Our primary goal has been to discover leukotriene biosynthesis inhibitors with characteristics that are appropriate for use as clinical agents. The success of the use of zileuton in the treatment of asthma led us to explore further the use of the N-hydroxyurea class of 5-lipoxygenase inhibitors as longer-acting compounds with good lung penetration. A variety of in vitro and in vivo methods were used to evaluate a large number of compounds, from which ABT-761 [(R)-N-(3-(5-(4-fluorophenylmethyl)thien-2-yl)-1-methyl-2-pr opynyl)-N-hydroxyurea] was selected for study. ABT-761 exhibited potent and selective inhibition of leukotriene formation both in vitro and in vivo. More importantly, the compound potently inhibited antigen-induced bronchospasm in guinea pigs when given either prophylactically or therapeutically. In addition, ABT-761 was a potent inhibitor of eosinophil influx into the lungs of Brown Norway rats. These data provide added support for the role of leukotrienes in both bronchospasm and eosinophilic inflammation and characterize ABT-761 as a particularly potent inhibitor of leukotrienes formed in pulmonary tissues. These data combined with the excellent pharmacokinetic characteristics of the compound indicate its potential use in the treatment of leukotriene-dependent human disease.
The epidemiological study of a focus of Brucella infection revealed that an outbreak of brucellosis occurred in a small town, and the source of this infection was a domestic cat. As the result of contacts with this cat, six persons, among them three children aged 3, 8 and 12 years, had brucellosis. In all these patients acute brucellosis was diagnosed. Simultaneously with the clinical manifestations of the disease, a rise in antibody titer from 1:50 to 1:1,600 was observed. Brucella cultures isolated from the blood of one of the patients and from the internal organs of the cat exhibited the properties, similar to those of "rodent" strains, i. e. their differential signs permit their classification with B. suis, serovar 5.
The correction of radiation-induced immunodeficiency and hematopoiesis depression in clinical setting (100 patients) and in experiments (160 animals) by peptide preparations of the thymus and bone marrow (thymalin, hemalin, thymogemine and synthetic thymalin analog thymogen) has been studied. Administration of the bone marrow and thymus recovery of damage to the thymus, bone marrow, spleen and lymph nodes, improved the function of circulating neutrophilic granulocytes. Thymalin was able to compensate for immune disturbances and reduce manifestations of asthenia.
The inotropic effects of noradrenaline (10(-7)-10(-5) M) and acetylcholine (10(-8)-10(-6) M) were studied in experiments carried out on preparations of the right atria and on papillary muscles of the right ventricle in adult (4-5 months) and old (18-24 months) guinea pigs. An age-related decrease in inotropic noradrenaline effects and the displacement of dose-effect relationships to the right was revealed. Similar changes of the dose-related effects of acetylcholine superfused against the background of noradrenaline action were observed. The direct inotropic action of the acetylcholine did not change with ageing. A lack of the essential atrial-ventricular differences in age-related changes in myocardial reactivity is apparently very significant for support of effective functional coupling of cardiac chambers in ageing.
The alpha-subunit composition of nicotinic acetylcholine receptors (nAChRs) in the submucosal plexus of the guinea-pig ileum were studied using the whole-cell patch-clamp technique and affinity-purified antibodies (Abs) against alpha3-, alpha4, alpha5 and alpha7-subunits of nAChRs. The independent addition of anti-alpha3 and anti-alpha5 Abs to extracellular bath solution induced depression of the acetylcholine (ACh)-evoked currents by 60% +/- 1.56% and 65% +/- 1.62% correspondingly. Successive application of anti-alpha5 Abs in the presence of anti-alpha3 Abs did not have any additional blocking effect on ACh-evoked currents. Anti-alpha7 Abs evoked depression of Ach-induced currents by 24% +/- 1.51% in 80% of investigated neurons and by 67% +/- 1.5% in 20% of neurons. The addition of anti-alpha4 Abs to extracellular bath solution did not have effect on membrane currents of the investigated neurons. Our data provide evidence of participation of alpha3-, alpha5 and alpha7-containing receptors in the response to ACh. Alpha3- and alpha5-subunits are associated in the same functional nAChRs that provide greater part of response to ACh in the most of submucosal neurons. However, in some neurones alpha7-containing nAChRs provide greater part of response to agonist.
Brown Norway (BN) rats are much less susceptible to experimental allergic encephalomyelitis (EAE) than Lewis rats. Nevertheless, BN rats developed severe EAE, even paralysis, when immunized with rat spinal cord and carbonyl iron adjuvant. Complete Freund's adjuvant (CFA) was much less effective. The use of both CFA and pertussis vaccine with rat cord was moderately, but not consistently, effective. Guinea pig spinal cord was weakly encephalitogenic to BN rats with all adjuvant combinations. We were not able to produce EAE in BN rats with purified myelin basic protein from either rat or guinea pig. Inoculations directly into lymph nodes or into the blood stream proved that the low susceptibility of BN rats was not due to lack of absorption from the site of inoculation, but may be related to peculiarities of processing antigen in draining lymph nodes. The severity of EAE in F1 hybrids was intermediate between the BN and Lewis parental strains when tested with an immunizing procedure of appropriate strength. The fact that F1 hybrids were less reactive than Lewis mandates modification of the theory that susceptibility to EAE is inherited through a single autosomal dominant gene.