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R Kovacević

Publications and source records attributed to R Kovacević.

At least 19 recordsLinked to original sources
PubMed2001

New D-modified androstane derivatives as aromatase inhibitors.

Starting from a 16-oximino derivative of 5-androstene the newly-synthesized 16-oximino-17-hydroxy-17-substituted derivatives 2-4 gave by the Beckmann fragmentation reaction the corresponding D-seco derivatives 6-9. Besides, in the case of the 17-hydroxy-17-methyl-16-oximino derivative 2, as a result of the rearrangement, the hydrolysis product 5 of the 16-oximino group with the opposite configuration at the C-17 was obtained. By the Oppenauer oxidation and/or by dehydration of 7 with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), the corresponding derivatives 12, 13, and 14 were obtained. The structures of 6 and 12 were unambiguously proved by the appropriate X-ray structural analysis. Kinetic analysis for anti-aromatase activity showed that compound 12 expressed the highest inhibition in the denucleated rat ovarian fraction in comparison to other androstene derivatives (IC(50) was 0.42 microM). In comparison to aminoglutethimide (AG) activity, it was 3.5 times lower. The inhibition was competitive, with K(i) of 0.27 microM. Introduction of additional units of unsaturation (compounds 13 and 14) in D-seco derivatives did not increase anti-aromatase activity.

Androstanes↗
PubMed1998

The involvement of nitric oxide in stress-impaired testicular steroidogenesis.

The participation of the nitric oxide (NO) pathway in downregulation of testicular steroidogenesis in normal and stressed rats was investigated both in vivo and in vitro. In Leydig cells from normal animals, isosorbide dinitrate, an NO donor, decreased the human chorionic gonadotropin (CG)-stimulated and progesterone-derived androgen production. Also, the intratesticular injection of a precursor of NO, arginine (10 mg/testis), transiently decreased serum androgen levels and inhibited human CG-stimulated androgen production in acute testicular cultures. These effects were eliminated in rats cotreated with Nomega-nitro-L-arginine methyl ester (L-NAME) (2 X 600 microg/each testis). Acute immobilization stress (2 h) decreased serum androgen levels and inhibited human CG-stimulated androgen production in vitro. These effects were accompanied by a significant increase in nitrite, a stable oxidation product of NO, in testicular cultures. Bilateral intratesticular injection of L-NAME prevented the stress-induced decrease of human CG-stimulated androgen production, and significantly reduced the nitrite levels. These results implicate NO in normal and stress-impaired testicular steroidogenesis.

Animals↗
PubMed1998

Management of war penetrating craniocerebral injuries during the war in Croatia.

From September 1991 to December 1992, during the war in Croatia, the General Hospital in Slavonski Brod served as an evacuation centre. During that period 197 patients with war-related penetrating craniocerebral injuries were admitted. They were analyzed according to wound characteristics, operability, mortality, operative and post-operative complications, and their condition after hospital discharge and follow-up. A less aggressive surgical approach was accepted in our surgical strategy, recommended in recent studies, followed by an aggressive intensive management. All patients received antibiotics ("war scheme") and anticonvulsants. Early results of treatment do not differ significantly from other recent studies (Vietnam, Israel) in respect to both mortality and complications. Follow-up was difficult. Most of the patients were Bosnia and Herzegovina citizens who were refugees and banished to foreign countries; thus their addresses were unknown. They are consequently lost to follow-up. A less aggressive surgical approach proved to be justified. Routine use of antibiotics and anticonvulsants lowered the infection rate and early seizure incidence to an acceptable level. Late seizure incidence is similar to those previously reported.

Adolescent↗
PubMed1998

The effect of acute stress and opioid antagonist on the activity of NADPH-P450 reductase in rat Leydig cells.

Previous studies indicate that acute immobilization stress (IMO; 2 h) impaired testicular steroidogenesis primarily at the testicular level decreasing the activity of certain steroidogenic enzymes. In the present study unstressed rats as well as IMO rats (2 h) were treated by intratesticular injection of naltrexone methobromide (NMB; peripheral opioid receptor antagonist; 36 microg/testis) or vehicle at the beginning of and at 1 h of the IMO period. In IMO rats the activity of P450c17 was significantly reduced as well as the activity of NADPH-P450 reductase (which catalyzes the transfer of electrons from NADPH to cytochrome P450), while the activity of NADH-b5 reductase was not affected. Present data confirmed previous results that acute IMO reduced testicular P450c17 activity and implicate that decreased activity of NADPH-P450 reductase could be responsible for the inhibition of P450c17 under IMO conditions, while NADH-b5 reductase is probably not involved. NMB treatment antagonized the inhibitory effect of IMO on P450c17 and NADPH-P450 reductase activities. Such results put forward the implication that endogenous opioid peptides are involved in mediating the inhibitory effect of IMO on testicular steroidogenesis, and allow the speculation that NADPH-P450 reductase could be a possible site of such an inhibition.

17-alpha-Hydroxyprogesterone↗
PubMed1997

The effect of opioid antagonists in local regulation of testicular response to acute stress in adult rats.

The present study examined the effects of naloxone (N) and naltrexone-methobromide (NMB; an opioid receptor antagonist that does not cross the blood-brain barrier) on testicular steroidogenesis during acute immobilization stress (IMO; 2 h) in adult rats. Unstressed rats as well as IMO rats were treated by unilateral intratesticular injection of N (20 micrograms/testis), NMB (36 micrograms/testis), or vehicle at the beginning of and at 1 h of the IMO period. In IMO rats serum T levels were significantly reduced, while serum luteinizing hormone levels were not affected. N and NMB normalized serum T levels in IMO rats and had no effects in controls. In IMO rats the activities of 3 beta-hydroxysteroid dehydrogenase (HSD) and P450(17 alpha, lyase) were significantly reduced, while the activity of 17 beta-HSD was not affected. N and NMB antagonized the inhibitory effect of IMO on 3 beta-HSD and P450(17 alpha, lyase) but did not alter enzyme activity in freely moving rats. Acute IMO decreased basal and human chorionic gonadotropin-stimulated androgen production by hemitestis preparation, but N (10(-4) M) added directly to the incubation medium blocked the decrease and had no effect on testes from freely moving control rats. These results support the conclusion that endogenous opioid peptides are potentially important paracrine regulators of testicular steroidogenesis under stress conditions.

3-Hydroxysteroid Dehydrogenases↗
PubMed1996

Effects of acute and chronic immobilization stress on rat Leydig cell steroidogenesis.

In rats, acute immobilization (IMO) stress (2 h) induced a fall in the serum androgen concentrations (T+DHT) without detectable changes in serum luteinizing hormone (LH) values. In vitro studies, using a suspension of Leydig cells from adult rat testis, demonstrated that acute stress inhibited conversion of progesterone (P) or 17hydroxyprogesterone (17OHP) to T while conversion of androstendione (delta 4 A) was not affected. Acute IMO reduced activity of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) and decreased basal and hCG-stimulated progesterone and androgen production. Chronic IMO stress (2 h daily for 10 days) induced a decrease in serum androgen level with decline in serum LH values. In vitro, hCG-stimulated progesterone and androgen production by suspension of Leydig cells, as well as conversion of P and 17OHP to T were not significantly altered. Our data demonstrates that acute IMO stress impaired testicular steroidogenesis primarily at the testicular level (decreasing the activity of certain enzymes), while chronic IMO stress exerts the effect mainly on the hypothalamic-pituitary axis; reduced serum LH levels elicit a decrease in serum androgen levels.

Animals↗
PubMed1995

Effect of PCBs on androgen production by suspension of adult rat Leydig cells in vitro.

The effects of PCBs (mixture of 2, 3, 4, 5-tetra; 2, 2', 4, 5, 5'-penta; 2, 2', 3, 3', 6, 6'-hexa and 2, 2', 3, 3', 4, 4', 5, 5'-octa congeners) on androgen production were investigated by suspension of Leydig cells from adult rat testis. hCG-stimulated androgen production was significantly inhibited by PCBs while progesterone level was not affected. Progesterone supported testosterone production was also decreased by PCBs, while conversion of androstenedione to testosterone was unchanged. These results suggest that the activity of microsomal enzyme C21 side-chain cleavage P450 was decreased by PCB treatment of Leydig cells in vitro.

Androgens↗
PubMed1987

Developmental pattern of the testicular androgen response to gonadotrophin stimulation in vitro and its modification by chronic hypoprolactinaemia.

Developing male rats were treated chronically with bromocriptine (BR, 3 mg/kg b.w. daily) to maintain severe hypoprolactinaemia throughout postnatal development. This treatment induced a precocious increase in Leydig cell numbers per testis and caused substantial, but age-dependent, modifications of the androgenic responsiveness of incubated hemi-testis preparations to stimulation with hCG. Most conspicuous were: (i) a decrease in sensitivity of the testis to hCG at the approach of adult age (due presumably to reduced responsiveness of the Leydig cells), and (ii) a precocious increase in the steroidogenic maximum of the testis at peripubertal age. This probably resulted from the precocious increase in Leydig cell numbers, which was able to mask the negative consequences of reduced androgenic capacity per Leydig cell. The precocious increase in number of Leydig cells induced by hypoprolactinaemia could have resulted from facilitation of the proliferative action of the high prepubertal LH levels on Leydig cell numbers. There were no clear-cut indications for an important effect of BR-induced changes in LH levels, or of a direct effect of BR on the testis.

Androgens↗
PubMed1987

Rapid naloxone-induced alterations of androgen variables in the growing male rat.

Contrary to earlier views on the inability of naloxone to affect androgen variables by way of general circulation, systemically applied naloxone (2.5 mg/kg body weight, single i.p. or i.v. injection) has been shown to rapidly induce (within an hour) a significant fall (-35.7% on the average) of the concentration of serum androgen (testosterone and dihydrotestosterone; (T + DHT) in peripubertal rats (51-58 days old). Such a response to the opiate antagonist was absent, however, in low-androgen prepubertal animals (37-44 days old) and in those among peripubertal rats which still showed subcritical initial levels of androgen in circulation (less than 1.5 ng/ml; experiments with repeated blood sampling in catheterized animals). In peripubertal rats naloxone was also shown to induce a significant decrease (-36%) in basal in vitro androgen production by testes removed 15 or 30 min following the intraperitoneal administration of the opiate antagonist. Such an inhibitory effect on basal steroidogenesis has not been observed in control multiple-dose experiments in which incubated testes from naloxone-naive rats have been directly challenged with naloxone; on the contrary, enhancing direct effects were recorded, but only with the highest concentration of naloxone tested (10(-4) M). The possibility thus remains open that indirect inhibitory effects of injected naloxone may be operational in intact animals. Hypoprolactinemia, known to interfere in an age-dependent manner with the responsiveness of Leyding cells to luteinizing hormone (LH), may be of particular relevance.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1982

Effects of bromocriptine-induced hypoprolactinaemia on the developmental pattern of androgen and LH levels in the male rat.

In immature male rats, receiving daily injections of bromocriptine (3 mg/kg bw), serum prolactin (Prl) remains low throughout development. In such hypoprolactinaemic males androgen variables are affected: a) the normally low pre-pubertal serum androgen (testosterone, dihydrotestosterone-T, DHT) is considerably increased, in correlation with a precocious development of the testicular Leydig cell population; b) the peri-pubertal rise of androgen is not prevented, but is is followed by significantly lower post-pubertal T, DHT levels, in correlation with moderately reduced Leydig cell counts and with strongly attenuated growth rates of sex accessory organs. Observed alterations of the post-natal androgen pattern cannot be related to LH changes since developmental LH values remained essentially unaltered. Results are in concordance with a marked age-dependent sensibility of androgen variables to a lack of Prl in the developing male.

Androgens↗
PubMed1982

[Peripelvic cyst of the kidney].

There is discussion of a peripylonic cyst of the kidney as a very rare disease difficult to diagnose before operation. A cyst is most frequently as an expansive kidney process i.e. kidney tumor. Demonstrating the diagnostic procedures, the authors, by presentation of one of 3 cases, evaluate the value of each procedure separately and stress that the echotomographic procedure is the most reliable in the estimating of the parenchimal structure of the expansive process. However, an absolutely exact preoperative diagnosis is not yet possible, and remains to be established on the basis of the kidney changes in the course of the operation. The authors point out that the exact nature of disease in all their 3 cases was established only by operation.

Adult↗
PubMed1980

Sleep-waking cycle and behaviour after diethyldithiocarbamate in the rat.

Young adult Louis rats were implanted for chronic sleep recording to test the effect of diethyldithiocarbamate (DDC) on sleep. Recordings of EEG and EMG were done continuously for 12 h during the 12 consecutive days. There were 2 days of baseline recording, 3 days of recording with a single daily injection of placebo, 3 days of recording with a single daily injection of DDC (500 mg/kg i.p.), and 3 days of DDC withdrawal recording with placebo injection. Placebo injections did not change the proportion of time spent in different behavioural states. With daily injection of DDC there was an increase in wakefulness, no change in slow-wave sleep and elimination or drastic reduction in paradoxical sleep (PS). There was no PS rebound during the DDC withdrawal days. These results suggest that the reduction of PS produced by DDC and the absence of PS rebound may be due to a lowering in norepinephrine in the brain. In other experiments rats were injected with DDC (500 mg/kg i.p.) daily for 3 days and whole brains were analysed chemically. Norepinephrine was significantly decreased, while 5-hydroxytryptamine, 5-hydroxyindolacetic acid, dopamine and homovanilic acid were unchanged. Seizure activity appeared during relaxed wakefulness in all rats treated with DDC. Taken together it seems that lowering of brain NE is responsible for the appearance of seizure activity and also, for PS reduction. PS reduction might, per se, produce seizure activity.

Animals↗
PubMed1977

Effects of clozapine (Leponex) on sleep patterns in the cat.

This study examined the effects of clozapine on sleep-wakefulness profile in cats prepared for chronic recording of sleep. Clozapine in single dose (i.p.) of 5 mg/kg drastically reduced slow-wave sleep (SWS) and paradoxical sleep (PS), while wakefulness and drowsy pattern were increased. These changes lasted approximately 24 h and were followed by sleep recovery. PS had a priority of recovery. Some similarities between clozapine effects on sleep in cat and human were mentioned.

Animals↗