AIM:The aim of this study was to determine the effect of desflurane on reproductive capacity in female rats through a study of biochemical evaluations.METHOD:After experimental procedure, the blood samples of female rats were collected, and the malondialdehyde, interleukin‑1‑beta, total glutathione and superoxide dismutase levels were measured to evaluate oxidative stress. In addition to biochemical evaluations, the reproductive performance of the experimental groups was also examined.RESULTS:The results of our study demonstrated that in blood samples of desflurane‑treated groups of rats, the parameters indicating oxidative stress and inflammation increased, and antioxidant parameters decreased (p < 0.05). It was also proven that repeated desflurane doses caused infertility in female rats, prolonged the gestation period and reduced the number of offspring.CONCLUSIONS:This study showed that recurrent desflurane application can cause infertility problems through oxidative stress in female rats (Tab. 3, Fig. 1, Ref. 25).

BACKGROUND Tacrolimus (Tac) is a calcineurin inhibitor (CNI). Its therapeutic range is narrow and pharmacokinetic properties vary among patients. CYP3A5 and MDR1 single-nucleotide polymorphisms (SNPs) are the most effective polymorphisms that play an significant role in the pharmacokinetics of Tac. METHODS We investigated the influence of CYP3A5 (A6986G) and MDR1 (C3435T) gene polymorphisms on Tac trough concentration (C0), dose requirements (mg/kg), and dose-adjusted concentrations (ng/mL per mg/kg/d). CYP3A5 [*1/*1 (expresser), *1/*3 (expresser); *3/*3 (non-expresser)] and MDR1 (CC, CT, TT) gene polymorphisms were determined by allele-specific polymerase chain reaction in 67 adult Turkish renal transplant patients. The Tac dose (mg/kg/d) and C0 of each patient was acquired from the patient's file and dose-adjusted concentrations (ng/mL per mg/kg/d) were calculated at the 1st, 3rd, 6th, and 12th months after transplantation. The correlated serum hematocrit, platelet, urea, creatinine, and albumin were also determined. RESULTS The CYP3A5*1/*3 and CYP3A5*3/*3 allelic frequencies were 5.97% and 94.03%, respectively. There were no patients with the CYP3A5*1/*1 genotype. Tac dose was significantly lower in *3/*3 genotype than in *1/*1 genotype (3rd and 6th months: p ≤ 0.001; 12th month: p ≤ 0.05). Dose-adjusted Tac concentration was statistically higher in the *3/*3 genotype than in *1/*1 genotype at the 3rd and 6th months (p ≤ 0.05). The allelic frequencies of MDR1 CC, CT, and TT were 26.87%, 49.25%, and 23.88%, respectively. No statistically significant differences were detected between MDR1 genotypes and in all analyzed laboratory parameters. CONCLUSIONS CYP3A5 but not MDR1 genetic polymorphisms affected the Tac pharmacokinetics and dose requirements in renal transplant recipients. Pharmacogenetic methods can be used for selecting the initial dose to individualize immunosuppressive therapy.

BACKGROUND:Galangin, a flavonoid compound with acetylcholinesterase inhibitory activity, may improve cognitive functions by enhancing cholinergic transmission.OBJECTIVES:We aimed to investigate the effects of galangin on spatial memory impairment in rats.METHODS:The effects of galangin (50 and 100 mg/kg) and reference anti-dementia drug donepezil (1mg/kg) administrations were examined on memory impairment induced by the muscarinic cholinergic receptor antagonist scopolamine or the nicotinic cholinergic receptor antagonist mecamylamine in the Morris water maze (MWM) test. Hippocampal acetylcholine concentrations were also determined.RESULTS:Galangin 50 and 100 mg/kg significantly decreased the mean distance to platform and increased the time spent in the escape platform quadrant in scopolamine-treated rats. Galangin 100 mg/kg significantly decreased the mean distance to platform and increased the time spent in the escape platform quadrant in mecamylamine-treated rats. The effects of galangin in the MWM were comparable with donepezil. Scopolamine and mecamylamine decreased acetylcholine concentrations, whereas galangin both alone and with mecamylamine or scopolamine administration increased acetylcholine concentrations.CONCLUSION:Galangin improved memory impairment comparable to donepezil and nicotinic and muscarinic receptors may be involved in this effect. Galangin may be considered as a promising flavonoid in the prevention and treatment of memory impairment in Alzheimer's disease and other dementias (Fig. 7,Ref. 37).

Cisplatin is a widely used antineoplastic agent in the treatment of various cancers. Peripheral neuropathy is a well-known side effect of cisplatin and has potential to result in limiting and/or reducing the dose, decreasing the quality of life. Thus, effective treatments are needed. Agmatine is an endogenous neuromodulator that has been shown to exert antiallodynic effects in various animal studies. The first aim of this study was to investigate the invitro effects of agmatine on cisplatin-induced neurotoxicity. Primary cultures of dorsal root ganglia (DRG) which are the primary target of drug injury were prepared. DRG cells were incubated with cisplatin (100, 200, 500m). Then, agmatine (10, 100, 500m) was administered with the submaximal concentration of cisplatin. Cisplatin caused concentration-dependent neurotoxicity, and agmatine did not alter this effect. The second aim was to investigate the effects of agmatine on cisplatin-induced peripheral neuropathy in rats and the influence of nitric oxide synthase (NOS) inhibitor, L-NAME, in this effect. Female Sprague Dawley rats received intraperitoneal saline (control), cisplatin (3mg/kg), cisplatin+agmatine (100mg/kg), or cisplatin+agmatine+L-NAME (10mg/kg) once a week for 5weeks. The mechanical allodynia, hot plate, and tail clip tests were performed, and DRG cells and sciatic nerves were analyzed. Agmatine and agmatine+L-NAME combination attenuated CIS-induced mechanical allodynia and degeneration in DRG cells and sciatic nerves. However, L-NAME did not potentiate the antiallodynic or neuroprotective effect of agmatine. These findings indicate that agmatine co-administration ameliorates cisplatin-induced neuropathy and may be a therapeutic alternative.

28 new 3-(4-fluorophenyl)-5-aryl-N-substituted-4,5-dihydro-1H-pyrazole-1-carbothioamide derivatives were synthesized and evaluated in vitro for their monoamine oxidase (MAO) A and B inhibitory activity and selectivity. The derivatives substituted by halogen on the fifth position of pyrazole ring, inhibited MAO-A enzyme with a high selectivity index. On the other hand, compounds substituted with 2-naphthyl inhibited MAO-B enzyme with a moderate selectivity index. Docking studies were done to highlight the interactions of the most active derivative with the active site of MAO-A. In addition, in vivo antidepressant and anxiolytic activities of the compounds having selective MAO-A inhibitory effects, were investigated by using Porsolt forced swimming and elevated plus-maze tests respectively. 3-(4-Fluorophenyl)-5-(4-chloro-phenyl)-N-allyl-4,5-dihydro-1H-pyrazole-1-carbothio-amide has antidepressant, 3-(4-fluorophenyl)-5-(4-chlorophenyl)-N-methyl-4,5-dihydro-1H-pyrazole-1-carbothioamide and 3-(4-fluoro-phenyl)-5-(4-bromophenyl)-N-ethyl-4,5-dihydro-1H-pyrazole-1-carbothioamide have anxiolytic activity.

BACKGROUND:To determine the contribution of cytochrome P4502C9 (CYP2C9), vitamin K epoxide reductase (VKORC1) and factor VII genotypes, age, body mass index (BMI), international normalized ratio (INR) and other individual patient characteristics on warfarin dose requirements in an adult Turkish population.METHODS:Blood samples were collected from 101 Turkish patients. Genetic analyses for CYP2C9*2 and *3, VKORC1 -1639 G>A and factor VII -401 G>T polymorphisms were performed. Age, INR, BMI values and other individual patient characteristics were also recorded.RESULTS:The mean daily warfarin dosage was significantly higher in patients with the CYP2C9*1/*1 genotype than in the CYP2C9*2/*2 and CYP2C9*1/*3 groups (p ≤ 0.05). With respect to the VKORC1 -1639 G>A polymorphism, the mean warfarin daily dose requirement was higher in the wild type group compared to the heterozygous group (p≤0.001). The mean daily dose requirement for patients with the GG form of factor VII was significantly higher than that of patients with the TT genotype (p ≤ 0.05). Age, gender, BMI, INR had no statistically significant correlation with warfarin dose (p ≥ 0.05).CONCLUSIONS:Polymorphisms in CYP2C9, VKORC1 and factor VII did partially affect daily warfarin dose requirements, while age, gender, BMI and INR do not. However, further case-control studies with a larger study size and different genetic loci are needed to confirm our study.

A rapid and efficient method was developed for synthesis of 6-acyl-1,3-benzothiazol-2(3H)-one derivatives under microwave irradiation (MWI) conditions. The reaction times were shortened compared to conventional heating. Additionally, we synthesized acetic acid and acetamide derivatives of 1,3-benzothiazol-2(3H)-one, 6-acyl-1,3-benzothiazol-2(3H)-one, 5-chloro-1,3-benzothiazol-2(3H)-one and 6-acyl-5-chloro-1,3-benzothiazol-2(3H)-one with the microwave-assisted method and analyzed their antinociceptive activity with the tail flick, tail clip, hot plate and writhing tests. Among the synthesized compounds, 3-[2-(4-ethylpiperazin-1-yl)-2-oxoethyl]-1,3-benzothiazol-2(3H)-one (6a), 5-chloro-3-{2-oxo-2-[4-(propan-2-yl) piperazin-1-yl]ethyl}-1,3-benzothiazol-2(3H)-one (7e) and 3-[2-(4-butylpiperazin-1-yl)-2-oxoethyl]-5-chloro-1,3-benzothiazol-2(3H)-one (8e) showed significant antinociceptive activity in the tail clip, tail flick, hot plate and writhing tests. Supporting Information available online at http://www.thieme-connect.de/ejournals/toc/amf.

A large number of physiological rhythms are controlled by the central nervous system, including hormone secretion. The potency and toxicity of many drugs also change according to the time when they are administered. There are also some studies of the biological rhythms in pain sensitivity. In the present study, central and peripheral antinociceptive effects of aspirin and dipyrone, commonly used analgesics, were evaluated chronopharmacologically in mice. The central antinociceptive activities of these drugs administered intraperiotoneally (100 mg/kg) were investigated in mice using tail clip, tail flick and hot plate tests, and the peripheral antinociceptive activities of these drugs were investigated using a stretching test with acetic acid when the drugs were administered at 9.00 a. m. or 9.00 p. m. The central nociception was not different between the two groups, while the sensitivity to pain was significantly greater with the acetic acid test (p < 0.05) at night than in the daylight in the control group. Similarly sensitivities to the stretching test were higher at night than in the daytime in aspirin and dipyrone groups.

It is known that digoxin, which is a liposoluble cardiac glycoside, is well absorbed from intestine. In the present study, the absorption rates of digoxin from rat duodenum and the proximal and terminal parts of small intestine were determined in vitro. The isolated everted duodenum and intestinal sacs were put into oxygenated Tyrode solution at 37 degrees C. The Tyrode solution on the outer, mucosal side of intestinal segments contained 0.3 microM digoxin. Samples from the internal serosal side of the intestinal sacs were taken at 30, 60 and 120 min after the start of the experiments. The concentration of digoxin in the samples of fluid were determined using a radioimmunoassay method. The effect of nimodipine (0.1 and 0.2 mM) on digoxin absorption was also evaluated on the terminal segment of rat intestine. The interaction of nimodipine (0.5 mg/kg) and digoxin (0.2 mg/kg) was investigated in vivo when they were given perorally to rats. The duodenal absorption of digoxin was lower than in the small intestine. The highest absorption occurred in the terminal segment of the small intestine. Nimodipine increased the absorption of digoxin from the terminal segment of intestine in vitro, while it did not affect the serum digoxin concentration in vivo.

The search for new analgesic compounds devoid of the side effects typical of morphine-like opioid agonists (respiratory depression, constipation, and physical dependence) as well as of the gastrointestinal irritation and kidney damage associated with nonsteroidal anti-inflammatory drugs has attracted considerable attention in recent years. 2-Oxobenzothiazoline derivatives bearing substituents at position 3 have also been reported to exhibit various pharmacological properties, such as antimicrobial, antiallergenic, diuretic, antihistaminic, and anticonvulsant activities. 3-Aminoalkyl-2-oxobenzothiazoline derivatives with significant antinociceptive activity were reported in our previous studies. We subsequently synthesized 1-phenyl-2-(2-oxobenzothiazolin-3-yl)ethanones, 1phenyl-2-(2-oxobenzothiazolin-3-yl)ethanols, and 3-(3-aminopropyl)-2-oxobenzothiazoline and found that some of these compounds possessed noteworthy antinociceptive activity. The synthesis of 1,3,4-thiadiazole derivatives, which were investigated for antibacterial9−11, antifungal, cardiotonic, antitubercular, and antidepressant activities, has been reported previously. More recently, researchers reported 1,3,4-thiadiazole derivatives that exhibited analgesic and antiinflammatory activities. 5-Arylamino substituted 3-nicotinoyl/isonicotinoyl-1,3,4-thiadiazol-2(3H)-one, 5-

It has been known that ciprofloxacin augments the humoral and cellular immune systems. The aim of the present study was to determine whether these properties affect the inflammatory response. Adult male rats, ciprofloxacin and pefloxacin were used. The healty rats were treated orally with an equal volumes of ciprofloxacin (50 mg/kg) pefloxacin (50 mg/kg) or distilled water for 10 days. Their effects on the inflammatory response were investigated by testing the formation of formaline-induced edema. The effects of two quinolones were also evaluated on gastic mucus secretion by using the Alcian blue dye binding method and haematological parameters. Ciprofloxacin and pefloxacin showed a significant anti inflammatory activity and decreased the white blood cell count (WBC). However, there was no significant difference in the other haematological parameters. These two quinolones stimulated gastric mucus secretions, but these increases were not statistically significant. These findings suggest that ciprofloxacin and pefloxacin (at 50 mg/kg p.o. doses) possess antiinflammatory activities and are well-tolerated orally. Further detailed investigations are needed to clarify the mechanisms of their antiinflammatory activities

In the present study the antiinflammatory activity of fusidic acid was investigated in a model of formalin-induced edema formation in rats. Fusidic acid at doses of 50 and 100 mg kg (-1) was administered p.o. to rats for ten days. It was observed that fusidic acid inhibited edema formation significantly (P< 0.05). After this period, gastric mucus secretions were evaluated by the Alcian blue dye binding method. Mucus secretion decreased significantly in the control group. Fusidic acid increased the amount of gastric mucus. Moreover, in all of the animals with paw edema, platelet count was also increased. Red blood cell count, haemoglobin concentration and haematocrit were all higher in the control group than those of the fusidic acid groups. The present observations suggest that fusidic acid suppressed the inflammatory response and stimulated the gastric mucus secretion and it prompts further experiments for delineation of the mechanism of these actions as well as clinical trials.

The syntheses of (2-benzothiazolinon-3-yl)propionamide and (2-benzoxazolinon-3-yl)propionamide derivatives are reported. The structures of these compounds are elucidated by their IR and 1H-NMR spectral data, as well as by elemental analysis. The compounds were tested for antinociceptive activity by hot plate, tail flick, tail clip, and modified Koster tests. Compounds 6b and 7d were found to be the most promising compounds among the substances investigated.

Digoxin, frequently used in the treatment of congestive heart failure, has a very narrow therapeutic index. We studied the differences in digoxin pharmacokinetics when ingested in the morning versus evening. A single digoxin (0.25 mg) dose was given orally to the same group of 10 diurnally active healthy (6 male and 4 female) volunteers in the morning at 08:00 and evening at 20:00 in separate experiments scheduled 2 weeks apart. Blood samples were collected at specific times for 48h after each timed dose; digoxin was determined by radioimmunoassay (RIA). Maximum plasma concentration Cmax; Tmax, the time to reach Cmax; area under plasma concentration curve AUC; and elimination half-time T1/2 of digoxin were determined. Tmax was statistically significantly shorter (54 min) following 08:00 dosing com pared to 20:00 dosing (96 min). Although the Cmax was higher after morning than evening dosing, it was not significantly so. No other parameter of digoxin pharmacokinetics except Tmax exhibited administration time dependency.