Antihypertensive and renal protective effect of Shunaoxin pill combined with captopril on spontaneous hypertension rats.

INTRODUCTION: According to previous reports, hypertension has become the most common chronic disease in the world. Captopril, an angiotensin-converting enzyme inhibitor, has been widely used for the therapy of arterial hypertension and cardiovascular diseases therapy. Besides, Shunaoxin pill (SNX) as a traditional Chinese prescription showed antihypertensive effect in our previous research. OBJECTIVE: This study means to investigate whether SNX combining with captopril could show antihypertensive and renal protective effects on spontaneous hypertension rats (SHRs). METHODS: SHRs were randomly assigned to four treatment groups, including non-treated group, captopril, SNX, and captopril + SNX-treated groups. Their body weight and systolic blood pressure (SBP) were measured weekly. Histopathological examination was analyzed through Masson staining and hematoxylin and eosin staining. Biochemical analyses, ELISA, and western blot were used to analyze their combining mechanism. RESULTS: In this experiment, this combinatorial therapy significantly reduced aortic wall thickness, increased the content of NO, NOS and eNOS, decreased the content of bradykinin and endothelin 1(ET-1), and regulated the levels of TG, TC and HDLC back to normal, which suggested they could induce vasodilation and lower blood pressure. Meanwhile, histological examination alleviated that captopril + SNX remarkably inhibited renal injury, including tubular disorder, inflammatory cell infiltration and fibrosis. They down-regulated the serum levels of BUN and Cr, protein expression of IL-1ß, NF-κB, Bax, Cyt c, caspase 3, 8 and 9 in kidney tissues and significantly increased the levels of Bcl-2 in kidney tissues compared with monotherapy group. CONCLUSION: The combinatorial treatment of SNX and captopril lowered blood pressure through adjusting NO/NOS, ET-1 and dyslipidemia profile. Furthermore, this treatment alleviated the kidney damage via reducing the release of inflammatory factors and the expression of apoptotic markers. Therefore, these results provided a rationale for future clinical use of SNX combined with captopril in antihypertensive and protecting renal functions in hypertension.

Virgin olive oil (unfiltered) extract contains peptides and possesses ACE inhibitory and antihypertensive activity.

BACKGROUND & AIMS: The peptide and protein composition of olive oil is mostly unknown and the few studies available have not focused on the study of its low molecular weight peptides. We hypothesised that olive oil could naturally contain low molecular weight peptides with antihypertensive effect. METHODS: We produced virgin olive oil (unfiltered, var. Picual) and obtained a water-soluble peptide extract. We fractionated the peptide extract by FPLC and studied its angiotensin converting enzyme (ACE) inhibitory activity. We studied the antihypertensive effect of olive oil peptides on the systolic blood pressure (SBP) and diastolic blood pressure (DBP) using an animal model of hypertension (spontaneously hypertensive rats, SHR). The animals were randomly distributed into 3 study groups (n = 8 per group) and received an oral dose of olive oil peptides (0.425 mg/kg of BW), or a dose of Captopril (50 mg/kg of BW) or water. SBP and DBP were registered in the rats before administration and a at 2, 4, 6, 8, 24 and 48 h post-administration of the corresponding dose. RESULTS: The peptide extract and FPLC purified fractions possessed angiotensin converting enzyme (ACE) inhibitory activity. Acute oral administration of olive oil water-soluble extract produced an average blood pressure reduction of 10 mmHg at 4 h (P < 0.01) and reached a maximum antihypertensive effect of 20 mmHg at 6 h, compared with baseline. CONCLUSION: Unfiltered virgin olive oil contains peptides and a water-soluble extract obtained from this oil possesses ACE inhibitory activity and in vivo antihypertensive effect.

Functional and neurometabolic asymmetry in SHR and WKY rats following vasoactive treatments.

A lateralized distribution of neuropeptidase activities in the frontal cortex of normotensive and hypertensive rats has been described depending on the use of some vasoactive drugs and linked to certain mood disorders. Asymmetrical neuroperipheral connections involving neuropeptidases from the left or right hemisphere and aminopeptidases from the heart or plasma have been suggested to play a role in this asymmetry. We hypothesize that such asymmetries could be extended to the connection between the brain and physiologic parameters and metabolic factors from plasma and urine. To assess this hypothesis, we analyzed the possible correlation between neuropeptidases from the left and right frontal cortex with peripheral parameters in normotensive (Wistar Kyoto [WKY]) rats and hypertensive rats (spontaneously hypertensive rats [SHR]) untreated or treated with vasoactive drugs such as captopril, propranolol and L-nitro-arginine methyl ester. Neuropeptidase activities from the frontal cortex were analyzed fluorometrically using arylamide derivatives as substrates. Physiological parameters and metabolic factors from plasma and urine were determined using routine laboratory techniques. Vasoactive drug treatments differentially modified the asymmetrical neuroperipheral pattern by changing the predominance of the correlations between peripheral parameters and central neuropeptidase activities of the left and right frontal cortex. The response pattern also differed between SHR and WKY rats. These results support an asymmetric integrative function of the organism and suggest the possibility of a different neurometabolic response coupled to particular mood disorders, depending on the selected vasoactive drug.

Comparison of the Neuroprotective Effects of Aspirin, Atorvastatin, Captopril and Metformin in Diabetes Mellitus.

OBJECTIVE: The aim of this study was to investigate the effect of combined intake of a high dose of aspirin, atorvastatin, captopril and metformin on oxidative stress in the brain cortex and hippocampus of streptozotocin (STZ)-induced diabetic rats. MATERIAL AND METHODS: Rats were randomly divided into the following 11 groups: control and diabetic (D), as well as 9 groups that were treated with metformin (M, 300 mg/kg) or aspirin (ASA, 120 mg/kg) alone or in different combinations with captopril (C, 50 mg/kg) and/or atorvastatin (AT, 40 mg/kg) as follows: (D + M), (D + ASA), (D + M + ASA), (D + M + C), (D + M + AT), (D + M + C + ASA), (D + M + C + AT), (D + M + AT + ASA) and (D + M + C + AT + ASA). The rats in treatment groups received drugs by gavage daily for six weeks. Serum lipid profile and levels of oxidative markers in the brain cortex and hippocampus tissues were evaluated. RESULTS: The levels of malondialdehyde in the brain cortex and hippocampus in all the treated groups decreased significantly (p < 0.05). There was a significant increase in the total thiol concentration as well as catalase activity in treated rats in (M + AT), (M + C + ASA), (M + C + AT), (M + AT + ASA) and (M + C + AT + ASA) groups in cortex and hippocampus in comparison with the diabetic rats (p < 0.05). Also, the superoxide dismutase activity in all treated rats with medications was significantly increased compared to the diabetic rats (p < 0.05⁻0.01). CONCLUSION: Our findings showed that the combined use of high-dose aspirin, metformin, captopril and atorvastatin potentiated their antioxidant effects on the brain, and hence could potentially improve cognitive function with their neuroprotective effects on hippocampus.

Evaluation of self-nanoemulsifying drug delivery systems using multivariate methods to optimize permeability of captopril oral films.

The present report demonstrates a quality by design approach to understand and optimize self-nanoemulsifying orodispersible films (SNEODF) of captopril for hypertension. A central composite experimental design was used to study the formulation parameters effects (primary emulsion, aqueous phase, and surfactant) on the film properties (globule size, film burst, adhesion, Young's moduli, disintegration time, tensile strength and dissolution). Principle component analysis (PCA) and principle component regression (PCR) were employed to identify and quantify the effects of formulation variables and physico-mechanical properties of the film on the drug permeability. PCA classified three distinct groups of film formulations based on their composition and properties. PCR quantified the impact of main variables, their interactions, and square effects on the drug permeability. The main effect of the aqueous phase exhibited a negative impact, while that of flux and tensile strength showed a positive impact on the permeability. Interactions of primary emulsions with disintegration time and tensile strength displayed a synergistic impact. Interactions of aqueous phase with flux, Young's moduli, and tensile strength, as well as between Young's moduli and tensile strength showed a significant positive effect on the permeability. A negative correlation of square effects of primary emulsion and flux, and a positive square effect of Young's moduli confirmed their non-linear influence on the drug permeability across porcine buccal mucosa. This research work demonstrates application of design of experiment and multivariate methods to achieve targeted product quality of captopril (SNEODF) having improved permeability and pH independent release profile.

Moderate Effect of Flavonoids on Vascular and Renal Function in Spontaneously Hypertensive Rats.

Many studies have shown that flavonoids are effective as antihypertensive drugs in arterial hypertension. In the present work, we have analyzed the effects of some flavonoid extracts in the spontaneous hypertensive rat model (SHR). An important feature of this study is that we have used a low dose, far from those that are usually applied in human therapy or experimental animals, a dose that responded to the criterion of a potential future commercial use in human subjects. Treatments were carried out for 6 and 12 weeks in two groups of SHR rats, which received apigenin, lemon extract, grapefruit + bitter orange (GBO) extracts, and cocoa extract. Captopril was used as a positive control in the SHR group treated for 6 weeks (SHR6) and Diosmin was used as the industry reference in the SHR group treated for 12 weeks (SHR12). Captopril and GBO extracts lowered the high arterial pressure of the SHR6 animals, but none of the extracts were effective in the SHR12 group. Apigenin, lemon extract (LE), GBO, and captopril also improved aortic vascular relaxation and increased plasma and urinary excretion of nitrites, but only in the SHR6 group. Kidney and urinary thiobarbituric acid reactive substances (TBARS) were also significantly reduced by GBO in the SHR6 rats. Apigenin also improved vascular relaxation in the SHR12 group and all the flavonoids studied reduced urinary thiobarbituric acid reactive substances (TBARS) excretion and proteinuria. Vascular abnormalities, such as lumen/wall ratio in heart arteries and thoracic aorta, were moderately improved by these treatments in the SHR6 group. In conclusion, the flavonoid-rich extracts included in this study, especially apigenin, LE and GBO improved vascular vasodilatory function of young adult SHRs but only the GBO-treated rats benefited from a reduction in blood pressure. These extracts may be used as functional food ingredients with a moderate therapeutic benefit, especially in the early phases of arterial hypertension.

Effects of late-onset and long-term captopril and nifedipine treatment in aged spontaneously hypertensive rats: Echocardiographic studies.

The purpose of the present study was to analyze the changes in blood pressure, left ventricular (LV) wall thickness and LV systolic function of aged spontaneously hypertensive rats (SHRs) either with or without antihypertensive therapy. Twenty-one SHRs aged 60.5±0.25 weeks were investigated over 22 weeks. They were divided into the following three groups (7 per group): untreated controls (CTRL), treatment with captopril (CAP, 60 mg kg(-1) daily) and treatment with captopril plus nifedipine (CAP+NIF, 60+10 mg kg(-1) daily). Systolic blood pressure (SBP) was regularly measured using the tail cuff method, and an echocardiogram was repeatedly obtained to examine the LV systolic and diastolic area, LV systolic fractional area change, cardiac output and LV myocardial wall thickness. Finally, heart catheterization was performed. While SBP remained stable in the CTRL animals over the experimental period, both of the antihypertensive treatments significantly reduced SBP by 20% in the treated animals (P<0.001). Echocardiography demonstrated that both the systolic and the diastolic LV function of the untreated SHRs deteriorated over time, whereas both types of antihypertensive treatments attenuated and delayed but did not completely prevent the decline in LV systolic function. Cardiac output, as determined by pulsed wave Doppler echocardiography, remained significantly higher in the treated animals than in CTRLs until week 20, but it then decreased. Heart catheterization showed a significant decrease in LV function, as reflected by the LV systolic pressure and contractility, in the CTRLs but not in treated animals. These findings clearly indicate that late-onset antihypertensive treatment with CAP or CAP+NIF is beneficial with respect to blood pressure reduction, LV hypertrophy attenuation and LV systolic function preservation.

Metformin exhibits radiation countermeasures efficacy when used alone or in combination with sulfhydryl containing drugs.

Metformin, a biguanide drug used in the treatment of type II diabetes, was evaluated alone and in combination with amifostine, captopril, MESNA or N-acetyl-cysteine (NAC) for its ability to protect when administered 24 h after irradiation. Mouse embryo fibroblasts (MEF), human microvascular endothelial cells (HMEC) and SA-NH mouse sarcoma cells were exposed to 4 Gy in vitro. C3H mice were exposed to 7 Gy and evaluated utilizing an endogenous spleen colony assay system. Amifostine and WR1065, administered 30 min prior to irradiation, were used as positive controls. Treatment of MEF, HMEC and SA-NH cells with metformin elevated survival levels by 1.4-, 1.5- and 1.3-fold compared to 1.9-, 1.8- and 1.6-fold for these same cells treated with WR1065, respectively. Metformin (250 mg/kg) was effective in protecting splenic cells from a 7 Gy dose in vivo (protection factor = 1.8). Amifostine (400 mg/kg), administered 30 min prior to irradiation resulted in a 2.6-fold survival elevation, while metformin administered 24 h after irradiation in combination with NAC (400 mg/kg), MESNA (300 mg/kg) or captopril (200 mg/kg) enhanced survival by 2.6-, 2.8- and 2.4-fold, respectively. Each of these agents has been approved by the FDA for human use and each has a well characterized human safety profile. Metformin alone or in combination with selected sulfhydryl agents possesses radioprotective properties when administered 24 h after radiation exposure comparable to that observed for amifostine administered 30 min prior to irradiation making it a potentially useful agent for radiation countermeasures use.

Human interventions to characterize novel relationships between the renin-angiotensin-aldosterone system and parathyroid hormone.

Observational studies in primary hyperaldosteronism suggest a positive relationship between aldosterone and parathyroid hormone (PTH); however, interventions to better characterize the physiological relationship between the renin-angiotensin-aldosterone system (RAAS) and PTH are needed. We evaluated the effect of individual RAAS components on PTH using 4 interventions in humans without primary hyperaldosteronism. PTH was measured before and after study (1) low-dose angiotensin II (Ang II) infusion (1 ng/kg per minute) and captopril administration (25 mg×1); study (2) high-dose Ang II infusion (3 ng/kg per minute); study (3) blinded crossover randomization to aldosterone infusion (0.7 µg/kg per hour) and vehicle; and study (4) blinded randomization to spironolactone (50 mg/daily) or placebo for 6 weeks. Infusion of Ang II at 1 ng/kg per minute acutely increased aldosterone (+148%) and PTH (+10.3%), whereas Ang II at 3 ng/kg per minute induced larger incremental changes in aldosterone (+241%) and PTH (+36%; P<0.01). Captopril acutely decreased aldosterone (-12%) and PTH (-9.7%; P<0.01). In contrast, aldosterone infusion robustly raised serum aldosterone (+892%) without modifying PTH. However, spironolactone therapy during 6 weeks modestly lowered PTH when compared with placebo (P<0.05). In vitro studies revealed the presence of Ang II type I and mineralocorticoid receptor mRNA and protein expression in normal and adenomatous human parathyroid tissues. We observed novel pleiotropic relationships between RAAS components and the regulation of PTH in individuals without primary hyperaldosteronism: the acute modulation of PTH by the RAAS seems to be mediated by Ang II, whereas the long-term influence of the RAAS on PTH may involve aldosterone. Future studies to evaluate the impact of RAAS inhibitors in treating PTH-mediated disorders are warranted.

A conceptually new treatment approach for relapsed glioblastoma: coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care.

To improve prognosis in recurrent glioblastoma we developed a treatment protocol based on a combination of drugs not traditionally thought of as cytotoxic chemotherapy agents but that have a robust history of being well-tolerated and are already marketed and used for other non-cancer indications. Focus was on adding drugs which met these criteria: a) were pharmacologically well characterized, b) had low likelihood of adding to patient side effect burden, c) had evidence for interfering with a recognized, well-characterized growth promoting element of glioblastoma, and d) were coordinated, as an ensemble had reasonable likelihood of concerted activity against key biological features of glioblastoma growth. We found nine drugs meeting these criteria and propose adding them to continuous low dose temozolomide, a currently accepted treatment for relapsed glioblastoma, in patients with recurrent disease after primary treatment with the Stupp Protocol. The nine adjuvant drug regimen, Coordinated Undermining of Survival Paths, CUSP9, then are aprepitant, artesunate, auranofin, captopril, copper gluconate, disulfiram, ketoconazole, nelfinavir, sertraline, to be added to continuous low dose temozolomide. We discuss each drug in turn and the specific rationale for use- how each drug is expected to retard glioblastoma growth and undermine glioblastoma's compensatory mechanisms engaged during temozolomide treatment. The risks of pharmacological interactions and why we believe this drug mix will increase both quality of life and overall survival are reviewed.

A study of prevention and regression of cardiac hypertrophy with a prolactin inhibitor in a biological model of ventricular hypertrophy caused by aorto caval fistulae in rat.

BACKGROUND: The possibility of decreasing or reverting left ventricular hypertrophy and, therefore, cardiac hypertrophy (CH) is an important medical issue. The aim of the present study was to evaluate these two possibilities with a 3-week daily dose of captopril, losartan, or bromocriptine in a preventive or corrective model. METHODS: After aorto caval fistulae (ACF) surgery on adult male Wistar rats to induce CH, animals were assigned to the preventive protocol (drug treatment began immediately after surgery) or corrective protocol (hypertrophy was allowed to develop before drug treatment). After treatments, isoproterenol was administered to half of the animals to further induce CH. The groups included the passive control, the sham-operated animals, those with ACF surgery but without drug treatment, and the 3-week treatments with captopril, losartan, or the low or high dose of bromocriptine. RESULTS: Three treatments, with captopril, losartan, or the high dose of bromocriptine, significantly impeded/reverted an increase in CH-related parameters in the preventive/corrective model compared to the surgically treated group without drug treatment. The same effect was found after isoproterenol administration. The present results show an avoidance/reversion of CH with these three treatments. Better results were found with the angiotensin converting enzyme inhibitor (captopril) than with the prolactin inhibitor (bromocriptine). CONCLUSIONS: Treatments with captopril, losartan, and the high dose of bromocriptine were effective in preventing/reversing the manifestation of CH in the preventive/corrective rat models. Further studies are needed to identify the initial mediator, the key component, and the molecular events involved in the pathogenesis of CH.

Dual influence of spontaneous hypertension on membrane properties and ATP production in heart and kidney mitochondria in rat: effect of captopril and nifedipine, adaptation and dysadaptation.

This study deals with changes, induced by hypertension and its treatment, in the function and properties of mitochondria in the heart and kidneys. Male, 16-week-old hypertensive rats were allocated to 3 groups: (i) animals treated daily for 4 weeks with captopril (CAP, 80 mg·(kg body mass)(-1), n = 45), (ii) animals treated with CAP + nifedipine (NIF, 10 mg·kg(-1), n = 45), or (iii) untreated hypertensive controls (n = 96). Wistar rats (n = 96) were used as normotensive controls. Systolic blood pressure (SBP), heart rate (HR), and heart mass / body mass (HW/BW) ratio were measured at the beginning and end of the experiments; measurements for mitochondrial Mg(2+)-ATPase activity, O(2)-consumption (QO(2)), respiratory control index (RCI), ADP/O, oxidative phosphorylation rate (OPR), conjugated diene content (CD), and membrane fluidity (MF) were also taken at different time intervals. In the heart, elevated SBP, HR, and HW/BW accompanied increased QO(2), OPR, and Mg(2+)-ATPase activity, indicating an adaptive response to hypertension-induced increase in the energy demands of the myocardium. Treatments with CAP or with CAP + NIF were very similar in their prevention of increase in SBP, HR, HW/BW, and the rise in OPR (all p < 0.05-0.01). In the kidneys, hypertension induced a drop in OPR; however, antihypertensive therapy aggravated the resulting energy deficiency, whereby treatment with CAP + NIF was more detrimental than treatment with CAP alone. Heart and kidney mitochondria exhibited negligible changes in CD and moderately increased MF, which was more potentiated by treatment with CAP alone than with CAP + NIF.

Involvement of brain ANG II in acute sodium depletion induced salty taste changes.

Many investigations have been devoted to determining the role of angiotensin II (ANG II) and aldosterone (ALD) in sodium-depletion-induced sodium appetite, but few were focused on the mechanisms mediating the salty taste changes accompanied with sodium depletion. To further elucidate the mechanism of renin-angiotensin-aldosterone system (RAAS) action in mediating sodium intake behavior and accompanied salty taste changes, the present study examined the salty taste function changes accompanied with sodium depletion induced by furosemide (Furo) combined with different doses of angiotensin converting enzyme (ACE) inhibitor, captopril (Cap). Both the peripheral and central RAAS activity and the nuclei Fos immunoreactivity (Fos-ir) expression in the forebrain area were investigated. Results showed that sodium depletion induced by Furo+low-Cap increased taste preference for hypertonic NaCl solution with amplified brain action of ANG II but without peripheral action, while Furosemide combined with a high dose of captopril can partially inhibit the formation of brain ANG II, with parallel decreased effects on salty taste changes. And the resulting elevating forebrain ANG II may activate a variety of brain areas including SFO, PVN, SON and OVLT in sodium depleted rats injected with Furo+low-Cap, which underlines salty taste function and sodium intake behavioral changes. Neurons in SFO and OVLT may be activated mainly by brain ANG II, while PVN and SON activation may not be completely ANG II dependent. These findings suggested that forebrain derived ANG II may play a critical role in the salty taste function changes accompanied with acute sodium depletion.

Effects of ethanolic extract from Radix Scrophulariae on ventricular remodeling in rats.

PURPOSE: To explore the effects of ethanolic extract of Radix Scrophulariae (EERS) on ventricular remodeling in rats. METHODS: Rats with coronary artery ligation (CAL) were randomly assigned to 5 groups: CAL model; CAL plus 40 mg/kg captopril; CAL plus 60 mg/kg, 120 mg/kg, 240 mg/kg EERS. Sham operation rats were randomly assigned to 2 groups, sham-operated control and sham-operated plus 120 mg/kg EERS. The rats were orally administered with the corresponding drugs or drinking water for 14 weeks. The left ventricular weight index (LVWI) and heart weight index (HWI) were determined. Myocardium tissue was stained with hematoxylin and eosin or picric acid/Sirius red for cardiomyocyte cross-section area or collagen content measurements respectively. The concentrations of hydroxyproline (Hyp), matrix metalloproteinase 2 (MMP-2), angiotensin II (Ang II), aldosterone (ALD), endothelin 1 (ET-1), atrial natriuretic peptide (ANP), tumor necrosis factor α (TNF-α) and renin activity (RA) in myocardium or serum were determined. Real-time RT-PCR was used to detect the mRNA expressions of angiotensin converting enzyme (ACE), ET-1 and ANP. RESULTS: EERS could significantly reduce the LVWI and HWI, decrease heart tissue concentrations of Hyp and collagen deposition, diminish cardiomyocyte cross-section area, reduce the tissue level of Ang II, ET-1, ANP and TNF-α. EERS could also down regulate the mRNA expression of ACE, ET-1 and ANP in myocardium. CONCLUSION: EERS attenuates ventricular remodeling. The mechanisms may be related to restraining the excessive activation of RAAS, TNF-α and modulating some gene expressions associated with cardiac hypertrophy.

Comparing different treatment schedules of Zomen (zofenopril).

BACKGROUND: Chronotherapy of hypertension became, during the last years, a main target in optimal BP values control, during 24 hours. Many clinical studies have demonstrated a different effect on blood pressure of the majority of angiotensin-converting enzyme inhibitors (ACEIs), studied as function of the moment of their administration. Until now, the majority of clinical proofs sustain the greater benefit offered by bedtime administration of ACEIs, concerning especially a significantly greater efficacy in reducing BP during the asleep period, thus increasing the prevalence of "dippers", the circadian profile considered to offer the best cardio-vascular prognosis, compared to at awakening administration. MATERIALS AND METHODS: This study investigated time-dependent effects of zofenopril (Zomen, 30 mg, Berlin-Chemie, Menarini Group, Romania) administration on ambulatory blood pressure values. We studied 33 consecutive untreated hypertensive patients (19 men, 14 women), 56 +/- 12.7 years old, with grade 1 or 2 uncomplicated essential hypertension (according to the European Society of Hypertension-European Society of Cardiology guidelines) (diagnostic formulated by casual determination and confirmed by an ABPM session at baseline), using zofenopril as monotherapy. The drug was initially administered in a single dose, at bedtime, during one month; after that period, we performed for all of them a new ABPM session, and, after that, for another month we administered the same drug, in single dose, at awakening. Blood pressure was measured for 48 hours before and after one month of treatment. RESULTS: The blood pressure reduction during diurnal activity was similar for both treatment schedules. Bedtime administration of zofenopril, however, was significantly more efficient than at awakening administration in reducing asleep blood pressure. The awake:asleep blood pressure ratio was decreased after zofenopril on awakening but significantly increased towards a more dipping pattern, (from 60.60% to 90.90%) after at bedtime administration. The proportion of patients with controlled ambulatory BP increased from 51.51% to 84.84% (p < 0.001) by bedtime administration. CONCLUSIONS: Nocturnal blood pressure regulation is significantly better achieved at bedtime as compared with at awakening administration of zofenopril, without any loss in efficacy during diurnal active hours; this might be clinically important, because nighttime blood pressure has been shown to be a more relevant marker of cardiovascular risks than diurnal mean values. The change in the dose-response curve, the increased proportion of controlled patients, and improved efficacy on nighttime BP values by bedtime administration of zofenopril should be taken into account when prescribing this ACEI for treatment of essential hypertension.

Availability, price and affordability of cardiovascular medicines: a comparison across 36 countries using WHO/HAI data.

BACKGROUND: The global burden of cardiovascular disease (CVD) continues to rise. Successful treatment of CVD requires adequate pharmaceutical management. The aim was to examine the availability, pricing and affordability of cardiovascular medicines in developing countries using the standardized data collected according to the World Health Organization/Health Action International methodology. METHODS: The following medicines were included: atenolol, captopril, hydrochlorothiazide, losartan and nifedipine. Data from 36 countries were analyzed. Outcome measures were percentage availability, price ratios to international reference prices and number of day's wages needed by the lowest-paid unskilled government worker to purchase one month of chronic treatment. Patient prices were adjusted for inflation and purchasing power, procurement prices only for inflation. Data were analyzed for both generic and originator brand products and the public and private sector and summarized by World Bank Income Groups. RESULTS: For all measures, there was great variability across surveys. The overall availability of cardiovascular medicines was poor (mean 26.3% in public sector, 57.3% private sector). Procurement prices were very competitive in some countries, whereas others consistently paid high prices. Patient prices were generally substantially higher than international references prices; some countries, however, performed well. Chronic treatment with anti-hypertensive medication cost more than one day's wages in many cases. In particular when monotherapy is insufficient, treatment became unaffordable. CONCLUSIONS: The results of this study emphasize the need of focusing attention and financing on making chronic disease medicines accessible, in particular in the public sector. Several policy options are suggested to reach this goal.

Renin-Angiotensin system suppression mitigates experimental radiation pneumonitis.

PURPOSE: To find the mitigators of pneumonitis induced by moderate doses of thoracic radiation (10-15 Gy). METHODS AND MATERIALS: Unanesthetized WAG/RijCmcr female rats received a single dose of X-irradiation (10, 12, or 15 Gy at 1.615 Gy/min) to the thorax. Captopril (an angiotensin-converting enzyme inhibitor) or losartan (an angiotensin receptor blocker) was administered in the drinking water after irradiation. Pulmonary structure and function were assessed after 8 weeks in randomly selected rats by evaluating the breathing rate, ex vivo vascular reactivity, and histopathologic findings. Survival analysis was undertaken on all animals, except those scheduled for death. RESULTS: Survival after a dose of 10 Gy to the thorax was not different from that of unirradiated rats for

Comparative study of vasodilators in an animal model of chronic volume overload caused by severe aortic regurgitation.

BACKGROUND: Aortic regurgitation (AR) is a disease of chronic left ventricular (LV) volume overload. Over time, AR will lead to LV dilatation, hypertrophy, and loss of function. There is currently no medical treatment proven effective to slow the evolution of this cardiomyopathy. Vasodilators were once thought to have protective effects, but recent publications have cast some doubts about their effectiveness. We hypothesized that drugs targeting the renin-angiotensin system should be more effective than those having no direct effect on the renin-angiotensin system. METHODS AND RESULTS: We designed a protocol comparing the effects of 3 vasodilators in a rat AR model (n=9 to 11 animals per group). The effects of a 6-month treatment of (1) nifedipine, (2) captopril, or (3) losartan were compared in male AR rats. Sham-operated and untreated AR animals were used as controls. Nifedipine-treated animals displayed hemodynamics, LV dilatation, hypertrophy, and loss of function similar to those of the untreated group. Both captopril and losartan were effective in improving hemodynamics, slow LV dilatation, hypertrophy, and dysfunction. Gene expression analysis confirmed the lack of effects of the nifedipine treatment at the molecular level. CONCLUSIONS: Using an animal model of severe AR, we found that vasodilators targeting the renin-angiotensin system were effective to slow the development of LV remodeling and to preserve LV function. As recently shown in the most recent human clinical trial, nifedipine was totally ineffective. Targeting the renin-angiotensin system seems a promising avenue in the treatment of this disease, and clinical trials should be carefully designed to re-evaluate the effectiveness of angiotensin I-converting enzyme inhibitors or angiotensin II receptor blockers in AR.

Potenciais interações medicamentosas em prescrições de um hospital-escola de Porto Alegre / Potential drug interactions among prescriptions of a teaching hospital in Porto Alegre

Introdução: Relatos das prevalências de interações medicamentosas em hospitais brasileiros são escassos. Objetivos: Descrever a prevalência de interações medicamentosas potenciais entre os fármacos prescritos nas enfermarias clínicas e cirúrgicas de um hospital-escola. secundariamente, descrever as características dessas interações e relacionar a sua ocorrência com o número de medicamentos prescritos e a idade dos pacientes. Pacientes e Métodos: Os dados foram coletados durante uma semana de out/2007, de 2a a 6a feira, a partir da última ficha de prescrição encontrada nos prontuários, envolvendo 128 fichas de prescrição com 10,5±4,1 fármacos. Os pacientes tinham 58,6±16,9 anos e 51,2% eram homens. A doença cardiovascular foi a enfermidade principal (23,4%) e a comorbidade (42,5%) mais frequentemente encontrada. A análise das interações foi feita através de consulta a um sistema interativo (Micromedex®). Resultados: 485 interações foram encontradas, estando presentes em 79,7% (IC95%: 72,6-86,8) das fichas de prescrição (média 3,8). A interação mais frequente foi captopril/dipirona (9,7%), seguida por dipirona/furosemida (4,5%), e os fármacos mais envolvidos foram dipirona (29,3%) e captopril (21,2%). A maioria das interações tinha mecanismo farmacodinâmico (65,5%), gravidade moderada (55,5%), começo tardio (61,3%) e bom embasamento científico (71,1%). A prevalência de interações esteve associada fortemente com o número de fármacos prescritos (r=0,65, p<0,001) e fracamente com a idade do paciente.

Introduction: Reports of the prevalence of drug interactions in Brazilian hospitals are scarce. Aims: To describe the prevalence of potential drug interactions among the medical drugs prescribed in the clinical and surgical units of a teaching hospital. Secondarily, to describe the characteristics of drug interactions and relate their occurrence to the number of prescribed medications and patient age. Patients and Methods: The data were collected from Monday to Friday of a week in Oct 2007, starting from the last prescription form found in the medical charts, and involved 128 prescription forms with 10.5±4.1 drugs. The patients’ mean age was 58.6±16.9 years and 51.2% were males. Cardiovascular disease was the main disease (23.4%) and the most frequently found comorbidity (42.5%). The analysis of interactions was done through consultation with an interactive system (Micromedex®). Results: 485 cases of drug interactions were found, being present in 79.7% (CI95%: 72.686.8) of the prescription forms (mean 3.8). The most frequent interaction was captopril/dipyrone (9.7%), followed by ipyrone/furosemide (4,5%), and the most frequently involved drugs were dipyrone (29.3%) and captopril (21.2%). Most of the interactions had a pharmacodynamic mechanism (65.5%), moderate severity (55.5%), late onset (61.3%), and a good scientific basis (71.1%). The prevalence of interactions was strongly associated with the number of drugs prescribed (r=0.65, p<0.001) and weakly associated with patient age.

Synergistic decrease in blood pressure by captopril combined with losartan in spontaneous hypertensive rats.

This study was designed to examine the anti-hypertensive effect of the combination therapy of captopril with losartan by oral administration using both independent and cross-over experimental protocols. In independent experimental protocols, four different groups of spontaneous hypertensive rats (SHR) were treated for 1 or 2 weeks: control, captopril (20 mg/kg/day), losartan (20 mg/kg/day), and combination captopril (10 mg/kg/day) with losartan (10 mg/kg/day). In cross-over protocols, each SHR received all four treatments for 1 or 3 days with an interval of several days between each injection for washing-out and return to high blood pressure (BP) levels. BP and heart rate (HR) were measured in conscious telemetered SHR. According to the results from the independent protocol, regardless of a 1- or 2-week administration period, combination therapy with low doses of captopril and losartan had a greater anti-hypertensive effect than individual high-dose monotherapy. Similarly, results from the cross-over protocol showed that regardless of 1-day or 3-day administration, the decrease in BP in the 11(th) and 12(th) hour after administration was greatest with the combination of low-dose captopril and losartan. Therefore, combination therapy with low doses of captopril with losartan lowered BP to a greater extent than a high dose of either individual monotherapy.