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Biomedical subjects

G Levy

Publications and source records attributed to G Levy.

At least 271 records · Page 15Linked to original sources
PubMed1986

Kinetics of drug action: an overview.

The intensity and time course of action of directly and reversibly acting drugs are related to and determined largely by the time course of drug and active drug metabolite concentrations in the body. When the pharmacokinetics and the concentration-effect relationship of a drug are known, it is often possible to predict the temporal pattern of its pharmacologic effect(s), including the maximum intensity and duration of action. Sites of action may not be immediately accessible to a drug even if it is injected intravenously; this may be reflected by a gradual increase in the intensity of effect despite decreasing drug concentrations in plasma, with maximum effects occurring later than maximum drug concentrations in plasma. Pharmacologic effects may persist well beyond the time when drug concentrations in plasma are no longer determinable; this is often caused by localization of the drug in an extravascular compartment. Drug distribution kinetics, pharmacologically active metabolites, and development of functional (as opposed to metabolic) tolerance may be responsible for time-dependent changes in drug concentration--pharmacologic effect relationships. Interindividual differences in patients' response to drug therapy may have a pharmacokinetic basis, a pharmacodynamic basis, or both. In clinical assessments of pharmacologic response, it is important to measure the therapeutically relevant effect, to determine interindividual and intraindividual variability, and to explore the possible influence of underlying diseases and other physiologic variables on drug concentration-effect relationships.

Dose-Response Relationship, Drug↗
PubMed1986

Chronic theophylline administration has no apparent effect on theophylline concentrations required to produce seizures in rats.

Theophylline, the widely used antiasthmatic drug, can cause life-threatening, generalized seizures when administered in excessive doses. The plasma concentrations of theophylline associated with these seizures vary widely among patients, thereby complicating efforts to prevent seizures by timely initiation of appropriate treatment. Some investigators suspect that chronic administration increases the neurotoxicity of theophylline but others have suggested the opposite. We have studied this problem in an animal model of theophylline-induced seizures. Osmotic pumps containing theophylline solution or drug-free solvent (for the surgical control group) were implanted in adult female Lewis rats, yielding almost constant serum theophylline concentrations of about 14 mg/liter for 7 days in the treated group. On the seventh day, theophylline was administered by much more rapid iv infusion to the two groups of animals and to one nonimplanted (nonsurgical) control group until onset of maximal seizures. There were no statistically significant differences between the three groups with respect to the concentrations of theophylline in serum, serum water, brain, and cerebrospinal fluid at onset of seizures. The concentrations of theophylline metabolites were either very low or undetectable. Under the experimental conditions, preexposure of rats for 7 days to theophylline in the human therapeutic concentration range had no apparent effect on the acute neurotoxicity of the drug.

Animals↗
PubMed1986

Sulfate conjugation in drug metabolism: role of inorganic sulfate.

Conjugation with sulfate is a major pathway for the biotransformation of phenolic drugs in humans and many animal species. It is a process of limited capacity; the extent of sulfate conjugate formation and the metabolic clearance of drugs subject to conjugation with sulfate depend therefore on the dose, the dosage form, the route of administration, and the rate and duration of administration as well as on the pharmacokinetic parameters of competing processes. The effect of these variables is exemplified by the pharmacokinetics of salicylamide and acetaminophen in humans and rats. In our experience so far, the proximate cause of the nonlinear pharmacokinetics of sulfate conjugation of phenolic drugs is the limited availability and consequent depletion of inorganic sulfate. When this is prevented by direct or indirect (via sulfate donors such as N-acetylcysteine) repletion, the saturability of phenol sulfotransferase (EC 2.8.2.1) activity can become evident. The major mechanism of inorganic sulfate homeostasis is nonlinear renal clearance, which is due largely to saturable renal tubular reabsorption. Systemic depletion of inorganic sulfate secondary to utilization of this anion for the sulfation of drugs affects the availability of sulfate in the central nervous system and may, therefore, modify the disposition of certain neurotransmitters and other endogenous substances that are subject to sulfate conjugation.

Acetaminophen↗
PubMed1986

Kinetics of drug action in disease states. XVI. Pharmacodynamics of theophylline-induced seizures in rats.

Seizures, often with fatal outcome, are a manifestation of pronounced theophylline intoxication. The purpose of this investigation was to characterize the relationship between theophylline concentrations and theophylline-induced convulsions and to develop an animal model suitable for exploring conditions that might predispose theophylline-treated individuals to seizures. Female Lewis rats (approximately 170 g) received an i.v. infusion of theophylline (as aminophylline) at one of three different rates (1.03-5.1 mg/min/rat) until the animals exhibited a maximal seizure (which occurred after 11 +/- 1 to 42 +/- 3 min of infusion). The total dose, the serum concentration (both total and unbound drug) and the brain concentration of theophylline at onset of seizures increased with increasing infusion rate. The theophylline concentration in cerebrospinal fluid at onset of seizures (mean +/- S.D., 232 +/- 17 mg/l, n = 41) was not affected by the infusion rate. The theophylline metabolites 1-methyluric acid and 1,3-dimethyluric acid were found in serum but at very much lower concentrations than those of theophylline. 1-Methylxanthine and caffeine were not detected in any serum sample, 3-methylxanthine was present in low concentrations in only some serum samples and 1-methyluric acid and 3-methylxanthine were found in the brain in low concentrations (less than 10 mg/kg). Theophylline metabolites were not detected in cerebrospinal fluid. Direct i.v. infusion of either 1-methyluric acid, 1,3-dimethyluric acid or 3-methylxanthine did not produce seizures despite high concentrations in serum. Ethylenediamine infusions also did not cause seizures.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Effect of prevention of inorganic sulfate depletion on the pharmacokinetics of acetaminophen in rats.

The elimination of large doses of acetaminophen is associated with substantial depletion of endogenous inorganic sulfate which is utilized for the formation of acetaminophen sulfate. This depletion has pronounced dose- and time-dependent effects on the pharmacokinetics of acetaminophen. The purposes of this investigation were to determine the pharmacokinetics of acetaminophen in rats when endogenous sulfate depletion is prevented by administration of inorganic sulfate and to develop a simple, physiologically based pharmacokinetic model for the elimination of acetaminophen under these conditions. Adult Sprague-Dawley rats received an i.v. injection and a continuous infusion of sodium sulfate as well as an i.v. injection of acetaminophen, either 15, 30, 150 or 300 mg/kg. Serum inorganic sulfate concentrations remained at or above the physiologic level at all times. Plasma concentrations of acetaminophen declined exponentially with time after the two lower doses but exhibited initial downward curvature in log-linear plots after the two larger doses. The time-averaged plasma clearance of acetaminophen decreased with increasing dose whereas the terminal half-life was dose-independent. Most of the drug was eliminated in the urine as acetaminophen sulfate but the dose fractions of acetaminophen glucuronide and unmetabolized drug excreted in the urine increased with increasing dose. The renal clearance of acetaminophen did not exhibit dose-dependence but the apparent formation clearance of acetaminophen glucuronide tended to decrease with increasing dose. The formation of acetaminophen sulfate is describable by Michaelis-Menten kinetics, with a Vmax of about 6.5 mumol/min/kg and an in vivo KM (referenced to plasma) of about 100 microM.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMed1985

Lactate provocation of panic attacks. II. Biochemical and physiological findings.

Thirty-one of 43 patients with panic disorder or agoraphobia with panic attacks and none of 20 normal controls panicked in response to infusions of sodium lactate. Before receiving lactate, patients showed higher heart rates than controls and also signs of hyperventilation. During lactate infusion, patients who did not panic, nevertheless, developed higher lactate and pyruvate levels and greater ionized calcium and pH changes than controls. Lactate-induced panic attacks were regularly accompanied by biological changes consistent with hyperventilation and central noradrenergic activation and irregularly by elevation of plasma norepinephrine and cortisol levels. Panic attacks were not associated with changes in epinephrine or calcium levels or pH. Baseline arousal increased the likelihood of panic during lactate infusion. It is hypothesized that lactate-induced panic primarily involves central noradrenergic discharge with inconsistent peripheral manifestations.

Adult↗
PubMed1985

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.

Animals↗
PubMed1985

Kinetics of drug action in disease states XI: effect of nicotine on the pharmacodynamics and pharmacokinetics of phenobarbital and ethanol in rats.

The purpose of this investigation was to determine if the reported prolongation of barbiturate- and ethanol-induced sleeping times by nicotine in rodents are pharmacodynamic or pharmacokinetic interactions. Adult female rats were pretreated with nicotine, either 0.5 or 1.5 mg/kg ip acutely or 0.5 mg/kg ip daily for 6 d, whereas control animals received saline solution. Phenobarbital or ethanol was infused intravenously at a slow rate until the rats lost their righting reflex. Acute pretreatment with nicotine reduced significantly the serum, brain, and cerebrospinal fluid (CSF) concentrations of phenobarbital and ethanol, respectively, at the onset of the loss of the righting reflex. Chronic pretreatment with nicotine had no such potentiating effects, indicative of rapid development of tolerance to nicotine. Neither acute nor chronic pretreatment with nicotine had any apparent effect on the elimination kinetics of phenobarbital or ethanol, on biochemical indices of hepatic integrity and renal function, or on the permeability of the blood-CSF barrier to protein. Nicotine, unlike morphine, did not increase the nociceptive threshold (tail squeeze) of rats under the experimental conditions. It is concluded that acute, but not chronic, pretreatment with nicotine increases the sensitivity of rats to the hypnotic effects of phenobarbital and ethanol, respectively. These interactions are entirely pharmacodynamic and have no apparent pharmacokinetic component.

Animals↗