Anti-inflammatory and antinociceptive activities of glucagon-like peptides: evaluation of their actions on serotonergic, nitrergic, and opioidergic systems.

RATIONALE: Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are gut derived hormones. GLP-1 and GLP-2 were shown to have pleiotropic effects in intestinal and pancreatic diseases. OBJECTIVE: We aimed to investigate the activities of GLP-1 and GLP-2 on nociception and inflammation in mice, involving their actions on serotonergic, nitrergic, and opioidergic systems. METHODS: Antinociceptive and anti-inflammatory activities of intraperitoneally injected GLPs were evaluated in hotplate latency test, formalin-induced behavioral, and paw edema tests. Ondansetron, a selective 5-HT3 receptor antagonist; L-NAME, a NOS inhibitor; and naloxone, an opioid antagonist were injected to determine the mechanisms of antinociception and anti-inflammation. We also measured blood glucose levels and performed rotarod test in order to evaluate whether the hypoglycemic effect of GLP compounds or alterations in locomotor activity may affect the latency in hotplate test and activity in formalin test. RESULTS: GLP-1 (0.2 mg/kg) and GLP-2 (0.05, 0.2 mg/kg) significantly increased pain threshold. GLP-1 (0.2 mg/kg) and GLP-2 (0.05, 0.1, 0.2 mg/kg) significantly decreased formalin-induced licking and shaking behaviors. GLP-1 or GLP-2 showed no significant inhibitory action on formalin-induced swelling in paws of mice. Antinociceptive actions of GLP-1 and GLP-2 were significantly decreased with ondansetron and naloxone, and paw shaking behavior significantly increased with naloxone. GLP-1 and GLP-2 did not impair rotarod performance, and did not cause a significant hypoglycemic effect in our normoglycemic mice after rotarod test. CONCLUSION: These finding indicated that the antinociceptive and anti-inflammatory effect of GLP-1 was related to opioidergic system. Antinociceptive effect of GLP-2 was partially related to 5-HT3 serotonergic or opioidergic system in hotplate test. However, the anti-inflammatory effect of GLP-2 was not directly related to 5-HT3, NO or opioids.

Ovarian-protective effects of clotrimazole on ovarian ischemia/reperfusion injury in a rat ovarian-torsion model.

BACKGROUND/AIMS: To evaluate the ovarian-protective effects of clotrimazole on ovarian ischemia/reperfusion injury in a rat ovarian-torsion model. METHODS: 32 Sprague-Dawley rats were randomly divided into four groups: (1) ischemia group (n = 8) in which only left adnexal torsion was performed for 2 h, but no treatment was given; (2) vehicle group (n = 8) in which left adnexal torsion was performed for 2 h and at the end of 2 h ischemia polyethylene glycol (3% PEG, 1 ml, i.p.) was administered and a 24-hour reperfusion was continued; (3) clotrimazole group (n = 8) in which left adnexal torsion was performed for 2 h and at the end of 2 h ischemia clotrimazole (30 mg/kg, i.p.) was administered and a 24-hour reperfusion was continued, and (4) control group (sham-operated, n = 6) in which no adnexal torsion and no treatment were given. The criteria for ovarian ischemia were follicular cell degeneration, vascular congestion, hemorrhage and infiltration by inflammatory cells. Each specimen was scored for each criterion (0, none; 1, mild; 2, moderate; 3, severe). RESULTS: Clotrimazole significantly decreased plasma levels of serum malondialdehyde, ischemia-modified albumin, and total oxidant status. CONCLUSION: This study showed the ovarian-protective effects of clotrimazole on ovarian ischemia/reperfusion injury.

The effect of simvastatin on picrotoxin-induced seizure in mice.

OBJECTIVE: To study the effect of simvastatin on picrotoxin-induce seizures in mice in order to understand the impact of gabaergic system on neuronal cell death. METHODS: The study was held between July and September 2011, at the Karadeniz Technical University in Trabzon, Turkey. Balb/c mice weighting 20-40g were randomly selected and divided into five groups of six each. The first group was designated as control group; and the second as the picrotoxin (10mg/kg; intraperitoneal) alone group. The rest of the groups were administered simvastatin in dozes of 10, 20 and 40mg/kg respectively. Onset, number and duration of seizures, and death time were measured in mice for one hour. At the end of the study, the brain was removed from mice and normal and degenerative pyramidal neurons were counted in hippocampal CA1, CA2, CA3 region by light microscope. Using SPSS 17, Mann=Whitney U and Chi square and student-T tests were performed for statistical analysis. RESULTS: Simvastatin (10mg/kg) significantly decreased the number and duration of picrotoxin-induced seizures in mice. In addition, Simvastatin (10, 20, and 40mg/kg) significantly reduced the total number of abnormal pyramidal cells in CA1 and CA3 hippocampal regions compared to the picrotoxin-alone group. CONCLUSION: The effect of simvastatin on picrotoxin-induced seizures may be the result of increase in gabaergic activity and decrease in glutamatergic activity. More studies are needed to validate these results.

The effects of sertraline on blood lipids, glucose, insulin and HBA1C levels: A prospective clinical trial on depressive patients.

BACKGROUND: In this study, we aimed to investigate the possible effects of sertraline on blood glucose and lipid levels as risk factors for cardiovascular disease in depressive patients. METHODS: Eight male and twelve female depressive patients, diagnosed according to DSM-IV criteria, were included in this study. The subjects aged 19-50 years, did not smoke, and had normal body mass index (BMI), homeostasis model assessment-estimated insulin resistance (HOMA-IR) values, blood pressure, blood glucose, insulin and lipid levels. Sertraline therapy (50 mg/day) was started. Patients with diabetes mellitus, heart disease, pregnancy, and those taking other drugs were excluded from the study. Blood glucose, insulin, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), and triglyceride values were measured in patients before, and at the 4(th), 8(th) and 12(th) weeks after treatment with sertraline. Moreover, HbA1C levels were measured at the beginning and at the end of the treatment (at 12(th) weeks). RESULTS: There were no significant differences in physical examination (blood pressure, BMI, body weight, height, waist circumference) and laboratory findings (glucose, HDL-C, LDL-C, HOMA-IR and HbA1C levels) at the 12(th) week after of treatment with sertraline compared to pretreatment values. However, insulin levels at the 4(th), 8(th) and 12(th) weeks significantly increased compared with pretreatment values. Likewise, triglyceride levels at the 8(th) and 12(th) weeks significantly increased compared with pretreatment values. CONCLUSIONS: Sertraline-treated patients have to be followed up for blood insulin and triglyceride levels. In addition, their treatment plan needs to be adjusted as necessary to prevent possible metabolic changes.

Paroxetine inhibited the relaxations induced by EFS in mice corpus cavernosum: is it a NOS inhibition?

Selective serotonin reuptake inhibitors are used in the treatment of psychiatric disorders but are associated with high incidence of sexual dysfunction such as ejaculation disorders by sertraline and fluoxetine, erection disorders by paroxetine. The aim of this study is to evaluate the effects of paroxetine, sertraline and fluoxetine on relaxation of smooth muscle of corpus cavernosum on the basis of nitric oxide (NO). Male mice were killed by cervical dislocation and their penile tissues were immediately removed. The tissues were incubated in organ baths containing Krebs solution at 37 degrees C and bubbled with 95% O(2) and 5% CO(2). The corpus cavernosum strips were contracted with 10(-5 )m phenylephrine (PHE) and relaxed with either paroxetine, sertraline, fluoxetine (10(-8)-10(-4 )m) or electrical field stimulation (EFS). The effects of paroxetine, sertraline and fluoxetine were examined on EFS-induced relaxations. While paroxetine did not show any effect on the corpus cavernosum strips precontracted with PHE, sertraline and fluoxetine caused a relaxation at concentrations of 3 x 10(-5)-10(-4 )m. The relaxations induced by sertraline and fluoxetine were completely abolished by L-NAME, but not D-NAME. The relaxations induced by EFS could be inhibited by L-NAME but not D-NAME. Paroxetine inhibited the relaxations at high concentrations. L-arginine potentiated the relaxations induced by EFS; however in the presence of paroxetine these relaxations were not observed. In contrast, sertraline (10(-8)-10(-5 )m) and fluoxetine (10(-8)-10(-5)m) increased the relaxations induced by EFS. Sertraline and fluoxetine seem to be releasing some relaxing factor(s) and this factor may be NO. Paroxetine probably has a NOS inhibitory activity either on nNOS or eNOS, in contrast to sertraline and fluoxetine.

Antinociceptive effects of fluoxetine and paroxetine with their related actions on glycemia in mice.

OBJECTIVES: Clinical and experimental trials have demonstrated that some of selective serotonin reuptake inhibitors (SSRIs) have some suspicious effects on blood glucose levels in different directions. Especially fluoxetine and sertraline are studied in this point of view. These drugs are also used in treatment of depression and peripheral neuropathy in diabetic patients. Paroxetine and fluoxetine, members of this drug group, besides having antidepressant effects were shown to have antinociceptive effects in animals and humans. They can be used in the treatment of chronic pain as an adjuvant drug or alone. But less is known about their actions on pain in case of diabetes. The aim of this study is to investigate the antinociceptive effects of fluoxetine and paroxetine in diabetic and non-diabetic mice while monitoring their effects on blood glucose levels. METHODS: Mice of either sex were randomly used in experiments. The antinociceptive effects of paroxetine and fluoxetine were evaluated using hot plate test both in diabetic and non-diabetic mice. The effects of these drugs on blood glucose levels were also evaluated in another group of mice both in diabetic and non-diabetic mice. RESULTS: Fluoxetine and paroxetine showed significant antinociceptive effect at all doses and at all times tested in non-diabetic mice, but they could not successfully show this effect in diabetic mice. They also had controversial effects on blood glucose levels. CONCLUSION: Although they showed increasing or decreasing effects on blood glucose levels in non-diabetic and diabetic mice, they showed antinociception on hot-plate test showing dissociation between blood glucose levels and analgesia.

Acute alterations in biochemistry, morphology and contractility of rat isolated urinary bladder via increased intra-abdominal pressure.

OBJECTIVE: To determine the acute effects of increased intra-abdominal pressure (IAP) on the biochemistry, morphology and contractility of the rat isolated urinary bladder using an experimental laparoscopy model. METHODS: We divided 24 adult female Sprague-Dawley rats into three groups. The control group (group I) was not subjected to increased IAP. In groups II and III, IAPs of 10 and 20 mm Hg, respectively, were established by carbon dioxide pneumoperitoneum for 60 min. Thirty minutes after desufflation, the rat urinary bladder dome was removed for in vitro pharmacological investigation, measurement of malondialdehyde (MDA) levels and histopathological examination. Statistical comparisons between groups were performed. RESULTS: Tissue MDA levels in groups II and III were significantly higher than in the control group. In group II, only the lamina propria was significantly damaged. However, the epithelium, lamina propria, and serosa were significantly damaged in group III. Acetylcholine potentiated contractions in both IAP groups. Increased responses to electrical field stimulation in the IAP groups were significant only in group II. CONCLUSIONS: In this experimental model, 10 and 20 mm Hg of IAP induced by pneumoperitoneum increased MDA levels and caused important changes in the morphology and contractile response of the urinary bladder.

Effect of gender on antinociceptive effect of paroxetine in hot plate test in mice.

PURPOSE: Many studies have reported both a gender difference in the rates of depression and its treatment by using any of the widely used antidepressant drug groups. Some studies suggest that females respond more poorly to tricyclic antidepressants than males and appear to respond better to selective serotonin reuptake inhibitors (SSRI). There is no study investigating the analgesic/antinociceptive effects of antidepressant drugs on the basis of gender difference. In this study, we aimed to investigate the antinociceptive effect of paroxetine on the basis of gender difference. METHODS: The antinociceptive effect of paroxetine was tested using hot plate test in Balb/c mice (30-40 g). The animals were divided into eight groups on the basis of gender. FINDINGS: While paroxetine did not induce an antinociceptive effect in both sex at a dose of 1 mg kg(-1), it showed significant antinociceptive effects in both sex at a dose of 5 or 10 mg kg(-1). None of the doses of paroxetine revealed a gender difference in its antinociceptive action. CONCLUSION: There are several studies showing positive or negative evidence on the gender difference of paroxetine's antidepressant effect, but in the literature there is no study about the gender difference of paroxetine's or any other SSRI drug's antinociceptive effect. In conclusion, our results do not show any gender difference in antinociceptive effect of paroxetine that may be important especially when it would be used as an adjuvant agent in some painful conditions.

The acute alterations in biochemistry, morphology, and contractility of rat-isolated terminal ileum via increased intra-abdominal pressure.

AIM AND SCOPE: To determine the acute effects of increased intra-abdominal pressure (IAP) on the biochemistry, morphology, and contractility of the isolated terminal ileum of rats. BACKGROUND: Laparoscopic procedures are used clinically in diagnostic and treatment modalities and experimentally as a model of ischemia-reperfusion injury induced by the elevation of IAP. Although some clinical and in vivo experimental studies investigate the results of ischemia-reperfusion injury whether induced by elevated IAP or clamping, there is no in vitro study that has investigated the acute effects of high IAP mimicked by a laparoscopic intervention in any of the intra-abdominal organs (like terminal ileum) on the basis of contractility which represents the motility. METHODS: Twenty-four adult with either sex Sprague-Dawley rats were divided into three groups. The control group (Group I) was not subjected to any IAP. In Groups II and III, an IAP of 10 and 20 mmHg, respectively, was established by carbon dioxide pneumoperitoneum for a period of 60 min. Thirty minutes after the desufflation, the terminal ileum was removed for in vitro pharmacological investigation, measurement of malondialdehyde (MDA) values, and histopathological examination. Statistical comparisons among groups were done using the Kruskal-Wallis variance analysis, with post hoc comparison performed with the Mann-Whitney U-test. RESULTS: Tissue MDA value and the damage scores of mucosa and submucosa were significantly increased in both IAP groups. The smooth muscle layer was significantly damaged only in Group III. The contractions obtained by electrical field stimulation (EFS) were inhibited in both IAP groups, and the contractions to acetylcholine were inhibited in Group III when compared to the control group. CONCLUSIONS: In conclusion, we can say that pneumoperitoneum induced IAP may inhibit contractile responses, cause structural alterations which may be related to ischemia-reperfusion injury in rat terminal ileum.

The contracting and relaxing responses of human internal mammary artery grafts harvested by two different methods.

Perioperative spasm of internal mammary artery is a common experience in coronary artery bypass grafting. Many techniques were described of harvesting the internal mammary artery to prevent vasospasm. We investigated the comparison of the contracting and relaxing responses of human internal mammary artery grafts harvested by two different methods. Patients were divided into two groups depending on the harvesting technique. In the first and second groups arteries were harvested by classical and carbon dioxide insufflation techniques, respectively. In both groups, endothelial function of arteries was assessed by precontracting the rings with phenylephrine (10(-5)M) and dilatating them by cumulative acetylcholine (10(-8) to 10(-5)M) concentrations. Cumulative concentration-response curves for phenylephrine (10(-8) to 10(-4)M), noradrenaline (10(-9) to 10(-4)M), and 5-hydroxytryptamine (10(-9) to 10(-4)M) were obtained in all groups. Endothelial integrity of arteries were histopathologically evaluated. In both groups, acetylcholine caused concentration-dependent relaxations in rings precontracted with phenylephrine (10(-5)M). In arteries harvested by carbon dioxide insufflation technique, acetylcholine caused significantly higher relaxations compared to the rings obtained by classical technique (p<0.05). In all rings of study groups, phenylephrine, noradrenaline and 5-hydroxytryptamine caused concentration-dependent contractions. There was not any significant difference in concentration-dependent responses of these contracting pharmacological agents between the groups. Histopathological evaluation revealed no major arterial damage in both groups. Carbon dioxide insufflation technique does seem not only to protect the integrity of the endothelium and the whole vessel, but also prevent the possible vasospasm of the internal mammary artery segments.

A case of rosiglitazone exposure in the second trimester of pregnancy.

AIM: Data about rosiglitazone use in pregnancy is limited. We aimed to present a pregnant woman who exposed to rosiglitazone in the second trimester and the fetal outcome. SUBJECT: The case was a 42-year-old, multigravid Caucasian woman with a history of diabetes mellitus type II for 4 years prior to her current pregnancy. Her diabetes was managed by diet and exercise and she has not received any drug therapy until the 13th week of her sixth (present) and unplanned pregnancy. The case was exposed to rosiglitazone (4 mg/day) between 13th and 17th gestational weeks. After the diagnosis of pregnancy at the 17th week, rosiglitazone was stopped and insulin therapy was started. At the 37th week, she had a healthy male infant (4500 g, 50 cm). The baby was examined and no major or minor malformations were observed. CONCLUSION: This is the first case present in the literature exposed to rosiglitazone in the second trimester of her pregnancy. The data from the present case may contribute to the existing limited knowledge about rosiglitazone in pregnancy.

Psychotropic drugs in pregnancy: a case-control study.

Psychotropic drug exposure during pregnancy is a common problem. Among the 601 cases exposed to drugs during pregnancy, who were followed by our Toxicology Information and Follow-up Service, 124 cases had used psychotropic drugs for depression, anxiety, or psychotic disorders. As the control group, 248 women, who did not use any drugs were selected. Of the 124 cases, 80 (64.5%) had healthy babies, and 17 (13.7%) decided to terminate the pregnancy. Spontaneous abortions, intrauterine death (in the 38th week) and premature deliveries were observed in the 9 (7.3%), 1 (0.8%) and 3 (2.4%) cases, respectively, in the drug exposure group. Pregnancies of the 14 (11.3%) cases were continuing during the preparation of this manuscript. Of the 248 controls, 151 (60.9%) had healthy babies, 9 (3.6%) experienced spontaneous abortion and 3 (1.2%) decided to terminate their pregnancies, 3 (1.2%) had premature deliveries, and we observed one (0.4%) congenital abnormality, 81 (32.7%) cases were still pregnant. Odds Ratio (95% confidence interval) for spontaneous abortion was found to be 1.35 (1.27-11.82) in the cases exposed to psychotropic drugs (P=0.02). No developmental problems were observed in the babies followed for 12 months. These data may give information about the early- but not the late-term effects of psychotropic drugs used in pregnant women.

The different roles of 5-HT(2) and 5-HT(3) receptors on antinociceptive effect of paroxetine in chemical stimuli in mice.

Serotonin (5-HT) is known to be an important mediator in pain modulation. Some centrally acting agents, like selective serotonin reuptake inhibitors (SSRIs), modulate pain. Activation of the endogenous opioid mechanisms or potentiation of analgesic effect by serotonergic and/or noradrenergic pathways might be involved in antinociception of SSRIs. However, peripheral mechanisms of nociception are not clear. In this study, the antinociceptive effect of paroxetine, its interaction with the opioidergic system and serotonin receptors were tested using the writhing test in mice. Paroxetine (5, 10, 20 mg/kg) induced an antinociceptive effect following i.p. administration in writhing test. For the groups in which the antagonists were tested, the dose of paroxetine that caused a significant and equipotent analgesic effect similar to 0.5 mg/kg morphine was selected. Naloxone significantly antagonized the antinociceptive effects of both paroxetine and morphine in a similar pattern and magnitude. Ketanserin (5-HT(2)-receptor antagonist) or ondansetron (5-HT(3)-receptor antagonist) alone did not alter the nociceptive action of acetic acid. While the antinociceptive effect of paroxetine was highly potentiated by ketanserin, ondansetron reduced that antinociception. In conclusion, our results indicate that the antinociceptive effect of paroxetine mainly depends on central opioidergic and serotonergic mechanisms. Peripheral serotonergic mechanisms/receptors may contribute to this antinociceptive effect, especially by 5-HT(3)-receptor subtypes.

Newer antidepressants in pregnancy: prospective outcome of a case series.

Antidepressant drug choice in pregnancy is a complex problem especially for new drugs. Among 590 cases exposed to drugs during pregnancy who were followed by our center, 21 cases used newer antidepressants, i.e., venlafaxine, mirtazapine, nefazodone. We present the gestational findings and fetal outcomes of these cases. Ten cases had used venlafaxine, one case had used both venlafaxine and mirtazapine, eight had used mirtazapine alone or with some other drugs and two had used nefazodone, in the first trimester. Of the 21 cases, 17 (80.9%) had healthy babies, 3 (14.3%) decided to terminate the pregnancy, and 1 (4.8%) spontaneous abortion was observed in a case exposed to mirtazapine, alprazolam, diazepam and trifluoperazine. All obstetrical findings were normal during the pregnancy of each case. No congenital abnormality and developmental problem was observed in the babies followed up for 12 months. The aim of the present study is to contribute the data to the limited knowledge available in the literature regarding human pregnancy.

Sibutramine use in pregnancy: report of two cases.

BACKGROUND: Sibutramine is a drug used for the medical treatment of obesity. No data are available on sibutramine use in pregnancy. We report the fetal outcomes of two pregnant women exposed to sibutramine. CASES: The first woman was exposed to 10 mg/day of sibutramine during gestational weeks 4-6. The second woman was exposed to 10 mg/day of sibutramine during gestational weeks 5-8. At weeks 37 and 39, they delivered healthy infants. CONCLUSIONS: To our knowledge, this is the first report of sibutramine exposure in pregnancy. These cases may contribute to the knowledge about sibutramine use during pregnancy.

Normal pregnancy outcome following inadvertent exposure to rosiglitazone, gliclazide, and atorvastatin in a diabetic and hypertensive woman.

The subject is a diabetic and hypertensive woman treated early during an unplanned pregnancy with a multi-drug regimen that included three drugs with no prior history for use in pregnant women (rosiglitazone, gliclazide, atorvastatin). She was under care for chronic hypertension, which she suffered for 14 years, and diabetes mellitus, hypercholesterolemia, anxiety disorder, morbid obesity and epilepsia for 5 years. She was exposed to rosiglitazone (4mg/day), gliclazide (60mg/day), and atorvastatin (40mg/day) in addition to acarbose, spironolactone, hydrochlorothiazide, carbamazepine, thioridazine, amitryptiline, chlordiazepoxide, and pipenzolate bromide during the first 7 weeks of gestation while unaware of pregnancy. Pharmacotherapy was adjusted following clinical recognition of pregnancy during the 8th week. She gave birth to a normal healthy infant at the 36th week of gestation. This is the first reported case of human exposure to rosiglitazone, gliclazide, and atorvastatin during pregnancy. Although the normal pregnancy outcome does not address the safety of these drugs for use in pregnancy, these data contribute to a limited knowledge regarding human exposure to these antidiabetic drugs.

Use of polypharmacotherapy in pregnancy: a prospective outcome in a case.

PURPOSE: Little is known about the risks associated with prenatal exposure to atypical antipsychotics. Our objective is to present a case of exposure to risperidone and quetiapine in pregnancy, and additionally to some other drugs. CASE: Our case (36-year old) has suffered schizophrenia (DSM-IV) for 5 years and used these drugs (risperidone, quetiapine, mirtazapine, thioridazine, diazepam, hydroxyzine, clomipramine, fluvoxamine, alprazolam, carbamazepine, biperiden, haloperidol, ampicillin+sulbactam, enoxaparin, oxerutine) in her third pregnancy. Because of her psychotic condition, Mrs. N.B. was not aware of her pregnancy until 22nd week and the pregnancy could not be terminated. She had a female infant (3000 g, 50 cm) with APGAR scores of 8-9 at the first and fifth minutes at 37th week with an uncomplicated vaginal delivery. The baby was normal. CONCLUSION: This case may contribute to the existing knowledge regarding use of atypical antipsychotics in pregnancy.