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.     

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.     

Über das bradykininbildende Prinzip des Schlangengiftes

Summary 1. The bradykinin releasing principle of the venom of Bothrops jararaca and of Crotalus atrox is partly dialysable through cellophane. With Crotalus venom about 10% of the total activity are found in the dialysate.2. The dialysates are free of the proteolytic and coagulating (Bothrops) as well as of the tryptic principle of the venoms as measured by the hydrolysis of benzoyl-argininamid. Beside the bradykinin releasing principle they contain an esteratic activity, which splits the methylester of benzoylarginin.3. It is concluded from the results that the bradykinin releasing principle may be identical with the esteratic principle but not with the proteolytic and tryptic nor with the fibrinogen coagulating principle. On the other hand it may belong to the group of Kontaktstoffe which like agar, inulin, starch and the dextranes, release anaphylatoxin when they get into contact with serumproteins.4. Rabbits are about 8 times more sensitive than cats against the bloodpressure lowering action of bradykinin.5. The question is discussed whether the snake venoms contain only one bradykinin releasing factor which is dialysable and of low molecular weight, or whether there are different factors, some of which have a high molecular weight and are therefore not dialysable.

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Herrn Professor Dr. Paul Wels zum 70. Geburtstag gewidmet.

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Die Arbeit wurde mit finanzieller Unterstützung der U.S. Department of the Army, European Research Office, durchgeführt.Eine kurze Mitteilung erfolgte in den Naturwissenschaften (Contzen, Holtz u. Raudonat 1959).     

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.     

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.     

A novel diterpenoid with a rearranged neoclerodane skeleton from Salvia leucantha CAV.

A new diterpenoid with a rearranged neoclerodane skeleton, spiroleucantholide (compound S1), along with four known diterpenoids—salvifaricin (compound S2), isosalvipuberulin (compound S3), salvileucantholide (compound S4), and salviandulin E (compound S5)—was isolated from the aerial parts of Salvia leucantha CAV.. The structures were established by spectroscopic methods, including the X-ray analysis of spiroleucantholide (S1).     

“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.     

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.     

Nature of adrenoceptor sites in bovine teat muscles

Summary The motility of smooth muscles excised from the wall of bovine teats was studied in vitro. These muscle preparations often show spontaneous rhythmic contractions. Administration of isoprenaline results in relaxation and decreased spontaneous motility, these effects being blocked by propranolol. Noradrenaline elicits contraction and stimulates rhythmical activity, these effects being inhibited by dibenamine. The effect of adrenaline is variable as it induces contraction or inhibition or biphasic responses. Dibenamine blocked contractions, whereas propranolol inhibited relaxations. It appears that alpha and beta adrenoceptors are present in teat muscles. Stimulation of the former clicits activation, whereas stimulation of the latter results in inhibition. These in vitro results are largely in agreement with in vivo responses described previously.     

A pilot study of mesterolone in impotence

Eighteen primarily impotent males untreated for at least 6 months participated in a pilot trial with the synthetic androgen mesterolone. In each subject there was a drug free run-in period for 3 weeks, 3 weeks mesterolone (25 mg t. i. d.) and a post drug period of 3 weeks. Throughout, daily self ratings and weekly investigator ratings were made. Although there was a slight trend towards improvement during the mesterolone period, this was not significant statistically.     

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.     

On the role of rate of brain norepinephrine release in the antibenzoquinolizine action of desipramine

Summary Desipramine (DMI) antagonizes and even reverses in rats autonomic and behavior changes of the reserpine-like syndrome elicited by reserpine and synthetic benzoquinolizines. The degree of this antagonism is related to the rate of brain norepinephrine-release and not to the degree of depletion of the monoamine. Since increasing the dose of the sedative benzoquinolizines (tetrabenazine, RO 4-1284, P-2565) enhances the rate of brain-norepinephrine-release, higher doses of the tranquilizers paradoxically increase in DMI-pretreated rats the score of total antagonism and the percentage of animals displaying the reversal phenomenon. The data are in keeping with the view that desipramine enhances the effect of free norepinephrine at central adrenergic effector sites.Presented in part before the American Society for Pharmacology and Experimental Therapeutics at Lawrence, Kansas, August, 1964.     

Proposal of a psychopharmacological test (“stimulation threshold”) for differentiating neurotic from psychotic depressions

Summary An attempt of evaluating the amount of intravenous amphetamine required to provoke psychological and vegetative responses in depressed patients is referred: preliminary report shows that these dosages (which we called stimulation threshold) are markedly higher in psychotic than in neurotic depressions, and tend to decrease in those cases presenting a higher degree of manifest anxiety...These data seem to agree with Shagass' results in sedation treshold to sodium amytal.     

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.     

“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     

Effect of haloperidol on reflex activation of rat α-motoneurones

Summary Effects of haloperidol on rat flexor and extensor -motoneurones were studied in ventral roots of laminectomized rats under halothane anesthesia. The -motoneurones were activated by tetanic stimulation of low-threshold afferents (group I and II), either of the ipsilateral peroneal nerve (flexor -motoneurones) or gastrocnemius-soleus nerve (extensor -motoneurones).Haloperidol, given in the doses of 0.075, 0.15 and 0.30 mg/kg i.p. inhibited the reflex activation of flexor -motoneurones; higher doses seemed to be more effective than lower ones. Apomorphine (2 mg/kg s.c.) partially antagonized the inhibitory action of haloperidol with some latency. Higher doses of haloperidol (0.15–0.60 mg/kg i.p.) also inhibited the reflex activation of extensor -motoneurones; this inhibitory effect was, at least for a short time, antagonized by apomorphine (2 mg/kg s.c.).The threshold for reflex activation both of flexor and extensor -motoneurones was raised by haloperidol and lowered by a subsequent administration of apomorphine.Our results suggest that akinesia and catalepsy, induced in rats by haloperidol might be, at least in part, due to a decrease in sensitivity of -motoneurones to proprioceptive stimuli.     

Structure-activity relationship studies on mescaline: II. Tolerance and Cross-tolerance between mescaline and its analogues in the rat

Summary Using the CAR shuttle box technique, with male hooded rats as subjects, the development of tolerance to mescaline, 3,4-dimethoxyphenyl-ethylamine (DMPE) and NN-dimethylmescaline (DMM) and possible cross-tolerance between these drugs was studied. It was found that seven successive daily doses of mescaline induced tolerance to its inhibitory effect, but that the excitatory effect was increased. Tolerance developed to the predominantly inhibitory effect of DMPE, and to the excitatory effect of DMM.Partial cross-tolerance existed between DMPE and mescaline, and when the procedure was reversed, between mescaline and DMPE. Cross-tolerance was shown in the same manner between DMM and mescaline, and mescaline and DMM.The problems of quantification and interpretation of these results is discussed. It was concluded, on the basis of subsidiary experiments, that the inhibitory effect of mescaline was probably not caused by ataxia or by a peripheral effect.     

Bispyridinium (oxime) compounds antagonize the “ganglion blocking” effect of pyridostigmine in isolated superior cervical ganglia of the rat

The antidotal effectiveness of several bispyridinium compounds (HGG 12, HGG 65, HGG 70, HI 6, HLö 7 and HLö 12) against the acetylcholinesterase (AChE) inhibitor pyridostigmine was evaluated in isolated superior cervical ganglia of the rat. Compound action potential amplitudes were inhibited by pyridostigmine in a concentration-dependent manner. HI 6 and atropine proved to be the most effective compounds in antagonizing the ganglion blocking action of pyridostigmine. Their relative effectiveness (PE value) was 5.4 and 4.2, respectively. All of the six bispyridinium compounds inhibited carbachol-induced, nicotinic, ganglionic surface depolarizations. The antinicotinic potencies of HI 6 and HLö 7 were about one order of magnitude lower (apparent K_I values: 294 and 330 mol/1) than the antinicotinic potencies of HGG 12, HGG 65, HGG 70 and HLö 12 (apparent K_I values ranging from 19 to 41 mol/1). The antinicotinic potencies of the bispyridinium compounds did not correlate with their in vitro protection of synaptic transmission in sympathetic ganglia. Moreover, the effectiveness of atropine points to the importance of antimuscarinic properties of possible antidotes for the maintenance of ganglionic transmission in cases of AChE poisoning.     

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     

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.