The evaluation of analgesic effects of milnacipran and sertraline in tail-flick test.

INTRODUCTION: Antidepressant drugs are used in the treatment of pain as an adjuvant or alone. It has been shown that antidepressant drugs have analgesic effects in various diseases (diabetic neuropathy, low back pain, cancer pain etc.) Sertraline is a potent serotonin re-uptake inhibitor. Some antidepressant drugs inhibited both of the reuptake of serotonin and of noradrenaline. These drugs are called serotonin-noradrenaline re-uptake inhibitors (SNRIs). Milnacipran is a serotonin-noradrenaline re-uptake inhibitor. We have studied the analgesic effects of sertraline and milnacipran after acute and chronic application in tail-flick test in mice. METHODS: The analgesic effects of milnacipran (10, 30, 50 mg/kg) and sertraline (10, 20, 50 mg/kg) were measured after acute and chronic application in tail flick test. The analgesic effects of milnacipran (30 mg/kg) or sertraline (50 mg/kg) were evaluated after the application of L-NAME (10 mg/kg), naloxone (5 mg/kg), prazosin (1 mg/kg), ondansetron (0.1 mg/kg) in tail flick test. RESULTS: Milnacipran (30 mg/kg) and sertraline (50 mg/kg) produced statistically significant analgesic effect compared to their control values after acute and chronic application in tail-flick test. The analgesic effects of both milnacipran (30 mg/kg) and sertraline (50 mg/kg) in the presence of L-NAME (10 mg/kg), naloxone (5 mg/kg), ondansetron (0.1 mg/kg) and prazosin (1 mg/kg) were inhibited in tail-flick test. CONCLUSION: These results indicate that the analgesic effects of milnacipran and sertraline are related to nitrergic, opioidergic, serotonergic and adrenergic system (Fig. 8, Ref. 23).

The evaluation of analgesic effects of simvastatin, pravastatin and atorvastatin in hot plate test.

OBJECTIVES: Simvastatin, pravastatin and atorvastatin have been evaluated whether to have analgesic effects in mice in hot plate test. MATERIALS AND METHODS: Simvastatin (5, 10, 30 mg/kg), pravastatin (5, 10, 30 mg/kg) and atorvastatin (5, 10, 30 mg/kg) were administered acute and chronically by oral gavage in mice. Control (pretreatment value) and posttreatment (after drugs application) values in 60th and 120th minutes were measured in hot-plate test. RESULTS: All three drugs at 10, 30 mg/kg doses produced analgesic effects compared with their control values in 60th and 120th minutes on acute and chronic application in mice. The analgesic effects of drugs were evaluated after the application of L-nitro arginine methyl ester (L-NAME) (10 mg/kg) or naloxone (0.5 mg/kg). L-NAME (10 mg/kg) has no effect compared to the control value on both minutes. The analgesic effects of both atorvastatin (30 mg/kg) and simvastatin (30 mg/kg) in the presence of L-NAME (10 mg/kg) were not inhibited. However, the analgesic effect of pravastatin (30 mg/kg) in the presence of L-NAME (10 mg/kg) was inhibited significantly on both minutes (p < 0.05). Naloxone (0.5 mg/kg) has no effect compared to the control value on both minutes. The analgesic effect of atorvastatin (30 mg/kg) in the presence of naloxone (0.5 mg/kg) was partially (43%) but significantly inhibited only on 60th minute (p < 0.05). The analgesic effect of pravastatin (30 mg/kg) in the presence of naloxone (0.5 mg/kg) was partially (48-40%) but significantly inhibited on both minutes (p < 0.05). However, the analgesic effect of simvastatin (30 mg/kg) in the presence of naloxone (0.5 mg/kg) was inhibited significantly on both minutes (p < 0.05). CONCLUSIONS: These finding indicated that the analgesic effect of pravastatin was related to nitrergic systems and partially opioidergic system; analgesic effect of simvastatin was related to opiodergic system in hot plate test. However, the analgesic effect of atorvastatin was not directly related to both system.

Ketanserin inhibits digoxin-induced arrhythmias in the anaesthetized guinea-pig.

Digoxin inhibits the membrane-bound ATPase enzyme, resulting in a rise in intracellular sodium and activated outward potassium current, predisposing to arrhythmias. In this study, the effect of ketanserin, thought to block outward potassium currents, was investigated on digoxin-induced arrhythmias. Twenty-four guinea-pigs were studied in four groups (control, ketanserin 0.5 mg/kg, ketanserin 1 mg kg, ketanserin 2 mg/kg). Under pentobarbital anaesthesia (40 mg/kg), 15 min after injection of saline or ketanserin, digoxin (0.6 mg/kg) was administered through the jugular vein. Carotid artery blood pressure and electrocardiogram (ECG) were recorded. The time for the onset of the first arrhythmia and incidence of ventricular tachycardia (VT), ventricular fibrillation (VF), and premature ventricular contraction (PVC) were determined. Arrhythmias were scored according to the MacLeod scale. Ketanserin produced minor haemodynamic effects and lacked, by itself, arrhythmogenic effects at the doses studied. However, it increased the time for the onset of the first digoxin-induced arrhythmia and decreased the incidence of VT, VF and PVC. We conclude that ketanserin inhibits digoxin-induced arrhythmias in guinea-pigs.

Evidence that the nitrergic neurotransmitter and endothelium-derived relaxing factor might be S-nitrosothiols in the mouse corpus cavernosum.

The effects of thimerosal, a sulfhydryl oxidizing agent on nitrergic, endothelium-dependent and -independent relaxations were investigated to examine the possibility that the nitrergic neurotransmitter and endothelium-derived relaxing factor (EDRF) could be S-nitrosothiol or free nitric oxide (NO) in the isolated mouse corpus cavernosum. Thimerosal (5 x 10(-6)-2 x 10(-5) M) inhibited or almost abolished electrical field stimulation--(EFS, 30V, 0.5 ms, 15 sec, 1, 2, 4, 8, 16 Hz), acetylcholine--(ACh, 5 x 10(-8)-1.25 x 10(-6) M), glyceryl trinitrate--(GTN, 3 x 10(-7)-3 x 10(-6) M), and S-nitrosoglutathione--(GSNO, 5 x 10(-6)-1.25 x 10(-4) M) induced relaxations. Thiomerosal inhibition seems to be specific to L-arginine NO pathways since it had no effect on acidified sodium nitrite--(10(-4)-5 x 10(-4) M), photoactivated sodium nitrite--(2 x 10(-4) M), isoprenaline--(10(-6) M), or papaverine--(10(-4) M) elicited relaxations. Moreover, the inhibitory effect of thimerosal on the nitrergic, ACh- or GTN-induced relaxations were partly reversed by sulfhydryl-containing compounds, L-cysteine (10(-3) M), dithiothreitol (10(-3) M), or glutathione (10(-3) M). However L-methionine (10(-3) M), which contains a methyl group on the sulphur atom, failed to restore the thimerosal inhibition. Thimerosal did not change the contraction produced by 10(-4) M NG-nitro-L-arginine methyl ester. These findings indicate that the nitrergic neurotransmitter as well as EDRF may not be free NO but NO-transferring molecules, probably S-nitrosothiols, in the mouse corpus cavernosum.

Effects of N-acetylcysteine on acute necrotizing pancreatitis in rats.

The aim of this study was to investigate the influence of N-acetylcysteine (NAC) on acute necrotizing pancreatitis (ANP) induced by glycodeoxycholic acid in rats. The induction of ANP resulted in significant increase in mortality rate, pancreatic necrosis and serum activity of amylase, alanine aspartate transferase (ALT), interleukin-6 (IL-6), lactate dehydrogenase (LDH) in bronchoalveolar lavage (BAL) fluid, serum concentration of urea, tissue activity of myeloperoxidase (MPO) and malondialdehyde (MDA) in the pancreas and lung, and significant decrease of concentrations of calcium, blood pressure, urine output and pO(2). The use of NAC inhibited the changes in urine output, pO(2), tissue activity of MPO and MDA in pancreas and lungs, and the serum activity of IL-6, ALT, and serum concentrations of urea and calcium. NAC reduced the mortality and pancreatic damage. The use of NAC has a beneficial effect on the course of ANP in rats. It may be used in the treatment of acute pancreatitis.

Sertraline inhibits the contractile responses to noradrenaline, KCl and electrical field stimulation of rat isolated vas deferens.

1. The aim of this study was to investigate the effect of sertraline, a selective serotonin re-uptake inhibitor, on contractile responses to noradrenaline (NA), KCl, serotonin (5-HT) and electrical field stimulation of rat isolated vas deferens. 2. Pre-treatment with 10(-4) M sertraline showed inhibitory effects on responses to NA, KCl, 5-HT and electrical field stimulation, while pre-treatment with 10(-6) and 10(-5) M sertraline caused potentiation of responses to NA (10(-7) and 10(-6) M). 3. A voltage-dependent calcium channel activator, Bay K 8644, restored the inhibited responses when sertraline was washed out of the organ bath, although restoration could not be seen when sertraline was not removed. 4. The inhibition of the contractile responses by sertraline pre-treatment may be via a mechanism through calcium channels which is additional to the selective serotonin re-uptake inhibitory effect of sertraline.

Effects of melatonin on acute necrotizing pancreatitis in rats.

The aim of this study was to investigate the influence of melatonin on acute necrotizing pancreatitis (ANP) induced by glycodeoxycholic acid in rats. The induction of ANP resulted in significant increases in mortality rate, pancreatic necrosis and increased serum activity of amylase, alanine aspartate transferase (ALT), interleukin 6 (IL-6), lactate dehydrogenase (LDH) in bronchoalveolar lavage (BAL) fluid, serum concentration of urea, tissue activity of myeloperoxidase (MPO) and malondialdehyde (MDA) in the pancreas and lung, and significant decrease of concentrations of calcium, blood pressure, urine output and pO (2). Melatonin inhibited the changes in blood pressure, urine output, pO (2), serum concentration of urea, and calcium, tissue activity of MPO and MDA in the pancreas and lung, LDH level in BAL fluid, and partially reduced serum activity of IL-6. Melatonin did not change serum activity of amylase, ALT, pancreatic damage and the mortality rate. The use of melatonin has a limited value on the course of ANP. It may be useful as a supportive treatment during ANP.

The effect of edothelium on the response to propofol on bovine coronary artery rings.

In this study, the effect of propofol on isolated bovine coronary artery tone was studied in artery rings precontracted with PGF2a. Propofol, in concentrations of 10-6-10-5 M did not change vascular smooth muscle tone, but at high concentrations (10-4-10-1 M) produced relaxation in rings with intact endothelium. In rings denuded of endothelium or treated with methylene blue, propofol produced relaxation at 10-3-10-1 M concentrations, but there was a significant decrease in relaxation compared to endothelium intact rings. In the presence of a calcium agonist (Bay K 8644; 10-5 M), propofol produced constriction in rings denuded of endothelium. These results suggest that high concentrations of propofol may have vasorelaxant effect on bovine coronary artery and that these effects may be due to actions on the endothelium and mediated by calcium channels.

Potentiating effect of Bay K 8644 on agonist-induced ileal contractions.

The effects of Bay K 8644 on agonist-induced ileal contractions were investigated. Histamine, serotonin and a acetylcholine (10(-8)-10(-4) M) produced a dose-dependent contraction. Maximum contraction was obtained by 10(-5) M serotonin. Its value was 1076 mg. Bay K 8644 (10(-6) M) increased the potency of histamine and serotonin-induced ileal contractions, but acetylcholine induced responses were not increased. All responses of agonists were inhibited by nifedipine (10(-6) M). This inhibition was decreased with increasing acetylcholine concentrations. These results suggest that histamine and serotonin induced/mediated contractions in guinea-pig ileum are independent of calcium influx through voltage operated channels.

Urinary tract infections in unplanned pregnancies and fetal outcome.

AIM: Many pregnant women are exposed to antibiotics for urinary tract infections during pregnancy. Our aim is to bring attention to antibiotherapy in unplanned pregnancies. METHOD: Among the 511 cases followed by our 'Toxicology Information and Follow-up Service' for drug exposure during pregnancy, 101 cases, unaware of their pregnancy, had been prescribed antibiotics and urinary antiseptic drugs in the first trimester of their unplanned pregnancies. The data on the outcome of these pregnancies and the babies were evaluated in this study. RESULTS: Of the 511 cases, 101 pregnant women were exposed to nine kinds of drugs. Seventy-five cases had healthy babies; two had babies with major malformations; one had a baby with congenital hypothyroidism; five had spontaneous abortions; and eight cases underwent induced abortions. The outcomes of eight pregnancies are unknown. Two pregnancies are still continuing without any problem. One baby had a fetal renal anomaly; however, the physical examination did not reveal any other malformations. The baby died 4 hours after delivery. Another baby had atrial septal defect, a major malformation, and one baby had congenital hypothyroidism. CONCLUSION: Urinary tract infection is one of the most frequently seen complications of pregnancy. Our study indicated that the possibility of pregnancy should be considered when prescribing antibiotics for urinary tract infections in women of reproductive age.