M. J. Mattila

GABAA-receptor Subtypes: Clinical Efficacy and Selectivity of Benzodiazepine Site Ligands

The main inhibitory neurotransmitter receptor of the brain, the gamma-aminobutyric acid type A receptor (GABA[A]), mediates the actions of several classes of clinically important drugs, such as benzodiazepines, barbiturates and general anaesthetics. This review summarizes the current knowledge on how classical benzodiazepines and novel nonbenzodiazepine compounds act on the benzodiazepine site of GABA(A) receptors and on their clinical pharmacology related to anxiolytic, sedative, hypnotic and cognitive effects or side-effects. Partial agonism, receptor subtype selectivity and novel binding sites are discussed as possible strategies to develop new drugs with fewer adverse effects than are seen in the clinical use of benzodiazepines.

Pharmacokinetics of Oxicam Nonsteroidal Anti-Inflammatory Agents

SummaryOxicam nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of structurally closely related substances with anti-inflammatory, analgesic and antipyretic activities. They have a weakly acidic character and are extensively bound to plasma proteins.Piroxicam, the most widely used oxicam, is well absorbed after oral administration. Peak plasma concentrations (Cmax) of the drug are reached within 2 to 4 hours. Piroxicam has a small volume of distribution and a low plasma clearance. It undergoes hepatic metabolism and only 5 to 10% is excreted unchanged in urine. The elimination half-life varies between 30 and 70 hours. Age of the patient and renal or hepatic dysfunction do not seem to have any major effect on the pharmacokinetics of piroxicam. The drug reduces the renal excretion of lithium to a clinically significant extent, but the clinical significance of piroxicam-aspirin (acetylsalicylic-acid) and piroxicam-acenocoumarol interaction has not been established. Ampiroxicam, droxicam and pivoxicam are prodrugs of piroxicam that have been synthesised to reduce piroxicam-related gastrointestinal irritation. All prodrugs are well absorbed, but Cmax values are reached later than those following administration of piroxicam.Tenoxicam is used in the management of rheumatic and inflammatory diseases. Mean Cmax values are achieved 2 hours postdose. Food reduces the rate but not the extent of absorption. The oral bioavailability of tenoxicam is 100% and rectal bioavailability is 80%. Like piroxicam, tenoxicam has a low volume of distribution and low plasma clearance. It is eliminated through hepatic metabolism. The mean elimination half-life is 60 to 75 hours. The pharmacokinetics of tenoxicam are independent of patient age, or concurrent liver or renal diseases. High doses of aspirin have been shown to increase the elimination of tenoxicam, but this has little clinical significance.Isoxicam was in widespread clinical use until its worldwide marketing was suspended because of fatal skin reactions. Isoxicam is completely absorbed, but Cmax values are not reached until 10 hours postdose. It has a low plasma clearance, approximately 5 ml/min (0.3 L/h), and low volume of distribution. The mean elimination half-life is 30 hours and does not appear to be affected by the age of the patient. Isoxicam potentiated the anticoagulant effect of warfarin, necessitating a 20% dosage reduction.Lornoxicam differs from other oxicam NSAIDs because it has a short elimination half-life of 3 to 4 hours. On the basis of limited data, some individuals seem to eliminate lornoxicam very slowly, suggesting the presence of polymorphic metabolism.The pharmacokinetics of cinnoxicam and sudoxicam have not been studied thoroughly. However, like other oxicams, they appear to be absorbed completely after oral administration. Although the development of sudoxicam was stopped because of frequent adverse effects, this drug is interesting because, unlike other oxicams, its appears to have nonlinear elimination pharmacokinetics.

Effects of alcohol on buspirone and lorazepam actions

Psychomotor and psychologic effects of single doses of buspirone (10 and 20 mg) and lorazepam (2.5 mg) alone or combined with alcohol (1 gm/kg) were investigated in 12 healthy young men. crossover study in 12 healthy young men. Lorazepam alone impaired psychomotor skills (tracking, body balance, extraocular muscle balance, and flicker recognition), the effects being maximal at 180 min. This impairment was not subjectively perceived by the subjects. Neither dose of buspirone alone impaired objective measurements, although buspirone, especially in the 20‐mg dose, was felt to cause drowsiness, weakness, and faintness. Lorazepam, but not buspirone, interacted with alcohol.

Oral activated charcoal and dapsone elimination

The effect of orally given activated charcoal on the elimination of therapeutic and toxic doses of dapsone was studied in 5 healthy subjects and in 2 intoxicated patients. In a randomized crossover study the subjects took a total dose of 500 mg dapsone over 4 days; 10 hr after the last 100‐mg dose of dapsone 50 gm activated charcoal as a water suspension (or water) was taken, followed by 4 consecutive doses of 17 gm at 12‐hr intervals. The half‐life (t½) of serum dapsone was 20.5 ±2.0 hr during the control period and 10.8 ± 0.4 hr during the charcoal period (p < 0.01). The t½ on serum monoacetyldapsone (MADDS) was shortened from 19.3 ± 1.2 hr to 9.5 ± 0.7 hr (p < 0.01) by charcoal. The t½s of dapsone and MADDS, calculated on the basis of urinary excretion rate, were shortened by charcoal. Two patients had taken large doses of dapsone in suicide attempts. The use of activated charcoal, 80 gm/day for 1 or 2 days, increased (3 to 5 times) the rate of elimination of both dapsone and MADDS, as reflected in serum concentration and urinary excretion data. The use of multiple doses of charcoal seems to be indicated as supplementary treatment of certain intoxications during the postabsorption phase if the drugs have a long t½ and if they are secreted into the gut with subsequent reabsorption.

Tofisopam, a novel 3,4,-benzodiazepine: Multiple-dose effects on psychomotor skills and memory. Comparison with diazepam and interactions with ethanol

Twelve healthy male volunteers were treated (double-blind crossover design) with tofisopam (a new 3,4-benzodiazepine), diazepam, or placebo, on 2 consecutive days each. Psychomotor skills were impaired after a single dose of diazepam (10 mg) given on day 1. Measurements on day 2 showed that some tolerance had developed to the diazepam-induced impairment of reactive and coordinative skills, but not to its effects on flicker fusion or on the extraocular muscle balance. Tofisopam failed to impair performance both as a single dose (100 mg) and after repeated doses (100+50+50+100 mg). The subjects felt more fatigue, dizziness, calmness, and passiveness after diazepam than after tofisopam. When either drug was given together with 0.8 g/kg ethanol on day 2, the breath ethanol concentrations were 0.7–1.0 mg/ml and all psychomotor skills were impaired. Diazepam+ethanol particularly impaired memory and learning as well. After this combination the subjects were classified (time anticipation test) as ‘disqualified drivers’ more often than after placebo. It is concluded that diazepam,as well as either benzodiazepine with ethanol, may reduce the ability to drive vehicles or operate machinery.

Acute and subacute actions on human performance and interactions with diazepam of temelastine (SK & F 93944) and diphenhydramine

SummaryThirteen healthy subjects participated in a combined acute and subacute double-blind, crossover trial of two H1-antihistamines diphenhydramine (DPH) and temelastine (SKF) against placebo. The doses were DPH 50 mg b.d. and SKF 100 mg b.d. Objective (digit symbol substitution, flicker fusion, Maddox wing, attention, tracking, choice reaction) and subjective (visual analogue scales, side-effects on questionnaire) tests were done on Days 1, 4 and 5, on each occasion before drug intake and after 90 min and 3 h.On Day 1 DPH caused clear sedation of unpleasant character and impaired flicker fusion, attention and digit symbol substitution. SKF shifted the VAS assessment “drowsy/alert” towards drowsiness at 90 min, without objective impairment. On Day 4 DPH reduced exophoria and impaired flicker fusion without subjective sedation. On Day 5, diazepam 0.3 mg/kg (DZ) given with the other drugs caused subjective sedation of pleasant character and impaired various functions in the objective tests. Neither SKF nor DPH increased the effects of DZ; DPH slightly counteracted the effect of DZ on exophoria. At home, SKF did not differ from placebo while DPH proved sedative. DPH did not improve sleep but caused dry mouth and blurred vision. Measurement of plasma levels of antihistamines on each test day revealed the development of tolerance to antihistamine-induced sedation. The concentration of DZ measured by bioassay was somewhat elevated in the presence of DPH. Since the majority of the performance tests were not influenced by temelastine, it appears to be an acceptable, novel H1-antihistamine for the treatment of allergic disorders.

Psychomotor, respiratory and neuroendocrinological effects of buprenorphine and amitriptyline in healthy volunteers

SummaryActions and interactions of buprenorphine (BUP) and amitriptyline (AMI) on performance and respiration were studied double-blind and cross-over in 12 healthy volunteers. After one-week pretreatments with AMI or placebo, the subjects received on Day 8 placebo, BUP or AMI so that the final treatments were 1) placebo, 2) acute AMI 50 mg, 3) acute BUP, 4) subchronic AMI + acute BUP and 5) subchronic AMI. The subacute treatments were started at two-week intervals.A Mapleson D rebreathing circuit including a pneumotachograph and an infrared capnograph was employed to study drug effects on respiration. Minute volume and end-tidal carbon dioxide as well as psychomotor performance were measured and the blood samples taken on Day 8 before the drug intake and 2 and 4 h thereafter. The performance tests included tracking, choice reaction, flicker fusion, exophoria, nystagmus, digit symbol substitution and the subjective assessment of mood.BUP depressed respiration, and subchronic AMI increased this depression. Both BUP and acute AMI 50 mg each alone impaired various measures of performance and rendered the subjects drowsy, feeble, mentally slow and muzzy but subchronic AMI did not enhance BUP effects. BUP increased plasma prolactin levels similarly after both pretreatments.The results suggest that both BUP and AMI moderately affect psychomotor performance but the interaction between these agents is mild and restricted mainly to respiration.

Coffee and caffeine and alcohol effects on psychomotor function

Interactions of alcohol and caffeine were studied in two double‐blind and crossover trials in which several psychophysiologic functions and subjective effects were measured in healthy men. The effects of alcohol (1 gm/kg) with and without caffeine (200 or 500 mg) were measured in 10 subjects. Two doses (0.7 or 7.5 gm/kg) of alcohol alone and in combination with caffeine (250 + 250 mg) were similarly studied in another 10 subjects. Alcohol impaired psychomotor functions to an extent dependent on dose whereas caffeinated and decaffeinated coffee did not. Both kinds of coffee also failed to modify alcohol effects. Subjectively, caffeine was indistinguishable from placebo and no particular interaction of alcohol and caffeine was detected. Alcohol did elevate serum caffeine concentrations. We conclude that coffee does not counteract alcohol inebriation.

Cardiovascular effects of amitriptyline, nortriptyline, protriptyline and doxepin in conscious rabbits

Abstract To evaluate the importance of noradrenaline potentiation by tricyclic antidepressants for their cardiotoxic action, amitriptyline, nortriptyline, protriptyline and doxepin were compared. Protriptyline proved strongest in potentiating noradrenaline on the rabbits isolated right atrium, and on the blood pressure of conscious rabbits. Nortriptyline and amitriptyline proved most potent in desensitizing the rabbit aortic spiral to noradrenaline. When antidepressants were slowly injected i.v. to conscious rabbits, all four drugs studied immediately lowered blood pressure and increased heart rate. Amitriptyline and doxepin proved most potent, and they also provoked severe arrhythmias on ECG. When the drugs were given during the noradrenaline infusion, their effects remained similar. The results suggest that in acute experiments the cardiotoxicity of tricyclic antidepressants does not correlate to their inhibitory effects on noradrenaline uptake.

Alcohol and Drug Interactions

Interactions of ethyl alcohol with various drugs are common. Their consequences vary depending on the effects of the drugs concerned, the doses of drugs and alcohol given and their mode of administration. Pharmacokinetic interactions refer to altered tissue concentrations of alcohol or drugs or both and their metabolites which sometimes lead to serious toxic reactions. The kinetic interactions take place in the absorption or metabolism of alcohol or the drug, whereas significant interactions in their distribution phase are rare. Pharmacodynamic interactions refer to the combined actions, even serious ones, which primarily take place at the tissue (receptor?) level, with or without an important pharmacokinetic component of interaction. Acute substantial doses of alcohol given quickly tend to inhibit microsomal drug metabolism and thus enhance the effects of drugs. Chronic administration of alcohol usually induces the synthesis of cytochrome P-450 isoenzyme P-450 II E1, thus accelerating the metabolism of its own and, depending on the circumstances, of various drugs as well. Reduced actions of the agents may then ensue. If the (toxic) effect of a drug (e.g., paracetamol) depends on the formation of active metabolites acute intake of alcohol may, paradoxically, reduce the drug effect, while chronic alcohol intake enhances it. Induction of hepatic enzymes by alcohol may affect the turnover of endogenous vitamins and hormones, or even produce carcinogenic substances.(ABSTRACT TRUNCATED AT 250 WORDS)