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81.
A pharmacokinetic interaction between carbamazepine and olanzapine: observations on possible mechanism 总被引:6,自引:0,他引:6
R. A. Lucas D. J. Gilfillan R. F. Bergstrom 《European journal of clinical pharmacology》1998,54(8):639-643
Objective: Olanzapine is a novel antipsychotic, which is effective against both the positive and negative symptoms of schizophrenia
and causes fewer extrapyramidal adverse effects than conventional antipsychotics. The purpose of the present study was to
assess the potential for a pharmacokinetic interaction between olanzapine and carbamazepine, since these agents are likely
to be used concomitantly in the treatment of manic psychotic disorder.
Method: The pharmacokinetics of two single therapeutic doses of olanzapine were determined in 11 healthy volunteers. The first dose
of olanzapine (10 mg) was taken alone and the second dose (10 mg) after 2 weeks of treatment with carbamazepine (200 mg BID).
Measurement of urinary 6-hydroxycortisol/cortisol excretion was used as an endogenous marker to confirm that induction of
CYP3A4 by carbamazepine had occurred.
Results: The dose of olanzapine given after a 2-week pre-treatment with carbamazepine was cleared more rapidly than olanzapine given
alone. Olanzapine pharmacokinetic values for Cmax and AUC were significantly lower after the second dose, the elimination half-life was significantly shorter, and the clearance
and volume of distribution were significantly increased.
Conclusion: Carbamazepine has been shown to induce several P450 cytochromes including CYP3A4 and CYP1A2. Since CYP1A2 plays a role in
the metabolic clearance of olanzapine, the interaction may be attributed to induction of CYP1A2 by carbamazepine, leading
to increased first-pass and systemic metabolism of olanzapine. The interaction is not considered to be of clinical significance
because olanzapine has a wide therapeutic index, and the changes in plasma concentration of olanzapine are within the fourfold
variation that occurs without concern for safety in a patient population.
Received: 22 July 1997 / Accepted in revised form: 1 June 1998 相似文献
82.
Sex differences in plasma cocaine levels and subjective effects after acute cocaine administration in human volunteers 总被引:3,自引:3,他引:0
S. E. Lukas M. Sholar L. H. Lundahl X. Lamas E. Kouri J. D. Wines L. Kragie J. H. Mendelson 《Psychopharmacology》1996,125(4):346-354
Gender differences after acute cocaine administration have received little attention in spite of the fact that males and females respond differently to many drugs. Seven male and seven female occasional cocaine users received both an intranasal dose of cocaine hydrochloride (0.9 mg/kg) and placebo powder in a randomized order and reported subjective effects via an instrumental joystick device and various questionnaires. Blood samples were withdrawn at 5-min intervals to assess pharmacokinetic differences. Male subjects achieved the highest peak plasma cocaine levels (144.4 ± 17.5 ng/ml), detected cocaine effects significantly faster than females and also experienced a greater number of episodes of intense good and bad effects. Women studied during the follicular phase of their menstrual cycle had peak plasma cocaine levels of 73.2 ± 9.9 ng/ml, which was significantly higher than when they were studied during their luteal phase (54.7 ± 8.7 ng/ml), but there were no differences in their subjective reports of cocaine effects. In spite of the different cocaine blood levels and subjective effects, peak heart rate increases did not differ between males and females suggesting that women may be more sensitive than males to the cardiovascular effects of cocaine. These data suggest that there are significant gender and menstrual cycle differences in the response to acute intranasal cocaine administration and these differences may have implications for the differential abuse of this drug.This paper is dedicated to Xavier Lamas, MD, PhD, who lost his life while ascending Mt. Everest, August 1995 相似文献
83.
进一步研究了抗三尖杉酯碱的HL-60细胞(HR20)抗细胞凋亡的机制及该抗性和抗药性的关系。结果表明,环孢菌素A(CsA)20,10μg·ml ̄(-1)诱导HL-60细胞发生凋亡,而阻断HR20细胞于G_1期,就不能诱导细胞发生凋亡。低浓度的CsA明显增加柔红霉素在HR20细胞内的积聚,其逆转抗药性作用与阻断细胞周期运行无关。CsA10μg·ml ̄(-1)处理HR20细胞,可引起50kDa的蛋白质高度磷酸化。结果提示:环孢菌素A阻断抗三尖杉酯碱的HL-60细胞于G_1期,而诱导敏感的HL-60细胞发生凋亡,其阻断作用与抗药性无关 相似文献
84.
Recent interest in the neurotoxicity of haloperidol is based on its oxidation in rodents to the pyridinium derivative, HPP+, a structural analog of the neurotoxin, 1-methyl-4-phenylpyridinium (MPP+). Recently, we reported that HPP+ and a newly identified reduced pyridinium, RHPP+, were present in blood and urine of haloperidol-treated schizophrenics and that the concentrations of RHPP+ exceeded those of HPP+. In this study, we examined pathways for formation of RHPP+ in subcellular fractions of human liver (n=5) and brain (basal ganglia;n=5). The major pathway was reduction of HPP+ (20 µM) to RHPP+ in cytosol (0.17–0.39 and 0.03–0.07 µM RHPP+/g cytosolic protein per h in liver and brain, respectively). The reactions were inhibited significantly by menadione and in brain also by daunorubicin. The inhibition profile, cytosolic location and strict NADPH dependence suggest that the enzymes involved are ketone reductases. A second pathway was oxidation of reduced haloperidol (50 µM), a major metabolite of haloperidol in blood and brain, to RHPP+. In liver microsomes, 0.17–0.63 µmol RHPP+ was formed /g microsomal protein per h. A potent inhibitor of the pathway was ketoconazole (IC50, 0.8 µM), which suggests that P-450 3A isozymes could be involved. In brain mitochondria but not microsomes, reduced haloperidol (120 µM) was oxidised to RHPP+ at a small but significant rate (0.005–0.020 µmol RHPP+/g mitochondrial protein per h) which was not attenuated by SKF 525A, quinidine, ketoconazole, or monoamine oxidase inhibitors. Further studies are warranted to establish the biological importance of these metabolites in vivo. 相似文献
85.
This study was conducted to assess the involvement of N-methyl-d-aspartate (NMDA) and γ-aminobutyric acid (GABA) receptor systems, located in specific limbic brain regions, in the discriminative
stimulus effects of ethanol. Male Long-Evans rats were trained to discriminate between intraperitoneal (IP) injections of
ethanol (1 g/kg) and saline on a two-lever drug discrimination task. The rats were then implanted with bilateral injector
guides aimed at the nucleus accumbens core (AcbC), prelimbic cortex (PrLC), hippocampus area CA1 (CA1), or extended amygdala
(i.e., at the border of the central and basolateral nuclei). Infusions of the non-competitive NMDA antagonist MK 801 in the
AcbC or CA1 resulted in dose-dependent full substitution for IP ethanol. MK 801 infusion in the PrLC or amygdala failed to
substitute for ethanol. Injection of the competitive NMDA antagonist CPP in the AcbC also failed to substitute for ethanol.
Co-infusion of MK 801 in the hippocampus potentiated the effects of MK 801 in the AcbC, whereas NMDA infusion in the hippocampus
attenuated the ability of MK 801 in the AcbC to substitute for ethanol. The direct GABAA agonist muscimol resulted in dose-dependent full substitution for IP ethanol when it was injected into the AcbC or amygdala,
but failed to substitute when administered in the PrLC. Co-infusion of MK 801, but not CPP, potentiated the effects of muscimol
in the AcbC. These results demonstrate that ethanol’s discriminative stimulus function is mediated centrally by NMDA and GABAA receptors located in specific limbic brain regions. The data also suggest that the discriminative stimulus effects of ethanol
are mediated by interactions between ionotropic GABAA and NMDA receptors in the nucleus accumbens, and by interactions among brain regions.
Received: 2 December 1997 / Final version: 24 January 1998 相似文献
86.
Neuropathology in non-human immunodeficiency virus-infected drug addicts: hypoxic brain damage after chronic intravenous drug abuse 总被引:3,自引:0,他引:3
Neuropathological studies were carried out on 180 human immunodeficiency virus-seronegative intravenous drug addicts. The
findings in victims of acute heroin intoxication (n = 116) were congestion (99.1%), capillary engorgement (68.1%), and/or perivascular bleeding (68.1%) – hemodynamic processes
attributable to toxic primary respiratory failure. In a high percentage of these cases (88%), cerebral edema was also present.
In 18 cases of acute heroin intoxication who survived for periods of hours or days, the sole postmortem finding was ischemic
nerve cell damage, resembling that typically seen in systemic hypoxia. Semiquantitative analysis revealed nerve cell loss
in the hippocampal formation and/ or Purkinje cell layer in 26% of the 162 chronic drug abusers. By contrast, in nearly 80%
of these cases, the hippocampus showed enhanced expression of glial fibrillary acid protein by astrocytes and/or a proliferation
of microglia, demonstrated by CD68 expression. Since such reactive processes are produced by primary neuronal damage, it can
be assumed that chronic intravenous drug abuse results in obviously ischemic nerve cell loss. This could be demonstrated in
the hippocampus, but it must also occur throughout the whole brain. The demonstration of ischemic nerve cell damage and neuronal
loss or secondary reactive alterations has not been described previously.
Received: 31 March 1995 / Revised, accepted: 27 November 1995 相似文献
87.
The role of the ethanol training dose on the ability of the selective 5-HT1 agonist TFMPP (m-trifluoromethylphenylpiperazine) to produce ethanol-like discriminative stimulus effects was evaluated in three groups of rats trained to discriminate 1.0 g/kg (n=5), 1.5 g/kg (n=6) or 2.0 g/kg (n=7) ethanol (IG) from water using a two-lever procedure with food reinforcement available under a fixed ratio 20 (FR 20) schedule. Ethanol generalization gradients were comparable in the three groups, indicating few potency differences in the ethanol stimulus across training dose. However, the ability of TFMPP (0.1–1.7 mg/kg; IP) to substitute for ethanol was dependent on the training dose. TFMPP resulted in partial substitution in the 1.0 g/kg group, complete substitution for 1.5 g/kg group and no substitution in the 2.0 g/kg ethanol training group. The results indicate a serotonergic component to the discriminative stimulus effects of an intermediate dose of ethanol that is not prominent as the dose of ethanol is raised. These data add further support for the hypothesis that ethanol produces a mixed discriminative cue, the components of which are not uniformly amplified when the dose of ethanol is increased. 相似文献
88.
A microcapsule form of nitrofurantoin was prepared by a simple coacervation method with carboxymethylcellulose and aluminium sulfate. 33 factorial design was performed for three independent variables, namely, the particle size of the drug, the size of the microcapsules and the pH of the dissolution medium. The dissolution tests with the formulated microcapsules were carried out according to the United States Pharmacopeia XXII rotating basket method at pH 1.2, 5 and 7.5, which represent the pH of gastrointestinal fluids. Release data were examined kinetically and the ideal kinetic models were estimated and t
63.2 values obtained from RRSBW distribution were used in the factorial design experiment. The influence of the independent variables on the dissolution of nitrofurantoin microcapsules could be expressed as the pH of the dissolution medium > particle size of the microcapsule > particle size of nitrofurantoin. The other aim of this study was to evaluate microcapsule formulation in terms of the United States Pharmacopeia criteria with a minimum of experiments. Our findings suggest that dosage forms which comply with the pharmacopoeia criteria for dissolution can be prepared and selected by factorial design. 相似文献
89.
Summary In Denmark it is legal to grow opium poppies for the production of poppy seeds and until 1986 for decoration purposes, too. Danish poppy capsules contain 0.3–5 mg morphine per capsule and the content of morphine in opium exuded from the capsules may amount to 24%. This has resulted in misuse as both fresh and dried poppy capsules have been used for the production of opium tea. During the period 1982–1985, seven casualties occurred among drug addicts in Denmark which were solely or partly caused by these opium poppies. 相似文献
90.
David V. Gauvin Bradley D. Youngblood Frank A. Holloway 《Alcoholism, clinical and experimental research》1992,16(2):336-341
Twenty male Sprague-Dawley rats were trained to discriminate pentylenetetrazole (PTZ, 15 mg/kg, intraperitoneally) from saline (SAL) under a drug discrimination procedure. Test sessions were conducted with 10 randomly selected subjects. Tests with various doses of PTZ resulted in a dose-dependent increase in the percentage of total session responses emitted on the PTZ-appropriate lever without a significant change in response rates across a wide range of test PTZ doses. Rats did not generalize the PTZ stimulus to ethanol (ETOH) up to ETOH test doses that completely suppressed responding. High acute ETOH doses (2, 3, and 4 g/kg) administered at various time points prior to discrimination test sessions engendered responding on the PTZ-appropriate level in a quantitative fashion, that was dose- and time-dependent. This acute ETOH delayed effect from these high doses replicates our previously published study using a Drug 1-Drug 2 discrimination task with Chlordiazepoxide and PTZ. More importantly, we suggest that the present behavioral assay may be a sensitive animal analogue of human "hangover" phenomena. 相似文献