Antihypertensive drugs can cause hypotension in the elderly and such an effect may lead to fall injuries. This thesis examined the association between antihypertensive drugs and hip fracture risk among elderly patients during the initiation of monotherapy. This population-based self-controlled case series study used healthcare administrative databases to identify Ontario residents aged ≥ 66 years with a first prescription for a thiazide diuretic, angiotension II converting-enzyme inhibitor, angiotensin II receptor antagonist, calcium channel blocker or beta-adrenergic blocker. A cohort of newly treated hypertensive elderly was then linked to the occurrence of hip fractures from April 1, 2000 to March 31, 2009. We found that hypertensive elderly initiated on an antihypertensive drug had a 43% increased risk of having a hip fracture during the first 45 days of treatment, IRR 1.43 (95% CI 1.19-1.72). Initiating antihypertensive drugs in community-dwelling elderly should be approached with caution due to increased fracture risk.

Antihypertensive drugs can cause hypotension in the elderly and such an effect may lead to fall injuries. This thesis examined the association between antihypertensive drugs and hip fracture risk among elderly patients during the initiation of monotherapy. This population-based self-controlled case series study used healthcare administrative databases to identify Ontario residents aged ≥ 66 years with a first prescription for a thiazide diuretic, angiotension II converting-enzyme inhibitor, angiotensin II receptor antagonist, calcium channel blocker or beta-adrenergic blocker. A cohort of newly treated hypertensive elderly was then linked to the occurrence of hip fractures from April 1, 2000 to March 31, 2009. We found that hypertensive elderly initiated on an antihypertensive drug had a 43% increased risk of having a hip fracture during the first 45 days of treatment, IRR 1.43 (95% CI 1.19-1.72). Initiating antihypertensive drugs in community-dwelling elderly should be approached with caution due to increased fracture risk.

Submitted by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2016-09-22T18:11:33Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) MARIA FERNANDA DE MOURA LEÃO.pdf: 2846166 bytes, checksum: f1e8c6a8d84f559be79cb61300900f00 (MD5) / Approved for entry into archive by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2016-09-22T18:12:09Z (GMT) No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) MARIA FERNANDA DE MOURA LEÃO.pdf: 2846166 bytes, checksum: f1e8c6a8d84f559be79cb61300900f00 (MD5) / Made available in DSpace on 2016-09-22T18:12:09Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) MARIA FERNANDA DE MOURA LEÃO.pdf: 2846166 bytes, checksum: f1e8c6a8d84f559be79cb61300900f00 (MD5) Previous issue date: 2016 / A hipertensão arterial é uma condição clínica de ocorrência multifatorial, sendo a mais frequente entre as doenças crônicas não transmissíveis no Brasil. É caracterizada pelo aumento e manutenção dos níveis pressóricos acima de 140mmHg (pressão sistólica) e 90mmHg (pressão diastólica). É também o maior agravante nas complicações cardiovasculares e está associada ao surgimento de outras co-morbidades. A OMS estima que 40% da população mundial acima dos 25 anos seja hipertensa, estando localizada majoritariamente em países onde a renda e o nível de escolaridade são menores. Depois de diagnosticada, a hipertensão arterial deve ser tratada com mudanças no estilo de vida e medicamentos que mantenham os níveis pressóricos controlados, sendo assim, várias classes de anti-hipertensivos são usados nesse tratamento. Visando ampliar o acesso a medicamentos básicos e permitir uma melhor adesão ao tratamento, o Governo Federal criou em 2004 o Programa Farmácia Popular do Brasil, uma parceria entre governo e instituições públicas e privadas para fornecer a população medicamentos para o controle da hipertensão, diabetes, asma, dislipidemias, anticoncepcionais, entre outros; de forma gratuita ou subsidiada em até 90% do valor. Para tratar a hipertensão, o Programa Farmácia Popular do Brasil distribui de forma gratuita os anti-hipertensivos – atenolol, captopril, cloridrato de propranolol, hidroclorotiazida, losartana e maleato de enalapril, todos estes sendo lançados no mercado anterior ao ano de 2004, quando testes de segurança genética ainda não eram obrigatórios, de acordo com a Resolução nº 90/2004 da ANVISA. Desta forma, o objetivo deste trabalho foi avaliar o potencial genotóxico de anti-hipertensivos distribuídos pela Farmácia Popular em células leucocitárias humanas, haja vista que são fármacos amplamente utilizados e se faz necessários maiores estudos que garantam a segurança genotoxicológica dos mesmos. Os testes foram desenvolvidos a partir de culturas celulares tratadas com cinco diferentes concentrações dos anti-hipertensivos, sendo avaliados parâmetros genotoxicológicos – viabilidade celular e índice de dano ao DNA (teste Cometa), e parâmetros mutagênicos – teste de micronúcleo e instabilidade cromossômica numérica. Os resultados mostram que captopril e maleato de enalapril foram capazes de diminuir a viabilidade celular e causar danos ao DNA conforme o aumento da dose, e que, o atenolol foi capaz de também diminuir a viabilidade celular de acordo com o aumento da dose. A hidroclorotiazida também mostrou causar dano ao DNA, porém esse dano ocorreu de forma igual para as cinco doses. Quanto aos parâmetros mutagênicos, nenhum dos seis anti-hipertensivos testados e, em nenhuma das cinco concentrações foi capaz de causar alterações mutagências. / Hypertension is an clinical condition of the multifactorial occurrence, the most frequent among chronic diseases not transferable in Brazil. It is characterized by increase and maintenance blood pressure levels above 140mmHg (sistolic pressure) and 90mmHg (diastolic pressure). It i also the most aggravating in the cardiovascular complications and it is associated with the appearance of others comorbidities. The WHO estimes that 40% of the world population over 25 years old is hypertensive, being located mostly in countries where income and educations levels are lower. After the diagnosed, hypertension must be treated with changes in the life style and drugs that maintain pressure levels controled, therefore, several classes of antihypertensive are used in this treatment. Aiming to expand access to basic drugs and allow a better adhesion to treatment, the federal government created in 2004 the “Farmácia Popular do Brasil” Program, an association among government and public and private institutions to provide the people medications for control of the hypertension, diabetes, asthma, dyslipidemia, contraceptives, etc, free or subsidized form by up to 90% of the value. To treat hypertension, the “Farmácia Popular do Brasil” Program distributes of free form antihypertensive – atenolol, captopril, propranolol hydrochloride, hydrochlorotiazhide, losartan and enalapril maleate, all these being released before the year 2004, when genetic safety tests still not required, according to Resolution nº 90/2004 of ANVISA. Thus, the objective this work was to evaluate the genotoxic potencial of the antihypertensives distributed by “Farmácia Popular” in human leukocytes cells, considering that they are widely used drugs and it is necessary larger studies that ensure the genotoxicology their safety. The tests are desenvolved from cell cultures treated with five different concentrations of the antihypertensives, being evaluated genotoxicological parameters – cell viability and DNA damage index, and mutagenic parameters – micronucleus test and numerical chromossomal aberrations. The results showed that captopril and enalapril maleate were able to reduce cell viability and cause damage to DNA wiht increasing dose. The hydrochlorothiazide also showed to cause DNA damage, but, this damage occorred equallity for five doses. As for mutagenic parameters , none of the six antihypertensives tested and, none of the five concentrations were capable to cause mutagenic changes.

Cardiovascular complications represent the leading cause of death in chronic kidney disease (CKD) patients. Significant renal mass reduction induced by 5/6 subtotal nephrectomy (Nx) animal model leads to a chain of events that culminates in hypertension and CKD. The renin angiotensin (Ang) system (RAS) is known to be dysregulated, specifically Ang type 1 receptor (AT1R) plays a major role in development and progression of the disease. However, conflicting results have been reported on intrarenal AT1R levels, and the impact of antihypertensive drugs on RAS signaling is divergent. We hypothesize that PET imaging will be able to quantify kidney AT1R expression reliably in healthy and disease states. The broad objectives of this research project were: (i) to develop a positron emission tomography (PET) probe capable of detecting changes in the AT1R binding in the kidney; (ii) to elucidate the nature/temporal role of renal AT1R in Nx rat model of CKD; and (iii) to explore the predictive value of non-invasive PET imaging of AT1R to guide the use of antihypertensive therapy in preventing the progression of the disease. The novel selective AT1R PET radioligand [18F]FPyKYNE-losartan was successfully used with PET in detecting renal AT1Rs at early and late stages of the CKD. The PET results correlated well with in vitro [125I]-[Sar1, Ile8]Ang II autoradiography. Over the time-course of the study (10-20 weeks), the Nx rats exhibited renal impairment, proteinuria and sustained hypertension. Echocardiography indicated the development of cardiac hypertrophy most likely secondary to the hyperdynamic circulation. These abnormalities were associated with increasing plasma and kidney levels of Ang II, and compensatory downregulation of renal AT1Rs. ACEI enalapril attenuated renal impairment, hypertension and prevented progression of cardiac hypertrophy in Nx rats. This was successfully accomplished through reduction of systemic and kidney Ang II, and consequent normalization of renal AT1R as measured by PET (and autoradiography). The non-dihydropyridine CCB diltiazem also reduced blood pressure but did not normalize renal AT1R expression. Diltiazem induced elevation in Ang II levels in plasma, kidney and heart, associated with exacerbation of renal and cardiac dysfunction, and no change in AT1R renal expression. This outcome adds value to the use of [18F]FPyKYNE-losartan PET for determination of receptor abnormalities with progression of the disease and monitoring of therapy.

Comme plusieurs pays du monde, Madagascar a fait rentrer dans sa politique de santé, l’utilisation des médicaments génériques, de moindre coût, pour faciliter l’accès aux soins de la population. La promotion des médicaments génériques impose de garantir leur qualité par rapport aux médicaments de référence. Une étude a été menée pour contribuer à l’amélioration des pratiques du système de réglementation et des contrôles pharmaceutiques de Madagascar. Pour cela, l’environnement pharmaceutique et le système d’enregistrement des médicaments de ce pays sont présentés en regard de ceux existants dans d’autres pays. Ensuite, des contrôles de qualité englobant des essais physico-chimiques, pharmaco-techniques et pharmacologiques, sont réalisés sur vingt-deux médicaments antihypertenseurs dont quatre spécialités de références et dix-huit spécialités considérées comme leurs génériques, échantillonnés à Madagascar. L’augmentation incessante du nombre de malades atteints d’hypertension artérielle, couplée avec la difficulté de son traitement, sont à l’origine du choix de la famille thérapeutique étudiée. Pour les dix-huit spécialités considérées comme génériques, des non conformités aux référentiels ont été révélées. Seulement une spécialité considérée comme générique a présenté des caractéristiques, dont la cinétique de dissolution et les résultats pharmacologiques, similaires à celles de la référence. Des préconisations impliquant tous les acteurs du domaine pharmaceutiques ont pu être dégagées à partir de l’étude. / Like many countries in the world, Madagascar has returned in its health policy, the use of generic drugs, because of their lower cost, to facilitate access to health care of the population. The promotion of generic drugs needs to ensure their quality compared to reference drugs. A study was conducted to contribute to the improvement of practices and drug regulatory system in Madagascar . For this, the pharmaceutical environment and the registration of generic drugs in this country with those of other countries are presented. Then quality control tests were performed on twenty two antihypertensive drugs including four referent specialties and eighteen specialties considered as their generic, sampled in Madagascar . The choice of this therapeutic family was governed by the constant increase in the number of patients suffering from hypertension, associated with the difficulty of treatment. For the eighteen specialties considered as generics, non-compliances with standards were recorded at the end of the physicochemical and pharmacotechnical tests and pharmacological studies. Only one specialty was shown to present similar characteristics, including dissolution kinetics and pharmacological results, as the reference. Recommendations involving all stakeholders of the pharmaceutical field have been brought from the study.

Nós investigamos em ratos espontaneamente hipertensos (SHR) jovens (28 semanas) e velhos (52 semanas) os efeitos hemodinâmicos e autonômicos cardiovasculares promovidos por diferentes terapias anti-hipertensivas farmacológicas associadas ao treinamento físico aeróbio. Para tanto, ratos SHR de 18 semanas de idade (N=128) foram alocados em quatro grandes grupos (N=32): tratado com água (Grupo Veículo); tratado com Enalapril; tratado com Losartan; e tratado com Amlodipina. Cada grupo foi subdivido em dois menores grupos (N=16) tratados durante 10 ou 34 semanas, sendo que metade de cada grupo (N=08) era também submetido ao treinamento físico aeróbio por meio da natação pelo mesmo período de tempo (10 ou 34 semanas). No penúltimo dia de tratamento todos os animais tiveram canuladas a artéria e veia femorais para registro da pressão arterial (PA) e injeção de drogas, respectivamente. 24 horas após a avaliação autonômica cardiovascular foi realizada por meio de diferentes abordagens; avaliação do balanço simpato/vagal por meio do duplo bloqueio autonômico cardíaco com atropina e propranolol; análise da variabilidade da frequência cardíaca (VFC) e pressão arterial sistólica (VPAS) por meio da análise espectral; e análise da sensibilidade barorreflexa (SBR) espontânea. Todos os tratamentos promoveram redução da PA, entretanto, nos grupos jovens, o tratamento com Enalapril promoveu as maiores reduções, independentemente do treinamento físico, enquanto que nos grupos velhos, a associação do treinamento físico ao Enalapril promoveu efeito adicional na redução da PA. Em relação ao controle autonômico cardiovascular, o tratamento com Amlodipina promoveu maiores adaptações benéficas no grupo de SHR sedentários jovens quando comparado às demais drogas, caracterizados pelo predomínio do tônus autonômico vagal, aumento da variância na VFC, além de aumento na SBR. Embora o treinamento físico tenha promovido algumas adaptações benéficas quando aplicado sozinho, não foi capaz de potencializar os achados observados para a Amlodipina. O tratamento com Enalapril ou Losartan promoveu menores adaptações autonômicas cardiovasculares quando administrado em SHR sedentários em comparação à Amlodipina, entretanto quando o Enalapril foi associado ao treinamento físico observamos sensível melhora no controle autonômico cardiovascular nos diferentes parâmetros avaliados, inclusive a redução das oscilações de baixa frequência (LF; 0,75-2.5Hz) na VPAS, além de aumento na SBR. Contrariamente, a Amlodipina sozinha não modificou os parâmetros autonômicos cardiovasculares nos SHR velhos, cabendo ao Enalapril e ao Losartan promoverem melhores efeitos quando aplicados sozinhos nesses animais. O treinamento físico também promoveu adaptações autonômicas benéficas nos SHR velhos, e em alguns parâmetros, como a VFC, as adaptações foram ainda melhores. Surpreendentemente, quando associado à Amlodipina, as adaptações foram ainda mais expressivas, com significativa atenuação do tônus autonômico simpático, redução da modulação simpática e aumento da modulação vagal na VFC, além de redução nas oscilações de LF na VPAS e aumento da SBR. Em conclusão, nos animais jovens, a Amlodipina foi mais eficaz na promoção de adaptações autonômicas cardiovasculares benéficas, enquanto que o Enalapril apresentou resultados autonômicos semelhantes somente quando associado ao treinamento físico aeróbio. Por sua vez, nos animais velhos, a Amlodipina teve pouco efeito sobre o controle autonômico cardiovascular, enquanto que o Enalapril e o Losartan foram mais eficazes. Nesse caso, nossos achados indicam que o envelhecimento representa um fator determinante que interfere no controle autonômico cardíaco e atenua os efeitos dos diferentes tratamentos farmacológicos. Por fim, o treinamento físico apresenta um papel fundamental no tratamento da hipertensão arterial, participando desse processo como um catalizador dos efeitos autonômicos cardiovasculares promovidos pelo tratamento farmacológico, tanto em SHR jovens, quando associado ao Enalapril, quanto em SHR velhos, quando associado à Amlodipina. / We investigated in spontaneously hypertensive rats (SHR) young (28 weeks) and old (52 weeks) hemodynamic and autonomic cardiovascular effects caused by different pharmacological antihypertensive therapy associated with aerobic exercise. For that purpose, 18-weeks-old SHR (N = 128) were divided into four groups (N = 32): Water treated (Vehicle Group); treated with Enalapril; treated with Losartan; and treated with Amlodipine. Each group was subdivided into two smaller groups (N = 16) treated for 10 or 34 weeks, with half of each group (N = 08) was also subjected to physical training through swimming the same period of time (10 or 34 weeks). On the last day of treatment all animals were cannulated the femoral artery and vein to record blood pressure (AP) and injection of drugs, respectively. 24 hours after cardiovascular autonomic assessment was performed by means of different approaches; evaluation of sympathetic / vagal balance through double cardiac autonomic blockade with atropine and propranolol; analysis of heart rate variability (HRV) and systolic blood pressure (SAPV) by means of spectral analysis; and analysis of spontaneous baroreflex sensitivity (BRS). All treatments promoted AP reduction, however, in youth groups, treatment with Enalapril promoted the greatest reductions, regardless of physical training, while in the older groups, the association of physical training to Enalapril promoted additionally reduce AP. Regarding the cardiovascular autonomic control, treatment with Amlodipine produced greater beneficial adaptations in sedentary young group compared to other drugs, characterized by the predominance of vagal autonomic tone, increased variance in HRV, and increase in BRS. While physical training has promoted some beneficial adjustments when used alone, it was unable to potentiate the findings observed for Amlodipine. Treatment with Enalapril and Losartan promoted lower cardiovascular autonomic adaptations when administered in sedentary SHR compared to Amlodipine, however when Enalapril was associated with physical training we observed significant improvement in cardiovascular autonomic control in the different evaluated parameters, including the reduction of low-frequency oscillations (LF; 0,75-2.5Hz) in SAPV, besides an increase in the BRS. In contrast, Amlodipine alone did not modify the cardiovascular autonomic parameters in the old SHR, leaving the Enalapril and Losartan promote better effects when applied alone in these animals. Physical training also promoted beneficial autonomic adaptations in old SHR, and in some parameters, such as HRV, adjustments were even better. Surprisingly, when combined with Amlodipine, adaptations have been even more significant, with significant attenuation of the sympathetic autonomic tone, decreased sympathetic modulation and increased vagal modulation on HRV as well as reduction in the LF oscillations in SAPV and increased BRS. In conclusion, in young animals Amlodipine was more effective in promoting beneficial cardiovascular autonomic adaptations, while Enalapril showed similar autonomic results only when combined with aerobic exercise. In turn, in old animals Amlodipine had little effect on the cardiovascular autonomic control, while Losartan and Enalapril were more effective. In this case, our findings indicate that aging is a factor that interferes with cardiac autonomic control and mitigate the effects of different pharmacological treatments. Finally, physical training has a key role in the treatment of hypertension, participating in this process as a catalyst of cardiovascular autonomic effects caused by drug treatment in both, young SHR, when combined with Enalapril, as in old SHR, when associated with Amlodipine.

Nós investigamos em ratos espontaneamente hipertensos (SHR) jovens (28 semanas) e velhos (52 semanas) os efeitos hemodinâmicos e autonômicos cardiovasculares promovidos por diferentes terapias anti-hipertensivas farmacológicas associadas ao treinamento físico aeróbio. Para tanto, ratos SHR de 18 semanas de idade (N=128) foram alocados em quatro grandes grupos (N=32): tratado com água (Grupo Veículo); tratado com Enalapril; tratado com Losartan; e tratado com Amlodipina. Cada grupo foi subdivido em dois menores grupos (N=16) tratados durante 10 ou 34 semanas, sendo que metade de cada grupo (N=08) era também submetido ao treinamento físico aeróbio por meio da natação pelo mesmo período de tempo (10 ou 34 semanas). No penúltimo dia de tratamento todos os animais tiveram canuladas a artéria e veia femorais para registro da pressão arterial (PA) e injeção de drogas, respectivamente. 24 horas após a avaliação autonômica cardiovascular foi realizada por meio de diferentes abordagens; avaliação do balanço simpato/vagal por meio do duplo bloqueio autonômico cardíaco com atropina e propranolol; análise da variabilidade da frequência cardíaca (VFC) e pressão arterial sistólica (VPAS) por meio da análise espectral; e análise da sensibilidade barorreflexa (SBR) espontânea. Todos os tratamentos promoveram redução da PA, entretanto, nos grupos jovens, o tratamento com Enalapril promoveu as maiores reduções, independentemente do treinamento físico, enquanto que nos grupos velhos, a associação do treinamento físico ao Enalapril promoveu efeito adicional na redução da PA. Em relação ao controle autonômico cardiovascular, o tratamento com Amlodipina promoveu maiores adaptações benéficas no grupo de SHR sedentários jovens quando comparado às demais drogas, caracterizados pelo predomínio do tônus autonômico vagal, aumento da variância na VFC, além de aumento na SBR. Embora o treinamento físico tenha promovido algumas adaptações benéficas quando aplicado sozinho, não foi capaz de potencializar os achados observados para a Amlodipina. O tratamento com Enalapril ou Losartan promoveu menores adaptações autonômicas cardiovasculares quando administrado em SHR sedentários em comparação à Amlodipina, entretanto quando o Enalapril foi associado ao treinamento físico observamos sensível melhora no controle autonômico cardiovascular nos diferentes parâmetros avaliados, inclusive a redução das oscilações de baixa frequência (LF; 0,75-2.5Hz) na VPAS, além de aumento na SBR. Contrariamente, a Amlodipina sozinha não modificou os parâmetros autonômicos cardiovasculares nos SHR velhos, cabendo ao Enalapril e ao Losartan promoverem melhores efeitos quando aplicados sozinhos nesses animais. O treinamento físico também promoveu adaptações autonômicas benéficas nos SHR velhos, e em alguns parâmetros, como a VFC, as adaptações foram ainda melhores. Surpreendentemente, quando associado à Amlodipina, as adaptações foram ainda mais expressivas, com significativa atenuação do tônus autonômico simpático, redução da modulação simpática e aumento da modulação vagal na VFC, além de redução nas oscilações de LF na VPAS e aumento da SBR. Em conclusão, nos animais jovens, a Amlodipina foi mais eficaz na promoção de adaptações autonômicas cardiovasculares benéficas, enquanto que o Enalapril apresentou resultados autonômicos semelhantes somente quando associado ao treinamento físico aeróbio. Por sua vez, nos animais velhos, a Amlodipina teve pouco efeito sobre o controle autonômico cardiovascular, enquanto que o Enalapril e o Losartan foram mais eficazes. Nesse caso, nossos achados indicam que o envelhecimento representa um fator determinante que interfere no controle autonômico cardíaco e atenua os efeitos dos diferentes tratamentos farmacológicos. Por fim, o treinamento físico apresenta um papel fundamental no tratamento da hipertensão arterial, participando desse processo como um catalizador dos efeitos autonômicos cardiovasculares promovidos pelo tratamento farmacológico, tanto em SHR jovens, quando associado ao Enalapril, quanto em SHR velhos, quando associado à Amlodipina. / We investigated in spontaneously hypertensive rats (SHR) young (28 weeks) and old (52 weeks) hemodynamic and autonomic cardiovascular effects caused by different pharmacological antihypertensive therapy associated with aerobic exercise. For that purpose, 18-weeks-old SHR (N = 128) were divided into four groups (N = 32): Water treated (Vehicle Group); treated with Enalapril; treated with Losartan; and treated with Amlodipine. Each group was subdivided into two smaller groups (N = 16) treated for 10 or 34 weeks, with half of each group (N = 08) was also subjected to physical training through swimming the same period of time (10 or 34 weeks). On the last day of treatment all animals were cannulated the femoral artery and vein to record blood pressure (AP) and injection of drugs, respectively. 24 hours after cardiovascular autonomic assessment was performed by means of different approaches; evaluation of sympathetic / vagal balance through double cardiac autonomic blockade with atropine and propranolol; analysis of heart rate variability (HRV) and systolic blood pressure (SAPV) by means of spectral analysis; and analysis of spontaneous baroreflex sensitivity (BRS). All treatments promoted AP reduction, however, in youth groups, treatment with Enalapril promoted the greatest reductions, regardless of physical training, while in the older groups, the association of physical training to Enalapril promoted additionally reduce AP. Regarding the cardiovascular autonomic control, treatment with Amlodipine produced greater beneficial adaptations in sedentary young group compared to other drugs, characterized by the predominance of vagal autonomic tone, increased variance in HRV, and increase in BRS. While physical training has promoted some beneficial adjustments when used alone, it was unable to potentiate the findings observed for Amlodipine. Treatment with Enalapril and Losartan promoted lower cardiovascular autonomic adaptations when administered in sedentary SHR compared to Amlodipine, however when Enalapril was associated with physical training we observed significant improvement in cardiovascular autonomic control in the different evaluated parameters, including the reduction of low-frequency oscillations (LF; 0,75-2.5Hz) in SAPV, besides an increase in the BRS. In contrast, Amlodipine alone did not modify the cardiovascular autonomic parameters in the old SHR, leaving the Enalapril and Losartan promote better effects when applied alone in these animals. Physical training also promoted beneficial autonomic adaptations in old SHR, and in some parameters, such as HRV, adjustments were even better. Surprisingly, when combined with Amlodipine, adaptations have been even more significant, with significant attenuation of the sympathetic autonomic tone, decreased sympathetic modulation and increased vagal modulation on HRV as well as reduction in the LF oscillations in SAPV and increased BRS. In conclusion, in young animals Amlodipine was more effective in promoting beneficial cardiovascular autonomic adaptations, while Enalapril showed similar autonomic results only when combined with aerobic exercise. In turn, in old animals Amlodipine had little effect on the cardiovascular autonomic control, while Losartan and Enalapril were more effective. In this case, our findings indicate that aging is a factor that interferes with cardiac autonomic control and mitigate the effects of different pharmacological treatments. Finally, physical training has a key role in the treatment of hypertension, participating in this process as a catalyst of cardiovascular autonomic effects caused by drug treatment in both, young SHR, when combined with Enalapril, as in old SHR, when associated with Amlodipine.

The aim of the study was to evaluate type 2 diabetes mellitus (DM) medicine management in Government Clinics in Maseru, Lesotho. A two-dimensional research method was employed, consisting of a literature review and an empirical investigation. The objective of the literature review was to provide information on the pathophysiology, signs and symptoms, diagnosis, treatment and clinical management of DM. The empirical investigation consisted of a descriptive pharmacoepidemiological study, in which data for analysis was collected retrospectively from patients‘ medical records (―bukanas‖) at dispensing points, a using data collection tool. The selected study sites were Domiciliary Health Center, Mabote, Likotsi, and Qoaling filter clinics in Maseru district of Lesotho. Data on costs of antidiabetic agents was collected from purchase invoices provided by the pharmacy department of Domiciliary Health Center. Results showed that the overall ratio of males to females was 1.3. There were no statistical difference in DM prevalence between males and females in the different clinics (p = 0.48). The mean age of males and females was 57.5 ± 14.2 years and 58.6 ± 11.3 years, respectively (Cohen‘s d = 0.07). DM was more prevalent in patients 59 to 69 years for both males and females, with the exception of Mabote and Qoaling filter clinics, where DM was more prevalent in patients 49 to 59 years. These differences in prevalence were not statically significant. Overall, 20% (n = 69) of the study sample had DM alone, while 80.0% of patients had DM concurrently with hypertension. The odds ratio implicated that women were 1.7 times more likely to have hypertension concurrently with Type 2 Diabetes Mellitus. The mean blood glucose level at 95% confidence interval for females and males were 10.1 ± 5.9 mmol/L (95% CI: 10.1–11.7) and 10.9 ± 6.2 mmol/L (95% CI: 11.0–14.0) respectively. The difference in the mean blood glucose levels of males vs. females was not statistically significant (p = 0.07). In both males and females there were outliers as high as 33.3 mmol/L. Metformin 850 mg given three times, metformin 500 mg three times a day, glibenclamide 10 mg daily and glibenclamide 5 mg twice daily are oral hypoglycaemic agents that were first, second, third and fourth choice treatment of DM at all four study sites at a frequency of 54.2% (n = 160), 27.7% (n = 82), 4% (n = 12) and 2.7% (n = 27), respectively. Actraphane® 20 units in the morning and 10 units in the evening was prescribed at a frequency of 11.6% (n = 432) in comparison to other Actraphane®-containing regimens. The frequencies of prescribing metformin and Actraphane® as combination therapies represented 10.6% (n = 40), 7.1% (n = 27), and 6.6% (n = 25), respectively, for Actraphane® 20 units in the morning and 10 units in the evening, plus metformin 500 mg three times per day; Actraphane® 20 units in the morning and 10 units in the evening plus metformin 850 mg three times per day; and Actraphane® 30 units in the morning and 15 units in the evening plus metformin 850 mg three times per day. The combination therapy of metformin and glibenclamide were prescribed at frequencies of 24.6% (n = 172), 22.9% (n = 160), and 13.4% (n = 94) respectively for glibenclamide 10 mg daily plus metformin 850 mg three times per day, glibenclamide 5 mg daily plus metformin 850 mg three times per day, and glibenclamide 5 mg once a day plus metformin 500 mg three times per day as first, second and third choice treatments at all study sites. The total cost incurred for all the oral drugs prescribed alone within different regimens was M75.6 with the weighted average cost per patient of M0.81 ± 2.06 per day compared to the cost of Actraphane® which was M40 660.52 per month at a weighted average daily cost of M21.43 ± 6.23 per patient. The overall cost of Actraphane® and metformin combination therapy amounted to M50 676.50, at an average cost per patient of M21.77 ± 6.80 per day. The cost of combination therapy consisting of metformin and glibenclamide amounted to M377.10, at a weighted average cost amounting to M0.49 ± 0.16 per patient, per day. Based on the results of this study some conclusions were reached on the prevalence of DM, prescribing patterns and the cost of antidiabetic agents. Recommendations pertaining to the clinics and further research were made. / MPham (Pharmacy Practice), North-West University, Potchefstroom Campus, 2014

The aim of the study was to evaluate type 2 diabetes mellitus (DM) medicine management in Government Clinics in Maseru, Lesotho. A two-dimensional research method was employed, consisting of a literature review and an empirical investigation. The objective of the literature review was to provide information on the pathophysiology, signs and symptoms, diagnosis, treatment and clinical management of DM. The empirical investigation consisted of a descriptive pharmacoepidemiological study, in which data for analysis was collected retrospectively from patients‘ medical records (―bukanas‖) at dispensing points, a using data collection tool. The selected study sites were Domiciliary Health Center, Mabote, Likotsi, and Qoaling filter clinics in Maseru district of Lesotho. Data on costs of antidiabetic agents was collected from purchase invoices provided by the pharmacy department of Domiciliary Health Center. Results showed that the overall ratio of males to females was 1.3. There were no statistical difference in DM prevalence between males and females in the different clinics (p = 0.48). The mean age of males and females was 57.5 ± 14.2 years and 58.6 ± 11.3 years, respectively (Cohen‘s d = 0.07). DM was more prevalent in patients 59 to 69 years for both males and females, with the exception of Mabote and Qoaling filter clinics, where DM was more prevalent in patients 49 to 59 years. These differences in prevalence were not statically significant. Overall, 20% (n = 69) of the study sample had DM alone, while 80.0% of patients had DM concurrently with hypertension. The odds ratio implicated that women were 1.7 times more likely to have hypertension concurrently with Type 2 Diabetes Mellitus. The mean blood glucose level at 95% confidence interval for females and males were 10.1 ± 5.9 mmol/L (95% CI: 10.1–11.7) and 10.9 ± 6.2 mmol/L (95% CI: 11.0–14.0) respectively. The difference in the mean blood glucose levels of males vs. females was not statistically significant (p = 0.07). In both males and females there were outliers as high as 33.3 mmol/L. Metformin 850 mg given three times, metformin 500 mg three times a day, glibenclamide 10 mg daily and glibenclamide 5 mg twice daily are oral hypoglycaemic agents that were first, second, third and fourth choice treatment of DM at all four study sites at a frequency of 54.2% (n = 160), 27.7% (n = 82), 4% (n = 12) and 2.7% (n = 27), respectively. Actraphane® 20 units in the morning and 10 units in the evening was prescribed at a frequency of 11.6% (n = 432) in comparison to other Actraphane®-containing regimens. The frequencies of prescribing metformin and Actraphane® as combination therapies represented 10.6% (n = 40), 7.1% (n = 27), and 6.6% (n = 25), respectively, for Actraphane® 20 units in the morning and 10 units in the evening, plus metformin 500 mg three times per day; Actraphane® 20 units in the morning and 10 units in the evening plus metformin 850 mg three times per day; and Actraphane® 30 units in the morning and 15 units in the evening plus metformin 850 mg three times per day. The combination therapy of metformin and glibenclamide were prescribed at frequencies of 24.6% (n = 172), 22.9% (n = 160), and 13.4% (n = 94) respectively for glibenclamide 10 mg daily plus metformin 850 mg three times per day, glibenclamide 5 mg daily plus metformin 850 mg three times per day, and glibenclamide 5 mg once a day plus metformin 500 mg three times per day as first, second and third choice treatments at all study sites. The total cost incurred for all the oral drugs prescribed alone within different regimens was M75.6 with the weighted average cost per patient of M0.81 ± 2.06 per day compared to the cost of Actraphane® which was M40 660.52 per month at a weighted average daily cost of M21.43 ± 6.23 per patient. The overall cost of Actraphane® and metformin combination therapy amounted to M50 676.50, at an average cost per patient of M21.77 ± 6.80 per day. The cost of combination therapy consisting of metformin and glibenclamide amounted to M377.10, at a weighted average cost amounting to M0.49 ± 0.16 per patient, per day. Based on the results of this study some conclusions were reached on the prevalence of DM, prescribing patterns and the cost of antidiabetic agents. Recommendations pertaining to the clinics and further research were made. / MPham (Pharmacy Practice), North-West University, Potchefstroom Campus, 2014

Public health aspects of pharmaceutical prescription patterns: Exemplified by treatments for prevention of cardiovascular disease. Louise Silwer. ISBN: 978-91-85721-18-4 ISSN: 0283-1961Main aim:To study patterns and trends of dispensed prescriptions, to explore what proportion of the population is exposed to some of the more prevalently prescribed pharmaceuticals, and to find possible ways of measuring drug-induced adverse symptoms in the population. Further, to illuminate conditions surrounding prescribing in primary prevention of cardiovascular disease. Methods: In three descriptive studies of prescription patterns, prescription data at aggregate level from a Swedish county were analysed retrospectively, and proportions were calculated. Data from the first ten years of the studies were obtained from a local prescription study, and data from another five years were local data from a national prescription survey. Data from a Danish database (OPED), with data at the individual level, were used for a prescription sequence symmetry analysis, and when Swedish national prescription data at the individual level became accessible, they were used for calculations of drug prevalence in the entire Swedish population. In a qualitative analysis of interview data, a phenomenographic approach was used. Main results: The purchase of pharmaceuticals on prescription almost doubled in the studied county in the period 1988-2002. Some common pharmaceuticals that increased to a great extent among the older part of the population were cardiovascular preventive drugs, such as antihypertensive and lipid modifying agents, and also hormone replacement therapy for women. In 2005, over half of all Swedish citizens, aged 60 or over, purchased antihypertensive or lipid modifying preparations during a six-month period. The different views that were found among GPs, regarding beliefs and practical management of primary prevention of CVD, could be interpreted as a reflection of the complexity of patient counselling in primary prevention in practice. Conclusion: The increase in dispensed prescriptions over the 15 years and the magnitude of the prevalence of the studied pharmaceuticals, such as antihypertensive, lipid modifying and hormonal treatments, which to a great extent are used by ‘healthy’ people, point to the need of following-up both beneficial and harmful consequences on public health. The prevalence of preventive treatments together with the variation in views of administration of primary prevention of cardiovascular disease, also point to the need of clarification of guidelines regarding pharmaceutical primary prevention and encouragement of therapy discussions among GPs.