In vivo receptor binding,neurochemical and functional studies with the dopamine D-1 receptor antagonist SCH 23390

Summary A series of in vivo experiments were undertaken, relating functional (motor activity, body temperature), dopamine (DA) receptor binding and neurochemical (catecholamine synthesis and utilization, DA release) aspects of the pharmacology of SCH 23390 in the rat.The compound inhibited the locomotor hyperactivity, but not the hypothermia, induced by the potent DA stimulant DP-5,6-ADTN. Interstingly, SCH 23390 simultaneously failed to displace DP-5,6-ADTN from its binding sites in the rat striatum—used as a direct in vivo biochemical index of DA (D-2) receptor interaction. The spontaneous locomotion in non-pretreated rats was likewise inhibited by SCH 23390. The locomotor-suppressive action, but not the DP-5,6-ADTN-displacing capcity of the D-2 blocker haloperidol was significantly enhanced by SCH 23390, suggesting that motility can be suppressed by either enhanced D-1 or D-2 (postsynaptic) receptor blockade, but also that the D-1 and D-2 sites involved may be physically distinct.SCH 23390 only slightly altered in vivo neurochemical of DA synthesis, release and nerve-impulse flow, indicating that, while similar in suppressing dopaminergic behaviour, the D-1 antagonist is less effective than traditional neuroleptics as an activator of DA neuronal feedback mechanisms. The weak increases of DA synthesis and release nonetheless obtained were equal in magnitude (30–40%) in the limbic vs. striatal brain areas; also in this respect, SCH 23390 thus differs from classical neuroleptics, which generally display more marked effects in the striatum than in limbic tissue.No major changes in the in vivo indices of NA synthesis and utilization (or in 5-HT synthesis) were found after SCH 23390 administration, by and large supporting the DA receptor specificity of the compound.In summary, the studies demonstrated that SCH 23390 can offset and accentuate, respectively, behavioural consequences of D-2 receptor stimulation and blockade. Importantly, at the same time no direct interaction at the level of D-2 DA receptor sites in the striatum was detected. Only slight, D-2 antagonist-like, changes in neurochemical indices of dopaminergic activity were observed after D-1 receptor blockade by means of SCH 23390. With regard to DA agonist hypothermia, SCH 23390 was without effect per se, but (at a high dose) attenuated the action of the D-2 antagonist haloperidol. The observations may indicate that the complex interactions between central D-1 and D-2 receptor-controlled mechanisms that influence behaviour, neurochemistry, and possibly autonomic nervous expression, are not identical.     

Inhibition or enhancement of kindling evolution by antiepileptics

Summary The influence of antiepileptics on the evolution of rat amygdaloid kindling was studied.Under placebo conditions clonic convulsions and a spike-wave EEG pattern developed. Diazepam, clonazepam, clobazam and phenobarbital were most effective in suppressing the evolution of kindling; the effects of valproate sodium, ethosuximide and acetazolamide were somewhat less pronounced in this respect. Carbamazepine, oxcarbazepine and phenytoin, on the other hand, enhanced kindling development, i.e. the increase in duration of after-discharge was faster than in the placebo group. The results indicate that under the above experimental conditions drugs with no anti-absence component can be distinguished from those with an anti-absence component. The mechanism of action underlying the observed effects is not yet known; the hypothesis that under special conditions protective inhibitory neuronal activity can develop to absence type seizures is proposed.     

Anthelmintic activity of some sudanese medicinal plants

The anthelmintic activity of aqueous extracts (0.25–50 mg/mL) from 14 plant species that represent seven families of the Sudanese flora was examined using the free living rhabditid nematode, Caenorhabditis elegans as a test organism. Extracts of Balanites aegyptiaca and Sesbania sesban were the most effective (LC₅₀, 0.8 and 8.0 mg/mL, respectively). Extracts of Albizzia anthelmintica, Cymbopogen narvatus, Abrus precatorius, Rhyncosia minima, Striga hermonthica and Anogeissus leiocarpa (LC₅₀, 9.5–84.6 mg/mL were less effective in this model test system. Extracts of six plant species, Albizzia malacophylla, Gardenia lutea, Physostigma mesoponticum, Salvadora persica, Xeromphis nilotica and Waltheria indica had no effect upon C. elegans survival.     

Aptitude for physical exercise in a population of female hospital workers

Summary The aim of this study was to evaluate the level of physical capacity in a female hospital population of Paris and its suburbs. A total of 1505 women working in the selected departments filled in a questionnaire concerning their working conditions, life habits and health and also attended a medical examination. The effort test performed consisted in flexing the legs 20 times with the chest held straigt, in 40 s. The heart rates were measured for the first, the second and the third minutes of recovery (first 15 s multiplied by 4). The blood pressure was measured just after the heart rate, for the first and the third minute. Recovery indices have been constituted from the results. The respective weights of anthropometric and sociodemographic risk factors for recovery indices were studied in multiple logistic regression models. The classification enables us to consider about 25%–30% of our population as having a satisfactory physical capacity, about 26%–27% as having an acceptable capacit, and about 24%–27% as having a weak capacity. About 21% of the population presented an excessive pressure reaction and 44% a questionable pressure reaction. Our results concerning the level of physical capacity of the female nursing staff should be taken into account especially in the future planning of work loads and architectural choices, which must avoid excessive physical burdens in relation to this level. An improvement in the level of physical capacity could be envisaged as well.     

Serum levels of interleukin-6 and tumour-necrosis-factor-alpha are not correlated to disease activity in patients with rheumatoid arthritis after treatment with low-dose methotrexate

Abstract. Cytokines are major mediators of inflammatory responses in rheumatoid arthritis. Some of them have been shown to correlate with the disease activity and thus are proposed to be used for monitoring patients. Therefore the effects of a low-dose therapy with methotrexate on serum concentrations of interleukin-6 (IL-6) and tumour-necrosis-factor-alpha (TNF-α) were examined in eight patients with seropositive rheumatoid arthritis. Serum levels of IL-6 and TNF-α were significantly elevated in patients compared to healthy controls. Before the onset of MTX treatment IL-6 concentrations were correlated to the c-reactive protein ( P < 0·05) but the correlation was abolished after treatment. For TNF-α no correlations neither before nor after treatment were observed. Both cytokines remained substantially elevated after MTX treatment despite a clear reduction in disease activity. Thus we suggest that one of the effects of MTX might be the inhibition of some of the actions of IL-6 and TNF-α.     

高血压病肠系膜动脉平滑肌细胞端粒酶活性表达的研究

目的 :探讨高血压病动脉平滑肌组织端粒酶活性与高血压的发病关系。方法 :采用PCR -ELISA法检测 30例高血压病患者和 2 0例血压正常者肠系膜动脉平滑肌细胞 (SMC)端粒酶活性。结果 :高血压患者端粒酶阳性表达 2 8例 (93.3% )。血压正常者端粒酶阳性表达 3例 (15 % )。差异非常显著 (P <0 .0 5 )。结论 :高血压病动脉平滑肌细胞端粒酶活性的表达升高 ,可能与高血压发病有关。     

Synthesis and antimalarial activity of new atovaquone derivatives

In this paper we describe the design and synthesis of 18 derivatives of the antimicrobial atovaquone which were substituted at the 3-hydroxy group by ester and ether functions. The compounds were evaluated in vitro for their activity against the growth of Plasmodium falciparum, the malaria causing parasite. All the compounds showed potent activity, with IC₅₀ values in the range of 1.25–50 nM, comparable to those of atovaquone and much higher than chloroquine or quinine.     

Genetic segregation analysis of red blood cell (RBC) histamine N-methyltransferase (HNMT) activity

Methylation is an important pathway in the biotransformation of many drugs, neurotransmitters, and xenobiotic compounds. Histamine N-methyltransferase (HNMT) catalyzes the Nτ-methylation of histamine and structurally related compounds. Measurement of HNMT activity in the RBC makes it possible to access variation in the enzyme activity that may reflect differences in less accessible tissues such as brain. Previously reported high family correlations for RBC HNMT activity suggested that genetic inheritance plays a major role in the regulation of variation in this enzyme. In the present study we completed complex segregation analyses of RBC HNMT activity of 241 individuals in 51 nuclear families that were randomly ascertained through children in the Rochester, Minnesota public school system in order to characterize the mode of inheritance of this important enzyme. We found evidence for major gene influence on the regulation of RBC HNMT activity. Both transformed and untransformed data support the presence of Mendelian major gene segregation, but the gene frequency differences do not indicate a direct correspondence between genotypes inferred from the two sets of analyses. Analyses of the skewed untransformed data indicated the presence of a relatively rare (Q = 0.121) additive major gene for high activity, with the three overlapping genotype distributions representing 77, 21, and 2 % of individuals. Analyses of the normalized transformed data indicated the presence of a common (Q = 0.71) additive major gene for high activity, with the three overlapping genotype distributions accounting for 9, 41, and 50 % of individuals. The analyses of transformed data give the best fit as well as the most parsimonious Mendelian major gene model. However, we cannot rule out the possibility of multiple alleles, and analyses of untransformed data provide some support for a third allele. Molecular studies will be needed to validate and characterize the alleles that regulate RBC HNMT activity levels in humans. © 1993 Wiley-Liss. Inc.     

Cholecystokinin Excites Neostriatal Neurons in Rats via CCKA or CCKB Receptors

The effect of iontophoretically applied cholecystokinin (CCK) on neurons of the neostriatum was studied in rats anaesthetized with urethane. The most frequently observed effect of the sulphated octapeptide (CCK-8S) on striatal neurons was excitation. Spontaneously active neurons responded more often to CCK-8S than quiescent cells. Silent, primarily non-responsive neurons could often be stimulated with CCK-8S using glutamate to induce an ongoing discharge. Thus, 45.8% of the 177 neurons studied changed their discharge rate by more than 30%. Certain CCK receptor antagonists could prevent the effect of CCK-8S, fully or at least partly, in the majority of CCK-responsive neurons. The data suggest that cholecystokinin modulates the firing of active neostriatal neurons via the CCKA or the CCKB receptor type. Furthermore, we compared neuronal responses to glutamate with those recorded during concomitant administration of CCK-8S in order to study the interaction of both transmitters, which may be colocalized in striatal afferents. CCK-8S mainly enhanced the excitatory effect of glutamate on striatal neurons, but in several neurons the response to glutamate was reduced. The CCKB receptor antagonist could prevent CCK-8S from increasing the glutamate-induced activation.