Oxazepam pharmacokinetics in thyroid disease.

The pharmacokinetics of oxazepam, a drug mainly eliminated by a single step glucuronidation reaction, were studied in seven hyperthyroid and six hypothyroid patients before and after treatment. Oxazepam elimination half-life was shorter and apparent oral clearance higher in untreated hyperthyroid patients than after treatment. There was no significant change in oxazepam elimination in hypothyroid subjects. Time to peak concentration (tmax) was reduced in the hyperthyroid state. Hypothyroidism had no significant effect on tmax. Serum bilirubin concentration was lower in the patients while hyperthyroid before treatment than when euthyroid and also lower than in the hypothyroid patients. There was no significant correlation between serum bilirubin concentrations and oxazepam elimination. These results suggest that glucuronyl transferase activity is increased in hyperthyroidism but is not altered in most patients with hypothyroidism. The extent of increase in glucuronyl transferase activity is similar to that produced by enzyme inducing drugs.     

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.     

Pharmacodynamics of the hypnotic effect of salicylamide in rats

Salicylamide (SAM) can produce sedation and sleep in humans and animals. To explore the potential utility of the drug as a research tool for assessing disease effects on the response of the central nervous system to depressant drugs, and to obtain a better understanding of the clinically evident sedative action of SAM, studies were performed to characterize the relationship between the concentrations and hypnotic effect of this drug in rats. Female Lewis rats weighing 170-200 g received SAM by intravenous infusion at a rate of 0.49, 1.22, or 2.47 mg/min until the onset of loss of the righting reflex. This well-defined pharmacological endpoint occurred from 16.7 +/- 2.3 min (fastest infusion rate) to 110 +/- 27 min (slowest infusion rate) after the start of the infusion. SAM concentrations at that time in serum, serum water, brain, and cerebrospinal fluid (CSF) were similar in animals that had received the 1.22- or 2.47-mg/min infusion and lower in animals that were infused at a rate of 0.49 mg/min. The slowest infusion rate group also exhibited increased serum protein binding of the drug. The SAM concentration ratio, CSF-serum water, was essentially unity in all three groups, indicative of rapid equilibration of the drug across the blood-CSF barrier. Gentisamide, the hydroxylated metabolite of SAM, was found in serum, CSF, and brain, but in low concentrations at which this metabolite alone had no hypnotic effect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Kinetics of Drug Action in Disease States. XXXIX. Effect of Orally Administered Activated Charcoal on the Hypnotic Activity of Phenobarbital and the Neurotoxicity of Theophylline Administered Intravenously to Rats with Renal Failure

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.     

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.     

Increased responsiveness to ethanol with advancing age in rats

Male CD strain rats of three different ages (young—5 months; middle—15; old—27 months) were tested for their responsiveness to doses of ethanol sufficient to produce hypothermia or hypnosis. Comparison dosages of ethanol across age groups were based upon the estimated equivalent dilution of the drug into the body water compartments of subjects. In the hypnosis study, there were no statistically significant differences among the groups with regard to the time elapsed until the righting reflex was lost or in total sleep time. However, old animals recovered the righting reflex in the presence of lower blood ethanol concentrations than those observed for young and middle animals, suggesting a greater sensitivity of target tissues to the hypnotic effects of ethanol in old rats. The responsiveness of old rats to the hypothermic effect of ethanol was greater than that of younger rats only when the experiment was conducted at an ambient room temperature of 10°C.     

THE EFFECTS OF THYROID STATUS ON DIGOXIN DISTRIBUTION IN THE RAT

1. Tritiated digoxin was injected intravenously into euthyroid, hyperthyroid and hypothyroid rats. The rats were killed at intervals up to 24 h and tritium in serum and tissues counted. 2. Serum concentrations of tritium in the hyperthyroid animals were less than in the control group, whereas the concentrations in the hypothyroid group were similar to those in the control group. 3. Cardiac tissue concentrations of tritium were higher in the hyperthyroid group than in the control group, but in the hypothyroid group were similar to the control group. 4. The decreased serum levels in the hyperthyroid rats were probably due to an increased volume of distribution. 5. Pharmacological resistance to digoxin in hyperthyroidism must be due to some alteration in cardiac function and it is suggested that this is an increase in Na/K ATPase receptors.     

Kinetics of Drug Action in Disease States. XXII. Effects of Contraceptive Steroids on the Pharmacodynamics of Ethanol in Rats

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^–1 day^–1), ethynyl estradiol and norethindrone (0.1 and 10 mg kg^–1 day^–1), 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.     

Increased susceptibility of the lungs of hyperthyroid rats to oxidant injury: specificity of effects

Results from previous studies indicate that hyperthyroidism increases the risk of ozone-induced lung toxicity. This observation raised the possibility that pulmonary damage from other oxidant substances might be greater in a hyperthyroid state. To address this hypothesis, pulmonary responses to crystalline silica, a particulate with oxidant properties, were evaluated in normal or hyperthyroid adult male rats. To induce a hyperthyroid condition, time-release pellets containing thyroxine were implanted subcutaneously; control rats received placebo pellets. After 7 days, the animals were exposed to saline or silica (0.1mg/100g BW or 1.0mg/100g BW) by intratracheal instillation. Following silica treatment, there was a dose-related increase in bronchoalveolar lavage (BAL) albumin levels and neutrophil numbers. However, the effects of silica were similar in both normal and hyperthyroid rats. These findings were confirmed and contrasted with those regarding ozone (1ppm, 4h inhalation) in a subsequent experiment. The results indicated that, although exposure to either ozone or silica resulted in increases in BAL albumin levels and neutrophil numbers, only responses to ozone were enhanced in hyperthyroid rats. These findings suggest that specificity exists in regards to the modulation of oxidant-induced lung damage and inflammation by thyroid hormones.     

Effect of di(n-butyl) phthalate on testicular oxidative damage and antioxidant enzymes in hyperthyroid rats

This study compared the effects of di(n-butyl) phthalate (DBP) on the oxidative damage and antioxidant enzymes activity in testes of hyperthyroid rats. Hyperthyroidism was induced in pubertal male rats by intraperitoneal injection of triiodothyronine (T3, 10 microg/kg body weight) for 30 days. An oral dose of DBP (750 mg/kg) was administered simultaneously to normal or hyperthyroid (T3) rats over a 30-day period. No changes in body weight were observed in the hyperthyroid groups (T3, T3 + DBP) compared with controls. There were significantly higher serum T3 levels observed in the hyperthyroid rats than in the control, but the serum thyroid stimulating hormone levels were markedly lower in the hyperthyroid rats. DBP significantly decreased the weight of the testes in the normal (DBP) and hyperthyroid (T3 + DBP) groups. The serum testosterone concentrations were significantly lower in only DBP group. DBP significantly increased the 8-hydroxy-2-deoxyguanosine (8-OHdG) level in the testes, whereas the DBP-induced 8-OHdG levels were slightly higher in T3 + DBP group. Superoxide dismutase and glutathione peroxidase activities were significantly higher in the testes of the DBP or T3 + DBP groups. Catalase (CAT) activity was significantly higher in the DBP treatment group, but the T3 + DBP group showed slightly lower DBP-induced CAT activity. The testicular expression of thyroid hormone receptor alpha-1 (TRalpha-1) was significantly higher in the DBP groups, and androgen receptor (AR) expression was not detected in the DBP treatment group. In addition, DBP significantly increased the peroxisome proliferator-activated receptor-r (PPAR-r) levels in the testis. These results suggest that hyperthyroidism can cause a change in the expression level of PPAR-r in testes, and may increase the levels of oxidative damage induced by the metabolic activation of DBP.     

Prolonged hypothermia after phenobarbital-induced anesthesia in adrenalectomized rats

Adrenalectomized rats are hypersensitive to the hypothermic as well as hypnotic effects of phenobarbital. The exaggerated hypnotic response is more pronounced in the chronic (10 day) than the acute (1 day) adrenalectomized rat and is reversed by glucocorticoid replacement. The prolonged hypothermia to a hypnotic dose of phenobarbital occurs in adrenalectomized but not adrenodemedullated rats. This hypersensitivity is characterized by an impaired ability to regain normal body temperatures for as long as 24 hours after regaining the righting reflex. The prolonged hypothermia is prevented by prior treatment with glucocorticoids but not mineralocorticoids. There appears to be no gross alteration in disposition of phenobarbital following adrenalectomy suggesting that the prolonged duration of hypothermia is not a consequence of accumulation of the drug.     

Increased ketogenesis in hyperthyroid rats metabolizing ethanol

The levels of various metabolites were measured in freeze-clamped samples of liver from triiodothyronine-treated and control rats to which either saline or ethanol (2.5 g/kg body weight) had been administered 2 hours earlier. It was found that ethanol led to a sharp increase in the hepatic acetate concentration in both hyperthyroid and euthyroid rats whereas lactate and pyruvate concentrations were lowered in both groups. The lactate/pyruvate ratio rose significantly in euthyroid animals that had received ethanol but the ratio remained relatively low in hyperthyroid rats. The adenine nucleotide phosphorylation potential, already low in hyperthyroid rats, was further lowered by ethanol. However, the most remarkable difference between the responses of euthyroid and hyperthyroid rats to ethanol was in the hepatic concentrations of ketone bodies, particularly 3-hydroxybutyrate. In control animals, administration of ethanol did not affect either the acetoacetate or 3-hydroxybutyrate concentration but, although the level of ketone bodies in the livers of hyperthyroid rats that had not received ethanol was the same as that of controls, there was a greater than fivefold increase in the 3-hydroxybutyrate level when ethanol was given. While this increase in ethanol-dependent ketogenesis is not explicable at this stage, hyperthyroidism did not increase the activity of cytoplasmic acetyl-CoA synthetase, an enzyme that is probably involved in the formation of ketone bodies from ethanol-derived acetate.     

Interaction of the hypnotic lormetazepam with central benzodiazepine receptor subtypes omega 1, omega 2 and omega 3]

To clarify the action of lormetazepam, 3-hydroxybenzodiazepine, on the benzodiazepine (BZ) receptor subtypes, effects of lormetazepam on motor performance in the traction test and hexobarbital-induced loss of righting reflex in mice and the binding to BZ receptor subtypes were investigated in comparison with those of other BZ hypnotics. Lormetazepam prolonged the duration of hexobarbital-induced loss of righting reflex. The minimal effective dose (1 mg/kg, p.o.) was higher than that of flunitrazepam, lower than those of diazepam and zopiclone, and the same as those of triazolam and brotizolam. Lormetazepam showed the ataxic effect at 10 mg/kg, p.o., but the separation between its effective doses for the hypnotic and ataxic effects was the largest among the hypnotics tested. In the displacement study on [3H]flumazenil binding to cerebellar and spinal cord membranes, lormetazepam bound with a higher affinity to omega 1 receptor (Ki = 10 nM) than to omega 2 receptor (Ki = 29 nM). The GABA-ratios of lormetazepam to omega 1 and omega 2 receptors were 3.9 and 4.0, respectively; and they were higher and lower than those of flunitrazepam to omega 1 and omega 2 receptors, respectively. In the displacement study on [3H] Ro5-4864 binding to kidney membranes, lormetazepam bound with a lower affinity to the omega 3 receptor (Ki = 213 nM) than flunitrazepam. Thus, lormetazepam was suggested to be a potent hypnotic with weaker ataxic effects than other BZ hypnotics, which may be due to its selective and potent agonistic action on central omega 1 receptors.     

Effect of age on the pharmacodynamics of phenobarbital and ethanol in rats

The purpose of this investigation was to determine the effect of age on the sensitivity of the central nervous system (CNS) to the depressant action of phenobarbital and ethanol. For this purpose, one or the other of these drugs was administered by slow iv infusion to male rats of various ages until the animals lost their righting reflex. The drug concentrations at that time in serum, brain, and cerebrospinal fluid were determined. The results obtained in studies on 1, 9, and 18-month-old Sprague-Dawley rats and on 7, 16, and 24-month-old Fischer-344 rats showed that phenobarbital concentrations at the pharmacologic end-point decreased with increasing age, indicative of an increased sensitivity of older animals to the CNS depressant effect of the barbiturate. Similar studies with ethanol on Sprague-Dawley rats (only) showed substantially higher drug concentrations at all sampling sites in 5-week-old animals than in 9- and 12-month-old animals at the onset of loss of righting reflex, but no significant differences between the 9- and 12-month-old groups. This investigation, which was designed to exclude or account for pharmacokinetic variables and to avoid confounding secondary effects, such as hypothermia and development of acute functional tolerance, showed a substantial increase in CNS sensitivity to phenobarbital and ethanol with increasing age in rats between the age of 1 and 9 months, and a less pronounced increase (phenobarbital) or no significant change (ethanol) in rats between 9 and 18 months of age.     

Amelioration of L-thyroxine-induced hyperthyroidism by coumarin (1,2-benzopyrone) in female rats

1. The efficacy of coumarin (1,2-benzopyrone) was examined for the regulation of hyperthyroidism in female rats. 2. Coumarin was administered (10 mg/kg per day for 15 days) to l-thyroxine (L-T(4))-induced hyperthyroid as well as to euthyroid rats and changes in serum concentrations of thyroid hormones and in associated parameters, such as serum cholesterol, activity of hepatic 5'-monodeiodinase (5'DI) and glucose-6-phosphatase (G-6-Pase), glycogen content, bodyweight and daily food consumption, were analysed. Simultaneously, changes in hepatic lipid peroxidation (LPO), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were also investigated. 3. Although L-T(4) administration increased serum levels of thyroid hormones, the activity of hepatic 5'DI, G-6-Pase and LPO and daily food consumption, it decreased the level of serum cholesterol, hepatic glycogen content and the activities of anti-oxidant enzymes, such as SOD, CAT and GSH. 4. However, simultaneous administration of coumarin for 15 days to a group of hyperthyroid animals reversed most of the aforementioned changes, indicating its potential to ameliorate hyperthyroidism. Moreover, the drug did not increase, but rather decreased, hepatic LPO, suggesting its safe nature. 5. The present findings reveal a positive role for coumarin in the regulation of hyperthyroidism without any hepatotoxicity. It also appears that the test compound inhibits thyroid function at both a glandular level and at the level of peripheral conversion of T(4) to tri-iodothyronine.     

Single dose pharmacokinetics and pharmacodynamics of oxazepam in normal and renal dysfunction rats.

The purpose of this work was to investigate the disposition characteristics and pharmacodynamics of a benzodiazepine, oxazepam, in renal dysfunction rats. For the in vivo experiment, normal and renal dysfunction rats were given 40 mg/kg of oxazepam as the bolus dose. A quantitative electroencephalographic (EEG) method was used as the surrogate measure of the pharmacological response. The oxazepam concentration in plasma and cerebrospinal fluid (CSF) was assayed by the HPLC method. The steady-state volume of distribution and clearance based on total and unbound plasma did not change in renal dysfunction rats. Amplitude changes in the EEG induced by oxazepam in normal and renal dysfunction rats were characterized by a log-concentration response model or sigmoidal Emax model. The pharmacodynamic parameters from these models were not altered in renal dysfunction. In in vitro binding studies for gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex, the oxazepam-induced effect was not potentiated by the plasma dialysate from renal dysfunction rats. Thus, it was suggested that the brain sensitivity to benzodiazepines was not altered in renal insufficiency.     

Evidence of strain differences in GABA-benzodiazepine coupling

The effects of a single dose of oxazepam on seizure threshold, receptor occupancy and brain oxazepam concentration were investigated at several time points after drug treatment in two inbred strains of mice (NIH and C3H/HE). The C3H/HE strain showed a greater sensitivity to the effects of both pentylenetetrazol and oxazepam. Furthermore, the C3H/HE strain showed decreases in both receptor occupancy and seizure threshold across time, whereas the NIH strain showed no change in either measure. Although within-strain correlations were observed between seizure threshold and receptor occupancy, the C3H/HE strain had similar seizure thresholds to the NIH strain throughout but lower percentage receptor occupancies, thus a between-strain correlation was not observed. The C3H/HE strain had a higher number of specific benzodiazepine binding sites and these results may reflect a strain difference in GABA-benzodiazepine receptor coupling. In a further experiment, the development of acute tolerance to the effects of oxazepam was investigated. Brain concentrations of oxazepam and receptor occupancies were determined for each strain of mouse, at two different time points (1.5 and 7.5 h after drug treatment), at which equivalent seizure thresholds were obtained by manipulating the starting dose of oxazepam. For each strain, when equivalent seizure thresholds were observed at different time points, equivalent receptor occupancies were also observed. However, a trend towards higher brain concentrations of oxazepam at the later time point was detected for the two strains, suggesting that there may be some decrease across time in the affinity of the receptor for oxazepam.     

Characterization of the pharmacokinetic and pharmacodynamic interaction between gamma-hydroxybutyrate and ethanol in the rat.

It has been reported that ethanol enhances the hypnotic effect of gamma-hydroxybutyrate (GHB). In order to clarify the nature of this interaction we studied the pharmacokinetics and pharmacodynamics of combinations of GHB and ethanol in rats. Intraperitoneal injections of the GHB precursor gamma-butyrolactone (300 mg/kg) together with ethanol (3000 mg/kg) (n = 4) resulted in a longer "sleeping time" than the sum of the individual times (n = 8). Pharmacokinetic analysis of GHB concentrations with a two-compartment model with Michaelis-Menten (M-M) elimination in rats receiving a bolus of GHB (400 mg/kg, i.v.) in addition to steady-state ethanol concentrations (300-3000 microg/ml) (n = 12) or saline (n = 15) showed no marked differences in the area under the curve. The nature of the pharmacodynamic interaction was studied using isobolographs and an interaction model for the loss of the startle and righting reflex and a reaction to a painful tail clamp in rats receiving combinations of steady state concentrations of ethanol (1000-3000 microg/ml) and GHB (200-1400 microg/ml). For the righting reflex, synergy was observed at high ethanol concentrations (>2000 microg/ml) and additivity at lower concentrations. For the startle reflex, it was antagonistic at ethanol concentrations below 1000 microg/ml, and additivity was seen at higher concentrations. For the tail clamp reaction, a slight but significant antagonism was found at all combined concentrations. It is concluded that ethanol prolongs the sleeping time induced by GHB in the rat, which may not be due to a pharmacokinetic interaction. Pharmacodynamic interactions between GHB and ethanol in the rat occur, and the nature varies with the reflex studied and the concentration of ethanol used.     

Anaesthesia in new-born animals

Pentobarbitone was more toxic to new-born than to adult rabbits and rats, produced a longer loss of righting reflex in new-born animals but did not anaesthetize them effectively in less than toxic doses. Urethane did not anaesthetize new-born animals in doses which anaesthetized adults. Ether produced loss of righting reflex at lower concentrations for new-born than for adults, but the new-born animals became anaesthetized more slowly.