Synthesis of some carbon-3 substituted 1,4-benzodiazepin-2-ones and their central nervous system effects.

Starting from 3-hydroxy-1,4-benzodiazepin-2-ones 1--3, via 3-chloro derivatives 4--6, 13 new C(3)-substituted 1,4-benzodiazepin-2-ones were synthesized. Reaction of 4--6 with ethylene glycol yielded 3-(beta-hydroxyethyl) derivatives 7--9. Similar reaction with the isopropylidene derivative of glycerol afforded 10--12, which on hydrolysis of the isopropylidene group hielded glycerol derivatives 13--15. Reaction of trichloroacetyl chloride with oxazepam and temazepam yielded the corresponding trichloroacetyl esters 16 and 17. The beta-hydroxyethyl derivative 7 was conjugated with an acetylated glucopyranose derivative to give isomeric 18 and 19. Partition coefficients (log Poct) and central nervous system activities (in six stranded tests) were determined for 7--15 as well as several standard compounds. Most of the compounds exhibiting beneficial central nervous system activity had Poct values between 1.71 and 2.48. No correlation between lipophilicity and central nervous system activity could be discerned for these compounds.

The chemical and biogenotoxic characterization of organic xenobiotics in aquatic sediment materials 1. The application and comparison of chemically non-specific and biogenotoxic methods.

The aim of this work was to evaluate the Ames assay and mixed function oxidase (MFO)-Induct Test used in parallel with chemical group tests (ECD fingerprint and PAH estimation) for the characterization of the organic pollution of water sediment materials. Sediment materials were collected from "clean" and relatively heavily polluted locations in the Middle Adriatic Sea, and from some locations in continental Croatia polluted with wastewaters from different enterprises. Characterization of the organic extracts of the sediment materials investigated was performed chemically using UV spectrofluorometry for the determination polyaromatic hydrocarbons (PAH) and gas chromatography for the determination of volatile EC detector sensitive materials. Genotoxic analysis of the extracts was performed using the MFO-Induct Test and mutagenicity testing using the Standard Plate Incorporation Test as described by Maron and Ames with Salmonella typhimurium TA 98. Measurement of the BaPMO enzyme activity in the livers of carp treated i.p. with total extracts of the sediment investigated confirmed that the methanol extracts generally contained more inducing matter than the petroleum ether extracts. Ames assay showed that for all the samples following the elimination of the sulfur, there was an increase in the number of revertants in comparison to the control number, which indicates that the samples contained mutagenic substances. The larger doses of extracts generally demonstrated cytotoxicity, as evidenced by a reduced number of spontaneous revertants in the SalmonellalMicrosome Test. Investigation of the correlation of the chemical parameters with the biological parameter showed that the induction of BaPMO exhibited a statistically significant correlation with the level of the ECD fingerprint of the petroleum ether sediment extract.

[Olfactory disorders in hypogonadism]. / Ofaktorische Störungen beim Hypogonadismus

On the basis of the study and particularly of the examination of the ofactive functions in three patients with hypogonadismus the relationship between the olfactive and the endocrine lesions is established. This syndrome, described by Kalmann and by De Morsier is not well known, but it deserves attention since it is indicative of pathologic changes in the region which lies between the hypothalamus and the hypophysis.

Organization and work of the War Hospital in Sturba near the town of Livno, Bosnia and Herzegovina.

The work of the Croatian Defense Council (armed forces of the Croatian citizens of Bosnia and Herzegovina) War Hospital at Sturba, outskirts of the town of Livno, is described. The hospital was established in the beginning of April and worked until September 1992. It provided services for the battlefield of approximately 100 km of a very difficult mountainous terrain. The hospital was situated in a concrete dugout taken from the Yugoslav Federal Army. It was well equipped and supplied exclusively by numerous donations. Medical personnel were recruited partly from local medical professionals and partly from volunteers from Croatia. During the 5-month period, 597 patients (571 soldiers and 26 civilians) were admitted. A total of 314 operations, 141 in general and 173 in regional anesthesia, were performed. None of the patients died in the hospital. There was not a single epidemic either among soldiers or civilians in the area.

NATO war medicine doctrine revisited in Bosnia and Herzegovina.

NATO war medical doctrine was applied in the war in Croatia, Bosnia and Herzegovina. However, due to rather specific martial and organizational circumstances, the doctrine had to be modified. sometimes substantially. A medical team from the war hospital in Livno, Bosnia and Herzegovina describes their work with respect to the four-echelon NATO doctrine. The team covered a relatively large and active battlefield, and treated 597 patients with 314 major surgical interventions. Due to the lack of surgeons and medical personnel in general, the second echelon concentrated on fast transportation, and the third echelon fulfilled the function of the fourth echelon, completing the surgical treatment except for 12 patients with head and spine injuries.

[The erythrocyte sedimentation test (part 2)]. / O testu sedimentacije eritrocita (drugi deo)]

The article deals with progression in the knowledge about erythrocyte sedimentation, and factors responsible of their sedimentation. Problems in the interpretation of results are also emphasized, as well as relation between some diseases and erythrocyte sedimentation velocity. Test indications are enumerated.

[On the 185th anniversary of the birth of David Gruby (1810-1898)]. / Povodom 185-godisnjice rodenja David Gruby (1810-1898).

David Gruby, the founder of Medical Microbiology, is better known abroad than in his homeland. The Yugoslav public has no knowledge of him and only a small number of physicians have heard of David Gruby and his contribution to medicine. At the beginning of his career he was a passionate explorer and later a very well known practitioner. Although he had lived abroad during his active period of life, he had never denied his origin and considering his contribution to science, he and his work deserve to be known about more at least among physicians.

[Inhibin and its characteristics]. / Inhibin i njegova svojstva.

On the basis of data from current literature a survey of the new hormone, inhibin, and its characteristics, is given, particularly with respect to its role in the regulation of fertility. There were also enumerated its other features and possibilities of its use in diagnostical and other practical purposes.

[Alzheimer's disease from the aspect of hormonal and metabolic disorders]. / Alzheimerova bolest sa stanovista hormonskih i metabolickih poremecaja.

Some facts of metabolical disturbances and functional changes of brain tissue hormones in Alzheimer's disease are reviewed. Characteristics of aetiopathogenesis, clinical picture and diagnostics are referred with observations on sociomedical importance of the disease. From the known data it can not yet be concluded if these changes are a cause or outcome of the illness.

[The effect of synthetic gonadotropin releasing hormone on the plasma levels of FH and LSH in women with hirsutism and polycystic ovaries]. / Uticaj sintetskog rilizing hormona za gonadotropine na nivo LH i FSH u plazmi u zena sa hirzutizmom i policisticnim ovarijumima.

GN-RH test was performed in 33 women with hirsutism and irregular menstrual cycles. Fourteen patients had polycystic ovary syndrome (PCO) and 19 had idiopathic hirsutism (IH). In the control group, there were 5 healthy women with regular menstrual cycles. Absolute cumulative increase of LH as significantly higher in the examinees with hirsutism than in the control group. A significantly higher net increase of LH was found only in the PCO group. However, absolute and net increase of FSH in examinees with hirsutism did not significantly differ from that in the control group. Patients with PCO had a significantly higher increase of FSH than the IH group. Only the PCO group had a significant correlation between basal LH and LH increase during the test. It was found that patients with hirsutism and irregular menstrual cycles had an increased reactivity of the hypophysis to a direct stimulation with synthetic GN-RH. The degree of disfunction of the gonad axis in women with PCO is significantly higher than in patients with IH.

Regional and international comparison in utilization of antidiabetic drugs.

Data are expressed in the comparable manner through the method of defined daily doses (DDD), which has been adopted for drugs in our country according to the internationally agreed method of drug utilization [Stanulovic et al. 1981]. Together with Iceland, Novi Sad had the lowest insulin utilization in 1976, the rate being 1.7 DDD/1000 inhabitants per day. Insulin was used 7.2 times less than in Sweden. However, the utilization of biguanide of 6 DDD/1000 inhabitants per day was 10 times greater than in other European countries. Prescribing rate of preparations of sulfonylurea in Novi Sad was high (8.2 DDD/1000 inhabitants per day); only Sweden came closer to these values. Causes contributing to these differences could be found in the relation between juvenile diabetes and adult onset diabetes as well as in physicians' attitudes towards therapy, in nutritional status and degree of obesity in the population, age structure of population, number of dietitians in the diabetological service, etc. Diabetologists and clinical pharmacologists should explain causes leading to these differences and determine side effects of available antidiabetic drugs, either positive or negative, in order to enable their optimum utilization.

Glucocorticoid receptor-Hsp90 interaction in the liver cytosol of cadmium-intoxicated rats.

The influence of cadmium on the rat liver glucocorticoid receptor (GR) binding capacity, on the cytosolic level of 90 kDa heat shock protein (Hsp90), and on the association of the two proteins was investigated. The results showed that the mode of metal application led to diverse alterations in hormone binding to the GR. Reduction of the GR binding capacity observed after in vitro treatment was proportional to the applied metal concentrations. In animals administered different doses of cadmium, GR binding capacity was not reduced, except in those that received the highest dose. A concomitant elevation of Hsp90 level was detected both in the cytosol and within the GR untransformed heterocomplexes. The results suggest that cadmium-induced reduction of the GR binding capacity seen in vitro was prevented in intact animals by the elevated level of Hsp90 within the GR heterocomplexes.

Synthesis and properties of some new 11-acyl-5,11-dihydro-6H-pyrido [2,3-b] [1,4]-benzodiazepin-6-ones.

The synthesis of 11-acyl-5,11-dihydro-6H-pyrido [2,3-b]-[1,4] benzodiazepin-6-ones (III), (V-IX), is described as well as their spectroscopic characteristics, dipole moments and partition coefficients. The same properties are determined for their N-oxide analogues (X) and (XI), while pharmacological data for some of the above compounds are compared with those of pirenzepin (I), a well known antiulcer drug.