Tianeptine's effects on spontaneous and Ca2+-induced uterine smooth muscle contraction.

Tianeptine is a novel anti-depressant with an efficacy equivalent to that of classical anti-depressants. Additional beneficial effects include neuroprotection, anti-stress and anti-ulcer properties whose molecular mechanisms are still not completely understood but may involve changes in the anti-oxidant defence system. Herein, we have studied the effects of tianeptine on both contractile activity of isolated rat uteri and components of the endogenous anti-oxidative defence system. Tianeptine-induced dose-dependent inhibition of both spontaneous and Ca2+-induced contraction of uterine smooth muscle. The effect was more pronounced in the latter. Tianeptine treatment increased glutathione peroxidase (GSH-Px) and catalase (CAT) activities in spontaneous and Ca2+-stimulated uteri. A significant decrease in glutathione-reductase (GR) activity in both spontaneous and Ca2+-induced uterine contractions after tianeptine treatment indicated a reduction in reduced glutathione and consequently a shift toward a more oxidised state in the treated uteri. In spontaneously contracting uteri, tianeptine caused a decrease in copper-zinc SOD (CuZnSOD) activity. Tianeptine's anti-depressant effects may be accomplished by triggering a cascade of cellular adaptations including inhibition of smooth muscle contractility and an adequate anti-oxidative protection response.

A case of pregabalin intoxication.

Pregabalin, or S-(+)-3-isobutylgaba, is a lipophilic analogue of GABA. Although pregabalin is structurally related to GABA, it is inactive at GABA receptors and does not appear to mimic GABA physiologically. Pregabalin is a potent ligand for the alpha-2-delta subunit of voltage-gated calcium channels in the central nervous system. It is currently being licensed for epilepsy, neuropathic pain, and generalized anxiety disorder. There are few case reports that have demonstrated safety of pregabalin in case of intoxication. We report here a case of pregabalin toxicity with a moderate pregabalin concentration that was successfully managed with conservative treatment only. The case report describes a 54-year-old man who was treated with pregabalin for generalized anxiety disorder. After having experienced a significant stress on a job the patient ingested huge amount of pregabalin (4,2 r) together with bromazepam (21 mg) and chlorimipramine (125 mg). On presentation he was conscious and alert with a stable condition of cardiovascular and respiratory systems. The serum pregabalin concentration was 20.8 mg/L but the patient did not have any signs of toxicity. Thanks to his good and stable somatic condition the patient was managed with supportive treatment only. Although anecdotal, our case report points toward safety of pregabalin following deliberate self-poisoning. Our observation is in accordance with the recent international literature underlining that pregabalin was listed as the drug ingested in only 1% of fatalities, usually in combination with other drugs.

[Manifestations of epileptic seizures after acute cerebrovascular disease]. / Pojava epileptickih napada nakon akutnih cerebrovascularnih bolesti.

The study included 80 patients hospitalized in Intensive Care Unit, in whom was with confirmed the occurrence of seizures after acute cerebrovascular diseases. They were classified according to sex, age, etiopathogenesis of stroke, latence from the onset of cerebrovascular disease to the occurrence of first seizure, hemispheric and intrahemispheric localization of cerebrovascular lesion, and clinical types of seizures.

Suppression of adjuvant arthritis by kappa-opioid receptor agonist: effect of route of administration and strain differences.

It is well established that kappa-opioid receptor agonists exert antiinflammatory and antihyperalgesic effects during nonspecific inflammation as well as suppressive effects on the development of humoral and cell-mediated immune responses to foreign antigens. The aim of this study was to investigate the ability of the kappa-opioid receptor agonist MR 2034 to modulate adjuvant arthritis in the rat. In the first series of experiments, treatments of Wistar rats were performed using several routes of drug administration: intraperitoneal (ip), intracaudal (ic), intracerebroventricular (icv) and intraplantar (ipl). MR 2034 significantly suppressed joint swelling after ip and ic treatment, slightly reduced inflammation after ipl treatment, and did not produce any effect after icv treatment. In the second series of experiments, the suppressive effect of ip injected MR 2034 was investigated using Wistar, Dark August (DA) and Lewis rats. In Wistar rats, MR 2034 significantly decreased the incidence of adjuvant arthritis, and suppressed mean joint score and aggregate joint score. Similarly, in DA rats treated with MR 2034, mean arthritic score was significantly suppressed, but other clinical parameters were not affected. In Lewis rats, however, ip treatment with MR 2034 failed to produce any suppressive effect on joint disease and even potentiated the initial development of arthritis. These data suggest that immunosuppressive and antiinflammatory action of MR 2034 markedly depend on the route of drug administration and strain susceptibility to opioids.

Opioid receptor-mediated suppression of humoral immune response in vivo and in vitro: involvement of kappa opioid receptors.

The selective kappa opioid receptor agonist MR 2034 exerted pronounced suppression of plaque-forming cell (PFC) response following intraperitoneal (i.p.) administration in the rat. Pretreatment with preferential kappa and mu opioid receptor antagonists MR 2266 and naloxone, respectively, revealed that this effect was mediated mainly by kappa, and to a low extent by mu opioid receptors. Intracerebroventricular (i.c.v.) administration of quaternary naltrexone (QNtx) moderately attenuated, whereas i.p. given QNtx completely prevented the suppressive effect of MR 2034, suggesting a peripheral mechanism of action, and only minor involvement of brain opioid receptors. MR 2034 markedly decreased the PFC response of spleen cells obtained from in vivo immunized rats, treated in vitro with the opiate. The immunosuppressive action of MR 2034 in vitro was completely and partially blocked by equimolar concentrations of MR 2266 and naloxone, respectively. Antagonists alone produced stimulation of PFC following i.p. administration in the rat, but did not affect PFC response upon in vitro treatment. These results suggest that peripheral kappa opioid receptors down-regulate primary humoral immune response in the rat, and that this effect may be produced by direct interference with plasma cell activity.

kappa-Opioid receptor functions: possible relevance to experimental allergic encephalomyelitis.

The present study deals with the influence of preferential kappa-opioid agonist MR 2034 on experimental allergic encephalomyelitis (EAE). For this purpose, 9-week-old male Dark August rats were treated intraperitoneally with 0.2 mg/kg of MR 2034 as follows: (a) from the day of EAE induction until sacrifice; (b) from the day of EAE induction until the appearance of neurological signs, and (c) from the appearance of neurological signs until sacrifice. Repeated injections of MR 2034 given during the whole period of observation produced the most pronounced suppression of EAE clinical signs, histological lesions in the brain and spinal cord, and anti-myelin basic protein antibody production. These results suggest that kappa-opioid receptors may be involved in the development of EAE.