The α2C-adrenoceptor antagonist JP-1302 controls behavioral parameters, tyrosine hydroxylase activity and receptor expression in a rat model of ketamine-induced schizophrenia-like deficits.

Schizophrenia is a chronic disabling disease affecting 1 % of the population. Current antipsychotics have limited efficacy in mitigating the severity of the symptoms of the disease. Therefore, searching for new therapeutic targets is essential. Previous studies have shown that α2C-adrenoceptor antagonists may have antipsychotic and pro-cognitive effects. Therefore, the current study evaluates the behavioral and neurochemical effects of JP-1302, a selective α2C-adrenoceptor antagonist, in a model of schizophrenia-like deficits induced by sub-chronic ketamine (KET) administration. Here, we administered ketamine (25 mg/kg, i.p.) to male and female Wistar rats for eight consecutive days. On the last two days of ketamine administration, rats were pretreated with either JP-1302 (1-3-10 µmol/kg, i.p.), chlorpromazine (0.1 mg/kg, i.p.), or saline, and the behavioral tests were performed. Behaviors related to positive (locomotor activity), negative (social interaction), and cognitive (novel object recognition) symptoms of schizophrenia were assessed. Glutamate, glutamine, GABA levels, and α2C-adrenoceptor expression were measured in the frontal cortex and the hippocampus. Tyrosine hydroxylase immunocytochemical reactivity was also shown in the midbrain regions. Sub-chronic ketamine administration increased locomotor activity and produced robust social interaction and object recognition deficits, and JP-1302 significantly ameliorated ketamine-induced cognitive deficits. Ketamine induced a hyperdopaminergic activity in the striatum, which was reversed by the treatment with JP-1302. Also, the α2C-adrenoceptor expression was higher in the frontal cortex and hippocampus in the ketamine-treated rats. Our findings confirm that α2C-adrenoceptor antagonism may be a potential drug target for treating cognitive disorders related to schizophrenia.

Escitalopram co-prescription in anastrozole-treated breast cancer patients.

OBJECTIVE: The purpose of the study was to evaluate the impact of escitalopram co-prescription on plasma anastrozole levels in post-menopausal breast cancer patients. METHODS: A total of 24 post-menopausal operated breast cancer patients co-prescribed with escitalopram and anastrozole were included. Blood samples were collected, before and 1-month after the onset of escitalopram to analyze plasma anastrozole and estradiol levels. RESULTS: No significant difference was noted in basal plasma anastrozole levels with respect to age, body mass index (BMI), tumor stage, previous antineoplastic treatments, concomitant medications, and serum estradiol levels. Overall, 17 patients completed the 1-month escitalopram treatment, while 7 patients discontinued escitalopram within the 1st week of the treatment. Basal anastrozole levels of 24 patients were 26.1±2.4 ng/mL. Among 17 patients who continued 1-month escitalopram treatment was associated with significant increase in plasma anastrozole levels (24.5±2.3 ng/mL to 32.2±3.2 ng/mL, p<0.05). Notably, 1-month escitalopram use was associated with significant increase in plasma anastrozole levels only in the subgroup of obese (BMI >29 kg/m2) patients (23.1±2.8 to 35.9±4.7 ng/mL, p<0.01), while no such interaction was noted among non-obese patients. The estradiol levels of the patients were below ≤10 pg/mL in 75% of patients and no change occurred after escitalopram administration. CONCLUSION: Escitalopram co-prescription resulted in significant increase in plasma anastrozole levels without affecting the serum estradiol levels. Our findings emphasize the need for close monitoring in case of concomitant use of anastrozole and escitalopram, especially in obese patients and the potential role of therapeutic drug monitoring.

Cross-talk of cholinergic and ß-adrenergic receptor signalling in chronic myeloid leukemia K562 cells.

In many studies on breast, skin and intestinal cancers, ß-adrenergic receptor antagonists have been shown to inhibit cell proliferation and angiogenesis and increase apoptosis in cancers. Carbachol inhibits chronic myeloid leukaemia K562 cell proliferation. Beta-blockers are known to inhibit cell progression. The aim of this study is to explain the mechanism of action of ß-adrenergic receptors agonists and antagonists on apoptosis in chronic myeloid leukaemia cells. We tried to determine the effect of combined treatment of ß-adrenergic and cholinergic drugs on adrenergic ß1 and ß2 gene expression, cell proliferation and apoptosis in chronic myeloid leukaemia K562 cells. Cell proliferation was evaluated by the 5-bromo-2-deoxy-uridine (BrdU) incorporation kit. Caspase 3, 8, 9 activities were measured by the caspase assay kit. Protein expression level was detected by western blotting. We found that exposure to propranolol either by combination with carbachol facilitates additive effects on inhibition of caspase 3 and 8 expression in chronic myeloid leukaemia K562 cells. However, caspase 9 expression level was increased by propranolol alone or with propranolol and carbachol combination. The combined therapy of cholinergic and adrenergic receptor drugs will decrease cell proliferation in K562 cells. This decrease in cell proliferation may be mediated by the mitochondrial-dependent intrinsic apoptosis pathway.

Evaluation of the pregnant women's approaches regarding drug utilization.

OBJECTIVE: Drug utilization habits of the pregnant are a critical aspect of rational use of the medicine (RUM). This study aimed to analyze the RUM related attitudes and the behaviors of women during their pregnancies. METHODS: The data were collected between May 2016-October 2016 by conducting surveys to 71 pregnant women admitted to the private and governmental hospitals in five districts of Northern Cyprus. The sociodemographic characteristics of the pregnant as well as their attitudes and behaviors concerning drug use were evaluated. RESULTS: The mean age and the gestational week of the patients was 29.7±4.3 years and 25.7±11.2 weeks, respectively. Planned pregnancies constituted 71.8% of all. The percentage of patients with an unplanned pregnancies who were using drugs at the time of the survey (25.0%) was lower than that in those with planned pregnancies (49.0%, p<0.05). Almost two-thirds (66.2%) of the women were exposed to a drug during pregnancy, mostly for "vitamin/mineral prophylaxis" (38.3%) and agents controlling nausea/vomiting (19.1%). Two out of eleven women (18.2%) were using folic acid when they learned about their pregnancy. One of the drugs used for the chronic disorder in the third trimester was acetylsalicylic acid (11.1%), a category D drug in this setting. Most of the patients stated that they frequently read the instructions (60.9%), "often" paying attention to side effects (56.5%). Considering some of the habits related to drug use, 8.7% and 10.9% of pregnant women declared that they sometimes "did not follow the instructions" and "dosage/duration of the drug usage", respectively. Seven patients (15.2%) declared that they did not consider side effects on the medication guide while more than half (56.5%) did it "often". Near one in five (19.6%) of the pregnant women stated that they hesitated about the drug usage due to teratogenicity risks. CONCLUSION: Our study highlights the drug utilization attitudes and behaviors of pregnant women during pregnancy in Northern Cyprus, indicating several shortcomings, including insufficient prenatal folic acid use, occasional use of risky drugs, and unsatisfactory medication guide handling. Available findings underline the necessity of education not only for patients but also for healthcare providers to disseminate RUM in pregnancy.

The Neurochemical Effects of Prazosin Treatment on Fear Circuitry in a Rat Traumatic Stress Model.

OBJECTIVE: The timing of administration of pharmacologic agents is crucial in traumatic stress since they can either potentiate the original fear memory or may cause fear extinction depending on the phase of fear conditioning. Brain noradrenergic system has a role in fear conditioning. Data regarding the role of prazosin in traumatic stress are controversial. METHODS: In this study, we examined the effects of prazosin and the noradrenergic system in fear conditioning in a predator stress rat model. We evaluated the direct or indirect effects of stress and prazosin on noradrenaline (NA), gamma-aminobuytyric acid (GABA), glutamate, glycine levels and choline esterase activity in the amygdaloid complex, the dorsal hippocampus, the prefrontal cortex and the rostral pons. RESULTS: Our results demonstrated that prazosin might alleviate defensive behaviors and traumatic stress symptoms when given during the traumatic cue presentation in the stressed rats. However prazosin administration resulted in higher anxiety levels in non stressed rats when the neutral cue was presented. CONCLUSION: Prazosin should be used in PTSD with caution because prazosin might exacerbate anxiety in non-traumatized subjects. However prazosin might as well alleviate stress responses very effectively. Stress induced changes included increased NA and GABA levels in the amygdaloid complex in our study, attributing noradrenaline a possible inhibitory role on fear acquisition. Acetylcholine also has a role in memory modulation in the brain. We also demonstrated increased choline esterase acitivity. Cholinergic modulation might be another target for indirect prazosin action which needs to be further studied.

The role of adenosine A1 receptors in the nucleus accumbens during morphine withdrawal.

Opioids are effective analgaesic agents, but serious adverse effects such as tolerance and withdrawal contribute to opioid dependence and limit their use. Opioid withdrawal is a common occurrence in human opiate addicts that is not life-threatening. Studies have shown that the mesocorticolimbic system, especially the nucleus accumbens, is an important region in drug addiction and adenosine receptors play a modulatory role in the mechanism of action of drug dependence and withdrawal. The aim of this study was to investigate the effects of the selective A1 receptor agonist CPA (N6 -cyclopentyladenosine) on withdrawal symptoms, and the concentration of dopamine and noradrenaline in the nucleus accumbens and locomotor activity behaviour during naloxone-precipitated withdrawal in morphine-dependent rats. The local administration of CPA (1.5, 3.0, and 6.0 mmol/L bilateral 250 nL) into the nucleus accumbens decreased the Gellert-Holtzman withdrawal scale, and increased concentrations of dopamine and noradrenaline in the same region during naloxone-induced withdrawal. Our findings suggest that administration of the A1 receptor agonist significantly decreased withdrawal behaviours and increased dopamine and noradrenaline concentrations in opioid withdrawal in a dose-dependent manner. These results demonstrate that adenosine receptors should be examined as a potential mechanism that could be exploited for the treatment of morphine withdrawal.

Contribution of M1 and M2 muscarinic receptor subtypes to convulsions in fasted mice treated with scopolamine and given food.

Treatment of fasted mice and rats with the nonselective muscarinic antagonist, scopolamine or atropine, causes convulsions after food intake. This study evaluated the effect of fasting on the expression of M1 and M2 muscarinic receptors in the brain regions, the relationship between receptor expression and seizure stages, and the muscarinic receptor subtype which plays a role in the occurrence of convulsions. Mice were grouped as allowed to eat ad lib (fed) and deprived of food for 24h (fasted). Fasted animals developed convulsions after being treated with scopolamine (60%) or the selective M1 receptor antagonist pirenzepine (10mg/kg; 20% and 60mg/kg; 70%) and given food. Fasting increased expression of M1 receptors in the frontal cortex and M2 receptors in the hippocampus, but produced no change in the expression of both receptors in the amygdaloid complex. Food intake after fasting decreased M1 receptor expression in the frontal cortex and M1 and M2 receptor expression in the hippocampus. Seizure severity was uncorrelated with muscarinic receptor expression in the brain regions. Taken together, these findings provide evidence for the role of M1 muscarinic receptor antagonism and fasting-induced increases in M1 and M2 expression possible underlying mechanism in the occurrence of convulsions in fasted animals.

Estimation of Chronological Age from Postmortem Tissues Based on Amino Acid Racemization.

Skin and cartilage tissue specimens from 32 male and 13 female corpses aged between 17 and 50 years were collected within 24 h after the death. Each specimen was analyzed for the composition of dextro (D) and levo (L) forms of aspartate, glutamate, and alanine. Linear regression models were constructed using ln [(1 + D/L)/(1 - D/L] equation to define the relationship between the extent of racemization and the chronological age. Aspartate D/L rates from cartilage showed high correlation (r = 0.779, p < 0.001, n = 45). Aspartate D/L rates from skin showed very low correlation (r = 0.356, p < 0.002, n = 44). The multilinear regression model of both aspartate D/L rates of cartilage and skin tissues in 44 cases yielded a coefficient of r = 0.828 (p < 0.001). In conclusion, only racemization rate of Aspartate both in the skin and the cartilage tissues correlated with the chronological age. Our results may imply that the age can be estimated more precisely if two different tissue specimens are obtained from one corpse.

Potential drug-drug interactions in a medical intensive care unit of a university hospital.

BACKGROUND/AIM: Drug-drug interactions (DDIs) can impact patient safety. Occurrence of clinically important DDIs is higher for intensive care unit (ICU) patients. This observational study aimed to evaluate the potential DDIs in medical ICU patients of a university hospital. MATERIALS AND METHODS: The Medical Pharmacology Department organized consultation reports for ICU patients in order to detect the DDIs. To focus on clinically important DDIs, interactions in the C, D, or X risk rating categories of the Lexi-Interact online database were analyzed. Frequency and clinical risk rating categories of DDIs were detected. Relationship between number of prescriptions and DDIs were assessed. The most frequent drug/drug groups were identified. RESULTS: Of 101 ICU patients, 45.5% were found to have DDIs. We detected 125 C (72.2%), 37 D (21.4%), and 11 X (6.4%) risk category interactions. A statistically significant increase in the number of DDIs was shown with the number of prescriptions (P = 0.002). The most frequent DDIs were between agents acting on the cardiovascular system and corticosteroids (12.8%). CONCLUSION: Results of this study show that pharmacological consultation plays a critical role in the recognition of DDIs for improvement of medication management and effective therapeutic endpoints without any adverse or toxic reactions.

The relationship between UGT1A4 polymorphism and serum concentration of lamotrigine in patients with epilepsy.

Lamotrigine (LTG) which has a widespread use in epilepsy treatment as an antiepileptic agent is metabolized by UDP-glucuronosyl transferase (UGT) enzymes. In this study, single nucleotide polymorphisms, P24T and L48V, of the UGT1A4 enzyme have been investigated in a Turkish population of patients with epilepsy (n=131) by comparing serum levels of LTG of wild type and polymorphic subjects. High performance liquid chromatography (HPLC) was used to measure serum concentrations of LTG. The P24T and L48V polymorphisms of the UGT1A4 enzyme were analyzed with a matrix assisted laser desorption-time of flight (MALDI-TOF) mass spectrometry method. The frequencies of the heterozygous alleles for L48V or P24T polymorphisms were 22.4% and 3.8%, respectively. L48V polymorphism was found to decrease the serum concentration of LTG in patients on monotherapy or polytherapy. The LTG levels of non smoking monotherapy patients were 52% lower for the L48V polymorphism than for wild type alleles. Also the LTG levels were significantly lower for non smoking or smoking polymorphic alleles than for normal. The high frequency of the L48V polymorphism detected in the Turkish population indicates that LTG dose adjustments in patients with the UGT1A4 L48V polymorphic enzyme should be taken into account.