Assessment of trazodone-induced cardiotoxicity after repeated doses in rats.

Trazodone (TRZ) is an antidepressant drug commonly used in the treatment of depression, anxiety, and insomnia. Although some studies demonstrated the adverse effects of TRZ related to cardiovascular system, the conflicting results were observed in these studies. Therefore, we aimed to investigate the cardiac adverse effects of TRZ in rats at repeated doses in our study. In accordance with this purpose, TRZ was administered orally to rats at 5, 10, and 20 mg/kg doses for 28 days. Electrocardiogram records, serum aspartate aminotransferase (AST), lactate dehydrogenase, creatine kinase-myoglobin band, cardiac troponin-T (cTn-T) levels, DNA damage in cardiomyocytes, and histologic view of heart tissues were evaluated. In addition, glutathione (GSH) and malondialdehyde (MDA) levels were measured to determine the oxidative status of cardiac tissue after TRZ administration. Heart rate was decreased, PR interval was prolonged, and QRS and T amplitudes were decreased in 20 mg/kg TRZ-administered group compared to the control group. Serum AST and cTn-T levels were significantly increased in 10 and 20 mg/kg TRZ-administered rats with respect to control rats. DNA damage was significantly increased in these groups. Additionally, degenerative histopathologic findings were observed in TRZ-administered groups. Although there was no difference in MDA levels between groups, GSH levels were significantly decreased in 10 and 20 mg/kg TRZ-administered groups compared to the control group. Our results have shown that TRZ induced cardiotoxicity in rats dose-dependently. It is assumed that oxidative stress related to GSH depletion may be accompanied by these adverse effects.

Reproductive toxic effects and possible mechanisms of zonisamide in male rats.

Zonisamide (ZNS) is an anticonvulsant which is used to treat the symptoms of epilepsy. Although it is frequently used during reproductive ages, studies that investigated the effects of ZNS on reproductive system are limited. Therefore, we aimed to assess the effects of ZNS on male reproductive system by oral administration to rats in 25, 50, and 100 mg/kg doses for 28 days. After the exposure period, sperm concentration, motility, morphology, and DNA damage, as biomarkers of reproductive toxic effects, were determined, and histopathological examination of testis was performed. In addition, levels of the hormones that play a role in the regulation of reproductive functions, such as follicle-stimulating hormone, luteinizing hormone (LH), and testosterone were measured and the levels of oxidative stress biomarkers that take part in the reproductive pathologies such as catalase, superoxide dismutase, glutathione, and malondialdehyde, were determined. Reproductive toxic effects related to ZNS administration were shown by the significant decrease of sperm concentration and normal sperm morphology in ZNS groups. Additionally, pathological findings were observed in the testicular tissues of ZNS-administered groups dose dependently. In addition, serum LH and testosterone levels were significantly decreased in the ZNS groups. Decreased catalase activities and increased malondialdehyde levels in ZNS groups were evaluated as oxidative stress findings in the testis tissue. It could be expressed that ZNS administration induced dose-dependent reproductive toxic effects in rats, and pathological findings associated with the reproductive system could be the result of that hormonal changes and testicular oxidative stress, which in turn might be considered as possible mechanisms of male reproductive toxicity.

Evidence for neurotoxicity associated with amoxicillin in juvenile rats.

Amoxicillin (AMX) is one of the most commonly prescribed antibiotics for children, and childhood is the period to have the highest risk for toxicity cases including drug-induced adverse reactions. Some neurological adverse effects (anxiety, hyperactivity, confusion, convulsions, and behavioral changes) have been reported related to AMX treatment. In the present study, we aimed to determine the neurotoxic effects of AMX administration at clinically relevant doses in female juvenile rats. AMX was administered in single oral daily doses of 25 and 50 mg/kg for 14 days. According to our results, while AMX administration caused a significant increase in the immobility time of animals, swimming time of these animals significantly decreased. AMX administration significantly reduced the onset of pentylenetetrazole-induced convulsions. The serotonin levels of brain tissues in the AMX-administered groups were decreased significantly, which is thought to be related to depression. The glutamate levels in brain tissues increased significantly in AMX-administered groups, which is thought to be related to convulsion. Otherwise, superoxide dismutase and catalase activities were significantly decreased in brain tissues of AMX-administered groups. In conclusion, AMX administration triggered depression and shortened the time of the appearance of first seizure in juvenile rats. Also, altered brain neurotransmitter levels and increased oxidative stress observed in our study were thought to be the possible underlying mechanisms of AMX-induced neurotoxicity.

Evaluation of the reproductive toxicity of naproxen sodium and meloxicam in male rats.

Nonsteroidal anti-inflammatory drugs that are cyclooxygenase (COX) enzyme inhibitors have generally been used in short-term pain management and also to treat inflammation chronically. It is known that COX enzyme and prostaglandins play important roles in the regulation of reproductive functions in females. However, there are relatively few studies for the male reproductive system, and the results of these studies are contradictory. In this study, sperm count and motility, COX-1, COX-2, prostaglandin E1 (PGE1), prostaglandin E2 (PGE2), and prostaglandin F2α (PGF2α) levels in testis tissue, plasma follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone levels, and histopathological examination of testis tissue were evaluated after naproxen sodium and meloxicam administration in male rats. Also, testis superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and glutathione (GSH) levels were measured to investigate the oxidation status. According to our results, sperm count and motility were significantly decreased in treatment groups. Plasma hormone levels did not show any statistical differences between the groups. COX-1, PGE2, and PGF2α levels were significantly decreased, while the decreases in COX-2 and PGE1 levels did not show any significance statistically. Testis SOD, catalase, GPx, and GSH levels were decreased significantly. According to the results of histopathological examination, damage in seminiferous tubules, where spermatogenesis developed, was observed. In conclusion, naproxen sodium and meloxicam decreased the sperm count and motility and also induced the damage of seminiferous tubules as a direct effect without affecting plasma hormone levels in our study. The mechanism of the reproductive toxicity induced by these agents may be based on the inhibition of prostaglandin synthesis and the induction of oxidative stress can be emphasized as a secondary factor.

Degree of thyrotropin suppression in differentiated thyroid cancer without recurrence or metastases.

Forty-eight patients with differentiated thyroid cancer (DTC), who had no evidence of tumor recurrence or metastases on studies such as radioiodine scanning, neck ultrasonography, and with thyrotropin (TSH) and thyroglobulin (Tg) levels less than 1 mU/L and 5 ng/mL, respectively, were included in the study. The mean age was 43 +/- 12 years (range 15-65) and all were receiving levothyroxine (LT4) treatment with a mean dose of 184 +/- 46 microg daily. Patients were divided into two groups; group A included patients that had baseline TSH levels of 0.4 mU/L or more, and group B patients had baseline TSH levels of less than 0.4 mU/L. LT4 doses for all patients were increased, and serum TSH and Tg measurements were reevaluated after 2 months of dose increments. The mean TSH of group A (patients with baseline TSH levels > or = 0.4 mU/L) decreased from 0.67 +/- 0.28 mU/L to 0.16 +/- 0.08 mU/L (p < 0.001), but mean serum Tg level showed no change after dose increments (2.92 +/- 1.36 ng/mL vs. 3.59 +/- 0.93 ng/mL at the second month; p > 0.05). Similar results were also observed in group B (patients with baseline TSH levels < 0.4 mU/L). Mean TSH level decreased from 0.26 +/- 0.07 mU/L to 0.1 +/- 0.05 mU/L (p = 0.006), but no decrease occurred in mean Tg level (3.0 +/- 1.16 ng/mL vs. 3.3 +/- 1.03 ng/mL; p > 0.05). The patients' data were reevaluated according to second-month TSH levels. Patients with a TSH level between 0.11 to 0.4 mU/L were set as "final TSH > 0.1 group," and patients with a TSH level equal or less than 0.1 mU/L were set as "final TSH < or = 0.1 group," and baseline and second-month Tg levels were assessed. The mean second month Tg levels did not differ in these two patient groups (3.7 +/- 0.74 ng/mL for final TSH > 0.1 group vs. 3.3 +/- 1.2 ng/mL for final TSH < or = 0.1 group; p > 0.05). No difference could be found between initial and second-month Tg levels in both groups (2.8 +/- 1.4 ng/mL vs. 3.7 +/- 0.74 ng/mL in final TSH > 0.1 group and 3.11 +/- 1.1 ng/mL vs. 3.3 +/- 1.2 in final TSH < or = 0.1 group; p > 0.05). In conclusion, these results indicate that serum Tg levels cannot be suppressed by maximal TSH suppression in tumor-free DTC patients. The suppression of TSH to less than 0.1 mU/L seems not to be necessary in most patients who have no evidence of active disease.

The effects of gender difference on monocrotaline-induced pulmonary hypertension in rats.

The present study aimed to compare the effect of gender difference on hemodynamic consequences in the development of monocrotaline (MCT)-induced pulmonary hypertension in rat. The effect of antioxidant enzyme systems on the development of pulmonary hypertension mediated by the phytotoxin MCT and the effect of gender on these antioxidant systems were also investigated. For this purpose, the right ventricular pressures (RVPs) and right ventricular/heart weight (HW) ratios were compared between groups and the glutathione (GSH) level and superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST) activities were determined in lung and liver tissue samples of rats. RVP and right ventricular/HW ratios significantly increased in the MCT group compared to the control group. In the MCT group, RVP was significantly higher in males than females. MCT-induced pulmonary hypertension resulted in decreased GSH level, decreased GST and SOD activities and increased CAT activity in lung and liver tissues of both male and female rats. In addition, the lung and liver GSH level and GST and SOD levels were higher in female control rats compared to male control rats. The results of the present study, that antioxidant enzyme activities were different between the groups, highlight the possible role of oxidative stress in the pathogenesis of MCT-induced pulmonary hypertension in rats. Moreover, the lower antioxidant defense capacity of male rats than female rats may be considered as a cause of more aggressive course of MCT-induced pulmonary hypertension in males compared to females.

The effects of gender difference on monocrotaline-induced pulmonary hypertension in rats.

The present study aimed to compare the effect of gender difference on hemodynamic consequences in the development of monocrotaline (MCT)-induced pulmonary hypertension in rat. The effect of antioxidant enzyme systems on the development of pulmonary hypertension mediated by the phytotoxin MCT and the effect of gender on these antioxidant systems were also investigated. For this purpose, the right ventricular pressures (RVPs) and right ventricular/heart weight (HW) ratios were compared between groups and the glutathione (GSH) level and superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST) activities were determined in lung and liver tissue samples of rats. RVP and right ventricular/HW ratios significantly increased in the MCT group compared to the control group. In the MCT group, RVP was significantly higher in males than females. MCT-induced pulmonary hypertension resulted in decreased GSH level, decreased GST and SOD activities and increased CAT activity in lung and liver tissues of both male and female rats. In addition, the lung and liver GSH level and GST and SOD levels were higher in female control rats compared to male control rats. The results of the present study, that antioxidant enzyme activities were different between the groups, highlight the possible role of oxidative stress in the pathogenesis of MCT-induced pulmonary hypertension in rats. Moreover, the lower antioxidant defense capacity of male rats than female rats may be considered as a cause of more aggressive course of MCT-induced pulmonary hypertension in males compared to females.

The effect of combination therapy on the plasma concentrations of traditional antiepileptics: a retrospective study.

The present study aimed at determining the differences in plasma concentrations of traditional antiepileptics such as phenytoin, carbamazepine, and valproic acid in patients receiving monotherapy and combination therapy. In addition, the effect of gender and age on plasma drug concentration was evaluated in these patients. For this purpose, plasma trough concentrations obtained during routine therapeutic monitoring of these drugs were assessed retrospectively. The average plasma concentrations reached the apparent therapeutic ranges, except for the average plasma concentration of phenytoin, which was below the therapeutic range in patients who received only phenytoin or in combination with the other agents. Phenytoin when combined with carbamazepine or valproic acid significantly decreased the average plasma concentrations of these drugs to subtherapeutic concentrations. The results showed that plasma carbamazepine concentrations were higher in men than in women, whereas plasma concentrations of valproic acid and phenytoin were higher in women than in men. The difference in this regard between men and women was found to be statistically significant for phenytoin. The difference between the average plasma concentrations of carbamazepine, phenytoin, and valproic acid among age groups was not significant. In conclusion, our study measured the average plasma antiepileptic drug concentrations in patients with epilepsy who were receiving monotherapy and combination therapy and were routinely monitored, and has thus shown the importance of drug monitoring in the evaluation of the effectiveness of these drugs.

Lymphocytic infundibuloneurohypophysitis presenting as diabetes insipidus in a man.

We report a patient with diabetes insipidus, whose sella magnetic resonance imaging revealed a normal hypophysis with a focal nodular thickening of the infundibulum and lack of hyper-intense signal of the normal neurohypophysis. The histopathologic examination of the lesion showed a lymphoplasmacytic, predominantly lymphocytic, infiltration. A diagnosis of lymphocytic infundibuloneurohypophysitis was made, by the exclusion of other infiltrative, granulomatous diseases.

Lymphocytic hypophysitis and infundibuloneurohypophysitis; clinical and pathological evaluations.

This report describes the clinical and pathological characteristics of two patients with lymphocytic hypophysitis (LHy) and two with infundibuloneurohypophysitis (INHy). Two of the patients were women and two were men, and their ages were between 27 and 38 years old. This disease was not associated with either pregnancy or the postpartum period in the female patients. Two of the patients presented with diabetes insipidus, one with panhypopituitarism and right abducens paralysis and one with headache and galactorrhea. At presentation three of the patients had mild to moderate hyperprolactinemia and one had low prolactin levels. All four had abnormal magnetic resonance imaging (MRI): focal nodular enlarging of the infundibulum and normal hypophysis in one, expanding sellar masses in two, and diffusely thickened stalk with slightly enlarged pituitary gland in one. Three cases showed no sign of adenohypophysial deficiency with stimulation tests. One patient had associated chronic lymphocytic thyroiditis. Of the first three patients, one patient underwent transcranial and two underwent transnasal transsphenoidal (TNTS) surgery for mass excisions since they were thought to have pituitary tumors. Endoscopic endonasal transsphenoidal biopsy was performed in the last one with a suspicion of LHy. The pathological and immunohistochemical examinations revealed lymphocytic infiltration. Hyperprolactinemia resolved with surgery in two patients and one developed diabetes insipidus as a complication. We conclude that LHy and infundibuloneurohypophysitis should be considered in the differential diagnosis of the mass lesions of the sellar region and also should be kept in the mind for the etiopathogenesis of cases of hyperprolactinemia, galactorrhea and diabetes insipidus. In suspected cases endoscopic endonasal biopsy for the histopathological diagnosis can be a safe approach.

Vitamin d-receptor gene polymorphisms and vertebral bone density in men with idiopathic hypogonadotrophic hypogonadism.

BACKGROUND: Optimal peak bone mass is closely related to sufficient and appropriately timed androgen release. However, attainment of peak bone mass in men, as in women, is under genetic control, as well as being subject to hormonal and mutational effects. With increasing recognition of osteoporosis and related fractures in men, it is of interest to consider whether there is relationship between bone density and vitamin D receptor (VDR) polymorphisms, as described in women. MATERIAL AND METHODS: To assess the influence of allelic variation in the VDR gene on vertebral bone density in men with idiopathic hypogonadrotrophic hypogonadism (IHH), 27 patients (mean age 21.4 +/- 0.4 yrs) and 25 age-and-BMI matched healthy males (mean age 21.2 +/- 0.3) were genotyped using three restriction enzymes (Apa I, Bsm I, and Taq I). Vertebral bone mineral density was measured using dual energy X-ray absorptiometry (DEXA). RESULTS: As expected, vertebral bone density was reduced significantly in patients with IHH (p < 0.001). Despite weak evidence for an association between Apa I polymorphism and vertebral bone density in the IHH group (r = 0.454, p = 0.017 and r2 = 0.20), VDR genotype was not associated with vertebral bone density in either group. When analyzing homozygous haplotypes, the probability of carrying the favorable BAt haplotype was greater in the control group (OR = 2.000 vs. 0.500). CONCLUSION: We conclude that VDR genotype has no influence on vertebral bone density in men with IHH. Thus, allelic variation in the VDR cannot help define those at increased risk for osteoporosis and related fractures among such patients.