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1. |
Criteria for judging proposals for national health care reform with respect to therapeutics |
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Clinical Pharmacology&Therapeutics,
Volume 55,
Issue 1,
1994,
Page 1-4
David W Nierenberg,
Marcus M Reidenberg,
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摘要:
Clinical Pharmacology and Therapeutics(1994)55,1–4; doi:10.1038/clpt.1994
ISSN:0009-9236
DOI:10.1038/clpt.1994.1
年代:1994
数据来源: WILEY
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2. |
Dietary fatty acids are also drugs |
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Clinical Pharmacology&Therapeutics,
Volume 55,
Issue 1,
1994,
Page 5-9
Andrew J Dannenberg,
Marcus M Reidenberg,
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摘要:
Clinical Pharmacology and Therapeutics(1994)55,5–9; doi:10.1038/clpt.1994
ISSN:0009-9236
DOI:10.1038/clpt.1994.2
年代:1994
数据来源: WILEY
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3. |
Debrisoquin oxidation genotype and susceptibility to lung cancer |
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Clinical Pharmacology&Therapeutics,
Volume 55,
Issue 1,
1994,
Page 10-14
José A G Agúndez,
Carmen Martínez,
José M Ladero,
María C Ledesma,
José M Ramos,
Ramón Martín,
Alvaro Rodriguez,
Carlos Jara,
Julio Benítez,
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摘要:
The association between the polymorphism of the cytochrome P450 debrisoquin hydroxylase (CYP2D6) and lung cancer is controversial. Previous reports suggested a link between CYP2D6 phenotype and lung cancer, with poor metabolizers having reduced susceptibility. Nevertheless, negative findings have also been published. By using allele‐specific amplification, we have studied the frequency of fourCYP2D6(wild type and mutant) alleles in 89 patients with histologically proved bronchogenic carcinoma and in 98 healthy volunteers. Our findings confirm that poor metabolizers are underpresented among patients with lung cancer because of a different genetic background. Our findings also reveal that the rareCYP2D6(C)mutant allele is sixfold more frequent among patients with lung cancer (p<0.0005). This suggests that theCYP2D6(C)allele could be considered as an additional risk factor because carriers could have higher susceptibility to the development of lung cancer.Clinical Pharmacology and Therapeutics(1994)55,10–14; doi:10.1038/clpt.19
ISSN:0009-9236
DOI:10.1038/clpt.1994.3
年代:1994
数据来源: WILEY
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4. |
Thiopurine methyltransferase activity in American white subjects and black subjects |
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Clinical Pharmacology&Therapeutics,
Volume 55,
Issue 1,
1994,
Page 15-20
Howard L McLeod,
Jin‐Sying Lin,
Edward P Scott,
Ching‐Hon Pui,
William E Evans,
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摘要:
BackgroundThiopurine methyltransferase (TPMT) is a cytoplasmic enzyme that preferentially catalyzes theS‐methylation of aromatic and heterocyclic sulfhydryl compounds, including 6‐mercaptopurine. TPMT exhibits genetic polymorphism in white populations, with 89% of individuals having high TPMT activity, 11% having intermediate activity, and one in 300 having extremely low or absent activity. TPMT activity is inversely correlated with formation of active 6‐mercaptopurine metabolites (thioguanine nucleotides), thereby influencing 6‐mercaptopurine toxicity and efficacy.MethodsTo investigate ethnic and gender differences in TPMT, we measured erythrocyte TPMT activity in 209 white healthy subjects and 196 black healthy subjects (202 women and 203 men).ResultsThe black population had lower TPMT activity than the white population (median, 14.4 versus 16.8 units/ml packed erythrocytes;p<0.001). Maximum likelihood estimation of TPMT activity distribution identified 91.9% and 93.9% with high activity and 7.7% and 6.1% with intermediate activity in the white and black groups, respectively.ConclusionsThese data indicate that TPMT activity is similarly polymorphic in American black subjects and white subjects, although median TPMT activity is approximately 17% lower in black subjects.Clinical Pharmacology and Therapeutics(1994)55,15–20; doi:10.1038/c
ISSN:0009-9236
DOI:10.1038/clpt.1994.4
年代:1994
数据来源: WILEY
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5. |
Enhanced covalent binding of tolmetin to proteins in humans after multiple dosing |
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Clinical Pharmacology&Therapeutics,
Volume 55,
Issue 1,
1994,
Page 21-27
Parnian Zia‐Amirhosseini,
Joseph C Ojingwa,
Hildegard Spahn‐Langguth,
Antony F McDonagh,
Leslie Z Benet,
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摘要:
The in vivo stability of tolmetin—plasma protein adducts was characterized in six healthy human volunteers after a 400 mg single dose and after a multiple‐dose regimen of 400 mg tolmetin every 12 hours for 10 days. Although the mean ± SD maximum bound concentration was only 2.72 ± 0.98 ng drug/mg protein after a single dose, it was almost an order of magnitude higher after multiple dosing. The protein adduct exhibited an average half‐life of 4.8 ± 0.9 days in contrast to the much shorter 5‐hour half‐lives for tolmetin and its glucuronide.Clinical Pharmacology and Therapeutics(1994)55,21–27; doi:10.1
ISSN:0009-9236
DOI:10.1038/clpt.1994.5
年代:1994
数据来源: WILEY
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6. |
Quinidine‐enhanced β‐blockade during treatment with propafenone in extensive metabolizer human subjects |
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Clinical Pharmacology&Therapeutics,
Volume 55,
Issue 1,
1994,
Page 28-34
Klaus E Mörike,
Dan M Roden,
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摘要:
Propafenone, a sodium channel blocking antiarrhythmic drug with β‐blocking properties, is metabolized to non‐β‐blocking metabolites in part by cytochrome P4502D6. Subtherapeutic doses of quinidine inhibit P4502D6 and increase plasma propafenone in extensive metabolizer subjects, in whom the active enzyme is present. In this study we tested the hypothesis that quinidine would enhance β‐blockade in extensive metabolizers receiving propafenone. Seven extensive and two poor metabolizers received propafenone (225 mg orally every 8 hours) plus quinidine sulfate (60 mg orally every 8 hours) or propafenone plus placebo for 7 days in a randomized, double‐blind, crossover fashion. In extensive metabolizers, the coadministration of quinidine significantly increased the extent of propafenone‐induced β‐blockade, assessed by a decrease in exercise heart rate and by sensitivity to isoproterenol. We conclude that low‐dose quinidine enhances propafenone‐induced β‐blockade in extensive metabolizers. Thus the polymorphic patterns of drug metabolism can result in clinically significant drug interactions on a genetic basis.Clinical Pharmacology and Therapeutics(1994)55,28–
ISSN:0009-9236
DOI:10.1038/clpt.1994.6
年代:1994
数据来源: WILEY
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7. |
Dispositional factors do not contribute to the enantiospecificity of the cardiovascular effects of phenylpropanolamine |
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Clinical Pharmacology&Therapeutics,
Volume 55,
Issue 1,
1994,
Page 35-43
Creina S Stockley,
Lindon M H Wing,
Anne L Tonkin,
John O Miners,
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摘要:
The pharmacokinetics and blood pressure response of the phenylpropanolamine enantiomers (i.e., d‐ andl‐phenylpropanolamine) were determined after the separate oral administration of racemicdl‐phenylpropanolamine (75 mg),l‐phenylpropanolamine (37.5 mg), andd‐phenylpropanolamine (37.5 mg) to six healthy volunteers. No significant differences were observed between any of the pharmacokinetic parameters ofd‐ andl‐phenylpropanolamine when the enantiomers were administered individually or as the racemate. There was also no difference in the ex vivo plasma protein binding ofd‐ andl‐phenylpropanolamine, determined individually or as the racemate. Significant increases from baseline in systolic and diastolic blood pressure (supine and standing) were observed fordl‐ andl‐phenylpropanolamine, whereasd‐phenylpropanolamine had no effect on blood pressure. The effects ofdl‐ andl‐phenylpropanolamine on blood pressure were not significantly different. The data from this study show that pharmacokinetic factors do not contribute to the stereospecificity of the cardiovascular effects of phenylpropanolamine or to the interindividual variability in the blood pressure response to phenylpropanolamine.Clinical Pharmacology and Therapeutics(1994)55,35
ISSN:0009-9236
DOI:10.1038/clpt.1994.7
年代:1994
数据来源: WILEY
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8. |
Verapamil decreases lymphocyte protein kinase C activity in humans |
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Clinical Pharmacology&Therapeutics,
Volume 55,
Issue 1,
1994,
Page 44-49
Paolo B Depetrillo,
Darrell R Abernethy,
Irving W Wainer,
Nabil S Andrawis,
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摘要:
To determine if clinically used doses of the calcium antagonist verapamil measurably alter intracellular transduction mechanisms associated with the phosphatidylinositol pathway, lymphocyte protein kinase C activity was determined in subjects in a drug‐free state, after 1 week of verapamil treatment (120 mg three times daily) and after a second week of verapamil treatment (240 mg sustained‐release preparation once daily). Nine healthy male volunteers were studied and in these subjects baseline protein kinase C activity (mean ± SEM; 5.07 ± 0.76 pmol/μg protein/min) tended to decrease after 1 week (3.50 ± 0.20 pmol/μg protein/min) and was significantly decreased after 2 weeks (3.14 ± 0.27 pmol/μg protein/min;p<0.05 from baseline) of verapamil treatment. These data indicate that verapamil, at usual clinical doses, decreases protein kinase C activity in a marker tissue, the circulating lymphocyte. If protein kinase C activity in this tissue is a surrogate for other verapamil target tissues, such as vascular smooth muscle and heart muscle, these findings may provide insight into the in vivo mechanism by which verapamil decreases protein synthesis, limits cell growth, and reverses cellular hypertrophy in these tissues.Clinical Pharmacology and Therapeutics(1994)55,44–49; doi:10.103
ISSN:0009-9236
DOI:10.1038/clpt.1994.8
年代:1994
数据来源: WILEY
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9. |
Pharmacodynamics of MK‐0963, a new 5α‐reductase inhibitor: Effects on serum androgen concentrations |
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Clinical Pharmacology&Therapeutics,
Volume 55,
Issue 1,
1994,
Page 50-54
Jules I Schwartz,
Oscar L Laskin,
Carol A Meeter,
Patricia M Patterson,
Stephen H Schneider,
Kenneth C Lasseter,
James R Seibold,
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摘要:
The hormonal effects after a 10‐day administration of a 4‐azasteroid inhibitor of 5α‐reductase, MK‐0963 (previously L‐654,066), were evaluated in 35 healthy male volunteers in an increasing‐dose, five‐panel design. Marked suppression of serum dihydrotestosterone was observed after the once‐daily administration at each active dose level (placebo, 0.1, 0.5, 1.0, 10, and 25 mg). Maximum dihydrotestosterone suppression occurred at doses greater than or equal to 10 mg. The mean percentage (±SE) decreases in dihydrotestosterone at 24 hours after the last dose in the groups treated with the 10 and 25 mg doses were 78% ± 4.9% and 80% ± 2.9%, respectively. The 25 mg dose maintained a dihydrotestosterone suppression of at least 70% for more than 6 days after the last dose. No consistent changes in serum testosterone were noted. This study shows that administration of multiple doses of MK‐0963 results in a substantial suppression of serum dihydrotestosterone with no consistent influence on serum testosterone concentrations.Clinical Pharmacology and Therapeutics(1994)55,50–54;
ISSN:0009-9236
DOI:10.1038/clpt.1994.9
年代:1994
数据来源: WILEY
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10. |
Pharmacokinetics and pharmacodynamics of a new cardiotonic vasodilator agent, 349U85, in normal subjects |
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Clinical Pharmacology&Therapeutics,
Volume 55,
Issue 1,
1994,
Page 55-63
G Dennis Clifton,
Michael R Harrison,
Daniel P Wermeling,
Robert A Long,
Richard J Fleck,
Robert L Rolleri,
Stephen Weller,
Alan R Brown,
Richard M Welch,
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摘要:
ObjectiveTo assess the pharmacodynamics and pharmacokinetics of single oral doses of a new vasodilator‐cardiotonic agent, 349U85 hydrochloride [6‐piperidino‐2(lH)‐quinolinone hydrochloride], in healthy male subjects.MethodsThis randomized, parallel, double‐blind, placebo‐controlled, dose escalation trial was conducted at a university‐based clinical research center among 27 healthy male subjects. Data measurements used in the study included cardiac index, supine and standing blood pressure, 24‐hour ambulatory electrocardiography, and 12‐lead electrocardiography.ResultsDoses from 2 mg to 250 mg were well tolerated. Cardiac index, supine heart rate, and orthostatic hypotension, indicators of inotropic, chronotropic, and vasodilator effects, respectively, correlated to plasma concentrations of 349U85 and of its metabolite, 661U88. Results suggest that 349U85 may be more responsible for inotropic effects, whereas 661U88 may be more responsible for vasodilatory and chronotropic effects. These results are consistent with the preclinical pharmacologic profile for these two compounds. Headache, orthostatic dizziness, and hypotension tended to occur more frequently at higher doses and were temporally related to drug administration. Pharmacokinetic analyses indicate nonlinearity of 349U85 and 661U88, suggestive of saturation of metabolism and large interindividual variability in maximum plasma drug concentration and area under the plasma concentration—time curve. The source of the variability is not known. The time to maximum distribution was approximately 0.7 hours for both 349U85 and 661U88; the terminal elimination half‐life was 1 hour for 349U85 and 3 hours for 661U88. Holter monitoring revealed asymptomatic increases in ventricular and supraventricular ectopic activity in some volunteers; ectopy appeared to be related to the dose of 349U85 and generally occurred at higher doses.Clinical Pharmacology and Therapeutics(1994)55,55–63;
ISSN:0009-9236
DOI:10.1038/clpt.1994.10
年代:1994
数据来源: WILEY
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