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［Abstract］Objective:To evaluate the efficacy and safety of fermented cordyceps powder combined with angiotensin-converting enzyme inhibitors （ACEI）/angiotensin Ⅱ receptor blocker （ARB） in the treatment of diabetic kidney disease （DKD）. Method:The randomized controlled trials （RCTs） concerning the treatment of DKD with fermented cordyceps powder plus ACEI/ARB were retrieved from Pubmed， Embase， Cochrane library， China National Knowledge Infrastructure （CNKI）， Chinese BioMedical Literature Database on disc （CBMdisc）， Wanfang Data Knowledge Service Platform， and Chongqing Weipu Database for Chinese Technical Periodicals （VIP）. The quality of the included articles was evaluated by the Cochrane Collaboration's tool， followed by data analysis using RevMan 5.3. Result:A total of 48 RCTs were included， involving 4 562 cases. As revealed by Meta-analysis， the effective rate of fermented cordyceps powder combined with ACEI/ARB was higher than that of ACEI/ARB ［risk ratio （RR）=1.20， 95% confidence interval （CI） （1.15，1.24）， <italic>P</italic><0.000 01］. Moreover， such combination effectively reduced urinary albumin excretion rate ［standardized mean difference （SMD）=-2.61，95%CI （-3.17，-2.05），<italic>P</italic><0.000 01］，24-h proteinuria［SMD=-1.75，95%CI （-2.15，-1.35），<italic>P</italic><0.000 01］， serum creatinine（Scr）［mean difference （MD）=-14.57，95%CI （-17.94，-11.21），<italic>P</italic><0.000 01］， blood urea nitrogen（BUN）［MD=-1.05，95%CI （-1.29，-0.81），<italic>P</italic><0.000 01］， cystatin C （Cys-C） ［MD=-0.52，95%CI （-0.68，-0.36），<italic>P</italic><0.000 01］， fasting blood glucose（FBG）［MD=-0.59，95%CI （-0.93，-0.25），<italic>P</italic>=0.000 6］， hemoglobin A1c（HbA1c）［MD=-0.50，95%CI（-0.75，-0.24），<italic>P</italic>=0.000 1］， tumor necrosis factor-<italic>α</italic>（TNF）-<italic>α </italic>［SMD=-1.68，95%CI （-2.21，-1.15），<italic>P</italic><0.000 01］， C-reactive protein（CRP） ［SMD=-1.35，95%CI （-1.77，-0.93），<italic>P</italic><0.000 01］， and interleukin-6 （IL-6） ［SMD=-1.52，95%CI （-1.98，-1.07），<italic>P</italic><0.000 01］. There was no significant difference in the incidence of adverse events between the two groups ［RR=0.77，95%CI （0.49，1.21），<italic>P</italic>=0.25］. Conclusion:Fermented cordyceps powder combined with ACEI/ARB is more effective than ACEI/ARB in the treatment of DKD， which is worthy of clinical promotion and use. More multi-center RCTs with a large sample size are needed for verification.
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Resumen Un nuevo coronavirus, llamado coronavirus 2 del síndrome respiratorio agudo severo (SARS-CoV-2), se descubrió en diciembre de 2019 en Wuhan, China; el virus se intensificó rápidamente y el 11 de marzo de 2020 la Organización Mundial de la Salud lo declaró pandemia. Los datos emergentes sugieren que los pacientes mayores con COVID-19 asociado a otras afecciones comórbidas, como diabetes, hipertensión, y enfermedades cardíacas y pulmonares, son, en particular, más susceptibles, en comparación con las poblaciones generales y tienen mayor mortalidad. Aún no está claro si esta mayor asociación de hipertensión arterial con COVID-19 y el mayor riesgo de mortalidad están directamente relacionados con la hipertensión arterial u otras comorbilidades asociadas, o con el tratamiento antihipertensivo. Si bien el mecanismo patogénico subyacente que une la hipertensión y la gravedad de la infección por COVID-19 aún no se ha dilucidado, se ha planteado la hipótesis de que la activación excesiva del sistema renina-angiotensina (RAS) podría contribuir a la progresión de la lesión pulmonar relacionada con COVID-19. La preocupación sobre si los bloqueadores del receptor de angiotensina II (BRA) y los inhibidores de la enzima convertidora de angiotensina (IECA) pueden tener efectos nocivos sobre la morbilidad y la mortalidad de los pacientes con COVID-19 se basa en la especulación de que estos medicamentos aumentarían la regulación de la enzima convertidora de angiotensina II (ACE2), un receptor para el SARS-CoV-2, que aumentaría la carga viral y la lesión pulmonar. Los estudios recientes concuerdan con las recomendaciones de las sociedades científicas que plantean evitar la suspensión o cambio de medicación antihipertensiva, pues no hay evidencia que muestre que estos puedan ser tomados como factores de riesgo para gravedad o mortalidad por COVID-19.
Abstract A new coronavirus, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was discovered in December 2019 in Wuhan, China; the virus escalated rapidly and on March 11, 2020, the World Health Organization declared it a pandemic. Emerging data suggests that older patients with COVID-19 associated with other comorbid conditions such as diabetes, hypertension, heart and lung diseases are particularly more susceptible, compared to general populations, and have higher mortality. It is not yet clear whether this increased association of high blood pressure with COVID-19 and the increased risk of mortality are directly related to high blood pressure or other associated comorbidities, or to antihypertensive treatment. Although the underlying pathogenic mechanism linking hypertension and severity of COVID-19 infection remains to be elucidated, it has been hypothesized that excessive activation of the renin-angiotensin system (RAS) could contribute to the progression of COVID-19 related lung injury. Concern about whether angiotensin II receptor blockers (ARBs) and angiotensin converting enzyme (ACE) inhibitors may have deleterious effects on morbidity and mortality in patients with COVID-19 is based on speculation that these drugs would increase the regulation of angiotensin II converting enzyme (ACE2), a receptor for SARS-CoV-2, which would increase viral load and lung damage. Recent studies are consistent with the recommendations of scientific societies that propose avoiding the suspension or change of antihypertensive medication, as there is no evidence that shows that these can be taken as risk factors for severity or mortality from COVID-19.
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Angiotensin-Converting Enzyme Inhibitors , Angiotensin Receptor Antagonists , SARS-CoV-2 , COVID-19 , Renin-Angiotensin System , Pharmaceutical Preparations , Simplified Sewerage , Heart Diseases , Lung DiseasesABSTRACT
The present study was conducted to extract ACE-I inhibitory peptides from duck egg using proteases from different sources viz. plant (papain and ficin), animal (trypsin) bacterial (Alcalase). Initially, the whole duck egg liquid was defatted with multiple washing with ethanol. The partially denatured whole duck egg proteins were subjected to hydrolysis using preoptimized conditions (enzyme substrate ratio, pH, temperature, incubation time) w.r.t. each enzyme. Four treatments viz duck egg hydrolysed with alcalase (DEA), duck egg hydrolysed with ficin (DEF), duck egg hydrolysed with papain (DEP) and duck egg hydrolysed with trypsin (DET) were prepared. The collected respective hydrolysates were fractionated using ultrafiltration to obtain different fractions on the basis of molecular weight (kilo dalton) viz. whole: DEPH, >10 kDa: DEPH-1, 5-10 kDa: DEPH-2, 1-5 kDa: DEPH-3 and <1 kDa: DEPH-4. The whole hydrolysates and their fractions were evaluated for their ACE-I inhibitory activity under in-vitro condition. Amongst all the hydrolysates and their fractions, the ACE-I inhibitory activity of DEPH were significantly (p<0.05) higher than their respective fractions and DEPH of DEP exhibited the highest activity. However, all the fractions displayed varied (p<0.05) ACE-I inhibitory activity with each other. Results suggested that the duck egg protein hydrolysates and their fractions have strong antihypertensive activity which can be exploited to develop nutraceuticals or functional foods
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Objective To evaluate the protective effect of ACEI drugs on radiation pneumonitis,and to compare ACEI with ARB,statin, steroid, and NSAID on the treatment of radiation induced lung injury through the network Meta-analysis. Methods A computer-based online search of PubMed, EMbase, Cochrane Library, as well as CNKI, CBM, VIP, Wanfang database was conduce. The NOS score was used to evaluate the quality of studies,and the results were analyzed by stata14. 0 software. Results ACEI drugs showed desired effect on the treatment of radiation pneumonia,which can effectively reduce the incidence of radiation-induced lung injury,but can not prolong the survival time of the patients.The protective effects of statins and non-steroid anti-inflammatory drugs are second only to those of ACEI.Meta-analysis results were proved to be stable and credible by the sensitive-analysis.The therapeutic effect of ACEI on radiation induced lung injury is not affected by sex and age of patients. Conclusion ACEI drugs have an optimum protective effect on radiation induced lung injury.
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OBJECTIVE:To explore the effects of angiotensin converting enzyme inhibitors (ACEI)/angiotensin Ⅱ receptor blockers (ARB) on the prognosis in patients with advanced gastric cancer complicated with hypertension.METHODS:By retrospective study,clinical information of histologically confnrned Ⅲ-Ⅳ stage advanced gastric cancer patients with hypertension receiving 2 cycles of first-line chemotherapy plan containing fluorouracil at least were collected from Zhejiang Tumor Hospital during Jan.1st,2009-Dec.31th,2012.The data were summarized and analyzed.The patients receiving ACEI/ARB drugs were included in trial group,and the patients receiving other antihypertensive drugs were included in control group.Telephone follow-up was conducted in 2 groups.RESULTS:A total of 124 patients meeting the inclusion criteria were enrolled in this study.There was no statistical significance in age,gender,smoking history,ECOG score,family history of disease,family history of tumor,TNM staging,pathological type,tumor site or chemotherapy plan between trial group (23 cases) and control group (101 cases),except for history of alcohol intake (P＞0.05).Total response rate of first-line chemotherapy was 73.9％ in trial group,which was significantly higher than 41.6％ of control group,with statistical significance (P＜0.05).There was no statistical significance in 1-year or 3-year survival rate between 2 groups (P＞0.05).Median survival time of trial group was 669 d,which was significantly longer than 410 d of control group,with statistical significance (P＜0.05).Results of COX regression analysis showed that therapeutic efficacy of first-line chemotherapy influenced the survival of patients in different antihypertensive agent groups (P＜0.05).CONCLUSIONS:Compared with other antihypertensive drugs,ACEI/ARB agents significantly improve response rate of first-line chemotherapy in patients with advanced gastric cancer complicated with hypertension,significantly prolong median survival time,but have no significant effect on survival rate;at the same time,statistical comparison of definite drinking amount are absent.It needs to be further confirmed by multi-center,prospective and large-scale sample.
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OBJECTIVE:To study related factors of ACEI/ARB drugs in hypertension patients with coronary heart disease. METHODS:Six hundred hypertension patients with coronary heart disease were selected from a hospital during Jan. 2012-Jan. 2015,310 patients receiving ACEI/ARB drugs were included in observation group,and 290 patients not receiving these drugs were included in control group. General information and lab indexes of 2 groups were collected and analyzed. RESULTS:There were sta-tistical significances in ambulatory arterial stiffness indexes [(0.57±0.13),(0.40±0.11)],24 h average systolic blood pressure [ (146.42±11.24)mmHg,(132.31±9.85)mmHg],24 h average diastolic blood pressure [(78.14±9.21)mmHg,(82.79±8.33) mmHg],24 h ambulatory pulse pressure [(64.89±13.57)mmHg,(53.54±9.78)mmHg],drinking rate(58.71%,28.28%),moder-ate intensity rate(31.29%,65.17%),BMI[(33.28±2.07)kg/m2,(23.17±2.86)kg/m2],LVEF [(35.65±11.42)%,(48.01± 12.45)%],dyslipidemia rate(66.77%,30.34%),myocardial infarction rate(68.39%,39.66%),revascularization rate(69.68%, 33.10%)and duration of coronary heart disease between 2 groups(P<0.05). The duration of coronary heart disease,dyslipid-emia,myocardial infarction,revascularization were included in multivariate Logistic regression analysis,with statistical signifi-cance(P<0.05). CONCLUSIONS:The application of ACEI/ARB drugs in hypertension patients complicated with coronary heart disease is influenced by many factors;dyslipidemia,myocardial infarction and revascularization are positive independent influential factors of ACEI/ARB drug use in the treatment,but drug use rate will decline with the duration increase.
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Objective To improve the rational use of angiotensin-converting enzyme inhibitors (ACEI).Methods Clinical pharmacists reviewed ACEI use for the patients admitted into coronary heart disease care unit (CCU) during May 2012 to May 2013 to analyze the rational use of ACEI according to the expert consensus standards, guidelines and drug instructions of ACEI without any interventions.Clinical pharmacists intervened the irrational use of ACEI based on the same standard from June 2013 to May 2015.Results By comparing the data before and after intervention, it was found that the percentage of ACEI use increased from 80.1％ to 98.9％.The percentage of initial ACEI overdose was dropped from 21.4％ to 0.9％, and the percentage of under dose was decreased from 4.7％ to 0.5％, which was statistically significant.Conclusion Clinical pharmacists can play a leading role in promoting the rational use of ACEI.
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OBJECTIVE: To discuss the efficacy and safety of agiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in patients with resistant hypertension and advanced chronic kidney disease. METHODS: The treatment of resistant hypertension in one patient with chronic kidney disease (stage 4) was analyzed. According to the latest guidelines and clinical trials, actual treatment situation was summarized and analyzed. RESULTS AND CONCLUSION: The efficacy and safety of ACEIs or ARBs in patients with advanced chronic kidney disease and hypertension remain uncertain, thus, cautions should be exercised. It's reasonable to use low dose ARBs for such a young patient, nevertheless, it is emphasised that pharmacists and physicians should regularly and constantly monitor the patients' serum levels of creatinine and potassium and late-onset renal failure resulted from angiotensin blockade in patients on ACEIs/ARBs in a collaborative way.
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En enfermedad renal crónica etapa IV (ERC-IV) es alta la mortalidad y progresión a insuficiencia renal extrema (IRE). Objetivo: Valorar la calidad asistencial en una Clínica de Enfermedad Renal Crónica Avanzada (CERCA). Métodos: Estudio prospectivo de pacientes ERC- IV asistidos con un equipo multidisciplinario formal mediante estrategia de educación, asesoramiento nutricional, seguimiento clínico mensual, y tratamiento según metas de presión arterial (<130/80) reducción de proteinuria, uso de inhibidores de enzima de conversión (IECA) y/o Bloqueantes de receptores de angiotensina (BRA), tratamiento de dislipemia, y preparación para diálisis. Resultados: Se analizaron 150 pacientes, 50% masculino, 62,0 ± 14,4 años, Nefropatías vascular 20,4%, diabética 34,2% y 62,5% proteinúricos, con Índice de Charlson 3,67±1,57. En seguimiento de 1,4 años (IQ: 0,6-2,4) disminuyó la PA (147±35 a 132 ± 28mm), colesterol (210±55 a 179±50 mg/dL) y LDL (129±52 a 108±37 mg/dL) con aumento del uso de IECA/BRA (55,9 a 60,6 %) y estatinas (32,2 a 63,3%). La tasa de Mortalidad fue 5,3 e IRE 14,5/100 Pt- año. El Riesgo pérdida de FG mayor a la mediana o IRE aumentó con HTA, Pru >1 g/d y glomerulopatias y se redujo 90% con IEC/BRA (p<0.001). Al ingreso a diálisis la Hemoglobina ≥10g%, vacunación hepatitis B y acceso permanente fueron más frecuentes que en la población general. Conclusiones: En una Clínica multidisciplinaria con estrategia de control de riesgos se alcanzó mejor las metas de tratamiento, disminuyendo los factores de riesgo de progresión y mejorando el cuidado médico al ingreso a diálisis.
In stage IV chronic kidney disease (stage-IV CKD), mortality and progression to extreme renal failure (ERF) are high. Objective: Assessing the quality of health care in an Advanced Kidney Disease Clinic (AKDC). Methods: Prospective study of patients with stage-IV CKD treated by a multidisciplinary formal team through an educational strategy, nutritional advice, clinical nephrology follow-up, aimed at achieving blood pressure goals (<130/80), proteinuria reduction, use of angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB), dyslipidemia treatment and preparation for dialysis. Results: 150 patients were analyzed, 50% were males, of 62.0 ± 14.4 years of age, 20.4% had vascular kidney diseases, 34.2% had diabetes and 62.5% had proteinuria with a Charlson index of 3.67 ± 1.57. In the 1.4-year follow-up (IQ: 0.6- 2.4), there were decreases in the BP (147±35 to 132±28 mm), cholesterol (210±55 to 179±50 mg/ dl) and LDL (129±52 to 108±37 mg/dl), and there was an increase in the use of ACEI/ARB (55.9to 60.6%) and statins (32.2 to 63.3%). The mortality rate was 5.3 and the ERF rate was 14.5/100 patient-years. The glomerular function loss risk, which was higher than the median or ERF, increased with HTN, Pru >1 g/d and glomerular diseases, and had a 90% decrease with ACEI/ARB(p<0.001). At dialysis entry, hemoglobin levels of≥10g%, hepatitis B vaccination and permanent access were more frequent than in the general population. Conclusions: Treatment goals were best achieved in a multidisciplinary clinic with a riskcontrol strategy, reducing progression risk factors and improving medical care upon dialysis entry.
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Humans , Quality of Health Care , Kidney Failure, ChronicABSTRACT
PURPOSE: To evaluate the effects of angiotensin-converting enzyme inhibitors (ACE-I) in retarding progression of severe non-proliferative diabetic retinopathy (NPDR) in normotensive type 2 diabetic patients. METHODS: This was a retrospective case control study of 128 patients with normotensive type 2 diabetes with lower than +1 dipstick proteinuria and severe NPDR who were classified into either an ACE-I treated group (Enalapril maleate 10 mg, n=12 , Ramipril 5 mg, n=17) or an ACE-I untreated group (n=99). Medical records were reviewed for endpoints of (a) occurrence of proliferative diabetic retinopathy (PDR) or macular edema (ME) for which laser phototherapy was necessary or (b) development of proteinuria of higher than +1 level requiring medication of ACE-I. RESULTS: From the total of 128 patients, there were 29 ACE-I treated patients and 99 ACE-I untreated patients. There were no differences in the average age, duration of diabetes, body mass indices, blood pressure and levels of hyperglycemia or HbA1C between the two groups. Blood pressure and HbA1C levels in both groups remained unchanged during the study. The mean follow-up period was 41.6 months. In the ACE-I group, 6 patients progressed to PDR, 5 to ME and 6 developed proteinuria of greater than +1 over the follow-up period. In the control group, 30 patients progressed to PDR, 6 to ME and 9 developed proteinuria of greater than +1 over the follow-up period. CONCLUSIONS: Small doses of ACE-I did not yield any beneficial effects in retarding the progression of severe NPDR.
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Middle Aged , Male , Humans , Female , Aged , Treatment Failure , Severity of Illness Index , Retrospective Studies , Ramipril/administration & dosage , Fundus Oculi , Enalapril/administration & dosage , Dose-Response Relationship, Drug , Disease Progression , Diabetic Retinopathy/drug therapy , Diabetes Mellitus, Type 2 , Case-Control Studies , Angiotensin-Converting Enzyme Inhibitors/administration & dosageABSTRACT
[Objective] To discuss effective method for early DN.[Method] On the base of routine treatment,the treatment group 56 cases were added with Astragalus Injection;the control one 52 only routine therapy.[Result] In treatment group,41 had marked effect,14 had effect,1 had no effect,total effective rate was 98.2%;they were 14,23,15 and 71.1% respectively for control one.There’s obvious difference of meaning on effective rates(P
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BACKGROUND: Renin-ngiotensin system (RAS) blockers have been used to delay the progression of various renal diseases, but these medications cause hyperkalemia and the elevation of serum creatinine which impede the continuation of the medications. So far, there have been no data on the changes of serum creatinine or serum potassium after withdrawal of the RAS blockers. METHODS: We reviewed medical records of 60 patients who stopped the RAS blockers due to the elevation of serum creatinine or hyperkalemia between March 1995 and May 2005. They were assigned to either the elevated creatinine group or the hyperkalemia group according to the cause of the withdrawal. RESULTS: In the elevated creatinine group (n=37), the serum creatinine and GFR values at the point of withdrawal were 4.0+/-1.8 mg/dL and 18.2+/-10.4 mL/min/1.73m2, respectively. After discontinuation of the medications, a decrease in serum creatinine and an increase in GFR were noted at one month. After one month, however, serum creatinine increased continuously up to 6 months. Serum potassium levels decreased significantly after the drug withdrawal until the end of the study period. In the hyperkalemia group (n=23), the serum creatinine and serum potassium values at the point of withdrawal were 3.0+/-1.0 mg/dL and 6.4+/-0.4 mEq/L, respectively. A significant decrease in serum potassium was also noted after the withdrawal and this decrease lasted up to 6 months. But the transient decrease of serum creatinine, observed in the creatinine group, was not seen in this group. CONCLUSION: It was found that there was a beneficial effect on serum creatinine and GFR immediately after the withdrawal of RAS blockers only when they were stopped due to elevation of the serum creatinine concentration. The serum potassium levels were consistently decreased after the withdrawal of RAS blockers in both elevated creatinine and hyperkalemia groups.
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Humans , Angiotensin II , Angiotensin Receptor Antagonists , Angiotensins , Creatinine , Hyperkalemia , Medical Records , Potassium , Renal Insufficiency, ChronicABSTRACT
Renin-angiotensin system (RAS) is correlative with many diseases. Angio tensin II (AngII) plays an important role as the final effective approach for RAS. This article reviews the main approach to the action and biosynthesis of AngII: including AngII receptor blocker (ARB), chymase inhibitor and ACE2 which were disscoverd recently.
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BACKGROUND: Unilateral ureteral obstruction(UUO) is an experimental model of tubulointerstitial injury, characterized by progression of interstitial fibrosis and tubular atrophy. In the pathogenic mechanism of renal injury, activation of renin-angiotensin system may play an important role. METHODS: We tested the hypothesis that tubulointerstitial injury begins with infiltration of macrophage, followed by enhanced expression of chemoattractants such as MCP-1 and osteopontin, which are affected by local angiotensin II activity. We examined the beneficial effects of ACEI and AT1RB and combination of these two drugs, with kidney after 5 days of ureter ligation. RESULTS: Monocyte/macrophage infiltration demonstrated by ED-1 staining was markedly increased in UUO group comparing to that of sham operared group, and it was reduced by administeration of ACEI, AT1RB and combination of both, but not statistically significant. MCP-1 mRNA expression increased significantly after 5 days of UUO. ACE inhibitor, enalapril treatment had suppressed significantly the MCP-1 mRNA expression level, but AT1RB, candesartan had not significance. Combination of both made no more reduction of MCP-1 mRNA level compared to ACEI alone. The other macrophage chemoattractant protein, osteopontin expression was examined by immunohistochemistry, and evaluated with image analysis. Marked up-regulated osteopontin expression was observed on the brushborder of proximal tubules after 5 days UUO. There was a great reduction of osteopontin expression in a enalapril treated group and more significant reduction was noted in the group, treated with combination of both. candesartan did not reduce osteopontin expression. CONCLUSION: This study suggest that activation of renin-angiotensin system has a major role in the pathogenesis of tubulointerstitial renal injury in UUO through expression of chemoattractants and infiltration of inflammatory cells. Blocking of this process may inhibit renal injury process and ACEI halts these process but AT1RB does not. Combination use of both drugs did not show more additive effect compare to ACEI use alone in the phase of early inflammatory process of renal injury.
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Animals , Rats , Angiotensin II , Angiotensins , Atrophy , Chemotactic Factors , Enalapril , Fibrosis , Immunohistochemistry , Kidney , Ligation , Macrophages , Models, Animal , Models, Theoretical , Osteopontin , Peptidyl-Dipeptidase A , Renin-Angiotensin System , RNA, Messenger , Ureter , Ureteral ObstructionABSTRACT
Objective To study on the research focus of angiotensin converting enzyme inhibitor(ACEI) and calcium channel blocker.Methods From 1999 to 2008,the literature which the "angiotensin converting enzyme inhibitor"and"angiotensin converting enzyme inhibitor" in SCI database were collected.CiteSpace visualization techniques were uesd to analyze hot fields,hot spot of the author and the hot article on two types of the drugs.Results There were 5 hot fields on two type of drugs,respectively were theray,ACEI,hypentesion,CCB and randomized-trial.The most frequent intermediate words were hypentesion and mortality,etc.The hotest fields were HARVARD UNIV and UNIV MILAN respectively,and the hotest magazine were Hypentesion,Hypentesions Rev respectively.Conclusion CiteSpace visualization techniques can make a scitific conclusion on ACEI and CCB.