Introduction: High-stress situations, such as military deployments, may be a risk factor for hypertension. The relationship between the stress triggered by combat deployment and hypertension is unknown. Acute stress from combat conditions can cause a temporary rise in blood pressure, which decreases within hours or days. Cross-sectional studies have shown no association between hypertension and deployment to the 1991 Gulf War or to Vietnam. Self-reported hypertension often is used as an outcome in large population studies. Fair to substantial agreement has been observed between self-reported hypertension and various sources of administrative data, medical records, and blood pressure measurements. The goal of this dissertation was to determine whether recent deployment to Iraq and Afghanistan was associated with new-onset hypertension.Methods: Baseline Millennium Cohort Study questionnaires (July 2001 to June 2003) were completed by 77,047 individuals. Follow-up questionnaires (June 2004 to February 2006) were completed by 55,021 responders. The relationship between new-onset hypertension and history of a recent military deployment was assessed through multivariable logistic regression (N=37,075). Baseline data were analyzed cross-sectionally to assess factors associated with prevalent hypertension (N=70,100). Kappa statistics were used to compare self-reported hypertension with provider diagnosed hypertension and prescription antihypertensive medication dispensed (N=41,129).Results: The 3-year incidence of hypertension was 6.9%. After adjusting for demographic and lifestyle characteristics, deployers without combat exposure were less likely to develop new-onset hypertension compared to nondeployers (odds ratio [OR]=0.74; 95% confidence interval [CI]: 0.64, 0.85). There was no association between deployment with combat exposure and hypertension compared to nondeployers (OR=0.94; 95% CI: 0.82, 1.07). Among deployers reporting combat exposures, the risk for incident hypertension was 1.31 (95% CI: 1.07, 1.61) compared to deployers not reporting combat exposures. The prevalence of self-reported hypertension at baseline among Cohort members was 10.4%. There was moderate agreement between self-reported hypertension and provider-diagnosed hypertension, as well as antihypertensive medications dispensed.Conclusion: Military service members are adversely affected by hypertension. Although deployers had lower incidence of hypertension compared to nondeployers, individuals reporting combat exposures were more likely to report new-onset hypertension. Self-reported hypertension had moderate reliability compared with provider-diagnosed hypertension and dispensed antihypertensive medication.

A direct and highly efficient synthesis has been developed for telmisartan, the active ingredient in the widely prescribed antihypertensive drug Micardis®. This approach brings together two functionalized benzimidazoles using a high-yielding Suzuki reaction that can be catalyzed by a homogeneous palladium source or palladium on a solid support. The ability to perform the cross-coupling reaction was facilitated by the regio-controlled preparation of a 2-bromo-1-methylbenzimidazole precursor. The method developed is the first reported selective bromination at the 2-position of a benzimidazole and produces the first major precursor in high yield (93%). The second precursor, potassium (4-methyl-2-propylbenzimidazol-6-yl) trifluoroborate, was prepared from commercially available 4-bromo-2-methyl-6-nitroaniline. An optimized preparation is described that provides a direct three-step process to prepare the benzimidazole and install the borate; this synthetic sequence yields the second precursor with a 90% yield and no isolated intermediates. The two prepared precursors were combined with a third, commercially available methyl-4’-(bromomethyl)-[1,1’-biphenyl]-2-carboxylate, utilizing a short sequence of high yielding reactions to produce the telmisartan with an 83% yield from these advanced intermediates. This new convergent approach provides the active drug ingredient with an overall yield of 74% while circumventing many issues associated with the previously reported processes. Additionally, a flow-based synthesis of telmisartan was achieved with no intermediate purifications or solvent exchanges. The continuous process utilizes a tubular reactor system coupled with a plug flow cartridge, ultimately delivering telmisartan in an 86% isolated yield.

Class of 2007 Abstract / Objectives: To determine the effect of antihypertensive use on renal function and other diabetic complications in adults over the age of 18 with type 2 diabetes mellitus (DM). Methods: A retrospective secondary analysis of the NIH Pima epidemiologic data included 1,828 individuals with type 2 DM were evaluated for antihypertensive use and DM complications. Statistical analysis was done using general linear model regression (GLM) or logistic regression models controlling for age, sex and DM duration. Three groups were established to evaluate antihypertensive use Group 1 those taking antihypertensives to those not taking antihypertensives, Group 2 those taking more than one (multiple) antihypertensives to those only taking one and Group 3 those taking an angiotensin converting enzyme (ACE) inhibitor to those not taking an ACE. Results: Group 1 those taking antihypertensives were significantly worse for all outcome measures than those taking no antihypertensives as evident with: renal function (ACR 43 mg/mmol versus 15.9 mg/mmol (ρ=0.0003) and albuminuria 55.8% versus 37.6% (p=0.0039), retinopathy, neuropathy and CVD. Group 2 those taking multiple antihypertensives had significantly worse renal function (ACR 69.2 mg/mmol versus 34.5 mg/mmol (p=0.0329) and albuminuria 63% versus 52% (p=0.0396)), CVD while retinopathy and neuropathy were not significantly different. Group 3 those taking ACE had significantly worse renal function (ACR 43.8 mg/mmol versus 35.2 mg/mmol (p=0.0329)) while CVD was improved and no difference was observed in retinopathy and neuropathy. Conclusions: Antihypertensive use had little impact on preventing diabetic complications. This is contrary to well- documented literature that supports the use of antihypertensives to slow disease progression and protect renal function.

Title: Analysis of pharmacotherapy and drug related problems in patients with arterial hypertension in Greece Student: Zisis Papadopoulos Tutor: Jiri Vlcek Department of Social and Clinical Pharmacy, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove Background: Arterial hypertension or high blood pressure is a chronic medical condition which is characterized by elevated blood pressure in the arteries and is an important risk factor for future development of cardiovascular disease. Also belongs to asymptomatic diseases because it usually does not cause symptoms for years until a vital organ is damaged. Moreover is a major cause of morbidity and mortality, due to its association with some other serious diseases like coronary heart disease, cerebrovascular disease, atherosclerosis, renal disease, dyslipidemia, diabetes, obesity and metabolic syndrome. Arterial hypertension for adults, who don't suffer from any other kind of diseases, is defined by an elevation of blood pressure to 140 / 90 mm Hg or to higher values. Aim: In the theoretical part the main aim is to analyze information regarding etiopathogenesis, diagnostic methods and treatment strategies of arterial hypertension, as well as classification and causes of drug-related-problems to antihypertensive agents. In the...

Introduction: Many medications have an unproven safety profile for use during pregnancy, leading to issues when chronic diseases, such as hypertension and depression, present during pregnancy. The focus of this research programme is to determine whether in utero exposure to antihypertensive and antidepressant medication is associated with increased risk of adverse events at birth, and up to 27 months of age in the child. Methods: Two systematic reviews were performed to identify current published literature and knowledge gaps. Following this, using Scottish healthcare data, a cohort of 268,711 children born 2010-2014 were identified. Following cleaning of the data, multiple imputation was used to account for missing values. Poisson, linear and multinomial regressions were performed to identify the relationship between in utero medication exposure and child outcomes. Results: In utero antihypertensive exposure was associated with preterm birth, low birth weight, small for gestational age, but not developmental issues. However, untreated hypertension was associated with low birth weight, preterm birth, and small for gestational age. In utero antidepressant exposure was associated with preterm birth, low birth weight, small for gestational age, preeclampsia, having a special needs indicator at 10 days and 6-8 weeks post-birth, developmental issues at 27 months Conclusions: This research programme identified several adverse outcomes following in utero exposure to antihypertensive and antidepressant medication.

Orientador: Valéria Cristina Sandrim / Resumo: A pré-eclâmpsia (PE) é a principal causa de mortalidade e morbidade entre as gestantes no Brasil e em vários países. A fisiopatologia desta doença é complexa e envolve vários processos. Um destes, amplamente validado na literatura, relaciona-se a um status oxidativo, onde há prevalência de produção de radicais livres e/ou redução da atividade antioxidante. Apesar destas evidências, a suplementação clínica com antioxidantes (vitamina C e E) não se demonstrou promissora em PE. Recentemente, vem sendo explorado como terapia em várias doenças, a ativação de um fator de transcrição, o NRF2 (do inglês - nuclear factor, erythroid 2-like 2), que atua induzindo a transcrição de diversos genes que promovem a proteção celular através da codificação de proteínas com atividade desintoxicante e antioxidante. Entre elas a heme oxigenase (HO-1) é a mais estudada, pois apresenta efeitos antiapoptóticos, antioxidantes e citoprotetor. Além disso, o aumento do estresse oxidativo na PE pode potencialmente reduzir a biodisponibilidade de óxido nítrico (NO) que pode ser modulado por alguns polimorfismos localizados no gene da óxido nítrico sintase (NOS3). Notavelmente, os haplótipos formados pela combinação de polimorfismos foram associados a diferentes subgrupos de resposta à terapia anti-hipertensiva em PE. No presente estudo, comparamos as distribuições dos polimorfismos localizados nos genes NFE2L2 rs35652124 (C/T) e no gene HMOX1 rs2071746 (A/T) em gestantes com PE que respondem à metildopa ou... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Preeclampsia (PE) is the leading cause of mortality and morbidity among pregnant women in Brazil and several countries. Its pathophysiology is complex and involves several processes, including the oxidative stress (increase of free radicals and/or decrease of antioxidant defense). Although evidences, clinical supplementation with vitamins (C and E) was not promising in preeclampsia. Currently, therapeutically the activation of transcription factor, NRF2 (nuclear factor, erythroid 2-like 2), has been explored in several diseases. This factor promote cytoprotection by activates the transcription of several antioxidant and detoxification proteins. Hemeoxigenase-1 (HO-1) is the most studied, because has antiapoptotic, anti-inflammatory and cytoprotection activities. In addition, the increased oxidative stress in PE can potentially reduce the bioavailability of nitric oxide (NO) which may impaired by some SNPs on endothelial nitric oxide synthase (NOS3) gene. Notably, haplotypes formed by the combination of polymorphisms of were associated with different subgroups of response to antihypertensive therapy in PE. Therefore, in the present study we compared the distributions of rs35652124 (C/T) NFE2L2 and rs2071746 (A/T) HMOX1 polymorphisms in PE patients who respond to methyldopa or antihypertensive therapy with those found in PE patients who do not respond to methyldopa or total antihypertensive therapy. We also examined whether NFE2L2 and HMOX1 polymorphisms affect plasma HO-1 leve... (Complete abstract click electronic access below) / Mestre

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ABSTRACT The aim of this work was to produce enzymatic hemp seed protein hydrolysates (HPH) followed by bioassay guided fractionation to identify antioxidant and antihypertensive peptides. Therefore, simulated gastrointestinal digestion of isolated hemp seed proteins was conducted using consecutive actions of pepsin and pancreatin to produce HPH, which was then separated by membrane ultrafiltration to obtain peptide sizes of <1, 1-3, 3-5, and 5-10 kDa. Evaluation of HPH and its membrane fractions for antioxidant and antihypertensive properties showed that they significantly (P<0.05) scavenged radicals, reduced and strongly chelated metal ions as well as inhibited lipid oxidation. During a 24-hr test, the HPH reduced systolic blood pressure (SBP) of spontaneously hypertensive rats (SHR) after oral administration by a maximum of -30 mmHg when compared to -15 mmHg for the membrane fractions. To reduce production cost, hemp seed protein meal (HPM) was directly hydrolyzed to a protein hydrolysate (HMH) and was shown to also reduce SBP during 4-8 weeks of dietary feeding. The attenuation of SBP correlated to suppressed plasma levels (0.047-0.059 U/mL and 0.040-0.054 µg/mL) of angiotensin converting enzyme (ACE) and renin, respectively, when compared to the control rats (0.123 U/mL and 0.151 µg/mL). A total of 23 peptides were identified to be present in the HPH. WVYY and PSLPA showed superior in vitro antioxidant properties, while ACE activity was inhibited by WYT (89%), WVYY (91%) and PSLPA (90%). Renin activity was inhibited by WYT (77%), SVYT (87%) and IPAGV (75%). However, oral administration to SHR showed that the pentapeptides (PSLPA and IPAGV) were more effective SBP-reducing agents (-40 mm Hg) when compared to the tri- (-13 mmHg) and tetrapeptides (-36 mmHg). These results show for the first time in literature, the bioactive properties of hemp seed peptides and indicate their potential use as ingredients to formulate antioxidant and antihypertensive functional foods and nutraceuticals.

ABSTRACT The aim of this work was to produce enzymatic hemp seed protein hydrolysates (HPH) followed by bioassay guided fractionation to identify antioxidant and antihypertensive peptides. Therefore, simulated gastrointestinal digestion of isolated hemp seed proteins was conducted using consecutive actions of pepsin and pancreatin to produce HPH, which was then separated by membrane ultrafiltration to obtain peptide sizes of <1, 1-3, 3-5, and 5-10 kDa. Evaluation of HPH and its membrane fractions for antioxidant and antihypertensive properties showed that they significantly (P<0.05) scavenged radicals, reduced and strongly chelated metal ions as well as inhibited lipid oxidation. During a 24-hr test, the HPH reduced systolic blood pressure (SBP) of spontaneously hypertensive rats (SHR) after oral administration by a maximum of -30 mmHg when compared to -15 mmHg for the membrane fractions. To reduce production cost, hemp seed protein meal (HPM) was directly hydrolyzed to a protein hydrolysate (HMH) and was shown to also reduce SBP during 4-8 weeks of dietary feeding. The attenuation of SBP correlated to suppressed plasma levels (0.047-0.059 U/mL and 0.040-0.054 µg/mL) of angiotensin converting enzyme (ACE) and renin, respectively, when compared to the control rats (0.123 U/mL and 0.151 µg/mL). A total of 23 peptides were identified to be present in the HPH. WVYY and PSLPA showed superior in vitro antioxidant properties, while ACE activity was inhibited by WYT (89%), WVYY (91%) and PSLPA (90%). Renin activity was inhibited by WYT (77%), SVYT (87%) and IPAGV (75%). However, oral administration to SHR showed that the pentapeptides (PSLPA and IPAGV) were more effective SBP-reducing agents (-40 mm Hg) when compared to the tri- (-13 mmHg) and tetrapeptides (-36 mmHg). These results show for the first time in literature, the bioactive properties of hemp seed peptides and indicate their potential use as ingredients to formulate antioxidant and antihypertensive functional foods and nutraceuticals.

Many bioactive peptides have been reported from various food proteins through the conventional activity-guided-purification approach; however, the rationale behind the selection of conditions for the production of the bioactive peptides has not been extensively explored. The purposes of the study were to provide the rationale behind the selection of conditions, and to develop an innovative strategy to explore the most potent peptides within egg proteins through an integrated QSAR and bioinformatics approach. Thermolysin-pepsin hydrolysate of ovotransferrin was predicted as the best condition for production of ACE-inhibitory peptides. Three predicted peptides, IRW, LKP and IQW, were successfully released from ovotransferrin. Simulated gastrointestinal incubation showed IQW was stable while IRW and LKP can be degraded into dipeptides (IR and KP respectively). Peptides produced from the study will have the potential to be developed as functional foods and nutraceuticals for the prevention of hypertension, a disease affecting ~ 31% of the adult population. / Food Science and Technology