Modulation by alcohol and methadone of 2-deoxyglucose-stimulated pancreatic secretion in the rat.

Alcohol intake is a major problem in drug addicts, and it is not clear whether the effects of alcohol and opiates are additive or potentiating. Vagally stimulated pancreatic secretion in rats is potently inhibited by opiates acting centrally at mu-receptors. In the present experiments, we determined the effects of methadone on 2-deoxyglucose (2DG)-stimulated pancreatic secretion in rats treated with acute (1.9 g/kg.3 h, intravenously) or chronic (1 or 3 month drinking) ethanol. In both acute and 1 month chronic alcoholic rats, methadone administered at its 50% inhibitory dose (ID50) reduced by about 50% 2DG-stimulated pancreatic secretion of sodium, bicarbonate and protein, and ethanol had only faint, nonsignificant inhibitory effects. In 3 month chronic alcoholic rats, similar results were obtained, but methadone inhibited 2DG-stimulated pancreatic secretion by 60 to 90% in these older rats. No significant interaction was found in any condition between ethanol and methadone, suggesting that they had only additive, but not potentiating effects in this method.

[Drug addicts in the Netherlands]. / Toxicomanies aux drogues aux Pays-Bas.

Dutch Government admit that tolerate attitude toward lower-risk drug abuse could reduce criminality and protect drug addict's health. Some Dutch psychiatrists disagree and try to struggle against this so called "normalization" politic. Morphine legal consumption, per million inhabitants is higher in Netherlands than in France, showing a certain latitudinarianism of health profession. During last years, illicit traffic data indicate an extensive increase, but drug addicts statistics are no more trustworthy than in France. International Narcotics Control Board (UNO) disapprove of the non application of 1961 Narcotics Convention in Netherlands. Recently dutch authorities suggest french government to develop bilateral cooperation in drug prevention. In fact, Netherlands liberate cannabis consumption which brings, as in other countries an increasing of drug addiction Nevertheless, this liberalization is still recommended by there who ignore the international last century experiences. In a word, acting toward supply and not only towards demand is necessary for a correct prevention as WHO and UNO recommend it.

[Effect of nalbuphine on external pancreatic secretion in rats]. / Action de la nalbuphine sur la sécrétion pancréatique externe chez le rat.

Pancreatic secretion is controlled by neural and endocrine mechanisms. The administration of 2-desoxyglucose (2DG) to rats stimulates pancreatic secretion through a mainly vagal pathway, and provides an useful pharmacological model to study the agents (especially opiates and adrenergic drugs) which can modulate this neural pathway. In the present study, basal and 2DG-stimulated pancreatic secretion were measured in anesthetized rats. Nalbuphine had no effect on basal secretion; it antagonized 2DG-induced pancreatic stimulation in a dose-related fashion between 0.5 and 15 mg/kg iv. The effect of nalbuphine was suppressed by naloxone, but not by alpha and beta-adrenoceptor blocking agents, indicating an essentially opiate effect. In order to test whether an inhibition of kappa receptors participates in the nalbuphine effect, centrally or peripherally acting kappa agonists were associated with nalbuphine. Neither U50488H, nor ICI204448 changed 2DG stimulation and nalbuphine effect. In conclusion, the effect of nalbuphine on 2DG-stimulated pancreatic secretion was similar to that of methadone and buprenorphine, required larger doses, and seemed to mainly involve mu receptors.

CRL41405: a drug with a new pharmacological profile on pancreatic exocrine secretion in the rat.

The recently described compound CRL41405 displays central effects suggesting possible antidepressive and awakening properties. In order to further analyze the pharmacology of this compound, its effects were studied on basal and stimulated pancreatic secretion in anaesthetized rats. CRL41405 alone (7-20 mg/kg, sc) had no effect on basal pancreatic secretion. Larger doses (67-200 mg/kg) increased basal secretion through the stimulation of cholinergic muscarinic receptors, the effect being antagonized by atropine. CRL41405 (20 mg/kg) suppressed the 2-deoxyglucose-induced (but not the acetylcholine-induced) stimulation of pancreatic secretion through an alpha-2 adrenoceptor inhibitory mechanism that was blocked by idazoxan (0.3 mg/kg, sc). In addition, a beta adrenoceptor mediated stimulation of sodium and bicarbonate excretion (blocked by propranolol) was evidenced when the alpha-2 inhibition was suppressed by idazoxan. Under alpha-2 adrenoceptor blockade, water and electrolyte stimulation by CRL41405 could be demonstrated on basal, 2-deoxyglucose-induced and acetylcholine-induced pancreatic secretion. This original profile makes CRL41405 a unique drug in pancreatic pharmacology.

[Multiple drug addiction]. / Polytoxicomanies.

The "polydrug use" well known at the USA, has sprayed in France and Europe during the last ten years. Harms of polydrug use were pointed out by some specialized centers. The aim of this work is to emphasize the dangers of the abuse of some drug associations. Animal pharmacology, clinical observations and epidemiology are the main research method involved animal in the study of "polydrug use". These methods are often difficult to perform in elderly persons and in pregnant women. It is not easy to extrapolate from animals to man. The pharmacokinetics of drugs often differs from a species to another. Animal models are nevertheless useful for studies dealing with drug interactions, especially with enzyme metabolism. Clinical studies will be dependent on the ethical questions. Some examples are mentioned. Alcohol use develops in many drug addicts, particularly in those on methadone maintenance. The association of cocaine and other amphetamine-type stimulants with morphinics or cannabis is very dangerous. Other associations are quite frequent including various hypnotics or cough suppressants (even nomorphinic). "Polydrug use" generally increase mortality in drug addicts. The medical profession is not well informed on this subject. Further research must be led on the harmful effects of drug associations and on the reasons leading drug addicts to multiplicate drug associations in an almost epidemic way.

Effect of modafinil on pancreatic exocrine secretion in the rat. A comparison with methadone.

Modafinil is a recently developed drug which increases wakefulness in several animal species and in man, an effect involving, at least in part, central adrenoceptors. In the present experiments, the effect of modafinil was studied on a model of neurally stimulated secretion, pancreatic secretion induced by 2-deoxyglucose (2DG) in the rat, and compared with that of the mu-opiate methadone. Modafinil induced a dose-related inhibition of 2DG-stimulated pancreatic secretion, reaching more than 80% after 250 mg/kg i.p. The modafinil effect was suppressed by idazoxan or by large doses of prazosin but not by naloxone. In addition modafinil (250 mg/kg i.p.) did not change the pancreatic response to electrical vagal stimulation. Methadone also potently suppressed 2DG-stimulated pancreatic secretion, but in contrast to modafinil, the methadone effect was blocked by naloxone, but not by the adrenoceptor antagonists idazoxan, prazosin and propranolol. It is concluded that modafinil decreases centrally 2DG-stimulated pancreatic secretion through a pathway involving alpha 1- and alpha 2-adrenoceptors, without an interaction with opiate receptors.

[Therapeutical injunction]. / L'injonction thérapeutique.

The opposition of specialists avoided the enforcement of the 1953 23rd december law settling the compulsory therapy of drug-addicted delinquents in France. So it was with the 1954 15th april law on the compulsory therapy of "dangerous alcoholics". The extend of drug-addictions led to the 1970 31st december law. But it was only in 1988-1989, that authorities give to the local agencies peremptory instructions for the enforcement of the so-called "therapeutical injunction" which the origin is judiciary. A survey published in 1990 allows a glimpse on the first data. Unfortunately, there are not reliable statistics on France, as a whole. Nevertheless, we know the difficulties better and better. For example, results obtained on ten cases, were favourable in only two cases. Its main advantage, emphasized by almost every medico-social team, is that the therapeutical injunction permits a first contact with a care service. Concerning the treatment of alcoholic patients, difficulties come, as D ENIKER has properly underlined, from the inadequacy of means at the departmental medical services, as a consequence of the suppression of former departmental health authorities. Sometimes, generalists have not a solid knowledge on drug-addicts and their psychotherapy. In the light of results obtained in other countries, it appears that we are on the way to success, provided that we help the local actors of this battle against the bane.

Effects of buflomedil and its two derivatives, CRL40634 and CRL40598, on pancreatic exocrine secretion in the rat.

Buflomedil is a vasoactive drug used in the treatment of peripheral vascular disease, and seems to be an antagonist of both alpha 1- and alpha 2-vascular adrenoceptors. CRL40634 and CRL40598 are metabolites of buflomedil and also possess vasoactive properties. The purpose of this study was to investigate whether buflomedil, CRL40634 and CRL40598 have antagonist activity on the alpha 2-adrenoceptors involved in the inhibition of exocrine pancreatic secretion. In acute pancreatic fistula rats, buflomedil, CRL40634 and CRL40598 did not suppress the inhibitory effect of clonidine against 2-deoxy-glucose-induced pancreatic secretion. However, all three drugs inhibited 2-deoxy-glucose-induced pancreatic secretion, their order of potency being CRL40598 greater than CRL40634 greater than buflomedil.

[Effect of buprenorphine on external pancreatic secretion in rats]. / Action de la buprénorphine sur la sécrétion pancréatique externe chez le rat.

2-deoxyglucose stimulates pancreatic secretion through a mainly vagal neural pathway. Buprenorphine antagonized this stimulation in a dose-related fashion between 0.017 and 0.45 mg/kg. i.v. The effect of buprenorphine was suppressed by naloxone, but not by alpha and beta-adrenoceptor blocking agents. The effect of methadone was similar, at doses about ten times larger.

[Substance abuse with inhalants]. / Des toxicomanies aux inhalants.

In this article, Charles Vaille maintains that for the past two decades there has been a renewed outbreak of substance abuse with inhalants among youth throughout the world. He asserts that this phenomenon can no longer be considered as limited to a few isolated incidents. The volatile substances are common place, inexpensive, and unlike other drugs, legal; they are subject to neither international nor national controls. The specificity of addicts to inhalants renders prevention very difficult. Vaille discusses this point after describing the following two types of inhalant addiction: 1. Inhalation of gas fumes: two examples of youths inhaling fumes are cited followed by a description of ways in which inhaling or "sniffing" is performed. Vaille then presents the short-term effects of the "high", both psychological and physical. He then proceeds to disclose the harmful long-term effects concluding that addiction due to inhaling fumes seems to be developed throughout Europe. 2. Forced hyperventilation: a detailed description of how the "game" of forced hyperventilation is played is followed by a discussion of its effects on health. In discussing regulatory measures, Vaille maintains that a country's first effort at preventing substance abuse is to limit and modify the existence of such substances. After describing the various means attempted, he concludes that these effects will always result in an elusive prevention, due to the extraordinary number of inhalant substances as well as the enticing aspect of the "forbidden fruit". Regulatory measures offer an answer to those seeking a clear conscience rather than attempting to get at the root of the problem.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of CRL 40827 and salbutamol on exocrine pancreatic secretion in rats.

The effects of the drug CRL 40827 and salbutamol, a structurally related compound, on exocrine pancreatic secretion in acutely fistulized anaesthetized rats and in chronically fistulized conscious rats were studied. CRL 40827 and salbutamol (0.05-0.45 mumol/kg per min, for 2 h) increased the basal secretion of fluid and bicarbonate in anaesthetized rats. The effect of CRL 40827 (15% of the maximal effect of secretin) was suppressed by propranolol (a non-specific beta-adrenoceptor antagonist), by ICI 118551 (a beta 2-antagonist) and by atenolol (a beta 1-antagonist). The effect of salbutamol (25% of the maximal effect of secretin) was suppressed by propranolol and ICI 118551 but was only slightly decreased by atenolol. The stimulant peak effects of CRL 40827 and salbutamol on volume and bicarbonate output were additive to those of 2-deoxy-glucose whereas the effect of 2-deoxy-glucose on protein output was not changed by either drug. CRL 40827 and salbutamol decreased the basal interdigestive protein output in a dose-related manner in conscious rats. CRL 40827 was 27 times less potent than salbutamol. The pancreatic outputs of fluid, bicarbonate and protein after an intragastric meal were decreased by both drugs. However, only salbutamol significantly decreased the cumulative effect of the meal on protein output compared to basal output. These results suggest that the stimulant effect of salbutamol on the pancreatic secretion of fluid and bicarbonate depends mainly on beta 2-adrenoceptors whereas that of CRL 40827 involves adrenoceptors of an as yet undefined subtype.

[Tetracosactide (ACTH 1-24) stimulates the external pancreatic secretion by a vagal mechanism in the rat]. / Le tetracosactide (ACTH 1-24) stimule la sécrétion pancréatique externe par un mécanisme vagal chez le rat.

The use of ACTH has been recently proposed in the therapy of the withdrawal syndrome in opiate addicts. By analogy with previous results obtained with opiates and clonidine, we looked for a possible central effect of ACTH 1-24 (tetracosactide) on the nervous pathways controlling the external pancreatic secretion in the rat. Tetracosactide displayed a central, vagally mediated, stimulant effect on the external pancreatic secretion, at variance with opiates and clonidine, which displayed central inhibitory effects in the same model. These results suggest that tetracosactide has a mechanism of action different from clonidine.

Effect of modafinil on pancreatic exocrine secretion in rats. A comparison with adrafinil and related drugs.

The effects of modafinil and adrafinil, 2 drugs that induce locomotor hyperactivity, and those of the parent compounds CRL 40467 and CRL 40385, were studied on the external pancreatic secretion of anaesthetized and conscious rats. In anaesthetized rats modafinil, adrafinil, and CRL 40385 antagonized the central vagal stimulation of protein output induced by 2-deoxy-D-glucose in the pancreatic juice. In conscious rats, modafinil and adrafinil inhibited the output of protein in the basal interdigestive pancreatic secretion. Modafinil was more active than adrafinil as an inhibitor of pancreatic secretion. The effects of modafinil and adrafinil were different from those of sympathetic amines and dopamine: they did not stimulate the output of bicarbonate in anaesthetized rats, and pancreatic inhibition observed in conscious rats was not inhibited by either yohimbine or prazosin.

Comparative effects of pirenzepine and atropine on pancreatic secretion in conscious rats.

The effects of pirenzepine and atropine on basal pancreatic exocrine secretion were studied in conscious rats fitted with a chronic pancreatic fistula. Pirenzepine was about 50 times less potent than atropine on a molar basis in inhibiting pancreatic secretion (respectively 44x for volume and 51x for protein output), while the efficacies of both drugs were in the same range. These results indicate that basal pancreatic secretion in vivo is mainly regulated by muscarinic mechanisms poorly sensitive to pirenzepine, and analogous to the M2 receptors described by others in vitro.

Etorphine inhibition of pancreatic exocrine secretion in rats: comparison with methadone.

The effects of etorphine, a potent opiate agonist without preferential affinity for mu, delta or kappa receptors, on exocrine pancreatic secretion were studied in rats fitted with chronic or acute pancreatic fistulas and compared to those of methadone, a well-documented mu agonist. In conscious rats etorphine (3 micrograms/kg s.c.) inhibited basal pancreatic secretion by about 50% for volume and bicarbonate output and by 70% for protein output. Pancreatic secretion returned to its basal level within 2 h. Methadone (5 mg/kg s.c.) was about equipotent but the inhibition lasted longer. The effects of both etorphine and methadone were completely antagonized by naloxone (1 mg/kg s.c.) and to a lesser extent by diprenorphine (10 microgram/kg s.c.). Yohimbine did not suppress the inhibitory effect of etorphine on protein output but showed some antagonism against the effects of etorphine on water and bicarbonate output. In anaesthetized rats etorphine (3 micrograms/kg) inhibited the pancreatic secretion stimulated by 2-deoxy glucose, a centrally acting vagal stimulatory agent, by 50-60% for volume and bicarbonate output and totally for protein output. The same dose of etorphine did not inhibit the pancreatic secretion evoked by vagal electrical stimulation, a peripheral stimulus. Methadone (5 mg/kg) inhibited the pancreatic secretion stimulated by 2-deoxy glucose to the same extent, but for a longer time than etorphine, and at the same dose did not suppress the pancreatic pancreatic response to vagal electrical stimulation. The inhibitory effects of etorphine and methadone in anaesthetized rats were completely suppressed by naloxone (1 mg/kg s.c.) and only reduced by diprenorphine (10 micrograms/kg s.c.).(ABSTRACT TRUNCATED AT 250 WORDS)

Risks incurred by children of drug-addicted women: some medical and legal aspects.

A review of recent literature shows a dramatic increase in the number of drug-addicted pregnant women, which increases the number of infants susceptible to the adverse effects of such addiction. The majority of new-born infants born to mothers addicted to opiates show a narcotic withdrawal syndrome. The risk of prematurity and other health disorders occurring in a new-born infant is substantially increased by the mother's abuse of narcotics during pregnancy. The microbial infection of children by a contaminated drug abused in the family, and accidental poisoning of children by drugs, have also been reported. The treatment of drug-addicted pregnant women has raised certain medical and legal questions, such as the breach of confidentiality of medical information and the criminal failure to report offences, as well as the failure to render assistance. The promotion of information and education about drug abuse during pregnancy, and the effects of such abuse on the pregnant women, her foetus and the future of a new-born infant is an urgent necessity.