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1. |
Survey of clinical pharmacology training in the United States and Canada |
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Clinical Pharmacology&Therapeutics,
Volume 60,
Issue 1,
1996,
Page 1-7
Louis R. Cantilena,
Raymond L. Woosley,
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摘要:
A survey of 139 medical schools in the United States and Canada was conducted in 1993–1994 to determine where active training programs in clinical pharmacology were located. A secondary survey of clinical pharmacology program directors followed in 1994–1995. Thirty‐nine active programs were identified where 113 fellows (84 physicians and 29 nonphysicians) were enrolled. Sixty‐eight percent of current physician fellows were trained in internal medicine before they entered their clinical pharmacology program. Forty‐four percent of trainees were reported to be U.S. citizens. Fewer than 20 fellows complete training each year. The reported content of training programs was 12% didactic, 72% research, 12% clinical service, and 9% supervised teaching. Funding sources for trainees varied considerably. Nearly 50% of trainees were supported all or in part by funds from the National Institutes of Health (NIH), and approximately 40% relied on international sources of support. No correlation between salary and funding source or fellow degree was found. Nearly two‐thirds of recent program graduates obtained employment in an academic setting, whereas 15% entered the pharmaceutical industry. These data indicate that subspecialty training in clinical pharmacology is available at 39 medical schools in the United States and Canada. Current fellowship training is primarily research based and nearly equally supported by NIH and international sources.Clinical Pharmacology&Therapeutics(1996)6
ISSN:0009-9236
DOI:10.1016/S0009-9236(96)90160-5
年代:1996
数据来源: WILEY
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2. |
Black Americans have an increased rate of angiotensin converting enzyme inhibitor‐associated angioedema |
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Clinical Pharmacology&Therapeutics,
Volume 60,
Issue 1,
1996,
Page 8-13
Nancy J. Brown,
Wayne A. Ray,
Mary Snowden,
Marie R. Griffin,
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摘要:
ObjectiveTo study the association of race and other patient characteristics associated with angiotensin converting enzyme (ACE) inhibitor‐associated angioedema.MethodsThis was a retrospective cohort study of participants in the Tennessee Medicaid Program (≥15 years of age) to whom ACE inhibitors had been prescribed from 1986 through 1992.ResultsWe identified 82 patients with confirmed angioedema during 51,752 person‐years of ACE inhibitor use, giving an overall rate of angioedema of 1.6 per 1000 person‐years of ACE inhibitor use. After potential confounding factors were controlled for, the adjusted relative risk (RR) of angioedema among black American users of ACE inhibitors was 4.5 (95% confidence interval [CI] 2.9 to 6.8) compared with white subjects. In addition to race, other factors associated with a significantly increased relative risk in the entire population were the first 30 days of ACE inhibitor use (RR, 4.6; 95% CI, 2.5 to 8.5) compared to>1 year of use, use of either lisinopril (RR, 2.2; 95% CI, 1.2 to 3.9) or enalapril (RR, 2.2; 95% CI, 1.4 to 3.5) compared to captopril, and previous hospitalization for any diagnosis within 30 days (RR, 2.0; 95% CI, 1.1 to 3.6). Neither ACE inhibitor dose nor concurrent diuretic use was associated with the risk of angioedema.ConclusionsThese data suggest that black Americans have a substantially increased risk of ACE inhibitor‐associated angioedema compared with white subjects and that this increased risk cannot be attributed to an effect of dose, specific ACE inhibitor, or concurrent medications.Clinical Pharmacology&Therapeutics(1996)60,
ISSN:0009-9236
DOI:10.1016/S0009-9236(96)90161-7
年代:1996
数据来源: WILEY
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3. |
First‐pass metabolism of midazolam by the human intestine |
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Clinical Pharmacology&Therapeutics,
Volume 60,
Issue 1,
1996,
Page 14-24
Mary F. Paine,
Danny D. Shen,
Kent L. Kunze,
James D. Perkins,
Christopher L. Marsh,
John P. McVicar,
Darlene M. Barr,
Bruce S. Gillies,
Kenneth E. Thummel,
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摘要:
The in vivo intestinal metabolism of the CYP3A probe midazolam to its principal metabolite, 1′‐hydroxymidazolam, was investigated during surgery in 10 liver transplant recipients. After removal of the diseased liver, five subjects received 2 mg midazolam intraduodenally, and the other five received 1 mg midazolam intravenously. Simultaneous arterial and hepatic portal venous blood samples were collected during the anhepatic phase; collection of arterial samples continued after reperfusion of the donor liver. Midazolam, 1′‐hydroxymidazolam, and 1′‐hydroxymidazolam glucuronide were measured in plasma. A mass balance approach that considered the net change in midazolam (intravenously) or midazolam and 1′‐hydroxymidazolam (intraduodenally) concentrations across the splanchnic vascular bed during the anhepatic phase was used to quantitate the intestinal extraction of midazolam after each route of administration. For the intraduodenal group, the mean fraction of the absorbed midazolam dose that was metabolized on transit through the intestinal mucosa was 0.43 ± 0.18. For the intravenous group, the mean fraction of midazolam extracted from arterial blood and metabolized during each passage through the splanchnic vascular bed was 0.08 ± 0.11. Although there was significant intersubject variability, the mean intravenous and intraduodenal extraction fractions were statistically different (p= 0.009). Collectively, these results show that the small intestine contributes significantly to the first‐pass oxidative metabolism of midazolam catalyzed by mucosal CYP3A4 and suggest that significant first‐pass metabolism may be a general phenomenon for all high‐turnover CYP3A4 substrates.Clinical Pharmacology&Therapeut
ISSN:0009-9236
DOI:10.1016/S0009-9236(96)90162-9b
年代:1996
数据来源: WILEY
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4. |
Erythromycin‐felodipine interaction: Magnitude, mechanism, and comparison with grapefruit juice |
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Clinical Pharmacology&Therapeutics,
Volume 60,
Issue 1,
1996,
Page 25-33
David G. Bailey,
John R. Bend,
J. Malcolm O. Arnold,
Lan T. Tran,
J. David Spence,
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摘要:
ObjectiveTo investigate a potentially marked effect by erythromycin on felodipine pharmacokinetics, to characterize the mechanism, and to compare the interaction with that between grapefruit juice and felodipine.MethodsFelodipine, 10 mg extended release, was administered with 250 ml water, 250 mg erythromycin, or 250 ml grapefruit juice in a randomized crossover study of 12 healthy men. Erythromycin base, 250 mg four times a day, was started the day before and continued on that study day. Pharmacokinetic values of felodipine, the primary metabolite dehydrofelodipine, and the major secondary derivative M3 metabolite were studied.ResultsCompared with water, erythromycin produced severalfold higher felodipine area under the plasma drug concentration‐time profile (AUC), plasma peak drug concentrations (Cmax), and apparent elimination half‐life (t12); however, the effect was variable among individuals. Erythromycin augmented dehydrofelodipine AUC, Cmax, and t12but decreased dehydrofelodipine/felodipine ratios. The AUC of the M3 metabolite and the M3 metabolite/dehydrofelodipine ratios were reduced. These findings support inhibition of both metabolic pathways likely mediated by CYP3A4. Grapefruit juice produced similar mean effects but did not prolong felodipine or dehydrofelodipine t12. Individually, felodipine AUC with erythromycin was greater than or similar to that with grapefruit juice. Relative felodipine AUC (erythromycin compared with grapefruit juice) correlated with relative felodipine Cmaxbut not with relative felodipine t12, suggesting felodipine AUC differed between these treatments, mainly from factors affecting presystemic drug elimination.ConclusionsErythromycin produced an important pharmacokinetic interaction with felodipine by inhibition of drug metabolism. Although erythromycin and grapefruit juice shared a common mechanism, erythromycin likely reduced felodipine biotransformation at the gut wall and liver, whereas single‐dose grapefruit juice had an effect mainly at the gut wall.Clinical Pharmacology&Therapeutics(1996)60, 25–
ISSN:0009-9236
DOI:10.1016/S0009-9236(96)90163-0
年代:1996
数据来源: WILEY
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5. |
Flavanone absorption after naringin, hesperidin, and citrus administration |
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Clinical Pharmacology&Therapeutics,
Volume 60,
Issue 1,
1996,
Page 34-40
Barbara Ameer,
Randy A. Weintraub,
Jodie V. Johnson,
Richard A. Yost,
Russell L. Rouseff,
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摘要:
Disposition of citrus flavonoids was evaluated after single oral doses of pure compounds (500 mg naringin and 500 mg hesperidin) and after multiple doses of combined grapefruit juice and orange juice and of once‐daily grapefruit. Cumulative urinary recovery indicated low bioavailability (<25%) of naringin and hesperidin. The aglycones naringenin and hesperitin were detected in urine and plasma by positive chemical ionization‐collisionally activated dissociation tandem mass spectrometry (PCI‐CAD MS/MS). After juice administration, PCI‐CAD MS/MS detected naringenin, hesperitin, and four related flavanones, tentatively identified as monomethoxy and dimethoxy derivatives. These methoxyflavanones appear to be absorbed from juice. Absorbed citrus flavanones may undergo glucuronidation before urinary excretion.Clinical Pharmacology&Therapeutics(1996)60, 34
ISSN:0009-9236
DOI:10.1016/S0009-9236(96)90164-2
年代:1996
数据来源: WILEY
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6. |
Steady‐state serum concentrations of the neuroleptic perphenazine in relation to CYP2D6 genetic polymorphism |
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Clinical Pharmacology&Therapeutics,
Volume 60,
Issue 1,
1996,
Page 41-47
Kristian Linnet,
Ove Wiborg,
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摘要:
Steady‐state serum concentration to dose ratios of the neuroleptic agent perphenazine were related to CYP2D6 metabolizer status for 96 psychiatric inpatients: 88 extensive metabolizers and eight poor metabolizers. The median concentration per dose of the poor metabolizer group (0.195 nmol/L per milligram) was about twice the median (0.098 nmol/L per milligram) of the 56 extensive metabolizers without interacting medicine (p<0.01). The rest of the extensive metabolizers (n= 32), who were comedicated with drugs that compete with perphenazine for metabolism by CYP2D6, had an intermediate median value of 0.140 nmol/L per milligram. The range of concentration/dose values for the total extensive metabolizer group extended from 0.025 to 0.688 nmol/L per milligram, that is, an almost thirtyfold variation. The concentration/dose range of the eight poor metabolizer subjects was 0.096 to 0.750 nmol/L per milligram. Serum levels not corrected for dose overlapped to a large degree among the groups, with a total range from 0.5 to 12 nmol/L. This study points toward a limited information value of CYP2D6 genotyping in the context of therapeutic drug monitoring of perphenazine.Clinical Pharmacology&Therapeutics(1996)60, 41–47;
ISSN:0009-9236
DOI:10.1016/S0009-9236(96)90165-4
年代:1996
数据来源: WILEY
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7. |
Effects of divalproex sodium on amitriptyline and nortriptyline pharmacokinetics |
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Clinical Pharmacology&Therapeutics,
Volume 60,
Issue 1,
1996,
Page 48-53
Shekman L. Wong,
John Cavanaugh,
Harry Shi,
Walid M. Awni,
G. Richard Granneman,
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摘要:
BackgroundDivalproex sodium has been found to be efficacious in the prophylaxis of migraine headaches and the management of the manic phase of bipolar syndrome. Because amitriptyline is also prescribed in these patient populations, data are needed on their potential for interaction.MethodsThe effect of concomitant administration of divalproex sodium on the pharmacokinetics of amitriptyline and its active metabolite, nortriptyline, was investigated in an open‐label, sequential, two‐period phase I study. Ten healthy male and five healthy female subjects received 50 mg amitriptyline hydrochloride on two occasions: (1) alone (period 1) and (2) 2 hours after receiving the ninth dose of 500 mg divalproex sodium (Depakote) administered once every 12 hours (period 2).ResultsAmitriptyline area under the curve was increased 31% from the combined effect of decreased first‐pass metabolism and inhibition of systemic metabolism. The elevated nortriptyline plasma levels reflected primarily the increase in amitriptyline concentrations but also appeared to involve modest inhibition of nortriptyline elimination. For the sum of amitriptyline and nortriptyline concentrations, the peak plasma concentration mean was 19% higher with concomitant divalproex dosing. The mean area under the curve for the sum of amitriptyline and nortriptyline concentrations was 42% higher with concomitant divalproex dosing than it was for dosing with amitriptyline alone.ConclusionThese results suggested that a lower dose of amitriptyline might be considered when divalproex is administered concomitantly.Clinical Pharmacology&Therapeutics(1996)60, 48–
ISSN:0009-9236
DOI:10.1016/S0009-9236(96)90166-6
年代:1996
数据来源: WILEY
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8. |
Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid |
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Clinical Pharmacology&Therapeutics,
Volume 60,
Issue 1,
1996,
Page 54-61
Pertti J. Neuvonen,
Kirsi‐Maija Jalava,
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摘要:
BackgroundLovastatin is a cholesterol‐lowering drug that can cause myopathy as a rare side effect. Concomitant use of certain drugs (e.g., cyclosporine) increases the risk of skeletal muscle toxicity. Lovastatin is metabolized by CYP3A4. Because itraconazole is a potent inhibitor of CYP3A4, we wanted to study a possible interaction between these drugs.MethodsIn this double‐blind, randomized, two‐phase crossover study, 12 healthy volunteers received either 200 mg itraconazole or placebo orally once a day for 4 days. On day 4, each subject ingested a single 40 mg dose of lovastatin. Plasma concentrations of lovastatin, lovastatin acid, itraconazole, hydroxyitraconazole, and creatine kinase were measured up to 24 hours.ResultsOn average, itraconazole increased the peak concentration (Cmax) of lovastatin and the area under the lovastatin concentration‐time curve (AUC) more than twentyfold (p<0.001). The mean Cmaxof the active metabolite, lovastatin acid, was increased 13‐fold (range, tenfold to 23‐fold;p<0.001) and the AUC(0–24) twentyfold (p<0.001). In one subject plasma creatine kinase was increased tenfold within 24 hours of lovastatin administration during the itraconazole phase but not during the placebo phase. No increase in creatine kinase was observed in the other subjects.ConclusionsItraconazole greatly increases plasma concentrations of lovastatin and lovastatin acid. Inhibition of CYP3A4‐mediated metabolism probably explains the increased toxicity of lovastatin caused not only by itraconazole but also by cyclosporine, erythromycin, and other inhibitors of CYP3A4. Their concomitant use with lovastatin and simvastatin should be avoided, or the dose of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors should be reduced accordingly.Clinical Pharmacology&Therapeutic
ISSN:0009-9236
DOI:10.1016/S0009-9236(96)90167-8
年代:1996
数据来源: WILEY
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9. |
N‐Acetyltransferase 2 polymorphism in patients infected with human immunodeficiency virus |
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Clinical Pharmacology&Therapeutics,
Volume 60,
Issue 1,
1996,
Page 62-67
Gilbert R. Kaufmann,
Markus Wenk,
Walter Taeschner,
Bettina Peterli,
Klaus Gyr,
Urs A. Meyer,
Walter E. Haefeli,
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摘要:
ObjectivesTo evaluate the prevalence of slow acetylation of hepaticN‐acetyltransferase 2 (NAT2) in patients with different stages of human immunodeficiency virus (HIV) infection, to assess the relationship between acetylation capacity and the degree of immunosuppression, and to study the concordance between NAT2 phenotype and genotype.MethodsThis prospective study in a consecutive sample of HIV‐infected patients was performed in the outpatient department of a university hospital that provides primary and tertiary care. TheNAT2genotype was assessed by polymerase chain reaction and restriction fragment length polymorphism, the NAT2 phenotype was determined by caffeine test (urinary metabolic ratio of the caffeine metabolites 5‐acetylamino‐6‐formylamino‐3‐methyluracil and 1‐methylxanthine).ResultsFifty patients with Centers for Disease Control HIV infection stages A (10 patients), B (20 patients), and C (20 patients) were included in the study after each gave informed consent. According to genotyping and phenotyping, 32 (64%) patients were slow acetylators, with a concordance of the two methods of 96%. The overall distribution was similar to distributions reported in other white populations. The slow acetylator phenotype was found in seven, 16, and nine patients with stage A, B, and C, respectively. Eight of the 10 patients with previous adverse reactions to sulfonamides had slow acetylator phenotypes. Acetylation capacity was independent of CD4 cell counts.ConclusionsThis study revealed an excellent agreement between genotypes and phenotypes of NAT2 in patients with HIV infection. There was no increase in prevalence of slow acetylation in patients with advanced stages of the disease. This apparent discrepancy to an earlier study may be the result of differences in co‐medication of the patients studied and may point to the relevance of drug interactions in the treatment of patients with HIV infection.Clinical Pharmacology&Therapeutics(19
ISSN:0009-9236
DOI:10.1016/S0009-9236(96)90168-X
年代:1996
数据来源: WILEY
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10. |
Thiopurine methyltransferase activity in a Korean population sample of children |
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Clinical Pharmacology&Therapeutics,
Volume 60,
Issue 1,
1996,
Page 68-74
Jeong Ok Park‐Hah,
Bjørg Klemetsdal,
Roy Lysaa,
Kwang Hae Choi,
Jarle Aarbakke,
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摘要:
Thiopurine methyltransferase (TPMT) is a cytoplasmic enzyme that catalyzes theS‐methylation of the cytotoxic drugs 6‐mercaptopurine and azathioprine. Red blood cell (RBC) TPMT activity is subject to genetic polymorphism, and we have previously demonstrated an interethnic difference in TPMT activity. To investigate whether there was a race‐related difference in RBC TPMT activity, TPMT was measured in a Korean population sample of 309 healthy children. Mean TPMT activity in healthy Korean children was 12.4 ± 2.4 units/ml RBC, which is similar to the earlier reported TPMT activities in white populations. In contrast to the bimodal or trimodal frequency distributions of RBC TPMT activity in most other population samples, the frequency distribution histogram, the probit plot, and the Shapiro‐Wilk test supported a normal distribution of TPMT activity in this Korean population sample of healthy children. Mean RBC TPMT activity showed a tendency to decrease with age, but it was not statistically significant. No gender‐related difference in RBC TPMT activity was found.Clinical Pharmacology&Therapeutics(1996)60,
ISSN:0009-9236
DOI:10.1016/S0009-9236(96)90169-1
年代:1996
数据来源: WILEY
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