Design of experiments assisted the development of inclusion complexes of ramipril using hydrophilic carriers for enhancement of solubility and dissolution rate

Abstract The goal of the present study was to develop inclusion complexes and polymers dispersions of ramipril prepared by physical mixing, kneading, co-evaporation, and solvent evaporation methods to enhance drug solubility and dissolution rate, and thereby to reduce drug dose and side effects using selected hydrophilic carriers such as β-CD, PVP-K25, PEG 4000, and HPMC K100M. The prepared formulations were characterized for solubility and in-vitro drug release studies. The systematic optimization of formulations was performed using I-Optimal experimental design by selecting factors such as type of carriers (X1), drug: carrier ratio (X2), and method of preparation (X3), and response variables including percent yield (Y1), solubility (Y2), Carr's index (Y3) and drug release in 30 min (Y4). Mathematical modeling was carried out using a quadratic polynomial model. The inclusion complex formulation (F27) was selected as an optimized batch by numerical desirability function and graphical optimization with the help of design space. The inclusion complex prepared by the co-evaporation method showed maximum drug solubility and released in pH 6.8 phosphate buffer compared to pure and other formulations. The inclusion complex is a feasible approach to improve the solubility, dissolution rate, bioavailability, and minimization of drugs' gastrointestinal toxicity upon oral administration of ramipril.

Formulation And Evaluation of Fast Dissolving Oral Films Incorporated With Ramipril and β-Cyclodextrin Complex

Abstract Ramipril being ACE inhibitor belongs to BCS class II drug with low solubility and undergoes first-pass metabolism that leads to reduced bioavailability of 28%. The current research is aimed at formulating and evaluating ramipril fast dissolving oral films (FDOF). Solubility enhancement of ramipril was done by formation of inclusion complex with β-cyclodextrin in 3 ratios (1:0.5, 1:1, 1:2). Based on higher drug content and dissolution values the physical mixture of ramipril with β-cyclodextrin in 1:1 ratio (IC2) was chosen for further studies. Total 12 formulations of ramipril FDOF containing IC2 prepared with various polymers and evaluated for physicochemical properties. The optimized formulation F9 shown better tensile strength (11.6 g/cm2), significant % elongation (9.8) and maximum % drug content of 99.98 %. The formulation F9 exhibited minimum disintegration time of 9 sec that is desirable for immediate onset of action and maximum drug release. The FTIR data of F9 assured the compatibility of drug and formulation excipients, found to be stable for 180 days at accelerated conditions. The study confirmed that ramipril FDOF lead to quicker onset of action and enhanced therapeutic efficiency in comparison to marketed product.

A New Validated Third Order Derivative Spectroscopic Method For Simultaneous Estimation Of Metoprolol Succinate And Ramipril In Tablet Dosage Form

Objective: The objective of the present work is to develop and validate a new UV derivative spectrophotometric method for simultaneous estimation of metoprolol succinate and ramipril in methanol: water (50:50v/v). Methods: “Zero crossing technique” was chosen for quantitative determination. The zero-crossing points (ZCP’s) were found to be 209 nm where metoprolol succinate was quantified and 211 nm where ramipril was quantified. This method was then subjected to accuracy, linearity, sensitivity and reproducibility according to ICH guidelines to ensure and confirm its validity. Results: The method was found to be obeying Beer’s law in the range of 10-50 µg/ml and 5-25 µg/ml for metoprolol succinate and ramipril, respectively. The % recoveries were observed between the range of 99.2-100.2 for metoprolol succinate and 99.57-99.86 for ramipril. The intra-day and inter-day results showed reproducibility. Conclusion: It can be concluded that the developed third-order UV derivative spectroscopic method for the simultaneous determination of metoprolol succinate and ramiprilcan be recommended for routine quantitative analysis.

The effect of Ramipril and Telmisartan on blood pressure and insulin resistance in hypertensive patients

Background: Angiotensin converting enzyme (ACE) inhibitors and Angiotensin II Receptor Blockers (ARBs) have become keystones of therapy for hypertension but there are very few studies where they have been compared with each other. This study attempted to compare the effect of Ramipril and Telmisartan on Blood Pressure and Insulin Resistance in Hypertensive patients (JNC 8).Methods: An open label, randomized, prospective and comparative study of twelve- week duration was conducted on 60 patients of hypertension (JNC-8), with the collaboration of Department of Pharmacology and Department of Medicine, Government Medical College, Amritsar. Group A and B were given Telmisartan 40mg and Ramipril 2.5 mg OD respectively. Blood Pressure was recorded on every visit, whereas, fasting plasma insulin and HOMA-IR values were recorded at the baseline and at the end of the study. Fasting blood sugar was done at 0, 4 and 12 weeks.Results: At the end of 12 weeks, a significant reduction in Systolic/Diastolic blood pressure was observed in group A with a drop of ~14/9 mmHg (p<0.001) and in group B too, the fall of ~11.6/7.2 mmHg was significant (p<0.001). However, in inter-group comparison only SBP difference was significant between two groups (p<0.05). Change in HOMA-IR value was also significant in both the groups (p<0.001). The inter-group difference for HOMA-IR between both the groups (A vs B) was also statistically significant (p<0.01).Conclusions: Telmisartan 40 mg OD was more effective than Ramipril 2.5 mg OD in controlling the SBP and improving Insulin resistance at the end of 12 weeks.

Ramipril can alleviate the accumulation of renal mesangial matrix in rats with diabetic nephropathy by inhibiting insulin-like growth factor-1

Abstract Purpose: To investigate the impact of Ramipril (RAM) on the expressions of insulin-like growth factor-1 (IGF-1) and renal mesangial matrix (RMM) in rats with diabetic nephropathy (DN). Methods: The Sprague Dawley rats were divided into normal control (NC) group (n = 12), DN group (n = 11), and DN+RAM group (n = 12). The ratio of renal weight to body weight (RBT), fasting blood glucose (FBG), HbA1c, 24-h urine protein (TPU), blood urea nitrogen (BUN), creatinine (Cr), renal pathological changes, the levels of IGF-1, fibronectin (FN), type IV collagen (Col-IV), and matrix metalloproteinases (MMP)-2 were compared among the groups. Results: Compared with NC group, the RBT, FBG, HbA1c, TPU, BUN, Cr, and RMM in DN group were significantly increased (P < 0.05), the IGF-1, FN, and Col-IV were significantly upregulated (P < 0.05), while MMP was significantly downregulated (P < 0.05). Compared with DN group, the indexes except for the FBG and HbA1c in DN+RAM group were significantly improved (P < 0.05), among which IGF-1 exhibited significant positive correlation with TPU(r=0.937), FN(r=0.896) and Col-IV(r=0.871), while significant negative correlation with MMP-2 (r=-0.826) (P<0.05). Conclusion: RAM may protect the kidneys by suppressing IGF-1 and mitigating the accumulation of RMM.

Therapeutic effect of ramipril and nifedipine on aged patients with hypertensive heart disease and its influence on cardiac function and inflammatory factor level ／ / 心血管康复医学杂志

Objective :To explore therapeutic effect of ramipril tablet and nifedipine controlled release tablet on aged patients with hypertensive heart disease and its influence on cardiac function and inflammatory factor level .Methods :A total of 186 aged patients with hypertensive heart disease were randomly equally divided into ramipril group ,nifedipine group and com‐bined treatment group (received ramipril + nifedipine).After eight weeks ,the therapeutic effect were observed and com‐pared among all groups.Results :Compared with before treatment , there were significant rise in LVEF ,cardiac index (CI) ,left ventricular early diastolic／late diastolic peak flow velocity (E／A) and 6min walking distance (6MWD) ,and sig‐nificant reductions in plasma levels of BNP ,CRP ,interleukin (IL)‐1 and IL‐6 after treatment in three groups , P＜0.01 all.Compared with ramipril group and nifedipine group after treatment ,there were significant rise in LVEF [ (43.44 ± 5.75)%,(43.41 ± 5.73)% vs.(49.89 ± 5.84)%] ,CI [(2.23 ± 0.64) L·min－1 ·m－2 ,(2.28 ± 0.69) L·min－1 ·m－2 vs.(2.87 ± 0.71) L·min－1 ·m－2 ] ,E／A [(0.87 ± 0.31) ,(0.90 ± 0.32) vs.(1.21 ± 0.39)] ,6MWD [(233.44 ± 38.95) m ,(236.45 ± 39.13) m vs.(299.77 ± 45.77) m] ,and significant reductions in plasma levels of BNP [ (199.67 ± 27.86) ng／L ,(194.55 ± 25.46) ng／L vs.(124.67 ± 29.45) ng／L] ,CRP [ (10.32 ± 3.18) mg／L ,(10.21 ± 2.89) mg／L vs. (8.35 ± 2.12) mg／L] , tumor necrosis factor (TNF)‐α [ (45.52 ± 14.56) pg／ml ,(45.45 ± 13.78) pg／ml vs.(37.86 ± 10.35) pg／ml] ,IL‐1 [ (6.34 ± 2.54) pg／ml ,(6.31 ± 2.31) pg／ml vs.(3.42 ± 1.89) pg／ml] and IL‐6 [ (6.71 ± 2.23) pg／ml ,(6.68 ± 2.11) pg／ml vs.(4.11 ± 1.75) pg／ml] , P＝0.001 all.Over all therapeutic effect of combined treatment was significantly higher than that of ramipril group ( Z＝ 3.747 , P＝ 0.001 ) and nifedipine group ( Z＝ 3.838 , P＝0.001).Conclusion :Ramipril combined nifedipine can improve therapeutic effect and cardiac function ,and reduce plasma levels of inflammatory factors in aged patients with hypertensive heart disease .

The study of effects of inhibition of the renin angiotensin system on memory in rats

Background: The existence of an independent renin angiotensin aldosterone system (RAAS) has been well-established and is known to modulate various pathological processes such as neuroinflammation, neurodegeneration, and neural injury, in addition to the RAAS in the cardiovascular system.Methods: Eighteen Wistar rats were divided into 3 study groups (n=6; Losartan, Ramipril, Normal Saline), trained on the Cook’s Pole climbing apparatus till the conditioned avoidance response (CAR) rate was 100%. The retention of CAR was tested each week for 4 consecutive weeks. The number of times that the animal successfully avoided the shock, and the time taken for this avoidance were measured and compared with placebo (Normal Saline). The values have been expressed as Mean±Standard Deviation (SD). A p-value of less than 0.05 has been considered as significant.Results: The retention of the conditioned avoidance response in the group receiving study drugs was significantly more than the placebo group. However, there was no show significant difference between Losartan and Ramipril in the rate of retention, or the time taken for avoidance.Conclusions: In this study, Ramipril and Losartan have a beneficial effect on learning and memory as compared to plcebo.

Effects of Different Doses of Ramipril on Blood Pressure and Renal Function of Patients with Early Diabet-ic Nephropathy / 中国药房

OBJECTIVE:To compare the effects of different doses of ramipril on blood pressure and renal function of early di-abetic nephropathy patients. METHODS:A total of 108 patients with early diabetic nephropathy selected from our hospital during May 2014-Dec. 2015 as research objects were divided into group A,B,C,with 36 cases in each group. All groups were given Ramipril tablets,5 mg for group A,2.5 mg for group B,1.25 mg for group C,qd,for 8 weeks. Blood pressure(SBP,DBP)and renal function indexes(24 h urine protein,β 2-microglobulin,UAE)were compared among 3 groups before and after treatment. The occurrence of ADR was also recorded in 3 groups. RESULTS:Before treatment,there was no statistical significance in blood pressure or renal function indexes among 3 groups(P>0.05). After treatment,blood pressures 24 h urine protein,β2-microglobulin and UAE of 3 groups were decreased significantly;those indexes of group A were significantly lower than group B and C,with sta-tistical significance(P0.05). Both hypoten-sion and hypoglycemia occurred in 3 groups during treatment,but were recovered after stopping treatment. CONCLUSIONS:High dose of ramipril(5 mg,qd)shows good effects on early diabetic nephropathy and reduces urinary protein excretion,but doesn't af-fect its safety.

Pharmacokinetic interaction between sunitinib and ramipril in rats / 中国药科大学学报

The purpose of this study was to investigate the pharmacokinetic interaction between sunitinib and ramipril in rats. Eighteen male SD rats were divided into three groups, with each group being assigned to orally receive sunitinib, ramipril, sunitinib and ramipril, respectively, for ten days. Blood samples were collected at dif-ferent times after first-day and tenth-day administration. The concentrations of ramiprilat and sunitinib in rat plasma were determined by LC/MS/MS and the pharmacokinetic parameters were calculated and statistically analyzed. Compared with the administration of ramipril alone, after a single-dose combined administration, tmax of ramiprilat decreased significantly and t1/2 prolonged, while AUC0-∞ remained unchanged. These results indicated that the ab-sorption rate of ramiprilat increased and the elimination rate decreased, but total absorption degree was not changed. After multiple-dose administrations, CL of ramiprilat decreased and AUC0-∞ increased obviously. It sug-gested that accumulation of ramiprilat occurred in body and the drug elimination became slower. No obvious difference of sunitinib pharmacokinetic behavior was found when it was given in combination with ramipril after a single-dose administration or multiple-dose administration. Sunitinib decreased the elimination of ramiprilat after co-administration in company with drug accumulation in body after multiple-dose co-administration. The study showed that there were pharmacokinetic interactions between sunitinib and ramipril in SD rats.

Efeitos do ramipril sobre a doença periodontal induzida experimentalmente em ratos / Effect of ramipril on periodontal disease experimentally induced in rats

A doença periodontal (DP) corresponde a um grupo de doenças inflamatórias que acomete as estruturas periodontais de proteção e de suporte e pode levar à perda dentária. A etiologia está relacionada à placa dentobacteriana que leva à produção de grande quantidade de citocinas pró-inflamatórias importantes na destruição tecidual. A angiotensina (Ang) II também pode contribuir para a inflamação e destruição tecidual no periodonto agindo como mediador chave. A utilização de drogas que atuem na cascata do sistema renina-angiotensina (SRA) poderia interferir no estado de saúde ou inflamação do tecido mole, na perda óssea alveolar e na expressão gênica dos componentes do SRA e mediadores inflamatórios. Portanto, o objetivo do presente trabalho foi investigar se o ramipril, um inibidor da enzima conversora de angiotensina (ECA), altera a progressão da DP induzida experimentalmente em ratos. Foi utilizado o modelo de indução da DP por colocação de ligadura ao redor do primeiro molar inferior direito de ratos. Os grupos com 10 animais cada, foram divididos em tratados com ramipril (via gavagem 10mg/kg/dia) ou água (veículo) durante 14 e 21 dias e o grupo Sham submetido à indução fictícia da DP. Outros quatro grupos foram submetidos ao pré-tratamento com ramipril durante os períodos de 7 e 14 dias e após a indução da DP e tratados por 14 ou 21 dias. As metodologias de avaliação foram: extração de RNA total, transcrição reversa seguida de reação em cadeia da polimerase quantitativa (RTqPCR),análises histológica e da perda óssea alveolar. Os dados foram analisados por meio de gráficos e os resultados foram submetidos à análise unidirecional de variância (ANOVA) e representaram médias e respectivos desvios-padrão. Diferenças entre os grupos foram consideradas estatisticamente significativas quando p < 0,05. Com base nos resultados obtidos pode-se concluir que o ramipril foi capaz de reduzir a progressão da perda óssea no grupo tratado por 21 dias (DP-21d-Rami)...

Periodontitis (PD) consists of a group of inflammatory diseases that affect the protecting and supporting periodontal structures, and may lead to tooth loss. Theetiology is related to the dentobacterial plaque that produces a large amount of proinflammatory cytokines with an important action on tissue destruction. Angiotensin(Ang) II may also contribute to the inflammation and periodontal tissue destruction byacting as a key mediator. The use of drugs that affect the cascade of the reninangiotensin system (RAS) might interfere with the healthy or inflammatory status ofthe soft tissue, alveolar bone loss and gene expression of RAS components and inflammatory mediators. Therefore, the aim of this work was to evaluate whether ramipril, an angiotensin-converting enzyme (ACE) inhibitor, alters the progression of experimentally-induced PD in rats. The model of PD induction by placement of a silk ligature around the right lower first molar was used. Groups with 10 animals each were divided into ramipril-treated (10 mg/kg/day, via gavage), water (vehicle) and thesham surgery group (sham) for 7 or 14 days previously to PD induction and after this period the drug was administered for 14 and 21 days. The techniques employed were: total RNA extraction, reverse transcription followed by quantitative polymerase chain reaction (RT-qPCR) as well as histological and alveolar bone loss analyses. Data were analyzed by means of graphs and the results submitted to unidirectional analysis of variance (ANOVA) and represent the means with respective standard deviations. Differences between groups were considered statistically significant whenp < 0.05. Based on the results obtained in this work, it was concluded that ramipril was able to reduce the progression of alveolar bone loss in the group treated for 21...

Efeitos do ramipril sobre a doença periodontal induzida experimentalmente em ratos / Effect of ramipril on periodontal disease experimentally induced in rats

A doença periodontal (DP) corresponde a um grupo de doenças inflamatórias que acomete as estruturas periodontais de proteção e de suporte e pode levar à perda dentária. A etiologia está relacionada à placa dentobacteriana que leva à produção de grande quantidade de citocinas pró-inflamatórias importantes na destruição tecidual. A angiotensina (Ang) II também pode contribuir para a inflamação e destruição tecidual no periodonto agindo como mediador chave. A utilização de drogas que atuem na cascata do sistema renina-angiotensina (SRA) poderia interferir no estado de saúde ou inflamação do tecido mole, na perda óssea alveolar e na expressão gênica dos componentes do SRA e mediadores inflamatórios. Portanto, o objetivo do presente trabalho foi investigar se o ramipril, um inibidor da enzima conversora de angiotensina (ECA), altera a progressão da DP induzida experimentalmente em ratos. Foi utilizado o modelo de indução da DP por colocação de ligadura ao redor do primeiro molar inferior direito de ratos. Os grupos com 10 animais cada, foram divididos em tratados com ramipril (via gavagem 10mg/kg/dia) ou água (veículo) durante 14 e 21 dias e o grupo Sham submetido à indução fictícia da DP. Outros quatro grupos foram submetidos ao pré-tratamento com ramipril durante os períodos de 7 e 14 dias e após a indução da DP e tratados por 14 ou 21 dias. As metodologias de avaliação foram: extração de RNA total, transcrição reversa seguida de reação em cadeia da polimerase quantitativa (RTqPCR),análises histológica e da perda óssea alveolar. Os dados foram analisados por meio de gráficos e os resultados foram submetidos à análise unidirecional de variância (ANOVA) e representaram médias e respectivos desvios-padrão. Diferenças entre os grupos foram consideradas estatisticamente significativas quando p < 0,05. Com base nos resultados obtidos pode-se concluir que o ramipril foi capaz de reduzir a progressão da perda óssea no grupo tratado por 21 dias (DP-21d-Rami)...

Periodontitis (PD) consists of a group of inflammatory diseases that affect the protecting and supporting periodontal structures, and may lead to tooth loss. Theetiology is related to the dentobacterial plaque that produces a large amount of proinflammatory cytokines with an important action on tissue destruction. Angiotensin(Ang) II may also contribute to the inflammation and periodontal tissue destruction byacting as a key mediator. The use of drugs that affect the cascade of the reninangiotensin system (RAS) might interfere with the healthy or inflammatory status ofthe soft tissue, alveolar bone loss and gene expression of RAS components and inflammatory mediators. Therefore, the aim of this work was to evaluate whether ramipril, an angiotensin-converting enzyme (ACE) inhibitor, alters the progression of experimentally-induced PD in rats. The model of PD induction by placement of a silk ligature around the right lower first molar was used. Groups with 10 animals each were divided into ramipril-treated (10 mg/kg/day, via gavage), water (vehicle) and thesham surgery group (sham) for 7 or 14 days previously to PD induction and after this period the drug was administered for 14 and 21 days. The techniques employed were: total RNA extraction, reverse transcription followed by quantitative polymerase chain reaction (RT-qPCR) as well as histological and alveolar bone loss analyses. Data were analyzed by means of graphs and the results submitted to unidirectional analysis of variance (ANOVA) and represent the means with respective standard deviations. Differences between groups were considered statistically significant whenp < 0.05. Based on the results obtained in this work, it was concluded that ramipril was able to reduce the progression of alveolar bone loss in the group treated for 21...

Effect of ramipril on glycosylated hemoglobin and liver function test in patients of diabetic nephropathy.

Background: Diabetic nephropathy (DN) is a chronic complication of diabetes mellitus with a growing incidence. Therefore, it is essential to have a better understanding of it, especially in relation to prevention and aggressive management to avoid progression to end-stage renal disease. Methods: This prospective randomized study represented the effects of ramipril on glycosylated hemoglobin (HbA1c), liver function tests (LFT), mean arterial blood pressure, and serum potassium level in patients diagnosed with DN, with concomitant mild to moderate hypertension. 135 diagnosed patients with DN treated with ramipril 5 mg daily for 3 months were involved in this study. Blood samples were taken from all patients and analyzed for HbA1c, LFT including alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum alkaline phosphatase (ALP), and bilirubin with serum potassium level. After 3 months of treatment with ramipril (5 mg daily), blood samples were collected and analyzed again to determine the same parameters. Results: Ramipril produced a signifi cant reduction in (HbA1c) of hypertensive patients (p<0.05), whereas, serum levels of ALT, AST, ALP, and bilirubin were signifi cantly elevated. The results indicated that ramipril may cause liver injury. Meanwhile, the mean arterial pressure was decreased signifi cantly by ramipril (p<0.05). Conclusion: The present study concluded that: ramipril signifi cantly reduced the percentage of HbA1c but may cause liver injury, monitoring of liver enzymes is advisable for patients on ramipril.

Effect of ramipril on urinary protein in elderly type 2 diabetic patients with nephropathy / 中华老年医学杂志

Objective To investigate the effect of ramipril on urinary protein in elderly type 2 diabetic patients with nephropathy in different periods.Methods 120 type 2 diabetic patients with nephropathy (64 males, 56 females) with mean aged (68±3) years were randomized into treatment group and control group (n =60, each).According to test results of 24 h proteinuria and renal function, they were divided into 3 subgroups: the normal urine albumin (normal control) group, the early diabetic nephropathy group, and the clinical diabetic nephropathy group.The control group received conventional treatment, while the treatment group used conventional treatment combined with ramipril 2.5 mg/d.Both groups had treatment course of 3 months.The changes in 24 h urinary total protein and urinary albumin before and 1 and 3 months after treatment, and the changes in blood urea nitrogen and serum creatinine levels in patients with renal dysfunction before and 3 months after treatment were observed and compared.Results 24 h urinary total protein and urinary albumin were significantly decreased along with the extended treatment time (P＜0.05 or 0.01).The blood urea nitrogen and serum creatinine levels were significantly declined at 3 months after treatment versus pre-treatment (P＜0.05 for both).There were no significant differences in 24h urinary total protein and urinary albumin in control group before versus after treatment (P＞0.05 for both).At 1 and 3 months after treatment, there were significant differences both in the decrement of 24h urinary total protein and urinary albumin, and in the blood urea nitrogen and serum creatinine levels between the clinical diabetic nephropathy treatment group and the control group (P＜0.05 or 0.01).Conclusions Ramipril combined with conventional treatment can effectively reduce proteinuria and promote the recovery of renal function for type 2 diabetic patients with nephropathy.

Effect of Ramipril and Trimetazidine on Renal Cell Apoptosis and Cytochrome C Expression in Experimental Rats With Chronic Heart Failure / 中国循环杂志

Objective: To explore the effects of ramipril, trimetazidine and the combination of ramipril and trimetazidine on renal cell apoptosis index (AI) and cytochrome C (Cyt-C) expression in experimental rats with chronic heart failure (CHF). Methods: CHF model was established by partially banding of abdominal aorta superior to renal artery in experimental rats. A total of 50 male Wistar rats were randomly divided into 5 groups: Sham operation group, Model group, Ramipril group, Trimetazidine group and Combination (ramipril and trimetazidine) group.n=10 in each group. Renal tubular cell AI was examined by TUNEL method, mRNA and protein expressions of Cyt-C were detected by RT-PCR and Western Blot analysis in each group respectively. Results: Compared with Sham operation group, Model group had increased AI of renal tubular cells, increased mRNA and protein expressions of Cyt-C,P Conclusion: Ramipril and trimetazidine can inhibit renal cell apoptosis and effectively improve the renal function in CHF rats. Combined medication is better than either of them alone.

Comparative Evaluation of Angiotensin-Converting Enzyme Inhibitors for their Beneficial Effects in Patients with Ischemic LV Systolic Dysfunction and Undergoing Coronary-Artery Bypass Surgery.

We compared three angiotensin-converting enzyme (ACE) inhibitors, captopril, perindopril, and ramipril, in the presented prospective study for their effectiveness in patients having left ventricular (LV) systolic dysfunction and undergoing coronaryartery bypass grafting (CABG). We enrolled 27 patients in captopril, 43 patients in perindopril, and 70 patients in ramipril group. There was about 25%–36% rise in LVEF after 3 and 6 months of ACE inhibitor administration in all three groups. The reduction in LV diameters did not differ significantly amongst the three groups. There was a significant decrease (p < 0.05) in LV end-diastolic diameter from baseline levels in captopril and perindopril groups after 3 months that got increased after 6 months but remained below pretreatment levels in both the groups. In ramipril group, there was no much change in this parameter from baseline levels at 3 and 6 months of treatment. After 6 months of treatment, the percent reduction in LV end-systolic diameter was also sustained in perindopril-treated patients. The percent reduction was greater in the perindopril group (3 and 6 months: 7.39 ± 5.94 and 7.73 ± 3.43, respectively) as compared to that observed in captopril group (3 and 6 months: 5.67 ± 1.05 and 2.52 ± 3.11, respectively) and ramipril group (3 and 6 months: 7.30 ± 2.75 and 4.93 ± 3.22, respectively). Mitral-valve regurgitation was greatly reduced in the captopril group at 3 as well 6 months of ACE inhibitor administration. However, the percent reduction from baseline levels was not statistically significant amongst the three groups. The percent improvement in functional status was significantly greater in the ramipril treatment group (36.46 ± 3.14) after 6 months of treatment as compared to that of captopril (6.67 ± 10.64) and perindopril (4.17 ± 2.73) group. In conclusion, our data show equal beneficial effects with all three ACE inhibitors under investigation in CABG patients with LV systolic dysfunction, with marginal superiority for perindopril.

Effects of ramipril on ventricular arrhythmia after myocardial infarction in rabbits / 世界急诊医学杂志（英文）

BACKGROUND:Ventricular arrhythmia (VA) is one of the most common complications of myocardial infarction (MI), and ventricular tachycardia and fibrillation are the main causes for sudden cardiac death. This study aimed to explore the effect of ramipril on the occurrence of VA and its mechanism after MI in rabbits. METHODS:Twenty-four New Zealand rabbits purchased from the Wuhan Laboratory Animal Research Center were divided into three groups:sham-operated (SHAM) group (n=8), MI group (n=8) and MI with ramipril (RAM) group (n=8). Rabbits in the SHAM group received a median sternotomy without ligation of the left ventricular coronary artery. Rabbits in the MI and RAM groups received a median sternotomy followed by ligation of the left coronary artery. The successful anterior MI was confirmed by elevation of the ST segment with more than 0.2 mV in lead II and III. After MI, rabbits in the RAM group were fed with intragastric ramipril (1 mg/kg per day ) for 12 weeks. Before and 12 weeks after MI in the three groups, ventricular tachycardia or fibrillation (VT/VF) episodes and MAP in cadiocytes of the epicardium, mid-myocardium and endocardium were recorded by a multichannel physiograph. Student'st test and ANOVA were used for statistical analysis. RESULTS:VT/VF episodes were decreased more markedly in the RAM group than in the MI group after 12 weeks (2.6±0.8 vs. 12.4±2.9,P<0.05). Twelve weeks after MI, the duration of repolarization for 90％ (APD90) of three-tier ventricular myocytes in the MI group was longer than that before MI (258.2±21.1 vs. 230.1±23.2, 278.0±23.8 vs. 245.8±25.4, 242.6±22.7 vs. 227.0±21.7,P<0.05). However, the APD90 was not significantly different at 12 weeks before and after MI in the RAM group (P>0.05). Moreover, the transmural dispersion of repolarization (TDR) was increased more markedly 12 weeks after MI in the MI group than in the SHAM and RAM groups (36.2±10.2 vs. 18.7±6.2, 24.9±8.7,P<0.05). But the TDR was not significantly different between the RAM and SHAM groups (18.7±6.2 vs. 24.9±8.7,P>0.05). CONCLUSION:Ramipril may reduce the incidence of malignant ventricular arrhythmia via improvement of transmembrance repolarization heterogeneity after MI.

Clinical reserch of stroke-associated pneumonia prevented with ramipril / 中华老年医学杂志

Objective To investigate the prevention of stroke-associated pneumonia (SAP) with Ramipril.Methods 404 acute stroke patients with primary hypertension were randomized into two groups.Group A received ramipril 2.5 mg once daily orally,and then were titrated up to 5 mg/d after a week.Group B received Candesartan 4 mg once daily orally,and then were titrated up to 8 mg/d after a week.The treatment course was 28 days.All patients received examination of Standardized Swallowing Assessment (SSA).The amelioration of swallow function and incidence of SAP after treatment were compared between the two groups.Results There were 10 patients suffering from SAP in group A and 21 patients in group B.The incidence of SAP was lower in group A(5.0％)than in group B(10.4％)(P＜0.05).The positive rate of SSA was 87.1 ％ in patients with SAP,higher than the total rate (47.5％).Dysphagia was improved in both groups after treatment.The rate of dysphagia improvement in group A and group B was 81.4％ and 66.3％ respectively.There was significant statistics difference in the positive case of SSA between two group (P＜ 0.05).Conclusions Orally treatment with ramipril is effective to prevent stroke-associated pneumonia and toimprove swallow function.

Anti-inflammatory effects of ramipril in experimentally induced rheumatoid arthritis.

Objective: To evaluate anti-inflammatory effects of ramipril in experimentally induced rheumatoid arthritis (RA).Materials and Methods: Adjuvant induced arthritis model is used in this study.Albino-Wistar rats of either sex were used. Arthritis was induced by single intradermal injection of Freund’s complete adjuvant (FCA) suspended in oil inplantar region of right hind paw. Rats were divided in to three groups (n=8) namely disease control, standard and test group. Drug treatment was carried out for 21 days. Effect of test drug on acute inflammatory phase was evaluated on day 5 by assessing right hind paw edema. After 21 days animals were sacrificed and evaluated for left hind paw edema, weight changes, histo-pathological synovitis grading in left hind limbs and secondary lesion score.Results: Results showed that ramiprilsignificantly reduced right hind paw edema on day 5 (p<0.05). Ramipril also showed statistically significant weight gain (p<0.05), reduction of histo-pathological synovitis grade (p<0.05) as well as secondary lesion score (p<0.05).Conclusion:Our study suggests that ramiprilmay be used as an adjuvant anti-inflammatory agent in patients with RA. However this speculation needs to be confirmed clinically.

Development and validation of an RP-HPLC method for simultaneous determination of Ramipril and Amlodipine in tablets / 药物分析学报

An RP-HPLC method for the simultaneous determination of and Amlodipine (AL)Ramipril (RP) in tablets was developed and validated by Chinese Pharmacopoeia 2010. The linearity of the proposed method was investigated in the range of 0.01-0.25 mg/mL (r2 ? 0.9998) for RP and 0.014-0.36 mg/mL (r2 ? 0.9997) for AL. The limits of detection (LOD) were 0.06μg/mL and 0.02μg/mL for RP and AL, and the limits of quantitation (LOQ) were 0.2μg/mL and 0.07μg/mL, respectively. Some major impurities and degradation products did not disturb the detection of RP and AL and the assay can thus be considered stability-indicating.

Simultaneous Estimation of Ramipril and Amlodipine in Bulk and tablet Dosage form by RP-HPLC Method.

A Simple and precise HPLC method was developed for the simultaneous estimation of Ramipril and Amlodipine in pure drug and pharmaceutical dosage forms. The separation was carried out using C18 Column (250 × 4.6 mm i.d. 5 μm particle size), with mobile phase compressing of Acetonitrile, Sodium phosphate buffer and Methanol in the ratio of 50: 20:25 v/v/v, pH= 6.8 (pH adjusted with OPA). The flow rate was 0.8 ml/min and the detection was carried out using PDA detector at 210 nm. The retention times were 2.64 and 7.45 mins for Ramipril and Amlodipine respectively. Calibration curves were linear with correlation coefficient 0.998 and 0.996 over concentration range of 1 - 16 μg/ml for Ramipril and 0.2 – 3.2 μg/ml for Amlodipine respectively. Recovery was found in between 100.21% and 100.82% for Ramipril and Amlodipine respectively. Method was found to be reproducible with relative standard deviation (R.S.D) for intra and inter day precision less than 2%. The method was validated by evaluation of different parameters such as accuracy, linearity, precision, LOD and LOQ.