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Biomedical subjects

K M Williamson

Publications and source records attributed to K M Williamson.

At least 19 recordsLinked to original sources
PubMed2001

Effect of fluoxetine on carvedilol pharmacokinetics, CYP2D6 activity, and autonomic balance in heart failure patients.

The objective of this study was to examine the pharmacokinetic and pharmacodynamic consequences of concomitant administration of fluoxetine and carvedilol in heart failure patients. Fluoxetine (20 mg) or matching placebo was administered in a randomized, double-blind, two-period crossover study to 10 patients previously identified as extensive metabolizers of CYP2D6 substrates. Patients were maintained on a carvedilol dose of 25 or 50 mg bid and given fluoxetine/placebo for a minimum of 28 days. Plasma was collected over the 12-hour carvedilol dosing interval, and the concentrations of the R(+) and S(-) enantiomers of carvedilol were measured. CYP2D6 phenotype was assessed during each study period using dextromethorphan (30 mg). Changes in autonomic modulation between study periods were measured by heart rate variability in the time and frequency domains using ambulatory electrocardiographic monitoring. Compared to placebo, fluoxetine coadministration resulted in a 77% increase in mean (+/- SD) R(+) enantiomer AUC0-12 (522 +/- 413 vs. 927 +/- 506 ng.h/mL, p = 0.01) and a nonsignificant increase in S(-) enantiomer AUC (244 +/- 185 vs. 330 +/- 179 ng.h/mL, p = 0.17). Mean apparent oral clearance for both enantiomers decreased significantly with fluoxetine administration (R(+): 10.3 +/- 7.2 vs. 4.5 +/- 2.2 mL/min/kg; S(-): 22.5 +/- 12.3 vs. 12.6 +/- 7.4 mL/min/kg; p = 0.004 and 0.03, respectively). No differences in adverse effects, blood pressure, or heart rate were noted between treatment groups, and there were no consistent changes in heart rate variability parameters. In conclusion, fluoxetine administration resulted in a stereospecific inhibition of carvedilol metabolism, with the R(+) enantiomer increasing to a greater extent than the S(-) enantiomer. However, this interaction was of little clinical significance in our sample population.

Adrenergic beta-Antagonists↗
PubMed2001

Lack of gender differences and large intrasubject variability in cytochrome P450 activity measured by phenotyping with dextromethorphan.

Gender-based differences in cytochrome P450 (CYP) activity may occur due to endogenous hormonal fluctuations with the menstrual cycle, which are altered by oral contraceptives. This study assessed the average activity and within-subject variability in CYP3A4 and CYP2D6 in men, women taking Triphasil, and regularly menstruating women not receiving oral contraceptives. Thirty-three healthy volunteers participated in this 28-day pilot study (12 women receiving Triphasil) (OCs), 11 regularly menstruating women not on exogenous progesterone or estrogen (no OCs), and 10 men. CYP3A4 and CYP2D6 activities were phenotyped with dextromethorphan (DM) on study days 7, 14, 21, and 28 using urinary ratios of DM:3-methoxymorphinan (3MM) and DM:dextrorphan (DX), respectively. Serial blood concentrations of estrogen and progesterone and menstrual diaries were used to determine menstrual phase in both groups of women. Average urinary DM:3MM and DM:DX in the 28 extensive metabolizers of CYP2D6 did not differ between the three study populations (p = 0.86 and 0.93, respectively). Post hoc power analysis indicated that more than 1000 subjects would be needed for 80% power (alpha = 0.05) to detect a +/- 15% difference from the population mean in the urinary ratios of dextromethorphan and its metabolites 3MM and DX. Variability in CYP3A4 and CYP2D6 activity, characterized by intrasubject standard deviation, also did not differ. The varying doses of levonorgesterol and ethinyl estradiol in Triphasil, fluctuations in estrogen and progesterone, and menstrual phase did not influence CYP3A4 or CYP2D6 activity. It was concluded that CYP3A4 and CYP2D6 activity and intrasubject variability were not different in the three study populations, and thus a clinically important difference between men, women on Triphasil, and women not receiving oral contraceptives is unlikely. High inter- and intrasubject variability in DM:3MM and DM:DX were clearly demonstrated and limit the use of dextromethorphan to phenotype endogenous CYP3A4 and CYP2D6 activity.

Adult↗
PubMed1999

The effects of fluvastatin, a CYP2C9 inhibitor, on losartan pharmacokinetics in healthy volunteers.

Losartan is an angiotensin II receptor antagonist that is metabolized by CYP2C9 and CYP3A4 to a more potent antihypertensive metabolite, E3174. Interaction studies with inhibitors of CYP3A4 have not demonstrated significant changes in the pharmacokinetics of losartan or E3174. The authors assessed the steady-state pharmacokinetics of losartan and E3174 when administered alone and concomitantly with fluvastatin, a specific CYP2C9 inhibitor. A prospective, open-label, crossover study was conducted in 12 healthy volunteers with losartan alone and in combination with fluvastatin. The baseline phase was 7 days of losartan (50 mg QAM), and the inhibition phase was 14 total days of fluvastatin (40 mg QHS), with the final 7 days including losartan. The authors found that fluvastatin did not significantly change the steady-state AUC0-24 or half-life of losartan or E3174. Losartan apparent oral clearance was not affected by fluvastatin. Inhibition of losartan metabolism appears to require both CYP2C9 and CYP3A4 inhibition.

Adolescent↗
PubMed1998

Effects of erythromycin or rifampin on losartan pharmacokinetics in healthy volunteers.

BACKGROUND: Losartan is metabolized by CYP2C9 and CYP3A4 to an active metabolite, E3174, which has greater antihypertensive activity than the parent compound. Coadministered drugs that inhibit or induce metabolic processes may therefore alter the pharmacokinetics and pharmacologic response of losartan and E3174. OBJECTIVE AND METHODS: Ten healthy volunteers were studied to assess the effects of CYP3A4 inhibition and nonspecific P450 enzyme induction on the pharmacokinetics of losartan and E3174. Subjects completed three 1-week phases separated by 6 days: 50 mg losartan every morning, losartan plus 500 mg erythromycin four times a day, and losartan plus 300 mg rifampin (INN, rifampicin) twice a day. On the eighth day of each phase, serial plasma concentrations of losartan and E3174 were obtained over 32 hours and steady-state pharmacokinetics were determined. RESULTS: Rifampin decreased the area under the concentration-time curve from time zero to 24 hours after the dose (AUC[0-24]) of losartan by 35% (349 +/- 246 versus 225 +/- 130; p = 0.0001) and decreased the AUC(0-24) of E3174 by 40% (1336 +/- 445 versus 792 +/- 302; p < 0.005). Losartan oral clearance was increased by 44% (p = 0.0001). The half-life values of both compounds were decreased by 50% (p < 0.005). In contrast, erythromycin did not significantly affect the AUC(0-24) or half-life of either losartan or E3174. CONCLUSIONS: Rifampin is a potent inducer of losartan and E3174 elimination. Given the magnitude of the effect, this interaction is likely to be clinically significant. On the basis of the minimal inhibitory effects observed with erythromycin, CYP3A4 appears to play a minor role in the in vivo metabolism of losartan to E3174. Further studies are needed to define the contribution of other isozymes, particularly CYP2C9, to the pharmacokinetics of losartan and E3174.

Adult↗
PubMed1998

Intraperitoneal bupivacaine or lidocaine does not provide analgesia after total abdominal hysterectomy.

We have compared pain scores at rest and on standardized movement, and morphine consumption using patient-controlled analgesia in 60 patients who had undergone total abdominal hysterectomy. Patients were allocated randomly to one of three groups: in the saline group, 0.9% sodium chloride 50 ml was administered into the pelvic cavity before closure of the peritoneum; in the second group, the solution administered was 20 ml of 0.5% bupivacaine solution with epinephrine 1:200,000 diluted with saline to a final volume of 50 ml; in the third group, the solution used was 20 ml [corrected] of 2% lidocaine with epinephrine 1:200,000 diluted with saline to a final volume of 50 ml. We found that there was no significant difference between the three groups in visual analogue pain scores at 8, 12, 36 or 48 h after operation at rest or on movement, and no significant difference in sedation or dose of antiemetic administered. Mean morphine consumption in the first 24 h was 54.6 (SEM 5.9) mg in the saline group, 55.5 (6.4) mg in the bupivacaine group and 52.5 (5.3) mg in the lidocaine group. In the second 24 h, morphine consumption was 34.9 (6.6) mg, 28.1 (3.5) mg and 28.0 (3.5) mg in the three groups, respectively. We conclude that i.p. administration of local anaesthetic solution into the pelvic cavity did not confer appreciable analgesia in patients undergoing abdominal hysterectomy.

Adult↗
PubMed1997

Intraperitoneal lignocaine for pain relief after total abdominal hysterectomy.

In this preliminary randomized study, we have measured pain scores at rest and on movement, 24 and 48 h after operation in 19 control patients, who received 50 ml of saline i.p., and in 20 test patients, in whom 50 ml of saline solution containing lignocaine 200 mg and adrenaline 1:500,000 were instilled into the peritoneal cavity after total abdominal hysterectomy. We found that there was no difference in linear analogue scores for nausea, pain on movement or morphine consumption after operation between the two groups, but pain scores at rest were significantly lower in the lignocaine group at 24 and 48 h compared with the saline group. In the lignocaine group, blood sampling over a 3-h period revealed a mean maximum serum concentration of 0.4 microgram ml-1 at 3 h and a highest concentration in any patient of 0.87 microgram ml-1.

Adult↗
PubMed1997

The AHCPR clinical practice guideline for heart failure revisited.

OBJECTIVE: To review the Agency for Health Care Policy and Research (AHCPR) clinical practice guideline for heart failure and comment on the guideline regarding pharmacotherapy from the perspective of the latest clinical trial data and the authors' clinical experience. DATA SOURCES: A MEDLINE search (1966 to June 1997) of English-language literature pertaining to the pharmacotherapy of heart failure was performed. Special emphasis was placed on literature published in the last 5 years. Additional literature was obtained from reference lists of key articles identified through the search. DATA SYNTHESIS: Pertinent clinical trials were reviewed and considered along with information from the authors' database of over 800 patients with heart failure. Evidence concerning the use of angiotensin-converting enzyme inhibitors at appropriate dosages in all New York Heart Association classes of heart failure and the inclusion of digoxin as part of triple therapy in all symptomatic patients with left ventricular systolic dysfunction are reviewed. Strategies to circumvent clinical problems that may limit the proper application of standard therapeutic agents are considered, and the possible future role of beta-blockers as the therapeutic agents in patients with heart failure is discussed. CONCLUSIONS: The AHCPR guideline provides the clinician with an excellent framework for treating the patient with heart failure. Building on the fundamentals of the guideline, the clinician can carefully apply current therapy at appropriate dosages and in the best combinations to individualize and thereby optimize pharmacologic therapy for this patient population.

Adrenergic beta-Antagonists↗
PubMed1996

Plasma concentrations of diltiazem and desacetyldiltiazem in an overdose situation.

OBJECTIVE: To describe the elimination of diltiazem and desacetyldiltiazem in an overdose situation. CASE SUMMARY: An 18-year-old woman ingested controlled delivery diltiazem 14.94 g in a suicide attempt. After arriving at the hospital unresponsive and hypotensive, her condition progressed to complete heart block, cardiogenic shock, asystole, and acute renal failure. Supportive care consisted of vasopressors, intravenous calcium, intravenous glucagon, charcoal hemoperfusion, temporary transvenous pacing, and an intraaortic balloon pump. After 12 days in the hospital, the patient recovered fully. DISCUSSION: We report a large, documented overdose of diltiazem and detail the pharmacokinetic profiles of both diltiazem and its active metabolite, desacetyldiltiazem. Nonlinear elimination of diltiazem appears to occur at higher concentrations. Although the patient improved clinically following charcoal hemoperfusion, no dramatic effects on diltiazem elimination were apparent. CONCLUSIONS: Survival following massive diltiazem overdose can be achieved with supportive care. Charcoal hemoperfusion had a limited effect on improving the clearance of diltiazem as evidenced by serial plasma concentrations.

Adolescent↗
PubMed1994

Meckel's diverticulum-rare complications and review of the literature.

Meckel's diverticulum is the most common congenital anomaly of the gastro-intestinal tract. It arises as a result of incomplete dissolution of the vitello-intestinal duct. Approximately 4% of patients with Meckel's diverticula develop complications, most commonly obstruction, gastro-intestinal bleeding and inflammation. We describe three unusual presentations of Meckel's diverticulum-perforation due to ingested foreign body, a smooth muscle neoplasm simulating an ovarian tumour, and a Littre's hernia.

Adult↗
PubMed1993

A qualitative study on the socialization of beginning physical education teacher educators.

Few studies have focused on how university faculty learn and understand expectations of their professional role. The purpose of this study was to describe the experiences of five female physical education teacher educators in their first positions as assistant professors in research oriented universities. Data were collected using primarily qualitative methods--weekly journals and in-depth interviews. Quantitative data were gathered to compare organizational factors such as salary, load allocation, equipment, and travel funds. Data yielded five main categories concerning how and what participants learned about their faculty roles. These categories included participants' perceptions of (a) organizational structure and job facilitation, (b) work tasks, (c) support systems, (d) evaluation and feedback, and (e) participants' psychological states. All participants reported experiencing role ambiguity and stress. Clear criteria for job performance, collegial support and mentoring, and regular evaluation and feedback were cited by all participants as important factors for reducing stress and facilitating their roles as faculty.

Educational Measurement↗
PubMed1990

National survey of infection control practitioners' educational needs.

The purpose of this study was to conduct a nationwide survey to determine the number of master's-prepared infection control practitioners (ICPs) and those eligible for admission to graduate programs. Continuing education needs also were assessed to determine whether they might best be met through formal education or in a continuing education format. ICPs at 3765 health care facilities listed by the American Hospital Association as having more than 100 beds were invited to participate, and 2197 usable responses were received. Respondents' perceived educational needs were categorized into the eight sections outlined by the Educational Committee of the Association for Practitioners in Infection Control (APIC). Whenever possible, demographic characteristics of subjects were compared with the findings of the 1976-1977 Study on the Efficacy of Nosocomial Infection Control; apparent shifts have occurred in age, basic educational preparation, and numbers of practitioners with advanced degrees. The major perceived educational needs of the respondents were in the areas of Management and Communication, followed by Infectious Diseases and Epidemiology and Statistics. Nationwide generalization of the results may be hampered by the skewed regional distribution of responses. ICPs, however, expressed a multiplicity of perceived educational needs in each of APIC's eight sections, which may indicate that many ICPs believe that their performance and effectiveness are hampered by knowledge deficits.

Adult↗