To evaluate the effects of antidepressant drugs on pregnancy outcomes in a university hospital of Turkey.

OBJECTIVE: To assess the effects of antidepressant use on pregnancy outcomes. METHODS: The cross-sectional study was conducted at the Department of Pharmacology, Manisa Celal Bayar University, Manisa, Turkey, and comprised pregnant women who were admitted to the Department of Gynaecology between 2008 and 2017 who had been prescribed antidepressant drugs before pregnancy and continued to use them during any week of their respective pregnancies. The women were contacted by telephone after delivery to obtain information about the pregnancy outcomes. Data was analysed using SPSS 23. RESULTS: There were 183 women with a mean age of 31.3 ± 5.3 years (range: 18-44 years). There were congenital defects in the newborn in 11(7.65%) cases. The most commonly used antidepressant group was selective serotonin reuptake inhibitor 138(75.4%), and escitalopram was the most frequently used drug 46(25.1%). Spontaneous abortion rate was higher with escitalopram than the other antidepressants (p=0.062). Induced abortion rate was significantly higher in multidrug users compared to those on a single drug (p<0.05). CONCLUSIONS: Selective serotonin reuptake inhibitor was found to be the most used class of antidepressants during pregnancy due to the low side effects and teratogenic effects. When antidepressant treatment is necessary during pregnancy, a single drug can be more suitable.

Mesenchymal Stem Cells: a Potential Treatment Approach for Refractory Chronic Spontaneous Urticaria.

The etiopathogenesis of chronic spontaneous urticaria (CSU) is not fully elucidated, and almost 30-40% of patients are resistant to treatments; therefore, there is still a need for the development of new and effective treatments. This study aimed to develop experimental cellular therapy for CSU patients resistant to current treatment options. Autologous adipose tissue mesenchymal stem cells (MSC) were administered to 10 refractory CSU patients who were then followed up for six months. The efficacy of treatment was evaluated according to the weekly urticaria activity scores (UAS7) and drug use scores (DUS7). To observe the effect of treatment on immune cells, CD4+ T cell subsets were analyzed by flow cytometry, and the serum IFN-γ, TNF-α, IL2, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17a, IL-21, IL-22, TGF-ß1, PGE2, IDO and anti-FcεRI levels were measured using the Luminex and ELISA methods. The values obtained were compared with 10 control refractory CSU patients and five healthy controls. We found that the T cell subsets and inflammatory molecules were not affected by MSC treatment during the follow-up period. In control patients, a significant decrease was detected only at the Th2 subset, TGF-ß1, PGE2, IDO and anti-FcεRI levels on the 14th day of treatment. The UAS7 and DUS7 values of the MSC-treated patients significantly decreased during the follow-up period, but in control patients, a significant but temporary decrease was seen. According to our findings, unlike conventional treatment, MSC therapy resulted in longer and more effective recovery. Our data indicate that MSCs may be an alternative and effective approach for treatment-resistant CSU patients. Graphical Abstract.

Birth outcomes after inadvertent use of category X drugs contraindicated in pregnancy: Where is the real risk?

Öztürk Z, Ölmez E, Gürpinar T, Vural K. Birth outcomes after inadvertent use of category X drugs contraindicated in pregnancy: Where is the real risk? Turk J Pediatr 2018; 60: 298-305. Drugs contraindicated in pregnancy are medicines that should be avoided by pregnant women, since they carry a concern for teratogenicity or there is no indication for their use during pregnancy. It does not mean that exposures to these drugs always cause harm. The aim of the present study was to investigate the risk of adverse outcomes following maternal exposure to the drugs contraindicated in pregnancy. We retrospectively analyzed prenatal drug exposure records of the pregnant patients referred to the clinical pharmacology consultation service in a tertiary-level university hospital from January 2007 until December 2012. Exposures to category X drugs (CXD) contraindicated in pregnancy were evaluated. After the expected date of delivery, we collected data about pregnancy complications and the outcomes. For comparison the women in the exposed group (N=52) were matched with a control group (N=162) of pregnant women without teratogenic exposure. We observed only one baby born with a birth defect (congenital cryptorchidism) in CXD group (2.6%) and four in control group (RR 0.91; 95% CI 0.10- 7.94). The rates of adverse pregnancy outcomes including miscarriage, preterm birth and congenital abnormality were not significantly different from controls. However, the rate of elective termination of pregnancy was higher in women exposed to CXD while pregnant (RR 2.54; 95% CI 1.11- 5.80, p = 0.027). Contraceptive failure and unintended pregnancy are the reasons for inadvertent drug exposure and choosing abortion. The high perception of teratogenic risk among pregnant women may cause terminations of pregnancies. Individual risk assessment and avoiding the phrase `CXD` or `contraindicated in pregnancy` in counseling may help to reduce maternal concerns about medication use in pregnancy.

A Study on the Anticarcinogenic Effects of Calcium Fructoborate.

Evidences about the preventive and therapeutic effects of boron compounds on cancer have been increasing in the last years. Although calcium fructoborate (CaFB) is used as a nutritional supplement, data about its preventive and therapeutic effects on neoplastic transformations are limited. In the present study, the various concentrations of CaFB were applied to the MDA-MB-231 metastatic breast cancer cell line. First, we examined the cytotoxic effect and IC50 value of CaFB by MTT assay. For the evaluation of the DNA damage, apoptosis and metastatic potential, expression levels of ATM, pATM, PARP, p53, p-p53, caspase-3, caspase-9, and VEGF were investigated by using immunoblotting and immunohistochemical methods. Cell viability was significantly reduced at 50 µM CaFB treatment. pATM, p-p53, and caspase-9 levels increased significantly in all groups; furthermore, there was approximately 12.5-, 2.4-, and 10.7-fold increase, respectively, for 100 µM CaFB treatment. ATM and p53 levels did not change with CaFB treatment, but PARP levels significantly 2.5-fold decreased. While VEGF immunoreactivity decreased in all groups, significant increase in caspase-3 immunoreactivity was observed only in the group treated with 50 µM CaFB (p < 0,001). Our results imply that CaFB may have therapeutic potential as well as preventive benefits in cancer.

Pregnancy outcomes following the use of thiocolchicoside.

Thiocolchicoside is a commonly used muscle relaxant in orthopedic, rheumatologic or musculoskeletal disorders to treat painful muscle spasms. It is contraindicated in pregnancy and lactation. There is no previously published experience with thiocolchicoside exposure during pregnancy. In this observational study, we collected and evaluated 18 pregnancy outcomes of the women referred to our prenatal consultation service for thiocolchicoside exposure between 2007-2012, and offspring were followed up until 2 years of age. There were 16 live births, 1 spontaneous abortion and 1 elective termination of pregnancy. No major birth defect was observed. The mothers and their babies were free of perinatal complications. No growth or developmental abnormalities were found during follow-up period. Our findings add information on inadvertent use of thiocolchicoside in pregnancy. Further large prospective cohort studies are required to investigate this issue.

Olive Leaf Extract Improves the Atherogenic Lipid Profile in Rats Fed a High Cholesterol Diet.

Coronary heart disease because of atherosclerosis is still the most common cause of mortality. Elevated levels of low-density lipoprotein and total cholesterol are major risk factors for atherosclerotic cardiovascular disease. The aim of this study was to evaluate the effects of the olive leaf extract on serum lipid profile, early changes of atherosclerosis and endothelium-dependent relaxations in cholesterol-fed rats. For this purpose, rats were fed by 2% cholesterol-enriched or standard chow for 8 weeks. Some rats in each group were also fed orally by olive leaf extract at doses of 50 or 100 mg/kg/day. Atorvastatin at dose of 20 mg/kg of body weight daily was also given as positive control. After 8 weeks, lipid profiles of rat serums were analyzed. Antioxidant enzyme activities (superoxide dismutase and glutathione peroxidase) and degree of lipid peroxidation (malondialdehyde levels) were also measured in the hearts isolated from rats. In addition, expression of adhesion molecules and endothelium-dependent relaxations of isolated thoracic aortas of rats were evaluated. Total cholesterol and LDL-cholesterol levels were found to be increased in cholesterol-fed rats, and both doses of olive leaf extract and atorvastatin significantly decreased those levels. In conclusion, because the olive leaf extract attenuates the increased cholesterol levels, it may have beneficial effects on atherosclerosis.

Commonly used intravenous anesthetics decrease bladder contractility: An in vitro study of the effects of propofol, ketamine, and midazolam on the rat bladder.

AIM: This study was designed to test the hypothesis that propofol, ketamine, and midazolam could alter the contractile activity of detrusor smooth muscle. MATERIALS AND METHODS: Four detrusor muscle strips isolated from each rat bladder (n = 12) were placed in 4 tissue baths containing Krebs-Henseleit solution. The carbachol (10 (-8)to 10(-4)mol/L)-induced contractile responses as well as 5, 10, 20, 30, 40, 50 Hz electrical field stimulation (EFS)-evoked contractile responses of the detrusor muscles were recorded using isometric contraction measurements. After obtaining basal responses, the in vitro effects of propofol, ketamine, midazolam (10(-5) to 10(-3) mol/L), and saline on the contractile responses of the detrusor muscle strips were recorded and evaluated. RESULTS: All the 3 drugs reduced the carbachol-induced and/or EFS-evoked contractile responses of rat detrusor smooth muscles in different degrees. Midazolam (10(-4) to 10(-3) mol/L) caused a significant decrease in the contractile responses elicited by either EFS or carbachol (P=0.000-0.013). Propofol (10(-3)mol/L) caused a decrease only in EFS-evoked contractile responses (P=0.001-0.004) and ketamine (10(-3)mol/L) caused a decrease only in carbachol-induced contractile responses (P=0.001-0.034). CONCLUSION: We evaluated the effects of the 3 different intravenous anesthetics on detrusor contractile responses in vitro and found that there are possible interactions between anesthetic agents and detrusor contractile activity. The depressant effects of midazolam on the contractile activity were found to be more significant than ketamine and propofol. Despite the necessity of further studies, it could be a piece of wise advice to clinicians to keep the probable alterations due to intravenous anesthetics in mind, while evaluating the results of urodynamic studies in children under sedation.

Beneficial effects of apricot-feeding on myocardial ischemia-reperfusion injury in rats.

The present study was undertaken to evaluate the cardio-protective potential of apricot-feeding in the ischemia-reperfusion (I/R) model of rats in vivo. Rats were divided into three groups of 12 rats each. Group 1 was fed with a standard rat chow, groups 2 and 3 were fed with a standard rat chow supplemented with 10% or 20% dried apricot during 3 months before the beginning of I/R studies. To produce I/R, the left main coronary artery was occluded for 30 min, followed by 120 min reperfusion, in anesthetized rats. Infarct sizes were found significantly decreased in 10% (55.0 +/- 4.3%) and 20% (57.0 +/- 2.9%) apricot-fed groups compared to control group (68.7 +/- 2.0%). Light and electron microscopic evaluations of hearts also demonstrated similar beneficial effects on I/R injury in apricot-fed both groups. Total phenolic contents, DPPH radical scavenging and ferric-reducing power as in vitro antioxidant capacities of rat chows were significantly increased after supplementation with apricot for each ratio. Cu, Zn Superoxide dismutase (Cu, Zn SOD) and catalase (CAT) activities were increased, and lipid peroxidation was decreased significantly in the hearts of 20% apricot-fed group after I/R. In conclusion, we clearly demonstrated in vivo cardio-protective activity of apricot-feeding related to its antioxidant phenolic contents in rats subjected to myocardial I/R.

Comparison of different regression analyses for identifying risk factors in obese and nonobese patients with coronary artery disease.

This study was designed to assess conventional and novel risk factors in obese and nonobese patients with coronary artery disease (CAD) by using multivariate forward and univariate logistic regression analysis and to find the best model of analysis for identifying these risk factors. The study group consisted of 398 patients who consecutively underwent coronary angiography for the investigation of chest pain, except overweight patients. In univariate logistic regression analysis, high C-reactive protein and cigarette smoking were found to be the strongest variables in obese and nonobese patients with CAD, respectively. In multivariate forward logistic regression analysis, some risk factors were not found as predictors of CAD. Multivariate forward logistic regression analysis with the advantage of a high predictable ratio may be more useful for the analysis of risk factors in patients with CAD.

Melatonin improves methanol intoxication-induced oxidative liver injury in rats.

This study was performed to evaluate the effect of melatonin on methanol-induced liver injury. We evaluated the levels of malondialdehyde (MDA), protein carbonylation (PC), myeloperoxidase (MPO) activities and to assess lipid peroxidation, protein oxidation, neutrophil accumulation and nitrite which is a stable end product of nitric oxide respectively. We also studied superoxide dismutase, catalase, and glutathione peroxidase activities of liver tissue to evaluate the changes in the antioxidant status. Histopathological alterations were also determined. The experiment was performed on Wistar rats, which received intragastric 3 g/kg methanol as a 50% solution in isotonic saline once. After 6 and 24 hr all the drug received and intoxicated rats were killed under anesthesia. Pretreatment with melatonin (10 mg/kg) decreased the MDA levels significantly, restored the PC levels to the control, prevented the increase of nitrite level and MPO activity significantly and reversed to the control levels, prevented the reduction in all of the antioxidant enzyme activities. Additionally in melatonin treated group piecemeal necrosis, lobular lytic necrosis, and portal inflammation returned to normal histologic appearances when compared with methanol administration. In conclusion, melatonin has protective effects against methanol-induced hepatic injury.

Remote organ injury induced by myocardial ischemia and reperfusion on reproductive organs, and protective effect of melatonin in male rats.

OBJECTIVE: Myocardial ischemia and reperfusion (MI-R) leads to remote organ injury associated with oxidative stress. Melatonin is a well-known antioxidant and free-radical scavenger. This study was conducted to examine whether MI-R causes damage in the testes and sperm quality, and to investigate the possible protective effect of exogenous melatonin on these parameters in an in vivo rat model. DESIGN: Experimental study. SETTING: Experimental Research Center, Firat University Medical School, Elazig, Turkey. PATIENT(S): Eight-week-old male Wistar rats (n = 18). INTERVENTION(S): To produce MI-R, a branch of the descending left coronary artery was occluded for 30 minutes, followed by 120-minute reperfusion. Melatonin (10 mg/kg) or vehicle was given 10 minutes before ischemia via the jugular vein. MAIN OUTCOME MEASURE(S): Reproductive organ weights and epididymal sperm concentration, sperm motility, abnormal sperm rate, and testicular-tissue malondialdehyde (MDA) and glutathione (GSH) levels were examined after reperfusion. RESULT(S): MI-R significantly decreased epididymal sperm motility, and increased the testes-tissue level of MDA, compared to the control group. Administration of melatonin reversed the harmful effects of MI-R significantly. However, MI-R did not change sperm concentration, GSH levels, and reproductive organ weights. CONCLUSION(S): These findings indicate that MI-R leads to damage of testis tissue and sperm motility, and melatonin protects against MI-R-induced reproductive-organ injury. These results may also encourage the use of antioxidants to reduce remote organ injury in the testis after MI-R.

Vascular reactivity to various vasoconstrictor agents and endothelium-dependent relaxations of rat thoracic aorta in the long-term period of pinealectomy.

In this study, the effects of reduced melatonin concentrations in the long-term period of pinealectomy on mean arterial blood pressure (BP) and vascular responses in isolated rat thoracic aorta were investigated. Rats were pinealectomized (Px) two months before the beginning of the studies. Rings of endothelium-intact and -denuded rat arteries were mounted in isolated tissue baths for the measurements of isometric contractile force. No significant difference was determined between the arterial BP of Px (88.1 +/- 1.9 mmHg) and control (83.8 +/- 1.2 mmHg) rats. All arteries isolated from control and Px rats showed essentially identical contractions in response to phenylephrine, serotonin, calcium, clonidine, vasopressin, and angiotensin-II. Only endothelin-1 (ET-1)-induced contractions in the endothelium-denuded vessels isolated from Px rats were found to be increased to some extent. Pinealectomy did not affect acetylcholine or sodium nitroprusside-induced relaxation in the rat aorta either. These data suggest that reduced melatonin levels two months after pinealectomy did not modify either the vascular reactivity to various vasoconstrictor agents except the partially increased contractile responses to ET-1 in the endothelium-denuded thoracic aortas of Px rats or the endothelium-dependent and -independent relaxations in rat thoracic aorta. Restoration of the increased vascular responses to some vasoconstrictor agents, which were reported previously, may be the reason of why the hypertension is temporary following pinealectomy.

Effect of melatonin and atenolol on carbon monoxide cardiotoxicity: an experimental study in rats.

The aim of this study was to define the characteristics of heart rates and myocardial changes in rats exposed to carbon monoxide (CO), and the effects of reoxygenation, atenolol (a beta-blocker) and melatonin after sublethal CO intoxication. Widespread use of beta-blockers in cardiology practice and growing literature on the positive effect of melatonin in ischaemia reperfusion lead us to question their effects in case of CO intoxication. Rats were exposed to CO. After sublethal intoxication the rats were reoxygenated with ambient air. Subsequently blood values, electrocardiographic recordings and pathological changes were examined for each groups. Five rats died after CO intoxication in the control group: no myocardial changes were seen in light microscopy. However, myocardium of seven reoxygenated rats presented contraction bands. Seven reoxygenated rats pretreated with atenolol had a higher number of contraction bands of myocardial cells. Seven reoxygenated rats pretreated with melatonin had more contraction bands than reoxygenated rats, and heart rate recordings of these animals revealed a profund and sustained bradycardia. Thus, melatonin and atenolol appear to have some adverse effects in CO intoxication on the myocardial cells.

Beneficial effects of melatonin on diaphragmatic contractility and fatigability in Escherichia coli endotoxemic rats.

Sepsis impairs diaphragmatic contractility and endurance capacity and increases diaphragmatic fatigability. Several investigations have shown that administration of a number of free radical scavengers, such as N-acetylcysteine (NAC), protects the diaphragm from the development of endotoxin-mediated diaphragmatic dysfunction. The aim of this study was to evaluate the effects of melatonin (CAS 73-31-4), a naturally occurring potent antioxidant, on diaphragmatic contractility and lipid peroxidation as a marker of oxidative stress in endotoxemic rats. Rats were randomly divided into four groups: control group, endotoxemic group, melatonin group and endotoxemic plus melatonin group. Melatonin was administered by intraperitoneal injection 30 min before endotoxin inoculation to animals. Diaphragmatic function and malondialdehyde (MDA) level analysis as an indicator of lipid peroxidation were assessed 17 h after endotoxin or saline inoculation. Endotoxemia decreased the development of diaphragm fatigue and diaphragmatic MDA levels. The effects of endotoxemia on diaphragmatic contractions and fatigability were reversed and returned to control levels by melatonin administration. However, melatonin did not prevent the increase in muscle MDA content. In conclusion, the present study demonstrated that melatonin attenuated the endotoxin-induced impairment of diaphragm function. This effect of melatonin does not seem to be related to its antioxidant properties.

Dose-dependent dual effect of melatonin on ototoxicity induced by amikacin in adult rats.

The aim of this animal study was to reveal the dose-dependent effects of melatonin on aminoglycoside ototoxicity by utilizing distortion product otoacoustic emissions (DPOAEs). Forty-four adult (aged 12 months) rats were divided into five groups. Rats of the control group (group C) were injected with vehicle, while the melatonin group (group M) received melatonin (4 mg/kg per day); there were four rats in each of these groups. The study groups consisted of 12 rats per group, and they were treated as follows: 600 mg/kg per day amikacin (group A), amikacin plus a low dose (0.4 mg/kg per day) melatonin (group AML) and amikacin plus high dose (4 mg/kg per day) melatonin (group AMH) for 14 days. During the serial measurements on days 0, 5, 10 and 15, the DPOAE results of groups C,M and AML were not significantly changed. Amikacin ototoxicity findings for input/output (I/O) functions were detected on the 3rd measurement of the study in group A. High-dose melatonin clearly enhanced and accelerated amikacin-induced ototoxicity. The DP-gram amplitudes and I/O amplitudes were reduced, and I/O thresholds were increased in group AMH. Group AMH was the group that was affected the most and earliest by amikacin. Our study results showed that while low-dose melatonin protected the inner ear from ototoxicity, high dose melatonin facilitated amikacin-induced ototoxicity, possibly via the vasodilatory effect, leading to an increased accumulation of amikacin in the inner ear. Probably, the protective effect of the melatonin at a dose of 0.4 mg/kg per day is related to its antioxidant properties. Apparently, the vasodilatory effect of melatonin seems to be more prominent than its antioxidant effect in high doses.

Determination of the pericardial to serum myoglobin ratio for the early diagnosis of perioperative myocardial infarction after coronary artery bypass grafting.

Pericardial fluid reflect the composition of cardiac interstitium in myocardial ischemia. This study investigated the value of the pericardial and serum myoglobin (MG) measurements for the diagnosis of perioperative myocardial infarction (MI) after coronary artery bypass grafting (CABG). Postoperative arterial and pericardial blood samples were taken in 64 subjects undergoing elective CABG allocated to two groups according to the 12-lead electrocardiogram (ECG) abnormalities observed during the first postoperative 24h. Group 1=normal and nonspecific ECG abnormalities, and Group 2=perioperative Q-wave MI. The occurrence of perioperative MI was associated with a dramatic increase in both serum and pericardial cardiac troponin I (CTnI) and MG concentrations. Pericardial concentrations were higher than serum concentrations during the first postoperative 24h in all subject. However, pericardial/serum CTnI ratio in subjects in Group 2 was not statistically different from Group 1 at the time of admission to the intensive care unit (ICU) and did not significantly change at time intervals. On the other hand, more than two-fold increase in the pericardial/serum MG ratio was determined for all patients who experienced perioperative Q-wave MI with the lowest value as 2.75, whereas only 1 of 59 patients in group 1 had the ratio higher than 2 with the highest value as 2.15 at the time of admission to the ICU. In conclusion, determination of pericardial/serum MG ratio may be a useful tool for the early diagnosis of the perioperative MI after CABG.

Melatonin attenuates alpha-adrenergic-induced contractions by increasing the release of vasoactive intestinal peptide in isolated rat penile bulb.

The effects of melatonin on alpha-adrenergic-induced contractions caused by electrical field stimulation (EFS) or the alpha(1)-adrenoceptor agonist phenylephrine (Phe) were investigated in isolated rat penile bulb. Melatonin as well as melatonin receptor agonists N-acetylserotonin and 2-iodomelatonin and melatonin antagonist luzindole attenuated the EFS-induced contractions and the concentration-response curve to Phe. The effect of melatonin on Phe-induced contractions was completely reversed by treatment with tetrodotoxin, guanethidine or vasoactive intestinal peptide (VIP) antagonist. On the other hand, pretreatment with N-methyl-l-arginine, atropine, and luzindole did not reverse the effect of melatonin. Thus, we demonstrated that melatonin at nanomolar concentrations inhibits the alpha-adrenergic responses in isolated rat penile bulb. Since alpha-adrenoceptor blocking agents are known to interfere with detumescence of the erect penis, serum levels or administration of this pineal hormone may affect erectile function. This effect of melatonin may be the result of its allosteric interaction with the presynaptic receptors on VIPergic neurons, which are affected by sympathetic transmission, and then an increase in VIP release from these neurons.

Myocardial ischemia-reperfusion in rats: reduction of infarct size by either supplemental physiological or pharmacological doses of melatonin.

Myocardial ischemia-reperfusion (I/R) represents a clinically relevant problem associated with thrombolysis, angioplasty and coronary bypass surgery. I/R injury is believed to be a consequence of free radical generation in the heart especially during the period of reperfusion. The pineal secretory product, melatonin, is known to be a potent free radical scavenger and pharmacological concentrations have been shown to reduce the I/R-induced cardiac damage in isolated rat hearts. However, the physiological role of melatonin in the prevention of this damage is unknown. Rats were pinealectomized or sham-operated (control) 2 months before the I/R studies. To produce cardiac damage, the left main coronary artery was occluded for 30 min, followed by 120 min reperfusion, in anesthetized rats. Infarct size, expressed as the percentage of the risk zone, was found significantly higher in pinealectomized rats (49+/-3.4%) than in the control group (34+/-3.6%). Melatonin administration (4 mg/kg, either before ischemia or reperfusion) to pinealectomized rats significantly reduced the infarct size values and returned them to the control values. On the other hand, melatonin administration (4 mg/kg) to sham-operated rats failed to attenuate significantly the I/R-induced infarct size. These results suggest that physiological melatonin concentrations are important in reducing the I/R-induced myocyte damage, while pharmacological concentrations of melatonin did not add to the beneficial effect. As melatonin levels have been reported to decrease with age, melatonin replacement therapy may attenuate I/R-induced myocardial injury, especially in older patients.

Amikacin ototoxicity enhanced by Ginkgo biloba extract (EGb 761).

An animal study was realized to investigate the possible beneficial effect of EGb 761 as an antioxidant agent on amikacin ototoxicity by measuring distortion product otoacoustic emissions (DPOAEs). Twenty-eight adult rats were grouped equally as follows. GROUP AMIKACIN: rats received amikacin 600 mg/kg/day intramuscularly between postnatal days (PND) 30 and PND44. Group amikacin/EGb 761: rats received amikacin 600 mg/kg/day intramuscularly between PND30 and PND44 and EGb 761 100 mg/kg/day orally between PND30 and PND50. Group EGb 761: rats received equivolume saline intramuscularly between PND30 and PND44 and EGb 761 100 mg/kg/day orally between PND30 and PND50. NO TREATMENT GROUP: rats received nothing. Group amikacin was found to be affected only on the last measurement day of study (PND57). The frequencies greater than 2002 Hz were significantly reduced compared with the amplitudes of PND30 (P<0.05). Group amikacin/EGb 761 was most and earliest affected by amikacin-induced ototoxicity. DPOAE amplitudes were found in this group to be decreased at 2-6 kHz starting on PND50. The results of Group EGb 761 and No treatment group were not significantly changed. For the DPOAE input/output amplitude thresholds, Group amikacin (P<0.05) and Group amikacin/EGb 761 (P<0.01) had significantly elevated thresholds on PND57, except at 5 kHz for Group amikacin (P=0,06). According to the results of the study, EGb 761 may be regarded as a facilitating drug for the development of amikacin ototoxicity. The results of the present study may warn against concomitant use of aminoglycosides, specifically amikacin, with EGb 761.

Effects of physiological and pharmacological concentrations of melatonin on ischemia-reperfusion arrhythmias in rats: can the incidence of sudden cardiac death be reduced?

Cardiac arrhythmias during ischemia-reperfusion (I/R) are believed to be related to free radicals generated in the heart especially during the period of reperfusion. The pineal secretory product, melatonin, is known to be a potent free radical scavenger and its pharmacological concentrations have been shown to reduce the I/R-induced arrhythmias in isolated rat hearts. However, the physiological role of melatonin in the prevention of these arrhythmias is unknown. Rats were pinealectomized (Px) or sham-operated (non-Px) (control) 2 months before the I/R studies. To produce arrhythmias, left main coronary artery was occluded for 7 min, followed by 7 min reperfusion, in anesthetized rats. The incidence of mortality resulted from irreversible ventricular fibrillation (VF) was found significantly higher in the Px rats (63%) than in the control group (25%). Melatonin administration (0.4 mg/kg, either before ischemia or reperfusion) to Px rats significantly reduced the incidence of total (irreversible plus reversible) and irreversible VF and returned them to control values. On the other hand, melatonin administration (0.4 and 4 mg/kg) to non-Px rats failed to attenuate the I/R arrhythmias, significantly. These results suggest that physiological melatonin concentrations are important to reduce the I/R-induced VF and mortality, while pharmacological concentrations of melatonin did not increase its beneficial effect on these arrhythmias. As melatonin levels have been reported to decrease with age, melatonin replacement therapy may attenuate the incidence of sudden cardiac death especially in older patients.