Clinical pharmacology and therapeutics
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Clin. Pharmacol. Ther. · Jan 2006
Clinical TrialEvidence for morphine-independent central nervous opioid effects after administration of codeine: contribution of other codeine metabolites.
Our objective was to investigate whether codeine or one of its metabolites contributes substantially to central nervous effects independent from the cytochrome P450 (CYP) 2D6-mediated O-demethylation to morphine. ⋯ CYP2D6-dependent formation of morphine does not explain exclusively the central nervous effects of codeine. Codeine-6-glucuronide is the most likely additional active moiety.
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Clin. Pharmacol. Ther. · Jan 2006
Modulation of the central nervous effects of levomethadone by genetic polymorphisms potentially affecting its metabolism, distribution, and drug action.
Our aim was to judge the importance of candidate pharmacogenetic modulators of the central nervous effects of levomethadone by both magnitude of the modulatory effect and frequency of the mutation to assess the utility of genotyping for clinical levomethadone therapy in a random sample of subjects that, by distribution of genotypes, resembled the clinical setting. ⋯ Among polymorphisms in OPRM1, ABCB1, and CYP genes previously associated with functional consequences in a different context, the most important pharmacogenetic factor modulating the short-term effects of levomethadone is a polymorphism (OPRM1 118A>G) affecting mu-opioid receptors.
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Clin. Pharmacol. Ther. · Dec 2005
Comparative Study Clinical TrialAssociation of the ABCB1 3435C>T polymorphism with antiemetic efficacy of 5-hydroxytryptamine type 3 antagonists.
Resistance to antiemetic treatment with 5-hydroxytryptamine type 3 (5-HT(3)) receptor antagonists is still a major problem resulting in patient discomfort and poor compliance to chemotherapy. We hypothesized that clinical resistance to 5-HT(3) antagonists is associated with the single-nucleotide polymorphism (3435C>T) in the gene that codes for the drug efflux transporter adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1). ⋯ These results suggest that ABCB1 3435C>T polymorphism is associated with antiemetic treatment efficacy in patients with cancer treated with 5-HT(3) antagonists, particularly in granisetron-treated patients, during the short-term phase of chemotherapy.
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Clin. Pharmacol. Ther. · Dec 2005
Comparative Study Clinical TrialArg16 homozygosity of the beta2-adrenergic receptor improves the outcome after beta2-agonist tocolysis for preterm labor.
Beta(2)-adrenergic receptor (beta(2)AR) agonists are not consistently successful when administered as tocolytic therapy. The beta(2)AR displays genetic variability; an arginine-to-glycine substitution at codon 16 (Arg16Gly) has been shown to increase receptor desensitization in response to agonist exposure, whereas a substitution of glutamate for glutamine at codon 27 (Gln27Glu) decreases down-regulation. We have demonstrated that homozygosity for Arg16 protects against preterm delivery. Our goal was to determine whether beta(2)-agonists are more effective in women with the Arg16 genotype and preterm labor. ⋯ This is the first study examining the pharmacogenetics of beta(2)AR agonist therapy for preterm labor. It appears that Arg16 homozygosity improves pregnancy outcome after beta(2)-agonist tocolysis. The relatively low frequency of Arg16 homozygotes in our population limited the power of this investigation. Future assessments of tocolytic therapy may need to assess beta(2)AR genotype.
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Clin. Pharmacol. Ther. · Nov 2005
Randomized Controlled TrialA pilot study indicating that bradykinin B2 receptor antagonism attenuates protamine-related hypotension after cardiopulmonary bypass.
The administration of protamine to patients who received heparin during cardiopulmonary bypass (CPB) induces hypotension. Protamine inhibits the carboxypeptidase N-mediated degradation of bradykinin, a peptide that causes vasodilation and tissue-type plasminogen activator (t-PA) release. This study tests the primary hypothesis that blocking the bradykinin B(2) receptor would attenuate protamine-related hypotension. ⋯ Increased bradykinin contributes to protamine-related hypotension through its B(2) receptor in ACE inhibitor-treated patients.