Guidelines for the treatment of acidaemia with THAM.

THAM (trometamol; tris-hydroxymethyl aminomethane) is a biologically inert amino alcohol of low toxicity, which buffers carbon dioxide and acids in vitro and in vivo. At 37 degrees C, the pK (the pH at which the weak conjugate acid or base in the solution is 50% ionised) of THAM is 7.8, making it a more effective buffer than bicarbonate in the physiological range of blood pH. THAM is a proton acceptor with a stoichiometric equivalence of titrating 1 proton per molecule. In vivo, THAM supplements the buffering capacity of the blood bicarbonate system, accepting a proton, generating bicarbonate and decreasing the partial pressure of carbon dioxide in arterial blood (paCO2). It rapidly distributes through the extracellular space and slowly penetrates the intracellular space, except for erythrocytes and hepatocytes, and it is excreted by the kidney in its protonated form at a rate that slightly exceeds creatinine clearance. Unlike bicarbonate, which requires an open system for carbon dioxide elimination in order to exert its buffering effect, THAM is effective in a closed or semiclosed system, and maintains its buffering power in the presence of hypothermia. THAM rapidly restores pH and acid-base regulation in acidaemia caused by carbon dioxide retention or metabolic acid accumulation, which have the potential to impair organ function. Tissue irritation and venous thrombosis at the site of administration occurs with THAM base (pH 10.4) administered through a peripheral or umbilical vein: THAM acetate 0.3 mol/L (pH 8.6) is well tolerated, does not cause tissue or venous irritation and is the only formulation available in the US. In large doses, THAM may induce respiratory depression and hypoglycaemia, which will require ventilatory assistance and glucose administration. The initial loading dose of THAM acetate 0.3 mol/L in the treatment of acidaemia may be estimated as follows: THAM (ml of 0.3 mol/L solution) = lean body-weight (kg) x base deficit (mmol/L). The maximum daily dose is 15 mmol/kg for an adult (3.5L of a 0.3 mol/L solution in a 70kg patient). When disturbances result in severe hypercapnic or metabolic acidaemia, which overwhelms the capacity of normal pH homeostatic mechanisms (pH < or = 7.20), the use of THAM within a 'therapeutic window' is an effective therapy. It may restore the pH of the internal milieu, thus permitting the homeostatic mechanisms of acid-base regulation to assume their normal function. In the treatment of respiratory failure, THAM has been used in conjunction with hypothermia and controlled hypercapnia. Other indications are diabetic or renal acidosis, salicylate or barbiturate intoxication, and increased intracranial pressure associated with cerebral trauma. THAM is also used in cardioplegic solutions, during liver transplantation and for chemolysis of renal calculi. THAM administration must follow established guidelines, along with concurrent monitoring of acid-base status (blood gas analysis), ventilation, and plasma electrolytes and glucose.

Effects of antidotes to cocaine on the deregulation of the baroreflex by the alkaloid.

Cocaine exerts in the rat an inhibitory effect on the baroreflex induced by bilateral clamping of the carotid arteries. The present series of experiments were designed to test the effectiveness of cocaine antidotes on this deregulation of the baroreflex. Sprague-Dawley rats were fitted under pentobarbital anesthesia with a catheter in the caudal artery, and their carotid arteries were exposed. The pressure signal from the caudal artery was treated on line by a microcomputer for continuous display of blood pressure and heart rate measurements. The animals were administered intraperitoneally either 50 mg cocaine or an equal volume of saline. Five minutes later, they were administered either saline or proven antidotes to cocaine (diltiazem, nicardipine, enzyme converting inhibitor [ECI], enalaprilat associated with diazepam). After 2 min, stimulation of the baroreceptor was performed by bilateral clamping of the two carotids for a period of 2 min. The measures of the maximal variation in systolic pressure before and after clamping indicated a significant difference between saline and cocaine treated animals (P < 0.05), with the former displaying a much greater increment in blood pressure after clamping. The cocaine-treated animals, administered diltiazem, nicardipine, and ECI associated with diazepam, presented after clamping of the carotid arteries a normal baroreflex with increments in blood pressure not significantly different from those occurring in the animals receiving saline, but significantly different from those administered cocaine only (P < 0.05). Baroreflex deregulation by cocaine may also be restored by an angiotensin II receptor antagonist. The possible role of this peptide in mediating in part baroreflex activity is discussed.

Catecholamines, cocaine toxicity, and their antidotes in the rat.

Acute lethal cocaine intoxication in the rat induces significant increases of plasma dopamine, norepinephrine, and epinephrine concentrations associated with cardiac functional and morphologic changes. Nitrendipine (a calcium channel antagonist) administered 5 min following cocaine administration lowers catecholamine concentration and restores cardiovascular function to normal, while preventing lethality, and so does enalaprilat (an enzyme-converting inhibitor) administration with diazepam. Cocaine cardiac toxicity in the rat appears to be associated with a significant stimulation of the sympathoadrenal and a sustained elevated plasma concentration of epinephrine. The renin angiotensin system also appears to be activated.

Antidotes to lethal cocaine toxicity in the rat.

Cocaine, like catecholamines or angiotensin II, may induce lethal cardiac or cerebral damage. Restrained rats were fitted with a caudal arterial catheter for on-line cardiovascular monitoring and antidote administration. They were given 60 mg/kg of cocaine i.p., a dose which produces behavioral and cardiovascular effects, convulsions and death in an average time of 10 min. Selected antidotes were administered 5 min after the lethal dose of cocaine. Incidence of lethality was not changed by propranolol, prazosin, labetalol, diazepam or enalaprilat, a converting enzyme inhibitor. Animals treated with any one of the following agents, alpha- or beta-blockers, diazepam or competitive inhibitors of angiotensin II [Sar-1-ile-8] and [Sar-1-thr-8] angiotensin II, presented myocardial infarction. All animals treated with calcium channel antagonists or enalaprilat, whether they survived or not, did not present myocardial infarction. Treatment with nitrendipine, flunarizine or diltiazem, resulted in survival of the animals with no observable aftereffects. Similar results were observed when enalaprilat was administered, with diazepam as an antidote, to a lethal dose of cocaine. Antagonists to the sympatho-adrenal system and to the renin angiotensin system appear to be effective antidotes to cocaine toxicity in the present experimental model.

Interactions of nimodipine and cocaine on endogenous catecholamines in the squirrel monkey.

The effects of nimodipine on the cocaine-induced alterations in blood pressure, heart rate, and plasma catecholamines were studied in the squirrel monkey. Cocaine in intravenously administered doses of 0.5, 1, and 2 mg/kg produced significant increases in blood pressure and significant decreases in heart rate. These cardiovascular changes were associated with transient episodes of arrhythmias and with significant increases in plasma concentrations of dopamine, epinephrine, and norepinephrine. Nimodipine, 1 micrograms/kg/min for 5 min administered intravenously 5 min after cocaine, corrects the cardiovascular and plasma catecholamine concentration changes induced by this alkaloid. The same dose of nimodipine administered 5 min before cocaine prevents elevations of blood pressure. Plasma catecholamine increments are also prevented except for the highest dose of cocaine. Cardiovascular changes induced by cocaine administration in the squirrel monkey are temporally associated with significant increments in plasma catecholamines. Administration of nimodipine prevents or minimizes these endocrine and physiologic changes.

The experimental use of cocaine in human subjects.

Continuation of the practice of experimental administration of cocaine to cocaine-addicted volunteers has been recommended by some investigators. The author's view is that the risk of experimental use of cocaine outweighs its benefits and that this practice should not be pursued. The author describes the damaging effects of cocaine on the cardiovascular system, particularly its ability to induce myocardial band necrosis, and the unique reinforcing properties of the drug. The legal and ethical issues raised by the experimental use of cocaine are also discussed.

[Calcium channel modulators as antidotes in fatal imipramine poisoning]. / Effets antidotes de certains modulateurs des canaux calciques dans l'intoxication létale à l'imipramine.

Calcium entry modulators were tested as antidotes to imipramine lethal toxicity. 42 rats were administered intraperitoneally 85 mg/kg of imipramine. In 6 control rats, hypotension and bradycardia were observed. Survival time was 15' +/- 5'. Survival time of rats treated with intraarterial nitrendipine was 21' +/- 11'. Survival time of 5 out of 6 rats treated by intraarterial verapamil or diltiazem was respectively 19'00" +/- 14'30" and 40'30" +/- 32'00". 5 out of 6 rats treated by intraarterial nimodipine, as well as all of the rats treated by flunarizine or nicardipine survived and were alive and active 48 hours later. Intoxication with imipramine may induce life threatening complications for which there are no specific medication. Nicardipine might be considered in the treatment of acute poisoning by imipramine and related tricyclic compounds.

In vivo inhibition of enterocyte metabolism by delta 9-tetrahydrocannabinol.

Mice were given 10 to 100 mg/kg by stomach tube of delta 9-tetrahydrocannabinol (THC) in a single dose or for 4 consecutive days. [3H]Thymidine or [3H]glucosamine was given 3 or 24 hr before sacrifice. Enterocytes were isolated, and the incorporation of radioactivity into the acid insoluble fraction was measured. THC significantly inhibits in a dose-related fashion (from 10 to 90%) in vivo enterocyte metabolism. This inhibition is found in all enterocytes whatever their position in the intestinal tract; it is also independent of the state of differentiation of enterocytes. After a single ingestion of THC, crypt cells which synthesize DNA incorporate 37 to 45% less thymidine, and villus cells, which synthesize important amounts of glycoproteins, incorporate 15 to 39% less glucosamine. After 4 days of THC administration, the inhibition of thymidine incorporation is even more significant (up to 88%).

A drug policy for our times.

Three erroneous assumptions have influenced illicit drug abuse control policy. The first states that dependence-producing drugs are not different from many other substances consumed by people. This assumption underestimates the inherent neuro-behavioural properties of dependence-producing drugs that lead their users to adopt a compulsive pattern of daily consumption that is damaging to health. The second assumption states that even a young person may learn to use these drugs in a reasonable and responsible fashion, taking advantage of their redeeming qualities and avoiding their damaging effects. This assumption overestimates the ability of the human neocortex (new brain) to override the chemical stimuli induced by dependence-producing drugs in the pleasure and reward centres, which seem to be located in the limbic system of the old primitive brain. The third assumption states that social acceptance and commercial availability of illicit drugs would eliminate the social costs associated with their illegal traffic, which breeds crime and corruption. This assumption ignores historical precedents and the results of epidemiological surveys that demonstrate the damaging effects that social acceptance of these drugs and their widespread use may have on the individual and society. Surveys of drug consumers indicate that the percentage of addicts is significantly related to the dependence-producing potential of the drug used. In a population where alcohol is commonly consumed, 7-9 per cent of the consumers drink in amounts that are damaging to health. In a population where cannabis is socially accepted and easily available, more than half of cannabis consumers use the drugs in doses damaging to health. Approximately 90-95 per cent of cocaine or heroin users consume their drug of choice on a daily basis. Therefore, the dependence-producing potential of cannabis and that of cocaine or heroin would be, respectively, 7 and 14 times greater than the dependence potential of alcohol. Current illicit drug control policy should be based on scientific evidence and successful historical precedents, some of which are summarized in this article. This policy should concurrently aim at curtailing the supply of illicit drugs and reducing their demand.