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Find video protocols related to scientific articles indexed in Pubmed.
Pharmacokinetics of cytisine, an ?4 ?2 nicotinic receptor partial agonist, in healthy smokers following a single dose.
Drug Test Anal
PUBLISHED: 06-24-2014
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Cytisine, an ?4 ?2 nicotinic receptor partial agonist, is a plant alkaloid that is commercially extracted for use as a smoking cessation medication. Despite its long history of use, there is very little understanding of the pharmacokinetics of cytisine. To date, no previous studies have reported cytisine concentrations in humans following its use as a smoking cessation agent. A high performance liquid chromatography-ultraviolet (HPLC-UV) method was developed and validated for analysis of Tabex® and nicotine-free oral strips, two commercial products containing cytisine. A sensitive liquid chromatography-mass spectrometry (LC-MS) method was developed and validated for the quantification of cytisine in human plasma and for the detection of cytisine in urine. Single-dose pharmacokinetics of cytisine was studied in healthy smokers. Subjects received a single 3?mg oral dose administration of cytisine. Cytisine was detected in all plasma samples collected after administration, including 15?min post-dose and at 24?h. Cytisine was renally excreted and detected as an unchanged drug. No metabolites were detected in plasma or urine collected in the study. No adverse reactions were reported. Copyright © 2014 John Wiley & Sons, Ltd.
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Adenosine amine congener as a cochlear rescue agent.
Biomed Res Int
PUBLISHED: 05-29-2014
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We have previously shown that adenosine amine congener (ADAC), a selective A1 adenosine receptor agonist, can ameliorate noise- and cisplatin-induced cochlear injury. Here we demonstrate the dose-dependent rescue effects of ADAC on noise-induced cochlear injury in a rat model and establish the time window for treatment.
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Synthesis and methemoglobinemia-inducing properties of benzocaine isosteres designed as humane rodenticides.
Bioorg. Med. Chem.
PUBLISHED: 02-03-2014
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A number of isosteres (oxadiazoles, thiadiazoles, tetrazoles and diazines) of benzocaine were prepared and evaluated for their capacity to induce methemoglobinemia-with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed within each series, with 1,2,4-oxadiazole 3 (metHb%=61.0±3.6) and 1,3,4-oxadiazole 10 (metHb%=52.4±0.9) demonstrating the greatest activity. Of the 5 candidates (compounds 3, 10, 11, 13 and 23) evaluated in vivo, failure to induce a lethal end-point at doses of 120mg/kg was observed in all cases. Inadequate metabolic stability, particularly towards hepatic enzymes such as the CYPs, was postulated as one reason for their failure.
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Synthesis and methemoglobinemia-inducing properties of analogues of para-aminopropiophenone designed as humane rodenticides.
Bioorg. Med. Chem. Lett.
PUBLISHED: 08-30-2013
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A number of structural analogues of the known toxicant para-aminopropiophenone (PAPP) have been prepared and evaluated for their capacity to induce methemoglobinemia-with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed for alkyl analogues of PAPP (aminophenones 1-20; compound 6 metHb%=74.1±2). Besides lipophilicity, this structural sub-class suggested there were certain structural requirements for activity, with both branched (10-16) and cyclic (17-20) alkyl analogues exhibiting inferior in vitro metHb induction. Of the four candidates (compounds 4, 6, 13 and 23) evaluated in vivo, 4 exhibited the greatest toxicity. In parallel, aminophenone bioisosteres, including oximes 30-32, sulfoxide 33, sulfone 34 and sulfonamides 35-36, were found to be inferior metHb inducers to lead ketone 4. Closer examination of Hammett substituent constants suggests that a particular combination of the field and resonance parameters may be significant with respect to the redox mechanisms behind PAPPs metHb toxicity.
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Glucuronidation of anticancer prodrug PR-104A: species differences, identification of human UDP-glucuronosyltransferases, and implications for therapy.
J. Pharmacol. Exp. Ther.
PUBLISHED: 03-22-2011
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PR-104, the phosphate ester of a dinitrobenzamide mustard [PR-104A; 2-((2-bromoethyl)-2-{[(2-hydroxyethyl) amino] carbonyl}-4,6-dinitroanilino)ethyl methanesulfonate], is currently in clinical trial as a hypoxia- and aldo-keto reductase 1C3 (AKR1C3)-activated prodrug for cancer therapy. Here, we investigate species (human, dog, rat, mouse) differences in metabolism to the corresponding O-glucuronide, PR-104G, and identify the human UDP-glucuronosyltransferase (UGT) isoforms responsible. After intravenous PR-104, plasma area under the concentration-time curve ratios (PR-104G/PR-104A) decreased in the order of dog (2.3) > human (1.3) > mouse (0.03) > rat (0.005). The kinetics of uridine 5-diphosphoglucuronic acid-dependent glucuronidation by liver microsomes in vitro fitted the single-enzyme Michaelis-Menten equation with similar K(m) (?150 ?M) but differing V(max) (472, 88, 37, and 14 nmol/h/mg for dog, human, rat, and mouse, respectively), suggesting that facile glucuronidation is responsible for the anomalously rapid clearance of PR-104A in dogs. In vitro-in vivo extrapolation of PR-104A glucuronidation kinetics is consistent with this also being a major clearance pathway in humans. Recombinant UGT screening identified UGT2B7 as the only commercially available human isoform able to conjugate PR-104A, and UGT2B7 protein concentrations were highly correlated (r = 0.93) with PR-104A glucuronidation by liver microsomes from 24 individuals. The active hydroxylamine metabolite of PR-104A, PR-104H, was also glucuronidated by UGT2B7, although with slightly lower specificity and much lower rates. UGT2B7 mRNA expression was highly variable in human tumor databases. Glucuronidation of PR-104A greatly suppressed nitroreduction by AKR1C3 and NADPH-supplemented anoxic human liver S9 (9000g postmitochondrial supernatant). In conclusion, PR-104A is glucuronidated by UGT2B7 with high specificity and seems to make a major contribution to clearance of PR-104A in humans, but it also has the potential to confer resistance in some human tumors.
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The combined impact of CYP2C19 and CYP2B6 pharmacogenetics on cyclophosphamide bioactivation.
Br J Clin Pharmacol
PUBLISHED: 12-24-2010
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The role of CYP pharmacogenetics in the bioactivation of cyclophosphamide is still controversial. Recent clinical studies have suggested a role for either CYP2C19 or CYP2B6. The aim of this study was to clarify the role of these pharmacogenes.
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Validation of an LC-MS method for the detection and quantification of BZP and TFMPP and their hydroxylated metabolites in human plasma and its application to the pharmacokinetic study of TFMPP in humans.
J. Forensic Sci.
PUBLISHED: 06-08-2010
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An LC-MS method was developed for benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP), constituents of "party pills" or "legal herbal highs," and their metabolites in human blood plasma. Compounds were resolved using a mixture of ammonium formate (pH 4.5, 0.01 M) and acetonitrile (flow rate of 1.0 mL/min) with a C18 column. Calibration curves were linear from 1 to 50 ng/mL (R(2) > 0.99); the lower limit of quantification (LLOQ) was 5 ng/mL; the accuracy was >90%; the intra- and interday relative standard deviations (R.S.D) were <5% and <10%, respectively. Human plasma concentrations of TFMPP were measured in blood samples taken from healthy adults (n = 6) over 24 h following a 60-mg oral dose of TFMPP: these peaked at 24.10 ng/mL (±1.8 ng/mL) (C(max) ) after 90 min (T(max)). Plasma concentrations of 1-(3-trifluoromethyl-4-hydroxyphenyl) piperazine peaked at 20.2 ng/mL (±4.6 ng/mL) after 90 min. TFMPP had two disposition phases (t(½) = 2.04 h (±0.19 h) and 5.95 h (±1.63 h). Apparent clearance (Cl/F) was 384 L/h (±45 L/h).
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In vivo interactions between BZP and TFMPP (party pill drugs).
N. Z. Med. J.
PUBLISHED: 10-24-2009
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This study explores potential drug-drug interactions between BZP and TFMPP. This was achieved by comparing the metabolism and pharmacokinetics of BZP and TFMPP when taken together with previously published data on their individual metabolism and pharmacokinetics.
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Metabolic interactions with piperazine-based party pill drugs.
J. Pharm. Pharmacol.
PUBLISHED: 07-11-2009
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Party pills have found use worldwide as a substitute for amphetamine-derived designer drugs. Whilst some information exists about the metabolism of these drugs, there is little information about their ability to inhibit the metabolism of co-administered drugs. This study aimed to determine whether predictions can be made about global interactions between party pills constituents and other drugs metabolised by the same cytochrome P450 (CYP) isoenzymes.
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Party pill drugs--BZP and TFMPP.
N. Z. Med. J.
PUBLISHED: 05-26-2009
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BZP and TFMPP are amphetamine-like recreational drugs and the major active components of party pills. The pharmacodynamic effects of these neurally active drugs are thought to be dependent on their activity at DA and 5-HT receptors and several studies report drug-drug interactions at a pharmacodynamic level. Their metabolism involves the hepatic P450 enzymes CYP2D6, CYP1A2 and CYP3A4 resulting in inhibited metabolism of other drugs and medicines, as well as compromised metabolism in poor metabolisers for CYP2D6. Basic pharmacokinetic properties are described for both BZP and TFMPP when taken alone and in combination. Several studies have shown that these drugs cause several drug-drug interactions.
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Party pills and drug-drug interactions.
N. Z. Med. J.
PUBLISHED: 05-19-2009
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This study aimed to explore the potential for drug-drug interactions involving benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP). This was achieved by determining the effects of BZP and TFMPP on the metabolism of drugs commonly found in the clinical setting by using pooled human liver microsomes.
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In vivo metabolism of norbormide in rats and mice.
Environ. Toxicol. Pharmacol.
PUBLISHED: 03-31-2009
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Norbormides species-selective lethality displays 150-fold and 40-fold more sensitivity to rats than mice and guinea pigs, respectively. Our previous study revealed marked inter-species differences in rate and route of metabolism in liver preparations from different species, with hydroxylation the major route. To examine whether rapid metabolic clearance or species-dependent formation of a toxic metabolite play a role in the marked species-sensitivity, we initiated in vivo metabolic studies in rats and mice. After oral dosing, norbormide was detected in mouse but not rat blood. In contrast, liver analysis revealed that norbormide concentration was significantly higher in rat compared with mouse, and that it underwent extensive metabolism tentatively identified via hydroxylation in rat, whilst none was detected in mouse. Although an unidentified metabolite (M3) was detected in rat blood after oral dosing, no metabolites were detected 1min after intravenous dosing, which proved lethal at 0.5mg/kg. Taken together, the data indicate that the toxicity resides with the parent compound, rather species-dependent formation of a potent metabolite and that species sensitivity may be controlled at the pharmacodynamic level.
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In vitro metabolism of norbormide in rat, mouse and guinea pig liver preparations.
Environ. Toxicol. Pharmacol.
PUBLISHED: 01-01-2009
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Differences between species in response to norbormide (NRB) may arise through differential pharmacodynamic and/or pharmacokinetic properties. We hypothesise that species-selectivity is at least partly determined by differences in metabolism based on in vitro data generated in liver preparations from rats, mice and guinea pigs. HPLC separation and LC/MS identification revealed that NRB undergoes metabolism primarily to hydroxylated form that was tentatively identified in both rat and non-rat species with NADPH as the preferred cofactor. However, the metabolic profile and the rate are different between species. Gender differences are also reported in the metabolic rate in rats and we postulate that this may be responsible for different toxic sensitivities seen between sexes. Using this knowledge, we aim to develop pharmacological tool(s) for use in designing a new class of drugs that can be targeted in a tissue-selective manner. Further in vivo pharmacokinetic with receptor affinity studies are warranted.
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