Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mirtazapine is the first of a new class of antidepressants, the noradrenergic and specific serotonergic antidepressants (NaSSA). Its antidepressant effect appears to be related to its dual enhancement of central noradrenergic and serotonin 5-HT1 receptor-mediated serotonergic neurotransmission. Mirtazapine possesses a number of useful pharmacokinetic characteristics such as good absorption, linear pharmacokinetics over the recommended dosage range (15 to 80 mg/day), and an elimination half-life of 20 to 40 hours, thereby allowing once-daily administration. However, since the drug is extensively metabolised by the hepatic cytochrome P450 (CYP) system and is excreted mainly in the urine, its clearance may be reduced by hepatic or renal impairment. In vitro data suggest that from a clinical point of view it is unlikely that mirtazapine would inhibit the metabolism of coadministered drugs metabolised by CYP1A2, CYP2D6 or CYP3A4. In vivo data from a study in extensive and poor metabolisers of debrisoquine indicate that strong inhibitors of CYP2D6 would have no effect on the concentration of racemic mirtazapine. In some placebo-controlled studies mirtazapine showed an early onset of antidepressant action, with significant reductions in total Hamilton Depression Rating Scale and Montgomery-Asberg Depression Rating Scale scores (relative to placebo) noted as early as 1 week after starting treatment. This therapeutic advantage was subsequently maintained during treatment, with mirtazapine proving significantly superior to placebo at treatment end-point in the majority of studies. In comparative trials, the antidepressant efficacy of mirtazapine was comparable with that of tricyclic antidepressants such as amitriptyline, clomipramine and doxepin, and in 2 studies superior to that of trazodone and fluoxetine. Mirtazapine appears to have a broad spectrum of activity, reflected in its efficacy in a variety of clinical settings. Its additional beneficial effects on the symptoms of anxiety and sleep disturbance associated with depression may reduce the need for concomitant anxiolytic and hypnotic medication seen with some antidepressants. Mirtazapine has demonstrated superior tolerability to the tricyclic antidepressants and trazodone, primarily on account of its relative absence of anticholinergic, adrenergic and serotonin-related adverse effects, in particular gastrointestinal adverse effects and sexual dysfunction. It appears that increased sedation associated with the drug is related to subtherapeutic dosages, and that it is reported in substantially fewer patients when the drug is used in appropriate dosages (> or = 15 mg as a single evening dose) from the beginning of treatment. Although 2 cases of reversible severe symptomatic neutropenia have been reported in clinical trials, there have been no additional reports of symptomatic neutropenia since the introduction of this drug to various countries in September 1994. Currently available data and initial clinical experience suggest that with its combination of dual action, simple pharmacokinetics, and clinical efficacy and tolerability, mirtazapine appears to be an important advance in the pharmacotherapy of depression.
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PMID:A risk-benefit assessment of mirtazapine in the treatment of depression. 935 61

Exatecan mesylate (DX-8951f) is a new hexacyclic camptothecin analogue with favorable attributes compared to topotecan and CPT-11, including watersolubility, greater potency against topoisomerase I, lack of esterase-dependent activation, broad antitumor activity, and low cross-resistance against MDR-1 overexpressing tumors. In preclinical studies, the compound demonstrated a favorable toxicology profile with hematologic dose-limiting toxicity and moderate gastrointestinal toxicity, linear pharmacokinetics, P450 hepatic metabolism (CYP3A4 and CYP1A2), and predominately fecal excretion. The results of six U.S. and European phase I clinical trials as well as two Japanese studies are presented including total DX-8951 and lactone DX-8951 pharmacokinetics. The toxicity profile was similar for all schedules of administration. Hematologic toxicity was dose-dependent and reversible. Neutropenia was dose-limiting in minimally pretreated patients, whereas neutropenia and thrombocytopenia were dose-limiting in heavily pretreated patients. Non-hematologic toxicity included moderate gastrointestinal toxicity (nausea, vomiting > diarrhea), transient elevation of hepatic transaminases, asthenia, and alopecia. Two cases of acute pancreatitis not predicted by preclinical toxicology were also observed. Antineoplastic activity was detected in several solid tumor types: non-small cell lung cancer, extrapulmonary small cell cancer, colorectal cancer, hepatocellular cancer, and sarcoma. Antitumor activity was seen in CPT-11 and topotecan-resistant tumors. Pharmacokinetics were linear within the dose range tested. A pharmacokinetic/pharmacodynamic model predictive of DX-8951f-induced neutropenia in individual patients was developed. The daily x5, every 3-week schedule with the drug administered as a 30-minute intravenous infusion was selected for future phase II clinical trials based on its superior antitumor activity.
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PMID:DX-8951f: summary of phase I clinical trials. 1119 1

Olanzapine is an effective and safe antipsychotic drug. Its pharmacokinetic properties are comparable to those of classical antipsychotics. Oxidative processes are mediated by the cytochrome P450 isoenzyme CYP1A2 and to a minor degree by CYP2D6. Olanzapine's main route of metabolism is by glucuronidation. Therapeutic doses result in a wide variability of serum levels; dose and serum concentration are linearly correlated. Smoking and carbamazepine induce cytochrome P450 isoenzymes and thus decrease olanzapine serum levels. Inhibition of CYP1A2 by fluvoxamine yields increased concentrations; however, clinically relevant CYP2D6 inhibition was observed only in combination with additional disposition factors, such as female gender or old age. As a rule dose adjustment is not necessary but moderate renal or hepatic impairment calls for control of serum levels to provide maximal safety during olanzapine therapy. Therapeutic drug monitoring (TDM) and toxicology studies are carried out by HPLC methods using UV or MS detection. The optimal therapeutic range of olanzapine serum levels is 20 to 40 ng/ml. Concentrations of 80 ng/ml are considered threshold for the occurrence of adverse events; however, toxicological studies showed that postmortem plasma levels are higher than antemortem levels. Lethality of high olanzapine was only observed in combination with other drugs. Moderate increases of prolactin levels were detected during administration of olanzapine. In relation to olanzapine therapy, several case reports of neutropenia and agranulocytosis appeared in the literature. Weight gain in olanzapine-treated patients does not correlate with serum levels. Olanzapine response is augmented when patients' serum levels are titrated to 20 to 40 ng/ml thereby minimizing the occurrence of side effects, thus TDM is recommended for patients treated with olanzapine.
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PMID:[Olanzapine: pharmacology, pharmacokinetics and therapeutic drug monitoring]. 1170 98

We investigated the association of genetic polymorphisms in drug metabolizing enzymes (DMEs) and transporters in patients with docetaxel-induced febrile neutropenia, by a new high-throughput DMEs and transporters (DMETPlus) microarray platform, characterizing 1936 single nucleotide polymorphisms (SNPs) in 225 genes. We recruited 100 Lebanese breast cancer patients from a consecutive cohort of 277 patients who received docetaxel either alone, or in combination with trastuzumab. Out of 100 patients, 18 had developed febrile neutropenia (cases). They were age- and treatment- matched with 18 patients who did not develop febrile neutropenia on docetaxel (controls). We found that 12 SNPs in seven genes (ABCC6, ABCG1, ABCG2, CYP1A2, CYP2D6, FMO2, and FMO3) were significantly associated with febrile neutropenia after docetaxel treatment. Many of these SNPs have not been previously reported to be associated with toxicity due to docetaxel treatment. Interestingly, one SNP in the FMO3 gene (rs909530) was significantly associated with three clinical endpoints: febrile neutropenia, reduced absolute neutrophil count, and hemoglobin reduction. To the best of our knowledge, this is the first study that evaluated the effect of a large array of nearly 2000 polymorphisms in DMEs and transporters on docetaxel toxicity in breast cancer patients, and in a previously understudied population. Additionally, it attests to the feasibility of genomics research in low- and middle-income countries (LMICs). In light of the current global epidemic of noncommunicable diseases (NCDs) such as breast cancer impacting LMICs, we suggest pharmacogenomics is considered as an integral part of the global health research agenda for NCDs and personalized therapeutics.
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PMID:Pharmacogenomics variation in drug metabolizing enzymes and transporters in relation to docetaxel toxicity in Lebanese breast cancer patients: paving the way for OMICs in low and middle income countries. 2375 76

Clozapine is a second-generation antipsychotic which has proven efficacy in treating the symptoms of schizophrenia. Although clozapine therapy is associated with a number of adverse drug reactions, it is frequently used. One of the most common adverse drug reactions is gastroesophageal reflux disease which is an indication for treatment with proton pump inhibitors (PPIs). Coadministration of clozapine and PPIs increases the risk of hematological adverse drug reactions, including neutropenia and agranulocytosis. The mechanism in idiosyncratic agranulocytosis is not dose related and involves either a direct toxic or an immune-allergic effect. It is suspected that the clozapine metabolites nitrenium ion and N-desmethylclozapine may cause apoptosis or impair growth of granulocytes. Formation of N-desmethylclozapine is correlated with activity of the cytochrome P450 enzymes 1A2 and 3A4 (CYP1A2 and CYP3A4). Nitrenium ion is produced by the flavin-containing monooxygenase system of leukocytes. A drug interaction between clozapine and a PPI is a consequence of the induction of common metabolic pathways either by the PPI or clozapine. Findings to date suggest that indirect induction of flavin-containing monooxygenase by omeprazole through the aryl hydrocarbon receptor increases the expression of the enzyme mRNA and in the long term may cause the increase in activity. Moreover, induction of CYP1A2, especially by omeprazole and lansoprazole, may increase the serum concentration of N-desmethylclozapine, which can accumulate in lymphocytes and may achieve toxic levels. Another hypothesis that may explain hematological adverse drug reactions is competitive inhibition of CYP2C19, which may contribute to increased serum concentrations of toxic metabolites.
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PMID:Potential Mechanisms of Hematological Adverse Drug Reactions in Patients Receiving Clozapine in Combination With Proton Pump Inhibitors. 2829 Oct 36