Drugs online research references
Biol Psychiatry. 2003 Oct 15;54(8):800-5.
In vivo activity of bupropion at the human dopamine transporter as measured by positron emission tomography.
Learned-Coughlin SM, Bergstrom M, Savitcheva I, Ascher J, Schmith VD, Langstrom B.
GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709, USA.
BACKGROUND: Converging lines of evidence are consistent with an inhibitory effect of the antidepressant and smoking-cessation aid bupropion on dopamine and norepinephrine reuptake, but the in vivo effects of the drug at the human dopamine transporter (DAT) have not been studied to date. This study employed positron emission tomography (PET) to assess the extent and duration of DAT receptor occupancy by bupropion and its metabolites under conditions of steady-state oral dosing with bupropion sustained-release (SR) in healthy volunteers. METHODS: Six healthy male volunteers received bupropion SR 150 mg daily on days 1 through 3 and 150 mg every 12 hours on day 4 through the morning of day 11. PET investigations were performed between 1 and 7 days before initiation of bupropion SR dosing, as well as 3, 12, and 24 hours after the last dose of bupropion SR on day 11. RESULTS: Bupropion and its metabolites inhibited striatal uptake of the selective DAT-binding radioligand (11)C-betaCIT-FE in vivo. Three hours after the last dose of bupropion SR, average DAT occupancy by bupropion and its metabolites was 26%-a level that was maintained through the last PET assessment at 24 hours after dosing. CONCLUSIONS: Bupropion and its metabolites induced a low occupancy of the striatal DAT over 24 hours under conditions of steady-state oral dosing with therapeutic doses of bupropion SR. These data are consistent with the hypothesis that dopamine reuptake inhibition may be responsible in part for the therapeutic effects of the drug.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14550679&dopt=Abstract
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J Pharmacol Exp Ther. 2004 Jan;308(1):189-97. Epub 2003 Oct 16.
Potent mechanism-based inhibition of human CYP2B6 by clopidogrel and ticlopidine.
Richter T, Murdter TE, Heinkele G, Pleiss J, Tatzel S, Schwab M, Eichelbaum M, Zanger UM.
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
The thienopyridine derivatives ticlopidine and clopidogrel are inhibitors of ADP-induced platelet aggregation. Pharmacological activity of these prodrugs depends on cytochrome P450 (P450)-dependent oxidation to the active antithrombotic agent. In this study, we investigated the interaction potential of clopidogrel and ticlopidine by using human liver microsomes and recombinantly expressed P450 isoforms. Both clopidogrel and ticlopidine inhibited CYP2B6 with highest potency and CYP2C19 with lower potency. Clopidogrel also inhibited CYP2C9, and ticlopidine also inhibited CYP1A2, with lower potency. Inhibition of CYP2B6 was time- and concentration-dependent, and as shown by dialysis experiments, it was irreversible and dependent on NADPH, suggesting a mechanism-based mode of action. Inactivation was of nonpseudo-firstorder type with maximal rates of inactivation (K(inact)) for clopidogrel and ticlopidine in microsomes (recombinant CYP2B6) of 0.35 (1.5 min(-1)) and 0.5 min(-1) (0.8 min(-1)), respectively, and half-maximal inactivator concentrations (KI) were 0.5 microM (1.1 microM) for clopidogrel and 0.2 microM (0.8 microM) for ticlopidine. Inhibition was attenuated by the presence of alternative active site ligands but not by nucleophilic trapping agents or reactive oxygen scavengers, further supporting mechanism-based action. A chemical mechanism is discussed based on the known metabolic activation of clopidogrel and on the finding that hemoprotein integrity of recombinant CYP2B6 was not affected by irreversible inhibition. These results suggest the possibility of drug interactions between thienopyridine derivates and drug substrates of CYP2B6 and CYP2C19.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14563790&dopt=Abstract
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stevenshof.nl
OBJECTIVE: To describe the patterns of use of bupropion in daily clinical practice and factors which determine successful smoking cessation. METHODS: Retrospective follow-up study in 36 pharmacies in the Netherlands. Patients who received at least one prescription for bupropion between January and April, 2000 were included. The pharmacists noted several characteristics relating to the patient, use of bupropion and co-medication. Patients were interviewed by telephone about their current and former smoking habits, the success of their smoking cessation and their experiences with bupropion. MAIN OUTCOME MEASURE: Abstinence rate and factors determining successful abstinence after six months. RESULTS: 322 patients with a least one prescription for bupropion were identified. In 93.5% of patients bupropion was prescribed by the general practitioner. Half of the patients were dispensed 30 or fewer tablets. Pharmacists interviewed 215 (66.8%) patients by telephone. Of these patients 58 (27.0%) still did not smoke six months after the prescription for bupropion. The number of tablets used, lack of co-morbidity, less than two previous attempts to stop smoking and private-insurance were associated with a higher rate of successful abstinence. CONCLUSION: Most patients do not use bupropion in accordance with the recommended period and did not receive the same degree of additional support provided in clinical trials. Nevertheless 27.0% of patients reported to have stopped smoking six months after the prescription for bupropion. This self-reported abstinence rate is only slightly lower than is reported in literature. This might be partly related to the fact that we did not validate smoking cessation by carbonmonoxide monitoring. Bupropion is not reimbursed in the Netherlands. It is difficult to assess whether patients' self-payment has led to the selection of motivated patients, or has been a barrier to finishing using bupropion.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14584227&dopt=Abstract
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