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The purpose of this investigation was to explore theoretically certain strategies for optimizing the therapeutic index of drugs and to assess these strategies experimentally with two diuretics. Diuretic agents allow dosing rate flexibilities because the temporal profile of diuretic action can vary considerably as long as the total diuretic effect per day is the same. They can also be used in combination. Experiments were designed to determine if the therapeutic index of furosemide and hydrochlorothiazide can be optimized by administering one or the other at a certain rate or by administering the two drugs together in a certain ratio and at a certain rate. Male Lewis rats received one or the other drug, or combinations of the two, by i.v. infusion at different rates. Several timed urine collections were made under steady-state conditions, with excreted urine replaced volume for volume by i.v. lactated Ringer's solution. The urine flow rates and the urinary excretion rates of the diuretics and of Na and K were determined. The relationship between the diuretic effect of either of the two drugs given alone and the respective drug excretion rate could be described by the Hill equation. The ratio of urine flow rate to K excretion rate exhibited a marked dependence on hydrochlorothiazide excretion rate (highest ratio at high excretion rates), whereas the K/Na excretion rate ratio was constant over a wide range of hydrochlorothiazide excretion rates. There was no significant change of these ratios with changing excretion rate of furosemide. Infusion of the two diuretics in combination of different ratios and at different combined rates under steady-state conditions revealed proportionality between the urinary excretion rates of Na and urine over a wide range and a decreasing K /urine excretion rate ratio with increasing urine flow rate. Hence, a favorable increase in the Na/K excretion rate ratio was attained with increasing urine flow rate. These experiments and computer simulations demonstrate in principle the feasibility of optimizing the therapeutic index by appropriate selection of a drug's dosing rate or by dosing a combination of two drugs at an appropriate ratio and rate. [ABSTRACT FROM AUTHOR]

The central nervous system (CNS) sensitivity to the hypnotic (general anesthetic) action of pheno-barbital and to the neurotoxic (convulsive) action of theophylline is greater in rats with acute renal failure than in normal animals, consistent with clinical observations. In the case of phenobarbital, this increased sensitivity can be produced in normal rats by infusion of a solution of the lyophilized dialysate of serum from rats with renal failure. It was hypothesized that the relevant constituent(s) of this dialysate may circulate between the blood and the intestinal lumen and that it (they) can be adsorbed by orally administered activated charcoal and thereby removed from the body. If so, treatment of renal failure rats with activated charcoal should partly reverse the increased CNS sensitivity to phenobarbital and to other drugs similarly affected. Accordingly, rats with renal failure produced by bilateral ligation of ureters were given an aqueous suspension of activated charcoal, about 1 g per kg body weight, orally every 8 hr for six doses. Uremic controls received equal volumes of water. About 2 hr after the last dose, the animals were infused i.v. with phenobarbital to onset of loss of righting reflex or with theophylline to onset of maximal seizures. In the phenobarbital study, charcoal treatment partly reversed the hypothermia associated with renal failure and caused a reduction of creatinine and total bilirubin concentrations in serum. The cerebrospinal fluid (CSF) concentration of phenobarbital at onset of loss of the righting reflex was significantly higher in charcoal treated rats than in their controls. In the theophylline experiment, charcoal treatment had no significant effect on the measured biochemical variables but caused a large increase in the dose and concentrations of theophylline required to produce maximal seizures. In both experiments, administration of activated charcoal caused a reversal of the hyperalgesia associated with renal failure, as determined before drug administration by tail flick latency. These results are consistent with the hypothesis that oral administration of activated charcoal can cause a reduction in the concentration of the circulating endogenous substance(s) that alters the pharmacodynamics of certain drugs in renal failure. [ABSTRACT FROM AUTHOR]

There is considerable evidence of gender differences in the pharmacokinetics of numerous drugs, particularly in rodents, but very limited information concerning the effect of gender on pharmacodynamic characteristics (concentration-activity relationships). In this study, heptabarbital or phenobarbital was administered to male and female rats and the concentrations of these drugs in the brain, cerebrospinal fluid and serum at onset or offset of loss of righting reflex were determined. For heptabarbital, offset concentrations were determined in Lewis rats and onset concentrations in Wistar rats. Onset concentrations of phenobarbital were determined in Wistar rats. In all cases, the barbiturate concentrations in males were significantly lower than those in females at the pharmacologic endpoint. The biologic (serum) half-life of heptabarbital is much shorter in males (∼10 min) than in females (∼90 min) and this pharmacokinetic difference is reflected by the considerably longer duration of effect of the drug in females. [ABSTRACT FROM AUTHOR]

This investigation was designed to determine the effect of experimental hyperthyroidism on the hypnotic activity of a benzodiazepine and on the binding characteristics of the benzodiazepine receptor complex. Rats were made hyperthyroid by subcutaneous implantation of slow release pellets containing L-thyroxine. This treatment produced the characteristic symptoms of hyperthyroidism: increased serum thyroxine concentrations, increased heart weight and body temperature, and decreased serum protein concentrations. The hyperthyroid rats and a parallel group of normal animals (with drug-free pellets implanted subcutaneously) were slowly infused intravenously with oxazepam until they lost their righting reflex. The hyperthyroid rats required a significantly larger dose of the benzodiazepine and their total serum and cerebrospinal fluid concentrations of oxazepam (but not the serum concentration of free drug and the brain concentration) at the onset of loss of the righting reflex were modestly but statistically significantly lower than those of the normal rats. The receptor density and affinity for diazepam in hyperthyroid rats were not significantly different from those of the normal animals. Hyperthyroidism apparently affects the pharmacokinetics of oxazepam but has, at best, only a small effect on the pharmacodynamics (hypnotic activity) of the drug. [ABSTRACT FROM AUTHOR]

Zoxazolamine is used for the pharmacologic assessment of possible changes in oxidative enzyme activity (paralysis time test) in rodents, whereas one of its metabolites, chlorzoxazone, is used clinically as a skeletal muscle relaxant. In this investigation, the pharmacodynamics of the two compounds were characterized in normal adult rats to determine their suitability for studies of the kinetics of drug action in disease states. Upon i.v. infusion 5 min beyond the onset of loss of the righting reflex (LRR) and concomitant blood sampling, serum concentrations of either drug were higher at the onset than at the offset of LRR, suggestive of a distribution disequilibrium. When Zoxazolamine was infused at three different rates to onset of LRR, the pharmacologic end point was reached in 10 to 53 min. Drug concentrations in serum and brain at onset of LRR increased with increasing infusion rate, whereas drug concentrations in cerebrospinal fluid (CSF) were infusion rate independent and essentially identical to CSF concentrations at offset of LRR. Similar experiments (five infusion rates) with chlorzoxazone revealed drug infusion rate dependence even of CSF concentrations at the onset of LRR; only at very slow infusion rates (onset of effect in ≥50 min) were onset concentrations in CSF essentially equal to offset concentrations. Neither drug produced measurable metabolite concentrations in the CSF. It is concluded that zoxazolamine but not chlorzoxazone distributes rapidly between CSF and the biophase, metabolites of either drug do not contribute measurably to the pharmacologic effect, and neither drug is subject to development of functional tolerance under the experimental conditions. Zoxazolamine is the more suitable agent for subsequent pharmacodynamic studies of disease effects in rats. [ABSTRACT FROM AUTHOR]

This investigation was designed to determine the effect of treatment with contraceptive steroids on the central nervous system depressant activity of ethanol. Adult female rats received oral doses of ethynyl estradiol (0.1 mg kg day), ethynyl estradiol and norethindrone (0.1 and 10 mg kg day), or vehicle only for 14 days. Ethanol was then infused slowly iv until the animals lost their righting reflex. The concentrations of ethanol at that time in serum and cerebrospinal fluid were statistically significantly higher in rats treated with the estrogen-progestin combination than in control animals. Ethanol concentrations in rats treated only with the estrogen were intermediate and did not differ significantly from control values. These results indicate that treatment with an estrogen-progestin combination is associated with a decreased sensitivity of the central nervous system to the hypnotic activity of ethanol. This evidence of a pharmacodynamic interaction between contraceptive steroids and ethanol in rats is consistent with a recent clinical report of significant contraceptive steroid-related improvement in tolerance to ethanol with no apparent effect on the pharmacokinetics of ethanol. [ABSTRACT FROM AUTHOR]

Purpose. To explore, by simulation procedures, the feasibility of characterizing, from sparse data, the concentration-effect relationship of drugs with pharmacodynamic hysteresis. Methods. For computer simulations, the concentration-effect relationship was assumed to be describable by the Sigmoid- E equation, the site of drug action was located in a distinct effect compartment ( k = 10 × k), and the pharmacokinetics were those of either a linear one- or two-compartment system. In view of the poor estimability of the parameters of the Sigmoid- E model under the usual clinical conditions, central compartment post-distributive drug concentrations required to elicit various intensities of effect within the therapeutic range were used as data descriptors. Effect intensities of 5 and 25, or 25 and 50 units (with the 'unknown' E = 100 units) were targeted in multiple-dose (steady state) trial designs. From these data, drug concentrations required to produce effect intensities of 15 and 50 units were estimated by both log-linear and linear interpolation and the actual effect intensities produced by these concentrations were calculated. These simulations were performed over a wide range of Hill coefficient values (0.5 to 4.0) and dosing intervals (0.1 to 1.5 × elimination t). Results. Acceptable results could be obtained by measuring drug concentrations and effect intensities at or near the end of a dosing interval. The largest deviations of effective concentration estimates (in terms of effect intensity) occurred at a Hill coefficient value of 0.5 and the results were very little affected by changing the dosing interval. Conclusions. Our results demonstrate that effect-controlled clinical trials, with sparse data, of drugs with pharmacodynamic hysteresis for determining concentration-effect relationship in the therapeutic range are feasible in principle. [ABSTRACT FROM AUTHOR]