Use of drugs subject to controlled prescriptions: a retrospective analysis.

OBJECTIVE: Use of drugs that may lead to abuse or dependence are subject to controlled prescriptions (CPs) in many countries, and these are closely monitored by health authorities. According to national regulations in Turkey, CPs may be red coloured (RCPs) or green coloured (GCPs). The aim of this study was to evaluate the use of such drugs in Istanbul. STUDY DESIGN: Retrospective case-control study. MATERIAL AND METHODS: During the study period (01/01-31/12 2009), 502874 CPs were reported. Among these, 4000 CPs each month were randomly selected and evaluated. RESULTS: The majority of GCPs were issued to women (55.6%), while the majority of RCPs were issued to men (68.4%). GCPs were most frequently prescribed by physicians working in private hospitals (33.6%) while RCPs by physicians working in university hospitals (39.7%). GCPs were mostly prescribed by psychiatrists (37.6%) while for RCPs were child and adolescent psychiatrists (35.9%). Psycholeptics (ATC code N05) were the most prescribed controlled drugs (CDs) (43.8%). Methylphenidate (53.9%) was the mostly prescribed on RCPs and alprazolam (39.6%) was on GCPs. CONCLUSION: We demonstrate that utilization of CDs shows demographical and institutional differences. These data could be of help to improve surveillance of CDs as well as to train prescribers and patients.

Fluoxetine partly exerts its actions through GABA: a neurochemical evidence.

Fluoxetine, as a serotonin re-uptake inhibitor augments serotonin concentration within the synapse by inhibiting the serotonin transporter. The contribution of amino acids has also been shown in depression. We hypothesized that fluoxetine exerts its actions at least in part by intervening brain signaling operated by amino acid transmitters. Therefore the aim of this study is to supply neurochemical evidence that fluoxetine produces changes in amino acids in cerebrospinal fluid of rats. Sprague-Dawley rats were anesthetized and concentric microdialysis probes were implanted stereotaxically into the right lateral ventricle. Intraperitoneal fluoxetine (2.5 or 5 mg/kg) or physiological saline was administered and the probes were perfused with artificial cerebrospinal fluid at a rate of 1 mul/min. In the chronic fluoxetine group, the rats were treated daily with oral fluoxetine solution or inert syrup for 3 weeks. The microdialysis probes were placed on the 21st day and perfused the next day. Fluoxetine was ineffective in changing the cerebrospinal fluid GABA levels at the dose of 2.5 mg/kg but produced a significant increase in the perfusates following injection of 5 mg/kg of fluoxetine (P < 0.05). Oral fluoxetine administration (5 mg/kg) for 21 days also elevated the CSF GABA levels by approximately 2-fold (P < 0.05). L: -glutamic acid levels were not affected in all groups. These neurochemical findings show that fluoxetine, a selective serotonin re-uptake inhibitor affects brain GABA levels indirectly, and our results suggest that acute or chronic effects may be involved in beneficial and/or adverse effects of the drug.

Effect of agmatine on brain L-citrulline production during morphine withdrawal in rats: a microdialysis study in nucleus accumbens.

Agmatine, an endogenous nitric oxide (NO) synthase inhibitor and ligand for imidazoline receptors, has been previously shown to prevent morphine dependence in rats. The present study was designed to investigate NO formation in nucleus accumbens core region (NAcc) during naloxone (NL)-precipitated morphine withdrawal in rats treated with agmatine or l-NAME by using intracerebral microdialysis in freely moving rats, through measuring extracellular l-citrulline concentrations, an indirect sign of NO production since equal amounts of l-citrulline and NO are produced from l-arginine. l-Citrulline levels in the NAcc core did not change following administration of agmatine (40 mg/kg i.p.) or l-NAME (100 mg/kg i.p.) in control rats. Both agmatine and l-NAME attenuated withdrawal symptoms of morphine in NL (2 mg/kg i.p.)-precipitated withdrawal. l-Citrulline levels showing the release of NO increased in morphine-dependent rats during NL-precipitated withdrawal. Agmatine and l-NAME treatments significantly suppressed the increase in l-citrulline levels compared to physiological saline-treated rats in this setting. The results suggest that the release of l-citrulline in NAcc may be involved in the processes of morphine withdrawal and agmatine as an endogenous inhibitor of NO synthase may be one of the factors involved in the changes in the physiology and behavioral state during opioid withdrawal and may have pharmacological importance.

Effect of systemic and intracortical administration of phenytoin in two genetic models of absence epilepsy.

1. Spontaneous 7-10 Hz spike-wave discharges (SWDs) are the electroencephalographic hallmark of absence seizures, as can be observed in WAG/Rij as well as in GAERS, two commonly used well-validated genetic rat models of absence epilepsy. A local upregulation of sodium channels within the perioral region of the primary somatosensory cortex indicated an initiation site for SWDs in WAG/Rij rats, in line with a new theory that assumes that SWDs have a cortical focal origin in the perioral region of the somatosensory cortex. We tested whether bilateral microinfusion at this focal site of the sodium channel blocker phenytoin, which is known to aggravate SWDs after systemic administration, reduces SWDs in both models. 2. WAG/Rij rats and GAERS, chronically provided with cortical EEG electrodes and bilateral cortical cannula's, were used. The EEGs were recorded before and after or systemic or bilateral infusion of phenytoin. 3. Microinfusion of phenytoin at the perioral region of the somatosensory cortex produced an immediate cessation of seizure activity in WAG/Rij rats, while systemic injection produced an increase in both genetic models. Microinfusion of the same and higher concentrations of phenytoin in GAERS at the same stereotactic coordinates showed no effect. Phenytoin was effective in GAERS 2 mm more posteriorly.4. The data suggest that both genetic models have a cortical area at which diametrically opposite effects of phenytoin can be found compared to systemic injections: a decrease after local microinfusion and aggravation after systemic administration, although the exact cortical location may be different. Moreover, a deficit in sodium channels might be an ethiological factor underlying an increased probability for the initiation of SWDs in the somatosensory cortex.

Therapeutic drug monitoring of immunosuppressant drugs in Marmara University Hospital.

Immunosuppressive therapy is the most crucial treatment of organ-transplanted patients. Both cyclosporin and tacrolimus have become a part of the standard immunosuppressive therapy for prevention of rejection. However, lower levels of these drugs are associated with insufficient therapy and eventually result in rejection of the organ, and, on the contrary, higher levels are associated with toxicity to certain organs such as liver and kidneys. Therefore, the levels of these drugs in body fluids should be monitored for the prevention of unwanted situations. In this retrospective study, the authors evaluated the 18-month profile of blood drug concentrations of cyclosporin and tacrolimus in patients admitted to the TDM Unit of the Marmara University Hospital (Istanbul, Turkey) between June 2000 and November 2001. A total of 578 blood samples (347 cyclosporin and 231 tacrolimus) from 134 patients (88 for cyclosporin, 46 for tacrolimus) were evaluated in this period. The therapeutic trough ranges were accepted as 100-350 ng/mL for cyclosporin and 5-20 ng/mL for tacrolimus, and levels below or above the identified levels were accepted to be subtherapeutic or toxic. Most of the results were found within the range of therapeutic levels (67.48% for cyclosporin and 82.71% for tacrolimus). Subtherapeutic levels were found in 19.92% of all cyclosporin and 10.53% of all tacrolimus assays, whereas toxic levels were seen in 12.60% and 6.77% of cyclosporin and tacrolimus results, respectively. In conclusion, this study gives information about the TDM practice in institutional clinical laboratory and also indicates the importance of critical information such as sampling time for individual decision making in dosage regiment.

The influence of dorsomedial hypothalamic nucleus on contralateral paraventricular nucleus in NMDA-mediated cardiovascular responses.

Dorsomedial (DMH) and paraventricular nuclei (PVN) are two important hypothalamic structures involved in the central regulation of cardiovascular regulation. L-Glutamic acid and gamma-aminobutyric acid (GABA) were demonstrated to elicit cardiovascular responses when administered via intracerebroventricular injection or parenchymal microinjections into the hypothalamic nuclei, participating in central cardiovascular regulation. In this study the interaction between the DMH and the PVN were investigated by means of microinjection and microdialysis techniques in Sprague-Dawley rats. Stereotaxic surgery was performed for the insertion of intracerebral parenchymal microinjection cannula into the right DMH and microdialysis probe into the left PVN. After a recovery period of 3 days, the iliac artery was cannulated for monitoring pulsatile blood pressure and heart rate by means of pressure transducer connected to a polygraph. Microinjection of 50 pmol NMDA into the DMH was performed and microdialysis perfusates were collected simultaneously from the PVN in the conscious rat model. L-Glutamic acid and GABA levels were analyzed by an isocratic HPLC method with the aid of a fluorescent detector. Microinjection of 50 pmol NMDA into the DMH produced significant increases in mean arterial pressure and heart rate. NMDA microinjection into the DMH produced a significant increase in L-glutamic acid release in the PVN, but no significant change in GABA release was observed. These results may indicate that stimulation of the DMH by NMDA results in subsequent stimulation of the PVN.

Effect of agmatine on electrically and chemically induced seizures in mice.

Agmatine, an amine and organic cation, is formed by the decarboxylation of L-arginine by arginine decarboxylase. It binds to alpha(2)-adrenergic and imidazoline receptors. It blocks N-methyl-D-aspartate (NMDA) subtype of glutamate receptors and inhibits nitric oxide (NO) synthase. Because the importance of NMDA receptors and the NO system are well known in seizure activity, this study was designed to investigate the effect of agmatine on electrically and chemically induced seizures by using maximal electroshock (MES) and pentilentetrazole (PTZ) models in mice. Initial studies established convulsive current 50 (CC(50)) for MES and effective dose 50 (ED(50)) for PTZ to produce seizures. Agmatine (20, 40, 80, and 100 mg/kg intraperitoneally) increased the threshold of seizures in MES dose dependently. In PTZ-induced convulsions, the highest dose of agmatine (100 mg/kg) increased the seizure onset time and decreased percent survival. The percentage of grade V seizures was found to be increased by agmatine doses greater than 20 mg/kg.

Effect of harmane on the convulsive threshold in epilepsy models in mice.

The study investigated the activity of harmane on maximal electroshock seizures (MES) and seizures induced by pentilentetrazole (PTZ) in mice. Initial studies established convulsive current 50 (CC(50)) values or MES and effective dose 50 (ED(50)) for PTZ to produce seizures. Harmane (2.5, 5.0, or 10 mg/kg intraperitoneally) increased the threshold of seizures in MES dose-dependently. The convulsions produced by PTZ were decreased by the low dose of harmane (2.5 mg/kg), but the high dose of harmane (10 mg/kg) resulted in worse grade V convulsions followed by more lethality compared with PTZ alone. Therefore, harmane seems to be protective against grand mal seizures in the MES model but not against a petit mal seizure model (PTZ) in mice.

Role of endothelin-1 in a cirrhotic rat model with endotoxin induced acute renal failure.

BACKGROUND/AIMS: Bacterial infections are known to trigger renal failure in patients with cirrhosis. However, the mechanisms for this process are unclear. The aim of this study was to investigate the role of endothelin-1 (ET-1) in a cirrhotic rat model with endotoxin induced renal failure by mixed ET-1 receptor antagonist, bosentan. METHODS: Cirrrhosis was induced by twice weekly intraperitoneal injections of CCl(4) together with phenobarbital in drinking water. Cirrhotic and non-cirrhotic rats were either pretreated with physiological saline or bosentan prior to administration of low dose endotoxin. Urine and blood samples were then collected within a period of 3 h for the estimation of ET-1, NO(3)(-)/NO(2)(-) levels ( nitric oxide metabolites: NO(x)) and renal function tests. RESULTS: Cirrhotic rats had higher ET-1 and NO(x) levels in comparison with non-cirrhotic rats. Endotoxin administration to cirrhotic rats led to the deterioration of the renal function, and elevation of plasma ET-1 and NO(x) levels. Bosentan pretreatment prior to endotoxin administration caused an increase in the urine volume and creatinine clearance of cirrhotic rats, but had no effect on Na(+) excretion. CONCLUSION: ET-1 has a significant role in endotoxin induced renal impairment in cirrhotic rats, and ET-1 receptor antagonism provides partial protection of the renal function.