Kinetics of drug action in disease states. XV: Effect of pregnancy on the convulsive activity of pentylenetetrazol in rats

The purpose of this investigation was to determine whether the pharmacodynamics of the central nervous system stimulant pentylenetetrazol (1) are altered in advanced pregnancy. Lewis rats that were 20 days pregnant and nonpregnant rats of the same age and strain received either a relatively fast or a relatively slow intravenous infusion of 1 until the onset of a maximal seizure, which occurred after about 11 or 31 min, respectively, of infusion. The concentrations of 1 at that time in serum, cerebrospinal fluid, (CSF) and brain were independent of the infusion rate and did not differ significantly between pregnant and nonpregnant animals. The ratio of concentrations of 1 in the cerebrospinal fluid to that in serum was unity in all groups, consistent with negligible serum protein binding and indicative of rapid penetration of 1 into the central nervous system. It is concluded that advanced pregnancy has no apparent effect on the response of the central nervous system of rats to the convulsive activity of 1.     

Kinetics of drug action in disease states. XXXVIII: Effect of body temperature on the convulsant activity of pentylenetetrazol in rats.

The purpose of this investigation was to determine the effect of body temperature on the pharmacodynamics (convulsant activity) of pentylenetetrazol (PTZ). Rats received an iv infusion of PTZ until the onset of maximal seizures, at which time samples of cerebrospinal fluid (CSF), brain, and blood (for serum) were obtained for subsequent determination of PTZ concentrations by HPLC. The PTZ infusion caused a decrease in body temperature of approximately 4 degrees C within 20 min and onset of seizures in approximately 40 min. Compared with animals whose temperature was maintained in the normal range by heating pads, the hypothermic rats required significantly larger doses and higher serum, brain, and CSF concentrations of PTZ to produce seizures. Other rats received an injection of brewer's yeast to produce fever. Then, PTZ was infused 6, 12, or 24 h later when body temperature was elevated by an average of 1.3, 1.1, or 0.4 degrees C, respectively. Compared with control rats, whose temperature was maintained in the normal range by heating pads, moderate hyperthermia had no significant effect on the dose and concentrations of PTZ required to produce maximum seizures. Pentylenetetrazol exemplifies a drug that can produce hypothermia which, in turn, reduces the sensitivity of rats to its pharmacologic action. Unlike the central nervous system (CNS) depressants phenobarbital and ethanol, whose pharmacologic activity in rats is enhanced at elevated body temperature, the activity of the CNS stimulant PTZ is apparently not altered by fever.     

Kinetics of drug action in disease states. XXI. Relationship between drug infusion rate and dose required to produce a pharmacologic effect

Computer simulations were performed to determine if the threshold dose of an infused drug (rather than the drug concentration in the biophase at onset of action) can be a suitable index for pharmacodynamic investigations as proposed by others. A two-compartment pharmacokinetic model with drug elimination from the central compartment was used for the simulations. Drug was administered into the central compartment by a constant-rate infusion, and concentrations in the central and peripheral compartments were calculated as a function of time. The pharmacologic effect was assumed to be reversible and to occur at a defined concentration (the effective concentration) in one or the other compartment. The dose required to produce an effective concentration (threshold dose) was determined as a function of infusion rate. The relationship between infusion rate and the dose required to produce an effective concentration in the peripheral compartment was found to be affected by drug distribution and elimination kinetics and by the effective concentration. The infusion rate-dose relationship showed a dose minimum at an infusion rate which others have designated as the "optimal dose rate" and have used for pharmacodynamic studies. No such minimum occurred for pharmacologic effects associated directly with drug concentrations in the central compartment. Since optimum dose rate and threshold dose are affected by both pharmacokinetic and pharmacodynamic alterations, it is concluded that this method (which avoids determination of drug concentrations) is not generally suitable for quantitative pharmacodynamic investigations.     

Kinetics of drug action in disease states. XXVI: Effect of fever on the pharmacodynamics of theophylline-induced seizures in rats

This investigation was designed to determine the effect of fever on the neurotoxicity of theophylline as reflected by the concentrations of this drug that cause convulsions in experimental animals. Fever was produced in male, inbred, adult Lewis rats (approximately 180 g) by sc injection of brewer's yeast; an elevation of body temperature of 1.2 +/- 0.4 degrees C (mean +/- SD) was achieved at the time of the pharmacodynamic measurements. Theophylline was infused iv at a rate of 1.03 mg/min until the onset of maximal seizures. Drug concentrations in serum, serum water, brain, and cerebrospinal fluid (CSF) at that time were determined by high-performance liquid chromatography. Compared with the control group, the group of febrile rats had statically significantly lower serum protein concentrations, decreased serum protein binding of theophylline, and slightly increased theophylline concentrations in the CSF at the onset of seizures. Inasmuch as theophylline concentrations in the CSF reflect the concentrations of this drug in the biophase, the results of this study show that fever does not increase the sensitivity of the central nervous system to the neurotoxic effects of theophylline in rats. In fact, a statistically significant positive correlation between theophylline concentrations in the CSF and body temperature was found in this investigation, suggesting a decreased sensitivity of the animals to the neurotoxic effects of theophylline at higher body temperature.     

Kinetics of drug action in disease states. XXXII: Effect of experimental hypertension on the pharmacodynamics of phenobarbital in rats

The purpose of this investigation was to determine the effect of experimental hypertension on the concentrations of phenobarbital required to produce a defined hypnotic effect (loss of righting reflex) in adult, female Lewis rats. Hypertension was induced with deoxycorticosterone acetate (DOCA), administered by im injection (first experiment) or by pellet implant (second experiment), and 1% NaCl in the drinking water. There were two control groups: one that received im injections of water or a drug-free pellet implant plus 1% NaCl in the drinking water, the other that received water injections or drug-free pellet implants and no NaCl in the drinking water. These treatments were carried out for 3 months and resulted in appreciable elevation of blood pressure and increased heart weight in the DOCA + NaCl-treated (but not in the NaCl alone) rats. All animals then received an infusion of phenobarbital until onset of loss of righting reflex. The concentrations of phenobarbital in the serum, serum water, brain, and CSF of the hypertensive rats at the pharmacologic endpoint did not differ significantly from corresponding concentrations in the control groups (except for a marginal difference of the drug concentration in serum water between the DOCA pellet group and the drug-free pellet control group). It is concluded that DOCA-induced hypertension has no apparent effect on the sensitivity of the central nervous system to the hypnotic action of a barbiturate in female rats.     

Kinetics of drug action in disease states. XXXVI: Effect of cyclosporine on the pharmacodynamics and pharmacokinetics of a barbiturate (heptabarbital) in rats

Pretreatment with cyclosporine reportedly prolongs the effect of certain general anesthetics in humans and the sleeping time of mice after pentobarbital administration. This investigation was designed to determine the mechanism(s) of the cyclosporine-barbiturate interaction. Adult female Wistar rats received cyclosporine (50 mg/kg im) or saline solution daily for 3 days. On the third day, they were injected with heptabarbital (45 mg/kg iv). Other cyclosporine-treated and control groups were infused with heptabarbital until they lost their righting reflex. Treatment for 3 d with cyclosporine was associated with decreased rectal temperature, decreased magnesium concentrations in serum and CSF, increased serum creatinine and urea nitrogen concentrations, elevated serum aspartate aminotransferase activity and total bilirubin concentration, decreased serum total protein concentration, and increased hematocrit. These physiologic changes are consistent with the clinically observed hypomagnesemia, nephrotoxicity, and hepatotoxicity in patients treated with cyclosporine. Control rats slept for 90 +/- 14 min (mean +/- SD, n = 9) after heptabarbital injection, whereas cyclosporine-pretreated rats slept for 154 +/- 22 min. Compared with controls, cyclosporine-pretreated rats awoke (after heptabarbital injection) and went to sleep (after heptabarbital infusion) with significantly lower barbiturate concentrations in serum and CSF. Pretreatment with a single 60-mg/kg im dose of cyclosporine 2 h before heptabarbital infusion caused no significant biochemical changes approximately 160 min later, except for elevated serum aspartate aminotransferase (which occurred also after injection of the surfactant-containing vehicle) and serum bilirubin. Again, heptabarbital concentrations at onset of sleep (loss of righting reflex) in serum, brain, and CSF of cyclosporine-treated rats were significantly lower than in saline-treated controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Kinetics of drug action in disease states XII: Effect of experimental liver diseases on the pharmacodynamics of phenobarbital and ethanol in rats

This investigation was designed to determine if liver diseases can modify the pharmacodynamics of the central nervous system depressants phenobarbital and ethanol. Two experimental models of liver diseases in rats were used: extrahepatic cholestasis produced by bile duct ligation and hepatic necrosis induced by carbon tetrachloride administration. Phenobarbital (both models) or ethanol (cholestasis model only) was infused slowly intravenously until the rats lost their righting reflex. Drug concentrations in serum, brain, and cerebrospinal fluid at that time were determined in the diseased animals as well as in sham-operated or solvent-treated controls. Phenobarbital concentrations at the onset of action were not significantly different between controls and either 5-d or 12-d cholestatic rats, except for total serum concentrations which were lower in the cholestatic groups due to reduced protein binding. Ethanol concentrations were slightly but statistically significantly lower in 12-d cholestatic rats as compared with controls. Neither 5-d nor 12-d carbon tetrachloride-induced hepatic dysfunction had any significant effect on phenobarbital concentrations at the onset of loss of righting reflex, except for a marginal decrease in the cerebrospinal fluid concentration of rats that had been treated for 5 d with the hepatotoxin. It was concluded that, under the experimental conditions, the hepatic diseases investigated did not have appreciable effects on the central nervous system response to the hypnotic action of phenobarbital and ethanol.     

Kinetics of d-tubocurarine disposition and pharmacologic response in rats

After bolus intravenous dosing of d-tubocurarine (d-TC) to rats, the twitch heights of the tibialis anterior muscle indirectly stimulated were followed, and its decrease was defined as pharmacologic response of d-TC. The relation between dose and response intensity was found to be well described with Hill's equation. According to a theory proposed by Smolen, Hill's equation was also applicable to the biophase d-TC concentration-response relation; the time courses of the relative biophase d-TC concentration indicated linear kinetics with dose levels 0.15 mg/kg and the occurrence of dose-dependent disposition with 0.30 mg/kg. After bolus i.v. dosing of³H-d-TC, plasma d-TC concentration obeyed a dose-independent two compartment model with doses 0.15mg/kg, but not with 0.30 mg/kg. This finding matched the above estimated with pharmacologic data. The active metabolite was not found in plasma and urine. The extent of d-TC plasma protein binding was independent of the wide range of plasma levels and its mean (±SD) value was 30.5 (±3.8). Plasma d-TC levels and pharmacologie response intensity were well correlated by Hill's equation and a three compartment model (the general two and the biophase compartments) in the dose range 0.15 mg/kg.This work was presented at the First Japanese-American Symposium on Pharmacokinetics and Biopharmaceutics, Tokyo, July 1981, which was held in memory of Dr. Sidney Riegelman.     

EEG effects of IV infusion of pentylenetetrazol in rats: A model for screening and classifying antiepileptic compounds

In order to validate a new animal model predictive of the profile of antiepileptic drugs, we studied the antagonism by standard antiepileptics of the EEG modifications induced by low-speed IV infusion of pentylenetetrazol (PTZ) in rats. The activity of the drugs was measured by their effects on temporal characteristics of the PTZ-induced EEG paroxysms. Most compounds had moderate to potent anti-PTZ effects, as shown by the changes in the EEG temporal parameters. However, these effects depended on the drugs and doses. Cluster analysis showed that drugs and doses which evoked similar changes were closely related and were included in separate clusters with respect to one another. In particular, the present results showed that benzodiazepines and antiepileptics cluster differently in their effects. Thus, this model could be a useful tool for assessing new antiepileptic drugs.     

Factors affecting the expression and function of P-glycoprotein in rats: drug treatments and diseased states

The expression and function of P-glycoprotein (P-gp), an ATP-dependent efflux pump, were examined in rats pretreated with dexamethasone (DEX), an inducer of P-gp, and in rats with glycerol-induced acute renal failure (ARF) and with CCl4-induced acute hepatic failure (AHF). DEX pretreatment increased the P-gp level and its functional activity in the intestine. In contrast, in ARF and AHF rats, the in vivo P-gp function was systemically suppressed, even though the level of P-gp remained unchanged or rather increased. In Caco-2 cells, the plasma collected from diseased rats exhibited a greater inhibitory effect on P-gp function than did plasma from control rats. A higher-plasma level of corticosterone, an endogenous P-gp substrate/inhibitor, was observed in the disease rats. These findings indicate that the actual in vivo function of P-gp cannot be predicted merely from the expression level of P-gp, and suggest that some endogenous P-gp-related compounds such as corticosterone participate in the regulation of in vivo P-gp function in diseased states.     

Potential beneficial effects of sacubitril-valsartan in renal disease: a new field for a new drug

Introduction: Patients with renal dysfunction are at a higher risk of cardiovascular disease (CVD), which often shares manifestations with heart failure (HF). Last year, the FDA approved the use of sacubitril-valsartan in patients with HF. This dual-acting agent enhances the functions of natriuretic peptides and inhibits the renin-angiotensin system.

Areas covered: This review summarizes the existing preclinical and clinical studies carried out with sacubitril-valsartan (and other drugs with similar pharmacological mechanisms) in HF and hypertensive patients. We put the focus on the renal data provided by these studies. Data were obtained from English peer-reviewed articles on PubMed and clinical trials registered in ClinicalTrials.gov.

Expert opinion: Overall, sacubitril-valsartan might be a promising therapeutic approach in patients with renal dysfunction. Renal conditions with marked CV risk, such as arterionephrosclerosis, could constitute a particular setting where to evaluate the impact of the drug. Nevertheless, large, randomized trials are needed to confirm the beneficial effects and safety profile of the drug in renal patients, as well as to elucidate some concerns observed in HF trials, such as the slight increase in proteinuria.     

Differential effects of pentylenetetrazol on REM sleep in naive and cobalt-epileptic rats

Spaced feeding of individual food pellets to food-deprived rats at 1-min intervals caused excessive drinking of 5 and 10% alcohol solutions, even though the solutions were available for only a 10-sec portion of each interval and even though the portion of availability occurred anywhere in the interval unpredictably from one interval to another. Thus schedule-induced ethanol polydipsia is not necessarily a post-reinforcement phenomenon.The diligent assistance of Marilyn Schwieder is gratefully acknowledged.