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Biomedical subjects

J M Sitsen

Publications and source records attributed to J M Sitsen.

At least 19 recordsLinked to original sources
PubMed2000

Concomitant use of mirtazapine and cimetidine: a drug-drug interaction study in healthy male subjects.

OBJECTIVE: The objective of this study was to examine the pharmacokinetics and the tolerability/safety of mirtazapine and cimetidine separately and in combination following oral administration of multiple doses. METHODS: This was a double-blind, placebo-controlled, two-period cross-over, multiple-dose pharmacokinetic interaction study in 12 healthy male subjects. They received either cimetidine (800 mg b.i.d.) or placebo in combination with (commercially available, racemic) mirtazapine (30 mg nocte). Cimetidine and placebo were administered for 14 days, with mirtazapine added during days 6-12 of each period. Serial blood samples for kinetic profiling were taken on day 5 and day 12 for cimetidine and on days 12-14 for mirtazapine. RESULTS: The co-administration of cimetidine resulted in a statistically significant increase in the area under the curve (AUC(0-24)) and Cmax of mirtazapine (54% and 22% respectively). The AUC(0-24) of demethylmirtazapine increased only slightly, and there was no effect on Cmax. The elimination half-lives for both mirtazapine and its demethyl metabolite were unaffected by cimetidine co-administration. The trough and average plasma concentrations during the steady state were elevated during cimetidine treatment (62% and 54%, respectively). Mirtazapine had no effect on the pharmacokinetics of cimetidine. CONCLUSION: Co-administration of cimetidine (800 mg b.i.d.) and mirtazapine (30 mg nocte) resulted in increased steady-state plasma levels of mirtazapine (C(ss,min) = +61%, P < 0.05; C(ss,av) = +54%, P < 0.05), probably as a result of increased bio-availability. The Cmax (+22%, P < 0.05) and AUC(0-24) (+54%, P < 0.05) also increased. Due to the variability of the mirtazapine plasma levels in patients, the clinical meaning of these increases is probably limited. Co-administration of mirtazapine did not alter cimetidine pharmacokinetics.

Administration, Oral↗
PubMed2000

Pharmacokinetics of mirtazapine and lithium in healthy male subjects.

A substantial proportion of patients diagnosed with depression and treated with antidepressants show no or insufficient response. In such patients, lithium is often added to the antidepressant for augmentation. The present study investigated the possible drug-drug interaction between mirtazapine and lithium in 12 healthy male subjects in a randomized, double-blind, placebo-controlled two-period cross-over design. Subjects meeting the inclusion and exclusion criteria were randomly assigned to one of two groups. After an overnight fast, they received either a single oral dose of 600 mg lithium carbonate (16 meq Li+) for 10 days at 08.00 h and a single oral dose of 30 mg mirtazapine at 21.00 h on day 9 or the same number (n = 4) of placebo capsules and and a single oral dose of 30 mg mirtazapine at 21.00 h on day 9. At pre-defined times, blood samples were drawn for the measurement of mirtazapine plasma concentrations and lithium serum concentrations. In addition, psychometric tests were performed and the safety and tolerability of the drugs were assessed. The results indicate that mirtazapine does not alter the pharmacokinetics of lithium and vice versa. In addition, the combination of mirtazapine and lithium appeared to be safe and well-tolerated. Extensive psychometric testing after the administration of mirtazapine did not reveal any differences on any tests in subjects on lithium and placebo, respectively.

Adolescent↗
PubMed2000

Clinical pharmacokinetics of mirtazapine.

Mirtazapine is the first noradrenergic and specific serotonergic antidepressant ('NaSSA'). It is rapidly and well absorbed from the gastrointestinal tract after single and multiple oral administration, and peak plasma concentrations are reached within 2 hours. Mirtazapine binds to plasma proteins (85%) in a nonspecific and reversible way. The absolute bioavailability is approximately 50%, mainly because of gut wall and hepatic first-pass metabolism. Mirtazapine shows linear pharmacokinetics over a dose range of 15 to 80mg. The presence of food has a minor effect on the rate, but does not affect the extent, of absorption. The pharmacokinetics of mirtazapine are dependent on gender and age: females and the elderly show higher plasma concentrations than males and young adults. The elimination half-life of mirtazapine ranges from 20 to 40 hours, which is in agreement with the time to reach steady state (4 to 6 days). Total body clearance as determined from intravenous administration to young males amounts to 31 L/h. Liver and moderate renal impairment cause an approximately 30% decrease in oral mirtazapine clearance; severe renal impairment causes a 50% decrease in clearance. There were no clinically or statistically significant differences between poor (PM) and extensive (EM) metabolisers of debrisoquine [a cytochrome P450 (CYP) 2D6 substrate] with regard to the pharmacokinetics of the racemate. The pharmacokinetics of mirtazapine appears to be enantioselective, resulting in higher plasma concentrations and longer half-life of the (R)-(-)-enantiomer (18.0 +/-2.5h) compared with that of the (S)-(+)-enantiomer (9.9+/-3. lh). Genetic CYP2D6 polymorphism has different effects on the enantiomers. For the (R)-(-)-enantiomer there are no differences between EM and PM for any of the kinetic parameters; for (S)-(+)-mirtazapine the area under the concentration-time curve (AUC) is 79% larger in PM than in EM, and a corresponding longer half-life was found. Approximately 100% of the orally administered dose is excreted via urine and faeces within 4 days. Biotransformation is mainly mediated by the CYP2D6 and CYP3A4 isoenzymes. Inhibitors of these isoenzymes, such as paroxetine and fluoxetine, cause modestly increased mirtazapine plasma concentrations (17 and 32%, respectively) without leading to clinically relevant consequences. Enzyme induction by carbamazepine causes a considerable decrease (60%) in mirtazapine plasma concentrations. Mirtazapine has little inhibitory effects on CYP isoenzymes and, therefore, the pharmacokinetics of coadministered drugs are hardly affected by mirtazapine. Although no concentration-effect relationship could be established, it was found that with therapeutic dosages of mirtazapine (15 to 45 mg/day), plasma concentrations range on average from 5 to 100 microg/L.

Animals↗
PubMed1999

Lack of drug interactions between mirtazapine and risperidone in psychiatric patients: a pilot study.

An open-label, non-randomized, pilot study has been performed in inpatients in need of treatment with an antipsychotic (risperidone) and an antidepressant (mirtazapine) with the objective to preliminarily assess a possible pharmacokinetic interaction and the tolerability of this combination. A 1-4-week single drug treatment phase (risperidone 1-3 mg bid or mirtazapine 30 mg nocte) was followed by a 2-4-week combined drug treatment phase at unchanged doses. Twelve patients were enrolled, nine of whom were treated with risperidone in the single drug phase. Results of plasma level measurements are available for six patients and indicate that adding mirtazapine to risperidone does not alter steady-state plasma concentrations of risperidone and its 9-hydroxy metabolite. Data from one patient suggest that adding risperidone to mirtazapine does not result in clinically relevant changes in plasma concentrations of either compound. The combination was well tolerated and no major or relevant adverse events were observed. Adding risperidone to mirtazapine probably does not necessitate a change of the dosage of either drug, but more extensive investigations are needed.

Adult↗
PubMed1987

Development of high blood pressure in spontaneously hypertensive rats is delayed by treatment with cyclosporin at an early age.

In spontaneously hypertensive rats the effect of the T-cell inhibitor cyclosporin was studied at different ages. If treatment was started at the age of 2 weeks the development of hypertension was delayed, but the ultimate level of blood pressure was not affected. These results indicate the involvement of immune mechanisms in the early development of hypertension in spontaneously hypertensive rats.

Aging↗
PubMed1987

Differential sensitivity to morphine in spontaneously hypertensive and normotensive Wistar-Kyoto and Wistar rats.

In spontaneously hypertensive rats (SHR) a diminished responsiveness for nociceptive stimuli is present, which might be associated with alterations in endogenous opioid peptide and receptor systems. In SHR, normotensive Wistar-Kyoto controls (WKY) and in Wistar rats the effects of acute morphine administration on pain sensitivity and body temperature have been investigated. Morphine potency decreases significantly in the rank order Wistar, SHR, WKY. Concerning body temperature, a low dose (2.5 mg/kg i.p) results in an initial and transient decrease in body temperature in SHR, which is not elicited in Wistar rats and WKY. After higher doses (10 and 20 mg/kg. i.p) in Wistar rats profound hypothermia occurs whilst SHR and WKY show a modest increase in body temperature. These differential effects in the three strains could not be explained by altered morphine concentrations in subcortical brain tissue.

Animals↗
PubMed1986

Bioavailability of paracetamol after oral administration to healthy volunteers. Influence of caffeine on rate and extent of absorption.

The absorption rate and the bioavailability of two commercially available paracetamol tablets were investigated in a panel of seven volunteers; one of these tablets contained a combination of 50 mg caffeine and paracetamol. Considering the urinary excretion data, it is concluded that the tablets release their contents completely; the absolute bioavailability, however, calculated from plasma concentrations, is lower than 100%, indicating a first-pass effect. A marked interindividual variation in first-pass effect was noticed. No general influence of caffeine on the extent of absorption of paracetamol could be established; there is, however, a slightly positive influence of caffeine on the absorption rate of paracetamol in six out of seven volunteers. It was concluded that this positive influence on absorption rate is not responsible for the established enhancement of paracetamol analgesia by caffeine.

Acetaminophen↗
PubMed1986

Buprenorphine versus domperidone in chemotherapy-induced emesis: a pilot study.

A randomized double-blind cross-over study was performed to evaluate the possible anti-emetic effect of the partial opiate antagonist buprenorphine in comparison to domperidone in chemotherapy-induced nausea and vomiting. Emesis was of significantly shorter duration on domperidone treatment. Most patients preferred domperidone, mainly due to adverse side-effects of buprenorphine. Nevertheless, emesis in buprenorphine treatment was less disabling. Therefore, it might be useful to search for new alternatives in this group of drugs or to use them in a combination regimen of anti-emetic agents.

Adult↗
PubMed1985

N alpha-Acetyl-gamma-endorphin is an endogenous non-opioid neuropeptide with biological activity.

N alpha-acetyl-gamma-endorphin (Ac gamma E) was identified in the rat neurointermediate pituitary, based on its immunological properties, comigration with synthetic Ac gamma E on HPLC and resistance to aminopeptidase-M degradation. The peptide appeared to be the main form of gamma-endorphin (gamma E) in this tissue and in brain areas remote from the hypothalamus (hippocampus, septum, amygdala). The anterior pituitary, the hypothalamus and the thalamus contained almost exclusively the non-acetylated form of gamma E. In contrast to gamma E, Ac gamma E was completely devoid of specific affinity for brain opiate binding sites. Yet, the peptide mimicked gamma E in that it potently attenuated passive avoidance behaviour in rats, when injected topically into the nucleus accumbens. It is concluded that Ac gamma E is an endogenous neuropeptide with non-opioid biological activity. N alpha-acetylation may not merely represent a mechanism for the inactivation of opioid activities of endorphins, but rather allow the organism to select specific sets of biological activities that reside in the endorphin structure.

Acetylation↗
PubMed1984

Is the hypothermic effect of alpha-methyldopa mediated by opioid peptides?

At an ambient temperature of 21 degrees C alpha-methyldopa (25-200 mg kg-1) induces a dose-dependent decrease in body temperature in rats. A relationship between adrenergic and opioid neuronal systems has been reported. Therefore, in this study the hypothesis that alpha-methyldopa produces hypothermia through release of endogenous opioid peptides has been investigated using the opiate antagonist naltrexone. The hypothermic effect of alpha-methyldopa is potentiated by naltrexone pointing to antagonism of an hyperthermic acting opioid system. However, at an ambient temperature of 6 degrees C, pretreatment with naltrexone did not significantly alter the hypothermic effect of alpha-methyldopa. Although the hypothesis proved not to be correct, it is concluded that depending on ambient temperature opioid peptides are involved in the determination of the ultimate effect of alpha-methyldopa on body temperature in rats.

Animals↗
PubMed1984

Observations on pain perception and hypertension in spontaneously hypertensive rats.

Pain sensitivity in Spontaneously Hypertensive Rats (SHR) and normotensive Wistar-Kyoto controls (WKY) as well as in experimentally hypertensive Wistar rats has been studied. Results indicate a diminished responsiveness to noxious stimuli in SHR when compared with WKY. This hypoalgesia is altered neither by chronic treatment with the antihypertensive drugs hydralazine and captopril nor by the peripherally acting opiate antagonist N-methylnaloxone. Induction of renal and DOCA-salt hypertension in Wistar rats and Wistar-Kyoto rats did not affect nociceptive responsiveness. It is concluded that opiate receptors within the central nervous system are involved in the hypoalgesia in SHR and that pain perception appears to be dissociated from blood pressure regulation in the rat strains used.

Animals↗
PubMed1983

Role of opioid peptides in brain mechanisms regulating blood pressure.

Beta-endorphin and related opioid peptides are neuropeptides which appear to play a role in cardiovascular regulation which is supported by altered nociceptive responsiveness in hypertensive animals. In spontaneously hypertensive rats the pain threshold for electric stimulation is elevated; these rats show increased response latency time in a hot plate test. The opiate antagonist naloxone reverses these values to that of the normotensive controls. In other forms of experimental hypertension, eg, renal hypertension (one-clip, two-kidney model), no change in pain sensitivity is apparent. Sinoaortic baroreceptor denervation causes a labile hypertension without changes in hot plate response. Administration of beta-endorphin into the nucleus of the solitary tract (NTS) gradually decreases blood pressure and heart rate without affecting respiratory frequency. These cardiovascular effects are blocked by naloxone as well as by an antibody to beta-endorphin. In contrast to the effects of beta-endorphin, microinjection of enkephalins into the NTS increases blood pressure and heart rate. The data suggest the existence of two separate endorphin systems at the level of the NTS, one a depressor and another a pressor system. The depressor influence of beta-endorphin may play a role in the mechanism of action of antihypertensive agents such as methyldopa and clonidine. Our data support a role of endorphins as neuropeptides involved in cardiovascular regulation, exerting a dual influence at the level of the NTS.

Animals↗
PubMed1983

Pain sensitivity is not affected by sino-aortic denervation in rats.

Genetic hypertension in rats appears to be associated with diminished pain sensitivity. Acute stimulation of the baroreceptors has also been reported to decrease responsiveness to a noxious stimulus. In this study the effect of sino-aortic denervation on pain sensitivity, as measured by means of a hot plate and threshold electric footshock method has been investigated. Deafferentation resulted in a labile hypertension and tachycardia. However, hot plate response latency times were not significantly different in the sino-aortic denervated rats as compared to sham operated controls under subchronic conditions. When tested for pain sensitivity three weeks after surgery using both methods on one occasion only, again the responsiveness to noxious stimuli was not different between the two groups. At the end of the experiments, the efficacy of denervation was confirmed by assessing lability of blood pressure and measuring heart rate responses to pharmacological manipulation of blood pressure. It is concluded that surgical interruption of the baroreceptor nerves in rats does not alter pain sensitivity under subchronic conditions.

Animals↗
PubMed1982

Leukotrienes, allergy and inflammation.

Immunological and non-immunological injury induce as a result of the action of the enzyme lipoxygenase the release of a series of arachidonic acid metabolites known as leukotrienes. The leukotrienes play an important role in allergic and inflammatory disease. Leukotrienes C4, D4 and E4 which recently have been recognized as constituents of the allergic mediator slow reacting substance of anaphylaxis (SRS-A) induce powerful bronchoconstriction, plasma exudation and weal and flare responses. Leukotriene B4 is involved in the regulation of chemotaxis, chemokinesis and other aspects of both cellular and vascular inflammation. The development of specific lipoxygenase inhibitors may lead to a new class of drugs for the treatment of bronchial asthma and chronic inflammatory diseases.

Arachidonic Acids↗