The effects of enalapril and losartan on mechanical ventilation-induced sympathoadrenal activation and oxidative stress in rats.

BACKGROUND: Mechanical ventilation (MV) is a method of maintaining appropriate gas exchange in patients who are unable to sustain adequate alveolar ventilation. While lifesaving in the short-term, prolonged MV leads to altered cardiovascular responses and enhanced lung injury, but the exact mechanism is unknown. Therefore, we investigated the involvement of the sympathoadrenergic and renin-angiotensin system in MV-induced altered cardiovascular responses. METHODS: Sprague-Dawley rats were divided into six groups: (1) spontaneous breathing (SB); (2) SB + enalapril (100 µg/kg intravenous infusion); (3) SB + losartan (100 µg/kg infusion); (4) 12 h of MV; (5) MV + enalapril; and (6) MV + losartan. After the animals were sacrificed, blood and tissue samples were collected. Tyrosine hydroxylase, dopamine beta hydroxylase, and neuropeptide Y were measured in adrenal medulla and hypothalamus, whereas AT1 was measured in lung tissues by Western blot. Norepinephrine enzyme-linked immunosorbent assay and total antioxidant capacity were assayed in plasma. RESULTS: Our findings indicated that MV increases the sympathetic activation markers in adrenal medulla and hypothalamus. Moreover, oxidative stress was increased in lung and brain tissues. Treatment with enalapril or losartan reduced the lipid peroxidation in lung and brain tissues, while preserving the tissue glutathione content and plasma antioxidant capacity. CONCLUSIONS: These data demonstrate that the inhibition of the renin-angiotensin system by enalapril or losartan may reduce the MV-induced increase in sympathetic activity markers and oxidative stress, and thus, may have a beneficial effect as adjuvant therapy.

Obestatin alleviates subarachnoid haemorrhage-induced oxidative injury in rats via its anti-apoptotic and antioxidant effects.

OBJECTIVE: The aim was to investigate the putative anti-inflammatory and anti-apoptotic effect of obestatin in a rat model of subarachnoidal haemorrhage (SAH). METHODS: To induce SAH, rats were injected with 0.3 mL blood into their cisterna magna. At 48 hours rats were decapitated after neurological examination. Blood-brain barrier (BBB) permeability, brain water content, oxidative stress markers and histological analysis were done in brain tissue. RESULTS: The results showed that neurological examination scores were increased in the SAH group and, moreover, BBB permeability was impaired and oedema formed. SAH resulted in increased levels of plasma tumour necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6 levels and caspase-3 activity. Lipid peroxidation and protein oxidation levels and myeloperoxidase activity were all increased in the brain tissue, with concomitant decreases in antioxidant enzymes. On the other hand, SAH-induced neurological impairment and oxidative brain injury were ameliorated in the obestatin-treated group. CONCLUSION: The present study provides the first evidence that peripheral administration of obestatin exerts potent anti-inflammatory and neuroprotective effects in SAH-induced oxidative damage by maintaining a balance in oxidant-antioxidant status through the augmentation of endogenous antioxidants and the inhibition of pro-inflammatory mediators.

Meloxicam exerts neuroprotection on spinal cord trauma in rats.

Traumatic injury to the central nervous system results in the delayed dysfunction and neuronal death. Impaired mitochondrial function, generation of reactive oxygen species (ROS), and lipid peroxidation occur soon after traumatic spinal cord injury (SCI), while the activation of compensatory molecules that neutralize ROS occurs at later time points. The aim of the current study was to investigate the putative neuroprotective effect of the COX2 inhibitor meloxicam in a rat model of SCI. In order to induce SCI, a standard weight-drop method that induced a moderately severe injury (100 g/cm force) at T10, was used. Injured animals were given either 2 mg/kg meloxicam or saline 30 min postinjury by intraperitoneal injection. At seven days postinjury, neurological examination was performed and rats were decapitated. Spinal cord samples were taken for histological examination or determination of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and DNA fragmentation. Formation of ROS in spinal cord tissue samples was monitored by using a chemiluminescence (CL) technique. SCI caused a significant decrease in spinal cord GSH content, which was accompanied with significant increases in CL, MDA levels, MPO activity, and DNA damage. On the other hand, meloxicam treatment reversed all these biochemical parameters as well as SCI-induced histopathological alterations. Furthermore, impairment of the neurological functions due to SCI was improved by meloxicam treatment. The present study suggests that meloxicam, reduces SCI-induced oxidative stress and exerts neuroprotection by inhibiting lipid peroxidation, GSH depletion, and DNA fragmentation.

A Proteomic Evaluation of Sympathetic Activity Biomarkers of the Hypothalamus-Pituitary-Adrenal Axis by Western Blotting Technique Following Experimental Traumatic Brain Injury.

Endocrine disorders and autonomic dysfunction are common paradigms following traumatic brain injury (TBI). Alterations in the hypothalamus-pituitary-adrenal (HPA) axis following TBI may result in impaired vasopressor response, energy imbalance, fatigue, depression, or neurological disorders. Autonomic dysfunction is a common disorder following TBI. The sympathetic activity markers on HPA axis can be measured by Western blot protein analysis. Tyrosine hydroxylase, dopamine beta hydroxylase are the key enzymes for the synthesis of norepinephrine; and neuropeptide Y (NPY) is the peptide that is co-stored and co-released with norepinephrine. Thus, the present chapter reviews the experimental protocols for Western blot protein analysis for the measurement of biomarkers that indicate sympathetic activity in brain regions (hypothalamus, pituitary, cerebral cortex, and cerebellum) following TBI.

Onset of leptin resistance shows temporal differences related to dose or pulsed treatment.

Leptin administration results in leptin resistance presenting a significant barrier to therapeutic use of leptin. Consequently, we examined two hypotheses. The first examined the relationship between leptin dose and development of physiological and biochemical signs of leptin resistance. We hypothesized lower doses of leptin would produce proportional reductions in body weight without the adverse leptin-induced leptin resistance. The second compared pulsed central leptin infusion to continuous leptin infusion. We hypothesized that pulsed infusion at specific times of the day would evoke favorable body weight reductions while tempering the development of leptin-induced leptin resistance. The first experiment examined leptin responsiveness, including food intake, body weight and hypothalamic STAT3 phosphorylation to increasing doses of viral gene delivery of leptin. Varying the dose proved inconsequential with respect to long-term therapy and demonstrated proportional development of leptin resistance. The second experiment examined leptin responsiveness to pulsed central leptin infusion, comparing pulsed versus constant infusion of 3µg/day leptin or a 2h morning versus a 2h evening pulsed leptin infusion. Pulsed delivery of the supramaximal dose of 3µg/day was not different than constant delivery. Morning pulsed infusion of the submaximal dose of 0.25µg reduces food intake only over subsequent immediate meal period and was associated with body weight reductions, but results in cellular leptin resistance. Evening pulsed infusion did not decrease food intake but reduces body weight and maintains full leptin signaling. The positive benefit for pulsed delivery remains speculative, yet potentially may provide an alternative mode of leptin therapy.

Rapamycin Normalizes Serum Leptin by Alleviating Obesity and Reducing Leptin Synthesis in Aged Rats.

This investigation examines whether a low intermittent dose of rapamycin will avoid the hyperlipidemia and diabetes-like syndrome associated with rapamycin while still decreasing body weight and adiposity in aged obese rats. Furthermore, we examined if the rapamycin-mediated decrease in serum leptin was a reflection of decreased adiposity, diminished leptin synthesis, or both. To these ends, rapamycin (1mg/kg) was administered three times a week to 3 and 24-month old rats. Body weight, food intake, body composition, mTORC1 signaling, markers of metabolism, as well as serum leptin levels and leptin synthesis in adipose tissue were examined and compared to that following a central infusion of rapamycin. Our data suggest that the dosing schedule of rapamycin acts on peripheral targets to inhibit mTORC1 signaling, preferentially reducing adiposity and sparing lean mass in an aged model of obesity resulting in favorable outcomes on blood triglycerides, increasing lean/fat ratio, and normalizing elevated serum leptin with age. The initial mechanism underlying the rapamycin responses appears to have a peripheral action and not central. The peripheral rapamycin responses may communicate an excessive nutrients signal to the hypothalamus that triggers an anorexic response to reduce food consumption. This coupled with potential peripheral mechanism serves to decrease adiposity and synthesis of leptin.

Promoting evidence-based practice in pharmacies.

Evidence-based medicine aims to optimize decision-making by using evidence from well-designed and conducted research. The concept of reliable evidence is essential, since the number of electronic information resources is increasing in parallel to the increasing number and type of drugs on the market. The decision-making process is a complex and requires an extensive evaluation as well as the interpretation of the data obtained. Different sources provide different levels of evidence for decision-making. Not all the data have the same value as the evidence. Rational use of medicine requires that the patients receive "medicines appropriate to their clinical needs, in doses that meet their own individual requirements, for an adequate period of time, and at the lowest cost to them and their community." Pharmacists have a crucial role in the health system to maintain the rational use of medicine and provide pharmaceutical care to patients, because they are the drug experts who are academically trained for this purpose. The rational use of the pharmacist's workforce will improve the outcome of pharmacotherapy as well as decreasing the global health costs.

WITHDRAWN: Riluzole alleviates early neutrophil infiltration, brain oedema and lipid peroxidation in the traumatic brain tissue but does not induce neurotoxicity in non-traumatic brain tissue in rats.

This article has been withdrawn at the request of the editor since, in breach of ethical guidelines and journal policies, the manuscript was submitted without the full knowledge and consent of all authors listed. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

Problem based pharmacotherapy teaching for pharmacy students and pharmacists.

Pharmacy profession also involves identifying, solving and preventing drug-related problems, as well as encouraging proper use of medications, thus improving clinical outcome of the treatment. Pharmacotherapy is usually thaught as lectures in pharmacy schools and many students have a difficulty in implementing the theoretical knowledge into practice. Therefore courses on "rational drug use or rational pharmacotherapy" should be given by problem based teaching methods. Since 2009, "Rational Drug Use" courses are given in Marmara University School of Pharmacy by such a method (based on simulated patients and dispensing score) developed by the 'Turkish Pharmacological Society'. The method enables problem based learning and it is also used in some of the pharmacy schools in Turkey and in Near East University in Northern Cyprus. This kind of learning will provide ability for critical thinking, improve problemsolving skills and decision making during pharmacotherapy.

The changing face of pharmacy practice and the need for a new model of pharmacy education.

Pharmacy profession has evolved from its conventional and traditional drug focused basis to an advanced patient focused basis over the years. In the past century the pharmacists were more involved in compounding and manufacturing of medicines, but this role has significantly reduced over time. This advancement in the role of pharmacist calls for them to be the part of the broader health care team working for providing better health care for the patients, thus contributing in achieving the global millennium development goals. To match up, the role of today's pharmacists needs to be expanded to include pharmaceutical care concepts, making the pharmacist a health care professional rather than a drug seller in a commercial enterprise. Therefore, pharmacy schools should prepare a program that has competence with the changing role of the pharmacist. The education should provide ability for critical thinking, improve problem-solving skills and decision making during pharmacotherapy. The student should be trained to create, transmit, and apply new knowledge based on cutting-edge research in the pharmaceutical, social, and clinical sciences; collaborate with other health professionals and learn to enhance the quality of life through improved health for the people of local society and as well as the global community.

Dispensing practice in the community pharmacies in the Turkish Republic of Northern Cyprus.

BACKGROUND: Good pharmacy practice is the process of supplying the accurate drug to the right patient for an adequate period of time with the lowest cost to the patient and the community. Pharmacist have a crucial role in promoting good pharmacy practice. OBJECTIVE: To assess the dispensing practice of the community pharmacists in the Turkish Republic of Northern Cyprus (TRNC) regarding RDU and to evaluate the quality of dispensing. Setting Community pharmacies in TRNC. Method The study consists of two parts: a face to face interview and a simulated patient visit to these pharmacies. MAIN OUTCOMES MEASURE: Rationality indicators (average dispensing time, stock availability and adequate labelling), presence of the pharmacist on the premises, dispenser characteristics, prescription checking, and the provided patient information. RESULTS: The majority of the prescriptions (73.3%) were dispensed by the pharmacists. None of the pharmacy employees had pharmacy based training. Eighty nine percent of the pharmacists believed that their employees could very well dispense drugs on their own. The declared average dispensing time for a prescription of a single drug was 233 s while the measured one was 149 s. Few dispensers in reality warned the patient about potential interactions. The difference between the average dispensing scores of the pharmacists and the non-pharmacist dispensers was not significant. CONCLUSIONS: The dispensing practice in the community pharmacies in the Turkish part of Cyprus seems inadequate in terms of GPP.

Ghrelin alleviates spinal cord injury in rats via its anti-inflammatory effects.

AIM: Spinal cord injury (SCI) leads to an inflammatory response that generates substantial secondary damage within the tissue besides the primary damage. Ghrelin, 28 amino-acid peptide, has been shown to modulate the release of proinflammatory cytokines and exert antiinflammatory effects. The aim of the current study was to investigate the anti-inflammatory effects of ghrelin, in a rat model of SCI. MATERIAL AND METHODS: Wistar albino rats were divided as control, SCI, and ghrelin-treated (10 µg/kg/day, ip) SCI groups. In order to induce SCI, a standard weight-drop method that induced a moderately severe injury (100 g/cm force) at T10, was used. Injured animals were given either ghrelin or saline 15 min post-injury. RESULTS: In plasma samples, neuron-specific enolase (NSE) and S-100ß protein levels were evaluated. Spinal cord samples were taken for histological examination or determination of myeloperoxidase (MPO) activity and DNA fragmentation. SCI caused significant increases in plasma NSE and S-100ß levels and tissue MPO activity and DNA damage. On the other hand, ghrelin treatment improved histological findings as well as biochemical parameters while it failed to improve the impairment of the neurological functions due to SCI. CONCLUSION: The present study suggests that ghrelin could reduce SCI-induced oxidative stress and exert anti-inflammatory effects in the spinal cord following trauma.

The knowledge and attitude of the Turkish community pharmacists toward pharmacovigilance in the Kadikoy district of Istanbul.

OBJECTIVE: We investigated the knowledge and attitudes of community pharmacists towards pharmacovigilance and adverse drug reactions (ADRs) in Kadiköy district of Istanbul (Turkey). SETTING: The community pharmacies in Kadikoy. Kadikoy is one of the biggest districts of Istanbul and has the largest number of pharmacies. Kadikoy district was divided into two regions, the central and the peripheral. METHOD: Between December 2005 and June 2006 we conducted a survey about the knowledge and attitude of community pharmacists (n = 219) using a face-to-face questionnaire. The questionnaire consisted of questions about the sociodemographic characteristics of the pharmacists, their knowledge of pharmacovigilance and their attitudes towards ADR reporting. MAIN OUTCOMES MEASURED: The knowledge of pharmacovigilance practice, ADR reporting compliance rates, reasons for not reporting ADR and perceptions of the Turkish community pharmacists on pharmacovigilance practice were evaluated. RESULTS: Although all 411 pharmacies in the Kadikoy district were visited, only 53% of the community pharmacists (n = 219) consented to participate in the study. Of those that did respond, only 17.2% of the pharmacists had any knowledge about 'pharmacovigilance'. Sixty-five percent of the pharmacists stated that patients reported an ADR to them during the previous 12 months, and 21% of pharmacists reported to the concerned organizations. Our survey showed that only 7% actually reported an ADR to the national pharmacovigilance center. On the other hand, 89% of the pharmacists believed that the role of the pharmacist in ADR reporting was essential. CONCLUSION: The results show that Turkish community pharmacists have poor knowledge about pharmacovigilance. There is an urgent need for educational programs to train them about pharmacovigilance and ADR reporting.