Galantamine: a cholinergic patch in the treatment of alcoholism: a randomized, placebo-controlled trial.

OBJECTIVES: The involvement of the central cholinergic system in alcohol abuse behavior is well known. It is possible that the reinforcing effects of ethanol are partially mediated by nicotinic receptors, which modulate neurotransmitter release. It was demonstrated that the application of a cholinesterase inhibitor reduces alcohol consumption in alcohol-preferring rats. This suggests that galantamine (GAL), a cholinesterase inhibitor, could be effective when seeking to prolong abstinence in recently detoxified alcoholics. This study represents the first reported clinical trial of a cholinergic drug in alcohol-relapse prevention. PATIENTS AND METHODS: We investigated the efficacy and safety of GAL by conducting a 24-week randomized, placebo-controlled, multicentric clinical trial on 149 recently detoxified alcoholics. Survival analyses (Kaplan-Meier) were performed to reveal evidence of prolonged abstinence periods in patients who received GAL. RESULTS: Our findings did not support our hypothesis. GAL did not extend the time to first severe relapse. However, additional post hoc analyses suggest that relapsed patients treated with GAL consume less ethanol per drinking day than patients treated with placebo. CONCLUSIONS: GAL seems to be ineffective when used in relapse prevention of detoxified alcoholics. It is possible that alcohol needs to be "on board" for GAL to be beneficial. This could explain why our post hoc analysis showed that GAL possibly reduces the alcohol consumption of relapsers. If confirmed, GAL could play a role in the reduction of harmful alcohol use and at-risk consumption.

Ipsapirone and 8-OH-DPAT reduce ethanol preference in rats: involvement of presynaptic 5-HT1A receptors.

The selective serotonin(5-HT)1A receptor agonists 8-OH-DPAT and ipsapirone were tested in selectively inbred Wistar rats, with high preference [70-90%: defined as the ratio of ethanol (EtOH) to total fluid intake] for EtOH (10% v/v) over water in a two-bottle free choice situation. Rats were injected shortly before the overnight test session (8:00 P.M.-8:00 A.M.). EtOH and water consumption were determined in 20-min intervals; food consumption after the session. 8-OH-DPAT (ED50: 2.4 mg/kg, SC) and ipsapirone (ED50: 12.5 mg/kg, SC) reduced EtOH preference in a dose-dependent manner. In addition, 8-OH-DPAT increased total fluid intake, whereas ipsapirone enhanced total food intake. The EtOH preference reduction was time-dependent and reached a maximum within the second 4 h after application of 8-OH-DPAT (-73%) and ipsapirone (-72%). The preference reducing effect of ipsapirone (20 mg/kg, PO) was completely blocked by the nonselective 5-HT1A antagonist spiperone (0.05 mg/kg, SC). Local application of 8-OH-DPAT (10 micrograms, 0.5 microliters) into the dorsal raphe nucleus (DRN, a brain area rich in somatodendritic 5-HT1A autoreceptors), reduced the EtOH preference significantly as compared to the saline injection in the same animal (-12%, 8:00-12:00 P.M.). Only marginal effects on ingestion behavior were observed after microinjection into the nucleus accumbens. Reduction of brain 5-HT levels by pretreatment with the 5-HT synthesis inhibitor pCPA (2 x 150 mg/kg, IP) resulted in a short lasting, marked reduction (-54%) and a long lasting, small attenuation of the EtOH preference. Total food consumption was strongly decreased but returned soon to normal; total fluid intake was only slightly decreased. The EtOH preference reducing effect of ipsapirone (5 and 20 mg/kg, SC) was attenuated in pCPA-pretreated rats. The present data suggest that 5-HT1A receptor ligands reduce EtOH preference via stimulation of 5-HT1A receptors in the DRN. The possibility of additional mechanism(s) is discussed.

The effect of clonidine and related substances on voluntary ethanol consumption in rats.

Clonidine, guanfacine and tiamenidine, in equihypotensive doses, significantly reduced alcohol intake in ethanol-preferring rats having free choice between 10% ethanol and drinking water. Water intake was only slightly reduced, especially during the first hours following the administration of clonidine. Simultaneous treatment with yohimbine attenuated the clonidine-induced reduction in ethanol intake. Putative central mechanisms underlying the observed inhibitory actions of clonidine and other alpha-2 adrenoceptor agonists on oral self-administration of alcohol are discussed.

Volitional oral intake of nicotine in tupaias: drug-induced alterations.

Non-deprived, unstressed tree shrews (Tupaia belangeri) preferred nicotine solution (10 mg/l nicotine tartrate) over water in a free-choice situation. This drug-taking behaviour was stable over 14 months. Several drugs, most of which known to attenuate ethanol consumption in other species, in doses that did not alter locomotive behavior, significantly reduced the volitional nicotine intake in tupaias.

Combination of behavioral smoking cessation with transdermal nicotine substitution.

Effects of a transdermal nicotine substitution on psychological smoking cessation were investigated in a double-blind prospective study. 131 smokers were randomly assigned to three treatment conditions: All smokers underwent nine weeks of self-controlled smoking cessation. During six weeks one group was additionally treated with nicotine patches continuously releasing nicotine through the skin into the blood circuit. The second group received placebo patches; while the third group was treated with behavioral training alone. Treatment effects were measured by daily cigarette consumption. Nicotine-treated subjects reached significantly higher abstinence rates during and at the end of treatment than both placebo- and control-subjects: 69% in the nicotine condition, 51.2% and 44.4% under placebo and control conditions respectively. Effects are influenced by initial cigarette consumption, with the light smokers benefitting most from the nicotine patch. Self-assessments suggest an aversive effect of transdermal nicotine on cigarette taste. Our results, although not yet verified by long-term observations, demonstrate that transdermal nicotine substitution significantly enhances the effectiveness of behavioral smoking cessation methods.

Tolerance and cross tolerance to the anorexigenic effect of appetite suppressants in rats.

Rats were treated chronically with various anorexigenic substances which were administered orally once (or twice) daily or bidaily. Complete tolerance to the anorectic effect of d-amphetamine, fenfluramine, benfluorex (780 SE), chlorphentermine, and mazindol developed in 11-17 days. Test doses were given at different points of time after withdrawal in order to recognize the presence or absence of direct or cross tolerance. Direct tolerance to fenfluramine and benfluorex persisted for 46 days, whereas tolerance to mazindol was no longer present at day 20. There was lasting bidirectional cross tolerance between chlorphentermine and fenfluramine, transient bidirectional cross tolerance between mazindol and amphetamine, but only unidirectional cross tolerance between amphetamine and fenfluramine.

The effect of lithium on food intake in rats.

The influence of lithium on ingestive behavior and body weight was studied in male and female rats. Single i.p. doses of LiCl (3.6-7.2 mmol/kg) reduced both food intake and water consumption. Repeated large doses of LiCl given intraperitoneally caused a prompt anorexia and delayed polydipsia as well as weight loss, effects that were much more pronounced in male than in female rats. Small doses of LiCl on the other hand, increased food intake and body weight during long-term treatment. The findings indicate that an increase in food intake can account for the increased body weight sometimes seen in rats given lithium.

[The calorigenic effect of glucagon]. / Untersuchung der calorigenen Wirkung von Glucagon

The calorigenic action of glucagon was studied in several species by measuring its effect on the oxygen comsumption. The calorigenic effect was most pronounced in the quail and also evident in young adult rats of two different strains but not in mice and guinea pigs. The influence of various drugs on the calorigenic effect of glucagon was investigated in rats. Ganglionic blocking agents (hexamethonium, mecamylamine, chlorisondamine) as well as adrenergic blocking drugs (propranolol, butoxamine, phentolamine) greatly reduced the glucagon-induced calorigenesis but after pretreatment with reserpine, guanethidine or chemical sympathectomy with 6-hydroxydopamine the calorigenic effect of glucagon was exaggerated. It was somewhat diminished by nicotinic acid but not by chlorpromazine or lithium and potentiated by cocaine but not by theophylline.--These results are not indicative for an involvement of adenly cyclase--cyclic AMP--system in glucagon-induced calorigenesis but they are compatible with the assumption that the hormone enhances the metabolic rate by releasing catecholamines from the adrenal medulla.

The influence of the kappa-agonist bremazocine on ingestive behaviour in mice and rats.

The effects of bremazocine on drinking and eating behaviour were studied in non-deprived mice and 12 hr food and water deprived rats. In both species, bremazocine (1-8 mg/kg) produced substantial increase in fluid intake (dose-dependent in rats). The concomitant alterations of food intake were less pronounced and opposite: increase in mice, decrease in rats. Morphine (1.25-10.0 mg/kg) invariably inhibited eating and drinking behaviour in mice. The afore-said effects of the kappa-receptor agonist bremazocine are not affected by naloxone which attenuates the effects of the mu-receptor agonist morphine.

An inexpensive apparatus for simultaneous automatic measurement of oxygen consumption in six small laboratory animals.

A closed-circuit system for the simultaneous measurement of oxygen consumption in six small laboratory animals is described. The system consisted of six glass chambers in a big water bath of constant temperature, an oxygen-supply unit, six pressure sensors, a microcomputer and a printer, or, optionally, a desk-top calculator. Ventilation within the chambers provided rapid equilibration of air temperature and humidity conditions. Easily sealing glass lids facilitated operation and maintenance of the system. Carbon dioxide was absorbed inside the chambers by soda lime. At 6-min intervals the consumed oxygen in each chamber was automatically replaced with oxygen from a low-pressure tank. The microcomputer, a self-constructed piece of equipment containing a Z 80 A central processing unit, received pressure data from the separately operating sensors, determined the decrements in chamber pressure due to oxygen consumption by the animal sitting in the chamber, and stored the calculated values in a 2 Kbyte RAM for outprint at the user's request. The apparatus proved to be sensitive, accurate, and easy to operate.

[Long-term effects of a combination of transdermal nicotine administration with behavior therapy for smoking cessation]. / Langfristige Effekte einer Kombination von transdermaler Nikotinzufuhr mit Verhaltenstherapie zur Raucherentwöhnung.

Effects of a transdermal nicotine substitution on psychological smoking cessation were investigated in a double-blind prospective study. 131 smokers have been randomly assigned to three treatment conditions: All smokers underwent nine weeks of self-controlled smoking cessation. During 6 weeks one group was additionally treated with nicotine patches continuously releasing nicotine through the skin into the blood circuit. The second group received placebo patches; while the third group was treated with behavioral training alone. Treatment effects were measured by daily cigarette consumption. Follow-up investigations were performed 3, 6 and 12 months after therapy. Nicotine-treated subjects reached significantly higher abstinence rates during and at the end of treatment as well as during the follow-up period, than both placebo- and control-subjects. No severe side effects of plasters have been reported. The results thus indicate good therapeutic effectiveness of transdermal nicotine substitution.

[Successful zinc treatment of a severe case of acrodermatitis enteropathica (author's tteropathica]. / Labensrettende Zinkbehandlung der Acrodermatitis enteropathica

A 24-year-old patient treated with hydroxychinoline preparations without cure for acrodermatitis enteropathica since he was nine years old was given zinc oxide orally, at first 50 mg three times, later twice daily. Zinc concentrations in blood plasma, whole blood and sputum were serially determined. At the start of treatment they were significantly below that in four healthy controls. One week after starting zinc therapy the blood level had returned to normal and with it the changes in skin, hair and nails had regressed, as had the emotional disturbances.

Solid and cystic acinar cell tumour of the pancreas. A tumour in young women with favourable prognosis.

The clinico-pathological features of five cases with a distinctive pancreatic tumour are presented. The tumours, which occurred only in young women and an adolescent girl, were of large size (2.5-10 cm), had an uncharacteristic symptomatology and showed fibrous encapsulation with no evidence of metastases. The histological features include (1) solid areas with a monomorphic cell pattern and intracellular PAS positive globules, and (2) large foci of degeneration with cystic necroses, haemorrhages and cholesterol granulomas. Some tumour cells were positive for alpha1-antitrypsin. The ultrastructural demonstration of zymogen-like granules suggests an acinar origin for the tumours. We therefore propose the term solid and cystic acinar cell tumour. This tumour resembles the so called pancreatoblastomas in small children in some respects. It must be clearly distinguished, on the other hand, from acinar cell carcinoma with its acinic structures and poor prognosis. This lesion is not included in the WHO classification of pancreatic neoplasms.