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Biomedical subjects

J Heykants

Publications and source records attributed to J Heykants.

At least 37 records · Page 2Linked to original sources
PubMed1992

Stimulation by risperidone of rat prolactin secretion in vivo and in cultured pituitary cells in vitro.

Risperidone, a new antipsychotic agent which antagonizes both 5-hydroxytryptamine-2 (5-HT2) and dopamine-2 (D2) receptors, was evaluated for its effects on prolactin release. One hr after either p.o. or i.p. dosing, risperidone was 3 to 5 times more potent than the classical D2 receptor antagonist haloperidol in stimulating rat prolactin levels in vivo. This result was unexpected because haloperidol is a more potent D2 receptor antagonist than risperidone in vitro. Mechanisms which might explain these observations were investigated. Compared to haloperidol, risperidone was 0.34 (95% confidence interval: 0.23, 0.48) times as potent in reversing the suppression by dopamine of rat anterior pituitary cell prolactin release in vitro, which is consistent with the compounds' striatal D2 receptor binding potencies in vitro. Administration of ketanserin, a 5-HT2 receptor antagonist, along with haloperidol did not modify haloperidol's activity on either in vitro pituitary cell prolactin release (up to 1000 nM ketanserin) or in vivo prolactin concentrations (5 mg/kg ketanserin, i.p.). In vitro incubation of haloperidol and risperidone with a liver homogenate supernatant (S-9) led to extensive (greater than 86%) metabolism of each compound. S-9 treatment abolished haloperidol's effects on pituitary cell prolactin release. Risperidone's ability to increase prolactin release was unchanged after S-9 treatment, and 9-hydroxy-risperidone, identified as a major metabolite in the S-9 conditioned media, was equipotent to risperidone in modulating prolactin release in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Pharmacokinetics of ritanserin in patients undergoing hemodialysis.

The pharmacokinetics of ritanserin were studied in five patients with chronic renal insufficiency and who were undergoing periodic hemodialysis. Immediately after breakfast, a single 10-mg ritanserin tablet was administered to each patient on a day that they did not undergo dialysis. Plasma ritanserin levels were measured by a specific high-performance liquid chromatographic assay sensitive to 2 ng/mL plasma. After the oral 10-mg dose, the average time to reach the peak plasma concentration, Tmax, was 4.4 +/- 2.2 hours in these uremic patients, with a range of 2 to 8 hours. The average peak plasma concentration was 73.6 +/- 26.9 ng/mL (range: 54.6-120.0 ng/mL). Compared with a previous study in healthy volunteers, the uremic patients had a slower absorption profile, with a 39% reduction in peak plasma concentration and mean delay of 2.5 hours in Tmax. The mean area under the plasma concentration-time curve for ritanserin (2031 +/- 636 ng.hr/mL) was 47% lower compared with that in healthy volunteers (3867 +/- 1413 ng.hr/mL). The observed delayed and lower ritanserin absorption in these uremic patients may be caused by the chronic use of antacids such as aluminum hydroxide and calcium carbonate in all patients and/or by concurrent pathologic changes in the gastrointestinal mucosa of these patients. The regular hemodialysis sessions every 2-3 days did not affect the elimination rate of ritanserin, as the terminal half-life in these patients (39 +/- 23 hr) is similar to that in healthy volunteers (41 +/- 14 hr).

Administration, Oral↗
PubMed1991

Clinical pharmacokinetics of ketanserin.

Ketanserin is a serotonin S2-receptor antagonist introduced for the treatment of arterial hypertension and vasospastic disorders. Plasma concentrations of ketanserin (and some metabolites) can be measured with high performance liquid chromatography using ultraviolet or fluorescence detection, or by radioimmunoassay. The methods are sensitive, accurate and specific. Following oral administration ketanserin is almost completely (more than 98%) and rapidly absorbed and peak concentrations in plasma are reached within 0.5 to 2 hours. It is subject to considerable extraction and metabolism in the liver (first-pass effect) and the absolute bioavailability is around 50%. The compound is extensively distributed to tissues and the volume of distribution is in the order of 3 to 6 L/kg. In plasma ketanserin binds avidly to plasma proteins, mainly albumin, and the free fraction is around 5%. Ketanserin is extensively metabolised and less than 2% is excreted as the parent compound. The major metabolic pathway is by ketone reduction leading to formation of ketanserin-ol which is mainly excreted in the urine. Ketanserin-ol, which by itself does not contribute to the overall pharmacological effect, is partly reoxidised into ketanserin, and it is likely that the terminal half-life of the parent compound is related to the slow ketanserin regeneration from the metabolite. Following intravenous administration plasma ketanserin concentrations decay triexponentially with sequential half-lives of 0.13, 2 and 14.3 h. The terminal half-life is similar after oral administration. Following long term oral dosing (20 or 40 mg twice daily) the pharmacokinetics remain linear and steady-state concentrations, which can be predicted from single-dose kinetics, are reached within 4 days. During long term treatment with the common dosage of 40 mg twice daily, steady-state concentrations fluctuate between 40 micrograms/L (trough) and 100 to 140 micrograms/L (peak). The pharmacokinetic properties of ketanserin are predictable in a wide group of patients and there is no influence from the duration of treatment, age and sex of the patient or concomitant treatment with beta-blockers or diuretics. There is no direct relationship between plasma concentrations of ketanserin and the antihypertensive effect in a group of patients. Side effects, including prolongation of the Q-T interval, are dose-dependent and, at least in the individual patient, related to peak plasma concentrations. In separate studies the pharmacokinetics of ketanserin were investigated in special patient groups, namely the elderly and patients with hepatic and renal insufficiency.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1990

Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives.

In the search for compounds active against human immunodeficiency virus (HIV), we have found that members of a novel series of tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepine-2(1H)-one and -thione (TIBO) derivatives inhibit the replication of HIV-1, the main aetiological agent of AIDS, but not of HIV-2, or of any other DNA or RNA viruses. In five cell systems, HIV-1 is inhibited by TIBO derivatives in nanomolar amounts, which are 10(4)-10(5) times lower than the cytotoxic concentration. The unprecedented specificity of these compounds may be due to an interaction with a reverse transcriptase-associated process. By contrast, AZT (3'-azido-2',3'-dideoxythymidine), which is used for the treatment of AIDS, and DDC (2',3'-dideoxycytidine) and DDI (2',3'-dideoxyinosine), whose clinical application is being assessed, inhibit both HIV-1 and HIV-2 at concentrations that, depending on the cell systems, are 2 to 4 orders of magnitude below their cytotoxic concentration. TIBO-derivatives are new chemicals unrelated to any other antiviral agents. We believe that they are the most specific and potent inhibitors of HIV-1 replication studied so far.

Animals↗
PubMed1990

Comparative bioavailability of a cisapride suppository and tablet formulation in healthy volunteers.

The comparative bioavailability of cisapride as a 30 mg suppository and three 5 mg oral tablets was investigated in 12 non-smoking, healthy male volunteers. The two formulations were administered on two separate occasions following an overnight fast, according to a randomized cross-over design. The plasma concentration of cisapride was measured over 48 h after drug administration. The 30 mg suppository exhibited a mean time to the peak plasma concentration of 3.8 h, while the tablets showed a significantly earlier peak time of 1.5 h. The maximum plasma concentration of cisapride after the 30 mg suppository (50.3 ng.ml-1) was significantly lower than after the tablets (74.3 ng.ml-1). The AUCs following the two treatments did not differ significantly from each other. The comparative bioavailability of the 30 mg cisapride suppository in relation to the three 5 mg oral tablets was 85%, with a 95%-confidence interval of 67% to 102% (not adjusted for dose). Normalizing the mean AUC by dose, the relative bioavailability of the suppository was 43% of that of the tablet. The elimination half-life of cisapride was not significantly different following the administration of the two formulations (9.3 h for the suppository and 9.8 h for the tablet).

Adult↗
PubMed1990

Levels of itraconazole in skin blister fluid after a single oral dose and during repetitive administration.

Oral itraconazole is effective in the treatment of mycoses. To measure its concentrations in the tissue, levels of total and non-protein-bound itraconazole were determined in serum, suction-induced blister fluid, and cantharides-induced blister fluid. Six healthy subjects received 200 mg as a single dose, followed by 100 mg/day for 10 days. Itraconazole binding in suction-induced blister fluid (99.54%) and cantharides-induced blister fluid (99.77%) was calculated from plasma protein binding (99.8%). The single-dose study showed the drug levels in blister fluid to increase more slowly than those in serum. The terminal half-life of itraconazole in serum was 22.5 +/- 3.2 hours. Suction- and cantharides-induced blister fluid levels declined in parallel. After the final dose, itraconazole penetration into cantharides-induced blister fluid was only 70%. Moreover, trough levels of unbound itraconazole in suction- and cantharides-induced blister fluid were 0.239 +/- 0.115 and 0.334 +/- 0.101 ng/ml and thus were significantly lower than free itraconazole levels in serum (0.422 +/- 0.125 ng/ml). Thus a distribution equilibrium between serum and blister fluids was not obtained. Free drug concentrations in suction- and cantharides-induced blister fluid were far lower than the minimal inhibitory concentration values for Candida ssp. and dermatophytes.

Administration, Oral↗
PubMed1990

Alfentanil pharmacokinetics in preterm infants.

The pharmacokinetics of alfentanil were studied during the first four days after birth in 22 ventilated preterm infants who were all receiving muscle relaxants. Five minutes after a single dose of 20 micrograms/kg alfentanil median serum concentration was 66 ng/ml (range: 20-606). The median clearance was 0.87 ml/kg/min (range: 0.4-9.62) and median elimination half life 321 mins (64-1251). There were wide differences in the manner in which individual infants handled the drug and transient depression of blood pressure and heart rate was observed. These data were used to calculate an infusion dosage. In four infants 20 micrograms/kg alfentanil given by infusion over 30 minutes followed by 5 micrograms/kg/hour produced steady state median alfentanil concentrations of 54.5 ng/ml (range: 7-73 ng/ml) with no evidence of drug accumulation.

Alfentanil↗
PubMed1990

Pharmacokinetics of oral antifungals and their clinical implications.

Orally active antifungals have different physicochemical and pharmacokinetic properties. Itraconazole is a broad-spectrum triazole antifungal with pronounced lipophilicity. This property determines to a large extent the pharmacokinetics of itraconazole and differentiates it from the hydrophilic bistriazole antifungal, fluconazole. The pharmacokinetics of itraconazole in man are characterised by good oral absorption (when taken with a meal), an extensive tissue distribution with tissue concentrations many times higher than in plasma, a relatively long elimination half-life of about one day, and biotransformation into a large number of metabolites. Distribution studies have shown that therapeutically active levels of intraconazole are maintained much longer in some infected tissues than in plasma. For instance, active levels persist for four days in the vaginal epithelium after a one-day treatment and for four weeks in the stratum corneum of the skin after treatment has been stopped. These unique distribution characteristics may explain why itraconazole with relatively low plasma concentrations (but with high tissue concentrations) is as effective as fluconazole. Fluconazole interacts with cytochrome P450-dependent enzyme activities in hepatic microsomes of rats and mice. These effects in rodents are seen at plasma and liver concentrations of fluconazole comparable to those obtained in man at therapeutic dose levels. Unlike fluconazole, itraconazole does not interfere with mammalian drug-metabolising enzymes, minimising the risk of interaction with concomitantly administered drugs. These pharmacokinetic properties may contribute to the high efficacy and safety of itraconazole in patients with various mycotic infections.

Absorption↗
PubMed1989

Deuterated ritanserin analysis by gas chromatography/mass spectrometry: a sensitive technique to study human ritanserin pharmacokinetics.

Ritanserin, a new selective serotonin-S2 antagonist, was labelled in one 4-fluorophenyl moiety to obtain a (2H4)-labelled analogue having the following isotopic distribution: 2H0: 0.0%, 2H1: 0.1%, 2H2: 1.9%, 2H3: 5.8%, 2H4: 92.2%. (2H0/2H4) Ritanserin and the internal standard were isolated from the plasma by liquid/liquid extraction and analysed by selected-ion monitoring gas chromatography/mass spectrometry in the 70 eV electron impact mode. A detection limit of 0.1 ng ml-1 could be obtained for both (2H0) and (2H4)ritanserin. The precision (per cent coefficient of variation) and accuracy (per cent relative error) of the method were 4.1% and 4.1%, respectively. The method was used to determine the plasma levels of ritanserin and tetradeuterated ritanserin in three healthy male subjects receiving an equimolar mixture of 5:5 mg (2H0/2H4)ritanserin. The pharmacokinetics of both isotopomers proved to be identical, indicating the absence of an isotope effect, so that this technique might be very promising for use in bioequivalence studies.

Gas Chromatography-Mass Spectrometry↗
PubMed1989

The effects of food and dose on the oral systemic availability of itraconazole in healthy subjects.

We have studied the influence of food and dose (50, 100, 200 mg) on the oral systemic availability of the broad spectrum antifungal itraconazole and the pharmacokinetics after repeated dosing of 100 mg in six healthy volunteers. The relative systemic availability of itraconazole capsules compared with solution averaged 39.8% in the fasting state but 102% in the post-prandial state. Food did not significantly affect the tmax of the capsules. Itraconazole AUC at single doses of 50, 100, and 200 mg had a ratio of 0.3:1:2.7, and the steady-state AUC (0-24) after 15 days of 100 mg was five times the single-dose AUC. These findings suggest non-linear itraconazole pharmacokinetics in the range of therapeutically used doses. Furthermore, capsules should be given shortly after a meal to ensure optimal oral systemic availability.

Administration, Oral↗
PubMed1989

On the terrestrial toxicity of the fungicide imazalil (enilconazole) to the earthworm species Eisenia foetida.

The toxicity of imazalil (enilconazole), of its sulfate salt, and of a principal environmental transformation product to the earthworm species Eisenia foetida was determined. The 48-hr contact test and the 14-day artificial soil test as described by OECD guideline 207 were carried out. Concentrations of the parent substance in earthworm tissues at the end of the exposure in soil were determined by gas chromatography. The LC50 of imazalil was 12.8 micrograms/cm2 in the contact test and 541 micrograms/g in the artificial soil test. The LC50 values of the sulfate salt were 11.6 micrograms/cm2 and 532 micrograms/g, respectively. The transformation product had a LC50 of 108 micrograms/cm2 in the contact test, and the survival in the soil test exceeded 90%, even at levels of 1000 micrograms/g. Tissue levels of imazalil in surviving worms were always lower than the concentrations in corresponding soil. The LC50 values largely exceeded the levels expected after normal use. Therefore, the fungicide is not considered to be harmful to earthworms in the soil environment.

Animals↗
PubMed1989

Pharmacokinetics of alfentanil during and after a fixed rate infusion.

Twenty-nine patients (age range 14-81 yr) undergoing orthopaedic surgery received alfentanil 100 micrograms kg-1 given as two i.v. boluses followed by a fixed rate infusion of 1 micrograms kg-1 min-1 for 44-445 min. Additional 1-mg bolus doses of alfentanil were administered as required. Plasma samples were assayed for alfentanil using radioimmunoassay. Pharmacokinetic parameters were estimated by a model-independent approach and by curve-fitting. Regression analysis showed no statistical relationship between T 1/2 beta, Cl or Vd and the duration of the infusion, total dose or body weight. We found no significant correlation between age and T 1/2 beta of alfentanil for patients younger than 40 yr. For patients older than 40 yr, T 1/2 beta increased linearly with age. There was no significant decrease in Cl with age, although the lower values for Cl (100-200 ml min-1) were generally found in subjects older than 60 yr. The present study demonstrated that a 100-micrograms kg-1 loading dose and a 1-micrograms kg-1 min-1 infusion may be appropriate for analgesia in general surgical procedures.

Adolescent↗
PubMed1989

Skin blister fluid levels of ketoconazole during repetitive administration in healthy man.

Ketoconazole administered orally is used in the treatment of superficial and deep mycoses. To evaluate its active concentrations in skin tissue, serum, suction blister fluid (SBF), and cantharides blister fluid (CBF) levels of total and non-protein bound ketoconazole were determined. In general, only the free drug is considered to be the active one. Six healthy subjects received 200 mg once daily for 5 days. Total ketoconazole concentrations were determined by HPLC. The unbound fractions of ketoconazole in SBF (2.3%) and CBF (1.2%) were calculated from plasma protein binding (99.0%). Before the ultimate dose, levels of unbound ketoconazole in SBF and CBF were 0.64 +/- 0.16 and 0.70 +/- 0.25 ng/ml and were thus in accordance with free ketoconazole serum levels (0.52 +/- 0.24 ng/ml; p greater than 0.05). Furthermore, following the ultimate dose, the areas under the blister fluid level-time curves of unbound ketoconazole did not differ from the respective areas under the serum level time curves, thus distribution equilibrium between serum and skin blister fluid was obtained. Peak concentrations of free ketoconazole were (SBF) 8.6 +/- 2.9 ng/ml and (CBF) 8.9 +/- 2.3 ng/ml. Free concentrations in SBF and CBF were far below the MIC values for dermatophytes and Candida ssp. reported in the literature, leaving the concentration-effect relationship of ketoconazole still open for discussion.

Adult↗
PubMed1989

The clinical pharmacokinetics of itraconazole: an overview.

Itraconazole (R 51211) is the prototype of a class of triazole antifungals characterized by a high lipophilicity. This property determines to a large extent the pharmacokinetics of itraconazole and differentiates it from the hydrophilic triazole antifungal fluconazole. The pharmacokinetics of itraconazole in man are characterized by a good oral absorption, an extensive tissue distribution with tissue concentrations many times higher than in plasma, a relatively long elimination half-life of about one day and a biotransformation into a large number of metabolites. One of them, hydroxy-itraconazole, is antifungally active and explains why antifungal plasma levels, when measured by bioassay, are about three times the itraconazole levels measured by a specific HPLC-method. Distribution studies have shown that therapeutically active levels of itraconazole are maintained much longer in some infected tissues than in plasma. For instance, active levels persist for four days in the vaginal epithelium after a one-day treatment and for 3 weeks in the stratum corneum of the skin after treatment has been stopped. Unlike fluconazole, itraconazole does not interfere with mammalian drug metabolizing enzymes, minimizing the risk of interaction with concomitantly administered drugs. These pharmacokinetic properties may contribute to the high efficacy and safety of itraconazole in patients with various mycotic infections. New pharmaceutical formulations are being explored in order to broaden the application field of itraconazole to intravenous and oral therapy of patients with malabsorption.

Absorption↗
PubMed1988

Pharmacokinetic profile of orally administered itraconazole in human skin.

Itraconazole is an orally effective antifungal agent with a high affinity for tissues. The skin kinetics in human volunteers have been studied after administration of 100 and 200 mg of itraconazole daily. From day 7 onward, tissue levels in the beard region and on the back were consistently higher than the corresponding plasma levels. The levels in the palmar stratum corneum were lower than the corresponding plasma levels but persisted for 3 weeks after discontinuation of therapy. Stratum corneum levels in the beard area were still measurable 4 weeks after the end of therapy. With the 200-mg dose, sweat levels became detectable 24 hours after the first drug intake. The sweat levels were usually lower than the corresponding plasma levels and followed the same curve as the plasma levels. Sebum levels of itraconazole were 10 times as high as the corresponding peak plasma levels. Sebum levels were undetectable 14 days after discontinuation of therapy. The results indicate that oral intake of itraconazole will result in therapeutic levels in the skin and these levels vary, depending on the region of skin tested. There are at least three routes of delivery of itraconazole to the skin: (1) passive uptake by keratinocytes in the basal layer (as shown by the continued presence of the drug in the palmar stratum corneum at a moment when plasma, sebum, and sweat levels are again undetectable); (2) a less significant excretion through the sweat glands (as shown by the lower drug levels compared with the plasma levels); and (3) a massive excretion through the sebaceous glands (as shown by the sebum levels compared with the plasma levels).

Administration, Oral↗
PubMed1988

Hepatic cytochrome P450-mediated oxidation function in migraine.

Hepatic cytochrome P450-dependent oxidation is deficient in 5% to 10% of the Caucasian population. A similar percentage seems to suffer from migraine. The hypothesis was tested that an oxidation deficiency possibly relevant to potential dietary triggers plays a role in the pathogenesis of migraine. In 37 migraine sufferers and 26 controls age- and sex-matched to 26 of these patients, debrisoquine hydroxylation following an oral dose of 10 mg was employed as a marker of oxidation status, determined by calculating the metabolic ratio (MR): urinary debrisoquine/urinary 4-hydroxydebrisoquine. MR was similarly distributed in migraineurs and controls. Three subjects in each group were poor metabolizers (MR greater than 30, versus normal range, 0.1-12). MR in patients did not depend on type of migraine (common versus classic), attack frequency, the presence of trigger factors, smoking or a history of adverse reactions or sensitivity to medicines.

Adult↗