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.     

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).     

Drug,doctor warmth,and clinic setting in the symptomatic response to minor tranquilizers

An NIMH-PRB collaborative double-blind clinical trial, concerned with the importance of the doctor variable for drug treatment outcome, was conducted with 485 anxious neurotic outpatients receiving either chlordiazepoxide, meprobamate, or placebo. The participating clinics were located at the Johns Hopkins Hospital, Philadelphia General Hospital, and the Hospital of the University of Pennsylvania. The doctor variable selected for presentation was doctor warmth. Data on the 169 patients completing the 4 week study according to protocol were analyzed using a factorial analysis of covariance procedure, and the main findings were as follows: 1. several main drug effects, present only at 2 weeks, indicated chlordiazepoxide to produce significantly more improvement than either meprobamate or placebo; 2. several main warmth effects, present only at 4 weeks, showed patients rating their physicians at the initial visit as warm to improve significantly more than patients rating their physicians as non-warm; and 3. several significant drug X clinic interaction effects at 4 weeks reflected the fact that while hardly any drug differences were seen in 2 clinics, at Philadelphia General Hospital, patients strongly favored chlordiazepoxide. Drug and warmth effects were particularly marked in initially sicker patients, and warmth appeared especially important in the improvement of initially sicker placebo patients.     

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.     

“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.     

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.     

The effect of nicotine on the swimming speed of pre-trained rats through a water alley

Summary In sessions of ten runs each, swimming time of rats through a 4 m long water alley was measured. Four doses of nicotine (0.05; 0.1; 0.2; 0.4 mg/kg given intraperitoneally 30 minutes before testing) were tested in sessions with a braking load on the tails of the animals either in all 10 runs of a session, or in every second run, or in none of the 10 runs. Regardless of the swimming condition, nicotine produced a considerable, and at doses of 0.1 mg/kg and over, significant decrease of performance in the first two runs. From the third to the 10th run, the changes caused by nicotine were smaller and differed depending on the swimming conditions.A dose of 0.1 mg nicotine/kg improved performance in the without-load-sessions and the without-load-runs of the alternating sessions, while both 0.1 and 0.2 mg/kg improved performance of the with-load-runs of the alternating sessions. Performance in the without-load-sessions and the without-load-runs was depressed by 0.4 mg/kg and that in the with-load-sessions by 0.2 and 0.4 mg/kg.     

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.     

Plasma levels and half lives of thioridazine and some of its metabolites

Summary Plasma-levels of thioridazine, mesoridazine, sulphoridazine and two other metabolites were determined in ten older chronic psychotic patients on thioridazine therapy. The plasma-level before the morning dose of thioridazine was the most reliable parameter for clinical studies. An intra-individual relationship between lower doses of thioridazine and plasma-levels was found. The percentage contribution of psychoactive compounds to the total sum of thioridazine plus metabolites ranged from 43–74%. The mean early disappearance half-life of thioridazine was 5 hours, and its mean late disapperance half-life was 26 hours.     

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.     

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.     

Role of brain amines in learning associated with “amphetamine-state”

Conditional avoidance responses acquired under amphetamine were recalled without deficit only when tested under amphetamine (amphetaminestate dependent learning). Hydroxyamphetamine was devoid of this property. Dihydroxyphenylalanine (DOPA) but not 5-hydroxytryptophan (5-HTP) substituted for amphetamine while reserpine but not syrosingopine eliminated the amphetamine-state. DOPA and 5-HTP, only when given together, restored the amphetamine-state in reserpinized animals. DOPA alleviated the deficit in retention which was caused by methyl-p-tyrosine. 5-HTP alleviated the similar deficit caused by p-chlorophenylalanine. Chlorpromazine or cyproheptadine antagonized the amphetamine-state. It is suggested that amphetamine, but not hydroxyamphetamine is capable of producing an asymmetric behavior-controlling state. The amphetamine-state is related to the stimulation of central and not peripheral amine-receptors and depends on newly synthesized catecholamines which stimulate central catecholamine receptors through serotonin modulation in this case.     

Behavioral and autonomic responses to intermittent social stress: differential protection by clonidine and metoprolol

The present study investigated physiological and pharmacological characteristics of socially stressed animals. Specifically, we examined (1) to what degree autonomic and behavioral stress reactions during intermittent confrontations between an intruder male adult Long-Evans rat with an aggressive resident undergo habituation, and (2) to what extent the defeat-experienced animal can be protected against these stress reactions with clonidine or metoprolol, two adrenergic agents with clinical anxiolytic effects. We developed an acute social stress situation that consisted of initially placing an experimental rat as an intruder into the homecage of a resident while the resident was not present, thereafter permitting brief physical agonistic interactions with the reintroduced resident until the intruder was forced into a submissive supine posture and emitted ultrasonic vocalizations (USV), and eventually exposing the intruder to the resident's threats for one hour, while being shielded from potentially injurious attacks (threat encounter). Over the course of the initial 4-weekly threat encounters the acute tachycardia but not the hyperthermic stress responses decreased in magnitude. Following the first three threat encounters core temperature (T_c) was significantly elevated for at least 3 h. The T_c was already elevated when the repeatedly defeated intruder was confronted with the olfactory cues of the resident's cage. This conditioned anticipatory hyperthermia developed in the course of the first three confrontations and was paralleled by a decrease in exploratory and motor behavior and by an increase in defensive behaviors and in both types of USV emitted in the low (20–30 kHz) and the high (31–70 kHz) frequency range. Clonidine (0.01–0.1 mg/kg, IP), an ₂-adrenergic agonist and metoprolol, a -adrenergic blocker (1.0–10.0 mg/kg, IP), dose-dependently prevented the tachycardic response to stress. Only clonidine, but not metoprolol, also attenuated the rise in T₀ during the 1-h agonistic interaction. Clonidine decreased those aspects of motor behavior (e.g. rearing, walking) that are of lesser cost for the individual but maintained high levels of defensive reactions and increased the duration of low USV. The high doses of clonidine (0.06, 0.1 mg/kg) attenuated the homeostatic regulation and sedated the intruder while exposed to threats during a social confrontation. The absence of attenuation of the high level of defensive behavior and the prolonged low USV suggest a stress intensification by the higher doses of clonidine. In conclusion, after the fourth encounter, the autonomic, behavioral and vocal response pattern prior to and during repeated weekly confrontations show no evidence for habituation for the following 6 weeks. Moreover, adrenergic therapeutic agents that are applied to treat symptoms of anxiety block the tachycardic response but may actually intensify defensive behavior and certain stress vocalizations.     

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.     

Inhalation pharmacokinetics based on gas uptake studies

On the basis of previous determinations of pharmacokinetic parameters for inhaled vinyl chloride in men, rhesus monkeys, and rats, and on improved pharmacokinetic models a pharmacokinetic treatment of the problem of peak concentrations of vinyl chloride, as occuring in industrial practice, became possible. For the calculations, metabolic elimination kinetics of vinyl chloride was assumed to be first order as experiments in different species including rhesus monkeys showed linear pharmacokinetics up to atmospheric exposures of 200–300 ppm. The distribution of vinyl chloride between atmosphere and organism under different conditions was evaluated using steady-state-kinetics. After treating the processes of influx, efflux, and metabolism, the numerical values for the parameters derived from a human kinetic experiment were used to theoretically calculate the time courses of concentration of vinyl chloride in the organism and of the cumulative amount of vinyl chloride metabolized, under the conditions of (a) a 2 h constant exposure to 5 ppm vinyl chloride and (b) two subsequent peaks of 50 ppm with a duration of 5 min each. This model calculation suggested that, regardless of the exposure profile, the amount of (reactive) metabolites formed from vinyl chloride would soleley be a function of the mean atmospheric vinyl chloride concentration over time. The general validity of this suggested rule could subsequently be demonstrated. As the concentration of the reactive metabolite of vinyl chloride responsible for the carcinogenic effect at the target site must be a resultant of both formation and inactivation, an evaluation of the differential risk of different exposure profiles can reasonably be based on biochemical examinations of the detoxifying pathways. This points out the relevance of studies of the patterns of different metabolites of vinyl chloride in man under varying exposure profiles.     

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.     

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.     

Thymidine transport in hepatocytes

Thymidine transport and phosphorylation were investigated in isolated rat hepatocytes and AS 30 D hepatoma cells. In contrast to hepatoma cells, hepatocytes exhibited a minimum of thymidine phosphorylation due to a 100-fold smaller thymidine kinase activity. In hepatocytes thymidine is transported by two transport systems: a specific concentrative high affinity system and an unspecific non-concentrative low affinity system. In hepatoma cells only the low affinity system could be detected. A single dose of 20 or 50 mg diethylnitrosamine/kg body weight induced in hepatocytes a remarkable increase of thymidine kinase activity and a decrease of the transport by the high affinity system. Thymidine transport and phosphorylation by hepatocytes are considered to be sensitive markers for early recognition of toxin-induced liver regeneration.

---

Zusammenfassung Thymidintransport und -phosphorylierung wurden in isolierten Rattenhepatozyten und AS 30 D-Hepatomzellen untersucht. Hepatozyten wiesen im Gegensatz zu Hepatomzellen aufgrund einer 100fach niedrigeren Thymidinkinaseaktivität eine äußerst niedrige Thymidinphosphorylierungsrate auf. In Hepatozyten wurde Thymidin durch zwei Transportsysteme aufgenommen: ein spezifisches, konzentratives high affinity System und ein unspezifisches, nichtkonzentratives low affinity System. In ATP-freien Hepatomzellen konnte nur das low affinity System nachgewiesen werden. Eine einmalige Dosis von 20 bzw. 50 mg Diäthylnitrosamin/kg Körpergewicht bewirkte in Hepatozyten einen Anstieg der Thymidinkinaseaktivität und eine Verminderung des Thymidintransports über das high affinity System. Thymidintransport und -phosphorylierung in Hepatozyten erwiesen sich als sensitives System zur frühen Erkennung beginnender Leberregeneration nach toxischer Vorschädigung.

     

Evidence for a displaceable non-specific [3H]neurotensin binding site in rat brain

Summary Levocabastine is a potent antihistamine drug, structurally unrelated to neurotensin. In rat and mouse brain but not in other animal species, it inhibited 60% of the [³H]neurotensin binding displaced by unlabelled neurotensin or neurotensin (8–13).The levocabastine-sensitive site or site 1 displayed high affinity properties for levocabastine (IC₅₀=25 nM) and was highly stereospecific (IC₅₀-value higher than 10 M for one of the isomers). Binding to the site 1 in rat brain corresponded to the [³H]neurotensin binding displaceable by 1 M levocabastine, whereas binding to the site 2 corresponded to the binding displaced by 1 M neurotensin when the site 1 was occluded by 1 M levocabastine.Both site 1 and site 2 appeared to be saturable. Scatchard plots obtained in rat bulbus olfactorius allowed to calculate a K _D-values of 7.1 nM and a B _max-values of 37.2 fmol/mg original tissue for site 1, while site 2 displayed a K _D-value of 0.7 nM and a B _max-value of 16.3 fmol/mg original tissue. The regional distributions of both sites showed marked differences. The site 1 was homogeneously distributed throughout all rat brain areas, whereas the amount of site 2 binding was markedly different in separate brain areas: bulbus olfactorius and substantia nigra had the highest amounts (8.9 and 7.8 fmol/mg tissue) while cerebellum had the lowest (0.4 fmol/mg tissue).In spite of its high affinity and stereospecificity, site 1 has to be considered as an acceptor or recognition site for [³H]neurotensin because of its species-link, low saturability and homogeneous distribution in all rat brain areas.On the other hand, site 2 had the characteristics of a physiological receptor: high affinity, saturability in the low nanomolar range and marked regional distribution in rat brain. Site 2 corresponds therefore most probably to the physiological neurotensin receptor. The foregoing experiments provide evidence for the presence of a drug displaceable, non-specific (=unrelated to a physiological receptor) neurotensin binding site in rat brain; levocabastine should be an important tool to occlude this site in order to reveal, by means of in vitro binding assays, the specific neurotensin binding site in rat brain.     

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.