Synthesis and pharmacological activity of new carbonyl derivatives of 1-aryl-2-iminoimidazolidine: part 2. Synthesis and pharmacological activity of 1,6-diaryl-5,7(1H)dioxo-2,3-dihydroimidazo[1,2-a][1,3,5]triazines

Synthesis and pharmacological activity of 1,6-diaryl-5,7(1H)dioxo-2,3-dihydroimidazo-[1,2-a][1,3,5]triazines (C) are presented. The title compounds were obtained from 1-arylimidazolinurea derivatives in cyclization reaction with difunctional carbonyl reagents--phosgene (method I) or carbonyldiimidazole (CDI) (method II). Their molecular structures were confirmed by the X-ray analysis of 1-phenyl-6-(4-chlorophenyl)-5,7(1H)-dioxo-2,3-dihydroimidazo[1,2-a][1,3,5]triazine (C2) crystals. Compounds C exhibited significant depressive action on the central nervous system (CNS) of the laboratory animals, correlated with very low acute toxicity (LD(50) > 2000 mg kg(-1) i.p.), and showed antinociceptive activity in behavioural models. Reversion of this effect by small dose of naloxone (5 mg kg(-1)) can suggest opioid-like mechanism of antinociception produced by these and other carbonyl derivatives of 1-aryl-2-iminoimidazolidine. Additionally, an effect on the serotonin neurotransmission pathway was also observed. The receptor mechanism of activity for investigated compounds was confirmed only for the opioid mu receptor in binding affinity assay test. Same tests performed for the serotonin 5-HT(2) and benzodiazepine BZD receptors showed no affinity for tested compounds. The opioid-like and serotonergic activities are similar to these described earlier for chain carbonyl 1-aryl-2-iminoimidazolidine derivatives containing urea moiety, mainly due to similar chemical structure, although compounds C are not able to adopt any of the higher energy conformations of urea derivatives. Rigid location of aromatic ring (Ar') at N6, acting as a spacer blocking any direct access to the carbonyl groups (e.g. through the hydrogen bonding), could be responsible for lack of affinity toward 5-HT(2) expressed in the binding assay test.     

Trimethyltin-evoked neuronal apoptosis and glia response in mixed cultures of rat hippocampal dentate gyrus: a new model for the study of the cell type-specific influence of neurotoxins

We investigated the effects of a potent neurotoxin, trimethyltin (TMT), on mixed neuronal/glial cultures derived from rat hippocampal dentate gyrus. We found that TMT induced neuronal cell death in a concentration dependent manner, which was estimated by microtubule degeneration, hematoxylin histological staining and the TUNEL method. This cell death is most probably of an apoptotic type as suggested by Hoechst staining. In parallel to studies the effects of TMT on neurons, its concentration dependent actions on astroglia and microglia were also examined using GFAP and GS-B4 isolectin as immunocytochemical markers, respectively. We found that neurotoxic concentrations of TMT evoked astrocytic swelling, whereas low, non-cytotoxic concentrations caused changes in microglia morphology characteristic of their active form. The combined results of our studies provide new data concerning the cell type-specific influence of TMT and indicate that the culture of dentate gyrus cells is a feasible in vitro modelforfurther studies of neuronal-glial interaction in response to toxic injury.     

Treatment of surfactant-damaged skin in humans with creams of different pH values

Skin surface has an acidic pH, whereas the body's internal environment maintains a near-neutral pH. The physiological role of the 'acidic mantle' and the function of the pH gradient throughout the stratum corneum remain unexplained. The pH gradient has been suggested to activate enzymes responsible for the maintenance of the skin barrier function and to facilitate the desquamation process in the stratum corneum. The aim of the study was to investigate the influence of pH of a moisturizing cream on barrier recovery in surfactant-damaged human skin. Volunteers had their skin damaged with sodium lauryl sulphate and treated those areas with the cream, adjusted to either pH 4.0 or 7.5. The study did not prove the superiority of a cream of pH 4.0 to a cream of pH 7.5 regarding promotion of skin barrier recovery, since no significant differences (p > 0.05) were found in transepidermal water loss, blood flow and skin capacitance between the treated areas.     

Value of exercise capacity and physical activity in the prevention of cardiovascular diseases—brief review of the current literature

A low level of physical activity and decreased exercise capacity are independent risk factors for cardiovascular and all-cause mortality. The assessment of the level of physical activity and its improvement following preventive procedures is methodologically difficult. In population studies, subjective methods, such as questionnaires, activity records and other somewhat imperfect measures (accelerometers, pedometers, and pulse monitors), are used. Direct and especially indirect assessment of physical capacity with exercise tests has become increasingly more accessible and cheap. Both methods have been proved to have high prognostic value. Assessment of physical capacity enables objectification of information on the level and effects of a subjects physical activity acquired via a questionnaire. Taking into account the above-mentioned issues, the role of the assessment of exercise capacity and its improvement is not adequately appreciated. Routine evaluation of exercise capacity has not been included in the current statements on epidemiology and prevention, even in those with an increased Framingham or SCORE risk index in whom low exercise tolerance has been proved to have an unfavorable influence on prognosis. The importance of an increase in the level of physical activity resulting in an improvement in exercise capacity in different population groups should be verified in the near future, but in our opinion there is indirect but strong evidence that actions to improve exercise capacity should become the main goals in the prevention of cardiovascular and all-cause mortality, such as cessation of cigarette smoking, body weight reduction, correction of lipid and carbohydrate metabolism disturbances, and a decrease in blood pressure.     

Coexistence of Addison-Biermer's anaemia with endocrine glands' dysfunctions

Addison-Biermer's anaemia is an autoimmune disease. It may coexist with other auto-aggressive diseases, precede them or join the other existing autoimmune diseases. It most often accompanies the Hashimoto disease but also may coexist polyglandular autoimmune syndrome (PGA). Three types of PGA are distinguished: PGA1--Blizzard's Syndrome, PGA2--Schmidt's Syndrome, and PGA3. The latter, unlike the remaining ones, is characterized by normal function of adrenal glands. Addison-Biermer's anaemia occurrence may be often difficult to diagnose as coexisting illnesses might ouflage its clinical symptoms. The aim of this paper was to analyse patients with different types of PGA with coexisting Addison-Biermer's anaemia. Group of 24 individuals was analysed: 2 women with PGA1, 10 patients with PGA2, 10 patients with PGA3. In 2 remaining ones PGA was not confirmed. Addison-Biermer's anaemia occurred in 7 patients (2 with PGA2 and 5 with PGA3 syndrome). Decreased concentration of vitamin B12 was diagnosed in 3 individuals among 24 examined patients (1 with type 3 and 2 with type 2), as well in 2 patients with unconfirmed PGA. Addison-Biermer's anaemia was not observed in patients with PGA1. We observed that megaloblastic anaemia occurred characteristic schedule depending on appearance of autoimmune diseases: in PGA2--many years after other immunopathies were found, in PGA3--as first auto-aggressive disease. Our analysis suggests the necessity of detailed check-ups on patients with Addison-Biermer's anaemia, as with time they may develop other diseases, especially hypothyroidism and/or PGA failure. On the contrary, in individuals with thyroid gland diseases and PGA syndromes further checkups should be megaloblastic anaemia-sensitive. In both cases it is important to consider substitutive treatment. The possibility of family coexisting both pernicious anaemia and autoimmune endocrinopathies needs diagnostics of members of the patient's family.     

Some aspects of pharmacotherapy of tinnitus. Compound therapy with Xylocaine and directive counseling--long-term results

29 out of 49 patients, who were treated in 1996-1998 with Xylocaine and directive counselling for their tinitus, were reevaluated. Non of the patients used any other pharmacological treatment of the tinnitus or underwent full tinnitus retraining therapy (TRT) since 10-days treatment with Xylocaine had been completed. Initially 65.3% of patients declared improvement in their tinnitus. After over 5 years of observation success rate decreased to only 41.3%. Since the positive effect of 10-days treatment with Xylocaine and directive counselling was not stable we concluded that tinnitus patients should receive full TRT.