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Sample records for ace inhibitor combinations

  1. ACE INHIBITORS: A COMPREHENSIVE REVIEW

    Pradeep Kumar Arora* and Ashish Chauhan

    2013-02-01

    Full Text Available Hypertension is a chronic increase in blood pressure, characterized as primary and secondary hypertension. The disorder is associated with various risk factors like obesity, diabetes, age, lack of exercise etc. Hypertension is being treated since ancient times by Ayurvedic, Chinese and Unani medicine. Now various allopathic drugs are available which include diuretics, calcium channel blockers, α-blockers, β-blockers, vasodilators, central sympatholytics and ACE-inhibitors. Non-pharmacological treatments include weight reduction, dietary sodium reduction, increased potassium intake and reduction in alcohol consumption. ACE-inhibitors are widely used in the treatment of hypertension by inhibiting the angiotensin converting enzyme responsible for the conversion of angiotensin I to angiotensin II (responsible for vasoconstriction. Various structure activity relationship studies led to the synthesis of ACE-inhibitors, some are under clinical development. This comprehensive review gives various guidelines on classification of hypertension, hypertension therapy including ancient, pharmacological, non-pharmacological therapies, pharmacoeconomics, historical perspectives of ACE, renin, renin angiotensin system (circulating vs local RAS, mechanism of ACE inhibitors, and development of ACE inhibitors. Review also emphasizes on the recent advancements on ACE inhibitors including drugs in clinical trials, computational studies on ACE-inhibitors, peptidomimetics, dual, natural, multi-functional ACE inhibitors, and conformational requirements for ACE-inhibitors.

  2. Choice of ACE inhibitor combinations in hypertensive patients with type 2 diabetes: update after recent clinical trials

    Gianpaolo Reboldi

    2009-05-01

    Full Text Available Gianpaolo Reboldi1, Giorgio Gentile1, Fabio Angeli2, Paolo Verdecchia2 1Department of Internal Medicine. University of Perugia, Italy; 2Department of Cardiology, Clinical Research Unit ‘Preventive Cardiology’ Hospital ‘Santa Maria della Misericordia’, Perugia, ItalyAbstract: The diabetes epidemic continues to grow unabated, with a staggering toll in micro- and macrovascular complications, disability, and death. Diabetes causes a two- to four-fold increase in the risk of cardiovascular disease, and represents the first cause of dialysis treatment both in the UK and the US. Concomitant hypertension doubles total mortality and stroke risk, triples the risk of coronary heart disease and significantly hastens the progression of microvascular complications, including diabetic nephropathy. Therefore, blood pressure reduction is of particular importance in preventing cardiovascular and renal outcomes. Successful antihypertensive treatment will often require a combination therapy, either with separate drugs or with fixed-dose combinations. Angiotensin converting enzyme (ACE inhibitor plus diuretic combination therapy improves blood pressure control, counterbalances renin-angiotensin system activation due to diuretic therapy and reduces the risk of electrolyte alterations, obtaining at the same time synergistic antiproteinuric effects. ACE inhibitor plus calcium channel blocker provides a significant additive effect on blood pressure reduction, may have favorable metabolic effects and synergistically reduce proteinuria and the rate of decline in glomerular filtration rate, as evidenced by the GUARD trial. Finally, the recently published ACCOMPLISH trial showed that an ACE inhibitor/calcium channel blocker combination may be particularly useful in reducing cardiovascular outcomes in high-risk patients. The present review will focus on different ACE inhibitor combinations in the treatment of patients with type 2 diabetes mellitus and hypertension

  3. Ace Inhibitors and Angioedema

    Vleeming W; van Amsterdam JGC; de Wildt DJ; Stricker B; TOX

    1995-01-01

    Dit rapport beschrijft de risico's die verbonden zijn aan het gebruik van angiotensine converting enzym (ACE) remmers. Hierbij staat de bijwerking angio-oedeem centraal. De benodigde literatuur is verzameld aan de hand van een zoekaktie middels MEDLINE. ACE-remmers zijn in gebruik ter behand

  4. ACE INHIBITORS: A COMPREHENSIVE REVIEW

    Pradeep Kumar Arora* and Ashish Chauhan

    2013-01-01

    Hypertension is a chronic increase in blood pressure, characterized as primary and secondary hypertension. The disorder is associated with various risk factors like obesity, diabetes, age, lack of exercise etc. Hypertension is being treated since ancient times by Ayurvedic, Chinese and Unani medicine. Now various allopathic drugs are available which include diuretics, calcium channel blockers, α-blockers, β-blockers, vasodilators, central sympatholytics and ACE-inhibitors. Non-pharmacological...

  5. Insertion/deletion polymorphism of the ACE gene and adherence to ACE inhibitors

    Schelleman, H; Klungel, O H; van Duijn, C M; Witteman, J C M; Hofman, A; de Boer, A; Stricker, B H Ch

    2005-01-01

    AIMS: We investigated whether the insertion/deletion (I/D) polymorphism of the ACE gene modified the adherence to ACE inhibitors as measured by the discontinuation of an ACE inhibitor, or addition of another antihypertensive drug. METHODS: This was a cohort study among 239 subjects who started ACE i

  6. Cough Syncope due to ACE Inhibitor

    Filiz Koc

    2015-09-01

    Full Text Available Syncope is defined as a transient loss of consciousness due to sudden temporary decline in cerebral perfusion. Cough syncope is classically seen in middle aged obese men with obstructive pulmonary disease. In patients that use Angiotensin converting enzyme (ACE inhibitors, a dry persistent cough can emerge due to the side effects of this medication. Seventy years old male patient that use ACE inhibitor for hypertension accepted to the clinic with the complaint of syncope. A bout of coughing has developed during electroencephalography recording and 10 seconds in duration of subcortical like epileptiform discharges were viewed. The ACE inhibitor the patient was receiving was replaced with calcium channel blocker and no complaint was observed during the follow up period. [Cukurova Med J 2015; 40(3.000: 619-622

  7. Insertion/deletion polymorphism of the ACE gene and adherence to ACE inhibitors

    H. Schelleman (Hedi); O.H. Klungel (Olaf); C.M. van Duijn (Cock); J.C.M. Witteman (Jacqueline); A. Hofman (Albert); A. de Boer (Anthonius); B.H.Ch. Stricker (Bruno)

    2005-01-01

    textabstractAims: We investigated whether the insertion/deletion (I/D) polymorphism of the ACE gene modified the adherence to ACE inhibitors as measured by the discontinuation of an ACE inhibitor, or addition of another antihypertensive drug. Methods: This was a cohort study among 239 subjects who s

  8. RU28318, an Aldosterone Antagonist, in Combination with an ACE Inhibitor and Angiotensin Receptor Blocker Attenuates Cardiac Dysfunction in Diabetes

    Benter, Ibrahim F.; Babiker, Fawzi; Al-Rashdan, Ibrahim; Yousif, Mariam; Akhtar, Saghir

    2013-01-01

    Aims. We evaluated the effects of RU28318 (RU), a selective mineralocorticoid receptor (MR) antagonist, Captopril (Capt), an angiotensin converting enzyme inhibitor, and Losartan (Los), an angiotensin receptor blocker, alone or in combination with ischemia/reperfusion- (I/R-) induced cardiac dysfunction in hearts obtained from normal and diabetic rats. Methods. Isolated hearts were perfused for 30 min and then subjected to 30 min of global ischemia (I) followed by a period of 30 min of reperfusion (R). Drugs were administered for 30 min either before or after ischemia. Drug regimens tested were RU, Capt, Los, RU + Capt, RU + Los, Capt + Los, and RU + Capt + Los (Triple). Recovery of cardiac hemodynamics was evaluated. Results. Recovery of cardiac function was up to 5-fold worse in hearts obtained from diabetic animals compared to controls. Treatment with RU was generally better in preventing or reversing ischemia-induced cardiac dysfunction in normal hearts compared to treatment with Capt or Los alone. In diabetic hearts, RU was generally similarly effective as Capt or Los treatment. Conclusions. RU treatment locally might be considered as an effective therapy or preventative measure in cardiac I/R injury. Importantly, RU was the most effective at improving −dP/dt (a measure of diastolic function) when administered to diabetic hearts after ischemia. PMID:24066305

  9. RU28318, an Aldosterone Antagonist, in Combination with an ACE Inhibitor and Angiotensin Receptor Blocker Attenuates Cardiac Dysfunction in Diabetes

    Ibrahim F. Benter

    2013-01-01

    Full Text Available Aims. We evaluated the effects of RU28318 (RU, a selective mineralocorticoid receptor (MR antagonist, Captopril (Capt, an angiotensin converting enzyme inhibitor, and Losartan (Los, an angiotensin receptor blocker, alone or in combination with ischemia/reperfusion- (I/R- induced cardiac dysfunction in hearts obtained from normal and diabetic rats. Methods. Isolated hearts were perfused for 30 min and then subjected to 30 min of global ischemia (I followed by a period of 30 min of reperfusion (R. Drugs were administered for 30 min either before or after ischemia. Drug regimens tested were RU, Capt, Los, RU + Capt, RU + Los, Capt + Los, and RU + Capt + Los (Triple. Recovery of cardiac hemodynamics was evaluated. Results. Recovery of cardiac function was up to 5-fold worse in hearts obtained from diabetic animals compared to controls. Treatment with RU was generally better in preventing or reversing ischemia-induced cardiac dysfunction in normal hearts compared to treatment with Capt or Los alone. In diabetic hearts, RU was generally similarly effective as Capt or Los treatment. Conclusions. RU treatment locally might be considered as an effective therapy or preventative measure in cardiac I/R injury. Importantly, RU was the most effective at improving -dP/dt (a measure of diastolic function when administered to diabetic hearts after ischemia.

  10. COMPARATIVE ASSESSMENT OF EFFECT OF COMBINED DRUGS OF ACE INHIBITOR AND DIURETIC (“NOLIPREL FORTE” AND “CAPOZIDE” ON CARDIOVASCULAR REMODELING IN HYPERTENSIVE PATIENTS

    T. D. Kaplanov

    2015-12-01

    Full Text Available Aim. To assess antihypertensive efficacy and effect on cardio-vascular remodeling of combined drugs of ACE inhibitor and diuretic, “Noliprel forte” (NF and “Capozide” (CA, in hypertensive high risk patients.Material and methods. 50 hypertensive (II grade patients (25 men and 25 women, 19-65 years old with high cardio-vascular risk took part in comparative opened randomized study. No one of patients received antihypertensive therapy before study. All patients were randomized for therapy with one of combined drug of ACE inhibitors and diuretic. 25 patients took NF (perindopril 4 mg and indapamide 1,25 mg, and 25 patients -CA (captopril 50 mg and hydrochlorothiazide 25 mg. Duration of observation period was 6 months. Before study, after 3 and 6 months of therapy ambulatory blood pressure monitoring (ABPM, echocardiography, cardiac and vessel Dopplerography, ultrasound scanning of general carotid arteries with detection of intima-media thickness (IMT, pulse wave speed (PWS were held in all patients. Blood bio-chemical analysis was done also.Results. After 3 months 2 patients in NF group and 4 ones in CA group were required to reinforce of ther-apy with additional administration of perindoprile 4 mg and captopril 50 mg respectively. As a result of 6-month of therapy in NF group systolic dlood pressure (BP decreased in 14,0% (р<0,001 and diastolic BP – на 12,9% (р<0,001. CA reduced systolic BP by 17,9% (р<0,0001 and diastolic BP – by 17,5% (р<0,001. 76% and 70% of patients in NF and CA groups, respectively, reached target BP level. Positive dynamic of daily profile of BP was observed according to ABPM data. Cerebral blood flow did not worsen despite of BP decrease. Both drugs decreased in thickness of inter-ventricular septum and left ventricular mass. Besides, NF decreased in thickness of left ventricular posterior wall. Both drugs reduced in IMT and decreased in PWS. NF therapy did not change of blood biochemical parameters. CA

  11. COMPARATIVE ASSESSMENT OF EFFECT OF COMBINED DRUGS OF ACE INHIBITOR AND DIURETIC (“NOLIPREL FORTE” AND “CAPOZIDE” ON CARDIOVASCULAR REMODELING IN HYPERTENSIVE PATIENTS

    T. D. Kaplanov

    2005-01-01

    Full Text Available Aim. To assess antihypertensive efficacy and effect on cardio-vascular remodeling of combined drugs of ACE inhibitor and diuretic, “Noliprel forte” (NF and “Capozide” (CA, in hypertensive high risk patients.Material and methods. 50 hypertensive (II grade patients (25 men and 25 women, 19-65 years old with high cardio-vascular risk took part in comparative opened randomized study. No one of patients received antihypertensive therapy before study. All patients were randomized for therapy with one of combined drug of ACE inhibitors and diuretic. 25 patients took NF (perindopril 4 mg and indapamide 1,25 mg, and 25 patients -CA (captopril 50 mg and hydrochlorothiazide 25 mg. Duration of observation period was 6 months. Before study, after 3 and 6 months of therapy ambulatory blood pressure monitoring (ABPM, echocardiography, cardiac and vessel Dopplerography, ultrasound scanning of general carotid arteries with detection of intima-media thickness (IMT, pulse wave speed (PWS were held in all patients. Blood bio-chemical analysis was done also.Results. After 3 months 2 patients in NF group and 4 ones in CA group were required to reinforce of ther-apy with additional administration of perindoprile 4 mg and captopril 50 mg respectively. As a result of 6-month of therapy in NF group systolic dlood pressure (BP decreased in 14,0% (р<0,001 and diastolic BP – на 12,9% (р<0,001. CA reduced systolic BP by 17,9% (р<0,0001 and diastolic BP – by 17,5% (р<0,001. 76% and 70% of patients in NF and CA groups, respectively, reached target BP level. Positive dynamic of daily profile of BP was observed according to ABPM data. Cerebral blood flow did not worsen despite of BP decrease. Both drugs decreased in thickness of inter-ventricular septum and left ventricular mass. Besides, NF decreased in thickness of left ventricular posterior wall. Both drugs reduced in IMT and decreased in PWS. NF therapy did not change of blood biochemical parameters. CA

  12. Treating High Blood Pressure: Is an ACE Inhibitor Drug Right for You?

    ... High Blood Pressure: Is an ACE Inhibitor Drug Right for You? What are ACE inhibitors? ACE inhibitors, ... talk with your doctor about which drugs are right for you. If your blood pressure is slightly ...

  13. Unraveling the Pivotal Role of Bradykinin in ACE Inhibitor Activity.

    Taddei, Stefano; Bortolotto, L

    2016-10-01

    Historically, the first described effect of an angiotensin converting enzyme (ACE) inhibitor was an increased activity of bradykinin, one of the substrates of ACE. However, in the subsequent years, molecular models describing the mechanism of action of ACE inhibitors in decreasing blood pressure and cardiovascular risk have focused mostly on the renin-angiotensin system. Nonetheless, over the last 20 years, the importance of bradykinin in regulating vasodilation, natriuresis, oxidative stress, fibrinolysis, inflammation, and apoptosis has become clearer. The affinity of ACE appears to be higher for bradykinin than for angiotensin I, thereby suggesting that ACE inhibitors may be more effective inhibitors of bradykinin degradation than of angiotensin II production. Data describing the effect of ACE inhibition on bradykinin signaling support the hypothesis that the most cardioprotective benefits attributed to ACE inhibition may be due to increased bradykinin signaling rather than to decreased angiotensin II signaling, especially when high dosages of ACE inhibitors are considered. In particular, modulation of bradykinin in the endothelium appears to be a major target of ACE inhibition. These new mechanistic concepts may lead to further development of strategies enhancing the bradykinin signaling. PMID:27260014

  14. Bradykinin potentiation by angiotensin-(1-7) and ACE inhibitors correlates with ACE C- and N-domain blockade

    B. Tom (Beril); R. de Vries (René); P.R. Saxena (Pramod Ranjan); A.H.J. Danser (Jan)

    2001-01-01

    textabstractACE inhibitors block B(2) receptor desensitization, thereby potentiating bradykinin beyond blocking its hydrolysis. Angiotensin (Ang)-(1-7) also acts as an ACE inhibitor and, in addition, may stimulate bradykinin release via angiotensin II type 2 receptors.

  15. Angioedema Due to use of ACE-Inhibitor

    Hulya Eyigor

    2014-03-01

    Full Text Available       Angioedema; which may be hereditary or non-hereditary, is defined as a sudden, severe, often in awkward, temporary swelling of skin, subcutaneous and mucous membranes of the face, tongue, lip, larynx, and gastrointestinal areas. Angiotensin Converting Enzyme (ACE inhibitor drugs are widely used in essential hypertension and congestive heart diseases and effective and safe drugs. Angioedema is quite rare due to the use of ACE inhibitors, the rate changes from 0.1 to 0.7% reported in the literature. The pathophysiology of angioedema induced by ACE inhibitors are not completely understood, this situation has been tought to be associated with an increased activity of bradykinin related vasodilatation, increased vascular permeability and interstitial edema. In this study, a case of 65-year-old male patient presented angioedema induced by lisinopril was presented and a very rare side effect of ACE inhibitor drugs was reviewed with the relevant literature.

  16. ACE INHIBITORS ARE RATIONAL PHARMACOTHERAPY OF ENDOTHELIAL DYSFUNCTION

    M. P. Metrova

    2008-01-01

    Full Text Available Aim. To study effects of ACE inhibitor perindopril on markers of endothelial dysfunction in therapy of patients with arterial hypertension (HT.Material and methods. 82 patients with HT, complicated by ischemic stroke were involved in the study. 30 patients with uncomplicated HT were included into control group. Antihypertensive therapy with perindopril (52 patients or amlodipine (30 patients was conducted additionally to standard neurotropic therapy in hypertensive patients with ischemic stroke. Phase-contrast microscopy and enzyme immunoassay were used for screening of endothelial dysfunction markers (blebbing, desquamated endothelial cells, membrane-liberated parts, sPECAM-1.Results. Reduction in levels of markers of endothelial dysfunction was observed among patients treated with perindopril in comparison with patients who did not receive ACE inhibitor or patients of control group. Target levels of blood pressure were reached in 96% of patients treated with perindopril. Сonclusion. ACE inhibitors in therapy patients with HT reduce endothelial dysfunction additionally to antihypertensive effect.

  17. ACE inhibitors and calcium antagonists in the treatment of congestive heart failure

    Hansen, J F

    1995-01-01

    The increased mortality after myocardial infarction is related to the risk of reinfarction, sudden death, and the development and progression of heart failure; in congestive heart failure it is due to the progression of heart failure and sudden death. ACE inhibitors have been proven to prevent...... cardiovascular events, especially the progression of heart failure, in postinfarct patients with reduced ejection fraction and heart failure in the SAVE and AIRE trials. In patients with congestive heart failure, ACE inhibitor treatment has prevented cardiovascular death and reduced morbidity due to progressive...... by prevention of reinfarction and sudden death. Combination treatment with both verapamil, which has pronounced antiischemic properties and prevents sudden death and reinfarction, and an ACE inhibitor, which prevents the progression of heart failure, is a possibility for future cardiovascular therapy...

  18. Life-threatening ACE inhibitor-induced angio-oedema successfully treated with icatibant

    Ostenfeld, Sarah; Bygum, Anette; Rasmussen, Eva Rye

    2015-01-01

    We present a case of a 75-year-old woman treated with an ACE inhibitor, who presented with angio-oedema of the tongue and had difficulty speaking. No symptoms of anaphylaxis or urticaria were present. The patient was treated intravenously with antihistamine and glucocorticoid in combination....... Although the angio-oedema was potentially life threatening, the patient avoided intubation and mechanical ventilation. ACE inhibitor-induced angio-oedema is most likely caused by an accumulation of bradykinin and substance P. Consequently, a bradykinin receptor antagonist is the rational treatment...

  19. Compliance, Persistence, and Switching Patterns for ACE Inhibitors and ARBs

    Vegter, S.; Nguyen, N.H.; Visser, S.T.; de Jong-van den Berg, LTW; Postma, M.J.; Boersma, C.

    2011-01-01

    Objectives: To investigate compliance, persistence, and switching patterns for angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). Study Design: Drug-utilization analysis using a large prescription database. Methods: Prescription data for more than 50,000 inciden

  20. Dosing of ACE inhibitors in left ventricular dysfunction : Does current clinical dosing provide optimal benefit?

    Pinto, YM; van Geel, PP; Alkfaji, H; van Veldhuisen, DJ; van Gilst, WH

    1999-01-01

    In the present review, we discuss the role of clinical dosing of angiotensin converting enzyme (ACE) inhibitors in the treatment of left ventricular dysfunction. Although the precise mechanism of action of ACE inhibitors is still unresolved, the clinical efficacy of ACE inhibitors in the treatment o

  1. Cricothyroidotomy in a angiotensin-converting enzyme (ACE Inhibitor tongue´s angioedema.

    Acle-Cervera L, Morales-Angulo C, García-Zornoza R, Rubio Suárez A

    2013-01-01

    Full Text Available Hereditary angioedema by inhibitors of Angiotensin Converting Enzyme(ACE is a very rare disorder. It usually affects the upper airway mucosa andproduce rapidly evolving acute exacerbations requiring urgent treatment.We repost the case of a patient being treated with ACE inhibitors and anreview of prevalence, pathophysiology and management of angioedemawith ACE inhibitors for treatment and the latest treatments.

  2. [Trials with ACE-inhibitors in acute myocardial infarction].

    Dalla Volta, S

    1994-12-01

    In acute myocardial infarction, the results of the trials with ACE-inhibitors have not been always good, in contrast with what has been observed in chronic heart failure. The comparison of these compounds with the placebo has demonstrated lack of reduction of mortality in the study CONSENSUS II, favorable results on the survival as first endpoint and on the secondary endpoints, as reinfarction, heart failure and stroke in the studies SOLVD, AIRE, GISSI 3, ISIS 4, and uncertain (interim report) results in the Chinese study. Nevertheless, the analysis of the recruitment of the patients with acute infarction and the way these patients have been treated seem to be the most important cause of the conflicting results. ACE-inhibitors have proved no efficacy in acute myocardial infarction without signs of left ventricular failure (CONSENSUS II), have worsened the clinical picture and the mortality in patients in shock or with severe heart failure in the acute phase. On the reverse, in presence of mild to moderate left ventricular dysfunction and failure, the use of ACE-inhibitors has been followed by reduction of mortality in the early (AIRE, GISSI 3, ISIS 4), medium term (GISSI 3) and long-term follow-up (up to 4 years in the AIRE study). In parallel with the reduction of the primary endpoint, also secondary endpoints have been favorably influenced by the different ACE-inhibitors. No differences have been observed among the different class of compounds. ACE-inhibitors seem, therefore, to have a clear indication in acute myocardial infarction with mild or moderate signs and symptoms of heart failure. PMID:7634258

  3. The Synthetic Strategy toward of ACE-Inhibitors

    CHANG; ChingYao

    2001-01-01

    Angiotensin II is an important octapeptide which is responsible for the increase in blood pressure in three major mechanisms. It acts as a hormone to attack the receptor on the blood vessels, which cause strong vasoconstriction. It is also the major stimulus for release another hormone, aldolsterone, which promote the excretion of potassium ion and retention of sodium and waster. Both of the above effects increase the blood pressure. On the other hand, ACE (Angiotensin Converting Enzyme) catalyzes the hydrolysis of bradykinin that is a potent vasodilator. Therefore, the inhibitor of ACE can act as an efficient anti-hypertensive agent through multiple routes.  ……

  4. The Synthetic Strategy toward of ACE-Inhibitors

    2001-01-01

    @@ Angiotensin II is an important octapeptide which is responsible for the increase in blood pressure in three major mechanisms. It acts as a hormone to attack the receptor on the blood vessels, which cause strong vasoconstriction. It is also the major stimulus for release another hormone, aldolsterone, which promote the excretion of potassium ion and retention of sodium and waster. Both of the above effects increase the blood pressure. On the other hand, ACE (Angiotensin Converting Enzyme) catalyzes the hydrolysis of bradykinin that is a potent vasodilator. Therefore, the inhibitor of ACE can act as an efficient anti-hypertensive agent through multiple routes.

  5. ACE INHIBITOR POSSIBILITIES IN CLINICAL PRACTICE: WHAT WE KNOW ABOUT THEM?

    D. V. Nebieridze

    2010-01-01

    Full Text Available New possibilities of ACE inhibitors application on the base of international trails review are presented. Traditional therapy areas of ACE inhibitors (hypertension, heart failure are well known. However recent studies have shown that ACE inhibitors improve prognosis in patients with clinically proved atherosclerosis. This ACE inhibitor ability is a result of their high vasoprotective effect. It provides new clinical possibilities for their use for slowing a progression of diseases associated with atherosclerosis. However this property can not be extended to all ACE inhibitors. Only ramipril and perindopril have a strong evidence base.

  6. Safety of ACE inhibitor therapies in patients with chronic kidney disease

    Sidorenkov, Grigory; Navis, Gerjan

    2014-01-01

    Introduction: ACE inhibitors are first-line therapy in patients with chronic kidney disease (CKD). The main adverse effects of ACE inhibitors are hypotension, renal function impairment and hyperkalemia. Areas covered: This paper reviews evidence from clinical studies regarding adverse effects of ACE

  7. Mortality in patients with hypertension on angiotensin-I converting enzyme (ACE)-inhibitor treatment is influenced by the ACE insertion/deletion polymorphism

    Bleumink, GS; Schut, Anna F.C.; Sturkenboom, MCJM; van Duijn, CM; Deckers, JW; Hofman, A; Kingma, J. Herre; Witteman, JCM; Stricker, BHC

    2005-01-01

    Background The response to angiotensin-l converting enzyme (ACE)-inhibitor therapy is highly variable. Residual ACE activity during treatment, potentially modified by the ACE insertion/deletion (I/D) polymorphism, may explain part of this variability. We studied the possible interaction between ACE-

  8. Characterization of angiotensin converting enzyme (ACE) in the testis and assessment of the in vivo effects of the ACE inhibitor perindopril

    Jackson, B.; Cubela, R.B.; Sakaguchi, K.; Johnston, C.I.

    1988-07-01

    Angiotensin converting enzyme (ACE) was characterized by radioligand studies utilizing the potent ACE inhibitor 351A, a derivative of lisinopril. Ligand binding characteristics were similar for ACE derived from testis, lung, and kidney, despite known differences in structure between ACe from these sources. This observation suggests that the ACE active enzymatic site is similar in different tissues. The effect of the orally active ACE inhibitor perindopril was studied ex vivo in tissues of the rat after oral gavage. Radioligand bound to tissue ACE was reduced after perindopril treatment, in tissue homogenates of lung and kidney, but not testis. Autoradiographs of radioligand binding to tissue sections obtained ex vivo after oral perindopril showed inhibition of ACE in the aorta, lung, and kidney, but did not reveal any inhibition of ACE in the testis. ACE in small vessels of the testis was inhibited as in the aorta, while at the same time testicular ACE was unaffected. ACE in rat testis appears to have a similar enzymatic binding site to ACE from the lung and kidney. Perindopril inhibited ACE in the lung and kidney but did not affect ACE in the testis, suggesting the drug is limited in testicular penetration by the blood-testis barrier. This may explain the lack of any reports of adverse effects of ACE inhibitors on testicular function.

  9. Preparation of ACE Inhibitor Peptides with Combination System of Hydrolysis-Membrane Separation%酶解-膜分离组合制备ACE抑制肽

    曾庆祝; 许庆陵

    2008-01-01

    测试了膜分离操作压力、温度、pH值、料液体积浓度等操作参数对酶活力、血管紧张素转换酶(ACE)抑制肽分离的影响,并建立分段酶解、分级膜分离组合模式实现从扇贝裙边酶解产物中分离ACE抑制肽.结果表明:膜分离操作操作参数对酶活力、ACE抑制肽分离均有较大影响;二段酶解-二级膜分离组合模式制备及分离ACE抑制肽的得率最高,为5.73%,其IC50为0.088mg/ml;一段酶解-二级膜分离组合模式制备及分离ACE抑制肽的得率为3.19%,其IC50为0.081mg/ml;一段酶解-单级膜分离组合模式制备及分离ACE抑制肽的得率只有2.31%,其IC50为0.078mg/ml.

  10. Tailored-therapy of ACE-inhibitors in Coronary Artery Disease: Pharmacogenetic Profiling of Treatment Benefit

    J.J. Brugts (Jasper)

    2010-01-01

    textabstractTo optimally treat patients, and to develop ways to guide ACE-inhibitor treatment, it remains essential to identify those patients most likely to benefit from therapy. New research to elucidate such heterogeneity is necessary. If feasible, guided-therapy of ACE-inhibitors will have a lar

  11. ACE-inhibitor induced angio-oedema treated with complement C1-inhibitor concentrate

    Rasmussen, Eva Rye; Bygum, Anette

    2013-01-01

    ACE-inhibitor is an antihypertensive drug which is increasingly used to treat a wide range of medical conditions. A known adverse reaction is angio-oedema of the head and neck, which can become fatal when the upper airway is involved, causing asphyxia. We present a Caucasian man, who developed...

  12. Angiotensin-I-Converting Enzyme (ACE Inhibitors from Marine Resources: Prospects in the Pharmaceutical Industry

    Isuru Wijesekara

    2010-03-01

    Full Text Available Hypertension or high blood pressure is one of the major independent risk factors for cardiovascular diseases. Angiotensin-I-converting enzyme (EC 3.4.15.1; ACE plays an important physiological role in regulation of blood pressure by converting angiotensin I to angiotensin II, a potent vasoconstrictor. Therefore, the inhibition of ACE activity is a major target in the prevention of hypertension. Recently, the search for natural ACE inhibitors as alternatives to synthetic drugs is of great interest to prevent several side effects and a number of novel compounds such as bioactive peptides, chitooligosaccharide derivatives (COS and phlorotannins have been derived from marine organisms as potential ACE inhibitors. These inhibitory derivatives can be developed as nutraceuticals and pharmaceuticals with potential to prevent hypertension. Hence, the aim of this review is to discuss the marine-derived ACE inhibitors and their future prospects as novel therapeutic drug candidates for treat hypertension.

  13. Does angiotensin (1-7) contribute to the anti-proteinuric effect of ACE-inhibitors

    van der Wouden, Els A; Henning, Robert H; Deelman, Leo E; Roks, Anton J M; Boomsma, Frans; de Zeeuw, Dick

    2005-01-01

    Angiotensin-converting enzyme inhibitors (ACE-I) reduce proteinuria and protect the kidney in proteinuric renal disease. During ACE-I therapy, circulating levels of angiotensin (1-7) [Ang (1-7)] are increased. As cardiac and renal protective effects of Ang (1-7) have been reported, we questioned whe

  14. Synthesis of angiotensin-converting enzyme (ACE inhibitors: an important class of antihypertensive drugs

    Lima Dênis Pires de

    1999-01-01

    Full Text Available This report outlines the discovery, the design and development of new compounds, and, structure-activity relationships for this drug category. Updated approaches to planned syntheses of new worthy ACE-inhibitors are also exploited.

  15. Isolation of an angiotensin converting enzyme (ACE) inhibitor from Olea europea and Olea lancea

    Hansen, K; Adsersen, A.; Brøgger Christensen, S.;

    1996-01-01

    The aqueous extract of the leaves of Olea europea and Olea lancea both inhibited Angiotensin Converting Enzyme (ACE) in vitro. A bioassay-directed fractionation resulted in the isolation of a strong ACE-inhibitor namely the secoiridoid 2-(3,4-dihydroxyphenyl)ethyl 4-formyl-3-(2-oxoethyl)-4E...... have not been described previously in the literature as inhibitors of ACE. Oleacin showed a low toxicity in the brine shrimp (Artemia salina) lethality test (LC50(24 h) = 969 ppm).......-hexenoate (oleacin)(IC50 = 26 myM). Five secoiridoid glucosides (oleuropein, ligstroside, excelsioside, oleoside 11-methyl ester, oleoside) isolated from Oleaceous plants showed no significant ACE-inhibition whereas, after enzymatic hydrolysis, the ACE-inhibition at 0.33 mg/ml was between 64% to 95%. Secoiridoids...

  16. Influence of ACE inhibitors on free radicals and reperfusion injury: pharmacological curiosity or therapeutic hope?

    McMurray, J.; Chopra, M

    1991-01-01

    1. The currently available evidence shows that thiol containing ACE inhibitors are free radical (FR) scavengers in vitro; in particular the OH. radical is effectively scavenged by these compounds. There is also good evidence that, in vivo, ACE inhibitors can preserve myocardial contractile function following a period of reversible ischaemia (by directly protecting myocytes and/or preserving coronary flow through protection of endothelial cells). These in vivo benefits are probably also due to...

  17. Angiotensin Converting Enzyme (ACE) Inhibitor Extends Caenorhabditis elegans Life Span.

    Kumar, Sandeep; Dietrich, Nicholas; Kornfeld, Kerry

    2016-02-01

    Animal aging is characterized by progressive, degenerative changes in many organ systems. Because age-related degeneration is a major contributor to disability and death in humans, treatments that delay age-related degeneration are desirable. However, no drugs that delay normal human aging are currently available. To identify drugs that delay age-related degeneration, we used the powerful Caenorhabditis elegans model system to screen for FDA-approved drugs that can extend the adult lifespan of worms. Here we show that captopril extended mean lifespan. Captopril is an angiotensin-converting enzyme (ACE) inhibitor used to treat high blood pressure in humans. To explore the mechanism of captopril, we analyzed the acn-1 gene that encodes the C. elegans homolog of ACE. Reducing the activity of acn-1 extended the mean life span. Furthermore, reducing the activity of acn-1 delayed age-related degenerative changes and increased stress resistance, indicating that acn-1 influences aging. Captopril could not further extend the lifespan of animals with reduced acn-1, suggesting they function in the same pathway; we propose that captopril inhibits acn-1 to extend lifespan. To define the relationship with previously characterized longevity pathways, we analyzed mutant animals. The lifespan extension caused by reducing the activity of acn-1 was additive with caloric restriction and mitochondrial insufficiency, and did not require sir-2.1, hsf-1 or rict-1, suggesting that acn-1 functions by a distinct mechanism. The interactions with the insulin/IGF-1 pathway were complex, since the lifespan extensions caused by captopril and reducing acn-1 activity were additive with daf-2 and age-1 but required daf-16. Captopril treatment and reducing acn-1 activity caused similar effects in a wide range of genetic backgrounds, consistent with the model that they act by the same mechanism. These results identify a new drug and a new gene that can extend the lifespan of worms and suggest new

  18. Angiotensin Converting Enzyme (ACE Inhibitor Extends Caenorhabditis elegans Life Span.

    Sandeep Kumar

    2016-02-01

    Full Text Available Animal aging is characterized by progressive, degenerative changes in many organ systems. Because age-related degeneration is a major contributor to disability and death in humans, treatments that delay age-related degeneration are desirable. However, no drugs that delay normal human aging are currently available. To identify drugs that delay age-related degeneration, we used the powerful Caenorhabditis elegans model system to screen for FDA-approved drugs that can extend the adult lifespan of worms. Here we show that captopril extended mean lifespan. Captopril is an angiotensin-converting enzyme (ACE inhibitor used to treat high blood pressure in humans. To explore the mechanism of captopril, we analyzed the acn-1 gene that encodes the C. elegans homolog of ACE. Reducing the activity of acn-1 extended the mean life span. Furthermore, reducing the activity of acn-1 delayed age-related degenerative changes and increased stress resistance, indicating that acn-1 influences aging. Captopril could not further extend the lifespan of animals with reduced acn-1, suggesting they function in the same pathway; we propose that captopril inhibits acn-1 to extend lifespan. To define the relationship with previously characterized longevity pathways, we analyzed mutant animals. The lifespan extension caused by reducing the activity of acn-1 was additive with caloric restriction and mitochondrial insufficiency, and did not require sir-2.1, hsf-1 or rict-1, suggesting that acn-1 functions by a distinct mechanism. The interactions with the insulin/IGF-1 pathway were complex, since the lifespan extensions caused by captopril and reducing acn-1 activity were additive with daf-2 and age-1 but required daf-16. Captopril treatment and reducing acn-1 activity caused similar effects in a wide range of genetic backgrounds, consistent with the model that they act by the same mechanism. These results identify a new drug and a new gene that can extend the lifespan of worms

  19. Angiotensin converting enzyme (ACE) inhibitors and renal function. A review of the current status

    Kamper, A L

    1991-01-01

    Angiotensin converting enzyme (ACE) inhibitors are well established in the treatment of hypertension and cardiac failure. Experimental studies in rats have suggested that these agents may protect renal function in chronic nephropathy by a mechanism other than simply lowering the systemic blood...... pressure. In human studies of incipient diabetic nephropathy, worsening of microalbuminuria was prevented during 3 years of ACE inhibition. ACE inhibitors reduce arterial blood pressure in chronic nephropathy, and may cause a fall in glomerular filtration rate. In diabetic nephropathy, proteinuria...... was reduced by 2 months' treatment with enalapril to less than half of the values obtained in a control group treated with metoprolol. Nonrandomised trials have suggested that ACE inhibitors may slow the deterioration of renal function, but no comparisons with other antihypertensive agents in prospective...

  20. Isolated oedema of the uvula induced by intense snoring and ACE inhibitor

    Rasmussen, Eva Rye; Mey, Kristianna; Bygum, Anette

    2014-01-01

    A case of snoring-induced angioedema of uvula is described in a patient who was treated with ACE inhibitor. The patient partially responded to complement C1-inhibitor concentrate and did not suffer any recurrences after the medication was withdrawn. When encountering a patient suffering from...

  1. Signatures of Interchange Reconnection: STEREO, ACE and Hinode Observations Combined

    Baker, D; Van Driel-Gesztelyi, L; Demoulin, P; Harra, L K; Lavraud, B; Davies, J A; Optiz, A; Luhmann, J G; Sauvaud, J A; Galvin, A B

    2009-01-01

    Combining STEREO, ACE and Hinode observations has presented an opportunity to follow a filament eruption and coronal mass ejection (CME) on the 17th of October 2007 from an active region (AR) inside a coronal hole (CH) into the heliosphere. This particular combination of `open' and closed magnetic topologies provides an ideal scenario for interchange reconnection to take place. With Hinode and STEREO data we were able to identify the emergence time and type of structure seen in the in-situ data four days later. On the 21st, ACE observed in-situ the passage of an ICME with `open' magnetic topology. The magnetic field configuration of the source, a mature AR located inside an equatorial CH, has important implications for the solar and interplanetary signatures of the eruption. We interpret the formation of an `anemone' structure of the erupting AR and the passage in-situ of the ICME being disconnected at one leg, as manifested by uni-directional suprathermal electron flux in the ICME, to be a direct result of i...

  2. Signatures of interchange reconnection: STEREO, ACE and Hinode observations combined

    D. Baker

    2009-10-01

    Full Text Available Combining STEREO, ACE and Hinode observations has presented an opportunity to follow a filament eruption and coronal mass ejection (CME on 17 October 2007 from an active region (AR inside a coronal hole (CH into the heliosphere. This particular combination of "open" and closed magnetic topologies provides an ideal scenario for interchange reconnection to take place. With Hinode and STEREO data we were able to identify the emergence time and type of structure seen in the in-situ data four days later. On the 21st, ACE observed in-situ the passage of an ICME with "open" magnetic topology. The magnetic field configuration of the source, a mature AR located inside an equatorial CH, has important implications for the solar and interplanetary signatures of the eruption. We interpret the formation of an "anemone" structure of the erupting AR and the passage in-situ of the ICME being disconnected at one leg, as manifested by uni-directional suprathermal electron flux in the ICME, to be a direct result of interchange reconnection between closed loops of the CME originating from the AR and "open" field lines of the surrounding CH.

  3. Pretreatment with ACE inhibitors improves acute outcome of electrical cardioversion in patients with persistent atrial fibrillation

    Van Veldhuisen Dirk J

    2005-01-01

    Full Text Available Abstract Background Persistent atrial fibrillation (AF is difficult to treat. In the absence of class I or III antiarrhythmic drugs sinus rhythm is maintained in only 30% of patients during the first year after electrical cardioversion (ECV. One of the remodeling processes induced by AF is fibrosis, which relates to inducibility and maintenance of AF. The renin-angiotensin system may play a important role in this. The aim of this study was to investigate the role of angiotensin-converting enzyme (ACE inhibitor use on efficacy of ECV, and occurrence of subacute recurrences. Methods One hundred-seven consecutive patients with persistent AF underwent ECV. In twenty-eight (26% patients ACE inhibitors had been started before initiation of the present episode of AF ('pre-treated' patients. Results ECV was successful in 96% of patients who were on ACE inhibitors before start of the present episode of AF compared to 80% of the patients not pre-treated (p = 0.04. After 1 month of follow-up 49% of the pre-treated patients and 50% of those not pre-treated with ACE inhibition were still in sinus rhythm (p=ns. Multivariate analysis showed that pre-treatment with ACE inhibitors and a smaller left atrial size were independent predictors of successful ECV (OR = 5.8, C.I. 1.3–26.1, and OR = 5.6, C.I. 1.2–25.3, respectively. Conclusions Pre-treatment with ACE inhibitors may improve acute success of ECV but does not prevend AF recurrences.

  4. Does the Angiotensin-converting enzyme (ACE gene insertion/deletion polymorphism modify the response to ACE inhibitor therapy? – A systematic review

    Perna Annalisa

    2005-10-01

    Full Text Available Abstract Background Pharmacogenetic testing to individualize ACE inhibitor therapy remains controversial. We conducted a systematic review to assess the effect modification of the insertion/deletion (I/D polymorphism of the ACE gene on any outcome in patients treated with ACE inhibitors for cardiovascular and/or renal disease. Methods Our systematic review involved searching six electronic databases, then contacting the investigators (and pharmaceutical industry representatives responsible for the creation of these databases. Two reviewers independently selected relevant randomized, placebo-controlled trials and abstracted from each study details on characteristics and quality. Results Eleven studies met our inclusion criteria. Despite repeated efforts to contact authors, only four of the eleven studies provided sufficient data to quantify the effect modification by genotypes. We observed a trend towards better response to ACE inhibitors in Caucasian DD carriers compared to II carriers, in terms of blood pressure, proteinuria, glomerular filtration rate, ACE activity and progression to end-stage renal failure. Pooling of the results was inappropriate, due to heterogeneity in ethnicity, clinical domains and outcomes. Conclusion Lack of sufficient genetic data from the reviewed studies precluded drawing any convincing conclusions. Better reporting of genetic data are needed to confirm our preliminary observations concerning better response to ACE inhibitors among Caucasian DD carriers as compared to II carriers.

  5. Pharmacogenetics of ACE inhibitor-induced angioedema and cough : a systematic review and meta-analysis

    Mahmoudpour, Seyed Hamidreza; Leusink, Maarten; van der Putten, Lisa; Terreehorst, Ingrid; Asselbergs, Folkert W.; de Boer, Anthonius; Maitland-van der Zee, Anke H.

    2013-01-01

    Aim: Angioedema and cough are the two most important adverse effects of ACE inhibitors (ACEIs). Evidence exists that ACEI-related angioedema/cough is partly genetically determined and several genes have been identified to play a role in the development of ACEI-related adverse effects. Materials & me

  6. ACE inhibitor use in patients with myocardial infarction. Summary ofevidence from clinical trials

    R. Latini; A.P. Maggioni; M. Flather (Marcus); P. Sleight (Peter); G. Tognoni; M.L. Simoons (Maarten)

    1995-01-01

    textabstractExperimental evidence for the beneficial effects on heart failure of chronic treatment with ACE inhibitors accumulated from early 1980 in experimental models of LV dysfunction secondary to AMI. These studies demonstrated an improvement in hemodynamics, LV remodeling, and mortality with A

  7. Ace inhibitors and cardiovascular regulation : the importance of autocrine and paracrine mechanisms

    Wijngaarden, Jan van

    1992-01-01

    As demonstrated in a large number of clinical studies, angiotensin converting enzyme (ACE) inhibitors are of great value for the treatment of cardiovascular disorders. Although the clinical merits of these drugs are now well recognized, their mechanism of action is not yet completely understood. The

  8. Cardiovascular risk reduction by reversing endothelial dysfunction: ARBs, ACE inhibitors,  or both? Expectations from The ONTARGET  Trial Programme

    Luis Miguel  Ruilope

    2007-03-01

    Full Text Available Luis Miguel  Ruilope1, Josep Redón2, Roland Schmieder31Servicio de Nefrologia, Unidad de Hipertension Hospital, 12 de Octubre, Madrid, Spain; 2Department of Internal Medicine, Hospital Clinico University of Valencia, Valencia, Spain; 3Department of Nephrology and Hypertension, Friedrich-Alexander-Universitat, Erlangen-Nurnberg, GermanyAbstract: Endothelial dysfunction is the initial pathophysiological step in a progression of vascular damage that leads to overt cardiovascular and chronic kidney disease. Angiotensin II, the primary agent of the renin–angiotensin system (RAS, has a central role in endothelial dysfunction. Therefore, RAS blockade with an angiotensin receptor blocker (ARB and/or angiotensin-converting enzyme (ACE inhibitor provides a rational approach to reverse endothelial dysfunction, reduce microalbuminuria, and, thus, improves cardiovascular and renal prognosis. ARBs and ACE inhibitors act at different points in the RAS pathway and recent evidence suggests that there are differences regarding their effects on endothelial dysfunction. In addition to blood pressure lowering, studies have shown that ARBs reduce target-organ damage, including improvements in endothelial dysfunction, arterial stiffness, the progression of renal dysfunction in patients with type 2 diabetes, proteinuria, and left ventricular hypertrophy. The ONgoing Telmisartan Alone in combination with Ramipril Global Endpoint Trial (ONTARGET Programme is expected to provide the ultimate evidence of whether improved endothelial func tion translates into reduced cardiovascular and renal events in high-risk patients, and to assess possible differential outcomes with telmisartan, the ACE inhibitor ramipril, or a combination of both (dual RAS blockade. Completion of ONTARGET is expected in 2008. Keywords: angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, endothelial dysfunction, ONTARGET, renin–angiotensin system, telmisartan

  9. Discovery of new angiotensin converting enzyme (ACE) inhibitors from medicinal plants to treat hypertension using an in vitro assay

    Sharifi, Niusha; Souri, Effat; Ziai, Seyed Ali; Amin, Gholamreza; Amanlou, Massoud

    2013-01-01

    Background and purpose of the study Angiotensin converting enzyme (ACE) inhibitors plays a critical role in treating hypertension. The purpose of the present investigation was to evaluate ACE inhibition activity of 50 Iranian medicinal plants using an in vitro assay. Methods The ACE activity was evaluated by determining the hydrolysis rate of substrate, hippuryl-L-histidyl-L-leucine (HHL), using reverse phase high performance liquid chromatography (RP-HPLC). Total phenolic content and antioxi...

  10. Use of ACE Inhibitors and Angiotensin Receptor Blockers and Primary Breast Cancer Outcomes

    Chae, Young Kwang; Brown, Erika N.; Lei, Xiudong; Melhem-Bertrandt, Amal; Giordano, Sharon H.; Litton, Jennifer K.; Hortobagyi, Gabriel N; Gonzalez-Angulo, Ana M.; Chavez-MacGregor, Mariana

    2013-01-01

    BACKGROUND: ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may have anti-tumor properties. We investigated whether the use of ACEI/ARBs affects the clinical outcomes of primary breast cancer patients receiving taxane and anthracycline-based neoadjuvant chemotherapy. METHODS: We included 1449 patients with diagnosis of invasive primary breast cancer diagnosed at the MD Anderson Cancer Center between 1995 and 2007 who underwent neoadjuvant chemotherapy. Of them, 160 (11%) patie...

  11. Investigation of interaction studies of cefpirome with ACE-inhibitors in various buffers

    Nawaz, Muhammad; Arayne, Muhammad Saeed; Sultana, Najma; Abbas, Hira Fatima

    2015-02-01

    This work describes a RP-HPLC method for the determination and interaction studies of cefpirome with ACE-inhibitors (captopril, enalapril and lisinopril) in various buffers. The separation and interaction of cefpirome with ACE-inhibitors was achieved on a Purospher Star, C18 (5 μm, 250 × 4.6 mm) column. Mobile phase consisted of methanol: water (80:20, v/v, pH 3.3); however, for the separation of lisinopril, it was modified to methanol-water (40:60, v/v, pH 3.3) and pumped at a flow rate of 1 mL min-1. In all cases, UV detection was performed at 225 nm. Interactions were carried out in physiological pH i.e., pH 1 (simulated gastric juice), 4 (simulated full stomach), 7.4 (blood pH) and 9 (simulated GI), drug contents were analyzed by reverse phase high performance liquid chromatography. Method was found linear in the concentration range of 1.0-50.0 μg mL-1 with correlation coefficient (r2) of 0.999. Precision (RSD%) was less than 2.0%, indicating good precision of the method and accuracy was 98.0-100.0%. Furthermore, cefpirome-ACE-inhibitors' complexes were also synthesized and results were elucidated on the basis of FT-IR, and 1H NMR. The interaction results show that these interactions are pH dependent and for the co-administration of cefpirome and ACE-inhibitors, a proper interval should be given.

  12. Evaluation of ACE inhibitors lipophilicity using in silico and chromatographically obtained hydrophobicity parameters

    Odović Jadranka V.

    2013-01-01

    Full Text Available The aim of this study was to compare different calculation methods to determine lipophilicity, expressed as logP value, of seven ACE inhibitors (enalapril, quinapril, fosinopril, lisinopril, cilazapril, ramipril, and benazapril with significantly different structure. Experimentally determined n-octanol/water partition coefficients, logPO/W values, were obtained from relevant literature. The correlations between all collected logP values were studied and the best agreements between calculated logP and experimentally determined logPO/W values, were observed for KOWWINlogP or MilogP values (r = 0.999 or r = 0.974, respectively. The correlations between all collected logP values and chromatographically (reversed-phase thin-layer chromatography obtained hydrophobicity parameters, RM0 and C0, were established. The good correlations (r > 0.90 were obtained in the majority of relationships. The KOWWINlogP was established as the most suitable hydrophobicity parameter of investigated group of ACE inhibitors with r = 0.981 for correlation with RM0 and r = 0.977 for correlation with C0 parameters (water-methanol mobile phase. Using multiple linear regressions, it was established that application of two selected logP, calculated by different mathematical approaches, led to very good correlation due to the benefits of both calculation methods. The good relationships indicate that the computed logP, with careful selection of method calculation, can be useful in ACE inhibitors lipophilicity evaluation, as high-throughput screening technique.

  13. Binding of ACE-inhibitors to in vitro and patient-derived amyloid-β fibril models

    Bhavaraju, Manikanthan; Phillips, Malachi; Bowman, Deborah; Aceves-Hernandez, Juan M.; Hansmann, Ulrich H. E.

    2016-01-01

    Currently, no drugs exist that can prevent or reverse Alzheimer's disease, a neurodegenerative disease associated with the presence, in the brain, of plaques that are composed of β-amyloid (Aβ) peptides. Recent studies suggest that angiotensin-converting enzyme (ACE) inhibitors, a set of drugs used to treat hypertension, may inhibit amyloid formation in vitro. In the present study, we investigate through computer simulations the binding of ACE inhibitors to patient-derived Aβ fibrils and contrast it with that of ACE inhibitors binding to in vitro generated fibrils. The binding affinities of the ACE inhibitors are compared with that of Congo red, a dye that is used to identify amyloid structures and that is known to be a weak inhibitor of Aβ aggregation. We find that ACE inhibitors have a lower binding affinity to the patient-derived fibrils than to in vitro generated ones. For patient-derived fibrils, their binding affinities are even lower than that of Congo red. Our observations raise doubts on the hypothesis that these drugs inhibit fibril formation in Alzheimer patients by interacting directly with the amyloids.

  14. ACE-inhibitorer er fortsat førstevalg ved behandling af hjertesvigt--en gennemgang af et Cochranereview

    Gadsbøll, Niels; Torp-Pedersen, Christian Tobias

    2013-01-01

    A new Cochrane metaanalysis has reviewed the literature on the use of angiotensin receptor blockers (ARB) in patients with heart failure and left ventricular systolic dysfunction. The conclusion supports the present recommendation from the European Society of Cardiology that angiotensin convertin...... enzyme inhibitors (ACE-I) are first choice and that ARBs should be reserved to patients who are intolerant to ACE-Is. Neither ACE-Is nor ARBs are effective in the treatment of heart failure patients with normal left ventricular function....

  15. The binding of metal ions and angiotensin converting enzyme (ACE) inhibitor by 13C NMR

    Sakamoto, Yohko; Sakamoto, Yuko; Ishii, Tomoko; Ohmoto, Taichi

    1991-06-01

    Enalaprilat (MK-422, 1- [ N- [1 (S)-carboxy-3-phenylpropyl]- L-alanyl]- L-proline (1)) and Lisinopril (MK521, N- N- [ (s)-l-carboxy-3- phenylpropyl]- L-lysyl- L-proline, (2)) exhibit the capacity to act as a chelate, unidentate or bridge towards metal ions in aqueous solution, as determined by 13C NMR. By adding metal ions, in the series of Zn 2+, Ni 2+, Pb 2+, Pd 2+ and Cd 2+, the active site of the ACE inhibitor was well defined. MK-521 was more influenced by nuclei that were distant from the active site than MK-422.

  16. ACE inhibitors can induce circulating antibodies directed to antigens of the superficial epidermal cells.

    Cozzani, Emanuele; Rosa, Gian Marco; Drosera, Massimo; Intra, Chiara; Barsotti, Antonio; Parodi, Aurora

    2011-07-01

    Drug-induced pemphigus has been reported in patients receiving angiotensin-converting enzyme inhibitors. The aim of this work was to study a group of hypertensive patients without skin diseases treated with angiotensin-converting enzyme (ACE) Inhibitors (I), to verify the presence of serum circulating anti-antibodies. The indirect immunofluorescence showed that 33 sera (52.38%) presented autoantibodies directed to an antigen of the cytoplasm of the superficial epidermal keratinocytes. Two of the 33 positive sera had antibodies to Dsg1 and/or 3 in ELISA. Immunoblot analyses were negative. All the 48 control sera were found to have no circulating antibodies using the three assays. Our results would confirm that ACEI drugs may trigger the production of circulating autoantibodies also in patients without clinical manifestations of pemphigus. PMID:20563876

  17. High prevalence of risk factors in coronary artery disease in EUROPA gives HOPE for ACE inhibitors after PEACE

    Pedersen, S.A.; Galatius, S.; Olsen, M.H.;

    2008-01-01

    Background: Routine use of ACE inhibitors (ACE-I) as secondary preventive therapy for all patients with coronary artery disease (CAD) is challenged by the PEACE trial. Currently it is unclear to what extent ACE-I should be used in CAD populations. Purpose: To analyze the prevalence of left...... ventricular systolic dysfunction, diabetes, myocardial infarction and hypertension in an unselected and consecutive population of patients with documented CAD and evaluate the potential need for ACE-I treatment in a real-life scenario. Methods: We searched a database containing all invasive cardiac...... investigations in three hospitals in Copenhagen from July 1, 2000 to June 30, 2003. Patients with no angiographic sign of CAD were excluded. Results: Among 7,345 patients, 4,180 had stable CAD and 3,165 had acute coronary syndrome (ACS). Among the stable CAD patients 78% had at least one of the following...

  18. Occurrence and fate of ACE-inhibitor peptides in cheeses and in their digestates following in vitro static gastrointestinal digestion.

    Stuknytė, Milda; Cattaneo, Stefano; Masotti, Fabio; De Noni, Ivano

    2015-02-01

    The occurrence of the casein-derived angiotensin converting enzyme-inhibitor (ACE-I) peptides VPP, IPP, RYLGY, RYLG, AYFYPEL, AYFYPE, LHLPLP and HLPLP were investigated in 12 different cheese samples by Ultra Performance Liquid Chromatography/High-Resolution Mass Spectrometry. The total amount of ACE-I peptides was in the range 0.87-331mgkg(-1). VPP and IPP largely prevailed in almost all cheeses. Following in vitro static gastrointestinal digestion of Cheddar, Gorgonzola, Maasdam and Grana Padano cheeses, type and amount of ACE-I peptides changed, and only VPP, IPP, HLPLP and LHLPLP were detected in the intestinal digestates. The results evidenced that the degree of proteolysis itself cannot be regarded as a promoting or hindering factor for ACE-I peptide release during cheese digestion. Moreover, the data indicated that the ACE-I potential of cheeses cannot be inferred based on the type and amount of ACE-I peptides present in undigested samples. PMID:25172679

  19. Life-threatening angio-oedema after the first dose of an ACE inhibitor-not an anaphylactic reaction

    Krogh Nielsen, Troels; Bygum, Anette; Rye Rasmussen, Eva

    2016-01-01

    We present a case of a 60-year-old Caucasian woman, with no prior history of swellings, who was admitted to a hospital due to life-threatening angio-oedema. She had, the previous day, been prescribed an ACE inhibitor for her essential hypertension. She had taken one tablet at night-time, and awoke...

  20. ACE and platelet aggregation inhibitors from Tamarix hohenackeri Bunge (host plant of Herba Cistanches) growing in Xinjiang

    Xing, Yachao; Liao, Jing; Tang, Yingzhan; Peng ZHANG; Tan, Chengyu; Ni, Hui; Wu, Xueqin; Li, Ning; Jia, Xiaoguang

    2014-01-01

    Background: Tamarix hohenackeri Bunge is a salt cedar that grows widespread in the desert mountains in Xinjiang. T. hohenackeri has not been investigated earlier, although there are many reports of phytochemical work on other Tamarix species. Materials and Methods: To find out natural angiotensin-converting enzyme (ACE) inhibitor and platelet aggregation inhibitors, the bioactive extract (ethyl acetate [EtOAc] fraction) from the dried aerial parts of T. hohenackeri were investigated. The acti...

  1. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group

    Flather, M D; Yusuf, S; Køber, L;

    2000-01-01

    BACKGROUND: We undertook a prospective systematic overview based on data from individual patients from five long-term randomised trials that assessed inhibitors of angiotensin-converting enzyme (ACE) in patients with left-ventricular dysfunction or heart failure. METHODS: Three of the trials...... was lower with ACE inhibitors than with placebo (702/2995 [23.4%] vs 866/2971 [29.1%]; odds ratio 0.74 [95% CI 0.66-0-83]), as were the rates of readmission for heart failure (355 [11.9%] vs 460 [15.5%]; 0.73 [0.63-0.85]), reinfarction (324 [10.8%] vs 391 [13.2%]; 0.80 [0.69-0.94]), or the composite...

  2. The effect of treatment with low dose ACE inhibitor and/or diuretic on coronary microvasculature in stroke-prone spontaneously hypertensive rats.

    Rakusan, K; Cicutti, N; Maurin, A; Guez, D; Schiavi, P

    2000-03-01

    Angiotensin II is considered to have angiogenic properties. Nevertheless, several authors reported an increase in coronary capillary density after treatment with ACE inhibitors. The aim of the present study was to evaluate the effect of treatment with low doses of ACE inhibitor perindopril, low doses of the diuretic indapamide, or a combination of the two on microvascular structure in hearts from stroke-prone spontaneously hypertensive rats (SHR-sp). Young adult male SHR treated with indapamide (0.24 mg/kg/day), perindopril (0.76 mg/kg/day), or both were compared with untreated animals after 8 or 14 weeks of treatment. Survival of SHR-sp was significantly increased after treatment. Only perindopril alone or in combination with indapamide significantly decreased blood pressure and cardiac mass. Treatment also significantly increased capillary and myocyte densities but arteriolar density tended to decrease. External and internal diameters significantly increased in treated animals while arteriolar thickness remained the same. Thus, thickness in vessels of the same size was the greatest in untreated animals, followed by indapamide- and perindopril-treated rats with the thinnest walls in rats with combined treatment, and the treatment resulted in a significant increase in the lumen to wall ratio. Capillary and arteriolar growth responses in treated animals seem to indicate that the two are independently regulated processes. Treatment with indapamide alone at this dosage did not significantly influence most responses but in combination with perindopril it strengthened the effect of perindopril. PMID:10684730

  3. Secoisolariciresinol Diglucoside (SDG) Isolated from Flaxseed, an Alternative to ACE Inhibitors in the Treatment of Hypertension

    Prasad, Kailash

    2013-01-01

    Secoisolariciresionol diglucoside (SDG) is a plant lignan isolated from flaxseed and is phytoestrogen. SDG is a potent and long-acting hypotensive agent. Plant phytoestrogens have inhibitory effects on angiotensin-converting enzyme (ACE). The hypotensive effects of SDG, a phytoestrogen, may be mediated through inhibition of ACE. The objective of this study was to investigate if SDG-induced hypotension is mediated through inhibition of ACE. The Sprague Dawley male rats were anesthetized and tr...

  4. The effects of drug market regulation on pharmaceutical prices in Europe: overview and evidence from the market of ACE inhibitors

    von der Schulenburg, Fritz; Vandoros, Sotiris; Kanavos, Panos

    2011-01-01

    This study provides an overview of policy measures targeting pharmaceutical expenditure in Europe and analyses their impact on originator pharmaceutical prices. Panel data methods are used to examine the market of ACE Inhibitors in six European countries (Denmark, France, Germany, Netherlands, Sweden, United Kingdom) over period 1991-2006. We find that although some measures are effective in reducing originator prices, others appear to have an insignificant effect. Results suggest that supply...

  5. Preclinical development and characterization of an intravenous dosage form for the ACE inhibitor RS-10029.

    Visor, G C; Lin, L H; Henry, P; Singer, L

    1989-01-01

    Preclinical development of an intravenous dosage form for the ACE inhibitor RS-10029 involved the formulation and characterization of the drug's chemical/physical stability in two prototype formulations (injectable solution and lyophilized powder). Included in these studies were quantitative evaluations of various processing and administration parameters (membrane qualification, terminal sterilization, compatibility/delivery of the drug with typical infusion fluids and administration sets) on finished product integrity and quality. Analytical methodology used in these studies consisted primarily of a stability specific HPLC assay and a light obscuration based sensor (HIAC) for particulate matter analysis. Results of these studies indicate that the drug is relatively stable at ambient temperature and under accelerated storage conditions (predicted T90 at 25 degrees C greater than 2 yr, and T90 at 50 degrees C greater than 2 mo). However, the ability of the product to withstand a full terminal sterilization cycle is limited, and therefore other approaches toward sterile processing were examined. With regard to the stability and compatibility of the drug in a variety of fluids and devices there appears to be no overt limitations in its use for either bolus or infusion delivery. PMID:2600732

  6. ADMET, Docking studies & binding energy calculations of some Novel ACE - inhibitors for the treatment of Diabetic Nephropathy

    Gade Deepak Reddy

    2012-09-01

    Full Text Available Diabetic Nephropathy (DN is one of the major complications of diabetes mellitus, representing the leading of cause of chronic renal disease and a major cause of morbidity and mortality in both type 1 and type 2 diabetic patients. The Renin-Angiotensin-Aldosterone System (RAAS has been implicated in the pathophysiology of DN, and suggests a therapeutic target for blocking this system. Therefore, inhibition of RAAS plays a crucial role in the treatment of DN and therapeutic intervention mostly involves administration of angiotensin converting enzyme (ACE inhibitors and angiotensin AT1 receptor blockers. In this current study, we have used computational methods to design 37 novel ACE-inhibitors and evaluated them for the interaction with the enzyme ACE through insilico analysis. The obtained results were compared with the standard drug enalapril to find out the potential inhibitors. Here we report that ligand 4 exhibited strongest inhibitory activity among all. All the analogs are also screened for their ADME & Toxicity profiles using insilico tools and ligand 9 is having better binding affinity next to ligand 4, and also having better ADMET profile when compared to that of ligand 4. Post docking calculations were also performed for the docked complexes in order to identify the individual ligand binding energies by employing Multi-Ligand Bimolecular Association with Energetics (Embrace

  7. Search for potential angiotensin converting enzyme (ACE)-inhibitors from plants.

    Lacaille-Dubois; Franck, U; Wagner, H

    2001-01-01

    MeOH extracts, fractions and pure substances from Musanga cecropioides, Cecropia species and Crataegus oxyacantha /C. monogyna were screened by using an in vitro bio-assay based on the inhibition of Angiotensin Converting Enzyme (ACE), as measured from the enzymatic cleavage of the chromophore-fluorophore-labelled substrate dansyltriglycine into dansylglycine and diglycine. Phenolic acids showed no significant ACE-inhibition whereas flavonoids and proanthocyanidins demonstrated inhibitory activity at 0.33 mg/ml using this test system. PMID:11292239

  8. Effects of Small Molecule Calcium-Activated Chloride Channel Inhibitors on Structure and Function of Accessory Cholera Enterotoxin (Ace of Vibrio cholerae.

    Tanaya Chatterjee

    Full Text Available Cholera pathogenesis occurs due to synergistic pro-secretory effects of several toxins, such as cholera toxin (CTX and Accessory cholera enterotoxin (Ace secreted by Vibrio cholerae strains. Ace activates chloride channels stimulating chloride/bicarbonate transport that augments fluid secretion resulting in diarrhea. These channels have been targeted for drug development. However, lesser attention has been paid to the interaction of chloride channel modulators with bacterial toxins. Here we report the modulation of the structure/function of recombinant Ace by small molecule calcium-activated chloride channel (CaCC inhibitors, namely CaCCinh-A01, digallic acid (DGA and tannic acid. Biophysical studies indicate that the unfolding (induced by urea free energy increases upon binding CaCCinh-A01 and DGA, compared to native Ace, whereas binding of tannic acid destabilizes the protein. Far-UV CD experiments revealed that the α-helical content of Ace-CaCCinh-A01 and Ace-DGA complexes increased relative to Ace. In contrast, binding to tannic acid had the opposite effect, indicating the loss of protein secondary structure. The modulation of Ace structure induced by CaCC inhibitors was also analyzed using docking and molecular dynamics (MD simulation. Functional studies, performed using mouse ileal loops and Ussing chamber experiments, corroborate biophysical data, all pointing to the fact that tannic acid destabilizes Ace, inhibiting its function, whereas DGA stabilizes the toxin with enhanced fluid accumulation in mouse ileal loop. The efficacy of tannic acid in mouse model suggests that the targeted modulation of Ace structure may be of therapeutic benefit for gastrointestinal disorders.

  9. Effects of Small Molecule Calcium-Activated Chloride Channel Inhibitors on Structure and Function of Accessory Cholera Enterotoxin (Ace) of Vibrio cholerae

    Chatterjee, Tanaya; Sheikh, Irshad Ali; Chakravarty, Devlina; Chakrabarti, Pinak; Sarkar, Paramita; Saha, Tultul; Chakrabarti, Manoj K.; Hoque, Kazi Mirajul

    2015-01-01

    Cholera pathogenesis occurs due to synergistic pro-secretory effects of several toxins, such as cholera toxin (CTX) and Accessory cholera enterotoxin (Ace) secreted by Vibrio cholerae strains. Ace activates chloride channels stimulating chloride/bicarbonate transport that augments fluid secretion resulting in diarrhea. These channels have been targeted for drug development. However, lesser attention has been paid to the interaction of chloride channel modulators with bacterial toxins. Here we report the modulation of the structure/function of recombinant Ace by small molecule calcium-activated chloride channel (CaCC) inhibitors, namely CaCCinh-A01, digallic acid (DGA) and tannic acid. Biophysical studies indicate that the unfolding (induced by urea) free energy increases upon binding CaCCinh-A01 and DGA, compared to native Ace, whereas binding of tannic acid destabilizes the protein. Far-UV CD experiments revealed that the α-helical content of Ace-CaCCinh-A01 and Ace-DGA complexes increased relative to Ace. In contrast, binding to tannic acid had the opposite effect, indicating the loss of protein secondary structure. The modulation of Ace structure induced by CaCC inhibitors was also analyzed using docking and molecular dynamics (MD) simulation. Functional studies, performed using mouse ileal loops and Ussing chamber experiments, corroborate biophysical data, all pointing to the fact that tannic acid destabilizes Ace, inhibiting its function, whereas DGA stabilizes the toxin with enhanced fluid accumulation in mouse ileal loop. The efficacy of tannic acid in mouse model suggests that the targeted modulation of Ace structure may be of therapeutic benefit for gastrointestinal disorders. PMID:26540279

  10. [Liver damage in a patient treated with a vitamin K antagonist, a statin and an ACE inhibitor].

    Bruggisser, M; Terraciano, L; Rätz Bravo, A; Haschke, M

    2010-10-20

    We report the case of a 71-year-old male patient who presented at the emergency room with episodes of epistaxis and jaundice. The patient was on therapy with phenprocoumon, atorvastatin and perindopril. Findings on admission included prominent elevation of transaminases and bilirubin and a high INR due to impaired liver function and oral anticoagulation. After exclusion of other causes like viral or autoimmune hepatitis and after having obtained a liver biopsy, a diagnosis of drug induced liver damage (DILI) was made. Epidemiology, pathophysiology and clinical signs of DILI are discussed with a special focus on coumarines, statins and ACE-inhibitors. PMID:20960395

  11. Questioning a class effect: does ACE inhibitor tissue penetration influence the degree of fibrinolytic balance alteration following an acute myocardial infarction?

    Tsikouris, James P; Suarez, Jose A; Meyerrose, Gary E; Ziska, Martin; Fike, David; Smith, Jack

    2004-02-01

    There is a common belief in a class effect among angiotensin-converting enzyme (ACE) inhibitors. This is unsubstantiated for acute myocardial infarction (AMI). Because vascular tissue is a source of the endogenous fibrinolytic markers, and ACE inhibition in vascular tissue favorably influences the fibrinolytic system, the authors hypothesized that a high-tissue-penetrating ACE inhibitor would provide a more favorable reduction in plasminogen activator inhibitor-1 (PAI-1) and an increase in tissue plasminogen activator (t-PA) after AMI compared to a low-tissue-penetrating ACE inhibitor. In a randomized open-label trial, patients received the high-tissue-penetrating quinapril (n = 15) or low-tissue-penetrating enalapril (n = 15) immediately following an AMI. PAI-1 and t-PA antigen (ng/mL) were measured at baseline and through 14 days of treatment. There was no difference in baseline PAI-1 or t-PA antigen between treatments. PAI-1 antigen trended toward being lower with quinapril versus enalapril on day 1 (24.44 +/- 14.96 vs. 36.94 +/- 19.49, respectively, p = 0.059) and was significantly lower on day 3 (17.32 +/- 9.57 vs. 27.49 +/- 9.61, respectively, p = 0.009). Analysis of PAI-1 antigen over time by two-factor ANOVA with replication found significantly lower concentrations of PAI-1 antigen over the entire treatment period with quinapril versus enalapril (p < 0.003). This investigation of ACE inhibitor tissue-penetrating influence on markers of reinfarction risk suggests there may be a greater early reduction in PAI-1 with a more highly tissue-penetrating ACE inhibitor. PMID:14747423

  12. The individual and combined influence of ACE and ACTN3 genotypes on muscle phenotypes before and after strength training.

    Erskine, R M; Williams, A G; Jones, D A; Stewart, C E; Degens, H

    2014-08-01

    Alternative measures of muscle size, strength, and power to those used in previous studies could help resolve the controversy surrounding associations between polymorphisms of the angiotensin-I converting enzyme (ACE) and α-actinin-3 (ACTN3) genes and skeletal muscle phenotypes, and the responses to resistance training (RT). To this end, we measured quadriceps femoris muscle volume (Vm), physiological cross-sectional area (PCSA), maximum isometric force (Ft), specific force (Ft per unit PCSA), maximum isoinertial strength (1-RM), and maximum power (Wmax ; n = 40) before and after 9-week knee extension RT in 51 previously untrained young men, who were genotyped for the ACE I/D and ACTN3 R577X polymorphisms. ACTN3 R-allele carriers had greater Vm, 1-RM, and Wmax than XX homozygotes at baseline (all P ACTN3 genotype (all P > 0.05). Muscle phenotypes were independent of ACE genotype before (all P > 0.05) and after RT (all P > 0.01). However, people with the "optimal" ACE+ACTN3 genotype combination had greater baseline 1-RM and Wmax compared to those with the "suboptimal" profile (both P ACTN3 R577X polymorphism is associated with human Vm and (independently and in combination with the ACE I/D polymorphism) influences 1-RM and Wmax. PMID:23384112

  13. Effect of ACE inhibitor trandolapril on life expectancy of patients with reduced left-ventricular function after acute myocardial infarction. TRACE Study Group. Trandolapril Cardiac Evaluation

    Torp-Pedersen, C; Køber, L

    1999-01-01

    BACKGROUND: The survival benefit from the use of inhibitors of angiotensin-converting enzyme (ACE) in patients with acute myocardial infarction is usually presented in terms of risk ratios and lives saved per 1000 people treated. A more relevant way to present the extent of benefit would......-blind treatment; continued use of trandolapril was recommended at study closure. INTERPRETATION: In patients with severely reduced left-ventricular function, long-term treatment with an ACE inhibitor during the critical period after myocardial infarction is associated with a substantial increase in life...

  14. 脂多糖对大鼠肺微血管内皮细胞ACE和ACE2表达的影响及血管紧张素转换酶抑制剂的干预作用%Effects of lipolysaccharide on expression of ACE and ACE2 in rat pulmonary microvascular endothelial cells and intervention effects of angiotensinconverting enzyme inhibitor

    李亚春; 李颖川; 周明; 江伟

    2012-01-01

    目的 观察脂多糖(LPS)对大鼠肺微血管内皮细胞(PMVECs)血管紧张素转换酶(ACE)和血管紧张素转换酶2(ACE2)表达的影响及血管紧张素转换酶抑制剂( ACEI) Captopril的干预作用.方法 组织块法体外培养大鼠PMVECs,观察LPS对PMVECs作用的时间和浓度相关毒性以及Captopril的干预作用;再将PMVECs随机分为4组:对照组(n=6),不加干预措施;Captopril组(n=6),10-5mol/L Captopril孵育细胞8 h;LPS组(n=6),1 mg/mL LPS孵育细胞8 h;Captoril+ LPS组(n=6),10-5 moL/L Captopril孵育细胞30 min后再加入1 mg/mL LPS孵育8h.CCK8检测细胞活性;Western blotting法检测各组细胞ACE和ACE2的表达.结果 LPS可对大鼠PMECs产生明显的毒性作用,并可使细胞ACE表达上调及ACE2表达下降;经Captopril干预后,可明显抑制LPS的细胞毒性作用,并逆转LPS对PMVECs中ACE及ACE2表达的影响,使ACE和ACE2表达水平回调至对照组水平.结论ACEI能减轻LPS所致的PMVECs毒性作用,而ACE及ACE2表达的变化可能在这一过程中起重要作用.%Objective To investigate the effects of lipolysaccharide (LPS) on expression of angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) in rat pulmonary microvaeculai endothelial cells (PMVECs) and the intervention effects of angiotensin-converting enzyme inhibitor (ACEI) Captopril. Methods Rat PMVECs were cultured in vitro with tissue explants adherant method, the toxic effects of LPS on PMVECs were investigated by treatment of PMVECs with different concentrations of LPS for different time, and the intervention effects of Captopril were observed. PMVECs were randomly divided into control group (without intervention, n = 6), Captopril group (treatment with 10 -5 mol/L Captopril for 8 h, n =6), LPS group (treatment with 1 mg/mL LPS for 8 h, n =6) and Captoril + LPS group (treatment with 10 -5 mol/L Captopril for 30 min and 1 mg/mL LPS for 8 h, n =6) . Cell viability was determined by CCK8, and the

  15. Individualised therapy of angiotensin converting enzyme (ACE) inhibitors in stable coronary artery disease: Overview of the primary results of the PERindopril GENEtic association (PERGENE) study

    J.J. Brugts (Jasper); M.P.M. de Maat (Moniek); A.H.J. Danser (Jan); H. Boersma (Eric); M.L. Simoons (Maarten)

    2012-01-01

    textabstractIn patients with stable coronary artery disease (CAD) without overt heart failure, ACE inhibitors are among the most commonly used drugs as these agents have been proven effective in reducing the risk of cardiovascular events. Considerable individual variations in the blood pressure resp

  16. Genetic variation and gender determine bradykinin type 1 receptor responses in human tissue: Implications for the ACE-inhibitor-induced effects in patients with coronary artery disease

    H. Wu (Haiyan); A.J.M. Roks (Anton); F.P.J. Leijten (Frank); I.M. Garrelds (Ingrid); U. Musterd-Bhaggoe (Usha); A. van den Bogaerdt (Antoon); M.P.M. de Maat (Moniek); M.L. Simoons (Maarten); A.H.J. Danser (Jan); H. Oeseburg (Hisko)

    2014-01-01

    textabstractThe efficacy of the ACE (angiotensin-converting enzyme) inhibitor perindopril in coronary artery disease [EUROPA (European trial on reduction of cardiac events with perindopril in stable coronary artery disease) study] is associated with the rs12050217 A/G single nucleotide polymorphism

  17. ACE INHIBITORS IN PATIENTS WITH ISCHEMIC HEART DISEASE WITHOUT HEART FAILURE: CLASS EFFECTS AND EFFICACY OF ITS REPRESENTATIVES

    Y. A. Karpov

    2005-01-01

    Full Text Available Results of large-scale studies (QUIET, HOPE, EUROPA, PEACE, CAMELOT, devoted to assessment of the role of ACE inhibitors in treatment of patients with stable form of ischemic heart disease without heart failure are analyzed. Different efficacy of the representatives of this class toward risks of coronary events development and cerebral-vascular complications is shown, as well as the overall mortality risk due to cardiovascular reasons. Favorable therapeutic effects of inhibiting RAS activity in patients without left ventricle dysfunction are demonstrated in studies EUROPA with perindopril 8 mg, and HOPE with ramipril 10 mg. That became the ground of inclusion of these drugs into recommendations for treatment of all patients with ischemic heart disease after myocardial infarction, in addition to antiplatelet, lipid reducing remedies and beta-blockers.

  18. ACE INHIBITORS IN PATIENTS WITH ISCHEMIC HEART DISEASE WITHOUT HEART FAILURE: CLASS EFFECTS AND EFFICACY OF ITS REPRESENTATIVES

    Y. A. Karpov

    2015-12-01

    Full Text Available Results of large-scale studies (QUIET, HOPE, EUROPA, PEACE, CAMELOT, devoted to assessment of the role of ACE inhibitors in treatment of patients with stable form of ischemic heart disease without heart failure are analyzed. Different efficacy of the representatives of this class toward risks of coronary events development and cerebral-vascular complications is shown, as well as the overall mortality risk due to cardiovascular reasons. Favorable therapeutic effects of inhibiting RAS activity in patients without left ventricle dysfunction are demonstrated in studies EUROPA with perindopril 8 mg, and HOPE with ramipril 10 mg. That became the ground of inclusion of these drugs into recommendations for treatment of all patients with ischemic heart disease after myocardial infarction, in addition to antiplatelet, lipid reducing remedies and beta-blockers.

  19. Renal expression of FGF23 in progressive renal disease of diabetes and the effect of ACE inhibitor.

    Cristina Zanchi

    Full Text Available Fibroblast growth factor 23 (FGF23 is a phosphaturic hormone mainly produced by bone that acts in the kidney through FGF receptors and Klotho. Here we investigated whether the kidney was an additional source of FGF23 during renal disease using a model of type 2 diabetic nephropathy. Renal expression of FGF23 and Klotho was assessed in Zucker diabetic fatty (ZDF and control lean rats at 2, 4, 6, 8 months of age. To evaluate whether the renoprotective effect of angiotensin converting enzyme (ACE inhibitor in this model was associated with changes in FGF23 and Klotho, ZDF rats received ramipril from 4, when proteinuric, to 8 months of age. FGF23 mRNA was not detectable in the kidney of lean rats, nor of ZDF rats at 2 months of age. FGF23 became measurable in the kidney of diabetic rats at 4 months and significantly increased thereafter. FGF23 protein localized in proximal and distal tubules. Renal Klotho mRNA and protein decreased during time in ZDF rats. As renal disease progressed, serum phosphate levels increased in parallel with decline of fractional phosphorus excretion. Ramipril limited proteinuria and renal injury, attenuated renal FGF23 upregulation and ameliorated Klotho expression. Ramipril normalized serum phosphate levels and tended to increase fractional phosphorus excretion. These data indicate that during progressive renal disease the kidney is a site of FGF23 production which is limited by ACE inhibition. Interfering pharmacologically with the delicate balance of FGF23 and phosphorus in diabetes may have implications in clinics.

  20. Misdiagnosis and mistreatment of ace-inhibitor induced cough decreases therapy compliance

    Vegter, S.; de Boer, P.; van Dijk, K. W.; Visser, S. T.; de Jong-van den Berg, L. T.

    2012-01-01

    OBJECTIVES: A common adverse effect of angiotensin-converting enzyme inhibitors (ACEi) is a persistent dry cough. Physicians and pharmacists who fail to recognise dry cough to be ACEi related may prescribe cough suppressants (antitussives), instead of recommended ACEi substitution. The aim of this s

  1. Comparison of the Efficacy and Safety of Different ACE Inhibitors in Patients With Chronic Heart Failure: A PRISMA-Compliant Network Meta-Analysis.

    Sun, WeiPing; Zhang, HaiBin; Guo, JinCheng; Zhang, XueKun; Zhang, LiXin; Li, ChunLei; Zhang, Ling

    2016-02-01

    Heart failure is a public health problem and a great economic burden for patients and healthcare systems. Suppression of the renin-angiotensin system (RAS) by angiotensin-converting enzyme (ACE)-inhibitors remains the mainstay of treatment for heart failure. However, the abundance of ACE inhibitors makes it difficult for doctors to choose.We performed this network meta-analysis of ACEIs in patients with heart failure in order to address this area of uncertainty.We searched PubMed, Embase, CENTRAL, and Medline.Any randomized controlled trial evaluating the efficacy and safety of captopril, enalapril, lisinopril, ramipril, or trandolapril or combined interventions of 2 or more of these drugs.Two reviewers extracted the data and made the quality assessment. At first, we used Stata software (version 12.0, StataCorp, College Station, TX) to make traditional pairwise meta-analyses for studies that directly compared different interventions. Then, network meta-analysis was performed using WinBUGS (version 1.4.3, MRC Biostatistics Unit, Cambridge, UK).A total of 29 studies were included. Lisinopril was associated with a higher rate of all-cause mortality compared with placebo (odds ratio 65.9, 95% credible interval 1.91 to 239.6) or ramipril (14.65, 1.23 to 49.5). Enalapril significantly reduced systolic blood pressure when compared with placebo (standardized mean differences -0.6, 95% credible interval -1.03 to -0.18). Both captopril (odds ratio 76.2, 95% credible interval 1.56 to 149.3) and enalapril (274.4, 2.4 to 512.9) were associated with a higher incidence of cough compared to placebo.Some important outcomes such as rehospitalization and cardiac death were not included. The sample size and the number of studies were limited, especially for ramipril.Our results suggest that enalapril might be the best option when considering factors such as increased ejection fraction, stroke volume, and decreased mean arterial pressure. However, enalapril was associated with the

  2. Differential associations between actual and expected GP practice prescribing rates for statins, ACE inhibitors, and beta-blockers: a cross-sectional study in England

    Ward, Paul R; Noyce, Peter R; St Leger, Antony S

    2005-01-01

    Aim To explore the relationship between actual and expected general medical practitioner (GP) practice prescribing rates for statins, angiotensin converting enzyme (ACE) inhibitors, and beta-blockers. Background There is a growing body of literature highlighting inequities in GP practice prescribing rates for many drug therapies. The equity of prescribing is of central importance in the area of therapeutics since it explores the interface between those patients who should and those who actual...

  3. WHAT CAN WE EXPECT USING ACE INHIBITOR RAMIPRIL IN PERSONS WITH HIGH CARDIOVASCULAR RISK AND EARLY DISORDERS OF CARBOHYDRATE METABOLISM? LESSONS OF DREAM TRIAL

    M. N. Mamedov; M. B. Stroeva

    2016-01-01

    Primary prevention of diabetes in persons with high cardiovascular risk is an actual problem. Results of DREAM trial are discussed. Influence of ACE inhibitor, ramipril, on risk of diabetes onset in patients with pre-diabetes and low cardiovascular risk is focused. Metabolic effects of other groups of antihypertensive drugs and their ability to prevent diabetes onset are compared. Ramipril three years therapy resulted in normalization in glucose level but did not have effect on frequency of d...

  4. A COMPARATIVE STUDY OF ACE-INHIBITORS WITH OTHER ANTI-HYPERTENSIVE DRUGS IN HYPERTENSIVE DIABETIC PATIENTS IN A TERTIARY CARE HOSPITAL

    Shrinivas

    2014-06-01

    Full Text Available The incidence of hypertension and diabetes mellitus is rising on an alarming rate in the developing countries; these two disorders frequently occur together in a patient. Hypertension is the most important modifiable risk factor for coronary heart disease, stroke, CHF, end stage renal disease and peripheral vascular disease. Drugs like ACE inhibitors used in the treatment of hypertension are known to have beneficial effects in reducing complications associated with diabetes mellitus. In this study an attempt is made to see the rationality among the prescriptions and also to compare the efficacy, safety and tolerability of ACE-inhibitors with other anti-hypertensive drugs among diabetic hypertensive patient and to see the rationality among the prescriptions. METHODS AND MATERIALS: This 15 month prospective study was conducted on 100 diabetic-hypertensive patients attending Basaveshwar Teaching and General Hospital, Gulbarga. CONCLUSION: We summarize the overall effectiveness of all our anti-hypertensive drugs based on the results obtained from this data. The fall in both average SBP and average DBP reflects the effectiveness of the treatment employed by the physicians in the hospital. We also observed a general decline in the blood sugar values. The results of this study indicate that by re-establishing the dominance of ACE inhibitors in the treatment of diabetic-hypertensive

  5. PREVENTION OF ANTRACYCLIN ANTIBIOTIC DOXORUBICIN СARDIOTOXICITY: A ROLE OF ACE-INHIBITOR PERINDOPRIL

    E. V. Pravdivtseva

    2014-07-01

    Full Text Available Aim – to study how anthracyclines influence on cardiovascular system in patients with lymphomas and whether angiotensin-converting enzyme inhibitor Perindopril is cardioprotective in these patients.Subjects and methods. 26 patients with Hodgkin’s disease and non-Hodgkin’s lymphomas were followed before and after treatment withdoxorubicin. 12 of these patients with arterial hypertension received angiotensin-converting enzyme inhibitor Рerindopril, 10 mg/d, duringtreatment with doxorubicin. Cardiological evaluation was performed before and the next day after chemotherapy. Average dose of Doxorubicin was 34,99 ± 13,23 mg/m2.Results. In patients receiving anthracyclines deceleration time DT increased significantly, a significant reduction in heart rate (HR, cardiacoutput (CO and cardiac index (CI were observed also (рDT = 0,037, pHR = 0,048, рСО = 0,007, рCI = 0,007. In patients simultaneouslytreated with Perindopril these parameters were not statistically different (рDT = 0,92, pHR = 0,22, рCO = 0,35, рCI = 0,39.Conclusion. Administration of anthracyclines (average dose of Doxorubicin 34,99 ± 13,23 mg/m2 leads to DT of the left ventricle andreduction in HR, CJ and CI. Simultaneous treatment with Perindopril in patients receiving anthracyclines preserves DF and prevents heart hemodynamics abnormalities.

  6. PREVENTION OF ANTRACYCLIN ANTIBIOTIC DOXORUBICIN СARDIOTOXICITY: A ROLE OF ACE-INHIBITOR PERINDOPRIL

    E. V. Pravdivtseva

    2011-01-01

    Full Text Available Aim – to study how anthracyclines influence on cardiovascular system in patients with lymphomas and whether angiotensin-converting enzyme inhibitor Perindopril is cardioprotective in these patients.Subjects and methods. 26 patients with Hodgkin’s disease and non-Hodgkin’s lymphomas were followed before and after treatment withdoxorubicin. 12 of these patients with arterial hypertension received angiotensin-converting enzyme inhibitor Рerindopril, 10 mg/d, duringtreatment with doxorubicin. Cardiological evaluation was performed before and the next day after chemotherapy. Average dose of Doxorubicin was 34,99 ± 13,23 mg/m2.Results. In patients receiving anthracyclines deceleration time DT increased significantly, a significant reduction in heart rate (HR, cardiacoutput (CO and cardiac index (CI were observed also (рDT = 0,037, pHR = 0,048, рСО = 0,007, рCI = 0,007. In patients simultaneouslytreated with Perindopril these parameters were not statistically different (рDT = 0,92, pHR = 0,22, рCO = 0,35, рCI = 0,39.Conclusion. Administration of anthracyclines (average dose of Doxorubicin 34,99 ± 13,23 mg/m2 leads to DT of the left ventricle andreduction in HR, CJ and CI. Simultaneous treatment with Perindopril in patients receiving anthracyclines preserves DF and prevents heart hemodynamics abnormalities.

  7. Chronic ACE inhibitor treatment increases angiotensin type 1 receptor binding in vivo in the dog kidney

    PET imaging has been recently introduced for investigating the type 1 angiotensin II receptor (AT1R) in vivo. The goal of the present study was to investigate the effects of acute and chronic exposure to angiotensin converting enzyme inhibitors (ACEI) on the AT1R in the dog kidney. Animals were imaged at baseline, after acute intravenous ACEI treatment and after a chronic 2-week exposure to an oral ACEI. Control animals were imaged at identical time points in the absence of ACEI treatment. In vivo AT1R binding expressed by Ki was increased in the renal cortex by chronic ACEI treatment (p 1R density (Bmax) also revealed significant increases in AT1R in isolated glomeruli (p 1R binding in vivo in the dog renal cortex. (orig.)

  8. Chronic ACE inhibitor treatment increases angiotensin type 1 receptor binding in vivo in the dog kidney

    Zober, Tamas G. [Johns Hopkins University, Departments of Radiology and Surgery, Baltimore, MD (United States); Semmelweis University, Department of Pathophysiology, Budapest (Hungary); Fabucci, Maria E.; Zheng, Wei; Sandberg, Kathryn [Georgetown University, Department of Medicine, Washington, DC (United States); Brown, Phillip R.; Seckin, Esen; Mathews, William B. [Johns Hopkins University, Departments of Radiology and Surgery, Baltimore, MD (United States); Szabo, Zsolt [Johns Hopkins University, Departments of Radiology and Surgery, Baltimore, MD (United States); Johns Hopkins Outpatient Center, Division of Nuclear Medicine, Baltimore, MD (United States)

    2008-06-15

    PET imaging has been recently introduced for investigating the type 1 angiotensin II receptor (AT{sub 1}R) in vivo. The goal of the present study was to investigate the effects of acute and chronic exposure to angiotensin converting enzyme inhibitors (ACEI) on the AT{sub 1}R in the dog kidney. Animals were imaged at baseline, after acute intravenous ACEI treatment and after a chronic 2-week exposure to an oral ACEI. Control animals were imaged at identical time points in the absence of ACEI treatment. In vivo AT{sub 1}R binding expressed by K{sub i} was increased in the renal cortex by chronic ACEI treatment (p < 0.05). In vitro measurements of AT{sub 1}R density (B{sub max}) also revealed significant increases in AT{sub 1}R in isolated glomeruli (p < 0.05). Plasma renin activity was increased, but angiotensin II (Ang II) and the Ang II/Ang I ratio showed a weak correlation with chronic ACEI treatment, consistent with an Ang II escape phenomenon. This study reveals, for the first time, that chronic ACEI treatment increases AT{sub 1}R binding in vivo in the dog renal cortex. (orig.)

  9. Non-disulfide-bridged peptides from Tityus serrulatus venom: Evidence for proline-free ACE-inhibitors.

    Pucca, Manuela Berto; Cerni, Felipe Augusto; Pinheiro-Junior, Ernesto Lopes; Zoccal, Karina Furlani; Bordon, Karla de Castro Figueiredo; Amorim, Fernanda Gobbi; Peigneur, Steve; Vriens, Kim; Thevissen, Karin; Cammue, Bruno Philippe Angelo; Júnior, Ronaldo Bragança Martins; Arruda, Eurico; Faccioli, Lúcia Helena; Tytgat, Jan; Arantes, Eliane Candiani

    2016-08-01

    The present study purifies two T. serrulatus non-disulfide-bridged peptides (NDBPs), named venom peptides 7.2 (RLRSKG) and 8 (KIWRS) and details their synthesis and biological activity, comparing to the synthetic venom peptide 7.1 (RLRSKGKK), previously identified. The synthetic replicate peptides were subjected to a range of biological assays: hemolytic, antifungal, antiviral, electrophysiological, immunological and angiotensin-converting enzyme (ACE) inhibition activities. All venom peptides neither showed to be cytolytic nor demonstrated significant antifungal or antiviral activities. Interestingly, peptides were able to modulate macrophages' responses, increasing IL-6 production. The three venom peptides also demonstrated potential to inhibit ACE in the following order: 7.2>7.1>8. The ACE inhibition activity was unexpected, since peptides that display this function are usually proline-rich peptides. In attempt to understand the origin of such small peptides, we discovered that the isolated peptides 7.2 and 8 are fragments of the same molecule, named Pape peptide precursor. Furthermore, the study discusses that Pape fragments could be originated from a post-splitting mechanism resulting from metalloserrulases and other proteinases cleavage, which can be seen as a clever mechanism used by the scorpion to enlarge its repertoire of venom components. Scorpion venom remains as an interesting source of bioactive proteins and this study advances our knowledge about three NDBPs and their biological activities. PMID:27221550

  10. Inhibitor and substrate binding by angiotensin-converting enzyme

    Wang, Xuemei; Wu, Shanshan; Xu, Dingguo;

    2011-01-01

    . In this work, we propose a model for an ACE Michaelis complex based on two known X-ray structures of inhibitor-enzyme complexes. Specifically, the human testis angiotensin-converting enzyme (tACE) complexed with two clinic drugs were first investigated using a combined quantum mechanical and molecular......Angiotensin-converting enzyme (ACE) is an important zinc-dependent hydrolase responsible for converting the inactive angiotensin I to the vasoconstrictor angiotensin II and for inactivating the vasodilator bradykinin. However, the substrate binding mode of ACE has not been completely understood...... computational protocol. Implications to ACE catalysis are discussed....

  11. A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough.

    Mosley, J D; Shaffer, C M; Van Driest, S L; Weeke, P E; Wells, Q S; Karnes, J H; Velez Edwards, D R; Wei, W-Q; Teixeira, P L; Bastarache, L; Crawford, D C; Li, R; Manolio, T A; Bottinger, E P; McCarty, C A; Linneman, J G; Brilliant, M H; Pacheco, J A; Thompson, W; Chisholm, R L; Jarvik, G P; Crosslin, D R; Carrell, D S; Baldwin, E; Ralston, J; Larson, E B; Grafton, J; Scrol, A; Jouni, H; Kullo, I J; Tromp, G; Borthwick, K M; Kuivaniemi, H; Carey, D J; Ritchie, M D; Bradford, Y; Verma, S S; Chute, C G; Veluchamy, A; Siddiqui, M K; Palmer, C N A; Doney, A; MahmoudPour, S H; Maitland-van der Zee, A H; Morris, A D; Denny, J C; Roden, D M

    2016-06-01

    The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency=0.33, odds ratio (OR)=1.3 (95% confidence interval (CI): 1.2-1.4), P=1.0 × 10(-8)). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n=926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n=4309). Replication was observed at rs7675300 (OR=1.32 (1.01-1.70), P=0.04) in eMERGE and at rs16870989 and rs1495509 (OR=1.15 (1.01-1.30), P=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 (1.15-1.32), P=1.9 × 10(-9)). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk. PMID:26169577

  12. The effect of ACE inhibition on the pulmonary vasculature in combined model of chronic hypoxia and pulmonary arterial banding in Sprague Dawley rats

    Clarke, Shanelle; Baumgardt, Shelley; Molthen, Robert

    2010-03-01

    Microfocal CT was used to image the pulmonary arterial (PA) tree in rodent models of pulmonary hypertension (PH). CT images were used to measure the arterial tree diameter along the main arterial trunk at several hydrostatic intravascular pressures and calculate distensibility. High-resolution planar angiographic imaging was also used to examine distal PA microstructure. Data on pulmonary artery tree morphology improves our understanding of vascular remodeling and response to treatments. Angiotensin II (ATII) has been identified as a mediator of vasoconstriction and proliferative mitotic function. ATII has been shown to promote vascular smooth muscle cell hypertrophy and hyperplasia as well as stimulate synthesis of extracellular matrix proteins. Available ATII is targeted through angiotensin converting enzyme inhibitors (ACEIs), a method that has been used in animal models of PH to attenuate vascular remodeling and decrease pulmonary vascular resistance. In this study, we used rat models of chronic hypoxia to induce PH combined with partial left pulmonary artery occlusion (arterial banding, PLPAO) to evaluate effects of the ACEI, captopril, on pulmonary vascular hemodynamic and morphology. Male Sprague Dawley rats were placed in hypoxia (FiO2 0.1), with one group having underwent PLPAO three days prior to the chronic hypoxia. After the twenty-first day of hypoxia exposure, treatment was started with captopril (20 mg/kg/day) for an additional twenty-one days. At the endpoint, lungs were excised and isolated to examine: pulmonary vascular resistance, ACE activity, pulmonary vessel morphology and biomechanics. Hematocrit and RV/LV+septum ratio was also measured. CT planar images showed less vessel dropout in rats treated with captopril versus the non-treatment lungs. Distensibility data shows no change in rats treated with captopril in both chronic hypoxia (CH) and CH with PLPAO (CH+PLPAO) models. Hemodynamic measurements also show no change in the pulmonary vascular

  13. Combined treatment of vitamin K2 and angiotensin-converting enzyme inhibitor ameliorates hepatic dysplastic nodule in a patient with liver cirrhosis

    Yoshiji, Hitoshi; NOGUCHI, RYUICHI; Yamazaki, Masaharu; IKENAKA, YASUHIDE; SAWAI, MASAYOSHI; Ishikawa, Masatoshi; Kawaratani, Hideto; MASHITANI, TSUYOSHI; Kitade, Mitsuteru; Kaji, Kosuke; Uemura, Masahito; YAMAO, JUNICHI; Fujimoto, Masao; Mitoro, Akira; Toyohara, Masahisa

    2007-01-01

    Although it is well known that the hepatocellular carcinoma (HCC) is an ominous complication in patients with liver cirrhosis, there has been no approved drug to prevent the development of HCC to date. We previously reported that the combined treatment of vitamin K2 (VK) and angiotensin-converting enzyme inhibitor (ACE-I) significantly suppressed the experimental hepatocarcinogenesis. A 66-year-old Japanese woman with hepatitis C virus (HCV)-related liver cirrhosis developed a dysplastic nodu...

  14. Essential fatty acids and their metabolites could function as endogenous HMG-CoA reductase and ACE enzyme inhibitors, anti-arrhythmic, anti-hypertensive, anti-atherosclerotic, anti-inflammatory, cytoprotective, and cardioprotective molecules

    Das Undurti N

    2008-10-01

    Full Text Available Abstract Lowering plasma low density lipoprotein-cholesterol (LDL-C, blood pressure, homocysteine, and preventing platelet aggregation using a combination of a statin, three blood pressure lowering drugs such as a thiazide, a β blocker, and an angiotensin converting enzyme (ACE inhibitor each at half standard dose; folic acid; and aspirin-called as polypill- was estimated to reduce cardiovascular events by ~80%. Essential fatty acids (EFAs and their long-chain metabolites: γ-linolenic acid (GLA, dihomo-GLA (DGLA, arachidonic acid, eicosapentaenoic acid (EPA, and docosahexaenoic acid (DHA and other products such as prostaglandins E1 (PGE1, prostacyclin (PGI2, PGI3, lipoxins (LXs, resolvins, protectins including neuroprotectin D1 (NPD1 prevent platelet aggregation, lower blood pressure, have anti-arrhythmic action, reduce LDL-C, ameliorate the adverse actions of homocysteine, show anti-inflammatory actions, activate telomerase, and have cytoprotective properties. Thus, EFAs and their metabolites show all the classic actions expected of the "polypill". Unlike the proposed "polypill", EFAs are endogenous molecules present in almost all tissues, have no significant or few side effects, can be taken orally for long periods of time even by pregnant women, lactating mothers, and infants, children, and adults; and have been known to reduce the incidence cardiovascular diseases including stroke. In addition, various EFAs and their long-chain metabolites not only enhance nitric oxide generation but also react with nitric oxide to yield their respective nitroalkene derivatives that produce vascular relaxation, inhibit neutrophil degranulation and superoxide formation, inhibit platelet activation, and possess PPAR-γ ligand activity and release NO, thus prevent platelet aggregation, thrombus formation, atherosclerosis, and cardiovascular diseases. Based on these evidences, I propose that a rational combination of ω-3 and ω-6 fatty acids and the co

  15. Comparative study on the ACE inhibitors Quinapril and Captopril for the (Angiotensin converting enzyme) treatment of the decompensated cardiac insufficiency in dog

    In a randomized study of 52 dogs the efficacy and safety of captopril and quinapril in the treatment of canine heart failure is studied. The drugs were found to be comparably effective. The recommended dosage schedule for the short acting captopril is three times daily 0.5 mg/kg body weight. Quinapril belongs to a newer generation of ACE inhibitors with a longer half life than captopril and the treatment was started with a single dose of 0.5 mg/kg body weight. This dosage schedule was sufficient for the successful therapy of most of the dogs with heart failure phase II (12 of 13), but in 4 of 7 dogs with heart failure phase III and in all of the patients with phase IV the single dose had to be increased and/or the dosing interval of quinapril had to be shortened, because they still showed complaints due to heart failure. We recommend to adjust the dosage schedule of quinapril individually to the severity of heart failure. Therapy should be started once daily with an application of 0,5 mg/kg body weight and the dog should be controlled about one week later. If there are still symptoms of decompensated heart failure, the dosage may be increased gradually until a maximum dosage of 0.5 mg/kg three times daily. Especially for patients with severe heart failure we recommend at least when treatment is started a concomitant diuretic therapy. Echocardiographic evaluation of cardiac function shows if there is an indication for positive inotropic support witha digitalis glycoside. Quinapril, a novel inhibitor of the angiotensin-converting enzyme can ease the management of canine heart failure, because at least in dogs with mild to moderate heart failure dosing interval is longer compared with captopril. Moreover, quinapril is available as 5 mg tablets whereas the smallest captopril tablets contain 12.5 mg agent. It has to be mentioned that expenses for a treatment with ACE inhibitors are significantly higher than for a therapy with digitalis, so frequently above all the

  16. A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough

    Mosley, J D; Shaffer, C M; Van Driest, S L;

    2016-01-01

    The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects...

  17. Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure : a combined analysis of three trials

    Dagenais, Gilles R.; Pogue, Janice; Fox, Kim; Simoons, Marteen L.; Yusuf, Salim

    2006-01-01

    Background Angiotensin-converting-enzyme (ACE) inhibitors reduce cardiovascular mortality and morbidity in patients with heart failure or left ventricular systolic dysfunction (LVSD). Three large trials have assessed the effect of ACE inhibitors in stable patients without these conditions but with a

  18. Combined effects of EGFR tyrosine kinase inhibitors and vATPase inhibitors in NSCLC cells

    Jin, Hyeon-Ok [KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Hong, Sung-Eun [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Kim, Chang Soon [Department of Microbiological Engineering, Kon-Kuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143–701 (Korea, Republic of); Park, Jin-Ah; Kim, Jin-Hee; Kim, Ji-Young; Kim, Bora [KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Chang, Yoon Hwan; Hong, Seok-Il; Hong, Young Jun [Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Park, In-Chul, E-mail: parkic@kirams.re.kr [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Lee, Jin Kyung, E-mail: jklee@kirams.re.kr [KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of)

    2015-08-15

    Despite excellent initial clinical responses of non-small cell lung cancer (NSCLC) patients to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), many patients eventually develop resistance. According to a recent report, vacuolar H + ATPase (vATPase) is overexpressed and is associated with chemotherapy drug resistance in NSCLC. We investigated the combined effects of EGFR TKIs and vATPase inhibitors and their underlying mechanisms in the regulation of NSCLC cell death. We found that combined treatment with EGFR TKIs (erlotinib, gefitinib, or lapatinib) and vATPase inhibitors (bafilomycin A1 or concanamycin A) enhanced synergistic cell death compared to treatments with each drug alone. Treatment with bafilomycin A1 or concanamycin A led to the induction of Bnip3 expression in an Hif-1α dependent manner. Knock-down of Hif-1α or Bnip3 by siRNA further enhanced cell death induced by bafilomycin A1, suggesting that Hif-1α/Bnip3 induction promoted resistance to cell death induced by the vATPase inhibitors. EGFR TKIs suppressed Hif-1α and Bnip3 expression induced by the vATPase inhibitors, suggesting that they enhanced the sensitivity of the cells to these inhibitors by decreasing Hif-1α/Bnip3 expression. Taken together, we conclude that EGFR TKIs enhance the sensitivity of NSCLC cells to vATPase inhibitors by decreasing Hif-1α/Bnip3 expression. We suggest that combined treatment with EGFR TKIs and vATPase inhibitors is potentially effective for the treatment of NSCLC. - Highlights: • Co-treatment with EGFR TKIs and vATPase inhibitors induces synergistic cell death • EGFR TKIs enhance cell sensitivity to vATPase inhibitors via Hif-1α downregulation • Co-treatment of these inhibitors is potentially effective for the treatment of NSCLC.

  19. Management of symptomatic erosive-ulcerative lesions of oral lichen planus in an adult Egyptian population using Selenium - ACE combined with topical corticosteroids plus antifungal agent

    Mahmoud Helmy Belal

    2015-01-01

    Full Text Available Aim: Oral lichen planus (OLP is a chronic mucocutaneous disease with an immunological etiology. This study was conducted to evaluate the effect of selenium combined with Vitamins A, C & E (Selenium-ACE in the treatment of erosive-ulcerative OLP as an adjunctive to topical corticosteroids plus antifungal agent. Subjects and Methods: Thirty patients with a confirmed clinical and histopathologic diagnosis of OLP participated in this clinical trial. Patients were randomly allocated into one of three groups and treated as follows: (I Topical corticosteroids, (II topical corticosteroids plus antifungal, and (III SE-ACE combined with topical corticosteroids plus antifungal. The patients were followed for 6 weeks. The pain and severity of the lesions were recorded at the initial and follow-up visits. All recorded data were analyzed using paired t-test and ANOVA test. A P ≤ 0.05 was considered significant. Results: The experimental groups showed a marked reduction in pain sensation and size of lesions, particularly in the final follow-up period, but there was no significant difference between the first two Groups I and II. However, healing of lesions and improvement of pain sensation was effective in Group III since a significant difference was found favoring Group III over both Groups I and II. Conclusion: No significant difference was found in treating erosive-ulcerative lesions of OLP by topical corticosteroids alone or combined with antifungal. However, when using SE-ACE in combination with topical corticosteroids plus antifungal, this approach may be effective in managing ulcerative lesions of OLP; but more research with a larger sample size and a longer evaluation period may be recommended.

  20. Neonatal ACE inhibition in rats interferes with lung development.

    Lasaitiene, Daina; Chen, Yun; Nannmark, Ulf; Wollmer, Per; Friberg, Peter

    2004-01-01

    The renin-angiotensin system (RAS) is developmentally up-regulated and it is essential for kidney development in several species. Given the fact that the rat lung undergoes postnatal development, the mammalian lung possesses the highest angiotensin-converting enzyme (ACE) levels and ACE activity increases during the first weeks postpartum, we tested the hypothesis that ACE inhibition influences postnatal lung development. Rats were given the ACE inhibitor enalapril (10 mg kg-1) from 0 to 9 da...

  1. New Aspects of Ace Inhibition: Importance of ACE co-localization with angiotensin and bradykinin receptors

    B. Tom (Beril)

    2003-01-01

    textabstractThe beneficial effect of angiotensin-converting enzyme (ACE) inhibitors in hypertension and heart failure may relate, at least in part, to their capacity to interfere with bradykinin metabolism. In addition, recent studies have provided evidence for bradykinin-potentiating effects of ACE

  2. CO emission and export from Asia: an analysis combining complementary satellite measurements (MOPITT, SCIAMACHY and ACE-FTS with global modeling

    P. F. Bernath

    2008-09-01

    Full Text Available This study presents the complementary picture of the pollution outflow provided by several satellite observations of carbon monoxide (CO, based on different observation techniques. This is illustrated by an analysis of the Asian outflow during the spring of 2005, through comparisons with simulations by the LMDz-INCA global chemistry transport model. The CO observations from the MOPITT and SCIAMACHY nadir sounders, which provide vertically integrated information with excellent horizontal sampling, and from the ACE-FTS solar occultation instrument, which has limited spatial coverage but allows the retrieval of vertical profiles, are used. Combining observations from MOPITT (mainly sensitive to the free troposphere and SCIAMACHY (sensitive to the full column allows a qualitative evaluation of the boundary layer CO. The model tends to underestimate this residual compared to the observations, suggesting underestimated emissions, especially in eastern Asia. However, a better understanding of the consistency and possible biases between the MOPITT and SCIAMACHY CO is necessary for a quantitative evaluation. Underestimated emissions, and possibly too low lofting and underestimated chemical production in the model, lead to an underestimate of the export to the free troposphere, as highlighted by comparisons with MOPITT and ACE-FTS. Both instruments observe large trans-Pacific transport extending from ~20° N to ~60° N, with high upper tropospheric CO observed by ACE-FTS above the eastern Pacific (with values of up to 300 ppbv around 50° N at 500 hPa and up to ~200 ppbv around 30° N at 300 hPa. The low vertical and horizontal resolutions of the global model do not allow the simulation of the strong enhancements in the observed plumes. However, the transport patterns are well captured, and are mainly attributed to export from eastern Asia, with increasing contributions from South Asia and Indonesia towards the tropics. Additional measurements of C2

  3. Immune Check Point Inhibitors Combination in Melanoma: Worth the Toxicity?

    Orloff, Marlana; Weight, Ryan; Valsecchi, Matias E; Sato, Takami

    2016-01-01

    The combination of immune checkpoint inhibitors ipilimumab and nivolumab has been recently been FDA approved for first line treatment of unresectable and metastatic BRAF wild type melanoma. The approval came following the impressive results of the CheckMate 067, where the combination of ipilimumab and nivolumab appeared to outperform each as a single agent in regards to response rate and progression free survival. Though we await final overall survival data, the combination will likely be adapted by many oncologists and integrated into the ever changing melanoma treatment algorithm. In this article we aim to summarize the data leading up to the recent FDA approval and publication by Larkin et al. that presents the results from the CheckMate 067 trial. We will also further explore the feasibility, challenges, and applicability of combination immune checkpoint inhibitor therapy. PMID:27028970

  4. COX-2 inhibitors are contraindicated for treatment of combined injury.

    Jiao, W; Kiang, J G; Cary, L; Elliott, T B; Pellmar, T C; Ledney, G D

    2009-12-01

    Casualties of radiation dispersal devices, nuclear detonation or major ionizing radiation accidents, in addition to radiation exposure, may sustain physical and/or thermal trauma. Radiation exposure plus additional tissue trauma is known as combined injury. There are no definitive therapeutic agents. Cyclooxygenase-2 (COX-2), an inducible enzyme expressed in pathological disorders and radiation injury, plays an important role in inflammation and the production of cytokines and prostaglandin E(2) (PGE(2)) and could therefore affect the outcome for victims of combined injury. The COX-2 inhibitors celecoxib and meloxicam were evaluated for their therapeutic value against combined injury in mice. In survival studies, the COX-2 inhibitors had no beneficial effect on 30-day survival, wound healing or body weight gain after radiation injury alone or after combined injury. Meloxicam accelerated death in both wounded and combined injury mice. These drugs also induced severe hepatic toxicity, exaggerated inflammatory processes, and did not enhance hematopoietic cell regeneration. This study points to potential contraindications for use of COX-2 inhibitors in patients undergoing therapy for radiation injury and combined injury. PMID:19929415

  5. ACE/ACE2 Ratio and MMP-9 Activity as Potential Biomarkers in Tuberculous Pleural Effusions

    Wen-Yeh Hsieh, Tang-Ching Kuan, Kun-Shan Cheng, Yan-Chiou Liao, Mu-Yuan Chen, Pei-Heng Lin, Yuan-Chang Hsu, Chen-Yi Huang, Wei-Hua Hsu, Sheng-Yao Yu, Chih-Sheng Lin

    2012-01-01

    Full Text Available Objective: Pleural effusion is common problem, but the rapid and reliable diagnosis for specific pathogenic effusions are lacking. This study aimed to identify the diagnosis based on clinical variables to differentiate pleural tuberculous exudates from other pleural effusions. We also investigated the role of renin-angiotensin system (RAS and matrix metalloproteinase (MMPs in the pathogenesis of pleural exudates.Experimental design: The major components in RAS and extracellular matrix metabolism, including angiotensin converting enzyme (ACE, ACE2, MMP-2 and MMP-9 activities, were measured and compared in the patients with transudative (n = 45 and exudative (n = 80 effusions. The exudative effusions were come from the patients with tuberculosis (n = 20, pneumonia (n = 32, and adenocarcinoma (n = 28.Results: Increased ACE and equivalent ACE2 activities, resulting in a significantly increased ACE/ACE2 ratio in exudates, were detected compared to these values in transudates. MMP-9 activity in exudates was significantly higher than that in transudates. The significant correlation between ACE and ACE2 activity that was found in transudates was not found in exudates. Advanced analyses showed significantly increased ACE and MMP-9 activities, and decreased ACE2 activity in tuberculous pleural effusions compared with those in pneumonia and adenocarcinoma effusions. The results indicate that increased ACE and MMP-9 activities found in the exudates were mainly contributed from a higher level of both enzyme activities in the tuberculous pleural effusions.Conclusion: Interplay between ACE and ACE2, essential functions in the RAS, and abnormal regulation of MMP-9 probably play a pivotal role in the development of exudative effusions. Moreover, the ACE/ACE2 ratio combined with MMP-9 activity in pleural fluid may be potential biomarkers for diagnosing tuberculous pleurisy.

  6. [Betalactam antibiotics combined with bectalactamases inhibitors. Amoxicillin-sulbactam].

    Barcelona, Laura; Marín, Marcelo; Stamboulian, Daniel

    2008-01-01

    Betalactamases production is one of the main bacterial resistance mechanisms to betalactam antibiotics. The use of bectalactamases inhibitors combined with betalactam antibiotics allows the inactivation of certain betalactamases produced by Gram positive, Gram negative and anaerobic organisms, and even by mycobacteria. Betalactamases inhibitors are an improved therapeutic alternative compared with the other betalactam since, in most cases, they cover a wider antimicrobial spectrum than their analogues. Betalactamases enzimatic activity is specifically directed to the betalactam ring hydrolisis, producing a compound without antibacterial activity. According to their genomic position within microorganisms, betalactamases can be either chromosomic or plasmidic. Currently there are three betalactamases inhibitors locally available: clavulanic acid, sulbactam and tazobactam. Of them, only sulbactam has an intrinsic antimicrobial activity against penicillin binding proteins. The clinical experience from over 20 years confirms that the combination of betalactam antibiotics is effective in the empirical initial treatment of respiratory, intraabdominal, urinary tract and gynecologic infections, including those of polymicrobial origin. In the specific case of amoxicillin-sulbactam, experiences have shown the effectiveness of the combination in the treatment of peritonsillar abscess, otitis media, sinusitis, community acquired pneumonia, acute exacerbation of chronic obstructive pulmonar disease (COPD), urinary tract infection and obstetric/gynecologic infections. The spectrum and pharmacologic properties of this combination makes it also an excellent option for the treatment of skin/soft tissue and intraabdominal infections. PMID:18416324

  7. ACE抑制剂在CPB围术期心肌保护中的机制研究%The Mechanism of ACE Inhibitor in the Protection of Myocardial during CPB

    杨威; 董啸; 周建良; 龚艺

    2015-01-01

    Objective:To investigate the relationship between ACE gene polymorphism and myocardial protection during perioperative period of CPB through observe the change of myocardial markers.Method:72 patients who suffered from rheumatic mitral stenosis in our hospital were selected from January to October 2015. According to the genotype of ACE they were divided into three groups:type Ⅱ group,type ID group and type DD group,24 cases in each group. The peripheral venous blood of three groups were selected at different moments, the ACE and the content changes of myocardial markers were detected and compared.Result:The level of ACE during CPB and after CPB were higher then those before CPB,the level of ACE with DD genotype was significantly higher than the ID and Ⅱ genotype, the differences were statistically significant(P<0.05).Conclusion:ACE inhibitors reduce myocardial cells injury at CPB perioperative after myocardial cells live myocardial longer ischaemia and then reperfusion, improve the safety of surgery,it is worthy of promotion and application.%目的:通过观察心肌标志物的变化,探究ACE抑制剂在CPB围术期心肌保护中的机制。方法:选取本院从2015年1-10月所接诊的72例风湿性的二尖瓣狭窄患者,根据多态性的ACE基因将患者分为II、ID和DD三组,每组各24例,在不同的时刻点抽取三组的外周静脉血,对其ACE及心肌标志物的含量变化进行检测与对比。结果:ACE及心肌标志物在CPB后及CPB中的含量均高于CPB前的,DD型血清中ACE及心肌标志物的含量都比ID型及II型的高,差异均有统计学意义(P<0.05)。结论:ACE抑制剂可以降低在CPB围手术时心肌的长时间缺血后进行的再灌注的心肌细跑损伤,提高了手术的安全性,值得推广和应用。

  8. 棉籽蛋白源ACE抑制肽的制备过程中脱盐技术的研究%Study on Desalination in Preparation Process of ACE-Inhibitor Peptide from Cottonseed Protein

    刘军; 徐志宏; 魏振承; 廖森泰; 穆利霞

    2013-01-01

    Cottonseed hydrolysates were desalted by 001 × 7,201 × 7 iron exchange resin,MWCO100 dialytic bags and DA201-C macroporous adsorption resin,their desalination effects were compared synthetically.The effect of ACE inhibitor activity and amino acid composition were analyzed after desalination by DA201-C resin,and the ACE inhibitor activity of several compositions after isolation with Sephadex G-25 was determined.The results showed that when the velocity of flow was controlled at 3 mL/min,DA201-C macroporous adsorption resin had the best desalination effect ;desalination ratio reached to 94.78% ;nitrogen recovery ratio was 86.32%.Hydrophobic amino acid was enriched and ACE inhibitor activity was improved effectively after desalination.Among several compositions after isolation and purification,the composition Ⅲ had the best ACE-Inhibitor activity with molecular weight less than 1 000 u.%综合比较了001 ×7、201 ×7离子交换树脂、MWCO100透析袋和DA201-C大孔吸附树脂对棉籽蛋白水解液的脱盐效果,分析了DA201-C树脂脱盐对棉籽蛋白水解液ACE抑制活性和氨基酸组成的影响,并对Sephadex G-25分离纯化获得ACE抑制肽各组分进行活性测定.结果表明:DA201-C大孔吸附树脂的脱盐效果最好,控制流速为3 mL/min时,脱盐率可达到94.78%,氮回收率为86.32%,脱盐后疏水性氨基酸得到了有效富集,ACE抑制率显著提高.分离纯化后的ACE抑制肽各组分中,组分Ⅲ的抑制率最高,分子质量小于1000u.

  9. Combined treatment of vitamin K2 and angiotensin-converting enzyme inhibitor ameliorates hepatic dysplastic nodule in a patient with liver cirrhosis

    Hitoshi Yoshiji; Kosuke Kaji; Masahito Uemura; Junichi Yamao; Masao Fujimoto; Akira Mitoro; Masahisa Toyohara; Motoyuki Yoshida; Hiroshi Fukui; Ryuichi Noguchi; Masaharu Yamazaki; Yasuhide Ikenaka; Masayoshi Sawai; Masatoshi Ishikawa; Hideto Kawaratani; Tsuyoshi Mashitani; Mitsuteru Kitade

    2007-01-01

    Although it is well known that the hepatocellular carcinoma (HCC) is an ominous complication in patients with liver cirrhosis, there has been no approved drug to prevent the development of HCC to date. We previously reported that the combined treatment of vitamin K2 (VK) and angiotensin-converting enzyme inhibitor(ACE-I) significantly suppressed the experimental hepatocarcinogenesis. A 66-year-old Japanese woman with hepatitis C virus (HCV)-related liver cirrhosis developed a dysplastic nodule in the liver detected by enhanced computed tomography along with elevation of the tumor markers, namely, alpha-fetoprotein (AFP)and lectin-reactive demarcation (AFP-L3), suggesting the presence of latent HCC. After oral administration of VK and ACE-I, the serum levels of both AFP and AFP-L3 gradually decreased without any marked alteration of the serum aminotransferase activity. After one-year treatment, not only the serum levels of AFP and AFP-L3 returned to the normal ranges, but also the dysplastic nodule disappeared. Since both VK and ACE-I are widely used without serious side effects, this combined regimen may become a new strategy for chemoprevention against HCC.

  10. Does the ACE I/D polymorphism, alone or in combination with the ACTN3 R577X polymorphism, influence muscle power phenotypes in young, non-athletic adults?

    Rodríguez Romo, Gabriel; Ruiz, Jonatan R.; Santiago, Catalina; Fiuza Luces, Carmen; Gonzalez Freire, Marta; Gomez Gallego, Felix; Moran, Maria; Lucía Mulas, Alejandro

    2010-01-01

    We investigated the association of the angiotensin converting enzyme gene (ACE) insertion/deletion (I/D) polymorphism, alone or in combination with the α-actinin-3 gene (ACTN3) R577X polymorphism, with jumping (vertical squat and counter-movement jump tests) and sprint ability (30 m dash) in non-athletic, healthy young adults [N = 281 (214 male), mean (SD) age 21 (2) years]. We did not observe any effect of the ACE I/D polymorphism on study phenotypes. We repeated the analyses separately in m...

  11. Evaluation of tyrosine kinase inhibitor combinations for glioblastoma therapy.

    Avadhut D Joshi

    Full Text Available Glioblastoma multiforme (GBM is the most common intracranial cancer but despite recent advances in therapy the overall survival remains about 20 months. Whole genome exon sequencing studies implicate mutations in the receptor tyrosine kinase pathways (RTK for driving tumor growth in over 80% of GBMs. In spite of various RTKs being mutated or altered in the majority of GBMs, clinical studies have not been able to demonstrate efficacy of molecular targeted therapies using tyrosine kinase inhibitors in GBMs. Activation of multiple downstream signaling pathways has been implicated as a possible means by which inhibition of a single RTK has been ineffective in GBM. In this study, we sought a combination of approved drugs that would inhibit in vitro and in vivo growth of GBM oncospheres. A combination consisting of gefitinib and sunitinib acted synergistically in inhibiting growth of GBM oncospheres in vitro. Sunitinib was the only RTK inhibitor that could induce apoptosis in GBM cells. However, the in vivo efficacy testing of the gefitinib and sunitinib combination in an EGFR amplified/PTEN wild type GBM xenograft model revealed that gefitinib alone could significantly improve survival in animals whereas sunitinib did not show any survival benefit. Subsequent testing of the same drug combination in a different syngeneic glioma model that lacked EGFR amplification but was more susceptible to sunitinib in vitro demonstrated no survival benefit when treated with gefitinib or sunitinib or the gefitinib and sunitinib combination. Although a modest survival benefit was obtained in one of two animal models with EGFR amplification due to gefitinib alone, the addition of sunitinib, to test our best in vitro combination therapy, did not translate to any additional in vivo benefit. Improved targeted therapies, with drug properties favorable to intracranial tumors, are likely required to form effective drug combinations for GBM.

  12. Effect of Ramipril (ACE inhibitor) on Renin Activity Response to Acute Renal Ischemia in the Ovariectomized and Uni-nephrectomized Rats

    MD, Atilla Semerciöz; MD, Mustafa K. Atikerler; MD, Haluk Keleştimur; MD, Bilal Üstündağ; MD, A Kasım Baltacı; PhD, Rasim Moğulkoç; MD, Can Baydinç

    1996-01-01

    Renin-angiotensin system is thought to be modulated by gonadal steroids. However, it has not been well established whether gonadal steroids also modulate the changes in plasma renin activity (PRA) occuring in response to stimuli such as acute renal ischemia and also the effects of angiotensin-converting enzyme (ACE) on PRA. The aim of the present experiment was to study the relationship between sex hormones and plasma renin activity during acute renal ischemia in the Wistar rats. For this pur...

  13. Concurrent neutral endopeptidase and ACE inhibition in experimental heart failure: renal and hormonal effects

    Helin, K

    1993-01-01

    Neutral endopeptidase (NEP) inhibitors have been shown to strengthen the effects of endogenous atrial natriuretic peptide (ANP). It has been well documented that angiotensin I-converting enzyme (ACE) inhibitors act beneficially in chronic congestive heart failure (CHF). In the present study, renal...... and hormonal effects of SCH 34826, an orally active NEP inhibitor, were studied in a coronary-ligation model of experimental CHF in the rat. The effects were compared to those of captopril. The drugs were also administered in combination. In anaesthetized rats with CHF, SCH 34826 (90 mg kg-1 sc) elevated...

  14. 酶解丝素蛋白制备ACE抑制肽的研究%Enzymatic Hydrolysis of Silk Fibroin for Production of ACE Inhibitors

    吴晖; 罗美琪; 唐语谦; 肖性龙; 袁坤; 李晓凤

    2011-01-01

    Silk fibroin was hydrolyzed by Alcalase to produce the peptide with high ACE-inhibition activity. The effects of several influential factors on the enzymatic hydrolysis were investigated and the optimum reaction conditions were determined as follows: pH 8.5, temperature 60 "C, substrate concentration 5%, enzyme dosage 1000 U/g protein, and reaction time 240 min, under which the DH. ACE-inhibition rate, peptide yield and protein recovery of the product were 17.12%, 74.07%, 50.31% and 77.37%, respectively. MALDI-TOF mass spectrometry of the hydrolysate showed that the molecular weight of (he peptides was below 2.4kDa.%本研究首次探讨利用Alcalase酶解丝素蛋白制备高活性ACE抑制肽.以水解度为主要评价指标,研究了温度、浓度、pH、加酶量以及反应时间对酶解反应的影响.分析了不同水解度下的酶解产物与ACE体外抑制活性、肽得率和蛋白回收率的关系.确定了制备ACE抑制肽的最佳酶解反应DH值为17.12%,此时所得丝素蛋白肽的肽得率为50.31%,蛋白回收率为77.37%,ACE抑制率可达74.07%.基质辅助激光解吸电离-飞行时间质谱仪(MALDI-TOF)分析表明,所制备的丝素蛋白肽的分子量小于2.4 kDa.

  15. Cancer risk and use of protease inhibitor or nonnucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy

    Bruyand, Mathias; Ryom, Lene; Shepherd, Leah;

    2015-01-01

    BACKGROUND: The association between combination antiretroviral therapy (cART) and cancer risk, especially regimens containing protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs), is unclear. METHODS: Participants were followed from the latest of D:A:D study entry or...

  16. Marketing ACE in Victoria.

    2001

    This publication presents options raised through various forums for marketing adult and community education (ACE) in Victoria, Australia, and suggested strategies. After an introduction (chapter 1), chapters 2 and 3 provide a broad view of the current situation for marketing ACE. Chapter 2 discusses general issues in the current position--ACE…

  17. Inhibitory Effect of Angiotensin-converting Enzyme Inhibitor Combined with Neda#atin on Hnmnu Nasopharyngeal Carcinoma CNE2 Cells%血管紧张素转换酶抑制剂联合奈达铂对鼻咽癌CNE2细胞的抑制作用

    莫正英; 李志玖; 梁清乐

    2009-01-01

    Objective To investigate the effect of angiotensin--converting enzyme inhibitor combined with nedaplatin on the growth of nasoph,taryngeal carcinoma CNE2 cells in vitro.Methods The effects of ACEI combined with nedaplatin on cell proliferation,cell cycle and VEGF expression of CNE2 were detected with MTr assay,flow cytometry,RT-PCR,Western blotting and ELISA,respectively.Results Neither NDP nor ACE-I had significant inhibitory effect on the CNE2 growth,while the combined application had significant inhibitory effect on the CNE2 growth VEGF expression.Conclusion The proliferation of CNE2 CoLdd be inhibited with the combination of ACE-I and NDP by inhibiting VEGF expression.%目的:研究血管紧张素转化酶抑制剂(ACE-I)联合奈达铂(NDP)在体外对鼻咽癌细胞生长的影响.方法:利用MTT比色法、流式细胞仪、RT-PCR、免疫印迹及酶联免疫等方法测定不同组(对照组、NDP组、ACE-I组、NDP+ACE-I组)对人鼻咽癌细胞CNE2生长、细胞周期及对血管内皮生长因子(VEGF)表达的影响.结果:单独NDP或ACE-I不能抑制CNE2细胞生长,联合应用能明显抑制CNE2细胞生长和VEGF的表达.结论:ACE-I和NDP联合抑制CNE2细胞增殖是通过抑制VEGF的表达实现的.

  18. Verapamil and angiotensin-converting enzyme inhibitors in patients with coronary artery disease and reduced left ventricular ejection fraction

    Hansen, J F; Tingsted, L; Rasmussen, Verner;

    1996-01-01

    Verapamil is effective as antianginal medication but contraindicated in patients with congestive heart failure. Angiotensin-converting enzyme (ACE) inhibitors improve survival in patients with congestive heart failure but have limited effect on patients with angina pectoris. No studies have been...... published on the combined treatment with verapamil and ACE inhibitors in patients with stable angina pectoris and left ventricular dysfunction. We performed an open study in 14 patients with angina pectoris and ejection fraction

  19. Choice of ACE inhibitor combinations in hypertensive patients with type 2 diabetes: update after recent clinical trials

    Gianpaolo Reboldi; Giorgio Gentile; Fabio Angeli; Paolo Verdecchia

    2009-01-01

    Gianpaolo Reboldi1, Giorgio Gentile1, Fabio Angeli2, Paolo Verdecchia2 1Department of Internal Medicine. University of Perugia, Italy; 2Department of Cardiology, Clinical Research Unit ‘Preventive Cardiology’ Hospital ‘Santa Maria della Misericordia’, Perugia, ItalyAbstract: The diabetes epidemic continues to grow unabated, with a staggering toll in micro- and macrovascular complications, disability, and death. Diabetes causes a two- to four-fold increa...

  20. Investigation of the energy barrier to the rotation of amide CN bonds in ACE inhibitors by NMR, dynamic HPLC and DFT.

    Bouabdallah, S; Ben Dhia, M T; Driss, M R; Touil, S

    2016-09-01

    The isomerizations of Enalapril, Perindopril, Enalaprilat and Lisinopril have been investigated using NMR spectroscopic, dynamic chromatographic, unified equation and DFT theoretical calculations. The thermodynamic parameters (ΔH, ΔS and ΔG) were determined by varying the temperature in the NMR experiments. At the coalescence temperature, we can evaluate the isomerization barrier to the rotation (ΔG(≠)) around the amide bond. Using dynamics chromatography and an unified equation introduced by Trap, we can determine isomerization rate constants and Gibbs activation energies. Molecular mechanics calculations also provided evidence for the presence of low energy conformers for the ACE due to restricted amide rotation. With the value of barriers (ΔE) between them of the order of (20kJmol(-1)), which is in agreement with the dynamic NMR results and DFT calculations. PMID:27344631

  1. Terapia com inibidor da ECA com dosagens relativamente altas e risco de agravamento renal na insuficiência cardíaca crônica ACE-inhibitor therapy at relatively high doses and risk of renal worsening in chronic heart failure

    Renato De Vecchis

    2011-12-01

    Full Text Available FUNDAMENTO: O efeito renoprotetor dos inibidores da ECA vem sendo questionado no caso de diminuição do volume circulante efetivo, como na insuficiência cardíaca crônica direita ou biventricular. Objetivo: Detectar os preditores clínicos de agravamento renal na população de pacientes com ICC, caracterizado por dois tipos de regime de dosagem de inibidores da ECA. MÉTODOS: De acordo com um desenho de coorte retrospectiva, seguimos dois grupos de pacientes com ICC - tanto direita quanto biventricular -, todos na classe III da NYHA, tratados com inibidores da ECA (enalapril ou lisinopril, e com fração de ejeção do ventrículo esquerdo (FEVE 10 mg por dia de enalapril ou lisinopril. A disfunção renal agravada (ARD foi definida pelo aumento de Cr > 30% com relação ao segmento basal. O modelo de risco proporcional de Cox foi utilizado para identificar os preditores da ARD entre as seguintes variáveis: os inibidores da ECA com "alta" dosagem, idade, FEVE basal, histórico de repetidas terapias intensivas com diuréticos de alça por via intravenosa (diurético intravenoso, diabete, Cr basal, histórico de hipertensão, pressão arterial sistólica BACKGROUND: Renoprotective effect of ACE-inhibitors has been questioned in case of decreased effective circulating volume, like in right or biventricular chronic heart failure. OBJECTIVE: To detect clinical predictors of renal worsening in CHF patient population characterized by two types of ACE-inhibitor dosing regimens. METHODS: According to a retrospective cohort design, we followed 2 groups of patients with CHF - whether right or biventricular -, all in III NYHA class treated with ACE-inhibitors (enalapril or lisinopril, and with left ventricular ejection fraction (LVEF 10 mg per day of enalapril or lisinopril. Worsened renal failure (ARD was defined by Cr increase >30% from baseline. Cox proportional hazards model was used to identify the predictors of ARD among the following variables

  2. Impact of clinically tested NEP/ACE inhibitors on tumor uptake of [111In-DOTA]MG11—first estimates for clinical translation

    Kaloudi, Aikaterini; Nock, Berthold A; Lymperis, Emmanouil; Valkema, Roelf; Krenning, Eric P.; de Jong, Marion; Maina, Theodosia

    2016-01-01

    Background We have recently shown that treatment of mice with the neutral endopeptidase (NEP) inhibitor phosphoramidon (PA) improves the bioavailability and tumor uptake of biodegradable radiopeptides. For the truncated gastrin radiotracer [111In-DOTA]MG11 ([(DOTA)DGlu10]gastrin(10–17)), this method led to impressively high tumor-to-kidney ratios. Translation of this concept in the clinic requires the use of certified NEP inhibitors, such as thiorphan (TO) and its orally administered prodrug ...

  3. The ACE experiment

    Maximilien Brice

    2006-01-01

    The Antiproton Cell Experiment (ACE) as shown by Michael Holzscheiter (spokesperson), Niels Bassler (co-spokesperson) and Helge Knudsen. ACE is located on the Antiproton Decelerator (AD) at CERN. An antiproton annihilates a proton in the nucleus of a cancer cell, producing a pair of gamma rays, destroying the entire cell and some surrounding cells. Many fewer antiprotons are required in this treatment than in the equivalent proton hadron therapy, so there is less risk of healthy tissue damage.

  4. Vitro Screening Models of ACE Inhibitors%血管紧张素转化酶抑制剂体外筛选模型的建立

    程艳霞; 任昉; 何林

    2004-01-01

    目的:本文通过紫外法与荧光法测定血管紧张素转化酶(ACE)活性,建立血管紧张素转化酶抑制剂(ACEI)的体外筛选模型.方法:采用紫外法和劳光法测ACE的活性.结果:两种方法均有良好的线性关系,测定卡托普利对ACE活性的抑制作用结果相符.荧光法避免了样品色素的干扰,可测定丹参提取液对ACE的抑制作用.结论:本筛选模型采用微量法,用酶标板进行测定,操作简便、快速、节约试剂和样品,具有高效、快速、可靠的特点.

  5. 一种新的转换酶抑制剂--福辛普利%A Novel Angiotensin-Converting Enzyme (ACE) Inhibitor: Fosinopril

    康建华

    2000-01-01

    福辛普利(蒙诺)是其活性二价酸福辛普利拉的酯类前体药物,也是新的磷酸类血管紧张素转换酶(ACE)抑制剂家族中的第一个成员.与其它ACE抑制剂一样,福辛普利主要通过阻断血管紧张素II的形成而降低血压,该药物在原发性高血压和心力衰竭等患者中已显示其临床效果.在ACE抑制剂中,福辛普利的特点是具有肝脏、肾脏双重清除途径,两者之间能保持平衡.研究表明,对于患慢性心力衰竭,并同时患有肾脏功能不全的患者来说,福辛普利可能是一种可与其它ACE抑制剂相替换的有价值的药物.

  6. mTOR inhibitors alone and in combination with JAK2 inhibitors effectively inhibit cells of myeloproliferative neoplasms.

    Costanza Bogani

    Full Text Available BACKGROUND: Dysregulated signaling of the JAK/STAT pathway is a common feature of chronic myeloproliferative neoplasms (MPN, usually associated with JAK2V617F mutation. Recent clinical trials with JAK2 inhibitors showed significant improvements in splenomegaly and constitutional symptoms in patients with myelofibrosis but meaningful molecular responses were not documented. Accordingly, there remains a need for exploring new treatment strategies of MPN. A potential additional target for treatment is represented by the PI3K/AKT/mammalian target of rapamycin (mTOR pathway that has been found constitutively activated in MPN cells; proof-of-evidence of efficacy of the mTOR inhibitor RAD001 has been obtained recently in a Phase I/II trial in patients with myelofibrosis. The aim of the study was to characterize the effects in vitro of mTOR inhibitors, used alone and in combination with JAK2 inhibitors, against MPN cells. FINDINGS: Mouse and human JAK2V617F mutated cell lines and primary hematopoietic progenitors from MPN patients were challenged with an allosteric (RAD001 and an ATP-competitive (PP242 mTOR inhibitor and two JAK2 inhibitors (AZD1480 and ruxolitinib. mTOR inhibitors effectively reduced proliferation and colony formation of cell lines through a slowed cell division mediated by changes in cell cycle transition to the S-phase. mTOR inhibitors also impaired the proliferation and prevented colony formation from MPN hematopoietic progenitors at doses significantly lower than healthy controls. JAK2 inhibitors produced similar antiproliferative effects in MPN cell lines and primary cells but were more potent inducers of apoptosis, as also supported by differential effects on cyclinD1, PIM1 and BcLxL expression levels. Co-treatment of mTOR inhibitor with JAK2 inhibitor resulted in synergistic activity against the proliferation of JAK2V617F mutated cell lines and significantly reduced erythropoietin-independent colony growth in patients with

  7. ACE and ACTN3 genes and muscle phenotypes in nonagenarians

    Bustamante-Ara, Natalia; Santiago Dorrego, Catalina; Verde Rello, Zoraida; Yvert, Thomas; Gómez Gallego, Félix; Rodríguez Romo, Gabriel; González Gil, Pedro; Serra-Rexach, José A.; Ruiz, Jonatan R.; Lucía Mulas, Alejandro

    2010-01-01

    We studied the association of ACE and ACTN3 polymorphisms with skeletal muscle phenotypes (i. e. upper and lower body muscular strength and functional tests) in Spanish nonagenarian subjects [n=41, 33 women, 8 men, age: 90-97 years]. Mean values of the study phenotypes were not significantly different (all P>0.05) between ACE and ACTN3 genotypes. The analyses of the combined effects between genotypes ( ACE DD & ACTN3 RR/RX vs. ACE II/ID & ACTN3 XX) did not yield any significant difference. Ou...

  8. Mechanical thrombectomy for cerebral venous sinus thrombosis employing a novel combination of Angiojet and Penumbra ACE aspiration catheters: the Triaxial Angiojet technique.

    Bress, Aaron; Hurst, Robert; Pukenas, Bryan; Smith, Michelle; Kung, David

    2016-09-01

    Cerebral venous sinus thrombosis (CVST) can be life threatening. A previously healthy woman in her early forties on oral contraceptives presented with global CVST and rapid clinical deterioration. A novel 'Triaxial Angiojet technique' (KSAW Shuttle [Cook Inc., Bloomington, IN, USA], 5 MAX ACE [Penumbra Inc., Alameda, CA, USA], and Angiojet [Boston Scientific, Marlborough, MA, USA]) was employed to gain access into the superior sagittal sinus. The 5 MAX ACE reperfusion catheter was shortened prior to placing a 4 Fr Angiojet catheter through it. This resulted in markedly improved recanalization with good anterograde flow. The patient was extubated on postoperative day 2 and discharged neurologically intact on postoperative day 10. We report the first case of placing an Angiojet catheter through a larger Penumbra reperfusion catheter when access through a tortuous sigmoid and transverse sinus could not be obtained with a 6 Fr support catheter. PMID:27052259

  9. 汉族人群中血管紧张素转换酶抑制剂所致咳嗽与血管紧张素转换酶基因及缓激肽β2受体基因多态性的关系%The Association between ACE Inhibitor (ACEI)-Induced Cough and the Polymorphism of Angiotensin Converting Enzyme (ACE) Gene and Bradykinin β2 Receptor(BDKRB2) Gene in Han Nationality

    王刚; 杨军; 唐振旺; 宁国庆; 曹燕; 万娟

    2012-01-01

    Objective: To investigate the association between angiotensin converting enzyme inhibitor (ACEI)-induced cough and the polymorphism of angiotensin converting enzyme (ACE) gene and bradykinin ($2 receptor (BDKRB2) gene in Han nationality. Methods: Polymerase chain reaction (PCR) was used to examine ACE I/D and BDKRB2 CT polymorphism in 151 ACEI-induced cough subjects and 151 no cough subjects in Han population. And UV-method was used to detect the ACE activity. Results:ACE gene distribution in the cough group: type II was 47.0%, ID genotype was 42.4%, DD genotype was 10.6%; Non-cough group were 39.7%, 47.0%, 13.3% respectively, and there was statistically significant difference between the two groups(P 0.05); The level of ACE activity in the Cough group [(28.3 ± 10.1) U / L,] was significantly lower than non-cough group [(40.2 ± 9.4) U / L,(P <0.01).]. Conclusions: For han population, ACEI-induced cough related to ACE gene polymorphism and serum ACE activity, and there was no statistically significant association between BDKRB2 C / T and cough.%目的:探讨汉族人群中血管紧张素转换酶抑制剂(ACEI)所致咳嗽与血管紧张素转换酶(ACE)基因及缓激肽β2受体(BDKRB2)基因多态性的关系.方法:应用聚合酶链反应(PCR)方法,检测汉族人群中151例由于服用ACEI引起的咳嗽患者及151例未发生咳嗽的患者的ACEI/D及BDKRB2C/T的多态性,并采用紫外法检测ACE活性.结果:发现ACE基因分布在咳嗽组中Ⅱ型为47.0%,ID型为42.4%,DD型为10.6%;无咳嗽组分别为39.7%、47.0%、13.3%,两组相比其差异具有统计学意义(P<0.01);BDKRB2基因分布在咳嗽组中CC型为21.3%,CT型为50.0%,TT型为28.7%,无咳嗽组分别为22.5%、47.7%、29.8%,两组相比其差异无统计学意义(P>0.05);咳嗽组ACE活性水平为[(28.3±10.1)U/L]明显低于无咳嗽组[(40.2± 9.4)U/L],两组相比其差异具有统计学意义(P<0.01).结论:汉族人群中ACEI所致咳嗽

  10. Combination treatment for myeloproliferative neoplasms using JAK and pan-class I PI3K inhibitors

    Choong, Meng Ling; Pecquet, Christian; Pendharkar, Vishal; Diaconu, Carmen C.; Yong, Jacklyn Wei Yan; Tai, Shi Jing; Wang, Si Fang; Defour, Jean-Philippe; Sangthongpitag, Kanda; Villeval, Jean-Luc; Vainchenker, William; Constantinescu, Stefan N.; Lee, May Ann

    2013-01-01

    Current JAK2 inhibitors used for myeloproliferative neoplasms (MPN) treatment are not specific enough to selectively suppress aberrant JAK2 signalling and preserve physiological JAK2 signalling. We tested whether combining a JAK2 inhibitor with a series of serine threonine kinase inhibitors, targeting nine signalling pathways and already used in clinical trials, synergized in inhibiting growth of haematopoietic cells expressing mutant and wild-type forms of JAK2 (V617F) or thrombopoietin rece...

  11. Corrosion inhibitors for carbon steel in neutral aqueous media based on the products of sugar cane processing. 3. Combined inhibitors

    Combined (mixed) inhibitors of metal corrosion in aqueous media are developed on the fasis of mixtures of 5-nitro furancarboxylic acid salts (nitrofuroat) with inorganic passivators (nitrite, phosphate, tetraborate) or with nitrogen-containing derivatives of furfural (furfurine, furfurylamine). Their efficiency is confirmed by electrochemical and weighing investigations carried outn under lamoratory and industrial conditions

  12. A crucial role in fertility for the oyster angiotensin-converting enzyme orthologue CgACE.

    Riviere, Guillaume; Fellous, Alexandre; Franco, Alban; Bernay, Benoit; Favrel, Pascal

    2011-01-01

    Angiotensin-converting enzyme (ACE) is a highly conserved metallopeptidase. In mammals, the somatic isoform governs blood pressure whereas the germinal isoform (tACE) is required for fertility. In Ecdysozoans, ACE-like enzymes are implicated in reproduction. Despite ACE orthologues being present from bacteria to humans, their function(s) remain(s) unknown in distant organisms such as Lophotrochozoans. In silico analysis of an oyster (Crassostrea gigas) EST library suggested the presence of an ACE orthologue in molluscs. Primer walking and 5'-RACE revealed that the 1.9 kb cDNA encodes CgACE, a 632 amino acid protein displaying a conserved single active site and a putative C-terminal transmembrane anchor, thus resembling human tACE, as supported by molecular modelling. FRET activity assays and Maldi-TOF spectrometry indicated that CgACE is a functional dipeptidyl-carboxypeptidase which is active on Angiotensin I and sensitive to ACE inhibitors and chloride ion concentration. Immunocytochemistry revealed that, as its human counterpart, recombinant CgACE is synthesised as a transmembrane enzyme. RT-qPCR, in-situ hybridization and immunohistochemistry shed light on a tissue, and development stage, specific expression pattern for CgACE, which is increased in the gonad during spermatogenesis. The use of ACE inhibitors in vivo indicates that the dipeptidase activity of CgACE is crucial for the oyster fertilization. Our study demonstrates that a transmembrane active ACE is present in the oyster Crassostrea gigas, and for the first time ascribes a functional role for ACE in Lophotrochozoans. Its biological function in reproduction is conserved from molluscs to humans, a finding of particular evolutionary interest especially since oysters represent the most important aquaculture resource worldwide. PMID:22174750

  13. A crucial role in fertility for the oyster angiotensin-converting enzyme orthologue CgACE.

    Guillaume Riviere

    Full Text Available Angiotensin-converting enzyme (ACE is a highly conserved metallopeptidase. In mammals, the somatic isoform governs blood pressure whereas the germinal isoform (tACE is required for fertility. In Ecdysozoans, ACE-like enzymes are implicated in reproduction. Despite ACE orthologues being present from bacteria to humans, their function(s remain(s unknown in distant organisms such as Lophotrochozoans. In silico analysis of an oyster (Crassostrea gigas EST library suggested the presence of an ACE orthologue in molluscs. Primer walking and 5'-RACE revealed that the 1.9 kb cDNA encodes CgACE, a 632 amino acid protein displaying a conserved single active site and a putative C-terminal transmembrane anchor, thus resembling human tACE, as supported by molecular modelling. FRET activity assays and Maldi-TOF spectrometry indicated that CgACE is a functional dipeptidyl-carboxypeptidase which is active on Angiotensin I and sensitive to ACE inhibitors and chloride ion concentration. Immunocytochemistry revealed that, as its human counterpart, recombinant CgACE is synthesised as a transmembrane enzyme. RT-qPCR, in-situ hybridization and immunohistochemistry shed light on a tissue, and development stage, specific expression pattern for CgACE, which is increased in the gonad during spermatogenesis. The use of ACE inhibitors in vivo indicates that the dipeptidase activity of CgACE is crucial for the oyster fertilization. Our study demonstrates that a transmembrane active ACE is present in the oyster Crassostrea gigas, and for the first time ascribes a functional role for ACE in Lophotrochozoans. Its biological function in reproduction is conserved from molluscs to humans, a finding of particular evolutionary interest especially since oysters represent the most important aquaculture resource worldwide.

  14. Study on extraction process of ACE inhibitor from kelp%海带ACE酶抑制剂的浸提工艺研究

    任丹丹; 汪秋宽; 吴超; 陈倩; 胡建恩

    2012-01-01

    以海带为研究对象,采用RP—HPLC法测定其水浸提液对ACE酶活性的抑制作用,从而探讨海带浸提液的降血压活性。通过单因素实验和正交实验,考察浸提料液比、浸提时间、浸提温度对海带浸提液活性的影响。结果表明.浸提的最佳工艺条件是料液比1:200,在30~C的水浴中浸提24h。在此条件下所得的海带根部浸提液、中部浸提液和假根浸提液对ACE酶活性的抑制率分别为66.7%、22.8%及80.7%,海带假根浸提液的活性最强。对浸提液的成分分析结果表明,海带假根浸提液中蛋白质、碘、总糖及岩藻聚糖硫酸酯含量最低,而氨基酸、钙离子和硫酸根含量最高。钠、镁、钾三种元素在海带根部、中部及假根浸提液中的会号差别不大.%RP-HPLC was used to evaluate the inhibitory activity of water extract from kelp to angiotensin converting enzyme(ACE) ,which could reveal its antihypertensive activity.Effects of three single factors including solid-liquid ratio,extraction time and temperature on activities of kelp extract were investigated by single factor and orthogonal test.The results showed that the optimum technological conditions were solid-liquid ratio 1 :200,30℃ in the water immersion for 24h.Inhibition rates of water extract from root, middle and rhizoid of kelp to ACE were 66.?% ,22.8% and 80.?%,respectively.Water extract from rhizoid of kelp was the most active part.The results of analysis on ingredients showed that water extract from rhizoid of kelp contained the lowest content of protein, iodine, total sugar and fucoidan, and the highest content of amino acid, calcium ion and sulfate radical.The contents of natrium, magnesium and kalium of different parts of kelp had no significant difference.

  15. The effects of ionizing radiation combined with autophagy inducers or inhibitors or inhibitors on human cervical cancer hela cells

    Objective: To detect the effects of ionizing radiation combined with autophagy inhibitors and inducers on the proliferation of human cervical cancer cell line. Methods: MTT and flowcytometry (FCM) were used to detect the surviving and proliferation of human cervical cancer cells,and analysis of the relationship of dose-effect and time-effect was made. Results: With the increase of irradiation doses (2, 4, 6, 8 and 10 Gy) and the elongation of irradiation time (24, 48 and 72 h), the inhibiting effect of ionizing radiation on the proliferation of human cervical cancer cells increased (P< 0.05 or P< 0.01). The inhibiting effect of 6 Gy combined with autophagy inducer rapamycin on the proliferation of Hela cells weakened (P< 0.05). The inhibiting effects of 6 Gy combined with autophagy inhibitor 3-MA on the cell proliferation were higher than those in 6 Gy group (P< 0.05). Conclusion: Ionizing radiation combined with autophagy inducers can inhibit apoptosis in Hela cells, while the ionizing radiation combined with autophagy inhibitors can promote their apoptosis. (authors)

  16. Titration of signalling output: insights into clinical combinations of MEK and AKT inhibitors

    STEWART, A.; Thavasu, P.; de Bono, J S; Banerji, U

    2015-01-01

    Background We aimed to understand the relative contributions of inhibiting MEK and AKT on cell growth to guide combinations of these agents. Materials and methods A panel of 20 cell lines was exposed to either the MEK inhibitor, PD0325901, or AKT inhibitor, AKT 1/2 inhibitor. p-ERK and p-S6 ELISAs were used to define degrees of MEK and AKT inhibition, respectively. Growth inhibition to different degrees of MEK and AKT inhibition, either singly or in combination using 96-h sulphorhodamine assa...

  17. Chlorine activation in the Arctic winter of 2009/2010 analyzed by combined use of JEM/SMILES and ACE-FTS

    Yuji, T.; Saitoh, N.; Sugita, T.; Kasai, Y.

    2013-12-01

    The Superconducting Submillimeter-Wave Limb-Emission Sounder (SMILES) equipped in the Japanese Experiment Module "KIBO" on board the International Space Station (ISS) had observed atmospheric minor constituents including ClO in the stratosphere and mesosphere from October 12, 2009 to April 21, 2010 with more than ten times the precision of other existing sensors due to its unprecedented high sensitivity with superconducting technology. The Atmospheric Chemistry Experiment-Fourier Transform Spectrometer (ACE-FTS), which is on board SCISAT-1, has been observing atmospheric minor constituents in the upper troposphere and stratosphere since March 11, 2004 by solar occultation technique. We have analyzed the SMILES Level 2 (L2) V2.1.5 research products and the ACE-FTS L2 V3.0 products to discuss the relationship between temperature and stratospheric minor gases related to ozone depletion and the time variation of 'Cl partitioning' in the Arctic winter of 2009/2010. The correlation between the SMILES L2r ClO concentration and temperature on 475 K and 525 K from mid-January to early February showed that the ClO concentrations were higher than 0.5 ppbv at equivalent latitudes higher than 70° and solar zenith angles lower than 96°, where the temperatures were well lower than 200 K; the ClO concentrations and the solar zenith angles had a positive correlation in the region where the ClO concentrations were higher than 0.5 ppbv. However, some data with high ClO concentration also occurred under relatively warmer conditions where PSCs were not expected to exist. The temperature histories of those data showed that they had experienced near ice frost point of ~187 K at 2-4 days before the observations, and then the temperatures drastically increased as much as 20 degrees just before the observations. We have analyzed a time-series of 'Cl partitioning' by using ClO, HOCl, and HCl observed by SMILES and HCl and ClONO2 observed by ACE-FTS inside the polar vortex in 2009/2010. HCl

  18. ZD6474, an inhibitor of VEGFR and EGFR tyrosine kinase activity in combination with radiotherapy

    Radiation enhances both epithelial growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) expression, which are a part of key pathways for tumor progression. Some tumors may not respond well to EGFR inhibitors alone or may develop resistance to EGFR inhibitors. Therefore, drug therapy targeted to VEGF receptors and EGFRs, when combined with radiotherapy (RT), may improve tumor control and provide wider applicability. This article focuses on ZD6474, an inhibitor of EGFR and VEGF receptor signaling in combination with RT. We discuss preclinical and clinical studies with RT and inhibitors of VEGF or EGFR signaling first. We then address issues associated with ZD6474 pharmacokinetic dosing, and scheduling when combined with RT. We also discuss ZD6474 in the context of anti-EGFR therapy resistance. Dual inhibition of EGFR and VEGF receptor signaling pathways shows promise in enhancing RT efficacy

  19. Combination with γ-secretase inhibitor prolongs treatment efficacy of BRAF inhibitor in BRAF-mutated melanoma cells.

    Zhu, Guannan; Yi, Xiuli; Haferkamp, Sebastian; Hesbacher, Sonja; Li, Chunying; Goebeler, Matthias; Gao, Tianwen; Houben, Roland; Schrama, David

    2016-06-28

    Oncogenic triggering of the MAPK pathway in melanocytes results in senescence, and senescence escape is considered as one critical step for melanocytic transformation. In melanoma, induction of a senescent-like state by BRAF-inhibitors (BRAFi) in a fraction of treated cells - instead of killing - contributes to the repression of tumor growth, but may also provide a source for relapse. Here, we demonstrate that NOTCH activation in melanocytes is not only growth-promoting but it also protects these cells against oncogene-induced senescence. In turn, treatment of melanoma cells with an inhibitor of the NOTCH-activating enzyme γ-secretase led to induction of a senescent-like status in a fraction of the cells but overall achieved only a moderate inhibition of melanoma cell growth. However, combination of γ-secretase inhibitor (GSI) with BRAFi markedly increased the treatment efficacy particularly in long-term culture. Moreover, even melanoma cells starting to regrow after continuous BRAFi treatment - the major problem of BRAFi therapy in patients - can still be affected by the combination treatment. Thus, combining GSI with BRAFi increases the therapeutic efficacy by, at least partially, prolonging the senescent-like state of treated cells. PMID:27000992

  20. Durability of Steel Fibres Reinforcement Concrete Beams in Chloride Environment Combined with Inhibitor

    AbdelMonem Masmoudi

    2016-01-01

    Full Text Available This paper presented the effect of the combination of an inhibitor and steel fibre reinforced concrete (SFRC for concrete structures in chloride environments. Twelve beams were cast and tested to study their flexural behavior. The morphology of steel surfaces using the inhibitor after observing the scanning electron microscope showed a low layer of corrosion products. The steel surface immersed in the inhibitor free solution was seen to have been subject to chloride ions attacks as shown in this study. The interest to the field of the present study is the relatively higher durability of the performance when using the inhibitor. Crack width and crack spacing for beams under the same load showed that the use of SFRC with the inhibitor for concrete structures in chloride environments must have transferred tension across cracks that led to reducing crack spacing without any chloride ions attack.

  1. Renal graft failure after addition of an angiotensin II receptor antagonist to an angiotensin-converting enzyme inhibitor

    Kamper, Anne-Lise; Nielsen, Arne Høj; Baekgaard, Niels;

    2002-01-01

    Combined treatment with an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II (Ang II) receptor blocker (ARB) has been suggested in order to achieve a more complete blockade of the renin-angiotensin-aldosterone system in cardiovascular and renal disease. The present report...... describes a case of acute renal graft dysfunction following the addition of an ARB to existing ACE inhibition. This unmasked an unknown iliac artery stenosis. The case indicates a possible important role of Ang II generated by non-ACE pathways in this situation....

  2. Combining the pan-aurora kinase inhibitor AMG 900 with histone deacetylase inhibitors enhances antitumor activity in prostate cancer

    Histone deacetylase inhibitors (HDACIs) are being tested in clinical trials for the treatment of solid tumors. While most studies have focused on the reexpression of silenced tumor suppressor genes, a number of genes/pathways are downregulated by HDACIs. This provides opportunities for combination therapy: agents that further disable these pathways through inhibition of residual gene function are speculated to enhance cell death in combination with HDACIs. A previous study from our group indicated that mitotic checkpoint kinases such as PLK1 and Aurora A are downregulated by HDACIs. We used in vitro and in vivo xenograft models of prostate cancer (PCA) to test whether combination of HDACIs with the pan-aurora kinase inhibitor AMG 900 can synergistically or additively kill PCA cells. AMG 900 and HDACIs synergistically decreased cell proliferation activity and clonogenic survival in DU-145, LNCaP, and PC3 PCA cell lines compared to single-agent treatment. Cellular senescence, polyploidy, and apoptosis was significantly increased in all cell lines after combination treatment. In vivo xenograft studies indicated decreased tumor growth and decreased aurora B kinase activity in mice treated with low-dose AMG 900 and vorinostat compared to either agent alone. Pharmacodynamics was assessed by scoring for phosphorylated histone H3 through immunofluorescence. Our results indicate that combination treatment with low doses of AMG 900 and HDACIs could be a promising therapy for future clinical trials against PCA

  3. New perspectives in the renin-angiotensin-aldosterone system (RAAS I: endogenous angiotensin converting enzyme (ACE inhibition.

    Miklós Fagyas

    Full Text Available Angiotensin-converting enzyme (ACE inhibitors represent the fifth most often prescribed drugs. ACE inhibitors decrease 5-year mortality by approximately one-fifth in cardiovascular patients. Surprisingly, there are reports dating back to 1979 suggesting the existence of endogenous ACE inhibitors, which endogenous inhibitory effects are much less characterized than that for the clinically administered ACE inhibitors. Here we aimed to investigate this endogenous ACE inhibition in human sera. It was hypothesized that ACE activity is masked by an endogenous inhibitor, which dissociates from the ACE when its concentration decreases upon dilution. ACE activity was measured by FAPGG hydrolysis first. The specific (dilution corrected enzyme activities significantly increased by dilution of human serum samples (23.2 ± 0.7 U/L at 4-fold dilution, 51.4 ± 0.3 U/L at 32-fold dilution, n = 3, p = 0.001, suggesting the presence of an endogenous inhibitor. In accordance, specific enzyme activities did not changed by dilution when purified renal ACE was used, where no endogenous inhibitor was present (655 ± 145 U/L, 605 ± 42 U/L, n = 3, p = 0.715, respectively. FAPGG conversion strongly correlated with angiotensin I conversion suggesting that this feature is not related to the artificial substrate. Serum samples were ultra-filtered to separate ACE (MW: 180 kDa and the hypothesized inhibitor. Filtering through 50 kDa filters was without effect, while filtering through 100 kDa filters eliminated the inhibiting factor (ACE activity after <100 kDa filtering: 56.4 ± 2.4 U/L, n = 4, control: 26.4 ± 0.7 U/L, n = 4, p<0.001. Lineweaver-Burk plot indicated non-competitive inhibition of ACE by this endogenous factor. The endogenous inhibitor had higher potency on the C-terminal active site than N-terminal active site of ACE. Finally, this endogenous ACE inhibition was also present in mouse, donkey, goat, bovine sera besides men (increasing of specific ACE activity

  4. The Pharmacogenetic Footprint of ACE Inhibition: A Population-Based Metabolomics Study.

    Altmaier, Elisabeth; Menni, Cristina; Heier, Margit; Meisinger, Christa; Thorand, Barbara; Quell, Jan; Kobl, Michael; Römisch-Margl, Werner; Valdes, Ana M; Mangino, Massimo; Waldenberger, Melanie; Strauch, Konstantin; Illig, Thomas; Adamski, Jerzy; Spector, Tim; Gieger, Christian; Suhre, Karsten; Kastenmüller, Gabi

    2016-01-01

    Angiotensin-I-converting enzyme (ACE) inhibitors are an important class of antihypertensives whose action on the human organism is still not fully understood. Although it is known that ACE especially cleaves COOH-terminal dipeptides from active polypeptides, the whole range of substrates and products is still unknown. When analyzing the action of ACE inhibitors, effects of genetic variation on metabolism need to be considered since genetic variance in the ACE gene locus was found to be associated with ACE-concentration in blood as well as with changes in the metabolic profiles of a general population. To investigate the interactions between genetic variance at the ACE-locus and the influence of ACE-therapy on the metabolic status we analyzed 517 metabolites in 1,361 participants from the KORA F4 study. We replicated our results in 1,964 individuals from TwinsUK. We observed differences in the concentration of five dipeptides and three ratios of di- and oligopeptides between ACE inhibitor users and non-users that were genotype dependent. Such changes in the concentration affected major homozygotes, and to a lesser extent heterozygotes, while minor homozygotes showed no or only small changes in the metabolite status. Two of these resulting dipeptides, namely aspartylphenylalanine and phenylalanylserine, showed significant associations with blood pressure which qualifies them-and perhaps also the other dipeptides-as readouts of ACE-activity. Since so far ACE activity measurement is substrate specific due to the usage of only one oligopeptide, taking several dipeptides as potential products of ACE into account may provide a broader picture of the ACE activity. PMID:27120469

  5. The Pharmacogenetic Footprint of ACE Inhibition: A Population-Based Metabolomics Study

    Altmaier, Elisabeth; Menni, Cristina; Heier, Margit; Meisinger, Christa; Thorand, Barbara; Quell, Jan; Kobl, Michael; Römisch-Margl, Werner; Valdes, Ana M.; Mangino, Massimo; Waldenberger, Melanie; Strauch, Konstantin; Illig, Thomas; Adamski, Jerzy; Spector, Tim; Gieger, Christian; Suhre, Karsten; Kastenmüller, Gabi

    2016-01-01

    Angiotensin-I-converting enzyme (ACE) inhibitors are an important class of antihypertensives whose action on the human organism is still not fully understood. Although it is known that ACE especially cleaves COOH-terminal dipeptides from active polypeptides, the whole range of substrates and products is still unknown. When analyzing the action of ACE inhibitors, effects of genetic variation on metabolism need to be considered since genetic variance in the ACE gene locus was found to be associated with ACE-concentration in blood as well as with changes in the metabolic profiles of a general population. To investigate the interactions between genetic variance at the ACE-locus and the influence of ACE-therapy on the metabolic status we analyzed 517 metabolites in 1,361 participants from the KORA F4 study. We replicated our results in 1,964 individuals from TwinsUK. We observed differences in the concentration of five dipeptides and three ratios of di- and oligopeptides between ACE inhibitor users and non-users that were genotype dependent. Such changes in the concentration affected major homozygotes, and to a lesser extent heterozygotes, while minor homozygotes showed no or only small changes in the metabolite status. Two of these resulting dipeptides, namely aspartylphenylalanine and phenylalanylserine, showed significant associations with blood pressure which qualifies them—and perhaps also the other dipeptides—as readouts of ACE-activity. Since so far ACE activity measurement is substrate specific due to the usage of only one oligopeptide, taking several dipeptides as potential products of ACE into account may provide a broader picture of the ACE activity. PMID:27120469

  6. Combination of PIM and JAK2 inhibitors synergistically suppresses cell proliferation and overcomes drug resistance of myeloproliferative neoplasms

    Huang, Shih-Min A.; Wang, Anlai; Greco, Rita; LI, Mrs Zhifang; Sun, Fangxian; Barberis, Claude; Tabart, Michel; Patel, Vinod; Schio, Laurent; Hurley, Raelene; Chen, Bo; Cheng, Hong; Lengauer, Christoph; Pollard, Jack; Watters, James

    2014-01-01

    Inhibitors of JAK2 kinase are emerging as an important treatment modality for myeloproliferative neoplasms (MPN). However, similar to other kinase inhibitors, resistance to JAK2 inhibitors may eventually emerge through a variety of mechanisms. Effective drug combination is one way to enhance therapeutic efficacy and combat resistance against JAK2 inhibitors. To identify potential combination partners for JAK2 compounds in MPN cell lines, we performed pooled shRNA screen targeting 5,000 genes ...

  7. A mathematical model of combined therapies against cancer using viruses and inhibitors

    2008-01-01

    This paper deals with a procedure for combined therapies against cancer using oncolytic viruses and inhibitors. Replicating genetically modified adenoviruses infect cancer cells, reproduce inside them and eventually cause their death (lysis). As infected cells die, the viruses inside them are released and then proceed to infect other tumor cells. The successful entry of virus into cancer cells is related to the presence of the coxsackie-adenovirus receptor (CAR). Mitogen-activated protein kinase kinase (known as MEK) inhibitors can promote CAR expression, resulting in enhanced adenovirus entry into cancer cells. However, MEK inhibitors can also cause G1 cell-cycle arrest, inhibiting reproduction of the virus. To design an effective synergistic therapy, the promotion of virus infection must be optimally balanced with inhibition of virus production. We introduce a mathematical model to describe the effects of MEK inhibitors and viruses on tumor cells, and use it to explore the reduction of the tumor size that can be achieved by the combined therapies. Furthermore, we find an optimal dose of inhibitor: Poptimal = 1 - μ/δ for a certain initial density of cells (where μ is the removal rate of the dead cells and δ is the death rate of the infected cells). The optimal timing of MEK inhibitors is also numerically studied.

  8. A mathematical model of combined therapies against cancer using viruses and inhibitors

    TAO YouShan; GUO Qian

    2008-01-01

    This paper deals with a procedure for combined therapies against cancer using oncolytic viruses and inhibitors. Replicating genetically modified adenoviruses infect cancer cells, reproduce inside them and eventually cause their death (lysis). As infected cells die, the viruses inside them are released and then proceed to infect other tumor cells. The successful entry of virus into cancer cells is related to the presence of the coxsackie-adenovirus receptor (CAR). Mitogen-activated protein kinase kinase (known as MEK) inhibitors can promote CAR expression, resulting in enhanced adenovirus entry into cancer cells. However, MEK inhibitors can also cause G1 cell-cycle arrest, inhibiting reproduction of the virus. To design an effective synergistic therapy, the promotion of virus infection must be optimally balanced with inhibition of virus production. We introduce a mathematical model to describe the effects of MEK inhibitors and viruses on tumor cells, and use it to explore the reduction of the tumor size that can be achieved by the combined therapies. Furthermore, we find an optimal dose of inhibitor: Poptimal = I - μ/δ for a certain initial density of cells (where μ is the removal rate of the dead cells and δ is the death rate of the infected cells). The optimal timing of MEK inhibitors is also numerically studied.

  9. Possible involvement of ATP-dependent K-channel related mechanisms in the antihypertensive and cough suppressant effects of the novel ACE inhibitor (2S, 3aS, 7aS)-1-(N2-nicotinoyl-L-lysyl-gamma-D-glutamyl)octahydro-1H- indole-2-carboxylic acid.

    Nagata, S; Takeyama, K; Hosoki, K; Karasawa, T

    1997-06-01

    The antihypertensive and cough suppressant mechanisms of DU-1777 ((2S,3aS,7aS)-1-(N2-nicotinoyl-L-lsyl-gamma-D-glutamyl )octahydro-1H-indole-2 -carboxylic acid, CAS 116662-73-8), a new long-acting angiotensin-1-converting enzyme (ACE) inhibitor, were investigated in vivo and in vitro. The antihypertensive effects of DU-1777 at 10 mg/kg p.o. and cromakalim at 0.3 mg/kg p.o. were partially (about 60%) or fully antagonized by glibenclamide at 10 mg/kg i.v. in 2-kidney, 1-clip renal hypertensive rats (2K-1C RHR). The antihypertensive effects of a Ca blocker (nifedipine) and other ACE inhibitors (captopril, alacepril, enalapril, lisinopril, imidapril and quanapril) were not antagonized by glibenclamide. In deoxycorticosterone acetate-salt hypertensive rats (DOCA-HR), the antihypertensive effects of DU-1777 at 3-30 mg/kg p.o. were fully antagonized by glibenclamide. However, in vitro, DU-1777 (10(-6)-10(-3) mol/l) did not affect aortic ring contractions induced by high K (30 mmol/l). In guinea pig, citric acid induced cough was increased by ACE inhibitors, captopril, alacepril, enalapril and lisinopril (10 and 30 mg/kg p.o.). DU-1777 had a tendency to decrease citric acid induced cough and the effect was antagonized by glibenclamide. These results suggest that while DU-1777 itself does not open ATP-dependent K channel, it indirectly produces these effects through unknown mechanisms in vivo. Moreover, these effects contributed to the antihypertensive effect in DOCA-HR and cough suppressant effect in guinea pigs. PMID:9239450

  10. Elevated ACE activity is not associated with asthma, COPD, and COPD co-morbidity

    Lee, Julie; Nordestgaard, Børge G; Dahl, Morten

    2009-01-01

    .4-1.2). The results were similar upon adjustment for sex, age, smoking status, body mass index, total cholesterol, and ACE inhibitor/angiotensin II type 1 receptor blocker use. These data suggest that lifelong genetically elevated ACE activity is not a major risk factor for asthma or COPD, or for ischemic heart......The angiotensin-converting enzyme (ACE) gene is a potential candidate gene for risk of asthma, COPD, and COPD co-morbidity. In 9034 Danish adults, we determined whether individuals homozygous or heterozygous for the ACE D allele are at greater risk of asthma, COPD, or COPD co-morbidity compared...... with ACE II homozygous individuals. In the general population, serum ACE activity increased with the number of D alleles (Kruskal-Wallis ANOVA: II vs. ID, p

  11. 血管紧张素转换酶抑制剂治疗高血压病人的疗效与血管紧张素转换酶基因多态性的关系%Relationship Between ACE I/D Gene Polymorphism and the Curative Effects of Angiotensin-converting Enzyme Inhibitor in Hypertensive Individuals

    李锡明; 高春江

    2001-01-01

    目的探讨具不同血管紧张素转换酶基因插入/缺矢基因型(Angiotension-converting enzyme gene I/D genotype, ACE I/D genotype)的高血压病人对血管紧张素转换酶抑制剂(Angiotension-converting enzyme inhibitor, ACEI)治疗的反应性.方法根据ACE Ⅰ/D 基因多态性,将高血压病人分为II 组(20例),ID 组(20例),及DD 组(18例),共58例.使用西拉普利2.5mg Q.D,两周后无效增至5mg Q.D共4周,观察降压疗效.结果 II组显效2例,有效12例,总有效率70%;ID组显效8例,有效8例,总有效率80%;DD组显效13例,有效4例,总有效率94%.ACEI 对DD组疗效最好(P<0.01),降压幅度最大,ID组次之,II组较差.结论 ACE I/D 基因多态性可做为高血压病人选用ACEI 时的参考指标之一.

  12. Antioxidant activity and ACE-inhibitory of Class II hydrophobin from wild strain Trichoderma reesei.

    Khalesi, Mohammadreza; Jahanbani, Raheleh; Riveros-Galan, David; Sheikh-Hassani, Vahid; Sheikh-Zeinoddin, Mahmoud; Sahihi, Mehdi; Winterburn, James; Derdelinckx, Guy; Moosavi-Movahedi, Ali Akbar

    2016-10-01

    There are several possible uses of the Class II hydrophobin HFBII in clinical applications. To fully understand and exploit this potential however, the antioxidant activity and ACE-inhibitory potential of this protein need to be better understood and have not been previously reported. In this study, the Class II hydrophobin HFBII was produced by the cultivation of wild type Trichoderma reesei. The crude hydrophobin extract obtained from the fermentation process was purified using reversed-phase liquid chromatography and the identity of the purified HFBII verified by MALDI-TOF (molecular weight: 7.2kDa). Subsequently the antioxidant activities of different concentrations of HFBII (0.01-0.40mg/mL) were determined. The results show that for HFBII concentrations of 0.04mg/mL and upwards the protein significantly reduced the presence of ABTS(+) radicals in the medium, the IC50 value found to be 0.13mg/mL. Computational modeling highlighted the role of the amino acid residues located in the conserved and exposed hydrophobic patch on the surface of the HFBII molecule and the interactions with the aromatic rings of ABTS. The ACE-inhibitory effect of HFBII was found to occur from 0.5mg/mL and upwards, making the combination of HFBII with strong ACE-inhibitors attractive for use in the healthcare industry. PMID:27211298

  13. ACE up the sleeve – are vascular patients medically optimized

    AP Coveney

    2011-01-01

    Full Text Available AP Coveney, GC O’Brien, GJ FultonDepartment of Vascular Surgery, Cork University Hospital and National University of Ireland, Cork, IrelandObjective: To examine the current medical management of arteriopathic patients attending a vascular surgical service at a university teaching hospital over a 6-month period. The prescribing of antiplatelets, statins, angiotensin-converting enzyme (ACE inhibitors, or angiotensin receptor blockers and beta-blockers was specifically examined. Vascular patients are often under the care of multiple specialties, and therefore the influence of different medical specialties on the patients’ medical management was also examined.Design: Between January and June 2009, data were recorded on sequential patients with arterial disease attending the vascular surgical service. Patients’ demographics, type of arterial disease, medical consultations within the previous 12 months, and current medications were recorded.Results: The study included 180 patients with a mean age of 69 years (39–88 years. All but 4% were taking an antiplatelet or anticoagulant, predominantly aspirin. There were 86% taking a statin, 44% taking a beta-blocker, and 51% taking an ACE inhibitor. Suboptimal prescription of ACE inhibitors and beta-blockers was evident regardless of the type of medical consultations in the previous year. No specialty group differed significantly from vascular surgeons in their prescribing pattern.Conclusions: While almost all arteriopaths receive some form of antiplatelet and statin in line with clinical evidence, ACE inhibitors and beta-blockers appear to be under-prescribed in this arteriopathic population. We conclude that opportunity exists for vascular surgeons to embrace recent guidelines and lead the way in both surgical and medical optimization of arteriopathic patients through improving links with primary care physicians or taking greater responsibility themselves for the medical as well as the surgical care

  14. Combination of a Selective HSP90α/β Inhibitor and a RAS-RAF-MEK-ERK Signaling Pathway Inhibitor Triggers Synergistic Cytotoxicity in Multiple Myeloma Cells

    Mimura, Naoya; Minami, Jiro; Ohguchi, Hiroto; Yoshida, Yasuhiro; Sagawa, Morihiko; Gorgun, Gullu; Cirstea, Diana; Cottini, Francesca; Jakubikova, Jana; Tai, Yu-Tzu; Chauhan, Dharminder; Richardson, Paul G.; Munshi, Nikhil; Ando, Kiyoshi; Utsugi, Teruhiro; Hideshima, Teru; Anderson, Kenneth C.

    2015-01-01

    Heat shock protein (HSP)90 inhibitors have shown significant anti-tumor activities in preclinical settings in both solid and hematological tumors. We previously reported that the novel, orally available HSP90α/β inhibitor TAS-116 shows significant anti-MM activities. In this study, we further examined the combination effect of TAS-116 with a RAS-RAF-MEK-ERK signaling pathway inhibitor in RAS- or BRAF-mutated MM cell lines. TAS-116 monotherapy significantly inhibited growth of RAS-mutated MM cell lines and was associated with decreased expression of downstream target proteins of the RAS-RAF-MEK-ERK signaling pathway. Moreover, TAS-116 showed synergistic growth inhibitory effects with the farnesyltransferase inhibitor tipifarnib, the BRAF inhibitor dabrafenib, and the MEK inhibitor selumetinib. Importantly, treatment with these inhibitors paradoxically enhanced p-C-Raf, p-MEK, and p-ERK activity, which was abrogated by TAS-116. TAS-116 also enhanced dabrafenib-induced MM cytotoxicity associated with mitochondrial damage-induced apoptosis, even in the BRAF-mutated U266 MM cell line. This enhanced apoptosis in RAS-mutated MM triggered by combination treatment was observed even in the presence of bone marrow stromal cells. Taken together, our results provide the rationale for novel combination treatment with HSP90α/β inhibitor and RAS-RAF-MEK-ERK signaling pathway inhibitors to improve outcomes in patients with in RAS- or BRAF-mutated MM. PMID:26630652

  15. Combination of Proteasomal Inhibitors Lactacystin and MG132 Induced Synergistic Apoptosis in Prostate Cancer Cells

    Robert B. Shirley

    2005-12-01

    Full Text Available The proteasome inhibitor Velcade (bortezomib/PS-341 has been shown to block the targeted proteolytic degradation of short-lived proteins that are involved in cell maintenance, growth, division, and death, advocating the use of proteasomal inhibitors as therapeutic agents. Although many studies focused on the use of one proteasomal inhibitor for therapy, we hypothesized that the combination of proteasome inhibitors Lactacystin (AG Scientific, Inc., San Diego, CA and MG132 (Biomol International, Plymouth Meeting, PA may be more effective in inducing apoptosis. Additionally, this regimen would enable the use of sublethal doses of individual drugs, thus reducing adverse effects. Results indicate a significant increase in apoptosis when LNCaP prostate cancer cells were treated with increasing levels of Lactacystin, MG132, or a combination of sublethal doses of these two inhibitors. Furthermore, induction in apoptosis coincided with a significant loss of IKKα, IKKβ, and IKKγ proteins and NFκB activity. In addition to describing effective therapeutic agents, we provide a model system to facilitate the investigation of the mechanism of action of these drugs and their effects on the IKK-NFκB axis.

  16. Cancer risk and use of protease inhibitor or nonnucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy: the D: A: D study

    Bruyand, M.; Ryom, L.; Shepherd, L.; Fatkenheuer, G.; Grulich, A.; Reiss, P.; Wit, S. de; Monforte, A.M.; Furrer, H.; Pradier, C.; Lundgren, J.; Sabin, C.; Warris, A.

    2015-01-01

    BACKGROUND: The association between combination antiretroviral therapy (cART) and cancer risk, especially regimens containing protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs), is unclear. METHODS: Participants were followed from the latest of D:A:D study entry or

  17. Cancer risk and use of protease inhibitor or nonnucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy : the D: A: D study

    Bruyand, Mathias; Ryom, Lene; Shepherd, Leah; Fatkenheuer, Gerd; Grulich, Andrew; Reiss, Peter; de Wit, Stéphane; D Arminio Monforte, Antonella; Furrer, Hansjakob; Pradier, Christian; Lundgren, Jens; Sabin, Caroline; Schölvinck, Elisabeth H.

    2015-01-01

    BACKGROUND: The association between combination antiretroviral therapy (cART) and cancer risk, especially regimens containing protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs), is unclear. METHODS: Participants were followed from the latest of D:A:D study entry or

  18. Lovastatin inhibits VEGFR and AKT activation: synergistic cytotoxicity in combination with VEGFR inhibitors.

    Tong T Zhao

    Full Text Available BACKGROUND: In a recent study, we demonstrated the ability of lovastatin, a potent inhibitor of mevalonate synthesis, to inhibit the function of the epidermal growth factor receptor (EGFR. Lovastatin attenuated ligand-induced receptor activation and downstream signaling through the PI3K/AKT pathway. Combining lovastatin with gefitinib, a potent EGFR inhibitor, induced synergistic cytotoxicity in a variety of tumor derived cell lines. The vascular endothelial growth factor receptor (VEGFR and EGFR share similar activation, internalization and downstream signaling characteristics. METHODOLOGY/PRINCIPAL FINDINGS: The VEGFRs, particularly VEGFR-2 (KDR, Flt-1, play important roles in regulating tumor angiogenesis by promoting endothelial cell proliferation, survival and migration. Certain tumors, such as malignant mesothelioma (MM, also express both the VEGF ligand and VEGFRs that act in an autocrine loop to directly stimulate tumor cell growth and survival. In this study, we have shown that lovastatin inhibits ligand-induced VEGFR-2 activation through inhibition of receptor internalization and also inhibits VEGF activation of AKT in human umbilical vein endothelial cells (HUVEC and H28 MM cells employing immunofluorescence and Western blotting. Combinations of lovastatin and a VEGFR-2 inhibitor showed more robust AKT inhibition than either agent alone in the H28 MM cell line. Furthermore, combining 5 µM lovastatin treatment, a therapeutically relevant dose, with two different VEGFR-2 inhibitors in HUVEC and the H28 and H2052 mesothelioma derived cell lines demonstrated synergistic cytotoxicity as demonstrated by MTT cell viability and flow cytometric analyses. CONCLUSIONS/SIGNIFICANCE: These results highlight a novel mechanism by which lovastatin can regulate VEGFR-2 function and a potential therapeutic approach for MM through combining statins with VEGFR-2 inhibitors.

  19. Advanced Customer Oriented Development of Software (ACES

    Stojan Russev

    2006-12-01

    Full Text Available Object oriented development languages and event driven programming, distributed or centralized data processing with thick or rich clients are used at present in information systems (IS development. Using of existing methodologies and methods In IS designing does not always mean reaching of needed project solution quality. In some cases it is more effective to use combination of structured and object oriented tools or new methodology, which is built according the newest information technologies. One of such methodologies is Advanced Customer Oriented Development of Software (ACES, which is oriented on IS of economic organization development and application of the newest information technologies. ACES was established by the authors at Faculty of Economic Informatics of University of Economics in Bratislava.

  20. Beginning RPG Maker VX Ace

    Perez, Darrin

    2014-01-01

    Beginning RPG Maker VX Ace takes you through the process of using the RPG Maker VX Ace game development engine to create your very own role playing game. The book has been designed with the complete beginner in mind who has little to no experience with the engine. Tutorials and exercises will take you from installing the software to putting the final touches upon your first project. Game design can be quite a daunting challenge, as it generally involves a large amount of programming know-how on top of having to plan everything out that makes a good game what it is. RPG Maker VX Ace

  1. Combining RNA interference and kinase inhibitors against cell signalling components involved in cancer

    Hanson Bonnie J

    2005-10-01

    Full Text Available Abstract Background The transcription factor activator protein-1 (AP-1 has been implicated in a large variety of biological processes including oncogenic transformation. The tyrosine kinases of the epidermal growth factor receptor (EGFR constitute the beginning of one signal transduction cascade leading to AP-1 activation and are known to control cell proliferation and differentiation. Drug discovery efforts targeting this receptor and other pathway components have centred on monoclonal antibodies and small molecule inhibitors. Resistance to such inhibitors has already been observed, guiding the prediction of their use in combination therapies with other targeted agents such as RNA interference (RNAi. This study examines the use of RNAi and kinase inhibitors for qualification of components involved in the EGFR/AP-1 pathway of ME180 cells, and their inhibitory effects when evaluated individually or in tandem against multiple components of this important disease-related pathway. Methods AP-1 activation was assessed using an ME180 cell line stably transfected with a beta-lactamase reporter gene under the control of AP-1 response element following epidermal growth factor (EGF stimulation. Immunocytochemistry allowed for further quantification of small molecule inhibition on a cellular protein level. RNAi and RT-qPCR experiments were performed to assess the amount of knockdown on an mRNA level, and immunocytochemistry was used to reveal cellular protein levels for the targeted pathway components. Results Increased potency of kinase inhibitors was shown by combining RNAi directed towards EGFR and small molecule inhibitors acting at proximal or distal points in the pathway. After cellular stimulation with EGF and analysis at the level of AP-1 activation using a β-lactamase reporter gene, a 10–12 fold shift or 2.5–3 fold shift toward greater potency in the IC50 was observed for EGFR and MEK-1 inhibitors, respectively, in the presence of RNAi

  2. Rational combination treatment with histone deacetylase inhibitors and immunomodulatory drugs in multiple myeloma

    Immunomodulatory drugs (IMiDs) thalidomide, lenalidomide (Len) and pomalidomide trigger anti-tumor activities in multiple myeloma (MM) by targetting cereblon and thereby impacting IZF1/3, c-Myc and IRF4. Histone deacetylase inhibitors (HDACi) also downregulate c-Myc. We therefore determined whether IMiDs with HDACi trigger significant MM cell growth inhibition by inhibiting or downregulating c-Myc. Combination treatment of Len with non-selective HDACi suberoylanilide hydroxamic acid or class-I HDAC-selective inhibitor MS275 induces synergic cytotoxicity, associated with downregulation of c-Myc. Unexpectedly, we observed that decreased levels of cereblon (CRBN), a primary target protein of IMiDs, was triggered by these agents. Indeed, sequential treatment of MM cells with MS275 followed by Len shows less efficacy than simultaneous treatment with this combination. Importantly ACY1215, an HDAC6 inhibitor with minimal effects on class-I HDACs, together with Len induces synergistic MM cytotoxicity without alteration of CRBN expression. Our results showed that only modest class-I HDAC inhibition is able to induce synergistic MM cytotoxicity in combination with Len. These studies may provide the framework for utilizing HDACi in combination with Len to both avoid CRBN downregulation and enhance anti-MM activities

  3. In Vitro Assessment of Combinations of Enterovirus Inhibitors against Enterovirus 71.

    Wang, Yizhuo; Li, Guiming; Yuan, Shilin; Gao, Qianqian; Lan, Ke; Altmeyer, Ralf; Zou, Gang

    2016-09-01

    Enterovirus 71 (EV-A71) is a major causative pathogen of hand, foot, and mouth disease (HFMD) epidemics. No antiviral therapies are currently available for treating EV-A71 infections. Here, we selected five reported enterovirus inhibitors (suramin, itraconazole [ITZ], GW5074, rupintrivir, and favipiravir) with different mechanisms of action to test their abilities to inhibit EV-A71 replication alone and in combination. All selected compounds have anti-EV-A71 activities in cell culture. The combination of rupintrivir and ITZ or favipiravir was synergistic, while the combination of rupintrivir and suramin was additive. The combination of suramin and favipiravir exerted a strong synergistic antiviral effect. The observed synergy was not due to cytotoxicity, as there was no significant increase in cytotoxicity when compounds were used in combinations at the tested doses. To investigate the potential inhibitory mechanism of favipiravir against enterovirus, two favipiravir-resistant EV-A71 variants were independently selected, and both of them carried an S121N mutation in the finger subdomain of the 3D polymerase. Reverse engineering of this 3D S121N mutation into an infectious clone of EV-A71 confirmed the resistant phenotype. Moreover, viruses resistant to ITZ or favipiravir remained susceptible to other inhibitors. Most notably, combined with ITZ, rupintrivir prevented the development of ITZ-resistant variants. Taken together, these results provide a rational basis for the design of combination regimens for use in the treatment of EV-A71 infections. PMID:27353263

  4. Combined HSP90 and kinase inhibitor therapy: Insights from The Cancer Genome Atlas.

    Schwartz, Harvey; Scroggins, Brad; Zuehlke, Abbey; Kijima, Toshiki; Beebe, Kristin; Mishra, Alok; Neckers, Len; Prince, Thomas

    2015-09-01

    The merging of knowledge from genomics, cellular signal transduction and molecular evolution is producing new paradigms of cancer analysis. Protein kinases have long been understood to initiate and promote malignant cell growth and targeting kinases to fight cancer has been a major strategy within the pharmaceutical industry for over two decades. Despite the initial success of kinase inhibitors (KIs), the ability of cancer to evolve resistance and reprogram oncogenic signaling networks has reduced the efficacy of kinase targeting. The molecular chaperone HSP90 physically supports global kinase function while also acting as an evolutionary capacitor. The Cancer Genome Atlas (TCGA) has compiled a trove of data indicating that a large percentage of tumors overexpress or possess mutant kinases that depend on the HSP90 molecular chaperone complex. Moreover, the overexpression or mutation of parallel activators of kinase activity (PAKA) increases the number of components that promote malignancy and indirectly associate with HSP90. Therefore, targeting HSP90 is predicted to complement kinase inhibitors by inhibiting oncogenic reprogramming and cancer evolution. Based on this hypothesis, consideration should be given by both the research and clinical communities towards combining kinase inhibitors and HSP90 inhibitors (H90Ins) in combating cancer. The purpose of this perspective is to reflect on the current understanding of HSP90 and kinase biology as well as promote the exploration of potential synergistic molecular therapy combinations through the utilization of The Cancer Genome Atlas. PMID:26070366

  5. Association of angiotensin-converting enzyme inhibitor therapy and comorbidity in diabetes: results from the Vermont diabetes information system

    MacLean Charles D; Ramos-Nino Maria E; Littenberg Benjamin

    2008-01-01

    Abstract Background Angiotensin converting enzyme inhibitors (ACE inhibitors) reduce peripheral vascular resistance via blockage of angiotensin converting enzyme (ACE). ACE inhibitors are commonly used to treat congestive heart failure and high blood pressure, but other effects have been reported. In this study, we explored the association between ACE inhibitor therapy and the prevalence of comorbid conditions in adults with diabetes Methods We surveyed 1003 adults with diabetes randomly sele...

  6. Advanced Cathode Electrolyzer (ACE) Project

    National Aeronautics and Space Administration — The proposed innovation is a static, cathode-fed, 2000 psi, balanced-pressure Advanced Cathode Electrolyzer (ACE) based on PEM electrolysis technology. It...

  7. ACE spectrum of LDPC codes

    Vukobratović Dejan

    2006-01-01

    Full Text Available Construction of short-length LDPC codes with good, both waterfall and error-floor, behavior is still an attractive research problem. Recently proposed construction algorithms in this field are based on remarkably simple ideas, but yet, their effectiveness can still be questioned. In this paper we investigate a novel measure of goodness of a given LDPC code namely its ACE spectrum, based on a previously introduced ACE metrics associated with each cycle in LDPC code graph.

  8. Inhibitors

    ... wrong place in the body. Immune Tolerance Induction (ITI) Therapy: The goal of ITI therapy is to stop the inhibitor reaction from ... body to accept clotting factor concentrate treatments. With ITI therapy, people receive large amounts of clotting factor ...

  9. Influences of combination of chemotherapy and autophagy inhibitor on the calreticulin expression in colon cancer cells

    Peng, Rui-Qing; Dan-dan LI; Ding, Ya; Zhang, Xing; Zhang, Xiao-Shi; Wu, Xiao-jun

    2016-01-01

    Objective  To investigate the influence of chemotherapy combined with autophagy inhibitor on apoptosis and calreticulin (CRT) expression on colonic cancer cells. Methods  The colon cancer cells HCT116 were taken as the target in the present study. The inhibition rates (IC50) of chemotherapeutics oxaliplatin, 5-Fu and SN-38 were assessed by MTT assay. The changes in CRT expression on the membrane of HCT116 and apoptosis were determined with flow cytometry before and after treatment with chemot...

  10. Fueling the engine and releasing the break:combinational therapy of cancer vaccines and immune checkpoint inhibitors

    Jennifer Kleponis; Richard Skelton; Lei Zheng

    2015-01-01

    Immune checkpoint inhibitors are increasingly drawing much attention in the therapeutic development for cancer treatment. However, many cancer patients do not respond to treatments with immune checkpoint inhibitors, partly because of the lack of tumor-inifltrating effector T cells. Cancer vaccines may prime patients for treatments with immune checkpoint inhibitors by inducing effector T-cell infiltration into the tumors and immune checkpoint signals. The combination of cancer vaccine and an immune checkpoint inhibitor may function synergistically to induce more effective antitumor immune responses, and clinical trials to test the combination are currently ongoing.

  11. Synergistic suppression of dengue virus replication using a combination of nucleoside analogs and nucleoside synthesis inhibitors.

    Yeo, Kim Long; Chen, Yen-Liang; Xu, Hao Ying; Dong, Hongping; Wang, Qing-Yin; Yokokawa, Fumiaki; Shi, Pei-Yong

    2015-04-01

    Dengue virus (DENV) is the most prevalent mosquito-borne viral pathogen in humans. Currently, there is no clinically approved vaccine or antiviral for DENV. Combination therapy is a common practice in antiviral treatment and a potential approach to search for new treatments for infectious pathogens. In this study, we performed a combination treatment in cell culture by using three distinct classes of inhibitors, including ribavirin (a guanosine analog with several antiviral mechanisms), brequinar (a pyrimidine biosynthesis inhibitor), and INX-08189 (a guanosine analog). The compound pairs were evaluated for antiviral activity by use of a DENV-2 luciferase replicon assay. Our result indicated that the combination of ribavirin and INX-08189 exhibited strong antiviral synergy. This result suggests that synergy can be achieved with compound pairs in which one compound suppresses the synthesis of the nucleoside for which the other compound is a corresponding nucleoside analog. In addition, we found that treatment of cells with brequinar alone could activate interferon-stimulated response elements (ISREs); furthermore, brequinar and NITD-982 (another pyrimidine biosynthesis inhibitor) potentiated interferon-induced ISRE activation. Compared to treatment with brequinar, treatment of cells with ribavirin alone could also induce ISRE activation, but to a lesser extent; however, when cells were cotreated with ribavirin and beta interferon, ribavirin did not augment the interferon-induced ISRE activation. PMID:25624323

  12. Combined therapeutic potential of nuclear receptors with receptor tyrosine kinase inhibitors in lung cancer

    Wairagu, Peninah M. [Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701 (Korea, Republic of); Institute of Lifestyle Medicine, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701 (Korea, Republic of); Nuclear Receptor Research Consortium, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701 (Korea, Republic of); Park, Kwang Hwa [Department of Pathology, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701 (Korea, Republic of); Kim, Jihye [Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701 (Korea, Republic of); Institute of Lifestyle Medicine, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701 (Korea, Republic of); Nuclear Receptor Research Consortium, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701 (Korea, Republic of); Choi, Jong-Whan; Kim, Hyun-Won; Yeh, Byung-Il [Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701 (Korea, Republic of); Jung, Soon-Hee [Department of Pathology, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701 (Korea, Republic of); Yong, Suk-Joong [Department of Internal Medicine, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701 (Korea, Republic of); Jeong, Yangsik, E-mail: yjeong@yonsei.ac.kr [Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701 (Korea, Republic of); Institute of Lifestyle Medicine, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701 (Korea, Republic of); Nuclear Receptor Research Consortium, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do 220-701 (Korea, Republic of)

    2014-05-09

    Highlights: • The 48 NR genes and 48 biological anti-cancer targets are profiled in paired-cells. • Growth inhibition by NR ligands or TKIs is target receptor level-dependent. • T0901317 with gefitinib/PHA665752 shows additive growth inhibition in lung cells. - Abstract: Cancer heterogeneity is a big hurdle in achieving complete cancer treatment, which has led to the emergence of combinational therapy. In this study, we investigated the potential use of nuclear receptor (NR) ligands for combinational therapy with other anti-cancer drugs. We first profiled all 48 NRs and 48 biological anti-cancer targets in four pairs of lung cell lines, where each pair was obtained from the same patient. Two sets of cell lines were normal and the corresponding tumor cell lines while the other two sets consisted of primary versus metastatic tumor cell lines. Analysis of the expression profile revealed 11 NRs and 15 cancer targets from the two pairs of normal versus tumor cell lines, and 9 NRs and 9 cancer targets from the primary versus metastatic tumor cell lines had distinct expression patterns in each category. Finally, the evaluation of nuclear receptor ligand T0901317 for liver X receptor (LXR) demonstrated its combined therapeutic potential with tyrosine kinase inhibitors. The combined treatment of cMET inhibitor PHA665752 or EGFR inhibitor gefitinib with T0901317 showed additive growth inhibition in both H2073 and H1993 cells. Mechanistically, the combined treatment suppressed cell cycle progression by inhibiting cyclinD1 and cyclinB expression. Taken together, this study provides insight into the potential use of NR ligands in combined therapeutics with other biological anti-cancer drugs.

  13. Combined therapeutic potential of nuclear receptors with receptor tyrosine kinase inhibitors in lung cancer

    Highlights: • The 48 NR genes and 48 biological anti-cancer targets are profiled in paired-cells. • Growth inhibition by NR ligands or TKIs is target receptor level-dependent. • T0901317 with gefitinib/PHA665752 shows additive growth inhibition in lung cells. - Abstract: Cancer heterogeneity is a big hurdle in achieving complete cancer treatment, which has led to the emergence of combinational therapy. In this study, we investigated the potential use of nuclear receptor (NR) ligands for combinational therapy with other anti-cancer drugs. We first profiled all 48 NRs and 48 biological anti-cancer targets in four pairs of lung cell lines, where each pair was obtained from the same patient. Two sets of cell lines were normal and the corresponding tumor cell lines while the other two sets consisted of primary versus metastatic tumor cell lines. Analysis of the expression profile revealed 11 NRs and 15 cancer targets from the two pairs of normal versus tumor cell lines, and 9 NRs and 9 cancer targets from the primary versus metastatic tumor cell lines had distinct expression patterns in each category. Finally, the evaluation of nuclear receptor ligand T0901317 for liver X receptor (LXR) demonstrated its combined therapeutic potential with tyrosine kinase inhibitors. The combined treatment of cMET inhibitor PHA665752 or EGFR inhibitor gefitinib with T0901317 showed additive growth inhibition in both H2073 and H1993 cells. Mechanistically, the combined treatment suppressed cell cycle progression by inhibiting cyclinD1 and cyclinB expression. Taken together, this study provides insight into the potential use of NR ligands in combined therapeutics with other biological anti-cancer drugs

  14. ACE inhibition, ACE2 and angiotensin-(1-7) axis in kidney and cardiac inflammation and fibrosis.

    Simões E Silva, Ana Cristina; Teixeira, Mauro Martins

    2016-05-01

    The Renin Angiotensin System (RAS) is a pivotal physiological regulator of heart and kidney homeostasis, but also plays an important role in the pathophysiology of heart and kidney diseases. Recently, new components of the RAS have been discovered, including angiotensin converting enzyme 2 (ACE2), Angiotensin(Ang)-(1-7), Mas receptor, Ang-(1-9) and Alamandine. These new components of RAS are formed by the hydrolysis of Ang I and Ang II and, in general, counteract the effects of Ang II. In experimental models of heart and renal diseases, Ang-(1-7), Ang-(1-9) and Alamandine produced vasodilation, inhibition of cell growth, anti-thrombotic, anti-inflammatory and anti-fibrotic effects. Recent pharmacological strategies have been proposed to potentiate the effects or to enhance the formation of Ang-(1-7) and Ang-(1-9), including ACE2 activators, Ang-(1-7) in hydroxypropyl β-cyclodextrin, cyclized form of Ang-(1-7) and nonpeptide synthetic Mas receptor agonists. Here, we review the role and effects of ACE2, ACE2 activators, Ang-(1-7) and synthetic Mas receptor agonists in the control of inflammation and fibrosis in cardiovascular and renal diseases and as counter-regulators of the ACE-Ang II-AT1 axis. We briefly comment on the therapeutic potential of the novel members of RAS, Ang-(1-9) and alamandine, and the interactions between classical RAS inhibitors and new players in heart and kidney diseases. PMID:26995300

  15. The in vitro activity of beta-lactamase inhibitors in combination with cephalosporins against M. tuberculosis.

    Chen, C H; Yang, M H; Lin, J S; Lee, Y C; Perng, R P

    1995-04-01

    Although there are reports that the addition of a beta-lactamase inhibitor to ampicillin or amoxicillin greatly improves their in vitro activity against M. tuberculosis, there are no written reports about the antituberculosis effects of beta-lactamase inhibitors in combination with cephalosporins against M. tuberculosis. In this report, we have determined the minimal inhibitory concentrations (MIC) of 5 cephalosporins with or without combination with beta-lactamase inhibitor against M. tuberculosis strains isolated from patients before antituberculosis treatment and checked the production of beta-lactamase by bacteria before this procedure. Four strains of M. tuberculosis were contaminated during the experiment, and all the other 16 strains hydrolyzed the nitrocefin disc, thus indicating a beta-lactamase producer. The MICs of cephalosporins alone against M. tuberculosis were 200-400 micrograms/ml for ceforanide, 100-400 micrograms/ml for cephapirin, 400-1600 micrograms/ml for cefamandole, 200-1600 micrograms/ml for cefotaxime, and 800-1600 micrograms/ml for ceftriaxone. After adding the equimolar concentrations of sulbactam, the MICs were reduced to 100-200 micrograms/ml for ceforanide, 12.5-100 micrograms/ml for cephapirin, 100-400 micrograms/ml for cefamandole, 25-200 micrograms/ml for cefotaxime, and 100-800 micrograms/ml for ceftriaxone. We concluded that sulbactam enhanced the antituberculosis effect of cephalosporins. PMID:7624446

  16. Enhanced effects by 4-phenylbutyrate in combination with RTK inhibitors on proliferation in brain tumor cell models

    Marino, Ana-Maria [Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (Sweden); Center for Molecular Medicine CMM, Karolinska University Hospital, Stockholm (Sweden); Sofiadis, Anastasios [Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm (Sweden); Department of Oncology-Pathology, Karolinska Institutet, Stockholm (Sweden); Center for Molecular Medicine CMM, Karolinska University Hospital, Stockholm (Sweden); Baryawno, Ninib; Johnsen, John Inge [Department of Women' s and Children' s Health, Karolinska Institutet, Stockholm (Sweden); Larsson, Catharina [Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm (Sweden); Center for Molecular Medicine CMM, Karolinska University Hospital, Stockholm (Sweden); Vukojevic, Vladana [Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (Sweden); Center for Molecular Medicine CMM, Karolinska University Hospital, Stockholm (Sweden); Ekstroem, Tomas J., E-mail: tomas.ekstrom@ki.se [Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (Sweden); Center for Molecular Medicine CMM, Karolinska University Hospital, Stockholm (Sweden)

    2011-07-22

    Highlights: {yields} The histone deacetylase inhibitor 4-phenylbutyrate substantially enhance efficacy of the receptor tyrosine kinase inhibitors gefitinib or vandetanib in glioma and medulloblastoma cell lines. {yields} Cell death increases and clonogenic survival is reduced in the combination treatments, over mono-therapy. {yields} Combination treatments with these drugs may improve clinical outcome for cancer therapy. -- Abstract: We have investigated in vitro effects of anticancer therapy with the histone deacetylase inhibitor (HDACi) 4-phenylbutyrate (4-PB) combined with receptor tyrosine kinase inhibitors (RTKi) gefitinib or vandetanib on the survival of glioblastoma (U343MGa) and medulloblastoma (D324Med) cells. In comparison with individual effects of these drugs, combined treatment with gefitinib/4-PB or vandetanib/4-PB resulted in enhanced cell killing and reduced clonogenic survival in both cell lines. Our results suggest that combined treatment using HDACi and RTKi may beneficially affect the outcome of cancer therapy.

  17. Enhanced effects by 4-phenylbutyrate in combination with RTK inhibitors on proliferation in brain tumor cell models

    Highlights: → The histone deacetylase inhibitor 4-phenylbutyrate substantially enhance efficacy of the receptor tyrosine kinase inhibitors gefitinib or vandetanib in glioma and medulloblastoma cell lines. → Cell death increases and clonogenic survival is reduced in the combination treatments, over mono-therapy. → Combination treatments with these drugs may improve clinical outcome for cancer therapy. -- Abstract: We have investigated in vitro effects of anticancer therapy with the histone deacetylase inhibitor (HDACi) 4-phenylbutyrate (4-PB) combined with receptor tyrosine kinase inhibitors (RTKi) gefitinib or vandetanib on the survival of glioblastoma (U343MGa) and medulloblastoma (D324Med) cells. In comparison with individual effects of these drugs, combined treatment with gefitinib/4-PB or vandetanib/4-PB resulted in enhanced cell killing and reduced clonogenic survival in both cell lines. Our results suggest that combined treatment using HDACi and RTKi may beneficially affect the outcome of cancer therapy.

  18. A meta-analysis of the effect of angiotensin-converting enzyme inhibitors on functional capacity in patients with symptomatic left ventricular systolic dysfunction

    Abdulla, Jawdat; Abildstrøm, Steen Zabell; Køber, Lars Valeur;

    2004-01-01

    AIM: To determine by meta-analysis whether angiotensin-converting enzyme (ACE) inhibitors improve exercise tolerance in patients with symptomatic left ventricular systolic dysfunction (LVSD). METHODS AND RESULTS: After literature search 13 multi-centre double blind parallel group trials...... that evaluated the effect of ACE inhibitors vs. placebo on exercise duration were selected. Ninety-four percent of patients were in New York Heart Association class II-IV. The studies were combined using the Cochrane meta-analysis program (Review manager version 4.1). Analyses according to treatment period......, exercise protocols and publication periods were performed. Treatment with ACE inhibitor over 4-12 weeks resulted in a beneficial effect on exercise duration (P=0.003 and P=0.0008 for 4- and 12-weeks treatment, respectively), but the magnitude of improvements did not exceed 30 s corresponding to only 5...

  19. ACE to Ulysses Coherences

    Thomson, D. J.; Maclennan, C. G.; Lanzerotti, L. J.

    2006-12-01

    The EPAM charged particle instrument on ACE is the backup for the HISCALE instrument on Ulysses making the two ideally suited for spatial coherence studies over large heliosphere distances. Fluxes of low-energy ( ~50 - 200 keV) electrons are detected in eight spatial sectors on both spacecraft. A spherical harmonic description of the particle flux as a function of time using only the l=0 and l=1 degree coefficients describes most of the observed flux. Here we concentrate on the three l=1 coefficients for the 60--100 kev electrons.Between the two spacecraft these result in nine coherence estimates that are all typically moderately coherent, but the fact that the different coefficients at each spacecraft are also coherent with each other makes interpretation difficult. To avoid this difficulty we estimated the canonical coherences between the two groups of three series. This, in effect, chooses an optimum coordinate system at each spacecraft and for each frequency and estimates the coherence in this frame. Using one--minute data, we find that the canonical coherences are generally larger at high frequencies (3 mHz and above) than they are at low frequencies. This appears to be generally true and does not depend particularly on time, range, etc. However, if the data segment is chosen too long, say > 30 days with 1--minute sampling, the coherence at high frequencies drops. This may be because the spatial and temporal features of the mode are confounded, or possibly because the solar modes p--modes are known to change frequency with solar activity, so do not appear coherent on long blocks.The coherences are not smooth functions of frequency, but have a bimodal distribution particularly in the 100 μHz to 5 mHz range. Classifying the data at frequencies where the canonical coherences are high in terms of apparent polarization and orientation, we note two major families of modes that appear to be organized by the Parker spiral. The magnetic field data on the two

  20. Natural products inhibitors of the angiotensin converting enzyme (ACE: a review between 1980 - 2000 Produtos naturais inibidores da enzima conversora de angiotensina (ECA: uma revisão entre 1980 - 2000

    José M. Barbosa-Filho

    2006-09-01

    Full Text Available Inhibition of Angiotensin Converting Enzyme (ACE is a modern therapeutic target in the treatment of hypertension. Within the enzyme cascade of the renin-angiotensin system, ACE removes histidyl-leucine from angiotensin I to form the physiologically active octapeptide angiotensin II, one of the most potent known vasoconstrictors. Therefore, a rationale for treating hypertension would be to administer drugs or natural compounds which selectively inhibit ACE. The present work constitutes a review of the literature of plants and chemically defined molecules from natural sources with in vitro anti-hypertensive potential based on the inhibition of ACE. The review refers to 321 plants, the parts utilized, type of extract and whether they are active or not. It includes also the names of 158 compounds isolated from higher plants, marine sponges and algae, fungi and snake venom. Some aspects of recent research with natural products directed to produce anti-hypertensive drugs are discussed. In this review, 148 references were cited.A inibição da Enzima Conversora da Angiotensina (ECA é um alvo terapêutico moderno e eficaz no tratamento da hipertensão arterial. Na cascata enzimática que envolve o sistema renina-angiotensina, a ECA promove a remoção dos aminoácidos histidil-leucina da angiotensina I para formar o octapeptídio angiotensina II, a qual é fisiologicamente ativa em diversos sistemas, e considerado como um dos mais potentes vasoconstrictores endógenos conhecido. Portanto, uma racionalidade no tratamento da hipertensão seria administrar drogas ou compostos de origem natural que inibam seletivamente a ECA. O presente estudo constitui uma revisão da literatura sobre plantas e moléculas de origem natural com potencial anti-hipertensivo, baseado na inibição in vitro da ECA. A revisão referencia 321 plantas, partes usadas, tipo de extrato e se é ativo ou não. Inclui ainda o nome de 158 compostos isolados de plantas superiores

  1. ACE up the sleeve - are vascular patients medically optimized?

    Coveney, A P

    2011-03-01

    To examine the current medical management of arteriopathic patients attending a vascular surgical service at a university teaching hospital over a 6-month period. The prescribing of antiplatelets, statins, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers and beta-blockers was specifically examined. Vascular patients are often under the care of multiple specialties, and therefore the influence of different medical specialties on the patients\\' medical management was also examined.

  2. Relationship between ACEI/D gene polymorphism and curative effects of angiotensinconverting enzyme inhibitor in elderlyhypertension patients%老年高血压患者 ACEI/D基因多态性与 ACE 抑制剂疗效的相关性

    梁冰; 胡丙清; 刘绪和

    2014-01-01

    Objective To explore the relationship between the ACE geneinsertion /deletion ( I/D ) polymorphism and the curative effects of angiotensin-converting enzyme inhibitor ( ACEI ) in elderly patients with hypertension.Methods Polymerase chain reaction(PCR) technique was used to detect ACE I/D polymorphism in 108 subjects of elderly hypertensionpatients who received no therapy ever , and the patients were classified as II, ID and DD genotype .Meanwhile captopril was administered for 6 weeks to all patients .Measure the blood pressure of all patients during the treatment and post treatment .Results The frequency of II genotype was 27%, the ID genotype was 33%and the DD genotype was 40%.4 patients in II group were markedly effective and 14 patients were effective , the effective rate was 61%.In ID group, 8 patients were markedly effective and 18 patients were effective , effective rate was 73%.In DD group 29 patients were markedly effective , 11 patients were effective , effective rate was 93%.Curative effect of captoprilwas significantly higher in DD group than in ID and II group(P<0.05).Conclusions ACE I/D gene polymorphism can be use as one of adjunctive indicators for predicting the effect of using ACEI inelderly patients with hypertension .%目的:探讨老年高血压患者ACE I/D基因多态性与血管紧张素转换酶抑制剂( ACEI )疗效的相关性。方法选取108例老年高血压未经降压治疗的患者;应用聚合酶链反应( PCR )方法检测其ACE I/D基因多态性,有三种表现形式:II型、DD型和ID型,根据其基因多态性分为三组,对所有高血压患者均给予卡托普利口服6周。治疗前后及治疗过程中对患者的血压进行监测。结果(1)108例高血压患者中II基因型频率为27%;ID型为33%;DD型为40%;(2)II组显著有效4例,有效14例,总有效率61%;ID组显著有效8例,有效18例,总有效率73%;DD组显著有效29例,有效11

  3. Study on ACE Inhibitor in Hydrolyzates of Rice Bran Protein%米糠蛋白酶解产物中血管紧张素转化酶抑制剂的研究

    毕昊; 刘志国; 屈伸; 王亚林; 吴琼

    2005-01-01

    目的从米糠蛋白酶解产物中提取制备血管紧张素转化酶(ACE)抑制剂.方法采用等电点沉淀的方法提取米糠中的蛋白质,先后经胃蛋白酶和胰蛋白酶水解后,采用凝胶层析法分离酶解组分,检测各组分ACE抑制性,对活性较强的组分用阳离子交换树脂SP-Sephadex C-25作进一步的分离检测.结果获得的ACE抑制肽分子量为307.1,其等电点在5~6之间.它在消化液中具有稳定性.其IC50为0.061 mg/ml.结论从米糠蛋白酶解产物中获取了ACE抑制剂.

  4. Influences of combination of chemotherapy and autophagy inhibitor on the calreticulin expression in colon cancer cells

    Rui-qing PENG

    2016-04-01

    Full Text Available Objective  To investigate the influence of chemotherapy combined with autophagy inhibitor on apoptosis and calreticulin (CRT expression on colonic cancer cells. Methods  The colon cancer cells HCT116 were taken as the target in the present study. The inhibition rates (IC50 of chemotherapeutics oxaliplatin, 5-Fu and SN-38 were assessed by MTT assay. The changes in CRT expression on the membrane of HCT116 and apoptosis were determined with flow cytometry before and after treatment with chemotherapeutics. CRT location in HCT116 was detected by fluorescent immunoassay before and after treatment with chemotherapeutic agents. The influence on HCT116 autophagy was determined by Western blotting after treatment with these chemotherapeutic agents. The changes in CRT expression on HCT116 membrane and apoptosis were determined with flow cytometry before and after treatment with the chemotherapeutics combined with autophagy inhibitor chloroquine (CQ. Results  The ratio of apoptosis and membrane expression of CRT were elevated 12 hours after treatment with Oxaliplatin, 5-Fu and SN38, but without statistical significance. Fluorescent immunoassay showed a transposition of CRT from cytoplasm to the membrane after oxaliplatin treatment. Western blotting revealed that oxaliplatin, 5Fu and SN38 induced autophagy of HCT116 cells, and the autophagy was inhibited by the addition of CQ. Flow cytometric analysis indicated that the percentages of annexin V+ cells and membrane expression of CRT were higher after treatment with the chemotherapy agents combined with CQ. The upregulation of CRT expression on membrane was obviously higher after treatment with oxaliplatin combined with CQ than that before the treatment with these agents (P=0.027. Conclusion  Oxaliplatin combined with CQ may increase the apoptosis rate of HCT116 cells and upregulate CRT expression in the membrane. DOI: 10.11855/j.issn.0577-7402.2016.04.03

  5. Development of an environmentally friendly combined scale/corrosion inhibitor for subsea application

    Jenkins, Alyn [M-I SWACO, Houston, TX (United States)

    2009-07-01

    In many offshore oil and gas fields, production chemicals are required to be applied subsea to mitigate the common flow assurance problems that are present either in the well or subsea gathering and flow lines. Common flow assurance issues include scale, hydrate formation, corrosion and also wax deposition. For subsea systems, production chemicals are applied either at the subsea wellhead, flow lines or downhole. However, for many fields there are an inadequate number of chemical umbilicals, chemical injection pumps or chemical storage tanks. Consequently, there is a strong requirement for combination or multifunctional products that help to minimize the amount of chemical injection equipment needed. This paper describes the work involved in developing an environmentally acceptable combined scale/corrosion inhibitor for deployment in subsea pipelines in a UK North Sea oil field. The paper details the laboratory testing performed and includes corrosion field data that has been used to confirm product performance. (author)

  6. Classification of cytochrome P450 inhibitors and noninhibitors using combined classifiers.

    Cheng, Feixiong; Yu, Yue; Shen, Jie; Yang, Lei; Li, Weihua; Liu, Guixia; Lee, Philip W; Tang, Yun

    2011-05-23

    Adverse side effects of drug-drug interactions induced by human cytochrome P450 (CYP) inhibition is an important consideration, especially, during the research phase of drug discovery. It is highly desirable to develop computational models that can predict the inhibitive effect of a compound against a specific CYP isoform. In this study, inhibitor predicting models were developed for five major CYP isoforms, namely 1A2, 2C9, 2C19, 2D6, and 3A4, using a combined classifier algorithm on a large data set containing more than 24,700 unique compounds, extracted from PubChem. The combined classifiers algorithm is an ensemble of different independent machine learning classifiers including support vector machine, C4.5 decision tree, k-nearest neighbor, and naïve Bayes, fused by a back-propagation artificial neural network (BP-ANN). All developed models were validated by 5-fold cross-validation and a diverse validation set composed of about 9000 diverse unique compounds. The range of the area under the receiver operating characteristic curve (AUC) for the validation sets was 0.764 to 0.815 for CYP1A2, 0.837 to 0.861 for CYP2C9, 0.793 to 0.842 for CYP2C19, 0.839 to 0.886 for CYP2D6, and 0.754 to 0.790 for CYP3A4, respectively, using the new developed combined classifiers. The overall performance of the combined classifiers fused by BP-ANN was superior to that of three classic fusion techniques (Mean, Maximum, and Multiply). The chemical spaces of data sets were explored by multidimensional scaling plots, and the use of applicability domain improved the prediction accuracies of models. In addition, some representative substructure fragments differentiating CYP inhibitors and noninhibitors were characterized by the substructure fragment analysis. These classification models are applicable for virtual screening of the five major CYP isoforms inhibitors or can be used as simple filters of potential chemicals in drug discovery. PMID:21491913

  7. Overcoming Resistance of Cancer Cells to PARP-1 Inhibitors with Three Different Drug Combinations.

    Michal Yalon

    Full Text Available Inhibitors of poly[ADP-ribose] polymerase 1 (PARPis show promise for treatment of cancers which lack capacity for homologous recombination repair (HRR. However, new therapeutic strategies are required in order to overcome innate and acquired resistance to these drugs and thus expand the array of cancers that could benefit from them. We show that human cancer cell lines which respond poorly to ABT-888 (a PARPi, become sensitive to it when co-treated with vorinostat (a histone deacetylase inhibitor (HDACi. Vorinostat also sensitized PARPis insensitive cancer cell lines to 6-thioguanine (6-TG-a drug that targets PARPis sensitive cells. The sensitizing effect of vorinostat was associated with increased phosphorylation of eukaryotic initiation factor (eIF 2α which in and of itself increases the sensitivity of cancer cells to ABT-888. Importantly, these drug combinations did not affect survival of normal fibroblasts and breast cells, and significantly increased the inhibition of xenograft tumor growth relative to each drug alone, without affecting the mice weight or their liver and kidney function. Our results show that combination of vorinostat and ABT-888 could potentially prove useful for treatment of cancer with innate resistance to PARPis due to active HRR machinery, while the combination of vorinostat and 6-TG could potentially overcome innate or acquired resistance to PARPis due to secondary or reversal BRCA mutations, to decreased PARP-1 level or to increased expression of multiple drug resistant proteins. Importantly, drugs which increase phosphorylation of eIF2α may mimic the sensitizing effect of vorinostat on cellular response to PARPis or to 6-TG, without activating all of its downstream effectors.

  8. Combination Therapy with Cholinesterase Inhibitors and Memantine for Alzheimer’s Disease: A Systematic Review and Meta-Analysis

    Matsunaga, Shinji; Kishi, Taro; Iwata, Nakao

    2015-01-01

    Background: We performed an updated meta-analysis of randomized controlled trials of combination therapy with cholinesterase inhibitors and memantine in patients with Alzheimer’s disease. Methods: We reviewed cognitive function, activities of daily living, behavioral disturbance, global assessment, discontinuation rate, and individual side effects. Results: Seven studies (total n=2182) were identified. Combination therapy significantly affected behavioral disturbance scores (standardized mean...

  9. Blood pressure-lowering peptides from neo-fermented buckwheat sprouts: a new approach to estimating ACE-inhibitory activity.

    Masahiro Koyama

    Full Text Available Neo-fermented buckwheat sprouts (neo-FBS contain angiotensin-converting enzyme (ACE inhibitors and vasodilators with blood pressure-lowering (BPL properties in spontaneously hypertensive rats (SHRs. In this study, we investigated antihypertensive mechanisms of six BPL peptides isolated from neo-FBS (FBPs by a vasorelaxation assay and conventional in vitro, in vivo, and a new ex vivo ACE inhibitory assays. Some FBPs demonstrated moderate endothelium-dependent vasorelaxation in SHR thoracic aorta and all FBPs mildly inhibited ACE in vitro. Orally administered FBPs strongly inhibited ACE in SHR tissues. To investigate detailed ACE-inhibitory mechanism of FBPs in living body tissues, we performed the ex vivo assay by using endothelium-denuded thoracic aorta rings isolated from SHRs, which demonstrated that FBPs at low concentration effectively inhibited ACE in thoracic aorta tissue and suppressed angiotensin II-mediated vasoconstriction directly associated with BPL. These results indicate that the main BPL mechanism of FBP was ACE inhibition in living body tissues, suggesting that high FBP's bioavailability including absorption, tissue affinity, and tissue accumulation was responsible for the superior ACE inhibition in vivo. We propose that our ex vivo assay is an efficient and reliable method for evaluating ACE-inhibitory mechanism responsible for BPL activity in vivo.

  10. Analysis of trypsin inhibitors and lectins in white kidney beans (Phaseolus vulgaris, var. Processor) in a combined method.

    Roozen, J P; de Groot, J

    1991-01-01

    Buffered saline extraction, affinity chromatography, and Folin-BSA protein assay were used consecutively to provide a combined method for analysis of trypsin inhibitors and lectins in white kidney beans (Phaseolus vulgaris, var. Processor). The method was tested by following the decrease of both antinutritional factors by germination of the beans for 7 days at 20 degrees C. Repeatability coefficients of variation were 2-7.4% for the trypsin inhibitors and 2.2-10% for the lectins. After 7 days of germination, trypsin inhibitors and lectins were reduced by 72 and 92%, respectively. PMID:1757418

  11. Combining targeted therapy and immune checkpoint inhibitors in the treatment of metastatic melanoma

    Teresa Kim; Rodabe N Amaria; Christine Spencer; Alexandre Reuben; Zachary A Cooper; Jennifer A Wargo

    2014-01-01

    Melanoma is the deadliest form of skin cancer and has an incidence that is rising faster than any other solid tumor. Metastatic melanoma treatment has considerably progressed in the past ifve years with the introduction of targeted therapy (BARF and MEK inhibitors) and immune checkpoint blockade (anti-CTLA4, anti-PD-1, and anti-PD-L1). However, each treatment modality has limitations. Treatment with targeted therapy has been associated with a high response rate, but with short-term responses. Conversely, treatment with immune checkpoint blockade has a lower response rate, but with long-term responses. Targeted therapy affects antitumor immunity, and synergy may exist when targeted therapy is combined with immunotherapy. hTis article presents a brief review of the rationale and evidence for the potential synergy between targeted therapy and immune checkpoint blockade. Challenges and directions for future studies are also proposed.

  12. Effects of combined MAO-B inhibitors and levodopa vs. monotherapy in Parkinson’s disease

    Krishna, Rakhee; Ali, Manal; Moustafa, Ahmed A.

    2014-01-01

    Background: Prior studies report that monoamine oxidases inhibitors (MAO-I) when used as an adjunct to levodopa ameliorate motor symptoms in Parkinson’s disease (PD), but this was not tested in relation to cognitive or psychiatric measures. Objective: Here, we tested the effects of MAO-I as an adjunct to levodopa, in comparison to levodopa or dopamine (DA) agonists alone, on various cognitive, affective and quality of life measures. Methods: We studied three groups of subjects: healthy controls, PD patients on combined levodopa and MAO-I, and PD patients on levodopa or DA agonists only. Results: We found that compared to monotherapy, combined MAO-I and levodopa seemed to improve cognition, including probabilistic learning, working memory and executive functions. There were no differences between the different medication regimes on deterministic learning, attention or memory recall. It was also found that MAO-I as an adjunct to levodopa improves affective measures such as depression, apathy, anxiety and quality of life. Interestingly, this enhancing effect of combined levodopa and MAO-I was more pronounced in PD patients with severe akinesia, compared to patients with severe tremor. Conclusion: Our data are in agreement with (a) the Continuous Dopaminergic Stimulation (CDS) theory which states that continuous stimulation of the basal ganglia enhances motor, psychiatric and cognitive functions in PD patients; and/or (b) findings that MAO-I increase the bioavailability of monoamines that have beneficial effects on motor and behavioral dysfunction in PD. PMID:25120478

  13. The polyamine inhibitor alpha-difluoromethylornithine modulates hippocampus-dependent function after single and combined injuries.

    Susanna Rosi

    Full Text Available Exposure to uncontrolled irradiation in a radiologic terrorism scenario, a natural disaster or a nuclear battlefield, will likely be concomitantly superimposed on other types of injury, such as trauma. In the central nervous system, radiation combined injury (RCI involving irradiation and traumatic brain injury may have a multifaceted character. This may entail cellular and molecular changes that are associated with cognitive performance, including changes in neurogenesis and the expression of the plasticity-related immediate early gene Arc. Because traumatic stimuli initiate a characteristic early increase in polyamine metabolism, we hypothesized that treatment with the polyamine inhibitor alpha-difluoromethylornithine (DFMO would reduce the adverse effects of single or combined injury on hippocampus structure and function. Hippocampal dependent cognitive impairments were quantified with the Morris water maze and showed that DFMO effectively reversed cognitive impairments after all injuries, particularly traumatic brain injury. Similar results were seen with respect to the expression of Arc protein, but not neurogenesis. Given that polyamines have been found to modulate inflammatory responses in the brain we also assessed the numbers of total and newly born activated microglia, and found reduced numbers of newly born cells. While the mechanisms responsible for the improvement in cognition after DFMO treatment are not yet clear, the present study provides new and compelling data regarding the potential use of DFMO as a potential countermeasure against the adverse effects of single or combined injury.

  14. Advanced Collaborative Emissions Study (ACES)

    Greenbaum, Daniel; Costantini, Maria; Van Erp, Annemoon; Shaikh, Rashid; Bailey, Brent; Tennant, Chris; Khalek, Imad; Mauderly, Joe; McDonald, Jacob; Zielinska, Barbara; Bemis, Jeffrey; Storey, John; Hallberg, Lance; Clark, Nigel

    2013-12-31

    The objective of the Advanced Collaborative Emissions Study (ACES) was to determine before widespread commercial deployment whether or not the new, energy-efficient, heavy duty diesel engines (2007 and 2010 EPA Emissions Standards Compliant) may generate anticipated toxic emissions that could adversely affect the environment and human health. ACES was planned to take place in three phases. In Phase 1, extensive emissions characterization of four production-intent prototype engine and control systems designed to meet 2007 standards for nitrogen oxides (NOx) and particulate matter (PM) was conducted at an existing emissions characterization facility: Southwest Research Institute (SwRI). One of the tested engines was selected (at random, after careful comparison of results) for health testing in Phase 3. In Phase 2, extensive emission characterization of three production-intent prototype engine and control systems meeting the 2010 standards (including more advanced NOx controls to meet the more stringent 2010 NOx standards) was conducted at the same test facility. In Phase 3, one engine/aftertreatment system selected from Phase 1 was further characterized during health effects studies (at an existing inhalation toxicology laboratory: Lovelace Respiratory Research Institute, [LRRI]) to form the basis of the ACES safety assessment. The Department of Energy (DOE) award provided funding for emissions characterization in Phases 1 and 2 as well as exposure characterization in Phase 3. The main health analyses in Phase 3 were funded separately and are not reported here.

  15. mTOR inhibitors alone and in combination with JAK2 inhibitors effectively inhibit cells of myeloproliferative neoplasms.

    Bogani C; Bartalucci N; Martinelli S; Tozzi L; Guglielmelli P; Bosi A; Vannucchi AM; Associazione Italiana per la Ricerca sul Cancro AGIMM Gruppo Italiano Malattie Mieloproliferative

    2013-01-01

    Background Dysregulated signaling of the JAK/STAT pathway is a common feature of chronic myeloproliferative neoplasms (MPN), usually associated with JAK2V617F mutation. Recent clinical trials with JAK2 inhibitors showed significant improvements in splenomegaly and constitutional symptoms in patients with myelofibrosis but meaningful molecular responses were not documented. Accordingly, there remains a need for exploring new treatment strategies of MPN. A potential additional target for treatm...

  16. ACE inhibitors in cardiac surgery: do they also benefit perioperatively ?%血管紧张素转换酶抑制药用于心脏手术围术期:是否同样有益?

    孙建中; 姚立农; 刘虹

    2012-01-01

    目前尚无有效方法减少心脏手术围术期心脑血管等重要器官的各种并发症.多项临床随机调查和荟萃分析证实血管紧张素转换酶(ACE)抑制药对非手术的冠状动脉疾病患者、糖尿病和肾疾病患者具有明显的脏器保护作用,能够降低死亡率和心脑血管、肾脏并发症.但心脏手术前是否应停用ACE抑制药及其对心脏手术患者的器官保护作用尚无一致意见.近期有研究证实围术期持续ACE抑制药治疗能显著改善心脏手术患者的生存状况,建议在严密监控的前提下心脏手术患者围术期应维持ACE抑制药治疗.

  17. Targeted in-vivo computed tomography (CT) imaging of tissue ACE using concentrated lisinopril-capped gold nanoparticle solutions

    Daniel, Marie-Christine; Aras, Omer; Smith, Mark F.; Nan, Anjan; Fleiter, Thorsten

    2010-04-01

    The development of cardiac and pulmonary fibrosis have been associated with overexpression of angiotensin-converting enzyme (ACE). Moreover, ACE inhibitors, such as lisinopril, have shown a benificial effect for patients diagnosed with heart failure or systemic hypertension. Thus targeted imaging of the ACE is of crucial importance for monitoring of the tissue ACE activity as well as the treatment efficacy in heart failure. In this respect, lisinopril-capped gold nanoparticles were prepared to provide a new type of probe for targeted molecular imaging of ACE by tuned K-edge computed tomography (CT) imaging. Concentrated solutions of these modified gold nanoparticles, with a diameter around 16 nm, showed high contrast in CT imaging. These new targeted imaging agents were thus used for in vivo imaging on rat models.

  18. Enhancement of the efficiency of photodynamic therapy by combination with the microtubule inhibitor vincristine

    Ma, Li Wei; Berg, Kristian; Danielsen, Havard E.; Iani, Vladimir; Moan, Johan

    1996-01-01

    Combination effects of photodynamic therapy (PDT) with meso-tetra (di-adjacent- sulfonatophenyl) porphine (TPPS2a) and the microtubule (MT) inhibitor, vincristine (VCR), were studied in the CaD2 mouse tumor model in mice. A synergistic effect was found when VCR, at an almost nontoxic dose (1 mg/kg), was injected i.p. into the mice 6 hr before PDT. The data on mitotic index show a 4 - 5 fold accumulation of the cells in mitosis 6 hr after injection of VCR into the mice. Cell cycle and ploidy distributions in tumor tissues were determined by means of image analysis with measurement of integrated optical density after Feulgen reaction on monolayers. Ploidy distribution of the tumors was not significantly changed 6 and 12 hr after administration of VCR only, while an increasing aneuploidy was observed 24 and 48 hr after VCR treatment. No prominent changes of the cell cycle and ploidy distributions were found in the tumor tissues after PDT or PDT combined with VCR.

  19. Effect of chronic treatment with the vasopeptidase inhibitor AVE 7688 and ramipril on endothelial function in atherogenic diet rabbits.

    Weckler, Nadine; Leitzbach, Daniela; Kalinowski, Leszek; Malinski, Tadeusz; Busch, Andreas E; Linz, Wolfgang; Kalinowski, Ludmila

    2003-09-01

    Cardiovascular disease is the major cause of death in Western nations, although improved possibilities regarding diagnosis and therapy now exist. Endothelial dysfunction is triggered by cardiovascular risk factors such as hypercholesterolaemia, hypertension, adiposity and smoking, contributing to the common endpoint of atherosclerosis. This study examined the pharmacological effects of angiotensin-converting enzyme (ACE) and combined ACE-neutral endopeptidase (NEP) (vasopeptidase) inhibitors on endothelial dysfunction in the model of hyperlipidaemic rabbits. The focus of the study was to assess endothelial function after treatment with the ACE-NEP inhibitor AVE 7688 (30 mg/kg/day) in comparison to the ACE inhibitor (ACE-I) ramipril (1 mg/kg/day). Different parameters, such as endothelial function, blood pressure (BP), expansion of plaques, endothelial nitric oxide (NO) and superoxide (O2-) release and plasma levels of various lipidaemic parameters were analysed. Control groups consisted of one group fed only with normal diet, one group fed only with atherogenic diet and the direct control group fed with varied diets (six weeks atherogenic diet followed by 12 weeks normal diet). Since for the treatment of atherosclerosis, a change in feeding is absolutely necessary, in the present study, at the start of the treatments with AVE 7688 and ramipril, the rabbits food was changed to a normal diet. At the end of the study, mean arterial blood pressure (MAP) was measured in the anaesthetised animals. The values in standard, atherogenic and varied diet-fed rabbits were around 73 2 mmHg. Angiotensin I (Ang I) given intravenous (i.v.) induced a strong increase in MAP of about 20%. In both the treated groups Ang I-induced BP increase was inhibited. In contrast, i.v. bradykinin led to a strong reduction in MAP in both the treated groups of around 50%. Six weeks feeding with an atherogenic diet in the rabbits induced an enduring endothelial dysfunction despite the food

  20. General relativistic observables for the ACES experiment

    Turyshev, Slava G; Toth, Viktor T

    2015-01-01

    We develop a high-precision model for relativistic observables of the Atomic Clock Ensemble in Space (ACES) experiment on the International Space Station (ISS). We develop all relativistic coordinate transformations that are needed to describe the motion of ACES in Earth orbit and to compute observable quantities. We analyze the accuracy of the required model as it applies to the proper-to-coordinate time transformations, light time equation, and spacecraft equations of motion. We consider various sources of nongravitational noise and their effects on ACES. We estimate the accuracy of orbit reconstruction that is needed to satisfy the ACES science objectives. Based on our analysis, we derive models for the relativistic observables of ACES, which also account for the contribution of atmospheric drag on the clock rate. We include the Earth's oblateness coefficient $J_2$ and the effects of major nongravitational forces on the orbit of the ISS. We demonstrate that the ACES reference frame is pseudo-inertial at th...

  1. The effect of angiotensin-converting-enzyme inhibitors on progression of advanced polycystic kidney disease

    Jafar, Tazeen H; Stark, Paul C; Schmid, Christopher H;

    2005-01-01

    BACKGROUND: It is not known whether angiotensin-converting-enzyme (ACE) inhibitors slow the progression of polycystic kidney disease (PKD). We performed a patient-level meta-analysis to compare the effect of antihypertensive regimens, including ACE inhibitors, to those without ACE inhibitors...... of doubling of baseline serum creatinine or onset of kidney failure). We also performed multivariable linear regression and Cox proportional hazards analyses. Based on previous findings, we searched for interactions between the treatment effect (effect of ACE inhibitors vs. controls) and baseline urine...... protein excretion in both models. RESULTS: Eight studies included a total of 142 subjects with PKD: 68 (48%) were randomized to ACE inhibitors and 74 (52%) were randomized to the control. Baseline mean (SD) urine protein excretion was 0.92 (1.40) g/day: 1.08 (1.50) g/day in the ACE inhibitor and 0.76 (1...

  2. POMB/ACE chemotherapy for mediastinal germ cell tumours.

    Bower, M; Brock, C; Holden, L; Nelstrop, A; Makey, A R; Rustin, G J; Newlands, E S

    1997-05-01

    Mediastinal germ cell tumours (MGCT) are rare and most published series reflect the experiences of individual institutions over many years. Since 1979, we have treated 16 men (12 non-seminomatous germ cell tumours and 4 seminomas) with newly diagnosed primary MGCT with POMB/ACE chemotherapy and elective surgical resection of residual masses. This approach yielded complete remissions in 15/16 (94%) patients. The median follow-up was 6.0 years and no relapses occurred more than 2 years after treatment. The 5 year overall survival in the non-seminomatous germ cell tumours (NSGCT) is 73% (95% confidence interval 43-90%). One patient with NSGCT developed drug-resistant disease and died without achieving remission and 2 patients died of relapsed disease. In addition, 4 patients with bulky and/or metastatic seminoma were treated with POMB/ACE. One died of treatment-related neutropenic sepsis in complete remission and one died of relapsed disease. Finally, 4 patients (2 NSGCT and 2 seminomas) referred at relapse were treated with POMB/ACE and one was successfully salvaged. The combination of POMB/ACE chemotherapy and surgery is effective management for MGCT producing high long-term survival rates. PMID:9291802

  3. Changes in Practice Patterns of Clopidogrel in Combination with Proton Pump Inhibitors after an FDA Safety Communication

    Guérin, Annie; Mody, Reema; Carter, Valerie; Ayas, Charles; Patel, Haridarshan; Lasch, Karen; Wu, Eric

    2016-01-01

    Objectives In 2009, the FDA issued a warning that omeprazole–a proton pump inhibitor (PPI)–reduces the antithrombotic effect of clopidogrel by almost half when taken concomitantly. This study aims to analyze the impact of the FDA Safety Communications on prescribing clopidogrel together with PPIs. Methods This retrospective study identified clopidogrel users from the Truven Health Analytics MarketScan Databases (01/2006–12/2012). Rates of clopidogrel-PPI combination therapy were estimated in 6-month intervals for patients with ≥1 clopidogrel prescription fill, then were analyzed pre- and post-safety communication (11/17/2009). Analyses were also conducted by grouping PPIs into CYP2C19 inhibitors (omeprazole and esomeprazole) and CYP2C19 non-inhibitors (pantoprazole, lansoprazole, dexlansoprazole, and rabeprazole). Results Overall, 483,074 patients met the selection criteria; of these, 157,248 used a clopidogrel-PPI combination. On average, 30.5% of patients in the pre- and 19.9% in the post-communication period used a clopidogrel-PPI combination therapy. Among clopidogrel users, the probability of using clopidogrel-PPI combinations fell by over 40% in the post-communication period (OR = 0.57; pomeprazole fell from 10.1% to 6.3%. Among combination therapy users, the probability of patients using a combination with a CYP2C19 inhibitor decreased by 53% (OR = 0.47; p<0.001); however, 31.5% of patients were still prescribed a clopidogrel-PPI combination therapy. Trends were similar for all and newly treated patients, regardless of clopidogrel indication and physician specialty. Conclusions The FDA Safety Communication resulted in a reduction in the number of patients undergoing combination therapy; however approximately one-third of patients still used combination therapy post-communication. PMID:26727382

  4. A population-based study of the drug interaction between clopidogrel and angiotensin converting enzyme inhibitors

    Cressman, Alex M; Macdonald, Erin M.; Fernandes, Kimberly A.; Gomes, Tara; Paterson, J. Michael; Muhammad M Mamdani; Juurlink, David N.; ,

    2015-01-01

    Aims Clopidogrel and angiotensin converting enzyme (ACE) inhibitors are commonly co-prescribed drugs. Clopidogrel inhibits carboxylesterase 1 (CES1), the enzyme responsible for converting prodrug ACE inhibitors (such as ramipril and perindopril) to their active metabolites. The clinical implications of this potential drug interaction are unknown. The clinical consequences of the potential drug interaction between clopidogrel and prodrug ACE inhibitors were examined. Methods We conducted a nes...

  5. Treatment of Breast Cancer Cells by IGF1R Tyrosine Kinase Inhibitor Combined with Conventional Systemic Drugs

    Hartog, H.; Van der Graaf, W. T. A.; Boezen, H. M.; Wesseling, J.

    2012-01-01

    Aim: Insulin-like growth factor-1 receptor (IGF1R) is a tyrosine kinase receptor mediating cell growth and survival of cancer cells. We studied responses to IGF1R tyrosine kinase inhibitor NVP-AEW541 combined with conventional systemic drugs in breast cancer cell lines of different clinical subtype.

  6. Treatment of breast cancer cells by IGF1R tyrosine kinase inhibitor combined with conventional systemic drugs.

    Hartog, H.; Graaf, W.T.A. van der; Boezen, H.M.; Wesseling, J.

    2012-01-01

    AIM: Insulin-like growth factor-1 receptor (IGF1R) is a tyrosine kinase receptor mediating cell growth and survival of cancer cells. We studied responses to IGF1R tyrosine kinase inhibitor NVP-AEW541 combined with conventional systemic drugs in breast cancer cell lines of different clinical subtype.

  7. Angiotensin-converting enzyme inhibitors in veterinary medicine.

    Lefebvre, H P; Brown, S A; Chetboul, V; King, J N; Pouchelon, J-L; Toutain, P L

    2007-01-01

    Angiotensin-converting enzyme (ACE) inhibitors represent one of the most commonly used categories of drugs in canine and feline medicine. ACE inhibitors currently approved for use in veterinary medicine are benazepril, enalapril, imidapril and ramipril. They are all pro-drugs administered by oral route. A physiologically based model taking into account the saturable binding to ACE has been developed for pharmacokinetic analysis. The bioavailability of the active compounds from their respective pro-drug is low. The active metabolites are eliminated by renal, hepatorenal or biliary excretion, according to the drug. The elimination half-life of the free fraction of the active compounds is very short (ranging from approximately 10 min to 2 h). ACE inhibitors are generally well tolerated. Benazepril, enalapril, imidapril and ramipril are approved for dogs with chronic heart failure (CHF). The efficacy of ACE inhibitors has been convincingly demonstrated in dogs with CHF, especially in those with chronic valvular disease. In such clinical settings, ACE inhibitors improve hemodynamics and clinical signs, and increase survival time. In cats with cardiovascular disease, little information is available except for reports of some benefit in cats with hypertrophic cardiomyopathy in two non-controlled investigations. ACE inhibitors have also a mild to moderate hypotensive effect. There is also evidence to recommend ACE inhibitors in dogs and cats with chronic renal failure (CRF). They decrease the glomerular capillary pressure, have antiproteinuric effects, tend to delay the progression of CRF and to limit the extent of renal lesions. PMID:17506720

  8. Identification of the Major ACE-Inhibitory Peptides Produced by Enzymatic Hydrolysis of a Protein Concentrate from Cuttlefish Wastewater

    Isabel Rodríguez Amado; José Antonio Vázquez; Pilar González; Diego Esteban-Fernández; Mónica Carrera; Carmen Piñeiro

    2014-01-01

    The aim of this work was the purification and identification of the major angiotensin converting enzyme (ACE) inhibitory peptides produced by enzymatic hydrolysis of a protein concentrate recovered from a cuttlefish industrial manufacturing effluent. This process consisted on the ultrafiltration of cuttlefish softening wastewater, with a 10 kDa cut-off membrane, followed by the hydrolysis with alcalase of the retained fraction. Alcalase produced ACE inhibitors reaching the highest activity (I...

  9. Chromosome damage induced by DNA topoisomerase II inhibitors combined with g-radiation in vitro

    Maria Cristina P. Araújo

    1998-09-01

    Full Text Available Combined radiation and antineoplastic drug treatment have important applications in cancer therapy. In the present work, an evaluation was made of two known topoisomerase II inhibitors, doxorubicin (DXR and mitoxantrone (MXN, with g-radiation. The effects of DXR or MXN on g-radiation-induced chromosome aberrations in Chinese hamster ovary (CHO cells were analyzed. Two concentrations of each drug, 0.5 and 1.0 µg/ml DXR, and 0.02 and 0.04 µg/ml MXN, were applied in combination with two doses of g-radiation (20 and 40 cGy. A significant potentiating effect on chromosomal aberrations was observed in CHO cells exposed to 1.0 µg/ml DXR plus 40 cGy. In the other tests, the combination of g-radiation with DXR or MXN gave approximately additive effects. Reduced mitotic indices reflected higher toxicity of the drugs when combined with radiation.A associação de radiação ionizante com drogas antineoplásicas tem importante aplicação na terapia do câncer. No presente trabalho, foram avaliados os efeitos de dois inibidores de topoisomerase II, doxorubicina (DXR e mitoxantrona (MXN, sobre as aberrações cromossômicas induzidas pelas radiações-g em células do ovário de hamster chinês (CHO. Foram usadas as concentrações 0,5 e 1,0 mg/ml de DXR e 0,02 e 0,04 mg/ml de MXN, combinadas com duas doses de radiações gama (20 e 40 cGy. Um significativo efeito potenciador das aberrações cromossômicas foi observado em células CHO tratadas com 1,0 mg/ml de DXR e expostas a 40 cGy de radiação. Nos outros testes, a combinação da radiação-g com a DXR ou MXN apresentou um efeito próximo ao aditivo. A redução dos índices mitóticos refletiu a alta citotoxicidade das drogas quando combinadas às radiações-g.

  10. ACE抑制剂和血管紧张肽Ⅱ受体阻滞剂门诊处方调查%Survey Prescription Pattern of ACE Inhibitors and Angiotensin Ⅱ Receptor Blockers

    季闽春; 孙思明; 耿晓芳

    2003-01-01

    目的:通过对医院门诊血管紧张素转换酶(ACE)抑制剂和血管紧张肽(AⅡ)受体阻滞剂的处方调查,以了解医生处方习惯和这两类药物的门诊应用情况.方法:回顾性调查华东医院2001-11~2002-01共3个月的门诊处方,包括ACE抑制剂和AⅡ受体阻滞剂的处方频度、药物类别、剂量、合并处方、患者的性别和年龄分布等情况.结果:3个月门诊处方量分别为18381、22186和20866张,其中ACE抑制剂的处方频度分别为4.2%、5.1%和4.7%,以福辛普利和苯那普利的处方频度最高,依那普利和赖诺普利的处方频度最低.患者平均年龄65.3±10.9岁,男性多于女性,89.9%的患者合并1种或以上处方药物.AⅡ受体阻滞剂氯沙坦的处方频度分别为0.70%、0.84%和0.88%,患者平均年龄65.1±11.7岁.处方剂量多数在治疗指南和建议推荐的剂量范围的低限.22张处方在用ACE抑制剂的同时合并处方AⅡ受体阻滞剂.结论:门诊ACE抑制剂和AⅡ受体阻滞剂的处方应根据患者的耐受性和经济情况等加以选择,并按治疗指南或建议进行给药方案调整.

  11. THE CAPABILITIES OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS IN CLINICAL PRACTICE: FOCUS ON VASOPROTECTION

    D. B. Nebieridze

    2015-12-01

    Full Text Available Data of large-scale research that shows comprehensive abilities of an angiotensin converting enzyme (ACE inhibitors in clinical practice were represented. The traditional usage of ACE inhibitors in patients with arterial hypertension and chronic heart failure has extended recently. The study results demonstrate the efficacy of ACE inhibitors in slowing down of disease progression related to atherosclerosis and prove the possibility of a new clinical approach. Evidences support new strategic abilities of a number of ACE inhibitors (ramipril, perindopril, which are associated with vasoprotection.

  12. THE CAPABILITIES OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS IN CLINICAL PRACTICE: FOCUS ON VASOPROTECTION

    D. B. Nebieridze

    2007-01-01

    Full Text Available Data of large-scale research that shows comprehensive abilities of an angiotensin converting enzyme (ACE inhibitors in clinical practice were represented. The traditional usage of ACE inhibitors in patients with arterial hypertension and chronic heart failure has extended recently. The study results demonstrate the efficacy of ACE inhibitors in slowing down of disease progression related to atherosclerosis and prove the possibility of a new clinical approach. Evidences support new strategic abilities of a number of ACE inhibitors (ramipril, perindopril, which are associated with vasoprotection.

  13. Screening for Enzyme Inhibitors by Surface Plasmon Resonance Combined with Mass Spectrometry

    Borch, Jonas; Roepstorff, Peter

    2004-01-01

    substrate and mass spectrometric analysis. If the bound compound inhibits the enzyme, the inhibitor is eluted from the enzyme and characterized by mass spectrometry. To test the strategy, it has been applied to the well-characterized interaction between trypsin and pure bovine pancreas trypsin inhibitor...

  14. Differential regulation of renal angiotensin-converting enzyme (ACE) and ACE2 during ACE inhibition and dietary sodium restriction in healthy rats

    Hamming, I.; van Goor, H.; Turner, A. J.; Rushworth, C. A.; Michaud, A. A.; Corvol, P.; Navis, G.

    2008-01-01

    Angiotensin-converting enzyme (ACE) 2 is thought to counterbalance ACE by breakdown of angiotensin (Ang) II and formation of Ang(1-7). Both enzymes are highly expressed in the kidney, but reports on their regulation differ. To enhance our understanding of the regulation of renal ACE and ACE2, we inv

  15. The effect of selective phosphodiesterase inhibitors, alone and in combination, on a murine model of allergic asthma

    Galbraith Deirdre

    2004-05-01

    Full Text Available Abstract Background The anti-inflammatory effects of the selective phosphodiesterase (PDE inhibitors cilostazol (PDE 3, RO 20-1724 (PDE 4 and sildenafil (PDE 5 were examined in a murine model of allergic asthma. These compounds were used alone and in combination to determine any potential synergism, with dexamethasone included as a positive control. Methods Control and ovalbumin sensitised Balb/C mice were administered orally with each of the possible combinations of drugs at a dose of 3 mg/Kg for 10 days. Results When used alone, RO 20-1724 significantly reduced eosinophil influx into lungs and lowered tumour necrosis factor-α, interleukin-4 and interleukin-5 levels in the bronchoalveolar lavage fluid when compared to untreated mice. Treatment with cilostazol or sildenafil did not significantly inhibit any markers of inflammation measured. Combining any of these PDE inhibitors produced no additive or synergistic effects. Indeed, the anti-inflammatory effects of RO 20-1724 were attenuated by co-administration of either cilostazol or sildenafil. Conclusions These results suggest that concurrent treatment with a PDE 3 and/or PDE 5 inhibitor will reduce the anti-inflammatory effectiveness of a PDE 4 inhibitor.

  16. New perspectives in the renin-angiotensin-aldosterone system (RAAS III: endogenous inhibition of angiotensin converting enzyme (ACE provides protection against cardiovascular diseases.

    Miklós Fagyas

    Full Text Available ACE inhibitor drugs decrease mortality by up to one-fifth in cardiovascular patients. Surprisingly, there are reports dating back to 1979 suggesting the existence of endogenous ACE inhibitors. Here we investigated the clinical significance of this potential endogenous ACE inhibition. ACE concentration and activity was measured in patient's serum samples (n = 151. ACE concentration was found to be in a wide range (47-288 ng/mL. ACE activity decreased with the increasing concentration of the serum albumin (HSA: ACE activity was 56 ± 1 U/L in the presence of 2.4 ± 0.3 mg/mL HSA, compared to 39 ± 1 U/L in the presence of 12 ± 1 mg/mL HSA (values are mean ± SEM. Effects of the differences in ACE concentration were suppressed in human sera: patients with ACE DD genotype exhibited a 64% higher serum ACE concentration (range, 74-288 ng/mL, median, 155.2 ng/mL, n = 52 compared to patients with II genotype (range, 47-194 ng/mL, median, 94.5 ng/mL, n = 28 while the difference in ACE activities was only 32% (range, 27.3-59.8 U/L, median, 43.11 U/L, and range 15.6-55.4 U/L, median, 32.74 U/L, respectively in the presence of 12 ± 1 mg/mL HSA. No correlations were found between serum ACE concentration (or genotype and cardiovascular diseases, in accordance with the proposed suppressed physiological ACE activities by HSA (concentration in the sera of these patients: 48.5 ± 0.5 mg/mL or other endogenous inhibitors. Main implications are that (1 physiological ACE activity can be stabilized at a low level by endogenous ACE inhibitors, such as HSA; (2 angiotensin II elimination may have a significant role in angiotensin II related pathologies.

  17. Combining carbon ion irradiation and non-homologous end-joining repair inhibitor NU7026 efficiently kills cancer cells

    Our previous data demonstrated that targeting non-homologous end-joining repair (NHEJR) yields a higher radiosensitivity than targeting homologous recombination repair (HRR) to heavy ions using DNA repair gene knockouts (KO) in mouse embryonic fibroblast (MEF). In this study, we determined if combining the use of an NHEJR inhibitor with carbon (C) ion irradiation was more efficient in killing human cancer cells compared with only targeting a HRR inhibitor. The TP53-null human non-small cell lung cancer cell line H1299 was used for testing the radiosensitizing effect of NHEJR-related DNA-dependent protein kinase (DNA-PK) inhibitor NU7026, HRR-related Rad51 inhibitor B02, or both to C ion irradiation using colony forming assays. The mechanism underlying the inhibitor radiosensitization was determined by flow cytometry after H2AX phosphorylation staining. HRR-related Rad54-KO, NHEJR-related Lig4-KO, and wild-type TP53-KO MEF were also included to confirm the suppressing effect specificity of these inhibitors. NU7026 showed significant sensitizing effect to C ion irradiation in a concentration-dependent manner. In contrast, B02 showed a slight sensitizing effect to C ion irradiation. The addition of NU7026 significantly increased H2AX phosphorylation after C ion and x-ray irradiations in H1299 cells, but not B02. NU7026 had no effect on radiosensitivity to Lig4-KO MEF and B02 had no effect on radiosensitivity to Rad54-KO MEF in both irradiations. These results suggest that inhibitors targeting the NHEJR pathway could significantly enhance radiosensitivity of human cancer cells to C ion irradiation, rather than targeting the HRR pathway. The online version of this article (doi:10.1186/s13014-015-0536-z) contains supplementary material, which is available to authorized users

  18. Sodium-glucose co-transporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors combination therapy in type 2 diabetes: A systematic review of current evidence

    Awadhesh Kumar Singh

    2016-01-01

    Full Text Available As type 2 diabetes mellitus (T2DM is a chronic and progressive disease with multiple pathophysiologic defects, no single anti-diabetic agent can tackle all these multi-factorial pathways. Consequently, multiple agents working through the different mechanisms will be required for the optimal glycemic control. Moreover, the combination therapies of different anti-diabetic agents may complement their actions and possibly act synergistic. Furthermore, these combinations could possess the additional properties to counter their undesired physiological compensatory response. Sodium-glucose co-transporter-2 inhibitors (SGLT-2I are newly emerging class of drugs, with a great potential to reduce glucose effectively with an additional quality of lowering cardiovascular events as demonstrated very recently by one of the agents of this class. However, increase in endogenous glucose production (EGP from the liver, either due to the increase in glucagon or compensatory response to glucosuria can offset the glucose-lowering potential of SGLT-2I. Interestingly, another class of drugs such as dipeptidyl peptidase-4 inhibitors (DPP-4I effectively decrease glucagon and reduce EGP. In light of these findings, combination therapies with SGLT-2I and DPP-4I are particularly appealing and are expected to produce a synergistic effect. Preclinical studies of combination therapies with DPP-4I and SGLT-2I have already demonstrated a significant lowering of hemoglobin A1c potential and human studies also find no drug-drug interaction between these agents. This article aims to systematically review the efficacy and safety of combination therapy of SGLT-2I and DPP-4I in T2DM.

  19. Sodium-glucose co-transporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors combination therapy in type 2 diabetes: A systematic review of current evidence.

    Singh, Awadhesh Kumar; Singh, Ritu

    2016-01-01

    As type 2 diabetes mellitus (T2DM) is a chronic and progressive disease with multiple pathophysiologic defects, no single anti-diabetic agent can tackle all these multi-factorial pathways. Consequently, multiple agents working through the different mechanisms will be required for the optimal glycemic control. Moreover, the combination therapies of different anti-diabetic agents may complement their actions and possibly act synergistic. Furthermore, these combinations could possess the additional properties to counter their undesired physiological compensatory response. Sodium-glucose co-transporter-2 inhibitors (SGLT-2I) are newly emerging class of drugs, with a great potential to reduce glucose effectively with an additional quality of lowering cardiovascular events as demonstrated very recently by one of the agents of this class. However, increase in endogenous glucose production (EGP) from the liver, either due to the increase in glucagon or compensatory response to glucosuria can offset the glucose-lowering potential of SGLT-2I. Interestingly, another class of drugs such as dipeptidyl peptidase-4 inhibitors (DPP-4I) effectively decrease glucagon and reduce EGP. In light of these findings, combination therapies with SGLT-2I and DPP-4I are particularly appealing and are expected to produce a synergistic effect. Preclinical studies of combination therapies with DPP-4I and SGLT-2I have already demonstrated a significant lowering of hemoglobin A1c potential and human studies also find no drug-drug interaction between these agents. This article aims to systematically review the efficacy and safety of combination therapy of SGLT-2I and DPP-4I in T2DM. PMID:27042423

  20. Combination of 5α-reductase inhibitor with combined androgen blockade (CAB) as a novel cytoreductive regimen before prostate brachytherapy: Ultra-CAB

    Muro, Yusuke; Kosaka, Takeo; Mizuno, Ryuichi; Ohashi, Toshio; Shigematsu, Naoyuki; Oya, Mototsugu

    2015-01-01

    We report a first case of using a 5α-reductase inhibitor (5ARI) and combined androgen blockade (CAB) as a cytoreductive regimen before prostate brachytherapy. Prostate volume reduction with CAB is limited to approximately 40% in most cases, making it difficult to meet anatomical constraints to perform these procedures in cases with large prostate volume. With the added administration of 5ARI, further volume reduction can be expected. Here, we describe this cytoreductive regimen used in a 63 y...

  1. Identifying New Drug Targets for Potent Phospholipase D Inhibitors: Combining Sequence Alignment, Molecular Docking, and Enzyme Activity/Binding Assays.

    Djakpa, Helene; Kulkarni, Aditya; Barrows-Murphy, Scheneque; Miller, Greg; Zhou, Weihong; Cho, Hyejin; Török, Béla; Stieglitz, Kimberly

    2016-05-01

    Phospholipase D enzymes cleave phospholipid substrates generating choline and phosphatidic acid. Phospholipase D from Streptomyces chromofuscus is a non-HKD (histidine, lysine, and aspartic acid) phospholipase D as the enzyme is more similar to members of the diverse family of metallo-phosphodiesterase/phosphatase enzymes than phospholipase D enzymes with active site HKD repeats. A highly efficient library of phospholipase D inhibitors based on 1,3-disubstituted-4-amino-pyrazolopyrimidine core structure was utilized to evaluate the inhibition of purified S. chromofuscus phospholipase D. The molecules exhibited inhibition of phospholipase D activity (IC50 ) in the nanomolar range with monomeric substrate diC4 PC and micromolar range with phospholipid micelles and vesicles. Binding studies with vesicle substrate and phospholipase D strongly indicate that these inhibitors directly block enzyme vesicle binding. Following these compelling results as a starting point, sequence searches and alignments with S. chromofuscus phospholipase D have identified potential new drug targets. Using AutoDock, inhibitors were docked into the enzymes selected from sequence searches and alignments (when 3D co-ordinates were available) and results analyzed to develop next-generation inhibitors for new targets. In vitro enzyme activity assays with several human phosphatases demonstrated that the predictive protocol was accurate. The strategy of combining sequence comparison, docking, and high-throughput screening assays has helped to identify new drug targets and provided some insight into how to make potential inhibitors more specific to desired targets. PMID:26691755

  2. Closing two doors of viral entry: Intramolecular combination of a coreceptor- and fusion inhibitor of HIV-1

    Cammack Nick

    2008-05-01

    Full Text Available Abstract We describe a novel strategy in which two inhibitors of HIV viral entry were incorporated into a single molecule. This bifunctional fusion inhibitor consists of an antibody blocking the binding of HIV to its co-receptor CCR5, and a covalently linked peptide which blocks envelope mediated virus-cell fusion. This novel bifunctional molecule is highly active on CCR5- and X4-tropic viruses in a single cycle assay and a reporter cell line with IC50 values of 0.03–0.05 nM. We demonstrated that both inhibitors contribute to the antiviral activity. In the natural host peripheral blood mononuclear cells (PBMC the inhibition of CXCR4-tropic viruses is dependant on the co-expression of CCR5 and CXCR4 receptors. This bifunctional inhibitor may offer potential for improved pharmacokinetic parameters for a fusion inhibitor in humans and the combination of two active antiviral agents in one molecule may provide better durability in controlling the emergence of resistant viruses.

  3. Economic Impact of Combining Metformin with Dipeptidyl Peptidase-4 Inhibitors in Diabetic Patients with Renal Impairment in Spanish Patients

    Antoni Sicras-Mainar

    2015-02-01

    Full Text Available BackgroundTo evaluate resource use and health costs due to the combination of metformin and dipeptidyl peptidase-4 (DPP-4 inhibitors in patients with diabetes and renal impairment in routine clinical practice.MethodsAn observational, retrospective study was performed. Patients aged ≥30 years treated with metformin who initiated a second oral antidiabetic treatment in 2009 to 2010 were included. Two groups of patients were analysed: metformin+DPP-4 inhibitors and other oral antidiabetics. The main measures were: compliance, persistence, metabolic control (glycosylated hemoglobin< 7% and complications (hypoglycemia, cardiovascular events and total costs. Patients were followed up for 2 years.ResultsWe included 395 patients, mean age 70.2 years, 56.5% male: 135 patients received metformin+DPP-4 inhibitors and 260 patients received metformin+other oral antidiabetics. Patients receiving DPP-4 inhibitors showed better compliance (66.0% vs. 60.1%, persistence (57.6% vs. 50.0%, and metabolic control (63.9% vs. 57.3%, respectively, compared with those receiving other oral antidiabetics (P<0.05, and also had a lower rate of hypoglycemia (20.0% vs. 47.7% and lower total costs (€ 2,486 vs. € 3,002, P=0.001.ConclusionDespite the limitations of the study, patients with renal impairment treated with DPP-4 inhibitors had better metabolic control, lower rates (association of hypoglycaemia, and lower health costs for the Spanish national health system.

  4. MEK inhibitors and their potential in the treatment of advanced melanoma: the advantages of combination therapy

    Tran, Khiem A; Cheng, Michelle Y; Mitra, Anupam; Ogawa, Hiromi; Shi, Vivian Y; Olney, Laura P; Kloxin, April M; Maverakis, Emanual

    2016-01-01

    The treatment of melanoma has improved markedly over the last several years with the advent of more targeted therapies. Unfortunately, complex compensation mechanisms, such as those of the mitogen-activated protein kinase (MAPK) pathway, have limited the clinical benefit of these treatments. Recently, a better understanding of melanoma resistance mechanisms has given way to intelligently designed multidrug regimes. Herein, we review the extensive pathways of BRAF inhibitor (vemurafenib and dabrafenib) resistance. We also review the advantages of dual therapy, including the addition of an MEK inhibitor (cobimetinib or trametinib), which has proven to increase progression-free survival when compared to BRAF inhibitor monotherapy. Finally, this review touches on future treatment strategies that are being developed for advanced melanoma, including the possibility of triple therapy with immune checkpoint inhibitors and the work on optimizing sequential therapy. PMID:26730180

  5. Angiotensin-converting enzyme inhibitors: measurement of relative inhibitory potency and serum drug levels by radioinhibitor binding displacement assay

    Radioinhibitor binding displacement, a new method for the measurement of angiotensin-converting enzyme (ACE) competitive inhibitors, has been used to assess the relative potency of nine synthetic ACE inhibitors. MK351A, tyrosyl derivative of enalaprilic acid was iodinated with 125I and used as the radioligand. [125I]MK351A bound to human serum ACE in a concentration-dependent manner. It was displaced in a concentration-dependent manner by all ACE inhibitors tested. Fifty percent displacement of bound [125I]MK351A (DD50) for each ACE inhibitor correlated well with inhibitor potency ID50, estimated using an ACE enzymatic activity assay using Hip-His-Leu as substrate (r = 0.96, p less than 0.001; n = 9). The radioinhibitor binding displacement assay was used to measure serum concentration of enalaprilic acid (MK422) in human serum samples. Drug concentration estimated by radioinhibitor binding displacement assay correlated closely (r = 0.96, p less than 0.001; n = 22) with the drug concentration measured by a specific radioimmunoassay. The radioinhibitor binding displacement technique using [125I]MK351A as the ligand for human serum ACE has general application to all competitive ACE inhibitors, allowing comparison of in vitro ACE inhibitor potencies and estimation of serum ACE inhibitor concentrations

  6. Sinus thrombectomy for purulent cerebral venous sinus thrombosis utilizing a novel combination of the Trevo stent retriever and the Penumbra ACE aspiration catheter: the stent anchor with mobile aspiration technique.

    Mascitelli, Justin R; Pain, Margaret; Zarzour, Hekmat K; Baxter, Peter; Ghatan, Saadi; Mocco, J

    2016-06-01

    Intracranial complications of sinusitis are rare but life threatening. We present a case of a 17-year-old woman with sinusitis who deteriorated over the course of 12 days from subdural empyema and global purulent cerebral venous sinus thrombosis. The patient was managed with surgery and mechanical thrombectomy utilizing a novel 'stent anchor with mobile aspiration technique', in which a Trevo stent retriever (Stryker) was anchored in the superior sagittal sinus (SSS) while a 5 MAX ACE reperfusion catheter (Penumbra) was passed back and forth from the SSS to the sigmoid sinus with resultant dramatic improvement in venous outflow. The patient was extubated on postoperative day 3 and was discharged with minimal lower extremity weakness on postoperative day 11. This is the first report using the Trevo stent retriever for sinus thrombosis. It is important to keep these rare complications in mind when evaluating patients with oral and facial infections. PMID:26019186

  7. Interferon augments the anti-fibrotic activity of an angiotensin-converting enzyme inhibitor in patients with refractory chronic hepatitis C

    Hitoshi Yoshiji; Masaharu Yamazaki; Masahisa Toyohara; Akira Mitoro; Hiroshi Fukui; Ryuichi Noguchi; Hideyuki Kojima; Yasuhide Ikenaka; Mitsuteru Kitade; Kosuke Kaji; Masahito Uemura; Junichi Yamao; Masao Fujimoto

    2006-01-01

    AIM:To evaluate the effect of combination treatment with the interferon (IFN) and angiotensin-converting enzyme inhibitor (ACE-I ) on several fibrotic indices in patients with refractory chronic hepatitis C (CHC).METHODS: Perindopril (an ACE-I; 4 mg/d) and/or natural IFN (3 MU/L; 3 times a week) were administered for 12 mo to refractory CHC patients, and several indices of serum fibrosis markers were analyzed.RESULTS:ACE-Ⅰ decreased the serum fibrosis markers,whereas single treatment with IFN did not exert these inhibitory effects. However, IFN significantly augmented the effects of ACE-Ⅰ, and the combination treatment exerted the most potent inhibitory effects. The serum levels of alanine transaminase and HCV-RNA were not significantly different between the groups, whereas the plasma level of transforming growth factor-β was significantly attenuated almost in parallel with suppression of the serum fibrosis markers.CONCLUSION:The combination therapy of an ACE-Ⅰand IFN may have a diverse effect on disease progression in patients with CHC refractory to IFN therapy through its anti-fibrotic effect.

  8. Clinical efficacy of second generation tyrosine kinase inhibitor and 5-azacytidine combination in chronic myelogenous leukaemia in myeloid blast crisis.

    Ghez, David; Micol, Jean-Baptiste; Pasquier, Florence; Auger, Nathalie; Saada, Véronique; Spentchian, Marc; Ianotto, Jean-Christophe; Bourhis, Jean-Henri; Bennaceur-Griscelli, Anelyse; Terré, Christine; Castaigne, Sylvie; Rigaudeau, Sophie; Rousselot, Philippe; de Botton, Stéphane

    2013-11-01

    Even in the tyrosine kinase inhibitors era, the prognosis of patients with chronic myeloid leukaemia in myeloid blast crisis remains dismal with few patients surviving longer than 6 months. Here we report the cases of 5 patients treated with the combination of 5-azacytidine and tyrosine kinase inhibitors for myeloid blast crisis CML. All patients achieved a complete haematological response including two with a complete cytogenetic and major molecular response. Two patients underwent an allogeneic stem cell transplantation. One died from relapse 34 months from diagnosis. The second is alive and free from disease at 11 months from diagnosis. The other 3 patients are still in complete haematological response after 15, 24 and 33 months of follow-up. These results suggest that the combination has a significant activity in myeloid blast crisis and may increase survival. PMID:23968731

  9. Combining a BCL2 Inhibitor with the Retinoid Derivative Fenretinide Targets Melanoma Cells Including Melanoma Initiating Cells

    Mukherjee, Nabanita; Reuland, Steven N.; Lu, Yan; Luo, Yuchun; Lambert, Karoline; Fujita, Mayumi; Robinson, William A.; Robinson, Steven E.; David A Norris; Yiqun G Shellman

    2014-01-01

    Investigations from multiple laboratories support the existence of melanoma initiating cells (MICs) that potentially contribute to melanoma's drug resistance. ABT-737, a small molecule BCL-2/BCL-XL/BCL-W inhibitor, is promising in cancer treatments, but not very effective against melanoma, with the anti-apoptotic protein MCL-1 as the main contributor to resistance. The synthetic retinoid fenretinide (4-HPR) has shown promise for treating breast cancers. Here, we tested whether the combination...

  10. The efficacy of therapy with DPP-4 inhibitors combined with insulin in patients with type 2 diabetes mellitus

    Alesandr Sergeevich Ametov; Ekaterina Vladimirovna Karpova

    2011-01-01

    Recently, researchers started to pay increasingly more attention to the role of gastrointestinal hormones in regulation of insulin secretion, i.e. glucose homeostasis. To-day, there are two approaches to the treatment of DM based on the use of GLP-1 effects. One takes advantage of DPP-4 inhibitors the other is combination of these agents with various drugs necessitated by heterogeneity of pathophysiological factors responsible for the development of DM2. The latter approach ensures m...

  11. PDE-5 inhibitors in monotherapy versus combination therapy in a sample of 1200 patients with erectile dysfunction

    Luis Labairu-Huerta; Bárbara Padilla-Fernández; José Luis Arrondo-Arrondo; Lauro Sebastián Valverde-Martínez; Agustín Martín-Rodríguez; Juan Miguel Silva-Abuín; María Begoña García-Cenador; José Antonio Mirón-Canelo; María Fernanda Lorenzo-Gómez

    2015-01-01

    Objectives: To compare the effectiveness in the treatment of erectile dysfunction when using PDE-5 inhibitors (PDE5i), alprostadil (PG-E1) and testosterone (TES) in monotherapy or combination therapy. Material and Methods: Observational multicentre retrospective study of men diagnosed and treated for ED between January 2008 and January 2014. Age, social and employment situation, pathological medical history, risk factors, usual treatments, IIEF-5 at the first consultation and at first and eac...

  12. In vitro and in vivo studies of the combination of IGF1R inhibitor figitumumab (CP-751,871) with HER2 inhibitors trastuzumab and neratinib.

    Chakraborty, Ashok K; Zerillo, Cynthia; DiGiovanna, Michael P

    2015-08-01

    The insulin-like growth factor I receptor (IGF1R) has been linked to resistance to HER2-directed therapy with trastuzumab (Herceptin). We examined the anti-tumor activity of figitumumab (CP-751,871), a human monoclonal antibody that blocks IGF1R ligand binding, alone and in combination with the therapeutic anti-HER2 antibody trastuzumab and the pan-HER family tyrosine kinase inhibitor neratinib, using in vitro and in vivo breast cancer model systems. In vitro assays of proliferation, apoptosis, and signaling, and in vivo anti-tumor experiments were conducted in HER2-overexpressing (BT474) and HER2-normal (MCF7) models. We find single-agent activity of the HER2-targeting drugs but not figitumumab in the BT474 model, while the reverse is true in the MCF7 model. However, in both models, combining figitumumab with HER2-targeting drugs shows synergistic anti-proliferative and apoptosis-inducing effects, and optimum inhibition of downstream signaling. In murine xenograft models, synergistic anti-tumor effects were observed in the HER2-normal MCF7 model for the combination of figitumumab with trastuzumab, and, in the HER2-overexpressing BT474 model, enhanced anti-tumor effects were observed for the combination of figitumumab with either trastuzumab or neratinib. Analysis of tumor extracts from the in vivo experiments showed evidence of the most optimal inhibition of downstream signaling for the drug combinations over the single-agent therapies. These results suggest promise for such combinations in treating patients with breast cancer, and that, unlike the case for single-agent therapy, the therapeutic effects of such combinations may be independent of expression levels of the individual receptors or the single-agent activity profile. PMID:26195122

  13. ACE-I/ARB Therapy prior to Contrast Exposure: What Should the Clinician Do?

    Robert Kalyesubula

    2014-01-01

    Full Text Available Contrast-induced nephropathy (CIN is now one of the three leading causes of acute kidney injury in the world. A lot is known about the risk factors of CIN, yet it remains a major cause of morbidity, end stage renal disease, prolonged hospital stay, and increased costs as well as a high mortality. Many patients undergoing contrast-based radiological investigations are treated with angiotensin converting inhibitors (ACE-Is or angiotensin receptor blockers (ARBs for their cardiac and renal benefits and their known mortality benefits. However, controversy exists among clinicians as to whether ACE-Is and ARBs should be continued or discontinued prior to contrast media exposure. In this paper we review the current evidence on ACE-I/ARB therapy for patients undergoing procedures involving use of contrast media and provide recommendations as to whether these drugs should be continued or held prior to contrast exposure.

  14. Synthesis of 3-(2-Cinnamamidoethylsulfonyl)-thiazolidine-4-carboxylate Derivatives as Novel Angiotensin Converting Enzyme (ACE) Inhibitors%新型的3-(2-肉桂酰胺基乙磺酰基)噻唑烷-4-羧酸酯类血管紧张素转化酶抑制剂的合成

    武磊芳; 谢建伟; 代斌; 张洁; 马晓伟; 应雪; 焦艳丽

    2012-01-01

    以牛磺酸、半胱氨酸甲酯(乙酯)盐酸盐、4-取代肉桂酸等为原料,经过7步反应,合成了7个新型的3-(2-肉桂酰胺基乙磺酰基)噻唑烷-4-羧酸酯类衍生物,结构经1H NMR、13C NMR、MS和IR表征确证.7个目标化合物均未见文献报道,这类化合物可作为潜在的血管紧张素转化酶抑制剂(ACEIs).实验采用的合成方法简单易行,可作为一系列3-(2-肉桂酰胺基乙磺酰基)噻唑烷-4-羧酸酯类ACE抑制剂的合成通法.%Seven novel 3-(2-cinnamamidoethylsulfonyl)-thiazolidine-4-carboxylate derivatives were designed and synthesized in seven steps from taurine, L-cystein methyl ester (ethyl ester) hydrochloride,4-substituted cinnamic acid and other materials. The structures of these seven products were verified by 1H NMR,13C NMR,MS and IR. All of the target compounds were not reported in the literature and could be used as potential angiotensin converting enzyme (ACE) inhibitors. The method is simple, easy and can be used as a general method to synthesize a series of the thiazolidine-4-carboxylate derivatives.

  15. New design of nucleotide excision repair (NER) inhibitors for combination cancer therapy.

    Gentile, Francesco; Tuszynski, Jack A; Barakat, Khaled H

    2016-04-01

    Many cancer chemotherapy agents act by targeting the DNA of cancer cells, causing substantial damage within their genome and causing them to undergo apoptosis. An effective DNA repair pathway in cancer cells can act in a reverse way by removing these drug-induced DNA lesions, allowing cancer cells to survive, grow and proliferate. In this context, DNA repair inhibitors opened a new avenue in cancer treatment, by blocking the DNA repair mechanisms from removing the chemotherapy-mediated DNA damage. In particular, the nucleotide excision repair (NER) involves more than thirty protein-protein interactions and removes DNA adducts caused by platinum-based chemotherapy. The excision repair cross-complementation group 1 (ERCC1)-xeroderma pigmentosum, complementation group A (XPA) protein (XPA-ERCC1) complex seems to be one of the most promising targets in this pathway. ERCC1 is over expressed in cancer cells and the only known cellular function so far for XPA is to recruit ERCC1 to the damaged point. Here, we build upon our recent advances in identifying inhibitors for this interaction and continue our efforts to rationally design more effective and potent regulators for the NER pathway. We employed in silico drug design techniques to: (1) identify compounds similar to the recently discovered inhibitors, but more effective at inhibiting the XPA-ERCC1 interactions, and (2) identify different scaffolds to develop novel lead compounds. Two known inhibitor structures have been used as starting points for two ligand/structure-hybrid virtual screening approaches. The findings described here form a milestone in discovering novel inhibitors for the NER pathway aiming at improving the efficacy of current platinum-based therapy, by modulating the XPA-ERCC1 interaction. PMID:26939044

  16. The Aerosol/Cloud/Ecosystems Mission (ACE)

    Schoeberl, Mark

    2008-01-01

    The goals and measurement strategy of the Aerosol/Cloud/Ecosystems Mission (ACE) are described. ACE will help to answer fundamental science questions associated with aerosols, clouds, air quality and global ocean ecosystems. Specifically, the goals of ACE are: 1) to quantify aerosol-cloud interactions and to assess the impact of aerosols on the hydrological cycle and 2) determine Ocean Carbon Cycling and other ocean biological processes. It is expected that ACE will: narrow the uncertainty in aerosol-cloud-precipitation interaction and quantify the role of aerosols in climate change; measure the ocean ecosystem changes and precisely quantify ocean carbon uptake; and, improve air quality forecasting by determining the height and type of aerosols being transported long distances. Overviews are provided of the aerosol-cloud community measurement strategy, aerosol and cloud observations over South Asia, and ocean biology research goals. Instruments used in the measurement strategy of the ACE mission are also highlighted, including: multi-beam lidar, multiwavelength high spectra resolution lidar, the ocean color instrument (ORCA)--a spectroradiometer for ocean remote sensing, dual frequency cloud radar and high- and low-frequency micron-wave radiometer. Future steps for the ACE mission include refining measurement requirements and carrying out additional instrument and payload studies.

  17. Exploring the prominent performance of CX-4945 derivatives as protein kinase CK2 inhibitors by a combined computational study.

    Wang, Xuwen; Pan, Peichen; Li, Youyong; Li, Dan; Hou, Tingjun

    2014-05-01

    Protein kinase CK2, also known as casein kinase II, is related to various cellular events and is a potential target for numerous cancers. In this study, we attempted to gain more insight into the inhibition process of CK2 by a series of CX-4945 derivatives through an integrated computational study that combines molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations. Based on the binding poses predicted by molecular docking, the MD simulations were performed to explore the dynamic binding processes for ten selected inhibitors. Then, both Molecular Mechanics/Poisson Boltzmann Surface Area (MM/PBSA) and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) techniques were employed to predict the binding affinities of the studied systems. The predicted binding energies of the selected inhibitors correlate well with their experimental activities (r(2) = 0.78). The van der Waals term is the most favorable component for the total energies. The free energy decomposition on a per residue basis reveals that the residue K68 is essential for the electrostatic interactions between CK2 and the studied inhibitors and numerous residues, including L45, V53, V66, F113, M163 and I174, play critical roles in forming van der Waals interactions with the inhibitors. Finally, a number of new derivatives were designed and the binding affinity and the predicted binding free energies of each designed molecule were obtained on the basis of molecular docking and MM/PBSA. It is expected that our research will benefit the future rational design of novel and potent inhibitors of CK2. PMID:24647611

  18. Combination of 5α-reductase inhibitor with combined androgen blockade (CAB) as a novel cytoreductive regimen before prostate brachytherapy: Ultra-CAB.

    Muro, Yusuke; Kosaka, Takeo; Mizuno, Ryuichi; Ohashi, Toshio; Shigematsu, Naoyuki; Oya, Mototsugu

    2015-01-01

    We report a first case of using a 5α-reductase inhibitor (5ARI) and combined androgen blockade (CAB) as a cytoreductive regimen before prostate brachytherapy. Prostate volume reduction with CAB is limited to approximately 40% in most cases, making it difficult to meet anatomical constraints to perform these procedures in cases with large prostate volume. With the added administration of 5ARI, further volume reduction can be expected. Here, we describe this cytoreductive regimen used in a 63 year-old prostate cancer patient who became eligible to receive brachytherapy after dutasteride (0.5 mg daily) was added to CAB and prostate volume reduction of 57% was achieved. PMID:26069888

  19. Blocking the RAAS at different levels: an update on the use of the direct renin inhibitors alone and in combination

    Francesca Cagnoni

    2010-06-01

    Full Text Available Francesca Cagnoni1, Christian Achiri Ngu Njwe1, Augusto Zaninelli4, Alessandra Rossi Ricci1, Diletta Daffra2, Antonio D’Ospina1, Paola Preti3, Maurizio Destro11Internal Medicine, Ospedale Unificato Broni-Stradella, Stradella (PV, Italy; 2Internal Medicine, S.S. Annunziata Hospital, Varzi (PV, Italy; 3Internal Medicine, University of Pavia, Pavia, Italy; 4School of Medicine, University of Florence, Florence, ItalyAbstract: The renin–angiotensin–aldosterone system (RAAS, an important regulator of blood pressure and mediator of hypertension-related complications, is a prime target for cardiovascular drug therapy. Angiotensin-converting enzyme inhibitors (ACEIs were the first drugs to be used to block the RAAS. Angiotensin II receptor blockers (ARBs have also been shown to be equally effective for treatment. Although these drugs are highly effective and are widely used in the management of hypertension, current treatment regimens with ACEIs and ARBs are unable to completely suppress the RAAS. Combinations of ACEIs and ARBs have been shown to be superior than to either agent alone for some, but certainly not all, composite cardiovascular and kidney outcomes, but dual RAAS blockade with the combination of an ACEI and an ARB is sometimes associated with an increase in the risk for adverse events, primarily hyperkalemia and worsening renal function. The recent introduction of the direct renin inhibitor, aliskiren, has made available new combination strategies to obtain a more complete blockade of the RAAS with fewer adverse events. Renin system blockade with aliskiren and another RAAS agent has been, and still is, the subject of many large-scale clinical trials and furthermore, is already available in some countries as a fixed combination. Keywords: angiotensin II receptor blockers, renin–angiotensin–aldosterone system, hypertension, angiotensin-converting enzyme inhibitors

  20. Triple Combination Therapy for Global Cardiovascular Risk: Atorvastatin, Perindopril, and Amlodipine.

    Bertrand, Michel E; Vlachopoulos, Charalambos; Mourad, Jean-Jacques

    2016-08-01

    Statins, angiotensin-converting enzyme (ACE) inhibitors, and calcium channel blockers (CCBs) have markedly changed the clinical progression of patients with coronary artery disease (CAD). The goal of this paper is to review the rationale and evidence for combining these three drug classes in hypertensive patients with hypercholesterolemia or CAD. Data sources include a literature search for publications on the use of a statin combined with various antihypertensive drugs in patients with hypertension and hypercholesterolemia or stable CAD. Hypercholesterolemia and hypertension constitute major physiological risk factors of ischemic heart disease. Current guidelines recommend a global approach to risk management, using agents that address as many risk factors as possible. Dual combination therapies are an important component of guideline-recommended therapy in hypertension. Our review of the literature indicates that triple therapy with a statin, ACE inhibitor, and CCB is associated with a significant reduction in major cardiovascular events. For example, a post hoc analysis in 1056 patients with stable CAD participating in the EUROPA trial indicated that the addition of perindopril to a CCB and a lipid-lowering agent was associated with a 46 % reduction in the composite of cardiovascular death, myocardial infarction, and resuscitated cardiac arrest (p = 0.023). In addition, single pill formulations are known to result in better adherence to the treatment. Single-pill formulations that combine a statin, an ACE inhibitor, and a CCB appear to offer an effective approach to the management of global cardiovascular risk. PMID:27256435

  1. COMBINED ANTIHYPERTENSIVE THERAPY IN PATIENTS WITH ARTERIAL HYPERTENSION AFTER THE STROKE

    O. A. Ageenkova

    2010-01-01

    Full Text Available Aim. To evaluate influence of the combined therapy with ACE inhibitor (perindopril, diuretic (indapamide and dihydropyridine calcium channel blocker (amlodipine on ambulatory blood pressure (BP monitoring indices and heart rate variability in hypertensive patients during early recovery period of stroke.Material and methods. 39 patients (28 men, 11 women with arterial hypertension of 1-3 degrees during early recovery period after stroke were examined. They received perindopril 10 mg QD, indapamide — 1.5 mg QD. Calcium channel blocker amlodipine (5 mg QD was added in case of insufficient effect of the ACE inhibitor plus diuretic combination.Results. The combined antihypertensive therapy in hypertensive patients after the stroke led to significant decrease of systolic and diastolic BP (by 23.5% and 18.9%, respectively, normalization of BP daily profile (a number of «dippers» enlarged by 42.2%, improvement of the wall vessel rigidity (decrease in pulse wave velocity by 12.9% and heart rhythm variability (increase in SDNN, PNN50 and RMSSD by 7%, 20% and 25%, respectively.Conclusion. Advantages of the combined antihypertensive therapy (ACE inhibitor, diuretic, calcium channel blocker in treatment of hypertensive patients after the stroke are shown.

  2. Use of angiotensin-converting enzyme inhibitors and cardiovascular outcomes following primary vascular surgery

    Høgh, Annette Langager; Lindholt, Jes S; Nielsen, Henrik;

    2012-01-01

    To examine the association between angiotensin-converting enzyme (ACE) inhibitor use and clinical outcome after primary vascular reconstruction in a population-based follow-up study.......To examine the association between angiotensin-converting enzyme (ACE) inhibitor use and clinical outcome after primary vascular reconstruction in a population-based follow-up study....

  3. The combination effects of PI3 kinase inhibitor and heavy ion irradiation

    The PI3K signaling pathway is activated by many types of stimuli and regulates fundamental cellular functions such as transcription, translation, proliferation, growth, and survival, and is up-regulated in many tumors. The antitumor effects by approaches of suppression of PI3K signaling have been shown in various cancer cells. In this study, we examined which PI3 kinase inhibitor functioned as radio-sensitizer using with heavy ion irradiation. (author)

  4. Assessing Cost-Effectiveness in Obesity (ACE-Obesity: an overview of the ACE approach, economic methods and cost results

    Swinburn Boyd

    2009-11-01

    Full Text Available Abstract Background The aim of the ACE-Obesity study was to determine the economic credentials of interventions which aim to prevent unhealthy weight gain in children and adolescents. We have reported elsewhere on the modelled effectiveness of 13 obesity prevention interventions in children. In this paper, we report on the cost results and associated methods together with the innovative approach to priority setting that underpins the ACE-Obesity study. Methods The Assessing Cost Effectiveness (ACE approach combines technical rigour with 'due process' to facilitate evidence-based policy analysis. Technical rigour was achieved through use of standardised evaluation methods, a research team that assembles best available evidence and extensive uncertainty analysis. Cost estimates were based on pathway analysis, with resource usage estimated for the interventions and their 'current practice' comparator, as well as associated cost offsets. Due process was achieved through involvement of stakeholders, consensus decisions informed by briefing papers and 2nd stage filter analysis that captures broader factors that influence policy judgements in addition to cost-effectiveness results. The 2nd stage filters agreed by stakeholders were 'equity', 'strength of the evidence', 'feasibility of implementation', 'acceptability to stakeholders', 'sustainability' and 'potential for side-effects'. Results The intervention costs varied considerably, both in absolute terms (from cost saving [6 interventions] to in excess of AUD50m per annum and when expressed as a 'cost per child' estimate (from Conclusion The use of consistent methods enables valid comparison of potential intervention costs and cost-offsets for each of the interventions. ACE-Obesity informs policy-makers about cost-effectiveness, health impact, affordability and 2nd stage filters for important options for preventing unhealthy weight gain in children. In related articles cost-effectiveness results and

  5. Rational use of nonsteroidal anti-inflammatory drugs and proton pump inhibitors in combination for rheumatic diseases

    Wolfgang W Bolten

    2010-09-01

    Full Text Available Wolfgang W BoltenDivision of Rheumatology, Klaus-Miehlke Klinik, Wiesbaden, GermanyAbstract: Nonsteroidal anti-inflammatory drugs (NSAIDs are successfully used to alleviate pain and inflammation in rheumatic diseases. In an appreciable percentage of cases, the use of systemic NSAIDs is associated with adverse lesions of the gastrointestinal (GI mucosa up to life-threatening perforations, ulcers, and bleeding. Reliable warning signals mostly do not arise. Therefore, it is important to take preventive measures to reduce the GI risk. One established method is to assign cyclooxygenase 2 (COX-2-specific inhibitors (coxibs instead of traditional NSAIDs (tNSAIDs. Coxibs spare in part the endogenous gastroprotective mechanisms. Another reliable choice to improve the GI safety is the comedication of proton pump inhibitors (PPIs to suppress gastric acid. A fixed NSAID/PPI combination ensures expected protective effects by improving patients’ PPI adherence and physicians’ PPI prescription persistence. A fixed combination of enteric-coated naproxen and immediate-release esomeprazole has just been approved by the US Food and Drug Administration. PPI combinations with aspirin, other tNSAIDs, and coxibs are desirable. Patients in all risk groups, even patients at low risk of GI adverse events, benefit from concomitant protective measures. Moreover, the literature suggests that NSAID/PPI combinations are cost effective, including for patients in low-GI-risk groups. Pricing of fixed NSAID/PPI combinations will play a pivotal role for their broad acceptance in the future.Keywords: PPI, NSAID, fixed combination, gastrointestinal, adverse events, prevention

  6. Synergistic enhancement of NK cell-mediated cytotoxicity by combination of histone deacetylase inhibitor and ionizing radiation

    The overexpression of histone deacetylase (HDAC) and a subsequent decrease in the acetylation levels of nuclear histones are frequently observed in cancer cells. Generally it was accepted that the deacetylation of histones suppressed expression of the attached genes. Therefore, it has been suggested that HDAC might contribute to the survival of cancer cells by altering the NKG2D ligands transcripts. By the way, the translational regulation of NKG2D ligands remaines unclear in cancer cells. It appears the modulation of this unclear mechanism could enhance NKG2D ligand expressions and the susceptibility of cancer cells to NK cells. Previously, it was reported that irradiation can increase the surface expressions of NKG2D ligands on several cancer cell types without increasing the levels of NKG2D ligand transcripts via ataxia telangiectasia mutated and ataxia telangiectasia and Rad3 related (ATM-ATR) pathway, and suggested that radiation therapy might be used to increase the translation of NKG2D ligands. Two NSCLC cell lines, that is, A549 and NCI-H23 cells, were used to investigate the combined effects of ionizing radiation and HDAC inhibitors on the expressions of five NKG2D ligands. The mRNA expressions of the NKG2D ligands were quantitated by multiplex reverse transcription-PCR. Surface protein expressions were measured by flow cytometry, and the susceptibilities of cancer cells to NK cells were assayed by time-resolved fluorometry using the DELFIA® EuTDA cytotoxicity kit and by flow cytometry. The expressions of NKG2D ligands were found to be regulated at the transcription and translation levels. Ionizing radiation and HDAC inhibitors in combination synergistically increased the expressions of NKG2D ligands. Furthermore, treatment with ATM-ATR inhibitors efficiently blocked the increased translations of NKG2D ligands induced by ionizing radiation but did not block the increased ligand translations induced by HDAC inhibitors. The study confirms that increased NKG

  7. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial

    NN, NN; Yusuf, S; Teo, K;

    2008-01-01

    BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors reduce major cardiovascular events, but are not tolerated by about 20% of patients. We therefore assessed whether the angiotensin-receptor blocker telmisartan would be effective in patients intolerant to ACE inhibitors with cardiovascular...... group). INTERPRETATION: Telmisartan was well tolerated in patients unable to tolerate ACE inhibitors. Although the drug had no significant effect on the primary outcome of this study, which included hospitalisations for heart failure, it modestly reduced the risk of the composite outcome...

  8. Radioprotective effects of combination broncho-vaxom, a macrophage activator, and indomethacin, an inhibitor of prostaglandin production. Relationship to myelopoiesis

    The effects of the bacterial extract broncho-vaxom (BV; radioprotective immunomodulator; 500 μg/mouse i.p., -24 h) and indomethacin (INDO; inhibitor of prostaglandin production; 2x40 μg/mouse i.m., - 24 h and - 3 h) on the post-irradiation recovery of hemopoietic functions in mice were investigated. Both agents were administered either alone or in combination. Endogenous spleen colony formation was increased in all treatment groups, with combination-treated mice exhibiting the greatest effects. Similarly, 24 h after combined administration of BV and INDO (i.e. at the time of presumed irradiation) to the non-irradiated mice granulocyte-macrophage colony-forming cell (GM-CFC) numbers were greater in the bone marrow and spleen. Also, as determined by hydroxyurea injection, there was an increase in the number of GM-CFC in the S-phase of the cell cycle in the bone marrow. However, GM-CFC in the spleen of combination pretreated mice was not stimulated to significant proliferation as compared to GM-CFC in the spleen of mice injected with BV alone. Combined modality treatment was also more effective than single agent treatments in accelerating bone marrow cellularity and GM-CFC regeneration, but not in accelerating GM-CFC regeneration in the spleen. Combined administration of BV and INDO to mice prior to lethal irradiation exerted and additional radioprotective effect and protected 95% of the C57B1/6 mice. (au) 42 refs

  9. Combined therapy with mutant-selective EGFR inhibitor and Met kinase inhibitor for overcoming erlotinib resistance in EGFR-mutant lung cancer.

    Nakagawa, Takayuki; Takeuchi, Shinji; Yamada, Tadaaki; Nanjo, Shigeki; Ishikawa, Daisuke; Sano, Takako; Kita, Kenji; Nakamura, Takahiro; Matsumoto, Kunio; Suda, Kenichi; Mitsudomi, Tetsuya; Sekido, Yoshitaka; Uenaka, Toshimitsu; Yano, Seiji

    2012-10-01

    Although the EGF receptor tyrosine kinase inhibitors (EGFR-TKI) erlotinib and gefitinib have shown dramatic effects against EGFR mutant lung cancer, patients become resistant by various mechanisms, including gatekeeper EGFR-T790M mutation, Met amplification, and HGF overexpression, thereafter relapsing. Thus, it is urgent to develop novel agents to overcome EGFR-TKI resistance. We have tested the effects of the mutant-selective EGFR-TKI WZ4002 and the mutant-selective Met-TKI E7050 on 3 EGFR mutant lung cancer cell lines resistant to erlotinib by different mechanisms: PC-9/HGF cells with an exon 19 deletion, H1975 with an L858R mutation, and HCC827ER with an exon 19 deletion, with acquired resistance to erlotinib because of HGF gene transfection, gatekeeper T790M mutation, and Met amplification, respectively. WZ4002 inhibited the growth of H1975 cells with a gatekeeper T790M mutation, but did not inhibit the growth of HCC827ER and PC-9/HGF cells. HGF triggered the resistance of H1975 cells to WZ4002, whereas E7050 sensitized HCC827ER, PC-9/HGF, and HGF-treated H1975 cells to WZ4002, inhibiting EGFR and Met phosphorylation and their downstream molecules. Combined treatment potently inhibited the growth of tumors induced in severe-combined immunodeficient mice by H1975, HCC827ER, and PC-9/HGF cells, without any marked adverse events. These therapeutic effects were associated with the inhibition of EGFR and Met phosphorylation in vivo. The combination of a mutant-selective EGFR-TKI and a Met-TKI was effective in suppressing the growth of erlotinib-resistant tumors caused by gatekeeper T790M mutation, Met amplification, and HGF overexpression. Further evaluations in clinical trials are warranted. PMID:22844075

  10. Combined Kinetic Studies and Computational Analysis on Kojic Acid Analogs as Tyrosinase Inhibitors

    Carlyle Ribeiro Lima

    2014-07-01

    Full Text Available Tyrosinase is a key enzyme in melanin synthesis and widely distributed in plants and animals tissues. In mammals, this enzyme is related to pigment production, involved in wound healing, primary immune response and it can also contribute to catecholamines synthesis in the brain. Consequently, tyrosinase enzyme represents an attractive and selective target in the field of the medicine, cosmetics and bio-insecticides. In this paper, experimental kinetics and computational analysis were used to study the inhibition of tyrosinase by analogous of Kojic acid. The main interactions occurring between inhibitors-tyrosinase complexes and the influence of divalent cation (Cu2+ in enzymatic inhibition were investigated by using molecular docking, molecular dynamic simulations and electrostatic binding free energy by using the Linear Interaction Energy (LIE method. The results showed that the electrostatic binding free energy are correlated with values of constant inhibition (r2 = 0.97.Thus, the model obtained here could contribute to future studies of this important system and, therefore, eventually facilitate development of tyrosinase inhibitors.