The peak concentration in serum was reached after 1--2 h, and the elimination half-life for the period 2--8 h was 1--1.5 h.

[Pharmacokinetics of pramiverine in rats, dogs, and monkeys (author's transl)]. / Pharmakokinetik von Pramiverin bei Ratten, Hunden and Rhesus-Affen

The pharmacokinetic properties of 4,4-diphenyl-N-isopropyl-cyclohexylamine-hydrochloride (pramiverine, Sistalgin) in Wistar rats, beagles, and rhesus monkeys are described. After i.v. injection of 14C-labelled pramiverine incorporation of radioactivity from the blood into organs and tissues is rapid. The radioactivity is eliminated from the blood with a half-life of 4-7 h in rats, 17-32 in dogs, and 8-26 h in rhesus monkeys. Unmetabolized pramiverine, in contrast, is eliminated much faster, the half-lives are 2 h in dogs and 3 h in rhesus monkeys. After oral administration maximum serum concentrations are reached after 4 h in rats and dogs and 2 h in rhesus monkeys. The drug undergoes a marked first-pass effect in the liver. In all species pramiverine is absorbed rapidly from the gastro-intestinal tract. Drug and/or metabolites are eliminated in rats and dogs predominantly with feces, in monkeys with urine, independent of the route of administration. During a 6 h interval, biliary elimination was found to be 50% after i.v. and 30% after oral administration. 90% of pramiverine present in the blood plasma is reversibly bound to proteins.

[Metabolism of pramiverine (author's transl)]. / Metabolismus von Pramiverin

The metabolite patterns of 4,4-diphenyl-N-isopropyl-cyclohexylamine-hydrochloride (pramiverine, Sistalgin) in urine, feces, bile and serum of Wistar rats, beagle dogs, rhesus monkey and man were analyzed with radio thin-layer chromatographic techniques. The structures of six pramiverine metabolites were elucidated. Pramiverine is eliminated unchanged in only minute amounts via the renal, the biliary and the fecal route. Consequently an almost quantitative absorption and metabolism takes place. Metabolite patterns in serum and urine differ considerably indicating that some of the metabolites are excreted preferentially by the kidney while others are reabsorbed to various degrees. The identified metabolites are products of dealkylation, deamination and hydroxylation reactions.

[Gaschromatographic determination of pramiverine in body fluids (author's transl)]. / Gaschromatographische Bestimmung von Pramiverin in Körperflüssigkeiten

A method for the quantitative determination of 4,4-diphenyl-N-isopropyl-cyclohexylamine-hydrochloride (pramiverine, Sistalgin) in serum and urine was developed. After the addition of a known amount of a pramiverine homolog as an internal standard the basic pramiverine and standard are separated from acidic and neutral constituents of the sample by the following extraction sequence: Extraction from the alkalized sample into n-hexane/ethyl acetate; reextraction into 0.1 N hydrochloric acid; alkalisation of the hydrochloric acid phase and reextraction into n-hexane/ethyl acetate. The constituents of this final extract are concentrated and separated on an OV 17 silicon oil phase. A thermoionic nitrogen-selective flame ionisation detector was used. The determination limit for 5-ml serum samples is about 0.5-1 ng pramiverine/ml. For samples in the concentration range of 4 ng/ml a relative standard deviation of 12% was found.