WorldWideScience

Sample records for ace inhibitor treatment

  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. 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-

  3. 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

  4. 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...

  5. 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

  6. 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...

  7. 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

  8. 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.

  9. 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

  10. 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...

  11. 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.)

  12. 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.)

  13. 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

  14. 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

  15. 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

  16. 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.

  17. 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

  18. 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 ...

  19. 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

  20. 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.

  1. 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

  2. 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.

  3. 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...

  4. 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.

  5. 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

  6. 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...

  7. [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

  8. 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.  ……

  9. 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.

  10. 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

  11. 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

  12. 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.

  13. 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.

  14. 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

  15. 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

  16. 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

  17. 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....

  18. 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...

  19. 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...

  20. 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.

  1. 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

  2. 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.

  3. 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

  4. 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...

  5. 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...

  6. 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...

  7. Comparison of dynamic of autonomic control indices in cardiovascular system under the treatment by ACE inhibitor (Enalapril and beta-blocker (Metoprolol in patients with hypertension

    A.R. Kiselev

    2010-03-01

    Full Text Available The objective of the present research was to compare the influence of Enalapril and Metoprolol on synchronization of 0.1 Hz-regulation of heart and blood microcirculation. 42 patients aged 49±9 years old with hypertension I, II were included in the study. 0.1 Hz-oscillations in heart rate variability (HRV and blood microcirculation were registered during the passive orthostatic sign while breathing spontaneously. The duration of each test was 10 minutes. Synchronization was estimated as a phase difference between 0.1 Hz-rhythms in heart rate and in filling of blood microcirculation. Quantitative measures of synchronization were also estimated. In addition frequency values of HRV spectrum in LF- and HF-ranges were assessed. Enalapril and Metoprolol had comparable effect on blood pressure reduction. Treatment with both Enalapril and Metoprolol in patients with significant vegetative dysfunction resulted in repair of functional interaction between 0.1 Hz-regulation of heart and blood microcirculation. Enalapril was preferred in hypertensive patients with prevalence of disorders of vegetative regulation of blood microcirculation. Metoprolol influenced positively on 0,1 Hz-rhythm synchronization in patients with predominance of heart vegetative regulation dysfunction and in patients with sympathicotonia. In patients with hypertension and initially normal level of synchronization of 0.1 Hz-mechanisms treatment with Enalapril or Metoprolol caused functional dissociation. Differentiated approach to the choice of hypertensive therapy should consider individual peculiarities of system vegetative dysfunction. The level of synchronization of 0.1 Hz-rhythms in cardiovascular system should especially be evaluated initially and during the treatment

  8. 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...

  9. 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.

  10. 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

  11. 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

  12. 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...

  13. 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

  14. 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.

  15. 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...

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. 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

  2. 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

  3. [A Case of Life-Threatening Angioedema Occurred During Prolonged Angiotensin-Converting Enzyme Inhibitor Treatment].

    Nakamura, Rintaro; Nihei, Shun-Ichi; Arai, Hideaki; Nagata, Keiji; Isa, Yasuki; Harayama, Nobuya; Aibara, Keiji; Kamochi, Msayuki

    2016-03-01

    Although angiotensin-converting enzyme (ACE) inhibitors are widely used as the first choice drug for treating hypertension, we have only a superficial understanding of their relationship to angioedema. We report a case of life-threatening angioedema. The case was a 60-year-old man who had been taking an ACE inhibitor for hypertension for 11 years. He visited his home doctor for dyspnea, and tongue and neck swelling. He was transported to our hospital because of the possibility of airway obstruction. On admission, his tongue and neck swelling became more severe. We performed an intubation using an endoscope and started airway management. We also stopped his ACE inhibitor. The severe tongue and neck swelling improved gradually and he was extubated on day 3. On the fifth day he was discharged. We diagnosed angioedema caused by an ACE inhibitor. Although the risk of airway obstruction with ACE inhibitors is acknowledged, we have only a superficial understanding of how prolonged ACE inhibitor treatment induces angioedema. So we should consider angioedema in cases of taking ACE inhibitors, especially in cases of prolonged treatment. PMID:26972946

  4. 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

  5. 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...

  6. 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...

  7. 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...

  8. 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...

  9. 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

  10. 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

  11. 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

  12. 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.

  13. 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

  14. [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

  15. 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.

  16. 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.

  17. 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

  18. 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

  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. Studies on the effect of antioxidant Selenium-ACE after treatment with Praziquantel and Mirazid in Schistosoma mansoni infected mice

    Muhammad Hamdy Emam*; Mona Abd El-Rahman **; Irene Sameh Gamil** and Marwa

    2009-12-01

    Full Text Available Background: This study deals with the evaluation of parasitological, histopathological and biochemical effect of Praziquantel (PZQ and Mirazid (MZ with or without Selenium-ACE (Se-ACE on male albino mice infected with S.mansoni and trying to evaluate the antioxidant effect of Se-ACE and its role in reducing the severity of the infection. Results: The obtained results indicated that treatment with PZQ produced more reduction in worm burden and ova count/gm liver than MZ compared to the infected control group. PZQ showed the highest reduction in liver granuloma number and diameter when compared to MZ group while both drugs showed a significant effect in restoration of the liver transaminases and protein fractions towards their normal levels indicating the safety of both drugs as anti S. mansoni chemotherapeutics, Se-ACE showed a high efficacy as a co-treatment, potentiating the effect of PZQ and MZ in reducing the worm burden, ova count/gm liver, number and diameter of liver granuloma and restoration of liver transaminases and protein fractions to their normal levels during treatment of S. mansoni infection. Conclusion: the rank order of potency in protection against liver cell damage was PZQ 500 mg/kg > MZ 600 mg/kg where Se-ACE showed a couraging criterion as a co- treatment potentiating the effect of the antischistosomal medications through its anti- oxidant activity.

  1. 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

  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. 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

  5. ACE gene polymorphism and losartan treatment in type 2 diabetic patients with nephropathy

    de, Zeeuw D.; Cooper, M.E.; Remuzzi, G.;

    2008-01-01

    Losartan treatment reduced renal outcomes in proteinuric patients with type 2 diabetes in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. It is unknown whether an insertion (I)/deletion (D) polymorphism in the angiotensin I-converting enzyme (ACE......) gene predicts renal outcomes and death and influences the effect of losartan in these patients. Pharmacogenetic analyses were performed comparing losartan with placebo administered with conventional blood pressure-lowering therapy in 1435 (95%) of the 1513 RENAAL study patients. The primary endpoint......, subjects with the ID or DD genotype were more likely than those with the II genotype to reach the composite endpoint (by 17.5% and 38.1%, respectively, P = 0.029) or its individual components. Within the losartan group, genotype did not correlate with reaching the composite endpoint. Compared with placebo...

  6. 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

  7. ACE inhibition with spirapril improves diastolic function at rest independent of vasodilation during treatment with spirapril in mild to moderate hypertension

    Petersen, J R; Drabaek, H; Fornitz, Gitte Gleerup;

    1996-01-01

    the patients entered three periods lasting four weeks each, wherein they were treated with placebo, spirapril, or hydrochlorothiazide. Blood pressure, hemodynamic variables (stroke volume, heart rate, cardiac output, index of contractility, and systemic vascular resistance), echocardiography (left......The effects of the ACE inhibitor spirapril and of hydrochlorothiazide on left ventricular diastolic function were studied. Thirteen patients with mild to moderate essential hypertension completed this randomized, double-blinded, placebo-controlled, crossover study. After a three-week run-in period...... the drug normalized the A/E-ratio VTI in those patients with elevated values. The hemodynamic variables, left ventricular mass, and end-systolic wall stress were unchanged during all three treatments. There were no significant changes in mean blood pressure during the treatment periods. These results...

  8. 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.

  9. Treatment of secondary erythromatosis following renal transplantation by ACE-in hibitors%血管紧张素转换酶抑制剂治疗肾移植后继发性红细胞增多症

    杨志豪; 张钊; 姜永金

    2001-01-01

    目的观察血管紧张素转换酶抑制剂类药物对肾移植后继发性红细胞增多症的治疗效果及安全性。方法对肾移植后临床诊断为红细胞增多症的24例患者给予血管紧张素转换酶抑制剂类药物治疗,用药期间监测患者的血红蛋白、红细胞压积变化及其不良反应。结果 24例中除1例因低血压停药外,其余全部有效,起效时间为用药后7~20 d;不良反应包括低血压伴头晕3例,血红蛋白≤90 g/L 2例,肾功能损害2例。结论血管紧张素转换酶抑制剂类药物对肾移植后的红细胞增多症有效;用药过程中需监测血、尿常规、血压和肾功能。%Objective To observe the therapeutic effects and safety of angiotensin-converting enzym e (ACE)-inhibitors in the treatment of the secondary erythromatosis following ren al transplantation.Methods Twenty-four patients with erythromatosis following renal transplantation recei ved the treatment with ACE-inhibitors. During the administration of ACE-inhibi tors, the hemoglobin, hematocrit and the side effects were observed. Results All the patients were recovered except one who ha d to be stopped the treatment of ACE-inhibitors because of the depressing of th e blood pressure. The time of producing the effects was 7-20 days. The side effe cts included lower blood pressure accompanied by dizzy in 3 cases, anemia in 2 cases and damage to renal function in 2 cases. Conclusions ACE-inhibitors were effective in the treatme nt of secondary erythromatosis following renal transplantation. It was important to monitor the hemogram and the renal function of the patients.

  10. ACE inhibition with spirapril improves diastolic function at rest independent of vasodilation during treatment with spirapril in mild to moderate hypertension

    Petersen, J R; Drabaek, H; Gleerup, Christian Peter-Ole G.;

    1996-01-01

    The effects of the ACE inhibitor spirapril and of hydrochlorothiazide on left ventricular diastolic function were studied. Thirteen patients with mild to moderate essential hypertension completed this randomized, double-blinded, placebo-controlled, crossover study. After a three-week run-in period...

  11. 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...

  12. 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

  13. 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

  14. 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.

  15. ACE (I/D polymorphism and response to treatment in coronary artery disease: a comprehensive database and meta-analysis involving study quality evaluation

    Kitsios Georgios

    2009-06-01

    Full Text Available Abstract Background The role of angiotensin-converting enzyme (ACE gene insertion/deletion (I/D polymorphism in modifying the response to treatment modalities in coronary artery disease is controversial. Methods PubMed was searched and a database of 58 studies with detailed information regarding ACE I/D polymorphism and response to treatment in coronary artery disease was created. Eligible studies were synthesized using meta-analysis methods, including cumulative meta-analysis. Heterogeneity and study quality issues were explored. Results Forty studies involved invasive treatments (coronary angioplasty or coronary artery by-pass grafting and 18 used conservative treatment options (including anti-hypertensive drugs, lipid lowering therapy and cardiac rehabilitation procedures. Clinical outcomes were investigated by 11 studies, while 47 studies focused on surrogate endpoints. The most studied outcome was the restenosis following coronary angioplasty (34 studies. Heterogeneity among studies (p ACE I/D polymorphism on the response to treatment for the rest outcomes (coronary events, endothelial dysfunction, left ventricular remodeling, progression/regression of atherosclerosis, individual studies showed significance; however, results were discrepant and inconsistent. Conclusion In view of available evidence, genetic testing of ACE I/D polymorphism prior to clinical decision making is not currently justified. The relation between ACE genetic variation and response to treatment in CAD remains an unresolved issue. The results of long-term and properly designed prospective studies hold the promise for pharmacogenetically tailored therapy in CAD.

  16. Proteasome inhibitor treatment in alcoholic liver disease

    Fawzia Bardag-Gorce

    2011-01-01

    Oxidative stress, generated by chronic ethanol consumption, is a major cause of hepatotoxicity and liver injury. Increased production of oxygen-derived free radicals due to ethanol metabolism by CYP2E1 is principally located in the cytoplasm and in the mitochondria, which does not only injure liver cells, but also other vital organs, such as the heart and the brain. Therefore, there is a need for better treatment to enhance the antioxidant response elements. To date, there is no established treatment to attenuate high levels of oxidative stress in the liver of alcoholic patients. To block this oxidative stress, proteasome inhibitor treatment has been found to significantly enhance the antioxidant response elements of hepatocytes exposed to ethanol. Recent studies have shown in an experimental model of alcoholic liver disease that proteasome inhibitor treatment at low dose has cytoprotective effects against ethanol-induced oxidative stress and liver steatosis. The beneficial effects of proteasome inhibitor treatment against oxidative stress occurred because antioxidant response elements (glutathione peroxidase 2, superoxide dismutase 2, glutathione synthetase, glutathione reductase, and GCLC) were upregulated when rats fed alcohol were treated with a low dose of PS-341 (Bortezomib, Velcade(r)). This is an important finding because proteasome inhibitor treatment up-regulated reactive oxygen species removal and glutathione recycling enzymes, while ethanol feeding alone down-regulated these antioxidant elements. For the first time, it was shown that proteasome inhibition by a highly specific and reversible inhibitor is different from the chronic ethanol feeding-induced proteasome inhibition. As previously shown by our group, chronic ethanol feeding causes a complex dysfunction in the ubiquitin proteasome pathway, which affects the proteasome system, as well as the ubiquitination system. The beneficial effects of proteasome inhibitor treatment in alcoholic liver disease

  17. Aromatase inhibitors in the treatment of endometriosis.

    Słopień, Radosław; Męczekalski, Błażej

    2016-03-01

    Endometriosis is a chronic inflammatory condition in which foci of endometrial tissue grow outside of the uterine cavity. Endometriosis was estimated to affect 176 million women of childbearing potential all over the world in 2010. The presence of extrauterine endometrial tissue is associated with pain and infertility. Typical symptoms of endometriosis include dysmenorrhoea, dyspareunia, heavy menstrual periods (menorrhagia), pelvic pain that is not related to menstrual cycles, dysuria, and chronic fatigue. Medical treatments for endometriosis include combined oral contraceptive pills, danazol, gestrinone, medroxyprogesterone acetate, and gonadotropin-releasing hormone agonists (aGnRHs). A new class of medications called aromatase inhibitors has been identified in recent years as potential therapeutic agents for endometriosis. This article provides general information about aromatase inhibitors, their use in gynaecology, and their adverse effects. In particular, the paper discusses the use of aromatase inhibitors in the treatment of endometriosis in postmenopausal women. Unlike oral contraceptives, gestagens, aGnRHs, and danazol, which suppress ovarian oestrogen synthesis, aromatase inhibitors inhibit mainly extra-ovarian synthesis of oestrogens. Therefore, the use of aromatase inhibitors seems to be particularly relevant in older patients, as most of the body's oestrogen is produced outside the ovaries after menopause. The paper discusses also the use of aromatase inhibitors in the treatment of pain associated with endometriosis and infertility caused by endometriosis. PMID:27095958

  18. Aromatase inhibitors in the treatment of endometriosis

    Męczekalski, Błażej

    2016-01-01

    Endometriosis is a chronic inflammatory condition in which foci of endometrial tissue grow outside of the uterine cavity. Endometriosis was estimated to affect 176 million women of childbearing potential all over the world in 2010. The presence of extrauterine endometrial tissue is associated with pain and infertility. Typical symptoms of endometriosis include dysmenorrhoea, dyspareunia, heavy menstrual periods (menorrhagia), pelvic pain that is not related to menstrual cycles, dysuria, and chronic fatigue. Medical treatments for endometriosis include combined oral contraceptive pills, danazol, gestrinone, medroxyprogesterone acetate, and gonadotropin-releasing hormone agonists (aGnRHs). A new class of medications called aromatase inhibitors has been identified in recent years as potential therapeutic agents for endometriosis. This article provides general information about aromatase inhibitors, their use in gynaecology, and their adverse effects. In particular, the paper discusses the use of aromatase inhibitors in the treatment of endometriosis in postmenopausal women. Unlike oral contraceptives, gestagens, aGnRHs, and danazol, which suppress ovarian oestrogen synthesis, aromatase inhibitors inhibit mainly extra-ovarian synthesis of oestrogens. Therefore, the use of aromatase inhibitors seems to be particularly relevant in older patients, as most of the body's oestrogen is produced outside the ovaries after menopause. The paper discusses also the use of aromatase inhibitors in the treatment of pain associated with endometriosis and infertility caused by endometriosis. PMID:27095958

  19. Angiotensin I-converting enzyme (ACE) inhibitory activities of sardinelle (Sardinella aurita) by-products protein hydrolysates obtained by treatment with microbial and visceral fish serine proteases.

    Bougatef, Ali; Nedjar-Arroume, Naima; Ravallec-Plé, Rozenn; Leroy, Yves; Guillochon, Didier; Barkia, Ahmed; Nasri, Moncef

    2008-11-15

    The angiotensin I-converting enzyme (ACE) inhibitory activities of protein hydrolysates prepared from heads and viscera of sardinelle (Sardinella aurita) by treatment with various proteases were investigated. Protein hydrolysates were obtained by treatment with Alcalase(®), chymotrypsin, crude enzyme preparations from Bacillus licheniformis NH1 and Aspergillus clavatus ES1, and crude enzyme extract from sardine (Sardina pilchardus) viscera. All hydrolysates exhibited inhibitory activity towards ACE. The alkaline protease extract from the viscera of sardine produced hydrolysate with the highest ACE inhibitory activity (63.2±1.5% at 2mg/ml). Further, the degrees of hydrolysis and the inhibitory activities of ACE increased with increasing proteolysis time. The protein hydrolysate generated with alkaline proteases from the viscera of sardine was then fractionated by size exclusion chromatography on a Sephadex G-25 into eight major fractions (P1-P8). Biological functions of all fractions were assayed, and P4 was found to display a high ACE inhibitory activity. The IC50 values for ACE inhibitory activities of sardinelle by-products protein hydrolysates and fraction P4 were 1.2±0.09 and 0.81±0.013mg/ml, respectively. Further, P4 showed resistance to in vitro digestion by gastrointestinal proteases. The amino acid analysis by GC/MS showed that P4 was rich in phenylalanine, arginine, glycine, leucine, methionine, histidine and tyrosine. The added-value of sardinelle by-products may be improved by enzymatic treatment with visceral serine proteases from sardine. PMID:26047434

  20. 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

  1. 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

  2. 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...

  3. 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.

  4. 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 ...

  5. 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...

  6. 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

  7. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group

    Køber, L; Torp-Pedersen, C; Carlsen, J E;

    1995-01-01

    BACKGROUND. Treatment with angiotensin-converting-enzyme (ACE) inhibitors reduces mortality among survivors of acute myocardial infarction, but whether to use ACE inhibitors in all patients or only in selected patients is uncertain. METHODS. We screened 6676 consecutive patients with 7001......, and the development of severe heart failure. That mortality was reduced in a randomized study enrolling 25 percent of consecutive patients screened should encourage the selective use of ACE inhibition after myocardial infarction....

  8. 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

  9. 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...

  10. The long-term impact of the angiotensin-converting enzyme inhibitor trandolapril on mortality and hospital admissions in patients with left ventricular dysfunction after a myocardial infarction: follow-up to 12 years

    Buch, Pernille; Rasmussen, Søren; Abildstrøm, Steen Zabell;

    2004-01-01

    AIMS: To investigate the long-term benefits of treatment with angiotensin-converting enzyme (ACE)-inhibitors in patients with myocardial infarction (MI) and left ventricular dysfunction (LVD). METHODS AND RESULTS: In the trandolapril cardiac evaluation (TRACE) study, 1749 patients with LVD...... (ejection fractionACE-inhibitor use. National registries were used to track...

  11. Calcineurin inhibitor minimisation versus continuation of calcineurin inhibitor treatment for liver transplant recipients

    Penninga, Luit; Wettergren, Andre; Chan, An-Wen;

    2012-01-01

    The therapeutic success of liver transplantation has been largely attributable to the development of effective immunosuppressive treatment regimens. In particular, calcineurin inhibitors were essential in reducing acute rejection and improving early survival. Currently, more than 90% of all liver...... transplant recipients are treated with the calcineurin inhibitor cyclosporine or tacrolimus. Unfortunately, calcineurin inhibitors cause adverse events, such as nephrotoxicity, and because of this, minimisation (reduction and withdrawal) regimens of calcineurin inhibitor have been developed and studied...

  12. Effect of ACE insertion/deletion and 12 other polymorphisms on clinical outcomes and response to treatment in the life study

    2010-01-01

    OBJECTIVE: This pharmacogenetics substudy from the Losartan Intervention for Endpoint reduction in Hypertension study in patients with hypertension and left ventricular hypertrophy (LVH) treated with the angiotensin receptor blocker losartan versus the beta-blocker atenolol for 4.8 years tested....... These polymorphisms were chosen because they could affect blood pressure control or the pharmacological action of losartan or atenolol. METHODS: We genotyped 3503 patients, 1774 on losartan and 1729 on atenolol. RESULTS: ACE and the 12 other genotypes did not affect the reduction in systolic blood...... pressure, diastolic blood pressure, pulse pressure, mean arterial pressure, or heart rate, or treatment differences between losartan and atenolol on these endpoints, as assessed by general linear models. Also, ACE and the 12 other genotypes did not affect risk of the primary composite endpoint or its...

  13. 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。

  14. 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.

  15. ACE Inhibition in Anti-Thy1 Glomerulonephritis Limits Proteinuria but Does Not Improve Renal Function and Structural Remodeling

    Peter E. Westerweel

    2012-01-01

    Full Text Available Background/Aims: ACE inhibitor (ACE-I treatment effectively inhibits proteinuria and ameliorates the course of various renal diseases. In experimental glomerulonephritis, however, angiotensin II (AngII infusion has also been shown to be renoprotective. We evaluated the long-term (28 days course of anti-Thy1 glomerulonephritis in animals with suppressed AngII formation by ACE-I treatment. Methods: Brown Norway rats received perindopril (2.8 mg/kg/day, n = 12, dihydropyridine calcium-antagonist amlodipine (Ca-A; 13 mg/kg/day, n = 6 or were left untreated (n = 14. All animals were monitored for blood pressure, proteinuria, and creatinine clearance after anti-Thy1 injection. Renal histology was assessed at day 7 and 28. Results: Systolic blood pressure was equally reduced by ACE-I and Ca-A treatment. AngII suppression prevented development of proteinuria, but did not protect against glomerular microaneurysm formation or reduction in creatinine clearance. After resolution of the microaneurysms, animals with suppressed AngII production showed a modest increase in glomerulosclerosis and vasculopathic thickening of intrarenal vessels. Conclusions: In anti-Thy1 glomerulonephritis, suppression of AngII formation does not protect against the induction of glomerular damage and is associated with mild aggravation of adverse renal fibrotic remodeling. Proteinuria, however, is effectively prevented by ACE-I treatment. Ca-A treatment did not affect the course of glomerulonephritis, indicating that ACE-I effects are blood pressure independent.

  16. Effects of long-term treatment with angiotensin-converting-enzyme inhibitors in the presence or absence of aspirin: a systematic review

    Teo, Koon K; Yusuf, Salim; Pfeffer, Marc;

    2002-01-01

    BACKGROUND: Results from a retrospective analysis of the Studies of Left Ventricular Dysfunction (SOLVD) study suggest that angiotensin-converting-enzyme (ACE) inhibitors may be less effective in patients receiving aspirin. We aimed to confirm or refute this theory. METHODS: We used the Peto......-Yusuf method to undertake a systematic overview of data for 22060 patients from six long-term randomised trials of ACE inhibitors to assess whether aspirin altered the effects of ACE inhibitor therapy on major clinical outcomes (composite of death, myocardial infarction, stroke, hospital admission...... between the proportional reductions in risk with ACE inhibitor therapy in the presence or absence of aspirin for the major clinical outcomes (p=0.15), or in any of its individual components, except myocardial infarction (interaction p=0.01). Overall, ACE inhibitor therapy significantly reduced the risk...

  17. 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...

  18. 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 ...

  19. 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

  20. The Place of protease inhibitors in antiretroviral treatment

    S.B. Tenore

    2009-10-01

    Full Text Available With the introduction of highly active antiretroviral therapy, a number of drugs have been developed. The best choice concerning which antiretroviral analogs to start is always under discussion, especially in the choice between non-nucleoside reverse transcriptase inhibitors-based therapies and ritonavir-boosted protease inhibitors. Both are proven to control viral replication and lead to immunological gain. The choice between a non-nucleoside analog reverse transcriptase inhibitor and a protease inhibitor as a third antiretroviral drug in the therapy should consider factors related to the individual, as well as the inclusion of the best therapy in the patient's daily activities and potential adherence. The protease inhibitor-based therapies showed similar efficacy among the various inhibitors with characteristics concerning the adverse events from each medicine. For the treatment of protease-resistant patients, darunavir and tipranavir showed good efficacy with higher genetic barrier to resistance.

  1. 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.

  2. Treatment Strategy for Non-Responders to PDE5 Inhibitors

    Park, Nam Cheol; Kim, Tae Nam; Park, Hyun Jun

    2013-01-01

    Currently, phosphodiesterase type 5 (PDE5) inhibitors are the initial treatment option for erectile dysfunction. The reported efficacy of PDE5 inhibitors is about 70%, although it is significantly lower in difficult-to-treat subpopulations. Treatment failures might be due to the severity of the underlying pathophysiology, improper use of medication, unrealistic patient expectations, difficult relationship dynamics, severe performance anxiety, and other psychological problems. Physicians must ...

  3. Chronic Treatment with Ang-(1-7 Reverses Abnormal Reactivity in the Corpus Cavernosum and Normalizes Diabetes-Induced Changes in the Protein Levels of ACE, ACE2, ROCK1, ROCK2 and Omega-Hydroxylase in a Rat Model of Type 1 Diabetes

    Mariam H. M. Yousif

    2014-01-01

    Full Text Available Angiotensin-(1-7 [Ang-(1-7] may have beneficial effects in diabetes mellitus-induced erectile dysfunction (DMIED but its molecular actions in the diabetic corpus cavernosum (CC are not known. We characterized the effects of diabetes and/or chronic in vivo administration of Ang-(1-7 on vascular reactivity in the rat corpus cavernosum (CC and on protein expression levels of potential downstream effectors of the renin-angiotensin-aldosterone system (RAAS such as angiotensin-converting enzyme (ACE, ACE2, Rho kinases 1 and 2 (ROCK1 and ROCK2, and omega-hydroxylase, the cytochrome-P450 enzyme that metabolizes arachidonic acid to form the vasoconstrictor, 20-hydroxyeicosatetraenoic acid. Streptozotocin-treated rats were chronicically administered Ang-(1-7 with or without A779, a Mas receptor antagonist, during weeks 4 to 6 of diabetes. Ang-(1-7 reversed diabetes-induced abnormal reactivity to vasoactive agents (endothelin-1, phenylepherine, and carbachol in the CC without correcting hyperglycemia. Six weeks of diabetes led to elevated ACE, ROCK1, ROCK 2, and omega-hydroxylase and a concomitant decrease in ACE2 protein expression levels that were normalized by Ang-(1-7 treatment but not upon coadministration of A779. These data are supportive of the notion that the beneficial effects of Ang-(1-7 in DMIED involve counterregulation of diabetes-induced changes in ACE, ACE2, Rho kinases, and omega-hydroxylase proteins in the diabetic CC via a Mas receptor-dependent mechanism.

  4. Chronic Treatment with Ang-(1-7) Reverses Abnormal Reactivity in the Corpus Cavernosum and Normalizes Diabetes-Induced Changes in the Protein Levels of ACE, ACE2, ROCK1, ROCK2 and Omega-Hydroxylase in a Rat Model of Type 1 Diabetes

    Yousif, Mariam H. M.; Makki, Batoul; El-Hashim, Ahmed Z.; Benter, Ibrahim F.

    2014-01-01

    Angiotensin-(1-7) [Ang-(1-7)] may have beneficial effects in diabetes mellitus-induced erectile dysfunction (DMIED) but its molecular actions in the diabetic corpus cavernosum (CC) are not known. We characterized the effects of diabetes and/or chronic in vivo administration of Ang-(1-7) on vascular reactivity in the rat corpus cavernosum (CC) and on protein expression levels of potential downstream effectors of the renin-angiotensin-aldosterone system (RAAS) such as angiotensin-converting enzyme (ACE), ACE2, Rho kinases 1 and 2 (ROCK1 and ROCK2), and omega-hydroxylase, the cytochrome-P450 enzyme that metabolizes arachidonic acid to form the vasoconstrictor, 20-hydroxyeicosatetraenoic acid. Streptozotocin-treated rats were chronicically administered Ang-(1-7) with or without A779, a Mas receptor antagonist, during weeks 4 to 6 of diabetes. Ang-(1-7) reversed diabetes-induced abnormal reactivity to vasoactive agents (endothelin-1, phenylepherine, and carbachol) in the CC without correcting hyperglycemia. Six weeks of diabetes led to elevated ACE, ROCK1, ROCK 2, and omega-hydroxylase and a concomitant decrease in ACE2 protein expression levels that were normalized by Ang-(1-7) treatment but not upon coadministration of A779. These data are supportive of the notion that the beneficial effects of Ang-(1-7) in DMIED involve counterregulation of diabetes-induced changes in ACE, ACE2, Rho kinases, and omega-hydroxylase proteins in the diabetic CC via a Mas receptor-dependent mechanism. PMID:25309930

  5. The effect of CCR2 inhibitor CCX140-B on residual albuminuria in patients with type 2 diabetes and nephropathy : a randomised trial

    de Zeeuw, Dick; Bekker, Pirow; Henkel, Elena; Hasslacher, Christopher; Gouni-Berthold, Ioanna; Mehling, Heidrun; Potarca, Antonia; Tesar, Vladimir; Lambers Heerspink, Hiddo J.; Schall, Thomas J.

    2015-01-01

    Background Patients with type 2 diabetes and nephropathy have high cardiorenal morbidity and mortality despite optimum treatment including angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Residual risk is related to residual albuminuria. We assessed whether CCX

  6. 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…

  7. 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

  8. CHOLINESTERASE INHIBITORS IN THE TREATMENT OF DEMENTIA ALZHEIMER’S

    Prameidya Primaniar S

    2013-03-01

    Full Text Available Dementia is the loss of intellectual abilities which include decreased ability to think, remember,understand, calculate, concentrate, and find the right words. The causes of dementia areAlzheimer’s, vascular dementia, alcohol. Dementia Alzheimer’s is a dementia type that iscurrently the most commonly found. Cholinesterase inhibitors are one of the therapies used totreat symptoms of cognitive decline and reduce neuropsychiatric symptoms in patient dementiaAlzheimer’s. Several studies have been conducted to demonstrate how the effects of severalclasses of cholinesterase inhibitors in the treatment of dementia Alzheimer’s. Effective dose,dosage and side effects of cholinesterase inhibitors is important to know before deciding to usecholinesterase inhibitors in the treatment of dementia Alzheimer’s.

  9. 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

  10. 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.

  11. 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

  12. 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

  13. 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.

  14. 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.

  15. 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.

  16. Old Tyrosine Kinase Inhibitors and Newcomers in Gastrointestinal Cancer Treatment.

    Erika, Giordani; Federica, Zoratto; Martina, Strudel; Anselmo, Papa; Luigi, Rossi; Marina, Minozzi; Davide, Caruso; Eleonora, Zaccarelli; Monica, Verrico; Silverio, Tomao

    2016-01-01

    Gastrointestinal cancer treatment is based more on molecular biology that has provided increasing knowledge about cancer pathogenesis on which targeted therapy is being developed. Precisely, targeted therapy is defined as a "type of treatment that uses drugs, such as monoclonal antibodies or tyrosine kinase inhibitors, to identify and attack specific cancer cells". Nowadays, the United States Food and Drug Administration has approved many targeted therapies for gastrointestinal cancer treatment, as many are in various phases of development as well. In a previous review we discussed the main monoclonal antibodies used and studied in gastrointestinal cancer. In addition to monoclonal antibodies, tyrosine kinase inhibitors represent another class of targeted therapy and following the approval of imatinib for gastrointestinal stromal tumours, other tyrosine kinase inhibitors have been approved for gastrointestinal cancers treatment such as sunitinib, regoragenib, sorafenib and erlotinib. Moving forward, the purpose of this review is to focus on the efficacy data of main tyrosine kinase inhibitors commonly used in the personalized treatment of each gastrointestinal tumour and to provide a comprehensive overview about experimental targeted therapies ongoing in this setting. PMID:26278713

  17. Microwave-assisted Solid-phase Synthesis, Biological Evaluation and Molecular Docking of Angiotensin I-converting Enzyme Inhibitors

    SUN Yang; HUANG Da-wei; LI Xiao-hui; HU Jian-en; XIU Zhi-long

    2012-01-01

    Short peptides based on the tripeptides,Leu-Arg-Pro and Leu-Lys-Pro,were synthesized by microwaveassisted solid-phase synthesis method,in order to make a search for potential inhibitors for angiotensin (I)-converting enzyme(ACE) with minimum side effects in the treatment of hypertension.One peptide with the sequence Leu-Arg-Pro-Phe-Phe shows the strongest inhibition towards ACE with an IC50 value of 0.26 μmol/L in vitro.The study of structure-activity relationship shows that the introduction of a bulky group into the N-terminal of this series of inhibitors may enlarge steric hindrance,resulting in the poor inhibitory activity towards ACE.The inhibitory activity decreased in turn when L-Pro,D-Pro or Ac6c was at the C-terminal respectively.The binding interaction between each of these inhibitors and testicular ACE(tACE) was performed by molecular docking.The results suggest that Leu-Arg-Pro-Phe-Phe mainly occupied the St subsite of tACE,and made contact with tACE via seven H-bonds.It appeared that the site on the peptide that bound with tACE was influenced by the configuration of the amino acid,L- or D-form,at the C-terminal of the peptide.

  18. 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

  19. Topical Calcineurin Inhibitors for Atopic Dermatitis: Review and Treatment Recommendations

    Carr, Warner W

    2013-01-01

    Atopic dermatitis (AD) is an inflammatory skin disease commonly affecting children and managed by pediatricians, primary care physicians, allergists, and dermatologists alike. For many years, the only available topical pharmacological treatment was topical corticosteroids. This changed in 2000–2001, when topical formulations of two calcineurin inhibitors (tacrolimus and pimecrolimus) were approved for short-term or chronic intermittent treatment of AD in patients ≥2 years of age, in whom othe...

  20. 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

  1. Icatibant er en ny behandlingsmulighed ved livstruende angiotensinkonverterende enzym-inhibitor-udløst angioødem

    Fast, Søren; Henningsen, Emil; Bygum, Anette

    2011-01-01

    A 78 year-old woman with life-threatening angiotensin-converting enzyme inhibitor (ACE-i) induced angioedema was unresponsive to conventional treatment with corticosteroids, antihistamines and epinephrine. She was successfully treated with icatibant licensed for treatment of hereditary angioedema...... knowing that both conditions involve bradykinin induced activation of bradykinin B2 receptors. Randomised, controlled trials are warranted to document the efficacy of icatibant in ACE-i angioedema....

  2. 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

  3. 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.

  4. 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.

  5. Strength training and testosterone treatment have opposing effects on migration inhibitor factor levels in ageing men

    Glintborg, D.; Christensen, L. L.; Kvorning, T.; Larsen, Rasmus; Brixen, K.; Hougaard, D. M.; Richelsen, B.; Bruun, J. M.; Andersen, M.

    2013-01-01

    Strength Training and Testosterone Treatment Have Opposing Effects on Migration Inhibitor Factor Levels in Ageing Men......Strength Training and Testosterone Treatment Have Opposing Effects on Migration Inhibitor Factor Levels in Ageing Men...

  6. SGLT-2 Inhibitors in Development for Type 2 Diabetes Treatment

    Bhartia, Mithun; Tahrani, Abd A; Anthony H Barnett

    2011-01-01

    The prevalence of type 2 diabetes is increasing worldwide. The majority of currently available glucose-lowering agents work via insulin-dependent mechanisms and have significant limitations. Hence, there is a need for newer treatments utilizing novel therapeutic targets. Drugs which inhibit the sodium glucose cotransporter in the renal tubules (SGLT-2 inhibitors), represent a novel class of drugs under development. By inhibiting SGLT-2, they promote increased renal glucose excretion and there...

  7. Treatment of pruritic diseases with topical calcineurin inhibitors

    Ständer, Sonja; Schürmeyer-Horst, Funda; Luger, Thomas A; Weisshaar, Elke

    2006-01-01

    The introduction of topical calcineurin inhibitors resulted in a significant improvement in the treatment of atopic dermatitis. In addition, rapid amelioration of pruritus could be observed. In case reports, other pruritic dermatoses such as chronic irritative hand dermatitis, rosacea, graft-versus-host-disease, and lichen sclerosus were also treated successfully with pimecrolimus and tacrolimus. Twenty patients were treated with tacrolimus and pimecrolimus in a surveillance study to evaluate...

  8. Angiotensin converting enzyme inhibitor and HMG-CoA reductase inhibitor as adjunct treatment for persons with HIV infection: a feasibility randomized trial.

    Jason V Baker

    Full Text Available BACKGROUND: Treatments that reduce inflammation and cardiovascular disease (CVD risk among individuals with HIV infection receiving effective antiretroviral therapy (ART are needed. DESIGN AND METHODS: We conducted a 2 × 2 factorial feasibility study of lisinopril (L (10 mg daily vs L-placebo in combination with pravastatin (P (20 mg daily vs P-placebo among participants receiving ART with undetectable HIV RNA levels, a Framingham 10 year risk score (FRS ≥ 3%, and no indication for ACE-I or statin therapy. Tolerability and adherence were evaluated. Longitudinal mixed models assessed changes in blood pressure (BP, blood lipids, and inflammatory biomarkers from baseline through months 1 and 4. RESULTS: Thirty-seven participants were randomized and 34 [lisinopril/pravastatin (n=9, lisinopril/P-placebo (n=8, L-placebo/pravastatin (n=9, L-placebo/P-placebo (n=8] attended at least one follow-up visit. Participants were 97% male, 41% white, 67% were current smokers, and 65% were taking a protease inhibitor. Median age was 48 years, CD4 count 483 cells/mm(3, FRS 7.79%, total cholesterol 184 mg/dL, and LDL-C 95 mg/dL. There was no treatment difference for pravastatin vs P-placebo in total cholesterol, LDL-C, or any of the inflammatory biomarkers. Participants randomized to lisinopril vs. L-placebo had significant declines in diastolic BP (-3.3 mmHg, p=0.05, hsCRP (-0.61 µg/mL, p=0.02 and TNF-α (-0.17 pg/mL, p=0.04. Participants taking lisinopril vs L-placebo were more likely to report missed doses (88 vs 35%; p=0.001 and have adherence <90% by pill count (42 vs. 0%; p=0.02. Few participants from either group reported side effects (n=3 vs. n=1. CONCLUSIONS: The modest BP changes and decreased adherence with lisinopril and absence of lipid differences with pravastatin suggest future studies of these drug classes should consider a run-in period to assess adherence and use a different statin. Our results also indicate that ACE-I therapy may have anti

  9. Aromatase inhibitors in the treatment of deep endometriosis

    Simone Ferrero

    2009-09-01

    Full Text Available Recent case reports and pilot studies suggested that aromatase inhibitors might be effective in treating pain symptoms related to the presence of endometriosis. We present the case of a 32-year-old woman who suffered dysmenorrhea, dyspareunia, chronic pelvic pain, and dyschezia caused by rectovaginal endometriosis. Pain symptoms recurred after treatment with the oral contraceptive pill; the patient refused surgery. Therefore a double-drug regimen including letrozole (2.5 mg/day and norethisterone acetate (2.5 mg/day was offered to the patient. The scheduled length of treatment was six months. This double-drug regimen determined a quick and significant improvement in all pain symptoms. During treatment, the patient complained mild arthralgia. After the interruption of treatment, pain symptoms quickly recurred and at 6-month follow-up their intensity was similar to baseline values. Operative laparoscopy was performed, the presence of rectovaginal endometriosis was confirmed and all visible endometriotic lesions were excised. Aromatase inhibitors might be offered when pain symptoms caused by endometriosis persist during the administration of other hormonal therapies and the patient refuses surgery. However, women must be informed that these drugs determine only a temporary relief of pain symptoms and might cause adverse effects (such as arthralgia.

  10. 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

  11. [Neurological complications during treatment of the tumor necrosis alpha inhibitors].

    Piusińska-Macoch, Renata

    2013-05-01

    Medications with TNF-alpha inhibitors family are successfully applicable in rheumatology, gastroenterology, dermatology and neurology. Still, the ongoing research on the safety assessment of their application, also due to neurological complications. The vast majority of these complications is associated with an increased risk of serious virus (Herpes simplex--JC) and bacterial (Listeria monocytogenes) neuroinfections. They can cause the occurrence of progressive multifocal leukoencephalopathy--PML with a severe clinical course and poor prognosis or herpes simplex encephalitis--HSE. Meta-analysis revealed a number of cases of PML and the HSE in the first 6 months of treatment with natalizumab, efalizumab, rituximab, abatacept and infliximab. Common complication occasionally turning on this biologics is chronic demyelinating polyneuropathy or Lewis-Sumner syndrome. Described are cases of central and peripheral demyelination typical of multiple sclerosis (MS). Are also reported cases of motor multifocal neuropathy with conduction block acute encephalithis with polyneuropathy or mononeuropathy in the form of anterior optic neuropathy Guillen-Barre' syndrome and its variant, Miller-Fisher syndrome have been confirmed as adverse events following treatment with infliximab. Also revealed several cases of myasthenia gravis after using etanercept. In the few cases of systemic lupus CNS involvement caused by treatment with TNF inhibitors, the mechanism of these disorders is still considered too vague. Due to the emerging reports on the number of neurological adverse events of TNF antagonists, significantly higher than those described in the literature, the safety of their use requires further monitoring and multicenter studies. PMID:23894783

  12. [Phosphodiesterase-5 inhibitors for the treatment of pulmonary arterial hypertension].

    Beltrán-Gámez, Miguel E; Sandoval-Zárate, Julio; Pulido, Tomás

    2015-01-01

    In experimental and clinical cardiology, phosphodiesterase type 5 (PDE-5) inhibitors have brought scientific interest as a therapeutic tool in pulmonary arterial hypertension (PAH) management in recent years. Phosphodiesterases are a superfamily of enzymes that inactivate cyclic adenosine monophosphate and cyclic guanosine monophosphate, the second messengers of prostacyclin and nitric oxide. The rationale for the use of PDE-5 inhibitors in PAH is based on their capacity to overexpresss the nitric oxide pathway pursued inhibition of cyclic guanosine monophosphate hydrolysis. By increasing cyclic guanosine monophosphate levels it promotes vasodilation, antiproliferative and pro-apoptotic effects that may reverse pulmonary vascular remodeling. There is also evidence that these drugs may directly enhance right ventricular contractility through an increase in cyclic adenosine monophosphate mediated by the inhibition of the cyclic guanosine monophosphate -sensitive PDE-3. Sildenafil, tadalafil and vardenafil are 3 specific PDE-5 inhibitors in current clinical use, which share similar mechanisms of action but present some significant differences regarding potency, selectivity for PDE-5 and pharmacokinetic properties. Sildenafil received approval in 2005 by the Food and Drug Administration and the European Medicines Agency and tadalafil in 2009 by the Food and Drug Administration and the European Medicines Agency for the treatment of PAH in patients classified as NYHA/WHO functional class II and III. In Mexico, sildenafil and tadalafil were approved by Comisión Federal de Protección contra Riesgos Sanitarios for this indication in 2010 and 2011, respectively. PMID:26047999

  13. Transformation to SCLC after Treatment with the ALK Inhibitor Alectinib.

    Fujita, Shiro; Masago, Katsuhiro; Katakami, Nobuyuki; Yatabe, Yasushi

    2016-06-01

    We report an anaplastic lymphoma receptor tyrosine kinase gene (ALK)-positive patient who showed a paradoxical response to the ALK inhibitor alectinib; the primary lesion increased in size, whereas other metastatic lesions decreased markedly. A biopsy of the primary lesion confirmed an ALK rearrangement; however, the tumor had transformed histologically into small cell lung cancer. The lack of reports of small cell lung cancer transformation in ALK-positive patients implies that this outcome was unusual; this patient was treated with alectinib, which is more selective and has a greater inhibitory effect than crizotinib. This case may reveal resistance mechanisms that differ according to the agent used for treatment. PMID:26751586

  14. 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

  15. 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

  16. 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....

  17. Pharmacological interventions into the renin-angiotensin system with ACE inhibitors and angiotensin II receptor antagonists: effects beyond blood pressure lowering.

    Düsing, Rainer

    2016-06-01

    Hypertension is recognized as an important risk factor for cardiovascular morbidity and mortality. Lowering of blood pressure has been shown to minimize the risk of cardiovascular events, with the majority of antihypertensives demonstrating a similar ability to reduce coronary events and stroke for a given reduction in blood pressure. Agents that modify the activity of the renin-angiotensin system (RAS) have been proposed to exhibit additional effects that might go beyond simple blood pressure lowering. The RAS is a crucial system that regulates extracellular fluid volume and blood pressure. Proposed potential benefits of RAS blockade that go beyond blood pressure lowering include a reduction in platelet aggregation and thrombosis, blunting of cardiac and vascular remodeling, favorable metabolic effects and reno- and cerebro-protection. However, factors such as treatment adherence, duration of action of antihypertensive agents and differences in effects on central versus brachial blood pressure may also result in apparent differences in efficacy of different antihypertensives. The aim of this review article is to examine the available data from clinical studies of antihypertensive drugs for evidence of effects that might legitimately be claimed to go beyond simple blood pressure lowering. PMID:27122491

  18. Selective serotonin reuptake inhibitors in the treatment of premature ejaculation

    WANG Wei-fu; CHANG Le; Suks Minhas; David J Ralph

    2007-01-01

    Objective To review and assess the update studies regarding se lective serotonin reuptake inhibitors (SSRIs) in the treatment of premature ejaculation (PE) and then provide practical recommendations and possible mechanisms concerning state of the art knowledge for the use of SSRIs in alleviating PE.Data sources Using the Medline, 48 articles published from January 1st, 1996 to August 1st, 2006 concerning the use of SSRIs and their possible mechanisms in alleviating PE were found and reviewed.Study selection PE, rapid ejaculation, early ejaculation and SSRIs were employed as the keywords, and relevant articles about the use of SSRIs and their possible mechanisms in the treatment of PE were selected.Results Many kinds of SSRIs, such as fluoxetine, sertraline, paroxetine and citalopram, have widely been employed to treat PE. However, their effects are moderate and there is no a universal agreement about the kind, dose, protocol and duration. Dapoxetine, as the first prescription treatment of PE, may change this bottle-neck situation. SSRIs are suggested to be used in young men with lifelong PE, and acquired PE when etiological factors are removed but PE still exists. Phosphodiesterase 5 inhibitors (PDE5-Is) are suggested to be employed alone or combined with SSRIs when SSRIs fail to treat PE or sexual dysfunction associated with SSRIs occurs. The protocol of taking drugs on demand based on taking them daily for a suitable period is proposed to be chosen firstly. The possible mechanisms include increasing serotonergic neurotransmission and activating 5-hydroxytryptamine 2C (5-HT2C) receptors, then switching the ejaculatory threshold to a higher level, decreasing the penile sensitivity and their own effect of antidepression.Conclusion The efficacies of the current SSRIs are moderate in the treatment of PE and they have not been approved by the FDA, therefore new SSRI like dapoxetine needs to be further evaluated.

  19. Topical calcineurin inhibitors for atopic dermatitis: review and treatment recommendations.

    Carr, Warner W

    2013-08-01

    Atopic dermatitis (AD) is an inflammatory skin disease commonly affecting children and managed by pediatricians, primary care physicians, allergists, and dermatologists alike. For many years, the only available topical pharmacological treatment was topical corticosteroids. This changed in 2000-2001, when topical formulations of two calcineurin inhibitors (tacrolimus and pimecrolimus) were approved for short-term or chronic intermittent treatment of AD in patients ≥ 2 years of age, in whom other treatments have been ineffective or contraindicated. These topical calcineurin inhibitors (TCIs) quickly became a popular treatment option due at least in part to concerns over adverse events associated with prolonged topical corticosteroid use, especially in children. However, based on theoretical concerns about a possible risk of lymphoma associated with TCI use, a Boxed Warning was placed on both products in 2006. Since then, despite an extensive body of evidence, no causal relationship has been demonstrated between TCI use and an increased risk of lymphoma; however, the US FDA has concluded that a link cannot be ruled out. In fact, based on post-marketing surveillance of spontaneous, literature, and solicited reports, we report here that the lymphoma incidence in the topical pimecrolimus-exposed population is up to approximately 54-fold less than that seen in the general US population. This review summarizes the mechanism of action of TCIs, the factors that prompted the Boxed Warning, and recent TCI safety and efficacy data. Based on these data, both topical corticosteroids and TCIs should have defined roles in AD management, with TCIs favored for sensitive skin areas (e.g., face) and instances where topical corticosteroids have proven ineffective, thereby minimizing the risk of adverse effects with both drug classes. PMID:23549982

  20. Clinical effects of early angiotensin-converting enzyme inhibitor treatment for acute myocardial infarction are similar in the presence and absence of aspirin: systematic overview of individual data from 96,712 randomized patients. Angiotensin-converting Enzyme Inhibitor Myocardial Infarction

    Latini, R; Tognoni, G; Maggioni, A P;

    2000-01-01

    OBJECTIVES: We sought to determine whether the clinical effects of early angiotensin-converting enzyme (ACE) inhibitor (ACEi) treatment for acute myocardial infarction (MI) are influenced by the concomitant use of aspirin (ASA). BACKGROUND: Aspirin and ACEi both reduce mortality when given early.......004). Angiotensin-converting enzyme inhibitor was associated with similar proportional reductions in 30-day mortality among the 86,484 patients who were taking ASA (6% [SD, 3%] reduction) and among the 10,228 patients who were not (10% [SD, 5%] reduction: chi-squared test of heterogeneity between these reductions...... = 0.4; p = 0.5). Angiotensin-converting enzyme inhibitor produced definite increases in the incidence of persistent hypotension (17.9% ACEi vs. 9.4% control) and of renal dysfunction (1.3% ACEi vs. 0.6% control), but there was no good evidence that these effects were different in the presence...

  1. 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

  2. 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

  3. Potential role of aromatase inhibitors in the treatment of endometriosis

    Abu Hashim H

    2014-07-01

    Full Text Available Hatem Abu HashimDepartment of Obstetrics and Gynecology, Faculty of Medicine, Mansoura University, Mansoura, EgyptAbstract: Endometriosis is an estrogen-dependent chronic inflammatory disease affecting 5%–10% of reproductive-age women, with a prevalence of 5%–50% in infertile women and >33% of women with chronic pelvic pain. Third-generation aromatase inhibitors (AIs are approved adjuvants for the treatment of estrogen receptor-positive breast cancer. Molecular studies have revealed the presence of aromatase P450, the key enzyme in the biosynthesis of ovarian estradiol, inside the endometriotic tissue, indicating local synthesis of estradiol. Thereby, AIs represent an appealing medical option for the management of different aspects of this enigmatic disease, especially pelvic pain and infertility. Accordingly, this review aims to evaluate the potential role of AIs in the treatment of endometriosis-associated symptoms, mainly pain and infertility. Notably, several studies have demonstrated that the combination of AIs with conventional therapy as oral contraceptive pills, progestins, or gonadotropin-releasing hormone analogs can be used to control endometriosis-associated pain and pain recurrence in premenopausal women, particularly those with pain due to rectovaginal endometriosis refractory to other medical or surgical treatment. Some case reports have shown promising results in the treatment of postmenopausal endometriosis as first-line treatment, when surgery is contraindicated, or as second-line treatment in the case of postoperative recurrence. Third-generation AIs, especially letrozole, have challenged clomiphene citrate as an ovulation-induction agent in patients with polycystic ovary syndrome and in cases of unexplained infertility. However, few studies are available regarding the use of AIs to treat endometriosis-associated infertility. Therefore, larger multicenter randomized trials using AIs for the treatment of endometriosis

  4. 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.

  5. Mammalian target of rapamycin inhibitors for treatment in tuberous sclerosis

    Won Seop Kim

    2013-06-01

    Full Text Available Korean J Pediatr 2011;54:241-5. &lt;a href='http://dx.doi.org/10.3345/kjp.2011.54.6.241'&gt;http://dx.doi.org/10.3345/kjp.2011.54.6.241&lt;/a&gt;. PMID: 21949518 [PubMed] &lt;div style="border-top:1px solid #0092C8"&gt;&lt;/div&gt; The following article&lt;sup&gt;1&lt;/sup&gt; is being retracted as a part of the manuscript was plagiarized. Yeong-Ho Rha, MD, PhD Editor-in-Chief, Korean J Pediatr 1.Kim WS. Mammalian target of rapamycin inhibitors for treatment in tuberous sclerosis. Korean J Pediatr 2011;54:241-5.

  6. CYP17 inhibitors for prostate cancer treatment--an update.

    Moreira, V M; Salvador, J A R; Vasaitis, T S; Njar, V C O

    2008-01-01

    It is almost 70 years since the discovery by Huggins et al. that androgens are essential for prostate cancer (PC) growth and progression, and there has been about 30 years experience using ketoconazole for PC therapy. Since then we have come a long way in learning about the disease and developing new strategies to approach it, among which is cytochrome 17alpha-hydroxylase-C(17,20)-lyase (CYP17) inhibition. This review focuses on the efforts to find prospective CYP17 inhibitors, both steroidal and nonsteroidal, in the absence of a 3D structure of the enzyme. It covers almost 4 decades of literature with highlights on the most significant achievements in this area, providing insight into PC pathophysiology, management and treatment options. PMID:18473796

  7. Treatment with tumor necrosis factor inhibitors in axial spondyloarthritis

    Ciurea, A.; Weber, U.; Stekhoven, D.;

    2015-01-01

    -TNF agents in private practices in comparison to academic centers, adherence to ASAS treatment recommendations for TNF inhibition was equally high, and similar response rates to TNF blockers were achieved in both clinical settings. (First Release Nov 1 2014; J Rheumatol 2015; 42:101-5; doi 10.3899/jrheum......Objective. To evaluate the initiation of and response to tumor necrosis factor (TNF) inhibitors for axial spondyloarthritis (axSpA) in private rheumatology practices versus academic centers. The Journal of Rheumatology, Methods.We compared newly initiated TNF inhibition for axSpA in 363 patients...... enrolled in private practices with 100 patients recruited in 6 university hospitals within the Swiss Clinical Quality Management (SCQM) cohort., Results. All patients had been treated with > 1 nonsteroidal antiinflammatory drug and > 70% of patients had a baseline Bath Ankylosing Spondylitis Disease...

  8. ACE-I Inhibitory Activity from Phaseolus lunatus and Phaseolus vulgaris Peptide Fractions Obtained by Ultrafiltration.

    Betancur-Ancona, David; Dávila-Ortiz, Gloria; Chel-Guerrero, Luis Antonio; Torruco-Uco, Juan Gabriel

    2015-11-01

    The involvement of angiotensin-I-converting enzyme (ACE-I) as one of the mechanisms controlling blood pressure is being studied to find alternative means of control of hypertension on human beings. On the market there are synthetic drugs that can control it, but these can cause undesirable health side effects. In this work was assessed the fractionation by ultrafiltration of the Lima bean (Phaseolus lunatus) and Jamapa bean (Phaseolus vulgaris), protein hydrolysates obtained with Alcalase(®) and Flavourzyme(®) on ACE-I inhibitory activity. Four membranes of different molecular cutoffs (10, 5, 3, and 1 kDa) were used. Fractions that had a higher inhibitory activity in both legumes were denominated as E (Alcalase and Flavourzyme, respectively, and for the Phaseolus vulgaris with Alcalase and Flavourzyme with about 63.8 and 65.8 μg/mL values, respectively. The amino acid composition of these fractions showed residues in essential amino acids, which make a good source of energy and amino acids. On the other hand, the presence of hydrophobic amino acids such as V and P is a determining factor in the ACE-I inhibitor effect. The results suggest the possibility of obtaining and utilizing these peptide fractions in the development and innovation of a functional product that helps with treatment and/or prevention of hypertension. PMID:26061663

  9. 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

  10. 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...

  11. Histone deacetylase inhibitors for treatment of hepatocellular carcinoma

    Danila CORADINI; Annalisa SPERANZA

    2005-01-01

    Hepatocellular carcinoma (HCC) is one of the most common cancers in the world.Surgical resection has been considered the optimal treatment approach, but only a small proportion of patients are suitable candidates for surgery, and the relapse rate is high. Approaches to prevent recurrence, including chemoemboliza-tion before and adjuvant therapy after surgery, have proven to have a limited benefit;liver transplantation is successful in treating limited-stage HCC because only a minority of patients qualify for transplantation. Therefore, new therapeutic strategies are urgently needed. Because in addition to the classical genetic mechanisms of deletion or inactivating point mutations, epigenetic alterations, such as hyperacetylation of the chromatin-associated histones (responsible for gene silencing), are believed to be involved in the development and progression of HCC, novel compounds endowed with a histone deacetylase (HDAC) inhibitory activity are an attractive therapeutic approach. In particular, pre-clinical results obtained using HA-But, an HDAC inhibitor in which butyric acid residues are esterified to a hyaluronic acid backbone and characterized by a high affinity for the membrane receptor CD44, indicated that this class of compounds may represent a promising approach for hepatocellular carcinoma treatment.

  12. 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

  13. Estimation of angiotensin-converting enzyme inhibitors protein binding degree using chromatographic hydrophobicity data

    Trbojević-Stanković Jasna

    2015-01-01

    Full Text Available Introduction. Angiotensin-converting enzyme (ACE inhibitors represent a significant group of drugs primarily used in the treatment of hypertension and congestive heart failure. Objective. Selected ACE inhibitors (enalapril, quinapril, fosinopril, lisinopril, cilazapril were studied in order to establish a fast and easy estimation method of their plasma protein binding degree based on their lipophilicity data. Methods. Chromatographic hydrophobicity data (parameter C0 were obtained on cellulose layers under conditions of normal-phase thin-layer chromatography (NPTLC, using different binary solvent systems. The ACE inhibitors lipophilicity descriptors (logP values were calculated using the software package Virtual Computational Chemistry Laboratory. The ACE inhibitors plasma protein binding data were collected from relevant literature. Results. ACE inhibitors protein binding data varied from negligible (lisinopril to 99% (fosinopril. The calculated lipophilicity descriptors, logPKOWWIN values ranged from -0.94 (lisinopril to 6.61 (fosinopril. Good correlations were established between plasma protein binding values and calculated logPKOWWIN values (R2=0.8026 as well as chromatographic hydrophobicity data, C0 parameters (R2=0.7662. Even though good correlation coefficients (R2 were obtained in both relations, unacceptable probability value with p>0.05 was found in relation between protein binding data and calculated logPKOWWIN values. Subsequently, taking into consideration the request for probability value lower than 0.05, a better relationship was observed between protein binding data and chromatographically obtained hydrophobicity parameters C0 values. Conclusion. Cellulose layers are easily available and cost effective sorbent to assess hydrophobicity. Experimentally obtained data on ACE inhibitors hydrophobicity and plasma protein binding estimation are important parameters in evaluating bioavailability of these drugs. [Projekat Ministarstva

  14. PARP Inhibitors for the Treatment and Prevention of Breast Cancer

    Vinayak, Shaveta; Ford, James M.

    2010-01-01

    Poly (ADP-ribose) polymerase (PARP) inhibitors, a novel class of drugs that target tumors with DNA repair defects, have received tremendous enthusiasm. Early preclinical studies identified BRCA1 and BRCA2 tumors to be highly sensitive to PARP inhibitors as a result of homologous recombination defect. Based on this premise, PARP inhibitors have been tested in early phase clinical trials as a single agent in BRCA1 or BRCA2 mutation carriers and in combination with chemotherapy in triple-negativ...

  15. 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...

  16. 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...

  17. 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.

  18. COX-2 Inhibitors for Cancer Treatment in Dogs

    Andrigo Barboza De Nardi*, Talita Mariana Morata Raposo1, Rafael Ricardo Huppes1, Carlos Roberto Daleck2 and Renée Laufer Amorim3

    2011-10-01

    Full Text Available Cancer is one of the main causes of death in canines and felines, and this fact is probably related to the increase in the longevity of these species. The longer the animals live, the higher the exposure to carcinogenic agents will be. With the high incidence of cancer in companion animals, new studies are currently being performed with the aim of finding therapeutic options which make the complete inhibition of the development of neoplasms in animals possible in the future. The correlation of cyclooxygenase-2 (COX-2 whith the development of cancer opens the way for the use of new therapeutic approaches. This relationship has been suggested based on various studies which established an association between the chronic use of nonsteroidal anti-inflammatory drugs (NSAID and a decrease in the incidence of colon carcinoma. As cancer progresses, COX-2 participates in the arachidonic acid metabolism by synthesizing prostaglandins which can mediate various mechanisms related to cancer development such as: increase in angiogenesis, inhibition of apoptosis, suppression of the immune response, acquisition of greater invasion capacity and metastasis. Accordingly, overexpression of this enzyme in tumors has been associated with the most aggressive, poor-prognosis cancer types, especially carcinomas. Therefore, treatments which use COX-2 inhibitors such as coxibs, whether administered as single agents or in combination with conventional antineoplastic chemotherapy, are an alternative for extending the survival of our cancer patients.

  19. How should we manage heart failure developing in patients already treated with angiotensin-converting enzyme inhibitors and beta-blockers for hypertension, diabetes or coronary disease?

    Gustafsson, Finn; Segura, Julian; Ruilope, Luis M

    2010-01-01

    An increasing number of patients in the community are being treated with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and beta-blockers for hypertension, coronary disease or diabetic renal and vascular complications. Some of these patients will develop heart...... failure despite such treatment. Based on data from hypertension trials it can be estimated that approximately 5% of treated patients will develop heart failure over 5 years. It is unclear whether patients developing heart failure on and off ACE-inhibitors or beta-blockers, respectively, at the time of...... heart failure diagnosis have similar prognosis.Treatment options for patients developing heart failure while already treated with ACE inhibitors/ARBs and beta-blockers are very limited if current heart failure guidelines are followed. In this review possible strategies are outlined and important areas...

  20. How should we manage heart failure developing in patients already treated with angiotensin-converting enzyme inhibitors and beta-blockers for hypertension, diabetes or coronary disease?

    Gustafsson, Finn; Segura, Julian; Ruilope, Luis M

    2010-01-01

    An increasing number of patients in the community are being treated with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and beta-blockers for hypertension, coronary disease or diabetic renal and vascular complications. Some of these patients will develop heart...... failure despite such treatment. Based on data from hypertension trials it can be estimated that approximately 5% of treated patients will develop heart failure over 5 years. It is unclear whether patients developing heart failure on and off ACE-inhibitors or beta-blockers, respectively, at the time...... of heart failure diagnosis have similar prognosis.Treatment options for patients developing heart failure while already treated with ACE inhibitors/ARBs and beta-blockers are very limited if current heart failure guidelines are followed. In this review possible strategies are outlined and important areas...

  1. Genetic determinants of treatment benefit of the angiotensin-converting enzyme-inhibitor perindopril in patients with stable coronary artery disease

    J.J. Brugts (Jasper); A.J. Isaacs (Aaron); H. Boersma (Eric); C.M. van Duijn (Cock); A.G. Uitterlinden (André); W.J. Remme (Willem); M.E. Bertrand (Michel); T. Ninomiya (T.); C. Ceconi (Claudio); J. Chalmers (John); S. MacmMahon (Stephen); K.M. Fox (Kim); R. Ferrari (Roberto); J.C.M. Witteman (Jacqueline); A.H.J. Danser (Jan); M.L. Simoons (Maarten); M.P.M. de Maat (Moniek)

    2010-01-01

    textabstractAims The efficacy of angiotensin-converting enzyme (ACE)-inhibitors in stable coronary artery disease (CAD) may be increased by targeting the therapy to those patients most likely to benefit. However, these patients cannot be identified by clinical characteristics. We developed a genetic

  2. Antiplatelet agents and proton pump inhibitors – personalizing treatment

    Eugene Lin

    2010-06-01

    Full Text Available Eugene Lin, Rajiv Padmanabhan, Majaz MoonisDepartment of Neurology, University of Massachusetts Medical School and UMass Memorial Medical Center, Worcester, Massachusetts, USAIntroduction: Antiplatelet therapy remains one of the cornerstones in the management of noncardioembolic ischemic stroke. However, a significant percentage of patients have concomitant gastroesophageal reflux or peptic ulcer disease that requires acid-reducing medications, the most powerful and effective being the proton pump inhibitors (PPIs. Antiplatelet efficacy, at least in vivo, and particularly for clopidogrel, has been shown to be reduced with concomitant proton pump inhibitor use. Whether this is clinically relevant is not clear from the limited studies available.Methods: We conducted an extensive review of studies available on Medline related to pharmacodynamic interactions between the antiplatelet medications and proton pump inhibitors as well as clinical studies that addressed this potential interaction.Results: Based on the present pharmacodynamic and clinical studies we did not find a significant interaction that would reduce the efficacy of antiplatelet agents with concomitant user of proton pump inhibitors.Conclusions: Patients on antiplatelet agents after a transient ischemic attack or ischemic stroke can safely use aspirin, and extended release dipyridamole/aspirin with proton pump inhibitors. Patients on clopidogrel may use other acid-reducing drugs besides proton pump inhibitors. In rare cases where proton pump inhibitors and clopidogrel have to be used concurrently, careful close monitoring for recurrent vascular events is required.Keywords: proton pump inhibitors, antiplatelet medications, clopidogrel, ischemic stroke, cardiovascular events

  3. 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

  4. ACE2 gene expression is up-regulated in the human failing heart

    Allen Jennifer C

    2004-05-01

    Full Text Available Abstract Background ACE2 is a novel homologue of angiotensin converting enzyme (ACE. ACE2 is highly expressed in human heart and animal data suggest that ACE2 is an essential regulator of cardiac function in vivo. Since overactivity of the renin-angiotensin system contributes to the progression of heart failure, this investigation assessed changes in gene expression of ACE2, ACE, AT1 receptor and renin in the human failing heart. Methods The sensitive technique of quantitative reverse transcriptase polymerase chain reaction was used to determine the level of mRNA expression of ACE and ACE2 in human ventricular myocardium from donors with non-diseased hearts (n = 9, idiopathic dilated cardiomyopathy (IDC, n = 11 and ischemic cardiomyopathy (ICM, n = 12. Following logarithmic transformation of the data, a one-way analysis of variance was performed for each target gene followed by a Dunnett's test to compare the two disease groups IDC and ICM versus control. Results As anticipated, ACE mRNA was found to be significantly increased in the failing heart with a 3.1 and 2.4-fold up-regulation found in IDC and ICM relative to non-diseased myocardium. Expression of ACE2 mRNA was also significantly up-regulated in IDC (2.4-fold increase and ICM (1.8-fold increase versus non-diseased myocardium. No change in angiotensin AT1 receptor mRNA expression was found in failing myocardium and renin mRNA was not detected. Conclusions These data suggest that ACE2 is up-regulated in human IDC and ICM and are consistent with the hypothesis that differential regulation of this enzyme may have important functional consequences in heart failure. This strengthens the hypothesis that ACE2 may be a relevant target for the treatment of heart failure and will hopefully spur further studies to clarify the functional effects in human myocardium of ACE2 derived peptides.

  5. 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...

  6. The Role of COX-2 Selective Inhibitors in the Treatment of Patients with Breast Cancer

    Kolyadina I.V.; Poddubnaya I.V.; Komov D.V.; Rostchin E.M.; Ozhereliev A.S.; Orinovsky M.B.

    2011-01-01

    The possibility of COX-2 selective inhibitor use in the treatment of patients with malignancies has been considered. A group of COX-2 selective inhibitors has been presented with coxibs: celecoxib, NS-398, nimesulide, meloxicam. There has been demonstrated the role of the COX-2 blockers in risk decrease of four most common malignant tumors: breast cancer (by 71%), prostate cancer (by 55%), colon cancer (by 70%) and lung cancer (by 79%). The role of COX-2 inhibitors in the prevention of develo...

  7. Clinical Use of Proteasome Inhibitors in the Treatment of Multiple Myeloma

    Noah M. Merin

    2014-12-01

    Full Text Available Multiple myeloma (MM is an incurable hematological malignancy characterized by the clonal proliferation of neoplastic plasma cells. The use of proteasome inhibitors in the treatment of MM has led to significant improvements in outcomes. This article reviews data on the use of the two approved proteasome inhibitors (bortezomib and carlfilzomib, as well as newer agents under development. Emphasis is placed on the clinical use of proteasome inhibitors, including management of side effects and combination with other agents.

  8. ACE2-mediated reduction of oxidative stress in the central nervous system is associated with improvement of autonomic function.

    Huijing Xia

    Full Text Available Oxidative stress in the central nervous system mediates the increase in sympathetic tone that precedes the development of hypertension. We hypothesized that by transforming Angiotensin-II (AngII into Ang-(1-7, ACE2 might reduce AngII-mediated oxidative stress in the brain and prevent autonomic dysfunction. To test this hypothesis, a relationship between ACE2 and oxidative stress was first confirmed in a mouse neuroblastoma cell line (Neuro2A cells treated with AngII and infected with Ad-hACE2. ACE2 overexpression resulted in a reduction of reactive oxygen species (ROS formation. In vivo, ACE2 knockout (ACE2(-/y mice and non-transgenic (NT littermates were infused with AngII (10 days and infected with Ad-hACE2 in the paraventricular nucleus (PVN. Baseline blood pressure (BP, AngII and brain ROS levels were not different between young mice (12 weeks. However, cardiac sympathetic tone, brain NADPH oxidase and SOD activities were significantly increased in ACE2(-/y. Post infusion, plasma and brain AngII levels were also significantly higher in ACE2(-/y, although BP was similarly increased in both genotypes. ROS formation in the PVN and RVLM was significantly higher in ACE2(-/y mice following AngII infusion. Similar phenotypes, i.e. increased oxidative stress, exacerbated dysautonomia and hypertension, were also observed on baseline in mature ACE2(-/y mice (48 weeks. ACE2 gene therapy to the PVN reduced AngII-mediated increase in NADPH oxidase activity and normalized cardiac dysautonomia in ACE2(-/y mice. Altogether, these data indicate that ACE2 gene deletion promotes age-dependent oxidative stress, autonomic dysfunction and hypertension, while PVN-targeted ACE2 gene therapy decreases ROS formation via NADPH oxidase inhibition and improves autonomic function. Accordingly, ACE2 could represent a new target for the treatment of hypertension-associated dysautonomia and oxidative stress.

  9. Effect of pretreatment on enzymatic hydrolysis of bovine collagen and formation of ACE-inhibitory peptides

    Zhang, Yuhao; Olsen, Karsten; Grossi, Alberto Blak;

    2013-01-01

    Bovine collagen was pre-treated (boiled or high pressure (HP)-treated) and then hydrolysed by 6 proteases. The degree of hydrolysis (DH) and the angiotensin-converting enzyme (ACE)-inhibitory activity of hydrolysates were measured. All enzymes used were able to partly degrade collagen and release...... ACEinhibitory peptides. The highest ACE-inhibitory activity was obtained with Alcalase. Pretreatment significantly influenced the DH and ACE-inhibition. For most enzymes, boiling for 5 min resulted in a significantly higher DH and ACE-inhibitory activity. With Alcalase and collagenase, hydrolysis and release of...... ACE-inhibitory peptides occurred without any pretreatment, but HP-treatment significantly improved the DH and ACE-inhibitory activity. HP did not markedly affect the hydrolysis with the other enzymes. The major peptides obtained with Alcalase were identified; all were released from the triple helix...

  10. Anhedonia Predicts Poorer Recovery among Youth with Selective Serotonin Reuptake Inhibitor Treatment-Resistant Depression

    McMakin, Dana L.; Olino, Thomas M.; Porta, Giovanna; Dietz, Laura J.; Emslie, Graham; Clarke, Gregory; Wagner, Karen Dineen; Asarnow, Joan R.; Ryan, Neal D.; Birmaher, Boris; Shamseddeen, Wael; Mayes, Taryn; Kennard, Betsy; Spirito, Anthony; Keller, Martin; Lynch, Frances L.; Dickerson, John F.; Brent, David A.

    2012-01-01

    Objective: To identify symptom dimensions of depression that predict recovery among selective serotonin reuptake inhibitor (SSRI) treatment-resistant adolescents undergoing second-step treatment. Method: The Treatment of Resistant Depression in Adolescents (TORDIA) trial included 334 SSRI treatment-resistant youth randomized to a medication…

  11. Overall survival after immunotherapy, tyrosine kinase inhibitors and surgery in treatment of metastatic renal cell cancer

    de Lichtenberg, Trine Honnens; Hermann, Gregers G.; Rorth, Mikael;

    2014-01-01

    Abstract Objective. The aim of this study was to evaluate overall survival (OS) after treatment of metastatic renal cell carcinoma (mRCC) following the introduction of tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors. Material and methods. One-hundred and fort...

  12. 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

  13. 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

  14. 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.

  15. 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.

  16. JAK Inhibitors: Treatment Efficacy and Safety Profile in Patients with Psoriasis

    Leeyen Hsu; Armstrong, April W.

    2014-01-01

    Janus kinase (JAK) pathways are key mediators in the immunopathogenesis of psoriasis. Psoriasis treatment has evolved with the advent of targeted therapies, which inhibit specific components of the psoriasis proinflammatory cascade. JAK inhibitors have been studied in early phase trials for psoriasis patients, and the data are promising for these agents as potential treatment options. Tofacitinib, an oral or topically administered JAK1 and JAK3 inhibitor, and ruxolitinib, a topical JAK1 and J...

  17. JAK kinase inhibitors for the treatment of acute lymphoblastic leukemia

    Degryse, Sandrine; Cools, Jan

    2015-01-01

    Recent studies of acute lymphoblastic leukemia have identified activating mutations in components of the interleukin-7 receptor complex (IL7R, JAK1, and JAK3). It will be of interest to investigate both JAK1 and JAK3 kinase inhibitors as targeted agents for these leukemias.

  18. 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

  19. Treatment of hereditary angioedema with plasma-derived C1 inhibitor

    Michael J Prematta

    2008-08-01

    Full Text Available Michael J Prematta, Tracy Prematta, Timothy J CraigSection of Allergy and Immunology, Penn State University, Milton S. Hershey Medical Center, PA, USABackground: Plasma-derived C1 inhibitor (C1-INH concentrate is a treatment option for acute hereditary angioedema (HAE attacks and is considered the standard-of-care in many countries, although it is not yet available in the United States. Studies are still being conducted to establish its safety and efficacy as required by the FDA.Objective: To review the medical literature to determine if C1-INH concentrate is a safe and effective treatment for acute HAE attacks.Methods: The following keywords were searched in PubMed and OVID: C1 esterase inhibitor, C1-inhibitor, C1 inhibitor, and hereditary angioedema treatment. English-language articles were searched from 1966 to the present to look for studies demonstrating the efficacy and the safety of C1-INH concentrate.Results: The English-language literature search revealed several studies showing significantly improved relief of HAE symptoms with the administration of C1-INH concentrate – many studies demonstrated some improvement of symptoms within 30 minutes. Side effects have been similar to placebo, and no proven cases of viral transmission have occurred in over 20 years.Conclusion: C1-INH concentrate appears to be a very safe and effective treatment option for HAE.Keywords: hereditary angioedema, c1 inhibitor, c1 esterase inhibitor, hereditary angioedema treatment

  20. Aerobic treatment of selective serotonin reuptake inhibitors in landfill leachate

    Bergersen, Ove; Østnes Hanssen, Kine; Vasskog, Terje

    2015-01-01

    Background: Pharmaceuticals used in human medical care are not completely eliminated in the human body and can enter the municipal sewage sludge system and leachate water from landfill both as the parent compound and as their biologically active metabolites. The selective serotonin reuptake inhibitors (SSRIs) have a large potential for unwanted effects on nontarget organisms in the environment. Leachates from active or old closed landfills are often treated with continuous stirrin...

  1. CHOLINESTERASE INHIBITORS IN THE TREATMENT OF DEMENTIA ALZHEIMER’S

    Prameidya Primaniar S

    2013-01-01

    Dementia is the loss of intellectual abilities which include decreased ability to think, remember,understand, calculate, concentrate, and find the right words. The causes of dementia areAlzheimer’s, vascular dementia, alcohol. Dementia Alzheimer’s is a dementia type that iscurrently the most commonly found. Cholinesterase inhibitors are one of the therapies used totreat symptoms of cognitive decline and reduce neuropsychiatric symptoms in patient dementiaAlzheimer’s. Several studies have been...

  2. 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

  3. PARP inhibitors: its role in treatment of cancer

    Alice Chen

    2011-01-01

    PARP is an important protein in DNA repair pathways especially the base excision repair (BER).BER is involved in DNA repair of single strand breaks (SSBs). If BER is impaired, inhibiting poly(ADP-ribose) polymerase (PARP), SSBs accumulate and become double stand breaks (DSBs). The cells with increasing number of DSBs become more dependent on other repair pathways, mainly the homologous recombination (HR) and the nonhomologous end joining. Patients with defective HR, like BRCA-deficient cell lines, are even more susceptible to impairment of the BER pathway. Inhibitors of PARP preferentially kill cancer cells in BRCA-mutation cancer cell lines over normal cells. Also, PARP inhibitors increase cytotoxicity by inhibiting repair in the presence of chemotherapies that induces SSBs. These two principles have been tested clinically. Over the last few years, excitement over this class of agents has escalated due to reported activity as single agent in BRCA1- or BRCA2-associated ovarian or breast cancers, and in combination with chemotherapy in tdple negative breast cancer. This review covers the current results of clinical trials testing those two principles. It also evaluates future directions for the field of PARP inhibitor development.

  4. FSD-C10: A more promising novel ROCK inhibitor than Fasudil for treatment of CNS autoimmunity

    Xin, Yan-Le; Yu, Jie-Zhong; Yang, Xin-Wang; Liu, Chun-Yun; Li, Yan-Hua; Feng, Ling; Chai, Zhi; Yang, Wan-Fang; Qing WANG; Jiang, Wei-Jia; Zhang, Guang-Xian; Xiao, Bao-Guo; Ma, Cun-Gen

    2015-01-01

    Compared with Fasudil, novel Rho kinase inhibitor FSD-C1 exhibited similar therapeutic potential and mechanisms in EAE, but had low cytotoxicity and vasodilation, providing a more promising novel ROCK inhibitor for the treatment of several neurological disorders.

  5. Potential benefits of sequential inhibitor-mutagen treatments of RNA virus infections.

    Celia Perales

    2009-11-01

    Full Text Available Lethal mutagenesis is an antiviral strategy consisting of virus extinction associated with enhanced mutagenesis. The use of non-mutagenic antiviral inhibitors has faced the problem of selection of inhibitor-resistant virus mutants. Quasispecies dynamics predicts, and clinical results have confirmed, that combination therapy has an advantage over monotherapy to delay or prevent selection of inhibitor-escape mutants. Using ribavirin-mediated mutagenesis of foot-and-mouth disease virus (FMDV, here we show that, contrary to expectations, sequential administration of the antiviral inhibitor guanidine (GU first, followed by ribavirin, is more effective than combination therapy with the two drugs, or than either drug used individually. Coelectroporation experiments suggest that limited inhibition of replication of interfering mutants by GU may contribute to the benefits of the sequential treatment. In lethal mutagenesis, a sequential inhibitor-mutagen treatment can be more effective than the corresponding combination treatment to drive a virus towards extinction. Such an advantage is also supported by a theoretical model for the evolution of a viral population under the action of increased mutagenesis in the presence of an inhibitor of viral replication. The model suggests that benefits of the sequential treatment are due to the involvement of a mutagenic agent, and to competition for susceptible cells exerted by the mutant spectrum. The results may impact lethal mutagenesis-based protocols, as well as current antiviral therapies involving ribavirin.

  6. Treatment of type 2 diabetes, lifestyle, GLP1 agonists and DPP4 inhibitors

    Gerald; H; Tomkin

    2014-01-01

    In recent years the treatment focus for type 2 diabetes has shifted to prevention by lifestyle change and to more aggressive reduction of blood sugars during the early stage of treatment. Weight reduction is an important goal for many people with type 2 diabetes.Bariatric surgery is no longer considered a last resort treatment. Glucagon-like peptide-1 agonists given by injection are emerging as a useful treatment since they not only lower blood sugar but are associated with a modest weight reduction. The role of the oral dipeptidyl peptidase 4 inhibitors is emerging as second line treatment ahead of sulphonylureas due to a possible beneficial effect on the beta cell and weight neutrality.Drugs which inhibit glucose re-absorption in the kidney,sodium/glucose co-transport 2 inhibitors, may have a role in the treatment of diabetes. Insulin treatment still remains the cornerstone of treatment in many patients with type 2 diabetes.

  7. The rationale and design of the perindopril genetic association study (PERGENE): A pharmacogenetic analysis of angiotensin-converting enzyme inhibitor therapy in patients with stable coronary artery disease

    J.J. Brugts (Jasper); M.P.M. de Maat (Moniek); H. Boersma (Eric); J.C.M. Witteman (Jacqueline); C.M. van Duijn (Cock); A.G. Uitterlinden (André); M.E. Bertrand (Michel); W.J. Remme (Willem); K.M. Fox (Kim); R. Ferrari (Roberto); A.H.J. Danser (Jan); M.L. Simoons (Maarten)

    2009-01-01

    textabstractBackground: Angiotensin-converting enzyme (ACE) inhibitors reduce clinical symptoms and improve outcome in patients with hypertension, heart failure, and stable coronary artery disease (CAD) and are among the most frequently used drugs in these patient groups. For hypertension, treatment

  8. Molecular regulation of MICA expression after HDAC inhibitor treatment of cancer cells

    Jensen, Helle

    and NKG2D-ligands are upregulated on the surface of abnormal cells. We have previously shown that cancer cells can be stimulated to express the NKG2D-ligands MICA/B after exposure to HDAC-inhibitors (HDAC-i), an occurrence that is not observed in healthy cells. Here we characterize the molecular...... signal pathways that lead to MICA expression after HDAC-inhibitor treatment of cancer cells. Chelating Calcium with Bapta-AM or EGTA potently inhibited HDAC-inhibitor and CMV mediated MICA/B expression. It was further observed that ER Calcium stores were depleted after HDAC-inhibitor treatment. NF......The immune system is critically dependent on the ability to recognize or sense infected, stressed and transformed cells. One of these sensing systems rely on NKG2D/NKG2D-ligand interaction, where NKG2D is an activating receptor constitutively expressed by several effector cells of the immune system...

  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. Poly (ADP-ribose polymerase inhibitor: an evolving paradigm in the treatment of prostate cancer

    Jingsong Zhang

    2014-06-01

    Full Text Available Recent phase I studies have reported single-agent activities of poly (ADP-ribose polymerase (PARP inhibitor in sporadic and in BRCA-mutant prostate cancers. Two of the most common genetic alterations in prostate cancer, ETS gene rearrangement and loss of PTEN, have been linked to increased sensitivity to PARP inhibitor in preclinical models. Emerging evidence also suggests that PARP1 plays an important role in mediating the transcriptional activities of androgen receptor (AR and ETS gene rearrangement. In this article, the preclinical work and early-phase clinical trials in developing PARP inhibitor-based therapy as a new treatment paradigm for metastatic prostate cancer are reviewed.

  11. Angiogenesis inhibitors under study for the treatment of lung cancer.

    Shepherd, Frances A; Sridhar, Srikala S

    2003-08-01

    Several classes of agents now exist that target the different steps involved in angiogenesis. These include drugs inhibiting matrix breakdown, the matrix metalloproteinase inhibitors (MMPIs), such as marimastat, prinomastat, BMS275291, BAY12-9566, and neovastat. Trials of this class of agents have all been negative to date. Drugs that block endothelial cell signaling via vascular endothelial growth factor (VEGF) and its receptor (VEGFR) including rhuMAb VEGF, SU5416, SU6668, ZD6474, CP-547,632 and ZD4190 are all in earlier stages of clinical trial. Drugs that are similar to endogenous inhibitors of angiogenesis including interferons have also been evaluated without success. Endostatin has been shown to have an acceptable toxicity profile, but clinical evidence of activity has not yet been demonstrated. There has also been renewed interest in thalidomide. Drugs such as squalamine, celecoxib, ZD6126, TNP-470 and those targeting the integrins are also being evaluated in lung cancer. Despite early enthusiasm for many of these agents, Phase III trials have not yet demonstrated significant increases in overall survival and toxicity remains an issue. It is hoped that as our understanding of the complex process of angiogenesis increases, so will our ability to design more effective targeted therapies. PMID:12867064

  12. Histomorphological changes in thymus and spleen after cyclooxygenase inhibitors treatment

    Poeta O.N.

    2009-01-01

    Full Text Available The influence of cyclooxygenase inhibitors on the lymphoid organs histomorphology has been examined in the matured outbread white mice. Diclofenac, meloxicam, celecoxib, but not rofecoxib has shown depressive action on the im-munocompetetive organs histomorphologic structure. Macroscopic study has revealed a decrease in the weight of the spleen and thymus. Light microscopy has shown a decrease in the number of thymocytes, due to degradation of cortex area. In the lobular medulla it has been observed microcirculation changes in the view of venules and capillaries distention, arteriolar wall thickening. In the spleen it has been shown a decrease in the white pulp volume, disappearing of the reactive centers in follicles. Also subcapsular edema and relative stroma volume increase has been seen frequently. The use of highly selective COG-2 inhibitor rofecoxib has not revealed statistically truthful changes in microscopic examination in comparison to the control group. That could vote for the absence of depressive action on the immune organ histomorphologic structure.

  13. DNA methylation analysis of the angiotensin converting enzyme (ACE gene in major depression.

    Peter Zill

    Full Text Available BACKGROUND: The angiotensin converting enzyme (ACE has been repeatedly discussed as susceptibility factor for major depression (MD and the bi-directional relation between MD and cardiovascular disorders (CVD. In this context, functional polymorphisms of the ACE gene have been linked to depression, to antidepressant treatment response, to ACE serum concentrations, as well as to hypertension, myocardial infarction and CVD risk markers. The mostly investigated ACE Ins/Del polymorphism accounts for ~40%-50% of the ACE serum concentration variance, the remaining half is probably determined by other genetic, environmental or epigenetic factors, but these are poorly understood. MATERIALS AND METHODS: The main aim of the present study was the analysis of the DNA methylation pattern in the regulatory region of the ACE gene in peripheral leukocytes of 81 MD patients and 81 healthy controls. RESULTS: We detected intensive DNA methylation within a recently described, functional important region of the ACE gene promoter including hypermethylation in depressed patients (p = 0.008 and a significant inverse correlation between the ACE serum concentration and ACE promoter methylation frequency in the total sample (p = 0.02. Furthermore, a significant inverse correlation between the concentrations of the inflammatory CVD risk markers ICAM-1, E-selectin and P-selectin and the degree of ACE promoter methylation in MD patients could be demonstrated (p = 0.01 - 0.04. CONCLUSION: The results of the present study suggest that aberrations in ACE promoter DNA methylation may be an underlying cause of MD and probably a common pathogenic factor for the bi-directional relationship between MD and cardiovascular disorders.

  14. Phosphodiesterase type 5 inhibitors as a treatment for erectile dysfunction: Current information and new horizons

    Ferguson, James E.; Carson, Culley C

    2013-01-01

    Introduction Over the past 15 years, the discovery and development of oral medications that selectively inhibit the enzyme phosphodiesterase type 5 (PDE5) have revolutionised the treatment of erectile dysfunction (ED). Currently, three PDE5 inhibitors are widely available clinically, i.e., sildenafil, vardenafil and tadalafil. New PDE5 inhibitors, including avanafil and udenafil, are now in clinical use in a few countries, and other compounds are under development. Methods We describe the cur...

  15. Treatment of isolated pistils with protease inhibitors overcomes the self-incompatibility response in buckwheat

    Miljuš-Đukić Jovanka D.

    2007-01-01

    Full Text Available Isolated pistils of distylous buckwheat (Fagopyrum esculentum Moench were treated with protease inhibitors (PMSF, pepstatin A, and antipain. Pistils were cross- or self- pollinated, and growth of pollen tubes was observed under a fluorescence microscope. Treatments with all inhibitors suppressed inhibition of self-pollen tube growth, suggesting that activity of proteases is involved in rejection of self-pollen during the SI response.

  16. A human surfactant peptide-elastase inhibitor construct as a treatment for emphysema

    Guarnieri, Frank; Spencer, Jean L.; Lucey, Edgar C.; Matthew A Nugent; Stone, Phillip J.

    2010-01-01

    Two million Americans suffer from pulmonary emphysema, costing $2.5 billion/year and contributing to 100,000 deaths/year. Emphysema is thought to result from an imbalance between elastase and endogenous inhibitors of elastase, leading to tissue destruction and a loss of alveoli. Decades of research have still not resulted in an effective treatment other than stopping cigarette smoking, a highly addictive behavior. On the basis of our previous work, we hypothesize that small molecule inhibitor...

  17. A novel strategy for the treatment of diabetes mellitus - sodium glucose co-transport inhibitors

    Asfandyar Khan Niazi

    2010-12-01

    Full Text Available Background: Diabetes is one of the most common chronic diseases, affecting almost 3 million in Canada alone and is characterized by increased blood glucose levels. Treatment varies from lifestyle changes to oral anti-diabetics and/or insulin. Sodium glucose co-transport inhibitors may offer promising treatment for patients suffering from diabetes. The inhibitors act by increasing the loss of glucose in urine by decreasing the reabsorption of glucose from the proximal tubules of nephrons. Aims: The aim of this review was to assess the efficacy of sodium glucose co-transport inhibitors in the treatment of diabetes as well as any adverse effects. Materials and Methods: Databases such as MEDLINE, COCHRANE and EMBASE were systematically searched for literature on the efficacy of sodium glucose co-transport inhibitors in improving the glycemic control of patients with diabetes. Results: Research showed that sodium glucose co-transport inhibitors significantly decreased blood glucose levels by increasing glucosuria. Due to the diuretic effects of these inhibitors, diabetic patients who were suffering from hypertension showed a decrease in blood pressure. The caloric loss associated with these inhibitors resulted in weight loss as well. The most common adverse effect seen in patients on these medications was mycotic infection of the urinary or genital tract. Conclusion: Sodium glucose co-transport inhibitors may be an effective line of treatment for diabetes. Although short-term research has shown these drugs to be safe and well-tolerated, studies should be conducted to assess the long-term effects of these drugs.

  18. A novel strategy for the treatment of diabetes mellitus - sodium glucose co-transport inhibitors

    Asfandyar Khan Niazi

    2010-01-01

    Full Text Available Background: Diabetes is one of the most common chronic diseases, affecting almost 3 million in Canada alone and is characterized by increased blood glucose levels. Treatment varies from lifestyle changes to oral anti-diabetics and/or insulin. Sodium glucose co-transport inhibitors may offer promising treatment for patients suffering from diabetes. The inhibitors act by increasing the loss of glucose in urine by decreasing the reabsorption of glucose from the proximal tubules of nephrons. Aims: The aim of this review was to assess the efficacy of sodium glucose co-transport inhibitors in the treatment of diabetes as well as any adverse effects. Materials and Methods : Databases such as MEDLINE, COCHRANE and EMBASE were systematically searched for literature on the efficacy of sodium glucose co-transport inhibitors in improving the glycemic control of patients with diabetes. Results: Research showed that sodium glucose co-transport inhibitors significantly decreased blood glucose levels by increasing glucosuria. Due to the diuretic effects of these inhibitors, diabetic patients who were suffering from hypertension showed a decrease in blood pressure. The caloric loss associated with these inhibitors resulted in weight loss as well. The most common adverse effect seen in patients on these medications was mycotic infection of the urinary or genital tract. Conclusion: Sodium glucose co-transport inhibitors may be an effective line of treatment for diabetes. Although short-term research has shown these drugs to be safe and well-tolerated, studies should be conducted to assess the long-term effects of these drugs.

  19. Potential Benefits of Sequential Inhibitor-Mutagen Treatments of RNA Virus Infections

    Celia Perales; Rubén Agudo; Hector Tejero; Manrubia, Susanna C.; Esteban Domingo

    2009-01-01

    Author Summary RNA viruses are associated with many important human and animal diseases such as AIDS, influenza, hemorrhagic fevers and several forms of hepatitis. RNA viruses mutate at very high rates and, therefore, can adapt easily to environmental changes. Viral mutants resistant to antiviral inhibitors are readily selected, resulting in treatment failure. The simultaneous administration of three or more inhibitors is a means to prevent or delay selection of resistant mutants. A new antiv...

  20. Rhucin, a recombinant C1 inhibitor for the treatment of hereditary angioedema and cerebral ischemia.

    Longhurst, Hilary

    2008-03-01

    Pharming NV and Esteve are developing Rhucin, a recombinant human C1 esterase inhibitor. Rhucin is currently undergoing phase III clinical trials in North America and is awaiting regulatory approval in Western Europe for the treatment of prophylactic and acute hereditary angioedema. Pharming is also investigating Rhucin for the potential treatment of cerebral ischemic injury. PMID:18311668

  1. Oral voclosporin: novel calcineurin inhibitor for treatment of noninfectious uveitis

    Roesel M

    2011-09-01

    Full Text Available Martin Roesel1, Christoph Tappeiner2, Arnd Heiligenhaus1,3, Carsten Heinz1,31Department of Ophthalmology, St Franziskus-Hospital, Muenster, Germany; 2Department of Ophthalmology, Inselspital, University of Bern, Switzerland; 3University Duisburg-Essen, GermanyAbstract: Voclosporin, a novel immunomodulatory drug inhibiting the calcineurin enzyme, was developed to prevent organ graft rejection and to treat autoimmune diseases. The chemical structure of voclosporin is similar to that of cyclosporine A, with a difference in one amino acid, leading to superior calcineurin inhibition and less variability in plasma concentration. Compared with placebo, voclosporin may significantly reduce inflammation and prevent recurrences of inflammation in patients with noninfectious uveitis. Future studies have to show if these advantages are accompanied by greater clinical efficacy and fewer side effects compared with the classic calcineurin inhibitors.Keywords: uveitis, immunosuppression, voclosporin

  2. Hereditary and acquired C1-inhibitor-dependent angioedema: from pathophysiology to treatment.

    Zeerleder, Sacha; Levi, Marcel

    2016-06-01

    Uncontrolled generation of bradykinin (BK) due to insufficient levels of protease inhibitors controlling contact phase (CP) activation, increased activity of CP proteins, and/or inadequate degradation of BK into inactive peptides increases vascular permeability via BK-receptor 2 (BKR2) and results in subcutaneous and submucosal edema formation. Hereditary and acquired angioedema due to C1-inhibitor deficiency (C1-INH-HAE and -AAE) are diseases characterized by serious and potentially fatal attacks of subcutaneous and submucosal edemas of upper airways, facial structures, abdomen, and extremities, due to inadequate control of BK generation. A decreased activity of C1-inhibitor is the hallmark of C1-INH-HAE (types 1 and 2) due to a mutation in the C1-inhibitor gene, whereas the deficiency in C1-inhibitor in C1-INH-AAE is the result of autoimmune phenomena. In HAE with normal C1-inhibitor, a significant percentage of patients have an increased activity of factor XIIa due to a FXII mutation (FXII-HAE). Treatment of C1-inhibitor-dependent angioedema focuses on restoring control of BK generation by inhibition of CP proteases by correcting the balance between CP inhibitors and BK breakdown or by inhibition of BK-mediated effects at the BKR2 on endothelial cells. This review will address the pathophysiology, clinical picture, diagnosis and available treatment in C1-inhibitor-dependent angioedema focusing on BK-release and its regulation. Key Messages Inadequate control of bradykinin formation results in the formation of characteristic subcutaneous and submucosal edemas of the skin, upper airways, facial structures, abdomen and extremities as seen in hereditary and acquired C1-inhibitor-dependent angioedema. Diagnosis of hereditary and acquired C1-inhibitor-dependent angioedema may be troublesome as illustrated by the fact that there is a significant delay in diagnosis; a certain grade of suspicion is therefore crucial for quick diagnosis. Submucosal edema formation in

  3. 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.

  4. Molecular regulation of MICA expression after HDAC-inhibitor treatment of Jurkat T cells

    Jensen, Helle; Andresen, Lars; Pedersen, Marianne T.; Hansen, Karen A.; Skov, Søren

    signal pathways that lead to MICA expression after HDAC-inhibitor treatment of Jurkat T cells. Chelating Calcium with Bapta-AM or EGTA potently inhibited HDAC-inhibitor mediated MICA/B expression. It was further observed that ER Calcium stores were depleted after HDAC-inhibitor treatment. NF-kB activity...... can be induced by HDAC-inhibitor treatment. However, nuclear translocation of NF-kB p65 was not observed after HDAC-inhibitor treatment of Jurkat T cells, and even though we could effectively inhibit p65 expression by siRNA, it did not modify MICA/B expression. To identify important elements in MICA......The immune system is critically dependent on the ability to recognize or sense infected, stressed and transformed cells. One of these sensing systems rely on NKG2D/NKG2D-ligand interaction, where NKG2D is an activating receptor constitutively expressed by several effector cells of the immune system...

  5. 为什么血管紧张素转化酶抑制剂能降低高血压患者死亡率?%Why can angiotensin-converting enzyme inhibitors reduce mortality in hypertension?

    廖玉华; 程龙献

    2012-01-01

    最新荟萃分析发现,肾素-血管紧张素(Ang)-醛固酮系统(RAAS)抑制剂能降低高血压患者死亡率,其治疗获益全部源于血管紧张素转化酶(ACE)抑制剂(ACEIs),而非血管紧张素受体拮抗剂(ARBs).RAAS可以归纳为2条轴:ACE-AngⅡ(1-8)-AT1受体轴和ACE2-Ang(1-7)-Mas受体轴,ACEIs对RAAS的2条轴均发挥良好作用,而ARBs主要作用于前者.各个指南推荐高血压相关心血管疾病治疗优先选择ACEIs,对不能够耐受者选择ARBs.我们应当重视ACEIs在高血压、冠心病、心肌梗死和心力衰竭防治中的应用,目的是降低心血管疾病患病率和死亡率的风险.%Latest meta-analysis has discovered that the renin-angiotensin-aldosterone system (RAAS) inhibitors can reduce mortality in hypertension, and the observed treatment effect resulted entirely from the class of ACE inhibitors rather than ARBs. RAAS may be summed up in two axes: ACE-Ang II (1-8)-ATi receptor axis and ACE2-Ang(l-7)-Mas receptor axis. ACE inhibitors developed fine effects in both axes, whereas ARBs was major effect on the former axis. All guidelines emphasized that ACE inhibitors should be started and continued indefinitely in all patients with hypertension-related cardiovascular diseases, and ARBs were recommended in patients who were intolerant to ACE-inhibitors. We should pay attention to ACE inhibitors used in patients with hypertension, coronary heart disease, myocardial infarction and heart failure, in order to reduce the long-term risk of cardiovascular morbidity and mortality.

  6. 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.

  7. 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

  8. 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...

  9. Selective Serotonin Reuptake Inhibitors for Treatment of Selective Mutism

    Mazlum Çöpür

    2012-03-01

    Full Text Available Some authors suggest that selective mutism should be considered as a variant of social phobia or a disorder in the obsessive-compulsive spectrum. Recent studies indicate that pharmacological treatments may be effective in the treatment of selective mutism. In this article, four cases who were treated with citalopram and escitalopram are presented. The results indicate that the drugs were well tolerated, and the level of social and verbal interactions improved significantly. These findings have shown that citalopram and escitalopram can be considered in medication of selective mutism; nevertheless, it is essential that research be done with more cases than previous ones, in order to prove their accuracy

  10. JAK Inhibitors: Treatment Efficacy and Safety Profile in Patients with Psoriasis

    Leeyen Hsu

    2014-01-01

    Full Text Available Janus kinase (JAK pathways are key mediators in the immunopathogenesis of psoriasis. Psoriasis treatment has evolved with the advent of targeted therapies, which inhibit specific components of the psoriasis proinflammatory cascade. JAK inhibitors have been studied in early phase trials for psoriasis patients, and the data are promising for these agents as potential treatment options. Tofacitinib, an oral or topically administered JAK1 and JAK3 inhibitor, and ruxolitinib, a topical JAK1 and JAK2 inhibitor, have been most extensively studied in psoriasis, and both improved clinical symptoms of psoriasis. Additional JAK1 or JAK3 inhibitors are being studied in clinical trials. In phase III trials for rheumatoid arthritis, tofacitinib was efficacious in patients with inadequate responses to tumor necrosis factor inhibitors, methotrexate monotherapy, or disease-modifying antirheumatic drugs. The results of phase III trials are pending for these therapies in psoriasis, and these agents may represent important alternatives for patients with inadequate responses to currently available agents. Further investigations with long-term clinical trials are necessary to verify their utility in psoriasis treatment and assess their safety in this patient population.

  11. Treatment of Selective Serotonin Reuptake Inhibitor-Resistant Depression in Adolescents: Predictors and Moderators of Treatment Response

    Asarnow, Joan Rosenbaum; Emslie, Graham; Clarke, Greg; Wagner, Karen Dineen; Spirito, Anthony; Vitiello, Benedetto; Iyengar, Satish; Shamseddeen, Wael; Ritz, Louise; Birmaher, Boris; Ryan, Neal; Kennard, Betsy; Mayes, Taryn; DeBar, Lynn; McCracken, James; Strober, Michael; Suddath, Robert; Leonard, Henrietta; Porta, Giovanna; Keller, Martin; Brent, David

    2009-01-01

    Adolescents who did not improve with Selective Serotonin Reuptake Inhibitor (SSRI) were provided an alternative SSRI plus cognitive-behavioral therapy (CBT). The superiority of the CBT/combined treatment as compared to medication alone is more evident in youths who had more comorbid disorders, no abuse history, and lower hopelessness.

  12. The potential use of histone deacetylase inhibitors in the treatment of depression.

    Fuchikami, Manabu; Yamamoto, Shigeto; Morinobu, Shigeru; Okada, Satoshi; Yamawaki, Yosuke; Yamawaki, Shigeto

    2016-01-01

    Numerous preclinical studies demonstrate that changes in gene expression in the brain occur in animal models of depression using exposure to stress, such as social defeat and leaned helplessness, and that repeated administration of antidepressants ameliorates these stress-induced changes in gene expression. These findings suggest that alteration in gene transcription in the central nervous system in response to stress plays an important role in the pathophysiology of depression. Recent advances in epigenetics have led to the realization that chromatin remodeling mediated by histone deacetylase (HDAC) is closely involved in the regulation of gene transcription. In this context, we first review several preclinical studies demonstrating the antidepressant-like efficacy of HDAC inhibitors. We then suggest the efficacy of HDAC inhibitors in treatment-resistant depression based on the mechanism of action of HDAC. Finally, we discuss the possibility of using HDAC inhibitors in patients with treatment-resistant depression. PMID:25818247

  13. Efficacy, safety, and patient preference of monoamine oxidase B inhibitors in the treatment of Parkinson's disease

    Bradley J Robottom

    2011-01-01

    Full Text Available Bradley J RobottomDepartment of Neurology, University of Maryland School of Medicine, Baltimore, MD, USAAbstract: Parkinson's disease (PD is the second most common neurodegenerative disease and the most treatable. Treatment of PD is symptomatic and generally focuses on the replacement or augmentation of levodopa. A number of options are available for treatment, both in monotherapy of early PD and to treat complications of advanced PD. This review focuses on rasagiline and selegiline, two medications that belong to a class of antiparkinsonian drugs called monoamine oxidase B (MAO-B inhibitors. Topics covered in the review include mechanism of action, efficacy in early and advanced PD, effects on disability, the controversy regarding disease modification, safety, and patient preference for MAO-B inhibitors.Keywords: monoamine oxidase inhibitors, rasagiline, selegiline, Parkinson's disease, efficacy, safety

  14. 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....

  15. 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...

  16. Successful treatment of murine muscular dystrophy with the proteinase inhibitor leupeptin.

    Sher, J H; Stracher, A.; Shafiq, S A; Hardy-Stashin, J

    1981-01-01

    Mice with genetic muscular dystrophy were treated with intraperitoneal injections of the proteinase inhibitor leupeptin, beginning before the onset of weakness. A significant number of the treated animals failed to develop histological evidence of dystrophy, compared with controls. Leupeptin treatment prevented (or delayed) the onset of muscular dystrophy in this experiment.

  17. Saxagliptin: a new dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes

    Deacon, Carolyn F; Holst, Jens J

    2009-01-01

    Saxagliptin is a potent and selective reversible inhibitor of dipeptidyl peptidase-4, which is being developed for the treatment of type 2 diabetes. It is absorbed rapidly after oral administration and has a pharmacokinetic profile compatible with once daily dosing. Saxagliptin is metabolized in ...

  18. Which Factors Influence Radiographic Progression During Treatment with Tumor Necrosis Factor Inhibitors in Clinical Practice?

    Ornbjerg, Lykke Midtbøll; Ostergaard, Mikkel; Bøyesen, Pernille; Krogh, Niels Steen; Thormann, Anja; Tarp, Ulrik; Poulsen, Uta Engling; Espesen, Jakob; Schlemmer, Annette; Graudal, Niels; Kollerup, Gina; Jensen, Dorte Vendelbo; Madsen, Ole Rintek; Glintborg, Bente; Christensen, Torben; Lindegaard, Hanne; Bøhme, Wolfgang; Hansen, Annette; Andersen, Anne Rødgaard; Hetland, Merete Lund

    2014-01-01

    -59), DAS28-CRP 5.0 (1.4-7.8), TSS median 15 [3-45 interquartile range (IQR)] and mean 31 (SD 40). Patients started treatment with infliximab (59%), etanercept (18%), or adalimumab (23%). At followup (median 526 days, IQR 392-735), 61% were treated with the initial anti-TNF, 29% had switched TNF inhibitor...

  19. 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

  20. Comparison of dynamic of autonomic control indices in cardiovascular system under the treatment by ACE inhibitor (Enalapril) and beta-blocker (Metoprolol) in patients with hypertension

    Kiselev, A.R.; Karavaev, A.S.; V.I. Gridnev; O.M. Posnenkova; V.A. Shvartz; Ponomarenko, V. I.; M. D. Prokhorov; B. P. Bezruchko

    2010-01-01

    The objective of the present research was to compare the influence of Enalapril and Metoprolol on synchronization of 0.1 Hz-regulation of heart and blood microcirculation. 42 patients aged 49±9 years old with hypertension I, II were included in the study. 0.1 Hz-oscillations in heart rate variability (HRV) and blood microcirculation were registered during the passive orthostatic sign while breathing spontaneously. The duration of each test was 10 minutes. Synchronization was estimated as a ph...

  1. [Hematopoietic prostaglandin D synthase inhibitors for the treatment of duchenne muscular dystrophy].

    Kamauchi, Shinya; Urade, Yoshihiro

    2011-11-01

    Duchenne muscular dystrophy (DMD) is a severe X-linked muscle disease, characterized by progressive skeletal muscle atrophy and weakness. DMD is caused by mutations in the dystrophin gene, which encodes for the cytoskeletal protein dystrophin. DMD is one of the most common types of muscular dystrophies, affecting approximately 1 in 3,500 boys. There is no complete cure for this disease. Clinical trials for gene transfer therapy as a treatment for DMD have been performed but mainly in animal models. Hematopoietic prostaglandin (PG) D synthase (H-PGDS) was found to be induced in grouped necrotic muscle fibers of DMD patients and animal models, mdx mice, and DMD dogs. We found an orally active H-PGDS inhibitor (HQL-79) and determined the 3D structure of the inhibitor-human H-PGDS complex by X-ray crystallography. Oral administration of HQL-79 markedly suppressed prostaglandin D2 (PGD2) production, reduced necrotic muscle volume, and improved muscle strength in mdx dystrophic mice. Based on the high-resolution 3D structures of the inhibitor-H-PGDS complex, we designed alternative H-PGDS inhibitors, which were 100- to 3000-times more potent than HQL-79, as assessed by in vitro and in vivo analyses. We used these novel inhibitors for the treatment of DMD dogs and confirmed that oral administration of these inhibitors prevented skeletal muscle atrophy and weakness by decreasing PGD2 production. These results indicate that PGD2, synthesized by H-PGDS, is involved in the expansion of muscle necrosis in DMD. Thus, inhibition of H-PGDS by using inhibitors is a novel therapy for DMD. PMID:22068479

  2. Clinical utility of the oral JAK inhibitor tofacitinib in the treatment of rheumatoid arthritis

    Cutolo M

    2013-11-01

    Full Text Available Maurizio Cutolo, Marianna Meroni Research Laboratories and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genova, Genova, Italy Abstract: Immune/inflammatory cells act in rheumatoid arthritis (RA-affected patients by synthesizing several inflammatory mediators, including cytokines that initiate intracellular signaling. Recently, small molecule inhibitors of transduction and transcription signals that influence the intracellular pathways (such as the Janus kinase [JAK] family of tyrosine kinases have been tested for RA treatment. Four members of the JAK family are known: JAK1, JAK2, JAK3, and TyK2. JAK1/JAK3 constitutively binds to the cytoplasmic portion of the cytokine receptor – the common gamma chain – that represents a common subunit of several cytokines involved in T-cell and natural killer cell development, as well as in B-cell activation. Tofacitinib is an oral JAK inhibitor that is now available and effective in RA treatment, as shown in multiple Phase II and Phase III clinical trials. However, long-term safety data and comparisons with other disease-modifying antirheumatic drugs and small molecule inhibitors are necessary to better determine the role of tofacitinib in RA. Keywords: Janus kinase inhibitors, tofacitinib, rheumatoid arthritis, kinases, small molecules inhibitors, intracellular signaling

  3. Current status of 5α-reductase inhibitors in the treatment of benign hyperplasia of prostate

    Kumar Vijay

    2008-04-01

    Full Text Available Benign prostatic hyperplasia (BPH is a common problem in aging men, which is associated with lower urinary tract symptoms. This condition is dependent on the presence of androgens for its progression, and medical therapy is the first-line treatment for BPH patients with moderate-to-severe symptoms and includes the use of either alpha 1-adrenergic blockers or 5α-reductase inhibitors. Adrenergic blocking drugs reduce the dynamic component while the 5α-reductase inhibitors reduce the static component of bladder outlet obstruction in BPH. By inhibiting the generation of active form of testosterone, viz., dihydrotestosterone, the 5α-reductase inhibitors not only reduce the symptoms of BPH but also decrease the need for surgery and further progression of BPH. Besides, prolonged use of combination of 5α-reductase inhibitors and alpha 1-adrenergic blockers has been found to be more beneficial than either of the two drugs given alone. This review gives a brief account of rationale and efficacy of treatment by 5α-reductase inhibitors in the management of BPH.

  4. 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...

  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. Histone Deacetylase Inhibitors in the Treatment of Muscular Dystrophies: Epigenetic Drugs for Genetic Diseases

    Consalvi, Silvia; Saccone, Valentina; Giordani, Lorenzo; Minetti, Giulia; Mozzetta, Chiara; Puri, Pier Lorenzo

    2011-01-01

    Histone deacetylases inhibitors (HDACi) include a growing number of drugs that share the ability to inhibit the enzymatic activity of some or all the HDACs. Experimental and preclinical evidence indicates that these epigenetic drugs not only can be effective in the treatment of malignancies, inflammatory diseases and degenerative disorders, but also in the treatment of genetic diseases, such as muscular dystrophies. The ability of HDACi to counter the progression of muscular dystrophies point...

  7. Memantine and Cholinesterase Inhibitors: Complementary Mechanisms in the Treatment of Alzheimer’s Disease

    Parsons, Chris G.; Danysz, Wojciech; Dekundy, Andrzej; Pulte, Irena

    2013-01-01

    This review describes the preclinical mechanisms that may underlie the increased therapeutic benefit of combination therapy—with the N-methyl-d-aspartate receptor antagonist, memantine, and an acetylcholinesterase inhibitor (AChEI)—for the treatment of Alzheimer’s disease (AD). Memantine, and the AChEIs target two different aspects of AD pathology. Both drug types have shown significant efficacy as monotherapies for the treatment of AD. Furthermore, clinical observations indicate that their c...

  8. 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.

  9. Checkpoint Inhibitors for the Treatment of Hodgkin Lymphoma.

    Bennani-Baiti, Nabila; Thanarajasingam, Gita; Ansell, Stephen

    2016-06-01

    Hodgkin lymphoma's (HL) tumor composition is characterized by a paucity of malignant cells and a preponderance of immune and stromal cells. Despite the rich immune milieu within the tumor microenvironment, malignant cells are able to effectively evade the immune system and use immune support to promote lymphoma cell growth and proliferation. Recognizing this has led to the identification of checkpoint inhibitory signals that enable immune evasion and to opening the door to therapeutic strategies on how to exploit the immune system in targeting tumor cells. We discuss herein some of the tumor evasion mechanisms in HL with a particular focus on the immune checkpoint pathways and focus on recent clinical data of checkpoint blockade in HL treatment. PMID:26818843

  10. Mesenchymal stem cells are sensitive to treatment with kinase inhibitors and ionizing radiation

    Mesenchymal stem cells (MSCs) can regenerate damaged tissues and may therefore be of importance for normal tissue repair after cancer treatment. Small molecule receptor kinase inhibitors (RKIs) have recently been introduced into cancer treatment. However, the influence of these drugs - particularly in combination with radiotherapy - on the survival of MSCs is largely unknown. The sensitivity of human primary MSCs from healthy volunteers and primary human fibroblast cells to small molecule kinase inhibitors of the vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and transforming growth factor β (TGFβ) receptors, as well to inhibitors of c-Kit, was examined in combination with ionizing radiation (IR); cell survival and proliferation were assessed. Expression patterns of different kinase receptors and ligands were investigated using gene arrays. MSCs were highly sensitive to the tyrosine kinase inhibitors SU14816 (imatinib) and SU11657 (sunitinib), but showed only moderate sensitivity to the selective TGFβ receptor 1 inhibitor LY2109761. Primary adult human fibroblasts were comparably resistant to all three inhibitors. The addition of IR had an additive or supra-additive effect in the MSCs, but this was not the case for differentiated fibroblasts. Proliferation was markedly reduced in MSCs following kinase inhibition, both with and without IR. Gene expression analysis revealed high levels of the PDGF α and β receptors, and lower levels of the TGFβ receptor 2 and Abl kinase. IR did not alter the expression of kinase receptors or their respective ligands in either MSCs or adult fibroblasts. These data show that MSCs are highly sensitive to RKIs and combination treatments incorporating IR. Expression analyses suggest that high levels of PDGF receptors may contribute to this effect. (orig.)

  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. Protein kinase C-β inhibitor treatment attenuates hepatic ischemia and reperfusion injury in diabetic rats

    MENG, GUANG-XING; Yuan, Qiang; WEI, LI-PING; Meng, Hua; Wang, Yi-Jun

    2015-01-01

    Hepatic ischemia and reperfusion (I/R) injury plays an active role in hepatic resection and transplantation. While the effects of protein kinase C (PKC)-βII activation and the role of PKC-β inhibitors are well understood in myocardial I/R in diabetes, they remain unclear in liver I/R. The aim of this study was to explore the effect of PKC-β inhibition and the potential mechanism by which PKC-β inhibitor treatment protects against hepatic I/R injury in diabetic rats. Diabetic rats were establi...

  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. Impact of tumour necrosis factor inhibitor treatment on radiographic progression in rheumatoid arthritis patients in clinical practice

    Ornbjerg, Lykke Midtbøll; Østergaard, Mikkel; Bøyesen, Pernille; Krogh, Niels Steen; Thormann, Anja; Tarp, Ulrik; Poulsen, Uta Engling; Espesen, Jakob; Ringsdal, Vibeke Stevenius; Graudal, Niels Albert; Kollerup, Gina Birgitte; Jensen, Dorte Vendelbo; Madsen, Ole Rintek; Glintborg, Bente; Christensen, Torben; Lindegaard, Hanne; Dencker, Ditte; Hansen, Annette; Andersen, Anne Rødgaard; Hetland, Merete Lund

    2013-01-01

    To compare radiographic progression during treatment with disease-modifying antirheumatic drugs (DMARD) and subsequent treatment with tumour necrosis factor α inhibitors (TNF-I) in rheumatoid arthritis (RA) patients in clinical practice....

  16. Angiotensin converting enzyme and vascular endothelial growth factor responses to exercise training in claudicants: the role of ace inhibition

    Ng, P

    2009-01-01

    Exercise training is well recognised as an effective treatment for intermittent claudication. The mechanism underlying exercise induced improvements is multi-factorial but remains poorly understood. Low angiotensin-converting enzyme (ACE) activity has been associated with enhanced responses to endurance training. Specifically, low ACE activity has been associated with improved muscle metabolism, endothelial function, and suppressed inflammatory responses; processes linked with exercise traini...

  17. Treatment and management of myelofibrosis in the era of JAK inhibitors

    Keohane C

    2013-08-01

    Full Text Available Clodagh Keohane, Deepti H Radia, Claire N HarrisonDepartment of Haematology, Guy's and St Thomas' NHS Foundation Trust, London, UKAbstract: Myelofibrosis (MF can present as a primary disorder or evolve from polycythemia vera (PV or essential thrombocythemia (ET to post-PV MF or post-ET MF, respectively. MF is characterized by bone marrow fibrosis, splenomegaly, leukoerythroblastosis, extramedullary hematopoiesis, and a collection of debilitating symptoms. Until recently, the therapeutic options for patients with MF consisted of allogeneic hematopoietic stem cell transplant (alloHSCT, the use of cytoreductive agents (ie, hydroxyurea, splenectomy and splenic irradiation for treatment of splenomegaly, and management of anemia with transfusions, erythropoiesis-stimulating agents (ESAs, androgens, and immunomodulatory agents. However, with increased understanding of the pathogenesis of MF resulting from dysregulated Janus kinase (JAK signaling, new targeted JAK inhibitor therapies, such as ruxolitinib, are now available. The purpose of this article is to review the clinical features of MF, discuss the use and future of JAK inhibitors, reassess when and how to use conventional MF treatments in the context of JAK inhibitors, and provide a perspective on the future of MF treatment.Keywords: myelofibrosis, ruxolitinib, JAK inhibitor

  18. The Role of COX-2 Selective Inhibitors in the Treatment of Patients with Breast Cancer

    Kolyadina I.V.

    2011-03-01

    Full Text Available The possibility of COX-2 selective inhibitor use in the treatment of patients with malignancies has been considered. A group of COX-2 selective inhibitors has been presented with coxibs: celecoxib, NS-398, nimesulide, meloxicam. There has been demonstrated the role of the COX-2 blockers in risk decrease of four most common malignant tumors: breast cancer (by 71%, prostate cancer (by 55%, colon cancer (by 70% and lung cancer (by 79%. The role of COX-2 inhibitors in the prevention of developing resistance to chemotherapy in the breast cancer cells has been studied. There has been presented the data of the COX-2 inhibitors use as an antitumor treatment component in patients with a metastatic breast cancer in combinations with hormonal treatment in a hormone-positive breast cancer, as well as the results of neoadjuvant combined therapy in patients with a locally advanced cancer in a menopause. The findings presented are indicative of the expediency of the COX-positive tumor selection into a separate group for management optimization and the use of the possibilities of the enzyme expression target control.

  19. 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.

  20. Glucagon-like peptide receptor agonists and dipeptidyl peptidase-4 inhibitors in the treatment of diabetes

    Madsbad, Sten; Krarup, Thure; Deacon, Carolyn F;

    2008-01-01

    PURPOSE OF REVIEW: To discuss the virtues and shortcomings of the glucagon-like peptide-1 receptor agonists and the dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes. RECENT FINDINGS: The injectable glucagon-like peptide-1 receptor agonists exenatide significantly improves...... glycaemic control, with average reductions in haemoglobin A1c of about 1.0%, fasting plasma glucose of about 1.4 mmol/l, and causes a weight loss of approximately 2-3 kg after 30 weeks of treatment in patients with type 2 diabetes. The adverse effects are transient nausea and vomiting. The long...... weight neutral and without gastrointestinal side-effects. SUMMARY: The benefits and position of the glucagon-like peptide-1 analogues and the dipeptidyl peptidase-4 inhibitors in the diabetes treatment algorithm will be clarified when we have long-term trials with hard cardiovascular endpoints and data...

  1. Heat Shock Protein 90 and Role of Its Chemical Inhibitors in Treatment of Hematologic Malignancies

    Haojian Zhang

    2012-07-01

    Full Text Available Heat shock protein 90 (Hsp90 is a conserved and constitutively expressed molecular chaperone and it has been shown to stabilize oncoproteins and facilitate cancer development. Hsp90 has been considered as a therapeutic target for cancers and three classes of Hsp90 inhibitors have been developed: (1 benzoquinone ansamycin and its derivatives, (2 radicicol and its derivates, and (3 small synthetic inhibitors. The roles of these inhibitors in cancer treatment have been studied in laboratories and clinical trials, and some encouraging results have been obtained. Interestingly, targeting of Hsp90 has been shown to be effective in inhibition of cancer stem cells responsible for leukemia initiation and progression, providing a strategy for finding a cure. Because cancer stem cells are well defined in some human leukemias, we will focus on hematologic malignancies in this review.

  2. The Use of Plasma-Derived Complement C1-Esterase Inhibitor Concentrate (Berinert®) in the Treatment of Angiotensin Converting Enzyme-Inhibitor Related Angioedema

    Hermanrud, Thorbjørn; Duus, Nicolaj; Bygum, Anette; Rasmussen, Eva Rye

    2016-01-01

    concentrate is a well-established treatment option of hereditary and acquired complement C1-esterase inhibitor deficiency, which are also mediated by an increased level of bradykinin resulting in recurrent angioedema. We here present a case of severe angiotensin converting enzyme-inhibitor related angioedema......Angioedema of the upper airways is a severe and potentially life-threatening condition. The incidence has been increasing in the past two decades, primarily due to pharmaceuticals influencing the generation or degradation of the vasoactive molecule bradykinin. Plasma-derived C1-esterase inhibitor...

  3. Dipeptidyl peptidase inhibitors as new drugs for the treatment of type 2 diabetes.

    Mest, H-J; Mentlein, R

    2005-04-01

    Inhibitors of the regulatory protease dipeptidyl peptidase-IV (DPP-IV) are currently under development in preclinical and clinical studies (several pharmaceutical companies, now in Phase III) as potential drugs for the treatment of type 2 diabetes. Their development is based on the observation that DPP-IV rapidly inactivates the incretin hormone glucagon-like peptide-1 (GLP-1), which is released postprandially from the gut and increases insulin secretion. DPP-IV inhibitors stabilise endogenous GLP-1 at physiological concentrations, and induce insulin secretion in a glucose-dependent manner; therefore, they do not demonstrate any hypoglycaemic effects. Furthermore, they are orally bioavailable. In addition to their ability to protect GLP-1 against degradation, DPP-IV inhibitors also stabilise other incretins, including gastric inhibitory peptide and pituitary adenylate cyclase-activating peptide. They also reduce the antagonistic and desensitising effects of the fragments formed by truncation of the incretins. In clinical studies, when used for the treatment of diabetes over a 1-year period, DPP-IV inhibitors show improved efficacy over time. This finding can be explained by a GLP-1-induced increase in the number of beta cells. Potential risks associated with DPP-IV inhibitors include the prolongation of the action of other peptide hormones, neuropeptides and chemokines cleaved by the protease, and their interaction with DPP-IV-related proteases. Based on their mode of action, DPP-IV inhibitors seem to be of particular value in early forms of type 2 diabetes, either alone or in combination with other types of oral agents. PMID:15770466

  4. Vascular endothelial growth factor inhibitors: investigational therapies for the treatment of psoriasis

    Weidemann AK

    2013-09-01

    Full Text Available Anja K Weidemann,1 Ania A Crawshaw,2 Emily Byrne,3 Helen S Young1 1The Dermatology Centre, Salford Royal NHS Foundation Trust, The University of Manchester, Manchester, UK; 2Royal Sussex County Hospital, Brighton, UK; 3University Hospital of South Manchester, Manchester, UK Abstract: Psoriasis is a common inflammatory autoimmune condition in which environmental factors and genetic predisposition contribute to the development of disease in susceptible individuals. Angiogenesis is known to be a key pathogenic feature of psoriasis. Local and systemic elevation of vascular endothelial growth factor (VEGF-A has been demonstrated in the skin and plasma of patients with psoriasis and is known to correlate with improvement following some traditional psoriasis treatments. A number of VEGF inhibitors are licensed for the treatment of malignancies and eye disease and isolated case reports suggest that some individuals with psoriasis may improve when exposed to these agents. The small number of cases and lack of unified reporting measures makes it difficult to draw generalizations and underline the heterogeneity of psoriasis as a disease entity. Though not yet licensed for the treatment of psoriasis in humans, experimental data supports the potential of VEGF inhibitors to influence relevant aspects of human cell biology (such as endothelial cell differentiation and to improve animal models of skin disease. Given the multi-factorial nature of psoriasis it is unlikely that VEGF inhibitors will be effective in all patients, however they have the potential to be a valuable addition to the therapeutic arsenal in selected cases. Current VEGF inhibitors in clinical use are associated with a number of potentially serious side effects including hypertension, left ventricular dysfunction, and gastrointestinal perforation. Such risks require careful consideration in psoriasis populations particularly in light of growing concerns linking psoriasis to increased

  5. Strong topical steroid, NSAID, and carbonic anhydrase inhibitor cocktail for treatment of cystoid macular edema

    Asahi MG

    2015-12-01

    Full Text Available Masumi G Asahi, Gabriela L Bobarnac Dogaru, Spencer M Onishi, Ron P GallemoreRetina Macula Institute, Torrance, CA, USA Purpose: To report the combination cocktail of strong steroid, non-steroidal anti-inflammatory drug (NSAID, and carbonic anhydrase inhibitor drops for treatment of cystoid macular edema. Methods: This is a retrospective case series of patients with cystoid macular edema managed with a topical combination of strong steroid (difluprednate, NSAID, and carbonic anhydrase inhibitor drops. The patients were followed with optical coherence tomography and fluorescein angiography. Results: In our six cases, resolution of the cystic edema with improvement in visual acuity was achieved with the use of a combination cocktail of drops. Leakage on fluorescein angiography and cystic edema on optical coherence tomography both responded to treatment with the topical cocktail of drops. Conclusion: A topical cocktail of strong steroid, NSAID, and carbonic anhydrase inhibitor drops are effective for managing cystoid macular edema. Further studies comparing this combination with more invasive treatments should be undertaken to determine the efficacy of this cocktail over other treatment options. Keywords: birdshot chorioretinopathy, diabetic macular edema, retinal vein occlusion

  6. The Role of mTOR Inhibitors for the Treatment of B-Cell Lymphomas

    Pinelopi Argyriou

    2012-01-01

    Full Text Available Despite the fact that the majority of lymphomas initially respond to treatment, many patients relapse and die from disease that is refractory to current regimens. The need for new treatment strategies in lymphomas has led to the investigation and evaluation of novel agents that target cellular pathways. The mammalian target of rapamycin (mTOR is a representative pathway that may be implicated in lymphomagenesis. Rapamycin and especially its derivatives (temsirolimus, everolimus, and deforolimus represent the first described mTOR inhibitors. These agents have shown promising results in the treatment of lymphoid malignancies. On the other hand, new ATP-competitive mTOR inhibitors that provoke a broader inhibition of mTOR activity are in early stages of clinical development. The purpose of this paper is to summarize the existing knowledge about mTOR inhibitors and their use in the treatment of B-cell lymphomas. Relevant issues regarding mTOR biology in general as well as in B-cell lymphoid neoplasms are also discussed in short.

  7. 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

  8. 5alpha-Reductase inhibitor treatment of prostatic diseases: background and practical implications.

    Dörsam, J; Altwein, J

    2009-01-01

    This literature review discusses the theoretical background of 5alpha-reductase inhibitor (5ARI) treatment and the resulting clinical implications. A Medline-based search for peer-reviewed articles addressing 5ARIs, benign prostatic hyperplasia and prostate cancer was performed. The 5ARIs Finasteride and Dutasteride, which specifically inhibit the production of dihydrotestosterone by acting as competitive inhibitors of 5alpha-reductase, are clinically well tolerated and represent an effective treatment option for benign prostatic obstruction. Finasteride is the first compound which has a proven efficacy in chemoprevention of prostate cancer. The aim of this review was to elucidate, if there are sufficient data available to point out clinically relevant differences between the drugs. Both compounds achieve a significant reduction of prostate volume, an improvement of symptoms and a lower risk of acute urinary retention. Whether the different pharmacokinetic and pharmacodynamic properties of Finasteride and Dutasteride are of clinical importance cannot be judged at this time. PMID:19030020

  9. What Is the Place of PARP Inhibitors in Ovarian Cancer Treatment?

    Liu, Joyce F; Matulonis, Ursula A

    2016-05-01

    Poly-ADP-ribose polymerase (PARP) inhibitors have been one of the most exciting developments in the treatment of ovarian cancer in recent years. Demonstration of anti-cancer activity has led to the European Medicines Agency (EMA) approval of the PARP inhibitor (PARPi) olaparib as maintenance therapy in women with BRCA-mutated (BRCAm) ovarian cancer with platinum-sensitive recurrence following response to platinum therapy and the US Food and Drug Administration (US FDA) approval of olaparib in relapsed germline BRCA-mutated (gBRCAm) ovarian cancer in women who have received at least three prior chemotherapy treatments, both occurring in 2014. Additional trials are underway or awaiting final analysis with olaparib, other PARPis, and PARPi combinations to further elucidate the activity of these drugs in various clinical settings. This review will focus on the current clinical experience and ongoing trials with PARPis in ovarian cancer. PMID:26984416

  10. Need for streamlined use of DPP-4 inhibitors in the treatment of type 2 diabetes

    Vitale, Cristiana; Rosano, Giuseppe M. C.; Prasad, Krishna

    2016-01-01

    Regulatory agencies request an assessment of cardiovascular safety for all “new” oral anti-diabetic drugs in order to avoid possible negative effects on cardiovascular events. Dipeptidyl peptidase 4 inhibitors have emerged as a new therapeutic alternative for the treatment of type 2 diabetes mellitus, but the several large post-marketing clinical trials have shown only a modest effect in glycaemic control and, more importantly, a neutral effect on total and cardiovascular events. Conversely a...

  11. Bioimpedance in monitoring of effects of selective serotonin reuptake inhibitor treatment

    Maarek, Albert

    2011-01-01

    Vasiliy Grigorievich Alexeev, Ludmila Vasilievna KuznecovaDepartment of Physiology, SP Botkin Moscow City Clinical Hospital, Moscow, RussiaBackground: Bioimpedance has been shown to be a safe technique when used in a number of biomedical applications. In this study, we used the Electro Interstitial Scan (EIS) to perform bioimpedance measurements to follow up the efficacy of selective serotonin reuptake inhibitor (SSRI) treatment in subjects diagnosed to have major depressive disorder.Methods:...

  12. The Use of Plasma-Derived Complement C1-Esterase Inhibitor Concentrate (Berinert®) in the Treatment of Angiotensin Converting Enzyme-Inhibitor Related Angioedema.

    Hermanrud, Thorbjørn; Duus, Nicolaj; Bygum, Anette; Rasmussen, Eva Rye

    2016-01-01

    Angioedema of the upper airways is a severe and potentially life-threatening condition. The incidence has been increasing in the past two decades, primarily due to pharmaceuticals influencing the generation or degradation of the vasoactive molecule bradykinin. Plasma-derived C1-esterase inhibitor concentrate is a well-established treatment option of hereditary and acquired complement C1-esterase inhibitor deficiency, which are also mediated by an increased level of bradykinin resulting in recurrent angioedema. We here present a case of severe angiotensin converting enzyme-inhibitor related angioedema (ACEi-AE) of the hypopharynx that completely resolved rapidly after the infusion of plasma-derived C1-inhibitor concentrate adding to the sparse reports in the existing literature. PMID:27123347

  13. The Use of Plasma-Derived Complement C1-Esterase Inhibitor Concentrate (Berinert®) in the Treatment of Angiotensin Converting Enzyme-Inhibitor Related Angioedema

    Hermanrud, Thorbjørn; Duus, Nicolaj; Bygum, Anette; Rasmussen, Eva Rye

    2016-01-01

    Angioedema of the upper airways is a severe and potentially life-threatening condition. The incidence has been increasing in the past two decades, primarily due to pharmaceuticals influencing the generation or degradation of the vasoactive molecule bradykinin. Plasma-derived C1-esterase inhibitor concentrate is a well-established treatment option of hereditary and acquired complement C1-esterase inhibitor deficiency, which are also mediated by an increased level of bradykinin resulting in recurrent angioedema. We here present a case of severe angiotensin converting enzyme-inhibitor related angioedema (ACEi-AE) of the hypopharynx that completely resolved rapidly after the infusion of plasma-derived C1-inhibitor concentrate adding to the sparse reports in the existing literature. PMID:27123347

  14. 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

  15. Nonnucleoside Reverse-transcriptase Inhibitor- vs Ritonavir-boosted Protease Inhibitor-based Regimens for Initial Treatment of HIV Infection

    Borges, Álvaro H; Lundh, Andreas; Tendal, Britta;

    2016-01-01

    BACKGROUND:  Previous studies suggest that nonnucleoside reverse-transcriptase inhibitors (NNRTIs) cause faster virologic suppression, while ritonavir-boosted protease inhibitors (PI/r) recover more CD4 cells. However, individual trials have not been powered to compare clinical outcomes. METHODS...

  16. 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.

  17. HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond.

    Maxwell, Patrick H; Eckardt, Kai-Uwe

    2016-03-01

    Small-molecule stabilizers of hypoxia inducible factor (HIF) are being developed for the treatment of renal anaemia. These molecules inhibit prolyl hydroxylase domain-containing (PHD) enzymes, resulting in HIF activation and increased production of erythropoietin. Currently, renal anaemia is treated with recombinant human erythropoietin or related analogues, referred to as conventional erythropoiesis stimulating agents (ESAs). Advantages of PHD enzyme inhibitors over conventional ESAs include their oral administration and their simpler - and potentially cheaper - production. Importantly, inhibition of PHD enzymes is likely to have a range of consequences other than increasing levels of erythropoietin, and these effects could be beneficial - for instance by reducing the need for parenteral iron - but might in some instances be harmful. Several companies are currently testing PHD enzyme inhibitors in patients with renal anaemia and have reported clear evidence of efficacy without serious safety concerns. A central question that current studies are beginning to address is whether using PHD enzyme inhibitors will influence hard end points, including mortality and the rate of cardiovascular events. In terms of approaches to therapy, the exquisite specificity of conventional ESAs is a striking contrast to the pleiotropic effects of activating HIF. Excitingly, PHD inhibitors could also be useful for conditions besides renal anaemia, such as protection from ischaemic injury. PMID:26656456

  18. Ecallantide is a novel treatment for attacks of hereditary angioedema due to C1 inhibitor deficiency

    Farkas H

    2011-05-01

    Full Text Available Henriette Farkas, Lilian Varga3rd Department of Internal Medicine, Semmelweis University, Budapest, HungaryAbstract: Hereditary angioedema (HAE resulting from the deficiency of the C1 inhibitor protein is a rare disease, characterized by paroxysms of edema formation in the subcutis and in the submucosa. Edema can cause obstruction of the upper airway, which may lead to suffocation. Prompt elimination of edema is necessary to save patients from this life-threatening condition. Essentially, these edematous attacks are related to the activation of the kinin-kallikrein system and the consequent release of bradykinin. Ecallantide (known as DX-88 previously, a potent and specific inhibitor of plasma kallikrein is an innovative medicinal product. This is the only agent approved recently by the FDA for all localizations of edematous HAE attacks. Its advantages include no risk of viral contamination, high selectivity, very rapid onset of action, good tolerability, and straightforward subcutaneous administration. Owing to the risk of anaphylaxis, ecallantide should be administered by a health care professional. A postmarketing survey to improve risk-assessment and risk-minimization has been launched. The results of these studies may lead to the approval of ecallantide for self-administration.Keywords: hereditary angioedema, C1-inhibitor deficiency, treatment, bradykinin, kallikrein inhibitor, subcutaneous administration

  19. 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.

  20. Review of integrase strand transfer inhibitors for the treatment of human immunodeficiency virus infection.

    Park, Tae Eun; Mohamed, Abdilahi; Kalabalik, Julie; Sharma, Roopali

    2015-10-01

    Integrase strand transfer inhibitors (INSTIs) are oral antiretroviral agents used against HIV infection. There are three agents available, including raltegravir, elvitegravir and dolutegravir, some of which are available as combination medications with other antiretroviral drugs. The efficacy and safety of INSTIs in treatment-naïve and experienced HIV-infected patients have been established by multiple studies. Based on the current practice guidelines, INSTI-based regimens are considered as one of the first-line therapies for treatment-naïve HIV-infected patients. There are new INSTIs in development to improve the resistance profile and to decrease the frequency of drug administration. PMID:26293294

  1. Irreversible LSD1 Inhibitors: Application of Tranylcypromine and Its Derivatives in Cancer Treatment.

    Zheng, Yi C; Yu, Bin; Jiang, Guo Z; Feng, Xue J; He, Peng X; Chu, Xiao Y; Zhao, Wen; Liu, Hong M

    2016-01-01

    Due to the increasing costs and time consuming for new drug discovery, a large number of pharmaceutical firms have chosen to modify the existing drug molecules for repositioning candidates with new or improved properties, especially those with severe adverse effects, thereby accelerating the drug discovery process. Such strategy has witnessed its success with several examples reported. As the first identified histone lysine specific demethylase, lysine specific demethylase 1 (LSD1) is classified as a member of monoamine oxidase (MAO) superfamily, and specifically removes mono- and dimethylated histone 3 lysine 4 (H3K4) and H3 lysine 9 (H3K9). It has been reported that LSD1 and its downstream targets are involved in cancer cell growth and metastasis. Meanwhile, it is overexpressed in a variety of tumor cells. Inactivating LSD1 specifically inhibits tumor progression and metastasis. Hence, LSD1 inhibition may represent a new and promising direction in anti-cancer drug discovery. Based on the structure and cofactor of LSD1, some clinical applied MAO inhibitors have been identified as LSD1 inactivators. Among them, tranylcypromine presented the most potency against LSD1 and its derivatives were further developed by medicinal chemists in order to develop potent and selective LSD1 inhibitors. Currently, a number of tranylcypromine based LSD1 inhibitors have been developed and two of them, ORY-1001 and GSK2879552, are in clinical trials for cancer treatment. This review highlights recent advances in the repurposing of tranylcypromine and its derivatives as irreversible LSD1 inhibitors for cancer treatment, which are conventionally used for the treatment of depression. PMID:26881714

  2. Ecallantide: a plasma kallikrein inhibitor for the treatment of acute attacks of hereditary angioedema.

    Stolz, L E; Horn, P T

    2010-08-01

    Hereditary angioedema (HAE) is a debilitating, potentially fatal disease characterized by variable and unpredictable acute attacks of swelling affecting the subcutaneous tissue and mucosa. It is an autosomal dominant disorder resulting from a genetic deficiency of functional C1-esterase inhibitor. Available treatments include long-term prophylaxis, short-term prophylaxis and treatment of acute attacks. Ecallantide is a novel, specific and potent inhibitor of plasma kallikrein that was recently approved in the United States for the treatment of acute attacks of HAE in patients aged 16 years and older. In two phase III clinical trials, the subcutaneous administration of 30 mg ecallantide resulted in significantly greater symptom improvement than placebo for acute attacks of HAE. Ecallantide was generally well tolerated throughout the clinical development program. The main safety concern following ecallantide treatment is hypersensitivity reactions, including anaphylaxis. A Risk Evaluation and Management Strategy (REMS) has been implemented to minimize this risk and a long-term observational safety study is currently under way to collect more information about hypersensitivity and immunogenicity. Ecallantide represents a novel treatment option for patients with HAE. PMID:20830315

  3. 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.

  4. A new trend in pathogenetic treatment of rheumatoid arthritis: tofacitinib, the first inhibitor of Janus kinase

    Dmitry Evgenyevich Karateev

    2014-01-01

    Full Text Available The Problem of effective treatment of rheumatoid arthritis (RA has not been solved yet. In patients with an inadequate response to the synthetic disease-modifying antirheumatic drugs (DMARDs, TNF inhibitors and other genetically engineered (GE drugs may give an incomplete effect or be totally ineffective in 20–40% of cases. The search for new therapeutic options is very active in many directions, including modulation of intracellular signaling pathways. The most impressive clinical results in RA patients have been achieved for Janus kinase (JAK inhibitor, tofacitinib, – Tofa (CP-690,550, a low molecular weight drug for oral administration. Unlike the conventional synthetic DMARD, Tofa belongs to targeted therapy drugs; its pharmacological effects largely resemble those of GE drugs (blockade of the biological effects of cytokines. In particular, some features of its mechanism of action (e.g., interleukin 6 inhibition make it similar to tocilizumab. In all trials, Tofa proved to exhibit high clinical efficacy and satisfactory safety. Tofa was shown to be significantly more effective than methotrexate and placebo (in monotherapy, as well as in combination with DMARDs in RA patients with an inadequate response to standard DMARDs and TNFa inhibitors (regarding response to treatment, individual parameters of disease activity, achievement of low disease activity and remission, functional impairment. Furthermore, Tofa can inhibit joint damage progression.

  5. Tyrosine Kinase Inhibitors Induced Thyroid Dysfunction: A Review of Its Incidence, Pathophysiology, Clinical Relevance, and Treatment

    Hala Ahmadieh

    2013-01-01

    Full Text Available Tyrosine kinase inhibitors (TKI belong to a new class of molecular multitargeted anticancer therapy which targets different growth factor receptors and hence attenuates cancer cell survival and growth. Since their introduction as adjunct treatment for renal cell carcinoma and gastrointestinal stromal tumors (GIST, a number of reports have demonstrated that TKI can induce thyroid dysfunction which was especially more common with sunitinib maleate. Many mechanisms with respect to this adverse effect of tyrosine kinase inhibitors have been proposed including their induction of thyroiditis, capillary regression in the thyroid gland, antithyroid peroxidase antibody production, and their ability to decrease iodine uptake by the thyroid gland. Of interest is the observation that TKI-induced thyroid dysfunction may actually be protective as it was shown to improve overall survival, and it was suggested that it may have a prognostic value. Followup on thyroid function tests while patients are maintained on tyrosine kinase inhibitor is strongly recommended. When thyroid dysfunction occurs, appropriate treatment should be individualized depending on patients symptoms and thyroid stimulating hormone level.

  6. Topical calcineurin inhibitors in the treatment of atopic dermatitis - an update on safety issues.

    Czarnecka-Operacz, Magdalena; Jenerowicz, Dorota

    2012-03-01

    Atopic dermatitis is a common chronic skin disorder whose management is complex. Topical corticosteroids have been the mainstay of atopic dermatitis treatment for more than 50 years but have multiple side effects. Topical calcineurin inhibitors including tacrolimus and pimecrolimus are safe and efficacious in atopic dermatitis. In 2005 the FDA issued "black box" warnings for pimecrolimus cream and tacrolimus ointment because of potential safety risks, including skin cancers and lymphomas. However, these concerns are not supported by current data. Topical calcineurin inhibitors are particularly indicated for treating patients with atopic dermatitis in whom topical corticosteroid therapy cannot be employed or may cause irreversible side effects. They can be used advantageously in problem zones. A novel regimen of proactive treatment has been shown to prevent, delay and reduce exacerbations of atopic dermatitis. Therapy with topical calcineurin inhibitors should be managed by an experienced specialist and each patient should receive proper education on how to use them and what possible unwanted effects may be expected. PMID:21974750

  7. 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.

  8. 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.

  9. Evaluation of candidate biomarkers to predict cancer cell sensitivity or resistance to PARP-1 inhibitor treatment

    Oplustilova, L.; Wolanin, K.; Bartkova, J.;

    2012-01-01

    (ADp-ribose) polymerase-1 (PARP-1), an enzyme critical for repair pathways alternative to HR. While promising, treatment with PARP-1 inhibitors (PARP-1i) faces some hurdles, including (1) acquired resistance, (2) search for other sensitizing, non-BRCA1/2 cancer defects and (3) lack of biomarkers to predict response......Impaired DNA damage response pathways may create vulnerabilities of cancer cells that can be exploited therapeutically. One such selective vulnerability is the sensitivity of BRCA1- or BRCA2-defective tumors (hence defective in DNA repair by homologous recombination, HR) to inhibitors of the poly...... to PARP-1i. Here we addressed these issues using PARP-1i on 20 human cell lines from carcinomas of the breast, prostate, colon, pancreas and ovary. Aberrations of the Mre11-Rad50-Nbs1 (MRN) complex sensitized cancer cells to PARP-1i, while p53 status was less predictive, even in response to PARP-1i...

  10. Discovery of the ROCK inhibitor netarsudil for the treatment of open-angle glaucoma.

    Sturdivant, Jill M; Royalty, Susan M; Lin, Cheng-Wen; Moore, Lori A; Yingling, Jeffrey D; Laethem, Carmen L; Sherman, Bryan; Heintzelman, Geoffrey R; Kopczynski, Casey C; deLong, Mitchell A

    2016-05-15

    Inhibition of Rho kinase (ROCK) to improve fluid outflow through the trabecular meshwork and lower intraocular pressure is a strategy for the development of new anti-glaucoma agents. Alpha-aryl-beta-amino isoquinoline analogs were identified as potent ROCK inhibitors. Compounds that provided a longer duration of intraocular pressure reduction in Dutch Belted rabbits also inhibited norepinephrine transporter. Ester 60 improved bioavailability of its parent ROCK inhibitor, 29 (Ki=0.2nM) and demonstrated an effective and sustained IOP reduction for 24h after dosing. From these studies, netarsudil (a.k.a. AR-13324) was discovered and is currently in clinical trials for the treatment of glaucoma and ocular hypertension. PMID:27072905

  11. Expanding horizons in the treatment of mantle cell lymphoma: Ibrutinib a novel BTK-targeting inhibitor

    Sameer Dhingra

    2014-02-01

    Full Text Available Mantle cell lymphoma (MCL is a non-Hodgkin lymphoma characterized by involvement of the lymph nodes, spleen, blood, and bone marrow with short remission duration to standard therapies and a median overall survival of 4–5 years. Small molecule inhibitors targeting dysregulated pathways (MAPK/ERK, PI3K/PKB/mTOR, JAK/STAT have significantly improved clinical outcomes in cancer patients. Recently Bruton’s tyrosine kinase (BTK, a crucial terminal kinase enzyme in the B-cell antigen receptor (BCR signaling pathway, has emerged as an attractive target for therapeutic intervention in human malignancies and autoimmune disorders. Ibrutinib, a novel first-in-human BTK-inhibitor, has demonstrated clinical effectiveness and tolerability in clinical trials, recently been approved by FDA in the treatment of MCL. [Int J Basic Clin Pharmacol 2014; 3(1.000: 249-254

  12. 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...

  13. A multi-center, double-blind, randomized, parallel group study to evaluate the effects of two different doses of losartan on morbidity and mortality in Chinese patients with symptomatic heart failure intolerant of angiotensin converting enzyme inhibitor t%A multi-center, double-blind, randomized, parallel group study to evaluate the effects of two different doses of losartan on morbidity and mortality in Chinese patients with symptomatic heart failure intolerant of angiotensin converting enzyme inhibitor treatment

    HU Da-yi; HUANG Jun; CAI Nai-sheng; ZHU Wen-ling; LI Yi-shi; Rachid Massaad; Mary E.Hanson; Kenneth Dickstein

    2012-01-01

    Background There have been no mortality/morbidity endpoint studies with losartan in Chinese heart failure patients.The objective was to evaluate the effects of high-dose vs.low-dose losartan on clinical outcomes in Chinese subjects with heart failure.Methods This study was a post hoc analysis of the Heart failure Endpoint evaluation of Angiotensin Ⅱ Antagonist losartan (HEAAL)trial (n=545).Chinese adults with symptomatic heart failure (New York Heart Association (NYHA) Ⅱ-Ⅳ)intolerant of treatment with angiotensin converting enzyme (ACE) inhibitors were randomized to losartan 150 mg or 50 mg daily.The primary endpoint was the composite event rate of all-cause death or hospitalization for heart failure.Safety and tolerability were assessed.Results Median follow-up was 4.8 years.Baseline characteristics were generally similar to the overall HEAAL cohort.Overall,120 (44.1%) subjects in the losartan 150 mg group and 137 (50.2%) subjects in the losartan 50 mg group died (any cause) or were hospitalized for heart failure (hazard ratio (OR) 0.807,95% CI0.631-1.031).There were no notable differences between treatment groups in the proportion of subjects with adverse experiences.Conclusion The results of this post hoc analysis in Chinese subjects,although not powered to show significance,were generally consistent with the main study results,which demonstrated a significantly reduced risk of all cause death or hospitalization for heart failure with daily losartan 150 mg vs.losartan 50 mg in subjects with symptomatic heart failure and intolerance to ACE inhibitors,supporting the use of the higher dose for optimum clinical benefit.

  14. Effect of the angiotensin-converting enzyme inhibitor trandolapril on mortality and morbidity in diabetic patients with left ventricular dysfunction after acute myocardial infarction. Trace Study Group

    Gustafsson, I; Torp-Pedersen, C; Køber, L;

    1999-01-01

    OBJECTIVES: This study evaluated the efficacy of long-term treatment with the angiotensin-converting enzyme (ACE) inhibitor trandolapril in diabetic patients with left ventricular dysfunction after acute myocardial infarction (AMI). BACKGROUND: Patients with diabetes mellitus have a high mortality...... following AMI, probably due to a high risk of congestive heart failure and reinfarction. Because ACE inhibition effectively reduces progression of heart failure, it could be particularly beneficial in diabetic patients after AMI. METHODS: The study is a retrospective analysis using data from.......21 to 0.67]), and no significant reduction of this end point was found in the nondiabetic group. CONCLUSIONS: The ACE inhibition after myocardial infarction complicated by left ventricular dysfunction appears to be of considerable importance in patients with diabetes mellitus by saving lives...

  15. 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....

  16. Therapeutic treatment with a novel hypoxia-inducible factor hydroxylase inhibitor (TRC160334 ameliorates murine colitis

    Gupta R

    2014-01-01

    Full Text Available Ram Gupta,1 Anita R Chaudhary,2 Binita N Shah,1 Avinash V Jadhav,3 Shitalkumar P Zambad,1 Ramesh Chandra Gupta,4 Shailesh Deshpande,4 Vijay Chauthaiwale,4 Chaitanya Dutt4 1Department of Pharmacology, 2Cellular and Molecular Biology, 3Preclinical Safety Evaluation, 4Discovery, Torrent Research Centre, Torrent Pharmaceuticals Ltd, Gandhinagar, Gujarat, India Background and aim: Mucosal healing in inflammatory bowel disease (IBD can be achieved by improvement of intestinal barrier protection. Activation of hypoxia-inducible factor (HIF has been identified as a critical factor for barrier protection during mucosal insult and is linked with improvement in symptoms of colitis. Although prophylactic efficacy of HIF hydroxylase inhibitors in murine colitis have been established, its therapeutic efficacy in clinically relevant therapeutic settings have not been established. In the present study we aim to establish therapeutic efficacy of TRC160334, a novel HIF hydroxylase inhibitor, in animal models of colitis. Methods: The efficacy of TRC160334 was evaluated in two different mouse models of colitis by oral route. A prophylactic efficacy study was performed in a 2,4,6-trinitrobenzene sulfonic acid-induced mouse model of colitis representing human Crohn's disease pathology. Additionally, a therapeutic efficacy study was performed in a dextran sulfate sodium-induced mouse model of colitis, a model simulating human ulcerative colitis. Results: TRC160334 treatment resulted in significant improvement in disease end points in both models of colitis. TRC160334 treatment resulted into cytoprotective heatshock protein 70 induction in inflamed colon. TRC160334 successfully attenuated the rate of fall in body weight, disease activity index, and macroscopic and microscopic scores of colonic damage leading to overall improvement in study outcome. Conclusion: Our findings are the first to demonstrate that therapeutic intervention with a HIF hydroxylase inhibitor

  17. A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria.

    Phillips, Margaret A; Lotharius, Julie; Marsh, Kennan; White, John; Dayan, Anthony; White, Karen L; Njoroge, Jacqueline W; El Mazouni, Farah; Lao, Yanbin; Kokkonda, Sreekanth; Tomchick, Diana R; Deng, Xiaoyi; Laird, Trevor; Bhatia, Sangeeta N; March, Sandra; Ng, Caroline L; Fidock, David A; Wittlin, Sergio; Lafuente-Monasterio, Maria; Benito, Francisco Javier Gamo; Alonso, Laura Maria Sanz; Martinez, Maria Santos; Jimenez-Diaz, Maria Belen; Bazaga, Santiago Ferrer; Angulo-Barturen, Iñigo; Haselden, John N; Louttit, James; Cui, Yi; Sridhar, Arun; Zeeman, Anna-Marie; Kocken, Clemens; Sauerwein, Robert; Dechering, Koen; Avery, Vicky M; Duffy, Sandra; Delves, Michael; Sinden, Robert; Ruecker, Andrea; Wickham, Kristina S; Rochford, Rosemary; Gahagen, Janet; Iyer, Lalitha; Riccio, Ed; Mirsalis, Jon; Bathhurst, Ian; Rueckle, Thomas; Ding, Xavier; Campo, Brice; Leroy, Didier; Rogers, M John; Rathod, Pradipsinh K; Burrows, Jeremy N; Charman, Susan A

    2015-07-15

    Malaria is one of the most significant causes of childhood mortality, but disease control efforts are threatened by resistance of the Plasmodium parasite to current therapies. Continued progress in combating malaria requires development of new, easy to administer drug combinations with broad-ranging activity against all manifestations of the disease. DSM265, a triazolopyrimidine-based inhibitor of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH), is the first DHODH inhibitor to reach clinical development for treatment of malaria. We describe studies profiling the biological activity, pharmacological and pharmacokinetic properties, and safety of DSM265, which supported its advancement to human trials. DSM265 is highly selective toward DHODH of the malaria parasite Plasmodium, efficacious against both blood and liver stages of P. falciparum, and active against drug-resistant parasite isolates. Favorable pharmacokinetic properties of DSM265 are predicted to provide therapeutic concentrations for more than 8 days after a single oral dose in the range of 200 to 400 mg. DSM265 was well tolerated in repeat-dose and cardiovascular safety studies in mice and dogs, was not mutagenic, and was inactive against panels of human enzymes/receptors. The excellent safety profile, blood- and liver-stage activity, and predicted long half-life in humans position DSM265 as a new potential drug combination partner for either single-dose treatment or once-weekly chemoprevention. DSM265 has advantages over current treatment options that are dosed daily or are inactive against the parasite liver stage. PMID:26180101

  18. In Silico Screening Identifies a Novel Potential PARP1 Inhibitor Targeting Synthetic Lethality in Cancer Treatment.

    Li, Jian; Zhou, Nan; Cai, Peiling; Bao, Jinku

    2016-01-01

    Synthetic lethality describes situations in which defects in two different genes or pathways together result in cell death. This concept has been applied to drug development for cancer treatment, as represented by Poly (ADP-ribose) polymerase (PARPs) inhibitors. In the current study, we performed a computational screening to discover new PARP inhibitors. Among the 11,247 compounds analyzed, one natural product, ZINC67913374, stood out by its superior performance in the simulation analyses. Compared with the FDA approved PARP1 inhibitor, olaparib, our results demonstrated that the ZINC67913374 compound achieved a better grid score (-86.8) and amber score (-51.42). Molecular dynamics simulations suggested that the PARP1-ZINC67913374 complex was more stable than olaparib. The binding free energy for ZINC67913374 was -177.28 kJ/mol while that of olaparib was -159.16 kJ/mol. These results indicated ZINC67913374 bound to PARP1 with a higher affinity, which suggest ZINC67913374 has promising potential for cancer drug development. PMID:26907257

  19. In Silico Screening Identifies a Novel Potential PARP1 Inhibitor Targeting Synthetic Lethality in Cancer Treatment

    Jian Li

    2016-02-01

    Full Text Available Synthetic lethality describes situations in which defects in two different genes or pathways together result in cell death. This concept has been applied to drug development for cancer treatment, as represented by Poly (ADP-ribose polymerase (PARPs inhibitors. In the current study, we performed a computational screening to discover new PARP inhibitors. Among the 11,247 compounds analyzed, one natural product, ZINC67913374, stood out by its superior performance in the simulation analyses. Compared with the FDA approved PARP1 inhibitor, olaparib, our results demonstrated that the ZINC67913374 compound achieved a better grid score (−86.8 and amber score (−51.42. Molecular dynamics simulations suggested that the PARP1-ZINC67913374 complex was more stable than olaparib. The binding free energy for ZINC67913374 was −177.28 kJ/mol while that of olaparib was −159.16 kJ/mol. These results indicated ZINC67913374 bound to PARP1 with a higher affinity, which suggest ZINC67913374 has promising potential for cancer drug development.

  20. Association of Angiotensin-Converting Enzyme (ACE Gene Polymorphism with Inflammation and Cellular Cytotoxicity in Vitiligo Patients.

    Laila Rashed

    Full Text Available Vitiligo is a disorder with profound heterogeneity in its aetio-pathophysiology. Angiotensin converting enzyme (ACE plays an important role in the physiology of the vasculature, blood pressure and inflammation. An insertion/deletion (I/D polymorphism of the ACE gene was reported be associated with the development of vitiligo.Our aim was to evaluate the ACE I/D polymorphism in vitiligo patients and controls. Our second aim was to find a possible association between ACE gene polymorphism and inflammatory mediators (as interleukin (IL-6 and/or cellular cytotoxicity induced by serum nitrite (as a breakdown product of the cytotoxic nitric oxide in vitiligo patients.This case-control study included 74 vitiligo patients and 75 apparently healthy controls. The distribution of ACE gene I/D genotype was investigated using PCR. Serum ACE, IL-6 and nitrite were measured by colorimetric method, ELISA and Griess assay respectively.The ACE allele frequency was significantly different between vitiligo patients and healthy controls (P = 0.026. However there was no significant difference between the ACE genotyping frequency in both groups (P = 0.115. There were statistically significant higher VIDA score (P = 0.007, and serum IL-6 (P < 0.001 in patients with the DD genotype when compared to other genotypes. Serum nitrite in patients with the DD genotype was significantly higher (P = 0.007 when compared to patients with II genotype. Serum levels of ACE, IL-6 and nitrite in vitiligo patients were statistically significantly higher than those in controls.As a conclusion, ACE gene polymorphism might grant susceptibility to develop vitiligo. Serum IL-6 and nitrite levels might have an important role in the pathogenesis of vitiligo. Targeting these two factors might have an implication in the treatment of some resistant cases.

  1. Mesenchymal stem cells are sensitive to treatment with kinase inhibitors and ionizing radiation

    Nicolay, Nils H.; Debus, Juergen; Huber, Peter E. [Heidelberg University Hospital, Department of Radiation Oncology, Heidelberg (Germany); German Cancer Research Center (dkfz), Department of Molecular and Radiation Oncology, Heidelberg (Germany); Sommer, Eva; Lopez Perez, Ramon; Wirkner, Ute [German Cancer Research Center (dkfz), Department of Molecular and Radiation Oncology, Heidelberg (Germany); Bostel, Tilman [Heidelberg University Hospital, Department of Radiation Oncology, Heidelberg (Germany); Ho, Anthony D.; Saffrich, Rainer [Heidelberg University Hospital, Department of Hematology, Oncology and Rheumatology, Heidelberg (Germany); Lahn, Michael [Lilly Research Laboratories, Oncology Early Clinical Investigation, Indianapolis, IN (United States)

    2014-11-15

    Mesenchymal stem cells (MSCs) can regenerate damaged tissues and may therefore be of importance for normal tissue repair after cancer treatment. Small molecule receptor kinase inhibitors (RKIs) have recently been introduced into cancer treatment. However, the influence of these drugs - particularly in combination with radiotherapy - on the survival of MSCs is largely unknown. The sensitivity of human primary MSCs from healthy volunteers and primary human fibroblast cells to small molecule kinase inhibitors of the vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and transforming growth factor β (TGFβ) receptors, as well to inhibitors of c-Kit, was examined in combination with ionizing radiation (IR); cell survival and proliferation were assessed. Expression patterns of different kinase receptors and ligands were investigated using gene arrays. MSCs were highly sensitive to the tyrosine kinase inhibitors SU14816 (imatinib) and SU11657 (sunitinib), but showed only moderate sensitivity to the selective TGFβ receptor 1 inhibitor LY2109761. Primary adult human fibroblasts were comparably resistant to all three inhibitors. The addition of IR had an additive or supra-additive effect in the MSCs, but this was not the case for differentiated fibroblasts. Proliferation was markedly reduced in MSCs following kinase inhibition, both with and without IR. Gene expression analysis revealed high levels of the PDGF α and β receptors, and lower levels of the TGFβ receptor 2 and Abl kinase. IR did not alter the expression of kinase receptors or their respective ligands in either MSCs or adult fibroblasts. These data show that MSCs are highly sensitive to RKIs and combination treatments incorporating IR. Expression analyses suggest that high levels of PDGF receptors may contribute to this effect. (orig.) [German] Mesenchymale Stammzellen (MSCs) koennen die Geweberegeneration unterstuetzen und haben daher moeglicherweise eine Rolle bei der Reparatur

  2. DPP-4 inhibitor des-F-sitagliptin treatment increased insulin exocytosis from db/db mice β cells

    Highlights: → Anti-diabetic new drug, DPP-4 inhibitor, can affect the insulin exocytosis. → DPP-4 inhibitor treatment altered syntaxin 1 expression. → Treatment of db/db mice with DPP-4 inhibitor increased insulin release. -- Abstract: Incretin promotes insulin secretion acutely. Recently, orally-administered DPP-4 inhibitors represent a new class of anti-hyperglycemic agents. Indeed, inhibitors of dipeptidyl peptidase-IV (DPP-4), sitagliptin, has just begun to be widely used as therapeutics for type 2 diabetes. However, the effects of sitagliptin-treatment on insulin exocytosis from single β-cells are yet unknown. We therefore investigated how sitagliptin-treatment in db/db mice affects insulin exocytosis by treating db/db mice with des-F-sitagliptin for 2 weeks. Perfusion studies showed that 2 weeks-sitagliptin treatment potentiated insulin secretion. We then analyzed insulin granule motion and SNARE protein, syntaxin 1, by TIRF imaging system. TIRF imaging of insulin exocytosis showed the increased number of docked insulin granules and increased fusion events from them during first-phase release. In accord with insulin exocytosis data, des-F-sitagliptin-treatment increased the number of syntaxin 1 clusters on the plasma membrane. Thus, our data demonstrated that 2-weeks des-F-sitagliptin-treatment increased the fusion events of insulin granules, probably via increased number of docked insulin granules and that of syntaxin 1 clusters.

  3. ace-3 plays an important role in phoxim resistance in Caenorhabditis elegans.

    Han, Yan; Song, Shaojuan; Guo, Yaping; Zhang, Jianzhen; Ma, Enbo

    2016-05-01

    Organophosphorus and carbamate are widely used in agricultural production. Caenorhabditis elegans is a model organism that is widely used in various toxicology studies. To understand the effects of two types of commonly used pesticides, phoxim (organophosphorus) and carbaryl (carbamate), we determined the activities of acetylcholinesterases (AChEs) and detected the expression of four ace genes by RT-qPCR in C. elegans following treatment with these pesticides. The results showed that phoxim and carbaryl could reduce acetylcholinesterase activities and up-regulate the ace-3 mRNA expression levels. We also detected the toxic effects of these pesticides on the ace-3 deletion mutant dc-2, and found that some characteristics, including LC50, development, movement, reproduction and lifespan, were reduced in the dc-2 mutant. However, the toxic effects of carbaryl were weaker than those of phoxim. Carbaryl treatment did not significantly affect the LC50, movement ability or lifespan. Interestingly, body and brood size increased with carbaryl treatment at low concentrations. These data showed that both phoxim and carbaryl could inhibit AChE but that the ace-3 was necessary for phoxim detoxification. The LC50 of phoxim and carbaryl in wild type N2 and the ace-3 deletion mutant dc-2. **Higher significant differences (P < 0.01). PMID:26947509

  4. 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...

  5. Decreased Risk of Radiation Pneumonitis With Incidental Concurrent Use of Angiotensin-Converting Enzyme Inhibitors and Thoracic Radiation Therapy

    Kharofa, Jordan [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI (United States); Cohen, Eric P. [Department of Medicine, Division of Nephrology, Medical College of Wisconsin, Milwaukee, WI (United States); Tomic, Rade [Department of Medicine, Division of Pulmonology, Medical College of Wisconsin, Milwaukee, WI (United States); Xiang Qun [Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI (United States); Gore, Elizabeth, E-mail: Egore@mcw.edu [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI (United States)

    2012-09-01

    Purpose: Angiotensin-converting enzyme (ACE) inhibitors have been shown to mitigate radiation-induced lung injury in preclinical models. The aim of this study was to evaluate whether ACE inhibitors decrease the risk of radiation pneumonitis in lung cancer patients receiving thoracic irradiation. Methods and Materials: Patients with Stage I through III small-cell and non-small-cell lung cancer treated definitively with radiation from 2004-2009 at the Clement J. Zablocki Veterans Affairs Medical Center were retrospectively reviewed. Acute pulmonary toxicity was quantified within 6 months of completion of treatment according to the Common Terminology Criteria for Adverse Events version 4. The use of ACE inhibitors, nonsteroidal anti-inflammatory drugs, inhaled glucocorticosteroids, statins, and angiotensin receptor blockers; dose-volume histogram parameters; and patient factors were assessed for association with Grade 2 or higher pneumonitis. Results: A total of 162 patients met the criteria for inclusion. The majority of patients had Stage III disease (64%) and received concurrent chemotherapy (61%). Sixty-two patients were identified as ACE inhibitor users (38%). All patients had acceptable radiation plans based on dose-volume histogram constraints (V20 [volume of lung receiving at least 20 Gy] {<=}37% and mean lung dose {<=}20 Gy) with the exception of 2 patients who did not meet both criteria. Grade 2 or higher pulmonary toxicity occurred in 12 patients (7.4%). The rate of Grade 2 or higher pneumonitis was lower in ACE inhibitor users vs. nonusers (2% vs. 11%, p = 0.032). Rates of Grade 2 or higher pneumonitis were significantly increased in patients aged greater than 70 years (16% vs. 2%, p = 0.005) or in whom V5 (volume of lung receiving at least 5 Gy) was 50% or greater (13% vs. 4%, p = 0.04). V10 (volume of lung receiving at least 10 Gy), V20, V30 (volume of lung receiving at least 30 Gy), and mean lung dose were not independently associated with Grade 2 or

  6. Positioning SGLT2 Inhibitors/Incretin-Based Therapies in the Treatment Algorithm.

    Wilding, John P H; Rajeev, Surya Panicker; DeFronzo, Ralph A

    2016-08-01

    Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are the most recent addition to the therapeutic options available for the treatment of type 2 diabetes and became available after the introduction of incretin-based therapies, dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs). These agents have potential advantages with regard to their weight loss-promoting effect, low risk of hypoglycemia, reduction in blood pressure, and reduction in cardiovascular events in high-risk patients (with empagliflozin). Apart from these clinically important outcomes, they may also correct core defects present in type 2 diabetes (i.e., improvement in β-cell function and insulin sensitivity). They do, however, have some adverse effects, notably, nausea with GLP-1 RAs and genital tract infections and potential for volume depletion with SGLT2i. Whether incretin-based therapies are associated with an increased risk of pancreatitis is unclear. Most recently, diabetic ketoacidosis has been reported with SGLT2i. Therefore, a key clinical question in relation to guidelines is whether these clinical advantages, in the context of the adverse effect profile, outweigh the additional cost compared with older, more established therapies. This article reviews the therapeutic rationale for the use of these newer drugs for diabetes treatment, considers their place in current guidelines, and discusses how this may change as new data emerge about their long-term efficacy and safety from ongoing outcome trials. PMID:27440828

  7. Computational investigation of pkcβ inhibitors for the treatment of diabetic retinopathy.

    Gogula, Susmitha Valli; Divakar, Ch; Satyanarayana, Ch; Kumar, Yedla Phani; Lavanaya, Vadapalli Santhosi

    2013-01-01

    Diabetic Retinopathy (DR) is one of the attenuating complications of diabetes mellitus. The key gene responsible for causing diabetic retinopathy is protein kinase C beta (PKCβ). Protein kinase C is a family of protein kinase enzymes which are involved in controlling the function of other proteins through phosphorylation mechanism and plays a crucial role in signal transduction mechanisms. Among all the PKC isoenzymes, PKCβ could be a significant isoenzyme involved in vascular dysfunction during hyperglycemia. Studies show that oral administration of PKCβ inhibitor Ruboxistaurin (LY333531), decreases vessel permeability and improves retinal condition. Thus compounds that decrease the PKCβ activation would be helpful in the treatment of diabetic retinopathy. The compounds similar to Ruboxistaurin are taken from Super Target database and docking analysis was performed. Maleimide derivative 3 showed highest binding affinities compared to Ruboxistaurin and so we advise that compound may be utilized in the treatment of diabetic retinopathy. PMID:24497733

  8. Induction of Female-to-Male Sex Change in Adult Zebrafish by Aromatase Inhibitor Treatment

    Takatsu, Kanae; Miyaoku, Kaori; Roy, Shimi Rani; Murono, Yuki; Sago, Tomohiro; Itagaki, Hideyuki; Nakamura, Masaru; Tokumoto, Toshinobu

    2013-12-01

    This study investigated whether undifferentiated germ and/or somatic stem cells remain in the differentiated ovary of a species that does not undergo sex changes under natural conditions and retain their sexual plasticity. The effect of aromatase inhibitor (AI)-treatment on sexually mature female zebrafish was examined. A 5-month AI treatment caused retraction of the ovaries after which testes-like organs appeared, and cyst structures filled with spermatozoa-like cells were observed in sections of these tissues. Electron microscopic observations revealed that these cells appeared as large sperm heads without tails. Sperm formation was re-examined after changing the diet to an AI-free food. A large number of normal sperm were obtained after eight weeks, and no formation of ovarian tissue was observed. Artificial fertilization using sperm from the sex-changed females was successful. These results demonstrated that sex plasticity remains in the mature ovaries of this species.

  9. The role of phosphodiesterase type-5 inhibitors in treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia.

    Umul, Mehmet; Serel, Tekin Ahmet

    2013-12-01

    Phosphodiesterase type-5 (PDE-5) inhibitors are approved as the first line of therapy for the treatment of erectile dysfunction. However, different studies have been performed to study the use of these agents in other areas of urology. There are many studies related to the use of PDE-5 inhibitors as a monotherapy or combination therapy with alpha-blockers for lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). It has been shown that contractions induced by various agents or electrical field stimulation in organ bath models of prostatic tissue can be reversed by PDE-5 inhibitors. Age, body mass index and the severity of LUTS are important factors for the selection of patients suitable for this treatment. It has also been reported that the use of PDE-5 inhibitors can relieve the chronic pelvic ischemia and endothelial dysfunction associated with metabolic syndrome. Most of the side effects observed with PDE-5 inhibitors are minimal and tolerable. The use of PDE-5 inhibitors is absolutely contraindicated in patients taking nitrate preparations. A significant interaction has not been observed even when a patient is taking several antihypertensive agents concurrently. Co-administration of alpha-blockers and PDE-5 inhibitors may result in orthostatic hypotension; therefore, patients should be stable on α-blocker therapy before the initiation of the combination therapy, and the initial PDE-5 inhibitor dose should be the lowest possible. In this review, our aim was to evaluate the role of PDE-5 inhibitors in the treatment of LUTS associated with BPH by analyzing the current literature. PMID:26328121

  10. Angiotensin converting enzyme inhibitor induced hyperkalaemic paralysis

    Dutta., D; Fischler, M; McClung, A

    2001-01-01

    Secondary hyperkalaemic paralysis is a rare condition often mimicking the Guillain-Barré syndrome. There have been a few case reports of hyperkalaemia caused by renal failure, trauma, and drugs where the presentation has been with muscle weakness. A case of hyperkalaemic paralysis caused by an angiotensin converting enzyme inhibitor is reported.


Keywords: hyperkalaemia; paralysis; ACE inhibitors

  11. Vicious Cycle of Multiple Invasive Treatments in a Hemophilic Inhibitor Positive Child with Resistant Knee Flexion Contracture, A Case Report

    Amir Reza Kachooei

    2013-12-01

    Full Text Available Uncontrolled recurrent hemarthrosis can end to contracture, deformity, pain, joint destruction and gait disorders which are disabling. We are going to report a challenge, a unilateral knee flexion contracture in a child with severe hemophilia A and inhibitor who underwent different treatment options with unsatisfactory improvement of knee range of motion. Mismanaging postoperatively, patient and parents irresponsibility in managing self-care, lack of access and affordability to treatment and unavailability of proper treatment can be the reasons of recurrence in addition to the tough nature of a patient with inhibitor.

  12. Treatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer.

    Tan, Chee-Seng; Gilligan, David; Pacey, Simon

    2015-09-01

    Discovery of activating mutations in EGFR and their use as predictive biomarkers to tailor patient therapy with EGFR tyrosine kinase inhibitors (TKIs) has revolutionised treatment of patients with advanced EGFR-mutant non-small-cell lung cancer (NSCLC). At present, first-line treatment with EGFR TKIs (gefitinib, erlotinib, and afatinib) has been approved for patients harbouring exon 19 deletions or exon 21 (Leu858Arg) substitution EGFR mutations. These agents improve response rates, time to progression, and overall survival. Unfortunately, patients develop resistance, limiting patient benefit and posing a challenge to oncologists. Optimum treatment after progression is not clearly defined. A more detailed understanding of the biology of EGFR-mutant NSCLC and the mechanisms of resistance to targeted therapy mean that an era of treatment approaches based on rationally developed drugs or therapeutic strategies has begun. Combination approaches-eg, dual EGFR blockade-to overcome resistance have been trialled and seem to be promising but are potentially limited by toxicity. Third-generation EGFR-mutant-selective TKIs, such as AZD9291 or rociletininb, which target Thr790Met-mutant tumours, the most common mechanism of EGFR TKI resistance, have entered clinical trials, and exciting, albeit preliminary, efficacy data have been reported. In this Review, we summarise the scientific literature and evidence on therapy options after EGFR TKI treatment for patients with NSCLC, aiming to provide a guide to oncologists, and consider how to maximise therapeutic advances in outcomes in this rapidly advancing area. PMID:26370354

  13. The role of phosphodiesterase type-5 inhibitors in treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia

    Umul, Mehmet; Serel, Tekin Ahmet

    2013-01-01

    Phosphodiesterase type-5 (PDE-5) inhibitors are approved as the first line of therapy for the treatment of erectile dysfunction. However, different studies have been performed to study the use of these agents in other areas of urology. There are many studies related to the use of PDE-5 inhibitors as a monotherapy or combination therapy with alpha-blockers for lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). It has been shown that contractions induced by ...

  14. Selective serotonin re-uptake inhibitors potentiate gene blunting induced by repeated methylphenidate treatment: Zif268 vs. Homer1a

    Van Waes, Vincent; Vandrevala, Malcolm; Beverley, Joel; Steiner, Heinz

    2013-01-01

    There is a growing use of psychostimulants such as methylphenidate (Ritalin; dopamine reuptake inhibitor) for medical treatments and as cognitive enhancers in the healthy. Methylphenidate is known to produce some addiction-related gene regulation. Recent findings in animal models show that selective serotonin reuptake inhibitors (SSRIs) including fluoxetine can potentiate acute induction of gene expression by methylphenidate, thus indicating an acute facilitatory role for serotonin in dopamin...

  15. Activation of angiotensin-converting enzyme 2 (ACE2) attenuates allergic airway inflammation in rat asthma model.

    Dhawale, Vaibhav Shrirang; Amara, Venkateswara Rao; Karpe, Pinakin Arun; Malek, Vajir; Patel, Deep; Tikoo, Kulbhushan

    2016-09-01

    Angiotensin-I converting enzyme (ACE) is positively correlated to asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) and is highly expressed in lungs. ACE2, the counteracting enzyme of ACE, was proven to be protective in pulmonary, cardiovascular diseases. In the present study we checked the effect of ACE2 activation in animal model of asthma. Asthma was induced in male wistar rats by sensitization and challenge with ovalbumin and then treated with ACE2 activator, diminazene aceturate (DIZE) for 2weeks. 48h after last allergen challenge, animals were anesthetized, blood, BALF, femoral bone marrow lavage were collected for leucocyte count; trachea for measuring airway responsiveness to carbachol; lungs and heart were isolated for histological studies and western blotting. In our animal model, the characteristic features of asthma such as altered airway responsiveness to carbachol, eosinophilia and neutrophilia were observed. Western blotting revealed the increased pulmonary expression of ACE1, IL-1β, IL-4, NF-κB, BCL2, p-AKT, p-p38 and decreased expression of ACE2 and IκB. DIZE treatment prevented these alterations. Intraalveolar interstitial thickening, inflammatory cell infiltration, interstitial fibrosis, oxidative stress and right ventricular hypertrophy in asthma control animals were also reversed by DIZE treatment. Activation of ACE2 by DIZE conferred protection against asthma as evident from biochemical, functional, histological and molecular parameters. To the best of our knowledge, we report for the first time that activation of ACE2 by DIZE prevents asthma progression by altering AKT, p38, NF-κB and other inflammatory markers. PMID:27343405

  16. Remarks on KERMA Factors in ACE files

    Konno, C.; Ochiai, K.; Takakura, K.; Sato, S.

    2014-04-01

    Some neutron KERMA factors in ACE files are negative and extremely large if nuclear data libraries do not keep energy-balance. The status of neutron KERMA factors in the official ACE file of ENDF/B-VII.1 is examined. As a result, it is found out that neutron KERMA factors of nuclei more than 200 in ENDF/B-VII.1 have some problems. Effects of the inadequate KERMA factor are also investigated, which are large for neutron heat while those are small for total (neutron + gamma) heat. Users who use only neutron KERMA factors should check if the factors are adequate or not before they use the factors.

  17. Cardiac metaiodobenzylguanidine activity can predict the long-term efficacy of angiotensin-converting enzyme inhibitors and/or beta-adrenoceptor blockers in patients with heart failure

    Nakata, Tomoaki; Wakabayashi, Takeru; Kyuma, Michifumi; Takahashi, Toru; Tsuchihashi, Kazufumi; Shimamoto, Kazuaki [Sapporo Medical University School of Medicine, Second Department of Internal Medicine (Cardiology), Sapporo (Japan)

    2005-02-01

    Although the benefits of treatment with angiotensin-converting enzyme (ACE) inhibitors and beta-blockers are well known, no method has as yet been established to predict the efficacy of drug therapy. This study tested whether cardiac{sup 123}I-metaiodobenzylguanidine (MIBG) activity is of prognostic value and can predict the improvement in heart failure patients resulting from treatment with ACE inhibitors and/or beta-blockers. Following quantification of the heart-to-mediastinum ratio (HMR) of MIBG activity, 88 patients with heart failure who were treated with ACE inhibitors and/or beta-blockers (treated group) and 79 patients with heart failure who were treated conventionally without the aforementioned agents, and who served as controls, were followed up for 43 months with a primary endpoint of cardiac death. The treated group had a significantly lower prevalence of cardiac death and a significantly lower mortality at 5 years compared with the control group (15% vs 37% and 21% vs 42%, p<0.05, respectively). Multivariate analysis revealed that significant predictors were HMR, age, nitrate use and ventricular tachycardia for the treated group, and HMR, nitrate use and NYHA class for the control group. The drug treatment significantly reduced mortality from 36% to 12% when HMR was 1.53 or more and from 53% to 37% when HMR was less than 1.53. The reduction in risk of mortality within 5 years in patients without a severe MIBG defect (67%) was twice that in patients with such a defect (32%) (p<0.05). The reduction in mortality risk achieved by using ACE inhibitors and/or beta-blockers is associated with the severity of impairment of cardiac MIBG uptake. Cardiac MIBG activity can consequently be of long-term prognostic value in predicting the effectiveness of such treatment in patients with heart failure. (orig.)

  18. Advanced basal cell carcinoma, the hedgehog pathway, and treatment options – role of smoothened inhibitors

    Fecher LA

    2015-11-01

    Full Text Available Leslie A Fecher,1,3 William H Sharfman2 1Department of Internal Medicine and Dermatology, Indiana University Health Simon Cancer Center, Indianapolis, IN, USA; 2The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA, 3Department of Internal Medicine and Dermatology, University of Michigan, MI, USA Abstract: Cutaneous basal cell carcinoma (BCC is the most common human cancer and its incidence is rising worldwide. Ultraviolet radiation exposure, including tanning bed use, as well as host factors play a role in its development. The majority of cases are treated and cured with local therapies including surgery. Yet, the health care costs of diagnosis and treatment of BCCs in the US is substantial. In the United States, the cost of nonmelanoma skin cancer care in the Medicare population is estimated to be US$426 million per year. While rare, locally advanced BCCs that can no longer be controlled with surgery and/or radiation, and metastatic BCCs do occur and can be associated with significant morbidity and mortality. Vismodegib (GDC-0449, a smoothened inhibitor targeted at the hedgehog pathway, is the first US Food and Drug Association (FDA-approved agent in the treatment of locally advanced, unresectable, and metastatic BCCs. This class of agents appears to be changing the survival rates in advanced BCC patients, but appropriate patient selection and monitoring are important. Multidisciplinary assessments are essential for the optimal care and management of these patients. For some patients with locally advanced BCC, treatment with a hedgehog inhibitor may eliminate the need for an excessively disfiguring or morbid surgery. Keywords: basal cell carcinoma, hedgehog, smoothened, vismodegib, Gorlin, basal cell nevus syndrome

  19. Target prices for mass production of tyrosine kinase inhibitors for global cancer treatment

    Hill, Andrew; Gotham, Dzintars; Fortunak, Joseph; Meldrum, Jonathan; Erbacher, Isabelle; Martin, Manuel; Shoman, Haitham; Levi, Jacob; Powderly, William G; Bower, Mark

    2016-01-01

    Objective To calculate sustainable generic prices for 4 tyrosine kinase inhibitors (TKIs). Background TKIs have proven survival benefits in the treatment of several cancers, including chronic myeloid leukaemia, breast, liver, renal and lung cancer. However, current high prices are a barrier to treatment. Mass production of low-cost generic antiretrovirals has led to over 13 million people being on HIV/AIDS treatment worldwide. This analysis estimates target prices for generic TKIs, assuming similar methods of mass production. Methods Four TKIs with patent expiry dates in the next 5 years were selected for analysis: imatinib, erlotinib, lapatinib and sorafenib. Chemistry, dosing, published data on per-kilogram pricing for commercial transactions of active pharmaceutical ingredient (API), and quotes from manufacturers were used to estimate costs of production. Analysis included costs of excipients, formulation, packaging, shipping and a 50% profit margin. Target prices were compared with current prices. Global numbers of patients eligible for treatment with each TKI were estimated. Results API costs per kg were $347–$746 for imatinib, $2470 for erlotinib, $4671 for lapatinib, and $3000 for sorafenib. Basing on annual dose requirements, costs of formulation/packaging and a 50% profit margin, target generic prices per person-year were $128–$216 for imatinib, $240 for erlotinib, $1450 for sorafenib, and $4020 for lapatinib. Over 1 million people would be newly eligible to start treatment with these TKIs annually. Conclusions Mass generic production of several TKIs could achieve treatment prices in the range of $128–$4020 per person-year, versus current US prices of $75161–$139 138. Generic TKIs could allow significant savings and scaling-up of treatment globally, for over 1 million eligible patients. PMID:26817636

  20. Effects of angiotensin-converting enzyme inhibitors and beta blockers on clinical outcomes in patients with and without coronary artery obstructions at angiography (from a Register-Based Cohort Study on Acute Coronary Syndromes).

    Manfrini, Olivia; Morrell, Christine; Das, Rajiv; Barth, Julian H; Hall, Alistair S; Gale, Christopher P; Cenko, Edina; Bugiardini, Raffaele

    2014-05-15

    We sought to determine the effectiveness of angiotensin-converting enzyme (ACE) inhibition and β-blocker treatment as a function of the degree of coronary artery disease (CAD) obstruction at angiography. The Evaluation of Methods and Management of Acute Coronary Events registry enrolled patients who had been hospitalized for an acute coronary syndrome. There were 1,602 patients who had cardiac catheterization that were used for this analysis. The main outcome measures were evidence-based therapies prescribed at discharge and 6-month incidence of all-cause mortality. The cohort consisted of 1,252 patients with obstructive CAD (>50% luminal diameter obstructed) and 350 patients with nonobstructive CAD. Multivariate logistic regression analysis adjusted for further medications and other clinical factors was performed. Patients with nonobstructive CAD had significantly (p <0.001) higher rates of β-blocker (77.8% vs 63.3%) and lower rates of ACE-inhibitor (57.7% vs 66.4%) prescriptions. In patients with nonobstructive CAD, ACE-inhibitor therapy was clearly associated with a lower 6-month mortality (odds ratio [OR] 0.31, 95% confidence interval [CI] 0.03 to 0.78, p = 0.004). No significant association between β-blocker use and death was found. In patients with obstructive CAD, both β blockers (OR 0.47, 95% CI 0.32 to 0.67, p <0.001) and ACE inhibitors (OR 0.47, 95% CI 0.26 to 0.87, p = 0.01) were significantly associated with a reduced risk of 6-month mortality. In conclusion, ACE-inhibitor therapy seems to be an effective first-line treatment for preventing the occurrence of mortality in patients with nonobstructive CAD. PMID:24698468

  1. Treatment with the Hyaluronic Acid Synthesis Inhibitor 4-Methylumbelliferone Suppresses SEB-Induced Lung Inflammation

    Olga N. Uchakina

    2013-10-01

    Full Text Available Exposure to bacterial superantigens, such as staphylococcal enterotoxin B (SEB, can lead to the induction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS. To date, there are no known effective treatments for SEB-induced inflammation. In the current study we investigated the potential use of the hyaluronic acid synthase inhibitor 4-methylumbelliferone (4-MU on staphylococcal enterotoxin B (SEB induced acute lung inflammation. Culturing SEB-activated immune cells with 4-MU led to reduced proliferation, reduced cytokine production as well as an increase in apoptosis when compared to untreated cells. Treatment of mice with 4-MU led to protection from SEB-induced lung injury. Specifically, 4-MU treatment led to a reduction in SEB-induced HA levels, reduction in lung permeability, and reduced pro-inflammatory cytokine production. Taken together, these results suggest that use of 4-MU to target hyaluronic acid production may be an effective treatment for the inflammatory response following exposure to SEB.

  2. Need for streamlined use of DPP-4 inhibitors in the treatment of type 2 diabetes.

    Vitale, Cristiana; Rosano, Giuseppe M C; Prasad, Krishna

    2016-01-01

    Regulatory agencies request an assessment of cardiovascular safety for all "new" oral anti-diabetic drugs in order to avoid possible negative effects on cardiovascular events. Dipeptidyl peptidase 4 inhibitors have emerged as a new therapeutic alternative for the treatment of type 2 diabetes mellitus, but the several large post-marketing clinical trials have shown only a modest effect in glycaemic control and, more importantly, a neutral effect on total and cardiovascular events. Conversely a recent trial with empagliflozin, a sodium-glucose co-transporter 2 inhibitor, has shown significant effect on overall and cardiovascular mortality. Although glycaemic control is an important aspect of diabetes management, the results of the EMPA-REG outcome trial suggest that it is possible to develop anti-diabetic drugs that may exert an overall beneficial effect beyond the mere improvement of glycaemic control. While the regulatory hurdles should not be increased, there is the need for evaluation of the net clinical impact and cost effectiveness of all anti-diabetic agents. Therefore, a better collaboration among all stakeholders is needed in order to develop studies with endpoints that will be both clinically meaningful including appropriate follow-up, and economically relevant in patients with type 2 diabetes mellitus. PMID:27039303

  3. Targeting angiogenesis: a review of angiogenesis inhibitors in the treatment of lung cancer.

    Sridhar, Srikala S; Shepherd, Frances A

    2003-12-01

    It has now been almost 30 years since Dr J. Folkman first proposed that inhibition of angiogenesis could play a key role in treating cancer; however, it is only recently that anti-angiogenesis agents have entered the clinical setting. The search for novel therapies is particularly important in lung cancer, where the majority of patients succumb to their disease despite aggressive treatments. Several classes of agents now exist that target the different steps involved in angiogenesis. These include drugs inhibiting matrix breakdown, the matrix metalloproteinase inhibitors (MMPIs), such as marimastat, prinomastat, BMS275291, BAY12-9566, and neovastat drugs that block endothelial cell signaling via vascular endothelial growth factor (VEGF) and its receptor (VEGFR) including rhuMAb VEGF, SU5416, SU6668, ZD6474, CP-547,632 and ZD4190. Drugs that are similar to endogenous inhibitors of angiogenesis including endostatin, angiostatin and interferons. There has also been renewed interest in thalidomide. Drugs such as squalamine, celecoxib, ZD6126, TNP-470 and those targeting the integrins are also being evaluated in lung cancer. Despite early enthusiasm for many of these agents, Phase III trials have not yet demonstrated significant increases in overall survival and toxicity remains an issue. It is hoped that as our understanding of the complex process of angiogenesis increases, so will our ability to design more effective targeted therapies. PMID:14611919

  4. ANGIOTENSIN CONVERTING ENZYME INHIBITORS IN ACUTE MYOCARDIAL INFARCTION: WHEN TO START THERAPY AND WHICH DRUG TO USE?

    S. Y. Martsevich; S. N. Tolpygina

    2015-01-01

    Data of studies devoted to application of angiotensin converting enzyme (ACE) inhibitors in acute myocardial infarction are reviewed. The reasons of ambiguous results are discussed. A point of view that different ACE inhibitors may have the various efficacy and safety in patients with acute myocardial infarction is suggested.

  5. Treatment-emergent mutations in NAEβ confer resistance to the NEDD8-activating enzyme inhibitor MLN4924.

    Milhollen, Michael A; Thomas, Michael P; Narayanan, Usha; Traore, Tary; Riceberg, Jessica; Amidon, Benjamin S; Bence, Neil F; Bolen, Joseph B; Brownell, James; Dick, Lawrence R; Loke, Huay-Keng; McDonald, Alice A; Ma, Jingya; Manfredi, Mark G; Sells, Todd B; Sintchak, Mike D; Yang, Xiaofeng; Xu, Qing; Koenig, Erik M; Gavin, James M; Smith, Peter G

    2012-03-20

    MLN4924 is an investigational small-molecule inhibitor of NEDD8-activating enzyme (NAE) in clinical trials for the treatment of cancer. MLN4924 is a mechanism-based inhibitor, with enzyme inhibition occurring through the formation of a tight-binding NEDD8-MLN4924 adduct. In cell and xenograft models of cancer, we identified treatment-emergent heterozygous mutations in the adenosine triphosphate binding pocket and NEDD8-binding cleft of NAEβ as the primary mechanism of resistance to MLN4924. Biochemical analyses of NAEβ mutants revealed slower rates of adduct formation and reduced adduct affinity for the mutant enzymes. A compound with tighter binding properties was able to potently inhibit mutant enzymes in cells. These data provide rationales for patient selection and the development of next-generation NAE inhibitors designed to overcome treatment-emergent NAEβ mutations. PMID:22439935

  6. Role of ACE and PAI-1 Polymorphisms in the Development and Progression of Diabetic Retinopathy.

    Saba Saleem

    Full Text Available In the present study we determined the association of angiotensin converting enzyme (ACE and plasminogen activator inhibitor-1 (PAI-1 gene polymorphisms with diabetic retinopathy (DR and its sub-clinical classes in Pakistani type 2 diabetic patients. A total of 353 diabetic subjects including 160 DR and 193 diabetic non retinopathy (DNR as well as 198 healthy controls were genotyped by allele specific polymerase chain reaction (PCR for ACE Insertion/Deletion (ID polymorphism, rs4646994 in intron 16 and PAI-1 4G/5G (deletion/insertion polymorphism, rs1799768 in promoter region of the gene. To statistically assess the genotype-phenotype association, multivariate logistic regression analysis was applied to the genotype data of DR, DNR and control individuals as well as the subtypes of DR. The ACE genotype ID was found to be significantly associated with DR (p = 0.009, odds ratio (OR 1.870 [95% confidence interval (CI = 1.04-3.36] and its sub-clinical class non-proliferative DR (NPDR (p = 0.006, OR 2.250 [95% CI = 1.098-4.620], while PAI polymorphism did not show any association with DR in the current cohort. In conclusion in Pakistani population the ACE ID polymorphism was observed to be significantly associated with DR and NPDR, but not with the severe form of the disease i.e. proliferative DR (PDR.

  7. Developing Communities: Serving ACE through Tertiary Education

    Sofo, Francesco

    2011-01-01

    Purpose: The purpose of this paper is to review the focus and practice of Adult and Community Education (ACE) as well as its conceptualization and delivery and to suggest parameters for an approach based on excellence, a balanced scorecard and performance to meet community needs. Design/methodology/approach: The review examines key aspects of the…

  8. Advanced Colloids Experiment (ACE-T1)

    Meyer, William V.; Sicker, Ron; Brown, Dan; Eustace, John

    2015-01-01

    Increment 45 - 46 Science Symposium presentation of Advanced Colloids Experiment (ACE-T1) to RPO. The purpose of this event is for Principal Investigators to present their science objectives, testing approach, and measurement methods to agency scientists, managers, and other investigators.

  9. Effects of the angiotensin-converting enzyme inhibitor enalapril on sympathetic neuronal function and β-adrenergic desensitization in heart failure after myocardial infarction in rats

    One of the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in the treatment of heart failure may derive from sympathoinhibition and the prevention of β-adrenergic desensitization. However, the roles of these properties in the overall effects of ACE inhibitor are not clear. We studied the effects of chronic enalapril treatment (20 mg/L in drinking water for 12 weeks) on left ventricular (LV) function, cardiac norepinephrine (NE), sympathetic neuronal function assessed by 131I-metaiodobenzylguanidine (MIBG), β-receptors, and isometric contraction of papillary muscle in rats with myocardial infarction (MI) induced by coronary artery ligation. Decreased LV function in the MI rats was associated with reduced cardiac NE content and MIBG uptake, and severely blunted responses of non-infarcted papillary muscle to isoproterenol, forskolin, and calcium. Enalapril attenuated LV remodeling in association with a reduction of the ventricular loading condition and restored baseline developed tension of non-infarcted papillary muscle to the level of sham-operated rats. However, enalapril did not improve cardiac NE content, MIBG uptake, or inotropic responsiveness to β-agonists. These results suggest that the major effect of the ACE inhibitor enalapril in the treatment of heart failure is not due to sympathoinhibition or restoration of β-adrenergic pathway in this model of heart failure. (author)

  10. Treatment response after repeated administration of C1 esterase inhibitor for successive acute hereditary angioedema attacks.

    Craig, Timothy J; Bewtra, Againdra K; Hurewitz, David; Levy, Robyn; Janss, Gerti; Jacobson, Kraig W; Packer, Flint; Bernstein, Jonathan A; Rojavin, Mikhail A; Machnig, Thomas; Keinecke, Heinz-Otto; Wasserman, Richard L

    2012-01-01

    Placebo-controlled studies established the efficacy of replacement therapy with C1 esterase inhibitor (C1-INH) concentrate for treating single acute hereditary angioedema (HAE) attacks, but only limited data from prospective studies are available on repeated treatment of successive HAE attacks. This study evaluates the association between repeated treatments with 20 U/kg of C1-INH concentrate (Berinert; CSL Behring, Marburg, Germany) for HAE attacks at any body location and treatment response. In a post hoc analysis of an open-label extension study (International Multicenter Prospective Angioedema C1-INH Trial [I.M.P.A.C.T.2]), the association between repeated treatment with C1-INH and times to onset of symptom relief and complete resolution of HAE symptoms was assessed in patients who were treated for at least 15 attacks by linear regression on the ordinal attack number. Eighteen patients received C1-INH concentrate for at least 15 HAE attacks over a mean duration of 34 months. Demographic and baseline characteristics of these patients were similar to those of all patients in the study. The distribution of body locations and the intensity of HAE attacks were similar for each of the first 15 attacks and subsequent attacks. The extent of previous use of C1-INH concentrate had no effect on the time to onset of symptom relief, the time to complete resolution of HAE symptoms, or the time between attacks treated with C1-INH concentrate; the median of individual linear regression coefficients was not statistically significantly different from 0. Treatment with 20 U/kg of C1-INH concentrate provided consistent treatment response in patients treated for multiple successive HAE attacks at any body location. (Clinicaltrials.gov identifier: NCT00292981). PMID:22856636

  11. Role of golimumab, a TNF-alpha inhibitor, in the treatment of the psoriatic arthritis

    Melissa A Michelon

    2010-05-01

    Full Text Available Melissa A Michelon1, Alice B Gottlieb1,21Tufts University School of Medicine, 2Department of Dermatology, Tufts Medical Center, Boston, MA, USAAbstract: Psoriatic arthritis (PsA is an inflammatory arthritis that affects many psoriasis patients and can often have a debilitating disease progression. Golimumab is a new tumor necrosis factor (TNF antagonist recently approved by the FDA for controlling signs and symptoms of psoriatic arthritis. In a Phase III clinical trial in patients with PsA, patients receiving golimumab showed significant improvement in the signs and symptoms of disease. It was usually well tolerated, but adverse events generally occurred more in patients receiving golimumab compared to placebo. Golimumab has also recently shown efficacy in slowing structural damage in PsA. This new biologic therapy provides physicians with another option in the treatment of this inflammatory arthritis while offering patients certain advantages over other TNF antagonists.Keywords: golimumab, psoriatic arthritis, TNF-alpha inhibitor

  12. Successful treatment of cytomegalovirus associated hemophagocytic lymphohistiocytosis with the interleukin 1 inhibitor - anakinra.

    Divithotawela, Chandima; Garrett, Peter; Westall, Glen; Bhaskar, Balu; Tol, Maneesha; Chambers, Daniel C

    2016-03-01

    Hemophagocytic lymphohistiocytosis (HLH) is a rare, frequently under-recognized condition associated with multi-organ failure and very high mortality. A 44-year-old woman was admitted with a 4-day history of fever, headache, delirium, and dyspnea. She progressed rapidly to type 1 respiratory failure and required intubation and mechanical ventilation. Laboratory tests showed pancytopenia, abnormal liver enzyme levels, elevated triglyceride level, and elevated ferritin level. Bone marrow biopsy showed features of HLH. Computed tomography scan showed bilateral consolidation. Bronchoalveolar lavage was positive for cytomegalovirus. She was treated with ganciclovir, methylprednisolone, broad spectrum antibiotics, and cytomegalovirus hyperimmunoglobulin without clinical response. Given the poor prognosis and reports of success in pediatric HLH, anakinra 100 µg subcutaneously daily was commenced. There was rapid defervescence, resolution of delirium, and improvement in gas exchange, leading to complete recovery. This case illustrates successful treatment of HLH associated with cytomegalovirus pneumonitis with the interleukin 1 inhibitor anakinra. PMID:26839691

  13. ROLE OF DPP-IV INHIBITORS IN TREATMENT OF TYPE II DIABETES

    Patel Kishan D

    2010-12-01

    Full Text Available Emerging as an epidemic of the 21st century type II diabetes has become a major health problem throughout the globe. Known treatments of type II diabetes mellitus have limitations such as weight gain and hypoglycaemias. A new perspective is the use of incretin hormones and incretin enhancers. Incretin mimetics are a new class of pharmacological agents with multiple antihyperglycemic actions that mimic the actions of incretin hormones such as glucagon-like peptide (GLP-1. DPP-4, a protease that specifically cleaves dipeptides from proteins and oligopeptides after a penultimate N-terminal proline or alanine, is involved in the degradation of a number of neuropeptides, peptide hormones and cytokines, including the incretins GLP-1 and GIP. Based on preliminary clinical data, incretin mimetics and DPP-IV inhibitors show potential for treating type II diabetes.

  14. [Reducing bone resorption by cathepsin K inhibitor and treatment of osteoporosis].

    Watanabe, Reiko; Okazaki, Ryo

    2014-01-01

    Cathepsin K is a lysosomal cysteine protease, secreted from osteoclasts. It plays a major role in the osteoclastic bone resorption by cleaving type 1 collagen, the major bone matrix protein, under acidic pH. In cathepsin K knockout mice, bone mineral density (BMD) is increased, bone resorption is decreased without reduction in the number of osteoclast whereas bone formation is decreased. Based on these results, cathepsin K inhibitors have been developed for the treatment of osteoporosis. Odanacatib is one of them and is perhaps closest for launching. In phase 1 and 2 trials, it markedly reduced bone resorption with a transient reduction in bone formation, thus resulted in a robust increase in both trabecular and cortical BMD in osteoporotics. Currently, Odanacatib is in phase 3 fracture prevention trial, of which results are anticipated in 2014. PMID:24369281

  15. Angiotensin-Converting Enzyme Inhibitor Use and Major Cardiovascular Outcomes in Type 2 Diabetes Mellitus Treated With the Dipeptidyl Peptidase 4 Inhibitor Alogliptin.

    White, William B; Wilson, Craig A; Bakris, George L; Bergenstal, Richard M; Cannon, Christopher P; Cushman, William C; Heller, Simon K; Mehta, Cyrus R; Nissen, Steven E; Zannad, Faiez; Kupfer, Stuart

    2016-09-01

    Activation of the sympathetic nervous system when there is dipeptidyl peptidase 4 inhibition in the presence of high-dose angiotensin-converting enzyme (ACE) inhibition has led to concerns of potential increases in cardiovascular events when the 2 classes of drugs are coadministered. We evaluated cardiovascular outcomes from the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin versus Standard of Care) trial according to ACE inhibitor use. Patients with type 2 diabetes mellitus and a recent acute coronary syndrome were randomly assigned to receive the dipeptidyl peptidase 4 inhibitor alogliptin or placebo added to existing antihyperglycemic and cardiovascular prophylactic therapies. Risks of adjudicated cardiovascular death, nonfatal myocardial infarction and stroke, and hospitalized heart failure were analyzed using a Cox proportional hazards model in patients according to ACE inhibitor use and dose. There were 3323 (62%) EXAMINE patients treated with an ACE inhibitor (1681 on alogliptin and 1642 on placebo). The composite rates of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke were comparable for alogliptin and placebo with ACE inhibitor (11.4% versus 11.8%; hazard ratio, 0.97; 95% confidence interval, 0.79-1.19; P=0.76) and without ACE inhibitor use (11.2% versus 11.9%; hazard ratio, 0.94; 95% confidence interval, 0.73-1.21; P=0.62). Composite rates for cardiovascular death and heart failure in patients on ACE inhibitor occurred in 6.8% of patients on alogliptin versus 7.2% on placebo (hazard ratio, 0.93; 95% confidence interval, 0.72-1.2; P=0.57). There were no differences for these end points nor for blood pressure or heart rate in patients on higher doses of ACE inhibitor. Cardiovascular outcomes were similar for alogliptin and placebo in patients with type 2 diabetes mellitus and coronary disease treated with ACE inhibitors. PMID:27480840

  16. Aromatase inhibitors, efficacy and metabolic risk in the treatment of postmenopausal women with early breast cancer

    Stefano Gonnelli

    2008-11-01

    Full Text Available Stefano Gonnelli1, Roberto Petrioli21Department of Internal Medicine, Endocrine-Metabolic Science and Biochemistry, University of Siena, Italy (Dir. R. Nuti.; 2Department of Human Pathology and Oncology, Medical Oncology Section, University of Siena, Italy (Dir. G. FranciniAbstract: The third-generation aromatase inhibitors (AIs, letrozole, anastrozole and exemestane, are becoming the first choice endocrine drugs for post-menopausal women with breast cancer, since they present greater efficacy when compared with tamoxifen in both adjuvant and metastatic setting. In particular, several large and well designed trials have suggested an important role for AIs in the adjuvant treatment of postmenopausal women with estrogen-receptor positive breast cancer either in the upfront, sequential or extended adjuvant mode. Overall, AIs are associated with a small but significant improvement in disease free survival. The expanding use of AIs in the treatment of early breast cancer means that individual patients will be exposed to the agents for longer durations, making it increasingly important to establish their long-term safety. This review focused on the effects of AIs on bone metabolism, serum lipids and cardiovascular risk. AIs have adverse effects on bone turnover with a reduction of bone mineral density and an increase in the rate of fragility fractures. With respect to tamoxifen AIs present lower thrombotic risk and a less favorable impact on lipid profile, whereas the true effects on cardiovascular risk still remain to be clarified. An adequate monitoring of bone mineral density (BMD and lipid profile could be recommended for post-menopausal women candidate to AIs.Keywords: breast cancer, aromatase inhibitors, bone loss, lipids, cardiovascular risk

  17. Experimental treatment of pancreatic cancer with two novel histone deacetylase inhibitors

    Martin Haefner; Thilo Bluethner; Manuel Niederhagen; Christian Moebius; Christian Wittekind; Joachim Mossner; Karel Caca; Marcus Wiedmann

    2008-01-01

    AIM: To investigate in vitro and in vivo treatment with histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 in pancreatic cancer.METHODS: Cell-growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in v/tro in 8 human pancreatic cancer cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (M-I-r) assay. In addition, the anti-tumoral effect of NVP-LBH589 was studied in a chimeric mouse model. Anti-tumoral activity of the drugs was assessed by immunoblotting for P21waf-1, acH4, cell cycle analysis, TUNEL assay, and immunohistochemistry for MIB-1.RESULTS: In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines and was associated with hyperacetylation of nucleosomal histone H4, increased expression of p21WAF-1, cell cycle arrest at G2/M-checkpoint, and increased apoptosis. In vivo, NVP-LBH589 alone significantly reduced tumor mass and potentiated the efficacy of gemcitabine. Further analysis of the tumor specimens revealed slightly increased apoptosis and no significant reduction of cell proliferation.CONCLUSION: Our findings suggest that NVP-LBH589 and NVP-LAQ824 are active against human pancreatic cancer, although the precise mechanism of in vivo drug action is not yet completely understood. Therefore, further preclinical and clinical studies for the treatment of pancreatic cancer are recommended.

  18. Association between tobacco smoking and response to tumour necrosis factor α inhibitor treatment in psoriatic arthritis

    Højgaard, Pil; Glintborg, Bente; Hetland, Merete Lund;

    2015-01-01

    OBJECTIVES: To investigate the association between tobacco smoking and disease activity, treatment adherence and treatment responses among patients with psoriatic arthritis (PsA) initiating the first tumour necrosis factor α inhibitor therapy (TNFi) in routine care. METHODS: Observational cohort...... study based on the Danish nationwide DANBIO registry. Kaplan-Meier plots, logistic and Cox regression analyses by smoking status (current/previous/never smoker) were calculated for treatment adherence, ACR20/50/70-responses and EULAR-good-response. Additional stratified analyses were performed according...... Body Mass Index (27 kg/m(2) (23-30)/28 kg/m(2) (24-31)) (median (IQR)), shorter disease duration (3 years (1-8)/5 years (2-10)), lower swollen joint count (2 (0-5)/3 (1-6)), higher visual-analogue-scale (VAS) patient global (72 mm (54-87)/68 mm (50-80)), VAS fatigue (72 mm (51-86)/63 mm (40-77)) and...

  19. Use of nitric oxide synthase inhibitors for the treatment of inflammatory disease and pain.

    Cheshire, D R

    2001-07-01

    This article reviews the recent literature on selective inhibitors of nitric oxide synthase (NOS) between 1999 and the first quarter of 2001. The introduction highlights the major therapeutic objectives for NOS inhibitors, including rheumatoid arthritis (RA), osteoarthritis (OA) and pain. The review attempts to cover the structural diversity of small molecule NOS inhibitors currently being explored in the pharmaceutical and academic communities. PMID:15995936

  20. Treatment of Arabidopsis thaliana seeds with an HSP90 inhibitor increases plant resistance

    Kozeko, Liudmyla

    2016-07-01

    Resistance of plants to unfavourable conditions is an important feature to use them as an autotrophic link of Life Support Systems in space exploration missions. It significantly depends on basic and stress-induced levels of heat shock proteins (HSP) in cells. It is known that HSP90 can bind and maintain heat shock transcription factors (HSF) as a monomer that lacks DNA binding activity and thereby regulate HSP expression. Modulation of activity of the HSP synthesis and resistance by HSP90 in plants is not well investigated. The objective of this study was to determine how treatment of seeds with an HSP90 inhibitor affects environmental responsiveness in Arabidopsis thaliana. Seed treatment with geldanamycin (GDA) was used to reduce HSP90 function. The affect of space flight stressors was simulated by gamma-irradiation and thermal upshift. Two series of experiments were carried out: 1) exposure of dry seeds to gamma-irradiation (1 kGy, ^{60}Co); 2) heat shock of seedlings. It was shown that GDA treatment of seeds stimulated the seedling growth after seed irradiation. It also increased both the basic thermotolerance (45°C for 45 min) and induced thermotolerance (45°C for 1,5-2,5 h after pretreatment at 37°C for 2 h) in seedlings. In addition, seed treatment with GDA had a prolonged effect on the HSP70 production in seedlings under normal and stressful conditions. It shows that the stimulatory effects of GDA may be caused by induction of HSP70 synthesis. The obtained data demonstrate that pre-treatment of seeds with GDA before planting allows inducing the stress resistance at least at early growth stages of plants.

  1. Effect of chronic treatment with a cyclooxygenase inhibitor on reproductive parameters in male rat

    Indomethacin is a member of non-steroidal anti-inflammatory drugs (NSAIDs) commonly used for treatment of gout, arthritis, and other inflammatory conditions. It has been shown to inhibit ovarian prostaglandins synthesis in mammals, birds, fish and reptiles. However, the effects of its chronic administration on male reproductive functions remain largely unknown. Using rat as a model, we studied the effect of chronic treatment with indomethacin on the male reproductive system. Methods: Testosterone was measured in the serum, testicular tissue, and testicular interstitial fluid by radioimmunoassay. Moreover, we also studied the direct effect of indomethacin in vitro on luteinizing hormone stimulated testosterone secretion from the Leydig cells isolated from various treatment groups. Results: Indomethacin treatment for 50 days caused a significant but reversible decrease in prostate weight, epididymal sperm reserves and sperm motility score compared with control rats (p<0.05). In vitro stimulation of Leydig cells isolated from treated rat's testes with luteinizing hormone (250 mu IU) produced significantly reduced testosterone compared with cells from control groups (p<0.05). Furthermore, stimulatory effect of luteinizing hormone on the control Leydig cells was significantly reduced when these cells were challenged with luteinizing hormone in the presence of indomethacin, (p<0.05). Testosterone concentration in the testicular tissue and testicular interstitial fluid reduced after indomethacin treatment (p<0.05). Conclusion: Due to its significant inhibition of key reproductive hormones, indomethacin effectively inhibits reproductive functions if used on a long-term basis. In his study, we have identified potential risks in the long-term use of cyclooxygenase inhibitors. (author)

  2. AceWiki: Collaborative Ontology Management in Controlled Natural Language

    Kuhn, Tobias

    2008-01-01

    AceWiki is a prototype that shows how a semantic wiki using controlled natural language - Attempto Controlled English (ACE) in our case - can make ontology management easy for everybody. Sentences in ACE can automatically be translated into first-order logic, OWL, or SWRL. AceWiki integrates the OWL reasoner Pellet and ensures that the ontology is always consistent. Previous results have shown that people with no background in logic are able to add formal knowledge to AceWiki without being instructed or trained in advance.

  3. AceWiki: Collaborative Ontology Management in Controlled Natural Language

    Kuhn, T.

    2008-01-01

    AceWiki is a prototype that shows how a semantic wiki using controlled natural language - Attempto Controlled English (ACE) in our case - can make ontology management easy for everybody. Sentences in ACE can automatically be translated into first-order logic, OWL, or SWRL. AceWiki integrates the OWL reasoner Pellet and ensures that the ontology is always consistent. Previous results have shown that people with no background in logic are able to add formal knowledge to AceWiki without being in...

  4. Histone deacetylase inhibitors stimulate the susceptibility of A549 cells to a plasma-activated medium treatment.

    Adachi, Tetsuo; Kano, Ayame; Nonomura, Saho; Kamiya, Tetsuro; Hara, Hirokazu

    2016-09-15

    The number of potential applications of non-thermal atmospheric pressure plasma (NTAPP) discharges in medicine, particularly in cancer therapy, has increased in recent years. NTAPP has been shown to affect cells not only by direct irradiation, but also by an indirect treatment with previously prepared plasma-activated medium (PAM). Histone deacetylase (HDAC) inhibitors have the potential to enhance susceptibility to anticancer drugs and radiation. The aim of the present study was to demonstrate the advantage of the combined application of PAM and HDAC inhibitors on A549 cancer cell survival and elucidate the underlying mechanisms. Cell death with DNA breaks in the nucleus was greater using combined regimens of PAM and HDAC inhibitors such as trichostatin A (TSA) and valproic acid (VPA) than a single PAM treatment and was accompanied by the activation of poly (ADP-ribose) polymerase-1 (PARP-1), depletion of ATP, and elevations in intracellular calcium levels. Moreover, the expression of Rad 51, a DNA repair factor in homologous recombination pathways, was significantly suppressed by the treatment with HDAC inhibitors. These results demonstrate that HDAC inhibitors may synergistically induce the sensitivity of cancer cells to PAM components. PMID:27470189

  5. Use of mTOR inhibitors in the treatment of breast cancer: an evaluation of factors that influence patient outcomes

    Jerusalem G

    2014-04-01

    Full Text Available Guy Jerusalem, Andree Rorive, Joelle Collignon Medical Oncology, CHU Sart Tilman Liege, Domaine Universitaire du Sart Tilman, Liege, Belgium Abstract: Many systemic treatment options are available for advanced breast cancer, including endocrine therapy, chemotherapy, anti-human epidermal growth factor receptor 2 (HER2 therapy, and other targeted agents. Recently, everolimus, a mammalian target of rapamycin (mTOR inhibitor, combined with exemestane, an aromatase inhibitor, has been approved in Europe and the USA for patients suffering from estrogen receptor-positive, HER2-negative advanced breast cancer previously treated by a nonsteroidal aromatase inhibitor, based on the results of BOLERO-2 (Breast cancer trials of OraL EveROlimus. This study showed a statistically significant and clinically meaningful improvement in median progression-free survival. Results concerning the impact on overall survival are expected in the near future. This clinically oriented review focuses on the use of mTOR inhibitors in breast cancer. Results reported with first-generation mTOR inhibitors (ridaforolimus, temsirolimus, everolimus are discussed. The current and potential role of mTOR inhibitors is reported according to breast cancer subtype (estrogen receptor-positive HER2-negative, triple-negative, and HER2-positive ER-positive/negative disease. Everolimus is currently being evaluated in the adjuvant setting in high-risk estrogen receptor-positive, HER2-negative early breast cancer. Continuing mTOR inhibition or alternatively administering other drugs targeting the phosphatidylinositol-3-kinase/protein kinase B-mTOR pathway after progression on treatments including an mTOR inhibitor is under evaluation. Potential biomarkers to select patients showing a more pronounced benefit are reviewed, but we are not currently using these biomarkers in routine practice. Subgroup analysis of BOLERO 2 has shown that the benefit is consistent in all subgroups and that it is

  6. Bioimpedance in monitoring of effects of selective serotonin reuptake inhibitor treatment

    Kuznecova LV

    2011-06-01

    Full Text Available Vasiliy Grigorievich Alexeev, Ludmila Vasilievna KuznecovaDepartment of Physiology, SP Botkin Moscow City Clinical Hospital, Moscow, RussiaBackground: Bioimpedance has been shown to be a safe technique when used in a number of biomedical applications. In this study, we used the Electro Interstitial Scan (EIS to perform bioimpedance measurements to follow up the efficacy of selective serotonin reuptake inhibitor (SSRI treatment in subjects diagnosed to have major depressive disorder.Methods: We recruited 59 subjects (38 women, 21 men aged 17–76 (mean 47 years diagnosed with major depressive disorder by psychiatric assessment at the Botkin Hospital according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV. Baseline Clinical Global Impression scores and EIS (electrical conductivity and dispersion α parameter measurements were done before starting SSRI therapy. Treatment follow-up was undertaken using EIS bioimpedance measurements and by treatment response based on the Hamilton Depression Scale and Clinical Global Impression, every 15 days for 60 days. At day 45, we classified the patients into two groups, ie, Group 1, including treatment responders, and Group 2, including nonresponders. At day 60, patients were classified into two further groups, ie, Group 3, comprising treatment responders, and Group 4, comprising nonresponders.Results: Comparing Group 1 and Group 2, electrical conductivity measurement of the pathway between the two forehead electrodes had a specificity of 72% and a sensitivity of 85.3% (P < 0.0001, with a cutoff >4.32. Comparing Group 3 and Group 4, electrical conductivity measurements in the same pathway had a specificity of 47.6% and a sensitivity of 76.3% (P < 0.16, with a cutoff >5.92. Comparing Group 1 and Group 2, the electrical dispersion α parameter of the pathway between the two disposable forehead electrodes had a specificity of 80% and a sensitivity of 85.2% (P < 0.0001 with a

  7. Synthesis and biological studies of highly concentrated lisinopril-capped gold nanoparticles for CT tracking of angiotensin converting enzyme (ACE)

    Ghann, William E.; Aras, Omer; Fleiter, Thorsten; Daniel, Marie-Christine

    2011-05-01

    For patients with a history of heart attack or stroke, the prevention of another cardiovascular or cerebrovascular event is crucial. The development of cardiac and pulmonary fibrosis has been associated with overexpression of tissue angiotensin-converting enzyme (ACE). Recently, gold nanoparticles (GNPs) have shown great potential as X-ray computed tomography (CT) contrast agents. Since lisinopril is an ACE inhibitor, it has been used as coating on GNPs for targeted imaging of tissue ACE in prevention of fibrosis. Herein, lisinopril-capped gold nanoparticles (LIS-GNPs) were synthesized up to a concentration of 55 mgAu/mL. Their contrast was measured using CT and the results were compared to Omnipaque, a commonly used iodine-based contrast agent. The targeting ability of these LIS-GNPs was also assessed.

  8. Angiotensin-converting enzyme inhibitor (enalapril maleate) accelerates recovery of mouse skin from UVB-induced wrinkles

    Matsuura-Hachiya, Yuko; Arai, Koji Y.; Ozeki, Rieko; Kikuta, Ayako; Nishiyama, Toshio, E-mail: toshio_n@cc.tuat.ac.jp

    2013-12-06

    Highlights: •Angiotensin converting enzyme (ACE) increases in UVB-irradiated skin. •Administration of an ACE inhibitor improved UVB-induced skin wrinkle. •ACE inhibitor improved UVB-induced epidermal hypertrophy. •ACE inhibitor improved transepidermal water loss in the UVB-irradiated skin. -- Abstract: Angiotensin-converting enzyme (ACE) activity and angiotensin II signaling regulate cell proliferation, differentiation, and tissue remodeling, as well as blood pressure, while in skin, angiotensin II signaling is involved in wound healing, inflammation, and pathological scar formation. Therefore, we hypothesized that angiotensin II is also involved in photoaging of skin. In this study, we examined the effect of enalapril maleate, an ACE inhibitor, on recovery of wrinkled skin of hairless mice exposed to long-term UVB irradiation. Immunohistochemical observation revealed that expression of ACE, angiotensin II, and angiotensin II type 1 (AT1) and type 2 (AT2) receptors in the skin was increased after UVB irradiation (3 times/week at increasing intensities for 8 weeks). Administration of enalapril maleate (5 times/week for 6 weeks, starting 1 week after 10-week irradiation) accelerated recovery from UVB-induced wrinkles, epidermal hyperplasia and epidermal barrier dysfunction, as compared with the vehicle control. Our results indicate that ACE and angiotensin II activity are involved in skin photoaging, and suggest that ACE inhibitor such as enalapril maleate may have potential for improvement of photoaged skin.

  9. Maastricht Ⅱ treatment scheme and efficacy of different proton pump inhibitors in eradicating Helicobacter pylori

    Engin Altintas; Orhan Sezgin; Oguz Ulu; Ozlem Aydin; Handan Camdeviren

    2004-01-01

    AIM: The Maastricht Ⅱ criteria suggest the use of amoxicillin and clarithromycin in addition to a proton pump inhibitor over 7-10 d as a first line therapy in the eradication of Helicobacter pylori(H pylori). For each proton pump inhibitor, various rates of eradication have been reported. The present study was to compare the efficacy of different proton pump inhibitors like omeprazole, lansoprazole and pantoprazole in combination with amoxicillin and clarithromycin in the first line eradication of H pylori and to investigate the success of H pylori eradication in our district.METHODS: A total of 139 patients were included having a Helicobacter pylori(+) gastroduodenal disorders diagnosed by means of histology and urease test. Besides amoxicillin (1 000 mg twice a day) and clarithromycin (500 mg twice a day), they were randomized to take omeprazole (20 mg twice a day), or lansoprazole (30 mg twice a day), or pantoprozole (40 mg twice a day) for 14 d. Four weeks after the therapy, the eradication was assessed by means of histology and urease test. It was evaluated as eradicated if the H pylori was found negative in both. The complaints (pain in epigastrium, nocturnal pain, pyrosis and bloating)were graded in accordance with the Licert scale. The compliance of the patients was recorded.RESULTS: The eradication was found to be 40.8% in the omeprazole group, 43.5% in the lansoprazole group and 47.4% in the pantoprazole group. Sixty-three out of 139patients (45%) had eradication. No statistically significant difference was observed between the groups. Significant improvements were seen in terms of the impact on the symptom scores in each group.CONCLUSION: There was no difference between omeprazole, lansoprazole and pantoprazole in H pylori eradication, and the rate of eradication was as low as 45%.Symptoms were improved independent of the eradication in each treatment group. The iow eradication rates suggest that the antibiotic resistance or the genetic differences of

  10. A first-in-human phase 1 study of ACE910, a novel factor VIII-mimetic bispecific antibody, in healthy subjects.

    Uchida, Naoki; Sambe, Takehiko; Yoneyama, Koichiro; Fukazawa, Naoki; Kawanishi, Takehiko; Kobayashi, Shinichi; Shima, Midori

    2016-03-31

    ACE910 is a recombinant humanized bispecific antibody that binds to activated factor IX and factor X and mimics the cofactor function of factor VIII (FVIII). This first-in-human study examined the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ACE910 in healthy male adults. A total of 40 Japanese and 24 white subjects were randomized to receive a single subcutaneous injection of ACE910 (Japanese: 0.001, 0.01, 0.1, 0.3, or 1 mg/kg; white: 0.1, 0.3, or 1 mg/kg; n = 6 per dose group) or placebo (n = 2 per dose group). ACE910 exhibited a linear PK profile and had a half-life of ∼4 to 5 weeks. In FVIII-neutralized plasma, ACE910 shortened activated partial thromboplastin time and increased peak height of thrombin generation in a dose-dependent manner. All adverse events were nonserious and did not lead to any subject's withdrawal. Neither clinical findings nor laboratory abnormalities indicating hypercoagulability were observed. Two of 48 subjects receiving ACE910 (1 Japanese and 1 white) were positive for anti-ACE910 antibodies (anti-drug antibodies [ADAs]). One subject tested positive for ADAs both before and after ACE910 administration, whereas the other became ADA positive after receiving ACE910. The PK and PD profiles of ACE910 were similar in healthy Japanese and white subjects and suggest that ACE910 will be an effective and convenient prophylactic treatment of hemophilia A. This trial was registered at www.clinicaltrials.jp as #JapicCTI-121934. PMID:26626991

  11. Treatment of medulloblastoma with oncolytic measles viruses expressing the angiogenesis inhibitors endostatin and angiostatin

    Medulloblastoma is the most common type of pediatric brain tumor. Although numerous factors influence patient survival rates, more than 30% of all cases will ultimately be refractory to conventional therapies. Current standards of care are also associated with significant morbidities, giving impetus for the development of new treatments. We have previously shown that oncolytic measles virotherapy is effective against medulloblastoma, leading to significant prolongation of survival and even cures in mouse xenograft models of localized and metastatic disease. Because medulloblastomas are known to be highly vascularized tumors, we reasoned that the addition of angiogenesis inhibitors could further enhance the efficacy of oncolytic measles virotherapy. Toward this end, we have engineered an oncolytic measles virus that express a fusion protein of endostatin and angiostatin, two endogenous and potent inhibitors of angiogenesis. Oncolytic measles viruses encoding human and mouse variants of a secretable endostatin/angiostatin fusion protein were designed and rescued according to established protocols. These viruses, known as MV-hE:A and MV-mE:A respectively, were then evaluated for their anti-angiogenic potential and efficacy against medulloblastoma cell lines and orthotopic mouse models of localized disease. Medulloblastoma cells infected by MV-E:A readily secrete endostatin and angiostatin prior to lysis. The inclusion of the endostatin/angiostatin gene did not negatively impact the measles virus’ cytotoxicity against medulloblastoma cells or alter its growth kinetics. Conditioned media obtained from these infected cells was capable of inhibiting multiple angiogenic factors in vitro, significantly reducing endothelial cell tube formation, viability and migration compared to conditioned media derived from cells infected by a control measles virus. Mice that were given a single intratumoral injection of MV-E:A likewise showed reduced numbers of tumor-associated blood

  12. Antiparkinsonian treatment for depression in Parkinson’s disease:Are selective serotonin reuptake inhibitors recommended?

    Philippe De Deurwaerdre; Yuqiang Ding

    2016-01-01

    Depression is a frequent comorbid syndrome in Parkinson’s disease. It is a difficult symptom to manage, as patients continuously receive antiparkinsonian medication and may also have to be treated for the amelioration of the side-effects of antiparkinsonian therapy. The first-line treatment for depression in Parkinson’s disease is the use of selective serotonin reuptake inhibitors (SSRIs). The clinical efficacy of these medications in patients with Parkinson’s disease is questionable. In fact, based on their mechanism of action, which requires at least a functional serotonergic system, it is predicted that SSRIs will have lower efficacy in patients with Parkinson’s disease. Here, we consider the mechanism of action of SSRIs in the context of Parkinson’s disease by investigating the fall in the levels of serotonergic markers and the inhibitory outcomes of antiparkinsonian treatment on serotonergic nerve activity. Because certain classes of antidepressant drugs are widely available, it is necessary to perform translational research to address different strategies used to manage depression in Parkinson’s disease.

  13. Vismodegib: A smoothened inhibitor for the treatment of advanced basal cell carcinoma

    Suruchi Aditya

    2013-01-01

    Full Text Available Incidence of basal cell carcinoma (BCC, the most common skin cancer in humans, is rising. Surgery is the mainstay of treatment but there is no standard of care for locally advanced or metastatic disease. Hedgehog signaling proteins are critical for cell growth and differentiation during embryogenesis; Hh pathway is silenced in adults. Dysregulated or aberrant Hh signaling has been implicated in the pathogenesis of BCC. This hyperactive pathway can be inhibited by use of smoothened inhibitors such as vismodegib. Food and drug administration approved this oral, once-daily medication in 2012 to treat adults with metastatic BCC or locally advanced, recurrent BCC after surgery and also for patients with locally advanced BCC who are not candidates for surgery or radiation treatment. Clinical studies have shown it to be highly efficacious and the most common adverse effects include, muscle spasms, alopecia and dysgeusia. Use of targeted biologic modifiers, exemplified by Hh directed therapeutics offer a new hope to patients with high-surgical morbidity or inoperable tumors.

  14. Levomilnacipran (Fetzima): A New Serotonin-Norepinephrine Reuptake Inhibitor for the Treatment of Major Depressive Disorder.

    Saraceni, Megan M; Venci, Jineane V; Gandhi, Mona A

    2014-08-01

    In July 2013, the US Food and Drug Administration approved levomilnacipran extended release (ER; Fetzima), a serotonin-norepinephrine reuptake inhibitor, for the treatment of adults with major depressive disorder. Levomilnacipran is an active enantiomer of the racemic drug milnacipran that is currently approved in the United States for the treatment of fibromyalgia. This article provides an overview of the mechanism of action, pharmacokinetic properties, clinical efficacy, safety, and tolerability of levomilnacipran ER. Relevant information was identified through a search of databases using the key word levomilnacipran. Additional information was obtained from fda.gov, by a review of the reference lists of identified articles, and from posters and abstracts from scientific meetings. Levomilnacipran ER, dosed once daily, is generally well tolerated and has demonstrated favorable effects compared to placebo in clinical trials of patients with major depressive disorder. The increased potency for norepinephrine reuptake inhibition is a characteristic that may represent a novel contribution for levomilnacipran. Additional studies comparing levomilnacipran ER to other commonly prescribed antidepressants are needed to further evaluate its place in therapy. PMID:24381243

  15. Differences in gene expression and alterations in cell cycle of acute myeloid leukemia cell lines after treatment with JAK inhibitors.

    Gunerka, Pawel; Dymek, Barbara; Stanczak, Aleksandra; Bujak, Anna; Grygielewicz, Paulina; Turowski, Pawel; Dzwonek, Karolina; Lamparska-Przybysz, Monika; Pietrucha, Tadeusz; Wieczorek, Maciej

    2015-10-15

    Janus kinase (JAK) inhibitors are a promising treatment strategy in several hematological malignancies and autoimmune diseases. A number of inhibitors are in clinical development, and two have already reached the market. Unfortunately, all of them are burdened with different toxicity profiles. To check if the JAK inhibitors of different selectivity evoke different responses on JAK2-dependent and independent cells, we have used three acute myeloid leukemia cell lines with confirmed JAK2 mutation status. We have found that JAK inhibitors exert distinct effect on the expression of BCLXL, CCND1 and c-MYC genes, regulated by JAK pathway, in JAK2 wild type cells in comparison to JAK2 V617F-positive cell lines. Moreover, cell cycle analysis showed that inhibitors alter the cycle by arresting cells in different phases. Our results suggest that observed effect of JAK2 inhibitors on transcription and cell cycle level in different cell lines are associated not with activity within JAK family, but presumably with other off-target activities. PMID:26300391

  16. 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.

  17. Intratumoral concentration of estrogens and clinicopathological changes in ductal carcinoma in situ following aromatase inhibitor letrozole treatment

    Takagi, K.; Ishida, T; Miki, Y; Hirakawa, H; Kakugawa, Y; Amano, G.; Ebata, A.; Mori, N; Nakamura, Y.; Watanabe, M.; Amari, M; Ohuchi, N.; Sasano, H; Suzuki, T

    2013-01-01

    Background: Estrogens have important roles in ductal carcinoma in situ (DCIS) of the breast. However, the significance of presurgical aromatase inhibitor treatment remains unclear. Therefore, we examined intratumoral concentration of estrogens and changes of clinicopathological factors in DCIS after letrozole treatment. Methods: Ten cases of postmenopausal oestrogen receptor (ER)-positive DCIS were examined. They received oral letrozole before the surgery, and the tumour size was evaluated by...

  18. Abiraterone acetate: oral androgen biosynthesis inhibitor for treatment of castration-resistant prostate cancer

    Rosenberg JE

    2012-01-01

    Full Text Available Yasser Rehman1, Jonathan E Rosenberg21Division of Hospital Medicine, UMass Memorial Healthcare, Worcester, MA, USA; 2Lank Center for Genitourinary Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USAAbstract: Prostate cancer is the second leading cause of cancer death in men in the US and Europe. The treatment of advanced-stage prostate cancer has been androgen deprivation. Medical castration leads to decreased production of testosterone and dihydrotestosterone by the testes, but adrenal glands and even prostate cancer tissue continue to produce androgens, which eventually leads to continued prostate cancer growth despite castrate level of androgens. This stage is known as castrate-resistant prostate cancer (CRPC, which continues to be a challenge to treat. Addition of androgen antagonists to hormonal deprivation has been successful in lowering the prostate-specific antigen levels further, but has not actually translated into life-prolonging options. The results of several contemporary studies have continued to demonstrate activation of the androgen receptor as being the key factor in the continued growth of prostate cancer. Blockade of androgen production by nongonadal sources has led to clinical benefit in this setting. One such agent is abiraterone acetate, which significantly reduces androgen production by blocking the enzyme, cytochrome P450 17 alpha-hydroxylase (CYP17. This has provided physicians with another treatment option for patients with CRPC. The landscape for prostate cancer treatment has changed with the approval of cabazitaxel, sipuleucel-T and abiraterone. Here we provide an overview of abiraterone acetate, its mechanism of action, and its potential place for therapy in CRPC.Keywords: CRPC, abiraterone, CYP17, inhibitors, androgens, castration resistant prostate cancer

  19. EFFECT OF CHRONIC ACE INHIBITION ON GLUCOSE TOLERANCE AND INSULIN SENSITIVITY IN HYPERTENSIVE TYPE 2 DIABETIC PATIENTS

    尹卫东; G.Seghieri; C.Boni,G,Sanna; R.Anichinl; G.Bartolomei; E.Ferrannini

    1994-01-01

    We studied 14 moderately overweight Type 2 diabetic patients with essential hypertension in stable metabolic control after a run-in period,and again after 3 months of antihypertensive treatment with the angiotensin-convert-ing enzyme(ACE)inhibitor captopril.Glucose tolerance was tested with a 75g oral glucose load (OGTT) and in-sulin sensitivity was measured by the insulin suppression test (IST)while dietary and drug treatment of the hyper-glycemia was maintained constant.In the whole group,mean blood pressure (MBP) fell progressively over 3 months from a baseline value of 123±3mmHg(1 mmHg=0.133kpa)to a final value of 115±2mmHg(P<0.005).After treatment,fasting plasma glucose,insulin,free fatty acid (FFA),potassium,and glycosylated hemoglobin concentrations were unchanged from baseling.There were no significant differences in glucose toler-ance and insulin sensitivity between pre-and post-trearment values.Neither endogenous (oral glucose)nor exoge-nous(IST)insulin caused any change in plasma potassium concentration. This resistance to the hypokalemic action of insulin was not affected by captopril.

  20. A new treatment for neurogenic inflammation caused by EV71 with CR2-targeted complement inhibitor

    Qiu Shaofu

    2012-11-01

    Full Text Available Abstract Background Enterovirus 71 (EV71, one of the most important neurotropic EVs, has caused death and long-term neurological sequelae in hundreds of thousands of young children in the Asia-Pacific region in the past decade. The neurological diseases are attributed to infection by EV71 inducing an extensive peripheral and central nervous system (CNS inflammatory response with abnormal cytokine production and lymphocyte depletion induced by EV71 infection. In the absence of specific antiviral agents or vaccines, an effective immunosuppressive strategy would be valuable to alleviate the severity of the local inflammation induced by EV71 infection. Presentation of the hypothesis The complement system plays a pivotal role in the inflammatory response. Inappropriate or excessive activation of the complement system results in a severe inflammatory reaction or numerous pathological injuries. Previous studies have revealed that EV71 infection can induce complement activation and an inflammatory response of the CNS. CR2-targeted complement inhibition has been proved to be a potential therapeutic strategy for many diseases, such as influenza virus-induced lung tissue injury, postischemic cerebral injury and spinal cord injury. In this paper, a mouse model is proposed to test whether a recombinant fusion protein consisting of CR2 and a region of Crry (CR2-Crry is able to specifically inhibit the local complement activation induced by EV71 infection, and to observe whether this treatment strategy can alleviate or even cure the neurogenic inflammation. Testing the hypothesis CR2-Crry is expressed in CHO cells, and its biological activity is determined by complement inhibition assays. 7-day-old ICR mice are inoculated intracranially with EV71 to duplicate the neurological symptoms. The mice are then divided into two groups, in one of which the mice are treated with CR2-Crry targeted complement inhibitor, and in the other with phosphate-buffered saline. A

  1. Comparison of efavirenz and protease inhibitor based combination antiretroviral therapy regimens in treatment-naïve people living with HIV with baseline resistance.

    Lim, Charlotte; McFaul, Katie; Kabagambe, Samuel; Sonecha, Sonali; Jones, Rachael; Asboe, David; Pozniak, Anton; Nwokolo, Nneka; Boffito, Marta

    2016-07-17

    A retrospective cohort analysis comparing the efficacy of boosted protease inhibitor-based and efavirenz-based combination antiretroviral therapy in treatment-naïve people living with HIV with baseline resistance found that efavirenz-based treatment led to a shorter mean time to undetectable viral load. A higher proportion of patients with nonnucleoside reverse transcriptase inhibitor related baseline resistance mutations in the efavirenz-treatment group achieved an undetectable viral load at both 6 and 12 months post-treatment initiation, compared with the boosted protease-inhibitor-treatment group.Supplementary content: http://links.lww.com/QAD/A930. PMID:27139315

  2. Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease

    Basi, Guriqbal S; Hemphill, Susanna; Brigham, Elizabeth F.; Liao, Anna; Aubele, Danielle L; Baker, Jeanne; Barbour, Robin; Bova, Michael; Chen, Xiao-Hua; Dappen, Michael S; Eichenbaum, Tovah; Goldbach, Erich; Hawkinson, Jon; Lawler-Herbold, Rose; Hu, Kang

    2010-01-01

    Introduction Inhibition of gamma-secretase presents a direct target for lowering Aβ production in the brain as a therapy for Alzheimer's disease (AD). However, gamma-secretase is known to process multiple substrates in addition to amyloid precursor protein (APP), most notably Notch, which has limited clinical development of inhibitors targeting this enzyme. It has been postulated that APP substrate selective inhibitors of gamma-secretase would be preferable to non-selective inhibitors from a ...

  3. The potential role of sodium glucose co‐transporter 2 inhibitors in the early treatment of type 2 diabetes mellitus

    Brunton, S. A.

    2015-01-01

    Summary Background Sodium glucose co‐transporter 2 (SGLT2) inhibitors are a new class of pharmacologic agents developed for the treatment of type 2 diabetes mellitus (T2DM). Their unique mechanism of action is independent of pancreatic beta‐cell function or the degree of insulin resistance, giving these agents the potential for use in combination with any of the existing classes of glucose‐lowering agents, including insulin. This makes SGLT2 inhibitors an option for patients with long‐standin...

  4. Discovery of SCH 900229, a Potent Presenilin 1 Selective γ-Secretase Inhibitor for the Treatment of Alzheimer's Disease.

    Wu, Wen-Lian; Domalski, Martin; Burnett, Duane A; Josien, Hubert; Bara, Thomas; Rajagopalan, Murali; Xu, Ruo; Clader, John; Greenlee, William J; Brunskill, Andrew; Hyde, Lynn A; Del Vecchio, Robert A; Cohen-Williams, Mary E; Song, Lixin; Lee, Julie; Terracina, Giuseppe; Zhang, Qi; Nomeir, Amin; Parker, Eric M; Zhang, Lili

    2012-11-01

    An exploration of the SAR of the side chain of a novel tricyclic series of γ-secretase inhibitors led to the identification of compound (-)-16 (SCH 900229), which is a potent and PS1 selective inhibitor of γ-secretase (Aβ40 IC50 = 1.3 nM). Compound (-)-16 demonstrated excellent lowering of Aβ after oral administration in preclinical animal models and was advanced to human clinical trials for further development as a therapeutic agent for the treatment of Alzheimer's disease. PMID:24900404

  5. Regulation of NKG2D-ligand cell surface expression by intracellular calcium after HDAC-inhibitor treatment

    Jensen, Helle; Hagemann-Jensen, Michael Henrik; Lauridsen, Felicia Kathrine Bratt;

    2013-01-01

    In this study we demonstrate that histone deacetylase (HDAC)-inhibitor mediated cell surface expression of the structural different NKG2D-ligands MICA/B and ULBP2 is calcium-dependent. Treatment with the calcium chelator EGTA inhibited constitutive as well as HDAC-inhibitor induced MICA/B and ULBP2...... cell surface expression on melanoma cells and Jurkat T-cells. A NKG2D-dependent cytolytic assay and staining with a recombinant NKG2D-Fc fusion protein showed that calcium chelation impaired the functional ability of NKG2D-ligands induced by HDAC-inhibitor treatment. The HDAC-inhibitor induced cell...... surface expression of ULBP2, but not MICA/B, was sensitive to treatment calmidazolium and trifluoperazine, two agents known to block calcium signaling. siRNA-mediated knock-down of the calcium-regulated proteins calmodulin or calpain did however not affect NKG2D-ligand cell surface expression on Jurkat T...

  6. Side Effects Related to 5 α-Reductase Inhibitor Treatment of Hair Loss in Women: A Review.

    Seale, Lauren R; Eglini, Ariana N; McMichael, Amy J

    2016-04-01

    5 α-reductase inhibitors such as finasteride and dutasteride have been studied for the treatment of hair loss in men, with finasteride being the only Food and Drug Administration-approved treatment. Increasingly, in recent years, off-label use of these drugs has been employed in the treatment of female pattern hair loss (FPHL) and frontal fibrosing alopecia (FFA) in women. Side effects with 5 α-reductase inhibitors can include changes in sexual function, and recent publications have characterized an increasing prevalence of these in men. A review of 20 peer-reviewed articles found that very few side effects, or adverse events, related to sexual function have been reported in studies in which dutasteride or finasteride has been used to treat hair loss in women. Future publications should investigate not only the efficacy of these drugs in treating FPHL and FFA, but the side effect profile in patients as well. PMID:27050696

  7. 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

  8. Peramivir: A Novel Intravenous Neuraminidase Inhibitor for Treatment of Acute Influenza Infections.

    Alame, Malak M; Massaad, Elie; Zaraket, Hassan

    2016-01-01

    Peramivir is a novel cyclopentane neuraminidase inhibitor of influenza virus. It was approved by the Food and Drug Administration in December 2014 for treatment of acute uncomplicated influenza in patients 18 years and older. For several months prior to approval, the drug was made clinically available under Emergency Use authorization during the 2009 H1N1 influenza pandemic. Peramivir is highly effective against human influenza A and B isolates as well as emerging influenza virus strains with pandemic potential. Clinical trials demonstrated that the drug is well-tolerated in adult and pediatric populations. Adverse events are generally mild to moderate and similar in frequency to patients receiving placebo. Common side effects include gastrointestinal disorders and decreased neutrophil counts but are self-limiting. Peramivir is administered as a single-dose via the intravenous route providing a valuable therapeutic alternative for critically ill patients or those unable to tolerate other administration routes. Successful clinical trials and post-marketing data in pediatric populations in Japan support the safety and efficacy of peramivir in this population where administration of other antivirals might not be feasible. PMID:27065996

  9. Study of Osteoarthritis Treatment with Anti-Inflammatory Drugs: Cyclooxygenase-2 Inhibitor and Steroids

    Hongsik Cho

    2015-01-01

    Full Text Available Patients with osteoarthritis (OA, a condition characterized by cartilage degradation, are often treated with steroids, nonsteroidal anti-inflammatory drugs (NSAIDs, and cyclooxygenase-2 (COX-2 selective NSAIDs. Due to their inhibition of the inflammatory cascade, the drugs affect the balance of matrix metalloproteinases (MMPs and inflammatory cytokines, resulting in preservation of extracellular matrix (ECM. To compare the effects of these treatments on chondrocyte metabolism, TNF-α was incubated with cultured chondrocytes to mimic a proinflammatory environment with increasing production of MMP-1 and prostaglandin E2 (PGE2. The chondrocytes were then treated with either a steroid (prednisone, a nonspecific COX inhibitor NSAID (piroxicam, or a COX-2 selective NSAID (celecoxib. Both prednisone and celecoxib decreased MMP-1 and PGE-2 production while the nonspecific piroxicam decreased only the latter. Both prednisone and celecoxib decreased gene expression of MMP-1 and increased expression of aggrecan. Increased gene expression of type II collagen was also noted with celecoxib. The nonspecific piroxicam did not show these effects. The efficacy of celecoxib in vivo was investigated using a posttraumatic OA (PTOA mouse model. In vivo, celecoxib increases aggrecan synthesis and suppresses MMP-1. In conclusion, this study demonstrates that celecoxib and steroids exert similar effects on MMP-1 and PGE2 production in vitro and that celecoxib may demonstrate beneficial effects on anabolic metabolism in vivo.

  10. ACED mechanical devices for the control of behaviour of nuclear structures to seismic events

    Treatment of seismic records and the analysis of behaviour of structure indicated that over 80% of the dwelt Romanian territory has a high seismic risk. The earthquakes produced during the last 60 years diminished the structure resistance capacity of most of existent buildings. Consequently, the behaviour control of the existing built structures or of the buildings under construction, particularly for nuclear stations, particularly to seismic events and, generally, to dynamic actions, is extremely important for diminishing as much as possible the consequences of major earthquakes. New ACED devices presented in this paper can be applied both to an efficient consolidation in a short time as well in building new constructions. The ACED devices are easy to achieve and the utilization will increase the quality of consolidation work, will reduce the work expense at the construction site, will improve the environmental protection and will allow an effective control of the behaviour of new and existent structure to dynamical actions. The control of the structure behaviour using ACED devices is achieved by: 1. embodying the ACED devices in the building resistance structure, so obtaining a 'telescoping' system which, within the elastic range of the stresses to which the resistance structure is submitted, dissipates a large amount of seismic energy; by its controlled deformation one gets a increased stiffness of the building structure; 2. emplacing the ACED device between a general raft and the construction's foundation, so obtaining an isolation of the building allowing ground motion under the building without a transmission of the seismic excitation to the building; 3. combined measures of isolation and improving the building behaviour by embodying ACED device in the resistance structure concomitantly with the isolation of the foundation. The ACED device have a compact structure, are reliable and can be guarantied over the life span of the building. The rigidity and damping

  11. Isolation and characterisation of acetylcholinesterase inhibitors from Aquilaria subintegra for the treatment of Alzheimer's disease (AD).

    Bahrani, Hirbod; Mohamad, Jamaludin; Paydar, Mohammad Javad; Rothan, Hussin A

    2014-02-01

    Aquilaria subintegra, locally known as "Gaharu", belongs to the Thymelaeceae family. This plant's leaves have been claimed to be effective for the treatment of Alzheimer's disease (AD) by Malay traditional practitioner in Malaysia. In this research, the chloroform extracts of the leaves and stem of A. subintegra were tested for acetylcholinesterase (AChE) inhibitory activity. The Thin Layer Chromatography (TLC) results indicated the presence of phenols, flavonoids, terpenoids, and alkaloids compounds in the extracts. Analysis of the stem chloroform extracts with LCMS/MS displayed that it contains kaempferol 3,4,7-trimethyl ether. The AChE inhibitory activity of leaves and stem chloroform extracts and kaempferol were 80%, 93% and 85.8%, respectively. The Brine Shrimp Lethality Assay (BSLA) exhibited low to moderate toxicity of the chloroform extract from leaves (LC50=531.18 ± 49.53 μg/ml), the stem chloroform extract (LC50=407.34 ± 68.05 μg/ml) and kaempferol (LC50=762.41 ± 45.09 μg/ml). The extracts and kaempferol were not cytotoxic to human umbilical vein endothelial cells (HUVEC), human normal gastric epithelial cell line (GES-1) and human normal hepatic cell line (WRL-68). The effect of leaf and stem chloroform extracts and kaempferol were determined in the Radial Arm Maze (RAM) after administration by oral gavage to ICR male and female mice with valium-impaired memory. Administration of kaempferol to the mice significantly reduced the number of repeated entries into the arms of maze in males and females. In conclusion, the inhibition of AChE by leaf and stem chloroform extracts of A. subintegra could be due to the presence of kaempferol. This extract is safe for use as a natural AChE inhibitor as an alternative to berberine for the treatment of AD. PMID:24479629

  12. Long-term treatment with proton pump inhibitor is associated with undesired weight gain

    Ichiro Yoshikawa; Makiko Nagato; Masahiro Yamasaki; Keiichiro Kume; Makoto Otsuki

    2009-01-01

    AIM: To examine the effects of long-term proton pump inhibitor (PPI) therapy on body weight (BW) and body mass index (BMI) in patients with gastroesophageal reflux disease (GERD). METHODS: The subjects were 52 patients with GERD and 58 sex- and age-matched healthy controls. GERD patients were treated with PPI for a mean of 2.2 years (range, 0.8-5.7 years), and also advised on lifestyle modifications (e.g. selective diet, weight management). BW, BMI and other parameters were measured at baseline and end of study. RESULTS: Twenty-four GERD patients were treated daily with 10 mg omeprazole, 12 with 20 mg omeprazole, 8 with 10 mg rabeprazole, 5 with 15 mg lansoprazole, and 3 patients with 30 mg lansoprazole. At baseline, there were no differences in BW and BMI between reflux patients and controls. Patients with GERD showed increases in BW (baseline: 56.4 ± 10.4 kg, end: 58.6 ± 10.8 kg, mean ± SD, P < 0.0001) and BMI (baseline: 23.1 ± 3.1 kg/m~2, end: 24.0 ± 3.1 kg/m~2, P < 0.001), but no such changes were noted in the control group. Mean BW increased by 3.5 kg (6.2% of baseline) in 37 (71%) reflux patients but decreased in only 6 (12%) patients during treatment. CONCLUSION: Long-term PPI treatment was associated with BW gain in patients with GERD. Reflux patients receiving PPI should be encouraged to manage BW through lifestyle modifications.

  13. AceWiki: A Natural and Expressive Semantic Wiki

    Kuhn, Tobias

    2008-01-01

    We present AceWiki, a prototype of a new kind of semantic wiki using the controlled natural language Attempto Controlled English (ACE) for representing its content. ACE is a subset of English with a restricted grammar and a formal semantics. The use of ACE has two important advantages over existing semantic wikis. First, we can improve the usability and achieve a shallow learning curve. Second, ACE is more expressive than the formal languages of existing semantic wikis. Our evaluation shows that people who are not familiar with the formal foundations of the Semantic Web are able to deal with AceWiki after a very short learning phase and without the help of an expert.

  14. Alternative therapies for the management of inhibitors.

    Shima, M; Lillicrap, D; Kruse-Jarres, R

    2016-07-01

    The development of inhibitors to factor VIII (FVIII) or factor IX (FIX) remains a major treatment complication encountered in the treatment of haemophilia. Not all patients with even the same severity and genotype develop inhibitors suggesting an underlying mechanism of tolerance against FVIII- or FIX-related immunity. One mechanism may be central tolerance observed in patients in whom the FVIII mutation enables some production of the protein. The other is a peripheral tolerance mechanism which may be evident in patients with null mutation. Recently, recombinant porcine FVIII (rpFVIII, Obixur, OBI-1, BAX801) has been developed for the haemostatic treatment of both congenital haemophilia with inhibitor (CHAWI) and acquired haemophilia A (AHA). In 28 subjects with AHA with life-/limb-threatening bleeding, rpFVIII reduced or stopped bleeding in all patients within 24 h. The cross-reactivity of anti-human FVIII antibodies to rpFVIII remains around 30-50%. Recently, new therapeutics based on the quite novel concepts have been developed and clinical studies are ongoing. These are humanized asymmetric antibody mimicking FVIIIa function by maintaining a suitable interaction between FIXa and FX (Emicizumab, ACE910), and small interfering RNAs (siRNA, ALN-AT3) suppress liver production of AT through post-transcriptional gene silencing and a humanized anti-TFPI monoclonal antibody (Concizumab). Their main advantages are longer half-life, subcutaneous applicability and efficacy irrespective of the presence of inhibitors which will make it easier to initiate more effective treatment especially early childhood. PMID:27405674

  15. Tissue-specific expression of transgenic secreted ACE in vasculature can restore normal kidney functions, but not blood pressure, of Ace-/- mice.

    Saurabh Chattopadhyay

    Full Text Available Angiotensin-converting enzyme (ACE regulates normal blood pressure and fluid homeostasis through its action in the renin-angiotensin-system (RAS. Ace-/- mice are smaller in size, have low blood pressure and defective kidney structure and functions. All of these defects are cured by transgenic expression of somatic ACE (sACE in vascular endothelial cells of Ace-/- mice. sACE is expressed on the surface of vascular endothelial cells and undergoes a natural cleavage secretion process to generate a soluble form in the body fluids. Both the tissue-bound and the soluble forms of ACE are enzymatically active, and generate the vasoactive octapeptide Angiotensin II (Ang II with equal efficiency. To assess the relative physiological roles of the secreted and the cell-bound forms of ACE, we expressed, in the vascular endothelial cells of Ace-/- mice, the ectodomain of sACE, which corresponded to only the secreted form of ACE. Our results demonstrated that the secreted form of ACE could normalize kidney functions and RAS integrity, growth and development of Ace-/- mice, but not their blood pressure. This study clearly demonstrates that the secreted form of ACE cannot replace the tissue-bound ACE for maintaining normal blood pressure; a suitable balance between the tissue-bound and the soluble forms of ACE is essential for maintaining all physiological functions of ACE.

  16. Immunological changes in human immunodeficiency virus (HIV)-infected individuals during HIV-specific protease inhibitor treatment

    Ullum, H; Katzenstein, T; Aladdin, H;

    1999-01-01

    The present study examines the influence of effective anti-retroviral treatment on immune function, evaluated by a broad array of immunological tests. We followed 12 individuals infected with human immunodeficiency virus (HIV) for 6 months after initiation of combination anti-retroviral treatment...... Vaccinia virus was increased after 3-6 months, whereas the specific HIV-directed CTL activity and the concentration and lytic activity of natural killer (NK) cells were unchanged during follow-up. These results demonstrate that the initiation of a treatment including an HIV protease inhibitor is followed...

  17. Place of sodium-glucose co-transporter type 2 inhibitors for treatment of type 2 diabetes

    Nasser; Mikhail

    2014-01-01

    Inhibitors of sodium-glucose co-transporter type 2(SGLT2), such as canagliflozin and dapagliflozin, are recently approved for treatment of type 2 diabetes. These agents lower blood glucose mainly by increasing urinary glucose excretion. Compared with placebo, SGLT2 inhibitors reduce hemoglobin A1c(Hb A1c) levels by an average of 0.5%-0.8% when used as monotherapy or add-on therapy. Advantages of this drug class include modest weight loss of approximately 2 kg, low risk of hypoglycemia, and decrease blood pressure of approximately 4 mm Hg systolic and 2 mm Hg diastolic. These characteristics make these agents potential add-on therapy in patients with Hb A1 c levels close to 7%-8.0%, particularly if these patients are obese, hypertensive, and/or prone for hypoglycemia. Meanwhile, these drugs are limited by high frequency of genital mycotic infections. Less common adverse effects include urinary tract infections, hypotension, dizziness, and worsening renal function. SGLT2 inhibitors should be used with caution in the elderly because of increased adverse effects, and should not be used in chronic kidney disease due to decreased or lack of efficacy and nephrotoxicity. Overall, SGLT2 inhibitors are useful addition for treatment of select groups of patients with type 2 diabetes,but their efficacy and safety need to be established in long-term clinical trials.

  18. Nationwide trends in the prescription of beta-blockers and angiotensin-converting enzyme inhibitors after myocardial infarction in Denmark, 1995-2002

    Gislason, Gunnar H; Abildstrom, Steen Z; Rasmussen, Jeppe Nørgaard;

    2005-01-01

    OBJECTIVES: To study the use of beta-blockers and angiotensin-converting enzyme (ACE) inhibitors after acute myocardial infarction (AMI) in Denmark from 1995 to 2002. DESIGN: Information about patients with first AMI aged > or = 30 years and the dispensing of beta-blockers and ACE inhibitors from......-diuretics and antidiabetic drugs received beta-blockers less frequently, but patients taking loop-diuretics or antidiabetic drugs had the greatest increase. ACE inhibitor use increased from 24.5 to 35.5% (OR = 1.86, CI: 1.72-2.01). Women, patients aged or = 80 years and patients not taking loop......-diuretics received ACE inhibitors less frequently, but patients not taking loop-diuretics had the greatest increase. CONCLUSIONS: Beta-blocker use increased markedly post-AMI from 1995 to 2002, whereas ACE inhibitor use increased modestly. The results suggested undertreatment of women, elderly patients and people...

  19. 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...

  20. User's manual ACE/ONED (Version 1.0)

    This report explains installation of ACE/ONED code, structure of input and output, how to prepare input and introduces some sample inputs. ACE/ONED developed by KAERI is a two-group one-dimensional diffusion theory code for nuclear design and reactor simulations. The usage of ACE/ONED encompasses core follow calculation, load-following calculation, plant power control simulation, xenon oscillation simulation, control rod maneuvering, and so on. ACE/ONED programmed of FORTRAN 77 in most part can be run on almost all kinds of computer including personal computer. 4 tabs., 4 figs., 8 refs. (Author) .new

  1. Treatment of human pre-B acute lymphoblastic leukemia with the Aurora kinase inhibitor PHA-739358 (Danusertib

    Fei Fei

    2012-06-01

    Full Text Available Abstract Background Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemias (Ph-positive ALL with clinically approved inhibitors of the Bcr/Abl tyrosine kinase frequently results in the emergence of a leukemic clone carrying the T315I mutation in Bcr/Abl, which confers resistance to these drugs. PHA-739358, an Aurora kinase inhibitor, was reported to inhibit the Bcr/Abl T315I mutant in CML cells but no preclinical studies have examined this in detail in human ALL. Results We compared the sensitivity of human Bcr/Abl T315I, Bcr/Abl wild type and non-Bcr/Abl ALL cells to this drug. PHA-739358 inhibited proliferation and induced apoptosis independently of Bcr/Abl, the T315I mutation, or presence of the tumor suppressor p53, but the degree of effectiveness varied between different ALL samples. Since short-term treatment with a single dose of drug only transiently inhibited proliferation, we tested combination treatments of PHA-739358 with the farnesyltransferase inhibitor Lonafarnib, with vincristine and with dasatinib. All combinations reduced viability and cell numbers compared to treatment with a single drug. Clonogenic assays showed that 25 nM PHA-739358 significantly reduced the colony growth potential of Ph-positive ALL cells, and combined treatment with a second drug abrogated colony growth in this assay. PHA-739358 further effectively blocked Bcr/Abl tyrosine kinase activity and Aurora kinase B in vivo, and mice transplanted with human Bcr/Abl T315I ALL cells treated with a 3x 7-day cycle of PHA-739358 as mono-treatment had significantly longer survival. Conclusions PHA-739358 represents an alternative drug for the treatment of both Ph-positive and negative ALL, although combined treatment with a second drug may be needed to eradicate the leukemic cells.

  2. Cholesteryl ester transfer protein inhibitors in the treatment of dyslipidemia: a systematic review and meta-analysis.

    Chuanwei Li

    Full Text Available Cholesteryl ester transfer protein (CETP inhibitors are gaining substantial research interest for raising high density lipoprotein cholesterol levels. The aim of the research was to estimate the efficacy and safety of cholesteryl ester transfer protein inhibitors as novel lipid modifying drugs. Systematic searches of English literature for randomized controlled trials (RCT were collected from MEDLINE, EBASE, CENTRAL and references listed in eligible studies. Two independent authors assessed the search results and only included the double-blind RCTs by using cholesteryl ester transfer protein inhibitors as exclusively or co-administrated with statin therapy irrespective of gender in enrolled adult subjects. Two independent authors extracted the data by using predefined data fields. Of 503 studies identified, 14 studies met the inclusion criteria, and 12 studies were included into the final meta-analysis. Our meta-analysis revealed that CETP inhibitors increased the HDL-c levels (n = 2826, p<0.00001, mean difference (MD = 20.47, 95% CI [19.80 to 21.15] and total cholesterol (n = 3423, p = 0.0002, MD = 3.57, 95%CI [1.69 to 5.44] to some extent combined with a reduction in triglyceride (n = 3739, p<0.00001, MD = -10.47, 95% CI [-11.91 to -9.03] and LDL-c (n = 3159, p<0.00001, MD = -17.12, 95% CI [-18.87 to -15.36] irrespective of mono-therapy or co-administration with statins. Subgroup analysis suggested that the lipid modifying effects varied according to the four currently available CETP inhibitors. CETP inhibitor therapy did not increase the adverse events when compared with control. However, we observed a slight increase in blood pressure (SBP, n = 2384, p<0.00001, MD = 2.73, 95% CI [2.14 to 3.31], DBP, n = 2384, p<0.00001, MD = 1.16, 95% CI [0.73 to 1.60] after CETP inhibitor treatment, which were mainly ascribed to the torcetrapib treatment subgroup. CETP inhibitors therapy is associated with significant increase in HDL-c and decrease in

  3. Treatment of renal colic by prostaglandin synthetase inhibitors and avafortan (analgesic antispasmodic).

    el-Sherif, A E; Foda, R; Norlen, L J; Yahia, H

    1990-12-01

    In a study of the pain-relieving effect of 3 drugs commonly used to treat acute renal colic in this hospital, intravenous indomethacin and intramuscular diclofenac (prostaglandin synthetase inhibitors) were compared with intravenous Avafortan (analgesic antispasmodic). As first-line analgesics, prostaglandin synthetase inhibitors, if given intravenously, offer an effective alternative to Avafortan. Of 145 patients studied, 32 required a second injection for complete relief of pain. Administering a second dose of prostaglandin synthetase inhibitors resulted in equally significant pain relief rate even though the route was intramuscular. PMID:2265331

  4. Lamotrigine Augmentation of Serotonin Reuptake Inhibitors in Severe and Long-Term Treatment-Resistant Obsessive-Compulsive Disorder

    Manuel Arrojo-Romero

    2013-01-01

    Full Text Available The treatment recommendations in obsessive-compulsive disorder (OCD after lack of response to selective serotonin reuptake inhibitors (SSRIs include augmentation with other drugs, particularly clomipramine, a more potent serotonin reuptake inhibitor (SRI, or antipsychotics. We present two cases of response to lamotrigine augmentation in treatment-refractory OCD; each received multiple SRI trials over a >10-year period. The first patient had eleven years of treatment with multiple combinations including clomipramine and SSRIs. She had a >50% decrease of Y-BOCS (from 29 to 14 by augmenting paroxetine (60 mg/day with lamotrigine (100 mg/day. The second patient had 22 years of treatment with multiple combinations, including combinations of SSRIs with clomipramine and risperidone. She had an almost 50% decrease of Y-BOCS (from 30 to 16 and disappearance of tics by augmenting clomipramine (225 mg/d with lamotrigine (200 mg/day. These two patients were characterized by lack of response to multiple treatments, making a placebo response to lamotrigine augmentation unlikely. Prospective randomized trials in treatment-resistant OCD patients who do not respond to combinations of SSRIs with clomipramine and/or antipsychotics are needed, including augmentation with lamotrigine. Until these trials are available, our cases suggest that clinicians may consider lamotrigine augmentation in such treatment-resistant OCD patients.

  5. SGLT2 inhibitors – an insulin-independent therapeutic approach for treatment of type 2 diabetes: focus on canagliflozin

    Seufert J

    2015-11-01

    Full Text Available Jochen SeufertDepartment of Endocrinology and Diabetology, Clinic for Internal Medicine II, Freiburg University Hospital, Freiburg, GermanyAbstract: Despite the availability of a great variety of medications, a significant proportion of people with type 2 diabetes mellitus (T2DM are not able to achieve or maintain adequate glycemic control. Beyond improved glucose control, novel treatments would ideally provide a reduction of cardiovascular risk, with a favorable impact on excess weight, and a low intrinsic hypoglycemia risk, as well as a synergistic mechanism of action for broad combination therapy. With the development of sodium glucose cotransporter 2 (SGLT2 inhibitors, an antidiabetic pharmacologic option has recently become available that comes close to meeting these requirements. For the first time, SGLT2 inhibitors offer a therapeutic approach acting directly on the kidneys without requiring insulin secretion or action. Canagliflozin, dapagliflozin, and empagliflozin are the SGLT2 inhibitors approved to date. Taken once a day, these medications can be combined with all other antidiabetic medications including insulin, due to their insulin-independent mechanism of action, with only a minimal risk of hypoglycemia. SGLT2 inhibitors provide additional reductions in body weight and blood pressure due to the therapeutically induced excretion of glucose and sodium through the kidneys. These "concomitant effects" are particularly interesting with regard to the increased cardiovascular risk in T2DM. In many cases, T2DM treatment requires a multidimensional approach where the treatment goals have to be adapted to the individual patient. While there is a consensus on the use of metformin as a first-line drug therapy, various antidiabetics are used for treatment intensification. New mechanisms of action like that of SGLT2 inhibitors such as canagliflozin, which can be used both in early and late stages of diabetes, are a welcome addition to expand

  6. Potential Therapeutic Value of a Novel FAAH Inhibitor for the Treatment of Anxiety.

    Eva M Marco

    Full Text Available Anxiety disorders are among the most prevalent psychiatric diseases with high personal costs and a remarkable socio-economic burden. However, current treatment of anxiety is far from satisfactory. Novel pharmacological targets have emerged in the recent years, and attention has focused on the endocannabinoid (eCB system, given the increasing evidence that supports its central role in emotion, coping with stress and anxiety. In the management of anxiety disorders, drug development strategies have left apart the direct activation of type-1 cannabinoid receptors to indirectly enhance eCB signalling through the inhibition of eCB deactivation, that is, the inhibition of the fatty acid amide hydrolase (FAAH enzyme. In the present study, we provide evidence for the anxiolytic-like properties of a novel, potent and selective reversible inhibitor of FAAH, ST4070, orally administered to rodents. ST4070 (3 to 30 mg/kg per os administered to CD1 male mice induced an increase of time spent in the exploration of the open arms of the elevated-plus maze. A partial reduction of anxiety-related behaviour by ST4070 was also obtained in Wistar male rats, which moderately intensified the time spent in the illuminated compartment of the light-dark box. ST4070 clearly inhibited FAAH activity and augmented the levels of two of its substrates, N-arachidonoylethanolamine (anandamide and N-palmitoylethanolamine, in anxiety-relevant brain regions. Altogether, ST4070 offers a promising anxiolytic-like profile in preclinical studies, although further studies are warranted to clearly demonstrate its efficacy in the clinic management of anxiety disorders.

  7. Treatment with polyamine oxidase inhibitor reduces microglial activation and limits vascular injury in ischemic retinopathy.

    Patel, C; Xu, Z; Shosha, E; Xing, J; Lucas, R; Caldwell, R W; Caldwell, R B; Narayanan, S P

    2016-09-01

    Retinal vascular injury is a major cause of vision impairment in ischemic retinopathies. Insults such as hyperoxia, oxidative stress and inflammation contribute to this pathology. Previously, we showed that hyperoxia-induced retinal neurodegeneration is associated with increased polyamine oxidation. Here, we are studying the involvement of polyamine oxidases in hyperoxia-induced injury and death of retinal vascular endothelial cells. New-born C57BL6/J mice were exposed to hyperoxia (70% O2) from postnatal day (P) 7 to 12 and were treated with the polyamine oxidase inhibitor MDL 72527 or vehicle starting at P6. Mice were sacrificed after different durations of hyperoxia and their retinas were analyzed to determine the effects on vascular injury, microglial cell activation, and inflammatory cytokine profiling. The results of this analysis showed that MDL 72527 treatment significantly reduced hyperoxia-induced retinal vascular injury and enhanced vascular sprouting as compared with the vehicle controls. These protective effects were correlated with significant decreases in microglial activation as well as levels of inflammatory cytokines and chemokines. In order to model the effects of polyamine oxidation in causing microglial activation in vitro, studies were performed using rat brain microvascular endothelial cells treated with conditioned-medium from rat retinal microglia stimulated with hydrogen peroxide. Conditioned-medium from activated microglial cultures induced cell stress signals and cell death in microvascular endothelial cells. These studies demonstrate the involvement of polyamine oxidases in hyperoxia-induced retinal vascular injury and retinal inflammation in ischemic retinopathy, through mechanisms involving cross-talk between endothelial cells and resident retinal microglia. PMID:27239699

  8. Potential Therapeutic Value of a Novel FAAH Inhibitor for the Treatment of Anxiety.

    Marco, Eva M; Rapino, Cinzia; Caprioli, Antonio; Borsini, Franco; Laviola, Giovanni; Maccarrone, Mauro

    2015-01-01

    Anxiety disorders are among the most prevalent psychiatric diseases with high personal costs and a remarkable socio-economic burden. However, current treatment of anxiety is far from satisfactory. Novel pharmacological targets have emerged in the recent years, and attention has focused on the endocannabinoid (eCB) system, given the increasing evidence that supports its central role in emotion, coping with stress and anxiety. In the management of anxiety disorders, drug development strategies have left apart the direct activation of type-1 cannabinoid receptors to indirectly enhance eCB signalling through the inhibition of eCB deactivation, that is, the inhibition of the fatty acid amide hydrolase (FAAH) enzyme. In the present study, we provide evidence for the anxiolytic-like properties of a novel, potent and selective reversible inhibitor of FAAH, ST4070, orally administered to rodents. ST4070 (3 to 30 mg/kg per os) administered to CD1 male mice induced an increase of time spent in the exploration of the open arms of the elevated-plus maze. A partial reduction of anxiety-related behaviour by ST4070 was also obtained in Wistar male rats, which moderately intensified the time spent in the illuminated compartment of the light-dark box. ST4070 clearly inhibited FAAH activity and augmented the levels of two of its substrates, N-arachidonoylethanolamine (anandamide) and N-palmitoylethanolamine, in anxiety-relevant brain regions. Altogether, ST4070 offers a promising anxiolytic-like profile in preclinical studies, although further studies are warranted to clearly demonstrate its efficacy in the clinic management of anxiety disorders. PMID:26360704

  9. The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia.

    Wiestner, Adrian

    2015-12-01

    Chronic lymphocytic leukemia is a malignancy of mature auto-reactive B cells. Genetic and functional studies implicate B-cell receptor signaling as a pivotal pathway in its pathogenesis. Full B-cell receptor activation requires tumor-microenvironment interactions in lymphoid tissues. Spleen tyrosine kinase, Bruton's tyrosine kinase, and the phosphatidylinositol 3-kinase (PI3K) δ isoform are essential for B-cell receptor signal transduction but also mediate the effect of other pathways engaged in chronic lymphocytic leukemia cells in the tissue-microenvironment. Orally bioavailable inhibitors of spleen tyrosine kinase, Bruton's tyrosine kinase, or PI3Kδ, induce high rates of durable responses. Ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, and idelalisib, a selective inhibitor of PI3Kδ, have obtained regulatory approval in chronic lymphocytic leukemia. Ibrutinib and idelalisib are active in patients with high-risk features, achieving superior disease control in difficult-to-treat patients than prior best therapy, making them the preferred agents for chronic lymphocytic leukemia with TP53 aberrations and for patients resistant to chemoimmunotherapy. In randomized trials, both ibrutinib, versus ofatumumab, and idelalisib in combination with rituximab, versus placebo with rituximab improved survival in relapsed/refractory chronic lymphocytic leukemia. Responses to B-cell receptor inhibitors are mostly partial, and within clinical trials treatment is continued until progression or occurrence of intolerable side effects. Ibrutinib and idelalisib are, overall, well tolerated; notable adverse events include increased bruising and incidence of atrial fibrillation on ibrutinib and colitis, pneumonitis and transaminase elevations on idelalisib. Randomized trials investigate the role of B-cell receptor inhibitors in first-line therapy and the benefit of combinations. This review discusses the biological basis for targeted therapy of chronic lymphocytic

  10. Acute Kidney Injury in Elderly Patients With Chronic Kidney Disease: Do Angiotensin-Converting Enzyme Inhibitors Carry a Risk?

    Chaumont, Martin; Pourcelet, Aline; van Nuffelen, Marc; Racapé, Judith; Leeman, Marc; Hougardy, Jean-Michel

    2016-06-01

    In contrast to angiotensin receptor blockers (ARBs), mainly excreted by the liver, the dosage of angiotensin-converting enzyme (ACE) inhibitors, cleared by the kidney, must be adapted to account for renal clearance in patients with chronic kidney disease (CKD) to avoid acute kidney injury (AKI). Community-acquired AKI and the use of ACE inhibitors or ARBs in the emergency department were retrospectively assessed in 324 patients with baseline stage 3 or higher CKD. After stepwise regression analysis, the use of ACE inhibitors (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.1-3.1; P=.02) and the presence of dehydration (OR, 30.8; 95% CI, 3.9-239.1) were associated with AKI. A total of 45% of patients using ACE inhibitors experienced overdosing, which causes most of the excess risk of AKI. These results suggest that dosage adjustment of ACE inhibitors to renal function or substitution of ACE inhibitors with ARBs could reduce the incidence of AKI. Moreover, ACE inhibitors and ARBs should be stopped in cases of dehydration. PMID:27080620

  11. Preoperative angiotensin converting enzyme inhibitor usage in patients with chronic subdural hematoma: Associations with initial presentation and clinical outcome.

    Neidert, Marian C; Schmidt, Tobias; Mitova, Tatyana; Fierstra, Jorn; Bellut, David; Regli, Luca; Burkhardt, Jan-Karl; Bozinov, Oliver

    2016-06-01

    The aim of this study is to analyze the association of preoperative usage of angiotensin converting enzyme (ACE) inhibitors with the initial presentation and clinical outcome of patients with chronic subdural hematoma (cSDH). Patients treated for cSDH between 2009 and 2013 at our institution were included in this retrospective case-control study. Medical charts were reviewed retrospectively and data were analyzed using descriptive and inferential statistics. Out of 203 patients (58 females, mean age 73.2years), 53 (26%) patients were on ACE inhibitors before their presentation with cSDH. Median initial hematoma volume in individuals with ACE inhibitors (179.2±standard error of the mean [SEM] 13.0ml) was significantly higher compared to patients without ACE inhibitors (140.4±SEM 6.2ml; p=0.007). There was an increased probability of surgical reintervention in the ACE inhibitor group (12/53, 23% versus 19/153, 12%; p=0.079), especially in patients older than 80years (6/23, 26% versus 3/45, 7%; p=0.026). ACE inhibitors are associated with higher hematoma volume in patients with cSDH and with a higher frequency of recurrences requiring surgery (especially in the very old). We hypothesize that these effects are due to ACE inhibitor induced bradykinin elevation causing increased vascular permeability of the highly vascularized neomembranes in cSDH. PMID:26898577

  12. Scleroderma renal crisis during intravenous cyclophosphamide pulse therapy for complicated interstitial lung disease was successfully treated with angiotensin converting enzyme inhibitor and plasma exchange.

    Nagamura, Norihiro; Kin, Seikon

    2016-08-01

    Systemic sclerosis (SSc) is a multiorgan disorder involving the skin, heart, lungs, kidneys, and intestines. Progressive interstitial lung disease (ILD) is a serious complication in SSc patients, and cyclophosphamide (CYC) is the only recommended therapy for this condition;(1)) however, its clinical effectiveness is not sufficient. Scleroderma renal crisis (SRC) is a rare complication, characterized by acute renal failure and progressive hypertension. Angiotensin-converting-enzyme inhibitor (ACE-i) is a widely accepted therapy for SRC. We report an SSc patient with SRC and progressive ILD who underwent treatment with CYC and successful treatment with ACE-i and plasma exchange (PE). SRC and ILD are significant contributors to morbidity and mortality among SSc patients, and the therapy for these disorders is of great interest to rheumatologists. This study presents the possibility of favorable effects of PE for SSc-associated ILD and SRC. PMID:27578917

  13. New-generation mutitargeted tyrosine kinase inhibitors in the treatment of radioactive iodine-refractory differentiated thyroid cancer

    A. M. Mudunov

    2015-01-01

    Background. Thyroid cancer (TC) is one of the common oncological disease of the head and neck. However, its treatment is sharply restricted in a locally advanced and metastatic cancer process. In the past decade, there have been fundamental changes in the understanding of the molecular bases of thyroid carcinogenesis, resulting in the design of novel targeted drugs aimed at disseminated and refractory TC control. Multikinase inhibitors that are able to block the processes of proliferation, in...

  14. Synthesis of Quinoline Derivatives: Discovery of a Potent and Selective Phosphodiesterase 5 Inhibitor for the Treatment of Alzheimer's disease

    Fiorito, Jole; Saeed, Faisal; Zhang, Hong; Staniszewski, Agnieszka; Feng, Yan; Francis, Yitshak I.; Rao, Sudha; Thakkar, Devarshi M.; Deng, Shi-Xian; Landry, Donald W.; Arancio, Ottavio

    2012-01-01

    Phosphodiesterase type 5 (PDE5) mediates the degradation of cGMP in a variety of tissues including brain. Recent studies have demonstrated the importance of the nitric oxide/cGMP/cAMP-responsive element-binding protein (CREB) pathway to the process of learning and memory. Thus, PDE5 inhibitors (PDE5Is) are thought to be promising new therapeutic agents for the treatment of Alzheimer's disease (AD), a neurodegenerative disorder characterized by memory loss. To explore this possibility, a serie...

  15. Treatment compliance and severe adverse events limit the use of tyrosine kinase inhibitors in refractory thyroid cancer

    Chrisoulidou A; Mandanas S; Margaritidou E; Mathiopoulou L; Boudina M; Georgopoulos K; Pazaitou-Panayiotou K

    2015-01-01

    Alexandra Chrisoulidou, Stylianos Mandanas, Efterpi Margaritidou, Lemonia Mathiopoulou, Maria Boudina, Konstantinos Georgopoulos, Kalliopi Pazaitou-PanayiotouDepartment of Endocrinology, Theagenio Cancer Hospital, Thessaloniki, GreeceObjective: The aim of the present study was to assess patient compliance with tyrosine kinase inhibitor (TKI) treatment used for refractory and progressive thyroid cancer, in addition to the efficacy and serious adverse events associated with these agents.Methods...

  16. PDE5 Inhibitors As Potential Tools In The Treatment Of Cystic Fibrosis

    TeresinhaLeal

    2012-01-01

    Despite great advances in the understanding of the genetics and pathophysiology of cystic fibrosis (CF), there is still no cure for the disease. Using phosphodiesterase type 5 (PDE5) inhibitors, we and others have provided evidence of rescued F508del-CFTR trafficking and corrected deficient chloride transport activity. Studies using PDE5 inhibitors in mice homozygous for the clinically relevant F508del mutation have been conducted with the aim of restoring F508del-CFTR protein function. We de...

  17. PDE5 Inhibitors as Potential Tools in the Treatment of Cystic Fibrosis

    Noel, Sabrina; Dhooghe, Barbara; Leal, Teresinha

    2012-01-01

    Despite great advances in the understanding of the genetics and pathophysiology of cystic fibrosis (CF), there is still no cure for the disease. Using phosphodiesterase type 5 (PDE5) inhibitors, we and others have provided evidence of rescued F508del-CFTR trafficking and corrected deficient chloride transport activity. Studies using PDE5 inhibitors in mice homozygous for the clinically relevant F508del mutation have been conducted with the aim of restoring F508del-CFTR protein function. We de...

  18. Bruton tyrosine kinase inhibitors: a promising novel targeted treatment for B cell lymphomas

    Aalipour, Amin; Advani, Ranjana H.

    2013-01-01

    Constitutive or aberrant signalling of the B cell receptor signalling cascade has been implicated in the propagation and maintenance of a variety of B cell malignancies. Small molecule inhibitors of Bruton tyrosine kinase (BTK), a protein early in this cascade and specifically expressed in B cells, have emerged as a new class of targeted agents. There are several BTK inhibitors, including ONO-WG-307, LFM-A13, dasatinib, CC-292, and PCI-32765 (ibrutinib), in preclinical and/or clinical develop...

  19. 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

  20. Reversion of Hormone Treatment Resistance with the Addition of an mTOR Inhibitor in Endometrial Stromal Sarcoma

    J. Martin-Liberal

    2014-01-01

    Full Text Available Background. Endometrial stromal sarcomas (ESS are a subtype of gynaecological sarcomas characterized by the overexpression of hormone receptors. Hormone treatment is widely used in ESS but primary or acquired resistance is common. The mammalian target of rapamycin (mTOR pathway has been suggested to play a key role in the mechanisms of hormone resistance. Recent studies in breast and prostate cancer demonstrate that this resistance can be reversed with the addition of an mTOR inhibitor. This phenomenon has never been reported in ESS. Methods. We report the outcome of one patient with pretreated, progressing low grade metastatic ESS treated with medroxyprogesterone acetate in combination with the mTOR inhibitor sirolimus. Results. Partial response was achieved following the addition of sirolimus to the hormone treatment. Response has been maintained for more than 2 years with minimal toxicity and treatment is ongoing. Conclusion. This case suggests that the resistance to the hormone manipulation in ESS can be reversed by the addition of an mTOR pathway inhibitor. This observation is highly encouraging and deserves further investigation.

  1. Inhaled tyrosine kinase inhibitors for pulmonary hypertension: a possible future treatment

    Pitsiou G

    2014-10-01

    Full Text Available Georgia Pitsiou,1 Paul Zarogoulidis,1 Dimitris Petridis,2 Ioannis Kioumis,1 Sofia Lampaki,1 John Organtzis,1 Konstantinos Porpodis,1 Antonis Papaiwannou,1 Theodora Tsiouda,3 Wolfgang Hohenforst-Schmidt,4 Stylianos Kakolyris,5 Konstantinos Syrigos,6 Haidong Huang,7 Qiang Li,7 J Francis Turner,8 Konstantinos Zarogoulidis1 1Pulmonary Department, G Papanikolaou General Hospital, Aristotle University of Thessaloniki, 2Department of Food Technology, School of Food Technology and Nutrition, Alexander Technological Educational Institute, 3Internal Medicine Department, Thegenio Anticancer Hospital, Thessaloniki, Greece; 4II Medical Department, Coburg Regional Hospital, Coburg, Germany; 5Oncology Department, Sotiria Hospital of Chest Diseases, University of Athens, Athens, 6Oncology Department, University General Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece; 7Department of Respiratory Diseases, Changhai Hospital/First Affiliated Hospital of the Second Military Medical University, Shanghai, People’s Republic of China; 8Division of Interventional Pulmonology and Medical Oncology, Cancer Treatment Centers of America, Western Regional Medical Center, Goodyear, AZ, USA Abstract: Pulmonary hypertension is a disease with severe consequences for the human body. There are several diseases and situations that induce pulmonary hypertension and are usually underdiagnosed. Treatments include conventional medical therapies and oral, inhaled, intravenous, and subcutaneous options. Depending on its severity, heart or lung transplant may also be an option. A possible novel treatment could be tyrosine kinase inhibitors. We conducted experiments with three jet nebulizers and three ultrasound nebulizers with erlotinib, gefitinib, and imatinib. Different residual cup designs and residual cup loadings were used in order to identify the best combination to produce droplets of less than 5 µm in mass median aerodynamic diameter. We

  2. Dual PDE3/4 and PDE4 inhibitors: novel treatments for COPD and other inflammatory airway diseases.

    Abbott-Banner, Katharine H; Page, Clive P

    2014-05-01

    Selective phosphodiesterase (PDE) 4 and dual PDE3/4 inhibitors have attracted considerable interest as potential therapeutic agents for the treatment of respiratory diseases, largely by virtue of their anti-inflammatory (PDE4) and bifunctional bronchodilator/anti-inflammatory (PDE3/4) effects. Many of these agents have, however, failed in early development for various reasons, including dose-limiting side effects when administered orally and lack of sufficient activity when inhaled. Indeed, only one selective PDE4 inhibitor, the orally active roflumilast-n-oxide, has to date received marketing authorization. The majority of the compounds that have failed were, however, orally administered and non-selective for either PDE3 (A,B) or PDE4 (A,B,C,D) subtypes. Developing an inhaled dual PDE3/4 inhibitor that is rapidly cleared from the systemic circulation, potentially with subtype specificity, may represent one strategy to improve the therapeutic index and also exhibit enhanced efficacy versus inhibition of either PDE3 or PDE4 alone, given the potential positive interactions with regard to anti-inflammatory and bronchodilator effects that have been observed pre-clinically with dual inhibition of PDE3 and PDE4 compared with inhibition of either isozyme alone. This MiniReview will summarize recent clinical data obtained with PDE inhibitors and the potential for these drugs to treat COPD and other inflammatory airways diseases such as asthma and cystic fibrosis. PMID:24517491

  3. A Divalent PAMAM-Based Matrix Metalloproteinase/Carbonic Anhydrase Inhibitor for the Treatment of Dry Eye Syndrome.

    Richichi, B; Baldoneschi, V; Burgalassi, S; Fragai, M; Vullo, D; Akdemir, A; Dragoni, E; Louka, A; Mamusa, M; Monti, D; Berti, D; Novellino, E; De Rosa, G; Supuran, C T; Nativi, C

    2016-01-26

    Synthetic sulfonamide derivatives are a class of potent matrix metalloproteinase inhibitors (MMPI) that have potential for the treatment of diseases related to uncontrolled expression of these enzymes. The lack of selectivity of the large majority of such inhibitors, leading to the inhibition of MMPs in tissues other than the targeted one, has dramatically reduced the therapeutic interest in MMPIs. The recent development of efficient drug delivery systems that allow the transportation of a selected drug to its site of action has opened the way to new perspectives in the use of MMPIs. Here, a PAMAM-based divalent dendron with two sulfonamidic residues was synthesized. This nanomolar inhibitor binds to the catalytic domain of two MMPs as well as to the transmembrane human carbonic anhydrases (hCAs) XII, which is present in the eye and considered an antiglaucoma target. In the animal model of an experimental dry eye, no occurrence of dotted staining in eyes treated with our inhibitor was observed, indicating no symptoms of corneal desiccation. PMID:26692423

  4. [GENDER AND AGE DIFFERENCES IN THE TREATMENT OF CHRONIC HEART FAILURE AT HOSPITAL OBSERVATIONS STAGE].

    Dadashova, G M

    2016-01-01

    Analysis of literature shows that very little data are available on gender differences and age-specific drug use in the treatment of chronic heart failure (CHF). In this work, the character of drug therapy was studied as dependent on the age and sex of patients with CHF under in-hospital observation conditions. Among hospitalized patients with CHF, an important role is played by modern drug therapy. Gender differences were found in respect of therapy with ACE inhibitors, which was used in men more frequently than in women (89 and 78%, respectively, p ACE inhibitors/ARBs (from 79.1 to 95.3%p < 0.01) and aldosterone antagonists (from 29.3 to 38.2% p < 0.001). PMID:27416677

  5. ACE and AGTR1 polymorphisms in elite rhythmic gymnastics.

    Di Cagno, Alessandra; Sapere, Nadia; Piazza, Marina; Aquino, Giovanna; Iuliano, Enzo; Intrieri, Mariano; Calcagno, Giuseppe

    2013-02-01

    In the angiotensin-converting enzyme (ACE) gene, Alu deletion, in intron 16, is associated with higher concentrations of ACE serum activity and this may be associated with elite sprint and power performance. The Alu insertion is associated with lower ACE levels and this could lead to endurance performance. Moreover, recent studies have identified a single-nucleotide polymorphism of the angiotensin type 1 receptor gene AGTR1, which seems to be related to ACE activity. The aim of this study was to examine the involvement of the ACE and the AGTR1 gene polymorphisms in 28 Italian elite rhythmic gymnasts (age range 21 ± 7.6 years), and compare them to 23 middle level rhythmic gymnasts (age range 17 ± 10.9 years). The ACE D allele was significantly more frequent in elite athletes than in the control population (χ(2)=4.07, p=0.04). Comparisons between the middle level and elite athletes revealed significant differences (p<0.0001) for the ACE DD genotype (OR=6.48, 95% confidence interval=1.48-28.34), which was more frequent in elite athletes. There were no significant differences in the AGTR1 A/C genotype or allele distributions between the middle level and elite athletes. In conclusion, the ACE D allele genotype could be a contributing factor to high-performance rhythmic gymnastics that should be considered in athlete development and could help to identify which skills should be trained for talent promotion. PMID:23145508

  6. Virginia Tech Hosts One Of Nation's 37 ACE Fellows

    Cox, Clara B.

    2003-01-01

    Diane Bell, professor of anthropology and director of women's studies at George Washington University and one of 37 American Council on Education (ACE) Fellows, will spend the current academic year in the provost's office at Virginia Tech, examining the globalization efforts of the university and its core curriculum as part of her ACE fellowship.

  7. Neuraminidase inhibitors in the treatment and post exposure prevention of influenza

    von der Schulenburg, Johann-Matthias

    2006-01-01

    Full Text Available Introduction: Influenza is a viral respiratory infection which presents itself as an acute febrile disease. It is contracted by virus-laden respiratory secretions from infected individuals. Symptoms usually last three to seven days and are accompanied by severely limited activities during this time. A definite diagnosis, however, can only be made by laboratory analysis. Every year, about 20% of children and 5% of adults develop symptomatic influenza of the serotypes A or B worldwide. Typical complications of influenza include viral or bacterial infections, as well as deterioration of an existing cardio-vascular or respiratory disease which may lead to hospitalization and death. Current policy recommends that individuals, who are at-risk of developing serious complications (patients over sixty years of age or patients with concomitant chronic diseases, as well as people in direct contact with high risk patients (i.e. nursing staff in living and care facilities, should be annually vaccinated with inactivated influenza strains. Various pharmaceutical agents for the treatment and prophylaxis of influenza have been approved. Amantadine, which inhibits the viral M2-ion channel, is only effective in influenza-serotype A. Neuraminidase inhibitors (NI represent a new class of antivirals for prophylaxis and treatment of influenza A and B. NI interrupt various central functions that are vital for the life cycle and spreading of the virus. Two drugs of this substance class, Zanamivir (RelenzaTM and Oseltamivir (Tamiflu®, are licensed for the treatment of influenza. For adults and teenagers over thirteen years of age Oseltamivir is also approved for the prophylaxis of influenza. Zanamivir is a powder which needs to be inhaled, whereas Oseltamivir is licensed as a capsule for oral administration. M2-inhibitors and NI are only effective at an early stage of the influenza infection, i.e. during the first 36 to 48 hours after symptom onset, before replication

  8. Intrinsic caspase-8 activation mediates sensitization of erlotinib-resistant tumor cells to erlotinib/cell-cycle inhibitors combination treatment

    Orzáez, M; Guevara, T; Sancho, M; Pérez-Payá, E

    2012-01-01

    Inhibitors of the tyrosine kinase activity of epidermal growth factor receptor, as erlotinib, have an established role in treating several cancer types. However, resistance to erlotinib, particularly in breast cancer cell lines, and erlotinib treatment-associated disorders have also been described. Also, methods and combination therapies that could reverse resistance and ameliorate non-desirable effects represent a clinical challenge. Here, we show that the ATP non-competitive CDK2/cyclin A inhibitor NBI1 sensitizes erlotinib-resistant tumor cells to the combination treatment (co-treatment) for apoptosis-mediated cell death. Furthermore, in erlotinib-sensitive cells, the effective dose of erlotinib was lower in the presence of NBI1. The analysis in the breast cancer MDA-MB-468 erlotinib-resistant and in lung cancer A549 cell lines of the molecular mechanism underlying the apoptosis induced by co-treatment highlighted that the accumulation of DNA defects and depletion of cIAP and XIAP activates the ripoptosome that ultimately activates caspases-8 and -10 and apoptosis. This finding could have significant implications for future treatment strategies in clinical settings. PMID:23096116

  9. Pneumonia Risk and Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers

    Liu, Chia-Lin; Shau, Wen-Yi; Chang, Chia-Hsuin; Wu, Chi-Shin; Lai, Mei-Shu

    2013-01-01

    Background Recent studies have shown that use of angiotensin-converting enzyme (ACE) inhibitors may decrease pneumonia risk in various populations. We investigated the effect of ACE inhibitors and angiotensin II receptor blockers (ARBs) on pneumonia hospitalization in the general population of Taiwan. Methods We conducted a case-crossover study using the Taiwan Longitudinal Health Insurance Database for the year 2005. Data from patients hospitalized for the first time for pneumonia during 199...

  10. Systemic effects of treatment with mTOR inhibitors in tuberous sclerosis complex: a comprehensive review.

    Sadowski, K; Kotulska, K; Schwartz, R A; Jóźwiak, S

    2016-04-01

    Tuberous sclerosis complex (TSC) is a genetic multisystem disorder associated with constitutive overactivation of the mammalian target of rapamycin (mTOR) pathway and characterized by development of benign tumours in various organs. mTOR inhibitors have proven to be effective in the targeted therapy of certain TSC-associated pathologies such as subependymal giant cell astrocytomas (SEGAs) and renal angiomyolipomas (AMLs). Accumulating experimental and clinical data suggest that mTOR inhibitors might have a systemic, disease-modifying influence on affected individuals. This systematic review provides an analysis of available clinical data concerning systemic effect of mTOR inhibitors and the influence of mTOR inhibition on different manifestations of TSC in individual patients. PMID:26403211

  11. Treatment of type I and II hereditary angioedema with Rhucin, a recombinant human C1 inhibitor.

    Varga, Lilian; Farkas, Henriette

    2008-11-01

    Hereditary and acquired angioedema are of outstanding clinical importance, as edematous attacks associated with these conditions can thrust afflicted patients into mortal danger. Currently, C1 inhibitor concentrate - a human blood product - is available as a replacement therapy. In view of the limited number of donors, as well as the risk of transmission of blood-borne infections, it is a reasonable expectation to develop a therapeutic alternative based on recombinant technology, which would eliminate all these shortcomings. Pharming (Leiden, The Netherlands) has developed Rhucin, a recombinant human C1 inhibitor, as a proprietary product, which is currently being evaluated in Phase III clinical trials. Ongoing studies conducted within the framework of the development program are almost complete and their interim findings are reassuring. This should facilitate successful regulatory approval in the near future, which is indispensable in order to make Rhucin available for patients with hereditary angioedema or other disorders amenable to C1 inhibitor replacement. PMID:20477114

  12. The angiotensin-converting enzyme (ACE) gene insertion/ deletion dimorphism tracks with higher serum ace activities in both younger and older subjects

    The absence of a 287 base pair alu sequence in the ACE gene (D allele) is associated with higher ACE levels than its presence (I allele) in adults. We carried out a case control study of thr ACE*I/D dimorphism in relation to circulating ACE activities to evaluate associations between the two variables in adults, compared to younger (18 years or less) individuals. Genotypes of the ACE*I/D dimorphism were determined on DNA samples from a population of 164 random (unrelated) Emirtaes nationals, composed of groups: 112 subjects above 18 years of age (range=20-77), and 52 subjects of 18 years or less (range=1-18) and analyzed for putative associations with serum ACE activities. ACE*I/D genotypes of the 164 individualds were determined by assays based on polymerase chain reaction. ACE activities were determined on serum samples of these subjects bu colorimetric assays. The D allele was associared with increasd ACE values in both adult and younger individuals. Mean ACE activity levels associated with II, ID and DD genotypes, however, were 42%-61% higher in the 18 years and under group of subjects. The ACE*I/D marker accounted for 28% of the variance of the phenomenon determining ACE levels in adults, and for 30% among youngsters. The ACE*I/D dimorphism is correlated strongly with circulating ACE activities in both and young Emirati, subjects and the corresponding mean ACE activities were significantly higher among the youngsters. (author)

  13. Adherence to treatment guidelines in the pharmacological management of chronic heart failure in an Australian population

    Dao-Kuo Yao; Le-Xin Wang; Shane Curran; Patrick Ball

    2011-01-01

    Background To document the pharmacotherapy of chronic heart failure (CHF) and to evaluate the adherence to treatment guidelines in Australian population.Methods The pharmacological management of 677 patients (female 46.7%,75.5±11.6 years) with CHF was retrospectively analyzed.Results The use of angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARB) and fl-blockers were 58.2%and 34.7%,respectively.Major reasons for non-use of ACE inhibitors/ARBs were hyperkalemia and elevated serum creatimne level.For patients who did not receive β-blockers,asthma and chronic obstructive pulmonary disease were the main contraindications.Treatment at or above target dosages for ACE inhibitors/ARBs and β-blockers was low for each medication (40.3% and 28.9%,respectively).Conclusions Evidenced-based medical therapies for heart failure were under used in a rural patient population.Further studies are required to develop processes to improve the optimal use of heart failure medications.

  14. PDE5 Inhibitors As Potential Tools In The Treatment Of Cystic Fibrosis

    Sabrina eNoel

    2012-09-01

    Full Text Available Despite great advances in the understanding of the genetics and pathophysiology of cystic fibrosis (CF, there is still no cure for the disease. Using phosphodiesterase type 5 (PDE5 inhibitors, we and others have provided evidence of rescued F508del-CFTR trafficking and corrected deficient chloride transport activity. Studies using PDE5 inhibitors in mice homozygous for the clinically relevant F508del mutation have been conducted with the aim of restoring F508del-CFTR protein function. We demonstrated, by measuring transepithelial nasal potential difference in F508del mice following intraperitoneal injection of sildenafil, vardenafil or taladafil at clinical doses are able to restore the decreased CFTR-dependent chloride transport across the nasal mucosa. Moreover, vardenafil, but not sildenafil, stimulates chloride transport through the normal CFTR protein. We developed a specific nebulizer setup for mice, with which we demonstrated, through a single inhalation of PDE5 inhibitors, local activation of CFTR protein in CF. Significant potential advantages of inhalation drug therapy over oral or intravenous routes include rapid onset of pharmacological action, reduced systemic secondary effects and reduced effective drug doses compared to the drug delivered orally; this underlines the relevance and impact of our work for translational science. More recently, we analyzed the bronchoalveolar lavage of CF and wild-type mice for cell infiltrates and expression of pro-inflammatory cytokines and chemokines; we found that the CFTR activating effect of vardenafil, selected as a representative long-lasting PDE5 inhibitor, breaks the vicious circle of lung inflammation which plays a major role in morbi-mortality in CF. Our data highlight the potential use of PDE5 inhibitors in CF. Therapeutic approaches using clinically approved PDE5 inhibitors to address F508del-CFTR defects could speed up the development of new therapies for CF.

  15. Design, synthesis and evaluation of novel dual monoamine-cholinesterase inhibitors as potential treatment for Alzheimer's disease.

    Liu, Wei; Lang, Ming; Youdim, Moussa B H; Amit, Tamar; Sun, Yewei; Zhang, Zaijun; Wang, Yuqiang; Weinreb, Orly

    2016-10-01

    Current novel therapeutic approach suggests that multifunctional compounds with diverse biological properties and a single bioavailability and pharmacokinetic metabolism, will produce higher significant advantages in treatment of neurodegenerative diseases, such as Alzheimer's disease (AD). Based on this rational, a new class of cholinesterase (ChE)-monoamine oxidase (MAO) inhibitors were designed and synthesized by amalgamating the propargyl moiety of the irreversible selective MAO-B inhibitor, neuroprotective/neurorestorative anti-Parkinsonian drug, rasagiline, into the "N-methyl" position of the ChE inhibitor, anti-AD drug rivastigmine. Initially, we examined the MAO and ChE inhibitory effect of these novel compounds, MT series in vitro and in vivo. Among MT series, MT-031 exhibited higher potency as a dual MAO-A and ChE inhibitor compared to other compounds in acute-treated mice. Additionally, MT-031 was found to increase the striatal levels of dopamine (DA), serotonin (5-HT) and norepinephrine (NE), and prevent the metabolism of DA and 5-HT. Finally, we have demonstrated that MT-031 exerted neuroprotective effect against H2O2-induced neurotoxicity and reactive oxygen species generation in human neuroblastoma SH-SY5Y cells. These findings provide evidence that MT-031 is a potent brain permeable novel multifunctional, neuroprotective and MAO-A/ChE inhibitor, preserves in one molecule entity some of the beneficial properties of its parent drugs, rasagiline and rivastigmine, and thus may be indicated as novel therapeutic approach for AD. PMID:27318273

  16. Diagnosis and treatment of hereditary angioedema with normal C1 inhibitor

    Bork Konrad

    2010-07-01

    Full Text Available Abstract Until recently it was assumed that hereditary angioedema is a disease that results exclusively from a genetic deficiency of the C1 inhibitor. In 2000, families with hereditary angioedema, normal C1 inhibitor activity and protein in plasma were described. Since then numerous patients and families with that condition have been reported. Most of the patients by far were women. In many of the affected women, oral contraceptives, hormone replacement therapy containing estrogens, and pregnancies triggered the clinical symptoms. Recently, in some families mutations in the coagulation factor XII (Hageman factor gene were detected in the affected persons.

  17. 7-Methoxytacrine-p-Anisidine Hybrids as Novel Dual Binding Site Acetylcholinesterase Inhibitors for Alzheimer’s Disease Treatment

    Jan Korabecny

    2015-12-01

    Full Text Available Alzheimer’s disease (AD is a debilitating progressive neurodegenerative disorder that ultimately leads to the patient’s death. Despite the fact that novel pharmacological approaches endeavoring to block the neurodegenerative process are still emerging, none of them have reached use in clinical practice yet. Thus, palliative treatment represented by acetylcholinesterase inhibitors (AChEIs and memantine are still the only therapeutics used. Following the multi-target directed ligands (MTDLs strategy, herein we describe the synthesis, biological evaluation and docking studies for novel 7-methoxytacrine-p-anisidine hybrids designed to purposely target both cholinesterases and the amyloid cascade. Indeed, the novel derivatives proved to be effective non-specific cholinesterase inhibitors showing non-competitive AChE inhibition patterns. This compounds’ behavior was confirmed in the subsequent molecular modeling studies.

  18. AngⅡ对肝星状细胞中ACE 2和Mas受体mRNA的影响

    许小妹; 申凤俊; 贾秀艳

    2014-01-01

    Objective To investigate the efects of angiotensin converting enzyme inhibitors benazepril on angiotensin converting enzyme 2(ACE 2) and Mas receptor production of in vitro cultured hepatic stellate cells (HSC). Methods HSC-T 6 rat hepatic stelate was chosen as the main study model of experiment,Cultured HSC were randomized into control group,AngⅡgroup,benazepril group and AngⅡ+benazepril group. The expression of ACE 2 and Mas receptor in different group was measured by by RTFQ PCR.Results The ACE 2 and Mas receptor expression level of HSC in AngⅡgroup were higher than control group(P<0.05).All index of AngⅡ+benazepril group were higher than AngⅡgroup (P<0.05). Conclusion After hepatic stelate cells was activated,Benazepril can elevated the ACE 2 and Mas receptor expression level of HSC,and play an important role in anti-hepatic fibrosis.%目的:体外培养肝星状细胞(HSC),从分子生物学的角度探索其是否有ACE 2和Mas受体mRNA的表达,以及血管紧张素转换酶抑制剂(ACEI)贝那普利对二者的影响。方法大鼠肝星状细胞株(HSC-T 6)按实验计划分组处理(正常对照组、AngⅡ组、AngⅡ+贝那普利组、贝那普利组),提取总RNA,逆转录后应用RTFQ PCR的方法测量ACE 2及Mas受体 mRNA的基因水平。结果 ACE 2、Mas受体mRNA在各组中均有表达;与对照组相比,AngⅡ组中二者的表达均较高,差异有统计学意义(P<0.05);在AngⅡ+贝那普利组,二者均较AngⅡ组升高,差异有统计学意义(P<0.05)。结论 AngⅡ可使肝星状细胞激活,活化后的HSC的ACE 2、Mas受体mRNA的基因表达水平升高,从而发挥其抗肝纤维化的作用。

  19. Early postnatal treatment with soluble epoxide hydrolase inhibitor or 15-deoxy-Δ(12,14)-prostagandin J2 prevents prenatal dexamethasone and postnatal high saturated fat diet induced programmed hypertension in adult rat offspring.

    Lu, Pei-Chen; Sheen, Jiunn-Ming; Yu, Hong-Ren; Lin, Yu-Ju; Chen, Chih-Cheng; Tiao, Mao-Meng; Tsai, Ching-Chou; Huang, Li-Tung; Tain, You-Lin

    2016-07-01

    Prenatal dexamethasone (DEX) exposure, postnatal high-fat (HF) intake, and arachidonic acid pathway are closely related to hypertension. We tested whether a soluble epoxide hydrolase (SEH) inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) or 15-deoxy-Δ(12,14)-prostagandin J2 (15dPGJ2) therapy can rescue programmed hypertension in the DEX+HF two-hit model. Four groups of Sprague Dawley rats were studied: control, DEX+HF, AUDA, and 15dPGJ2. Dexamethasone (0.1mg/kg body weight) was intraperitoneally administered to pregnant rats from gestational day 16-22. Male offspring received high-fat diet (D12331, Research Diets) from weaning to 4 months of age. In AUDA group, mother rats received 25mg/L in drinking water during lactation. In the 15dPGJ2 group, male offspring received 15dPGJ2 1.5mg/kg BW by subcutaneous injection once daily for 1 week after birth. We found postnatal HF diet aggravated prenatal DEX-induced programmed hypertension, which was similarly prevented by early treatment with AUDA or 15dPGJ2. The beneficial effects of AUDA and 15d-PGJ2 therapy include inhibition of SEH, increases of renal angiotensin converting enzyme-2 (ACE2) and angiotensin II type 2 receptor (AT2R) protein levels, and restoration of nitric oxide bioavailability. Better understanding of the impact of arachidonic acid pathway in the two-hit model will help prevent programmed hypertension in children exposed to corticosteroids and postnatal HF intake. PMID:27210044

  20. Hyperlipidemia related to the use of HIV-protease inhibitors: natural history and results of treatment with fenofibrate

    Caramelli Bruno

    2001-01-01

    Full Text Available Hyperlipidemia has been frequently recorded as a side effect of treating HIV patients with protease inhibitors (PI. This study was initiated to analyze the modifications on blood lipids in HIV-patients receiving PI and the safety and efficacy of the treatment with fenofibrate. Total (TC and HDL-cholesterol, triglycerides (TG, and CD4+ T-cell counts were measured in 30 HAART-naive patients (Group I before and after PI introduction. In a second phase of the study, the effects of fenofibrate on lipids, CPK, CD4+, and viral load were determined in 13 patients (Group II with elevated TC or TG. In Group I, 60% of the patients showed TC or TG elevations. Average increments of 31% and 146% in TC and TG respectively (p<0.0006 and p<0.0001 were observed. In Group II, fenofibrate treatment was associated with decrements of 6.6% (TC and 45.7% (TG (p=0.07 and 0.0002 and no modifications on CPK, CD4+, and viral load. In conclusion, hyperlipidemia is common during the treatment of HIV with protease inhibitors, and fenofibrate appears to be an effective and safe choice for its treatment.

  1. Are proton pump inhibitors the first choice for acute treatment of gastric ulcers? A meta analysis of randomized clinical trials

    Ward Alexandra

    2002-07-01

    Full Text Available Abstract Background Gastric ulcers are a frequent problem in the United States. Proton pump inhibitors have been shown to increase healing rates and improve clinical symptoms. The objective of this study is to compare gastric ulcer healing rates for patients treated with a proton pump inhibitor (PPI (omeprazole, rabeprazole, pantoprazole, or lansoprazole, an histamine 2- receptor antagonist (ranitidine or placebo. Methods A literature search was conducted to identify randomized, controlled clinical trials that included a PPI in at least one treatment arm and assessed the gastric ulcer healing rates endoscopically. The healing rates were estimated for each treatment at specific time points, and Rate Ratios (RR and 95% confidence intervals (CI were estimated for each trial. Results Sixteen trials met the inclusion criteria: four compared a PPI versus placebo, nine compared a PPI versus ranitidine (no trials of rabeprazole versus ranitidine met the inclusion criteria, and three compared a newer PPI (lansoprazole, pantoprazole or rabeprazole versus omeprazole. In relation to ranitidine, the pooled RR of PPIs (lansoprazole, omeprazole and pantoprazole was 1.33 (95% CI 1.24 to 1.42 at four weeks. In each trial, greater improvement in the studied clinical symptoms was found with the newer PPIs (rabeprazole, pantoprazole and lansoprazole when compared to omeprazole. Conclusion In this study treatment with PPIs resulted in higher healing rates than ranitidine or placebo. This evidence suggests that the first choice for gastric ulcer treatment for the greater relief of symptoms is one of the newer PPIs.

  2. Phosphodiesterase type 5 inhibitors in the treatment of pulmonary arterial hypertension

    Kadriye Kılıçkesmez; M. Serdar Küçükoğlu

    2010-01-01

    The pathology of pulmonary arterial hypertension (PAH) is characterized by vascular vasoconstriction, smooth muscle cell proliferation, and thrombosis. Experimental studies have shown the beneficial effect of phosphodiesterase type 5 (PDE-5) inhibitors on pulmonary vascular remodeling and vasodilatation. Randomized clinical trials in monotherapy or combination therapy have been conducted in PAH with sildenafil and tadalafil which significantly improve clinical status, exercise capacity and he...

  3. Pyridone Methylsulfone Hydroxamate LpxC Inhibitors for the Treatment of Serious Gram-Negative Infections

    Montgomery, Justin I.; Brown, Matthew F.; Reilly, Usa; Price, Loren M.; Abramite, Joseph A.; Arcari, Joel; Barham, Rose; Che, Ye; Chen, Jinshan Michael; Chung, Seung Won; Collantes, Elizabeth M.; Desbonnet, Charlene; Doroski, Matthew; Doty, Jonathan; Engtrakul, Juntyma J.; Harris, Thomas M.; Huband, Michael; Knafels, John D.; Leach, Karen L.; Liu, Shenping; Marfat, Anthony; McAllister, Laura; McElroy, Eric; Menard, Carol A.; Mitton-Fry, Mark; Mullins, Lisa; Noe, Mark C.; O’Donnell, John; Oliver, Robert; Penzien, Joseph; Plummer, Mark; Shanmugasundaram, Veerabahu; Thoma, Christy; Tomaras, Andrew P.; Uccello, Daniel P.; Vaz, Alfin; Wishka, Donn G. (Pfizer)

    2012-11-09

    The synthesis and biological activity of a new series of LpxC inhibitors represented by pyridone methylsulfone hydroxamate 2a is presented. Members of this series have improved solubility and free fraction when compared to compounds in the previously described biphenyl methylsulfone hydroxamate series, and they maintain superior Gram-negative antibacterial activity to comparator agents.

  4. Clinical utility of the oral JAK inhibitor tofacitinib in the treatment of rheumatoid arthritis

    Cutolo M; Meroni M

    2013-01-01

    Maurizio Cutolo, Marianna Meroni Research Laboratories and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genova, Genova, Italy Abstract: Immune/inflammatory cells act in rheumatoid arthritis (RA)-affected patients by synthesizing several inflammatory mediators, including cytokines that initiate intracellular signaling. Recently, small molecule inhibitors of transduction and transcription signals that influence the intracellular pathways (such as t...

  5. Approaches to hepatitis C treatment and cure using NS5A inhibitors

    Kohler JJ

    2014-03-01

    Full Text Available James J Kohler,1,2 James H Nettles,1,2 Franck Amblard,1,2 Selwyn J Hurwitz,1,2 Leda Bassit,1,2 Richard A Stanton,1 Maryam Ehteshami,1 Raymond F Schinazi1,2 1Center for AIDS Research and Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA; 2Atlanta Veterans Affairs Medical Center, Decatur, GA, USA Abstract: Recent progress in the understanding of hepatitis C virus (HCV biology and the availability of in vitro models to study its replication have facilitated the development of direct-acting antiviral agents (DAAs that target specific steps in the viral replication cycle. Currently, there are three major classes of DAA in clinical development: NS3/4A protease inhibitors, NS5B polymerase inhibitors, and NS5A directed inhibitors. Several compounds thought to bind directly with NS5A are now in various clinical trial phases, including the most advanced, daclatasvir (BMS-790052, ledipasvir (GS-5885, and ABT-267. While many NS5A-targeted compounds demonstrate picomolar potency, the exact mechanism(s of their action is still unclear. In the clinic, NS5A HCV inhibitors show promise as important components in DAA regimens and have multifunctionality. In addition to inhibiting viral replication, they may synergize with other DAAs, possibly by modulating different viral proteins, to help suppress the emergence of resistant viruses. Structure-based models have identified target interaction domains and spatial interactions that explain drug resistance for mutations at specific positions (eg, residues 93 and 31 within NS5A and potential binding partners. This review provides, insights into the unique complexity of NS5A as a central platform for multiple viral/host protein interactions, and possible mechanism(s for the NS5A inhibitors currently undergoing clinical trials that target this nonstructural viral protein. Keywords: HCV replication complex, direct acting antivirals (DAAs, clinical trials

  6. Knee cartilage quality assessed with dGEMRIC in rheumatoid arthritis patients before and after treatment with a TNF inhibitor

    Tiderius, Carl Johan; Dahlberg, Leif E. (Dept. of Orthopedics, Malmoe Univ. Hospital, Lund Univ., Malmoe (Sweden)), e-mail: carl-johan.tiderius@skane.se; Svensson, Jonas (Dept. of Radiation Physics, Malmoe Univ. Hospital, Lund Univ., Malmoe (Sweden)); Sandin, Joakim; Jacobsson, Lennart (Dept. of Rheumatology, Malmoe Univ. Hospital, Lund Univ., Malmoe (Sweden))

    2010-11-15

    Background: TNF-a inhibitors are potent anti-inflammatory drugs that have revolutionized the treatment of rheumatoid arthritis (RA). Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) is a non-invasive method to study cartilage quality, in particular the glycosaminoglycan (GAG) content. Purpose: To evaluate knee cartilage quality before and after treatment with a TNF-a inhibitor (infliximab) in patients with RA using dGEMRIC and to study clinical parameters and serum cartilage oligomeric protein (COMP) after the same treatment. Material and Methods: Seven patients with chronic RA received infusions of 3 mg/kg infliximab at weeks 0, 2, 6, 14, and 22. Clinical examination, serum COMP level, and dGEMRIC scans (1.5 T) were performed at baseline and after 7 months. The dGEMRIC index (ms), reflecting cartilage GAG content, was calculated using an inversion recovery sequence in the femoral weight-bearing cartilage. Seven years after treatment, charts were reviewed regarding joint replacement surgery (T{sub k}A). Results: Clinical parameters showed an improvement for all patients after the 7-month treatment period. Serum COMP decreased from 13+-4.5 to 11+-3.4 (mug, mean +- SD) mug/ml (P<0.05). The dGEMRIC index was lower at follow-up than at baseline, 332+-85 and 382+-69 (ms, mean +- SD), respectively (P<0.05), indicating loss of GAG. The two patients with the lowest dGEMRIC index had received a T{sub k}A 7 years after treatment. Conclusion: This longitudinal study indicates a substantial GAG loss from the knee cartilage matrix in patients with chronic RA. Treatment with infliximab does not seem to protect the cartilage from further deterioration despite improvements in clinical parameters and decreased serum COMP

  7. Inibidores de calcineurina no tratamento das dermatoses alérgicas Calcineurin inhibitors in the treatment of allergic dermatitis

    Ana Paula Beltran Moschione Castro

    2006-11-01

    Full Text Available OBJETIVO: Revisar o papel dos inibidores da calcineurina no tratamento das dermatoses alérgicas, com ênfase nos mecanismos de ação, eficácia e efeitos adversos tópicos e sistêmicos. FONTES DOS DADOS: Artigos de língua inglesa publicados na MEDLINE, considerando as palavras chave: pimecrolimus, tacrolimo, calcineurin inhibitors. Foram selecionados os artigos originais que apresentaram estudos controlados e estudos abertos para avaliação da eficácia, tolerabilidade e eventos adversos. Também foram avaliados artigos de revisão e relatos e série de casos, sendo estes últimos considerados apenas para avaliação de efeitos adversos. Foram consultados os sites oficiais da Food and Drug Administration e dos fabricantes de inibidores da calcineurina. SÍNTESE DOS DADOS: Os dados mostraram que inibidores de calcineurina são eficientes no tratamento da dermatite atópica leve a grave, levando a melhora dos sintomas, diminuição do número de crises e necessidade de corticoterapia tópica. Apresentam boa tolerabilidade e poucos efeitos adversos tópicos. Até o momento, não há evidências que sustentem a maior prevalência de neoplasias nos pacientes que utilizam esses medicamentos; entretanto, um adequado sistema de farmacovigilância está montado para avaliar esse aspecto. CONCLUSÕES: Os inibidores de calcineurina são uma nova classe de medicamentos para o tratamento das dermatoses alérgicas. São eficazes, tolerados e com poucos efeitos adversos. Devem ser sempre utilizados de acordo com as orientações preconizadas, e os pacientes devem ser sempre acompanhados pelo médico durante e após sua administração.OBJECTIVE: To review the role of calcineurin inhibitors in the treatment of allergic dermatitis, focusing on mechanisms of action, efficacy and topical and systemic adverse effects. SOURCES: Articles written in English and published in MEDLINE using the following keywords: pimecrolimus, tacrolimus, calcineurin inhibitors

  8. Changes in TSH-binding inhibitor immunoglobulins and human thyroid stimulator activities in Graves' disease after radioiodine treatment

    The changes in the activities of TSH-binding inhibitor immunoglobulins (TBII) and human thyroid stimulator (HTS) were studied after I-131 treatment of Graves' disease. TBII were measured by the radioreceptor assay of TSH and HTS was measured by the increase in cyclic AMP in cultured human thyroid adenoma cells. Before the treatment TBII were positive in 10 out of 14 patients and mean activity was 79.2%, while only 1 out of 12 were positive in HTS. Three months after the treatment, TBII were positive in 11 out of 12, mean activity being 58.1% (p < 0.05). HTS was positive in 7 out of 11 (p < 0.02). Subsequently, both of these activities showed gradual decrease to the pretreatment level. Changes of TBII and HTS in 5 patients were not parallel, indicating heterogeneity in TSH-receptor related antibodies

  9. Treatment of gastrointestinal neuroendocrine tumors with inhibitors of growth factor receptors and their signaling pathways: Recent advances and future perspectives

    Michael H(o)pfner; Detlef Schuppan; Hans Scherübl

    2008-01-01

    The limited efficacy of conventional cytotoxic treatment regimes for advanced gastrointestinal neuroendocrine cancers emphasizes the need for novel and more effective medical treatment options.Recent findings on the specific biological features of this family of neoplasms has led to the development of new targeted therapies,which take into account the high vascularization and abundant expression of specific growth factors and cognate tyrosine kinase receptors.This review will briefly summarize the status and future perspectives of antiangiogenic, mTOR- or growth factor receptor-based pharmacological approaches for the innovative treatment of gastrointestinal neuroendocrine tumors.In view of the multitude of novel targeted approaches, the rationale for innovative combination therapies, i.e.combining growth factor (receptor)-targeting agents with chemoor biotherapeutics or with other novel anticancer drugs such as HDAC or proteasome inhibitors will be taken into account.

  10. Impact of tobacco smoking on response to tumour necrosis factor-alpha inhibitor treatment in patients with ankylosing spondylitis

    Glintborg, Bente; Højgaard, Pil; Lund Hetland, Merete;

    2016-01-01

    .29-4.95)), P < 0.0001). Similar results were found in multivariate analyses (current versus never smokers, HR 1.41 (95% CI 1.21-1.65), P < 0.001), most pronounced among men. Current smokers had poorer 6 months' BASDAI50%/20 mm-response rate than never smokers (42%/58%, P < 0.001). In multivariate analyses......OBJECTIVES: To investigate the association between tobacco smoking and disease activity, treatment adherence and treatment responses in patients with AS treated with their first tumour necrosis factor-alpha inhibitor (TNFi) therapy in routine care. METHODS: Observational cohort study based on the...... Danish nationwide DANBIO registry. Kaplan-Meier plots, Cox and logistic regression analyses by smoking status (current/never/previous) were calculated for treatment adherence and BASDAI 50%/20 mm-response. Additional stratified analyses were performed for gender and TNFi-type. RESULTS: Of 1576 AS...

  11. Selective serotonin re-uptake inhibitors potentiate gene blunting induced by repeated methylphenidate treatment: Zif268 versus Homer1a.

    Van Waes, Vincent; Vandrevala, Malcolm; Beverley, Joel; Steiner, Heinz

    2014-11-01

    There is a growing use of psychostimulants, such as methylphenidate (Ritalin; dopamine re-uptake inhibitor), for medical treatments and as cognitive enhancers in the healthy. Methylphenidate is known to produce some addiction-related gene regulation. Recent findings in animal models show that selective serotonin re-uptake inhibitors (SSRIs), including fluoxetine, can potentiate acute induction of gene expression by methylphenidate, thus indicating an acute facilitatory role for serotonin in dopamine-induced gene regulation. We investigated whether repeated exposure to fluoxetine, in conjunction with methylphenidate, in adolescent rats facilitated a gene regulation effect well established for repeated exposure to illicit psychostimulants such as cocaine-blunting (repression) of gene inducibility. We measured, by in situ hybridization histochemistry, the effects of a 5-day repeated treatment with methylphenidate (5 mg/kg), fluoxetine (5 mg/kg) or a combination on the inducibility (by cocaine) of neuroplasticity-related genes (Zif268, Homer1a) in the striatum. Repeated methylphenidate treatment alone produced minimal gene blunting, while fluoxetine alone had no effect. In contrast, fluoxetine added to methylphenidate robustly potentiated methylphenidate-induced blunting for both genes. This potentiation was widespread throughout the striatum, but was most robust in the lateral, sensorimotor striatum, thus mimicking cocaine effects. For illicit psychostimulants, blunting of gene expression is considered part of the molecular basis of addiction. Our results thus suggest that SSRIs, such as fluoxetine, may increase the addiction liability of methylphenidate. PMID:23763573

  12. The Emerging Role of SGLT2 Inhibitors in the Treatment of Type 2 Diabetes. Focus on Dapagliflozin

    Timar Bogdan

    2016-03-01

    Full Text Available Type 2 diabetes is a progressive metabolic disorder, accounting for more than 90% of all cases of diabetes. Treatment strategies target blood glucose reduction and non-glycemic effects that can reduce long-term complications, such as cardiovascular disease. Although metformin is often initially effective as monotherapy, the progressive nature of diabetes frequently requires additional therapies. Sodium-glucose transporter 2 (SGLT2 became a very attractive therapeutic target in diabetes management. The mechanism of action of SGLT2 inhibitors is not dependent on insulin, thus making them attractive options anytime over the course of the disease. Dapagliflozin is a stable and highly selective inhibitor of SGLT2. The reductions in fasting plasma glucose concentration and bodyweight recorded during the first week of treatment in the dapagliflozin groups continued over weeks and years of treatment. Early weight loss with dapagliflozin might be partly due to a mild osmotic diuresis, while the gradual progressive reduction in bodyweight is consistent with a reduction of fat mass. Although dapagliflozin is well tolerated, signs and symptoms suggestive for urinary and/or genital infections were reported during clinical trials in more patients assigned to the drug than in placebo groups.

  13. FSD-C10: A more promising novel ROCK inhibitor than Fasudil for treatment of CNS autoimmunity.

    Xin, Yan-Le; Yu, Jie-Zhong; Yang, Xin-Wang; Liu, Chun-Yun; Li, Yan-Hua; Feng, Ling; Chai, Zhi; Yang, Wan-Fang; Wang, Qing; Jiang, Wei-Jia; Zhang, Guang-Xian; Xiao, Bao-Guo; Ma, Cun-Gen

    2015-01-01

    Rho-Rho kinase (Rho-ROCK) triggers an intracellular signalling cascade that regulates cell survival, death, adhesion, migration, neurite outgrowth and retraction and influences the generation and development of several neurological disorders. Although Fasudil, a ROCK inhibitor, effectively suppressed encephalomyelitis (EAE), certain side effects may limit its clinical use. A novel and efficient ROCK inhibitor, FSD-C10, has been explored. In the present study, we present chemical synthesis and structure of FSD-C10, as well as the relationship between compound concentration and ROCK inhibition. We compared the inhibitory efficiency of ROCKI and ROCK II, the cell cytotoxicity, neurite outgrowth and dendritic formation, neurotrophic factors and vasodilation between Fasudil and FSD-C10. The results demonstrated that FSD-C10, like Fasudil, induced neurite outgrowth of neurons and dendritic formation of BV-2 microglia and enhanced the production of neurotrophic factor brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and neurotrophin-3 (NT-3). However, the cell cytotoxicity and vasodilation of FSD-C10 were relatively small compared with Fasudil. Although Fasudil inhibited both ROCK I and ROCK II, FSD-C10 more selectively suppressed ROCK II, but not ROCK I, which may be related to vasodilation insensitivity and animal mortality. Thus, FSD-C10 may be a safer and more promising novel ROCK inhibitor than Fasudil for the treatment of several neurological disorders. PMID:26223433

  14. Comparison of paroxetine and dapoxetine, a novel selective serotonin reuptake inhibitor in the treatment of premature ejaculation

    Abdulmuttalip Simsek; Sinan Levent Kirecci; Onur Kucuktopcu; Faruk Ozgor; Mehmet Fatih Akbulut; Omer Sarilar; Unsal Ozkuvanci; Zafer Gokhan Gurbuz

    2014-01-01

    Dapoxetine hydrochloride is a selective serotonin reuptake inhibitor and the first drug approved for the on-demand treatment of premature ejaculation (PE). Our objective in this study was to characterize the efficacy of on-demand dapoxetine (30 and 60 mg) and daily paroxetine (20 mg) usage in treating PE. We conducted a 1 month study involving a total of 150 patients. Patients were divided into three groups of 50. Group 1 were treated with on-demand dapoxetine (30 mg), Group 2 with on-demand ...

  15. Treatment of type 2 diabetes mellitus with agonists of the GLP-1 receptor or DPP-IV inhibitors

    Holst, Jens Juul

    2004-01-01

    in the treatment of Type 2 diabetes, causing marked improvements in glycaemic profile, insulin sensitivity and beta-cell performance, as well as weight reduction. The hormone is metabolised rapidly by the enzyme dipeptidyl peptidase IV (DPP-IV) and, therefore, cannot be easily used clinically. Instead, resistant...... analogues of the hormone (or agonists of the GLP-1 receptor) are in development, along with DPP-IV inhibitors, which have been demonstrated to protect the endogenous hormone and enhance its activity. Agonists include both albumin-bound analogues of GLP-1 and exendin-4, a lizard peptide. Clinical studies...

  16. Treatment and management of myelofibrosis in the era of JAK inhibitors [Corrigendum

    Keohane C

    2013-10-01

    Full Text Available Keohane C, Radia DH, Harrison CN. Biologics: Targets and Therapy. 2013;7:189–198. On page 193 note that the paragraph beginning "Pacritinib (SB1518; Cell Technology, Inc, Mountain View, CA, USA is a JAK2 and FLT3 inhibitor currently being evaluated at a dose of 400 mg daily in a Phase II study (N=34 that included patients with low platelet counts (<50 × 109/L." should have been "Pacritinib (SB1518; Cell Therapeutics, Inc, Seattle, WA, USA is a JAK2 and FLT3 inhibitor which was evaluated at a dose of 400 mg daily in a Phase II study (N=34 that included patients with low platelet counts (<50 × 109/L." On page 193 in the same paragraph note that "Post-Essential Thrombocythemia Myelofibrosis: PERSIST." should have been "Post-Essential Thrombocythemia Myelofibrosis-1: PERSIST-1."Read the original article

  17. Treatment of radiation osteomyelitis of the mandible in a patient with acquired factor VIII inhibitor

    A case of radiation osteomyelitis of mandible in a 56-year-old man with acquired factor VIII inhibitor is presented. He had undergone radiation therapy for malignant lymphoma of the tonsilar region seven years earlier, and also had received steroids to treat acquired factor VIII inhibitor for a year. On initial examination, he was given a diagnosis of phlegmon of the cheek caused by pericoronitis of the left lower wisdom tooth. To prevent the recurrence of inflammation, the wisdom tooth was extracted carefully, but radiation osteomyelitis occurred in association with a pathological fracture of the condylar head. After mini-pulse therapy with methylpredonisolone, segmental mandibulectomy and reconstruction with a titanium metal plate were performed. The postoperative course was satisfactory with no complications such as bleeding or infection. (author)

  18. Treatment of Staphylococcus aureus Biofilm Infection by the Quorum-Sensing Inhibitor RIP▿

    Balaban, Naomi; Cirioni, Oscar; Giacometti, Andrea; Ghiselli, Roberto; Braunstein, Joel B.; Silvestri, Carmela; Mocchegiani, Federico; Saba, Vittorio; Scalise, Giorgio

    2007-01-01

    The quorum-sensing inhibitor RIP inhibits staphylococcal TRAP/agr systems and both TRAP- and agr-negative strains are deficient in biofilm formation in vivo, indicating the importance of quorum sensing to biofilms in the host. RIP injected systemically into rats has been found to have strong activity in preventing methicillin-resistant Staphylococcus aureus graft infections, suggesting that RIP can be used as a therapeutic agent.

  19. Teneligliptin: a DPP-4 inhibitor for the treatment of type 2 diabetes

    Kishimoto M

    2013-05-01

    Full Text Available Miyako KishimotoDepartment of Diabetes and Metabolic Medicine, Center Hospital, Tokyo, Japan; Diabetes and Metabolism Information Center, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, JapanAbstract: Dipeptidyl peptidase-4 (DPP-4 inhibitors have recently emerged as a new class of antidiabetic that show favorable results in improving glycemic control with a minimal risk of hypoglycemia and weight gain. Teneligliptin, a novel DPP-4 inhibitor, exhibits a unique structure characterized by five consecutive rings, which produce a potent and long-lasting effect. Teneligliptin is currently used in cases showing insufficient improvement in glycemic control even after diet control and exercise or a combination of diet control, exercise, and sulfonylurea- or thiazolidine-class drugs. In adults, teneligliptin is orally administered at a dosage of 20 mg once daily, which can be increased up to 40 mg per day. Because the metabolites of this drug are eliminated via renal and hepatic excretion, no dose adjustment is necessary in patients with renal impairment. The safety profile of teneligliptin is similar to those of other available DPP-4 inhibitors. However, caution needs to be exercised when administering teneligliptin to patients who are prone to QT prolongation. One study has reported that the postprandial blood glucose-lowering effects of teneligliptin administered prior to breakfast were sustained throughout the day, and the effects observed after dinner were similar to those observed after breakfast or lunch. Thus, although clinical data for this new drug are limited, this drug shows promise in stabilizing glycemic fluctuations throughout the day and consequently suppressing the progression of diabetic complications. However, continued evaluation in long-term studies and clinical trials is required to evaluate the efficacy and safety of the drug as well as to identify additional indications for its clinical use

  20. A Small-Molecule Inhibitor of PIM Kinases as a Potential Treatment for Urothelial Carcinomas

    Jason M. Foulks

    2014-05-01

    Full Text Available The proto-oncogene proviral integration site for moloney murine leukemia virus (PIM kinases (PIM-1, PIM-2, and PIM-3 are serine/threonine kinases that are involved in a number of signaling pathways important to cancer cells. PIM kinases act in downstream effector functions as inhibitors of apoptosis and as positive regulators of G1-S phase progression through the cell cycle. PIM kinases are upregulated in multiple cancer indications, including lymphoma, leukemia, multiple myeloma, and prostate, gastric, and head and neck cancers. Overexpression of one or more PIM family members in patient tumors frequently correlates with poor prognosis. The aim of this investigation was to evaluate PIM expression in low- and high-grade urothelial carcinoma and to assess the role PIM function in disease progression and their potential to serve as molecular targets for therapy. One hundred thirty-seven cases of urothelial carcinoma were included in this study of surgical biopsy and resection specimens. High levels of expression of all three PIM family members were observed in both noninvasive and invasive urothelial carcinomas. The second-generation PIM inhibitor, TP-3654, displays submicromolar activity in pharmacodynamic biomarker modulation, cell proliferation studies, and colony formation assays using the UM-UC-3 bladder cancer cell line. TP-3654 displays favorable human ether-à-go-go-related gene and cytochrome P450 inhibition profiles compared with the first-generation PIM inhibitor, SGI-1776, and exhibits oral bioavailability. In vivo xenograft studies using a bladder cancer cell line show that PIM kinase inhibition can reduce tumor growth, suggesting that PIM kinase inhibitors may be active in human urothelial carcinomas.

  1. Moguntinones--new selective inhibitors for the treatment of human colorectal cancer.

    Maderer, Annett; Plutizki, Stanislav; Kramb, Jan-Peter; Göpfert, Katrin; Linnig, Monika; Khillimberger, Katrin; Ganser, Christopher; Lauermann, Eva; Dannhardt, Gerd; Galle, Peter R; Moehler, Markus

    2014-06-01

    3-Indolyl and 3-azaindolyl-4-aryl maleimide derivatives, called moguntinones (MOG), have been selected for their ability to inhibit protein kinases associated with angiogenesis and induce apoptosis. Here, we characterize their mode of action and their potential clinical value in human colorectal cancer in vitro and in vivo. MOG-19 and MOG-13 were characterized in vitro using kinase, viability, and apoptosis assays in different human colon cancer (HT-29, HCT-116, Caco-2, and SW480) and normal colon cell lines (CCD-18Co, FHC, and HCoEpiC) alone or in combination with topoisomerase I inhibitors. Intracellular signaling pathways were analyzed by Western blotting. To determine their potential to inhibit tumor growth in vivo, the human HT-29 tumor xenograft model was used. Moguntinones prominently inhibit several protein kinases associated with tumor growth and metastasis. Specific signaling pathways such as GSK3β and mTOR downstream targets were inhibited with IC(50) values in the nanomolar range. GSK3β signaling inhibition was independent of KRAS, BRAF, and PI3KCA mutation status. While moguntinones alone induced apoptosis only in concentrations >10 μmol/L, MOG-19 in combination with topoisomerase I inhibitors induced apoptosis synergistically at lower concentrations. Consistent with in vitro data, MOG-19 significantly reduced tumor volume and weight in combination with a topoisomerase I inhibitor in vivo. Our in vitro and in vivo data present significant proapoptotic, antiangiogenic, and antiproliferative effects of MOG-19 in different human colon cancer cells. Combination with clinically relevant topoisomerase I inhibitors in vitro and xenograft mouse model demonstrate a high potency of moguntinones to complement and improve standard chemotherapy options in human colorectal cancer. PMID:24743703

  2. Proteinase treatment of intact hepatic mitochondria has differential effects on inhibition of carnitine palmitoyltransferase by different inhibitors.

    Kashfi, K; Cook, G A

    1992-01-01

    Proteolysis of intact mitochondria by Nagarse (subtilisin BPN') and papain resulted in limited loss of activity of the outer-membrane carnitine palmitoyltransferase, but much greater loss of sensitivity to inhibition by malonyl-CoA. In contrast with a previous report [Murthy & Pande (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 378-382], we found that trypsin had no effect on malonyl-CoA sensitivity. Even when 80% of activity was destroyed by trypsin, there was no difference in the malonyl-CoA sensitivity of the enzyme remaining. Trypsin caused release of the intermembrane-space enzyme adenylate kinase, indicating loss of integrity of the mitochondrial outer membrane, whereas Nagarse and papain caused no release of that enzyme. Citrate synthase was not released by any of the three proteinases, indicating no damage to the mitochondrial inner membrane. When we examined the effects of proteolysis on the inhibition of carnitine palmitoyltransferase by a wide variety of inhibitors having different mechanisms of inhibition, we found differential proteolytic effects that were specific for those inhibitors (malonyl-CoA and hydroxyphenylglyoxylate) that have their inhibitory potencies diminished by changes in physiological state. Both of those inhibitors protected carnitine palmitoyltransferase from the effects of proteolysis, but did not inhibit the proteinases directly. Inhibition by two other inhibitors (DL-2-bromopalmitoyl-CoA and N-benzyladriamycin 14-valerate) was not altered by proteinase treatment, even when most of the enzyme activity had been destroyed. Inhibition by glyburide, which is minimally affected by physiological state, was affected only to a slight extent at the highest concentration of trypsin tested. Proteolysis by Nagarse appeared to produce loss of co-operativity in malonyl-CoA inhibition. The effects of proteolysis are discussed and compared with changes in Ki occurring with changing physiological states. PMID:1554374

  3. A novel angiotensin-І converting enzyme (ACE) inhibitory peptide from gastrointestinal protease hydrolysate of silkworm pupa (Bombyx mori) protein: Biochemical characterization and molecular docking study.

    Wu, Qiongying; Jia, Junqiang; Yan, Hui; Du, Jinjuan; Gui, Zhongzheng

    2015-06-01

    Silkworm pupa (Bombyx mori) protein was hydrolyzed using gastrointestinal endopeptidases (pepsin, trypsin and α-chymotrypsin). Then, the hydrolysate was purified sequentially by ultrafiltration, gel filtration chromatography and RP-HPLC. A novel ACE inhibitory peptide, Ala-Ser-Leu, with the IC50 value of 102.15μM, was identified by IT-MS/MS. This is the first report of Ala-Ser-Leu from natural protein. Lineweaver-Burk plots suggest that the peptide is a competitive inhibitor against ACE. The molecular docking studies revealed that the ACE inhibition of Ala-Ser-Leu is mainly attributed to forming very strong hydrogen bonds with the S1 pocket (Ala354) and the S2 pocket (Gln281 and His353). The results indicate that silkworm pupa (B. mori) protein or its gastrointestinal protease hydrolysate could be used as a functional ingredient in auxiliary therapeutic foods against hypertension. PMID:25111373

  4. Experimental in vivo and in vitro treatment with a new histone deacetylase inhibitor belinostat inhibits the growth of pancreatic cancer

    Dovzhanskiy Dmitriy I

    2012-06-01

    Full Text Available Abstract Background Treatment options for pancreatic ductal adenocarcinoma (PDAC are limited. Histone deacetylase inhibitors are a new and promising drug family with strong anticancer activity. The aim of this study was to examine the efficacy of in vitro and in vivo treatment with the novel pan-HDAC inhibitor belinostat on the growth of human PDAC cells. Methods The proliferation of tumour cell lines (T3M4, AsPC-1 and Panc-1 was determined using an MTT assay. Apoptosis was analysed using flow cytometry. Furthermore, p21Cip1/Waf1 and acetylated histone H4 (acH4 expression were confirmed by immunoblot analysis. The in vivo effect of belinostat was studied in a chimeric mouse model. Antitumoural activity was assessed by immunohistochemistry for Ki-67. Results Treatment with belinostat resulted in significant in vitro and in vivo growth inhibition of PDAC cells. This was associated with a dose-dependent induction of tumour cell apoptosis. The apoptotic effect of gemcitabine was further enhanced by belinostat. Moreover, treatment with belinostat increased expression of the cell cycle regulator p21Cip1/Waf1 in Panc-1, and of acH4 in all cell lines tested. The reductions in xenograft tumour volumes were associated with inhibition of cell proliferation. Conclusion Experimental treatment of human PDAC cells with belinostat is effective in vitro and in vivo and may enhance the efficacy of gemcitabine. A consecutive study of belinostat in pancreatic cancer patients alone, and in combination with gemcitabine, could further clarify these effects in the clinical setting.

  5. Experimental in vivo and in vitro treatment with a new histone deacetylase inhibitor belinostat inhibits the growth of pancreatic cancer

    Treatment options for pancreatic ductal adenocarcinoma (PDAC) are limited. Histone deacetylase inhibitors are a new and promising drug family with strong anticancer activity. The aim of this study was to examine the efficacy of in vitro and in vivo treatment with the novel pan-HDAC inhibitor belinostat on the growth of human PDAC cells. The proliferation of tumour cell lines (T3M4, AsPC-1 and Panc-1) was determined using an MTT assay. Apoptosis was analysed using flow cytometry. Furthermore, p21Cip1/Waf1 and acetylated histone H4 (acH4) expression were confirmed by immunoblot analysis. The in vivo effect of belinostat was studied in a chimeric mouse model. Antitumoural activity was assessed by immunohistochemistry for Ki-67. Treatment with belinostat resulted in significant in vitro and in vivo growth inhibition of PDAC cells. This was associated with a dose-dependent induction of tumour cell apoptosis. The apoptotic effect of gemcitabine was further enhanced by belinostat. Moreover, treatment with belinostat increased expression of the cell cycle regulator p21Cip1/Waf1 in Panc-1, and of acH4 in all cell lines tested. The reductions in xenograft tumour volumes were associated with inhibition of cell proliferation. Experimental treatment of human PDAC cells with belinostat is effective in vitro and in vivo and may enhance the efficacy of gemcitabine. A consecutive study of belinostat in pancreatic cancer patients alone, and in combination with gemcitabine, could further clarify these effects in the clinical setting

  6. Chelation: A Fundamental Mechanism of Action of AGE Inhibitors, AGE Breakers, and Other Inhibitors of Diabetes Complications

    Nagai, Ryoji; Murray, David B.; Metz, Thomas O.; Baynes, John W.

    2012-01-01

    This article outlines evidence that advanced glycation end product (AGE) inhibitors and breakers act primarily as chelators, inhibiting metal-catalyzed oxidation reactions that catalyze AGE formation. We then present evidence that chelation is the most likely mechanism by which ACE inhibitors, angiotensin receptor blockers, and aldose reductase inhibitors inhibit AGE formation in diabetes. Finally, we note several recent studies demonstrating therapeutic benefits of chelators for diabetic car...

  7. Polarimetric Multiwavelength Focal Plane Arrays for ACE and CLARREO Project

    National Aeronautics and Space Administration — High-performance polarimetric and nonpolarimetric sensing is crucial to upcoming NASA missions, including ACE and CLARREO and the multi-agency VIIRS NPP project....

  8. Structure-Based Discovery of Novel Cyclophilin A Inhibitors for the Treatment of Hepatitis C Virus Infections.

    Yang, Suhui; K R, Jyothi; Lim, Sangbin; Choi, Tae Gyu; Kim, Jin-Hwan; Akter, Salima; Jang, Miran; Ahn, Hyun-Jong; Kim, Hee-Young; Windisch, Marc P; Khadka, Daulat B; Zhao, Chao; Jin, Yifeng; Kang, Insug; Ha, Joohun; Oh, Byung-Chul; Kim, Meehyein; Kim, Sung Soo; Cho, Won-Jea

    2015-12-24

    Hepatitis C virus (HCV) is a major cause of end-stage liver disease. Direct-acting antivirals (DAAs), including inhibitors of nonstructural proteins (NS3/4A protease, NS5A, and NS5B polymerase), represent key components of anti-HCV treatment, but these are associated with increased drug resistance and toxicity. Thus, the development of host-targeted antiviral agents, such as cyclophilin A inhibitors, is an alternative approach for more effective, selective, and safer treatment. Starting with the discovery of a bis-amide derivative 5 through virtual screening, the lead compound 25 was developed using molecular modeling-based design and systematic exploration of the structure-activity relationship. The lead 25 lacked cytotoxicity, had potent anti-HCV activity, and showed selective and high binding affinity for CypA. Unlike cyclosporin A, 25 lacked immunosuppressive effects, successfully inhibited the HCV replication, restored host immune responses without acute toxicity in vitro and in vivo, and exhibited a high synergistic effect in combination with other drugs. These findings suggest that the bis-amides have significant potential to extend the arsenal of HCV therapeutics. PMID:26613291

  9. Treatment compliance and severe adverse events limit the use of tyrosine kinase inhibitors in refractory thyroid cancer

    Chrisoulidou A

    2015-09-01

    Full Text Available Alexandra Chrisoulidou, Stylianos Mandanas, Efterpi Margaritidou, Lemonia Mathiopoulou, Maria Boudina, Konstantinos Georgopoulos, Kalliopi Pazaitou-PanayiotouDepartment of Endocrinology, Theagenio Cancer Hospital, Thessaloniki, GreeceObjective: The aim of the present study was to assess patient compliance with tyrosine kinase inhibitor (TKI treatment used for refractory and progressive thyroid cancer, in addition to the efficacy and serious adverse events associated with these agents.Methods: We retrospectively analyzed data from adult patients with metastatic differentiated or medullary thyroid cancer unresponsive to conventional treatment and treated with TKIs. Patients received treatment until disease progression or onset of serious adverse events, or until they expressed an intention to stop treatment.Results: Twenty-four patients received TKIs. The median duration of treatment was four (range: 1–19 cycles. The most frequent adverse events were fatigue, nausea, diarrhea, hypertension, and stomatitis, and the most severe were nasal bleeding, diarrhea, heart failure, rhabdomyolysis, renal failure, QT prolongation, neutropenia, and severe fatigue. Dose reduction was required in eight patients, while five decided to terminate TKI therapy because adverse events impaired their everyday activities. During therapy, two patients showed a partial response and three showed stable disease. The lungs were the metastatic sites favoring a response to treatment.Conclusion: Patient selection and meticulous pretreatment education are necessary in order to ensure adherence with TKI therapy. If adverse events appear, dose reduction or temporary treatment interruption may be offered because some adverse events resolve with continuation of treatment. In the event of serious adverse events, treatment discontinuation is necessary. Keywords: medullary thyroid carcinoma, differentiated thyroid cancer, TKIs, sorafenib, sunitinib, vandetanib

  10. [Dasatinib. A novel tyrosine kinase inhibitor for the treatment of chronic myeloid leukaemia

    Dufva, I.H.; Stentoft, J.; Hasselbalch, H.C.;

    2008-01-01

    Chronic myeloid leukaemia is characterized by an abnormal tyrosin kinase in the cytoplasm of the clonal cells. The enzyme is derived from a fusion gene on the Philadelphia-chromosome, evolved by a translocation between chromosomes 9 and 22. Understanding the biology of the tyrosin kinase led to t...... targeted therapy, inhibiting the ATP-binding site by a small molecule--imatinib (Glivec). A novel 2nd generation tyrosin kinase inhibitor--dasatinib (Sprycel)--is now available in cases of insufficient response or intolerance to imatinib Udgivelsesdato: 2008/1/28...

  11. Progress in mechanisms of acetylcholinesterase inhibitors and memantine for the treatment of Alzheimer's disease

    Shao-Min Li

    2015-01-01

    Full Text Available Alzheimer's disease (AD is the most common causes of dementia in the elderly. Currently, only two classes of drugs, acetylcholinesterase inhibitors (AChEIs and memantine are approved. AChEIs ameliorate cognitive and psychiatric symptoms in AD patients through activation of acetylcholine (ACh receptors by increased synaptic ACh levels and also have protective effects against glutamate neurotoxicity and inflammation, whereas memantine appears to mainly protect against excitotoxicity and neurodegeneration. Herein, we review the pharmacologic properties of the available AChEIs and memantine, and focus on recent progress in the mechanisms of AD in relation to acetylcholinergic and glutamatergic involvement.

  12. Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes

    Deacon, Carolyn F; Holst, Jens Juul

    2013-01-01

    although their mechanism of action (inhibition of the catalytic activity of DPP-4) is the same, there are fundamental differences between them. AREAS COVERED: The authors discuss the differences between different DPP-4 inhibitors and review their therapeutic efficacy and key safety data. The literature...... covered includes original studies and meta-analyses identified in PubMed, recent abstracts presented at major diabetes scientific conferences, and clinical trials registered at ClinicalTrials.gov. EXPERT OPINION: Although there are some differences in the pharmacokinetic and pharmacodynamic profiles of...

  13. ACE View � an ontology and rule editor based on controlled English

    Kaljurand, K

    2008-01-01

    We describe the architecture of a novel ontology and rule editor ACE View. The goal of ACE View is to simplify viewing and editing expressive and syntactically complex OWL/SWRL knowledge bases by making most of the interaction with the knowledge base happen via Attempto Controlled English (ACE). This makes ACE View radically different from current OWL/SWRL editors which are based on formal logic syntaxes and general purpose graphical user interface widgets. ACE Vie...

  14. The danish protease inhibitor study: a randomized study comparing the virological efficacy of 3 protease inhibitor-containing regimens for the treatment of human immunodeficiency virus type 1 infection

    Katzenstein, T L; Kirk, O; Pedersen, C; Lundgren, J D; Nielsen, H; Obel, N; Nielsen, C; Mathiesen, Lars Reinhardt; Gerstoft, J

    2000-01-01

    The Danish Protease Inhibitor (PI) Study has enrolled 318 human immunodeficiency virus (HIV)-infected, PI-naive patients for the purpose of comparing 3 PI-containing regimens for the treatment of HIV infection. The regimens include 2 nucleoside analogues in combination with indinavir (Idr...

  15. The danish protease inhibitor study: a randomized study comparing the virological efficacy of 3 protease inhibitor-containing regimens for the treatment of human immunodeficiency virus type 1 infection

    Katzenstein, TL; Kirk, O; Pedersen, C; Lundgren, Jens Dilling; Nielsen, H; Obel, N; Nielsen, C; Mathiesen, Lars Reinhardt; Gerstoft, J

    2000-01-01

    The Danish Protease Inhibitor (PI) Study has enrolled 318 human immunodeficiency virus (HIV)-infected, PI-naive patients for the purpose of comparing 3 PI-containing regimens for the treatment of HIV infection. The regimens include 2 nucleoside analogues in combination with indinavir (Idr), riton...

  16. Anti-Tumor Effect in Human Lung Cancer by a Combination Treatment of Novel Histone Deacetylase Inhibitors: SL142 or SL325 and Retinoic Acids

    Shaoteng Han; Takuya Fukazawa; Tomoki Yamatsuji; Junji Matsuoka; Hiroyuki Miyachi; Yutaka Maeda; Mary Durbin; Yoshio Naomoto

    2010-01-01

    Histone deacetylase (HDAC) inhibitors arrest cancer cell growth and cause apoptosis with low toxicity thereby constituting a promising treatment for cancer. In this study, we investigated the anti-tumor activity in lung cancer cells of the novel cyclic amide-bearing hydroxamic acid based HDAC inhibitors SL142 and SL325. In A549 and H441 lung cancer cells both SL142 and SL325 induced more cell growth inhibition and cell death than the hydroxamic acid-based HDAC inhibitor suberoylanilide hydrox...

  17. Use of p38 MAPK Inhibitors for the Treatment of Werner Syndrome

    Mark C. Bagley

    2010-06-01

    Full Text Available Werner syndrome provides a convincing model for aspects of the normal ageing phenotype and may provide a suitable model for therapeutic interventions designed to combat the ageing process. Cultured primary fibroblast cells from Werner syndrome patients provide a powerful model system to study the link between replicative senescence in vitro and in vivo pathophysiology. Genome instability, together with an increased pro-oxidant state, and frequent replication fork stalling, all provide plausible triggers for intracellular stress in Werner syndrome cells, and implicates p38 MAPK signaling in their shortened replicative lifespan. A number of different p38 MAPK inhibitor chemotypes have been prepared rapidly and efficiently using microwave heating techniques for biological study in Werner syndrome cells, including SB203580, VX-745, RO3201195, UR-13756 and BIRB 796, and their selectivity and potency evaluated in this cellular context. Werner syndrome fibroblasts treated with a p38 MAPK inhibitor reveal an unexpected reversal of the accelerated ageing phenotype. Thus the study of p38 inhibition and its effect upon Werner pathophysiology is likely to provide new revelations into the biological mechanisms operating in cellular senescence and human ageing in the future.

  18. Long-term safety of aromatase inhibitors in the treatment of breast cancer

    Jean-Marc A Nabholtz

    2008-03-01

    Full Text Available Jean-Marc A NabholtzBreast Cancer Research Institute La Prandie, Valojoulx, FranceAbstract: Following promising data for metastatic breast cancer in terms of efficacy and safety profile, third-generation aromatase inhibitors (AI, anastrozole, letrozole, and exemestane, underwent a full development in early setting. If recent results consistently show the superiority of these agents over tamoxifen, the therapeutic strategies of AIs in adjuvant setting are still debated. Beyond the choice of clinical strategy, the long duration of exposure to AI in adjuvant setting required a full determination of the long-term toxicity profile of these agents. While all three AIs have either favorable (decreased incidence of hot flashes, gynecologic and thromboembolic side-effects or unfavorable (skeletal complications, arthralgia, musculoskeletal pain, sexual dysfunction class adverse events, some variability between AIs has been reported in side-effects as well as gastrointestinal, urogenital, neurologic, and visual disturbances, confirming the lack of interchangeability between the three AIs. The overall therapeutic index of AIs appears today superior to that of tamoxifen with proven improved efficacy and better toxicity profile. This review will explore the results from the available adjuvant AIs trials with a particular emphasis on safety profiles, quality of life, and therapeutic index, helping to define the present role of AIs in the adjuvant management of postmenopausal patients with breast cancer.Keywords: breast cancer, aromatase inhibitors, adjuvant, safety profile

  19. Do rheumatoid arthritis patients have equal access to treatment with new medicines? Tumour necrosis factor-alpha inhibitors use in four European countries

    Hoebert, Joelle M.; Mantel-Teeuwisse, Aukje K.; van Dijk, Liset; Bijlsma, Johannes W. J.; Leufkens, Hubert G. M.

    2012-01-01

    Purpose: To explore the use of the biological tumour necrosis factor alpha (TNFalpha) inhibitors used in the treatment of rheumatoid arthritis as a measure of access to treatment with new medicines. In addition, characteristics both related to national health systems and spending will be assessed to

  20. Do rheumatoid arthritis patients have equal access to treatment with new medicines? Tumour necrosis factor-alpha inhibitors use in four European countries.

    Hoebert, J.M.; Mantel-Teeuwisse, A.K.; Dijk, L. van; Bijlsma, J.W.J.; Leufkens, H.G.M.

    2012-01-01

    Purpose: To explore the use of the biological tumour necrosis factor alpha (TNFalpha) inhibitors used in the treatment of rheumatoid arthritis as a measure of access to treatment with new medicines. In addition, characteristics both related to national health systems and spending will be assessed to

  1. TREATMENT OF PATIENTS WITH CHRONIC ISCHEMIC HEART DISEASE IN REAL CLINICAL PRACTICE ACCORDING TO THE DATA FROM PROGNOZ IBS REGISTER. (Part 1

    S. N. Tolpygina

    2015-09-01

    Full Text Available According to the data from PROGNOZ IBS register drugs with proven efficacy in secondary prevention of cardiovascular complications (antiplatelets, β-blockers, ACE inhibitors, statins were not often prescribed in patients with stable ischemic heart disease prior to hospitalization. Significant improvement of the treatment quality was found during the cardiology hospital stay. The prescription rate of ACE inhibitors increased from 20% to 84.4%, statins - from 10% to 85.5%, β-blockers - from 20% to 91%, acetylsalicylic acid - from 74% to 96%. However, some drugs (statins have been used in inadequate doses. Low-density lipoprotein level <2.5 mmol/L was achieved at discharge only in 6.3% of patients.

  2. Angiotensin-Converting Enzyme (ACE) 2 Overexpression Ameliorates Glomerular Injury in a Rat Model of Diabetic Nephropathy: A Comparison with ACE Inhibition

    Liu, Chun Xi; Hu, Qin; Yan WANG; Zhang, Wei; Ma, Zhi Yong; Feng, Jin Bo; Wang, Rong; Wang, Xu Ping; Dong, Bo; Gao, Fei; Zhang, Ming Xiang; Zhang, Yun

    2010-01-01

    The reduced expression of angiotensin-converting enzyme (ACE) 2 in the kidneys of animal models and patients with diabetes suggests ACE2 involvement in diabetic nephrology. To explore the renoprotective effects of ACE2 overexpression, ACE inhibition (ACEI) or both on diabetic nephropathy and the potential mechanisms involved, 50 Wistar rats were randomly divided into a normal group that received an injection of sodium citrate buffer and a diabetic model group that received an injection of 60 ...

  3. Aerosol physical properties and processes in the lower marine boundary layer: a comparison of shipboard sub-micron data from ACE-1 and ACE-2

    Bates, Timothy S.; Quinn, Patricia K.; Covert, David S.; Coffman, Derek J; Johnson, James E.; Wiedensohler, Alfred

    2011-01-01

    The goals of the IGAC Aerosol Characterization Experiments (ACE) are to determine and understand the properties and controlling processes of the aerosol in a globally representative range of natural and anthropogenically perturbed environments. ACE-1 was conducted in the remote marine atmosphere south of Australia while ACE-2 was conducted in the anthropogenically modified atmosphere of the Eastern North Atlantic. In-situ shipboard measurements from the RV Discoverer(ACE-1) and the RV Profess...

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

    Swinburn Boyd; Vos Theo; Magnus Anne; Markwick Alison; Moodie Marj; Carter Rob; Haby Michele M

    2009-01-01

    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...

  5. SGLT-2 inhibitors and their potential in the treatment of diabetes

    Rosenwasser RF

    2013-11-01

    Full Text Available Rebecca F Rosenwasser,1 Senan Sultan,2 David Sutton,2 Rushab Choksi,1 Benjamin J Epstein3 1East Coast Institute for Research, Jacksonville, FL, USA; 2Northeast Florida Endocrine and Diabetes Associates, Jacksonville, FL, USA; 3Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, FL, USA Abstract: Diabetes remains a burgeoning global problem, necessitating ongoing efforts on the part of pharmaceutical and device manufacturers, patients, and society to curb the frightening trends in morbidity and mortality attributable to the malady. Since 1835 when phlorizin was discovered, sodium glucose co-transporter 2 (SGLT-2 inhibitors have rested tantalizingly on the horizon, promising a more physiological approach to glucose control. These agents lower glucose by enhancing its excretion by blocking reabsorption in the renal tubules, thus eliminating glucose from the body along with the molecules' attendant effects on caloric balance, plasma osmolality, and lipids. Consequently, SGLT-2 inhibitors improve glucose control to an extent comparable to other hypoglycemic agents while simultaneously reducing body weight, blood pressure, and cholesterol – an admirable portfolio. One agent, canagliflozin, has recently been approved by the US Food and Drug Administration (FDA and two other agents have progressed through Phase III trials, including dapagliflozin and empagliflozin. Collectively, when used as monotherapy, these agents have demonstrated reductions in hemoglobin A1c (HbA1c, body weight, and blood pressure of –0.34% to –1.03%, –2.0 to -3.4 kg, and –1.7 to –6.4 mmHg/–0.3 to –2.6 mmHg (systolic blood pressure/diastolic blood pressure, respectively. SGLT-2 inhibitors have been well tolerated, with hypoglycemia (0.9% to 4.3% occurring infrequently in clinical trials. Safety signals related to breast and bladder cancer have arisen with dapagliflozin, though these are unsubstantiated

  6. Targeted therapies and immune checkpoint inhibitors in the treatment of metastatic melanoma patients: a guide and update for pathologists.

    Kakavand, Hojabr; Wilmott, James S; Long, Georgina V; Scolyer, Richard A

    2016-02-01

    The previously dismal prospects for patients with advanced stage metastatic melanoma have greatly improved in recent years. Enhanced understanding of both the pathogenesis of melanoma and its molecular drivers, as well as the importance and regulation of anti-tumour immune responses, have provided new therapeutic opportunities for melanoma patients. There are two major distinct categories of systemic treatments with activity for patients with metastatic melanoma: (1) targeted therapies, which act to inhibit the oncogenes that drive the aberrant growth and dissemination of the tumour; and (2) immune checkpoint inhibitor therapies, which act to enhance anti-tumour immune responses by blocking negative regulators of immunity. Pathologists play a critical and expanding role in the selection of the most appropriate treatment for individual metastatic melanoma patients in the modern era of personalised/precision medicine. The molecular pathology testing of melanoma tumour tissue for the presence of targetable oncogenic mutations is already part of routine practice in many institutions. In addition, other potential oncogenic therapeutic targets continue to be identified and pathology testing techniques must readily adapt to this rapidly changing field. Recent research findings suggest that pathological assessment of tumour associated immune cells and immunosuppressive ligand expression of the tumour are likely to be important in identifying patients most likely to benefit from immune checkpoint inhibitors. Similarly, pathological and molecular observations of on-treatment tumour tissue biopsies taken from patients on targeted therapies have provided new insights into the mechanisms of action of targeted molecular therapies, have contributed to the identification of resistance mechanisms to these novel therapies and may be of higher value for selecting patients most likely to benefit from therapies. These data have already provided a rational biological basis for the

  7. A novel approach in treatment of rheumatoid arthritis: Janus kinase inhibitors

    Sangeeta Bhanwra

    2015-06-01

    Full Text Available Janus kinase (JAK inhibitors are a new class of drugs that inhibit JAK enzymes, which are the main signal transducers for the majority of cytokines, growth factors, and interferons. These drugs work from inside the cell and are unique in a way that their action interrupts the signaling involved in the inflammation. They include drugs like ruxolitinib, tofacitinib, both of which have been US Food and Drug Administration (USFDA approved, and many others which are currently under trials. Tofacitinib was approved by USFDA in November 2012 for oral use in patients suffering with moderate to severe rheumatoid arthritis and do not respond to methotrexate. [Int J Basic Clin Pharmacol 2015; 4(3.000: 598-600

  8. Clinical and preclinical treatment of urologic diseases with phosphodiesterase isoenzymes 5 inhibitors: an update

    Wen-Hao Zhang

    2016-01-01

    Full Text Available Phosphodiesterase isoenzymes 5 inhibitors (PDE5-Is are the first-line therapy for erectile dysfunction (ED. The constant discoveries of nitric oxide (NO/cyclic guanosine monophosphate (cGMP cell-signaling pathway for smooth muscle (SM control in other urogenital tracts (UGTs make PDE5-Is promising pharmacologic agents against other benign urological diseases. This article reviews the literature and contains some previously unpublished data about characterizations and activities of PDE5 and its inhibitors in treating urological disorders. Scientific discoveries have improved our understanding of cell-signaling pathway in NO/cGMP-mediated SM relaxation in UGTs. Moreover, the clinical applications of PDE5-Is have been widely recognized. On-demand PDE5-Is are efficacious for most cases of ED, while daily-dosing and combination with testosterone are recommended for refractory cases. Soluble guanylate cyclase (sGC stimulators also have promising role in the management of severe ED conditions. PDE5-Is are also the first rehabilitation strategy for postoperation or postradiotherapy ED for prostate cancer patients. PDE5-Is, especially combined with α-adrenoceptor antagonists, are very effective for benign prostatic hyperplasia (BPH except on maximum urinary flow rate (Q max with tadalafil recently proved for BPH with/without ED. Furthermore, PDE5-Is are currently under various phases of clinical or preclinical researches with promising potential for other urinary and genital illnesses, such as priapism, premature ejaculation, urinary tract calculi, overactive bladder, Peyronie′s disease, and female sexual dysfunction. Inhibition of PDE5 is expected to be an effective strategy in treating benign urological diseases. However, further clinical studies and basic researches investigating mechanisms of PDE5-Is in disorders of UGTs are required.

  9. A systematic review on randomized control trials on rennin angiotensin aldosterone system inhibitors role in managing hypertension among hemodialysis patients.

    Aftab, Raja Ahsan; Khan, Amer Hayat; Adnan, Azreen Syazril; Jannah, Nurul

    2016-01-01

    Randomized control trials (RCTs) are considered as most rigors way of determining the cause-effect relationship of a treatment and outcome. Activation of rennin angiotensin aldosterone system (RAAS) is an important contributor to hypertension in hemodialysis patients. The prevalence of hypertension in hemodialysis patients varies from 60% to 80% and hypertension management alone with conventional hemodialysis is insufficient. Hence, the current review was aimed to investigate the effect of RAAS inhibitors in managing hypertension among hemodialysis patients in a randomized control trial. Using PUBMED and EMBASE databases, randomized control trial with primary or secondary outcomes related to the effect of RAAS inhibitors on blood pressure among hemodialysis patients were included for analysis. The current review also assessed the quality of reporting of RCT. A total of eight RCT met inclusion criteria for current review. According to modified jaded scale, one (12.5%) study scored four points for quality reporting, whereas two (25%) studies scored one point that was the least score. The mean score for all included studies was 2.25. Six (75%) of the eight RCT included, involved ARB in hypertension management among hemodialysis patients, whereas two (25%) studies involved angiotensin-converting enzyme (ACE) inhibitors. Of the siz RCT involving ARB, two (33.3%) RCT also included ACE inhibitors comparison group. Altogether six (75%) studies report a reduction in blood pressure with the use of RAAS inhibitors compared to control group; however, of the six studies, two (33.3%) reported that the reduction in blood pressure was not significant. Whereas, two (25%) studies reported no reduction in blood pressure compared to the control group. The findings from current review do not indicate a clear pattern for a role of RAAS inhibitors for hypertension control among hemodialysis patients. PMID:26853680

  10. Comparison of paroxetine and dapoxetine, a novel selective serotonin reuptake inhibitor in the treatment of premature ejaculation

    Abdulmuttalip Simsek

    2014-10-01

    Full Text Available Dapoxetine hydrochloride is a selective serotonin reuptake inhibitor and the first drug approved for the on-demand treatment of premature ejaculation (PE. Our objective in this study was to characterize the efficacy of on-demand dapoxetine (30 and 60 mg and daily paroxetine (20 mg usage in treating PE. We conducted a 1 month study involving a total of 150 patients. Patients were divided into three groups of 50. Group 1 were treated with on-demand dapoxetine (30 mg, Group 2 with on-demand dapoxetine (60 mg and Group 3 with daily paroxetine (20 mg. Our outcome measurement was increased from baseline intravaginal ejaculatory latency time (IELT after treatment. The IELT increased from baseline to posttreatment by 117%, 117% and 170% in the paroxetine group (P 0.05, while the 60 mg dapoxetine group had a larger posttreatment IELT increase compared with the 30 mg dapoxetine (P < 0.05 and paroxetine (P < 0.01 groups. Dapoxetine (60 mg 1-3 h before planned intercourse is a very effective treatment modality for PE. However, an on-demand dose of 30 mg dapoxetine is no more effective than the currently prescribed paroxetine treatment.

  11. Combining oral contraceptives with a natural nuclear factor-kappa B inhibitor for the treatment of endometriosis-related pain.

    Maia, Hugo; Haddad, Clarice; Casoy, Julio

    2013-01-01

    Endometriosis is a chronic disease in which a persistent state of heightened inflammation is maintained by nuclear factor-kappa B (NF-κB) activation. The progestins present in oral contraceptives are potent inhibitors of NF-κB translocation to cell nuclei, while Pycnogenol® (Pinus pinaster) acts by blocking post-translational events. In this study, the effects of Pycnogenol on pain scores were investigated in patients with endometriosis using oral contraceptives containing either gestodene or drospirenone in extended regimens. Pain scores were determined using a visual analog scale before and after 3 months of treatment. Oral contraceptives, used alone (groups 1 and 3) or in association with Pycnogenol (groups 2 and 4), resulted in significant decreases in pain scores after 3 months of treatment; however, this reduction was significantly greater in the groups using oral contraceptives + Pycnogenol (groups 2 and 4) compared with those using oral contraceptives alone (groups 1 and 3). In the groups using oral contraceptives alone, 50% of patients became pain-free by the end of the third month of treatment. These results suggest that Pycnogenol increases the efficacy of oral contraceptives for the treatment of endometriosis-related pain. PMID:24379702

  12. Comparison of paroxetine and dapoxetine, a novel selective serotonin reuptake inhibitor in the treatment of premature ejaculation

    Abdulmuttalip Simsek; Sinan Levent Kirecci; Onur Kucuktopcu; Faruk Ozgor; Mehmet Fatih Akbulut; Omer Sarilar; Unsal Ozkuvanci; Zafer Gokhan Gurbuz

    2014-01-01

    Dapoxetine hydrochloride is a selective serotonin reuptake inhibitor and the ifrst drug approved for the on‑demand treatment of premature ejaculation(PE). Our objective in this study was to characterize the efifcacy of on‑demand dapoxetine(30 and 60mg) and daily paroxetine(20mg) usage in treating PE. We conducted a 1 month study involving a total of 150patients. Patients were divided into three groups of 50. Group1 were treated with on‑demand dapoxetine(30mg), Group2 with on‑demand dapoxetine(60mg) and Group3 with daily paroxetine(20mg). Our outcome measurement was increased from baseline intravaginal ejaculatory latency time(IELT) after treatment. The IELT increased from baseline to posttreatment by 117%, 117% and 170% in the paroxetine group(P0.05), while the 60mg dapoxetine group had a larger posttreatment IELT increase compared with the 30mg dapoxetine(P<0.05) and paroxetine(P<0.01) groups. Dapoxetine(60mg) 1–3h before planned intercourse is a very effective treatment modality for PE. However, an on‑demand dose of 30mg dapoxetine is no more effective than the currently prescribed paroxetine treatment.

  13. Structure-Based Design and Synthesis of Novel Inhibitors Targeting HDAC8 from Schistosoma mansoni for the Treatment of Schistosomiasis.

    Heimburg, Tino; Chakrabarti, Alokta; Lancelot, Julien; Marek, Martin; Melesina, Jelena; Hauser, Alexander-Thomas; Shaik, Tajith B; Duclaud, Sylvie; Robaa, Dina; Erdmann, Frank; Schmidt, Matthias; Romier, Christophe; Pierce, Raymond J; Jung, Manfred; Sippl, Wolfgang

    2016-03-24

    Schistosomiasis is a major neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy consists of mass treatment with the only available drug, praziquantel. In this study, a series of new benzohydroxamates were prepared as potent inhibitors of Schistosoma mansoni histone deacetylase 8 (smHDAC8). Crystallographic analysis provided insights into the inhibition mode of smHDAC8 activity by these 3-amidobenzohydroxamates. The newly designed inhibitors were evaluated in screens for enzyme inhibitory activity against schistosome and human HDACs. Twenty-seven compounds were found to be active in the nanomolar range, and some of them showed selectivity toward smHDAC8 over the major human HDACs (1 and 6). The active benzohydroxamates were additionally screened for lethality against the schistosome larval stage using a fluorescence-based assay. Four of these showed significant dose-dependent killing of the schistosome larvae and markedly impaired egg laying of adult worm pairs maintained in culture. PMID:26937828

  14. Nationwide Experience of Treatment with Protease Inhibitors in Chronic Hepatitis C Patients in Denmark

    Sølund, Christina; Krarup, Henrik; Ramirez, Santseharay; Thielsen, Peter; Røge, Birgit T; Lunding, Suzanne; Barfod, Toke S; Madsen, Lone G; Tarp, Britta; Christensen, Peer B; Gerstoft, Jan; Laursen, Alex L; Bukh, Jens; Weis, Nina

    2014-01-01

    patients. Thus, treatment response and development of viral resistance during triple therapy in a routine clinical setting needs to be determined. The aims of this study were to investigate treatment outcome and identify sequence variations after triple therapy in patients with chronic HCV genotype 1...... infection in a routine clinical setting. METHODS: 80 patients, who initiated and completed triple therapy in Denmark between May 2011 and November 2012, were included. Demographic data and treatment response were obtained from the Danish Database for Hepatitis B and C. Direct sequencing and clonal analysis...

  15. Cellular correlates of enhanced anxiety caused by acute treatment with the selective serotonin reuptake inhibitor fluoxetine in rats

    Shilpa Ravinder

    2011-12-01

    Full Text Available Selective serotonin reuptake inhibitors (SSRIs are used extensively in the treatment of depression and anxiety disorders. The therapeutic benefits of SSRIs typically require several weeks of continuous treatment. Intriguingly, according to clinical reports, symptoms of anxiety may actually increase during the early stages of treatment although more prolonged treatment alleviates affective symptoms. Consistent with earlier studies that have used animal models to capture this paradoxical effect of SSRIs, we find that rats exhibit enhanced anxiety-like behavior on the elevated plus-maze one hour after a single injection of the SSRI fluoxetine. Next we investigated the potential neural substrates underlying the acute anxiogenic effects by analyzing the morphological and physiological impact of acute fluoxetine treatment on principal neurons of the basolateral amygdala (BLA, a brain area that plays a pivotal role in fear and anxiety. Although earlier studies have shown that behavioral or genetic perturbations that are anxiogenic for rodents also increase dendritic spine-density in the BLA, we find that a single injection of fluoxetine does not cause spinogenesis on proximal apical dendritic segments on BLA principal neurons an hour later. However, at the same time point when a single dose of fluoxetine caused enhanced anxiety, it also enhanced action potential firing in BLA neurons in ex vivo slices. Consistent with this finding, in vitro bath application of fluoxetine caused higher spiking frequency and this increase in excitability was correlated with an increase in the input resistance of these neurons. Our results suggest that enhanced excitability of amygdala neurons may contribute to the increase in anxiety-like behavior observed following acute fluoxetine treatment.

  16. Overcoming multidrug resistance in Dox-resistant neuroblastoma cell lines via treatment with HPMA copolymer conjugates containing anthracyclines and P-gp inhibitors.

    Koziolová, Eva; Janoušková, Olga; Cuchalová, Lucie; Hvězdová, Zuzana; Hraběta, Jan; Eckschlager, Tomáš; Sivák, Ladislav; Ulbrich, Karel; Etrych, Tomáš; Šubr, Vladimír

    2016-07-10

    Water-soluble N-(2-hydroxypropyl)methacrylamide copolymer conjugates bearing the anticancer drugs doxorubicin (Dox) or pirarubicin (THP), P-gp inhibitors derived from reversin 121 (REV) or ritonavir (RIT)), or both anticancer drug and P-gp inhibitor were designed and synthesized. All biologically active molecules were attached to the polymer carrier via pH-sensitive spacer enabling controlled release in mild acidic environment modeling endosomes and lysosomes of tumor cells. The cytotoxicity of the conjugates against three sensitive and Dox-resistant neuroblastoma (NB) cell lines, applied alone or in combination, was studied in vitro. All conjugates containing THP displayed higher cytotoxicity against all three Dox-resistant NB cell lines compared with the corresponding Dox-containing conjugates. Furthermore, the cytotoxicity of conjugates containing both drug and P-gp inhibitor was up to 10 times higher than that of the conjugate containing only drug. In general, the polymer-drug conjugates showed higher cytotoxicity when conjugates containing inhibitors were added 8 or 16h prior to treatment compared with conjugates bearing both the inhibitor and the drug. The difference in cytotoxicity was more pronounced at the 16-h time point. Moreover, higher inhibitor:drug ratios resulted in higher cytotoxicity. The cytotoxicity of the polymer-drug used in combination with polymer P-gp inhibitor was up to 84 times higher than that of the polymer-drug alone. PMID:27189135

  17. Inhibitor treatment of peripheral mononuclear cells from Parkinson’s disease patients further validates LRRK2 dephosphorylation as a pharmacodynamic biomarker

    Perera, G.; Ranola, M.; Rowe, D. B.; Halliday, G. M.; Dzamko, N.

    2016-01-01

    Activating mutations in leucine-rich repeat kinase 2 (LRRK2) are strongly associated with increased risk of Parkinson’s disease (PD). Thus, LRRK2 kinase inhibitors are in development as potential Parkinson’s disease therapeutics. A reduction in the constitutive levels of phosphorylation on leucine-rich repeat kinase 2 (LRRK2) is currently used to measure target engagement of LRRK2 kinase inhibitors in cell and animal models. We aimed to determine if reduced phosphorylation of LRRK2 following inhibitor treatment is also a valid measure of target engagement in peripheral mononuclear cells from Parkinson’s disease patients. Peripheral mononuclear cells from idiopathic Parkinson’s disease patients and controls were treated ex vivo with two structurally distinct inhibitors of LRRK2, at four different doses, and immunoblotting was used to assess the reduction in LRRK2 phosphorylation at Ser910, Ser935, Ser955 and Ser973. Both inhibitors showed no acute toxicity in primary cells and both inhibitors reduced the constitutive phosphorylation of LRRK2 at all measured residues equally in both control and Parkinson’s disease groups. Measuring the reduction in LRRK2 phosphorylation resulting from LRRK2 kinase inhibition, is thus a valid measure of acute peripheral target engagement in Parkinson’s disease patients. This is important if LRRK2 kinase inhibitors are to be used in a clinical setting. PMID:27503089

  18. Elevation of radiolabelled thymidine uptake in RIF-1 fibrosarcoma and HT29 colon adenocarcinoma cells after treatment with thymidylate synthase inhibitors

    We recently showed an increase in tumour uptake of 2-[11C]thymidine in patients with gastrointestinal malignancies after thymidylate synthase (TS) inhibition. To understand the phenomenon in more detail, we investigated whether TS inhibition by different TS inhibitors leads to a dose- and time-dependent change in the uptake of radiolabelled thymidine, and whether radiotracer uptake is related to changes in cell viability resulting from treatment. RIF-1 and HT29 cells were treated with the TS inhibitors 5-fluorouracil (5-FU) and AG337 (nolatrexed dihydrochloride), as well as cisplatin as control. The cell viability and net accumulation of [3H]thymidine after a 1-h pulse was determined at different times after drug treatment. In both cell lines, [3H]thymidine uptake increased after a 2-h treatment with 5-FU, in a dose- and time-dependent manner. [3H]thymidine uptake decreased at 24 and 48 h post treatment. AG337 also produced a similar effect. In contrast to the TS inhibitors, cisplatin decreased [3H]thymidine uptake in RIF-1 and HT29 cells at all time points. Cell viability was compromised only after 24 h. Using two types of TS inhibitor, we have shown an increase in [3H]thymidine uptake, in a dose-dependent manner, a few hours after TS inhibition when the cell viability was not compromised. This effect was not seen with a non-TS inhibitor. These findings suggest that 2-[11C]thymidine positron emission tomography can be used to study TS inhibition in vivo at early time points when cell viability is not compromised and may therefore be helpful in the development of new TS inhibitors and in differentiating between patients with tumours sensitive to TS inhibitors and those unlikely to respond. (orig.)

  19. The Role of a Single Angiogenesis Inhibitor in the Treatment of Recurrent Glioblastoma Multiforme: A Meta-Analysis and Systematic Review

    Yawei Wang; Dan Xing; Meng Zhao; Jie Wang; Yang Yang

    2016-01-01

    Background Currently, the standard treatment for newly diagnosed glioblastoma multiforme (GBM) is maximal safe surgical resection followed by radiation therapy with concurrent and adjuvant temozolomide. However, disease recurs in almost all patients, and the optimal salvage treatment for recurrent GBM remains unclear. We conducted a systematic review and meta-analysis of published clinical trials to assess the efficacy and toxicities of angiogenesis inhibitors alone as salvage treatment in th...

  20. Condition Optimization of Bioconversion Shrimp Processing Wastes with Cantharellus cibarius for Angiotensin I-Converting Enzyme (ACE) Inhibitors%鸡油菌转化虾副产品产血管紧张素转换酶抑制剂的条件优化

    高秀君; 闫培生

    2016-01-01

    为探索高附加值回收利用虾加工废弃物的方法,利用鸡油菌(Cantharellus cibarius)转化虾加工废弃物,以PB设计、最陡爬坡试验和响应面设计对转化条件进行优化,以血管紧张素转换酶(ACE)抑制活性为指标考察了转化产物的抗高血压活性.结果表明,鸡油菌转化虾加工废弃物最优液体发酵条件(兼顾菌丝产量和ACE抑制活性)为料液比1∶1.857,冰醋酸加入量1.25%;对该转化条件的验证实验结果与发酵条件数学模型预测值无显著性差异(P>0.05),在此条件下菌丝体产量为(27.837±1.011) g/L,较优化前提高21.231%;菌丝体水提物ACE抑制IC50为(0.394±0.071) mg/mL,显著低于优化前(P<0.05),脱腥得分为3.611 ±0.044.以药用价值和经济价值较高的鸡油菌转化虾加工废弃物,其产物具有较高的ACE抑制活性,可从其中分离得到较高活性的ACE抑制剂,而且可使产物脱腥.

  1. Advances in breast cancer treatment and prevention: preclinical studies on aromatase inhibitors and new selective estrogen receptor modulators (SERMs)

    Intensive basic and clinical research over the past 20 years has yielded crucial molecular understanding into how estrogen and the estrogen receptor act to regulate breast cancer and has led to the development of more effective, less toxic, and safer hormonal therapy agents for breast cancer management and prevention. Selective potent aromatase inhibitors are now challenging the hitherto gold standard of hormonal therapy, the selective estrogen-receptor modulator tamoxifen. Furthermore, new selective estrogen-receptor modulators such as arzoxifene, currently under clinical development, offer the possibility of selecting one with a more ideal pharmacological profile for treatment and prevention of breast cancer. Two recent studies in preclinical model systems that evaluate mechanisms of action of these new drugs and suggestions about their optimal clinical use are discussed

  2. Specific MAPK inhibitors prevent hyperglycemia-induced renal diseases in type 1 diabetic mouse model.

    Hong, Zhe; Hong, Zongyuan; Wu, Denglong; Nie, Hezhongrong

    2016-08-01

    Mitogen-activated protein kinase (MAPK) and renin-angiotensin system (RAS) play critical roles in the process of renal diseases, but their interaction has not been comprehensively discussed. In the present studies, we investigated the renoprotective effects of MPAK inhibitors on renal diseases in type 1 diabetic mouse model, and clarify the crosstalk among MAPK signaling. Type 1 diabetic mouse model was established in male C57BL/6 J mice, and treated with or without 10 mg/kg MAPK blockers, including ERK inhibitor PD98059, p38 inhibitor SB203850, and JNK inhibitor SP600125 for four weeks. Hyperglycemia induced renal injuries, but treating them with MAPK inhibitors significantly decreased glomerular volume and glycogen in renal tissues. Although slightly changed body weight and fasting blood glucose levels, MAPK inhibitors attenuated blood urea nitrogen, urea protein, and microalbuminuria. Administration also reduced the diabetes-induced RAS activation, including angiotensin II converting enzyme (c) and Ang II, which contributed to its renal protective effects in the diabetic mice. In addition, the anti-RAS of MAPK inhibitor treatment markedly reduced gene expression of tumor necrosis factor-α, interleukin-6, and inducible nitric oxide synthase, fibrotic accumulation, and transforming growth factor-β1 levels in renal tissues. Furthermore, chemical inhibitors and genetic siRNA results identified the crosstalk among the three MAPK signaling, and proved JNK signaling played a critical role in MAPK-mediated ACE pathway in hyperglycemia state. Collectively, these results support the therapeutic effects of MAPK-specific inhibitors, especially JNK inactivation, on hyperglycemia-induced renal damages. PMID:27389030

  3. The angiotensin-converting enzyme (ACE gene family of Anopheles gambiae

    Isaac R Elwyn

    2005-12-01

    Full Text Available Abstract Background Members of the M2 family of peptidases, related to mammalian angiotensin converting enzyme (ACE, play important roles in regulating a number of physiological processes. As more invertebrate genomes are sequenced, there is increasing evidence of a variety of M2 peptidase genes, even within a single species. The function of these ACE-like proteins is largely unknown. Sequencing of the A. gambiae genome has revealed a number of ACE-like genes but probable errors in the Ensembl annotation have left the number of ACE-like genes, and their structure, unclear. Results TBLASTN and sequence analysis of cDNAs revealed that the A. gambiae genome contains nine genes (AnoACE genes which code for proteins with similarity to mammalian ACE. Eight of these genes code for putative single domain enzymes similar to other insect ACEs described so far. AnoACE9, however, has several features in common with mammalian somatic ACE such as a two domain structure and a hydrophobic C terminus. Four of the AnoACE genes (2, 3, 7 and 9 were shown to be expressed at a variety of developmental stages. Expression of AnoACE3, AnoACE7 and AnoACE9 is induced by a blood meal, with AnoACE7 showing the largest (approximately 10-fold induction. Conclusion Genes coding for two-domain ACEs have arisen several times during the course of evolution suggesting a common selective advantage to having an ACE with two active-sites in tandem in a single protein. AnoACE7 belongs to a sub-group of insect ACEs which are likely to be membrane-bound and which have an unusual, conserved gene structure.

  4. Effect of chronic treatment with the GABA transaminase inhibitors γ-vinyl GABA and ethanolamine O-sulphate on the in vitro GABA release from rat hippocampus

    Qume, M; Fowler, L. J.

    1997-01-01

    The effects of 2, 8 and 21 day oral treatment with the specific γ-aminobutyric acid transaminase (GABA-T) inhibitors γ-vinyl GABA (GVG) and ethanolamine O-sulphate (EOS) on brain GABA levels, GABA-T activity, and basal and stimulated GABA release from rat cross-chopped brain hippocampal slices was investigated.Treatment with GABA-T inhibitors lead to a reduction in brain GABA-T activity by 65–80% compared with control values, with a concomitant increase in brain GABA content of 40–100%.Basal ...

  5. [Current treatment of systemic sclerosis. Part II. Vascular and antifibrotic treatment].

    Sicińska, Justyna; Rudnicka, Lidia

    2008-08-01

    Microvascular abnormalities and fibrosis are important targets of therapy in systemic sclerosis (scleroderma). Calcium channel blockers, ACE inhibitors, sartans, phosphodiesterase-5 inhibitors and serotonin re-uptake blockers are used for Raynaud's phenomenon. Intravenous prostanoids (alprostadil, iloprost, epoprostenol, treprostinil) and endothelin receptor antagonists (bosentan, sitaxsentan, ambrisentan) show efficacy in treatment of pulmonary hypertension and distal ischemia. Successful treatment of digital ulcers secondary to systemic sclerosis was possible with sildenafil and bosentan. A platelet gel is currently in clinical trials for scleroderma-related digital ulcers. Several drugs, which directly reduce excessive production of collagens and other connective tissue proteins have been applied in systemic sclerosis. These include interferon gamma, d-penicillamine, kolchichicine, calcitriol, and imanitib. However, so far, strategies to control fibrosis by directly reducing excessive connective tissue production have been disappointing in controlled studies. PMID:18942347

  6. Reduction of intraspecific aggression in adult rats by neonatal treatment with a selective serotonin reuptake inhibitor

    Manhães de Castro R.

    2001-01-01

    Full Text Available Most studies suggest that serotonin exerts an inhibitory control on the aggression process. According to experimental evidence, this amine also influences growth and development of the nervous tissue including serotoninergic neurons. Thus, the possibility exists that increased serotonin availability in young animals facilitates a long-lasting effect on aggressive responses. The present study aimed to investigate the aggressive behavior of adult rats (90-120 days treated from the 1st to the 19th postnatal day with citalopram (CIT, a selective serotonin reuptake inhibitor (20 mg/kg, sc, every 3 days. Aggressive behavior was induced by placing a pair of rats (matched by weight in a box (20 x 20 x 20 cm, and submitting them to a 20-min session of electric footshocks (five 1.6-mA - 2-s current pulses, separated by a 4-min intershock interval. When compared to the control group (rats treated for the same period with equivalent volumes of saline solution, the CIT group presented a 41.4% reduction in the duration of aggressive response. The results indicate that the repeated administration of CIT early in life reduces the aggressive behavior in adulthood and suggest that the increased brain serotoninergic activity could play a role in this effect.

  7. TP53 mutations emerge with HDM2 inhibitor SAR405838 treatment in de-differentiated liposarcoma.

    Jung, Joonil; Lee, Joon Sang; Dickson, Mark A; Schwartz, Gary K; Le Cesne, Axel; Varga, Andrea; Bahleda, Rastilav; Wagner, Andrew J; Choy, Edwin; de Jonge, Maja J; Light, Madelyn; Rowley, Steve; Macé, Sandrine; Watters, James

    2016-01-01

    In tumours that harbour wild-type p53, p53 protein function is frequently disabled by the mouse double minute 2 protein (MDM2, or HDM2 in humans). Multiple HDM2 antagonists are currently in clinical development. Preclinical data indicate that TP53 mutations are a possible mechanism of acquired resistance to HDM2 inhibition; however, this resistance mechanism has not been reported in patients. Utilizing liquid biopsies, here we demonstrate that TP53 mutations appear in circulating cell-free DNA obtained from patients with de-differentiated liposarcoma being treated with an inhibitor of the HDM2-p53 interaction (SAR405838). TP53 mutation burden increases over time and correlates with change in tumour size, likely representing selection of TP53 mutant clones resistant to HDM2 inhibition. These results provide the first clinical demonstration of the emergence of TP53 mutations in response to an HDM2 antagonist and have significant implications for the clinical development of this class of molecules. PMID:27576846

  8. An Unusual Case of Systemic Inflammatory Myofibroblastic Tumor with Successful Treatment with ALK-Inhibitor

    Sanjivini V. Jacob

    2014-01-01

    Full Text Available Systemic inflammatory myofibroblastic tumor is an exceedingly rare entity. A 45-year-old Hispanic female presented with a 6-month history of left-sided thigh pain, low back pain, and generalized weakness. PET/CT scan revealed abnormal activity in the liver, adrenal gland, and pancreas. MRI of the abdomen demonstrated two 6-7 cm masses in the liver. MRI of the lumbar spine demonstrated lesions in the L2 to L4 spinous processes, paraspinal muscles, and subcutaneous tissues, as well as an 8 mm enhancing intradural lesion at T11, all thought to be metastatic disease. A biopsy of the liver showed portal tract expansion by a spindle cell proliferation rich in inflammation. Tumor cells showed immunoreactivity for smooth muscle actin and anaplastic lymphoma kinase 1 (ALK1. Tissue from the L5 vertebra showed a process histologically identical to that seen in the liver. FISH analysis of these lesions demonstrated an ALK (2p23 gene rearrangement. The patient was successfully treated with an ALK-inhibitor, Crizotinib, and is now in complete remission. We present the first reported case, to our knowledge, of inflammatory myofibroblastic tumor with systemic manifestations and ALK translocation. This case is a prime example of how personalized medicine has vastly improved patient care through the use of molecular-targeted therapy.

  9. Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia

    FMS-like tyrosine kinase 3 (FLT3) is the most commonly mutated gene found in acute myeloid leukemia (AML) patients and its activating mutations have been proven to be a negative prognostic marker for clinical outcome. Pacritinib (SB1518) is a tyrosine kinase inhibitor (TKI) with equipotent activity against FLT3 (IC50=22 n) and Janus kinase 2 (JAK2, IC50=23 n). Pacritinib inhibits FLT3 phosphorylation and downstream STAT, MAPK and PI3 K signaling in FLT3-internal-tandem duplication (ITD), FLT3-wt cells and primary AML blast cells. Oral administration of pacritinib in murine models of FLT3-ITD-driven AML led to significant inhibition of primary tumor growth and lung metastasis. Upregulation of JAK2 in FLT3-TKI-resistant AML cells was identified as a potential mechanism of resistance to selective FLT3 inhibition. This resistance could be overcome by the combined FLT3 and JAK2 activities of pacritinib in this cellular model. Our findings provide a rationale for the clinical evaluation of pacritinib in AML including patients resistant to FLT3-TKI therapy

  10. Discharge of three benzotriazole corrosion inhibitors with municipal wastewater and improvements by membrane bioreactor treatment and ozonation.

    Weiss, Stefan; Jakobs, Jutta; Reemtsma, Thorsten

    2006-12-01

    A set of three benzotriazole corrosion inhibitors was analyzed by liquid chromatography-mass spectrometry in wastewaters and in a partially closed water cycle in the Berlin region. Benzotriazole (BTri) and two isomers of tolyltriazole (TTri) were determined in untreated municipal wastewater with mean dissolved concentrations of 12 microg/L (BTri), 2.1 microg/L (4-TTri), and 1.3 microg/L (5-TTri). Removal in conventional activated sludge (CAS) municipal wastewater treatment ranged from 37% for BTri to insignificant removal for 4-TTri. In laboratory batch tests 5-TTri was mineralized completely and 4-TTri was mineralized to only 25%. This different behavior of the three benzotriazoles was confirmed by following the triazoles through a partially closed water cycle, into bank filtrate used for drinking water production, where BTri (0.1 microg/L) and 4-TTri (0.03 microg/ L) but no 5-TTri were detected after a travel time of several months. The environmental half-life appears to increase from 5-TTri over BTri to 4-TTri. Treatment of municipal wastewater by a lab-scale membrane bioreactor (MBR) instead of CAS improved the removal of BTri and 5-TTri but could not avoid their discharge. Almost complete removal was achieved by ozonation of the treatment plant effluent with 1 mg O3/mg DOC. PMID:17180966

  11. Single photon emission computed tomography before and after treatment of anxiety using a selective serotonin reuptake inhibitor

    Background: The selective serotonin reuptake inhibitors (SSRIs) are currently recommended as first line medications for a number of different anxiety disorders, including obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and social anxiety disorder (social phobia) (SAD). This raises the question of what effects these agents have on the functional neuroanatomy of anxiety disorders. Methods: Single photon emission computed tomography (SPECT) brain scanning was undertaken in patients with OCD, PTSD, and SAD before and after treatment with citalopram, the most selective of the SSRIs. Statistical parametric mapping (SPM) was used to compare scans (pre- vs post-medication, and responders vs nonresponders) in the combined group of subjects. Results: Citalopram pharmacotherapy resulted in significant deactivation within anterior and superior cingulate and left hippocampus. Deactivation within the anterior cingulate, left paracingular cortex, and right inferior frontal cortex was more marked in treatment responders. Baseline activation did not, however, predict response to pharmacotherapy. Conclusion: Although each of the anxiety disorders may be mediated by different neurocircuits, there are some overlaps in the functional neuroanatomy of their response to SSRI treatment. The current data is consistent with previous work demonstrating the importance of limbic circuits in this spectrum of disorders. These play a crucial role in cognitive-affective processing, and are innervated by serotonergic neurons

  12. Non small-cell lung cancer and treatment options after tyrosine kinase inhibitors failure in the first line

    Introduction: Advanced non-small cell lung cancer with present epidermal growth factor receptor (EGFR) sensitising mutation is standardly treated with tyrosine kinase inhibitors (TKI). During treatment a resistance to TKI develops, disease progresses. We differ primary and secondary resistance. The most effective treatment after TKI failure is not definitively proven. Standard chemotherapy is usually introduced, eventually it is possible to use other TKI in the next lines. Case: The author presents a case of 60-year old patient with lung adenocarcinoma with EGFR sensitising mutation, where primary resistance to TKI was observed. Chemotherapy after progression was introduced. Planned therapy with afatnib was not carried out due to deterioration of patient´s condition. Conclusion: Presented case of EGFR mutation-positive patient represents an example of not very frequent primary resistance to TKI. Mechanisms of primary resistance are not well understood. Treatment after first line TKI failure in non-small cell lung cancer with EGFR mutation represents a challenge for medical research. (author)

  13. Treatment of Pneumocystis carinii pneumonia with 1,3-beta-glucan synthesis inhibitors.

    Schmatz, D M; Romancheck, M A; Pittarelli, L A; Schwartz, R. E.; Fromtling, R A; Nollstadt, K H; Vanmiddlesworth, F L; Wilson, K E; Turner, M J

    1990-01-01

    Pneumocystis carinii pneumonia is a major cause of death in AIDS patients in the United States. The presently available treatments have limited use due to a high incidence of adverse reactions. Therefore, there is an urgent need for a safer method for treatment and prevention of this disease. Recent evidence has suggested that P. carinii is related to fungi and that the wall of the cyst form contains 1,3-beta-glucan as a major constituent. Based on this, several proposed 1,3-beta-glucan synth...

  14. Proton pump inhibitors in acid-related diseases. Issues in diagnosis, treatment and outcome

    Jonasson, Christian

    2013-01-01

    Acid-related disease (ARD) is a term used to describe a range of conditions in which acid is involved in the generation of symptoms and/or complications. Two of the most common ARDs are gastro-esophageal reflux disease (GERD) and peptic ulcer disease (PUD). PPIs are today regarded as the gold standard in the treatment of both symptoms and mucosal injury in patients with GERD as well as for prevention and acute treatment of PUD. Since the PPIs were introduced in the late 1980-ie...

  15. Serotonin neuronal function and selective serotonin reuptake inhibitor treatment in anorexia and bulimia nervosa.

    Kaye, W; Gendall, K; Strober, M

    1998-11-01

    Anorexia nervosa (AN) and bulimia nervosa (BN) are disorders characterized by aberrant patterns of feeding behavior and weight regulation, and disturbances in attitudes toward weight and shape and the perception of body shape. Emerging data support the possibility that substantial biologic and genetic vulnerabilities contribute to the pathogenesis of AN and BN. Multiple neuroendocrine and neurotransmitter abnormalities have been documented in AN and BN, but for the most part, these disturbances are state-related and tend to normalize after symptom remission and weight restoration; however, elevated concentrations of 5-hydroxyindoleacetic acid in the cerebrospinal fluid after recovery suggest that altered serotonin activity in AN and BN is a trait-related characteristic. Elevated serotonin activity is consistent with behaviors found after recovery from AN and BN, such as obsessionality with symmetry and exactness, harm avoidance, perfectionism, and behavioral over control. In BN, serotonergic modulating antidepressant medications suppress symptoms independently of their antidepressant effects. Selective serotonin reuptake inhibitors (SSRIs) are not useful when AN subjects are malnourished and under-weight; however, when given after weight restoration, fluoxetine may significantly reduce the extremely high rate of relapse normally seen in AN. Nonresponse to SSRI medication in ill AN subjects could be a consequence of an inadequate supply of nutrients, which are essential to normal serotonin synthesis and function. These data raise the possibility that a disturbance of serotonin activity may create a vulnerability for the expression of a cluster of symptoms that are common to both AN and BN and that nutritional factors may affect SSRI response in depression, obsessive-compulsive disorder, or other conditions characterized by disturbances in serotonergic pathways. PMID:9807638

  16. MEK 1/2 inhibitors for the treatment of peritoneal fibrosis

    Pozo Barriuso, Miguel Ángel del; López Cabrera, Manuel; Strippoli, Raffaele

    2008-01-01

    [EN] Drugs useful in the prevention and treatment of fibrosis of the peritoneal membrane (peritoneal opacification, tanned peritoneum syndrome, mural fibrosis and sclerosing peritonitis syndrome), which arises as a consequence of long-term peritoneal dialysis, method for selecting such dmgs and method for collecting data that are useful in the diagnosis of said disease.

  17. Treatment of fistulating pouchitis with tumour necrosis factor-alpha-inhibitor (infliximab)

    Semb, S.; Nordgaard-Lassen, I.

    2008-01-01

    The surgical first choice treatment for patients with ulcerative colitis (UC) involves total proctocolectomy with ileal pouch-anal anastomosis (IPAA). Postoperative development of pouch-related fistula is a rare complication, but it is associated with significant morbidity, a high recurrence rate...

  18. The efficacy and safety of dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus patients with severe renal impairment: a meta-analysis.

    Chen, Maosheng; Liu, Yueming; Jin, Juan; He, Qiang

    2016-05-01

    Aims/introduction Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of oral antidiabetic agents, and have been increasingly and widely used in the treatment of diabetes mellitus (DM). However, information of DPP-4 inhibitors in type 2 DM patients with severe renal impairment (RI) is limited. Our study aimed to assess the efficacy and safety of DPP-4 inhibitors as compared to placebos or other hypoglycemic drugs in type 2 DM patients with severe RI. Materials and methods A meta-analysis was conducted to examine the literature comparing the effects of DPP-4 inhibitors on hemoglobin A1c (HbA1c) and fasting blood glucose (FBG). Randomized control trials (RCTs) including adults with type 2 DM and severe RI were analyzed. Safety was evaluated based on the percentage of patients who developed hypoglycemia and the occurrence of adverse events (AEs) as well as the incidence of peripheral edema, urinary tract infection, diarrhea, and death. Results Five RCTs including 503 patients were analyzed. Compared with a placebo or no treatment, DPP-4 inhibitors were associated with a larger decline in HbA1c (mean difference (MD) = -0.57, 95% confidence interval (CI): -0.73 to -0.41; p glipizide monotherapy, no significant differences in HbA1c (MD = 0.15, 95% CI: -0.19 to 0.49; p = 0.38) or FBG (MD = -0.26, 95% CI: -1.16 to 0.64; p = 0.57) were found. Similar odds of experiencing an AE were found in both the DPP-4 inhibitor groups and comparison groups. Conclusions In type 2 DM patients with severe RI, treatment with DPP-4 inhibitors is safe and it effectively lowers HbA1c. PMID:26915531

  19. ACE-2 HILLCLOUD. An overview of the ACE-2 ground-based cloud experiment

    Bower, B.K.N.; Choularton, T.W.; Gallagher, M.W.;

    2000-01-01

    excess over SO2 throughout the experiment). Occasions of significant aerosol growth following cloud processing were observed, particularly in cleaner cases. Observations and modelling suggested this was due mainly to the take up of nitric acid, hydrochloric acid and ammonia by the smallest activated......The ACE-2 HILLCLOUD experiment was carried out on the island of Tenerife in June-July 1997 to investigate the interaction of the boundary layer aerosol with a hill cap cloud forming over a ridge to the north-east of the island. The cloud was used as a natural flow through reactor to investigate the...... dependence of the cloud microphysics and chemistry on the characteristics of the aerosols and trace gases entering cloud, and to simultaneously study the influence of the physical and chemical processes occurring within the cloud on the size distribution, chemical and hygroscopic properties of the aerosol...

  20. ACE project Phases C and D: ACE/MCCI and MACE tests

    Programs of experiments and related analysis are underway at Argonne National Laboratory investigating the interaction of molten core material with concrete and its coolability. The major objectives are: (1) obtain data on fission product release during molten corium concrete interactions (MCCI); and (2) investigate the conditions for successful cooling and stabilization of core melt attacking the concrete basemat. The fission product release tests have been completed, and data analysis is in progress. The experiments will be analyzed by several groups to validate the various MCCI codes, e.g., CORCON and VANESA, WECHSL and MAAP-DECOMP. A scoping melt attach and coolability experiment (MACE) involving the addition of water atop an on-going MCCI has been performed. A facility to conduct larger scale tests is currently being constructed, and two addition tests are planned to be completed before the end of CY91. This paper describes the progress of the MCCI and the MACE testing programs in the ACE project