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Biomedical subjects

G R Matzke

Publications and source records attributed to G R Matzke.

At least 37 records · Page 2Linked to original sources
PubMed1996

The effect of renal insufficiency and hemodialysis on the pharmacokinetics of nalmefene.

The disposition of nalmefene, an opioid antagonist intended for the reversal of opioid-induced respiratory depression, and its primary metabolite nalmefene glucuronide, were characterized in adult volunteers with normal renal function and in patients with end-stage renal disease (ESRD). The effect of hemodialysis on the elimination of nalmefene and nalmefene glucuronide also was assessed. Participants with normal renal function received a single intravenous dose of 2 mg, and patients with ESRD received two separate doses of 1 mg nalmefene hydrochloride. Terminal elimination half-life (t1/2) of both nalmefene and nalmefene glucuronide was prolonged in patients with ESRD compared with that in participants with normal renal function. The steady-state volume of distribution (Vdss) of nalmefene was significantly higher and total body clearance lower in patients with ESRD than in participants with normal renal function. Hemodialysis clearance of nalmefene was approximately 3.3% of total body clearance. Although the hemodialysis clearance of nalmefene glucuronide was 179.3 +/- 24.1 mL/min and its t1/2 was significantly reduced during dialysis to 5.2 +/- 2.3 hours, a dramatic rebound of nalmefene glucuronide concentrations of 75.7% was observed 7.7 +/- 5.4 hours after the end of hemodialysis. Thus, hemodialysis does not result in clinically significant alterations in the disposition of nalmefene or its primary metabolite, nalmefene glucuronide. These data suggest that there is no pharmacokinetic basis for modification of the initial dosage, but maintenance doses, if needed, should be administered less frequently due to the prolonged elimination of the active moiety, nalmefene.

Adult↗
PubMed1996

Pharmacokinetics of abecarnil in patients with renal insufficiency.

OBJECTIVE: To characterize the pharmacokinetics of a single 5 mg oral dose of abecarnil in subjects with varying degrees of renal impairment. METHODS: Twenty-six subjects were enrolled in this open-label parallel-group study. Ten subjects had normal renal function (NRF; creatinine clearance [CLCR] > or = 85 ml/min/1.73 m2), six subjects had mild to moderate renal insufficiency (MMRI; CLCR between 25 and 73 ml/min/1.73 m2), and 10 subjects had severe renal insufficiency (SRI; CLCR < or = 10 ml/min/1.73 m2). Abecarnil plasma concentrations were determined by means of HPLC, and plasma protein binding was determined by use of ultracentrifugation. Pharmacokinetic parameters were obtained with use of model-independent and model-dependent methods. RESULTS: In subjects with SRI, area under the concentration-time curve and maximum plasma concentration were reduced by 36% and 31%, respectively, compared with demographically matched subjects with NRF. The apparent total body clearance in the NRF, MMRI, and SRI groups was 13.0 +/- 6.89, 12.9 +/- 3.64, and 25.0 +/- 13 ml/min/kg, and the apparent volume of distribution was 14.0 +/- 3.78, 12.8 +/- 2.4, and 19.4 +/- 5.76 L/kg, respectively (mean +/- SD). The patients with SRI had a significantly lower protein bound fraction than subjects with NRF (0.850 +/- 0.077 versus 0.948 +/- 0.023). Despite an increase in the free fraction of abecarnil (f(u)), there was no significant change in the apparent unbound total body clearance and unbound volume of distribution between the SRI and NRF groups. The anticipated full effect of the increase in f(u) among the patients with SRI was not realized and suggests that the f(u) in tissue may be increased in patients with SRI. CONCLUSION: Dose adjustment will need to be made on the basis of titration to the desired clinical response and tolerability in patients with SRI just as in subjects with NRF.

Administration, Oral↗
PubMed1996

Nonrenal toxicities of acetaminophen, aspirin, and nonsteroidal anti-inflammatory agents.

Approximately 2% of the United States population consumes an analgesic, antipyretic, or nonsteroidal antiinflammatory drug (NSAID) each day. Aspirin and acetaminophen have been available to the public without a prescription (over-the-counter) for decades, while most NSAIDs are still only available with a prescription from a physician. The recent trend of switching NSAIDs from prescription to over-the-counter status may be perceived by some as an indication of their inherent safety. However, all these agents have been associated with a unique but overlapping safety profile. In fact, significant adverse events (AEs) on multiple organ systems, including the kidney and gastrointestinal tract, have been reported with most of these agents. In this review, the incidence of the nonrenal AEs of aspirin, acetaminophen, and selected NSAIDs are tabulated. The strengths of the causative associations are highlighted, the relative risks for the gastrointestinal and cardiovascular AEs are discussed, and the relationship to patient risk factors and drug characteristics, such as dose and half-life, are reviewed. The selection of the optimal agent for an individual patient depends on the balance between the desired pharmacodynamic response, the patient's pharmacotherapy history, and the degree of AE risk one is willing to accept. Therapy should be initiated in all settings with the lowest possible dosage since the incidence of the major AEs is dose related.

Acetaminophen↗
PubMed1996

The effect of age on the pharmacokinetics of the opioid antagonist nalmefene.

1. The disposition of nalmefene was evaluated in young and elderly normal healthy volunteers. Subjects received either a single 1 mg (n = 18 young; n = 11 elderly) or 2 mg (n = 8 young; n = 15 elderly) intravenous bolus dose of nalmefene. 2. Following the administration of nalmefene, the initial plasma concentrations were significantly higher in elderly vs young subjects. The higher concentrations were the result of the 30 to 40% smaller central compartment apparent volume of distribution that was observed in the elderly subjects as compared with the young volunteers (2.8 +/- 1.1 vs 3.9 +/- 1.11 kg-1 for 1 mg dose). The elderly volunteers also had a significantly shorter distributional half-life (t1/2 lambda 1) than young volunteers (0.7 +/- 0.7 vs 1.3 +/- 0.8 h for 1 mg dose). No significant differences between groups were observed for the elimination half-life, clearance or steady-state apparent volume of distribution. 3. Although transiently higher nalmefene plasma concentrations were observed in the elderly immediately following drug administration, there was no association between this observation and adverse events. We conclude that no dosage alteration is warranted in elderly patients.

Adult↗
PubMed1996

Disposition of foscarnet during peritoneal dialysis.

OBJECTIVE: To report the disposition of foscarnet in a patient undergoing peritoneal dialysis. CASE SUMMARY: A 34-year-old man with AIDS received foscarnet for the treatment of esophageal cytomegalovirus. We characterized the clearance of foscarnet in this patient during continuous cyclic peritoneal dialysis (CCPD) and continuous ambulatory peritoneal dialysis (CAPD). DISCUSSION: The foscarnet half-lives during CCPD and CAPD were 41.4 and 45.8 hours, respectively. These values are significantly greater than the half-life of 4.5 hours observed in patients with normal renal function and about half that reported in anuric patients undergoing hemodialysis during the interdialytic period. The CCPD and CAPD clearances of foscarnet were 5.8 and 4.5 mL/min, respectively; the CAPD clearances of creatinine and urea nitrogen were 4.1 and 6.0 mL/min, respectively. The patient's estimated total body clearance values of foscarnet during CCPD and CAPD were 9.8 and 8.8 mL/min, respectively. Thus, CCPD and CAPD augmented the patient's residual clearance of foscarnet by 145% and 105%, respectively. CONCLUSIONS: Since incremental increases in residual clearance of 30% or more generally will result in clinically significant changes in a drug's serum concentration, foscarnet dosage needs to be individualized for patients receiving peritoneal dialysis.

Acute Kidney Injury↗
PubMed1995

Medication knowledge and compliance among patients receiving long-term dialysis.

The extent to which patients receiving longterm dialysis understood and complied with their drug therapy regimens was studied. Patients undergoing long-term hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) in a university-affiliated outpatient dialysis center were surveyed to determine their knowledge about and compliance with prescribed regimens for antihypertensives, phosphate binders, and calcitriol. They were asked to list their prescribed medications and state the medications' indications, the frequency with which they missed doses, and the actions they took after missing a dose. The patients were also asked where they obtained their medications and who their primary source of drug information was. Seventy-two patients (51 receiving hemodialysis and 21 receiving CAPD) were surveyed. Although 80% of the patients could recall the three target medications, only 39% of the hemodialysis patients and 57% of CAPD patients could recall all of their medications. Significantly more patients knew the indication for their antihypertensive medication and calcitriol than for their phosphate binder. The hemodialysis and CAPD patients reported they missed an average of 13.0 and 4.7 phosphate binder doses, 2.6 and 5.6 antihypertensive doses, and 6.7 and 7.0 calcitriol doses, respectively, per month. Despite the fact that 70% of the patients received their medications from a community pharmacy, less than 15% identified the pharmacist as their primary source of drug information. Patients receiving long-term hemodialysis or CAPD were more knowledgeable about and compliant with their antihypertensive and calcitriol regimens than their phosphate binder regimens.

Drug Therapy↗
PubMed1995

Pharmacokinetics of bepridil and two of its metabolites in patients with end-stage renal disease.

The pharmacokinetics of bepridil and 2 of its major metabolites (McN-A-2600 and McN-6303) were studied in 6 patients with end-stage renal disease (ESRD) before and after hemodialysis. Patients underwent dialysis 1 day after a single oral 200-mg dose of bepridil hydrochloride; blood was sampled for up to 7 days. The mean (+/- SD) peak plasma concentration, time of peak concentration, and area under the plasma concentration-time curve (0-168 hours) for each agent were as follows: bepridil, 806 +/- 321 ng/mL, 2.6 +/- 1.6 hours, 4.87 +/- 1.21 micrograms.h/mL; McN-A-2600, 57 +/- 16 ng/mL, 4.2 +/- 2.0 hours, 0.53 +/- 0.29 microgram.h/mL; McN-6303, 284 +/- 120 ng/mL, 4.7 +/- 1.5 hours, 4.06 +/- 1.11 micrograms.h/mL. The bepridil area under the curve corrected for dose was similar to that in healthy volunteers, suggesting that plasma clearance was unaffected by severe renal impairment. None of the compounds were removed by dialysis, and no rebound in plasma concentrations was observed after the end of dialysis. The disposition of bepridil appears to be unchanged in patients with ESRD; and is unaffected by hemodialysis. Thus, no dosage adjustment will be required for ESRD patients and those receiving hemodialysis with cuprophane filters.

Administration, Oral↗
PubMed1995

Effects of hemodialysis on plasma protein binding of bepridil.

The effects of end-stage renal disease (ESRD) and hemodialysis on the in vitro plasma protein binding of bepridil hydrochloride were investigated. The possible influence of bepridil metabolites on bepridil-protein binding in ESRD patients was also examined. Plasma samples were obtained from six patients with ESRD. Bepridil-plasma protein binding was measured by microequilibrium dialysis after addition of freshly prepared bepridil-14C (239 microCi/mg) at a final concentration of 2 micrograms/mL. The percentage of free bepridil in peripheral venous samples drawn on a nondialysis day was lower (i.e., binding was greater) in the patients with ESRD relative to previous observations in healthy subjects (0.15% +/- 0.04% versus 0.31% +/- 0.05% (mean +/- SD). The plasma concentrations of alpha-1-acid glycoprotein (AAG), the principal bepridil binding protein, were also higher in ESRD patients (110 +/- 32 mg/dL) than previously reported in healthy subjects. Although hemodialysis resulted in significant increases in AAG, total protein, and albumin concentrations, no significant difference in bepridil-plasma protein binding was detected between predialysis and postdialysis peripheral venous samples in the presence (0.16 versus 0.18) or absence (0.20 versus 0.17) of bepridil metabolites. The percentage of free bepridil in plasma from both the arterial and venous limbs of the dialyzer during hemodialysis (means of free bepridil ranged from 0.24-0.28%) was higher than in samples drawn from a peripheral vein. This displacement of bepridil from its binding sites as blood passes through the dialyzer may have been owing to the presence of high local concentrations of plasticizers. Confirmation of this hypothesis will require further investigation.

Adult↗
PubMed1994

Evaluation of two intravenous single-bolus methods for measuring effective renal plasma flow.

This open-label, three-way crossover study examined the feasibility of measuring effective renal plasma flow (ERPF) using a single intravenous (IV) bolus method. Eight healthy young adults (four women aged 28 +/- 5 years [mean +/- SD] and four men aged 30 +/- 7 years) received on separate days an IV bolus of p-aminohippurate (PAH) 10 mg/kg, an IV bolus of phenolsulfonphthalein (PSP) 1 mg/kg, and the standard constant-rate IV infusion of PAH. The renal clearance (CLR) and plasma clearance (CLP) of PAH after constant infusion were 623.7 +/- 62.9 and 869.0 +/- 58.8 mL/min/1.73 m2, respectively. After PAH bolus injection, CLR and CLP were 538.9 +/- 110.8 and 677.6 +/- 122.4 mL/min/1.73 m2, respectively. After PSP bolus injection, CLR and CLP were 252.8 +/- 57.9 and 350.0 +/- 41.3 mL/min/1.73 m2, respectively. The ERPF measured by PSP bolus injection was significantly lower (P < 0.05) than by PAH infusion. The CLP of PAH after IV bolus injection was significantly lower than after IV infusion when men and women were analyzed together (P < 0.05). However, there appeared to be a greater magnitude of difference between the CLR after IV bolus and infusion of PAH for women than for men. In summary, PSP administered as an IV bolus injection does not appear to be a reliable marker of ERPF. The difference in ERPF determined by the PAH infusion and bolus methods may require further evaluation.

Adult↗
PubMed1994

The pharmacokinetics of intravenous and oral torsemide in patients with chronic renal insufficiency.

Torsemide is a diuretic that acts in the thick ascending limb of the loop of Henle. Unlike furosemide, it undergoes substantial hepatic elimination and should not accumulate in patients with renal insufficiency. Therefore the pharmacokinetics of intravenous and oral torsemide and its metabolites were investigated in patients with chronic renal insufficiency. Two groups of 24 patients stratified by creatinine clearance (30 to 60 ml/min and < 30 ml/min) were studied in two separate randomized dose escalating crossover studies, one using intravenous torsemide and the other using oral torsemide. The pharmacokinetics of both intravenous and oral torsemide were linear over the dosage range studied. Absolute bioavailability was essentially 100%. Renal clearance was greatly diminished and correlated with renal function. Total plasma clearance and half-life were not related to renal function and were found to be similar to those of healthy subjects. The substantial nonrenal clearance of torsemide prevents accumulation in patients with chronic renal insufficiency.

Administration, Oral↗
PubMed1994

The pharmacodynamics of intravenous and oral torsemide in patients with chronic renal insufficiency.

The pharmacodynamics of intravenous and oral torsemide were determined in two randomized cross-over clinical trials in patients with chronic renal insufficiency. There was no significant difference in the rate or magnitude of the diuretic response between oral and intravenous administration. As has been shown with other loop diuretics, patients with chronic renal insufficiency have a reduced diuretic response compared with healthy subjects. This diuretic resistance is primarily related to a diminished delivery of drug to the urinary site of action. The response of torsemide at the tubular level is not different from that seen in subjects with normal renal function. Metabolites of torsemide do not appear to contribute to the diuretic response. A dose of 50 to 100 mg dependent on renal function is required to obtain a maximal response. A ceiling dose of approximately 100 mg in patients with chronic renal insufficiency is therefore recommended.

Administration, Oral↗
PubMed1992

Bioavailability of labetalol in patients with end-stage renal disease.

The pharmacokinetics and pharmacodynamics of labetalol were assessed after a single oral and intravenous dose in eight patients with end-stage renal disease (ESRD) maintained on chronic hemodialysis, and in eight age-and sex-matched normal volunteers. The mean area under the serum concentration-time curve, volume of distribution, clearance, and terminal elimination half-life values after a single intravenous dose of 0.5 mg/kg of labetalol were not significantly different between ESRD patients and normal volunteers. Similarly, the absolute bioavailability of an oral dose of 200 mg of labetalol was 0.33 in ESRD patients and was not significantly different from that of normal volunteers (0.26). However, a significant decrease in the area under the mean blood pressure-time curve was found after a single oral dose in ESRD patients, which was not observed in normal volunteers. The pharmacokinetics of labetalol were not associated with changes in blood pressure. Thus, when given orally to the ESRD patient, labetalol should be slowly titrated and the blood pressure closely monitored.

Administration, Oral↗
PubMed1992

Safety and pharmacokinetics of multiple doses of intravenous ofloxacin in healthy volunteers.

The safety and pharmacokinetics of ofloxacin in 48 healthy male volunteers were studied in a two-center, randomized, double-blind, placebo-controlled study. Ofloxacin (200 or 400 mg) or placebo was administered as 1-h infusions every 12 h for 7 days. Plasma ofloxacin concentrations were measured by high-performance liquid chromatography. Mean harmonic half-lives ranged from 4.28 to 4.98 h in the 200-mg dosing group and from 5.06 to 6.67 h in the 400-mg dosing group. Intragroup comparisons of trough plasma concentration-versus-time data from study days 2 through 7 revealed that steady state was achieved by day 2 of both multiple-dose regimens. Intergroup comparisons of mean harmonic half-lives, the areas under the concentration-time curve from 0 to 12 and 0 to 60 h, clearance, and apparent volume of distribution (area method) revealed that the pharmacokinetics of ofloxacin are dose independent. Both ofloxacin dosage regimens appeared to be reasonably well tolerated. The two dosage regimens of ofloxacin, 200 or 400 mg every 12 h, appear to be safe and provide serum drug concentrations in excess of the MICs for most susceptible pathogens over the entire dosing interval.

Adolescent↗
PubMed1991

Pharmacokinetics of cefprozil in healthy subjects and patients with renal impairment.

Cefprozil, a new broad-spectrum oral cephalosporin, is composed of cis and trans isomers in an approximate 90:10 ratio. The pharmacokinetics of a single oral 1000-mg dose of cefprozil were evaluated in 6 healthy subjects and 24 patients with various degrees of renal impairment. Six of these subjects were studied both while receiving hemodialysis and during an interdialytic period. Plasma, urine, and hemodialysate that were collected at predetermined times were analyzed for concentrations of the cis and trans isomers of cefprozil using reverse-phase HPLC assay with UV detection. The maximum plasma concentration of the cis isomer ranged from 12.3 micrograms/mL in subjects with normal renal function to 36.7 micrograms/mL in hemodialysis patients. Similarly the area under the plasma concentration-time curve and the elimination half-life increased from 46 micrograms.h/mL to 373 micrograms.h/mL and from 1.72 hours to 5.94 hours, respectively. Renal clearance of the cis isomer decreased from 198 mL/min in normal subjects to 19 mL/min in volunteers with creatinine clearances of less than or equal to 30 mL/min; there was a strong correlation (r2 greater than or equal to .93) between the renal clearance of the cis isomer and creatinine clearance. Urinary recovery of the cis isomer decreased from 57% in those with normal renal function to 24% in the group with a creatinine clearance of less than or equal to 30 mL/min. Hemodialysis decreased the half-life of the cis isomer to 2 hours and removed approximately 55% of it from the body during a 3-hour dialysis period (hemodialysis clearance equaled approximately 87 mL/min). The pharmacokinetics of the trans isomer were similar to those observed for the cis isomer and were affected similarly by declining renal function. A reduction in dosage is recommended in patients with a creatinine clearance of 30 mL/min or less. It may be necessary to administer a dose after hemodialysis to maintain therapeutic plasma concentrations.

Administration, Oral↗
PubMed1991

Pharmacokinetics of ceftibuten-cis and its trans metabolite in healthy volunteers and in patients with chronic renal insufficiency.

The impact of renal insufficiency on the dispositions of 300 mg of orally administered ceftibuten-cis, a new broad-spectrum oral cephalosporin, and its primary metabolite ceftibuten-trans was characterized in 30 adult subjects. Subjects were divided into five groups of six subjects each on the basis of their 24-h ambulatory creatinine clearances (CLCR). The apparent total body clearance (CLP/F; where F is absolute bioavailability) and renal clearance of ceftibuten-cis were significantly lower in subjects with end-stage renal disease (on maintenance hemodialysis; group V) and in those with severe (CLCR, 5 to 29 ml/min; group IV) and moderate (CLCR, 30 to 49 ml/min; group III) renal insufficiency than in those with mild renal insufficiency (CLCR, 50 to 80 ml/min; group II) or normal renal function (CLCR, greater than 80 ml/min; group I). A significant correlation was observed between CLCR and ceftibuten-cis CLP/F. The mean apparent steady-state volume of distribution (V beta/F) of ceftibuten-cis ranged from 0.21 to 0.24 liter/kg in subjects in group I, II, III, and IV. V beta/F was significantly greater in the group V subjects with end-stage renal disease (V beta/F, 0.39 +/- 0.27 liters/kg). These changes in V beta/F cannot be separated from possible changes in bioavailability. The maximum concentration of ceftibuten-trans in plasma was significantly higher and occurred significantly later in group IV subjects than it did in subjects in the other groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Antimicrobial treatment of peritonitis associated with continuous ambulatory peritoneal dialysis.

A multitude of therapeutic regimens have been proposed for the management of peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD). There are, however, few clinical trials that have evaluated the efficacy of these proposed regimens in a prospective, comparative fashion. This retrospective report is a tabulation of the published data on antimicrobial treatment of CAPD-related peritonitis. The results are presented for combination and mono-drug therapies; Gram-positive bacterial, Gram-negative bacterial and fungal infections; intravenous, oral and intraperitoneal (i.p.) routes of drug administration; various dosages and dosing intervals; and clinical response and relapse rates. The apparent optimal combination regimen for empiric treatment of peritonitis is vancomycin administered in 1 dialysis exchange/week with ceftazidime. This regimen avoids the toxicity associated with the use of aminoglycosides while maintaining effectiveness.

Anti-Bacterial Agents↗
PubMed1991

Teicoplanin measurement in patients with renal failure: comparison of fluorescence polarization immunoassay, microbiological assay, and high-performance liquid chromatographic assay.

Characterization of antibiotic pharmacokinetics in patients with renal insufficiency may be complicated by interfering substances within the assay. We compared three different assays for teicoplanin in serum and dialysate of 10 hemodialysis and six continuous ambulatory peritoneal dialysis (CAPD) patients. The microbiological assay (micro) had a within-run and between-run coefficient of variation (% CV) of less than 7.5% for concentrations ranging from 0.2 to 96 micrograms/ml. The high-performance liquid chromatographic assay (HPLC) within- and between-run %CV was less than 8% for concentrations ranging from 1 to 80 micrograms/ml. The fluorescence polarization immunoassay (FPIA) within- and between-run %CV was less than 7% for concentrations ranging from 5 to 100 micrograms/ml. In serum of hemodialysis patients FPIA results were slightly higher than HPLC results: FPIA = 1.11 HPLC + 2.37 (r = 0.975, n = 202), and FPIA concentrations in serum were also slightly higher than those measured by micro (FPIA = 1.21 micro - 1.57, r = 0.972, n = 161). The HPLC and micro serum results were also comparable in hemodialysis patients: micro = 0.92 HPLC + 2.89, r = 0.953, n = 160. However, in CAPD patients micro results were lower than HPLC results in serum (micro = 0.82 HPLC + 0.49, r = 0.981, n = 262). In peritoneal dialysate, HPLC values were approximately 60% of the micro values. Thus, FPIA may be the optimal technique for therapeutic monitoring of teicoplanin in the clinical setting due to its simplicity, specificity, and good correlation to HPLC and micro.

Adult↗