In vitro effect of hyoscine-N-butyl bromide and diclofenac sodium in human tuba uterina.

INTRODUCTION: To investigate the in vitro effect of diclofenac on tubal smooth muscle as an alternative to hyoscine-N-butyl bromide, which is used for premedication before hysterosalpingography (HSG). MATERIAL AND METHODS: Fallopian tubes were retrieved from seven healthy women after bilateral tubal ligation and in vitro contractility and histological studies were conducted using tissue bath and immunohistochemistry. RESULTS: Diclofenac sodium and hyoscine-N-butyl bromide did not significantly change the basal mean tension; however, they decreased the contractions induced by potassium chloride (KCl). The relaxant effect of diclofenac sodium and hyoscine-N-butyl bromide was not statistically significantly different. The presence of cyclooxygenase (COX)-2 enzyme in the fallopian tube was demonstrated by immunohistochemical studies. CONCLUSIONS: The in vitro relaxant effect of diclofenac sodium on the fallopian tube is similar to hyoscine-N-butyl bromide. Diclofenac may have the potential to be used as an alternative to hyoscine-N-butyl bromide in premedication in HSG.

Functional and Histological Changes in Umbilical Artery and Myometrium Isolated from IUGR Complicated Pregnancies.

Objective: To investigate the relaxation responses mediated by L-type Ca2+ channels and big-conductance Ca2+-activated K+ (BKCa) channels and histological changes in the human umbilical artery (HUA) and myometrium smooth muscle isolated from pregnancies complicated with intrauterine growth restriction (IUGR).Methods: The muscle reactivity and the histology of the smooth muscle of the HUA and myometrium retrieved from 14 women with IUGR and 14 controls were investigated by the isolated tissue bath and immunohistochemical method.Results: In HUA, the maximum relaxation responses and pD2 values of nifedipine and NS11021 (BKCa channel opener) were significantly increased and significant histopathological changes are observed in the IUGR group.Conclusions: The pathogenesis of IUGR might be associated with the impairment in the functional responses of L-type Ca2+ channels and BKCa channels in HUA smooth muscle. The increased staining of myometrium and UC with HIF-1α in IUGR may indicate apoptosis, histological damage, and impaired fetal growth.

Comparison of relaxant effects of nifedipine and NS11021 on isolated umbilical arteries of healthy and preeclamptic pregnant women.

OBJECTIVES: Potassium (K+) channel openers and calcium (Ca2+) channel blockers are currently used to treat acute severe hypertension in pregnancy. We aimed to investigate the vasorelaxant effect of NS11021, a potent and specific big-conductance Ca2+-activated K+ (BKCa) channel activator, and to compare it with the vasorelaxant effect of nifedipine on human umbilical arteries (HUAs) isolated from healthy and preeclamptic pregnants. STUDY DESIGN: A total of 29 HUAs were isolated immediately after delivery from 14 healthy and 15 preeclamptic pregnant with severe features. The concentration-dependent relaxation responses were obtained to nifedipine and NS11021 on HUAs precontracted with endothelin-1 (ET-1) (10-8 M) in an isolated tissue bath. RESULTS: Both nifedipine and NS11021 caused concentration-dependent relaxation responses in HUAs from healthy and preeclamptic pregnants. While the maximum responses (Emax) and pD2 values of nifedipine did not change significantly in both groups, the Emax and pD2 values of NS11021 were significantly decreased in the preeclampsia group (Emax ± SEM; %75.57 ± 4.53 and %43.75 ± 14.00 and pD2 ± SEM; 6.92 ± 0.26 and 5.24 ± 0.53 respectively, p < 0.05). In addition, the pD2 value of NS11021 was not significantly different from that of nifedipine in the control group, but decreased significantly in the preeclampsia group (pD2 ± SEM 7.1 ± 0.41 and 5.2 ± 0.53, p < 0.05, respectively). CONCLUSIONS: Efficacy and potency of NS11021 decreased in HUAs from preeclamptic pregnants. Also, NS11021 is less potent than nifedipine in the preeclampsia group. BKCa channels may have a role in the pathogenesis of preeclampsia, however, further experimental studies are needed to elucidate that.

Pregnancy outcomes following maternal macrolide use: A systematic review and meta-analysis.

To determine whether gestational use of all or specific macrolides (azithromycin, clarithromycin, roxithromycin or erythromycin) lead to an increase in rates of overall major congenital malformations, organ-specific malformations, and other adverse pregnancy outcomes in infants. PubMed/MEDLINE, Cochrane Central Register of Controlled Trials and Reprotox® databases were searched. Dichotomous outcomes or calculated log odds ratios and standard errors from observational studies are combined using the random-effects method in Review Manager 5.3. No significant increased risks for major congenital malformation (OR 1.06 [95% CI 0.99, 1.13]) and congenital heart defect (OR 1.05 [95% CI 0.92, 1.19]) following all macrolides use during the first trimester were detected. Prenatal azithromycin use was associated with a significantly increased risk of major congenital malformations in the analysis of cohort studies (OR 1.21 [95% CI 1.08-1.36]). This significance was also present in the sensitivity analysis. There were no statistically significant associations between the risk of organ specific malformations and all or specific macrolide exposures except for the decreased risk in hypospadias following erythromycin use in the meta-analysis of case-control studies (OR 0.38 [95% CI 0.18, 0.81]. Also, a significant 1.5-fold increased risk for spontaneous abortion following macrolide use was detected. A slight yet significantly increased rate of major congenital malformation with azithromycin exposure during pregnancy may be associated with maternal confounders. Nevertheless, level II ultrasound can be suggested following maternal azithromycin use during the first trimester. Future studies should take into account the inclusion of a disease-matched control group and accurate classification of the malformations.

Pregnancy outcomes following maternal exposure to statins: A systematic review and meta-analysis.

AIMS: The objective of this meta-analysis was to determine whether maternal exposure to statins is associated with increased rates of major congenital malformations and other adverse pregnancy outcomes. METHODS: PubMed/Medline, Web of Science and Reprotox® databases were searched. Cohort and case control studies with prenatal exposure to statins were included. RESULTS: Analysis of five cohort studies and one case-control study showed no significant increase in rate of major congenital malformations when the exposed group was compared with the control ([OR 1.27; 95% CI 0.80-2.04], [aOR 1.05; 95% CI 0.84-1.31]). A significant increase in heart defect risk was detected in the statin-exposed group when unadjusted ORs were combined (OR 2.47; 95% CI 1.36-4.49). Further analysis of the same outcome by using adjusted ORs showed no significant increase in heart defect risk in the statin-exposed group compared with the controls (aOR 1.24; 95% CI 0.93-1.66). A significantly lower live birth rate (OR 0.60, 95% CI 0.49-0.75) and a higher spontaneous abortion rate (OR 1.36; 95% Cl 1.06-1.75) were detected in the statin-exposed group. CONCLUSIONS: Gestational statin exposure was not associated with a significant increase in risk of major congenital malformations, heart defects and other adverse pregnancy outcomes, except spontaneous abortion and live birth rate, which may be associated with maternal comorbidity and other unadjusted risk factors. Further research focusing on particular statins is needed to draw more definitive conclusions.

Paroxetine overdose during pregnancy.

Paroxetine is a selective serotonin reuptake inhibitor (SSRI) used in the treatment of depression and anxiety disorders. In some epidemiological studies, slightly increased risks of major malformations and cardiac malformations have been reported following paroxetine exposure in the first trimester of pregnancy. However, such findings have been inconsistent. There is only one report of any overdose of an SSRI during pregnancy, and that involved escitalopram. The aim of this case report was to describe the impact of a paroxetine overdose in the first trimester of pregnancy on the health of the foetus. A 21-year-old mother of one child who was pregnant with a second child was prescribed 20 mg/day paroxetine hydrochloride for the treatment of anxiety/depression. The patient ingested 15 or 16 20-mg tablets of paroxetine hydrochloride (300-320 mg) during the 5th week of pregnancy as a suicide attempt. Within 15 min of ingestion, she was admitted to hospital and treated for intoxication. No evidence of maternal SSRI intoxication was observed after treatment. The patient consulted our teratology information service for further risk assessment regarding possible major congenital malformations following the paroxetine overdose. We were unable to find previous reports of paroxetine overdose during pregnancy in the literature. The timely administration of the overdose treatment and the lack of maternal intoxication symptoms were considered positive for the foetal well-being, and the patient was referred for perinatology and psychiatry follow-ups. A healthy, 3 500-g male infant was born at 38 weeks' gestation, and his development at the age of 2 years was normal. This is the first reported case of paroxetine overdose during pregnancy. Comprehensive studies are needed to evaluate pregnancy outcomes after SSRI overdose.Key PointsThere are no reported data on paroxetine overdose during pregnancy.The aim of this case report was to describe the impact of a maternal paroxetine overdose in the first trimester of pregnancy on the health of the foetus. No evidence of maternal SSRI intoxication was observed.No congenital malformations or developmental disorders were observed in the child at 2 years of age.Comprehensive studies are needed to evaluate pregnancy outcomes following SSRI overdose.

Pregnancy outcomes after maternal betahistine exposure: A case series.

OBJECTIVE: To investigate the pregnancy outcomes of women who were exposed to betahistine during their pregnancies. METHODS: We identified and evaluated the outcomes of 27 pregnant women who were referred to Terafar (Teratology Information Service, Izmir, Turkey) for a teratological risk assessment. RESULTS: Of 24 pregnancies with known outcomes, 21 resulted in live births (including two pairs of twins) whereas two ended with miscarriage and three with elective terminations. Among the 20 live births for whom the malformation details were available, there were 17 normal outcomes, one major and two minor congenital malformations. CONCLUSIONS: Despite a number of limitations, this case series may be of value regarding counseling pregnant women with inadvertent betahistine exposure. Further epidemiological studies with larger sample sizes and control groups are necessary to draw more definite conclusions.

Pregnancy outcomes after maternal use of thiocolchicoside: A case series.

OBJECTIVE: The 2014 report by European Medicines Agency (EMA) restricted the use of thiocolchicoside for all reproductive-age women. In this study, we aim to expand the systematically-collected human data and discuss it within the frame provided by this report. METHODS: We identified and evaluated the outcomes of 48 prospectively recorded pregnancies referred to Terafar (Teratology Information Service, Izmir, Turkey). RESULTS: Of 42 pregnancies with first-trimester exposure and known outcomes, 31 resulted in live births, four in miscarriage and seven ended with elective terminations. There were 26 normal outcomes, two major and three minor congenital malformations among the live births. CONCLUSIONS: Despite a number of limitations, our results and previous case series collectively strengthen the view that thiocolchicoside is unlikely to be a major teratogen. EMA's 2014 report should be revised to reflect this finding, while current restrictions on use should continue until more detailed safety information is available.

Counselling pregnant women at the crossroads of Europe and Asia: effect of Teratology Information Service in Turkey.

Background Previous studies from western countries demonstrated the effectiveness of Teratology Information Service (TIS) counselling in reducing the teratogenic risk perception of pregnant women. Objective To assess whether TIS counselling would be effective in reducing the teratogenic risk perception of the Turkish pregnant women. Setting A TIS (Terafar) operating in a university hospital in Turkey. Methods A cross-sectional survey study. Pregnant women with non-teratogenic medication exposures were asked to assign scores on visual analogue scales (VAS) in response to the questions aiming to measure their teratogenic risk perception. The mean score before and after counselling were compared and the associations with maternal socio-demographic characteristics were analysed using SPSS (Version 20.0). Main outcome measures The differences in the mean scores of the perception regarding the baseline risk of pregnancy, own teratogenic risk and the likelihood of termination of pregnancy before and after counselling and their possible associations with maternal socio-demographic characteristics. Results 102 pregnant women participated in the study. The counselling significantly reduced the mean own teratogenic risk perception score and the mean score for the likelihood of termination of pregnancy whereas the mean baseline risk perception score was not significantly changed. Pregnancy week <8 and the exposed number of active ingredients <3 were significantly associated with the difference in the mean score for the likelihood of termination of pregnancy. Conclusions TIS counselling lowers the teratogenic risk perception of Turkish pregnant women and increases their likelihood to continue the pregnancy as it does in the western countries.

Dermatological aspects of synthetic cannabinoid addiction.

CONTEXT: Synthetic cannabinoids (SCs) have recently become one of the most abused substances among young population and have caused severe health consequences in our country and worldwide. OBJECTIVE: The aim of this study was to investigate sociodemographic and dermatological findings in SC addicts. MATERIALS AND METHODS: A total of 136 SC users who applied to our hospital's Substance Dependence Center outpatient clinic and diagnosed with drug addiction according to DSM-4 criteria between September 2014 and September 2015 were enrolled to our study. Patients were evaluated by dermatologist and psychiatrist with sociodemographic and clinical data sheets. Data were obtained by direct conversation with patients, clinical examination findings, and laboratory tests, if necessary. RESULTS: Of 136 patients, 12 (8.8%) were female and 124 (91.2%) were male, aged between 17 and 53 with mean age of 25.8 ± 9.2. Most common use way of SC was smoking and patients majorly used opiates before SC. The majority of the patients enrolled to our study were low-educated and almost 50% did not have a regular job. The most frequent dermatologic complaints were periorbital darkening, hallowed-cheeks and premature aging, hair loss and gray hair, and acnes, whereas most frequent dermatologic examination findings were artifact lesions such as blade scars and tobacco scars-stains, tattoos, and acnes. DISCUSSION AND CONCLUSIONS: Given the increased prevalence of SC use in our country and around the world, dermatologists should continue to familiarize themselves with the common mucocutaneous markers of this substance use. Awareness of signs of SCs use will facilitate earlier diagnose, intervention, and directed treatment.

Effect of nitrergic system on colonic motility in a rat model of irritable bowel syndrome.

AIM: The aim of this study is to investigate whether nitric oxide (NO)-mediated colonic motility was altered in rat irritable bowel syndrome (IBS) model, using different isoforms of NO-synthase (NOS) inhibitors. MATERIALS AND METHODS: The animal model of IBS-like visceral hypersensitivity was induced by intra-colonic infusion of 0.5% acetic acid (AA) in saline once daily from postnatal days 8 to 21. Control animals received saline instead of AA. Experiments were performed at the end of 8 weeks. Distal colon tissues were resected and direct effects of different NOS inhibitors; N-omega-nitro-L-arginine methyl ester hydrochloride, (L-NAME), ARL-17477 dihydrochloride hydrate (ARL 17477), N-[3-(Aminomethyl) phenyl] methyl]-ethanimidamidedihydrochloride (1400 W), and N5-(1-Iminoethyl)-L-ornithine dihydrochloride (L-NIO) were evaluated concentration-dependently in vitro tissue bath. Besides, morphology of both groups was assessed with hematoxylin and eosin (H and E) staining and the impact of NO antibodies was determined using the immunohistochemical method. RESULTS: The mean pressure values of spontaneous contractions and KCL (80 mmol/L) responses of distal colonic segments were similar in normal and IBS rats. L-NAME and ARL-17477 significantly increased the mean pressure of spontaneous colonic contractions in normal rats versus own base values (P < 0.05), but this increase did not significantly different when compared to IBS rats. In H and E staining, there was no difference with regard to morphology between two groups. Neuronal NOS (nNOS) immunoreactivity was found to be significantly decreased in IBS when compared to control groups (P < 0.05). CONCLUSION: L-NAME and ARL-17477 mediated mean pressure values were found to be slightly decreased in IBS rats. These findings may be related to a decrease in nNOS level in IBS.

Pregnancy outcome after varenicline exposure in the first trimester.

To the best of our knowledge this is the first case report describing exposure to varenicline, an α 4 ß 2 nicotinic acetylcholine partial receptor agonist used for smoking cessation therapy in pregnancy. A 29-year-old multiparous woman with an unplanned pregnancy has used varenicline 2 mg/day unintentionally yet regularly 4 weeks from her last menstrual period. Fetal ultrasound performed at each trimester, detailed anomaly scan, and fetal echocardiography which were performed at the 22nd gestational week showed normal fetal growth with no malformations. The patient delivered a healthy baby at the 38th week of gestation with normal Apgar score and physical examination findings. Age-appropriate physical and neurological development of the child has been observed for 6 months. Although it is not possible to draw definitive conclusions, this case report may contribute to the current available limited data regarding the safety of varenicline use in pregnancy.

Investigation of the role of the NO-cGMP pathway on YC-1 and DEA/NO effects on thoracic aorta smooth muscle responses in a rat preeclampsia model.

The present study was designed to investigate the effects of YC-1, a nitric oxide (NO)-independent soluble guanylate cyclase (sGC) activator, and DEA/NO, a NO donor, on smooth muscle responses in the preeclampsia model with suramin-treated rats and on the levels of cyclic guanosine monophosphate (cGMP) of thoracic aorta rings isolated from term-pregnant rats. Rats of 2 groups, control group and suramin group, were given intraperitoneal injection of saline or suramin, respectively. Suramin injection caused increased blood pressure, protein in urine, and fetal growth retardation. Thoracic aorta rings were exposed to contractile and relaxant agents. KCl contraction and papaverine relaxation responses were similar. Relaxation responses of YC-1 and DEA/NO decreased in suramin group. In both groups in the presence of ODQ, a sGC inhibitor, the relaxation responses of YC-1 and DEA/NO decreased. The cGMP content was determined by radioimmunoassay technique. The content of cGMP in the suramin group decreased. In the presence of YC-1 and DEA/NO in both groups, cGMP content increased, but in ODQ-added groups, there was a significant decrease. We conclude that in preeclampsia, the decrease of relaxation responses and the decrease of cGMP content could be due to the reduction in stimulation of sGC and the decrease in cGMP levels.

Effects and selectivity of CL 316243, beta-3-adrenoceptor agonist, in term-pregnant rat myometrium.

BACKGROUND/AIMS: Recent evidence supports a predominant role of ß(3)-adrenoceptors at the end of pregnancy in myometrium. This study was designed to characterize the pharmacology of the selective ß(3)-adrenoceptor agonist CL 316243 on oxytocin-induced myometrial contractions and the levels of cAMP and cGMP of myometrial strips isolated from term-pregnant rats. METHODS: Myometrial strips were obtained from term-pregnant Wistar albino rats (n = 10), mounted in organ baths and tested for changes in isometric tension in response to CL 316243 (10(-10)-10(-5) M) on oxytocin-induced myometrial contractions. Effects of CL 316243 on cAMP and cGMP levels in isolated myometrial strips (n = 8) were evaluated by radioimmunoassay kits. We evaluated the effect of increasing concentrations of CL 316243 on myometrial contractions and on contractions of myometrial smooth muscle pretreated with metoprolol, ICI 118.551 and SR 59230A (ß(1)-, ß(2)-, ß(3)-adrenoceptor antagonists, respectively, 10(-6) M). RESULTS: The inhibition of the amplitude of oxytocin-induced contractions by CL 316243 were antagonized with SR 59230A (10(-6) M), but they were not changed by metoprolol (10(-6) M) or ICI 118.551 (10(-6) M). CL 316243 increased cAMP levels compared to the control group. CL 316243 increased cGMP levels, in the CL 316243 group more than in the control group, but this increase is less significant than cAMP levels. CONCLUSION: These results demonstrate that the inhibition of rat myometrial contractions with CL 316243 is mediated by ß(3)-adrenoceptor subtype and increased cAMP and cGMP levels.

Nifedipine enhances the relaxant effects of cyclo-oxygenase inhibitors on the bovine ciliary muscle.

BACKGROUND/AIMS: The inhibition of cyclo-oxygenase (COX) enzymes and the blockade of Ca (2+) channels play an important role in the regulation of smooth muscle relaxation. This study was designed to investigate the relaxant effects of celecoxib, DFU (5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furanone), and indomethacin, cyclo-oxygenase (COX-1 and -2) inhibitors, in the absence or presence of a nifedipine, L-type Ca(2+) channel blocker, on bovine ciliary muscle. METHODS: Ciliary muscle strips (n = 12) were mounted in organ baths and tested for changes in isometric tension in response to celecoxib, DFU, and indomethacin. The relaxant effects of celecoxib, DFU, and indomethacin on carbachol-induced contractions in the presence or absence of nifedipine were investigated. RESULTS: Celecoxib (10(-7)-10(-4) M), DFU (10(-7)-10(-4) M), indomethacin (10(-7)-10(-4) M), and nifedipine (10(-7)-10(-4) M) inhibited the carbachol-induced contractions in a concentration-dependent manner. The E(max) value of indomethacin was significantly higher than the E(max) values of celecoxib and DFU in ciliary muscle (P < 0.05), with no significant change in pD(2) values (P > 0.05). The relaxation responses by celecoxib, DFU, and indomethacin were significantly increased in the presence of nifedipine (10(-6) M). There were no significant differences between pEC50 and values of celecoxib, DFU, and indomethacin in the absence of nifedipine (10(-6) M) (P > 0.05), but E(max)values were significantly increased (P < 0.05). CONCLUSIONS: These results suggest that the celecoxib, DFU, and indomethacin cause relaxation in ciliary muscle precontracted with carbachol. Blockade of calcium channels with nifedipine in ciliary muscle may increase the relaxant effect of celecoxib, DFU, and indomethacin. The topical or systemic use of celecoxib, DFU, and indomethacin with nifedipine can cause blurred near vision due to ciliary muscle relaxation, and in ocular pain conditions caused by ciliary spasm, the pain can be decreased more easily by combined use of these drugs.

The effect of sildenafil on the altered thoracic aorta smooth muscle responses in rat pre-eclampsia model.

The pathophysiology of pre-eclampsia is still unknown thus effective primary prevention is not possible at the stage. The present study was conducted to research the smooth muscle responses in the pre-eclampsia model with suramin treated rats and the effect of phosphodiesterase-5 (PDE5) inhibitor on these responses. Rats of three groups; control, suramin and suramin+sildenafil were given intraperitoneal injections of saline, suramin or sildenafil citrate. Suramin injections caused increased blood pressure, protein in urine and caused fetal growth retardation. The use of sildenafil citrate straightened significantly both blood pressure and average fetus weight, but did not reach to control values. At the end of pregnancy, thoracic aorta rings were exposed to contractile and relaxant agents. KCl contraction responses, sodium nitroprusside and papaverine relaxation responses were similar in three groups. Contraction responses of phenylephrine, increased significantly in suramin group. Relaxation responses of acethylcholine and bradykinin decreased in suramin group. The use of sildenafil citrate partially straightened both relaxation and contraction responses, but did not reach to control values. In all groups in the presence of L-nitromonomethylarginine (L-NAME), 1H-(1, 2, 4) oxadiazole (4, 3-a) guinoxalin-1-one (ODQ) and indomethacin decreased the relaxation responses of acetylcholine and bradykinin. The cyclic guanosine monophosphate (cGMP) content of thoracic aorta tissue was determined by radioimmunoassay technique. The content of cGMP in suramin group decreased and use of sildenafil citrate increased the cGMP content but did not reach to control values. We conclude that in pre-eclampsia, the increase of contraction responses, the decrease of relaxation responses and the decrease of cGMP content can depend on insufficiency about synthesis or release of relaxant factors which was released from the vessel endothelium. The results in this study show that in pre-eclampsia; PDE5 inhibitors enhance endothelial function and may be used for protection. Further studies are needed to clear the efficiency and safety of PDE5 inhibitors.

Alterations in spontaneous contractions of rat ileum and jejunum after peritonitis.

The aim of this study was to investigate the effects of peritonitis on spontaneous contractions of ileum and jejunum smooth muscles isolated from rats. Peritonitis was induced by cecal ligation and puncture in 8 rats. Another group of 8 rats underwent a sham operation and acted as controls. Twenty-four hours after the operation, the rats were killed, and their ileum and jejunum smooth muscles were excised and placed in circular muscle direction in a 10 ml organ bath. Changes in the amplitude and frequency of spontaneous contractions were analyzed before and after the addition of different antagonists. Peritonitis induced the decrease in the amplitude and frequency of spontaneous contractions in ileum and jejunum smooth muscles. In control groups, both ileum and jejunum, the amplitude and frequency of spontaneous contractions were significantly elevated in the presence of N(G)-nitro-L-arginine (L-NNA) and indomethacin. In peritonitis groups, both ileum and jejunum, the amplitude and frequency of spontaneous contractions were significantly enhanced in the presence of L-NNA, aminoguanidine, indomethacin and celecoxib compared to control values. In conclusion, peritonitis induces the decrease in the amplitude and frequency of spontaneous contractions of ileum and jejunum that can be attributed to the rise of nitric oxide synthase and cyclooxygenase isoforms levels.