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Biomedical subjects

G R Matzke

Publications and source records attributed to G R Matzke.

124 records · Page 7Linked to original sources
PubMedDate not supplied

Acute phenytoin and primidone intoxication: a pharmacokinetic analysis.

Serial plasma levels of phenytoin, primidone, and phenobarbital were determined in a patient following massive overdose of phenytoin and primidone. The patient's neurologic status improved slowly over a period of 10 days and correlated best with the rise and fall of phenytoin plasma concentrations. The pharmacokinetics of all three agents were characterized by nonlinear regression analysis of their respective plasma concentration-time profiles during the elimination phase, followed by analog computer simulations of their entire plasma concentration-time profile closely resembled the observed values. Average values of Km and Vmax obtained from patients undergoing chronic therapy were used in the simulation and appear to adequately describe phenytoin elimination in this overdose situation. The elimination half-lives of primidone and phenobarbital of 6.2 and 83.5 hours, respectively, were within the "normal range" for patients on chronic therapy. Two distinct absorption phases for primidone and three for phenytoin were noted. The marked decrease in the estimated absorption rate constant between phases 1 and 2 for each drug may have been due to slow dissolution of a large congealed mass of phenytoin and primidone in the gut. The analysis of serial plasma samples following a massive overdose is recommended to provide a reliable data base for therapeutic decisions.

Adult↗
PubMedDate not supplied

Antihypertensive therapy with once-daily administration of terazosin, a new alpha 1-adrenergic-receptor blocker.

The antihypertensive activity of terazosin, an investigational alpha 1-adrenergic-receptor blocker, and its effect on blood lipids were compared with placebo in a double-blind study. After a 3-week placebo baseline period, patients were randomized to receive terazosin (n = 22) or placebo (n = 16). The dose of terazosin was titrated over 2 weeks to a maintenance dosage of 10 mg once daily for 4 weeks. Antihypertensive efficacy was assessed: (1) at the end of the 24-hour dosing interval by comparing the average blood pressure (BP) after 3 and 4 weeks of maintenance therapy to the average BP after 2 and 3 weeks of placebo therapy, and (2) for 3 hours after drug ingestion at the final visit in comparison to the predose BP at that visit. At the end of the 24-hour dosing interval, 10 mg of terazosin reduced the mean supine systolic BP from 155.6 to 152.2 mm Hg and mean supine diastolic BP from 101.9 to 99.0 mm Hg (p less than 0.05). During the 3 hours after drug ingestion, mean supine systolic and diastolic pressures decreased maximally from 151.8 to 142.7 mm Hg (p less than 0.05) and from 99.5 to 91.0 mm Hg (p less than 0.05) respectively. No supine BP reduction differed significantly from the placebo response. During terazosin therapy there was a nonsignificant increase in mean body weight of 1.4 +/- 2.9 kg and no change in blood lipids. Thus the drug demonstrated greater antihypertensive activity 1-3 hours after ingestion than at the end of the 24-hour dosing interval.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Analytical specificity of commercially available methods for serum phenytoin determination.

Phenytoin concentrations in serum obtained from uremic patients and patients with normal renal function were measured by fluorescence polarization immunoassay (FPI), rate nephelometric inhibition immunoassay ( RNII ), and homogeneous enzyme immunoassay (EIA) and compared to corresponding values determined by high performance liquid chromatography (HPLC). In serum specimens from patients with normal renal function, phenytoin concentrations measured by FPI, RNII , and EIA averaged within 12% of the corresponding concentrations determined by HPLC. Phenytoin concentrations in uremic serum were 20% (FPI), 60% (EIA), and 83% ( RNII ) higher than corresponding values determined by HPLC. Accumulation of phenytoin metabolites in patients with end-stage renal disease was associated with artifactually elevated measured serum concentrations of phenytoin. FPI was the most specific of the three commercial methods evaluated.

Chromatography, High Pressure Liquid↗
PubMedDate not supplied

Controlled comparison of gentamicin and tobramycin nephrotoxicity.

317 patients with suspected or documented infections other than cystitis were randomly assigned to receive gentamicin or tobramycin dosed according to the Sawchuk/Zaske method or a modification of the McHenry method. 196 patients completed 6 days of therapy, had serial determinations of serum creatinine and were evaluated for nephrotoxicity. Within each dosing method group those patients receiving gentamicin and tobramycin had a similar mean age, initial serum creatinine level, total dose, duration of therapy and trough serum aminoglycoside concentration. Nephrotoxicity developed in 5 of 49 (10.2%) given gentamicin via the McHenry method compared to 9 of 49 (18.4%) given tobramycin. Similarily, 4 of 50 (8.0%) given gentamicin via the Sawchuk/Zaske method developed nephrotoxicity compared to 8 of 48 (16.7%) given tobramycin. Within the Sawchuk/Zaske and the modified McHenry dosing method groups, no significant difference was noted in the incidence of nephrotoxicity associated with gentamicin and tobramycin. 34% of patients with elevated trough serum aminoglycoside concentrations developed nephrotoxicity compared to 3.7% of those with nonelevated troughs (p less than 0.0005).

Anti-Bacterial Agents↗
PubMedDate not supplied

Clinical pharmacokinetics of vancomycin.

Vancomycin utilisation has increased dramatically in the last 10 years due to the increasing clinical significance of infections with methicillin-resistant staphylococci. Recent studies have focused on characterising the disposition of vancomycin in patients and assessing the relationship between serum concentrations and therapeutic as well as adverse effects. Although vancomycin is not appreciably absorbed from the intact gastrointestinal tract, several recent case reports have documented the attainment of therapeutic and potentially toxic vancomycin serum concentrations following oral administration to patients with pseudomembranous colitis. The disposition of parenterally administered vancomycin has been best characterised by a triexponential model. The half-life of the initial phase (t1/2 pi) is approximately 7 minutes, that of the second phase (t1/2 alpha) is approximately 0.5 to 1 hour, while the terminal elimination half-life (t1/2 beta) ranges from 3 to 9 hours in subjects with normal renal function. The volume of the central compartment (Vc) in adults is approximately 0.15 L/kg while the steady-state volume of distribution (Vdss) ranges from 0.39 to 0.97 L/kg. More than 80% of a vancomycin dose is excreted unchanged in the urine within 24 hours after administration, and the concentration of vancomycin in liver tissue and bile has been reported to be at or below detection limits. Vancomycin renal clearance approximates 0.5 to 0.8 of simultaneously determined creatinine or 125I-iothalamate clearances, suggesting that the primary route of renal excretion is glomerular filtration. Recently, non-renal factors such as hepatic conjugation have been proposed as an important route of vancomycin elimination. However, these data are difficult to reconcile with other studies showing minimal non-renal clearance of vancomycin in subjects with end-stage renal disease. As yet, the disposition of vancomycin in patients with hepatic disease has not been adequately defined. Only limited data are available regarding the concentrations of vancomycin in biological fluids other than plasma. The penetration of vancomycin into cerebrospinal fluid (CSF) in patients with and without meningitis has been quite variable. Although early studies suggested that adequate CSF concentrations may not be achieved in subjects with uninflamed meninges, more recent investigations have reported contradictory results. Therapeutic concentrations of vancomycin, i.e. greater than 2.5 mg/L, have, however, been reported in ascitic, pericardial, pleural and synovial fluids. Tissue concentrations of vancomycin have exceeded simultaneous serum concentrations in heart, kidney, liver and lung sp

Adult↗
PubMedDate not supplied

Disposition of the cephalosporin cefepime in normal and renally impaired subjects.

The metabolism and disposition of an iv-administered, 1000 mg (100 microCi) single dose of the 14C-labeled cephalosporin cefepime was studied in healthy and renally impaired male volunteers. The 14C-label was located in the methyl group of the N-methyl pyrrolidine (NMP) moiety at the 3'-position of cefepime. Concentrations of cefepime and its metabolites were determined in plasma and urine as a function of time after drug administration. Cefepime comprised 95 and 76% of the total plasma radioactivity in subjects with normal and impaired renal functions, respectively. The elimination half-life of cefepime was 2 hr in normal volunteers and increased to 4 and 12 hr in subjects with moderate and severe renal impairment, respectively. Steady-state volume of distribution was about 18 liters and was independent of the degree of renal impairment. Cefepime was primarily excreted unchanged in the urine of normal subjects, as 87.9% of the total recovered radioactivity. The major cefepime metabolites, NMP N-oxide, the 7-epimer of cefepime and NMP, constituted 6.8, 2.5, and less than 1% of the total radioactivity excreted in urine, respectively. As the severity of renal impairment increased, the proportion of radioactivity recovered in urine as cefepime decreased and that of NMP-N-oxide increased. Our results indicate that cefepime undergoes minimal metabolism and is excreted primarily as unchanged drug in urine in humans with normal kidney functions.

Adult↗
PubMedDate not supplied

Evaluation of the vancomycin-clearance:creatinine-clearance relationship for predicting vancomycin dosage.

Four methods of predicting vancomycin maintenance doses on the basis of the relationship between total-body or renal clearance of the drug and creatinine clearance were evaluated retrospectively using data from 24 patients who received vancomycin hydrochloride. Data for 18 men and 6 women with creatinine clearances of 10-130 mL/min were used; the mean (+/- S.D.) vancomycin maintenance dose was 22.0 +/- 11.2 mg/kg/day. The actual vancomycin maintenance dose needed to sustain an average steady-state vancomycin concentration of 15 mg/L was determined based on individual pharmacokinetic values. Predicted vancomycin maintenance doses were generated using the vancomycin-clearance:creatinine-clearance relationships derived separately by Nielsen, Moellering, Rotschafer, and Matzke. Orthogonal regression analysis was used to determine relationships between actual and predicted maintenance doses. Predictive ability of each method was assessed for bias (mean error) and precision (root mean squared error). Mean error and root mean squared error (+/- S.D.), respectively, for the four methods were as follows: Nielsen -262 +/- 451, 522 +/- 718; Moellering -91 +/- 439, 448 +/- 547; Rotschafer 192 +/- 602, 632 +/- 682; and Matzke -76 +/- 101, 408 +/- 517. Doses predicted by the Nielsen relationship were significantly lower than the actual vancomycin maintenance doses. Use of the Rotschafer relationship resulted in substantial overprediction, which increased as creatinine clearance declined. Doses predicted by the Moellering and Matzke relationships were slightly less than but not significantly different from the actual dose. The Matzke method demonstrated the least bias and was the most precise.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

Treating severe metabolic alkalosis.

The pathophysiology, symptomatology, and treatment of metabolic alkalosis are reviewed, with emphasis on treatment with intravenous hydrochloric acid. Three buffering systems are used by the body to correct an arterial pH above 7.45--tissue, respiratory, and renal systems. The kidneys have the primary responsibility for correcting a severe metabolic alkalosis, but several conditions (e.g., severe volume contraction) can interfere with the renal mechanisms. No unique symptoms are associated with metabolic alkalosis. Conventional conservative treatment of metabolic alkalosis involves meeting the patient's fluid and electrolyte needs and allowing the body to correct the alkalosis through its own mechanisms. However, when more rapid resolution of the alkalosis is needed or the patient cannot tolerate fluid and electrolyte therapy, mineral acids may be administered. Ammonium chloride and arginine monohydrochloride infusions may both be used; since both require hepatic conversion for full activity, patients with hepatic dysfunction may require alternative therapy. Dilute hydrochloric acid (0.1-0.2 N) may be given intravenously to these patients through a central-venous catheter. Dosage guidelines and formulation procedures are described in the paper, as are other possible therapeutic alternatives (dialysis, acetazolamide, cimetidine). Most cases of metabolic alkalosis can be managed with fluid and electrolyte therapy. When metabolic alkalosis needs to be resolved quickly or when conventional therapy cannot be tolerated, mineral acid administration should be instituted. The primary drug of choice for these patients is intravenous ammonium chloride; patients with hepatic or severe renal dysfunction should receive dilute hydrochloric acid via a central-venous catheter.

Acetazolamide↗
PubMedDate not supplied

Hemodialysis clearance of total and unbound lidocaine.

The hemodialysis clearance and protein binding of lidocaine was determined in two acutely ill patients with end-stage renal disease. Patient A was a 74-year-old white man admitted for severe thrombocytopenia; lidocaine was started to control ventricular tachycardia. Patient B was a 66-year-old white man admitted for a myocardial infarction (MI); prophylactic treatment with lidocaine was begun after a second MI. Lidocaine hemodialysis clearance was evaluated during a five-hour dialysis procedure. Paired arterial and venous blood samples for lidocaine concentrations were collected at the midpoint of each hour of dialysis. Before dialysis and two hours after dialysis, venous samples were collected and assayed for alpha-1-acid glycoprotein (AAG) and lidocaine. The hemodialysis clearance of total and unbound lidocaine was calculated. The total amount of lidocaine removed was 8.9 and 12.5 mg for patients A and B, respectively. These amounts represented the removal of 5.6 and 2.8% of the total lidocaine dose administered to patients A and B, respectively, during the dialysis procedure. For patient A, the mean plasma dialysis clearance (Clp) was 28.2 +/- 6.3 ml/min for total lidocaine and 41.3 +/- 15.6 ml/min for unbound lidocaine. The Clp could not be calculated for patient B. The mean dialysate clearance (Cld) of total lidocaine was 28.6 +/- 7.8 and 26.3 +/- 6.5 ml/min for patients A and B, respectively. The Cld of unbound lidocaine was 42.7 +/- 6.7 and 44.5 +/- 9.9 for patients A and B, respectively. Although both patients A and B had substantial elevations in AAG concentrations (254 and 247 mg/dl, respectively), they exhibited high lidocaine unbound fractions of 0.55 and 0.68 before dialysis. The lidocaine unbound fraction was further increased in patient A after fat emulsion infusion to 0.80 and in patient B after heparin administration to 0.90. The clearance of lidocaine by hemodialysis in these two patients was negligible and clinically unimportant. No dose adjustment or supplementation was required after hemodialysis.

Aged↗
PubMedDate not supplied

Comparison of bioavailability and pharmacokinetics of cimetidine in subjects with normal and impaired renal function.

The bioavailability and pharmacokinetics of cimetidine were studied following single oral and intravenous doses in subjects with severely impaired renal function (SIRF) and normal renal function (NRF). Eight subjects with NRF and five patients with SIRF participated. Multiple blood samples were obtained up to 1440 minutes following both doses. Urine was also collected for 24 hours after each dose. The bioavailability of cimetidine was not significantly different between the two groups (78 +/- 15% in patients with SIRF and 62 +/- 17% in the NRF subjects). In subjects with NRF, a mean of 50.4% of the i.v. dose was excreted renally as unchanged drug and the mean serum half-life (t1/2) was 2.00 hours. The mean total body and renal clearances were 710.0 and 370.7 ml/min, respectively. In the SIRF group, a mean of 1.7% of the i.v. dose was excreted renally unchanged, and the mean t1/2 was 12.71 hours. The total body and renal clearances were 147.1 and 2.5 ml/min, respectively. Nonrenal clearance was 62% lower in the subjects with SIRF than in the NRF subjects. There is no significant difference in bioavailability of cimetidine between the patients with NRF and SIRF. The significantly lower nonrenal clearance of the patients with SIRF suggests that cimetidine metabolism may be impaired in uremic patients.

Administration, Oral↗