Clinically relevant endothelial nitric oxide synthase polymorphisms and their impact on drug response.

INTRODUCTION: Nitric oxide (NO) is a molecule with multiple functions. Several drugs involve the modulation of NO levels in their mechanism of action. NO is mainly produced in vessels by endothelial NO synthase, which is encoded by NOS3 gene. This gene shows genetic polymorphisms associated with hypertension and other cardiovascular diseases, inflammation, psychiatric disorders, cancer, and others. AREAS COVERED: Four functional polymorphisms of NOS3 were selected: rs2070744, rs3918226, rs61722009, and rs1799983 and their association with differential drug responses was explored. This review explores beyond the cardiovascular area, including drugs regardless of their clinical indications. EXPERT OPINION: While there is good evidence of the clinical importance of NOS3 single nucleotide polymorphisms, the current knowledge is superficial in most clinical settings and further studies are needed. Basic science advances are also needed to help to interpret genetic association data. While there are controversies, most data from chronic treatment studies show a trend for loss-of-function alleles, that predispose to higher risk for disease, associating with better clinical response across different drug classes and clinical settings. Acute pharmacological responses were poorly explored, although there seem to be a trend where gain-of-function alleles associate with better clinical responses when observed in the scale of minutes to hours.

Association of 11ß-hydroxysteroid dehydrogenase type1 (HSD11b1) gene polymorphisms with outcome of antidepressant therapy and suicide attempts.

The hypothalamic-pituitary-adrenal axis has been implicated in the pathophysiology of depressive disorders. HSD11B1 encodes 11ß-hydroxysteroid dehydrogenase type1 enzyme, responsible for converting cortisone to cortisol. Genetic polymorphisms in HSD11B1 may impact in depression outcome and risk of suicide. This study aimed to assess whether HSD11B1 genotypes and haplotypes are associated with depression risk, severity of symptoms and suicidal attempts, considering early-life stress as an environmental factor. Here, 142 depressive patients and 103 healthy controls were included. Patients were enrolled from the Affective Disorders ambulatory and day hospital units, both within the University General Hospital of Ribeirao Preto. All subjects were clinically assessed applying the Mini-PLUS International Neuropsychiatric Interview, followed by the 21-item GRID-Hamilton Depression Scale, Childhood Trauma Questionnaire and Beck Scale for Suicidal Ideation (BSI). All subjects underwent antecubital vein puncture to obtain blood for DNA extraction. Genotyping of rs11119328 and rs11811440 were performed using allele-specific oligonucleotide polymerase chain reaction. We found a significant association of rs11119328 variant genotypes with increased risk for at least one suicide attempt (OR: 7.10, p = 0.049) and an association of variant genotypes of rs11811440 with euthymic mood under optimized pharmacological treatment (OR: 0.05, P = 0.014). These tests included correction for confounding factors. The association of genetic markers with depression risk, GRID-HAM-D21 and BSI scores and the number of suicidal attempts were nonsignificant. Haplotypes combining both markers were not associated with the studied phenotypes. We conclude that HSD11B1 polymorphisms may be relevant biomarkers for detecting subjects genetically vulnerable to poorer antidepressant response and higher risk of suicide attempts.

Association of endothelial nitric oxide synthase (eNOS) gene polymorphisms and physical fitness levels with plasma nitrite concentrations and arterial blood pressure values in older adults.

Endothelial nitric oxide synthase (eNOS) gene polymorphisms are associated with reduced eNOS activity and nitric oxide (NO) production leading to an increase in blood pressure (BP). Regular exercise is the main strategy to minimize the deleterious effects of polymorphisms. However, due to the differences that physical exercise can be performed, some controversial results are found. Therefore it seems reasonable to evaluate the training status (TS). Thus, this study aimed to investigate the association of eNOS gene haplotypes and different levels of TS on nitrite concentrations (NO2-) and BP values in older adult. 424 elderly performed the following assessments: General Functional Fitness Index (GFFI) to estimate TS, systolic and diastolic blood pressure (SBP and DBP), blood collection for analysis of NO2- and g.-786T>C, intron 4b/a (VNTR) and 894G>T polymorphisms. Multivariate logistic regression showed that NO2- was influenced by GFFI and 4b/4a Intron 4. Regarding BP, GFFI influenced SBP and DBP, and just intron 4 was associated with variations in DBP. It can be observed that GFFI affected the NO2-, SBP and DBP independently of haplotypes. Therefore, maintenance of good level of TS can overcome the negative influence of genetics factors (intron 4) by increasing NO2- concentration and decreasing BP values.

Interações medicamentosas potencias em unidades de terapia intensiva de um hospital do Sul do Brasil / Potential drug-drug interactions in intensive care units of a hospital in Southern Brazil

As interações medicamentosas são importantes causas de reações adversas em unidades de saúde. O elevado consumo de medicamentos em unidades de terapia intensiva predispõe os pacientes a um risco potencial de ocorrência de interações medicamentosas. O objetivo deste estudo foi determinar a frequência e as características das interações medicamentosas potenciais em unidades de terapia intensiva do Hospital Universitário da Universidade Estadual de Londrina Foram analisadas as prescrições de pacientes maiores de 18 anos internados no período de janeiro a maio de 2010, com permanência de pelo menos quatro dias.A análise das interações medicamentosas foi realizada utilizando-se o sistema Micromedex Drug-Reax®. As interações foram classificadas por gravidade, tempo necessário para o início dos efeitos adversos, mecanismo de ação e qualidade da evidência científica. Além disso, foram analisados os possíveis eventos adversos relacionados às interações, bem como as estratégias de manejo e monitoramento recomendadas. Ao todo foram identificadas 198 diferentes interações medicamentosas potenciais com a ocorrência de 1242 episódios. Destes, 43% foram caracterizados por interações de gravidade moderada, 35% graves,16% leves e 6% contra-indicadas. A ineficácia terapêutica foi o possível evento adverso mais frequente(18%) e a principal estratégia de manejo recomendada foi o ajuste de dose (35,6%). As interações mais frequentes foram: fentanil + midazolam (8,6%), fenitoína + ranitidina (5,5%) e midazolam + ranitidina(4,8%). Os resultados identificados demonstram a importância das interações medicamentosas como evento adverso significativo em unidades de terapia intensiva e, portanto, medidas preventivas são necessárias para minimizar este problema. .

Drug-drug interactions are important causes of adverse reactions in health units. The high consumption of medicines in intensive care units predisposes patients to potential drug-drug interactions. The aim of this study was to examine the frequency and the characteristics of drug-drug interactions in intensive care units of University Hospital of State University of Londrina. We analyzed the prescriptions of patients over 18 years, admitted from January to May 2010, who remained hospitalized for at least four days. The analysis of drugdrug interactions was carried out using the Micromedex Drug-Reax® system. The interactions were classified by severity, time required for the onset of adverse effects, mechanism of action and quality of scientific evidence. Moreover, the possible adverse events were analyzed, as well as the recommended strategies of management and monitoring. Altogether, 198 different potential drug-drug interactions were identified with the occurrence of 1242 episodes. Of these, 43% were characterized by moderate interactions, 35% major,16% minor and 6% contraindicated. The therapeutic inefficacy was the most frequent possible adverse event(18%) and the main recommended strategy of management was the dose adjustment (35.6%). The most frequent interactions were: fentanyl + midazolam (8.6%), phenytoin + ranitidine (5.5%) and midazolam + ranitidine (4.8%). These results demonstrate the importance of drug-drug interactions as a significant adverseevent in intensive care units and thus, preventive measures are required to minimize this problem.

Effects of angiotensin-converting enzyme inhibition on leptin and adiponectin levels in essential hypertension.

Activation of the renin-angiotensin-aldosterone system (RAAS) and abnormal adipokine levels are biological alterations that affect blood pressure regulation and interact to link hypertension, obesity and metabolic diseases. While imbalanced levels of hormones produced by adipocytes including hypo-adiponectinaemia and hyperleptinaemia were reported in hypertension, little is known about how antihypertensive therapy affects these alterations. This study aimed to evaluate the effects of enalapril on plasma adiponectin and leptin levels in hypertensive individuals. Thirty-seven untreated hypertensive patients were prospectively treated with enalapril for 8 weeks. Blood samples were collected at baseline and after the treatment with enalapril. Plasma adiponectin and leptin levels were measured by enzyme-linked immunoassay. We found significant increases in adiponectin levels after enalapril treatment (5.4 ± 3.7 versus 6.0 ± 4.5 µg/mL, mean ± S.D., p = 0.04). Conversely, leptin levels were unchanged (18.0 ± 14.7 versus 18.4 ± 14.8 ng/mL, mean ± S.D., p = 0.31). Multiple linear regression revealed that baseline leptin is a significant predictor of systolic blood pressure reduction (ß=0.269, p = 0.01) in hypertensive individuals treated with enalapril. While enalapril increases adiponectin levels in hypertensive individuals, baseline leptin levels predict blood pressure reduction in response to this therapy. These findings support the idea of an important relationship between RAAS and adipose tissue in hypertension and suggest that enalapril improves the adipokine profile, possibly allowing beneficial effects to overweight or obese hypertensive individuals.