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PubMed1992

Polymorphism of dextromethorphan metabolism: relationships between phenotype, genotype and response to the administration of encainide in humans.

The polymorphism of dextromethorphan and encainide metabolism is genetically determined and is related to the activity of hepatic CYP2D6. In order to examine the relations between CYP2D6 phenotype, genotype and the electrocardiographic response to the oral administration of encainide, 110 healthy subjects were studied. Metabolic ratios were calculated in urine after oral administration of 40 mg of dextromethorphan and in plasma obtained 2.5 h after oral administration of 50 mg of encainide. Encainide-induced electrocardiographic changes were measured 2.5 h after oral administration of the drug. Genotype was determined in 52 subjects. Results showed that phenotype, either extensive or poor metabolizer, for CYP2D6-dependent metabolism could be identified from the dextromethorphan metabolic ratio calculated in urine, from the encainide metabolic ratio calculated in plasma and from the genotype. However, despite the fact that the changes in atrioventricular (PR) and intraventricular (QRS) conduction times produced by encainide were different in extensive and poor metabolizer subjects and correlated with CYP2D6 activity, the electrocardiographic response was never 100% specific and sensitive for the identification of either phenotype. Moreover, genotypic identification of heterozygous and homozygous extensive metabolizer subjects did not predict CYP2D6 activity, as determined by dextromethorphan and encainide metabolic ratios, or encainide response, as determined by intraventricular and atrioventricular changes. Thus, CYP2D6 activity does not fully predict the electrocardiographic effects of encainide, and genotype, as determined in our study, cannot replace the determination of metabolic ratio in predicting CYP2D6 activity and encainide response in extensive metabolizer subjects.

Adult↗
PubMed1991

Ischaemic brain damage--prevention with competitive and non-competitive antagonists of N-methyl-D-aspartate receptors.

Excessive activation of glutamate receptors, most notably the N-methyl-D-aspartate (NMDA) subtype, appears to be a crucial factor in the sequence of cellular events which lead to irreversible ischaemic damage to neurones. The ability of newly developed antagonists of the NMDA receptor to reduce ischaemic brain damage has been assessed in cat and rodent models of focal cerebral ischemia. Non-competitive NMDA receptor antagonists such as dizocilpine (CAS 77086-21-6) which act at a site within the receptor operated ion channel markedly reduce (by more than 50%) ischaemic brain damage when administered prior to the ischaemic episode or 2 h after the onset of ischaemia. Competitive NMDA receptor antagonists, such as D-(E)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid, which act at the neurotransmitter recognition site are equally effective in reducing the ischaemic brain damage when administered prior to the onset of the ischaemic episode. The clinical utility of competitive and non-competitive NMDA receptor antagonists in man will, however, be determined not by their tremendous anti-ischaemic efficacy, but by their profile of adverse effects. Careful selection of the therapeutic target for NMDA antagonists will be necessary if beneficial effects are to be established in man.

Animals↗
PubMed1979

Effect of morphine on synaptosomal Ca++ uptake.

The effect of morphine on the uptake of 45Ca++ was studied in synaptosomes from mouse brain using two procedures, centrifugation and filtration. The addition of morphine (1.7 x 10(-7) or 3.4 x 10(-7) M) reduced 45CA++ uptake by either technique, although the basal 45Ca++ uptake by the filtration method was approximately 7-fold higher than that by the centrifugation procedure. Similar effects were obtained after acute morphine treatment with 10 mg/kg s.c. Previous naloxone in vitro treatment (1.9 x 10(-8) M) or in vivo administration (2 mg/kg s.c.) reversed the morphine inhibition of the 45Ca++ uptake. On the other hand, after the animal was rendered tolerant and dependent by morphine pellet implantation, an enhancement of the synaptosomal 45Ca++ uptake was observed. It is concluded that changes in Ca++ fluxes in synaptosomes observed after acute and chronic morphine treatment may be involved with morphine pharmacological action related with analgesia, tolerance and physical dependence.

Animals↗
PubMed1979

Changes in plasma corticosterone levels as a measure of acute dependence upon levorphanol in rats.

Changes in plasma corticosterone levels have been utilized as a sensitive and reliable indicator of opiate withdrawal. By using rats prepared with chronic indwelling i.v. catheters, drug injections and sequential blood sampling were accompanied in conscious undisturbed animals. Acute administration of levorphanol tartrate (LT) at 0.5, 1.0 or 2.0 mg/kg b.wt. caused an elevation in circulating corticosterone. With the lowest dose of LT, hormone levels returned to pretreatment values by 180 min. Naloxone hydrochloride (NX), 0.4 mg/kg, administered 3 hr after pretreatment with LT, 0.5 mg/kg, produced a significant elevation in plasma corticosterone. In contrast, animals pretreated with saline did not show the same increase in hormone levels after NX. NX, administered at several doses, along with LT, suppressed the plasma corticosterone increase which is normally observed when LT is given acutely. When NX is administered at sufficient dosage, along with LT pretreatment, the subsequent administration of the antagonist did not elicit the withdrawal response. These data indicate that a similar increase in plasma corticosterone, upon challenge with NX after a single dose of morphine, generalizes to other opiates. Blockade of the initial rise in plasma corticosterone and subsequent increase upon injection of the antagonist speak to the probability of the responses being related and opiate specific.

Animals↗
PubMed1981

History of drug exposure as a determinant of drug self-administration.

Drug self-administration is controlled, in part, by the subject's history of drug exposure. Although a history of drug administration is not necessary for many drugs to function as reinforcers, prior exposure can increase the likelihood that certain drugs, such as ethanol, will maintain behavior. While it has been demonstrated that physiological dependence is not necessary for a drug to function as a reinforcer, the conditions under which such dependence is maintained can control the later self-administration of the drug. Once drug-maintained behaviors are established, the particular drug that maintains behavior can influence the initial pattern of intake of a new drug and thus the dose of that drug that will maintain behavior. Additionally, under certain conditions, similarity between the discriminative stimulus effects of the drug that previously maintained behavior and those of a new drug can increase the likelihood that the new drug will function as a reinforcer. Finally, stimuli that have been paired with drug administration can powerfully control later drug-maintained behavior, the direction of such control being determined by the conditions under which such pairing occurred. In summary, both the type of drug with which a subject has experience as well as the contingencies governing that experience contribute to subsequent drug self-administration.

Animals↗