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Koup, Jeffrey R.; Jusko, William J.; Elwood, Charles M.; Kohli, Romesh K.
doi: 10.1002/cpt19751819pmid: 1149366
Radioimmunoassayed serum concentration and urinary excretion data for digoxin from azotemic patients were characterized using a 2‐compartment open model. Urinary excretion rates of digoxin as well as serum concentration data are needed to accurately characterize the disposition of the drug. Seven patients with renal failure showed highly variable steady‐state volumes of distribution (VSSD = 195 to 489 liters/1.73 m2) and tÛβ values (1.5 to 5.2 days). This variability is a major limiting factor in the use of dosage regimen nomograms that assume a constant VSSD and a rigorous relationship between tÛβ and creatinine clearance (ClCR). Body clearance (ClB) is a parameter that is affected by both elimination and distribution of drugs. A linear relationship between ClB and renal clearance of digoxin or ClCR was found and was used to develop a model‐independent approach to calculation of maintenance doses of digoxin. Several methods for calculating steady‐state serum concentrations of digoxin (CSSD) were compared with actual measurements obtained in 16 chronically medicated patients. Optimum computation of CSSD is obtained by use of digoxin renal and body clearances. Variability in the digoxin: creatinine renal clearance ratio is the major limiting factor in prediction of digoxin dosage regimens.
doi: 10.1002/cpt197518122pmid: 1149358
The effects of glucagon (5, 10, and 40 µg/ml) on the amplitude and duration of action potential, effective refractory period, dv Idt of phase 0 of action potential, membrane responsiveness, and contraction in human papillary muscles obtained from patients undergoing corrective open heart surgery were investigated. Glucagon, in none of the concentrations, produced any significant change in the amplitude and duration of action potential, or in force of contraction. Shortening of the effective refractory period was not significant. Glucagon enhanced the conduction and the membrane responsiveness by increasing the dvldt of phase 0 of action potential and a shift of curve to the left. It is suggested that the latter properties of glucagon would abolish the “re‐entrant” type of cardiac arrhythmias produced by cardiac glycosides or other drugs that initiate and perpetuate arrhythmias due to altered conduction.
Leenen, Frans H. H.; Redmond, Daniel P.; McDonald, Robert H.
doi: 10.1002/cpt197518131pmid: 1149359
Changes in hemodynamic variables and renin release, induced with both alpha and beta adrenergic agonists, were studied in 5 normal men. Saline (0.9% NaCl), methoxamine (1.6 and 5.9 µg/kg/min), and isoproterenol (0.015 and 0.026 µg/kg/min) were infused individually in a random order for 30 min. Methoxamine and isoproterenol caused the predicted directionally opposite cardiovascular changes but caused nearly equal and dose‐related increases in plasma renin activity, as measured by radioimmunoassay. Saline irifusion had no effect. Propranolol (0.125 mg/kg) caused decreases in systolic pressure and heart rate, and a significant decrease in plasma renin activity. Propranolol prevented the renin‐releasing effects of isoproterenol and methoxamine, but only the cardiovascular effects of isoproterenol. It appears that alpha or beta agonists stimulate renin release equally in man and that at least one step in renin release is propranolol‐sensitive. Such sensitivity may be independent of its beta receptor blocking activity.
O'Malley, Kevin; McNay, John L.
doi: 10.1002/cpt197518139pmid: 1149360
Twelve patients with essential hypertension were treated aggressively with oral minoxidil in order to achieve blood pressure control as expeditiously as possible. Pretreatment blood pressure ranged from 159/109 to 238/161 mm Hg. Following an initial dose of 5 mg, subsequent dosage increments were administered every 6 hr until a fall in blood pressure was observed. The size of additional doses was determined by the magnitude of, and response to, the lowest effective dose and the therapeutic objective. Over a time interval of 24 to 42 hr, the blood pressure was reduced to normal or near normal in each case. Untoward hypotension was uniformly avoided. Analysis of the relationship between blood pressure response and cumulative dose indicates that at suboptimal blood pressure responses, it is safe and efficacious to give half the antecedent cumulative dose as a single dose in arriving at the therapeutic objective. The use of such a regimen should be considered as an alternative to parenteral drug administration in severe hypertension when immediate control of blood pressure is not required.
Welling, P. G.; Craig, W. A.; Kunin, C. M.
doi: 10.1002/cpt197518145pmid: 1149361
A one‐compartment model designed to predict alterations in persistence of drugs in uremic patients was constructed using information obtained from normal subjects. Data obtained from the literature in which the fraction of absorbed drug eliminated unchanged in the urine and the apparent elimination rate constants were compared in both normal control subjects and in severely uremic patients. Twenty‐two drugs were examined. Despite changes in apparent volume of distribution and metabolism reported in uremia, the model was able to predict overall elimination rate constants in severe uremia with an error under 10% for 12 and under 20% for 7 additional drugs. The method appears to be most informative for drugs that tend to be retained in the presence of renal failure. Great error was observed with doxycycline and erythromycin. Studies with erythromycin lactobionate and a cupplate assay reduced the error for this drug from 56% for the glucoheptonate to 18%. Doxcycline is known to have a complex enterohepatic circulation. The model is offered as a useful approach to predict dosage adjustment in uremic patients with drugs for which data are not available.
O'Malley, Kevin; Velasco, Manuel; Pruitt, Albert; McNay, John L.
doi: 10.1002/cpt197518153pmid: 1149362
The effect of uremia on the binding of diazoxide to plasma proteins was studied. An equilibrium dialysis technique, using diazoxide‐14C at approximately 30 and 300 µg/ml in the plasma phase, was used to measure diazoxide binding to plasma. Serum albumin concentration (Alb) and serum creatinine (Cr) or blood urea nitrogen (BUN) were negatively correlated. By single regression analysis, per cent free diazoxide (%FD) correlated negatively with Alb and positively with Cr or BUN. When %FD was regressed simultaneously against Alb and Cr or BUN, Alb emerged as the sole determinant of %FD (p < 0.001), indicating that creatinine or BUN correlated with %FD by their inverse correlation to Alb rather than by an effect on drug protein binding. At the levels of Alb studied, %FD varied over a 2‐fold range. In a retrospective study of the influence of uremia on diazoxide effect in hypertensive patients, a relatively low correlation (r, 0.59) was found between BUN and hypotensive effect. Prospective studies involving correlations of drug effect with renal function and %FD are required to assess the clinical importance of decreased binding of diazoxide to uremic plasma.
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