Inhibition of iNOS induces antidepressant-like effects in mice: Pharmacological and genetic evidence

Recent evidence has suggested that systemic administration of non-selective NOS inhibitors induces antidepressant-like effects in animal models. However, the precise involvement of the different NOS isoforms (neuronal-nNOS and inducible-iNOS) in these effects has not been clearly defined yet. Considering that mediators of the inflammatory response, that are able to induce iNOS expression, can be increased by exposure to stress, the aim of the present study was to investigate iNOS involvement in stress-induced behavioral consequences in the forced swimming test (FST), an animal model sensitive to antidepressant drugs. Therefore, we investigated the effects induced by systemic injection of aminoguanidine (preferential iNOS inhibitor), 1400W (selective iNOS inhibitor) or n-propyl-L-arginine (NPA, selective nNOS inhibitor) in mice submitted to the FST. We also investigated the behavior of mice with genetic deletion of iNOS (knockout) submitted to the FST. Aminoguanidine significantly decreased the immobility time (IT) in the FST. 1400W but not NPA, when administered at equivalent doses considering the magnitude of their Ki values for iNOS and nNOS, respectively, reduced the IT, thus suggesting that aminoguanidine-induced effects would be due to selective iNOS inhibition. Similarly, iNOS KO presented decreased IT in the FST when compared to wild-type mice. These results are the first to show that selective inhibition of iNOS or its knockdown induces antidepressant-like effects, therefore suggesting that iNOS-mediated NO synthesis is involved in the modulation of stress-induced behavioral consequences. Moreover, they further support NO involvement in the neurobiology of depression. This article is part of a Special Issue entitled 'Anxiety and Depression'. (C) 2011 Elsevier Ltd. All rights reserved.

LIQUID-PHASE MICROEXTRACTION FOR SIMULTANEOUS CHROMATOGRAPHIC ANALYSIS OF THREE ANTIDEPRESSANT DRUGS IN PLASMA

A method using Liquid Phase Microextraction for simultaneous detection of citalopram (CIT), paroxetine (PAR) and fluoxetine (FLU), using venlafaxine as internal standard, in plasma by high performance liquid chromatography with fluorescence detection was developed. The linearity was evaluated between 5.0 and 500 ng mL(-1) (r > 0.99) and the limit of quantification was 2.0, 3.0 and 5.0 ng mL-1 for CIT. PAR and FLU, respectively. Therefore, it can be applied to therapeutic drug monitoring, pharmacokinetics or bioavailability studies and its advantages are that it necessary relatively inexpensive equipment and sample preparation techniques.

Relapse of Intravenous Drug Use Triggered by Enfuvirtide, a Parenteral Antiretroviral Medication

Fuzeon (R) (enfuvirtide; Hoffmann-LaRoche, Nutley, NJ) is a parenteral medication prescribed to antiretroviral-experienced HIV patients. Clinicians are frequently concerned when prescribing enfuvirtide to former drug addicts because of the risk of triggering relapse, however, no previous report has described this adverse event. We describe two HIV-infected patients, previously abstinent from injection drug use, who experienced relapse or near-relapse situations after starting treatment with enfuvirtide. Along with the concerns related to adherence and to injection site reactions, clinicians who prescribe enfuvirtide should consider and discuss the risk of triggering relapse among former or recovering drug addicts.

Post-trial access to study medication: a Brazilian e-survey with major stakeholders in clinical research

Objectives To analyse the perspective of clinical research stakeholders concerning post-trial access to study medication. Methods Questionnaires and informed consents were sent through e-mail to 599 ethics committee (EC) members, 290 clinical investigators (HIV/AIDS and Diabetes) and 53 sponsors in Brazil. Investigators were also asked to submit the questionnaire to their research patients. Two reminders were sent to participants. Results The response rate was 21%, 20% and 45% in EC, investigators and sponsors' groups, respectively. 54 patients answered the questionnaire through their doctors. The least informative item in the consent form was how to obtain the study medication after trial. If a benefit were demonstrated in the study, 60% of research participants and 35% of EC answered that all patients should continue receiving study medication after trial; 43% of investigators believed the medication should be given to participants, and 40% to subjects who participated and benefited from treatment. For 50% of the sponsors, study medication should be assured to participants who had benefited from treatment. The majority of responders answered that medication should be provided free by sponsors; investigators and sponsors believed the medication should be kept until available in the public health sector; EC members said that the patient should keep the benefit; patients answered that benefits should be assured for life. Conclusions Due to the study limitations, the results cannot be generalised; however, the data can contribute to discussion of this complex topic through analysing the views of stakeholders in clinical research in Brazil.

Critical analysis of the regulations regarding the disposal of medication waste

Expired or unused medication at people's homes is normally disposed of in normal garbage, sewage system or, in certain cases, returned to the public health system. There is still no specific legislation regarding this leftover medication to regulate and orient the handling and correct disposal of medication waste. However, there is defined regulation regarding health services' solid waste. This article has the objective of discussing management models for the disposal of medication waste and the recommendations made by pertinent national and international legislation. By means of literature reviews, the management structure for medication waste of international legislation and the regulations regarding the environment, as well as the national legislation for the solid waste from health services was analyzed. Through the analysis it was possible to present better clarifications as to the possible impacts to the environment, to the public's health and alternatives in order to obtain the efficient disposal of medication, reducing and/or avoiding sanitary risk, guaranteeing the quality and safety of public health.

Neuronal NOS Inhibitor and Conventional Antidepressant Drugs Attenuate Stress-induced Fos Expression in Overlapping Brain Regions

Recent evidence indicates that the administration of inhibitors of neuronal nitric oxide synthase (nNOS) induces antidepressant-like effects in animal models such as the forced swimming test (FST). However, the neural circuits involved in these effects are not yet known. Therefore, this study investigated the expression of Fos protein, a marker of neuronal activity, in the brain of rats submitted to FST and treated with the preferential nNOS inhibitor, 7-nitroindazole (7-NI), or with classical antidepressant drugs (Venlafaxine and Fluoxetine). Male Wistar rats were submitted to a forced swimming pretest (PT) and, immediately after, started receiving a sequence of three ip injections (0, 5, and 23 h after PT) of Fluoxetine (10 mg/kg), Venlafaxine (10 mg/kg), 7-NI (30 mg/kg) or respective vehicles. One hour after the last drug injection the animals were submitted to the test session, when immobility time was recorded. After the FST they were sacrificed and had their brains removed and processed for Fos immunohistochemistry. Independent group of non-stressed animals received the same drug treatments, or no treatment (naive). 7-NI, Venlafaxine or Fluoxetine reduced immobility time in the FST, an antidepressant-like effect. None of the treatments induce significant changes in Fos expression per se. However, swimming stress induced significant increases in Fos expression in the following brain regions: medial prefrontal cortex, nucleus accumbens, locus coeruleus, raphe nuclei, striatum, hypothalamic nucleus, periaqueductal grey, amygdala, habenula, paraventricular nucleus of hypothalamus, and bed nucleus of stria terminalis. This effect was attenuated by 7-NI, Venlafaxine or Fluoxetine. These results show that 7-NI produces similar behavioral and neuronal activation effects to those of typical antidepressants, suggesting that these drugs share common neurobiological substrates.

17 beta-Estradiol replacement in young, adult and middle-aged female ovariectomized rats promotes improvement of spatial reference memory and an antidepressant effect and alters monoamines and BDNF levels in memory- and depression-related brain areas

Clinical and experimental evidence suggest that estrogens have a major impact on cognition, presenting neurotrophic and neuroprotective actions in regions involved in such function. In opposite, some studies indicate that certain hormone therapy regimens may provoke detrimental effects over female cognitive and neurological function. Therefore, we decided to investigate how estrogen treatment would influence cognition and depression in different ages. For that matter, this study assessed the effects of chronic 17 beta-estradiol treatment over cognition and depressive-like behaviors of young (3 months old), adult (7 months old) and middle-aged (12 months old) reproductive female Wistar rats. These functions were also correlated with alterations in the serotonergic system, as well as hippocampal BDNF. 17 beta-Estradiol treatment did not influence animals' locomotor activity and exploratory behavior, but it was able to improve the performance of adult and middle-aged rats in the Morris water maze, the latter being more responsive to the treatment. Young and adult rats displayed decreased immobility time in the forced swimming test, suggesting an effect of 17 beta-estradiol also over such depressive-like behavior. This same test revealed increased swimming behavior, triggered by serotonergic pathway, in adult rats. Neurochemical evaluations indicated that 17 beta-estradiol treatment was able to increase serotonin turnover rate in the hippocampus of adult rats. Interestingly, estrogen treatment increased BDNF levels from animals of all ages. These findings support the notion that the beneficial effects of 17 beta-estradiol over spatial reference memory and depressive-like behavior are evident only when hormone therapy occurs at early ages and early stages of hormonal decline. (C) 2011 Elsevier B.V. All rights reserved.

Liquid-phase microextraction for simultaneous chromatographic analysis of three antidepressant drugs in plasma

A method using Liquid Phase Microextraction for simultaneous detection of citalopram (CIT), paroxetine (PAR) and fluoxetine (FLU), using venlafaxine as internal standard, in plasma by high performance liquid chromatography with fluorescence detection was developed. The linearity was evaluated between 5.0 and 500 ng mL-1 (r > 0.99) and the limit of quantification was 2.0, 3.0 and 5.0 ng mL-1 for CIT, PAR and FLU, respectively. Therefore, it can be applied to therapeutic drug monitoring, pharmacokinetics or bioavailability studies and its advantages are that it necessary relatively inexpensive equipment and sample preparation techniques.

Medication adherence in frail elderly outpatients with dementia

Since drug therapy in the elderly is complex and longterm and aged people commonly present some level of impairment and disability, medication adherence tend to decrease with age. Cognitive function is a key factor associated with medication adherence and professional or caregiver assistance may be necessary to maintain correct drug use. This study aims to analyze frail elderly outpatients aged 80 years or over diagnosed with dementia. The study is cross-sectional and is being conducted at the Ambulatory of Frailty of the University Hospital of the University of São Paulo (AF-UH). It is being based on information collected through an interview conducted with the patient or its caregiver. Medication adherence is assessed by the proportion of the prescribed drugs used in concordance with the prescription. Here it is presented the results of a pilot study. Thirty patients were included in the pilot study of which 23 (76.7%) were female and 7 (23.3%) males. The mean(SD) age, number of dwelling relatives, living children and prescribed drugs was, respectively, 86(5) years, 3(2), 3(2) and 6(3). The AF-UH consultation is the only regular physician encounter for 60.7% of the patients. Out of 30 patients, 5 (16.7%) live alone. Medication is a caregiver responsibility in 22 (73.4%) patients; the others (26.6%) self-administer their medicines. 13 (43.3%) of patients regularly use at least one drug not prescribed. Dementia was present in 8 patients all of which have a caregiver responsible for the management and,or the administration of the medicines; on the other hand, only 4 of the 22 nondemented patients (18.2%) have assistance of a caregiver (p<.001). The mean(SD) number of prescribed drugs was higher in nondemented patients [6.5(2.4)] than in those with dementia[3.5(2.3)] (p=.004). Educational level was similar between caregivers and patients (p=.503) as well as between caregivers of demented and non demented patients (p=.582). Among patients without dementia, those with caregiver assistance pre-presented the same mean(SD) medication adherence [0.93(0.14)] than those without it [0.78(0.28)] (p=.305). When compared to nondemented patients without caregivers, demented patients showed higher medication adherence [1.00(0.00)] (p=.013) since all of them used their drugs as recommended. The lower number of prescribed drugs and caregiver assistance seem to play an important role in the adherence of pharmacotherapy of demented patients in the studied population.

Medication reconciliation and adherence: a call for clinical pharmacist

Introduction and Objectives: With the population ageing, there is a growing number of people who have several comorbidities and make use of a variety of drugs. These factors lead to a greater predisposition to adverse drug events, as well as to medication errors. The clinical pharmacist is the most indicated health professional to target these issues. The aims of this study were to analyze the profile of medication reconciliation and assess the role of the clinical pharmacist regarding medication adherence. Material and Methods: Prospective observational cohort study conducted from Jan-Mar 2013 at the Surgical Clinic of the University Hospital of the University of Sao Paulo. 117 admitted patients - over the age of 18 years, under continuous medication use and with length of hospitalization up to 120h - were included. Discrepancies were classified as intentional/unintentional and according to their risk to cause harm, and interventions were divided into accepted/not accepted. Medication adherence was measured by Morisky questionnaire. Results and Conclusions: Only 30% of hospital prescriptions showed no discrepancies between the medications that the patient was using at home and those which were being prescribed at the hospital and more than one third of those had the potential to cause moderate discomfort or clinical deterioration. One third of total discrepancies were classified as unintentional. About 90% of the interventions were accepted by the medical staff. In addition, about 63% of patients had poor adherence to drug therapy. The study revealed the importance of the medication reconciliation at patient admission, ensuring greater safety and therapeutic efficacy of the treatment during hospitalization, and orienting the patient at discharge, assuring the therapy safety.