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Sample records for ace inhibitor therapy

  1. Combination ACE inhibitor and angiotensin receptor blocker therapy - future considerations.

    PubMed

    Sica, Domenic A

    2007-01-01

    Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are regularly prescribed for the management of hypertension. Each of these drug classes has also been shown to provide survival benefits for patients with heart failure, proteinuric chronic kidney disease, and/or a high cardiac risk profile. The individual gains seen with each of these drug classes have led to speculation that their combination might offer additive if not synergistic outcome benefits. The foundation of this hypothesis, although biologically possible, has thus far not been sufficiently well proven to support the everyday use of these 2 drug classes in combination. Additional outcomes trials, which are currently proceeding to their conclusion, may provide the necessary proof to support an expanded use of these 2 drug classes in combination.

  2. Dual ACE and neutral endopeptidase inhibitors: novel therapy for patients with cardiovascular disorders.

    PubMed

    Tabrizchi, Reza

    2003-01-01

    Elevated blood pressure is a risk factor for a variety of cardiovascular disorders, including coronary heart disease, peripheral vascular disease, cardiac failure and cerebrovascular disease. The prevailing view is that an elevated systolic rather than diastolic blood pressure is the major contributor in mortality and morbidity attributed to cardiovascular disorders. Isolated high systolic blood pressure, especially in the elderly, is a major risk factor and should undoubtedly be a target for drug treatment. In the general population, systolic and diastolic blood pressure are highly correlated, and thus it is difficult to dissociate the effects of these two components of the blood pressure and specifically ascribe cardiovascular risk factors to just elevated systolic blood pressure. Therefore, the goal in therapy of an individual with hypertension must be to reduce elevated systolic and diastolic blood pressure in order to reduce mortality and morbidity. ACE and neutral peptidase inhibitors are a new class of drugs that may be beneficial in the treatment of patients with hypertension and heart failure. They may also be useful in the treatment of diabetic patients with hypertension and/or heart failure. Drugs of this class are dual inhibitors of ACE and neutral endopeptidase, and are capable of affecting vascular tone and fluid balance. They are capable of producing vasodilatation by virtue of inhibiting the production of angiotensin II, degradation of natriuretic peptides and bradykinin. They also appear to promote natriuresis and diuresis by amplifying the actions of natriuretic peptidase and reducing aldosterone effects. In addition, they should also attenuate trophogenic actions of the renin angiotensin system and the sympathetic nervous system. Omapatrilat is one drug that appears to be at the advanced stages of clinical development. This drug has been shown to be quite effective in the treatment of hypertension. Evidence also seems to indicate that treatment

  3. Bradykinin-mediated cardiovascular protective actions of ACE inhibitors. A new dimension in anti-ischaemic therapy?

    PubMed

    Remme, W J

    1997-01-01

    In addition to being accepted therapy in hypertension and heart failure, ACE inhibitors may well offer a new dimension in anti-ischaemic therapy. Currently, anti-ischaemic properties have been demonstrated by ACE inhibitors in selected patient groups, including patients with left ventricular dysfunction with or without a direct temporal relationship with myocardial infarction. Anti-ischaemic effects of ACE inhibitors become apparent late after initiation of treatment and suggest a structural rather than a functional effect. Underlying mechanisms may include a reduction in ventricular dilatation and (abnormal) cardiac hypertrophy, leading to less myocardial oxygen demand and, possibly, improved subendocardial blood supply, and vasculoprotective effects, i.e. anti-atherosclerotic and antiremodelling properties, a beneficial effect on the fibrinolytic system and an improvement in abnormal endothelial vasodilator function. The latter aspect is most probably the pivotal mode of action where the anti-ischaemic profile of ACE inhibition is concerned. An improvement in endothelial dysfunction has been shown in patients with mild to moderate coronary artery disease [Trial on Reversing ENdothelial Dysfunction (TREND)]. It is of importance that, in both clinical experiments and human studies, the role of bradykinin appears central in the structural and functional cardiovascular effects of ACE inhibition. This is particularly true for the improvement of impaired endothelial function. Myocardial ischaemia evokes vasoconstrictor neurohormonal activation, which may lead to coronary vasoconstriction in diseased coronary segments. The subsequent abnormal endothelial function leads to diminished coronary flow and also increases systemic vasotone and afterload, thus unfavourably altering the myocardial oxygen supply/demand ratio. Under laboratory conditions, acute ACE inhibition counteracts this activation in humans. However, it is speculated that this anti-ischaemic mechanism may

  4. [ACE inhibitors and the kidney].

    PubMed

    Hörl, W H

    1996-01-01

    Treatment with ACE inhibitors results in kidney protection due to reduction of systemic blood pressure, intraglomerular pressure, an antiproliferative effect, reduction of proteinuria and a lipid-lowering effect in proteinuric patients (secondary due to reduction of protein excretion). Elderly patients with diabetes melitus, coronary heart disease or peripheral vascular occlusion are at risk for deterioration of kidney function due to a high frequency of renal artery stenosis in these patients. In patients with renal insufficiency dose reduction of ACE inhibitors is necessary (exception: fosinopril) but more important is the risk for development of hyperkalemia. Patients at risk for renal artery stenosis and patients pretreated with diuretics should receive a low ACE inhibitor dosage initially ("start low - go slow"). For compliance reasons once daily ACE inhibitor dosage is recommended.

  5. Ace inhibitor therapy for heart failure in patients with impaired renal function: a review of the literature.

    PubMed

    Valika, Ali A; Gheorghiade, Mihai

    2013-03-01

    Heart failure syndromes are often associated with multi-organ dysfunction, and concomitant liver, renal, and neurologic involvement is very common. Neuro-hormonal antagonism plays a key role in the management of this syndrome, and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are one of the cornerstones of therapy. Cardiorenal physiology is becoming more recognized in these patients with advanced heart failure, and the role of neuro-hormonal blockade in this setting is vaguely defined in the literature. Often, angiotensin-converting enzyme inhibitors are decreased or even withheld in these circumstances. The purpose of this article is to review the role and pathophysiology of ace inhibition and angiotensin receptor blockade in patients with acute and chronic heart failure syndromes and concomitant cardiorenal physiology.

  6. Renoprotective effects of combined SGLT2 and ACE inhibitor therapy in diabetic Dahl S rats

    PubMed Central

    Kojima, Naoki; Williams, Jan M; Slaughter, Tiffani N; Kato, Sota; Takahashi, Teisuke; Miyata, Noriyuki; Roman, Richard J

    2015-01-01

    This study examined whether control of hyperglycemia with a new SGLT2 inhibitor, luseogliflozin, given alone or in combination with lisinopril could prevent the development of renal injury in diabetic Dahl salt-sensitive (Dahl S) rats treated with streptozotocin (Dahl-STZ). Blood glucose levels increased from normoglycemic to hyperglycemic levels after treatment of STZ in Dahl S rats. Chronic treatment of Dahl-STZ rats with luseogliflozin (10 mg/kg/day) increased the fractional excretion of glucose and normalized blood glucose and HbA1c levels. Lisinopril (20 mg/kg/day) reduced blood pressure from 145 ± 9 to 120 ± 5 mmHg in Dahl-STZ rats, while luseogliflozin had no effect on blood pressure. Combination therapy reduced blood pressure more than that seen in the rats treated with luseogliflozin or lisinopril alone. Dahl-STZ rats exhibited hyperfiltration, mesangial matrix expansion, severe progressive proteinuria, focal glomerulosclerosis and interstitial fibrosis. Control of hyperglycemia with luseogliflozin reduced the degree of hyperfiltration and renal injury but had no effect on blood pressure or the development of proteinuria. Treatment with lisinopril reduced hyperfiltration, proteinuria and renal injury in Dahl-STZ rats. Combination therapy afforded greater renoprotection than administration of either drug alone. These results suggest that long-term control of hyperglycemia with luseogliflozin, especially in combination with lisinopril to lower blood pressure, attenuates the development of renal injury in this rat model of advanced diabetic nephropathy. PMID:26169541

  7. EARLY Treatment with azilsartan compared to ACE-inhibitors in anti-hypertensive therapy – rationale and design of the EARLY hypertension registry

    PubMed Central

    2013-01-01

    Background Arterial hypertension is highly prevalent but poorly controlled. Blood pressure (BP) reduction substantially reduces cardiovascular morbidity and mortality. Recent randomized, double-blind clinical trials demonstrated that azilsartan medoxomil (AZM) is more effective in reducing BP than the ubiquitary ACE inhibitor ramipril. Therefore, we aimed to test whether these can be verified under clinical practice conditions. Methods/Design The “Treatment with Azilsartan Compared to ACE-Inhibitors in Anti-Hypertensive Therapy” (EARLY) registry is a prospective, observational, national, multicenter registry with a follow-up of up to 12 months. It will include up to 5000 patients on AZM or ACE-inhibitor monotherapy in a ratio of 7 to 3. A subgroup of patients will undergo 24-hour BP monitoring. EARLY has two co-primary objectives: 1) Description of the safety profile of azilsartan and 2) achievement of BP targets based on recent national and international guidelines for patients treated with azilsartan in comparison to those treated with ACE-inhibitors. The most important secondary endpoints are the determination of persistence with treatment and the documentation of cardiovascular and renal events. Recruitment commenced in January 2012 and will be completed by February 2013. Conclusions The data obtained will supplement previous results from randomized controlled trials to document the potential value of utilizing azilsartan medoxomil in comparison to ACE-inhibitor treatment for target BP achievement in clinical practice. PMID:23819631

  8. Angiotensin-converting enzyme (ACE) dimerization is the initial step in the ACE inhibitor-induced ACE signaling cascade in endothelial cells.

    PubMed

    Kohlstedt, Karin; Gershome, Cynthia; Friedrich, Matthias; Müller-Esterl, Werner; Alhenc-Gelas, François; Busse, Rudi; Fleming, Ingrid

    2006-05-01

    The binding of angiotensin-converting enzyme (ACE) inhibitors to ACE initiates a signaling cascade that involves the phosphorylation of the enzyme on Ser1270 as well as activation of the c-Jun NH2-terminal kinase (JNK) and leads to alterations in gene expression. To clarify how ACE inhibitors activate this pathway, we determined their effect on the ability of the enzyme to dimerize and the role of ACE dimerization in the initiation of the ACE signaling cascade. In endothelial cells, ACE was detected as a monomer as well as a dimer in native gel electrophoresis and dimerization/oligomerization was confirmed using the split-ubiquitin assay in yeast. ACE inhibitors elicited a rapid, concentration-dependent increase in the dimer/monomer ratio that correlated with that of the ACE inhibitorinduced phosphorylation of ACE. Cell treatment with galactose and glucose to prevent the putative lectin-mediated self-association of ACE or with specific antibodies shielding the N terminus of ACE failed to affect either the basal or the ACE inhibitor-induced dimerization of the enzyme. In ACE-expressing Chinese hamster ovary cells, ACE inhibitors elicited ACE dimerization and phosphorylation as well as the activation of JNK with similar kinetics to those observed in endothelial cells. However, these effects were prevented by the mutation of the essential Zn2+-complexing histidines in the C-terminal active site of the enzyme. Mutation of the N-terminal active site of ACE was without effect. Together, our data suggest that ACE inhibitors can initiate the ACE signaling pathway by inducing ACE dimerization, most probably via the C-terminal active site of the enzyme.

  9. Cromolyn sodium for ACE inhibitor-induced cough.

    PubMed

    Allen, T L; Gora-Harper, M L

    1997-06-01

    There are several theories on the cause of ACE inhibitor-induced cough, but the exact mechanism is not known. In many patients, if cough develops, the ACE inhibitor can be discontinued and a drug in another therapeutic class used in its place. However, in patients with CHF, diabetic nephropathy, and patients who have experienced a myocardial infarction, discontinuing the ACE inhibitor may not be in the best interest of the patient. In this patient population it would be reasonable to try cromolyn sodium to treat cough, while continuing the ACE inhibitor. Data are not available to support the efficacy of cromolyn sodium to treat cough in patients with diabetic nephropathy, but these patients clearly benefit from the use of an ACE inhibitor. Other factors not addressed in the case reports and the clinical trial such as patient adherence, cost, and quality of life should also play a role in the decision to use cromolyn sodium. Cromolyn sodium has been effective for the treatment of ACE inhibitor-induced cough in many case reports and has had mild success in one small clinical trial. Although none of the reports adequately assessed adverse effects, studies examining cromolyn for other indications have demonstrated a relatively benign adverse effect profile. It is difficult to recommend an exact dose to use because of the dosing variability in the case reports. The majority of the case reports and the one clinical trial used dosages similar to recommendations for bronchial asthma (i.e., 2 puffs [1.6 mg] 4 times daily via MDI or 20-mg capsules 4 times daily via breath-activated inhalation). At this time, the use of cromolyn sodium is a viable option, but more controlled studies are needed to fully elucidate its role in the treatment of ACE inhibitor-induced cough.

  10. Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors.

    PubMed

    Vuille-dit-Bille, Raphael N; Camargo, Simone M; Emmenegger, Luca; Sasse, Tom; Kummer, Eva; Jando, Julia; Hamie, Qeumars M; Meier, Chantal F; Hunziker, Schirin; Forras-Kaufmann, Zsofia; Kuyumcu, Sena; Fox, Mark; Schwizer, Werner; Fried, Michael; Lindenmeyer, Maja; Götze, Oliver; Verrey, François

    2015-04-01

    Sodium-dependent neutral amino acid transporter B(0)AT1 (SLC6A19) and imino acid (proline) transporter SIT1 (SLC6A20) are expressed at the luminal membrane of small intestine enterocytes and proximal tubule kidney cells where they exert key functions for amino acid (re)absorption as documented by their role in Hartnup disorder and iminoglycinuria, respectively. Expression of B(0)AT1 was shown in rodent intestine to depend on the presence of the carboxypeptidase angiotensin-converting enzyme 2 (ACE2). This enzyme belongs to the renin-angiotensin system and its expression is induced by treatment with ACE-inhibitors (ACEIs) or angiotensin II AT1 receptor blockers (ARBs) in many rodent tissues. We show here in the Xenopus laevis oocyte expression system that human ACE2 also functionally interacts with SIT1. To investigate in human intestine the potential effect of ACEIs or ARBs on ACE2, we analysed intestinal biopsies taken during routine gastroduodenoscopy and ileocolonoscopy from 46 patients of which 9 were under ACEI and 13 ARB treatment. Analysis of transcript expression by real-time PCR and of proteins by immunofluorescence showed a co-localization of SIT1 and B(0)AT1 with ACE2 in the brush-border membrane of human small intestine enterocytes and a distinct axial expression pattern of the tested gene products along the intestine. Patients treated with ACEIs displayed in comparison with untreated controls increased intestinal mRNA levels of ACE2, peptide transporter PEPT1 (SLC15A1) and AA transporters B(0)AT1 and PAT1 (SLC36A1). This study unravels in human intestine the localization and distribution of intestinal transporters involved in amino acid absorption and suggests that ACEIs impact on their expression.

  11. ACE

    NASA Technical Reports Server (NTRS)

    Lumia, R.

    1999-01-01

    This document describes the progress made during the fourth year of the Center for Autonomous Control Engineering (ACE). We currently support 30 graduate students, 52 undergraduate students, 9 faculty members, and 4 staff members. Progress will be divided into two categories. The first category explores progress for ACE in general. The second describes the results of each specific project supported within ACE.

  12. [ACE inhibitors from the viewpoint of the clinical pharmacologist].

    PubMed

    Hitzenberger, G

    1996-01-01

    For treatment of hypertension drugs are desirable which exert a 24 hours lasting blood pressure control. Among the ACE-inhibitors some drugs exist which have this action. The elimination pathway plays a minor role in this respect. Not only the inhibition of Angiotensin II generation but also the decreased inhibition of bradykinin-degeneration plays a crucial role with regard to several endothelial functions controlling the so called remodeling of the cardiovascular system.

  13. ACE Inhibitor-Induced Angioedema following Cervical Spine Surgery

    PubMed Central

    Sabbagh, Hussam

    2017-01-01

    Angioedema is a well-known side effect of angiotensin converting enzyme inhibitors (ACEi). However, ACE inhibitors induced angioedema after cervical surgery is a rare condition. They result in increased levels of circulating bradykinins. Rare cases of angioedema following local trauma in patients using ACE inhibitors have been published. We present such a case. A 54-year-old Caucasian female with a history significant for hypertension, controlled with lisinopril, was admitted for routine cervical spine surgery. She has severe degenerative cervical disc disease and was admitted to the hospital for an elective cervical diskectomy. The patient failed weaning off the ventilator on multiple attempts postoperatively. There were no observed symptoms of an allergic reaction. A CT scan of the neck showed extensive soft tissue edema at the level of the arytenoids. Dexamethasone was given to reduce the edema without successful resolution. On review of her medications, it was found that the patient was resumed on lisinopril following the procedure. It was subsequently discontinued. By the following day the patient had a positive leak around the ET tube cuff and patient was successfully extubated. PMID:28348897

  14. ACE2 and Microbiota: Emerging Targets for Cardiopulmonary Disease Therapy

    PubMed Central

    Cole-Jeffrey, Colleen T; Liu, Meng; Katovich, Michael J; Raizada, Mohan K; Shenoy, Vinayak

    2015-01-01

    The health of the cardiovascular and pulmonary systems is inextricably linked to the renin-angiotensin system (RAS). Physiologically speaking, a balance between the vasodeleterious (ACE/Ang II/AT1R) and vasoprotective (ACE2/Ang-(1–7)/MasR) components of the RAS is critical for cardiopulmonary homeostasis. Upregulation of the ACE/Ang II/AT1R axis shifts the system toward vasoconstriction, proliferation, hypertrophy, inflammation, and fibrosis, all factors that contribute to the development and progression of cardiopulmonary diseases. Conversely, stimulation of the vasoprotective ACE2/Ang-(1–7)/MasR axis produces a counter-regulatory response that promotes cardiovascular health. Current research is investigating novel strategies to augment actions of the vasoprotective RAS components, particularly ACE2, in order to treat various pathologies. While multiple approaches to increase the activity of ACE2 have displayed beneficial effects against experimental disease models, the mechanisms behind its protective actions remain incompletely understood. Recent work demonstrating a non-catalytic role for ACE2 in amino acid transport in the gut has led us to speculate that the therapeutic effects of ACE2 can be mediated, in part, by its actions on the gastrointestinal tract and/or gut microbiome. This is consistent with emerging data which suggests that dysbiosis of the gut and lung microbiomes is associated with cardiopulmonary disease. This review highlights new developments in the protective actions of ACE2 against cardiopulmonary disorders, discusses innovative approaches to targeting ACE2 for therapy, and explores an evolving role for gut and lung microbiota in cardiopulmonary health. PMID:26322922

  15. ACE2 and Microbiota: Emerging Targets for Cardiopulmonary Disease Therapy.

    PubMed

    Cole-Jeffrey, Colleen T; Liu, Meng; Katovich, Michael J; Raizada, Mohan K; Shenoy, Vinayak

    2015-12-01

    The health of the cardiovascular and pulmonary systems is inextricably linked to the renin-angiotensin system (RAS). Physiologically speaking, a balance between the vasodeleterious (Angiotensin-converting enzyme [ACE]/Angiotensin II [Ang II]/Ang II type 1 receptor [AT1R]) and vasoprotective (Angiotensin-converting enzyme 2 [ACE2]/Angiotensin-(1-7) [Ang-(1-7)]/Mas receptor [MasR]) components of the RAS is critical for cardiopulmonary homeostasis. Upregulation of the ACE/Ang II/AT1R axis shifts the system toward vasoconstriction, proliferation, hypertrophy, inflammation, and fibrosis, all factors that contribute to the development and progression of cardiopulmonary diseases. Conversely, stimulation of the vasoprotective ACE2/Ang-(1-7)/MasR axis produces a counter-regulatory response that promotes cardiovascular health. Current research is investigating novel strategies to augment actions of the vasoprotective RAS components, particularly ACE2, in order to treat various pathologies. Although multiple approaches to increase the activity of ACE2 have displayed beneficial effects against experimental disease models, the mechanisms behind its protective actions remain incompletely understood. Recent work demonstrating a non-catalytic role for ACE2 in amino acid transport in the gut has led us to speculate that the therapeutic effects of ACE2 can be mediated, in part, by its actions on the gastrointestinal tract and/or gut microbiome. This is consistent with emerging data which suggest that dysbiosis of the gut and lung microbiomes is associated with cardiopulmonary disease. This review highlights new developments in the protective actions of ACE2 against cardiopulmonary disorders, discusses innovative approaches to targeting ACE2 for therapy, and explores an evolving role for gut and lung microbiota in cardiopulmonary health.

  16. Structure of human ACE gives new insights into inhibitor binding and design.

    PubMed

    Brew, Keith

    2003-08-01

    Angiotensin-converting enzyme (ACE) is a primary target of drugs used for controlling hypertension. A new X-ray crystallographic structure of the key catalytic domain of ACE provides detailed information about the structure of its active site, located in a deep channel, and its interactions with an inhibitor. Such information might facilitate the rational design of ACE inhibitors that are more potent and more selective and therefore of clinical use.

  17. Targeting ACE and ECE with dual acting inhibitors.

    PubMed

    Hanessian, Stephen; Guesné, Sébastien; Riber, Ludivine; Marin, Julien; Benoist, Alain; Mennecier, Philippe; Rupin, Alain; Verbeuren, Tony J; De Nanteuil, Guillaume

    2008-02-01

    A series of urea analogues related to SA6817 and a GSK phosphonic acid with reported ACE inhibitory activity were prepared and tested for dual ACE and ECE activities. Although excellent ACE and NEP inhibition was achieved, only modest ECE inhibition was observed with one analogue.

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

    PubMed

    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

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

    PubMed Central

    Wijesekara, Isuru; Kim, Se-Kwon

    2010-01-01

    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. PMID:20479968

  20. ACE inhibitors could be therapeutic for antisocial personality disorder.

    PubMed

    Hobgood, Donna K

    2013-11-01

    Antisocial personality traits are an important topic for research. The societal cost of these behaviors encourages efforts at a better understanding of central nervous system causes. Catecholamine genes are being studied to facilitate this understanding, and some tentative findings are being reached about several of these genes. It seems that many genes play a role to produce antisocial behaviors so complexity of elucidating each gene is obvious. One conclusion that could be drawn from the current research findings is that DA2 like receptors (DRD2, DRD3, DRD4) with alleles that decrease neurotransmission are facilitatory of antisocial behaviors. DA2 like receptors cause neuronal firing to inhibit many peripheral functions through adenylyl cyclase inhibition. When these receptors are less active by genetically decreased density, lower affinity, or by low dopamine levels as final common pathways then inhibition is released and a state of disinhibition can be said to describe this state. Peripheral metabolism is increased and behavioral activation is noted. Renin is disinhibited in this setting thus allowing sympathetic nervous system activation. The fight or flight behaviors thus produced, in the extreme, would be the setting of antisocial behavior. Research validates this hypothesis. Understanding this final common pathway toward antisocial behavior should lead to better treatment for individuals with this pattern of behavior before they have caused harm to themselves and others. ACE inhibitors are well tolerated drugs used in the treatment of hypertension and heart failure and would also treat antisocial behavior disorders.

  1. A prospective study of frequency and characteristics of cough during ACE inhibitor treatment.

    PubMed

    Sato, Atsuhisa; Fukuda, Seiichi

    2015-01-01

    Angiotensin converting enzyme (ACE) inhibitors are reportedly effective, and positively indicated in patients with chronic heart failure with decreased contractility, after myocardial infarction, after cerebrovascular disorders, and in those with chronic kidney disease. However, the biggest challenge to continuous use of ACE inhibitors is the adverse reaction of cough. Accordingly, in the present study, we investigated the present state and characteristics of ACE inhibitor-induced cough in patients with essential hypertension currently being treated with an ACE inhibitor for an average of 18 months, who could be regularly checked for cough. Subjects in this study were 176 patients overall (mean age 67 ± 11 years old), 90 men and 86 women. The adverse reaction of cough was observed in 20% of patients, and more frequently in women than in men. However, in 26 of the patients with cough, the cough either resolved naturally or completely disappeared while the treatment continued, after which patients could continue taking the medication. Specifically, ACE inhibitor treatment was eventually discontinued due to cough in 5.1% of patients. Cough occurred less frequently with concomitant calcium antagonists or diuretics than with ACE inhibitor monotherapy. Cough as an adverse reaction occurred at a low frequency when medication was taken at bedtime. We considered a number of measures to counteract cough, then in addition to starting the ACE inhibitor treatment as early as possible, it is important to devise ways for the ACE inhibitor treatment to be continued for as long as possible, through the adept use of these measures.

  2. Angiotensin converting enzyme (ACE) inhibitors from Jasminum azoricum and Jasminum grandiflorum.

    PubMed

    Somanadhan, B; Smitt, U W; George, V; Pushpangadan, P; Rajasekharan, S; Duus, J O; Nyman, U; Olsen, C E; Jaroszewski, J W

    1998-04-01

    Bioactivity-guided fractionation of extracts of the aerial parts of Jasminum azoricum var. travancorense, using an in vitro ACE inhibition assay, led to isolation of three oligomeric, iridoid-type compounds, which were named sambacein I-III. Their structures are based on spectroscopic and chemical evidence. Similarly, fractionation of extracts of aerial parts of J. grandiflorum resulted in the isolation of the previously reported ACE inhibitor, oleacein. The IC50 values of purified ACE inhibitors were 26-36 microM. Moreover, 2-(3,4-dihydroxyphenyl)-ethanol, isoquercitrin and ursolic acid were isolated from J. grandiflorum. Sambaceins and oleacein are formed from genuine iridoid glucosides during processing of the plant material. NMR spectroscopy was used to measure the level of the ACE inhibitors in the traditional medicines prepared in Kerala from these Jasminum species.

  3. Effects of ACE-inhibitors and beta-blockers on left ventricular remodeling in chronic heart failure.

    PubMed

    Khattar, R S

    2003-04-01

    In recent years, it has become increasingly recognised that a central feature of the disease progression associated with heart failure is the process of left ventricular remodeling. The remodeling process manifests as an increase in left ventricular volumes, leading to a rise in wall stress and a compensatory increase in myocardial mass. The left ventricle also gradually assumes a more spherical shape, resulting in functional mitral regurgitation leading to further haemodynamic overload, worsening myocardial function and an unfavourable clinical course. Accumulating clinical data support the hypothesis that the benefits in clinical outcome with ACE-inhibitors and beta-blockers may relate to modification of the remodeling process resulting in slowing of disease progression and preservation of contractile function. The general trend from a number of clinical studies indicates that whereas ACE-inhibitors seem to prevent progressive left ventricular dilatation, the third generation beta-blocker, carvedilol, may actually reverse the remodelling process by reducing left ventricular volumes and improving systolic function. Direct comparisons indicate that carvedilol has a similar safety and tolerability profile to ACE-inhibitors and thereby support the feasibility of administering this drug as first-line therapy in selected patients with mild to moderate chronic heart failure. Therefore, the decision to initiate treatment with carvedilol or an ACE-inhibitor might in future be tailored on an individual basis and followed thereafter by combination therapy at the earliest and safest opportunity. Finally, the possible development of treatment strategies addressing the cellular and molecular mechanisms responsible for the remodeling process and the recently published benefits of device therapies herald a combined, synergistic approach to the future management of heart failure.

  4. [The new drug is much more effective than ACE inhibitors in chronic heart failure].

    PubMed

    Sr, Jiří Widimský

    2015-02-01

    PARADIGM-HF study observed clinical outcomes after treatment by new drug LCZ696 or enalapril in patients with systolic chronic heart failure. It was randomized double-blind trial with LCZ696 (200 mg twice a day) and enalapril (10 mg twice a day). 8442 patients were enrolled with NYHA class II or III and left ventricular ejection fiction of 40% or less. Study drugs were added to other recommended medication. The trial was prematurely terminated after median follow-up of 27 months. The primary endpoint of the study was a combination of cardiovascular mortality and the first hospitalization for heart failure. LCZ696 drug, an inhibitor of angiotensin receptor and neprilysin (Arnie), has led to a reduction in the primary composite target by 20% (p <0.001). The treatment has decreased cardiovascular mortality by 20%, p <0.001 and hospitalization for worsening heart failure by 21%, p <0.001. LCZ696 has also decreased total mortality by 16%, p <0.001. The use of LCZ696 has been accompanied by frequent symptomatic hypotension and hypotension with a decrease in systolic blood pressure below 90 mm Hg, however, LCZ696 was less often associated with an increase in serum creatinine and serum potassium than enalapril. In addition, cough has occurred less frequently after LCZ696 than after enalapril. Discontinuation of therapy occurred in 746 patients (17.8%) treated with LCZ696 and in 833 patients (19.8%) treated with enalapril (19.8%) (p = 0.02). PARADIGM-HF study has also shown superiority of LCZ696 compared to ACE inhibitors in stable outpatients with chronic systolic heart failure NYHA stages II and III. Therefore, LCZ696 is more effective than ACE inhibitors (and angiotensin receptor blockers). Moreover, it is well tolerated. LCZ696 seems to replace the ACE inhibitors in mentioned patients. The authors also discuss the results of the first randomized study PARAMOUNT investigating LCZ696 efficacy in patients with chronic heart failure and good left ventricular ejection

  5. Potential advantages of cell administration on the inflammatory response compared to standard ACE inhibitor treatment in experimental myocardial infarction

    PubMed Central

    Ciulla, Michele M; Montelatici, Elisa; Ferrero, Stefano; Braidotti, Paola; Paliotti, Roberta; Annoni, Giuseppe; De Camilli, Elisa; Busca, Giuseppe; Chiappa, Luisa; Rebulla, Paolo; Magrini, Fabio; Lazzari, Lorenza

    2008-01-01

    Background Bone Marrow (BM) progenitor cells can target the site of myocardial injury, contributing to tissue repair by neovascolarization and/or by a possible direct paracrine effect on the inflammatory cascade. Angiotensin Converting Enzyme inhibitors (ACE-I) are effective in reducing mortality and preventing left ventricular (LV) function deterioration after myocardial infarction. Methods We investigated the short term effects of BM mononuclear cells (BMMNCs) therapy on the pro-inflammatory cytokines (pro-CKs) and on LV remodelling and compared these effects over a standard ACE-I therapy in a rat model of myocardial cryodamage. Forty two adult inbread Fisher-F344 rats were randomized into three groups: untreated (UT; n = 12), pharmacological therapy (ACE-I; n = 14, receiving quinapril), and cellular therapy (BMMNCs; n = 16, receiving BMMNCs infusion). Rats underwent to a standard echocardiogram in the acute setting and 14 days after the damage, before the sacrifice. Pro-CKs analysis (interleukin (IL)1β, IL-6, tumor necrosis factor (TNF)α was performed (multiplex proteome arrays) on blood samples obtained by direct aorta puncture before the sacrifice; a control group of 6 rats was considered as reference. Results Concerning the extension of the infarcted area as well as the LV dimensions, no differences were observed among the animal groups; treated rats had lower left atrial diameters and higher indexes of LV function. Pro-Cks were increased in infarcted-UT rats if compared with controls, and significantly reduced by BMMNCs and ACE-I ; TNFα inversely correlated with LV fractional shortening. Conclusion After myocardial infarction, both BMMNCs and ACE-I reduce the pattern of pro-Ck response, probably contributing to prevent the deterioration of LV function observed in UT rats. PMID:18549470

  6. Angiotensin-converting enzyme (ACE) inhibitors modulate cellular retinol-binding protein 1 and adiponectin expression in adipocytes via the ACE-dependent signaling cascade.

    PubMed

    Kohlstedt, Karin; Gershome, Cynthia; Trouvain, Caroline; Hofmann, Wolf-Karsten; Fichtlscherer, Stephan; Fleming, Ingrid

    2009-03-01

    Inhibitors of the angiotensin-converting enzyme (ACE) decrease angiotensin II production and activate an intracellular signaling cascade that affects gene expression in endothelial cells. Because ACE inhibitors have been reported to delay the onset of type 2 diabetes, we determined ACE signaling-modulated gene expression in endothelial cells and adipocytes. Using differential gene expression analysis, several genes were identified that were 3-fold up- or down-regulated by ramiprilat in cells expressing wild-type ACE versus cells expressing a signaling-dead ACE mutant. One up-regulated gene was the cellular retinol-binding protein 1 (CRBP1). In adipocytes, the overexpression of CRBP1 enhanced (4- to 5-fold) the activity of promoters containing response elements for retinol-dependent nuclear receptors [retinoic acid receptor (RAR) and retinoid X receptor (RXR)] or peroxisome proliferator-activated receptors (PPAR). CRBP1 overexpression also enhanced the promoter activity (by 470 +/- 40%) and expression/release of the anti-inflammatory and antiatherogenic adipokine adiponectin (cellular adiponectin by 196 +/- 24%, soluble adiponectin by 228 +/- 74%). Significantly increased adiponectin secretion was also observed after ACE inhibitor treatment of human preadipocytes, an effect prevented by small interfering RNA against CRBP1. Furthermore, in ob/ob mice, ramipril markedly potentiated both the basal (approximately 2-fold) and rosiglitazonestimulated circulating levels of adiponectin. In patients with coronary artery disease or type 2 diabetes, ACE inhibition also significantly increased plasma adiponectin levels (1.6- or 2.1-fold, respectively). In summary, ACE inhibitors affect adipocyte homeostasis via CRBP1 through the activation of RAR/RXR-PPAR signaling and up-regulation of adiponectin. The latter may contribute to the beneficial effects of ACE inhibitors on the development of type 2 diabetes in patients with an activated renin-angiotensin system.

  7. A novel design of combining the angiotensin converting enzyme (ACE) inhibitor captopril with the angiotensin receptor blocker (ARB) losartan using homo coupling via PEG diacid linker.

    PubMed

    Hashemzadeh, Mehrnoosh; Park, Shery; Ju, Hee; Movahed, Mohammad R

    2013-12-01

    Cardiovascular disease is the leading cause of death in American adults. Furthermore, the incidence of congestive heart failure is on the rise as a major cause of hospitalization and mortality in this population. Angiotensin Converting Enzyme (ACE) inhibitors prevent the production of angiotensin II, which has been shown to reduce mortality in patients with congestive heart failure. Angiotensin II receptor blockers (ARB) were developed as a direct inhibitor of angiotensin II. ARBs have been shown to be effective in the treatment of patients with systolic heart failure but do not cause chronic coughing which is a common side effect of ACE inhibitors. In theory, a compound that has the combined effect of an ACE inhibitor and an ARB should be more effective in treating heart failure patients than either agents alone. Therefore, the purpose of this manuscript is to design and discuss the benefits of a new molecule, which combines captopril, an ACE inhibitor, with losartan, an ARB. In this experiment Captopril and Losartan were modified and synthesized separately and combined by homo or mono coupling. This was achieved by taking advantage of PEG (Polyethylene glycol) as a linker. It is expected that this molecule will have the combined modes of action of both ACEs and ARBs. Benefits from combination therapy include; increased efficacy, reduced adverse effects, convenience, compliance, and prolonged duration. Consequently, this combined molecule is expected to block the production of angiotensin II more efficiently and effectively. Although captopril and losartan work in the same system by blocking the effect of angiotensin II they have different action sites and mechanisms some patents are also discussed. Losartan blocks the AT1 receptor which is expressed on the cell surface, while captopril inhibits ACE, preventing production of angiotensin II, which is present in both the plasma and on the cell surface, especially on endothelial and smooth muscle cells.

  8. A novel aggregation-induced emission based fluorescent probe for an angiotensin converting enzyme (ACE) assay and inhibitor screening.

    PubMed

    Wang, Haibo; Huang, Yi; Zhao, Xiaoping; Gong, Wan; Wang, Yi; Cheng, Yiyu

    2014-12-11

    A 'turn-on' fluorescent probe based on aggregation-induced emission (AIE) has been developed. It exhibits excellent selectivity and sensitivity for monitoring angiotensin converting enzyme (ACE) activity both in solutions and in living cells as well as for screening ACE inhibitors in vitro.

  9. Evolution of diuretics and ACE inhibitors, their renal and antihypertensive actions—parallels and contrasts

    PubMed Central

    Lant, Ariel F.

    1987-01-01

    1 The emergence of diuretic drugs and angiotensin converting enzyme (ACE) inhibitors ranks amongst the major therapeutic advances of modern medicine. The discovery of these drug groups arose largely by chance, yet each has dramatically influenced the treatment of congestive cardiac failure and arterial hypertension. 2 The central role which diuretics have had in the management of both oedema and hypertension hinges on their ability to induce a net renal excretion of solute and water by selective interference with either active or passive ion transport processes in different segments of the nephron. Irrespective of sites of action, the continued antihypertensive action of diuretics is characterized by a reduction in plasma volume and extracellular fluid (ECF) volume that lasts for as long as the diuretic is given. The mechanism of this effect remains unclear but may involve autoregulatory reactions that leave cardiac output unaltered but maintain a sustained reduction in total peripheral resistance. 3 ACE inhibitors also lower blood pressure by decreasing total peripheral resistance, leaving cardiac output, plasma volume and ECF volume unchanged. The detailed way these haemodynamic changes are achieved remains unknown but inhibition of converting enzyme present not only in the kidney but also in many extrarenal tissue sites, appears important. In both hypertension and cardiac failure, however, the kidney acts as a key target organ for ACE inhibitors. The increased renal vascular resistance and inappropriate renal salt excretion are reversed with enhanced renal blood flow and saluresis. Both angiotensin II (AII) and vasopressin-mediated contraction of glomerular mesangial cells is inhibited, making glomerular filtration more efficient. Reduced aldosterone secondary to blockade of AII formation contributes to saluresis whilst encouraging positive potassium balance. ACE inhibition also impairs breakdown of kinins which may contribute to intrarenal and peripheral

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

    PubMed

    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.

  11. Effects of ACE Inhibitors on Insulin Resistance and Lipid Profile in Children with Metabolic Syndrome

    PubMed Central

    Çelebi Bitkin, Eda; Boyraz, Mehmet; Taşkın, Necati; Akçay, Arzu; Ulucan, Korkut; Akyol, Mehmet Bedir; Akçay, Teoman

    2013-01-01

    Objective: The aim of this study was to evaluate the effects of using ACE inhibitors on insulin resistance, glucose metabolism, body fat composition, and lipid profile in children over 10 years of age with obesity-associated metabolic syndrome (MS). Methods: A total of 53 children with MS, who had been followed for at least one year were included in the study. The sample was divided into two groups: Group 1-30 obese children (13 female, 17 male) who were not using an ACE inhibitor and Group 2-23 obese children (13 female, 10 male) who were using an ACE inhibitor. Anthropometric and laboratory dataobtained at baseline and at the 3rd, 6th, and 12th months of follow-up were compared in the two groups. Results: Comparison of the data in the two groups at 3rd, 6th, and 12th months revealed no statistically significant differences in terms of weight standard deviation score (SDS), body mass index SDS, weight for height percentile, body fat percentage, and very low-density lipoprotein (VLDL)values. However, there were statistically significant differences in mean glucose and insulin levels, homeostasis model assessment for insulin resistance, LDL and high-density lipoprotein values, and highly significant differences in mean triglyceride values. Conclusions: The positive effects of ACE inhibitor drugs, particularly on hypertriglyceridemia and insulin resistance, might bring them forth as first-line drugs in the treatment of obese and hypertensive children. Randomized, controlled, double-blind, and long-term studies are needed for a definitive conclusion. Conflict of interest:None declared. PMID:24072084

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

    NASA Astrophysics Data System (ADS)

    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.

  13. Inequity of access to ACE inhibitors in Swedish heart failure patients: a register-based study

    PubMed Central

    Lindahl, Bertil; Hanning, Marianne; Westerling, Ragnar

    2016-01-01

    Background Several international studies suggest inequity in access to evidence-based heart failure (HF) care. Specifically, studies of ACE inhibitors (ACEIs) point to reduced ACEI access related to female sex, old age and socioeconomic position. Thus far, most studies have either been rather small, lacking diagnostic data, or lacking the possibility to account for several individual-based sociodemographic factors. Our aim was to investigate differences, which could reflect inequity in access to ACEIs based on sex, age, socioeconomic status or immigration status in Swedish patients with HF. Methods Individually linked register data for all Swedish adults hospitalised for HF in 2005–2010 (n=93 258) were analysed by multivariate regression models to assess the independent risk of female sex, high age, low employment status, low income level, low educational level or foreign country of birth, associated with lack of an ACEI dispensation within 1 year of hospitalisation. Adjustment for possible confounding was made for age, comorbidity, Angiotensin receptor blocker therapy, period and follow-up time. Results Analysis revealed an adjusted OR for no ACEI dispensation for women of 1.31 (95% CI 1.27 to 1.35); for the oldest patients of 2.71 (95% CI 2.53 to 2.91); and for unemployed patients of 1.59 (95% CI 1.46 to 1.73). Conclusions Access to ACEI treatment was reduced in women, older patients and unemployed patients. We conclude that access to ACEIs is inequitable among Swedish patients with HF. Future studies should include clinical data, as well as mortality outcomes in different groups. PMID:26261264

  14. Synthesis and evaluation of novel triazoles and mannich bases functionalized 1,4-dihydropyridine as angiotensin converting enzyme (ACE) inhibitors.

    PubMed

    Kumbhare, Ravindra M; Kosurkar, Umesh B; Bagul, Pankaj K; Kanwal, Abhinav; Appalanaidu, K; Dadmal, Tulshiram L; Banerjee, Sanjay Kumar

    2014-11-01

    A series of novel diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate embedded triazole and mannich bases were synthesized, and evaluated for their angiotensin converting enzyme (ACE) inhibitory activity. Screening of above synthesized compounds for ACE inhibition showed that triazoles functionalized compounds have better ACE inhibitory activity compared to that of mannich bases analogues. Among all triazoles we found 6 h, 6 i and 6 j to have good ACE inhibition activity with IC50 values 0.713 μM, 0.409 μM and 0.653 μM, respectively. Among mannich bases series compounds, only 7c resulted as most active ACE inhibitor with IC50 value of 0.928 μM.

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

    NASA Astrophysics Data System (ADS)

    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.

  16. Are ACE-inhibitors or ARB's still needed for cardiovascular prevention in high risk patients? Insights from profess and transcend.

    PubMed

    Van Mieghem, W; Billiouw, J M; Brohet, C; Dupont, A G; Gazagnes, M D; Heller, F; Krzesinski, J M; Missault, L; Persu, A; Piérard, L; Rottiers, R; Vanhooren, G; Vervaet, P; Herman, A G

    2010-01-01

    The HOPE and EUROPA clinical studies have shown that treatment with the angiotensin-converting enzyme (ACE) inhibitors, ramipril and perindopril, may reduce the occurrence of major cardiovascular events in patients with proven atherosclerotic disease. The recently published results of the PRoFESS and TRANSCEND trials completed the much needed information concerning the use of an angiotensin receptor blocker for patients at high risk of cardiovascular events. PROFESS compared a therapy of telmisartan 80 mg daily with placebo in patients with a recent ischemic stroke. The difference in the primary outcome of first recurrent stroke was not statistically significant between telmisartan and placebo. The secondary outcome of major cardiovascular events showed a relative risk reduction (RRR) of 7% in favour of telmisartan. This tended to be significant (p = 0.06) despite a rather short follow-up period of only 28 months. In TRANSCEND 5926 patients at high risk for cardiovascular events were randomized to a treatment with telmisartan 80 mg daily or placebo for a mean duration of follow-up of 56 months. The primary composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization for heart failure showed a non-significant 8% RRR in favour of the telmisartan treated patients. The main secondary outcome of cardiovascular death and myocardial infarction or stroke as used in the HOPE trial showed a non-significant RRR of 13% in favour of telmisartan treated patients (p = 0.068 adjusted for multiplicity of comparisons). In comparing the Kaplan-Meier curves for the endpoint of major cardiovascular events used in HOPE, EUROPA, TRANSCEND and PRoFESS, the trends are similar. Results of most of the recently published trials have been neutral.This could partly be explained by major improvements in the optimal background therapy of the patients included. Nevertheless, the results of PRoFESS and TRANSCEND do not contradict the results from previous studies with

  17. ACE inhibitors

    MedlinePlus

    ... In: Mann DL, Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald's Heart Disease: A Textbook ... In: Mann DL, Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald's Heart Disease: A Textbook ...

  18. Radiation damage to the lung: mitigation by angiotensin converting enzyme (ACE) inhibitors

    PubMed Central

    Medhora, Meetha; Gao, Feng; Jacobs, Elizabeth R.; Moulder, John E.

    2011-01-01

    Concern regarding accidental overexposure to radiation has been raised after the devastating Tohuku earthquake and tsunami which initiated the Fukushima Daiichi nuclear disaster in Japan, in March 2011. Radiation exposure is toxic and can be fatal depending on the dose received. Injury to the lung is often reported as part of multi-organ failure in victims of accidental exposures. Doses of radiation >8 Gray to the chest can induce pneumonitis with right ventricular hypertrophy starting after ~2 months. Higher doses may be followed by pulmonary fibrosis that presents months to years after exposure. Though the exact mechanisms of radiation lung damage are not known, experimental animal models have been widely used to study this injury. Rodent models for pneumonitis and fibrosis exhibit vascular, parenchymal and pleural injuries to the lung. Inflammation is a part of the injuries suggesting involvement of the immune system. Researchers world-wide have tested a number of interventions to prevent or mitigate radiation lung injury. One of the first and most successful class of mitigators are inhibitors of angiotensin converting enzyme (ACE), an enzyme that is abundant in the lung. These results offer hope that lung injury from radiation accidents may be mitigated, since the ACE inhibitor captopril was effective when started up to one week after irradiation. PMID:22023053

  19. Absence of Cardiac Benefit with Early Combination ACE Inhibitor and Beta Blocker Treatment in mdx Mice.

    PubMed

    Blain, Alison; Greally, Elizabeth; Laval, Steven H; Blamire, Andrew M; MacGowan, Guy A; Straub, Volker W

    2015-04-01

    Most patients with Duchenne muscular dystrophy (DMD) will develop cardiomyopathy; however, the evidence for prophylactic treatment of children with cardiac medications is limited. We have used the mdx mouse model of DMD to assess if early combination treatment with beta blocker (BB) and ACE inhibitor (AI) is superior to single treatment with either one of these drugs. Mice were assessed with cardiac MRI (ventricular structure and function, in vivo calcium influx (manganese-enhanced MRI)), pressure-volume loops, and histopathology. Combination treatment did not show benefits over treatment with AI or BB alone. Indeed, some beneficial aspects of BB and AI were lost when used in combination. None of the treatments impacted RV function. Combination treatment had no significant effect on sarcolemmal damage or histopathology. The study suggests that combined BB and AI may not confer an advantage at an early stage in DMD cardiomyopathy. However, limitations of the mdx model should be considered.

  20. Lysozyme and bilirubin bind to ACE and regulate its conformation and shedding

    PubMed Central

    Danilov, Sergei M.; Lünsdorf, Heinrich; Akinbi, Henry T.; Nesterovitch, Andrew B.; Epshtein, Yuliya; Letsiou, Eleftheria; Kryukova, Olga V.; Piegeler, Tobias; Golukhova, Elena Z.; Schwartz, David E.; Dull, Randal O.; Minshall, Richard D.; Kost, Olga A.; Garcia, Joe G. N.

    2016-01-01

    Angiotensin I-converting enzyme (ACE) hydrolyzes numerous peptides and is a critical participant in blood pressure regulation and vascular remodeling. Elevated tissue ACE levels are associated with increased risk for cardiovascular and respiratory disorders. Blood ACE concentrations are determined by proteolytic cleavage of ACE from the endothelial cell surface, a process that remains incompletely understood. In this study, we identified a novel ACE gene mutation (Arg532Trp substitution in the N domain of somatic ACE) that increases blood ACE activity 7-fold and interrogated the mechanism by which this mutation significantly increases blood ACE levels. We hypothesized that this ACE mutation disrupts the binding site for blood components which may stabilize ACE conformation and diminish ACE shedding. We identified the ACE-binding protein in the blood as lysozyme and also a Low Molecular Weight (LMW) ACE effector, bilirubin, which act in concert to regulate ACE conformation and thereby influence ACE shedding. These results provide mechanistic insight into the elevated blood level of ACE observed in patients on ACE inhibitor therapy and elevated blood lysozyme and ACE levels in sarcoidosis patients. PMID:27734897

  1. Investigation of the biochemical effects of renin inhibition in normal volunteers treated by an ACE inhibitor.

    PubMed Central

    Chauveau, D; Guyenne, T T; Cumin, F; Chatellier, G; Corvol, P; Ménard, J

    1992-01-01

    1. In order to investigate accurately the biochemical effects of renin inhibition in man, we have developed a sensitive assay to measure angiotensin I (1-10) decapeptide. 2. Angiotensins were extracted from plasma by adsorption to phenylsilylsilica, and angiotensin I (Ang I) was quantified by radioimmunoassay. The detection limit was 0.77 fmol ml-1, and the extraction recovery of [125I]-Ang I added to albumin buffer was 83% at the inflection point (10 fmol ml-1) of the standard curve. The overall recovery was 98.5 +/- 3.5%. The intra- and inter-assay reproducibility was 10.4% and 9.7% respectively. Cross-reactivity of the antiserum used was low (less than 0.3%) with all angiotensin peptides tested except Ang (2-10) nonapeptide. 3. A human pharmacological model was subsequently used to assess in vivo the biochemical effects of the renin inhibitor CGP 38560A. Six healthy volunteers received 20 mg lisinopril, a long-acting ACE-inhibitor. During the following 24 h, the renin-angiotensin system was reset with typically elevated active plasma renin and Ang I, at respectively 275 and 429% of basal values. 4. In a randomized three-way cross-over protocol, the six volunteers received a 30 min infusion of the renin inhibitor CGP 38560A (125 or 250 micrograms kg-1) or 5% glucose. The fall in plasma Ang I was 92% and 97.5% after the lowest and highest dose of the renin inhibitor, respectively. A concomitant increase in active plasma renin was observed.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1315560

  2. Antifibrotic medication using a combination of N-acetyl-L-cystein (NAC) and ACE inhibitors can prevent the recurrence of Dupuytren's disease.

    PubMed

    Knobloch, Karsten; Redeker, Joern; Vogt, Peter M

    2009-11-01

    Dupuytren's disease is a progress fibromatosis of unknown origin first described in 1831. Nonoperative treatment options have been suggested involving radiation therapy, vitamin E, local injection therapy suing calcium channel blockers, interferon, corticosteroids or collagenase. Transforming growth factor-beta1 (TGF-beta1) and its downstream Smad signalling system is well established as a key player during fibrogenesis. A number of in vitro experiments have been assessed the blockade of TGF-beta1 and TGF-beta 2. Clinically, a number of antifibrotic agents are available such as N-acetyl-L-cysteins (NAC) as well as angiotensin-converting enzyme (ACE) inhibitors or AT II antagonists. However, to date none of the well known substances has been tested clinically in fibromatosis such as Dupuytren's disease especially to prevent recurrences after surgical release. Antifibrotic medication using a combination of N-acetyl-L-cystein (NAC) and ACE inhibitor can prevent the recurrence of Dupyutren's disease. Given the fact that recurrence rate in Dupuytren's disease is high and unpredictable after surgical release, an antifibrotic intervention might be worthwhile to consider in the clinical setting. Antifibrotic agents inhibit TGF-beta1, which play a key role in fibromatosis. Thus, antifibrotic medication might reduce the recurrence rate in fibromatosis such as Dupuytren's disease in a clinical significant way.

  3. A role for the extracellular matrix component hyaluronan in kidney dysfunction during ACE-inhibitor fetopathy.

    PubMed

    Hansell, P; Palm, F

    2015-04-01

    Despite data showing that inhibitors of the renin-angiotensin system increase the risks of fetal morbidity and dysfunctionality later in life, their use during pregnancy has increased. The fetopathy induced by angiotensin converting enzyme (ACE) inhibitors is characterized by anuria, hypotension and growth restriction, but can also be associated with pulmonary hypoplasia. In the kidney, this fetopathy includes atrophy of the medulla, reduced number of glomeruli, developmental lesions of tubules and vessels, tubulointerstitial inflammation and extracellular matrix accumulation. Although angiotensin II (Ang II) inhibition during nephrogenesis interferes with normal growth and development, this review will focus on effects of the heavily accumulated matrix component hyaluronan (HA). An important mechanism of HA accumulation during nephrogenesis is disruption of its normal reduction as a consequence of lack of Ang II activation of hyaluronidase. Hyaluronan has very large water-attracting properties and is pro-inflammatory when fragmented. The ensuing inflammation and interstitial oedema affect kidney function. Hyaluronan is colocalized with CD44 overexpression and infiltrating immune cells. These properties make HA a plausible contributor to the observed structural and functional kidney defects associated with the fetopathy. Available data support an involvement of HA in kidney dysfunction of the foetus and during adulthood due to the physico-chemical characteristics of HA. No clinical treatment for HA accumulation exists. Treatment with the HA-degrading enzyme hyaluronidase and an HA synthesis inhibitor has been tested successfully in experimental models in the kidney, heart and pancreas. Reduced HA accumulation to reduce interstitial oedema and inflammation may improve organ function, but this concept needs to be tested in a controlled study before causal relationships can be established.

  4. Efficacy and Safety of Complete RAAS Blockade with ALISKIREN in Patients with Refractory Proteinuria Who were already on Combined ACE Inhibitor, ARB, and Aldosterone Antagonist

    PubMed Central

    Sreelatha, M

    2016-01-01

    Introduction Proteinuria is always associated with intrinsic kidney disese and is a strong predictor of later development of End Stage Renal Disease (ESRD). As Renin Angiotensin Aldosterone System (RAAS) has a role in mediating proteinuria, inhibitors of this system are renoprotective and patients with refractory proteinuria are put on a combination of these agents. The routinely employed triple blockade of RAAS with Angiotensin Converting Enzyme (ACE) inhibitor, ARB and Aldosterone antagonist has many limitations. Addition of Aliskiren to this combination suppresses the RAAS at the earliest stage and can offset many of these limitations. Aim This study was conducted to assess the safety and efficacy of complete RAAS blockade by the addition of Aliskiren in those patients with refractory proteinuria who were already on triple blockade with ACE inhibitor, ARB and Aldosterone antagonist. Settings This study was conducted in Nephrology Department, Calicut Medical College. Materials and Methods A total of 36 patients with refractory proteinuria who were already on ACE inhibitor, ARB and Aldosterone antagonist were divided in to two groups A and B. Group A received Aliskiren in addition to the above combination whereas group B continued the same treatment for 12 weeks. Efficacy of the treatment was assessed by recording 24hr urine protein and safety by S.Creatinine, S.Potassium every 2 weeks of the treatment period. Statistical Analysis Statistical analysis of the lab values was done using SPSS software. Unpaired t-test, Paired t-test and Chi-square test were done for data analysis. Results Statistical analysis revealed that addition of Aliskiren to the combination therapy with ACE inhibitor+ ARB+ Aldosterone antagonist offers no advantage. But mean reduction in proteinuria was more with Group A than Group B. There is no statistically significant change in S.Creatinine and S.Potassium at the end of treatment. Conclusion As proteinuria is a strong risk factor for

  5. Do ACE Inhibitors Improve the Response to Exercise Training in Functionally Impaired Older Adults? A Randomized Controlled Trial

    PubMed Central

    Band, Margaret; Miller, Suzanne; Cvoro, Vera; Witham, Miles; Struthers, Allan; McConnachie, Alex; Lloyd, Suzanne M.; McMurdo, Marion

    2014-01-01

    Background. Loss of muscle mass and strength with ageing is a major cause for falls, disability, and morbidity in older people. Previous studies have found that angiotensin-converting enzyme inhibitors (ACEi) may improve physical function in older people. It is unclear whether ACEi provide additional benefit when added to a standard exercise training program. We examined the effects of ACEi therapy on physical function in older people undergoing exercise training. Methods. Community-dwelling people aged ≥65 years with functional impairment were recruited through general (family) practices. All participants received progressive exercise training. Participants were randomized to receive either 4 mg perindopril or matching placebo daily for 20 weeks. The primary outcome was between-group change in 6-minute walk distance from baseline to 20 weeks. Secondary outcomes included changes in Short Physical Performance Battery, handgrip and quadriceps strength, self-reported quality of life using the EQ-5D, and functional impairment measured using the Functional Limitations Profile. Results. A total of 170 participants (n = 86 perindopril, n = 84 placebo) were randomized. Mean age was 75.7 (standard deviation [SD] 6.8) years. Baseline 6-minute walk distance was 306 m (SD 99). Both groups increased their walk distance (by 29.6 m perindopril, 36.4 m placebo group) at 20 weeks, but there was no statistically significant treatment effect between groups (−8.6m [95% confidence interval: −30.1, 12.9], p = .43). No statistically significant treatment effects were observed between groups for the secondary outcomes. Adverse events leading to withdrawal were few (n = 0 perindopril, n = 4 placebo). Interpretation. ACE inhibitors did not enhance the effect of exercise training on physical function in functionally impaired older people. PMID:24201696

  6. [ACE inhibitors and its usefulness in the prevention of aspiration pneumonia in chronic cerebrovascular disease patients with asymptomatic swallowing dysfunction].

    PubMed

    Shibuya, Seiji; Murahashi, Makoto; Inoue, Masahiko; Jimi, Takahiro; Wakayama, Yoshihiro

    2002-03-01

    The double contrast pharyngogram by use of computed radiography (DCP-CR) has been found to be useful in detection of asymptomatic swallowing dysfunction. Following the DCP-CR examination, we investigated the incidence of aspiration pneumonia in 143 patients with chronic cerebrovascular disease (CVD) for 3 years and the effects of ACE inhibitors on the prevention of pneumonia. Aspiration pneumonia occurred in 29 out of 143 patients, and more frequently in the elderly chronic CVD patients with multiple brain lesions. Aspiration pneumonia was confirmed in 26 out of 85 patients (30.6%) with abnormal barium adhesion to the pharyngeal wall on the double contrast pharyngogram image by DCP-CR; whereas pneumonia occurred in 3 out of 58 patients (5.2%) with normal findings of DCP-CR pharyngogram. Among chronic CVD patients with abnormal findings of DCP-CR pharyngogram, the incidence of aspiration pneumonia was significantly lower in the patients treated with ACE inhibitors than in those treated with other antihypertensive agents or without antihypertensive agents (chi 2 value = 7.163, p < 0.05). Accordingly, ACE inhibitors may prevent the aspiration pneumonia and reduce the incidence of aspiration pneumonia in the chronic CVD patients with abnormal DCP-CR pharyngogram images.

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

    PubMed Central

    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 antioxidant activity were determined by Folin-Ciocalteu colorimetric method and DPPH radical scavenging assay respectively. Results Six extracts revealed > 50% ACE inhibition activity at 330 μg/ml concentration. They were Berberis integerrima Bunge. (Berberidaceae) (88.2 ± 1.7%), Crataegus microphylla C. Koch (Rosaceae) (80.9 ± 1.3%), Nymphaea alba L. (Nymphaeaceae) (66.3 ± 1.2%), Onopordon acanthium L. (Asteraceae) (80.2 ± 2.0%), Quercus infectoria G. Olivier. (Fagaceae) (93.9 ± 2.5%) and Rubus sp. (Rosaceae) (51.3 ± 1.0%). Q. infectoria possessed the highest total phenolic content with 7410 ± 101 mg gallic acid/100 g dry plant. Antioxidant activity of Q. infectoria (IC50 value 1.7 ± 0.03 μg/ml) was more than that of BHT (IC50 value of 10.3 ± 0.15 μg/ml) and Trolox (IC50 value of 3.2 ± 0.06 μg/ml) as the positive controls. Conclusions In this study, we introduced six medicinal plants with ACE inhibition activity. Despite the high ACE inhibition and antioxidant activity of Q. infectoria, due to its tannin content (tannins interfere in ACE activity), another plant, O. acanthium, which also had high ACE inhibition and antioxidant activity, but contained no tannin, could be utilized in further studies for isolation of active compounds. PMID:24359711

  8. STAT inhibitors for cancer therapy

    PubMed Central

    2013-01-01

    Signal Transducer and Activator of Transcription (STAT) proteins are a family of cytoplasmic transcription factors consisting of 7 members, STAT1 to STAT6, including STAT5a and STAT5b. STAT proteins are thought to be ideal targets for anti-cancer therapy since cancer cells are more dependent on the STAT activity than their normal counterparts. Inhibitors targeting STAT3 and STAT5 have been developed. These included peptidomimetics, small molecule inhibitors and oligonucleotides. This review summarized advances in preclinical and clinical development of these compounds. PMID:24308725

  9. ACE inhibitors in heart failure--switching from enalapril to perindopril.

    PubMed

    Masuell, Marcelo; Brusca, Gustavo; Pardo, Augusto; Piñeiro, Daniel; Checkerdhemian, Sergio; Forcada, Pedro

    2002-01-01

    Although ACE inhibitors have demonstrated their beneficial effects in heart failure, whether different agents may induce different benefits remains unclear. We designed an open, sequential, prospective study switching heart failure patients receiving enalapril to perindopril which has been reported to be longer acting and better tolerated. The objective of the study was to find out if clinical and functional status could be further improved by changing from enalapril 30 mg daily to a perindopril 4 mg daily. Assessments of clinical status, echocardiography and nuclear ventriculography were performed at baseline under enalapril (30 mg mean dose (b.i.d.)), then 6 and 12 months after the switch to perindopril (4 mg/day mean dose). Thirty-one patients were included (90% men, aged 56.5 +/- 11.8 years, mean radionuclide left ventricular (LV) ejection fraction 22.4 +/- 8.5 %). After 6 months of treatment, NYHA functional class was significantly improved; the percentage of patients in class I increased to 57% after perindopril versus 20% at baseline (p < 0.001), and 50% of the total study population gained at least one NYHA class. After 12 months of treatment, 80% of the patients were in NYHA class I. Blood pressure decreased significantly with a good tolerance at 6 months and then remained stable. After 12 months of treatment, significant reductions of LV end-diastolic diameter (61.4 +/- 5.3 vs. 64.5 +/- 6.5 mm; p = 0.001) and LV mass index (143.3 +/- 21.5 vs. 164.2 +/- 40.2 g/m2; p < 0.001) were observed, reflecting a positive effect on the LV remodelling process. Despite some limitations, because it is of an open-label design with a small number of patients, our study found significant differences in clinical and objective parameters in heart failure patients switched from enalapril to perindopril. The prognostic significance of these findings remains to be investigated.

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

    PubMed Central

    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

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

    PubMed

    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.

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

    PubMed Central

    Xing, Yachao; Liao, Jing; Tang, Yingzhan; Zhang, Peng; 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 active fraction was purified by repeated column chromatography, including silica gel, Sephadex LH-20 column, medium-pressure liquid chromatography (MPLC) (polyamide column) and high-performance liquid chromatography (HPLC). The isolated major constituents were tested for their anti-platelet aggregation activity. Results: Bioassay-directed separation of the EtOAc fraction of the 70% ethanol extract from the air-dried aerial parts of T. hohenackeri led to the isolation of a new triterpenoid lactone (1), together with 13 known compounds (2-14). It was the first time to focus on screening bioactive constituents for this plant. The chemical structures were established on the basis of spectral data (ESI-MS and NMR). The results showed that the flavonoid compounds (7 and 8) and phenolic compounds (9, 10, 11, and 14) were potential ACE inhibitors. And the flavonoid compounds (5 and 7) showed significant anti-platelet aggregation activities. Conclusion: On the basis of the chemical and biological data, the material basis of ACE inhibitory activity for the active part was the phenolic constituents. However, the flavonoid compounds were responsible for the anti-platelet aggregation. The primary structure and activity relationship were also discussed respectively. PMID:24914275

  13. Prostacyclin: its pathogenic role in essential hypertension and the class effect of ACE inhibitors on prostaglandin metabolism.

    PubMed

    Rodríguez-García, J L; Villa, E; Serrano, M; Gallardo, J; García-Robles, R

    1999-01-01

    Angiotensin-converting enzyme inhibitors (ACEI) block degradation of bradykinin, and bradykinin stimulates prostacyclin synthesis. Therefore, we set out to determine whether the effects of ACE inhibitors on prostaglandin production in essential hypertensive patients are class effects or are dependent on ACE inhibitor structure. In addition, we studied whether hypertensives show an impaired capacity to synthesize vasodilator prostaglandins. To address these questions, we compared the effects of captopril (sulfhydryl-containing inhibitor), enalapril and ramipril (carboxyl-containing inhibitors) and fosinopril (phosphoryl-containing inhibitor) on blood pressure and urinary excretion of 6-keto-prostaglandin (PG) F1-alpha (the breakdown product of prostacyclin) in 44 mild-to-moderate essential hypertensive subjects before and 8 weeks after administration of an ACEI. We also studied prostacyclin excretion in 15 normotensive healthy controls. Levels of urinary 6-keto-PGF1-alpha (pg/ml) were measured by specific radioimmunoassay. Hypertensive subjects showed a lower excretion of 6-keto-PGF1-alpha than normotensive controls (212+/-147 vs 353+/-98 pg/ml, p < 0.001). All ACEI induced a significant decrease in MAP and increased the rate of excretion of the prostacyclin metabolite: C, 211+/-200 to 338+/-250 pg/ml, p < 0.05; E, 202+/-133 to 296+/-207 pg/ml, p < 0.05; R, 205+/-127 to 342+/-211 pg/ml, p < 0.05; F, 235+/-128 to 347+/-241 pg/ml, p < 0.05. In hypertensives (n = 44) the decrease in blood pressure correlated negatively with the rise in 6-keto-PGF1-alpha excretion (r = -0.51, p < 0.001). These data suggest that impaired prostacyclin biosynthesis in hypertensive patients could account for haemodynamic changes leading to the hypertensive state. Moreover, the hypotensive mechanisms of ACEI may be mediated by an increase in prostacyclin production; this effect seems to be class-dependent.

  14. Effects of centrally acting ACE inhibitors on the rate of cognitive decline in dementia

    PubMed Central

    Gao, Yang; O'Caoimh, Rónán; Healy, Liam; Kerins, David M; Eustace, Joseph; Guyatt, Gordon; Sammon, David; Molloy, D William

    2013-01-01

    Objectives There is growing evidence that antihypertensive agents, particularly centrally acting ACE inhibitors (CACE-Is), which cross the blood–brain barrier, are associated with a reduced rate of cognitive decline. Given this, we compared the rates of cognitive decline in clinic patients with dementia receiving CACE-Is (CACE-I) with those not currently treated with CACE-Is (NoCACE-I), and with those who started CACE-Is, during their first 6 months of treatment (NewCACE-I). Design Observational case–control study. Setting 2 university hospital memory clinics. Participants 817 patients diagnosed with Alzheimer's disease, vascular or mixed dementia. Of these, 361 with valid cognitive scores were included for analysis, 85 CACE-I and 276 NoCACE-I. Measurements Patients were included if the baseline and end-point (standardised at 6 months apart) Standardised Mini-Mental State Examination (SMMSE) or Quick Mild Cognitive Impairment (Qmci) scores were available. Patients with comorbid depression or other dementia subtypes were excluded. The average 6-month rates of change in scores were compared between CACE-I, NoCACE-I and NewCACE-I patients. Results When the rate of decline was compared between groups, there was a significant difference in the median, 6-month rate of decline in Qmci scores between CACE-I (1.8 points) and NoCACE-I (2.1 points) patients (p=0.049), with similar, non-significant changes in SMMSE. Median SMMSE scores improved by 1.2 points in the first 6 months of CACE treatment (NewCACE-I), compared to a 0.8 point decline for the CACE-I (p=0.003) group and a 1 point decline for the NoCACE-I (p=0.001) group over the same period. Multivariate analysis, controlling for baseline characteristics, showed significant differences in the rates of decline, in SMMSE, between the three groups, p=0.002. Conclusions Cognitive scores may improve in the first 6 months after CACE-I treatment and use of CACE-Is is associated with a reduced rate of cognitive

  15. ACE Inhibitor and ARB Medication Use among Medicaid Enrollees with Diabetes

    PubMed Central

    Lora, Claudia M.; Sokolovsky, Alexander W.; Touchette, Daniel R.; Jin, Jing; Xiaojing, Hu; Gao, Weihua; Gerber, Ben S.

    2013-01-01

    Objective To examine Ace-Inhibitor (ACEI)and Angiotensin Receptor Blockers (ARB) prescription and adherence patterns by race in diabetic Public Aid recipients. Design, Subjects, and Measures We analyzed prescription records of 27,529 adults age 18–64 with diabetes enrolled in the State of Illinois Public Aid program during 2007 who had at least one clinical indication for receiving an ACEI/ARB prescription. We calculated Proportion of Days Covered (PDC) to assess adherence. Multivariate models adjusted for age, gender, ACEI/ARB indication, and any significant interaction terms. Results Only 47.4% of individuals with at least one indication for ACEI/ARB had filled an ACEI/ARB prescription. African American men were more likely than Caucasian men to ever fill an ACEI/ARB prescription [Adjusted Odds Ratio, AOR (95% CI) 1.69 (1.55–1.83)]. Hispanic English and Spanish speaking men were also more likely than Caucasian men to ever fill an ACEI/ARB prescription [AOR (95% CI) 1.37 (1.16–1.62) and 1.27 (1.05–1.53), respectively]. Similarly, African American and Hispanic English and Spanish speaking women were more likely than Caucasian women to ever fill an ACEI/ARB prescription [AOR (95% CI) 1.70 (1.59–1.81)], 1.55 (1.36–1.76), and 1.98 (1.73–2.28), respectively]. However, African-Americans and Hispanics were less likely than Caucasians to achieve a PDC ≥ 80%. Compared to Caucasians, Hispanic Spanish speakers were the least likely to be adherent [AOR (95% CI) 0.49 (0.41–0.58)]. Furthermore, older individuals were more likely to achieve a PDC ≥ 80% than younger individuals. Conclusion African Americans and Hispanics with diabetes receiving public aid in Illinois were more likely than Caucasians to have filled at least one ACEI/ARB prescription. However, they were less adherent with these medications. Future studies should assess barriers to medication adherence in this population. PMID:23530300

  16. ACE inhibitors hypothesis generation for selective design, synthesis and biological evaluation of 3-mercapto-2-methyl-propanoyl-pyrrolidine-3-imine derivatives as antihypertensive agents.

    PubMed

    Ismail, Mohamed A H; Nabil Aboul-Enein, M; Abouzid, Khaled A M; Abou El Ella, Dalal A; Ismail, Nasser S M

    2009-05-15

    A series of new 3-mercapto-2-methyl-propanoyl-pyrrolidine derivatives (V, VIa-e) were designed. A new validated ACE inhibitors pharmacophore model (hypothesis) was generated for the first time in this research from the biologically active (frozen) conformation of Lisinopril-Human ACE complex that was downloaded from PDB, using stepwise technique of CATALYST modules. The molecular modeling compare-fit study of the designed molecules (V, VIa-e), with such ACE inhibitors hypothesis was fulfilled, and several compounds showed significant high simulation fit values. The compounds with high fit values were synthesized and biologically evaluated in vivo as hypotensive agents. It appears that the in vivo hypotensive activity of compounds V, VIa, VIb, and VIe was consistent with their molecular modeling results, and compound VIe showed the highest activity in comparison to Captopril.

  17. The sulphydryl containing ACE inhibitor Zofenoprilat protects coronary endothelium from Doxorubicin-induced apoptosis.

    PubMed

    Monti, Martina; Terzuoli, Erika; Ziche, Marina; Morbidelli, Lucia

    2013-10-01

    Pediatric and adult cancer patients, following the use of the antitumor drug Doxorubicin develop cardiotoxicity. Pharmacological protection of microvascular endothelium might produce a double benefit: (i) reduction of myocardial toxicity (the primary target of Doxorubicin action) and (ii) maintenance of the vascular functionality for the adequate delivery of chemotherapeutics to tumor cells. This study was aimed to evaluate the mechanisms responsible of the protective effects of the angiotensin converting enzyme inhibitor (ACEI) Zofenoprilat against the toxic effects exerted by Doxorubicin on coronary microvascular endothelium. We found that exposure of endothelial cells to Doxorubicin (0.1-1μM range) impaired cell survival by promoting their apoptosis. ERK1/2 related p53 activation, but not reactive oxygen species, was responsible for Doxorubicin induced caspase-3 cleavage. P53 mediated-apoptosis and impairment of survival were reverted by treatment with Zofenoprilat. The previously described PI-3K/eNOS/endogenous fibroblast growth factor signaling was not involved in the protective effect, which, instead, could be ascribed to cystathionine gamma lyase dependent availability of H2S from Zofenoprilat. Furthermore, considering the tumor environment, the treatment of endothelial/tumor co-cultures with Zofenoprilat did not affect the antitumor efficacy of Doxorubicin. In conclusion the ACEI Zofenoprilat exerts a protective effect on Doxorubicin induced endothelial damage, without affecting its antitumor efficacy. Thus, sulfhydryl containing ACEI may be a useful therapy for Doxorubicin-induced cardiotoxicity.

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

    PubMed

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

    2011-11-21

    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 side measures such as mandatory generic substitution, regressive pharmacy mark-ups and claw-backs are effective in reducing pharmaceuticals prices. Results are not as strong for demand side measures. Profit controls and the use of cost-effectiveness analysis appear to have a negative effect on prices, while results on reference pricing are inconclusive. Findings also indicate that, although originator prices are not immediately affected by generic entry, they may be influenced by changes in generic prices post patent expiry.

  19. Refill Adherence in Relation to Substitution and the Use of Multiple Medications: A Nationwide Population Based Study on New ACE-Inhibitor Users

    PubMed Central

    Jönsson, Anna K.; Lesén, Eva; Mårdby, Ann-Charlotte; Sundell, Karolina Andersson

    2016-01-01

    Objective Generic substitution has contributed to economic savings but switching products may affect patient adherence, particularly among those using multiple medications. The aim was to analyse if use of multiple medications influenced the association between switching products and refill adherence to angiotensin-converting-enzyme (ACE) inhibitors in Sweden. Study Design and Setting New users of ACE-inhibitors, starting between 1 July 2006 and 30 June 2007, were identified in the Swedish Prescribed Drug Register. Refill adherence was assessed using the continuous measure of medication acquisition (CMA) and analysed with linear regression and analysis of covariance. Results The study population included 42735 individuals whereof 51.2% were exposed to switching ACE-inhibitor and 39.6% used multiple medications. Refill adherence was higher among those exposed to switching products than those not, but did not vary depending on the use of multiple medications or among those not. Refill adherence varied with age, educational level, household income, country of birth, previous hospitalisation and previous cardiovascular diagnosis. Conclusion The results indicate a positive association between refill adherence and switching products, mainly due to generic substitution, among new users of ACE-inhibitors in Sweden. This association was independent of use of multiple medications. PMID:27192203

  20. Screening of inhibitors of angiotensin-converting enzyme (ACE) employing high performance liquid chromatography-electrospray ionization triple quadrupole mass spectrometry (HPLC-ESI-QqQ-MS).

    PubMed

    Musharraf, Syed Ghulam; Bhatti, Muhammad Salman; Choudhary, Muhammad Iqbal; Rahman, Atta-Ur

    2017-04-01

    Angiotensin-converting enzyme (ACE) plays a key role in regulating blood pressure in the body by converting the angiotensin I (AI) into angiotensin II (AII). Angiotensin II is a potent vaso-active peptide that causes arterioles to constrict, resulting in increased blood pressure. A rapid and sensitive method for the identification of inhibitors of ACE was developed, and optimized employing HPLC-ESI-QqQ-MS. In this assay, angiotensin I substrate was converted into the product angiotensin II with the catalytic action of ACE. A calibration curve for depleting concentration of angiotensin I was developed and linearity of R(2)=0.999 with a remarkably low concentration of substrate range 20-200nM. The limit of detection and quantification of angiotensin I was found to be 1.93 and 5.84nM, respectively. The enzymatic reaction was optimized for incubation time, concentration, and volume of enzyme and substrate. All reactions were performed at 37°C at pH7.5 with standard incubation time of 20min. Two standard inhibitors, Captopril and Lisinopril, were checked through the newly developed method for their inhibitory potential, and their IC50 values were found to be 3.969 and 0.852μM, respectively. Reproducibility and precision analysis of different experiments showed <9.9% RSD. The developed method can be used for the identification of new ACE inhibitors.

  1. The ACE inhibitor ( sup 3 H)SQ29,852 identifies a high affinity recognition site located in the human temporal cortex

    SciTech Connect

    Barnes, N.M.; Costall, B.; Egli, P.; Horovitz, Z.P.; Ironside, J.W.; Naylor, R.J.; Williams, T.J. )

    1990-07-01

    The angiotensin converting enzyme (ACE) inhibitor ({sup 3}H)SQ29,852 identified a single high affinity recognition site (defined by 10.0 microM captopril) in the human temporal cortex (pKD 8.62 +/- 0.03; Bmax 248 +/- 24 fmol mg-1 protein, mean +/- S.E.M., n = 4). ACE inhibitors and thiorphan competed to a similar level for the ({sup 3}H)SQ29,852 binding site in the human temporal cortex with a rank order of affinity (pKi values mean +/- S.E.M., n = 3), lisinopril (9.49 +/- 0.02), captopril (9.16 +/- 0.08), SQ29,852 (8.58 +/- 0.04), epicaptopril (7.09 +/- 0.08), fosinopril (7.08 +/- 0.05) and thiorphan (6.40 +/- 0.04). Since this rank order of affinity is similar to the affinity of these compounds to inhibit brain ACE activity it is concluded that ({sup 3}H)SQ29,852 selectively labels the inhibitor recognition site of ACE in the human temporal cortex.

  2. Renal Expression of FGF23 in Progressive Renal Disease of Diabetes and the Effect of Ace Inhibitor

    PubMed Central

    Benigni, Ariela; Corna, Daniela; Tomasoni, Susanna; Rottoli, Daniela; Gaspari, Flavio; Remuzzi, Giuseppe; Zoja, Carlamaria

    2013-01-01

    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. PMID:23967103

  3. The ACE inhibitors enalapril and captopril modulate cytokine responses in Balb/c and C57Bl/6 normal mice and increase CD4(+)CD103(+)CD25(negative) splenic T cell numbers.

    PubMed

    Albuquerque, Deijanira; Nihei, Jorge; Cardillo, Fabíola; Singh, Ram

    2010-01-01

    Increasing evidence implies beneficial effects of angiotensin-converting enzyme (ACE) inhibitors beyond those of their original indications to control hypertension. One of the most attractive non-hemodynamic properties of ACE inhibitors is their ability to regulate cytokine production. The mechanism(s) underlying the role of ACE inhibitors on cytokine synthesis are not well understood but they have traditionally been attributed to the inhibition of angiotensin (Ang) II formation. In fact, it has been extensively demonstrated that ACE inhibitors decrease Ang II-induced production of proinflammatory cytokines and chemokines. However, it is not well described if inhibition of endogenous Ang II generation by ACE inhibitors modulates systemic cytokine production in mice. To verify that, in this work, we investigated the effects of treatment with the ACE inhibitors enalapril and captopril on cytokine synthesis in C57Bl/6 and Balb/c mice. Our results show that enalapril up regulates IL-10 produced by splenocytes from Balb/c and C57Bl/6 mice and captopril increased it only in Balb/c mice. Furthermore, CD4(+)CD103(+) presented increased IL-10 production after enalapril treatment. Enalapril as well as captopril short-term treatment enhanced IL-2 synthesis in Balb/c mice. Besides, enhanced IL-2 and IL-10 levels correlates with increased CD4(+)CD103(+)CD25(negative) T cells numbers in spleens from enalapril-treated mice.

  4. ACE Inhibitor and Angiotensin Receptor Blocker Use and Mortality in Patients with Chronic Kidney Disease

    PubMed Central

    Molnar, Miklos Z; Kalantar-Zadeh, Kamyar; Lott, Evan H; Lu, Jun Ling; Malakauskas, Sandra M; Ma, Jennie Z; Quarles, Darryl L; Kovesdy, Csaba P

    2014-01-01

    Objective To assess the association between ACEI/ARB use and mortality in CKD patients. Background There is insufficient evidence about the association of angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARBs) with mortality in chronic kidney disease (CKD) patients. Methods A logistic regression analysis was used to calculate the propensity of ACEI/ARB initiation in 141,413 US veterans with non-dialysis CKD previously unexposed to ACEI/ARB treatment. We examined the association of ACEI/ARB administration with all-cause mortality in patients matched by propensity scores, using the Kaplan-Meier method and Cox models in “intention-to-treat” analyses, and in generalized linear models with binary outcomes and inverse probability treatment weighing (IPTW) in “as-treated” analyses. Results The mean±SD age of the patients at baseline was 75±10 years, 8% of patients were black, and 22% were diabetic. ACEI/ARB administration was associated with significantly lower risk of mortality both in the intention-to-treat analysis (HR=0.81; 95%CI: 0.78-0.84, p<0.001) and in the as-treated analysis with IPTW (OR=0.37; 95%CI: 0.34-0.41, p<0.001). The association of ACEI/ARB treatment with lower risk of mortality was present in all examined subgroups. Conclusions In this large contemporary cohort of non-dialysis dependent CKD patients, ACEI/ARB administration was associated with greater survival. PMID:24269363

  5. Combination of ACE inhibitor with nicorandil provides further protection in chronic kidney disease.

    PubMed

    Shiraishi, Takeshi; Tamura, Yoshifuru; Taniguchi, Kei; Higaki, Masato; Ueda, Shuko; Shima, Tomoko; Nagura, Michito; Nakagawa, Takahiko; Johnson, Richard J; Uchida, Shunya

    2014-12-15

    An inhibition in the renin-angiotensin system (RAS) is one of the most widely used therapies to treat chronic kidney disease. However, its effect is occasionally not sufficient and additional treatments may be required. Recently, we reported that nicorandil exhibited renoprotective effects in a mouse model of diabetic nephropathy. Here we examined if nicorandil can provide an additive protection on enalapril in chronic kidney disease. Single treatment with either enalapril or nicorandil significantly ameliorated glomerular and tubulointerstitial injury in the rat remnant kidney while the combination of these two compounds provided additive effects. In addition, an increase in oxidative stress in remnant kidney was also blocked by either enalapril or nicorandil while the combination of the drugs was more potent. A mechanism was likely due for nicorandil to preventing manganase superoxide dismutase (MnSOD) and sirtuin (Sirt)3 from being reduced in injured kidneys. A study with cultured podocytes indicated that the antioxidative effect could be mediated through sulfonylurea receptor (SUR) in the mitochondrial KATP channel since blocking SUR with glibenclamide reduced MnSOD and Sirt3 expression in podocytes. In conclusion, nicorandil may synergize with enalapril to provide superior protection in chronic kidney disease.

  6. Sources of heterogeneity in case-control studies on associations between statins, ACE-inhibitors, and proton pump inhibitors and risk of pneumonia.

    PubMed

    de Groot, Mark C H; Klungel, Olaf H; Leufkens, Hubert G M; van Dijk, Liset; Grobbee, Diederick E; van de Garde, Ewoudt M W

    2014-10-01

    The heterogeneity in case-control studies on the associations between community-acquired pneumonia (CAP) and ACE-inhibitors (ACEi), statins, and proton pump inhibitors (PPI) hampers translation to clinical practice. Our objective is to explore sources of this heterogeneity by applying a common protocol in different data settings. We conducted ten case-control studies using data from five different health care databases. Databases varied on type of patients (hospitalised vs. GP), level of case validity, and mode of exposure ascertainment (prescription or dispensing based). Identified CAP patients and controls were matched on age, gender, and calendar year. Conditional logistic regression was used to calculate odds ratios (OR) for the associations between the drugs of interest and CAP. Associations were adjusted by a common set of potential confounders. Data of 38,742 cases and 118,019 controls were studied. Comparable patterns of variation between case-control studies were observed for ACEi, statins and PPI use and pneumonia risk with adjusted ORs varying from 1.04 to 1.49, 0.82 to 1.50 and 1.16 to 2.71, respectively. Overall, higher ORs were found for hospitalised CAP patients matched to population controls versus GP CAP patients matched to population controls. Prevalence of drug exposure was higher in dispensing data versus prescription data. We show that case-control selection and methods of exposure ascertainment induce bias that cannot be adjusted for and to a considerable extent explain the heterogeneity in results obtained in case-control studies on statins, ACEi and PPIs and CAP. The common protocol approach helps to better understand sources of variation in observational studies.

  7. Dipeptidyl peptidase IV inhibitors and diabetes therapy.

    PubMed

    McIntosh, Christopher H S

    2008-01-01

    Current type 2 diabetes therapies are mainly targeted at stimulating pancreatic beta-cell secretion and reducing insulin resistance. A number of alternative therapies are currently being developed to take advantage of the actions of the incretin hormones Glucagon-Like Peptide-1 (GLP-1) and Glucose-dependent Insulinotropic Polypeptide (GIP). These hormones are released from the small intestine in response to nutrient ingestion and stimulate insulin secretion in a glucose-dependent manner. One approach to potentiating their actions is based on inhibiting dipeptidyl peptidase IV (DPP IV), the major enzyme responsible for degrading the incretins in vivo. DPP IV exhibits characteristics that have allowed the development of specific orally administered inhibitors with proven efficacy in improving glucose tolerance in animal models of diabetes. A number of clinical trials have demonstrated that DPP IV inhibitors are effective in improving glucose disposal and reducing hemoglobin A1c levels in type 2 diabetic patients and one inhibitor, sitagliptin, is now in therapeutic use, with others likely to receive FDA approval in the near future. Studies aimed at elucidating the mode of action of the inhibitors are still ongoing. Both enhancement of insulin secretion and reduction in glucagon secretion, resulting from the blockade of incretin degradation, are believed to play important roles in DPP IV inhibitor action. Preclinical studies indicate that increased levels of incretins improve beta-cell secretory function and exert effects on beta-cell mitogenesis and survival that can preserve beta-cell mass. Roles for other hormones, neuropeptides and cytokines in DPP IV inhibitor-medicated responses are also possible.

  8. Effectively nursing patients receiving aromatase inhibitor therapy.

    PubMed

    Wengström, Y

    2008-06-01

    Inhibiting estrogen production is a common means of preventing breast cancer recurrence. The aromatase inhibitors (AIs) are becoming the preferred treatment over tamoxifen as adjuvant therapy for postmenopausal women with hormone-sensitive early breast cancer. Like all adjuvant therapies, AIs have adverse events (AEs) associated with their use, many of which resemble symptoms common to menopause. Because of the greater efficacy of AIs in preventing breast cancer recurrence over tamoxifen, these AEs may be considered tolerable by many patients and often can be effectively managed and/or prevented. Educating patients about anticipated AEs may help them understand, accept, and cope with these AEs. This article reviews the AEs associated with different adjuvant AI treatments and highlights some strategies to manage them effectively. It also highlights the importance of patient education regarding AI therapy and involvement in treatment decisions, which may lead to better long-term adherence and ultimately to better outcomes.

  9. Investigational protease inhibitors as antiretroviral therapies

    PubMed Central

    Midde, Narasimha M.; Patters, Benjamin J.; Rao, PSS; Cory, Theodore J.; Kumar, Santosh

    2017-01-01

    Introduction Highly Active Antiretroviral Therapy (HAART) has tremendously improved the life expectancy of the HIV-infected population over the past three decades. Protease inhibitors have been one of the major classes of drugs in HAART regimens that are effective in treating HIV. However, the emergence of resistance and cross-resistance against protease inhibitors encourages researchers to develop new PIs with broad-spectrum activity, as well as novel means of enhancing the efficacy of existing PIs. Areas covered In this article we discuss recent advances in HIV protease inhibitor (PI) development, focusing on both investigational and experimental agents. We also include a section on pharmacokinetic booster drugs for improved bioavailability of protease inhibitors. Further, we discuss novel drug delivery systems using a variety of nanocarriers for the delivery of PIs across the blood-brain barrier to treat the HIV in the brain. Expert opinion We discuss our opinion on the promises and challenges on the development of novel investigational and experimental PIs that are less toxic and more effective in combating drug-resistance. Further, we discuss the future of novel nanocarriers that have been developed to deliver PIs to the brain cells. Although these are promising findings, many challenges need to be overcome prior to making them a viable option. PMID:27415449

  10. mTOR inhibitors in cancer therapy

    PubMed Central

    Xie, Jianling; Wang, Xuemin; Proud, Christopher G.

    2016-01-01

    The mammalian target of rapamycin, mTOR, plays key roles in cell growth and proliferation, acting at the catalytic subunit of two protein kinase complexes: mTOR complexes 1 and 2 (mTORC1/2). mTORC1 signaling is switched on by several oncogenic signaling pathways and is accordingly hyperactive in the majority of cancers. Inhibiting mTORC1 signaling has therefore attracted great attention as an anti-cancer therapy. However, progress in using inhibitors of mTOR signaling as therapeutic agents in oncology has been limited by a number of factors, including the fact that the classic mTOR inhibitor, rapamycin, inhibits only some of the effects of mTOR; the existence of several feedback loops; and the crucial importance of mTOR in normal physiology. PMID:27635236

  11. ACE inhibitors and angiotensin II receptor blockers in IgA nephropathy with mild proteinuria: the ACEARB study.

    PubMed

    Pozzi, Claudio; Del Vecchio, Lucia; Casartelli, Donatella; Pozzoni, Pietro; Andrulli, Simeone; Amore, Alessandro; Peruzzi, Licia; Coppo, Rosanna; Locatelli, Francesco

    2006-01-01

    Few studies have investigated IgA nephropathy patients presenting with 'favorable' clinical features at onset, such as normal renal function, proteinuria<1 g/24 hours and the absence of hypertension, and no controlled clinical trials have tested the effects of treatment in such patients who may nevertheless develop end-stage renal disease. It is therefore important to find a well-tolerated and economic therapy capable of decreasing their risk of high proteinuria and blood pressure levels. The aim of this multicenter open-label randomized clinical trial is to test whether blocking the renin-angiotensin system (RAS) decreases the risk of progression in patients aged 3-60 years with biopsy-proven benign IgA glomerulonephritis, proteinuria levels of 0.3-0.9 g/24 hours, and normal renal function and blood pressure. The RAS is blocked by first using a single drug class (angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker), and then combining the 2 classes as soon as the 1-drug blockade has become ineffective. We plan to enroll 378 patients over the next 3 years and randomize them to receive ramipril 5 mg/day (3 mg/m2 in children) (group A), irbesartan 300 mg/day (175 mg/m 2 in children) (group B) or supportive therapy (group C); if an increase in proteinuria of at least 50% from baseline is detected after 6 months of treatment, the other RAS inhibitor will be added. The observation period will be at least 5 years (except in the case of the development of the primary end point).

  12. Effects of the angiotensin converting enzyme inhibitor enalapril compared with diuretic therapy in elderly hypertensive patients.

    PubMed

    Verza, M; Cacciapuoti, F; Spiezia, R; D'Avino, M; Arpino, G; D'Errico, S; Sepe, J; Varricchio, M

    1988-11-01

    The aim of this study was to evaluate the usefulness of the angiotensin converting enzyme (ACE) inhibitor enalapril in a group of 30 patients (mean age 73.3 years) with moderate hypertension and normal haematological and chemical parameters (170 +/- 8.1 mmHg systolic and 104 +/- 5.8 mmHg diastolic blood pressure), who were receiving diuretic therapy with chlorthalidone (12.5 mg/day). This therapy caused a significant decrease in systolic and diastolic blood pressure (to 165 +/- 6.7 and 98 +/- 4.7 mmHg, respectively; P less than 0.001) but it also induced hypokalaemia (3.04 +/- 0.7 mmol/l; P less than 0.001) and multiple (greater than 10/h) and complex premature ventricular depolarizations (2nd, 3rd and 4th Lown grade). Enalapril treatment (5 mg/day for 5 days and 10 mg thereafter) was added to the diuretic therapy and after 2 months a further decrease in blood pressure was observed (to 158 +/- 5.6 mmHg systolic, P less than 0.001; 87.2 +/- 5.0 mmHg diastolic, P less than 0.001). Moreover, there was a significant reduction in the mean heart rate (from 79 to 72 beats/min, P less than 0.005) and an increase in serum potassium (to 4.19 +/- 0.2 mmol/l; P less than 0.001). In 80% of patients a 24-h dynamic electrocardiogram showed a significant reduction in both the number and complexity of premature ventricular depolarizations. Our findings suggest that ACE inhibitors can be useful in patients developing hypokalaemia during therapy. However, we are not yet able to explain the beneficial effects of enalapril in decreasing the frequency of premature ventricular depolarizations.

  13. TNF inhibitor therapy for rheumatoid arthritis

    PubMed Central

    MA, XIXI; XU, SHENGQIAN

    2013-01-01

    Immunotherapy has markedly improved treatment outcomes in rheumatoid arthritis (RA). Tumor necrosis factor (TNF)-α antagonists, such as infliximab (IFX), etanercept (ETN), adalimumab (ADA), golimumab (GOLI) and certolizumab pegol (CZP) have been widely used for the treatment of RA. IFX provides significant, clinically relevant improvement in physical function and the quality of life, inhibits progressive joint damage and sustains improvement in the signs and symptoms of patients with RA. ETN is effective and safe for patients with RA. Combination therapy with ETN plus methotrexate (MTX) reduces disease activity, decreases total joint score progression, slows the pace of joint destruction and improves function more effectively compared to any of the monotherapies. ADA with or without MTX also relieves the signs and symptoms of RA. CZP and GOLI expand the therapeutic schedule for patients with RA. The TNF-α inhibitors have similar efficacy, but distinct clinical pharmacokinetic and -dynamic properties. The common adverse events of these TNF-α antagonists include adverse reactions, infections and injection-site reaction. Additionally, these adverse events are mostly mild or moderate and their incidence is low. Certain patients exhibit a lack of response to anti-TNF-α therapies. Some patients may discontinue the initial drug and switch to a second anti-TNF-α agent. The shortage of clinical response to one agent may not predict deficiency of response to another. This review mainly addresses the latest developments of these biological agents in the treatment of RA. PMID:24648915

  14. Experiences with ACE inhibitors early after acute myocardial infarction. Rationale and design of the German Multicenter Study on the Effects of Captopril on Cardiopulmonary Exercise parameters post myocardial infarction (ECCE).

    PubMed

    Kleber, F X; Reindl, I; Wenzel, M; Rodewyk, P; Beil, S; Kosloswki, B; Doering, W; Sabin, G V; Hinzmann, S; Winter, U J

    1993-12-01

    Left ventricular damage by necrosis of myocardial tissue can lead to compromise of left ventricular function, to left ventricular volume increase and ultimately to development of heart failure. This sequence in the pathophysiology has been shown to be blunted by ACE inhibitors. Volume increase, however, can also be helpful in restoring stroke volume and ameliorate elevation of filling pressures. Furthermore, very early institution of ACE inhibition has failed to improve short-term mortality after myocardial infarction in one large trial. The aim of the ECCE trial therefore is, to investigate the early effects of the ACE inhibitor captopril on compromise of exercise capacity, thought to be a first measurable sign of developing heart failure. The ECCE trial is a randomized, seven-center investigation, studying the effects of ACE inhibition on oxygen uptake in a double blind, placebo controlled design in a group of 204 patients. Sample size was calculated on the basis of a pilot trial. The study design and first not unblinded data of 104 patients are presented. The population consists of predominantly male patients with mostly first myocardial infarction. They were admitted to hospital within five hours of onset of chest pain. End-diastolic volumes were normal, but ejection fraction was moderately compromised. ACE inhibition was started after the first day, but within 72 hours of onset of chest pain. After four and after twelve weeks, oxygen uptake was considerably below expected values and one third of the patients had severe compromise of exercise capacity.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. An additive effect of anti-PAI-1 antibody to ACE inhibitor on slowing the progression of diabetic kidney disease.

    PubMed

    Gu, Chunyan; Zhang, Jiandong; Noble, Nancy A; Peng, Xiao-Rong; Huang, Yufeng

    2016-11-01

    While angiotensin II blockade slows the progression of diabetic nephropathy, current data suggest that it alone cannot stop the disease process. New therapies or drug combinations will be required to further slow or halt disease progression. Inhibition of plasminogen activator inhibitor type 1 (PAI-1) aimed at enhancing ECM degradation has shown therapeutic potential in diabetic nephropathy. Here, using a mouse model of type diabetes, the maximally therapeutic dose of the PAI-1-neutralizing mouse monoclonal antibody (MEDI-579) was determined and compared with the maximally effective dose of enalapril. We then examined whether addition of MEDI-579 to enalapril would enhance the efficacy in slowing the progression of diabetic nephropathy. Untreated uninephrectomized diabetic db/db mice developed progressive albuminuria and glomerulosclerosis associated with increased expression of transforming growth factor (TGF)-β1, PAI-1, type IV collagen, and fibronectin from weeks 18 to 22, which were reduced by MEDI-579 at 3 mg/kg body wt, similar to enalapril given alone from weeks 12 to 22 Adding MEDI-579 to enalapril from weeks 18 to 22 resulted in further reduction in albuminuria and markers of renal fibrosis. Renal plasmin generation was dramatically reduced by 57% in diabetic mice, a decrease that was partially reversed by MEDI-579 or enalapril given alone but was further restored by these two treatments given in combination. Our results suggest that MEDI-579 is effective in slowing the progression of diabetic nephropathy in db/db mice and that the effect is additive to ACEI. While enalapril is renal protective, the add-on PAI-1 antibody may offer additional renoprotection in progressive diabetic nephropathy via enhancing ECM turnover.

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

    PubMed Central

    Nagamura, Norihiro; Kin, Seikon

    2016-01-01

    ABSTRACT 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

  17. Renin-angiotensin-aldosterone system inhibition: overview of the therapeutic use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and direct renin inhibitors.

    PubMed

    Mercier, Kelly; Smith, Holly; Biederman, Jason

    2014-12-01

    Angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy in hypertensive diabetic patients with macroalbuminuria, microalbuminuria, or normoalbuminuria has been repeatedly shown to improve cardiovascular mortality and reduce the decline in glomerular filtration rate. Renin-angiotensin-aldosterone system (RAAS) blockade in normotensive diabetic patients with normoalbuminuria or microalbuminuria cannot be advocated at present. Dual RAAS inhibition with ACE inhibitors plus ARBs or ACE inhibitors plus direct renin inhibitors has failed to improve cardiovascular or renal outcomes but has predisposed patients to serious adverse events.

  18. Role of angiotensin converting enzyme and angiotensinogen gene polymorphisms in angiotensin converting enzyme inhibitor-mediated antiproteinuric action in type 2 diabetic nephropathy patients

    PubMed Central

    Aggarwal, Neerja; Kare, Pawan Kumar; Varshney, Parul; Kalra, Om Prakash; Madhu, Sri Venkata; Banerjee, Basu Dev; Yadav, Anil; Raizada, Alpana; Tripathi, Ashok Kumar

    2017-01-01

    AIM To investigate the role of genetic variants of angiotensin converting enzyme (ACE) and angiotensinogen (AGT) genes in the antiproteinuric efficacy of ACE inhibitor therapy in diabetic nephropathy (DN) patients. METHODS In the present study, 270 type 2 diabetes mellitus patients with nephropathy were enrolled and treated with ACE inhibitor (ramipril) and followed at 6 mo for renal function and albumin excretion by estimating serum creatinine, end stage renal disease, and albumin/creatinine ratio (ACR) in urine. Genotyping of ACE I/D and AGT M235T polymorphisms were performed by using primer specific polymerase chain reaction (PCR) and PCR-RFLP techniques, respectively. RESULTS Forty-eight percent of DN patients (responders) benefited with respect to proteinuria from ACE inhibitor therapy at 6 mo follow-up. A significant reduction in ACR was observed after 6 mo treatment with ACE inhibitor irrespective of whether DN patients were micro-albuminuric (≥ 30 and < 300 mg/g creatinine) or macro-albuminuric (≥ 300 mg/g creatinine) at the time of enrollment. However, macro-albuminuric patients (55%) showed better response to therapy. A reduction in urinary ACR was found independent of genotypes of ACE I/D and AGT M235T polymorphisms although macro-albuminuric patients having TT genotype showed statistically insignificant increased response (72%). CONCLUSION ACE inhibitor therapy reduced urinary ACR by ≥ 30% in 50% of DN patients and the response is independent of ACE I/D and AGT M235T polymorphisms. PMID:28344754

  19. Adverse cardiac effects of exogenous angiotensin 1-7 in rats with subtotal nephrectomy are prevented by ACE inhibition

    PubMed Central

    Griggs, Karen; Patel, Sheila K.

    2017-01-01

    We previously reported that exogenous angiotensin (Ang) 1–7 has adverse cardiac effects in experimental kidney failure due to its action to increase cardiac angiotensin converting enzyme (ACE) activity. This study investigated if the addition of an ACE inhibitor (ACEi) to Ang 1–7 infusion would unmask any beneficial effects of Ang 1–7 on the heart in experimental kidney failure. Male Sprague–Dawley rats underwent subtotal nephrectomy (STNx) and were treated with vehicle, the ACEi ramipril (oral 1mg/kg/day), Ang 1–7 (subcutaneous 24 μg/kg/h) or dual therapy (all groups, n = 12). A control group (n = 10) of sham-operated rats were also studied. STNx led to hypertension, renal impairment, cardiac hypertrophy and fibrosis, and increased both left ventricular ACE2 activity and ACE binding. STNx was not associated with changes in plasma levels of ACE, ACE2 or angiotensin peptides. Ramipril reduced blood pressure, improved cardiac hypertrophy and fibrosis and inhibited cardiac ACE. Ang 1–7 infusion increased blood pressure, cardiac interstitial fibrosis and cardiac ACE binding compared to untreated STNx rats. Although in STNx rats, the addition of ACEi to Ang 1–7 prevented any deleterious cardiac effects of Ang 1–7, a limitation of the study is that the large increase in plasma Ang 1–7 with ramipril may have masked any effect of infused Ang 1–7. PMID:28192475

  20. Outcomes of preoperative angiotensin-converting enzyme inhibitor therapy in patients undergoing isolated coronary artery bypass grafting.

    PubMed

    Bandeali, Salman J; Kayani, Waleed T; Lee, Vei-Vei; Pan, Wei; Elayda, Mac Arthur A; Nambi, Vijay; Jneid, Hani M; Alam, Mahboob; Wilson, James M; Birnbaum, Yochai; Ballantyne, Christie M; Virani, Salim S

    2012-10-01

    The association between preoperative use of angiotensin-converting enzyme (ACE) inhibitors and outcomes after coronary artery bypass grafting (CABG) remain controversial. Our aim was to study in-hospital outcomes after isolated CABG in patients on preoperative ACE inhibitors. A retrospective analysis of 8,889 patients who underwent isolated CABG from 2000 through 2011 was conducted. The primary outcome of interest was the incidence of major adverse events (MAEs) defined as a composite of mortality, postoperative renal dysfunction, myocardial infarction, stroke, and atrial fibrillation during index hospitalization. The secondary outcome was the incidence of individual outcomes included in MAEs. Logistic regression analyses were performed. Of 8,889 patients, 3,983 (45%) were on preoperative ACE inhibitors and 4,906 (55%) were not. Overall incidence of MAEs was 38.1% (n = 1,518) in the ACE inhibitor group compared to 33.6% (n = 1,649) in the no-ACE inhibitor group. Preoperative use of ACE inhibitors was independently associated with MAEs (odds ratio 1.13, 95% confidence interval 1.03 to 1.24), most of which was driven by a statistically significant increase in postoperative renal dysfunction (odds ratio 1.18, 95% confidence interval 1.03 to 1.36) and atrial fibrillation (odds ratio 1.15, 95% confidence interval 1.05 to 1.27). In-hospital mortality, postoperative myocardial infarction, and stroke were not significantly associated with preoperative ACE inhibitor use. Analyses performed after excluding patients with low ejection fractions yielded similar results. In conclusion, preoperative ACE inhibitor use was associated with an increased risk of MAEs after CABG, in particular postoperative renal dysfunction and atrial fibrillation.

  1. ACE--Some Issues.

    ERIC Educational Resources Information Center

    Campbell, Annie, Ed.; Curtin, Penelope, Ed.

    This publication contains four papers that identify issues within the adult and community education (ACE) sector. "Overview" (Annie Campbell, Peter Thomson) considers what defines ACE; who offers ACE programs; who participates in ACE programs and who does not participate; what are the barriers to participation; who is responsible for…

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

    PubMed

    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.

  3. ACE and ACE2 in kidney disease

    PubMed Central

    Mizuiri, Sonoo; Ohashi, Yasushi

    2015-01-01

    Renin angiotensin system (RAS) activation has a significant influence on renal disease progression. The classical angiotensin-converting enzyme (ACE)-angiotensin II (Ang II)-Ang II type 1 (AT1) axis is considered to control the effects of RAS activation on renal disease. However, since its discovery in 2000 ACE2 has also been demonstrated to have a significant impact on the RAS. The synthesis and catabolism of Ang II are regulated via a complex series of interactions, which involve ACE and ACE2. In the kidneys, ACE2 is expressed in the proximal tubules and less strongly in the glomeruli. The synthesis of inactive Ang 1-9 from Ang I and the catabolism of Ang II to produce Ang 1-7 are the main functions of ACE2. Ang 1-7 reduces vasoconstriction, water retention, salt intake, cell proliferation, and reactive oxygen stress, and also has a renoprotective effect. Thus, in the non-classical RAS the ACE2-Ang 1-7-Mas axis counteracts the ACE-Ang II-AT1 axis. This review examines recent human and animal studies about renal ACE and ACE2. PMID:25664248

  4. Trial Watch: Proteasomal inhibitors for anticancer therapy

    PubMed Central

    Obrist, Florine; Manic, Gwenola; Kroemer, Guido; Vitale, Ilio; Galluzzi, Lorenzo

    2015-01-01

    The so-called “ubiquitin-proteasome system” (UPS) is a multicomponent molecular apparatus that catalyzes the covalent attachment of several copies of the small protein ubiquitin to other proteins that are generally (but not always) destined to proteasomal degradation. This enzymatic cascade is crucial for the maintenance of intracellular protein homeostasis (both in physiological conditions and in the course of adaptive stress responses), and regulates a wide array of signaling pathways. In line with this notion, defects in the UPS have been associated with aging as well as with several pathological conditions including cardiac, neurodegenerative, and neoplastic disorders. As transformed cells often experience a constant state of stress (as a result of the hyperactivation of oncogenic signaling pathways and/or adverse microenvironmental conditions), their survival and proliferation are highly dependent on the integrity of the UPS. This rationale has driven an intense wave of preclinical and clinical investigation culminating in 2003 with the approval of the proteasomal inhibitor bortezomib by the US Food and Drug Administration for use in multiple myeloma patients. Another proteasomal inhibitor, carfilzomib, is now licensed by international regulatory agencies for use in multiple myeloma patients, and the approved indications for bortezomib have been extended to mantle cell lymphoma. This said, the clinical activity of bortezomib and carfilzomib is often limited by off-target effects, innate/acquired resistance, and the absence of validated predictive biomarkers. Moreover, the antineoplastic activity of proteasome inhibitors against solid tumors is poor. In this Trial Watch we discuss the contribution of the UPS to oncogenesis and tumor progression and summarize the design and/or results of recent clinical studies evaluating the therapeutic profile of proteasome inhibitors in cancer patients. PMID:27308423

  5. Novel Thioredoxin Inhibitors for Breast Cancer Therapy

    DTIC Science & Technology

    2002-07-01

    generation inhibitors. Antiproliferative activity . Antiproliferative activity was examined with estrogen receptor positive, p53-replete, MCF-7 and...research activity demanded that we develop semi-automated synthetic methodology. We ultimately intend to select one or more lead compounds that could...approaches. The scope of the research activity demanded that we develop semi-automated synthetic methodology. We ultimately intend to select one or more

  6. Patient compliance with MAO inhibitor therapy.

    PubMed

    Walker, J I; Davidson, J; Zung, W W

    1984-07-01

    Exaggerated fears of monoamine oxidase inhibitors (MAOIs) and of their interactions with foods often restrict their use. A review of the literature reveals seven food items most likely to produce a hypertensive crisis in combination with MAOI administration: aged cheeses, smoked or pickled fish, beef or chicken liver, dry fermented sausage, pods of broad beans, brewer's yeast products, and certain alcoholic beverages. Improved understanding of the dietary restrictions, benefits, and mechanism of action of the MAOIs can enhance cooperation with the prescribed treatment program.

  7. Triple ACE-ECE-NEP inhibition in heart failure: a comparison with ACE and dual ECE-NEP inhibition.

    PubMed

    Mellin, Virginie; Jeng, Arco Y; Monteil, Christelle; Renet, Sylvanie; Henry, Jean Paul; Thuillez, Christian; Mulder, Paul

    2005-09-01

    Mortality remains high in chronic heart failure (CHF) because under ACE inhibitor treatment other neurohumoral systems remain/become (de)activated, such as the endothelin and atrial natriuretic peptide pathways. Dual endothelin-converting enzyme-neutral endopeptidase (ECE-NEP) inhibition exerts beneficial effects in experimental CHF, but whether "triple" ACE-ECE-NEP inhibition is superior to ACE or ECE-NEP inhibition is unknown. We compared, in rats with CHF, ACE-ECE-NEP to ACE or ECE-NEP inhibition in terms of left ventricular (LV) hemodynamics and remodeling. Benazepril (2 mg/kg/d) or the ECE-NEP inhibitor CGS26303 (10 mg/kg/d) were administered alone or in combination (subcutaneously for 28 days starting 7 days after coronary ligation). ACE-ECE-NEP inhibition reduced blood pressure more markedly than ACE or ECE-NEP inhibition. All treatments increased cardiac output to the same extent, but ACE-ECE-NEP inhibition reduced LV diameter and LV end-diastolic pressure more markedly than ACE or ECE-NEP inhibition. The reduction of LV weight and collagen accumulation in the "viable" myocardium was most pronounced after ACE-ECE-NEP inhibition. These results, obtained in experimental CHF, illustrate a further improvement of LV hemodynamics and structure after ACE-ECE-NEP inhibition compared with either ACE or ECE-NEP inhibition, but whether this is associated with a further improvement of exercise tolerance and/or survival remains to be determined.

  8. Validated ligand mapping of ACE active site

    NASA Astrophysics Data System (ADS)

    Kuster, Daniel J.; Marshall, Garland R.

    2005-08-01

    Crystal structures of angiotensin-converting enzyme (ACE) complexed with three inhibitors (lisinopril, captopril, enalapril) provided experimental data for testing the validity of a prior active site model predicting the bound conformation of the inhibitors. The ACE active site model - predicted over 18 years ago using a series of potent ACE inhibitors of diverse chemical structure - was recreated using published data and commercial software. Comparison between the predicted structures of the three inhibitors bound to the active site of ACE and those determined experimentally yielded root mean square deviation (RMSD) values of 0.43-0.81 Å, among the distances defining the active site map. The bound conformations of the chemically relevant atoms were accurately deduced from the geometry of ligands, applying the assumption that the geometry of the active site groups responsible for binding and catalysis of amide hydrolysis was constrained. The mapping of bound inhibitors at the ACE active site was validated for known experimental compounds, so that the constrained conformational search methodology may be applied with confidence when no experimentally determined structure of the enzyme yet exists, but potent, diverse inhibitors are available.

  9. The effectiveness of aerobic training, cognitive behavioural therapy, and energy conservation management in treating MS-related fatigue: the design of the TREFAMS-ACE programme

    PubMed Central

    2013-01-01

    Background TREFAMS is an acronym for TReating FAtigue in Multiple Sclerosis, while ACE refers to the rehabilitation treatment methods under study, that is, Aerobic training, Cognitive behavioural therapy, and Energy conservation management. The TREFAMS-ACE research programme consists of four studies and has two main objectives: (1) to assess the effectiveness of three different rehabilitation treatment strategies in reducing fatigue and improving societal participation in patients with MS; and (2) to study the neurobiological mechanisms of action that underlie treatment effects and MS-related fatigue in general. Methods/Design Ambulatory patients (n = 270) suffering from MS-related fatigue will be recruited to three single-blinded randomised clinical trials (RCTs). In each RCT, 90 patients will be randomly allocated to the trial-specific intervention or to a low-intensity intervention that is the same for all RCTs. This low-intensity intervention consists of three individual consultations with a specialised MS-nurse. The trial-specific interventions are Aerobic Training, Cognitive Behavioural Therapy, and Energy Conservation Management. These interventions consist of 12 individual therapist-supervised sessions with additional intervention-specific home exercises. The therapy period lasts 16 weeks. All RCTs have the same design and the same primary outcome measures: fatigue - measured with the Checklist Individual Strength, and participation - measured with the Impact on Participation and Autonomy questionnaire. Outcomes will be assessed 1 week prior to, and at 0, 8, 16, 26 and 52 weeks after randomisation. The assessors will be blinded to allocation. Pro- and anti-inflammatory cytokines in serum, salivary cortisol, physical fitness, physical activity, coping, self-efficacy, illness cognitions and other determinants will be longitudinally measured in order to study the neurobiological mechanisms of action. Discussion The TREFAMS-ACE programme is unique in its aim to

  10. Influence of ACE I/D Polymorphism on Circulating Levels of Plasminogen Activator Inhibitor 1, D-Dimer, Ultrasensitive C-Reactive Protein and Transforming Growth Factor β1 in Patients Undergoing Hemodialysis

    PubMed Central

    de Carvalho, Sara Santos; Simões e Silva, Ana Cristina; Sabino, Adriano de Paula; Evangelista, Fernanda Cristina Gontijo; Gomes, Karina Braga; Dusse, Luci Maria SantAna; Rios, Danyelle Romana Alves

    2016-01-01

    Background There is substantial evidence that chronic renal and cardiovascular diseases are associated with coagulation disorders, endothelial dysfunction, inflammation and fibrosis. Angiotensin-Converting Enzyme Insertion/Deletion polymorphism (ACE I/D polymorphism) has also be linked to cardiovascular diseases. Therefore, this study aimed to compare plasma levels of ultrassensible C-reactive protein (usCRP), PAI-1, D-dimer and TGF-β1 in patients undergoing HD with different ACE I/D polymorphisms. Methods The study was performed in 138 patients at ESRD under hemodialysis therapy for more than six months. The patients were divided into three groups according to the genotype. Genomic DNA was extracted from blood cells (leukocytes). ACE I/D polymorphism was investigated by single polymerase chain reaction (PCR). Plasma levels of D-dimer, PAI-1 and TGF-β1 were measured by enzyme-linked immunosorbent assay (ELISA), and the determination of plasma levels of usCRP was performed by immunonephelometry. Data were analyzed by the software SigmaStat 2.03. Results Clinical characteristics were similar in patients with these three ACE I/D polymorphisms, except for interdialytic weight gain. I allele could be associated with higher interdialytic weight gain (P = 0.017). Patients genotyped as DD and as ID had significantly higher levels of PAI-1 than those with II genotype. Other laboratory parameters did not significantly differ among the three subgroups (P = 0.033). Despite not reaching statistical significance, plasma levels of usCRP were higher in patients carrying the D allele. Conclusion ACE I/D polymorphisms could be associated with changes in the regulation of sodium, fibrinolytic system, and possibly, inflammation. Our data showed that high levels of PAI-1 are detected when D allele is present, whereas greater interdialytic gain is associated with the presence of I allele. However, further studies with different experimental designs are necessary to elucidate the

  11. Trial watch: IDO inhibitors in cancer therapy

    PubMed Central

    Vacchelli, Erika; Aranda, Fernando; Eggermont, Alexander; Sautès-Fridman, Catherine; Tartour, Eric; Kennedy, Eugene P; Platten, Michael; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

    2014-01-01

    Indoleamine 2,3-dioxigenase 1 (IDO1) is the main enzyme that catalyzes the first, rate-limiting step of the so-called “kynurenine pathway”, i.e., the metabolic cascade that converts the essential amino acid L-tryptophan (Trp) into L-kynurenine (Kyn). IDO1, which is expressed constitutively by some tissues and in an inducible manner by specific subsets of antigen-presenting cells, has been shown to play a role in the establishment and maintenance of peripheral tolerance. At least in part, this reflects the capacity of IDO1 to restrict the microenvironmental availability of Trp and to favor the accumulation of Kyn and some of its derivatives. Also, several neoplastic lesions express IDO1, providing them with a means to evade anticancer immunosurveillance. This consideration has driven the development of several IDO1 inhibitors, some of which (including 1-methyltryptophan) have nowadays entered clinical evaluation. In animal tumor models, the inhibition of IDO1 by chemical or genetic interventions is indeed associated with the (re)activation of therapeutically relevant anticancer immune responses. This said, several immunotherapeutic regimens exert robust clinical activity in spite of their ability to promote the expression of IDO1. Moreover, 1-methyltryptophan has recently been shown to exert IDO1-independent immunostimulatory effects. Here, we summarize the preclinical and clinical studies testing the antineoplastic activity of IDO1-targeting interventions. PMID:25941578

  12. Comprehensive Database Service : ACE

    NASA Astrophysics Data System (ADS)

    Hiroki, Morio; Abe, Tetsuya

    The Data base, ACE commercialized by Chunichi Shimbun in Feb. 1986, aims at covering not only newspaper articles but also the other information which composes different data bases. This paper introduces newspaper articles, new material information and character information which are included in ACE. The content of ACE, how to use the online service, and future subjects are described.

  13. ACE2/Ang-(1-7)/Mas axis stimulates vascular repair-relevant functions of CD34+ cells.

    PubMed

    Singh, Neha; Joshi, Shrinidh; Guo, Lirong; Baker, Matthew B; Li, Yan; Castellano, Ronald K; Raizada, Mohan K; Jarajapu, Yagna P R

    2015-11-15

    CD34(+) stem/progenitor cells have been identified as a promising cell population for the autologous cell-based therapies in patients with cardiovascular disease. The counter-regulatory axes of renin angiotensin system, angiotensin converting enzyme (ACE)/Ang II/angiotensin type 1 (AT1) receptor and ACE2/Ang-(1-7)/Mas receptor, play an important role in the cardiovascular repair. This study evaluated the expression and vascular repair-relevant functions of these two pathways in human CD34(+) cells. CD34(+) cells were isolated from peripheral blood mononuclear cells (MNCs), obtained from healthy volunteers. Expression of ACE, ACE2, AT1, and angiotensin type 2 and Mas receptors were determined. Effects of Ang II, Ang-(1-7), Norleu(3)-Ang-(1-7), and ACE2 activators, xanthenone (XNT) and diminazene aceturate (DIZE) on proliferation, migration, and adhesion of CD34(+) cells were evaluated. ACE2 and Mas were relatively highly expressed in CD34(+) cells compared with MNCs. Ang-(1-7) or its analog, Norleu(3)-Ang-(1-7), stimulated proliferation of CD34(+) cells that was associated with decrease in phosphatase and tensin homologue deleted on chromosome 10 levels and was inhibited by triciribin, an AKT inhibitor. Migration of CD34(+) cells was enhanced by Ang-(1-7) or Norleu(3)-Ang-(1-7) that was decreased by a Rho-kinase inhibitor, Y-27632. In the presence of Ang II, XNT or DIZE enhanced proliferation and migration that were blocked by DX-600, an ACE2 inhibitor. Treatment of MNCs with Ang II, before the isolation of CD34(+) cells, attenuated the proliferation and migration to stromal derived factor-1α. This attenuation was reversed by apocynin, an NADPH oxidase inhibitor. Adhesion of MNCs or CD34(+) cells to fibronectin was enhanced by Ang II and was unaffected by Ang-(1-7). This study suggests that ACE2/Ang-(1-7)/Mas pathway stimulates functions of CD34(+) cells that are cardiovascular protective, whereas Ang II attenuates these functions by acting on MNCs. These findings

  14. Therapeutic Applications of PARP Inhibitors: Anticancer Therapy and Beyond

    PubMed Central

    Curtin, Nicola; Szabo, Csaba

    2013-01-01

    The aim of this article is to describe the current and potential clinical translation of pharmacological inhibitors of poly(ADP-ribose) polymerase (PARP) for the therapy of various diseases. The first section of the present review summarizes the available preclinical and clinical data with PARP inhibitors in various forms of cancer. In this context, the role of PARP in single-strand DNA break repair is relevant, leading to replication-associated lesions that cannot be repaired if homologous recombination (HRR) repair is defective, and the synthetic lethality of PARP inhibitors in HRR-defective cancer. HRR defects are classically associated with BRCA1 and 2 mutations associated with familial breast and ovarian cancer, but there may be many other causes of HRR defects. Thus, PARP inhibitors may be the drugs of choice for BRCA mutant breast and ovarian cancers, and extend beyond these tumors if appropriate biomarkers can be developed to identify HRR defects. Multiple lines of preclinical data demonstrate that PARP inhibition increases cytotoxicity and tumor growth delay in combination with temozolomide, topoisomerase inhibitors and ionizing radiation. Both single agent and combination clinical trials are underway. The final part of the first section of the present review summarizes the current status of the various PARP inhibitors that are in various stages of clinical development. The second section of the present review summarizes the role of PARP in selected non-oncologic indications. In a number of severe, acute diseases (such as stroke, neurotrauma, circulatory shock and acute myocardial infarction) the clinical translatability of PARP inhibition is supported by multiple lines of preclinical data, as well as observational data demonstrating PARP activation in human tissue samples. In these disease indications, PARP overactivation due to oxidative and nitrative stress drives cell necrosis and pro-inflammatory gene expression, which contributes to disease pathology

  15. PCSK9 inhibitors: A new era of lipid lowering therapy

    PubMed Central

    Chaudhary, Rahul; Garg, Jalaj; Shah, Neeraj; Sumner, Andrew

    2017-01-01

    Hyperlipidemia is a well-established risk factor for developing cardiovascular disease (CVD). The recent American College of Cardiology and American Heart Association guidelines on lipid management emphasize treatment of individuals at increased risk for developing CVD events with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) at doses proven to reduce CVD events. However, there are limited options for patients who are either intolerant to statin therapy, develop CVD despite being on maximally tolerated statin therapy, or have severe hypercholesterolemia. Recently the Food and Drug Administration approved two novel medications for low-density lipoprotein (LDL)-cholesterol reduction: Evolocumab and Alirocumab. These agents target and inactivate proprotein convertase subtilsin-kexin type 9 (PCSK9), a hepatic protease that attaches and internalizes LDL receptors into lysosomes hence promoting their destruction. By preventing LDL receptor destruction, LDL-C levels can be lowered 50%-60% above that achieved by statin therapy alone. This review explores PCSK-9 biology and the mechanisms available to alter it; clinical trials targeting PCSK9 activity, and the current state of clinically available inhibitors of PCSK9. PMID:28289523

  16. Inhibitors of Angiogenesis in Cancer Therapy - Synthesis and Biological Activity.

    PubMed

    Gensicka, Monika; Głowacka, Agnieszka; Dzierzbicka, Krystyna; Cholewinski, Grzegorz

    2015-01-01

    Angiogenesis is the process of formation of new capillaries from preexisting blood vessels. Angiogenesis is involved in normal physiological processes, and plays an important role in tumor invasion and development of metastases. Vascular endothelial growth factor (VEGF) plays a key role in angiogenesis. VEGF is a mitogen for vascular endothelial cells and stimulates their proliferation. By inhibiting the biological activity of VEGF, and then signal cascades with neutralizing VEGF antibodies and signal inhibitors, may negatively regulate the growth and metastasis. Anti-angiogenesis therapy is less toxic than chemotherapy. Angiogenesis is a multistep and multifactorial process, and therefore, can be blocked at different levels. In this review article, the authors present the synthesis of novel inhibitors of angiogenesis, together with the results of biological tests in vitro, and in some cases, state trials.

  17. Combining HDAC inhibitors with oncolytic virotherapy for cancer therapy.

    PubMed

    Nakashima, Hiroshi; Nguyen, Tran; Chiocca, Ennio Antonio

    2015-01-01

    Histone deacetylase (HDAC) enzymes play a critical role in the epigenetic regulation of cellular functions and signaling pathways in many cancers. HDAC inhibitors (HDACi) have been validated for single use or in combination with other drugs in oncologic therapeutics. An even more novel combination therapy with HDACi is to use them with an oncolytic virus. HDACi may lead to an amplification of tumor-specific lytic effects by facilitating increased cycles of viral replication, but there may also be direct anticancer effects of the drug by itself. Here, we review the molecular mechanisms of anti-cancer effects of the combination of oncolytic viruses with HDACi.

  18. Ergotism associated with HIV antiviral protease inhibitor therapy.

    PubMed

    Baldwin, Zachary K; Ceraldi, Chris C

    2003-03-01

    Ergotism is a rare condition of acute vasospasm found classically in young and middle-aged women taking ergot alkaloid agents to treat migraine headache. We report the case of a young man with human immunodeficiency virus (HIV) positivity and describe the drug interaction between protease inhibitors and ergot alkaloid agents, which most likely predisposed to development of ergot toxicity. The HIV-positive population receiving antiviral therapy may be an under-recognized group at risk for ergotism through decreased hepatic metabolism of ergot preparations.

  19. Minocycline Improves the Efficacy of EGFR Inhibitor Therapy: A Hypothesis

    PubMed Central

    Venniyoor, Ajit; Al Bahrani, Bassim

    2016-01-01

    Skin rash is a side effect of drugs that inhibit epithelial growth factor receptor (EGFR) as a part of targeted therapy of cancer. Its appearance and severity correlates with survival. Minocycline, an oral tetracycline antibiotic, is recommended as treatment (and increasingly, for prevention) of the rash, though infection is seen in only one-third of the patients. Minocycline has additional anticancer properties such as poly(ADP-ribose) polymerase inhibition. It is proposed that such properties contribute to the efficacy of EGFR inhibitors and can also explain the positive correlation between grade of rash and survival as patients with higher grades of rash are more likely to receive minocycline. Early concurrent administration of minocycline is recommended in patients planned for EGFR therapy while awaiting trials proving this hypothesis. PMID:27833902

  20. Marketing ACE in Victoria.

    ERIC Educational Resources Information Center

    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…

  1. Methylation inhibitor therapy in the treatment of myelodysplastic syndrome.

    PubMed

    Silverman, Lewis R; Mufti, Ghulam J

    2005-12-01

    The class of DNA methyltransferase inhibitors is represented by azacitidine and decitabine. Azacitidine is approved for the treatment of patients in both low- and high-risk subtypes of myelodysplastic syndrome (MDS), and decitabine is currently under review by the FDA. Azacitidine phase III trial data, based upon the Cancer and Leukemia Group B (CALGB) study 9221, showed durable clinical and symptomatic improvement in bone marrow function, a reduction in the risk of leukemic transformation, and significant improvements in the quality of life of patients treated with azacitidine compared with supportive care alone. This study also provided data suggestive of improvement in survival in MDS patients. The experience with decitabine comprises a number of phase I/II studies and a phase III trial yet to be published. While there is a strong base of experience supporting the efficacy of DNA methyltransferase inhibitors in the treatment of MDS, a number of practical issues need to be explored further. These include the optimization of the timing and duration of treatment, and the prediction of response to therapy. Along with current experience, future studies will lead to the development of treatment algorithms, strategies for selecting patients (e.g. according to age, risk, classification, and cytogenetic profile), and the combination strategies, particularly with histone deacetylase inhibitors, in the management of MDS.

  2. NAAG peptidase inhibitors and their potential for diagnosis and therapy.

    PubMed

    Zhou, Jia; Neale, Joseph H; Pomper, Martin G; Kozikowski, Alan P

    2005-12-01

    Modulation of N-acetyl-L-aspartyl-L-glutamate peptidase activity with small-molecule inhibitors holds promise for a wide variety of diseases that involve glutamatergic transmission, and has implications for the diagnosis and therapy of cancer. This new class of compounds, of which at least one has entered clinical trials and proven to be well tolerated, has demonstrated efficacy in experimental models of pain, schizophrenia, amyotrophic lateral sclerosis, traumatic brain injury and, when appropriately functionalized, can image prostate cancer. Further investigation of these promising drug candidates will be needed to bring them to the marketplace. The recent publication of the X-ray crystal structure for the enzymatic target of these compounds should facilitate the development of other new agents with enhanced activity that could improve both the diagnosis and treatment of neurological disorders.

  3. Arctic Collaborative Environment (ACE)

    DTIC Science & Technology

    2012-08-01

    distribution is unlimited. Key Data Requirements • Sea Ice – Location: Area, Onset, Growth, Drift, and Decay – Characterization: % Coverage, Thickness...Cloud ACE Developmental Server hosted at UAHuntsville ACE User Community Public Internet Tailored Ice Product Generation (NIC) Arctic Research...distribution is unlimited. Arctic Map 26 July 2012 13 Multi-sensor Analyzed Sea Ice Extent; National Data Buoy Center DISTRIBUTION STATEMENT A

  4. Specific Inhibitors of Histone Demethylases: Novel Chemical Agents for Breast Cancer Therapy

    DTIC Science & Technology

    2011-08-01

    AD_________________ Award Number: W81XWH-10-1-0442 TITLE: Specific Inhibitors of Histone...4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Specific Inhibitors of Histone Demethylases: Novel Chemical Agents for Breast Cancer Therapy 5b...specific inhibitors for these enzymes using an enzyme-templated approach that takes advantage of the enzyme’s substrate specificity. The identified

  5. Insulin treatment attenuates renal ADAM17 and ACE2 shedding in diabetic Akita mice.

    PubMed

    Salem, Esam S B; Grobe, Nadja; Elased, Khalid M

    2014-03-15

    Angiotensin-converting enzyme 2 (ACE2) is located in several tissues and is highly expressed in renal proximal tubules, where it degrades the vasoconstrictor angiotensin II (ANG II) to ANG-(1-7). Accumulating evidence supports protective roles of ACE2 in several disease states, including diabetic nephropathy. A disintegrin and metalloprotease (ADAM) 17 is involved in the shedding of several transmembrane proteins, including ACE2. Our previous studies showed increased renal ACE2, ADAM17 expression, and urinary ACE2 in type 2 diabetic mice (Chodavarapu H, Grobe N, Somineni HK, Salem ES, Madhu M, Elased KM. PLoS One 8: e62833, 2013). The aim of the present study was to determine the effect of insulin on ACE2 shedding and ADAM17 in type 1 diabetic Akita mice. Results demonstrate increased renal ACE2 and ADAM17 expression and increased urinary ACE2 fragments (≈70 kDa) and albumin excretion in diabetic Akita mice. Immunostaining revealed colocalization of ACE2 with ADAM17 in renal tubules. Renal proximal tubular cells treated with ADAM17 inhibitor showed reduced ACE2 shedding into the media, confirming ADAM17-mediated shedding of ACE2. Treatment of Akita mice with insulin implants for 20 wk normalized hyperglycemia and decreased urinary ACE2 and albumin excretion. Insulin also normalized renal ACE2 and ADAM17 but had no effect on tissue inhibitor of metalloproteinase 3 (TIMP3) protein expression. There was a positive linear correlation between urinary ACE2 and albuminuria, blood glucose, plasma creatinine, glucagon, and triglycerides. This is the first report showing an association between hyperglycemia, cardiovascular risk factors, and increased shedding of urinary ACE2 in diabetic Akita mice. Urinary ACE2 could be used as a biomarker for diabetic nephropathy and as an index of intrarenal ACE2 status.

  6. Management of arthralgias associated with aromatase inhibitor therapy.

    PubMed

    Thorne, C

    2007-12-01

    For the upfront adjuvant therapy of postmenopausal estrogen receptor-positive breast cancer, the third-generation aromatase inhibitors (AIS) have shown a more favourable overall risk-benefit profile than has tamoxifen. Benefits of the ais include less frequent gynecologic, cerebrovascular, and thromboembolic adverse events; greater disease-free survival; and lower tumour recurrence. Although approximately 25% of postmenopausal women with early breast cancer report experiencing symptoms of arthralgia with ai therapy, 68-month data from the Arimidex, Tamoxifen, Alone or in Combination trial showed that, compared with tamoxifen, anastrozole treatment was associated with only a modest increase in the incidence of joint symptoms. The events, which were mostly mild-to-moderate in intensity, led to treatment withdrawal in 2% of patients on anastrozole as compared with 1% in the tamoxifen arm. The symptoms and changes correlate with clinical, biochemical, and radiologic findings in symptomatic women. To determine appropriate intervention, it is therefore essential to perform a comprehensive evaluation of musculoskeletal complaints to distinguish natural menopause-related degenerative disease from AI-related effects. The present review explores the advantages of differential diagnosis with an emphasis on history and physical and musculoskeletal examination; laboratory investigations are used to corroborate or rule out clinical impressions. The transient symptoms associated with the ais are manageable with an appropriate combination of lifestyle changes, including exercise and joint protection in conjunction with pharmacologic approaches.

  7. Angiotensin-converting enzyme-2 (ACE2): comparative modeling of the active site, specificity requirements, and chloride dependence.

    PubMed

    Guy, Jodie L; Jackson, Richard M; Acharya, K Ravi; Sturrock, Edward D; Hooper, Nigel M; Turner, Anthony J

    2003-11-18

    Angiotensin-converting enzyme 2 (ACE2), a homologue of ACE, represents a new and potentially important target in cardio-renal disease. A model of the active site of ACE2, based on the crystal structure of testicular ACE, has been developed and indicates that the catalytic mechanism of ACE2 resembles that of ACE. Structural differences exist between the active site of ACE (dipeptidyl carboxypeptidase) and ACE2 (carboxypeptidase) that are responsible for the differences in specificity. The main differences occur in the ligand-binding pockets, particularly at the S2' subsite and in the binding of the peptide carboxy-terminus. The model explains why the classical ACE inhibitor lisinopril is unable to bind to ACE2. On the basis of the ability of ACE2 to cleave a variety of biologically active peptides, a consensus sequence of Pro-X-Pro-hydrophobic/basic for the protease specificity of ACE2 has been defined that is supported by the ACE2 model. The dipeptide, Pro-Phe, completely inhibits ACE2 activity at 180 microM with angiotensin II as the substrate. As with ACE, the chloride dependence of ACE2 is substrate-specific such that the hydrolysis of angiotensin I and the synthetic peptide substrate, Mca-APK(Dnp), are activated in the presence of chloride ions, whereas the cleavage of angiotensin II is inhibited. The ACE2 model is also suggestive of a possible mechanism for chloride activation. The structural insights provided by these analyses for the differences in inhibition pattern and substrate specificity among ACE and its homologue ACE2 and for the chloride dependence of ACE/ACE2 activity are valuable in understanding the function and regulation of ACE2.

  8. Regulation of urinary ACE2 in diabetic mice.

    PubMed

    Wysocki, Jan; Garcia-Halpin, Laura; Ye, Minghao; Maier, Christoph; Sowers, Kurt; Burns, Kevin D; Batlle, Daniel

    2013-08-15

    Angiotensin-converting enzyme-2 (ACE2) enhances the degradation of ANG II and its expression is altered in diabetic kidneys, but the regulation of this enzyme in the urine is unknown. Urinary ACE2 was studied in the db/db model of type 2 diabetes and stretozotocin (STZ)-induced type 1 diabetes during several physiological and pharmacological interventions. ACE2 activity in db/db mice was increased in the serum and to a much greater extent in the urine compared with db/m controls. Neither a specific ANG II blocker, telmisartan, nor an ACE inhibitor, captopril, altered the levels of urinary ACE2 in db/db or db/m control mice. High-salt diet (8%) increased whereas low-salt diet (0.1%) decreased urinary ACE2 activity in the urine of db/db mice. In STZ mice, urinary ACE2 was also increased, and insulin decreased it partly but significantly after several weeks of administration. The increase in urinary ACE2 activity in db/db mice reflected an increase in enzymatically active protein with two bands identified of molecular size at 110 and 75 kDa and was associated with an increase in kidney cortex ACE2 protein at 110 kDa but not at 75 kDa. ACE2 activity was increased in isolated tubular preparations but not in glomeruli from db/db mice. Administration of soluble recombinant ACE2 to db/m and db/db mice resulted in a marked increase in serum ACE2 activity, but no gain in ACE2 activity was detectable in the urine, further demonstrating that urinary ACE2 is of kidney origin. Increased urinary ACE2 was associated with more efficient degradation of exogenous ANG II (10(-9) M) in urine from db/db compared with that from db/m mice. Urinary ACE2 could be a potential biomarker of increased metabolism of ANG II in diabetic kidney disease.

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

    SciTech Connect

    Kharofa, Jordan; Cohen, Eric P.; Tomic, Rade; Xiang Qun; Gore, Elizabeth

    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

  10. ACES--Today and Tomorrow.

    ERIC Educational Resources Information Center

    Hackney, Harold

    1991-01-01

    Presents text of Presidential Address delivered March 24, 1991, at the Association for Counselor Education and Supervision (ACES) luncheon, part of the American Association for Counseling and Development Convention held in Reno, Nevada. Comments on past, present, and future of ACES, particularly on future challenges and role of ACES. (ABL)

  11. Calmodulin interacts with angiotensin-converting enzyme-2 (ACE2) and inhibits shedding of its ectodomain.

    PubMed

    Lambert, Daniel W; Clarke, Nicola E; Hooper, Nigel M; Turner, Anthony J

    2008-01-23

    Angiotensin-converting enzyme-2 (ACE2) is a regulatory protein of the renin-angiotensin system (RAS) and a receptor for the causative agent of severe-acute respiratory syndrome (SARS), the SARS-coronavirus. We have previously shown that ACE2 can be shed from the cell surface in response to phorbol esters by a process involving TNF-alpha converting enzyme (TACE; ADAM17). In this study, we demonstrate that inhibitors of calmodulin also stimulate shedding of the ACE2 ectodomain, a process at least partially mediated by a metalloproteinase. We also show that calmodulin associates with ACE2 and that this interaction is decreased by calmodulin inhibitors.

  12. Human ACE gene polymorphism and distilled water induced cough

    PubMed Central

    Morice, A. H.; Turley, A. J.; Linton, T. K.

    1997-01-01

    BACKGROUND: Inhibitors of angiotensin converting enzyme (ACE) cause a non-productive cough. The insertion/deletion polymorphism of ACE was used as a genetic marker to investigate the relationship between ACE genotype and cough sensitivity. METHODS: A double blind cough challenge was performed in 66 normotensive subjects (34 men) of mean age 34.8 years (range 18-80) using aerosols of distilled water. The number of coughs during the one minute exposure to water was recorded. DNA samples from venous blood were amplified by the polymerase chain reaction and resolved on a 1% agarose gel. They were analysed for the presence of a polymorphism in intron 16 of the ACE gene consisting of an insertion (I) or deletion (D) of an Alu repetitive sequence 287 base pairs long. RESULTS: The distribution of genotypes was 20 II, 26 ID, and 20 DD. The cough response was significantly (p < 0.01) related to the ACE genotype, the mean number of coughs being 15.8, 11.3, and 9.6, respectively, in subjects with the II, ID, and DD genotypes. CONCLUSIONS: The observation that cough challenge is dependent on ACE genotype in normal subjects is evidence of a link between ACE activity and the cough reflex. 


 PMID:9059468

  13. Effects of a novel ACE inhibitor, 3-(3-thienyl)-l-alanyl-ornithyl-proline, on endothelial vasodilation and hepatotoxicity in l-NAME-induced hypertensive rats.

    PubMed

    Seth, Mahesh Kumar; Hussain, M Ejaz; Pasha, Santosh; Fahim, Mohammad

    2016-01-01

    Nitric oxide (NO) is a widespread biological mediator involved in many physiological and pathological processes, eg, in the regulation of vascular tone and hypertension. Chronic inhibition of NO synthase by N(G)-nitro-l-arginine methyl ester (l-NAME) hydrochloride results in the development of hypertension accompanied by an increase in vascular responsiveness to adrenergic stimuli. Recently, we developed a novel sulfur-containing angiotensin-converting enzyme inhibitor: 3-(3-thienyl)-l-alanyl-ornithyl-proline (TOP). Our previous studies indicated a superior nature of the molecule as an antihypertensive agent in spontaneously hypertensive rats (showing the involvement of renin-angiotensin-aldosterone system) in comparison to captopril. The aim of the present study was to investigate the effect of TOP on NO pathway in l-NAME-induced hypertensive rats, and captopril was included as the standard treatment group. Treatment with both TOP (20 mg/kg) and captopril (40 mg/kg) prevented the development of hypertension in l-NAME model, but TOP showed better restoration of NO and normal levels of angiotensin-converting enzyme. In addition, in vitro vasorelaxation assay showed an improvement in endothelium-dependent vasodilation in both the cases. Further, the biochemical (malondialdehyde, alanine aminotransferase, and aspartate aminotransferase) and the histopathological effects of TOP on rat liver tissues revealed a protective nature of TOP in comparison to captopril in the l-NAME model. In conclusion, TOP at 50% lesser dose than captopril was found to be better in the l-NAME model.

  14. Positioning of aminopeptidase inhibitors in next generation cancer therapy.

    PubMed

    Hitzerd, Sarina M; Verbrugge, Sue Ellen; Ossenkoppele, Gert; Jansen, Gerrit; Peters, Godefridus J

    2014-04-01

    Aminopeptidases represent a class of (zinc) metalloenzymes that catalyze the cleavage of amino acids nearby the N-terminus of polypeptides, resulting in hydrolysis of peptide bonds. Aminopeptidases operate downstream of the ubiquitin-proteasome pathway and are implicated in the final step of intracellular protein degradation either by trimming proteasome-generated peptides for antigen presentation or full hydrolysis into free amino acids for recycling in renewed protein synthesis. This review focuses on the function and subcellular location of five key aminopeptidases (aminopeptidase N, leucine aminopeptidase, puromycin-sensitive aminopeptidase, leukotriene A4 hydrolase and endoplasmic reticulum aminopeptidase 1/2) and their association with different diseases, in particular cancer and their current position as target for therapeutic intervention by aminopeptidase inhibitors. Historically, bestatin was the first prototypical aminopeptidase inhibitor that entered the clinic 35 years ago and is still used for the treatment of lung cancer. More recently, new generation aminopeptidase inhibitors became available, including the aminopeptidase inhibitor prodrug tosedostat, which is currently tested in phase II clinical trials for acute myeloid leukemia. Beyond bestatin and tosedostat, medicinal chemistry has emerged with additional series of potential aminopeptidases inhibitors which are still in an early phase of (pre)clinical investigations. The expanded knowledge of the unique mechanism of action of aminopeptidases has revived interest in aminopeptidase inhibitors for drug combination regimens in anti-cancer treatment. In this context, this review will discuss relevant features and mechanisms of action of aminopeptidases and will also elaborate on factors contributing to aminopeptidase inhibitor efficacy and/or loss of efficacy due to drug resistance-related phenomena. Together, a growing body of data point to aminopeptidase inhibitors as attractive tools for

  15. Cerebrovascular Complications of Diabetes: Alpha Glucosidase Inhibitor as Potential Therapy.

    PubMed

    Patel, S S

    2016-02-01

    Increased risk of cerebrovascular accident in diabetes cannot be fully explained by traditional risk factors. Epidemiological studies show that postprandial hyperglycemia is strongly associated with cerebrovascular events and cerebrovascular-associated mortality. Postprandial hyperglycemia contributes to vascular damage by several mechanisms such as endothelial dysfunction, arthrosclerosis, oxidative stress, inflammation, and hypercoagulability. Hyperglycemia has deleterious effects on the vascular endothelium and leads to the development of cerebrovascular disease. Thus, an important strategy to reduce cerebrovascular risk in patients with diabetes is to reduce postprandial hyperglycemia. Glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and α-glucosidase inhibitors predominantly reduce postprandial plasma glucose levels. Among all of these, α-glucosidase inhibitors reduces postprandial hyperglycemia by delaying carbohydrate absorption from the intestine and this mechanism provides glycemic control without exacerbating coexisting cerebrovascular risk factors. Good glycemic control is proven to reduce the risk of cardiovascular complications, but equivalent evidence for cerebrovascular risk reduction is lacking. This review examines the evidences that postprandial hyperglycemia plays a major role in vascular damage, along with the complex interplay between hyperglycemia and coexisting risk factors. Furthermore, the mechanism by which α-glucosidase inhibitors may prevent this vascular damage as well as risk of hypoglycemia with α-glucosidase inhibitors are examined. Thus, this review suggests that α-glucosidase inhibitors are useful in reducing the risk of cerebrovascular events in patients with diabetes.

  16. Dipeptidyl peptidase-4 inhibitors as add-on therapy to insulin: rationale and evidences.

    PubMed

    Singh, Awadhesh Kumar; Singh, Ritu

    2016-01-08

    Type 2 diabetes mellitus being a progressive disease will eventually require insulin therapy. While insulin therapy is the ultimate option, many patients still fall short of target glycemic goals. This could, perhaps be due to the fear, unwillingness and practical barriers to insulin intensification. Hypoglycemia, oedema and weight gain is another limitation. Newer therapies with dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose co-transporter-2 (SGLT-2) inhibitors are exciting options as both classes do not cause hypoglycemia and are either weight neutral or cause weight loss. DPP-4 inhibitors are an appealing option as an add-on therapy to insulin especially in elderly and patients with renal impairment. Moreover, glucose-dependent insulinotropic polypeptide (GIP) mediated augmentation of glucagon by DPP-4 inhibitors could also protect against hypoglycemia. These collective properties make these class a potential add-on candidate to insulin therapy. This article will review the efficacy and safety of DPP-4 inhibitors as an add-on to insulin therapy.

  17. A possible usage of a CDK4 inhibitor for breast cancer stem cell-targeted therapy

    SciTech Connect

    Han, Yu Kyeong; Lee, Jae Ho; Park, Ga-Young; Chun, Sung Hak; Han, Jeong Yun; Kim, Sung Dae; Lee, Janet; Lee, Chang-Woo; Yang, Kwangmo; Lee, Chang Geun

    2013-01-25

    Highlights: ► A CDK4 inhibitor may be used for breast cancer stem cell-targeted therapy. ► The CDK4 inhibitor differentiated the cancer stem cell population (CD24{sup −}/CD44{sup +}) of MDA-MB-231. ► The differentiation of the cancer stem cells by the CDK4 inhibitor radiosensitized MDA-MB-231. -- Abstract: Cancer stem cells (CSCs) are one of the main reasons behind cancer recurrence due to their resistance to conventional anti-cancer therapies. Thus, many efforts are being devoted to developing CSC-targeted therapies to overcome the resistance of CSCs to conventional anti-cancer therapies and decrease cancer recurrence. Differentiation therapy is one potential approach to achieve CSC-targeted therapies. This method involves inducing immature cancer cells with stem cell characteristics into more mature or differentiated cancer cells. In this study, we found that a CDK4 inhibitor sensitized MDA-MB-231 cells but not MCF7 cells to irradiation. This difference appeared to be associated with the relative percentage of CSC-population between the two breast cancer cells. The CDK4 inhibitor induced differentiation and reduced the cancer stem cell activity of MDA-MB-231 cells, which are shown by multiple marker or phenotypes of CSCs. Thus, these results suggest that radiosensitization effects may be caused by reducing the CSC-population of MDA-MB-231 through the use of the CDK4 inhibitor. Thus, further investigations into the possible application of the CDK4 inhibitor for CSC-targeted therapy should be performed to enhance the efficacy of radiotherapy for breast cancer.

  18. p53 as an Effector or Inhibitor of Therapy Response.

    PubMed

    Ablain, Julien; Poirot, Brigitte; Esnault, Cécile; Lehmann-Che, Jacqueline; de Thé, Hugues

    2015-12-04

    Although integrity of the p53 signaling pathway in a given tumor was expected to be a critical determinant of response to therapies, most clinical studies failed to link p53 status and treatment outcome. Here, we present two opposite situations: one in which p53 is an essential effector of cure by targeted leukemia therapies and another one in advanced breast cancers in which p53 inactivation is required for the clinical efficacy of dose-dense chemotherapy. If p53 promotes or blocks therapy response, therapies must be tailored on its status in individual tumors.

  19. An additive effect of eplerenone to ACE inhibitor on slowing the progression of diabetic nephropathy in the db/db mice

    PubMed Central

    Zhou, Guangyu; Johansson, Ulrika; Peng, Xiao-Rong; Bamberg, Krister; Huang, Yufeng

    2016-01-01

    Although blockade of the renin-angiotensin-system (RAS) has become standard therapy for diabetic nephropathy (DN), decline in kidney function towards end-stage renal disease is seen in many patients. Elevated plasma aldosterone often accompanies RAS blockade by a phenomenon known as “aldosterone escape” and activates the mineralocorticoid receptor (MR). We therefore examined whether addition of the MR antagonist eplerenone to an ACEI would enhance the efficacy in slowing the progression of DN. Untreated uninephrectomized diabetic db/db mice developed progressive albuminuria and glomerulosclerosis between weeks 18 and 22, associated with decreased number of podocytes and increased renal expression of fibrotic markers. The therapeutic effect of eplerenone at 100 mg/kg BW/d on albuminuria, podocyte injury and renal fibrosis was similar to that of enalapril given alone at maximally effective doses. Adding eplerenone to enalapril resulted in further reduction in these measurements. Renal expressions of TNF-α, MCP-1, Nox2 and p47phox and renal TBARS levels, markers of inflammation and oxidative stress, were increased during disease progression in diabetic mice, which were reduced by eplerenone or enalapril given alone and further reduced by the two drugs given in combination. However, there were no treatment related effects on plasma K+. Our results suggest that eplerenone is effective in slowing the progression of DN in db/db mice and that the effect is additive to an ACEI. The addition of an MR antagonist void of effects on plasma K+ to an ACEI may offer additional renoprotection in progressive DN via blocking the effects of aldosterone due to escape or diabetes-induction. PMID:27186263

  20. Calcium channel blockers: monotherapy and dual therapy considerations in the treatment of hypertension.

    PubMed

    Sica, Domenic A

    2007-01-01

    The papers in this supplement speak to several of the issues pertinent to contemporary therapy with CCBs. The article by Dr Weir thoughtfully describes important pharmacokinetic and pharmacodynamic features of CCBs. In so doing he establishes the basis for combination CCB and ACE inhibitor therapy. Dr Frishman provides a scholarly description of the cardiovascular effects of CCBs and further elaborates on the distinctiveness of the various CCB subclasses. Finally, Dr Bakris et al. provides data from INVEST (INternational VErapamil-Trandolapril STudy), which shows the particular utility of a CCB and ACE inhibitor combination in bringing elderly hypertensive patients with CAD to goal BP when monotherapy

  1. Designing Polyamide Inhibitors of TWIST 1 for Prosenescence Therapy

    DTIC Science & Technology

    2014-09-01

    Page 1 AWARD NUMBER: W81XWH-13-1-0182 TITLE: Designing Polyamide Inhibitors of TWIST 1 for...S) 12 . DISTRIBUTION / AVAILABILITY STATEMENT Approved for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT...Pyrrole-Imidazole Polyamides ; TWIST1; KRAS; non-small cell lung cancer (NSCLC); senescence 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF

  2. Small Molecule Inhibitors of EGFR Ectodomain for Breast Cancer Therapy

    DTIC Science & Technology

    2009-08-01

    ectodomain inhibitor EL1-FD1 on cell proliferation in human breast cancer cell line MDA-MB-468. 5 mg/ml Poly(2- hydroxyethyl methacrylate ) (PolyHEMA) powder...poly- HEMA assay. The compound effectively inhibited tumor growth in mice with MDA-MB-468 xenografts and had a moderate effect in MDA-MB-231 xenografts

  3. ACEE composite structures technology

    NASA Technical Reports Server (NTRS)

    Klotzsche, M. (Compiler)

    1984-01-01

    The NASA Aircraft Energy Efficiency (ACEE) Composite Primary Aircraft Structures Program has made significant progress in the development of technology for advanced composites in commercial aircraft. Commercial airframe manufacturers have demonstrated technology readiness and cost effectiveness of advanced composites for secondary and medium primary components and have initiated a concerted program to develop the data base required for efficient application to safety-of-flight wing and fuselage structures. Oral presentations were compiled into five papers. Topics addressed include: damage tolerance and failsafe testing of composite vertical stabilizer; optimization of composite multi-row bolted joints; large wing joint demonstation components; and joints and cutouts in fuselage structure.

  4. Overview of Proteasome Inhibitor-Based Anti-cancer Therapies: Perspective on Bortezomib and Second Generation Proteasome Inhibitors versus Future Generation Inhibitors of Ubiquitin-Proteasome System

    PubMed Central

    Dou, Q. Ping; Zonder, Jeffrey A.

    2014-01-01

    Over the past ten years, proteasome inhibition has emerged as an effective therapeutic strategy for treating multiple myeloma (MM) and some lymphomas. In 2003, Bortezomib (BTZ) became the first proteasome inhibitor approved by the U.S. Food and Drug Administration (FDA). BTZ-based therapies have become a staple for the treatment of MM at all stages of the disease. The survival rate of MM patients has improved significantly since clinical introduction of BTZ and other immunomodulatory drugs. However, BTZ has several limitations. Not all patients respond to BTZ-based therapies and relapse occurs in many patients who initially responded. Solid tumors, in particular, are often resistant to BTZ. Furthermore, BTZ can induce dose-limiting peripheral neuropathy (PN). The second generation proteasome inhibitor Carfizomib (CFZ; U.S. FDA approved in August 2012) induces responses in a minority of MM patients relapsed from or refractory to BTZ. There is less PN compared to BTZ. Four other second-generation proteasome inhibitors (Ixazomib, Delanzomib, Oprozomib and Marizomib) with different pharmacologic properties and broader anticancer activities, have also shown some clinical activity in bortezomib-resistant cancers. While the mechanism of resistance to bortezomib in human cancers still remains to be fully understood, targeting the immunoproteasome, ubiquitin E3 ligases, the 19S proteasome and deubiquitinases in pre-clinical studies represents possible directions for future generation inhibitors of ubiquitin-proteasome system in the treatment of MM and other cancers. PMID:25092212

  5. Serious infection from Staphylococcus aureus in 2 HIV-infected patients receiving fusion inhibitor therapy.

    PubMed

    Gaughan, Elizabeth M; Ritter, Michelle L; Kumar, Princy N; Timpone, Joseph G

    2008-05-01

    Fusion inhibitors are novel antiretroviral agents, administered as subcutaneous injections, approved for use in treatment-experienced HIV-infected patients. HIV-infected patients are at increased risk for Staphylococcus aureus colonization, specifically with methicillin-resistant S aureus (MRSA), and subsequent systemic infection. We present the cases of 2 patients without a history of MRSA infection in whom a series of severe S aureus infections developed after fusion inhibitor therapy.

  6. Prospect of JAK2 inhibitor therapy in myeloproliferative neoplasms

    PubMed Central

    Atallah, Ehab; Verstovsek, Srdan

    2016-01-01

    The discovery of the Janus kinase (JAK)2 V617F mutation in patients with myeloproliferative neoplasms was a major milestone in understanding the biology of those disorders. Several groups simultaneously reported on the high incidence of this mutation in patients with myeloproliferative neoplasms: almost all patients with polycythemia vera harbor the mutation and about 50% of patients with essential thrombocythemia and primary myelofibrosis have the mutation, making the development of JAK2 tyrosine kinase inhibitors an attractive therapeutic goal. In addition, inhibition of JAK2 kinase may have a therapeutic role in other hematologic malignancies, such as chronic myeloid leukemia or lymphoma. A number of molecules that inhibit JAK2 kinase have been described in the literature, and several are being evaluated in a clinical setting. Here, we summarize current clinical experience with JAK2 inhibitors. PMID:19445582

  7. Cyclin Dependent Kinase 9 Inhibitors for Cancer Therapy.

    PubMed

    Sonawane, Yogesh A; Taylor, Margaret A; Napoleon, John Victor; Rana, Sandeep; Contreras, Jacob I; Natarajan, Amarnath

    2016-10-13

    Cyclin dependent kinase (CDK) inhibitors have been the topic of intense research for nearly 2 decades due to their widely varied and critical functions within the cell. Recently CDK9 has emerged as a druggable target for the development of cancer therapeutics. CDK9 plays a crucial role in transcription regulation; specifically, CDK9 mediated transcriptional regulation of short-lived antiapoptotic proteins is critical for the survival of transformed cells. Focused chemical libraries based on a plethora of scaffolds have resulted in mixed success with regard to the development of selective CDK9 inhibitors. Here we review the regulation of CDK9, its cellular functions, and common core structures used to target CDK9, along with their selectivity profile and efficacy in vitro and in vivo.

  8. Patients With Newly Diagnosed Hypertension Treated With the Renin Angiotensin Receptor Blocker Azilsartan Medoxomil vs Angiotensin-Converting Enzyme Inhibitors: The Prospective EARLY Registry.

    PubMed

    Schmieder, Roland E; Potthoff, Sebastian A; Bramlage, Peter; Baumgart, Peter; Mahfoud, Felix; Buhck, Hartmut; Ouarrak, Taoufik; Ehmen, Martina; Senges, Jochen; Gitt, Anselm K

    2015-12-01

    For patients with newly diagnosed hypertension, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are usually the first-line therapies. There is, however, no real-life data regarding the relative clinical effectiveness and tolerability of either drug class. The prospective registry, Treatment With Azilsartan Compared to ACE Inhibitors in Antihypertensive Therapy (EARLY), was conducted to evaluate the effectiveness of the ARB azilsartan medoxomil (AZL-M) vs ACE inhibitors in real-world patients. Of the 1153 patients with newly diagnosed hypertension who were included in the registry, 789 were prescribed AZL-M and 364 were prescribed an ACE inhibitor. After multivariate adjustment, AZL-M was found to provide superior blood pressure reduction and better target blood pressure (<140/90 mm Hg) achievement. The proportion of patients with adverse events was not statistically different between groups. The authors conclude that in newly diagnosed hypertensive patients, AZL-M provides superior blood pressure control with a similar safety profile compared with ACE inhibitors.

  9. Effects of Incretin-Based Therapies and SGLT2 Inhibitors on Skeletal Health.

    PubMed

    Egger, Andrea; Kraenzlin, Marius E; Meier, Christian

    2016-12-01

    Anti-diabetic drugs are widely used and are essential for adequate glycemic control in patients with type 2 diabetes. Recently, marketed anti-diabetic drugs include incretin-based therapies (GLP-1 receptor agonists and DPP-4 inhibitors) and sodium-glucose co-transporter 2 (SGLT2) inhibitors. In contrast to well-known detrimental effects of thiazolidinediones on bone metabolism and fracture risk, clinical data on the safety of incretin-based therapies is limited. Based on meta-analyses of trials investigating the glycemic-lowering effect of GLP-1 receptor agonists and DPP4 inhibitors, it seems that incretin-based therapies are not associated with an increase in fracture risk. Sodium-glucose co-transporter 2 inhibitors may alter calcium and phosphate homeostasis as a result of secondary hyperparathyroidism induced by increased phosphate reabsorption. Although these changes may suggest detrimental effects of SGLT-2 inhibitors on skeletal integrity, treatment-related direct effects on bone metabolism seem unlikely. Observed changes in BMD, however, seem to result from increased bone turnover in the early phase of drug-induced weight loss. Fracture risk, which is observed in older patients with impaired renal function and elevated cardiovascular disease risk treated with SGLT2 inhibitors, seems to be independent of direct effects on bone but more likely to be associated with falls and changes in hydration status secondary to osmotic diuresis.

  10. Therapy with JAK2 inhibitors for Myeloproliferative Neoplasms

    PubMed Central

    Santos, Fabio P. S.; Verstovsek, Srdan

    2015-01-01

    The development of JAK2 inhibitors followed the discovery of activating mutation of JAK2 (JAK2V617F) in patients with classic Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPNs). It is now known that mutations activating the JAK-STAT pathway are ubiquitous in Ph-negative MPNs, and that deregulated JAK-STAT pathway plays a central role in the pathogenesis of these disorders. JAK2 inhibitors thus are effective in both patients with and without the JAK2V617F mutation. Clinical trials conducted in patients with myelofibrosis have demonstrated that these drugs lead to substantial improvements in systemic symptoms, splenomegaly, leukocytosis and thrombocytosis. Results of one randomized clinical trial suggest that JAK2 inhibition may also lead to improved survival. There are still significant challenges to be overcome, as these drugs do not improve bone marrow fibrosis and do not lead to significant reduction in the allele burden of JAK2V617F. In this manuscript we review the rationale for using JAK2 inhibitors in Ph-negative MPNs and results of more recent clinical trials with these drugs. PMID:23009939

  11. Improving L-dopa therapy: the development of enzyme inhibitors.

    PubMed

    Gershanik, Oscar S

    2015-01-01

    The introduction of levodopa produced a monumental change in the treatment of Parkinson's disease (PD). Limitations in its bioavailability and tolerability led to the search for drugs that could improve its pharmacokinetics and safety profile. Dopa-decarboxylase inhibitors were the first such drugs that were developed, and their use in combination with L-dopa has become standard practice. Increasing knowledge on the metabolism of L-dopa allowed the identification of additional targets for intervention in an attempt to improve the symptomatic efficacy of L-dopa. Monoamineoxidase inhibitors, enhancing the central bioavailability of dopamine by blocking its metabolism, were the next step, and despite controversies regarding their efficacy, they have remained as valuable adjuncts to l-dopa in the treatment of PD. More recently, the introduction of potent, selective catechol-O-methyl transferase inhibitors have found their place in the therapeutic armamentarium of PD and are prescribed in combination with l-dopa to prolong the duration of its action.

  12. ACES's Challenges: Past Presidents Comment.

    ERIC Educational Resources Information Center

    Sheeley, Vernon Lee

    1990-01-01

    Recognizes the golden anniversary of the Association for Counselor Education and Supervision (ACES) and presents the statements of 15 past presidents of the association. Presidential leaders briefly review the association's past and suggest opportunities to help create a promising future for ACES. Outlines nine challenges which confront members of…

  13. FIRE_ACE_SHIP_SSFR

    Atmospheric Science Data Center

    2015-10-28

    FIRE_ACE_SHIP_SSFR Project Title:  FIRE III ACE Discipline:  ... Level:  L3 Platform:  SHEBA Ship Instrument:  Solar Spectral Flux Radiometer ... Info:  Surface Heat Budget of the Arctic Ocean (SHEBA) Ship SCAR-B Block:  SCAR-B Products ...

  14. FIRE_ACE_UTRECHT_TOWER

    Atmospheric Science Data Center

    2015-10-28

    FIRE_ACE_UTRECHT_TOWER Project Title:  FIRE II ACE Discipline:  ... L3 Platform:  SHEBA Ship Site; Meteorological tower Instrument:  Eppley precision pyrgeometers Meteorological tower Spatial Coverage:  Fairbanks, Alaska and the surrounding ...

  15. SGLT2 inhibitor/DPP-4 inhibitor combination therapy - complementary mechanisms of action for management of type 2 diabetes mellitus.

    PubMed

    Dey, Jayant

    2017-04-03

    Type 2 diabetes mellitus is a progressive disease with multiple underlying pathophysiologic defects. Monotherapy alone cannot maintain glycemic control and leads to treatment failure. Ideally, a combination of glucose-lowering agents should have complementary mechanisms of action that address multiple pathophysiologic pathways, can be used at all stages of the disease, and be generally well tolerated with no increased risk of hypoglycemia, cardiovascular events, or weight gain. The combination should also provide conveniences for patients, such as oral dosing, single-pill formulations, and once-daily administration, potentially translating to improved adherence. Two classes of glucose-lowering agents that meet these criteria are the sodium glucose cotransporter-2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors. This article reviews the rationale for combination therapy with these agents, and evidence from clinical trials with empagliflozin and linagliptin or dapagliflozin and saxagliptin in the management of type 2 diabetes mellitus. Both combinations have been approved as single-pill formulations.

  16. New Perspectives in the Renin-Angiotensin-Aldosterone System (RAAS) II: Albumin Suppresses Angiotensin Converting Enzyme (ACE) Activity in Human

    PubMed Central

    Fagyas, Miklós; Úri, Katalin; Siket, Ivetta M.; Fülöp, Gábor Á.; Csató, Viktória; Daragó, Andrea; Boczán, Judit; Bányai, Emese; Szentkirályi, István Elek; Maros, Tamás Miklós; Szerafin, Tamás; Édes, István; Papp, Zoltán; Tóth, Attila

    2014-01-01

    About 8% of the adult population is taking angiotensin-converting enzyme (ACE) inhibitors to treat cardiovascular disease including hypertension, myocardial infarction and heart failure. These drugs decrease mortality by up to one-fifth in these patients. We and others have reported previously that endogenous inhibitory substances suppress serum ACE activity, in vivo, similarly to the ACE inhibitor drugs. Here we have made an effort to identify this endogenous ACE inhibitor substance. ACE was crosslinked with interacting proteins in human sera. The crosslinked products were immunoprecipitated and subjected to Western blot. One of the crosslinked products was recognized by both anti-ACE and anti-HSA (human serum albumin) antibodies. Direct ACE-HSA interaction was confirmed by binding assays using purified ACE and HSA. HSA inhibited human purified (circulating) and human recombinant ACE with potencies (IC50) of 5.7±0.7 and 9.5±1.1 mg/mL, respectively. Effects of HSA on the tissue bound native ACE were tested on human saphenous vein samples. Angiotensin I evoked vasoconstriction was inhibited by HSA in this vascular tissue (maximal force with HSA: 6.14±1.34 mN, without HSA: 13.54±2.63 mN), while HSA was without effects on angiotensin II mediated constrictions (maximal force with HSA: 18.73±2.17 mN, without HSA: 19.22±3.50 mN). The main finding of this study is that HSA was identified as a potent physiological inhibitor of the ACE. The enzymatic activity of ACE appears to be almost completely suppressed by HSA when it is present in its physiological concentration. These data suggest that angiotensin I conversion is limited by low physiological ACE activities, in vivo. PMID:24691203

  17. Angiogenesis inhibitors in cancer therapy: mechanistic perspective on classification and treatment rationales.

    PubMed

    El-Kenawi, Asmaa E; El-Remessy, Azza B

    2013-10-01

    Angiogenesis, a process of new blood vessel formation, is a prerequisite for tumour growth to supply the proliferating tumour with oxygen and nutrients. The angiogenic process may contribute to tumour progression, invasion and metastasis, and is generally accepted as an indicator of tumour prognosis. Therefore, targeting tumour angiogenesis has become of high clinical relevance. The current review aimed to highlight mechanistic details of anti-angiogenic therapies and how they relate to classification and treatment rationales. Angiogenesis inhibitors are classified into either direct inhibitors that target endothelial cells in the growing vasculature or indirect inhibitors that prevent the expression or block the activity of angiogenesis inducers. The latter class extends to include targeted therapy against oncogenes, conventional chemotherapeutic agents and drugs targeting other cells of the tumour micro-environment. Angiogenesis inhibitors may be used as either monotherapy or in combination with other anticancer drugs. In this context, many preclinical and clinical studies revealed higher therapeutic effectiveness of the combined treatments compared with individual treatments. The proper understanding of synergistic treatment modalities of angiogenesis inhibitors as well as their wide range of cellular targets could provide effective tools for future therapies of many types of cancer.

  18. Angiogenesis inhibitors in cancer therapy: mechanistic perspective on classification and treatment rationales

    PubMed Central

    El-Kenawi, Asmaa E; El-Remessy, Azza B

    2013-01-01

    Angiogenesis, a process of new blood vessel formation, is a prerequisite for tumour growth to supply the proliferating tumour with oxygen and nutrients. The angiogenic process may contribute to tumour progression, invasion and metastasis, and is generally accepted as an indicator of tumour prognosis. Therefore, targeting tumour angiogenesis has become of high clinical relevance. The current review aimed to highlight mechanistic details of anti-angiogenic therapies and how they relate to classification and treatment rationales. Angiogenesis inhibitors are classified into either direct inhibitors that target endothelial cells in the growing vasculature or indirect inhibitors that prevent the expression or block the activity of angiogenesis inducers. The latter class extends to include targeted therapy against oncogenes, conventional chemotherapeutic agents and drugs targeting other cells of the tumour micro-environment. Angiogenesis inhibitors may be used as either monotherapy or in combination with other anticancer drugs. In this context, many preclinical and clinical studies revealed higher therapeutic effectiveness of the combined treatments compared with individual treatments. The proper understanding of synergistic treatment modalities of angiogenesis inhibitors as well as their wide range of cellular targets could provide effective tools for future therapies of many types of cancer. PMID:23962094

  19. Dynamics of ADAM17-Mediated Shedding of ACE2 Applied to Pancreatic Islets of Male db/db Mice

    PubMed Central

    Pedersen, Kim Brint; Chodavarapu, Harshita; Porretta, Constance; Robinson, Leonie K.

    2015-01-01

    Angiotensin-converting enzyme 2 (ACE2) gene therapy aimed at counteracting pancreatic ACE2 depletion improves glucose regulation in two diabetic mouse models: db/db mice and angiotensin II-infused mice. A disintegrin and metalloproteinase 17 (ADAM17) can cause shedding of ACE2 from the cell membrane. The aim of our studies was to determine whether ADAM17 depletes ACE2 levels in pancreatic islets and β-cells. Dynamics of ADAM17-mediated ACE2 shedding were investigated in 832/13 insulinoma cells. Within a wide range of ACE2 expression levels, including the level observed in mouse pancreatic islets, overexpression of ADAM17 increases shed ACE2 and decreases cellular ACE2 levels. We provide a mathematical description of shed and cellular ACE2 activities as a function of the ADAM17 activity. The effect of ADAM17 on the cellular ACE2 content was relatively modest with an absolute control strength value less than 0.25 and approaching 0 at low ADAM17 activities. Although we found that ADAM17 and ACE2 are both expressed in pancreatic islets, the β-cell is not the major cell type expressing ACE2 in islets. During diabetes progression in 8-, 12-, and 15-week-old db/db mice, ACE2 mRNA and ACE2 activity levels in pancreatic islets were not decreased over time nor significantly decreased compared with nondiabetic db/m mice. Levels of ADAM17 mRNA and ADAM17 activity were also not significantly changed. Inhibiting basal ADAM17 activity in mouse islets failed to affect ACE2 levels. We conclude that whereas ADAM17 has the ability to shed ACE2, ADAM17 does not deplete ACE2 from pancreatic islets in diabetic db/db mice. PMID:26441236

  20. Using combination therapy to override stromal-mediated chemoresistance in mutant FLT3-positive AML: Synergism between FLT3 inhibitors, dasatinib/multi-targeted inhibitors, and JAK inhibitors

    PubMed Central

    Weisberg, Ellen; Liu, Qingsong; Nelson, Erik; Kung, Andrew L.; Christie, Amanda L.; Bronson, Rod; Sattler, Martin; Sanda, Takaomi; Zhao, Zheng; Hur, Wooyoung; Mitsiades, Constantine; Smith, Robert; Daley, John F.; Stone, Richard; Galinsky, Ilene; Griffin, James D.; Gray, Nathanael

    2014-01-01

    Acute myeloid leukemia (AML) progenitors are frequently characterized by activating mutations in the receptor tyrosine kinase FLT3. Protein tyrosine kinases are integral components of signaling cascades that play a role in both FLT3-mediated transformation as well as viability pathways that are advantageous to leukemic cell survival. The bone marrow microenvironment can diminish AML sensitivity to tyrosine kinase inhibitors (TKIs). We hypothesized that inhibition of protein kinases in addition to FLT3 may be effective in overriding drug resistance in AML. We used a cell-based model mimicking stromal protection as part of an unbiased high-throughput chemical screen to identify kinase inhibitors with the potential to override microenvironment-mediated drug resistance in mutant FLT3-positive AML. Several related multi-targeted kinase inhibitors, including dasatinib, with the capability of reversing microenvironment-induced resistance to FLT3 inhibition were identified and validated. We validated synergy in vitro and demonstrated effective combination potential in vivo. In particular Janus kinase (JAK) inhibitors were effective in overriding stromal protection and potentiating FLT3 inhibition in primary AML and cell lines. These results hint at a novel concept of using combination therapy to override drug resistance in mutant FLT3-positive AML in the bone marrow niche and suppress or eradicate residual disease. PMID:22469781

  1. The Clinical Development of Thalidomide as an Angiogenesis Inhibitor Therapy for Prostate Cancer

    DTIC Science & Technology

    2006-10-01

    AD_________________ Award Number: DAMD17-01-1-0069 TITLE: The Clinical Development of Thalidomide ...Development of Thalidomide as an Angiogenesis Inhibitor Therapy for Prostate Cancer 5b. GRANT NUMBER DAMD17-01-1-0069 5c. PROGRAM ELEMENT NUMBER 6...implicated in stromal epithelial interaction and have demonstrated that they are expressed in the context of Thalidomide treated patients. This

  2. Plant Protease Inhibitors in Therapeutics-Focus on Cancer Therapy

    PubMed Central

    Srikanth, Sandhya; Chen, Zhong

    2016-01-01

    Plants are known to have many secondary metabolites and phytochemical compounds which are highly explored at biochemical and molecular genetics level and exploited enormously in the human health care sector. However, there are other less explored small molecular weight proteins, which inhibit proteases/proteinases. Plants are good sources of protease inhibitors (PIs) which protect them against diseases, insects, pests, and herbivores. In the past, proteinaceous PIs were considered primarily as protein-degrading enzymes. Nevertheless, this view has significantly changed and PIs are now treated as very important signaling molecules in many biological activities such as inflammation, apoptosis, blood clotting and hormone processing. In recent years, PIs have been examined extensively as therapeutic agents, primarily to deal with various human cancers. Interestingly, many plant-based PIs are also found to be effective against cardiovascular diseases, osteoporosis, inflammatory diseases and neurological disorders. Several plant PIs are under further evaluation in in vitro clinical trials. Among all types of PIs, Bowman-Birk inhibitors (BBI) have been studied extensively in the treatment of many diseases, especially in the field of cancer prevention. So far, crops such as beans, potatoes, barley, squash, millet, wheat, buckwheat, groundnut, chickpea, pigeonpea, corn, and pineapple have been identified as good sources of PIs. The PI content of such foods has a significant influence on human health disorders, particularly in the regions where people mostly depend on these kind of foods. These natural PIs vary in concentration, protease specificity, heat stability, and sometimes several PIs may be present in the same species or tissue. However, it is important to carry out individual studies to identify the potential effects of each PI on human health. PIs in plants make them incredible sources to determine novel PIs with specific pharmacological and therapeutic effects due

  3. Plant Protease Inhibitors in Therapeutics-Focus on Cancer Therapy.

    PubMed

    Srikanth, Sandhya; Chen, Zhong

    2016-01-01

    Plants are known to have many secondary metabolites and phytochemical compounds which are highly explored at biochemical and molecular genetics level and exploited enormously in the human health care sector. However, there are other less explored small molecular weight proteins, which inhibit proteases/proteinases. Plants are good sources of protease inhibitors (PIs) which protect them against diseases, insects, pests, and herbivores. In the past, proteinaceous PIs were considered primarily as protein-degrading enzymes. Nevertheless, this view has significantly changed and PIs are now treated as very important signaling molecules in many biological activities such as inflammation, apoptosis, blood clotting and hormone processing. In recent years, PIs have been examined extensively as therapeutic agents, primarily to deal with various human cancers. Interestingly, many plant-based PIs are also found to be effective against cardiovascular diseases, osteoporosis, inflammatory diseases and neurological disorders. Several plant PIs are under further evaluation in in vitro clinical trials. Among all types of PIs, Bowman-Birk inhibitors (BBI) have been studied extensively in the treatment of many diseases, especially in the field of cancer prevention. So far, crops such as beans, potatoes, barley, squash, millet, wheat, buckwheat, groundnut, chickpea, pigeonpea, corn, and pineapple have been identified as good sources of PIs. The PI content of such foods has a significant influence on human health disorders, particularly in the regions where people mostly depend on these kind of foods. These natural PIs vary in concentration, protease specificity, heat stability, and sometimes several PIs may be present in the same species or tissue. However, it is important to carry out individual studies to identify the potential effects of each PI on human health. PIs in plants make them incredible sources to determine novel PIs with specific pharmacological and therapeutic effects due

  4. Alternative Agents in Type 1 Diabetes in Addition to Insulin Therapy: Metformin, Alpha-Glucosidase Inhibitors, Pioglitazone, GLP-1 Agonists, DPP-IV Inhibitors, and SGLT-2 Inhibitors.

    PubMed

    DeGeeter, Michelle; Williamson, Bobbie

    2016-04-01

    Insulin is the mainstay of current treatment for patients with type 1 diabetes mellitus (T1DM). Due to increasing insulin resistance, insulin doses are often continually increased, which may result in weight gain for patients. Medications currently approved for the treatment of type 2 diabetes offer varying mechanisms of action that can help to reduce insulin resistance and prevent or deter weight gain. A MEDLINE search was conducted to review literature evaluating the use of metformin, alpha-glucosidase inhibitors, pioglitazone, glucagon-like peptide 1 agonists, dipeptidyl peptidase, and sodium-dependent glucose transporter 2 inhibitors, in patients with T1DM. Varying results were found with some benefits including reductions in hemoglobin A1c, decreased insulin doses, and favorable effects on weight. Of significance, a common fear of utilizing multiple therapies for diabetes treatment is the risk of hypoglycemia, and this review displayed limited evidence of hypoglycemia with multiple agents.

  5. Chelation: a fundamental mechanism of action of AGE inhibitors, AGE breakers, and other inhibitors of diabetes complications.

    PubMed

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

    2012-03-01

    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 cardiovascular and renal disease. We conclude that chronic, low-dose chelation therapy deserves serious consideration as a clinical tool for prevention and treatment of diabetes complications.

  6. DNA methyltransferase-1 inhibitors as epigenetic therapy for cancer.

    PubMed

    Singh, Varinder; Sharma, Prince; Capalash, Neena

    2013-05-01

    DNA methylation is an epigenetic modification involved in gene expression regulation. In cancer, the DNA methylation pattern becomes aberrant, causing an array of tumor suppressor genes to undergo promoter hypermethylation and become transcriptionally silent. Reexpression of methylation silenced tumor suppressor genes by inhibiting the DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B) has emerged as an effective strategy against cancer. The expression of DNA methyltransferase 1 (DNMT1) being high in S-phase of cell cycle makes it a specific target for methylation inhibition in rapidly dividing cells as in cancer. This review discusses nucleoside analogues (azacytidine, decitabine, zebularine, SGI-110, CP-4200), non-nucleoside ihibitors both synthetic (hydralazine, RG108, procaine, procainamide, IM25, disulfiram) and natural compounds (curcumin, genistein, EGCG, resveratrol, equol, parthenolide) which act through different mechanisms to inhibit DNMTs. The issues of bioavailability, toxicity, side effects, hypomethylation resistance and combinatorial therapies have also been highlighted.

  7. Atmospheric Constituent Explorer System (ACES)

    NASA Astrophysics Data System (ADS)

    Darrach, M. R.; Madzunkov, S.; Neidholdt, E.; Simcic, J.

    2016-10-01

    We report on the Atmospheric Constituent Explorer System (ACES), a mass spectrometer based instrument for atmospheric probe missions (e.g. Venus and ice giant) that can determine abundances and isotopic ratios of the noble-gases and trace species.

  8. ACE3 Draft Indicators: Health

    EPA Pesticide Factsheets

    The page information was provided by EPA in conjunction with the opportunity for public comment on the draft indicators for ACE3, which ran from March 8 – April 21, 2011. The public comment period is now closed.

  9. ACE3 Draft Indicators: Biomonitoring

    EPA Pesticide Factsheets

    The page information was provided by EPA in conjunction with the opportunity for public comment on the draft indicators for ACE3, which ran from March 8 – April 21, 2011. The public comment period is now closed.

  10. Options for combination therapy in type 2 diabetes: comparison of the ADA/EASD position statement and AACE/ACE algorithm.

    PubMed

    Bailey, Timothy

    2013-09-01

    Treating patients with diabetes is one of the most challenging and important activities a physician (primary care physician or specialist) can undertake. A key to successful therapy for type 2 diabetes is the insight that this condition is progressive and that the need for additional agents over time is normative. The ability to individualize therapy by patient and medication characteristics comes from experience and knowledge of pertinent clinical studies. However, guidelines from expert bodies such as the American Diabetes Association/European Association for the Study of Diabetes and American Association of Clinical Endocrinologists/American College of Endocrinology can help clinicians of all levels of expertise to approach therapy choices more rationally. There is unity across these guidelines about the role and benefits of metformin as first-line pharmacological treatment, probability of good efficacy, low risk of hypoglycemia, modest weight loss, and overall long-term data. Unfortunately, this unity does not extend to recommendations for subsequent pharmacological agents and their use in combination to intensify treatment when insulin is not (yet) appropriate. Across both statements, some drug classes seem more prominent, and looking at their benefit-risk profile, it is clear why this is the case. The most profound recent change in diabetes therapy has been the introduction of incretin therapies. Incretin therapies minimize 2 important adverse effects seen with many other therapies: hypoglycemia and weight gain. These agents have increased the range of options available for early intensification of treatment of type 2 diabetes. In combination with more established therapies, there are more opportunities than ever to accommodate patient preferences while improving glycemic control and harnessing extraglycemic benefits of a second (or third) agent.

  11. Small-molecule inhibitors of the receptor tyrosine kinases: promising tools for targeted cancer therapies.

    PubMed

    Hojjat-Farsangi, Mohammad

    2014-08-08

    Chemotherapeutic and cytotoxic drugs are widely used in the treatment of cancer. In spite of the improvements in the life quality of patients, their effectiveness is compromised by several disadvantages. This represents a demand for developing new effective strategies with focusing on tumor cells and minimum side effects. Targeted cancer therapies and personalized medicine have been defined as a new type of emerging treatments. Small molecule inhibitors (SMIs) are among the most effective drugs for targeted cancer therapy. The growing number of approved SMIs of receptor tyrosine kinases (RTKs) i.e., tyrosine kinase inhibitors (TKIs) in the clinical oncology imply the increasing attention and application of these therapeutic tools. Most of the current approved RTK-TKIs in preclinical and clinical settings are multi-targeted inhibitors with several side effects. Only a few specific/selective RTK-TKIs have been developed for the treatment of cancer patients. Specific/selective RTK-TKIs have shown less deleterious effects compared to multi-targeted inhibitors. This review intends to highlight the importance of specific/selective TKIs for future development with less side effects and more manageable agents. This article provides an overview of: (1) the characteristics and function of RTKs and TKIs; (2) the recent advances in the improvement of specific/selective RTK-TKIs in preclinical or clinical settings; and (3) emerging RTKs for targeted cancer therapies by TKIs.

  12. Hsp90 inhibitor as a sensitizer of cancer cells to different therapies (review).

    PubMed

    Solárová, Zuzana; Mojžiš, Ján; Solár, Peter

    2015-03-01

    Hsp90 is a molecular chaperone that maintains the structural and functional integrity of various client proteins involved in signaling and many other functions of cancer cells. The natural inhibitors, ansamycins influence the Hsp90 chaperone function by preventing its binding to client proteins and resulting in their proteasomal degradation. N- and C-terminal inhibitors of Hsp90 and their analogues are widely tested as potential anticancer agents in vitro, in vivo as well as in clinical trials. It seems that Hsp90 competitive inhibitors target different tumor types at nanomolar concentrations and might have therapeutic benefit. On the contrary, some Hsp90 inhibitors increased toxicity and resistance of cancer cells induced by heat shock response, and through the interaction of survival signals, that occured as side effects of treatments, could be very effectively limited via combination of therapies. The aim of our review was to collect the data from experimental and clinical trials where Hsp90 inhibitor was combined with other therapies in order to prevent resistance as well as to potentiate the cytotoxic and/or antiproliferative effects.

  13. Proteasome inhibitors in cancer therapy: Treatment regimen and peripheral neuropathy as a side effect.

    PubMed

    Kaplan, Gulce Sari; Torcun, Ceyda Corek; Grune, Tilman; Ozer, Nesrin Kartal; Karademir, Betul

    2017-02-01

    Proteasomal system plays an important role in protein turnover, which is essential for homeostasis of cells. Besides degradation of oxidized proteins, it is involved in the regulation of many different signaling pathways. These pathways include mainly cell differentiation, proliferation, apoptosis, transcriptional activation and angiogenesis. Thus, proteasomal system is a crucial target for treatment of several diseases including neurodegenerative diseases, cystic fibrosis, atherosclerosis, autoimmune diseases, diabetes and cancer. Over the last fifteen years, proteasome inhibitors have been tested to highlight their mechanisms of action and used in the clinic to treat different types of cancer. Proteasome inhibitors are mainly used in combinational therapy along with classical chemo-radiotherapy. Several studies have proved their significant effects but serious side effects such as peripheral neuropathy, limits their use in required effective doses. Recent studies focus on peripheral neuropathy as the primary side effect of proteasome inhibitors. Therefore, it is important to delineate the underlying mechanisms of peripheral neuropathy and develop new inhibitors according to obtained data. This review will detail the role of proteasome inhibition in cancer therapy and development of peripheral neuropathy as a side effect. Additionally, new approaches to prevent treatment-limiting side effects will be discussed in order to help researchers in developing effective strategies to overcome side effects of proteasome inhibitors.

  14. Indoleamine 2,3-dioxygenase attenuates inhibitor development in gene-therapy-treated hemophilia A mice.

    PubMed

    Liu, L; Liu, H; Mah, C; Fletcher, B S

    2009-06-01

    A serious impediment to gene and protein replacement therapy in hemophilia A is the development of inhibitors. Mechanisms responsible for inhibitor development include T-cell-dependent adaptive immune responses and the CD28-B7 signaling pathway that eventually leads to the formation of antibodies directed against factor VIII (FVIII). Indoleamine 2,3-dioxygenase (IDO) is a potent immunosuppressive enzyme that can inhibit T-cell responses and induce T-cell apoptosis by regulation of tryptophan metabolism. Kynurenine, one of the metabolites of tryptophan, has been implicated as an immune modulator. Here we hypothesize that co-delivery of the genes for FVIII and IDO can attenuate inhibitor formation. Using transposon-based gene delivery, we observed long-term therapeutic FVIII expression and significantly reduced inhibitor titers when the genes were co-delivered. Co-expression of FVIII and IDO in the liver was associated with increased plasma kynurenine levels, an inhibition of T-cell infiltration and increased apoptosis of T cells within the liver. These experiments suggest that modulation of tryptophan catabolism through IDO expression provides a novel strategy to reduce inhibitor development in hemophilia gene/protein therapy.

  15. HDAC inhibitors as cognitive enhancers in fear, anxiety and trauma therapy: where do we stand?

    PubMed Central

    Whittle, Nigel; Singewald, Nicolas

    2014-01-01

    A novel strategy to treat anxiety and fear-related disorders such as phobias, panic and PTSD (post-traumatic stress disorder) is combining CBT (cognitive behavioural therapy), including extinction-based exposure therapy, with cognitive enhancers. By targeting and boosting mechanisms underlying learning, drug development in this field aims at designing CBT-augmenting compounds that help to overcome extinction learning deficits, promote long-term fear inhibition and thus support relapse prevention. Progress in revealing the role of epigenetic regulation of specific genes associated with extinction memory generation has opened new avenues in this direction. The present review examines recent evidence from pre-clinical studies showing that increasing histone acetylation, either via genetic or pharmacological inhibition of HDACs (histone deacetylases) by e.g. vorinostat/SAHA (suberoylanilide hydroxamic acid), entinostat/MS-275, sodium butyrate, TSA (trichostatin A) or VPA (valproic acid), or by targeting HATs (histone acetyltransferases), augments fear extinction and, importantly, generates a long-term extinction memory that can protect from return of fear phenomena. The molecular mechanisms and pathways involved including BDNF (brain-derived neurotrophic factor) and NMDA (N-methyl-D-aspartate) receptor signalling are just beginning to be revealed. First studies in healthy humans are in support of extinction-facilitating effects of HDAC inhibitors. Very recent evidence that HDAC inhibitors can rescue deficits in extinction-memory-impaired rodents indicates a potential clinical utility of this approach also for exposure therapy-resistant patients. Important future work includes investigation of the long-term safety aspects of HDAC inhibitor treatment, as well as design of isotype(s)-specific inhibitors. Taken together, HDAC inhibitors display promising potential as pharmacological adjuncts to augment the efficacy of exposure-based approaches in anxiety and trauma therapy

  16. Therapy of Experimental NASH and Fibrosis with Galectin Inhibitors

    PubMed Central

    Traber, Peter G.; Zomer, Eliezer

    2013-01-01

    Non-alcoholic steatohepatitis (NASH) and resultant liver fibrosis is a major health problem without effective therapy. Some data suggest that galectin-3 null mice are resistant to the development of NASH with fibrosis. We examined the ability of two complex carbohydrate drugs that bind galectin-3, GM-CT-01 and GR-MD-02, to treat NASH with fibrosis in a murine model. GR-MD-02 treatment resulted in marked improvement in liver histology with significant reduction in NASH activity and collagen deposition. Treatments seemed also to improve both glomerulopathy and interstitial fibrosis observed in kidneys. The improvement in liver histology was evident when animals were treated early in disease or after establishment of liver fibrosis. In all measures, GM-CT-01 had an intermediate effect between vehicle and GR-MD-02. Galectin-3 protein expression was increased in NASH with highest expression in macrophages surrounding lipid laden hepatocytes, and reduced following treatment with GR-MD-02, while the number of macrophages was unchanged. Treatment with GR-MD-02 also reduced the expression of pathological indicators including iNOS, an important TH1 inflammatory mediator, CD36, a scavenger receptor for lipoproteins on macrophages, and α-smooth muscle actin, a marker for activated stellate cells which are the primary collagen producing cells in liver fibrosis. We conclude that treatment with these galectin-3 targeting drugs improved histopathological findings of NASH and markedly reduced fibrosis in a murine model of NASH. While the mechanisms require further investigation, the treatment effect is associated with a reduction of galectin-3 expressed by activated macrophages which was associated with regression of NASH, including hepatocellular fat accumulation, hepatocyte ballooning, intra-portal and intra-lobular inflammatory infiltrate, and deposition of collagen. Similar effects were found with GM-CT-01, but with approximately four-fold lower potency than GR-MD-02. The

  17. Therapy of experimental NASH and fibrosis with galectin inhibitors.

    PubMed

    Traber, Peter G; Zomer, Eliezer

    2013-01-01

    Non-alcoholic steatohepatitis (NASH) and resultant liver fibrosis is a major health problem without effective therapy. Some data suggest that galectin-3 null mice are resistant to the development of NASH with fibrosis. We examined the ability of two complex carbohydrate drugs that bind galectin-3, GM-CT-01 and GR-MD-02, to treat NASH with fibrosis in a murine model. GR-MD-02 treatment resulted in marked improvement in liver histology with significant reduction in NASH activity and collagen deposition. Treatments seemed also to improve both glomerulopathy and interstitial fibrosis observed in kidneys. The improvement in liver histology was evident when animals were treated early in disease or after establishment of liver fibrosis. In all measures, GM-CT-01 had an intermediate effect between vehicle and GR-MD-02. Galectin-3 protein expression was increased in NASH with highest expression in macrophages surrounding lipid laden hepatocytes, and reduced following treatment with GR-MD-02, while the number of macrophages was unchanged. Treatment with GR-MD-02 also reduced the expression of pathological indicators including iNOS, an important TH1 inflammatory mediator, CD36, a scavenger receptor for lipoproteins on macrophages, and α-smooth muscle actin, a marker for activated stellate cells which are the primary collagen producing cells in liver fibrosis. We conclude that treatment with these galectin-3 targeting drugs improved histopathological findings of NASH and markedly reduced fibrosis in a murine model of NASH. While the mechanisms require further investigation, the treatment effect is associated with a reduction of galectin-3 expressed by activated macrophages which was associated with regression of NASH, including hepatocellular fat accumulation, hepatocyte ballooning, intra-portal and intra-lobular inflammatory infiltrate, and deposition of collagen. Similar effects were found with GM-CT-01, but with approximately four-fold lower potency than GR-MD-02. The

  18. Pharmacokinetic Characteristics and Clinical Efficacy of an SGLT2 Inhibitor Plus DPP-4 Inhibitor Combination Therapy in Type 2 Diabetes.

    PubMed

    Scheen, André J

    2016-12-30

    Type 2 diabetes (T2D) generally requires a combination of several pharmacological approaches to control hyperglycaemia. Combining a sodium-glucose cotransporter type 2 inhibitor (SGLT2I, also known as gliflozin) and a dipeptidyl peptidase-4 inhibitor (DPP-4I, also known as gliptin) appears to be an attractive strategy because of complementary modes of action. This narrative review analyzes the pharmacokinetics and clinical efficacy of different combined therapies with an SGLT2I (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, tofogliflozin) and DPP-4I (linagliptin, saxagliptin, sitagliptin, teneligliptin). Drug-drug pharmacokinetic interaction studies do not show any significant changes in peak concentrations (C max) and total exposure (area under the curve of plasma concentrations [AUC]) of either drug when they were administered together orally compared with corresponding values when each of them was absorbed alone. Two fixed-dose combinations (FDCs) are already available (dapagliflozin-saxagliptin, empagliflozin-linagliptin) and others are in development (ertugliflozin-sitagliptin). Preliminary results show bioequivalence of the two medications administered as FDC tablets when compared with coadministration of the individual tablets. Dual therapy is more potent than either monotherapy in patients treated with diet and exercise or already treated with metformin. SGLT2I and DPP-4I could be used as initial combination or in a stepwise approach. The additional glucose-lowering effect appears to be more marked when a gliflozin is added to a gliptin than when a gliptin is added to a gliflozin. Combining the two pharmacological options is safe and does not induce hypoglycaemia.

  19. Combination therapy with selective serotonin reuptake inhibitors and phosphodiesterase-5 inhibitors in the treatment of premature ejaculation.

    PubMed

    Polat, E C; Ozbek, E; Otunctemur, A; Ozcan, L; Simsek, A

    2015-06-01

    We aimed to evaluate the effectiveness of paroxetine and tadalafil combination in the treatment of premature ejaculation (PE). A total of 150 primary (lifelong)PE patients were randomly distributed into three groups of 50 patients each. Group 1 received 20 mg paroxetine every day for 1 month, Group 2 received 20 mg tadalafil on demand 2 h before intercourse, and Group 3 received paroxetine and tadalafil on demand 2 h before intercourse. Intravaginal ejaculatory latency times (IELT) scores were evaluated at baseline, at the end of the first month of therapy and 1 month after discontinuation of the treatment, while International Index of Erectile Function (IIEF) questionnaire scores were evaluated both prior to and after the treatment. At the end of the first month of therapy, IELT scores were compared with the basal values and statistically significant changes were detected (60.6 ± 30.2-117.3 ± 67.3, 68.5 ± 21.4-110.2 ± 37.3, 71.56 ± 40.23-175.2 ± 60.2)(P < 0.01). IELT scores after discontinuation of treatment were found to be close to the baseline IELT scores (P > 0.05). IIEF scores were evaluated both prior to and after the treatment, and no statistically significant difference was detected (P > 0.05). It is concluded that utilisation of selective serotonin reuptake inhibitors (SSRI) and phosphodiesterase-5 inhibitors (PDE5i) combination before intercourse seems to provide significantly longer ejaculatory latency times as compared with SSRI alone for a long time in patients with PE.

  20. Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy

    PubMed Central

    Eroglu, Zeynep; Ribas, Antoni

    2016-01-01

    Treatment with BRAF inhibitors such as vemurafenib or dabrafenib in patients with advanced BRAFV600 mutated melanoma has shown objective tumor responses in approximately half of the patients. However, the duration of responses is limited in a majority of these patients, with progression-free survival rates around 6 months due to tumor progression from development of acquired resistance. Preclinical studies have suggested that concurrent inhibition of the BRAF kinases and MEK of the mitogen-activated protein kinase (MAPK) pathway could decrease MAPK-driven acquired resistance, resulting in longer duration of responses, higher rate of tumor responses, and a decrease in the cutaneous toxicities observed from paradoxical MAPK pathway activation with BRAF inhibitor monotherapy. This review provides an overview of the currently available clinical trial data on BRAF and MEK inhibitors together and in combinations with other therapeutic agents. PMID:26753005

  1. Inhibitors of DNA Methylation, Histone Deacetylation, and Histone Demethylation: A Perfect Combination for Cancer Therapy.

    PubMed

    Zahnow, C A; Topper, M; Stone, M; Murray-Stewart, T; Li, H; Baylin, S B; Casero, R A

    2016-01-01

    Epigenetic silencing and inappropriate activation of gene expression are frequent events during the initiation and progression of cancer. These events involve a complex interplay between the hypermethylation of CpG dinucleotides within gene promoter and enhancer regions, the recruitment of transcriptional corepressors and the deacetylation and/or methylation of histone tails. These epigenetic regulators act in concert to block transcription or interfere with the maintenance of chromatin boundary regions. However, DNA/histone methylation and histone acetylation states are reversible, enzyme-mediated processes and as such, have emerged as promising targets for cancer therapy. This review will focus on the potential benefits and synergistic/additive effects of combining DNA-demethylating agents and histone deacetylase inhibitors or lysine-specific demethylase inhibitors together in epigenetic therapy for solid tumors and will highlight what is known regarding the mechanisms of action that contribute to the antitumor response.

  2. Possibility of Acetylcholinesterase Overexpression in Alzheimer Disease Patients after Therapy with Acetylcholinesterase Inhibitors.

    PubMed

    Kračmarová, Alžběta; Drtinová, Lucie; Pohanka, Miroslav

    2015-01-01

    Acetylcholinesterase is an enzyme responsible for termination of excitatory transmission at cholinergic synapses by the hydrolyzing of a neurotransmitter acetylcholine. Nowadays, other functions of acetylcholinesterase in the organism are considered, for example its role in regulation of apoptosis. Cholinergic nervous system as well as acetylcholinesterase activity is closely related to pathogenesis of Alzheimer disease. The mostly used therapy of Alzheimer disease is based on enhancing cholinergic function using inhibitors of acetylcholinesterase like rivastigmine, donepezil or galantamine. These drugs can influence not only the acetylcholinesterase activity but also other processes in treated organism. The paper is aimed mainly on possibility of increased expression and protein level of acetylcholinesterase caused by the therapy with acetylcholinesterase inhibitors.

  3. Pulmonary Hypertension Therapy and a Systematic Review of Efficacy and Safety of PDE-5 Inhibitors.

    PubMed

    Unegbu, Chinwe; Noje, Corina; Coulson, John D; Segal, Jodi B; Romer, Lewis

    2017-03-01

    Pulmonary hypertension (PH) is a syndrome that is of growing concern to pediatricians worldwide. Recent data led to concerns about the safety of phosphodiesterase type 5 (PDE5) inhibitors in children and a US Food and Drug Administration safety advisory. Our objective is to provide insight into therapies for PH in children and to systematically review the comparative effectiveness and safety of PDE5 inhibitors in the management of pediatric patients with PH. We searched the following databases through February 2015: Medline, Embase, SCOPUS, and the Cochrane Central Register of Controlled Trials. We included studies that examined PDE5 inhibitor use in children with PH. Allowed comparators were either no medication or other classes of medication for management of PH. Study inclusion was via a 2-stage process with 2 reviewers and a predesigned form. Of 1270 papers identified by the literature search, 21 were included: 8 randomized controlled trials and 13 observational studies (9 retrospective, 4 prospective). There is strong evidence that PDE5 inhibitor use improves echocardiography measurements, cardiac catheterization parameters, and oxygenation compared with baseline or placebo in pediatric patients with PH. Evidence suggests that low- and moderate-dose sildenafil are safe regimens for children. There are a relatively small number of randomized controlled trials that address use of PDE5 inhibitors in pediatric patients with PH. PDE5 inhibitors are effective agents for cardiovascular and oxygenation end points in pediatric PH and important components of a multimodal pharmacotherapeutic approach to this growing challenge. Additional studies are needed to define optimal PH therapy in childhood.

  4. Rasagiline – a novel MAO B inhibitor in Parkinson’s disease therapy

    PubMed Central

    Lecht, Shimon; Haroutiunian, Simon; Hoffman, Amnon; Lazarovici, Philip

    2007-01-01

    Parkinson’s disease (PD) is a progressive neurodegenerative, dopamine deficiency disorder. The main therapeutic strategies for PD treatment relies on dopamine precursors (levodopa), inhibition of dopamine metabolism (monoamine oxidase [MAO] B and catechol-O-methyl transferase inhibitors), and dopamine receptor agonists. Recently, a novel selective and irreversible MAO B propargylamine inhibitor rasagiline (N-propargyl-1-R-aminoindan, Azilect®) was approved for PD therapy. In contrast to selegiline, the prototype of MAO B inhibitors, rasagiline is not metabolized to potentially toxic amphetamine metabolites. The oral bioavailability of rasagiline is 35%, it reaches Tmax after 0.5–1 hours and its half-life is 1.5–3.5 hours. Rasagiline undergoes extensive hepatic metabolism primarily by cytochrome P450 type 1A2 (CYP1A2). Rasagiline is initiated at 1 mg once-daily dosage as monotherapy in early PD patients and at 0.5–1 mg once-daily as adjunctive to levodopa in advanced PD patients. Rasagiline treatment was not associated with “cheese effect” and up to 20 mg per day was well tolerated. In PD patients with hepatic impairment, rasagiline dosage should be carefully adjusted. Rasagiline should not be administered with other MAO inhibitors and co-administration with certain antidepressants and opioids should be avoided. Although further clinical evidence is needed on the neuroprotective effects of rasagiline in PD patients, this drug provides an additional tool for PD therapy. PMID:18488080

  5. Current European practice in immune tolerance induction therapy in patients with haemophilia and inhibitors.

    PubMed

    Astermark, J; Morado, M; Rocino, A; van den Berg, H M; von Depka, M; Gringeri, A; Mantovani, L; Garrido, R P; Schiavoni, M; Villar, A; Windyga, J

    2006-07-01

    The management of patients with inhibitors is an important challenge in haemophilia care. The lack of randomized controlled trials means that clinical decisions are generally based on subjective opinions, and purchasers' attention is likely to focus on the costs of treatment. In order to assess the current management of inhibitor patients and use of immune tolerance induction therapy (ITI) in Europe, we performed a survey within a European network of 21 comprehensive care centres from 14 countries (the European Haemophilia Therapy Standardisation Board). The survey identified a total of 381 patients with inhibitors attending the centres, 211 (55.4%) of whom had never been exposed to ITI. Between 1998 and 2003, the centres performed 233 procedures and 114 (48.9%) were successful. The survey demonstrated that dosing, which is the time to start and stop the ITI, the type of concentrate to use and the definition of success varied among the centres. Well-designed trials are warranted to guide decision-making, but in the absence of these studies we have developed consensus guidance for the management of inhibitor patients based on current clinical practice, as identified by the survey, and review of the literature.

  6. The Clinical Development of Thalildomide as an Angiogenesis Inhibitor Therapy for Prostate Cancer

    DTIC Science & Technology

    2005-10-01

    AD_________________ Award Number: DAMD17-01-1-0069 TITLE: The Clinical Development of Thalidomide ... Thalidomide as an Angiogenesis Inhibitor Therapy for Prostate Cancer 5b. GRANT NUMBER DAMD17-01-1-0069 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d...in stromal epithelial interaction and have demonstrated that they are expressed in the context of Thalidomide treated patients. This information will

  7. Combination therapy with copanlisib and ABL tyrosine kinase inhibitors against Philadelphia chromosome-positive resistant cells

    PubMed Central

    Okabe, Seiichi; Tauchi, Tetsuzo; Tanaka, Yuko; Sakuta, Juri; Ohyashiki, Kazuma

    2016-01-01

    ABL tyrosine kinase inhibitor (TKI) therapy has improved the survival of patients with Philadelphia (Ph) chromosome-positive leukemia. However, ABL TKIs cannot eradicate leukemia stem cells. Therefore, new therapeutic approaches for Ph-positive leukemia are needed. Aberrant activation of phosphoinositide 3-kinase (PI3K) signaling is important for the initiation and maintenance of human cancers. Copanlisib (BAY80-6946) is a potent inhibitor of PI3Kα and PI3K-δ. Here we investigated the efficacy of combination therapy of copanlisib with an ABL TKI (imatinib, nilotinib, or ponatinib) using BCR-ABL-positive cells. Although the effects of the ABL TKI treatment were reduced in the presence of the feeder cell line, HS-5, copanlisib inhibited cell growth. Upon combining ABL TKI and copanlisib, cell growth was reduced. Ponatinib and copanlisib combined therapy reduced tumor volume and increased survival in mouse allograft models, respectively. These results indicate that the PI3Kα and -δ inhibitors overcame the chemoprotective effects of the feeder cells and enhanced ABL TKI cytotoxicity. Thus, co-treatment with ABL TKI and copanlisib may be a powerful strategy against ABL TKI-resistant cells, including those harboring the related T315I mutation. PMID:27437766

  8. Combination therapy with copanlisib and ABL tyrosine kinase inhibitors against Philadelphia chromosome-positive resistant cells.

    PubMed

    Okabe, Seiichi; Tauchi, Tetsuzo; Tanaka, Yuko; Sakuta, Juri; Ohyashiki, Kazuma

    2016-08-16

    ABL tyrosine kinase inhibitor (TKI) therapy has improved the survival of patients with Philadelphia (Ph) chromosome-positive leukemia. However, ABL TKIs cannot eradicate leukemia stem cells. Therefore, new therapeutic approaches for Ph-positive leukemia are needed. Aberrant activation of phosphoinositide 3-kinase (PI3K) signaling is important for the initiation and maintenance of human cancers. Copanlisib (BAY80-6946) is a potent inhibitor of PI3Kα and PI3K-δ. Here we investigated the efficacy of combination therapy of copanlisib with an ABL TKI (imatinib, nilotinib, or ponatinib) using BCR-ABL-positive cells. Although the effects of the ABL TKI treatment were reduced in the presence of the feeder cell line, HS-5, copanlisib inhibited cell growth. Upon combining ABL TKI and copanlisib, cell growth was reduced. Ponatinib and copanlisib combined therapy reduced tumor volume and increased survival in mouse allograft models, respectively. These results indicate that the PI3Kα and -δ inhibitors overcame the chemoprotective effects of the feeder cells and enhanced ABL TKI cytotoxicity. Thus, co-treatment with ABL TKI and copanlisib may be a powerful strategy against ABL TKI-resistant cells, including those harboring the related T315I mutation.

  9. Recent advances in melanoma systemic therapy. BRAF inhibitors, CTLA4 antibodies and beyond.

    PubMed

    Menzies, Alexander M; Long, Georgina V

    2013-10-01

    Metastatic melanoma has a poor prognosis and until recently systemic therapy was ineffective. Advances in the understanding of tumour biology and immune regulation have led to the development of targeted agents that have changed clinical practice, with further improvements expected with new compounds and combinations. The first major advance was the development of selective mitogen-activated protein (MAP) kinase inhibitors (BRAF and MEK inhibitors) and immune checkpoint blockade with a CTLA4 antibody (ipilimumab). These drugs proved vastly superior to conventional chemotherapy, however response, resistance and toxicity were limitations. The second major advance is the development of other immune checkpoint blocking agents, including PD-1 and PD-L1 antibodies, and the use of BRAF and MEK inhibitors in combination, with a higher proportion of durable responses coupled with less toxicity. In an effort to improve outcomes for patients with melanoma further, trials are underway examining the combination of MAPK inhibitors, immunotherapies and other pathway inhibitors and adjuvant studies of many of these agents have commenced.

  10. Targeting the TGF-β receptor with kinase inhibitors for scleroderma therapy.

    PubMed

    Cong, Lin; Xia, Zhi-Kuan; Yang, Rong-Ya

    2014-09-01

    Scleroderma (systemic sclerosis) is a connective tissue disease that affects various organ systems; the treatment of scleroderma is still difficult and remains a challenge to the clinician. Recently, kinase inhibitors have shown great potential against fibrotic diseases and, specifically, the transforming growth factor-β receptor (TGF-βR) was found as a new and promising target for scleroderma therapy. In the current study, we propose that the large pool of existing kinase inhibitors could be exploited for inhibiting the TGF-βR to suppress scleroderma. In this respect, we developed a modeling protocol to systematically profile the inhibitory activities of 169 commercially available kinase inhibitors against the TGF-βR, from which five promising candidates were selected and tested using a standard kinase assay protocol. Consequently, two molecular entities, namely the PKB inhibitor MK-2206 and the mTOR C1/C2 inhibitor AZD8055, showed high potency when bound to the TGF-βR, with IC50 values of 97 and 86 nM, respectively, which are close to those of the recently developed TGF-βR selective inhibitors SB525334 and LY2157299 (IC50 = 14.3 and 56 nM, respectively). We also performed atomistic molecular dynamics simulations and post-molecular mechanics/Poisson-Boltzmann surface area analyses to dissect the structural basis and energetic properties of intermolecular interactions between the TGF-βR kinase domain and these potent compounds, highlighting intensive nonbonded networks across the tightly packed interface of non-cognate TGF-βR-inhibitor complexes.

  11. Matrix metalloproteinase inhibitor therapy to prevent complications as well as therapy for Ehler-Danlos syndrome.

    PubMed

    Sastry, P S R K

    2002-09-01

    Matrixmetalloproteinase inhibitors have been developed as anti-cancer agents. Their usage in pancreatic cancer and other such malignancies is under trial at present. An interesting undesired-effect of one of these agents is contracture of the hand. Ehler-Danlos syndrome is an inherited group of diseases with varying types. At present there is no known treatment or prevention for the complications associated with this inherited condition. Sometimes it is the adverse events of a drug, which provides an insight into its efficacy for another indication. It is hereby being hypothesized that the matrixmetalloproteinase inhibitors especially marimastat may be an effective drug for treatment of Ehler-Danlos syndrome and/or prevention of its major complications.

  12. Effect of phlorotannins isolated from Ecklonia cava on angiotensin I-converting enzyme (ACE) inhibitory activity

    PubMed Central

    Wijesinghe, W.A.J.P.; Ko, Seok-Chun

    2011-01-01

    Inhibition of angiotensin I-converting enzyme (ACE) activity is the most common mechanism underlying the lowering of blood pressure. In the present study, five organic extracts of a marine brown seaweed Ecklonia cava were prepared by using ethanol, ethyl acetate, chloroform, hexane, and diethyl ether as solvents, which were then tested for their potential ACE inhibitory activities. Ethanol extract showed the strongest ACE inhibitory activity with an IC50 value of 0.96 mg/ml. Five kinds of phlorotannins, phloroglucinol, triphlorethol-A, eckol, dieckol, and eckstolonol, were isolated from ethanol extract of E. cava, which exhibited potential ACE inhibition. Dieckol was the most potent ACE inhibitor and was found to be a non-competitive inhibitor against ACE according to Lineweaver-Burk plots. Dieckol had an inducible effect on the production of NO in EAhy926 cells without having cytotoxic effect. The results of this study indicate that E. cava could be a potential source of phlorotannins with ACE inhibitory activity for utilization in production of functional foods. PMID:21556221

  13. Effect of phlorotannins isolated from Ecklonia cava on angiotensin I-converting enzyme (ACE) inhibitory activity.

    PubMed

    Wijesinghe, W A J P; Ko, Seok-Chun; Jeon, You-Jin

    2011-04-01

    Inhibition of angiotensin I-converting enzyme (ACE) activity is the most common mechanism underlying the lowering of blood pressure. In the present study, five organic extracts of a marine brown seaweed Ecklonia cava were prepared by using ethanol, ethyl acetate, chloroform, hexane, and diethyl ether as solvents, which were then tested for their potential ACE inhibitory activities. Ethanol extract showed the strongest ACE inhibitory activity with an IC(50) value of 0.96 mg/ml. Five kinds of phlorotannins, phloroglucinol, triphlorethol-A, eckol, dieckol, and eckstolonol, were isolated from ethanol extract of E. cava, which exhibited potential ACE inhibition. Dieckol was the most potent ACE inhibitor and was found to be a non-competitive inhibitor against ACE according to Lineweaver-Burk plots. Dieckol had an inducible effect on the production of NO in EAhy926 cells without having cytotoxic effect. The results of this study indicate that E. cava could be a potential source of phlorotannins with ACE inhibitory activity for utilization in production of functional foods.

  14. Breast Cancer, Aromatase Inhibitor Therapy, and Sexual Functioning: A Pilot Study of the Effects of Vaginal Testosterone Therapy

    PubMed Central

    Dahir, Melissa; Travers-Gustafson, Dianne

    2014-01-01

    Introduction Women with breast cancer have better cancer-related outcomes with the use of aromatase inhibitors (AIs), but the physiological suppression of estradiol can negatively affect sexual functioning because of unpleasant urogenital and vaginal symptoms. Local health care practitioners have observed that the benefits of vaginal testosterone in allaying these unpleasant symptoms in women with breast cancer are similar to the benefits of vaginal estrogen in women without breast cancer. Aim The aim of this study was to evaluate the effects of using a daily vaginal testosterone cream on the reported sexual health quality of life in women with breast cancer taking AI therapy. Methods Thirteen postmenopausal women with breast cancer on AI therapy and experiencing symptoms of sexual dysfunction were recruited from an oncology practice. The women were prescribed a 300 μg testosterone vaginal cream daily for 4 weeks. During the first study visit, a vaginal swab was obtained to rule out the presence of Candida species or Gardnerella vaginalis in participants. Women with positive vaginal swabs were treated prior to starting the vaginal testosterone therapy. Main Outcome Measure  The Female Sexual Function Index (FSFI) survey, measuring female sexual health quality of life, was administered during the first study visit and at the final study visit, after completing testosterone therapy. Results Twelve patients completed 4 weeks of daily vaginal testosterone therapy. When compared with baseline FSFI scores, there was a statistically significant improvement for individual domain scores of desire (P = 0.000), arousal (P = 0.002), lubrication (P = 0.018), orgasm (P = 0.005), satisfaction (P = 0.001), and pain (P = 0.000). Total domain scores reflecting sexual health quality of life also improved when compared with baseline (P = 0.000). Conclusions The use of a compounded testosterone vaginal cream applied daily for 4 weeks improves reported sexual health quality of life

  15. Polymorphisms of ACE2 gene are associated with essential hypertension and antihypertensive effects of Captopril in women.

    PubMed

    Fan, X; Wang, Y; Sun, K; Zhang, W; Yang, X; Wang, S; Zhen, Y; Wang, J; Li, W; Han, Y; Liu, T; Wang, X; Chen, J; Wu, H; Hui, R

    2007-08-01

    ACE2 appears to counterbalance the vasopressor effect of angiotensin I converting enzyme (ACE) in the reninangiotensin system. We hypothesized that ACE2 polymorphisms could confer a high risk of hypertension and have an impact on the antihypertensive response to ACE inhibitors. The hypothesis was tested in two casecontrol studies and a clinical trial of 3,408 untreated hypertensive patients randomized to Atenolol, Hydrochlorothiazide, Captopril, or Nifedipine treatments for 4 weeks. ACE2 rs2106809 T allele was found to confer a 1.6-fold risk for hypertension in women (95% confidence interval (CI), 1.132.06), whereas when combined with the effect of the ACE DD genotype, the risk was 2.34-fold (95% CI, 1.754.85) in two independent samples. The adjusted diastolic blood pressure response to Captopril was 3.3 mm Hg lower in ACE2 T allele carriers than in CC genotype carriers (P=0.019) in women. We conclude that the ACE2 T allele confers a high risk for hypertension and reduced antihypertensive response to ACE inhibitors.

  16. Reducing the Burden of Difficult-to-Treat Major Depressive Disorder: Revisiting Monoamine Oxidase Inhibitor Therapy

    PubMed Central

    2013-01-01

    Objective: Difficult-to-treat depression (eg, depression with atypical or anxious symptoms, treatment-resistant depression, or depression with frequent recurrence) is a challenging real-world health issue. This critical review of the literature focuses on monoamine oxidase inhibitor (MAOI) therapy and difficult-to-treat forms of depression. Data Sources: A PubMed literature search was performed in November 2012 and refreshed through January 2013 with no date restrictions using key search terms including MAO inhibitor therapy or MAOI and depression and anxiety, atypical, treatment-resistant, recurrent, relapse, or refractory. Study Selection: Articles were selected to summarize the current needs in difficult-to-treat depression as well as the use of MAOI therapies in this area. Results: Two strategies have fallen out of favor in the care of patients with major depressive disorder. The first is the use of MAOI therapy and the second is the proactive recognition of difficult-to-treat depression that may not respond as well to more frequently used antidepressants. The infrequent use of MAOIs stems from the perception that other oral therapies for depression are safer and easier to use than oral MAOIs; however, transdermal delivery is one potential strategy to improve the safety of this class of agents. Although food-related interactions with transdermal delivery of MAOI therapy can be lessened, clinicians still need to be vigilant for drug-drug interactions and serotonin syndrome. Conclusions: Clinicians should consider MAOIs for patients who have had several unsuccessful trials of antidepressants. Guidelines generally reserve MAOIs as third- and fourth-line treatments due to concerns over safety and tolerability; however, transdermal delivery of an MAOI may allay some of the safety and tolerability concerns. Patients should be provided education about MAOIs and their risks. PMID:24511450

  17. Topical therapy for psoriasis: a promising future. Focus on JAK and phosphodiesterase-4 inhibitors.

    PubMed

    Rafael, Adilia; Torres, Tiago

    2016-01-01

    Psoriasis is a common, chronic and disabling skin disorder affecting approximately 2% of the population, associated with significant negative impact on the patient's quality of life. Approximately 80% of those affected with psoriasis have mild-to-moderate forms and are usually treated with topical therapy, whereas phototherapy and systemic therapies are used for those with severe disease. In the past three decades, the major advances in psoriasis therapy have been in systemic agents for the treatment of moderate-to-severe psoriasis, particularly new immunomodulatory and biological molecules, while topical therapies have remained relatively unchanged over the past decades. Indeed, topical corticosteroids and vitamin D3 analogs are still the gold standard of therapy for mild-to-moderate psoriasis. Thus, there is a need to develop new and more effective topical agents in the short and long term, with a better efficacy and safety profile than corticosteroids and vitamin D3 analogs. Over the past five years, investigation into topical therapy has expanded, with exciting new drugs being developed. Preliminary results of these emerging agents that selectively target disease-defining pathogenic pathways seem to be promising, although long-term and large-scale studies assessing safety and efficacy are still lacking. The aim of this article was to review the clinical and research data of some emerging topical agents, focusing on Janus kinase-signal transducer and activator of transcription and phosphodiesterase type 4 inhibitors, which are currently being investigated.

  18. Effects of AKT inhibitor therapy in response and resistance to BRAF inhibition in melanoma

    PubMed Central

    2014-01-01

    Background The clinical use of BRAF inhibitors for treatment of metastatic melanoma is limited by the development of drug resistance. In this study we investigated whether co-targeting the MAPK and the PI3K-AKT pathway can prevent emergence of resistance or provide additional growth inhibitory effects in vitro. Methods Anti-tumor effects of the combination of the BRAF inhibitor (BRAFi) dabrafenib and GSK2141795B (AKTi) in a panel of 23 BRAF mutated melanoma cell lines were evaluated on growth inhibition by an ATP-based luminescent assay, on cell cycle and apoptosis by flow cytometry and on cell signaling by western blot. Moreover, we investigated the possibilities of delaying or reversing resistance or achieving further growth inhibition by combining AKTi with dabrafenib and/or the MEK inhibitor (MEKi) trametinib by using long term cultures. Results More than 40% of the cell lines, including PTEN-/- and AKT mutants showed sensitivity to AKTi (IC50 < 1.5 μM). The combination of dabrafenib and AKTi synergistically potentiated growth inhibition in the majority of cell lines with IC50 > 5 nM dabrafenib. Combinatorial treatment induced apoptosis only in cell lines sensitive to AKTi. In long term cultures of a PTEN-/- cell line, combinatorial treatment with the MAPK inhibitors, dabrafenib and trametinib, and AKTi markedly delayed the emergence of drug resistance. Moreover, combining AKTi with the MAPK inhibitors from the beginning provided superior growth inhibitory effects compared to addition of AKTi upon development of resistance to MAPK inhibitors in this particular cell line. Conclusions AKTi combined with BRAFi-based therapy may benefit patients with tumors harboring BRAF mutations and particularly PTEN deletions or AKT mutations. PMID:24735930

  19. Efficacious proteasome/HDAC inhibitor combination therapy for primary effusion lymphoma.

    PubMed

    Bhatt, Shruti; Ashlock, Brittany M; Toomey, Ngoc L; Diaz, Luis A; Mesri, Enrique A; Lossos, Izidore S; Ramos, Juan Carlos

    2013-06-01

    Primary effusion lymphoma (PEL) is a rare form of aggressive B cell lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV). Current chemotherapy approaches result in dismal outcomes, and there is an urgent need for new PEL therapies. Previously, we established, in a direct xenograft model of PEL-bearing immune-compromised mice, that treatment with the proteasome inhibitor, bortezomib (Btz), increased survival relative to that after treatment with doxorubicin. Herein, we demonstrate that the combination of Btz with the histone deacetylase (HDAC) inhibitor suberoylanilidehydroxamic acid (SAHA, also known as vorinostat) potently reactivates KSHV lytic replication and induces PEL cell death, resulting in significantly prolonged survival of PEL-bearing mice. Importantly, Btz blocked KSHV late lytic gene expression, terminally inhibiting the full lytic cascade and production of infectious virus in vivo. Btz treatment led to caspase activation and induced DNA damage, as evidenced by the accumulation of phosphorylated γH2AX and p53. The addition of SAHA to Btz treatment was synergistic, as SAHA induced early acetylation of p53 and reduced interaction with its negative regulator MDM2, augmenting the effects of Btz. The eradication of KSHV-infected PEL cells without increased viremia in mice provides a strong rationale for using the proteasome/HDAC inhibitor combination therapy in PEL.

  20. C-Peptide Levels Predict the Effectiveness of Dipeptidyl Peptidase-4 Inhibitor Therapy

    PubMed Central

    Demir, Sevin; Sargin, Mehmet

    2016-01-01

    Background. Our aim was to define the conditions that affect therapeutic success when dipeptidyl peptidase-4 (DPP-4) inhibitor is added to metformin monotherapy. Materials and Methods. We reviewed the medical records of 56 patients who had received DPP-4 inhibitor as an add-on to metformin monotherapy and evaluated their response in the first year of therapy. Fasting blood glucose (FBG), HbA1c, C-peptide, and weight of the patients were recorded at 3-month intervals during the first year of treatment. Results. Patients who added DPP-4 inhibitor to metformin monotherapy had significant weight loss (P = 0.004) and FBG and HbA1c levels were significantly lowered during the first 6 months (both P < 0.001). Baseline levels of C-peptide were predictive for success of the treatment (P = 0.02), even after correction for confounding factors, for example, age, gender, or BMI (P = 0.03). Duration of diabetes was not a predictor of response to treatment (P = 0.60). Conclusion. Our study demonstrates that in patients having inadequate glycemic control, the addition of a DPP-4 inhibitor as a second oral agent to metformin monotherapy provides better glycemic control, protects β-cell reserves, and does not cause weight gain. These effects depend on baseline C-peptide levels. PMID:27882332

  1. Use of Nanotechnology to Develop Multi-Drug Inhibitors For Cancer Therapy

    PubMed Central

    Gowda, Raghavendra; Jones, Nathan R.; Banerjee, Shubhadeep; Robertson, Gavin P.

    2014-01-01

    Therapeutic agents that inhibit a single target often cannot combat a multifactorial disease such as cancer. Thus, multi-target inhibitors (MTIs) are needed to circumvent complications such as the development of resistance. There are two predominant types of MTIs, (a) single drug inhibitor (SDIs) that affect multiple pathways simultaneously, and (b) combinatorial agents or multi-drug inhibitors (MDIs) that inhibit multiple pathways. Single agent multi-target kinase inhibitors are amongst the most prominent class of compounds belonging to the former, whereas the latter includes many different classes of combinatorial agents that have been used to achieve synergistic efficacy against cancer. Safe delivery and accumulation at the tumor site is of paramount importance for MTIs because inhibition of multiple key signaling pathways has the potential to lead to systemic toxicity. For this reason, the development of drug delivery mechanisms using nanotechnology is preferable in order to ensure that the MDIs accumulate in the tumor vasculature, thereby increasing efficacy and minimizing off-target and systemic side effects. This review will discuss how nanotechnology can be used for the development of MTIs for cancer therapy and also it concludes with a discussion of the future of nanoparticle-based MTIs as well as the continuing obstacles being faced during the development of these unique agents.’ PMID:25013742

  2. Use of Nanotechnology to Develop Multi-Drug Inhibitors For Cancer Therapy.

    PubMed

    Gowda, Raghavendra; Jones, Nathan R; Banerjee, Shubhadeep; Robertson, Gavin P

    2013-12-01

    Therapeutic agents that inhibit a single target often cannot combat a multifactorial disease such as cancer. Thus, multi-target inhibitors (MTIs) are needed to circumvent complications such as the development of resistance. There are two predominant types of MTIs, (a) single drug inhibitor (SDIs) that affect multiple pathways simultaneously, and (b) combinatorial agents or multi-drug inhibitors (MDIs) that inhibit multiple pathways. Single agent multi-target kinase inhibitors are amongst the most prominent class of compounds belonging to the former, whereas the latter includes many different classes of combinatorial agents that have been used to achieve synergistic efficacy against cancer. Safe delivery and accumulation at the tumor site is of paramount importance for MTIs because inhibition of multiple key signaling pathways has the potential to lead to systemic toxicity. For this reason, the development of drug delivery mechanisms using nanotechnology is preferable in order to ensure that the MDIs accumulate in the tumor vasculature, thereby increasing efficacy and minimizing off-target and systemic side effects. This review will discuss how nanotechnology can be used for the development of MTIs for cancer therapy and also it concludes with a discussion of the future of nanoparticle-based MTIs as well as the continuing obstacles being faced during the development of these unique agents.'

  3. The Atmospheric Chemistry Experiment (ACE)

    NASA Astrophysics Data System (ADS)

    Bernath, P. F.

    2017-01-01

    The Atmospheric Chemistry Experiment (ACE), also called SCISAT, is a Canadian-led small satellite mission for remote sensing of the Earth's atmosphere. ACE was launched into a low Earth circular orbit by NASA on August 12, 2003 and it continues to function nominally. The ACE instruments are a high spectral resolution (0.02 cm-1) Fourier Transform Spectrometer (FTS) operating from 2.2 to 13.3 μm (750-4400 cm-1), a spectrophotometer known as Measurement of Aerosol Extinction in the Stratosphere and Troposphere Retrieved by Occultation (MAESTRO) with wavelength coverage of 285-1020 nm and two filtered detector arrays to image the Sun at 0.525 and 1.02 μm. ACE operates in solar occultation mode to provide altitude profiles of temperature, pressure, atmospheric extinction and the volume mixing ratios (VMRs) for several dozen molecules and related isotopologues. This paper presents a mission overview and a summary of selected scientific results.

  4. Myostatin inhibitors as therapies for muscle wasting associated with cancer and other disorders

    PubMed Central

    Smith, Rosamund C.; Lin, Boris K.

    2013-01-01

    Purpose of review This review summarizes recent progress in the development of myostatin inhibitors for the treatment of muscle wasting disorders. It also focuses on findings in myostatin biology that may have implications for the development of antimyostatin therapies. Recent findings There has been progress in evaluating antimyostatin therapies in animal models of muscle wasting disorders. Some programs have progressed into clinical development with initial results showing positive impact on muscle volume. In normal mice myostatin deficiency results in enlarged muscles with increased total force but decreased specific force (total force/total mass). An increase in myofibrillar protein synthesis without concomitant satellite cell proliferation and fusion leads to muscle hypertrophy with unchanged myonuclear number. A specific force reduction is not observed when atrophied muscle, the predominant therapeutic target of myostatin inhibitor therapy, is made myostatindeficient. Myostatin has been shown to be expressed by a number of tumor cell lines in mice and man. Summary Myostatin inhibition remains a promising therapeutic strategy for a range of muscle wasting disorders. PMID:24157714

  5. ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A

    PubMed Central

    Williamson, Chris T.; Miller, Rowan; Pemberton, Helen N.; Jones, Samuel E.; Campbell, James; Konde, Asha; Badham, Nicholas; Rafiq, Rumana; Brough, Rachel; Gulati, Aditi; Ryan, Colm J.; Francis, Jeff; Vermulen, Peter B.; Reynolds, Andrew R.; Reaper, Philip M.; Pollard, John R.; Ashworth, Alan; Lord, Christopher J.

    2016-01-01

    Identifying genetic biomarkers of synthetic lethal drug sensitivity effects provides one approach to the development of targeted cancer therapies. Mutations in ARID1A represent one of the most common molecular alterations in human cancer, but therapeutic approaches that target these defects are not yet clinically available. We demonstrate that defects in ARID1A sensitize tumour cells to clinical inhibitors of the DNA damage checkpoint kinase, ATR, both in vitro and in vivo. Mechanistically, ARID1A deficiency results in topoisomerase 2A and cell cycle defects, which cause an increased reliance on ATR checkpoint activity. In ARID1A mutant tumour cells, inhibition of ATR triggers premature mitotic entry, genomic instability and apoptosis. The data presented here provide the pre-clinical and mechanistic rationale for assessing ARID1A defects as a biomarker of single-agent ATR inhibitor response and represents a novel synthetic lethal approach to targeting tumour cells. PMID:27958275

  6. Inhibitors of emerging epigenetic targets for cancer therapy: a patent review (2010-2014).

    PubMed

    Tanaka, Minoru; Roberts, Justin M; Qi, Jun; Bradner, James E

    2015-01-01

    Gene regulatory pathways comprise an emerging and active area of chemical probe discovery and investigational drug development. Emerging insights from cancer genome sequencing and chromatin biology have identified leveraged opportunities for development of chromatin-directed small molecules as cancer therapies. At present, only six agents in two epigenetic target classes have been approved by the US FDA, limited to treatment of hematological malignancies. Recently, new classes of epigenetic inhibitors have appeared in literatures. First-in-class compounds have successfully transitioned to clinical investigation, importantly also in solid tumors and pediatric malignancies. This review considers patent applications for small-molecule inhibitors of selected epigenetic targets from 2010 to 2014. Included are exemplary classes of chromatin-associated epigenomic writers (DOT1L and EZH2), erasers (LSD1) and readers (BRD4).

  7. Angiotensin-II mediates ACE2 Internalization and Degradation through an Angiotensin-II type I receptor-dependent mechanism

    PubMed Central

    Lazartigues, Eric; Filipeanu, Catalin M.

    2014-01-01

    Angiotensin Converting Enzyme type 2 (ACE2) is a pivotal component of the renin-angiotensin system, promoting the conversion of Angiotensin (Ang)-II to Ang-(1-7). We previously reported that decreased ACE2 expression and activity contribute to the development of Ang-II-mediated hypertension in mice. The present study aimed to investigate the mechanisms involved in ACE2 down-regulation during neurogenic hypertension. In ACE2-transfected Neuro-2A cells, Ang-II treatment resulted in a significant attenuation of ACE2 enzymatic activity. Examination of the subcellular localization of ACE2 revealed that Ang-II treatment leads to ACE2 internalization and degradation into lysosomes. These effects were prevented by both the Ang-II type 1 receptor (AT1R) blocker losartan and the lysosomal inhibitor leupeptin. In contrast, in HEK293T cells, which lack endogenous AT1R, Ang-II failed to promote ACE2 internalization. Moreover, this effect could be induced after AT1R transfection. Further, co-immunoprecipitation experiments demonstrated that AT1R and ACE2 form complexes and these interactions were decreased by Ang-II treatment, which also enhanced ACE2 ubiquitination. In contrast, ACE2 activity was not changed by transfection of AT2 or Mas receptors. In vivo, Ang-II-mediated hypertension was blunted by chronic infusion of leupeptin in wildtype C57Bl/6, but not in ACE2 knockout mice. Overall, this is the first demonstration that elevated Ang-II levels reduce ACE2 expression and activity by stimulation of lysosomal degradation through an AT1R-dependent mechanism. PMID:25225202

  8. An Update on Poly(ADP-ribose)polymerase-1 (PARP-1) Inhibitors: Opportunities and Challenges in Cancer Therapy.

    PubMed

    Wang, Ying-Qing; Wang, Ping-Yuan; Wang, Yu-Ting; Yang, Guang-Fu; Zhang, Ao; Miao, Ze-Hong

    2016-11-10

    Poly(ADP-ribose)polymerase-1 (PARP-1) is a critical DNA repair enzyme in the base excision repair pathway. Inhibitors of this enzyme comprise a new type of anticancer drug that selectively kills cancer cells by targeting homologous recombination repair defects. Since 2010, important advances have been achieved in PARP-1 inhibitors. Specifically, the approval of olaparib in 2014 for the treatment of ovarian cancer with BRCA mutations validated PARP-1 as an anticancer target and established its clinical importance in cancer therapy. Here, we provide an update on PARP-1 inhibitors, focusing on breakthroughs in their clinical applications and investigations into relevant mechanisms of action, biomarkers, and drug resistance. We also provide an update on the design strategies and the structural types of PARP-1 inhibitors. Opportunities and challenges in PARP-1 inhibitors for cancer therapy will be discussed based on the above advances.

  9. Addition of cranberry to proton pump inhibitor-based triple therapy for Helicobacter pylori eradication

    PubMed Central

    Seyyedmajidi, Mohammadreza; Ahmadi, Anahita; Hajiebrahimi, Shahin; Seyedmajidi, Seyedali; Rajabikashani, Majid; Firoozabadi, Mona; Vafaeimanesh, Jamshid

    2016-01-01

    Objective: Proton pump inhibitor-based triple therapy with two antibiotics for Helicobacter pylori eradication is widely accepted, but this combination fails in a considerable number of cases. Some studies have shown that cranberry inhibits the adhesion of a wide range of microbial pathogens, including H. pylori. The aim of this study was to assess the effect of cranberry on H. pylori eradication with a standard therapy including lansoprazole, clarithromycin, and amoxicillin (LCA) in patients with peptic ulcer disease (PUD). Methods: In this study, H. pylori-positive patients with PUD were randomized into two groups: Group A: A 14-day LCA triple therapy with 30 mg lansoprazole bid, 1000 mg amoxicillin bid, and 500 mg clarithromycin bid; Group B: A 14-day 500 mg cranberry capsules bid plus LCA triple therapy. A 13C-urea breath test was performed for eradication assessment 6 weeks after the completion of the treatment. Findings: Two hundred patients (53.5% males, between 23 and 77 years, mean age ± standard deviation: 50.29 ± 17.79 years) continued treatment protocols and underwent 13C-urea breath testing. H. pylori eradication was achieved in 74% in Group A (LCA without cranberry) and 89% in Group B (LCA with cranberry) (P = 0.042). Conclusion: The addition of cranberry to LCA triple therapy for H. pylori has a higher rate of eradication than the standard regimen alone (up to 89% and significant). PMID:27843960

  10. Linagliptin: a novel dipeptidyl peptidase 4 inhibitor with a unique place in therapy.

    PubMed

    Barnett, Anthony H

    2011-06-01

    The dipeptidyl peptidase 4 (DPP-4) inhibitors comprise a promising new class of agent for the management of type 2 diabetes. They possess a range of physiological effects associated with improved glycemic control including stimulation of glucose-dependent insulin secretion and suppression of glucagon secretion, and lower blood glucose levels through different, but potentially complementary, mechanisms to standard oral therapies. Linagliptin is the latest DPP-4 inhibitor to complete pivotal phase 3 trials. The data show that linagliptin provides significant, clinically meaningful and sustained improvements in glycemic control, with an incidence of adverse events similar to placebo and an excellent tolerability profile. In addition, linagliptin has been shown to be weight neutral and, importantly, there was no increased risk of hypoglycemia attributed to linagliptin use in monotherapy or combination therapy with metformin or pioglitazone. A unique characteristic of linagliptin that differentiates it from other members of the class is its primarily nonrenal route of excretion. The linagliptin phase 3 program included several hundred patients with type 2 diabetes and different stages of renal disease and the data suggest that the drug would not need dose adjustment, regardless of the degree of renal impairment. There is a particular need for safe and effective therapeutic agents that can be used when renal function declines. Linagliptin has recently been approved by the US Food and Drug Administration and may find a place in therapy as a treatment option for the significant number of patients in whom metformin and the other DPP-4 inhibitors are either contraindicated or require dose adjustment because of moderate to severe renal impairment.

  11. Neurocognitive Impairment in Patients Treated with Protease Inhibitor Monotherapy or Triple Drug Antiretroviral Therapy

    PubMed Central

    Pérez-Valero, Ignacio; González-Baeza, Alicia; Estébanez, Miriam; Montes-Ramírez, María L.; Bayón, Carmen; Pulido, Federico; Bernardino, José I.; Zamora, Francisco X.; Monge, Susana; Gaya, Francisco; Lagarde, María; Rubio, Rafael; Hernando, Asunción; Arnalich, Francisco; Arribas, José R.

    2013-01-01

    Background In patients who remain virologically suppressed in plasma with triple-drug ART a switch to protease inhibitor monotherapy maintains high rates of suppression; however it is unknown if protease inhibitor monotherapy is associated to a higher rate of neurocognitive impairment. Methods In this observational, cross-sectional study we included patients with plasma virological suppression (≥1 year) without concomitant major neurocognitive confounders, currently receiving for ≥1 year boosted lopinavir or darunavir as monotherapy or as triple ART. Neurocognitive impairment was defined as per the 2007 consensus of the American Association of Neurology. The association between neurocognitive impairment and protease inhibitor monotherapy, adjusted by significant confounders, was analysed. Results Of the 191 included patients - triple therapy: 96, 1–2 years of monotherapy: 40 and >2 years of monotherapy: 55 - proportions (95% CI) with neurocognitive impairment were: overall, 27.2% (20.9–33.6); triple therapy, 31.6% (22.1–41.0); short-term monotherapy, 25.0% (11.3–38.7); long-term monotherapy: 21.4% (10.5–32.3); p = 0.38. In all groups, neurocognitive impairment was mildly symptomatic or asymptomatic by self-report. There were not significant differences in Global Deficit Score by group. In the regression model confounding variables for neurocognitive impairment were years on ART, ethnicity, years of education, transmission category and the HOMA index. Adjusted by these variables the Odds Ratio (95% CI) for neurocognitive impairment of patients receiving short-term monotherapy was 0.85 (0.29–2.50) and for long-term monotherapy 0.40 (0.14–1.15). Conclusions Compared to triple drug antiretroviral therapy, monotherapy with lopinavir/ritonavir or darunavir/ritonavir in patients with adequate plasma suppression was not associated with a higher rate of asymptomatic neurocognitive impairment than triple drug ART. PMID:23936029

  12. Isolation, Purification and Molecular Mechanism of a Peanut Protein-Derived ACE-Inhibitory Peptide

    PubMed Central

    Shi, Aimin; Liu, Hongzhi; Liu, Li; Hu, Hui; Wang, Qiang; Adhikari, Benu

    2014-01-01

    Although a number of bioactive peptides are capable of angiotensin I-converting enzyme (ACE) inhibitory effects, little is known regarding the mechanism of peanut peptides using molecular simulation. The aim of this study was to obtain ACE inhibiting peptide from peanut protein and provide insight on the molecular mechanism of its ACE inhibiting action. Peanut peptides having ACE inhibitory activity were isolated through enzymatic hydrolysis and ultrafiltration. Further chromatographic fractionation was conducted to isolate a more potent peanut peptide and its antihypertensive activity was analyzed through in vitro ACE inhibitory tests and in vivo animal experiments. MALDI-TOF/TOF-MS was used to identify its amino acid sequence. Mechanism of ACE inhibition of P8 was analyzed using molecular docking and molecular dynamics simulation. A peanut peptide (P8) having Lys-Leu-Tyr-Met-Arg-Pro amino acid sequence was obtained which had the highest ACE inhibiting activity of 85.77% (half maximal inhibitory concentration (IC50): 0.0052 mg/ml). This peanut peptide is a competitive inhibitor and show significant short term (12 h) and long term (28 days) antihypertensive activity. Dynamic tests illustrated that P8 can be successfully docked into the active pocket of ACE and can be combined with several amino acid residues. Hydrogen bond, electrostatic bond and Pi-bond were found to be the three main interaction contributing to the structural stability of ACE-peptide complex. In addition, zinc atom could form metal-carboxylic coordination bond with Tyr, Met residues of P8, resulting into its high ACE inhibiting activity. Our finding indicated that the peanut peptide (P8) having a Lys-Leu-Tyr-Met-Arg-Pro amino acid sequence can be a promising candidate for functional foods and prescription drug aimed at control of hypertension. PMID:25347076

  13. Suicide Inhibitors of Reverse Transcriptase in the Therapy of AIDS and Other Retroviruses

    DTIC Science & Technology

    1991-07-01

    AD-A241 945 AD_________ CONTRACT NO: DAMD17-87-C-7171 TITLE: SUICIDE INHIBITORS OF REVERSE TRANSCRIPTASE IN THE THERAPY OF AIDS AND OTHER...20052 REPORT nATE: July 1, 1991 D I. Ic OCT 2 11991 TYPE OF REPORT: Final Report SR PREPARED FOR: U.S. ARMY MEDICAL RESEARCH AND DEVELOPMENT COMMAND Fort...tior Proect(0704-018$ Aasnntoa --’( 20503 I. AGENCY USE ONLY (Leave olanii) 12. REPORT DATE 3. REPORT TYPE AND DATES COVERED 1 .""’ly 1991 Final Report

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

    PubMed

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

    2016-04-01

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

  15. Gene therapy for haemophilia: prospects and challenges to prevent or reverse inhibitor formation.

    PubMed

    Scott, David W; Lozier, Jay N

    2012-02-01

    Monogenic hereditary diseases, such as haemophilia A and B, are ideal targets for gene therapeutic approaches. While these diseases can be treated with protein therapeutics, such as factor VIII (FVIII) or IX (FIX), the notion that permanent transfer of the genes encoding these factors can cure haemophilia is very attractive. An underlying problem with a gene therapy approach, however, is the patient's immune response to the therapeutic protein (as well as to the transmission vector), leading to the formation of inhibitory antibodies. Even more daunting is reversing an existing immune response in patients with pre-existing inhibitors. In this review, we will describe the laboratory and clinical progress, and the challenges met thus far, in achieving the goal of gene therapy efficacy, with a focus on the goal of tolerance induction.

  16. Management of sexual dysfunction in postmenopausal breast cancer patients taking adjuvant aromatase inhibitor therapy

    PubMed Central

    Derzko, C.; Elliott, S.; Lam, W.

    2007-01-01

    Treatment with aromatase inhibitors for postmenopausal women with breast cancer has been shown to reduce or obviate invasive procedures such as hysteroscopy or curettage associated with tamoxifen-induced endometrial abnormalities. The side effect of upfront aromatase inhibitors, diminished estrogen synthesis, is similar to that seen with the natural events of aging. The consequences often include vasomotor symptoms (hot flushes) and vaginal dryness and atrophy, which in turn may result in cystitis and vaginitis. Not surprisingly, painful intercourse (dyspareunia) and loss of sexual interest (decreased libido) frequently occur as well. Various interventions, both non-hormonal and hormonal, are currently available to manage these problems. The purpose of the present review is to provide the practitioner with a wide array of management options to assist in treating the sexual consequences of aromatase inhibitors. The suggestions in this review are based on recent literature and on the recommendations set forth both by the North American Menopause Association and in the clinical practice guidelines of the Society of Gynaecologists and Obstetricians of Canada. The complexity of female sexual dysfunction necessitates a biopsychosocial approach to assessment and management alike, with interventions ranging from education and lifestyle changes to sexual counselling, pelvic floor therapies, sexual aids, medications, and dietary supplements—all of which have been reported to have a variable, but often successful, effect on symptom amelioration. Although the use of specific hormone replacement—most commonly local estrogen, and less commonly, systemic estrogen with or without an androgen, progesterone, or the additional of an androgen in an estrogenized woman (or a combination)—may be highly effective, the concern remains that in patients with estrogen-dependent breast cancer, including those receiving anti-estrogenic adjuvant therapies, the use of these hormones may be

  17. Management of sexual dysfunction in postmenopausal breast cancer patients taking adjuvant aromatase inhibitor therapy.

    PubMed

    Derzko, C; Elliott, S; Lam, W

    2007-12-01

    Treatment with aromatase inhibitors for postmenopausal women with breast cancer has been shown to reduce or obviate invasive procedures such as hysteroscopy or curettage associated with tamoxifen-induced endometrial abnormalities. The side effect of upfront aromatase inhibitors, diminished estrogen synthesis, is similar to that seen with the natural events of aging. The consequences often include vasomotor symptoms (hot flushes) and vaginal dryness and atrophy, which in turn may result in cystitis and vaginitis. Not surprisingly, painful intercourse (dyspareunia) and loss of sexual interest (decreased libido) frequently occur as well. Various interventions, both non-hormonal and hormonal, are currently available to manage these problems. The purpose of the present review is to provide the practitioner with a wide array of management options to assist in treating the sexual consequences of aromatase inhibitors. The suggestions in this review are based on recent literature and on the recommendations set forth both by the North American Menopause Association and in the clinical practice guidelines of the Society of Gynaecologists and Obstetricians of Canada. The complexity of female sexual dysfunction necessitates a biopsychosocial approach to assessment and management alike, with interventions ranging from education and lifestyle changes to sexual counselling, pelvic floor therapies, sexual aids, medications, and dietary supplements-all of which have been reported to have a variable, but often successful, effect on symptom amelioration. Although the use of specific hormone replacement-most commonly local estrogen, and less commonly, systemic estrogen with or without an androgen, progesterone, or the additional of an androgen in an estrogenized woman (or a combination)-may be highly effective, the concern remains that in patients with estrogen-dependent breast cancer, including those receiving anti-estrogenic adjuvant therapies, the use of these hormones may be

  18. Vitamin D insufficiency and musculoskeletal symptoms in breast cancer survivors on aromatase inhibitor therapy.

    PubMed

    Waltman, Nancy L; Ott, Carol D; Twiss, Janice J; Gross, Gloria J; Lindsey, Ada M

    2009-01-01

    Breast cancer survivors (BCSs) on aromatase inhibitor (AI) therapy often experience musculoskeletal symptoms (joint pain and stiffness, bone and muscle pain, and muscle weakness), and these musculoskeletal symptoms may be related to low serum levels of vitamin D. The primary purpose of this pilot exploratory study was to determine whether serum levels of 25-hydroxyvitamin D (25[OH]D) concentration were below normal (<30 ng/mL) in 29 BCSs on AI therapy and if musculoskeletal symptoms were related to these low vitamin D levels. The mean (SD) serum 25(OH)D level was 25.62 (4.93) ng/mL; 86% (n = 25) had levels below 30 ng/mL. Patients reported muscle pain in the neck and back, and there was a significant inverse correlation between pain intensity and serum 25(OH)D levels (r = -0.422; P < .05 [2 tailed]). This sample of BCSs taking AIs had below normal levels of serum 25(OH)D despite vitamin D supplements. This is one of the few studies to document a significant relationship between vitamin D levels and muscle pain in BCSs on AI therapy. Findings from this pilot study can be used to inform future studies examining musculoskeletal symptoms in BCSs on AI therapy and relationships with low serum levels of vitamin D.

  19. Angiotensin II receptor antagonists and heart failure: angiotensin-converting-enzyme inhibitors remain the first-line option.

    PubMed

    2005-10-01

    per year per 100 patients), but increased the risk of renal failure and hyperkalemia. (7) In patients with heart failure and incapacitating dyspnea despite ACE inhibitor + diuretic combination therapy, there are no trials comparing the addition of an angiotensin II receptor antagonist versus spironolactone. Adjunctive spironolactone therapy prevents 5 to 6 deaths per year per 100 patients in this setting. (8) In patients with heart failure who do not have markedly altered cardiac contractility, candesartan appears to have no clinical advantages over placebo. (9) In some of these trials, mortality was higher with angiotensin II receptor antagonist therapy than with placebo among patients who were already taking a betablocker. (10) Two trials have compared an angiotensin II receptor antagonist with an ACE inhibitor in patients with recent myocardial infarction who had heart failure or an altered left ventricular ejection fraction, but who did not have hypotension or severe renal failure. However, there are no placebo-controlled randomised trials assessing the effects of angiotensin II receptor antagonists on mortality. (11) In patients with recent myocardial infarction, these trials showed no difference in mortality between angiotensin II receptor antagonist treatment (losartan or valsartan) and captopril. They did not rule out the possibility that these angiotensin II receptor antagonists are moderately less effective than captopril. Adding valsartan to ongoing captopril therapy did not reduce mortality or morbidity as compared with placebo, but did increase the risk of adverse effects. (12) Overall, these trials confirm the advantage of angiotensin II receptor antagonists over ACE inhibitors with respect to some adverse effects (cough, skin rash, etc.). However, the two drug classes share certain serious adverse effects such as hyperkalemia, renal failure and hypotension. In one trial, angioedema was less frequent with angiotensin II receptor antagonist therapy (one

  20. Invention of a novel photodynamic therapy for tumors using a photosensitizing PI3K inhibitor.

    PubMed

    Hayashida, Yushi; Ikeda, Yuka; Sawada, Koichi; Kawai, Katsuhisa; Kato, Takuma; Kakehi, Yoshiyuki; Araki, Nobukazu

    2016-08-01

    XL147 (SAR245408, pilaralisib), an ATP-competitive pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, is a promising new anticancer drug. We examined the effect of the PI3K inhibitor on PC3 prostate cancer cells under a fluorescence microscope and found that XL147-treated cancer cells are rapidly injured by blue wavelength (430 nm) light irradiation. During the irradiation, the cancer cells treated with 0.2-2 μM XL147 showed cell surface blebbing and cytoplasmic vacuolation and died within 15 min. The extent of cell injury/death was dependent on the dose of XL147 and the light power of the irradiation. These findings suggest that XL147 might act as a photosensitizing reagent in photodynamic therapy (PDT) for cancer. Moreover, the cytotoxic effect of photosensitized XL147 was reduced by pretreatment with other ATP-competitive PI3K inhibitors such as LY294002, suggesting that the cytotoxic effect of photosensitized XL147 is facilitated by binding to PI3K in cells. In a single-cell illumination analysis using a fluorescent probe to identify reactive oxygen species (ROS), significantly increased ROS production was observed in the XL147-treated cells when the cell was illuminated with blue light. Taken together, it is conceivable that XL147, which is preferentially accumulated in cancer cells, could be photosensitized by blue light to produce ROS to kill cancer cells. This study will open up new possibilities for PDT using anticancer drugs.

  1. Personalized antiplatelet therapy with P2Y12 receptor inhibitors: benefits and pitfalls

    PubMed Central

    Winter, Max-Paul; Koziński, Marek; Kubica, Jacek; Aradi, Daniel

    2015-01-01

    Antiplatelet therapy with P2Y12 receptor inhibitors has become the cornerstone of medical treatment in patients with acute coronary syndrome, after percutaneous coronary intervention and in secondary prevention of atherothrombotic events. Clopidogrel used to be the most broadly prescribed P2Y12 receptor inhibitor with undisputable benefits especially in combination with aspirin, but a considerable number of clopidogrel-treated patients experience adverse thrombotic events in whom insufficient P2Y12-inhibition and a consequential high on-treatment platelet reactivity is a common finding. This clinically relevant limitation of clopidogrel has driven the increased use of new antiplatelet agents. Prasugrel (a third generation thienopyridine) and ticagrelor (a cyclopentyl-triazolo-pyrimidine) feature more potent and predictable P2Y12-inhibition compared to clopidogrel, which translates into improved ischemic outcomes. However, excessive platelet inhibition and consequential low on-treatment platelet reactivity comes at the price of increased risk of major bleeding. The majority of randomized clinical trials failed to demonstrate improved clinical outcomes with platelet function testing and tailored antiplatelet therapy, but results of all recent trials of potent antiplatelets and prolonged antiplatelet durations point towards a need for individualized antiplatelet approach in order to decrease thrombotic events without increasing bleeding. This review focuses on potential strategies for personalizing antiplatelet treatment. PMID:26677375

  2. Anti-TNF-refractory colitis after checkpoint inhibitor therapy: Possible role of CMV-mediated immunopathogenesis

    PubMed Central

    Lankes, Katharina; Hundorfean, Gheorghe; Harrer, Thomas; Pommer, Ansgar J.; Agaimy, Abbas; Angelovska, Irena; Tajmir-Riahi, Azadeh; Göhl, Jonas; Schuler, Gerold; Neurath, Markus F.; Hohenberger, Werner; Heinzerling, Lucie

    2016-01-01

    ABSTRACT Immune-related adverse events (irAEs) induced by checkpoint inhibitors are well known. Since fatal outcomes have been reported early detection and adequate management are crucial. In particular, colitis is frequently observed and can result in intestinal perforation. This is the first report of an autoimmune colitis that was treated according to algorithms but became resistant due to a CMV reactivation. The 32-y-old male patient with metastatic melanoma treated within an anti-PD-1/ipilimumab combination study developed severe immune-mediated colitis (CTCAE grade 3) with up to 18 watery stools per day starting 2 weeks after treatment initiation. After improving upon therapy with immunosuppressive treatment (high dose steroids and infliximab) combined with parenteral nutrition diarrhea again exacerbated. Additionally, the patient had asymptomatic grade 3 CTCAE amylase and lipase elevation. Colitis was monitored by weekly endoscopies and colon biopsies were analyzed histologically with CMV staining, multi-epitope ligand cartography (MELC) and qRT-PCR for inflammatory genes. In the course, CMV reactivation was detected in the colon and treated with antiviral medication in parallel to a reduction of corticosteroids. Subsequently, symptoms improved. The patient showed a complete response for 2 y now including regression of bone metastases. CMV reactivation under checkpoint inhibitor therapy in combination with immunosuppressive treatment for autoimmune side effects has to be considered in these patients and if present treated. Potentially, CMV reactivation is underdiagnosed. Treatment algorithms should include CMV diagnostics. PMID:27471608

  3. Advanced Collaborative Emissions Study (ACES)

    SciTech Connect

    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. Photodynamic therapy for inactivating endodontic bacterial biofilms and effect of tissue inhibitors on antibacterial efficacy

    NASA Astrophysics Data System (ADS)

    Shrestha, Annie; Kishen, Anil

    Complex nature of bacterial cell membrane and structure of biofilm has challenged the efficacy of antimicrobial photodynamic therapy (APDT) to achieve effective disinfection of infected root canals. In addition, tissue-inhibitors present inside the root canals are known to affect APDT activity. This study was aimed to assess the effect of APDT on bacterial biofilms and evaluate the effect of tissue-inhibitors on the APDT. Rose-bengal (RB) and methylene-blue (MB) were tested on Enterococcus faecalis (gram-positive) and Pseudomonas aeruginosa (gram-negative) biofilms. In vitro 7- day old biofilms were sensitized with RB and MB, and photodynamically activated with 20-60 J/cm2. Photosensitizers were pre-treated with different tissue-inhibitors (dentin, dentin-matrix, pulp tissue, bacterial lipopolysaccharides (LPS), and bovine serum albumin (BSA)) and tested for antibacterial effect of APDT. Microbiological culture based analysis was used to analyze the cell viability, while Laser Scanning Confocal Microscopy (LSCM) was used to examine the structure of biofilm. Photoactivation resulted in significant reduction of bacterial biofilms with RB and MB. The structure of biofilm under LSCM was found to be disrupted with reduced biofilm thickness. Complete biofilm elimination could not be achieved with both tested photosensitizers. APDT effect using MB and RB was inhibited in a decreasing order by dentin-matrix, BSA, pulp, dentin and LPS (P< 0.05). Both strains of bacterial biofilms resisted complete elimination after APDT and the tissue inhibitors existing within the root canal reduced the antibacterial activity at varying degrees. Further research is required to enhance the antibacterial efficacy of APDT in an endodontic environment.

  5. Prophylactic Leukotriene Inhibitor Therapy for the Reduction of Capsular Contracture in Primary Silicone Breast Augmentation: Experience with over 1100 Cases

    PubMed Central

    2017-01-01

    Background: The role of leukotriene inhibitors used immediately postoperatively to potentially influence the development of capsular contracture is unknown. The purpose of this study was to evaluate the incidence of capsular contracture among women undergoing primary smooth silicone gel breast augmentation, with or without postoperative leukotriene inhibitor therapy. Methods: Between 2007 and 2013, 1122 consecutive women undergoing primary silicone gel breast augmentation were evaluated retrospectively. All underwent augmentation with smooth, Mentor Memory Gel implants, using a dual-plane technique, with periareolar or inframammary approaches. Patients were treated voluntarily with either no leukotriene inhibitor, montelukast (Singulair), or zafirlukast (Accolate) for 3 months. All patients received informed consent for the off-label use of leukotriene inhibitors. Liver function studies were obtained for all patients undergoing Accolate therapy after 1 month of therapy. The presence of capsular contracture was measured by the Baker scale at 1 year postoperatively. Results: Patients receiving Accolate therapy (n = 520) demonstrated an encapsulation rate of 2.19 percent. Women receiving Singulair therapy (n = 247) had an encapsulation rate of 3.27 percent. Patients not receiving leukotriene inhibitor therapy had an encapsulation rate of 5.02 percent. There were no long-term complications among patients evaluated. Conclusions: Accolate therapy used for 3 months postoperatively was associated with significantly lower capsular contracture rates compared with untreated patients at 1-year follow-up (p < 0.05). Patients treated with Singulair demonstrated lower contracture rates compared with controls, but the differences were not statistically significant. The findings suggest that Accolate therapy, with monitoring and consent, reduces the incidence of capsular contracture following primary smooth silicone gel breast augmentation. CLINICAL QUESTION/LEVEL OF EVIDENCE

  6. Potentiated antitumor effects of a combination therapy with a farnesyltransferase inhibitor L-744,832 and butyrate in vitro.

    PubMed

    Kopec, Maciej; Strusinska, Katarzyna; Legat, Magdalena; Makowski, Marcin; Jakobisiak, Marek; Golab, Jakub

    2004-05-01

    Farnesyltransferase inhibitors, butyrate and butyric acid derivatives have previously been reported to exert anti-tumor activity in experimental models in vitro and in vivo and have recently gained acceptance as potential anticancer agents. In our study, we examined antitumor effects of a combination of a farnesyltransferase inhibitor L-744,832 and butyrate in vitro against MDA-MB-231 and MIA PaCa-2 human cancer cells. This combination therapy showed synergistic antitumor activity against MDA-MB-231 cells, which was at least in part due to induction of p27KIP1 expression. Both drugs increased intracellular levels of p53 as well but there was no significant difference between the groups treated with single drugs and the group treated with their combination. In MIA PaCa-2 cells, the combination therapy exerted additive antitumor activity. Our results illustrate possible application of the farnesyltransferase inhibitor L-744,832 and butyrate as a combination therapy of cancer.

  7. Second-Generation Tyrosine Kinase Inhibitors (Tki) as Salvage Therapy for Resistant or Intolerant Patients to Prior TKIs.

    PubMed

    Breccia, Massimo; Alimena, Giuliana

    2014-01-02

    With the advent of target therapies, imatinib became the mainstay for treatment of chronic myeloid leukemia. However, despite the brilliant results obtained with this drug, more than 30% of patients discontinue therapy in long-term due to several reasons, including failure and/or intolerance. Second-generation tyrosine kinase inhibitors (TKIs) are more potent drugs and have expanded inhibition against a broad spectrum of mutations resistant to imatinib. Both nilotinib and dasatinib have demonstrated in vitro and in vivo clinical activity against different types of mutations and various forms of resistance. However, patients with T315I mutation do not obtain an advantage from these drugs and a third generation inhibitor ponatinib, a pan-BCR drug, was tested with significant results. In this review, we report the results of second-and third-generation TKIs tested as second or third line therapy in patients resistant and/or intolerant to previous inhibitors.

  8. Comparative study: Vonoprazan and proton pump inhibitors in Helicobacter pylori eradication therapy

    PubMed Central

    Sakurai, Kouichi; Suda, Hiroko; Ido, Yumi; Takeichi, Takayuki; Okuda, Ayako; Hasuda, Kiwamu; Hattori, Masahiro

    2017-01-01

    AIM To compare the effectiveness and safety of vonoprazan-based therapy with proton pump inhibitor (PPI)-based therapies to treat Helicobacter pylori (H. pylori). METHODS We retrospectively analysed data from first-line (vonoprazan or PPI with 200 mg clarithromycin and 750 mg amoxicillin twice daily for 7 d) (n = 1353) and second-line (vonoprazan or PPI with 250 mg metronidazole and 750 mg amoxicillin twice daily for 7 d) (n = 261) eradication treatments for H. pylori -positive patients with associated gastrointestinal diseases from April 2014 to December 2015 at Hattori Clinic, Japan. The primary endpoint was the eradication rate, which was assessed with a full analysis set. The secondary endpoints were adverse events and related factors. RESULTS After the first-line treatments, the eradication rates for vonoprazan, esomeprazol, rabeprazole, and lansoprazole were 87.9% (95%CI: 84.9%-90.5%), 71.6% (95%CI: 67.5%-75.5%), 62.9% (95%CI: 52.0%-72.9%), and 57.3% (95%CI: 50.4%-64.1%), respectively. The vonoprazan eradication rate was significantly higher than that of the PPIs (P < 0.01). Interestingly, smoking did not affect the H. pylori eradication rate in the vonoprazan group (P = 0.34), whereas it decreased the rates in the PPI groups (P = 0.013). The incidence of adverse events in the vonoprazan group was not different from the PPI group (P = 0.054), although the vonoprazan group exhibited a wider range of adverse events. Vonoprazan-based triple therapy was highly effective as a second-line treatment, with an eradication rate similar to that of PPI-based therapy. CONCLUSION Vonoprazan might be superior to PPIs in first-line H. pylori therapy, particularly for smokers. However, caution is required due to possible adverse events. PMID:28216974

  9. Histone deacetylase inhibitor pracinostat in doublet therapy: a unique strategy to improve therapeutic efficacy and to tackle herculean cancer chemoresistance.

    PubMed

    Ganai, Shabir Ahmad

    2016-09-01

    Context Histone deacetylase inhibitors (HDACi) have shown promising results in neurodegeneration and cancer. Hydroxamate HDACi, including vorinostat, have shown encouraging results in haematological malignancies, but the poor pharmacokinetic of these inhibitors leads to insufficient tumour concentration limiting their application against solid malignancies. Objective This article deals with novel HDAC inhibitor pracinostat (SB939) and delineates its therapeutic role in solid and haematological malignancies. The article provides rigorous details about the underlying molecular mechanisms modulated by pracinostat to exert cytotoxic effect. The article further highlights the doublet therapy that may be used to tackle monotonous cancer chemoresistance. Methods Both old and the latest literature on pracinostat was retrieved from diverse sources, such as PubMed, Science Direct, Springer Link, general Google search using both pracinostat and SB939 keywords in various ways: after thorough evaluation the topic which can fulfil the current gap was chosen. Results Pracinostat shows potent anticancer activity against both solid and haematological malignancies compared to the FDA-approved drug vorinostat. This marvellous inhibitor has better physicochemical, pharmaceutical and pharmacokinetic properties than the defined inhibitor vorinostat. Pracinostat has  >100-fold more affinity towards HDACs compared to other zinc-dependent metalloenzymes and shows maximum efficacy when used in doublet therapy. Conclusion Pracinostat shows potent anticancer activity even against therapeutically challenging cancers when used in doublet therapy. However, the triplet combination studies of the defined inhibitor that may prove even more beneficial are still undone, emphasizing the desperate need of further research in the defined gap.

  10. Tyrosine Kinase Inhibitors as Initial Therapy for Patients with Chronic Myeloid Leukemia in Accelerated Phase

    PubMed Central

    Ohanian, Maro; Kantarjian, Hagop M.; Quintas-Cardama, Alfonso; Jabbour, Elias; Abruzzo, Lynne; Verstovsek, Srdan; Borthakur, Gautam; Ravandi, Farhad; Garcia-Manero, Guillermo; Champlin, Richard; Pierce, Sherry; Alattar, Mona Lisa; Trinh, Long Xuan; Luthra, Raja; Ferrajoli, Alessandra; Kadia, Tapan; O’Brien, Susan; Cortes, Jorge E.

    2013-01-01

    Background Accelerated phase CML (CML-AP) most frequently represents a progression state in CML. However, some patients present with AP features at the time of diagnosis. There is limited information on the outcome of these patients when receiving tyrosine kinase inhibitors (TKI) as initial therapy. Methods We analyzed the outcome of 51 consecutive patients with CML who presented with features of AP at the time of diagnosis, including blasts ≥15% (n=6), basophils ≥20%, (n=22), platelets <100×109/L (n=3), cytogenetic clonal evolution (n=17), or more than 1 feature (n=3). Patients received initial therapy with imatinib (n=30), dasatinib (n=5) or nilotinib (n=16). Results The rate of complete cytogenetic response (CCyR) for patients treated with imatinib was 80%, and with dasatinib or nilotinib was 90%. Major molecular response (MMR, BCR-ABL/ABL ≤0.1%, by International Scale [IS]) was achieved in 69% including complete molecular responses (MR4.5, BCR-ABL/ABL ≤0.0032% IS) in 49%. MMR rates for patients treated with imatinib were 63%, and with second generation TKI (2GTKIs) 76%. Overall survival at 36 months was 87% with imatinib and 95% with 2GTKI’s. Conclusion TKIs should be considered standard initial therapy for patients with AP at the time of diagnosis. PMID:24332214

  11. A Mathematical Model of Prostate Tumor Growth Under Hormone Therapy with Mutation Inhibitor

    NASA Astrophysics Data System (ADS)

    Tao, Youshan; Guo, Qian; Aihara, Kazuyuki

    2010-04-01

    This paper extends Jackson’s model describing the growth of a prostate tumor with hormone therapy to a new one with hypothetical mutation inhibitors. The new model not only considers the mutation by which androgen-dependent (AD) tumor cells mutate into androgen-independent (AI) ones but also introduces inhibition which is assumed to change the mutation rate. The tumor consists of two types of cells (AD and AI) whose proliferation and apoptosis rates are functions of androgen concentration. The mathematical model represents a free-boundary problem for a nonlinear system of parabolic equations, which describe the evolution of the populations of the above two types of tumor cells. The tumor surface is a free boundary, whose velocity is equal to the cell’s velocity there. Global existence and uniqueness of solutions of this model is proved. Furthermore, explicit formulae of tumor volume at any time t are found in androgen-deprived environment under the assumption of radial symmetry, and therefore the dynamics of tumor growth under androgen-deprived therapy could be predicted by these formulae. Qualitative analysis and numerical simulation show that controlling the mutation may improve the effect of hormone therapy or delay a tumor relapse.

  12. Anti-interleukin-6 therapy through application of a monogenic protein inhibitor via gene delivery

    PubMed Central

    Görtz, Dieter; Braun, Gerald S.; Maruta, Yuichi; Djudjaj, Sonja; van Roeyen, Claudia R.; Martin, Ina V.; Küster, Andrea; Schmitz-Van de Leur, Hildegard; Scheller, Jürgen; Ostendorf, Tammo; Floege, Jürgen; Müller-Newen, Gerhard

    2015-01-01

    Anti-cytokine therapies have substantially improved the treatment of inflammatory and autoimmune diseases. Cytokine-targeting drugs are usually biologics such as antibodies or other engineered proteins. Production of biologics, however, is complex and intricate and therefore expensive which might limit therapeutic application. To overcome this limitation we developed a strategy that involves the design of an optimized, monogenic cytokine inhibitor and the protein producing capacity of the host. Here, we engineered and characterized a receptor fusion protein, mIL-6-RFP-Fc, for the inhibition of interleukin-6 (IL-6), a well-established target in anti-cytokine therapy. Upon application in mice mIL-6-RFP-Fc inhibited IL-6-induced activation of the transcription factor STAT3 and ERK1/2 kinases in liver and kidney. mIL-6-RFP-Fc is encoded by a single gene and therefore most relevant for gene transfer approaches. Gene transfer through hydrodynamic plasmid delivery in mice resulted in hepatic production and secretion of mIL-6-RFP-Fc into the blood in considerable amounts, blocked hepatic acute phase protein synthesis and improved kidney function in an ischemia and reperfusion injury model. Our study establishes receptor fusion proteins as promising agents in anti-cytokine therapies through gene therapeutic approaches for future targeted and cost-effective treatments. The strategy described here is applicable for many cytokines involved in inflammatory and other diseases. PMID:26423228

  13. ACE2 alterations in kidney disease

    PubMed Central

    Soler, María José; Wysocki, Jan; Batlle, Daniel

    2013-01-01

    Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase that degrades angiotensin (Ang) II to Ang-(1–7). ACE2 is highly expressed within the kidneys, it is largely localized in tubular epithelial cells and less prominently in glomerular epithelial cells and in the renal vasculature. ACE2 activity has been shown to be altered in diabetic kidney disease, hypertensive renal disease and in different models of kidney injury. There is often a dissociation between tubular and glomerular ACE2 expression, particularly in diabetic kidney disease where ACE2 expression is increased at the tubular level but decreased at the glomerular level. In this review, we will discuss alterations in circulating and renal ACE2 recently described in different renal pathologies and disease models as well as their possible significance. PMID:23956234

  14. Aspirin and proton pump inhibitor combination therapy for prevention of cardiovascular disease and Barrett's esophagus.

    PubMed

    Peura, David A; Wilcox, C Mel

    2014-01-01

    Aspirin, used at low doses (75-325 mg daily), prevents aggregation of platelets and is prescribed for patients as pharmacologic prevention of cardiovascular disease. Despite the well-documented beneficial effects of aspirin, prolonged use is associated with damage to the gastrointestinal (GI) mucosa in the upper and lower GI tract. Patient risk of hemorrhage and peptic ulcer formation is increased with older age, previous ulcer history, Helicobacter pylori infection, and concomitant use of nonsteroidal anti-inflammatory drugs, corticosteroids, or antithrombotic agents. As termination of aspirin therapy can precipitate a cardiovascular event, patients at risk need co-therapy with gastroprotective agents, such as proton pump inhibitors (PPIs), to reduce the GI side effects of aspirin treatment. Fixed-dose combinations of low-dose aspirin and gastroprotective agents have been designed to increase medication compliance, improve clinical outcomes, and reduce the overall cost of therapy. Prolonged use of PPIs may, however, lead to serious adverse effects or, in some cases, reduce the cardioprotective effects of aspirin. Hence, physicians need to carefully consider the benefits and risks associated with the condition of each patient to optimize clinical outcomes of combination therapy. A growing body of clinical evidence indicates that aspirin may decrease the risk of colorectal and other GI cancers, as well as reduce progression from Barrett's esophagus (BE) to esophageal adenocarcinoma. Furthermore, PPIs have recently been shown to reduce neoplastic transformation in patients with BE. Thus, the use of a fixed-dose aspirin/PPI combination could potentially provide chemopreventive benefit to patients with BE, and, at the same time, treat the underlying gastroesophageal reflux responsible for the condition.

  15. Characterization of ACE and ACE2 Expression within Different Organs of the NOD Mouse.

    PubMed

    Roca-Ho, Heleia; Riera, Marta; Palau, Vanesa; Pascual, Julio; Soler, Maria Jose

    2017-03-05

    Renin angiotensin system (RAS) is known to play a key role in several diseases such as diabetes, and renal and cardiovascular pathologies. Its blockade has been demonstrated to delay chronic kidney disease progression and cardiovascular damage in diabetic patients. In this sense, since local RAS has been described, the aim of this study is to characterize angiotensin converting enzyme (ACE) and ACE2 activities, as well as protein expression, in several tissues of the non-obese diabetic (NOD) mice model. After 21 or 40 days of diabetes onset, mouse serums and tissues were analyzed for ACE and ACE2 enzyme activities and protein expression. ACE and ACE2 enzyme activities were detected in different tissues. Their expressions vary depending on the studied tissue. Thus, whereas ACE activity was highly expressed in lungs, ACE2 activity was highly expressed in pancreas among the studied tissues. Interestingly, we also observed that diabetes up-regulates ACE mainly in serum, lung, heart, and liver, and ACE2 mainly in serum, liver, and pancreas. In conclusion, we found a marked serum and pulmonary alteration in ACE activity of diabetic mice, suggesting a common regulation. The increase of ACE2 activity within the circulation in diabetic mice may be ascribed to a compensatory mechanism of RAS.

  16. Characterization of ACE and ACE2 Expression within Different Organs of the NOD Mouse

    PubMed Central

    Roca-Ho, Heleia; Riera, Marta; Palau, Vanesa; Pascual, Julio; Soler, Maria Jose

    2017-01-01

    Renin angiotensin system (RAS) is known to play a key role in several diseases such as diabetes, and renal and cardiovascular pathologies. Its blockade has been demonstrated to delay chronic kidney disease progression and cardiovascular damage in diabetic patients. In this sense, since local RAS has been described, the aim of this study is to characterize angiotensin converting enzyme (ACE) and ACE2 activities, as well as protein expression, in several tissues of the non-obese diabetic (NOD) mice model. After 21 or 40 days of diabetes onset, mouse serums and tissues were analyzed for ACE and ACE2 enzyme activities and protein expression. ACE and ACE2 enzyme activities were detected in different tissues. Their expressions vary depending on the studied tissue. Thus, whereas ACE activity was highly expressed in lungs, ACE2 activity was highly expressed in pancreas among the studied tissues. Interestingly, we also observed that diabetes up-regulates ACE mainly in serum, lung, heart, and liver, and ACE2 mainly in serum, liver, and pancreas. In conclusion, we found a marked serum and pulmonary alteration in ACE activity of diabetic mice, suggesting a common regulation. The increase of ACE2 activity within the circulation in diabetic mice may be ascribed to a compensatory mechanism of RAS. PMID:28273875

  17. Myeloproliferative neoplasms: From JAK2 mutations discovery to JAK2 inhibitor therapies

    PubMed Central

    Passamonti, Francesco; Maffioli, Margherita; Caramazza, Domenica; Cazzola, Mario

    2011-01-01

    Most BCR-ABL1-negative myeloproliferative neoplasms (MPN) carry an activating JAK2 mutation. Approximately 96% of patients with polycythemia vera (PV) harbors the V617F mutation in JAK2 exon 14, whereas the minority of JAK2 (V617F)-negative subjects shows several mutations in exon 12. Other mutation events as MPL, TET2, LNK, EZH2 have been described in chronic phase, while NF1, IDH1, IDH2, ASX1, CBL and Ikaros in blast phase of MPN. The specific pathogenic implication of these mutations is under investigation, but they may have a role in refinement of diagnostic criteria and in development of new prognostic models. Several trials with targeted therapy (JAK inhibitors) are ongoing mostly involving patients with PMF, post-PV MF and post-essential thrombocythemia (ET) MF. Treatment with ruxolitinib and TG101348 has shown clinically significant benefits, particularly in improvement of splenomegaly and constitutional symptoms in MF patients. On the other hand, JAK inhibitors have not thus far shown disease-modifying activity therefore any other deduction on these new drugs seems premature. PMID:21646683

  18. Glycolytic inhibitors 2-deoxyglucose and 3-bromopyruvate synergize with photodynamic therapy respectively to inhibit cell migration.

    PubMed

    Feng, Xiaolan; Wang, Pan; Liu, Quanhong; Zhang, Ting; Mai, Bingjie; Wang, Xiaobing

    2015-06-01

    Most cancer cells have the specially increased glycolytic phenotype, which makes this pathway become an attractive therapeutic target. Although glycolytic inhibitor 2-deoxyglucose (2-DG) has been demonstrated to potentiate the cytotoxicity of photodynamic therapy (PDT), the impacts on cell migration after the combined treatment has never been reported yet. The present study aimed to analyze the influence of glycolytic inhibitors 2-DG and 3-bromopyruvate (3-BP) combined with Ce6-PDT on cell motility of Triple Negative Breast Cancer MDA-MB-231 cells. As determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltertrazolium-bromide-Tetraz-olium (MTT) assay, more decreased cell viability was observed in 2-DG + PDT and 3-BP + PDT groups when compared with either monotherapy. Under optimal conditions, synergistic potentiation on cell membrane destruction and the decline of cell adhesion and cells migratory ability were observed in both 2-DG + PDT and 3-BP + PDT by electron microscope observation (SEM), wound healing and trans-well assays. Besides, serious microfilament network collapses as well as impairment of matrix metalloproteinases-9 (MMP-9) were notably improved after the combined treatments by immunofluorescent staining. These results suggest that 2-DG and 3-BP can both significantly potentiated Ce6-PDT efficacy of cell migration inhibition.

  19. Emerging therapies for dyslipidemia: known knowns and known unknowns of MTP inhibitors.

    PubMed

    Raval, Saurin K; Raval, Preeti S; Jain, Mukul R

    2012-01-01

    Last decade had witnessed enormous efforts to develop therapies to treat one or more components of metabolic syndrome, a cluster of diseases including diabetes, obesity and dyslipidemia. Several newer targets are identified and evaluated to treat these metabolic disorders. Microsomal triglyceride transfer protein (MTP) has been identified as one of the promising target for the treatment of dyslipidemia. MTP plays crucial role in the assembly of triglyceride rich chylomicrones in enterocytes and VLDL in hepatocytes and several lines of evidence suggested that MTP inhibitors can be instrumental in combating familial hypercholesterolemia. Several first generation compounds are currently being evaluated in clinic and fatty liver is found to be the main adverse effect of these agents. Recently development of enterocyte specific inhibitor of MTP is emphasized in order to deal with fatty liver issue. In this review, we have dealt with important mechanistic aspects of MTP inhibition, patent scenario and clinical trial outcomes and some of the recent patents related to newly discover chemical scaffolds.

  20. Finding Inhibitors of Mutant Superoxide Dismutase-1 for Amyotrophic Lateral Sclerosis Therapy from Traditional Chinese Medicine

    PubMed Central

    Huang, Hung-Jin; Chang, Tung-Ti; Chen, Hsin-Yi; Chen, Calvin Yu-Chian

    2014-01-01

    Superoxide dismutase type 1 (SOD1) mutations cause protein aggregation and decrease protein stability, which are linked to amyotrophic lateral sclerosis (ALS) disease. This research utilizes the world's largest traditional Chinese medicine (TCM) database to search novel inhibitors of mutant SOD1, and molecular dynamics (MD) simulations were used to analyze the stability of protein that interacted with docked ligands. Docking results show that hesperidin and 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (THSG) have high affinity to mutant SOD1 and then dopamine. For MD simulation analysis, hesperidin and THSG displayed similar value of RMSD with dopamine, and the migration analysis reveals stable fluctuation at the end of MD simulation time. Interestingly, distance between the protein and ligand has distinct difference, and hesperidin changes the position from initial binding site to the other place. In flexibility of residues analysis, the secondary structure among all complexes does not change, indicating that the structure are not affect ligand binding. The binding poses of hesperidin and THSG are similar to dopamine after molecular simulation. Our result indicated that hesperidin and THSG might be potential lead compound to design inhibitors of mutant SOD1 for ALS therapy. PMID:24963318

  1. New bifunctional metalloproteinase inhibitors: an integrated approach towards biological improvements and cancer therapy.

    PubMed

    Marques, Sérgio M; Abate, Claudia C; Chaves, Sílvia; Marques, Fernanda; Santos, Isabel; Nuti, Elisa; Rossello, Armando; Santos, M Amélia

    2013-10-01

    The key role of some matrix metalloproteinases (MMPs) on several pathological processes, including carcinogenesis and tumor growth, makes the development of MMP inhibitors (MMPIs) an attractive approach for cancer therapy. We present herein an integrated approach for the development of a new series of inhibitors of MMP2 and MMP14, two enzymes over-expressed by human ovarian cancer. As a first step, a new series of single model compounds bearing different zinc-binding groups (ZBGs), such as carboxylic, hydroxamic acid, hydrazide and sulfonylhydrazide groups, were studied and revealed reasonably good capacity for the Zn(II) chelation in solution and for the MMP inhibition. Aimed at further reinforcing the biological activity of these MMPIs as anti-cancer agents, a selection of those models was extra-functionalized with benzothiazole (BTA), a group with recognized antitumor activity. Analysis of the results obtained for these bifunctional compounds, in particular the inhibitory activity against MMP2 and MMP14 as well as the anti-proliferative activity on the A2780 ovarian cancer cell line, allowed to understand the activity dependence on the type of ZBG, as well as the relevance of the BTA moiety. Overall, the evidenced BTA-associated activity improvements on enzyme inhibition and cell antiproliferactivity, combined with the hydrolytic stability revealed by the hydrazide group, suggest that these new bifunctional BTA-hydrazide derivatives should be taken in consideration for the development of new generations of MMPIs with anti-cancer activity.

  2. Evaluation of a tyrosine kinase peptide microarray for tyrosine kinase inhibitor therapy selection in cancer

    PubMed Central

    Labots, Mariette; Gotink, Kristy J; Dekker, Henk; Azijli, Kaamar; van der Mijn, Johannes C; Huijts, Charlotte M; Piersma, Sander R; Jiménez, Connie R; Verheul, Henk M W

    2016-01-01

    Personalized cancer medicine aims to accurately predict the response of individual patients to targeted therapies, including tyrosine kinase inhibitors (TKIs). Clinical implementation of this concept requires a robust selection tool. Here, using both cancer cell lines and tumor tissue from patients, we evaluated a high-throughput tyrosine kinase peptide substrate array to determine its readiness as a selection tool for TKI therapy. We found linearly increasing phosphorylation signal intensities of peptides representing kinase activity along the kinetic curve of the assay with 7.5–10 μg of lysate protein and up to 400 μM adenosine triphosphate (ATP). Basal kinase activity profiles were reproducible with intra- and inter-experiment coefficients of variation of <15% and <20%, respectively. Evaluation of 14 tumor cell lines and tissues showed similar consistently high phosphorylated peptides in their basal profiles. Incubation of four patient-derived tumor lysates with the TKIs dasatinib, sunitinib, sorafenib and erlotinib primarily caused inhibition of substrates that were highly phosphorylated in the basal profile analyses. Using recombinant Src and Axl kinase, relative substrate specificity was demonstrated for a subset of peptides, as their phosphorylation was reverted by co-incubation with a specific inhibitor. In conclusion, we demonstrated robust technical specifications of this high-throughput tyrosine kinase peptide microarray. These features required as little as 5–7 μg of protein per sample, facilitating clinical implementation as a TKI selection tool. However, currently available peptide substrates can benefit from an enhancement of the differential potential for complex samples such as tumor lysates. We propose that mass spectrometry-based phosphoproteomics may provide such an enhancement by identifying more discriminative peptides. PMID:27980342

  3. Reinduction of PD1-inhibitor therapy: first experience in eight patients with metastatic melanoma.

    PubMed

    Blasig, Hanna; Bender, Carolin; Hassel, Jessica C; Eigentler, Thomas K; Sachse, Michael M; Hiernickel, Julia; Koop, Anika; Satzger, Imke; Gutzmer, Ralf

    2017-03-02

    Significant progress has been made in the treatment of metastatic melanoma during the last years. Approval of immune-checkpoint inhibitors and targeted therapies has been achieved recently. The sequencing of these therapies is an important issue. Here, we report our experience with the treatment and retreatment with PD1-inhibitors (PD1i) in eight patients. The patients (two female and seven male with a median age of 70 years, all melanoma stage IV, M1c) underwent a first treatment period with PD1i for a median of 5.5 months. Three (37.5%) patients had a stable disease as best response, two (25%) showed progression, two (25%) showed partial response, and one (12.5%) achieved complete remission. PD1i was discontinued due to disease progression in seven patients and due to side effects (pancreatitis) in one patient. Patients were subsequently treated with ipilimumab (n=2), or chemotherapy (n=4), or no other medical treatment (n=2). All eight patients were subsequently retreated with PD1i for a median of 2.5 months. One (12.5%) developed a partial response, whereas in three patients (37.5%) the disease was stabilized. PD1i have shown a high and durable response rate in the first-line treatment of metastatic melanoma. Our study suggests PD1i retreatment as a reasonable option for selected patients. Further investigations are needed to verify the value of PD1i re-exposure and to identify subgroups of patients who can benefit.

  4. Sunitinib: a multitargeted receptor tyrosine kinase inhibitor in the era of molecular cancer therapies.

    PubMed

    Papaetis, Georgios S; Syrigos, Kostas N

    2009-01-01

    Sunitinib is an oral oxindole multitargeted kinase inhibitor that inhibits certain receptor tyrosine kinases (RTKs). These include vascular endothelial growth factor receptors (VEGFR type 1 and 2), platelet-derived growth factor receptors (PDGFR-alpha and PDGFR-beta), stem cell factor receptor (KIT), FMS-like tyrosine kinase-3 (FLT3), glial cell-line derived neurotrophic factor receptor (RET) and the receptor of macrophage-colony stimulating factor (CSF1R). Examination of the antitumor effect of sunitinib in a variety of cell lines in vitro suggested an antiproliferative activity that is dependent on the presence of constitutively active RTK targets. The use of sunitinib as first-line therapy in advanced renal cell carcinoma (RCC) has improved the overall survival compared with that observed after cytokine therapy, while its administration in patients with gastrointestinal stromal tumors (GISTs) after progression or intolerance to imatinib achieved an objective response of 7%. Sunitinib is currently approved for the treatment of GISTs in this setting, and as first-line therapy for the treatment of advanced RCC. The relatively long half-life of sunitinib and its major metabolite allow for a once-daily dosing schedule. An interesting antitumor activity of sunitinib was reported in phase II studies of patients with a variety of malignancies, such as hepatocellular cancer, pancreatic neuroendocrine tumors, and non-small cell lung cancer; results of phase III studies are urgently anticipated. Fatigue is one of the most common adverse effects of sunitinib, as 50-70% of patients with advanced RCC and GIST complained of this adverse effect. Other adverse effects are diarrhea, anorexia, nausea and vomiting, oral changes and bleeding events. Most toxicities are reversible and should not result in discontinuation of sunitinib. If necessary, dose adjustments or interruptions should be made. Hypothyroidism has been described in the first 2 weeks of sunitinib therapy and its

  5. Cost-Effectiveness of Angiotensin-Converting Enzyme Inhibitors for the Prevention of Diabetic Nephropathy in The Netherlands – A Markov Model

    PubMed Central

    Adarkwah, Charles Christian; Gandjour, Afschin; Akkerman, Maren; Evers, Silvia M.

    2011-01-01

    Objective Type 2 diabetes is the main cause of end-stage renal disease (ESRD) in Europe and the USA. Angiotensin-converting enzyme (ACE) inhibitors have a potential to slow down the progression of renal disease and therefore provide a renal-protective effect. The aim of our study was to assess the most cost-effective time to start an ACE inhibitor (or an angiotensin II receptor blocker [ARB] if coughing as a side effect occurs) in patients with newly diagnosed type 2 diabetes in The Netherlands. Methods A lifetime Markov decision model with simulated 50-year-old patients with newly diagnosed diabetes mellitus was developed using published data on costs and health outcomes and simulating the progression of renal disease. A health insurance perspective was adopted. Three strategies were compared: treating all patients at the time of diagnosing type 2 diabetes, screening for microalbuminuria, and screening for macroalbuminuria. Results In the base-case analysis, the treat-all strategy is associated with the lowest costs and highest benefit and therefore dominates screening both for macroalbuminuria and microalbuminuria. A multivariate sensitivity analysis shows that the probability of savings is 70%. Conclusions In The Netherlands for patients with type 2 diabetes prescription of an ACE inhibitor immediately after diagnosis should be considered if they do not have contraindications. An ARB should be considered for those patients developing a dry cough under ACE inhibitor therapy. The potential for cost savings would be even larger if the prevention of cardiovascular events were considered. PMID:22022539

  6. The Atmospheric Chemistry Experiment (ACE): MLT Results

    NASA Astrophysics Data System (ADS)

    Bernath, Peter

    2010-05-01

    ACE (also known as SCISAT) is making a comprehensive set of simultaneous measurements of numerous trace gases, thin clouds, aerosols and temperature by solar occultation from a satellite in low earth orbit. A high inclination (74 degrees) low earth orbit (650 km) gives ACE coverage of tropical, mid-latitudes and polar regions. The primary instrument is a high-resolution (0.02 cm-1) infrared Fourier Transform Spectrometer (FTS) operating from 2 to 13 microns (750-4400 cm-1). ACE was launched by NASA on 12 August 2003 for a nominal 2-year mission; after 6 years on orbit the ACE-FTS performance is still excellent. The first results of ACE have been presented in a special issue of Geophysics Research Letters (http://www.agu.org/journals/ss/ACECHEM1/) in 2005 and recently a special issue on ACE validation has been prepared for Atmospheric Chemistry and Physics (http://www.atmos-chem-phys.net/special_issue114.html) by K. Walker and K. Strong; more information can be found at http://www.ace.uwaterloo.ca. The ACE mission goals were initially focussed mainly on polar ozone chemistry, and more recently have shifted more to the troposphere where organic pollutants such as methanol and formaldehyde have been detected. ACE makes limb observations from about 5 km (cloud free scenes) up to nearly 150 km in the lower thermosphere, where CO2 absorption is still weakly detectable. This talk will review ACE-FTS results in the mesosphere and lower thermosphere. Topics covered will include the mesospheric descent of NOx in the polar winter, spectra of polar mesospheric clouds, concentration profiles of CO2 (which do not match model predictions), and combined Odin-Osiris/ACE-FTS observations.

  7. Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes

    PubMed Central

    Clar, Christine; Gill, James Alexander; Court, Rachel; Waugh, Norman

    2012-01-01

    Background Despite the number of medications for type 2 diabetes, many people with the condition do not achieve good glycaemic control. Some existing glucose-lowering agents have adverse effects such as weight gain or hypoglycaemia. Type 2 diabetes tends to be a progressive disease, and most patients require treatment with combinations of glucose-lowering agents. The sodium glucose co-transporter 2 (SGLT2) receptor inhibitors are a new class of glucose-lowering agents. Objective To assess the clinical effectiveness and safety of the SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. Data sources MEDLINE, Embase, Cochrane Library (all sections); Science Citation Index; trial registries; conference abstracts; drug regulatory authorities; bibliographies of retrieved papers. Inclusion criteria Randomised controlled trials of SGLT2 receptor inhibitors compared with placebo or active comparator in type 2 diabetes in dual or combination therapy. Methods Systematic review. Quality assessment used the Cochrane risk of bias score. Results Seven trials, published in full, assessed dapagliflozin and one assessed canagliflozin. Trial quality appeared good. Dapagliflozin 10 mg reduced HbA1c by −0.54% (weighted mean differences (WMD), 95% CI −0.67 to −0.40) compared to placebo, but there was no difference compared to glipizide. Canagliflozin reduced HbA1c slightly more than sitagliptin (up to −0.21% vs sitagliptin). Both dapagliflozin and canagliflozin led to weight loss (dapagliflozin WMD −1.81 kg (95% CI −2.04 to −1.57), canagliflozin up to −2.3 kg compared to placebo). Limitations Long-term trial extensions suggested that effects were maintained over time. Data on canagliflozin are currently available from only one paper. Costs of the drugs are not known so cost-effectiveness cannot be assessed. More data on safety are needed, with the Food and Drug Administration having concerns about breast and bladder cancers. Conclusions

  8. Combination therapy with renin-angiotensin-aldosterone system inhibitor telmisartan and serine protease inhibitor camostat mesilate provides further renoprotection in a rat chronic kidney disease model.

    PubMed

    Narita, Yuki; Ueda, Miki; Uchimura, Kohei; Kakizoe, Yutaka; Miyasato, Yoshikazu; Mizumoto, Teruhiko; Morinaga, Jun; Hayata, Manabu; Nakagawa, Terumasa; Adachi, Masataka; Miyoshi, Taku; Sakai, Yoshiki; Kadowaki, Daisuke; Hirata, Sumio; Mukoyama, Masashi; Kitamura, Kenichiro

    2016-02-01

    We previously reported that camostat mesilate (CM) had renoprotective and antihypertensive effects in rat CKD models. In this study, we examined if CM has a distinct renoprotective effect from telmisartan (TE), a renin-angiotensin-aldosterone system (RAS) inhibitor, on the progression of CKD. We evaluated the effect of CM (400 mg/kg/day) and/or TE (10 mg/kg/day) on renal function, oxidative stress, renal fibrosis, and RAS components in the adenine-induced rat CKD model following 5-weeks treatment period. The combination therapy with CM and TE significantly decreased the adenine-induced increase in serum creatinine levels compared with each monotherapy, although all treatment groups showed similar reduction in blood pressure. Similarly, adenine-induced elevation in oxidative stress markers and renal fibrosis markers were significantly reduced by the combination therapy relative to each monotherapy. Furthermore, the effect of the combination therapy on plasma renin activity (PRA) and plasma aldosterone concentration (PAC) was similar to that of TE monotherapy, and CM had no effect on both PRA and PAC, suggesting that CM has a distinct pharmacological property from RAS inhibition. Our findings indicate that CM could be a candidate drug for an add-on therapy for CKD patients who had been treated with RAS inhibitors.

  9. Effects of rikkunshito on quality of life in patients with gastroesophageal reflux disease refractory to proton pump inhibitor therapy

    PubMed Central

    Kawai, Takashi; Hirayama, Yoji; Oguchi, Aiko; Ishii, Fumi; Matushita, Masanao; Kitayama, Naoya; Morishita, Shinji; Hiratsuka, Noboru; Ohata, Ken; Konishi, Hiroyuki; Kishino, Maiko; Nakamura, Shinichi

    2017-01-01

    We investigated the effects of rikkunshito, in combination with a proton pump inhibitor, on symptoms and quality of life in patients with proton pump inhibitor-refractory gastroesophageal reflux disease. The subjects were 47 patients with gastroesophageal reflux disease with residual symptoms such as heartburn following 8 weeks of proton pump inhibitor therapy. We administered these subjects rikkunshito in combination with a proton pump inhibitor for 6–8 weeks. We scored their symptoms of heartburn, fullness, abdominal discomfort, and abdominal pain, and surveyed their quality of life using the Reflux Esophagitis Symptom Questionnaire, comprising questions concerning daily activities, meals (changes in amount and favorite foods), and sleep (getting to sleep and early morning waking). Improvement was seen in all symptoms, and quality of life scores for meals and sleep also improved. These results indicate that combination therapy with rikkunshito and a proton pump inhibitor improves quality of life related to eating and sleep in patients with patients with proton pump inhibitor-refractory gastroesophageal reflux disease.

  10. CNS-accessible Inhibitor of Glucosylceramide Synthase for Substrate Reduction Therapy of Neuronopathic Gaucher Disease

    PubMed Central

    Marshall, John; Sun, Ying; Bangari, Dinesh S; Budman, Eva; Park, Hyejung; Nietupski, Jennifer B; Allaire, Amy; Cromwell, Mary A; Wang, Bing; Grabowski, Gregory A; Leonard, John P; Cheng, Seng H

    2016-01-01

    Gaucher disease (GD) is caused by a deficiency of glucocerebrosidase and the consequent lysosomal accumulation of unmetabolized glycolipid substrates. Enzyme-replacement therapy adequately manages the visceral manifestations of nonneuronopathic type-1 Gaucher patients, but not the brain disease in neuronopathic types 2 and 3 GD. Substrate reduction therapy through inhibition of glucosylceramide synthase (GCS) has also been shown to effectively treat the visceral disease. Here, we evaluated the efficacy of a novel small molecule inhibitor of GCS with central nervous system (CNS) access (Genz-682452) to treat the brain disease. Treatment of the conduritol β epoxide-induced mouse model of neuronopathic GD with Genz-682452 reduced the accumulation of liver and brain glycolipids (>70% and >20% respectively), extent of gliosis, and severity of ataxia. In the genetic 4L;C* mouse model, Genz-682452 reduced the levels of substrate in the brain by >40%, the extent of gliosis, and paresis. Importantly, Genz-682452-treated 4L;C* mice also exhibited an ~30% increase in lifespan. Together, these data indicate that an orally available antagonist of GCS that has CNS access is effective at attenuating several of the neuropathologic and behavioral manifestations associated with mouse models of neuronopathic GD. Therefore, Genz-682452 holds promise as a potential therapeutic approach for patients with type-3 GD. PMID:26948439

  11. Tumor necrosis factor-α inhibitor therapy and fetal risk: A systematic literature review

    PubMed Central

    Marchioni, Renée M; Lichtenstein, Gary R

    2013-01-01

    Tumor necrosis factor-α inhibitors (anti-TNFs) are effective in the treatment of inflammatory bowel disease (IBD) recalcitrant to conventional medical therapy. As the peak incidence of IBD overlaps with the prime reproductive years, it is crucial to establish pharmacologic regimens for women of childbearing age that achieve effective disease control without posing significant fetal harm. A systematic literature review was performed to identify all human studies with birth outcomes data after maternal exposure to infliximab, adalimumab, or certolizumab pegol within 3 mo of conception or during any trimester of pregnancy. Live births, spontaneous abortions or stillbirths, preterm or premature births, low birth weight or small for gestational age infants, and congenital abnormalities were recorded. Fifty selected references identified 472 pregnancy exposures. The subsequent review includes general information regarding anti-TNF therapy in pregnancy followed by a summary of our findings. The benefits of biologic modalities in optimizing disease control during pregnancy must be weighed against the potential toxicity of drug exposure on the developing fetus. Although promising overall, there is insufficient evidence to prove absolute safety for use of anti-TNFs during pregnancy given the limitations of available data and lack of controlled trials. PMID:23674866

  12. Development of inhibitor-directed enzyme prodrug therapy (IDEPT) for prostate cancer.

    PubMed

    Martin, Stacy E; Ganguly, Tanushree; Munske, Gerhard R; Fulton, Melody D; Hopkins, Mark R; Berkman, Clifford E; Black, Margaret E

    2014-10-15

    Prostate cancer (PCa) is the second most common cause of cancer death among American men after lung cancer. Unfortunately, current therapies do not provide effective treatments for patients with advanced, metastatic, or hormone refractory disease. Therefore, we seek to generate therapeutic agents for a novel PCa treatment strategy by delivering a suicide enzyme (yCDtriple) to a cell membrane bound biomarker found on PCa cells (prostate-specific membrane antigen (PSMA)). This approach has resulted in a new PCa treatment strategy reported here as inhibitor-directed enzyme prodrug therapy (IDEPT). The therapeutic agents described were generated using a click chemistry reaction between the unnatural amino acid (p-azidophenylalanine (pAzF)) incorporated into yCDtriple and the dibenzylcyclooctyne moiety of our PSMA targeting agent (DBCO-PEG4-AH2-TG97). After characterization of the therapeutic agents, we demonstrate significant PCa cell killing of PSMA-positive cells. Importantly, we demonstrate that this click chemistry approach can be used to efficiently couple a therapeutic protein to a targeting agent and may be applicable to the ablation of other types of cancers and/or malignancies.

  13. Combination Therapy with a Sodium-Glucose Cotransporter 2 Inhibitor and a Dipeptidyl Peptidase-4 Inhibitor Additively Suppresses Macrophage Foam Cell Formation and Atherosclerosis in Diabetic Mice

    PubMed Central

    Hiromura, Munenori; Mori, Yusaku; Kohashi, Kyoko; Kushima, Hideki; Ohara, Makoto; Watanabe, Takuya; Andersson, Olov

    2017-01-01

    Dipeptidyl peptidase-4 inhibitors (DPP-4is), in addition to their antihyperglycemic roles, have antiatherosclerotic effects. We reported that sodium-glucose cotransporter 2 inhibitors (SGLT2is) suppress atherosclerosis in a glucose-dependent manner in diabetic mice. Here, we investigated the effects of combination therapy with SGLT2i and DPP-4i on atherosclerosis in diabetic mice. SGLT2i (ipragliflozin, 1.0 mg/kg/day) and DPP-4i (alogliptin, 8.0 mg/kg/day), either alone or in combination, were administered to db/db mice or streptozotocin-induced diabetic apolipoprotein E-null (Apoe−/−) mice. Ipragliflozin and alogliptin monotherapies improved glucose intolerance; however, combination therapy did not show further improvement. The foam cell formation of peritoneal macrophages was suppressed by both the ipragliflozin and alogliptin monotherapies and was further enhanced by combination therapy. Although foam cell formation was closely associated with HbA1c levels in all groups, DPP-4i alone or the combination group showed further suppression of foam cell formation compared with the control or SGLT2i group at corresponding HbA1c levels. Both ipragliflozin and alogliptin monotherapies decreased scavenger receptors and increased cholesterol efflux regulatory genes in peritoneal macrophages, and combination therapy showed additive changes. In diabetic Apoe−/− mice, combination therapy showed the greatest suppression of plaque volume in the aortic root. In conclusion, combination therapy with SGLT2i and DPP4i synergistically suppresses macrophage foam cell formation and atherosclerosis in diabetic mice.

  14. ACE program/UNIX user manual

    SciTech Connect

    Feng-Berman, S.K.

    1993-01-12

    This report the following: How to use the ace program?; Introduction to the ace program; Online command; Define a macro file; Macro commands; Counters and MCA; Counters usage; Counters database; Feedback Counter Database; MCA functions and macro command; X window Interclient Communication; and How to get around in UNIX?

  15. ACE program/UNIX user manual

    SciTech Connect

    Feng-Berman, S.K.

    1993-01-12

    This report the following: How to use the ace program ; Introduction to the ace program; Online command; Define a macro file; Macro commands; Counters and MCA; Counters usage; Counters database; Feedback Counter Database; MCA functions and macro command; X window Interclient Communication; and How to get around in UNIX

  16. Factors associated with residual gastroesophageal reflux disease symptoms in patients receiving proton pump inhibitor maintenance therapy

    PubMed Central

    Kawara, Fumiaki; Fujita, Tsuyoshi; Morita, Yoshinori; Uda, Atsushi; Masuda, Atsuhiro; Saito, Masaya; Ooi, Makoto; Ishida, Tsukasa; Kondo, Yasuyuki; Yoshida, Shiei; Okuno, Tatsuya; Yano, Yoshihiko; Yoshida, Masaru; Kutsumi, Hiromu; Hayakumo, Takanobu; Yamashita, Kazuhiko; Hirano, Takeshi; Hirai, Midori; Azuma, Takeshi

    2017-01-01

    AIM To elucidate the factors associated with residual gastroesophageal reflux disease (GERD) symptoms in patients receiving proton pump inhibitor (PPI) maintenance therapy in clinical practice. METHODS The study included 39 GERD patients receiving maintenance PPI therapy. Residual symptoms were assessed using the Frequency Scale for Symptoms of GERD (FSSG) questionnaire and the Gastrointestinal Symptom Rating Scale (GSRS). The relationships between the FSSG score and patient background factors, including the CYP2C19 genotype, were analyzed. RESULTS The FSSG scores ranged from 1 to 28 points (median score: 7.5 points), and 19 patients (48.7%) had a score of 8 points or more. The patients’ GSRS scores were significantly correlated with their FSSG scores (correlation coefficient = 0.47, P < 0.005). In erosive esophagitis patients, the FSSG scores of the CYP2C19 rapid metabolizers (RMs) were significantly higher than the scores of the poor metabolizers and intermediate metabolizers (total scores: 16.7 ± 8.6 vs 7.8 ± 5.4, P < 0.05; acid reflux-related symptom scores: 12 ± 1.9 vs 2.5 ± 0.8, P < 0.005). In contrast, the FSSG scores of the CYP2C19 RMs in the non-erosive reflux disease patients were significantly lower than those of the other patients (total scores: 5.5 ± 1.0 vs 11.8 ± 6.3, P < 0.05; dysmotility symptom-related scores: 1.0 ± 0.4 vs 6.0 ± 0.8, P < 0.01). CONCLUSION Approximately half of the GERD patients receiving maintenance PPI therapy had residual symptoms associated with a lower quality of life, and the CYP2C19 genotype appeared to be associated with these residual symptoms. PMID:28373773

  17. Adjunctive Phosphodiesterase-4 Inhibitor Therapy Improves Antibiotic Response to Pulmonary Tuberculosis in a Rabbit Model

    PubMed Central

    Subbian, Selvakumar; Tsenova, Liana; Holloway, Jennifer; Peixoto, Blas; O'Brien, Paul; Dartois, Véronique; Khetani, Vikram; Zeldis, Jerome B.; Kaplan, Gilla

    2016-01-01

    Objectives Adjunctive host-directed therapy is emerging as a new potential approach to improve the outcome of conventional antimicrobial treatment for tuberculosis (TB). We tested the ability of a phosphodiesterase-4 inhibitor (PDE4i) CC-11050, co-administered with the first-line anti-TB drug isoniazid (INH), to accelerate bacillary killing and reduce chronic inflammation in the lungs of rabbits with experimental Mycobacterium tuberculosis (Mtb) infection. Methods A rabbit model of pulmonary TB that recapitulates the pathologic manifestations seen in humans was used. Rabbits were infected with virulent Mtb by aerosol exposure and treated for eight weeks with INH with or without CC-11050, starting at four weeks post infection. The effect of CC-11050 treatment on disease severity, pathology, bacillary load, T cell proliferation and global lung transcriptome profiles were analyzed. Results Significant improvement in bacillary clearance and reduced lung pathology and fibrosis were noted in the rabbits treated for eight weeks with INH + CC-11050, compared to those treated with INH or CC-11050 only. In addition, expression of host genes associated with tissue remodeling, tumor necrosis factor alpha (TNF-α) regulation, macrophage activation and lung inflammation networks was dampened in CC-11050-treated, compared to the untreated rabbits. Conclusions Adjunctive CC-11050 therapy significantly improves the response of rabbits with experimental pulmonary TB to INH treatment. We propose that CC-11050 may be a promising candidate for host directed therapy of patients with pulmonary TB, reducing the duration and improving clinical outcome of antibiotic treatment. PMID:26981575

  18. Validation of the Reflux Symptom Questionnaire Electronic Diary in Partial Responders to Proton Pump Inhibitor Therapy

    PubMed Central

    Vakil, Nimish; Björck, Karin; Denison, Hans; Halling, Katarina; Karlsson, Maria; Paty, Jean; Silberg, Debra G; Rydén, Anna

    2012-01-01

    OBJECTIVES: We aimed to develop and validate the Reflux Symptom Questionnaire electronic Diary (RESQ-eD) for use in clinical trials in patients with a partial response to proton pump inhibitor (PPI) therapy, using methods that meet US Food & Drug Administration (FDA) regulatory standards. METHODS: Patient interviews were performed to elicit new items and evaluate existing items from the Reflux Disease Questionnaire. The instrument's measurement properties were evaluated, based on data from two clinical trials of patients with gastroesophageal reflux disease (GERD) with a partial response to PPIs who received lesogaberan or placebo as an add-on to PPI therapy. RESULTS: The content validity phase resulted in 13 RESQ-eD items. Principal component analysis supported a four-domain structure. All domains had a high inter-item correlation (Cronbach's alpha lower 95% confidence limit: 0.87–0.95). Test-retest reliability was good to excellent (intraclass correlation coefficient: 0.65–0.85). Convergent and discriminant validity was confirmed by correlation assessments referencing the Gastrointestinal Symptom Rating Scale. The RESQ-eD demonstrated a good ability to capture change in mean intensity and proportion of symptom-free days. Confirmatory psychometric evaluation verified internal consistency reliability, test-retest reliability, and ability to capture change. CONCLUSIONS: The RESQ-eD demonstrated good content validity and psychometric properties in the clinical trial setting in patients with GERD who have a partial response to PPI therapy. To our knowledge, the RESQ-eD is the first electronic symptom diary for use in partial responders to PPI that has been developed in line with the FDA guidance on patient-reported outcomes. PMID:23238029

  19. Neutrophil biomarkers predict response to therapy with tumor necrosis factor inhibitors in rheumatoid arthritis.

    PubMed

    Wright, Helen L; Cox, Trevor; Moots, Robert J; Edwards, Steven W

    2017-03-01

    Neutrophils are implicated in the pathology of rheumatoid arthritis (RA), but the mechanisms regulating their activation are largely unknown. RA is a heterogeneous disease, and whereas many patients show clinical improvement during TNF inhibitor (TNFi) therapy, a significant proportion fails to respond. In vitro activation of neutrophils with agents, including TNF, results in rapid and selective changes in gene expression, but how neutrophils contribute to TNF signaling in RA and whether TNFi sensitivity involves differential neutrophil responses are unknown. With the use of RNA sequencing (RNA-Seq), we analyzed blood neutrophils from 20 RA patients, pre-TNFi therapy, to identify biomarkers of response, measured by a decrease in disease activity score based on 28 joint count (DAS28), 12 wk post-therapy. Biomarkers were validated by quantitative PCR (qPCR) of blood neutrophils from 2 further independent cohorts of RA patients: 16 pre-TNFi and 16 predisease-modifying anti-rheumatic drugs (DMARDs). Twenty-three neutrophil transcripts predicted a 12-wk response to TNFi: 10 (IFN-regulated) genes predicting a European League against Rheumatism (EULAR) good response and 13 different genes [neutrophil granule protein (NGP) genes] predicting a nonresponse. Statistical analysis indicated a predictive sensitivity and specificity of each gene in the panel of >80%, with some 100% specific. A combination of 3 genes [cytidine monophosphate kinase 2 (CMPK2), IFN-induced protein with tetratricopeptide repeats 1B (IFIT1B), and RNASE3] had the greatest predictive power [area under the curve (AUC) 0.94]. No correlation was found for a response to DMARDs. We conclude that this panel of genes is selective for predicting a response to TNFi and is not a surrogate marker for disease improvement. We also show that in RA, there is great plasticity in neutrophil phenotype, with circulating cells expressing genes normally only expressed in more immature cells.

  20. Benefit/risk for adjuvant breast cancer therapy with tamoxifen or aromatase inhibitor use by age, and race/ethnicity.

    PubMed

    Chlebowski, R T; Haque, R; Hedlin, H; Col, N; Paskett, E; Manson, J E; Kubo, J T; Johnson, K C; Wactawski-Wende, J; Pan, K; Anderson, G

    2015-12-01

    In early adjuvant breast cancer trial reports, aromatase inhibitors more effectively reduced breast recurrence with lower risk of thromboembolic events and endometrial cancer than tamoxifen, while aromatase inhibitors had higher fracture and cardiovascular disease risk. We used data from updated patient-level meta-analyses of adjuvant trials in analyses to summarize the benefits and risks of these agents in various clinical circumstances. Baseline incidence rates for health outcomes by age and race/ethnicity, absent aromatase inhibitor, or tamoxifen use were estimated from the Women's Health Initiative. Aromatase inhibitor and tamoxifen effects on distant recurrence were obtained from a meta-analysis of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) and Breast International Group (Big-1-98) clinical trials. Impact on other health outcomes were obtained from meta-analyses of randomized trials comparing aromatase inhibitor to tamoxifen use and from placebo-controlled chemoprevention trials. All health outcomes were given equal weight when modeling net benefit/risk for aromatase inhibitor compared to tamoxifen use by breast cancer recurrence risk, age (decade), race/ethnicity, hysterectomy (yes/no), and by prior myocardial infarction. Over a 10-year period, the benefit/risk index was more favorable for aromatase inhibitor than for tamoxifen as adjuvant breast cancer therapy in almost all circumstances regardless of patient age, race/ethnicity, breast cancer recurrence risk, or presence or absence of a uterus. Only in older women with prior myocardial infarction and low recurrence risk was an advantage for tamoxifen seen. Using a benefit/risk index for endocrine adjuvant breast cancer therapy in postmenopausal women, benefit was higher for aromatase inhibitor use in almost all circumstances.

  1. The Aerosol, Clouds and Ecosystem (ACE) Mission

    NASA Astrophysics Data System (ADS)

    Schoeberl, M.; Remer, L.; Kahn, R.; Starr, D.; Hildebrand, P.; Colarco, P.; Diner, D.; Vane, D.; Im, E.; Behrenfeld, M.; Stephens, G.; Maring, H.; Bontempi, P.; Martins, J. V.

    2008-12-01

    The Aerosol, Clouds and Ecosystem (ACE) Mission is a second tier Decadal Survey mission designed to characterize the role of aerosols in climate forcing, especially their impact on precipitation and cloud formation. ACE also includes ocean biosphere measurements (chlorophyll and dissolved organic materials) which will be greatly improved by simultaneous measurements of aerosols. The nominal ACE payload includes lidar and multiangle spectropolarimetric polarimetric measurements of aerosols, radar measurements of clouds and multi-band spectrometer for the measurement of ocean ecosystems. An enhancement to ACE payload under consideration includes µ-wave radiometer measurements of cloud ice and water outside the nadir path of the radar/lidar beams. This talk will cover ACE instrument and science options, updates on the science team definition activity and science potential.

  2. [Indoleamine 2,3-Dioxygenase Activity during Fulvestrant Therapy for Aromatase Inhibitor-Resistant Metastatic Breast Cancer].

    PubMed

    Sakurai, Kenichi; Fujisaki, Shigeru; Suzuki, Shuhei; Adachi, Keita; Nagashima, Saki; Masuo, Yuki; Tomita, Ryouichi; Gonda, Kenji; Enomoto, Katsuhisa; Amano, Sadao; Matsuo, Sadanori; Umeda, Nao

    2015-10-01

    We evaluated the clinical significance of indoleamine 2,3-dioxygenase (IDO) during fulvestrant therapy for aromatase inhibitor (AI)-resistant metastatic breast cancer. IDO activity can be measured by the tryptophan (Trp)/kynurenine (Kyn) ratio. Trp and Kyn were measured with high performance liquid chromatography (HPLC). Patients with AI resistant metastatic breast cancer had a 28.6% response rate to fulvestrant therapy, and the clinical benefit rate was 76.2%. AI-resistant metastatic breast cancer patients with distant metastases had a lower serum Trp/Kyn level than patients who had local recurrences. During fulvestrant therapy, IDO activity significantly decreased in the fulvestrant responder group compared to that in the fulvestrant non-responder group. During fulvestrant therapy, the IDO activity correlated with the number of metastatic lesions. These results suggest that measuring the Trp/Kyn ratio is useful for evaluating immunological metastatic status during endocrine therapy.

  3. Potentiation of Peptide Receptor Radionuclide Therapy by the PARP Inhibitor Olaparib

    PubMed Central

    Nonnekens, Julie; van Kranenburg, Melissa; Beerens, Cecile E.M.T.; Suker, Mustafa; Doukas, Michael; van Eijck, Casper H.J.; de Jong, Marion; van Gent, Dik C.

    2016-01-01

    Metastases expressing tumor-specific receptors can be targeted and treated by binding of radiolabeled peptides (peptide receptor radionuclide therapy or PRRT). For example, patients with metastasized somatostatin receptor-positive neuroendocrine tumors (NETs) can be treated with radiolabeled somatostatin analogues, resulting in strongly increased progression-free survival and quality of life. There is nevertheless still room for improvement, as very few patients can be cured at this stage of disease. We aimed to specifically sensitize replicating tumor cells without further damage to healthy tissues. Thereto we investigated the DNA damaging effects of PRRT with the purpose to enhance these effects through modulation of the DNA damage response. Although PRRT induces DNA double strand breaks (DSBs), a larger fraction of the induced lesions are single strand breaks (expected to be similar to those induced by external beam radiotherapy) that require poly-[ADP-ribose]-polymerase 1 (PARP-1) activity for repair. If these breaks cannot be repaired, they will cause replication fork arrest and DSB formation during replication. Therefore, we used the PARP-1 inhibitor Olaparib to increase the number of cytotoxic DSBs. Here we show that this new combination strategy synergistically sensitized somatostatin receptor expressing cells to PRRT. We observed increased cell death and reduced cellular proliferation compared to the PRRT alone. The enhanced cell death was caused by increased numbers of DSBs that are repaired with remarkably slow kinetics, leading to genome instability. Furthermore, we validated the increased DSB induction after PARP inhibitor addition in the clinically relevant model of living human NET slices. We expect that this combined regimen can thus augment current PRRT outcomes. PMID:27570553

  4. Nonclinical Safety Profile of BMS-986001, a Nucleoside Transcriptase Inhibitor for Combination Retroviral Therapy.

    PubMed

    Mausumee, Guha; Frank, Simutis; Shawn, Clark; Dara, Hawthorne; Zhao, Yue; Soleil, Piche Marie; Sanderson, Thomas P; Michael, Graziano; Marc, Davies

    2014-05-01

    Nucleoside reverse transcriptase inhibitors (NRTIs)/nucleotide reverse transcriptase inhibitors are key components of combination antiretroviral therapy for HIV infection. First-generation NRTIs are associated with mitochondrial toxicity in patients, mainly due to inhibition of human DNA polymerase γ (hDNA polγ) that manifests as adverse events such as lipodystrophy, lactic acidosis, myopathy, cardiomyopathy, or nephropathy in patients. In chronic nonclinical studies in rodents and nonrodents, eukaryotic (host) mitochondrial toxicity manifests as some drug-specific toxicities similar to human toxicity. BMS-986001, a novel thymidine analog with minimal hDNA polγ inhibition, has demonstrated antiretroviral activity in early clinical studies. The primary toxicity of BMS-986001 in rats and monkeys is bone marrow dyserythropoiesis with associated decreases in red blood cell mass. Additionally, at high doses, severe platelet reductions accompanied by cutaneous petechiae began during weeks 8 and 11 in 3 of 60 monkeys in chronic toxicity studies. In a 6-month study, platelet reductions required euthanasia of the 2 affected monkeys (300 mg/kg/d) at week 14, but with dose reduction (200 mg/kg/d) remaining monkeys had no platelet changes. One affected monkey (200 mg/kg/d) in a 9-month study completed dosing and its platelet counts recovered during a 1-month recovery. Formation of platelet-bound immunoglobulin in the presence of BMS-986001, together with rapid and complete platelet recovery in the absence of BMS-986001, suggested that platelet decreases in monkeys may be immune mediated. No findings indicative of mitochondrial toxicity were observed in rats or monkeys given BMS-986001, suggesting an improved safety profile compared to marketed NRTI or tenofovir disoproxil fumarate.

  5. Dipeptidyl peptidase-4 inhibitors or sodium glucose co-transporter-2 inhibitors as an add-on to insulin therapy: A comparative review.

    PubMed

    Singh, Awadhesh Kumar; Singh, Ritu

    2016-01-01

    The gradual decline in β-cell function is inevitable in type 2 diabetes mellitus and therefore, substantial proportions of patients require insulin subsequently, in order to achieve optimal glucose control. While weight gain, hypoglycemia, and fluid retention especially during dose intensification is a known limitation to insulin therapy, these adverse effects also reduce patient satisfaction and treatment adherence. It is also possible that the benefits of intensive control achieved by insulin therapy, perhaps get nullified by the weight gain and hypoglycemia. In addition, improvement in plasma glucose or glycated hemoglobin (HbA1c) itself is associated with weight gain. Notably, studies have already suggested that reduction in body weight by ~3-5%, may allow a significantly better glycemic control. Thus, a class of drugs, which can reduce HbA1c effectively, yet are weight neutral or preferably reduce body weight, could be the most sought out strategy as an add-on therapy to insulin. While sulfonylureas (SUs) are associated with weight gain and hypoglycemia, pioglitazone increases body weight and fluid retention. Moreover, SUs are not recommended once premix or prandial insulin is commenced. The addition of newer agents, such as glucagon-like peptide-1 receptor agonist to insulin certainly appears to be an effective tool in reducing both HbA1c and body weight as is evident across the studies; however, this approach incurs an additional injection as well as cost. Dipeptidyl peptidase-4 inhibitors (DPP-4I) and sodium-glucose co-transporter-2 inhibitors (SGLT-2I) are other exciting options, as an add-on to insulin therapy primarily because these are oral drugs and do not possess any intrinsic potential of hypoglycemia. Furthermore, these are either weight neutral or induce significant weight loss. This review article aims to comparatively analyze the safety and efficacy of DPP-4I and SGLT-2I, as an add-on therapy to insulin.

  6. HIV-1 replication in central nervous system increases over time on only protease inhibitor therapy.

    PubMed

    Donath, Maximilian; Wolf, Timo; Stürmer, Martin; Herrmann, Eva; Bickel, Markus; Khaykin, Pavel; Göpel, Siri; Gute, Peter; Haberl, Annette; de Leuw, Philipp; Schüttfort, Gundolf; Berger, Annemarie; Stephan, Christoph

    2016-12-01

    There are concerns about central nervous system (CNS)-replication of HIV-1 in patients on boosted protease inhibitors. Purpose of this study was to compare HIV-1 viral loads (VLs) from patients treated with only boosted dual protease inhibitor (bdPI), versus combination antiretroviral therapy (cART group), containing two nucleoside analogue reverse transcriptase inhibitors (NRTI) and a third partner. All patients from a large German HIV-treatment cohort with available medication, clinical and demographic data, including results from simultaneous HIV-1 viral load (VL) assessments in cerebrospinal fluid (CSF) and blood plasma, were retrospectively evaluated as controlled cross-sectional study. CSF had been obtained from patients with variable neurological symptoms during 2005-2014. Statistical analysis comprised nonparametric tests, regression and correlation techniques accounting for undetectable quantifications. Statistical analysis comprised nonparametric tests, regression and correlation techniques accounting for undetectable quantifications. Overall, 155 patients were evaluable (bdPI: 24; cART: 131). At time of CSF-collection, both groups were comparable in age, gender, CD4-cell counts, or primary HIV-transmission risks, though bdPI patients were clinically more advanced. The proportion of patients with undetectable HIV-1 (<50 copies/ml) in CSF was lower for bdPI group (25 vs 49.6 %; p = 0.026), but similar in plasma (46 vs 41 %). Median CSF-VL was higher in bdPI group (600 vs 50 copies/ml; p = 0.027) and similar in plasma. Mean VL CSF/plasma ratio was 342.91 for bdPI- and 54.48 for cART patients (p < 0.001). Pearson's regression analysis revealed a trend for an elevated VL-ratio over time within bdPI group. HIV-1 replication was higher and more frequently detectable in CSF from bdPI patients, indicating a worse CNS penetration effectiveness of used boosted PI. Within bdPI group, measured CNS-viral replication was increasing over time, suggesting an over

  7. Dipeptidyl peptidase-4 inhibitors in type 2 diabetes therapy--focus on alogliptin.

    PubMed

    Capuano, Annalisa; Sportiello, Liberata; Maiorino, Maria Ida; Rossi, Francesco; Giugliano, Dario; Esposito, Katherine

    2013-01-01

    Type 2 diabetes mellitus is a complex and progressive disease that is showing an apparently unstoppable increase worldwide. Although there is general agreement on the first-line use of metformin in most patients with type 2 diabetes, the ideal drug sequence after metformin failure is an area of increasing uncertainty. New treatment strategies target pancreatic islet dysfunction, in particular gut-derived incretin hormones. Inhibition of the enzyme dipeptidyl peptidase-4 (DPP-4) slows degradation of endogenous glucagon-like peptide-1 (GLP-1) and thereby enhances and prolongs the action of the endogenous incretin hormones. The five available DPP-4 inhibitors, also known as 'gliptins' (sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin), are small molecules used orally with similar overall clinical efficacy and safety profiles in patients with type 2 diabetes. The main differences between the five gliptins on the market include: potency, target selectivity, oral bioavailability, long or short half-life, high or low binding to plasma proteins, metabolism, presence of active or inactive metabolites, excretion routes, dosage adjustment for renal and liver insufficiency, and potential drug-drug interactions. On average, treatment with gliptins is expected to produce a mean glycated hemoglobin (HbA1c) decrease of 0.5%-0.8%, with about 40% of diabetic subjects at target for the HbA1c goal <7%. There are very few studies comparing DPP-4 inhibitors. Alogliptin as monotherapy or added to metformin, pioglitazone, glibenclamide, voglibose, or insulin therapy significantly improves glycemic control compared with placebo in adult or elderly patients with inadequately controlled type 2 diabetes. In the EXAMINE trial, alogliptin is being compared with placebo on cardiovascular outcomes in approximately 5,400 patients with type 2 diabetes. In clinical studies, DPP-4 inhibitors were generally safe and well tolerated. However, there are limited data on their tolerability

  8. Phthalocyanine photodynamic therapy: disparate effects of pharmacologic inhibitors on cutaneous photosensitivity and on tumor regression.

    PubMed

    Anderson, C; Hrabovsky, S; McKinley, Y; Tubesing, K; Tang, H P; Dunbar, R; Mukhtar, H; Elmets, C A

    1997-05-01

    The phthalocyanines are promising second-generation photosensitizers that are being evaluated for the photodynamic therapy (PDT) of malignant tumors. In vivo studies with the silicon phthalocyanine Pc 4 have shown that it is highly effective at causing regression of RIF-1 tumors in C3H/HeN mice in PDT protocols. Because cutaneous photosensitivity is the major complication of photosensitizers used for PDT, experiments were performed to evaluate the effect of inhibitors of the inflammatory response (cyproheptadine, dexamethasone, pentoxifylline, and tumor necrosis factor alpha [TNF-alpha] antibodies) on Pc 4-induced cutaneous photosensitivity and tumor regression. The C3H/HeN mice were injected with either Pc 4 or Photofrin and were exposed to 86 J/cm2 of filtered radiation emitted from a solar simulator. Animals were irradiated at 1, 3, 7, 10, 14 and 28 days postinjection. Cutaneous photosensitivity was assessed using the murine ear-swelling response. Cyproheptadine, dexamethasone, pentoxifylline and TNF-alpha antibodies were administered prior to illumination to assess their ability to block Pc 4-induced cutaneous photosensitivity and to evaluate whether such treatment adversely influenced Pc 4 PDT-induced tumor regression. Compared to Photofrin, Pc 4 produced cutaneous photosensitivity that was transient, resolving within 24 h, and that could be elicited for only 10 days after administration. In contrast, Photofrin caused photosensitivity that required 4 days to resolve and could be elicited for at least 1 month after it was administered. The Pc 4-induced cutaneous photosensitivity could be blocked by corticosteroids and an inhibitor of vasoactive amines (cyproheptadine). The TNF-alpha gene transcription was found to increase in keratinocytes following treatment with Pc 4 and light. The anti-TNF-alpha antibodies and pentoxifylline, an inhibitor of cytokine transcription, also prevented cutaneous photosensitivity, implicating TNF-alpha in the pathogenesis of Pc 4

  9. Analysis of CXCR5(+)Th17 cells in relation to disease activity and TNF inhibitor therapy in Rheumatoid Arthritis.

    PubMed

    Singh, Deepika; Henkel, Matthew; Sendon, Bernadette; Feng, June; Fabio, Anthony; Metes, Diana; Moreland, Larry W; McGeachy, Mandy J

    2016-12-22

    Th17 and TfH cells are thought to promote tissue inflammation and autoantibody production, respectively, in autoimmune diseases including rheumatoid arthritis (RA). TfH cells that co-express Th17 markers (CXCR5(+)Th17) encompass both of these pathogenic functions, and are increased in some human autoimmune settings including juvenile dermatomyositis. We investigated CXCR5(+)Th17 cells in RA subjects with stable or active disease and before and after TNF inhibitor therapy. CXCR5(+)Th17 cell frequency was increased in RA compared to healthy controls, but other helper T cell subsets were not different. CXCR5(+)Th17 cells correlated with disease activity in subjects with active RA prior to initiation of TNF inhibitor therapy. Baseline CXCR5(+)Th17 cells also correlated with numbers of swollen joints as late as one year post-therapy. CXCR5(+)Th17 cell frequencies were unaltered by TNF blockade and in fact remained remarkably stable within individuals. We conclude that CXCR5(+)Th17 cells are not a direct target of TNF blockade and therefore cannot serve as a biomarker of current disease activity. However, basal CXCR5(+)Th17 cell frequency may indicate underlying differences in disease phenotype between patients and predict ultimate success of TNF inhibitor therapy.

  10. Analysis of CXCR5+Th17 cells in relation to disease activity and TNF inhibitor therapy in Rheumatoid Arthritis

    PubMed Central

    Singh, Deepika; Henkel, Matthew; Sendon, Bernadette; Feng, June; Fabio, Anthony; Metes, Diana; Moreland, Larry W.; McGeachy, Mandy J.

    2016-01-01

    Th17 and TfH cells are thought to promote tissue inflammation and autoantibody production, respectively, in autoimmune diseases including rheumatoid arthritis (RA). TfH cells that co-express Th17 markers (CXCR5+Th17) encompass both of these pathogenic functions, and are increased in some human autoimmune settings including juvenile dermatomyositis. We investigated CXCR5+Th17 cells in RA subjects with stable or active disease and before and after TNF inhibitor therapy. CXCR5+Th17 cell frequency was increased in RA compared to healthy controls, but other helper T cell subsets were not different. CXCR5+Th17 cells correlated with disease activity in subjects with active RA prior to initiation of TNF inhibitor therapy. Baseline CXCR5+Th17 cells also correlated with numbers of swollen joints as late as one year post-therapy. CXCR5+Th17 cell frequencies were unaltered by TNF blockade and in fact remained remarkably stable within individuals. We conclude that CXCR5+Th17 cells are not a direct target of TNF blockade and therefore cannot serve as a biomarker of current disease activity. However, basal CXCR5+Th17 cell frequency may indicate underlying differences in disease phenotype between patients and predict ultimate success of TNF inhibitor therapy. PMID:28004828

  11. Gold nanoparticles enhance the effect of tyrosine kinase inhibitors in acute myeloid leukemia therapy

    PubMed Central

    Petrushev, Bobe; Boca, Sanda; Simon, Timea; Berce, Cristian; Frinc, Ioana; Dima, Delia; Selicean, Sonia; Gafencu, Grigore-Aristide; Tanase, Alina; Zdrenghea, Mihnea; Florea, Adrian; Suarasan, Sorina; Dima, Liana; Stanciu, Raluca; Jurj, Ancuta; Buzoianu, Anca; Cucuianu, Andrei; Astilean, Simion; Irimie, Alexandru; Tomuleasa, Ciprian; Berindan-Neagoe, Ioana

    2016-01-01

    Background and aims Every year, in Europe, acute myeloid leukemia (AML) is diagnosed in thousands of adults. For most subtypes of AML, the backbone of treatment was introduced nearly 40 years ago as a combination of cytosine arabinoside with an anthracycline. This therapy is still the worldwide standard of care. Two-thirds of patients achieve complete remission, although most of them ultimately relapse. Since the FLT3 mutation is the most frequent, it serves as a key molecular target for tyrosine kinase inhibitors (TKIs) that inhibit FLT3 kinase. In this study, we report the conjugation of TKIs onto spherical gold nanoparticles. Materials and methods The internalization of TKI-nanocarriers was proved by the strongly scattered light from gold nanoparticles and was correlated with the results obtained by transmission electron microscopy and dark-field microscopy. The therapeutic effect of the newly designed drugs was investigated by several methods including cell counting assay as well as the MTT assay. Results We report the newly described bioconjugates to be superior when compared with the drug alone, with data confirmed by state-of-the-art analyses of internalization, cell biology, gene analysis for FLT3-IDT gene, and Western blotting to assess degradation of the FLT3 protein. Conclusion The effective transmembrane delivery and increased efficacy validate its use as a potential therapeutic. PMID:26929621

  12. Histone deacetylase inhibitors for cancer therapy: An evolutionarily ancient resistance response may explain their limited success.

    PubMed

    Halsall, John A; Turner, Bryan M

    2016-11-01

    Histone deacetylase inhibitors (HDACi) are in clinical trials against a variety of cancers. Despite early successes, results against the more common solid tumors have been mixed. How is it that so many cancers, and most normal cells, tolerate the disruption caused by HDACi-induced protein hyperacetylation? And why are a few cancers so sensitive? Here we discuss recent results showing that human cells mount a coordinated transcriptional response to HDACi that mitigates their toxic effects. We present a hypothetical signaling system that could trigger and mediate this response. To account for the existence of such a response, we note that HDACi of various chemical types are made by a variety of organisms to kill or suppress competitors. We suggest that the resistance response in human cells is a necessary evolutionary consequence of exposure to environmental HDACi. We speculate that cancers sensitive to HDACi are those in which the resistance response has been compromised by mutation. Identifying such mutations will allow targeting of HDACi therapy to potentially susceptible cancers. Also see the video abstract here.

  13. Novel selective inhibitors of nuclear export CRM1 antagonists for therapy in mantle cell lymphoma.

    PubMed

    Zhang, Kejie; Wang, Michael; Tamayo, Archito T; Shacham, Sharon; Kauffman, Michael; Lee, John; Zhang, Liang; Ou, Zhishuo; Li, Changping; Sun, Luhong; Ford, Richard J; Pham, Lan V

    2013-01-01

    Overexpression of the cellular nuclear exportin 1, more commonly called chromosomal region maintenance 1 (CRM1), has been associated with malignant progression and mortality. Therefore, activation of nuclear export can play a significant etiologic role in some forms of human neoplasia and serve as a novel target for the treatment of these cancers. Mantle cell lymphoma (MCL) is an aggressive histotype of B-cell non-Hodgkin lymphoma that remains incurable. The objective of this study was to investigate the functional significance of CRM1 in MCL by evaluating the therapeutic efficacy of CRM1 inhibition in MCL in vitro and in vivo. Our results showed that CRM1 is highly expressed in MCL cells and is involved in regulating growth and survival mechanisms through the critical nuclear factor-κB survival pathway, which is independent of p53 status. Inhibition of CRM1 by two novel selective inhibitors of nuclear export (SINE), KPT-185 and KPT-276, in MCL cells resulted in significant growth inhibition and apoptosis induction. KPT-185 also induced CRM1 accumulation in the nucleus, resulting in CRM1 degradation by the proteasome. Oral administration of KPT-276 significantly suppressed tumor growth in an MCL-bearing severe combined immunodeficient mouse model, without severe toxicity. Our data suggest that SINE CRM1 antagonists are a potential novel therapy for patients with MCL, particular in relapsed/refractory disease.

  14. Effect of Tumor Necrosis Factor Inhibitor Therapy on Osteoclasts Precursors in Rheumatoid Arthritis

    PubMed Central

    Rodrigues, Ana Maria; Campanilho-Marques, Raquel; Ponte, Cristina; Canhão, Helena; Ainola, Mari

    2017-01-01

    Objective. Tumor necrosis factor (TNF) increases circulating osteoclast (OC) precursors numbers by promoting their proliferation and differentiation. The aim of this study was to assess the effect of TNF inhibitors (TNFi) on the differentiation and activity of OC in rheumatoid arthritis (RA) patients. Methods. Seventeen RA patients treated with TNFi were analyzed at baseline and after a minimum follow-up period of 6 months. Blood samples were collected to assess receptor activator of nuclear factor kappa-B ligand (RANKL) surface expression on circulating leukocytes and frequency and phenotype of monocyte subpopulations. Quantification of serum levels of bone turnover markers, in vitro OC differentiation assays, and qRT-PCR for OC specific genes was performed. Results. After TNFi therapy, patients had reduced RANKL surface expression in B-lymphocytes and the frequency of circulating classical CD14brightCD16− monocytes was decreased. Serum levels of sRANKL, sRANKL/OPG ratio, and CTX-I were reduced in RA patients after TNFi treatment. Moreover, after exposure to TNFi, osteoclast differentiation and activity were decreased, as well as the expression of TRAF6 and cathepsin K. Conclusion. We propose that TNFi arrests bone loss and erosion, through two pathways: direct reduction of osteoclast precursor numbers and inhibition of intracellular signaling pathways acting through TRAF6. PMID:28286757

  15. Nutritional status changes in HIV-infected children receiving combined antiretroviral therapy including protease inhibitors.

    PubMed

    Fiore, P; Donelli, E; Boni, S; Pontali, E; Tramalloni, R; Bassetti, D

    2000-11-01

    Maintaining linear growth and weight gain in HIV-infected children is often difficult. Nutritional evaluation and support are recognised as important factors to improve their quality of life. Combination antiretroviral therapy including protease inhibitors (HAART) reduces HIV-viral load and improves survival, quality of life and nutritional status. Our study aimed to determine changes in nutrional status based on body weight, height and nutritional habits, of HIV-infected children receiving HAART. Possible side effects of lipid metabolism were also studied. Twenty five children, 13 treated with HAART (group B) were followed up for 12 months. We did not observe statistically significant differences in nutritional status over that time or between groups A and B. Inadequate energy intake was more common in patients with advanced HIV-disease. Hyperlipidemia was found in 70% of children receiving ritonavir and in approximately 50% of children receiving nelfinavir. We observed an important although not statistically significative modification in the height of those in group B.

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

    NASA Astrophysics Data System (ADS)

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

    1996-01-01

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

  17. KSHV Targeted Therapy: An Update on Inhibitors of Viral Lytic Replication

    PubMed Central

    Coen, Natacha; Duraffour, Sophie; Snoeck, Robert; Andrei, Graciela

    2014-01-01

    Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi’s sarcoma, primary effusion lymphoma and multicentric Castleman’s disease. Since the discovery of KSHV 20 years ago, there is still no standard treatment and the management of virus-associated malignancies remains toxic and incompletely efficacious. As the majority of tumor cells are latently infected with KSHV, currently marketed antivirals that target the virus lytic cycle have shown inconsistent results in clinic. Nevertheless, lytic replication plays a major role in disease progression and virus dissemination. Case reports and retrospective studies have pointed out the benefit of antiviral therapy in the treatment and prevention of KSHV-associated diseases. As a consequence, potent and selective antivirals are needed. This review focuses on the anti-KSHV activity, mode of action and current status of antiviral drugs targeting KSHV lytic cycle. Among these drugs, different subclasses of viral DNA polymerase inhibitors and compounds that do not target the viral DNA polymerase are being discussed. We also cover molecules that target cellular kinases, as well as the potential of new drug targets and animal models for antiviral testing. PMID:25421895

  18. BRAF inhibitors and radiotherapy for melanoma brain metastases: potential advantages and disadvantages of combination therapy

    PubMed Central

    Chowdhary, Mudit; Patel, Kirtesh R; Danish, Hasan H; Lawson, David H; Khan, Mohammad K

    2016-01-01

    Melanoma is an aggressive malignancy that frequently spreads to the brain, resulting in rapid deterioration in both quality and quantity of life. Historically, treatment options for melanoma brain metastases (MBM) have predominantly consisted of surgery and radiotherapy. While these options can help provide local control, the majority of patients still develop intracranial progression. Indeed, novel therapeutic options, including molecularly targeted agents and immunotherapy, have improved outcomes and are now changing the role of radiotherapy. Up to 50% of melanomas contain an activating BRAF mutation, resulting in hyperactive cellular proliferation and survival. Drugs that target BRAF have been introduced for the treatment of metastatic melanoma and offer hope in improving disease outcomes; however, many of these trials either excluded or had a limited amount of patients with MBM. Recent studies have revealed that melanoma cell lines become more radiosensitive following BRAF inhibition, thus providing a potential synergistic mechanism when combining BRAF inhibitor (BRAFi) and radiotherapy. However, neurotoxicity concerns also exist with this combination. This article reviews the efficacy and limitations of BRAFi therapy for MBM, describes current evidence for combining BRAFis with radiation, discusses the rationale and evidence for combination modalities, and highlights emerging clinical trials specifically investigating this combination in MBM. PMID:28003758

  19. Histone deacetylase inhibitors for cancer therapy: An evolutionarily ancient resistance response may explain their limited success

    PubMed Central

    Halsall, John A.

    2016-01-01

    Histone deacetylase inhibitors (HDACi) are in clinical trials against a variety of cancers. Despite early successes, results against the more common solid tumors have been mixed. How is it that so many cancers, and most normal cells, tolerate the disruption caused by HDACi‐induced protein hyperacetylation? And why are a few cancers so sensitive? Here we discuss recent results showing that human cells mount a coordinated transcriptional response to HDACi that mitigates their toxic effects. We present a hypothetical signaling system that could trigger and mediate this response. To account for the existence of such a response, we note that HDACi of various chemical types are made by a variety of organisms to kill or suppress competitors. We suggest that the resistance response in human cells is a necessary evolutionary consequence of exposure to environmental HDACi. We speculate that cancers sensitive to HDACi are those in which the resistance response has been compromised by mutation. Identifying such mutations will allow targeting of HDACi therapy to potentially susceptible cancers. Also see the video abstract here. PMID:27717012

  20. Advanced control evaluation for structures (ACES) programs

    NASA Technical Reports Server (NTRS)

    Pearson, Jerome; Waites, Henry

    1988-01-01

    The ACES programs are a series of past, present, and future activities at the Marshall Space Flight Center (MSFC) Ground facility for Large Space Structure Control Verification (GF/LSSCV). The main objectives of the ACES programs are to implement control techniques on a series of complex dynamical systems, to determine the control/structure interaction for the control techniques, and to provide a national facility in which dynamics and control verification can be effected. The focus is on these objectives and how they are implemented under various engineering and economic constraints. Future plans that will be effected in upcoming ACES programs are considered.

  1. Concurrent Intervention With Exercises and Stabilized Tumor Necrosis Factor Inhibitor Therapy Reduced the Disease Activity in Patients With Ankylosing Spondylitis

    PubMed Central

    Liang, Hui; Li, Wen-Rong; Zhang, Hua; Tian, Xu; Wei, Wei; Wang, Chun-Mei

    2015-01-01

    Abstract Since the use of tumor necrosis factor (TNF) inhibitor therapy is becoming wider, the effects of concurrent intervention with exercises and stabilized TNF inhibitors therapy in patients with ankylosing spondylitis (AS) are different. The study aimed to objectively evaluate whether concurrent intervention with exercises and stabilized TNF inhibitors can reduce the disease activity in patients with AS. A search from PubMed, Web of Science, EMBASE, and the Cochrane Library was electronically performed to collect studies which compared concurrent intervention with exercise and TNF inhibitor to conventional approach in terms of disease activity in patients with AS published from their inception to June 2015. Studies that measured the Bath Ankylosing Spondylitis Functional Index (BASFI), the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Metrology Index (BASMI), and chest expansion as outcomes were included. Two independent investigators screened the identified articles, extracted the data, and assessed the methodological quality of the included studies. Quantitative analysis was performed with Review Manager (RevMan) software (version 5.3.0). A total of 5 studies comprising 221 participants were included in the study. Meta-analyses showed that concurrent intervention with exercises and stabilized TNF inhibitors therapy significantly reduced the BASMI scores (MD, −0.99; 95% CI, −1.61 to −0.38) and BASDAI scores (MD, −0.58; 95% CI, −1.10 to −0.06), but the BASFI scores (MD, −0.31; 95% CI, −0.76 to 0.15) was not reduced, and chest expansion (MD, 0.80; 95% CI, −0.18 to 1.78) was not increased. Concurrent intervention with exercises and stabilized TNF inhibitors therapy can reduce the disease activity in patients with AS. More randomized controlled trials (RCTs) with high-quality, large-scale, and appropriate follow-up are warranted to further establish the benefit of concurrent intervention with

  2. Rational combination of targeted therapies as a strategy to overcome the mechanisms of resistance to inhibitors of EGFR signaling.

    PubMed

    Bianco, Roberto; Damiano, Vincenzo; Gelardi, Teresa; Daniele, Gennaro; Ciardiello, Fortunato; Tortora, Giampaolo

    2007-01-01

    The epidermal growth factor receptor (EGFR) has been widely used as a target for novel anticancer agents, such as blocking antibodies and small molecular weight tyrosine kinase compounds. In spite of recent advances in cancer cell biology, leading to the introduction of clinically active new drugs, such as cetuximab, panitumumab and erlotinib, unfortunately disease control remains unsuccessful due to the presence of constitutive resistance to EGFR inhibitors in most patients and the development of acquired resistance in the responders. A large number of molecular abnormalities in tumor cells seem to partly contribute to their resistance to anti-EGFR therapy: increased angiogenesis, constitutive activation of downstream mediators, overexpression of other tyrosine kinase receptors. Moreover, some mutations in the EGFR receptor kinase domain seem to play a crucial role in determining the sensitivity of cancer cells to specific inhibitors by altering the conformation of the receptor and its activity. The development of rational combinations of anticancer agents and EGFR inhibitors, able to exert synergistic cytotoxic interactions, has been widely accepted and used in both preclinical and clinical studies. Although the failure of large clinical trial based on empirical combination of anti-EGFR and classic chemotherapeutic agents, several preclinical data seems to support the hypothesis that combining EGFR inhibitors and other novel agents could efficiently inhibit tumor growth and overcome intrinsic resistance to a single-agent based therapy. This review focuses on the role of complementary signalling pathways in the development of resistance to EGFR targeting agents and the rationale to combine novel inhibitors as anticancer therapy.

  3. ACE3 Draft Indicators: Environments and Contaminants

    EPA Pesticide Factsheets

    The information on this page was provided by EPA in conjunction with the opportunity for public comment on the draft indicators for ACE3, which ran from March 8 – April 21, 2011. The public comment period is now closed.

  4. FIRE_ACE_ER2_MAS

    Atmospheric Science Data Center

    2015-10-28

    ... First ISCCP Regional Experiment (FIRE) Arctic Cloud Experiment (ACE) NASA ER-2 Moderate Resolution Imaging ... SSFR Location:  Northern Alaska Arctic Ocean Spatial Coverage:  Fairbanks, Alaska and the surrounding ...

  5. ACE3 Draft Indicators: Special Features

    EPA Pesticide Factsheets

    The page information was provided by EPA in conjunction with the opportunity for public comment on the draft indicators for ACE3, which ran from March 8 – April 21, 2011. The public comment period is now closed.

  6. ACE-FTS measurements of HCFC-22

    NASA Astrophysics Data System (ADS)

    Kolonjari, F.; Walker, K. A.; Boone, C. D.; Strahan, S.; McLinden, C. A.; Manney, G. L.; Daffer, W. H.; Bernath, P. F.

    2012-04-01

    In the 1980s scientists discovered an annual springtime minimum in stratospheric ozone over the Antarctic. It was determined that the decline in ozone concentration was primarily caused by catalytic reactions of ozone and chlorine. The emissions of anthropogenic chlorofluorocarbons (CFCs) were determined to be major sources of the chlorine. The Montreal Protocol on Substances that Deplete the Ozone Layer (with its subsequent amendments) restricts the emissions of ozone depleting substances. To fulfill the need for safe, stable replacements of CFCs, hydrochlorofluorocarbons (HCFCs) and hydrofluorocarbons (HFCs) were developed. The use of HCFC-22 as a replacement has led to an increase in its atmospheric abundance. This is of concern due to its ozone depletion potential and its global warming potential. The Atmospheric Chemistry Experiment (ACE) is a mission on-board the Canadian satellite SCISAT. The primary instrument on SCISAT is a high-resolution infrared Fourier Transform Spectrometer (ACE-FTS). With its wide spectral range, the ACE-FTS is capable of measuring an extensive range of gases including key CFC and HCFC species. The altitude distribution from the ACE-FTS profiles provides information that is complementary to the ground-based measurements that have been used to monitor these species. The global distribution of HCFC-22 has been computed from measurements by ACE-FTS. Both seasonal variations and an inter-hemispheric difference are observed. Additionally, a rapid increase in the global concentration of HCFC-22 has been observed since the start of the ACE mission in 2004. Comparisons to ground-based and air-borne measurements show good agreement with the ACE-FTS measurements. The global distributions of HCFC-22 have also been compared to a chemistry and transport model (CTM), the Global Modelling Initiative Combined Stratospheric-Tropospheric Model. There are distinct differences between the model results and ACE-FTS measurements. The causes and

  7. Role of angiotensin-converting enzyme 2 (ACE2) in diabetic cardiovascular complications.

    PubMed

    Patel, Vaibhav B; Parajuli, Nirmal; Oudit, Gavin Y

    2014-04-01

    Diabetes mellitus results in severe cardiovascular complications, and heart disease and failure remain the major causes of death in patients with diabetes. Given the increasing global tide of obesity and diabetes, the clinical burden of diabetes-induced cardiovascular disease is reaching epidemic proportions. Therefore urgent actions are needed to stem the tide of diabetes which entails new prevention and treatment tools. Clinical and pharmacological studies have demonstrated that AngII (angiotensin II), the major effector peptide of the RAS (renin-angiotensin system), is a critical promoter of insulin resistance and diabetes mellitus. The role of RAS and AngII has been implicated in the progression of diabetic cardiovascular complications and AT1R (AngII type 1 receptor) blockers and ACE (angiotensin-converting enzyme) inhibitors have shown clinical benefits. ACE2, the recently discovered homologue of ACE, is a monocarboxypeptidase which converts AngII into Ang-(1-7) [angiotensin-(1-7)] which, by virtue of its actions on the MasR (Mas receptor), opposes the effects of AngII. In animal models of diabetes, an early increase in ACE2 expression and activity occurs, whereas ACE2 mRNA and protein levels have been found to decrease in older STZ (streptozotocin)-induced diabetic rats. Using the Akita mouse model of Type 1 diabetes, we have recently shown that loss of ACE2 disrupts the balance of the RAS in a diabetic state and leads to AngII/AT1R-dependent systolic dysfunction and impaired vascular function. In the present review, we will discuss the role of the RAS in the pathophysiology and treatment of diabetes and its complications with particular emphasis on potential benefits of the ACE2/Ang-(1-7)/MasR axis activation.

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

    NASA Technical Reports Server (NTRS)

    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. Increased Hematocrit During Sodium-Glucose Cotransporter 2 Inhibitor Therapy Indicates Recovery of Tubulointerstitial Function in Diabetic Kidneys

    PubMed Central

    Sano, Motoaki; Takei, Makoto; Shiraishi, Yasuyuki; Suzuki, Yoshihiko

    2016-01-01

    Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been attracting attention for cardiovascular as well as antidiabetic effects since the results of the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME Trial) were reported. The hematocrit increases during treatment with SGLT2 inhibitors, which have a diuretic effect but do not cause sufficient hemoconcentration to increase the risk of cerebral infarction. Elevation of the hematocrit during SGLT2 inhibitor therapy is presumed to involve enhancement of erythropoiesis in addition to hemoconcentration. In patients with diabetes, the erythropoietin level increases after initiation of treatment with the SGLT2 inhibitor dapagliflozin and reaches a plateau in 2 - 4 weeks. The reticulocyte count increases simultaneously, followed by elevation of hemoglobin and hematocrit. In patients with diabetes, the proximal tubules are overtaxed by excessive glucose reabsorption and the increased oxygen requirement causes tubulointerstitial hypoxia. Consequently, erythropoietin production is impaired because “neural crest-derived” fibroblasts surrounding the damaged renal tubules undergo transformation into dysfunctional fibroblasts. SGLT2 inhibitors reduce the workload of the proximal tubules and improve tubulointerstitial hypoxia, allowing fibroblasts to resume normal erythropoietin production. These drugs represent a new class of diuretics that have a renoprotective effect by improving tubulointerstitial hypoxia, which is the final common pathway to end-stage renal disease. In patients with diabetes, elevation of hematocrit may be a surrogate marker for recovery from reversible tubulointerstitial injury. PMID:27829948

  10. Treatment-limiting toxicities associated withnucleoside analogue reverse transcriptase inhibitor therapy: A prospective, observational study**

    PubMed Central

    Palacios, Rosario; Santos, Jesús; Camino, Xavier; Arazo, Piedad; Torres Perea, Rafael; Echevarrfa, Santiago; Ribera, Esteban; Sánchez de la Rosa, Rainel; Moreno Guillen, Santiago

    2005-01-01

    Background: The Recover Study is an ongoing, prospective study designed 10 to assess toxicity associated with the use of nucleoside analogue reverse transcriptase inhibitors (NRTIs) (stavudine, zidovudine, lamivudine, didanosine, abacavir) in HIV-1-infected patients receiving highly active antiretroviral therapy (HAART) in routine clinical practice. This project is being conducted at 120 HIV units at teaching hospitals across Spain. Objective: The aim of this study was to identify the most common treatment-limiting 10 moderate to severe clinical and laboratory adverse effects (AEs), and the individual NRTIs involved in the development of these effects, in HIV-1-infected patients receiving HAART who discontinued use of an NRTI in the Recover Study. Methods: Patients eligible for participation in the Recover Study are aged10 ≥18 years; have virologically documented HIV-1 infection; have sustained viral suppression (viral load <200 cells/mL or stable, heavily experienced [ie, have received ≥3 antiretroviral regimens] patients with viral load <5000 cells/mL) for ≥6 months; are receiving HAART; are undergoing active follow-up; and have developed 2:1 NRTI-associated AE that, in the opinion of a study investigator and under the conditions of routine clinical practice, justified discontinuation of treatment with the offending drug (principal AE/offending NRTI). The present study included patients recruited for the Recover Study between September 2002 and May 2003. Results: A total of 1391 patients were enrolled (966 men, 425 women; mean 1 age, 42 years [range, 18–67 years]). Five hundred six patients (36.4%) had been diagnosed with AIDS. The mean duration of treatment with the offending NRTI was 74 months (range, 6–156 months). Seven hundred nine patients (51.0%) were receiving fourth-line (or more) therapy. Eight hundred twenty-one patients (59.0%) were receiving nonnucleoside analogues, and 552 patients (39.7%), protease inhibitors, as components of their HAART

  11. Cognitive Evaluation in Liver Transplant Patients Under Calcineurin Inhibitor Maintenance Therapy

    PubMed Central

    Heits, Nils; Keserovic, Dalibor; Mund, Niclas; Ehmke, Nicola; Bernsmeier, Alexander; Hendricks, Alexander; Gunther, Rainer; Witt, Karsten; Becker, Thomas; Braun, Felix

    2017-01-01

    Background Neurological disorders due to calcineurin inhibitor (CNI) treatment pose a well-known problem after liver transplantation (LTx). In this study, the impact of CNIs on cognitive functioning during maintenance therapy was analyzed. A possible improvement of cognitive functioning, compliance and health-related quality of life (HRQoL) after conversion to a once-daily tacrolimus formulation was prospectively assessed. Methods In a cross-section analysis cognitive functioning of living donors (LD), waiting list patients and LTx patients was tested using a 4 times trail making test (4-TTMT). In a further investigator-initiated trial a possible improvement of cognitive functioning, HRQoL and compliance after conversion to the once-daily tacrolimus formulation was prospectively assessed over 1 year. HRQoL was assessed using an EORTC-QLQ C30 questionnaire and patient’s compliance was assessed by the Basel Assessment of Compliance with Immunosuppressive Medication Scales questionnaire. Correlated data were sex, age, time after surgery, liver disease, model of end-stage liver disease score, creatinine, CNI type, and CNI trough levels. Results Two hundred eleven patients were included in this cross-section analysis. Twenty-seven patients agreed to participate in the investigator-initiated trial. LTx patients completed the 4-TTMT slower than living donor patients and faster than waiting list patients. Patients with twice daily cyclosporine A (CSA) formulation needed longer to finish the 4-TTMT than patients with the once-daily tacrolimus formulation. After drug conversion of a twice-daily CNI formulation to a once-daily tacrolimus formulation, CSA-treated patients needed longer to improve their cognitive functioning. HRQoL and compliance did not improve after drug conversion. Conclusions Patients with once-daily tacrolimus formulation had a better psychomotor speed than CSA-treated patients. The conversion to once-daily tacrolimus formulation significantly improved

  12. Adherence and Viral Suppression among Infants and Young Children Initiating Protease Inhibitor-Based Antiretroviral Therapy

    PubMed Central

    Teasdale, Chloe A; Abrams, Elaine J; Coovadia, Ashraf; Strehlau, Renate; Martens, Leigh; Kuhn, Louise

    2012-01-01

    Background High levels of adherence to antiretroviral therapy (ART) are considered necessary to achieve viral suppression. We analyzed data from a cohort of HIV-infected children who were less than 2 years of age receiving protease inhibitor (PI)-based ART to investigate associations between viral suppression and adherence ascertained using different methods. Methods Data were from the pre-randomization phase of a clinical trial in South Africa of HIV-infected children initiating either ritonavir-boosted lopinavir (LPV/r)- or ritonavir-based ART. At scheduled visits during the first 24 weeks of enrollment, study pharmacists measured quantities of medications returned (MR) to the clinic. Caregivers answered questionnaires on missed doses and adherence barriers. Associations between adherence and viral suppression (HIV-1 RNA <400 copies/mL) were investigated by regimen. Results By 24 weeks, 197/269 (73%) children achieved viral suppression. There was no association between viral suppression and caregiver reported missed doses or adherence barriers. For children receiving the LPV/r-based regimen, MR adherence to each of the three drugs in the regimen (LPV/r, lamivudine or stavudine) individually or together was associated with viral suppression at different adherence thresholds. For example, <85% adherence to any of the three medications significantly increased odds of lack of viral suppression (Odds Ratio [OR] 2.30 [95% CI: 1.30–4.07], p=.004). In contrast, for children receiving the ritonavir-based regimen, there was no consistent pattern of association between MR and viral suppression. Conclusions Caregiver reports of missed doses did not predict virologic response to treatment. Pharmacist medication reconciliation correlated strongly with virologic response for children taking a LPV/r-based regimen and appears to be a valid method for measuring pediatric adherence. PMID:23249913

  13. Effect of Tumor Necrosis Factor Inhibitor Therapy on Osteoclasts Precursors in Ankylosing Spondylitis

    PubMed Central

    Caetano-Lopes, Joana; Vieira-Sousa, Elsa; Campanilho-Marques, Raquel; Ponte, Cristina; Canhão, Helena; Ainola, Mari; Fonseca, João E.

    2015-01-01

    Introduction Ankylosing Spondylitis (AS) is characterized by excessive local bone formation and concomitant systemic bone loss. Tumor necrosis factor (TNF) plays a central role in the inflammation of axial skeleton and enthesis of AS patients. Despite reduction of inflammation and systemic bone loss, AS patients treated with TNF inhibitors (TNFi) have ongoing local bone formation. The aim of this study was to assess the effect of TNFi in the differentiation and activity of osteoclasts (OC) in AS patients. Methods 13 AS patients treated with TNFi were analyzed at baseline and after a minimum follow-up period of 6 months. 25 healthy donors were recruited as controls. Blood samples were collected to assess receptor activator of nuclear factor kappa-B ligand (RANKL) surface expression on circulating leukocytes and frequency and phenotype of monocyte subpopulations. Quantification of serum levels of bone turnover markers and cytokines, in vitro OC differentiation assay and qRT-PCR for OC specific genes were performed. Results RANKL+ circulating lymphocytes (B and T cells) and IL-17A, IL-23 and TGF-β levels were decreased after TNFi treatment. We found no differences in the frequency of the different monocyte subpopulations, however, we found decreased expression of CCR2 and increased expression of CD62L after TNFi treatment. OC number was reduced in patients at baseline when compared to controls. OC specific gene expression was reduced in circulating OC precursors after TNFi treatment. However, when cultured in OC differentiating conditions, OC precursors from AS TNFi-treated patients showed increased activity as compared to baseline. Conclusion In AS patients, TNFi treatment reduces systemic pro osteoclastogenic stimuli. However, OC precursors from AS patients exposed to TNFi therapy have increased in vitro activity in response to osteoclastogenic stimuli. PMID:26674064

  14. HDAC Inhibitors as Epigenetic Regulators of the Immune System: Impacts on Cancer Therapy and Inflammatory Diseases

    PubMed Central

    Montgomery, McKale R.; Leyva, Kathryn J.

    2016-01-01

    Histone deacetylase (HDAC) inhibitors are powerful epigenetic regulators that have enormous therapeutic potential and have pleiotropic effects at the cellular and systemic levels. To date, HDAC inhibitors are used clinically for a wide variety of disorders ranging from hematopoietic malignancies to psychiatric disorders, are known to have anti-inflammatory properties, and are in clinical trials for several other diseases. In addition to influencing gene expression, HDAC enzymes also function as part of large, multisubunit complexes which have many nonhistone targets, alter signaling at the cellular and systemic levels, and result in divergent and cell-type specific effects. Thus, the effects of HDAC inhibitor treatment are too intricate to completely understand with current knowledge but the ability of HDAC inhibitors to modulate the immune system presents intriguing therapeutic possibilities. This review will explore the complexity of HDAC inhibitor treatment at the cellular and systemic levels and suggest strategies for effective use of HDAC inhibitors in biomedical research, focusing on the ability of HDAC inhibitors to modulate the immune system. The possibility of combining the documented anticancer effects and newly emerging immunomodulatory effects of HDAC inhibitors represents a promising new combinatorial therapeutic approach for HDAC inhibitor treatments. PMID:27556043

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

    PubMed Central

    Kleponis, Jennifer; Skelton, Richard; Zheng, Lei

    2015-01-01

    Immune checkpoint inhibitors are increasingly drawing much attention in the therapeutic development for cancer treatment. However, many cancer patients do not respond to treatments with immune checkpoint inhibitors, partly because of the lack of tumor-infiltrating effector T cells. Cancer vaccines may prime patients for treatments with immune checkpoint inhibitors by inducing effector T-cell infiltration into the tumors and immune checkpoint signals. The combination of cancer vaccine and an immune checkpoint inhibitor may function synergistically to induce more effective antitumor immune responses, and clinical trials to test the combination are currently ongoing. PMID:26487965

  16. Current concepts in combination therapy for the treatment of hypertension: combined calcium channel blockers and RAAS inhibitors

    PubMed Central

    Rubio-Guerra, Alberto F; Castro-Serna, David; Barrera, Cesar I Elizalde; Ramos-Brizuela, Luz M

    2009-01-01

    Recent guidelines for the management of hypertension recommend target blood pressures <140/90 mmHg in hypertensive patients, or <130/80 mmHg in subjects with diabetes, chronic kidney disease, or coronary artery disease. Despite the availability and efficacy of antihypertensive drugs, most hypertensive patients do not reach the recommended treatment targets with monotherapy, making combination therapy necessary to achieve the therapeutic goal. Combination therapy with 2 or more agents is the most effective method for achieving strict blood pressure goals. Fixed-dose combination simplifies treatment, reduces costs, and improves adherence. There are many drug choices for combination therapy, but few data are available about the efficacy and safety of some specific combinations. Combination therapy of calcium antagonists and inhibitors of the renin-angiotensin-aldosterone system (RAAS) are efficacious and safe, and have been considered rational by both the JNC 7 and the 2007 European Society of Hypertension – European Society of Cardiology guidelines for the management of arterial hypertension. The aim of this review is to discuss some relevant issues about the use of combinations with calcium channel blockers and RAAS inhibitors in the treatment of hypertension. PMID:21949615

  17. Anti-tumour activity of tivozanib, a pan-inhibitor of VEGF receptors, in therapy-resistant ovarian carcinoma cells

    PubMed Central

    Momeny, Majid; Sabourinejad, Zahra; Zarrinrad, Ghazaleh; Moghaddaskho, Farima; Eyvani, Haniyeh; Yousefi, Hassan; Mirshahvaladi, Shahab; Poursani, Ensieh M.; Barghi, Farinaz; Poursheikhani, Arash; Dardaei, Leila; Bashash, Davood; Ghazi-Khansari, Mahmoud; Tavangar, Seyyed M.; Dehpour, Ahmad R.; Yaghmaie, Marjan; Alimoghaddam, Kamran; Ghavamzadeh, Ardeshir; Ghaffari, Seyed H.

    2017-01-01

    Epithelial ovarian cancer (EOC) is the most fatal gynaecological malignancy. Despite initial therapeutic response, the majority of advanced-stage patients relapse and succumb to chemoresistant disease. Overcoming drug resistance is the key to successful treatment of EOC. Members of vascular endothelial growth factor (VEGF) family are overexpressed in EOC and play key roles in its malignant progression though their contribution in development of the chemoresistant disease remains elusive. Here we show that expression of the VEGF family is higher in therapy-resistant EOC cells compared to sensitive ones. Overexpression of VEGFR2 correlated with resistance to cisplatin and combination with VEGFR2-inhibitor apatinib synergistically increased cisplatin sensitivity. Tivozanib, a pan-inhibitor of VEGF receptors, reduced proliferation of the chemoresistant EOC cells through induction of G2/M cell cycle arrest and apoptotic cell death. Tivozanib decreased invasive potential of these cells, concomitant with reduction of intercellular adhesion molecule-1 (ICAM-1) and diminishing the enzymatic activity of urokinase-type plasminogen activator (uPA) and matrix metalloproteinase-2 (MMP-2). Moreover, tivozanib synergistically enhanced anti-tumour effects of EGFR-directed therapies including erlotinib. These findings suggest that the VEGF pathway has potential as a therapeutic target in therapy-resistant EOC and VEGFR blockade by tivozanib may yield stronger anti-tumour efficacy and circumvent resistance to EGFR-directed therapies. PMID:28383032

  18. Racial differences in blood pressure response to angiotensin-converting enzyme inhibitors in children: a meta-analysis.

    PubMed

    Li, J S; Baker-Smith, C M; Smith, P B; Hasselblad, V; Murphy, M D; Califf, R M; Benjamin, D K

    2008-09-01

    Angiotensin-converting enzyme (ACE) inhibitors are frequently used to treat hypertension in children.(1) ACE inhibitors alter the balance between the vasoconstrictive, salt-retentive, and cardiac hypertrophic properties of angiotensin II and the vasodilatory and natriuretic properties of bradykinin; they also alter the metabolism of other vasoactive substances.(2) Through these mechanisms, ACE inhibitors decrease systemic vascular resistance and promote natriuresis without increasing heart rate. This study evaluated the results of six trials of ACE inhibitors in children, using meta-analytic techniques to estimate the effect of race on blood pressure response.

  19. Novel Cancer Therapeutics with Allosteric Modulation of the Mitochondrial C-Raf-DAPK Complex by Raf Inhibitor Combination Therapy.

    PubMed

    Tsai, Yi-Ta; Chuang, Mei-Jen; Tang, Shou-Hung; Wu, Sheng-Tang; Chen, Yu-Chi; Sun, Guang-Huan; Hsiao, Pei-Wen; Huang, Shih-Ming; Lee, Hwei-Jen; Yu, Cheng-Ping; Ho, Jar-Yi; Lin, Hui-Kuan; Chen, Ming-Rong; Lin, Chung-Chih; Chang, Sun-Yran; Lin, Victor C; Yu, Dah-Shyong; Cha, Tai-Lung

    2015-09-01

    Mitochondria are the powerhouses of cells. Mitochondrial C-Raf is a potential cancer therapeutic target, as it regulates mitochondrial function and is localized to the mitochondria by its N-terminal domain. However, Raf inhibitor monotherapy can induce S338 phosphorylation of C-Raf (pC-Raf(S338)) and impede therapy. This study identified the interaction of C-Raf with S308 phosphorylated DAPK (pDAPK(S308)), which together became colocalized in the mitochondria to facilitate mitochondrial remodeling. Combined use of the Raf inhibitors sorafenib and GW5074 had synergistic anticancer effects in vitro and in vivo, but targeted mitochondrial function, rather than the canonical Raf signaling pathway. C-Raf depletion in knockout MEF(C-Raf-/-) or siRNA knockdown ACHN renal cancer cells abrogated the cytotoxicity of combination therapy. Crystal structure simulation showed that GW5074 bound to C-Raf and induced a C-Raf conformational change that enhanced sorafenib-binding affinity. In the presence of pDAPK(S308), this drug-target interaction compromised the mitochondrial targeting effect of the N-terminal domain of C-Raf, which induced two-hit damages to cancer cells. First, combination therapy facilitated pC-Raf(S338) and pDAPK(S308) translocation from mitochondria to cytoplasm, leading to mitochondrial dysfunction and reactive oxygen species (ROS) generation. Second, ROS facilitated PP2A-mediated dephosphorylation of pDAPK(S308) to DAPK. PP2A then dissociated from the C-Raf-DAPK complex and induced profound cancer cell death. Increased pDAPK(S308) modification was also observed in renal cancer tissues, which correlated with poor disease-free survival and poor overall survival in renal cancer patients. Besides mediating the anticancer effect, pDAPK(S308) may serve as a predictive biomarker for Raf inhibitors combination therapy, suggesting an ideal preclinical model that is worthy of clinical translation.

  20. The role of combination therapy in the treatment of hypertension.

    PubMed

    Ruilope, L M; Coca, A

    1998-01-01

    Antihypertensive therapy is indicated for reducing the risk of cardiovascular morbidity and mortality that accompanies arterial hypertension. Usually, pharmacological treatment is started as monotherapy, which, if unsuccessful, is followed by sequential monotherapy, or by combination therapy. Recent data indicate that combination therapy is required in more than 50% of the hypertensive population when the goal is to reduce blood pressure to below 140/90 mm Hg. The choice and doses of drugs used in combination therapy should be such that their synergistic effect on blood pressure is maximized, the tolerability of the drugs is maintained and side-effects are minimized. The combination of a dihydropyridine calcium antagonist with a beta-blocker or an angiotensin-converting enzyme (ACE) inhibitor is one of the most commonly used combination therapies. Two randomized, double-blind, parallel-group studies compared the antihypertensive effects of the dihydropyridine, barnidipine, with the beta-blocker, atenolol (n = 247), and the ACE inhibitor, enalapril (n = 155). The efficacy and tolerability of barnidipine in combination with either atenolol or enalapril was also investigated. Monotherapy with barnidipine was as effective in reducing blood pressure as monotherapy with either atenolol or enalapril. Combining barnidipine with either atenolol or enalapril reduced blood pressure further, and significantly increased the percentage of patients attaining the required reduction in blood pressure. When patients whose blood pressure was not adequately controlled by enalapril monotherapy were switched to barnidipine monotherapy, the majority then achieved the desired reduction in blood pressure. These results indicate that if barnidipine monotherapy fails to lower blood pressure to the desired values, its combination with either a beta-blocker or an ACE inhibitor is effective and well tolerated.

  1. Proton pump inhibitor-amoxicillin-clarithromycin versus proton pump inhibitor-amoxicillin-metronidazole as first-line Helicobacter pylori eradication therapy.

    PubMed

    Nishizawa, Toshihiro; Suzuki, Hidekazu; Suzuki, Masayuki; Takahashi, Masahiko; Hibi, Toshifumi

    2012-09-01

    The aim of this study was to compare the efficacy and tolerability of the first-line Helicobacter pylori (H. pylori) eradication regimen composed of proton pump inhibitor, clarithromycin, and amoxicillin, with those of a regimen composed of proton pump inhibitor, metronidazole, and amoxicillin. Data of patients, who were administered the first-line H. pylori eradication regimen at Tokyo Medical Center between 2008 and 2011, were reviewed. All patients had H. pylori gastritis without peptic ulcer disease. The 7-day triple regimen composed of lansoprazole, clarithromycin, and amoxicillin was administered to 55 patients, and that composed of omeprazole, metronidazole, and amoxicillin was administered to 55 patients. Intention-to-treat and per-protocol eradication rates were 74.5 and 80.4%, respectively, for the regimen of lansoprazole, clarithromycin, and amoxicillin, whereas the corresponding rates were 96.4 and 100%, respectively, for the regimen of omeprazole, metronidazole, and amoxicillin. In conclusion, first-line H. pylori eradication therapy composed of omeprazole, metronidazole, and amoxicillin was significantly more effective than that composed of lansoprazole, clarithromycin, and amoxicillin, without differences in tolerability.

  2. Efficacy and safety of phosphodiesterase type 5 inhibitors on primary premature ejaculation in men receiving selective serotonin reuptake inhibitors therapy: a systematic review and meta-analysis.

    PubMed

    Men, C; Yu, L; Yuan, H; Cui, Y

    2016-11-01

    We performed a systematic review and meta-analysis to assess whether selective serotonin reuptake inhibitors (SSRIs) and phosphodiesterase type 5 inhibitors (PDE5-Is) may have an additive therapeutic effect. A literature review was performed to identify all published randomised controlled trials (RCT) that used SSRIs combined with PDE5-Is therapy for the treatment of primary PE. The search included the following databases: EMBASE, MEDLINE and the Cochrane Controlled Trials Register. The reference lists of the retrieved studies were also investigated. Five publications involving a total of 419 patients were used in the analysis, including 5 RCTs that compared PDE5-Is plus SSRIs with SSRIs treating primary PE. Primary efficacy endpoints: IELT (the standardised mean difference (SMD) = 1.07, 95% confidence interval (CI) = 1.00 to 1.14, P < 0.00001) indicated that utilisation of PDE5-Is and SSRIs was more effective than the SSRIs alone for a long time in patients with primary PE. Safety assessments included headache (odds ratio (OR) = 3.16, 95% CI = 1.63 to 6.11, P = 0.0006), and flushing indicated that PDE5-Is plus SSRIs were well tolerated. This meta-analysis indicates that PDE5-Is combined with SSRIs seem to provide significantly better ejaculatory latency time as compared with SSRIs alone in patients with primary PE.

  3. PARP inhibitors in cancer therapy: two modes of attack on the cancer cell widening the clinical applications.

    PubMed

    Drew, Yvette; Plummer, Ruth

    2009-12-01

    The abundant nuclear enzyme poly(ADP-ribose)polymerase-1 (PARP-1) represents an important novel target in cancer therapy. PARP-1 is essential to the repair of single strand DNA breaks via the base excision repair pathway. Inhibitors of PARP-1 have been shown to enhance the cytotoxic effects of ionising radiation and DNA damaging chemotherapy agents such as the methylating agents and topoisomerase-I inhibitors. There are currently at least eight PARP inhibitors in clinical trial development. In vitro data, in vivo preclinical data and most recently early clinical trial data suggests that PARP inhibitors could be used not only as chemo/radiotherapy sensitizers but also as single agents to selectively kill cancers defective in DNA repair, specifically cancers with mutations in the breast cancer associated (BRCA)1 and BRCA2 genes. This theory of selectively exploiting cells defective in one DNA repair pathway by inhibiting another is a major breakthrough in the treatment of cancer. The current clinical data are discussed within this review with reference to the preclinical models which predicted activity and also future directions and the possible dangers/pitfalls of this clinical strategy are explored.

  4. Resistance to mTORC1 Inhibitors in Cancer Therapy: From Kinase Mutations to Intratumoral Heterogeneity of Kinase Activity

    PubMed Central

    Faes, Seraina; Demartines, Nicolas

    2017-01-01

    Targeting mTORC1 has been thoroughly explored in cancer therapy. Following encouraging preclinical studies, mTORC1 inhibitors however failed to provide substantial benefits in cancer patients. Several resistance mechanisms have been identified including mutations of mTOR and activation of alternate proliferation pathways. Moreover, emerging evidence discloses intratumoral heterogeneity of mTORC1 activity that further contributes to a reduced anticancer efficacy of mTORC1 inhibitors. Genetic heterogeneity as well as heterogeneous conditions of the tumor environment such as hypoxia profoundly modifies mTORC1 activity in tumors and hence influences the response of tumors to mTORC1 inhibitors. Intriguingly, the heterogeneity of mTORC1 activity also occurs towards its substrates at the single cell level, as mutually exclusive pattern of activation of mTORC1 downstream effectors has been reported in tumors. After briefly describing mTORC1 biology and the use of mTORC1 inhibitors in patients, this review will give an overview on concepts of resistance to mTORC1 inhibition in cancer with a particular focus on intratumoral heterogeneity of mTORC1 activity. PMID:28280521

  5. Association Between Ischemic Stroke and Tumor Necrosis Factor Inhibitor Therapy in Patients With Rheumatoid Arthritis

    PubMed Central

    Low, Audrey S. L.; Lunt, Mark; Mercer, Louise K.; Watson, Kath D.; Dixon, William G.; Symmons, Deborah P. M.

    2016-01-01

    Objective Patients with rheumatoid arthritis (RA) are at an increased risk of ischemic stroke. Tumor necrosis factor inhibitors (TNFi) may influence risk and mortality after ischemic stroke by reducing inflammation. This study was undertaken to examine the association of TNFi with the risk of incident ischemic stroke and with 30‐day and 1‐year mortality after ischemic stroke. Methods Patients with RA starting therapy with TNFi and a biologics‐naive comparator group treated with synthetic disease‐modifying antirheumatic drugs (DMARDs) only were recruited to the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis from 2001 to 2009. Patients were followed up via clinical and patient questionnaires as well as the national death register. Incident strokes were classified as ischemic if brain imaging reports suggested ischemia or if ischemic stroke was reported as the underlying cause of death on a death certificate. Patients with a previous stroke were excluded. Risk of ischemic stroke was compared between patients receiving synthetic DMARDs only and those ever‐exposed to TNFi using a Cox proportional hazards regression model adjusted for potential confounders. Mortality after ischemic stroke was compared between synthetic DMARD–treated patients and TNFi‐treated patients using logistic regression, adjusted for age and sex. Results To April 2010, 127 verified incident ischemic strokes (21 in 3,271 synthetic DMARD–treated patients and 106 in 11,642 TNFi‐treated patients) occurred during 11,973 and 61,226 person‐years of observation, respectively (incidence rate 175 versus 173 per 100,000 person‐years). After adjustment for confounders, there was no association between ever‐exposure to TNFi and ischemic stroke (hazard ratio 0.99 [95% confidence interval (95% CI) 0.54–1.81]). Mortality 30 days or 1 year after ischemic stroke was not associated with concurrent TNFi exposure (odds ratio 0.18 [95% CI 0.03–1.21] and 0.60 [95

  6. Comparison of Subjective and Objective Hot Flash Measures Over Time Among Breast Cancer Survivors Initiating Aromatase Inhibitor Therapy

    PubMed Central

    Otte, Julie L.; Flockhart, David; Storniolo, Anna Maria; Schneider, Bryan; Azzouz, Faouzi; Lemler, Suzanne; Jeter, Stacie; Carpenter, Janet S.; Hayes, Daniel; Stearns, Vered; Henry, N. Lynn; Nguyen, Anne; Hayden, Jill; Wright, Laurie

    2009-01-01

    Objective Hot flashes are valuable indicators of physiologic condition and drug effect; however, subjective and objective measures do not always agree. No study has examined both subjective and objective hot flashes in women prescribed aromatase inhibitors. The study (1) compared subjective and objective hot flash measures, (2) examined changes in subjective and objective hot flashes over time, and (3) evaluated predictors of change in hot flashes in aromatase inhibitor-treated women. Design Subjects (n=135) were enrolled in a randomized clinical trial comparing exemestane and letrozole for the treatment of breast cancer. Hot flashes were assessed prior to starting drug and 1, 3, and 6 months later. Subjects wore a sternal skin conductance monitor for ≥ 24 hours at each time point. With each perceived hot flash, women pressed an event button and rated intensity and bother in a paper diary. Results Subjects were a mean age of 60 years and mainly Caucasian (92%). Across time points, monitor hot flashes were (1) significantly more frequent than diary and/or event button flashes (p<.05) and (2) moderately correlated with subjective measures (.35< r <.56). Monitor hot flashes did not significantly change over time with aromatase inhibitor therapy, whereas both diary and event button frequency significantly varied but in dissimilar patterns (51% non-linear). No consistent predictors of hot flashes across measures or time points were identified. Conclusions Findings indicated dissimilarities between subjective and objective measures of hot flashes. Despite statistical significance, there was little clinically meaningful change in hot flashes after initiating aromatase inhibitor therapy. PMID:19455068

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

    PubMed Central

    Kishi, Taro; Iwata, Nakao

    2015-01-01

    Background: We performed an updated meta-analysis of randomized controlled trials of combination therapy with cholinesterase inhibitors and memantine in patients with Alzheimer’s disease. Methods: We reviewed cognitive function, activities of daily living, behavioral disturbance, global assessment, discontinuation rate, and individual side effects. Results: Seven studies (total n=2182) were identified. Combination therapy significantly affected behavioral disturbance scores (standardized mean difference=−0.13), activity of daily living scores (standardized mean difference=−0.10), and global assessment scores (standardized mean difference=−0.15). In addition, cognitive function scores (standardized mean difference=−0.13, P=.06) exhibited favorable trends with combination therapy. The effects of combination therapy were more significant in the moderate-to-severe Alzheimer’s disease subgroup in terms of all efficacy outcome scores. The discontinuation rate was similar in both groups, and there were no significant differences in individual side effects. Conclusions: Combination therapy was beneficial for the treatment of moderate-to-severe Alzheimer’s disease in terms of cognition, behavioral disturbances, activities of daily living, and global assessment was well tolerated. PMID:25548104

  8. Bromodomain inhibitors, JQ1 and I-BET 762, as potential therapies for pancreatic cancer.

    PubMed

    Leal, Ana S; Williams, Charlotte R; Royce, Darlene B; Pioli, Patricia A; Sporn, Michael B; Liby, Karen T

    2017-05-28

    Bromodomain inhibitors (JQ1 and I-BET 762) are a new generation of selective, small molecule inhibitors that target BET (bromodomain and extra terminal) proteins. By impairing their ability to bind to acetylated lysines on histones, bromodomain inhibitors interfere with transcriptional initiation and elongation. BET proteins regulate several genes responsible for cell cycle, apoptosis and inflammation. In this study, JQ1 and I-BET 762 decreased c-Myc and p-Erk 1/2 protein levels and inhibited proliferation in pancreatic cancer cells. The tumor microenvironment is known to play an important role in pancreatic cancer, and these drugs suppressed the production of nitric oxide and a variety of inflammatory cytokines, including IL-6, CCL2, and GM-CSF, in both immune and pancreatic cancer cells in vitro. Notably, the bromodomain inhibitors also reduced protein levels of p-Erk 1/2 and p-STAT3 in mouse models of pancreatic cancer. All of these proteins are essential for tumor promotion, progression and metastasis. In conclusion, the bromodomain inhibitors JQ1 and I-BET 762 targeted and suppressed multiple pathways in pancreatic cancer. I-BET 762 and a number of other bromodomain inhibitors are currently being tested in several clinical trials, making them potentially promising drugs for the treatment of pancreatic cancer, an often-fatal disease.

  9. Attenuation of myocardial fibrosis with curcumin is mediated by modulating expression of angiotensin II AT1/AT2 receptors and ACE2 in rats

    PubMed Central

    Pang, Xue-Fen; Zhang, Li-Hui; Bai, Feng; Wang, Ning-Ping; Garner, Ron E; McKallip, Robert J; Zhao, Zhi-Qing

    2015-01-01

    Curcumin is known to improve cardiac function by balancing degradation and synthesis of collagens after myocardial infarction. This study tested the hypothesis that inhibition of myocardial fibrosis by curcumin is associated with modulating expression of angiotensin II (Ang II) receptors and angiotensin-converting enzyme 2 (ACE2). Male Sprague Dawley rats were subjected to Ang II infusion (500 ng/kg/min) using osmotic minipumps for 2 and 4 weeks, respectively, and curcumin (150 mg/kg/day) was fed by gastric gavage during Ang II infusion. Compared to the animals with Ang II infusion, curcumin significantly decreased the mean arterial blood pressure during the course of the observation. The protein level of the Ang II type 1 (AT1) receptor was reduced, and the Ang II type 2 (AT2) receptor was up-regulated, evidenced by an increased ratio of the AT2 receptor over the AT1 receptor in the curcumin group (1.2±0.02%) vs in the Ang II group (0.7±0.03%, P<0.05). These changes were coincident with less locally expressed AT1 receptor and enhanced AT2 receptor in the intracardiac vessels and intermyocardium. Along with these modulations, curcumin significantly decreased the populations of macrophages and alpha smooth muscle actin-expressing myofibroblasts, which were accompanied by reduced expression of transforming growth factor beta 1 and phosphorylated-Smad2/3. Collagen I synthesis was inhibited, and tissue fibrosis was attenuated, as demonstrated by less extensive collagen-rich fibrosis. Furthermore, curcumin increased protein level of ACE2 and enhanced its expression in the intermyocardium relative to the Ang II group. These results suggest that curcumin could be considered as an add-on therapeutic agent in the treatment of fibrosis-derived heart failure patient who is intolerant of ACE inhibitor therapy. PMID:26648693

  10. ACE and response to pulmonary rehabilitation in COPD: two observational studies

    PubMed Central

    Kon, Samantha S C; Jolley, Caroline J; Shrikrishna, Dinesh; Montgomery, Hugh E; Skipworth, James R A; Puthucheary, Zudin; Moxham, John; Polkey, Michael I; Man, William D-C

    2017-01-01

    Introduction Skeletal muscle impairment is an important feature of chronic obstructive pulmonary disease (COPD). Renin–angiotensin system activity influences muscle phenotype, so we wished to investigate whether it affects the response to pulmonary rehabilitation. Methods Two studies are described; in the first, the response of 168 COPD patients (mean forced expiratory volume in one second 51.9% predicted) to pulmonary rehabilitation was compared between different ACE insertion/deletion polymorphism genotypes. In a second, independent COPD cohort (n=373), baseline characteristics and response to pulmonary rehabilitation were compared between COPD patients who were or were not taking ACE inhibitors or angiotensin receptor antagonists (ARB). Results In study 1, the incremental shuttle walk distance improved to a similar extent in all three genotypes; DD/ID/II (n=48/91/29) 69(67)m, 61 (76)m and 78 (78)m, respectively, (p>0.05). In study 2, fat free mass index was higher in those on ACE-I/ARB (n=130) than those who were not (n=243), 17.8 (16.0, 19.8) kg m−2 vs 16.5 (14.9, 18.4) kg/m2 (p<0.001). However change in fat free mass, walking distance or quality of life in response to pulmonary rehabilitation did not differ between groups. Conclusions While these data support a positive association of ACE-I/ARB treatment and body composition in COPD, neither treatment to reduce ACE activity nor ACE (I/D) genotype influence response to pulmonary rehabilitation. PMID:28321311

  11. Diminazene aceturate enhances ACE2 activity and attenuates ischemia-induced cardiac pathophysiology

    PubMed Central

    Qi, YanFei; Zhang, Juan; Cole-Jeffrey, Colleen T; Shenoy, Vinayak; Espejo, Andrew; Hanna, Mina; Song, Chunjuan; Pepine, Carl J; Katovich, Michael J; Raizada, Mohan K

    2013-01-01

    Angiotensin-converting enzyme 2 (ACE2) plays a critical role against myocardial infarction (MI). We hypothesized that activation of intrinsic ACE2 would be protective against ischemia-induced cardiac pathophysiology. Diminazine aceturate (DIZE), a small molecule ACE2 activator has been used to evaluate this hypothesis. DIZE (15 mg/kg/day, s.c.) was injected two days prior to MI surgery and continued throughout the study-period. MI rats showed a 62% decrease in fractional shortening (FS,%) [control (Con): 51.1 ± 3.2; DIZE alone (D) : 52.1 ± 3.2; MI (M): 19.1± 3.0], a 55% decrease in contractility (dP/dtmax mmHg/s) (Con: 9480 ± 425.3; D: 9585 ± 597.4; M: 4251 ± 657.7), and a 27% increase in ventricular hypertrophy [VH, mg/mm (Con: 26.5 ± 1.5; D: 26.9 ± 1.4; M: 33.4± 1.1)]. DIZE attenuated the MI-induced decrease in FS by 89%, improved dP/dtmax by 92%, and reversed VH by 18%. MI also significantly increased ACE and angiotensin type 1 receptor levels while decreased ACE2 activity by 40% (Con: 246.2 ± 25.1; D: 254.2 ± 20.6; M: 148.9 ± 29.2, RFU/min), which was reversed by DIZE treatment. Thus, DIZE treatment decreased the infarct area, attenuated LV remodeling post-MI and restored normal balance of the cardiac renin angiotensin system. Additionally, DIZE treatment increased circulating endothelial progenitor cells, increased engraftment of cardiac progenitor cells and decreased inflammatory cells in peri-infarct cardiac regions. All of the beneficial effects associated with DIZE treatment were abolished by C-16, an ACE2 inhibitor. Collectively, DIZE and DIZE-like small molecules may represent promising new therapeutic agents for MI. PMID:23959549

  12. Stiffening of the ACES deployable space boom

    NASA Technical Reports Server (NTRS)

    Sidwell, Vince

    1994-01-01

    The purpose of this design project was to design an active planar stiffening device for the existing ACES (Acoustic Containerless Experiment System) structure. the ACES structure was modeled using simple beam theory. Various concepts were generated about how the stiffening device should be configured in order to perform at an optimum level. The optimum configuration was selected to be a single set of spreaders located approximately 63% of the distance down the beam. Actuation was to be provided by a DC electric motor. From the test results, the design group was able to draw conclusions and make recommendations about the utility of further research into this area.

  13. Antioxidant therapies for the management of atrial fibrillation

    PubMed Central

    Korantzopoulos, Panagiotis; Li, Guangping

    2012-01-01

    Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice, representing a major public health problem. Recent evidence suggests oxidative stress may play an important role in the pathogenesis and perpetuation of AF. In the past few years, experimental data and clinical evidence have tested the concept of antioxidant therapies to prevent AF. Besides statins, ACE-inhibitors (ACEIs) and/or angiotensin-receptor blockers (ARBs), and omega-3 polyunsaturated fatty acids, several other interventions with antioxidant properties, such as Vitamin C and E, thiazolidinediones, N-acetylcysteine, probucol, nitric oxide donors or precursors, NADPH oxidase inhibitors, Xanthine oxidase inhibitors have emerged as novel strategies for the management of AF. We aim to review recent evidence regarding antioxidant therapies in the prevention and treatment of atrial fibrillation. PMID:24282730

  14. Clinical Significance of Two Real-Time PCR Assays for Chronic Hepatitis C Patients Receiving Protease Inhibitor-Based Therapy

    PubMed Central

    Inoue, Takako; Hmwe, Su Su; Shimada, Noritomo; Kato, Keizo; Ide, Tatsuya; Torimura, Takuji; Kumada, Takashi; Toyoda, Hidenori; Tsubota, Akihito; Takaguchi, Koichi; Wakita, Takaji; Tanaka, Yasuhito

    2017-01-01

    The aim of this study was to determine the efficacy of two hepatitis C virus (HCV) real-time PCR assays, the COBAS AmpliPrep/COBAS TaqMan HCV test (CAP/CTM) and the Abbott RealTime HCV test (ART), for predicting the clinical outcomes of patients infected with HCV who received telaprevir (TVR)-based triple therapy or daclatasvir/asunaprevir (DCV/ASV) dual therapy. The rapid virological response rates in patients receiving TVR-based triple therapy were 92% (23/25) and 40% (10/25) for CAP/CTM and ART, respectively. The false omission rate (FOR) of ART was 93.3% (14/15), indicating that CAP/CTM could accurately predict clinical outcome in the early phase. In an independent examination of 20 patients receiving TVR-based triple therapy who developed viral breakthrough or relapse, the times to HCV disappearance by ART were longer than by CAP/CTM, whereas the times to HCV reappearance were similar. In an independent experiment of WHO standard HCV RNA serially diluted in serum containing TVR, the analytical sensitivities of CAP/CTM and ART were similar. However, cell cultures transfected with HCV and grown in medium containing TVR demonstrated that ART detected HCV RNA for a longer time than CAP/CTM. Similar results were found for 42 patients receiving DCV/ASV dual therapy. The FOR of ART was 73.3% (11/15) at week 8 after initiation of therapy, indicating that ART at week 8 could not accurately predict the clinical outcome. In conclusion, although CAP/CTM and ART detected HCV RNA with comparable analytical sensitivity, CAP/CTM might be preferable for predicting the clinical outcomes of patients receiving protease inhibitor-based therapy. PMID:28118381

  15. Non-length-dependent and length-dependent small-fiber neuropathies associated with tumor necrosis factor (TNF)-inhibitor therapy in patients with rheumatoid arthritis: Expanding the spectrum of neurological disease associated with TNF-inhibitors

    PubMed Central

    Birnbaum, Julius; Bingham, Clifton O.

    2015-01-01

    Objective Small-fiber neuropathy causes severe burning pain, requires diagnostic approaches such as skin biopsy, and encompasses two subtypes based on distribution of neuropathic pain. Such biopsy-proven subtypes of small-fiber neuropathies have not been previously described as complications of tumor necrosis factor (TNF)-inhibitor therapy. Methods We therefore characterized clinical and skin biopsy findings in three rheumatoid arthritis (RA) patients who developed small-fiber neuropathies associated with TNF-inhibitors. We also conducted a systematic review of the literature to characterize subtypes of neuropathies previously reported in association with TNF-inhibitor therapy. Results Two patients presented with a “non-length-dependent” small-fiber neuropathy, experiencing unorthodox patterns of burning pain affecting the face, torso, and proximal extremities. Abnormal skin biopsy findings were limited to the proximal thigh, which is a marker of proximal-most dorsal root ganglia degeneration. In contrast, one patient presented with a “length-dependent” small-fiber neuropathy, experiencing burning pain only in the feet. Abnormal skin biopsy findings were limited to the distal feet, which is a marker of distal-most axonal degeneration. One patient developed a small-fiber neuropathy in the context of TNF-inhibitor-induced lupus. In all patients, neuropathies occurred during TNF-inhibitor-induced remission of RA disease activity and improved on withdrawal of TNF-inhibitors. Conclusions We describe a spectrum of small-fiber neuropathies not previously reported in association with TNF-inhibitor therapy, with clinical and skin biopsy findings suggestive of dorsal root ganglia as well as axonal degeneration. The development of small-fiber neuropathies during inactive joint disease and improvement of neuropathic pain upon withdrawal of TNF-inhibitor suggest a causative role of TNF-inhibitors. PMID:24439654

  16. Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2).

    PubMed

    Lambert, Daniel W; Yarski, Mike; Warner, Fiona J; Thornhill, Paul; Parkin, Edward T; Smith, A Ian; Hooper, Nigel M; Turner, Anthony J

    2005-08-26

    Angiotensin-converting enzyme-2 (ACE2) is a critical regulator of heart function and a cellular receptor for the causative agent of severe-acute respiratory syndrome (SARS), SARS-CoV (coronavirus). ACE2 is a type I transmembrane protein, with an extracellular N-terminal domain containing the active site and a short intracellular C-terminal tail. A soluble form of ACE2, lacking its cytosolic and transmembrane domains, has been shown to block binding of the SARS-CoV spike protein to its receptor. In this study, we examined the ability of ACE2 to undergo proteolytic shedding and investigated the mechanisms responsible for this shedding event. We demonstrated that ACE2, heterologously expressed in HEK293 cells and endogenously expressed in Huh7 cells, undergoes metalloproteinase-mediated, phorbol ester-inducible ectodomain shedding. By using inhibitors with differing potency toward different members of the ADAM (a disintegrin and metalloproteinase) family of proteases, we identified ADAM17 as a candidate mediator of stimulated ACE2 shedding. Furthermore, ablation of ADAM17 expression using specific small interfering RNA duplexes reduced regulated ACE2 shedding, whereas overexpression of ADAM17 significantly increased shedding. Taken together, these data provided direct evidence for the involvement of ADAM17 in the regulated ectodomain shedding of ACE2. The identification of ADAM17 as the protease responsible for ACE2 shedding may provide new insight into the physiological roles of ACE2.

  17. The Atmospheric Chemistry Experiment (ACE): Mission Overview

    NASA Astrophysics Data System (ADS)

    Bernath, P. F.; Boone, C.; Walker, K.; McLeod, S.; Nassar, R.

    2003-12-01

    The ACE mission goals are: (1) to measure and to understand the chemical and dynamical processes that control the distribution of ozone in the upper troposphere and stratosphere, with a particular emphasis on the Arctic region; (2) to explore the relationship between atmospheric chemistry and climate change; (3) to study the effects of biomass burning in the free troposphere; (4) to measure aerosol number density, size distribution and composition in order to reduce the uncertainties in their effects on the global energy balance. ACE will make a comprehensive set of simultaneous measurements of trace gases, thin clouds, aerosols, and temperature by solar occultation from a satellite in low earth orbit. A high inclination (74 degrees) low earth orbit (650 km) gives ACE coverage of tropical, mid-latitudes and polar regions. The solar occultation advantages are high sensitivity and self-calibration. A high-resolution (0.02 cm-1) infrared Fourier Transform Spectrometer (FTS) operating from 2 to 13 microns (750-4100 cm-1) will measure the vertical distribution of trace gases, and the meteorological variables of temperature and pressure. The ACE concept is derived from the now-retired ATMOS FTS instrument, which flew on the Space Shuttle in 1985, 1992, 1993, 1994. Climate-chemistry coupling may lead to the formation of an Arctic ozone hole. ACE will provide high quality data to confront these model predictions and will monitor polar chemistry as chlorine levels decline. The ACE-FTS can measure water vapor and HDO in the tropical tropopause region to study dehydration and strat-trop exchange. The molecular signatures of massive forest fires will evident in the ACE infrared spectra. The CO2 in our spectra can be used to either retrieve atmospheric pressure or (if the instrument pointing knowledge proves to be satisfactory) for an independent retrieval of a CO2 profile for carbon cycle science. Aerosols and clouds will be monitored using the extinction of solar radiation at

  18. The Atmospheric Chemistry Experiment (ACE): Mission Overview

    NASA Astrophysics Data System (ADS)

    Bernath, P.

    2003-04-01

    The ACE mission goals are: (1) to measure and to understand the chemical and dynamical processes that control the distribution of ozone in the upper troposphere and stratosphere, with a particular emphasis on the Arctic region; (2) to explore the relationship between atmospheric chemistry and climate change; (3) to study the effects of biomass burning in the free troposphere; (4) to measure aerosol number density, size distribution and composition in order to reduce the uncertainties in their effects on the global energy balance. ACE will make a comprehensive set of simultaneous measurements of trace gases, thin clouds, aerosols, and temperature by solar occultation from a satellite in low earth orbit. A high inclination (74 degrees) low earth orbit (650 km) will give ACE coverage of tropical, mid-latitudes and polar regions. The solar occultation advantages are high sensitivity and self-calibration. A high-resolution (0.02 cm-1) infrared Fourier Transform Spectrometer (FTS) operating from 2 to 13 microns (750-4100 cm-1) will measure the vertical distribution of trace gases, and the meteorological variables of temperature and pressure. The ACE concept is derived from the now-retired ATMOS FTS instrument, which flew on the Space Shuttle in 1985, 1992, 1993, 1994. Climate-chemistry coupling may lead to the formation of an Arctic ozone hole. ACE will provide high quality data to confront these model predictions and will monitor polar chemistry as chlorine levels decline. The ACE-FTS can measure water vapor and HDO in the tropical tropopause region to study dehydration and strat-trop exchange. The molecular signatures of massive forest fires will evident in the ACE infrared spectra. The CO_2 in our spectra can be used to either retrieve atmospheric pressure or (if the instrument pointing knowledge proves to be satisfactory) for an independent retrieval of a CO_2 profile for carbon cycle science. Aerosols and clouds will be monitored using the extinction of solar

  19. The role of intracavernosal injection therapy and the reasons of withdrawal from therapy in patients with erectile dysfunction in the era of PDE5 inhibitors.

    PubMed

    Sung, H H; Ahn, J S; Kim, J J; Choo, S H; Han, D H; Lee, S W

    2014-01-01

    There has been little data regarding the role of intracavernosal injection (ICI) treatment, its discontinuation rate and the reasons of withdrawal in patients with erectile dysfunction (ED) in the era of phosphodiesterase type 5 (PDE5) inhibitors. The aim of this study was to investigate the rate of withdrawal and its associated reasons in patients undergoing ICI therapy. Patients who were prescribed with ICI treatment two times or more were included since the introduction of sildenafil in Korea in 1999. Telephone surveys were performed to evaluate intercourse rates, withdrawal rates and their associated reasons, adverse events and the patients' satisfaction with their sex lives after the ICI treatments. Two hundred and ninety-four men were contacted by telephone. The mean age was 61.8 ± 7.9 years with a follow-up duration of 25.6 ± 32.1 months. At the last follow-up, 79.9% had discontinued the treatment. Most patients had previously failed PDE5 inhibitor treatment prior to the ICI therapy, and more than half had two or more risk factors of ED. Adequate penile rigidity after ICI therapy was restored in 60.2% of patients. The reasons for discontinuation of ICI were poor response (43.1%), inconvenience of use (18.3%), switch to other treatments (10.7%), loss of libido (6.7%), adverse events (5.5%) and return of spontaneous erection (2.8%). Pain was the most common adverse event in the withdrawal group, whereas prolonged erection was most common in the continuing group. Following ICI treatment, PDE5 inhibitors were the most common therapeutic option (63.1%). The overall satisfaction rate regarding sex life was significantly high in the treatment-continuing group. In conclusion, patients on ICI treatment had severe ED and high withdrawal rates in the era of PDE5 inhibitors. The most common reason for treatment discontinuation was poor response. Before initiating ICI treatments, sufficient counselling is necessary.

  20. Captopril improves postresuscitation hemodynamics protective against pulmonary embolism by activating the ACE2/Ang-(1-7)/Mas axis.

    PubMed

    Xiao, Hong-Li; Li, Chun-Sheng; Zhao, Lian-Xing; Yang, Jun; Tong, Nan; An, Le; Liu, Qi-Tong

    2016-11-01

    Acute pulmonary embolism (APE) has a very high mortality rate, especially at cardiac arrest and even after the return of spontaneous circulation (ROSC). This study investigated the protective effect of the angiotensin-converting enzyme (ACE) inhibitor captopril on postresuscitation hemodynamics, in a porcine model of cardiac arrest established by APE. Twenty-nine Beijing Landrace pigs were infused with an autologous thrombus leading to cardiac arrest and subjected to standard cardiopulmonary resuscitation and thrombolysis. Ten resuscitated pigs were randomly and equally apportioned to receive either captopril (22.22 mg/kg) infusion or the same volume saline, 30 min after ROSC. Hemodynamic changes and ACE-Ang II-angiotensin II type 1 receptor (AT1R) and ACE2/Ang-(1-7)/Mas receptor axis levels were determined. APE was associated with a decline in mean arterial pressure and a dramatic increase in pulmonary artery pressure and mean right ventricular pressure. After ROSC, captopril infusion was associated with significantly lower mean right ventricular pressure and systemic and pulmonary vascular resistance, faster heart rate, and higher Ang-(1-7) levels, ACE2/ACE, and Ang-(1-7)/Ang II, compared with the saline infusion. The ACE2/Ang-(1-7)/Mas pathway correlated negatively with external vascular lung water and pulmonary vascular permeability and positively with the right cardiac index. In conclusion, in a pig model of APE leading to cardiac arrest, captopril infusion was associated with less mean right ventricular pressure overload after resuscitation, compared with saline infusion. The reduction in systemic and pulmonary vascular resistance associated with captopril may be by inhibiting the ACE-Ang II-AT1R axis and activating the ACE2/Ang-(1-7)/Mas axis.

  1. Inhibition of MAPK-mediated ACE expression by compound C66 prevents STZ-induced diabetic nephropathy.

    PubMed

    Pan, Yong; Huang, Yi; Wang, Zhe; Fang, Qilu; Sun, Yusheng; Tong, Chao; Peng, Kesong; Wang, Yangwei; Miao, Lining; Cai, Lu; Zhao, Yunjie; Liang, Guang

    2014-02-01

    A range of in vitro, experimental and clinical intervention studies have implicated an important role for hyperglycaemia-induced activation of the renin-angiotensin system (RAS) in the development and progression of diabetic nephropathy (DN). Blockade of RAS by angiotensin converting enzyme (ACE) inhibitors is an effective strategy in treating diabetic kidney diseases. However, few studies demonstrate the mechanism by which hyperglycaemia up-regulates the expression of ACE gene. Our previous studies have identified a novel curcumin analogue, (2E,6E)-2,6-bis(2-(trifluoromethyl)benzylidene)cyclohexanone (C66), which could inhibit the high glucose (HG)-induced phosphorylation of mitogen-activated protein kinases in mouse macrophages. In this study, we found that the renal protection of C66 in diabetic mice was associated with mitogen-activated protein kinase (MAPK) inactivation and ACE/angiotensin II (Ang II) down-regulation. Generally, MAPKs have been considered as a downstream signalling of Ang II and a mediator for Ang II-induced pathophysiological actions. However, using C66 and specific inhibitors as small molecule probes, in vitro experiments demonstrate that the MAPK signalling pathway regulates ACE expression under HG stimulation, which contributes to renal Ang II activation and the development of DN. This study indicates that C66 is a potential candidate of DN therapeutic agents, and more importantly, that reduction in ACE expression by MAPKs inhibition seems to be an alternative strategy for the treatment of DN.

  2. Methods for Investigation of Targeted Kinase Inhibitor Therapy using Chemical Proteomics and Phosphorylation Profiling

    PubMed Central

    Fang, Bin; Haura, Eric B.; Smalley, Keiran S.; Eschrich, Steven A.; Koomen, John M.

    2010-01-01

    Phosphorylation acts as a molecular switch for many regulatory events in signaling pathways that drive cell division, proliferation, and apoptosis. Because of the critical nature of these protein post-translational modifications in cancer, drug development programs often focus on inhibitors for kinases and phosphatases, which control protein phosphorylation. Numerous kinase inhibitors have entered clinical use, but prediction of their efficacy and a molecular basis for patient response remain uncertain. Chemical proteomics, the combination of drug affinity chromatography with mass spectrometry, identifies potential target proteins that bind to the drugs. Phosphorylation profiling can complement chemical proteomics by cataloging modifications in the target kinases and their downstream substrates using phosphopeptide enrichment and quantitative mass spectrometry. These experiments shed light on the mechanism of disease development and illuminate candidate biomarkers to guide personalized therapeutic strategies. In this review, commonly applied technologies and workflows are discussed to illustrate the role of proteomics in examining tumor biology and therapeutic intervention using kinase inhibitors. PMID:20361944

  3. Review article: immediate-release proton-pump inhibitor therapy--potential advantages.

    PubMed

    Howden, C W

    2005-12-01

    The absorption of most oral proton-pump inhibitors is delayed by the enteric coating required to protect the acid-labile proton-pump inhibitor from degradation in the stomach and, as a result, antisecretory effect is also delayed. This article provides an overview of the pharmacokinetics and pharmacodynamics of a new immediate-release omeprazole [(IR-OME) Zegerid power for oral suspension; Santarus Inc., San Diego, CA, USA] and its potential advantages over delayed-release proton-pump inhibitors. Immediate-release omeprazole has a higher mean peak plasma omeprazole concentration (C(max)) and a significantly shorter mean time to reach C(max) (t(max)) than delayed-release omeprazole. Immediate-release omeprazole 40 mg has a prolonged antisecretory effect with median intragastric pH above 4.0 for 18.6 h/day at steady-state, after 7 days of once daily dosing. The sodium bicarbonate in immediate-release omeprazole protects the uncoated omeprazole from degradation by gastric acid. The accelerated antisecretory action of immediate-release omeprazole compared with delayed-release omeprazole may be due to the activation of proton pumps by the rapid neutralization of intragastric acid by the sodium bicarbonate. The faster onset of action seen with immediate-release omeprazole is not achieved by using an antacid with a delayed-release proton-pump inhibitor, because administering antacids with conventional delayed-release proton-pump inhibitors does not significantly enhance absorption of the proton-pump inhibitor. In conclusion, immediate-release omeprazole is associated with rapid absorption of omeprazole and rapid onset of antisecretory effect, without compromising the duration of acid suppression.

  4. Developing Communities: Serving ACE through Tertiary Education

    ERIC Educational Resources Information Center

    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…

  5. Advanced Colloids Experiment (ACE-T1)

    NASA Technical Reports Server (NTRS)

    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.

  6. Advanced Colloids Experiment (ACE-H-2)

    NASA Technical Reports Server (NTRS)

    Meyer, William V.; Sicker, Ron; Chmiel, Alan J.; Eustace, John; LaBarbera, Melissa

    2015-01-01

    Increment 43 - 44 Science Symposium presentation of Advanced Colloids Experiment (ACE-H-2) 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.

  7. Ace the Verbal on the SAT

    ERIC Educational Resources Information Center

    Meierding, Loren

    2005-01-01

    Many students are not accepted in to certain colleges and universities because of low SAT scores. Loren Meierding has written Ace the Verbal on the SAT to help students with minimal preparation do well by improving their vocabulary and use better techniques for finding the answers to the questions. This book provides strategies needed to score…

  8. Bevacizumab salvage therapy following progression in high-grade glioma patients treated with VEGF receptor tyrosine kinase inhibitors.

    PubMed

    Scott, Brian J; Quant, Eudocia C; McNamara, Margaret B; Ryg, Peter A; Batchelor, Tracy T; Wen, Patrick Y

    2010-06-01

    Agents targeting the vascular endothelial growth factor (VEGF) pathway are being used with increasing frequency in patients with recurrent high-grade glioma. The effect of more than one antiangiogenic therapy given in succession has not been established. We reviewed the efficacy of bevacizumab, a VEGF-A monoclonal antibody, in patients who progressed following prior therapy with VEGF receptor tyrosine kinase inhibitors (R-TKi). Seventy-three patients with recurrent high-grade gliomas received VEGF R-TKi (cediranib, sorafenib, pazopanib, or sunitinib) as part of phase I or II clinical trials. Twenty-four of these patients with glioblastoma progressed and received bevacizumab-containing regimens immediately after R-TKi. Those who stopped R-TKi therapy for reasons other than disease progression, or received a treatment that did not include bevacizumab, were excluded from the analysis. The efficacy of bevacizumab-containing regimens in these 24 patients was evaluated. During R-TKi therapy, 6 of 24 patients (25%) had a partial response (PR) to treatment. The 6-month progression-free survival (APF6) was 16.7% and median time-to-progression (TTP) was 14.3 weeks. Grade III/IV toxicities were seen in 13 of 24 patients (54%). Subsequently with bevacizumab salvage therapy, 5 of 24 patients (21%) had a PR, the APF6 was 12.5%, and the median TTP was 8 weeks. Five of 24 patients had grade III/IV toxicities (21%). The median overall survival (OS) from the start of R-TKi therapy was 9.2 months (range: 2.8-34.1+), whereas the median OS after bevacizumab was 5.2 months (range: 1.3-28.9+). Bevacizumab retains modest activity in high-grade glioma patients who progress on R-TKi. However, the APF6 of 12.5% in this cohort of patients indicates that durable tumor control is not achieved for most patients.

  9. Cutaneous lymphocyte-associated antigen as a novel predictive marker of TNF-alpha inhibitor biological therapy in psoriasis.

    PubMed

    Jókai, Hajnalka; Szakonyi, József; Kontár, Orsolya; Barna, Gábor; Inotai, Dóra; Kárpáti, Sarolta; Holló, Péter

    2013-03-01

    A considerable number of patients with psoriasis show secondary resistance during long-term TNF-alpha inhibitor therapy, necessitating the identification of reliable predictive markers. Predictive role of cutaneous lymphocyte-associated antigen (CLA) was investigated. Thirty-eight severe patients with psoriasis were treated for a 24-week-long study period. Clinical responsiveness (PASI) and changes in flow cytometry-measured peripheral lymphocyte CLA expression (week 0-2-6) were statistically analysed. Regarding 24-week-long treatment outcome patients were divided into two groups: During the first 6 weeks, mean CLA expression showed significant (P = 0.034604) increase among responders (32/38), while after a preliminary increase, it was significantly (P = 0.012539) decreasing in the relapsing group (6/38). Pearson's correlation analysis showed significant negative correlation between PASI and CLA changes. Responders showed (not significantly) lower initial CLA expression than relapsing patients. Our observations suggest change in CLA expression during the first 6 weeks of induction period to serve as a potential predictive marker of TNF-alpha inhibitor therapy in psoriasis.

  10. Photothermal therapy improves the efficacy of a MEK inhibitor in neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors

    NASA Astrophysics Data System (ADS)

    Sweeney, Elizabeth E.; Burga, Rachel A.; Li, Chaoyang; Zhu, Yuan; Fernandes, Rohan

    2016-11-01

    Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive tumors with low survival rates and the leading cause of death in neurofibromatosis type 1 (NF1) patients under 40 years old. Surgical resection is the standard of care for MPNSTs, but is often incomplete and can generate loss of function, necessitating the development of novel treatment methods for this patient population. Here, we describe a novel combination therapy comprising MEK inhibition and nanoparticle-based photothermal therapy (PTT) for MPNSTs. MEK inhibitors block activity driven by Ras, an oncogene constitutively activated in NF1-associated MPNSTs, while PTT serves as a minimally invasive method to ablate cancer cells. Our rationale for combining these seemingly disparate techniques for MPNSTs is based on several reports demonstrating the efficacy of systemic chemotherapy with local PTT. We combine the MEK inhibitor, PD-0325901 (PD901), with Prussian blue nanoparticles (PBNPs) as PTT agents, to block MEK activity and simultaneously ablate MPNSTs. Our data demonstrate the synergistic effect of combining PD901 with PBNP-based PTT, which converge through the Ras pathway to generate apoptosis, necrosis, and decreased proliferation, thereby mitigating tumor growth and increasing survival of MPNST-bearing animals. Our results suggest the potential of this novel local-systemic combination “nanochemotherapy” for treating patients with MPNSTs.

  11. The effect of BIM deletion polymorphism on intrinsic resistance and clinical outcome of cancer patient with kinase inhibitor therapy.

    PubMed

    Ying, Hou-Qun; Chen, Jie; He, Bang-Shun; Pan, Yu-Qin; Wang, Feng; Deng, Qi-Wen; Sun, Hui-Ling; Liu, Xian; Wang, Shu-Kui

    2015-06-15

    A common deletion polymorphism within B-cell chronic lymphocytic leukemia-lymphoma like 11 gene (BIM) was deemed to be a genetic cause leading to compromised kinase inhibitor therapeutic efficacy in cancer individuals. However, the results reported were not consistent. Thus, a comprehensive meta-analysis containing 12 eligible studies including 1,532 Asian patients was conducted to investigate a steady and reliable conclusion. The results showed that BIM deletion polymorphism was significantly associated with tyrosine kinase inhibitor (TKI) clinical efficacy in term of response rate (Ph = 0.349, HR = 0.438, 95%CI = 0.274-0.699) and disease control rate (Ph = 0.941, HR = 0.370, 95%CI = 0.202-0.678) in EGFR-mutated NSCLC population, not in CML and HCC subgroups. Additionally, EGFR-mutated NSCLC patient harbored BIM deletion polymorphism was associated with a shorter progression-free survival (PFS) than those with BIM wild polymorphism (Ph = 0.580, adjusted HR = 2.194, 95%CI = 1.710-2.814). However, no significant association was examined between BIM deletion polymorphism and overall survival (OS) and toxic adverse events in EGFR-mutated NSCLC population and it was not associated with PFS and OS in HCC subgroup. These findings revealed that BIM deletion polymorphism might be a genetic cause of intrinsic resistance to TKI therapy and it could be emerged as an independent predictor to identify patients who would benefit from TKI targeted therapy in EGFR-mutated NSCLC.

  12. Photothermal therapy improves the efficacy of a MEK inhibitor in neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors

    PubMed Central

    Sweeney, Elizabeth E.; Burga, Rachel A.; Li, Chaoyang; Zhu, Yuan; Fernandes, Rohan

    2016-01-01

    Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive tumors with low survival rates and the leading cause of death in neurofibromatosis type 1 (NF1) patients under 40 years old. Surgical resection is the standard of care for MPNSTs, but is often incomplete and can generate loss of function, necessitating the development of novel treatment methods for this patient population. Here, we describe a novel combination therapy comprising MEK inhibition and nanoparticle-based photothermal therapy (PTT) for MPNSTs. MEK inhibitors block activity driven by Ras, an oncogene constitutively activated in NF1-associated MPNSTs, while PTT serves as a minimally invasive method to ablate cancer cells. Our rationale for combining these seemingly disparate techniques for MPNSTs is based on several reports demonstrating the efficacy of systemic chemotherapy with local PTT. We combine the MEK inhibitor, PD-0325901 (PD901), with Prussian blue nanoparticles (PBNPs) as PTT agents, to block MEK activity and simultaneously ablate MPNSTs. Our data demonstrate the synergistic effect of combining PD901 with PBNP-based PTT, which converge through the Ras pathway to generate apoptosis, necrosis, and decreased proliferation, thereby mitigating tumor growth and increasing survival of MPNST-bearing animals. Our results suggest the potential of this novel local-systemic combination “nanochemotherapy” for treating patients with MPNSTs. PMID:27833160

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

    PubMed Central

    Weidemann, Anja K; Crawshaw, Ania A; Byrne, Emily; Young, Helen S

    2013-01-01

    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 cardiovascular risk. PMID:24101875

  14. Overcoming resistance of glioblastoma to conventional cytotoxic therapies by the addition of PARP inhibitors.

    PubMed

    Chalmers, Anthony J

    2010-09-01

    This article will present the rationale for combining chemical inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) with conventional cytotoxic agents to improve the treatment of glioblastoma. After a brief review of the current therapeutic options for these aggressive tumours, the possible reasons for their resistance to radiation and chemotherapy will be discussed, highlighting the important role of DNA damage response pathways in many key resistance mechanisms. The dose-limiting toxicities associated with radiation and chemotherapy treatment will be described in order to illustrate the importance of tumour specificity in any attempt to increase the effectiveness of conventional treatments. There will then be a summary of the reasons why targeting DNA repair pathways might achieve tumour specific sensitization. After a brief summary of the key DNA damage response pathways, the biology, biochemistry and pharmacology of PARP and the existing PARP inhibitors will be presented. The major part of the review will cover the effects of combining PARP inhibitors with radiation and chemotherapy in vitro and in vivo, commenting on the underlying mechanisms and indicating where the data are predictive of tumour specific sensitization. Finally, we will consider specific scenarios where PARP inhibitors might contribute to the treatment of glioblastoma patients, discuss the challenges and opportunities associated with early phase clinical testing of these agents, and describe the clinical trials that are either underway or in development.

  15. Is angiotensin-converting enzyme inhibitors/angiotensin receptor blockers therapy protective against prostate cancer?

    PubMed Central

    Mao, Yeqing; Xu, Xin; Wang, Xiao; Zheng, Xiangyi; Xie, Liping

    2016-01-01

    Emerging evidence suggests that renin-angiotensin system (RAS) may act as a molecular and therapeutic target for treating site-specific cancers, including prostate cancer. However, previous observational studies regarding the association between RAS inhibitors and prostate cancer risk have reported inconsistent results. We examined this association by performing a systematic review and meta-analysis. A total of 20,267 patients from nine cohort studies were enrolled. Compared with non-users of RAS inhibitors, individuals using RAS inhibitors had a reduced risk of prostate cancer (RR 0.92, 95 % CI 0.87-0.98), without statistically significant heterogeneity among studies (P = 0.118 for heterogeneity, I2 = 37.6 %). In addition, when subgroup analyses by study quality and number of cases, more statistically significant associations were observed in studies of high quality (RR 0.93, 95 % CI 0.88-0.97) and large sample size (RR 0.94, 95 % CI 0.91-0.98). There was no evidence of significant publication bias with Begg's test (P = 0.602) or with Egger's test (P = 0.350). Overall, this study indicates that use of RAS inhibitors may be associated with a decreased risk of prostate cancer. Large-scale well designed studies are needed to further explore this association. PMID:26760503

  16. A recommended practical approach to the management of target therapy and angiogenesis inhibitors cardiotoxicity: an opinion paper of the working group on drug cardiotoxicity and cardioprotection, Italian Society of Cardiology

    PubMed Central

    Maurea, Nicola; Spallarossa, Paolo; Cadeddu, Christian; Madonna, Rosalinda; Mele, Donato; Monte, Ines; Novo, Giuseppina; Pagliaro, Pasquale; Pepe, Alessia; Tocchetti, Carlo G.; Zito, Concetta; Mercuro, Giuseppe

    2016-01-01

    The US National Cancer Institute estimates that cardiotoxicity (CTX) from target therapy refers mostly to four groups of drugs: epidermal growth factor receptor 2 inhibitors, angiogenic inhibitors, directed Abelson murine leukemia viral oncogene homolog inhibitors, and proteasome inhibitors. The main cardiotoxic side-effects related to antiepidermal growth factor receptor 2 therapy are left ventricular systolic dysfunction and heart failure. Angiogenesis inhibitors are associated with hypertension, left ventricular dysfunction/heart failure, myocardial ischemia, QT prolongation, and thrombosis. Moreover, other agents may be related to CTX induced by treatment. In this study, we review the guidelines for a practical approach for the management of CTX in patients under anticancer target therapy. PMID:27183530

  17. Factors Associated with the Development of Drug Resistance Mutations in HIV-1 Infected Children Failing Protease Inhibitor-Based Antiretroviral Therapy in South Africa

    PubMed Central

    Melikian, George; van Dyk, Gisela; Thomas, Winifred; du Plessis, Nicolette M.; Avenant, Theunis

    2015-01-01

    Objective Limited data are available from the developing world on antiretroviral drug resistance in HIV-1 infected children failing protease inhibitor-based antiretroviral therapy, especially in the context of a high tuberculosis burden. We describe the proportion of children with drug resistance mutations after failed protease inhibitor-based antiretroviral therapy as well as associated factors. Methods Data from children initiated on protease inhibitor-based antiretroviral therapy with subsequent virological failure referred for genotypic drug resistance testing between 2008 and 2012 were retrospectively analysed. Frequencies of drug resistance mutations were determined and associations with these mutations identified through logistic regression analysis. Results The study included 65 young children (median age 16.8 months [IQR 7.8; 23.3]) with mostly advanced clinical disease (88.5% WHO stage 3 or 4 disease), severe malnutrition (median weight-for-age Z-score -2.4 [IQR -3.7;-1.5]; median height-for-age Z-score -3.1 [IQR -4.3;-2.4]), high baseline HIV viral load (median 6.04 log10, IQR 5.34;6.47) and frequent tuberculosis co-infection (66%) at antiretroviral therapy initiation. Major protease inhibitor mutations were found in 49% of children and associated with low weight-for-age and height-for-age (p = 0.039; p = 0.05); longer duration of protease inhibitor regimens and virological failure (p = 0.001; p = 0.005); unsuppressed HIV viral load at 12 months of antiretroviral therapy (p = 0.001); tuberculosis treatment at antiretroviral therapy initiation (p = 0.048) and use of ritonavir as single protease inhibitor (p = 0.038). On multivariate analysis, cumulative months on protease inhibitor regimens and use of ritonavir as single protease inhibitor remained significant (p = 0.008; p = 0.033). Conclusion Major protease inhibitor resistance mutations were common in this study of HIV-1-infected children, with the timing of tuberculosis treatment and subsequent

  18. Gene Therapy with Endogenous Inhibitors of Angiogenesis for Neovascular Age-Related Macular Degeneration: Beyond Anti-VEGF Therapy.

    PubMed

    Prea, Selwyn M; Chan, Elsa C; Dusting, Gregory J; Vingrys, Algis J; Bui, Bang V; Liu, Guei-Sheung

    2015-01-01

    Age-related macular degeneration (AMD) is the leading cause of substantial and irreversible vision loss amongst elderly populations in industrialized countries. The advanced neovascular (or "wet") form of the disease is responsible for severe and aggressive loss of central vision. Current treatments aim to seal off leaky blood vessels via laser therapy or to suppress vessel leakage and neovascular growth through intraocular injections of antibodies that target vascular endothelial growth factor (VEGF). However, the long-term success of anti-VEGF therapy can be hampered by limitations such as low or variable efficacy, high frequency of administration (usually monthly), potentially serious side effects, and, most importantly, loss of efficacy with prolonged treatment. Gene transfer of endogenous antiangiogenic proteins is an alternative approach that has the potential to provide long-term suppression of neovascularization and/or excessive vascular leakage in the eye. Preclinical studies of gene transfer in a large animal model have provided impressive preliminary results with a number of transgenes. In addition, a clinical trial in patients suffering from advanced neovascular AMD has provided proof-of-concept for successful gene transfer. In this mini review, we summarize current theories pertaining to the application of gene therapy for neovascular AMD and the potential benefits when used in conjunction with endogenous antiangiogenic proteins.

  19. PDE 7 Inhibitors: New Potential Drugs for the Therapy of Spinal Cord Injury

    PubMed Central

    Paterniti, Irene; Mazzon, Emanuela; Gil, Carmen; Impellizzeri, Daniela; Palomo, Valle; Redondo, Myriam; Perez, Daniel I.; Esposito, Emanuela; Martinez, Ana; Cuzzocrea, Salvatore

    2011-01-01

    Background Primary traumatic mechanical injury to the spinal cord (SCI) causes the death of a number of neurons that to date can neither be recovered nor regenerated. During the last years our group has been involved in the design, synthesis and evaluation of PDE7 inhibitors as new innovative drugs for several neurological disorders. Our working hypothesis is based on two different facts. Firstly, neuroinflammation is modulated by cAMP levels, thus the key role for phosphodiesterases (PDEs), which hydrolyze cAMP, is undoubtedly demonstrated. On the other hand, PDE7 is expressed simultaneously on leukocytes and on the brain, highlighting the potential crucial role of PDE7 as drug target for neuroinflammation. Methodology/Principal Findings Here we present two chemically diverse families of PDE7 inhibitors, designed using computational techniques such as virtual screening and neuronal networks. We report their biological profile and their efficacy in an experimental SCI model induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5–T8 laminectomy. We have selected two candidates, namely S14 and VP1.15, as PDE7 inhibitors. These compounds increase cAMP production both in macrophage and neuronal cell lines. Regarding drug-like properties, compounds were able to cross the blood brain barrier using parallel artificial membranes (PAMPA) methodology. SCI in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and production of a range of inflammatory mediators, tissue damage, and apoptosis. Treatment of the mice with S14 and VP1.15, two PDE7 inhibitors, significantly reduced the degree of spinal cord inflammation, tissue injury (histological score), and TNF-α, IL-6, COX-2 and iNOS expression. Conclusions/Significance All these data together led us to propose PDE7 inhibitors, and specifically S14 and VP1.15, as potential drug candidates to be further studied for the treatment of SCI. PMID:21297958

  20. Pharmacophore development and screening for discovery of potential inhibitors of ADAMTS-4 for osteoarthritis therapy.

    PubMed

    Verma, Priyanka; Dalal, Krishna; Chopra, Madhu

    2016-08-01

    In the development of osteoarthritis, aggrecan degrades prior to cartilage destruction. Aggrecanase-1 (ADAMTS-4) is considered to be the major enzyme responsible for cleaving the Glu373-Ala374 bond in the interglobular domain of aggrecan in humans. Therefore, inhibitors of ADAMTS-4 have therapeutic potential in the treatment of osteoarthritis. In the present work, we developed a chemical feature based pharmacophore model of ADAMTS-4 inhibitors using the HipHop module within the Catalyst program package in order to elucidate the structure-activity relationship and to carry out in-silico screening. The Maybridge database was screened using Hypo1 as a 3D query, and the best-fit hits that followed Lipinski's rule of five were subsequently screened to select the compounds. The hit compounds were then docked into the active site of ADAMTS-4, and interactions were visualized to determine the potential lead molecules. After subjecting all of the hits to various screening and filtering processes, 13 compounds were finally evaluated for their in vitro inhibitory activities. This study resulted in the identification of two lead compounds with potent inhibitory effects on ADAMTS-4 activity, with IC50 values of 0.042 μM and 0.028 μM, respectively. These results provide insight into the pharmacophoric requirements for the development of more potent ADAMTS-4 inhibitors. Graphical Abstract The aggrecan-degrading metalloprotease ADAMTS-4 has been identified as a novel therapeutic target for osteoarthritis. In this work, we used HipHop-based pharmacophore modeling and virtual screening of the Maybridge database to identify novel ADAMTS-4 inhibitors. These novel lead compounds act as potent and specific inhibitors for the ADAMTS-4 enzyme and could have therapeutic potential in the treatment of OA.

  1. In Vitro Targeted Photodynamic Therapy with a Pyropheophorbide-a Conjugated Inhibitor of Prostate Specific Membrane Antigen

    PubMed Central

    Liu, Tiancheng; Wu, Lisa Y.; Choi, Joseph K.; Berkman, Clifford E.

    2009-01-01

    BACKROUND The lack of specific delivery of photosensitizers (PSs), represents a significant limitation of photodynamic therapy (PDT) of cancer. The biomarker prostate-specific membrane antigen (PSMA) has attracted considerable attention as a target for imaging and therapeutic applications for prostate cancer. Although recent efforts have been made to conjugate inhibitors of PSMA with imaging agents, there have been no reports on photosensitizer-conjugated PSMA inhibitors for targeted PDT of prostate cancer. The present study focuses on the use of a PSMA inhibitor-conjugate of pyropheophorbide-a (Ppa-conjugate 2) for targeted PDT to achieve apoptosis in PSMA+ LNCaP cells. METHODS Confocal laser scanning microscopy with a combination of nuclear staining and immunofluorescence methods were employed to monitor the specific imaging and PDT-mediated apoptotic effects on PSMA-positive LNCaP and PSMA-negative (PC-3) cells. RESULTS Our results demonstrated that PDT-mediated effects by Ppa-conjugate 2 were specific to LNCaP cells, but not PC-3 cells. Cell permeability was detected as early as 2 h by HOE33342/PI double-staining, becoming more intense by 4 h. Evidence for the apoptotic caspase cascade being activated was based on the appearance of PARP p85 fragment. TUNEL assay detected DNA fragmentation 16 h post-PDT, confirming apoptotic events. CONCLUSIONS Cell permeability by HOE33342/PI double-staining as well as PARP p85 fragment and TUNEL assays confirm cellular apoptosis in PSMA+ cells when treated with PS-inhibitor conjugate 2 and subsequently irradiated. It is expected that the PSMA targeting small-molecule of this conjugate can serve as a delivery vehicle for PDT and other therapeutic applications for prostate cancer. PMID:19142895

  2. Anoctamin 6 Contributes to Cl- Secretion in Accessory Cholera Enterotoxin (Ace)-stimulated Diarrhea: AN ESSENTIAL ROLE FOR PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE (PIP2) SIGNALING IN CHOLERA.

    PubMed

    Aoun, Joydeep; Hayashi, Mikio; Sheikh, Irshad Ali; Sarkar, Paramita; Saha, Tultul; Ghosh, Priyanka; Bhowmick, Rajsekhar; Ghosh, Dipanjan; Chatterjee, Tanaya; Chakrabarti, Pinak; Chakrabarti, Manoj K; Hoque, Kazi Mirajul

    2016-12-23

    Accessory cholera enterotoxin (Ace) of Vibrio cholerae has been shown to contribute to diarrhea. However, the signaling mechanism and specific type of Cl(-) channel activated by Ace are still unknown. We have shown here that the recombinant Ace protein induced ICl of apical plasma membrane, which was inhibited by classical CaCC blockers. Surprisingly, an Ace-elicited rise of current was neither affected by ANO1 (TMEM16A)-specific inhibitor T16A(inh)-AO1(TAO1) nor by the cystic fibrosis transmembrane conductance regulator (CFTR) blocker, CFTR inh-172. Ace stimulated whole-cell current in Caco-2 cells. However, the apical ICl was attenuated by knockdown of ANO6 (TMEM16F). This impaired phenotype was restored by re-expression of ANO6 in Caco-2 cells. Whole-cell patch clamp recordings of ANO currents in HEK293 cells transiently expressing mouse ANO1-mCherry or ANO6-GFP confirmed that Ace induced Cl(-) secretion. Application of Ace produced ANO6 but not the ANO1 currents. Ace was not able to induce a [Ca(2+)]i rise in Caco-2 cells, but cellular abundance of phosphatidylinositol 4,5-bisphosphate (PIP2) increased. Identification of the PIP2-binding motif at the N-terminal sequence among human and mouse ANO6 variants along with binding of PIP2 directly to ANO6 in HEK293 cells indicate likely PIP2 regulation of ANO6. The biophysical and pharmacological properties of Ace stimulated Cl(-) current along with intestinal fluid accumulation, and binding of PIP2 to the proximal KR motif of channel proteins, whose mutagenesis correlates with altered binding of PIP2, is comparable with ANO6 stimulation. We conclude that ANO6 is predominantly expressed in intestinal epithelia, where it contributes secretory diarrhea by Ace stimulation in a calcium-independent mechanism of RhoA-ROCK-PIP2 signaling.

  3. Activation of HER3 Interferes with Antitumor Effects of Axl Receptor Tyrosine Kinase Inhibitors: Suggestion of Combination Therapy1

    PubMed Central

    Torka, Robert; Pénzes, Kinga; Gusenbauer, Simone; Baumann, Christine; Szabadkai, István; Őrfi, Lászlȯ; Kéri, György; Ullrich, Axel

    2014-01-01

    The Axl receptor tyrosine kinase (RTK) has been established as a strong candidate for targeted therapy of cancer. However, the benefits of targeted therapies are limited due to acquired resistance and activation of alternative RTKs. Therefore, we asked if cancer cells are able to overcome targeted Axl therapies. Here, we demonstrate that inhibition of Axl by short interfering RNA or the tyrosine kinase inhibitor (TKI) BMS777607 induces the expression of human epidermal growth factor receptor 3 (HER3) and the neuregulin 1(NRG1)–dependent phosphorylation of HER3 in MDA-MB231 and Ovcar8 cells. Moreover, analysis of 20 Axl-expressing cancer cell lines of different tissue origin indicates a low basal phosphorylation of RAC-α serine/threonine-protein kinase (AKT) as a general requirement for HER3 activation on Axl inhibition. Consequently, phosphorylation of AKT arises as an independent biomarker for Axl treatment. Additionally, we introduce phosphorylation of HER3 as an independent pharmacodynamic biomarker for monitoring of anti-Axl therapy response. Inhibition of cell viability by BMS777607 could be rescued by NRG1-dependent activation of HER3, suggesting an escape mechanism by tumor microenvironment. The Axl-TKI MPCD84111 simultaneously blocked Axl and HER2/3 signaling and thereby prohibited HER3 feedback activation. Furthermore, dual inhibition of Axl and HER2/3 using BMS777607 and lapatinib led to a significant inhibition of cell viability in Axl-expressing MDA-MB231 and Ovcar8 cells. Therefore, we conclude that, in patient cohorts with expression of Axl and low basal activity of AKT, a combined inhibition of Axl and HER2/3 kinase would be beneficial to overcome acquired resistance to Axl-targeted therapies. PMID:24862757

  4. Development of farnesyltransferase inhibitors for clinical cancer therapy: focus on hematologic malignancies.

    PubMed

    Karp, Judith E; Lancet, Jeffrey E

    2007-09-01

    Farnesyltransferase inhibitors (FTIs) target and inhibit the peptide prenylating enzyme farnesyltransferase. This new class of signal transduction inhibitors is being tested clinically in diverse malignancies, with encouraging results in hematololgic malignancies and breast cancer in particuarl. Critical questions have yet to be answered, for example, optimal dose and schedule, disease subgroups most likely to respond, and appropriate combinations with standard cytotoxics and new biologics. Gene profiling studies of malignant target cells obtained during FTI clinical trials will help to identify patients who are likely to respond to FTIs and to develop mechanisms for overcoming FTI resistance. Clinical trials and correlative laboratory studies in progress and under development will define the optimal roles of FTIs in cancer patients.

  5. Enhancing the Cytotoxic Effects of PARP Inhibitors with DNA Demethylating Agents - A Potential Therapy for Cancer.

    PubMed

    Muvarak, Nidal E; Chowdhury, Khadiza; Xia, Limin; Robert, Carine; Choi, Eun Yong; Cai, Yi; Bellani, Marina; Zou, Ying; Singh, Zeba N; Duong, Vu H; Rutherford, Tyler; Nagaria, Pratik; Bentzen, Søren M; Seidman, Michael M; Baer, Maria R; Lapidus, Rena G; Baylin, Stephen B; Rassool, Feyruz V

    2016-10-10

    Poly (ADP-ribose) polymerase inhibitors (PARPis) are clinically effective predominantly for BRCA-mutant tumors. We introduce a mechanism-based strategy to enhance PARPi efficacy based on DNA damage-related binding between DNA methyltransferases (DNMTs) and PARP1. In acute myeloid leukemia (AML) and breast cancer cells, DNMT inhibitors (DNMTis) alone covalently bind DNMTs into DNA and increase PARP1 tightly bound into chromatin. Low doses of DNMTis plus PARPis, versus each drug alone, increase PARPi efficacy, increasing amplitude and retention of PARP1 directly at laser-induced DNA damage sites. This correlates with increased DNA damage, synergistic tumor cytotoxicity, blunting of self-renewal, and strong anti-tumor responses, in vivo in unfavorable AML subtypes and BRCA wild-type breast cancer cells. Our combinatorial approach introduces a strategy to enhance efficacy of PARPis in treating cancer.

  6. Natural AChE Inhibitors from Plants and their Contribution to Alzheimer’s Disease Therapy

    PubMed Central

    Murray, Ana Paula; Faraoni, María Belén; Castro, María Julia; Alza, Natalia Paola; Cavallaro, Valeria

    2013-01-01

    As acetylcholinesterase (AChE) inhibitors are an important therapeutic strategy in Alzheimer’s disease, efforts are being made in search of new molecules with anti-AChE activity. The fact that naturally-occurring compounds from plants are considered to be a potential source of new inhibitors has led to the discovery of an important number of secondary metabolites and plant extracts with the ability of inhibiting the enzyme AChE, which, according to the cholinergic hypothesis, increases the levels of the neurotransmitter acetylcholine in the brain, thus improving cholinergic functions in patients with Alzheimer’s disease and alleviating the symptoms of this neurological disorder. This review summarizes a total of 128 studies which correspond to the most relevant research work published during 2006-2012 (1st semester) on plant-derived compounds, plant extracts and essential oils found to elicit AChE inhibition. PMID:24381530

  7. Small Bowel Angioedema Secondary to Angiotensin-Converting Enzyme Inhibitors

    PubMed Central

    Hurairah, Abu

    2016-01-01

    Small bowel angioedema induced by angiotensin-converting enzyme (ACE) inhibitors is a rare clinicopathologic entity. It frequently poses a diagnostic challenge and is often not recognized before surgical exploration. The present study illustrates that clinical awareness for this condition and adequate use of radiologic investigations can help make the correct diagnosis of ACE inhibitor-associated angioedema, thus avoiding the cost and morbidity associated with unnecessary interventions. PMID:28133581

  8. Novel Inhibitors of Protein-Protein Interaction for Prostate Cancer Therapy

    DTIC Science & Technology

    2014-04-01

    inhibitors; cellular reactive oxygen species; cyclin D1 INTRODUCTION Advanced hormone refractory metastatic prostate cancer (PCa) is the second leading...sufficiently deplete androgen content while limiting the adverse growth effects not related to hormone depletion that occur with the use of 5% stripped...Scientific Publishing Co. Pte.Ltd; 2011. 3. Jorgenson TC, Zhang W, Oberley TD. Redox imbalance and biochemical changes in cancer. Cancer Res 2013;73(20

  9. The relationship between long-term proton pump inhibitor therapy and skeletal frailty.

    PubMed

    Lau, Arthur N; Tomizza, Michael; Wong-Pack, Matthew; Papaioannou, Alexandra; Adachi, Jonathan D

    2015-08-01

    Proton pump inhibitors (PPIs) are a commonly prescribed class of medications. Their use has been associated with an increased rate of fractures, most notably hip fractures. However, there does not seem to be a clear association between PPI use and bone mineral density measurements, assessed by dual X-ray absorptiometry. The mechanism by which PPI use increases the risk of fractures remains unclear. This review will summarize the current evidence on this topic.

  10. Adjuvant therapy with tamoxifen compared to aromatase inhibitors for 257 male breast cancer patients.

    PubMed

    Eggemann, Holm; Ignatov, Atanas; Smith, Bobbie J; Altmann, Udo; von Minckwitz, Gunter; Röhl, Freidrich W; Jahn, Mark; Costa, Serban-Dan

    2013-01-01

    To determine the impact of adjuvant treatment with tamoxifen and aromatase inhibitors (AI) on the survival of men with breast cancer. We analyzed 257 male patients with hormone-receptor-positive breast cancer from numerous German population-based cancer registries treated with tamoxifen (N = 207) or aromatase inhibitors (N = 50). The median follow-up was 42.2 (range 2-115) months. Median age at diagnosis was 68 (range 36-91) years. Thirty-seven (17.9 %) patients treated with tamoxifen and 16 (32.0 %) patients treated with AI died (log rank p = 0.007). After the adjustment for the patient's age, tumor size, node status, and tumor grading, the AI treatment was linked to a 1.5-fold increase in risk of mortality compared to tamoxifen (HR 1.55; 95 % CI: 1.13-2.13; p = 0.007). The overall survival in male breast cancer was significantly better after adjuvant treatment with tamoxifen compared to an aromatase inhibitor. Tamoxifen should be considered as the treatment of choice for hormone-receptor-positive male breast cancer.

  11. Potent and Selective Inhibitors of Human Reticulocyte 12/15-Lipoxygenase as Anti-Stroke Therapies

    PubMed Central

    2015-01-01

    A key challenge facing drug discovery today is variability of the drug target between species, such as with 12/15-lipoxygenase (12/15-LOX), which contributes to ischemic brain injury, but its human and rodent isozymes have different inhibitor specificities. In the current work, we have utilized a quantitative high-throughput (qHTS) screen to identify compound 1 (ML351), a novel chemotype for 12/15-LOX inhibition that has nanomolar potency (IC50 = 200 nM) against human 12/15-LOX and is protective against oxidative glutamate toxicity in mouse neuronal HT22 cells. In addition, it exhibited greater than 250-fold selectivity versus related LOX isozymes, was a mixed inhibitor, and did not reduce the active-site ferric ion. Lastly, 1 significantly reduced infarct size following permanent focal ischemia in a mouse model of ischemic stroke. As such, this represents the first report of a selective inhibitor of human 12/15-LOX with demonstrated in vivo activity in proof-of-concept mouse models of stroke. PMID:24684213

  12. The Rates of Serious Infections in HIV-infected Patients Who Received Tumor Necrosis Factor (TNF)-α Inhibitor Therapy for Concomitant Autoimmune Diseases

    PubMed Central

    Wangsiricharoen, Sintawat; Ligon, Colin; Gedmintas, Lydia; Dehrab, Admad; Tungsiripat, Marisa; Bingham, Clifton; Lozada, Carlos; Calabrese, Leonard

    2016-01-01

    Objectives To estimate the incidence of serious infections in patients with HIV infection and autoimmune disease who were treated with tumor necrosis factor (TNF) -α inhibitor therapy, and to compare these rates among stratified viral load levels. Methods Using a unified search strategy, four centers identified HIV-infected patients exposed to TNF-α inhibitors. Patient characteristics and infection data were assessed via chart review in all patients who were ≥18 years old and received TNF-α inhibitor therapy after HIV diagnosis between January 1999 and March 2015. Results Twenty-three patients with 26 uses of TNF-α inhibitor therapy provided 86.7 person-years of follow-up. Two (8.7%) experienced at least 1 serious infection episode, an overall incidence rate of 2.55 per 100 patient-years (95% CI 0.28–9.23). The incidence rate per 100 patient-years was 3.28 (95% CI 0.04–18.26) among patients with viral load > 500 copies/mL at therapy initiation and 2.09 (0.03–11.65) among patients with viral load ≤ 500 copies/mL. Conclusion This study suggests that TNF-α inhibitors may have a comparable rate of serious infections to the range of those observed in registry databases when used in patients with HIV infection under active care. PMID:27332039

  13. Combination therapy with monoamine oxidase inhibitors and other antidepressants or stimulants: strategies for the management of treatment-resistant depression.

    PubMed

    Thomas, Samantha J; Shin, Mirae; McInnis, Melvin G; Bostwick, Jolene R

    2015-04-01

    combination treatment certainly exist with selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, or clomipramine, the current literature supports cautious use of combining MAOIs with other antidepressants in patients with TRD who have failed multiple treatment modalities. In addition, the data from the 29 patients receiving combination therapy with an MAOI and another antidepressant or stimulant medication revealed that 21% improved significantly, with no complications. This case series and literature review suggest that when used under close supervision and under the care of an experienced clinician in psychiatry, combination therapy may be a consideration for the management of TRD in patients not responding to monotherapy or other combinations of antidepressants.

  14. Mutation analysis of circulating plasma DNA to determine response to EGFR tyrosine kinase inhibitor therapy of lung adenocarcinoma patients

    PubMed Central

    Riediger, Anja Lisa; Dietz, Steffen; Schirmer, Uwe; Meister, Michael; Heinzmann-Groth, Ingrid; Schneider, Marc; Muley, Thomas; Thomas, Michael; Sültmann, Holger

    2016-01-01

    Long-lasting success in lung cancer therapy using tyrosine kinase inhibitors (TKIs) is rare since the tumors develop resistance due to the occurrence of molecularly altered subclones. The aim of this study was to monitor tumors over time based on the quantity of mutant plasma DNA and to identify early indications for therapy response and tumor progression. Serial plasma samples from lung adenocarcinoma patients treated with TKIs were used to quantify EGFR and KRAS mutations in circulating DNA by digital PCR. Mutant DNA levels were compared with the courses of responses to treatment with TKIs, conventional chemotherapy, radiotherapy, or combinations thereof. Variations in plasma DNA mutation levels over time were found in 15 patients. We categorize three major courses: First, signs of therapy response are associated with a fast clearing of plasma DNA mutations within a few days. Second, periods of stable disease are accompanied by either absence of mutations or fluctuation at low levels. Finally, dramatic increase of mutational load is followed by rapid tumor progression and poor patient survival. In summary, the serial assessment of EGFR mutations in the plasma of NSCLC patients allows conclusions about controlled disease and tumor progression earlier than currently available methods. PMID:27640882

  15. Evaluation of the virological and metabolic effects of switching protease inhibitor combination antiretroviral therapy to nevirapine-based therapy for the treatment of HIV infection.

    PubMed

    Tebas, Pablo; Yarasheski, Kevin; Henry, Keith; Claxton, Sherri; Kane, E; Bordenave, B; Klebert, Michael; Powderly, William G

    2004-06-01

    In spite of indisputable benefits, the use of antiretroviral therapy is associated with multiple metabolic complications. Switching to simpler regimens might maintain viral suppression, improve metabolic side effects, and provide insight into the pathogenesis of these complications. Our objective was to carefully characterize the virological and metabolic effects of switching from a successful protease inhibitor (PI)-based antiretroviral regimen to a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen with nevirapine (NVP). Forty patients, taking their first successful (less than 40 HIV RNA copies/ml) PI-based regimen, switched their PI to NVP. If patients did not tolerate NVP, substitution with efavirenz was allowed. The duration of the study was 48 weeks. At 12 weeks intervals subjects had multiple virological and metabolic parameters including glucose, insulin, C-peptide, glucagon, proinsulin, blood lipids, and lipoproteins. A subgroup of 18 patients also had body composition evaluations with DEXA scans and MRIs of the abdomen and the thighs as well as insulin tolerance tests. Ninety-five percent of the patients maintained viral suppression (95% CI 88-100%); only one patient failed and another developed hepatitis. There were improvements in glucose (decreased fasting glucose, insulin, and improved insulin tolerance) and lipid metabolism (decreased triglycerides and increased HDL), but no changes in body composition and bone mineral density. Our study supports a pathogenic role for PIs in the development of hypertriglyceridemia and insulin resistance, but a more limited role in the fat redistribution syndrome.

  16. CD8+ T Cells Specific to Apoptosis-Associated Antigens Predict the Response to Tumor Necrosis Factor Inhibitor Therapy in Rheumatoid Arthritis

    PubMed Central

    Citro, Alessandra; Scrivo, Rossana; Martini, Helene; Martire, Carmela; De Marzio, Paolo; Vestri, Anna Rita; Sidney, John; Sette, Alessandro; Barnaba, Vincenzo; Valesini, Guido

    2015-01-01

    CD8+ T cells specific to caspase-cleaved antigens derived from apoptotic T cells (apoptotic epitopes) represent a principal player in chronic immune activation, which is known to amplify immunopathology in various inflammatory diseases. The purpose of the present study was to investigate the relationship involving these autoreactive T cells, the rheumatoid arthritis immunopathology, and the response to tumor necrosis factor-α inhibitor therapy. The frequency of autoreactive CD8+ T cells specific to various apoptotic epitopes, as detected by both enzyme-linked immunospot assay and dextramers of major histocompatibility complex class I molecules complexed with relevant apoptotic epitopes, was longitudinally analyzed in the peripheral blood of rheumatoid arthritis patients who were submitted to etanercept treatment (or other tumor necrosis factor inhibitors as a control). The percentage of apoptotic epitope-specific CD8+ T cells was significantly higher in rheumatoid arthritis patients than in healthy donors, and correlated with the disease activity. More important, it was significantly more elevated in responders to tumor necrosis factor-α inhibitor therapy than in non-responders before the start of therapy; it significantly dropped only in the former following therapy. These data indicate that apoptotic epitope-specific CD8+ T cells may be involved in rheumatoid arthritis immunopathology through the production of inflammatory cytokines and that they may potentially represent a predictive biomarker of response to tumor necrosis factor-α inhibitor therapy to validate in a larger cohort of patients. PMID:26061065

  17. Interaction of angiotensin-converting enzyme (ACE) with membrane-bound carboxypeptidase M (CPM) - a new function of ACE.

    PubMed

    Sun, Xiaoou; Wiesner, Burkhard; Lorenz, Dorothea; Papsdorf, Gisela; Pankow, Kristin; Wang, Po; Dietrich, Nils; Siems, Wolf-Eberhard; Maul, Björn

    2008-12-01

    Angiotensin-converting enzyme (ACE) demonstrates, besides its typical dipeptidyl-carboxypeptidase activity, several unusual functions. Here, we demonstrate with molecular, biochemical, and cellular techniques that the somatic wild-type murine ACE (mACE), stably transfected in Chinese Hamster Ovary (CHO) or Madin-Darby Canine Kidney (MDCK) cells, interacts with endogenous membranal co-localized carboxypeptidase M (CPM). CPM belongs to the group of glycosylphosphatidylinositol (GPI)-anchored proteins. Here we report that ACE, completely independent of its known dipeptidase activities, has GPI-targeted properties. Our results indicate that the spatial proximity between mACE and the endogenous CPM enables an ACE-evoked release of CPM. These results are discussed with respect to the recently proposed GPI-ase activity and function of sperm-bound ACE.

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

    NASA Astrophysics Data System (ADS)

    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.

  19. Dermatologic Reactions to Targeted Therapy: A Focus on Epidermal Growth Factor Receptor Inhibitors and Nursing Care.

    PubMed

    Barton-Burke, Margaret; Ciccolini, Kathryn; Mekas, Maria; Burke, Sean

    2017-03-01

    Cancer treatments usually have side effects of bone marrow depression, mucositis, hair loss, and gastrointestinal issues. Rarely do we think of skin side effects until patients have been treated successfully with epidermal growth factor receptor inhibitors (EGFRi). Those reactions include papulopustular rash, hair changes, radiation dermatitis enhancement, pruritus, mucositis, xerosis, fissures, and paronychia. This article discusses the common skin reactions seen when using EGFRi and presents an overview of skin as the largest and important organ of the body, including an overview of skin assessment, pathophysiology of the skin reactions, nursing care involved, and introduction to oncodermatology.

  20. Novel Inhibitors of Protein-Protein Interaction for Prostate Cancer Therapy

    DTIC Science & Technology

    2011-04-01

    MS analysis and testing of compounds for oral biovailability and pharmacokinetics REPORTABLE OUTCOMES  Kegel S, Mehraein-Ghomi F, Reuter Q...8 APPENDIX 1 Targeting a novel pathway for prostate cancer therapy Stacy Kegel , Farideh Mehraein-Ghomi, Quentin Reuter, Joseph Schmidt, Dawn

  1. Cholinesterase Inhibitor Therapy in Alzheimer’s: The limits and tolerability of Irreversible CNS-selective Acetylcholinesterase Inhibition in Primates

    PubMed Central

    Moss, Donald E.; Perez, Ruth G.; Kobayashi, Haruo

    2016-01-01

    Irreversible acetylcholinesterase (AChE) inhibition accumulates to high levels in the central nervous system (CNS) because AChE turnover in the brain is much slower than in peripheral tissues. As expected from this CNS selectivity, the irreversible AChE inhibitor methanesulfonyl fluoride (MSF) produces significant cognitive improvement in Alzheimer’s patients without the gastrointestinal toxicity that plagues other AChE inhibitors. However, without dose-limiting gastrointestinal toxicity, one shortcoming of the prior human studies of MSF is that the upper limits of CNS AChE inhibition that might be tolerated could not be tested. Therefore, in this study, monkeys were treated with escalating intramuscular doses of MSF that culminated with several weeks of 1.5 mg/kg dosing, more than eight times the prior human clinical dose, still without signs of toxicity. Brain biopsies showed that ~ 80% AChE inhibition had been produced and that the new synthesis of cortical AChE had a half-time (t1/2) of ~ 12 days. A single IM dose of 1.5 mg/kg MSF produced ~ 59% inhibition in cerebrospinal fluid (CSF) AChE as measured one day later. This corresponds to a peak of ~ 80% inhibition in CSF AChE at the time of the injection, recovering with a t1/2 of 2.4 days. Computational analyses suggest that MSF at clinically relevant doses could theoretically produce a steady-state AChE inhibition between 65% and 85% in the CNS. These data suggest that the full therapeutic advantage of AChE inhibition therapy can be realized without interference from dose-limiting gastrointestinal toxicity if an irreversible inhibitor is employed. PMID:27858711

  2. Current drug therapy of patients with BPH-LUTS with the special emphasis on PDE5 inhibitors

    PubMed Central

    Govorov, Alexander; Kasyan, George; Priymak, Diana; Pushkar, Dmitry

    2016-01-01

    Introduction Benign prostatic hyperplasia (BPH) is the most common cause of lower urinary tract symptom (LUTS) development in men [1]. The intensity of the symptoms may vary from mild to severe, significantly affecting the quality of life. Erectile dysfunction (ED) is one of the most challenging issues in modern urology that significantly influences the quality of life in men worldwide. The objective of this literature review was to analyze the current drug therapies of patients with BPH-LUTS, with the special emphasis on PDE5 inhibitors. Material and methods The authors searched the literature for the period from 2000 until 2015 in MEDLINE and PubMed. Results Twenty-three articles were selected based on their reliability. A detailed analysis of the selected papers was performed. Primary attention was given to articles describing the use of PDE5. Works describing the use of different groups of drugs in patients with BPH-LUTS were also selected. Conclusions The current literature analysis suggests that the introduction of PDE5 inhibitors in clinical practice for the treatment of patients with BPH-LUTS will allow for significant expansion of the therapeutic options for the treatment of this disease. PMID:28127458

  3. Treating Trichotillomania: A Meta-Analysis of Treatment Effects and Moderators for Behavior Therapy and Serotonin Reuptake Inhibitors

    PubMed Central

    McGuire, Joseph F.; Ung, Danielle; Selles, Robert R.; Rahman, Omar; Lewin, Adam B.; Murphy, Tanya K.; Storch, Eric A.

    2014-01-01

    Few randomized controlled trials (RCTs) exist examining the efficacy of behavior therapy (BT) or serotonin reuptake inhibitors (SRIs) for the treatment of trichotillomania (TTM), with no examination of treatment moderators. The present meta-analysis synthesized the treatment effect sizes (ES) of BT and SRI relative to comparison conditions, and examined moderators of treatment. A comprehensive literature search identified 11 RCTs that met inclusion criteria. Clinical characteristics (e.g., age, comorbidity, therapeutic contact hours), outcome measures, treatment subtypes (e.g., SRI subtype, BT subtype), and ES data were extracted. The standardized mean difference of change in hair pulling severity was the outcome measure. A random effects meta-analysis found a large pooled ES for BT (ES= 1.41, p< 0.001). BT trials with greater therapeutic contact hours exhibited larger ES (p= 0.009). Additionally, BT trials that used mood enhanced therapeutic techniques exhibited greater ES relative to trials including only traditional BT components (p= 0.004). For SRI trials, a random effects meta-analysis identified a moderate pooled ES (ES= 0.41, p= 0.02). Although clomipramine exhibited larger ES relative to selective serotonin reuptake inhibitors, the difference was not statistically significant. Publication bias was not identified for either treatment. BT yields large treatment effects for TTM, with further examination needed to disentangle confounded treatment moderators. SRI trials exhibited a moderate pooled ES, with no treatment moderators identified. Sensitivity analyses highlighted the need for further RCTs of SRIs, especially among youth with TTM. PMID:25108618

  4. Ret function in muscle stem cells points to tyrosine kinase inhibitor therapy for facioscapulohumeral muscular dystrophy

    PubMed Central

    Moyle, Louise A; Blanc, Eric; Jaka, Oihane; Prueller, Johanna; Banerji, Christopher RS; Tedesco, Francesco Saverio; Harridge, Stephen DR; Knight, Robert D; Zammit, Peter S

    2016-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) involves sporadic expression of DUX4, which inhibits myogenesis and is pro-apoptotic. To identify target genes, we over-expressed DUX4 in myoblasts and found that the receptor tyrosine kinase Ret was significantly up-regulated, suggesting a role in FSHD. RET is dynamically expressed during myogenic progression in mouse and human myoblasts. Constitutive expression of either RET9 or RET51 increased myoblast proliferation, whereas siRNA-mediated knockdown of Ret induced myogenic differentiation. Suppressing RET activity using Sunitinib, a clinically-approved tyrosine kinase inhibitor, rescued differentiation in both DUX4-expressing murine myoblasts and in FSHD patient-derived myoblasts. Importantly, Sunitinib also increased engraftment and differentiation of FSHD myoblasts in regenerating mouse muscle. Thus, DUX4-mediated activation of Ret prevents myogenic differentiation and could contribute to FSHD pathology by preventing satellite cell-mediated repair. Rescue of DUX4-induced pathology by Sunitinib highlights the therapeutic potential of tyrosine kinase inhibitors for treatment of FSHD. DOI: http://dx.doi.org/10.7554/eLife.11405.001 PMID:27841748

  5. Histone Deacetylase Inhibitors Delivery using Nanoparticles with Intrinsic Passive Tumor Targeting Properties for Tumor Therapy

    PubMed Central

    el Bahhaj, Fatima; Denis, Iza; Pichavant, Loic; Delatouche, Régis; Collette, Floraine; Linot, Camille; Pouliquen, Daniel; Grégoire, Marc; Héroguez, Valérie; Blanquart, Christophe; Bertrand, Philippe

    2016-01-01

    Fast clearance, metabolism and systemic toxicity are major limits for the clinical use of anti-cancer drugs. Histone deacetylase inhibitors (HDACi) present these defects despite displaying promising anti-tumor properties on tumor cells in vitro and in in vivo model of cancers. Specific delivery of anti-cancer drugs into the tumor should improve their clinical benefit by limiting systemic toxicity and by increasing the anti-tumor effect. In this work, we describe a simple and flexible polymeric nanoparticle platform highly targeting the tumor in vivo and triggering impressive tumor weight reduction when functionalized with HDACi. Our nanoparticles were produced by Ring-Opening Metathesis Polymerization of azido-polyethylene oxide-norbornene macromonomers and functionalized using click chemistry. Using an orthotopic model of peritoneal invasive cancer, a highly selective accumulation of the particles in the tumor was obtained. A combination of epigenetic drugs involving a pH-responsive histone deacetylase inhibitor (HDACi) polymer conjugated to these particles gave 80% reduction of tumor weight without toxicity whereas the free HDACi has no effect. Our work demonstrates that the use of a nanovector with theranostic properties leads to an optimized delivery of potent HDACi in tumor and then, to an improvement of their anti-tumor properties in vivo. PMID:27162550

  6. Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970.

    PubMed

    Hall, Amy B; Newsome, Dave; Wang, Yuxin; Boucher, Diane M; Eustace, Brenda; Gu, Yong; Hare, Brian; Johnson, Mac A; Milton, Sean; Murphy, Cheryl E; Takemoto, Darin; Tolman, Crystal; Wood, Mark; Charlton, Peter; Charrier, Jean-Damien; Furey, Brinley; Golec, Julian; Reaper, Philip M; Pollard, John R

    2014-07-30

    Platinum-based DNA-damaging chemotherapy is standard-of-care for most patients with lung cancer but outcomes remain poor. This has been attributed, in part, to the highly effective repair network known as the DNA-damage response (DDR). ATR kinase is a critical regulator of this pathway, and its inhibition has been shown to sensitize some cancer, but not normal, cells in vitro to DNA damaging agents. However, there are limited in vivo proof-of-concept data for ATR inhibition. To address this we profiled VX-970, the first clinical ATR inhibitor, in a series of in vitro and in vivo lung cancer models and compared it with an inhibitor of the downstream kinase Chk1. VX-970 markedly sensitized a large proportion of a lung cancer cell line and primary tumor panel in vitro to multiple DNA damaging drugs with clear differences to Chk1 inhibition observed. In vivo VX-970 blocked ATR activity in tumors and dramatically enhanced the efficacy of cisplatin across a panel of patient derived primary lung xenografts. The combination led to complete tumor growth inhibition in three cisplatin-insensitive models and durable tumor regression in a cisplatin-sensitive model. These data provide a strong rationale for the clinical evaluation of VX-970 in lung cancer patients.

  7. Progress of antibody-based inhibitors of the HGF–cMET axis in cancer therapy

    PubMed Central

    Kim, Ki-Hyun; Kim, Hyori

    2017-01-01

    Dysregulated receptor tyrosine kinase signaling in human cancer cells leads to tumor progression, invasion and metastasis. The receptor tyrosine kinase cMET is frequently overexpressed in cancer tissue, and activation of cMET signaling is related to drug resistance and the processes of carcinogenesis, invasion and metastasis. For that reason, cMET and its ligand, hepatocyte growth factor (HGF), are considered prime targets for the development of anticancer drugs. At least eight anti-cMET and four anti-HGF antibodies have been tested or are being tested in clinical trials. However, to date none of these HGF/cMET inhibitors have shown significant efficacy in clinical trials. Furthermore, no receptor tyrosine kinase inhibitors primarily targeting cMET have been approved. Given that neutralization of HGF or cMET does not cause significant adverse effects, inhibition of the HGF/cMET signaling pathway appears to be safe. In this review, we summarized the completed and ongoing clinical trials testing antibody- or protein-based anticancer drugs targeting cMET and HGF. PMID:28336955

  8. Progress of antibody-based inhibitors of the HGF-cMET axis in cancer therapy.

    PubMed

    Kim, Ki-Hyun; Kim, Hyori

    2017-03-24

    Dysregulated receptor tyrosine kinase signaling in human cancer cells leads to tumor progression, invasion and metastasis. The receptor tyrosine kinase cMET is frequently overexpressed in cancer tissue, and activation of cMET signaling is related to drug resistance and the processes of carcinogenesis, invasion and metastasis. For that reason, cMET and its ligand, hepatocyte growth factor (HGF), are considered prime targets for the development of anticancer drugs. At least eight anti-cMET and four anti-HGF antibodies have been tested or are being tested in clinical trials. However, to date none of these HGF/cMET inhibitors have shown significant efficacy in clinical trials. Furthermore, no receptor tyrosine kinase inhibitors primarily targeting cMET have been approved. Given that neutralization of HGF or cMET does not cause significant adverse effects, inhibition of the HGF/cMET signaling pathway appears to be safe. In this review, we summarized the completed and ongoing clinical trials testing antibody- or protein-based anticancer drugs targeting cMET and HGF.

  9. [CLINICAL AND PHARMACOECONOMIC RESULTS OF THE USAGE OF VARIOUS HIV REVERSE TRANSCRIPTASE INHIBITORS IN THE SCHEMES OF ANTIRETROVIRAL THERAPY OF PATIENT RECEIVING THERAPY FOR THE CHRONIC HEPATITIS C VIRUS].

    PubMed

    Moshkovich, G F; Minaeva, S V; Varlova, L W; Goryaeva, M P; Gulyaeva, S S; Tichonova, E V

    2016-01-01

    Efficacy, safety, and economical aspects of treatment with abacavir, zidovudine, stavudine, and phosphazide in the schemes of antiretroviral therapy of the HIV-infected patients receiving therapy for hepatitis C virus were tested. Clinical, immunological, and virologic efficacy of treatment and dynamics of hemoglobin, thrombocytes, and alanine aminotransferase as markers of common adverse events recorded at the start of the antiviral therapy of chronic hepatitis C and after 4, 8, 12, 24, 48 weeks of the treatment were evaluated. The usage of these drugs in the schemes of antiretroviral therapy exhibited efficacy, high tolerability and safety for all HIV reverse transcriptase inhibitors.

  10. Nicotianamine is a novel angiotensin-converting enzyme 2 inhibitor in soybean.

    PubMed

    Takahashi, Saori; Yoshiya, Taku; Yoshizawa-Kumagaye, Kumiko; Sugiyama, Toshihiro

    2015-01-01

    Angiotensin-converting enzyme 2 (ACE2) is a carboxypeptidase which is highly homologous to angiotensin-converting enzyme (ACE). ACE2 produces vasodilator peptides angiotensin 1-7 from angiotensin II. In the present study, we synthesized various internally quenched fluorogenic (IQF) substrates (fluorophore-Xaa-Pro-quencher) based on the cleavage site of angiotensin II introducing N-terminal fluorophore N-methylanthranilic acid (Nma) and C-terminal quencher N(ε)-2,4- dinitrophenyl-lysine [Lys(Dnp)]. The synthesized mixed substrates "Nma-Xaa-Pro-Lys(Dnp)" were hydrolyzed by recombinant human (rh) ACE2. The amount of each product was determined by liquid chromatography mass spectrometry (LC-MS) with fluorescence detection and it was found that Nma-His-Pro-Lys(Dnp) is the most suitable substrate for rhACE2. The K(m), k(cat), and k(cat)/K(m) values of Nma-His-Pro-Lys(Dnp) on rhACE2 were determined to be 23.3 μM, 167 s(-1), and 7.17 μM(-1) s(-1), respectively. Using the rhACE2 and the newly developed IQF substrate, we found rhACE2 inhibitory activity in soybean and isolated the active compound soybean ACE2 inhibitor (ACE2iSB). The physicochemical data on the isolated ACE2iSB were identical to those of nicotianamine. ACE2iSB strongly inhibited rhACE2 activity with an IC50 value of 84 nM. This is the first demonstration of an ACE2 inhibitor from foodstuffs.

  11. ACE inhibition with captopril retards the development of signs of neurodegeneration in an animal model of Alzheimer's disease.

    PubMed

    AbdAlla, Said; Langer, Andreas; Fu, Xuebin; Quitterer, Ursula

    2013-08-16

    Increased generation of reactive oxygen species (ROS) is a significant pathological feature in the brains of patients with Alzheimer's disease (AD). Experimental evidence indicates that inhibition of brain ROS could be beneficial in slowing the neurodegenerative process triggered by amyloid-beta (Abeta) aggregates. The angiotensin II AT1 receptor is a significant source of brain ROS, and AD patients have an increased brain angiotensin-converting enzyme (ACE) level, which could account for an excessive angiotensin-dependent AT1-induced ROS generation. Therefore, we analyzed the impact of ACE inhibition on signs of neurodegeneration of aged Tg2576 mice as a transgenic animal model of AD. Whole genome microarray gene expression profiling and biochemical analyses demonstrated that the centrally active ACE inhibitor captopril normalized the excessive hippocampal ACE activity of AD mice. Concomitantly, the development of signs of neurodegeneration was retarded by six months of captopril treatment. The neuroprotective profile triggered by captopril was accompanied by reduced amyloidogenic processing of the amyloid precursor protein (APP), and decreased hippocampal ROS, which is known to enhance Abeta generation by increased activation of beta- and gamma-secretases. Taken together, our data present strong evidence that ACE inhibition with a widely used cardiovascular drug could interfere with Abeta-dependent neurodegeneration.

  12. Angiotensin I-converting enzyme (ACE) activity and expression in rat central nervous system after sleep deprivation.

    PubMed

    Visniauskas, Bruna; Oliveira, Vitor; Carmona, Adriana K; D'Almeida, Vânia; de Melo, Robson L; Tufik, Sérgio; Chagas, Jair R

    2011-04-01

    Proteases are essential either for the release of neuropeptides from active or inactive proteins or for their inactivation. Neuropeptides have a fundamental role in sleep-wake cycle regulation and their actions are also likely to be regulated by proteolytic processing. Using fluorescence resonance energy transfer substrates, specific protease inhibitors and real-time PCR we demonstrate changes in angiotensin I-converting enzyme (ACE) expression and proteolytic activity in the central nervous system in an animal model of paradoxical sleep deprivation during 96 h (PSD). Male rats were distributed into five groups (PSD, 24 h, 48 h and 96 h of sleep recovery after PSD and control). ACE activity and mRNA levels were measured in hypothalamus, hippocampus, brainstem, cerebral cortex and striatum tissue extracts. In the hypothalamus, the significant decrease in activity and mRNA levels, after PSD, was only totally reversed after 96 h of sleep recovery. In the brainstem and hippocampus, although significant, changes in mRNA do not parallel changes in ACE specific activity. Changes in ACE activity could affect angiotensin II generation, angiotensin 1-7, bradykinin and opioid peptides metabolism. ACE expression and activity modifications are likely related to some of the physiological changes (cardiovascular, stress, cognition, metabolism function, water and energy balance) observed during and after sleep deprivation.

  13. Novel Inhibitors of Protein-Protein Interaction for Prostate Cancer Therapy

    DTIC Science & Technology

    2012-04-01

    REPORTABLE OUTCOMES Kegel S, Mehraein-Ghomi F, Reuter Q, Schmidt J, Church D, Hoffmann FM, Basu H, and Wilding G. Targeting a novel pathway for...Year 2 Research; 2011 Apr 2-6; Orlando, Florida. Philadelphia (PA): AACR; 2011. Abstract nr 2583 (see Appendix 1) Schmidt J, Kegel S, Mehraein...therapy Stacy Kegel , Farideh Mehraein-Ghomi, Quentin Reuter, Joseph Schmidt, Dawn Church, F. Michael Hoffmann, Hirak Basu, George Wilding. University

  14. Novel Inhibitors of Protein-Protein Interaction for Prostate Cancer Therapy

    DTIC Science & Technology

    2013-04-01

    Kegel S, Mehraein-Ghomi F, Reuter Q, Schmidt J, Church D, Hoffmann FM, Basu H, and Wilding G. Targeting a novel pathway for prostate cancer therapy...PA): AACR; 2011. Abstract nr 2583 (see Appendix 1)  Schmidt J, Kegel S, Mehraein-Ghomi F, Saphner E, Reuter Q, Church D, Hoffmann FM, Basu H, and...Stacy Kegel , Farideh Mehraein-Ghomi, Quentin Reuter, Joseph Schmidt, Dawn Church, F. Michael Hoffmann, Hirak Basu, George Wilding. University of

  15. TNF receptor inhibitor therapy for the treatment of children with idiopathic pneumonia syndrome (IPS)

    PubMed Central

    Yanik, Gregory A.; Grupp, Stephan A.; Pulsipher, Michael A.; Levine, John E.; Schultz, Kirk R.; Wall, Donna A.; Langholz, Bryan; Dvorak, Christopher C.; Alangaden, Keith; Goyal, Rakesh K.; White, Eric S.; Collura, Jennifer M.; Skeens, Micah A.; Eid, Saada; Pierce, Elizabeth M; Cooke, Kenneth R.

    2014-01-01

    Idiopathic pneumonia syndrome (IPS) is an acute, non-infectious lung disorder associated with high morbidity and mortality following hematopoietic cell transplantation. Previous studies have suggested a role for TNFα in the pathogenesis of IPS. We report a multi-center phase II trial investigating a soluble TNF binding protein, etanercept (Enbrel®, Amgen) for the treatment of pediatric patients with IPS. Eligible patients were <18 years, within 120 days post-transplant, with radiographic evidence of a diffuse pneumonitis. All patients underwent a pre-therapy broncho-alveolor lavage (BAL) to establish the diagnosis of IPS. Systemic corticosteroids (2.0 mg/kg/day) plus etanercept (0.4 mg/kg twice weekly × 8 doses) were administered. Response was defined as survival and discontinuation of supplemental oxygen support by day 28 of study. Thirty-nine patients (median age 11y, range 1–17y) were enrolled, with 11 of 39 patients non-evaluable due to identification of pathogens from their pre-therapy BAL. In the remaining 28 patients, the median FiO2 at study entry was 45%, with 17 of 28 requiring mechanical ventilation. Complete responses were seen in 20 (71%) patients, with a median time to response 10 days (range 1–24). Response rates were higher for patients not requiring mechanical ventilation at study entry (100% vs. 53%,p=0.01). Overall survival at 28 days and 1-year post-therapy were 89% (95% CI:70–96) and 63% (95% CI:42–79) respectively. Plasma levels of pro-inflammatory cytokines were significantly increased at onset of therapy, subsequently decreasing in responding patients. The addition of etanercept to high dose corticosteroids was associated with high response rates and survival in children with IPS. PMID:25270958

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

    SciTech Connect

    Matsuura-Hachiya, Yuko; Arai, Koji Y.; Ozeki, Rieko; Kikuta, Ayako; Nishiyama, Toshio

    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.

  17. Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapies.

    PubMed

    Bauer, Renato A

    2015-09-01

    Drugs that covalently bond to their biological targets have a long history in drug discovery. A look at drug approvals in recent years suggests that covalent drugs will continue to make impacts on human health for years to come. Although fraught with concerns about toxicity, the high potencies and prolonged effects achievable with covalent drugs may result in less-frequent drug dosing and in wide therapeutic margins for patients. Covalent inhibition can also dissociate drug pharmacodynamics (PD) from pharmacokinetics (PK), which can result in desired drug efficacy for inhibitors that have short systemic exposure. Evidence suggests that there is a reduced risk for the development of resistance against covalent drugs, which is a major challenge in areas such as oncology and infectious disease.

  18. Tetrahydropyranodiquinolin-8-amines as new, non hepatotoxic, antioxidant, and acetylcholinesterase inhibitors for Alzheimer's disease therapy.

    PubMed

    Dgachi, Youssef; Sokolov, Olga; Luzet, Vincent; Godyń, Justyna; Panek, Dawid; Bonet, Alexandre; Martin, Hélène; Iriepa, Isabel; Moraleda, Ignacio; García-Iriepa, Cristina; Janockova, Jana; Richert, Lysiane; Soukup, Ondrej; Malawska, Barbara; Chabchoub, Fakher; Marco-Contelles, José; Ismaili, Lhassane

    2017-01-27

    Herein we report an efficient two step synthesis and biological assessment of 12 racemic tetrahydropyranodiquinolin-8-amines derivatives as antioxidant, cholinesterase inhibitors and non-hepatotoxic agents. Based on the results of the primary screening, we identified 7-(3-methoxyphenyl)-9,10,11,12-tetrahydro-7H-pyrano[2,3-b:5,6-h']diquinolin-8-amine (2h) as a particularly interesting non-hepatotoxic compound that shows moderate antioxidant activity (1.83 equiv Trolox in the ORAC assay), a non competitive inhibition of hAChE (IC50 = 0.75 ± 0.01 μM), and brain permeable as determined by the PAMPA-Blood Brain Barrier assay.

  19. Recombinant replacement therapy for hereditary angioedema due to C1 inhibitor deficiency.

    PubMed

    Moldovan, Dumitru; Bernstein, Jonathan A; Cicardi, Marco

    2015-01-01

    Hereditary angioedema is a rare genetic condition transmitted as an autosomal dominant trait and characterized most commonly by the production of either inadequate or nonfunctioning C1 esterase inhibitor (C1-INH), a blood protein that regulates proteases in the complement, fibrinolytic and contact systems. Patients with hereditary angioedema suffer from episodic, unpredictable manifestations of edema affecting multiple anatomical locations, including the GI tract, facial tissue, the upper airway, oropharynx, urogenital region and/or the arms and legs. A rational approach to treatment is replacement of C1-INH protein, to normalize the levels of C1-INH activity and halt the progression of the biochemical activation processes underlying the edema formation. Ruconest is a highly purified recombinant human C1-INH. This article will focus on the results of ten clinical studies demonstrating the efficacy and safety of Ruconest(®) (Pharming Group NV, Leiden, the Netherlands), which is now approved for use in Europe, Israel and the USA.

  20. Persistent gastro-oesophageal reflux symptoms despite proton pump inhibitor therapy

    PubMed Central

    Ang, Daphne; How, Choon How; Ang, Tiing Leong

    2016-01-01

    About one-third of patients with suspected gastro-oesophageal reflux disease (GERD) do not respond symptomatically to proton pump inhibitors (PPIs). Many of these patients do not suffer from GERD, but may have underlying functional heartburn or atypical chest pain. Other causes of failure to respond to PPIs include inadequate acid suppression, non-acid reflux, oesophageal hypersensitivity, oesophageal dysmotility and psychological comorbidities. Functional oesophageal tests can exclude cardiac and structural causes, as well as help to confi rm or exclude GERD. The use of PPIs should only be continued in the presence of acid reflux or oesophageal hypersensitivity for acid reflux-related events that is proven on functional oesophageal tests. PMID:27779277

  1. Debate: angiotensin-converting enzyme inhibitors versus angiotensin II receptor blockers--a gap in evidence-based medicine.

    PubMed

    Ball, Stephen G; White, William B

    2003-05-22

    In this article, 2 leading physicians debate the strength of outcome data on the efficacy of angiotensin-converting enzyme (ACE) inhibitors versus angiotensin II receptor blockers (ARBs) for reducing the incidence of cardiovascular, cerebrovascular, and renovascular events. Dr. Stephen G. Ball notes that the efficacy of ACE inhibitors for reducing the risk for myocardial infarction independent of their effects on blood pressure is controversial. In the Heart Outcomes Prevention Evaluation (HOPE) study, ramipril treatment in high-risk patients was associated with a 20% reduction in the risk for myocardial infarction; mean reduction in blood pressure was 3 mm Hg for systolic blood pressure and 1 mm Hg for diastolic blood pressure. The HOPE investigators propose that the 20% reduction was much greater than would be expected based on the observed blood pressure reduction. However, a meta-regression analysis of blood pressure reduction in >20 antihypertensive therapy outcome trials found that the reduction in myocardial infarction risk with ramipril observed in HOPE was consistent with the modest blood pressure reduction seen with that agent. Nevertheless, there are convincing data for prevention of myocardial infarction with ACE inhibitors in patients with heart failure, including those with heart failure after myocardial infarction, as well as supportive evidence from studies in patients with diabetes mellitus and concomitant hypertension. On the other hand, Dr. William B. White takes the position that ARBs are well-tolerated antihypertensive agents that specifically antagonize the angiotensin II type 1 (AT(1)) receptor and provide a more complete block of the pathologic effects of angiotensin II-which are mediated via the AT(1) receptor-than ACE inhibitors. The Evaluation of Losartan in the Elderly (ELITE) II study and the Valsartan Heart Failure Trial (ValHeFT) suggest that ARBs reduce the risk for mortality in patients with congestive heart failure. The Losartan

  2. Anti-EGFR monoclonal antibodies and EGFR tyrosine kinase inhibitors as combination therapy for triple-negative breast cancer

    PubMed Central

    Guerrab, Abderrahim El; Bamdad, Mahchid; Kwiatkowski, Fabrice; Aubel, Corinne

    2016-01-01

    Triple-negative breast cancer (TNBC) is characterized by overexpression of epidermal growth factor receptor (EGFR) and activation of its downstream signaling pathways. Dual targeting of EGFR using one monoclonal antibody (mAb; cetuximab or panitumumab) and one tyrosine kinase inhibitor (EGFR-TKI; gefitinib or erlotinib) is a potential therapeutic approach. We investigated the effect of these therapies in EGFR-expressing TNBC cell lines that do or do not harbor the main activating mutations of EGFR pathways. Cell lines were sensitive to EGFR-TKIs, whereas mAbs were active only in MDA-MB-468 (EGFR amplification) and SUM-1315 (KRAS and PTEN wild-type) cells. MDA-MB-231 (KRAS mutated) and HCC-1937 (PTEN deletion) cells were resistant to mAbs. The combined treatment resulted in a synergistic effect on cell proliferation and superior inhibition of the RAS/MAPK signaling pathway in mAb-sensitive cells. The anti-proliferative effect was associated with G1 cell cycle arrest followed by apoptosis. Sensitivity to therapies was characterized by induction of positive regulators and inactivation of negative regulators of cell cycle. These results suggest that dual EGFR inhibition might result in an enhanced antitumor effect in a subgroup of TNBC. The status of EGFR, KRAS and PTEN could be used as a molecular marker for predicting the response to this therapeutic strategy. PMID:27655662

  3. Enhancement of human sodium iodide symporter gene therapy for breast cancer by HDAC inhibitor mediated transcriptional modulation.

    PubMed

    Kelkar, Madhura G; Senthilkumar, Kalimuthu; Jadhav, Smita; Gupta, Sudeep; Ahn, Beyong-Cheol; De, Abhijit

    2016-01-18

    The aberrant expression of human sodium iodide symporter (NIS) in breast cancer (BC) has raised the possibility of using targeted radioiodide therapy. Here we investigate modulation of endogenous, functional NIS expression by histone deacetylase inhibitors (HDACi) in vitro and in vivo. Luciferase reporter based initial screening of six different HDACi shows 2-10 fold enhancement of NIS promoter activity in majority of the cell types tested. As a result of drug treatment, endogenous NIS transcript and protein shows profound induction in BC cells. To get an insight on the mechanism of such transcriptional activation, role of Stat4, CREB and other transcription factors are revealed by transcription factor profiling array. Further, NIS-mediated intracellular iodide uptake also enhances substantially (p < 0.05) signifying functional relevance of the transcriptional modulation strategy. Gamma camera imaging confirms 30% higher uptake in VPA or NaB treated BC tumor xenograft. Corroborating with such functional impact of NIS, significant reduction in cell survival (p < 0.005) is observed in VPA, NaB or CI994 drug and (131)I combination treatment in vivo indicating effective radioablation. Thus, for the first time this study reveals the mechanistic basis and demonstrates functional relevance of HDACi pre-treatment strategy in elevating NIS gene therapy approach for BC management in clinic.

  4. Primary Double-Strike Therapy for Cancers to Overcome EGFR Kinase Inhibitor Resistance: Proposal from the Bench

    PubMed Central

    Suda, Kenichi; Bunn, Paul A.; Rivard, Christopher J.; Mitsudomi, Tetsuya; Hirsch, Fred R.

    2017-01-01

    Diverse molecular mechanisms that confer acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in lung cancers with sensitive EGFR mutations have been reported. However, it is not realistic to analyze for all these mechanisms at the time of resistance in clinical practice and establish adequate treatment targeting these numerous resistance mechanisms. Therefore, we believe that we should move our research focus from the exploration of “established” diverse resistance mechanisms to the elucidation of molecular mechanisms that enable cancer cells to remain alive at the early phase of the treatment. Here in this review, we summarize up-to-date molecular mechanisms that maintain residual tumor cells against EGFR TKI monotherapy in lung cancers with EGFR mutations. We classified these mechanisms into three categories. The first is a pre-existing minor subpopulation with a resistance mechanism such as a pretreatment T790M mutation that can be detected by highly sensitivity methods. The second is the reversible drug-tolerant state that is often observed in cell line models and accounts for the lack of complete response and continued survival of cells exposed to EGFR TKIs in patients. And the last is the role of the microenvironment, including survival signaling from fibroblasts or dying cancer cells and the role of poor vascularization. Primary double-strike cancer therapy, or even initial multiple-strike therapy, to cancer cells that cotarget EGFR and survival mechanism(s) simultaneously would be a promising strategy to improve the outcomes of patients with EGFR mutations. PMID:27642065

  5. Enhancement of human sodium iodide symporter gene therapy for breast cancer by HDAC inhibitor mediated transcriptional modulation

    PubMed Central

    Kelkar, Madhura G.; Senthilkumar, Kalimuthu; Jadhav, Smita; Gupta, Sudeep; Ahn, Beyong-Cheol; De, Abhijit

    2016-01-01

    The aberrant expression of human sodium iodide symporter (NIS) in breast cancer (BC) has raised the possibility of using targeted radioiodide therapy. Here we investigate modulation of endogenous, functional NIS expression by histone deacetylase inhibitors (HDACi) in vitro and in vivo. Luciferase reporter based initial screening of six different HDACi shows 2–10 fold enhancement of NIS promoter activity in majority of the cell types tested. As a result of drug treatment, endogenous NIS transcript and protein shows profound induction in BC cells. To get an insight on the mechanism of such transcriptional activation, role of Stat4, CREB and other transcription factors are revealed by transcription factor profiling array. Further, NIS-mediated intracellular iodide uptake also enhances substantially (p < 0.05) signifying functional relevance of the transcriptional modulation strategy. Gamma camera imaging confirms 30% higher uptake in VPA or NaB treated BC tumor xenograft. Corroborating with such functional impact of NIS, significant reduction in cell survival (p < 0.005) is observed in VPA, NaB or CI994 drug and 131I combination treatment in vivo indicating effective radioablation. Thus, for the first time this study reveals the mechanistic basis and demonstrates functional relevance of HDACi pre-treatment strategy in elevating NIS gene therapy approach for BC management in clinic. PMID:26777440

  6. HS-133, a novel fluorescent phosphatidylinositol 3-kinase inhibitor as a potential imaging and anticancer agent for targeted therapy

    PubMed Central

    Lee, Hyunseung; Son, Mi Kwon; Yun, Sun-Mi; Ahn, Sung-Hoon; Lee, Kyeong-Ryoon; Lee, Soyoung; Kim, Donghee; Hong, Sungwoo; Hong, Soon-Sun

    2014-01-01

    As PI3K/Akt signaling is frequently deregulated in a wide variety of human tumors, PI3K inhibitors are an emerging class of drugs for cancer treatment. The monitoring of the drug behavior and distribution in the biological system can play an important role for targeted therapy and provide information regarding the response or resistance to available therapies. In this study, therefore, we have developed a family of xanthine derivatives, serving as a dual function exhibiting fluorescence, as well as inhibiting PI3K. Among them, HS-133 showed anti-proliferative effects and was monitored for its subcellular localization by a fluorescence microscopy. HS-133 suppressed the PI3K/Akt pathway and induced cell cycle arrest at the G0/G1 phase. The induction of apoptosis by HS-133 was confirmed by the increases of the cleaved PARP, caspase-3, and caspase-8. Furthermore, HS-133 decreased the protein expression of HIF-1α and VEGF, as well inhibited the tube formation and migration of the human umbilical vein endothelial cells. In vivo imaging also showed that tumors were visualized fluorescent with HS-133, and its oral administration significantly inhibited the growth of tumor in SkBr3 mouse xenograft models. Thus, we suggest that HS-133 may be used as a fluorescent anticancer agent against human breast cancer. PMID:25338206

  7. Hemophilia A Pseudoaneurysm in a Patient with High Responding Inhibitors Complicating Total Knee Arthroplasty: Embolization: A Cost-Reducing Alternative to Medical Therapy

    SciTech Connect

    Kickuth, Ralph Anderson, Suzanne; Peter-Salonen, Kristiina; Laemmle, Bernhard; Eggli, Stefan; Triller, Juergen

    2006-12-15

    Joint hemorrhages are very common in patients with severe hemophilia. Inhibitors in patients with hemophilia are allo-antibodies that neutralize the activity of the clotting factor. After total knee replacement, rare intra-articular bleeding complications might occur that do not respond to clotting factor replacement. We report a 40-year-old male with severe hemophilia A and high responding inhibitors presenting with recurrent knee joint hemorrhage after bilateral knee prosthetic surgery despite adequate clotting factor treatment. There were two episodes of marked postoperative hemarthrosis requiring extensive use of subsititution therapy. Eleven days postoperatively, there was further hemorrhage into the right knee. Digital subtraction angiography diagnosed a complicating pseudoaneurysm of the inferior lateral geniculate artery and embolization was successfully performed. Because clotting factor replacement therapy has proved to be excessively expensive and prolonged, especially in patients with inhibitors, we recommend the use of cost-effective early angiographic embolization.

  8. Irreversible multitargeted ErbB family inhibitors for therapy of lung and breast cancer.

    PubMed

    Subramaniam, Deepa; He, Aiwu Ruth; Hwang, Jimmy; Deeken, John; Pishvaian, Michael; Hartley, Marion L; Marshall, John L

    2015-01-01

    Overactivation of the ErbB protein family, which is comprised of 4 receptor tyrosine kinase members (ErbB1/epidermal growth factor receptor [EGFR]/HER1, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4), can drive the development and progression of a wide variety of malignancies, including colorectal, head and neck, and certain non-small cell lung cancers (NSCLCs). As a result, agents that target a specific member of the ErbB family have been developed for the treatment of cancer. These agents include the reversible EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib; the EGFR-targeting monoclonal antibodies cetuximab and panitumumab; and the HER2-targeting monoclonal antibody trastuzumab. Lapatinib is a dual TKI that targets both EGFR and HER2. In addition, TKIs that inhibit multiple members of the ErbB family and also bind their targets irreversibly are under evaluation for the treatment of cancer. Three such compounds have progressed into clinical studies: the EGFR, HER2, and HER4 inhibitors afatinib, dacomitinib, and neratinib. Phase I studies of these agents have shown clinical activity in NSCLC, breast cancer, and other malignancies. Currently, afatinib is approved for EGFR mutation-positive NSCLC and is in development for squamous NSCLC, and dacomitinib is in phase III of clinical development for NSCLC, neratinib is in phase III of clinical development for the treatment of breast cancer, and afatinib is also in phase III development in head and neck cancer. Final results from clinical trials may lead to the potential approval of these agents in a variety of solid tumor malignancies.

  9. Implementation of GLP-1 based therapy of type 2 diabetes mellitus using DPP-IV inhibitors.

    PubMed

    Holst, Jens Juul

    2003-01-01

    GLP-1 is a peptide hormone from the intestinal mucosa. It is secreted in response to meal ingestion and normally functions in the so-called ileal brake i. e. inhibition of upper gastrointestinal motility and secretion when nutrients are present in the distal small intestine. It also induces satiety and promotes tissue deposition of ingested glucose by stimulating insulin secretion. Thus, it is an essential incretin hormone. In addition, the hormone has been demonstrated to promote insulin biosynthesis and insulin gene expression and to have trophic effects on the beta cells. The trophic effects include proliferation of existing beta cells, maturation of new cells from duct progenitor cells and inhibition of apoptosis. Furthermore glucagon secretion is inhibited. Because of these effects, the hormone effectively improves metabolism in patients with type 2 diabetes mellitus. However, continuous administration of the peptide is necessary because of an exceptionally rapid rate of degradation catalyzed the enzyme dipeptidyl peptidase IV. With inhibitors of this enzyme, it is possible to protect the endogenous hormone and thereby elevate both fasting and postprandial levels of the active hormone. This leads to enhanced insulin secretion and glucose turnover. But will DPP-IV inhibition enhance all effects of the endogenous peptide? The mode of action of GLP-1 is complex involving also interactions with sensory neurons and the central nervous system, where a DPP-IV mediated degradation does not seem to occur. Therefore, it is as yet uncertain wether DDP-IV inhibitors will affect gastrointestinal motility, appetite and food intake. Even the effects of GLP-1 effects on the pancreatic islets may be partly neurally mediated and therefore uninfluenced by DPP-IV inhibition.

  10. Antiproteinuric therapy and Fabry nephropathy: factors associated with preserved kidney function during agalsidase-beta therapy

    PubMed Central

    Warnock, David G; Thomas, Christie P; Vujkovac, Bojan; Campbell, Ruth C; Charrow, Joel; Laney, Dawn A; Jackson, Leslie L; Wilcox, William R; Wanner, Christoph

    2015-01-01

    Background Nephropathy is an important feature of classical Fabry disease, which results in alpha-galactosidase A deficiency and cellular globotriaosylceramide accumulation. We report the safety and efficacy of antiproteinuric therapy with ACE inhibitors or angiotensin II receptor blockers (ARBs) in a study of classical Fabry patients receiving recombinant agalsidase-beta therapy. Methods and design The goal was maintenance of urine protein to creatinine ratio (UPCR) <0.5 g/g or a 50% reduction in baseline UPCR for 24 patients at eight study sites. The change in estimated glomerular filtration rate (eGFR) was assessed over 21 months of treatment. Results 18 out of 24 patients achieved the UPCR goal with eGFR slopes that were significantly better than six patients who did not achieve the UPCR goal (−3.6 (−4.8 to −1.1) versus −7.0 (−9.0 to −5.6) mL/min/1.73 m2/year, respectively, p=0.018). Despite achieving the UPCR goal, 67% (12/18 patients) still progressed with an eGFR slope <−2 mL/min/1.73 m2/year. Regression analysis showed that increased age at initiation of agalsidase-beta therapy was significantly associated with worsened kidney outcome. Hypotension and hyperkalaemia occurred in seven and eight patients, respectively, which required modification of antiproteinuric therapy but was not associated with serious adverse events. Conclusions This study documents the effectiveness of agalsidase-beta (1 mg/kg/2 weeks) and antiproteinuric therapy with ACE inhibitors and/or ARB in patients with severe Fabry nephropathy. Patients had preservation of kidney function if agalsidase-beta treatment was initiated at a younger age, and UPCR maintained at or below 0.5 g/g with antiproteinuric therapy. Trial registration number NCT00446862. PMID:26490103

  11. Structure based drug design of angiotensin-I converting enzyme inhibitors.

    PubMed

    Anthony, C S; Masuyer, G; Sturrock, E D; Acharya, K R

    2012-01-01

    Cardiovascular disease (CVD) is responsible for ∼27% of deaths worldwide, with 80% of these occuring in developing countries. Hypertension is one of the most important treatable factors in the prevention of CVD. Angiotensin-I converting enzyme (ACE) is a two-domain dipeptidylcarboxypeptidase that is a key regulator of blood pressure as a result of its critical role in the reninangiotensin- aldosterone and kallikrien-kinin systems. Consequently, ACE is an important drug target in the treatment of CVD. ACE is primarily known for its ability to cleave angiotensin-I to the vasoactive octapeptide angiotensin-II, but is also able to cleave a number of other substrates including the vasodilator bradykinin and N-acetyl-seryl-aspartyl-lysyl-proline (acetyl-SDKP), a physiological modulator of hematopoiesis. Numerous ACE inhibiors are available clinically, and these are generally effective in treating hypertension. However some adverse effects are associated with ACE inhibition, such as the persistent dry cough and the potentially fatal angioedema. The solution of ACE crystal structures over the last decade has facilitated rational drug design which has contributed to the development of domain-selective ACE inhibitors, the most notable of which include RXP407 (N-domain) and RXPA380 (C-domain), which in principle may herald new therapeutic approaches for ACE inhibition. Additionally, dual inhibitors to ACE and other targets such as neprilysin, endothelin converting enzyme and chymase have been developed. The success of ACE inhibitors has also led to the search for novel inhibitors in food and natural products and the structure guided screening of such libraries may well reveal a number of new ACE inhibitors.

  12. Tissue-Specific Expression of Transgenic Secreted ACE in Vasculature Can Restore Normal Kidney Functions, but Not Blood Pressure, of Ace-/- Mice

    PubMed Central

    Chattopadhyay, Saurabh; Kessler, Sean P.; Colucci, Juliana Almada; Yamashita, Michifumi; Senanayake, Preenie deS; Sen, Ganes C.

    2014-01-01

    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. PMID:24475296

  13. Anaplastic lymphoma kinase: role in cancer pathogenesis and small-molecule inhibitor development for therapy

    PubMed Central

    Webb, Thomas R; Slavish, Jake; George, Rani E; Look, A Thomas; Xue, Liquan; Jiang, Qin; Cui, Xiaoli; Rentrop, Walter B; Morris, Stephan W

    2009-01-01

    Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase in the insulin receptor superfamily, was initially identified in constitutively activated oncogenic fusion forms – the most common being nucleophosmin-ALK – in anaplastic large-cell lymphomas, and subsequent studies have identified ALK fusions in diffuse large B-cell lymphomas, systemic histiocytosis, inflammatory myofibroblastic tumors, esophageal squamous cell carcinomas and non-small-cell lung carcinomas. More recently, genomic DNA amplification and protein overexpression, as well as activating point mutations, of ALK have been described in neuroblastomas. In addition to those cancers for which a causative role for aberrant ALK activity is well validated, more circumstantial links implicate the full-length, normal ALK receptor in the genesis of other malignancies – including glioblastoma and breast cancer – via a mechanism of receptor activation involving autocrine and/or paracrine growth loops with the reported ALK ligands, pleiotrophin and midkine. This review summarizes normal ALK biology, the confirmed and putative roles of ALK in the development of human cancers and efforts to target ALK using small-molecule kinase inhibitors. PMID:19275511

  14. Long-term renin-angiotensin blocking therapy in hypertensive patients with normal aorta may attenuate the formation of abdominal aortic aneurysms.

    PubMed

    Silverberg, Daniel; Younis, Anan; Savion, Naphtali; Harari, Gil; Yakubovitch, Dmitry; Sheick Yousif, Basheer; Halak, Moshe; Grossman, Ehud; Schneiderman, Jacob

    2014-08-01

    Renin-angiotensin system (RAS) has been implicated in the pathogenesis of abdominal aortic aneurysm (AAA). Angiotensin II type 1 receptor blocker (ARB), when given with angiotensin II prevents AAA formation in mice, but found ineffective in attenuating the progression of preexisting AAA. This study was designed to evaluate the effect of chronic RAS blockers on abdominal aortic diameter in hypertensive patients without known aortic aneurysm. Consecutive hypertensive outpatients (n = 122) were stratified according to antihypertensive therapy they received for 12 months or more, consisting of ARB (n = 45), angiotensin converting enzyme inhibitor (ACE-I; n = 45), or nonARB/nonACE-I (control therapy; n = 32). Abdominal ultrasonography was performed to measure maximal subrenal aortic diameter. Eighty-four patients were reexamined by ultrasonography 8 months later. The correlation between the different antihypertensive therapies and aortic diameter was examined. Aortic diameters were significantly smaller in ARB than in control patients in the baseline and follow-up measurements (P = .004; P = .0004, respectively). Risk factor adjusted covariance analysis showed significant differences between ARB or ACE-I treated groups and controls (P = .006 or P = .046, respectively). Ultrasound that was performed 8 months later showed smaller increases in mean aortic diameters of the ARB and ACE-I groups than in controls. Both ARB and ACE-I therapy attenuated expansion of nonaneurysmal abdominal aorta in humans. These results indicate that RAS blockade given before advancement of aortic medial remodeling may slow down the development of AAA.

  15. Multiphysics Applications of ACE3P

    SciTech Connect

    K.H. Lee, C. Ko, Z. Li, C.-K. Ng, L. Xiao, G. Cheng, H. Wang

    2012-07-01

    The TEM3P module of ACE3P, a parallel finite-element electromagnetic code suite from SLAC, focuses on the multiphysics simulation capabilities, including thermal and mechanical analysis for accelerator applications. In this pa- per, thermal analysis of coupler feedthroughs to supercon- ducting rf (SRF) cavities will be presented. For the realistic simulation, internal boundary condition is implemented to capture RF heating effects on the surface shared by a di- electric and a conductor. The multiphysics simulation with TEM3P matched the measurement within 0.4%.

  16. Farnesyl transferase inhibitors: a major breakthrough in anticancer therapy? Naples, 12 April 2002.

    PubMed

    Caponigro, Francesco

    2002-09-01

    An international meeting focused on farnesyl transferase inhibitors (FTIs) was held in Naples on 12 April 2002 and represented an excellent occasion to gather most of the clinicians who are involved in clinical trials with this class of new compounds. Oncogene mutations of the gene occur in approximately 30% of all human cancers and may have prognostic significance. Ras protein is normally synthesized as pro-Ras, which undergoes a number of post-translational modifications, among which farnesylation. Processed Ras proteins localize to the inner surface of the plasma membrane, and function as a molecular switch that cycles between an inactive and an active form. When in its active form, either because of the binding of an external ligand or because of its constitutive activation, Ras activates several downstream effectors, such as Raf-1, Rac, Rho and phospahtidylinositol-3 kinase, which mediate important cellular functions, such as proliferation, cytoskeletal organization and others. Interruption of the Ras signaling pathway can be basically achieved in three ways, i.e. inhibition of Ras protein expression through antisense oligonucleotides, prevention of Ras membrane localization and inhibition of Ras downstream effectors. SCH 66336 (lonafarnib; Sarasar), a tricyclic orally active FTI, has been the first of these compounds to undergo clinical development. The toxicity profile observed in all completed phase I/II trials has been fairly similar, since gastrointestinal tract toxicity (nausea, vomiting and diarrhea) and fatigue have generally qualified as dose-limiting toxicity (DLT). One objective response in a patient with pretreated non-small cell lung cancer (NSCLC) was observed. Based on preclinical evidence of synergism between lonafarnib and other anticancer agents, combination studies have been started. In particular, lonafarnib has been combined both with gemcitabine and with paclitaxel in phase I studies. Nausea, vomiting, diarrhea and myelosuppression

  17. Philadelphia chromosome-positive leukemia stem cells in acute lymphoblastic leukemia and tyrosine kinase inhibitor therapy.

    PubMed

    Thomas, Xavier

    2012-06-26

    Leukemia stem cells (LSCs), which constitute a minority of the tumor bulk, are functionally defined on the basis of their ability to transfer leukemia into an immunodeficient recipient animal. The presence of LSCs has been demonstrated in acute lymphoblastic leukemia (ALL), of which ALL with Philadelphia chromosome-positive (Ph(+)). The use of imatinib, a tyrosine kinase inhibitor (TKI), as part of front-line treatment and in combination with cytotoxic agents, has greatly improved the proportions of complete response and molecular remission and the overall outcome in adults with newly diagnosed Ph(+) ALL. New challenges have emerged with respect to induction of resistance to imatinib via Abelson tyrosine kinase mutations. An important recent addition to the arsenal against Ph(+) leukemias in general was the development of novel TKIs, such as nilotinib and dasatinib. However, in vitro experiments have suggested that TKIs have an antiproliferative but not an antiapoptotic or cytotoxic effect on the most primitive ALL stem cells. None of the TKIs in clinical use target the LSC. Second generation TKI dasatinib has been shown to have a more profound effect on the stem cell compartment but the drug was still unable to kill the most primitive LSCs. Allogeneic stem cell transplantation (SCT) remains the only curative treatment available for these patients. Several mechanisms were proposed to explain the resistance of LSCs to TKIs in addition to mutations. Hence, TKIs may be used as a bridge to SCT rather than monotherapy or combination with standard chemotherapy. Better understanding the biology of Ph(+) ALL will open new avenues for effective management. In this review, we highlight recent findings relating to the question of LSCs in Ph(+) ALL.

  18. Histone Deacetylase Inhibitor SAHA as Potential Targeted Therapy Agent for Larynx Cancer Cells

    PubMed Central

    Grabarska, Aneta; Łuszczki, Jarogniew J.; Nowosadzka, Ewa; Gumbarewicz, Ewelina; Jeleniewicz, Witold; Dmoszyńska-Graniczka, Magdalena; Kowalczuk, Krystyna; Kupisz, Krzysztof; Polberg, Krzysztof; Stepulak, Andrzej

    2017-01-01

    Objective: Laryngeal squamous cell carcinoma is one of the most common malignant tumors in the head and neck region. Due to the poor response to chemotherapeutics in patients and low survival rate, successful treatment of larynx cancer still remains a challenge. Therefore, the identification of novel treatment options is needed. We investigated the anticancer effects of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on two different laryngeal cancer cell lines RK33 and RK45. We also studied the antiproliferative action of SAHA in combination with cisplatin and defined the type of pharmacological interaction between these drugs. Materials and Methods: Viability and proliferation of larynx cancer cell lines were studied by methylthiazolyldiphenyl-tetrazolium bromide method and 5-bromo-2-deoxyuridine incorporation assay, respectively. The type of interaction between SAHA and cisplatin was determined by an isobolographic analysis. Western blotting, flow cytometry and quantitative polymerase chain reaction method were used to determine acetylation of histone H3, cell cycle progression and genes expression, respectively. Apoptosis was assessed by means of nucleosomes released to cytosol. Results: SAHA alone or in combination with cisplatin inhibited larynx cancer cells proliferation, whereas displayed relatively low toxicity against normal cells - primary cultures of human skin fibroblasts. The mixture of SAHA with cisplatin exerted additive and synergistic interaction in RK33 and RK45 cells, respectively. We showed that SAHA induced hyperacetylation of histone H3 K9, K14 and K23 and triggered apoptosis. SAHA also caused cell cycle arrest by upregulation of CDKN1A and downregulation of CCND1 encoding p21WAF1/CIP1 and cyclin D1 proteins, respectively. Conclusion: Our studies demonstrated that SAHA may be considered as a potential therapeutic agent against larynx tumors. PMID:28123594

  19. Proton-pump inhibitor therapy and vitamin B12 status in an inpatient hospital setting.

    PubMed

    Hartman, Brenda; Donnelly-VanderLoo, Mary; Watson, Tiffany; O'Connor, Colleen; Madill, Janet

    2016-06-23

    The risk for impaired vitamin B12 status increases with age, as does the use of proton pump inhibitors (PPI). Long-term use of PPIs is associated with several nutritional deficiencies including B12. Currently, there are no recommendations for B12 screening among patients taking PPIs. Data were abstracted on B12 concentrations, B12-containing supplement use, medications, and select hematological values from a retrospective chart review of 658 adults, 391 with serum B12 concentrations, admitted to 6 different medical units at 2 regional hospitals in Southwestern Ontario between 2010 and 2012. We found no difference between PPI users and nonusers and serum B12 concentrations (404 ± 224 vs 369 ± 213 pmol/L; P = 0.0690). This may be due to use of B12 containing multivitamins in 41% of PPI users. Regression modelling found that aging increases the odds of having an impaired B12 status (<220 pmol/L) by 1.4 times and those using B12 supplements are almost 4 times more likely to have an impaired status. Mean corpuscular volume was not related to B12 status. In this population, older PPI users are more likely to be using multivitamins, which may delay nutritional deficiencies. However, the lower B12 concentrations of PPI users taking only B12 supplements is a concern and requires further research. Finally, physicians need to be aware that mean corpuscular volume is no longer recommended as an effective biomarker for B12 screening and updated screening protocols need to be used to reduce the possibility of adverse neurological effects from impaired B12 status.

  20. Angiotensin II Receptor Blocker Neprilysin Inhibitor (ARNI): New Avenues in Cardiovascular Therapy.

    PubMed

    Volpe, M; Tocci, G; Battistoni, A; Rubattu, S

    2015-09-01

    The burden of cardiovascular disease (CVD) is continuously and progressively raising worldwide. Essential hypertension is a major driver of cardiovascular events, including coronary artery disease, myocardial infarction, ischemic stroke and congestive heart failure. This latter may represent the final common pathway of different cardiovascular diseases, and it is often mediated by progressive uncontrolled hypertension. Despite solid advantages derived from effective and sustained blood pressure control, and the widespread availability of effective antihypertensive medications, the vast majority of the more than 1 billion hypertensive patients worldwide continue to have uncontrolled hypertension. Among various factors that may be involved, the abnormal activation of neurohormonal systems is one consistent feature throughout the continuum of cardiovascular diseases. These systems may initiate biologically meaningful "injury responses". However, their sustained chronic overactivity often may induce and maintain the progression from hypertension towards congestive heart failure. The renin-angiotensin-aldosteron system, the sympathetic nervous system and the endothelin system are major neurohormonal stressor systems that are not only able to elevate blood pressure levels by retaining water and sodium, but also to play a role in the pathophysiology of cardiovascular diseases. More recently, the angiotensin receptor neprilysin inhibitor (ARNI) represents a favourable approach to inhibit neutral endopeptidase (NEP) and suppress the RAAS via blockade of the AT1 receptors, without the increased risk of angioedema. LCZ696, the first-in-class ARNI, has already demonstrated BP lowering efficacy in patients with hypertension, in particular with respect to systolic blood pressure levels, improved cardiac biomarkers, cardiac remodelling and prognosis in patients with heart failure. This manuscript will briefly overview the main pathophysiological and therapeutic aspects of ARNI in

  1. Histone Deacetylase Inhibitor SAHA as Potential Targeted Therapy Agent for Larynx Cancer Cells.

    PubMed

    Grabarska, Aneta; Łuszczki, Jarogniew J; Nowosadzka, Ewa; Gumbarewicz, Ewelina; Jeleniewicz, Witold; Dmoszyńska-Graniczka, Magdalena; Kowalczuk, Krystyna; Kupisz, Krzysztof; Polberg, Krzysztof; Stepulak, Andrzej

    2017-01-01

    Objective: Laryngeal squamous cell carcinoma is one of the most common malignant tumors in the head and neck region. Due to the poor response to chemotherapeutics in patients and low survival rate, successful treatment of larynx cancer still remains a challenge. Therefore, the identification of novel treatment options is needed. We investigated the anticancer effects of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on two different laryngeal cancer cell lines RK33 and RK45. We also studied the antiproliferative action of SAHA in combination with cisplatin and defined the type of pharmacological interaction between these drugs. Materials and Methods: Viability and proliferation of larynx cancer cell lines were studied by methylthiazolyldiphenyl-tetrazolium bromide method and 5-bromo-2-deoxyuridine incorporation assay, respectively. The type of interaction between SAHA and cisplatin was determined by an isobolographic analysis. Western blotting, flow cytometry and quantitative polymerase chain reaction method were used to determine acetylation of histone H3, cell cycle progression and genes expression, respectively. Apoptosis was assessed by means of nucleosomes released to cytosol. Results: SAHA alone or in combination with cisplatin inhibited larynx cancer cells proliferation, whereas displayed relatively low toxicity against normal cells - primary cultures of human skin fibroblasts. The mixture of SAHA with cisplatin exerted additive and synergistic interaction in RK33 and RK45 cells, respectively. We showed that SAHA induced hyperacetylation of histone H3 K9, K14 and K23 and triggered apoptosis. SAHA also caused cell cycle arrest by upregulation of CDKN1A and downregulation of CCND1 encoding p21WAF1/CIP1 and cyclin D1 proteins, respectively. Conclusion: Our studies demonstrated that SAHA may be considered as a potential therapeutic agent against larynx tumors.

  2. A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid For Patients With Glioblastoma

    PubMed Central

    Krauze, Andra V.; Myrehaug, Sten D.; Chang, Michael G.; Holdford, Diane J.; Smith, Sharon; Shih, Joanna; Tofilon, Philip J.; Fine, Howard A.; Camphausen, Kevin

    2015-01-01

    Purpose Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor (HDACi) activity shown to sensitize glioblastoma (GBM) cells to radiation in pre-clinical models. We evaluated the addition of VPA to standard radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed GBM. Methods and Materials Thirty-seven patients with newly diagnosed GBM were enrolled between July 2006 and April 2013. Patients received VPA, 25 mg/kg orally, divided into 2 daily doses concurrent with RT and TMZ. The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently increased up to 25 mg/kg/day over the week prior to radiation. VPA- and TMZ-related acute toxicities were evaluated using Common Toxicity Criteria version 3.0 (National Cancer Institute Cancer Therapy Evaluation Program) and Cancer Radiation Morbidity Scoring Scheme for toxicity and adverse event reporting (Radiation Therapy Oncology Group/European Organization for Research and Treatment). Results A total of 81% of patients took VPA according to protocol. Median overall survival (OS) was 29.6 months (range: 21–63.8 months), and median progression-free survival (PFS) was 10.5 months (range: 6.8–51.2 months). OS at 6, 12, and 24 months was 97%, 86%, and 56%, respectively. PFS at 6, 12, and 24 months was 70%, 43%, and 38% respectively. The most common grade 3/4 toxicities of VPA in conjunction with RT/TMZ therapy were blood and bone marrow toxicity (32%), neurological toxicity (11%), and metabolic and laboratory toxicity (8%). Younger age and class V recursive partitioning analysis results were significant for both OS and PFS. VPA levels were not correlated with grade 3/4 toxicity levels. Conclusions Addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated. Additionally, VPA may result in improved outcomes compared to historical data and merits further study. PMID:26194676

  3. A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients With Glioblastoma

    SciTech Connect

    Krauze, Andra V.; Chang, Michael G.; Holdford, Diane J.; Smith, Sharon; Shih, Joanna; Tofilon, Philip J.; Camphausen, Kevin

    2015-08-01

    Purpose: Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor (HDACi) activity shown to sensitize glioblastoma (GBM) cells to radiation in preclinical models. We evaluated the addition of VPA to standard radiation therapy (RT) plus temozolomide (TMZ) in patients with newly diagnosed GBM. Methods and Materials: Thirty-seven patients with newly diagnosed GBM were enrolled between July 2006 and April 2013. Patients received VPA, 25 mg/kg orally, divided into 2 daily doses concurrent with RT and TMZ. The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently increased up to 25 mg/kg/day over the week prior to radiation. VPA- and TMZ-related acute toxicities were evaluated using Common Toxicity Criteria version 3.0 (National Cancer Institute Cancer Therapy Evaluation Program) and Cancer Radiation Morbidity Scoring Scheme for toxicity and adverse event reporting (Radiation Therapy Oncology Group/European Organization for Research and Treatment). Results: A total of 81% of patients took VPA according to protocol. Median overall survival (OS) was 29.6 months (range: 21-63.8 months), and median progression-free survival (PFS) was 10.5 months (range: 6.8-51.2 months). OS at 6, 12, and 24 months was 97%, 86%, and 56%, respectively. PFS at 6, 12, and 24 months was 70%, 43%, and 38% respectively. The most common grade 3/4 toxicities of VPA in conjunction with RT/TMZ therapy were blood and bone marrow toxicity (32%), neurological toxicity (11%), and metabolic and laboratory toxicity (8%). Younger age and class V recursive partitioning analysis (RPA) results were significant for both OS and PFS. VPA levels were not correlated with grade 3 or 4 toxicity levels. Conclusions: Addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated. Additionally, VPA may result in improved outcomes compared to historical data and merits further study.

  4. The ACES Mission: System Tests Results and Development Status

    NASA Astrophysics Data System (ADS)

    Cacciapuoti, Luigi

    Atomic Clock Ensemble in Space (ACES) is a mission of the European Space Agency (ESA) testing fundamental laws of physics with high-performance atomic clocks1 . Operated on-board the International Space Station, the ACES payload will distribute a clock signal with fractional frequency instability and inaccuracy of 1·10-16 . This frequency reference is resulting from the medium-term stability of an active hydrogen maser (SHM) and the long-term stability and accuracy of a primary standard based on samples of laser cooled Cs atoms (PHARAO). The ACES clocks are combined by two servo-loops, the first stabilizing the PHARAO local oscillator on SHM, the second controlling the long-term instabilities of SHM using the error signal generated by the PHARAO Cesium resonator. A link in the microwave domain (MWL) and an optical link (ELT) will make the ACES clock signal available to ground laboratories equipped with atomic clocks, connecting them in a worldwide network. Space-to-ground and ground-to-ground comparisons of atomic frequency standards will be used to test Einstein's theory of general relativity including a precision measurement of the gravitational red-shift, a search for time variations of fundamental constants, and Lorentz Invariance tests. Applications in geodesy, optical time transfer, and ranging will also be supported. The ACES main instruments and subsystems have now reached an advanced status of devel-opment, demonstrated by the completion and the successful test of their engineering models. In particular, a dedicated test campaign has recently verified the performance of the ACES system, where PHARAO and SHM, locked together via the ACES servo loops, are operated as a unique oscillator to generate the ACES frequency reference. The test campaign conducted 1 Luigi Cacciapuoti and Christophe Salomon, Space Clocks and Fundamental Tests: The ACES Experiment, EPJ Special topics 172, 57 (2009). at CNES premises in Toulouse between July and November 2009 concluded

  5. BCR-ABL–specific T-cell therapy in Ph+ ALL patients on tyrosine-kinase inhibitors

    PubMed Central

    Riva, Giovanni; Guido, Ilaria; Gurrado, Antonella; Quartuccio, Giuseppe; Rubert, Laura; Lagreca, Ivana; Vallerini, Daniela; Forghieri, Fabio; Morselli, Monica; Bresciani, Paola; Cuoghi, Angela; Paolini, Ambra; Colaci, Elisabetta; Marasca, Roberto; Cuneo, Antonio; Iughetti, Lorenzo; Trenti, Tommaso; Narni, Franco; Foà, Robin

    2017-01-01

    Although the emergence of bone marrow (BM)–resident p190BCR-ABL–specific T lymphocytes has been correlated with hematologic and cytogenetic remissions in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) undergoing maintenance tyrosine-kinase inhibitor treatment, little is known about the possibility of culturing these cells ex vivo and using them in T-cell therapy strategies. We investigated the feasibility of expanding/priming p190BCR-ABL–specific T cells in vitro by stimulation with dendritic cells pulsed with p190BCR-ABL peptides derived from the BCR-ABL junctional region and alternative splicing, and of adoptively administering them to patients with relapsed disease. We report on the feasibility of producing clinical-grade BCR-ABL–specific cytotoxic T lymphocytes (CTLs), endowed with antileukemia activity, from Ph+ ALL patients and healthy donors. We treated 3 patients with Ph+ ALL with autologous or allogeneic p190BCR-ABL–specific CTLs. No postinfusion toxicity was observed, except for a grade II skin graft-versus-host disease in the patient treated for hematologic relapse. All patients achieved a molecular or hematologic complete remission (CR) after T-cell therapy, upon emergence of p190BCR-ABL–specific T cells in the BM. Our results show that p190BCR-ABL–specific CTLs are capable of controlling treatment-refractory Ph+ ALL in vivo, and support the development of adoptive immunotherapeutic approaches with BCR-ABL CTLs in Ph+ ALL. PMID:27927646

  6. Active Control Evaluation for Spacecraft (ACES)

    NASA Technical Reports Server (NTRS)

    Pearson, J.; Yuen, W.

    1986-01-01

    The Air Force goal is to develop vibration control techniques for large flexible spacecraft by addressing sensor, actuator, and control hardware and dynamic testing. The Active Control Evaluation for Spacecraft (ACES) program will address the Air Force goal by looking at two leading control techniques and implementing them on a structural model of a flexible spacecraft under laboratory testing. The first phase in the ACES program is to review and to assess the High Authority Control/Low Authority Control (HAC/LAC) and Filter accomodated Model Error Sensitivity Suppression (FAMESS) control techniques for testing on the modified VCOSS structure. Appropriate sensors and actuators will be available for use with both techniques; locations will be the same for both techniques. The control actuators will be positioned at the midpoint and free end of the structure. The laser source for the optical sensor is mounted on the feed mast. The beam will be reflected from a mirror on the offset antenna onto the detectors mounted above the shaker table bay. The next phase is to develop an analysis simulation with the control algorithms implemented for dynamics verification. The third phase is to convert the control laws into high level computer language and test them in the NASA-MSFC facility. The final phase is to compile all analytical and test results for performance comparisons.

  7. ACE: Detecting Volatile Organic Compounds from Orbit

    NASA Astrophysics Data System (ADS)

    Harrison, Jeremy J.; Allen, Nicholas D. C.; Bernath, Peter F.

    2010-12-01

    High-resolution infrared absorption cross sections for ethane, propane (both in the 3 μm region) and acetone (in the 3 μm and 5-8 μm regions) have been determined from spectra recorded using a high-resolution FTIR spectrometer (Bruker IFS 125/HR). Data are presented for mixtures with dry synthetic air at 0.015 cm-1 resolution (calculated as 0.9/MOPD using the Bruker definition of resolution), at a number of temperatures and pressures appropriate for atmospheric conditions. Intensities were calibrated using spectra taken from the Pacific Northwest National Laboratory (PNNL) IR database. Methane measurements are currently being performed in the 3 μm region in order to retrieve line mixing parameters, which will be used in an improved ACE forward model to minimize CH4 residuals in the retrievals of organic species. Preliminary retrievals of acetone from ACE spectra using a microwindow from 1364.7 to 1367.1 cm-1 have been performed.

  8. Long-term effectiveness of initiating non-nucleoside reverse transcriptase inhibitor- versus ritonavir-boosted protease inhibitor-based antiretroviral therapy: implications for first-line therapy choice in resource-limited settings

    PubMed Central

    Lima, Viviane D; Hull, Mark; McVea, David; Chau, William; Harrigan, P Richard; Montaner, Julio SG

    2016-01-01

    Introduction In many resource-limited settings, combination antiretroviral therapy (cART) failure is diagnosed clinically or immunologically. As such, there is a high likelihood that patients may stay on a virologically failing regimen for a substantial period of time. Here, we compared the long-term impact of initiating non-nucleoside reverse transcriptase inhibitor (NNRTI)- versus boosted protease inhibitor (bPI)-based cART in British Columbia (BC), Canada. Methods We followed prospectively 3925 ART-naïve patients who started NNRTIs (N=1963, 50%) or bPIs (N=1962; 50%) from 1 January 2000 until 30 June 2013 in BC. At six months, we assessed whether patients virologically failed therapy (a plasma viral load (pVL) >50 copies/mL), and we stratified them based on the pVL at the time of failure ≤500 versus >500 copies/mL. We then followed these patients for another six months and calculated their probability of achieving subsequent viral suppression (pVL <50 copies/mL twice consecutively) and of developing drug resistance. These probabilities were adjusted for fixed and time-varying factors, including cART adherence. Results At six months, virologic failure rates were 9.5 and 14.3 cases per 100 person-months for NNRTI and bPI initiators, respectively. NNRTI initiators who failed with a pVL ≤500 copies/mL had a 16% higher probability of achieving subsequent suppression at 12 months than bPI initiators (0.81 (25th–75th percentile 0.75–0.83) vs. 0.72 (0.61–0.75)). However, if failing NNRTI initiators had a pVL >500 copies/mL, they had a 20% lower probability of suppressing at 12 months than pVL-matched bPI initiators (0.37 (0.29–0.45) vs. 0.46 (0.38–0.54)). In terms of evolving HIV drug resistance, those who failed on NNRTI performed worse than bPI in all scenarios, especially if they failed with a viral load >500 copies/mL. Conclusions Our results show that patients who virologically failed at six months on NNRTI and continued on the same regimen had a

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

    PubMed

    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 (<1 kDa) with IC50 of 30.3 and 51.8 μg/mL values for the P. lunatus with 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.

  10. Phosphate May Promote CKD Progression and Attenuate Renoprotective Effect of ACE Inhibition

    PubMed Central

    Ruggenenti, Piero; Perna, Annalisa; Leonardis, Daniela; Tripepi, Rocco; Tripepi, Giovanni; Mallamaci, Francesca; Remuzzi, Giuseppe

    2011-01-01

    Phosphate may promote the onset and progression of chronic nephropathies. Here we evaluated the relationships between baseline serum phosphate levels, disease progression, and response to ACE inhibition in 331 patients with proteinuric nephropathies in the prospective Ramipril Efficacy In Nephropathy (REIN) trial. Independent of treatment, patients with phosphate levels in the highest two quartiles progressed significantly faster either to ESRD or to a composite endpoint of doubling of serum creatinine or ESRD compared with patients with phosphate levels below the median (P < 0.001). Results were similar when we analyzed phosphate as a continuous variable (P ≤ 0.004). The renoprotective effect of ramipril decreased as serum phosphate increased (P ≤ 0.008 for interaction); this modification of the treatment effect by phosphate persisted despite adjusting for potential confounders such as GFR and urinary protein. In summary, these data suggest that phosphate is an independent risk factor for progression of renal disease among patients with proteinuric CKD, and high levels of phosphate may even attenuate the renoprotective effect of ACE inhibitors. Future trials should test whether reducing serum phosphate improves renal outcomes and optimizes the renoprotective effect of ACE inhibition. PMID:21852581

  11. Three generations of epidermal growth factor receptor tyrosine kinase inhibitors developed to revolutionize the therapy of lung cancer

    PubMed Central

    Zhang, Haijun

    2016-01-01

    Lung cancer, ~80%–85% of which is non-small-cell lung cancer (NSCLC), is the leading cause of cancer-related mortality worldwide. Sensitizing mutations in epidermal growth factor receptor (EGFR) gene (EGFRm+), such as exon 19 deletions and exon 21 L858R point mutations, are the most important drivers in NSCLC patients. In this respect, small-molecule EGFR tyrosine kinase inhibitors (TKIs) have been designed and developed, which launched the era of targeted, personalized and precise medicine for lung cancer. Patients with EGFRm+ could achieve good responses to the treatment with the first-generation EGFR TKIs, such as erlotinib and gefitinib. However, most patients develop acquired drug resistance mostly driven by the T790M mutation occurring within exon 20. Although the second-generation EGFR TKIs, such as afatinib, dacomitinib and neratinib, demonstrated promising activity against T790M in preclinical models, they have failed to overcome resistance in patients due to dose-limiting toxicity. Recently, the third-generation EGFR TKIs have shown to be effective against cell lines and murine models harboring T790M mutations while sparing wild-type EGFR, which represents a promising breakthrough approach in overcoming T790M-mediated resistance in NSCLC patients. This article provides a comprehensive review of the therapy revolution for NSCLC with three generations of EGFR TKIs. PMID:27920501

  12. A Protease Inhibitor with Induction Therapy with Natural Interferon-β in Patients with HCV Genotype 1b Infection.

    PubMed

    Kishida, Yutaka; Imaizumi, Naohiko; Tanimura, Hirohisa; Kashiwamura, Shinichiro; Kashiwagi, Toru

    2016-03-09

    The restoration of innate immune responses has potential as a novel therapeutic strategy for chronic hepatitis C (CHC). We compared the efficacy and safety of induction therapy (IT) with natural interferon-β (n-IFN-β) followed by pegylated-IFN-α/ribavirin (PR) alone (group A, n = 30) and IT with a protease inhibitor (PI) (simeprevir or vaniprevir)/PR (group B, n = 13) in CHC patients with genotype 1b and high viral loads. During IT with nIFN-β, virologic response rates in group A and group B were 10% and 8% (p = 0.6792) at week 4, 30% and 16% (p = 0.6989) at week 12 and 47% and 20% (p = 0.0887) at week 24 respectively. During and after the treatment with PR alone or PI/PR, virologic response rates in groups A and B were 50% and 82% (p = 0.01535) at week 4, 53% and 91% (p = 0.006745) at week 8, 57% and 91% (p = 0.001126) at week 12, 57% and 100% (p < 0.001845) at the end of the treatment and 57% and 80% (p < 0.005166) after treatment cessation. IT with PI/PR linked to the restoration of innate immune response was tolerated well, overcame virological breakthrough, enhanced early virologic responses, and resulted in a sustained virologic response in difficult-to-treat CHC patients. IT with PI/PR is beneficial for treating difficult-to-treat CHC patients.

  13. A Protease Inhibitor with Induction Therapy with Natural Interferon-β in Patients with HCV Genotype 1b Infection

    PubMed Central

    Kishida, Yutaka; Imaizumi, Naohiko; Tanimura, Hirohisa; Kashiwamura, Shinichiro; Kashiwagi, Toru

    2016-01-01

    The restoration of innate immune responses has potential as a novel therapeutic strategy for chronic hepatitis C (CHC). We compared the efficacy and safety of induction therapy (IT) with natural interferon-β (n-IFN-β) followed by pegylated-IFN-α/ribavirin (PR) alone (group A, n = 30) and IT with a protease inhibitor (PI) (simeprevir or vaniprevir)/PR (group B, n = 13) in CHC patients with genotype 1b and high viral loads. During IT with nIFN-β, virologic response rates in group A and group B were 10% and 8% (p = 0.6792) at week 4, 30% and 16% (p = 0.6989) at week 12 and 47% and 20% (p = 0.0887) at week 24 respectively. During and after the treatment with PR alone or PI/PR, virologic response rates in groups A and B were 50% and 82% (p = 0.01535) at week 4, 53% and 91% (p = 0.006745) at week 8, 57% and 91% (p = 0.001126) at week 12, 57% and 100% (p < 0.001845) at the end of the treatment and 57% and 80% (p < 0.005166) after treatment cessation. IT with PI/PR linked to the restoration of innate immune response was tolerated well, overcame virological breakthrough, enhanced early virologic responses, and resulted in a sustained virologic response in difficult-to-treat CHC patients. IT with PI/PR is beneficial for treating difficult-to-treat CHC patients. PMID:27005617

  14. Association between Proton Pump Inhibitor Therapy and Clostridium difficile Infection: A Contemporary Systematic Review and Meta-Analysis

    PubMed Central

    Tleyjeh, Imad M.; Alasmari, Faisal A.; Garbati, Musa A.; AlGhamdi, Mushabab; Khan, Abdur Rahman; Tannir, Mohamad Al; Erwin, Patricia J.; Ibrahim, Talal; AlLehibi, Abed; Baddour, Larry M.; Sutton, Alex J.

    2012-01-01

    Introduction Emerging epidemiological evidence suggests that proton pump inhibitor (PPI) acid-suppression therapy is associated with an increased risk of Clostridium difficile infection (CDI). Methods Ovid MEDLINE, EMBASE, ISI Web of Science, and Scopus were searched from 1990 to January 2012 for analytical studies that reported an adjusted effect estimate of the association between PPI use and CDI. We performed random-effect meta-analyses. We used the GRADE framework to interpret the findings. Results We identified 47 eligible citations (37 case-control and 14 cohort studies) with corresponding 51 effect estimates. The pooled OR was 1.65, 95% CI (1.47, 1.85), I2 = 89.9%, with evidence of publication bias suggested by a contour funnel plot. A novel regression based method was used to adjust for publication bias and resulted in an adjusted pooled OR of 1.51 (95% CI, 1.26–1.83). In a speculative analysis that assumes that this association is based on causality, and based on published baseline CDI incidence, the risk of CDI would be very low in the general population taking PPIs with an estimated NNH of 3925 at 1 year. Conclusions In this rigorously conducted systemic review and meta-analysis, we found very low quality evidence (GRADE class) for an association between PPI use and CDI that does not support a cause-effect relationship. PMID:23236397

  15. Perspectives on the combination of radiotherapy and targeted therapy with DNA repair inhibitors in the treatment of pancreatic cancer

    PubMed Central

    Yang, Shih-Hung; Kuo, Ting-Chun; Wu, Hsu; Guo, Jhe-Cyuan; Hsu, Chiun; Hsu, Chih-Hung; Tien, Yu-Wen; Yeh, Kun-Huei; Cheng, Ann-Lii; Kuo, Sung-Hsin

    2016-01-01

    Pancreatic cancer is highly lethal. Current research that combines radiation with targeted therapy may dramatically improve prognosis. Cancerous cells are characterized by unstable genomes and activation of DNA repair pathways, which are indicated by increased phosphorylation of numerous factors, including H2AX, ATM, ATR, Chk1, Chk2, DNA-PKcs, Rad51, and Ku70/Ku80 heterodimers. Radiotherapy causes DNA damage. Cancer cells can be made more sensitive to the effects of radiation (radiosensitization) through inhibition of DNA repair pathways. The synergistic effects, of two or more combined non-lethal treatments, led to co-administration of chemotherapy and radiosensitization in BRCA-defective cells and patients, with promising results. ATM/Chk2 and ATR/Chk1 pathways are principal regulators of cell cycle arrest, following DNA double-strand or single-strand breaks. DNA double-stranded breaks activate DNA-dependent protein kinase, catalytic subunit (DNA-PKcs). It forms a holoenzyme with Ku70/Ku80 heterodimers, called DNA-PK, which catalyzes the joining of nonhomologous ends. This is the primary repair pathway utilized in human cells after exposure to ionizing radiation. Radiosensitization, induced by inhibitors of ATM, ATR, Chk1, Chk2, Wee1, PP2A, or DNA-PK, has been demonstrated in preclinical pancreatic cancer studies. Clinical trials are underway. Development of agents that inhibit DNA repair pathways to be clinically used in combination with radiotherapy is warranted for the treatment of pancreatic cancer. PMID:27621574

  16. ACE and AGTR1 polymorphisms in elite rhythmic gymnastics.

    PubMed

    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.

  17. Identifying p53 Transactivation Domain 1-Specific Inhibitors to Alleviate the Side Effects of Prostate Cancer Therapy

    DTIC Science & Technology

    2015-12-01

    cancer. 15. SUBJECT TERMS p53 inhibitor, p53 transactivation mutants 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES...gene regulatory elements. Keywords p53 inhibitor, p53 transactivation mutants , p53 transcriptional activation domain inhibitor Overall Project

  18. Effects of prolonged angiotensin-converting enzyme inhibitor treatment on amyloid beta-protein metabolism in mouse models of Alzheimer disease.

    PubMed

    Hemming, Matthew L; Selkoe, Dennis J; Farris, Wesley

    2007-04-01

    Genetic and pathologic studies have associated angiotensin-converting enzyme (ACE) with Alzheimer disease. Previously, we and others have reported that ACE degrades in vitro the amyloid beta-protein (Abeta), a putative upstream initiator of Alzheimer disease. These studies support the hypothesis that deficiency in ACE-mediated Abeta proteolysis could increase Alzheimer disease risk and raise the question of whether ACE inhibitors, a commonly prescribed class of anti-hypertensive medications, can elevate Abeta levels in vivo. To test this hypothesis, we administered the ACE inhibitor captopril to two lines of APP transgenic mice harboring either low levels of Abeta or high levels of Abeta with associated plaque deposition. In both models, we show that captopril does not affect cerebral Abeta levels in either soluble or insoluble pools. Furthermore, we find no change in plaque deposition or in peripheral Abeta levels. Data from these Alzheimer models suggest that captopril and similar ACE inhibitors do not cause Abeta accumulation in vivo.

  19. [Persistence in drug therapy of hypertension among different treatment groups and comparison between fixed-dose combinations of ara II + calcium channel blockers vs ace inhibitors + calcium channel blockers].

    PubMed

    Waisman, Gabriel Dario; Garfi, Leonardo Guillermo; Izbizky, Gustavo Hernan; Tortella, Juan Jose

    2012-01-01

    La hipertensión arterial (HTA) es una enfermedad crónica, y prevalente, que requiere un tratamiento sostenido en el tiempo donde existen medidas farmacológicas y no farmacológicas para su control. La “persistencia” es la continuidad de los tratamientos farmacológicos. Conocer cual es la persistencia de los diferentes grupos terapéuticos antihipertensivos podría ayudar a priorizar aquellos con mejores resultados. El objetivo es describir la persistencia al tratamiento antihipertensivo en una cohorte de pacientes utilizando diferentes métodos y comparar la persistencia en los diferentes grupos farmacológicos utilizados para el tratamiento de la HTA. Materiales y Métodos: Estudio observacional, de cohorte retrospectiva utilizando bases de datos secundarias obtenidas durante la dispensación de medicamentos y de los registros hospitalarios electrónicos del Hospital Italiano de Buenos Aires. Población adulta con diagnóstico de HTA y seguimiento por 2 años. Resultados: Los diuréticos, betabloqueantes de primera generación e inhibidores de la enzima convertidora de angiotensina son los grupos con la caída más importante en la persistencia. Los antagonistas de la angiotensina en monoterapia o junto con diurético y los betabloqueantes de segunda generación demostraron los mejores resultados de persistencia. La persistencia nunca llegó al 60% de los pacientes tratados a los 2 años. Conclusión: Pese a haber realizado la medición de la persistencia a través de distintos métodos los resultados fueron similares y demostraron una baja persistencia al tratamiento antihipertensivo. No encontramos variables extra farmacológicas que pudieran explicar la diferente persistencia en los diferentes grupos terapéuticos.

  20. Desert Dust Layers Over Polluted Marine Boundary Layers: ACE-2 Measurements and ACE-Asia Plans

    NASA Technical Reports Server (NTRS)

    Russell, Philip B.; Schmid, B.; Livingston, J. M.; Redemann, J.; Bergstrom, R. W.; Condon, Estelle P. (Technical Monitor)

    2000-01-01

    Aerosols in ACE-Asia are expected to have some commonalties with those in ACE-2, along with important differences. Among the commonalities are occurrences of desert dust layers over polluted marine boundary layers. Differences include the nature of the dust (yellowish in the East Asia desert outflow, vs. reddish-brown in the Sahara Outflow measured in ACE-2) and the composition of boundary-layer aerosols (e.g., more absorbing, soot and organic aerosol in-the Asian plume, caused by coal and biomass burning, with limited controls). In this paper we present ACE-2 measurements and analyses as a guide to our plans for ACE-2 Asia. The measurements include: (1) Vertical profiles of aerosol optical depth and extinction (380-1558 nm), and of water vapor column and concentration, from the surface through the elevated desert dust, measured by the 14-channel Ames Airborne Tracking Sunphotometer (AATS-14); (2) Comparisons of airborne and shipborne sunphotometer optical depths to satellite-retrieved values, with and without desert dust; (3) Comparisons between airborne Sunphotometer optical depth and extinction spectra and those derived from coincident airborne in situ measurements of aerosol size distribution, scattering and absorption; (4) Comparisons between size distributions measured in situ and retrieved from sunphotometer optical depth spectra; (5) Comparisons between aerosol single scattering albedo values obtained by several techniques, using various combinations of measurements of backscatter, extinction, size distribution, scattering, absorption, and radiative flux. We show how analyses of these data can be used to address questions important to ACE-Asia, such as: (1) How do dust and other absorbing aerosols affect the accuracy of satellite optical depth retrievals? How important are asphericity effects? (2) How important are supermicron dust and seasalt aerosols to overall aerosol optical depth and radiative forcing? How well are these aerosols sampled by aircraft

  1. The solar array is installed on ACE in SAEF-2

    NASA Technical Reports Server (NTRS)

    1997-01-01

    Applied Physics Laboratory engineers and technicians from Johns Hopkins University install solar array panels on the Advanced Composition Explorer (ACE) in KSC's Spacecraft Assembly and Encapsulation Facility-II. The panel on which they are working is identical to the panel (one of four) seen in the foreground on the ACE spacecraft. Scheduled for launch on a Delta II rocket from Cape Canaveral Air Station on Aug. 25, ACE will study low- energy particles of solar origin and high-energy galactic particles for a better understanding of the formation and evolution of the solar system as well as the astrophysical processes involved. The ACE observatory will be placed into an orbit almost a million miles (1.5 million kilometers) away from the Earth, about 1/100 the distance from the Earth to the Sun. The collecting power of instrumentation aboard ACE is at least 100 times more sensitive than anything previously flown to collect similar data by NASA.

  2. The toxicity of angiotensin converting enzyme inhibitors to larvae of the disease vectors Aedes aegypti and Anopheles gambiae

    PubMed Central

    Abu Hasan, Zatul-’Iffah; Williams, Helen; Ismail, Nur M.; Othman, Hidayatulfathi; Cozier, Gyles E.; Acharya, K. Ravi; Isaac, R. Elwyn

    2017-01-01

    The control of mosquitoes is threatened by the appearance of insecticide resistance and therefore new control chemicals are urgently required. Here we show that inhibitors of mosquito peptidyl dipeptidase, a peptidase related to mammalian angiotensin-converting enzyme (ACE), are insecticidal to larvae of the mosquitoes, Aedes aegypti and Anopheles gambiae. ACE inhibitors (captopril, fosinopril and fosinoprilat) and two peptides (trypsin-modulating oostatic factor/TMOF and a bradykinin-potentiating peptide, BPP-12b) were all inhibitors of the larval ACE activity of both mosquitoes. Two inhibitors, captopril and fosinopril (a pro-drug ester of fosinoprilat), were tested for larvicidal activity. Within 24 h captopril had killed >90% of the early instars of both species with 3rd instars showing greater resistance. Mortality was also high within 24 h of exposure of 1st, 2nd and 3rd instars of An. gambiae to fosinopril. Fosinopril was also toxic to Ae. aegypti larvae, although the 1st instars appeared to be less susceptible to this pro-drug even after 72 h exposure. Homology models of the larval An. gambiae ACE proteins (AnoACE2 and AnoACE3) reveal structural differences compared to human ACE, suggesting that structure-based drug design offers a fruitful approach to the development of selective inhibitors of mosquito ACE enzymes as novel larvicides. PMID:28345667

  3. The toxicity of angiotensin converting enzyme inhibitors to larvae of the disease vectors Aedes aegypti and Anopheles gambiae.

    PubMed

    Abu Hasan, Zatul-'Iffah; Williams, Helen; Ismail, Nur M; Othman, Hidayatulfathi; Cozier, Gyles E; Acharya, K Ravi; Isaac, R Elwyn

    2017-03-27

    The control of mosquitoes is threatened by the appearance of insecticide resistance and therefore new control chemicals are urgently required. Here we show that inhibitors of mosquito peptidyl dipeptidase, a peptidase related to mammalian angiotensin-converting enzyme (ACE), are insecticidal to larvae of the mosquitoes, Aedes aegypti and Anopheles gambiae. ACE inhibitors (captopril, fosinopril and fosinoprilat) and two peptides (trypsin-modulating oostatic factor/TMOF and a bradykinin-potentiating peptide, BPP-12b) were all inhibitors of the larval ACE activity of both mosquitoes. Two inhibitors, captopril and fosinopril (a pro-drug ester of fosinoprilat), were tested for larvicidal activity. Within 24 h captopril had killed >90% of the early instars of both species with 3(rd) instars showing greater resistance. Mortality was also high within 24 h of exposure of 1(st), 2(nd) and 3(rd) instars of An. gambiae to fosinopril. Fosinopril was also toxic to Ae. aegypti larvae, although the 1(st) instars appeared to be less susceptible to this pro-drug even after 72 h exposure. Homology models of the larval An. gambiae ACE proteins (AnoACE2 and AnoACE3) reveal structural differences compared to human ACE, suggesting that structure-based drug design offers a fruitful approach to the development of selective inhibitors of mosquito ACE enzymes as novel larvicides.

  4. Addition of the p110α inhibitor BYL719 overcomes targeted therapy resistance in cells from Her2-positive-PTEN-loss breast cancer.

    PubMed

    Zhang, Chen; Xu, Bingfei; Liu, Pian

    2016-11-01

    Breast cancer is one of the leading causes of death for women worldwide. Among various subtypes of breast cancer, human epidermal growth factor receptor 2 (HER2)-positive and phosphatase and tensin homolog (PTEN) loss breast cancer is a cause of great concern in terms of its resistance to HER2-targeted therapies and its poor prognosis. Phosphatidylinositol 3-kinase (PI3K)/AKT hyperphosphorylation is considered one of key mechanisms leading to this resistance, thus combination therapy of PI3K inhibitors and HER2 antibodies is promising for overcoming this problem, and more specific regimens should be designed in this age of precision medicine. In this study, we established an HER2-positive and PTEN loss cell line and confirmed it by western blot analysis. This cell line and its orthotopic xenograft models were exposed to p110α-specific inhibitor BYL719, p110β-specific inhibitor AZD6482, or pan-PI3K inhibitor BKM120, respectively, and the results showed sensitivity to both BYL719 and BKM120 but not AZD6482, which indicated a p110α-reliance for HER2-positive-PTEN-loss breast cancer. Then, the addition of BYL719 to HER2 antibody greatly reduced tumor growth both in vitro and in vivo, accompanied by inhibited PI3K effector phosphorylation. Therefore, our findings suggest that the combination of p110α-selective inhibitor BYL719 with HER2 antibody could be a potential strategy for more personalized treatment of HER2-posistive-PTEN-loss breast cancer; and in addition, the optimal schedule of this combination therapy needs to be further explored.

  5. [Laboratory monitoring of efficiency of different approaches to the therapy of patients with inhibitor form of haemophilia A].

    PubMed

    Nabieva, M I

    2009-01-01

    Revealing of inhibitors form of hemophilia A form patients of hemophilia in Republic of Uzbekistan was studied and peculiarities of this form of hemophilia also was studied. Shown, that revealing of inhibitors form from 405 patients of hemophilia A was 7,7%. Shown that from patients with inhibitors form more patients with low titr of inhibitors (77,1%). In patients with high titr of inhibitors in high degree was more heavy degree of hemophilia A, in patients with low titr of inhibitors more heavy form and heavy form of hemophilia A was in equal degree. Shown, that Cogenait drug and plasmapheresis in Pph-3 - Pph-5 regime render equal effect in reducing of inhibitor titr.

  6. SGLT2 inhibitors or GLP-1 receptor agonists as second-line therapy in type 2 diabetes: patient selection and perspectives

    PubMed Central

    Gurgle, Holly E; White, Karen; McAdam-Marx, Carrie

    2016-01-01

    Controversy exists regarding the selection of second-line therapy for patients with type 2 diabetes mellitus (T2DM) who are unable to achieve glycemic control with metformin therapy alone. Newer pharmacologic treatments for T2DM include glucagon-like peptide-1 receptor agonists and sodium–glucose cotransporter 2 inhibitors. Both the classes of medication are efficacious, exhibit positive effects on weight, and are associated with minimal risk of hypoglycemia. The purpose of this review is to compare the clinical trial and real-world effectiveness data of glucagon-like peptide-1 receptor agonists versus sodium–glucose cotransporter 2 inhibitors related to A1c reduction, weight loss, cost-effectiveness, cardiovascular outcomes, and safety in patients with T2DM. This review summarizes comparative evidence for providers who are determining which of the two classes may be the most appropriate for a specific patient. PMID:27350752

  7. Sodium–glucose cotransporter-2 inhibitor combination therapy to optimize glycemic control and tolerability in patients with type 2 diabetes: focus on dapagliflozin–metformin

    PubMed Central

    Schwartz, Stanley S; Katz, Arie

    2016-01-01

    In type 2 diabetes (T2D), early combination therapy using agents that target a number of the underlying pathophysiologic defects contributing to hyperglycemia may improve patient outcomes. For many patients, the combination of metformin with a sodium–glucose cotransporter-2 (SGLT-2) inhibitor may be a good option because these agents have complementary mechanisms of action, neutral-to-positive effects on body weight, and a low risk of hypoglycemia. This review focuses on the combination of metformin with dapagliflozin, a member of the SGLT-2 inhibitor class of antidiabetes agents. In clinical trials, the combination of dapagliflozin with metformin produced significant and sustained reductions in glycated hemoglobin and body weight in a broad range of adult patients with T2D, including those initiating pharmacotherapy and those with more advanced disease. These reductions were accompanied by modest decreases in blood pressure. Dapagliflozin as add-on therapy to metformin was well tolerated and associated with low rates of hypoglycemia. Genital infections and, in some studies, urinary tract infections were more frequent with dapagliflozin than with placebo. Early combination therapy with dapagliflozin and metformin may be a safe and appropriate treatment option that enables patients with T2D to achieve individualized glycemic goals as either initial combination therapy in treatment-naïve patients or as dapagliflozin add-on in patients inadequately controlled with metformin therapy. PMID:27042132

  8. Patterns of antihypertensive use among patients in the US Department of Defense database initially prescribed an angiotensin-converting enzyme inhibitor or calcium channel blocker.

    PubMed

    Okano, G J; Rascati, K L; Wilson, J P; Remund, D D; Grabenstein, J D; Brixner, D I

    1997-01-01

    The US Department of Defense recently assembled electronic records of outpatient prescriptions dispensed through the Uniformed Services Prescription Database Project (USPDP) going back to 1990. The objectives of this portion of a larger study were: (1) to examine longitudinally the patterns of antihypertensive drug use during the first year of therapy in patients whose initial therapy was with an angiotensin-converting enzyme (ACE) inhibitor or a calcium channel blocker (CCB); (2) to determine continuous and noncontinuous users of antihypertensive drugs; and (3) to estimate the direct medication costs for each pattern of medication use. Filtering criteria for patient and prescription identification were developed, because the USPDP contains no records of confirmatory diagnoses of hypertension. Once data filters were implemented, information for 771 patients was analyzed. An ACE inhibitor was the initial therapy for 328 patients, accounting for 1935 antihypertensive medication prescription fills, and a CCB was the initial therapy for 443 patients, accounting for 2459 fills (including refills). Slightly more than half of the patients (n = 401, 52.0%) were classified as continuous users (> or = 80% medication-possession ratio [supply of medication in days divided by the number of days in the 12-month study period]). In the first year, 177 of these continuous users (44.1%) had no change in therapy in the first year, 49 (12.2%) had an increase in dose, 8 (2.0%) had a decrease in dose, 15 (3.7%) had a change to a different therapeutic class of antihypertensive medication, 14 (3.5%) were changed to a different medication in the same therapeutic class, 20 (5.0%) had a new medication added to the regimen, and 118 (29.4%) had complex regimens involving more than one change. For continuous users, the mean medication supply in days was 354.6, and the average time before a medication change was 152.1 days for those continuous users who had one change in therapy. The overall

  9. Active Control Technique Evaluation for Spacecraft (ACES)

    DTIC Science & Technology

    1988-06-16

    Due to Test Results 3-9 3.5 Representative Data 3-11 3.6 Control Model 3-21 4.0 Simulation 4-1 5.0 HAC/LAC 5-1 5.1 Theory 5-1...5.1.1 HAC Theory 5-1 5.1.2 LAC Theory 5-4 5.1.3 HAC/LAC Combined Control 5-6 5.1.4 HAC/LAC Applied to ACES 5-7 5.2 Model Selection and...5-39 5-50 6.0 Positivity 6-1 6-1 6-9 6-9 6-17 6-31 5.4 Observation 5.5 Test Results 5.6 Conclusions 6.1 Theory 6.2 Model

  10. Randomized controlled clinical trial of a combination therapy of vildagliptin plus an α-glucosidase inhibitor for patients with type II diabetes mellitus.

    PubMed

    Su, Yong; Su, Ya-Li; Lv, Li-Fang; Wang, Li-Min; Li, Quan-Zhong; Zhao, Zhi-Gang

    2014-06-01

    The aim of this study was to assess the efficacy of a combination therapy of vildagliptin plus an α-glucosidase inhibitor for patients with type II diabetes mellitus. Type II diabetic patients exhibiting poor glycemic control following α-glucosidase inhibitor treatment for at least two months were selected and randomly distributed into vildagliptin and placebo groups. The body weight, fasting blood glucose (FBG), postprandial glucose (PPG), glycated hemoglobin (HBA1c) and blood lipid levels and hepatorenal functions of the patients were determined before and 12 weeks after the trial. Following the trial, the FBG, PPG, HbA1c, cholesterol (CHOL) and triglyceride (TG) levels in the vildagliptin group were significantly decreased compared with the pretreatment levels (P<0.05), whereas only the PPG level in the placebo group decreased (P<0.05). The FBG, PPG and HbA1c levels in the vildagliptin group were markedly lower than those in the placebo group 12 weeks after the trial. A comparison of the body weights and hepatorenal functions before and after the trial or between groups did not show statistically significant differences. The combination therapy of vildagliptin plus an α-glucosidase inhibitor effectively reduced the FBG, PPG and HbA1c levels in patients without inducing weight gain or hepatorenal dysfunction. However, the therapy may have caused a reduction in the blood lipid levels.

  11. A retrospective study of the effects of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in diabetic nephropathy

    PubMed Central

    Pathak, Jahnavi V.; Dass, Ervilla E.

    2015-01-01

    Objective: Till date, several studies have compared angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in terms of delaying the progression of diabetic nephropathy. But the superiority of one drug class over the other remains unsettled. This study has retrospectively compared the effects of ACE inhibitors and ARBs in diabetic nephropathy. The study aims to compare ACE inhibitors and ARBs in terms of delaying or preventing the progression of diabetic nephropathy, association between blood pressure (B.P) and urinary albumin and also B.P and serum creatinine with ACE inhibitor and ARB, know the percentage of hyperkalemia in patients of diabetic nephropathy receiving ACE inhibitor or ARB. Settings and Design: A total of 134 patients diagnosed with diabetic nephropathy during the years 2001–2010 and having a complete follow-up were studied, out of which 99 were on ARB (63 patients of Losartan and 36 of Telmisartan) and 35 on ACE inhibitor (Ramipril). Subjects and Methods: There was at least 1-month of interval between each observation made and also between the date of treatment started and the first reading that is, the observation of the 1st month. In total, three readings were taken that is, of the 1st, 2nd and 3rd month after the treatment started. Comparison of the 1st and 3rd month after the treatment started was done. Mean ± standard deviation, Paired t-test, and Chi-square were used for the analysis of the data. Results: The results reflect that ARBs (Losartan and Telmisartan) when compared to ACE inhibitor (Ramipril) are more effective in terms of delaying the progression of diabetic nephropathy and also in providing renoprotection. Also, ARBs have the property of simultaneously decreasing the systolic B.P and albuminuria when compared to ACE inhibitor (Ramipril). Conclusions: Angiotensin receptor blockers are more renoprotective than ACE inhibitors and also provide better cardioprotection. PMID:25878372

  12. Comparison of outcomes of tyrosine kinase inhibitor in first- or second-line therapy for advanced non-small-cell lung cancer patients with sensitive EGFR mutations.

    PubMed

    Xu, Jianlin; Zhang, Xueyan; Yang, Haitang; Ding, Guozheng; Jin, Bo; Lou, Yuqing; Zhang, Yanwei; Wang, Huimin; Han, Baohui

    2016-10-18

    Direct comparisons between the use of first- and second-line EGFR tyrosine kinase inhibitor (TKI) in patients with sensitive EGFR mutations are limited. A total of 264 advanced non-small-cell lung cancer (NSCLC) patients with sensitive mutations received EGFR TKI therapy as the first-line therapy, and a total of 187 patients received TKI as the second-line therapy at Shanghai Chest Hospital. First-line EGFR TKI therapy [12.9 months, 95% confidence interval (CI), 10.7-15.2] provided longer progression-free survival (PFS) than did second-line EGFR TKI therapy (9.0 months, 95% CI, 7.7-10.2) [hazard ratio (HR): 0.78, P = 0.034]. The objective response rate (ORR) of first-, and second-line TKI therapy were 67.8% (159/233) and 55.6% (94/169), respectively (P = 0.001). The overall survival (OS) for patients (n = 141) receiving first-line TKI followed by second-line chemotherapy were longer than those for patients (n = 187) receiving first-line chemotherapy followed by second-line TKI (HR: 0.69, P = 0.02).Compared with second-line TKI, first-line therapy achieved a significant and longer PFS, and higher ORR in the sensitive EGFR mutated NSCLC patients. The therapeutic strategy of using TKI followed by chemotherapy achieved longer OS than that using chemotherapy followed by TKI.

  13. The effect of subgingival antimicrobial therapy on the levels of stromelysin and tissue inhibitor of metalloproteinases in gingival crevicular fluid.

    PubMed

    Pourtaghi, N; Radvar, M; Mooney, J; Kinane, D F

    1996-09-01

    Recent investigations imply that a key mechanism in the pathogenesis of periodontal disease may be the ability of oral microorganisms to induce production and/or activation of matrix metalloproteinases (MMPs) in the host tissues. It has been suggested that the pharmacologic inhibition of MMP activity could play an important role in achieving a desirable outcome in periodontal therapy. The efficacy of locally delivered antibiotics on the level of gingival crevicular fluid (GCF) stromelysin (SL) and tissue inhibitor of metalloproteinases (TIMP) on sites with a history of a poor response to mechanical treatment was studied. Fifty-two patients with 4 periodontal pockets > or = 5 mm and bleeding on probing were randomized into four groups of 13 patients. One group received scaling and root planing alone and the other three groups received scaling and root planing plus a locally delivered antimicrobial system. These included 25% tetracycline fiber, 2% minocycline gel, and 25% metronidazole gel. The GCF samples taken at baseline and 6 weeks after treatments were analyzed using an enzyme linked immunosorbent assay (ELISA). GCF SL levels significantly decreased after adjunctive tetracycline fiber (paired t-test, P = 0.020) and minocycline gel (paired t-test, P = 0.023) treatments whereas it remained almost unchanged in the other two groups. While the GCF TIMP level did not change significantly in the scaling and root planing alone group, it significantly increased for all three adjunctive antimicrobial treatments (for tetracycline fiber P < 0.001, minocycline gel P = 0.005, metronidazole gel P < 0.001). The use of adjunctive locally delivered antimicrobial systems, particularly the tetracycline family, may offer an advantage in changing the metalloproteinase profile of the GCF to one more compatible with periodontal health.

  14. AceCloud: Molecular Dynamics Simulations in the Cloud.

    PubMed

    Harvey, M J; De Fabritiis, G

    2015-05-26

    We present AceCloud, an on-demand service for molecular dynamics simulations. AceCloud is designed to facilitate the secure execution of large ensembles of simulations on an external cloud computing service (currently Amazon Web Services). The AceCloud client, integrated into the ACEMD molecular dynamics package, provides an easy-to-use interface that abstracts all aspects of interaction with the cloud services. This gives the user the experience that all simulations are running on their local machine, minimizing the learning curve typically associated with the transition to using high performance computing services.

  15. ACE--Alliance for Clinical Enhancement: a collaborative model.

    PubMed

    Poirrier, G P; Granger, M; Todaro, M

    1993-01-01

    This paper introduces an innovative collaborative model developed by nursing educators and practitioners, the Alliance for Clinical Enhancement Program (ACE), that combines components of traditional internship and extender programs. The goals of ACE are opportunities for role socialization, role transition, and role modeling for nursing students; enhancing clinical competence and provision of financial assistance to the students; increased recruitment of RN graduates by the involved hospital; and decreased RN time spent on non-nursing tasks by hospital RNs. The total development, implementation, and analysis of ACE Program is discussed.

  16. ACE-Asia Chemical Transport Modeling Overview

    NASA Astrophysics Data System (ADS)

    UNO, I.; Chin, M.; Collins, W.; Ginoux, P.; Rasch, P.; Carmichael, G. R.; Yienger, J. J.

    2001-12-01

    ACE-Asia (Asia Pacific Regional Aerosol Characterization Experiment) was designed to increase our understanding of how atmospheric aerosol particles affect the Earth?s climate system. The intensive observation period was carried out during March to May, 2001, and more than 100 researchers from several countries (United States, Japan, Korea, China, and many other Asian countries) participated using aircraft, a research vessel, surface stations and numerical models. Aerosol transport forecast activities played an important role during the ACE-Asia intensive observation period. Three independent modeling groups operated chemical transport models in forecast mode and participated in flight planning activities at the operations center. These models were: MATCH (Model of Atmospheric Transport and Chemistry; Rasch and Collins); GOCART (Georgia Tech/Goddard Global Ozone Chemistry Aerosol Radiation and Transport model; Chin and Ginour) and CFORS (Research Institute for Applied Mechanics, Kyushu University + University of Iowa - Chemical weather FORecast System; Uno, Carmichael and Yienger). The MATCH model used in ACE-Asia was a transport model applied for the Asia region, driven by NCEP forecast meteorology. A unique feature of this model was that it assimilated satellite derived optical depths into its forecast algorithm. The GOCART model provided global aerosol forecast using forecast meteorological fields provided by the Goddard Earth Observing System Data Assimilation System (GEOS DAS). The CFORS model provided regional forecasts using a limited area transport model coupled with Regional Meteorological Modeling System (RAMS), initialized by NCEP and JMA forecasts. All models produced 3-d aerosol forecast products consisting of aerosol mass distributions and optical depths for sulfate, black carbon, organic carbon, sea salt, and dust. In the field these model products were made available to all participating scientists via the Web, and were also presented during the

  17. Preconception and pregnancy management of women with diabetic nephropathy on angiotensin converting enzyme inhibitors.

    PubMed

    Podymow, Tiina; Joseph, Geena

    2015-02-01

    Angiotensin converting enzyme (ACE) inhibitors are the mainstay of treatment for diabetic nephropathy to slow progression of disease. Diabetic women of childbearing age with nephropathy should be treated with ACE inhibitors as per guidelines in the pre-pregnancy period. ACE inhibitor use and exposure in the first trimester is controversial and requires counselling pre-pregnancy regarding the risks and benefits of use up to the first trimester, as well as the need to stop ACE inhibitors prior to the second trimester. Current evidence does not suggest that ACE inhibitors in the first trimester are associated with a greater risk of fetal malformations when compared to other antihypertensives. This topic is reviewed in depth, along with blood pressure targets in pregnant women with diabetic proteinuric disease, evidence for prevention of pre-eclampsia, self-monitoring of blood pressures at home in the latter half of pregnancy and the signs and symptoms of pre-eclampsia, proteinuria evolution in pregnancy, renal function prognosis, and restarting ACE inhibitors when breast feeding in the post-partum period.

  18. The Canadian Arctic Atmospheric Chemistry Experiment (ACE) Validation Project: Overview and results from ten years of ACE operations

    NASA Astrophysics Data System (ADS)

    Walker, Kaley; Strong, Kimberly

    2014-05-01

    As of February 2014, the Canadian-led Atmospheric Chemistry Experiment (ACE) satellite mission has been making measurements of the Earth's atmosphere for ten years. As ACE operations have extended beyond the initial two-year mission, there is a continuing need to validate the trace gas data products from the ACE-Fourier Transform Spectrometer (ACE-FTS) and the Measurement of Aerosol Extinction in the Stratosphere and Troposphere Retrieved by Occultation (ACE-MAESTRO) instruments. Ground-based measurements provide critical data for the validation of satellite retrievals of trace gases and for the assessment of long-term stability of these measurements. In particular, validation comparisons are needed for ACE during Arctic springtime to understand better the measurements of species involved in stratospheric ozone chemistry. To this end, eleven Canadian Arctic Atmospheric Chemistry Experiment (ACE) Validation Campaigns have been conducted during the spring period (February - April in 2004 - 2014) at the Polar Environment Atmospheric Research Laboratory (PEARL) in Eureka, Nunavut (80°N, 86°W). This period coincides with the most chemically active time of year in the Arctic, as well as a significant number of satellite overpasses. A suite of as many as 12 ground-based instruments, as well as frequent balloon-borne ozonesonde and radiosonde launches, have been used in each campaign. These instruments include: a ground-based version of the ACE-FTS (PARIS - Portable Atmospheric Research Interferometric Spectrometer), a terrestrial version of the ACE-MAESTRO, a SunPhotoSpectrometer, two zenith-viewing UV-visible grating spectrometers, a Bomem DA8 Fourier transform spectrometer, a Bruker 125HR Fourier transform spectrometer, a Systeme d'Analyse par Observations Zenithales (SAOZ) instrument, and several Brewer spectrophotometers. In the past several years, these results have been used to validate the measurements by the ACE-FTS and ACE-MAESTRO instruments on SCISAT as well

  19. The solar array is installed on ACE in SAEF-2

    NASA Technical Reports Server (NTRS)

    1997-01-01

    Applied Physics Laboratory Engineer Cliff Willey (kneeling) and Engineering Assistant Jim Hutcheson from Johns Hopkins University install solar array panels on the Advanced Composition Explorer (ACE) in KSC's Spacecraft Assembly and Encapsulation Facility-II. Scheduled for launch on a Delta II rocket from Cape Canaveral Air Station on Aug. 25, ACE will study low-energy particles of solar origin and high-energy galactic particles for a better understanding of the formation and evolution of the solar system as well as the astrophysical processes involved. The ACE observatory will be placed into an orbit almost a million miles (1.5 million kilometers) away from the Earth, about 1/100 the distance from the Earth to the Sun. The collecting power of instrumentation aboard ACE is at least 100 times more sensitive than anything previously flown to collect similar data by NASA.

  20. The solar array is installed on ACE in SAEF-2

    NASA Technical Reports Server (NTRS)

    1997-01-01

    Applied Physics Laboratory engineers and technicians from Johns Hopkins University assist in guiding the Advanced Composition Explorer (ACE) as it is hoisted over a platform for solar array installation in KSC's Spacecraft Assembly and Encapsulation Facility-II. Scheduled for launch on a Delta II rocket from Cape Canaveral Air Station on Aug. 25, ACE will study low-energy particles of solar origin and high-energy galactic particles. The ACE observatory will contribute to the understanding of the formation and evolution of the solar system as well as the astrophysical processes involved. The collecting power of instruments aboard ACE is 10 to 1,000 times greater than anything previously flown to collect similar data by NASA.

  1. Dasatinib synergizes with both cytotoxic and signal transduction inhibitors in heterogeneous breast cancer cell lines--lessons for design of combination targeted therapy.

    PubMed

    Park, Brian J; Whichard, Zakary L; Corey, Seth J

    2012-07-01

    Molecularly targeted therapies have emerged as the leading theme in cancer therapeutics. Multi-cytotoxic drug regimens have been highly successful, yet many studies in targeted therapeutics have centered on a single agent. We investigated whether the Src/Abl kinase inhibitor dasatinib displays synergy with other agents in molecularly heterogeneous breast cancer cell lines. MCF-7, SKBR-3, and MDA-MB-231 display different signaling and gene signatures profiles due to expression of the estrogen receptor, ErbB2, or neither. Cell proliferation was measured following treatment with dasatinib±cytotoxic (paclitaxel, ixabepilone) or molecularly targeted agents (tamoxifen, rapamycin, sorafenib, pan PI3K inhibitor LY294002, and MEK/ERK inhibitor U0126). Dose-responses for single or combination drugs were calculated and analyzed by the Chou-Talalay method. The drugs with the greatest level of synergy with dasatinib were rapamycin, ixabepilone, and sorafenib, for the MDA-MB-231, MCF-7, and SK-BR-3 cell lines respectively. However, dasatinib synergized with both cytotoxic and molecularly targeted agents in all three molecularly heterogeneous breast cancer cell lines. These results suggest that effectiveness of rationally designed therapies may not entirely rest on precise identification of gene signatures or molecular profiling. Since a systems analysis that reveals emergent properties cannot be easily performed for each cancer case, multi-drug regimens in the near future will still involve empirical design.

  2. 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.

    PubMed

    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.

  3. Aircraft Command in Emergency Situations (ACES). Phase 1. Concept. Development

    DTIC Science & Technology

    1991-04-01

    63 6-3 Schematic Layout of the York Fiber- Optic DTS System... optic thermal detection system. XS Federal Aviation Administration Aircraft Command in Emergency Situations (ACES) Final Report II N ’(0) 1 ( .i...fiber optic (York) 2.1 (OBECTIVES OF STUDY S;ivo n Imoli.0it ,moke, fire emergency: The oh1cctivc tf the ACES study was to develop two system concepts

  4. XPO1 inhibitor combination therapy with bortezomib or carfilzomib induces nuclear localization of IκBα and overcomes acquired proteasome inhibitor resistance in human multiple myeloma.

    PubMed

    Turner, Joel G; Kashyap, Trinayan; Dawson, Jana L; Gomez, Juan; Bauer, Alexis A; Grant, Steven; Dai, Yun; Shain, Kenneth H; Meads, Mark; Landesman, Yosef; Sullivan, Daniel M

    2016-11-29

    Acquired proteasome-inhibitor (PI) resistance is a major obstacle in the treatment of multiple myeloma (MM). We investigated whether the clinical XPO1-inhibitor selinexor, when combined with bortezomib or carfilzomib, could overcome acquired resistance in MM. PI-resistant myeloma cell lines both in vitro and in vivo and refractory myeloma patient biopsies were treated with selinexor/bortezomib or carfilzomib and assayed for apoptosis. Mechanistic studies included NFκB pathway protein expression assays, immunofluorescence microscopy, ImageStream flow-cytometry, and proximity-ligation assays. IκBα knockdown and NFκB activity were measured in selinexor/bortezomib-treated MM cells. We found that selinexor restored sensitivity of PI-resistant MM to bortezomib and carfilzomib. Selinexor/bortezomib treatment inhibited PI-resistant MM tumor growth and increased survival in mice. Myeloma cells from PI-refractory MM patients were sensitized by selinexor to bortezomib and carfilzomib without affecting non-myeloma cells. Immunofluorescence microscopy, Western blot, and ImageStream analyses of MM cells showed increases in total and nuclear IκBα by selinexor/bortezomib. Proximity ligation found increased IκBα-NFκB complexes in treated MM cells. IκBα knockdown abrogated selinexor/bortezomib-induced cytotoxicity in MM cells. Selinexor/bortezomib treatment decreased NFκB transcriptional activity. Selinexor, when used with bortezomib or carfilzomib, has the potential to overcome PI drug resistance in MM. Sensitization may be due to inactivation of the NFκB pathway by IκBα.

  5. Malaria in HIV-Infected Children Receiving HIV Protease-Inhibitor- Compared with Non-Nucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy, IMPAACT P1068s, Substudy to P1060

    PubMed Central

    Hobbs, Charlotte V.; Gabriel, Erin E.; Kamthunzi, Portia; Tegha, Gerald; Tauzie, Jean; Petzold, Elizabeth; Barlow-Mosha, Linda; Chi, Benjamin H.; Li, Yonghua; Ilmet, Tiina; Kirmse, Brian; Neal, Jillian; Parikh, Sunil; Deygoo, Nagamah; Jean Philippe, Patrick; Mofenson, Lynne; Prescott, William; Chen, Jingyang; Musoke, Philippa; Palumbo, Paul; Duffy, Patrick E.; Borkowsky, William

    2016-01-01

    Background HIV and malaria geographically overlap. HIV protease inhibitors kill malaria parasites in vitro and in vivo, but further evaluation in clinical studies is needed. Methods Thirty-one children from Malawi aged 4–62 months were followed every 3 months and at intercurrent illness visits for ≤47 months (September 2009-December 2011). We compared malaria parasite carriage by blood smear microscopy (BS) and confirmed clinical malaria incidence (CCM, or positive BS with malaria symptoms) in children initiated on HIV antiretroviral therapy (ART) with zidovudine, lamivudine, and either nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor, or lopinavir-ritonavir (LPV-rtv), a protease inhibitor. Results We found an association between increased time to recurrent positive BS, but not CCM, when anti-malarial treatment and LPV-rtv based ART were used concurrently and when accounting for a LPV-rtv and antimalarial treatment interaction (adjusted HR 0.39; 95% CI (0.17,0.89); p = 0.03). Conclusions LPV-rtv in combination with malaria treatment was associated with lower risk of recurrent positive BS, but not CCM, in HIV-infected children. Larger, randomized studies are needed to confirm these findings which may permit ART optimization for malaria-endemic settings. Trial Registration ClinicalTrials.gov NCT00719602 PMID:27936233

  6. The Louisiana ACES Student-built BalloonSat Program

    NASA Astrophysics Data System (ADS)

    Ellison, B.; Giammanco, J.; Guzik, T. G.; Johnson, K.; Wefel, J. P.

    The Aerospace Catalyst Experiences for Students (ACES) pilot project was funded at Louisiana State University by NASA's National Space Grant College and Fellowship program during the 2002-2003 academic year with the primary goal of giving students a true hands-on experience with project management, life-cycle, experiment construction, data collection, analysis and interpretation. In this project students design, build, fly and analyze the data returned from small payloads (typical dimensions 10 cm x 10 cm x 10 cm, typical weight ˜ 500 grams) carried up to ˜ 100,000 feet by a helium-filled latex sounding balloon. During the pilot project the 13 students that participated in the program, grouped in 4 teams, built payloads that included studies in atmospheric science, cosmic rays and remote sensing. These payloads were then launched from the NASA National Scientific Balloon Facility in Palestine, Texas on May 21, 2003. Most recently, the LaACES (Louisiana ACES) program has been selected for funding by NASA. During LaACES we will expand the pilot program to institutions across the state including developing student training materials, holding a workshop for institution representatives, awarding payload development grants to student teams, monitoring the progress of these teams and supporting the balloon flight of the completed payloads. Here we describe the ACES pilot, the outcomes, and plans for La ACES.

  7. Progressive Resistance to a Selective Serotonin Reuptake Inhibitor but Not to Cognitive Therapy in the Treatment of Major Depression

    ERIC Educational Resources Information Center

    Leykin, Yan; Amsterdam, Jay D.; DeRubeis, Robert J.; Gallop, Robert; Shelton, Richard C.; Hollon, Steven D.

    2007-01-01

    Recent research suggests that there may be a reduction in therapeutic response after multiple administrations of antidepressant drug (AD) therapy in patients with major depressive disorder. This study assessed the response to AD therapy and cognitive therapy (CT) of patients with a history of prior AD exposures. A sample of 240 patients with…

  8. Long-term Combination Therapy With α-Blockers and 5α-Reductase Inhibitors in Benign Prostatic Hyperplasia: Patient Adherence and Causes of Withdrawal From Medication

    PubMed Central

    2016-01-01

    Purpose To investigate long-term therapeutic effects and patient adherence to a combination therapy of a 5α-reductase inhibitor and an α-blocker and to identify causes of withdrawal from medication in patients with clinical benign prostatic hyperplasia (BPH). Methods BPH patients with lower urinary tract symptoms (LUTS) receiving combination therapy with follow-ups for 1–12 years were retrospectively analyzed. Therapeutic effects were assessed at baseline and annually by measuring International Prostatic Symptoms Score, quality of life index, total prostate volume (TPV), maximal flow rate, voided volume, postvoid residual volume and prostate-specific antigen level. Causes of discontinued combination therapy were also investigated. Results A total of 625 patients, aged 40–97 years (mean, 73 years) were retrospectively analyzed. All measured parameters showed significant improvements after combination therapy. Three hundred sixty-nine patients (59%) discontinued combination therapy with a mean treatment duration of 2.2 years. The most common reasons for discontinued treatment were changing medication to monotherapy with α-blockers or antimuscarinics (124 patients, 19.8%), receiving surgical intervention (39 patients, 6.2%), and LUTS improvement (53 patients, 8.5%). Only 64 patients (10.2%) were loss to follow-up and 6 (1.0%) discontinued combined treatment due to adverse effects. Smaller TPV after short-term combination treatment caused withdrawal from combination therapy. Conclusions BPH patients receiving long-term combination therapy showed significant improvement in all measured parameters. Changing medication, improved LUTS and choosing surgery are common reasons for discontinuing combination herapy. A smaller TPV after short-term combination treatment was among the factors that caused withdrawal from combination therapy. PMID:28043104

  9. Comparative safety of BRAF and MEK inhibitors (vemurafenib, dabrafenib and trametinib) in first-line therapy for BRAF-mutated metastatic melanoma

    PubMed Central

    Cebollero, Ana; Puértolas, Teresa; Pajares, Isabel; Calera, Lourdes; Antón, Antonio

    2016-01-01

    A retrospective observational study was conducted on patients diagnosed with serine/threonine-protein kinase B-Raf (BRAF)-mutated metastatic melanoma, who underwent first-line therapy with BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors (vemurafenib, dabrafenib or a combination of dabrafenib and trametinib) at the Miguel Servet University Hospital (Zaragoza, Spain) between November, 2011 and August, 2015. The aim of this study was to analyse the toxicity produced by BRAF and MEK inhibitors. The most common toxicities were similar to those published in clinical trials, particularly arthralgia, alopecia and photosensitivity in the vemurafenib group; asthenia, hyperkeratosis and dry skin in the dabrafenib group; and diarrhoea and dry skin in the dabrafenib plus trametinib group. Toxicities that had not been described in clinical trials were also identified. Thus, the present study confirmed that the results obtained in clinical trials are similar to those obtained in clinical practice. PMID:27699043

  10. Efficacy of non-nucleoside reverse transcriptase inhibitor-based highly active antiretroviral therapy in Thai HIV-infected children aged two years or less.

    PubMed

    Puthanakit, Thanyawee; Aurpibul, Linda; Sirisanthana, Thira; Sirisanthana, Virat

    2009-03-01

    Twenty-six Thai HIV-infected children, aged 2 years or less were prospectively enrolled to receive non-nucleoside reverse transcription inhibitor-based highly active antiretroviral therapy (HAART). Twenty-two children (85%) had World Health Organization clinical stage 3 or 4. The median baseline CD4 cell percentage and plasma HIV RNA were 17% and 5.9 log 10 copies/mL, respectively. The median age at HAART initiation was 9.8 months (range, 1.5-24.0). One child died. The mean CD4 cell percentages at 24, 48, and 96 weeks of treatment were 26%, 31%, and 37%, respectively. The proportions of children with virologic suppression (<400 copies/mL) at week 24 and 48 were 14/26 (54%) and 19/26 (73%), respectively. Non-nucleoside reverse transcription inhibitor-based HAART is safe and effective in HIV-infected young children in a resource-limited setting.

  11. Molecular and recombinational mapping of mutations in the Ace locus of Drosophila melanogaster

    SciTech Connect

    Nagoshi, R.N.; Gelbart, W.M.

    1987-11-01

    The Ace locus in Drosophila melanogaster is known to be the structural gene for acetylcholinesterase. Ace is located in a region of chromosome arm 3R which has been subjected to intensive genetic and molecular analysis. Previous deletion mapping studies have identified a 40-kb region with which the Ace gene resides. This report focuses on the further localization of Ace within this 40-kb interval. Within this region, selective fine structure recombinational analysis was employed to localize three recessive Ace lethals relative to unselected restriction site variations. These three mutations fall into a segment of 7 kb within the Ace interval. Fine structure recombinational analysis was also used to confirm that the Ace/sup -/ phenotype of one deletion, Df(3R)Ace/sup HD1/, co-segregated with the molecular deletion. This deletion does not fully remove Ace activity, but it behaves as a recessive Ace lethal. Df(3R)Ace/sup HD1/ is the most distal Ace lesion identified and indicates that the Ace locus must extend at least 16 kb. Several poly(A)transcripts are detectable in the region defined by the Ace lesions. The position and extent of the Ace locus, as well as the types of transcripts found, is consistent with the recent findings which identified Torpedo-AChE homologous cDNA sequences in this region.

  12. Molecular and Recombinational Mapping of Mutations in the Ace Locus of Drosophila melanogaster

    PubMed Central

    Nagoshi, Rodney N.; Gelbart, William M.

    1987-01-01

    The Ace locus in Drosophila melanogaster is known to be the structural gene for acetylcholinesterase. Ace is located in a region of chromosome arm 3R which has been subjected to intensive genetic and molecular analysis. Previous deletion mapping studies have identified a 40-kb region within which the Ace gene resides. This report focuses on the further localization of Ace within this 40-kb interval. Within this region, selective fine structure recombinational analysis was employed to localize three recessive Ace lethals relative to unselected restriction site variations. These three mutations fall into a segment of 7 kb within the Ace interval. Fine structure recombinational analysis was also used to confirm that the Ace- phenotype of one deletion, Df(3R)AceHD1, co-segregated with the molecular deletion. This deletion does not fully remove Ace activity, but it behaves as a recessive Ace lethal. Df(3R)AceHD1 is the most distal Ace lesion identified and indicates that the Ace locus must extend at least 16 kb. Several poly(A)transcripts are detectable in the region defined by the Ace lesions. The position and extent of the Ace locus, as well as the types of transcripts found, is consistent with the recent findings which identified Torpedo-AChE homologous cDNA sequences in this region. PMID:2826288

  13. XPO1 inhibitor combination therapy with bortezomib or carfilzomib induces nuclear localization of IκBα and overcomes acquired proteasome inhibitor resistance in human multiple myeloma

    PubMed Central

    Turner, Joel G.; Kashyap, Trinayan; Dawson, Jana L.; Gomez, Juan; Bauer, Alexis A.; Grant, Steven; Dai, Yun; Shain, Kenneth H.; Meads, Mark; Landesman, Yosef; Sullivan, Daniel M.

    2016-01-01

    Acquired proteasome-inhibitor (PI) resistance is a major obstacle in the treatment of multiple myeloma (MM). We investigated whether the clinical XPO1-inhibitor selinexor, when combined with bortezomib or carfilzomib, could overcome acquired resistance in MM. PI-resistant myeloma cell lines both in vitro and in vivo and refractory myeloma patient biopsies were treated with selinexor/bortezomib or carfilzomib and assayed for apoptosis. Mechanistic studies included NFκB pathway protein expression assays, immunofluorescence microscopy, ImageStream flow-cytometry, and proximity-ligation assays. IκBα knockdown and NFκB activity were measured in selinexor/bortezomib-treated MM cells. We found that selinexor restored sensitivity of PI-resistant MM to bortezomib and carfilzomib. Selinexor/bortezomib treatment inhibited PI-resistant MM tumor growth and increased survival in mice. Myeloma cells from PI-refractory MM patients were sensitized by selinexor to bortezomib and carfilzomib without affecting non-myeloma cells. Immunofluorescence microscopy, Western blot, and ImageStream analyses of MM cells showed increases in total and nuclear IκBα by selinexor/bortezomib. Proximity ligation found increased IκBα-NFκB complexes in treated MM cells. IκBα knockdown abrogated selinexor/bortezomib-induced cytotoxicity in MM cells. Selinexor/bortezomib treatment decreased NFκB transcriptional activity. Selinexor, when used with bortezomib or carfilzomib, has the potential to overcome PI drug resistance in MM. Sensitization may be due to inactivation of the NFκB pathway by IκBα. PMID:27806331

  14. Addition of an Indoleamine-2,3,-dioxygenase Inhibitor to B cell Depletion Therapy Blocks Autoreactive B Cell Activation and Recurrence of Arthritis

    PubMed Central

    Pigott, Elizabeth; Mandik-Nayak, Laura

    2012-01-01

    Objective Define the role indoleamine-2,3-dioxygenase (IDO) plays in driving pathogenic B cells responses leading to arthritis and determine if inhibitors of the IDO pathway can be used in conjunction with B cell depletion therapy to prevent the re-emergence of autoantibodies and arthritis following reconstitution of the B cell repertoire. Methods Immunoglobulin transgenic mice were treated with the IDO inhibitor 1-methyl-tryptophan (1MT) and followed for the extent of autoreactive B cell activation. Arthritic mice (K/BxN) were treated with B cell depletion therapy alone or in combination with 1MT. Mice were followed for the presence of autoantibody secreting cells, inflammatory cytokines, and joint inflammation. Results 1MT did not affect the initial activation or survival of autoreactive B cells, but did inhibit their ability to differentiate into autoantibody secreting cells. Treatment with anti-CD20 depleted the B cell repertoire and attenuated arthritis symptoms; however, arthritis symptoms rapidly returned as B cells repopulated the repertoire. Administration of 1MT prior to B cell repopulation prevented the production of autoantibodies, inflammatory cytokines, and flare in arthritis symptoms. Conclusion IDO activity is essential for the differentiation of autoreactive B cells into antibody secreting cells, but is not necessary for their initial stages of activation. Addition of 1MT to B cell depletion therapy prevents the differentiation of autoantibody secreting cells and recurrence of autoimmune arthritis following reconstitution of the B cell repertoire. These data suggest that IDO inhibitors could be used in conjunction with B cell depletion as an effective co-therapeutic strategy in the treatment of rheumatoid arthritis. PMID:22294267

  15. Durable response of glioblastoma to adjuvant therapy consisting of temozolomide and a weekly dose of AMD3100 (plerixafor), a CXCR4 inhibitor, together with lapatinib, metformin and niacinamide

    PubMed Central

    Rios, Adan; Hsu, Sigmund H.; Blanco, Angel; Buryanek, Jamie; Day, Arthur L.; McGuire, Mary F.; Brown, Robert E.

    2016-01-01

    Glioblastoma multiforme (GBM) is a CNS (central nervous system) malignancy with a low cure rate. Median time to progression after standard treatment is 7 months and median overall survival is 15 months [1]. Post-treatment vasculogenesis promoted by recruitment of bone marrow derived cells (BMDCs, CD11b+ myelomonocytes) is one of main mechanisms of GBM resistance to initial chemoradiotherapy treatment [2]. Local secretion of SDF-1, cognate ligand of BMDCs CXCR4 receptors attracts BMDCs to the post-radiation tumor site.[3]. This SDF-1 hypoxia-dependent effect can be blocked by AMD3100 (plerixafor) [4]. We report a GBM case treated after chemo- radiotherapy with plerixafor and a combination of an mTOR, a Sirt1 and an EGFRvIII inhibitor. After one year temozolomide and the EGFRvIII inhibitor were stopped. Plerixafor, and the MTOR and Sirt-1 inhibitors were continued. He is in clinical and radiologic remission 30 months from the initiation of his adjuvant treatment. To our knowledge, this is the first report of a patient treated for over two years with a CXCR4 inhibitor (plerixafor), as part of his adjuvant treatment. We believe there is sufficient experimental evidence to consider AMD3100 (plerixafor) part of the adjuvant treatment of GBM. Significance The adjuvant inhibition of GBM vasculogenesis(a process different from local angiogenesis) by specifically blocking the migration of BMDCs to the primary tumor site with inhibitors of the CXCR4/SDF-1 axis represents a potential novel therapeutic approach to GBM. There is significant pre-clinical evidence and validation for its use as demonstrated in a patient derived tumor xenograft model of GBM. Together with other specific anti-tumoral therapies, the active inhibition of vasculogenesis in the adjuvant treatment of GBM is deserving of further exploration. PMID:27489862

  16. Dolutegravir Plus Two Nucleoside Reverse Transcriptase Inhibitors versus Efavirenz Plus Two Nucleoside Reverse Transcriptase Inhibitors As Initial Antiretroviral Therapy for People with HIV: A Systematic Review

    PubMed Central

    Rutherford, George W.; Horvath, Hacsi

    2016-01-01

    Background Dolutegravir (DTG) is a once-daily unboosted second-generation integrase-inhibitor that along with two nucleoside reverse transcriptase inhibitors is one of several regimens recommended by the United States, United Kingdom and European Union for first-line antiretroviral treatment of people with HIV infection. Our objective was to review the evidence for the efficacy and safety of DTG-based first-line regimens compared to efavirenz (EFV)-based regimens. Methods We conducted a systematic review. We comprehensively searched a range of databases as well as conference abstracts and a trials registry. We used Cochrane methods in screening and data collection and assessed each study’s risk of bias with the Cochrane tool. We meta-analyzed data using a fixed-effects model. We used GRADE to assess evidence quality. Results From 492 search results, we identified two randomized controlled trials, reported in five peer-reviewed articles and one conference abstract. One trial tested two DTG-based regimens (DTG + abacavir (ABC) + lamivudine (3TC) or DTG + tenofovir + emtricitabine) against an EFV-based regimen (EFV+ ABC+3TC). The other trial tested DTG+ABC+3TC against EFV+ABC+3TC. In meta-analysis, DTG-containing regimens were superior to EFV-containing regimens at 48 weeks and at 96 weeks (RR = 1.10, 95% CI 1.04–1.16; and RR = 1.12, 95% CI 1.04–1.21, respectively). In one trial, the DTG-containing regimen was superior at 144 weeks (RR = 1.13, 95% CI 1.02–1.24). DTG-containing regimens were superior in reducing treatment discontinuation compared to those containing EFV at 96 weeks and at 144 weeks (RR = 0.27, 95% CI 0.15–0.50; and RR = 0.28, 95% CI 0.16–0.48, respectively). Risk of serious adverse events was similar in each regimen at 96 weeks (RR = 1.15, 95% CI 0.80–1.63) and 144 weeks (RR = 0.93, 95% CI 0.68–1.29). Risk of bias was moderate overall, as was GRADE evidence quality. Conclusions DTG-based regimens should be considered in future World

  17. Molecular Profiling of Prostate Cancer to Determine Predictive Markers of Response to Radiation and Receptor Tyrosine Kinase Inhibitor Therapy

    DTIC Science & Technology

    2006-09-01

    therapy of anaplastic thyroid carcinoma with AEE788. Mol Cancer Ther 2005;4:632-640. 28. Goudar RK, Shi Q, Hjelmeland MD, et al. Combination therapy of...antiangiogenic activity. Cancer Res 2004;64:4931-4941. 30. Younes MN, Yigitbasi OG, Park YW, et al. Antivascular therapy of human follicular thyroid cancer...decreased proliferation. A & A.1. Tumor blood flow assessment was performed using Doppler ultrasonography at day 5 following indicated treatments. Doses for

  18. Investigating the selectivity of metalloenzyme inhibitors.

    PubMed

    Day, Joshua A; Cohen, Seth M

    2013-10-24

    The inhibitory activity of a broad group of known metalloenzyme inhibitors against a panel of metalloenzymes was evaluated. Clinically approved inhibitors were selected as well as several other reported metalloprotein inhibitors in order to represent a broad range of metal binding groups (MBGs), including hydroxamic acid, carboxylate, hydroxypyridinonate, thiol, and N-hydroxyurea functional groups. A panel of metalloenzymes, including carbonic anhydrase (hCAII), several matrix metalloproteinases (MMPs), angiotensin converting enzyme (ACE), histone deacetylase (HDAC-2), and tyrosinase (TY), was selected based on their clinical importance for a range of pathologies. In addition, each inhibitor was evaluated for its ability to remove Fe(3+) from holo-transferrin to gauge the ability of the inhibitors to access Fe(3+) from a primary transport protein. The results show that the metalloenzyme inhibitors are quite selective for their intended targets, suggesting that despite their ability to bind metal ions, metalloprotein inhibitors are not prone to widespread off-target enzyme inhibition activity.

  19. Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy.

    PubMed

    Leverson, Joel D; Phillips, Darren C; Mitten, Michael J; Boghaert, Erwin R; Diaz, Dolores; Tahir, Stephen K; Belmont, Lisa D; Nimmer, Paul; Xiao, Yu; Ma, Xiaoju Max; Lowes, Kym N; Kovar, Peter; Chen, Jun; Jin, Sha; Smith, Morey; Xue, John; Zhang, Haichao; Oleksijew, Anatol; Magoc, Terrance J; Vaidya, Kedar S; Albert, Daniel H; Tarrant, Jacqueline M; La, Nghi; Wang, Le; Tao, Zhi-Fu; Wendt, Michael D; Sampath, Deepak; Rosenberg, Saul H; Tse, Chris; Huang, David C S; Fairbrother, Wayne J; Elmore, Steven W; Souers, Andrew J

    2015-03-18

    The BCL-2/BCL-XL/BCL-W inhibitor ABT-263 (navitoclax) has shown promising clinical activity in lymphoid malignancies such as chronic lymphocytic leukemia. However, its efficacy in these settings is limited by thrombocytopenia caused by BCL-XL inhibition. This prompted the generation of the BCL-2-selective inhibitor venetoclax (ABT-199/GDC-0199), which demonstrates robust activity in these cancers but spares platelets. Navitoclax has also been shown to enhance the efficacy of docetaxel in preclinical models of solid tumors, but clinical use of this combination has been limited by neutropenia. We used venetoclax and the BCL-XL-selective inhibitors A-1155463 and A-1331852 to assess the relative contributions of inhibiting BCL-2 or BCL-XL to the efficacy and toxicity of the navitoclax-docetaxel combination. Selective BCL-2 inhibition suppressed granulopoiesis in vitro and in vivo, potentially accounting for the exacerbated neutropenia observed when navitoclax was combined with docetaxel clinically. By contrast, selectively inhibiting BCL-XL did not suppress granulopoiesis but was highly efficacious in combination with docetaxel when tested against a range of solid tumors. Therefore, BCL-XL-selective inhibitors have the potential to enhance the efficacy of docetaxel in solid tumors and avoid the exacerbation of neutropenia observed with navitoclax. These studies demonstrate the translational utility of this toolkit of selective BCL-2 family inhibitors and highlight their potential as improved cancer therapeutics.

  20. Impact of combination therapy on managed care. Based on a presentation by Lisa Latts, MD, MSPH.

    PubMed

    1999-06-01

    The major objectives of managed care are particularly applicable to hypertension, a very common disease that affects about 30% of the adult population. Although managed care organizations know that adequate blood pressure control has a considerable impact on reducing hypertension-related morbidity and mortality, managed care is, at present, doing a generally poor job of monitoring antihypertensive therapy. One of the major reasons for this is the difficulty in gathering the necessary data from administrative sources; only chart review, which is very costly and very time consuming, can provide the data needed. The value of disease management lies in its capacity to optimize clinical and economic outcomes as well as to improve service and quality of life, using inputs such as cost, time, clinical resources, and patient satisfaction. Disease management programs are instituted because they can lead to improved quality of life and reduced costs. While the focus in managed care has traditionally been on promoting risk modification behavior, providing patient education, and encouraging medication compliance, the treatment of hypertension itself has not been a major focus in most disease management programs. Measuring the effectiveness of the hypertension treatment is, however, one of the proposed measures for the Health Plan Employer Data and Information Set (HEDIS 2000) to profile health plan quality. From a managed care perspective, the potential benefits of combination therapy for hypertension include improved blood pressure control and improved patient compliance as a result of needing fewer pills and experiencing fewer side effects with low-dose therapy. Among the obstacles to combination therapy in the managed care setting are the addition of the combinations onto a formulary and lack of acceptance among physicians. Fixed-dose combination therapy with a calcium channel blocker and an angiotensin-converting enzyme (ACE) inhibitor can potentially reduce pharmacy costs

  1. [Benefit of L-DOPA-without-DCI (decarboxylase inhibitor) therapy on wearing-off phenomenon in advanced stages of Parkinson's disease patients].

    PubMed

    Hironishi, Masaya; Miwa, Hideto; Kondo, Tomoyoshi

    2002-02-01

    Motor fluctuation is the most annoying complication experienced by patients in the advanced stages of Parkinson's disease. A Combination therapy of a dopamine receptor agonist and levodopa/DCI(DOPA-decarboxylase inhibitor) is commonly used to control the complication. Although administration of levodopa/DCI is useful in minimizing peripheral side effects of levodopa, it increases the incidence of motor complications due to the marked fluctuation of plasma levodopa level. The use of levodopa without DCI might be an option for controlling motor fluctuation, because the extent of plasma levodopa level fluctuation is smaller when levodopa is administered without DCI than with DCI. Six patients with Parkinson's disease who had troublesome motor complications under levodopa/DCI and DA agonist combination therapy were compared in terms of the extent of motor complications and their satisfaction after changing their therapy from levodopa/DCI to levodopa without DCI. The change from levodopa/DCI to levodopa(without DCI) was carried out all at once, and the levodopa/DCI to levodopa dose ratio was started at 1:4. The dose of levodopa(without DCI) was then increased gradually until motor complications improved or side effects were observed in patients. Except two patients who voluntarily quitted levodopa and restarted DOPA/DCI before the dose of levodopa fixed, all cases showed improvement of wearing-off phenomenon. No adverse event was observed. Levodopa-without-DCI-therapy was effective for controlling motor fluctuation in patients of Parkinson's disease in advanced stages.

  2. Cost and burden of gastroesophageal reflux disease among patients with persistent symptoms despite proton pump inhibitor therapy: an observational study in France

    PubMed Central

    2013-01-01

    Background Gastrointestinal reflux disease (GERD) is a common disorder that negatively impacts health-related quality of life (HRQL) and work productivity. Many patients have only a partial response to proton pump inhibitor (PPI) therapy and continue to experience GERD symptoms despite optimized treatment. This observational study aimed to provide information on symptoms, HRQL, resource usage, costs and treatment pathways associated with partial response to PPI therapy in French patients with GERD. Methods Patients with partial response to PPI therapy, defined as persistent GERD symptoms ≥3 days/week despite optimized treatment with a PPI, were recruited for this 12-month observational study. GERD symptoms, HRQL, work productivity and resource use were assessed by patient surveys. Costs were calculated based on lost work productivity and resource use. Results The patient population (n=262; mean age, 54 years; 40% men) carried a significant symptom burden, with 98% of patients having moderate-to-severe GERD symptoms and 65% of patients experiencing daily symptoms at baseline. HRQL and work productivity were significantly impaired, with a greater degree of impairment in patients with higher symptom burden. The mean total cost per patient over the 12-month follow-up period was €5237, of which €4674 (89%) was due to lost work productivity. Conclusions Partial response to PPI therapy for GERD is associated with a high symptom burden, significant impairment of HRQL and work productivity, and substantial GERD-related costs. PMID:23448382

  3. Contemplating Synergistic Algorithms for the NASA ACE Mission

    NASA Technical Reports Server (NTRS)

    Mace, Gerald G.; Starr, David O.; Marchand, Roger; Ackerman, Steven A.; Platnick, Steven E.; Fridlind, Ann; Cooper, Steven; Vane, Deborah G.; Stephens, Graeme L.

    2013-01-01

    ACE is a proposed Tier 2 NASA Decadal Survey mission that will focus on clouds, aerosols, and precipitation as well as ocean ecosystems. The primary objective of the clouds component of this mission is to advance our ability to predict changes to the Earth's hydrological cycle and energy balance in response to climate forcings by generating observational constraints on future science questions, especially those associated with the effects of aerosol on clouds and precipitation. ACE will continue and extend the measurement heritage that began with the A-Train and that will continue through Earthcare. ACE planning efforts have identified several data streams that can contribute significantly to characterizing the properties of clouds and precipitation and the physical processes that force these properties. These include dual frequency Doppler radar, high spectral resolution lidar, polarimetric visible imagers, passive microwave and submillimeter wave radiometry. While all these data streams are technologically feasible, their total cost is substantial and likely prohibitive. It is, therefore, necessary to critically evaluate their contributions to the ACE science goals. We have begun developing algorithms to explore this trade space. Specifically, we will describe our early exploratory algorithms that take as input the set of potential ACE-like data streams and evaluate critically to what extent each data stream influences the error in a specific cloud quantity retrieval.

  4. The absence of intrarenal ACE protects against hypertension

    PubMed Central

    Gonzalez-Villalobos, Romer A.; Janjoulia, Tea; Fletcher, Nicholas K.; Giani, Jorge F.; Nguyen, Mien T.X.; Riquier-Brison, Anne D.; Seth, Dale M.; Fuchs, Sebastien; Eladari, Dominique; Picard, Nicolas; Bachmann, Sebastian; Delpire, Eric; Peti-Peterdi, Janos; Navar, L. Gabriel; Bernstein, Kenneth E.; McDonough, Alicia A.

    2013-01-01

    Activation of the intrarenal renin-angiotensin system (RAS) can elicit hypertension independently from the systemic RAS. However, the precise mechanisms by which intrarenal Ang II increases blood pressure have never been identified. To this end, we studied the responses of mice specifically lacking kidney angiotensin-converting enzyme (ACE) to experimental hypertension. Here, we show that the absence of kidney ACE substantially blunts the hypertension induced by Ang II infusion (a model of high serum Ang II) or by nitric oxide synthesis inhibition (a model of low serum Ang II). Moreover, the renal responses to high serum Ang II observed in wild-type mice, including intrarenal Ang II accumulation, sodium and water retention, and activation of ion transporters in the loop of Henle (NKCC2) and distal nephron (NCC, ENaC, and pendrin) as well as the transporter activating kinases SPAK and OSR1, were effectively prevented in mice that lack kidney ACE. These findings demonstrate that ACE metabolism plays a fundamental role in the responses of the kidney to hypertensive stimuli. In particular, renal ACE activity is required to increase local Ang II, to stimulate sodium transport in loop of Henle and the distal nephron, and to induce hypertension. PMID:23619363

  5. The absence of intrarenal ACE protects against hypertension.

    PubMed

    Gonzalez-Villalobos, Romer A; Janjoulia, Tea; Fletcher, Nicholas K; Giani, Jorge F; Nguyen, Mien T X; Riquier-Brison, Anne D; Seth, Dale M; Fuchs, Sebastien; Eladari, Dominique; Picard, Nicolas; Bachmann, Sebastian; Delpire, Eric; Peti-Peterdi, Janos; Navar, L Gabriel; Bernstein, Kenneth E; McDonough, Alicia A

    2013-05-01

    Activation of the intrarenal renin-angiotensin system (RAS) can elicit hypertension independently from the systemic RAS. However, the precise mechanisms by which intrarenal Ang II increases blood pressure have never been identified. To this end, we studied the responses of mice specifically lacking kidney angiotensin-converting enzyme (ACE) to experimental hypertension. Here, we show that the absence of kidney ACE substantially blunts the hypertension induced by Ang II infusion (a model of high serum Ang II) or by nitric oxide synthesis inhibition (a model of low serum Ang II). Moreover, the renal responses to high serum Ang II observed in wild-type mice, including intrarenal Ang II accumulation, sodium and water retention, and activation of ion transporters in the loop of Henle (NKCC2) and distal nephron (NCC, ENaC, and pendrin) as well as the transporter activating kinases SPAK and OSR1, were effectively prevented in mice that lack kidney ACE. These findings demonstrate that ACE metabolism plays a fundamental role in the responses of the kidney to hypertensive stimuli. In particular, renal ACE activity is required to increase local Ang II, to stimulate sodium transport in loop of Henle and the distal nephron, and to induce hypertension.

  6. Multiple duplications of the rare ace-1 mutation F290V in Culex pipiens natural populations.

    PubMed

    Alout, Haoués; Labbé, Pierrick; Berthomieu, Arnaud; Pasteur, Nicole; Weill, Mylène

    2009-12-01

    Two amino acid substitutions in acetylcholinesterase 1 (AChE1), G119S and F290V, are responsible for resistance to organophosphate and carbamate insecticides in Culex pipiens mosquitoes. These mutations generate very different levels of insensitivity to insecticide inhibitors. We described here a biochemical method that rapidly identifies AChE1 variants (susceptible, G119S and F290V, named S, R and V, respectively) present in individual mosquitoes. We investigated the frequency of AChE1 phenotypes in 41 field samples collected around the Mediterranean Sea. F290V substitution was found only in 15 samples and at low frequency, whereas G119S was highly spread in all samples. However, seven V distinct alleles were identified whereas only one R allele was present. The [V] enzymatic phenotype was never observed alone, and the V allele was always found associated with the susceptible and/or G119S AChE1 ([VS], [VR] or [VRS] phenotypes). Furthermore, we showed the presence of duplicated alleles, associating a susceptible and a V copy of the ace-1 gene, in most individuals analyzed for its presence. Evolutionary forces driving the large number of F290V ace-1 alleles and their low frequency in Mediterranean countries are discussed.

  7. A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer

    PubMed Central

    Munster, P N; Thurn, K T; Thomas, S; Raha, P; Lacevic, M; Miller, A; Melisko, M; Ismail-Khan, R; Rugo, H; Moasser, M; Minton, S E

    2011-01-01

    Background: Histone deacetylases (HDACs) are crucial components of the oestrogen receptor (ER) transcriptional complex. Preclinically, HDAC inhibitors can reverse tamoxifen/aromatase inhibitor resistance in hormone receptor-positive breast cancer. This concept was examined in a phase II combination trial with correlative end points. Methods: Patients with ER-positive metastatic breast cancer progressing on endocrine therapy were treated with 400 mg of vorinostat daily for 3 of 4 weeks and 20 mg tamoxifen daily, continuously. Histone acetylation and HDAC2 expression in peripheral blood mononuclear cells were also evaluated. Results: In all, 43 patients (median age 56 years (31–71)) were treated, 25 (58%) received prior adjuvant tamoxifen, 29 (67%) failed one prior chemotherapy regimen, 42 (98%) progressed after one, and 23 (54%) after two aromatase inhibitors. The objective response rate by Response Evaluation Criteria in Solid Tumours criteria was 19% and the clinical benefit rate (response or stable disease >24 weeks) was 40%. The median response duration was 10.3 months (confidence interval: 8.1–12.4). Histone hyperacetylation and higher baseline HDAC2 levels correlated with response. Conclusion: The combination of vorinostat and tamoxifen is well tolerated and exhibits encouraging activity in reversing hormone resistance. Correlative studies suggest that HDAC2 expression is a predictive marker and histone hyperacetylation is a useful pharmacodynamic marker for the efficacy of this combination. PMID:21559012

  8. Virtual screening, optimization, and identification of a novel specific PTP-MEG2 Inhibitor with potential therapy for T2DM

    PubMed Central

    Chen, Xiubo; Xu, Weiren; Wang, Runling

    2016-01-01

    Megakaryocyte protein tyrosine phosphatase 2 (PTP-MEG2) is a tyrosine phosphatase expressed in megakaryocytic cells, and causes insulin sensitization when down regulated. Therefore, specific inhibitors of PTP-MEG2 are potential candidates for novel Type 2 Diabetes (T2DM)therapy. In this study, we discovered PTP-MEG2 inhibitors using high throughput and virtual screening (HTS/VS) and structural optimization in silicon. Eight compound-candidates were identified from the interactions with PTP-MEG2, protein tyrosine phosphatase 1B (PTP1B) and T cell protein tyrosine phosphatase (TCPTP). Results from enzymatic assays show compounds 4a and 4b inhibited PTP-MEG2 activity with an IC50 of 3.2 μM and 4.3 μM, respectively. Further, they showed a 7.5 and 5.5 fold change against PTP1B and TCPTP, respectively. We propose compounds 4a and 4b are PTP-MEG2 inhibitors with potential therapeutic use in T2DM treatment. PMID:27384997

  9. Promising Diabetes Therapy Based on the Molecular Mechanism for Glucose Toxicity: Usefulness of SGLT2 Inhibitors as well as Incretin-Related Drugs.

    PubMed

    Kaneto, Hideaki; Obata, Atsushi; Shimoda, Masashi; Kimura, Tomohiko; Hirukawa, Hidenori; Okauchi, Seizo; Matsuoka,