A new technique for the investigation of some analgesic drugs on a reflexive behavior in the rat

Summary The analgetic action of a series of analgesic and psychotropic agents was tested in a situation in which variable intensities of electric shock to a rat's feet were used to elicit two distinguishable reflexive responses: a flinching response at low shock values, and a jumping response at higher shock values,By using a modified method of limits, reliable threshold for the two responses were obtained.Chlorpromazine, perphenazine, morphine, codeine, nalorphine and acetylsalicylate were found to raise the threshold to jump, but had little or no effect on the threshold to flinch.PIH, JB 835, iproniazid, reserpine, tetrabenazine, and amphetamine were found to have no effect on either the jump or the flinch thresholds.A combination of amphetamine and codeine was found to produce a synergistic potentiation. A combination of morphine and nalorphine was found to produce an antagonism.The results were discussed in terms of Beecher's hypothesis that the analgetic action of drugs is due to a diminution of the emotional components of an animal's reaction to pain and in terms of the relationship of brain amine change to analgetic action.     

Cocaine-induced cocaine craving

In nine experienced users of cocaine, we examined the urge to use cocaine or other drugs following a 40 mg dose of intravenous (IV) cocaine with and without oral pretreatment with 2.5 mg bromocriptine. The urge to use cocaine was assessed with a questionnaire constructed to assess both wanting and craving for cocaine or other drugs. Fifteen minutes after the administration of cocaine (but not after placebo), subjects' ratings for both drug wanting and drug craving were significantly increased. Our results provide a laboratory demonstration of cocaine-induced increases in the urge to use drugs in humans. The findings, stressing the role of internal stimuli associated with drug administration, suggest the possibility of distinguishing among related, but perhaps distinct, components of the fluctuating levels of motivation to reuse drugs.     

Toxic effects of some “mono-n-butyl-tin compounds” on white mice

The toxic effects of mono-n-butyl-tin-trichloride, mono-n-butyl-tin-tris-(2-ethyl-hexyl-mercaptoacetate), mono-n-butyl-tin acid and mono-n-butyl-thiotin acid on white mice were investigated. These compounds were administered to white mice by means of a stomach tube in a single dose of 4000 mg/ kg b.w. at the start of the experiment. All mice were sacrificed 24 hours after the administration.The clinical course as well as the macroscopic findings in all experimental groups indicated general signs of an acute intoxication. The histological findings in the mono-n-butyl-tin-trichloride group showed pronounced changes in the digestive tract, where haemorrhages in the mucous membrane and in the inner layer of the gastric and intestinal walls had been found. In the mice of the other experimental groups, steatosis of the hepatocytes and an irregular steatosis of the renal tubular epithelium were observed.     

The effects of different doses of methylpentynol on escape/avoidance conditioning in two strains of rats selectively bred for high and low “emotionality”

Summary Animals from strains selectively inbred for high and low emotionality have been administered varying doses of methylpentynol and then subjected to a discrete escape/avoidance task (buzzer-shock). Results indicate an initial increase in avoidance scores associated with dose level followed by a decrease. There is also a clear dose and strain effect. No direct difference between the sexes was noted but there is a strong sex X strain interaction. The usual superiority of the non-emotional strain on tasks of this type of conditioning is reversed by the drug. The possible biphasic and dual effect of methylpentynol is discussed.We are indebted to The Nicholas Research Institute Ltd., Slough for the supply of Oblivon used throughout this experiment and for the partial financial support of one of us, B.D.G.     

“Medicamentation” of society, non-diseases and non-medications: a point of view from social pharmacology

This review presents the definition and goals of social pharmacology, a new branch of clinical pharmacology, investigating relationships between drugs and society through the example of medicamentation, defined as the use of drugs for social problems previously not requiring drug utilisation (ageing, smoking cessation, vigilance troubles, sleep synchronisation, loss of libido, etc.). The involvement of the different actors from our society (patients, physicians, pharmaceutical industries, clinical pharmacologists, regulatory agencies, etc.) in this phenomenon is also discussed.     

Nicotine and smoking: Effects upon subjective changes in mood

A Mood Adjective Check List and an activation scale were used to measure subjective reports on mood changes in 24 male habitual smokers before and after smoking cigarettes with known content of nicotine, at different times of day and rates of puffing. Ratings on pleasantness were dose related. Aggression and anxiety showed effects attributable to circadian influence and slight decreases in both factors occurred after smoking the highest nicotine cigarette. The MACL scores were greatly affected by the experimental procedure. Levels of inner tension were found related to the nicotine inhaled. The heuristic value of the concept of activation in these studies is suggested.This work was supported by the Tobacco Research Council, and carried out at the Institute of Psychiatry, London.     

Effective serum concentration and action in pharmacokinetics

Summary A formula has been derived for the calculation of effective serum concentration based on the assumption of both exponential absorption and exponential elimination of an administered drug. In order to permit quantitative comparisons of different drugs and/or different dosage schedules, a new term is proposed called action or COTT (for concentration times time).This paper is dedicated to Prof. Heinz Oeser, M. D., on his 60th birthday.     

Factors in the estimated response of acne vulgaris to antibiotics

Summary The data of a double-blind cooperative trial of thiamphenicol (TP), tetracycline (TE) and placebo (PL) in a two-week oral treatment of acne vulgaris were subjected to a study of the observers' attitudes. The study provided no evidence that the PL-optimistic doctors judged either antibiotic more favorably than the PL-pessimistic. A technique for analyzing factorial experiments when the data are frequencies m unbalanced groups was used in a computerized form to evaluate the effects of the oral treatments as well as the interactions with the factors Sex, Severity and Topical treatment. The advantage of TP (63% satisfactory responses) over PL (34%) was proved beyond doubt, irrespective of any factors studied; the addition of a topical treatment is a useful cofactor only in the severe forms in female patients. The advantage of TE (50% overall satisfactory responses) over PL was detected in female patients only. This finding, as well as the potent action of TP, are discussed in view of the acne ameliorating mechanism/s of these antibiotics.     

A comparison of the acute behavioral effects of flunitrazepam and triazolam in healthy volunteers

Flunitrazepam is an hypnotic benzodiazepine marketed in different European countries. Epidemiological studies have shown that it is frequently abused by opioid addicts. In a survey, liking scores for flunitrazepam in methadone maintenance patients were higher than ratings for other benzodiazepines. A double-blind, placebo controlled, crossover clinical trial was conducted to assess the acute behavioral effects of flunitrazepam (0.05 and 2 mg) and triazolam (0.25 and 0.50 mg) in healthy male volunteers. Drug effects on physiological measures, psychomotor performance, and subjective rating scales, including specific questionnaires to evaluate abuse liability (e.g., ARCI or liking scores), were assessed before and 6 h after drug administration. Flunitrazepam 2 mg produced the most intense disruptive effects on all the performance tasks, triazolam 0.50 impaired performance except balance. All study drugs at all doses produced sedation symptoms in all or part of the subjective effects questionnaires. Only flunitrazepam 2 mg induced significative increases in some of the scales (liking, good effects, high) that could be related to a possible abuse potential. The results seem to indicate that flunitrazepam, when administered to healthy subjects, produces some pleasurable subjective feelings, that could indicate a higher abuse liability of this drug as compared with other benzodiazepines.Presented in part at the 54th Annual Scientific Meeting of the College on Problems of Drug Dependence, Toronto, 1993     

Clockwise hysteresis or proteresis

The authors propose the word proteresis to designate the clockwise hysteresis, i.e., when an effect increases more rapidly than the observed drug concentrations. Such a phenomenon has been recently described for aspirin and nicotine. Indeed hysteresis means which comes after, while proteresis, the greek symmetrical word, means which comes earlier, a more appropriate term for the described situation.     

Sleeplessness in acute and chronic schizophrenia — Response to haloperidol and anti-Parkinsonism agents

Ten acute and seven chronic schizophrenics were longitudinally investigated in two separate double-blind studies. In both studies, after a washout and settling in period of two or more weeks, the patients were placed on placebo for about a month and then on individualized dosages of haloperidol for four months. During the haloperidol periods, the acute patients received two three-week courses of benztropine and the chronic patients, a single two-week course of trihexyphenidyl. The anti-Parkinsonism drugs were given non-blind. Nine times every night, the patients were rated for sleeplessness, and once every week they were rated for psychopathology.The results indicated that marked, predominantly early night sleeplessness was present in the patients studied. The acute subjects were more sleepless than the chronics but the pattern of sleeplessness was similar. The degree of sleeplessness seemed related to total psychopathology, hallucinations and thought disorder. No relationship was found with affective symptoms. Haloperidol reduced sleeplessness promptly and had the effect of normalizing sleep in these patients. Concurrently used anti-Parkinsonism medication seemed to have the opposite effect in chronic patients. These data did not support the notion that haloperidol was a stimulating neuroleptic, and the general distinction made between activating and sedative neuroleptics was questioned. It was suggested that the stimulating effect noticed with some neuroleptics may be attributable to the anti-Parkinsonism drugs often used with them.     

Which smokers report most relief from craving when using nicotine chewing gum?

Seventy-seven smoker clinic clients who managed at least 2 weeks of smoking abstinence while chewing 2 mg nicotine gum reported the degree to which the gum reduced their craving for cigarettes, their daily gum consumption and the extent of urges to smoke despite the gum. Greatest relief from craving by the gum was reported by smokers with higher pre-abstinence expired-air carbon monoxide (CO) concentrations and higher stimulant and dependent scores on a smoking motivation questionaire but not greater usual daily cigarette consumption. Gum consumption correlated positively with expired-air CO, usual daily cigarette consumption, and stimulant and dependent smoking scores. Despite the gum, urges to smoke and difficulty not smoking were reported and the severity of these was associated with indulgent, stimulant and dependent smoking scores but not CO or usual daily cigarette consumption. The results are discussed in terms of the possible role of pharmacological and non-pharmacological factors in craving.     

Mild analgesics evaluated with the “Submaximum Effort Tourniquet Technique”

In a first study with the Submaximum Effort Tourniquet Technique mild analgesics were better discriminated from placebo by subjects, demonstrating a calm behavior in the test-situation than by individuals with prominent arousal reactions.In the present study a tranquilizer-benzoctadiene-was given in order to induce relaxation, with the aim to enhance the subjects ability to discriminate analgesics from placebo.The homogeneity of the variances (Bartlett-test) were between P 0.1 and 0.05. Therefore an analysis of variance and additionally a non-parametric test (Mann-Whitney U test) were done.Pain tolerance times in the six groups (placebo, C-44328-Ba, paracetamol, alone, or in combination with benzoctadiene) on the four pain-levels slight, moderate, severe and unbearable were not significantly different when compared by means of analysis of variance.The comparison of the groups by means of the Mann-Whitney U test showed a) that the combination of the analgesics with benzoctadiene was more effective than either analgesic given alone on three, resp. one of the four pain-levels, b) that in the Non Benzoctadiene Group the analgesics were not differentiated from placebo, and c) that within the Benzoctadiene Group each analgesic was more effective than placebo on two pain-levels.     

“A” esterases and their role in regulating the toxicity of organophosphates

Esterases which can hydrolyse organophosphates without being inhibited by them are termed A esterases. Using paraoxon and pirimiphos-methyl oxon as substrates, high A esterase activity is found in the liver and plasma or serum of a range of mammalian species. In a study of serum A esterases of sheep and humans, over 80% of the activity separated into the high density lipoprotein (HDL) fraction following ultracentrifugation. When HDL fractions from sheep serum were run on Sepharose gel columns, most of the paraoxonase activity separated as a single peak of estimated molecular weight 360000, which corresponds to that of HDL₂ of humans.During the course of purification of A esterases by three different column procedures, contrasting esterase elution profiles were obtained with organophosphate and pyrethroid substrates. This was strong evidence for the existence of multiple forms of HDL A esterases.Levels of A esterase activity in plasma and liver of birds were much lower than those of mammals. This appears to be the main reason why birds are much more susceptible than mammals to organophosphates such as pirimiphos-methyl and diazinon which form active oxons that are good substrates for mammalian A esterases.No A esterase was detected in strains of rust red flour beetle (Tribolium castaneum) which were resistant to organophosphates. Similar observations have been made with strains of other insects resistant to organophosphates, raising the question to what extent esterases of this type are present in insects.Dedicated to Professor Dr. med. Herbert Remmer on the occasion of his 65th birthday     

Failure of “antigastrin” (SC-15 396) to inhibit gastric acid and pepsin secretion in anaesthetized gastric fistula cats

Summary 1. The effect of antigastrin (SC-15 396) on gastric acid and pepsin secretion produced by the gastrin-analogue tetrapeptide amide Try. Met. Asp. Phe-NH₂ and by electrical stimulation of the vagus was investigated in anaesthetized gastric fistula cats.2. Antigastrin failed to inhibit both acid and pepsin response stimulated by either the tetrapeptide or vagus excitation.3. It was concluded that the ineffectiveness of antigastrin in cats is due to a species difference between rats and dogs on the one hand and cats on the other, and that antigastrin is not a specific gastrin antagonist.Supported by the Deutsche Forschungsgemeinschaft and by the Alfred Teufel-Stiftung.     

Potentiation of catalepsy induced by narcotic agents during Haffner's test for analgesia

Potentiation of morphine catalepsy in the mouse during Haffner's (tail-clip) test for analgesia has been investigated. Very marked potentiation occurred in the presence of the clip. Both native and clip catalepsy were antagonised by nalorphine. Atropine antagonised morphine native catalepsy in a dose-dependent fashion, but produced a parallel increase in both analgesia and clip catalepsy at higher doses. Haloperidol catalepsy was abolished in the presence of the clip but reappeared on its removal. It is suggested that morphine must have at least two sites of action in producing catalepsy to account for these results.     

Über die Beeinflussung experimenteller Verkalkungen durch Eisendextran

Zusammenfassung Calciphylaxie wird als eine besondere Überempfindlichkeitsreaktion beschrieben, durch welche der Organismus Calcium selektiv in bestimmte Organe senden kann. Dieses neue biologische Phänomen ist als Abwehrreaktion zur Steuerung pathologischer Verkalkungen aufzufassen und weder mit der typischen metastatischen noch mit einer rein dystrophischen Verkalkung identisch. An Hand von Rattenversuchen wird gezeigt, daß man bei mit Dihydrotachysterin sensibilisierten Tieren die Calciumverteilung im Organismus durch eine unterschiedliche Dosierung von Eisendextran wesentlich ändern kann.

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Summary Calciphylaxis is a new biological phenomenon by means of which the organism is able to send calcium selectively to certain tissues; it is interpreted as a defence reaction and not identical with either the typical metastatic or the merely dystrophic calcification. It is demonstrated that in animals sensitized with dihydrotachysterol, the distribution of calcium can be greatly varied by administering different doses of iron dextran.

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Die Untersuchungen wurden mit Unterstützung der Benger Laboratories Ltd. und der Canadian Arthritis and Rheumatism Society durchgeführt. Der Pfizer Company Ltd. danken wir für das uns zur Verfügung gestellte Polymyxin-B-Sulfat.     

Methylxanthines are the psycho-pharmacologically active constituents of chocolate

Rationale Liking, cravings and addiction for chocolate (chocoholism) are often explained through the presence of pharmacologically active compounds. However, mere presence does not guarantee psycho-activity.Objectives Two double-blind, placebo-controlled studies measured the effects on cognitive performance and mood of the amounts of cocoa powder and methylxanthines found in a 50 g bar of dark chocolate.Methods In study 1, participants (n=20) completed a test battery once before and twice after treatment administration. Treatments included 11.6 g cocoa powder and a caffeine and theobromine combination (19 and 250 mg, respectively). Study 2 (n=22) comprised three post-treatment test batteries and investigated the effects of milk and dark chocolate levels of these methylxanthines. The test battery consisted of a long duration simple reaction time task, a rapid visual information processing task, and a mood questionnaire.Results Identical improvements on the mood construct energetic arousal and cognitive function were found for cocoa powder and the caffeine+theobromine combination versus placebo. In chocolate, both milk chocolate and dark chocolate methylxanthine doses improved cognitive function compared with white chocolate. The effects of white chocolate did not differ significantly from those of water.Conclusions A normal portion of chocolate exhibits psychopharmacological activity. The identical profile of effects exerted by cocoa powder and its methylxanthine constituents shows this activity to be confined to the combination of caffeine and theobromine. Methylxanthines may contribute to the popularity of chocolate; however, other attributes are probably much more important in determining chocolates special appeal and in explaining related self-reports of chocolate cravings and chocoholism.     

Begriff und Bedeutung der Antidottherapie im Wandel der Zeiten

Zusammenfassung Antidote sind schon im Altertum bekannt gewesen. Neben dem Einsatz einzelner Antidote gegen definierte Giftstoffe sind aber schon in der Antike Antidotgemische mit universellen Indikationen eingesetzt worden. Als Alexipharmaka, Mithridatia und Theriaka haben sie die Antidottherapie der Vergiftungen bis in die Neuzeit hinein beherrscht. Im 18. und 19. Jahrhundert konnten nach der Erforschung der chemischen Verhaltensweisen der Gifte zahlreiche spezifische chemische Antidote, durch die Kenntnis der pharmakologischen Eigenschaften dynamische Antidote eingeführt werden. Gemische aus mehreren chemischen Antidoten bringen dann als Universalantidote einen Rückschritt, da InkompatibilitÄten auftreten. Der Fortschritt der Molekulartoxikologie hat es ermöglicht, seit etwa 30 Jahren Antidote zu schaffen, die imstande sind, die biochemische LÄsion durch spezifische Bindung der Giftstoffe zu lösen.     

Transplacental passage and breast milk concentrations of hydralazine

Summary The concentrations of real and apparent (= real hydralazine + acid-labile hydrazones) hydralazine in maternal and umbilical plasma obtained at delivery of 6 women treated with hydralazine and atenolol for pregnancy hypertension were measured by gas chromatography. In one of the patients, the concentrations of the same substances were subsequently measured in breast milk. Apparent hydralazine reached higher levels in umbilical than in maternal blood. The concentration of real hydralazine seemed to be at least as high in the fetus as in the mother. On the other hand, even though the fraction of real (i.e. presumably active) hydralazine was greater in milk than in plasma, the total concentration was smaller, and the estimated dose per milk feed of 75ml would not exceed 0.013mg. Thus, hydralazine treatment of the pregnant woman would expose her fetus to effective concentrations of the drug, but breast feeding would not result in a clinically relevant concentration in the infant.