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Sample records for enzyme inhibitor therapy

  1. Imminent angiotensin-converting enzyme inhibitor from microbial source for cancer therapy

    Directory of Open Access Journals (Sweden)

    Lida Ebrahimi

    2017-01-01

    Full Text Available Background: Drugs targeting Angiotensin I-converting enzyme (ACE have been used broadly in cancer chemotherapy. The recent past coupled with our results demonstrates the effective use of ACE inhibitors (ACEi as anticancer agents, and they are potentially relevant in deriving new inhibitors. Methods: Bacterial strains were isolated from cow milk collected in Coimbatore, Tamil Nadu, India and plated on nutrient agar medium. The identity of the strain was ascertained by 16s rRNA gene sequencing method and was submitted to the NCBI GenBank nucleotide database. Various substrates were screened for ACEi production by the fermentation with the isolated strain. ACEi was purified by sequential steps of ethanol precipitation, ion exchange column chromatography and gel filtration column chromatography. The apparent molecular mass was determined by SDS-PAGE. The anticancer property was analyzed by studying the cytotoxicity effects of ACEi using Breast cancer MCF-7 cell lines Results: The isolate coded as BUCTL09 was selected and identified as Micrococcus luteus. Among the seven substrates, only beef extract fermented broth showed an inhibition of 79% and was reported as the best substrate. The peptide was purified and molecular mass was determined. The IC50 value of peptide was found to be 59.5 μg/ ml. The purified peptide has demonstrated to induce apoptosis of cancer cell.Conclusions: The results of this study revealed that Peptide has been determined as an active compound that inhibited the activity of ACE. These properties indicate the possibilities of the use of purified protein as a potent anticancer agent.

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

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    MacLean Charles D

    2008-12-01

    Full Text Available Abstract Background Angiotensin converting enzyme inhibitors (ACE inhibitors reduce peripheral vascular resistance via blockage of angiotensin converting enzyme (ACE. ACE inhibitors are commonly used to treat congestive heart failure and high blood pressure, but other effects have been reported. In this study, we explored the association between ACE inhibitor therapy and the prevalence of comorbid conditions in adults with diabetes Methods We surveyed 1003 adults with diabetes randomly selected from community practices. Patients were interviewed at home and self-reported their personal and clinical characteristics including comorbidity. Current medications were obtained by direct observation of medication containers. We built logistic regression models with the history of comorbidities as the outcome variable and the current use of ACE inhibitors as the primary predictor variable. We adjusted for possible confounding by social (age, sex, alcohol drinking, cigarette smoking and clinical factors (systolic blood pressure, body mass index (BMI, glycosolated hemoglobin (A1C, number of comorbid conditions, and number of prescription medications. Results ACE users reported a history of any cancer (except the non-life-threatening skin cancers less frequently than non-users (10% vs. 15%; odd ratio = 0.59; 95% confidence interval [0.39, 0.89]; P = 0.01; and a history of stomach ulcers or peptic ulcer disease less frequently than non-users (12% vs. 16%, odd ratio = 0.70, [0.49, 1.01], P = 0.06. After correcting for potential confounders, ACE inhibitors remained significantly inversely associated with a personal history of cancer (odds ratio = 0.59, [0.39, 0.89]; P = 0.01 and peptic ulcer disease (odd ratio = 0.68, [0.46, 1.00], P = 0.05. Conclusion ACE inhibitor use is associated with a lower likelihood of a history of cancer and peptic ulcers in patients with diabetes. These findings are limited by the cross sectional study design, self-report of comorbid

  3. Positron emitter labeled enzyme inhibitors

    International Nuclear Information System (INIS)

    Fowler, J.S.; MacGregor, R.R.; Wolf, A.P.; Langstrom, B.

    1990-01-01

    This invention involves a new strategy for imagining and mapping enzyme activity in the living human and animal body using positron emitter-labeled suicide enzyme inactivators or inhibitors which become covalently bound to the enzyme as a result of enzymatic catalysis. Two such suicide inactivators for monoamine oxidase have been labeled with carbon-11 and used to map the enzyme subtypes in the living human and animal body using PET. By using positron emission tomography to image the distribution of radioactivity produced by the body penetrating radiation emitted by carbon-11, a map of functionally active monoamine oxidase activity is obtained. Clorgyline and L-deprenyl are suicide enzyme inhibitors and irreversibly inhibit monoamine oxidase. When these inhibitors are labeled with carbon-11 they provide selective probes for monoamine oxidase localization and reactivity in vivo using positron emission tomography

  4. Weight loss for reduction of proteinuria in diabetic nephropathy: Comparison with angiotensin-converting enzyme inhibitor therapy

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    M R Patil

    2013-01-01

    Full Text Available Reduction of weight in obese type 2 diabetes mellitus (T2DM individuals is emerging as a significant strategy in the reduction of proteinuria in diabetic nephropathy along with control of hyperglycemia, hypertension, and dyslipidemia. The objective was to evaluate the reduction in 24-h proteinuria in T2DM patients with nephropathy by weight loss, with conventional therapy (angiotensin-converting enzyme [ACE] inhibitors as the control arm. A prospective, randomized controlled trial was conducted between June 2010 and May 2011. T2DM patients with confirmed nephropathy by 24-h urinary protein estimation with a body mass index (BMI of >25 kg/m 2 were studied. Patients who had nondiabetic nephropathy, uncontrolled hypertension (>125/75 mmHg irrespective of antihypertensive drugs, excess weight due to edema or obesity due to other specific diseases, alcoholics, smokers, and patients who were on hemodialysis were excluded from the study. The patients were divided into three groups, namely, group A, patients on ACE inhibitor therapy; group B, patients on lifestyle modifications for weight loss; and group C, patients on an antiobesity drug (orlistat and lifestyle modifications. At the end of 6 months, all the three groups were compared. Data were analyzed using software SPSS version 15.0. This study encompassed a total of 88 patients; 12 patients were dropped during the study period and 76 (group A: 22, group B: 23, and group C: 31 patients remained. The mean age of the patients was 58.36 ± 10.87 years (range: 30-70 years. At baseline, age, gender, mean BMI, waist-to-hip ratio (WHR, and 24-h proteinuria did not vary significantly among the three groups. At 6 months, the mean BMI significantly decreased in group C ( P < 0.001 compared to that in the other two groups. Among the parameters BMI and WHR, the proportional form of BMI correlated well with the degree of reduction in proteinuria (r = 0.397, P = 0.01. Reduction in weight using lifestyle

  5. Targeted enzyme prodrug therapies.

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    Schellmann, N; Deckert, P M; Bachran, D; Fuchs, H; Bachran, C

    2010-09-01

    The cure of cancer is still a formidable challenge in medical science. Long-known modalities including surgery, chemotherapy and radiotherapy are successful in a number of cases; however, invasive, metastasized and inaccessible tumors still pose an unresolved and ongoing problem. Targeted therapies designed to locate, detect and specifically kill tumor cells have been developed in the past three decades as an alternative to treat troublesome cancers. Most of these therapies are either based on antibody-dependent cellular cytotoxicity, targeted delivery of cytotoxic drugs or tumor site-specific activation of prodrugs. The latter is a two-step procedure. In the first step, a selected enzyme is accumulated in the tumor by guiding the enzyme or its gene to the neoplastic cells. In the second step, a harmless prodrug is applied and specifically converted by this enzyme into a cytotoxic drug only at the tumor site. A number of targeting systems, enzymes and prodrugs were investigated and improved since the concept was first envisioned in 1974. This review presents a concise overview on the history and latest developments in targeted therapies for cancer treatment. We cover the relevant technologies such as antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT) as well as related therapies such as clostridial- (CDEPT) and polymer-directed enzyme prodrug therapy (PDEPT) with emphasis on prodrug-converting enzymes, prodrugs and drugs.

  6. Severe hepatic encephalopathy in a patient with liver cirrhosis after administration of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker combination therapy: a case report

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    Podda Mauro

    2010-05-01

    Full Text Available Abstract Introduction A combination therapy of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers has been used to control proteinuria, following initial demonstration of its efficacy. However, recently concerns about the safety of this therapy have emerged, prompting several authors to urge for caution in its use. In the following case report, we describe the occurrence of a serious and unexpected adverse drug reaction after administration of a combination of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers to a patient with nephrotic syndrome and liver cirrhosis with severe portal hypertension. Case presentation We administered this combination therapy to a 40-year-old Caucasian man with liver cirrhosis in our Hepatology Clinic, given the concomitant presence of glomerulopathy associated with severe proteinuria. While the administration of one single drug appeared to be well-tolerated, our patient developed severe acute encephalopathy after the addition of the second one. Discontinuation of the therapy led to the disappearance of the side-effect. A tentative rechallenge with the same drug combination led to a second episode of acute severe encephalopathy. Conclusion We speculate that this adverse reaction may be directly related to the effect of angiotensin II on the excretion of blood ammonia. Therefore, we suggest that patients with liver cirrhosis and portal hypertension are at risk of developing clinically relevant encephalopathy when angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker combination therapy is administered, thus indicating the need for a careful clinical follow-up. In addition, the incidence of this serious side-effect should be rigorously evaluated in all patients with liver cirrhosis administered with this common treatment combination.

  7. Enzyme structure and interaction with inhibitors

    International Nuclear Information System (INIS)

    London, R.E.

    1983-01-01

    This article reviews some of the results of studies on the 13 C-labeled enzyme dihydrofolate reductase (DHFR). Nuclear magnetic resonance (NMR) techniques are used in combination with isotopic labeling to learn about the structure and dynamics of this enzyme. 13 C-labeling is used for the purpose of studying enzyme/substrate and enzyme/inhibitor interactions. A second set of studies with DHFR was designed to investigate the basis for the high affinity between the inhibitor methotrexate and DHFR. The label was placed on the inhibitor, rather than the enzyme

  8. Radiolabeled enzyme inhibitors and binding agents targeting PSMA: Effective theranostic tools for imaging and therapy of prostate cancer

    International Nuclear Information System (INIS)

    Pillai, Maroor Raghavan Ambikalmajan; Nanabala, Raviteja; Joy, Ajith; Sasikumar, Arun; Knapp, Furn F.

    2016-01-01

    Because of the broad incidence, morbidity and mortality associated with prostate-derived cancer, the development of more effective new technologies continues to be an important goal for the accurate detection and treatment of localized prostate cancer, lymphatic involvement and metastases. Prostate-specific membrane antigen (PSMA; Glycoprotein II) is expressed in high levels on prostate-derived cells and is an important target for visualization and treatment of prostate cancer. Radiolabeled peptide targeting technologies have rapidly evolved over the last decade and have focused on the successful development of radiolabeled small molecules that act as inhibitors to the binding of the N-acetyl-L-aspartyl-L-glutamate (NAAG) substrate to the PSMA molecule. A number of radiolabeled PSMA inhibitors have been described in the literature and labeled with SPECT, PET and therapeutic radionuclides. Clinical studies with these agents have demonstrated the improved potential of PSMA-targeted PET imaging agents to detect metastatic prostate cancer in comparison with conventional imaging technologies. Although many of these agents have been evaluated in humans, by far the most extensive clinical literature has described use of the 68 Ga and 177 Lu agents. This review describes the design and development of these agents, with a focus on the broad clinical introduction of PSMA targeting motifs labeled with 68 Ga for PET-CT imaging and 177 Lu for therapy. In particular, because of availability from the long-lived 68 Ge (T 1/2 = 270 days)/ 68 Ga (T 1/2 = 68 min) generator system and increasing availability of PET-CT, the 68 Ga-labeled PSMA targeted agent is receiving widespread interest and is one of the fastest growing radiopharmaceuticals for PET-CT imaging.

  9. Adenoviral delivery of pan-caspase inhibitor p35 enhances bystander killing by P450 gene-directed enzyme prodrug therapy using cyclophosphamide+

    International Nuclear Information System (INIS)

    Doloff, Joshua C; Su, Ting; Waxman, David J

    2010-01-01

    Cytochrome P450-based suicide gene therapy for cancer using prodrugs such as cyclophosphamide (CPA) increases anti-tumor activity, both directly and via a bystander killing mechanism. Bystander cell killing is essential for the clinical success of this treatment strategy, given the difficulty of achieving 100% efficient gene delivery in vivo using current technologies. Previous studies have shown that the pan-caspase inhibitor p35 significantly increases CPA-induced bystander killing by tumor cells that stably express P450 enzyme CYP2B6 (Schwartz et al, (2002) Cancer Res. 62: 6928-37). To further develop this approach, we constructed and characterized a replication-defective adenovirus, Adeno-2B6/p35, which expresses p35 in combination with CYP2B6 and its electron transfer partner, P450 reductase. The expression of p35 in Adeno-2B6/p35-infected tumor cells inhibited caspase activation, delaying the death of the CYP2B6 'factory' cells that produce active CPA metabolites, and increased bystander tumor cell killing compared to that achieved in the absence of p35. Tumor cells infected with Adeno-2B6/p35 were readily killed by cisplatin and doxorubicin, indicating that p35 expression is not associated with acquisition of general drug resistance. Finally, p35 did not inhibit viral release when the replication-competent adenovirus ONYX-017 was used as a helper virus to facilitate co-replication and spread of Adeno-2B6/p35 and further increase CPA-induced bystander cell killing. The introduction of p35 into gene therapeutic regimens constitutes an effective approach to increase bystander killing by cytochrome P450 gene therapy. This strategy may also be used to enhance other bystander cytotoxic therapies, including those involving the production of tumor cell toxic protein products

  10. Angiotensin-converting enzyme-inhibitor therapy in adolescents with type 1 diabetes in a regional cohort: Auckland, New Zealand from 2006 to 2016.

    Science.gov (United States)

    Hornung, Rosalie J; Reed, Peter W; Mouat, Fran; Jefferies, Craig; Gunn, Alistair J; Hofman, Paul L

    2018-05-01

    To review indications and use of angiotensin-converting enzyme-inhibitor (ACEI) therapy for the treatment of persistent microalbuminuria (MA) and/or hypertension (HTN) in adolescents with type 1 diabetes mellitus (T1DM). Retrospective chart review of adolescent patients with T1DM seen within the paediatric diabetes service in Auckland, New Zealand, from 2006 to 2016. MA, HTN, patient demographic characteristics and ACEI prescribing and monitoring indices were examined. Five hundred adolescents with T1DM were included. There were 26 patients (5%) with MA and/or HTN. MA alone was present in 16, HTN alone in 3 and both HTN and MA in 7. The 5-year MA/HTN-free rate was 98%, and the 10-year MA/HTN-free rate was 93%. Longer disease duration and earlier diagnosis were predictors of MA/HTN. There was no significant difference in standard clinical indices between study patients and others. ACEI was prescribed for 17 of 26 patients for either HTN or MA. Within 6 weeks of ACEI commencement, less than half of the subjects had repeat serum creatinine and MA screens and no record of repeat blood pressure measurement. Despite this, all patients had 3-monthly reviews within outpatient clinics where adjustments of ACEI doses were made. In our regional adolescent population with T1DM, there were low rates of both MA and/or HTN. In those who required treatment with ACEI, clinical monitoring post-commencement of therapy was inconsistent. Local consensus guidelines for the management of persistent MA in children and adolescents with diabetes mellitus were developed in response to this study. © 2017 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).

  11. Epigenetic mismatches with mutated transcribing genes at leukemogenic S-phase binding/start sites--potential targets for therapy with enzyme inhibitors.

    Science.gov (United States)

    Prindull, Gregor

    2012-11-01

    This review focuses on gene transcription patterns of leukemogenic S-phases in mitotic cell cycles for identification of enzymatic reactions as potential targets for epigenetics-based drug therapy. Transcription of leukemic genes is triggered by reprogrammed transcription factors (TFs) mediated by chromatin histones. Reprogrammed TFs originate from transcriptional alterations of CpG methylation patterns of mutated epigenetic genes. They preserve memory information of earlier leukemogenic exposures, even transgenerationally via the zygote, through small (e.g. pi)RNA transmitted between cells by exosomes. Normally, reprogrammed TFs are enzymatically silenced and stored as markers in heterochromatic domains. Failure of intra S-phase surveillance (IS) permits the formation and continual operation of DNA replication forks in spite of persisting genotoxic stress. Silenced TFs are re-activated by euchromatin, most likely through leakages of insulator barriers of cis-regulating chromatin modulators (CRM) that normally separate hetero- from euchromatin domains. During transport by sliding nucleosomes, reprogrammed leukemogenic TFs are misplaced at transcription factor binding-/starting-sites (TFBS /TSS) allowing them to interact with and trigger replication of mutated leukemic genes. Interactions of enzymatically reprogrammed TFs, transcribed from mutated epigenetic genes, with replicating leukemic genes at TFBS/TSSs are key driving forces in leukemogenesis. Probably, epigenetic genes, although mutated, still retain their control of replication of leukemic genes. Epigenetics-based enzyme inhibitors must target reprogrammed TFs. Prudently, therapeutic corrections should be introduced within the frame of conventional, cytoreductive treatment protocols. Alternatively, reprogrammed TFs could be replaced by cell populations with regular TF production. Clinically, classification of leukemias should be based on their epigenetic presentation.

  12. Different angiotensin-converting enzyme inhibitors have similar clinical efficacy after myocardial infarction

    DEFF Research Database (Denmark)

    Hansen, Morten L; Gislason, Gunnar H; Køber, Lars

    2008-01-01

    What is already known about this subject: Treatment with an angiotensin-converting enzyme (ACE) inhibitor benefits many patients with cardiovascular disease. ACE inhibitors are generally assumed to be equally effective, but this has never been fully verified in clinical trials. What this study adds...... important and not which ACE inhibitor is used. AIM: Therapy with angiotensin-converting enzyme (ACE) inhibitors is common after myocardial infarction (MI). Given the lack of randomized trials comparing different ACE inhibitors, the association among ACE inhibitors after MI in risk for mortality...

  13. Substrate mediated enzyme prodrug therapy

    DEFF Research Database (Denmark)

    Fejerskov, Betina; Jarlstad Olesen, Morten T; Zelikin, Alexander N

    2017-01-01

    Substrate mediated enzyme prodrug therapy (SMEPT) is a biomedical platform developed to perform a localized synthesis of drugs mediated by implantable biomaterials. This approach combines the benefits and at the same time offers to overcome the drawbacks for traditional pill-based drug administra......Substrate mediated enzyme prodrug therapy (SMEPT) is a biomedical platform developed to perform a localized synthesis of drugs mediated by implantable biomaterials. This approach combines the benefits and at the same time offers to overcome the drawbacks for traditional pill-based drug...

  14. Pancreatic enzyme replacement therapy.

    Science.gov (United States)

    Layer, P; Keller, J; Lankisch, P G

    2001-04-01

    Malabsorption due to severe pancreatic exocrine insufficiency is one of the most important late features of chronic pancreatitis. Generally, steatorrhea is more severe and occurs several years prior to malabsorption of other nutrients because synthesis and secretion of lipase are impaired more rapidly, its intraluminal survival is shorter, and the lack of pancreatic lipase activity is not compensated for by nonpancreatic mechanisms. Patients suffer not only from nutritional deficiencies but also from increased nutrient delivery to distal intestinal sites, causing symptoms by profound alteration of upper gastrointestinal secretory and motor functions. Adequate nutrient absorption requires delivery of sufficient enzymatic activity into the duodenal lumen simultaneously with meal nutrients. The following recommendations are based on modern therapeutic concepts: 25,000 to 40,000 units of lipase per meal using pH-sensitive pancreatin microspheres, with dosage increases, compliance checks, and differential diagnosis in case of treatment failure. Still, in most patients, lipid digestion cannot be completely normalized by current standard therapy, and future developments are needed to optimize treatment.

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

    Directory of Open Access Journals (Sweden)

    Perna Annalisa

    2005-10-01

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

  16. [Inhibitors of proteolytic enzymes under abiotic stresses in plants (review)].

    Science.gov (United States)

    Mosolov, V V; Valueva, T A

    2011-01-01

    Data on the role of proteolytic enzyme inhibitors in plant adaptation to various unfavorable environmental abiotic factors--water deficiency, salinization of soil, extreme temperatures, etc.--and also probable functions of proteinases inhibitors in natural plant senescense are considered.

  17. Enzymes and Inhibitors in Neonicotinoid Insecticide Metabolism

    Science.gov (United States)

    Shi, Xueyan; Dick, Ryan A.; Ford, Kevin A.; Casida, John E.

    2009-01-01

    Neonicotinoid insecticide metabolism involves considerable substrate specificity and regioselectivity of the relevant CYP450, aldehyde oxidase, and phase II enzymes. Human CYP450 recombinant enzymes carry out the following conversions: CYP3A4, 2C19 and 2B6 for thiamethoxam (TMX) to clothianidin (CLO); 3A4, 2C19 and 2A6 for CLO to desmethyl-CLO; 2C19 for TMX to desmethyl-TMX. Human liver aldehyde oxidase reduces the nitro substituent of CLO to nitroso much more rapidly than that of TMX. Imidacloprid (IMI), CLO and several of their metabolites do not give detectable N-glucuronides but 5-hydroxy-IMI, 4,5-diol-IMI and 4-hydroxy-thiacloprid are converted to O-glucuronides in vitro with mouse liver microsomes and UDP-glucuronic acid or in vivo in mice. Mouse liver cytosol with S-adenosylmethionine converts desmethyl-CLO to CLO but not desmethyl-TMX to TMX. Two organophosphorus CYP450 inhibitors partially block IMI, thiacloprid and CLO metabolism in vivo in mice, elevating the brain and liver levels of the parent compounds while reducing amounts of the hydroxylated metabolites. PMID:19391582

  18. Substrate mediated enzyme prodrug therapy.

    Directory of Open Access Journals (Sweden)

    Betina Fejerskov

    Full Text Available In this report, we detail Substrate Mediated Enzyme Prodrug Therapy (SMEPT as a novel approach in drug delivery which relies on enzyme-functionalized cell culture substrates to achieve a localized conversion of benign prodrug(s into active therapeutics with subsequent delivery to adhering cells or adjacent tissues. For proof-of-concept SMEPT, we use surface adhered micro-structured physical hydrogels based on poly(vinyl alcohol, β-glucuronidase enzyme and glucuronide prodrugs. We demonstrate enzymatic activity mediated by the assembled hydrogel samples and illustrate arms of control over rate of release of model fluorescent cargo. SMEPT was not impaired by adhering cells and afforded facile time - and dose - dependent uptake of the in situ generated fluorescent cargo by hepatic cells, HepG2. With the use of a glucuronide derivative of an anticancer drug, SN-38, SMEPT afforded a decrease in cell viability to a level similar to that achieved using parent drug. Finally, dose response was achieved using SMEPT and administration of judiciously chosen concentration of SN-38 glucuronide prodrug thus revealing external control over drug delivery using drug eluting surface. We believe that this highly adaptable concept will find use in diverse biomedical applications, specifically surface mediated drug delivery and tissue engineering.

  19. [Advances on enzymes and enzyme inhibitors research based on microfluidic devices].

    Science.gov (United States)

    Hou, Feng-Hua; Ye, Jian-Qing; Chen, Zuan-Guang; Cheng, Zhi-Yi

    2010-06-01

    With the continuous development in microfluidic fabrication technology, microfluidic analysis has evolved from a concept to one of research frontiers in last twenty years. The research of enzymes and enzyme inhibitors based on microfluidic devices has also made great progress. Microfluidic technology improved greatly the analytical performance of the research of enzymes and enzyme inhibitors by reducing the consumption of reagents, decreasing the analysis time, and developing automation. This review focuses on the development and classification of enzymes and enzyme inhibitors research based on microfluidic devices.

  20. Effect of Angiotensin-Converting Enzyme Inhibitor/Calcium Antagonist Combination Therapy on Renal Function in Hypertensive Patients With Chronic Kidney Disease: Chikushi Anti-Hypertension Trial - Benidipine and Perindopril.

    Science.gov (United States)

    Okuda, Tetsu; Okamura, Keisuke; Shirai, Kazuyuki; Urata, Hidenori

    2018-02-01

    Appropriate blood pressure control suppresses progression of chronic kidney disease (CKD). If an angiotensin-converting enzyme (ACE) inhibitor is ineffective, adding a calcium antagonist is recommended. We compared the long-term effect of two ACE inhibitor/calcium antagonist combinations on renal function in hypertensive patients with CKD. Patients who failed to achieve the target blood pressure (systolic/diastolic: < 130/80 mm Hg) with perindopril monotherapy were randomized to either combined therapy with perindopril and the L-type calcium antagonist amlodipine (group A) or perindopril and the T/L type calcium antagonist benidipine (group B). The primary endpoint was the change of the estimated glomerular filtration rate (eGFR) after 2 years. Eligible patients had a systolic pressure ≥ 130 mm Hg and/or diastolic pressure ≥ 80 mm Hg and CKD (urine protein (+) or higher, eGFR < 60 min/mL/1.73 m 2 ). After excluding 38 patients achieving the target blood pressure with perindopril monotherapy, 121 patients were analyzed (62 in group A and 59 in group B). Blood pressure decreased significantly in both groups, but there was no significant change of the eGFR. However, among patients with diabetes, eGFR unchanged in group B (n = 37, 59.1 ± 15.1 vs. 61.2 ± 27.9, P = 0.273), whereas decreased significantly in group A (n = 31, 57.3 ± 16.0 vs. 53.7 ± 16.7, P = 0.005). In hypertensive patients with diabetic nephropathy, combined therapy with an ACE inhibitor and T/L type calcium antagonist may prevent deterioration of renal function more effectively than an ACE inhibitor/L type calcium antagonist combination.

  1. The evolution of renin-angiotensin blockade: angiotensin-converting enzyme inhibitors as the starting point.

    Science.gov (United States)

    Sica, Domenic A

    2010-04-01

    The renin-angiotensin system has been a target in the treatment of hypertension for close to three decades. Several medication classes that block specific aspects of this system have emerged as useful therapies, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and, most recently, direct renin inhibitors. There has been a natural history to the development of each of these three drug classes, starting with their use as antihypertensive agents; thereafter, in each case they have been employed as end-organ protective agents. To date, there has been scant evidence to favor angiotensin receptor blockers or direct renin inhibitors over angiotensin-converting enzyme inhibitors in treating hypertension or in affording end-organ protection; thus, angiotensin-converting enzyme inhibitors remain the standard of care when renin-angiotensin system blockade is warranted.

  2. The effect of chemical anti-inhibitors on fibrinolytic enzymes and inhibitors

    DEFF Research Database (Denmark)

    Sidelmann, Johannes Jakobsen; Jespersen, J; Kluft, C

    1997-01-01

    proteases. We studied the influence of chemical anti-inhibitors (chloramine T, flufenamate, sodium lauryl sulfate, and methylamine) on fibrinolytic serine proteases and fibrinolytic enzyme inhibitors using the physiological substrate fibrin as plasmin substrate. Low concentrations of chloramine T (0.01 mmol......%) and plasminogen activators (apparent recovery > 200%). Sodium lauryl sulfate eliminates the major fibrinolytic enzyme inhibitors, but increases the activity of plasmin (apparent recovery > 200%) and plasminogen activator, urokinase type (apparent recovery 130%). Methylamine affects only plasmin inhibition. We...

  3. Biosensors for the determination of environmental inhibitors of enzymes

    Energy Technology Data Exchange (ETDEWEB)

    Evtugyn, Gennadii A; Budnikov, Herman C [Kazan State University, Kazan (Russian Federation); Nikolskaya, Elena B [I.M. Sechenov Institute of Evolution Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg (Russian Federation)

    1999-12-31

    Characteristic features of functioning and practical application of enzyme-based biosensors for the determination of environmental pollutants as enzyme inhibitors are considered with special emphasis on the influence of the methods used for the measurement of the rates of enzymic reactions, of enzyme immobilisation procedure and of the composition of the reaction medium on the analytical characteristics of inhibitor assays. The published data on the development of biosensors for detecting pesticides and heavy metals are surveyed. Special attention is given to the use of cholinesterase-based biosensors in environmental and analytical monitoring. The approaches to the estimation of kinetic parameters of inhibition are reviewed and the factors determining the selectivity and sensitivity of inhibitor assays in environmental objects are analysed. The bibliography includes 195 references.

  4. Biosensors for the determination of environmental inhibitors of enzymes

    International Nuclear Information System (INIS)

    Evtugyn, Gennadii A; Budnikov, Herman C; Nikolskaya, Elena B

    1999-01-01

    Characteristic features of functioning and practical application of enzyme-based biosensors for the determination of environmental pollutants as enzyme inhibitors are considered with special emphasis on the influence of the methods used for the measurement of the rates of enzymic reactions, of enzyme immobilisation procedure and of the composition of the reaction medium on the analytical characteristics of inhibitor assays. The published data on the development of biosensors for detecting pesticides and heavy metals are surveyed. Special attention is given to the use of cholinesterase-based biosensors in environmental and analytical monitoring. The approaches to the estimation of kinetic parameters of inhibition are reviewed and the factors determining the selectivity and sensitivity of inhibitor assays in environmental objects are analysed. The bibliography includes 195 references.

  5. Trends in co-prescribing of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in Ireland.

    LENUS (Irish Health Repository)

    Wan Md Adnan, Wan A H

    2011-03-01

    (i) To examine the trends in co-prescribing of angiotensin converting enzyme inhibitor (ACEI) and angiotensin-II receptor blocker (ARB) therapy and (ii) to examine the influence of major clinical trials (CALM, COOPERATE, VALIANT and ONTARGET) on co-prescribing.

  6. A pan-inhibitor of DASH family enzymes induces immune-mediated regression of murine sarcoma and is a potent adjuvant to dendritic cell vaccination and adoptive T-cell therapy.

    Science.gov (United States)

    Duncan, Brynn B; Highfill, Steven L; Qin, Haiying; Bouchkouj, Najat; Larabee, Shannon; Zhao, Peng; Woznica, Iwona; Liu, Yuxin; Li, Youhua; Wu, Wengen; Lai, Jack H; Jones, Barry; Mackall, Crystal L; Bachovchin, William W; Fry, Terry J

    2013-10-01

    Multimodality therapy consisting of surgery, chemotherapy, and radiation will fail in approximately 40% of patients with pediatric sarcomas and result in substantial long-term morbidity in those who are cured. Immunotherapeutic regimens for the treatment of solid tumors typically generate antigen-specific responses too weak to overcome considerable tumor burden and tumor suppressive mechanisms and are in need of adjuvant assistance. Previous work suggests that inhibitors of DASH (dipeptidyl peptidase IV activity and/or structural homologs) enzymes can mediate tumor regression by immune-mediated mechanisms. Herein, we demonstrate that the DASH inhibitor, ARI-4175, can induce regression and eradication of well-established solid tumors, both as a single agent and as an adjuvant to a dendritic cell (DC) vaccine and adoptive cell therapy (ACT) in mice implanted with the M3-9-M rhabdomyosarcoma cell line. Treatment with effective doses of ARI-4175 correlated with recruitment of myeloid (CD11b) cells, particularly myeloid DCs, to secondary lymphoid tissues and with reduced frequency of intratumoral monocytic (CD11bLy6-CLy6-G) myeloid-derived suppressor cells. In immunocompetent mice, combining ARI-4175 with a DC vaccine or ACT with tumor-primed T cells produced significant improvements in tumor responses against well-established M3-9-M tumors. In M3-9-M-bearing immunodeficient (Rag1) mice, ACT combined with ARI-4175 produced greater tumor responses and significantly improved survival compared with either treatment alone. These studies warrant the clinical investigation of ARI-4175 for treatment of sarcomas and other malignancies, particularly as an adjuvant to tumor vaccines and ACT.

  7. Natural and Synthetic Macrocyclic Inhibitors of the Histone Deacetylase Enzymes

    DEFF Research Database (Denmark)

    Maolanon, Alex; Kristensen, Helle; Leman, Luke

    2017-01-01

    Inhibition of histone deacetylase (HDAC) enzymes has emerged as a target for development of cancer chemotherapy. Four compounds have gained approval for clinical use by the Food and Drug Administration (FDA) in the US, and several are currently in clinical trials. However, none of these compounds...... HDAC enzymes may hold an advantage over traditional hydroxamic acid-containing inhibitors, which rely on chelation to the conserved active site zinc ion. Here, we review the literature on macrocyclic HDAC inhibitors obtained from natural sources and structure-activity relationship studies inspired...

  8. Heme-containing enzymes and inhibitors for tryptophan metabolism.

    Science.gov (United States)

    Yan, Daojing; Lin, Ying-Wu; Tan, Xiangshi

    2017-09-20

    Iron-containing enzymes such as heme enzymes play crucial roles in biological systems. Three distinct heme-containing dioxygenase enzymes, tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase 1 (IDO1) and indoleamine 2,3-dioxygenase 2 (IDO2) catalyze the initial and rate-limiting step of l-tryptophan catabolism through the kynurenine pathway in mammals. Overexpression of these enzymes causes depletion of tryptophan and the accumulation of metabolic products, which contributes to tumor immune tolerance and immune dysregulation in a variety of disease pathologies. In the past few decades, IDO1 has garnered the most attention as a therapeutic target with great potential in cancer immunotherapy. Many potential inhibitors of IDO1 have been designed, synthesized and evaluated, among which indoximod (d-1-MT), INCB024360, GDC-0919 (formerly NLG-919), and an IDO1 peptide-based vaccine have advanced to the clinical trial stage. However, recently, the roles of TDO and IDO2 have been elucidated in immune suppression. In this review, the current drug discovery landscape for targeting TDO, IDO1 and IDO2 is highlighted, with particular attention to the recent use of drugs in clinical trials. Moreover, the crystal structures of these enzymes, in complex with inhibitors, and the mechanisms of Trp catabolism in the first step, are summarized to provide information for facilitating the discovery of new enzyme inhibitors.

  9. Enzyme Replacement Therapy for Fabry Disease

    Directory of Open Access Journals (Sweden)

    Maria Dolores Sanchez-Niño PhD

    2016-11-01

    Full Text Available Fabry disease is a rare X-linked disease caused by the deficiency of α-galactosidase that leads to the accumulation of abnormal glycolipid. Untreated patients develop potentially lethal complications by age 30 to 50 years. Enzyme replacement therapy is the current standard of therapy for Fabry disease. Two formulations of recombinant human α-galactosidase A (agalsidase are available in most markets: agalsidase-α and agalsidase-β, allowing a choice of therapy. However, the US Food and Drug Administration rejected the application for commercialization of agalsidase-α. The main difference between the 2 enzymes is the dose. The label dose for agalsidase-α is 0.2 mg/kg/2 weeks, while the dose for agalsidase-β is 1.0 mg/kg/2 weeks. Recent evidence suggests a dose-dependent effect of enzyme replacement therapy and agalsidase-β is 1.0 mg/kg/2 weeks, which has been shown to reduce the occurrence of hard end points (severe renal and cardiac events, stroke, and death. In addition, patients with Fabry disease who have developed tissue injury should receive coadjuvant tissue protective therapy, together with enzyme replacement therapy, to limit nonspecific progression of the tissue injury. It is likely that in the near future, additional oral drugs become available to treat Fabry disease, such as chaperones or substrate reduction therapy.

  10. Do Angiotensin-Converting Enzyme Inhibitors Reduce the Risk of Symptomatic Radiation Pneumonitis in Patients With Non-Small Cell Lung Cancer After Definitive Radiation Therapy? Analysis of a Single-Institution Database

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Hongmei [Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, P.R. of China (China); Liao, Zhongxing, E-mail: zliao@mdanderson.org [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Zhuang, Yan; Xu, Ting; Nguyen, Quynh-Nhu; Levy, Lawrence B.; O' Reilly, Michael [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Gold, Kathryn A. [Department of Thoracic Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Gomez, Daniel R. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

    2013-12-01

    Purpose: Preclinical studies have suggested that angiotensin-converting enzyme inhibitors (ACEIs) can mitigate radiation-induced lung injury. We sought here to investigate possible associations between ACEI use and the risk of symptomatic radiation pneumonitis (RP) among patients undergoing radiation therapy (RT) for non–small cell lung cancer (NSCLC). Methods and Materials: We retrospectively identified patients who received definitive radiation therapy for stages I to III NSCLC between 2004 and 2010 at a single tertiary cancer center. Patients must have received a radiation dose of at least 60 Gy for a single primary lung tumor and have had imaging and dosimetric data available for analysis. RP was quantified according to Common Terminology Criteria for Adverse Events, version 3.0. A Cox proportional hazard model was used to assess potential associations between ACEI use and risk of symptomatic RP. Results: Of 413 patients analyzed, 65 were using ACEIs during RT. In univariate analysis, the rate of RP grade ≥2 seemed lower in ACEI users than in nonusers (34% vs 46%), but this apparent difference was not statistically significant (P=.06). In multivariate analysis of all patients, ACEI use was not associated with the risk of symptomatic RP (hazard ratio [HR] = 0.66; P=.07) after adjustment for sex, smoking status, mean lung dose (MLD), and concurrent carboplatin and paclitaxel chemotherapy. Subgroup analysis showed that ACEI use did have a protective effect from RP grade ≥2 among patients who received a low (≤20-Gy) MLD (P<.01) or were male (P=.04). Conclusions: A trend toward reduction in symptomatic RP among patients taking ACEIs during RT for NSCLC was not statistically significant on univariate or multivariate analyses, although certain subgroups may benefit from use (ie, male patients and those receiving low MLD). The evidence at this point is insufficient to establish whether the use of ACEIs does or does not reduce the risk of RP.

  11. Soluble inhibitors/deactivators of cellulase enzymes from lignocellulosic biomass.

    Science.gov (United States)

    Kim, Youngmi; Ximenes, Eduardo; Mosier, Nathan S; Ladisch, Michael R

    2011-04-07

    Liquid hot water, steam explosion, and dilute acid pretreatments of lignocellulose generate soluble inhibitors which hamper enzymatic hydrolysis as well as fermentation of sugars to ethanol. Toxic and inhibitory compounds will vary with pretreatment and include soluble sugars, furan derivatives (hydroxymethyl fulfural, furfural), organic acids (acetic, formic and, levulinic acid), and phenolic compounds. Their effect is seen when an increase in the concentration of pretreated biomass in a hydrolysis slurry results in decreased cellulose conversion, even though the ratio of enzyme to cellulose is kept constant. We used lignin-free cellulose, Solka Floc, combined with mixtures of soluble components released during pretreatment of wood, to prove that the decrease in the rate and extent of cellulose hydrolysis is due to a combination of enzyme inhibition and deactivation. The causative agents were extracted from wood pretreatment liquid using PEG surfactant, activated charcoal or ethyl acetate and then desorbed, recovered, and added back to a mixture of enzyme and cellulose. At enzyme loadings of either 1 or 25mg protein/g glucan, the most inhibitory components, later identified as phenolics, decreased the rate and extent of cellulose hydrolysis by half due to both inhibition and precipitation of the enzymes. Full enzyme activity occurred when the phenols were removed. Hence detoxification of pretreated woods through phenol removal is expected to reduce enzyme loadings, and therefore reduce enzyme costs, for a given level of cellulose conversion. Copyright © 2011 Elsevier Inc. All rights reserved.

  12. An angiotensin-converting enzyme inhibitor in the combination treatment of rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    E. B. Komarova

    2017-01-01

    Full Text Available Angiotensin-converting enzyme (ACE inhibitors have anti-inflammatory and antiproliferative properties and can affect the processes of angiogenesis, by reducing the effects of angiotensin II (ATII. The use of ACE inhibitors in the combination therapy of rheumatoid arthritis (RA can be also effective for monitoring disease activity and for reducing a cardiovascular risk.Objective: to evaluate the efficacy of an ACE inhibitor in the combination therapy of RA.Patients and methods. Eighty-four patients with RA and endothelial dysfunction were examined; the mean age was 40.12±10.2 years; the mean disease duration was 4.22±3.43 years. All the patients had a blood level of ATII of >9 pg/ml. Enzyme immunoassay was used to measure the levels of tumor necrosis factor-α (TNF-α (Vector-Best, Russia, intercellular adhesion molecules 1 (ICAM-1 (Diaclone, France, vascular endothelial growth factor (VEGF and ATII (Diagnostic, Canada. Wrist ultrasonography using the Doppler ultrasound apparatus ESAOTE MyLAB40 was carried out to assess synovial vascularization. The patients were divided into two groups. Group 1 included 43 patients who were assigned to receive standard therapy for RA according to the rheumatic disease treatment protocols; Group 2 comprised 41 patients who received the standard therapy plus ACE inhibitors 2.5–5 mg/day.Results. The use of ACE inhibitors in the 12-month combination therapy of RA patients led to an improvement in the endothelial regulation of vascular tone, to a decrease in the blood concentration of ICAM-1, to a reduction in the intensity of synovial angiogenesis and in the blood level of VEGF by 39%, and a more significant drop in the levels of CRP and TNF-? and in DAS28 by 1.2 scores as compared to those in the standard therapy.

  13. A metal-based inhibitor of NEDD8-activating enzyme.

    Directory of Open Access Journals (Sweden)

    Hai-Jing Zhong

    Full Text Available A cyclometallated rhodium(III complex [Rh(ppy(2(dppz](+ (1 (where ppy=2-phenylpyridine and dppz=dipyrido[3,2-a:2',3'-c]phenazine dipyridophenazine has been prepared and identified as an inhibitor of NEDD8-activating enzyme (NAE. The complex inhibited NAE activity in cell-free and cell-based assays, and suppressed the CRL-regulated substrate degradation and NF-κB activation in human cancer cells with potency comparable to known NAE inhibitor MLN4924. Molecular modeling analysis suggested that the overall binding mode of 1 within the binding pocket of the APPBP1/UBA3 heterodimer resembled that for MLN4924. Complex 1 is the first metal complex reported to suppress the NEDDylation pathway via inhibition of the NEDD8-activating enzyme.

  14. Structural Principles in the Development of Cyclic Peptidic Enzyme Inhibitors

    Science.gov (United States)

    Xu, Peng; Andreasen, Peter A.; Huang, Mingdong

    2017-01-01

    This review summarizes our studies in the development of small cyclic peptides for specifically modulating enzyme activity. Serine proteases share highly similar active sites but perform diverse physiological and pathological functions. From a phage-display peptide library, we isolated two mono-cyclic peptides, upain-1 (CSWRGLENHRMC) and mupain-1 (CPAYSRYLDC), which inhibit the activity of human and murine urokinase-type plasminogen activators (huPA and muPA) with Ki values in the micromolar or sub-micromolar range, respectively. The following affinity maturations significantly enhanced the potencies of the two peptides, 10-fold and >250-fold for upain-1 and mupain-1, respectively. The most potent muPA inhibitor has a potency (Ki = 2 nM) and specificity comparable to mono-clonal antibodies. Furthermore, we also found an unusual feature of mupain-1 that its inhibitory potency can be enhanced by increasing the flexibility, which challenges the traditional viewpoint that higher rigidity leading to higher affinity. Moreover, by changing a few key residues, we converted mupain-1 from a uPA inhibitor to inhibitors of other serine proteases, including plasma kallikrein (PK) and coagulation factor XIa (fXIa). PK and fXIa inhibitors showed Ki values in the low nanomolar range and high specificity. Our studies demonstrate the versatility of small cyclic peptides to engineer inhibitory potency against serine proteases and to provide a new strategy for generating peptide inhibitors of serine proteases. PMID:29104489

  15. Characterization of inhibitor(s) of β-glucuronidase enzyme activity in GUS-transgenic wheat

    KAUST Repository

    Ramadan, Ahmed M Ali; Eissa, Hala F.; El-Domyati, Fotouh M.; Saleh, Osama Mesilhy; Ibrahim, Nasser E.; Salama, M. I.; Mahfouz, Magdy M.; Bahieldin, Ahmed M.

    2011-01-01

    The uidA gene, encoding for β-glucuronidase (GUS), is the most frequently used reporter gene in plants. As a reporter enzyme, GUS can be assayed both qualitatively and quantitatively. In wheat, there are numerous reports of failure in detecting GUS enzyme activity in tissues of transgenic plants, while other reports have suggested presence of β-glucuronidase inhibitor(s) in wheat tissues. In the present study, we show that the β-glucuronidase enzyme activity is not only tissue-specific but also genotype-dependent. Our data demonstrate that the glucuronic acid could be the candidate inhibitor for β-glucuronidase enzyme activity in wheat leaves and roots. It should be noted that the assays to detect β-glucuronidase enzyme activity in wheat should be interpreted carefully. Based on the data of our present study, we recommend studying the chemical pathways, the unintended effects and the possible loss-of-function of any candidate transgene prior to transformation experiments. © 2011 Springer Science+Business Media B.V.

  16. Characterization of inhibitor(s) of β-glucuronidase enzyme activity in GUS-transgenic wheat

    KAUST Repository

    Ramadan, Ahmed M Ali

    2011-06-26

    The uidA gene, encoding for β-glucuronidase (GUS), is the most frequently used reporter gene in plants. As a reporter enzyme, GUS can be assayed both qualitatively and quantitatively. In wheat, there are numerous reports of failure in detecting GUS enzyme activity in tissues of transgenic plants, while other reports have suggested presence of β-glucuronidase inhibitor(s) in wheat tissues. In the present study, we show that the β-glucuronidase enzyme activity is not only tissue-specific but also genotype-dependent. Our data demonstrate that the glucuronic acid could be the candidate inhibitor for β-glucuronidase enzyme activity in wheat leaves and roots. It should be noted that the assays to detect β-glucuronidase enzyme activity in wheat should be interpreted carefully. Based on the data of our present study, we recommend studying the chemical pathways, the unintended effects and the possible loss-of-function of any candidate transgene prior to transformation experiments. © 2011 Springer Science+Business Media B.V.

  17. DNA-directed control of enzyme-inhibitor complex formation: a modular approach to reversibly switch enzyme activity

    NARCIS (Netherlands)

    Janssen, B.M.G.; Engelen, W.; Merkx, M.

    2015-01-01

    DNA-templated reversible assembly of an enzyme–inhibitor complex is presented as a new and highly modular approach to control enzyme activity. TEM1-ß-lactamase and its inhibitor protein BLIP were conjugated to different oligonucleotides, resulting in enzyme inhibition in the presence of template

  18. Determinants of angiotensin-converting enzyme inhibitor (ACEI) intolerance and angioedema in the UK Clinical Practice Research Datalink

    NARCIS (Netherlands)

    Mahmoudpour, Seyed Hamidreza; Baranova, Ekaterina Vitalievna; Souverein, Patrick C.; Asselbergs, Folkert W.; de Boer, Anthonius; Maitland-van der Zee, Anke Hilse

    2016-01-01

    AimThe aim of the present study was to describe the occurrence and determinants of angiotensin-converting enzyme (ACE) inhibitor (ACEI) intolerance and angioedema (AE) among patients initiating ACEI therapy in a real-world primary care population. MethodsTwo nested case-control studies were

  19. DNA-linked Inhibitor Antibody Assay (DIANA) for sensitive and selective enzyme detection and inhibitor screening

    Czech Academy of Sciences Publication Activity Database

    Navrátil, Václav; Schimer, Jiří; Tykvart, Jan; Knedlík, Tomáš; Vik, V.; Majer, Pavel; Konvalinka, Jan; Šácha, Pavel

    2017-01-01

    Roč. 45, č. 2 (2017), č. článku e10. ISSN 0305-1048 R&D Projects: GA MŠk LO1302 Institutional support: RVO:61388963 Keywords : quantitative PCR * enzyme detection * inhibitor screening Subject RIV: CE - Biochemistry OBOR OECD: Biochemical research methods Impact factor: 10.162, year: 2016 https:// academic .oup.com/nar/article-lookup/doi/10.1093/nar/gkw853

  20. Future prospects of antibacterial metal nanoparticles as enzyme inhibitor

    International Nuclear Information System (INIS)

    Ahmed, Khan Behlol Ayaz; Raman, Thiagarajan; Veerappan, Anbazhagan

    2016-01-01

    Nanoparticles are being widely used as antibacterial agents with metal nanoparticles emerging as the most efficient antibacterial agents. There have been many studies which have reported the mechanism of antibacterial activity of nanoparticles on bacteria. In this review we aim to emphasize on all the possible mechanisms which are involved in the antibacterial activity of nanoparticles and also to understand their mode of action and role as bacterial enzyme inhibitor by comparing their antibacterial mechanism to that of antibiotics with enzyme inhibition as a major mechanism. With the emergence of widespread antibiotic resistance, nanoparticles offer a better alternative to our conventional arsenal of antibiotics. Once the biological safety of these nanoparticles is addressed, these nanoparticles can be of great medical importance in our fight against bacterial infections. - Highlights: • Mechanisms of antibiotics and metal nanoparticles resemble one another. • Bactericidal mechanisms of NPs are cell wall damage, and ROS generation. • Metal NPs inhibit membrane synthesis enzyme. • NPs can be used as antibacterial agents. • NP as antibacterial strategy important due to widespread antibiotic resistance

  1. Future prospects of antibacterial metal nanoparticles as enzyme inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Ahmed, Khan Behlol Ayaz; Raman, Thiagarajan, E-mail: raman@biotech.sastra.edu; Veerappan, Anbazhagan, E-mail: anbazhagan@scbt.sastra.edu

    2016-11-01

    Nanoparticles are being widely used as antibacterial agents with metal nanoparticles emerging as the most efficient antibacterial agents. There have been many studies which have reported the mechanism of antibacterial activity of nanoparticles on bacteria. In this review we aim to emphasize on all the possible mechanisms which are involved in the antibacterial activity of nanoparticles and also to understand their mode of action and role as bacterial enzyme inhibitor by comparing their antibacterial mechanism to that of antibiotics with enzyme inhibition as a major mechanism. With the emergence of widespread antibiotic resistance, nanoparticles offer a better alternative to our conventional arsenal of antibiotics. Once the biological safety of these nanoparticles is addressed, these nanoparticles can be of great medical importance in our fight against bacterial infections. - Highlights: • Mechanisms of antibiotics and metal nanoparticles resemble one another. • Bactericidal mechanisms of NPs are cell wall damage, and ROS generation. • Metal NPs inhibit membrane synthesis enzyme. • NPs can be used as antibacterial agents. • NP as antibacterial strategy important due to widespread antibiotic resistance.

  2. Plant Protein Inhibitors of Enzymes: Their Role in Animal Nutrition and Plant Defence.

    Science.gov (United States)

    Richardson, Michael

    1981-01-01

    Current information and research related to plant protein inhibitors of enzymes are reviewed, including potential uses of the inhibitors for medical treatment and for breeding plant varieties with greater resistance to insects. (DC)

  3. TO THE 110-TH ANNIVERSARY OF RENIN FINDING. FIGHT OF TITANS: ANGIOTENSIN CONVERTING ENZYME INHIBITORS AND SARTANS

    Directory of Open Access Journals (Sweden)

    L. N. Malay

    2009-01-01

    Full Text Available Angiotensin converting enzyme (ACE inhibitors and angiotensin II receptor blockers (ARB slow down progression of cardiovascular diseases and reduce risk of mortality and life threatening complications. What it is better to prescribe for patient in a concrete clinical case – ACE inhibitors or ARB? Authors compare these drug classes (mechanism of action, indications, evidense base of clinical trails, treatment costs and safety. The place of ACE inhibitors and ARB in modern therapy of cardiovascular diseases is defined. Results of the recent trails (ONTARGET, TRANCEND, PRoFESS, I-PRESERVE are discussed.

  4. [Arteriosclerosis obliterans. Treatment with angiotensin-converting enzyme inhibitors].

    Science.gov (United States)

    Orea, A; Valdés, R; Niebla, L; Rivas, R; Camacho, B

    1990-01-01

    We compare the effects of two of the main angiotensin convertase enzyme inhibitors, captopril and enalapril, aiming to evaluate their effects in the arterial circulation performance, micro-circulation, and changes in regional blood flow, assuming their property of lowering the angiotensin II blood levels, a very strong peripheral vasoconstrictor. We studied 22 patients: all of them with hypertension and/or skin ulcerations, dropping out those who had venous. They were evaluated periodically, clinically and with photoelectric plethysmography of lower extremities. To interpret the traces we designed an ideogram which gathered the plethysmographic behavior before and after the treatment. Nearly 80% showed considerable improvement in pain, functional capacity and plethysmographic traces patterns. healing of the ulcerations was achieved in all case. We propose some hypothesis to explain the good effect that we have observed.

  5. Neuromuscular complications of immune checkpoint inhibitor therapy.

    Science.gov (United States)

    Kolb, Noah A; Trevino, Christopher R; Waheed, Waqar; Sobhani, Fatemeh; Landry, Kara K; Thomas, Alissa A; Hehir, Mike

    2018-01-17

    Immune checkpoint inhibitor (ICPI) therapy unleashes the body's natural immune system to fight cancer. ICPIs improve overall cancer survival, however, the unbridling of the immune system may induce a variety of immune-related adverse events. Neuromuscular immune complications are rare but they can be severe. Myasthenia gravis and inflammatory neuropathy are the most common neuromuscular adverse events but a variety of others including inflammatory myopathy are reported. The pathophysiologic mechanism of these autoimmune disorders may differ from that of non-ICPI-related immune diseases. Accordingly, while the optimal treatment for ICPI-related neuromuscular disorders generally follows a traditional paradigm, there are important novel considerations in selecting appropriate immunosuppressive therapy. This review presents 2 new cases, a summary of neuromuscular ICPI complications, and an approach to the diagnosis and treatment of these disorders. Muscle Nerve, 2018. © 2018 Wiley Periodicals, Inc.

  6. Inhibitors of the bacterial cell wall biosynthesis enzyme MurC.

    Science.gov (United States)

    Reck, F; Marmor, S; Fisher, S; Wuonola, M A

    2001-06-04

    A series of phosphinate transition-state analogues of the L-alanine adding enzyme (MurC) of bacterial peptidoglycan biosynthesis was prepared and tested as inhibitors of the Escherichia coli enzyme. Compound 4 was identified as a potent inhibitor of MurC from Escherichia coli with an IC(50) of 49nM.

  7. Enzyme replacement therapy for murine hypophosphatasia.

    Science.gov (United States)

    Millán, José Luis; Narisawa, Sonoko; Lemire, Isabelle; Loisel, Thomas P; Boileau, Guy; Leonard, Pierre; Gramatikova, Svetlana; Terkeltaub, Robert; Camacho, Nancy Pleshko; McKee, Marc D; Crine, Philippe; Whyte, Michael P

    2008-06-01

    Hypophosphatasia (HPP) is the inborn error of metabolism that features rickets or osteomalacia caused by loss-of-function mutation(s) within the gene that encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNALP). Consequently, natural substrates for this ectoenzyme accumulate extracellulary including inorganic pyrophosphate (PPi), an inhibitor of mineralization, and pyridoxal 5'-phosphate (PLP), a co-factor form of vitamin B6. Babies with the infantile form of HPP often die with severe rickets and sometimes hypercalcemia and vitamin B6-dependent seizures. There is no established medical treatment. Human TNALP was bioengineered with the C terminus extended by the Fc region of human IgG for one-step purification and a deca-aspartate sequence (D10) for targeting to mineralizing tissue (sALP-FcD10). TNALP-null mice (Akp2-/-), an excellent model for infantile HPP, were treated from birth using sALP-FcD10. Short-term and long-term efficacy studies consisted of once daily subcutaneous injections of 1, 2, or 8.2 mg/kg sALP-FcD10 for 15, 19, and 15 or 52 days, respectively. We assessed survival and growth rates, circulating levels of sALP-FcD10 activity, calcium, PPi, and pyridoxal, as well as skeletal and dental manifestations using radiography, microCT, and histomorphometry. Akp2-/- mice receiving high-dose sALP-FcD10 grew normally and appeared well without skeletal or dental disease or epilepsy. Plasma calcium, PPi, and pyridoxal concentrations remained in their normal ranges. We found no evidence of significant skeletal or dental disease. Enzyme replacement using a bone-targeted, recombinant form of human TNALP prevents infantile HPP in Akp2-/- mice.

  8. Enzyme Replacement Therapy for Murine Hypophosphatasia*

    Science.gov (United States)

    Millán, José Luis; Narisawa, Sonoko; Lemire, Isabelle; Loisel, Thomas P; Boileau, Guy; Leonard, Pierre; Gramatikova, Svetlana; Terkeltaub, Robert; Camacho, Nancy Pleshko; McKee, Marc D; Crine, Philippe; Whyte, Michael P

    2008-01-01

    Introduction Hypophosphatasia (HPP) is the inborn error of metabolism that features rickets or osteomalacia caused by loss-of-function mutation(s) within the gene that encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNALP). Consequently, natural substrates for this ectoenzyme accumulate extracellulary including inorganic pyrophosphate (PPi), an inhibitor of mineralization, and pyridoxal 5`-phosphate (PLP), a co-factor form of vitamin B6. Babies with the infantile form of HPP often die with severe rickets and sometimes hypercalcemia and vitamin B6-dependent seizures. There is no established medical treatment. Materials and Methods Human TNALP was bioengineered with the C terminus extended by the Fc region of human IgG for one-step purification and a deca-aspartate sequence (D10) for targeting to mineralizing tissue (sALP-FcD10). TNALP-null mice (Akp2−/−), an excellent model for infantile HPP, were treated from birth using sALP-FcD10. Short-term and long-term efficacy studies consisted of once daily subcutaneous injections of 1, 2, or 8.2 mg/kg sALP-FcD10 for 15, 19, and 15 or 52 days, respectively. We assessed survival and growth rates, circulating levels of sALP-FcD10 activity, calcium, PPi, and pyridoxal, as well as skeletal and dental manifestations using radiography, μCT, and histomorphometry. Results Akp2−/− mice receiving high-dose sALP-FcD10 grew normally and appeared well without skeletal or dental disease or epilepsy. Plasma calcium, PPi, and pyridoxal concentrations remained in their normal ranges. We found no evidence of significant skeletal or dental disease. Conclusions Enzyme replacement using a bone-targeted, recombinant form of human TNALP prevents infantile HPP in Akp2−/− mice. PMID:18086009

  9. Use of proteasome inhibitors in anticancer therapy

    Directory of Open Access Journals (Sweden)

    Sara M. Schmitt

    2011-10-01

    Full Text Available The importance of the ubiquitin-proteasome pathway to cellular function has brought it to the forefront in the search for new anticancer therapies. The ubiquitin-proteasome pathway has proven promising in targeting various human cancers. The approval of the proteasome inhibitor bortezomib for clinical treatment of relapsed/refractory multiple myeloma and mantle cell lymphoma has validated the ubiquitin-proteasome as a rational target. Bortezomib has shown positive results in clinical use but some toxicity and side effects, as well as resistance, have been observed, indicating that further development of novel, less toxic drugs is necessary. Because less toxic drugs are necessary and drug development can be expensive and time-consuming, using existing drugs that can target the ubiquitin-proteasome pathway in new applications, such as cancer therapy, may be effective in expediting the regulatory process and bringing new drugs to the clinic. Toward this goal, previously approved drugs, such as disulfiram, as well as natural compounds found in common foods, such as green tea polyphenol (--EGCG and the flavonoid apigenin, have been investigated for their possible proteasome inhibitory and cell death inducing abilities. These compounds proved quite promising in preclinical studies and have now moved into clinical trials, with preliminary results that are encouraging. In addition to targeting the catalytic activity of the proteasome pathway, upstream regulators, such as the 19S regulatory cap, as well as E1, E2, and E3, are now being investigated as potential drug targets. This review outlines the development of novel proteasome inhibitors from preclinical to clinical studies, highlighting their abilities to inhibit the tumor proteasome and induce apoptosis in several human cancers.

  10. Adverse drug reactions of angiotensin converting enzyme inhibitors : towards precision medicine

    NARCIS (Netherlands)

    Mahmoud Pour, S.H.

    2016-01-01

    Worldwide, millions of patients with cardiovascular diseases are treated with angiotensin converting enzyme inhibitors (ACEIs) according to the international treatment guidelines. Although this class of medications is generally well tolerated, adverse drug reactions (ADRs) may prevent their use in

  11. [Enzyme kinetic glucose determination by the glucose dehydrogenase method. Enzyme kinetic substrate determination using competitive inhibitors, II (author's transl)].

    Science.gov (United States)

    Müller-Matthesius, R

    1975-05-01

    The sensitivity of enzyme kinetic substrate determinations can be improved with the aid of competitive inhibitors. As an example, the determination of glucose dehydrogenase in the presence of potassium thiocyanate is described. The method has the advantage of rapid operation with satisfactory precision.

  12. Angiotensin I-converting enzyme inhibitor derived from cottonseed ...

    African Journals Online (AJOL)

    Six proteolytic enzymes, including alcalase, flavourzyme, trypsin, neutrase, papain and pepsin, were employed to hydrolyze cottonseed protein to produce the hydrolysates of Angiotensin I-converting enzyme (ACE) inhibitory activity. The result indicated that the cottonseed protein hydrolysate (CPH) produced by papain had ...

  13. Carprofen analogues as sirtuin inhibitors: enzyme and cellular studies.

    Science.gov (United States)

    Mellini, Paolo; Carafa, Vincenzo; Di Rienzo, Barbara; Rotili, Dante; De Vita, Daniela; Cirilli, Roberto; Gallinella, Bruno; Provvisiero, Donatella Paola; Di Maro, Salvatore; Novellino, Ettore; Altucci, Lucia; Mai, Antonello

    2012-11-01

    The best of both: SIRT1/2 inhibitors were developed by combining chemical features of selisistat (SIRT1-selective inhibitor; blue) and carprofen (anti-inflammatory drug; red). The most potent compound (shown) increased acetyl-p53 and acetyl-α-tubulin levels, and induced slight apoptosis at 50 μM in U937 cells, differently from selisistat and carprofen. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Enzyme replacement therapy in Fabry disease, towards individualized treatment

    NARCIS (Netherlands)

    Arends, M.

    2017-01-01

    Fabry disease is a very heterogeneous disorder for which expensive enzyme replacement therapy is available since more than 15 years. Because of the variety of symptoms and disease course, individual choices need to be made to improve the appropriate use of therapy. Supported by ZONWM, we have been

  15. Long-term compliance with beta-blockers, angiotensin-converting enzyme inhibitors, and statins after acute myocardial infarction

    DEFF Research Database (Denmark)

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

    2006-01-01

    AIMS: To study initiation, dosages, and compliance with beta-blockers, angiotensin-converting enzyme (ACE)-inhibitors, and statins in patients after acute myocardial infarction (AMI) and to identify likely targets for improvement. METHODS AND RESULTS: Patients admitted with first AMI between 1995...... and 2002 were identified by linking nationwide administrative registers. A total of 55 315 patients survived 30 days after discharge and were included; 58.3% received beta-blockers, 29.1% ACE-inhibitors, and 33.5% statins. After 1, 3, and 5 years, 78, 64, and 58% of survivors who had started therapy were...... still receiving beta-blockers, 86, 78, and 74% were receiving ACE-inhibitors, and 85, 80, and 82% were receiving statins, respectively. Increased age and female sex were associated with improved compliance. The dosages prescribed were generally 50% or less of the dosages used in clinical trials...

  16. Effectiveness of Phosphodiesterase-5 Inhibitor Therapy for Portopulmonary Hypertension

    Directory of Open Access Journals (Sweden)

    Jolene H Fisher

    2015-01-01

    Full Text Available BACKGROUND: Portopulmonary hypertension is associated with significant morbidity and mortality. Phosphodiesterase-5 inhibitor therapy is efficacious in other causes of WHO group I pulmonary arterial hypertension.

  17. Enhancing Immune Checkpoint Inhibitor Therapy in Kidney Cancer

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-15-1-0141 TITLE: Enhancing Immune Checkpoint Inhibitor therapy in Kidney Cancer PRINCIPAL INVESTIGATOR: Hans-Joerg Hammers...SUBTITLE Enhancing Immune Checkpoint Inhibitor therapy in Kidney Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH- 15-1-0141 5c. PROGRAM ELEMENT NUMBER...immune checkpoint inhibition in kidney cancer . The work is designed to test different strategies to induce or enhance the abscopal in a kidney cancer

  18. Perioceutics: Matrix metalloproteinase inhibitors as an adjunctive therapy for inflammatory periodontal disease

    Directory of Open Access Journals (Sweden)

    Esther Nalini Honibald

    2012-01-01

    Full Text Available Matrix metalloproteinases (MMPs form a group of more than 20 zinc-dependent enzymes that are crucial in the degradation of the main components in the extracellular matrix, and thereby play important roles in cell migration, wound healing, and tissue remodeling. MMPs have outgrown the field of extracellular matrix biology and have progressed toward being important regulatory molecules in inflammation, and hence are key components in the pathogenesis of periodontitis. This rise in status has led to the development of MMP inhibitors which can act as switches or delicate tuners in acute and chronic inflammation and the regenerative phase after inflammation. The new challenge in MMP research is to better understand the complex role these enzymes play in periodontal disease and to design inhibitors that are successful in the clinic. Perioceutics or the use of the pharmacological agents specifically developed to manage periodontitis is an interesting and emerging aid in the management of periodontal diseases along with mechanical debridement. The purpose of this review is to provide an introduction to MMPs and their inhibitors, the pathologic effects of a disturbance in the functions of enzyme cascades in balance with natural inhibitors, and highlight on the adjunctive use of MMP inhibitors in periodontal therapy and some of the current challenges with an overview of what has been achieved till date.

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

    DEFF Research Database (Denmark)

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

    2005-01-01

    BACKGROUND: It is not known whether angiotensin-converting-enzyme (ACE) inhibitors slow the progression of polycystic kidney disease (PKD). We performed a patient-level meta-analysis to compare the effect of antihypertensive regimens, including ACE inhibitors, to those without ACE inhibitors...... of doubling of baseline serum creatinine or onset of kidney failure). We also performed multivariable linear regression and Cox proportional hazards analyses. Based on previous findings, we searched for interactions between the treatment effect (effect of ACE inhibitors vs. controls) and baseline urine......%) in the ACE inhibitor group and 30 patients (41%) in the control group (P= 0.17). ACE inhibitors had a greater effect on lowering urine protein excretion and slowing kidney disease progression in patients with higher levels of baseline urine protein excretion (interaction P

  20. Assessment of 105 Patients with Angiotensin Converting Enzyme-Inhibitor Induced Angioedema

    DEFF Research Database (Denmark)

    Rasmussen, Eva Rye; von Buchwald, Christian; Wadelius, Mia

    2017-01-01

    Objective. To asses a cohort of 105 consecutive patients with angiotensin converting enzyme-inhibitor induced angioedema with regard to demographics, risk factors, family history of angioedema, hospitalization, airway management, outcome, and use of diagnostic codes used for the condition. Study...... gender was associated with a significantly higher risk of angiotensin converting enzyme-inhibitor induced angioedema. 6.7% had a positive family history of angioedema. Diabetes seemed to be a protective factor with regard to angioedema. 95% experienced angioedema of the head and neck. 4.7% needed...... Design. Cohort study. Methods. This was a retrospective cohort study of 105 patients with angiotensin converting enzyme-inhibitor induced angioedema in the period 1995-2014. Results. The cohort consisted of 67 females and 38 males (F : M ratio 1.8), with a mean age of 63 [range 26-86] years. Female...

  1. Action of plant proteinase inhibitors on enzymes of physiopathological importance

    Directory of Open Access Journals (Sweden)

    Maria Luiza V. Oliva

    2009-09-01

    Full Text Available Obtained from leguminous seeds, various plant proteins inhibit animal proteinases, including human, and can be considered for the development of compounds with biological activity. Inhibitors from the Bowman-Birk and plant Kunitz-type family have been characterized by proteinase specificity, primary structure and reactive site. Our group mostly studies the genus Bauhinia, mainly the species bauhinioides, rufa, ungulata and variegata. In some species, more than one inhibitor was characterized, exhibiting different properties. Although proteins from this group share high structural similarity, they present differences in proteinase inhibition, explored in studies using diverse biological models.Obtidas de sementes leguminosas, várias proteínas inibem proteinases de origem animal, incluindo humanas, e podem ser consideradas para o desenvolvimento de compostos com atividade biológica. Inibidores da família Bowman-Birk e da família Kunitz vegetal tem sido caracterizados em relação a especificidade para proteinase, estrutura primária e sitio reativo. O nosso grupo majoritariamente vem estudando o gênero Bauhinia, principalmente as espécies bauhinioides, rufa, ungulatae variegata. Em algumas espécies, mais de um inibidor com propriedades diferentes foi caracterizado. Embora tais proteínas apresentem alta similaridade estrutural, diferem quanto à inibição de proteinases, e foram exploradas em estudos utilizando diversos modelos biológicos.

  2. MEROPS: the database of proteolytic enzymes, their substrates and inhibitors.

    Science.gov (United States)

    Rawlings, Neil D; Waller, Matthew; Barrett, Alan J; Bateman, Alex

    2014-01-01

    Peptidases, their substrates and inhibitors are of great relevance to biology, medicine and biotechnology. The MEROPS database (http://merops.sanger.ac.uk) aims to fulfill the need for an integrated source of information about these. The database has hierarchical classifications in which homologous sets of peptidases and protein inhibitors are grouped into protein species, which are grouped into families, which are in turn grouped into clans. Recent developments include the following. A community annotation project has been instigated in which acknowledged experts are invited to contribute summaries for peptidases. Software has been written to provide an Internet-based data entry form. Contributors are acknowledged on the relevant web page. A new display showing the intron/exon structures of eukaryote peptidase genes and the phasing of the junctions has been implemented. It is now possible to filter the list of peptidases from a completely sequenced bacterial genome for a particular strain of the organism. The MEROPS filing pipeline has been altered to circumvent the restrictions imposed on non-interactive blastp searches, and a HMMER search using specially generated alignments to maximize the distribution of organisms returned in the search results has been added.

  3. Elucidating the structural basis for differing enzyme inhibitor potency by cryo-EM.

    Science.gov (United States)

    Rawson, Shaun; Bisson, Claudine; Hurdiss, Daniel L; Fazal, Asif; McPhillie, Martin J; Sedelnikova, Svetlana E; Baker, Patrick J; Rice, David W; Muench, Stephen P

    2018-02-20

    Histidine biosynthesis is an essential process in plants and microorganisms, making it an attractive target for the development of herbicides and antibacterial agents. Imidazoleglycerol-phosphate dehydratase (IGPD), a key enzyme within this pathway, has been biochemically characterized in both Saccharomyces cerevisiae ( Sc_ IGPD) and Arabidopsis thaliana ( At_ IGPD). The plant enzyme, having been the focus of in-depth structural analysis as part of an inhibitor development program, has revealed details about the reaction mechanism of IGPD, whereas the yeast enzyme has proven intractable to crystallography studies. The structure-activity relationship of potent triazole-phosphonate inhibitors of IGPD has been determined in both homologs, revealing that the lead inhibitor (C348) is an order of magnitude more potent against Sc_ IGPD than At_ IGPD; however, the molecular basis of this difference has not been established. Here we have used single-particle electron microscopy (EM) to study structural differences between the At and Sc_ IGPD homologs, which could influence the difference in inhibitor potency. The resulting EM maps at ∼3 Å are sufficient to de novo build the protein structure and identify the inhibitor binding site, which has been validated against the crystal structure of the At_ IGPD/C348 complex. The structure of Sc _IGPD reveals that a 24-amino acid insertion forms an extended loop region on the enzyme surface that lies adjacent to the active site, forming interactions with the substrate/inhibitor binding loop that may influence inhibitor potency. Overall, this study provides insights into the IGPD family and demonstrates the power of using an EM approach to study inhibitor binding. Copyright © 2018 the Author(s). Published by PNAS.

  4. Aktivitas Antioksidan Danangiotensin-I Converting Enzyme Inhibitor oleh Yogurt dengan Ekstrak Daun Ficus glomerata Roxb

    Directory of Open Access Journals (Sweden)

    Baiq Rani Dewi Wulandani

    2018-01-01

    ABSTRAK  Ficus glomerata Roxb. telah diketahui memiliki senyawa flavonoid. Senyawa flavonoid yang terdapat didalam tanaman diketahui memiliki kemampuan sebagai antioksidan dan mampu sebagai Angiotensin Converting Enzyme I- inhibitor. Penelitian ini diawali dengan melakukan ekstraksi dengan menggunakan air pada daun Ficus glomerata Roxb untuk mendapatkan profil senyawa phenolik pada ekstrak daun Ficus glomerata Roxb [gallic acid, flavonol (quercetin dan rutin, flavanol (catechin, dan flavanone]. Tahap berikutnya adalah inokulasi dan perbanyakan starter yogurt untuk selanjutnya melakukan proses pembuatan yogurt dengan penambahan ekstrak daun Ficus glomerata Roxb. Pengujian aktivitas antioksidan, pengujian terhadap nilai o-phthalaldehyde (OPA dan pengujan terhadap angiotensin converting enzyme I- inhibitor dilakukan terhadap yogurt dengan ekstrak daun Ficus glomerata Roxb selama proses penyimpanan. Tujuan dari penelitian ini adalah untuk mempelajari kemampuan aktivitas antioksidan dan Angiotensin Converting Enzyme I- inhibitor pada yogurt dengan penambahan ekstrak daun Ficus glomerata Roxb selama penyimpanan (1, 7, 14, 21, dan 28 hari pada suhu 4 °C. Hasil yang diperoleh menunjukkan bahwa aktivitas antioksidan, nilai o-phthalaldehyde (OPA dan Angiotensin Converting Enzyme I- inhibitor pada yogurt dengan ekstrak daun Ficus glomerata Roxb selama proses penyimpanan di dalam refrigerator (4 °C adalah lebih tinggi dan menunjukkan perbedaan yang nyata (p < 0,05 dibandingkan dengan plain yogurt yang mencapai optimalnya pada hari ke-7 penyimpanan. Kata kunci: Angiotensin converting enzyme; Ficus glomerata Roxb; yogurt

  5. Can Angiotensin-Converting Enzyme Inhibitors Reduce the Incidence, Severity, and Duration of Radiation Proctitis?

    International Nuclear Information System (INIS)

    Alashkham, Abduelmenem; Paterson, Catherine; Rauchhaus, Petra; Nabi, Ghulam

    2016-01-01

    Purpose: To determine whether participants taking angiotensin-converting enzyme inhibitors (ACEIs) and treated with radical radiation therapy with neoadjuvant/adjuvant hormone therapy have less incidence, severity, and duration of radiation proctitis. Methods and Materials: A propensity score analysis of 817 patients who underwent radical radiation therapy with neoadjuvant or adjuvant hormone therapy as primary line management in a cohort study during 2009 to 2013 was conducted. Patients were stratified as follows: group 1, hypertensive patients taking ACEIs (as a study group); group 2, nonhypertensive patients not taking ACEIs; and group 3, hypertensive patients not taking ACEIs (both as control groups). The incidence, severity, and duration of proctitis were the main outcome. χ"2 tests, Mann-Whitney U tests, analysis of variance, risk ratio (RR), confidence interval (CI), Kaplan-Meier plots, and log-rank tests were used. Results: The mean age of the participants was 68.91 years, with a follow-up time of 3.38 years. Based on disease and age-matched comparison, there was a statistically significant difference of proctitis grading between the 3 groups: χ"2 (8, n=308) = 72.52, P<.001. The Mann-Whitney U test indicated that grades of proctitis were significantly lower in hypertensive patients taking ACEIs than in nonhypertensive patients not taking ACEIs and hypertensive patients not taking ACEIs (P<.001). The risk ratio (RR) of proctitis in hypertensive patients taking ACEIs was significantly lower than in hypertensive patients not taking ACEIs (RR 0.40, 95% CI 0.30-0.53, P<.001) and in nonhypertensive patients not taking ACEIs (RR 0.58, 95% CI 0.44-0.77, P<.001). Time to event analysis revealed that hypertensive patients taking ACEIs were significantly different from the control groups (P<.0001). Furthermore, hypertensive patients taking ACEIs had significantly faster resolution of proctitis (P<.0001). Conclusion: Patients who were taking ACEIs were

  6. Can Angiotensin-Converting Enzyme Inhibitors Reduce the Incidence, Severity, and Duration of Radiation Proctitis?

    Energy Technology Data Exchange (ETDEWEB)

    Alashkham, Abduelmenem, E-mail: alashkham@yahoo.com [Academic Section of Urology, Division of Cancer Research, School of Medicine, University of Dundee, Scotland (United Kingdom); Paterson, Catherine [Academic Section of Urology, Division of Cancer Research, School of Medicine, University of Dundee, Scotland (United Kingdom); Rauchhaus, Petra [Tayside Clinical Trials Unit, School of Medicine, University of Dundee, Scotland (United Kingdom); Nabi, Ghulam [Academic Section of Urology, Division of Cancer Research, School of Medicine, University of Dundee, Scotland (United Kingdom)

    2016-01-01

    Purpose: To determine whether participants taking angiotensin-converting enzyme inhibitors (ACEIs) and treated with radical radiation therapy with neoadjuvant/adjuvant hormone therapy have less incidence, severity, and duration of radiation proctitis. Methods and Materials: A propensity score analysis of 817 patients who underwent radical radiation therapy with neoadjuvant or adjuvant hormone therapy as primary line management in a cohort study during 2009 to 2013 was conducted. Patients were stratified as follows: group 1, hypertensive patients taking ACEIs (as a study group); group 2, nonhypertensive patients not taking ACEIs; and group 3, hypertensive patients not taking ACEIs (both as control groups). The incidence, severity, and duration of proctitis were the main outcome. χ{sup 2} tests, Mann-Whitney U tests, analysis of variance, risk ratio (RR), confidence interval (CI), Kaplan-Meier plots, and log-rank tests were used. Results: The mean age of the participants was 68.91 years, with a follow-up time of 3.38 years. Based on disease and age-matched comparison, there was a statistically significant difference of proctitis grading between the 3 groups: χ{sup 2} (8, n=308) = 72.52, P<.001. The Mann-Whitney U test indicated that grades of proctitis were significantly lower in hypertensive patients taking ACEIs than in nonhypertensive patients not taking ACEIs and hypertensive patients not taking ACEIs (P<.001). The risk ratio (RR) of proctitis in hypertensive patients taking ACEIs was significantly lower than in hypertensive patients not taking ACEIs (RR 0.40, 95% CI 0.30-0.53, P<.001) and in nonhypertensive patients not taking ACEIs (RR 0.58, 95% CI 0.44-0.77, P<.001). Time to event analysis revealed that hypertensive patients taking ACEIs were significantly different from the control groups (P<.0001). Furthermore, hypertensive patients taking ACEIs had significantly faster resolution of proctitis (P<.0001). Conclusion: Patients who were taking ACEIs were

  7. Enzyme replacement and substrate reduction therapy for Gaucher disease.

    Science.gov (United States)

    Shemesh, Elad; Deroma, Laura; Bembi, Bruno; Deegan, Patrick; Hollak, Carla; Weinreb, Neal J; Cox, Timothy M

    2015-03-27

    Gaucher disease, a rare disorder, is caused by inherited deficiency of the enzyme glucocerebrosidase. It is unique among the ultra-orphan disorders in that four treatments are currently approved by various regulatory authorities for use in routine clinical practice. Hitherto, because of the relatively few people affected worldwide, many of whom started therapy during a prolonged period when there were essentially no alternatives to imiglucerase, these treatments have not been systematically evaluated in studies such as randomized controlled trials now considered necessary to generate the highest level of clinical evidence. To summarize all available randomized controlled study data on the efficacy and safety of enzyme replacement therapies and substrate reduction therapy for treating Gaucher disease. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register. Additional searches were conducted on ClinicalTrials.gov for any ongoing studies with potential interim results, and through PubMed. We also searched the reference lists of relevant articles and reviews.Date of last search: 07 August 2014. All randomized and quasi-randomized controlled studies (including open-label studies and cross-over studies) assessing enzyme replacement therapy or substrate reduction therapy, or both, in all types of Gaucher disease were included. Two authors independently assessed the risk of bias in the included studies, and extracted relevant data. Of the 488 studies retrieved by the electronic searches, eight met the inclusion criteria and were analysed (300 participants). Response parameters were restricted to haemoglobin concentration, platelet count, spleen and liver volume and serum biomarkers (chitotriosidase and CCL18). Only one publication reported a 'low risk of bias' score in all parameters assessed, and all studies included were randomized.Four studies reported the responses to enzyme replacement therapy of previously

  8. Trial Watch: Proteasomal inhibitors for anticancer therapy.

    Science.gov (United States)

    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.

  9. Inhibitors of steroidal cytochrome p450 enzymes as targets for drug development.

    Science.gov (United States)

    Baston, Eckhard; Leroux, Frédéric R

    2007-01-01

    Cytochrome P450's are enzymes which catalyze a large number of biological reactions, for example hydroxylation, N-, O-, S- dealkylation, epoxidation or desamination. Their substrates include fatty acids, steroids or prostaglandins. In addition, a high number of various xenobiotics are metabolized by these enzymes. The enzyme 17alpha-hydroxylase-C17,20-lyase (P450(17), CYP 17, androgen synthase), a cytochrome P450 monooxygenase, is the key enzyme for androgen biosynthesis. It catalyzes the last step of the androgen biosynthesis in the testes and adrenal glands and produces androstenedione and dehydroepiandrosterone from progesterone and pregnenolone. The microsomal enzyme aromatase (CYP19) transforms these androgens to estrone and estradiol. Estrogens stimulate tumor growth in hormone dependent breast cancer. In addition, about 80 percent of prostate cancers are androgen dependent. Selective inhibitors of these enzymes are thus important alternatives to treatment options like antiandrogens or antiestrogens. The present article deals with recent patents (focus on publications from 2000 - 2006) concerning P450 inhibitor design where steroidal substrates are involved. In this context a special focus is provided for CYP17 and CYP19. Mechanisms of action will also be discussed. Inhibitors of CYP11B2 (aldosterone synthase) will also be dealt with.

  10. PARP1 inhibitors: contemporary attempts at their use in anticancer therapy and future perspective

    Directory of Open Access Journals (Sweden)

    Ewelina Wiśnik

    2016-04-01

    Full Text Available Current cancer therapies are based mainly on the use of compounds that cause DNA damage. Unfortunately, even the combination therapies do not give rewarding effects, due to the high efficiency of DNA damage repair mechanisms in tumor cells. Therefore, the present studies should be focused on proteins that are involved in DNA repair systems. Poly(ADP-ribose polymerase-1 is an example of a protein commonly known as an enzyme that plays a role in the detection of DNA damage and repair. Activation of PARP1 in response to DNA damage leads to poly-ADP-ribosylation of proteins contributing to DNA repair systems, therefore facilitating the maintenance of genome stability. On the other hand, inhibition of PARP1 enzyme results in the accumulation of DNA damage, which in turn contributes to cell death. Studies on inhibitors of PARP1 are still ongoing, and some of them are currently in the third phase of clinical trials. To date, only one representative of the PARP1 inhibitors, called olaparib, has been approved for anti-cancer therapy in the EU and the USA. Moreover, a growing body of evidence indicates a role of this protein in various intracellular processes such as bioenergetics, proliferation, regulation of gene expression, cell death as well as immunoregulation. A number of different intracellular processes regulated by PARP1 give rise to potential wider use of PARP1 inhibitors in treatment of other diseases, including immune or autoimmune disorders.

  11. Trial watch – inhibiting PARP enzymes for anticancer therapy

    Science.gov (United States)

    Sistigu, Antonella; Manic, Gwenola; Obrist, Florine; Vitale, Ilio

    2016-01-01

    ABSTRACT Poly(ADP-ribose) polymerases (PARPs) are a members of family of enzymes that catalyze poly(ADP-ribosyl)ation (PARylation) and/or mono(ADP-ribosyl)ation (MARylation), two post-translational protein modifications involved in crucial cellular processes including (but not limited to) the DNA damage response (DDR). PARP1, the most abundant family member, is a nuclear protein that is activated upon sensing distinct types of DNA damage and contributes to their resolution by PARylating multiple DDR players. Recent evidence suggests that, along with DDR, activated PARP1 mediates a series of prosurvival and proapoptotic processes aimed at preserving genomic stability. Despite this potential oncosuppressive role, upregulation and/or overactivation of PARP1 or other PARP enzymes has been reported in a variety of human neoplasms. Over the last few decades, several pharmacologic inhibitors of PARP1 and PARP2 have been assessed in preclinical and clinical studies showing potent antineoplastic activity, particularly against homologous recombination (HR)-deficient ovarian and breast cancers. In this Trial Watch, we describe the impact of PARP enzymes and PARylation in cancer, discuss the mechanism of cancer cell killing by PARP1 inactivation, and summarize the results of recent clinical studies aimed at evaluating the safety and therapeutic profile of PARP inhibitors in cancer patients. PMID:27308587

  12. Pancreatic enzyme replacement therapy for people with cystic fibrosis.

    Science.gov (United States)

    Somaraju, Usha Rani; Solis-Moya, Arturo

    2016-11-23

    Most people with cystic fibrosis (80% to 90%) need pancreatic enzyme replacement therapy to prevent malnutrition. Enzyme preparations need to be taken whenever food is taken, and the dose needs to be adjusted according to the food consumed. A systematic review on the efficacy and safety of pancreatic enzyme replacement therapy is needed to guide clinical practice, as there is variability between centres with respect to assessment of pancreatic function, time of commencing treatment, dose and choice of supplements. This is an updated version of a published review. To evaluate the efficacy and safety of pancreatic enzyme replacement therapy in children and adults with cystic fibrosis and to compare the efficacy and safety of different formulations of this therapy and their appropriateness in different age groups. Also, to compare the effects of pancreatic enzyme replacement therapy in cystic fibrosis according to different diagnostic subgroups (e.g. different ages at introduction of therapy and different categories of pancreatic function). We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Most recent search: 15 July 2016.We also searched an ongoing trials website and the websites of the pharmaceutical companies who manufacture pancreatic enzyme replacements for any additional trials. Most recent search: 22 July 2016. Randomised and quasi-randomised controlled trials in people of any age, with cystic fibrosis and receiving pancreatic enzyme replacement therapy, at any dosage and in any formulation, for a period of not less than four weeks, compared to placebo or other pancreatic enzyme replacement therapy preparations. Two authors independently assessed trials and extracted outcome data. They also assessed the risk of bias of the trials included in the review. One

  13. Angiotensin-converting enzyme inhibitor treatment and the development of urinary tract infection

    NARCIS (Netherlands)

    Pouwels, Koen; Visser, Sipke; Bos, Jens; Hak, Eelko

    2013-01-01

    Background: Angiotensin-converting enzyme inhibitors (ACEi) can reduce the urine output, especially when treatment is started. Since bacterial clearance from the urinary tract is dependent on the urine output, it was hypothesized that ACEi may also increase the risk of urinary tract infections

  14. Angiotensin-converting enzyme inhibitor use and protection against pneumonia in patients with diabetes

    NARCIS (Netherlands)

    van de Garde, Ewoudt M W; Souverein, Patrick C; Hak, Eelko; Deneer, Vera H M; van den Bosch, Jules M M; Leufkens, Hubert G M

    OBJECTIVES: Because of the high risk of pneumonia in patients with diabetes, we aimed to assess the effect of angiotensin-converting enzyme (ACE) inhibitor use on the occurrence of pneumonia in a general population of patients with diabetes. METHODS: The study population comprised all patients in

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

    DEFF Research Database (Denmark)

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

    1996-01-01

    The aqueous extract of the leaves of Olea europea and Olea lancea both inhibited Angiotensin Converting Enzyme (ACE) in vitro. A bioassay-directed fractionation resulted in the isolation of a strong ACE-inhibitor namely the secoiridoid 2-(3,4-dihydroxyphenyl)ethyl 4-formyl-3-(2-oxoethyl)-4E...

  16. Isoprostane 8-epi-PGF2alpha is frequently increased in patients with muscle pain and/or CK-elevation after HMG-Co-enzyme-A-reductase inhibitor therapy.

    Science.gov (United States)

    Sinzinger, H; Lupattelli, G; Chehne, F; Oguogho, A; Furberg, C D

    2001-08-01

    Muscle pains with or without CK-elevation are among the most frequently observed side-effects in patients with hyperlipoproteinemia on various statins. The pathophysiological background, however, remains obscure. We examined isoprostane 8-epi-PGF2alpha, a marker of in-vivo oxidation injury, in plasma, serum and urine in these patients at baseline, when muscle problems manifested and different time intervals after withdrawing the respective statin. A healthy control group and a group of untreated patients with hyperlipoproteinemia were run as controls. The majority of patients with muscular side-effects show elevated 8-epi-PGF2alpha in plasma and urine, whereas serum values were elevated only to a lesser extent. Stopping statin therapy or successfully changing to another member of this family of compounds resulted in a normalization of the values in all patients. These findings indicate a significant involvement of oxidative injury in the muscular side-effects of statins in patients suffering from hyperlipoproteinemia.

  17. Insights on Cytochrome P450 Enzymes and Inhibitors Obtained Through QSAR Studies

    Directory of Open Access Journals (Sweden)

    Maryam Foroozesh

    2012-08-01

    Full Text Available The cytochrome P450 (CYP superfamily of heme enzymes play an important role in the metabolism of a large number of endogenous and exogenous compounds, including most of the drugs currently on the market. Inhibitors of CYP enzymes have important roles in the treatment of several disease conditions such as numerous cancers and fungal infections in addition to their critical role in drug-drug interactions. Structure activity relationships (SAR, and three-dimensional quantitative structure activity relationships (3D-QSAR represent important tools in understanding the interactions of the inhibitors with the active sites of the CYP enzymes. A comprehensive account of the QSAR studies on the major human CYPs 1A1, 1A2, 1B1, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4 and a few other CYPs are detailed in this review which will provide us with an insight into the individual/common characteristics of the active sites of these enzymes and the enzyme-inhibitor interactions.

  18. A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment.

    Science.gov (United States)

    Hyer, Marc L; Milhollen, Michael A; Ciavarri, Jeff; Fleming, Paul; Traore, Tary; Sappal, Darshan; Huck, Jessica; Shi, Judy; Gavin, James; Brownell, Jim; Yang, Yu; Stringer, Bradley; Griffin, Robert; Bruzzese, Frank; Soucy, Teresa; Duffy, Jennifer; Rabino, Claudia; Riceberg, Jessica; Hoar, Kara; Lublinsky, Anya; Menon, Saurabh; Sintchak, Michael; Bump, Nancy; Pulukuri, Sai M; Langston, Steve; Tirrell, Stephen; Kuranda, Mike; Veiby, Petter; Newcomb, John; Li, Ping; Wu, Jing Tao; Powe, Josh; Dick, Lawrence R; Greenspan, Paul; Galvin, Katherine; Manfredi, Mark; Claiborne, Chris; Amidon, Benjamin S; Bence, Neil F

    2018-02-01

    The ubiquitin-proteasome system (UPS) comprises a network of enzymes that is responsible for maintaining cellular protein homeostasis. The therapeutic potential of this pathway has been validated by the clinical successes of a number of UPS modulators, including proteasome inhibitors and immunomodulatory imide drugs (IMiDs). Here we identified TAK-243 (formerly known as MLN7243) as a potent, mechanism-based small-molecule inhibitor of the ubiquitin activating enzyme (UAE), the primary mammalian E1 enzyme that regulates the ubiquitin conjugation cascade. TAK-243 treatment caused depletion of cellular ubiquitin conjugates, resulting in disruption of signaling events, induction of proteotoxic stress, and impairment of cell cycle progression and DNA damage repair pathways. TAK-243 treatment caused death of cancer cells and, in primary human xenograft studies, demonstrated antitumor activity at tolerated doses. Due to its specificity and potency, TAK-243 allows for interrogation of ubiquitin biology and for assessment of UAE inhibition as a new approach for cancer treatment.

  19. SGLT2 inhibitors: a novel choice for the combination therapy in diabetic kidney disease.

    Science.gov (United States)

    Zou, Honghong; Zhou, Baoqin; Xu, Gaosi

    2017-05-16

    Diabetic kidney disease (DKD) is the most common cause of end stage renal disease. The comprehensive management of DKD depends on combined target-therapies for hyperglycemia, hypertension, albuminuria, and hyperlipaemia, etc. Sodium-glucose co-transporter 2 (SGLT2) inhibitors, the most recently developed oral hypoglycemic agents acted on renal proximal tubules, suppress glucose reabsorption and increase urinary glucose excretion. Besides improvements in glycemic control, they presented excellent performances in direct renoprotective effects and the cardiovascular (CV) safety by decreasing albuminuria and the independent CV risk factors such as body weight and blood pressure, etc. Simultaneous use of SGLT-2 inhibitors and renin-angiotensin-aldosterone system (RAAS) blockers are novel strategies to slow the progression of DKD via reducing inflammatory and fibrotic markers induced by hyperglycaemia more than either drug alone. The available population and animal based studies have described SGLT2 inhibitors plus RAAS blockers. The present review was to systematically review the potential renal benefits of SGLT2 inhibitors combined with dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, mineralocorticoid receptor antagonists, and especially the angiotensin-converting enzyme inhibitors/angiotensin receptor blockers.

  20. Novel concept of enzyme selective nicotinamide adenine dinucleotide (NAD)-modified inhibitors based on enzyme taxonomy from the diphosphate conformation of NAD.

    Science.gov (United States)

    Fujii, Mikio; Kitagawa, Yasuyuki; Iida, Shui; Kato, Keisuke; Ono, Machiko

    2015-11-15

    The dihedral angle θ of the diphosphate part of NAD(P) were investigated to distinguish the differences in the binding-conformation of NAD(P) to enzymes and to create an enzyme taxonomy. Furthermore, new inhibitors with fixed dihedral angles showed that enzymes could recognize the differences in the dihedral angle θ. We suggest the taxonomy and the dihedral angle θ are important values for chemists to consider when designing inhibitors and drugs that target enzymes. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Immune Checkpoint Inhibitor Therapy Associated Hypophysitis

    Directory of Open Access Journals (Sweden)

    Moeber Mahzari

    2015-01-01

    Full Text Available Ipilimumab is a monoclonal antibody directed against CTLA4 T-lymphocyte antigen used as cancer therapy. Immune-related adverse events are common side effects and may include hypophysitis-related hypopituitarism. The clinical features of six patients with ipilimumab-induced hypophysitis (IH are described. The clinical features of IH reported in clinical trials, including the incidence of IH by gender and the likelihood of adrenal axis recovery, are summarized. Following the development of IH, most patients remain on glucocorticoid replacement despite efforts to withdraw therapy. Analysis of gender information in published clinical trials suggests that men are more prone to developing IH than women, and few patients fully recover the pituitary-adrenal axis function. Ipilimumab and other drugs within its class are likely to be used to treat many forms of cancer. Endocrinologists should anticipate a significant increase in the incidence of autoimmune hypophysitis. Strategies for early detection of IH and long-term management should be considered.

  2. REDUCTION OF CUMULATIVE CARDIOVASCULAR RISK IN PATIENTS WITH ARTERIAL HYPERTENSION: THE ROLE OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS ACCORDING TO THE NEW EUROPEAN RECOMMENDATIONS

    Directory of Open Access Journals (Sweden)

    M. N. Mamedov

    2015-12-01

    Full Text Available Conception of total cardio-vascular risk plays important role in defining tactics of arterial hypertension therapy according to the new European recommendations. Choice of antihypertensive therapy is based on meta-analysis of large clinical studies with hard end points. It is recommended to use five classes of antihypertensive drugs in mono- and combined therapy. Angiotensin converting enzyme (ACE inhibitors keep important place in the therapy of arterial hypertension accompanying with risk factors and associated diseases. Enalapril is one of the widely used ACE inhibitors, its efficiency was proved in prospective clinical studies. In high risk patients monotherapy with Enam (enalapril, Dr. Reddy’s decreases blood pressure and leads to positive metabolic changes. This results in significant risk reduction of cardio-vascular complications.

  3. REDUCTION OF CUMULATIVE CARDIOVASCULAR RISK IN PATIENTS WITH ARTERIAL HYPERTENSION: THE ROLE OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS ACCORDING TO THE NEW EUROPEAN RECOMMENDATIONS

    Directory of Open Access Journals (Sweden)

    M. N. Mamedov

    2007-01-01

    Full Text Available Conception of total cardio-vascular risk plays important role in defining tactics of arterial hypertension therapy according to the new European recommendations. Choice of antihypertensive therapy is based on meta-analysis of large clinical studies with hard end points. It is recommended to use five classes of antihypertensive drugs in mono- and combined therapy. Angiotensin converting enzyme (ACE inhibitors keep important place in the therapy of arterial hypertension accompanying with risk factors and associated diseases. Enalapril is one of the widely used ACE inhibitors, its efficiency was proved in prospective clinical studies. In high risk patients monotherapy with Enam (enalapril, Dr. Reddy’s decreases blood pressure and leads to positive metabolic changes. This results in significant risk reduction of cardio-vascular complications.

  4. JCL Roundtable: enzyme replacement therapy for lipid storage disorders.

    Science.gov (United States)

    Brown, W Virgil; Desnick, Robert J; Grabowski, Gregory A

    2014-01-01

    There are several inherited disorders that involve abnormal storage of lipids in tissues leading to severe compromise of organs. Sadly, these are often accompanied by lifelong morbidity and early mortality. Disorders such as Gaucher, Fabry, and lysosomal acid lipase deficiencies (Wolman and cholesteryl ester storage diseases) have been known for many years, and provide a difficult and frustrating set of problems for patients, their families, and their physicians. With recombinant methods of protein synthesis, it is now possible to literally replace the defective enzymes that underlie the basic pathophysiology of many such disorders. The delivery of these enzymes into the affected cells is possible because of their location in the lysosomes where the natural degradation of their lipid substrates occurs. I have asked 2 well-known investigators to join us for this Roundtable. These are professors who have been involved with the research that has made this type of therapy possible and who have participated in the clinical trials that demonstrated the value of enzyme replacement therapy. They are Dr. Robert Desnick, dean of Genetic and Genomic Medicine and professor and chairman emeritus of the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai in New York City, and Dr. Gregory Grabowski, professor of Microbiology, Biochemistry, and Pediatrics, at the University of Cincinnati College of Medicine. Dr. Grabowski recently retired from that school to become the chief science officer of Synageva, a company involved in producing enzymes for this type of therapy. Copyright © 2014 National Lipid Association. Published by Elsevier Inc. All rights reserved.

  5. Angiotensin converting enzyme inhibitors and Alzheimer disease in the presence of the apolipoprotein E4 allele.

    Science.gov (United States)

    Qiu, Wendy Wei Qiao; Lai, Angela; Mon, Timothy; Mwamburi, Mkaya; Taylor, Warren; Rosenzweig, James; Kowall, Neil; Stern, Robert; Zhu, Haihao; Steffens, David C

    2014-02-01

    The effect of angiotensin converting enzyme (ACE) inhibitors on Alzheimer disease (AD) remains unclear, with conflicting results reported. We studied the interaction of the Apolipoprotein E (ApoE) genotype and ACE inhibitors on AD. This was a cross-sectional study of homebound elderly with an AD diagnosis and documentation of medications taken. ApoE genotype was determined. A total of 355 subjects with status on ApoE alleles and cognitive diagnoses were studied. The average age (mean ± SD) of this population was 73.3 ± 8.3 years old, and 73% were female. Cross-sectionally, there was no difference in the number of AD cases between ApoE4 carriers and ApoE4 non-carriers or between ACE inhibitor users and non-users in the homebound elderly. ApoE4 carriers treated with ACE inhibitors, however, had more diagnoses of AD compared with those who did not have the treatment (28% versus 6%, p = 0.01) or ApoE4 non-carriers treated with an ACE inhibitor (28% versus 10%, p = 0.03). ACE inhibitor use was associated with AD diagnosis only in the presence of an E4 allele. Using multivariate logistic regression analysis, we found that in diagnosed AD cases there was a significant interaction between ApoE4 and ACE inhibitor use (odds ratio: 20.85; 95% confidence interval: 3.08-140.95; p = 0.002) after adjusting for age, sex, ethnicity, and education. The effects of ACE inhibitors on AD may be different depending on ApoE genotype. A prospective study is needed to determine whether ACE inhibitor use accelerates or poorly delays AD development in ApoE4 carriers compared with ApoE4 non-carriers. Copyright © 2014. Published by Elsevier Inc.

  6. Improved Peak Capacity for Capillary Electrophoretic Separations of Enzyme Inhibitors with Activity-Based Detection Using Magnetic Bead Microreactors

    Science.gov (United States)

    Yan, Xiaoyan; Gilman, S. Douglass

    2010-01-01

    A technique for separating and detecting enzyme inhibitors was developed using capillary electrophoresis with an enzyme microreactor. The on-column enzyme microreactor was constructed using NdFeB magnet(s) to immobilize alkaline phosphatase-coated superparamagnetic beads (2.8 μm diameter) inside a capillary before the detection window. Enzyme inhibition assays were performed by injecting a plug of inhibitor into a capillary filled with the substrate, AttoPhos. Product generated in the enzyme microreactor was detected by laser-induced fluorescence. Inhibitor zones electrophoresed through the capillary, passed through the enzyme microreactor, and were observed as negative peaks due to decreased product formation. The goal of this study was to improve peak capacities for inhibitor separations relative to previous work, which combined continuous engagement electrophoretically mediated microanalysis (EMMA) and transient engagement EMMA to study enzyme inhibition. The effects of electric field strength, bead injection time and inhibitor concentrations on peak capacity and peak width were investigated. Peak capacities were increased to ≥20 under optimal conditions of electric field strength and bead injection time for inhibition assays with arsenate and theophylline. Five reversible inhibitors of alkaline phosphatase (theophylline, vanadate, arsenate, L-tryptophan and tungstate) were separated and detected to demonstrate the ability of this technique to analyze complex inhibitor mixtures. PMID:20024913

  7. Overview of the Classical Histone Deacetylase Enzymes and Histone Deacetylase Inhibitors

    OpenAIRE

    Ververis, Katherine; Karagiannis, Tom C.

    2012-01-01

    The important role of histone deacetylase enzymes in regulating gene expression, cellular proliferation, and survival has made them attractive targets for the development of histone deacetylase inhibitors as anticancer drugs. Suberoylanilide hydroxamic acid (Vorinostat, Zolinza), a structural analogue of the prototypical Trichostatin A, was approved by the US Food and Drug Administration for the treatment of advanced cutaneous T-cell lymphoma in 2006. This was followed by approval of the cycl...

  8. Marketing research on the angiotensin-converting enzyme inhibitors antihypertensive medicines

    OpenAIRE

    BOBOIA, ANAMARIA; GRIGORESCU, MARIUS RARE?; TURCU - ?TIOLIC?, ADINA

    2017-01-01

    Background and aims The research aimed at investigating sales trends of angiotensin-converting enzyme inhibitors antihypertensive medicines, both in terms of quantity and value, in ten community pharmacies, for a period of three years. The research on the antihypertensive medicines consumption is important for highlighting the ever increasing impact of hypertension among the population. Methods The methods used in this research were the following: marketing research, method of sampling, descr...

  9. Angiotensin converting enzyme inhibitors mitigate collagen synthesis induced by a single dose of radiation to the whole thorax

    International Nuclear Information System (INIS)

    Kma, L.; Gao, F.; Fish, B.L.; Moulder, J.E.; Jacobs, E.R.; Medhora, M.

    2012-01-01

    Our long-term goal is to use angiotensin converting enzyme (ACE) inhibitors to mitigate the increase in lung collagen synthesis that is induced by irradiation to the lung, which could result from accidental exposure or radiological terrorism. Rats (WAG/RijCmcr) were given a single dose of 13 Gy (dose rate of 1.43 Gy/min) of X-irradiation to the thorax. Three structurally-different ACE inhibitors, captopril, enalapril and fosinopril were provided in drinking water beginning 1 week after irradiation. Rats that survived acute pneumonitis (at 6-12 weeks) were evaluated monthly for synthesis of lung collagen. Other endpoints included breathing rate, wet to dry lung weight ratio, and analysis of lung structure. Treatment with captopril (145-207 mg/m 2 /day) or enalapril (19-28 mg/m 2 /day), but not fosinopril (19-28 mg/m 2 /day), decreased morbidity from acute pneumonitis. Lung collagen in the surviving irradiated rats was increased over that of controls by 7 months after irradiation. This increase in collagen synthesis was not observed in rats treated with any of the three ACE inhibitors. Analysis of the lung morphology at 7 months supports the efficacy of ACE inhibitors against radiation-induced fibrosis. The effectiveness of fosinopril against fibrosis, but not against acute pneumonitis, suggests that pulmonary fibrosis may not be a simple consequence of injury during acute pneumonitis. In summary, three structurally-different ACE inhibitors mitigate the increase in collagen synthesis 7 months following irradiation of the whole thorax and do so, even when therapy is started one week after irradiation. (author)

  10. Therapies based on inhibitors of the epidermal growth factor receptor: enclosing the future

    International Nuclear Information System (INIS)

    Diaz, Arlhee; Lage, Agustin

    2007-01-01

    The Epidermal Growth Factor Receptor (EGFR) is considered an important target for rational drug design due to its key role in numerous tumors. Potential contribution of EGFR-related signaling pathways to promote tumorigenic processes, including cell proliferation, angiogenesis, and resistance to apoptosis has been well established. Two classes of anti-EGFR agents in late-stage clinical testing include monoclonal antibodies against extracellular EGFR domain (Cetuximab, Nimotuzumab) and small molecules tyrosine kinase inhibitors, which inhibit the receptor enzyme activity (Gefitinib, Erlotinib). A considerable body of evidence has emerged since its introduction in the treatment of cancer patients. However, important questions such as reliable surrogate markers to predict response to the treatment, or optimal sequence and combination of these agents with conventional therapies remain to be addressed. Identify and validate predictive factors to select patients likely to respond to EGFR inhibitors, such as mutations that confer resistance versus those associated with sensitivity is required. A better understanding of molecular mechanisms associated with antitumor activity will useful to predict the interaction of these agents with other therapies in order to avoid antagonisms or overlapping effects resulting in no adding effects. Finally, the benefits derived from EGFR inhibitors as first-line therapy in selected populations, and the optimal doses and ways to delivery to the tumor site resulting in optimal target modulation should be established by the ongoing investigation. (Author)

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

    Directory of Open Access Journals (Sweden)

    Isuru Wijesekara

    2010-03-01

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

  12. Bystander or No Bystander for Gene Directed Enzyme Prodrug Therapy

    Directory of Open Access Journals (Sweden)

    Adam V. Patterson

    2009-11-01

    Full Text Available Gene directed enzyme prodrug therapy (GDEPT of cancer aims to improve the selectivity of chemotherapy by gene transfer, thus enabling target cells to convert nontoxic prodrugs to cytotoxic drugs. A zone of cell kill around gene-modified cells due to transfer of toxic metabolites, known as the bystander effect, leads to tumour regression. Here we discuss the implications of either striving for a strong bystander effect to overcome poor gene transfer, or avoiding the bystander effect to reduce potential systemic effects, with the aid of three successful GDEPT systems. This review concentrates on bystander effects and drug development with regard to these enzyme prodrug combinations, namely herpes simplex virus thymidine kinase (HSV-TK with ganciclovir (GCV, cytosine deaminase (CD from bacteria or yeast with 5-fluorocytodine (5-FC, and bacterial nitroreductase (NfsB with 5-(azaridin-1-yl-2,4-dinitrobenzamide (CB1954, and their respective derivatives.

  13. PENGARUH DEGRADASI ENZIM PROTEOLITIK TERHADAP AKTIVITAS ANGIOTENSIN CONVERTING ENZYME INHIBITOR BEKASAM DENGAN Lactobacillus plantarum B1765 (The Effect of Degradation of Proteolitic Enzyme on Angiotensin Converting Enzyme Inhibitor Activity of Bekasam with Lactobacillus plantarum B1765

    Directory of Open Access Journals (Sweden)

    Prima Retno Wikandari

    2016-10-01

    Full Text Available This research studied the effect of digestive enzyme degradation on the Angiotensin Converting Enzyme Inhibitor (ACEI activity and the stability of bekasam peptide and ACEI activity. Water extract of bekasam was subjected to pepsin and trypsin. The stability of peptide was measured from the changes of peptide concentration before and after treatment by those enzymes. The stability of ACEI activity was measured by hypuric acid liberated from Hip-His-Leu as ACE substrate and determined by spectrophotometer. The results showed that proteolytic enzyme degradation did not affect the concentration of peptide (p>0,05 and the mean concentration 36.72. It was closely related with the ACEI activity that did not change significantly before and after digestion by pepsin and trypsin (p>0,05 and the mean ACEI activity was 70.73. It showed that ACEI activity of bekasam did not change by the degradation of digestive enzyme. Keywords: bekasam, fermented fish, peptides, ACEI activity ABSTRAK Penelitian ini bertujuan untuk mengkaji pengaruh degradasi enzim pencernaan proteolitik terhadap stabilitas peptida dan aktivitas Angiotensin Converting Enzyme Inhibitor (ACEI bekasam yang difermentasi dengan kultur starter Lactobacillus plantarum B1765. Terhadap ekstrak bekasam diberi perlakuan enzim proteolitik pepsin dan tripsin. Pengujian stabilitas peptida diukur dengan ada tidaknya perubahan jumlah peptida setelah perlakuan enzim menggunakan metode formol, sedangkan aktivitas ACEI dilakukan dengan mengetahui jumlah asam hipurat dari substrat Hip-His-Leu yang dibebaskan oleh ACE diukur dengan spektrofotometer. Hasil pengujian menunjukkan perlakuan enzim proteolitik tidak berpengaruh pada konsentrasi peptida dengan p>0,05 dengan nilai rata-rata konsentrasi peptida sebesar 36,72. Hal ini berkorelasi dengan aktivitas ACEI yang juga menunjukkan tidak ada pengaruh antara perlakuan sebelum dan setelah degradasi enzim (p>0,05 dengan rata-rata aktivitas ACEI sebesar 70,73. Hasil

  14. Antidepressant-like effects of the xanthine oxidase enzyme inhibitor allopurinol in rats. A comparison with fluoxetine.

    Science.gov (United States)

    Gürbüz Özgür, Börte; Aksu, Hatice; Birincioğlu, Mustafa; Dost, Turhan

    2015-11-01

    Allopurinol is a xanthine oxidase enzyme inhibitor that is widely used for the treatment of hyperuricemia and gout. The activity of tryptophan 2,3-dioxygenase, which metabolizes tryptophan (TRP), is decreased by xanthine oxidase inhibitors, causing TRP levels in the body to be increased. Increases in TRP levels in the brain might have antidepressant effects. The purpose of this study is to evaluate the antidepressant effects of allopurinol compared to those of fluoxetine, which is a proven antidepressant. Thirty-two Wistar albino male rats were divided into four groups (control, 10mg/kg fluoxetine, 50mg/kg allopurinol, 50mg/kg allopurinol+10 mg/kg fluoxetine; n=8 per group), and forced swimming tests were performed before and after 14days of drug administration. Serotonin, 5-hydroxyindolacetic acid and uric acid levels were measured in blood samples after the final treatment. When allopurinol and fluoxetine were administered separately, a decrease in the duration of immobility and an increased duration of swimming were observed in the forced swimming test. The results showed similar antidepressant efficacies between allopurinol and fluoxetine. However, we found no statistically significant difference in the antidepressant effect of the combined therapy versus single drug therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Enzyme replacement therapy for infantile-onset Pompe disease.

    Science.gov (United States)

    Chen, Min; Zhang, Lingli; Quan, Shuyan

    2017-11-20

    Infantile-onset Pompe disease is a rare and progressive autosomal-recessive disorder caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). Current treatment involves enzyme replacement therapy (with recombinant human alglucosidase alfa) and symptomatic therapies (e.g. to control secretions). Children who are cross-reactive immunological material (CRIM)-negative require immunomodulation prior to commencing enzyme replacement therapy.Enzyme replacement therapy was developed as the most promising therapeutic approach for Pompe disease; however, the evidence is lacking, especially regarding the optimal dose and dose frequency. To assess the effectiveness, safety and appropriate dose regimen of enzyme replacement therapy for treating infantile-onset Pompe disease. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register, which is compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the Cochrane Central Register of Controlled Trials (CENTRAL), Embase (Ovid), PubMed and LILACS, and CBM, CNKI, VIP, and WANFANG for literature published in Chinese. In addition, we searched three online registers: WHO International Clinical Trials Registry Platform ClinicalTrials.gov, and www.genzymeclinicalresearch.com. We also searched the reference lists of relevant articles and reviews.Date of last search of the Group's Inborn Errors of Metabolism Trials Register: 24 November 2016. Randomized and quasi-randomized controlled trials of enzyme replacement therapy in children with infantile-onset Pompe disease. Two authors independently selected relevant trials, assessed the risk of bias and extracted data. We contacted investigators to obtain important missing information. We found no trials comparing the effectiveness and safety of enzyme replacement therapy to another intervention, no intervention or placebo.We found one trial (18 participants

  16. Biosensors based on enzyme field-effect transistors for determination of some substrates and inhibitors.

    Science.gov (United States)

    Dzyadevych, Sergei V; Soldatkin, Alexey P; Korpan, Yaroslav I; Arkhypova, Valentyna N; El'skaya, Anna V; Chovelon, Jean-Marc; Martelet, Claude; Jaffrezic-Renault, Nicole

    2003-10-01

    This paper is a review of the authors' publications concerning the development of biosensors based on enzyme field-effect transistors (ENFETs) for direct substrates or inhibitors analysis. Such biosensors were designed by using immobilised enzymes and ion-selective field-effect transistors (ISFETs). Highly specific, sensitive, simple, fast and cheap determination of different substances renders them as promising tools in medicine, biotechnology, environmental control, agriculture and the food industry. The biosensors based on ENFETs and direct enzyme analysis for determination of concentrations of different substrates (glucose, urea, penicillin, formaldehyde, creatinine, etc.) have been developed and their laboratory prototypes were fabricated. Improvement of the analytical characteristics of such biosensors may be achieved by using a differential mode of measurement, working solutions with different buffer concentrations and specific agents, negatively or positively charged additional membranes, or genetically modified enzymes. These approaches allow one to decrease the effect of the buffer capacity influence on the sensor response in an aim to increase the sensitivity of the biosensors and to extend their dynamic ranges. Biosensors for the determination of concentrations of different toxic substances (organophosphorous pesticides, heavy metal ions, hypochlorite, glycoalkaloids, etc.) were designed on the basis of reversible and/or irreversible enzyme inhibition effect(s). The conception of an enzymatic multibiosensor for the determination of different toxic substances based on the enzyme inhibition effect is also described. We will discuss the respective advantages and disadvantages of biosensors based on the ENFETs developed and also demonstrate their practical application.

  17. Association between Angiotensin-Converting Enzyme Inhibitors and Troponin in Acute Coronary Syndrome

    Directory of Open Access Journals (Sweden)

    Luiz Minuzzo

    2014-12-01

    Full Text Available Background: Cardiovascular disease is the leading cause of mortality in the western world and its treatment should be optimized to decrease severe adverse events. Objective: To determine the effect of previous use of angiotensin-converting enzyme inhibitors on cardiac troponin I measurement in patients with acute coronary syndrome without ST-segment elevation and evaluate clinical outcomes at 180 days. Methods: Prospective, observational study, carried out in a tertiary center, in patients with acute coronary syndrome without ST-segment elevation. Clinical, electrocardiographic and laboratory variables were analyzed, with emphasis on previous use of angiotensin-converting enzyme inhibitors and cardiac troponin I. The Pearson chi-square tests (Pereira or Fisher's exact test (Armitage were used, as well as the non-parametric Mann-Whitney's test. Variables with significance levels of 0.5 ng / mL were high blood glucose at admission (p = 0.0034 and ST-segment depression ≥ 0.5 mm in one or more leads (p = 0.0016. The use of angiotensin-converting inhibitors prior to hospitalization was associated with troponin ≤ 0.5 ng / mL (p = 0.0482. The C-statistics for this model was 0.77. Conclusion: This study showed a correlation between prior use of angiotensin-converting enzyme inhibitors and reduction in the myocardial necrosis marker troponin I in patients admitted for acute coronary syndrome without ST-segment elevation. However, there are no data available yet to state that this reduction could lead to fewer severe clinical events such as death and re-infarction at 180 days.

  18. Research progress on criteria for discontinuation of EGFR inhibitor therapy

    Directory of Open Access Journals (Sweden)

    Zhuang HQ

    2012-10-01

    Full Text Available Hong-qing Zhuang, Zhi-yong Yuan, Jun Wang, Ping Wang, Lu-jun Zhao, Bai-lin ZhangDepartment of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin Lung Cancer Center, Tianjin, People's Republic of ChinaAbstract: The clinical success of the epidermal growth factor receptor (EGFR tyrosine kinase inhibitors (TKI as therapeutic agents has prompted great interest in their further development and clinical testing for a wide variety of malignancies. However, most studies have focused on the efficacy of TKI, and few studies have been done on the criteria for their discontinuation. The current standard for drug discontinuation is “until progression”, based on change in tumor size. However, tumor size is not related to the gene expression which determines the efficacy of TKI in the final analysis, and it is also difficult to make a thorough and correct prediction based on tumor size when the TKI is discontinued. Nevertheless, clinical evaluation of the criteria for TKI discontinuation is still in its early days. Some promising findings have started to emerge. With the improving knowledge of EGFR and its inhibitors, it is expected that the criteria for discontinuation of EGFR inhibitor therapy will become clearer.Keywords: epidermal growth factor receptor, drug discontinuation, acquired drug-resistance

  19. CHECKPOINT INHIBITOR IMMUNE THERAPY: Systemic Indications and Ophthalmic Side Effects.

    Science.gov (United States)

    Dalvin, Lauren A; Shields, Carol L; Orloff, Marlana; Sato, Takami; Shields, Jerry A

    2018-06-01

    To review immune checkpoint inhibitor indications and ophthalmic side effects. A literature review was performed using a PubMed search for publications between 1990 and 2017. Immune checkpoint inhibitors are designed to treat system malignancies by targeting one of three ligands, leading to T-cell activation for attack against malignant cells. These ligands (and targeted drug) include cytotoxic T-lymphocyte antigen-4 (CTLA-4, ipilimumab), programmed death protein 1 (PD-1, pembrolizumab, nivolumab), and programmed death ligand-1 (PD-L1, atezolizumab, avelumab, durvalumab). These medications upregulate the immune system and cause autoimmune-like side effects. Ophthalmic side effects most frequently manifest as uveitis (1%) and dry eye (1-24%). Other side effects include myasthenia gravis (n = 19 reports), inflammatory orbitopathy (n = 11), keratitis (n = 3), cranial nerve palsy (n = 3), optic neuropathy (n = 2), serous retinal detachment (n = 2), extraocular muscle myopathy (n = 1), atypical chorioretinal lesions (n = 1), immune retinopathy (n = 1), and neuroretinitis (n = 1). Most inflammatory side effects are managed with topical or periocular corticosteroids, but advanced cases require systemic corticosteroids and cessation of checkpoint inhibitor therapy. Checkpoint inhibitors enhance the immune system by releasing inhibition on T cells, with risk of autoimmune-like side effects. Ophthalmologists should include immune-related adverse events in their differential when examining cancer patients with new ocular symptoms.

  20. Inhibitors of the Hydrolytic Enzyme Dimethylarginine Dimethylaminohydrolase (DDAH: Discovery, Synthesis and Development

    Directory of Open Access Journals (Sweden)

    Rhys B. Murphy

    2016-05-01

    Full Text Available Dimethylarginine dimethylaminohydrolase (DDAH is a highly conserved hydrolytic enzyme found in numerous species, including bacteria, rodents, and humans. In humans, the DDAH-1 isoform is known to metabolize endogenous asymmetric dimethylarginine (ADMA and monomethyl arginine (l-NMMA, with ADMA proposed to be a putative marker of cardiovascular disease. Current literature reports identify the DDAH family of enzymes as a potential therapeutic target in the regulation of nitric oxide (NO production, mediated via its biochemical interaction with the nitric oxide synthase (NOS family of enzymes. Increased DDAH expression and NO production have been linked to multiple pathological conditions, specifically, cancer, neurodegenerative disorders, and septic shock. As such, the discovery, chemical synthesis, and development of DDAH inhibitors as potential drug candidates represent a growing field of interest. This review article summarizes the current knowledge on DDAH inhibition and the derived pharmacokinetic parameters of the main DDAH inhibitors reported in the literature. Furthermore, current methods of development and chemical synthetic pathways are discussed.

  1. Rho-associated kinase inhibitors: a novel glaucoma therapy.

    Science.gov (United States)

    Inoue, Toshihiro; Tanihara, Hidenobu

    2013-11-01

    The rho-associated kinase (ROCK) signaling pathway is activated via secreted bioactive molecules or via integrin activation after extracellular matrix binding. These lead to polymerization of actin stress fibers and formation of focal adhesions. Accumulating evidence suggests that actin cytoskeleton-modulating signals are involved in aqueous outflow regulation. Aqueous humor contains various biologically active factors, some of which are elevated in glaucomatous eyes. These factors affect aqueous outflow, in part, through ROCK signaling modulation. Various drugs acting on the cytoskeleton have also been shown to increase aqueous outflow by acting directly on outflow tissue. In vivo animal studies have shown that the trabecular meshwork (TM) actin cytoskeleton in glaucomatous eyes is more disorganized and more randomly oriented than in non-glaucomatous control eyes. In a previous study, we introduced ROCK inhibitors as a potential glaucoma therapy by showing that a selective ROCK inhibitor significantly lowered rabbit IOP. Rho-associated kinase inhibitors directly affect the TM and Schlemm's canal (SC), differing from the target sight of other glaucoma drugs. The TM is affected earlier and more strongly than ciliary muscle cells by ROCK inhibitors, largely because of pharmacological affinity differences stemming from regulatory mechanisms. Additionally, ROCK inhibitors disrupt tight junctions, result in F-actin depolymerization, and modulate intracellular calcium level, effectively increasing SC-cell monolayer permeability. Perfusion of an enucleated eye with a ROCK inhibitor resulted in wider empty spaces in the juxtacanalicular (JCT) area and more giant vacuoles in the endothelial cells of SC, while the endothelial lining of SC was intact. Interestingly, ROCK inhibitors also increase retinal blood flow by relaxing vascular smooth muscle cells, directly protecting neurons against various stresses, while promoting wound healing. These additional effects may help

  2. Meta-analysis of genome-wide association studies on the intolerance of angiotensin-converting enzyme inhibitors

    NARCIS (Netherlands)

    Mahmoudpour, Seyed H.; Veluchamy, Abirami; Siddiqui, Moneeza K.; Asselbergs, Folkert W.; Souverein, Patrick C.; De Keyser, Catherine E.; Hofman, Albert; Lang, Chim C.; Doney, Alexander S.F.; Stricker, Bruno H.; De Boer, Anthonius; Maitland-Van Der Zee, Anke H.; Palmer, Colin N.A.

    2017-01-01

    Objectives To identify single nucleotide polymorphisms (SNPs) associated with switching from an angiotensin-converting enzyme (ACE)-inhibitor to an angiotensin receptor blocker. Methods Two cohorts of patients starting ACE-inhibitors were identified within the Rotterdam Study in the Netherlands and

  3. Angiotensin-Converting Enzyme Inhibitors and the Risk of Congenital Malformations.

    Science.gov (United States)

    Bateman, Brian T; Patorno, Elisabetta; Desai, Rishi J; Seely, Ellen W; Mogun, Helen; Dejene, Sara Z; Fischer, Michael A; Friedman, Alexander M; Hernandez-Diaz, Sonia; Huybrechts, Krista F

    2017-01-01

    To examine the association between first-trimester angiotensin-converting enzyme (ACE) inhibitor exposure and the risk of overall major congenital, cardiac, and central nervous system malformations. We used a cohort of completed pregnancies linked to liveborn neonates derived from Medicaid claims from 2000 to 2010. We examined the risk of malformations associated with first-trimester exposure to an ACE inhibitor. Propensity score-based methods were used to control for potential confounders including maternal demographics, medical conditions, exposure to other medications, and measures of health care utilization. The cohort included 1,333,624 pregnancies, of which 4,107 (0.31%) were exposed to ACE inhibitors during the first trimester. The prevalence of overall malformations in the ACE inhibitor-exposed pregnancies was 5.9% compared with 3.3% in the unexposed (unadjusted relative risk, 1.82; 95% confidence interval [CI] 1.61-2.06), of cardiac malformations was 3.4% compared with 1.2% (relative risk 2.95, 95% CI 2.50-3.47), and of central nervous system malformations was 0.27% compared with 0.18% (relative risk 1.46, 95% CI 0.81-2.64). After restricting the cohort to pregnancies complicated by chronic hypertension (both exposed and unexposed) and accounting for other confounding factors, there was no significant increase in the risk of any of the outcomes assessed. Relative risks associated with first-trimester ACE inhibitor exposure were 0.89 (95% CI 0.75-1.06) for overall malformations, 0.95 (95% CI 0.75-1.21) for cardiac malformations, and 0.54 (95% CI 0.26-1.11) for CNS malformations. After accounting for confounders, among women with hypertension, exposure to ACE inhibitors during the first trimester was not associated with an increased risk of major congenital malformations.

  4. Interruption of enzyme replacement therapy in Gaucher disease.

    Science.gov (United States)

    Goldblatt, J; Fletcher, J M; McGill, J; Szer, J; Wilson, M

    2016-05-25

    In Australia, 58 patients with Gaucher disease were managed by a Gaucher Disease Advisory Committee (GDAC) through a centrally adminis-tered national programme, the Life Savings Drug Program (LSDP). In June 2009, Genzyme Corporation, which manufactures imiglucerase (Cerezyme), the only enzyme replacement therapy (ERT) registered for the treatment of Gaucher disease in Australia at that time, announced that due to a viral contamination problem there would be no further shipments of Cerezyme to Australia prior to the end of 2009. The GDAC allocated available drug supplies in order to maintain treatment to those most in need on a hierarchal clinical severity basis. A cohort of 24 patients with Type 1 Gaucher disease was withdrawn from therapy, 22 of whom had no discernible clinically significant adverse effects when reviewed off therapy for up to 6 months. In this paper, we review the course of 20 of the patients who have been on imiglucerase for periods of at least 24 months after the end of their 'drug holiday'. No patient experienced a bone crisis nor clinical nor magnetic resonance imaging evidence of new avascular necrosis events during this period. Two years after recommencing ERT after a 6-month drug holiday, no patient had developed an overt irreversible complication of their Gaucher disease, with the majority returning to their previous clinical status.

  5. Parental experience of enzyme replacement therapy for Hunter syndrome.

    Science.gov (United States)

    Buraczewska, M; O'Leary, D; Walsh, O; Monavari, A; Crushell, E

    2013-04-01

    We aimed to establish the profile of Irish patients with Hunter Syndrome (Mucopolysaccharidosis type II, MPS II) receiving weekly intravenous Enzyme Replacement Therapy (ERT) with recombinant iduronate-2-sulfatase and to assess the social impact and parental opinion of ERT through the use of a parental questionnaire. Nine patients aged 3.5- 14 years have received a mean of 2 (range 0.5-3.5) years of ERT. Treatment was associated with clinical improvements from baseline in hepatosplenomegaly in 6/7 (85%) respiratory manifestations in 4/6 (67%) and a mean reduction in urinary glycosaminoglycan excretion of 62%. Changes noted by parents included increased energy 3/9 (33%) and softening of skin, hair and facial features 8/9 (89%). Parents report that seven hours weekly were spent on hospitalizations for ERT. Parental employment was adversely affected in 8 (89%) families. One day of school/preschool (20%) was lost every week for 8 (89%) children. All parents believed the benefits of ERT out-weigh the difficulties involved. All families would welcome the introduction of home based therapy. In conclusion the social and educational burden of hospital-based ERT on these children and their families is significant. The introduction of home-based therapy is likely to improve overall quality of life for MPSII patients and their families.

  6. Affinity Crystallography: A New Approach to Extracting High-Affinity Enzyme Inhibitors from Natural Extracts.

    Science.gov (United States)

    Aguda, Adeleke H; Lavallee, Vincent; Cheng, Ping; Bott, Tina M; Meimetis, Labros G; Law, Simon; Nguyen, Nham T; Williams, David E; Kaleta, Jadwiga; Villanueva, Ivan; Davies, Julian; Andersen, Raymond J; Brayer, Gary D; Brömme, Dieter

    2016-08-26

    Natural products are an important source of novel drug scaffolds. The highly variable and unpredictable timelines associated with isolating novel compounds and elucidating their structures have led to the demise of exploring natural product extract libraries in drug discovery programs. Here we introduce affinity crystallography as a new methodology that significantly shortens the time of the hit to active structure cycle in bioactive natural product discovery research. This affinity crystallography approach is illustrated by using semipure fractions of an actinomycetes culture extract to isolate and identify a cathepsin K inhibitor and to compare the outcome with the traditional assay-guided purification/structural analysis approach. The traditional approach resulted in the identification of the known inhibitor antipain (1) and its new but lower potency dehydration product 2, while the affinity crystallography approach led to the identification of a new high-affinity inhibitor named lichostatinal (3). The structure and potency of lichostatinal (3) was verified by total synthesis and kinetic characterization. To the best of our knowledge, this is the first example of isolating and characterizing a potent enzyme inhibitor from a partially purified crude natural product extract using a protein crystallographic approach.

  7. Cerebral magnetic resonance findings during enzyme replacement therapy in mucopolysaccharidosis

    International Nuclear Information System (INIS)

    Matsubara, Yoshiko; Miyazaki, Osamu; Nosaka, Shunsuke; Kosuga, Motomichi; Okuyama, Torayuki

    2017-01-01

    Although enzyme replacement therapy (ERT) is an effective treatment for mucopolysaccharidosis (MPS) types I, II, IVA and VI, its effectiveness in children with central nervous system (CNS) disorders is said to be poor because the blood-brain barrier cannot be penetrated by ERT drugs. To assess CNS involvement in mucopolysaccharidosis at the start of enzyme replacement therapy and to investigate the time course of ERT in the central nervous system. We performed brain MRI in 17 children and young adults who underwent ERT. The clinical severity was classified as attenuated or severe by a specialist pediatrician, based on the clinical symptoms and genotypes. At the start of ERT, we scored nine parameters using two- or three-point scales based on the severity of the disease revealed on MRI scans. After the start of ERT, we compared the initial and follow-up MRI scans, and classified the findings as no change, improved or worse. We then compared the results with the changes in clinical findings. At the start of ERT, comparison of the clinical symptoms and image scores revealed differences between severe and attenuated mucopolysaccharidosis. The scores in patients with severe MPS ranged from 9 to 16 (mean 12.2); for patients with attenuated MPS, they ranged from 2 to 11 (mean 6.4). Images of the four patients with severe MPS showed ventricular dilation and brain atrophy. Such findings were made in only 2 of 13 patients with attenuated MPS. The results after the start of ERT showed that 11/17 (65%) patients manifested improvement or no change. All five patients with MPS I experienced improvement in some regions. There were no new lesions. One patient with MPS II experienced worsening of his CNS symptoms, and his MRI findings revealed more severe ventricular dilation, brain atrophy and white matter lesions. Ventricular dilation and brain atrophy on imaging studies might represent useful markers in predicting the severity of mucopolysaccharidosis and worsening of CNS

  8. Cerebral magnetic resonance findings during enzyme replacement therapy in mucopolysaccharidosis

    Energy Technology Data Exchange (ETDEWEB)

    Matsubara, Yoshiko [Division of Radiology, National Center for Child Health and Development, Tokyo (Japan); Hiroshima University, Department of Diagnostic Radiology, Hiroshima (Japan); Miyazaki, Osamu; Nosaka, Shunsuke [Division of Radiology, National Center for Child Health and Development, Tokyo (Japan); Kosuga, Motomichi [Division of Medical Genetics, National Center for Child Health and Development, Tokyo (Japan); Okuyama, Torayuki [Department of Clinical Laboratory Medicine, National Center for Child Health and Development, Tokyo (Japan)

    2017-11-15

    Although enzyme replacement therapy (ERT) is an effective treatment for mucopolysaccharidosis (MPS) types I, II, IVA and VI, its effectiveness in children with central nervous system (CNS) disorders is said to be poor because the blood-brain barrier cannot be penetrated by ERT drugs. To assess CNS involvement in mucopolysaccharidosis at the start of enzyme replacement therapy and to investigate the time course of ERT in the central nervous system. We performed brain MRI in 17 children and young adults who underwent ERT. The clinical severity was classified as attenuated or severe by a specialist pediatrician, based on the clinical symptoms and genotypes. At the start of ERT, we scored nine parameters using two- or three-point scales based on the severity of the disease revealed on MRI scans. After the start of ERT, we compared the initial and follow-up MRI scans, and classified the findings as no change, improved or worse. We then compared the results with the changes in clinical findings. At the start of ERT, comparison of the clinical symptoms and image scores revealed differences between severe and attenuated mucopolysaccharidosis. The scores in patients with severe MPS ranged from 9 to 16 (mean 12.2); for patients with attenuated MPS, they ranged from 2 to 11 (mean 6.4). Images of the four patients with severe MPS showed ventricular dilation and brain atrophy. Such findings were made in only 2 of 13 patients with attenuated MPS. The results after the start of ERT showed that 11/17 (65%) patients manifested improvement or no change. All five patients with MPS I experienced improvement in some regions. There were no new lesions. One patient with MPS II experienced worsening of his CNS symptoms, and his MRI findings revealed more severe ventricular dilation, brain atrophy and white matter lesions. Ventricular dilation and brain atrophy on imaging studies might represent useful markers in predicting the severity of mucopolysaccharidosis and worsening of CNS

  9. Δ9-tetrahydrocannabinol and endocannabinoid degradative enzyme inhibitors attenuate intracranial self-stimulation in mice.

    Science.gov (United States)

    Wiebelhaus, Jason M; Grim, Travis W; Owens, Robert A; Lazenka, Matthew F; Sim-Selley, Laura J; Abdullah, Rehab A; Niphakis, Micah J; Vann, Robert E; Cravatt, Benjamin F; Wiley, Jenny L; Negus, S Stevens; Lichtman, Aron H

    2015-02-01

    A growing body of evidence implicates endogenous cannabinoids as modulators of the mesolimbic dopamine system and motivated behavior. Paradoxically, the reinforcing effects of Δ(9)-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, have been difficult to detect in preclinical rodent models. In this study, we investigated the impact of THC and inhibitors of the endocannabinoid hydrolytic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on operant responding for electrical stimulation of the medial forebrain bundle [intracranial self-stimulation (ICSS)], which is known to activate the mesolimbic dopamine system. These drugs were also tested in assays of operant responding for food reinforcement and spontaneous locomotor activity. THC and the MAGL inhibitor JZL184 (4-[bis(1,3-benzodioxol-5-yl)hydroxymethyl]-1-piperidinecarboxylic acid 4-nitrophenyl ester) attenuated operant responding for ICSS and food, and also reduced spontaneous locomotor activity. In contrast, the FAAH inhibitor PF-3845 (N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidinecarboxamide) was largely without effect in these assays. Consistent with previous studies showing that combined inhibition of FAAH and MAGL produces a substantially greater cannabimimetic profile than single enzyme inhibition, the dual FAAH-MAGL inhibitor SA-57 (4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester) produced a similar magnitude of ICSS depression as that produced by THC. ICSS attenuation by JZL184 was associated with increased brain levels of 2-arachidonoylglycerol (2-AG), whereas peak effects of SA-57 were associated with increased levels of both N-arachidonoylethanolamine (anandamide) and 2-AG. The cannabinoid receptor type 1 receptor antagonist rimonabant, but not the cannabinoid receptor type 2 receptor antagonist SR144528, blocked the attenuating effects of THC, JZL184, and SA-57 on

  10. Electroconvulsive therapy in patients taking monoamine oxidase inhibitors.

    Science.gov (United States)

    Dolenc, Tamara J; Habl, Samar S; Barnes, Roxann D; Rasmussen, Keith G

    2004-12-01

    Concerns have been expressed regarding the use of general anesthesia for electroconvulsive therapy (ECT) in patients taking monoamine oxidase inhibitors (MAOIs). We review the published literature and present 4 new cases and conclude that there is no evidence of a dangerous interaction between ECT and MAOI use. In general, a cautious approach would be to discontinue MAOIs before ECT if the medication has not been helpful; however, there is no need for a washout interval before starting ECT. Furthermore, if there is otherwise a reason for continuing the MAOI, it can be continued during index ECT or initiated during maintenance ECT.

  11. Pharmacogenetic Risk Stratification in Angiotensin-Converting Enzyme Inhibitor-Treated Patients with Congestive Heart Failure

    DEFF Research Database (Denmark)

    Nelveg-Kristensen, Karl Emil; Busk Madsen, Majbritt; Torp-Pedersen, Christian

    2015-01-01

    BACKGROUND: Evidence for pharmacogenetic risk stratification of angiotensin-converting enzyme inhibitor (ACEI) treatment is limited. Therefore, in a cohort of ACEI-treated patients with congestive heart failure (CHF), we investigated the predictive value of two pharmacogenetic scores...... SNPs of the angiotensin-converting enzyme gene (rs4343) and ABO blood group genes (rs495828 and rs8176746). METHODS: Danish patients with CHF enrolled in the previously reported Echocardiography and Heart Outcome Study were included. Subjects were genotyped and categorized according to pharmacogenetic.......05 [95% CI 0.79-1.40]), respectively. CONCLUSIONS: We found no association between either of the analyzed pharmacogenetic scores and fatal outcomes in ACEI-treated patients with CHF....

  12. Phage display-derived inhibitor of the essential cell wall biosynthesis enzyme MurF

    Directory of Open Access Journals (Sweden)

    Blewett Ann

    2008-12-01

    Full Text Available Abstract Background To develop antibacterial agents having novel modes of action against bacterial cell wall biosynthesis, we targeted the essential MurF enzyme of the antibiotic resistant pathogen Pseudomonas aeruginosa. MurF catalyzes the formation of a peptide bond between D-Alanyl-D-Alanine (D-Ala-D-Ala and the cell wall precursor uridine 5'-diphosphoryl N-acetylmuramoyl-L-alanyl-D-glutamyl-meso-diaminopimelic acid (UDP-MurNAc-Ala-Glu-meso-A2pm with the concomitant hydrolysis of ATP to ADP and inorganic phosphate, yielding UDP-N-acetylmuramyl-pentapeptide. As MurF acts on a dipeptide, we exploited a phage display approach to identify peptide ligands having high binding affinities for the enzyme. Results Screening of a phage display 12-mer library using purified P. aeruginosa MurF yielded to the identification of the MurFp1 peptide. The MurF substrate UDP-MurNAc-Ala-Glumeso-A2pm was synthesized and used to develop a sensitive spectrophotometric assay to quantify MurF kinetics and inhibition. MurFp1 acted as a weak, time-dependent inhibitor of MurF activity but was a potent inhibitor when MurF was pre-incubated with UDP-MurNAc-Ala-Glu-meso-A2pm or ATP. In contrast, adding the substrate D-Ala-D-Ala during the pre-incubation nullified the inhibition. The IC50 value of MurFp1 was evaluated at 250 μM, and the Ki was established at 420 μM with respect to the mixed type of inhibition against D-Ala-D-Ala. Conclusion MurFp1 exerts its inhibitory action by interfering with the utilization of D-Ala-D-Ala by the MurF amide ligase enzyme. We propose that MurFp1 exploits UDP-MurNAc-Ala-Glu-meso-A2pm-induced structural changes for better interaction with the enzyme. We present the first peptide inhibitor of MurF, an enzyme that should be exploited as a target for antimicrobial drug development.

  13. Substrate reduction augments the efficacy of enzyme therapy in a mouse model of Fabry disease.

    Directory of Open Access Journals (Sweden)

    John Marshall

    Full Text Available Fabry disease is an X-linked glycosphingolipid storage disorder caused by a deficiency in the activity of the lysosomal hydrolase α-galactosidase A (α-gal. This deficiency results in accumulation of the glycosphingolipid globotriaosylceramide (GL-3 in lysosomes. Endothelial cell storage of GL-3 frequently leads to kidney dysfunction, cardiac and cerebrovascular disease. The current treatment for Fabry disease is through infusions of recombinant α-gal (enzyme-replacement therapy; ERT. Although ERT can markedly reduce the lysosomal burden of GL-3 in endothelial cells, variability is seen in the clearance from several other cell types. This suggests that alternative and adjuvant therapies may be desirable. Use of glucosylceramide synthase inhibitors to abate the biosynthesis of glycosphingolipids (substrate reduction therapy, SRT has been shown to be effective at reducing substrate levels in the related glycosphingolipidosis, Gaucher disease. Here, we show that such an inhibitor (eliglustat tartrate, Genz-112638 was effective at lowering GL-3 accumulation in a mouse model of Fabry disease. Relative efficacy of SRT and ERT at reducing GL-3 levels in Fabry mouse tissues differed with SRT being more effective in the kidney, and ERT more efficacious in the heart and liver. Combination therapy with ERT and SRT provided the most complete clearance of GL-3 from all the tissues. Furthermore, treatment normalized urine volume and uromodulin levels and significantly delayed the loss of a nociceptive response. The differential efficacies of SRT and ERT in the different tissues indicate that the combination approach is both additive and complementary suggesting the possibility of an improved therapeutic paradigm in the management of Fabry disease.

  14. A specific and potent inhibitor of glucosylceramide synthase for substrate inhibition therapy of Gaucher disease.

    Science.gov (United States)

    McEachern, Kerry Anne; Fung, John; Komarnitsky, Svetlana; Siegel, Craig S; Chuang, Wei-Lien; Hutto, Elizabeth; Shayman, James A; Grabowski, Gregory A; Aerts, Johannes M F G; Cheng, Seng H; Copeland, Diane P; Marshall, John

    2007-07-01

    An approach to treating Gaucher disease is substrate inhibition therapy which seeks to abate the aberrant lysosomal accumulation of glucosylceramide. We have identified a novel inhibitor of glucosylceramide synthase (Genz-112638) and assessed its activity in a murine model of Gaucher disease (D409V/null). Biochemical characterization of Genz-112638 showed good potency (IC(50) approximately 24nM) and specificity against the target enzyme. Mice that received drug prior to significant accumulation of substrate (10 weeks of age) showed reduced levels of glucosylceramide and number of Gaucher cells in the spleen, lung and liver when compared to age-matched control animals. Treatment of older mice that already displayed significant amounts of tissue glucosylceramide (7 months old) resulted in arrest of further accumulation of the substrate and appearance of additional Gaucher cells in affected organs. These data indicate that substrate inhibition therapy with Genz-112638 represents a viable alternate approach to enzyme therapy to treat the visceral pathology in Gaucher disease.

  15. Regulatory proteins (inhibitors or activators) affect estimates of Msub(r) of enzymes and receptors by radiation inactivation

    International Nuclear Information System (INIS)

    Potier, M.; Giroux, S.

    1985-01-01

    The radiation-inactivation method allows the determination of the Msub(r) of enzymes and receptors by monitoring the decay of biological activity as a function of absorbed dose. The presence of regulatory or effector proteins (inhibitors or activators) associated with an enzyme or receptor, or released in the preparation after tissue homogenization, may affect the decay of biological activity. How the activity is affected, however, will depend on the type of inhibition (competitive or non-competitive), the inhibitor or activator concentration, the dissociation constant of the enzyme-effector system, and the effector Msub(r) relative to that of the enzyme. Since little is known on how effector proteins influence radiation inactivation of enzymes and receptors, we have considered a theoretical model in an effort to provide a framework for the interpretation of experimentally obtained data. Our model predicts that competitive and non-competitive inhibitors of enzymes could be distinguished by analysing irradiated samples with various substrate concentrations. Inhibitors will decrease whereas activators will increase the apparent target size of enzymes or receptors. (author)

  16. Marketing research on the angiotensin-converting enzyme inhibitors antihypertensive medicines

    Science.gov (United States)

    BOBOIA, ANAMARIA; GRIGORESCU, MARIUS RAREŞ; TURCU - ŞTIOLICĂ, ADINA

    2017-01-01

    Background and aims The research aimed at investigating sales trends of angiotensin-converting enzyme inhibitors antihypertensive medicines, both in terms of quantity and value, in ten community pharmacies, for a period of three years. The research on the antihypertensive medicines consumption is important for highlighting the ever increasing impact of hypertension among the population. Methods The methods used in this research were the following: marketing research, method of sampling, descriptive methods, retrospective analysis, method of comparison. Results The results showed that the drugs containing the active substances of the angiotensin converting enzyme inhibitors class had had significant increases in quantitative and value sales, bringing substantial revenues to pharmacies. From the quantitative perspective, the best-selling products were those containing Enalaprilum, while in terms of value, the best-selling medicines were those containing Perindoprilum. We evidenced that spectacular sales were also achieved for products that have Lisinoprilum, respectively Captoprilum, as active substances. The largest quantities were marketed for the Captopril Terapia® product and the highest earnings were recorded for the Prestarium® medicine. Conclusion This paper approaches an interesting and topical issue, which can be helpful to professionals (pharmacists, doctors) and other categories, such as economists, statisticians, representatives of companies manufacturing medicines, as well as to hypertensive patients, as it could be used to warn population regarding the incidence of cardiovascular diseases, and, at the same time, trace sales trends in order to accomplish profitable business plans. PMID:28246502

  17. Marketing research on the angiotensin-converting enzyme inhibitors antihypertensive medicines.

    Science.gov (United States)

    Boboia, Anamaria; Grigorescu, Marius Rareş; Turcu-Ştiolică, Adina

    2017-01-01

    The research aimed at investigating sales trends of angiotensin-converting enzyme inhibitors antihypertensive medicines, both in terms of quantity and value, in ten community pharmacies, for a period of three years. The research on the antihypertensive medicines consumption is important for highlighting the ever increasing impact of hypertension among the population. The methods used in this research were the following: marketing research, method of sampling, descriptive methods, retrospective analysis, method of comparison. The results showed that the drugs containing the active substances of the angiotensin converting enzyme inhibitors class had had significant increases in quantitative and value sales, bringing substantial revenues to pharmacies. From the quantitative perspective, the best-selling products were those containing Enalaprilum, while in terms of value, the best-selling medicines were those containing Perindoprilum. We evidenced that spectacular sales were also achieved for products that have Lisinoprilum, respectively Captoprilum, as active substances. The largest quantities were marketed for the Captopril Terapia® product and the highest earnings were recorded for the Prestarium® medicine. This paper approaches an interesting and topical issue, which can be helpful to professionals (pharmacists, doctors) and other categories, such as economists, statisticians, representatives of companies manufacturing medicines, as well as to hypertensive patients, as it could be used to warn population regarding the incidence of cardiovascular diseases, and, at the same time, trace sales trends in order to accomplish profitable business plans.

  18. Engineering of GlcNAc-1-Phosphotransferase for Production of Highly Phosphorylated Lysosomal Enzymes for Enzyme Replacement Therapy.

    Science.gov (United States)

    Liu, Lin; Lee, Wang-Sik; Doray, Balraj; Kornfeld, Stuart

    2017-06-16

    Several lysosomal enzymes currently used for enzyme replacement therapy in patients with lysosomal storage diseases contain very low levels of mannose 6-phosphate, limiting their uptake via mannose 6-phosphate receptors on the surface of the deficient cells. These enzymes are produced at high levels by mammalian cells and depend on endogenous GlcNAc-1-phosphotransferase α/β precursor to phosphorylate the mannose residues on their glycan chains. We show that co-expression of an engineered truncated GlcNAc-1-phosphotransferase α/β precursor and the lysosomal enzyme of interest in the producing cells resulted in markedly increased phosphorylation and cellular uptake of the secreted lysosomal enzyme. This method also results in the production of highly phosphorylated acid β-glucocerebrosidase, a lysosomal enzyme that normally has just trace amounts of this modification.

  19. Metabolic complications associated with HIV protease inhibitor therapy.

    Science.gov (United States)

    Nolan, David

    2003-01-01

    HIV protease inhibitors were introduced into clinical practice over 7 years ago as an important component of combination antiretroviral drug regimens which in many ways revolutionised the treatment of HIV infection. The significant improvements in prognosis that have resulted from the use of these regimens, combined with the need for lifelong treatment, have increasingly focused attention on the adverse effects of antiretroviral drugs and on the metabolic complications of HIV protease inhibitors in particular. In this review, the cluster of metabolic abnormalities characterised by triglyceride-rich dyslipidaemia and insulin resistance associated with HIV protease inhibitor therapy are considered, along with implications for cardiovascular risk in patients affected by these complications. Toxicity profiles of individual drugs within the HIV protease inhibitor class are examined, as there is an increased recognition of significant intra-class differences both in terms of absolute risk of metabolic complications as well as the particular metabolic phenotype associated with these drugs. Guidelines for clinical assessment and treatment are emphasised, along with pathophysiological mechanisms that may provide a rational basis for the treatment of metabolic complications. Finally, these drug-specific effects are considered within the context of HIV-specific effects on lipid metabolism as well as lifestyle factors that have contributed to a rapidly increasing incidence of similar metabolic syndromes in the general population. These data highlight the importance of individualising patient management in terms of choice of antiretroviral regimen, assessment of metabolic outcomes and use of therapeutic interventions, based on the assessment of baseline (pre-treatment) metabolic status as well as the presence of potentially modifiable cardiovascular risk factors.

  20. Peripheral artery disease: potential role of ACE-inhibitor therapy

    Directory of Open Access Journals (Sweden)

    Giuseppe Coppola

    2008-12-01

    Full Text Available Giuseppe Coppola, Giuseppe Romano, Egle Corrado, Rosa Maria Grisanti, Salvatore NovoDepartment of Internal Medicine, Cardiovascular and Nephro-Urological Diseases, Chair of Cardiovascular Disease, University of Palermo, Palermo, ItalyAbstract: Subjects with peripheral arterial disease (PAD of the lower limbs are at high risk for cardiovascular and cerebrovascular events and the prevalence of coronary artery disease in such patients is elevated. Recent studies have shown that regular use of cardiovascular medications, such as therapeutic and preventive agents for PAD patients, seems to be promising in reducing long-term mortality and morbidity. The angiotensin-converting-enzyme (ACE system plays an important role in the pathogenesis and progression of atherosclerosis, and ACE-inhibitors (ACE-I seem to have vasculoprotective and antiproliferative effects as well as a direct antiatherogenic effect. ACE-I also promote the degradation of bradykinin and the release of nitric oxide, a potent vasodilator; further, thay have shown important implications for vascular oxidative stress. Other studies have suggested that ACE-I may also improve endothelial dysfunction. ACE-I are useful for reducing the risk of cardiovascular events in clinical and subclinical PAD. Particularly, one agent of the class (ie, ramipril has shown in many studies to able to significantly reduce cardiovascular morbidity and mortality in patients with PAD.Keywords: atherosclerosis, peripheral arterial disease, endothelial dysfunction, ACE-inhibitors

  1. Development of novel arginase inhibitors for therapy of endothelial dysfunction

    Directory of Open Access Journals (Sweden)

    Jochen eSteppan

    2013-09-01

    Full Text Available Endothelial dysfunction and resulting vascular pathology have been identified as an early hallmark of multiple diseases, including diabetes mellitus. One of the major contributors to endothelial dysfunction is a decrease in nitric oxide (NO bioavailability, impaired NO signaling and an increase in the amount of reactive oxygen species (ROS. In the endothelium NO is produced by eNOS (endothelial nitric oxide synthase, for which L-arginine is a substrate. Arginase, an enzyme critical in the urea cycle also metabolizes L-arginine, thereby directly competing with eNOS for their common substrate and constraining its bioavailability for eNOS, thereby compromising NO production. Arginase expression and activity is upregulated in many cardiovascular diseases including ischemia reperfusion injury, hypertension, atherosclerosis, and diabetes mellitus. More importantly, since the 1990s, specific arginase inhibitors such as N-hydroxy-guanidinium or N-hydroxy-nor-L-arginine, and boronic acid derivatives, such as, 2(S-amino-6-boronohexanoic acid, and S-(2-boronoethyl-L-cysteine (BEC, that can bridge the binuclear manganese cluster of arginase have been developed. These highly potent and specific inhibitors can now be used to probe arginase function and thereby modulate the redox milieu of the cell by changing the balance between NO and ROS. Inspired by this success, drug discovery programs have recently led to the identification of α-α-disubstituted amino acid based arginase inhibitors (such as (R-2-amino-6-borono-2-(2-(piperidin-1-ylethylhexanoic acid, that are currently under early investigation as therapeutics. Finally, some investigators concentrate on identification of plant derived compounds with arginase inhibitory capability, such as piceatannol-3'-O-β-D-glucopyranoside (PG. All of these synthesized or naturally derived small molecules may represent novel therapeutics for vascular disease particularly that associated with diabetes.

  2. Transition-state characterization: a new approach combining inhibitor analogues and variation in enzyme structure.

    Science.gov (United States)

    Phillips, M A; Kaplan, A P; Rutter, W J; Bartlett, P A

    1992-02-04

    A new strategy of potentially broad application for probing transition-state (TS) analogy in enzymatic systems is described in this paper. The degree to which a series of phosphonate inhibitors act as TS analogues of rat carboxypeptidase A1 has been determined for the wild-type enzyme, for the R127K, R127M, and R127A mutants, and for the R127A mutant in the presence of 0.5 M guanidine hydrochloride. The impact that the mutations have on the inverse second-order rate constants (Km/kcat) for substrate hydrolysis is mirrored by the effect on the inhibition constants (Ki) for the corresponding phosphonate inhibitors. These results demonstrate that the phosphonate moiety mimics some of the electronic as well as the geometric characteristics of the TS. A similar but distinctly separate correlation is observed for tripeptide analogues in comparison to analogues of the dipeptide Cbz-Gly-Phe, reflecting an anomalous mode of binding for the latter system. The selective rate increases and corresponding enhancement in inhibitor binding observed on addition of 0.5 M guanidine hydrochloride to the R127A mutant indicate that the exogenous cation can assume the role played by Arg-127 in stabilizing the TS and in providing substrate selectivity at the P2 position.

  3. Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones.

    Science.gov (United States)

    Maianti, Juan Pablo; McFedries, Amanda; Foda, Zachariah H; Kleiner, Ralph E; Du, Xiu Quan; Leissring, Malcolm A; Tang, Wei-Jen; Charron, Maureen J; Seeliger, Markus A; Saghatelian, Alan; Liu, David R

    2014-07-03

    Despite decades of speculation that inhibiting endogenous insulin degradation might treat type-2 diabetes, and the identification of IDE (insulin-degrading enzyme) as a diabetes susceptibility gene, the relationship between the activity of the zinc metalloprotein IDE and glucose homeostasis remains unclear. Although Ide(-/-) mice have elevated insulin levels, they exhibit impaired, rather than improved, glucose tolerance that may arise from compensatory insulin signalling dysfunction. IDE inhibitors that are active in vivo are therefore needed to elucidate IDE's physiological roles and to determine its potential to serve as a target for the treatment of diabetes. Here we report the discovery of a physiologically active IDE inhibitor identified from a DNA-templated macrocycle library. An X-ray structure of the macrocycle bound to IDE reveals that it engages a binding pocket away from the catalytic site, which explains its remarkable selectivity. Treatment of lean and obese mice with this inhibitor shows that IDE regulates the abundance and signalling of glucagon and amylin, in addition to that of insulin. Under physiological conditions that augment insulin and amylin levels, such as oral glucose administration, acute IDE inhibition leads to substantially improved glucose tolerance and slower gastric emptying. These findings demonstrate the feasibility of modulating IDE activity as a new therapeutic strategy to treat type-2 diabetes and expand our understanding of the roles of IDE in glucose and hormone regulation.

  4. The Evaluation of Angiotensin-Converting Enzyme Inhibitors in Renal Elimination with Selected Molecular Descriptors

    Directory of Open Access Journals (Sweden)

    Trbojevic Jovana

    2017-06-01

    Full Text Available Angiotensin-converting enzyme (ACE inhibitors modulate the function of the renin-angiotensin-aldosterone system, and they are commonly prescribed antihypertensive drugs especially in patients with renal failure. In this study, the relationships between several molecular properties of eight ACE inhibitors (enalapril, quinapril, fosinopril, ramipril, benazepril, perindopril, moexipril, trandolapril and their renal elimination data, from relevant literature, were investigated. The ’molecular descriptors of the ACE inhibitors, which included aqueous solubility data (logS; an electronic descriptor, polar surface area (PSA;, a constitutional parameter, molecular mass (Mr; and a geometric descriptor, volume value (Vol, as well as lipophilicity descriptors (logP values, were calculated using different software packages. Simple linear regression analysis showed the best correlation between renal elimination data and lipophilicity descriptor AClogP values (R2 = 0.5742. In the next stage of the study, multiple linear regression was applied to assess a higher correlation between the ACE inhibitors’ renal elimination data and lipophilicity, AClogP, with one additional descriptor as an independent variable. Good correlations were established between renal elimination data from the literature and the AClogP lipophilicity descriptor using the constitutional parameter (molecular mass (R2 = 0.7425 or the geometric descriptor (volume value (R2 = 0.7224 as an independent variable. The application of computed molecular descriptors in evaluating drug elimination is of great importance in drug research.

  5. Pyrimidine nucleoside analogues, potential chemotherapeutic agents, and substrates/inhibitors in various enzyme systems

    International Nuclear Information System (INIS)

    Kulikowski, T.; Bretner, M.; Felczak, K.; Drabikowska, A.; Shugar, D.

    1998-01-01

    Full text. Pyrimidine nucleoside analogues are an important class of compounds with antimetabolic (antitumor, antiparasitic and antiviral) properties. The synthesis of thiated nucleoside and nucleotide analogues, determination of structures, conformation and dissociation constans, their potential chemotherapeutic activities, and their substrate/inhibitor properties in various enzyme systems, with emphasis on enzymes related to chemotherapeutic activities, were investigated. In the series of thionated inhibitors of thymidylate synthase (TS), potential antitumor agents, regioselective syntheses were elaborated for 2- and 4-thio, and 2,4-dithio derivatives of 2'-deoxyuridine (dUrd), 5-fluoro-2'-deoxyuridine (FdUrd), and several other 5-fluoro-, 5-bromo- and 5-trifluoromethyl congeners, and the 2-thio derivatives of FdUrd and its α-anomer, which proved to be selective agents with high cytotoxicities correlated with the inhibitory activities vs TS of their corresponding 5'-monophosphates. Regioslective syntheses were also elaborated for 2'-deoxycytidin e and 5-fluoro-2'-deoxycitidine derivatives. Solution conformation of these nucleosides were deduced from high-resolution (500 MHz) 1 H NMR spectra. Substrate/inhibitor properties of 2-thio-2'-deoxycitidine (S 2 dCyd) and 5-fluoro-2-thio-2'-deoxycitidine ( S 2 FdCyd) with respect to human leukemic spleen deoxycytidine kinase have been examined. Both are substrates, and also good inhibitors, of phosphorylation of 2'-deoxycitidine and 2'-deoxyadenosine. Particular attention was directed to the specificity of t he NTP phosphate donor for several nucleoside kinases, and procedures have been developed for distinguishing between ATP and other NTP donors, a problem of importance in chemotherapy with nucleoside analogues. Biological properties of the newly synthetize d thiated pyrimidine 2',3'-dideoxy-3'-fluoronucleosides, S 2 ,3'-FddUrd and S 2 ,3'-FddThd, were also investigated. Thiated 3'-fluoronucleosides were moderate

  6. Characterization of Cellulase Enzyme Inhibitors Formed During the Chemical Pretreatments of Rice Straw

    Science.gov (United States)

    Rajan, Kalavathy

    Production of fuels and chemicals from a renewable and inexpensive resource such as lignocellulosic biomass is a lucrative and sustainable option for the advanced biofuel and bio-based chemical platform. Agricultural residues constitute the bulk of potential feedstock available for cellulosic fuel production. On a global scale, rice straw is the largest source of agricultural residues and is therefore an ideal crop model for biomass deconstruction studies. Lignocellulosic biofuel production involves the processes of biomass conditioning, enzymatic saccharification, microbial fermentation and ethanol distillation, and one of the major factors affecting its techno-economic feasibility is the biomass recalcitrance to enzymatic saccharification. Preconditioning of lignocellulosic biomass, using chemical, physico-chemical, mechanical and biological pretreatments, is often practiced such that biomass becomes available to downstream processing. Pretreatments, such as dilute acid and hot water, are effective means of biomass conversion. However, despite their processing importance, preconditioning biomass also results in the production of carbohydrate and lignin degradation products that are inhibitory to downstream saccharification enzymes. The saccharification enzyme cocktail is made up of endo-cellulase, exo-cellulase and beta-glucosidase enzymes, whose role is to cleave cellulose polymers into glucose monomers. Specifically, endo-cellulase and exo-cellulase enzymes cleave cellulose chains in the middle and at the end, resulting in cellobiose molecules, which are hydrolyzed into glucose by beta-glucosidase. Unfortunately, degradation compounds generated during pretreatment inhibit the saccharification enzyme cocktail. Various research groups have identified specific classes of inhibitors formed during biomass pretreatment and have studied their inhibitory effect on the saccharification cocktail. These various research groups prepared surrogate solutions in an attempt to

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

    DEFF Research Database (Denmark)

    Hermanrud, Thorbjørn; Duus, Nicolaj; Bygum, Anette

    2016-01-01

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

  8. Enzyme-coupled nanoparticles-assisted laser desorption ionization mass spectrometry for searching for low-mass inhibitors of enzymes in complex mixtures.

    Science.gov (United States)

    Salwiński, Aleksander; Da Silva, David; Delépée, Raphaël; Maunit, Benoît

    2014-04-01

    In this report, enzyme-coupled magnetic nanoparticles (EMPs) were shown to be an effective affinity-based tool for finding specific interactions between enzymatic targets and the low-mass molecules in complex mixtures using classic MALDI-TOF apparatus. EMPs used in this work act as nonorganic matrix enabling ionization of small molecules without any interference in the low-mass range (enzyme-coupled nanoparticles-assisted laser desorption ionization MS, ENALDI MS) and simultaneously carry the superficial specific binding sites to capture inhibitors present in a studied mixture. We evaluated ENALDI approach in two complementary variations: 'ion fading' (IF-ENALDI), based on superficial adsorption of inhibitors and 'ion hunting' (IH-ENALDI), based on selective pre-concentration of inhibitors. IF-ENALDI was applied for two sets of enzyme-inhibitor pairs: tyrosinase-glabridin and trypsin-leupeptin and for the real plant sample: Sparrmannia discolor leaf and stem methanol extract. The efficacy of IH-ENALDI was shown for the pair of trypsin-leupeptin. Both ENALDI approaches pose an alternative for bioassay-guided fractionation, the common method for finding inhibitors in the complex mixtures.

  9. Obscure bleeding colonic duplication responds to proton pump inhibitor therapy.

    Science.gov (United States)

    Jacques, Jérémie; Projetti, Fabrice; Legros, Romain; Valgueblasse, Virginie; Sarabi, Matthieu; Carrier, Paul; Fredon, Fabien; Bouvier, Stéphane; Loustaud-Ratti, Véronique; Sautereau, Denis

    2013-09-21

    We report the case of a 17-year-old male admitted to our academic hospital with massive rectal bleeding. Since childhood he had reported recurrent gastrointestinal bleeding and had two exploratory laparotomies 5 and 2 years previously. An emergency abdominal computed tomography scan, gastroscopy and colonoscopy, performed after hemodynamic stabilization, were considered normal. High-dose intravenous proton pump inhibitor (PPI) therapy was initiated and bleeding stopped spontaneously. Two other massive rectal bleeds occurred 8 h after each cessation of PPI which led to a hemostatic laparotomy after negative gastroscopy and small bowel capsule endoscopy. This showed long tubular duplication of the right colon, with fresh blood in the duplicated colon. Obscure lower gastrointestinal bleeding is a difficult medical situation and potentially life-threatening. The presence of ulcerated ectopic gastric mucosa in the colonic duplication explains the partial efficacy of PPI therapy. Obscure gastrointestinal bleeding responding to empiric anti-acid therapy should probably evoke the diagnosis of bleeding ectopic gastric mucosa such as Meckel's diverticulum or gastrointestinal duplication, and gastroenterologists should be aware of this potential medical situation.

  10. Kinetic modelling of in vitro data of PI3K, mTOR1, PTEN enzymes and on-target inhibitors Rapamycin, BEZ235, and LY294002.

    Science.gov (United States)

    Goltsov, Alexey; Tashkandi, Ghassan; Langdon, Simon P; Harrison, David J; Bown, James L

    2017-01-15

    The phosphatidylinositide 3-kinases (PI3K) and mammalian target of rapamycin-1 (mTOR1) are two key targets for anti-cancer therapy. Predicting the response of the PI3K/AKT/mTOR1 signalling pathway to targeted therapy is made difficult because of network complexities. Systems biology models can help explore those complexities but the value of such models is dependent on accurate parameterisation. Motivated by a need to increase accuracy in kinetic parameter estimation, and therefore the predictive power of the model, we present a framework to integrate kinetic data from enzyme assays into a unified enzyme kinetic model. We present exemplar kinetic models of PI3K and mTOR1, calibrated on in vitro enzyme data and founded on Michaelis-Menten (MM) approximation. We describe the effects of an allosteric mTOR1 inhibitor (Rapamycin) and ATP-competitive inhibitors (BEZ235 and LY294002) that show dual inhibition of mTOR1 and PI3K. We also model the kinetics of phosphatase and tensin homolog (PTEN), which modulates sensitivity of the PI3K/AKT/mTOR1 pathway to these drugs. Model validation with independent data sets allows investigation of enzyme function and drug dose dependencies in a wide range of experimental conditions. Modelling of the mTOR1 kinetics showed that Rapamycin has an IC 50 independent of ATP concentration and that it is a selective inhibitor of mTOR1 substrates S6K1 and 4EBP1: it retains 40% of mTOR1 activity relative to 4EBP1 phosphorylation and inhibits completely S6K1 activity. For the dual ATP-competitive inhibitors of mTOR1 and PI3K, LY294002 and BEZ235, we derived the dependence of the IC 50 on ATP concentration that allows prediction of the IC 50 at different ATP concentrations in enzyme and cellular assays. Comparison of drug effectiveness in enzyme and cellular assays showed that some features of these drugs arise from signalling modulation beyond the on-target action and MM approximation and require a systems-level consideration of the whole PI3K

  11. Use of different types of angiotensin converting enzyme inhibitors and mortality in systolic heart failure

    DEFF Research Database (Denmark)

    Svanström, Henrik; Pasternak, Björn; Melbye, Mads

    2015-01-01

    BACKGROUND: Angiotensin converting enzyme-inhibitors (ACEIs) are the first-line treatment for patients with heart failure (HF) with reduced ejection fraction (EF). The benefit of ACEIs in HF is regarded as a class effect and different types of agents are used interchangeably. However, evidence......-2012, were identified using the Danish HF Registry. New users of enalapril (n=1807), perindopril (n=1064), ramipril (n=3270), or trandolapril (n=1150), who started treatment within 60days of first-time hospital diagnosis of HF, were selected for inclusion. Subgroup analyses were conducted by sex, age, NYHA...... with ramipril. No significant differences were observed in subgroup analyses. CONCLUSIONS: These findings suggest equal effect of different types of ACEIs on mortality in systolic HF....

  12. A focused fragment library targeting the antibiotic resistance enzyme - Oxacillinase-48: Synthesis, structural evaluation and inhibitor design.

    Science.gov (United States)

    Akhter, Sundus; Lund, Bjarte Aarmo; Ismael, Aya; Langer, Manuel; Isaksson, Johan; Christopeit, Tony; Leiros, Hanna-Kirsti S; Bayer, Annette

    2018-02-10

    β-Lactam antibiotics are of utmost importance when treating bacterial infections in the medical community. However, currently their utility is threatened by the emergence and spread of β-lactam resistance. The most prevalent resistance mechanism to β-lactam antibiotics is expression of β-lactamase enzymes. One way to overcome resistance caused by β-lactamases, is the development of β-lactamase inhibitors and today several β-lactamase inhibitors e.g. avibactam, are approved in the clinic. Our focus is the oxacillinase-48 (OXA-48), an enzyme reported to spread rapidly across the world and commonly identified in Escherichia coli and Klebsiella pneumoniae. To guide inhibitor design, we used diversely substituted 3-aryl and 3-heteroaryl benzoic acids to probe the active site of OXA-48 for useful enzyme-inhibitor interactions. In the presented study, a focused fragment library containing 49 3-substituted benzoic acid derivatives were synthesised and biochemically characterized. Based on crystallographic data from 33 fragment-enzyme complexes, the fragments could be classified into R 1 or R 2 binders by their overall binding conformation in relation to the binding of the R 1 and R 2 side groups of imipenem. Moreover, binding interactions attractive for future inhibitor design were found and their usefulness explored by the rational design and evaluation of merged inhibitors from orthogonally binding fragments. The best inhibitors among the resulting 3,5-disubstituted benzoic acids showed inhibitory potential in the low micromolar range (IC 50  = 2.9 μM). For these inhibitors, the complex X-ray structures revealed non-covalent binding to Arg250, Arg214 and Tyr211 in the active site and the interactions observed with the mono-substituted fragments were also identified in the merged structures. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  13. Plant Proteinase Inhibitors in Therapeutics – Focus on Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Sandhya Srikanth

    2016-12-01

    Full Text Available 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 has 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

  14. Enzyme

    Science.gov (United States)

    Enzymes are complex proteins that cause a specific chemical change in all parts of the body. For ... use them. Blood clotting is another example of enzymes at work. Enzymes are needed for all body ...

  15. Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML.

    Science.gov (United States)

    Swords, Ronan T; Coutre, Steven; Maris, Michael B; Zeidner, Joshua F; Foran, James M; Cruz, Jose; Erba, Harry P; Berdeja, Jesus G; Tam, Wayne; Vardhanabhuti, Saran; Pawlikowska-Dobler, Iwona; Faessel, Hélène M; Dash, Ajeeta B; Sedarati, Farhad; Dezube, Bruce J; Faller, Douglas V; Savona, Michael R

    2018-03-29

    Pevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We performed a phase 1b study of pevonedistat (PEV) with azacitidine (AZA) based on synergistic activity seen preclinically. Primary objectives included safety and tolerability, and secondary objectives included pharmacokinetics (PK) and disease response. Patients ≥60 years with treatment-naive AML (unfit for standard induction therapy) received PEV 20 or 30 mg/m 2 IV on days 1, 3, and 5 combined with fixed-dose AZA (75 mg/m 2 IV/subcutaneously) on days 1 to 5, 8, and 9, every 28 days. The most common treatment-emergent adverse events were constipation (48%), nausea (42%), fatigue (42%), and anemia (39%). In total, 11 deaths were observed and considered unrelated to study therapy by the investigators. Transient elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were dose limiting. The recommended phase 2 dose (RP2D) of PEV in this combination is 20 mg/m 2 PEV PK was not altered by the addition of AZA. Overall response rate (ORR) based on an intent-to-treat analysis was 50% (20 complete remissions [CRs], 5 complete remission with incomplete peripheral count recovery, 7 partial remissions [PRs]), with an 8.3-month median duration of remission. In patients receiving ≥6 cycles of therapy (n = 23, 44%), ORR was 83%. In patients with TP53 mutations, the composite CR/PR rate was 80% (4/5). Two of these patients stayed on study for >10 cycles. Baseline bone marrow blast percentage or cytogenetic/molecular risk did not influence ORR. This study was registered at www.clinicaltrials.gov as #NCT01814826. © 2018 by The American Society of Hematology.

  16. Angiotensin Converting Enzyme Inhibitor Has a Protective Effect on Decompression Sickness in Rats

    Directory of Open Access Journals (Sweden)

    Aleksandra Mazur

    2018-03-01

    Full Text Available Introduction: Commercial divers, high altitude pilots, and astronauts are exposed to some inherent risk of decompression sickness (DCS, though the mechanisms that trigger are still unclear. It has been previously showed that diving may induce increased levels of serum angiotensin converting enzyme. The renin angiotensin aldosterone system (RAAS is one of the most important regulators of blood pressure and fluid volume. The purpose of the present study was to control the influence of angiotensin II on the appearance of DCS.Methods: Sprague Dawley rats have been pre-treated with inhibitor of angiotensin II receptor type 1 (losartan; 10 mg/kg, angiotensin-converting enzyme (ACE inhibitor (enalapril; 10 mg/kg, and calcium-entry blocker (nifedipine; 20 mg/kg. The experimental groups were treated for 4 weeks before exposure to hyperbaric pressure while controls were not treated. Seventy-five rats were subjected to a simulated dive at 1000 kPa absolute pressure for 45 min before starting decompression. Clinical assessment took place over a period of 60 min after surfacing. Blood samples were collected for measurements of TBARS, interleukin 6 (IL-6, angiotensin II (ANG II and ACE.Results: The diving protocol induced 60% DCS in non-treated animals. This ratio was significantly decreased after treatment with enalapril, but not other vasoactive drugs. Enalapril did not change ANG II or ACE concentration, while losartant decreased post dive level of ACE but not ANG II. None of the treatment modified the effect of diving on TBARS and IL-6 values.Conclusion: Results suggests that the rennin angiotensin system is involved in a process of triggering DCS but this has to be further investigated. However, a vasorelaxation mediated process, which potentially could increase the load of inert gas during hyperbaric exposure, and antioxidant properties were excluded by our results.

  17. CORRELATION BETWEEN ANGIOTENSIN-CONVERTING ENZYME INHIBITORS LIPOPHILICITY AND PROTEIN BINDING DATA

    Directory of Open Access Journals (Sweden)

    Jasna Trbojević-Stanković

    2012-01-01

    Full Text Available Angiotensin-converting enzyme (ACE inhibitors represent a significant group of drugs primarily used in the treatment of hypertension and congestive heart failure. In this research, seven ACE inhibitors (enalapril, quinapril, fosinopril, lisinopril, cilazapril, ramipril, benazepril were studied to evaluate the relationship between their protein binding and calculated (logP values or ultra-high performance liquid chromatographytandem mass spectrometry (UHPLC-MS and reversed-phase thin-layer chromatography (RP-TLC lipophilicity data (ϕ0, CHI or C0 parameters, respectively. Their protein binding data varied from negligible (lisinopril to 99% (fosinopril, while calculated logPKOWWINvalues ranged from -0.94 (lisinopril to 6.61 (fosinopril. The good correlations were established between protein binding values and logPKOWWIN data (R2=0.7520 as well as between protein binding and chromatographic hydrophobicity data, ϕ0, CHI or C0parameters (R2 were 0.6160, 0.6242 and 0.6547, respectively. The possible application of hydrophobicity data in drugs protein binding evaluation can be of great importance in drug bioavailability.

  18. Droplet-based microfluidics for dose-response assay of enzyme inhibitors by electrochemical method.

    Science.gov (United States)

    Gu, Shuqing; Lu, Youlan; Ding, Yaping; Li, Li; Zhang, Fenfen; Wu, Qingsheng

    2013-09-24

    A simple but robust droplet-based microfluidic system was developed for dose-response enzyme inhibition assay by combining concentration gradient generation method with electrochemical detection method. A slotted-vials array and a tapered tip capillary were used for reagents introduction and concentration gradient generation, and a polydimethylsiloxane (PDMS) microfluidic chip integrated with microelectrodes was used for droplet generation and electrochemical detection. Effects of oil flow rate and surfactant on electrochemical sensing were investigated. This system was validated by measuring dose-response curves of three types of acetylcholinesterase (AChE) inhibitors, including carbamate pesticide, organophosphorus pesticide, and therapeutic drugs regulating Alzheimer's disease. Carbaryl, chlorpyrifos, and tacrine were used as model analytes, respectively, and their IC50 (half maximal inhibitory concentration) values were determined. A whole enzyme inhibition assay was completed in 6 min, and the total consumption of reagents was less than 5 μL. This microfluidic system is applicable to many biochemical reactions, such as drug screening and kinetic studies, as long as one of the reactants or products is electrochemically active. Copyright © 2013 Elsevier B.V. All rights reserved.

  19. Cholinesterase Enzymes Inhibitors from the Leaves of Rauvolfia Reflexa and Their Molecular Docking Study

    Directory of Open Access Journals (Sweden)

    Vikneswaran Murugaiyah

    2013-03-01

    Full Text Available Plants of the Apocynaceae family have been traditionally used in the treatment of age-related brain disorders. Rauvolfia reflexa, a member of the family, has been used as an antidote for poisons and to treat malaria. The dichloromethane, ethanol and methanol extracts from the leaves of Rauvolfia reflexa showed potential acetylcholinesterase (AChE and butyrylcholinesterase (BChE inhibitory activities, with IC50 values in the 8.49 to 52.23 g/mL range. Further cholinesterase inhibitory-guided isolation of these extracts afforded four bioactive compounds, namely: (E-3-(3,4,5-trimethoxyphenylacrylic acid (1, (E-methyl 3-(4-hydroxy-3,5-dimethoxyphenyl acrylate (2, 17-methoxycarbonyl-14-heptadecaenyl-4-hydroxy-3-methoxycinnamate (3 and 1,2,3,4-tetrahydro-1-oxo-β-carboline (4. The isolated compounds showed moderate cholinesterase inhibitory activity compared to the reference standard, physostigmine. Compounds 1 and 2 showed the highest inhibitory activity against AChE (IC50 = 60.17 µM and BChE (IC50 = 61.72 µM, respectively. Despite having similar molecular weight, compounds 1 and 2 were structurally different according to their chemical substitution patterns, leading to their different enzyme inhibition selectivity. Compound 2 was more selective against BChE, whereas compound 1 was a selective inhibitor of AChE. Molecular docking revealed that both compounds 1 and 2 were inserted, but not deeply into the active site of the cholinesterase enzymes.

  20. Cholinesterase enzymes inhibitors from the leaves of Rauvolfia reflexa and their molecular docking study.

    Science.gov (United States)

    Fadaeinasab, Mehran; Hadi, A Hamid A; Kia, Yalda; Basiri, Alireza; Murugaiyah, Vikneswaran

    2013-03-25

    Plants of the Apocynaceae family have been traditionally used in the treatment of age-related brain disorders. Rauvolfia reflexa, a member of the family, has been used as an antidote for poisons and to treat malaria. The dichloromethane, ethanol and methanol extracts from the leaves of Rauvolfia reflexa showed potential acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities, with IC50 values in the 8.49 to 52.23 g/mL range. Further cholinesterase inhibitory-guided isolation of these extracts afforded four bioactive compounds, namely: (E)-3-(3,4,5-trimethoxyphenyl)acrylic acid (1), (E)-methyl 3-(4-hydroxy-3,5-dimethoxyphenyl) acrylate (2), 17-methoxycarbonyl-14-heptadecaenyl-4-hydroxy-3-methoxycinnamate (3) and 1,2,3,4-tetrahydro-1-oxo-β-carboline (4). The isolated compounds showed moderate cholinesterase inhibitory activity compared to the reference standard, physostigmine. Compounds 1 and 2 showed the highest inhibitory activity against AChE (IC50 = 60.17 µM) and BChE (IC50 = 61.72 µM), respectively. Despite having similar molecular weight, compounds 1 and 2 were structurally different according to their chemical substitution patterns, leading to their different enzyme inhibition selectivity. Compound 2 was more selective against BChE, whereas compound 1 was a selective inhibitor of AChE. Molecular docking revealed that both compounds 1 and 2 were inserted, but not deeply into the active site of the cholinesterase enzymes.

  1. Extracts, Anthocyanins and Procyanidins from Aronia melanocarpa as Radical Scavengers and Enzyme Inhibitors

    Directory of Open Access Journals (Sweden)

    Hilde Barsett

    2013-03-01

    Full Text Available Extracts, subfractions, isolated anthocyanins and isolated procyanidins B2, B5 and C1 from the berries and bark of Aronia melanocarpa were investigated for their antioxidant and enzyme inhibitory activities. Four different bioassays were used, namely scavenging of the diphenylpicrylhydrazyl (DPPH radical, inhibition of 15-lipoxygenase (15-LO, inhibition of xanthine oxidase (XO and inhibition of α-glucosidase. Among the anthocyanins, cyanidin 3-arabinoside possessed the strongest and cyanidin 3-xyloside the weakest radical scavenging and enzyme inhibitory activity. These effects seem to be influenced by the sugar units linked to the anthocyanidin. Subfractions enriched in procyanidins were found to be potent α-glucosidase inhibitors; they possessed high radical scavenging properties, strong inhibitory activity towards 15-LO and moderate inhibitory activity towards XO. Trimeric procyanidin C1 showed higher activity in the biological assays compared to the dimeric procyanidins B2 and B5. This study suggests that different polyphenolic compounds of A. melanocarpa can have beneficial effects in reducing blood glucose levels due to inhibition of α-glucosidase and may have a potential to alleviate oxidative stress.

  2. Angiotensin I-converting enzyme inhibitors potentiate bradykinin's inotropic effects independently of blocking its inactivation.

    Science.gov (United States)

    Minshall, R D; Erdös, E G; Vogel, S M

    1997-08-04

    The positive inotropic effects of bradykinin (BK) and 2 analogs resistant to angiotensin I-converting enzyme (ACE) were potentiated on isolated guinea pig atrial preparations by enalaprilat. The stable BK analogs, dextran-BK and [Hyp3-Tyr(Me)8]-BK, were as active as BK. Pretreatment for 5 min with enalaprilat augmented the maximal positive inotropic effect of [Hyp3-Tyr(Me)8]-BK 2.8-fold, from 19% to 53% and that of BK from 28% to 42% over baseline; inotropic responses to dextran-BK (1 microM) were similarly increased. The activity of atrial ACE, a zinc-requiring enzyme, was completely inhibited by 8-hydroxyquinoline-5-sulfonic acid (QSA, 10 mM), which raised the maximal inotropic effect of BK to 39% above baseline. This value rose to 67% when in addition to QSA, 1 microM enalaprilat was added; enalaprilat thus, potentiated the effects of BK independently of enzyme inhibition. The positive inotropic effects to BK and its analogs decline with time in the presence of these agonists. After 10 min of exposure, the response to 1 microM [Hyp3-Tyr(Me)8]-BK decreased to about half, and after 20 min, to 0. Enalaprilat, when present in the tissue bath, prevented the decline in inotropy; even after tachyphylaxis occurred, it reversed this decrease in activity when added. The effects of 1 microM [Hyp3-Tyr(Me)8]-BK, in the absence or presence of enalaprilat, were abolished by the BK B2 receptor antagonist icatibant (0.75 microM). The results indicate that ACE inhibitors, by potentiating the BK effects and blocking BK B2-receptor desensitization, may contribute to the beneficial cardiac effects of BK independently of blocking its inactivation.

  3. Pancreatic enzyme replacement therapy for pancreatic exocrine insufficiency in the 21(st) century.

    Science.gov (United States)

    Trang, Tony; Chan, Johanna; Graham, David Y

    2014-09-07

    Restitution of normal fat absorption in exocrine pancreatic insufficiency remains an elusive goal. Although many patients achieve satisfactory clinical results with enzyme therapy, few experience normalization of fat absorption, and many, if not most, will require individualized therapy. Increasing the quantity of lipase administered rarely eliminates steatorrhea but increases the cost of therapy. Enteric coated enzyme microbead formulations tend to separate from nutrients in the stomach precluding coordinated emptying of enzymes and nutrients. Unprotected enzymes mix well and empty with nutrients but are inactivated at pH 4 or below. We describe approaches for improving the results of enzyme therapy including changing to, or adding, a different product, adding non-enteric coated enzymes, (e.g., giving unprotected enzymes at the start of the meal and acid-protected formulations later), use of antisecretory drugs and/or antacids, and changing the timing of enzyme administration. Because considerable lipid is emptied in the first postprandial hour, it is prudent to start therapy with enteric coated microbead prior to the meal so that some enzymes are available during that first hour. Patients with hyperacidity may benefit from adjuvant antisecretory therapy to reduce the duodenal acid load and possibly also sodium bicarbonate to prevent duodenal acidity. Comparative studies of clinical effectiveness of different formulations as well as the characteristics of dispersion, emptying, and dissolution of enteric-coated microspheres of different diameter and density are needed; many such studies have been completed but not yet made public. We discuss the history of pancreatic enzyme therapy and describe current use of modern preparations, approaches to overcoming unsatisfactory clinical responses, as well as studies needed to be able to provide reliably effective therapy.

  4. Pancreatic enzyme replacement therapy for pancreatic exocrine insufficiency in the 21st century

    Science.gov (United States)

    Trang, Tony; Chan, Johanna; Graham, David Y

    2014-01-01

    Restitution of normal fat absorption in exocrine pancreatic insufficiency remains an elusive goal. Although many patients achieve satisfactory clinical results with enzyme therapy, few experience normalization of fat absorption, and many, if not most, will require individualized therapy. Increasing the quantity of lipase administered rarely eliminates steatorrhea but increases the cost of therapy. Enteric coated enzyme microbead formulations tend to separate from nutrients in the stomach precluding coordinated emptying of enzymes and nutrients. Unprotected enzymes mix well and empty with nutrients but are inactivated at pH 4 or below. We describe approaches for improving the results of enzyme therapy including changing to, or adding, a different product, adding non-enteric coated enzymes, (e.g., giving unprotected enzymes at the start of the meal and acid-protected formulations later), use of antisecretory drugs and/or antacids, and changing the timing of enzyme administration. Because considerable lipid is emptied in the first postprandial hour, it is prudent to start therapy with enteric coated microbead prior to the meal so that some enzymes are available during that first hour. Patients with hyperacidity may benefit from adjuvant antisecretory therapy to reduce the duodenal acid load and possibly also sodium bicarbonate to prevent duodenal acidity. Comparative studies of clinical effectiveness of different formulations as well as the characteristics of dispersion, emptying, and dissolution of enteric-coated microspheres of different diameter and density are needed; many such studies have been completed but not yet made public. We discuss the history of pancreatic enzyme therapy and describe current use of modern preparations, approaches to overcoming unsatisfactory clinical responses, as well as studies needed to be able to provide reliably effective therapy. PMID:25206255

  5. Overweight, insulin resistance and type II diabetes in type I Gaucher disease patients in relation to enzyme replacement therapy

    NARCIS (Netherlands)

    Langeveld, M.; de Fost, M.; Aerts, J. M. F. G.; Sauerwein, H. P.; Hollak, C. E. M.

    2008-01-01

    Type I Gaucher disease, a lysosomal storage disorder is associated with metabolic abnormalities such as high resting energy expenditure, low circulating adiponectin and peripheral insulin resistance. Treatment with enzyme replacement therapy (enzyme therapy) leads to a decrease in resting energy

  6. Combined miglustat and enzyme replacement therapy in two patients with type 1 Gaucher disease: two case reports.

    Science.gov (United States)

    Amato, Dominick; Patterson, Mary Anne

    2018-01-27

    Intravenous enzyme replacement therapy is a first-line therapy for Gaucher disease type 1, and substrate reduction therapy represents an oral treatment alternative. Both enzyme replacement therapy and substrate reduction therapy are generally used as monotherapies in Gaucher disease. However, one randomized study and several case reports have described combination therapy over short time periods. We report two female Gaucher disease type 1 patients of mainly Anglo-Saxon descent, where combined enzyme replacement therapy and miglustat substrate reduction therapy were administered to overcome refractory clinical symptoms. The first patient was diagnosed at age 17 and developed Gaucher disease-related bone manifestations that worsened despite starting imiglucerase enzyme replacement therapy. After switching to miglustat substrate reduction therapy, her bone symptoms improved, but she developed tremors and eventually switched back to enzyme replacement therapy. Miglustat was later recommenced in combination with ongoing enzyme replacement therapy due to continued bone pain, and her bone symptoms improved along with maintained visceral manifestations. Enzyme replacement therapy was subsequently tapered off and the patient has since been successfully maintained on miglustat. The second patient was diagnosed aged 3, and commenced imiglucerase enzyme replacement therapy aged 15. After 9 years on enzyme replacement therapy she switched to miglustat substrate reduction therapy and her core symptoms were maintained/stable for 3 years. Imiglucerase enzyme replacement therapy was later added as a boost to therapy and her symptoms were subsequently maintained over a 2.3-year period. However, miglustat was discontinued due to her relocation, necessitating an increase in enzyme replacement therapy dose. Overall, both patients benefited from combination therapy. While the majority of Gaucher disease type 1 patients will not need treatment with both substrate reduction therapy

  7. Angiotensin-converting enzyme inhibitor treatment and the development of urinary tract infections : a prescription sequence symmetry analysis

    NARCIS (Netherlands)

    Pouwels, Koen B; Visser, Sipke T; Bos, H Jens; Hak, Eelko

    2013-01-01

    BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEi) can reduce urine output, especially when treatment is first started. Since bacterial clearance from the urinary tract is dependent on urine output, it was hypothesized that ACEi may also increase the risk of urinary tract infections (UTIs).

  8. CONVERTING ENZYME-INHIBITORS AND THE ROLE OF THE SULFHYDRYL-GROUP IN THE POTENTIATION OF EXOGENOUS AND ENDOGENOUS NITROVASODILATORS

    NARCIS (Netherlands)

    VANGILST, WH; DEGRAEFF, PA; DELEEUW, MJ; WESSELING, H

    In this study, the effect of bradykinin on coronary flow in the isolated rat heart was significantly potentiated when cysteine or the sulfhydryl-containing converting enzyme inhibitors captopril and zofenoprilat were administered simultaneously. In contrast, the effect of concomitant administration

  9. Renin-angiotensin system inhibitors, angiotensin I-converting enzyme gene insertion/deletion polymorphism, and cancer: The Rotterdam study

    NARCIS (Netherlands)

    R. van der Knaap (Ronald); C. Siemes (Claire); J.W.W. Coebergh (Jan Willem); P. Tikka-Kleemola (Päivi); A. Hofman (Albert); B.H.Ch. Stricker (Bruno)

    2008-01-01

    textabstractBACKGROUND. Angiotensin I-converting enzyme (ACE) inhibitors, angiotensin II antagonists, and the ACE insertion/deletion (I/D) gene polymorphism all influence serum angiotensin II action. Because angiotensin II levels have been associated with cancer, the objective of the current

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

    DEFF Research Database (Denmark)

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

    2002-01-01

    Combined treatment with an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II (Ang II) receptor blocker (ARB) has been suggested in order to achieve a more complete blockade of the renin-angiotensin-aldosterone system in cardiovascular and renal disease. The present report descri...

  11. Prognostic impact of carboxylesterase 1 gene variants in patients with congestive heart failure treated with angiotensin-converting enzyme inhibitors

    DEFF Research Database (Denmark)

    Nelveg-Kristensen, Karl E.; Madsen, Majbritt B.; Torp-Pedersen, Christian

    2016-01-01

    OBJECTIVE: Most angiotensin-converting enzyme inhibitors (ACEIs) are prodrugs activated by carboxylesterase 1 (CES1). We investigated the prognostic importance of CES1 gene (CES1) copy number variation and the rs3815583 single-nucleotide polymorphism in CES1 among ACEI-treated patients with conge...

  12. Synthesis and discovery of highly functionalized mono- and bis-spiro-pyrrolidines as potent cholinesterase enzyme inhibitors.

    Science.gov (United States)

    Kia, Yalda; Osman, Hasnah; Suresh Kumar, Raju; Basiri, Alireza; Murugaiyah, Vikneswaran

    2014-04-01

    Novel mono and bis spiropyrrolidine derivatives were synthesized via an efficient ionic liquid mediated, 1,3-dipolar cycloaddition methodology and evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 1.68 to 21.85 μM, wherein compounds 8d and 8j were found to be most active inhibitors against AChE and BChE with IC50 values of 1.68 and 2.75 μM, respectively. Molecular modeling simulation on Torpedo californica AChE and human BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. [Association between visual improvement after photocoagulation and the use of angiotensin converting enzyme inhibitors in diabetic macular oedema].

    Science.gov (United States)

    Somilleda-Ventura, Selma Alin; García-Rubio, Yatzul Zuhaila; Razo Blanco-Hernández, Dulce Milagros; Lima-Gómez, Virgilio

    2016-01-01

    Angiotensin converting enzyme inhibitors are effective in delaying the progression of diabetic retinopathy. It is unknown if their use is associated with a better visual outcome in patients with diabetic macular oedema. A non-experimental, comparative, longitudinal and retrospective study was performed on patients with diabetic macular oedema treated by focal photocoagulation, and with systemic arterial hypertension treated with angiotensin converting enzyme inhibitors (Group 1), and without hypertension (Group 2). The dependent variable was the proportion with visual improvement, operatively defined as the gain of one or more lines of vision three weeks after photocoagulation. The independent variable was the use of angiotensin converting enzyme inhibitors. The proportion of eyes with visual improvement after treatment was compared between groups using the Chi squared (χ(2)) test. A total of 33 eyes (51.6%) were assigned to group 1, and 31 (48.2%), to group 2. The mean of visual acuity improved after three weeks, compared with baseline (p=0.002). The proportion of eyes with visual improvement did not differ between patients treated with angiotensin converting enzyme inhibitors (45.5%) and those that did not use them (51.6%, p=0.4). There was no statistical difference in the proportion of eyes with visual improvement between patients treated with angiotensin converting enzyme inhibitors and in those where they were not used. There is no support for the inhibition of angiotensin II in addition to photocoagulation for improving the outcome in patients with diabetic macular oedema. Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.

  14. Neoadjuvant therapy of endometrial cancer with the aromatase inhibitor letrozole: endocrine and clinical effects.

    Science.gov (United States)

    Berstein, Lev; Maximov, Sergei; Gershfeld, Eduard; Meshkova, Irina; Gamajunova, Vera; Tsyrlina, Evgenia; Larionov, Alexei; Kovalevskij, Anatolii; Vasilyev, Dmitry

    2002-11-15

    To investigate the short-term hormonal and clinical effects of the aromatase inhibitor letrozole (Femara) in patients with endometrial cancer. Ten previously untreated, post-menopausal patients (mean age 59 years) with endometrial cancer, predominantly stage I disease, received letrozole 2.5mg per day for 14 days before surgery. Clinical, sonographic, morphologic, cytologic, and hormonal-metabolic parameters (blood estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), glucose, and cholesterol by radioimmunoassay, enzyme immune assay, or enzyme-colorimetric methods; tumor progesterone receptors by ligand-binding assay; and aromatase activity by 3H-water release assay) were evaluated before and after treatment. Treatment was well-tolerated in all patients. In two patients, pain relief in the lower part of the belly and/or decrease in intensity of uterine discharge was reported. In the three cases, substantial decreases in endometrial M-echo (ultrasound) signal were noted; the mean value of this parameter after treatment was 31.1% lower than before treatment. Blood estradiol concentration decreased by an average of 37.8% after letrozole therapy, and tumor progesterone receptor levels and aromatase activity decreased by 34.4 and 17.5%, respectively. Treatment with letrozole did not influence surgery. These data show that short-term treatment with letrozole in the neoadjuvant setting resulted in some positive clinical changes. Longer-term and larger-scale trials of neoadjuvant letrozole in endometrial cancer are warranted.

  15. Rethinking the Combination of Proton Exchanger Inhibitors in Cancer Therapy.

    Science.gov (United States)

    Iessi, Elisabetta; Logozzi, Mariantonia; Mizzoni, Davide; Di Raimo, Rossella; Supuran, Claudiu T; Fais, Stefano

    2017-12-23

    Microenvironmental acidity is becoming a key target for the new age of cancer treatment. In fact, while cancer is characterized by genetic heterogeneity, extracellular acidity is a common phenotype of almost all cancers. To survive and proliferate under acidic conditions, tumor cells up-regulate proton exchangers and transporters (mainly V-ATPase, Na⁺/H⁺ exchanger (NHE), monocarboxylate transporters (MCTs), and carbonic anhydrases (CAs)), that actively extrude excess protons, avoiding intracellular accumulation of toxic molecules, thus becoming a sort of survival option with many similarities compared with unicellular microorganisms. These systems are also involved in the unresponsiveness or resistance to chemotherapy, leading to the protection of cancer cells from the vast majority of drugs, that when protonated in the acidic tumor microenvironment, do not enter into cancer cells. Indeed, as usually occurs in the progression versus malignancy, resistant tumor clones emerge and proliferate, following a transient initial response to a therapy, thus giving rise to more malignant behavior and rapid tumor progression. Recent studies are supporting the use of a cocktail of proton exchanger inhibitors as a new strategy against cancer.

  16. Antimalarial activity of potential inhibitors of Plasmodium falciparum lactate dehydrogenase enzyme selected by docking studies.

    Directory of Open Access Journals (Sweden)

    Julia Penna-Coutinho

    Full Text Available The Plasmodium falciparum lactate dehydrogenase enzyme (PfLDH has been considered as a potential molecular target for antimalarials due to this parasite's dependence on glycolysis for energy production. Because the LDH enzymes found in P. vivax, P. malariae and P. ovale (pLDH all exhibit ∼90% identity to PfLDH, it would be desirable to have new anti-pLDH drugs, particularly ones that are effective against P. falciparum, the most virulent species of human malaria. Our present work used docking studies to select potential inhibitors of pLDH, which were then tested for antimalarial activity against P. falciparum in vitro and P. berghei malaria in mice. A virtual screening in DrugBank for analogs of NADH (an essential cofactor to pLDH and computational studies were undertaken, and the potential binding of the selected compounds to the PfLDH active site was analyzed using Molegro Virtual Docker software. Fifty compounds were selected based on their similarity to NADH. The compounds with the best binding energies (itraconazole, atorvastatin and posaconazole were tested against P. falciparum chloroquine-resistant blood parasites. All three compounds proved to be active in two immunoenzymatic assays performed in parallel using monoclonals specific to PfLDH or a histidine rich protein (HRP2. The IC(50 values for each drug in both tests were similar, were lowest for posaconazole (<5 µM and were 40- and 100-fold less active than chloroquine. The compounds reduced P. berghei parasitemia in treated mice, in comparison to untreated controls; itraconazole was the least active compound. The results of these activity trials confirmed that molecular docking studies are an important strategy for discovering new antimalarial drugs. This approach is more practical and less expensive than discovering novel compounds that require studies on human toxicology, since these compounds are already commercially available and thus approved for human use.

  17. Phosphorylated hydroxyethylamines as novel inhibitors of the bacterial cell wall biosynthesis enzymes MurC to MurF.

    Science.gov (United States)

    Sova, Matej; Kovac, Andreja; Turk, Samo; Hrast, Martina; Blanot, Didier; Gobec, Stanislav

    2009-12-01

    Enzymes involved in the biosynthesis of bacterial peptidoglycan represent important targets for development of new antibacterial drugs. Among them, Mur ligases (MurC to MurF) catalyze the formation of the final cytoplasmic precursor UDP-N-acetylmuramyl-pentapeptide from UDP-N-acetylmuramic acid. We present the design, synthesis and biological evaluation of a series of phosphorylated hydroxyethylamines as new type of small-molecule inhibitors of Mur ligases. We show that the phosphate group attached to the hydroxyl moiety of the hydroxyethylamine core is essential for good inhibitory activity. The IC(50) values of these inhibitors were in the micromolar range, which makes them a promising starting point for the development of multiple inhibitors of Mur ligases as potential antibacterial agents. In addition, 1-(4-methoxyphenylsulfonamido)-3-morpholinopropan-2-yl dihydrogen phosphate 7a was discovered as one of the best inhibitors of MurE described so far.

  18. Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease

    DEFF Research Database (Denmark)

    Biegstraaten, Marieke; Arngrímsson, Reynir; Barbey, Frederic

    2015-01-01

    INTRODUCTION: Fabry disease (FD) is a lysosomal storage disorder resulting in progressive nervous system, kidney and heart disease. Enzyme replacement therapy (ERT) may halt or attenuate disease progression. Since administration is burdensome and expensive, appropriate use is mandatory. We aimed ...

  19. Development of an ELISA assay for screening inhibitors against divalent metal ion dependent alphavirus capping enzyme.

    Science.gov (United States)

    Kaur, Ramanjit; Mudgal, Rajat; Narwal, Manju; Tomar, Shailly

    2018-06-26

    Alphavirus non-structural protein, nsP1 has a distinct molecular mechanism of capping the viral RNAs than the conventional capping mechanism of host. Thus, alphavirus capping enzyme nsP1 is a potential drug target. nsP1 catalyzes the methylation of guanosine triphosphate (GTP) by transferring the methyl group from S-adenosylmethionine (SAM) to a GTP molecule at its N7 position with the help of nsP1 methyltransferase (MTase) followed by guanylylation (GT) reaction which involves the formation of m 7 GMP-nsP1 covalent complex by nsP1 guanylyltransferase (GTase). In subsequent reactions, m 7 GMP moiety is added to the 5' end of the viral ppRNA by nsP1 GTase resulting in the formation of cap0 structure. In the present study, chikungunya virus (CHIKV) nsP1 MTase and GT reactions were confirmed by an indirect non-radioactive colorimetric assay and western blot assay using an antibody specific for the m 7 G cap, respectively. The purified recombinant CHIKV nsP1 has been used for the development of a rapid and sensitive non-radioactive enzyme linked immunosorbent assay (ELISA) to identify the inhibitors of CHIKV nsP1. The MTase reaction is followed by GT reaction and resulted in m 7 GMP-nsP1 covalent complex formation. The developed ELISA nsP1 assay measures this m 7 GMP-nsP1 complex by utilizing anti-m 7 G cap monoclonal antibody. The mutation of a conserved residue Asp63 to Ala revealed its role in nsP1 enzyme reaction. Inductively coupled plasma mass spectroscopy (ICP-MS) was used to determine the presence of magnesium ions (Mg 2+ ) in the purified nsP1 protein. The divalent metal ion selectivity and investigation show preference for Mg 2+ ion by CHIKV nsP1. Additionally, using the developed ELISA nsP1 assay, the inhibitory effects of sinefungin, aurintricarboxylic acid (ATA) and ribavirin were determined and the IC 50 values were estimated to be 2.69 µM, 5.72 µM and 1.18 mM, respectively. Copyright © 2018. Published by Elsevier B.V.

  20. Application of 3D-QSAR in the rational design of receptor ligands and enzyme inhibitors.

    Science.gov (United States)

    Mor, Marco; Rivara, Silvia; Lodola, Alessio; Lorenzi, Simone; Bordi, Fabrizio; Plazzi, Pier Vincenzo; Spadoni, Gilberto; Bedini, Annalida; Duranti, Andrea; Tontini, Andrea; Tarzia, Giorgio

    2005-11-01

    Quantitative structure-activity relationships (QSARs) are frequently employed in medicinal chemistry projects, both to rationalize structure-activity relationships (SAR) for known series of compounds and to help in the design of innovative structures endowed with desired pharmacological actions. As a difference from the so-called structure-based drug design tools, they do not require the knowledge of the biological target structure, but are based on the comparison of drug structural features, thus being defined ligand-based drug design tools. In the 3D-QSAR approach, structural descriptors are calculated from molecular models of the ligands, as interaction fields within a three-dimensional (3D) lattice of points surrounding the ligand structure. These descriptors are collected in a large X matrix, which is submitted to multivariate analysis to look for correlations with biological activity. Like for other QSARs, the reliability and usefulness of the correlation models depends on the validity of the assumptions and on the quality of the data. A careful selection of compounds and pharmacological data can improve the application of 3D-QSAR analysis in drug design. Some examples of the application of CoMFA and CoMSIA approaches to the SAR study and design of receptor or enzyme ligands is described, pointing the attention to the fields of melatonin receptor ligands and FAAH inhibitors.

  1. Effects of Angiotensin Converting Enzyme Inhibitors on Liver Fibrosis in HIV and Hepatitis C Coinfection

    Directory of Open Access Journals (Sweden)

    Lindsey J. Reese

    2012-01-01

    Full Text Available Background. Liver fibrosis is accelerated in HIV and hepatitis C coinfection, mediated by profibrotic effects of angiotensin. The objective of this study was to determine if angiotensin converting enzyme inhibitors (ACE-Is attenuate liver fibrosis in coinfection. Methods. A retrospective review of 156 coinfected subjects was conducted to analyze the association between exposure to ACE-Is and liver fibrosis. Noninvasive indices of liver fibrosis (APRI, FIB-4, Forns indices were compared between subjects who had taken ACE-Is and controls who had not taken them. Linear regression was used to evaluate ACE-I use as an independent predictor of fibrosis. Results. Subjects taking ACE-Is for three years were no different than controls on the APRI and the FIB-4 but had significantly higher scores than controls on the Forns index, indicating more advanced fibrosis. The use of ACE-Is for three years remained independently associated with an elevated Forns score when adjusted for age, race, and HIV viral load (P<0.001. There were significant associations between all of the indices and significant fibrosis, as determined clinically and radiologically. Conclusions. There was not a protective association between angiotensin inhibition and liver fibrosis in coinfection. These noninvasive indices may be useful for ruling out significant fibrosis in coinfection.

  2. Can the epirubicin cardiotoxicity in cancer patients be prevented by angiotensin converting enzyme inhibitors?

    Science.gov (United States)

    Radulescu, D; Buzdugan, E; Ciuleanu, T E; Todor, N; Stoicescu, L

    2013-01-01

    The aim of this study was to assess whether treatment with angiotensin converting enzyme inhibitors (ACEI) can prevent the alteration of left ventricular systolic and diastolic performance in cancer patients treated with different chemotherapy regimens containing epirubicin. In this prospective study , 68 patients with different malignant tumors treated with epirubicin and perindopril in different chemotherapy protocols (study group), and a gender- and age-matched group of 68 patients with different malignant tumors treated with epirubicin without perindopril in different chemotherapy protocols (control group), were assessed by Doppler echocardiography. Left ventricular systolic function was assessed by measuring left ventricular ejection fraction (EF). Left ventricular diastolic function was assessed by Doppler ultrasound by evaluating the transmitral flow. We also assessed the QTc on the 12 lead electrocardiograms. At the end of chemotherapy the left ventricular systolic function was less altered in the study group compared to the control group and was superior in the study group (epirubicin+ACEI) compared to the control group (epirubicin alone). We documented a significantly deteriorated left ventricular diastolic function in both groups at the completion of chemotherapy. QTc time in both arms was also significantly prolonged. In the present echo-Doppler study we documented a preserved left ventricular systolic performance in patients with various malignancies treated with epirubicin plus perindopril. Although co-treatment with ACEI prevented the alteration of systolic performance, it failed to prevent the deterioration of the left ventricular diastolic performance impairment due to poor left ventricular compliance.

  3. Imaging the adrenal glands with radiolabeled inhibitors of enzymes: concise communication

    International Nuclear Information System (INIS)

    Beierwaltes, W.H.; Wieland, D.M.; Mosley, S.T.; Swanson, D.P.; Sarkar, S.D.; Freitas, J.E.; Thrall, J.H.; Herwig, K.R.

    1978-01-01

    Although radioiodinated cholesterols furnished the first noninvasive imaging of the adrenal glands, it would be desirable to decrease the time for imaging and decrease the radiation dose. The relative tissue distributions of two radiolabeled enzyme inhibitors [ 3 H] metyrapol and 1-125-SKF-12185 were studied in dogs and man. Their percentage uptakes and target-to-nontarget ratios were similar. The adrenals of three dogs were imaged sharply at 2 hr after injection with 4-6 mCi of I-131-SKF-12185, confirmed by subsequent imaging with 1 mCi of I-131-6-beta-19-nor cholesterol at 5 days after injection. The use of 1 mCi of I-123-SKF will pemit imaging of the adrenals in 1-2 hr and will decrease the radiation dose in the human to 0.76 rads to the adrenal, 0.18 rads to the ovaries and 1.7 rads to the liver

  4. Cyclooxygenase inhibitors potentiate receptor tyrosine kinase therapies in bladder cancer cells in vitro

    Directory of Open Access Journals (Sweden)

    Bourn J

    2018-06-01

    Full Text Available Jennifer Bourn,1,2 Maria Cekanova1,2 1Department of Small Animal Clinical Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, USA; 2UT-ORNL Graduate School of Genome Science and Technology, The University of Tennessee, Knoxville, TN, USA Purpose: Receptor tyrosine kinase inhibitors (RTKIs are used as targeted therapies for patients diagnosed with cancer with highly expressed receptor tyrosine kinases (RTKs, including the platelet-derived growth factor receptor (PDGFR and c-Kit receptor. Resistance to targeted therapies is partially due to the activation of alternative pro-survival signaling pathways, including cyclooxygenase (COX-2. In this study, we validated the effects of two RTKIs, axitinib and AB1010, in combination with COX inhibitors on the V-akt murine thymoma oncogene homolog 1 (Akt and COX-2 signaling pathways in bladder cancer cells.Methods: The expression of several RTKs and their downstream signaling targets was analyzed by Western blot (WB analysis in human and canine bladder transitional cell carcinoma (TCC cell lines. The effects of RTKIs and COX inhibitors in bladder TCC cells were assessed by MTS for cell viability, by Caspase-3/7 and Annexin V assay for apoptosis, by WB analysis for detection of COX-2 and Akt signaling pathways, and by enzyme-linked immunosorbent assay for detection of prostaglandin E2 (PGE2 levels.Results: All tested TCC cells expressed the c-Kit and PDGFRα receptors, except human 5637 cells that had low RTKs expression. In addition, all tested cells expressed COX-1, COX-2, Akt, extracellular signal regulated kinases 1/2, and nuclear factor kappa-light-chain-enhance of activated B cells proteins, except human UM-UC-3 cells, where no COX-2 expression was detected by WB analysis. Both RTKIs inhibited cell viability and increased apoptosis in a dose-dependent manner in tested bladder TCC cells, which positively correlated with their expression levels of the PDGFRα and c

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

    Directory of Open Access Journals (Sweden)

    Melissa Dahir, DNP, IF

    2014-04-01

    Conclusions: The use of a compounded testosterone vaginal cream applied daily for 4 weeks improves reported sexual health quality of life in women with breast cancer taking AIs. Dahir M and Travers‐Gustafson D. Breast cancer, aromatase inhibitor therapy, and sexual functioning: A pilot study of the effects of vaginal testosterone therapy. Sex Med 2014;2:8–15.

  6. Enzymes in therapy of biofilm-related oral diseases.

    Science.gov (United States)

    Pleszczyńska, Małgorzata; Wiater, Adrian; Bachanek, Teresa; Szczodrak, Janusz

    2017-05-01

    Biofilm-related infections of the oral cavity, including dental caries and periodontitis, represent the most prevalent health problems. For years, the treatment thereof was largely based on antibacterial chemical agents. Recently, however, there has been growing interest in the application of more preventive and minimally invasive biotechnological methods. This review focuses on the potential applications of enzymes in the treatment and prevention of oral diseases. Dental plaque is a microbial community that develops on the tooth surface, embedded in a matrix of extracellular polymeric substances of bacterial and host origin. Both cariogenic microorganisms and the key components of oral biofilm matrix may be the targets of the enzymes. Oxidative salivary enzymes inhibit or limit the growth of oral pathogens, thereby supporting the natural host defense system; polysaccharide hydrolases (mutanases and dextranases) degrade important carbohydrate components of the biofilm matrix, whereas proteases disrupt bacterial adhesion to oral surfaces or affect cell-cell interactions. The efficiency of the enzymes in in vitro and in vivo studies, advantages and limitations, as well as future perspectives for improving the enzymatic strategy are discussed. © 2016 International Union of Biochemistry and Molecular Biology, Inc.

  7. Reconversion of bone marrow in Gaucher disease treated with enzyme therapy documented by MR

    International Nuclear Information System (INIS)

    Allison, J.W.; James, C.A.; Arnold, G.L.; Stine, K.C.; Becton, D.L.; Bell, J.M.

    1998-01-01

    Background. Skeletal complications are responsible for significant morbidity in Gaucher patients. Plain radiographs have been unreliable in assessing bone marrow infiltration and activity. A way to assess bone marrow improvement is needed during enzyme therapy. Objective. The purpose of this paper is to assess the usefulness of MR in following improvement of abnormal bone marrow in Gaucher patients on enzyme therapy. Materials and methods. Three patients aged 2, 7, and 24 years underwent serial MR scans of the lower extremities before and during treatment with Alglucerase (two patients) and Imiglucerase (one patient). T1-weighted, T2-weighted, STIR and FSE T2-weighted images were utilized. Two patients were imaged after 16 months of therapy, and one patient was imaged after 6 months of therapy. Results. All patients had improvement in marrow signal consistent with partial reconversion to fatty marrow during treatment. The findings were more marked after prolonged therapy. T1-weighted images demonstrated findings most clearly. Conclusion. MR consistently showed improvement in marrow signal in Gaucher patients on enzyme therapy. As smaller doses of enzyme therapy are the trend, MR can be utilized to determine if therapy is effecting a change in the bone marrow. (orig.)

  8. Identification of genetic factors associated with susceptibility to angiotensin-converting enzyme inhibitors-induced cough.

    Science.gov (United States)

    Grilo, Antonio; Sáez-Rosas, María P; Santos-Morano, Juan; Sánchez, Elena; Moreno-Rey, Concha; Real, Luis M; Ramírez-Lorca, Reposo; Sáez, María E

    2011-01-01

    Angiotensin-converting enzyme inhibitors (ACEi) are the first selected drugs for hypertensive patients because of its protective properties against heart and kidney diseases. Persistent cough is a common adverse reaction associated with ACEi, which can bind to the treatment cessation, but its etiology remains an unresolved issue. The most accepted mechanism is that the inhibition of ACEi increases kinins levels, resulting in the activation of proinflammatory mechanisms and nitric oxide generation. However, relatively little is known about the genetic susceptibility to ACEi-induced cough in hypertensive patients. We carried out a monogenic association analysis of 39 polymorphisms and haplotypes in genes encoding key proteins related to ACEi activity with the occurrence of ACEi-induced cough. We also carried out a digenic association analysis and investigated the existence of epistatic interactions between the analyzed polymorphisms using a logistic regression procedure. Finally, we investigated the predictive value of the identified associations for ACEi-induced cough. We found that genetic polymorphisms in MME [rs2016848, P=0.002, odds ratio (OR)=1.795], BDKRB2 (rs8012552, P=0.012, OR=1.609), PTGER3 (rs11209716, P=0.002, OR=0.565), and ACE (rs4344) genes are associated with ACEi-related cough. For the latter, the effect is sex specific, having a protective effect in males (P=0.027, OR=0.560) and increasing the risk in females (P=0.031, OR=1.847). In addition, genetic interactions between peptidases involved in kinins levels (CPN1 and XPNPEP1) and proteins related to prostaglandin metabolism (PTGIS and PTGIR) strongly modify the risk of ACEi-induced cough presentation (0.102≤OR≤0.384 for protective combinations and 2.732≤OR≤7.216 for risk combinations). These results are consistent with the hypothesis that the mechanism of cough is related to the accumulation of bradykinin, substance P, and prostaglandins.

  9. Mitigation of radiation-induced lung fibrosis by angiotensin converting enzyme inhibitors

    International Nuclear Information System (INIS)

    Kma, Lakhan; Gao, Feng; Jacobs, Elizabeth R.; Medhora, Meetha; Fish, Brian L.; Moulder, John E.

    2014-01-01

    The aim of this study was to test the mitigating potential of angiotensin converting enzyme inhibitors (ACEi) against radiation-induced pulmonary fibrosis, which could result from accidental exposure or radiological terrorism. Rats (WAG/RijCmcr) were exposed to a single dose of 13 Gy of X-irradiation to the whole thorax, at the dose rate of 1.43 Gy/min. Three structurally-different ACEi's, captopril (145-207 mg/m 2 /day), enalapril (19-28 mg/m 2 /day) and fosinopril (19-28 mg/m 2 /day) were administered in drinking water beginning 1 week after whole thoracic irradiation. Rats that survived acute pneumonitis (6-12 weeks) were accessed monthly after irradiation for the effects on lung structure and function. Endpoints included breathing rate, wet:dry weight ratio, collagen content and histolopathological studies. Treatment with captopril or enalapril, but not fosinopril, beginning 1 week after 13 Gy X-irradiation improved survival of rats. Mortality of 30-35% was observed with administration of captopril or enalapril compared to 70% for 13 Gy alone. All three ACEi's attenuated radiation-induced lung fibrosis at 7 months after irradiation based on histological indices and measurement of lung collagen. After whole-thoracic irradiation, ACEi's mitigate radiation induced pulmonary fibrosis based on histological and biochemical endpoints. These treatments were effective even when administration was not started until one week after irradiation. Our findings support the therapeutic potential of ACEi's against chronic radiation induced lung injury. (author)

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

    DEFF Research Database (Denmark)

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

    1996-01-01

    Verapamil is effective as antianginal medication but contraindicated in patients with congestive heart failure. Angiotensin-converting enzyme (ACE) inhibitors improve survival in patients with congestive heart failure but have limited effect on patients with angina pectoris. No studies have been.......4 to 2.5 +/- 0.6 (p attacks were both significantly reduced after 3 months of treatment. These findings support the hypothesis that the combination of verapamil and trandolapril is useful in patients with attenuated left ventricular function...

  11. Manual therapy in the treatment of patients with hemophilia B and inhibitor.

    Science.gov (United States)

    Cuesta-Barriuso, Rubén; Trelles-Martínez, Roberto O

    2018-01-22

    The main clinical manifestations of hemophilia are muscle and joint bleeding. Recurrent bleeding leads to a degenerative process known as hemophilic arthropathy. The development of inhibitors (antibodies against FVIII/FIX concentrates) is the main complication in the treatment of hemophilia. The objective was to assess the safety and efficacy of manual therapy treatment in a patient with hemophilia and inhibitor. A 26-year-old patient with hemophilia B and inhibitor received physiotherapy treatment based on manual therapy for 3 months, with a frequency of 2 sessions per week. The joint status was evaluated using the Hemophilia Joint Health Score; pain was assessed with the Visual Analog Scale; and the range of movement was evaluated using a universal goniometer. The patient developed no joint bleeding in the knees or ankles as a result of the physiotherapy treatment. Following treatment, improvements were noted in the range of movement of knees and ankles, the perception of pain in both knees, and ankle functionality. Until now, manual therapy using joint traction was contraindicated in patients with hemophilia and inhibitor, as it was feared to cause possible joint bleeding. This is the first case study to address the safety and efficacy of manual therapy in a patient with hemophilia and an inhibitor. The results of this study may help to establish which manual therapy treatments are indicated in patients with hemophilic arthropathy and inhibitors. Thus, a physiotherapy program based on manual therapy may be safe in patients with hemophilia and inhibitor and such therapy may improve joint condition, pain, and joint range of motion in patients with hemophilia and inhibitor. Randomized clinical trials are needed to confirm the results of this case study.

  12. Some Investigations on Protease Enzyme Production Kinetics Using Bacillus licheniformis BBRC 100053 and Effects of Inhibitors on Protease Activity

    Directory of Open Access Journals (Sweden)

    Zahra Ghobadi Nejad

    2014-01-01

    Full Text Available Due to great commercial application of protease, it is necessary to study kinetic characterization of this enzyme in order to improve design of enzymatic reactors. In this study, mathematical modeling of protease enzyme production kinetics which is derived from Bacillus licheniformis BBRC 100053 was studied (at 37°C, pH 10 after 73 h in stationary phase, and 150 rpm. The aim of the present paper was to determine the best kinetic model and kinetic parameters for production of protease and calculating Ki (inhibition constant of different inhibitors to find the most effective one. The kinetic parameters Km (Michaelis-Menten constant and Vm (maximum rate were calculated 0.626 mM and 0.0523 mM/min. According to the experimental results, using DFP (diisopropyl fluorophosphate and PMSF (phenylmethanesulfonyl fluoride as inhibitors almost 50% of the enzyme activity could be inhibited when their concentrations were 0.525 and 0.541 mM, respectively. Ki for DFP and PMSF were 0.46 and 0.56 mM, respectively. Kinetic analysis showed that the Lineweaver-Burk model was the best fitting model for protease production kinetics DFP was more effective than PMSF and both of them should be covered in the group of noncompetitive inhibitors.

  13. Exploring the water-binding pocket of the type II dehydroquinase enzyme in the structure-based design of inhibitors.

    Science.gov (United States)

    Blanco, Beatriz; Sedes, Antía; Peón, Antonio; Otero, José M; van Raaij, Mark J; Thompson, Paul; Hawkins, Alastair R; González-Bello, Concepción

    2014-04-24

    Structural and computational studies to explore the WAT1 binding pocket in the structure-based design of inhibitors against the type II dehydroquinase (DHQ2) enzyme are reported. The crystal structures of DHQ2 from M. tuberculosis in complex with four of the reported compounds are described. The electrostatic interaction observed between the guanidinium group of the essential arginine and the carboxylate group of one of the inhibitors in the reported crystal structures supports the recently suggested role of this arginine as the residue that triggers the release of the product from the active site. The results of the structural and molecular dynamics simulation studies revealed that the inhibitory potency is favored by promoting interactions with WAT1 and the residues located within this pocket and, more importantly, by avoiding situations where the ligands occupy the WAT1 binding pocket. The new insights can be used to advantage in the structure-based design of inhibitors.

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

    Directory of Open Access Journals (Sweden)

    Capuano A

    2013-09-01

    Full Text Available Annalisa Capuano,1 Liberata Sportiello,1 Maria Ida Maiorino,2 Francesco Rossi,1 Dario Giugliano,2 Katherine Esposito3 1Department of Experimental Medicine, 2Department of Medical, Surgical, Neurological, Metabolic Sciences, and Geriatrics, 3Department of Clinical and Experimental Medicine and Surgery, Second University of Naples, Naples, Italy Abstract: 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

  15. Structure-activity relationships of new cyanothiophene inhibitors of the essential peptidoglycan biosynthesis enzyme MurF.

    Science.gov (United States)

    Hrast, Martina; Turk, Samo; Sosič, Izidor; Knez, Damijan; Randall, Christopher P; Barreteau, Hélène; Contreras-Martel, Carlos; Dessen, Andréa; O'Neill, Alex J; Mengin-Lecreulx, Dominique; Blanot, Didier; Gobec, Stanislav

    2013-08-01

    Peptidoglycan is an essential component of the bacterial cell wall, and enzymes involved in its biosynthesis represent validated targets for antibacterial drug discovery. MurF catalyzes the final intracellular peptidoglycan biosynthesis step: the addition of D-Ala-D-Ala to the nucleotide precursor UDP-MurNAc-L-Ala-γ-D-Glu-meso-DAP (or L-Lys). As MurF has no human counterpart, it represents an attractive target for the development of new antibacterial drugs. Using recently published cyanothiophene inhibitors of MurF from Streptococcus pneumoniae as a starting point, we designed and synthesized a series of structurally related derivatives and investigated their inhibition of MurF enzymes from different bacterial species. Systematic structural modifications of the parent compounds resulted in a series of nanomolar inhibitors of MurF from S. pneumoniae and micromolar inhibitors of MurF from Escherichia coli and Staphylococcus aureus. Some of the inhibitors also show antibacterial activity against S. pneumoniae R6. These findings, together with two new co-crystal structures, represent an excellent starting point for further optimization toward effective novel antibacterials. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  16. Inhibitor design strategy based on an enzyme structural flexibility: a case of bacterial MurD ligase.

    Science.gov (United States)

    Perdih, Andrej; Hrast, Martina; Barreteau, Hélène; Gobec, Stanislav; Wolber, Gerhard; Solmajer, Tom

    2014-05-27

    Increasing bacterial resistance to available antibiotics stimulated the discovery of novel efficacious antibacterial agents. The biosynthesis of the bacterial peptidoglycan, where the MurD enzyme is involved in the intracellular phase of the UDP-MurNAc-pentapeptide formation, represents a collection of highly selective targets for novel antibacterial drug design. In our previous computational studies, the C-terminal domain motion of the MurD ligase was investigated using Targeted Molecular Dynamic (TMD) simulation and the Off-Path Simulation (OPS) technique. In this study, we present a drug design strategy using multiple protein structures for the identification of novel MurD ligase inhibitors. Our main focus was the ATP-binding site of the MurD enzyme. In the first stage, three MurD protein conformations were selected based on the obtained OPS/TMD data as the initial criterion. Subsequently, a two-stage virtual screening approach was utilized combining derived structure-based pharmacophores with molecular docking calculations. Selected compounds were then assayed in the established enzyme binding assays, and compound 3 from the aminothiazole class was discovered to act as a dual MurC/MurD inhibitor in the micomolar range. A steady-state kinetic study was performed on the MurD enzyme to provide further information about the mechanistic aspects of its inhibition. In the final stage, all used conformations of the MurD enzyme with compound 3 were simulated in classical molecular dynamics (MD) simulations providing atomistic insights of the experimental results. Overall, the study depicts several challenges that need to be addressed when trying to hit a flexible moving target such as the presently studied bacterial MurD enzyme and show the possibilities of how computational tools can be proficiently used at all stages of the drug discovery process.

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

    International Nuclear Information System (INIS)

    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

    2013-01-01

    Highlights: ► A CDK4 inhibitor may be used for breast cancer stem cell-targeted therapy. ► The CDK4 inhibitor differentiated the cancer stem cell population (CD24 − /CD44 + ) 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. CD8+ T Cells Specific to Apoptosis-Associated Antigens Predict the Response to Tumor Necrosis Factor Inhibitor Therapy in Rheumatoid Arthritis.

    Directory of Open Access Journals (Sweden)

    Alessandra Citro

    Full Text Available 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.

  19. Inhibitors of Deubiquitinating Enzymes Block HIV-1 Replication and Augment the Presentation of Gag-Derived MHC-I Epitopes.

    Science.gov (United States)

    Setz, Christian; Friedrich, Melanie; Rauch, Pia; Fraedrich, Kirsten; Matthaei, Alina; Traxdorf, Maximilian; Schubert, Ulrich

    2017-08-12

    In recent years it has been well established that two major constituent parts of the ubiquitin proteasome system (UPS)-the proteasome holoenzymes and a number of ubiquitin ligases-play a crucial role, not only in virus replication but also in the regulation of the immunogenicity of human immunodeficiency virus type 1 (HIV-1). However, the role in HIV-1 replication of the third major component, the deubiquitinating enzymes (DUBs), has remained largely unknown. In this study, we show that the DUB-inhibitors (DIs) P22077 and PR-619, specific for the DUBs USP7 and USP47, impair Gag processing and thereby reduce the infectivity of released virions without affecting viral protease activity. Furthermore, the replication capacity of X4- and R5-tropic HIV-1 NL4-3 in human lymphatic tissue is decreased upon treatment with these inhibitors without affecting cell viability. Most strikingly, combinatory treatment with DIs and proteasome inhibitors synergistically blocks virus replication at concentrations where mono-treatment was ineffective, indicating that DIs can boost the therapeutic effect of proteasome inhibitors. In addition, P22077 and PR-619 increase the polyubiquitination of Gag and thus its entry into the UPS and the major histocompatibility complex (MHC)-I pathway. In summary, our data point towards a model in which specific inhibitors of DUBs not only interfere with virus spread but also increase the immune recognition of HIV-1 expressing cells.

  20. High-resolution crystal structures of Drosophila melanogaster angiotensin-converting enzyme in complex with novel inhibitors and antihypertensive drugs.

    Science.gov (United States)

    Akif, Mohd; Georgiadis, Dimitris; Mahajan, Aman; Dive, Vincent; Sturrock, Edward D; Isaac, R Elwyn; Acharya, K Ravi

    2010-07-16

    Angiotensin I-converting enzyme (ACE), one of the central components of the renin-angiotensin system, is a key therapeutic target for the treatment of hypertension and cardiovascular disorders. Human somatic ACE (sACE) has two homologous domains (N and C). The N- and C-domain catalytic sites have different activities toward various substrates. Moreover, some of the undesirable side effects of the currently available and widely used ACE inhibitors may arise from their targeting both domains leading to defects in other pathways. In addition, structural studies have shown that although both these domains have much in common at the inhibitor binding site, there are significant differences and these are greater at the peptide binding sites than regions distal to the active site. As a model system, we have used an ACE homologue from Drosophila melanogaster (AnCE, a single domain protein with ACE activity) to study ACE inhibitor binding. In an extensive study, we present high-resolution structures for native AnCE and in complex with six known antihypertensive drugs, a novel C-domain sACE specific inhibitor, lisW-S, and two sACE domain-specific phosphinic peptidyl inhibitors, RXPA380 and RXP407 (i.e., nine structures). These structures show detailed binding features of the inhibitors and highlight subtle changes in the orientation of side chains at different binding pockets in the active site in comparison with the active site of N- and C-domains of sACE. This study provides information about the structure-activity relationships that could be utilized for designing new inhibitors with improved domain selectivity for sACE. 2010 Elsevier Ltd. All rights reserved.

  1. Cognitive Development in Infantile-Onset Pompe Disease Under Very Early Enzyme Replacement Therapy.

    Science.gov (United States)

    Lai, Chih-Jou; Hsu, Ting-Rong; Yang, Chia-Feng; Chen, Shyi-Jou; Chuang, Ya-Chin; Niu, Dau-Ming

    2016-12-01

    Most patients with infantile-onset Pompe disease die in early infancy before beginning enzyme replacement therapy, which has made it difficult to evaluate the impact of Pompe disease on cognitive development. Patients with infantile-onset Pompe disease can survive with enzyme replacement therapy, and physicians can evaluate cognitive development in these patients. We established an effective newborn screening program with quick clinical diagnostic criteria. Cognitive and motor development were evaluated using the Bayley Scales of Infant and Toddler Development-Third Edition at 6, 12, and 24 months of age. The patients who were treated very early demonstrate normal cognitive development with no significant change in cognition during this period (P = .18 > .05). The cognitive development was positively correlated with motor development (r = 0.533, P = .011). The results indicated that very early enzyme replacement therapy could protect cognitive development in patients with infantile-onset Pompe disease up to 24 months of age. © The Author(s) 2016.

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

    DEFF Research Database (Denmark)

    Kamper, A L

    1991-01-01

    studies have been published to date. In chronic renal failure, ACE inhibitors may worsen anaemia and hyperkalaemia. Renovascular hypertension can be treated with ACE inhibitors, but the treatment may lead to a compromised renal function. The dosage of these drugs should be reduced in renal failure...

  3. Inhibitors

    Science.gov (United States)

    ... JM, and the Hemophilia Inhibitor Research Study Investigators. Validation of Nijmegen-Bethesda assay modifications to allow inhibitor ... webinars on blood disorders Language: English (US) Español (Spanish) File Formats Help: How do I view different ...

  4. Fetzima (levomilnacipran), a drug for major depressive disorder as a dual inhibitor for human serotonin transporters and beta-site amyloid precursor protein cleaving enzyme-1.

    Science.gov (United States)

    Rizvi, Syed Mohd Danish; Shaikh, Sibhghatulla; Khan, Mahiuddin; Biswas, Deboshree; Hameed, Nida; Shakil, Shazi

    2014-01-01

    Pharmacological management of Major Depressive Disorder includes the use of serotonin reuptake inhibitors which targets serotonin transporters (SERT) to increase the synaptic concentrations of serotonin. Beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1) is responsible for amyloid β plaque formation. Hence it is an interesting target for Alzheimer's disease (AD) therapy. This study describes molecular interactions of a new Food and Drug Administration approved antidepressant drug named 'Fetzima' with BACE-1 and SERT. Fetzima is chemically known as levomilnacipran. The study has explored a possible link between the treatment of Depression and AD. 'Autodock 4.2' was used for docking study. The free energy of binding (ΔG) values for 'levomilnacipran-SERT' interaction and 'levomilnacipran-BACE1' interaction were found to be -7.47 and -8.25 kcal/mol, respectively. Levomilnacipran was found to interact with S438, known to be the most important amino acid residue of serotonin binding site of SERT during 'levomilnacipran-SERT' interaction. In the case of 'levomilnacipran-BACE1' interaction, levomilnacipran interacted with two very crucial aspartic acid residues of BACE-1, namely, D32 and D228. These residues are accountable for the cleavage of amyloid precursor protein and the subsequent formation of amyloid β plaques in AD brain. Hence, Fetzima (levomilnacipran) might act as a potent dual inhibitor of SERT and BACE-1 and expected to form the basis of a future dual therapy against depression and AD. It is an established fact that development of AD is associated with Major Depressive Disorder. Therefore, the design of new BACE-1 inhibitors based on antidepressant drug scaffolds would be particularly beneficial.

  5. Resolution of Hydronephrosis in a Patient With Mucopolysaccharidosis Type II With Enzyme Replacement Therapy.

    Science.gov (United States)

    Nishiyama, Kei; Imai, Takashi; Ohkubo, Kazuhiro; Sanefuji, Masafumi; Takada, Hidetoshi

    2017-03-01

    Mucopolysaccharidosis type II (MPS II) is caused by deficiency of lysosomal enzyme iduronate-2-sulfatase. Insufficient activity of the enzyme results in accumulation of glycosaminoglycans leading to progressive multisystem pathologies. MPS II is less likely to be complicated by kidney and urinary tract problems. We report a boy with MPS II, who developed left hydronephrosis. His hydronephrosis improved after starting enzyme replacement therapy. It was suggested that MPS II was closely associated with the pathogenesis of hydronephrosis. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Calcium channel blockers, angiotensin receptor blockers, and angiotensin-converting enzyme inhibitors: Effectiveness in combination with diuretics or β-blockers for treating hypertension

    Directory of Open Access Journals (Sweden)

    John D Bisognano

    2007-11-01

    Full Text Available John D Bisognano1, Trent McLaughlin2, Craig S Roberts3, Simon SK Tang31Internal Medicine Department, Cardiology Division, the University of Rochester Medical Center, Rochester, NY, USA; 2NDC Health, Phoenix, Arizona, USA; 3Pfizer Inc, New York, NY, USAAbstract: This retrospective database analysis compared the effectiveness of dihydropyridine calcium channel blockers (DHPs, angiotensin-converting enzyme (ACE inhibitors, and angiotensin receptor blockers (ARBs added to diuretics or β-blockers. Adults with hypertension treated with diuretic or β-blocker monotherapy between 1998 and 2001 were identified from a large US electronic medical records database of primary care practices. Patients were required to have a baseline blood pressure (BP ≥140/90 mmHg (≥130/80 mmHg for diabetes mellitus and recorded BP measurements within 6 months before and 1–12 months following index date. Patients were matched 1:1:1 by propensity score to correct for differences in baseline characteristics. 1875 patients met study criteria and 660 (220 in each cohort were matched based on propensity scores. Matched cohorts had no significant differences in baseline characteristics. Mean changes in systolic/diastolic BP were –17.5/–8.8, –15.7/–6.3, and –13.0/–8.0 mmHg with DHPs, ACE inhibitors, and ARBs, respectively. Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High BP 6/7 goal attainment for each regimen was 47.3%, 40.0%, and 32.2%, respectively. DHPs, ACE inhibitors, and ARBs improved BP when added to patients’ β-blocker or diuretic therapy. The greatest benefits were observed with DHPs, followed by ACE inhibitors, then ARBs.Keywords: hypertension, amlodipine besylate, lisinopril, valsartan, Joint National Committee (JNC 6 and 7

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2005-02-01

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

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

    International Nuclear Information System (INIS)

    Nakata, Tomoaki; Wakabayashi, Takeru; Kyuma, Michifumi; Takahashi, Toru; Tsuchihashi, Kazufumi; Shimamoto, Kazuaki

    2005-01-01

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

  9. ARTERIAL HYPERTENSION DURING THERAPY OF ONCOLOGICAL DISEASES WITH ANGIOGENESIS INHIBITORS: SERIOUS IMPEDIMENT OR CONTROLLED REACTION?

    Directory of Open Access Journals (Sweden)

    Zh. D. Kobalava

    2017-01-01

    Full Text Available Vascular endothelial growth factor signaling pathway (VSP inhibitors are drugs for which arterial hypertension (AH is a class effect, occurring with a frequency of up to 73 % of treated patients. Blockade of vascular endothelial growth factor or its receptor is accompanied by inhibition of the synthesis of nitric oxide, which is considered a major pathogenic mechanism for the development of AH. VSP-inhibitors therapy will be as safe as possible, if the patient prior to treatment will take a minimum assessment, allowing to identify the category of patients with high/very high cardiovascular risk. Risk evaluation is necessary not to abandon an effective therapy of VSP-inhibitors, and to provide a systematic approach to reduce the likelihood of potential cardiovascular toxicity. Blood pressure during VSP-inhibitors therapy is characterized by a rapid rise after the first dose of target therapy, as a rule, in the first cycle of treatment, ranging from no increase to double the systolic blood pressure. Usually iatrogenic AH spontaneously resolves after stopping chemotherapy. Timely prescribed antihypertensive therapy help to avoids dose reduction or interruption of the course of VSP-inhibitors, which significantly improves the survival of patients.

  10. Monoterpenes as inhibitors of digestive enzymes and counter-adaptations in a specialist avian herbivore.

    Science.gov (United States)

    Kohl, Kevin D; Pitman, Elizabeth; Robb, Brecken C; Connelly, John W; Dearing, M Denise; Forbey, Jennifer Sorensen

    2015-05-01

    Many plants produce plant secondary metabolites (PSM) that inhibit digestive enzymes of herbivores, thus limiting nutrient availability. In response, some specialist herbivores have evolved digestive enzymes that are resistant to inhibition. Monoterpenes, a class of PSMs, have not been investigated with respect to the interference of specific digestive enzymes, nor have such interactions been studied in avian herbivores. We investigated this interaction in the Greater Sage-Grouse (Phasianidae: Centrocercus urophasianus), which specializes on monoterpene-rich sagebrush species (Artemisia spp.). We first measured the monoterpene concentrations in gut contents of free-ranging sage-grouse. Next, we compared the ability of seven individual monoterpenes present in sagebrush to inhibit a protein-digesting enzyme, aminopeptidase-N. We also measured the inhibitory effects of PSM extracts from two sagebrush species. Inhibition of aminopeptidase-N in sage-grouse was compared to inhibition in chickens (Gallus gallus). We predicted that sage-grouse enzymes would retain higher activity when incubated with isolated monoterpenes or sagebrush extracts than chicken enzymes. We detected unchanged monoterpenes in the gut contents of free-ranging sage-grouse. We found that three isolated oxygenated monoterpenes (borneol, camphor, and 1,8-cineole) inhibited digestive enzymes of both bird species. Camphor and 1,8-cineole inhibited enzymes from chickens more than from sage-grouse. Extracts from both species of sagebrush had similar inhibition of chicken enzymes, but did not inhibit sage-grouse enzymes. These results suggest that specific monoterpenes may limit the protein digestibility of plant material by avian herbivores. Further, this work presents additional evidence that adaptations of digestive enzymes to plant defensive compounds may be a trait of specialist herbivores.

  11. Studies on non-steroidal inhibitors of aromatase enzyme; 4-(aryl/heteroaryl)-2-(pyrimidin-2-yl)thiazole derivatives.

    Science.gov (United States)

    Sahin, Zafer; Ertas, Merve; Berk, Barkın; Biltekin, Sevde Nur; Yurttas, Leyla; Demirayak, Seref

    2018-05-01

    Steroidal and non-steroidal aromatase inhibitors target the suppression of estrogen biosynthesis in the treatment of breast cancer. Researchers have increasingly focused on developing non-steroidal derivatives for their potential clinical use avoiding steroidal side-effects. Non-steroidal derivatives generally have planar aromatic structures attached to the azole ring system. One part of this ring system comprises functional groups that inhibit aromatization through the coordination of the haem group of the aromatase enzyme. Replacement of the triazole ring system and development of aromatic/cyclic structures of the side chain can increase selectivity over aromatase enzyme inhibition. In this study, 4-(aryl/heteroaryl)-2-(pyrimidin-2-yl)thiazole derivatives were synthesized and physical analyses and structural determination studies were performed. The IC 50 values were determined by a fluorescence-based aromatase inhibition assay and compound 1 (4-(2-hydroxyphenyl)-2-(pyrimidine-2-yl)thiazole) were found potent inhibitor of enzyme (IC 50 :0.42 nM). Then, their antiproliferative activity over MCF-7 and HEK-293 cell lines was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Compounds 1, 7, 8, 13, 15, 18, 21 were active against MCF-7 breast cancer cells. Lastly, a series of docking experiments were undertaken to analyze the crystal structure of human placental aromatase and identify the possible interactions between the most active structure and the active site. Copyright © 2018 Elsevier Ltd. All rights reserved.

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

    DEFF Research Database (Denmark)

    NN, NN; Yusuf, S; Teo, K

    2008-01-01

    BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors reduce major cardiovascular events, but are not tolerated by about 20% of patients. We therefore assessed whether the angiotensin-receptor blocker telmisartan would be effective in patients intolerant to ACE inhibitors with cardiovascular...

  13. Improved management of lysosomal glucosylceramide levels in a mouse model of type 1 Gaucher disease using enzyme and substrate reduction therapy.

    Science.gov (United States)

    Marshall, John; McEachern, Kerry Anne; Chuang, Wei-Lien; Hutto, Elizabeth; Siegel, Craig S; Shayman, James A; Grabowski, Greg A; Scheule, Ronald K; Copeland, Diane P; Cheng, Seng H

    2010-06-01

    Gaucher disease is caused by a deficiency of the lysosomal enzyme glucocerebrosidase (acid beta-glucosidase), with consequent cellular accumulation of glucosylceramide (GL-1). The disease is managed by intravenous administrations of recombinant glucocerebrosidase (imiglucerase), although symptomatic patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy (ERT) is not an option may also be treated by substrate reduction therapy (SRT) with miglustat. To determine whether the sequential use of both ERT and SRT may provide additional benefits, we compared the relative pharmacodynamic efficacies of separate and sequential therapies in a murine model of Gaucher disease (D409V/null). As expected, ERT with recombinant glucocerebrosidase was effective in reducing the burden of GL-1 storage in the liver, spleen, and lung of 3-month-old Gaucher mice. SRT using a novel inhibitor of glucosylceramide synthase (Genz-112638) was also effective, albeit to a lesser degree than ERT. Animals administered recombinant glucocerebrosidase and then Genz-112638 showed the lowest levels of GL-1 in all the visceral organs and a reduced number of Gaucher cells in the liver. This was likely because the additional deployment of SRT following enzyme therapy slowed the rate of reaccumulation of GL-1 in the affected organs. Hence, in patients whose disease has been stabilized by intravenously administered recombinant glucocerebrosidase, orally administered SRT with Genz-112638 could potentially be used as a convenient maintenance therapy. In patients naïve to treatment, ERT followed by SRT could potentially accelerate clearance of the offending substrate.

  14. Prostatic-Like Syndrome in a Woman with Chronic Lymphocytic Leukemia: Sequential Kinase Inhibitor Therapy

    Directory of Open Access Journals (Sweden)

    Diego Velasco-Rodríguez

    2017-01-01

    Full Text Available Chronic lymphocytic leukemia (CLL is an incurable lymphoproliferative disorder with a heterogeneous genetic and clinical course. Two kinase inhibitors, ibrutinib and idelalisib, have demonstrated achievement of complete and durable remissions in relapse/refractory genetically unselected CLL patients. We present a case of relapsed CLL with extensive disease and hourglass deformity of urinary bladder as a result of the compression of two extraperitoneal paravesical soft tissue bulky masses, with excellent response to sequential kinase inhibitor therapy.

  15. Initiation of TNF Inhibitor Therapy and Change in Physiologic Measures in Psoriasis

    Science.gov (United States)

    Wu, Jashin J.; Liu, Liyan; Asgari, Maryam M.; Curtis, Jeffrey R.; Harrold, Leslie; Salman, Craig; Herrinton, Lisa J.

    2014-01-01

    Background Psoriasis may predispose to cardiovascular disease and diabetes. However, the role of TNF inhibitor in mediating this risk is controversial. Objective To assess this relationship, we estimated change in metabolic physiologic measures before and after initiation of TNF inhibitor therapy compared with methotrexate therapy among psoriasis patients. Methods We conducted a retrospective cohort study, 2007–2012, using computerized clinical data for 1,274 new users of TNF inhibitor and 979 new users of methotrexate therapy to compare change in blood pressure, lipids, triglycerides, fasting plasma glucose, and body mass index before and after start of TNF inhibitors or methotrexate. The study was restricted to new users. We computed within-person change in each measure, so that each patient served as their own control. In addition, we compared TNF inhibitor patients to methotrexate patients, by computing the adjusted difference in their group means. In secondary analyses, we examined phototherapy as a comparator. Results Among starters of TNF inhibitor and MTX therapy, within-person change in physiologic measures at 6 months did not differ significantly. We observed no important or significant changes in any of the physiologic measures with initiation of TNF inhibitor compared with methotrexate. The same results were found in subgroup analyses focused on men, and on those with hypertension, diabetes mellitus, or obesity. The same results were observed with phototherapy, except that diastolic blood pressure declined by 0.6 mm Hg within-person during the 6 months after starting phototherapy (p<0.05). Conclusions The study provides no evidence for improvement of physiologic measures associated with the metabolic syndrome resulting from TNF inhibitor use for psoriasis. PMID:24708441

  16. The discovery of novel tartrate-based TNF-[alpha] converting enzyme (TACE) inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Rosner, Kristin E.; Guo, Zhuyan; Orth, Peter; Shipps, Jr., Gerald W.; Belanger, David B.; Chan, Tin Yau; Curran, Patrick J.; Dai, Chaoyang; Deng, Yongqi; Girijavallabhan, Vinay M.; Hong, Liwu; Lavey, Brian J.; Lee, Joe F.; Li, Dansu; Liu, Zhidan; Popovici-Muller, Janeta; Ting, Pauline C.; Vaccaro, Henry; Wang, Li; Wang, Tong; Yu, W.; Zhou, G.; Niu, X.; Sun, J.; Kozlowski, J.A.; Lundell, D.J.; Madison, V.; McKittrick, B.; Piwinski, J.J.; Shih, N.Y.; Siddiqui, M. Arshad; Strickland, Corey O. (SPRI)

    2010-09-17

    A novel series of TNF-{alpha} convertase (TACE) inhibitors which are non-hydroxamate have been discovered. These compounds are bis-amides of L-tartaric acid (tartrate) and coordinate to the active site zinc in a tridentate manner. They are selective for TACE over other MMP's. We report the first X-ray crystal structure for a tartrate-based TACE inhibitor.

  17. Identification of novel inhibitors of Pseudomonas aeruginosa MurC enzyme derived from phage-displayed peptide libraries.

    Science.gov (United States)

    El Zoeiby, Ahmed; Sanschagrin, François; Darveau, André; Brisson, Jean-Robert; Levesque, Roger C

    2003-03-01

    The machinery of peptidoglycan biosynthesis is an ideal site at which to look for novel antimicrobial targets. Phage display was used to develop novel peptide inhibitors for MurC, an essential enzyme involved in the early steps of biosynthesis of peptidoglycan monomer. We cloned and overexpressed the murA, -B and -C genes from Pseudomonas aeruginosa in the pET expression vector, adding a His-tag to their C termini. The three proteins were overproduced in Escherichia coli and purified to homogeneity in milligram quantities. MurA and -B were combinatorially used to synthesize the MurC substrate UDP-N-acetylmuramate, the identity of which was confirmed by mass spectrometry and nuclear magnetic resonance analysis. Two phage-display libraries were screened against MurC in order to identify peptide ligands to the enzyme. Three rounds of biopanning were carried out, successively increasing elution specificity from round 1 to 3. The third round was accomplished with both non-specific elution and competitive elution with each of the three MurC substrates, UDP-N-acetylmuramic acid (UNAM), ATP and L-alanine. The DNA of 10 phage, selected randomly from each group, was extracted and sequenced, and consensus peptide sequences were elucidated. Peptides were synthesized and tested for inhibition of the MurC-catalysed reaction, and two peptides were shown to be inhibitors of MurC activity with IC(50)s of 1.5 and 0.9 mM, respectively. The powerful selection technique of phage display allowed us to identify two peptide inhibitors of the essential bacterial enzyme MurC. The peptide sequences represent the basis for the synthesis of inhibitory peptidomimetic molecules.

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

    Science.gov (United States)

    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.

  19. The increasing role of monoamine oxidase type B inhibitors in Parkinson's disease therapy.

    Science.gov (United States)

    Elmer, Lawrence W; Bertoni, John M

    2008-11-01

    The role of monoamine oxidase type B inhibitors in the treatment of Parkinson's disease has expanded with the new monoamine oxidase B inhibitor rasagiline and a new formulation, selegiline oral disintegrating tablets. As primary therapy in early disease monoamine oxidase B inhibitors reduce motor disability and delay the need for levodopa. In more advanced disease requiring levodopa, adjunctive monoamine oxidase B inhibitors reduce 'off' time and may improve gait and freezing. Rasagiline and selegiline oral disintegrating tablets may reduce the safety risks associated with the amfetamine and methamfetamine metabolites of conventional oral selegiline while retaining or improving therapeutic efficacy. Articles were identified by searches of PubMed and searches on the Internet and reviewed. All articles and other referenced materials were retrieved using the keywords 'Parkinson's disease', 'treatment' and 'monoamine oxidase B inhibitor' and were published between 1960 and 2007, with older references selected for historical significance. Only papers published in English were reviewed. Accumulating data support the use of monoamine oxidase B inhibitors as monotherapy for early and mild Parkinson's disease and as adjunctive therapy for more advanced Parkinson's disease with levodopa-associated motor fluctuations. The recently released monoamine oxidase B inhibitor rasagiline and a new formulation, selegiline oral disintegrating tablets, have potential advantages over conventional oral selegiline.

  20. Extended interval between enzyme therapy infusions for adult patients with Gaucher′s disease type 1.

    Directory of Open Access Journals (Sweden)

    Pérez-Calvo J

    2003-01-01

    Full Text Available BACKGROUND: Enzyme replacement therapy (ERT for Gaucher′s disease with alglucerase or imiglucerase is efficacious, well-tolerated and safe. However, cost considerations, visits to medical facilities, potentially duration of theray for life, are issues of major concern to a proportion of treated patients and has, in some cases, led to the withdrawal of therapy. AIMS: To elucidate whether an extension of the interval between enzyme infusions to once every three weeks is as effective in maintaining the clinical responses achieved with the bi-monthly regimen. MATERIALS AND METHODS: Four patients with an optimal response to ERT (at 30 units/kg every two weeks for an average of 27 months, were subjected to enzyme dose/frequency changes that essentially constituted a reduction in cumulative dose over the treatment period. Patients were assessed every 6 months for alterations in haematological parameters, plasma chitotriosidase levels, liver and spleen size, and bone symptoms. RESULTS: All patients had to resume the previous infusion schedule of once every two weeks; one because of new bone marrow infiltrates, two because of visceral enlargement, and the fourth due to progressive anaemia. CONCLUSIONS: This limited experience suggests that a reduction in enzyme dose associated with an extended interval between infusions may lead to variable disease control, and underscores the need for individualization of enzyme therapy.

  1. Inhibitors of the glyoxylate cycle enzyme ICL1 in Candida albicans for potential use as antifungal agents.

    Directory of Open Access Journals (Sweden)

    Hong-Leong Cheah

    Full Text Available Candida albicans is an opportunistic pathogen that causes candidiasis in humans. In recent years, metabolic pathways in C. albicans have been explored as potential antifungal targets to treat candidiasis. The glyoxylate cycle, which enables C. albicans to survive in nutrient-limited host niches and its. Key enzymes (e.g., isocitrate lyase (ICL1, are particularly attractive antifungal targets for C. albicans. In this study, we used a new screening approach that better reflects the physiological environment that C. albicans cells experience during infection to identify potential inhibitors of ICL. Three compounds (caffeic acid (CAFF, rosmarinic acid (ROS, and apigenin (API were found to have antifungal activity against C. albicans when tested under glucose-depleted conditions. We further confirmed the inhibitory potential of these compounds against ICL using the ICL enzyme assay. Lastly, we assessed the bioavailability and toxicity of these compounds using Lipinski's rule-of-five and ADMET analysis.

  2. Pancreatic Enzyme Replacement Therapy in Children with Severe Acute Malnutrition : A Randomized Controlled Trial

    NARCIS (Netherlands)

    Bartels, Rosalie H.; Bourdon, Celine; Potani, Isabel; Mhango, Brian; van den Brink, Deborah A.; Mponda, John S.; Kobold, Anneke C. Muller; Bandsma, Robert H.; van Hensbroek, Michael Boele; Voskuijl, Wieger P.

    Objective: To assess the benefits of pancreatic enzyme replacement therapy (PERT) in children with complicated severe acute malnutrition. Study design: We conducted a randomized, controlled trial in 90 children aged 6-60 months with complicated severe acute malnutrition at the Queen Elizabeth

  3. Pancreatic Enzyme Replacement Therapy in Children with Severe Acute Malnutrition: A Randomized Controlled Trial

    NARCIS (Netherlands)

    Bartels, Rosalie H.; Bourdon, Céline; Potani, Isabel; Mhango, Brian; van den Brink, Deborah A.; Mponda, John S.; Muller Kobold, Anneke C.; Bandsma, Robert H.; Boele van Hensbroek, Michael; Voskuijl, Wieger P.

    2017-01-01

    Objective To assess the benefits of pancreatic enzyme replacement therapy (PERT) in children with complicated severe acute malnutrition. Study design We conducted a randomized, controlled trial in 90 children aged 6-60 months with complicated severe acute malnutrition at the Queen Elizabeth Central

  4. Hearing loss in adult patients with Fabry disease treated with enzyme replacement therapy

    NARCIS (Netherlands)

    Suntjens, Eefje B.; Smid, Bouwien E.; Biegstraaten, Marieke; Dreschler, Wouter A.; Hollak, Carla E. M.; Linthorst, Gabor E.

    2015-01-01

    Data on prevalence, natural history, and effect of enzyme replacement therapy (ERT) on hearing loss (HL) in Fabry disease (FD) are scarce. This is a retrospective study with cross-sectional and longitudinal analyses. Low and high-frequency HL in the Dutch FD cohort was studied in four groups:

  5. Children with Pompe disease: clinical characteristics, peculiar features and effects of enzyme replacement therapy

    NARCIS (Netherlands)

    C.I. van Capelle (Carine)

    2014-01-01

    markdownabstract__Abstract__ Pompe disease is a metabolic myopathy. Since the first description of the disease in 1932 by J.C. Pompe,1 tremendous progress has been made from discovering the biochemical and genetic basis of the disease to developing enzyme replacement therapy (ERT). With this

  6. Long term enzyme replacement therapy for Fabry disease: effectiveness on kidney, heart and brain

    NARCIS (Netherlands)

    Rombach, Saskia M.; Smid, Bouwien E.; Bouwman, Machtelt G.; Linthorst, Gabor E.; Dijkgraaf, Marcel G. W.; Hollak, Carla E. M.

    2013-01-01

    Fabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase A deficiency leading to renal, cardiac, cerebrovascular disease and premature death. Treatment with α-galactosidase A (enzyme replacement therapy, ERT) stabilises disease in some patients, but long term effectiveness

  7. Modulation of porcine biotransformation enzymes by anthelmintic therapy with fenbendazole and flubendazole.

    Science.gov (United States)

    Savlík, M; Fimanová, K; Szotáková, B; Lamka, J; Skálová, L

    2006-06-01

    Fenbendazole (FEN) and flubendazole (FLU) are benzimidazole anthelmintics often used in pig management for the control of nematodoses. The in vivo study presented here was designed to test the influence of FLU and FEN on cytochrome P4501A and other cytochrome P450 (CYP) isoforms, UDP-glucuronosyl transferase and several carbonyl reducing enzymes. The results indicated that FEN (in a single therapeutic dose as well as in repeated therapeutic doses) caused significant induction of pig CYP1A, while FLU did not show an inductive effect towards this isoform. Some of the other hepatic and intestinal biotransformation enzymes that were assayed were moderately influenced by FEN or FLU. Strong CYP1A induction following FEN therapy in pigs may negatively affect the efficacy and pharmacokinetics of FEN itself or other simultaneously or consecutively administered drugs. From the perspective of biotransformation enzyme modulation, FLU would appear to be a more convenient anthelmintic therapy of pigs than FEN.

  8. New clinical developments in histone deacetylase inhibitors for epigenetic therapy of cancer

    Directory of Open Access Journals (Sweden)

    Ma Yuehua

    2009-06-01

    Full Text Available Abstract DNA methylation and histone acetylation are two well known epigenetic chromatin modifications. Epigenetic agents leading to DNA hypomethylation and histone hyperacetylation have been approved for treatment of hematological disorders. The first histone deacetylase inhibitor, vorinostat, has been licensed for cutaneous T cell lymphoma treatment. More than 11 new epigenetic agents are in various stages of clinical development for therapy of multiple cancer types. In this review we summarize novel histone deacetylase inhibitors and new regimens from clinical trials for epigenetic therapy of cancer.

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

    International Nuclear Information System (INIS)

    Morisse, B.; Kersten, U.

    1994-01-01

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

  10. An investigation of the concomitant use of angiotensin-converting enzyme inhibitors, non-steroidal anti-inflammatory drugs and diuretics.

    Science.gov (United States)

    Bucsa, C; Moga, D C; Farcas, A; Mogosan, C; Dumitrascu, D L

    2015-08-01

    To determine in retrospective data the prevalence at hospital discharge of co-prescribing angiotensin-converting enzyme inhibitors (ACE-I) and non-steroidal anti-inflammatory drugs (NSAIDs) and ACE-I/NSAIDs and diuretics and to identify factors associated with the co-prescription. Secondary, we evaluated the extent of serum creatinine and potassium monitoring in patients treated with ACE-I and these associations and determined the prevalence of values above the upper normal limit (UNL) in monitored patients. Hospitalized patients with ACE-I in their therapy at discharge were included in 3 groups as follows: ACE-I, DT (double therapy with ACE-I and NSAIDs) and TT (triple therapy with ACE-I, NSAIDs and diuretics) groups. We evaluated differences on demographic characteristics, co-morbidities, medications, laboratory monitoring and quantified the patients with serum creatinine and potassium levels above the UNL using descriptive statistics. Logistic regression analysis with backward elimination was performed to identify significant predictors of combination therapy. Of 9960 admitted patients, 1214 were prescribed ACE-I, 40 were prescribed ACE-I/NSAIDs and 22 were prescribed ACE-I/NSAIDs/diuretics (3.13% and 1.72%, respectively, of the patients prescribed with ACE-I). Serum creatinine and potassium were monitored for the great majority of patients from all groups. The highest percentage of hyperkalemia was found in the DT group (10% of the patients) and of serum creatinine above UNL in the TT group (45.45%). The logistic regression final model showed that younger patients and monitoring for potassium were significantly associated with combination therapy. The prevalence of patients receiving DT/TT was relatively low and their monitoring during hospitalization was high. Factors associated with the combinations were younger patients and patients not tested for serum potassium.

  11. Discriminative Stimulus Properties of the Endocannabinoid Catabolic Enzyme Inhibitor SA-57 in Mice

    OpenAIRE

    Owens, Robert A.; Ignatowska-Jankowska, Bogna; Mustafa, Mohammed; Beardsley, Patrick M.; Wiley, Jenny L.; Jali, Abdulmajeed; Selley, Dana E.; Niphakis, Micah J.; Cravatt, Benjamin F.; Lichtman, Aron H.

    2016-01-01

    Whereas the inhibition of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), the respective major hydrolytic enzymes of N-arachidonoyl ethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), elicits no or partial substitution for Δ9-tetrahydrocannabinol (THC) in drug-discrimination procedures, combined inhibition of both enzymes fully substitutes for THC, as well as produces a constellation of cannabimimetic effects. The present study tested whether C57BL/6J mice would learn t...

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

    OpenAIRE

    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 le...

  13. HDAC inhibition amplifies gap junction communication in neural progenitors: Potential for cell-mediated enzyme prodrug therapy

    International Nuclear Information System (INIS)

    Khan, Zahidul; Akhtar, Monira; Asklund, Thomas; Juliusson, Bengt; Almqvist, Per M.; Ekstroem, Tomas J.

    2007-01-01

    Enzyme prodrug therapy using neural progenitor cells (NPCs) as delivery vehicles has been applied in animal models of gliomas and relies on gap junction communication (GJC) between delivery and target cells. This study investigated the effects of histone deacetylase (HDAC) inhibitors on GJC for the purpose of facilitating transfer of therapeutic molecules from recombinant NPCs. We studied a novel immortalized midbrain cell line, NGC-407 of embryonic human origin having neural precursor characteristics, as a potential delivery vehicle. The expression of gap junction protein connexin 43 (C x 43) was analyzed by western blot and immunocytochemistry. While C x 43 levels were decreased in untreated differentiating NGC-407 cells, the HDAC inhibitor 4-phenylbutyrate (4-PB) increased C x 43 expression along with increased membranous deposition in both proliferating and differentiating cells. Simultaneously, Ser 279/282-phosphorylated form of C x 43 was declined in both culture conditions by 4-PB. The 4-PB effect in NGC-407 cells was verified by using HNSC.100 human neural progenitors and Trichostatin A. Improved functional GJC is of imperative importance for therapeutic strategies involving intercellular transport of low molecular-weight compounds. We show here an enhancement by 4-PB, of the functional GJC among NGC-407 cells, as well as between NGC-407 and human glioma cells, as indicated by increased fluorescent dye transfer

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

    NARCIS (Netherlands)

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

    2015-01-01

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

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

    NARCIS (Netherlands)

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

    2015-01-01

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

  16. Role of Acid and Weakly Acidic Reflux in Gastroesophageal Reflux Disease Off Proton Pump Inhibitor Therapy

    OpenAIRE

    Sung, Hea Jung; Cho, Yu Kyung; Moon, Sung Jin; Kim, Jin Su; Lim, Chul Hyun; Park, Jae Myung; Lee, In Seok; Kim, Sang Woo; Choi, Myung-Gye

    2012-01-01

    Background/Aims Available data about reflux patterns and symptom determinants in the gastroesophageal reflux disease (GERD) subtypes off proton pump inhibitor (PPI) therapy are lacking. We aimed to evaluate reflux patterns and determinants of symptom perception in patients with GERD off PPI therapy by impedance-pH monitoring. Methods We retrospectively reviewed the impedance-pH data in patients diagnosed as GERD based on results of impedance-pH monitoring, endoscopy and/or typical symptoms. T...

  17. Combining aspirin with angiotensin converting enzyme inhibitors in heart failure: how safe is it?

    Science.gov (United States)

    Mehta, H; Mahajan, A; Bansal, N; Vaidya, S; Pathak, L

    1998-11-01

    The above discussion on the interaction of aspirin and ACE inhibitors seems to suggest that aspirin in high doses may have adverse interaction with ACE inhibitors in patients with heart failure but the data obtained is not sufficient or conclusive to recommended omission of aspirin in patients with heart failure. This raises a query in the mind of the physician whether to use a combination or not? The role of aspirin in the early period after myocardial infarction is well established so is the role of ACE inhibitors. Hence in patients with myocardial infarction and preserved left ventricular function it would not be wrong to administer combination of ACE inhibitors and aspirin. Albeit at a lower dose. In patients with large myocardial infarction or heart failure, warfarin may be an option but still needs to be documented in large trials. As suggested long term use of aspirin after infarction is still ambiguous and may be harmful in patients with heart failure with its anticedent side effects. But long term benefits of ACE inhibitors in heart failure are well documented. Hence if a choice has to be made whether to discontinue either of the two drugs it would be preferable to stop the aspirin. To answer the issue of use of aspirin in patients with heart failure it would be essential to conduct a double blind randomized trial comparing known anti-thrombotic treatment, aspirin and anti-coagulants on mortality in patients with heart failure, especially caused by coronary artery disease. Such a trial is underway at the present and till the results are available it should be left to clinical judgement of the physician whether to administer aspirin in patients with heart failure after weighing the benefits versus risk.

  18. Immunological changes with kinase inhibitor therapy for chronic lymphocytic leukemia.

    Science.gov (United States)

    Pleyer, Christopher; Wiestner, Adrian; Sun, Clare

    2018-05-15

    Ibrutinib and idelalisib are kinase inhibitors that have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Capable of inducing durable remissions, these agents also modulate the immune system. Both ibrutinib and idelalisib abrogate the tumor-supporting microenvironment by disrupting cell-cell interactions, modulating the T-cell compartment, and altering the cytokine milieu. Ibrutinib also partially restores T-cell and myeloid defects associated with CLL. In contrast, immune-related adverse effects, including pneumonitis, colitis, hepatotoxicity, and infections are of particular concern with idelalisib. While opportunistic infections and viral reactivations occur with both ibrutinib and idelalisib, these complications are less common and less severe with ibrutinib, especially when used as monotherapy without additional immunosuppressive agents. This review discusses the impact of ibrutinib and idelalisib on the immune system, including infectious and auto-immune complications as well as their specific effects on the B-cell, T-cell, and myeloid compartment.

  19. The role of multikinase inhibitors target therapy in radioiodine-resistant differentiated thyroid cancer

    Directory of Open Access Journals (Sweden)

    P O Rumyantsev

    2015-06-01

    Full Text Available About 5-15% of patients with differentiated thyroid cancer (DTC primary or within follow-up have had distant metastases or inoperable tumor mass that are resistant to radioiodine therapy as well as dramatically deteriorate survival prognosis. Other treatment modalities (radiotherapy, chemotherapy etc. also ineffective. Certain expectances are associated with target therapy with multikinase inhibitors with are selectively blocking onco-kinase molecular pathways. This review is devoted to analysis of those multikinase inhibitors which have been implemented in patients with radioiodine DTC. Comparative analysis of two most perspective multikinase inhibitors (sorafenib and lenvatinib with evaluation of efficacy and adverse effects was conducted. Both of them successfully underwent 3 rd phase of clinical trial and were recommended as treatment of choice in progressive radioiodine-resistant DTC patients.

  20. Cediranib, a pan-VEGFR inhibitor, and olaparib, a PARP inhibitor, in combination therapy for high grade serous ovarian cancer.

    Science.gov (United States)

    Ivy, S Percy; Liu, Joyce F; Lee, Jung-Min; Matulonis, Ursula A; Kohn, Elise C

    2016-01-01

    An estimated 22,000 women are diagnosed annually with ovarian cancer in the United States. Initially chemo-sensitive, recurrent disease ultimately becomes chemoresistant and may kill ~14,000 women annually. Molecularly targeted therapy with cediranib (AZD2171), a vascular endothelial growth factor receptor (VEGFR)-1, 2, and 3 signaling blocker, and olaparib (AZD2281), a poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, administered orally in combination has shown anti-tumor activity in the treatment of high grade serous ovarian cancer (HGSOC). This combination has the potential to change the treatment of HGSOC. Preclinical and clinical studies of single agent cediranib and olaparib or their combination are reviewed. Data are presented from peer-reviewed published manuscripts, completed and ongoing early phase clinical trials registered in ClinicalTrials.gov, National Cancer Institute-sponsored clinical trials, and related recent abstracts. Advances in the treatment of HGSOC that improve progression-free and overall survival have proven elusive despite examination of molecularly targeted therapy. HGSOC patients with deleterious germline or somatic mutations in BRCA1 or BRCA2 (BRCAm) are most responsive to PARP inhibitors (PARPi). PARPi combined with angiogenesis inhibition improved anti-cancer response and duration in both BRCAm and BRCA wild type HGSOC patients, compared to olaparib single agent treatment, demonstrating therapeutic chemical and contextual synthetic lethality.

  1. Molecular mechanisms for synergistic effect of proteasome inhibitors with platinum-based therapy in solid tumors.

    Science.gov (United States)

    Chao, Angel; Wang, Tzu-Hao

    2016-02-01

    The successful development of the proteasome inhibitor bortezomib as an anticancer drug has improved survival in patients with multiple myeloma. With the emergence of the newly US Food and Drug Administration-approved proteasome inhibitor carfilzomib, ongoing trials are investigating this compound and other proteasome inhibitors either alone or in combination with other chemotherapy drugs. However, in solid tumors, the efficacy of proteasome inhibitors has not lived up to expectations. Results regarding the potential clinical efficacy of bortezomib combined with other agents in the treatment of solid tumors are eagerly awaited. Recent identification of the molecular mechanisms (involving apoptosis and autophagy) by which bortezomib and cisplatin can overcome chemotherapy resistance and sensitize tumor cells to anticancer therapy can provide insights into the development of novel therapeutic strategies for patients with solid malignancies. Copyright © 2016. Published by Elsevier B.V.

  2. Tubulin Inhibitor-Based Antibody-Drug Conjugates for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Hao Chen

    2017-08-01

    Full Text Available Antibody-drug conjugates (ADCs are a class of highly potent biopharmaceutical drugs generated by conjugating cytotoxic drugs with specific monoclonal antibodies through appropriate linkers. Specific antibodies used to guide potent warheads to tumor tissues can effectively reduce undesired side effects of the cytotoxic drugs. An in-depth understanding of antibodies, linkers, conjugation strategies, cytotoxic drugs, and their molecular targets has led to the successful development of several approved ADCs. These ADCs are powerful therapeutics for cancer treatment, enabling wider therapeutic windows, improved pharmacokinetic/pharmacodynamic properties, and enhanced efficacy. Since tubulin inhibitors are one of the most successful cytotoxic drugs in the ADC armamentarium, this review focuses on the progress in tubulin inhibitor-based ADCs, as well as lessons learned from the unsuccessful ADCs containing tubulin inhibitors. This review should be helpful to facilitate future development of new generations of tubulin inhibitor-based ADCs for cancer therapy.

  3. Elevation of antioxidant enzymes in the clinical effects of radon and thermal therapy for bronchial asthma

    International Nuclear Information System (INIS)

    Mitsunobu, Fumihiro; Hosaki, Yasuhiro; Ashida, Kozo; Tanizaki, Yoshiro; Yamaoka, Kiyonori; Hanamoto, Katsumi; Sugita, Katsuhiro; Kojima, Shuji

    2003-01-01

    An increased systemic production of oxygen-free radicals by activated inflammatory cells is thought to be involved in the pathophysiology of asthma. The aim of this study is to evaluate the clinical effects of radon and thermal therapy on asthma in relation to antioxidant enzymes and lipid peroxide. Radon and thermal therapy were performed once a week. All subjects went to a hot bathroom with a high concentration of radon, and nasal inhalation of vapor from a hot spring was performed for 40 min once a day under conditions of high humidity. The room temperature was 48 deg C; the room radon concentration was 2,080 Bq/m 3 . Blood samples were collected at 2 h, 14, and 28 days after the first therapy. A blood sample also was collected before the first therapy (at body temperature and background radon level) to be used as the control. The forced expiratory volume in one second (%FEV 1 ) was significantly increased 28 days after the first therapy. On day 28, the catalase (CAT) activity was significantly increased in comparison with the control. The superoxide dismutase (SOD) activity was significantly increased compared to the control after first inhalation. On days 14 and 28, the lipid peroxide level was significantly decreased in comparison with the control. In conclusion, the present pilot study has shown that radon and thermal therapy improved the pulmonary function of asthmatics by increasing the reduced activities of antioxidant enzymes. (author)

  4. Combination therapy with DPP-4 inhibitors and pioglitazone in type 2 diabetes: theoretical consideration and therapeutic potential

    Directory of Open Access Journals (Sweden)

    Nasser Mikhail

    2008-12-01

    Full Text Available Nasser MikhailEndocrinology Division, Olive View-UCLA Medical Center, David-Geffen School of Medicine, CA, USAAbstract: Sitagliptin and vildagliptin represent a new class of anti-diabetic agents that enhance the action of incretin hormones through inhibition of dipeptidyl peptidase-4 (DPP-4, the enzyme that normally inactivates incretin hormones. Because of their distinct mechanism of action, DPP-4 inhibitors can be used as add-on therapy to other classes of drugs for treatment of type 2 diabetes. The objective of this review is to critically evaluate clinical trials of sitagliptin and vildagliptin in combination with pioglitazone. The addition of either sitagliptin or vildagliptin to ongoing pioglitazone therapy is associated with reduction in average hemoglobin A1c (HbA1c levels of approximately 0.7% compared with placebo and 1% compared with baseline after 24 weeks. When started concomitantly in drug-naïve patients, the combination of pioglitazone 30 mg and vildagliptin 100 mg qd reduces HbA1c by 1.9% after 24 weeks, compared with 1.1% with pioglitazone monotherapy. In general, the addition of DPP-4 inhibitors to pioglitazone was well tolerated, did not increase the incidence of hypoglycemia, and did not substantially worsen the weight-gain induced by pioglitazone. The combination of sitagliptpin or vildagliptin with pioglitazone can be a useful therapeutic approach in patients with type 2 diabetes who cannot tolerate metformin or a sulfonylurea.Keywords: incretins, sitagliptin, vildagliptin, dipeptidyl peptidase inhibitors, pioglitazone, type 2 diabetes

  5. Fabry disease: the importance of the enzyme replacement therapy (TRE, treating quickly and efficiently

    Directory of Open Access Journals (Sweden)

    Juan Manuel Politei

    2014-06-01

    Full Text Available Fabry Disease is a lysosomal disorder due to the absence or deficiency of the Alpha galactosidase A enzyme that causes a pathological accumulation of glycosphingolipids mainly in the endothelial cells, vascular smooth muscle cells and podocytes among others. Enzyme replacement therapy is the only option for a specific treatment at present. Increasing knowledge of the physiopathological mechanisms has changed the management of the disease and above all, when treatment should begin. At present, beginning treatment at an early age seems to be a way of preventing and in some cases reverting some of the signs and symptoms of Fabry disease.

  6. Cognitive enhancing effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on learning and memory

    Science.gov (United States)

    Nade, V. S.; Kawale, L. A.; Valte, K. D.; Shendye, N. V.

    2015-01-01

    Objective: The present study was designed to investigate cognitive enhancing property of angiotensin-converting enzymes inhibitors (ACEI) and angiotensin receptor blockers (ARBs) in rats. Materials and Methods: The elevated plus maze (EPM), passive avoidance test (PAT), and water maze test (WMT) were used to assess cognitive enhancing activity in young and aged rats. Ramipril (10 mg/kg, p.o.), perindopril (10 mg/kg, i.p), losartan (20 mg/kg, i.p), and valsartan (20 mg/kg, p.o) were administered to assess their effect on learning and memory. Scopolamine (1 mg/kg, i.p) was used to impair cognitive function. Piracetam (200 mg/kg, i.p) was used as reference drug. Results: All the treatments significantly attenuated amnesia induced by aging and scopolamine. In EPM, aged and scopolamine-treated rats showed an increase in transfer latency (TL) whereas, ACEI and ARBs showed a significant decrease in TL. Treatment with ACEI and ARBs significantly increased step down latencies and decreased latency to reach the platform in target quadrant in young, aged and scopolamine-treated animals in PAT and WMT, respectively. The treatments inhibited acetylcholinesterase (AChE) enzyme in the brain. Similarly, all the treatments attenuated scopolamine-induced lipid peroxidation and normalize antioxidant enzymes. Conclusion: The results suggest that the cognitive enhancing effect of ACEI and ARBs may be due to inhibition of AChE or by regulation of antioxidant system or increase in formation of angiotensin IV. PMID:26069362

  7. A targeted enzyme approach to sensitization of tyrosine kinase inhibitor-resistant breast cancer cells.

    Science.gov (United States)

    Giordano, Courtney R; Mueller, Kelly L; Terlecky, Laura J; Krentz, Kendra A; Bollig-Fischer, Aliccia; Terlecky, Stanley R; Boerner, Julie L

    2012-10-01

    Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) of potential use in patients with breast cancer. Unfortunately, in clinical studies, gefitinib is often ineffective indicating that resistance to EGFR inhibitors may be a common occurrence in cancer of the breast. EGFR has been shown to be overexpressed in breast cancer, and in particular remains hyperphosphorylated in cell lines such as MDA-MB-468 that are resistant to EGFR inhibitors. Here, we investigate the cause of this sustained phosphorylation and the molecular basis for the ineffectiveness of gefitinib. We show that reactive oxygen species (ROS), known to damage cellular macromolecules and to modulate signaling cascades in a variety of human diseases including cancers, appear to play a critical role in mediating EGFR TKI-resistance. Furthermore, elimination of these ROS through use of a cell-penetrating catalase derivative sensitizes the cells to gefitinib. These results suggest a new approach for the treatment of TKI-resistant breast cancer patients specifically, the targeting of ROS and attendant downstream oxidative stress and their effects on signaling cascades. Copyright © 2012. Published by Elsevier Inc.

  8. Reflection on design and testing of pancreatic alpha-amylase inhibitors: an in silico comparison between rat and rabbit enzyme models

    Directory of Open Access Journals (Sweden)

    Khalil-Moghaddam Shiva

    2012-11-01

    Full Text Available Abstract Background Inhibitors of pancreatic alpha-amylase are potential drugs to treat diabetes and obesity. In order to find compounds that would be effective amylase inhibitors, in vitro and in vivo models are usually used. The accuracy of models is limited, but these tools are nonetheless valuable. In vitro models could be used in large screenings involving thousands of chemicals that are tested to find potential lead compounds. In vivo models are still used as preliminary mean of testing compounds behavior in the whole organism. In the case of alpha-amylase inhibitors, both rats and rabbits could be chosen as in vivo models. The question was which animal could present more accuracy with regard to its pancreatic alpha-amylase. Results As there is no crystal structure of these enzymes, a molecular modeling study was done in order to compare the rabbit and rat enzymes with the human one. The overall result is that rabbit enzyme could probably be a better choice in this regard, but in the case of large ligands, which could make putative interactions with the −4 subsite of pancreatic alpha-amylase, interpretation of results should be made cautiously. Conclusion Molecular modeling tools could be used to choose the most suitable model enzyme that would help to identify new enzyme inhibitors. In the case of alpha-amylase, three-dimensional structures of animal enzymes show differences with the human one which should be taken into account when testing potential new drugs.

  9. Histone Deacetylase Inhibitor Therapy in Epithelial Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Noriyuki Takai

    2010-01-01

    Full Text Available Since epigenetic alterations are believed to be involved in the repression of tumor suppressor genes and promotion of tumorigenesis in ovarian cancers, novel compounds endowed with a histone deacetylase (HDAC inhibitory activity are an attractive therapeutic approach. In this review, we discuss the biologic and therapeutic effects of HDAC inhibitors (HDACIs in treating ovarian cancer. HDACIs were able to mediate inhibition of cell growth, cell cycle arrest, apoptosis, and expression of genes related to the malignant phenotype in a variety of ovarian cancer cell lines. Furthermore, HDACIs were able to induce the accumulation of acetylated histones in the chromatin of the p21WAF1 gene in human ovarian carcinoma cells. In xenograft models, some of HDACIs have demonstrated antitumor activity with only few side effects. Some clinical trials demonstrate that HDACI drugs provide an important class of new mechanism-based therapeutics for ovarian cancer. In this review, we discuss the biologic and therapeutic effects of HDACIs in treating ovarian cancer, especially focusing on preclinical studies and clinical trials.

  10. Polyphenols as enzyme inhibitors in different degraded peat soils: Implication for microbial metabolism in rewetted peatlands

    Science.gov (United States)

    Zak, Dominik; Roth, Cyril; Gelbrecht, Jörg; Fenner, Nathalie; Reuter, Hendrik

    2015-04-01

    Recently, more than 30,000 ha of drained minerotrophic peatlands (= fens) in NE Germany were rewetted to restore their ecological functions. Due to an extended drainage history, a re-establishment of their original state is not expected in the short-term. Elevated concentrations of dissolved organic carbon, ammonium and phosphate have been measured in the soil porewater of the upper degraded peat layers of rewetted fens at levels of one to three orders higher than the values in pristine systems; an indicator of increased microbial activity in the upper degraded soil layers. On the other hand there is evidence that the substrate availability within the degraded peat layer is lowered since the organic matter has formerly been subject to intense decomposition over the decades of drainage and intense agricultural use of the areas. Previously however, it was suggested that inhibition of hydrolytic enzymes by polyphenolic substances is suspended during aeration of peat soils mainly due to the decomposition of the inhibiting polyphenols by oxidising enzymes such as phenol oxidase. Accordingly we hypothesised a lack of enzyme inhibiting polyphenols in degraded peat soils of rewetted fens compared to less decomposed peat of more natural fens. We collected both peat samples at the soil surface (0-20 cm) and fresh roots of dominating vascular plants and mosses (as peat parent material) from five formerly drained rewetted sites and five more natural sites of NE Germany and NW Poland. Less decomposed peat and living roots were used to obtain an internal standard for polyphenol analysis and to run enzyme inhibition tests. For all samples we determined the total phenolic contents and in addition we distinguished between the contents of hydrolysable and condensed tannic substances. From a methodical perspective the advantage of internal standards compared to the commercially available standards cyanidin chloride and tannic acid became apparent. Quantification with cyanidin or

  11. New degradation compounds from lignocellulosic biomass pretreatment: routes for formation of potent oligophenolic enzyme inhibitors

    DEFF Research Database (Denmark)

    Rasmussen, H.; Tanner, David Ackland; Sørensen, H. R.

    2017-01-01

    -condensation reactions involving aldol condensations, 1,4 additions to α,β unsaturated carbonyl compounds, 3-keto acid decarboxylations and oxidations. Furthermore, pentose reactions with phenolic lignin components are suggested. The identification of the central role of xylose in the reaction routes for oligophenolic...... inhibitor formation led to the solution to protect the reactive anomeric center in xylose. It is shown that protection of the anomeric center in in situ generated xylose with ethylene glycol monobutyl ether, during pretreatment of wheat straw, reduces the level of oligophenols by 73%. The results pave...

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

    Science.gov (United States)

    Whittle, Nigel; Singewald, Nicolas

    2014-04-01

    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.

  13. Interprofessional Collaboration with Immune Checkpoint Inhibitor Therapy: the Roles of Gastroenterology, Endocrinology and Neurology.

    Science.gov (United States)

    Seery, Virginia

    2017-11-01

    To discuss immune checkpoint inhibitor therapy and identify opportunities for interprofessional collaboration in the management of toxicities in the areas of gastroenterology, endocrinology, and neurology. Published research and education articles in oncology, nursing, and various specialties. The use of immune checkpoint inhibitors is expanding; timely management of toxicity is critical for positive patient outcomes. There are many opportunities for interprofessional collaboration in the diagnosis and treatment of immune-related adverse events. Nurses play key roles in recognizing immune-related adverse events, providing patient education, and helping to facilitate interprofessional collaboration. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. [Memantine as add-on medication to acetylcholinesterase inhibitor therapy for Alzheimer dementia].

    Science.gov (United States)

    Haussmann, R; Donix, M

    2017-01-01

    Currently available data indicate superior therapeutic effects of combination treatment for Alzheimer dementia with memantine and acetylcholine esterase inhibitors in certain clinical contexts. Out of five randomized, placebo-controlled, double-blind trials two showed superior therapeutic effects in comparison to monotherapy with acetylcholinesterase inhibitors regarding various domains. Recently published meta-analyses and cost-benefit analyses also showed positive results. Recently published German guidelines for dementia treatment also take these new data into account and recommend combination treatment in patients with severe dementia on stable donepezil medication. This article gives an overview of current evidence for combination therapy.

  15. The effect of an angiotensin-converting enzyme inhibitor on water and electrolyte balance in water-restricted sheep

    Directory of Open Access Journals (Sweden)

    R.A. Meintjies

    1999-07-01

    Full Text Available The importance of angiotensin II in the regulation of water and electrolyte balance in sheep is questionable. In this trial the effects of an angiotensin-converting enzyme (ACE inhibitor were quantified in sheep on restricted water intake. Comparing the phase of water restriction only with that of water restriction plus ACE inhibition, significant increases were observed during the latter phase in urine volume, sodium and potassium excretion via the urine, sodium concentration in the plasma and osmolar clearance. Urine osmolarity decreased with inhibition of angiotensin II formation while variables such as water, sodium and potassium loss via the faeces were unaffected. Most of the renal effects of ACE inhibition, except the increase in urinary potassium excretion, were explicable in terms of the established functions of angiotensin II. Furthermore, results of this trial indicate that angiotensin II has no significant effect on the intestine in regulating water and electrolyte excretion via the faeces.

  16. Activity of certain enzymes of the gastrointestinal tract and of their inhibitors under the action of radiation and thiophosphamide

    Energy Technology Data Exchange (ETDEWEB)

    Savitskii, I V; Korpovich, G A [Odesskij Meditsinskij Inst. (Ukrainian SSR)

    1975-01-01

    Total-body X-irradiation (600 r) of rats and administration of thiophosphamide (13 mg/kg) increased the activity of trypsin of pancreas and serum of rats, six hours after treatment. An increased activity is maintained over a long period of time after the exposure (up to 60 days), whereas after treatment with thiophosphamide, it starts decreasing below normal on the 7th day. The pepsin activity in the gastric wall decreases early after the irradiation, then it rises (days 3 to 7) and falls again. The administration of thiophosphamide does not substantially influence the activity of pepsin. One of the factors responsible for the variations observed in the activity of enzymes may be the changes in the contents of serum inhibitors of trypsin and pepsin.

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

    DEFF Research Database (Denmark)

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

    2004-01-01

    AIM: To determine by meta-analysis whether angiotensin-converting enzyme (ACE) inhibitors improve exercise tolerance in patients with symptomatic left ventricular systolic dysfunction (LVSD). METHODS AND RESULTS: After literature search 13 multi-centre double blind parallel group trials that eval......% compared with placebo. CONCLUSION: In addition to the pronounced effect on mortality and morbidity in patients with symptomatic LVSD, ACE inhibitors have improving effect on functional capacity measured as exercise tolerance time....

  18. Does early use of enzyme replacement therapy alter the natural history of mucopolysaccharidosis I? Experience in three siblings.

    Science.gov (United States)

    Laraway, Sarah; Breen, Catherine; Mercer, Jean; Jones, Simon; Wraith, James E

    2013-07-01

    Enzyme replacement therapy is widely used as treatment for mucopolysaccharidosis I (MPS I), and there is evidence that this produces improvement in certain clinical domains. There does appear to be variation in the response of clinical features to treatment once these are established. In a reported sibling pair, when enzyme replacement therapy was commenced pre-symptomatically in the younger child, the natural history of the condition appeared to be affected. We present data from three siblings treated with enzyme replacement therapy at different ages which supports this finding. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. Combination therapy for hepatitis C virus with heat-shock protein 90 inhibitor 17-AAG and proteasome inhibitor MG132.

    Science.gov (United States)

    Ujino, Saneyuki; Yamaguchi, Saori; Shimotohno, Kunitada; Takaku, Hiroshi

    2010-03-09

    Hepatitis C virus (HCV) infection is a major cause of chronic liver disease. Here, we report a new and effective strategy for inhibiting HCV replication using an inhibitor of heat-shock protein 90, 17-AAG (17-allylamino-17demethoxygeldanamycin), and a proteasome inhibitor, MG132. To explore the virological basis of combination therapy, we analysed the effects of 17-AAG and MG132, singly and in combination on HCV replication in an HCV replicon cell system. In HCV replicon cells, HCV RNA replication was suppressed by 17-AAG in a dose-dependent manner. As shown in the present study, the 50% inhibitory concentration values were 0.82 nM for 17-AAG and 0.21 nM for MG132. Low concentrations of MG132 had strong synergistic inhibitory effects with low toxicity on HCV replicon cells. The results of this study suggest that the different effects and synergistic actions of 17-AAG and MG132 could provide a new therapeutic approach to HCV infection.

  20. Effects of angiotensin converting enzyme inhibitor and angiotensin II antagonist receptor on neointima hyperplasia after vascular balloon injury

    International Nuclear Information System (INIS)

    Wang Yeling; Zhao Lihua

    2004-01-01

    Objective: To study the effects of angiotensin converting enzyme inhibitor (captopril) and angiotensin II antagonist receptor (valsartan) on neointima hyperplasia after vascular balloon injury. Methods: Thirty-six rabbit models were randomly divided into three groups: injuried group, captopril group and valsartan group. Captopril (2 mg·kg -1 ·d -1 po) and valsartan (10 mg·kg -1 ·d -1 po) were given to twelve rabbits respectively from 1 day before the right carotidarteries were injuried by 2.0 mm ballon cathether to 14 days after injury in captopil group and valsartan group. The medicine was not administered in the injuried group. The tissue plasminogen activator (tPA), plaminogen activor inhibitor-1 (PAI-1) antigen level and plasma endothelin (ET) levels were measured before injury, and 7, 14 days after vascular injury. The pathomorphoiogical examination were carried out 14 days after angioplasty. Results: The levels of plasma PAI-1 and ET in captopril group and valsartan group were significantly lower than those in the injuried group (P<0.05). The intimal thickness and extent of lumen stenosis in captopril and valsartan groups were significantly lower than those in the injuried group (P<0.05). Conclusion: Captopril and valsartan can inhibit neointima hyperplasia after vascular ballon injury. (authors)

  1. Natural products inhibitors of the angiotensin converting enzyme (ACE: a review between 1980 - 2000

    Directory of Open Access Journals (Sweden)

    José M. Barbosa-Filho

    Full Text Available Inhibition of Angiotensin Converting Enzyme (ACE is a modern therapeutic target in the treatment of hypertension. Within the enzyme cascade of the renin-angiotensin system, ACE removes histidyl-leucine from angiotensin I to form the physiologically active octapeptide angiotensin II, one of the most potent known vasoconstrictors. Therefore, a rationale for treating hypertension would be to administer drugs or natural compounds which selectively inhibit ACE. The present work constitutes a review of the literature of plants and chemically defined molecules from natural sources with in vitro anti-hypertensive potential based on the inhibition of ACE. The review refers to 321 plants, the parts utilized, type of extract and whether they are active or not. It includes also the names of 158 compounds isolated from higher plants, marine sponges and algae, fungi and snake venom. Some aspects of recent research with natural products directed to produce anti-hypertensive drugs are discussed. In this review, 148 references were cited.

  2. Versatility of 7-Substituted Coumarin Molecules as Antimycobacterial Agents, Neuronal Enzyme Inhibitors and Neuroprotective Agents

    Directory of Open Access Journals (Sweden)

    Erika Kapp

    2017-09-01

    Full Text Available A medium-throughput screen using Mycobacterium tuberculosis H37Rv was employed to screen an in-house library of structurally diverse compounds for antimycobacterial activity. In this initial screen, eleven 7-substituted coumarin derivatives with confirmed monoamine oxidase-B and cholinesterase inhibitory activities, demonstrated growth inhibition of more than 50% at 50 µM. This prompted further exploration of all the 7-substituted coumarins in our library. Four compounds showed promising MIC99 values of 8.31–29.70 µM and 44.15–57.17 µM on M. tuberculosis H37Rv in independent assays using GAST-Fe and 7H9+OADC media, respectively. These compounds were found to bind to albumin, which may explain the variations in MIC between the two assays. Preliminary data showed that they were able to maintain their activity in fluoroquinolone resistant mycobacteria. Structure-activity relationships indicated that structural modification on position 4 and/or 7 of the coumarin scaffold could direct the selectivity towards either the inhibition of neuronal enzymes or the antimycobacterial effect. Moderate cytotoxicities were observed for these compounds and slight selectivity towards mycobacteria was indicated. Further neuroprotective assays showed significant neuroprotection for selected compounds irrespective of their neuronal enzyme inhibitory properties. These coumarin molecules are thus interesting lead compounds that may provide insight into the design of new antimicrobacterial and neuroprotective agents.

  3. Comparison between SGLT2 inhibitors and DPP4 inhibitors added to insulin therapy in type 2 diabetes: a systematic review with indirect comparison meta-analysis.

    Science.gov (United States)

    Min, Se Hee; Yoon, Jeong-Hwa; Hahn, Seokyung; Cho, Young Min

    2017-01-01

    Both sodium glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP4) inhibitors can be used to treat patients with type 2 diabetes mellitus (T2DM) that is inadequately controlled with insulin therapy, and yet there has been no direct comparison of these two inhibitors. We searched MEDLINE, EMBASE, LILACS, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov through June 2015. Randomized controlled trials published in English that compare SGLT2 inhibitor plus insulin (SGLT2i/INS) with placebo plus insulin or DPP4 inhibitor plus insulin (DPP4i/INS) with placebo plus insulin in patients with T2DM were selected. Data on the study characteristics, efficacy and safety outcomes were extracted. We compared the efficacy and safety between SGLT2i/INS and DPP4i/INS indirectly with covariates adjustment. Risk of potential bias was assessed. Fourteen eligible randomized controlled trials comprising 6980 patients were included (five SGLT2 inhibitor studies and nine DPP4 inhibitor studies). Covariate-adjusted indirect comparison using meta-regression analyses revealed that SGLT2i/INS achieved greater reduction in HbA 1c [weighted mean difference (WMD) -0.24%, 95% confidence interval (CI) -0.43 to -0.05%], fasting plasma glucose (WMD -18.0 mg/dL, 95% CI -28.5 to -7.6 mg/dL) and body weight (WMD -2.38 kg, 95% CI -3.18 to -1.58 kg) from baseline than DPP4i/INS without increasing the risk of hypoglycaemia (relative risks 1.19, 95% CI 0.78 to 1.82). Sodium glucose cotransporter 2 inhibitors achieved better glycaemic control and greater weight reduction than DPP4 inhibitors without increasing the risk of hypoglycaemia in patients with T2DM that is inadequately controlled with insulin. There has been no direct comparison of SGLT2 inhibitors and DPP4 inhibitors in patients with T2DM inadequately controlled with insulin therapy. In this study, we performed indirect meta-analysis comparing SGLT2 inhibitors and DPP4 inhibitors added to insulin

  4. Discovery of novel hydroxamates as highly potent tumor necrosis factor-[alpha] converting enzyme inhibitors. Part II: Optimization of the S3′ pocket

    Energy Technology Data Exchange (ETDEWEB)

    Mazzola Jr., Robert D.; Zhu, Zhaoning; Sinning, Lisa; McKittrick, Brian; Lavey, Brian; Spitler, James; Kozlowski, Joseph; Neng-Yang, Shih; Zhou, Guowei; Guo, Zhuyan; Orth, Peter; Madison, Vincent; Sun, Jing; Lundell, Daniel; Niu, Xiaoda (SPRI)

    2010-10-01

    A series of cyclopropyl hydroxamic acids were prepared. Many of the compounds displayed picomolar affinity for the TACE enzyme while maintaining good to excellent selectivity profiles versus MMP-1, -2, -3, -7, -14, and ADAM-10. X-ray analysis of an inhibitor in the TACE active site indicated that the molecules bound to the enzyme in the S1{prime}-S3{prime} pocket.

  5. Enzyme inhibition by iminosugars

    DEFF Research Database (Denmark)

    López, Óscar; Qing, Feng-Ling; Pedersen, Christian Marcus

    2013-01-01

    Imino- and azasugar glycosidase inhibitors display pH dependant inhibition reflecting that both the inhibitor and the enzyme active site have groups that change protonation state with pH. With the enzyme having two acidic groups and the inhibitor one basic group, enzyme-inhibitor complexes...

  6. Combination Therapy of PPAR Ligands and Inhibitors of Arachidonic Acid in Lung Cancer

    Directory of Open Access Journals (Sweden)

    Jordi Tauler

    2008-01-01

    Full Text Available Lung cancer is the leading cause of cancer death in the United States and five-year survival remains low. Numerous studies have shown that chronic inflammation may lead to progression of carcinogenesis. As a result of inflammatory stimulation, arachidonic acid (AA metabolism produces proliferation mediators through complex and dynamic interactions of the products of the LOX/COX enzymes. One important mediator in the activation of the AA pathways is the nuclear protein PPAR. Targeting LOX/COX enzymes and inducing activation of PPAR have resulted in significant reduction of cell growth in lung cancer cell lines. However, specific COX-inhibitors have been correlated with an increased cardiovascular risk. Clinical applications are still being explored with a novel generation of dual LOX/COX inhibitors. PPAR activation through synthetic ligands (TZDs has revealed a great mechanistic complexity since effects are produced through PPAR-dependent and -independent mechanisms. Furthermore, PPAR could also be involved in regulation of COX-2. Overexpression of PPAR has reported to play a role in control of invasion and differentiation. Exploring the function of PPAR, in this new context, may provide a better mechanistic model of its role in cancer and give an opportunity to design a more efficient therapeutic approach in combination with LOX/COX inhibitors.

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

    Directory of Open Access Journals (Sweden)

    Peter G Traber

    Full Text Available 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

  8. Effects of pancreatic digestive enzymes, sodium bicarbonate, and a proton pump inhibitor on steatorrhoea caused by pancreatic diseases.

    Science.gov (United States)

    Nakamura, T; Takebe, K; Kudoh, K; Ishii, M; Imamura, K; Kikuchi, H; Kasai, F; Tandoh, Y; Yamada, N; Arai, Y

    1995-01-01

    Forty-five patients with pancreatic steatorrhoea (27 with calcified pancreatitis, 13 with non-calcified pancreatitis, two with pancreaticoduodenectomy, one with total pancreatectomy, and two with pancreatic cancer) were divided into four groups and given the following medication for 2 to 4 weeks: 4 to 6 g/day of sodium bicarbonate (group I); 9 g/day of high-lipase pancreatin (lipase, 56,600 U/g, Fédération Internationale Pharmaceutique (FIP); group II); 12 to 24 tablets or 9.0 g of commercial pancreatic enzyme preparations (group III); or 50 mg of omeprazole (group IV). Faecal fat excretion was evaluated before and after drug administration. Faecal fat excretion was reduced by 2.9 g (range, 1.7 to 5.0 g) in group I; 8.8 g (range, 2.9 to 39.9 g) in group II; 10.8 g (range, 2.3 to 21.8 g) in group III; and 4.3 g (range, 3.6 to 5.6 g) in group IV. The pancreatic digestive enzyme preparation was more effective than sodium bicarbonate and agents that raise the pH of the upper small intestine (such as proton-pump inhibitors) in reducing faecal fat excretion. The results indicate that all of the preparations used are effective against mild pancreatic steatorrhoea. If the condition is more advanced, however, a massive dosage of pancreatic digestive enzyme and possibly the combined use of an agent to raise the pH of the upper small intestine are likely to be effective.

  9. Frequency of cough during therapy with ACE inhibitors in Greek hypertensives.

    Science.gov (United States)

    Efstratopoulos, A D; Meikopoulos, M; Voyaki, S

    1993-12-01

    Persistent dry cough is one of the most common side-effects during therapy with ACE inhibitors. The frequency of cough ranges widely (from 0.2% to 15%) in different series, being higher in small studies and smaller in retrospective studies with large number of patients. The aim of the present study was to evaluate the true frequency of cough induced by treatment with ACE inhibitors in Greek hypertensives and to determine various possibly correlated parameters, including sex, duration of therapy and kind and dose of ACE inhibitors. All hypertensive patients followed in our Hypertension Clinic and treated with ACE inhibitors participated in the study. A total of 228 patients, 103 males and 125 females, 24-80 years of age, were treated with ACE inhibitors for a period of 1-41 months: 121 with enalapril, 40 with captopril, 39 with lisinopril, 25 with perindopril and 3 with ramipril. During treatment with ACE inhibitors persistent dry cough occurred in 15 patients, 12 women and 3 men, giving a frequency of 6.58%. Eleven patients (4.82%) volunteered the information and three after questioning. The mean age of these 15 patients with cough was significantly higher from that of the group (n = 213) without cough (64.27 +/- 2.5 vs. 57.9 +/- 0.74 years, mean +/- SEM, P = 0.024). The 12 women with cough were significantly older than the 113 without cough (67.77 +/- 2.8 vs. 57.8 +/- 1.04 years, P = 0.032).(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Therapeutic peptides for cancer therapy. Part I - peptide inhibitors of signal transduction cascades.

    Science.gov (United States)

    Bidwell, Gene L; Raucher, Drazen

    2009-10-01

    Therapeutic peptides have great potential as anticancer agents owing to their ease of rational design and target specificity. However, their utility in vivo is limited by low stability and poor tumor penetration. The authors review the development of peptide inhibitors with potential for cancer therapy. Peptides that inhibit signal transduction cascades are discussed. The authors searched Medline for articles concerning the development of therapeutic peptides and their delivery. Given our current knowledge of protein sequences, structures and interaction interfaces, therapeutic peptides that inhibit interactions of interest are easily designed. These peptides are advantageous because they are highly specific for the interaction of interest, and they are much more easily developed than small molecule inhibitors of the same interactions. The main hurdle to application of peptides for cancer therapy is their poor pharmacokinetic and biodistribution parameters. Therefore, successful development of peptide delivery vectors could potentially make possible the use of this new and very promising class of anticancer agents.

  11. A Chimeric SERM-Histone Deacetylase Inhibitor Approach to Breast Cancer Therapy

    OpenAIRE

    Patel, Hitisha K.; Siklos, Marton I.; Abdelkarim, Hazem; Mendonca, Emma L.; Vaidya, Aditya; Petukhov, Pavel A.; Thatcher, Gregory R. J.

    2013-01-01

    Breast cancer remains a significant cause of death in women and few therapeutic options exist for estrogen receptor negative ER(−) cancers. Epigenetic re-activation of target genes using histone deacetylase (HDAC) inhibitors has been proposed in ER(−) cancers to resensitize to therapy using selective estrogen receptor modulators (SERMs) that are effective in ER(+) cancer treatment. Based upon preliminary studies in ER(+) and ER(−) breast cancer cells treated with combinations of HDAC inhibito...

  12. Modelling Gaucher disease progression: long-term enzyme replacement therapy reduces the incidence of splenectomy and bone complications

    NARCIS (Netherlands)

    van Dussen, Laura; Biegstraaten, Marieke; Dijkgraaf, Marcel Gw; Hollak, Carla Em

    2014-01-01

    Long-term complications and associated conditions of type 1 Gaucher Disease (GD) can include splenectomy, bone complications, pulmonary hypertension, Parkinson disease and malignancies. Enzyme replacement therapy (ERT) reverses cytopenia and reduces organomegaly. To study the effects of ERT on

  13. Plasma oxidative stress level of IgA nephropathy in children and the effect of early intervention with angiotensin-converting enzyme inhibitors.

    Science.gov (United States)

    Pei, Yuxin; Xu, Yuanyuan; Ruan, Jingwei; Rong, Liping; Jiang, Mengjie; Mo, Ying; Jiang, Xiaoyun

    2016-01-01

    The purpose of this study was to investigate the change of the plasma oxidative stress level in children with IgA nephropathy (IgAN) and analyze its relativity to the clinical and pathological classification. To discuss the early effects of angiotensin-converting enzyme inhibitors (ACEIs) on the plasma oxidative stress level in children with IgA nephropathy. Thirty-eight children with IgAN were divided into groups according to their clinical features, pathologic grades, and treatments. Twenty healthy children were included in the control group. The plasma level of advanced oxidation protein products (AOPPs), malonaldehyde (MDA), and superoxide dismutase (SOD) were detected. The plasma level of oxidative stress was significantly increased in the IgAN group, including a higher plasma level of AOPP and MDA and a lower plasma level of SOD. After treatment, the plasma level of oxidative stress was significantly decreased in the ACEI group. The children with IgAN had an increase in the plasma level of oxidative stress, expressed as an increased plasma level of AOPP and MDA and a decreased plasma level of SOD. Oxidative stress was associated with the progression of IgAN in children. Early treatment with ACEI therapy can significantly reduce the plasma level of oxidative stress in children with IgAN. © The Author(s) 2016.

  14. Proton pump inhibitor step-down therapy for GERD: A multi-center study in Japan

    Science.gov (United States)

    Tsuzuki, Takao; Okada, Hiroyuki; Kawahara, Yoshiro; Takenaka, Ryuta; Nasu, Junichiro; Ishioka, Hidehiko; Fujiwara, Akiko; Yoshinaga, Fumiya; Yamamoto, Kazuhide

    2011-01-01

    AIM: To investigate the predictors of success in step-down of proton pump inhibitor and to assess the quality of life (QOL). METHODS: Patients who had heartburn twice a week or more were treated with 20 mg omeprazole (OPZ) once daily for 8 wk as an initial therapy (study 1). Patients whose heartburn decreased to once a week or less at the end of the initial therapy were enrolled in study 2 and treated with 10 mg OPZ as maintenance therapy for an additional 6 mo (study 2). QOL was investigated using the gastrointestinal symptom rating scale (GSRS) before initial therapy, after both 4 and 8 wk of initial therapy, and at 1, 2, 3, and 6 mo after starting maintenance therapy. RESULTS: In study 1, 108 patients were analyzed. Their characteristics were as follows; median age: 63 (range: 20-88) years, sex: 46 women and 62 men. The success rate of the initial therapy was 76%. In the patients with successful initial therapy, abdominal pain, indigestion and reflux GSRS scores were improved. In study 2, 83 patients were analyzed. Seventy of 83 patients completed the study 2 protocol. In the per-protocol analysis, 80% of 70 patients were successful for step-down. On multivariate analysis of baseline demographic data and clinical information, no previous treatment for gastroesophageal reflux disease (GERD) [odds ratio (OR) 0.255, 95% CI: 0.06-0.98] and a lower indigestion score in GSRS at the beginning of step-down therapy (OR 0.214, 95% CI: 0.06-0.73) were found to be the predictors of successful step-down therapy. The improved GSRS scores by initial therapy were maintained through the step-down therapy. CONCLUSION: OPZ was effective for most GERD patients. However, those who have had previous treatment for GERD and experience dyspepsia before step-down require particular monitoring for relapse. PMID:21472108

  15. ORGANOPROTECTIVE EFFECTS OF THE FIXED COMBINATION OF ANGIOTENSIN-CONVERTING ENZYME INHIBITOR LISINOPRIL AND DIURETIC HYDROCHLOROTHIAZIDE

    Directory of Open Access Journals (Sweden)

    E. A. Ryabikhin

    2016-01-01

    Full Text Available Aim. To compare the antihypertensive and metabolic effects of combined therapy (carvedilol reception and «School of the hypertensive patient» with these of the carvedilol monotherapy in young patients with arterial hypertension (HT of 1-2 degrees with overweight and obesity.Material and methods. 63 out-patients with HT of 1-2 degrees (aged 18-27 y.o. with overweight and obesity were included in the open parallel randomized clinical preventive trail. Patients wеre randomized into 2 groups. All hypertensive patients received the carvedilol (Vedicardol, Sintez, Russia 25 mg daily. Carvedilol dose was enlarged twice in case of insufficient antihypertensive effect. Patients of the main group (n=32 also passed through the special educational program «School for hypertensive patients». Changes in blood pressure (BP level, body mass index, biochemical markers and risk factors were evaluated initially and in 24 weeks of therapy.Results. Patients of the main group had more significant risk factor manifestations decrease than in group of comparison. More significant body mass index decrease was also observed in the main group in comparison with group of comparison: from 32,5±0,4 to 26,4±0,7 kg/m2 (p<0,01 and from 31,8±0,8 to 28,9±1,18 kg/m2 (p<0,05, respectively. In patients of the main group systolic and diastolic BP decreased by 20,1% and 25,6%, respectively, wile in patients of the group of comparison – by 18,9% and 26%, respectively.Conclusion. It is reasonable to combine carvedilol therapy with special training in the young hypertensive patients with overweight and obesity.

  16. ORGANOPROTECTIVE EFFECTS OF THE FIXED COMBINATION OF ANGIOTENSIN-CONVERTING ENZYME INHIBITOR LISINOPRIL AND DIURETIC HYDROCHLOROTHIAZIDE

    Directory of Open Access Journals (Sweden)

    E. A. Ryabikhin

    2009-01-01

    Full Text Available Aim. To compare the antihypertensive and metabolic effects of combined therapy (carvedilol reception and «School of the hypertensive patient» with these of the carvedilol monotherapy in young patients with arterial hypertension (HT of 1-2 degrees with overweight and obesity.Material and methods. 63 out-patients with HT of 1-2 degrees (aged 18-27 y.o. with overweight and obesity were included in the open parallel randomized clinical preventive trail. Patients wеre randomized into 2 groups. All hypertensive patients received the carvedilol (Vedicardol, Sintez, Russia 25 mg daily. Carvedilol dose was enlarged twice in case of insufficient antihypertensive effect. Patients of the main group (n=32 also passed through the special educational program «School for hypertensive patients». Changes in blood pressure (BP level, body mass index, biochemical markers and risk factors were evaluated initially and in 24 weeks of therapy.Results. Patients of the main group had more significant risk factor manifestations decrease than in group of comparison. More significant body mass index decrease was also observed in the main group in comparison with group of comparison: from 32,5±0,4 to 26,4±0,7 kg/m2 (p<0,01 and from 31,8±0,8 to 28,9±1,18 kg/m2 (p<0,05, respectively. In patients of the main group systolic and diastolic BP decreased by 20,1% and 25,6%, respectively, wile in patients of the group of comparison – by 18,9% and 26%, respectively.Conclusion. It is reasonable to combine carvedilol therapy with special training in the young hypertensive patients with overweight and obesity.

  17. Natural AChE Inhibitors from Plants and their Contribution to Alzheimer's Disease Therapy.

    Science.gov (United States)

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

    2013-07-01

    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.

  18. Dose-response relationships for enzyme replacement therapy with imiglucerase/alglucerase in patients with Gaucher disease type 1

    NARCIS (Netherlands)

    Grabowski, Gregory A.; Kacena, Katherine; Cole, J. Alexander; Hollak, Carla E. M.; Zhang, Lin; Yee, John; Mistry, Pramod K.; Zimran, Ari; Charrow, Joel; vom Dahl, Stephan

    2009-01-01

    Purpose: To determine whether enzyme therapy with imiglucerase/ alglucerase demonstrates dose-response relationships with doses and disease parameters used in routine clinical practice for Gaucher disease type 1 patients. Methods: Analyses included all patients with Gaucher disease type 1 on enzyme

  19. Characterization of New Bioactive Enzyme Inhibitors from Endophytic Bacillus amyloliquefaciens RWL-1

    Directory of Open Access Journals (Sweden)

    Raheem Shahzad

    2018-01-01

    Full Text Available Endophytic bacteria are known to produce a wide array of bioactive secondary metabolites with beneficial effects on human health. In the current study, a novel endophytic bacterial strain, Bacillus amyloliquefaciens RWL-1, was isolated from the seeds of Oryza sativa. Initially, the crude extract of RWL-1 was assessed for potential biological effects of enzyme inhibition and cytotoxicity and was found to exhibit a broad spectrum inhibition for α-glucosidase (37 ± 0.09% and urease (49.4 ± 0.53%. The screening results were followed by bioassay-guided isolation of secondary metabolite(s from RWL-1. Extensive chromatographic and spectrophotometry analyses revealed the presence of compound 1 (S-2-hydroxy-N-((S-1-((S-8-hydroxy-1-oxoisochroman-3-yl-3-methylbutyl-2-((S-5-oxo-2,5-dihydrofuran-2-ylacetamide. Further bioassays of compound 1 showed significant inhibition of α-glucosidase (52.98 ± 0.8% and urease (51.27 ± 1.0%, compared with positive control values of 79.14 ± 1.9% and 88.24 ± 2.2%, and negative controls (0.08 ± 0.1% and 0.05 ± 0.01%, respectively. The current study suggests that bacterial endophytes are a rich source of novel bioactive compounds with high therapeutic value.

  20. Angiotensin I-Converting Enzyme Inhibitor Derived from Cross-Linked Oyster Protein

    Directory of Open Access Journals (Sweden)

    Cheng-Liang Xie

    2014-01-01

    Full Text Available Following cross-linking by microbial transglutaminase, modified oyster proteins were hydrolyzed to improve inhibitory activity against angiotensin-converting enzyme (ACE inhibitory activity with the use of a single protease, or a combination of six proteases. The oyster hydrolysate with the lowest 50% ACE inhibitory concentration (IC50 of 0.40 mg/mL was obtained by two-step hydrolysis of the cross-linked oyster protein using Protamex and Neutrase. Five ACE inhibitory peptides were purified from the oyster hydrolysate using a multistep chromatographic procedure comprised of ion-exchange, size exclusion, and reversed-phase liquid chromatography. Their sequences were identified as TAY, VK, KY, FYN, and YA, using automated Edman degradation and mass spectrometry. These peptides were synthesized, and their IC50 values were measured to be 16.7, 29.0, 51.5, 68.2, and 93.9 μM, respectively. Toxicity of the peptides on the HepG2 cell line was not detected. The oyster hydrolysate also significantly decreased the systolic blood pressure of spontaneously hypertensive rats (SHR. The antihypertensive effect of the oyster hydrolysate on SHR was rapid and long-lasting, compared to commercially obtained sardine hydrolysate. These results suggest that the oyster hydrolysate could be a source of effective nutraceuticals against hypertension.

  1. O-Alkyl Hydroxamates as Metaphors of Enzyme-Bound Enolate Intermediates in Hydroxy Acid Dehydrogenases. Inhibitors of Isopropylmalate Dehydrogenase, Isocitrate Dehydrogenase, and Tartrate Dehydrogenase(1).

    Science.gov (United States)

    Pirrung, Michael C.; Han, Hyunsoo; Chen, Jrlung

    1996-07-12

    The inhibition of Thermus thermophilus isopropylmalate dehydrogenase by O-methyl oxalohydroxamate was studied for comparison to earlier results of Schloss with the Salmonella enzyme. It is a fairly potent (1.2 &mgr;M), slow-binding, uncompetitive inhibitor against isopropylmalate and is far superior to an oxamide (25 mM K(i) competitive) that is isosteric with the ketoisocaproate product of the enzyme. This improvement in inhibition was attributed to its increased NH acidity, which presumably is due to the inductive effect of the hydroxylamine oxygen. This principle was extended to the structurally homologous enzyme isocitrate dehydrogenase from E. coli, for which the compound O-(carboxymethyl) oxalohydroxamate is a 30 nM inhibitor, uncompetitive against isocitrate. The pH dependence of its inhibition supports the idea that it is bound to the enzyme in the anionic form. Another recently discovered homologous enzyme, tartrate dehydrogenase from Pseudomonas putida, was studied with oxalylhydroxamate. It has a relatively low affinity for the enzyme, though it is superior to tartrate. On the basis of these leads, squaric hydroxamates with increased acidity compared to squaric amides directed toward two of these enzymes were prepared, and they also show increased inhibitory potency, though not approaching the nanomolar levels of the oxalylhydroxamates.

  2. Implementation of GLP-1 based therapy of type 2 diabetes mellitus using DPP-IV inhibitors

    DEFF Research Database (Denmark)

    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...... 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...

  3. Renal function in heart transplant patients after switch to combined mammalian target of rapamycin inhibitor and calcineurin inhibitor therapy

    Directory of Open Access Journals (Sweden)

    Helmschrott M

    2017-06-01

    Full Text Available Matthias Helmschrott,1 Rasmus Rivinius,1 Thomas Bruckner,2 Hugo A Katus,1 Andreas O Doesch1 1Department of Cardiology, Angiology, Pneumology, 2Institute for Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany Background: A calcineurin inhibitor (CNI-based immunosuppression combined with mammalian target of rapamycin inhibitors (mTORs seems to be attractive in patients after heart transplantation (HTX in special clinical situations, for example, in patients with adverse drug effects of prior immunosuppression. Previous studies in patients after HTX detected advantageous effects regarding renal function of a tacrolimus (TAC-based vs cyclosporine-A (CSA-based immunosuppression (in combination with mycophenolate mofetil. However, data regarding renal function after HTX in mTOR/CNI patients remain limited. Aim: Primary end point of the present study was to analyze renal function in HTX patients 1 year after switch to an mTOR/CNI-based immunosuppression. Methods: Data of 80 HTX patients after change to mTOR/CNI-based immunosuppression were retrospectively analyzed. Renal function was assessed by measured serum creatinine and by estimated glomerular filtration rate (eGFR calculated from Modification of Diet in Renal Disease equation. Results: Twenty-nine patients received mTOR/CSA-based treatment and 51 patients received mTOR/TAC-based therapy. At time of switch and at 1-year follow-up, serum creatinine and eGFR did not differ significantly between both study groups (all P=not statistically significant. Analysis of variances with repeated measurements detected a similar change of renal function in both study groups. Conclusion: The present study detected no significant differences between both mTOR/CNI study groups, indicating a steady state of renal function in HTX patients after switch of immunosuppressive regimen. Keywords: heart transplantation, cyclosporine A, tacrolimus, risk factors

  4. Kinetic analysis of enzyme systems with suicide substrate in the presence of a reversible competitive inhibitor, tested by simulated progress curves.

    Science.gov (United States)

    Moruno-Dávila, M A; Garrido-del Solo, C; García-Moreno, M; Havsteen, B H; Garcia-Sevilla, F; Garcia-Cánovas, F; Varón, R

    2001-02-01

    The use of suicide substrates remains a very important and useful method in enzymology for studying enzyme mechanisms and designing potential drugs. Suicide substrates act as modified substrates for the target enzymes and bind to the active site. Therefore the presence of a competitive reversible inhibitor decreases the rate of substrate-induced inactivation and protects the enzyme from this inactivation. This lowering on the inactivation rate has evident physiological advantages, since it allows the easy acquisition of experimental data and facilitates kinetic data analysis by providing another variable (inhibitor concentration). However despite the importance of the simultaneous action of a suicide substrate and a competitive reversible inhibition, to date no corresponding kinetic analysis has been carried out. Therefore we present a general kinetic analysis of a Michaelis-Menten reaction mechanism with double inhibition caused by both, a suicide substrate and a competitive reversible inhibitor. We assume rapid equilibrium of the reversible reaction steps involved, while the time course equations for the reaction product have been derived with the assumption of a limiting enzyme. The goodness of the analytical solutions has been tested by comparison with the simulated curves obtained by numerical integration. A kinetic data analysis to determine the corresponding kinetic parameters from the time progress curve of the product is suggested. In conclusion, we present a complete kinetic analysis of an enzyme reaction mechanism as described above in an attempt to fill a gap in the theoretical treatment of this type of system.

  5. Antioxidative sulphated polygalactans from marine macroalgae as angiotensin-I converting enzyme inhibitors.

    Science.gov (United States)

    Makkar, Fasina; Chakraborty, Kajal

    2017-08-17

    Antioxidant and antihypertensive potential of the sulphated polygalactans isolated from the marine macroalgae Kappaphycus alvarezii and Gracilaria opuntia were assessed by utilising different in vitro systems. The galactans isolated from K. alvarezii possessed significantly greater antioxidative properties as determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH IC 90 0.97 mg/mL) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid (ABTS .+ IC 90 0.72 mg/mL) scavenging activities than those isolated from G. opuntia (DPPH IC 90 1.2 mg/mL and ABTS 0.86 mg/mL). The sulphated polygalactan →4)-4-O-sulphonato-(2-O-methyl)-β-D-galactopyranosyl-(1→4)-3,6-anhydro-(2-O-methyl)-α-D-galactopyranan from K. alvarezii showed greater angiotensin-I-converting enzyme (ACE) inhibitory activity (IC 50 0.02 μg/mL) than →3)-4-O-sulphonato-(6-O-acetyl)-β-D-galactopyranosyl-(1→4)-3,6-anhydro-(2-O-sulphonato)-α-D-galactopyranosyl-(1→3)-4-O-sulphonato-(6-O-acetyl)-β-D-xylosyl-(1→3)-4-O-sulphonato-(6-O-acetyl)-β-D-galactopyranosyl-(1→4)-3,6-anhydro-(2-O-sulphonato)-α-D-galactopyranan motif extracted from G. opuntia (IC 50 0.70 μg/mL). Structure activity correlation studies displayed that the ACE inhibitory properties of titled polygalactans were directly proportional to their electronic properties and inversely with the steric and hydrophobic characteristics. Putative ACE inhibitory mechanism of action of sulphated galactans from marine macroalgae corroborated the structure bioactivity correlation analysis.

  6. Wild-type and mutated IDH1/2 enzymes and therapy responses.

    Science.gov (United States)

    Molenaar, Remco J; Maciejewski, Jaroslaw P; Wilmink, Johanna W; van Noorden, Cornelis J F

    2018-04-01

    Isocitrate dehydrogenase 1 and 2 (IDH1/2) are key enzymes in cellular metabolism, epigenetic regulation, redox states, and DNA repair. IDH1/2 mutations are causal in the development and/or progression of various types of cancer due to supraphysiological production of D-2-hydroxyglutarate. In various tumor types, IDH1/2-mutated cancers predict for improved responses to treatment with irradiation or chemotherapy. The present review discusses the molecular basis of the sensitivity of IDH1/2-mutated cancers with respect to the function of mutated IDH1/2 in cellular processes and their interactions with novel IDH1/2-mutant inhibitors. Finally, lessons learned from IDH1/2 mutations for future clinical applications in IDH1/2 wild-type cancers are discussed.

  7. SGLT2 inhibitors as adjunct therapy to insulin in type 1 diabetes: Meta analysis

    Directory of Open Access Journals (Sweden)

    Jiao CHEN

    2017-02-01

    Full Text Available Objective To evaluate the efficacy and safety of sodium glucose co-transporter-2 (SGLT-2 inhibitors as adjunct therapy to insulin in type 1 diabetes (T1DM. Methods The PubMed, The Cochrane Library, EMbase, CENTRRAI, CBM, CNKI, VIP and WangFang database were searched from inception to April 5, 2016 for systematic reviews, references screen was performed manually. The trials of SGLT2 inhibitors versus placebo add to insulin carried out in patients with T1DM were collected, and their bias risk was assessed and meta-analysis was conducted by using RevMan 5.3 software. Results Four randomized control trials (RCTs were yielded for meta-analysis, including 529 patients. Compared with control group, SGLT2 inhibitors as adjunct therapy to insulin significantly reduced fasting plasma glucose (FPG [weighted mean difference (WMD=–0.65mmol/L, 95% confidence interval (CI=–1.30 to –0.08, P<0.05], glycated hemoglobin A1C (HbA1c (WMD=–0.37%, 95%CI=–0.54 to –0.20, P<0.00001, body weight (WMD=–2.54kg, 95%CI=–3.48 to –1.60, P<0.0001 and total daily insulin dose (WMD=–6.23IU, 95% CI=–8.05 to –4.40, P<0.0001, but the total adverse events (AEs, hypoglycemia, genital and urinary infections showed no significant difference. Conclusions Based on current studies, SGLT-2 inhibitors are effective as adjunct therapy to insulin in T1DM, may improve glycemic control, reduce body weight and total daily insulin dose without increase of total AEs, hypoglycemia, and genital and urinary infections. DOI: 10.11855/j.issn.0577-7402.2016.12.15

  8. Enzyme immunoassay for measurement of murine plasminogen activator inhibitor-1, employing a specific antibody produced by the DNA vaccine method.

    Science.gov (United States)

    Yamada, Takayuki; Takagi, Akira; Takeshita, Kyosuke; Yamamoto, Koji; Ito, Masafumi; Matsushita, Tadashi; Murate, Takashi; Saito, Hidehiko; Kojima, Tetsuhito

    2003-01-01

    We developed a sensitive immunoassay to determine the concentration of mouse plasminogen activator inhibitor-1. The assay was a non-competitive sandwich enzyme-linked immunosorbent assay (ELISA) based on the production of a specific polyclonal antibody against mouse plasminogen activator inhibitor type-1 (PAI-1) used both as a trapping and detecting antibody. This antibody was raised in a rabbit by direct introduction of the expression vector plasmid DNA encoding mouse PAI-1, instead of conventional immunization with the purified protein. The standard curve was constructed with a recombinant glutathione S-transferase (GST)-mouse PAI-1 fusion protein (GST-mPAI-1) and dose-response of the assay was linear for GST-mPAI-1 between 6.25 and 100 pM. In order to assess the consistency of the assay, we measured PAI-1 antigen in normal mouse pooled plasma several times. We found that the intra-assay and inter-assay coefficients of variation (CV) were 4.8% and 9.2%, respectively, indicating that the ELISA would be sufficiently repeatable and reproducible. In this assay, lipopolysaccharide (LPS)-injected mice showed substantially higher levels (22-fold) of plasma PAI-1 antigen than did control mice (12.5+/-2.4 vs. 0.58+/-0.16 nM), similar to results reported elsewhere. Taken together, the DNA vaccine method is extremely useful for preparing specific antibodies against mouse PAI-1, which can be utilized to establish the ELISA and analyze the profile of PAI-1 distributions in mice under various conditions. This approach might also be useful for immunological investigation of other coagulation factors and related proteins.

  9. 5-Bromo-2-aryl benzimidazole derivatives as non-cytotoxic potential dual inhibitors of α-glucosidase and urease enzymes.

    Science.gov (United States)

    Arshad, Tanzila; Khan, Khalid Mohammed; Rasool, Najma; Salar, Uzma; Hussain, Shafqat; Asghar, Humna; Ashraf, Mohammed; Wadood, Abdul; Riaz, Muhammad; Perveen, Shahnaz; Taha, Muhammad; Ismail, Nor Hadiani

    2017-06-01

    On the basis of previous report on promising α-glucosidase inhibitory activity of 5-bromo-2-aryl benzimidazole derivatives, these derivatives were further screened for urease inhibitory and cytotoxicity activity in order to get more potent and non-cytotoxic potential dual inhibitor for the patients suffering from diabetes as well as peptic ulcer. In this study, all compounds showed varying degree of potency in the range of (IC 50 =8.15±0.03-354.67±0.19μM) as compared to standard thiourea (IC 50 =21.25±0.15μM). It is worth mentioning that derivatives 7 (IC 50 =12.07±0.05μM), 8 (IC 50 =10.57±0.12μM), 11 (IC 50 =13.76±0.02μM), 14 (IC 50 =15.70±0.12μM) and 22 (IC 50 =8.15±0.03μM) were found to be more potent inhibitors than standard. All compounds were also evaluated for cytotoxicity towards 3T3 mouse fibroblast cell line and found to be completely non-toxic. Previously benzimidazole 1-25 were also showed α-glucosidase inhibitory potential. In silico studies were performed on the lead molecules i.e.2, 7, 8, 11, 14, and 22, in order to rationalize the binding interaction of compounds with the active site of urease enzyme. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

    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.

  11. Isozyme-specific enzyme inhibitors. 14. 5'(R)-C-[(L-homocystein-S-yl)methyl]adenosine 5'-(beta,gamma-imidotriphosphate), a potent inhibitor of rat methionine adenosyltransferases.

    Science.gov (United States)

    Kappler, F; Vrudhula, V M; Hampton, A

    1987-09-01

    The title compound is a covalent adduct of L-methionine (Met) and beta,gamma-imido-ATP. In its synthesis the N-Boc derivative of 5'(R)-C-(aminomethyl)-N6-benzoyl-5'-O-tosyl-2',3'-O- isopropylidenadenosine was converted by the successive actions of CF3CO2H and HNO2 into the corresponding 5'(R)-C-hydroxymethyl derivative. Treatment of this with disodium L-homocysteinate led to attack of sulfur at C6', apparently via a 5',6'-epoxide, and to total stereoselective inversion at C5' to furnish, after debenzoylation, 5'(R)-C-(L-homocystein-S-ylmethyl)-2',3'-O-isopropylidene ade nosine. The 5' configuration was established by conversion of this into the known 5'(S)-C-methyl-2',3'-O-isopropylidene adenosine with Raney nickel. The alpha-amino acid residue was protected as an N-Boc methyl ester, after which the 5'-hydroxyl was phosphorylated with benzyl phosphate and dicyclohexylcarbodiimide. The phosphoanhydride bond with inorganic imidodiphosphate was then created by established methods. Finally, blocking groups were removed under conditions that gave the desired adduct with no racemization of its L-methionine residue. It was a potent inhibitor [KM(ATP)/Ki = 1080; KM(Met)/Ki = 7.7] of the M-2 (normal tissue) form of rat methionine adenosyltransferase and of the M-T (hepatoma tissue) form [KM(ATP)/Ki = 670; KM(Met)/Ki = 22]. Inhibitions were competitive with respect to ATP or to L-methionine, indicating a dual substrate site mode of binding to the enzyme forms.

  12. Engineering N-terminal domain of tissue inhibitor of metalloproteinase (TIMP)-3 to be a better inhibitor against tumour necrosis factor-alpha-converting enzyme.

    Science.gov (United States)

    Lee, Meng-Huee; Verma, Vandana; Maskos, Klaus; Nath, Deepa; Knäuper, Vera; Dodds, Philippa; Amour, Augustin; Murphy, Gillian

    2002-01-01

    We previously reported that full-length tissue inhibitor of metalloproteinase-3 (TIMP-3) and its N-terminal domain form (N-TIMP-3) displayed equal binding affinity for tissue necrosis factor-alpha (TNF-alpha)-converting enzyme (TACE). Based on the computer graphic of TACE docked with a TIMP-3 model, we created a number of N-TIMP-3 mutants that showed significant improvement in TACE inhibition. Our strategy was to select those N-TIMP-3 residues that were believed to be in actual contact with the active-site pockets of TACE and mutate them to amino acids of a better-fitting nature. The activities of these mutants were examined by measuring their binding affinities (K(app)(i)) and association rates (k(on)) against TACE. Nearly all mutants at position Thr-2 exhibited slightly impaired affinity as well as association rate constants. On the other hand, some Ser-4 mutants displayed a remarkable increase in their binding tightness with TACE. In fact, the binding affinities of several mutants were less than 60 pM, beyond the sensitivity limits of fluorimetric assays. Further studies on cell-based processing of pro-TNF-alpha demonstrated that wild-type N-TIMP-3 and one of its tight-binding mutants, Ser-4Met, were capable of inhibiting the proteolytic shedding of TNF-alpha. Furthermore, the Ser-4Met mutant was also significantly more active (P<0.05) than the wild-type N-TIMP-3 in its cellular inhibition. Comparison of N-TIMP-3 and full-length TIMP-3 revealed that, despite their identical TACE-interaction kinetics, the latter was nearly 10 times more efficient in the inhibition of TNF-alpha shedding, with concomitant implications for the importance of the TIMP-3 C-terminal domain in vivo. PMID:11988096

  13. Identification of an inhibitor of the MurC enzyme, which catalyzes an essential step in the peptidoglycan precursor synthesis pathway.

    Science.gov (United States)

    Zawadzke, Laura E; Norcia, Michael; Desbonnet, Charlene R; Wang, Hong; Freeman-Cook, Kevin; Dougherty, Thomas J

    2008-02-01

    The pathway for synthesis of the peptidoglycan precursor UDP-N-acetylmuramyl pentapeptide is essential in Gram-positive and Gram-negative bacteria. This pathway has been exploited in the recent past to identify potential new antibiotics as inhibitors of one or more of the Mur enzymes. In the present study, a high-throughput screen was employed to identify potential inhibitors of the Escherichia coli MurC (UDP-N-acetylmuramic acid:L-alanine ligase), the first of four paralogous amino acid-adding enzymes. Inhibition of ATP consumed during the MurC reaction, using an adaptation of a kinase assay format, identified a number of potential inhibitory chemotypes. After nonspecific inhibition testing and chemical attractiveness were assessed, C-1 emerged as a compound for further characterization. The inhibition of MurC by this compound was confirmed in both a kinetic-coupled enzyme assay and a direct nuclear magnetic resonance product detection assay. C-1 was found to be a low micromolar inhibitor of the E. coli MurC reaction, with preferential inhibition by one of two enantiomeric forms. Experiments indicated that it was a competitive inhibitor of ATP binding to the MurC enzyme. Further work with MurC enzymes from several bacterial sources revealed that while the compound was equally effective at inhibiting MurC from genera (Proteus mirabilis and Klebsiella pneumoniae) closely related to E. coli, MurC enzymes from more distant Gram-negative species such as Haemophilus influenzae, Acinetobacter baylyi, and Pseudomonas aeruginosa were not inhibited.

  14. Successful switch from enzyme replacement therapy to miglustat in an adult patient with type 1 Gaucher disease: a case report.

    Science.gov (United States)

    Giuffrida, Gaetano; Lombardo, Rita; Di Francesco, Ernesto; Parrinello, Laura; Di Raimondo, Francesco; Fiumara, Agata

    2016-11-08

    Gaucher disease is one of the most common lipid-storage disorders, affecting approximately 1 in 75,000 births. Enzyme replacement therapy with recombinant glucocerebrosidase is currently considered the first-line treatment choice for patients with symptomatic Gaucher disease type 1. Oral substrate reduction therapy is generally considered a second-line treatment option for adult patients with mild to moderate Gaucher disease type 1 who are unable or unwilling to receive lifelong intravenous enzyme infusions. The efficacy and safety of the oral substrate reduction therapy miglustat (Zavesca®) in patients with Gaucher disease type 1 have been established in both short-term clinical trials and long-term, open-label extension studies. Published data indicate that miglustat can be used as maintenance therapy in patients with stable Gaucher disease type 1 switched from previous enzyme replacement therapy. We report a case of a 44-year-old Caucasian man with Gaucher disease type 1 who was initially treated with enzyme replacement therapy but, owing to repeated cutaneous allergic reactions, had to be switched to miglustat after several attempts with enzyme replacement therapy. Despite many attempts, desensitization treatment did not result in improved toleration of imiglucerase infusions, and the patient became unwilling to continue with any intravenous enzyme replacement therapy. He subsequently agreed to switch to oral substrate reduction therapy with miglustat 100 mg twice daily titrated up to 100 mg three times daily over a short period. Long-term miglustat treatment maintained both hemoglobin and platelet levels within acceptable ranges over 8 years. The patient's spleen volume decreased, his plasma chitotriosidase levels stayed at reduced levels, and his bone mineral density findings have remained stable throughout follow-up. The patient's quality of life has remained satisfactory. Miglustat showed good gastrointestinal tolerability in this patient, and no

  15. Potential efficacy of enzyme replacement and substrate reduction therapy in three siblings with Gaucher disease type III

    NARCIS (Netherlands)

    Cox-Brinkman, J.; van Breemen, M. J.; van Maldegem, B. T.; Bour, L.; Donker, W. E.; Hollak, C. E. M.; Wijburg, F. A.; Aerts, J. M. F. G.

    2008-01-01

    We report three siblings with Gaucher disease type III, born between 1992 and 2004. During this period, new developments resulted in different potential therapies, changing clinical practice. The two eldest siblings received enzyme replacement therapy (ERT) from the age of 24 and 5 months

  16. Pancreatic Enzyme Therapy and Coefficient of Fat Absorption in Children and AdolReplacement escents With Cystic Fibrosis

    NARCIS (Netherlands)

    Woestenenk, Janna W; van der Ent, Cornelis K.; Houwen, Roderick H J; van der Ent, CK

    Objectives: Pancreatic enzyme replacement therapy (PERT) is the proven therapy to substantially reduce fat malabsorption in patients with cystic fibrosis (CF). Few details of the daily practice regarding PERT and the resulting coefficient of fat absorption (CFA) are known. We therefore recorded the

  17. Cost-effectiveness of enzyme replacement therapy with alglucosidase alfa in classic-infantile patients with Pompe disease

    NARCIS (Netherlands)

    T.A. Kanters (Tim A.); I Hoogenboom-Plug (Iris); M.P.M.H. Rutten-van Mölken (Maureen); W.K. Redekop (Ken); A.T. van der Ploeg (Ans); L. van Hakkaart-van Roijen (Leona)

    2014-01-01

    textabstractBackground: Infantile Pompe disease is a rare metabolic disease. Patients generally do not survive the first year of life. Enzyme replacement therapy (ERT) has proven to have substantial effects on survival in infantile Pompe disease. However, the costs of therapy are very high. In this

  18. Immune checkpoint inhibitors and targeted therapies for metastatic melanoma: A network meta-analysis.

    Science.gov (United States)

    Pasquali, Sandro; Chiarion-Sileni, Vanna; Rossi, Carlo Riccardo; Mocellin, Simone

    2017-03-01

    Immune checkpoint inhibitors and targeted therapies, two new class of drugs for treatment of metastatic melanoma, have not been compared in randomized controlled trials (RCT). We quantitatively summarized the evidence and compared immune and targeted therapies in terms of both efficacy and toxicity. A comprehensive search for RCTs of immune checkpoint inhibitors and targeted therapies was conducted to August 2016. Using a network meta-analysis approach, treatments were compared with each other and ranked based on their effectiveness (as measured by the impact on progression-free survival [PFS]) and acceptability (the inverse of high grade toxicity). Twelve RCTs enrolling 6207 patients were included. Network meta-analysis generated 15 comparisons. Combined BRAF and MEK inhibitors were associated with longer PFS as compared to anti-CTLA4 (HR: 0.22; 95% confidence interval [CI]: 0.12-0.41) and anti-PD1 antibodies alone (HR: 0.38; CI: 0.20-0.72). However, anti-PD1 monoclonal antibodies were less toxic than anti-CTLA4 monoclonal antibodies (RR: 0.65; CI: 0.40-0.78) and their combination significantly increased toxicity compared to either single agent anti-CTLA4 (RR: 2.06; CI: 1.45-2.93) or anti-PD1 monoclonal antibodies (RR: 3.67; CI: 2.27-5.96). Consistently, ranking analysis suggested that the combination of targeted therapies is the most effective strategy, whereas single agent anti-PD1 antibodies have the best acceptability. The GRADE level of evidence quality for these findings was moderate to low. The simultaneous inhibition of BRAF and MEK appears the most effective treatment for melanomas harboring BRAF V600 mutation, although anti-PD1 antibodies appear to be less toxic. Further research is needed to increase the quality of evidence. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Proton pump inhibitors therapy vs H2 receptor antagonists therapy for upper gastrointestinal bleeding after endoscopy: A meta-analysis.

    Science.gov (United States)

    Zhang, Ying-Shi; Li, Qing; He, Bo-Sai; Liu, Ran; Li, Zuo-Jing

    2015-05-28

    To compare the therapeutic effects of proton pump inhibitors vs H₂ receptor antagonists for upper gastrointestinal bleeding in patients after successful endoscopy. We searched the Cochrane library, MEDLINE, EMBASE and PubMed for randomized controlled trials until July 2014 for this study. The risk of bias was evaluated by the Cochrane Collaboration's tool and all of the studies had acceptable quality. The main outcomes included mortality, re-bleeding, received surgery rate, blood transfusion units and hospital stay time. These outcomes were estimated using odds ratios (OR) and mean difference with 95% confidence interval (CI). RevMan 5.3.3 software and Stata 12.0 software were used for data analyses. Ten randomized controlled trials involving 1283 patients were included in this review; 678 subjects were in the proton pump inhibitors (PPI) group and the remaining 605 subjects were in the H₂ receptor antagonists (H₂RA) group. The meta-analysis results revealed that after successful endoscopic therapy, compared with H₂RA, PPI therapy had statistically significantly decreased the recurrent bleeding rate (OR = 0.36; 95%CI: 0.25-0.51) and receiving surgery rate (OR = 0.29; 95%CI: 0.09-0.96). There were no statistically significant differences in mortality (OR = 0.46; 95%CI: 0.17-1.23). However, significant heterogeneity was present in both the numbers of patients requiring blood transfusion after treatment [weighted mean difference (WMD), -0.70 unit; 95%CI: -1.64 - 0.25] and the time that patients remained hospitalized [WMD, -0.77 d; 95%CI: -1.87 - 0.34]. The Begg's test (P = 0.283) and Egger's test (P = 0.339) demonstrated that there was no publication bias in our meta-analysis. In patients with upper gastrointestinal bleeding after successful endoscopic therapy, compared with H₂RA, PPI may be a more effective therapy.

  20. Transdermal delivery of angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs) and others for management of hypertension.

    Science.gov (United States)

    Ahad, Abdul; Al-Mohizea, Abdullah Mohammed; Al-Jenoobi, Fahad Ibrahim; Aqil, Mohd

    2016-01-01

    Angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs) are some of the most commonly prescribed medications for hypertension. Most of all conventional dosage forms of ARBs and ACEIs undergo extensive first-pass metabolism, which significantly reduces bioavailability. Majority of ARBs and ACEIs are inherently short acting due to a rapid elimination half-life. In addition, oral dosage forms of ARBs and ACEIs have many high incidences of adverse effects due to variable absorption profiles, higher frequency of administration and poor patient compliance. Many attempts have been made globally at the laboratory level to investigate the skin permeation and to develop transdermal therapeutic systems of various ARBs, ACEIs and other anti-hypertensives, to circumvent the drawbacks associated with their conventional dosage form. This manuscript presents an outline of the transdermal research specifically in the area of ARBs, ACEIs and other anti-hypertensives reported in various pharmaceutical journals. The transdermal delivery has gained a significant importance for systemic treatment as it is able to avoid first-pass metabolism and major fluctuations of plasma levels typical of repeated oral administration. As we can experience from this review article that transdermal delivery of different ARBs and ACEIs improves bioavailability as well as patient compliance by many folds. In fact, the rationale development of some newer ARBs, ACEIs and other anti-hypertensives transdermal systems will provide new ways of treatment, circumventing current limitations for conventional dosage forms.

  1. Angiotensin-converting enzyme inhibitors of Bothrops jararaca snake venom affect the structure of mice seminiferous epithelium.

    Science.gov (United States)

    Alberto-Silva, Carlos; Gilio, Joyce M; Portaro, Fernanda C V; Querobino, Samyr M; Camargo, Antonio C M

    2015-01-01

    Considering the similarity between the testis-specific isoform of angiotensin-converting enzyme and the C-terminal catalytic domain of somatic ACE as well as the structural and functional variability of its natural inhibitors, known as bradykinin-potentiating peptides (BPPs), the effects of different synthetic peptides, BPP-10c (

  2. Effect of combined treatment of angiotensin converting enzyme inhibitors and diuretics on serum creatinine levels among elderly patients

    International Nuclear Information System (INIS)

    Sweileh, Waleed M.

    2006-01-01

    The adverse effects of angiotensin converting enzyme inhibitors (ACE-I) and diuretics when given together need extensive research and attention. We performed a cross-sectional study of patients admitted to the internal department of a general medical hospital to investigate the effect of drug combinations on serum creatinine level and creatinine clearance upon admission. Age, sex, disease, status and prior consumption of the target drugs: diuretics and ACE-I were correlated with creatnine and creatinine clearance on admission. The levels of serum creatinine for groups receiving the target combination in both sexes were significantly higher than groups who were not receiving the target combination. Computing an estimate of creatinine clearance based on Cockroft equation yields similar results to that for serum level creatinine. The levels of creatinine clearance in both sexes were significantly higher in the control group compared to those receiving the target combinations. Low dose aspirin seems to have a synergistic negative effect on renal function when given in combination with the target medications. Taking ACE-I/diuretic combination was associated with significant changes in creatinine levels and creatinine clearance. Attention should be made to balance positive effects of theses medications against their negative effect on renal function. (author)

  3. A comparative study of neuroprotective effect of angiotensin converting enzyme inhibitors against scopolamine-induced memory impairments in rats

    Directory of Open Access Journals (Sweden)

    Talha Jawaid

    2015-01-01

    Full Text Available The comparative study of neuroprotective effect of angiotensin converting enzyme inhibitors against scopolamine-induced neuroinflammation in albino Wistar rats was studied. Male albino rats were administered with scopolamine to induce memory impairment. The standard nootropic agent, piracetam (200 mg/kg b.w., [i.p.], perindopril (0.1 mg/kg b.w., [i.p.], enalapril (0.1 mg/kg b.w., [i.p.], and ramipril (0.1 mg/kg b.w., [i.p.] were administered in different group of animals for 5 days. On 5 th day, scopolamine (1 mg/kg b.w., i.p. was administered after 60 min of the last dose of test drug. Memory function was evaluated in Morris water maze (MWM test and pole climbing test (PCT. Biochemical estimations like glutathione (GSH, malondialdehyde (MDA, and acetylcholinesterase activity in the brain were estimated after completion of behavior study. All three test groups shows improvement in learning and memory in comparison to control group. Perindopril treated group showed a more effective significant decrease in escape latency time and transfer latency time compared to enalapril and ramipril treated group on day 4 in MWM test and PCT, respectively. Perindopril shows a significant reduction in MDA level and acetylcholinesterase activity and a significant rise in GSH level compared to enalapril and ramipril. The finding of this study indicates that Perindopril is more effective in memory retention compared to enalapril and ramipril.

  4. Benazepril, an angiotensin converting enzyme inhibitor: drug interaction with salbutamol and bronchial response to histamine in normal subjects

    Science.gov (United States)

    Bauer, K. G.; Brunel, P.; Nell, G.; Quinn, G.; Kaik, G. A.

    1997-01-01

    Aims To investigate the effect of the angiotensin converting enzyme inhibitor, benazepril, on pulmonary function. Methods We investigated the influence of benazepril, on lung function and the interaction with inhaled salbutamol (0.1 to 6.6 mg) and histamine (0.03 to 30.69 g l−1 ) in normal subjects. Benazepril 20 mg, salbutamol 8 mg, propranolol 160 mg, and placebo were given orally once daily over 10 days. Results On day 8, there was no difference in the area under the salbutamol dose-response curves between benazepril, placebo and oral salbutamol (P >0.05), propranolol shifted the curves to the right (Pbenazepril 1.04 (0.99–1.08), salbutamol 1.19 (1.13–1.25), propranolol 0.57 (0.50–0.65). Conclusions Benazepril had no influence on baseline lung function, caused no interaction with inhaled salbutamol and the bronchial response to histamine was similar to placebo. However, our findings in normal subjects cannot be extrapolated automatically to asthmatics. PMID:9431834

  5. A study of the prevalence of significant increases in serum creatinine following angiotension-converting enzyme inhibitor administration.

    Science.gov (United States)

    Thorp, M L; Ditmer, D G; Nash, M K; Wise, R; Jaderholm, P L; Smith, J D; Chan, W

    2005-05-01

    Angiontension-converting enzyme inhibitors (ACEIs) are beneficial in the treatment of diabetic and nondiabetic kidney disease, coronary artery disease and congestive heart failure. One adverse effect of ACEIs use is a rise in serum creatinine and potential renal failure. This paper attempts to quantify this risk and assess the need for pre- and post-ACEI serum creatinine measurements. A computerized search of Kaiser Permanente Northwest's electronic medical record was conducted to find patients over the age of 40 years taking lisinopril between July 1, 2000 and June 30, 2002. Patient demographic information and presence in diabetes and coronary artery disease registries was collected. A subsequent search for pre- and postlisinopril serum creatinine levels within 6 months of initial lisinopril prescription was conducted. Patients with prelisinopril creatinine 2.5 mg/dl underwent chart review to discern adverse events associated with the rise in serum creatinine. A total of 18,977 patients were prescribed lisinopril between July 1, 2000 and June 30, 2002. In all 13 166 patients had a pre- and postlisinopril creatinine checked. In all, 31 patients had a rise in creatinine from 2.5 mg/dl (0.2%). Possible contributors to rise in creatinine included congestive heart failure, dehydration and infection. No patients developed end-stage renal disease, although three died. In conclusion, end-stage renal disease is an unlikely outcome among patients prescribed lisinopril and is most likely associated with other events.

  6. The role of cyclooxygenase-2 in the malignant tissue and possible applicability of cyclooxygenase-2 inhibitors in the therapy of cancer

    International Nuclear Information System (INIS)

    Legan, M.

    2003-01-01

    Cyclooxygenase-2 (COX-2), an inducible prostaglandin (PG) synthase, is elevated in many types of malignant and pre-malignant tissues. This enzyme is localized in neoplastic (epithelial) cells, microvascular endothelial cells, and stromal fibroblasts. Through the released PG it enhances carcinogenesis with increasing angiogenesis, inhibiting apoptosis, activating matrix metalloproteinases, suppressing of cell mediated antitumor immune response and protection against damage by cytotoxic agents. Evidences from in vitro studies, studies on animal models as well as first clinical outcomes suggest that the inhibition of COX-2 may suppress carcinogenesis by affecting a number of pathways: inhibiting angiogenesis, invasiveness of tumors and promoting apoptosis. References forecast that COX-2 inhibitors, mostly COX-2 selective inhibitors, may get a role in the therapy of cancer as an adjuvant therapy or as an co-chemotherapeutic agent. The purpose of the present article is to summarize the most important facts about the role of COX-2 in the malignant tissue and discuss possible ways for potential therapeutic place of COX-2 inhibitors in clinical practice. (author)

  7. A simpler sampling interface of venturi easy ambient sonic-spray ionization mass spectrometry for high-throughput screening enzyme inhibitors.

    Science.gov (United States)

    Liu, Ning; Liu, Yang; Yang, YuHan; He, Lan; Ouyang, Jin

    2016-03-24

    High-throughput screening (HTS) is often required in enzyme inhibitor drugs screening. Mass spectrometry (MS) provides a powerful method for high-throughput screening enzyme inhibitors because its high speed, sensitivity and property of lable free. However, most of the MS methods need complicated sampling interface system. Overall throughput was limited by sample loading in these cases. In this study, we develop a simple interface which coupled droplet segmented system to a venturi easy ambient sonic-spray ionization mass spectrometer. It is fabricated by using a single capillary to act as both sampling probe and the emitter, which simplifies the construction, reduces the cost and shorten the sampling time. Samples sucked by venturi effect are segmented to nanoliter plugs by air, then the plugs can be detected by MS directly. This system eliminated the need for flow injection which was popular used in classic scheme. The new system is applied to screen angiotensin converting enzyme inhibitors. High-throughput was achieved in analyzing 96 samples at 1.6 s per sample. The plugs formation was at 0.5s per sample. Carry-over between samples was less than 5%, the peak height RSD was 2.92% (n = 15). Dose-response curves of 3 known inhibitors were also measured to validate its potential in drug discovery. The calculated IC50 agreed well with reported values. Copyright © 2016 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

    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

  9. Esophageal mucosal breaks in gastroesophageal reflux disease partially responsive to proton pump inhibitor therapy.

    Science.gov (United States)

    Shaheen, Nicholas J; Denison, Hans; Björck, Karin; Silberg, Debra G

    2013-04-01

    Approximately 20-30% of patients with gastroesophageal reflux disease (GERD) do not experience complete symptom resolution during proton pump inhibitor (PPI) therapy. The aim of this study was to determine the prevalence of esophageal mucosal breaks among patients who have a partial response to PPI therapy. This was an analysis of data from a phase 2b clinical trial carried out to assess the efficacy and safety of a reflux inhibitor, lesogaberan (AZD3355), as an add-on to PPI therapy in this patient population (clinicaltrials.gov reference: NCT01005251). A total of 661 patients with persistent GERD symptoms who had received a minimum of 4 weeks of PPI therapy were included in the study. The prevalence of esophageal mucosal breaks was assessed according to (i) the most recent endoscopy results from within the previous 24 months, if available ("historical" endoscopies), and (ii) the results of endoscopies performed at study baseline ("baseline" endoscopies). Baseline endoscopies were not carried out in patients who had a historical endoscopy showing an absence of esophageal mucosal breaks. Historical endoscopy results were available for 244 patients, of whom 48 (19.7%) had esophageal mucosal breaks. Baseline endoscopies were carried out in 465 patients, of whom 146 (31.4%) had esophageal mucosal breaks. Sensitivity analyses showed a prevalence of esophageal mucosal breaks of 20-30%. In both the historical and baseline endoscopies, most esophageal mucosal breaks were Los Angeles grades A or B. In patients with GERD symptoms partially responsive to PPI therapy, mild-to-moderate severity esophageal mucosal breaks are common (prevalence 20-30%), and may contribute to symptom etiology.

  10. Two-step polymer- and liposome-enzyme prodrug therapies for cancer: PDEPT and PELT concepts and future perspectives.

    Science.gov (United States)

    Scomparin, Anna; Florindo, Helena F; Tiram, Galia; Ferguson, Elaine L; Satchi-Fainaro, Ronit

    2017-09-01

    Polymer-directed enzyme prodrug therapy (PDEPT) and polymer enzyme liposome therapy (PELT) are two-step therapies developed to provide anticancer drugs site-selective intratumoral accumulation and release. Nanomedicines, such as polymer-drug conjugates and liposomal drugs, accumulate in the tumor site due to extravasation-dependent mechanism (enhanced permeability and retention - EPR - effect), and further need to cross the cellular membrane and release their payload in the intracellular compartment. The subsequent administration of a polymer-enzyme conjugate able to accumulate in the tumor tissue and to trigger the extracellular release of the active drug showed promising preclinical results. The development of polymer-enzyme, polymer-drug conjugates and liposomal drugs had undergone a vast advancement over the past decades. Several examples of enzyme mimics for in vivo therapy can be found in the literature. Moreover, polymer therapeutics often present an enzyme-sensitive mechanism of drug release. These nanomedicines can thus be optimal substrates for PDEPT and this review aims to provide new insights and stimuli toward the future perspectives of this promising combination. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Prolonged Treatment Duration is Required for Successful Helicobacter pylori Eradication with Proton Pump Inhibitor Triple Therapy in Canada

    Directory of Open Access Journals (Sweden)

    Carlo A Fallone

    2013-01-01

    Full Text Available BACKGROUND: Traditional seven-day proton pump inhibitor triple therapy for Helicobacter pylori eradication has recently shown disappointing results outside of Canada. Prolonging therapy may be associated with poorer compliance and, hence, may not have a better outcome in a real-world setting.

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

    DEFF Research Database (Denmark)

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

    2010-01-01

    An increasing number of patients in the community are being treated with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and beta-blockers for hypertension, coronary disease or diabetic renal and vascular complications. Some of these patients will develop heart...... failure despite such treatment. Based on data from hypertension trials it can be estimated that approximately 5% of treated patients will develop heart failure over 5 years. It is unclear whether patients developing heart failure on and off ACE-inhibitors or beta-blockers, respectively, at the time...

  13. Potent, selective, orally bioavailable inhibitors of tumor necrosis factor-alpha converting enzyme (TACE): discovery of indole, benzofuran, imidazopyridine and pyrazolopyridine P1' substituents.

    Science.gov (United States)

    Lu, Zhonghui; Ott, Gregory R; Anand, Rajan; Liu, Rui-Qin; Covington, Maryanne B; Vaddi, Krishna; Qian, Mingxin; Newton, Robert C; Christ, David D; Trzaskos, James; Duan, James J-W

    2008-03-15

    Potent and selective inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) were discovered with several new heterocyclic P1' groups in conjunction with cyclic beta-amino hydroxamic acid scaffolds. Among them, the pyrazolopyridine provided the best overall profile when combined with tetrahydropyran beta-amino hydroxamic acid scaffold. Specifically, inhibitor 49 showed IC(50) value of 1 nM against porcine TACE and 170 nM in the suppression of LPS-induced TNF-alpha of human whole blood. Compound 49 also displayed excellent selectivity over a wide panel of MMPs as well as excellent oral bioavailability (F%>90%) in rat n-in-1 PK studies.

  14. Gene Directed Enzyme Prodrug Therapy Using Rabbit Cytochrome P450 4B1 in Murine Colon Adenocarcinoma

    International Nuclear Information System (INIS)

    Kim, Sung Joo; Kang, Joo Hyun; Lee, Tae Sup; Kim, Kyeong Min; Woo, Kwang Sun; Chung, Wee Sup; Cheon, Gi Jeong; Choi, Chang Woon; Lim, Sang Moo

    2007-01-01

    The conventional cancer therapy is chemotherapy, surgical resection and/or radiotherapy. Chemotherapy using cytotoxic drug has some problems with lack of tumor selectivity resulting in toxicity to normal tissues. To enhance the tumor selectivity of cytotoxic drug, the application of suicidal gene therapy technology was designed. Suicidal gene therapy is based on the expression in tumor cells of a gene encoding an enzyme that converts a non-toxic prodrug into a cytotoxic product. Representative suicidal genes are Herpes simplex virus type 1 thymidine kinase (HSV1- tk) and cytosine deaminase (cd). Recently, a new prodrug-converting enzyme based on rabbit cytochrome P450 4B1 gene (cyp4B1) has been reported for therapy of experimental brain tumor. This enzyme activates the prodrugs such as 4-ipomeanol (4-IM) and 2- aminoanthracene (2-AA) to highly reactive furane epoxide and unsaturated dialdehyde intermediate, respectively. DNA alkylation seems to be the main mechanism of cytotoxicity of these activated drugs. In this study, we isolated cyp4B1 cDNA from rabbit lung, transduced cyp4B1 expression vector into murine colon cancer cell, and then analyzed the cytotoxic properties of cyp4b1-activated 2-AA in cyp4B1 transduced cells to verify the cyp4B1 enzyme system for gene directed enzyme prodrug therapy

  15. Gene Directed Enzyme Prodrug Therapy Using Rabbit Cytochrome P450 4B1 in Murine Colon Adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sung Joo; Kang, Joo Hyun; Lee, Tae Sup; Kim, Kyeong Min; Woo, Kwang Sun; Chung, Wee Sup; Cheon, Gi Jeong; Choi, Chang Woon; Lim, Sang Moo [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2007-07-01

    The conventional cancer therapy is chemotherapy, surgical resection and/or radiotherapy. Chemotherapy using cytotoxic drug has some problems with lack of tumor selectivity resulting in toxicity to normal tissues. To enhance the tumor selectivity of cytotoxic drug, the application of suicidal gene therapy technology was designed. Suicidal gene therapy is based on the expression in tumor cells of a gene encoding an enzyme that converts a non-toxic prodrug into a cytotoxic product. Representative suicidal genes are Herpes simplex virus type 1 thymidine kinase (HSV1- tk) and cytosine deaminase (cd). Recently, a new prodrug-converting enzyme based on rabbit cytochrome P450 4B1 gene (cyp4B1) has been reported for therapy of experimental brain tumor. This enzyme activates the prodrugs such as 4-ipomeanol (4-IM) and 2- aminoanthracene (2-AA) to highly reactive furane epoxide and unsaturated dialdehyde intermediate, respectively. DNA alkylation seems to be the main mechanism of cytotoxicity of these activated drugs. In this study, we isolated cyp4B1 cDNA from rabbit lung, transduced cyp4B1 expression vector into murine colon cancer cell, and then analyzed the cytotoxic properties of cyp4b1-activated 2-AA in cyp4B1 transduced cells to verify the cyp4B1 enzyme system for gene directed enzyme prodrug therapy.

  16. The angiotensin converting enzyme (ACE) inhibitor, captopril disrupts the motility activation of sperm from the silkworm, Bombyx mori.

    Science.gov (United States)

    Nagaoka, Sumiharu; Kawasaki, Saori; Kawasaki, Hideki; Kamei, Kaeko

    2017-11-01

    Angiotensin I-converting enzyme (also known as peptidyl dicarboxypeptidase A, ACE, and EC 3.4.15.1), which is found in a wide range of organisms, cleaves C-terminal dipeptides from relatively short oligopeptides. Mammalian ACE plays an important role in the regulation of blood pressure. However, the precise physiological functions of insect ACE homologs have not been understood. As part of our effort to elucidate new physiological roles of insect ACE, we herein report a soluble ACE protein in male reproductive secretions from the silkmoth, Bombyx mori. Seminal vesicle sperm are quiescent in vitro, but vigorous motility is activated by treatment with either a glandula (g.) prostatica homogenate or trypsin in vitro. When seminal vesicle sperm were pre-incubated with captopril, a strong and specific inhibitor of mammalian ACE, and then stimulated to initiate motility by the addition of the g. prostatica homogenate or trypsin, the overall level of acquired motility was reduced in an inhibitor-concentration-dependent manner. In the course of this project, we detected ACE-related carboxypeptidase activity that was inhibited by captopril in both the vesicular (v.) seminalis of the noncopulative male reproductive tract and in the spermatophore that forms in the female bursa copulatrix at the time of mating, just as in an earlier report on the tomato moth, Lacanobia oleracea, which belongs to a different lepidopteran species (Ekbote et al., 2003a). Two distinct genes encoding ACE-like proteins were identified by analysis of B. mori cDNA, and were named BmAcer and BmAcer2, respectively [the former was previously reported by Quan et al. (2001) and the latter was first isolated in this paper]. RT-qPCR and Western blot analyses indicated that the BmAcer2 was predominantly produced in v. seminalis and transferred to the spermatophore during copulation, while the BmAcer was not detected in the adult male reproductive organs. A recombinant protein of BmAcer2 (devoid of a signal

  17. Gene therapy/bone marrow transplantation in ADA-deficient mice: roles of enzyme-replacement therapy and cytoreduction

    Science.gov (United States)

    Jin, Xiangyang; Wang, Xingchao; Yu, Xiao-Jin; Rozengurt, Nora; Kaufman, Michael L.; Wang, Xiaoyan; Gjertson, David; Zhou, Yang; Blackburn, Michael R.; Kohn, Donald B.

    2012-01-01

    Gene therapy (GT) for adenosine deaminase–deficient severe combined immune deficiency (ADA-SCID) can provide significant long-term benefit when patients are given nonmyeloablative conditioning and ADA enzyme-replacement therapy (ERT) is withheld before autologous transplantation of γ-retroviral vector-transduced BM CD34+ cells. To determine the contributions of conditioning and discontinuation of ERT to the therapeutic effects, we analyzed these factors in Ada gene knockout mice (Ada−/−). Mice were transplanted with ADA-deficient marrow transduced with an ADA-expressing γ-retroviral vector without preconditioning or after 200 cGy or 900 cGy total-body irradiation and evaluated after 4 months. In all tissues analyzed, vector copy numbers (VCNs) were 100- to 1000-fold greater in mice receiving 900 cGy compared with 200 cGy (P < .05). In mice receiving 200 cGy, VCN was similar whether ERT was stopped or given for 1 or 4 months after GT. In unconditioned mice, there was decreased survival with and without ERT, and VCN was very low to undetectable. When recipients were conditioned with 200 cGy and received transduced lineage-depleted marrow, only recipients receiving ERT (1 or 4 months) had detectable vector sequences in thymocytes. In conclusion, cytoreduction is important for the engraftment of gene-transduced HSC, and short-term ERT after GT did not diminish the capacity of gene-corrected cells to engraft and persist. PMID:22833548

  18. Gene therapy/bone marrow transplantation in ADA-deficient mice: roles of enzyme-replacement therapy and cytoreduction.

    Science.gov (United States)

    Carbonaro, Denise A; Jin, Xiangyang; Wang, Xingchao; Yu, Xiao-Jin; Rozengurt, Nora; Kaufman, Michael L; Wang, Xiaoyan; Gjertson, David; Zhou, Yang; Blackburn, Michael R; Kohn, Donald B

    2012-11-01

    Gene therapy (GT) for adenosine deaminase-deficient severe combined immune deficiency (ADA-SCID) can provide significant long-term benefit when patients are given nonmyeloablative conditioning and ADA enzyme-replacement therapy (ERT) is withheld before autologous transplantation of γ-retroviral vector-transduced BM CD34+ cells. To determine the contributions of conditioning and discontinuation of ERT to the therapeutic effects, we analyzed these factors in Ada gene knockout mice (Ada(-/-)). Mice were transplanted with ADA-deficient marrow transduced with an ADA-expressing γ-retroviral vector without preconditioning or after 200 cGy or 900 cGy total-body irradiation and evaluated after 4 months. In all tissues analyzed, vector copy numbers (VCNs) were 100- to 1000-fold greater in mice receiving 900 cGy compared with 200 cGy (P < .05). In mice receiving 200 cGy, VCN was similar whether ERT was stopped or given for 1 or 4 months after GT. In unconditioned mice, there was decreased survival with and without ERT, and VCN was very low to undetectable. When recipients were conditioned with 200 cGy and received transduced lineage-depleted marrow, only recipients receiving ERT (1 or 4 months) had detectable vector sequences in thymocytes. In conclusion, cytoreduction is important for the engraftment of gene-transduced HSC, and short-term ERT after GT did not diminish the capacity of gene-corrected cells to engraft and persist.

  19. Real life Dosages and Costs of TNFα inhibitor therapy for RA patients in Denmark

    DEFF Research Database (Denmark)

    Hostenkamp, Gisela; Sørensen, Jan; Hetland, Merete Lund

    2009-01-01

    Background: When estimating the cost of biological treatment many analyses rely on cross sectional data or standard consumption patterns indicated in the manufacturers' instruction leaflet. Unless such consumption patterns truly reflect routine clinical practice they may result in wrong assumptions...... ordinary least square (OLS) or Cox regression analysis with the type of biological drug, age, gender, disease duration, functional status and disease activity at treatment start as independent variables. Comparisons between TNF-inhibitor therapies were analysed using t-tests. Results: During the first year...... of treatment. Cost estimates based on short term observational data or on instruction leaflets from manufacturers may provide wrong cost assessments of TNF-alpha therapy. It is important to take the long term cost structure into account to arrive at unbiased treatment cost estimates....

  20. Pharmacogenetic effects of angiotensin-converting enzyme inhibitors over age-related urea and creatinine variations in patients with dementia due to Alzheimer disease.

    Science.gov (United States)

    Ferreira de Oliveira, Fabricio; Berretta, Juliana Marília; Suchi Chen, Elizabeth; Cardoso Smith, Marilia; Ferreira Bertolucci, Paulo Henrique

    2016-06-30

    Renal function declines according to age and vascular risk factors, whereas few data are available regarding genetically-mediated effects of anti-hypertensives over renal function. To estimate urea and creatinine variations in dementia due to Alzheimer disease (AD) by way of a pharmacogenetic analysis of the anti-hypertensive effects of angiotensin-converting enzyme inhibitors (ACEis). Consecutive outpatients older than 60 years-old with AD and no history of kidney transplant or dialytic therapy were recruited for prospective correlations regarding variations in fasting blood levels of urea and creatinine in one year, considering ACE genotypes of rs1800764 and rs4291 and their respective haplotypes, and treatment with ACEis along with blood pressure variations. For 190 patients, 152 had arterial hypertension, and 122 used ACEis. Minor allele frequencies were 0.492 for rs1800764-C and 0.337 for rs4291-T, both in Hardy-Weinberg equilibrium. There were no overall significant yearly variations in levels of urea and creatinine, but their concurrent variations were positively correlated (ρ <0.0001). Each A allele of rs4291 led to an yearly urea increase of 3,074 mg/dL, and an yearly creatinine increase of 0.044 mg/dL, while the use of ACEis was protective regarding creatinine variations. The use of ACEis was also protective for carriers of rs1800764-CT/rs4291-AA, while carriers of rs1800764-CT/rs4291-AT had steeper reductions in creatinine levels, particularly when they were treated with ACEis. Effects of ACEis over creatinine variations are genetically mediated and independent of blood pressure variations in older people with AD.

  1. Murine Efficacy and Pharmacokinetic Evaluation of the Flaviviral NS5 Capping Enzyme 2-Thioxothiazolidin-4-One Inhibitor BG-323.

    Science.gov (United States)

    Bullard, Kristen M; Gullberg, Rebekah C; Soltani, Elnaz; Steel, J Jordan; Geiss, Brian J; Keenan, Susan M

    2015-01-01

    Arthropod-borne flavivirus infection continues to cause significant morbidity and mortality worldwide. Identification of drug targets and novel antiflaviviral compounds to treat these diseases has become a global health imperative. A previous screen of 235,456 commercially available small molecules identified the 2-thioxothiazolidin-4-one family of compounds as inhibitors of the flaviviral NS5 capping enzyme, a promising target for antiviral drug development. Rational drug design methodologies enabled identification of lead compound BG-323 from this series. We have shown previously that BG-323 potently inhibits NS5 capping enzyme activity, displays antiviral effects in dengue virus replicon assays and inhibits growth of West Nile and yellow fever viruses with low cytotoxicity in vitro. In this study we further characterized BG-323's antiviral activity in vitro and in vivo. We found that BG-323 was able to reduce replication of WNV (NY99) and Powassan viruses in culture, and we were unable to force resistance into WNV (Kunjin) in long-term culture experiments. We then evaluated the antiviral activity of BG-323 in a murine model. Mice were challenged with WNV NY99 and administered BG-323 or mock by IP inoculation immediately post challenge and twice daily thereafter. Mice were bled and viremia was quantified on day three. No significant differences in viremia were observed between BG-323-treated and control groups and clinical scores indicated both BG-323-treated and control mice developed signs of illness on approximately the same day post challenge. To determine whether differences in in vitro and in vivo efficacy were due to unfavorable pharmacokinetic properties of BG-323, we conducted a pharmacokinetic evaluation of this small molecule. Insights from pharmacokinetic studies indicate that BG-323 is cell permeable, has a low efflux ratio and does not significantly inhibit two common cytochrome P450 (CYP P450) isoforms thus suggesting this molecule may be less

  2. Murine Efficacy and Pharmacokinetic Evaluation of the Flaviviral NS5 Capping Enzyme 2-Thioxothiazolidin-4-One Inhibitor BG-323.

    Directory of Open Access Journals (Sweden)

    Kristen M Bullard

    Full Text Available Arthropod-borne flavivirus infection continues to cause significant morbidity and mortality worldwide. Identification of drug targets and novel antiflaviviral compounds to treat these diseases has become a global health imperative. A previous screen of 235,456 commercially available small molecules identified the 2-thioxothiazolidin-4-one family of compounds as inhibitors of the flaviviral NS5 capping enzyme, a promising target for antiviral drug development. Rational drug design methodologies enabled identification of lead compound BG-323 from this series. We have shown previously that BG-323 potently inhibits NS5 capping enzyme activity, displays antiviral effects in dengue virus replicon assays and inhibits growth of West Nile and yellow fever viruses with low cytotoxicity in vitro. In this study we further characterized BG-323's antiviral activity in vitro and in vivo. We found that BG-323 was able to reduce replication of WNV (NY99 and Powassan viruses in culture, and we were unable to force resistance into WNV (Kunjin in long-term culture experiments. We then evaluated the antiviral activity of BG-323 in a murine model. Mice were challenged with WNV NY99 and administered BG-323 or mock by IP inoculation immediately post challenge and twice daily thereafter. Mice were bled and viremia was quantified on day three. No significant differences in viremia were observed between BG-323-treated and control groups and clinical scores indicated both BG-323-treated and control mice developed signs of illness on approximately the same day post challenge. To determine whether differences in in vitro and in vivo efficacy were due to unfavorable pharmacokinetic properties of BG-323, we conducted a pharmacokinetic evaluation of this small molecule. Insights from pharmacokinetic studies indicate that BG-323 is cell permeable, has a low efflux ratio and does not significantly inhibit two common cytochrome P450 (CYP P450 isoforms thus suggesting this molecule

  3. Preclinical rationale for PI3K/Akt/mTOR pathway inhibitors as therapy for epidermal growth factor receptor inhibitor-resistant non-small-cell lung cancer.

    Science.gov (United States)

    Gadgeel, Shirish M; Wozniak, Antoinette

    2013-07-01

    Mutations in the epidermal growth factor receptor gene (EGFR) are frequently observed in non-small-cell lung cancer (NSCLC), occurring in about 40% to 60% of never-smokers and in about 17% of patients with adenocarcinomas. EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have transformed therapy for patients with EGFR-mutant NSCLC and have proved superior to chemotherapy as first-line treatment for this patient group. Despite these benefits, there are currently 2 key challenges associated with EGFR inhibitor therapy for patients with NSCLC. First, only 85% to 90% of patients with the EGFR mutation derive clinical benefit from EGFR TKIs, with the remainder demonstrating innate resistance to therapy. Second, acquired resistance to EGFR TKIs inevitably occurs in patients who initially respond to therapy, with a median duration of response of about 10 months. Mutant EGFR activates various subcellular signaling cascades, including the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, which demonstrates maintained activity in a variety of TKI-resistant cancers. Given the fundamental role of the PI3K/Akt/mTOR pathway in tumor oncogenesis, proliferation, and survival, PI3K pathway inhibitors have emerged as a possible solution to the problem of EGFR TKI resistance. However resistance to EGFR TKIs is associated with considerable heterogeneity and complexity. Preclinical experiments investigating these phenomena suggest that in some patients, PI3K inhibitors will have to be paired with other targeted agents if they are to be effective. This review discusses the preclinical data supporting PI3K/Akt/mTOR pathway inhibitor combinations in EGFR TKI-resistant NSCLC from the perspective of the various agents currently being investigated in clinical trials. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase.

    Science.gov (United States)

    Zhang, Jie; Liu, Hongchuan; Zhu, Kongkai; Gong, Shouzhe; Dramsi, Shaynoor; Wang, Ya-Ting; Li, Jiafei; Chen, Feifei; Zhang, Ruihan; Zhou, Lu; Lan, Lefu; Jiang, Hualiang; Schneewind, Olaf; Luo, Cheng; Yang, Cai-Guang

    2014-09-16

    Methicillin-resistant Staphylococcus aureus (MRSA) is the most frequent cause of hospital-acquired infection, which manifests as surgical site infections, bacteremia, and sepsis. Due to drug-resistance, prophylaxis of MRSA infection with antibiotics frequently fails or incites nosocomial diseases such as Clostridium difficile infection. Sortase A is a transpeptidase that anchors surface proteins in the envelope of S. aureus, and sortase mutants are unable to cause bacteremia or sepsis in mice. Here we used virtual screening and optimization of inhibitor structure to identify 3-(4-pyridinyl)-6-(2-sodiumsulfonatephenyl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole and related compounds, which block sortase activity in vitro and in vivo. Sortase inhibitors do not affect in vitro staphylococcal growth yet protect mice against lethal S. aureus bacteremia. Thus, sortase inhibitors may be useful as antiinfective therapy to prevent hospital-acquired S. aureus infection in high-risk patients without the side effects of antibiotics.

  5. JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials.

    Science.gov (United States)

    Pardanani, A

    2008-01-01

    The recent identification of somatic mutations such as JAK2V617F that deregulate Janus kinase (JAK)-signal transducer and activator of transcription signaling has spurred development of orally bioavailable small-molecule inhibitors that selectively target JAK2 kinase as an approach to pathogenesis-directed therapy of myeloproliferative disorders (MPD). In pre-clinical studies, these compounds inhibit JAK2V617F-mediated cell growth at nanomolar concentrations, and in vivo therapeutic efficacy has been demonstrated in mouse models of JAK2V617F-induced disease. In addition, ex vivo growth of progenitor cells from MPD patients harboring JAK2V617F or MPLW515L/K mutations is also potently inhibited. JAK2 inhibitors currently in clinical trials can be grouped into those designed to primarily target JAK2 kinase (JAK2-selective) and those originally developed for non-MPD indications, but that nevertheless have significant JAK2-inhibitory activity (non-JAK2 selective). This article discusses the rationale for using JAK2 inhibitors for the treatment of MPD, as well as relevant aspects of clinical trial development for these patients. For instance, which group of MPD patients is appropriate for initial Phase I studies? Should JAK2V617F-negative MPD patients be included in the initial studies? What are the likely consequences of 'off-target' JAK3 and wild-type JAK2 inhibition? How should treatment responses be monitored?

  6. Association of plasminogen activator inhibitor-1 and angiotensin converting enzyme polymorphisms with recurrent pregnancy loss in Iranian women

    Directory of Open Access Journals (Sweden)

    Fatemeh Shakarami

    2015-10-01

    Full Text Available Background: Recurrent pregnancy loss (RPL defined by two or more failed pregnancies before 20 weeks of gestation. Several factors play a role in RPL including thrombophilic conditions which can be influenced by gene polymorphisms. Plasminogen activator inhibitor-1 (PAI-1 and angiotensin converting enzyme (ACE genes are closely related to fibrinolytic process, embryonic development and pregnancy success. Objective: The aim of this study was to investigate the relationship between RPL and common polymorphisms in ACE and PAI-1 genes. Materials and Methods: In this case control study, 100 women with recurrent abortions (at least two were selected as cases and 100 healthy women with two or more normal term deliveries without a history of abortion as controls. Total genomic DNA was isolated from blood leukocytes. The status of the PAI-1 4G/5G and ACE (D/I polymorphism was determined by PCR-RFLP. Results: Homozygosity for PAI-1 4G polymorphism was seen in 17 cases (17%, and 5 controls (5% (p=0.006 so patients with homozygote 4G mutation were significantly more prone to RPL in contrast to control group (OR: 4.63, % 95 CI: 1.55-13.84. In addition, 7 patients (7 %, and no one from the control group, were homozygote (I/I for ACE polymorphism (p=0.034, suggesting no significant associations between ACE D allele or DD genotype and RPL. Conclusion: Considering these results, because 4G/4G polymorphism for PAI-1 gene could be a thrombophilic variant leading to abortion, analysis of this mutation and other susceptibility factors are recommended in patients with RPL.

  7. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers reduced dementia risk in patients with diabetes mellitus and hypertension.

    Science.gov (United States)

    Kuan, Yi-Chun; Huang, Kuang-Wei; Yen, Der-Jen; Hu, Chaur-Jong; Lin, Cheng-Li; Kao, Chia-Hung

    2016-10-01

    The effects of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) on dementia risk in patients with type 2 diabetes mellitus (DM) and hypertension remain unknown. We investigated the effects of ACEIs and ARBs on dementia risk in patients with type 2 DM and hypertension. We conducted a cohort study by using the Taiwan National Health Insurance Research Database. We included 2377 patients receiving ACEIs and 1780 patients receiving ARBs in the ACEI and ARB cohorts, respectively. We included a comparable number of patients not receiving ACEIs and ARBs as controls in the non-ACEI and non-ARB cohorts through propensity score matching. The effect of ACEIs and ARBs on dementia risk was estimated through multivariate Cox proportional hazard regression after adjustment for several confounding factors. During the 12-year follow-up period, compared with the non-ACEI cohort, all-cause dementia risk decreased by 26% in the ACEI cohort [hazard ratio (HR)=0.74, 95% confidence interval (CI)=0.56-0.96]. The all-cause dementia risk was nearly 40% lower in the ARB cohort than in the non-ARB cohort (HR=0.60, 95% CI=0.37-0.97). These drugs prevented the occurrence of vascular dementia (VD), however, this effect was nonsignificant for Alzheimer's dementia (AD). Treatment duration- and dosage-related protection effects on dementia occurrence were observed. ACEIs and ARBs may effectively prevent all-cause dementia, particularly VD, in patients with type 2 DM and hypertension. Moreover, compared with ACEIs, ARBs appear to be more advantageous in dementia prevention. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  8. Multi-scaled explorations of binding-induced folding of intrinsically disordered protein inhibitor IA3 to its target enzyme.

    Directory of Open Access Journals (Sweden)

    Jin Wang

    2011-04-01

    Full Text Available Biomolecular function is realized by recognition, and increasing evidence shows that recognition is determined not only by structure but also by flexibility and dynamics. We explored a biomolecular recognition process that involves a major conformational change - protein folding. In particular, we explore the binding-induced folding of IA3, an intrinsically disordered protein that blocks the active site cleft of the yeast aspartic proteinase saccharopepsin (YPrA by folding its own N-terminal residues into an amphipathic alpha helix. We developed a multi-scaled approach that explores the underlying mechanism by combining structure-based molecular dynamics simulations at the residue level with a stochastic path method at the atomic level. Both the free energy profile and the associated kinetic paths reveal a common scheme whereby IA3 binds to its target enzyme prior to folding itself into a helix. This theoretical result is consistent with recent time-resolved experiments. Furthermore, exploration of the detailed trajectories reveals the important roles of non-native interactions in the initial binding that occurs prior to IA3 folding. In contrast to the common view that non-native interactions contribute only to the roughness of landscapes and impede binding, the non-native interactions here facilitate binding by reducing significantly the entropic search space in the landscape. The information gained from multi-scaled simulations of the folding of this intrinsically disordered protein in the presence of its binding target may prove useful in the design of novel inhibitors of aspartic proteinases.

  9. A Rhodium(III) Complex as an Inhibitor of Neural Precursor Cell Expressed, Developmentally Down-Regulated 8-Activating Enzyme with in Vivo Activity against Inflammatory Bowel Disease.

    Science.gov (United States)

    Zhong, Hai-Jing; Wang, Wanhe; Kang, Tian-Shu; Yan, Hui; Yang, Yali; Xu, Lipeng; Wang, Yuqiang; Ma, Dik-Lung; Leung, Chung-Hang

    2017-01-12

    We report herein the identification of the rhodium(III) complex [Rh(phq) 2 (MOPIP)] + (1) as a potent and selective ATP-competitive neural precursor cell expressed, developmentally down-regulated 8 (NEDD8)-activating enzyme (NAE) inhibitor. Structure-activity relationship analysis indicated that the overall organometallic design of complex 1 was important for anti-inflammatory activity. Complex 1 showed promising anti-inflammatory activity in vivo for the potential treatment of inflammatory bowel disease.

  10. Pharmacogenetic effects of angiotensin-converting enzyme inhibitors over age-related urea andcreatinine variations in patients with dementia due to Alzheimer disease

    OpenAIRE

    Ferreira de Oliveira, Fabricio; Berretta, Juliana Marília; Suchi Chen, Elizabeth; Cardoso Smith, Marilia; Ferreira Bertolucci, Paulo Henrique

    2016-01-01

    Background: Renal function declines according to age and vascular risk factors, whereas few data are available regarding geneticallymediated effects of anti-hypertensives over renal function. Objective: To estimate urea and creatinine variations in dementia due to Alzheimer disease (AD) by way of a pharmacogenetic analysis of the anti-hypertensive effects of angiotensin-converting enzyme inhibitors (ACEis). Methods: Consecutive outpatients older than 60 years-old with AD and no history of kid...

  11. Predictors of hepatitis B cure using gene therapy to deliver DNA cleavage enzymes: a mathematical modeling approach.

    Directory of Open Access Journals (Sweden)

    Joshua T Schiffer

    Full Text Available Most chronic viral infections are managed with small molecule therapies that inhibit replication but are not curative because non-replicating viral forms can persist despite decades of suppressive treatment. There are therefore numerous strategies in development to eradicate all non-replicating viruses from the body. We are currently engineering DNA cleavage enzymes that specifically target hepatitis B virus covalently closed circular DNA (HBV cccDNA, the episomal form of the virus that persists despite potent antiviral therapies. DNA cleavage enzymes, including homing endonucleases or meganucleases, zinc-finger nucleases (ZFNs, TAL effector nucleases (TALENs, and CRISPR-associated system 9 (Cas9 proteins, can disrupt specific regions of viral DNA. Because DNA repair is error prone, the virus can be neutralized after repeated cleavage events when a target sequence becomes mutated. DNA cleavage enzymes will be delivered as genes within viral vectors that enter hepatocytes. Here we develop mathematical models that describe the delivery and intracellular activity of DNA cleavage enzymes. Model simulations predict that high vector to target cell ratio, limited removal of delivery vectors by humoral immunity, and avid binding between enzyme and its DNA target will promote the highest level of cccDNA disruption. Development of de novo resistance to cleavage enzymes may occur if DNA cleavage and error prone repair does not render the viral episome replication incompetent: our model predicts that concurrent delivery of multiple enzymes which target different vital cccDNA regions, or sequential delivery of different enzymes, are both potentially useful strategies for avoiding multi-enzyme resistance. The underlying dynamics of cccDNA persistence are unlikely to impact the probability of cure provided that antiviral therapy is given concurrently during eradication trials. We conclude by describing experiments that can be used to validate the model, which

  12. Potential role for epidermal growth factor receptor inhibitors in combined-modality therapy for non-small-cell lung cancer

    International Nuclear Information System (INIS)

    Kim, Dong Wook; Choy, Hak

    2004-01-01

    There has been a surge of interest in the translation of discoveries in molecular biology into clinically relevant therapies in the field of hematology/oncology. The epidermal growth factor receptor (EGFR) has been a molecular target of significant interest and investigation, and preclinical and clinical studies support a role for targeted therapy in a variety of cancers, including non-small-cell lung cancer (NSCLC) via compounds that specifically inhibit EGFR. ZD1839, IMC-C225, and OSI-774 are the most clinically developed of these compounds. Interestingly, preclinical studies have demonstrated that EGFR inhibitors may have radiation-sensitizing properties, as well as increased cytotoxic activity in combination with chemotherapeutic agents, suggesting a potential role for EGFR inhibitors as an adjunct to the current combined-modality approach for therapy of Stage III NSCLC. Therefore, clinical trials have been proposed and initiated to address the issue of determining the impact of the addition of EGFR inhibitors to the standard combined-modality regimen (chemotherapy/radiation therapy ± surgery) for Stage III NSCLC. This article reviews preclinical and clinical data supporting the role for EGFR inhibitors alone or in combination with chemotherapy/radiation therapy for locally advanced NSCLC. Also, it will provide an overview of ongoing and proposed clinical studies investigating the potential role for EGFR inhibitors in Stage III NSCLC

  13. Hepatic Enzyme Alterations in HIV Patients on Antiretroviral Therapy: A Case-Control Study in a Hospital Setting in Ghana.

    Science.gov (United States)

    Osakunor, Derick Nii Mensah; Obirikorang, Christian; Fianu, Vincent; Asare, Isaac; Dakorah, Mavis

    2015-01-01

    Diagnosing hepatic injury in HIV infection can be a herculean task for clinicians as several factors may be involved. In this study, we sought to determine the effects of antiretroviral therapy (ART) and disease progression on hepatic enzymes in HIV patients. A case-control study conducted from January to May 2014 at the Akwatia Government Hospital, Eastern region, Ghana, The study included 209 HIV patients on ART (designated HIV-ART) and 132 ART-naive HIV patients (designated HIV-Controls). Data gathered included demography, clinical history and results of blood tests for hepatic enzymes. We employed the Fisher's, Chi-square, unpaired t-test and Pearson's correlation in analysis, using GraphPad Prism and SPSS. A P value 0.05). There was a significant positive correlation between hepatic enzymes (ALP, ALT, AST and GGT) for both groups (p enzymes for both groups was small. Antiretroviral therapy amongst this population has minimal effects on hepatic enzymes and does not suggest modifications in therapy. Hepatic injury may occur in HIV, even in the absence of ART and other traditional factors. Monitoring of hepatic enzymes is still important in HIV patients.

  14. Efficacy of pancreatic enzyme replacement therapy in chronic pancreatitis: systematic review and meta-analysis.

    Science.gov (United States)

    de la Iglesia-García, Daniel; Huang, Wei; Szatmary, Peter; Baston-Rey, Iria; Gonzalez-Lopez, Jaime; Prada-Ramallal, Guillermo; Mukherjee, Rajarshi; Nunes, Quentin M; Domínguez-Muñoz, J Enrique; Sutton, Robert

    2017-08-01

    The benefits of pancreatic enzyme replacement therapy (PERT) in chronic pancreatitis (CP) are inadequately defined. We have undertaken a systematic review and meta-analysis of randomised controlled trials of PERT to determine the efficacy of PERT in exocrine pancreatic insufficiency (EPI) from CP. Major databases were searched from 1966 to 2015 inclusive. The primary outcome was coefficient of fat absorption (CFA). Effects of PERT versus baseline and versus placebo, and of different doses, formulations and schedules were determined. A total of 17 studies (511 patients with CP) were included and assessed qualitatively (Jadad score). Quantitative data were synthesised from 14 studies. PERT improved CFA compared with baseline (83.7±6.0 vs 63.1±15.0, pregression analyses revealed that sample size, CP diagnostic criteria, study design and enzyme dose contributed to heterogeneity; data on health inequalities were lacking. PERT is indicated to correct EPI and malnutrition in CP and may be improved by higher doses, enteric coating, administration during food and acid suppression. Further studies are required to determine optimal regimens, the impact of health inequalities and long-term effects on nutrition. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  15. Guidelines to start enzyme replacement therapy in classic Fabry Disease patients in Latin America

    Directory of Open Access Journals (Sweden)

    Juan Manuel Politei

    2017-01-01

    Full Text Available Introduction: Fabry disease is a rare inherited X-linked disorder resulting from the absence or deficient activity of the α-galactosidase A enzyme. Objetive: To provide the first guideline on the best time to start enzyme replacement therapy to treat classic Fabry disease, based on the knowledge and experience of experts from ten Latin American countries: Argentina, Brazil, Colombia, Costa Rica, Chile, Ecuador, Mexico, Peru, Uruguay and Venezuela. Methods: The project coordinator designed a survey based on the criteria for starting the treatment which are established in different international guidelines published to date. This document was later sent to all the participants for its evaluation. Results: Fifty experts responded to the survey, whose criteria was divided into 5 sections according to specialty, and they arrived at a consensus. Discussion: The criteria for an early treatment were defined given the growing evidence of a better response and prognosis associated with it. Conclusion: We believe that the importance of this guideline relies on the participation of experts from ten Latin American countries. However, as it deals with a systemic disease whose physiopathological mechanisms and complications are still being described, some manifestations have not been included in the criteria, making it necessary to revise this guideline in order to report any changes that may arise in the future.

  16. Extraction and identification of α-amylase inhibitor peptides from Nephelium lappacheum and Nephelium mutabile seed protein using gastro-digestive enzymes.

    Science.gov (United States)

    Evaristus, Natashya Anak; Wan Abdullah, Wan Nadiah; Gan, Chee-Yuen

    2018-04-01

    The potential of N. lappacheum and N. mutabile seed as a source of α-amylase inhibitor peptides was explored based on the local traditional practice of using the seed. Different gastro-digestive enzymes (i.e. pepsin or chymotrypsin) or a sequential digestion were used to extract the peptides. The effects of digestion time and enzyme to substrate (E:S) ratio on the α-amylase inhibitory activity were investigated. Results showed that chymotrypsin was effective in producing the inhibitor peptides from rambutan seed protein at E:S ratio 1:20 for 1 h, whereas pepsin was more effective for pulasan seed protein under the same condition. A total of 20 and 31 novel inhibitor peptides were identified, respectively. These peptides could bind with the subsites of α-amylase (i.e. Trp58, Trp59, Tyr62, Asp96, Arg195, Asp197, Glu233, His299, Asp300, and His305) and formed a sliding barrier that preventing the formation of enzyme/substrate intermediate leading to lower α-amylase activity. Copyright © 2018 Elsevier Inc. All rights reserved.

  17. Effect of specific enzyme inhibitors on replication, total genome DNA repair and on gene-specific DNA repair after UV irradiation in CHO cells

    Energy Technology Data Exchange (ETDEWEB)

    Jones, J.C.; Stevsner, Tinna; Bohr, Vilhelm A. (National Cancer Institute, NIH, Bethesda, MD (USA). Division of Cancer Treatment, Laboratory of Molecular Pharmacology); Mattern, M.R. (Smith Kline Beecham Pharmaceuticals, King of Prussia, PA (USA). Department of Biomolecular Discovery)

    1991-09-01

    The effects were studied of some specific enzyme inhibitors on DNA repair and replication after UV damage in Chinese hamster ovary cells. The DNA repair was studied at the level of the average, overall genome and also in the active dihydrofolate reductase gene. Replication was measured in the overall genome. The inhibitors were tested of DNA poly-merase {alpha} and {delta} (aphidicolin), of poly(ADPr) polymerase (3-aminobenzamide), of ribonucleotide reductase (hydroxyurea), of topo-isomerase I (camptothecin), and of topoisomerase II (merbarone, VP-16). In addition, the effects were tested of the potential topoisomerase I activator, {beta}-lapachone. All of these compounds inhibited genome replication and all topoisomerase inhibitors affected the overall genome repair; {beta}-lapachone stimulated it. None of these compounds had any effect on the gene-specific repair. (author). 36 refs.; 3 figs.; 2 tabs.

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

    DEFF Research Database (Denmark)

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

    2010-01-01

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

  19. Where do the immunostimulatory effects of oral proteolytic enzymes ('systemic enzyme therapy') come from? Microbial proteolysis as a possible starting point.

    Science.gov (United States)

    Biziulevicius, Gediminas A

    2006-01-01

    Enteric-coated proteolytic enzyme preparations like Wobenzym and Phlogenzym are widely used for the so-called 'systemic enzyme therapy' both in humans and animals. Numerous publications reveal that oral proteolytic enzymes are able to stimulate directly the activity of immune competent cells as well as to increase efficiency of some of their products. But origins of the immunostimulatory effects of oral proteolytic enzymes are still unclear. The hypothesis described here suggests that it may be proteolysis of intestinal microorganisms that makes the immune competent cells to work in the immunostimulatory manner. The hypothesis was largely formed by several scientific observations: First, microbial lysis products (lipopolysaccharides, muropeptides and other peptidoglycan fragments, beta-glucans, etc.) are well known for their immunostimulatory action. Second, a normal human being hosts a mass of intestinal microorganisms equivalent to about 1 kg. The biomass (mainly due to naturally occurring autolysis) continuously supplies the host's organism with immunostimulatory microbial cell components. Third, the immunostimulatory effects resulting from the oral application of exogenously acting antimicrobial (lytic) enzyme preparations, such as lysozyme and lysosubtilin, are likely to be a result of the action of microbial lysis products. Fourth, cell walls of most microorganisms contain a considerable amount of proteins/peptides, a possible target for exogenous proteolytic enzymes. In fact, several authors have already shown that a number of proteases possess an ability to lyse the microbial cells in vitro. Fifth, the pretreatment of microbial cells (at least of some species) in vitro with proteolytic enzymes makes them more sensitive to the lytic action of lysozyme and, otherwise, pretreatment with lysozyme makes them more susceptible to proteolytic degradation. Sixth, exogenous proteases, when in the intestines, may participate in final steps of food-protein digestion

  20. Metabolism of citral, the major constituent of lemongrass oil, in the cabbage looper, Trichoplusia ni, and effects of enzyme inhibitors on toxicity and metabolism.

    Science.gov (United States)

    Tak, Jun-Hyung; Isman, Murray B

    2016-10-01

    Although screening for new and reliable sources of botanical insecticides remains important, finding ways to improve the efficacy of those already in use through better understanding of their modes-of-action or metabolic pathways, or by improving formulations, deserves greater attention as the latter may present lesser regulation hurdles. Metabolic processing of citral (a combination of the stereoisomers geranial and neral), a main constituent of lemongrass (Cymbopogon citratus) essential oil has not been previously examined in insects. To address this, we investigated insecticidal activities of lemongrass oil and citral, as well as the metabolism of citral in larvae of the cabbage looper, Trichoplusia ni, in associations with well-known enzyme inhibitors. Among the inhibitors tested, piperonyl butoxide showed the highest increase in toxicity followed by triphenyl phosphate, but no synergistic interaction between the inhibitors was observed. Topical application of citral to fifth instar larvae produced mild reductions in food consumption, and frass analysis after 24h revealed geranic acid (99.7%) and neric acid (98.8%) as major metabolites of citral. Neither citral nor any other metabolites were found following in vivo analysis of larvae after 24h, and no significant effect of enzyme inhibitors was observed on diet consumption or citral metabolism. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Survey of findings in patients having persistent heartburn on proton pump inhibitor therapy.

    Science.gov (United States)

    Mandaliya, R; DiMarino, A J; Cohen, S

    2016-01-01

    In patients with refractory heartburn while on proton pump inhibitor (PPI) therapy, changing drugs or increasing treatment to a twice a day (b.i.d.) dose has become a common practice. This study aims to study patients with persistent heartburn while on PPI therapy and to determine if persistent symptom indicates the need for more aggressive or different therapy. A retrospective review of impedance-pH tracings on PPI therapy (q.d. or b.i.d.) for patients with persistent heartburn was performed. DeMeester score, impedance, and symptom sensitive index (SSI) were used as indices. Statistical analyses were performed using chi-squared test with Yates correction and paired t-test. One hundred consecutive patients, (female 50%, male 50%, mean age 54 [range 16-83] years) were studied on q.d. (n = 45) or b.i.d. PPI (n = 55). Only 20% of the patients had abnormal DeMeester score; 41% had an abnormal impedance score and 56% had abnormal SSI; 29% had all indices normal. There was no difference between patients taking q.d. versus b.i.d. PPI for abnormal DeMeester score (22 vs. 18%), impedance (38 vs. 44%) and SSI (53 vs. 58%); P = 0.80, 0.69, and 0.77, respectively. In 56 patients with positive SSI, symptoms were due to acid reflux in 8 (14%) patients, nonacid reflux in 31 (55%) patients, and combined acid and nonacid reflux in 17 (30%) patients. Patients with persistent heartburn on PPI therapy show a variety of disorders: (i) acid reflux (20%); (ii) nonacid reflux (26%); (iii) positive SSI (56%); (iv) all normal indices (29%). These studies indicate that persistent heartburn on PPI therapy is a complex problem that may not respond to simply increasing acid inhibition. © 2014 International Society for Diseases of the Esophagus.

  2. Tyrosine kinase, aurora kinase and leucine aminopeptidase as attractive drug targets in anticancer therapy - characterisation of their inhibitors.

    Science.gov (United States)

    Ziemska, Joanna; Solecka, Jolanta

    Cancers are the leading cause of deaths all over the world. Available anticancer agents used in clinics exhibit low therapeutic index and usually high toxicity. Wide spreading drug resistance of cancer cells induce a demanding need to search for new drug targets. Currently, many on-going studies on novel compounds with potent anticancer activity, high selectivity as well as new modes of action are conducted. In this work, we describe in details three enzyme groups, which are at present of extensive interest to medical researchers and pharmaceutical companies. These include receptor tyrosine kinases (e.g. EGFR enzymes) and non-receptor tyrosine kinases (Src enzymes), type A, B and C Aurora kinases and aminopeptidases, especially leucine aminopeptidase. We discuss classification of these enzymes, biochemistry as well as their role in the cell cycle under normal conditions and during cancerogenesis. Further on, the work describes enzyme inhibitors that are under in vitro, preclinical, clinical studies as well as drugs available on the market. Both, chemical structures of discovered inhibitors and the role of chemical moieties in novel drug design are discussed. Described enzymes play essential role in cell cycle, especially in mitosis (Aurora kinases), cell differentiation, growth and apoptosis (tyrosine kinases) as well as G1/S transition (leucine aminopeptidase). In cancer cells, they are overexpressed and only their inhibition may stop tumor progression. This review presents the clinical outcomes of selected inhibitors and argues the safety of drug usage in human volunteers. Clinical studies of EGFR and Src kinase inhibitors in different tumors clearly show the need for molecular selection of patients (to those with mutations in genes coding EGFR and Src) to achieve positive clinical response. Current data indicates the great necessity for new anticancer treatment and actions to limit off-target activity.

  3. Antibody-mediated enzyme replacement therapy targeting both lysosomal and cytoplasmic glycogen in Pompe disease.

    Science.gov (United States)

    Yi, Haiqing; Sun, Tao; Armstrong, Dustin; Borneman, Scott; Yang, Chunyu; Austin, Stephanie; Kishnani, Priya S; Sun, Baodong

    2017-05-01

    Pompe disease is characterized by accumulation of both lysosomal and cytoplasmic glycogen primarily in skeletal and cardiac muscles. Mannose-6-phosphate receptor-mediated enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) targets the enzyme to lysosomes and thus is unable to digest cytoplasmic glycogen. Studies have shown that anti-DNA antibody 3E10 penetrates living cells and delivers "cargo" proteins to the cytosol or nucleus via equilibrative nucleoside transporter ENT2. We speculate that 3E10-mediated ERT with GAA will target both lysosomal and cytoplasmic glycogen in Pompe disease. A fusion protein (FabGAA) containing a humanized Fab fragment derived from the murine 3E10 antibody and the 110 kDa human GAA precursor was constructed and produced in CHO cells. Immunostaining with an anti-Fab antibody revealed that the Fab signals did not co-localize with the lysosomal marker LAMP2 in cultured L6 myoblasts or Pompe patient fibroblasts after incubation with FabGAA. Western blot with an anti-GAA antibody showed presence of the 150 kDa full-length FabGAA in the cell lysates, in addition to the 95- and 76 kDa processed forms of GAA that were also seen in the rhGAA-treated cells. Blocking of mannose-6-phosphate receptor with mannose-6-phosphate markedly reduced the 95- and the 76 kDa forms but not the 150 kDa form. In GAA-KO mice, FabGAA achieved similar treatment efficacy as rhGAA at an equal molar dose in reducing tissue glycogen contents. Our data suggest that FabGAA retains the ability of rhGAA to treat lysosomal glycogen accumulation and has the beneficial potential over rhGAA to reduce cytoplasmic glycogen storage in Pompe disease. FabGAA can be delivered to both the cytoplasm and lysosomes in cultured cells. FabGAA equally reduced lysosomal glycogen accumulation as rhGAA in GAA-KO mice. FabGAA has the beneficial potential over rhGAA to clear cytoplasmic glycogen. This study suggests a novel antibody-enzyme fusion protein therapy

  4. Toxicologic study of carboxyatractyloside (active principle in cocklebur--Xanthium strumarium) in rats treated with enzyme inducers and inhibitors and glutathione precursor and depletor.

    Science.gov (United States)

    Hatch, R C; Jain, A V; Weiss, R; Clark, J D

    1982-01-01

    Male rats (10 rats/group) were treated with phenobarbital (PB), phenylbutazone (PBZ), stanozolol (3 inducers of cytochrome P450-dependent enzymes), piperonyl butoxide (PBO; a P450 inhibitor), cobaltous chloride (CoCl2; an inhibitor of hemoprotein synthesis), 5,6-benzoflavone (BNF; an inducer of cytochrome P448 dependent enzymes), cysteine [CYS; a glutathione (GSH) precursor], or ethyl maleate (EM; a GSH depletor). The rats were then given a calculated LD50 dosage (13.5 mg/kg of body weight) of carboxyatractyloside (CAT) intraperitoneally. Clinical signs of toxicosis, duration of illness, lethality, gross lesions, and hepatic and renal histopathologic lesions were recorded. Seemingly, (i) CAT toxicosis has independent lethal and cytotoxic components (PBZ decreased lethality and cytotoxicity; CoCl2 decreased cytotoxicity but not lethality; BNF decreased duration of illness, and perhaps lethality, but not cytotoxicity); (ii) CAT cytotoxicity could be partly due to an active metabolite formed by de novo-synthesized, P450-/P448-independent hemoprotein (PBZ and CoCl2 had anticytotoxic effects, but PB, stanozolol, PBO, and BNF did not); (iii) CAT detoxification may occur partly through a hemoprotein-independent, PBZ-inducible enzyme, and partly through a P448-dependent (BNF-inducible) enzyme; and (iv) CAT detoxification apparently is not P450 or GSH-dependent because PB, stanozolol, and CYS had no beneficial effects, and PBO, CoCl2, and EM did not enhance toxicosis. Metabolism of CAT may have a role in its cytotoxic and lethal effects.

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

    Science.gov (United States)

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

    2016-08-01

    Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are the most recent addition to the therapeutic options available for the treatment of type 2 diabetes and became available after the introduction of incretin-based therapies, dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs). These agents have potential advantages with regard to their weight loss-promoting effect, low risk of hypoglycemia, reduction in blood pressure, and reduction in cardiovascular events in high-risk patients (with empagliflozin). Apart from these clinically important outcomes, they may also correct core defects present in type 2 diabetes (i.e., improvement in β-cell function and insulin sensitivity). They do, however, have some adverse effects, notably, nausea with GLP-1 RAs and genital tract infections and potential for volume depletion with SGLT2i. Whether incretin-based therapies are associated with an increased risk of pancreatitis is unclear. Most recently, diabetic ketoacidosis has been reported with SGLT2i. Therefore, a key clinical question in relation to guidelines is whether these clinical advantages, in the context of the adverse effect profile, outweigh the additional cost compared with older, more established therapies. This article reviews the therapeutic rationale for the use of these newer drugs for diabetes treatment, considers their place in current guidelines, and discusses how this may change as new data emerge about their long-term efficacy and safety from ongoing outcome trials. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  6. An Archaeosome-Adjuvanted Vaccine and Checkpoint Inhibitor Therapy Combination Significantly Enhances Protection from Murine Melanoma

    Directory of Open Access Journals (Sweden)

    Felicity C. Stark

    2017-10-01

    Full Text Available Archaeosomes constitute archaeal lipid vesicle vaccine adjuvants that evoke a strong CD8+ T cell response to antigenic cargo. Therapeutic treatment of murine B16-ovalbumin (B16-OVA melanoma with archaeosome-OVA eliminates small subcutaneous solid tumors; however, they eventually resurge despite an increased frequency of circulating and tumor infiltrating OVA-CD8+ T cells. Herein, a number of different approaches were evaluated to improve responses, including dose number, interval, and the combination of vaccine with checkpoint inhibitors. Firstly, we found that tumor protection could not be enhanced by repetitive and/or delayed boosting to maximize the CD8+ T cell number and/or phenotype. The in vivo cytotoxicity of vaccine-induced OVA-CD8+ T cells was impaired in tumor-bearing mice. Additionally, tumor-infiltrating OVA-CD8+ T cells had an increased expression of programmed cell death protein-1 (PD-1 compared to other organ compartments, suggesting impaired function. Combination therapy of tumor-bearing mice with the vaccine archaeosome-OVA, and α-CTLA-4 administered concurrently as well as α-PD-1 and an α-PD-L1 antibody administered starting 9 days after tumor challenge given on a Q3Dx4 schedule (days 9, 12, 15 and 18, significantly enhanced survival. Following multi-combination therapy ~70% of mice had rapid tumor recession, with no detectable tumor mass after >80 days in comparison to a median survival of 17–22 days for untreated or experimental groups receiving single therapies. Overall, archaeosomes offer a powerful platform for delivering cancer antigens when used in combination with checkpoint inhibitor immunotherapies.

  7. Phosphodiesterase 4 inhibitor and phosphodiesterase 5 inhibitor combination therapy has antifibrotic and anti-inflammatory effects in mdx mice with Duchenne muscular dystrophy.

    Science.gov (United States)

    Nio, Yasunori; Tanaka, Masayuki; Hirozane, Yoshihiko; Muraki, Yo; Okawara, Mitsugi; Hazama, Masatoshi; Matsuo, Takanori

    2017-12-01

    Duchenne muscular dystrophy (DMD) is the most common inherited muscular dystrophy. Patients experience DMD in their 20s from cardiac or respiratory failure related to progressive muscle wasting. Currently, the only treatments for the symptoms of DMD are available. Muscle fibrosis, a DMD feature, leads to reduced muscle function and muscle mass, and hampers pharmaceutical therapeutic efficacy. Although antifibrotic agents may be useful, none is currently approved. Phosphodiesterase 4 (PDE4) inhibitors have exhibited antifibrotic effects in human and animal models. In this study, we showed beneficial effects of the PDE4 inhibitor piclamilast in the DMD mdx mouse. Piclamilast reduced the mRNA level of profibrotic genes, including collagen 1A1, in the gastrocnemius and diaphragm, in the mdx mouse, and significantly reduced the Sirius red staining area. The PDE5 inhibitors sildenafil and tadalafil ameliorated functional muscle ischemia in boys with DMD, and sildenafil reversed cardiac dysfunction in the mdx mouse. Single-treatment piclamilast or sildenafil showed similar antifibrotic effects on the gastrocnemius; combination therapy showed a potent antifibrotic effect, and piclamilast and combination therapy increased peroxisome proliferator-activated receptor γ coactivator-1α mRNA in mouse gastrocnemius. In summary, we confirmed that piclamilast has significant antifibrotic effects in mdx mouse muscle and is a potential treatment for muscle fibrosis in DMD.-Nio, Y., Tanaka, M., Hirozane, Y., Muraki, Y., Okawara, M., Hazama, M., Matsuo, T. Phosphodiesterase 4 inhibitor and phosphodiesterase 5 inhibitor combination therapy has antifibrotic and anti-inflammatory effects in mdx mice with Duchenne muscular dystrophy. © FASEB.

  8. Structural determinants of enzyme binding affinity: the E1 component of pyruvate dehydrogenase from Escherichia coli in complex with the inhibitor thiamin thiazolone diphosphate.

    Science.gov (United States)

    Arjunan, Palaniappa; Chandrasekhar, Krishnamoorthy; Sax, Martin; Brunskill, Andrew; Nemeria, Natalia; Jordan, Frank; Furey, William

    2004-03-09

    Thiamin thiazolone diphosphate (ThTDP), a potent inhibitor of the E1 component from the Escherichia coli pyruvate dehydrogenase multienzyme complex (PDHc), binds to the enzyme with greater affinity than does the cofactor thiamin diphosphate (ThDP). To identify what determines this difference, the crystal structure of the apo PDHc E1 component complex with ThTDP and Mg(2+) has been determined at 2.1 A and compared to the known structure of the native holoenzyme, PDHc E1-ThDP-Mg(2+) complex. When ThTDP replaces ThDP, reorganization occurs in the protein structure in the vicinity of the active site involving positional and conformational changes in some amino acid residues, a change in the V coenzyme conformation, addition of new hydration sites, and elimination of others. These changes culminate in an increase in the number of hydrogen bonds to the protein, explaining the greater affinity of the apoenzyme for ThTDP. The observed hydrogen bonding pattern is not an invariant feature of ThDP-dependent enzymes but rather specific to this enzyme since the extra hydrogen bonds are made with nonconserved residues. Accordingly, these sequence-related hydrogen bonding differences likewise explain the wide variation in the affinities of different thiamin-dependent enzymes for ThTDP and ThDP. The sequence of each enzyme determines its ability to form hydrogen bonds to the inhibitor or cofactor. Mechanistic roles are suggested for the aforementioned reorganization and its reversal in PDHc E1 catalysis: to promote substrate binding and product release. This study also provides additional insight into the role of water in enzyme inhibition and catalysis.

  9. Enzyme replacement therapy for Mucopolysaccharidosis Type I among patients followed within the MPS Brazil Network

    Directory of Open Access Journals (Sweden)

    Alícia Dorneles Dornelles

    2014-01-01

    Full Text Available Mucopolysaccharidosis type I (MPS I is a rare lysosomal disorder caused by deficiency of alph-L-iduronidase. Few clinical trials have assessed the effect of enzyme replacement therapy (ERT for this condition. We conducted an exploratory, open-label, non-randomized, multicenter cohort study of patients with MPS I. Data were collected from questionnaires completed by attending physicians at the time of diagnosis (T1; n = 34 and at a median time of 2.5 years later (T2; n = 24/34. The 24 patients for whom data were available at T2 were allocated into groups: A, no ERT (9 patients; median age at T1 = 36 months; 6 with severe phenotype; B, on ERT (15 patients; median age at T1 = 33 months; 4 with severe phenotype. For all variables in which there was no between-group difference at baseline, a delta of ;±20% was considered clinically relevant. The following clinically relevant differences were identified in group B in T2: lower rates of mortality and reported hospitalization for respiratory infection; lower frequency of hepatosplenomegaly; increased reported rates of obstructive sleep apnea syndrome and hearing loss; and stabilization of gibbus deformity. These changes could be due to the effect of ERT or of other therapies which have also been found more frequently in group B. Our findings suggest MPS I patients on ERT also receive a better overall care. ERT may have a positive effect on respiratory morbidity and overall mortality in patients with MPS I. Additional studies focusing on these outcomes and on other therapies should be performed.

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

    Science.gov (United States)

    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

    2017-03-21

    To elucidate the factors associated with residual gastroesophageal reflux disease (GERD) symptoms in patients receiving proton pump inhibitor (PPI) maintenance therapy in clinical practice. 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. 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 reflux-related symptom scores: 12 ± 1.9 vs 2.5 ± 0.8, P 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). 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.

  11. [Adherence with proton pump inhibitor therapy, by continuously taking nonsteroidal anti-inflammatory drugs].

    Science.gov (United States)

    Pimanov, S I; Makarenko, E V; Dikareva, E A

    2015-01-01

    To estimate the impact of adherence with proton pump inhibitor (PPI) therapy on the incidence of nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy (NSAID gastropathy) in patients with rheumatoid arthritis (RA). PPI pharmacotherapy adherence was estimated using the Medication Adherence Questionnaire (MAQ) in 92 patients with RA, including 32 patients did not take a PPI and 60 used a PPI. The groups were matched for age, disease duration, and used NSAIDs. All those asked underwent video esophagogastroduodenoscopy. According to the data of MAQ survey, low, moderate, and high adherence subgroups could be identified among the patients treated with a PPI. NSAID gastropathy was detected in 43.8% of the patients taking no PPI, in 50% of those with low PPI treatment adherence, in 12.5% with moderate adherence, and in 4.5% with high adherence. In the patients with low adherence to PPI therapy, NSAID gastropathy was recorded 11 times more frequently than in those with high adherence (c2 = 7.77; p = 0.005). This condition occurred in 28.6% of the patients taking NSAID without preventively using a PPI in the absence of risk factors for NSAID gastropathy. Only 36.7% patients who had been recommended to use a PPI for the prevention of NSAID gastropathy strictly observed their doctor's directions. Low PPI pharmacotherapy adherence may serve as an additional risk factor for NSAID gastropathy in patients in whom preventive antisecretory therapy used in combination with NSAID is indicated.

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

    Science.gov (United States)

    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

  13. Interactive Effectiveness of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers or Their Combination on Survival of Hemodialysis Patients

    Science.gov (United States)

    Kido, Ryo; Akizawa, Tadao; Fukagawa, Masafumi; Onishi, Yoshihiro; Yamaguchi, Takuhiro; Fukuhara, Shunichi

    2018-01-01

    Background Does the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers individually or as a combination confer a survival benefit in hemodialysis patients? The answer to this question is yet unclear. Methods We performed a case-cohort study using data from the Mineral and Bone Disorder Outcomes Study for Japanese CKD stage 5D patients (MBD-5D), a 3-year multicenter prospective case-cohort study, including 8,229 hemodialysis patients registered from 86 facilities in Japan. All patients had secondary hyperparathyroidism, a condition defined as a parathyroid hormone level ≥180 pg/mL and/or receiving vitamin D receptor activators. We compared all-cause mortality rates between those receiving ACEI, ARB, and their combination and non-users with interaction testing. We used marginal structural Poisson regression (causal model) to estimate the causal effect and interaction adjusted for possible time-dependent confounding. Cardiovascular mortality was also evaluated. Results Among 3,762 randomly sampled subcohort patients, those taking ACEI, ARB, and their combination at baseline accounted for 4.0, 31.6, and 3.8%, respectively. Over 3 years, 1,226 all-cause and 462 cardiovascular deaths occurred. Compared to non-users, ARB-alone users had a lower all-cause mortality rate (adjusted incident rate ratio [aIRR] 0.62, 95% CI 0.50–0.76), whereas ACEI-alone users showed a statistically similar rate (aIRR 1.01, 95% CI 0.57–1.77). On the contrary, combination users had a greater mortality rate (aIRR 2.56, 95% CI 1.22–5.37), showing significant interaction (p = 0.03). Analysis for cardiovascular mortality showed similar results. Conclusion Among hemodialysis patients with secondary hyperparathyroidism, unlike ACEI use, ARB use was associated with greater survival than non-use. Conversely, combination use was associated with greater mortality. Controlled trials are warranted to verify the causality factors of these associations. PMID:29161689

  14. Enzyme replacement therapy for Fabry disease: some answers but more questions

    Directory of Open Access Journals (Sweden)

    Majid Alfadhel

    2011-02-01

    Full Text Available Majid Alfadhel1, Sandra Sirrs21Division of Biochemical Diseases, Department of Paediatrics, BC Children’s and Women’s Hospital, University of British Columbia, Vancouver, BC, Canada; 2Adult Metabolic Diseases Clinic, Division of Endocrinology, Department of Medicine, Vancouver Hospital and Health Sciences Centre, University of British Columbia, Vancouver, BC, CanadaAbstract: Fabry disease (FD is a multisystem, X-linked disorder of glycosphingolipid metabolism caused by enzyme deficiency of α-galactosidase A. Affected patients have symptoms including acroparesthesias, angiokeratomas, and hypohidrosis. More serious manifestations include debilitating pain and gastrointestinal symptoms, proteinuria and gradual deterioration of renal function leading to end-stage renal disease, hypertrophic cardiomyopathy, and stroke. Heterozygous females may have symptoms as severe as males with the classic phenotype. Before 2001, treatment of patients with FD was supportive. The successful development of enzyme replacement therapy (ERT has been a great advancement in the treatment of patients with FD and can stabilize renal function and cardiac size, as well as improve pain and quality of life of patients with FD. In this review, we have provided a critical appraisal of the literature on the effects of ERT for FD. This analysis shows that data available on the treatment of FD are often derived from studies which are not controlled, rely on surrogate markers, and are of insufficient power to detect differences on hard clinical endpoints. Further studies of higher quality are needed to answer the questions that remain concerning the efficacy of ERT for FD.Keywords: Fabry disease, agalsidase α, agalsidase β, Replagal, Fabrazyme, critical appraisal, evidence-based medicine

  15. Uveitis induced by programmed cell death protein 1 inhibitor therapy with nivolumab in metastatic melanoma patient.

    Science.gov (United States)

    Kanno, Hiroaki; Ishida, Kyoko; Yamada, Wataru; Nishida, Takashi; Takahashi, Nobumichi; Mochizuki, Kiyofumi; Mizuno, Yuki; Matsuyama, Kanako; Takahashi, Tomoko; Seishima, Mariko

    2017-11-01

    Nivolumab, a new immune checkpoint inhibitor, binds to programmed cell death-protein 1 receptors on T cell, blockades binding of its ligands, and augments the immunologic reaction against tumor cells. Augmented immune response, however, may lead to immune-related adverse events. Herein we describe a rare case of bilateral anterior uveitis induced by nivolumab treatment for metastatic melanoma. A 54-year-old woman presented with mild conjunctival redness and blurred vision two months after initiating nivolumab treatment. Ophthalmological examination revealed bilateral non-granulomatous anterior uveitis. The flare values in the anterior chamber were monitored as an objective inflammatory index during nivolumab therapy and clinical time course was reported in this paper. Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Hung-Jin Huang

    2014-01-01

    Full Text Available 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.

  18. Unique cytologic features of thyroiditis caused by immune checkpoint inhibitor therapy for malignant melanoma

    Directory of Open Access Journals (Sweden)

    Trevor E. Angell

    2018-03-01

    Full Text Available Blockade of immune checkpoint molecules to reverse cancer-induced immune suppression can improve anti-tumor immune responses in cancer patients. Monoclonal antibodies targeting two such molecules, Programmed cell death protein 1 (PD-1 and cytotoxic T-lymphocyte associated protein 4 (CTLA-4 have shown clinical benefit in the treatment of advanced malignancies, including metastatic melanoma. Adverse effects of these immune checkpoint inhibitors include immune-related adverse events (irAE, of which one of the most common is autoimmune thyroiditis. Though thyroiditis is increasingly recognized, there are no reports of the pathological findings that occur in immunotherapy-induced thyroiditis. We present a case of immunotherapy-induced thyroiditis demonstrating its unique cytopathologic features. A 51-year-old woman with metastatic melanoma was found to have a suppressed TSH and elevated free thyroxine concentration 14 days after starting treatment with nivolumab (PD-1 antagonist plus ipilimumab (CTLA-4 antagonist therapy. A thyroid biopsy was performed based on ultrasound findings and cytopathology revealed unique features including abundant clusters of necrotic cells, lymphocytes and CD163-positive histiocytes. This case reports cytopathologic features found in immune checkpoint inhibitor related thyroiditis. These appear to be unique findings and may help inform future research regarding the pathophysiology and mechanisms of this condition.

  19. Biological therapy with TNF-inhibitors in pediatric rheumatology. Review of the litterature and personal experience

    Directory of Open Access Journals (Sweden)

    F. Fantini

    2011-09-01

    Full Text Available The therapeutic approach to JIA is sometimes very troublesome and progression to erosive polyarthritis may occur in all JIA categories. Only Methotrexate has shown efficacy and safety in a large controlled trial. Nevertheless, in many cases, drug resistance or intolerance has led to try other therapeutic options, with still debatable results. Therefore, there has been space, in the last few years, for new therapies as the TNF-inhibitors. This therapeutic approach has shown a dramatic clinical benefit in active polyarticular refractory JIA: the rate and rapidity of response have exceeded those of all other studied DMARDs. Preliminary data show that they are efficacious also for other pediatric rheumatic disease (spondyloarthropathies, autoimmune uveitis, dermatomyositis, Kawasaki syndrome and some auto- inflammatory diseases. TNF-inhibitors in JIA have demonstrated a favourable benefit-to-risk profile. However, as their use has increased worldwide, some unusual, usually not serious, adverse events have emerged. Severe infections, including TB, and deaths have been reported. Long-lasting active disease, systemic disease, concurrent and previous immunosuppressive therapies, all contribute to risk of infection and other serious AEs. Given the evidence that TNF has a primary role in the pathogenesis of JIA, particularly in joint destruction, neutralizing this cytokine early, within the window of opportunity, could halt or delay progression of joint damage and debilitating consequences of the disease. Thus, for JIA patients whose disease is not quickly controlled with MTX, TNF blockers may be considered as first-line treatment, although long-term safety data still need to be established.

  20. Sensitivity of MRI tumor biomarkers to VEGFR inhibitor therapy in an orthotopic mouse glioma model.

    Directory of Open Access Journals (Sweden)

    Christian T Farrar

    Full Text Available MRI biomarkers of tumor edema, vascular permeability, blood volume, and average vessel caliber are increasingly being employed to assess the efficacy of tumor therapies. However, the dependence of these biomarkers on a number of physiological factors can compromise their sensitivity and complicate the assessment of therapeutic efficacy. Here we examine the response of these MRI tumor biomarkers to cediranib, a potent vascular endothelial growth factor receptor (VEGFR inhibitor, in an orthotopic mouse glioma model. A significant increase in the tumor volume and relative vessel caliber index (rVCI and a slight decrease in the water apparent diffusion coefficient (ADC were observed for both control and cediranib treated animals. This contrasts with a clinical study that observed a significant decrease in tumor rVCI, ADC and volume with cediranib therapy. While the lack of a difference between control and cediranib treated animals in these biomarker responses might suggest that cediranib has no therapeutic benefit, cediranib treated mice had a significantly increased survival. The increased survival benefit of cediranib treated animals is consistent with the significant decrease observed for cediranib treated animals in the relative cerebral blood volume (rCBV, relative microvascular blood volume (rMBV, transverse relaxation time (T2, blood vessel permeability (K(trans, and extravascular-extracellular space (ν(e. The differential response of pre-clinical and clinical tumors to cediranib therapy, along with the lack of a positive response for some biomarkers, indicates the importance of evaluating the whole spectrum of different tumor biomarkers to properly assess the therapeutic response and identify and interpret the therapy-induced changes in the tumor physiology.

  1. 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

    Directory of Open Access Journals (Sweden)

    Yuki Narita

    2016-02-01

    Full Text Available 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.

  2. Comparison of the effects of stimulators and inhibitors of resorption on the release of lysosomal enzymes and radioactive calcium from fetal bone in organ culture

    International Nuclear Information System (INIS)

    Eilon, G.; Raisz, L.G.

    1978-01-01

    The release of lysosomal enzymes, collagenase, and previously incorporated 45 Ca from fetal rat long bones cultured in a chemically defined medium is compared. Parathyroid hormone (PTH) and prostaglandin E 2 increased the release of β-glucuronidase, acetylglucosaminidase, and cathepsin D, but showed little effect on collagenase activity in the medium at 48 h. The dose-response relations for β-glucuronidase and 45 Ca release were similar. However, the increase in lysosomal enzyme release was proportionally greater and occurred earlier than the increase in 45 Ca release. PTH also caused a significant increase in total β-glucuronidase activity in bone plus medium. Several agents which stimulate 45 Ca release at an optimal concentration, but not at a higher concentration, including dibutyryl cAMP, isobutylmethylxanthine, and the calcium ionophore, A23187, all increased lysosomal enzyme release at the concentration which increased 45 Ca release. Three inhibitors of bone resorption (calcitonin, cortisol, and colchicine) blocked lysosomal enzyme release at the same time that 45 Ca release decreased. When the bones escaped from calcitonin inhibition, both 45 Ca and lysosomalenzyme release increased. While colchicine blocked both lysosomal enzymes and 45 CA release, it actually increased the release of bone collagenase, and together with PTH or prostaglandin E 2 caused a large increase in free collagenase activity in the medium. These data indicate that lysosomal enzyme release is closely linked to bone resorption and suggest that lysosomal enzymes may have a primary role in initiating resorption, perhaps by acting on noncollagenous matrix or tissue components before mineral removal and collagen degradation

  3. Proteinaceous inhibitors of carbohydrate-active enzymes in cereals – Implication in agriculture, cereal-processing and nutrition

    DEFF Research Database (Denmark)

    Juge, N.; Svensson, Birte

    2006-01-01

    Enzymes that degrade, modify, or create glycosidic bonds are involved in carbohydrate biosynthesis and remodelling. Microbial carbohydrate-active enzymes form the basis of current green technology in the food, feed, starch, paper and pulp industries and the revolution in genomics may offer long...... knowledge on their structure, function, and implication in cereal processing, agriculture and nutrition. (c) 2006 Society of Chemical Industry...

  4. Pancreatic enzyme replacement therapy in cystic fibrosis: dose, variability and coefficient of fat absorption.

    Science.gov (United States)

    Calvo-Lerma, Joaquim; Martínez-Barona, Sandra; Masip, Etna; Fornés, Victoria; Ribes-Koninckx, Carmen

    2017-10-01

    Pancreatic enzyme replacement therapy (PERT) remains a backbone in the nutritional treatment of cystic fibrosis. Currently, there is a lack of an evidence-based tool that allows dose adjustment. To date, no studies have found an association between PERT dose and fat absorption. Therefore, the aim of the study was to assess the influence of both the PERT dose and the variability in this dose on the coefficient of fat absorption (CFA). This is a retrospective longitudinal study of 16 pediatric patients (192 food records) with three consecutive visits to the hospital over a twelve-month period. Dietary fat intake and PERT were assessed via a four-day food record and fat content in stools was determined by means of a three-day stool sample collection. A beta regression model was built to explain the association between the CFA and the interaction between the PERT dose (lipase units [LU]/g dietary fat) and the variability in the PERT dose (standard deviation [SD]). The coefficient of fat absorption increased with the PERT dose when the variability in the dose was low. In contrast, even at the highest PERT dose values, the CFA decreased when the variability was high. The confidence interval suggested an association, although the analysis was not statistically significant. The variability in the PERT dose adjustment should be taken into consideration when performing studies on PERT efficiency. A clinical goal should be the maintenance of a constant PERT dose rather than trying to obtain an optimal value.

  5. Pancreatic Enzyme Replacement Therapy in Children with Severe Acute Malnutrition: A Randomized Controlled Trial.

    Science.gov (United States)

    Bartels, Rosalie H; Bourdon, Céline; Potani, Isabel; Mhango, Brian; van den Brink, Deborah A; Mponda, John S; Muller Kobold, Anneke C; Bandsma, Robert H; Boele van Hensbroek, Michael; Voskuijl, Wieger P

    2017-11-01

    To assess the benefits of pancreatic enzyme replacement therapy (PERT) in children with complicated severe acute malnutrition. We conducted a randomized, controlled trial in 90 children aged 6-60 months with complicated severe acute malnutrition at the Queen Elizabeth Central Hospital in Malawi. All children received standard care; the intervention group also received PERT for 28 days. Children treated with PERT for 28 days did not gain more weight than controls (13.7 ± 9.0% in controls vs 15.3 ± 11.3% in PERT; P = .56). Exocrine pancreatic insufficiency was present in 83.1% of patients on admission and fecal elastase-1 levels increased during hospitalization mostly seen in children with nonedematous severe acute malnutrition (P Children who died had low fecal fatty acid split ratios at admission. Exocrine pancreatic insufficiency was not improved by PERT, but children receiving PERT were more likely to be discharged with every passing day (P = .02) compared with controls. PERT does not improve weight gain in severely malnourished children but does increase the rate of hospital discharge. Mortality was lower in patients on PERT, a finding that needs to be investigated in a larger cohort with stratification for edematous and nonedematous malnutrition. Mortality in severe acute malnutrition is associated with markers of poor digestive function. ISRCTN.com: 57423639. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Enzyme replacement therapy prevents dental defects in a model of hypophosphatasia.

    Science.gov (United States)

    McKee, M D; Nakano, Y; Masica, D L; Gray, J J; Lemire, I; Heft, R; Whyte, M P; Crine, P; Millán, J L

    2011-04-01

    Hypophosphatasia (HPP) occurs from loss-of-function mutation in the tissue-non-specific alkaline phosphatase (TNALP) gene, resulting in extracellular pyrophosphate accumulation that inhibits skeletal and dental mineralization. TNALP-null mice (Akp2(-/-)) phenocopy human infantile hypophosphatasia; they develop rickets at 1 week of age, and die before being weaned, having severe skeletal and dental hypomineralization and episodes of apnea and vitamin B(6)-responsive seizures. Delay and defects in dentin mineralization, together with a deficiency in acellular cementum, are characteristic. We report the prevention of these dental abnormalities in Akp2(-/-) mice receiving treatment from birth with daily injections of a mineral-targeting, human TNALP (sALP-FcD(10)). sALP-FcD(10) prevented hypomineralization of alveolar bone, dentin, and cementum as assessed by micro-computed tomography and histology. Osteopontin--a marker of acellular cementum--was immuno-localized along root surfaces, confirming that acellular cementum, typically missing or reduced in Akp2(-/-) mice, formed normally. Our findings provide insight concerning how acellular cementum is formed on tooth surfaces to effect periodontal ligament attachment to retain teeth in their osseous alveolar sockets. Furthermore, they provide evidence that this enzyme-replacement therapy, applied early in post-natal life--where the majority of tooth root development occurs, including acellular cementum formation--could prevent the accelerated tooth loss seen in individuals with HPP.

  7. HMG-CoA reductase inhibitors, other lipid-lowering medication, antiplatelet therapy, and the risk of venous thrombosis

    NARCIS (Netherlands)

    Ramcharan, A.S.; van Stralen, K.J.; Snoep, J.D.; Mantel-Teeuwisse, A.K.; Doggen, Catharina Jacoba Maria

    2009-01-01

    Background: Statins [3-hydroxymethyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors] and antiplatelet therapy reduce the risk of atherosclerotic disease. Besides a reduction of lipid levels, statins might also have antithrombotic and anti-inflammatory properties, and anti-platelet

  8. Early conversion from calcineurin inhibitor- to everolimus-based therapy following kidney transplantation : Results of the randomized ELEVATE trial

    NARCIS (Netherlands)

    de Fijter, Johan W; Holdaas, Hallvard; Øyen, Ole; Sanders, Jan Stephan; Sundar, Sankaran; Bemelman, Frederike J; Sommerer, Claudia; Pascual, Julio; Avihingsanon, Yingyos; Pongskul, Cholatip; Oppenheimer, Frederic; Toselli, Lorenzo; Russ, Graeme; Wang, Zailong; Lopez, Patricia; Kochuparampil, Jossy; Cruzado, Josep M; van der Giet, Markus

    In a 24-month, multicenter, open-label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10-14 weeks to convert to everolimus (n=359) or remain on standard calcineurin inhibitor (CNI) therapy (n=356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and

  9. Screening and purification of a novel trypsin inhibitor from Prosopis juliflora seeds with activity toward pest digestive enzymes.

    Science.gov (United States)

    Sivakumar, S; Franco, O L; Tagliari, P D; Bloch, C; Mohan, M; Thayumanavan, B

    2005-08-01

    Several pests are capable of decreasing crop production causing severe economical and social losses. Aiming to find novel molecules that could impede the digestion process of different pests, a screening of alpha-amylase and trypsin-like proteinase inhibitors was carried out in Prosopis juliflora, showing the presence of both in dry seeds. Furthermore, a novel trypsin inhibitor, with molecular mass of 13,292 Da, was purified showing remarkable in vitro activity against T. castaneum and C. maculatus.

  10. Discovery of new inhibitors of the bacterial peptidoglycan biosynthesis enzymes MurD and MurF by structure-based virtual screening.

    Science.gov (United States)

    Turk, Samo; Kovac, Andreja; Boniface, Audrey; Bostock, Julieanne M; Chopra, Ian; Blanot, Didier; Gobec, Stanislav

    2009-03-01

    The ATP-dependent Mur ligases (MurC, MurD, MurE and MurF) successively add L-Ala, D-Glu, meso-A(2)pm or L-Lys, and D-Ala-D-Ala to the nucleotide precursor UDP-MurNAc, and they represent promising targets for antibacterial drug discovery. We have used the molecular docking programme eHiTS for the virtual screening of 1990 compounds from the National Cancer Institute 'Diversity Set' on MurD and MurF. The 50 top-scoring compounds from screening on each enzyme were selected for experimental biochemical evaluation. Our approach of virtual screening and subsequent in vitro biochemical evaluation of the best ranked compounds has provided four novel MurD inhibitors (best IC(50)=10 microM) and one novel MurF inhibitor (IC(50)=63 microM).

  11. Overcoming resistance to beta-lactamase inhibitors: comparing sulbactam to novel inhibitors against clavulanate resistant SHV enzymes with substitutions at Ambler position 244.

    Science.gov (United States)

    Thomson, Jodi M; Distler, Anne M; Bonomo, Robert A

    2007-10-09

    Amino acid changes at Ambler position R244 in class A TEM and SHV beta-lactamases confer resistance to ampicillin/clavulanate, a beta-lactam/beta-lactamase inhibitor combination used to treat serious infections. To gain a deeper understanding of this resistance phenotype, we investigated the activities of sulbactam and two novel penem beta-lactamase inhibitors with sp2 hybridized C3 carboxylates and bicyclic R1 side chains against a library of SHV beta-lactamase variants at the 244 position. Compared to SHV-1 expressed in Escherichia coli, all 19 R244 variants exhibited increased susceptibility to ampicillin/sulbactam, an important difference compared to ampicillin/clavulanate. Kinetic analyses of SHV-1 and three SHV R244 (-S, -Q, and -L) variants revealed the Ki for sulbactam was significantly elevated for the R244 variants, but the partition ratios, kcat/kinact, were markedly reduced (13 000 --> inhibitors effectively restored ampicillin susceptibility in vitro. Compared to that of sulbactam, the kcat/kinact values of penems for SHV-1 and R244S were low (inhibitors with strategic chemical properties that improve affinity and impair turnover.

  12. Modeling of pharmacokinetics of cocaine in human reveals the feasibility for development of enzyme therapies for drugs of abuse.

    Directory of Open Access Journals (Sweden)

    Fang Zheng

    Full Text Available A promising strategy for drug abuse treatment is to accelerate the drug metabolism by administration of a drug-metabolizing enzyme. The question is how effectively an enzyme can actually prevent the drug from entering brain and producing physiological effects. In the present study, we have developed a pharmacokinetic model through a combined use of in vitro kinetic parameters and positron emission tomography data in human to examine the effects of a cocaine-metabolizing enzyme in plasma on the time course of cocaine in plasma and brain of human. Without an exogenous enzyme, cocaine half-lives in both brain and plasma are almost linearly dependent on the initial cocaine concentration in plasma. The threshold concentration of cocaine in brain required to produce physiological effects has been estimated to be 0.22±0.07 µM, and the threshold area under the cocaine concentration versus time curve (AUC value in brain (denoted by AUC2(∞ required to produce physiological effects has been estimated to be 7.9±2.7 µM·min. It has been demonstrated that administration of a cocaine hydrolase/esterase (CocH/CocE can considerably decrease the cocaine half-lives in both brain and plasma, the peak cocaine concentration in brain, and the AUC2(∞. The estimated maximum cocaine plasma concentration which a given concentration of drug-metabolizing enzyme can effectively prevent from entering brain and producing physiological effects can be used to guide future preclinical/clinical studies on cocaine-metabolizing enzymes. Understanding of drug-metabolizing enzymes is key to the science of pharmacokinetics. The general insights into the effects of a drug-metabolizing enzyme on drug kinetics in human should be valuable also in future development of enzyme therapies for other drugs of abuse.

  13. Modeling of pharmacokinetics of cocaine in human reveals the feasibility for development of enzyme therapies for drugs of abuse.

    Science.gov (United States)

    Zheng, Fang; Zhan, Chang-Guo

    2012-01-01

    A promising strategy for drug abuse treatment is to accelerate the drug metabolism by administration of a drug-metabolizing enzyme. The question is how effectively an enzyme can actually prevent the drug from entering brain and producing physiological effects. In the present study, we have developed a pharmacokinetic model through a combined use of in vitro kinetic parameters and positron emission tomography data in human to examine the effects of a cocaine-metabolizing enzyme in plasma on the time course of cocaine in plasma and brain of human. Without an exogenous enzyme, cocaine half-lives in both brain and plasma are almost linearly dependent on the initial cocaine concentration in plasma. The threshold concentration of cocaine in brain required to produce physiological effects has been estimated to be 0.22±0.07 µM, and the threshold area under the cocaine concentration versus time curve (AUC) value in brain (denoted by AUC2(∞)) required to produce physiological effects has been estimated to be 7.9±2.7 µM·min. It has been demonstrated that administration of a cocaine hydrolase/esterase (CocH/CocE) can considerably decrease the cocaine half-lives in both brain and plasma, the peak cocaine concentration in brain, and the AUC2(∞). The estimated maximum cocaine plasma concentration which a given concentration of drug-metabolizing enzyme can effectively prevent from entering brain and producing physiological effects can be used to guide future preclinical/clinical studies on cocaine-metabolizing enzymes. Understanding of drug-metabolizing enzymes is key to the science of pharmacokinetics. The general insights into the effects of a drug-metabolizing enzyme on drug kinetics in human should be valuable also in future development of enzyme therapies for other drugs of abuse.

  14. Rational optimization of drug-target residence time: Insights from inhibitor binding to the S. aureus FabI enzyme-product complex

    Science.gov (United States)

    Chang, Andrew; Schiebel, Johannes; Yu, Weixuan; Bommineni, Gopal R.; Pan, Pan; Baxter, Michael V.; Khanna, Avinash; Sotriffer, Christoph A.; Kisker, Caroline; Tonge, Peter J.

    2013-01-01

    Drug-target kinetics has recently emerged as an especially important facet of the drug discovery process. In particular, prolonged drug-target residence times may confer enhanced efficacy and selectivity in the open in vivo system. However, the lack of accurate kinetic and structural data for series of congeneric compounds hinders the rational design of inhibitors with decreased off-rates. Therefore, we chose the Staphylococcus aureus enoyl-ACP reductase (saFabI) - an important target for the development of new anti-staphylococcal drugs - as a model system to rationalize and optimize the drug-target residence time on a structural basis. Using our new, efficient and widely applicable mechanistically informed kinetic approach, we obtained a full characterization of saFabI inhibition by a series of 20 diphenyl ethers complemented by a collection of 9 saFabI-inhibitor crystal structures. We identified a strong correlation between the affinities of the investigated saFabI diphenyl ether inhibitors and their corresponding residence times, which can be rationalized on a structural basis. Due to its favorable interactions with the enzyme, the residence time of our most potent compound exceeds 10 hours. In addition, we found that affinity and residence time in this system can be significantly enhanced by modifications predictable by a careful consideration of catalysis. Our study provides a blueprint for investigating and prolonging drug-target kinetics and may aid in the rational design of long-residence-time inhibitors targeting the essential saFabI enzyme. PMID:23697754

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

    DEFF Research Database (Denmark)

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

    1999-01-01

    OBJECTIVES: This study evaluated the efficacy of long-term treatment with the angiotensin-converting enzyme (ACE) inhibitor trandolapril in diabetic patients with left ventricular dysfunction after acute myocardial infarction (AMI). BACKGROUND: Patients with diabetes mellitus have a high mortality...... the Trandolapril Cardiac Evaluation (TRACE) study, which was a randomized, double-blind, placebo-controlled trial of trandolapril in 1,749 patients with AMI and ejection fraction history of diabetes was found in 237 (14%) of the 1,749 patients. Treatment...

  16. Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy.

    LENUS (Irish Health Repository)

    O'Brien, Sinead M

    2012-02-03

    OBJECTIVE: Approximately 30% of patients with depression fail to respond to a selective serotonin reuptake inhibitor (SSRI). Few studies have attempted to define these patients from a biological perspective. Studies suggest that overall patients with depression show increased production of proinflammatory cytokines. We examined pro- and anti-inflammatory cytokine levels in patients who were SSRI resistant. METHODS: Plasma concentrations of IL-6, IL-8, IL-10, TNF-alpha and sIL-6R were measured with enzyme linked immunosorbent assays (ELISA) in DSM-1V major depressives who were SSRI resistant, in formerly SSRI resistant patients currently euthymic and in healthy controls. RESULTS: Patients with SSRI-resistant depression had significantly higher production of the pro-inflammatory cytokines IL-6 (p=0.01) and TNF-alpha (p=0.004) compared to normal controls. Euthymic patients who were formerly SSRI resistant had proinflammatory cytokine levels which were similar to the healthy subject group. Anti-inflammatory cytokine levels did not differ across the 3 groups. CONCLUSION: Suppression of proinflammatory cytokines does not occur in depressed patients who fail to respond to SSRIs and is necessary for clinical recovery.

  17. Respiratory muscle training with enzyme replacement therapy improves muscle strength in late - onset Pompe disease.

    Science.gov (United States)

    Jevnikar, Mitja; Kodric, Metka; Cantarutti, Fabiana; Cifaldi, Rossella; Longo, Cinzia; Della Porta, Rossana; Bembi, Bruno; Confalonieri, Marco

    2015-12-01

    Pompe disease is an autosomal recessive metabolic disorder caused by the deficiency of the lysosomal enzyme acid α-glucosidase. This deficiency leads to glycogen accumulation in the lysosomes of muscle tissue causing progressive muscular weakness particularly of the respiratory system. Enzyme replacement therapy (ERT) has demonstrated efficacy in slowing down disease progression in infants. Despite the large number of studies describing the effects of physical training in juvenile and adult late onset Pompe disease (LOPD). There are very few reports that analyze the benefits of respiratory muscle rehabilitation or training. The effectiveness of respiratory muscle training was investigated using a specific appliance with adjustable resistance (Threshold). The primary endpoint was effect on respiratory muscular strength by measurements of MIP and MEP. Eight late-onset Pompe patients (aged 13 to 58 years; 4 female, 4 male) with respiratory muscle deficiency on functional respiratory tests were studied. All patients received ERT at the dosage of 20 mg/kg/every 2 weeks and underwent training with Threshold at specified pressures for 24 months. A significant increase in MIP was observed during the follow-up of 24 month: 39.6 cm H 2 O (+ 25.0%) at month 3; 39.5 cm H 2 O (+ 24.9%) at month 6; 39.1 cm H 2 O (+ 23.7%) at month 9; 37.3 cm H 2 O (+ 18.2%) at month 12; and 37.3 cm H 2 O (+ 17.8%) at month 24. Median MEP values also showed a significant increase during the first 9 months: 29.8 cm H 2 O, (+ 14.3%) at month 3; 31.0 cm H 2 O (+ 18.6) at month 6; and 29.5 cm H 2 O (+ 12.9) at month 9. MEP was then shown to be decreased at months 12 and 24; median MEP was 27.2 cm H 2 O (+ 4.3%) at 12 months and 26.6 cm H 2 O (+ 1.9%) at 24 months. The FVC remain stable throughout the study. An increase in respiratory muscular strength was demonstrated with Threshold training when used in combination with ERT.

  18. COMPARING THE ENZYME REPLACEMENT THERAPY COST IN POST PANCREATECTOMY PATIENTS DUE TO PANCREATIC TUMOR AND CHRONIC PANCREATITIS.

    Science.gov (United States)

    Fragoso, Anna Victoria; Pedroso, Martha Regina; Herman, Paulo; Montagnini, André Luis

    2016-01-01

    Among late postoperative complications of pancreatectomy are the exocrine and endocrine pancreatic insufficiencies. The presence of exocrine pancreatic insufficiency imposes, as standard treatment, pancreatic enzyme replacement. Patients with chronic pancreatitis, with intractable pain or any complications with surgical treatment, are likely to present exocrine pancreatic insufficiency or have this condition worsened requiring adequate dose of pancreatic enzymes. The aim of this study is to compare the required dose of pancreatic enzyme and the enzyme replacement cost in post pancreatectomy patients with and without chronic pancreatitis. Observational cross-sectional study. In the first half of 2015 patients treated at the clinic of the Department of Gastrointestinal Surgery at Hospital das Clínicas, Universidade de São Paulo, Brazil, who underwent pancreatectomy for at least 6 months and in use of enzyme replacement therapy were included in this series. The study was approved by the Research Ethics Committee. The patients were divided into two groups according to the presence or absence of chronic pancreatitis prior to pancreatic surgery. For this study, Ptreatment was R$ 2150.5 ± 729.39; R$ 2118.18 ± 731.02 in patients without pancreatitis and R$ 2217.74 ± 736.30 in patients with pancreatitis. There was no statistically significant difference in the cost of treatment of enzyme replacement post pancreatectomy in patients with or without chronic pancreatitis prior to surgical indication.

  19. Pharmacology of a selective cyclooxygenase-2 inhibitor, HN-56249: a novel compound exhibiting a marked preference for the human enzyme in intact cells.

    Science.gov (United States)

    Berg, J; Fellier, H; Christoph, T; Kremminger, P; Hartmann, M; Blaschke, H; Rovensky, F; Towart, R; Stimmeder, D

    2000-04-01

    HN-56249 (3-(2,4-dichlorothiophenoxy)-4-methylsulfonylamino-benzenesu lfonamide), a highly selective cyclooxygenase (COX)-2 inhibitor, is the prototype of a novel series of COX inhibitors comprising bicyclic arylethersulfonamides; of this series HN-56249 is the most potent and selective human COX-2 inhibitor. HN-56249 inhibited platelet aggregation as a measure of COX-1 activity only moderately (IC50 26.5+/-1.7 microM). In LPS-stimulated monocytic cells the release of prostaglandin (PG) F1alpha as a measure of COX-2 was markedly inhibited (IC50 0.027+/-0.001 microM). Thus, HN-56249 showed an approximately 1000-fold selectivity for COX-2 in intact cells. In whole blood assays HN-56249 showed a potent inhibitory activity for COX-2 (IC50 0.78+/-0.37 microM) only. COX-1 was only weakly inhibited (IC50 867+/-181 microM). Hence, HN-56249 exhibited a greater than 1000-fold selectivity for whole blood COX-2. HN-56249 surpassed the COX-2 selectivities of the COX-2 selective inhibitors 3-cyclohexyloxy-4-methylsulfonylamino-nitrobenzene (NS-398) and 6-(2,4-difluorophenoxy)-5-methyl-sulfonylamino-1-indanone (flosulide) in the intact cell assays by eight- and threefold, respectively, and in the whole blood assays by approximately 40-fold. Following i.v. administration HN-56249 inhibited carrageenan-induced rat paw oedema only moderately (ID50 26.2+/-5.7 mg/kg, mean +/- SEM), approximately tenfold less potent than indomethacin (ID50 2.1+/-0.2 mg/kg, mean +/- SEM). After oral administration HN-56249 reversed thermal hyperalgesia in the carrageenan-induced rat paw oedema test, however, some 30-fold less potently than diclofenac. Comparing the inhibitory potency of HN-56249 against human COX-2 with that against murine COX-2 in intact cells revealed a 300-fold selectivity for the human enzyme. Similar effects were observed with other COX-2-selective arylethersulfonamides. In contrast, non-COX-2-selective arylethersulfonamides, including a highly selective COX-1 inhibitor, inhibited

  20. Partial resolution of bone lesions. A child with severe combined immunodeficiency disease and adenosine deaminase deficiency after enzyme-replacement therapy

    International Nuclear Information System (INIS)

    Yulish, B.S.; Stern, R.C.; Polmar, S.H.

    1980-01-01

    A child with severe combined immunodeficiency disease and adenosine deaminase deficiency, with characteristic bone dysplasia, was treated with transfusions of frozen irradiated RBCs as a means of enzyme replacement. This therapy resulted in restoration of immunologic competence and partial resolution of the bone lesions. Although the natural history of these lesions without therapy is not known, enzyme-replacement therapy may have played a role in the resolution of this patient's bone lesions

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

    Directory of Open Access Journals (Sweden)

    Chowdhary M

    2016-12-01

    Full Text Available Mudit Chowdhary,1,2 Kirtesh R Patel,1 Hasan H Danish,1 David H Lawson,3 Mohammad K Khan1 1Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, 2Department of Radiation Oncology, Rush University Medical Center, Chicago, IL, 3Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA Abstract: 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. Keywords: brain metastases, melanoma, radiation, BRAF inhibitors, vemurafenib, dabrafenib

  2. Histone deacetylase inhibitors (HDACIs): multitargeted anticancer agents.

    Science.gov (United States)

    Ververis, Katherine; Hiong, Alison; Karagiannis, Tom C; Licciardi, Paul V

    2013-01-01

    Histone deacetylase (HDAC) inhibitors are an emerging class of therapeutics with potential as anticancer drugs. The rationale for developing HDAC inhibitors (and other chromatin-modifying agents) as anticancer therapies arose from the understanding that in addition to genetic mutations, epigenetic changes such as dysregulation of HDAC enzymes can alter phenotype and gene expression, disturb homeostasis, and contribute to neoplastic growth. The family of HDAC inhibitors is large and diverse. It includes a range of naturally occurring and synthetic compounds that differ in terms of structure, function, and specificity. HDAC inhibitors have multiple cell type-specific effects in vitro and in vivo, such as growth arrest, cell differentiation, and apoptosis in malignant cells. HDAC inhibitors have the potential to be used as monotherapies or in combination with other anticancer therapies. Currently, there are two HDAC inhibitors that have received approval from the US FDA for the treatment of cutaneous T-cell lymphoma: vorinostat (suberoylanilide hydroxamic acid, Zolinza) and depsipeptide (romidepsin, Istodax). More recently, depsipeptide has also gained FDA approval for the treatment of peripheral T-cell lymphoma. Many more clinical trials assessing the effects of various HDAC inhibitors on hematological and solid malignancies are currently being conducted. Despite the proven anticancer effects of particular HDAC inhibitors against certain cancers, many aspects of HDAC enzymes and HDAC inhibitors are still not fully understood. Increasing our understanding of the effects of HDAC inhibitors, their targets and mechanisms of action will be critical for the advancement of these drugs, especially to facilitate the rational design of HDAC inhibitors that are effective as antineoplastic agents. This review will discuss the use of HDAC inhibitors as multitargeted therapies for malignancy. Further, we outline the pharmacology and mechanisms of action of HDAC inhibitors while

  3. Fluorescent Inhibitors as Tools To Characterize Enzymes: Case Study of the Lipid Kinase Phosphatidylinositol 4-Kinase IIIβ (PI4KB).

    Science.gov (United States)

    Humpolickova, Jana; Mejdrová, Ivana; Matousova, Marika; Nencka, Radim; Boura, Evzen

    2017-01-12

    The lipid kinase phosphatidylinositol 4-kinase IIIβ (PI4KB) is an essential host factor for many positive-sense single-stranded RNA (+RNA) viruses including human pathogens hepatitis C virus (HCV), Severe acute respiratory syndrome (SARS), coxsackie viruses, and rhinoviruses. Inhibitors of PI4KB are considered to be potential broad-spectrum virostatics, and it is therefore critical to develop a biochemical understanding of the kinase. Here, we present highly potent and selective fluorescent inhibitors that we show to be useful chemical biology tools especially in determination of dissociation constants. Moreover, we show that the coumarin-labeled inhibitor can be used to image PI4KB in cells using fluorescence-lifetime imaging microscopy (FLIM) microscopy.

  4. Mutational analysis of target enzyme recognition of the beta-trefoil fold barley alpha-amylase/subtilisin inhibitor

    DEFF Research Database (Denmark)

    Bønsager, Birgit Christine; Nielsen, Per K.; Abou Hachem, Maher

    2005-01-01

    The barley alpha-amylase/subtilisin inhibitor ( BASI) inhibits alpha-amylase 2 (AMY2) with subnanomolar affinity. The contribution of selected side chains of BASI to this high affinity is discerned in this study, and binding to other targets is investigated. Seven BASI residues along the AMY2-BASI...... interface and four residues in the putative protease-binding loop on the opposite side of the inhibitor were mutated. A total of 15 variants were compared with the wild type by monitoring the alpha-amylase and protease inhibitory activities using Blue Starch and azoalbumin, respectively, and the kinetics...

  5. Pancreatic enzyme replacement therapy in cystic fibrosis: dose, variability and coefficient of fat absorption

    Directory of Open Access Journals (Sweden)

    Joaquim Calvo-Lerma

    Full Text Available Objectives: Pancreatic enzyme replacement therapy (PERT remains a backbone in the nutritional treatment of cystic fibrosis. Currently, there is a lack of an evidence-based tool that allows dose adjustment. To date, no studies have found an association between PERT dose and fat absorption. Therefore, the aim of the study was to assess the influence of both the PERT dose and the variability in this dose on the coefficient of fat absorption (CFA. Methods: This is a retrospective longitudinal study of 16 pediatric patients (192 food records with three consecutive visits to the hospital over a twelve-month period. Dietary fat intake and PERT were assessed via a four-day food record and fat content in stools was determined by means of a three-day stool sample collection. A beta regression model was built to explain the association between the CFA and the interaction between the PERT dose (lipase units [LU]/g dietary fat and the variability in the PERT dose (standard deviation [SD]. Results: The coefficient of fat absorption increased with the PERT dose when the variability in the dose was low. In contrast, even at the highest PERT dose values, the CFA decreased when the variability was high. The confidence interval suggested an association, although the analysis was not statistically significant. Conclusion: The variability in the PERT dose adjustment should be taken into consideration when performing studies on PERT efficiency. A clinical goal should be the maintenance of a constant PERT dose rather than trying to obtain an optimal value.

  6. AAV Gene Therapy for Alcoholism: Inhibition of Mitochondrial Aldehyde Dehydrogenase Enzyme Expression in Hepatoma Cells.

    Science.gov (United States)

    Sanchez, Anamaria C; Li, Chengwen; Andrews, Barbara; Asenjo, Juan A; Samulski, R Jude

    2017-09-01

    Most ethanol is broken down in the liver in two steps by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH2) enzymes, which metabolize down ethanol into acetaldehyde and then acetate. Some individuals from the Asian population who carry a mutation in the aldehyde dehydrogenase gene (ALDH2*2) cannot metabolize acetaldehyde as efficiently, producing strong effects, including facial flushing, dizziness, hypotension, and palpitations. This results in an aversion to alcohol intake and protection against alcoholism. The large prevalence of this mutation in the human population strongly suggests that modulation of ALDH2 expression by genetic technologies could result in a similar phenotype. scAAV2 vectors encoding ALDH2 small hairpin RNA (shRNA) were utilized to validate this hypothesis by silencing ALDH2 gene expression in human cell lines. Human cell lines HEK-293 and HepG2 were transduced with scAAV2/shRNA, showing a reduction in ALDH2 RNA and protein expression with the two viral concentration assayed (1 × 10 4 and 1 × 10 5 vg/cell) at two different time points. In both cell lines, ALDH2 RNA levels were reduced by 90% and protein expression was inhibited by 90% and 52%, respectively, 5 days post infection. Transduced HepG2 VL17A cells (ADH+) exposed to ethanol resulted in a 50% increase in acetaldehyde levels. These results suggest that gene therapy could be a useful tool for the treatment of alcoholism by knocking down ALDH2 expression using shRNA technology delivered by AAV vectors.

  7. Development of Targeted, Enzyme-Activated Nano-Conjugates for Hepatic Cancer Therapy

    Science.gov (United States)

    Kuruvilla, Sibu Philip

    Hepatocellular carcinoma (HCC) is the 5th most commonly-occurring cancer worldwide and the 2nd highest cause for cancer-related deaths globally. The current treatment strategy is the direct injection of a chemotherapeutic agent (e.g. doxorubicin; DOX) into the hepatic artery, through a process called hepatic arterial infusion (HAI). Unfortunately, HAI is severely hindered by limited therapeutic efficacy against the tumor and high systemic toxicity to surrounding organs (e.g. cardiotoxicity). This thesis focuses on the development of a targeted, nanoparticle-based drug delivery system aimed to improve the clinical treatment of HCC. In particular, we employ generation 5 (G5) poly(amido amine) (PAMAM) dendrimers targeted to hepatic cancer cells via N-acetylgalactosamine (NAcGal) ligands attached to the surface through a poly(ethylene glycol) (PEG) brush. DOX is attached to the G5 surface through two different enzyme-sensitive linkages, L3 or L4, to achieve controllable release of the drug inside hepatic cancer cells. The combination of NAcGal-PEG targeting branches with either L3- or L4-DOX linkages led to the development of P1 and P2 particles, respectively. In Part 1, we discuss the development of these particles and measure their ability to target and kill hepatic cancer cells in vitro. In Part 2, we investigate the antitumor activity of P1 and P2 particles in tumor-bearing mice in comparison to the free drug, and we measure the cardiac function of mice undergoing treatment to assess differences in DOX-induced cardiotoxicity. Finally, in Part 3, we explore multi-valent targeting of G5 dendrimers in pursuit of further improving their specificity to hepatic cancer cells. Ultimately, this thesis provides insight into the utility of nanoparticle-based drug delivery systems that can potentially be translated to the clinic to improve cancer therapy.

  8. Aromatase inhibitors in pediatrics.

    Science.gov (United States)

    Wit, Jan M; Hero, Matti; Nunez, Susan B

    2011-10-25

    Aromatase, an enzyme located in the endoplasmic reticulum of estrogen-producing cells, catalyzes the rate-limiting step in the conversion of androgens to estrogens in many tissues. The clinical features of patients with defects in CYP19A1, the gene encoding aromatase, have revealed a major role for this enzyme in epiphyseal plate closure, which has promoted interest in the use of inhibitors of aromatase to improve adult height. The availability of the selective aromatase inhibitors letrozole and anastrozole--currently approved as adjuvant therapy for breast cancer--have stimulated off-label use of aromatase inhibitors in pediatrics for the following conditions: hyperestrogenism, such as aromatase excess syndrome, Peutz-Jeghers syndrome, McCune-Albright syndrome and functional follicular ovarian cysts; hyperandrogenism, for example, testotoxicosis (also known as familial male-limited precocious puberty) and congenital adrenal hyperplasia; pubertal gynecomastia; and short stature and/or pubertal delay in boys. Current data suggest that aromatase inhibitors are probably effective in the treatment of patients with aromatase excess syndrome or testotoxicosis, partially effective in Peutz-Jeghers and McCune-Albright syndrome, but probably ineffective in gynecomastia. Insufficient data are available in patients with congenital adrenal hyperplasia or functional ovarian cysts. Although aromatase inhibitors appear effective in increasing adult height of boys with short stature and/or pubertal delay, safety concerns, including vertebral deformities, a decrease in serum HDL cholesterol levels and increase of erythrocytosis, are reasons for caution.

  9. Chemometrics Optimized Extraction Procedures, Phytosynergistic Blending and in vitro Screening of Natural Enzyme Inhibitors Amongst Leaves of Tulsi, Banyan and Jamun.

    Science.gov (United States)

    De, Baishakhi; Bhandari, Koushik; Singla, Rajeev K; Katakam, Prakash; Samanta, Tanmoy; Kushwaha, Dilip Kumar; Gundamaraju, Rohit; Mitra, Analava

    2015-10-01

    Tulsi, Banyan, and Jamun are popular Indian medicinal plants with notable hypoglycemic potentials. Now the work reports chemo-profiling of the three species with in-vitro screening approach for natural enzyme inhibitors (NEIs) against enzymes pathogenic for type 2 diabetes. Further along with the chemometrics optimized extraction process technology, phyto-synergistic studies of the composite polyherbal blends have also been reported. Chemometrically optimized extraction procedures, ratios of polyherbal composites to achieve phyto-synergistic actions, and in-vitro screening of NEIs amongst leaves of Tulsi, Banyan, and Jamun. The extraction process parameters of the leaves of three plant species (Ficus benghalensis, Syzigium cumini and Ocimum sanctum) were optimized by rotatable central composite design of chemometrics so as to get maximal yield of bio-actives. Phyto-blends of three species were prepared so as to achieve synergistic antidiabetic and antioxidant potentials and the ratios were optimized by chemometrics. Next, for in vitro screening of natural enzyme inhibitors the individual leaf extracts as well as composite blends were subjected to assay procedures to see their inhibitory potentials against the enzymes pathogenic in type 2 diabetes. The antioxidant potentials were also estimated by DPPH radical scavenging, ABTS, FRAP and Dot Blot assay. Considering response surface methodology studies and from the solutions obtained using desirability function, it was found that hydro-ethanolic or methanolic solvent ratio of 52.46 ± 1.6 and at a temperature of 20.17 ± 0.6 gave an optimum yield of polyphenols with minimal chlorophyll leaching. The species also showed the presence of glycosides, alkaloids, and saponins. Composites in the ratios of 1:1:1 and 1:1:2 gave synergistic effects in terms of polyphenol yield and anti-oxidant potentials. All composites (1:1:1, 1:2:1, 2:1:1, 1:1:2) showed synergistic anti-oxidant actions. Inhibitory activities against the

  10. A novel reflux inhibitor lesogaberan (AZD3355) as add-on treatment in patients with GORD with persistent reflux symptoms despite proton pump inhibitor therapy: a randomised placebo-controlled trial

    NARCIS (Netherlands)

    Boeckxstaens, Guy E.; Beaumont, Hanneke; Hatlebakk, Jan G.; Silberg, Debra G.; Björck, Karin; Karlsson, Maria; Denison, Hans

    2011-01-01

    o evaluate the efficacy and tolerability of add-on treatment with lesogaberan (AZD3355), a novel reflux inhibitor, in patients with persistent gastro-oesophageal reflux disease (GORD) symptoms despite proton pump inhibitor (PPI) therapy. double-blind, placebo-controlled, randomised, parallel-group,

  11. A distinct urinary biomarker pattern characteristic of female Fabry patients that mirrors response to enzyme replacement therapy.

    Directory of Open Access Journals (Sweden)

    Andreas D Kistler

    Full Text Available Female patients affected by Fabry disease, an X-linked lysosomal storage disorder, exhibit a wide spectrum of symptoms, which renders diagnosis, and treatment decisions challenging. No diagnostic test, other than sequencing of the alpha-galactosidase A gene, is available and no biomarker has been proven useful to screen for the disease, predict disease course and monitor response to enzyme replacement therapy. Here, we used urine proteomic analysis based on capillary electrophoresis coupled to mass spectrometry and identified a biomarker profile in adult female Fabry patients. Urine samples were taken from 35 treatment-naïve female Fabry patients and were compared to 89 age-matched healthy controls. We found a diagnostic biomarker pattern that exhibited 88.2% sensitivity and 97.8% specificity when tested in an independent validation cohort consisting of 17 treatment-naïve Fabry patients and 45 controls. The model remained highly specific when applied to additional control patients with a variety of other renal, metabolic and cardiovascular diseases. Several of the 64 identified diagnostic biomarkers showed correlations with measures of disease severity. Notably, most biomarkers responded to enzyme replacement therapy, and 8 of 11 treated patients scored negative for Fabry disease in the diagnostic model. In conclusion, we defined a urinary biomarker model that seems to be of diagnostic use for Fabry disease in female patients and may be used to monitor response to enzyme replacement therapy.

  12. Role of Acid and Weakly Acidic Reflux in Gastroesophageal Reflux Disease Off Proton Pump Inhibitor Therapy

    Science.gov (United States)

    Sung, Hea Jung; Moon, Sung Jin; Kim, Jin Su; Lim, Chul Hyun; Park, Jae Myung; Lee, In Seok; Kim, Sang Woo; Choi, Myung-Gye

    2012-01-01

    Background/Aims Available data about reflux patterns and symptom determinants in the gastroesophageal reflux disease (GERD) subtypes off proton pump inhibitor (PPI) therapy are lacking. We aimed to evaluate reflux patterns and determinants of symptom perception in patients with GERD off PPI therapy by impedance-pH monitoring. Methods We retrospectively reviewed the impedance-pH data in patients diagnosed as GERD based on results of impedance-pH monitoring, endoscopy and/or typical symptoms. The characteristics of acid and weakly acidic reflux were evaluated. Symptomatic and asymptomatic reflux were compared according to GERD subtypes and individual symptoms. Results Forty-two patients (22 males, mean age 46 years) were diagnosed as GERD (17 erosive reflux disease, 9 pH(+) non-erosive reflux disease [NERD], 9 hypersensitive esophagus and 7 symptomatic NERD). A total of 1,725 reflux episodes were detected (855 acid [50%], 857 weakly acidic [50%] and 13 weakly alkaline reflux [reflux was more frequently symptomatic and bolus clearance was longer compared with weakly acidic reflux. In terms of globus, weakly acidic reflux was more symptomatic. Symptomatic reflux was more frequently acid and mixed reflux; these associations were more pronounced in erosive reflux disease and symptomatic NERD. The perception of regurgitation was related to acid reflux, while that of globus was more related to weakly acidic reflux. Conclusions In patients not taking PPI, acid reflux was more frequently symptomatic and had longer bolus clearance. Symptomatic reflux was more frequently acid and mixed type; however, weakly acidic reflux was associated more with globus. These data suggest a role for impedance-pH data in the evaluation of globus. PMID:22837877

  13. [Selective serotonin reuptake inhibitors in the therapy of various types of endogenous depressions].

    Science.gov (United States)

    Panteleeva, G P; Abramova, L I; Korenev, A N

    2000-01-01

    In order to specify differential indications for the use of selective serotonin reuptake inhibitors (SSRI) their therapeutic effect was investigated in apathic-adynamic, melancholic and anxious depressions. Group of 151 patients received monotherapy with one of SSRI-drugs: citalopram--22 patients (mean daily dosage--27.4 mg), paroxetine--47 patients (23 mg), sertraline--19 patients (107 mg), fluvoxamine--28 patients (162 mg), fluoxetine--35 patients (20 mg). The state of the patients was estimated 5 times during 42 days of therapy by clinical estimations and according to Hamilton Depression Scale (HAM-D). Therapeutic effects of the drugs were determined according to the degree of reduction of the total HAM-D scores and they were considered as "significant" (a reduction of the scores by 50% and more), "moderate" (by 21-49%), and "insignificant" (by 1-20%). Positive antidepressive effect, including "significant" was obtained in the case of the use of all the drugs studied. Differential evaluation of the three components of antidepressive activity (thymoleptic, sedative-anxiolytic, and stimulative) according to the degrees and data of expression of drugs' therapeutic effect has allowed to determine indications for the therapy of endogenous depressions by each of SSRI: to recommend cytalopram for the treatment of various types of depressive states mainly, for anxious and apatho-adynamic types; paroxetin--for treatment of melancholic depressions as well as for anxious and apatho-dynamic ones; sertralin++--for depression with anxiety and fobic disorders; fluvoxamine--for melancholic and anxious depression; fluoxetine--for apatho-adynamic depressions.

  14. Role of Acid and weakly acidic reflux in gastroesophageal reflux disease off proton pump inhibitor therapy.

    Science.gov (United States)

    Sung, Hea Jung; Cho, Yu Kyung; Moon, Sung Jin; Kim, Jin Su; Lim, Chul Hyun; Park, Jae Myung; Lee, In Seok; Kim, Sang Woo; Choi, Myung-Gye

    2012-07-01

    Available data about reflux patterns and symptom determinants in the gastroesophageal reflux disease (GERD) subtypes off proton pump inhibitor (PPI) therapy are lacking. We aimed to evaluate reflux patterns and determinants of symptom perception in patients with GERD off PPI therapy by impedance-pH monitoring. We retrospectively reviewed the impedance-pH data in patients diagnosed as GERD based on results of impedance-pH monitoring, endoscopy and/or typical symptoms. The characteristics of acid and weakly acidic reflux were evaluated. Symptomatic and asymptomatic reflux were compared according to GERD subtypes and individual symptoms. Forty-two patients (22 males, mean age 46 years) were diagnosed as GERD (17 erosive reflux disease, 9 pH(+) non-erosive reflux disease [NERD], 9 hypersensitive esophagus and 7 symptomatic NERD). A total of 1,725 reflux episodes were detected (855 acid [50%], 857 weakly acidic [50%] and 13 weakly alkaline reflux [Acid reflux was more frequently symptomatic and bolus clearance was longer compared with weakly acidic reflux. In terms of globus, weakly acidic reflux was more symptomatic. Symptomatic reflux was more frequently acid and mixed reflux; these associations were more pronounced in erosive reflux disease and symptomatic NERD. The perception of regurgitation was related to acid reflux, while that of globus was more related to weakly acidic reflux. In patients not taking PPI, acid reflux was more frequently symptomatic and had longer bolus clearance. Symptomatic reflux was more frequently acid and mixed type; however, weakly acidic reflux was associated more with globus. These data suggest a role for impedance-pH data in the evaluation of globus.

  15. Purification and Partial Characterization of Catalase from Chicken Erythrocytes and the Effect of Various Inhibitors on Enzyme Activity

    OpenAIRE

    AYDEMİR, Tülin; KURU, Kevser

    2003-01-01

    Catalase plays a major role in the protection of tissues from the toxic effects of H2O2 and partially reduced oxygen species. A nearly 136-fold enzyme purification was obtained from chicken erythrocyte by acetone precipitation, ethanol-chloroform treatment, CM-cellulose and Sephadex G-200 chromatography. The specific activity of purified enzyme was 42,556 U/mg. The molecular weight of the native chicken erythrocyte catalase was estimated at 240 kDa by gel filtration. SDS-gel electr...

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

    Energy Technology Data Exchange (ETDEWEB)

    Igawa, Akihiko; Nozawa, Takashi; Yoshida, Naohiro [Toyama Medical and Pharmaceutical Univ. (Japan)] [and others

    2002-11-01

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

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

    DEFF Research Database (Denmark)

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

    2005-01-01

    OBJECTIVES: To study the use of beta-blockers and angiotensin-converting enzyme (ACE) inhibitors after acute myocardial infarction (AMI) in Denmark from 1995 to 2002. DESIGN: Information about patients with first AMI aged > or = 30 years and the dispensing of beta-blockers and ACE inhibitors from...... pharmacies within 30 d from discharge was obtained from the National Patient Registry and the Danish Registry of Medicinal Product Statistics. RESULTS: Beta-blocker use increased from 38.1% of patients in 1995 to 67.9% in 2002 (OR = 3.85, CI: 3.58-4.13). Women, elderly patients and patients taking loop......-diuretics and antidiabetic drugs received beta-blockers less frequently, but patients taking loop-diuretics or antidiabetic drugs had the greatest increase. ACE inhibitor use increased from 24.5 to 35.5% (OR = 1.86, CI: 1.72-2.01). Women, patients aged or = 80 years and patients not taking loop...

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

    International Nuclear Information System (INIS)

    Igawa, Akihiko; Nozawa, Takashi; Yoshida, Naohiro

    2002-01-01

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

  19. Insight into the binding interactions of CYP450 aromatase inhibitors with their target enzyme: a combined molecular docking and molecular dynamics study.

    Science.gov (United States)

    Galeazzi, Roberta; Massaccesi, Luca

    2012-03-01

    CYP450 aromatase catalyzes the terminal and rate-determining step in estrogen synthesis, the aromatization of androgens, and its inhibition is an efficient approach to treating estrogen-dependent breast cancer. Insight into the molecular basis of the interaction at the catalytic site between CYP450 aromatase inhibitors and the enzyme itself is required in order to design new and more active compounds. Hence, a combined molecular docking-molecular dynamics study was carried out to obtain the structure of the lowest energy association complexes of aromatase with some third-generation aromatase inhibitors (AIs) and with other novel synthesized letrozole-derived compounds which showed high in vitro activity. The results obtained clearly demonstrate the role of the pharmacophore groups present in the azaheterocyclic inhibitors (NSAIs)-namely the triazolic ring and highly functionalized aromatic moieties carrying H-bond donor or acceptor groups. In particular, it was pointed out that all of them can contribute to inhibition activity by interacting with residues of the catalytic cleft, but the amino acids involved are different for each compound, even if they belong to the same class. Furthermore, the azaheterocyclic group strongly coordinates with the Fe(II) of heme cysteinate in the most active NSAI complexes, while it prefers to adopt another orientation in less active ones.

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

    Science.gov (United States)

    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.

  1. Upper gastrointestinal bleeding in a patient with depression receiving selective serotonin reuptake inhibitor therapy.

    Science.gov (United States)

    Kumar, Deepak; Saaraswat, Tanuj; Sengupta, S N; Mehrotra, Saurabh

    2009-02-01

    Serotonin plays an important role in the normal clotting phenomenon and is released by platelets. Platelets are dependent on a serotonin transporter for the uptake of serotonin, as they cannot synthesize it themselves. Selective serotonin reuptake inhibitors (SSRIs) block the uptake of serotonin into platelets and can cause problems with clotting leading to bleeding. This case report highlights the occurrence of upper gastrointestinal bleeding in the index case on initiating SSRI therapy for depression and the prompt resolution of the same on its discontinuation on two separate occasions. SSRIs may cause upper gastrointestinal (GI) bleeding. Physicians should be aware of the same and should try to rule out previous episodes of upper GI bleed or the presence of other risk factors which might predispose to it before prescribing SSRIs; they should also warn the patients about this potential side effect. Also, the presence of thalassemia trait in the index patient deserves special attention and needs to be explored to see if it might in any way contribute in potentiating this side effect of SSRIs.

  2. Designing Isoform-selective Inhibitors Against Classical HDACs for Effective Anticancer Therapy: Insight and Perspectives from In Silico.

    Science.gov (United States)

    Ganai, Shabir Ahmad

    2018-01-01

    Histone deacetylase inhibitors, the small molecules modulating the biological activity of histone deacetylases are emerging as potent chemotherapeutic agents. Despite their considerable therapeutic benefits in disease models, the lack of isoform specificity culminates in debilitating off target effects, raising serious concerns regarding their applicability. This emphasizes the pressing and unmet medical need of designing isoform selective inhibitors for safe and effective anticancer therapy. Keeping these grim facts in view, the current article sheds light on structural basis of off-targeting. Furthermore, the article discusses extensively the role of in silico strategies such as Molecular Docking, Molecular Dynamics Simulation and Energetically-optimized structure based pharmacophore approach in designing on-target inhibitors against classical HDACs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  3. [Effect of Azospirillum lectins on the Activity of Proteolytic Enzymes and Their Inhibitors in Wheat Seedling Roots].

    Science.gov (United States)

    Alen'kina, S A; Nikitina, V E

    2015-01-01

    The lectins of associative nitrogen-fixing strains Azospirillum brasilense Sp7 and Sp245 were shown to exerte a multidirectional effect on the activity of acidic (pH 3.5), neutral (6.8), and alkaline (pH 7.8) proteinases. The lectin of the epiphytic A. brasilense Sp7 decreased proteolytic activity at all pH values, whereas the lectin of the endophytic A. brasilense Sp245 activated neutral and alkaline proteinases, while not affecting the alkaline ones. Experiments with protease inhibitors made it possible to conclude that the lectins of the studied A. brasilense strains alter the ratio between the activities of different protease types in germinating seeds. The activity of trypsin inhibitors in wheat seedling roots was found to increase in the presence of the lectins. Our results indicate a broader spectrum of effects of azospirilla lectins on the host plant organism.

  4. The outcome of clinical parameters in adults with severe Type I Gaucher disease using very low dose enzyme replacement therapy.

    Science.gov (United States)

    Wilson, Callum; Spearing, Ruth; Teague, Lochie; Robertson, Patsy; Blacklock, Hilary

    2007-01-01

    Enzyme replacement therapy is now well established as the treatment of choice in Type I Gaucher disease. Historically higher dosage regimens have been used in preference to lower doses despite the little clinical evidence in the way of large controlled clinical trials to support this. Moreover, the extraordinary cost of therapy means that not all eligible patients are able to be treated at the higher dose. Twelve type I adult patients with relatively severe disease were commenced on a very low dose of 7.5U of alglucerase/imiglucerase per kg every two weeks (initially given thrice weekly and later weekly). Follow-up 5 year data reveal a good visceral and haematological response with outcomes consistent with recently published treatment guidelines. Satisfactory clinical and radiological skeletal improvement was also demonstrated in most patients. Three patients had an inadequate overall skeletal response to therapy. Biomarkers also steadily improved although perhaps not quite at the same rate as that seen in higher doses. Very low dose enzyme replacement therapy may be appropriate for adult type I Gaucher patients with mild-moderate skeletal disease.

  5. Potential inhibitors of dapE and argE enzymes as the new antimicrobial agents: Synthesis and characterization

    Czech Academy of Sciences Publication Activity Database

    Hlaváček, Jan; Pícha, Jan; Vaněk, Václav; Jiráček, Jiří; Slaninová, Jiřina; Fučík, Vladimír; Holz, R. C.

    2008-01-01

    Roč. 14, č. 8 (2008), s. 83-84 ISSN 1075-2617. [European Peptide Symposium /30./. 31.08.2008-05.09.2008, Helsinki] R&D Projects: GA AV ČR IAA400550614 Institutional research plan: CEZ:AV0Z40550506 Keywords : antimicrobial agents * dapE and argE inhibitors * synthesis and activity Subject RIV: CC - Organic Chemistry

  6. The role of lipid and carbohydrate digestive enzyme inhibitors in the management of obesity: a review of current and emerging therapeutic agents

    Directory of Open Access Journals (Sweden)

    Tucci S

    2010-05-01

    Full Text Available Sonia A Tucci, Emma J Boyland, Jason CG HalfordKissileff Laboratory for the Study of Human Ingestive Behaviour, School of Psychology, University of Liverpool, Liverpool, UKAbstract: Obesity is a global epidemic associated with significant morbidity and mortality in adults and ill health in children. A proven successful approach in weight management has been the disruption of nutrient digestion, with orlistat having been used to treat obesity for the last 10 years. Although orlistat-induced weight loss remains modest, it produces meaningful reductions in risk factors for obesity-related conditions such as diabetes and cardiovascular disease. Moreover, this lipase inhibitor is free of the serious side effects that have dogged appetite-suppressing drugs. This success had driven investigation into new generation nutraceuticals, supplements and pharmaceutical agents that inhibit the breakdown of complex carbohydrates and fats within the gut. This review focuses on agents purported to inhibit intestinal enzymes responsible for macronutrient digestion. Except for some synthetic products, the majority of agents reviewed are either botanical extracts or bacterial products. Currently, carbohydrate digestion inhibitors are under development to improve glycemic control and these may also induce some weight loss. However, colonic fermentation induced side effects, such as excess gas production, remain an issue for these compounds. The α-glucosidase inhibitor acarbose, and the α-amylase inhibitor phaseolamine, have been used in humans with some promising results relating to weight loss. Nonetheless, few of these agents have made it into clinical studies and without any clinical proof of concept or proven efficacy it is unlikely any will enter the market soon.Keywords: lipase, amylase, saccharidases, overweight, orlistat, Alli®, digestion, body weight

  7. Elafin, an elastase-specific inhibitor, is cleaved by its cognate enzyme neutrophil elastase in sputum from individuals with cystic fibrosis.

    LENUS (Irish Health Repository)

    Guyot, Nicolas

    2008-11-21

    Elafin is a neutrophil serine protease inhibitor expressed in lung and displaying anti-inflammatory and anti-bacterial properties. Previous studies demonstrated that some innate host defense molecules of the cystic fibrosis (CF) and chronic obstructive pulmonary disease airways are impaired due to increased proteolytic degradation observed during lung inflammation. In light of these findings, we thus focused on the status of elafin in CF lung. We showed in the present study that elafin is cleaved in sputum from individuals with CF. Pseudomonas aeruginosa-positive CF sputum, which was found to contain lower elafin levels and higher neutrophil elastase (NE) activity compared with P. aeruginosa-negative samples, was particularly effective in cleaving recombinant elafin. NE plays a pivotal role in the process as only NE inhibitors are able to inhibit elafin degradation. Further in vitro studies demonstrated that incubation of recombinant elafin with excess of NE leads to the rapid cleavage of the inhibitor. Two cleavage sites were identified at the N-terminal extremity of elafin (Val-5-Lys-6 and Val-9-Ser-10). Interestingly, purified fragments of the inhibitor (Lys-6-Gln-57 and Ser-10-Gln-57) were shown to still be active for inhibiting NE. However, NE in excess was shown to strongly diminish the ability of elafin to bind lipopolysaccharide (LPS) and its capacity to be immobilized by transglutamination. In conclusion, this study provides evidence that elafin is cleaved by its cognate enzyme NE present at excessive concentration in CF sputum and that P. aeruginosa infection promotes this effect. Such cleavage may have repercussions on the innate immune function of elafin.

  8. Renal function predicts long-term outcome on enzyme replacement therapy in patients with Fabry disease.

    Science.gov (United States)

    Lenders, Malte; Schmitz, Boris; Stypmann, Jörg; Duning, Thomas; Brand, Stefan-Martin; Kurschat, Christine; Brand, Eva

    2017-12-01

    Renal and cardiac involvement is responsible for substantial morbidity and mortality in Fabry disease (FD). We analysed the incidence of FD-related renal, cardiac and neurologic end points in patients with FD on long-term enzyme replacement therapy (ERT). A retrospective analysis of prospectively collected data from two German FD centres was performed. The impact of renal and cardiac function at ERT-naïve baseline on end point development despite ERT was analysed. Fifty-four patients (28 females) receiving ERT (mean 81 ± 21 months) were investigated. Forty per cent of patients were diagnosed with clinical end points before ERT initiation and 50% of patients on ERT developed new clinical end points. In patients initially diagnosed with an end point before ERT initiation, the risk for an additional end point on ERT was increased {hazard ratio [HR] 3.83 [95% confidence interval (CI) 1.61-9.08]; P = 0.0023}. A decreased glomerular filtration rate (eGFR) ≤75 mL/min/1.73 m2 in ERT-naïve patients at baseline was associated with an increased risk for cardiovascular end points [HR 3.59 (95% CI 1.15-11.18); P = 0.0273] as well as for combined renal, cardiac and neurologic end points on ERT [HR 4.77 (95% CI 1.93-11.81); P = 0.0007]. In patients with normal kidney function, left ventricular hypertrophy at baseline predicted a decreased end point-free survival [HR 6.90 (95% CI 2.04-23.27); P = 0.0018]. The risk to develop an end point was independent of sex. In addition to age, even moderately impaired renal function determines FD progression on ERT. In patients with FD, renal and cardiac protection is warranted to prevent patients from deleterious manifestations of the disease. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

  9. Comparing exercise responses to aerobic plus resistance training between postmenopausal breast cancer survivors undergoing aromatase inhibitor therapy and healthy women.

    Science.gov (United States)

    Paulo, Thais R S de; Winters-Stone, Kerri M; Viezel, Juliana; Rossi, Fabricio E; Aro, Bruna L; Trindade, Ana Carolina A C; Codogno, Jamile S; Freitas Junior, Ismael F

    2018-04-12

    The aim of this study was to explore whether postmenopausal breast cancer survivors undergoing aromatase inhibitor therapy differ from healthy postmenopausal women in their response to the same aerobic + resistance training. The participants were separated into two groups: postmenopausal breast cancer survivors undergoing aromatase inhibitor therapy for an average of 20 months (18 women) and healthy postmenopausal women (24 women). We assessed aerobic capacity (predicted maximum oxygen uptake (VO 2 max) and maximum running velocity test (Vmax)) through a walking test, upper and lower body muscle strength using an estimated one-repetition maximum test, and body composition by dual-energy X-ray absorptiometry at baseline and at three, six, and nine months, respectively. The exercise program was performed three times/week over nine months and consisted of 40 min of machine-based strength training (seated cable row, bench press, leg extension, leg press, and leg curl, as well as bridge, abdominal, and standard plank exercises) followed by 30 min of treadmill walking. Analysis of variance (ANOVA) with repeated measures was used to compare the groups over time. Postmenopausal breast cancer survivors undergoing aromatase inhibitor therapy and healthy postmenopausal women presented similar improvements in estimated lower body strength, predicted VO 2max and V max , and body fat mass. For maximal upper body strength, there was a significant group x time interaction after six months of training (p = 0.01). The healthy postmenopausal women presented a significant increase in upper body strength after six months, while postmenopausal breast cancer survivors undergoing aromatase inhibitor therapy demonstrated an improvement only at nine months of training. The breast cancer survivors undergoing aromatase inhibitor therapy presented increased lean mass while healthy postmenopausal women maintained values over time (Breast cancer: 33.7 ± 3.9(Pre) vs. 34.1

  10. The Kunitz-protease inhibitor domain in amyloid precursor protein reduces cellular mitochondrial enzymes expression and function.

    Science.gov (United States)

    Chua, Li-Min; Lim, Mei-Li; Wong, Boon-Seng

    2013-08-09

    Mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD) and this can be contributed by aberrant metabolic enzyme function. But, the mechanism causing this enzymatic impairment is unclear. Amyloid precursor protein (APP) is known to be alternatively spliced to produce three major isoforms in the brain (APP695, APP751, APP770). Both APP770 and APP751 contain the Kunitz Protease Inhibitory (KPI) domain, but the former also contain an extra OX-2 domain. APP695 on the other hand, lacks both domains. In AD, up-regulation of the KPI-containing APP isoforms has been reported. But the functional contribution of this elevation is unclear. In the present study, we have expressed and compared the effect of the non-KPI containing APP695 and the KPI-containing APP751 on mitochondrial function. We found that the KPI-containing APP751 significantly decreased the expression of three major mitochondrial metabolic enzymes; citrate synthase, succinate dehydrogenase and cytochrome c oxidase (COX IV). This reduction lowers the NAD(+)/NADH ratio, COX IV activity and mitochondrial membrane potential. Overall, this study demonstrated that up-regulation of the KPI-containing APP isoforms is likely to contribute to the impairment of metabolic enzymes and mitochondrial function in AD. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. COMPARING THE ENZYME REPLACEMENT THERAPY COST IN POST PANCREATECTOMY PATIENTS DUE TO PANCREATIC TUMOR AND CHRONIC PANCREATITIS

    Directory of Open Access Journals (Sweden)

    Anna Victoria FRAGOSO

    Full Text Available ABSTRACT Background - Among late postoperative complications of pancreatectomy are the exocrine and endocrine pancreatic insufficiencies. The presence of exocrine pancreatic insufficiency imposes, as standard treatment, pancreatic enzyme replacement. Patients with chronic pancreatitis, with intractable pain or any complications with surgical treatment, are likely to present exocrine pancreatic insufficiency or have this condition worsened requiring adequate dose of pancreatic enzymes. Objective - The aim of this study is to compare the required dose of pancreatic enzyme and the enzyme replacement cost in post pancreatectomy patients with and without chronic pancreatitis. Methods - Observational cross-sectional study. In the first half of 2015 patients treated at the clinic of the Department of Gastrointestinal Surgery at Hospital das Clínicas, Universidade de São Paulo, Brazil, who underwent pancreatectomy for at least 6 months and in use of enzyme replacement therapy were included in this series. The study was approved by the Research Ethics Committee. The patients were divided into two groups according to the presence or absence of chronic pancreatitis prior to pancreatic surgery. For this study, P<0.05 was considered statistically significant. Results - The annual cost of the treatment was R$ 2150.5 ± 729.39; R$ 2118.18 ± 731.02 in patients without pancreatitis and R$ 2217.74 ± 736.30 in patients with pancreatitis. Conclusion - There was no statistically significant difference in the cost of treatment of enzyme replacement post pancreatectomy in patients with or without chronic pancreatitis prior to surgical indication.

  12. Negative Impact of Testosterone Deficiency and 5α-Reductase Inhibitors Therapy on Metabolic and Sexual Function in Men.

    Science.gov (United States)

    Traish, Abdulmaged M

    2017-01-01

    elevated activities of liver function enzymes concomitant with reduction in circulating T levels, worsening erectile dysfunction (ED), and reduced quality of life.Although we have attempted to summarize the current literature pertaining to this critical topic "androgen deficiency" and its impact on men's health and quality of life, there remain many gaps in the knowledge regarding the biochemical pathways that are involved in the pathophysiology of androgen deficiency. We wish to clearly state that there are areas of controversies, including whether age-related androgen deficiency (functional hypogonadism) merits treatment and whether T therapy provided real proven benefits. Finally, considerable debate exists with respect to the potential and purported cardiovascular (CV) risks of treating TD with exogenous T. For brevity sake, we will not discuss in detail the benefits of T therapy in men with TD since this topic is comprehensively covered by Dr. F. Saad's chapter in this book, entitled "Testosterone Therapy and Glucose Homeostasis in Men with Testosterone Deficiency (Hypogonadism)."We have made a concerted effort to address the controversy of T therapy in men with TD in the discussion. However, we wish to acknowledge that these issues will remain a matter of debate for some time to come. Only with advances in fundamental basic science and clinical research, some of these controversial issues may be laid to rest. Nevertheless, we believe that there is considerable body of credible evidence to suggest that T therapy of men with TD is safe and effective and provides a host of health benefits and therefore merits considerations in men with TD, irrespective of the underlying cause or etiology. An additional aspect of androgen deficiency is the drug-induced reduction in 5α-DHT levels by the use of 5α-reductase inhibitors. We also believe that physicians prescribing 5α-reductase inhibitors (i.e., finasteride or dutasteride) for relief of BPH symptoms or treatment of

  13. Risk Factors for New Hypothyroidism During Tyrosine Kinase Inhibitor Therapy in Advanced Nonthyroidal Cancer Patients.

    Science.gov (United States)

    Lechner, Melissa G; Vyas, Chirag M; Hamnvik, Ole-Petter R; Alexander, Erik K; Larsen, P Reed; Choueiri, Toni K; Angell, Trevor E

    2018-04-01

    Thyroid dysfunction during tyrosine kinase inhibitor (TKI) cancer treatment is common, but predisposing risk factors have not been determined. Recommendations for monitoring patients treated with one or multiple TKI and in conjunction with other relevant cancer therapies could be improved. The study objective was to assess the risk factors for new thyroid dysfunction in TKI-treated previously euthyroid cancer patients. A retrospective cohort study of patients with advanced nonthyroidal cancer treated with TKI from 2000 to 2017, having available thyroid function tests showing initial euthyroid status, excluding patients with preexisting thyroid disease or lack of follow-up thyroid function tests. During TKI treatment, patients were classified as euthyroid (thyrotropin [TSH] normal), subclinical hypothyroidism (TSH 5-10 mIU/L, or higher TSH if free thyroxine normal), or overt hypothyroidism (TSH >10 mIU/L, low free thyroxine, or requiring thyroid hormone replacement). The timing of thyroid dysfunction and TKI used were assessed. Risk factors for incident hypothyroidism were evaluated using multivariate models. In 538 adult patients included, subclinical hypothyroidism occurred in 71 (13.2%) and overt hypothyroidism occurred in 144 (26.8%) patients with TKI therapy, following a median cumulative TKI exposure of 196 days (interquartile range [IQR] 63.5-518.5 days). The odds of hypothyroidism were greatest during the first six months on a TKI. Median exposure time on the TKI concurrent with thyroid dysfunction in patients treated with only one TKI was 85 days (IQR 38-293.5 days) and was similar to the 74 days (IQR 38-133.3 days) in patients treated previously with other TKI (p = 0.41). Patients who developed hypothyroidism compared to those who remained euthyroid had greater odds of being female (odds ratio = 1.99 [confidence interval 1.35-2.93], p < 0.01), but greater cumulative TKI exposure and greater number of TKI received were not associated with

  14. Functional response to cholinesterase inhibitor therapy in a naturalistic Alzheimer’s disease cohort

    Directory of Open Access Journals (Sweden)

    Wattmo Carina

    2012-11-01

    Full Text Available Abstract Background Activities of daily living (ADL are an essential part of the diagnostic criteria for Alzheimer’s disease (AD. A decline in ADL affects independent living and has a strong negative impact on caregiver burden. Functional response to cholinesterase inhibitor (ChEI treatment and factors that might influence this response in naturalistic AD patients need investigating. The aim of this study was to identify the socio-demographic and clinical factors that affect the functional response after 6 months of ChEI therapy. Methods This prospective, non-randomised, multicentre study in a routine clinical setting included 784 AD patients treated with donepezil, rivastigmine or galantamine. At baseline and after 6 months of treatment, patients were assessed using several rating scales, including the Instrumental Activities of Daily Living (IADL scale, Physical Self-Maintenance Scale (PSMS and Mini-Mental State Examination (MMSE. Demographic and clinical characteristics were investigated at baseline. The functional response and the relationships of potential predictors were analysed using general linear models. Results After 6 months of ChEI treatment, 49% and 74% of patients showed improvement/no change in IADL and in PSMS score, respectively. The improved/unchanged patients exhibited better cognitive status at baseline; regarding improved/unchanged PSMS, patients were younger and used fewer anti-depressants. A more positive functional response to ChEI was observed in younger individuals or among those having the interaction effect of better preserved cognition and lower ADL ability. Patients with fewer concomitant medications or those using NSAIDs/acetylsalicylic acid showed a better PSMS response. Conclusions Critical characteristics that may influence the functional response to ChEI in AD were identified. Some predictors differed from those previously shown to affect cognitive response, e.g., lower cognitive ability and older age

  15. Molecular docking and 3D-QSAR studies on inhibitors of DNA damage signaling enzyme human PARP-1.

    Science.gov (United States)

    Fatima, Sabiha; Bathini, Raju; Sivan, Sree Kanth; Manga, Vijjulatha

    2012-08-01

    Poly (ADP-ribose) polymerase-1 (PARP-1) operates in a DNA damage signaling network. Molecular docking and three dimensional-quantitative structure activity relationship (3D-QSAR) studies were performed on human PARP-1 inhibitors. Docked conformation obtained for each molecule was used as such for 3D-QSAR analysis. Molecules were divided into a training set and a test set randomly in four different ways, partial least square analysis was performed to obtain QSAR models using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Derived models showed good statistical reliability that is evident from their r², q²(loo) and r²(pred) values. To obtain a consensus for predictive ability from all the models, average regression coefficient r²(avg) was calculated. CoMFA and CoMSIA models showed a value of 0.930 and 0.936, respectively. Information obtained from the best 3D-QSAR model was applied for optimization of lead molecule and design of novel potential inhibitors.

  16. CRA-024781: a novel synthetic inhibitor of histone deacetylase enzymes with antitumor activity in vitro and in vivo.

    Science.gov (United States)

    Buggy, Joseph J; Cao, Z Alexander; Bass, Kathryn E; Verner, Erik; Balasubramanian, Sriram; Liu, Liang; Schultz, Brian E; Young, Peter R; Dalrymple, Stacie A

    2006-05-01

    CRA-024781 is a novel, broad spectrum hydroxamic acid-based inhibitor of histone deacetylase (HDAC) that shows antitumor activity in vitro and in vivo preclinically and is under evaluation in phase I clinical trials for cancer. CRA-024781 inhibited pure recombinant HDAC1 with a K(i) of 0.007 mumol/L, and also inhibited the other HDAC isozymes HDAC2, HDAC3/SMRT, HDAC6, HDAC8, and HDAC10 in the nanomolar range. Treatment of cultured tumor cell lines grown in vitro with CRA-024781 resulted in the accumulation of acetylated histone and acetylated tubulin, resulting in an inhibition of tumor cell growth and the induction of apoptosis. CRA-024781 parenterally administered to mice harboring HCT116 or DLD-1 colon tumor xenografts resulted in a statistically significant reduction in tumor growth at doses that were well tolerated as measured by body weight. Inhibition of tumor growth was accompanied by an increase in the acetylation of alpha-tubulin in peripheral blood mononuclear cells, and an alteration in the expression of many genes in the tumors, including several involved in apoptosis and cell growth. These results reveal CRA-024781 to be a novel HDAC inhibitor with potent antitumor activity.

  17. In-silico design of novel myocilin inhibitors for glaucoma therapy ...

    African Journals Online (AJOL)

    Purpose: To explore newer computational approaches in the design of novel myocilin inhibitors for the treatment of glaucoma. Methods: An in-silico virtual screening technique based on simulation of molecular docking was utilised to design a novel myocilin inhibitors for the treatment of glaucoma. The designed novel ...

  18. Association of insertion/deletion polymorphism of angiotensin-converting enzyme gene among Malay male hypertensive subjects in response to ACE inhibitors.

    Science.gov (United States)

    Heidari, Farzad; Vasudevan, Ramachandran; Mohd Ali, Siti Zubaidah; Ismail, Patimah; Etemad, Ali; Pishva, Seyyed Reza; Othman, Fauziah; Abu Bakar, Suhaili

    2015-12-01

    Several studies show that the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been associated with hypertension in various populations. The present study sought to determine the association of the I/D gene polymorphism among Malay male essential hypertensive subjects in response to ACE inhibitors (enalapril and lisinopril). A total of 72 patients with newly diagnosed hypertension and 72 healthy subjects were recruited in this study. Blood pressure was recorded from 0 to 24 weeks of treatment with enalapril or lisinopril. Genotyping of the I/D polymorphism was carried out using a standard PCR method. Statistically significant association of the D allele of the ACE gene was observed between the case and control subjects (p ACE gene. Patients carrying the DD genotype had higher blood pressure-lowering response when treated with ACE inhibitors enalapril or lisinopril than those carrying ID and II genotypes, suggesting that the D allele may be a possible genetic marker for essential hypertension among Malay male subjects. © The Author(s) 2014.

  19. TMG-chitotriomycin, an enzyme inhibitor specific for insect and fungal beta-N-acetylglucosaminidases, produced by actinomycete Streptomyces anulatus NBRC 13369.

    Science.gov (United States)

    Usuki, Hirokazu; Nitoda, Teruhiko; Ichikawa, Misato; Yamaji, Nahoko; Iwashita, Takashi; Komura, Hajime; Kanzaki, Hiroshi

    2008-03-26

    A novel beta-N-acetylglucosaminidase (GlcNAcase) inhibitor named TMG-chitotriomycin (1) was isolated from the culture filtrate of Streptomyces anulatus NBRC13369. The strain produced 1 only when colloidal chitin was used as the sole carbon source in the production medium. The structure of 1 was determined by spectral and constitutive sugar analyses of the corresponding alditol derivatives to be an equilibrated mixture of alpha-d-N,N,N-triMeGlcNH2-(1,4)-beta-d-GlcNAc-(1,4)-beta-d-GlcNAc-(1,4)-d-GlcNAc and its C-2 epimer of the reducing end residue. TMG-chitotriomycin (1) showed potent and selective inhibition of insect and fungal GlcNAcases with no inhibition of mammalian and plant GlcNAcases. In contrast, the known GlcNAcase inhibitor nagstatin potently inhibited all GlcNAcases. It should be emphasized that synthesized d-N,N,N-triMeGlcNH2, which is the component sugar of 1, showed no inhibition of the insect Spodoptera litura GlcNAcase. These results suggest that the (GlcNAc)3 unit positioned at the reducing end of 1 is essential for its enzyme inhibitory activity. The unique inhibitory spectrum of 1 will be useful to study chitinolytic systems and to develop selective fungicides or pesticides.

  20. Crystal structure of the N domain of human somatic angiotensin I-converting enzyme provides a structural basis for domain-specific inhibitor design.

    Science.gov (United States)

    Corradi, Hazel R; Schwager, Sylva L U; Nchinda, Aloysius T; Sturrock, Edward D; Acharya, K Ravi

    2006-03-31

    Human somatic angiotensin I-converting enzyme (sACE) is a key regulator of blood pressure and an important drug target for combating cardiovascular and renal disease. sACE comprises two homologous metallopeptidase domains, N and C, joined by an inter-domain linker. Both domains are capable of cleaving the two hemoregulatory peptides angiotensin I and bradykinin, but differ in their affinities for a range of other substrates and inhibitors. Previously we determined the structure of testis ACE (C domain); here we present the crystal structure of the N domain of sACE (both in the presence and absence of the antihypertensive drug lisinopril) in order to aid the understanding of how these two domains differ in specificity and function. In addition, the structure of most of the inter-domain linker allows us to propose relative domain positions for sACE that may contribute to the domain cooperativity. The structure now provides a platform for the design of "domain-specific" second-generation ACE inhibitors.

  1. The renoprotective effect of angiotensin-converting enzyme inhibitors in experimental chronic renal failure is not dependent on enhanced kinin activity.

    Science.gov (United States)

    Nabokov, A; Amann, K; Gassmann, P; Schwarz, U; Orth, S R; Ritz, E

    1998-01-01

    Angiotensin-converting enzyme (ACE) inhibitors have been shown to ameliorate the progression of glomerulosclerosis both in experimental models of uraemia and in patients with renal failure. It has not been documented, however, whether this is due to a decrease in angiotensin II generation or is a consequence of elevated local level of bradykinin. Morphometric investigation of renal tissue was performed in 5/6 nephrectomized (SNx) rats, i.e. untreated or treated with the ACE inhibitor ramipril (SNx-RAM), the B2 kinin receptor antagonist HOE 140 (SNx-HOE), or a combination of both (SNx-RAM + HOE) over 8 weeks. A further group of SNx received delayed treatment with ramipril from week 5 onward (SNx-RAMD). In addition, a sham-operated (SHAM) control group was studied. Systolic blood pressure was significantly lower in both SNx-RAM and SNx-RAM + HOE groups compared to (untreated) SNx. The glomerulosclerosis index (GSI) was substantially higher in the (untreated) SNx group (0.24 +/- 0.04) vs SHAM (0.02 +/- 0.01). A significantly higher GSI was found in the SNx-HOE group (0.45 +/- 0.08) as compared to (untreated) SNx. However, in the SNx-RAM, SNx-RAM + HOE, and SNx-RAMD groups, the GSI was lowered to a similar extent (0.1 +/- 0.02, 0.09 +/- 0.02, and 0.07 +/- 0.01 respectively). In addition, a concomitant attenuation of tubulointerstitial damage was noted in all the above groups. Increased kinin activity does not appear to play a major role in the renoprotective effect of ACE inhibitors in the remnant kidney model.

  2. The effect of haem biosynthesis inhibitors and inducers on intestinal iron absorption and liver haem biosynthetic enzyme activities

    International Nuclear Information System (INIS)

    Laftah, A.H.; Simpson, R.J.; Peters, T.J.; Raja, K.B.

    2008-01-01

    The relation between haem biosynthesis and intestinal iron absorption is not well understood, we therefore investigated the effect of compounds that alter haem metabolism on duodenal iron absorption. CD1 mice were treated with either an inhibitor (succinyl acetone (SA)) or stimulator (2-allyl-2-isopropylacetamide (AIA)) of haem biosynthesis. 5-Aminolaevulinic acid (ALA) dehydratase and urinary ALA and porphobilinogen (PBG) levels, were determined. Intestinal iron absorption was assayed with in vivo and in vitro techniques. Liver hepcidin (Hamp1) and duodenal iron transporter mRNA levels were measured using RT-PCR. AIA caused increased hepatic ALA synthase (1.6-fold) and ALA dehydratase (1.4-fold, both p < 0.005) activities and increased urinary ALA and PBG excretion (2.1- and 1.4-fold, p < 0.005, p < 0.05, respectively). In vivo intestinal iron absorption was reduced to 49% of control (p < 0.005). Mice treated with SA showed decreased urinary ALA and PBG levels (75 and 55% control, both p < 0.005) and reductions in both ALA synthase and ALA dehydratase activities (77 and 56% control, p < 0.05, p < 0.005, respectively) in the liver. Liver and duodenal haem and cytochrome oxidase levels were not significantly decreased. Iron absorption was enhanced (1.26-fold, p < 0.05) and hepatic Hamp1 mRNA was reduced (53% of control, p < 0.05). In vitro duodenal iron uptake after mice were injected with SA also demonstrated an increase in Fe(III) reduction and uptake (1.27- and 1.41-fold, p < 0.01 respectively). Simultaneous injections of SA and ALA blocked the enhancing effect on iron absorption seen with SA alone. We conclude that alterations in haem biosynthesis can influence iron absorption and in particular, the intermediate ALA seems to be an inhibitor of iron absorption

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

    DEFF Research Database (Denmark)

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

    2000-01-01

    (and for none of 1,556 patients in the one other eligible trial). RESULTS: Overall 30-day mortality was 7.1% among patients allocated to ACEi and 7.6% among those allocated to control, corresponding to a 7% (standard deviation [SD], 2%) proportional reduction (95% confidence interval 2% to 11%, p = 0...... = 0.4; p = 0.5). Angiotensin-converting enzyme inhibitor produced definite increases in the incidence of persistent hypotension (17.9% ACEi vs. 9.4% control) and of renal dysfunction (1.3% ACEi vs. 0.6% control), but there was no good evidence that these effects were different in the presence...

  4. In vitro and in vivo evaluations of a radioiodinated thymidine phosphorylase inhibitor as a tumor diagnostic agent for angiogenic enzyme imaging

    International Nuclear Information System (INIS)

    Akizawa, Hiromichi; Zhao, Songji; Takahashi, Masayuki; Nishijima, Ken-ichi; Kuge, Yuji; Tamaki, Nagara; Seki, Koh-ichi; Ohkura, Kazue

    2010-01-01

    Introduction: The expression of thymidine phosphorylase (TP) is closely associated with angiogenesis, tumor invasiveness and activation of antitumor agents. We evaluated radioiodinated 5-iodo-6-[(2-iminoimidazolidinyl)methyl]uracil ([ 125 I]IIMU) having high TP-inhibitory potency as the new radiotracer for SPECT targeting of TP expression in tumors. Methods: The characteristics of the radioiodinated TP inhibitor IIMU were determined by evaluating the uptake by tumor cells in vitro and by biodistribution studies in vivo. The distribution of the radiotracer and the extent of TP-specific uptake by tumors were evaluated by a counting method in tumor-bearing mice. Results: The in vitro uptake of radiolabeled IIMU by A431 cells along with high TP expressions was attributed to the binding of the radiotracer to its target enzyme, i.e., TP. In vivo distribution of the radiotracer in A431 tumor-bearing mice revealed tumor/blood and tumor/muscle activity uptake ratios of 36 and 106, respectively, at 3 h after the radiotracer injection. On using low TP-expressing tumors and TP blocking studies as controls, minor TP-specific accumulation of the radiotracer was detected in these studies. Conclusion: According to the binding of radioiodinated IIMU to the angiogenic enzyme TP, it can be concluded that radioiodinated IIMU might be suitable as a SPECT tracer for tumor imaging.

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

    Directory of Open Access Journals (Sweden)

    Alberto F Rubio-Guerra

    2009-11-01

    Full Text Available Alberto F Rubio-Guerra1, David Castro-Serna2, Cesar I Elizalde Barrera2, Luz M Ramos-Brizuela21Metabolic and Research Clinic, 2Internal Medicine Department, Hospital General de Ticomán SS DF, MéxicoAbstract: 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.Keywords: hypertension, calcium channel blockers, renin-angiotensin-aldosterone system inhibitors, fixed-dose combination, adherence

  6. Survival, Quality of Life and Effects of Enzyme Replacement Therapy in Adults with Pompe Disease

    NARCIS (Netherlands)

    D. Güngör (Deniz)

    2013-01-01

    textabstractPompe disease, or glycogen storage disorder type II, is a rare inherited metabolic disorder caused by deficiency of the lysosomal enzyme acid α-glucosidase. This results in accumulation of glycogen in cells throughout the body, particularly muscle cells. The disease presents

  7. Enzyme-triggered nanomedicine: Drug release strategies in cancer therapy (Invited Review)

    DEFF Research Database (Denmark)

    Andresen, Thomas Lars; Thompson, David H.; Kaasgaard, Thomas

    2010-01-01

    -based strategies are particularly interesting as they require no prior knowledge of the tumour localization. The basis of this review is an evaluation of the current status of drug delivery strategies focused on triggered drug release by disease-associated enzymes. We limit ourselves to reviewing the liposome...

  8. Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease

    DEFF Research Database (Denmark)

    Hughes, Derralynn A.; Nicholls, Kathleen; Shankar, Suma P.

    2017-01-01

    Background Fabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in α-galactosidase (α-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement t...

  9. Study of the role of epididymal alpha-glucosidase in the fertility of male rats by the administration of the enzyme inhibitor castanospermine.

    Science.gov (United States)

    Yeung, C H; Cooper, T G

    1994-11-01

    The activity of epididymal alpha-glucosidase in adult rats was rapidly suppressed to histochemically undetectable levels within 2 days by the continuous release of the enzyme inhibitor castanospermine via a peritoneal osmotic pump at a rate of 100-200 nmol h-1. It was established that mating activities overnight depleted 72% of the spermatozoa in the distal cauda, which was replenished in 2 days, and that fertility began to decline 3 weeks after efferent duct ligation. Male rats of proven mating proficiency and fertility were treated with castanospermine, or buffered saline as control, for up to 30 days and enzyme inhibition was confirmed at the end of treatment by histochemistry. Fertility was normal at the first mating test on day 7, significantly decreased at the second mating on day 9, but recovered in a stepwise manner at subsequent matings on days 12 and 14. Delaying the third mating until day 25 did not sustain the transient subfertility. However, prolonging sperm storage in the distal cauda epididymides and preventing replenishment with freshly matured spermatozoa, by efferent duct ligation for 14 days performed on day 15 during castanospermine administration, caused a decrease in fertility and a change in the kinematics of epididymal spermatozoa of the castanospermine-treated group. In control rats, binding of epididymal spermatozoa to Vicia faba, a lectin specific for glucose and glucosamine, and mannose and mannosamine residues, decreased from the proximal caput to the distal corpus coincident with the increase in alpha-glucosidase activity on the epithelial brush border. Lectin binding then increased in the cauda where enzyme activity was absent. However, castanospermine treatment did not significantly alter this binding profile. The findings suggest that epididymal alpha-glucosidase does not play a crucial role in the development of sperm fertilizing capacity, but may be involved in the preparation of spermatozoa for storage.

  10. Enzyme kinetics, inhibitors, mutagenesis and electron paramagnetic resonance analysis of dual-affinity nitrate reductase in unicellular N(2)-fixing cyanobacterium Cyanothece sp. PCC 8801.

    Science.gov (United States)

    Wang, Tung-Hei; Chen, Yung-Han; Huang, Jine-Yung; Liu, Kang-Cheng; Ke, Shyue-Chu; Chu, Hsiu-An

    2011-11-01

    The assimilatory nitrate reductase (NarB) of N(2)-fixing cyanobacterium Cyanothece sp. PCC 8801 is a monomeric enzyme with dual affinity for substrate nitrate. We purified the recombinant NarB of Cyanothece sp. PCC 8801 and further investigated it by enzyme kinetics analysis, site-directed mutagenesis, inhibitor kinetics analysis, and electron paramagnetic resonance (EPR) spectroscopy. The NarB showed 2 kinetic regimes at pH 10.5 or 8 and electron-donor conditions methyl viologen or ferredoxin (Fd). Fd-dependent NR assay revealed NarB with very high affinity for nitrate (K(m)1, ∼1μM; K(m)2, ∼270μM). Metal analysis and EPR results showed that NarB contains a Mo cofactor and a [4Fe-4S] cluster. In addition, the R352A mutation on the proposed nitrate-binding site of NarB greatly altered both high- and low-affinity kinetic components. Furthermore, the effect of azide on the NarB of Cyanothece sp. PCC 8801 was more complex than that on the NarB of Synechococcus sp. PCC 7942 with its single kinetic regime. With 1mM azide, the kinetics of the wild-type NarB was transformed from 2 kinetic regimes to hyperbolic kinetics, and its activity was enhanced significantly under medium nitrate concentrations. Moreover, EPR results also suggested a structural difference between the two NarBs. Taken together, our results show that the NarB of Cyanothece sp. PCC 8801 contains only a single Mo-catalytic center, and we rule out that the enzyme has 2 independent, distinct catalytic sites. In addition, the NarB of Cyanothece sp. PCC 8801 may have a regulatory nitrate-binding site. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  11. BRAF and MEK Inhibitors Influence the Function of Reprogrammed T Cells: Consequences for Adoptive T-Cell Therapy

    Directory of Open Access Journals (Sweden)

    Jan Dörrie

    2018-01-01

    Full Text Available BRAF and MEK inhibitors (BRAFi/MEKi, the standard treatment for patients with BRAFV600 mutated melanoma, are currently explored in combination with various immunotherapies, notably checkpoint inhibitors and adoptive transfer of receptor-transfected T cells. Since two BRAFi/MEKi combinations with similar efficacy are approved, potential differences in their effects on immune cells would enable a rational choice for triple therapies. Therefore, we characterized the influence of the clinically approved BRAFi/MEKi combinations dabrafenib (Dabra and trametinib (Tram vs. vemurafenib (Vem and cobimetinib (Cobi on the activation and functionality of chimeric antigen receptor (CAR-transfected T cells. We co-cultured CAR-transfected CD8+ T cells and target cells with clinically relevant concentrations of the inhibitors and determined the antigen-induced cytokine secretion. All BRAFi/MEKi reduced this release as single agents, with Dabra having the mildest inhibitory effect, and Dabra + Tram having a clearly milder inhibitory effect than Vem + Cobi. A similar picture was observed for the upregulation of the activation markers CD25 and CD69 on CAR-transfected T cells after antigen-specific stimulation. Most importantly, the cytolytic capacity of the CAR-T cells was significantly inhibited by Cobi and Vem + Cobi, whereas the other kinase inhibitors showed no effect. Therefore, the combination Dabra + Tram would be more suitable for combining with T-cell-based immunotherapy than Vem + Cobi.

  12. Splenomegaly in myelofibrosis—new options for therapy and the therapeutic potential of Janus kinase 2 inhibitors

    Directory of Open Access Journals (Sweden)

    Randhawa Jasleen

    2012-08-01

    Full Text Available Abstract Splenomegaly is a common sign of primary myelofibrosis (PMF, post-polycythemia vera myelofibrosis (post-PV MF, and post-essential thrombocythemia myelofibrosis (post-ET MF that is associated with bothersome symptoms, which have a significant negative impact on patients’ quality of life. It may also be present in patients with advanced polycythemia vera (PV or essential thrombocythemia (ET. Until recently, none of the therapies used to treat MF were particularly effective in reducing splenomegaly. The discovery of an activating Janus kinase 2 (JAK2 activating mutation (JAK2V617F that is present in almost all patients with PV and in about 50-60 % of patients with ET and PMF led to the initiation of several trials investigating the clinical effectiveness of various JAK2 (or JAK1/JAK2 inhibitors for the treatment of patients with ET, PV, and MF. Some of these trials have documented significant clinical benefit of JAK inhibitors, particularly in terms of regression of splenomegaly. In November 2011, the US Food and Drug Administration approved the use of the JAK1- and JAK2-selective inhibitor ruxolitinib for the treatment of patients with intermediate or high-risk myelofibrosis, including PMF, post-PV MF, and post-ET MF. This review discusses current therapeutic options for splenomegaly associated with primary or secondary MF and the treatment potential of the JAK inhibitors in this setting.

  13. Clinical factors related to the efficacy of tyrosine kinase inhibitor therapy in radioactive iodine refractory recurrent differentiated thyroid cancer patients.

    Science.gov (United States)

    Sugino, Kiminori; Nagahama, Mitsuji; Kitagawa, Wataru; Ohkuwa, Keiko; Uruno, Takashi; Matsuzu, Kenichi; Suzuki, Akifumi; Masaki, Chie; Akaishi, Junko; Hames, Kiyomi Y; Tomoda, Chisato; Ogimi, Yuna; Ito, Koichi

    2018-03-28

    New insights in thyroid cancer biology propelled the development of targeted therapies as salvage treatment for radioiodine-refractory differentiated thyroid cancer (RR-DTC), and the tyrosine kinase inhibitor (TKI) lenvatinib has recently become available as a new line of therapy for RR-DTC. The aim of this study is to investigate clinical factors related to the efficacy of TKI therapy in recurrent RR-DTC patients and identify the optimal timing for the start of TKI therapy. The subjects consisted of 29 patients with progressive RR-DTC, 9 males and 20 females, median age 66 years. A univariate analysis was conducted in relation to progression free survival (PFS) and overall survival (OS) by the Kaplan-Meier method for the following variables: age, sex, histology of the primary tumor, thyroglobulin doubling time before the start of lenvatinib therapy, site of the target lesions, presence of a tumor-mediated symptom at the start of lenvatinib therapy, and baseline tumor size of the target lesions. Median duration of lenvatinib therapy was 14.7 months and median drug intensity was 9.5 mg. At the time of the data cut-off for the analysis, 9 patients (31.0%) have died of their disease (DOD), and a PR (partial response), SD (stable disease), and PD (progressive disease) were observed in 20 patients (69%), 6 patients (20.7%), 3 patients (10.3%), respectively. Univariate analyses showed that the presence of a symptom was the only factor significantly related to poorer PFS and OS. Clinical benefit of TKI therapy will be possibly limited when the therapy starts after tumor-mediated symptoms appear.

  14. Clonal evolution of AML on novel FMS-like tyrosine kinase-3 (FLT3 inhibitor therapy with evolving actionable targets

    Directory of Open Access Journals (Sweden)

    Pashtoon M. Kasi

    2016-01-01

    Full Text Available For acute myeloid leukemia (AML, identification of activating mutations in the FMS-like tyrosine kinase-3 (FLT3 has led to the development of several FLT3-inhibitors. Here we present clinical and next generation sequencing data at the time of progression of a patient on a novel FLT3-inhibitor clinical trial (ASP2215 to show that employing therapeutic interventions with these novel targeted therapies can lead to consequences secondary to selective pressure and clonal evolution of cancer. We describe novel findings alongside data on treatment directed towards actionable aberrations acquired during the process. (Clinical Trial: NCT02014558; registered at: 〈https://clinicaltrials.gov/ct2/show/NCT02014558〉

  15. Photobiomodulation Therapy Decreases Oxidative Stress in the Lung Tissue after Formaldehyde Exposure: Role of Oxidant/Antioxidant Enzymes

    Directory of Open Access Journals (Sweden)

    Rodrigo Silva Macedo

    2016-01-01

    Full Text Available Formaldehyde is ubiquitous pollutant that induces oxidative stress in the lung. Several lung diseases have been associated with oxidative stress and their control is necessary. Photobiomodulation therapy (PBMT has been highlighted as a promissory treatment, but its mechanisms need to be better investigated. Our objective was to evaluate the effects of PBMT on the oxidative stress generated by FA exposure. Male Wistar rats were submitted to FA exposure of 1% or vehicle (3 days and treated or not with PBMT (1 and 5 h after each FA exposure. Rats treated only with laser were used as control. Twenty-four hours after the last FA exposure, we analyzed the effects of PBMT on the generation of nitrites and hydrogen peroxide, oxidative burst, glutathione reductase, peroxidase, S-transferase enzyme activities, the gene expression of nitric oxide, cyclooxygenase, superoxide dismutase, the catalase enzyme, and heme oxygenase-1. PBMT reduced the generation of nitrites and hydrogen peroxide and increased oxidative burst in the lung cells. A decreased level of oxidant enzymes was observed which were concomitantly related to an increased level of antioxidants. This study provides new information about the antioxidant mechanisms of PBMT in the lung and might constitute an important tool for lung disease treatment.

  16. Comparative impact of AAV and enzyme replacement therapy on respiratory and cardiac function in adult Pompe mice

    Directory of Open Access Journals (Sweden)

    Darin J Falk

    Full Text Available Pompe disease is an autosomal recessive genetic disorder characterized by a deficiency of the enzyme responsible for degradation of lysosomal glycogen (acid α-glucosidase (GAA. Cardiac dysfunction and respiratory muscle weakness are primary features of this disorder. To attenuate the progressive and rapid accumulation of glycogen resulting in cardiorespiratory dysfunction, adult Gaa−/− mice were administered a single systemic injection of rAAV2/9-DES-hGAA (AAV9-DES or bimonthly injections of recombinant human GAA (enzyme replacement therapy (ERT. Assessment of cardiac function and morphology was measured 1 and 3 months after initiation of treatment while whole-body plethysmography and diaphragmatic contractile function was evaluated at 3 months post-treatment in all groups. Gaa−/− animals receiving either AAV9-DES or ERT demonstrated a significant improvement in cardiac function and diaphragmatic contractile function as compared to control animals. AAV9-DES treatment resulted in a significant reduction in cardiac dimension (end diastolic left ventricular mass/gram wet weight; EDMc at 3 months postinjection. Neither AAV nor ERT therapy altered minute ventilation during quiet breathing (eupnea. However, breathing frequency and expiratory time were significantly improved in AAV9-DES animals. These results indicate systemic delivery of either strategy improves cardiac function but AAV9-DES alone improves respiratory parameters at 3 months post-treatment in a murine model of Pompe disease.

  17. [Effect of components and some protocols of anti-ulcer therapy on content and activity of monooxigenase system enzymes of the stomach mucosa in experimental stomach ulcer].

    Science.gov (United States)

    Iakubov, A V; Pattakhova, M Kh

    2009-01-01

    The influence of components and some schemata of antiulcerous therapy on content and activity of monooxigenase system's enzymes in mucous membrane of stomach are studied on the model of experimental stomach ulcer in rats. It is established, that among components of antiulcerous therapy such as omeprazole, clarithromycin and metronidazole inhibit content and activity of MOS enzymes. Tinidazol, amoxicillin and azithromycin do not affect the function of MOS. Rifampicin and pantoprazole induce enzyme system of monooxigenase. In triple therapy with omeprazole, clarithromycin and metronidazole the inhibit effect of preparations to system of MOS is exponentiated and it leads to suppression of mucous cytoprotaction of gastro duodenal zone. Triple therapy of ulcerous disease with pantoprazole, rifampicin and azithromycin is effective planning to stimulate defense mechanisms of the organism.

  18. Ambulatory blood pressure parameters after canrenone addition to existing treatment regimens with maximum tolerated dose of angiotensin-converting enzyme inhibitors/angiotensin II type 1 receptor blockers plus hydrochlorothiazide in uncontrolled hypertensive patients

    Directory of Open Access Journals (Sweden)

    Guasti L

    2017-08-01

    Full Text Available Luigina Guasti,1,* Giovanni Gaudio,2,* Alessandro Lupi,3 Marinella D’Avino,4 Carla Sala,5,6 Amedeo Mugellini,7 Vito Vulpis,8 Salvatore Felis,9 Riccardo Sarzani,10,11 Massimo Vanasia,12 Pamela Maffioli,7 Giuseppe Derosa7 1Research Center on Dyslipidemia, Internal Medicine 1, University of Insubria, Varese, Italy; 2Internal Medicine Division, Ospedale Angelo Bellini, ASST Valle Olona Somma, Varese, Italy; 3Cardiology Unit, ASL VCO Verbania-Domodossola, Verbania, Italy; 4Unit for the Treatment of Arterial Hypertension, Ospedale Cardarelli, Napoli, Italy; 5Department of Clinical Sciences and Community Health, University of Milan, Milano, Italy; 6Cardiovascular Unit, Fondazione IRCCSS Policlinico, Milano, Italy; 7Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy; 8Unit for the Diagnosis and Treatment of Arterial Hypertension, Department of Internal Medicine, Policlinico di Bari, Bari, Italy; 9Cardiology Unit, Ospedale Garibaldi, Catania, Italy; 10ESH Center of Hypertension, Internal Medicine and Geriatrics, University Politecnica delle Marche, Ancona, Italy; 11IRCCS-INRCA, Ancona, Italy; 12THERABEL GiEnne Pharma, Milano, Italy *These authors contributed equally to this work Background: Blockade of the renin–angiotensin–aldosterone system is a cornerstone in cardiovascular disease prevention and hypertension treatment. The relevance of ambulatory blood pressure monitoring (ABPM has been widely confirmed for both increasing the accuracy of blood pressure (BP measurements, particularly in pharmacological trials, and focusing on 24 h BP prognostic parameters. The aim of this study was to assess the effects of canrenone addition on ambulatory BP in uncontrolled hypertensive patients already treated with the highest tolerated dose of angiotensin-converting enzyme (ACE inhibitors or angiotensin II type 1 receptor (AT1R antagonists plus hydrochlorothiazide (HCT. Methods: ABPM was performed at baseline and after 3

  19. Survival, Quality of Life and Effects of Enzyme Replacement Therapy in Adults with Pompe Disease

    OpenAIRE

    Güngör, Deniz

    2013-01-01

    textabstractPompe disease, or glycogen storage disorder type II, is a rare inherited metabolic disorder caused by deficiency of the lysosomal enzyme acid α-glucosidase. This results in accumulation of glycogen in cells throughout the body, particularly muscle cells. The disease presents with (progressive) muscle weakness and can hence be categorized as a lysosomal storage disorder, a glycogen storage disorder and also a neuromuscular disorder. Pompe disease was the first neuromuscular disorde...

  20. Towards the development of an enzyme replacement therapy for the metabolic disorder propionic acidemia

    Directory of Open Access Journals (Sweden)

    Mahnaz Darvish-Damavandi

    2016-09-01

    Full Text Available Propionic acidemia (PA is a life-threatening disease caused by the deficiency of a mitochondrial biotin-dependent enzyme known as propionyl coenzyme-A carboxylase (PCC. This enzyme is responsible for degrading the metabolic intermediate, propionyl coenzyme-A (PP-CoA, derived from multiple metabolic pathways. Currently, except for drastic surgical and dietary intervention that can only provide partial symptomatic relief, no other form of therapeutic option is available for this genetic disorder. Here, we examine a novel approach in protein delivery by specifically targeting and localizing our protein candidate of interest into the mitochondrial matrix of the cells. In order to test this concept of delivery, we have utilized cell penetrating peptides (CPPs and mitochondria targeting sequences (MTS to form specific fusion PCC protein, capable of translocating and localizing across cell membranes. In vitro delivery of our candidate fusion proteins, evaluated by confocal images and enzymatic activity assay, indicated effectiveness of this strategy. Therefore, it holds immense potential in creating a new paradigm in site-specific protein delivery and enzyme replacement therapeutic for PA.

  1. Updates on the role of adrenal steroidogenesis inhibitors in Cushing's syndrome: a focus on novel therapies.

    Science.gov (United States)

    Fleseriu, Maria; Castinetti, Frederic

    2016-12-01

    Endogenous Cushing's syndrome (CS) is a rare disease that results from exposure to high levels of cortisol; Cushing's disease (CD) is the most frequent form of CS. Patients with CS suffer from a variety of comorbidities that increase the risk of mortality. Surgical resection of the disease-causing lesion is generally the first-line treatment of CS. However, some patients may not be eligible for surgery due to comorbidities, and approximately 25 % of patients, especially those with CD, have recurrent disease. For these patients, adrenal steroidogenesis inhibitors may control cortisol elevation and subsequent symptomatology. CS is rare overall, and clinical studies of adrenal steroidogenesis inhibitors are often small and, in many cases, data are limited regarding the efficacy and safety of these treatments. Our aim was to better characterize the profiles of efficacy and safety of currently available adrenal steroidogenesis inhibitors, including drugs currently in development. We performed a systematic review of the literature regarding adrenal steroidogenesis inhibitors, focusing on novel drugs. Currently available adrenal steroidogenesis inhibitors, including ketoconazole, metyrapone, etomidate, and mitotane, have variable efficacy and significant side effects, and none are approved by the US Food and Drug Administration for CS. Therefore, there is a clear need for novel, prospectively studied agents that have greater efficacy and a low rate of adverse side effects. Efficacy and safety data of current and emerging adrenal steroidogenesis inhibitors, including osilodrostat (LCI699) and levoketoconazole (COR-003), show promising results that will have to be confirmed in larger-scale phase 3 studies (currently ongoing). The management of CS, and particularly CD, remains challenging. Adrenal steroidogenesis inhibitors can be of major interest to control the hypercortisolism at any time point, either before or after surgery, as discussed in this review.

  2. Application of inhibitor JAK1 and JAK2 ruxolitinib as pre- and posttransplant therapy in patients with myelofibrosis

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    M. V. Barabanshchikova

    2016-01-01

    Full Text Available Primary myelofibrosis (PMF is а chronic BCRABL–negative myeloproliferative disorder with progressive clinical course. Allogeneic stem cell transplantation is the only treatment optionin patients with PMF with curative potential. Most of PMF patients have active disease phase at the moment of alloHSCT. The Januskinase inhibitor ruxolitinib is effective in decreasingof tumor mass before alloHSCT. Here we report our experience in administration of ruxolitinib as pre and posttransplant therapy of patients with PMF as well as patients with polycythemia vera and essential thrombocythaemia with transformation into myelofibrosis.

  3. Can Inhibitors of Snake Venom Phospholipases A₂ Lead to New Insights into Anti-Inflammatory Therapy in Humans? A Theoretical Study.

    Science.gov (United States)

    Sales, Thaís A; Marcussi, Silvana; da Cunha, Elaine F F; Kuca, Kamil; Ramalho, Teodorico C

    2017-10-25

    Human phospholipase A₂ ( h PLA₂) of the IIA group (HGIIA) catalyzes the hydrolysis of membrane phospholipids, producing arachidonic acid and originating potent inflammatory mediators. Therefore, molecules that can inhibit this enzyme are a source of potential anti-inflammatory drugs, with different action mechanisms of known anti-inflammatory agents. For the study and development of new anti-inflammatory drugs with this action mechanism, snake venom PLA₂ ( sv PLA₂) can be employed, since the sv PLA₂ has high similarity with the human PLA₂ HGIIA. Despite the high similarity between these secretory PLA₂s , it is still not clear if these toxins can really be employed as an experimental model to predict the interactions that occur with the human PLA₂ HGIIA and its inhibitors. Thus, the present study aims to compare and evaluate, by means of theoretical calculations, docking and molecular dynamics simulations, as well as experimental studies, the interactions of human PLA₂ HGIIA and two sv PLA₂s , Bothrops toxin II and Crotoxin B (BthTX-II and CB, respectively). Our theoretical findings corroborate experimental data and point out that the human PLA₂ HGIIA and sv PLA₂ BthTX-II lead to similar interactions with the studied compounds. From our results, the sv PLA₂ BthTX-II can be used as an experimental model for the development of anti-inflammatory drugs for therapy in humans.

  4. Review of current classification, molecular alterations, and tyrosine kinase inhibitor therapies in myeloproliferative disorders with hypereosinophilia

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    Havelange V

    2013-08-01

    Full Text Available Violaine Havelange,1,2 Jean-Baptiste Demoulin1 1de Duve Institute, Université catholique de Louvain, Brussels, Belgium; 2Department of Hematology, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium Abstract: Recent advances in our understanding of the molecular mechanisms underlying hypereosinophilia have led to the development of a 'molecular' classification of myeloproliferative disorders with eosinophilia. The revised 2008 World Health Organization classification of myeloid neoplasms included a new category called “myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1.” Despite the molecular heterogeneity of PDGFR (platelet-derived growth factor receptor rearrangements, tyrosine kinase inhibitors at low dose induce rapid and complete hematological remission in the majority of these patients. Other kinase inhibitors are promising. Further discoveries of new molecular alterations will direct the development of new specific inhibitors. In this review, an update of the classifications of myeloproliferative disorders associated with hypereosinophilia is discussed together with open and controversial questions. Molecular mechanisms and promising results of tyrosine kinase inhibitor treatments are reviewed. Keywords: hypereosinophilia, classification, myeloproliferative disorders, molecular alterations, tyrosine kinase inhibitor

  5. Inhibition of peripheral aromatization in baboons by an enzyme-activated aromatase inhibitor (MDL 18,962)

    International Nuclear Information System (INIS)

    Longcope, C.; Femino, A.; Johnston, J.O.

    1988-01-01

    The peripheral aromatization ([rho]BM) of androstenedione (A) and testosterone (T) was measured before and after administration of the aromatase inhibitor 10-(2 propynyl)estr-4-ene-3,17-dione (MDL-18,962) to five mature female baboons, Papio annubis. The measurements were made by infusing [3H]androstenedione/[14C]estrone or [3H]testosterone/[14C]estradiol for 3.5 h and collecting blood samples during the infusions and all urine for 96 h from the start of the infusion. Blood samples were analyzed for radioactivity as infused and product steroids, and the data were used to calculate MCRs. An aliquot of the pooled urine was analyzed for the glucuronides of estrone and estradiol and used to calculate the [rho]BM. MDL-18,962 was administered as a pulse in polyethylene glycol-400 (1-5 ml) either iv or via gastric tube 30 min before administration of the radiolabeled steroids. Control studies were done with and without polyethylene glycol-400 administration. When MDL-18,962 was given iv at 4 mg/kg, the aromatization of A was decreased 91.8 +/- 0.9% from the control value of 1.23 +/- 0.13% to 0.11 +/- 0.01%. At the same dose, aromatization of T was decreased 82.0 +/- 7.1%, from a control value of 0.20 +/- 0.03% to 0.037 +/- 0.018%. When MDL-18,962 was given iv at doses of 0.4, 0.1, 0.04, and 0.01 mg/kg, the values for aromatization of A were 0.16 +/- 0.03%, 0.18 +/- 0.06%, 0.37 +/- 11%, and 0.65 +/- 0.09%, respectively. The administration of MDL-18,962 via gastric tube at 4 mg/kg as a pulse decreased the aromatization of A from 1.35 +/- 0.06% to 0.43 +/- 0.12%, an inhibition of 67.2 +/- 10.7%. When administered via gastric tube daily for 5 days at 4 mg/kg, the aromatization of A fell from 1.35 +/- 0.06% to 0.063 +/- 0.003%, an inhibition of 84.4 +/- 0.5%

  6. Rapid intranasal delivery of chloramphenicol acetyltransferase in the active form to different brain regions as a model for enzyme therapy in the CNS.

    Science.gov (United States)

    Appu, Abhilash P; Arun, Peethambaran; Krishnan, Jishnu K S; Moffett, John R; Namboodiri, Aryan M A

    2016-02-01

    The blood brain barrier (BBB) is critical for maintaining central nervous system (CNS) homeostasis by restricting entry of potentially toxic substances. However, the BBB is a major obstacle in the treatment of neurotoxicity and neurological disorders due to the restrictive nature of the barrier to many medications. Intranasal delivery of active enzymes to the brain has therapeutic potential for the treatment of numerous CNS enzyme deficiency disorders and CNS toxicity caused by chemical threat agents. The aim of this work is to provide a sensitive model system for analyzing the rapid delivery of active enzymes into various regions of the brain with therapeutic bioavailability. We tested intranasal delivery of chloramphenicol acetyltransferase (CAT), a relatively large (75kD) enzyme, in its active form into different regions of the brain. CAT was delivered intranasally to anaesthetized rats and enzyme activity was measured in different regions using a highly specific High Performance Thin Layer Chromatography (HP-TLC)-radiometry coupled assay. Active enzyme reached all examined areas of the brain within 15min (the earliest time point tested). In addition, the yield of enzyme activity in the brain was almost doubled in the brains of rats pre-treated with matrix metalloproteinase-9 (MMP-9). Intranasal administration of active enzymes in conjunction with MMP-9 to the CNS is both rapid and effective. The present results suggest that intranasal enzyme therapy is a promising method for counteracting CNS chemical threat poisoning, as well as for treating CNS enzyme deficiency disorders. Published by Elsevier B.V.

  7. A comparative study of the prevalence of hyperkalemia with the use of angiotensin-converting enzyme inhibitors versus angiotensin receptor blockers

    Directory of Open Access Journals (Sweden)

    Seyed Ali Sadjadi

    2009-07-01

    Full Text Available Seyed Ali Sadjadi1, James I McMillan1, Navin Jaipaul1, Patricia Blakely1, Su Su Hline21Section of Nephrology (111N, Jerry L Pettis Memorial Veterans Medical Center, Loma Linda, CA, USA; 2Divison of Nephrology, Loma Linda University Medical Center, Loma Linda, CA, USABackground and objectives: Angiotensin-converting enzyme inhibitors (ACEI and angiotensin receptor blockers (ARB are increasingly used in a variety of settings including heart failure, renal failure, arterial hypertension, and diabetic nephropathy. The objective of this study was to investigate the prevalence of hyperkalemia with ACEI and ARB use, in a population of the United States veterans.Design, settings, material, and measurements: Retrospective observational cohort study of 1163 patients on ACEIs and 1168 patients on ARBs in a single Veterans Affairs Medical Center. Electronic medical records were reviewed over a 12-month period with data collected on various demographic, laboratory, comorbidity, and medication related variables. Results: Hyperkalemia (>5 mEq/L was observed in 20.4% of patients on ACEIs and 31.0% on ARBs. Severe hyperkalemia (6 mEq/L or higher, was observed in 0.8% of ACEI and 2.8% of ARB users. In univariate logistic regression analyses, diabetes mellitus; serum glucose, total carbon dioxide content, creatinine, and estimated glomerular filtration rate (GFR were significantly associated with hyperkalemia. ARB use, when compared to ACEI, was associated with a 42% increase in odds of hyperkalemia (odds ratio [OR] = 1.42; p = 0.001 in a model including adjustment for GFR and a 56% increase in odds of hyperkalemia (OR = 1.56; p < 0.001 in a model including adjustment for serum creatinine.Conclusions: Hyperkalemia, associated with the use of ACEIs and ARBs, is usually mild and severe hyperkalemia is rare. Hyperkalemia is more common with ARBs than ACEIs. ARB use, when compared to ACEI use, may significantly and independently be associated with increased odds of

  8. Potentiation of the actions of bradykinin by angiotensin I-converting enzyme inhibitors. The role of expressed human bradykinin B2 receptors and angiotensin I-converting enzyme in CHO cells.

    Science.gov (United States)

    Minshall, R D; Tan, F; Nakamura, F; Rabito, S F; Becker, R P; Marcic, B; Erdös, E G

    1997-11-01

    Part of the beneficial effects of angiotensin I-converting enzyme (ACE) inhibitors are due to augmenting the actions of bradykinin (BK). We studied this effect of enalaprilat on the binding of [3H]BK to Chinese hamster ovary (CHO) cells stably transfected to express the human BK B2 receptor alone (CHO-3B) or in combination with ACE (CHO-15AB). In CHO-15AB cells, enalaprilat (1 mumol/L) increased the total number of low-affinity [3H]BK binding sites on the cells at 37 degrees C, but not at 4 degrees C, from 18.4 +/- 4.3 to 40.3 +/- 11.9 fmol/10(6) cells (P potentiated the release of [3H]arachidonic acid and the liberation of inositol 1,4,5-trisphosphate (IP3) induced by BK and [Hyp3-Tyr(Me)8]BK. Moreover, enalaprilat (1 mumol/L) completely and immediately restored the response of the B2 receptor, desensitized by the agonist (1 mumol/L [Hyp3-Tyr(Me)8]BK); this effect was blocked by the antagonist, HOE 140. Finally, enalaprilat, but not the prodrug enalapril, decreased internalization of the receptor from 70 +/- 9% to 45 +/- 9% (P desensitization, and decrease internalization, thereby potentiating BK beyond blocking its hydrolysis.

  9. Safety of C1-Esterase Inhibitor in Acute and Prophylactic Therapy of Hereditary Angioedema

    DEFF Research Database (Denmark)

    Busse, Paula; Bygum, Anette; Edelman, Jonathan

    2014-01-01

    BACKGROUND: The plasma-derived, pasteurized C1-inhibitor (C1-INH) concentrate, Berinert has a 4-decade history of use in hereditary angioedema (HAE), with a substantial literature base that demonstrates safety and efficacy. Thromboembolic events have rarely been reported with C1-INH products......, typically with off-label use or at supratherapeutic doses. OBJECTIVES: Active surveillance of safety and clinical usage patterns of pasteurized C1-inhibitor concentrate and the more recent pasteurized, nanofiltered C1-INH, with a particular interest in thromboembolic events. METHODS: A registry...

  10. Risk of severe hematologic toxicities in cancer patients treated with PARP inhibitors: results of monotherapy and combination therapy trials

    Directory of Open Access Journals (Sweden)

    Alecu I

    2018-02-01

    Full Text Available Iulian Alecu, Tsveta Milenkova, Simon R Turner Research and Development, AstraZeneca UK Limited, Cambridge, UKThe tolerability profile of PARP inhibitors often includes hematologic toxicities, and the characterization of these adverse events is important to allow effective management by clinicians. Zhou et al1 recently carried out a meta-analysis of the incidence and relative risks of severe neutropenia, thrombocytopenia, and anemia events in 12 randomized controlled trials of PARP inhibitors, either as monotherapy or in combination with chemotherapy or radiotherapy. The authors concluded that olaparib resulted in a higher incidence of severe (common terminology criteria for adverse events [CTCAE] grade $3 neutropenia when compared with niraparib and veliparib; however, these conclusions are based on inappropriate and incomplete comparisons of hematologic toxicity with olaparib or veliparib in combination with myelotoxic chemotherapy versus niraparib monotherapy. While both monotherapy and combination therapy olaparib studies are discussed in the paper, the neutropenia analysis is based on olaparib data solely from studies in combination with paclitaxel or paclitaxel plus carboplatin. In order to inform the practicing clinician of the relative risk of hematologic toxicity associated with different PARP inhibitors, direct comparison needs to be conducted based on monotherapy, where applicable, as per the approved drug indication, otherwise the reader is given misleading information.View the original paper by Zhou et al.

  11. Cancer Cell Resistance to Aurora Kinase Inhibitors: Identification of Novel Targets for Cancer Therapy

    Czech Academy of Sciences Publication Activity Database

    Hrabáková, Rita; Kollaredy, M.; Tylečková, Jiřina; Halada, Petr; Hajdúch, M.; Gadher, S. J.; Kovářová, Hana

    2013-01-01

    Roč. 12, č. 1 (2013), s. 455-469 ISSN 1535-3893 R&D Projects: GA MŠk LC07017 Institutional support: RVO:67985904 ; RVO:61388971 Keywords : Aurora kinase inhibitors * resistance * p53 * apoptosis Subject RIV: CE - Biochemistry Impact factor: 5.001, year: 2013

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

    Science.gov (United States)

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

    2013-09-26

    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.

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

    Directory of Open Access Journals (Sweden)

    Weidemann AK

    2013-09-01

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

  14. PDE 7 inhibitors: new potential drugs for the therapy of spinal cord injury.

    Directory of Open Access Journals (Sweden)

    Irene Paterniti

    Full Text Available 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.

  15. A pilot randomized trial to prevent sexual dysfunction in postmenopausal breast cancer survivors starting adjuvant aromatase inhibitor therapy.

    Science.gov (United States)

    Advani, Pragati; Brewster, Abenaa M; Baum, George P; Schover, Leslie R

    2017-08-01

    A randomized pilot trial evaluated the hypothesis that early intervention lessens sexual dysfunction in the first year on aromatase inhibitors. A secondary aim was comparing the efficacy of two vaginal moisturizers. Fifty-seven postmenopausal women with early stage breast cancer starting aromatase inhibitors were randomized to three treatment groups. All received a handout on managing sexual and other side effects. The Usual Care group received no additional therapy. The Active Treatment groups received a 6-month supply of a vaginal moisturizer (hyaluronic acid-based in Active Group-H and prebiotic in Active Group-P) and a vaginal lubricant and dilator, plus access to an educational website and phone coaching. Questionnaires completed at baseline, 6, and 12 months included the Female Sexual Function Index (FSFI), Menopausal Sexual Interest Questionnaire (MSIQ), Female Sexual Distress Scale-Revised (FSDS-R), and a menopausal symptom scale. Forty-nine women (86%) provided follow-up data. Mean age was 59 and 77% were non-Hispanic Caucasian. Sexual function was impaired at baseline, but remained stable over 12 months for all groups. The combined active treatment group had less dyspareunia (P = 0.07) and sexual distress (P = 0.02) at 6 months than the Usual Care group. At 6 months, the Active-H group improved significantly more than the Active-P group on FSFI total score (P = 0.04). Sexual counseling helped women maintain stable sexual function on aromatase inhibitors. Active intervention resulted in better outcomes at 6 months. This promising pilot trial suggests a need for more research on preventive counseling to maintain sexual function during aromatase inhibitor treatment.

  16. Synthesis and discovery of potent carbonic anhydrase, acetylcholinesterase, butyrylcholinesterase, and α-glycosidase enzymes inhibitors: The novel N,N'-bis-cyanomethylamine and alkoxymethylamine derivatives.

    Science.gov (United States)

    Taslimi, Parham; Caglayan, Cuneyt; Farzaliyev, Vagif; Nabiyev, Oruj; Sujayev, Afsun; Turkan, Fikret; Kaya, Ruya; Gulçin, İlhami

    2018-04-01

    During this investigation, N,N'-bis-azidomethylamines, N,N'-bis-cyanomethylamine, new alkoxymethylamine and chiral derivatives, which are considered to be a new generation of multifunctional compounds, were synthesized, functional properties were investigated, and anticholinergic and antidiabetic properties of those compounds were studied through the laboratory tests, and it was approved that they contain physiologically active compounds rather than analogues. Novel N-bis-cyanomethylamine and alkoxymethylamine derivatives were effective inhibitors of the α-glycosidase, cytosolic carbonic anhydrase I and II isoforms, butyrylcholinesterase (BChE), and acetylcholinesterase (AChE) with K i values in the range of 0.15-13.31 nM for α-glycosidase, 2.77-15.30 nM for human carbonic anhydrase isoenzymes I (hCA I), 3.12-21.90 nM for human carbonic anhydrase isoenzymes II (hCA II), 23.33-73.23 nM for AChE, and 3.84-48.41 nM for BChE, respectively. Indeed, the inhibition of these metabolic enzymes has been considered as a promising factor for pharmacologic intervention in a diversity of disturbances. © 2018 Wiley Periodicals, Inc.

  17. Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study.

    Science.gov (United States)

    Swords, Ronan T; Erba, Harry P; DeAngelo, Daniel J; Bixby, Dale L; Altman, Jessica K; Maris, Michael; Hua, Zhaowei; Blakemore, Stephen J; Faessel, Hélène; Sedarati, Farhad; Dezube, Bruce J; Giles, Francis J; Medeiros, Bruno C

    2015-05-01

    This trial was conducted to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the first in class NEDD8-activating enzyme (NAE) inhibitor, pevonedistat, and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Pevonedistat was administered via a 60-min intravenous infusion on days 1, 3 and 5 (schedule A, n = 27), or days 1, 4, 8 and 11 (schedule B, n = 26) every 21-days. Dose escalation proceeded using a standard '3 + 3' design. Responses were assessed according to published guidelines. The MTD for schedules A and B were 59 and 83 mg/m(2) , respectively. On schedule A, hepatotoxicity was dose limiting. Multi-organ failure (MOF) was dose limiting on schedule B. The overall complete (CR) and partial (PR) response rate in patients treated at or below the MTD was 17% (4/23, 2 CRs, 2 PRs) for schedule A and 10% (2/19, 2 PRs) for schedule B. Pevonedistat plasma concentrations peaked after infusion followed by elimination in a biphasic pattern. Pharmacodynamic studies of biological correlates of NAE inhibition demonstrated target-specific activity of pevonedistat. In conclusion, administration of the first-in-class agent, pevonedistat, was feasible in patients with MDS and AML and modest clinical activity was observed. © 2015 John Wiley & Sons Ltd.

  18. Potential Therapeutic Applications of Mucuna pruriens Peptide Fractions Purified by High-Performance Liquid Chromatography as Angiotensin-Converting Enzyme Inhibitors, Antioxidants, Antithrombotic and Hypocholesterolemic Agents.

    Science.gov (United States)

    Herrera-Chalé, Francisco; Ruiz-Ruiz, Jorge Carlos; Betancur-Ancona, David; Segura-Campos, Maira Rubi

    2016-02-01

    A Mucuna pruriens protein concentrate was hydrolyzed with a digestive (pepsin-pancreatin) enzymatic system. The soluble portion of the hydrolysate was fractionated by ultrafiltration and the ultrafiltered peptide fraction (PF) with lower molecular weight was purified by reversed-phase high-performance liquid chromatography. The PF obtained were evaluated by testing the biological activity in vitro. Fractions showed that the ability to inhibit the angiotensin-converting enzyme had IC50 values that ranged from 2.7 to 6.2 μg/mL. Trolox equivalent antioxidant capacity values ranged from 132.20 to 507.43 mM/mg. The inhibition of human platelet aggregation ranged from 1.59% to 11.11%, and the inhibition of cholesterol micellar solubility ranged from 0.24% to 0.47%. Hydrophobicity, size, and amino acid sequence could be factors in determining the biological activity of peptides contained in fractions. This is the first report that M. pruriens peptides act as antihypertensives, antioxidants, and inhibitors for human platelet aggregation and cholesterol micellar solubility in vitro.

  19. A phage display selected 7-mer peptide inhibitor of the Tannerella forsythia metalloprotease-like enzyme Karilysin can be truncated to Ser-Trp-Phe-Pro.

    Science.gov (United States)

    Skottrup, Peter Durand; Sørensen, Grete; Ksiazek, Miroslaw; Potempa, Jan; Riise, Erik

    2012-01-01

    Tannerella forsythia is a gram-negative bacteria, which is strongly associated with the development of periodontal disease. Karilysin is a newly identified metalloprotease-like enzyme, that is secreted from T. forsythia. Karilysin modulates the host immune response and is therefore considered a likely drug target. In this study peptides were selected towards the catalytic domain from Karilysin (Kly18) by phage display. The peptides were linear with low micromolar binding affinities. The two best binders (peptide14 and peptide15), shared the consensus sequence XWFPXXXGGG. A peptide15 fusion with Maltose Binding protein (MBP) was produced with peptide15 fused to the N-terminus of MBP. The peptide15-MBP was expressed in E. coli and the purified fusion-protein was used to verify Kly18 specific binding. Chemically synthesised peptide15 (SWFPLRSGGG) could inhibit the enzymatic activity of both Kly18 and intact Karilysin (Kly48). Furthermore, peptide15 could slow down the autoprocessing of intact Kly48 to Kly18. The WFP motif was important for inhibition and a truncation study further demonstrated that the N-terminal serine was also essential for Kly18 inhibition. The SWFP peptide had a Ki value in the low micromolar range, which was similar to the intact peptide15. In conclusion SWFP is the first reported inhibitor of Karilysin and can be used as a valuable tool in structure-function studies of Karilysin.

  20. A phage display selected 7-mer peptide inhibitor of the Tannerella forsythia metalloprotease-like enzyme Karilysin can be truncated to Ser-Trp-Phe-Pro.

    Directory of Open Access Journals (Sweden)

    Peter Durand Skottrup

    Full Text Available Tannerella forsythia is a gram-negative bacteria, which is strongly associated with the development of periodontal disease. Karilysin is a newly identified metalloprotease-like enzyme, that is secreted from T. forsythia. Karilysin modulates the host immune response and is therefore considered a likely drug target. In this study peptides were selected towards the catalytic domain from Karilysin (Kly18 by phage display. The peptides were linear with low micromolar binding affinities. The two best binders (peptide14 and peptide15, shared the consensus sequence XWFPXXXGGG. A peptide15 fusion with Maltose Binding protein (MBP was produced with peptide15 fused to the N-terminus of MBP. The peptide15-MBP was expressed in E. coli and the purified fusion-protein was used to verify Kly18 specific binding. Chemically synthesised peptide15 (SWFPLRSGGG could inhibit the enzymatic activity of both Kly18 and intact Karilysin (Kly48. Furthermore, peptide15 could slow down the autoprocessing of intact Kly48 to Kly18. The WFP motif was important for inhibition and a truncation study further demonstrated that the N-terminal serine was also essential for Kly18 inhibition. The SWFP peptide had a Ki value in the low micromolar range, which was similar to the intact peptide15. In conclusion SWFP is the first reported inhibitor of Karilysin and can be used as a valuable tool in structure-function studies of Karilysin.

  1. Cardioprotective effects of benazepril, an angiotensin-converting enzyme inhibitor, in an ischaemia-reperfusion model of myocardial infarction in rats.

    Science.gov (United States)

    Charan Sahoo, Kanhei; Arora, Sachin; Goyal, Sameer; Kishore, Kamal; Ray, Ruma; Chandra Nag, Tapas; Singh Arya, Dharamvir

    2009-12-01

    The present study evaluated the effects of benazepril, an angiotensin-converting enzyme inhibitor on haemodynamic, biochemical, and immunohistochemical (Bax and Bcl-2 protein) indices in ischaemia and reperfusion (IR) injury. Male Wistar albino rats were divided into three groups and were orally administered saline once daily (IR-sham and IR-control) or benazepril (30 mg/kg/day; IR-benazepril) for 14 days. On the 15(th) day, in the IR-control and IR-benazepril groups, rats were subjected to left anterior descending coronary artery occlusion for 45 minutes followed by a one-hour reperfusion. Haemodynamic parameters were recorded and rats were sacrificed; hearts were isolated for biochemical estimation and immunohistochemistry. In the IR-control group, significant ventricular dysfunctions (pBenazepril pretreatment significantly improved mean arterial pressure (pbenazepril treatment significantly decreased the level of thiobarbituric acid reactive substances and restored the activity of lactate dehydrogenase towards normal value (pbenazepril upregulated Bcl-2 protein and decreased Bax protein expression, thus exhibiting anti-apoptotic effects. These beneficial effects of benazepril will have an important implication in the therapeutic use of benazepril in ischaemic heart disease.

  2. Hypovolemic Shock Caused by Angiotensin-Converting Enzyme Inhibitor-Induced Visceral Angioedema: A Case Series and A Simple Method to Diagnose this Complication in the Emergency Department.

    Science.gov (United States)

    Myslinski, Joseph; Heiser, Andrew; Kinney, Ashley

    2018-03-01

    Visceral angioedema is a rarely reported side effect of angiotensin-converting-enzyme inhibitors (ACEI). Because signs and symptoms tend to be nonspecific, the diagnosis is difficult to make, especially in the emergency department (ED). We describe 2 patients presenting with signs of hypovolemic shock, in which the diagnosis of ACEI-induced visceral angioedema was made in the ED. We surmise that patients with abdominal pain, who present with hypovolemic shock and are taking medications that can predispose to angioedema, may have this complication if their hemoglobin level is elevated compared with their previous levels. An abdominal computed tomography scan, if it does not identify any other significant etiology, will increase the probability that ACEI-induced visceral angioedema is the diagnosis when there is nonspecific bowel wall thickening or edema. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Identification of ACEI-induced visceral angioedema in the ED will avoid prolonged admissions, unnecessary procedures, and future recurrences. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Case report of unexpected gastrointestinal involvement in type 1 Gaucher disease: comparison of eliglustat tartrate treatment and enzyme replacement therapy.

    Science.gov (United States)

    Kim, Yoo-Mi; Shin, Dong Hoon; Park, Su Bum; Cheon, Chong Kun; Yoo, Han-Wook

    2017-05-15

    Gastrointestinal involvement in Gaucher disease is very rare, and appears to be unresponsive to enzyme replacement therapy (ERT). Here, we describe identical twin, splenectomized, non-neuronopathic Gaucher patients on long-term ERT for 9 years, who complained of epigastric discomfort due to Gaucher cell infiltration of the gastroduodenal mucosa. Rare compound heterozygous mutations (p.Arg48Trp and p.Arg257Gln) of the GBA gene were found in both. Improvement in the gastroduodenal infiltration and reduced chitotriosidase levels were observed in one who switched to eliglustat tartrate for 1 year, whereas the other one who maintained ERT showed no improvement of chitotriosidase level and persistent duodenal lesions. This shows that eliglustat might be an effective treatment for Gaucher disease patients having lesions resistant to ERT.

  4. Long-term proton pump inhibitor therapy and falls and fractures in elderly women: a prospective cohort study.

    Science.gov (United States)

    Lewis, Joshua R; Barre, Deka; Zhu, Kun; Ivey, Kerry L; Lim, Ee Mun; Hughes, Jeff; Prince, Richard L

    2014-11-01

    Proton pump inhibitors (PPIs) are widely used in the elderly. Recent studies have suggested that long-term PPI therapy is associated with fractures in the elderly, however the mechanism remains unknown. We investigated the association between long-term PPI therapy ≥1 year and fracture risk factors including bone structure, falls, and balance-related function in a post hoc analysis of a longitudinal population-based prospective cohort of elderly postmenopausal women and replicated the findings in a second prospective study of falling in elderly postmenopausal women. Long-term PPI therapy was associated with increased risk of falls and fracture-related hospitalizations; adjusted odds ratio (AOR) 2.17; 95% CI, 1.25-3.77; p = 0.006 and 1.95; 95% CI, 1.20-3.16; p = 0.007, respectively. In the replication study, long-term PPI use was associated with an increased risk of self-reported falling; AOR, 1.51; 95% CI, 1.00-2.27; p = 0.049. No association of long-term PPI therapy with bone structure was observed; however, questionnaire-assessed falls-associated metrics such as limiting outdoor activity (p = 0.002) and indoor activity (p = 0.001) due to fear of falling, dizziness (p risk in subjects on long-term PPI therapy. This increase in fracture risk in elderly women, already at high risk of fracture, appears to be mediated via increased falls risk and falling rather than impaired bone structure and should be carefully considered when prescribing long-term PPI therapy. © 2014 American Society for Bone and Mineral Research.

  5. Impact of Bee Venom Enzymes on Diseases and Immune Responses.

    Science.gov (United States)

    Hossen, Md Sakib; Shapla, Ummay Mahfuza; Gan, Siew Hua; Khalil, Md Ibrahim

    2016-12-27

    Bee venom (BV) is used to treat many diseases and exhibits anti-inflammatory, anti-bacterial, antimutagenic, radioprotective, anti-nociceptive immunity promoting, hepatocyte protective and anti-cancer activity. According to the literature, BV contains several enzymes, including phospholipase A2 (PLA2), phospholipase B, hyaluronidase, acid phosphatase and α-glucosidase. Recent studies have also reported the detection of different classes of enzymes in BV, including esterases, proteases and peptidases, protease inhibitors and other important enzymes involved in carbohydrate metabolism. Nevertheless, the physiochemical properties and functions of each enzyme class and their mechanisms remain unclear. Various pharmacotherapeutic effects of some of the BV enzymes have been reported in several studies. At present, ongoing research aims to characterize each enzyme and elucidate their specific biological roles. This review gathers all the current knowledge on BV enzymes and their specific mechanisms in regulating various immune responses and physiological changes to provide a basis for future therapies for various diseases.

  6. Impact of Bee Venom Enzymes on Diseases and Immune Responses

    Directory of Open Access Journals (Sweden)

    Md. Sakib Hossen

    2016-12-01

    Full Text Available Bee venom (BV is used to treat many diseases and exhibits anti-inflammatory, anti-bacterial, antimutagenic, radioprotective, anti-nociceptive immunity promoting, hepatocyte protective and anti-cancer activity. According to the literature, BV contains several enzymes, including phospholipase A2 (PLA2, phospholipase B, hyaluronidase, acid phosphatase and α-glucosidase. Recent studies have also reported the detection of different classes of enzymes in BV, including esterases, proteases and peptidases, protease inhibitors and other important enzymes involved in carbohydrate metabolism. Nevertheless, the physiochemical properties and functions of each enzyme class and their mechanisms remain unclear. Various pharmacotherapeutic effects of some of the BV enzymes have been reported in several studies. At present, ongoing research aims to characterize each enzyme and elucidate their specific biological roles. This review gathers all the current knowledge on BV enzymes and their specific mechanisms in regulating various immune responses and physiological changes to provide a basis for future therapies for various diseases.

  7. AB073. Classic infantile-onset Pompe disease: phenotypes and outcomes of 5 Vietnamese patients receiving enzyme replacement therapy

    Science.gov (United States)

    Nguyen, Khanh Ngoc; Do, Mai Thi Thanh; Can, Ngoc Thi Bich; Hwu, Wuh-Liang; Vu, Dung Chi

    2017-01-01

    Background Pompe disease (PD) or glycogen storage disease type II is a lysosomal storage disorder, caused by mutations of GAA gene which results in deficiency of acid alpha-glucosidase (GAA) enzyme that involves in metabolism of glycogen in the lysosomes. Its incidence is 1/14,000–1/100,000. PD is divided into three types: classic infantile onset, non-classic infantile onset, and late onset. Early enzyme replacement therapy (ERT) before developing respiratory distress may lead to good outcome. Since 2013, we have identified 16 cases with classic infantile-onset and 5 cases were treated with ERT. Herein, we describe phenotypes and outcomes of five infantile-onset PD patients who received ERT. Methods GAA enzyme assay was done at National Taiwan University Hospital. Results Ages of diagnosis were 12, 38 and 70 days, 5 and 9 months of age. Clinical presentations included macroglossia (5/5), hypertrophic cardiomyopathy (5/5), failure to thrive (5/5), facial weakness and hypotonia (3 patients diagnosed after 70 days of age), respiratory failure (1 patient diagnosed at 9 months of age). All patients had mildly elevated plasma CK (270–380 UI/L) and transaminase (60–260 UI/l). Ages at starting ERT were 28 and 58 days, 3, 6 and 10 months. The time intervals from diagnosis to starting ERT were between 14 days and 1 month. The durations of ERT were 4–22 months. The outcomes were good. All patients had improvement of cardiac functions shown on echocardiography, respiratory status, and motor development. The patient who first received ERT at 10 months of age was reportedly dead at home due to food obstruction at 18 months of age. Current ages of the survivors were 5–24 months. Conclusions Patients with classic infantile-onset PD will have good outcomes if ERT is started early. Newborn screening for this disease is necessary to yield an early diagnosis.

  8. Virus-directed enzyme prodrug therapy and the assessment of the cytotoxic impact of some benzimidazole derivatives.

    Science.gov (United States)

    Szewczuk, Michał; Boguszewska, Karolina; Żebrowska, Marta; Balcerczak, Ewa; Stasiak, Marta; Świątkowska, Maria; Błaszczak-Świątkiewicz, Katarzyna

    2017-07-01

    Virus-directed enzyme prodrug therapy is one of the major strategy of increasing cytotoxicity of bioreductive agents. This research intended to examine new selected benzimidazole derivatives as a substrate for nitroreductase, the enzyme involved in nitroreduction which is responsible to the production of cytotoxic metabolites. In this way, the selectivity and strength of cytotoxicity can be raised. The effect of benzimidazoles on virus transfected cells and non-virus transfected cells A549 cell line was established by Annexin V + propidium iodide test, western blot, and polymerase chain reaction analysis of specific pro- and anti-apoptotic proteins in the corresponding gene expression and additionally nitroreductase gene expression. Our results proved the pro-apoptotic properties of all tested compounds in normoxia and hypoxia, especially according to virused A549 cells where the time of exposition was reduced from 48 to 4 h. In this shorten period of time, the strongest activity was shown by N-oxide compounds with nitro-groups. The apoptosis was confirmed by generation of BAX gene and protein and reduction of BCL2 gene and protein.

  9. Analysis of enzyme targeting intraoperative radiosensitization therapy (KORTUC-IORT) for abdominal malignant tumors

    International Nuclear Information System (INIS)

    Nishioka, Akihito; Kariya, Shinji; Kataoka, Y.; Miyatake, Kana; Tadokoro, Michiko; Hamada, Norihiko; Kubota, Kei; Ogawa, Yasuhiro

    2013-01-01

    We developed a new radiosensitizer injection containing hydrogen peroxide and sodium hyaluronate just followed by intraoperative radiotherapy (IORT) for locally advanced pancreatic cancer, named KORTUC-IORT (Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas+IORT). Fourteen patients were treated with KORTUC-IORT, external beam radiotherapy, and systemic chemotherapy. All treatments related with KORTUC-IORT were well tolerated, with few adverse effects. The 1- and 2-year survival rates were 75% and 25%, respectively. The median survival period is 15 months. The present formulation can be delivered safely and effectively under the conditions used. (author)

  10. Hypoxia-Inducible Regulation of a Prodrug-Activating Enzyme for Tumor-Specific Gene Therapy

    Directory of Open Access Journals (Sweden)

    Toru Shibata

    2002-01-01

    Full Text Available Previous studies have suggested that tumor hypoxia could be exploited for cancer gene therapy. Using hypoxia-responsive elements derived from the human vascular endothelial growth factor gene, we have generated vectors expressing a bacterial nitroreductase. (20NTR gene that can activate the anticancer prodrug CB1954. Stable transfectants of human HT1080 tumor cells with hypoxia-inducible vectors were established with G418 selection. Hypoxic induction of NTR protein correlated with increased sensitivity to in vitro exposure of HT 1080 cells to the prodrug. Growth delay assays were performed with established tumor xenografts derived from the same cells to detect the in vivo efficacy of CB1954 conversion to its cytotoxic form. Significant antitumor effects were achieved with intraperitoneal injections of CB1954 both in tumors that express NTR constitutively or with a hypoxia-inducible promoter. In addition, respiration of 10% O2 increased tumor hypoxia in vivo and enhanced the antitumor effects. Taken together, these results demonstrate that hypoxia-inducible vectors may be useful for tumor-selective gene therapy, although the problem of delivery of the vector to the tumors, particularly to the hypoxic cells in the tumors, is not addressed by these studies.

  11. Validation of the 2nd Generation Proteasome Inhibitor Oprozomib for Local Therapy of Pulmonary Fibrosis.

    Directory of Open Access Journals (Sweden)

    Nora Semren

    Full Text Available Proteasome inhibition has been shown to prevent development of fibrosis in several organs including the lung. However, effects of proteasome inhibitors on lung fibrosis are controversial and cytotoxic side effects of the overall inhibition of proteasomal protein degradation cannot be excluded. Therefore, we hypothesized that local lung-specific application of a novel, selective proteasome inhibitor, oprozomib (OZ, provides antifibrotic effects without systemic toxicity in a mouse model of lung fibrosis. Oprozomib was first tested on the human alveolar epithelial cancer cell line A549 and in primary mouse alveolar epithelial type II cells regarding its cytotoxic effects on alveolar epithelial cells and compared to the FDA approved proteasome inhibitor bortezomib (BZ. OZ was less toxic than BZ and provided high selectivity for the chymotrypsin-like active site of the proteasome. In primary mouse lung fibroblasts, OZ showed significant anti-fibrotic effects, i.e. reduction of collagen I and α smooth muscle actin expression, in the absence of cytotoxicity. When applied locally into the lungs of healthy mice via instillation, OZ was well tolerated and effectively reduced proteasome activity in the lungs. In bleomycin challenged mice, however, locally applied OZ resulted in accelerated weight loss and increased mortality of treated mice. Further, OZ failed to reduce fibrosis in these mice. While upon systemic application OZ was well tolerated in healthy mice, it rather augmented instead of attenuated fibrotic remodelling of the lung in bleomycin challenged mice. To conclude, low toxicity and antifibrotic effects of OZ in pulmonary fibroblasts could not be confirmed for pulmonary fibrosis of bleomycin-treated mice. In light of these data, the use of proteasome inhibitors as therapeutic agents for the treatment of fibrotic lung diseases should thus be considered with caution.

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

    Science.gov (United States)

    2014-04-01

    treated mice compared to vehicle control. A subset of mice was followed by longitudinal MRI imaging for prostate tumor growth. As shown in Figure...treated (N=7) mice were followed by longitudinal MRI imaging for tumor growth (bottom panel). 9 KEY RESEARCH ACCOMPLISHMENTS • Identified...EDTA) containing a tablet of complete protease inhibitors from Roche (Indianapolis, IN). Total protein from each sample was separated on a 4–12% Bis

  13. Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy

    Directory of Open Access Journals (Sweden)

    Kay Andrea

    2009-10-01

    Full Text Available Abstract The mammalian target of rapamycin (mTOR is an intracellular serine/threonine protein kinase positioned at a central point in a variety of cellular signaling cascades. The established involvement of mTOR activity in the cellular processes that contribute to the development and progression of cancer has identified mTOR as a major link in tumorigenesis. Consequently, inhibitors of mTOR, including temsirolimus, everolimus, and ridaforolimus (formerly deforolimus have been developed and assessed for their safety and efficacy in patients with cancer. Temsirolimus is an intravenously administered agent approved by the US Food and Drug Administration (FDA and the European Medicines Agency (EMEA for the treatment of advanced renal cell carcinoma (RCC. Everolimus is an oral agent that has recently obtained US FDA and EMEA approval for the treatment of advanced RCC after failure of treatment with sunitinib or sorafenib. Ridaforolimus is not yet approved for any indication. The use of mTOR inhibitors, either alone or in combination with other anticancer agents, has the potential to provide anticancer activity in numerous tumor types. Cancer types in which these agents are under evaluation include neuroendocrine tumors, breast cancer, leukemia, lymphoma, hepatocellular carcinoma, gastric cancer, pancreatic cancer, sarcoma, endometrial cancer, and non-small-cell lung cancer. The results of ongoing clinical trials with mTOR inhibitors, as single agents and in combination regimens, will better define their activity in cancer.

  14. Invasive pulmonary aspergillosis mimicking organizing pneumonia after mTOR inhibitor therapy: A case report

    Directory of Open Access Journals (Sweden)

    Yuki Iijima

    2018-04-01

    Full Text Available A 67-year-old man presented to the hospital with complaints of fever and cough. He had a past medical history of renal cell carcinoma and had just started treatment with temsirolimus, a mammalian target of rapamycin (mTOR inhibitor. A 1-week course of antibiotics did not have any effect on his symptoms. A chest computed tomography (CT scan showed the reversed halo sign (RHS. Organizing pneumonia induced by mTOR inhibitor treatment was initially considered. However, transbronchial biopsy revealed clusters of fungal organisms, suggesting infection with Aspergillus spp. Within just 2 weeks, a CT scan showed drastic enlargement of the cavitary lesion, with multiple newly formed consolidations. The patient was diagnosed with invasive pulmonary aspergillosis. Concomitant treatment with voriconazole and micafungin was started. Two weeks after the initiation of treatment, he became afebrile with gradual regression of the cavitary lesion and consolidations. Keywords: mTOR inhibitor, Organizing pneumonia, Reversed halo sign, Invasive pulmonary aspergillosis, Immunocompromise

  15. Efficacy of HER2-targeted therapy in metastatic breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors

    DEFF Research Database (Denmark)

    Nielsen, Dorte L; Kümler, Iben; Palshof, Jesper Andreas

    2013-01-01

    to those obtained for capecitabine plus lapatinib (48%), continuing trastuzumab in combination with capecitabine (48%), pertuzumab plus trastuzumab (24%), and neratinib (24%). Strategies combining multiple HER2-directed therapies might yield additive or synergistic effects and lead to improved outcome...

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

    National Research Council Canada - National Science Library

    Dlaiani, Danai

    2002-01-01

    ...), assessed by wound healing and peri-operative bleeding; 2) Efficacy of neo-adjuvant thalidomide treatment, as measured by the rate of tumor reduction I PSA decline while on thalidomide therapy; 3...

  17. Potentiation of peptide receptor radionuclide therapy by the PARP inhibitor olaparib

    NARCIS (Netherlands)

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

    2016-01-01

    textabstractMetastases 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

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

    Directory of Open Access Journals (Sweden)

    Selwyn M. Prea

    2015-01-01

    Full Text Available 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. The impact of the immune system on the safety and efficiency of enzyme replacement therapy in lysosomal storage disorders.

    Science.gov (United States)

    Broomfield, A; Jones, S A; Hughes, S M; Bigger, B W

    2016-07-01

    In the light of clinical experience in infantile onset Pompe patients, the immunological impact on the tolerability and long-term efficacy of enzyme replacement therapy (ERT) for lysosomal storage disorders has come under renewed scrutiny. This article details the currently proposed immunological mechanisms involved in the development of anti-drug antibodies and the current therapies used in their treatment. Given the current understanding of the adaptive immune response, it focuses particularly on T cell dependent mechanisms and the paradigm of using lymphocytic negative selection as a predictor of antibody formation. This concept originally postulated in the 1970s, stipulated that the genotypically determined lack of production or production of a variant protein determines an individual's lymphocytic repertoire. This in turn is the key factor in determining the potential severity of an individual's immunological response to ERT. It also highlights the need for immunological assay standardization particularly those looking at describing the degree of functional impact, robust biochemical or clinical endpoints and detailed patient subgroup identification if the true evaluations of impact are to be realised.

  20. Timing of initiation of enzyme replacement therapy after diagnosis of type 1 Gaucher disease: effect on incidence of avascular necrosis

    Science.gov (United States)

    Mistry, Pramod K; Deegan, Patrick; Vellodi, Ashok; Cole, J Alexander; Yeh, Michael; Weinreb, Neal J

    2009-01-01

    Data from the International Collaborative Gaucher Group Gaucher Registry were analysed to assess the relationship between enzyme replacement therapy with imiglucerase (ERT) and incidence of avascular necrosis (AVN) in type 1 Gaucher disease (GD1), and to determine whether the time interval between diagnosis and initiation of ERT influences the incidence rate of AVN. All patients with GD1 enrolled in the Gaucher Registry who received ERT and did not report AVN prior to starting therapy (n = 2700) were included. The incidence rate of AVN following initiation of ERT was determined. An incidence rate of AVN of 13·8 per 1000 person-years was observed in patients receiving ERT. Patients who initiated ERT within 2 years of diagnosis had an incidence rate of 8·1 per 1000 person-years; patients who started ERT ≥2 years after diagnosis had an incidence rate of 16·6 per 1000 person-years. The adjusted incidence rate ratio was 0·59 [95% confidence interval (CI) 0·36–0·96, P = 0·0343]. Splenectomy was an independent risk factor for AVN (adjusted incidence rate ratio 2·23, 95% CI 1·61–3·08, P < 0·0001). In conclusion, the risk of AVN was reduced among patients who initiated ERT within 2 years of diagnosis, compared to initiating treatment ≥2 years after diagnosis. A higher risk of AVN was observed among patients who had previously undergone splenectomy. PMID:19732054

  1. Histone deacetylase inhibitors (HDACIs: multitargeted anticancer agents

    Directory of Open Access Journals (Sweden)

    Ververis K

    2013-02-01

    Full Text Available Katherine Ververis,1 Alison Hiong,1 Tom C Karagiannis,1,* Paul V Licciardi2,*1Epigenomic Medicine, Alfred Medical Research and Education Precinct, 2Allergy and Immune Disorders, Murdoch Childrens Research Institute, Melbourne, VIC, Australia*These authors contributed equally to this workAbstract: Histone deacetylase (HDAC inhibitors are an emerging class of therapeutics with potential as anticancer drugs. The rationale for developing HDAC inhibitors (and other chromatin-modifying agents as anticancer therapies arose from the understanding that in addition to genetic mutations, epigenetic changes such as dysregulation of HDAC enzymes can alter phenotype and gene expression, disturb homeostasis, and contribute to neoplastic growth. The family of HDAC inhibitors is large and diverse. It includes a range of naturally occurring and synthetic compounds that differ in terms of structure, function, and specificity. HDAC inhibitors have multiple cell type-specific effects in vitro and in vivo, such as growth arrest, cell differentiation, and apoptosis in malignant cells. HDAC inhibitors have the potential to be used as monotherapies or in combination with other anticancer therapies. Currently, there are two HDAC inhibitors that have received approval from the US FDA for the treatment of cutaneous T-cell lymphoma: vorinostat (suberoylanilide hydroxamic acid, Zolinza and depsipeptide (romidepsin, Istodax. More recently, depsipeptide has also gained FDA approval for the treatment of peripheral T-cell lymphoma. Many more clinical trials assessing the effects of various HDAC inhibitors on hematological and solid malignancies are currently being conducted. Despite the proven anticancer effects of particular HDAC inhibitors against certain cancers, many aspects of HDAC enzymes and HDAC inhibitors are still not fully understood. Increasing our understanding of the effects of HDAC inhibitors, their targets and mechanisms of action will be critical for the

  2. Promising therapy of XDR-TB/MDR-TB with thioridazine an inhibitor of bacterial efflux pumps

    DEFF Research Database (Denmark)

    Amaral, L; Martins, M; Viveiros, M

    2008-01-01

    -TB) - a M. tuberculosis organism that is resistant to the most effective second line drugs available for the treatment of TB. This review provides detailed, significant evidence that supports the use of an old neuroleptic compound, thioridazine (TZ), for the management of MDR-TB and XDR-TB infections...... therapy predictably ineffective and death is inevitable, compassionate therapy with TZ should be contemplated. The risks are small and the rewards great....

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

    OpenAIRE

    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 prevent...

  4. Safety and efficacy of enzyme targeting intraoperative radiosensitization therapy (KORTUC-IORT) for advanced pancreatic cancer

    International Nuclear Information System (INIS)

    Nishioka, Akihito; Hamada, Norihiko; Kariya, Shinji; Ogawa, Yasuhiro

    2012-01-01

    We developed a new radiosensitizer injection containing hydrogen peroxide and sodium hyaluronate just followed by intraoperative radiotherapy (IORT) for locally advanced pancreatic cancer, named KORTUC-IORT (Kochi Oxydol-Radiation Therapy for Unresectable Carcinoma + IORT). Fourteen patients were treated with KORTUC-IORT, external beam radiotherapy (EBRT), and systemic chemotherapy. With KORTUC-IORT, the agent containing hydrogen peroxide and sodium hyaluronate, was injected into tumor tissue just prior to administration of IORT under ultrasonic guidance. All treatments related with KORTUC-IORT were well tolerated, with few adverse effects. One year survival rate is 67% and median survival period is 15 months. The present formulation can be delivered safely and effectively under the conditions used. (author)

  5. The effect of tumor necrosis factor inhibitor therapy on the incidence of myocardial infarction in patients with psoriasis: a retrospective study.

    Science.gov (United States)

    Shaaban, Dalia; Al-Mutairi, Nawaf

    2018-02-01

    Psoriasis has been shown to be associated with increased incidence of myocardial infarction (MI). The data on the effect of tumor necrosis factor (TNF) inhibitors on MI in psoriasis are scarce. To evaluate the effect of TNF inhibitors on the risk of MI in psoriasis patients compared with methotrexate (MTX) and topical agents. Data were obtained from the Electronic Health Records database of Farwaniya Hospital from psoriasis patients seen from January 2008 to December 2014. Patients were categorized into TNF inhibitor, MTX and topical cohorts. The study included 4762 psoriasis patients. Both TNF inhibitor and MTX cohorts showed a statistically lower rate of MI compared with topical cohort. However, there was no statistically significant difference in MI rate between TNF inhibitor and MTX cohorts (P = .32). The probability of MI was lower in TNF inhibitor responders compared with non-responders (p = .001). The use of TNF inhibitors in psoriasis showed a significant reduction in the risk of MI compared with topical agents and a non-significant reduction compared with MTX. Responders to TNF inhibitor therapy showed a reduction in MI rate compared with non-responders.

  6. HER2-targeted therapy in breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors

    DEFF Research Database (Denmark)

    Nielsen, Dorte Lisbet; Andersson, Michael; Kamby, Claus

    2008-01-01

    There is strong clinical evidence that trastuzumab, a monoclonal antibody targeting the human epidermal growth factor receptor (HER) two tyrosine kinase receptor, is an important component of first-line treatment of patients with HER2-positive metastatic breast cancer. In particular the combination...... of trastuzumab to chemotherapy improves disease-free and overall survival. The use of lapatinib, a dual tyrosine kinase inhibitor of both HER1 and HER2, in combination with capecitabine in the second-line treatment of HER2-positive patients with metastatic breast cancer previously treated with trastuzumab has...

  7. Comparative effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on the risk of pneumonia and severe exacerbations in patients with COPD

    Directory of Open Access Journals (Sweden)

    Lai CC

    2018-03-01

    Full Text Available Chih-Cheng Lai,1 Ya-Hui Wang,2 Cheng-Yi Wang,3 Hao-Chien Wang,4 Chong-Jen Yu,4 Likwang Chen5 On behalf of the Taiwan Clinical Trial Consortium for Respiratory Diseases (TCORE 1Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Taiwan; 2Medical Research Center, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 3Department of Internal Medicine, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 4Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; 5Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan Objectives: This study aimed to compare the effects of angiotensin-converting-enzyme inhibitors (ACEis and angiotensin receptor blockers (ARBs on the risk of pneumonia and severe exacerbations in patients with COPD.Patients and methods: All patients with COPD who used ACEis and ARBs for >90 days between 2000 and 2005 were recruited. Pairwise matching (1:1 of the ACEi and ARB groups resulted in two similar subgroups, with 6,226 patients in each. The primary outcomes were pneumonia and COPD exacerbations, and the secondary outcome was death.Results: During the follow-up period, the incidence of pneumonia was 7.20 per 100 person-years in the ACEi group and 5.89 per 100 person-years in the ARB group. The ACEi group had a higher risk of pneumonia (adjusted hazard ratio [aHR], 1.22; 95% CI, 1.15–1.29 than the ARB group. The incidence of severe exacerbations was 0.65 per person-year for the patients receiving ACEis and 0.52 per person-year for those receiving ARBs. The patients receiving ACEis had a higher risk of severe exacerbations (aHR, 1.19; 95% CI, 1.16–1.21 than those receiving ARBs. Similar trends were noted in terms of severe exacerbations requiring

  8. Angiotensin Converting-Enzyme Inhibitors, Angiotensin Receptor Blockers, and Calcium Channel Blockers Are Associated with Prolonged Vascular Access Patency in Uremic Patients Undergoing Hemodialysis.

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    Fu-An Chen

    Full Text Available Vascular access failure is a huge burden for patients undergoing hemodialysis. Many efforts have been made to maintain vascular access patency, including pharmacotherapy. Angiotensin converting enzyme inhibitor (ACE-I, angiotensin receptor blocker (ARB, and calcium channel blocker (CCB are known for their antihypertensive and cardio-protective effects, however, their effects on long-term vascular access patency are still inconclusive.We retrospectively enrolled patients commencing maintenance hemodialysis between January 1, 2000, and December 31, 2006 by using National Health Insurance Research Database in Taiwan. Primary patency was defined as the date of first arteriovenous fistula (AVF or arteriovenous graft (AVG creation to the time of access thrombosis or any intervention aimed to maintain or re-establish vascular access patency. Cox proportional hazards models were used to adjust the influences of patient characteristics, co-morbidities and medications.Total 42244 patients were enrolled in this study, 37771 (89.4% used AVF, 4473 (10.6% used AVG as their first long term dialysis access. ACE-I, ARB, and CCB use were all associated with prolonged primary patency of AVF [hazard ratio (HR 0.586, 95% confidence interval (CI 0.557-0.616 for ACE-I use; HR 0.532, CI 0.508-0.556 for ARB use; HR 0.485, CI 0.470-0.501 for CCB use] and AVG (HR 0.557, CI 0.482-0.643 for ACE-I use, HR 0.536, CI 0.467-0.614 for ARB use, HR 0.482, CI 0.442-0.526 for CCB use.In our analysis, ACE-I, ARB, and CCB were strongly associated with prolonged primary patency of both AVF and AVG. Further prospective randomized studies are still warranted to prove the causality.

  9. Association between exposure to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers prior to septic shock and acute kidney injury.

    Science.gov (United States)

    Suberviola, B; Rodrigo, E; González-Castro, A; Serrano, M; Heras, M; Castellanos-Ortega, Á

    To evaluate the association between angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) use prior to a septic shock episode and the development, prognosis and long-term recovery from acute kidney injury (AKI). A single-centre, prospective observational study was carried out between September 2005 and August 2010. Patients admitted to the ICU of a third level hospital. A total of 386 septic shock patients were studied. None. Use of ACEIs/ARBs, AKI development, recovery of previous creatinine levels and time to recovery. A total of 386 patients were included, of which 312 (80.8%) developed AKI during ICU stay and 23% were receiving ACEIs/ARBs. The percentage of patients on ACEIs/ARBs increased significantly in relation to more severe stages of AKI irrespective of the kind of AKI score. After adjusting for confounders, the development of AKI was independently associated to the use of ACEIs/ARBs (OR 2.19; 95%CI 1.21-3.84; p=.04). With respect to the recovery of kidney function, the group of patients on ACEIs/ARBs had significantly higher creatinine levels at ICU discharge and needed hemodialysis more frequently thereafter. However, use of ACEIs/ARBs affected neither recovery of previous creatinine levels nor significantly delayed recovery. The use of ACEIs/ARBs before septic shock episodes was correlated to AKI development and severity, but did not affect the recovery of kidney function after sepsis resolution. Copyright © 2016 Elsevier España, S.L.U. y SEMICYUC. All rights reserved.

  10. Mortality benefit of long-term angiotensin-converting enzyme inhibitors or angiotensin receptor blockers after successful percutaneous coronary intervention in non-ST elevation acute myo