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Biomedical subjects

D F Brophy

Publications and source records attributed to D F Brophy.

14 recordsLinked to original sources
PubMed2006

Thrombin generation time is a novel parameter for monitoring enoxaparin therapy in patients with end-stage renal disease.

BACKGROUND: Patients with end-stage renal disease (ESRD) who receive enoxaparin are at increased risk for adverse bleeding episodes. This phenomenon appears to occur despite judicious monitoring of antifactor Xa (aFXa) activity. Better monitoring parameters are needed to quantify the anticoagulant effects of enoxaparin in the ESRD population. OBJECTIVES: The objective of this study was to determine the utility of using thrombin generation time (TGT), platelet contractile force (PCF) and clot elastic modulus (CEM) to monitor the degree of anticoagulation in ESRD subjects, and to compare these results to aFXa activity, the current gold-standard monitoring parameter. METHODS: Eight healthy volunteers without renal dysfunction and eight ESRD subjects were enrolled into this study. Subjects received a single dose of enoxaparin 1 mg kg(-1) subcutaneously, and blood samples were obtained for the determination of aFXa activity, TGT, PCF and CEM at baseline, 4, 8, and 12 h postdose. RESULTS: Baseline, 4, 8, and 12-h aFXa activity concentrations were not different between groups. However, the corresponding TGT at 8 and 12 h was significantly prolonged in the ESRD group (P = 0.04, and P = 0.008, respectively). The 4-h peak TGT trended toward significance (P = 0.06). There were no differences in PCF or CEM across time. CONCLUSIONS: These data suggest that the parameter aFXa activity is a poor predictor of the anticoagulant effect of enoxaparin in patients with ESRD. Thrombin generation time appears to be more sensitive to the antithrombotic effects of enoxaparin in this population. Further large-scale trials are needed to corroborate these data.

Adult↗
PubMed2004

Antifactor Xa activity correlates to thrombin generation time, platelet contractile force and clot elastic modulus following ex vivo enoxaparin exposure in patients with and without renal dysfunction.

Antifactor Xa activity is the gold standard monitoring parameter for low molecular weight heparin (LMWH) derivatives. It is frequently measured in high-risk populations, such as patients with renal dysfunction. Despite antifactor Xa monitoring, however, bleeding in renal dysfunction patients receiving LMWH remains a problem. This study determined the relationship between antifactor Xa activity and three novel coagulation monitoring parameters: thrombin generation time (TGT), platelet contractile force (PCF) and clot elastic modulus (CEM). This study also assessed the effect of renal dysfunction on these relationships. This was an ex vivo pharmacodynamic study of the relationship between antifactor Xa activity and TGT, PCF and CEM in subjects both with and without renal dysfunction. Thirty subjects completed this study (10 controls, 10 chronic kidney disease subjects, and 10 end-stage renal disease subjects receiving hemodialysis). Blood samples obtained from participants were spiked with increasing enoxaparin concentrations (0.25, 0.5, 1.0 and 3.0 IU mL(-1)). Samples were analyzed for TGT, PCF and CEM. The relationship between antifactor Xa activity and TGT, PCF and CEM was determined by Pearson's correlation. The effect of renal dysfunction on the relationship between antifactor Xa activity and TGT, PCF and CEM was determined by analysis of covariance. There is strong correlation between antifactor Xa activity and TGT, CEM and PCF. The presence of renal dysfunction significantly prolongs the TGT, and decreases the CEM relative to controls. These results suggest that patients with renal dysfunction have a greater pharmacodynamic response to LMWH, independent of the pharmacokinetics of LMWH.

Adult↗
PubMed2001

Pharmacokinetic Interaction between amprenavir and rifabutin or rifampin in healthy males.

The objective of this study was to determine if there is a pharmacokinetic interaction when amprenavir is given with rifabutin or rifampin and to determine the effects of these drugs on the erythromycin breath test (ERMBT). Twenty-four healthy male subjects were randomized to one of two cohorts. All subjects received amprenavir (1,200 mg twice a day) for 4 days, followed by a 7-day washout period, followed by either rifabutin (300 mg once a day [QD]) (cohort 1) or rifampin (600 mg QD) (cohort 2) for 14 days. Cohort 1 then received amprenavir plus rifabutin for 10 days, and cohort 2 received amprenavir plus rifampin for 4 days. Serial plasma and urine samples for measurement of amprenavir, rifabutin, and rifampin and their 25-O-desacetyl metabolites, were measured by high-performance liquid chromatography. Rifabutin did not significantly affect amprenavir's pharmacokinetics. Amprenavir significantly increased the area under the curve at steady state (AUC(ss)) of rifabutin by 2.93-fold and the AUC(ss) of 25-O-desacetylrifabutin by 13.3-fold. Rifampin significantly decreased the AUC(ss) of amprenavir by 82%, but amprenavir had no effect on rifampin pharmacokinetics. Amprenavir decreased the results of the ERMBT by 83%. The results of the ERMBT after 2 weeks of rifabutin and rifampin therapy were increased 187 and 156%, respectively. Amprenavir plus rifampin was well tolerated. Amprenavir plus rifabutin was poorly tolerated, and 5 of 11 subjects discontinued therapy. Rifampin markedly increases the metabolic clearance of amprenavir, and coadministration is contraindicated. Amprenavir significantly decreases clearance of rifabutin and 25-O-desacetylrifabutin, and the combination is poorly tolerated. Amprenavir inhibits the ERMBT, and rifampin and rifabutin are equipotent inducers of the ERMBT.

Adolescent↗
PubMed2001

The pharmacokinetics of subcutaneous enoxaparin in end-stage renal disease.

STUDY OBJECTIVE: To evaluate the pharmacokinetics of enoxaparin in end-stage renal disease (ESRD), and determine if dosage reduction is necessary to maintain antifactor Xa activity concentrations within the therapeutic range. DESIGN: Prospective, single-dose pharmacokinetic study. SETTING: University-affiliated general clinical research center. PATIENTS: Eight nonthrombosed patients with ESRD requiring hemodialysis. INTERVENTION: All subjects received a single dose of enoxaparin sodium 1 mg/kg subcutaneously and had serial plasma antifactor Xa activity concentrations measured over 24 hours. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetics of enoxaparin were determined from plasma antifactor Xa activity concentrations, and various multiple-dose regimens were simulated. After administration of the drug, total body clearance was 14.6 ml/minute and there was a 2-fold prolongation in antifactor Xa activity half-life compared with values reported in healthy subjects. All other pharmacokinetic parameters were similar to those in healthy subjects and patients with chronic renal insufficiency. An accumulation ratio of 1.6 was estimated for a dosing interval of every 12 hours based on single-dose pharmacokinetics. When various therapeutic regimens were simulated to predict average steady-state antifactor Xa activity, standard enoxaparin dosages of 1 mg/kg subcutaneously every 12 hours and 1.5 mg/kg every 24 hours resulted in average steady-state concentrations within the therapeutic range. CONCLUSIONS: Based on antifactor Xa activity, ESRD has little effect on the pharmacokinetics of enoxaparin, and dosing adjustments are unnecessary.

Adult↗
PubMed2000

Pharmacokinetic interaction between amprenavir and clarithromycin in healthy male volunteers.

The P450 enzyme, CYP3A4, extensively metabolizes both amprenavir and clarithromycin. To determine if an interaction exists when these two drugs are coadministered, the pharmacokinetics of amprenavir and clarithromycin were investigated in healthy adult male volunteers. This was a Phase I, open-label, randomized, balanced, multiple-dose, three-period crossover study. Fourteen subjects received the following three regimens: amprenavir, 1,200 mg twice daily over 4 days (seven doses); clarithromycin, 500 mg twice daily over 4 days (seven doses); and the combination of the above regimens over 4 days (seven doses of each drug). Twelve subjects completed all treatments and the follow-up period. The erythromycin breath test (ERMBT) was administered at baseline, 2 h after the final dose of each of the three regimens and at the first follow-up visit. Coadministration of clarithromycin and amprenavir significantly increased the mean amprenavir AUC(ss), C(max,ss), and C(min,ss) by 18, 15, and 39%, respectively. Amprenavir had no significant effect on the AUC(ss) of clarithromycin, but the median T(max,ss)for clarithromycin increased by 2.0 h, renal clearance increased by 34%, and the AUC(ss) for 14-(R)-hydroxyclarithromycin decreased by 35% when it was given with amprenavir. Amprenavir and clarithromycin reduced the ERMBT result by 85 and 67%, respectively, and by 87% when the two drugs were coadministered. The baseline ERMBT value did not correlate with clearance of amprenavir or clarithromycin. A pharmacokinetic interaction occurs when amprenavir and clarithromycin are coadministered, but the effects are not likely to be clinically important, and coadministration does not require a dosage adjustment for either drug.

Adolescent↗
PubMed2000

The pharmacokinetics and pharmacodynamics of losartan in continuous ambulatory peritoneal dialysis.

The pharmacokinetics and pharmacodynamics of losartan and its active metabolite, E-3174, were studied in 8 stable, hypertensive continuous ambulatory peritoneal dialysis (CAPD) patients. Following a 1-week washout period, subjects received 100 mg of losartan orally for 7 days. On Days 1 and 7, hemodynamic and hormonal responses were determined, as were PK parameters on Day 7. Peritoneal equilibration testing was performed pre-Day 1 and on Day 7. AUC0-24 and t1/2 for losartan and E-3174 were 95 +/- 49.9 micrograms.min/mL and 176 +/- 82.1 micrograms.min/mL and 172.5 +/- 86.7 minutes and 628 +/- 575 minutes, respectively. These values are similar to those of normal subjects and subjects on hemodialysis. Peritoneal clearance of losartan and E-3174 was negligible. All subjects demonstrated a substantial reduction in blood pressure with at least a 10 mmHg drop in diastolic BP. Plasma renin activity (PRA) values increased, but aldosterone, endothelin, norepinephrine, and epinephrine values did not change following 7 days of losartan. Losartan was well tolerated in all study subjects.

Adult↗
PubMed2000

Amiloride for the prevention of amphotericin B-induced hypokalemia and hypomagnesemia.

OBJECTIVE: To review the published clinical data assessing the role of amiloride in the prevention of amphotericin B (AmB)induced electrolyte disorders. DATA SOURCES: A MEDLINE search (January 1966-April 1999) of English-language literature pertaining to AmB, amiloride, potassium, and magnesium was performed. Tertiary sources were also used. DATA EXTRACTION: In vivo and in vitro human and animal data and case reports were included due to the lack of published clinical trials. DATA SYNTHESIS: AmB administration can result in severe hypokalemia and hypomagnesemia requiring chronic supplementation. In one prospective, controlled study of hypokalemia with AmB administration, patients receiving concomitant amiloride had significantly greater potassium concentrations (p < 0.01) and required significantly less potassium supplementation (p < 0.001). Amiloride may also reduce the amount of magnesium supplementation required by sparing elimination through the kidneys. CONCLUSIONS: Amiloride may be considered for the prevention of AmB-induced hypokalemia and hypomagnesemia, especially in patients at high risk for complications resulting from these electrolyte disorders. Further studies are needed to assess concomitant use of other potassium-sparing diuretics and AmB.

Amiloride↗
PubMed2000

Cost-effectiveness of sevelamer versus calcium carbonate plus atorvastatin to reduce LDL in patients with chronic renal insufficiency with dyslipidemia and hyperphosphatemia.

We conducted a cost-effectiveness analysis to compare costs and clinical outcomes of sevelamer versus calcium carbonate plus atorvastatin for treatment of dyslipidemia in patients with chronic renal insufficiency. The model was from the third-party payer perspective. Efficacy and adverse event rates for each regimen were obtained from published clinical trials. Drug costs were based on average wholesale prices; monitoring costs were based on Medicare reimbursement rates. Our model suggests that the combination of calcium carbonate plus atorvastatin is substantially more cost-effective than sevelamer in reducing low-density lipoprotein (LDL) in these patients. One-way sensitivity analyses were performed to assess if 25% and 50% price reductions in sevelamer affected overall cost-effectiveness results. A 50% sevelamer price reduction was less expensive than combination therapy but remained less cost-effective. A two-way sensitivity analysis on the probability that a patient achieves the goal of a 35% LDL reduction resulted in calcium carbonate plus atorvastatin remaining more cost-effective. Further cost-effectiveness studies are necessary to corroborate our data.

Atorvastatin↗
PubMed1999

Pharmacotherapy of dyslipidemia in postmenopausal women: weighing the evidence.

In the United States, coronary heart disease (CHD) is the leading cause of death in women. The incidence of CHD rises dramatically in women following menopause, which can be partially attributed to a more atherogenic lipoprotein profile. For years, observational and epidemiological data have suggested that estrogen and progesterone therapy reduced CHD end points. However, the first prospective trial that evaluated hormone replacement therapy (HRT) for secondary CHD prevention demonstrated no positive cardiovascular benefit of HRT compared with placebo. In interventional studies, the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)reductase inhibitors significantly reduced CHD outcomes in postmenopausal women, and these agents have emerged as the drugs of choice for primary and secondary CHD prevention. The selective estrogen receptor modulators (SERMs) may have a role in CHD prevention, but long-term clinical trials evaluating end points are needed. An evidence-based approach is necessary when deciding the appropriate pharmacotherapy of dyslipidemia in postmenopausal women.

Aged↗
PubMed1997

Automated peritoneal dialysis: new implications for pharmacists.

OBJECTIVE: To review the new automated peritoneal dialysis (APD) modalities that are available to patients with end-stage renal disease (ESRD), and to examine their potential pharmacokinetic and drug dosing consequences. DATA SOURCES: A MEDLINE search (from January 1966 to June 1996) of English-language literature pertaining to peritoneal dialysis was performed. Additional references were obtained by reviewing the references of pertinent articles identified through the search. Tertiary sources were also used. DATA EXTRACTION: Data regarding peritoneal dialysis techniques and pharmacokinetics were extracted from the literature. Data were evaluated according to the study design, population, results, and conclusions. DATA SYNTHESIS: ESRD is the result of progressive chronic renal insufficiency and requires renal replacement therapy. APD is the fastest growing renal replacement therapy by percentage in the US and provides dialysis exchanges via a machine while the patient sleeps, thereby improving patient convenience, peritoneal dialysis compliance rates, and decreasing peritonitis rates. Well-designed pharmacokinetic studies involving APD have not been conducted. Consequently, no formal drug dosing recommendations are available for APD, and pharmacists must rely on established dosing guidelines for continuous ambulatory peritoneal dialysis (CAPD) when recommending dosing regimens. This article describes the new APD treatment modalities available and the potential pharmacokinetic differences between CAPD and APD. CONCLUSIONS: Well-designed studies are needed to fully characterize the pharmacokinetic parameters of drugs in APD. Until then, pharmacists should recommend that intraperitoneally administered drugs be given during the longest peritoneal dialysate dwell of the day and that serum concentrations of drugs with narrow therapeutic indices be monitored closely.

Anti-Bacterial Agents↗
PubMedDate not supplied

Small and middle molecular weight solute clearance in nocturnal intermittent peritoneal dialysis.

OBJECTIVES: To determine the dialysate-to-plasma (D/P) concentration ratios and peritoneal dialytic clearance (CI(D)) of substances with a wide range of molecular weights in subjects receiving a simulated nocturnal intermittent peritoneal dialysis (NIPD) session. DESIGN: Open-label single-dose study. SUBJECTS: Six end-stage renal disease patients undergoing peritoneal dialysis (PD). SETTING: Clinical research center of a university-affiliated hospital. INTERVENTIONS: Subjects received intravenous gentamicin and vancomycin on the first day of the study. Subjects received no PD until their return on the following day, when subjects underwent a simulated NIPD session utilizing four 2- to 2.5-L peritoneal dialysate dwells of 2 hours. Blood and dialysate samples were collected immediately before the session and after each dialysate dwell for determination of urea, creatinine, gentamicin, vancomycin, and beta2-microglobulin (beta2M) concentrations. Each solute's D/P concentration ratio and peritoneal CI(D) were calculated. MEASUREMENTS AND MAIN RESULTS: The (mean +/- SD) 2-hour D/P concentration ratios were 0.78 +/- 0.05 (urea), 0.49 +/- 0.11 (creatinine), 0.38 +/- 0.08 (gentamicin), 0.11 +/- 0.06 (vancomycin), and 0.07 +/- 0.03 (beta2M). Peritoneal CI(D) values (mL/min of dialysis) were 19.0 +/- 2.8 (urea), 12.1 +/- 3.5 (creatinine), 8.4 +/- 2.8 (gentamicin), 2.7 +/- 1.5 (vancomycin), and 1.7 +/- 0.8 (beta2M). The D/P concentration ratios and peritoneal CI(D) values for urea, creatinine, and gentamicin were significantly different from vancomycin and beta2M (repeated measures ANOVA, p < 0.05). Beta2-microglobulin peritoneal CI(D) was strongly related to gentamicin peritoneal CI(D) (r = 0.96, p < 0.05). CONCLUSION: Small molecular weight solutes have significantly greater D/P and peritoneal CI(D) than middle molecular weight solutes in NIPD. In NIPD, daily peritoneal CI(D) of beta2M is lower than that reported in continuous ambulatory PD. NIPD also results in lower drug CI(D) than that reported in continuous ambulatory PD studies.

Adult↗
PubMedDate not supplied

Warfarin resistance in a patient with short bowel syndrome.

Drug therapy in short bowel syndrome can be complicated by inadequate or incomplete absorption of drugs in the small intestine. Many case reports claim that warfarin absorption is not affected by the syndrome. We treated a patient with oral warfarin for recurring deep vein thrombosis; up to 20 mg/day was administered with no increase in the international normalized ratio. Drug-drug interactions that may prevent absorption, increase metabolism, or antagonize the effects of warfarin were ruled out. Intravenous lipid administration, which is anecdotally reported to precipitate warfarin resistance, may have contributed to the condition, but dosing was less frequent than in published reports. The most probable explanation of warfarin resistance is the reduced surface area for drug absorption secondary to surgical removal of the patient's duodenum and gastrojejunostomy.

Adult↗