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Sample records for inhibitors including isoniazid

  1. Isoniazid

    Science.gov (United States)

    ... beverages include certain cheeses, red wine, and certain fish (e.g., tuna, other tropical fish). Talk to your doctor or dietitian about which ... victim has collapsed, had a seizure, has trouble breathing, or can't be awakened, immediately call emergency ...

  2. Isoniazid toxicosis in dogs: 137 cases (2004-2014).

    Science.gov (United States)

    Schmid, Dustin R; Lee, Justine A; Wismer, Tina A; Diniz, Pedro Paulo V P; Murtaugh, Robert J

    2017-09-15

    OBJECTIVE To establish the minimum toxic dose of isoniazid in dogs, characterize the clinical signs and outcomes for dogs following isoniazid ingestion, and determine whether IV administration of pyridoxine to dogs with isoniazid toxicosis is protective against death. DESIGN Retrospective case series. ANIMALS 137 dogs with isoniazid toxicosis. PROCEDURES The electronic database of the American Society for the Prevention of Cruelty to Animals Animal Poison Control Center was reviewed from January 2004 through December 2014 to identify dogs with isoniazid toxicosis. For each dog identified, information extracted from the medical record included signalment, estimated dose of isoniazid ingested, clinical signs, treatment, and outcome. Follow-up communication with pet owners or primary care veterinarians was performed when necessary to obtain missing information. RESULTS Clinical signs of isoniazid toxicosis were observed in 134 of 137 (98%) dogs and included seizures (n = 104), CNS signs without seizures (94), and gastrointestinal (41), cardiovascular (19), urogenital (4), and respiratory (1) abnormalities. Of the 87 dogs for which the outcome was available, 61 survived, 18 died, and 8 were euthanized. Probability of survival was positively associated with body weight and IV administration of pyridoxine and negatively associated with dose of isoniazid ingested and presence of seizures. Dogs that received pyridoxine IV were 29 times as likely to survive as dogs that did not receive pyridoxine IV. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated rapid diagnosis of isoniazid toxicosis and prompt treatment of affected dogs with pyridoxine and other supportive care were imperative for achieving a successful outcome.

  3. Phenotypic low-level isoniazid resistance as a marker to predict ethionamide resistance in Mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Salima Qamar

    2017-01-01

    Full Text Available Background: Tuberculosis is one of the most prevalent diseases in Pakistan. Pakistan has the highest burden of MDR-TB in the Eastern Mediterranean region. Ethionamide is an anti-tuberculous drug frequently used to treat MDR-TB. Its drug susceptibility testing is not easily available in resource limited settings. Since it acts on the same target protein as isoniazid (inhA protein encoded by inhA gene, we sought to find out if phenotypic isoniazid resistance can be a marker of ethionamide resistance. Materials and Methods: This was a retrospective observational study conducted at the Aga Khan University hospital section of microbiology. Data was retrieved between 2011 to 2014 for all culture positive MTB strains. All culture positive MTB isolates with susceptibilities to isoniazid and ethionamide recorded were included in the study. Isoniazid and ethionamide susceptibilities were performed using agar proportion method on Middlebrook 7H10 agar. Rate of Ethionamide resistance between low-level isoniazid resistant, high level isoniazid resistant and isoniazid sensitive MTB was compared. Results: A total of 11,274 isolates were included in the study. A statistically significant association (P < 0.001 was found between Ethionamide resistance and low-level isoniazid resistance (26.6% as compared to high-level isoniazid resistance (8.85% and isoniazid sensitivity (0.71% in MTB strains. However this association was not seen in XDR-TB strains. Conclusion: Low level isoniazid resistance may be used as marker for phenotypic ethionamide resistance and hence guide clinicians' choice of antituberculous agent for MDR-TB in Pakistan. Further studies involving detection of genotypic association of isoniazid and ethionamide susceptibilities are needed before a final conclusion can be derived.

  4. Compound list: isoniazid [Open TG-GATEs

    Lifescience Database Archive (English)

    Full Text Available isoniazid INAH 00002 ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Human/i...n_vitro/isoniazid.Human.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vit...ro/isoniazid.Rat.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Liver.../Single/isoniazid.Rat.in_vivo.Liver.Single.zip ftp://ftp.biosciencedbc.jp/archive

  5. Acute Psychosis after Recent Isoniazid Initiation

    Science.gov (United States)

    Sukhija, Gagandeep; Singh, Harpreet

    2015-01-01

    Isoniazid as part of Directly Observed Treatment-Short course (DOTS) regimen is universally used. Although, associated psychosis in certain cases is documented earlier, type of symptoms and onset of symptoms remains highly variable. We describe a case of 54-year-old female on anti-tubercular therapy with onset of psychosis within three days of Isoniazid initiation characterised by agitation, loosening of association, echolalia with spontaneous remission after drug stoppage. This case highlights the importance of remaining vigilant and considering isoniazid as possible causative agent for psychosis even within days of its intiation and avoiding delay in management. PMID:26266198

  6. Peptidase inhibitors reduce opiate narcotic withdrawal signs, including seizure activity, in the rat.

    Science.gov (United States)

    Pinsky, C; Dua, A K; LaBella, F S

    1982-07-15

    Narcotic withdrawal was precipitated by administration of naloxone in a low dose at 2 h after the final dose of morphine in a 9-day dependency-inducing schedule. Withdrawal was characterized by leaps, increased nocifensor activity and by cerebral cortical epileptiform activity, the latter not generally reported to be prominent in narcotic withdrawal. Single large doses of morphine did not provoke epileptiform activity at 2 h postinjection but did induce an acute opioid dependency wherein a moderately high dose of naloxone, ineffective in non-dependent rats, provoked upward leaping and electrocortical epileptiform activity. Pretreatment of the 9-day dependent rats with peptidase inhibitors, administered intracerebroventricularly, significantly reduced withdrawal severity including the epileptiform activity. We propose that peptidase inhibitors protect certain species of endogenous opioids and/or other neuropeptides that tend to suppress expression of the narcotic withdrawal syndrome. Furthermore, our findings suggest that epileptiform activity is a nascent form of cerebral activity hitherto largely unnoticed in narcotic withdrawal and that neuropeptides may be involved in certain epileptic states.

  7. [The use of fenazid in patients with pulmonary tuberculosis with poor isoniazid tolerance].

    Science.gov (United States)

    Borisova, M I; Stakhanov, V A; Sharkova, T I; Ivashchenko, N A

    2003-01-01

    The paper shows the experience gained in the use of the new Russian antituberculous drug fenazid in patients with different forms of active pulmonary tuberculosis and with neuro- and angiotoxic reactions to isoniazid. The study group comprised 25 patients aged 23 to 70 years who received fenazid as tablets in a daily dose of 0.5 g for 2 months at the first stage of the basic course of chemotherapy. The control group including 24 patients of the same age was given the routine antituberculous chemotherapy regimen, including isoniazid. The use of fenazid permits adequate therapy in patients with poor isoniazid tolerance, which may recommend fenazid to individuals at high risk for adverse reactions as their prevention.

  8. Simultaneous determination of isoniazid and pyrazinamide in ...

    African Journals Online (AJOL)

    Finally, 20 µL was injected into the HPLC system. HPLC analysis ... The method was accurate, and relative error ... Keywords: HPLC, Isoniazid, Pyrazinamide, Plasma, Simultaneous analysis. Tropical ... work, we describe a new HPLC method with UV ... pooled human plasma. ..... License, which permits unrestricted use,.

  9. High-performance liquid chromatographic determination of isoniazid and 1-isonicotinyl-2-lactosylhydrazine in isoniazid tablet formulations.

    Science.gov (United States)

    Butterfield, A G; Lovering, E G; Sears, R W

    1980-02-01

    A high-performance liquid chromatographic procedure is presented for the simultaneous determination of isoniazid and 1-isonicotinyl-2-lactosylhydrazine (I) in isoniazid tablet formulations. An aliquot of a diluted aqueous tablet extract is introduced onto a microparticulate cyanopropyl bonded-phase column using a valve-loop injector and chromatographed using a mobile phase of acetonitrile--0.01 M, pH 3.5 aqueous acetate buffer (5:95). Compound I can be determined at levels as low as 0.5% of the isoniazid label claim. The relative standard deviations are 0.4 and 0.7% for the simultaneous determination of isoniazid and I, respectively. Seven commercial tablet formulations contained 93.8--97.0% of the labeled isoniazid amounts and 0.3--5.8% of I, expressed as equivalent isoniazid relative to the labeled isoniazid level.

  10. 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 ...

  11. FORMULATION AND EVALUATION OF ISONIAZID AND ETHAMBUTOL HYDROCHLORIDE COMBINATION TABLETS

    OpenAIRE

    Margret Chandira R; Jayakar B; Palanisamy P.

    2012-01-01

    Ethambutol hydrochloride and Isoniazid Drugs are used as Antituberculosis agents. It is mainly used in the initial Treatment of pulmonary tuberculosis. Here in present study compressed tablet of Ethambutol hydrochloride and Isoniazid prepared by using HPMC, HPC, and PVPK -30 as binders. Compressed tablets of Ethambutol hydrochloride and Isoniazid were prepared by wet granulation method. Among different trials of F1 to F9 with wet granulation, the trial F1 showed satisfactory in-vitro drug re...

  12. Prevalence, Risk Factors, and Treatment Outcomes of Isoniazid- and Rifampicin-Mono-Resistant Pulmonary Tuberculosis in Lima, Peru.

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    Leonela Villegas

    Full Text Available Isoniazid and rifampicin are the two most efficacious first-line agents for tuberculosis (TB treatment. We assessed the prevalence of isoniazid and rifampicin mono-resistance, associated risk factors, and the association of mono-resistance on treatment outcomes.A prospective, observational cohort study enrolled adults with a first episode of smear-positive pulmonary TB from 34 health facilities in a northern district of Lima, Peru, from March 2010 through December 2011. Participants were interviewed and a sputum sample was cultured on Löwenstein-Jensen (LJ media. Drug susceptibility testing was performed using the proportion method. Medication regimens were documented for each patient. Our primary outcomes were treatment outcome at the end of treatment. The secondary outcome included recurrent episodes among cured patients within two years after completion of the treatment.Of 1292 patients enrolled, 1039 (80% were culture-positive. From this subpopulation, isoniazid mono-resistance was present in 85 (8% patients and rifampicin mono-resistance was present in 24 (2% patients. In the multivariate logistic regression model, isoniazid mono-resistance was associated with illicit drug use (adjusted odds ratio (aOR = 2.10; 95% confidence interval (CI: 1.1-4.1, and rifampicin mono-resistance was associated with HIV infection (aOR = 9.43; 95%CI: 1.9-47.8. Isoniazid mono-resistant patients had a higher risk of poor treatment outcomes including treatment failure (2/85, 2%, p-value<0.01 and death (4/85, 5%, p<0.02. Rifampicin mono-resistant patients had a higher risk of death (2/24, 8%, p<0.01.A high prevalence of isoniazid and rifampicin mono-resistance was found among TB patients in our low HIV burden setting which were similar to regions with high HIV burden. Patients with isoniazid and rifampicin mono-resistance had an increased risk of poor treatment outcomes.

  13. Effect of antacids in didanosine tablet on bioavailability of isoniazid.

    OpenAIRE

    Gallicano, K; Sahai, J; Zaror-Behrens, G; Pakuts, A

    1994-01-01

    The antacids in two didanosine placebo tablets had no significant effect on the plasma pharmacokinetics of a single oral dose of 300 mg of isoniazid administered to 12 healthy volunteers. These results suggest that isoniazid bioavailability will be unaffected by the antacids in didanosine tablets when the two medications are administered simultaneously to human immunodeficiency virus-seropositive patients.

  14. Effect of antacids in didanosine tablet on bioavailability of isoniazid.

    Science.gov (United States)

    Gallicano, K; Sahai, J; Zaror-Behrens, G; Pakuts, A

    1994-04-01

    The antacids in two didanosine placebo tablets had no significant effect on the plasma pharmacokinetics of a single oral dose of 300 mg of isoniazid administered to 12 healthy volunteers. These results suggest that isoniazid bioavailability will be unaffected by the antacids in didanosine tablets when the two medications are administered simultaneously to human immunodeficiency virus-seropositive patients.

  15. Controlled-release tablet formulation of isoniazid.

    Science.gov (United States)

    Jain, N K; Kulkarni, K; Talwar, N

    1992-04-01

    Guar (GG) and Karaya gums (KG) alone and in combination with hydroxy-propylmethylcellulose (HPMC) were evaluated as release retarding materials to formulate a controlled-release tablet dosage form of isoniazid (1). In vitro release of 1 from tablets followed non-Fickian release profile with rapid initial release. Urinary excretion studies in normal subjects showed steady-state levels of 1 for 13 h. In vitro and in vivo data correlated (r = 0.9794). The studies suggested the potentiality of GG and KG as release retarding materials in formulating controlled-release tablet dosage forms of 1.

  16. Emergency department management of children with acute isoniazid poisoning.

    Science.gov (United States)

    Parish, R A; Brownstein, D

    1986-06-01

    We suggest that the following therapeutic regimen be followed in cases of isoniazid poisoning in children. In cases of intractable seizure activity in a child which remains unexplained, consider isoniazid poisoning. Give pyridoxine as an intravenous bolus to all children in whom isoniazid toxicity is suspected, who exhibit seizure activity and are known to have been exposed to isoniazid, or who have a history of ingesting one gram or more of isoniazid. It should be given on a gram-for-gram basis, and the clinician need not await serum isoniazid levels before administering pyridoxine. It can be safely given at a rate of five grams per three minutes in a 50 ml volume. In fact, serum isoniazid determinations are not available in many emergency departments and have not been shown to correlate closely with symptomatology. When available, serum isoniazid levels at best are subject to variability owing to sampling procedures (serum protein must be removed within two hours of sampling). The result is that serum isoniazid levels play only a minor role in the emergency department management of isoniazid poisoning. To potentiate the antidotal effects of pyridoxine, diazepam (0.1 mg/kg) may be given intravenously, preferably at a second intravenous site. Because the lactic acidosis seen after seizures resolves spontaneously, and because metabolic alkalosis may result following excess lactate loading, administration of bicarbonate is usually not necessary, and may be harmful in some cases. After pyridoxine treatment, syrup of ipecac may be given to empty the stomach.(ABSTRACT TRUNCATED AT 250 WORDS)

  17. [Application of wavelet transform-radial basis function neural network in NIRS for determination of rifampicin and isoniazide tablets].

    Science.gov (United States)

    Lu, Jia-hui; Zhang, Yi-bo; Zhang, Zhuo-yong; Meng, Qing-fan; Guo, Wei-liang; Teng, Li-rong

    2008-06-01

    A calibration model (WT-RBFNN) combination of wavelet transform (WT) and radial basis function neural network (RBFNN) was proposed for synchronous and rapid determination of rifampicin and isoniazide in Rifampicin and Isoniazide tablets by near infrared reflectance spectroscopy (NIRS). The approximation coefficients were used for input data in RBFNN. The network parameters including the number of hidden layer neurons and spread constant (SC) were investigated. WT-RBFNN model which compressed the original spectra data, removed the noise and the interference of background, and reduced the randomness, the capabilities of prediction were well optimized. The root mean square errors of prediction (RMSEP) for the determination of rifampicin and isoniazide obtained from the optimum WT-RBFNN model are 0.00639 and 0.00587, and the root mean square errors of cross-calibration (RMSECV) for them are 0.00604 and 0.00457, respectively which are superior to those obtained by the optimum RBFNN and PLS models. Regression coefficient (R) between NIRS predicted values and RP-HPLC values for rifampicin and isoniazide are 0.99522 and 0.99392, respectively and the relative error is lower than 2.300%. It was verified that WT-RBFNN model is a suitable approach to dealing with NIRS. The proposed WT-RBFNN model is convenient, and rapid and with no pollution for the determination of rifampicin and isoniazide tablets.

  18. Spectroscopic and theoretical study of the o-vanillin hydrazone of the mycobactericidal drug isoniazid

    Science.gov (United States)

    González-Baró, Ana C.; Pis-Diez, Reinaldo; Parajón-Costa, Beatriz S.; Rey, Nicolás A.

    2012-01-01

    A complete and detailed study of the hydrazone obtained from condensation of antituberculous isoniazid (hydrazide of the isonicotinic acid, INH) and o-vanillin (2-hydroxy-3-methoxybenzaldehyde, o-HVa) is performed. It includes structural and spectroscopic analyses, comparing experimental and theoretical results. The compound was obtained as a chloride of the pyridinic salt (INHOVA +Cl -) but it will be referred as INHOVA for the sake of simplicity. The conformational space was searched and optimized geometries were determined both in gas phase and including solvent effects. Vibrational (IR and Raman), electronic and NMR spectra were registered and assigned with the help of computational methods based on the Density Functional Theory. Isoniazid hydrazones are good candidates for therapeutic agents against tuberculosis with conserved efficiency and lower toxicity and resistance than parent INH.

  19. Discovery of cofactor-specific, bactericidal Mycobacterium tuberculosis InhA inhibitors using DNA-encoded library technology.

    Science.gov (United States)

    Soutter, Holly H; Centrella, Paolo; Clark, Matthew A; Cuozzo, John W; Dumelin, Christoph E; Guie, Marie-Aude; Habeshian, Sevan; Keefe, Anthony D; Kennedy, Kaitlyn M; Sigel, Eric A; Troast, Dawn M; Zhang, Ying; Ferguson, Andrew D; Davies, Gareth; Stead, Eleanor R; Breed, Jason; Madhavapeddi, Prashanti; Read, Jon A

    2016-12-06

    Millions of individuals are infected with and die from tuberculosis (TB) each year, and multidrug-resistant (MDR) strains of TB are increasingly prevalent. As such, there is an urgent need to identify novel drugs to treat TB infections. Current frontline therapies include the drug isoniazid, which inhibits the essential NADH-dependent enoyl-acyl-carrier protein (ACP) reductase, InhA. To inhibit InhA, isoniazid must be activated by the catalase-peroxidase KatG. Isoniazid resistance is linked primarily to mutations in the katG gene. Discovery of InhA inhibitors that do not require KatG activation is crucial to combat MDR TB. Multiple discovery efforts have been made against InhA in recent years. Until recently, despite achieving high potency against the enzyme, these efforts have been thwarted by lack of cellular activity. We describe here the use of DNA-encoded X-Chem (DEX) screening, combined with selection of appropriate physical properties, to identify multiple classes of InhA inhibitors with cell-based activity. The utilization of DEX screening allowed the interrogation of very large compound libraries (10 11 unique small molecules) against multiple forms of the InhA enzyme in a multiplexed format. Comparison of the enriched library members across various screening conditions allowed the identification of cofactor-specific inhibitors of InhA that do not require activation by KatG, many of which had bactericidal activity in cell-based assays.

  20. Spirulina maxima Protects Liver From Isoniazid and Rifampicin Drug Toxicity.

    Science.gov (United States)

    Jatav, Santosh Kumar; Kulshrestha, Archana; Zacharia, Anish; Singh, Nita; Tejovathi, G; Bisen, P S; Prasad, G B K S

    2014-07-01

    Hepatotoxicity associated with isoniazid and rifampicin is one of the major impediments in antituberculosis therapy. The present study explored the prophylactic and therapeutic efficacies of Spirulina maxima in isoniazid and rifampicin induced hepatic damage in a rat model. Hepatic damage induced in Wistar rats by isoniazid and rifampicin resulted in significant alterations in biomarkers of liver function, namely, bilirubin, aspartate transaminase, alanine transaminase, alkaline phosphatase, and oxidative stress markers such as superoxide dismutase, catalase, glutathione, and thiobarbituric acid reactive substances. Co-administration of Spirulina maxima along with antituberculosis drugs protected liver from hepatotoxicity due to isoniazid and rifampicin. Administration of Spirulina maxima consecutively for 2 weeks to hepatodamaged animals resulted in restoration of hepatic function as evident from normalization of serum markers of liver function. Thus, the present study revealed remarkable prophylactic and therapeutic potential of Spirulina maxima. Co-administration of Spirulina maxima and antituberculosis drugs is advantageous as it provides extra nutritional benefit. © The Author(s) 2014.

  1. Implications of the 2015 World Health Organization isoniazid ...

    African Journals Online (AJOL)

    Isoniazid preventive therapy (IPT) is a key strategy recommended by the World ... In its continued effort to attain its vision of a Namibia where TB is no longer a ... In its health budget planning, the government of Namibia needs ... STATEMENT.

  2. HPLC identification of isoniazid residues in bovine milk

    Directory of Open Access Journals (Sweden)

    Leite R.M.H.

    2000-01-01

    Full Text Available The high pressure liquid chromatography (HPLC was used for the identification of isoniazid (isonicotinic acid hydrazide in the milk of cattle treated with a dose of 25 mg/kg/day in alternated days. The effect of milk pasteurization on the isoniazid residue concentration was also studied. The drug excretion presented a cyclic variation, with higher levels in the first day after administration (aa, a mean of 1104.48µg/l, and a decrease two days aa, with a mean of 104.12µg/l. Four days after the last administration of the drug it was not possible to identify residues of isoniazid in the milk of treated animals. Body weight and milk yield influenced the amount of the excreted drug, and pasteurization decreased (mean 47.07% the concentration of isoniazid residue in milk.

  3. Effects of isoniazid and niacin on experimental wound-healing

    DEFF Research Database (Denmark)

    Weinreich, Jürgen; Ågren, Sven Per Magnus; Bilali, Erol

    2010-01-01

    There is a need for effective treatments of ischemic wounds. Our aim was to test the hypothesis that systemic administration of isoniazid or niacin can enhance wound healing in ischemic as well as nonischemic tissues.......There is a need for effective treatments of ischemic wounds. Our aim was to test the hypothesis that systemic administration of isoniazid or niacin can enhance wound healing in ischemic as well as nonischemic tissues....

  4. Isoniazid release from suppositories compounded with selected bases.

    Science.gov (United States)

    Hudson, Kristofer C; Asbill, C Scott; Webster, Andrew A

    2007-01-01

    There is an increasing need for an alternative route of isoniazid adminstration for prophylaxis and treatment of tuberculosis in children. The purpose of this study is to evaluate the in vitro release of isoniazid from extemporaneously compounded isoniazid suppositories with a goal of optimizing the suppository dosage form for this indication. Suppositories were compounded using three different base formulations (cocoa butter, Witepsol H15 Base F, and a combination of polyethylene glycols 3350, 1000, and 400). The release profiles of six compounded suppositories with isoniazid (100 mg) were tested with a United States Pharmacopeial Convention-approved dissolution apparatus. Isoniazid concentrations at predetermined time points were determined using high-performance liquid chromatographic analysis. The results show that drug release from the water-solutble base (mixed polyethylene glycols) was significantly greater than that from the lipophilic bases (cocoa butter and Witepsol H15). The percentage of isoniazid release form the polyethylene glycol suppository formulation (70 +/- 1.4 mg/mL) was greater than that from the cocoa butter (55 +/- 1.1 mg/mL) and Witepsol H15 Base F (18 +/- 0.36 mg/mL) suppository formulations.

  5. A patient on RIPE therapy presenting with recurrent isoniazid-associated pleural effusions: a case report

    Directory of Open Access Journals (Sweden)

    Varenika Vanja

    2011-11-01

    Full Text Available Abstract Introduction The clinical scenario of a new or worsening pleural effusion following the initiation of antituberculous therapy has been classically referred to as a 'paradoxical' pleural response, presumably explained by an immunological rebound phenomenon. Emerging evidence suggests that there also may be a role for a lupus-related reaction in the pathophysiology of this disorder. Case presentation An 84-year-old Asian man treated with isoniazid, along with rifampin, pyrazinamide and ethambutol for suspected extrapulmonary tuberculosis, presented with a recurrent pleural effusion, his third episode since the initiation of this therapy. The first effusion occurred one month after the start of treatment, without any prior evidence of pulmonary tuberculosis involvement. Follow-up testing, including thoracoscopic pleural biopsies, never confirmed tuberculosis infection. Further evaluation yielded serological evidence suggesting drug-induced lupus. No effusions recurred following the discontinuation of isoniazid, although other antituberculosis medications were continued. Conclusion The immunological rebound construct is inconsistent with the evolution of this case, which indicates rather that drug-induced lupus may explain at least some cases of new pleural effusions following the initiation of isoniazid.

  6. [Determination of isoniazide concentration in pleural effusion and its pleural permeability in patients with tuberculous pleurisy].

    Science.gov (United States)

    Liu, Yuan; Zhang, Qing; Zhang, Junfeng; Huang, Guohua; Zhu, Shunfang; Liu, Sijia; Li, Guofeng

    2012-05-01

    To establish a high-performance liquid chromatography (HPLC)-based method for determining isoniazide concentration in pleural effusion and plasma of patients with tuberculous pleurisy, and evaluate the permeability of isoniazide from blood into pleural effusion. We collected pleural effusion from 15 patients with tuberculous pleurisy 2 h after administration 300 mg isoniazide in the morning of day 1. Pleural effusion and plasma were obtained 2 h after isoniazide administration on day 3. Isoniazide concentration was measured using HPLC, and the penetration rate of isoniazide in pleural effusion was calculated. Isoniazide concentration in the pleural effusion averaged 1.156∓1.190 µg/ml in the 15 patients at 2 h after isoniazide administration on day 1. On day 3, isoniazide concentration was 1.920∓1.294 µg/ml in the pleural effusion and 2.445∓1.463 µg/ml in the plasma, and the mean penetration rate of isoniazide from blood into the pleural effusion was 86.0%. As isoniazide has a high penetration rate into the pleural effusion in most patients, continuous oral administration of isoniazid has been sufficient to achieve an effective treatment concentration, and intrapleural injection of isoniazide may seem unnecessary for non-drug-resistant tuberculosis pleurisy.

  7. Development and Evaluation of Isoniazid Loaded Silk Fibroin Microsphere

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    Narinder Singh

    Full Text Available Aim: Current experimental investigation is dedicated to prepare microspheres with small size and good sphericity by Phase Separation method using Isoniazid (INH as model drug. Silk fibroin has unique intrinsic qualities like biodegradability, biocompatibility or release properties and their tunable drug loading capacity. The delivery loading proficiency of the drug molecules in silk spheres be contingent on their charge, and hydrophobicity or subsequent in altered drug release profiles. Methods: In the present work Isoniazid loaded silk fibroin microsphere was prepared by using phase separation method. Microsphere was evaluated for Ultraviolet-visible spectroscopy, Fourier Transform infrared spectroscopy, Entrapment efficiency, Scanning electron microscopy Studies. Results: Scanning electron microscopy studies revealed that Isoniazid Loaded Silk Fibroin Microspheres were spherical. Entrapment Efficiency of Isoniazid loaded Microspheres of different Formulation from F1 to F5 was in range of 53 to 68 %. F3 showed 68.47 % entrapment Efficiency and the optimized formulation drug release was 93.56 % at 24 hours. Conclusion: Experimental report disclosed a new aqueous based formulation method for silk spheres with controllable shape or size and sphere. Isoniazid loaded silk microspheres may act as ideal nano formulation with elaborated studies.

  8. Population pharmacokinetics of rifampicin, pyrazinamide and isoniazid in children with tuberculosis: in silico evaluation of currently recommended doses.

    Science.gov (United States)

    Zvada, Simbarashe P; Denti, Paolo; Donald, Peter R; Schaaf, H Simon; Thee, Stephanie; Seddon, James A; Seifart, Heiner I; Smith, Peter J; McIlleron, Helen M; Simonsson, Ulrika S H

    2014-05-01

    To describe the population pharmacokinetics of rifampicin, pyrazinamide and isoniazid in children and evaluate the adequacy of steady-state exposures. We used previously published data for 76 South African children with tuberculosis to describe the population pharmacokinetics of rifampicin, pyrazinamide and isoniazid. Monte Carlo simulations were used to predict steady-state exposures in children following doses in fixed-dose combination tablets in accordance with the revised guidelines. Reference exposures were derived from an ethnically similar adult population with tuberculosis taking currently recommended doses. The final models included allometric scaling of clearance and volume of distribution using body weight. Maturation was included for clearance of isoniazid and clearance and absorption transit time of rifampicin. For a 2-year-old child weighing 12.5 kg, the estimated typical oral clearances of rifampicin and pyrazinamide were 8.15 and 1.08 L/h, respectively. Isoniazid typical oral clearance (adjusted for bioavailability) was predicted to be 4.44, 11.6 and 14.6 L/h for slow, intermediate and fast acetylators, respectively. Higher oral clearance values in intermediate and fast acetylators also resulted from 23% lower bioavailability compared with slow acetylators. Simulations based on our models suggest that with the new WHO dosing guidelines and utilizing available paediatric fixed-dose combinations, children will receive adequate rifampicin exposures when compared with adults, but with a larger degree of variability. However, pyrazinamide and isoniazid exposures in many children will be lower than in adults. Further studies are needed to confirm these findings in children administered the revised dosages and to optimize pragmatic approaches to dosing.

  9. Fast BIA-amperometric determination of isoniazid in tablets.

    Science.gov (United States)

    Quintino, Maria S M; Angnes, Lúcio

    2006-09-26

    This paper proposes a new, fast and precise method to analyze isoniazid based on the electrochemical oxidation of the analyte at a glassy carbon electrode in 0.1M NaOH. The quantification was performed utilizing amperometry associated with batch injection analysis (BIA) technique. Fast sequential analysis (60 determinations h(-1)) in an unusually wide linear dynamic range (from 2.5 x 10(-8) to 1.0 x 10(-3)M), with high sensitivity and low limits of detection (4.1 x 10(-9)M) and quantification (1.4 x 10(-8)M), was achieved. Such characteristics allied to a good repeatability of the current responses (relative standard deviation of 0.79% for 30 measurements), were explored for the specific determination of isoniazid in isoniazid-rifampin tablet.

  10. Eligibility for isoniazid preventive therapy in South African gold mines.

    Directory of Open Access Journals (Sweden)

    James J Lewis

    Full Text Available The "Thibela TB" cluster randomised trial of community-wide isoniazid preventive therapy (IPT to reduce tuberculosis incidence in the South African gold mines.To determine the proportion of participants eligible for IPT and the reasons and risk factors for ineligibility, to inform the scale-up of IPT.Cross-sectional survey of participants in intervention clusters (mine shafts consenting to tuberculosis screening and assessment for eligibility to start IPT.Among 27,126 consenting participants, 94.7% were male, the median age was 41 years, 12.2% reported previous tuberculosis, 0.6% reported ever taking IPT and 2.5% reported currently taking antiretroviral therapy. There were 24,430 (90.1% assessed as eligible to start IPT, of whom 23,659 started IPT. The most common reasons for ineligibility were having suspected tuberculosis that was subsequently confirmed by a positive smear and/or culture (n=705, excessive alcohol consumption (n=427 and being on tuberculosis treatment at time of initial screen (n=241. Ineligibility was associated with factors including older age, female gender, prior history of tuberculosis and being in "HIV care". However, at least 78% were eligible for IPT in all of these sub-groups.The vast majority of participants in this community-wide intervention were eligible for IPT.

  11. Metabolism of isoniazid by neutrophil myeloperoxidase leads to isoniazid-NAD(+) adduct formation: A comparison of the reactivity of isoniazid with its known human metabolites.

    Science.gov (United States)

    Khan, Saifur R; Morgan, Andrew G M; Michail, Karim; Srivastava, Nutan; Whittal, Randy M; Aljuhani, Naif; Siraki, Arno G

    2016-04-15

    The formation of isonicotinyl-nicotinamide adenine dinucleotide (INH-NAD(+)) via the mycobacterial catalase-peroxidase enzyme, KatG, has been described as the major component of the mode of action of isoniazid (INH). However, there are numerous human peroxidases that may catalyze this reaction. The role of neutrophil myeloperoxidase (MPO) in INH-NAD(+) adduct formation has never been explored; this is important, as neutrophils are recruited at the site of tuberculosis infection (granuloma) through infected macrophages' cell death signals. In our studies, we showed that neutrophil MPO is capable of INH metabolism using electron paramagnetic resonance (EPR) spin-trapping and UV-Vis spectroscopy. MPO or activated human neutrophils (by phorbol myristate acetate) catalyzed the oxidation of INH and formed several free radical intermediates; the inclusion of superoxide dismutase revealed a carbon-centered radical which is considered to be the reactive metabolite that binds with NAD(+). Other human metabolites, including N-acetyl-INH, N-acetylhydrazine, and hydrazine did not show formation of carbon-centered radicals, and either produced no detectable free radicals, N-centered free radicals, or superoxide, respectively. A comparison of these free radical products indicated that only the carbon-centered radical from INH is reducing in nature, based on UV-Vis measurement of nitroblue tetrazolium reduction. Furthermore, only INH oxidation by MPO led to a new product (λmax=326nm) in the presence of NAD(+). This adduct was confirmed to be isonicotinyl-NAD(+) using LC-MS analysis where the intact adduct was detected (m/z=769). The findings of this study suggest that neutrophil MPO may also play a role in INH pharmacological activity. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Synthesis and antitubercular activity of isoniazid condensed with carbohydrate derivatives

    Directory of Open Access Journals (Sweden)

    Sílvia H. Cardoso

    2009-01-01

    Full Text Available A series of 13 compounds analogous of isoniazid condensed with carbohydrate was synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv using Alamar Blue susceptibility test and the activity expressed as the minimum inhibitory concentration (MIC90 in μg/mL. Several compounds exhibited antitubercular activity (0.31-3.12 μg/mL when compared with first line drugs such as isoniazid (INH and rifampicin (RIP and could be a good starting point to develop new compounds against tuberculosis.

  13. Penetapan Kadar Campuran Isoniazid dan Vitamin B6 dalam Sediaan Tablet Campuran Etambutol, Isoniazid dan Vitamin B6 Secara Spektrofotometri Derivatif dengan Metode Zero Crossing

    OpenAIRE

    Daulay, Elisa Fitri

    2016-01-01

    The compound of isoniazid and pyridoxine hydrochloride is one of combination in tablet. Determination of content of isoniazid and pyridoxine hydrochloride in tablet where not found in monography, either in the fourth edition Farmakope Indonesia (1995) or USP (United States Pharmacopeia) 30th edition (2007) that requires an analysis method that meets the test of validity in determining the content. The purpose of this research is to determine isoniazid and pyridoxine hydrochloride mixture us...

  14. Isoniazid prophylactic therapy for tuberculosis in HIV-seropositive ...

    African Journals Online (AJOL)

    Sensitivity analysis suggests that although a 6-month chemoprophylaxis policy appears justifiable on economic considerations, this is critically dependent on the annual risk of developing tuberculosis, patient compliance and the validity of assumptions on the efficacy and duration of protection of isoniazid prophylaxis.

  15. Mixed metal complexes of isoniazid and ascorbic acid: chelation ...

    African Journals Online (AJOL)

    Novel mixed complexes of isoniazid and ascorbic acid have been synthesized and characterized using infrared, electronic absorption data, elemental analysis, molar conductivity, melting point, thin layer chromatography and solubility. The metal ions involved in the complex formation are Cu2+, Zn2+ and Cd2+. The melting ...

  16. Uptake of isoniazid preventive therapy and its associated factors ...

    African Journals Online (AJOL)

    Background: Isoniazid Preventive Therapy (IPT) is an effective intervention for prevention of tuberculosis (TB) among HIV positive patients, and its use is recommended by the World Health Organization (WHO). Unfortunately the uptake of IPT in Kenya remains low (33%-40%) with limited knowledge on the factors that affect ...

  17. Mixed Metal Complexes of Isoniazid and Ascorbic Acid: Chelation ...

    African Journals Online (AJOL)

    HP

    these ligands and their metal complexes have revealed the bi-dentate coordination of isoniazid ligand to ... of the drugs on coordination with a metal is enhanced ..... James, O.O., Nwinyi, C.O. and. Allensela, M.A. (2008). Cobalt(II) complexes of mixed antibiotics: Synthesis,. Characterization, antimicrobial potential and their.

  18. Isoniazid prophylactic therapy for tuberculosis in HIV-seropositive ...

    African Journals Online (AJOL)

    hypothetical cohort of 100 000 HIV-seropositive people in. South Africa over a ... health sector resources can be utilised in an optimal manner. This article ... second part we estimate the costs and benefits of isoniazid preventive ... The cohort was stratified into ... population risk of dying from any cause, the number of dual.

  19. Enhancement of the infectivity of SARS-CoV in BALB/c mice by IMP dehydrogenase inhibitors, including ribavirin.

    Science.gov (United States)

    Barnard, Dale L; Day, Craig W; Bailey, Kevin; Heiner, Matthew; Montgomery, Robert; Lauridsen, Larry; Winslow, Scott; Hoopes, Justin; Li, Joseph K-K; Lee, Jongdae; Carson, Dennis A; Cottam, Howard B; Sidwell, Robert W

    2006-08-01

    Because of the conflicting data concerning the SARS-CoV inhibitory efficacy of ribavirin, an inosine monophosphate (IMP) dehydrogenase inhibitor, studies were done to evaluate the efficacy of ribavirin and other IMP dehydrogenase inhibitors (5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR), mizoribine, and mycophenolic acid) in preventing viral replication in the lungs of BALB/c mice, a replication model for severe acute respiratory syndrome (SARS) infections (Subbarao, K., McAuliffe, J., Vogel, L., Fahle, G., Fischer, S., Tatti, K., Packard, M., Shieh, W.J., Zaki, S., Murphy, B., 2004. Prior infection and passive transfer of neutralizing antibody prevent replication of severe acute respiratory syndrome coronavirus (SARS-CoV) in the respiratory tract of mice. J. Virol. 78, 3572-3577). Ribavirin given at 75 mg/kg 4 h prior to virus exposure and then given twice daily for 3 days beginning at day 0 was found to increase virus lung titers and extend the length of time that virus could be detected in the lungs of mice. Other IMP dehydrogenase inhibitors administered near maximum tolerated doses using the same dosing regimen as for ribavirin were found to slightly enhance virus replication in the lungs. In addition, ribavirin treatment seemed also to promote the production of pro-inflammatory cytokines 4 days after cessation of treatment, although after 3 days of treatment ribavirin inhibited pro-inflammatory cytokine production in infected mice, significantly reducing the levels of the cytokines IL-1alpha, interleukin-5 (IL-5), monocyte chemotactic protein-1 (MCP-1), and granulocyte-macrophage colony stimulating factor (GM-CSF). These findings suggest that ribavirin may actually contribute to the pathogenesis of SARS-CoV by prolonging and/or enhancing viral replication in the lungs. By not inhibiting viral replication in the lungs of infected mice, ribavirin treatment may have provided a continual source of stimulation for the inflammatory response

  20. Relative bioavailability of rifampicin, isoniazid and ethambutol from a combination tablet vs. concomitant administration of a capsule containing rifampicin and a tablet containing isoniazid and ethambutol.

    Science.gov (United States)

    Schall, R; Müller, F O; Duursema, L; Groenewoud, G; Hundt, H K; Middle, M V; Mogilnicka, E M; Swart, K J

    1995-11-01

    Twenty male volunteers who were slow metabolisers of isoniazid, completed this single-blind, single-dose, randomised, cross-over study to compare the bioavailability of rifampicin (CAS 13292-46-1), isoniazid (CAS 54-85-3) and ethambutol (CAS 1070-11-7) from Myrin tablets (test preparation) with the bioavailability of these drugs from a combination of capsules containing rifampicin and tablets containing isoniazid and ethambutol (reference). There were 2 treatment periods and on clinic days volunteers were given either the reference (300 mig rifampicin plus 200 mg isoniazid and 600 mg ethambutol HCl), or the test preparation (300 mg rifampicin, 150 mg isoniazid and 600 mg ethambutol HCl). Serial blood samples were drawn from the volunteers and rifampicin, isoniazid and ethambutol assays were performed. The results of this study indicate that the test preparation is equivalent to the reference with respect to both the rate and the extent of absorption of rifampicin, isoniazid (after adjustment for the different doses of isoniazid and ethambutol).

  1. Phosphodiesterase-4 inhibition combined with isoniazid treatment of rabbits with pulmonary tuberculosis reduces macrophage activation and lung pathology.

    Science.gov (United States)

    Subbian, Selvakumar; Tsenova, Liana; O'Brien, Paul; Yang, Guibin; Koo, Mi-Sun; Peixoto, Blas; Fallows, Dorothy; Zeldis, Jerome B; Muller, George; Kaplan, Gilla

    2011-07-01

    Tuberculosis (TB) is responsible for significant morbidity and mortality worldwide. Even after successful microbiological cure of TB, many patients are left with residual pulmonary damage that can lead to chronic respiratory impairment and greater risk of additional TB episodes due to reinfection with Mycobacterium tuberculosis. Elevated levels of the proinflammatory cytokine tumor necrosis factor-α and several other markers of inflammation, together with expression of matrix metalloproteinases, have been associated with increased risk of pulmonary fibrosis, tissue damage, and poor treatment outcomes in TB patients. In this study, we used a rabbit model of pulmonary TB to evaluate the impact of adjunctive immune modulation, using a phosphodiesterase-4 inhibitor that dampens the innate immune response, on the outcome of treatment with the antibiotic isoniazid. Our data show that cotreatment of M. tuberculosis infected rabbits with the phosphodiesterase-4 inhibitor CC-3052 plus isoniazid significantly reduced the extent of immune pathogenesis, compared with antibiotic alone, as determined by histologic analysis of infected tissues and the expression of genes involved in inflammation, fibrosis, and wound healing in the lungs. Combined treatment with an antibiotic and CC-3052 not only lessened disease but also improved bacterial clearance from the lungs. These findings support the potential for adjunctive immune modulation to improve the treatment of pulmonary TB and reduce the risk of chronic respiratory impairment. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  2. MicroRNA-122 is involved in oxidative stress in isoniazid-induced liver injury in mice.

    Science.gov (United States)

    Song, L; Zhang, Z R; Zhang, J L; Zhu, X B; He, L; Shi, Z; Gao, L; Li, Y; Hu, B; Feng, F M

    2015-10-27

    Many studies have shown that the pathogenesis of liver injury includes oxidative stress. MicroRNA-122 may be a marker for the early diagnosis of drug-induced liver injury. However, the relationship between microRNA-122 and oxidative stress in anti-tuberculosis drug-induced liver injury remains unknown. We measured changes in tissue microRNA-122 levels and indices of oxidative stress during liver injury in mice after administration of isoniazid, a first-line anti-tuberculosis drug. We quantified microRNA-122 expression and indices of oxidative stress at 7 time points, including 1, 3, and 5 days and 1, 2, 3, and 4 weeks. The tissue microRNA-122 levels and oxidative stress significantly changed at 3 and 5 days, suggesting that isoniazid-induced liver injury reduces oxidative stress and microRNA-122 expression compared to in the control group (P microRNA-122, began to change at 5 days (P microRNA-122 profile may affect oxidative stress by regulating mitochondrial ribosome protein S11 gene during isoniazid-induced liver injury, which may contribute to the response mechanisms of microRNA-122 and oxidative stress.

  3. Penggunaan Pati Sitrat sebagai Bahan Pengembang Tablet Isoniazid

    OpenAIRE

    Darmayasari, Intan

    2016-01-01

    inder. The modified starch is a starch which its hydroxyl group has been modified or given specific treatment for example by heating. Citrate starch is a modified starch which has good flow property and ability to expand and improve the dissolution rate of poorly soluble drugs. Based on descriptions above, the researcher to do research about use of citrate starch that synthesizing from cassava starch as swelling substance of isoniazid tablet. Objective: The aim of this study is to know abo...

  4. Isoniazid-Associated Uric Acid Retention in the Lizard, Uromastix ...

    African Journals Online (AJOL)

    Reduction in uric acid excretion was observed following oral administration of 0.06 mg isoniazid per day for 5, 10 and 15 days to three groups of Uromastix hardwickii lizards. The rise of serum uric acid levels in the treated groups was 60 per cent higher on day 5, and about 4 and 5 times greater than in control groups on day ...

  5. Ultrastructural characteristics of type A epithelioid cells during BCG-granulomatosis and treatment with lysosomotropic isoniazid.

    Science.gov (United States)

    Shkurupii, V A; Kozyaev, M A; Nadeev, A P

    2006-04-01

    We studied BCG-granulomas, their cellular composition, and ultrastructure of type A epithelioid cells in the liver of male BALB/c mice with spontaneous granulomatous inflammation. The animals received free isoniazid or isoniazid conjugated with lysosomotropic intracellularly prolonged matrix (dialdehyde dextran, molecular weight 65-75 kDa). Lysosomotropic isoniazid was accumulated in the vacuolar apparatus of epithelioid cells and produced a stimulatory effect on plastic processes in these cells.

  6. Histomorphological effects of isoniazid induced hepatotoxicity in male albino mice

    International Nuclear Information System (INIS)

    Humayun, F.; Zareen, N.

    2017-01-01

    To observe the histomorphological changes of isoniazid induced hepatotoxicity in male albino mice. Methodology: This experimental study was carried out at University of Health Sciences, Lahore, Pakistan from January to December 2013. Forty male albino mice selected by simple random technique, were divided into two groups; A-Control, and B-experimental. Group A comprised of 15, while Group B comprised 25 mice. Both the groups were kept under identical conditions and diet. However, experimental group was treated with an additional oral hepatotoxic dose of isoniazid i.e. 100mg/kg bodyweight daily for 30 days. After 30 days, the animals were sacrificed and livers were dissected out. Gross comparison of the organ and stained sections were histologically compared for morphological differences between the groups. Fischer Exact test was used to analyze the qualitative data and a p<0.05 was considered significant. Results: Group A animals showed the normal liver architecture. Whereas, those of Group B showed deranged hepatic histomorphology. Conclusion: Hepatotoxic dose of Isoniazid caused histomorphological alterations in the liver of male albino mice. (author)

  7. CYP2E1-dependent elevation of serum cholesterol, triglycerides, and hepatic bile acids by isoniazid

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Jie; Krausz, Kristopher W. [Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States); Li, Feng; Ma, Xiaochao [Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, 4089 KLSIC, MS 1018, 3901 Rainbow Boulevard, Kansas City, KS 66160 (United States); Gonzalez, Frank J., E-mail: fjgonz@helix.nih.gov [Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States)

    2013-01-15

    Isoniazid is the first-line medication in the prevention and treatment of tuberculosis. Isoniazid is known to have a biphasic effect on the inhibition–induction of CYP2E1 and is also considered to be involved in isoniazid-induced hepatotoxicity. However, the full extent and mechanism of involvement of CYP2E1 in isoniazid-induced hepatotoxicity remain to be thoroughly investigated. In the current study, isoniazid was administered to wild-type and Cyp2e1-null mice to investigate the potential toxicity of isoniazid in vivo. The results revealed that isoniazid caused no hepatotoxicity in wild-type and Cyp2e1-null mice, but produced elevated serum cholesterol and triglycerides, and hepatic bile acids in wild-type mice, as well as decreased abundance of free fatty acids in wild-type mice and not in Cyp2e1-null mice. Metabolomic analysis demonstrated that production of isoniazid metabolites was elevated in wild-type mice along with a higher abundance of bile acids, bile acid metabolites, carnitine and carnitine derivatives; these were not observed in Cyp2e1-null mice. In addition, the enzymes responsible for bile acid synthesis were decreased and proteins involved in bile acid transport were significantly increased in wild-type mice. Lastly, treatment of targeted isoniazid metabolites to wild-type mice led to similar changes in cholesterol, triglycerides and free fatty acids. These findings suggest that while CYP2E1 is not involved in isoniazid-induced hepatotoxicity, while an isoniazid metabolite might play a role in isoniazid-induced cholestasis through enhancement of bile acid accumulation and mitochondria β-oxidation. -- Highlights: ► Isoniazid metabolites were elevated only in wild-type mice. ► Isoniazid caused no hepatotoxicity in wild-type and Cyp2e1-null mice. ► Isoniazid elevated serum cholesterol and triglycerides, and hepatic bile acids. ► Bile acid transporters were significantly decreased in isoniazid-treated mice.

  8. CYP2E1-dependent elevation of serum cholesterol, triglycerides, and hepatic bile acids by isoniazid

    International Nuclear Information System (INIS)

    Cheng, Jie; Krausz, Kristopher W.; Li, Feng; Ma, Xiaochao; Gonzalez, Frank J.

    2013-01-01

    Isoniazid is the first-line medication in the prevention and treatment of tuberculosis. Isoniazid is known to have a biphasic effect on the inhibition–induction of CYP2E1 and is also considered to be involved in isoniazid-induced hepatotoxicity. However, the full extent and mechanism of involvement of CYP2E1 in isoniazid-induced hepatotoxicity remain to be thoroughly investigated. In the current study, isoniazid was administered to wild-type and Cyp2e1-null mice to investigate the potential toxicity of isoniazid in vivo. The results revealed that isoniazid caused no hepatotoxicity in wild-type and Cyp2e1-null mice, but produced elevated serum cholesterol and triglycerides, and hepatic bile acids in wild-type mice, as well as decreased abundance of free fatty acids in wild-type mice and not in Cyp2e1-null mice. Metabolomic analysis demonstrated that production of isoniazid metabolites was elevated in wild-type mice along with a higher abundance of bile acids, bile acid metabolites, carnitine and carnitine derivatives; these were not observed in Cyp2e1-null mice. In addition, the enzymes responsible for bile acid synthesis were decreased and proteins involved in bile acid transport were significantly increased in wild-type mice. Lastly, treatment of targeted isoniazid metabolites to wild-type mice led to similar changes in cholesterol, triglycerides and free fatty acids. These findings suggest that while CYP2E1 is not involved in isoniazid-induced hepatotoxicity, while an isoniazid metabolite might play a role in isoniazid-induced cholestasis through enhancement of bile acid accumulation and mitochondria β-oxidation. -- Highlights: ► Isoniazid metabolites were elevated only in wild-type mice. ► Isoniazid caused no hepatotoxicity in wild-type and Cyp2e1-null mice. ► Isoniazid elevated serum cholesterol and triglycerides, and hepatic bile acids. ► Bile acid transporters were significantly decreased in isoniazid-treated mice.

  9. Isoniazid-resistant tuberculosis in Denmark: mutations, transmission and treatment outcome

    DEFF Research Database (Denmark)

    Bang, Didi; Andersen, Peter Henrik; Andersen, Ase Bengaard

    2010-01-01

    A retrospective study on isoniazid-resistant tuberculosis (TB) was conducted in the low-burden country, Denmark (DK). The aim was to describe treatment outcome and transmission and to evaluate a mutation analysis for high- and low-level isoniazid resistance detection.......A retrospective study on isoniazid-resistant tuberculosis (TB) was conducted in the low-burden country, Denmark (DK). The aim was to describe treatment outcome and transmission and to evaluate a mutation analysis for high- and low-level isoniazid resistance detection....

  10. Do not overlook acute isoniazid poisoning in children with status epilepticus.

    Science.gov (United States)

    Caksen, Hüseyin; Odabas, Dursun; Erol, Mehmet; Anlar, Omer; Tuncer, Oguz; Atas, Bülent

    2003-02-01

    A previously healthy 2-year-old girl was admitted with generalized convulsive status epilepticus. She was in a stupor and could respond only to painful stimuli. She also had severe metabolic acidosis. Although initial liver function tests were normal, they were found to be moderately high on the fifth day of admission; however, they dropped to their normal ranges on the twelfth day of admission. Initially, the patient was diagnosed as having idiopathic status epilepticus, and classic anticonvulsant agents, including diazepam, phenytoin, and then phenobarbital, were given. However, her seizures did not subside, and diazepam infusion was initiated. After initiation of diazepam infusion, the seizures were completely controlled. On the fourth day of admission, her parents said that she had accidentally received 20 tablets (a total dose of 2000 mg) of isoniazid just before admission to our hospital. Later, we injected 200 mg of pyridoxine intravenously. During follow-up, her general condition improved, and anticonvulsant agents were discontinued because an electroencephalogram was found to be norma. She was discharged from the hospital on the twelfth day of admission. At the fourth month of follow-up, she was seizure free. Because of this case, we would like to re-emphasize that acute isoniazid poisoning should also be considered in a child with unexplained status epilepticus.

  11. Antioxidant activity of Green tea extract against Isoniazid induced hepatotoxicity in the rats

    Directory of Open Access Journals (Sweden)

    2011-08-01

    Full Text Available Tuberculosis continues to be a common health problem worldwide. Isoniazid, an antibiotic used routinely for tuberculosis chemotherapy is documented to be a potent hepatotoxicant. The aim of the present study was to assess the antioxidant activity of Green tea extract (GTE against Isoniazid induced hepatotoxicity in the rats. Male Wistar rats were randomly assigned into 4 groups of 10 animals each including 1- normal healthy control rats, 2- healthy rats receiving (GTE 3- toxicant control, and 4- toxicant drug+ GTE treatment group. In groups 2 and 4 GTE (1.5%, w/v was given as only source of drinking for 8 weeks. In the midst stage of experiment (4th and 5th weeks, Isonizid (50 mg/kg b.w./day, i.p. was administrated for groups 3 and 4 for a period of 2 weeks. At the end of experiment, product of lipid peroxidation (MDA, activities of superoxide dismutase (SOD, catalase (CAT, glutathione peroxidase (GPX and glutathione reductase (GR were assayed in liver homogenates to evaluate antioxidant activity. Significant differences among the groups were determined by one-way analysis of variance followed by Tukey post-test. Statistical significance was considered at p

  12. Penetapan Kadar Campuran Isoniazid Dan Vitamin B6 Dalam Sediaan Tablet Secara Spektrofotometri Ultraviolet Dengan Perhitungan Multikomponen Dan Persamaan Matriks

    OpenAIRE

    Sari, Wardah Kumala

    2011-01-01

    Isoniazid is a drug that is effective in the treatment of tuberculosis. In trading Isoniazid is often combined with Vitamin B6 which aims to prevent side effects of Isoniazid in the form of peripheral neuritis. The combination of active ingredients that can cause problems in quantitative analysis for quality control preparations. In this research, determination of the combination tablet Vitamin B6 and Isoniazid by Ultraviolet spectrophotometry with multicomponent calculation and use the matri...

  13. Penetapan Kadar Campuran Rifampisin dan Isoniazid dalam Sediaan Tablet Secara Spektrofotometri Ultraviolet dengan Metode Panjang Gelombang Berganda

    OpenAIRE

    Sitorus, Riris Anugrah Rema

    2016-01-01

    The drugs used for tuberculosis were classified into two groups, there is primary drugs and secondary drugs. Rifampicin and isoniazid are the primary drugs. Combination of rifampicin and isoniazid in the tablet is one of the drugs that used in tuberculosis treatment. Combination of rifampicin and isoniazid in the tablet is one of the drugs that used in tuberculosis treatment. The purpose of this study is to determination value of rifampicin and isoniazid in tablets which circulates in the gen...

  14. Computer-aided construction and investigation of a thermodynamically stable mouth-dissolving film containing isoniazid

    CSIR Research Space (South Africa)

    Adeleke, Oluwatoyin A

    2015-10-01

    Full Text Available The purpose of this abstract is to design and characterize a thermodynamically stable mouth-dissolving film containing isoniazid employing in silico and in vitro techniques. Isoniazid (solubility = 140 mg/mL and log P = -0.64 at 25°C) is a first...

  15. Influence of isoniazid on naturally acquired tuberculin allergy and on induction of allergy by BCG vaccination*

    Science.gov (United States)

    Narain, Raj; Bagga, A. S.; Naganna, K.; Mayurnath, S.

    1970-01-01

    Previous studies on the influence of isoniazid on the size of the tuberculin reaction have given conflicting results. A controlled study in an area with high prevalence of low-grade allergy has been carried out by the administration of isoniazid or placebo tablets. For those not vaccinated with BCG, isoniazid in a single daily dose of 5 mg/kg body-weight tended to reduce somewhat the size of the tuberculin reaction among those with reactions of 12 mm or more at the initial tuberculin test. In people who were vaccinated with BCG, isoniazid given simultaneously resulted in significantly less increase in the size of post-vaccination tuberculin reactions as compared with controls; the difference was still significant, in tests conducted 4½ months after the discontinuation of isoniazid. However, in spite of isoniazid, the post-vaccination allergy induced by BCG was quite considerable. This considerable increase in post-vaccination allergy suggests that the vaccination was successful in spite of the administration of isoniazid and makes it clear that primary chemoprophylaxis could be combined with BCG vaccination. Administration of isoniazid for 2 months is estimated to have killed about 90% of the bacilli in the BCG vaccine injected intracutaneously. PMID:5312322

  16. Efficacy of a protocol including heparin ointment for treatment of multikinase inhibitor-induced hand-foot skin reactions.

    Science.gov (United States)

    Li, Jian-ri; Yang, Chi-rei; Cheng, Chen-li; Ho, Hao-chung; Chiu, Kun-yuan; Su, Chung-Kuang; Chen, Wen-Ming; Wang, Shian-Shiang; Chen, Chuan-Shu; Yang, Cheng-Kuang; Ou, Yen-chuan

    2013-03-01

    The purpose of this study is to evaluate the efficacy of a protocol including topical heparin therapy for hand-foot skin reactions (HFSR) during multikinase (MKI) treatment. We prospectively collected 26 patients who had HFSRs during treatment with the MKIs, sunitinib, sorafenib, or axitinib. The age distribution ranged from 46 to 87 years, with a mean of 66 years. The distribution of HFSR severity was 12 patients with grade 1, 12 with grade 2, and 2 with grade 3. A heparin-containing topical ointment treatment, combined with hand-foot shock absorbers and skin moisturizers, was used at the lesion sites. Changes in the grade of HFSR, MKI dosage, and interruptions of MKI therapy were recorded. The results showed that 66.7% of grade 1 patients were cured of disease, 83.3% of grade 2 patients had improved symptoms, and both grade 3 patients (100%) had improved symptoms and were downgraded to grade 2. Four (15.4%) patients required reduction of MKI dosage, but there were no treatment interruptions or dropouts. Our protocol is beneficial in promoting resolution of HFSRs induced by MKIs. Further validation in large control studies should be investigated.

  17. Isoniazid completion rates for latent tuberculosis infection among college students managed by a community pharmacist.

    Science.gov (United States)

    Hess, Karl; Goad, Jeffery; Wu, Joanne; Johnson, Kathleen

    2009-01-01

    The authors' objective was to document 9-month and previously recommended 6-month treatment completion rates for latent tuberculosis infection (LTBI) in a pharmacist-managed LTBI clinic in a community pharmacy on a college campus, and to describe patient characteristics. Participants were university students diagnosed with LTBI. The authors conducted a retrospective review of pharmacy records from 2000 to 2006. Main outcome measures included 6-month and 9-month LTBI treatment completion rates, total isoniazid (INH) tablets taken, characteristics of completers versus noncompleters, average time to treatment completion, and reported adverse drug events. The 9-month completion rate was 59%, and the 6-month completion rate was 67%. Among those not completing treatment, 15.2% experienced fatigue and 2.2% experienced a rash (p=.04 and p=.03, respectively). LTBI clinics are a unique niche for community pharmacies and can provide individualized patient care to ensure LTBI treatment adherence, monitoring for disease progression, and safety of INH.

  18. Highly active antiretroviral therapy including protease inhibitors does not confer a unique CD4 cell benefit. The AVANTI and INCAS Study Groups.

    Science.gov (United States)

    2000-07-07

    To determine if triple combination therapy, particularly including HIV protease inhibitors (PI), confers an unique immunological benefit that is independent of reductions of plasma viral load (pVL). The correlation between changes from baseline in CD4 cell count and pVL was examined at all time points up to 52 weeks in three randomized clinical trials (AVANTI-2, AVANTI-3 and INCAS) that compared dual nucleoside therapy with triple combination therapy. Individual pVL and CD4 cell counts changes from baseline were entered into multivariate linear regression models for patients receiving double therapy and for those receiving triple therapy including a PI and/or a non-nucleoside reverse transcriptase inhibitor (NNRTI), and the null hypothesis was tested. After 52 weeks of therapy, the relationship between changes from baseline CD4 cell count and pVL was independent of whether patients were assigned double or triple therapy (P = 0.23 and 0.69 for intercept and slope, respectively), or whether patients were assigned triple therapy including a PI or triple therapy including an NNRTI (P = 0.92 and 0.95, respectively). Less than 5% of patients ever had 'discordant' increases in both CD4 cell count and pVL compared with baseline, and this proportion was unrelated to the class of therapy used. 'Discordant' decreases from baseline in both parameters were observed in up to 35% of individuals. The correlation between pVL and CD4 cell count changes from baseline improved over time on therapy, regardless of the therapeutic regimen involved. The data provide no evidence for a CD4 cell count benefit of highly active antiretroviral therapy (HAART) unique to triple therapy or PI-containing regimens.

  19. Development of a three component complex to increase isoniazid efficacy against isoniazid resistant and nonresistant Mycobacterium tuberculosis.

    Science.gov (United States)

    Manning, Thomas; Plummer, Sydney; Baker, Tess; Wylie, Greg; Clingenpeel, Amy C; Phillips, Dennis

    2015-10-15

    The bacterium responsible for causing tuberculosis has evolved resistance to antibiotics used to treat the disease, resulting in new multidrug resistant Mycobacterium tuberculosis (MDR-TB) and extensively drug resistant M. tuberculosis (XDR-TB) strains. Analytical techniques (1)H and (13)C Nuclear Magnetic Resonance (NMR), Fourier Transform-Ion Cyclotron Resonance with Electrospray Ionization (FT-ICR/ESI), and Matrix Assisted Laser Desorption Ionization-Mass Spectrometry (MALDI-TOF-MS) were used to study different aspects of the Cu(II)-polyethylene glycol (PEG-3350)-sucrose-isoniazid and Cu(II)-polyethylene glycol (PEG3350)-glucose-isoniazid complexes. The Cu(II) cation, sucrose or glucose, and the aggregate formed by PEG primarily serve as a composite drug delivery agent for the frontline antibiotic, however the improvement in MIC values produced with the CU-PEG-SUC-INH complex suggest an additional effect. Several Cu-PEG-SUC-INH complex variations were tested against INH resistant and nonresistant strains of M. tuberculosis. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. PREPARATION OF ISONIAZID AS DRY POWDER FORMULATIONS FOR INHALATION BY PHYSICAL MIXING AND SPRAY DRYING

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    SOMCHAI SAWATDEE

    2006-01-01

    Full Text Available The main purpose of this study is to develop isoniazid as dry powder aerosol for delivery to the lower airways and to study the susceptibility of M. bovis and M. tuberculosis to the formulationsstudied. Isoniazid was formulated with trehalose, mannose and lactose by physical mixing and spray drying techniques. All formulations were evaluated for delivery efficiency and stability.Susceptibility tests of Mycobacterium species to the drug formulations were carried out. Isoniazid mixed with fine trehalose, micronised mannose or fine lactose produced the formulations whichgave fine particle fraction ( 0.05.

  1. Flow-injection system for automated dissolution testing of isoniazid tablets with chemiluminescence detection.

    Science.gov (United States)

    Li, B; Zhang, Z; Liu, W

    2001-05-30

    A simple and sensitive flow-injection chemiluminescence (CL) system for automated dissolution testing is described and evaluated for monitoring of dissolution profiles of isoniazid tablets. The undissolved suspended particles in the dissolved solution were eliminated via on-line filter. The novel CL system of KIO(4)-isoniazid was also investigated. The sampling frequency of the system was 120 h(-1). The dissolution profiles of isoniazid fast-release tablets from three sources were determined, which demonstrates the stability, great sensitivity, large dynamic measuring range and robustness of the system.

  2. Pregnancy Outcomes in HIV-Infected Women Receiving Long-Term Isoniazid Prophylaxis for Tuberculosis and Antiretroviral Therapy

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    Allan W. Taylor

    2013-01-01

    Full Text Available Objective. While 6- to 12-month courses of isoniazid for tuberculosis prevention are considered safe in pregnant women, the effects of longer-term isoniazid prophylaxis or isoniazid in combination with antiretroviral therapy (ART are not established in human-immunodeficiency-virus-(HIV- infected women who experience pregnancy during the course of therapy. Design. Nested study of pregnancy outcomes among HIV-infected women participating in a placebo-controlled, TB-prevention trial using 36 months daily isoniazid. Pregnancy outcomes were collected by interview and record review. Results. Among 196 pregnant women, 103 (52.6% were exposed to isoniazid during pregnancy; all were exposed to antiretroviral drugs. Prior to pregnancy they had received a median of 341 days (range 1–1095 of isoniazid. We observed no isoniazid-associated hepatitis or other severe isoniazid-associated adverse events in the 103 women. Pregnancy outcomes were 132 term live births, 42 premature births, 11 stillbirths, 8 low birth weight, 6 spontaneous abortions, 4 neonatal deaths, and 1 congenital abnormality. In a multivariable model, neither isoniazid nor ART exposure during pregnancy was significantly associated with adverse pregnancy outcome (adjusted odds ratios 0.6, 95% CI: 0.3–1.1 and 1.8, 95% CI 0.9–3.6, resp.. Conclusions. Long-term isoniazid prophylaxis was not associated with adverse pregnancy outcomes, such as preterm delivery, even in the context of ART exposure.

  3. Poly(amidosulfonic acid) modified glassy carbon electrode for determination of isoniazid in pharmaceuticals.

    Science.gov (United States)

    Yang, Gongjun; Wang, Cunxiao; Zhang, Rui; Wang, Chenying; Qu, Qishu; Hu, Xiaoya

    2008-06-01

    Amidosulfonic acid was electropolymerized by cyclic voltammetry onto the surface of glassy carbon electrode (GCE) to fabricate the chemically modified electrode, which showed high stability, good selectivity and reproducibility for determination of isoniazid. The modified electrode showed an excellent electrocatalytical effect on the oxidation of isoniazid. Under the optimum conditions, there was a good linear relationship between anodic peak current and isoniazid concentration in the range of 5.0 x 10(-8)- 1.0 x 10(-5) M, and a detection limit of 1.0 x 10(-8) M (S/N = 3) was obtained after 120 s at the accumulation potential of - 0.2 V (vs. SCE). This developed method had been applied to the direct determination of isoniazid in injection and tablet samples with satisfactory results.

  4. Penetration of isoniazid, rifampicin and pyrazinamide in tuberculous pleural effusion and psoas abscess

    NARCIS (Netherlands)

    Jutte, P.C.; Rutgers, S.R.; Van Altena, R.; Uges, D.R.; van Horn, J.R.

    2004-01-01

    SETTING: Tuberculosis Centre, University Medical Centre, Groningen, The Netherlands. OBJECTIVES: To study intralesional concentrations of isoniazid (INH), rifampicin (RMP) and pyrazinamide (PZA) in tuberculous pleural effusions and psoas abscesses, and to compare these to reference serum values and

  5. Penetration of isoniazid, refampicin and pyrazinamide in tuberculous pleural effusion and psoas abscess

    NARCIS (Netherlands)

    Jutte, PC; Rutgers, [No Value; Van Altena, R; Uges, DR; Van Horn, [No Value

    SETTING: Tuberculosis Centre, University Medical Centre, Groningen, The Netherlands. OBJECTIVES: To study intralesional concentrations of isoniazid (INH), rifampicin (RMP) and pyrazinamide (PZA) in tuberculous pleural effusions and psoas abscesses, and to compare these to reference serum values and

  6. Electrocatalytic Determination of Isoniazid by a Glassy Carbon Electrode Modified with Poly (Eriochrome Black T)

    OpenAIRE

    Karim Asadpour-Zeynali; Venus Baghalabadi

    2017-01-01

    In this work poly eriochrome black T (EBT) was electrochemically synthesized on the glassy carbon electrode as electrode modifier. On the modified electrode, voltammetric behavior of isoniazid (INH) was investigated. The poly (EBT)-modified glassy carbon electrode has excellent electrocatalytic ability for the electrooxidation of isoniazid. This fact was appeared as a reduced overpotential of INH oxidation in a wide operational pH range from 2 to 13. It has been found that the catalytic peak ...

  7. PHARMACOECONOMIC ASPECTS OF TREATMENT WITH THE INHIBITORS OF TUMOR NECROSIS FACTOR OF THE CHRONIC UVEITIS REFRACTORY TO THE BASIC THERAPY (INCLUDING AN ASSOCIATED WITH JUVENILE IDIOPATHIC ARTHRITIS

    Directory of Open Access Journals (Sweden)

    A.V. Rudakova

    2011-01-01

    Full Text Available Therapy of chronic uveitis refractory to the basic treatment, in juvenile idiopathic arthritis (JIA is a very complex problem in pediatrics. Substantial progress in this area resulted after the implementation in practice of inhibitors of tumor necrosis factor (TNF, as the most effective in such clinical situation drugs adalimumab and infliximab are considered (although infliximab was not officially approved in JIA. Objective. To estimate the cost effectiveness of TNF inhibitors — adalimumab, and infliximab in chronic uveitis, refractory to the basic therapy (including associated with juvenile rheumatoid arthritis. Methods. A modeling on the basis of a comparative prospective cohort clinical study was carried out. The analysis was performed by the method «cost–effectiveness» from a position of health and social accounting perspective. Results. It was shown that the frequency and time of remission did not differ when treatment with infliximab (5 mg/kg at 0–2–6 weeks and further once in 6–8 weeks and adalimumab (24 mg/m2 once in 2 weeks. Adalimumab provides a long-term maintenance of remission (no recurrence in 60% of patients within 40 months of observation, whereas 1 year after the treatment with infliximab the frequency of exacerbations was returned to that observed before therapy. The proportion of patients without relapse in the treatment with infliximab for 40 months was 18.8%. Similar results were obtained in a subset of patients with chronic uveitis associated with JIA (with follow-up of 20 months of in a group of infliximab number patients without relapse was 11.1%, with adalimumab therapy — 63.6%. In the general population of patients with refractory chronic uveitis the factor «cost–effectiveness» calculated for a patient with the maintenance of remission for 3 years with adalimumab therapy was in 2,1–2,8 times less than in the treatment with infliximab. In chronic uveitis associated with JIA, the coefficient of

  8. Isoniazid-induced flu-like syndrome: A rare side effect

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    Sudipta Pandit

    2013-01-01

    Full Text Available Drug-induced flu-like syndrome is very rare. It is mainly produced by rifampicin. We report a case of pulmonary tuberculosis (PTB that developed isoniazid-induced flu-like syndrome, but could be cured with a modified regimen replacing isoniazid with levofloxacin. A 10-year-old girl with PTB was treated with isoniazid (H, rifampicin (R, ethambutol (E, and pyrazinamide (Z. She developed features of flu from the sixth day. Symptoms recurred everyday within 1 h of drug ingestion and subsided automatically by next 12 h. After admission, HREZ were continued. She developed symptoms of flu after 1 h of drug ingestion. Antitubercular therapy (ATT was stopped and symptoms subsided automatically. Individual drug was started one by one after three days. Severe symptoms of flu developed after taking isoniazid, while other drugs were tolerated well. Levofloxacin was used as an alternative to isoniazid. She was cured after 6 months of chemotherapy. Isoniazid can possibly cause flu-like syndrome and the treating physician should be aware of this possible side effect when using ATT.

  9. Gastric-resistant isoniazid pellets reduced degradation of rifampicin in acidic medium

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    Fátima Duarte Freire

    2014-12-01

    Full Text Available Isoniazid and rifampicin are considered the first-line medication for preventing and treating tuberculosis. Rifampicin is degraded in the stomach acidic environment, especially when combined with isoniazid, factor contributing to treatment failure. In this study, gastric-resistant isoniazid pellets were obtained to physical contact of this drug with rifampicin and to bypass the stomach´s acidic environment. The pellets were fabricated using the extrusion-spheronization technique. The coating process was conducted in a fluid spray coater using Acrycoat L 100(r solution as the coating agent. The pellets obtained were submitted to a dissolution test in HCl 0.1 N and phosphate buffer media. The results indicated that optimum gastric-resistance was only attained with the highest amount of coating material, with isoniazid almost fully released in phosphate buffer. The amount of rifampicin released from its mixture with non-coated isoniazid pellets in HCl 0.1 N was less than that released from its mixture with the enteric-coated pellets. Acrycoat L 100(r was shown to be an effective enteric/gastric-resistant coating since the stability of rifampicin appeared to be enhanced when physical contact of this drug with isoniazid was prevented at low pH.

  10. Electrocatalytic Determination of Isoniazid by a Glassy Carbon Electrode Modified with Poly (Eriochrome Black T

    Directory of Open Access Journals (Sweden)

    Karim Asadpour-Zeynali

    2017-06-01

    Full Text Available In this work poly eriochrome black T (EBT was electrochemically synthesized on the glassy carbon electrode as electrode modifier. On the modified electrode, voltammetric behavior of isoniazid (INH was investigated. The poly (EBT-modified glassy carbon electrode has excellent electrocatalytic ability for the electrooxidation of isoniazid. This fact was appeared as a reduced overpotential of INH oxidation in a wide operational pH range from 2 to 13. It has been found that the catalytic peak current depends on the concentration of INH and solution pH. The number of electrons involved in the rate determining step was found 1. The diffusion coefficient of isoniazid was also estimated using chronoamperometry technique. The experimental results showed that the mediated oxidation peak current of isoniazid is linearly dependent on the concentration of isoniazid in the ranges of 8.0 × 10-6 – 1.18 × 10-3 M and 2.90 × 10-5 M – 1.67× 10-3 M with differential pulse voltammetry (DPV and amperometry methods, respectively. The detection limits (S/N = 3 were found to be 6.0 μM and 16.4 μM by DPV and amperometry methods, respectively. This developed method was applied to the determination of isoniazid in tablet samples with satisfactory results.

  11. Successful retreatment with grazoprevir and elbasvir for patients infected with hepatitis C virus genotype 1b, who discontinued prior treatment with NS5A inhibitor-including regimens due to adverse events.

    Science.gov (United States)

    Kanda, Tatsuo; Yasui, Shin; Nakamura, Masato; Nakamoto, Shingo; Takahashi, Koji; Wu, Shuang; Sasaki, Reina; Haga, Yuki; Ogasawara, Sadahisa; Saito, Tomoko; Kobayashi, Kazufumi; Kiyono, Soichiro; Ooka, Yoshihiko; Suzuki, Eiichiro; Chiba, Tetsuhiro; Maruyama, Hitoshi; Moriyama, Mitsuhiko; Kato, Naoya

    2018-03-23

    Sustained virologic response (SVR) by interferon and interferon-free treatment can results in the reduction of advanced liver fibrosis and the occurrence of hepatocellular carcinoma in patients infected with hepatitis C virus (HCV). Recent interferon-free treatment for HCV shortens the duration of treatment and leads to higher SVR rates, without any serious adverse events. However, it is important to retreat patients who have had treatment-failure with HCV non-structural protein 5A (NS5A) inhibitor-including regimens. Combination of sofosbuvir and ledipasvir only leads to approximately 100% SVR rates in HCV genotype (GT1b), NS5A inhibitor-naïve patients in Japan. This combination is not an indication for severe renal disease or heart disease, and these patients should be treated or retreated with a different regimen. Retreatment with HCV non-structural protein 3/4A inhibitor, grazoprevir, and HCV NS5A inhibitor, elbasvir, successfully eradicated HCV RNA in three patients with HCV genotype 1b infection who discontinued prior interferon-free treatments including HCV NS5A inhibitors due to adverse events within 2 weeks. Retreatment with the 12-week combination regimen of grazoprevir and elbasvir is effective for HCV GT1b patients who discontinue the HCV NS5A inhibitor-including regimens within 2 weeks. The treatment response may be related to the short duration of initial treatment, which did not produce treatment-emergent RASs.

  12. Transdermal delivery of isoniazid and rifampin in guinea pigs by electro-phonophoresis.

    Science.gov (United States)

    Chen, Suting; Han, Yi; Yu, Daping; Huo, Fengmin; Wang, Fen; Li, Yunxu; Dong, Lingling; Liu, Zhidong; Huang, Hairong

    2017-11-01

    Electro-phonophoresis (EP) has been used as a drug delivery approach in clinical fields. The objective of the present study is to evaluate the skin permeability of isoniazid and rifampin in guinea pigs by EP to provide reference basis for clinical applications of such transdermal delivery system in the treatment of patients with superficial tuberculosis. Isoniazid and rifampin solutions were delivered transdermally with or without EP in health guinea pigs for 0.5 h. Local skin and blood samples were collected serially at 0, 1/2, 1, 2, 4, 6 and 24 h after dosing. Drug concentrations in local skin and blood were evaluated by high-performance liquid chromatography. Isoniazid concentrations in local skin of guinea pigs receiving isoniazid through EP transdermal delivery were significantly higher than in animals receiving only isoniazid with transdermal patch. However, for rifampin, patches alone group presented almost uniform concentration versus time curve with that of EP group, and both groups had concentrations much higher than the therapeutic concentration of the drug over sustainable time. After EP transdermal delivery, the mean peak concentrations of isoniazid and rifampin in skin were 771.0 ± 163.4 μg/mL and 81.2 ± 17.3 μg/mL respectively. Neither isoniazid nor rifampin concentration in blood could be detected (below the lower detection limit of 1 μg/mL) at any time point. The present study showed that application of EP significantly enhanced INH penetration through skin in guinea pigs, while RIF patch alone obtained therapeutic concentration in local skin. Our work suggests several possible medication approaches for efficient treatment of superficial tuberculosis.

  13. A novel solid dosage form of rifampicin and isoniazid with improved functionality.

    Science.gov (United States)

    Gohel, Mukesh C; Sarvaiya, Krishnakant G

    2007-08-24

    The aim of the present investigation was to develop a novel dosage form of rifampicin and isoniazid to minimize degradation of rifampicin in acidic medium and to modulate the release of rifampicin in the stomach and isoniazid in the intestine. Gastroretentive tablets of rifampicin (150 mg) were prepared by the wet granulation method using hydroxypropyl methylcellulose, calcium carbonate, and polyethylene glycol 4000. The granules and tablets of rifampicin were characterized. Hard gelatin capsules (size 4) containing a compacted mass of isoniazid (150 mg) and dicalcium phosphate (75 mg) were enteric coated. Two tablets of rifampicin and 1 capsule (size 4) of isoniazid were put into a hard gelatin capsule (size 00). The in vitro drug release and in vitro drug degradation studies were performed. Rifampicin was released over 4 hours by zero-order kinetics from the novel dosage form. More than 90% of isoniazid was released in alkaline medium in 30 minutes. The results of dissolution studies with the US Pharmacopeia XXIII method revealed that a substantial amount of rifampicin was degraded from the immediate release capsule containing rifampicin and isoniazid powder owing to drug accumulation in the dissolution vessel and also to the presence of isoniazid. The degradation of rifampicin to 3-formyl rifampicin SV (3FRSV) was arrested (3.6%-4.8% degradation of rifampicin at 4 hours) because of the minimization of physical contact between the 2 drugs and controlled release of rifampicin in acidic medium in the modified Rossett-Rice apparatus. This study concludes that the problem of rifampicin degradation can be alleviated to a certain extent by this novel dosage form.

  14. Activity of levofloxacin alone and in combination with a DnaK inhibitor against gram-negative rods, including levofloxacin-resistant strains.

    Science.gov (United States)

    Credito, Kim; Lin, Gengrong; Koeth, Laura; Sturgess, Michael A; Appelbaum, Peter C

    2009-02-01

    Synergy time-kill testing of levofloxacin alone and in combination with CHP-105, a representative DnaK inhibitor, against 50 gram-negative rods demonstrated that 34 of the 50 strains tested showed significant synergy between levofloxacin and CHP-105 after 12 h and 24 h. Fourteen of these 34 organisms were quinolone resistant (levofloxacin MICs of > or =4 microg/ml).

  15. Pyrosequencing for Rapid Detection of Mycobacterium tuberculosis Resistance to Rifampin, Isoniazid, and Fluoroquinolones ▿

    Science.gov (United States)

    Bravo, Lulette Tricia C.; Tuohy, Marion J.; Ang, Concepcion; Destura, Raul V.; Mendoza, Myrna; Procop, Gary W.; Gordon, Steven M.; Hall, Geraldine S.; Shrestha, Nabin K.

    2009-01-01

    After isoniazid and rifampin (rifampicin), the next pivotal drug class in Mycobacterium tuberculosis treatment is the fluoroquinolone class. Mutations in resistance-determining regions (RDR) of the rpoB, katG, and gyrA genes occur with frequencies of 97%, 50%, and 85% among M. tuberculosis isolates resistant to rifampin, isoniazid, and fluoroquinolones, respectively. Sequences are highly conserved, and certain mutations correlate well with phenotypic resistance. We developed a pyrosequencing assay to determine M. tuberculosis genotypic resistance to rifampin, isoniazid, and fluoroquinolones. We characterized 102 M. tuberculosis clinical isolates from the Philippines for susceptibility to rifampin, isoniazid, and ofloxacin by using the conventional submerged-disk proportion method and validated our pyrosequencing assay using these isolates. DNA was extracted and amplified by using PCR primers directed toward the RDR of the rpoB, katG, and gyrA genes, and pyrosequencing was performed on the extracts. The M. tuberculosis H37Rv strain (ATCC 25618) was used as the reference strain. The sensitivities and specificities of pyrosequencing were 96.7% and 97.3%, 63.8% and 100%, and 70.0% and 100% for the detection of resistance to rifampin, isoniazid, and ofloxacin, respectively. Pyrosequencing is thus a rapid and accurate method for detecting M. tuberculosis resistance to these three drugs. PMID:19846642

  16. Barriers in the implementation of isoniazid preventive therapy for people living with HIV in Northern Ethiopia: a mixed quantitative and qualitative study

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    Gebrehiwot Teklay

    2016-08-01

    Full Text Available Abstract Background Isoniazid preventive therapy is a key public health intervention for the prevention of tuberculosis disease among people living with HIV. Despite the confirmed efficacy of isoniazid preventive therapy and global recommendations existing for decades, its implementation remains limited. In resource constrained settings, few have investigated why isoniazid preventive therapy is not implemented on full scale. This study was designed to investigate the level of isoniazid preventive therapy implementation and reasons for suboptimal implementation in Tigray region of Ethiopia. Methods A review of patient records combined with a qualitative study using in-depth interviews and focus group discussions was conducted in 11 hospitals providing isoniazid preventive therapy in the Tigray Region. The study participants were health providers working in the HIV clinics of the 11 hospitals in the province. Health providers were interviewed about their experience of providing isoniazid preventive therapy and challenges faced during its implementation. All conversations were audio-recorded. Record review of 16,443 HIV patients registered for care in these hospitals between September 2011 and April 2014 was done to determine isoniazid preventive therapy utilization. Data were collected from April to August 2014. Results Fifty health providers participated in the study. Overall isoniazid preventive therapy coverage of the region was estimated to be 20 %. Isoniazid stock out, fear of creating isoniazid resistance, problems in patient acceptance, and lack of commitment of health managers to scale up the program were indicated by health providers as the main barriers hindering implementation of isoniazid preventive therapy. Conclusion Implementation of isoniazid preventive therapy in Tigray region of Ethiopia had low coverage. Frequent interruption of isoniazid supplies raises the concern of interrupted therapy resulting in creation of isoniazid

  17. Preparation of labelled antituberculotics for clarifying specific problems in therapy optimization. 1. Preparation of tritiated isoniazid and injectable solutions, investigation of the stability of labelling

    Energy Technology Data Exchange (ETDEWEB)

    Winsel, K.; Iwainsky, H. (Forschungsinstitut fuer Lungenkrankheiten und Tuberkulose, Berlin-Buch (German Democratic Republic)); Mittag, E.; Kiessling, M. (Zentralinstitut fuer Kernforschung, Rossendorf bei Dresden (German Democratic Republic)); Koehler, H. (Zentralklinik fuer Herz- und Lungenkrankheiten, Bad Berka (German Democratic Republic))

    1985-09-01

    The preparation of tritium labelled isoniazid according to the Wilzbach method and by catalytic exchange is described. The purified labelled isoniazid is adjusted to an activity of 37 MBq/300 mg isoniazid. It meets the requirements for an injectable pharmaceutical. The tritium labelling is stable under in vitro conditions and in the macroorganism.

  18. The use of isoniazid as a marker to monitor the self-administration of medicaments.

    Science.gov (United States)

    Stark, J E; Ellard, G A; Gammon, P T; Fox, W

    1975-01-01

    1. Isoniazid was used as a marker to monitor the regularity of drug self-administration in a trial of chemoprophylaxis against natural influenza infection. Two hundred and sixty-two volunteers were treated for five weeks with a synthetic isoquinoline compound (U.K. 2371) or a matching placebo. 2. Five marker tablets containing isoniazid (150 mg) were incorporated into each regimen and their ingestion monitored by testing for acetylisoniazid in the urine. 3. Positive evidence of marker tablet consumption was obtained on 75% of the occasions on which urine samples were requested. The results obtained among the volunteers from each treatment group who returned urine specimens as requested (92%) indicated that they had swallowed at least 81% of their prescribed tablets. 4. The findings of the study suggest that when used in this way isoniazid is a very suitable compound for use on a few occasions for monitoring the self-administration of drugs in clinical trials. PMID:788733

  19. Assessment of the Isoniazid Preventive Therapy Uptake and Associated Characteristics: A Cross-Sectional Study

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    Francine Mwayuma Birungi

    2018-01-01

    Full Text Available Objective. To assess the uptake of isoniazid preventive therapy (IPT by eligible children in Kigali, Rwanda, and associated individual, households, and healthcare systems characteristics. Methods. A cross-sectional study was conducted among child contacts of index cases having sputum smear-positive pulmonary tuberculosis. Data were collected from 13 selected primary health centres. Descriptive statistics were used to generate frequency tables and figures. Logistic regression models were performed to determine characteristics associated with IPT uptake. Results. Of 270 children (under 15 years, who were household contacts of 136 index cases, 94 (35% children were less than 5 years old and eligible for IPT; and 84 (89%, 95% CI 81–94 were initiated on IPT. The reasons for not initiating IPT in the remaining 10 children were parents/caregivers’ lack of information on the need for IPT, refusal to give IPT to their children, and poor quality services offered at health centres. Factors associated with no uptake of IPT included children older than 3 years, unfriendly healthcare providers, HIV infected index cases, and the index case not being the child’s parent. Conclusion. The National Tuberculosis Program’s policy on IPT delivery was effectively implemented. Future interventions should find strategies to manage factors associated with IPT uptake.

  20. [Considerations about the efficiency of treatment regimens with fixed Rifampicin-Isoniazid combinations in pulmonary tuberculosis].

    Science.gov (United States)

    Munteanu, Ioana; Husar, Iulia; Didilescu, C; Stoicescu, I P

    2004-01-01

    Here are presented the results of a prospective, randomized study regarding the efficiency of regimens with fixed drug combination Rifampicin-Isoniazide manufactured by Antibiotics S.A. of Iasi in comparison with single drugs routinely used in treatment of patients with pulmonary tuberculosis. Newly diagnosed (confirmed by smear and culture) pulmonary tuberculosis patients were selected, and those who accepted to be included in the study, were admitted to the National Institute of Pneumology "Marius Nasta" between August 2001 and September 2002. At the time of admission, they were randomized into two groups: 20 patients received fixed drug combination RMP300 HIN150, and 18 patients received RMP and HIN in single drug tablets (2 patients were excluded). The follow-up of the patients was for one year from the date of enclosure. The smear conversion rate was 83,3% for the patients using single drug tablets, and 70% for those using fixed drug combination, motivated with some more severe TB patterns. The success rate was 100% for all TB patients. Although the present study was done for few patients, we can say that it demonstrated the same efficiency of fixed drug combination produced in Romania, with the single drug tablets, and it suggests a better compliance to treatment with a lower price.

  1. Simultaneous determination of isoniazid and p-aminosalicylic acid by capillary electrophoresis using chemiluminescence detection.

    Science.gov (United States)

    Zhang, Xinfeng; Xuan, Yuelan; Sun, Aimin; Lv, Yi; Hou, Xiandeng

    2009-01-01

    It was found that isoniazid (ISO) or p-aminosalicylic acid (PAS) could enhance the chemiluminescence (CL) emission from Cu (II)-luminol-hydrogen peroxide system, and the increased chemiluminescence signals were proportional to their concentrations, respectively. Based on this phenomenon, a chemiluminescence method coupled to capillary electrophoresis (CE) was established for simultaneous determination of ISO and PAS. The CE conditions including running buffer and running voltage were investigated in detail. The effects of the pH of H(2)O(2) solution and the concentrations of luminol, H(2)O(2) and Cu (II) on the CL signal were also investigated carefully. Under the optimized conditions, the analysis could be accomplished within 10 min, with the limits of detection of 0.3 microg mL(-1) for ISO and 1.1 microg mL(-1) for PAS, corresponding to 7.2 and 26.4 pg per injection (24 nL), respectively. Finally, the method was validated by determining the two analytes in pharmaceutical preparation and spiked human serum samples. The results of pharmaceutical tablet analysis were in good agreement with the labeled amounts. The recoveries for ISO and PAS in human serum were in the range of 92-104% and 90-113%, respectively. Copyright 2008 John Wiley & Sons, Ltd.

  2. Novel Isoniazid cocrystals with aromatic carboxylic acids: Crystal engineering, spectroscopy and thermochemical investigations

    Science.gov (United States)

    Diniz, Luan F.; Souza, Matheus S.; Carvalho, Paulo S.; da Silva, Cecilia C. P.; D'Vries, Richard F.; Ellena, Javier

    2018-02-01

    Four novel cocrystals of the anti-tuberculosis drug Isoniazid (INH), including two polymorphs, with the aromatic carboxylic acids p-nitrobenzoic (PNBA), p-cyanobenzoic (PCNBA) and p-aminobenzoic (PABA) were rationally designed and synthesized by solvent evaporation. Aiming to explore the possible supramolecular synthons of this API, these cocrystals were fully characterized by X-ray diffraction (SCXRD, PXRD), spectroscopic (FT-IR) and thermal (TGA, DSC, HSM) techniques. The cocrystal formation was found to be mainly driven by the synthons formed by the pyridine and hydrazide moieties. In both INH-PABA polymorphs, the COOH acid groups are H-bonded to pyridine and hydrazide groups giving rise to the acid⋯pyridine and acid⋯hydrazide heterosynthons. In INH-PNBA and INH-PCNBA cocrystals these acid groups are only related to the pyridine moiety. In addition to the structural study, supramolecular and Hirshfeld surface analysis were also performed based on the structural data. The cocrystals were identified from the FT-IR spectra and their thermal behaviors were studied by a combination of DSC, TGA and HSM techniques.

  3. [Comparative data regarding two HPLC methods for determination of isoniazid].

    Science.gov (United States)

    Gârbuleţ, Daniela; Spac, A F; Dorneanu, V

    2009-01-01

    For the determination of isoniazide (isonicotinic acid hydrazide - HIN) two different HPLC methods were developed and validated. Both experiments were performed using a Waters 2695 liquid chromatograph and a UV - Waters 2489 detector. The first method (I) used a Nucleosil 100-10 C18 column (250 x 4.6 mm), a mobile phase formed by a mixture of acetonitrile/10(-2) M oxalic acid (80/20) and a flow of 1.5 mL/ min; detection was done at 230 nm. The second method (II) used a Luna 100-5 C18 column (250 x 4.6 mm), a mobile phase formed by a mixture of methanol/acetate buffer, pH = 5.0 (20/ 80), a flow of 1 mL/min; detection was done at 270 nm. Both methods were validated, the correlation coefficients were 0.9998 (I) and 0.9999 (II), the detection limits were 0.6 microg/mL (I) and 0.055 microg/mL (II), the quantitation limits were 1.9 microg/mL (I) and 0.2 microg/ mL (II). There were also studied: the system precision (RSD = 0.1692% (I) and 0.2000% (II)), the method precision (RSD = 1.1844% (I) and 0.6170% (II)) and the intermediate precision (RSD = 1.8058% (I) and 0.5970% (II)). The accuracy was good, the calculated recoveries were 102.66% (I) and 101.36 (II). Both validated methods were applied for HIN determination from tablets with good and comparable results.

  4. Activity of Levofloxacin Alone and in Combination with a DnaK Inhibitor against Gram-Negative Rods, Including Levofloxacin-Resistant Strains▿

    Science.gov (United States)

    Credito, Kim; Lin, Gengrong; Koeth, Laura; Sturgess, Michael A.; Appelbaum, Peter C.

    2009-01-01

    Synergy time-kill testing of levofloxacin alone and in combination with CHP-105, a representative DnaK inhibitor, against 50 gram-negative rods demonstrated that 34 of the 50 strains tested showed significant synergy between levofloxacin and CHP-105 after 12 h and 24 h. Fourteen of these 34 organisms were quinolone resistant (levofloxacin MICs of ≥4 μg/ml). PMID:19015359

  5. Penetapan Kadar Rifampisin dan Isoniazid dalam Sediaan Tablet Secara Multikomponen dengan Metode Spektrofotometri Ultraviolet

    OpenAIRE

    Hastia, Faula

    2011-01-01

    Tuberculosis is the most deadly infectious diseases and the number two cause of death after heart disease. The number of tuberculosis patients in Indonesia as many as 583,000 people, China 2 million and 1.5 million Indians. Combination of rifampicin and isoniazid in the tablet is one of the drugs which is usually use for TBC treatment. The aim of this study is to determination value of rifampicin and isoniazid in the tablet which circulates in the general by ultraviolet spectrophotometry. ...

  6. Hydrazine levels in formulations of hydralazine, isoniazid, and phenelzine over a 2-year period.

    Science.gov (United States)

    Lovering, E G; Matsui, F; Curran, N M; Robertson, D L; Sears, R W

    1983-08-01

    Hydrazine levels in formulations of hydralazine, isoniazid, and phenelzine have been measured over a 2-year period under ambient conditions and under temperature and humidity stress. Hydralazine tablets are stable under ambient conditions, but the hydrazine level in an injectable formulation increased from 4.5 to 10 micrograms/ml over a 23-month period. Isoniazid tablets are also stable, but hydrazine levels in an elixir and a pyridoxine combination product doubled to 44 micrograms/ml and 19 micrograms/tablet, respectively. Levels in phenelzine tablets appeared to remain constant at approximately 60 micrograms/tablet, with considerable tablet-to-tablet variation.

  7. Synthesis and antimycobacterial activity of isoniazid derivatives from renewable fatty acids.

    Science.gov (United States)

    Rodrigues, Marieli O; Cantos, Jéssica B; D'Oca, Caroline R Montes; Soares, Karina L; Coelho, Tatiane S; Piovesan, Luciana A; Russowsky, Dennis; da Silva, Pedro A; D'Oca, Marcelo G Montes

    2013-11-15

    This work describes the synthesis of a series of fatty acid hydrazide derivatives of isoniazid (INH). The compounds were tested against Mycobacterium tuberculosis H37Rv (ATCC 27294) as well as INH-resistant (ATCC 35822 and 1896 HF) and rifampicin-resistant (ATCC 35338) M. tuberculosis strains. The fatty acid derivatives of INH showed high antimycobacterial potency against the studied strains, which is desirable for a pharmaceutical compound, suggesting that the increased lipophilicity of isoniazid plays an important role in its antimycobacterial activity. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. Tuberculosis contact screening and isoniazid preventive therapy in a South Indian district: operational issues for programmatic consideration.

    Science.gov (United States)

    Pothukuchi, Madhavi; Nagaraja, Sharath Burugina; Kelamane, Santosha; Satyanarayana, Srinath; Shashidhar; Babu, Sai; Dewan, Puneet; Wares, Fraser

    2011-01-01

    Under India's Revised National Tuberculosis Control Programme (RNTCP), all household contacts of sputum smear positive Pulmonary Tuberculosis (PTB) patients are screened for TB. In the absence of active TB disease, household contacts aged Isoniazid Preventive Therapy (IPT) (5 milligrams/kilogram body weight/day) for 6 months. To estimate the number of household contacts aged tablets in peripheral health centers. The reasons for non-evaluation of the remaining eligible children (n = 56, 33%) include no home visit by the health staff in 25 contacts, home visit done but not evaluated in 31 contacts. House-hold contacts in rural areas were less likely to be evaluated and initiated on IPT [risk ratio 6.65 (95% CI; 3.06-14.42)]. Contact screening and IPT implementation under routine programmatic conditions is sub-optimal. There is an urgent need to sensitize all concerned programme staff on its importance and establishment of mechanisms for rigorous monitoring.

  9. Bioequivalence assessment of rifampicin, isoniazid and pyrazinamide in a fixed dose combination of rifampicin, isoniazid, pyrazinamide and ethambutol vs. separate formulations.

    Science.gov (United States)

    Agrawal, S; Singh, I; Kaur, K J; Bhade, S R; Kaul, C L; Panchagnula, R

    2002-10-01

    Depending on the patient category, tuberculosis requires treatment with 3 to 5 drugs which means that patient's compliance to therapy may not be optimal. To increase patient's adherence to treatment schedules, these drugs can be given as single drug preparations or fixed dose combinations (FDCs) of 2 or more drugs in a single formulation. However, an important issue associated with a rifampicin-containing FDC is its quality. Hence, to avoid spurious formulations entering the market, the World Health Organization and the International Union Against Tuberculosis and Lung Disease have recommended FDCs only of proven bioavailability. In this study, the relative bioavailability of rifampicin, isoniazid and pyrazinamide was assessed in a group of 14 healthy male subjects using the FDC tablet containing 4 drugs versus separate formulations at the same dose levels. The study was designed as an open, crossover trial. A total of 9 blood samples were collected over a period of 24 h. The concentration of rifampicin, its main metabolite desacetyl rifampicin, isoniazid and pyrazinamide in plasma were assessed using HPLC analysis. The pharmacokinetic parameters AUC(0-24) and Cmax were subjected to parametric and non-parametric statistical tests at 90% confidence interval. In addition, time to reach peak concentration (tmax), elimination rate constant (Kel) and terminal elimination half-life (t1/2) for each drug were also calculated. It was concluded that the FDC tablet containing 4 drugs is bioequivalent to separate rifampicin, isoniazid and pyrazinamide formulations at the same dose levels.

  10. Five-year examination of utilization and drug cost outcomes associated with benefit design changes including reference pricing for proton pump inhibitors in a state employee health plan.

    Science.gov (United States)

    Johnson, Jill T; Neill, Kathryn K; Davis, Dwight A

    2011-04-01

    The Arkansas State Employee Benefits Division (EBD) is a self-insured program comprising public school and other state employees, their spouses, and dependents. Previous research published in JMCP (2006) showed drug cost savings of $2.20 per member per month (PMPM; 37.6%) or annualized savings of $3.4 million associated with a benefit design change and coverage of the proton pump inhibitor (PPI) omeprazole over-the-counter (OTC) beginning in March 2004. On May 1, 2005, brand esomeprazole was excluded from coverage, with current users grandfathered for 4 months until September 2005. Reference pricing for PPIs, including esomeprazole but excluding generic omeprazole, was implemented on September 1, 2005, and the beneficiary cost share for all PPIs except generic omeprazole was determined from comparison of the PPI actual price to the $0.90 omeprazole OTC reference price per unit. To examine PPI utilization and drug costs before and after (a) excluding esomeprazole from coverage (with grandfathering current users) and (b) implementing a therapeutic maximum allowable cost (TMAC), or reference-pricing benefit design, for the PPI class in a large state employee health plan with fairly stable enrollment of approximately 127,500 members in 2005 through 2008 and approximately 128,000 members in 2009 Q1. The pharmacy claims database for the EBD was used to examine utilization and cost data for PPIs in a longitudinal analysis for the 61-month period from March 1, 2004, through March 31, 2009. Pharmacy claims data were compared for the period 14 months prior to esomeprazole exclusion (preperiod), 4 months during the esomeprazole exclusion (postperiod 1), and the ensuing 43 months of PPI reference pricing (postperiod 2). PPI cost and utilization data for the intervention group of approximately 127,500 beneficiaries were compared with a group of 122 self-insured employers with a total of nearly 1 million beneficiaries whose pharmacy benefits did not include reference pricing for

  11. Comparison of different treatments for isoniazid-resistant tuberculosis: an individual patient data meta-analysis.

    NARCIS (Netherlands)

    Fregonese, Federica; Ahuja, Shama D; Akkerman, Onno W; Arakaki-Sanchez, Denise; Ayakaka, Irene; Baghaei, Parvaneh; Bang, Didi; Bastos, Mayara; Benedetti, Andrea; Bonnet, Maryline; Cattamanchi, Adithya; Cegielski, Peter; Chien, Jung-Yien; Cox, Helen; Dedicoat, Martin; Erkens, Connie; Escalante, Patricio; Falzon, Dennis; Garcia-Prats, Anthony J; Gegia, Medea; Gillespie, Stephen H; Glynn, Judith R; Goldberg, Stefan; Griffith, David; Jacobson, Karen R; Johnston, James C; Jones-López, Edward C; Khan, Awal; Koh, Won-Jung; Kritski, Afranio; Lan, Zhi Yi; Lee, Jae Ho; Li, Pei Zhi; Maciel, Ethel L; Galliez, Rafael Mello; Merle, Corinne S C; Munang, Melinda; Narendran, Gopalan; Nguyen, Viet Nhung; Nunn, Andrew; Ohkado, Akihiro; Park, Jong Sun; Phillips, Patrick P J; Ponnuraja, Chinnaiyan; Reves, Randall; Romanowski, Kamila; Seung, Kwonjune; Schaaf, H Simon; Skrahina, Alena; Soolingen, Dick van; Tabarsi, Payam; Trajman, Anete; Trieu, Lisa; Banurekha, Velayutham V; Viiklepp, Piret; Wang, Jann-Yuan; Yoshiyama, Takashi; Menzies, Dick

    Isoniazid-resistant, rifampicin-susceptible (INH-R) tuberculosis is the most common form of drug resistance, and is associated with failure, relapse, and acquired rifampicin resistance if treated with first-line anti-tuberculosis drugs. The aim of the study was to compare success, mortality, and

  12. Comparison of different treatments for isoniazid-resistant tuberculosis : an individual patient data meta-analysis

    NARCIS (Netherlands)

    Fregonese, Federica; Ahuja, Shama D; Akkerman, Onno W; Arakaki-Sanchez, Denise; Ayakaka, Irene; Baghaei, Parvaneh; Bang, Didi; Bastos, Mayara; Benedetti, Andrea; Bonnet, Maryline; Cattamanchi, Adithya; Cegielski, Peter; Chien, Jung-Yien; Cox, Helen; Dedicoat, Martin; Erkens, Connie; Escalante, Patricio; Falzon, Dennis; Garcia-Prats, Anthony J; Gegia, Medea; Gillespie, Stephen H; Glynn, Judith R; Goldberg, Stefan; Griffith, David; Jacobson, Karen R; Johnston, James C; Jones-López, Edward C; Khan, Awal; Koh, Won-Jung; Kritski, Afranio; Lan, Zhi Yi; Lee, Jae Ho; Li, Pei Zhi; Maciel, Ethel L; Galliez, Rafael Mello; Merle, Corinne S C; Munang, Melinda; Narendran, Gopalan; Nguyen, Viet Nhung; Nunn, Andrew; Ohkado, Akihiro; Park, Jong Sun; Phillips, Patrick P J; Ponnuraja, Chinnaiyan; Reves, Randall; Romanowski, Kamila; Seung, Kwonjune; Schaaf, H Simon; Skrahina, Alena; Soolingen, Dick van; Tabarsi, Payam; Trajman, Anete; Trieu, Lisa; Banurekha, Velayutham V; Viiklepp, Piret; Wang, Jann-Yuan; Yoshiyama, Takashi; Menzies, Dick

    BACKGROUND: Isoniazid-resistant, rifampicin-susceptible (INH-R) tuberculosis is the most common form of drug resistance, and is associated with failure, relapse, and acquired rifampicin resistance if treated with first-line anti-tuberculosis drugs. The aim of the study was to compare success,

  13. Isoniazid Pharmacokinetics-Pharmacodynamics in an Aerosol Infection Model of Tuberculosis

    Science.gov (United States)

    Jayaram, Ramesh; Shandil, Radha. K.; Gaonkar, Sheshagiri; Kaur, Parvinder; Suresh, B. L.; Mahesh, B. N.; Jayashree, R.; Nandi, Vrinda; Bharath, Sowmya; Kantharaj, E.; Balasubramanian, V.

    2004-01-01

    Limited data exist on the pharmacokinetic-pharmacodynamic (PK-PD) parameters of the bactericidal activities of the available antimycobacterial drugs. We report on the PK-PD relationships for isoniazid. Isoniazid exhibited concentration (C)-dependent killing of Mycobacterium tuberculosis H37Rv in vitro, with a maximum reduction of 4 log10 CFU/ml. In these studies, 50% of the maximum effect was achieved at a C/MIC ratio of 0.5, and the maximum effect did not increase with exposure times of up to 21 days. Conversely, isoniazid produced less than a 0.5-log10 CFU/ml reduction in two different intracellular infection models (J774A.1 murine macrophages and whole human blood). In a murine model of aerosol infection, isoniazid therapy for 6 days produced a reduction of 1.4 log10 CFU/lung. Dose fractionation studies demonstrated that the 24-h area under the concentration-time curve/MIC (r2 = 0.83) correlated best with the bactericidal efficacy, followed by the maximum concentration of drug in serum/MIC (r2 = 0.73). PMID:15273105

  14. Transient electromyographic findings in serotonergic toxicity due to combination of essitalopram and isoniazid

    Directory of Open Access Journals (Sweden)

    Çagdas Erdogan

    2013-01-01

    Full Text Available Here, we report a case of serotonergic toxicity due to combination of essitalopram and isoniazid, which was rarely reported before. Moreover, we observed transient neurogenic denervation potentials in needle electromyography, which disappeared with the treatment of serotonergic toxicity. As to our best knowledge, this is the first case, reporting transient electromyographic changes probably due to serotonergic toxicity.

  15. A rare case of unilateral gynecomastia during antituberculous chemotherapy with isoniazid.

    Science.gov (United States)

    Goud, B K Manjunatha; Devi, Oinam Sarsina; Nayal, Bhavna; Devaki, R N

    2012-01-01

    Gynecomastia refers to enlargement of male breast (s) due to benign proliferation of glandular tissue and is caused by excessive estrogen. The etiology may be pathological, pharmacological, or idiopathic reasons. The present report describes a case of gynecomastia due to isoniazid therapy.

  16. Isoniazid Toxicity among an Older Veteran Population: A Retrospective Cohort Study.

    Science.gov (United States)

    Vinnard, Christopher; Gopal, Anand; Linkin, Darren R; Maslow, Joel

    2013-01-01

    our objective was to determine the incidence of toxicity among veterans initiating isoniazid therapy for latent tuberculosis infection (LTBI) and determine whether advancing age was a risk factor for toxicity. we performed a retrospective cohort study among all adults initiating isoniazid treatment for LTBI at a Veterans Medical Center from 1999 to 2005. We collected data on patient demographics, co-morbidities, site of initiation, and treatment outcome. 219 patients initiated isoniazid therapy for LTBI during the period of observation, and the completion of therapy was confirmed in 100 patients (46%). Among 18/219 patients (8%) that discontinued therapy due to a documented suspected toxicity, the median time to onset was 3 months (IQR 1-5 months). In an adjusted Cox regression model, there was no association between discontinuation due to suspected toxicity and advancing age (HR 1.03, 95% CI 0.99, 1.07). In contrast, hepatitis C infection was a significant predictor of cessation due to toxicity in the adjusted analysis (HR 3.03, 95% CI 1.08, 8.52). cessation of isoniazid therapy due to suspected toxicity was infrequently observed among a veteran population and was not associated with advancing age. Alternative LTBI treatment approaches should be further examined in the veteran population.

  17. Isoniazid Toxicity among an Older Veteran Population: A Retrospective Cohort Study

    Directory of Open Access Journals (Sweden)

    Christopher Vinnard

    2013-01-01

    Full Text Available Background: our objective was to determine the incidence of toxicity among veterans initiating isoniazid therapy for latent tuberculosis infection (LTBI and determine whether advancing age was a risk factor for toxicity. Methods: we performed a retrospective cohort study among all adults initiating isoniazid treatment for LTBI at a Veterans Medical Center from 1999 to 2005. We collected data on patient demographics, co-morbidities, site of initiation, and treatment outcome. Results: 219 patients initiated isoniazid therapy for LTBI during the period of observation, and the completion of therapy was confirmed in 100 patients (46%. Among 18/219 patients (8% that discontinued therapy due to a documented suspected toxicity, the median time to onset was 3 months (IQR 1–5 months. In an adjusted Cox regression model, there was no association between discontinuation due to suspected toxicity and advancing age (HR 1.03, 95% CI 0.99, 1.07. In contrast, hepatitis C infection was a significant predictor of cessation due to toxicity in the adjusted analysis (HR 3.03, 95% CI 1.08, 8.52. Conclusions: cessation of isoniazid therapy due to suspected toxicity was infrequently observed among a veteran population and was not associated with advancing age. Alternative LTBI treatment approaches should be further examined in the veteran population.

  18. Bioavailability of rifampicin following concomitant administration of ethambutol or isoniazid or pyrazinamide or a combination of the three drugs.

    Science.gov (United States)

    Immanuel, Chandra; Gurumurthy, Prema; Ramachandran, Geetha; Venkatesan, P; Chandrasekaran, V; Prabhakar, R

    2003-09-01

    Poor bioavailability of rifampicin (R) in combination with other anti-tuberculosis drugs such as isoniazid (H), pyrazinamide (Z), and ethambutol (E) is a subject of much concern for the last few decades. This could be due to an interaction between R and other drugs. An investigation was therefore undertaken to examine the bioavailability of R in the presence of H, Z and E or a combination of the three drugs. The study included eight healthy volunteers, each being investigated on four occasions at weekly intervals once with R alone and with three of the four combinations on the three remaining occasions. A partially balanced incomplete block design was employed and the allocation of R or the drug combinations was random. Plasma concentrations of R at intervals up to 12 h were determined by microbiological assay using Staphylococcus aureus as the test organism. The proportion (%) dose of R as R plus desacetyl R (DR) in urine excreted over the periods 0-8 and 8-12 h was also determined. Bioavailability was expressed as an index (BI) of area under time concentration curve (AUC) calculated from the plasma concentrations or proportion of dose of R excreted as R plus DR in urine with the combinations to that with R alone. The bioavailability indices based on AUC were 0.96 with RE, 0.76 with RH, 1.08 with RZ and 0.65 with REHZ. The indices based on urine estimations (0-8 h) were similar, the values being 0.94, 0.84, 0.94 and 0.75, respectively. A second investigation revealed that the decrease of bioavailability of R with H was not due to the excipients present in H tablets. Isoniazid alone or in combination with E and Z reduces the bioavailability of R. Urinary excretion data offer a simple and non invasive method for the assessment of bioavailability of R.

  19. 19-Hydroxyeicosatetraenoic acid and isoniazid protect against angiotensin II-induced cardiac hypertrophy

    Energy Technology Data Exchange (ETDEWEB)

    Elkhatali, Samya; El-Sherbeni, Ahmed A.; Elshenawy, Osama H. [Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2E1 (Canada); Abdelhamid, Ghada [Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2E1 (Canada); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Helwan (Egypt); El-Kadi, Ayman O.S., E-mail: aelkadi@ualberta.ca [Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2E1 (Canada)

    2015-12-15

    We have recently demonstrated that 19-hydroxyeicosatetraenoic acid (19-HETE) is the major subterminal-HETE formed in the heart tissue, and its formation was decreased during cardiac hypertrophy. In the current study, we examined whether 19-HETE confers cardioprotection against angiotensin II (Ang II)-induced cardiac hypertrophy. The effect of Ang II, with and without 19-HETE (20 μM), on the development of cellular hypertrophy in cardiomyocyte RL-14 cells was assessed by real-time PCR. Also, cardiac hypertrophy was induced in Sprague–Dawley rats by Ang II, and the effect of increasing 19-HETE by isoniazid (INH; 200 mg/kg/day) was assessed by heart weight and echocardiography. Also, alterations in cardiac cytochrome P450 (CYP) and their associated arachidonic acid (AA) metabolites were determined by real-time PCR, Western blotting and liquid-chromatography–mass-spectrometry. Our results demonstrated that 19-HETE conferred a cardioprotective effect against Ang II-induced cellular hypertrophy in vitro, as indicated by the significant reduction in β/α-myosin heavy chain ratio. In vivo, INH improved heart dimensions, and reversed the increase in heart weight to tibia length ratio caused by Ang II. We found a significant increase in cardiac 19-HETE, as well as a significant reduction in AA and its metabolite, 20-HETE. In conclusion, 19-HETE, incubated with cardiomyocytes in vitro or induced in the heart by INH in vivo, provides cardioprotection against Ang II-induced hypertrophy. This further confirms the role of CYP, and their associated AA metabolites in the development of cardiac hypertrophy. - Highlights: • We found 19-hydroxy arachidonic acid to protect cardiomyocytes from hypertrophy. • We validated the use of isoniazid as a cardiac 19-hydroxy arachidonic acid inducer. • We found isoniazid to increase protective and inhibit toxic eicosanoides. • We found isoniazid to protect against angiotensin-induced cardiac hypertrophy. • This will help to

  20. Mecanismos de acción y de resistencia a rifampicina e isoniacida en Mycobacterium tuberculosis: nueva información sobre viejos conocidos Mechanisms of action of and resistance to rifampicin and isoniazid in Mycobacterium tuberculosis: new information on old friends

    Directory of Open Access Journals (Sweden)

    A. I. De la Iglesia

    2006-04-01

    encoding the molecular targets for these drugs. Rifampicin is an inhibitor of the beta-subunit of the RNA polymerase of prokaryotes, including M. tuberculosis. Resistance to rifampicin is mediated by mutations clustered in a small region of the rpoB gene. A fraction of resistant strains showed no mutations in rpoB, suggesting that other mechanisms of resistance, possibly efflux pumps, may exist. Isoniazid is a pro-drug activated by KatG, a catalase-peroxidase. Mutations in katG, the most commonly found in M. tuberculosis clinical isolates, give high levels of resistance. In spite of this, the molecular target for isoniazid is InhA, an enoyl-ACP-reductase involved in the biosynthesis of mycolic acids. Other mutations causing resistance to isoniazid have been mapped to ndh, a gene encoding the NADH dehydrogenase.

  1. Insect-specific irreversible inhibitors of acetylcholinesterase in pests including the bed bug, the eastern yellowjacket, German and American cockroaches, and the confused flour beetle.

    Science.gov (United States)

    Polsinelli, Gregory A; Singh, Sanjay K; Mishra, Rajesh K; Suranyi, Robert; Ragsdale, David W; Pang, Yuan-Ping; Brimijoin, Stephen

    2010-09-06

    Insecticides directed against acetylcholinesterase (AChE) are facing increased resistance among target species as well as increasing concerns for human toxicity. The result has been a resurgence of disease vectors, insects destructive to agriculture, and residential pests. We previously reported a free cysteine (Cys) residue at the entrance to the AChE active site in some insects but not higher vertebrates. We also reported Cys-targeting methanethiosulfonate molecules (AMTSn), which, under conditions that spared human AChE, caused total irreversible inhibition of aphid AChE, 95% inhibition of AChE from the malaria vector mosquito (Anopheles gambia), and >80% inhibition of activity from the yellow fever mosquito (Aedes aegypti) and northern house mosquito (Culex pipiens). We now find the same compounds inhibit AChE from cockroaches (Blattella germanica and Periplaneta americana), the flour beetle (Tribolium confusum), the multi-colored Asian ladybird beetle (Harmonia axyridis), the bed bug (Cimex lectularius), and a wasp (Vespula maculifrons), with IC(50) values of approximately 1-11muM. Our results support further study of Cys-targeting inhibitors as conceptually novel insecticides that may be free of resistance in a range of insect pests and disease vectors and, compared with current compounds, should demonstrate much lower toxicity to mammals, birds, and fish. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

  2. Phosphodiesterase-4 inhibition alters gene expression and improves isoniazid-mediated clearance of Mycobacterium tuberculosis in rabbit lungs.

    Directory of Open Access Journals (Sweden)

    Selvakumar Subbian

    2011-09-01

    Full Text Available Tuberculosis (TB treatment is hampered by the long duration of antibiotic therapy required to achieve cure. This indolent response has been partly attributed to the ability of subpopulations of less metabolically active Mycobacterium tuberculosis (Mtb to withstand killing by current anti-TB drugs. We have used immune modulation with a phosphodiesterase-4 (PDE4 inhibitor, CC-3052, that reduces tumor necrosis factor alpha (TNF-α production by increasing intracellular cAMP in macrophages, to examine the crosstalk between host and pathogen in rabbits with pulmonary TB during treatment with isoniazid (INH. Based on DNA microarray, changes in host gene expression during CC-3052 treatment of Mtb infected rabbits support a link between PDE4 inhibition and specific down-regulation of the innate immune response. The overall pattern of host gene expression in the lungs of infected rabbits treated with CC-3052, compared to untreated rabbits, was similar to that described in vitro in resting Mtb infected macrophages, suggesting suboptimal macrophage activation. These alterations in host immunity were associated with corresponding down-regulation of a number of Mtb genes that have been associated with a metabolic shift towards dormancy. Moreover, treatment with CC-3052 and INH resulted in reduced expression of those genes associated with the bacterial response to INH. Importantly, CC-3052 treatment of infected rabbits was associated with reduced ability of Mtb to withstand INH killing, shown by improved bacillary clearance, from the lungs of co-treated animals compared to rabbits treated with INH alone. The results of our study suggest that changes in Mtb gene expression, in response to changes in the host immune response, can alter the responsiveness of the bacteria to antimicrobial agents. These findings provide a basis for exploring the potential use of adjunctive immune modulation with PDE4 inhibitors to enhance the efficacy of existing anti-TB treatment.

  3. Treatment outcomes for isoniazid-resistant tuberculosis under program conditions in British Columbia, Canada.

    Science.gov (United States)

    Romanowski, Kamila; Chiang, Leslie Y; Roth, David Z; Krajden, Mel; Tang, Patrick; Cook, Victoria J; Johnston, James C

    2017-09-04

    Every year, over 1 million people develop isoniazid (INH) resistant tuberculosis (TB). Yet, the optimal treatment regimen remains unclear. Given increasing prevalence, the clinical efficacy of regimens used by physicians is of interest. This study aims to examine treatment outcomes of INH resistant TB patients, treated under programmatic conditions in British Columbia, Canada. Medical charts were retrospectively reviewed for cases of culture-confirmed INH mono-resistant TB reported to the BC Centre for Disease Control (BCCDC) from 2002 to 2014. Treatment regimens, patient and strain characteristics, and clinical outcomes were analysed. One hundred sixty five cases of INH mono-resistant TB were included in analysis and over 30 different treatment regimens were prescribed. Median treatment duration was 10.5 months (IQR 9-12 months) and treatment was extended beyond 12 months for 26 patients (15.8%). Fifty six patients (22.6%) experienced an adverse event that resulted in a drug regimen modification. Overall, 140 patients (84.8%) had a successful treatment outcome while 12 (7.2%) had an unsuccessful treatment outcome of failure (n = 2; 1.2%), relapse (n = 4; 2.4%) or all cause mortality (n = 6; 3.6%). Our treatment outcomes, while consistent with findings reported from other studies in high resource settings, raise concerns about current recommendations for INH resistant TB treatment. Only a small proportion of patients completed the recommended treatment regimens. High quality studies to confirm the effectiveness of standardized regimens are urgently needed, with special consideration given to trials utilizing fluoroquinolones.

  4. Mycobacterium tuberculosis Is Resistant to Isoniazid at a Slow Growth Rate by Single Nucleotide Polymorphisms in katG Codon Ser315.

    Directory of Open Access Journals (Sweden)

    Rose E Jeeves

    Full Text Available An important aim for improving TB treatment is to shorten the period of antibiotic therapy without increasing relapse rates or encouraging the development of antibiotic-resistant strains. In any M. tuberculosis population there is a proportion of bacteria that are drug-tolerant; this might be because of pre-existing populations of slow growing/non replicating bacteria that are protected from antibiotic action due to the expression of a phenotype that limits drug activity. We addressed this question by observing populations of either slow growing (constant 69.3h mean generation time or fast growing bacilli (constant 23.1h mean generation time in their response to the effects of isoniazid exposure, using controlled and defined growth in chemostats. Phenotypic differences were detected between the populations at the two growth rates including expression of efflux mechanisms and the involvement of antisense RNA/small RNA in the regulation of a drug-tolerant phenotype, which has not been explored previously for M. tuberculosis. Genotypic analyses showed that slow growing bacilli develop resistance to isoniazid through mutations specifically in katG codon Ser315 which are present in approximately 50-90% of all isoniazid-resistant clinical isolates. The fast growing bacilli persisted as a mixed population with katG mutations distributed throughout the gene. Mutations in katG codon Ser315 appear to have a fitness cost in vitro and particularly in fast growing cultures. Our results suggest a requirement for functional katG-encoded catalase-peroxide in the slow growers but not the fast-growing bacteria, which may explain why katG codon Ser315 mutations are favoured in the slow growing cultures.

  5. One-year mortality of HIV-positive patients treated for rifampicin- and isoniazid-susceptible tuberculosis in Eastern Europe, Western Europe, and Latin America.

    Science.gov (United States)

    2017-01-28

    The high mortality among HIV/tuberculosis (TB) coinfected patients in Eastern Europe is partly explained by the high prevalence of drug-resistant TB. It remains unclear whether outcomes of HIV/TB patients with rifampicin/isoniazid-susceptible TB in Eastern Europe differ from those in Western Europe or Latin America. One-year mortality of HIV-positive patients with rifampicin/isoniazid-susceptible TB in Eastern Europe, Western Europe, and Latin America was analysed and compared in a prospective observational cohort study. Factors associated with death were analysed using Cox regression modelsRESULTS:: Three hundred and forty-one patients were included (Eastern Europe 127, Western Europe 165, Latin America 49). Proportions of patients with disseminated TB (50, 58, 59%) and initiating rifampicin + isoniazid + pyrazinamide-based treatment (93, 94, 94%) were similar in Eastern Europe, Western Europe, and Latin America respectively, whereas receipt of antiretroviral therapy at baseline and after 12 months was lower in Eastern Europe (17, 39, 39%, and 69, 94, 89%). The 1-year probability of death was 16% (95% confidence interval 11-24%) in Eastern Europe, vs. 4% (2-9%) in Western Europe and 9% (3-21%) in Latin America; P Eastern Europe were at nearly 3-fold increased risk of death compared with those in Western Europe/Latin America (aHR 2.79 (1.15-6.76); P = 0.023). Despite comparable use of recommended anti-TB treatment, mortality of patients with rifampicin/isoniazid-susceptible TB remained higher in Eastern Europe when compared with Western Europe/Latin America. The high mortality in Eastern Europe was only partially explained by IDU, use of ART and CD4 cell count. These results call for improvement of care for TB/HIV patients in Eastern Europe.

  6. Effect of isoniazid preventive therapy on tuberculosis or death in persons with HIV : a retrospective cohort study

    NARCIS (Netherlands)

    Ayele, Henok Tadesse; van Mourik, Maaike S M; Bonten, Marc J M

    2015-01-01

    Background: Isoniazid preventive therapy (IPT) is a recommended strategy for prevention of tuberculosis (TB) in persons with Human Immunodeficiency Virus (HIV) although the benefits have not been unequivocally demonstrated in routine clinical practice with widespread ART adoption. Therefore, we

  7. PCR-Restriction Fragment Length Polymorphism for Rapid, Low-Cost Identification of Isoniazid-Resistant Mycobacterium tuberculosis▿

    Science.gov (United States)

    Caws, Maxine; Tho, Dau Quang; Duy, Phan Minh; Lan, Nguyen Thi Ngoc; Hoa, Dai Viet; Torok, Mili Estee; Chau, Tran Thi Hong; Van Vinh Chau, Nguyen; Chinh, Nguyen Tran; Farrar, Jeremy

    2007-01-01

    PCR-restriction fragment length poymorphism (PCR-RFLP) is a simple, robust technique for the rapid identification of isoniazid-resistant Mycobacterium tuberculosis. One hundred consecutive isolates from a Vietnamese tuberculosis hospital were tested by MspA1I PCR-RFLP for the detection of isoniazid-resistant katG_315 mutants. The test had a sensitivity of 80% and a specificity of 100% against conventional phenotypic drug susceptibility testing. The positive and negative predictive values were 1 and 0.86, respectively. None of the discrepant isolates had mutant katG_315 codons by sequencing. The test is cheap (less than $1.50 per test), specific, and suitable for the rapid identification of isoniazid resistance in regions with a high prevalence of katG_315 mutants among isoniazid-resistant M. tuberculosis isolates. PMID:17428939

  8. Localized surface plasmon resonance of gold nanoparticles as colorimetric probes for determination of Isoniazid in pharmacological formulation

    Science.gov (United States)

    Zargar, Behrooz; Hatamie, Amir

    2013-04-01

    Isoniazid is an important antibiotic, which is widely used to treat tuberculosis. This study presents a colorimetric method for the determination of Isoniazid based on localized surface plasmon resonance (LSPR) property of gold nanoparticles. An LSPR band is produced by reducing gold ions in solution using Isoniazid as the reducing agent. Influences of the following relevant variables were examined and optimized in the experiment, formation time of gold nanoparticles, pH, buffer and stabilizer. These tests demonstrated that under optimum conditions the absorbance of Au nanoparticles at 530 nm related linearly to the concentration of Isoniazid in the range of 1.0-8.0 μg mL-1 with a detection limit of 0.98 μg mL-1. This colorimetric method has been successfully applied to the determine Isoniazid in tablets and spiked serum samples. The proposed colorimetric assay exhibits good reproducibility and accuracy, providing a simple and rapid method for analysis of Isoniazid.

  9. Simultaneous determination of rifampicin, isoniazid and pyrazinamide in tablet preparations by multivariate spectrophotometric calibration.

    Science.gov (United States)

    Goicoechea, H C; Olivieri, A C

    1999-08-01

    The use of multivariate spectrophotometric calibration is presented for the simultaneous determination of the active components of tablets used in the treatment of pulmonary tuberculosis. The resolution of ternary mixtures of rifampicin, isoniazid and pyrazinamide has been accomplished by using partial least squares (PLS-1) regression analysis. Although the components show an important degree of spectral overlap, they have been simultaneously determined with high accuracy and precision, rapidly and with no need of nonaqueous solvents for dissolving the samples. No interference has been observed from the tablet excipients. A comparison is presented with the related multivariate method of classical least squares (CLS) analysis, which is shown to yield less reliable results due to the severe spectral overlap among the studied compounds. This is highlighted in the case of isoniazid, due to the small absorbances measured for this component.

  10. Isoniazid concentrations in hair and plasma area-under-the-curve exposure among children with tuberculosis.

    Directory of Open Access Journals (Sweden)

    Vidya Mave

    Full Text Available We measured hair and plasma concentrations of isoniazid among sixteen children with tuberculosis who underwent personal or video-assisted directly observed therapy and thus had 100% adherence. This study therefore defined typical isoniazid exposure parameters after two months of treatment among fully-adherent patients in both hair and plasma (plasma area under the concentration-time curve, AUC, estimated using pharmacokinetic data collected 0, 2, 4, and 6 hours after drug administration. We found that INH levels in hair among highly-adherent individuals did not correlate well with plasma AUC or trough concentrations, suggesting that each measure may provide incremental and complementary information regarding drug exposure in the context of TB treatment.

  11. Characterization of mutations causing rifampicin and isoniazid resistance of Mycobacterium tuberculosis in Syria.

    Science.gov (United States)

    Madania, Ammar; Habous, Maya; Zarzour, Hana; Ghoury, Ifad; Hebbo, Barea

    2012-01-01

    In order to characterize mutations causing rifampicin and isoniazid resistance of M. tuberculosis in Syria, 69 rifampicin resistant (Rif(r)) and 72 isoniazid resistant (Inh(r)) isolates were screened for point mutations in hot spots of the rpoB, katG and inhA genes by DNA sequencing and real time PCR. Of 69 Rif(r) isolates, 62 (90%) had mutations in the rifampin resistance determining region (RRDR) of the rpoB gene, with codons 531 (61%), 526 (13%), and 516 (8.7%) being the most commonly mutated. We found two new mutations (Asp516Thr and Ser531Gly) described for the first time in the rpoB-RRDR in association with rifampicin resistance. Only one mutation (Ile572Phe) was found outside the rpoB-RRDR. Of 72 Inh(r) strains, 30 (41.6%) had a mutation in katGcodon315 (with Ser315Thr being the predominant alteration), and 23 (32%) harbored the inhA(-15C-->T) mutation. While the general pattern of rpoB-RRDR and katG mutations reflected those found worldwide, the prevalence of the inhA(-15C-->T mutation was above the value found in most other countries, emphasizing the great importance of testing the inhA(-15C-->T) mutation for prediction of isoniazid resistance in Syria. Sensitivity of a rapid test using real time PCR and 3'-Minor groove binder (MGB) probes in detecting Rif(r) and Inh(r) isolates was 90% and 69.4%, respectively. This demonstrates that a small set of MGB-probes can be used in real time PCR in order to detect most mutations causing resistance to rifampicin and isoniazid.

  12. Isoniazid suppresses antioxidant response element activities and impairs adipogenesis in mouse and human preadipocytes

    International Nuclear Information System (INIS)

    Chen, Yanyan; Xue, Peng; Hou, Yongyong; Zhang, Hao; Zheng, Hongzhi; Zhou, Tong; Qu, Weidong; Teng, Weiping; Zhang, Qiang; Andersen, Melvin E.; Pi, Jingbo

    2013-01-01

    Transcriptional signaling through the antioxidant response element (ARE), orchestrated by the Nuclear factor E2-related factor 2 (Nrf2), is a major cellular defense mechanism against oxidative or electrophilic stress. Here, we reported that isoniazid (INH), a widely used antitubercular drug, displays a substantial inhibitory property against ARE activities in diverse mouse and human cells. In 3T3-L1 preadipocytes, INH concentration-dependently suppressed the ARE-luciferase reporter activity and mRNA expression of various ARE-dependent antioxidant genes under basal and oxidative stressed conditions. In keeping with our previous findings that Nrf2-ARE plays a critical role in adipogenesis by regulating expression of CCAAT/enhancer-binding protein β (C/EBPβ) and peroxisome proliferator-activated receptor γ (PPARγ), suppression of ARE signaling by INH hampered adipogenic differentiation of 3T3-L1 cells and human adipose-derived stem cells (ADSCs). Following adipogenesis induced by hormonal cocktails, INH-treated 3T3-L1 cells and ADSCs displayed significantly reduced levels of lipid accumulation and attenuated expression of C/EBPα and PPARγ. Time-course studies in 3T3-L1 cells revealed that inhibition of adipogenesis by INH occurred in the early stage of terminal adipogenic differentiation, where reduced expression of C/EBPβ and C/EBPδ was observed. To our knowledge, the present study is the first to demonstrate that INH suppresses ARE signaling and interrupts with the transcriptional network of adipogenesis, leading to impaired adipogenic differentiation. The inhibition of ARE signaling may be a potential underlying mechanism by which INH attenuates cellular antioxidant response contributing to various complications. - Highlights: • Isoniazid suppresses ARE-mediated transcriptional activity. • Isoniazid inhibits adipogenesis in preadipocytes. • Isoniazid suppresses adipogenic gene expression during adipogenesis

  13. Formulation and characterization of modified release tablets containing isoniazid using swellable polymers.

    Science.gov (United States)

    Akhtar, M F; Rabbani, M; Sharif, A; Akhtar, B; Saleem, A; Murtaza, G

    2011-01-01

    The aim of this work was to develop swellable modified release (MR) isoniazid tablets using different combinations of polyvinyl acetate (PVAc) and sodium-carboxymethylcellulose (Na-CMC). Granules were prepared by moist granulation technique and then compressed into tablets. In vitro release studies for 12 hr were carried out in dissolution media of varying pH i.e. pH 1.2, 4.5, 7.0 and 7.5. Tablets of all formulations were found to be of good physical quality with respect to appearance (width and thickness), content uniformity, hardness, weight variation and friability. In vitro release data showed that increasing total polymer content resulted in more retarding effect. Formulation with 35% polymer content exhibited zero order release profile and it released 35% of the drug in first hr, later on, controlled drug release was observed upto the 12(th) hour. Formulations with PVAc to Na-CMC ratio 20:80 exhibited zero order release pattern at levels of studied concentrations, which suggested that this combination can be used to formulate zero order release tablets of water soluble drugs like isoniazid. Korsmeyer-Peppas modeling of drug release showed that non-Fickian transport is the primary mechanism of isoniazid release from PVAc and Na-CMC based tablets. The value of mean dissolution time decreased with the increase in the release rate of drug clearly showing the retarding behavior of the swellable polymers. The application of a mixture of PVAc to Na-CMC in a specific ratio may be feasible to formulate zero order release tablets of water soluble drugs like isoniazid.

  14. Polymorphisms in Isoniazid and Prothionamide Resistance Genes of the Mycobacterium tuberculosis Complex

    KAUST Repository

    Projahn, M.; Koser, C. U.; Homolka, S.; Summers, D. K.; Archer, John A.C.; Niemann, S.

    2011-01-01

    Sequence analyses of 74 strains that encompassed major phylogenetic lineages of the Mycobacterium tuberculosis complex revealed 10 polymorphisms in mshA (Rv0486) and four polymorphisms in inhA (Rv1484) that were not responsible for isoniazid or prothionamide resistance. Instead, some of these mutations were phylogenetically informative. This genetic diversity must be taken into consideration for drug development and for the design of molecular tests for drug resistance.

  15. Polymorphisms in Isoniazid and Prothionamide Resistance Genes of the Mycobacterium tuberculosis Complex

    KAUST Repository

    Projahn, M.

    2011-06-27

    Sequence analyses of 74 strains that encompassed major phylogenetic lineages of the Mycobacterium tuberculosis complex revealed 10 polymorphisms in mshA (Rv0486) and four polymorphisms in inhA (Rv1484) that were not responsible for isoniazid or prothionamide resistance. Instead, some of these mutations were phylogenetically informative. This genetic diversity must be taken into consideration for drug development and for the design of molecular tests for drug resistance.

  16. Sonocrystallization—Case Studies of Salicylamide Particle Size Reduction and Isoniazid Derivative Synthesis and Crystallization

    Directory of Open Access Journals (Sweden)

    Zhen-Yu Yang

    2018-06-01

    Full Text Available Two case studies of salicylamide particle size reduction and isoniazid derivative synthesis and crystallization realized using sonocrystallization were investigated. The size, habit, structure, thermal behavior, and spectrometric properties of sonocrystallized crystals were analyzed through scanning electron microscopy (SEM, powder X-ray diffractometry (PXRD, differential scanning calorimetry (DSC, and Fourier transform infrared (FTIR spectroscopy. The effects of the operating parameters, such as sonication intensity, sonication duration, and solution concentration, on sonocrystallization were compared. The crystal size of salicylamide was reduced from 595 μm (the original size and was efficiently manipulated to be between 40 and 80 μm. Moreover, compared with the crystal habits of unprocessed crystals and recrystallized crystals fabricated through conventional methods, the crystal habit of salicylamide could be modified to present a regular shape. The structure, thermal behavior, and spectrometric properties of sonocrystallized salicylamide were found to be in agreement with those of an unprocessed sample. For producing isoniazid derivative crystals, N′-(propan-2-ylidene-isonicotinohydrazide was synthesized using isoniazid in acetone at 318 K. The resulting solution was then cooled by applying power ultrasound to isolate N′-(propan-2-ylidene-isonicotinohydrazide crystals. The solid-state properties of the synthesized N′-(propan-2-ylidene-isonicotinohydrazide was verified through PXRD, DSC, and FTIR spectroscopy. The feasibility of particle size manipulation was then demonstrated through sonocrystallization.

  17. Analytical and clinical performance characteristics of the Abbott RealTime MTB RIF/INH Resistance, an assay for the detection of rifampicin and isoniazid resistant Mycobacterium tuberculosis in pulmonary specimens.

    Science.gov (United States)

    Kostera, Joshua; Leckie, Gregor; Tang, Ning; Lampinen, John; Szostak, Magdalena; Abravaya, Klara; Wang, Hong

    2016-12-01

    Clinical management of drug-resistant tuberculosis patients continues to present significant challenges to global health. To tackle these challenges, the Abbott RealTime MTB RIF/INH Resistance assay was developed to accelerate the diagnosis of rifampicin and/or isoniazid resistant tuberculosis to within a day. This article summarizes the performance of the Abbott RealTime MTB RIF/INH Resistance assay; including reliability, analytical sensitivity, and clinical sensitivity/specificity as compared to Cepheid GeneXpert MTB/RIF version 1.0 and Hain MTBDRplus version 2.0. The limit of detection (LOD) of the Abbott RealTime MTB RIF/INH Resistance assay was determined to be 32 colony forming units/milliliter (cfu/mL) using the Mycobacterium tuberculosis (MTB) strain H37Rv cell line. For rifampicin resistance detection, the Abbott RealTime MTB RIF/INH Resistance assay demonstrated statistically equivalent clinical sensitivity and specificity as compared to Cepheid GeneXpert MTB/RIF. For isoniazid resistance detection, the assay demonstrated statistically equivalent clinical sensitivity and specificity as compared to Hain MTBDRplus. The performance data presented herein demonstrate that the Abbott RealTime MTB RIF/INH Resistance assay is a sensitive, robust, and reliable test for realtime simultaneous detection of first line anti-tuberculosis antibiotics rifampicin and isoniazid in patient specimens. Copyright © 2016 The Author. Published by Elsevier Ltd.. All rights reserved.

  18. Risk Factors for Acquired Rifamycin and Isoniazid Resistance: A Systematic Review and Meta-Analysis.

    Directory of Open Access Journals (Sweden)

    Neesha Rockwood

    Full Text Available Studies looking at acquired drug resistance (ADR are diverse with respect to geographical distribution, HIV co-infection rates, retreatment status and programmatic factors such as regimens administered and directly observed therapy. Our objective was to examine and consolidate evidence from clinical studies of the multifactorial aetiology of acquired rifamycin and/or isoniazid resistance within the scope of a single systematic review. This is important to inform policy and identify key areas for further studies.Case-control and cohort studies and randomised controlled trials that reported ADR as an outcome during antitubercular treatment regimens including a rifamycin and examined the association of at least 1 risk factor were included. Post hoc, we carried out random effects Mantel-Haenszel weighted meta-analyses of the impact of 2 key risk factors 1 HIV and 2 baseline drug resistance on the binary outcome of ADR. Heterogeneity was assessed used I2 statistic. As a secondary outcome, we calculated median cumulative incidence of ADR, weighted by the sample size of the studies.Meta-analysis of 15 studies showed increased risk of ADR with baseline mono- or polyresistance (RR 4.85 95% CI 3.26 to 7.23, heterogeneity I2 58%, 95% CI 26 to 76%. Meta-analysis of 8 studies showed that HIV co-infection was associated with increased risk of ADR (RR 3.02, 95% CI 1.28 to 7.11; there was considerable heterogeneity amongst these studies (I2 81%, 95% CI 64 to 90%. Non-adherence, extrapulmonary/disseminated disease and advanced immunosuppression in HIV co-infection were other risk factors noted. The weighted median cumulative incidence of acquired multi drug resistance calculated in 24 studies (assuming whole cohort as denominator, regardless of follow up DST was 0.1% (5th to 95th percentile 0.07 to 3.2%.Baseline drug resistance and HIV co-infection were significant risk factors for ADR. There was a trend of positive association with non-adherence which is likely

  19. Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor

    Directory of Open Access Journals (Sweden)

    María Martínez-Hoyos

    2016-06-01

    Full Text Available Despite being one of the first antitubercular agents identified, isoniazid (INH is still the most prescribed drug for prophylaxis and tuberculosis (TB treatment and, together with rifampicin, the pillars of current chemotherapy. A high percentage of isoniazid resistance is linked to mutations in the pro-drug activating enzyme KatG, so the discovery of direct inhibitors (DI of the enoyl-ACP reductase (InhA has been pursued by many groups leading to the identification of different enzyme inhibitors, active against Mycobacterium tuberculosis (Mtb, but with poor physicochemical properties to be considered as preclinical candidates. Here, we present a series of InhA DI active against multidrug (MDR and extensively (XDR drug-resistant clinical isolates as well as in TB murine models when orally dosed that can be a promising foundation for a future treatment.

  20. Bioavailability of isoniazid, rifampicin and pyrazinamide (in free combination or fixed-triple formulation) in intermittent antituberculous chemotherapy.

    Science.gov (United States)

    Acocella, G; Luisetti, M; Grassi, G G; Peona, V; Pozzi, E; Grassi, C

    1993-01-01

    A study was carried out in six human volunteers, to assess the blood kinetics of isoniazid, rifampicin and pyrazinamide, administered in a fixed-triple combination intended for use in intermittent chemotherapy of tuberculosis. The formulation employed contained 125 mg of isoniazid (H), 100 mg of rifampicin (R) and 375 mg of pyrazinamide (Z) per tablet; six tablets were administered to every subject, giving a total dosage of 750 mg of isoniazid, 600 mg of rifampicin and 2,250 mg of pyrazinamide. In each subject, the same dose of each drug was administered individually in separate sessions and the results compared. The results indicated that, at the level of dose of the intermittent tablet, no negative interactions between the drugs were observed.

  1. Ternary mutual diffusion of isoniazid in aqueous sodium chloride, sodium hydroxide, and hydrochloric acid at T = 298.15 K

    Energy Technology Data Exchange (ETDEWEB)

    Ribeiro, Ana C.F., E-mail: anacfrib@ci.uc.p [Department of Chemistry, University of Coimbra, 3004-535 Coimbra (Portugal); Santos, Ana C.G., E-mail: anacatarinasantos123@gmail.co [Department of Chemistry, University of Coimbra, 3004-535 Coimbra (Portugal); Lobo, Victor M.M., E-mail: vlobo@ci.uc.p [Department of Chemistry, University of Coimbra, 3004-535 Coimbra (Portugal); Sobral, Abilio J.F.N., E-mail: asobral@ci.uc.p [Department of Chemistry, University of Coimbra, 3004-535 Coimbra (Portugal); Cabral, Ana M.T.D.P.V., E-mail: acabral@ff.uc.p [Faculty of Pharmacy, University of Coimbra, 3000-295 Coimbra (Portugal); Esteso, Miguel A., E-mail: miguel.esteso@uah.e [Departamento de Quimica Fisica, Facultad de Farmacia, Universidad de Alcala, 28871 Alcala de Henares, Madrid (Spain)

    2010-07-15

    Ternary mutual diffusion coefficients measured by Taylor dispersion method (D{sub 11}, D{sub 22}, D{sub 12}, and D{sub 21}) are reported for aqueous solutions containing isoniazid and different electrolytes (NaCl, NaOH, or HCl) at T = 298.15 K at different carrier concentrations. These diffusion coefficients have been measured having in mind a better understanding of the structure of these systems and the thermodynamic behaviour of isoniazid in different media. For example, it is possible to make conclusions about the influence of these electrolytes in diffusion of isoniazid, and to obtain information concerning the number of moles of each component transported per mole of the other component driven by its own concentration gradient.

  2. The implementation of isoniazid preventive therapy in HIV clinics: the experience from the TB/HIV in Rio (THRio) study.

    Science.gov (United States)

    Durovni, Betina; Cavalcante, Solange C; Saraceni, Valeria; Vellozo, Vitoria; Israel, Giselle; King, Bonnie S; Cohn, Silvia; Efron, Anne; Pacheco, Antonio G; Moulton, Lawrence H; Chaisson, Richard E; Golub, Jonathan E

    2010-11-01

    The TB/HIV in Rio (THRio) study was launched in September 2005 to assess the impact of integrated tuberculosis (TB) and HIV treatment strategies in 29 HIV clinics in Rio de Janeiro, Brazil. THRio is a cluster-randomized trial (CRT) to determine whether routine screening for and treatment of latent TB in HIV clinic patients with access to antiretroviral therapy will reduce TB incidence at the clinic level. THRio is part of the Consortium to Respond Effectively to AIDS/TB Epidemic that is implementing research studies to assess the impact of bold, new public health paradigms for controlling the AIDS/TB epidemic. Twenty-nine public primary HIV clinics were randomly assigned a date to begin implementing TB screening procedures and provision of isoniazid preventive therapy (IPT) for TB/HIV coinfected patients. Final analysis of the CRT is expected in 2011. Starting at date of tuberculin skin test (TST)/IPT implementation at each clinic through August 2010, 1670 HIV-infected patients initiated IPT, of which 215 are still receiving treatment. Of the remaining 1455 patients, 1230 (85%) completed therapy and only 20 (1.2%) patients initiating IPT reported adverse reactions leading to discontinuation of therapy. IPT completion was higher among HIV-infected patients receiving HAART (87%) than those not yet receiving HAART (79%, P effort requires a package of activities including training, advocacy and reorganization of services.

  3. Controlled release hydrophilic matrix tablet formulations of isoniazid: design and in vitro studies.

    Science.gov (United States)

    Hiremath, Praveen S; Saha, Ranendra N

    2008-01-01

    The aim of the present investigation was to develop oral controlled release matrix tablet formulations of isoniazid using hydroxypropyl methylcellulose (HPMC) as a hydrophilic release retardant polymer and to study the influence of various formulation factors like proportion of the polymer, polymer viscosity grade, compression force, and release media on the in vitro release characteristics of the drug. The formulations were developed using wet granulation technology. The in vitro release studies were performed using US Pharmacopoeia type 1 apparatus (basket method) in 900 ml of pH 7.4 phosphate buffer at 100 rpm. The release kinetics was analyzed using Korsmeyer-Peppas model. The release profiles were also analyzed using statistical method (one-way analysis of variance) and f (2) metric values. The release profiles found to follow Higuchi's square root kinetics model irrespective of the polymer ratio and the viscosity grade used. The results in the present investigation confirm that the release rate of the drug from the HPMC matrices is highly influenced by the drug/HPMC ratio and viscosity grade of the HPMC. Also, the effect of compression force and release media was found to be significant on the release profiles of isoniazid from HPMC matrix tablets. The release mechanism was found to be anomalous non-Fickian diffusion in all the cases. In the present investigation, a series of controlled release formulations of isoniazid were developed with different release rates and duration so that these formulations could further be assessed from the in vivo bioavailability studies. The formulations were found to be stable and reproducible.

  4. Ginecomastia: um efeito colateral raro da isoniazida Gynecomastia: a rare adverse effect of isoniazid

    Directory of Open Access Journals (Sweden)

    Nelson Morrone

    2008-11-01

    Full Text Available Relata-se o caso de um paciente que desenvolveu ginecomastia duas vezes após tratamento para tuberculose. Homem de 18 anos de idade foi tratado com o esquema isoniazida-rifampicina-pirazinamida; no terceiro mês desenvolveu ginecomastia bilateral, dolorosa, com regressão parcial ao final do tratamento. Foi retratado oito anos após com o mesmo regime, e a ginecomastia recorreu após seis meses de tratamento. Dosagens hormonais foram normais, e a mamografia revelou ginecomastia bilateral. A isoniazida foi suspensa, tendo a ginecomastia regredido parcialmente no final do tratamento. Quatro anos após, não foi constatada ginecomastia. Conclui-se que a ginecomastia relacionada à isoniazida regride totalmente após a suspensão da droga e, portanto, o tratamento cirúrgico ou medicamentoso deve ser evitado.We report the case of a patient who twice developed gynecomastia following tuberculosis treatment. An 18-year-old male developed painful bilateral gynecomastia after three months of treatment with the isoniazid-rifampin-pyrazinamide regimen. Partial resolution of gynecomastia was achieved at the end of treatment. The patient was retreated with the same regimen eight years later, and gynecomastia recurred after six months of treatment. Hormone levels were normal, and a mammogram revealed bilateral gynecomastia. The isoniazid was discontinued, and the gynecomastia was partially resolved by the end of treatment. Four years later, gynecomastia was not detected. We conclude that isoniazid-related gynecomastia completely resolves when the medication is discontinued. Therefore, pharmacological and surgical treatment should be avoided.

  5. Notes from the field: national shortage of isoniazid 300 mg tablets.

    Science.gov (United States)

    2012-12-21

    On November 16, 2012, the Illinois State tuberculosis (TB) program notified CDC's Division of Tuberculosis Elimination of a national shortage of 300 mg tablets of the antituberculosis medication isoniazid (INH). Subsequently, other state TB programs (e.g., California, Indiana, Maryland, New York, Virginia, and Wisconsin) reported difficulty obtaining INH 300 mg tablets. Other programs (e.g., San Diego) have experienced difficulties obtaining at least one of the commercially available anti-TB preparations containing the combination of rifampin and INH (IsonaRif [VersaPharm]).

  6. Health system challenges: An obstacle to the success of isoniazid ...

    African Journals Online (AJOL)

    TB a global public health emergency because of 7 - 8 million recor- ded cases, the spread .... deliver, including the procurement of drugs to ensure the availability of IPT. ... research design and instrument development, data interpretation and.

  7. Structure and function of the liver in conditions of chrome-isoniazid-rifampicin affection of rats after applying of sorbex

    OpenAIRE

    N. I. Burmas; L. S. Fira

    2014-01-01

    The aim of this research was to assess the activity of marker enzymes of the liver and its biliary formation function in conditions of the affection of animals by hexavalent chromium compounds, isoniazid and rifampicin, after applying of sorbex. The experimental affection of rats of different age was carried in the conditions of combined injection of hexavalent chromium compounds (solution of potassium dichromate, 3 mg/kg), isoniazid (0.05 g/kg) and rifampicin (0.25 g/kg) during the 7th and 1...

  8. Isoniazid Mono-Resistant Tuberculosis: Impact on Treatment Outcome and Survival of Pulmonary Tuberculosis Patients in Southern Mexico 1995-2010.

    Science.gov (United States)

    Báez-Saldaña, Renata; Delgado-Sánchez, Guadalupe; García-García, Lourdes; Cruz-Hervert, Luis Pablo; Montesinos-Castillo, Marlene; Ferreyra-Reyes, Leticia; Bobadilla-Del-Valle, Miriam; Canizales-Quintero, Sergio; Ferreira-Guerrero, Elizabeth; Téllez-Vázquez, Norma; Montero-Campos, Rogelio; Yanes-Lane, Mercedes; Mongua-Rodriguez, Norma; Martínez-Gamboa, Rosa Areli; Sifuentes-Osornio, José; Ponce-de-León, Alfredo

    2016-01-01

    Isoniazid mono-resistance (IMR) is the most common form of mono-resistance; its world prevalence is estimated to range between 0.0 to 9.5% globally. There is no consensus on how these patients should be treated. To describe the impact of IMR tuberculosis (TB) on treatment outcome and survival among pulmonary TB patients treated under programmatic conditions in Orizaba, Veracruz, Mexico. We conducted a prospective cohort study of pulmonary TB patients in Southern Mexico. From 1995 to 2010 patients with acid-fast bacilli or culture proven Mycobacterium tuberculosis in sputum samples underwent epidemiological, clinical and microbiological evaluation. We included patients who harbored isoniazid mono-resistant (IMR) strains and patients with strains susceptible to isoniazid, rifampicin, ethambutol and streptomycin. All patients were treated following Mexican TB Program guidelines. We performed annual follow-up to ascertain treatment outcome, recurrence, relapse and mortality. Between 1995 and 2010 1,243 patients with pulmonary TB were recruited; 902/1,243 (72.57%) had drug susceptibility testing; 716 (79.38%) harbored pan-susceptible and 88 (9.75%) IMR strains. Having any contact with a person with TB (adjusted odds ratio (aOR)) 1.85, 95% Confidence interval (CI) 1.15-2.96) and homelessness (adjusted odds ratio (aOR) 2.76, 95% CI 1.08-6.99) were associated with IMR. IMR patients had a higher probability of failure (adjusted hazard ratio (HR) 12.35, 95% CI 3.38-45.15) and death due to TB among HIV negative patients (aHR 3.30. 95% CI 1.00-10.84). All the models were adjusted for socio-demographic and clinical variables. The results from our study provide evidence that the standardized treatment schedule with first line drugs in new and previously treated cases with pulmonary TB and IMR produces a high frequency of treatment failure and death due to tuberculosis. We recommend re-evaluating the optimal schedule for patients harboring IMR. It is necessary to strengthen

  9. Short-course chemotherapy for pulmonary tuberculosis with a rifampicin-isoniazid-pyrazinamide combination tablet.

    Science.gov (United States)

    Cowie, R L; Brink, B A

    1990-04-21

    The effectiveness of a tablet containing a combination of rifampicin, isoniazid and pyrazinamide (Rifater; Mer-National) in the treatment of pulmonary tuberculosis was examined by comparing it with a previously evaluated four-drug regimen. Of 150 black goldminers with a first case of pulmonary tuberculosis, 69 were randomly allocated to receive the combination tablet (RHZ), 5 tablets per day on weekdays for 100 treatment-days, and 81 the four-drug regimen (streptomycin, rifampicin, isoniazid and pyrazinamide) (RHZS). Non-compliance was detected in 42% of the RHZ group and in 16% of the RHZS group. Two patients in the RHZ group and 4 in the RHZS group had to have their treatment altered because routine investigations revealed drug-resistant mycobacteria. Treatment was unsuccessful in 10 patients in the RHZ group, with 4 men failing to complete the regimen and being lost to follow-up, 3 cases of failure of conversion of sputum on the regimen, and 3 relapses. The results for the RHZS group were similar, with 4 failures to complete the regimen, 2 treatment failures and 4 relapses. Evaluation of RHZ showed it to be comparable with a previously evaluated, successful short-course regimen (RHZS). The high incidence of non-compliance probably reflects reduced supervision of this wholly oral regimen.

  10. Simultaneous chemometric determination of pyridoxine hydrochloride and isoniazid in tablets by multivariate regression methods.

    Science.gov (United States)

    Dinç, Erdal; Ustündağ, Ozgür; Baleanu, Dumitru

    2010-08-01

    The sole use of pyridoxine hydrochloride during treatment of tuberculosis gives rise to pyridoxine deficiency. Therefore, a combination of pyridoxine hydrochloride and isoniazid is used in pharmaceutical dosage form in tuberculosis treatment to reduce this side effect. In this study, two chemometric methods, partial least squares (PLS) and principal component regression (PCR), were applied to the simultaneous determination of pyridoxine (PYR) and isoniazid (ISO) in their tablets. A concentration training set comprising binary mixtures of PYR and ISO consisting of 20 different combinations were randomly prepared in 0.1 M HCl. Both multivariate calibration models were constructed using the relationships between the concentration data set (concentration data matrix) and absorbance data matrix in the spectral region 200-330 nm. The accuracy and the precision of the proposed chemometric methods were validated by analyzing synthetic mixtures containing the investigated drugs. The recovery results obtained by applying PCR and PLS calibrations to the artificial mixtures were found between 100.0 and 100.7%. Satisfactory results obtained by applying the PLS and PCR methods to both artificial and commercial samples were obtained. The results obtained in this manuscript strongly encourage us to use them for the quality control and the routine analysis of the marketing tablets containing PYR and ISO drugs. Copyright © 2010 John Wiley & Sons, Ltd.

  11. Intestinal permeability and malabsorption of rifampin and isoniazid in active pulmonary tuberculosis

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    Valéria G. F. Pinheiro

    Full Text Available Low antimycobacterial drug concentrations have been observed in tuberculosis (TB patients under treatment. The lactulose/mannitol urinary excretion test (L/M, normally used to measure intestinal permeability, may be useful to assess drug absorption. The objective of this research was to study intestinal absorptive function and bioavailability of rifampin and isoniazid in TB patients. A cross sectional study was done with 41 patients and 28 healthy controls, using the L/M test. The bioavailabilities of rifampin (R and isoniazid (H were evaluated in 18 patients receiving full doses. Urinary excretion of mannitol and lactulose, measured by HPLC, was significantly lower in TB patients. The serum concentrations of the drugs were below the expected range for R (8-24 mcg/mL or H (3-6 mcg/mL in 16/18 patients. Analyzing the drugs individually, 12/18 patients had low serum concentrations of R, 13/18 for H and 8/18 for both drugs. We suggest that there is a decrease in the functional absorptive area of the intestine in TB patients, which would explain the reduced serum concentrations of antituberculosis drugs. There is a need for new approaches to improve drug bioavailability in TB patients.

  12. Solution thermodynamics of pyrazinamide, isoniazid, and p-aminobenzoic acid in buffers and octanol

    International Nuclear Information System (INIS)

    Blokhina, Svetlana V.; Ol’khovich, Marina V.; Sharapova, Angelica V.; Volkova, Tatyana V.; Perlovich, German L.

    2015-01-01

    Highlights: • Solubility of pyrazinamide, isoniazid, p-aminobenzoic acid were measured. • The activity coefficients of the compounds at infinite dilution were determined. • Thermodynamic functions of dissolution and solvation were calculated. - Abstract: The solubility values of pyrazinamide, isoniazid, and p-aminobenzoic acid in buffers (pH 2.0 and 7.4) and octanol were measured in the temperature range of 293.15 to 313.15 K. The dissolution Gibbs energy, enthalpy, and entropy were calculated. The dissolving process was endothermic and enthalpy-determined. The activity coefficients of the compounds at infinite dilution were determined based on the solubility data and thermophysical parameters. A positive deviation from the ideality was observed in all the solutions. A common tendency of the solubility increase with a decrease in the activity coefficients at T = 298.15 K was revealed for the investigated solute-solvent systems. The excess thermodynamic solubility functions were calculated from the temperature dependences of the activity coefficients. The solvation processes were found to have a considerable influence on the solubility of the substances in solutions studied.

  13. Detection of mutation in isoniazid-resistant Mycobacterium tuberculosis isolates from tuberculosis patients in Belarus

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    Bostanabad S

    2008-01-01

    Full Text Available The aim of this study was to investigate the frequency, location and type of katG mutations in Mycobacterium tuberculosis strains isolated from patients in Belarus. Forty two isoniazid-resistant isolates were identified from sputum of 163 patients with active pulmonary tuberculosis. Drug susceptibility testing was determined by using CDC standard conventional proportional method and BACTEC system. Standard PCR method for detection of isoniazid resistance associated mutations was performed by katG gene amplification and DNA sequencing. Most mutations were found in katG gene codons 315, 316 and 309. Four types of mutations were identified in codon 315: AGC→ACC ( n = 36 85%, AGC→AGG ( n = 1 2.3%, AGC→AAC ( n = 2 4.7%, AGC→GGC ( n = 1 2.3%. One type of mutation was found in codon 316: GGC→AGC ( n = 1841.4%, four types of mutations were detected in codon 309: GGT→GGT ( n = 716.1%, GGT→GCT ( n = 49.2%, GGT→GTC ( n = 36.9%, GGT→GGG ( n = 12.7%. The highest frequency of mutations sharing between primary and secondary infections was found in codon 315.

  14. Perceived barriers to the implementation of Isoniazid preventive therapy for people living with HIV in resource constrained settings: a qualitative study.

    Science.gov (United States)

    Mindachew, Mesele; Deribew, Amare; Memiah, Peter; Biadgilign, Sibhatu

    2014-01-01

    Isoniazid preventive therapy (IPT) reduces the risk of active TB. IPT is a key public health intervention for the prevention of TB among people living with HIV and has been recommended as part of a comprehensive HIV and AIDS care strategy. However, its implementation has been very slow and has been impeded by several barriers. The Objective of the study is to assess the perceived barriers to the implementation of Isoniazid preventive therapy for people living with HIV in resource constrained settings in Addis Ababa, Ethiopia in 2010. A qualitative study using a semi-structured interviewed guide was used for the in-depth interview. A total of 12 key informants including ART Nurse, counselors and coordinators found in four hospitals were included in the interview. Each session of the in-depth interview was recorded via audio tape and detailed notes. The interview was transcribed verbatim. The data was analyzed manually. The findings revealed that poor patient adherence was a major factor; with the following issues cited as the reasons for poor adherence; forgetfulness; lack of understanding of condition and patient non- disclosure of HIV sero-status leading to insubstantial social support; underlying mental health issues resulting in missed or irregular patient appointments; weak patient/healthcare provider relationship due to limited quality interaction; lack of patient information, patient empowerment and proper counseling on IPT; and the deficient reinforcement by health officials and other stakeholders on the significance of IPT medication adherence as a critical for positive health outcomes. Uptake of the implementation of IPT is facing a challenge in resource limited settings. This recalled provision of training/capacity building and awareness creation mechanism for the health workers, facilitating disclosure and social support for the patients is recommended.

  15. The Non-Linear Child: Ontogeny, Isoniazid Concentration, and NAT2 Genotype Modulate Enzyme Reaction Kinetics and Metabolism.

    Science.gov (United States)

    Rogers, Zoe; Hiruy, Hiwot; Pasipanodya, Jotam G; Mbowane, Chris; Adamson, John; Ngotho, Lihle; Karim, Farina; Jeena, Prakash; Bishai, William; Gumbo, Tawanda

    2016-09-01

    N-acetyltransferase 2 (NAT2) catalyzes the acetylation of isoniazid to N-acetylisoniazid. NAT2 polymorphism explains 88% of isoniazid clearance variability in adults. We examined the effects of clinical and genetic factors on Michaelis-Menten reaction kinetic constants of maximum velocity (V max ) and affinity (K m ) in children 0-10years old. We measured the rates of isoniazid elimination and N-acetylisoniazid production in the blood of 30 children. Since maturation effects could be non-linear, we utilized a pharmacometric approach and the artificial intelligence method, multivariate adaptive regression splines (MARS), to identify factors predicting NAT2 V max and K m by examining clinical, genetic, and laboratory factors in toto. Isoniazid concentration predicted both V max and K m and superseded the contribution of NAT2 genotype. Age non-linearly modified the NAT2 genotype contribution until maturation at ≥5.3years. Thus, enzyme efficiency was constrained by substrate concentration, genes, and age. Since MARS output is in the form of basis functions and equations, it allows multiscale systems modeling from the level of cellular chemical reactions to whole body physiological parameters, by automatic selection of significant predictors by the algorithm. Copyright © 2016 Forschungsgesellschaft für Arbeitsphysiologie und Arbeitschutz e.V. Published by Elsevier B.V. All rights reserved.

  16. The Non-Linear Child: Ontogeny, Isoniazid Concentration, and NAT2 Genotype Modulate Enzyme Reaction Kinetics and Metabolism

    Directory of Open Access Journals (Sweden)

    Zoe Rogers

    2016-09-01

    Full Text Available N-acetyltransferase 2 (NAT2 catalyzes the acetylation of isoniazid to N-acetylisoniazid. NAT2 polymorphism explains 88% of isoniazid clearance variability in adults. We examined the effects of clinical and genetic factors on Michaelis-Menten reaction kinetic constants of maximum velocity (Vmax and affinity (Km in children 0–10 years old. We measured the rates of isoniazid elimination and N-acetylisoniazid production in the blood of 30 children. Since maturation effects could be non-linear, we utilized a pharmacometric approach and the artificial intelligence method, multivariate adaptive regression splines (MARS, to identify factors predicting NAT2 Vmax and Km by examining clinical, genetic, and laboratory factors in toto. Isoniazid concentration predicted both Vmax and Km and superseded the contribution of NAT2 genotype. Age non-linearly modified the NAT2 genotype contribution until maturation at ≥5.3 years. Thus, enzyme efficiency was constrained by substrate concentration, genes, and age. Since MARS output is in the form of basis functions and equations, it allows multiscale systems modeling from the level of cellular chemical reactions to whole body physiological parameters, by automatic selection of significant predictors by the algorithm.

  17. [DNA mutations associated to rifampicin or isoniazid resistance in M. tuberculosis clinical isolates from Sonora, Mexico].

    Science.gov (United States)

    Bolado-Martínez, Enrique; Pérez-Mendoza, Ansix; Alegría-Morquecho, Francisco Monserrat; Candia-Plata, María del Carmen; Aguayo-Verdugo, María del Rosario; Alvarez-Hernández, Gerardo

    2012-01-01

    To perform the analysis of specific regions of the major genes associated with resistance to isoniazid or rifampin. Twenty two M. tuberculosis strains, isolated from human samples obtained in Sonora, Mexico. Specific primers for hotspots of the rpoB, katG, inhA genes and the ahpC-oxyR intergenic region were used. The purified PCR products were sequenced. Mutations in the promoter of inhA, the ahpC-oxyR region, and codon 315 of katG and in 451 or 456 codons of rpoB, were identified. Detection of mutations not previously reported requires further genotypic analysis of Mycobacterium tuberculosis isolates in Sonora.

  18. Inhibitory activity of pentacyano(isoniazid)ferrate(II), IQG-607, against promastigotes and amastigotes forms of Leishmania braziliensis

    Science.gov (United States)

    Amorim, Camila F.; Galina, Luiza; Carvalho, Natália B.; Sperotto, Nathalia D. M.; Pissinate, Kenia; Machado, Pablo; Campos, Maria M.; Basso, Luiz A.; Carvalho, Edgar M.; Santos, Diógenes Santiago

    2017-01-01

    M. tuberculosis and parasites of the genus Leishmania present the type II fatty acid biosynthesis system (FASII). The pentacyano(isoniazid)ferrate(II) compound, named IQG-607, inhibits the enzyme 2-trans-enoyl-ACP(CoA) reductase from M. tuberculosis, a key component in the FASII system. Here, we aimed to evaluate the inhibitory activity of IQG-607 against promastigote and amastigote forms of Leishmania (Viannia) braziliensis isolated from patients with different clinical forms of L. braziliensis infection, including cutaneous, mucosal and disseminated leishmaniasis. Importantly, IQG-607 inhibited the proliferation of three different isolates of L. braziliensis promastigotes associated with cutaneous, mucosal and disseminated leishmaniasis. The IC50 values for IQG-607 ranged from 32 to 75 μM, for these forms. Additionally, IQG-607 treatment decreased the proliferation of intracellular amastigotes in infected macrophages, after an analysis of the percentage of infected cells and the number of intracellular parasites/100 cells. IQG-607 reduced from 58% to 98% the proliferation of L. braziliensis from cutaneous, mucosal and disseminated strains. Moreover, IQG-607 was also evaluated regarding its potential toxic profile, by using different cell lines. Cell viability of the lineages Vero, HaCat and HepG2 was significantly reduced after incubation with concentrations of IQG-607 higher than 2 mM. Importantly, IQG-607, in a concentration of 1 mM, did not induce DNA damage in HepG2 cells, when compared to the untreated control group. Future studies will confirm the mechanism of action of IQG-607 against L. braziliensis. PMID:29281707

  19. Adherence with isoniazid for prevention of tuberculosis among HIV-infected adults in South Africa

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    Muller F James

    2006-06-01

    Full Text Available Abstract Background Tuberculosis (TB is the most common opportunistic infection in HIV-infected adults in developing countries. Isoniazid (INH is recommended for treatment of latent TB infection, however non-adherence is common. The purpose of this study was to apply in-house prepared isoniazid (INH urine test strips in a clinical setting, and identify predictors of positive test results in an adherence questionnaire in HIV-infected adults taking INH for prevention of TB. Methods Cross-sectional study of adherence using a questionnaire and urine test strips for detection of INH metabolites at two hospitals in Pietermaritzburg, South Africa. Participants were aged at least 18 years, HIV positive, and receiving INH for prevention of tuberculosis disease. Univariate and multivariate analyses are used to identify factors relevant to adherence. Results 301 consecutive patients were recruited. 28% of participants had negative urine tests. 32 (37.2%, 95% CI25.4, 45.0 of the 86 patients who received INH from peripheral pharmacies said the pharmacy had run out of INH at some time, compared with central hospital pharmacies (p = 0.0001. In univariate analysis, a negative test was associated with self-reported missed INH doses (p = 0.043. Each 12-hour increment since last reported dose increased the likelihood of a negative test by 34% (p = 0.0007. Belief in INH safety was associated with a positive test (p = 0.021. In multivariate analysis, patients who believed INH is important for prevention of TB disease were more likely to be negative (p = 0.0086. Conclusion Adequate drug availability at peripheral pharmacies remains an important intervention for TB prevention. Key questions may identify potentially non-adherent patients. In-house prepared urine tests strips are an effective and cheap method of objectively assessing INH adherence, and could be used an important tool in TB control programs.

  20. Self-reported adherence and associated factors to isoniazid preventive therapy for latent tuberculosis among people living with HIV/AIDS at health centers in Gondar town, North West Ethiopia

    Directory of Open Access Journals (Sweden)

    Ayele AA

    2017-04-01

    Full Text Available Asnakew Achaw Ayele,1 Seyfe Asrade Atnafie,2 Demis Driba Balcha,1 Asegedech Tsegaw Weredekal,2 Birhanu Alemayehu Woldegiorgis,1 Mulgeta Melaku Wotte,1 Begashaw Melaku Gebresillasie1 1Department of Clinical Pharmacy, 2Department of Pharmacology, School of Pharmacy, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia Purpose: This study aimed to assess self-reported adherence and associated factors to isoniazid preventive therapy (IPT for latent tuberculosis among people living with HIV/AIDS (PLWHA at health centers in Gondar town, North West Ethiopia.Patients and methods: An institution-based prospective cross-sectional study was conducted from March 10 to June 11, 2016. A total of 154 eligible participants were included in the study, using the simple random sampling method, from the available four health centers and one teaching referral hospital that provided antiretroviral therapy (ART for HIV/AIDS patients. Adherence was measured by self-report of isoniazid (INH tablets taken for the preceding 7 days. Participants were recruited through in-depth interviews. The collected data were entered and analyzed using the statistical packages for social sciences (SPSS version 20.Results: The adherence level to IPT was 90.3% for the last 7 days of the study. ART was initiated for 84.4%, and all of them were on a first-line regimen. Isoniazid-related side effects were reported by 48 (31.2% participants, of which the most commonly identified were abdominal pain, vomiting, skin rash, jaundice, and numbness. Only 3 (2% participants discontinued from the study. In the bivariate logistic regression analysis, respondents who had received an explanation about IPT were 83% times more likely to be adherent compared to those who had not received it (95% CI, AOR: 0.266 [0.23–3.127]. Respondents who had taken IPT for ≥5 months were more likely to be adherent than those who had taken it for 1–2 months [95% CI, COR: 1.484]. On the

  1. Pengembangan Metode Kromatografi Cair Kinerja Tinggi Spektrometri Massa untuk Penetapan Kadar Rifampisin, Isoniazid dan Pirazinamid dari Plasma Manusia dan Sediaan Tablet

    OpenAIRE

    Nerdy

    2012-01-01

    The drugs used in the treatment of tuberculosis can be divided into two categories, i.e.: primary anti-tuberculosis and secondary anti-tuberculosis. The primary anti-tuberculosis have a higher efficacy and better safety than those of secondary anti-tuberculosis drugs. Primary anti-tuberculosis drugs are rifampicin, isoniazid, pyrazinamide and ethambutol. In their use rifampicin, isoniazid and pyrazinamide are usually combined. According to the Law of the Republic of Indonesia number 36 yea...

  2. Phase I dose-escalation study of the c-Met tyrosine kinase inhibitor SAR125844 in Asian patients with advanced solid tumors, including patients with MET-amplified gastric cancer.

    Science.gov (United States)

    Shitara, Kohei; Kim, Tae Min; Yokota, Tomoya; Goto, Masahiro; Satoh, Taroh; Ahn, Jin-Hee; Kim, Hyo Song; Assadourian, Sylvie; Gomez, Corinne; Harnois, Marzia; Hamauchi, Satoshi; Kudo, Toshihiro; Doi, Toshihido; Bang, Yung-Jue

    2017-10-03

    SAR125844 is a potent and selective inhibitor of the c-Met kinase receptor. This was an open-label, phase I, multicenter, dose-escalation, and dose-expansion trial of SAR125844 in Asian patients with solid tumors, a subgroup of whom had gastric cancer and MET amplification (NCT01657214). SAR125844 was administered by intravenous infusion (260-570 mg/m 2 ) on days 1, 8, 15, and 22 of each 28-day cycle. Objectives were to determine the maximum tolerated dose (MTD) and to evaluate SAR125844 safety and pharmacokinetic profile. Antitumor activity was also assessed. Of 38 patients enrolled (median age 64.0 years), 22 had gastric cancer, including 14 with MET amplification. In the dose-escalation cohort ( N = 19; unselected population, including three patients with MET -amplification [two with gastric cancer and one with lung cancer]), the MTD was not reached, and the recommended dose was established at 570 mg/m 2 . Most frequent treatment-emergent adverse events (AEs) were nausea (36.8%), vomiting (34.2%), decreased appetite (28.9%), and fatigue or asthenia, constipation, and abdominal pains (each 21.1%); none appeared to be dose-dependent. Grade ≥ 3 AEs were observed in 39.5% of patients and considered drug-related in 7.9%. SAR125844 exposure increased slightly more than expected by dose proportionality; dose had no significant effect on clearance. No objective responses were observed in the dose-escalation cohort, with seven patients (three gastric cancer, two colorectal cancer, one breast cancer, and one with cancer of unknown primary origin) having stable disease. Modest antitumor activity was observed at 570 mg/m 2 in the dose-expansion cohort, comprising patients with MET -amplified tumors ( N = 19). Two gastric cancer patients had partial responses, seven patients had stable disease (six gastric cancer and one kidney cancer), and 10 patients had progressive disease. Single-agent SAR125844 administered up to 570 mg/m 2 has acceptable tolerability and modest

  3. Implications of the 2015 World Health Organization isoniazid preventive therapy recommendations on tuberculosis prevention efforts in Namibia.

    Science.gov (United States)

    Oloo, Stella Anne

    2016-07-01

    The World Health Organization recently released guidelines recommending 36-month use of isoniazid preventive therapy in adults and adolescents living with HIV in resource-limited settings. Namibia continues to grapple with one of the highest incidences of tuberculosis (TB) worldwide. Implementation of these guidelines requires considerations of TB epidemiology, health infrastructure, programmatic priorities and patient adherence. This article explores the challenges Namibia currently faces in its fight against TB and the implications of the new guidelines on Namibian TB prevention efforts.

  4. Development of a biocompatible nanodelivery system for tuberculosis drugs based on isoniazid-Mg/Al layered double hydroxide

    Directory of Open Access Journals (Sweden)

    Saifullah B

    2014-10-01

    Full Text Available Bullo Saifullah,1 Palanisamy Arulselvan,2 Mohamed Ezzat El Zowalaty,2,3 Sharida Fakurazi,2,4 Thomas J Webster,5,6 Benjamin M Geilich,5 Mohd Zobir Hussein1 1Materials Synthesis and Characterization Laboratory, Institute of Advanced Technology, 2Laboratory of Vaccines and Immunotherapeutics, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor, Malaysia; 3Department of Environmental Health, Faculty of Public Health and Tropical Medicine, Jazan University, Jazan, Saudi Arabia; 4Department of Human Anatomy, Faculty of Medicine and Health Science, Universiti Putra Malaysia, Serdang, Selangor, Malaysia; 5Department of Chemical Engineering and Program in Bioengineering, Northeastern University, Boston, MA, USA; 6Center of Excellence for Advanced Materials Research, King Abdulaziz University, Jeddah, Saudi Arabia Abstract: The primary challenge in finding a treatment for tuberculosis (TB is patient non-compliance to treatment due to long treatment duration, high dosing frequency, and adverse effects of anti-TB drugs. This study reports on the development of a nanodelivery system that intercalates the anti-TB drug isoniazid into Mg/Al layered double hydroxides (LDHs. Isoniazid was found to be released in a sustained manner from the novel nanodelivery system in humans in simulated phosphate buffer solutions at pH 4.8 and pH 7.4. The nanodelivery formulation was highly biocompatible compared to free isoniazid against human normal lung and 3T3 mouse fibroblast cells. The formulation was active against Mycobacterium tuberculosis and gram-positive bacteria and gram-negative bacteria. Thus results show significant promise for the further study of these nanocomposites for the treatment of TB. Keywords: tuberculosis, isoniazid, Mg/Al LDH, nanodelivery system

  5. Bioequivalence of isoniazid in a two drug fixed dose combination and in a single drug dosage form.

    Science.gov (United States)

    Agrawal, S; Kaul, C L; Panchagnula, R

    2001-08-01

    To increase the patient compliance and reduce the risk of drug resistant strains, WHO and IUATLD recommend the use of Fixed Dose Combination (FDC) tablets as a routine therapeutic regimen in Directly Observed Treatment Shortcourse (DOTS). But the main issue in the use of FDC is the quality of the formulation. At present WHO and IUATLD suggest the bioequivalence assessment of only rifampicin from FDC compared to separate formulations. For the therapeutic effectiveness all the components of the FDCs should be bioavailable at tissue site. Also, the primary and acquired resistance rate of isoniazid is much higher compared to other anti-tubercular drugs. Hence, a comparative bioavailability study of isoniazid from a two drugs FDC compared to a separate formulation was carried out on a group of 12 healthy volunteers. When evaluated by normal or log transformed confidence interval, Two Way ANOVA and Hauschke analysis, the bioequivalence limits for AUC0-8 and AUC0-24 were within 0.8-1.25. For Cmax and Tmax, these limits were within 0.7-1.43. Hence, isoniazid from a FDC formulation was found to be bioequivalent to a separate formulation at same dose levels.

  6. Preparation and characterization of isoniazid-loaded crude soybean lecithin liposomes.

    Science.gov (United States)

    Nkanga, Christian Isalomboto; Krause, Rui Werner; Noundou, Xavier Siwe; Walker, Roderick Bryan

    2017-06-30

    Tuberculosis (TB) is a poverty related infectious disease that is rapidly giving rise to public health concerns. Lengthy drug administration and frequent adverse side-effects associated with TB treatment make anti-tubercular drugs (ATDs) good candidates for drug delivery studies. This work aimed to formulate and prepare liposomes as a cost-effective option for ATD delivery. Liposomes were prepared by film hydration using crude soybean lecithin (CL) and not pure phospholipids as in the normal practice. Cholesterol was also used (up to 25% mass ratio), and isoniazid (INH) was encapsulated as model drug using a freeze-thaw loading technique. Purified soybean lecithin (PL) was also used for comparative purposes, under the same conditions. INH-loaded liposomes were characterized for particle size, Zeta Potential (ZP), encapsulation efficiency (EE) and drug release. Physicochemical properties were investigated using thermogravimetric analysis, differential scanning calorimetry, X-ray diffraction and Fourier transform infrared. INH-loaded CL-based liposomes showed high EE (79±2.45%). The average particle size (813.00±9.21nm) and ZP (-42.80±4.31mV) of this formulation are promising for the treatment of TB by pulmonary delivery. These findings suggest the possibility of encapsulating ATDs in liposomes made of crude soybean lecithin that is cheap and readily available. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Design and evaluation of enteric-coated tablets for rifampicin and isoniazid combinations.

    Science.gov (United States)

    Wang, Yongjun; Liu, Hongzhuo; Liu, Kai; Sun, Jin; He, Zhonggui

    2013-01-01

    In order to improve the bioavailability of rifampicin (RIF) from rifampicin and isoniazid (INH) combination formulations, the physicochemical characteristics of RIF, stability of RIF in different pH buffers in the presence of INH, as well as the effect of particle size of RIF materials on the dissolution rate were investigated. On the basis of the above examinations, enteric-coated tablets for RIF and INH combinations were designed and prepared. RIF showed low solubility and high apparent distribution coefficient in the intestinal pH (pH 4.0-7.4). With the decrease in pH, the degradation of RIF increase and the presence of INH deepen the degradation. Enteric-coated tablets were prepared after grinding the RIF materials by dry granulation technique. The pharmacokinetics of RIF and INH of self-made enteric-coated tablets in dogs were studied by comparing with the reference tablets. The AUC(0-48) of RIF in both reference and test tablets were 304.77 ± 42.27 and 353.79 ± 31.63 µg·h·mL(-1), respectively. The AUC(0-48) of INH in both reference and test tablets were 17.14 ± 8.59 and 19.62 ± 10.57 µg·h·mL(-1), respectively. Enteric-coated tablets may minimize the decomposition of RIF in gastrointestinal tract and improve the bioavailability.

  8. Tailored release drug delivery system for rifampicin and isoniazid for enhanced bioavailability of rifampicin.

    Science.gov (United States)

    Avachat, Amelia M; Bhise, Satish B

    2011-04-01

    The front line antitubercular drugs rifampicin (RMP) and isoniazid (INH), when co-administered, face the problem of reduced bioavailability of RMP. Stabilization of RMP in the presence of INH under acidic environment may improve the bioavailability of RMP. In vitro degradation studies showed around 15-25% degradation of RMP under the aforesaid conditions if the ratio of RMP: INH is above 1:0.5.This degradation is reduced to less than 10% when the ratio of RMP: INH is below 1:0.25. Based on these findings, an innovative drug delivery system was designed with the immediate release of RMP and tailored prolonged release of INH. The bilayer tablets prepared with this concept were subjected to relative bioavailability studies in healthy human volunteers in an open label, balanced, randomized, single-dose, cross-over study under fasted state. A validated LC-MS/MS bioanalytical method was employed for estimation of RMP and INH in plasma. Bioavailability studies revealed that C(max) and AUC for RMP increased by 18 and 20%, respectively, confirming the above innovative concept. Even in the case of INH, AUC increased significantly by around 30% and thus time above minimum inhibitory concentration (MIC) would also increase, which may result in further improved clinical outcome.

  9. Enhanced electrocatalytic oxidation of isoniazid at electrochemically modified rhodium electrode for biological and pharmaceutical analysis.

    Science.gov (United States)

    Cheemalapati, Srikanth; Chen, Shen-Ming; Ali, M Ajmal; Al-Hemaid, Fahad M A

    2014-09-01

    A simple and sensitive electrochemical method has been proposed for the determination of isoniazid (INZ). For the first time, rhodium (Rh) modified glassy carbon electrode (GCE) has been employed for the determination of INZ by linear sweep voltammetry technique (LSV). Compared with the unmodified electrode, the proposed Rh modified electrode provides strong electrocatalytic activity toward INZ with significant enhancement in the anodic peak current. Scanning electron microscopy (SEM) and field emission scanning electron microscopy (FESEM) results reveal the morphology of Rh particles. With the advantages of wide linearity (70-1300μM), good sensitivity (0.139μAμM(-1)cm(-2)) and low detection limit (13μM), this proposed sensor holds great potential for the determination of INZ in real samples. The practicality of the proposed electrode for the detection of INZ in human urine and blood plasma samples has been successfully demonstrated using LSV technique. Through the determination of INZ in commercially available pharmaceutical tablets, the practical applicability of the proposed method has been validated. The recovery results are found to be in good agreement with the labeled amounts of INZ in tablets, thus showing its great potential for use in clinical and pharmaceutical analysis. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Isoniazid, pyrazinamide and rifampicin content variation in split fixed-dose combination tablets.

    Science.gov (United States)

    Pouplin, Thomas; Phuong, Pham Nguyen; Toi, Pham Van; Nguyen Pouplin, Julie; Farrar, Jeremy

    2014-01-01

    In most developing countries, paediatric tuberculosis is treated with split tablets leading to potential inaccuracy in the dose delivery and drug exposure. There is no data on the quality of first-line drugs content in split fixed-dose combination tablets. To determine Isoniazid, Pyrazinamide and Rifampicin content uniformity in split FDC tablets used in the treatment of childhood tuberculosis. Drug contents of 15 whole tablets, 30 half tablets and 36 third tablets were analysed by high performance liquid chromatography. The content uniformity was assessed by comparing drug content measured in split portions with their expected amounts and the quality of split portions was assessed applying qualitative specifications for whole tablets. All whole tablets measurements fell into the USP proxy for the three drugs. But a significant number of half and third portions was found outside the tolerated variation range and the split formulation failed the requirements for content uniformity. To correct for the inaccuracy of splitting the tablets into equal portions, a weight-adjustment strategy was used but this did not improve the findings. In split tablets the content of the three drugs is non-uniform and exceeded the USP recommendations. There is an absolute need to make child-friendly formulations available for the treatment of childhood tuberculosis.

  11. PROPOSAL OF ANTI-TUBERCULOSIS REGIMENS BASED ON SUSCEPTIBILITY TO ISONIAZID AND RIFAMPICIN

    Science.gov (United States)

    Mendoza-Ticona, Alberto; Moore, David AJ; Alarcón, Valentina; Samalvides, Frine; Seas, Carlos

    2014-01-01

    Objective To elaborate optimal anti-tuberculosis regimens following drug susceptibility testing (DST) to isoniazid (H) and rifampicin (R). Design 12 311 M. tuberculosis strains (National Health Institute of Peru 2007-2009) were classified in four groups according H and R resistance. In each group the sensitivity to ethambutol (E), pirazinamide (Z), streptomycin (S), kanamycin (Km), capreomycin (Cm), ciprofloxacin (Cfx), ethionamide (Eto), cicloserine (Cs) and p-amino salicilic acid (PAS) was determined. Based on resistance profiles, domestic costs, and following WHO guidelines, we elaborated and selected optimal putative regimens for each group. The potential efficacy (PE) variable was defined as the proportion of strains sensitive to at least three or four drugs for each regimen evaluated. Results Selected regimes with the lowest cost, and highest PE of containing 3 and 4 effective drugs for TB sensitive to H and R were: HRZ (99,5%) and HREZ (99,1%), respectively; RZECfx (PE=98,9%) and RZECfxKm (PE=97,7%) for TB resistant to H; HZECfx (96,8%) and HZECfxKm (95,4%) for TB resistant to R; and EZCfxKmEtoCs (82.9%) for MDR-TB. Conclusion Based on resistance to H and R it was possible to select anti-tuberculosis regimens with high probability of success. This proposal is a feasible alternative to tackle tuberculosis in Peru where the access to rapid DST to H and R is improving progressively. PMID:23949502

  12. Determination of isoniazid concentration in rabbit vertebrae by isotope tracing technique in conjunction with HPLC.

    Science.gov (United States)

    Liu, Peng; Fu, Zhaozong; Jiang, Jianming; Yuan, Liang; Lin, Zhen

    2013-09-01

    Medications compounded with isoniazid (INH) are usually applied to surgical sites at the completion of surgery to locally kill postoperative residual tubercle bacilli. However, the distribution and elimination of INH in the vertebrae in vivo are not known. In this study, isotope tracing was used in conjunction with high-pressure liquid chromatography (HPLC) to address this. INH and technetium-99 m-labeled INH were applied to the vertebrae of rabbits. After 2 and 6 h, osseous tissues containing INH, as determined by radionuclide imaging, were collected for detection with HPLC. The results showed that INH mainly stayed around the vertebrae 6 h after its application and did not permeate widely into the blood or other organs, except for the kidneys. The standard deviations of INH concentrations in the technetium-99 m-INH group were approximately four-fold smaller than those in the INH group. This method of coupling isotope tracing and HPLC can effectively limit experimental error during sample collection, allowing accurate and reliable identification of the concentration levels of INH in osseous tissues in vivo. Copyright © 2013 John Wiley & Sons, Ltd.

  13. Therapeutic drug monitoring of isoniazid and rifampicin during anti-tuberculosis treatment in Auckland, New Zealand.

    Science.gov (United States)

    Maze, M J; Paynter, J; Chiu, W; Hu, R; Nisbet, M; Lewis, C

    2016-07-01

    There is uncertainty as to the optimal therapeutic concentrations of anti-tuberculosis drugs to achieve cure. To characterise the use of therapeutic drug monitoring (TDM), and identify risk factors and outcomes for those with concentrations below the drug interval. Patients treated for tuberculosis (TB) who had rifampicin (RMP) or isoniazid (INH) concentrations measured between 1 January 2005 and 31 December 2012 were studied retrospectively. Matched concentrations and drug dosing time were assessed according to contemporary regional drug intervals (RMP > 6 μmol/l, INH > 7.5 μmol/l) and current international recommendations (RMP > 10 μmol/l, INH > 22 μmol/l). Outcomes were assessed using World Health Organization criteria. Of 865 patients, 121 had concentrations of either or both medications. RMP concentrations were within the regional drug intervals in 106/114 (93%) and INH in 91/100 (91%). Concentrations were within international drug intervals for RMP in 76/114 (67%) and INH in 53/100 (53%). Low weight-based dose was the only statistically significant risk factor for concentrations below the drug interval. Of the 35 patients with low concentrations, 21 were cured, 9 completed treatment and 5 transferred out. There were no relapses during follow-up (mean 66.5 months). There were no clinically useful characteristics to guide use of TDM. Many patients had concentrations below international therapeutic intervals, but were successfully treated.

  14. Isoniazid Prophylaxis of Latent Tuberculous Infection among Healthcare Workers in Bamrasnaradura Infectious Diseases Institute

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    Patama Suttha

    2016-07-01

    Full Text Available Background: Treatment of latent tuberculosis infection (LTBI is one of the essential measures for tuberculosis (TB control. The tuberculin skin test (TST is an important tool for the detection of LTBI and the identification of healthcare workers (HCWs who require chemoprophylaxis. Also, the rate of active TB should be evaluated among HCWs with and without isoniazid (INH prophylactic treatment for LTBI. Objective: To evaluate the rate of active TB disease among HCWs with or without INH prophylaxis for LTBI. Methods: We retrospectively studied the clinical records of HCWs with LTBI at the employee TB screening clinic in Bamrasnaradura Infectious Diseases Institute from January 2008 to December 2010. Voluntary INH prophylaxis was recommended by physicians and nurses at the TB clinic in case of recent positive 2-step TST. The rate of active TB disease in HCWs with and without INH prophylaxis for LTBI was evaluated and followed during a period of 5 years. As well, the compliance and adverse effects of INH prophylaxis were identified by history taking. Results: There were 29 from 113 HCWS (25.7% receiving INH prophylaxis for 6 months (23 HCWs and 9 months (6 HCWs. 2 HCWs in each 6- and 9-month group did not complete INH prophylaxis for LTBI. After 5 years of TST, no case of active TB disease was found in HCWS with or without INH prophylaxis. Moreover, no adverse drug reactions were reported. Conclusion: No active tuberculosis disease was noted between the INH treatment and the control groups.

  15. Significance of Coexisting Mutations on Determination of the Degree of Isoniazid Resistance in Mycobacterium tuberculosis Strains.

    Science.gov (United States)

    Karunaratne, Galbokka Hewage Roshanthi Eranga; Wijesundera, Sandhya Sulochana; Vidanagama, Dhammika; Adikaram, Chamila Priyangani; Perera, Jennifer

    2018-04-23

    The emergence and spread of drug-resistant tuberculosis (TB) pose a threat to TB control in Sri Lanka. Isoniazid (INH) is a key element of the first-line anti-TB treatment regimen. Resistance to INH is mainly associated with point mutations in katG, inhA, and ahpC genes. The objective of this study was to determine mutations of these three genes in INH-resistant Mycobacterium tuberculosis (MTb) strains in Sri Lanka. Complete nucleotide sequence of the three genes was amplified by polymerase chain reaction and subjected to DNA sequencing. Point mutations in the katG gene were identified in 93% isolates, of which the majority (78.6%) were at codon 315. Mutations at codons 212 and 293 of the katG gene have not been reported previously. Novel mutations were recognized in the promoter region of the inhA gene (C deletion at -34), fabG1 gene (codon 27), and ahpC gene (codon 39). Single S315T mutation in the katG gene led to a high level of resistance, while a low level of resistance with high frequency (41%) was observed when katG codon 315 coexisted with the mutation at codon 463. Since most of the observed mutations of all three genes coexisted with the katG315 mutation, screening of katG315 mutations will be a useful marker for molecular detection of INH resistance of MTb in Sri Lanka.

  16. Oral pyridoxine can substitute for intravenous pyridoxine in managing patients with severe poisoning with isoniazid and rifampicin fixed dose combination tablets: a case report.

    Science.gov (United States)

    Dilrukshi, M D S A; Ratnayake, C A P; Gnanathasan, C A

    2017-08-08

    Fixed drug combination of isoniazid and rifampicin is a rare cause of poisoning even in endemic countries for tuberculosis infection. Severe poisoning can cause severe morbidity and mortality if not treated promptly. Though intravenous pyridoxine is the preferred antidote for severe standard isoniazid poisoning it is not freely available even in best of care centers. We describe a case of severe poisoning with fixed drug combination of isoniazid and rifampicin successfully managed with oral pyridoxine at national hospital of Sri Lanka. A 22 year old, Sri Lankan female presented to a local hospital 1 h after self-ingestion of 28 tablets of fixed drug combination of isoniazid and rifampicin which contained 4.2 g of standard isoniazid and 7.2 g of rifampicin. One and half hours after ingestion she developed generalized tonic-clonic seizure with loss of consciousness. She was given intravenous diazepam 5 mg immediately and transferred to national hospital of Sri Lanka, for further care. Upon arrival to tertiary care hospital in 3.5 h of poisoning she had persistent vomiting, dizziness and headache. On examination, she was drowsy but arousable, orange-red discoloration of the body was noted even with the dark skin complexion. She also had orange-red colour urine and vomitus. Pulse rate was 104 beats/min, blood pressure 130/80 mmHg, respiratory rate was 20 breaths/min. The arterial blood gas analysis revealed compensated metabolic acidosis and mildly elevated lactic acid level. Considering the clinical presentation with neurological toxicity and the large amount of isoniazid dose ingested, crushed oral tablets of pyridoxine 4.2 g (equal to standard isoniazid dose ingested) administered immediately via a nasogastric tube since intravenous preparation was not available in the hospital. Simultaneously forced diuresis using intravenous 0.9% saline was commenced in order to enhance excretion of toxic metabolites via kidneys. She had no recurrence of seizures but had

  17. Interpreting meta-analysis according to the adequacy of sample size. An example using isoniazid chemoprophylaxis for tuberculosis in purified protein derivative negative HIV-infected individuals

    Directory of Open Access Journals (Sweden)

    Kristian Thorlund

    2010-04-01

    Full Text Available Kristian Thorlund1,2, Aranka Anema3, Edward Mills41Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada; 2The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; 3British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia, Vancouver, British Columbia, Canada; 4Faculty of Health Sciences, University of Ottawa, Ottawa, Ontario, CanadaObjective: To illustrate the utility of statistical monitoring boundaries in meta-analysis, and provide a framework in which meta-analysis can be interpreted according to the adequacy of sample size. To propose a simple method for determining how many patients need to be randomized in a future trial before a meta-analysis can be deemed conclusive.Study design and setting: Prospective meta-analysis of randomized clinical trials (RCTs that evaluated the effectiveness of isoniazid chemoprophylaxis versus placebo for preventing the incidence of tuberculosis disease among human immunodeficiency virus (HIV-positive individuals testing purified protein derivative negative. Assessment of meta-analysis precision using trial sequential analysis (TSA with LanDeMets monitoring boundaries. Sample size determination for a future trials to make the meta-analysis conclusive according to the thresholds set by the monitoring boundaries.Results: The meta-analysis included nine trials comprising 2,911 trial participants and yielded a relative risk of 0.74 (95% CI, 0.53–1.04, P = 0.082, I2 = 0%. To deem the meta-analysis conclusive according to the thresholds set by the monitoring boundaries, a future RCT would need to randomize 3,800 participants.Conclusion: Statistical monitoring boundaries provide a framework for interpreting meta-analysis according to the adequacy of sample size and project the required sample size for a future RCT to make a meta-analysis conclusive

  18. Phase I dose-escalation study of the c-Met tyrosine kinase inhibitor SAR125844 in Asian patients with advanced solid tumors, including patients with MET-amplified gastric cancer

    OpenAIRE

    Shitara, Kohei; Kim, Tae Min; Yokota, Tomoya; Goto, Masahiro; Satoh, Taroh; Ahn, Jin-Hee; Kim, Hyo Song; Assadourian, Sylvie; Gomez, Corinne; Harnois, Marzia; Hamauchi, Satoshi; Kudo, Toshihiro; Doi, Toshihido; Bang, Yung-Jue

    2017-01-01

    SAR125844 is a potent and selective inhibitor of the c-Met kinase receptor. This was an open-label, phase I, multicenter, dose-escalation, and dose-expansion trial of SAR125844 in Asian patients with solid tumors, a subgroup of whom had gastric cancer and MET amplification (NCT01657214). SAR125844 was administered by intravenous infusion (260–570 mg/m2) on days 1, 8, 15, and 22 of each 28-day cycle. Objectives were to determine the maximum tolerated dose (MTD) and to evaluate SAR125844 safety...

  19. Public health impact of isoniazid-resistant Mycobacterium tuberculosis strains with a mutation at amino-acid position 315 of katG: a decade of experience in The Netherlands

    NARCIS (Netherlands)

    van Doorn, H. R.; de Haas, P. E. W.; Kremer, K.; Vandenbroucke-Grauls, C. M. J. E.; Borgdorff, M. W.; van Soolingen, D.

    2006-01-01

    A previous limited study demonstrated that Mycobacterium tuberculosis isolates with a mutation at amino-acid position 315 of katG (Delta315) exhibited high-level resistance to isoniazid and were more frequently resistant to streptomycin. In the present study, isoniazid-resistant M. tuberculosis

  20. Reagent Precoated Targets for Rapid In-Tissue Derivatization of the Anti-Tuberculosis Drug Isoniazid Followed by MALDI Imaging Mass Spectrometry

    Science.gov (United States)

    Manier, M. Lisa; Reyzer, Michelle L.; Goh, Anne; Dartois, Veronique; Via, Laura E.; Barry, Clifton E.; Caprioli, Richard M.

    2011-08-01

    Isoniazid (INH) is an important component of front-line anti-tuberculosis therapy with good serum pharmacokinetics but unknown ability to penetrate tuberculous lesions. However, endogenous background interferences hinder our ability to directly analyze INH in tissues. Chemical derivatization has been successfully used to measure isoniazid directly from tissue samples using matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS). MALDI targets were pretreated with trans-cinnamaldehyde (CA) prior to mounting tissue slices. Isoniazid present in the tissues was efficiently derivatized and the INH-CA product measured by MS/MS. Precoating of MALDI targets allows the tissues to be directly thaw-mounted and derivatized, thus simplifying the preparation. A time-course series of tissues from tuberculosis infected/INH dosed animals were assayed and the MALDI MS/MS response correlates well with the amount of INH determined to be in the tissues by high-performance liquid chromatography (HPLC)-MS/MS.

  1. Characterisation of the membrane affinity of an isoniazide peptide conjugate by tensiometry, atomic force microscopy and sum-frequency vibrational spectroscopy, using a phospholipid Langmuir monolayer model.

    Science.gov (United States)

    Hill, Katalin; Pénzes, Csanád Botond; Schnöller, Donát; Horváti, Kata; Bosze, Szilvia; Hudecz, Ferenc; Keszthelyi, Tamás; Kiss, Eva

    2010-10-07

    Tensiometry, sum-frequency vibrational spectroscopy, and atomic force microscopy were employed to assess the cell penetration ability of a peptide conjugate of the antituberculotic agent isoniazide. Isoniazide was conjugated to peptide (91)SEFAYGSFVRTVSLPV(106), a functional T-cell epitope of the immunodominant 16 kDa protein of Mycobacterium tuberculosis. As a simple but versatile model of the cell membrane a phospholipid Langmuir monolayer at the liquid/air interface was used. Changes induced in the structure of the phospholipid monolayer by injection of the peptide conjugate into the subphase were followed by tensiometry and sum-frequency vibrational spectroscopy. The drug penetrated lipid films were transferred to a solid support by the Langmuir-Blodgett technique, and their structures were characterized by atomic force microscopy. Peptide conjugation was found to strongly enhance the cell penetration ability of isoniazide.

  2. Comparative bioequivalence study of rifampicin and isoniazid combinations in healthy volunteers.

    Science.gov (United States)

    Padgaonkar, K A; Revankar, S N; Bhatt, A D; Vaz, J A; Desai, N D; D'Sa, S; Shah, V; Gandewar, K

    1999-07-01

    To assess the bioavailability of rifampicin (RMP) in three brands of combination formulations of anti-tuberculosis drugs. A three-way double-blind, cross-over bioavailability study of RMP and isoniazid (INH), consisting of a comparison of a two-drug combination of tablets of RMP and INH each separately (reference brand R) and a tablet of RMP + INH (brand N), and a capsule of RMP + INH (brand L) was carried out in 12 healthy male volunteers. Coded plasma samples were analysed for levels of RMP as well as INH and acetylisoniazid (ACINH) by two high performance liquid chromatography (HPLC) methods. The mean values of RMP in brand N (Cmax 6.49+/-0.52 microg/mL, Tmax 2.33+/-0.18 h, AUC(0-24h) 39.83+/-3.44 microg/mL.h) were comparable with those obtained with brand R (Cmax 5.22+/-0.59 microg/mL, Tmax 2.50+/-0.12 h, AUC(0-24h) 33.33+/-3.47 microg/mL.h). The mean values of RMP in brand L (Cmax 3.05+/-0.52 microg/ mL, Tmax 3.79+/-0.57 h and AUC(0-24h) 21.78+/-3.67 microg/ mL.h) were significantly different from those in brand R. Nevertheless, all of the pharmacokinetic parameters obtained for INH and ACINH in all three brands were comparable. Using brand R as a comparison, brand N was bioequivalent and brand L was not bioequivalent.

  3. Comparative bioavailability of rifampicin, isoniazid and pyrazinamide from a four drug fixed dose combination with separate formulations at the same dose levels.

    Science.gov (United States)

    Agrawal, Shrutidevi; Singh, Inderjit; Kaur, Kanwal Jit; Bhade, Shantaram R; Kaul, Chaman Lal; Panchagnula, Ramesh

    2004-05-19

    Fixed dose combination (FDC) formulations became popular in the treatment of tuberculosis (TB) because of the better patient compliance, reduced risk of monotherapy and emergence of drug resistance in contrast to treatment with separate formulations of two to four first-line drugs. However, its successful implementation in national programs is limited by probable bioinequivalency of rifampicin if present in FDC form. In this regard, World Health Organization (WHO) and International Union Against Tuberculosis and Lung Disease (IUATLD) recommend FDCs only of proven bioavailability. Hence, bioequivalence study of four drug FDC tablet was conducted using 22 healthy male volunteers according to WHO recommended protocol to determine bioavailability of rifampicin, isoniazid and pyrazinamide compared to standard separate combination at the same dose level. The study was designed as two period, two treatment crossover experiment with a washout period of 1 week. Bioequivalence of rifampicin was estimated by plasma and urinary method for both rifampicin and its active metabolite, des-acetyl rifampicin whereas isoniazid and pyrazinamide were estimated from plasma. Mean concentration time profiles and all the pharmacokinetic parameters of rifampicin, isoniazid and pyrazinamide from FDC tablet were comparable to individual formulations and passed the bioequivalence test with power of the test above 95%. Further, bioequivalence of both rifampicin and isoniazid shows that in vitro interaction of rifampicin and isoniazid is clinically insignificant. Thus, it was concluded that FDC formulation is bioequivalent for rifampicin, isoniazid and pyrazinamide and ensures the successful treatment of TB without compromising therapeutic efficacy of any of these components of anti-TB therapy.

  4. Tuberculosis Prevention in the Private Sector: Using Claims-Based Methods to Identify and Evaluate Latent Tuberculosis Infection Treatment With Isoniazid Among the Commercially Insured.

    Science.gov (United States)

    Stockbridge, Erica L; Miller, Thaddeus L; Carlson, Erin K; Ho, Christine

    Targeted identification and treatment of people with latent tuberculosis infection (LTBI) are key components of the US tuberculosis elimination strategy. Because of recent policy changes, some LTBI treatment may shift from public health departments to the private sector. To (1) develop methodology to estimate initiation and completion of treatment with isoniazid for LTBI using claims data, and (2) estimate treatment completion rates for isoniazid regimens from commercial insurance claims. Medical and pharmacy claims data representing insurance-paid services rendered and prescriptions filled between January 2011 and March 2015 were analyzed. Four million commercially insured individuals 0 to 64 years of age. Six-month and 9-month treatment completion rates for isoniazid LTBI regimens. There was an annual isoniazid LTBI treatment initiation rate of 12.5/100 000 insured persons. Of 1074 unique courses of treatment with isoniazid for which treatment completion could be assessed, almost half (46.3%; confidence interval, 43.3-49.3) completed 6 or more months of therapy. Of those, approximately half (48.9%; confidence interval, 44.5-53.3) completed 9 months or more. Claims data can be used to identify and evaluate LTBI treatment with isoniazid occurring in the commercial sector. Completion rates were in the range of those found in public health settings. These findings suggest that the commercial sector may be a valuable adjunct to more traditional venues for tuberculosis prevention. In addition, these newly developed claims-based methods offer a means to gain important insights and open new avenues to monitor, evaluate, and coordinate tuberculosis prevention.

  5. Self-administered Versus Directly Observed Once-Weekly Isoniazid and Rifapentine Treatment of Latent Tuberculosis Infection

    Science.gov (United States)

    Belknap, Robert; Holland, David; Feng, Pei-Jean; Millet, Joan-Pau; Caylà, Joan A.; Martinson, Neil A.; Wright, Alicia; Chen, Michael P.; Moro, Ruth N.; Scott, Nigel A.; Arevalo, Bert; Miró, José M.; Villarino, Margarita E.; Weiner, Marc; Borisov, Andrey S.

    2017-01-01

    Background Expanding latent tuberculosis treatment is important to decrease active disease globally. Once-weekly isoniazid and rifapentine for 12 doses is effective but limited by requiring direct observation. Objective To compare treatment completion and safety of once-weekly isoniazid and rifapentine by self-administration versus direct observation. Design An open-label, phase 4 randomized clinical trial designed as a noninferiority study with a 15% margin. Seventy-five percent or more of study patients were enrolled from the United States for a prespecified subgroup analysis. (ClinicalTrials.gov: NCT01582711) Setting Outpatient tuberculosis clinics in the United States, Spain, Hong Kong, and South Africa. Participants 1002 adults (aged ≥18 years) recommended for treatment of latent tuberculosis infection. Intervention Participants received once-weekly isoniazid and rifapentine by direct observation, self-administration with monthly monitoring, or self-administration with weekly text message reminders and monthly monitoring. Measurements The primary outcome was treatment completion, defined as 11 or more doses within 16 weeks and measured using clinical documentation and pill counts for direct observation, and self-reports, pill counts, and medication event–monitoring devices for self-administration. The main secondary outcome was adverse events. Results Median age was 36 years, 48% of participants were women, and 77% were enrolled at the U.S. sites. Treatment completion was 87.2% (95% CI, 83.1% to 90.5%) in the direct-observation group, 74.0% (CI, 68.9% to 78.6%) in the self-administration group, and 76.4% (CI, 71.3% to 80.8%) in the self-administration–with–reminders group. In the United States, treatment completion was 85.4% (CI, 80.4% to 89.4%), 77.9% (CI, 72.7% to 82.6%), and 76.7% (CI, 70.9% to 81.7%), respectively. Self-administered therapy without reminders was noninferior to direct observation in the United States; no other comparisons met

  6. Self-reported adherence and associated factors to isoniazid preventive therapy for latent tuberculosis among people living with HIV/AIDS at health centers in Gondar town, North West Ethiopia.

    Science.gov (United States)

    Ayele, Asnakew Achaw; Asrade Atnafie, Seyfe; Balcha, Demis Driba; Weredekal, Asegedech Tsegaw; Woldegiorgis, Birhanu Alemayehu; Wotte, Mulgeta Melaku; Gebresillasie, Begashaw Melaku

    2017-01-01

    This study aimed to assess self-reported adherence and associated factors to isoniazid preventive therapy (IPT) for latent tuberculosis among people living with HIV/AIDS (PLWHA) at health centers in Gondar town, North West Ethiopia. An institution-based prospective cross-sectional study was conducted from March 10 to June 11, 2016. A total of 154 eligible participants were included in the study, using the simple random sampling method, from the available four health centers and one teaching referral hospital that provided antiretroviral therapy (ART) for HIV/AIDS patients. Adherence was measured by self-report of isoniazid (INH) tablets taken for the preceding 7 days. Participants were recruited through in-depth interviews. The collected data were entered and analyzed using the statistical packages for social sciences (SPSS) version 20. The adherence level to IPT was 90.3% for the last 7 days of the study. ART was initiated for 84.4%, and all of them were on a first-line regimen. Isoniazid-related side effects were reported by 48 (31.2%) participants, of which the most commonly identified were abdominal pain, vomiting, skin rash, jaundice, and numbness. Only 3 (2%) participants discontinued from the study. In the bivariate logistic regression analysis, respondents who had received an explanation about IPT were 83% times more likely to be adherent compared to those who had not received it (95% CI, AOR: 0.266 [0.23-3.127]). Respondents who had taken IPT for ≥5 months were more likely to be adherent than those who had taken it for 1-2 months [95% CI, COR: 1.484]. On the other hand, respondents who experienced side effects were 36% less likely to be adherent compared to those who did not experience any. The level of adherence to IPT among PLWHA was high. Among the predictors reported, carelessness and/or forgetfulness, side effects, and absence from home were the major factors identified for being nonadherent. Health professionals and the Ministry of Health should

  7. Routine implementation of isoniazid preventive therapy in HIV-infected patients in seven pilot sites in Zimbabwe

    Science.gov (United States)

    Choto, R. C.; Harries, A. D.; Mutasa-Apollo, T.; Chakanyuka-Musanhu, C.

    2017-01-01

    Setting: Seven pilot sites in Zimbabwe implementing 6 months of isoniazid preventive therapy (IPT) for people living with the human immunodeficiency virus (PLHIV). Objectives: To determine, among PLHIV started on IPT, the completion rates for a 6-month course of IPT and factors associated with non-adherence. Design: A retrospective cohort study. Results: Of 578 patients, 466 (81%) completed IPT. Of the 112 patients who failed to complete IPT, 69 (60%) were lost to follow-up, 30 (27%) stopped treatment with no documented reasons, 8 (7%) developed toxicity/adverse reactions, 5 (5%) were documented as having drug stock-outs and the remainder transferred out or refused to continue treatment. Currently being on antiretroviral therapy (ART) (aOR 0.09, 95%CI 0.03–0.28) and receiving a ⩾2 month supply of isoniazid at the start of treatment were associated with a lower risk of not completing IPT, while missing clinic visits prior to starting IPT (aOR 5.25, 95%CI 2.10–13.14) was associated with a higher risk of non-completion. Conclusion: IPT completion rates in seven pilot sites of Zimbabwe were comparatively high, showing that IPT roll-out in public health facilities is feasible. Enhanced adherence counselling or active tracing among pre-ART patients and those with a history of loss to follow-up may improve IPT completion rates, along with synchronising IPT and ART resupplies. PMID:28775944

  8. A Prospective Study of Tuberculosis Drug Susceptibility in Sabah, Malaysia, and an Algorithm for Management of Isoniazid Resistance

    Science.gov (United States)

    Rashid Ali, Muhammad Redzwan S.; Parameswaran, Uma; William, Timothy; Bird, Elspeth; Wilkes, Christopher S.; Lee, Wai Khew; Yeo, Tsin Wen; Anstey, Nicholas M.; Ralph, Anna P.

    2015-01-01

    Introduction. The burden of tuberculosis is high in eastern Malaysia, and rates of Mycobacterium tuberculosis drug resistance are poorly defined. Our objectives were to determine M. tuberculosis susceptibility and document management after receipt of susceptibility results. Methods. Prospective study of adult outpatients with smear-positive pulmonary tuberculosis (PTB) in Sabah, Malaysia. Additionally, hospital clinicians accessed the reference laboratory for clinical purposes during the study. Results. 176 outpatients were enrolled; 173 provided sputum samples. Mycobacterial culture yielded M. tuberculosis in 159 (91.9%) and nontuberculous Mycobacterium (NTM) in three (1.7%). Among outpatients there were no instances of multidrug resistant M. tuberculosis (MDR-TB). Seven people (4.5%) had isoniazid resistance (INH-R); all were switched to an appropriate second-line regimen for varying durations (4.5–9 months). Median delay to commencement of the second-line regimen was 13 weeks. Among 15 inpatients with suspected TB, 2 had multidrug resistant TB (one extensively drug resistant), 2 had INH-R, and 4 had NTM. Conclusions. Current community rates of MDR-TB in Sabah are low. However, INH-resistance poses challenges, and NTM is an important differential diagnosis in this setting, where smear microscopy is the usual diagnostic modality. To address INH-R management issues in our setting, we propose an algorithm for the treatment of isoniazid-resistant PTB. PMID:25838829

  9. Synthesis, characterization, and efficacy of antituberculosis isoniazid zinc aluminum-layered double hydroxide based nanocomposites

    Directory of Open Access Journals (Sweden)

    Saifullah B

    2016-07-01

    Full Text Available Bullo Saifullah,1 Mohamed Ezzat El Zowalaty,2,3 Palanisamy Arulselvan,3 Sharida Fakurazi,3,4 Thomas J Webster,5–7 Benjamin Mahler Geilich,5,6 Mohd Zobir Hussein1 1Materials Synthesis and Characterization Laboratory, Institute of Advanced Technology, (ITMA, Universiti Putra Malaysia, Serdang, Selangor, Malaysia; 2School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, South Africa; 3Laboratory of Vaccines and Immunotherapeutics, Institute of Bioscience, 4Department of Human Anatomy, Faculty of Medicine and Health Science, Universiti Putra Malaysia, Serdang, Selangor, Malaysia; 5Department of Chemical Engineering, 6Department of Bioengineering, Northeastern University, Boston, MA, USA; 7Center of Excellence for Advanced Materials Research, King Abdulaziz University, Jeddah, Saudi Arabia Abstract: The chemotherapy for tuberculosis (TB is complicated by its long-term treatment, its frequent drug dosing, and the adverse effects of anti-TB drugs. In this study, we have developed two nanocomposites (A and B by intercalating the anti-TB drug isoniazid (INH into Zn/Al-layered double hydroxides. The average size of the nanocomposites was found to be ~164 nm. The efficacy of the Zn/Al-layered double hydroxides intercalated INH against Mycobacterium tuberculosis was increased by approximately three times more than free INH. The nanocomposites were also found to be active against Gram-positive and -negative bacteria. Compared to the free INH, the nanodelivery formulation was determined to be three times more biocompatible with human normal lung fibroblast MRC-5 cells and 3T3 fibroblast cells at a very high concentration of 50 µg/mL for up to 72 hours. The in vitro release of INH from the Zn/Al-layered double hydroxides was found to be sustained in human body-simulated buffer solutions of pH 4.8 and 7.4. This research is a step forward in making the TB chemotherapy patient friendly. Keywords: tuberculosis, Zn/Al-LDHs, drug

  10. The Genotype MTBDRplus ver. 2.0 test as a quick indicator of resistance to rifampicin and isoniazid in Mycobacterium tuberculosis strains

    Directory of Open Access Journals (Sweden)

    Salvatore Nisticò

    2013-08-01

    Full Text Available Tuberculosis is still a global emergency and a major public health problem, in some cases related to the appearance of strains of multi drug resistance (MDR and extensive drug resistance (XDR Mycobacterium tuberculosis complex.The correct determination of antibiotic sensitivity profiles is therefore crucial to carry out appropriate treatment aimed to decrease the infectivity of each patient and to reduce mortality. The poor adherence to treatment by the patient or the use of therapies based on a single drug, as a result of incorrect requirements, promote the development of drug-resistance. Have some time on the market of molecular diagnostic tests that allow, quickly and directly from biological sample to search for resistance genes some key drugs of anti-TB therapy (Rifampicin and Isoniazid. One of the tests in question is the Genotype MTBDRplus ver 2.0 which can reveal the presence of genes for resistance to Isoniazid (INH and Rifampin (RMP.The loci analyzed are those corresponding to the rpoB gene for rifampicin, katG and inhA for isoniazid. Our study is based on the analysis of 83 strains of tubercular Mycobacteria identified and isolated from patients with tuberculosis disease and subjected to the tests sensitivity, searching for mutations and phenotypic susceptibility testing for Rifampicin and Isoniazid.The comparison of the results has shown that the results obtained using the Genotype MTBDRplus ver 2.0 test, were similar to the results obtained by the traditional susceptibility testing.

  11. Theoretically Guided Analytical Method Development and Validation for the Estimation of Rifampicin in a Mixture of Isoniazid and Pyrazinamide by UV Spectrophotometer.

    Science.gov (United States)

    Khan, Mohammad F; Rita, Shamima A; Kayser, Md Shahidulla; Islam, Md Shariful; Asad, Sharmeen; Bin Rashid, Ridwan; Bari, Md Abdul; Rahman, Muhammed M; Al Aman, D A Anwar; Setu, Nurul I; Banoo, Rebecca; Rashid, Mohammad A

    2017-01-01

    A simple, rapid, economic, accurate, and precise method for the estimation of rifampicin in a mixture of isoniazid and pyrazinamide by UV spectrophotometeric technique (guided by the theoretical investigation of physicochemical properties) was developed and validated. Theoretical investigations revealed that isoniazid and pyrazinamide both were freely soluble in water and slightly soluble in ethyl acetate whereas rifampicin was practically insoluble in water but freely soluble in ethyl acetate. This indicates that ethyl acetate is an effective solvent for the extraction of rifampicin from a water mixture of isoniazid and pyrazinamide. Computational study indicated that pH range of 6.0-8.0 would favor the extraction of rifampicin. Rifampicin is separated from isoniazid and pyrazinamide at pH 7.4 ± 0.1 by extracting with ethyl acetate. The ethyl acetate was then analyzed at λ max of 344.0 nm. The developed method was validated for linearity, accuracy and precision according to ICH guidelines. The proposed method exhibited good linearity over the concentration range of 2.5-35.0 μg/mL. The intraday and inter-day precision in terms of % RSD ranged from 1.09 to 1.70% and 1.63 to 2.99%, respectively. The accuracy (in terms of recovery) of the method varied from of 96.7 ± 0.9 to 101.1 ± 0.4%. The LOD and LOQ were found to be 0.83 and 2.52 μg/mL, respectively. In addition, the developed method was successfully applied to determine rifampicin combination (isoniazid and pyrazinamide) brands available in Bangladesh.

  12. Proteinaceous alpha-araylase inhibitors

    DEFF Research Database (Denmark)

    Svensson, Birte; Fukuda, Kenji; Nielsen, P.K.

    2004-01-01

    -amylase inhibitors belong to seven different protein structural families, most of which also contain evolutionary related proteins without inhibitory activity. Two families include bifunctional inhibitors acting both on alpha-amylases and proteases. High-resolution structures are available of target alpha...

  13. Corrosion inhibitors. Manufacture and technology

    International Nuclear Information System (INIS)

    Ranney, M.W.

    1976-01-01

    Detailed information is presented relating to corrosion inhibitors. Areas covered include: cooling water, boilers and water supply plants; oil well and refinery operations; fuel and lubricant additives for automotive use; hydraulic fluids and machine tool lubes; grease compositions; metal surface treatments and coatings; and general processes for corrosion inhibitors

  14. The Wonders of Phosphodiesterase‑5 Inhibitors: A Majestic History

    African Journals Online (AJOL)

    A milestone in drug discovery was the selective inhibitors of. PDE‑5 that ... the pharmacotherapeutics of PDE‑5 inhibitors and the majestic history that led to their discovery. ..... including HIV protease inhibitors, ketoconazole, itraconazole,.

  15. [Syk inhibitors].

    Science.gov (United States)

    Kimura, Yukihiro; Chihara, Kazuyasu; Takeuchi, Kenji; Sada, Kiyonao

    2013-07-01

    Non-receptor type of protein-tyrosine kinase Syk (spleen tyrosine kinase) was isolated in the University of Fukui in 1991. Syk is known to be essential for the various physiological functions, especially in hematopoietic lineage cells. Moreover, ectopic expression of Syk by epigenetic changes is reported to cause retinoblastoma. Recently, novel Syk inhibitors were developed and its usefulness has been evaluated in the treatment of allergic rhinitis, rheumatoid arthritis, and idiopathic thrombocytopenic purpura. In this review, we will summarize the history, structure, and function of Syk, and then describe the novel Syk inhibitors and their current status. Furthermore, we will introduce our findings of the adaptor protein 3BP2 (c-Abl SH3 domain-binding protein-2), as a novel target of Syk.

  16. JAK inhibitors in autoinflammation.

    Science.gov (United States)

    Hoffman, Hal M; Broderick, Lori

    2018-06-11

    Interferonopathies are a subset of autoinflammatory disorders with a prominent type I IFN gene signature. Treatment of these patients has been challenging, given the lack of response to common autoinflammatory therapeutics including IL-1 and TNF blockade. JAK inhibitors (Jakinibs) are a family of small-molecule inhibitors that target the JAK/STAT signaling pathway and have shown clinical efficacy, with FDA and European Medicines Agency (EMA) approval for arthritic and myeloproliferative syndromes. Sanchez and colleagues repurposed baricitinib to establish a significant role for JAK inhibition as a novel therapy for patients with interferonopathies, demonstrating the power of translational rare disease research with lifesaving effects.

  17. Syk inhibitors.

    Science.gov (United States)

    Chihara, Kazuyasu; Kimura, Yukihiro; Honjo, Chisato; Takeuchi, Kenji; Sada, Kiyonao

    2013-01-01

    Non-receptor type of protein-tyrosine kinase Syk (spleen tyrosine kinase) was isolated in University of Fukui in 1991. Syk is most highly expressed by haemopoietic cells and known to play crucial roles in the signal transduction through various immunoreceptors of the adaptive immune response. However, recent reports demonstrate that Syk also mediates other biological functions, such as innate immune response, osteoclast maturation, platelet activation and cellular adhesion. Moreover, ectopic expression of Syk by epigenetic changes is reported to cause retinoblastoma. Because of its critical roles on the cellular functions, the development of Syk inhibitors for clinical use has been desired. Although many candidate compounds were produced, none of them had progressed to clinical trials. However, novel Syk inhibitors were finally developed and its usefulness has been evaluated in the treatment of allergic rhinitis, rheumatoid arthritis and idiopathic thrombocytopenic purpura. In this review, we will summarize the history, structure and function of Syk, and then the novel Syk inhibitors and their current status. In addition, we will introduce our research focused on the functions of Syk on Dectin-1-mediated mast cell activation.

  18. 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.

  19. The effect of partner HIV status on motivation to take antiretroviral and isoniazid preventive therapies: a conjoint analysis.

    Science.gov (United States)

    Kim, Hae-Young; Hanrahan, Colleen F; Dowdy, David W; Martinson, Neil; Golub, Jonathan; Bridges, John F P

    2018-03-29

    Antiretroviral therapy (ART) and isoniazid preventive therapy (IPT) are important to reduce morbidity and mortality among people newly diagnosed of HIV. The successful uptake of ART and IPT requires a comprehensive understanding of patients' motivation to take such therapies. Partners also play an important role in the decision to be initiated and retained in care. We quantified patients' motivation to take preventive therapies (ART and IPT) and compared by partner HIV status among people newly diagnosed of HIV. We enrolled and surveyed adults (≥18 years) with a recent HIV diagnosis (ART and 334 (79%) had a partner or spouse. Keeping themselves healthy for their family was the most important motivator to take preventive therapies (p motivation for ART and IPT initiation and adherence compared to individual health benefits. These messages should be emphasized to provide effective patient-centered care and counseling.

  20. Symptom-based screening tool in ruling out active tuberculosis among HIV-infected patients eligible for isoniazid preventive therapy in Tanzania.

    Science.gov (United States)

    Shayo, Grace A; Minja, Lilian T; Egwaga, Said; Bakari, Muhammad; Mugusi, Ferdinand M

    2014-06-01

    We assessed the usefulness of the National TB and Leprosy Control Program (NTLP) symptom-based tuberculosis (TB) screening tool in identifying HIV-infected patients eligible for isoniazid preventive therapy in Muhimbili National Hospital, Dar es Salaam Tanzania. Descriptive cross-sectional study. Data collected included socio-demographic and clinical data. Chest X-ray, sputum for acid-fast bacilli (AFB) microscopy, mycobacterial culture, CD4 + count and complete blood count were performed. Patients were considered not having active TB if they presented with no symptom in the screening tool, which comprised these symptoms: cough, fever and excessive night sweats for ≥2 weeks; weight loss of ≥3 kg in 4 weeks and haemoptysis of any duration. The reference standard was a negative culture for Mycobacterium tuberculosis. We enroled 373 patients, of whom 72.1% were females. Active pulmonary TB was found in 4.1% (14/338) of the participants as defined by a positive culture. The sensitivity and specificity of the NTLP screening tool were 71.4% (10/14) and 75.9% (246/324), respectively. False-negative rate was 28.6% (4/10). Cough, fever for ≥2 weeks and weight loss were independent predictors of NTLP-defined TB. Cough ≥2 weeks predicted TB when a positive culture was used to define TB. The screening tool had fairly good sensitivity and specificity for TB screening; however, there is a possibility that about 29% of the screened population will be given IPT while they are supposed to receive a full course of TB treatment. © 2014 John Wiley & Sons Ltd.

  1. Dissolution testing of isoniazid, rifampicin, pyrazinamide and ethambutol tablets using near-infrared spectroscopy (NIRS) and multivariate calibration.

    Science.gov (United States)

    de Oliveira Neves, Ana Carolina; Soares, Gustavo Mesquita; de Morais, Stéphanie Cavalcante; da Costa, Fernanda Saadna Lopes; Porto, Dayanne Lopes; de Lima, Kássio Michell Gomes

    2012-01-05

    This work utilized the near-infrared spectroscopy (NIRS) and multivariate calibration to measure the percentage drug dissolution of four active pharmaceutical ingredients (APIs) (isoniazid, rifampicin, pyrazinamide and ethambutol) in finished pharmaceutical products produced in the Federal University of Rio Grande do Norte (Brazil). The conventional analytical method employed in quality control tests of the dissolution by the pharmaceutical industry is high-performance liquid chromatography (HPLC). The NIRS is a reliable method that offers important advantages for the large-scale production of tablets and for non-destructive analysis. NIR spectra of 38 samples (in triplicate) were measured using a Bomen FT-NIR 160 MB in the range 1100-2500nm. Each spectrum was the average of 50 scans obtained in the diffuse reflectance mode. The dissolution test, which was initially carried out in 900mL of 0.1N hydrochloric acid at 37±0.5°C, was used to determine the percentage a drug that dissolved from each tablet measured at the same time interval (45min) at pH 6.8. The measurement of the four API was performed by HPLC (Shimadzu, Japan) in the gradiente mode. The influence of various spectral pretreatments (Savitzky-Golay smoothing, Multiplicative Scatter Correction (MSC), and Savitzky-Golay derivatives) and multivariate analysis using the partial least squares (PLS) regression algorithm was calculated by the Unscrambler 9.8 (Camo) software. The correlation coefficient (R(2)) for the HPLC determination versus predicted values (NIRS) ranged from 0.88 to 0.98. The root-mean-square error of prediction (RMSEP) obtained from PLS models were 9.99%, 8.63%, 8.57% and 9.97% for isoniazid, rifampicin, ethambutol and pyrazinamide, respectively, indicating that the NIR method is an effective and non-destructive tool for measurement of drug dissolution from tablets. Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.

  2. Evaluation of rapid MTT tube method for detection of drug susceptibility of mycobacterium tuberculosis to rifampicin and isoniazid

    Directory of Open Access Journals (Sweden)

    Raut U

    2008-01-01

    Full Text Available Purpose: To evaluate MTT method for detection of drug resistance to rifampicin and isoniazid in M.tuberculosis . This method utilises the ability of viable mycobacterial cells to reduce MTT( 3-4,5-dimethylthiazol-2-yl-2, 5-diphenyl tetrazolium bromide. Methods: The method was standardised with known resistant and sensitive strains of M.tuberculosis and was then extended to 50 clinical isolates. An inoculum of 10 7 cfu/mL was prepared in Middlebrook 7H9 medium supplemented with oleic acid, albumin, dextrose and catalase. For each drug three tubes were used, one with INH(0.2μg/mL or RIF(1μg/mL, another as inoculum control and third as blank control. These were incubated at 37°C for four and seven days respectively for RIF and INH after which MTT assay was performed. Results were read visually and by colorimeter at 570 nm. Relative optical density unit (RODU of 0.2 was taken as cut off. Results were compared with drug sensitivity obtained by proportion method using LJ medium. Results: For rifampicin, concordance with proportion method was 90% by visual and 94% by RODU. Sensitivity and specificity was 86.8% and 100% respectively by visual method and 95.2% and 87.5% respectively by RODU. For Isoniazid, concordance was 94% and sensitivity and specificity was 94.7 and 91.7% respectively by both visual and RODU. Conclusions: MTT assay proved to be rapid and cheap method for performing drug sensitivity of M.tuberculosis

  3. Diagnostic moléculaire du complexe Mycobacterium tuberculosis résistant à l'isoniazide et à la rifampicine au Burkina Faso

    Science.gov (United States)

    Désire, Ilboudo; Cyrille, Bisseye; Florencia, Djigma; Souba, Diande; Albert, Yonli; Valerie, Bazie Jean Telesphore; Rebecca, Compaore; Charlemagne, Gnoula; Tamboura, Djibril; Rémy, Moret; Virginio, Pietra; Simplice, Karou Damintoti; Martial, Ouedraogo; Jacques, Simpore

    2015-01-01

    Introduction Cette étude a eu pour objectifs de diagnostiquer la tuberculose pulmonaire par l'examen microscopique et par la PCR des crachats et de déterminer les bases moléculaires de la résistance à la rifampicine et à l'isoniazide. Méthodes Le diagnostic du Complexe Mycobacterium Tuberculosis (CMTB) a été effectué par microscopie après coloration au Ziehl Nielsen et par PCR en temps réel en utilisant le kit d'identification du complexe MTB (Sacace Biotechnologie, Italie). Les résistances à la Rifampicine et à l'Isoniazide ont été étudiées par la technique de la PCR en utilisant le kit MTB résistance 8 (Sacace, Biotechnologie). Résultats Sur les 59 patients diagnostiqués pour la tuberculose pulmonaire, 59,3% étaient positifs en microscopie optique et 44,1% étaient positifs par PCR en Temps réel. Les résistances à la rifampicine (rpoB) et à l'isoniazide (katG et inhA) ont été observées chez 9 patients. La résistance à la rifampicine était due aux mutations (Asp516Val, Ser531Trp, Leu533Pro) et celle à l'isoniazide par les substitutions Ser315Thr du gène katG et C209T du gène inhA. Les multi résistances à la rifampicine et à l'isoniazide ont été observées dans 55,5% des échantillons et concernaient les associations: ropBAsp513Val + inhAC209T et rpoBLeu533Pro + katGSer315Thr. Conclusion La PCR en temps réel qui permet l'identification des allèles mutants rpoB, katG et inhA de M. tuberculosis est un outil de diagnostic épidémiologique de grande importance car elle permet de déterminer le niveau de résistance à la rifampicine et à l'isoniazide. PMID:26491516

  4. WCK 5107 (Zidebactam) and WCK 5153 Are Novel Inhibitors of PBP2 Showing Potent “β-Lactam Enhancer” Activity against Pseudomonas aeruginosa, Including Multidrug-Resistant Metallo-β-Lactamase-Producing High-Risk Clones

    Science.gov (United States)

    Barcelo, Isabel M.; Bhagwat, Sachin; Patel, Mahesh; Bou, German; Papp-Wallace, Krisztina M.; Bonomo, Robert A.; Oliver, Antonio

    2017-01-01

    ABSTRACT Zidebactam and WCK 5153 are novel β-lactam enhancers that are bicyclo-acyl hydrazides (BCH), derivatives of the diazabicyclooctane (DBO) scaffold, targeted for the treatment of serious infections caused by highly drug-resistant Gram-negative pathogens. In this study, we determined the penicillin-binding protein (PBP) inhibition profiles and the antimicrobial activities of zidebactam and WCK 5153 against Pseudomonas aeruginosa, including multidrug-resistant (MDR) metallo-β-lactamase (MBL)-producing high-risk clones. MIC determinations and time-kill assays were conducted for zidebactam, WCK 5153, and antipseudomonal β-lactams using wild-type PAO1, MexAB-OprM-hyperproducing (mexR), porin-deficient (oprD), and AmpC-hyperproducing (dacB) derivatives of PAO1, and MBL-expressing clinical strains ST175 (blaVIM-2) and ST111 (blaVIM-1). Furthermore, steady-state kinetics was used to assess the inhibitory potential of these compounds against the purified VIM-2 MBL. Zidebactam and WCK 5153 showed specific PBP2 inhibition and did not inhibit VIM-2 (apparent Ki [Ki app] > 100 μM). MICs for zidebactam and WCK 5153 ranged from 2 to 32 μg/ml (amdinocillin MICs > 32 μg/ml). Time-kill assays revealed bactericidal activity of zidebactam and WCK 5153. LIVE-DEAD staining further supported the bactericidal activity of both compounds, showing spheroplast formation. Fixed concentrations (4 or 8 μg/ml) of zidebactam and WCK 5153 restored susceptibility to all of the tested β-lactams for each of the P. aeruginosa mutant strains. Likewise, antipseudomonal β-lactams (CLSI breakpoints), in combination with 4 or 8 μg/ml of zidebactam or WCK 5153, resulted in enhanced killing. Certain combinations determined full bacterial eradication, even with MDR MBL-producing high-risk clones. β-Lactam–WCK enhancer combinations represent a promising β-lactam “enhancer-based” approach to treat MDR P. aeruginosa infections, bypassing the need for MBL inhibition. PMID:28289035

  5. WCK 5107 (Zidebactam) and WCK 5153 Are Novel Inhibitors of PBP2 Showing Potent "β-Lactam Enhancer" Activity against Pseudomonas aeruginosa, Including Multidrug-Resistant Metallo-β-Lactamase-Producing High-Risk Clones.

    Science.gov (United States)

    Moya, Bartolome; Barcelo, Isabel M; Bhagwat, Sachin; Patel, Mahesh; Bou, German; Papp-Wallace, Krisztina M; Bonomo, Robert A; Oliver, Antonio

    2017-06-01

    Zidebactam and WCK 5153 are novel β-lactam enhancers that are bicyclo-acyl hydrazides (BCH), derivatives of the diazabicyclooctane (DBO) scaffold, targeted for the treatment of serious infections caused by highly drug-resistant Gram-negative pathogens. In this study, we determined the penicillin-binding protein (PBP) inhibition profiles and the antimicrobial activities of zidebactam and WCK 5153 against Pseudomonas aeruginosa , including multidrug-resistant (MDR) metallo-β-lactamase (MBL)-producing high-risk clones. MIC determinations and time-kill assays were conducted for zidebactam, WCK 5153, and antipseudomonal β-lactams using wild-type PAO1, MexAB-OprM-hyperproducing ( mexR ), porin-deficient ( oprD ), and AmpC-hyperproducing ( dacB ) derivatives of PAO1, and MBL-expressing clinical strains ST175 ( bla VIM-2 ) and ST111 ( bla VIM-1 ). Furthermore, steady-state kinetics was used to assess the inhibitory potential of these compounds against the purified VIM-2 MBL. Zidebactam and WCK 5153 showed specific PBP2 inhibition and did not inhibit VIM-2 (apparent K i [ K i app ] > 100 μM). MICs for zidebactam and WCK 5153 ranged from 2 to 32 μg/ml (amdinocillin MICs > 32 μg/ml). Time-kill assays revealed bactericidal activity of zidebactam and WCK 5153. LIVE-DEAD staining further supported the bactericidal activity of both compounds, showing spheroplast formation. Fixed concentrations (4 or 8 μg/ml) of zidebactam and WCK 5153 restored susceptibility to all of the tested β-lactams for each of the P. aeruginosa mutant strains. Likewise, antipseudomonal β-lactams (CLSI breakpoints), in combination with 4 or 8 μg/ml of zidebactam or WCK 5153, resulted in enhanced killing. Certain combinations determined full bacterial eradication, even with MDR MBL-producing high-risk clones. β-Lactam-WCK enhancer combinations represent a promising β-lactam "enhancer-based" approach to treat MDR P. aeruginosa infections, bypassing the need for MBL inhibition. Copyright © 2017

  6. Allosteric small-molecule kinase inhibitors

    DEFF Research Database (Denmark)

    Wu, Peng; Clausen, Mads Hartvig; Nielsen, Thomas E.

    2015-01-01

    current barriers of kinase inhibitors, including poor selectivity and emergence of drug resistance. In spite of the small number of identified allosteric inhibitors in comparison with that of inhibitors targeting the ATP pocket, encouraging results, such as the FDA-approval of the first small...

  7. One-year mortality of HIV-positive patients treated for rifampicin- and isoniazid-susceptible tuberculosis in Eastern Europe, Western Europe, and Latin America

    DEFF Research Database (Denmark)

    Podlekareva, DN; Schultze, A; Panteleev, A

    2017-01-01

    in Western Europe or Latin America. METHODS: One-year mortality of HIV-positive patients with rifampicin/isoniazid-susceptible TB in Eastern Europe, Western Europe, and Latin America was analysed and compared in a prospective observational cohort study. Factors associated with death were analysed using Cox......OBJECTIVES: The high mortality among HIV/tuberculosis (TB) coinfected patients in Eastern Europe is partly explained by the high prevalence of drug-resistant TB. It remains unclear whether outcomes of HIV/TB patients with rifampicin/isoniazid-susceptible TB in Eastern Europe differ from those...... cell count. These results call for improvement of care for TB/HIV patients in Eastern Europe....

  8. Effect of medium acidity on the thermodynamics and kinetics of the reaction of pyridoxal 5'-phosphate with isoniazid in an aqueous solution

    Science.gov (United States)

    Gamov, G. A.; Zavalishin, M. N.; Usacheva, T. R.; Sharnin, V. A.

    2017-05-01

    Thermodynamic characteristics of the formation of the Schiff base between isoniazid and pyridoxal 5'-phosphate in an aqueous solution at different pH values of a medium are determined by means of spectrophotometry and calorimetric titration. The process kinetics is studied spectrophotometrically, and the reaction rate constants for the formation of the imine at different acidities of a medium are determined. Biochemical aspects of the binding of pyridoxal 5'-phosphate into stable compounds are discussed.

  9. Electrochemical behavior of the antituberculosis drug isoniazid and its square-wave adsorptive stripping voltammetric estimation in bulk form, tablets and biological fluids at a mercury electrode.

    Science.gov (United States)

    Ghoneim, M M; el-Baradie, K Y; Tawfik, A

    2003-11-24

    Isoniazid, pyridine-4-carboxylic acid hydrazide, is an antituberculosis-agent, which is used to prevent the development of clinical tuberculosis. A validated square-wave adsorptive cathodic stripping voltammetric procedure for the trace determination of the bulk drug at the hanging mercury drop electrode (HMDE) has been developed. Under the optimized conditions, (accumulation potential=-0.9 V, accumulation time=50-300 s, scan increment=8 mV, pulse-amplitude=25 mV, frequency=120 Hz and acetate buffer at pH 5.5) isoniazed generated two irreversible cathodic peaks. The first peak current showed a linear dependence with the drug concentration over the range 5 x 10(-10)-21 x 0(-6) M. The mean percentage recoveries, based on the average of five replicate measurements, for 7 x 10(-9) and 5 x 10(-8) M isoniazid were 97.71+/-2.93 and 99.76+/-0.77, respectively. The achieved limits of detection (LOD) and quantitation (LOQ) were 1.18 x 10(-10) and 3.93 x 10(-10) M isoniazid, respectively. The procedure was applied to the assay of the drug in tablets (Isocid and T.B. Zide), spiked human serum and urine with mean percentage recoveries of 97.81+/-1.49, 97.45+/-2.09, and 97.08+/-1.06, respectively. The limits of detection of 1.47 x 10(-9) and 2.4 x 10(-8) M, and quantitation of 4.9 x 10(-9) and 8 x 10(-8) M drug in human serum and urine, respectively, were achieved. The mean values of the various pharmackinetic parameters of isoniazid (C(max), T(max), t(1/2), AUC, and K(e)), estimated from analysis of plasma of two volunteers by means of the proposed procedure were similar to literature values.

  10. Structure and function of the liver in conditions of chrome-isoniazid-rifampicin affection of rats after applying of sorbex

    Directory of Open Access Journals (Sweden)

    N. I. Burmas

    2014-09-01

    Full Text Available The aim of this research was to assess the activity of marker enzymes of the liver and its biliary formation function in conditions of the affection of animals by hexavalent chromium compounds, isoniazid and rifampicin, after applying of sorbex. The experimental affection of rats of different age was carried in the conditions of combined injection of hexavalent chromium compounds (solution of potassium dichromate, 3 mg/kg, isoniazid (0.05 g/kg and rifampicin (0.25 g/kg during the 7th and 14th days, and sorbex enterosorbent was introduced in quantity of 150 mg/kg. The activity of marker enzymes of the liver was evaluated by the activity of alanine and aspartate aminotransferases (ALT and AST and alkaline phosphatase (ALP. The state of biliary formation function of the liver was evaluated by the content of total bilirubin (TB and bile acids (BA in blood. The most significant changes in ALT activity were observed in the liver of old animals by the combined effects of the abovementioned xenobiotics – the activity of ALT was decreased by the end of the experiment by 58% compared with the animals of intact control. Using of sorbex led to decreasing in blood serum and increasing in the liver of affected animals of the different age of ALT activity throughout the experiment. AST activity in blood serum increased, and it was the highest in old animals upon chrome-isoniazid-rifampicin affection on the 14th day of the research. With the use of sorbex, there was a tendency to normalization of this index in blood serum and liver of affected animals on the 7th day from the beginning of the experiment. It was found that the largest increase in ALP took place in blood serum of immature animals by the combined effects of toxicants. In the liver of affected animals the activity of ALP decreased throughout the experiment in all age groups of animals. Maximum corrective effect on the activity of ALP was shown by the enterosorbent in the liver of mature animals on

  11. Improved Stability of Tuberculosis Drug Fixed-Dose Combination Using Isoniazid-Caffeic Acid and Vanillic Acid Cocrystal.

    Science.gov (United States)

    Battini, Swapna; Mannava, M K Chaitanya; Nangia, Ashwini

    2018-06-01

    The classic fixed-dose combination (FDC) of 4 tuberculosis drugs, namely rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol dihydrochloride (EDH) has the twin issues of physical stability and RIF cross-reaction in the 4-FDC. The major reason for these quality issues is the interaction between RIF and INH to yield isonicotinyl hydrazone in drug tablets. Pharmaceutical cocrystals of INH with caffeic acid (CFA) (PZA + EDH + RIF + INH-CFA cocrystal) and vanillic acid (VLA) (PZA + EDH + RIF + INH-VLA cocrystal) are able to stabilize the FDC formulation compared with the reference batch (PZA + EDH + RIF + INH). Stability studies under accelerated humidity and temperature stress conditions of 40°C and 75% relative humidity showed that the physical stability of the cocrystal formulation was superior by powder X-ray diffraction and scanning electron microscopy analysis, and chemical purity was analyzed by high-performance liquid chromatography. Changes in the composition and structure were monitored on samples drawn at 7, 15, 22, and 30 days of storage. FDC-INH-CFA cocrystal batch exhibited greater stability compared with FDC-INH-VLA cocrystal and FDC reference drug batches. The superior stability of INH-CFA cocrystal is attributed to the presence of stronger hydrogen bonds and cyclic O-H⋯O synthon in the crystal structure. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  12. Development and Validation of an HPLC Method for Simultaneous Determination of Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol Hydrochloride in Pharmaceutical Formulations.

    Science.gov (United States)

    Chellini, Paula R; Lages, Eduardo B; Franco, Pedro H C; Nogueira, Fernando H A; César, Isabela C; Pianetti, Gerson A

    2015-01-01

    Tuberculosis treatment consists of a fixed dose combination of rifampicin (RIF), isoniazid (INH), pyrazinamide (PYZ), and ethambutol hydrochloride (EMB). The combined treatment using various drugs is necessary for patient curing, without recrudescence, and for prevention of drug-resistant mutants, which may occur during treatment. An HPLC-diode array detector (DAD) method for the simultaneous determination of RIF, INH, PYZ, and EMB in fixed dose combination tablets was developed and validated. Chromatographic experiments were performed on an Agilent 1200 HPLC system, and the separation was carried out on a Purospher STAR RP18e (250×4.6 mm id, 5 μm, Merck) analytical column. Gradient elution was carried out with a mobile phase of 20 mM monobasic sodium phosphate buffer with 0.2% triethylamine (pH 7.0) and acetonitrile at a flow rate of 1.5 mL/min. The total run time was 12 min, and the re-equilibration time was 5 min. EMB detection was performed at 210 nm, and RIF, INH, and PYZ were detected at 238 nm, using a DAD. The method proved to be specific, linear (r2>0.99), precise (RSD<2%), accurate, and robust and may be applied to the QC analysis of pharmaceutical formulations.

  13. It's hard work, but it's worth it: the task of keeping children adherent to isoniazid preventive therapy.

    Science.gov (United States)

    Skinner, D; Hesseling, A C; Francis, C; Mandalakas, A M

    2013-09-21

    Isoniazid preventive therapy (IPT) offers children protection against tuberculosis (TB), but it has been difficult to implement, particularly in developing countries. To understand what encourages or inhibits children from adhering to IPT. In-depth interviews were conducted with two parents of children adherent to IPT and two staff members from three primary health care clinics in high TB prevalence communities. Themes explored were knowledge and attitudes towards IPT, problems in accessing and adhering to treatment, and community responses. Parents administering treatment valued it positively, realised their children's risk of TB, and were positive about the clinic. Nurses acknowledged that resistance to treatment remained, with some parents not wanting to acknowledge risk nor willing to make the effort for their children; there was also considerable misinformation about IPT. Clinic nurses acknowledged problems of staff shortages, lengthy waiting times and conflict between staff and community members. Adherence was affected by social problems, stigma about TB and its link to the human immunodeficiency virus, and the extended treatment period. Parents who maintained adherence to the IPT regimen showed that it was possible even in very difficult circumstances. Further effort is required to improve some of the clinic services, correct misinformation, reduce stigma and provide support to parents.

  14. Wild-type catalase peroxidase vs G279D mutant type: Molecular basis of Isoniazid drug resistance in Mycobacterium tuberculosis.

    Science.gov (United States)

    Singh, Aishwarya; Singh, Aditi; Grover, Sonam; Pandey, Bharati; Kumari, Anchala; Grover, Abhinav

    2018-01-30

    Mycobacterium tuberculosis katG gene is responsible for production of an enzyme catalase peroxidase that peroxidises and activates the prodrug Isoniazid (INH), a first-line antitubercular agent. INH interacts with catalase peroxidase enzyme within its heme pocket and gets converted to an active form. Mutations occurring in katG gene are often linked to reduced conversion rates for INH. This study is focussed on one such mutation occurring at residue 279, where glycine often mutates to aspartic acid (G279D). In the present study, several structural analyses were performed to study the effect of this mutation on functionality of KatG protein. On comparison, mutant protein exhibited a lower docking score, smaller binding cavity and reduced affinity towards INH. Molecular dynamics analysis revealed the mutant to be more rigid and less compact than the native protein. Essential dynamics analysis determined correlated motions of residues within the protein structure. G279D mutant was found to have many residues that showed related motions and an undesirable effect on the functionality of protein. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. NANOBIOCATALYTIC SYSTEMS BASED ON LIPASE-Fe3O4 AND CONVENTIONAL SYSTEMS FOR ISONIAZID SYNTHESIS: A COMPARATIVE STUDY

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    V. M. Costa

    Full Text Available Abstract Superparamagnetic nanomaterials have attracted interest in many areas due to the high saturation magnetization and surface area. For enzyme immobilization, these properties favor the enzyme-support contact during the immobilization reaction and easy separation from the reaction mixture by use of low-cost magnetic processes. Iron oxide magnetic nanoparticles (Fe3O4, MNPs, produced by the co-precipitation method, functionalized with 3-aminopropyltriethoxysilane (APTES and glutaraldehyde (GLU, were evaluated as a solid support for Candida antarctica lipase B (CALB immobilization. The nanomagnetic derivative (11nm obtained after CALB immobilization (MNPs/APTES/GLU/CALB was evaluated as biocatalyst in isoniazide (INH synthesis using ethyl isonicotinate (INE and hydrazine hydrate (HID as substrates, in 1,4-dioxane. The results showed that MNPs/APTES/CALB had a similar performance when compared to a commercial enzyme Novozym 435, showing significant advantages over other biocatalysts, such as Rhizhomucor miehei lipase (RML and CALB immobilized on non-conventional, low-cost, chitosan-based supports.

  16. A new rapid colourimetric method for testing Mycobacterium tuberculosis susceptibility to isoniazid and rifampicin: a crystal violet decolourisation assay

    Directory of Open Access Journals (Sweden)

    Ahmet Yilmaz Coban

    2014-04-01

    Full Text Available The aim of this study was to investigate the performance of a new and accurate method for the detection of isoniazid (INH and rifampicin (RIF resistance among Mycobacterium tuberculosis isolates using a crystal violet decolourisation assay (CVDA. Fifty-five M. tuberculosis isolates obtained from culture stocks stored at -80ºC were tested. After bacterial inoculation, the samples were incubated at 37ºC for seven days and 100 µL of CV (25 mg/L stock solution was then added to the control and sample tubes. The tubes were incubated for an additional 24-48 h. CV (blue/purple was decolourised in the presence of bacterial growth; thus, if CV lost its colour in a sample containing a drug, the tested isolate was reported as resistant. The sensitivity, specificity, positive predictive value, negative predictive value and agreement for INH were 92.5%, 96.4%, 96.1%, 93.1% and 94.5%, respectively, and 88.8%, 100%, 100%, 94.8% and 96.3%, respectively, for RIF. The results were obtained within eight-nine days. This study shows that CVDA is an effective method to detect M. tuberculosis resistance to INH and RIF in developing countries. This method is rapid, simple and inexpensive. Nonetheless, further studies are necessary before routine laboratory implementation.

  17. Effect of isoniazid preventive therapy on tuberculosis incidence in people living with HIV-AIDS at Hasan Sadikin hospital

    Science.gov (United States)

    Satiavan, I.; Hartantri, Y.; Werry, B.; Nababan, Y.; Wisaksana, R.; Alisjahban, B.

    2018-03-01

    Indonesia is the second largest number of tuberculosis (TB) in the world. Isoniazid Preventive Therapy (IPT) as one of the three I’s TB-HIV collaboration to manage TB in people living with HIV / AIDS (PLHIV) has not been fully performed. It is related to doubt to get rid of TB in PLHIV. This study aims to see the effect of IPT on the incidence of TB in PLHIV. This issue is a retrospective cohort study based on medical record data in HIV clinic. Inclusion criteria are PLHIV ≥ 15 years of age who were registered to visit the CST service and obtain IPT with good adherence if they were receiving ART. Of 462 patients, HIV- infected patients receiving IPT were 154 (33.3%). IPT administration has a protective effect on PLHIV where the rate of TB incidence in PLHIV who received IPT were 0.21 times lower than those who did not receive IPT (IRR = 0.21, 95% CI 0.023-0.881, p 0.008). In this population, IPT administration reduces 79% risk of PLHIV to suffer TB.IPT administration reduces the incidence of TB.

  18. Conjugation of isoniazid to a zinc phthalocyanine via hydrazone linkage for pH-dependent liposomal controlled release

    Science.gov (United States)

    Nkanga, Christian Isalomboto; Krause, Rui Werner Maçedo

    2018-05-01

    Tuberculosis (TB) remains the leading cause of mortality from infectious diseases. Extended TB treatment and frequent adverse effects, due to poor bioavailability of anti-tubercular drugs (ATBDs), represent the main rationales behind liposomal encapsulation for controlled delivery. Liposomes have been reported as potential vehicles for targeted delivery of ATBDs due to their rapid uptake by macrophages, which are known as the main host cells for TB causative agent (Mycobacterium tuberculosis). Additionally, the need for controlled release of ATBDs arises because leakage is part of the key liposome challenges for hydrophilic compounds like isoniazid (INH). In this study, INH was conjugated to a highly hydrophobic photosensitizer, zinc (II) phthalocyanine (PC), through hydrazone bonding. The obtained conjugate (PC-INH) was encapsulated in liposomes by film hydration method. PC-INH loaded liposomes (PILs) were characterized using dynamic light scattering, transmission electron microscopy, energy-dispersive X-ray spectrometry and UV-Vis absorption spectrometry, which was used also for estimation of encapsulation efficiency (%EE). INH release was evaluated in different pH media using dialysis. Particle size, zeta potential and %EE of PILs were about 506 nm, - 55 mV and 72%, respectively. Over 12 h, PILs exhibited 22, 41, 97 and 100% of INH, respectively, released in pH 7.4, 6.4, 5.4 and 4.4 media. This pH-dependent behavior is attractive for site-specific delivery. These findings suggest the conjugation of chemotherapeutics to phthalocyanines using pH-labile linkages as a potential strategy for liposomal controlled release.

  19. Clinical characteristics and treatment outcomes of patients with low- and high-concentration isoniazid-monoresistant tuberculosis.

    Directory of Open Access Journals (Sweden)

    Tsai-Yu Wang

    Full Text Available BACKGROUND: Isoniazid (INH resistance is now the most common type of tuberculosis (TB infection resistance worldwide. The aim of this study was to evaluate the clinical characteristics and treatment outcomes of patients with low- and high-concentration INH-monoresistant TB. METHODS: One hundred and thirty-four patients with culture-confirmed INH-monoresistant TB during 2006 January to 2007 December were retrospectively enrolled. INH resistance was classified as either low-concentration or high-concentration resistance according to the critical concentrations of 0.2 µg/mL or 1 µg/mL of INH, respectively. The patients' clinical outcomes, treatment regimens, and treatment duration were analyzed. RESULTS: The treatment success rates between low- and high-concentration INH-resistant TB were similar (81.8% vs. 86.7%. The treatment regimens and treatment duration were similar between both groups. Only a minor percentage of the patients in both groups received 6-month treatment regimens (low vs. high concentration resistance, 9.1% vs. 13.3%; respectively, p = 0.447 The most common reason for treatment duration longer than 6 months was pyrazinamide given for less than 6 months, followed by a delay in clinical response to treatment. Multivariable analysis showed that prior tuberculosis treatment (Odds ratio, 2.82, 95% C.I., 1.02-7.77, p = 0.045 was the only independent risk factor for unsuccessful treatment outcome. CONCLUSION: Different levels of INH resistance did not affect the treatment outcomes of patients with INH-monoresistant tuberculosis. Prolonged Rifampin-containing regimens may achieve those good outcomes in patients with low- and high-concentration INH-monoresistant TB.

  20. Mutation of katG in a clinical isolate of Mycobacterium tuberculosis: effects on catalase-peroxidase for isoniazid activation.

    Science.gov (United States)

    Purkan; Ihsanawati; Natalia, D; Syah, Y M; Retnoningrum, D S; Kusuma, H S

    2016-01-01

    Mutations in katG gene are often associated with isoniazid (INH) resistance in Mycobacterium tuberculosis strain. This research was perfomed to identify the katG mutation in clinical isolate (L8) that is resistant to INH at 1 μg/ml. In addition to characterize the catalase-peroxidase of KatG L8 and perform the ab initio structural study of the protein to get a more complete understanding in drug activation and the resistan­ce mechanism. The katG gene was cloned and expressed in Escherichia coli, then followed by characterization of catalase-peroxidase of KatG. The structure modelling was performed to know a basis of alterations in enzyme activity. A substitution of A713G that correspond to Asn238Ser replacement was found in the L8 katG. The Asn238Ser modification leads to a decline in the activity of catalase-peroxidase and INH oxidation of the L8 KatG protein. The catalytic efficiency (Kcat/KM) of mutant KatGAsn238Ser respectively decreases to 41 and 52% for catalase and peroxidase. The mutant KatGAsn238Ser also shows a decrease of 62% in INH oxidation if compared to a wild type KatG (KatGwt). The mutant Asn238Ser might cause instability in the substrate binding­ site of KatG, because of removal of a salt bridge connecting the amine group of Asn238 to the carbo­xyl group of Glu233, which presents in KatGwt. The lost of the salt bridge in the substrate binding site in mutant KatGAsn238Ser created changes unfavorable for enzyme activities, which in turn emerge as INH resistan­ce in the L8 isolate of M. tuberculosis.

  1. 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

  2. [Description of Mycobacterium tuberculosis mutations conferring resistance to rifampicin and isoniazid detected by GenoType® MTBDRplus V.2 in Colombia].

    Science.gov (United States)

    Llerena, Claudia; Medina, Raquel

    2017-01-24

    The GenoType®MTBDRplusV.2 assay is a molecular technique endorsed by the World Health Organization and the Pan American Health Organization that allows for the identification of the Mycobacterium tuberculosis complex and the detection of mutations in the rpoβ gene for rifampicin resistance, and katG and inhA genes for isoniazid resistance. Due to the genetic variability in the circulating strains around the world, the national tuberculosis control programs should assess the performance of these new diagnostic technologies and their use under program conditions as rapid tests. To describe the mutations identified by the GenoType®MTBDRplusV.2 assay in pulmonary samples and Mycobacterium tuberculosis isolates in the Laboratorio Nacional de Referencia of the Instituto Nacional de Salud in 2014. We conducted a retrospective, descriptive study to detect the expression of inhA, KatG and rpoβ genes, responsible for resistence against isoniazid and rifampicin using the GenoType® MTBDRplus V.2 assay in 837 samples and isolates from tuberculosis cases. Several mutations in the rpoβ gene were identified. Ser531Leu was the most frequent (36.6%) followed by Asp516Val (21.6%), while Ser315Thr1 was the most frequent mutation in the katG gene (91.9%). We were able to identify different mutations present in MDR-TB strains in the country, with frequencies similar to those reported in other countries in the South American region.

  3. Benefits of combined preventive therapy with co-trimoxazole and isoniazid in adults living with HIV: time to consider a fixed-dose, single tablet coformulation.

    Science.gov (United States)

    Harries, Anthony D; Lawn, Stephen D; Suthar, Amitabh B; Granich, Reuben

    2015-12-01

    Antiretroviral therapy (ART) is the main intervention needed to reduce morbidity and mortality and to prevent tuberculosis in adults living with HIV. However, in most resource-limited countries, especially in sub-Saharan Africa, ART is started too late to have an effect with substantial early morbidity and mortality, and in high tuberculosis burden settings ART does not reduce the tuberculosis risk to that reported in individuals not infected with HIV. Co-trimoxazole preventive therapy started before or with ART, irrespective of CD4 cell count, reduces morbidity and mortality with benefits that continue indefinitely. Isoniazid preventive therapy as an adjunct to ART prevents tuberculosis in high-exposure settings, with long-term treatment likely to be needed to sustain this benefit. Unfortunately, both preventive therapies are underused in low-income and high-burden settings. ART development has benefited from patient-centred simplification with several effective regimens now available as a one per day pill. We argue that co-trimoxazole and isoniazid should also be combined into a single fixed-dose pill, along with pyridoxine (vitamin B6), that would be taken once per day to help with individual uptake and national scale-up of therapies. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. [The effects of various factors on the in vitro velocity of drug release from repository tablets. Part 4: Isoniazid (Rimicid) respository tablets (author's transl)].

    Science.gov (United States)

    Tomassini, L; Michailova, D; Naplatanova, D; Slavtschev, P

    1979-12-01

    The authors investigated the release of isoniazid from repository tablets as related to form, processing technology, strength constant and storage for 5 years. On determining the diffusion coefficient (D), the initial dissolution rate (Vo) and the time required for the diffusion of the releasing medium to the middle of the tablet (t1/2), it was found that the difference in release rate between the flat and the biconvex tablets is small. Furthermore, it was stated that the three-layer tablets have very high D and Vo values and very low t1/2 values, for what reason they are unsuited for repository tablets of the composition under investigation. Moreover, it was found that an increase of the strength constant does not affect the D, t1/2 and Vo values, and that the release of isoniazid is retarded only in flat tablets with the highest strength constant. Storage exerts no effect on the drug release from these tablets. The industrial production of these tablets is under way.

  5. Evaluation of the isoniazid preventive therapy (IPT) program in Shurugwi District, Midlands Province, Zimbabwe, January 2013 to August 2014.

    Science.gov (United States)

    Makoni, Annamercy; Chemhuru, Milton; Tshimanga, Mufuta; Gombe, Notion Tafara; Mungati, More; Bangure, Donewell

    2015-09-25

    Midlands Province started implementing the Isoniazid (INH) preventive therapy (IPT) program in January 2013. Shurugwi and Gokwe North were the piloting district hospitals. In May 2014, four more districts hospitals (Gokwe South, Gweru, Kwekwe and Zvishavane) started implementing IPT. Shurugwi District decentralized the program to its rural health facilities in January 2014. A review of the Shurugwi IPT program, 2013 data, indicated that the majority of eligible clients were not started on IPT. None out of the 400 eligible clients were started on IPT in November against the 100% target according to the World Health Organization and the National Tuberculosis (TB) Program. We conducted a study to evaluate the IPT program in Shurugwi District from January 2013 to August 2014. The logical framework approach was used to evaluate inputs, processes, outputs and outcomes of the IPT program. An interviewer administered questionnaire was used to collect data from key informants. Checklists were used to collect data from IPT program records. Sixteen health facilities were implementing IPT in Shurugwi District. All the facilities had TB screening tools and three did not have TB screening algorithms. The district experienced medicine stock outs in 2013. One formal training at district level and on job trainings in implementing health facilities were done. From January 2013 to August 2014, Shurugwi District screened 6794 antiretroviral (ART) clients for TB. Out of those screened, 5255 were eligible for IPT and 2831 (54%) were started on IPT. A total of 700 clients had completed the IPT 6 month's course by August 2014. The dropout rate due to INH toxicity and TB was 0.6% (n = 18) and 0.3% (n = 8) respectively. Fifty-three advocacy and community sensitization meetings were done. The program had no Information Education and Communication (IEC) materials. The IPT program in Shurugwi District achieved half its target. This could be due to inadequate formally trained staff, lack of IEC

  6. Rifapentine Pharmacokinetics and Tolerability in Children and Adults Treated Once Weekly With Rifapentine and Isoniazid for Latent Tuberculosis Infection.

    Science.gov (United States)

    Weiner, Marc; Savic, Radojka M; Kenzie, William R Mac; Wing, Diane; Peloquin, Charles A; Engle, Melissa; Bliven, Erin; Prihoda, Thomas J; Gelfond, Jonathan A L; Scott, Nigel A; Abdel-Rahman, Susan M; Kearns, Gregory L; Burman, William J; Sterling, Timothy R; Villarino, M Elsa

    2014-06-01

    In a phase 3, randomized clinical trial (PREVENT TB) of 8053 people with latent tuberculosis infection, 12 once-weekly doses of rifapentine and isoniazid had good efficacy and tolerability. Children received higher rifapentine milligram per kilogram doses than adults. In the present pharmacokinetic study (a component of the PREVENT TB trial), rifapentine exposure was compared between children and adults. Rifapentine doses in children ranged from 300 to 900 mg, and adults received 900 mg. Children who could not swallow tablets received crushed tablets. Sparse pharmacokinetic sampling was performed with 1 rifapentine concentration at 24 hours after drug administration (C24). Rifapentine area under concentration-time curve (AUC) was estimated from a nonlinear, mixed effects regression model (NLME). There were 80 children (age: median, 4.5 years; range, 2-11 years) and 77 adults (age: median, 40 years; all ≥18 years) in the study. The geometric mean rifapentine milligram per kilogram dose was greater in children than in adults (children, 23 mg/kg; adults, 11 mg/kg). Rifapentine geometric mean AUC and C24 were 1.3-fold greater in children (all children combined) than in adults. Children who swallowed whole tablets had 1.3-fold higher geometric mean AUC than children who received crushed tablets, and children who swallowed whole tablets had a 1.6-fold higher geometric mean AUC than adults. The higher rifapentine doses in children were well tolerated. To obtain rifapentine exposures comparable in children to adults, dosing algorithms modeled by NLME were developed. A 2-fold greater rifapentine dose for all children resulted in a 1.3-fold higher AUC compared to adults administered a standard dose. Use of higher weight-adjusted rifapentine doses for young children are warranted to achieve systemic exposures that are associated with successful treatment of latent tuberculosis infection in adults. Published by Oxford University Press on behalf of the Pediatric Infectious

  7. Systematic review of TST responses in people living with HIV in under-resourced settings: implications for isoniazid preventive therapy.

    Directory of Open Access Journals (Sweden)

    Andrew D Kerkhoff

    Full Text Available People living with HIV (PLWH who have positive tuberculin skin tests (TST benefit from isoniazid preventive therapy (IPT whereas those testing TST-negative do not. Revised World Health Organization guidelines explicitly state that assessment of TST is not a requirement for initiation of IPT. However, it is not known what proportions of patients will benefit from IPT if implemented without targeting according to TST status. We therefore determined the proportions of PLWH who test TST-positive.We systematically reviewed the literature published between January 1990 and February 2012 to determine the proportions of patients without active tuberculosis attending HIV care services in low and middle-income countries who tested TST-positive (≥5 mm induration. Proportions were also determined for different CD4 count strata. Data from 19 studies with 9,478 PLWH from sub-Saharan Africa, Asia and Central and South America were summarized. The vast majority were not receiving antiretroviral therapy (ART. A sub-analysis was conducted of 5 studies (5,567 subjects from high TB prevalence countries of PLWH with negative TB screens attending HIV care and treatment settings for whom CD4 stratified data were available. The median proportion of PLWH testing TST-positive overall was 22.8% (range, 19.5-32.6%. The median (range proportions with CD4 cell counts of <200, 200-499 or ≥500 cells/µL who tested positive were 12.4% (8.2-15.3%, 28.4% (20.1-36.9% and 37.4% (31.3-56.3%, respectively. Heterogeneity in the data precluded calculation of pooled summary estimates.In most settings, if IPT is administered to PLWH pre-ART without assessment of TST status, only a minority of those treated are likely to benefit, especially among those with the lowest CD4 cell counts. This may be inefficient use of resources and cost-effectiveness analyses should take this into account. Local knowledge of TST response rates may help inform policies. New simple means of identifying

  8. Adherence to and outcome of isoniazid chemoprophylaxis among household contact children of adults having pulmonary tuberculosis in Alexandria, Egypt.

    Science.gov (United States)

    Mohamed, Aida M

    2012-08-01

    Current international guidelines recommend 6-9 months of isoniazid (INH) preventive chemotherapy to prevent the development of active tuberculosis (TB) in susceptible children exposed to Mycobacterium tuberculosis. However, this is dependent on good adherence, as shown by previous studies. This study was conducted to describe the outcome of screening of contact children aged 5 years or less with household exposure to an adult pulmonary TB index case to determine the prevalence and possible risk factors of infection among contact children and to determine the extent and outcome of adherence of contact children to unsupervised INH chemoprophylaxis for 6 months. A descriptive facility-based cross-sectional study was conducted from March 2009 to August 2010. Research settings were three of the National TB control program chest dispensaries (primary care facilities) in Alexandria, Egypt. Facility-based TB treatment registers of the previous 3 months were used to identify all new adult pulmonary TB cases. All children aged 5 years or less living in the same house as the index cases were identified and screened for TB. The contact children were given unsupervised INH preventive chemotherapy once active TB was excluded. Adherence to and outcome of preventive chemotherapy were followed up. Preventive chemotherapy consisted of unsupervised INH monotherapy for 6 months with monthly collection of tablets from the clinic. Adherence was documented after completion of the 6-month preventive treatment period. Adherence was considered reasonable if tablets were collected for more than 4 months, poor if collected for 2-4 months, and very poor if collected for less than 2 months. (a) Prevalence of infection and disease and the possible risk factors among contacts. (b) The extent and outcome of adherence to unsupervised INH chemoprophylaxis among contact children. (c) Factors behind poor adherence. In total, 197 adult TB index cases from 187 households were identified. In all, 297

  9. Potential physiological role of plant glycosidase inhibitors

    DEFF Research Database (Denmark)

    Bellincampi, D.; Carmadella, L.; Delcour, J.A.

    2004-01-01

    Carbohydrate-active enzymes including glycosidases, transglycosidases, glycosyltransferases, polysaccharide lyases and carbohydrate esterases are responsible for the enzymatic processing of carbohydrates in plants. A number of carbohydrate-active enzymes are produced by microbial pathogens...... and insects responsible of severe crop losses. Plants have evolved proteinaceous inhibitors to modulate the activity of several of these enzymes. The continuing discovery of new inhibitors indicates that this research area is still unexplored and may lead to new exciting developments. To date, the role...... of the inhibitors is not completely understood. Here we review recent results obtained on the best characterised inhibitors, pointing to their possible biological role in vivo. Results recently obtained with plant transformation technology indicate that this class of inhibitors has potential biotechnological...

  10. Phosphodiesterase inhibitors in clinical urology.

    Science.gov (United States)

    Ückert, Stefan; Kuczyk, Markus A; Oelke, Matthias

    2013-05-01

    To date, benign diseases of the male and female lower urinary and genital tract, such as erectile dysfunction, bladder overactivity, lower urinary tract symptomatology secondary to benign prostatic hyperplasia and symptoms of female sexual dysfunction (including arousal and orgasmic disorders), can be therapeutically approached by influencing the function of the smooth musculature of the respective tissues. The use of isoenzyme-selective phosphodiesterase (PDE) inhibitors is considered a great opportunity to treat various diseases of the human urogenital tract. PDE inhibitors, in particular the PDE5 (cyclic GMP PDE) inhibitors avanafil, lodenafil, sildenafil, tadalafil, udenafil and vardenafil, are regarded as efficacious, having a fast onset of drug action and an improved effect-to-adverse event ratio, combining a high response rate with the advantage of an on-demand intake. The purpose of this review is to summarize recent as well as potential future indications, namely, erectile dysfunction, Peyronie's disease, overactive bladder, urinary stone disease, lower urinary tract symptomatology secondary to benign prostatic hyperplasia and premature ejaculation, for the use of PDE inhibitors in clinical urology.

  11. 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

  12. Structure-Based Search for New Inhibitors of Cholinesterases

    Directory of Open Access Journals (Sweden)

    Barbara Malawska

    2013-03-01

    Full Text Available Cholinesterases are important biological targets responsible for regulation of cholinergic transmission, and their inhibitors are used for the treatment of Alzheimer’s disease. To design new cholinesterase inhibitors, of different structure-based design strategies was followed, including the modification of compounds from a previously developed library and a fragment-based design approach. This led to the selection of heterodimeric structures as potential inhibitors. Synthesis and biological evaluation of selected candidates confirmed that the designed compounds were acetylcholinesterase inhibitors with IC50 values in the mid-nanomolar to low micromolar range, and some of them were also butyrylcholinesterase inhibitors.

  13. Squash inhibitor family of serine proteinases

    International Nuclear Information System (INIS)

    Otlewski, J.; Krowarsch, D.

    1996-01-01

    Squash inhibitors of serine proteinases form an uniform family of small proteins. They are built of 27-33 amino-acid residues and cross-linked with three disulfide bridges. The reactive site peptide bond (P1-P1') is between residue 5 (Lys, Arg or Leu) and 6 (always Ile). High resolution X-ray structures are available for two squash inhibitors complexed with trypsin. NMR solution structures have also been determined for free inhibitors. The major structural motif is a distorted, triple-stranded antiparallel beta-sheet. A similar folding motif has been recently found in a number of proteins, including: conotoxins from fish-hunting snails, carboxypeptidase inhibitor from potato, kalata B1 polypeptide, and in some growth factors (e.g. nerve growth factor, transforming growth factor β2, platelet-derived growth factor). Squash inhibitors are highly stable and rigid proteins. They inhibit a number of serine proteinases: trypsin, plasmin, kallikrein, blood clotting factors: X a and XII a , cathepsin G. The inhibition spectrum can be much broadened if specific amino-acid substitutions are introduced, especially at residues which contact proteinase. Squash inhibitors inhibit proteinases via the standard mechanism. According to the mechanism, inhibitors are substrates which exhibit at neutral pH a high k cat /K m index for hydrolysis and resynthesis of the reactive site, and a low value of the hydrolysis constant. (author)

  14. Histone Deacetylase Inhibitors as Anticancer Drugs.

    Science.gov (United States)

    Eckschlager, Tomas; Plch, Johana; Stiborova, Marie; Hrabeta, Jan

    2017-07-01

    Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC) and histone acetyltransferases (HAT). HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities.

  15. Histone Deacetylase Inhibitors as Anticancer Drugs

    Directory of Open Access Journals (Sweden)

    Tomas Eckschlager

    2017-07-01

    Full Text Available Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC and histone acetyltransferases (HAT. HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities.

  16. New seismograph includes filters

    Energy Technology Data Exchange (ETDEWEB)

    1979-11-02

    The new Nimbus ES-1210 multichannel signal enhancement seismograph from EG and G geometrics has recently been redesigned to include multimode signal fillers on each amplifier. The ES-1210F is a shallow exploration seismograph for near subsurface exploration such as in depth-to-bedrock, geological hazard location, mineral exploration, and landslide investigations.

  17. Monoamine Oxidase Inhibitors (MAOIs)

    Science.gov (United States)

    ... health-medications/index.shtml. Accessed May 16, 2016. Hirsch M, et al. Monoamine oxidase inhibitors (MAOIs) for ... www.uptodate.com/home. Accessed May 16, 2016. Hirsch M, et al. Discontinuing antidepressant medications in adults. ...

  18. Analytic device including nanostructures

    KAUST Repository

    Di Fabrizio, Enzo M.; Fratalocchi, Andrea; Totero Gongora, Juan Sebastian; Coluccio, Maria Laura; Candeloro, Patrizio; Cuda, Gianni

    2015-01-01

    A device for detecting an analyte in a sample comprising: an array including a plurality of pixels, each pixel including a nanochain comprising: a first nanostructure, a second nanostructure, and a third nanostructure, wherein size of the first nanostructure is larger than that of the second nanostructure, and size of the second nanostructure is larger than that of the third nanostructure, and wherein the first nanostructure, the second nanostructure, and the third nanostructure are positioned on a substrate such that when the nanochain is excited by an energy, an optical field between the second nanostructure and the third nanostructure is stronger than an optical field between the first nanostructure and the second nanostructure, wherein the array is configured to receive a sample; and a detector arranged to collect spectral data from a plurality of pixels of the array.

  19. Saskatchewan resources. [including uranium

    Energy Technology Data Exchange (ETDEWEB)

    1979-09-01

    The production of chemicals and minerals for the chemical industry in Saskatchewan are featured, with some discussion of resource taxation. The commodities mentioned include potash, fatty amines, uranium, heavy oil, sodium sulfate, chlorine, sodium hydroxide, sodium chlorate and bentonite. Following the successful outcome of the Cluff Lake inquiry, the uranium industry is booming. Some developments and production figures for Gulf Minerals, Amok, Cenex and Eldorado are mentioned.

  20. SGLT2 Inhibitors May Predispose to Ketoacidosis.

    Science.gov (United States)

    Taylor, Simeon I; Blau, Jenny E; Rother, Kristina I

    2015-08-01

    Sodium glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic drugs that increase urinary excretion of glucose, thereby improving glycemic control and promoting weight loss. Since approval of the first-in-class drug in 2013, data have emerged suggesting that these drugs increase the risk of diabetic ketoacidosis. In May 2015, the Food and Drug Administration issued a warning that SGLT2 inhibitors may lead to ketoacidosis. Using PubMed and Google, we conducted Boolean searches including terms related to ketone bodies or ketoacidosis with terms for SGLT2 inhibitors or phlorizin. Priority was assigned to publications that shed light on molecular mechanisms whereby SGLT2 inhibitors could affect ketone body metabolism. SGLT2 inhibitors trigger multiple mechanisms that could predispose to diabetic ketoacidosis. When SGLT2 inhibitors are combined with insulin, it is often necessary to decrease the insulin dose to avoid hypoglycemia. The lower dose of insulin may be insufficient to suppress lipolysis and ketogenesis. Furthermore, SGLT2 is expressed in pancreatic α-cells, and SGLT2 inhibitors promote glucagon secretion. Finally, phlorizin, a nonselective inhibitor of SGLT family transporters decreases urinary excretion of ketone bodies. A decrease in the renal clearance of ketone bodies could also increase the plasma ketone body levels. Based on the physiology of SGLT2 and the pharmacology of SGLT2 inhibitors, there are several biologically plausible mechanisms whereby this class of drugs has the potential to increase the risk of developing diabetic ketoacidosis. Future research should be directed toward identifying which patients are at greatest risk for this side effect and also to optimizing pharmacotherapy to minimize the risk to patients.

  1. One-tube loop-mediated isothermal amplification combined with restriction endonuclease digestion and ELISA for colorimetric detection of resistance to isoniazid, ethambutol and streptomycin in Mycobacterium tuberculosis isolates.

    Science.gov (United States)

    Lee, Mei-Feng; Chen, Yen-Hsu; Hsu, Hui-Jine; Peng, Chien-Fang

    2010-10-01

    In this study, we designed a simple and rapid colorimetric detection method, a one-tube loop-mediated isothermal amplification (LAMP)-PCR-hybridization-restriction endonuclease-ELISA [one-tube LAMP-PCR-HY-RE-ELISA] system, to detect resistance to isoniazid, ethambutol and streptomycin in strains of Mycobacterium tuberculosis isolated from clinical specimens. The clinical performance of this method for detecting isoniazid-resistant, ethambutol-resistant and streptomycin-resistant isolates of M. tuberculosis showed 98.9%, 94.3% and 93.8%, respectively. This assay is rapid and convenient that can be performed within one working day. One-tube LAMP-PCR-HY-RE-ELISA system was designed based on hot spot point mutations in target drug-resistant genes, using LAMP-PCR, hybridization, digestion with restriction endonuclease and colorimetric method of ELISA. In this study, LAMP assay was used to amplify DNA from drug-resistant M. tuberculosis, and ELISA was used for colorimetrical determination. This assay will be a useful tool for rapid diagnosis of mutant codons in strains of M. tuberculosis for isoniazid at katG 315 and katG 463, ethambutol at embB 306 and embB 497, and streptomycin at rpsL 43. Crown Copyright © 2010. Published by Elsevier B.V. All rights reserved.

  2. Natural inhibitors of tumor-associated proteases

    International Nuclear Information System (INIS)

    Magdolen, U.; Krol, J.; Sato, S.; Schmitt, M.; Magdolen, V.; Krueger, A.; Mueller, M.M.; Sperl, S.

    2002-01-01

    The turnover and remodelling of extracellular matrix (ECM) is an essential part of many normal biological processes including development, morphogenesis, and wound healing. ECM turnover also occurs in severe pathological situations like artherosclerosis, fibrosis, tumor invasion and metastasis. The major proteases involved in this turnover are serine proteases (especially the urokinase-type plasminogen activator/plasmin system), matrix metalloproteases (a family of about 20 zinc-dependent endopeptidases including collagenases, gelatinases, stromelysins, and membrane-type metalloproteases), and cysteine proteases. In vivo, the activity of these proteases is tightly regulated in the extracellular space by zymogen activation and/or controlled inhibition. In the present review, we give an overview on the structure and biochemical properties of important tumor-associated protease inhibitors such as plasminogen activator inhibitor type 1 and type 2 (PAI-1, PAI-2), tissue inhibitors of metalloproteinases (TIMP-1, -2, -3, and -4), and the cysteine protease inhibitor cystatin C. Interestingly, some of these inhibitors of tumor-associated proteases display multiple functions which rather promote than inhibit tumor progression, when the presence of inhibitors in the tumor tissue is not balanced. (author)

  3. Being Included and Excluded

    DEFF Research Database (Denmark)

    Korzenevica, Marina

    2016-01-01

    Following the civil war of 1996–2006, there was a dramatic increase in the labor mobility of young men and the inclusion of young women in formal education, which led to the transformation of the political landscape of rural Nepal. Mobility and schooling represent a level of prestige that rural...... politics. It analyzes how formal education and mobility either challenge or reinforce traditional gendered norms which dictate a lowly position for young married women in the household and their absence from community politics. The article concludes that women are simultaneously excluded and included from...... community politics. On the one hand, their mobility and decision-making powers decrease with the increase in the labor mobility of men and their newly gained education is politically devalued when compared to the informal education that men gain through mobility, but on the other hand, schooling strengthens...

  4. ELISA analysis of soybean trypsin inhibitors in processed foods.

    Science.gov (United States)

    Brandon, D L; Bates, A H; Friedman, M

    1991-01-01

    Soybean proteins are widely used in human foods in a variety of forms, including infant formulas, flour, protein concentrates, protein isolates, soy sauces, textured soy fibers, and tofu. The presence of inhibitors of digestive enzymes in soy proteins impairs the nutritional quality and possibly the safety of soybeans and other legumes. Processing, based on the use of heat or fractionation of protein isolates, does not completely inactivate or remove these inhibitors, so that residual amounts of inhibitors are consumed by animals and humans. New monoclonal antibody-based immunoassays can measure low levels of the soybean Kunitz trypsin inhibitor (KTI) and the Bowman-Birk trypsin and chymotrypsin inhibitor (BBI) and the Bowman-Birk foods. The enzyme-linked immunosorbent assay (ELISA) was used to measure the inhibitor content of soy concentrates, isolates, and flours, both heated and unheated; a commercial soy infant formula; KTI and BBI with rearranged disulfide bonds; browning products derived from heat-treatment of KTI with glucose and starch; and KTI exposed to high pH. The results indicate that even low inhibitor isolates contain significant amounts of specific inhibitors. Thus, infants on soy formula consume about 10 mg of KTI plus BBI per day. The immunoassays complement the established enzymatic assays of trypsin and chymotrypsin inhibitors, and have advantages in (a) measuring low levels of inhibitors in processed foods; and (b) differentiating between the Kunitz and Bowman-Birk inhibitors. The significance of our findings for food safety are discussed.

  5. SGLT2 inhibitors.

    Science.gov (United States)

    Dardi, I; Kouvatsos, T; Jabbour, S A

    2016-02-01

    Diabetes mellitus is a serious health issue and an economic burden, rising in epidemic proportions over the last few decades worldwide. Although several treatment options are available, only half of the global diabetic population achieves the recommended or individualized glycemic targets. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents with a novel insulin-independent action. SGLT2 is a transporter found in the proximal renal tubules, responsible for the reabsorption of most of the glucose filtered by the kidney. Inhibition of SGLT2 lowers the blood glucose level by promoting the urinary excretion of excess glucose. Due to their insulin-independent action, SGLT2 inhibitors can be used with any degree of beta-cell dysfunction or insulin resistance, related to a very low risk of hypoglycemia. In addition to improving glycemic control, SGLT2 inhibitors have been associated with a reduction in weight and blood pressure when used as monotherapy or in combination with other antidiabetic agents in patients with type 2 diabetes mellitus (T2DM). Treatment with SGLT2 inhibitors is usually well tolerated; however, they have been associated with an increased incidence of urinary tract and genital infections, although these infections are usually mild and easy to treat. SGLT2 inhibitors are a promising new option in the armamentarium of drugs for patients with T2DM. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Monoamine Oxidase B Inhibitors in Parkinson's Disease.

    Science.gov (United States)

    Dezsi, Livia; Vecsei, Laszlo

    2017-01-01

    Parkinson's disease (PD) is a neurodegenerative disorder with a prevalence increasing with age. Oxidative stress and glutamate toxicity are involved in its pathomechanism. There are still many unmet needs of PD patients, including the alleviation of motor fluctuations and dyskinesias, and the development of therapies with neuroprotective potential. To give an overview of the pharmacological properties, the efficacy and safety of the monoamine oxidase B (MAO-B) inhibitors in the treatment of PD, with special focus on the results of randomized clinical trials. A literature search was conducted in PubMed for 'PD treatment', 'MAO-B inhibitors', 'selegiline', 'rasagiline', 'safinamide' and 'clinical trials' with 'MAO-B inhibitors' in 'Parkinson' disease'. MAO-B inhibitors have a favorable pharmacokinetic profile, improve the dopamine deficient state and may have neuroprotective properties. Safinamide exhibits an anti-glutamatergic effect as well. When applied as monotherapy, MAO-B inhibitors provide a modest, but significant improvement of motor function and delay the need for levodopa. Rasagiline and safinamide were proven safe and effective when added to a dopamine agonist in early PD. As add-on to levodopa, MAO-B inhibitors significantly reduced off-time and were comparable in efficacy to COMT inhibitors. Improvements were achieved as regards certain non-motor symptoms as well. Due to the efficacy shown in clinical trials and their favorable side-effect profile, MAO-B inhibitors are valuable drugs in the treatment of PD. They are recommended as monotherapy in the early stages of the disease and as add-on therapy to levodopa in advanced PD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  7. Crystallization inhibitors for amorphous oxides

    International Nuclear Information System (INIS)

    Reznitskij, L.A.; Filippova, S.E.

    1993-01-01

    Data for the last 10 years, in which experimental results of studying the temperature stabilization of x-ray amorphous oxides (including R 3 Fe 5 O 12 R-rare earths, ZrO 2 , In 2 O 3 , Sc 2 O 3 ) and their solid solution are presented, are generalized. Processes of amorphous oxide crystallization with the production of simple oxides, solid solutions and chemical compounds with different polyhedral structure, are investigated. Energy and crystallochemical criteria for selecting the doping inhibitor-components stabilizing the amorphous state are ascertained, temperatures and enthalpies of amorpous oxide crystallization are determined, examination of certain provisions of iso,orphous miscibility theory is conducted

  8. Assessment of bioequivalence of rifampicin, isoniazid and pyrazinamide in a four drug fixed dose combination with separate formulations at the same dose levels.

    Science.gov (United States)

    Agrawal, Shrutidevi; Kaur, Kanwal Jit; Singh, Inderjit; Bhade, Shantaram R; Kaul, Chaman Lal; Panchagnula, Ramesh

    2002-02-21

    Tuberculosis (TB) needs treatment with three to five different drugs simultaneously, depending on the patient category. These drugs can be given as single drug preparations or fixed dose combinations (FDCs) of two more drugs in a single formulation. World Health Organization and International Union against Tuberculosis and Lung Disease (IUATLD) recommend FDCs only of proven bioavailability. The relative bioavailability of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PYZ) was assessed on a group of 13 healthy male subjects from a four drug FDC versus separate formulations at the same dose levels. The study was designed to be an open, crossover experiment. A total of nine blood samples each of 3 ml volume were collected over a period of 24-h. The concentrations of RIF, its main metabolite desacetyl RIF (DRIF), INH and PYZ in plasma were assessed by HPLC analysis. Pharmacokinetic parameters namely AUC(0-24), AUC(0-inf), C(max), T(max), were calculated and subjected to different statistical tests (Hauschke analysis, two way ANOVA, normal and log transformed confidence interval) at 90% confidence interval. In addition, elimination rate constant (K(el)) and absorption efficiencies for each drug were also calculated. It was concluded that four drugs FDC tablet is bioequivalent for RIF, INH and PYZ to separate formulation at the same dose levels.

  9. Novel pH- and temperature-responsive blend hydrogel microspheres of sodium alginate and PNIPAAm-g-GG for controlled release of isoniazid.

    Science.gov (United States)

    Kajjari, Praveen B; Manjeshwar, Lata S; Aminabhavi, Tejraj M

    2012-12-01

    This paper reports the preparation and characterization of novel pH- and thermo-responsive blend hydrogel microspheres of sodium alginate (NaAlg) and poly(N-isopropylacrylamide)(PNIPAAm)-grafted-guar gum (GG) i.e., PNIPAAm-g-GG by emulsion cross-linking method using glutaraldehyde (GA) as a cross-linker. Isoniazid (INZ) was chosen as the model antituberculosis drug to achieve encapsulation up to 62%. INZ has a plasma half-life of 1.5 h, whose release was extended up to 12 h. Fourier transform infrared spectroscopy was used to confirm the grafting reaction and chemical stability of INZ during the encapsulation. Differential scanning calorimetry was used to investigate the drug's physical state, while powder X-ray diffraction confirmed the molecular level dispersion of INZ in the matrix. Scanning electron microscopy confirmed varying surface morphologies of the drug-loaded microspheres. Temperature- and pH-responsive nature of the blend hydrogel microspheres were investigated by equilibrium swelling, and in vitro release experiments were performed in pH 1.2 and pH 7.4 buffer media at 37°C as well as at 25°C. Kinetics of INZ release was analyzed by Ritger-Peppas empirical equation to compute the diffusional exponent parameter (n), whose value ranged between 0.27 and 0.58, indicating the release of INZ follows a diffusion swelling controlled release mechanism.

  10. Isoniazid-resistant Mycobacterium kansasii in an HIV-positive patient, and possible development of immune reconstitution inflammatory syndrome after initiation of highly active antiretroviral therapy: case report

    Directory of Open Access Journals (Sweden)

    A. Despotovic

    2016-01-01

    Full Text Available Non-tuberculous mycobacteria are rare but important causes of infection in HIV-positive individuals. A 28-year-old HIV-positive male presented with a high fever, non-productive cough, right subcostal pain, splenomegaly, a very low CD4 count, elevated C-reactive protein and erythrocyte sedimentation rate, and a normal white blood cell count. The suspicion of tuberculosis (TB was very high, and sputum samples were positive for acid-fast bacilli. Standard quadruple anti-TB therapy was initiated, but once culture of the sample revealed Mycobacterium kansasii, pyrazinamide was withdrawn. Highly active antiretroviral therapy (HAART was initiated soon after, consisting of abacavir/lamivudine and efavirenz. The patient's general condition deteriorated 2 weeks after HAART initiation, which could have been due to the development of immune reconstitution inflammatory syndrome (IRIS. The patient recovered and was discharged in good condition. However, the results of resistance testing of the isolated organism arrived after discharge, and showed isoniazid and streptomycin resistance. This is the first case report of M. kansasii infection from Serbia and shows the difficulties encountered during the course of treatment.

  11. Cathepsin D inhibitors

    Directory of Open Access Journals (Sweden)

    M. Gacko

    2007-11-01

    Full Text Available Inhibitors of cathepsin D belong to chemical compounds that estrify carboxyl groups of the Asp33 and Asp231residues of its catalytic site, penta-peptides containing statin, i.e. the amino acid similar in structure to the tetraedric indirectproduct, and polypeptides found in the spare organs of many plants and forming permanent noncovalent complexes withcathepsin. Cathepsin D activity is also inhibited by alpha2-macroglobulin and antibodies directed against this enzyme.Methods used to determine the activity and concentration of these inhibitors and their analytical, preparative and therapeuticapplications are discussed.

  12. Transglutaminase inhibitor from milk

    NARCIS (Netherlands)

    Jong, G.A.H. de; Wijngaards, G.; Koppelman, S.J.

    2003-01-01

    Cross-linking experiments of skimmed bovine milk with bacterial transglutaminase isolated from Streptoverticillium mobaraense showed only some degree of formation of high-molecular-weight casein polymers. Studies on the nature of this phenomenon revealed that bovine milk contains an inhibitor of

  13. Inhibitors of histone demethylases

    DEFF Research Database (Denmark)

    Lohse, Brian; Kristensen, Jesper L; Kristensen, Line H

    2011-01-01

    Methylated lysines are important epigenetic marks. The enzymes involved in demethylation have recently been discovered and found to be involved in cancer development and progression. Despite the relative recent discovery of these enzymes a number of inhibitors have already appeared. Most of the i...

  14. Cysteine peptidases and their inhibitors in breast and genital cancer.

    Directory of Open Access Journals (Sweden)

    Magdalena Milan

    2010-11-01

    Full Text Available Cysteine proteinases and their inhibitors probably play the main role in carcinogenesis and metastasis. The metastasis process need external proteolytic activities that pass several barriers which are membranous structures of the connective tissue which includes, the basement membrane of blood vessels. Activities of the proteinases are regulated by endogenous inhibitors and activators. The imbalance between cysteine proteinases and cystatins seems to be associated with an increase in metastatic potential in some tumors. It has also been reported that proteinase inhibitors, specific antibodies for these enzymes and inhibition of the urokinase receptor may prevent cancer cell invasion. Some proteinase inhibitor could serve as agents for cancer treatment.

  15. Hepatitis C Virus NS3 Inhibitors: Current and Future Perspectives

    Directory of Open Access Journals (Sweden)

    Kazi Abdus Salam

    2013-01-01

    Full Text Available Currently, hepatitis C virus (HCV infection is considered a serious health-care problem all over the world. A good number of direct-acting antivirals (DAAs against HCV infection are in clinical progress including NS3-4A protease inhibitors, RNA-dependent RNA polymerase inhibitors, and NS5A inhibitors as well as host targeted inhibitors. Two NS3-4A protease inhibitors (telaprevir and boceprevir have been recently approved for the treatment of hepatitis C in combination with standard of care (pegylated interferon plus ribavirin. The new therapy has significantly improved sustained virologic response (SVR; however, the adverse effects associated with this therapy are still the main concern. In addition to the emergence of viral resistance, other targets must be continually developed. One such underdeveloped target is the helicase portion of the HCV NS3 protein. This review article summarizes our current understanding of HCV treatment, particularly with those of NS3 inhibitors.

  16. 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)

  17. SGLT2 Inhibitors and the Diabetic Kidney.

    Science.gov (United States)

    Fioretto, Paola; Zambon, Alberto; Rossato, Marco; Busetto, Luca; Vettor, Roberto

    2016-08-01

    Diabetic nephropathy (DN) is the most common cause of end-stage renal disease worldwide. Blood glucose and blood pressure control reduce the risk of developing this complication; however, once DN is established, it is only possible to slow progression. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, the most recent glucose-lowering oral agents, may have the potential to exert nephroprotection not only through improving glycemic control but also through glucose-independent effects, such as blood pressure-lowering and direct renal effects. It is important to consider, however, that in patients with impaired renal function, given their mode of action, SGLT2 inhibitors are less effective in lowering blood glucose. In patients with high cardiovascular risk, the SGLT2 inhibitor empagliflozin lowered the rate of cardiovascular events, especially cardiovascular death, and substantially reduced important renal outcomes. Such benefits on DN could derive from effects beyond glycemia. Glomerular hyperfiltration is a potential risk factor for DN. In addition to the activation of the renin-angiotensin-aldosterone system, renal tubular factors, including SGLT2, contribute to glomerular hyperfiltration in diabetes. SGLT2 inhibitors reduce sodium reabsorption in the proximal tubule, causing, through tubuloglomerular feedback, afferent arteriole vasoconstriction and reduction in hyperfiltration. Experimental studies showed that SGLT2 inhibitors reduced hyperfiltration and decreased inflammatory and fibrotic responses of proximal tubular cells. SGLT2 inhibitors reduced glomerular hyperfiltration in patients with type 1 diabetes, and in patients with type 2 diabetes, they caused transient acute reductions in glomerular filtration rate, followed by a progressive recovery and stabilization of renal function. Interestingly, recent studies consistently demonstrated a reduction in albuminuria. Although these data are promising, only dedicated renal outcome trials will clarify whether

  18. Acid corrosion inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Chen, N G

    1964-04-28

    An acid corrosion inhibitor is prepared by a 2-stage vacuum evaporation of effluents obtained from the ammonia columns of the coking oven plant. The effluent, leaving a scrubber in which the phenols are removed at a temperature of 98$C, passes through a quartz filter and flows into a heated chamber in which it is used for preheating a solution circulating through a vacuum unit, maintaining the temperature of the solution at 55$ to 60$C. The effluent enters a large tank in which it is boiled at 55$ to 60$C under 635 to 640 mm Hg pressure. Double evaporation of this solution yields a very effective acid corrosion inhibitor. Its corrosion-preventing effect is 97.9% compared with 90.1% for thiourea and 88.5% for urotropin under identical conditions.

  19. Benzoylurea Chitin Synthesis Inhibitors.

    Science.gov (United States)

    Sun, Ranfeng; Liu, Chunjuan; Zhang, Hao; Wang, Qingmin

    2015-08-12

    Benzoylurea chitin synthesis inhibitors are widely used in integrated pest management (IPM) and insecticide resistance management (IRM) programs due to their low toxicity to mammals and predatory insects. In the past decades, a large number of benzoylurea derivatives have been synthesized, and 15 benzoylurea chitin synthesis inhibitors have been commercialized. This review focuses on the history of commercial benzolyphenylureas (BPUs), synthetic methods, structure-activity relationships (SAR), action mechanism research, environmental behaviors, and ecotoxicology. Furthermore, their disadvantages of high risk to aquatic invertebrates and crustaceans are pointed out. Finally, we propose that the para-substituents at anilide of benzoylphenylureas should be the functional groups, and bipartite model BPU analogues are discussed in an attempt to provide new insight for future development of BPUs.

  20. An explanation for the physical instability of a marketed fixed dose combination (FDC) formulation containing isoniazid and ethambutol and proposed solutions.

    Science.gov (United States)

    Bhutani, Hemant; Mariappan, T T; Singh, Saranjit

    2004-07-01

    An investigation was carried out to explore the possible reason for the physical instability of a marketed strip packaged anti-TB fixed dose combination (FDC) tablet containing 300 mg of isoniazid (H) and 800 mg of ethambutol hydrochloride (E). The instability was in the form of distribution of white powder inside the strip pockets. High-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS-MS) studies confirmed that both H and E were present in the powder. The same was also confirmed through Fourier-transform infrared (FTIR) spectroscopy, which also indicated absence of interaction between the two drugs. No sublimation of the drugs was observed up to 110 degrees C, indicating that the observed instability was not due to this reason. Subsequently, attention was paid to the possibility of moisture gain by the tablets through defective packaging (which was established) due to hygroscopicity of E. To understand the phenomenon further, pure drugs and their mixtures were stored under accelerated conditions of temperature and humidity [40 degrees C/75% relative humidity (RH)] and both increase in weight and physical changes were recorded periodically. The mixtures gained moisture at a higher rate than pure E and those with higher content of E became liquid, which on withdrawal from the chambers, became crystallized. The drug mixture containing H:E at a ratio of 30:70 w/w, which was similar to the ratio of the drugs in the tablets (27:73 w/w), crystallized fastest, indicating formation of a rapid crystallizing saturated system at this ratio of the drugs. It is postulated that the problem of instability arises because of the formation of a saturated layer of drugs upon moisture gain through the defective packaging material and drying of this layer with time. The study suggests that barrier packaging free from defects and alternatively (or in combination) film coating of the tablets with water-resistant polymers are essential for this

  1. Validation of a rapid micellar electrokinetic capillary chromatographic method for the simultaneous determination of isoniazid and pyridoxine hydrochloride in pharmaceutical formulation.

    Science.gov (United States)

    Nemutlu, E; Celebier, M; Uyar, B; Altinöz, S

    2007-07-01

    An efficient and reliable micellar electrokinetic capillary chromatography (MEKC) method has been developed for the simultaneous determination of isoniazid (ISO) and pyridoxine hydrochloride (PYR) in pharmaceutical formulations. A chemometric two level full factorial design approach was used to search for the optimum conditions of separation. Three parameters were selected for this study: the buffer pH, the buffer concentration and sodium dodecyl sulphate (SDS) concentrations. Resolution, peak symmetry and analysis time were established as response. The two analytes were separated within 6 min with the optimized conditions: 50 mM borate buffer, 25 mM SDS pH 7.8, 35 degrees C, at 50 mbar 4s injection and 30 kV by using a fused silica capillary (72 cm effective length, 50 microm i.d.). The detection wavelength was set to 205 nm. Meloxicam was used as internal standard. The method was validated with respect to stability, linearity range, limit of quantitation and detection, precision, accuracy, specificity and robustness. The detection limits of the method were 1.0 microg mL(-1) for ISO and 0.40 microg mL(-1) for PYR and the method was linear at least in the range of 3.0-100 microg mL(-1) for ISO and 1.0-100 microg mL(-1) for PYR with excellent correlation coefficients (0.9995 for ISO and 0.9998 for PYR). Relative standard deviations (R.S.D.s) of the described method ranged between 0.54 and 2.27% for intra-day precision and between 0.65 and 2.69% for inter-day precision. The developed method was applied to the tablet form of ISO and PYR-containing the pharmaceutical preparations and the data were compared with obtained from the standard addition method. No statistically significant difference was found.

  2. Simultaneous Voltammetric Determination of Acetaminophen and Isoniazid (Hepatotoxicity-Related Drugs) Utilizing Bismuth Oxide Nanorod Modified Screen-Printed Electrochemical Sensing Platforms.

    Science.gov (United States)

    Mahmoud, Bahaa G; Khairy, Mohamed; Rashwan, Farouk A; Banks, Craig E

    2017-02-07

    To overcome the recent outbreaks of hepatotoxicity-related drugs, a new analytical tool for the continuously determination of these drugs in human fluids is required. Electrochemical-based analytical methods offer an effective, rapid, and simple tool for on-site determination of various organic and inorganic species. However, the design of a sensitive, selective, stable, and reproducible sensor is still a major challenge. In the present manuscript, a facile, one-pot hydrothermal synthesis of bismuth oxide (Bi 2 O 2.33 ) nanostructures (nanorods) was developed. These BiO nanorods were cast onto mass disposable graphite screen-printed electrodes (BiO-SPEs), allowing the ultrasensitive determination of acetaminophen (APAP) in the presence of its common interference isoniazid (INH), which are both found in drug samples. The simultaneous electroanalytical sensing using BiO-SPEs exhibited strong electrocatalytic activity toward the sensing of APAP and INH with an enhanced analytical signal (voltammetric peak) over that achievable at unmodified (bare) SPEs. The electroanalytical sensing of APAP and INH are possible with accessible linear ranges from 0.5 to 1250 μM and 5 to 1760 μM with limits of detection (3σ) of 30 nM and 1.85 μM, respectively. The stability, reproducibility, and repeatability of BiO-SPE were also investigated. The BiO-SPEs were evaluated toward the sensing of APAP and INH in human serum, urine, saliva, and tablet samples. The results presented in this paper demonstrate that BiO-SPEs sensing platforms provide a potential candidate for the accurate determination of APAP and INH within human fluids and pharmaceutical formulations.

  3. The role of agency in the implementation of Isoniazid Preventive Therapy (IPT): Lessons from oMakoti in uMgungundlovu District, South Africa.

    Science.gov (United States)

    Boffa, Jody; Mayan, Maria; Ndlovu, Sithembile; Mhlaba, Tsholofelo; Williamson, Tyler; Sauve, Reginald; Fisher, Dina

    2018-01-01

    In response to revisions in global and national policy in 2011, six-month isoniazid preventive therapy (IPT) became freely available as a preventive measure for people living with HIV in the uMgungundlovu District of KwaZulu-Natal province, South Africa. Given a difference in uptake and completion by sex, we sought to explore the reasons why Zulu women were more likely to accept and complete IPT compared to men in an effort to inform future implementation. Utilising a community-based participatory research approach and ethnographic methods, we undertook 17 individual and group interviews, and met regularly with grassroots community advisory teams in three Zulu communities located in uMgungundlovu District between March 2012-December 2016. Three categories described women's willingness to initiate IPT: women are caregivers, women are obedient, and appearance is important. The findings suggest that the success of IPT implementation amongst clinic-utilising women of uMgungundlovu is related to the cultural gender norms of uMakoti, isiZulu for "the bride" or "the wife." We invoke the cultural concept of inhlonipho, meaning "to show respect," to discuss how the cultural values of uMakoti may conflict with biomedical expectations of adherence. Such conflict can result in misinterpretations by healthcare providers or patients, and lead some patients to fear the repercussions of asking questions or contemplating discontinuation with the provider, preferring instead to appear obedient. We propose a shift in emphasis from adherence-focussed strategies, characteristic of the current biomedical approach, to practices that promote patient agency in an effort to offer IPT more appropriately. Building on existing tools, namely the harm reduction model and the use of mini-ethnography, we provide guidance on how to support women to participate as agents in the decision to initiate or continue IPT, decisions which may also impact the health and choices of the family.

  4. The role of agency in the implementation of Isoniazid Preventive Therapy (IPT: Lessons from oMakoti in uMgungundlovu District, South Africa.

    Directory of Open Access Journals (Sweden)

    Jody Boffa

    Full Text Available In response to revisions in global and national policy in 2011, six-month isoniazid preventive therapy (IPT became freely available as a preventive measure for people living with HIV in the uMgungundlovu District of KwaZulu-Natal province, South Africa. Given a difference in uptake and completion by sex, we sought to explore the reasons why Zulu women were more likely to accept and complete IPT compared to men in an effort to inform future implementation.Utilising a community-based participatory research approach and ethnographic methods, we undertook 17 individual and group interviews, and met regularly with grassroots community advisory teams in three Zulu communities located in uMgungundlovu District between March 2012-December 2016.Three categories described women's willingness to initiate IPT: women are caregivers, women are obedient, and appearance is important. The findings suggest that the success of IPT implementation amongst clinic-utilising women of uMgungundlovu is related to the cultural gender norms of uMakoti, isiZulu for "the bride" or "the wife." We invoke the cultural concept of inhlonipho, meaning "to show respect," to discuss how the cultural values of uMakoti may conflict with biomedical expectations of adherence. Such conflict can result in misinterpretations by healthcare providers or patients, and lead some patients to fear the repercussions of asking questions or contemplating discontinuation with the provider, preferring instead to appear obedient. We propose a shift in emphasis from adherence-focussed strategies, characteristic of the current biomedical approach, to practices that promote patient agency in an effort to offer IPT more appropriately.Building on existing tools, namely the harm reduction model and the use of mini-ethnography, we provide guidance on how to support women to participate as agents in the decision to initiate or continue IPT, decisions which may also impact the health and choices of the family.

  5. Vanadium Compounds as PTP Inhibitors

    Directory of Open Access Journals (Sweden)

    Elsa Irving

    2017-12-01

    Full Text Available Phosphotyrosine signaling is regulated by the opposing actions of protein tyrosine kinases (PTKs and protein tyrosine phosphatases (PTPs. Here we discuss the potential of vanadium derivatives as PTP enzyme inhibitors and metallotherapeutics. We describe how vanadate in the V oxidized state is thought to inhibit PTPs, thus acting as a pan-inhibitor of this enzyme superfamily. We discuss recent developments in the biological and biochemical actions of more complex vanadium derivatives, including decavanadate and in particular the growing number of oxidovanadium compounds with organic ligands. Pre-clinical studies involving these compounds are discussed in the anti-diabetic and anti-cancer contexts. Although in many cases PTP inhibition has been implicated, it is also clear that many such compounds have further biochemical effects in cells. There also remain concerns surrounding off-target toxicities and long-term use of vanadium compounds in vivo in humans, hindering their progress through clinical trials. Despite these current misgivings, interest in these chemicals continues and many believe they could still have therapeutic potential. If so, we argue that this field would benefit from greater focus on improving the delivery and tissue targeting of vanadium compounds in order to minimize off-target toxicities. This may then harness their full therapeutic potential.

  6. Inhibitory Effects of Respiration Inhibitors on Aflatoxin Production

    Directory of Open Access Journals (Sweden)

    Shohei Sakuda

    2014-03-01

    Full Text Available Aflatoxin production inhibitors, which do not inhibit the growth of aflatoxigenic fungi, may be used to control aflatoxin without incurring a rapid spread of resistant strains. A respiration inhibitor that inhibits aflatoxin production was identified during a screening process for natural, aflatoxin-production inhibitors. This prompted us to evaluate respiration inhibitors as potential aflatoxin control agents. The inhibitory activities of four natural inhibitors, seven synthetic miticides, and nine synthetic fungicides were evaluated on aflatoxin production in Aspergillus parasiticus. All of the natural inhibitors (rotenone, siccanin, aptenin A5, and antimycin A inhibited fungal aflatoxin production with IC50 values around 10 µM. Among the synthetic miticides, pyridaben, fluacrypyrim, and tolfenpyrad exhibited strong inhibitory activities with IC50 values less than 0.2 µM, whereas cyflumetofen did not show significant inhibitory activity. Of the synthetic fungicides, boscalid, pyribencarb, azoxystrobin, pyraclostrobin, and kresoxim-methyl demonstrated strong inhibitory activities, with IC50 values less than 0.5 µM. Fungal growth was not significantly affected by any of the inhibitors tested at concentrations used. There was no correlation observed between the targets of respiration inhibitors (complexes I, II, and III and their IC50 values for aflatoxin-production inhibitory activity. This study suggests that respiration inhibitors, including commonly used pesticides, are useful for aflatoxin control.

  7. Inhibitory Effects of Respiration Inhibitors on Aflatoxin Production

    Science.gov (United States)

    Sakuda, Shohei; Prabowo, Diyan Febri; Takagi, Keiko; Shiomi, Kazuro; Mori, Mihoko; Ōmura, Satoshi; Nagasawa, Hiromichi

    2014-01-01

    Aflatoxin production inhibitors, which do not inhibit the growth of aflatoxigenic fungi, may be used to control aflatoxin without incurring a rapid spread of resistant strains. A respiration inhibitor that inhibits aflatoxin production was identified during a screening process for natural, aflatoxin-production inhibitors. This prompted us to evaluate respiration inhibitors as potential aflatoxin control agents. The inhibitory activities of four natural inhibitors, seven synthetic miticides, and nine synthetic fungicides were evaluated on aflatoxin production in Aspergillus parasiticus. All of the natural inhibitors (rotenone, siccanin, aptenin A5, and antimycin A) inhibited fungal aflatoxin production with IC50 values around 10 µM. Among the synthetic miticides, pyridaben, fluacrypyrim, and tolfenpyrad exhibited strong inhibitory activities with IC50 values less than 0.2 µM, whereas cyflumetofen did not show significant inhibitory activity. Of the synthetic fungicides, boscalid, pyribencarb, azoxystrobin, pyraclostrobin, and kresoxim-methyl demonstrated strong inhibitory activities, with IC50 values less than 0.5 µM. Fungal growth was not significantly affected by any of the inhibitors tested at concentrations used. There was no correlation observed between the targets of respiration inhibitors (complexes I, II, and III) and their IC50 values for aflatoxin-production inhibitory activity. This study suggests that respiration inhibitors, including commonly used pesticides, are useful for aflatoxin control. PMID:24674936

  8. ROS inhibitor N-acetyl-L-cysteine antagonizes the activity of proteasome inhibitors.

    Science.gov (United States)

    Halasi, Marianna; Wang, Ming; Chavan, Tanmay S; Gaponenko, Vadim; Hay, Nissim; Gartel, Andrei L

    2013-09-01

    NAC (N-acetyl-L-cysteine) is commonly used to identify and test ROS (reactive oxygen species) inducers, and to inhibit ROS. In the present study, we identified inhibition of proteasome inhibitors as a novel activity of NAC. Both NAC and catalase, another known scavenger of ROS, similarly inhibited ROS levels and apoptosis associated with H₂O₂. However, only NAC, and not catalase or another ROS scavenger Trolox, was able to prevent effects linked to proteasome inhibition, such as protein stabilization, apoptosis and accumulation of ubiquitin conjugates. These observations suggest that NAC has a dual activity as an inhibitor of ROS and proteasome inhibitors. Recently, NAC was used as a ROS inhibitor to functionally characterize a novel anticancer compound, piperlongumine, leading to its description as a ROS inducer. In contrast, our own experiments showed that this compound depicts features of proteasome inhibitors including suppression of FOXM1 (Forkhead box protein M1), stabilization of cellular proteins, induction of ROS-independent apoptosis and enhanced accumulation of ubiquitin conjugates. In addition, NAC, but not catalase or Trolox, interfered with the activity of piperlongumine, further supporting that piperlongumine is a proteasome inhibitor. Most importantly, we showed that NAC, but not other ROS scavengers, directly binds to proteasome inhibitors. To our knowledge, NAC is the first known compound that directly interacts with and antagonizes the activity of proteasome inhibitors. Taken together, the findings of the present study suggest that, as a result of the dual nature of NAC, data interpretation might not be straightforward when NAC is utilized as an antioxidant to demonstrate ROS involvement in drug-induced apoptosis.

  9. Identification of fermentation inhibitors in wood hydrolyzates and removal of inhibitors by ion exchange and liquid-liquid extraction

    Science.gov (United States)

    Luo, Caidian

    1998-12-01

    Common methods employed in the ethanol production from biomass consist of chemical or enzymatic degradation of biomass into sugars and then fermentation of sugars into ethanol or other chemicals. However, some degradation products severely inhibit the fermentation processes and substantially reduce the efficiency of ethanol production. How to remove inhibitors from the reaction product mixture and increase the production efficiency are critical in the commercialization of any processes of energy from biomass. The present study has investigated anion exchange and liquid-liquid extraction as potential methods for inhibitor removal. An analytical method has been developed to identify the fermentation inhibitors in a hydrolyzate. The majority of inhibitors present in hybrid poplar hydrolyzate have positively been identified. Ion exchange with weak basic Dowex-MWA-1 resin has been proved to be an effective mean to remove fermentation inhibitors from hybrid poplar hydrolyzate and significantly increase the fermentation productivity. Extraction with n-butanol might be a preferred way to remove inhibitors from wood hydrolyzates and improve the fermentability of sugars in the hydrolyzates. n-Butanol also removes some glucose, mannose and xylose from the hydrolyzate. Inhibitor identification reveals that lignin and sugar degradation compounds including both aromatic and aliphatic aldehydes and carboxylic acids formed in hydrolysis, plus fatty acids and other components from wood extractives are major fermentation inhibitors in Sacchromyces cerevisiae fermentation. There are 35 components identified as fermentation inhibitors. Among them, 4-hydroxy benzoic acid, 3,4-dihydroxy benzoic acid, syringic acid, syringaldehyde, and ferulic acid are among the most abundant aromatic inhibitors in hybrid poplar hydrolyzate. The conversion of aldehyde groups into carboxylic acid groups in the nitric acid catalyzed hydrolysis reduces the toxicity of the hydrolyzate. A wide spectrum of

  10. DGAT inhibitors for obesity.

    Science.gov (United States)

    Matsuda, Daisuke; Tomoda, Hiroshi

    2007-10-01

    Obesity is characterized by the accumulation of triacylglycerol in adipocytes. Diacylglycerol acyltransferase (DGAT) catalyzes the final reaction of triacylgycerol synthesis. Two isozymes of DGAT, DGAT1 and DGAT2, have been reported. Increased DGAT2 activity has a role in steatosis, while DGAT1 plays a role in very (V)LDL synthesis; increased plasma VLDL concentrations may promote obesity and thus DGAT1 is considered a potential therapeutic target of inhibition for obesity control. Several DGAT inhibitors of natural and synthetic origin have been reported, and their future prospect as anti-obesity drugs is discussed in this review.

  11. Optimization of a reversed-phase-high-performance thin-layer chromatography method for the separation of isoniazid, ethambutol, rifampicin and pyrazinamide in fixed-dose combination antituberculosis tablets.

    Science.gov (United States)

    Shewiyo, D H; Kaale, E; Risha, P G; Dejaegher, B; Smeyers-Verbeke, J; Vander Heyden, Y

    2012-10-19

    This paper presents the development of a new RP-HPTLC method for the separation of pyrazinamide, isoniazid, rifampicin and ethambutol in a four fixed-dose combination (4 FDC) tablet formulation. It is a single method with two steps in which after plate development pyrazinamide, isoniazid and rifampicin are detected at an UV wavelength of 280 nm. Then ethambutol is derivatized and detected at a VIS wavelength of 450 nm. Methanol, ethanol and propan-1-ol were evaluated modifiers to form alcohol-water mobile phases. Systematic optimization of the composition of each alcohol in the mobile phase was carried out using the window diagramming concept to obtain the best separation. Examination of the Rf distribution of the separated compounds showed that separation of the compounds with the mobile phase containing ethanol at the optimal fraction was almost situated within the optimal Rf-values region of 0.20-0.80. Therefore, ethanol was selected as organic modifier and the optimal mobile phase composition was found to be ethanol, water, glacial acetic acid (>99% acetic acid) and 37% ammonia solution (70/30/5/1, v/v/v/v). The method is new, quick and cheap compared to the actual method in the International Pharmacopoeia for the assay of the 4 FDC tablets, which involves the use of two separate HPLC methods. Copyright © 2012 Elsevier B.V. All rights reserved.

  12. Pulmonary Toxicity of Cholinesterase Inhibitors

    National Research Council Canada - National Science Library

    Hilmas, Corey; Adler, Michael; Baskin, Steven I; Gupta, Ramesh C

    2006-01-01

    .... Whereas nerve agents were produced primarily for military deployment, other cholinesterase inhibitors were used for treating conditions such as myasthenia gravis and as pretreaunents for nerve agent exposure...

  13. Isoniazid acetylating phenotype in patients with paracoccidioidomycosis and its relationship with serum sulfadoxin levels, glucose-6-phosphate dehydrogenase and glutathione reductase activities

    Directory of Open Access Journals (Sweden)

    Benedito Barraviera

    1991-06-01

    Full Text Available The authors evaluated the isoniazid acetylating phenotype and measured hematocrit, hemoglobin, glucose-6-phosphate dehydrogenase and glutathione reductase activities plus serum sulfadoxin levels in 39 patients with paracoccidioidomycosis (33 males and 6 females aged 17 to 58 years. Twenty one (53.84% of the patients presented a slow acetylatingphenotype and 18(46.16% a fast acetylating phenotype. Glucose-6-phosphate- dehydrogenase (G6PD acti vity was decreased in 5(23.80% slow acetylators and in 4(22.22% fast acetylators. Glutathione reductase activity was decreased in 14 (66.66% slow acetylators and in 12 (66.66% fast acetylators. Serum levels of free and total sulfadoxin Were higher in slow acetylator (p Os autores avaliaram o fenótipo acetilador da isoniazida, hematócrito, hemoglobina, atividade da glicose-6- fosfato desidrogenase, glutationa redutase e os níveis séricos de sulfadoxina de 39 doentes com paracoccidíoidomicose, senão 33 do sexo masculino e 6 do feminino, com idades compreendidas entre 17 e 58 anos. Vinte e um (53,84% doentes apresentaram fenótipo acetilador lento e 18 (46,16% rápido. A atividade da glicose-6-fosfato desidrogenase (G6PD esteve diminuída em 5 (23,80% acetiladores lentos e 4 (22,22% rápidos. A atividade da glutationa redutase esteve diminuída em 14 (66,66% acetiladores lentos e 12 (66,66% rápidos. Os níveis séricos de sulfadoxina livre e total foram maiores nos acetiladores lentos (p < 0,02. A análise dos resultados permite concluir que os níveis séricos de sulfadoxina relaciona-se com o fenótipo acetilador. Além disso, os níveis estiveram sempre acima de 50 µg/ml, níveis estes considerados terapêuticos. Por outro lado, a deficiência de glutationa redutase pode estar relacionada com a má absorção intestinal de nutrientes, entre eles riboflavina, vitamina precursora de FAD.

  14. The effect of isoniazid preventive therapy on incidence of tuberculosis among HIV-infected clients under pre-ART care, Jimma, Ethiopia: a retrospective cohort study.

    Science.gov (United States)

    Assebe, Lelisa Fekadu; Reda, Hailemariam Lemma; Wubeneh, Alem Desta; Lerebo, Wondwossen Terefe; Lambert, Saba Maria

    2015-04-10

    Tuberculosis (TB) is a major public health problem that accounts for almost half a million human immunodeficiency virus (HIV) associated deaths. Provision of isoniazid preventive therapy (IPT) is one of the public health interventions for the prevention of TB in HIV infected individuals. However, in Ethiopia, the coverage and implementation of IPT is limited. The objective of this study is to compare the incidence rate of TB, TB-free survival time and identify factors associated with development TB among HIV-infected individuals on pre-ART follow up. A retrospective cohort study was conducted from January, 2008 to February 31, 2012 in Jimma hospital. Kaplan-Meier survival plots were used to calculate the crude effect in both groups on TB-free survival probabilities and compared using the log rank test. A Cox proportional hazard model was used to identify predictors of TB. A total of 588 patients on pre-ART care (294 IPT and 294 non-IPT group) were followed retrospectively for a median duration of 24.1 months. The median CD4 (+) cell count was 422 cells/μl (IQR 344-589). During the follow up period, 49 individuals were diagnosed with tuberculosis, giving an overall incidence of 3.78 cases per 100 person year (PY). The incidence rate of TB was 5.06 per 100 PY in non-IPT group and 2.22 per 100 PY in IPT user group. Predictors of higher TB risk were: being on clinical WHO stage III/IV (adjusted hazard ratio (AHR = 3.05, 95% confidence interval (CI): 1.61, 5.81); non-IPT user (AHR = 2.02, 95% CI: 1.04, 3.92); having CD4 (+) cell count less than 350 cells/μl (AHR = 3.16, 95% CI: 1.04, 3.92) and between 350-499 cells/μl, (AHR = 2.87; 95% CI: 1.37-6.03) and having episode of opportunistic infection (OI) in the past (AHR = 2.41, 95% CI: 1.33-4.34). IPT use was associated with fifty percent reduction in new cases of tuberculosis and probability of developing TB was higher in non-IPT group. Implementing the widespread use of IPT has the potential to

  15. Encoded library technology as a source of hits for the discovery and lead optimization of a potent and selective class of bactericidal direct inhibitors of Mycobacterium tuberculosis InhA.

    Science.gov (United States)

    Encinas, Lourdes; O'Keefe, Heather; Neu, Margarete; Remuiñán, Modesto J; Patel, Amish M; Guardia, Ana; Davie, Christopher P; Pérez-Macías, Natalia; Yang, Hongfang; Convery, Maire A; Messer, Jeff A; Pérez-Herrán, Esther; Centrella, Paolo A; Alvarez-Gómez, Daniel; Clark, Matthew A; Huss, Sophie; O'Donovan, Gary K; Ortega-Muro, Fátima; McDowell, William; Castañeda, Pablo; Arico-Muendel, Christopher C; Pajk, Stane; Rullás, Joaquín; Angulo-Barturen, Iñigo; Alvarez-Ruíz, Emilio; Mendoza-Losana, Alfonso; Ballell Pages, Lluís; Castro-Pichel, Julia; Evindar, Ghotas

    2014-02-27

    Tuberculosis (TB) is one of the world's oldest and deadliest diseases, killing a person every 20 s. InhA, the enoyl-ACP reductase from Mycobacterium tuberculosis, is the target of the frontline antitubercular drug isoniazid (INH). Compounds that directly target InhA and do not require activation by mycobacterial catalase peroxidase KatG are promising candidates for treating infections caused by INH resistant strains. The application of the encoded library technology (ELT) to the discovery of direct InhA inhibitors yielded compound 7 endowed with good enzymatic potency but with low antitubercular potency. This work reports the hit identification, the selected strategy for potency optimization, the structure-activity relationships of a hundred analogues synthesized, and the results of the in vivo efficacy studies performed with the lead compound 65.

  16. Recent Natural Corrosion Inhibitors for Mild Steel: An Overview

    Directory of Open Access Journals (Sweden)

    Marko Chigondo

    2016-01-01

    Full Text Available Traditionally, reduction of corrosion has been managed by various methods including cathodic protection, process control, reduction of the metal impurity content, and application of surface treatment techniques, as well as incorporation of suitable alloys. However, the use of corrosion inhibitors has proven to be the easiest and cheapest method for corrosion protection and prevention in acidic media. These inhibitors slow down the corrosion rate and thus prevent monetary losses due to metallic corrosion on industrial vessels, equipment, or surfaces. Inorganic and organic inhibitors are toxic and costly and thus recent focus has been turned to develop environmentally benign methods for corrosion retardation. Many researchers have recently focused on corrosion prevention methods using green inhibitors for mild steel in acidic solutions to mimic industrial processes. This paper provides an overview of types of corrosion, corrosion process, and mainly recent work done on the application of natural plant extracts as corrosion inhibitors for mild steel.

  17. Potent Inhibitors against Newcastle Disease Virus Hemagglutinin-Neuraminidase.

    Science.gov (United States)

    Rota, Paola; La Rocca, Paolo; Piccoli, Marco; Montefiori, Marco; Cirillo, Federica; Olsen, Lars; Orioli, Marica; Allevi, Pietro; Anastasia, Luigi

    2018-02-06

    Neuraminidase activity is essential for the infection and propagation of paramyxoviruses, including human parainfluenza viruses (hPIVs) and the Newcastle disease virus (NDV). Thus, many inhibitors have been developed based on the 2-deoxy-2,3-didehydro-d-N-acetylneuraminic acid inhibitor (DANA) backbone. Along this line, herein we report a series of neuraminidase inhibitors, having C4 (p-toluenesulfonamido and azido substituents) and C5 (N-perfluorinated chains) modifications to the DANA backbone, resulting in compounds with 5- to 15-fold greater potency than the currently most active compound, the N-trifluoroacetyl derivative of DANA (FANA), toward the NDV hemagglutinin-neuraminidase (NDV-HN). Remarkably, these inhibitors were found to be essentially inactive against the human sialidase NEU3, which is present on the outer layer of the cell membrane and is highly affected by the current NDV inhibitor FANA. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Hepatoprotective agent tethered isoniazid for the treatment of drug-induced hepatotoxicity: Synthesis, biochemical and histopathological evaluation

    Directory of Open Access Journals (Sweden)

    Charan Singh

    2014-01-01

    Full Text Available The aim of the study was to investigate the protective effect of isoniazid–curcumin conjugate (INH–CRM in INH-induced hepatic injury by biochemical analysis and histology examination of liver in Wistar rats. The biochemical analysis included determination of the levels of plasma cholesterol, triglycerides (TG, albumin content, and lipid peroxidation (MDA. INH–CRM administration resulted in a significant decrease in plasma cholesterol, TG, and MDA levels in the liver tissue homogenate with an elevation in albumin level indicating its hepatoprotective activity. Histology of the liver further confirmed the reduction in hepatic injury. The hepatoprotective with INH–CRM can be attributed to the antioxidant activity of curcumin. The conjugate probably stabilizes the curcumin molecule, preventing its presystemic metabolism thereby enhancing its bioavailability and therefore, its hepatoprotective activity. Thus, the novel INH–CRM has the potential to alleviate INH-induced liver toxicity in antitubercular treatment.

  19. Participation of mitochondrial diazepam binding inhibitor receptors in the anticonflict, antineophobic and anticonvulsant action of 2-aryl-3-indoleacetamide and imidazopyridine derivatives.

    Science.gov (United States)

    Auta, J; Romeo, E; Kozikowski, A; Ma, D; Costa, E; Guidotti, A

    1993-05-01

    The 2-hexyl-indoleacetamide derivative, FGIN-1-27 [N,N-di-n-hexyl-2- (4-fluorophenyl)indole-3-acetamide], and the imidazopyridine derivative, alpidem, both bind with high affinity to glial mitochondrial diazepam binding inhibitor receptors (MDR) and increase mitochondrial steroidogenesis. Although FGIN-1-27 is selective for the MDR, alpidem also binds to the allosteric modulatory site of the gamma-aminobutyric acidA receptor where the benzodiazepines bind. FGIN-1-27 and alpidem, like the neurosteroid 3 alpha,21-dehydroxy-5 alpha-pregnane-20-one (THDOC), clonazepam and zolpidem (the direct allosteric modulators of gamma-aminobutyric acidA receptors) delay the onset of isoniazid and metrazol-induced convulsions. The anti-isoniazid convulsant action of FGIN-1-27 and alpidem, but not that of THDOC, is blocked by PK 11195. In contrast, flumazenil blocked completely the anticonvulsant action of clonazepam and zolpidem and partially blocked that of alpidem, but it did not affect the anticonvulsant action of THDOC and FGIN-1-27. Alpidem, like clonazepam, zolpidem and diazepam, but not THDOC or FGIN-1-27, delay the onset of bicuculline-induced convulsions. In two animal models of anxiety, the neophobic behavior in the elevated plus maze test and the conflict-punishment behavior in the Vogel conflict test, THDOC and FGIN-1-27 elicited anxiolytic-like effects in a manner that is flumazenil insensitive, whereas alpidem elicited a similar anxiolytic effect, but is partially blocked by flumazenil. Whereas PK 11195 blocked the effect of FGIN-1-27 and partially blocked alpidem, it did not affect THDOC in both animal models of anxiety.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. SEARCH OF NEW SYNTHETIC INHIBITORS OF TYROSINASE

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    Yu. Shesterenko

    2017-11-01

    Full Text Available Melanin pigmentation of skin plays the most important role in the protection of organism against UV-irradiation, but the excessive accumulation of melanin brings to toxic melanodermia, melasma, lentigo and other skin lesions. Tyrosinase is the key enzyme of skin melanin pigment biosynthesis. In spite of certain progress in investigation of natural and synthetic tyrosinase inhibitors, actuality of such studies is of a high level, because the existing inhibitors are in some cases unstable, expensive, toxic, requires complex methods of synthesis or isolation from natural sources. The aim of the work is screening of new tyrosinase inhibitors, using the enzyme, isolated from Agaricus bisporus. Tyrosinase was isolated from Agaricus bisporus mushrooms by a modified method. It was found, that the introduction of polyethylene glycol 4000 in the extraction process promotes 3-fold reduction of polyphenol content, which leads to increase purity of enzyme with an increase in its activity by 25%. A search for new tyrosinase inhibitors among a wide range of compounds, including derivatives of 3-chloro-1,4-naphthoquinone, isatin, 3-hydroxy-2-naphthoic acid, etc was conducted. The studied substances did not displayed inhibitory effect at concentration of 0,1-0,5 mmol/dm3.

  1. Biological abatement of cellulase inhibitors

    Science.gov (United States)

    Bio-abatement uses a fungus to metabolize and remove fermentation inhibitors. To determine whether bio-abatement could alleviate enzyme inhibitor effects observed in biomass liquors after pretreatment, corn stover at 10% (w/v) solids was pretreated with either dilute acid or liquid hot water. The ...

  2. RENAL SAFETY OF PROTON PUMP INHIBITORS

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    A. I. Dyadyk

    2017-01-01

    Full Text Available Proton pump inhibitors are a widely used in clinical practice, and are taken by millions of patients around the world for a long time. While proton pump inhibitors are well-tolerated class of drugs, the number of publications has been raised about adverse renal effects, specially their association with acute tubulointerstitial nephritis. It is one of the leading causes of acute renal injury and have catastrophic long-term consequences called chronic kidney disease. In this review, we consider epidemiology, pathogenesis, diagnostic criteria (including biopsy and morphological pattern, clinical manifestations and treatment of proton pump inhibitors-induced acute tubulointerstitial nephritis. A subclinical course without classical manifestations of a cell-mediated hypersensitivity reaction (fever, skin rash, eosinophilia, arthralgia is characteristic of acute tubulointerstitial nephritis. Increased serum creatinine, decreased glomerular filtration rate, electrolyte disorders, pathological changes in urine tests are not highly specific indicators, but allow to suspect the development of acute tubulointerstitial nephritis. The “gold” standard of diagnosis is the intravital morphological examination of the kidney tissue. Timely diagnosis and immediate discontinuation of the potentially causative drug is the mainstay of therapy and the first necessary step in the early management of suspected or biopsy-proven drug-induced acute tubulointerstitial nephritis. The usage of proton pump inhibitors should be performed only on strict indications with optimal duration of treatment and careful monitoring of kidney function. Multiple comorbidities (older age, heart failure, diabetes, cirrhosis, chronic kidney disease, hypovolemia increase potential nephrotoxicity. Awareness of this iatrogenic complication will improve diagnosis of proton pump inhibitors-induced acute tubulointerstitial nephritis by multidisciplinary specialists and increase the possibility

  3. F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort

    Science.gov (United States)

    Schwarz, John; Astermark, Jan; Menius, Erika D.; Carrington, Mary; Donfield, Sharyne M.; Gomperts, Edward D.; Nelson, George W.; Oldenburg, Johannes; Pavlova, Anna; Shapiro, Amy D.; Winkler, Cheryl A.; Berntorp, Erik

    2012-01-01

    Background Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII (FVIII) in hemophilia A. It has been suggested that differences in the distribution of factor VIII gene (F8) haplotypes, and mismatch between endogenous F8 haplotypes and those comprising products used for treatment could contribute to risk. Design and Methods Data from the HIGS Combined Cohort were used to determine the association between F8 haplotype 3 (H3) vs. haplotypes 1 and 2 (H1+H2) and inhibitor risk among individuals of genetically-determined African descent. Other variables known to affect inhibitor risk including type of F8 mutation and HLA were included in the analysis. A second research question regarding risk related to mismatch in endogenous F8 haplotype and recombinant FVIII products used for treatment was addressed. Results H3 was associated with higher inhibitor risk among those genetically-identified (N=49) as of African ancestry, but the association did not remain significant after adjustment for F8 mutation type and the HLA variables. Among subjects of all racial ancestries enrolled in HIGS who reported early use of recombinant products (N=223), mismatch in endogenous haplotype and the FVIII proteins constituting the products used did not confer greater risk for inhibitor development. Conclusion H3 was not an independent predictor of inhibitor risk. Further, our findings did not support a higher risk of inhibitors in the presence of a haplotype mismatch between the FVIII molecule infused and that of the individual. PMID:22958194

  4. High-throughput screening to identify inhibitors of lysine demethylases.

    Science.gov (United States)

    Gale, Molly; Yan, Qin

    2015-01-01

    Lysine demethylases (KDMs) are epigenetic regulators whose dysfunction is implicated in the pathology of many human diseases including various types of cancer, inflammation and X-linked intellectual disability. Particular demethylases have been identified as promising therapeutic targets, and tremendous efforts are being devoted toward developing suitable small-molecule inhibitors for clinical and research use. Several High-throughput screening strategies have been developed to screen for small-molecule inhibitors of KDMs, each with advantages and disadvantages in terms of time, cost, effort, reliability and sensitivity. In this Special Report, we review and evaluate the High-throughput screening methods utilized for discovery of novel small-molecule KDM inhibitors.

  5. HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

    DEFF Research Database (Denmark)

    Vanangamudi, Murugesan; Poongavanam, Vasanthanathan; Namasivayam, Vigneshwaran

    2017-01-01

    BACKGROUND: Design of inhibitors for HIV-1 reverse transcriptase inhibition (HIV-1 RT) is one of the successful chemotherapies for the treatment of HIV infection. Among the inhibitors available for HIV-1 RT, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have shown to be very promising......: The conformation dependent-alignment based (CoMFA and CoMSIA) methods have been proven very successful ligand based strategy in the drug design. Here, CoMFA and CoMSIA studies reported for structurally distinct NNRTIs including thiazolobenzimidazole, dipyridodiazepinone, 1,1,3-trioxo [1,2,4]-thiadiazine...

  6. Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus : Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications

    NARCIS (Netherlands)

    Heerspink, Hiddo J. L.; Perkins, Bruce A.; Fitchett, David H.; Husain, Mansoor; Cherney, David Z. I.

    2016-01-01

    Sodium-glucose cotransporter-2 (SGLT2) inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, are now widely approved antihyperglycemic therapies. Because of their unique glycosuric mechanism, SGLT2 inhibitors also reduce weight. Perhaps more important are the osmotic diuretic and

  7. A novel class of small molecule inhibitors of HDAC6.

    Science.gov (United States)

    Inks, Elizabeth S; Josey, Benjamin J; Jesinkey, Sean R; Chou, C James

    2012-02-17

    Histone deacetylases (HDACs) are a family of enzymes that play significant roles in numerous biological processes and diseases. HDACs are best known for their repressive influence on gene transcription through histone deacetylation. Mapping of nonhistone acetylated proteins and acetylation-modifying enzymes involved in various cellular pathways has shown protein acetylation/deacetylation also plays key roles in a variety of cellular processes including RNA splicing, nuclear transport, and cytoskeletal remodeling. Studies of HDACs have accelerated due to the availability of small molecule HDAC inhibitors, most of which contain a canonical hydroxamic acid or benzamide that chelates the metal catalytic site. To increase the pool of unique and novel HDAC inhibitor pharmacophores, a pharmacological active compound screen was performed. Several unique HDAC inhibitor pharmacophores were identified in vitro. One class of novel HDAC inhibitors, with a central naphthoquinone structure, displayed a selective inhibition profile against HDAC6. Here we present the results of a unique class of HDAC6 inhibitors identified using this compound library screen. In addition, we demonstrated that treatment of human acute myeloid leukemia cell line MV4-11 with the selective HDAC6 inhibitors decreases levels of mutant FLT-3 and constitutively active STAT5 and attenuates Erk phosphorylation, all of which are associated with the inhibitor's selective toxicity against leukemia.

  8. Serine protease inhibitors of parasitic helminths.

    Science.gov (United States)

    Molehin, Adebayo J; Gobert, Geoffrey N; McManus, Donald P

    2012-05-01

    Serine protease inhibitors (serpins) are a superfamily of structurally conserved proteins that inhibit serine proteases and play key physiological roles in numerous biological systems such as blood coagulation, complement activation and inflammation. A number of serpins have now been identified in parasitic helminths with putative involvement in immune regulation and in parasite survival through interference with the host immune response. This review describes the serpins and smapins (small serine protease inhibitors) that have been identified in Ascaris spp., Brugia malayi, Ancylostoma caninum Onchocerca volvulus, Haemonchus contortus, Trichinella spiralis, Trichostrongylus vitrinus, Anisakis simplex, Trichuris suis, Schistosoma spp., Clonorchis sinensis, Paragonimus westermani and Echinococcus spp. and discusses their possible biological functions, including roles in host-parasite interplay and their evolutionary relationships.

  9. Secreted and Transmembrane Wnt Inhibitors and Activators

    Science.gov (United States)

    Cruciat, Cristina-Maria; Niehrs, Christof

    2013-01-01

    Signaling by the Wnt family of secreted glycoproteins plays important roles in embryonic development and adult homeostasis. Wnt signaling is modulated by a number of evolutionarily conserved inhibitors and activators. Wnt inhibitors belong to small protein families, including sFRP, Dkk, WIF, Wise/SOST, Cerberus, IGFBP, Shisa, Waif1, APCDD1, and Tiki1. Their common feature is to antagonize Wnt signaling by preventing ligand–receptor interactions or Wnt receptor maturation. Conversely, the Wnt activators, R-spondin and Norrin, promote Wnt signaling by binding to Wnt receptors or releasing a Wnt-inhibitory step. With few exceptions, these antagonists and agonists are not pure Wnt modulators, but also affect additional signaling pathways, such as TGF-β and FGF signaling. Here we discuss their interactions with Wnt ligands and Wnt receptors, their role in developmental processes, as well as their implication in disease. PMID:23085770

  10. Raltegravir: first in class HIV integrase inhibitor

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    Zelalem Temesgen

    2008-06-01

    Full Text Available Zelalem Temesgen1, Dawd S Siraj21Mayo Clinic, Rochester, MN, USA; 2East Carolina University Greenville, NC, USAAbstract: On October 16, 2007, the US Food and Drug Administration (FDA approved raltegravir for treatment of human immunodeficiency virus (HIV-1 infection in combination with other antiretroviral agents in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. Raltegravir is first in a novel class of antiretroviral drugs known as integrase inhibitors. It has demonstrated potent anti HIV activity in both antiretroviral treatment-naïve and experienced patients. The most common adverse events reported with raltegravir during phase 2 and 3 clinical trials were diarrhea, nausea, and headache. Laboratory abnormalities include mild elevations in liver transaminases and creatine phosphokinase.Keywords: raltegravir, HIV, antiretroviral agents, integrase inhibitors

  11. Potent peptidic fusion inhibitors of influenza virus

    Energy Technology Data Exchange (ETDEWEB)

    Kadam, Rameshwar U.; Juraszek, Jarek; Brandenburg, Boerries; Buyck, Christophe; Schepens, Wim B. G.; Kesteleyn, Bart; Stoops, Bart; Vreeken, Rob J.; Vermond, Jan; Goutier, Wouter; Tang, Chan; Vogels, Ronald; Friesen, Robert H. E.; Goudsmit, Jaap; van Dongen, Maria J. P.; Wilson, Ian A.

    2017-09-28

    Influenza therapeutics with new targets and mechanisms of action are urgently needed to combat potential pandemics, emerging viruses, and constantly mutating strains in circulation. We report here on the design and structural characterization of potent peptidic inhibitors of influenza hemagglutinin. The peptide design was based on complementarity-determining region loops of human broadly neutralizing antibodies against the hemagglutinin (FI6v3 and CR9114). The optimized peptides exhibit nanomolar affinity and neutralization against influenza A group 1 viruses, including the 2009 H1N1 pandemic and avian H5N1 strains. The peptide inhibitors bind to the highly conserved stem epitope and block the low pH–induced conformational rearrangements associated with membrane fusion. These peptidic compounds and their advantageous biological properties should accelerate the development of new small molecule– and peptide-based therapeutics against influenza virus.

  12. Reverse transcriptase inhibitors as microbicides.

    Science.gov (United States)

    Lewi, Paul; Heeres, Jan; Ariën, Kevin; Venkatraj, Muthusamy; Joossens, Jurgen; Van der Veken, Pieter; Augustyns, Koen; Vanham, Guido

    2012-01-01

    The CAPRISA 004 study in South Africa has accelerated the development of vaginal and rectal microbicides containing antiretrovirals that target specific enzymes in the reproduction cycle of HIV, especially reverse transcriptase inhibitors (RTI). In this review we discuss the potential relevance of HIV-1 RTIs as microbicides, focusing in the nucleotide RTI tenofovir and six classes of nonnucleoside RTIs (including dapivirine, UC781, urea and thiourea PETTs, DABOs and a pyrimidinedione). Although tenofovir and dapivirine appear to be most advanced in clinical trials as potential microbicides, several issues remain unresolved, e.g., the importance of nonhuman primates as a "gatekeeper" for clinical trials, the emergence and spread of drug-resistant mutants, the combination of microbicides that target different phases of viral reproduction and the accessibility to microbicides in low-income countries. Thus, here we discuss the latest research on RTI as microbicides in the light of the continuing spread of the HIV pandemic from the point of view of medicinal chemistry, virological, and pharmaceutical studies.

  13. Use of selective-serotonin reuptake inhibitors and platelet aggregation inhibitors among individuals with co-occurring atherosclerotic cardiovascular disease and depression or anxiety

    Directory of Open Access Journals (Sweden)

    J Douglas Thornton

    2016-12-01

    Full Text Available Objective: Medications commonly used to treat heart disease, anxiety, and depression can interact resulting in an increased risk of bleeding, warranting a cautious approach in medical decision making. This retrospective, descriptive study examined the prevalence and the factors associated with the use of both selective-serotonin reuptake inhibitor and platelet aggregation inhibitor among individuals with co-occurring atherosclerotic cardiovascular disease and anxiety or depression. Methods: Respondents aged 22 years and older, alive throughout the study period, and diagnosed with co-occurring atherosclerotic cardiovascular disease and anxiety or depression (n = 1507 in years 2007 through 2013 of the Medical Expenditures Panel Survey were included. The use of treatment was grouped as follows: selective-serotonin reuptake inhibitor and platelet aggregation inhibitor, selective-serotonin reuptake inhibitor or platelet aggregation inhibitor, and neither selective-serotonin reuptake inhibitor nor platelet aggregation inhibitor. Results: Overall, 16.5% used both selective-serotonin reuptake inhibitor and platelet aggregation inhibitor, 61.2% used selective-serotonin reuptake inhibitor or platelet aggregation inhibitor, and 22.3% used neither selective-serotonin reuptake inhibitor nor platelet aggregation inhibitor. Respondents aged over 65 years (adjusted odds ratio = 1.93 (95% confidence interval = 1.08–3.45 and having a diagnosis of diabetes (adjusted odds ratio = 1.63 (95% confidence interval = 1.15–2.31 and hypertension (adjusted odds ratio = 1.84 (95% confidence interval = 1.04–3.27 were more likely to be prescribed the combination. Conclusion: The drug interaction was prevalent in patients who are already at higher risk of health disparities and worse outcomes thus requiring vigilant evaluation.

  14. [ACE inhibitors and the kidney].

    Science.gov (United States)

    Hörl, W H

    1996-01-01

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

  15. Tetomilast: new promise for phosphodiesterase-4 inhibitors?

    Science.gov (United States)

    Bickston, Stephen J; Snider, Kenneth R; Kappus, Matthew R

    2012-12-01

    Tetomilast is a novel thiazole phosphodiesterase-4 (PDE-4) inhibitor, which may prove useful in both the treatment of inflammatory bowel disease (IBD) and chronic obstructive pulmonary disease (COPD). Here, the authors review the pharmacology of the drug, and offer critical review of the available data for use of tetomilast in the treatment of IBD. Peer-reviewed publications, including Phase I and II clinical trials, all other formats included. Tetomilast may be beneficial in IBD. Small differences in molecules and in recombinant proteins can translate into substantial differences in clinical effects and toxicity in IBD. This is a reasonable approach when exploring new options like tetomilast.

  16. Janus Associated Kinases Inhibitors in the Pharmacological Thera

    Directory of Open Access Journals (Sweden)

    Daniela Santos1

    2017-01-01

    Full Text Available Janus associated kinases inhibitors are a new strategy for the treatment of different clinical conditions like immunologic, inflammatory and oncology disorders. The aim of this study was to perform a review of all Janus associated kinases inhibitors available in national and international pharmaceutical market, their therapeutic indications and adverse effects, and the potential indications for investigation of those already available in the pharmaceutical market. It was also performed a review of the main new Janus associated kinases inhibitors that are still in clinical research. A literature review was conducted by consulting the summary of product characteristics of Janus associated kinases inhibitors available in the pharmaceutical market and a research in the bibliographic database PubMed using the terms «JAK inhibitors», «Janus associated kinases inhibitors» and «Janus kinases inhibitors». Ninety-five publications were included in the present review, published from January 2014 to January 2015. Drug databases of the European Medicines Agency and United States Food and Drug Administration were also consulted to search for Janus associated kinases inhibitors authorized in clinical practice. Currently, ruxolitinib and tofacitinib are available in the pharmaceutical market and oclatinib is approved as a veterinary medicinal product. Both drugs approved for human use have major adverse effects at hematological and immunological levels, which enhance the importance of the pharmacist’s role in the monitoring of patients involved in these treatments. However, several molecules are in pre-clinical and clinical studies trying to prove its potential in the treatment of several immunologic, inflammatory and oncology disorders. Thus, it is still necessary to deepen the knowledge in this area in order to overcome the risks of therapy with these agents. These risks weighed against the benefits of its clinical use have compromised the progress of

  17. Acquired high titre factor VIII inhibitor with underlying polyarteritis nodosa.

    Science.gov (United States)

    Snowden, J A; Hutchings, M; Spearing, R; Patton, W N

    1997-05-01

    We here present the case of a 70-year-old woman referred to our unit for investigation of bleeding. Investigations confirmed a high titre acquired Factor VIII inhibitor. In association there was relapse of systemic illness associated with anti-neutrophil cytoplasmic antibodies (atypical pattern) for which she had been treated five years previously. Immunosuppression was attempted, but it failed to have an impact both on the inhibitor titre and on the underlying disorder. The patient died from multi-organ failure and massive chest hemorrhage. Post-mortem showed necrotizing vasculitis of medium sized vessels at several sites, including the kidney, consistent with a diagnosis of polyarteritis nodosa. Although it is well recognised that Factor VIII inhibitors are found in conjunction with autoimmune disorders, this case is significant in that it is the first associated with histologically proven polyarteritis nodosa type vasculitis. The case illustrates the difficulties in the investigation and management of patients with acquired high titre Factor VIII inhibitors.

  18. Inhibitors of polyamine metabolism: review article.

    Science.gov (United States)

    Wallace, H M; Fraser, A V

    2004-07-01

    The identification of increased polyamine concentrations in a variety of diseases from cancer and psoriasis to parasitic infections has led to the hypothesis that manipulation of polyamine metabolism is a realistic target for therapeutic or preventative intervention in the treatment of certain diseases. The early development of polyamine biosynthetic single enzyme inhibitors such as alpha-difluoromethylornithine (DFMO) and methylglyoxal bis(guanylhydrazone) showed some interesting early promise as anticancer drugs, but ultimately failed in vivo. Despite this, DFMO is currently in use as an effective anti-parasitic agent and has recently also been shown to have further potential as a chemopreventative agent in colorectal cancer. The initial promise in vitro led to the development and testing of other potential inhibitors of the pathway namely the polyamine analogues. The analogues have met with greater success than the single enzyme inhibitors possibly due to their multiple targets. These include down regulation of polyamine biosynthesis through inhibition of ornithine decarboxylase and S-adenosylmethionine decarboxylase and decreased polyamine uptake. This coupled with increased activity of the catabolic enzymes, polyamine oxidase and spermidine/spermine N1-acetyltransferase, and increased polyamine export has made the analogues more effective in depleting polyamine pools. Recently, the identification of a new oxidase (PAO-h1/SMO) in polyamine catabolism and evidence of induction of both PAO and PAO-h1/SMO in response to polyamine analogue treatment, suggests the analogues may become an important part of future chemotherapeutic and/or chemopreventative regimens.

  19. Recent advances in botulinum neurotoxin inhibitor development.

    Science.gov (United States)

    Kiris, Erkan; Burnett, James C; Kane, Christopher D; Bavari, Sina

    2014-01-01

    Botulinum neurotoxins (BoNTs) are endopeptidases that target motor neurons and block acetylcholine neurotransmitter release. This action results in the muscle paralysis that defines the disease botulism. To date, there are no FDA-approved therapeutics to treat BoNT-mediated paralysis after intoxication of the motor neuron. Importantly, the rationale for pursuing treatments to counter these toxins is driven by their potential misuse. Current drug discovery efforts have mainly focused on small molecules, peptides, and peptidomimetics that can directly and competitively inhibit BoNT light chain proteolytic activity. Although this is a rational approach, direct inhibition of the Zn(2+) metalloprotease activity has been elusive as demonstrated by the dearth of candidates undergoing clinical evaluation. Therefore, broadening the scope of viable targets beyond that of active site protease inhibitors represents an additional strategy that could move the field closer to the clinic. Here we review the rationale, and discuss the outcomes of earlier approaches and highlight potential new targets for BoNT inhibition. These include BoNT uptake and processing inhibitors, enzymatic inhibitors, and modulators of neuronal processes associated with toxin clearance, neurotransmitter potentiation, and other pathways geared towards neuronal recovery and repair.

  20. Enhancement of antibiotic activity by efflux inhibitors against multidrug resistant Mycobacterium tuberculosis clinical isolates from Brazil

    Directory of Open Access Journals (Sweden)

    Tatiane eCoelho

    2015-04-01

    Full Text Available Drug resistant tuberculosis continues to increase and new approaches for its treatment are necessary. The identification of M. tuberculosis clinical isolates presenting efflux as part of their resistant phenotype has a major impact in tuberculosis treatment. In this work, we used a checkerboard procedure combined with the tetrazolium microplate-based assay (TEMA to study single combinations between antituberculosis drugs and efflux inhibitors (EIs against multidrug resistant M. tuberculosis clinical isolates using the fully susceptible strain H37Rv as reference. Efflux activity was studied on a real-time basis by a fluorometric method that uses ethidium bromide as efflux substrate. Quantification of efflux pump genes mRNA transcriptional levels were performed by RT-qPCR. The fractional inhibitory concentrations (FIC indicated synergistic activity for the interactions between isoniazid, rifampicin, amikacin, ofloxacin, and ethidium bromide plus the EIs verapamil, thioridazine and chlorpromazine. The FICs ranged from 0.25, indicating a four-fold reduction on the MICs, to 0.015, 64-fold reduction. The detection of active efflux by real-time fluorometry showed that all strains presented intrinsic efflux activity that contributes to the overall resistance which can be inhibited in the presence of the EIs. The quantification of the mRNA levels of the most important efflux pump genes on these strains shows that they are intrinsically predisposed to expel toxic compounds as the exposure to subinhibitory concentrations of antibiotics were not necessary to increase the pump mRNA levels when compared with the non-exposed counterpart. The results obtained in this study confirm that the intrinsic efflux activity contributes to the overall resistance in multidrug resistant clinical isolates of M. tuberculosis and that the inhibition of efflux pumps by the EIs can enhance the clinical effect of antibiotics that are their substrates.

  1. GSK-3 inhibitors induce chromosome instability

    Directory of Open Access Journals (Sweden)

    Staples Oliver D

    2007-08-01

    Full Text Available Abstract Background Several mechanisms operate during mitosis to ensure accurate chromosome segregation. However, during tumour evolution these mechanisms go awry resulting in chromosome instability. While several lines of evidence suggest that mutations in adenomatous polyposis coli (APC may promote chromosome instability, at least in colon cancer, the underlying mechanisms remain unclear. Here, we turn our attention to GSK-3 – a protein kinase, which in concert with APC, targets β-catenin for proteolysis – and ask whether GSK-3 is required for accurate chromosome segregation. Results To probe the role of GSK-3 in mitosis, we inhibited GSK-3 kinase activity in cells using a panel of small molecule inhibitors, including SB-415286, AR-A014418, 1-Azakenpaullone and CHIR99021. Analysis of synchronised HeLa cells shows that GSK-3 inhibitors do not prevent G1/S progression or cell division. They do, however, significantly delay mitotic exit, largely because inhibitor-treated cells have difficulty aligning all their chromosomes. Although bipolar spindles form and the majority of chromosomes biorient, one or more chromosomes often remain mono-oriented near the spindle poles. Despite a prolonged mitotic delay, anaphase frequently initiates without the last chromosome aligning, resulting in chromosome non-disjunction. To rule out the possibility of "off-target" effects, we also used RNA interference to selectively repress GSK-3β. Cells deficient for GSK-3β exhibit a similar chromosome alignment defect, with chromosomes clustered near the spindle poles. GSK-3β repression also results in cells accumulating micronuclei, a hallmark of chromosome missegregation. Conclusion Thus, not only do our observations indicate a role for GSK-3 in accurate chromosome segregation, but they also raise the possibility that, if used as therapeutic agents, GSK-3 inhibitors may induce unwanted side effects by inducing chromosome instability.

  2. 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.

  3. Adverse Effects of COX-2 Inhibitors

    Directory of Open Access Journals (Sweden)

    Jagdish N. Sharma

    2005-01-01

    Full Text Available Cyclooxygenase-2 selective inhibitors (COXIBs were developed with the prime object of minimizing gastrointestinal adverse effects, which are seen with the use of traditional nonsteroidal anti-inflammatory drugs (NSAIDs. Their long-term use is limited by the development of hypertension, edema, and congestive heart failure in a significant proportion of patients. NSAIDs block the activity of both COX isozymes, COX-1 and COX-2, which mediate the enzymatic conversion of arachidonate to prostaglandin H2 (PGH2 and other prostaglandin (PG metabolites. It is well established that the cardiovascular profile of COX-2 inhibitors can be accounted for by inhibition of COX-dependent PG synthesis. Following the COX-mediated synthesis of PGH2 from arachidonate, PGH2 is metabolized to one of at least five bioactive PGs, including PGE2, PGI2, PGF2, PGD2, or thromboxane A2 (TXA2. These prostanoids have pleiotropic cardiovascular effects, altering platelet function and renal function, and they are acting either as vasodilators or vasoconstrictors. Although COX-1 and COX-2 exhibit similar biochemical activity in converting arachidonate to PGH2in vitro, the ultimate prostanoids they produce in vivo may be different due to differential regulation of COX-1 and COX-2, tissue distribution, and availability of the prostanoid synthases. PGs have been established as being critically involved in mitigating hypertension, helping to maintain medullary blood flow (MBF, promoting urinary salt excretion, and preserving the normal homeostasis of thrombosis, and the researchers found that the use of COX-2 inhibitors caused many serious complications in altering the normal body homeostasis. The purpose of the present research is to explain briefly the side effects of COX-2 inhibitors on the renal and cardiovascular system.

  4. (including travel dates) Proposed itinerary

    Indian Academy of Sciences (India)

    Ashok

    31 July to 22 August 2012 (including travel dates). Proposed itinerary: Arrival in Bangalore on 1 August. 1-5 August: Bangalore, Karnataka. Suggested institutions: Indian Institute of Science, Bangalore. St Johns Medical College & Hospital, Bangalore. Jawaharlal Nehru Centre, Bangalore. 6-8 August: Chennai, TN.

  5. Metal corrosion inhibitors and ecology

    International Nuclear Information System (INIS)

    Krasts, H.; Svarce, J.; Berge, B.

    1999-01-01

    The use of metal corrosion inhibitors in water is one of the cheapest method to protect metals against corrosion. However, the used inhibitors can come to surface water in the course of time and can become as source of environmental pollution. It is important to co-ordinate amount of substances in the elaborated inhibitors not only with demands for metal protection, but also with demands for quality of surface water and drinking water according to normative statements: 3.5 mg/l (as PO 4 ) for hexametaphosphate, tripolyphosphate and phosphonate; 40 mg/l (as SiO 2 for silicate, up to 1 mg/l for CU 2+ ; up to 5 mg/l for Zn 2+ ; up to 1 mg/l for B; up to 0.5 mg/l for Mo 2+ . The examples of the elaborated inhibitors are given. Many organic substances can be used as corrosion inhibitors, but there is shortage of standard methods for their analysis in water in Latvia. Removing of salt's deposits from boilers needs elaboration of a separate normative statement for dispersing waste water which content chloride at high concentration and heavy metals. (authors)

  6. Theory including future not excluded

    DEFF Research Database (Denmark)

    Nagao, K.; Nielsen, H.B.

    2013-01-01

    We study a complex action theory (CAT) whose path runs over not only past but also future. We show that, if we regard a matrix element defined in terms of the future state at time T and the past state at time TA as an expectation value in the CAT, then we are allowed to have the Heisenberg equation......, Ehrenfest's theorem, and the conserved probability current density. In addition,we showthat the expectation value at the present time t of a future-included theory for large T - t and large t - T corresponds to that of a future-not-included theory with a proper inner product for large t - T. Hence, the CAT...

  7. 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

  8. ROCK inhibitors in ocular disease

    Directory of Open Access Journals (Sweden)

    Eva Halasz

    2016-12-01

    Full Text Available Rho kinases (ROCKs have a crucial role in actin-cytoskeletal reorganization and thus are involved in broad aspects of cell motility, from smooth muscle contraction to neurite outgrowth. The first marketed ROCK inhibitor, called fasudil, has been used safely for treatment of cerebral vasospasm since 1995 in Japan. During the succeeding decades ROCK inhibitors have been applied in many pathological conditions from central nervous system disorders to cardiovascular disease as potential therapeutic agents or experimental tools to help understand the underlying (pathomechanisms. In 2014, a fasudil derivate named ripasudil was accepted for clinical use in glaucoma and ocular hypertension. Since ROCK kinases are widely expressed in ocular tissues, they have been implicated in the pathology of many ocular conditions such as corneal dysfunction, glaucoma, cataract, diabetic retinopathy, age-related macular degeneration, and retinal detachment. This paper aims to provide an overview of the most recent status/application of ROCK inhibitors in the field of eye disease.

  9. Synthesis and Application of Pyrrolidone-containing Shale Inhibitors

    Science.gov (United States)

    Liu, Yonggui; Hou, Jie; Zhang, Yang; Yan, Jing; Song, Tao; Xu, Yongjun

    2018-03-01

    New generation polyamine inhibitors are amino-terminated polyethers with excellent inhibiting capabilities; they play a key role in borehole stabilization and reservoir protection. However, polyamine inhibitors are limited by their poor thermal stability, which can be attributed to the presence of ether bonds in their molecular structures. We propose a three-step synthesis approach fora novel pyrrolidone-containing polyamine inhibitor (DYNP) by introducing N-vinyl-2-pyrrolidone (NVP) on divinyloxyethane. This polyamine inhibitor exhibits an optimized molecular structure and has enhanced heat resistance. Characterizations by infrared (IR) spectroscopy and evaluation tests demonstrate several advantages of DYNP inhibitors, including excellent inhibiting capability (superior to similar materials such as polyamines), improved heat resistance (reasonable stability at temperatures up to 240°C), and good compatibility with both fresh water and salt water drilling fluids. These can be attributed to the presence of considerable amounts of amino groups in the repeating unit of DYNP molecules. The DYNP inhibitor was applied in over 20 boreholes in tight oil blocks in Daqing Oilfield to relieve hydration of formations with high shale contents. For instance, drilling in the 2033.5m horizontal section of Dragon 2 borehole was smooth, with a borehole diameter expansion ratio below 10%.

  10. Inhibition of matrix metalloproteinase-2 by PARP inhibitors

    International Nuclear Information System (INIS)

    Nicolescu, Adrian C.; Holt, Andrew; Kandasamy, Arulmozhi D.; Pacher, Pal; Schulz, Richard

    2009-01-01

    Matrix metalloproteinase-2 (MMP-2), a ubiquitously expressed zinc-dependent endopeptidase, and poly(ADP-ribosyl) polymerase (PARP), a nuclear enzyme regulating DNA repair, are activated by nitroxidative stress associated with various pathologies. As MMP-2 plays a detrimental role in heart injuries resulting from enhanced nitroxidative stress, where PARP and MMP inhibitors are beneficial, we hypothesized that PARP inhibitors may affect MMP-2 activity. Using substrate degradation assays to determine MMP-2 activity we found that four PARP inhibitors (3-AB, PJ-34, 5-AIQ, and EB-47) inhibited 64 kDa MMP-2 in a concentration-dependent manner. The IC 50 values of PJ-34 and 5-AIQ were in the high micromolar range and comparable to those of known MMP-2 inhibitors doxycycline, minocycline or o-phenanthroline, whereas those for 3-AB and EB-47 were in the millimolar range. Co-incubation of PARP inhibitors with doxycycline showed an additive inhibition of MMP-2 that was significant for 3-AB alone. These data demonstrate that the protective effects of some PARP inhibitors may include inhibition of MMP-2 activity.

  11. Inhibition of matrix metalloproteinase-2 by PARP inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Nicolescu, Adrian C.; Holt, Andrew; Kandasamy, Arulmozhi D. [Departments of Pharmacology and Pediatrics, Cardiovascular Research Centre, University of Alberta, Edmonton, Alta., Canada T6G 2S2 (Canada); Pacher, Pal [National Institutes of Health, NIAAA, Laboratory of Physiologic Studies, Bethesda, MD (United States); Schulz, Richard, E-mail: richard.schulz@ualberta.ca [Departments of Pharmacology and Pediatrics, Cardiovascular Research Centre, University of Alberta, Edmonton, Alta., Canada T6G 2S2 (Canada)

    2009-10-02

    Matrix metalloproteinase-2 (MMP-2), a ubiquitously expressed zinc-dependent endopeptidase, and poly(ADP-ribosyl) polymerase (PARP), a nuclear enzyme regulating DNA repair, are activated by nitroxidative stress associated with various pathologies. As MMP-2 plays a detrimental role in heart injuries resulting from enhanced nitroxidative stress, where PARP and MMP inhibitors are beneficial, we hypothesized that PARP inhibitors may affect MMP-2 activity. Using substrate degradation assays to determine MMP-2 activity we found that four PARP inhibitors (3-AB, PJ-34, 5-AIQ, and EB-47) inhibited 64 kDa MMP-2 in a concentration-dependent manner. The IC{sub 50} values of PJ-34 and 5-AIQ were in the high micromolar range and comparable to those of known MMP-2 inhibitors doxycycline, minocycline or o-phenanthroline, whereas those for 3-AB and EB-47 were in the millimolar range. Co-incubation of PARP inhibitors with doxycycline showed an additive inhibition of MMP-2 that was significant for 3-AB alone. These data demonstrate that the protective effects of some PARP inhibitors may include inhibition of MMP-2 activity.

  12. Thermal runaway inhibitors

    Science.gov (United States)

    Mandal, Braja K.; Filler, Robert

    2004-06-08

    The present invention provides for a battery having an anode, a cathode, and a flame-retarding electrolyte with a conductivity greater than about 10.sup.-3 S/cm at ambient temperature and which includes a compound that chemically interferes with flame propagation.

  13. Inhibitors of histone deacetylase

    DEFF Research Database (Denmark)

    2015-01-01

    of the invention are useful for treating, alleviating, and/or preventing various conditions, including for example, a metabolic disorder such as type 1 or type 2 diabetes, dyslipidemias, lipodystrophies, liver disease associated with metabolic syndrome, polycystic ovarian syndrome, or obesity; inflammatory disease...

  14. Costs and utilization of hemophilia A and B patients with and without inhibitors.

    Science.gov (United States)

    Armstrong, Edward P; Malone, Daniel C; Krishnan, Sangeeta; Wessler, Maj Jacob

    2014-11-01

    To evaluate the health system costs among patients with hemophilia A and B with and without inhibitors over 5 years. This was a retrospective, observational study utilizing medical and pharmacy electronic medical records and administrative encounters/claims data tracking US patients between 2006-2011. Patients with diagnosis codes for hemophilia A and B were identified. Patients with inhibitors were characterized by utilization of bypassing agents activated prothrombin complex concentrate or factor VIIa on two or more distinct dates. Severity was classified as mild, moderate, or severe based on laboratory tests of clotting factor. There were 160 hemophilia A patients and 54 hemophilia B patients identified. From this group, seven were designated as patients with inhibitors (five with hemophilia A and two with hemophilia B). Hemophilia A patients without inhibitors reported 65 (41.9%) as being severe, 19 (12.3%) as moderate, and 71 (45.8%) as mild. Hemophilia B patients without inhibitors reported nine (17.3%) had severe, 13 (25.0%) had moderate, and 30 (57.7%) had mild hemophilia. All patients with inhibitors had been hospitalized in the previous 5 years compared to 64 (41.3%) with hemophilia A without inhibitors and 22 (42.3%) with hemophilia B without inhibitors. The median aggregate cost per year (including factor and health resource use) was $325,780 for patients with inhibitors compared to $98,334 for hemophilia A patients without inhibitors and $23,265 for hemophilia B patients without inhibitors. The results suggest that, while the frequency of inhibitors within the hemophilia cohort was low, there was a higher frequency of hospitalizations, and the associated median aggregate costs per year were 3-fold higher than those patients without inhibitors. In contrast, hemophilia B patients experience less severe disease and account for lower aggregate yearly costs compared to either patients with hemophilia A or patients with inhibitors.

  15. Device including a contact detector

    DEFF Research Database (Denmark)

    2011-01-01

    arms (12) may extend from the supporting body in co-planar relationship with the first surface. The plurality of cantilever arms (12) may extend substantially parallel to each other and each of the plurality of cantilever arms (12) may include an electrical conductive tip for contacting the area......The present invention relates to a probe for determining an electrical property of an area of a surface of a test sample, the probe is intended to be in a specific orientation relative to the test sample. The probe may comprise a supporting body defining a first surface. A plurality of cantilever...... of the test sample by movement of the probe relative to the surface of the test sample into the specific orientation.; The probe may further comprise a contact detector (14) extending from the supporting body arranged so as to contact the surface of the test sample prior to any one of the plurality...

  16. Neoclassical transport including collisional nonlinearity.

    Science.gov (United States)

    Candy, J; Belli, E A

    2011-06-10

    In the standard δf theory of neoclassical transport, the zeroth-order (Maxwellian) solution is obtained analytically via the solution of a nonlinear equation. The first-order correction δf is subsequently computed as the solution of a linear, inhomogeneous equation that includes the linearized Fokker-Planck collision operator. This equation admits analytic solutions only in extreme asymptotic limits (banana, plateau, Pfirsch-Schlüter), and so must be solved numerically for realistic plasma parameters. Recently, numerical codes have appeared which attempt to compute the total distribution f more accurately than in the standard ordering by retaining some nonlinear terms related to finite-orbit width, while simultaneously reusing some form of the linearized collision operator. In this work we show that higher-order corrections to the distribution function may be unphysical if collisional nonlinearities are ignored.

  17. Aromatic inhibitors derived from ammonia-pretreated lignocellulose hinder bacterial ethanologenesis by activating regulatory circuits controlling inhibitor efflux and detoxification

    Directory of Open Access Journals (Sweden)

    David H. Keating

    2014-08-01

    Full Text Available Efficient microbial conversion of lignocellulosic hydrolysates to biofuels is a key barrier to the economically viable deployment of lignocellulosic biofuels. A chief contributor to this barrier is the impact on microbial processes and energy metabolism of lignocellulose-derived inhibitors, including phenolic carboxylates, phenolic amides (for ammonia-pretreated biomass, phenolic aldehydes, and furfurals. To understand the bacterial pathways induced by inhibitors present in ammonia-pretreated biomass hydrolysates, which are less well studied than acid-pretreated biomass hydrolysates, we developed and exploited synthetic mimics of ammonia-pretreated corn stover hydrolysate (ACSH. To determine regulatory responses to the inhibitors normally present in ACSH, we measured transcript and protein levels in an Escherichia coli ethanologen using RNA-seq and quantitative proteomics during fermentation to ethanol of synthetic hydrolysates containing or lacking the inhibitors. Our study identified four major regulators mediating these responses, the MarA/SoxS/Rob network, AaeR, FrmR, and YqhC. Induction of these regulons was correlated with a reduced rate of ethanol production, buildup of pyruvate, depletion of ATP and NAD(PH, and an inhibition of xylose conversion. The aromatic aldehyde inhibitor 5-hydroxymethylfurfural appeared to be reduced to its alcohol form by the ethanologen during fermentation, whereas phenolic acid and amide inhibitors were not metabolized. Together, our findings establish that the major regulatory responses to lignocellulose-derived inhibitors are mediated by transcriptional rather than translational regulators, suggest that energy consumed for inhibitor efflux and detoxification may limit biofuel production, and identify a network of regulators for future synthetic biology efforts.

  18. Azidoblebbistatin, a photoreactive myosin inhibitor

    Science.gov (United States)

    Képiró, Miklós; Várkuti, Boglárka H.; Bodor, Andrea; Hegyi, György; Drahos, László; Kovács, Mihály; Málnási-Csizmadia, András

    2012-01-01

    Photoreactive compounds are important tools in life sciences that allow precisely timed covalent crosslinking of ligands and targets. Using a unique technique we have synthesized azidoblebbistatin, which is a derivative of blebbistatin, the most widely used myosin inhibitor. Without UV irradiation azidoblebbistatin exhibits identical inhibitory properties to those of blebbistatin. Using UV irradiation, azidoblebbistatin can be covalently crosslinked to myosin, which greatly enhances its in vitro and in vivo effectiveness. Photo-crosslinking also eliminates limitations associated with the relatively low myosin affinity and water solubility of blebbistatin. The wavelength used for photo-crosslinking is not toxic for cells and tissues, which confers a great advantage in in vivo tests. Because the crosslink results in an irreversible association of the inhibitor to myosin and the irradiation eliminates the residual activity of unbound inhibitor molecules, azidoblebbistatin has a great potential to become a highly effective tool in both structural studies of actomyosin contractility and the investigation of cellular and physiological functions of myosin II. We used azidoblebbistatin to identify previously unknown low-affinity targets of the inhibitor (EC50 ≥ 50 μM) in Dictyostelium discoideum, while the strongest interactant was found to be myosin II (EC50 = 5 μM). Our results demonstrate that azidoblebbistatin, and potentially other azidated drugs, can become highly useful tools for the identification of strong- and weak-binding cellular targets and the determination of the apparent binding affinities in in vivo conditions. PMID:22647605

  19. Biological abatement of cellulase inhibitors.

    Science.gov (United States)

    Cao, Guangli; Ximenes, Eduardo; Nichols, Nancy N; Zhang, Leyu; Ladisch, Michael

    2013-10-01

    Removal of enzyme inhibitors released during lignocellulose pretreatment is essential for economically feasible biofuel production. We tested bio-abatement to mitigate enzyme inhibitor effects observed in corn stover liquors after pretreatment with either dilute acid or liquid hot water at 10% (w/v) solids. Bio-abatement of liquors was followed by enzymatic hydrolysis of cellulose. To distinguish between inhibitor effects on enzymes and recalcitrance of the substrate, pretreated corn stover solids were removed and replaced with 1% (w/v) Solka Floc. Cellulose conversion in the presence of bio-abated liquors from dilute acid pretreatment was 8.6% (0.1x enzyme) and 16% (1x enzyme) higher than control (non-abated) samples. In the presence of bio-abated liquor from liquid hot water pretreated corn stover, 10% (0.1x enzyme) and 13% (1x enzyme) higher cellulose conversion was obtained compared to control. Bio-abatement yielded improved enzyme hydrolysis in the same range as that obtained using a chemical (overliming) method for mitigating inhibitors. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. Inhibitors of mTOR

    NARCIS (Netherlands)

    Klümpen, Heinz-Josef; Beijnen, Jos H.; Gurney, Howard; Schellens, Jan H. M.

    2010-01-01

    Inhibitors of mammalian target of rapamycin (mTOR) have been approved for the treatment of renal cell carcinoma and appear to have a role in the treatment of other malignancies. The primary objective of this drug review is to provide pharmacokinetic and dynamic properties of the commonly used drugs

  1. Retroviral proteinases and their inhibitors

    Czech Academy of Sciences Publication Activity Database

    Sedláček, Juraj

    2000-01-01

    Roč. 3, 3,4 (2000), s. 23-24 [ Proteolytic enzymes and their inhibitors in physiology and pathogenesis. 14.09.2000, Plzen] Institutional research plan: CEZ:AV0Z5052915 Subject RIV: EB - Genetics ; Molecular Biology

  2. Monoamine depletion by reuptake inhibitors

    Directory of Open Access Journals (Sweden)

    Hinz M

    2011-10-01

    Full Text Available Marty Hinz1, Alvin Stein2, Thomas Uncini31Clinical Research, NeuroResearch Clinics Inc, Cape Coral, FL; 2Stein Orthopedic Associates, Plantation, FL; 3DBS Labs Inc, Duluth, MN, USABackground: Disagreement exists regarding the etiology of cessation of the observed clinical results with administration of reuptake inhibitors. Traditionally, when drug effects wane, it is known as tachyphylaxis. With reuptake inhibitors, the placebo effect is significantly greater than the drug effect in the treatment of depression and attention deficit hyperactivity disorder, leading some to assert that waning of drug effects is placebo relapse, not tachyphylaxis.Methods: Two groups were retrospectively evaluated. Group 1 was composed of subjects with depression and Group 2 was composed of bariatric subjects treated with reuptake inhibitors for appetite suppression.Results: In Group 1, 200 subjects with depression were treated with citalopram 20 mg per day. A total of 46.5% (n = 93 achieved relief of symptoms (Hamilton-D rating score ≤ 7, of whom 37 (39.8% of whom experienced recurrence of depression symptoms, at which point an amino acid precursor formula was started. Within 1–5 days, 97.3% (n = 36 experienced relief of depression symptoms. In Group 2, 220 subjects were treated with phentermine 30 mg in the morning and citalopram 20 mg at 4 pm. In this group, 90.0% (n = 198 achieved adequate appetite suppression. The appetite suppression ceased in all 198 subjects within 4–48 days. Administration of an amino acid precursor formula restored appetite suppression in 98.5% (n = 195 of subjects within 1–5 days.Conclusion: Reuptake inhibitors do not increase the total number of monoamine molecules in the central nervous system. Their mechanism of action facilitates redistribution of monoamines from one place to another. In the process, conditions are induced that facilitate depletion of monoamines. The "reuptake inhibitor monoamine depletion theory" of this paper

  3. Clinical trials for BET inhibitors run ahead of the science.

    Science.gov (United States)

    Andrieu, Guillaume; Belkina, Anna C; Denis, Gerald V

    2016-03-01

    Several cancer clinical trials for small molecule inhibitors of BET bromodomain proteins have been initiated. There is enthusiasm for the anti-proliferative effect of inhibiting BRD4, one of the targets of these inhibitors, which is thought to cooperate with MYC, a long-desired target for cancer therapeutics. However, no current inhibitor is selective for BRD4 among the three somatic BET proteins, which include BRD2 and BRD3; their respective functions are partially overlapping and none are functionally redundant with BRD4. Each BET protein controls distinct transcriptional pathways that are important for functions beyond cancer cell proliferation, including insulin production, cytokine gene transcription, T cell differentiation, adipogenesis and most seriously, active repression of dangerous latent viruses like HIV. BET inhibitors have been shown to reactivate HIV in human cells. Failure to appreciate that at concentrations used, no available BET inhibitor is member-selective, or to develop a sound biological basis to understand the diverse functions of BET proteins before undertaking for these clinical trials is reckless and likely to lead to adverse events. More mechanistic information from new basic science studies should enable proper focus on the most relevant cancers and define the expected side effect profiles. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Renal Effects of DPP-4 Inhibitors: A Focus on Microalbuminuria

    Directory of Open Access Journals (Sweden)

    Martin Haluzík

    2013-01-01

    Full Text Available Incretin-based therapies represent one of the most promising options in type 2 diabetes treatment owing to their good effectiveness with low risk of hypoglycemia and no weight gain. Other numerous potential beneficial effects of incretin-based therapies have been suggested based mostly on experimental and small clinical studies including its beta-cell- and vasculo-protective actions. One of the recently emerged interesting features of dipeptidyl peptidase-4 (DPP-4 inhibitors is its possible protective effect on the diabetic kidney disease. Here, we review the renal effects of DPP-4 inhibitors with special focus on its influence on the onset and progression of microalbuminuria, as presence of microalbuminuria represents an important early sign of kidney damage and is also associated with increased risk of hypoglycemia and cardiovascular complications. Mechanisms underlying possible nephroprotective properties of DPP-4 inhibitors include reduction of oxidative stress and inflammation and improvement of endothelial dysfunction. Effects of DPP-4 inhibitors may be both glucagon-like peptide-1 (GLP-1 dependent and independent. Ongoing prospective studies focused on the nephroprotective effects of DPP-4 inhibitors will further clarify its possible role in the prevention/attenuation of diabetic kidney disease beyond its glucose lowering properties.

  5. Replication and Inhibitors of Enteroviruses and Parechoviruses

    Directory of Open Access Journals (Sweden)

    Lonneke van der Linden

    2015-08-01

    Full Text Available The Enterovirus (EV and Parechovirus genera of the picornavirus family include many important human pathogens, including poliovirus, rhinovirus, EV-A71, EV-D68, and human parechoviruses (HPeV. They cause a wide variety of diseases, ranging from a simple common cold to life-threatening diseases such as encephalitis and myocarditis. At the moment, no antiviral therapy is available against these viruses and it is not feasible to develop vaccines against all EVs and HPeVs due to the great number of serotypes. Therefore, a lot of effort is being invested in the development of antiviral drugs. Both viral proteins and host proteins essential for virus replication can be used as targets for virus inhibitors. As such, a good understanding of the complex process of virus replication is pivotal in the design of antiviral strategies goes hand in hand with a good understanding of the complex process of virus replication. In this review, we will give an overview of the current state of knowledge of EV and HPeV replication and how this can be inhibited by small-molecule inhibitors.

  6. Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

    Science.gov (United States)

    Serotonin and norepinephrine reuptake inhibitors (SNRIs) Antidepressant SNRIs help relieve depression symptoms, such as irritability and sadness, ... effects they may cause. By Mayo Clinic Staff Serotonin and norepinephrine reuptake inhibitors (SNRIs) are a class ...

  7. Contemporary protease inhibitors and cardiovascular risk

    DEFF Research Database (Denmark)

    Lundgren, Jens; Mocroft, Amanda; Ryom, Lene

    2018-01-01

    PURPOSE OF REVIEW: To review the evidence linking use of HIV protease inhibitors with excess risk of cardiovascular disease (CVD) in HIV+ populations. RECENT FINDINGS: For the two contemporary most frequently used protease inhibitors, darunavir and atazanavir [both pharmacologically boosted...

  8. A Coupled CFD/FEM Structural Analysis to Determine Deformed Shapes of the RSRM Inhibitors

    Science.gov (United States)

    Dill, Richard A.; Whitesides, R. Harold

    1996-01-01

    Recent trends towards an increase in the stiffness of the acrylonitrile butadiene rubber (NBR) insulation material used in the construction of the redesigned solid rocket motor (RSRM) propellant inhibitors prompted questions about possible effects on RSRM performance. The specific objectives of the computational fluid dynamics (CFD) task included: (1) the definition of pressure loads to calculate the deformed shape of stiffer inhibitors, (2) the calculation of higher port velocities over the inhibitors to determine shifts in the vortex shedding or edge tone frequencies, and (3) the quantification of higher slag impingement and collection rates on the inhibitors and in the submerged nose nozzle cavity.

  9. The application of neutron reflectometry and atomic force microscopy in the study of corrosion inhibitor films

    International Nuclear Information System (INIS)

    John, Douglas; Blom, Annabelle; Bailey, Stuart; Nelson, Andrew; Schulz, Jamie; De Marco, Roland; Kinsella, Brian

    2006-01-01

    Corrosion inhibitor molecules function by adsorbing to a steel surface and thus prevent oxidation of the metal. The interfacial structures formed by a range of corrosion inhibitor molecules have been investigated by in situ measurements based on atomic force microscopy and neutron reflectometry. Inhibitors investigated include molecules cetyl pyridinium chloride (CPC), dodecyl pyridinium chloride (DPC), 1-hydroxyethyl-2-oleic imidazoline (OHEI) and cetyl dimethyl benzyl ammonium chloride (CDMBAC). This has shown that the inhibitor molecules adsorb onto a surface in micellar structures. Corrosion measurements confirmed that maximum inhibition efficiency coincides with the solution critical micelle concentration

  10. 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

  11. Towards ligand docking including explicit interface water molecules.

    Directory of Open Access Journals (Sweden)

    Gordon Lemmon

    Full Text Available Small molecule docking predicts the interaction of a small molecule ligand with a protein at atomic-detail accuracy including position and conformation the ligand but also conformational changes of the protein upon ligand binding. While successful in the majority of cases, docking algorithms including RosettaLigand fail in some cases to predict the correct protein/ligand complex structure. In this study we show that simultaneous docking of explicit interface water molecules greatly improves Rosetta's ability to distinguish correct from incorrect ligand poses. This result holds true for both protein-centric water docking wherein waters are located relative to the protein binding site and ligand-centric water docking wherein waters move with the ligand during docking. Protein-centric docking is used to model 99 HIV-1 protease/protease inhibitor structures. We find protease inhibitor placement improving at a ratio of 9:1 when one critical interface water molecule is included in the docking simulation. Ligand-centric docking is applied to 341 structures from the CSAR benchmark of diverse protein/ligand complexes [1]. Across this diverse dataset we see up to 56% recovery of failed docking studies, when waters are included in the docking simulation.

  12. Reduction rules for reset/inhibitor nets

    NARCIS (Netherlands)

    Verbeek, H.M.W.; Wynn, M.T.; Aalst, van der W.M.P.; Hofstede, ter A.H.M.

    2010-01-01

    Reset/inhibitor nets are Petri nets extended with reset arcs and inhibitor arcs. These extensions can be used to model cancellation and blocking. A reset arc allows a transition to remove all tokens from a certain place when the transition fires. An inhibitor arc can stop a transition from being

  13. Bosutinib induced pleural effusions: Case report and review of tyrosine kinase inhibitors induced pulmonary toxicity

    Directory of Open Access Journals (Sweden)

    Natalia I. Moguillansky, MD

    2017-01-01

    Full Text Available Tyrosine kinase inhibitors are known to cause pulmonary complications. We report a case of bosutinib related bilateral pleural effusions in a patient with chronic myeloid leukemia. Characteristics of the pleural fluid are presented. We also discuss other tyrosine kinase inhibitors induced pulmonary toxicities, including pulmonary hypertension and interstitial lung disease.

  14. Treating ER+ Breast Cancer with CDK4/6 Inhibitors.

    Science.gov (United States)

    2017-08-01

    Data from the MONARCH2, PALOMA-1, and TREnd trials strongly support using CDK4/6 inhibitors alongside standard endocrine therapy for advanced ER-positive breast cancer. Including these targeted agents not only improves progression-free survival but may reverse acquired resistance to hormone treatment. ©2017 American Association for Cancer Research.

  15. Employment of People with Disabilities in Malaysia: Drivers and Inhibitors

    Science.gov (United States)

    Lee, Melissa Ng; Abdullah, Yen; Mey, See Ching

    2011-01-01

    This study attempts to identify the drivers and inhibitors of employment for people with disabilities in Malaysia. It explores the skills and psychological traits needed by people with disabilities in order to get jobs and the barriers to their employment. Data include interviews detailing the viewpoints of 24 teachers with visual impairments.…

  16. Plasma tissue inhibitor of metalloproteinases-1 as a biological marker?

    DEFF Research Database (Denmark)

    Lomholt, Anne F.; Frederiksen, Camilla B.; Christensen, Ib J.

    2007-01-01

    Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) may be a valuable biological marker in Colorectal Cancer (CRC). However, prospective validation of TIMP-1 as a biological marker should include a series of pre-analytical considerations. TIMP-1 is stored in platelets, which may degranulate during...

  17. Use of selective serotonin reuptake inhibitors reduces fertility in men

    DEFF Research Database (Denmark)

    Nørr, L; Bennedsen, Birgit; Fedder, Jens

    2016-01-01

    Clinical review of the present data on the effects of selective serotonin reuptake inhibitors (SSRIs) on male fertility was the objective of the study. PubMed and Scopus were searched for publications in English or Danish and reviewed. Human trials, animal studies and in vitro studies were included...

  18. Stabilization versus inhibition of TAFIa by competitive inhibitors in vitro

    NARCIS (Netherlands)

    Walker, J.B.; Hughes, B.; James, I.; Haddock, P.; Kluft, C.; Bajzar, L.

    2003-01-01

    Two competitive inhibitors of TAFIa (activated thrombin-activable fibrinolysis inhibitor), 2-guanidinoethyl-mercaptosuccinic acid and potato tuber carboxypeptidase inhibitor, variably affect fibrinolysis of clotted human plasma. Depending on their concentration, the inhibitors shortened, prolonged,

  19. The Nonglycemic Actions of Dipeptidyl Peptidase-4 Inhibitors

    Directory of Open Access Journals (Sweden)

    Na-Hyung Kim

    2014-01-01

    Full Text Available A cell surface serine protease, dipeptidyl peptidase 4 (DPP-4, cleaves dipeptide from peptides containing proline or alanine in the N-terminal penultimate position. Two important incretin hormones, glucagon-like peptide-1 (GLP-1 and glucose-dependent insulinotropic peptide (GIP, enhance meal-stimulated insulin secretion from pancreatic β-cells, but are inactivated by DPP-4. Diabetes and hyperglycemia increase the DPP-4 protein level and enzymatic activity in blood and tissues. In addition, multiple other functions of DPP-4 suggest that DPP-4 inhibitor, a new class of antidiabetic agents, may have pleiotropic effects. Studies have shown that DPP-4 itself is involved in the inflammatory signaling pathway, the stimulation of vascular smooth cell proliferation, and the stimulation of oxidative stress in various cells. DPP-4 inhibitor ameliorates these pathophysiologic processes and has been shown to have cardiovascular protective effects in both in vitro and in vivo experiments. However, in recent randomized clinical trials, DPP-4 inhibitor therapy in high risk patients with type 2 diabetes did not show cardiovascular protective effects. Some concerns on the actions of DPP-4 inhibitor include sympathetic activation and neuropeptide Y-mediated vascular responses. Further studies are required to fully characterize the cardiovascular effects of DPP-4 inhibitor.

  20. SGLT2 Inhibitors as a Therapeutic Option for Diabetic Nephropathy

    Directory of Open Access Journals (Sweden)

    Daiji Kawanami

    2017-05-01

    Full Text Available Diabetic nephropathy (DN is a major cause of end-stage renal disease (ESRD worldwide. Glycemic and blood pressure (BP control are important but not sufficient to attenuate the incidence and progression of DN. Sodium–glucose cotransporter (SGLT 2 inhibitors are a new class of glucose-lowering agent suggested to exert renoprotective effects in glucose lowering-dependent and independent fashions. Experimental studies have shown that SGLT2 inhibitors attenuate DN in animal models of both type 1 diabetes (T1D and type 2 diabetes (T2D, indicating a potential renoprotective effect beyond glucose reduction. Renoprotection by SGLT2 inhibitors has been demonstrated in T2D patients with a high cardiovascular risk in randomized controlled trials (RCTs. These favorable effects of SGLT2 inhibitors are explained by several potential mechanisms, including the attenuation of glomerular hyperfiltration, inflammation and oxidative stress. In this review article, we discuss the renoprotective effects of SGLT2 inhibitors by integrating experimental findings with the available clinical data.

  1. SGLT2 Inhibitors as a Therapeutic Option for Diabetic Nephropathy.

    Science.gov (United States)

    Kawanami, Daiji; Matoba, Keiichiro; Takeda, Yusuke; Nagai, Yosuke; Akamine, Tomoyo; Yokota, Tamotsu; Sango, Kazunori; Utsunomiya, Kazunori

    2017-05-18

    Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD) worldwide. Glycemic and blood pressure (BP) control are important but not sufficient to attenuate the incidence and progression of DN. Sodium-glucose cotransporter (SGLT) 2 inhibitors are a new class of glucose-lowering agent suggested to exert renoprotective effects in glucose lowering-dependent and independent fashions. Experimental studies have shown that SGLT2 inhibitors attenuate DN in animal models of both type 1 diabetes (T1D) and type 2 diabetes (T2D), indicating a potential renoprotective effect beyond glucose reduction. Renoprotection by SGLT2 inhibitors has been demonstrated in T2D patients with a high cardiovascular risk in randomized controlled trials (RCTs). These favorable effects of SGLT2 inhibitors are explained by several potential mechanisms, including the attenuation of glomerular hyperfiltration, inflammation and oxidative stress. In this review article, we discuss the renoprotective effects of SGLT2 inhibitors by integrating experimental findings with the available clinical data.

  2. 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

  3. Novel β-amyloid aggregation inhibitors possessing a turn mimic.

    Science.gov (United States)

    Hamada, Yoshio; Miyamoto, Naoko; Kiso, Yoshiaki

    2015-04-01

    Amyloid β peptide, the main component of senile plaques found in the brain of Alzheimer disease (AD) patients, is a molecular target for AD therapeutic intervention. A number of potential AD therapeutics have been reported, including inhibitors of β-secretase, γ-secretase, and Aβ aggregation, and anti-amyloid agents, such as neprilysin, insulin degrading enzyme (IDE), and Aβ antibodies. Recently, we reported potent small-sized β-secretase (BACE1) inhibitors, which could serve as anti-AD drugs. However AD is a progressive disorder, where dementia symptoms gradually worsen over several decades, and therefore may require many years to get cured. One possible way to achieve a greater therapeutic effect is through simultaneous administration of multiple drugs, similar to those used in Highly Active Anti-Retroviral Therapy (HAART) used to treat AIDS. In order to overcome AD, we took a drug discovery approach to evaluate, novel β-amyloid aggregation inhibitors. Previously, we reported that a tong-type compound possessing a turn mimic as the inhibitor of HIV-1 protease dimerization. Oligomerized amyloid β peptides contain a turn structure within the molecule. Here, we designed and synthesized novel β-amyloid aggregation inhibitors with a turn-mimic template, based on the turn conformer of the oligomerized amyloid β peptides. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. Polyphenol Compound as a Transcription Factor Inhibitor

    Directory of Open Access Journals (Sweden)

    Seyeon Park

    2015-10-01

    Full Text Available A target-based approach has been used to develop novel drugs in many therapeutic fields. In the final stage of intracellular signaling, transcription factor–DNA interactions are central to most biological processes and therefore represent a large and important class of targets for human therapeutics. Thus, we focused on the idea that the disruption of protein dimers and cognate DNA complexes could impair the transcriptional activation and cell transformation regulated by these proteins. Historically, natural products have been regarded as providing the primary leading compounds capable of modulating protein–protein or protein-DNA interactions. Although their mechanism of action is not fully defined, polyphenols including flavonoids were found to act mostly as site-directed small molecule inhibitors on signaling. There are many reports in the literature of screening initiatives suggesting improved drugs that can modulate the transcription factor interactions responsible for disease. In this review, we focus on polyphenol compound inhibitors against dimeric forms of transcription factor components of intracellular signaling pathways (for instance, c-jun/c-fos (Activator Protein-1; AP-1, c-myc/max, Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB and β-catenin/T cell factor (Tcf.

  5. Polyphenol Compound as a Transcription Factor Inhibitor.

    Science.gov (United States)

    Park, Seyeon

    2015-10-30

    A target-based approach has been used to develop novel drugs in many therapeutic fields. In the final stage of intracellular signaling, transcription factor-DNA interactions are central to most biological processes and therefore represent a large and important class of targets for human therapeutics. Thus, we focused on the idea that the disruption of protein dimers and cognate DNA complexes could impair the transcriptional activation and cell transformation regulated by these proteins. Historically, natural products have been regarded as providing the primary leading compounds capable of modulating protein-protein or protein-DNA interactions. Although their mechanism of action is not fully defined, polyphenols including flavonoids were found to act mostly as site-directed small molecule inhibitors on signaling. There are many reports in the literature of screening initiatives suggesting improved drugs that can modulate the transcription factor interactions responsible for disease. In this review, we focus on polyphenol compound inhibitors against dimeric forms of transcription factor components of intracellular signaling pathways (for instance, c-jun/c-fos (Activator Protein-1; AP-1), c-myc/max, Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and β-catenin/T cell factor (Tcf)).

  6. Identification and detoxification of glycolaldehyde, an unattended bioethanol fermentation inhibitor.

    Science.gov (United States)

    Jayakody, Lahiru N; Ferdouse, Jannatul; Hayashi, Nobuyuki; Kitagaki, Hiroshi

    2017-03-01

    Although there have been approximately 60 chemical compounds identified as potent fermentation inhibitors in lignocellulose hydrolysate, our research group recently discovered glycolaldehyde as a key fermentation inhibitor during second generation biofuel production. Accordingly, we have developed a yeast S. cerevisiae strain exhibiting tolerance to glycolaldehyde. During this glycolaldehyde study, we established novel approaches for rational engineering of inhibitor-tolerant S. cerevisiae strains, including engineering redox cofactors and engineering the SUMOylation pathway. These new technical dimensions provide a novel platform for engineering S. cerevisiae strains to overcome one of the key barriers for industrialization of lignocellulosic ethanol production. As such, this review discusses novel biochemical insight of glycolaldehyde in the context of the biofuel industry.

  7. 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors: From Chemical Biology to Agrochemicals.

    Science.gov (United States)

    Ndikuryayo, Ferdinand; Moosavi, Behrooz; Yang, Wen-Chao; Yang, Guang-Fu

    2017-10-04

    The development of new herbicides is receiving considerable attention to control weed biotypes resistant to current herbicides. Consequently, new enzymes are always desired as targets for herbicide discovery. 4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is an enzyme engaged in photosynthetic activity and catalyzes the transformation of 4-hydroxyphenylpyruvic acid (HPPA) into homogentisic acid (HGA). HPPD inhibitors constitute a promising area of discovery and development of innovative herbicides with some advantages, including excellent crop selectivity, low application rates, and broad-spectrum weed control. HPPD inhibitors have been investigated for agrochemical interests, and some of them have already been commercialized as herbicides. In this review, we mainly focus on the chemical biology of HPPD, discovery of new potential inhibitors, and strategies for engineering transgenic crops resistant to current HPPD-inhibiting herbicides. The conclusion raises some relevant gaps for future research directions.

  8. 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.

  9. 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.

  10. 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

  11. Structural Mechanism of the Pan-BCR-ABL Inhibitor Ponatinib (AP24534): Lessons for Overcoming Kinase Inhibitor Resistance

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Tianjun; Commodore, Lois; Huang, Wei-Sheng; Wang, Yihan; Thomas, Mathew; Keats, Jeff; Xu, Qihong; Rivera, Victor M.; Shakespeare, William C.; Clackson, Tim; Dalgarno, David C.; Zhu, Xiaotian (ARIAD)

    2012-01-20

    The BCR-ABL inhibitor imatinib has revolutionized the treatment of chronic myeloid leukemia. However, drug resistance caused by kinase domain mutations has necessitated the development of new mutation-resistant inhibitors, most recently against the T315I gatekeeper residue mutation. Ponatinib (AP24534) inhibits both native and mutant BCR-ABL, including T315I, acting as a pan-BCR-ABL inhibitor. Here, we undertook a combined crystallographic and structure-activity relationship analysis on ponatinib to understand this unique profile. While the ethynyl linker is a key inhibitor functionality that interacts with the gatekeeper, virtually all other components of ponatinib play an essential role in its T315I inhibitory activity. The extensive network of optimized molecular contacts found in the DFG-out binding mode leads to high potency and renders binding less susceptible to disruption by single point mutations. The inhibitory mechanism exemplified by ponatinib may have broad relevance to designing inhibitors against other kinases with mutated gatekeeper residues.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-03-01

    Advanced glycation or glycoxidation end-products (AGE) increase in tissue proteins with age, and their rate of accumulation is increased in diabetes, nephropathy and inflammatory diseases. AGE inhibitors include a range of compounds that are proposed to act by trapping carbonyl and dicarbonyl intermediates in AGE formation. However, some among the newer generation of AGE inhibitors lack reactive functional groups that would trap reaction intermediates, indicating an alternative mechanism of action. We propose that AGE inhibitors function primarily as chelators, inhibiting metal-catalyzed oxidation reactions. The AGE-inhibitory activity of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers is also consistent with their chelating activity. Finally, compounds described as AGE breakers, or their hydrolysis products, also have strong chelating activity, suggesting that these compounds also act through their chelating activity. We conclude that chelation is the common, and perhaps the primary, mechanism of action of AGE inhibitors and breakers, and that chronic, mild chelation therapy should prove useful in treatment of diabetes and age-related diseases characterized by oxidative stress, inflammation and increased chemical modification of tissue proteins by advanced glycoxidation and lipoxidation end-products.

  13. 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.

  14. Calcineurin-inhibitor pain syndrome.

    Science.gov (United States)

    Prommer, Eric

    2012-07-01

    There has been increased recognition of calcineurin, a phosphoprotein serine/threonine phosphatase enzyme, in the regulation of many physiologic systems. Calcineurin mediates activation of lymphocytes, which play a role in immune response. Widely distributed in the central nervous system, calcinuerin also plays an important role in sensory neural function, via its role in the regulation of newly discovered 2-pore potassium channels, which greatly influence neuronal resting membrane potentials. Calcinuerin inhibition is the mechanism of action of immunomodulatory drugs such as cyclosporine and tacrolimus, which are widely used in transplantation medicine to prevent rejection. While important for immunosuppression, the use of calcineurin inhibitors has been associated with the development of a new pain syndrome called the calcineurin pain syndrome, which appears to be an untoward complication of the interruption of the physiologic function of calcineurin. This is a narrative review focusing on the epidemiology, pathophysiology, characterization of a newly recognized pain syndrome associated with the use of calcineurin inhibitors. The use of immunosuppressants however is associated with several well-known toxicities to which the calcineurin pain syndrome can be added. The development of this syndrome most likely involves altered nociceptive processing due to the effect of calcineurin inhibition on neuronal firing, as well as effects of calcineurin on vascular tone. The most striking aspect of the treatment of this syndrome is the response to calcium channel blockers, which suggest that the effects of calcineurin inhibition on vascular tone play an important role in the development of the calcineurin pain syndrome. The calcineurin syndrome is a newly recognized complication associated with the use of calcineurin inhibitors. There is no standard therapy at this time but anecdotal reports suggest the effectiveness of calcium channel blockers.

  15. 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.

  16. Phosphodiesterase Type 5 Inhibitors, Sport and Doping.

    Science.gov (United States)

    Di Luigi, Luigi; Sansone, Massimiliano; Sansone, Andrea; Ceci, Roberta; Duranti, Guglielmo; Borrione, Paolo; Crescioli, Clara; Sgrò, Paolo; Sabatini, Stefania

    Phosphodiesterase type 5 inhibitors (PDE5i) (e.g., sildenafil, tadalafil, vardenafil, and avanafil) are drugs commonly used to treat erectile dysfunction, pulmonary arterial hypertension, and benign prostatic hyperplasia. PDE5i are not prohibited by the World Anti-Doping Agency (WADA) but are alleged to be frequently misused by healthy athletes to improve sporting performance. In vitro and in vivo studies have reported various effects of PDE5i on cardiovascular, muscular, metabolic, and neuroendocrine systems and the potential, therefore, to enhance performance of healthy athletes during training and competition. This suggests well-controlled research studies to examine the ergogenic effects of PDE5i on performance during activities that simulate real sporting situations are warranted to determine if PDE5i should be included on the prohibited WADA list. In the meantime, there is concern that some otherwise healthy athletes will continue to misuse PDE5i to gain an unfair competitive advantage over their competitors.

  17. New Acetylcholinesterase Inhibitors for Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Mona Mehta

    2012-01-01

    Full Text Available Acetylcholinesterase (AChE remains a highly viable target for the symptomatic improvement in Alzheimer's disease (AD because cholinergic deficit is a consistent and early finding in AD. The treatment approach of inhibiting peripheral AchE for myasthenia gravis had effectively proven that AchE inhibition was a reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, and galantamine were developed and approved for the symptomatic treatment of AD. Since then, multiple cholinesterase inhibitors (ChEI continue to be developed. These include newer ChEIs, naturally derived ChEIs, hybrids, and synthetic analogues. In this paper, we summarize the different types of ChEIs in development and their respective mechanisms of actions. This pharmacological approach continues to be active with many promising compounds.

  18. Molecular modeling of auxin transport inhibitors

    International Nuclear Information System (INIS)

    Gardner, G.; Black-Schaefer, C.; Bures, M.G.

    1990-01-01

    Molecular modeling techniques have been used to study the chemical and steric properties of auxin transport inhibitors. These bind to a specific site on the plant plasma membrane characterized by its affinity for N-1-naphthylphthalamic acid (NPA). A three-dimensional model was derived from critical features of ligands for the NPA receptor, and a suggested binding conformation is proposed. This model, along with three-dimensional structural searching techniques, was then used to search the Abbott corporate database of chemical structures. Of the 467 compounds that satisfied the search criteria, 77 representative molecules were evaluated for their ability to compete for [ 3 H]NPA binding to corn microsomal membranes. Nineteen showed activity that ranged from 16 to 85% of the maximum NPA binding. Four of the most active of these, from chemical classes not included in the original compound set, also inhibited polar auxin transport through corn coleoptile sections

  19. Inhibitors of plant hormone transport

    Czech Academy of Sciences Publication Activity Database

    Klíma, Petr; Laňková, Martina; Zažímalová, Eva

    2016-01-01

    Roč. 253, č. 6 (2016), s. 1391-1404 ISSN 0033-183X R&D Projects: GA MŠk(CZ) LD15088 Institutional support: RVO:61389030 Keywords : polar auxin transport * acid-binding protein * gnom arf-gef * equilibrative nucleoside transporter * efflux carrier polarity * plasma-membrane-protein * cultured tobacco cells * arabidopsis-thaliana * gravitropic response * brefeldin-a * Plant hormones * Transport * Inhibitors * Auxin * Cytokinins * Strigolactones * Abscisic acid * Cell biology Subject RIV: ED - Physiology Impact factor: 2.870, year: 2016

  20. Cyclooxygenase-2 inhibitors and free flap complications after autologous breast reconstruction

    DEFF Research Database (Denmark)

    Bonde, Christian; Khorasani, Hoda; Hoejvig, Jens

    2017-01-01

    BACKGROUND: A key component of modern analgesics is the use of multimodal opioid-sparing analgesia (MOSA). In the past, our analgesic regime after autologous breast reconstruction (ABR) included either NSAID or a selective cyclooxygenase-2 (COX-2) inhibitor. COX-2 inhibitors are superior to NSAID...... or gastrointestinal bleeding. CONCLUSIONS: Multimodal analgesia using a COX-2 inhibitor is safe in ABR with free flaps and does not increase flap failure. COX-2 inhibitors seem superior to NSAID with reduced risk of post-operative haematomas.......BACKGROUND: A key component of modern analgesics is the use of multimodal opioid-sparing analgesia (MOSA). In the past, our analgesic regime after autologous breast reconstruction (ABR) included either NSAID or a selective cyclooxygenase-2 (COX-2) inhibitor. COX-2 inhibitors are superior to NSAIDs...... because of the well-known side effects of NSAID treatment (bleeding/gastrointestinal ulcers). However, COX-2 inhibitors have been suggested to increase flap failure rates. We report our experience in using COX-2 inhibitors as part of our post-operative MOSA after ABR using free flaps. MATERIALS...

  1. Checkpoint inhibitors in endometrial cancer: preclinical rationale and clinical activity.

    Science.gov (United States)

    Mittica, Gloria; Ghisoni, Eleonora; Giannone, Gaia; Aglietta, Massimo; Genta, Sofia; Valabrega, Giorgio

    2017-10-27

    Treatment of advanced and recurrent endometrial cancer (EC) is still an unmet need for oncologists and gynecologic oncologists. The Cancer Genome Atlas Research Network (TCGA) recently provided a new genomic classification, dividing EC in four subgroups. Two types of EC, the polymerase epsilon (POLE)-ultra-mutated and the microsatellite instability-hyper-mutated (MSI-H), are characterized by a high mutation rate providing the rationale for a potential activity of checkpoint inhibitors. We analyzed all available evidence supporting the role of tumor microenvironment (TME) in EC development and the therapeutic implications offered by immune checkpoint inhibitors in this setting. We performed a review on Pubmed with Mesh keywords 'endometrial cancer' and the name of each checkpoint inhibitor discussed in the article. The same search was operated on clinicaltrial.gov to identify ongoing clinical trials exploring PD-1/PD-L1 and CTLA-4 axis in EC, particularly focusing on POLE-ultra-muted and MSI-H cancer types. POLE-ultra-mutated and MSI-H ECs showed an active TME expressing high number of neo-antigens and an elevated amount of tumor infiltrating lymphocytes (TILs). Preliminary results from a phase-1 clinical trial (KEYNOTE-028) demonstrated antitumor activity of Pembrolizumab in EC. Moreover, both Pembrolizumab and Nivolumab reported durable clinical responses in POLE-ultra-mutated patients. Immune checkpoint inhibitors are an attractive option in POLE-ultra-mutated and MSI-H ECs. Future investigations in these subgroups include combinations of checkpoints inhibitors with chemotherapy and small tyrosine kinase inhibitors (TKIs) to enhance a more robust intra-tumoral immune response.

  2. Do pigeons prefer alternatives that include near-hit outcomes?

    Science.gov (United States)

    Stagner, Jessica P; Case, Jacob P; Sticklen, Mary F; Duncan, Amanda K; Zentall, Thomas R

    2015-07-01

    Pigeons show suboptimal choice on a gambling-like task similar to that shown by humans. Humans also show a preference for gambles in which there are near hits (losses that come close to winning). In the present research, we asked if pigeons would show a preference for alternatives with near-hit-like trials. In Experiment 1, we included an alternative that presented a near hit, in which a stimulus associated with reinforcement (a presumed conditioned reinforcer) changed to a stimulus associated with the absence of reinforcement (a presumed conditioned inhibitor). The pigeons tended to avoid this alternative. In Experiment 2, we varied the duration of the presumed conditioned reinforcer (2 vs. 8 s) that changed to a presumed conditioned inhibitor (8 vs. 2 s) and found that the longer the conditioned reinforcer was presented, the more the pigeons avoided it. In Experiment 3, the near-hit alternative involved an ambiguous stimulus for 8 s that changed to a presumed conditioned reinforcer (or a presumed conditioned inhibitor) for 2 s, but the pigeons still avoided it. In Experiment 4, we controlled for the duration of the conditioned reinforcer by presenting it first for 2 s followed by the ambiguous stimulus for 8 s. Once again, the pigeons avoided the alternative with the near-hit trials. In all 4 experiments, the pigeons tended to avoid alternatives that provided near-hit-like trials. We concluded that humans may be attracted to near-hit trials because near-hit trials give them the illusion of control, whereas this does not appear to be a factor for pigeons. (c) 2015 APA, all rights reserved).

  3. Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis.

    Science.gov (United States)

    Robertson, Lindsay; Kesteven, Patrick; McCaslin, James E

    2015-06-30

    Deep vein thrombosis (DVT) is a condition in which a clot forms in the deep veins, most commonly of the leg. It occurs in approximately 1 in 1,000 people. If left untreated, the clot can travel up to the lungs and cause a potentially life-threatening pulmonary embolism (PE). Previously, a DVT was treated with the anticoagulants heparin and vitamin K antagonists. However, two forms of novel oral anticoagulants (NOACs) have been developed: oral direct thrombin inhibitors (DTI) and oral factor Xa inhibitors. The new drugs have characteristics that may be favourable over conventional treatment, including oral administration, a predictable effect, lack of frequent monitoring or re-dosing and few known drug interactions. To date, no Cochrane review has measured the effectiveness and safety of these drugs in the treatment of DVT. To assess the effectiveness of oral DTIs and oral factor Xa inhibitors for the treatment of DVT. The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched January 2015) and the Cochrane Register of Studies (last searched January 2015). We searched clinical trials databases for details of ongoing or unpublished studies and the reference lists of relevant articles retrieved by electronic searches for additional citations. We included randomised controlled trials in which people with a DVT confirmed by standard imaging techniques, were allocated to receive an oral DTI or an oral factor Xa inhibitor for the treatment of DVT. Two review authors (LR, JM) independently extracted the data and assessed the risk of bias in the trials. Any disagreements were resolved by discussion with the third review author (PK). We performed meta-analyses when we considered heterogeneity low. The two primary outcomes were recurrent VTE and PE. Other outcomes included all-cause mortality and major bleeding. We calculated all outcomes using an odds ratio (OR) with a 95% confidence interval (CI). We included

  4. Laura: Soybean variety lacking Kunitz trypsin inhibitor

    Directory of Open Access Journals (Sweden)

    Srebrić Mirjana

    2010-01-01

    Full Text Available Grain of conventional soybean varieties requires heat processing to break down trypsin inhibitor's activity before using as food or animal feed. At the same time, protein denaturation and other qualitative changes occur in soybean grain, especially if the temperature of heating is not controlled. Two types of trypsin inhibitor were found in soybean grain the Kunitz trypsin inhibitor and the Bowman-Birk inhibitor. Mature grain of soybean Laura is lacking Kunitz trypsin inhibitor. Grain yield of variety Laura is equal to high yielding varieties from the maturity group I, where it belongs. Lacking of Kunitz-trypsin inhibitor makes soybean grain suitable for direct feeding in adult non ruminant animals without previous thermal processing. Grain of variety Laura can be processed for a shorter period of time than conventional soybeans. This way we save energy, and preserve valuable nutritional composition of soybean grain, which is of interest in industrial processing.

  5. Proton pump inhibitors and osteoporosis

    DEFF Research Database (Denmark)

    Andersen, Bjarne Nesgaard; Johansen, Per Birger; Abrahamsen, Bo

    2016-01-01

    PURPOSE OF REVIEW: The purpose of the review is to provide an update on recent advances in the evidence based on proton pump inhibitors (PPI) as a possible cause of osteoporosis and osteoporotic fractures. This review focuses, in particular, on new studies published in the last 18 months and a di......PURPOSE OF REVIEW: The purpose of the review is to provide an update on recent advances in the evidence based on proton pump inhibitors (PPI) as a possible cause of osteoporosis and osteoporotic fractures. This review focuses, in particular, on new studies published in the last 18 months...... and a discussion of these findings and how this has influenced our understanding of this association, the clinical impact and the underlying pathophysiology. RECENT FINDINGS: New studies have further strengthened existing evidence linking use of PPIs to osteoporosis. Short-term use does not appear to pose a lower...... risk than long-term use. There is a continued lack of conclusive studies identifying the pathogenesis. Direct effects on calcium absorption or on osteoblast or osteoclast action cannot at present plausibly explain the mechanism. SUMMARY: The use of PPIs is a risk factor for development of osteoporosis...

  6. Mutaciones asociadas con resistencia a rifampicina o isoniazida en aislamientos clínicos de M. tuberculosis de Sonora, México DNA mutations associated to rifampicin or isoniazid resistance in M. tuberculosis clinical isolates from Sonora, Mexico

    Directory of Open Access Journals (Sweden)

    Enrique Bolado-Martínez

    2012-04-01

    Full Text Available OBJETIVO: Realizar el análisis de regiones específicas de genes asociados con resistencia a isoniazida o rifampicina. MATERIAL Y MÉTODOS: Se estudiaron 22 cepas de M. tuberculosis, aisladas en Sonora, México. Se utilizaron iniciadores para regiones específicas de los genes rpoB, katG e inhA y la región ahpC-oxyR. Los productos de PCR se secuenciaron y analizaron. RESULTADOS: Se identificaron mutaciones en la región promotora del gen inhA, región ahpC-oxyR, codón 315 del gen katG y codones 451 ó 456 del gen rpoB. CONCLUSIONES: La identificación de mutaciones no descritas previamente obliga a continuar el análisis genotípico de cepas aisladas en Sonora.OBJECTIVE: To perform the analysis of specific regions of the major genes associated with resistance to isoniazid or rifampin. MATERIALS AND METHODS: Twenty two M. tuberculosis strains, isolated from human samples obtained in Sonora, Mexico. Specific primers for hotspots of the rpoB, katG, inhA genes and the ahpC-oxyR intergenic region were used. The purified PCR products were sequenced. RESULTS: Mutations in the promoter of inhA, the ahpC-oxyR region, and codon 315 of katG and in 451 or 456 codons of rpoB, were identified. CONCLUSIONS: Detection of mutations not previously reported requires further genotypic analysis of Mycobacterium tuberculosis isolates in Sonora.

  7. [Sodium Glucose Co-transporter Type 2 (SGLT2) Inhibitors in CKD].

    Science.gov (United States)

    Insalaco, Monica; Zanoli, Luca; Rastelli, Stefania; Lentini, Paolo; Rapisarda, Francesco; Fatuzzo, Pasquale; Castellino, Pietro; Granata, Antonio

    2015-01-01

    Among the new drugs used for the treatment of Diabetes Mellitus type 2, sodium-glucose cotransporter 2 (SGLT2) inhibitors represent a promising therapeutic option. Since their ability to lower glucose is proportional to GFR, their effect is reduced in patients with chronic kidney disease (CKD). The antidiabetic mechanism of these drugs is insulin-independent and, therefore, complimentary to that of others antihyperglicaemic agents. Moreover, SGLT2 inhibitors are able to reduce glomerular hyperfiltration, systemic and intraglomerular pressure and uric acid levels, with consequent beneficial effects on the progression of kidney disease in non diabetic patients as well. Only few studies have been performed to evaluate the effects of SGLT2 inhibitors in patients with CKD. Therefore, safety and efficacy of SGLT2 inhibitors should be better clarified in the setting of CKD. In this paper, we will review the use of SGLT2 inhibitors in diabetic patients, including those with CKD.

  8. 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.

  9. Impact of sodium–glucose cotransporter 2 inhibitors on blood pressure

    Directory of Open Access Journals (Sweden)

    Reed JW

    2016-10-01

    Full Text Available James W Reed Morehouse School of Medicine, Atlanta, GA, USA Abstract: SGLT2 inhibitors are glucose-lowering agents used to treat type 2 diabetes mellitus (T2DM. These agents target the kidney to promote urinary glucose excretion, resulting in improved blood glucose control. SGLT2-inhibitor therapy is also associated with weight loss and blood pressure (BP lowering. Hypertension is a common comorbidity in patients with T2DM, and is associated with excess morbidity and mortality. This review summarizes data on the effect of SGLT2 inhibitors marketed in the US (namely canagliflozin, dapagliflozin, or empagliflozin on BP in patients with T2DM. Boolean searches were conducted that included terms related to BP or hypertension with terms for SGLT2 inhibitors, canagliflozin, dapagliflozin, or empagliflozin using PubMed, Google, and Google Scholar. Data from numerous randomized controlled trials of SGLT2 inhibitors in patients with T2DM demonstrated clinically relevant reductions in both systolic and diastolic BP, assessed via seated office measurements and 24-hour ambulatory BP monitoring. Observed BP lowering was not associated with compensatory increases in heart rate. Circadian BP rhythm was also maintained. The mechanism of SGLT2 inhibitor-associated BP reduction is not fully understood, but is assumed to be related to osmotic diuresis and natriuresis. Other factors that may also contribute to BP reduction include SGLT2 inhibitor-associated decreases in body weight and reduced arterial stiffness. Local inhibition of the renin–angiotensin–aldosterone system secondary to increased delivery of sodium to the juxtaglomerular apparatus during SGLT2 inhibition has also been postulated. Although SGLT2 inhibitors are not indicated as BP-lowering agents, the modest decreases in systolic and diastolic BP observed with SGLT2 inhibitors may provide an extra clinical advantage for the majority of patients with T2DM, in addition to improving blood glucose

  10. PD-1/PD-L1 Inhibitors for Immuno-oncology: From Antibodies to Small Molecules.

    Science.gov (United States)

    Geng, Qiaohong; Jiao, Peifu; Jin, Peng; Su, Gaoxing; Dong, Jinlong; Yan, Bing

    2018-02-12

    The recent regulatory approvals of immune checkpoint protein inhibitors, such as ipilimumab, pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab ushered a new era in cancer therapy. These inhibitors do not attack tumor cells directly but instead mobilize the immune system to re-recognize and eradicate tumors, which endows them with unique advantages including durable clinical responses and substantial clinical benefits. PD-1/PD-L1 inhibitors, a pillar of immune checkpoint protein inhibitors, have demonstrated unprecedented clinical efficacy in more than 20 cancer types. Besides monoclonal antibodies, diverse PD- 1/PD-L1 inhibiting candidates, such as peptides, small molecules have formed a powerful collection of weapons to fight cancer. The goal of this review is to summarize and discuss the current PD-1/PD-L1 inhibitors including candidates under clinical development, their molecular interactions with PD-1 or PD-L1, the disclosed structureactivity relationships of peptides and small molecules as inhibitors. Current PD-1/PD-L1 inhibitors under clinical development are exclusively dominated by antibodies. The molecular interactions of therapeutic antibodies with PD-1 or PD-L1 have been gradually elucidated for the design of novel inhibitors. Various peptides and traditional small molecules have been investigated in preclinical model to discover novel PD-1/PD-L1 inhibitors. Peptides and small molecules may play an important role in immuno-oncology because they may bind to multiple immune checkpoint proteins via rational design, opening opportunity for a new generation of novel PD-1/PD-L1 inhibitors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  11. TYROSINE KINASE INHIBITORS AND PREGNANCY

    Directory of Open Access Journals (Sweden)

    Elisabetta Abruzzese

    2014-04-01

    Full Text Available The management of patients with chronic myeloid leukemia (CML during pregnancy has became recently a matter of continuous debate.  The introduction of the Tyrosine Kinase Inhibitors (TKIs in clinical practice has dramatically changed the prognosis of CML patients.  Patients diagnosed in chronic phase can reasonably expect many years of excellent disease control and good quality of life, as well as a normal life expectancy.  This fact has come the necessity to address issues relating to fertility and pregnancy. Physicians are not infrequently being asked for advice regarding the need for, and or the appropriateness of, stopping treatment in order to conceive. In this report we will review the data published in terms of fertility, conception, pregnancy, pregnancy outcome and illness control for all the approved TKIs, as well as suggest how to manage a planned and/or unplanned pregnancy.

  12. Renoprotective Effects of SGLT2 Inhibitors: Beyond Glucose Reabsorption Inhibition.

    Science.gov (United States)

    Tsimihodimos, V; Filippatos, T D; Filippas-Ntekouan, S; Elisaf, M

    2017-01-01

    Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that inhibit glucose and sodium reabsorption at proximal tubules. These drugs may exhibit renoprotective properties, since they prevent the deterioration of the glomerular filtration rate and reduce the degree of albuminuria in patients with diabetes-associated kidney disease. In this review we consider the pathophysiologic mechanisms that have been recently implicated in the renoprotective properties of SGLT2 inhibitors. The beneficial effects of SGLT2 inhibitors on the conventional risk factors for kidney disease (such as blood pressure, hyperglycaemia, body weight and serum uric acid levels) may explain, at least in part, the observed renal-protecting properties of these compounds. However, it has been hypothesized that the most important mechanisms for this phenomenon include the reduction in the intraglomerular pressure, the changes in the local and systemic degree of activation of the renin-aldosterone-angiotensin system and a shift in renal fuel consumption towards more efficient energy substrates such as ketone bodies. The beneficial effects of SGLT2 inhibitors on various aspects of renal function make them an attractive choice in patients with (and possibly without) diabetes-associated renal impairment. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  13. Novel endogenous angiogenesis inhibitors and their therapeutic potential.

    Science.gov (United States)

    Rao, Nithya; Lee, Yu Fei; Ge, Ruowen

    2015-10-01

    Angiogenesis, the formation of new blood vessels from the pre-existing vasculature is essential for embryonic development and tissue homeostasis. It also plays critical roles in diseases such as cancer and retinopathy. A delicate balance between pro- and anti-angiogenic factors ensures normal physiological homeostasis. Endogenous angiogenesis inhibitors are proteins or protein fragments that are formed in the body and have the ability to limit angiogenesis. Many endogenous angiogenesis inhibitors have been discovered, and the list continues to grow. Endogenous protein/peptide inhibitors are relatively less toxic, better tolerated and have a lower risk of drug resistance, which makes them attractive as drug candidates. In this review, we highlight ten novel endogenous protein angiogenesis inhibitors discovered within the last five years, including ISM1, FKBPL, CHIP, ARHGAP18, MMRN2, SOCS3, TAp73, ZNF24, GPR56 and JWA. Although some of these proteins have been well characterized for other biological functions, we focus on their new and specific roles in angiogenesis inhibition and discuss their potential for therapeutic application.

  14. Oxindole based oxadiazole hybrid analogs: Novel α-glucosidase inhibitors.

    Science.gov (United States)

    Taha, Muhammad; Imran, Syahrul; Rahim, Fazal; Wadood, Abdul; Khan, Khalid Mohammed

    2018-02-01

    Inhibition of α-glucosidase is an effective strategy for controlling post-prandial hyperglycemia in diabetic patients. Beside these α-glucosidase inhibitors has been also used as anti-obesity and anti-viral drugs. Keeping in view the greater importance of α-glucosidase inhibitors here in this study we are presenting oxindole based oxadiazoles hybrid analogs (1-20) synthesis, characterized by different spectroscopic techniques including 1 H NMR and EI-MS and their α-glucosidase inhibitory activity. All compounds were found potent inhibitors for the enzyme with IC 50 values ranging between 1.25 ± 0.05 and 268.36 ± 4.22 µM when compared with the standard drug acarbose having IC 50 value 895.09 ± 2.04 µM. Our study identifies novel series of potent α-glucosidase inhibitors and further investigation on this may led to the lead compounds. A structure activity relationship has been established for all compounds. The interactions of the active compounds and enzyme active site were established with the help of molecular docking studies. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Imaging findings in a child with calcineurin inhibitor-induced pain syndrome after bone marrow transplant for beta thalassemia major

    International Nuclear Information System (INIS)

    Ayyala, Rama S.; Arnold, Staci D.; Bhatia, Monica; Dastgir, Jahannaz

    2016-01-01

    Calcineurin inhibitor-induced pain syndrome is an entity recognized in patients on immunosuppressive therapy after transplantation. Diagnosis is characterized by onset of pain beginning in the setting of an elevated calcineurin-inhibitor trough level. Reducing the medication dose relieves symptoms. Imaging findings can be nonspecific, including bone marrow edema and periosteal reaction. We present the unique case of calcineurin inhibitor-induced pain syndrome in a child and review the imaging findings. (orig.)

  16. Imaging findings in a child with calcineurin inhibitor-induced pain syndrome after bone marrow transplant for beta thalassemia major

    Energy Technology Data Exchange (ETDEWEB)

    Ayyala, Rama S.; Arnold, Staci D.; Bhatia, Monica; Dastgir, Jahannaz [Columbia University Medical Center, Morgan Stanley Children' s Hospital, Department of Radiology, New York, NY (United States)

    2016-10-15

    Calcineurin inhibitor-induced pain syndrome is an entity recognized in patients on immunosuppressive therapy after transplantation. Diagnosis is characterized by onset of pain beginning in the setting of an elevated calcineurin-inhibitor trough level. Reducing the medication dose relieves symptoms. Imaging findings can be nonspecific, including bone marrow edema and periosteal reaction. We present the unique case of calcineurin inhibitor-induced pain syndrome in a child and review the imaging findings. (orig.)

  17. PARP Inhibitors in Ovarian Cancer.

    Science.gov (United States)

    Mittica, Gloria; Ghisoni, Eleonora; Giannone, Gaia; Genta, Sofia; Aglietta, Massimo; Sapino, Anna; Valabrega, Giorgio

    2018-03-05

    Treatment of Epithelial Ovarian Cancer (EOC), historically based on surgery and platinum doublet chemotherapy, is associated with high risk of relapse and poor prognosis for recurrent disease. In this landscape, the innovative treatment with PARP inhibitors (PARPis) demonstrated an outstanding activity in EOC, and is currently changing clinical practice in BRCA mutant patients. To highlight the mechanism of action, pharmacokinetics, clinical activity, indications and current strategies of development of Olaparib, Niraparib, Rucaparib, Talazoparib and Veliparib, the 5 most relevant PARPis. We performed a review on Pubmed using 'ovarian cancer' and the name of each PARPi (PARP inhibitor) discussed in the review as Medical Subject Headings (MeSH) keywords. The same search was performed on "clinicaltrial.gov" to identify ongoing clinical trials and on "google.com/patents" and "uspto.gov" for recent patents exploring PARPIs in ovarian cancer. Olaparib, Niraparib and Rucaparib are already approved for treatment of recurrent EOC and their indications are partially overlapping. Talazoparib and Veliparib are promising PARPis, but currently under investigation in early phase trials. Several studies are evaluating PARPis in monotherapy or in associations, in a wide range of settings (i.e. first line, neoadjuvant, platinum-sensitive and resistant disease). PARPis are valuable options in patients with recurrent ovarian cancer with promising activity in different stages of this disease. Further studies are required to better define optimal clinical settings, predictors of response beyond BRCA mutations and strategies to overcome secondary resistance of PARPis therapy in EOC. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  18. Discovery and SAR of hydantoin TACE inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Wensheng; Guo, Zhuyan; Orth, Peter; Madison, Vincent; Chen, Lei; Dai, Chaoyang; Feltz, Robert J.; Girijavallabhan, Vinay M.; Kim, Seong Heon; Kozlowski, Joseph A.; Lavey, Brian J.; Li, Dansu; Lundell, Daniel; Niu, Xiaoda; Piwinski, John J.; Popovici-Muller, Janeta; Rizvi, Razia; Rosner, Kristin E.; Shankar, Bandarpalle B.; Shih, Neng-Yang; Siddiqui, M.A.; Sun, J.; Tong, L.; Umland, S.; Wong, M.K.; Yang, D.Y.; Zhou, G. (Merck)

    2010-09-03

    We disclose inhibitors of TNF-{alpha} converting enzyme (TACE) designed around a hydantoin zinc binding moiety. Crystal structures of inhibitors bound to TACE revealed monodentate coordination of the hydantoin to the zinc. SAR, X-ray, and modeling designs are described. To our knowledge, these are the first reported X-ray structures of TACE with a hydantoin zinc ligand.

  19. Does plasminogen activator inhibitor-1 drive lymphangiogenesis?

    DEFF Research Database (Denmark)

    Bruyère, Françoise; Melen-Lamalle, Laurence; Blacher, Silvia

    2010-01-01

    The purpose of this study is to explore the function of plasminogen activator inhibitor-1 (PAI-1) during pathological lymphangiogenesis. PAI-1, the main physiological inhibitor of plasminogen activators is involved in pathological angiogenesis at least by controlling extracellular proteolysis and...

  20. Electrochemical Behaviour of Environmentally Friendly Inhibitor of ...

    African Journals Online (AJOL)

    Electrochemical Behaviour of Environmentally Friendly Inhibitor of Aloe Secundiflora Extract in Corrosion Control of Carbon Steel in Soft Water Media. ... The investigation was performed at different inhibitor concentrations under static and dynamic conditions using a Rotating Disk Electrode (RDE). The impedance and ...

  1. Structure-Based Design of Novel HIV-1 Protease Inhibitors to Combat Drug Resistance

    Energy Technology Data Exchange (ETDEWEB)

    Ghosh,A.; Sridhar, P.; Leshchenko, S.; Hussain, A.; Li, J.; Kovalevsky, A.; Walters, D.; Wedelind, J.; Grum-Tokars, V.; et al.

    2006-01-01

    Structure-based design and synthesis of novel HIV protease inhibitors are described. The inhibitors are designed specifically to interact with the backbone of HIV protease active site to combat drug resistance. Inhibitor 3 has exhibited exceedingly potent enzyme inhibitory and antiviral potency. Furthermore, this inhibitor maintains impressive potency against a wide spectrum of HIV including a variety of multi-PI-resistant clinical strains. The inhibitors incorporated a stereochemically defined 5-hexahydrocyclopenta[b]furanyl urethane as the P2-ligand into the (R)-(hydroxyethylamino)sulfonamide isostere. Optically active (3aS,5R,6aR)-5-hydroxy-hexahydrocyclopenta[b]furan was prepared by an enzymatic asymmetrization of meso-diacetate with acetyl cholinesterase, radical cyclization, and Lewis acid-catalyzed anomeric reduction as the key steps. A protein-ligand X-ray crystal structure of inhibitor 3-bound HIV-1 protease (1.35 Angstroms resolution) revealed extensive interactions in the HIV protease active site including strong hydrogen bonding interactions with the backbone. This design strategy may lead to novel inhibitors that can combat drug resistance.

  2. Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors.

    Directory of Open Access Journals (Sweden)

    Christina Gavegnano

    2017-12-01

    Full Text Available Despite advances in the treatment of HIV infection with ART, elucidating strategies to overcome HIV persistence, including blockade of viral reservoir establishment, maintenance, and expansion, remains a challenge. T cell homeostasis is a major driver of HIV persistence. Cytokines involved in regulating homeostasis of memory T cells, the major hub of the HIV reservoir, trigger the Jak-STAT pathway. We evaluated the ability of tofacitinib and ruxolitinib, two FDA-approved Jak inhibitors, to block seeding and maintenance of the HIV reservoir in vitro. We provide direct demonstration for involvement of the Jak-STAT pathway in HIV persistence in vivo, ex vivo, and in vitro; pSTAT5 strongly correlates with increased levels of integrated viral DNA in vivo, and in vitro Jak inhibitors reduce the frequency of CD4+ T cells harboring integrated HIV DNA. We show that Jak inhibitors block viral production from infected cells, inhibit γ-C receptor cytokine (IL-15-induced viral reactivation from latent stores thereby preventing transmission of infectious particles to bystander activated T cells. These results show that dysregulation of the Jak-STAT pathway is associated with viral persistence in vivo, and that Jak inhibitors target key events downstream of γ-C cytokine (IL-2, IL-7 and IL-15 ligation to their receptors, impacting the magnitude of the HIV reservoir in all memory CD4 T cell subsets in vitro and ex vivo. Jak inhibitors represent a therapeutic modality to prevent key events of T cell activation that regulate HIV persistence and together, specific, potent blockade of these events may be integrated to future curative strategies.

  3. Thioredoxin Inhibitors Attenuate Platelet Function and Thrombus Formation.

    Science.gov (United States)

    Metcalfe, Clive; Ramasubramoni, Anjana; Pula, Giordano; Harper, Matthew T; Mundell, Stuart J; Coxon, Carmen H

    2016-01-01

    Thioredoxin (Trx) is an oxidoreductase with important physiological function. Imbalances in the NADPH/thioredoxin reductase/thioredoxin system are associated with a number of pathologies, particularly cancer, and a number of clinical trials for thioredoxin and thioredoxin reductase inhibitors have been carried out or are underway. Due to the emerging role and importance of oxidoreductases for haemostasis and the current interest in developing inhibitors for clinical use, we thought it pertinent to assess whether inhibition of the NADPH/thioredoxin reductase/thioredoxin system affects platelet function and thrombosis. We used small molecule inhibitors of Trx (PMX 464 and PX-12) to determine whether Trx activity influences platelet function, as well as an unbiased proteomics approach to identify potential Trx substrates on the surface of platelets that might contribute to platelet reactivity and function. Using LC-MS/MS we found that PMX 464 and PX-12 affected the oxidation state of thiols in a number of cell surface proteins. Key surface receptors for platelet adhesion and activation were affected, including the collagen receptor GPVI and the von Willebrand factor receptor, GPIb. To experimentally validate these findings we assessed platelet function in the presence of PMX 464, PX-12, and rutin (a selective inhibitor of the related protein disulphide isomerase). In agreement with the proteomics data, small molecule inhibitors of thioredoxin selectively inhibited GPVI-mediated platelet activation, and attenuated ristocetin-induced GPIb-vWF-mediated platelet agglutination, thus validating the findings of the proteomics study. These data reveal a novel role for thioredoxin in regulating platelet reactivity via proteins required for early platelet responses at sites of vessel injury (GPVI and GPIb). This work also highlights a potential opportunity for repurposing of PMX 464 and PX-12 as antiplatelet agents.

  4. Thioredoxin Inhibitors Attenuate Platelet Function and Thrombus Formation.

    Directory of Open Access Journals (Sweden)

    Clive Metcalfe

    Full Text Available Thioredoxin (Trx is an oxidoreductase with important physiological function. Imbalances in the NADPH/thioredoxin reductase/thioredoxin system are associated with a number of pathologies, particularly cancer, and a number of clinical trials for thioredoxin and thioredoxin reductase inhibitors have been carried out or are underway. Due to the emerging role and importance of oxidoreductases for haemostasis and the current interest in developing inhibitors for clinical use, we thought it pertinent to assess whether inhibition of the NADPH/thioredoxin reductase/thioredoxin system affects platelet function and thrombosis. We used small molecule inhibitors of Trx (PMX 464 and PX-12 to determine whether Trx activity influences platelet function, as well as an unbiased proteomics approach to identify potential Trx substrates on the surface of platelets that might contribute to platelet reactivity and function. Using LC-MS/MS we found that PMX 464 and PX-12 affected the oxidation state of thiols in a number of cell surface proteins. Key surface receptors for platelet adhesion and activation were affected, including the collagen receptor GPVI and the von Willebrand factor receptor, GPIb. To experimentally validate these findings we assessed platelet function in the presence of PMX 464, PX-12, and rutin (a selective inhibitor of the related protein disulphide isomerase. In agreement with the proteomics data, small molecule inhibitors of thioredoxin selectively inhibited GPVI-mediated platelet activation, and attenuated ristocetin-induced GPIb-vWF-mediated platelet agglutination, thus validating the findings of the proteomics study. These data reveal a novel role for thioredoxin in regulating platelet reactivity via proteins required for early platelet responses at sites of vessel injury (GPVI and GPIb. This work also highlights a potential opportunity for repurposing of PMX 464 and PX-12 as antiplatelet agents.

  5. Developing selective histone deacetylases (HDACs) inhibitors through ebselen and analogs.

    Science.gov (United States)

    Wang, Yuren; Wallach, Jason; Duane, Stephanie; Wang, Yuan; Wu, Jianghong; Wang, Jeffrey; Adejare, Adeboye; Ma, Haiching

    2017-01-01

    Histone deacetylases (HDACs) are key regulators of gene expression in cells and have been investigated as important therapeutic targets for cancer and other diseases. Different subtypes of HDACs appear to play disparate roles in the cells and are associated with specific diseases. Therefore, substantial effort has been made to develop subtype-selective HDAC inhibitors. In an effort to discover existing scaffolds with HDAC inhibitory activity, we screened a drug library approved by the US Food and Drug Administration and a National Institutes of Health Clinical Collection compound library in HDAC enzymatic assays. Ebselen, a clinical safe compound, was identified as a weak inhibitor of several HDACs, including HDAC1, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, and HDAC9 with half maximal inhibitory concentrations approximately single digit of µM. Two ebselen analogs, ebselen oxide and ebsulfur (a diselenide analog of ebselen), also inhibited these HDACs, however with improved potencies on HDAC8. Benzisothiazol, the core structure of ebsulfur, specifically inhibited HDAC6 at a single digit of µM but had no inhibition on other HDACs. Further efforts on structure-activity relationship based on the core structure of ebsulfur led to the discovery of a novel class of potent and selective HDAC6 inhibitors with RBC-2008 as the lead compound with single-digit nM potency. This class of histone deacetylase inhibitor features a novel pharmacophore with an ebsulfur scaffold selectively targeting HDAC6. Consistent with its inhibition on HDAC6, RBC-2008 significantly increased the acetylation levels of α-tubulin in PC-3 cells. Furthermore, treatment with these compounds led to cell death of multiple tumor cell lines in a dose-dependent manner. These results demonstrated that ebselen and ebsulfur analogs are inhibitors of HDACs, supporting further preclinical development of this class of compounds for potential therapeutic applications.

  6. Suppression of Coronavirus Replication by Cyclophilin Inhibitors

    Directory of Open Access Journals (Sweden)

    Takashi Sasaki

    2013-05-01

    Full Text Available Coronaviruses infect a variety of mammalian and avian species and cause serious diseases in humans, cats, mice, and birds in the form of severe acute respiratory syndrome (SARS, feline infectious peritonitis (FIP, mouse hepatitis, and avian infectious bronchitis, respectively. No effective vaccine or treatment has been developed for SARS-coronavirus or FIP virus, both of which cause lethal diseases. It has been reported that a cyclophilin inhibitor, cyclosporin A (CsA, could inhibit the replication of coronaviruses. CsA is a well-known immunosuppressive drug that binds to cellular cyclophilins to inhibit calcineurin, a calcium-calmodulin-activated serine/threonine-specific phosphatase. The inhibition of calcineurin blocks the translocation of nuclear factor of activated T cells from the cytosol into the nucleus, thus preventing the transcription of genes encoding cytokines such as interleukin-2. Cyclophilins are peptidyl-prolyl isomerases with physiological functions that have been described for many years to include chaperone and foldase activities. Also, many viruses require cyclophilins for replication; these include human immunodeficiency virus, vesicular stomatitis virus, and hepatitis C virus. However, the molecular mechanisms leading to the suppression of viral replication differ for different viruses. This review describes the suppressive effects of CsA on coronavirus replication.

  7. SGLT2 inhibitors in the management of type 2 diabetes.

    Science.gov (United States)

    Monica Reddy, R P; Inzucchi, Silvio E

    2016-08-01

    The glucose-lowering pharmacopeia continues to grow for patients with type 2 diabetes. The latest drug category, the SGLT2 inhibitors reduce glycated hemoglobin concentrations by increasing urinary excretion of glucose. They are used mainly in combination with metformin and other antihyperglycemic agents, including insulin. Their glucose-lowering potency is modest. Advantages include lack of hypoglycemia as a side effect, and mild reduction in blood pressure and body weight. Side effects include increased urinary frequency, owing to their mild diuretic action, symptoms of hypovolemia, genitourinary infections. There are also recent reports of rare cases of diabetic ketoacidosis occurring in insulin-treated patients. Recently, a large cardiovascular outcome trial reported that a specific SGLT2 inhibitor, empagliflozin, led to a reduction in the primary endpoint of major cardiovascular events. This effect was mainly the result of a surprising 38 % reduction in cardiovascular death, and the drug was also associated with nearly as large a reduction in heart failure hospitalization. These findings were notable because most drugs used in type 2 diabetes have not been shown to improve cardiovascular outcomes. Accordingly, there is growing interest in empagliflozin and the entire SGLT2 inhibitor class as drugs that could potentially change the manner in which we approach the management of hyperglycemia in patients with type 2 diabetes.

  8. A luciferase-based assay for rapid assessment of drug activity against Mycobacterium tuberculosis including monitoring of macrophage viability.

    Science.gov (United States)

    Larsson, Marie C; Lerm, Maria; Ängeby, Kristian; Nordvall, Michaela; Juréen, Pontus; Schön, Thomas

    2014-11-01

    The intracellular (IC) effect of drugs against Mycobacterium tuberculosis (Mtb) is not well established but increasingly important to consider when combining current and future multidrug regimens into the best possible treatment strategies. For this purpose, we developed an IC model based on a genetically modified Mtb H37Rv strain, expressing the Vibrio harvei luciferase (H37Rv-lux) infecting the human macrophage like cell line THP-1. Cells were infected at a low multiplicity of infection (1:1) and subsequently exposed to isoniazid (INH), ethambutol (EMB), amikacin (AMI) or levofloxacin (LEV) for 5days in a 96-well format. Cell viability was evaluated by Calcein AM and was maintained throughout the experiment. The number of viable H37Rv-lux was determined by luminescence and verified by a colony forming unit analysis. The results were compared to the effects of the same drugs in broth cultures. AMI, EMB and LEV were significantly less effective intracellularly (MIC90: >4mg/L, 8mg/L and 2mg/L, respectively) compared to extracellularly (MIC90: 0.5mg/L for AMI and EMB; 0.25mg/L for LEV). The reverse was the case for INH (IC: 0.064mg/L vs EC: 0.25mg/L). In conclusion, this luciferase based method, in which monitoring of cell viability is included, has the potential to become a useful tool while evaluating the intracellular effects of anti-mycobacterial drugs. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. What Are The Benefits In The Association Of SGLT2 Inhibitors And Other Drugs?

    Directory of Open Access Journals (Sweden)

    Deici Aparecida Gomes Rodrigues

    2017-11-01

    Full Text Available The SGLT2 inhibitors are a class of drugs that blocks the sodium-glucose co-transport, which is responsible for 90% of the nephron glucose. Objective: To show the benefits of the SGLT2 inhibitors in monotherapy and in association with other drugs. Results: The association of SGLT2 inhibitors and other drugs has shown several additional benefits after their interaction, including weight loss, reduction of body fat, reduction of triglycerides level, decrease of glycated hemoglobin, decrease in postprandial glucose level, reduction of arterial pressure, decrease of hypoglycemia risk and improvement of glucose metabolism. Therefore, this is a promising interaction for type 2 diabetes.

  10. Removal of PCR inhibitors using dielectrophoresis as a selective filter in a microsystem

    DEFF Research Database (Denmark)

    Perch-Nielsen, Ivan Ryberg; Bang, Dang Duong; Poulsen, Claus Riber

    2003-01-01

    , the removal of PCR inhibitors in sample preparation steps is essential and several methods have been published. The methods are either chemical or based on filtering. Conventional ways of filtering include mechanical filters or washing e. g. by centrifugation. Another way of filtering is the use of electric...... to manipulate cells in many microstructures. In this study, we used DEP as a selective filter for holding cells in a microsystem while the PCR inhibitors were flushed out of the system. Haemoglobin and heparin-natural components of blood-were selected as PCR inhibitors, since the inhibitory effects...

  11. SALO, a novel classical pathway complement inhibitor from saliva of the sand fly Lutzomyia longipalpis

    OpenAIRE

    Viviana P. Ferreira; Vladimir Fazito Vale; Michael K. Pangburn; Maha Abdeladhim; Antonio Ferreira Mendes-Sousa; Iliano V. Coutinho-Abreu; Manoochehr Rasouli; Elizabeth A. Brandt; Claudio Meneses; Kolyvan Ferreira Lima; Ricardo Nascimento Araújo; Marcos Horácio Pereira; Michalis Kotsyfakis; Fabiano Oliveira; Shaden Kamhawi

    2016-01-01

    Blood-feeding insects inject potent salivary components including complement inhibitors into their host's skin to acquire a blood meal. Sand fly saliva was shown to inhibit the classical pathway of complement; however, the molecular identity of the inhibitor remains unknown. Here, we identified SALO as the classical pathway complement inhibitor. SALO, an 11 kDa protein, has no homology to proteins of any other organism apart from New World sand flies. rSALO anti-complement activity has the sa...

  12. Recent Advances in the Development of Mammalian Geranylgeranyl Diphosphate Synthase Inhibitors

    Directory of Open Access Journals (Sweden)

    Staci L. Haney

    2017-05-01

    Full Text Available The enzyme geranylgeranyl diphosphate synthase (GGDPS catalyzes the synthesis of the 20-carbon isoprenoid geranylgeranyl diphosphate (GGPP. GGPP is the isoprenoid donor for protein geranylgeranylation reactions catalyzed by the enzymes geranylgeranyl transferase (GGTase I and II. Inhibitors of GGDPS result in diminution of protein geranylgeranylation through depletion of cellular GGPP levels, and there has been interest in GGDPS inhibitors as potential anti-cancer agents. Here we discuss recent advances in the development of GGDPS inhibitors, including insights gained by structure-function relationships, and review the preclinical data that support the continued development of this novel class of drugs.

  13. Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of pulmonary embolism.

    Science.gov (United States)

    Robertson, Lindsay; Kesteven, Patrick; McCaslin, James E

    2015-12-04

    Pulmonary embolism is a potentially life-threatening condition in which a clot can travel from the deep veins, most commonly in the leg, up to the lungs. Previously, a pulmonary embolism was treated with the anticoagulants heparin and vitamin K antagonists. Recently, however, two forms of direct oral anticoagulants (DOACs) have been developed: oral direct thrombin inhibitors (DTI) and oral factor Xa inhibitors. The new drugs have characteristics that may be favourable over conventional treatment, including oral administration, a predictable effect, lack of frequent monitoring or re-dosing and few known drug interactions. To date, no Cochrane review has measured the effectiveness and safety of these drugs in the long-term treatment (minimum duration of three months) of pulmonary embolism. To assess the effectiveness of oral DTIs and oral factor Xa inhibitors for the long-term treatment of pulmonary embolism. The Cochrane Vascular Trials Search Co-ordinator searched the Specialised Register (last searched January 2015) and the Cochrane Register of Studies (last searched January 2015). Clinical trials databases were also searched for details of ongoing or unpublished studies. We searched the reference lists of relevant articles retrieved by electronic searches for additional citations. We included randomised controlled trials in which patients with a pulmonary embolism confirmed by standard imaging techniques were allocated to receive an oral DTI or an oral factor Xa inhibitor for the long-term (minimum duration three months) treatment of pulmonary embolism. Two review authors (LR, JM) independently extracted the data and assessed the risk of bias in the trials. Any disagreements were resolved by discussion with the third author (PK). We used meta-analyses when we considered heterogeneity low. The two primary outcomes were recurrent venous thromboembolism and pulmonary embolism. Other outcomes included all-cause mortality and major bleeding. We calculated all outcomes

  14. AZT as a telomerase inhibitor

    International Nuclear Information System (INIS)

    Gomez, Daniel E.; Armando, Romina G.; Alonso, Daniel F.

    2012-01-01

    Telomerase is a highly specialized reverse transcriptase (RT) and the maintenance of telomeric length is determined by this specific enzyme. The human holoenzyme telomerase is a ribonucleoprotein composed by a catalytic subunit, hTERT, an RNA component, hTR, and a group of associated proteins. Telomerase is normally expressed in embryonic cells and is repressed during adulthood. The enzyme is reexpressed in around 85% of solid tumors. This observation makes it a potential target for developing drugs that could be developed for therapeutic purposes. The identification of the hTERT as a functional catalytic RT prompted studies of inhibiting telomerase with the HIV RT inhibitor azidothymidine (AZT). Previously, we have demonstrated that AZT binds preferentially to telomeres, inhibits telomerase and enhances tumor cell senescence, and apoptosis after AZT treatment in breast mammary adenocarcinoma cells. Since then, several studies have considered AZT for telomerase inhibition and have led to potential clinical strategies for anticancer therapy. This review covers present thinking of the inhibition of telomerase by AZT and future treatment protocols using the drug.

  15. Proton pump inhibitors and gastroenteritis

    International Nuclear Information System (INIS)

    Hassing, Robert-Jan; Verbon, Annelies; Visser, Herman de; Hofman, Albert; Stricker, Bruno H.

    2016-01-01

    An association between proton pump inhibitor (PPI) therapy and bacterial gastroenteritis has been suggested as well as contradicted. The aim of this study was to examine the association between the use of PPIs and occurrence of bacterial gastroenteritis in the prospective Rotterdam Study. The Rotterdam Study is a population-based cohort study among 14,926 subjects aged 45 years and older with up to 24 years of follow-up. Analyses were performed with a generalized estimating equations method in participants who handed-in a diagnostic stool sample. Furthermore, a nested case–control analysis was performed using the total cohort as a reference group. A bacterial microorganism was isolated in 125 samples, whereas 1174 samples were culture negative. In the generalized estimating equations analysis, we found that participants with a bacterial gastroenteritis were more likely than controls to be current users of PPIs (adjusted OR 1.94; 95 % CI 1.15–3.25). Different sensitivity analyses did not change this result. A considerably higher effect was observed (adjusted OR 6.14; 95 % CI 3.81–9.91), using the total cohort as a reference in a nested case–control analysis. Current PPI therapy is associated with an increased risk of bacterial gastroenteritis. However, by reducing the risk of selection and information bias in our study design, we demonstrated that the effect is lower than previously assumed.

  16. ALK inhibitors, a pharmaceutical perspective

    Directory of Open Access Journals (Sweden)

    Arturo eGalvani

    2012-02-01

    Full Text Available In 2007, the ALK tyrosine kinase, already known to be translocated and activated in Anaplastic Large Cell Lymphoma, and a few other rare cancers, was described as a potential therapeutic target for a subset of non small-cell lung cancer (NSCLC patients. Clinical proof of concept, culminating in the recent approval by the FDA of the Pfizer drug Xalkori (crizotinib, formerly known as PF-02341066 followed in record time. The drug was approved together with a companion diagnostic, the Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular, Inc. for detection of eligible patients. This remarkable example of the coming of age of personalized medicine in cancer therapy is hopefully only an auspice of things to come in this rapidly developing field. Perhaps unsurprisingly, however, the appearance of clinical acquired resistance to crizotinib has already been observed early on in clinical testing, with the identification of several ALK secondary point mutations which diminish drug efficacy, and which open the way for development of second-generation inhibitors. It is also emerging that acquired resistance to crizotinib may also occur through ALK-independent mechanisms, which still need to be elucidated in detail.

  17. Impact of sodium–glucose cotransporter 2 inhibitors on blood pressure

    Science.gov (United States)

    Reed, James W

    2016-01-01

    SGLT2 inhibitors are glucose-lowering agents used to treat type 2 diabetes mellitus (T2DM). These agents target the kidney to promote urinary glucose excretion, resulting in improved blood glucose control. SGLT2-inhibitor therapy is also associated with weight loss and blood pressure (BP) lowering. Hypertension is a common comorbidity in patients with T2DM, and is associated with excess morbidity and mortality. This review summarizes data on the effect of SGLT2 inhibitors marketed in the US (namely canagliflozin, dapagliflozin, or empagliflozin) on BP in patients with T2DM. Boolean searches were conducted that included terms related to BP or hypertension with terms for SGLT2 inhibitors, canagliflozin, dapagliflozin, or empagliflozin using PubMed, Google, and Google Scholar. Data from numerous randomized controlled trials of SGLT2 inhibitors in patients with T2DM demonstrated clinically relevant reductions in both systolic and diastolic BP, assessed via seated office measurements and 24-hour ambulatory BP monitoring. Observed BP lowering was not associated with compensatory increases in heart rate. Circadian BP rhythm was also maintained. The mechanism of SGLT2 inhibitor-associated BP reduction is not fully understood, but is assumed to be related to osmotic diuresis and natriuresis. Other factors that may also contribute to BP reduction include SGLT2 inhibitor-associated decreases in body weight and reduced arterial stiffness. Local inhibition of the renin–angiotensin–aldosterone system secondary to increased delivery of sodium to the juxtaglomerular apparatus during SGLT2 inhibition has also been postulated. Although SGLT2 inhibitors are not indicated as BP-lowering agents, the modest decreases in systolic and diastolic BP observed with SGLT2 inhibitors may provide an extra clinical advantage for the majority of patients with T2DM, in addition to improving blood glucose control. PMID:27822054

  18. Nutrient content of wheat and corn in response to the application of urea and the urease inhibitor NPBT

    Science.gov (United States)

    A field study was conducted to evaluate the effects of the addition of two different urease inhibitors on the volatilization of ammonia from top dressed ammonia sources on winter wheat and dent corn. Two commercial urease inhibitors (NY and AG) were tested. Treatments included compost, compost+NY, u...

  19. 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

  20. An Updated Review of Tyrosinase Inhibitors

    Directory of Open Access Journals (Sweden)

    Te-Sheng Chang

    2009-05-01

    Full Text Available Tyrosinase is a multifunctional, glycosylated, and copper-containing oxidase, which catalyzes the first two steps in mammalian melanogenesis and is responsible for enzymatic browning reactions in damaged fruits during post-harvest handling and processing. Neither hyperpigmentation in human skin nor enzymatic browning in fruits are desirable. These phenomena have encouraged researchers to seek new potent tyrosinase inhibitors for use in foods and cosmetics. This article surveys tyrosinase inhibitors newly discovered from natural and synthetic sources. The inhibitory strength is compared with that of a standard inhibitor, kojic acid, and their inhibitory mechanisms are discussed.

  1. [Research progress of dipeptidyl peptidase 4 inhibitors on healing of chronic diabetic foot ulcers].

    Science.gov (United States)

    Gao, Yunyi; Liang, Yujie; Ran, Xingwu

    2018-05-01

    To review the effect of dipeptidyl peptidase 4 (DPP-4) inhibitors on the wound healing and its mechanisms in chronic diabetic foot ulcers. The latest literature concerning DPP-4 inhibitors for chronic diabetic foot ulcers was extensively reviewed, as well as the potential benefit and mechanism of DPP-4 inhibitors on wound healing of diabetic foot ulcers was analyzed thoroughly. DPP-4 inhibitors can accelerated the ulcer healing. The mechanisms probably include inhibiting the expression of the matrix metalloproteinase (MMP) and restoring the balance of the wound MMP and the tissue inhibitors of MMP; promoting recruitment of endothelial progenitor cells and augmenting angiogenesis; optimizing extracellular matrix construction and the immune response to persistent hypoxia in chronic diabetes wounds, and so on. At present, clinical researches show that DPP-4 inhibitors may be considered as an adjuvant treatment for chronic diabetic foot ulcers. DPP-4 inhibitors show promise in the local wound healing of chronic diabetic foot ulcers. However, more strictly designed, adequately powered, long-term follow-up, and high-quality randomized control trials are needed to further verify their efficacy and safety for chronic diabetic foot ulcers.

  2. Comparative gene expression profiling of P. falciparum malaria parasites exposed to three different histone deacetylase inhibitors.

    Directory of Open Access Journals (Sweden)

    Katherine T Andrews

    Full Text Available Histone deacetylase (HDAC inhibitors are being intensively pursued as potential new drugs for a range of diseases, including malaria. HDAC inhibitors are also important tools for the study of epigenetic mechanisms, transcriptional control, and other important cellular processes. In this study the effects of three structurally related antimalarial HDAC inhibitors on P. falciparum malaria parasite gene expression were compared. The three hydroxamate-based compounds, trichostatin A (TSA, suberoylanilide hydroxamic acid (SAHA; Vorinostat® and a 2-aminosuberic acid derivative (2-ASA-9, all caused profound transcriptional effects, with ~2-21% of genes having >2-fold altered expression following 2 h exposure to the compounds. Only two genes, alpha tubulin II and a hydrolase, were up-regulated by all three compounds after 2 h exposure in all biological replicates examined. The transcriptional changes observed after 2 h exposure to HDAC inhibitors were found to be largely transitory, with only 1-5% of genes being regulated after removing the compounds and culturing for a further 2 h. Despite some structural similarity, the three inhibitors caused quite diverse transcriptional effects, possibly reflecting subtle differences in mode of action or cellular distribution. This dataset represents an important contribution to our understanding of how HDAC inhibitors act on malaria parasites and identifies alpha tubulin II as a potential transcriptional marker of HDAC inhibition in malaria parasites that may be able to be exploited for future development of HDAC inhibitors as new antimalarial agents.

  3. Novel polymers as scale inhibitors for squeeze treatments

    Energy Technology Data Exchange (ETDEWEB)

    Duccini, Y.

    1996-12-31

    Squeeze treatments are increasingly important to recover oil from offshore platforms. During production deposition occurs and scale inhibitors are widely used. Different chemicals are already used to inhibit several scaling components, including BaSO{sub 4} which appears to be the major problem in wells of the North Sea. Phosphonates, polyacrylates, phosphinocarboxylates and polyvinylsulfonates are the leading products. All of them do not fulfill end users requirements, especially for harsh conditions such as low pHs, high barium and extreme temperatures and pressures. The paper describes new inhibitors both for standard conditions and harsh conditions which are overcoming most of the present drawbacks. In both sets of conditions, the results on performances, stability and absorption-desorption properties are presented. 7 refs., 9 figs., 4 tabs.

  4. Red wine contains a potent inhibitor of phenolsulphotransferase.

    Science.gov (United States)

    Littlewood, J T; Glover, V; Sandler, M

    1985-01-01

    Many ethanolic drinks, especially red wine, contain potent inhibitors of phenolsulphotransferase. At a dilution of 1/75 from the original beverage, extracts from six types of red wine inhibited human platelet phenolsulphotransferase P by a mean of 99% and human platelet phenolsulphotransferase M by 12%. Such extracts had no significant effect on rat liver monoamine oxidase A or human platelet monoamine oxidase B. The inhibitors, which have not yet been identified, can be extracted into ethyl acetate at acid or neutral pH. Thus, they are not monoamines. Flavonoid phenols are plausible candidates. As phenolsulphotransferase M and P are involved in the metabolism of many phenols, including drugs, the inhibition of these enzymes could result in the enhancement of pharmacological potency and have important clinical consequences. PMID:3857069

  5. Hepatocyte growth factor inhibitor-2 prevents shedding of matritpase

    DEFF Research Database (Denmark)

    Larsen, Brian R; Steffensen, Simon D; Nielsen, Nis V L

    2013-01-01

    Hepatocyte growth factor activator inhibitor-2 (HAI-2) is an inhibitor of many proteases in vitro, including the membrane-bound serine protease, matriptase. Studies of knock-out mice have shown that HAI-2 is essential for placental development only in mice expressing matriptase, suggesting that HAI......-2 is important for regulation of matriptase. Previous studies have shown that recombinant expression of matriptase was unsuccessful unless co-expressed with another HAI, HAI-1. In the present study we show that when human matriptase is recombinantly expressed alone in the canine cell line MDCK......, then human matriptase mRNA can be detected and the human matriptase ectodomain is shed to the media, suggesting that matriptase expressed alone is rapidly transported through the secretory pathway and shed. Whereas matriptase expressed together with HAI-1 or HAI-2 accumulates on the plasma membrane where...

  6. Tyrosine-like condensed derivatives as tyrosinase inhibitors.

    Science.gov (United States)

    Matos, Maria João; Santana, Lourdes; Uriarte, Eugenio; Serra, Silvia; Corda, Marcella; Fadda, Maria Benedetta; Era, Benedetta; Fais, Antonella

    2012-05-01

    We report the pharmacological evaluation of a new series of 3-aminocoumarins differently substituted with hydroxyl groups, which have been synthesized because they include in their structures the tyrosine fragment (tyrosine-like compounds), with the aim of discovering structural features necessary for tyrosinase inhibitory activity. The synthesized compounds 4 and 7-9 were evaluated in vitro as mushroom tyrosinase inhibitors. Two of the described compounds showed lower IC50 (concentration giving 50% inhibition of tyrosinase activity) than umbelliferone, used as a reference compound. Compound 7 (IC50=53µm) was the best tyrosinase inhibitor of this small series, having an IC50 value 10-fold lower than umbelliferone. Compound 7 (3-amino-7-hydroxycoumarin) had amino and hydroxyl groups precisely mimicking the same positions that both groups occupy on the tyrosine molecule. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

  7. Effect of Inhibitors on Atom Transfer Radical Polymerization of MMA

    Institute of Scientific and Technical Information of China (English)

    张鸿; 徐冬梅; 张可达

    2005-01-01

    Effect of a series of inhibitors as additives on atom transfer radical polymerization (ATRP) of methyl methacrylate (MMA) with FeCl2/PPh3 as catalyst system was studied, including 2,4,6-trinitrophenol (TNP), 4-methoxyphenol (4-MP), hydroquinone (HQ) and nitrobenzene (NB). It was found that TNP was the only. efficient additive for ATRP among these inhibitors. In the presence of small amounts of TNP, the polymerization proceeded rapidly after induction period to yield the polymers with controlled molecular weights and narrow molecular weight distributions (MWD). The initiating efficiency of the modified catalyst system with TNP was increased. The mechanism was proposed and confirmed by the end group analysis of the polymer.

  8. Immunomodulatory effects of histone deacetylase inhibitors.

    Science.gov (United States)

    Licciardi, P V; Ververis, K; Tang, M L; El-Osta, A; Karagiannis, T C

    2013-05-01

    Histone deacetylase inhibitors (HDACi) have emerged as a new generation of anticancer therapeutics. The classical broad-spectrum HDACi typically alter the cell cycle distribution and induce cell death, apoptosis and differentiation in malignant and transformed cells. This provides the basis for the clinical potential of HDACi in cancer therapy. Currently two compounds, suberoylanilide hydroxamic acid (SAHA, Vorinostat, Zolinza™) and depsipeptide (Romidepsin, Istodax™) have been approved for by the US Food and Drug Administration for the treatment of refractory cutaneous T-cell lymphoma. Apart from clinical application in oncology, HDACi have also been investigated as potential therapeutics for various pathologies including those of the central nervous system (such as Huntington's disease and multiple sclerosis), cardiac conditions (particularly hypertrophy), arthritis and malaria. Further, evidence is accumulating for potent immunomodulatory effects of classical HDACi which is the focus of this review. We review the antiinflammatory effects of HDACi and in particular findings implicating regulation of the innate and adaptive immune systems by HDAC enzymes. The recent findings highlighting the immunomodulatory function of HDAC11 which relates to balancing immune activation versus tolerance are also discussed.

  9. Clinically Applicable Inhibitors Impacting Genome Stability.

    Science.gov (United States)

    Prakash, Anu; Garcia-Moreno, Juan F; Brown, James A L; Bourke, Emer

    2018-05-13

    Advances in technology have facilitated the molecular profiling (genomic and transcriptomic) of tumours, and has led to improved stratification of patients and the individualisation of treatment regimes. To fully realize the potential of truly personalised treatment options, we need targeted therapies that precisely disrupt the compensatory pathways identified by profiling which allow tumours to survive or gain resistance to treatments. Here, we discuss recent advances in novel therapies that impact the genome (chromosomes and chromatin), pathways targeted and the stage of the pathways targeted. The current state of research will be discussed, with a focus on compounds that have advanced into trials (clinical and pre-clinical). We will discuss inhibitors of specific DNA damage responses and other genome stability pathways, including those in development, which are likely to synergistically combine with current therapeutic options. Tumour profiling data, combined with the knowledge of new treatments that affect the regulation of essential tumour signalling pathways, is revealing fundamental insights into cancer progression and resistance mechanisms. This is the forefront of the next evolution of advanced oncology medicine that will ultimately lead to improved survival and may, one day, result in many cancers becoming chronic conditions, rather than fatal diseases.

  10. SGLT2 Inhibitors in Diabetes Mellitus Treatment.

    Science.gov (United States)

    Rosas-Guzman, Juan; Rosas-Saucedo, Juan; Romero-Garcia, Alma R J

    2017-01-01

    Type 2 Diabetes Mellitus (T2DM) is a chronic illness with high prevalence in Mexico, Latin- America, and the world and is associated to high morbidity, disability, and mortality rate, especially in developing countries. T2DM physiopathology is very complex; insulin resistance in the muscle, liver, and adipose tissue, a reduction in the production of incretins (mainly GLP-1) in the intestine, increased glucagon synthesis, an insufficient response of insulin generation, and increased glucose reabsorption in the kidney lead all together to an hyperglycemic state, which has been closely associated with the development of micro and macrovascular complications. Sodium Glucose Linked Transporter 2 inhibitors (SGLT2i) are the most recent therapeutic class available for treating T2DM. SGLT2i central effect is a glycosuric action, and they can reverse the deleterious effect of tubular reabsorption of glucose in the diabetic patient resulting in greater hyperglycemia. Because their mechanism of action is completely different to current drugs, they can be considered as monotherapy or in combination with any other oral or parenteral medication, including different types of insulin or its analogues. This therapeutic synergy accomplishes a greater percentage of patients achieving glycemic control goals. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  11. Strategies for discontinuation of proton pump inhibitors

    DEFF Research Database (Denmark)

    Haastrup, Peter; Paulsen, Maja S; Begtrup, Luise M

    2014-01-01

    PURPOSE: Proton pump inhibitors (PPIs) are considered to be overprescribed. Consensus on how to attempt discontinuation is, however, lacking. We therefore conducted a systematic review of clinical studies on discontinuation of PPIs. METHODS: Systematic review based on clinical studies investigating...

  12. Predicting the Performance of Organic Corrosion Inhibitors

    Directory of Open Access Journals (Sweden)

    David A. Winkler

    2017-12-01

    Full Text Available The withdrawal of effective but toxic corrosion inhibitors has provided an impetus for the discovery of new, benign organic compounds to fill that role. Concurrently, developments in the high-throughput synthesis of organic compounds, the establishment of large libraries of available chemicals, accelerated corrosion inhibition testing technologies, and the increased capability of machine learning methods have made discovery of new corrosion inhibitors much faster and cheaper than it used to be. We summarize these technical developments in the corrosion inhibition field and describe how data-driven machine learning methods can generate models linking molecular properties to corrosion inhibition that can be used to predict the performance of materials not yet synthesized or tested. We briefly summarize the literature on quantitative structure–property relationships models of small organic molecule corrosion inhibitors. The success of these models provides a paradigm for rapid discovery of novel, effective corrosion inhibitors for a range of metals and alloys in diverse environments.

  13. Novel diamide-based inhibitors of IMPDH.

    Science.gov (United States)

    Gu, Henry H; Iwanowicz, Edwin J; Guo, Junqing; Watterson, Scott H; Shen, Zhongqi; Pitts, William J; Dhar, T G Murali; Fleener, Catherine A; Rouleau, Katherine; Sherbina, N Z; Witmer, Mark; Tredup, Jeffrey; Hollenbaugh, Diane

    2002-05-06

    A series of novel amide-based small molecule inhibitors of inosine monophosphate dehydrogenase is described. The synthesis and the structure-activity relationships (SARs) derived from in vitro studies are presented.

  14. 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...

  15. Development of Radiosensitizer using farnesyltransferase inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Jong Seok; Choe, Yong Kyung; Han, Mi Young; Kim, Kwang Dong [Korea Research Institute of Bioscience and Biotechnology, Taejon (Korea)

    1999-03-01

    We selected some compounds that were reported to have an activity of farneyltransferase inhibitor and tested the hypothesis that they might be used to radiosensitize cells transformed by ras oncogenes. The inhibition of ras processing using some, but not all, inhibitors resulted in higher levels of cell death after {gamma}-irradiation and increased radiosensitivity in H-ras-transformed NIH3T3 cells and MCF-10A human tumor cells. They did not induce additional cell death in control cells that doe not have ras mutation. Furthermore, the treatment of inhibitors alone induced a weak G0/G1 block, whereas inhibitors in combination with {gamma}-irradiation induced an additional enrichment in the G2/M phase of the cell cycle that typically represents irradiation-induced growth arrest. At present, the underling mechanism by which the farnesylltransferase inhibitors exert radiosensitizing effect is not known. In summary, our results suggest and lead to the possibility that some of farnesylation inhibitors may prove clinically useful not only as antitumor agents, but also radiosensitizers of tumors whose growth is dependent on ras function. (author). 15 refs., 10 figs., 4 tabs.

  16. Emerging Corrosion Inhibitors for Interfacial Coating

    Directory of Open Access Journals (Sweden)

    Mona Taghavikish

    2017-12-01

    Full Text Available Corrosion is a deterioration of a metal due to reaction with environment. The use of corrosion inhibitors is one of the most effective ways of protecting metal surfaces against corrosion. Their effectiveness is related to the chemical composition, their molecular structures and affinities for adsorption on the metal surface. This review focuses on the potential of ionic liquid, polyionic liquid (PIL and graphene as promising corrosion inhibitors in emerging coatings due to their remarkable properties and various embedment or fabrication strategies. The review begins with a precise description of the synthesis, characterization and structure-property-performance relationship of such inhibitors for anti-corrosion coatings. It establishes a platform for the formation of new generation of PIL based coatings and shows that PIL corrosion inhibitors with various heteroatoms in different form can be employed for corrosion protection with higher barrier properties and protection of metal surface. However, such study is still in its infancy and there is significant scope to further develop new structures of PIL based corrosion inhibitors and coatings and study their behaviour in protection of metals. Besides, it is identified that the combination of ionic liquid, PIL and graphene could possibly contribute to the development of the ultimate corrosion inhibitor based coating.

  17. Discovery of natural mouse serum derived HIV-1 entry inhibitor(s).

    Science.gov (United States)

    Wei, M; Chen, Y; Xi, J; Ru, S; Ji, M; Zhang, D; Fang, Q; Tang, B

    Among rationally designed human immunodeficiency virus 1 (HIV-1) inhibitors, diverse natural factors have showed as potent anti-HIV activity in human blood. We have discovered that the boiled supernatant of healthy mouse serum could suppress HIV-1 entry, and exhibited reduced inhibitory activity after trypsin digestion. Further analysis demonstrated that only the fraction containing 10-25 K proteins could inhibit HIV-1 mediated cell-cell fusion. These results suggest that the 10-25 K protein(s) is novel natural HIV-1 entry inhibitor(s). Our findings provide important information about novel natural HIV entry inhibitors in mouse serum.

  18. A multiple treatment comparison meta-analysis of monoamine oxidase type B inhibitors for Parkinson's disease.

    Science.gov (United States)

    Binde, C D; Tvete, I F; Gåsemyr, J; Natvig, B; Klemp, M

    2018-05-30

    To the best of our knowledge, there are no systematic reviews or meta-analyses that compare rasagiline, selegiline and safinamide. Therefore, we aimed to perform a drug class review comparing all available monoamine oxidase type B (MAO-B) inhibitors in a multiple treatment comparison. We performed a systematic literature search to identify randomized controlled trials assessing the efficacy of MAO-B inhibitors in patients with Parkinson's disease. MAO-B inhibitors were evaluated either as monotherapy or in combination with levodopa or dopamine agonists. Endpoints of interest were change in the Unified Parkinson's Disease Rating Scale (UPDRS) score and serious adverse events. We estimated the relative effect of each MAO-B inhibitor versus the comparator drug by creating three networks of direct and indirect comparisons. For each of the networks, we considered a joint model. The systematic literature search and study selection process identified 27 publications eligible for our three network analyses. We found the relative effects of rasagiline, safinamide and selegiline treatment given alone and compared to placebo in a model without explanatory variables to be 1.560 (1.409, 1.734), 1.449 (0.873, 2.413) and 1.532 (1.337, 1.757) respectively. We also found all MAO-B inhibitors to be efficient when given together with levodopa. When ranking the MAO-B inhibitors given in combination with levodopa, selegiline was the most effective and rasagiline was the second best. All of the included MAO-B inhibitors were effective compared to placebo when given as monotherapy. Combination therapy with MAO-B inhibitors and levodopa showed that all three MAO-B inhibitors were effective compared to placebo, but selegiline was the most effective drug. © 2018 The British Pharmacological Society.

  19. Metabolic responses in Candida tropicalis to complex inhibitors during xylitol bioconversion.

    Science.gov (United States)

    Wang, Shizeng; Li, Hao; Fan, Xiaoguang; Zhang, Jingkun; Tang, Pingwah; Yuan, Qipeng

    2015-09-01

    During xylitol fermentation, Candida tropicalis is often inhibited by inhibitors in hemicellulose hydrolysate. The mechanisms involved in the metabolic responses to inhibitor stress and the resistances to inhibitors are still not clear. To understand the inhibition mechanisms and the metabolic responses to inhibitors, a GC/MS-based metabolomics approach was performed on C. tropicalis treated with and without complex inhibitors (CI, including furfural, phenol and acetic acid). Partial least squares discriminant analysis was used to determine the metabolic variability between CI-treated groups and control groups, and 25 metabolites were identified as possible entities responsible for the discrimination caused by inhibitors. We found that xylose uptake rate and xylitol oxidation rate were promoted by CI treatment. Metabolomics analysis showed that the flux from xylulose to pentose phosphate pathway increased, and tricarboxylic acid cycle was disturbed by CI. Moreover, the changes in levels of 1,3-propanediol, trehalose, saturated fatty acids and amino acids showed different mechanisms involved in metabolic responses to inhibitor stress. The increase of 1,3-propanediol was considered to be correlated with regulating redox balance and osmoregulation. The increase of trehalose might play a role in protein stabilization and cellular membranes protection. Saturated fatty acids could cause the decrease of membrane fluidity and make the plasma membrane rigid to maintain the integrity of plasma membrane. The deeper understanding of the inhibition mechanisms and the metabolic responses to inhibitors will provide us with more information on the metabolism regulation during xylitol bioconversion and the construction of industrial strains with inhibitor tolerance for better utilization of bioresource. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Inhibitor Risk Stratification and Individualized Treatment in Patients With Nonsevere Hemophilia A: A Single-Institution Practice Audit.

    Science.gov (United States)

    Sun, Haowei Linda; Chan, Stella; Yenson, Paul; Jackson, Shannon

    2018-03-01

    Inhibitor risk in nonsevere hemophilia A increases with cumulative factor VIII (FVIII) exposure days and high-risk mutations. A standardized approach to minimize inhibitor risk is warranted. Following establishment of a systematic approach to reduce inhibitor risk in nonsevere hemophilia, we evaluated the uptake of these strategies into clinical practice. All adult males with nonsevere hemophilia A followed by British Columbia Adult Hemophilia Program from 2004 to 2016 were included in this retrospective audit. Quality-of-care indicators on inhibitor prevention were examined. Of 108 patients, 18 patients had high-risk FVIII mutations for inhibitor development. Rates of FVIII genotyping and 1-deamino-8-d-arginine-vasopressin (DDAVP) testing in mild patients without contraindications were both over 90%, although DDAVP was used for surgical prophylaxis in only 70% of procedures. Inhibitor testing and clinic visits occurred at a median interval of 22 months. Over 80% of patients with high-risk mutations had documentation and education on their inhibitor risk. Our practice audit demonstrated a high level of recognition and patient education of individual inhibitor risk. Impact of our standardized approach on the incidence of inhibitor development is yet to be determined.

  1. Developing selective histone deacetylases (HDACs inhibitors through ebselen and analogs

    Directory of Open Access Journals (Sweden)

    Wang Y

    2017-05-01

    Full Text Available Yuren Wang,1 Jason Wallach,2 Stephanie Duane,1 Yuan Wang,1 Jianghong Wu,1 Jeffrey Wang,1 Adeboye Adejare,2 Haiching Ma1 1Reaction Biology Corp., Malvern, 2Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, PA, USA Abstract: Histone deacetylases (HDACs are key regulators of gene expression in cells and have been investigated as important therapeutic targets for cancer and other diseases. Different subtypes of HDACs appear to play disparate roles in the cells and are associated with specific diseases. Therefore, substantial effort has been made to develop subtype-selective HDAC inhibitors. In an effort to discover existing scaffolds with HDAC inhibitory activity, we screened a drug library approved by the US Food and Drug Administration and a National Institutes of Health Clinical Collection compound library in HDAC enzymatic assays. Ebselen, a clinical safe compound, was identified as a weak inhibitor of several HDACs, including HDAC1, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, and HDAC9 with half maximal inhibitory concentrations approximately single digit of µM. Two ebselen analogs, ebselen oxide and ebsulfur (a diselenide analog of ebselen, also inhibited these HDACs, however with improved potencies on HDAC8. Benzisothiazol, the core structure of ebsulfur, specifically inhibited HDAC6 at a single digit of µM but had no inhibition on other HDACs. Further efforts on structure–activity relationship based on the core structure of ebsulfur led to the discovery of a novel class of potent and selective HDAC6 inhibitors with RBC-2008 as the lead compound with single-digit nM potency. This class of histone deacetylase inhibitor features a novel pharmacophore with an ebsulfur scaffold selectively targeting HDAC6. Consistent with its inhibition on HDAC6, RBC-2008 significantly increased the acetylation levels of α-tubulin in PC-3 cells. Furthermore, treatment with these compounds led to

  2. 42 CFR 410.100 - Included services.

    Science.gov (United States)

    2010-10-01

    ... service; however, maintenance therapy itself is not covered as part of these services. (c) Occupational... increase respiratory function, such as graded activity services; these services include physiologic... rehabilitation plan of treatment, including physical therapy services, occupational therapy services, speech...

  3. Static, Lightweight Includes Resolution for PHP

    NARCIS (Netherlands)

    M.A. Hills (Mark); P. Klint (Paul); J.J. Vinju (Jurgen)

    2014-01-01

    htmlabstractDynamic languages include a number of features that are challenging to model properly in static analysis tools. In PHP, one of these features is the include expression, where an arbitrary expression provides the path of the file to include at runtime. In this paper we present two

  4. Article Including Environmental Barrier Coating System

    Science.gov (United States)

    Lee, Kang N. (Inventor)

    2015-01-01

    An enhanced environmental barrier coating for a silicon containing substrate. The enhanced barrier coating may include a bond coat doped with at least one of an alkali metal oxide and an alkali earth metal oxide. The enhanced barrier coating may include a composite mullite bond coat including BSAS and another distinct second phase oxide applied over said surface.

  5. Rare thoracic cancers, including peritoneum mesothelioma

    NARCIS (Netherlands)

    Siesling, Sabine; van der Zwan, Jan Maarten; Izarzugaza, Isabel; Jaal, Jana; Treasure, Tom; Foschi, Roberto; Ricardi, Umberto; Groen, Harry; Tavilla, Andrea; Ardanaz, Eva

    Rare thoracic cancers include those of the trachea, thymus and mesothelioma (including peritoneum mesothelioma). The aim of this study was to describe the incidence, prevalence and survival of rare thoracic tumours using a large database, which includes cancer patients diagnosed from 1978 to 2002,

  6. Rare thoracic cancers, including peritoneum mesothelioma

    NARCIS (Netherlands)

    Siesling, Sabine; Zwan, J.M.V.D.; Izarzugaza, I.; Jaal, J.; Treasure, T.; Foschi, R.; Ricardi, U.; Groen, H.; Tavilla, A.; Ardanaz, E.

    2012-01-01

    Rare thoracic cancers include those of the trachea, thymus and mesothelioma (including peritoneum mesothelioma). The aim of this study was to describe the incidence, prevalence and survival of rare thoracic tumours using a large database, which includes cancer patients diagnosed from 1978 to 2002,

  7. Peptide-Based Selective Inhibitors of Matrix Metalloproteinase-Mediated Activities

    Directory of Open Access Journals (Sweden)

    Margaret W. Ndinguri

    2012-11-01

    Full Text Available The matrix metalloproteinases (MMPs exhibit a broad array of activities, some catalytic and some non-catalytic in nature. An overall lack of selectivity has rendered small molecule, active site targeted MMP inhibitors problematic in execution. Inhibitors that favor few or individual members of the MMP family often take advantage of interactions outside the enzyme active site. We presently focus on peptide-based MMP inhibitors and probes that do not incorporate conventional Zn2+ binding groups. In some cases, these inhibitors and probes function by binding only secondary binding sites (exosites, while others bind both exosites and the active site. A myriad of MMP mediated-activities beyond selective catalysis can be inhibited by peptides, particularly cell adhesion, proliferation, motility, and invasion. Selective MMP binding peptides comprise highly customizable, unique imaging agents. Areas of needed improvement for MMP targeting peptides include binding affinity and stability.

  8. Immune-checkpoint inhibitors in the era of precision medicine: What radiologists should know

    Energy Technology Data Exchange (ETDEWEB)

    Braschi-Amirfarzan, Marta; Tirumani, Sree Harsha; Hodi, Frank Stephan Jr; Nishno, Mizuki [Dept. of Radiology, Brigham and Women' s Hospital and Dana Farber Cancer Institute, Boston (United States)

    2017-01-15

    Over the past five years immune-checkpoint inhibitors have dramatically changed the therapeutic landscape of advanced solid and hematologic malignancies. The currently approved immune-checkpoint inhibitors include antibodies to cytotoxic T-lymphocyte antigen-4, programmed cell death (PD-1), and programmed cell death ligand (PD-L1 and PD-L2). Response to immune-checkpoint inhibitors is evaluated on imaging using the immune-related response criteria. Activation of immune system results in a unique toxicity profile termed immune-related adverse events. This article will review the molecular mechanism, clinical applications, imaging of immune-related response patterns and adverse events associated with immune-checkpoint inhibitors.

  9. Serine proteinase inhibitors from nematodes and the arms race between host and pathogen.

    Science.gov (United States)

    Zang, X; Maizels, R M

    2001-03-01

    Serine proteinase inhibitors are encoded by a large gene family of long evolutionary standing. Recent discoveries of parasite proteins that inhibit human serine proteinases, together with the complete genomic sequence from Caenorhabditis elegans, have provided a set of new serine proteinase inhibitors from more primitive metazoan animals such as nematodes. The structural features (e.g. reactive centre residues), gene organization (including intron arrangements) and inhibitory function and targets (e.g. inflammatory and coagulation pathway proteinase) all contribute important new insights into proteinase inhibitor evolution. Some parasite products have evolved that block enzymes in the mammalian host, but the human host responds with a significant immune response to the parasite inhibitors. Thus, infection produces a finely balanced conflict between host and pathogen at the molecular level, and this might have accelerated the evolution of these proteins in parasitic species as well as their hosts.

  10. Acquired Factor XI Inhibitor Presenting as Spontaneous Bilateral Subdural Hematoma in an Elderly Patient

    Directory of Open Access Journals (Sweden)

    Natale Vazzana

    2014-01-01

    Full Text Available Development of autoantibodies against coagulation factors is an uncommon bleeding disorder associated with cancer, autoimmune conditions, pregnancy, or no apparent disease. Spontaneous FVIII inhibitors are the most frequently encountered; those against FXI have been only anecdotally reported. We report a case of acquired FXI inhibitor presenting as fatal intracranial spontaneous bleeding in an elderly patient with history of cancer and previous transfusions. Few cases of acquired FXI inhibitor have been reported in association with connective tissue disease, cancer, or surgery. Bleeding includes mucocutaneous bleeding, postsurgical hemorrhage, or life-threatening events. Treatment consists of arresting the bleeding and inhibitor eradication. High degree of suspicion is essential to promptly diagnose and treat this uncommon condition.

  11. Immune-checkpoint inhibitors in the era of precision medicine: What radiologists should know

    International Nuclear Information System (INIS)

    Braschi-Amirfarzan, Marta; Tirumani, Sree Harsha; Hodi, Frank Stephan Jr; Nishno, Mizuki

    2017-01-01

    Over the past five years immune-checkpoint inhibitors have dramatically changed the therapeutic landscape of advanced solid and hematologic malignancies. The currently approved immune-checkpoint inhibitors include antibodies to cytotoxic T-lymphocyte antigen-4, programmed cell death (PD-1), and programmed cell death ligand (PD-L1 and PD-L2). Response to immune-checkpoint inhibitors is evaluated on imaging using the immune-related response criteria. Activation of immune system results in a unique toxicity profile termed immune-related adverse events. This article will review the molecular mechanism, clinical applications, imaging of immune-related response patterns and adverse events associated with immune-checkpoint inhibitors

  12. Protective effects of an aptamer inhibitor of neutrophil elastase in lung inflammatory injury

    DEFF Research Database (Denmark)

    Bless, N M; Smith, D; Charlton, J

    1997-01-01

    Neutrophils play an important part in the development of acute inflammatory injury. Human neutrophils contain high levels of the serine protease elastase, which is stored in azurophilic granules and is secreted in response to inflammatory stimuli. Elastase is capable of degrading many components...... of extracellular matrix [1-4] and has cytotoxic effects on endothelial cells [5-7] and airway epithelial cells. Three types of endogenous protease inhibitors control the activity of neutrophil elastase, including alpha-1 protease inhibitor (alpha-1PI), alpha-2 macroglobulin and secreted leukoproteinase inhibitor...... (SLPI) [8-10]. A disturbed balance between neutrophil elastase and these inhibitors has been found in various acute clinical conditions (such as adult respiratory syndrome and ischemia-reperfusion injury) and in chronic diseases. We investigated the effect of NX21909, a selected oligonucleotide (aptamer...

  13. Inactivation of proteinaceous protease inhibitors of soybeans by isolated fungi

    NARCIS (Netherlands)

    Meijer, M.M.T.; Spekking, W.T.J.; Sijtsma, L.; Bont, de J.A.M.

    1995-01-01

    Proteinaceous protease inhibitors, Kunitz Soybean Trypsin Inhibitor (KSTI) and Bowman Birk Inhibitor (BBI), in legume seeds reduce the digestibility of proteins in feed of monogastric animals. Enzymatic inactivation of these inhibitors will increase the nutritional value of the feed. The aim of this

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-08-15

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

  15. Discovery and Characterization of Novel Nonsubstrate and Substrate NAMPT Inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Wilsbacher, Julie L.; Cheng, Min; Cheng, Dong; Trammell, Samuel A.J.; Shi, Yan; Guo, Jun; Koeniger, Stormy L.; Kovar, Peter J.; He, Yupeng; Selvaraju, Sujatha; Heyman, H. Robin; Sorensen, Bryan K.; Clark, Richard F.; Hansen, T. Matthew; Longenecker, Kenton L.; Raich, Diana; Korepanova, Alla V.; Cepa, Steven; Towne, Danli L.; Abraham, Vivek C.; Tang, Hua; Richardson, Paul L.; McLoughlin, Shaun M.; Badagnani, Ilaria; Curtin, Michael L.; Michaelides, Michael R.; Maag, David; Buchanan, F. Gregory; Chiang, Gary G.; Gao, Wenqing; Rosenberg, Saul H.; Brenner, Charles; Tse, Chris (AbbVie)

    2017-05-03

    Cancer cells are highly reliant on NAD+-dependent processes, including glucose metabolism, calcium signaling, DNA repair, and regulation of gene expression. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ salvage from nicotinamide, has been investigated as a target for anticancer therapy. Known NAMPT inhibitors with potent cell activity are composed of a nitrogen-containing aromatic group, which is phosphoribosylated by the enzyme. Here, we identified two novel types of NAM-competitive NAMPT inhibitors, only one of which contains a modifiable, aromatic nitrogen that could be a phosphoribosyl acceptor. Both types of compound effectively deplete cellular NAD+, and subsequently ATP, and produce cell death when NAMPT is inhibited in cultured cells for more than 48 hours. Careful characterization of the kinetics of NAMPT inhibition in vivo allowed us to optimize dosing to produce sufficient NAD+ depletion over time that resulted in efficacy in an HCT116 xenograft model. Our data demonstrate that direct phosphoribosylation of competitive inhibitors by the NAMPT enzyme is not required for potent in vitro cellular activity or in vivo antitumor efficacy. Mol Cancer Ther; 16(7); 1236–45.

  16. Do non-nucleoside reverse transcriptase inhibitors contribute to lipodystrophy?

    Science.gov (United States)

    Nolan, David

    2005-01-01

    Lipodystrophy complications, including lipoatrophy (pathological fat loss) and metabolic complications, have emerged as important long-term toxicities associated with antiretroviral therapy in the current era. The wealth of data that has accumulated over the past 6 years has now clarified the contribution of specific antiretroviral drugs to the risk of these clinical endpoints, with evidence that lipoatrophy is strongly associated with the choice of nucleoside reverse transcriptase inhibitor therapy (specifically, stavudine and to a lesser extent zidovudine). The aetiological basis of metabolic complications of antiretroviral therapy has proven to be complex, in that the risk appears to be modulated by a number of lifestyle factors that have made the metabolic syndrome highly prevalent in the general population, with additional contributions from HIV disease status itself, as well as from individual drugs within the HIV protease inhibitor class. The currently licensed non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs, efavirenz and nevirapine, have been proven to have a favourable safety profile in terms of lipodystrophy complications. However, it must be noted that NNRTI drugs also have individual toxicity profiles that must be accounted for when considering and/or monitoring their use in the treatment of HIV infection.

  17. Multimerized CHR-derived peptides as HIV-1 fusion inhibitors.

    Science.gov (United States)

    Nomura, Wataru; Hashimoto, Chie; Suzuki, Takaharu; Ohashi, Nami; Fujino, Masayuki; Murakami, Tsutomu; Yamamoto, Naoki; Tamamura, Hirokazu

    2013-08-01

    To date, several HIV-1 fusion inhibitors based on the carboxy-terminal leucine/isoleucine heptad repeat (CHR) region of an HIV-1 envelope protein gp41 have been discovered. We have shown that a synthetic peptide mimetic of a trimer form of the CHR-derived peptide C34 has potent inhibitory activity against the HIV-1 fusion mechanism, compared to a monomer C34 peptide. The present study revealed that a dimeric form of C34 is evidently structurally critical for fusion inhibitors, and that the activity of multimerized CHR-derived peptides in fusion inhibition is affected by the properties of the unit peptides C34, SC34EK, and T20. The fluorescence-based study suggested that the N36-interactive sites of the C34 trimer, including hydrophobic residues, are exposed outside the trimer and that trimerization of C34 caused a remarkable increase in fusion inhibitory activity. The present results could be useful in the design of fusion inhibitors against viral infections which proceed via membrane fusion with host cells. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

  18. Acquired resistance to EGFR inhibitors: mechanisms and prevention strategies

    International Nuclear Information System (INIS)

    Viloria-Petit, Alicia M.; Kerbel, Robert S.

    2004-01-01

    Potent and specific, or relatively specific, inhibitors of epidermal growth factor receptor (EGFR) signaling, including monoclonal antibodies and small molecular weight compounds, have been successfully developed. Both types of agent have been found to have significant antitumor activity, especially when used in combination with radio- hormone- and chemotherapy in preclinical studies. Because of the potentiation of the conventional drug activity in these combination settings, inhibitors of EGFR signaling have often been referred to as sensitizers for chemotherapy or radiation, as well as drug resistance reversal agents. Phase II clinical trials in head-and-neck as well as lung cancer suggested this concept of chemosensitization might translate into the clinic, but this remains to be definitively proven in randomized, double-blind Phase III trials. Given the extensive preclinical literature on EGFR blocking drugs and the advanced clinical development of such agents, it is surprising that the possibility of development of acquired resistance to the EGFR inhibitors themselves, a common clinical problem with virtually all other currently used anticancer drugs, remains a largely unexplored subject of investigation. Here we summarize some of the possible mechanisms that can result in acquired resistance to EGFR-targeting drugs. Alternative combination therapies to circumvent and delay this problem are suggested

  19. QStatin, a Selective Inhibitor of Quorum Sensing in Vibrio Species

    Directory of Open Access Journals (Sweden)

    Byoung Sik Kim

    2018-01-01

    Full Text Available Pathogenic Vibrio species cause diseases in diverse marine animals reared in aquaculture. Since their pathogenesis, persistence, and survival in marine environments are regulated by quorum sensing (QS, QS interference has attracted attention as a means to control these bacteria in aquatic settings. A few QS inhibitors of Vibrio species have been reported, but detailed molecular mechanisms are lacking. Here, we identified a novel, potent, and selective Vibrio QS inhibitor, named QStatin [1-(5-bromothiophene-2-sulfonyl-1H-pyrazole], which affects Vibrio harveyi LuxR homologues, the well-conserved master transcriptional regulators for QS in Vibrio species. Crystallographic and biochemical analyses showed that QStatin binds tightly to a putative ligand-binding pocket in SmcR, the LuxR homologue in V. vulnificus, and changes the flexibility of the protein, thereby altering its transcription regulatory activity. Transcriptome analysis revealed that QStatin results in SmcR dysfunction, affecting the expression of SmcR regulon required for virulence, motility/chemotaxis, and biofilm dynamics. Notably, QStatin attenuated representative QS-regulated phenotypes in various Vibrio species, including virulence against the brine shrimp (Artemia franciscana. Together, these results provide molecular insights into the mechanism of action of an effective, sustainable QS inhibitor that is less susceptible to resistance than other antimicrobial agents and useful in controlling the virulence of Vibrio species in aquacultures.

  20. Role of mTOR Inhibitors in Kidney Disease

    Directory of Open Access Journals (Sweden)

    Moto Kajiwara

    2016-06-01

    Full Text Available The first compound that inhibited the mammalian target of rapamycin (mTOR, sirolimus (rapamycin was discovered in the 1970s as a soil bacterium metabolite collected on Easter Island (Rapa Nui. Because sirolimus showed antiproliferative activity, researchers investigated its molecular target and identified the TOR1 and TOR2. The mTOR consists of mTOR complex 1 (mTORC1 and mTORC2. Rapalogues including sirolimus, everolimus, and temsirolimus exert their effect mainly on mTORC1, whereas their inhibitory effect on mTORC2 is mild. To obtain compounds with more potent antiproliferative effects, ATP-competitive inhibitors of mTOR targeting both mTORC1 and mTORC2 have been developed and tested in clinical trials as anticancer drugs. Currently, mTOR inhibitors are used as anticancer drugs against several solid tumors, and immunosuppressive agents for transplantation of various organs. This review discusses the role of mTOR inhibitors in renal disease with a particular focus on renal cancer, diabetic nephropathy, and kidney transplantation.

  1. Screening of protein kinase inhibitors identifies PKC inhibitors as inhibitors of osteoclastic acid secretion and bone resorption

    Directory of Open Access Journals (Sweden)

    Boutin Jean A

    2010-10-01

    Full Text Available Abstract Background Bone resorption is initiated by osteoclastic acidification of the resorption lacunae. This process is mediated by secretion of protons through the V-ATPase and chloride through the chloride antiporter ClC-7. To shed light on the intracellular signalling controlling extracellular acidification, we screened a protein kinase inhibitor library in human osteoclasts. Methods Human osteoclasts were generated from CD14+ monocytes. The effect of different kinase inhibitors on lysosomal acidification in human osteoclasts was investigated using acridine orange for different incubation times (45 minutes, 4 and 24 hours. The inhibitors were tested in an acid influx assay using microsomes isolated from human osteoclasts. Bone resorption by human osteoclasts on bone slices was measured by calcium release. Cell viability was measured using AlamarBlue. Results Of the 51 compounds investigated only few inhibitors were positive in both acidification and resorption assays. Rottlerin, GF109203X, Hypericin and Ro31-8220 inhibited acid influx in microsomes and bone resorption, while Sphingosine and Palmitoyl-DL-carnitine-Cl showed low levels of inhibition. Rottlerin inhibited lysosomal acidification in human osteoclasts potently. Conclusions In conclusion, a group of inhibitors all indicated to inhibit PKC reduced acidification in human osteoclasts, and thereby bone resorption, indicating that acid secretion by osteoclasts may be specifically regulated by PKC in osteoclasts.

  2. MMpI: A WideRange of Available Compounds of Matrix Metalloproteinase Inhibitors.

    Directory of Open Access Journals (Sweden)

    Charuvaka Muvva

    Full Text Available Matrix metalloproteinases (MMPs are a family of zinc-dependent proteinases involved in the regulation of the extracellular signaling and structural matrix environment of cells and tissues. MMPs are considered as promising targets for the treatment of many diseases. Therefore, creation of database on the inhibitors of MMP would definitely accelerate the research activities in this area due to its implication in above-mentioned diseases and associated limitations in the first and second generation inhibitors. In this communication, we report the development of a new MMpI database which provides resourceful information for all researchers working in this field. It is a web-accessible, unique resource that contains detailed information on the inhibitors of MMP including small molecules, peptides and MMP Drug Leads. The database contains entries of ~3000 inhibitors including ~72 MMP Drug Leads and ~73 peptide based inhibitors. This database provides the detailed molecular and structural details which are necessary for the drug discovery and development. The MMpI database contains physical properties, 2D and 3D structures (mol2 and pdb format files of inhibitors of MMP. Other data fields are hyperlinked to PubChem, ChEMBL, BindingDB, DrugBank, PDB, MEROPS and PubMed. The database has extensive searching facility with MMpI ID, IUPAC name, chemical structure and with the title of research article. The MMP inhibitors provided in MMpI database are optimized using Python-based Hierarchical Environment for Integrated Xtallography (Phenix software. MMpI Database is unique and it is the only public database that contains and provides the complete information on the inhibitors of MMP. Database URL: http://clri.res.in/subramanian/databases/mmpi/index.php.

  3. MMpI: A WideRange of Available Compounds of Matrix Metalloproteinase Inhibitors

    Science.gov (United States)

    Muvva, Charuvaka; Patra, Sanjukta; Venkatesan, Subramanian

    2016-01-01

    Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the regulation of the extracellular signaling and structural matrix environment of cells and tissues. MMPs are considered as promising targets for the treatment of many diseases. Therefore, creation of database on the inhibitors of MMP would definitely accelerate the research activities in this area due to its implication in above-mentioned diseases and associated limitations in the first and second generation inhibitors. In this communication, we report the development of a new MMpI database which provides resourceful information for all researchers working in this field. It is a web-accessible, unique resource that contains detailed information on the inhibitors of MMP including small molecules, peptides and MMP Drug Leads. The database contains entries of ~3000 inhibitors including ~72 MMP Drug Leads and ~73 peptide based inhibitors. This database provides the detailed molecular and structural details which are necessary for the drug discovery and development. The MMpI database contains physical properties, 2D and 3D structures (mol2 and pdb format files) of inhibitors of MMP. Other data fields are hyperlinked to PubChem, ChEMBL, BindingDB, DrugBank, PDB, MEROPS and PubMed. The database has extensive searching facility with MMpI ID, IUPAC name, chemical structure and with the title of research article. The MMP inhibitors provided in MMpI database are optimized using Python-based Hierarchical Environment for Integrated Xtallography (Phenix) software. MMpI Database is unique and it is the only public database that contains and provides the complete information on the inhibitors of MMP. Database URL: http://clri.res.in/subramanian/databases/mmpi/index.php. PMID:27509041

  4. Inhibitor chymotrypsynowy nasion wiechliny łąkowej (Poa pratensis [Chymotrypsin inhibitor from Poa pratensis seeds

    Directory of Open Access Journals (Sweden)

    I. Lorenc-Kubis

    2015-01-01

    Full Text Available A chymotrypsin inhibitor was isolated from Poa pratensis seeds. The inhibitor showed also antytriptic activity. It is a termostable protein, soluble in water, sodium chloride, but insoluble in 5% trichloracetic acid and 0.15 M sulphosalicylic acid.

  5. Efficacy of secondary isoniazid preventive therapy among ...

    African Journals Online (AJOL)

    Objective. To determine the efficacy of secondary preventive therapy against tuberculosis (TB) among goldminers working in South Africa. Design. An observational study. Methods. The incidence of recurrent TB was compared between two cohorts of HIV-infected miners: one cohort had received secondary preventive ...

  6. Niosomal Delivery of Isoniazid - Development and Characterization

    African Journals Online (AJOL)

    Erah

    high as 61.8 %, a level that is capable of achieving effective treatment of tuberculosis. Conclusion: The ... inactivation of the drug, targets the ... bath for 1 h and at room temperature over- .... culture medium, RPMI 1640 supplemented with 5% ...

  7. QStatin, a Selective Inhibitor of Quorum Sensing in Vibrio Species.

    Science.gov (United States)

    Kim, Byoung Sik; Jang, Song Yee; Bang, Ye-Ji; Hwang, Jungwon; Koo, Youngwon; Jang, Kyung Ku; Lim, Dongyeol; Kim, Myung Hee; Choi, Sang Ho

    2018-01-30

    Pathogenic Vibrio species cause diseases in diverse marine animals reared in aquaculture. Since their pathogenesis, persistence, and survival in marine environments are regulated by quorum sensing (QS), QS interference has attracted attention as a means to control these bacteria in aquatic settings. A few QS inhibitors of Vibrio species have been reported, but detailed molecular mechanisms are lacking. Here, we identified a novel, potent, and selective Vibrio QS inhibitor, named QStatin [1-(5-bromothiophene-2-sulfonyl)-1H-pyrazole], which affects Vibrio harveyi LuxR homologues, the well-conserved master transcriptional regulators for QS in Vibrio species. Crystallographic and biochemical analyses showed that QStatin binds tightly to a putative ligand-binding pocket in SmcR, the LuxR homologue in V. vulnificus , and changes the flexibility of the protein, thereby altering its transcription regulatory activity. Transcriptome analysis revealed that QStatin results in SmcR dysfunction, affecting the expression of SmcR regulon required for virulence, motility/chemotaxis, and biofilm dynamics. Notably, QStatin attenuated representative QS-regulated phenotypes in various Vibrio species, including virulence against the brine shrimp ( Artemia franciscana ). Together, these results provide molecular insights into the mechanism of action of an effective, sustainable QS inhibitor that is less susceptible to resistance than other antimicrobial agents and useful in controlling the virulence of Vibrio species in aquacultures. IMPORTANCE Yields of aquaculture, such as penaeid shrimp hatcheries, are greatly affected by vibriosis, a disease caused by pathogenic Vibrio infections. Since bacterial cell-to-cell communication, known as quorum sensing (QS), regulates pathogenesis of Vibrio species in marine environments, QS inhibitors have attracted attention as alternatives to conventional antibiotics in aquatic settings. Here, we used target-based high-throughput screening to identify

  8. The effects of GLP-1 analogues, DPP-4 inhibitors and SGLT2 inhibitors on the renal system.

    Science.gov (United States)

    Schernthaner, Guntram; Mogensen, Carl Erik; Schernthaner, Gerit-Holger

    2014-09-01

    Diabetic nephropathy (DN) affects an estimated 20%-40% of patients with type 2 diabetes mellitus (T2DM). Key modifiable risk factors for DN are albuminuria, anaemia, dyslipidaemia, hyperglycaemia and hypertension, together with lifestyle factors, such as smoking and obesity. Early detection and treatment of these risk factors can prevent DN or slow its progression, and may even induce remission in some patients. DN is generally preceded by albuminuria, which frequently remains elevated despite treatment in patients with T2DM. Optimal treatment and prevention of DN may require an early, intensive, multifactorial approach, tailored to simultaneously target all modifiable risk factors. Regular monitoring of renal function, including urinary albumin excretion, creatinine clearance and glomerular filtration rate, is critical for following any disease progression and making treatment adjustments. Dipeptidyl peptidase (DPP)-4 inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels without additional risk of hypoglycaemia, and may also reduce albuminuria. Further investigation of the potential renal benefits of DPP-4 and SGLT2 inhibitors is underway. © The Author(s) 2014.

  9. PI3K inhibitors as new cancer therapeutics: implications for clinical trial design

    Directory of Open Access Journals (Sweden)

    Massacesi C

    2016-01-01

    Full Text Available Cristian Massacesi,1 Emmanuelle Di Tomaso,2 Patrick Urban,3 Caroline Germa,4 Cornelia Quadt,5 Lucia Trandafir,1 Paola Aimone,3 Nathalie Fretault,1 Bharani Dharan,4 Ranjana Tavorath,4 Samit Hirawat4 1Novartis Oncology, Paris, France; 2Novartis Institutes for BioMedical Research Inc, Cambridge, MA, USA; 3Novartis Pharma AG, Basel, Switzerland; 4Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 5Novartis Pharmaceuticals KK, Tokyo, Japan Abstract: The PI3K–AKT–mTOR pathway is frequently activated in cancer. PI3K inhibitors, including the pan-PI3K inhibitor buparlisib (BKM120 and the PI3Kα-selective inhibitor alpelisib (BYL719, currently in clinical development by Novartis Oncology, may therefore be effective as anticancer agents. Early clinical studies with PI3K inhibitors have demonstrated preliminary antitumor activity and acceptable safety profiles. However, a number of unanswered questions regarding PI3K inhibition in cancer remain, including: what is the best approach for different tumor types, and which biomarkers will accurately identify the patient populations most likely to benefit from specific PI3K inhibitors? This review summarizes the strategies being employed by Novartis Oncology to help maximize the benefits of clinical studies with buparlisib and alpelisib, including stratification according to PI3K pathway activation status, selective enrollment/target enrichment (where patients with PI3K pathway-activated tumors are specifically recruited, nonselective enrollment with mandatory tissue collection, and enrollment of patients who have progressed on previous targeted agents, such as mTOR inhibitors or endocrine therapy. An overview of Novartis-sponsored and Novartis-supported trials that are utilizing these approaches in a range of cancer types, including breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, lymphoma, and glioblastoma multiforme, is also described. Keywords: PI3K

  10. SGLT2 inhibitors: are they safe?

    Science.gov (United States)

    Filippas-Ntekouan, Sebastian; Filippatos, Theodosios D; Elisaf, Moses S

    2018-01-01

    Sodium-glucose linked transporter type 2 (SGLT2) inhibitors are a relatively new class of antidiabetic drugs with positive cardiovascular and kidney effects. The aim of this review is to present the safety issues associated with SGLT2 inhibitors. Urogenital infections are the most frequently encountered adverse events, although tend to be mild to moderate and are easily manageable with standard treatment. Although no increased acute kidney injury risk was evident in the major trials, the mechanism of action of these drugs requires caution when they are administered in patients with extracellular volume depletion or with drugs affecting renal hemodynamics. Canagliflozin raised the risk of amputations and the rate of fractures in the CANVAS trial, although more data are necessary before drawing definite conclusions. The risk of euglycemic diabetic ketoacidosis seems to be minimal when the drugs are prescribed properly. Regarding other adverse events, SGLT2 inhibitors do not increase the risk of hypoglycemia even when co-administered with insulin, but a decrease in the dose of sulphonylureas may be needed. The available data do not point to a causative role of SGLT2 inhibitors on malignancy risk, however, these drugs should be used with caution in patients with known hematuria or history of bladder cancer. SGLT2 inhibitors seem to be safe and effective in the treatment of diabetes but more studies are required to assess their long-term safety.

  11. Aromatase inhibitors and breast cancer prevention.

    Science.gov (United States)

    Litton, Jennifer Keating; Arun, Banu K; Brown, Powel H; Hortobagyi, Gabriel N

    2012-02-01

    Endocrine therapy with selective estrogen receptor modulators (SERMs) has been the mainstay of breast cancer prevention trials to date. The aromatase inhibitors, which inhibit the final chemical conversion of androgens to estrogens, have shown increased disease-free survival benefit over tamoxifen in patients with primary hormone receptor-positive breast cancer, as well as reducing the risk of developing contralateral breast cancers. The aromatase inhibitors are being actively evaluated as prevention agents for women with a history of ductal carcinoma in situ as well as for women who are considered to be at high risk for developing primary invasive breast cancer. This review evaluates the available prevention data, as evidenced by the decrease in contralateral breast cancers, when aromatase inhibitors are used in the adjuvant setting, as well as the emerging data of the aromatase inhibitors specifically tested in the prevention setting for women at high risk. Exemestane is a viable option for breast cancer prevention. We continue to await further follow-up on exemestane as well as other aromatase inhibitors in the prevention setting for women at high risk of developing breast cancer or with a history of ductal carcinoma in situ.

  12. Janus kinase inhibitors: jackpot or potluck?

    Directory of Open Access Journals (Sweden)

    Pavithran Keechilat

    2012-06-01

    Full Text Available The reports of a unique mutation in the Janus kinase-2 gene (JAK2 in polycythemia vera by several independent groups in 2005 quickly spurred the development of the Janus kinase inhibitors. In one of the great victories of translational research in recent times, the first smallmolecule Janus kinase inhibitor ruxolitinib entered a phase I trial in 2007. With the approval of ruxolitinib by the US Federal Drug Administration in November 2011 for high-risk and intermediate-2 risk myelofibrosis, a change in paradigm has occurred in the management of a subset of myeloproliferative neoplasms (MPN: primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Whereas the current evidence for ruxolitinib only covers high-risk and intermediate-2 risk myelofibrosis, inhibitors with greater potency are likely to offer better disease control and survival advantage in patients belonging to these categories, and possibly to the low-risk and intermediate-1 risk categories of MPN as well. But use of the Janus kinase inhibitors also probably has certain disadvantages, such as toxicity, resistance, withdrawal phenomenon, non-reversal of histology, and an implausible goal of disease clone eradication, some of which could offset the gains. In spite of this, Janus kinase inhibitors are here to stay, and for use in more than just myeloproliferative neoplasms.

  13. Small molecule inhibitor screening identifified HSP90 inhibitor 17-AAG as potential therapeutic agent for gallbladder cancer.

    Science.gov (United States)

    Weber, Helga; Valbuena, José R; Barbhuiya, Mustafa A; Stein, Stefan; Kunkel, Hana; García, Patricia; Bizama, Carolina; Riquelme, Ismael; Espinoza, Jaime A; Kurtz, Stephen E; Tyner, Jeffrey W; Calderon, Juan Francisco; Corvalán, Alejandro H; Grez, Manuel; Pandey, Akhilesh; Leal-Rojas, Pamela; Roa, Juan C

    2017-04-18

    Gallbladder cancer (GBC) is a lethal cancer with poor prognosis associated with high invasiveness and poor response to chemotherapy and radiotherapy. New therapeutic approaches are urgently needed in order to improve survival and response rates of GBC patients. We screened 130 small molecule inhibitors on a panel of seven GBC cell lines and identified the HSP90 inhibitor 17-AAG as one of the most potent inhibitory drugs across the different lines. We tested the antitumor efficacy of 17-AAG and geldanamycin (GA) in vitro and in a subcutaneous preclinical tumor model NOD-SCID mice. We also evaluated the expression of HSP90 by immunohistochemistry in human GBC tumors.In vitro assays showed that 17-AAG and GA significantly reduced the expression of HSP90 target proteins, including EGFR, AKT, phospho-AKT, Cyclin B1, phospho-ERK and Cyclin D1. These molecular changes were consistent with reduced cell viability and cell migration and promotion of G2/M cell cycle arrest and apoptosis observed in our in vitro studies.In vivo, 17-AAG showed efficacy in reducing subcutaneous tumors size, exhibiting a 69.6% reduction in tumor size in the treatment group compared to control mice (p < 0.05).The HSP90 immunohistochemical staining was seen in 182/209 cases of GBC (87%) and it was strongly expressed in 70 cases (33%), moderately in 58 cases (28%), and weakly in 54 cases (26%).Our pre-clinical observations strongly suggest that the inhibition of HSP90 function by HSP90 inhibitors is a promising therapeutic strategy for gallbladder cancer that may benefit from new HSP90 inhibitors currently in development.

  14. JTP-103237, a monoacylglycerol acyltransferase inhibitor, prevents fatty liver and suppresses both triglyceride synthesis and de novo lipogenesis

    Directory of Open Access Journals (Sweden)

    Chihiro Okuma

    2015-07-01

    Conclusion: In the present study, JTP-103237 prevented carbohydrate-induced fatty liver and suppressed both TG synthesis and de novo lipogenesis, suggesting MGAT inhibitor may prevent carbohydrate-induced metabolic disorders, including NAFLD, obesity and diabetes.

  15. Big enough for an aromatase inhibitor? How adiposity affects male fertility.

    Science.gov (United States)

    Stephens, Sahar M; Polotsky, Alex J

    2013-07-01

    Obesity is a pandemic and is associated with multiple medical problems including subfertility. Male obesity has been associated with altered semen parameters and reproductive hormonal levels, including a reduced testosterone:estradiol (T:E₂) ratio. Treatment methods employed for obesity-related male subfertility include gonadotropin administration, weight loss, and aromatase inhibitors. Letrozole is a highly effective nonsteroidal aromatase inhibitor that has been used to treat male subfertility in several case series with promising results. Adequately designed randomized controlled studies are needed to produce evidence-based data on the role of aromatase inhibitors in male subfertility management and evaluate the side-effect profile. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  16. A cyclic peptidic serine protease inhibitor

    DEFF Research Database (Denmark)

    Zhao, Baoyu; Xu, Peng; Jiang, Longguang

    2014-01-01

    Peptides are attracting increasing interest as protease inhibitors. Here, we demonstrate a new inhibitory mechanism and a new type of exosite interactions for a phage-displayed peptide library-derived competitive inhibitor, mupain-1 (CPAYSRYLDC), of the serine protease murine urokinase...... pocket, its carbonyl group aligning improperly relative to Ser195 and the oxyanion hole, explaining why the peptide is an inhibitor rather than a substrate. Substitution of the P1 Arg with novel unnatural Arg analogues with aliphatic or aromatic ring structures led to an increased affinity, depending......, in spite of a less favorable binding entropy and loss of a polar interaction. We conclude that increased flexibility of the peptide allows more favorable exosite interactions, which, in combination with the use of novel Arg analogues as P1 residues, can be used to manipulate the affinity and specificity...

  17. SGLT-2 Inhibitors and Cardiovascular Risk

    DEFF Research Database (Denmark)

    Cavender, Matthew A; Norhammar, Anna; Birkeland, Kåre I

    2018-01-01

    BACKGROUND: Prior studies found patients treated with sodium-glucose co-transporter-2 inhibitors (SGLT-2i) had lower rates of death and heart failure (HF). Whether the benefits of SGLT-2i vary based upon the presence of cardiovascular disease (CVD) is unknown. OBJECTIVES: This study sought...... to determine the association between initiation of SGLT-2i therapy and HF or death in patients with and without CVD. METHODS: The CVD-REAL (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors) study was a multinational, observational study in which adults with type 2 diabetes...... evidence regarding the benefit of SGLT-2i in patients without established CVD. (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors [CVD-REAL]; NCT02993614)....

  18. Effect of inorganic inhibitors on the corrosion behavior of 1018 carbon steel in the LiBr + ethylene glycol + H2O mixture

    International Nuclear Information System (INIS)

    Samiento-Bustos, E.; Rodriguez, J.G. Gonzalez; Uruchurtu, J.; Dominguez-Patino, G.; Salinas-Bravo, V.M.

    2008-01-01

    The effect of inorganic inhibitors on the corrosion behavior of 1018 carbon steel in the mixture LiBr (55%) + ethylene glycol + H 2 O at room temperature has been evaluated. Used inhibitors included LiNO 3 (Lithium Nitrate), Li 2 MoO 4 (Lithium Molybdate) and Li 2 CrO 4 (Lithium Chromate) at concentrations of 5, 20 and 50 ppm. Electrochemical techniques included potentiodynamic polarization curves, electrochemical noise resistance (EN) and electrochemical impedance spectroscopy (EIS) measurements. Additionally, adsorption isotherms were calculated. The results obtained showed that both, the corrosion rate and the passive current density decreased with inhibitors, and, in general terms, inhibitors efficiency increased with inhibitor concentration, except in the case of Li 2 CrO 4, where the highest efficiency was obtained with 20 ppm of inhibitor. Pitting potential with 5 ppm of inhibitor, regardless its chemical composition, was more active than in absence of inhibitor, increased at 20 ppm, especially with Li 2 CrO 4 , and remained unaltered with 50 ppm. EN measurements showed that at 5 ppm of inhibitor, the number of film rupture/repassivation events was higher than that obtained at 20 or 50 ppm. Adsorption isotherms suggested a different adsorption mechanism for each inhibitor, whereas EIS results suggested that the corrosion process when nitrates were added was under charge transfer control, but in the case of molybdates or chromates was under diffusion control

  19. Effect of inorganic inhibitors on the corrosion behavior of 1018 carbon steel in the LiBr + ethylene glycol + H{sub 2}O mixture

    Energy Technology Data Exchange (ETDEWEB)

    Samiento-Bustos, E. [Centro de Investigacion en Ingenieria y Ciencias Aplicadas, Universidad Autonoma del Estado de Morelos. Av. Universidad 1001, Col. Chamilpa, CP 62210, Cuernavaca, Morelos (Mexico); Rodriguez, J.G. Gonzalez [Centro de Investigacion en Ingenieria y Ciencias Aplicadas, Universidad Autonoma del Estado de Morelos. Av. Universidad 1001, Col. Chamilpa, CP 62210, Cuernavaca, Morelos (Mexico)], E-mail: ggonzalez@uaem.mx; Uruchurtu, J. [Centro de Investigacion en Ingenieria y Ciencias Aplicadas, Universidad Autonoma del Estado de Morelos. Av. Universidad 1001, Col. Chamilpa, CP 62210, Cuernavaca, Morelos (Mexico); Dominguez-Patino, G. [Centro de Investigacion en Ingenieria y Ciencias Aplicadas, Universidad Autonoma del Estado de Morelos. Av. Universidad 1001, Col. Chamilpa, CP 62210, Cuernavaca, Morelos (Mexico); U.A.E.M. Facultad de Ciencias Quimicas e Ingenieria, Av. Universidad 1001, 62209, Cuernavaca, Morelos (Mexico); Salinas-Bravo, V.M. [Instituto de Investigaciones Electricas, Gerencia de Materiales y Proceso Quimicos, Av. Reforma 113, Col. Palmira, CP 62490, Cuernavaca, Morelos (Mexico)

    2008-08-15

    The effect of inorganic inhibitors on the corrosion behavior of 1018 carbon steel in the mixture LiBr (55%) + ethylene glycol + H{sub 2}O at room temperature has been evaluated. Used inhibitors included LiNO{sub 3} (Lithium Nitrate), Li{sub 2}MoO{sub 4} (Lithium Molybdate) and Li{sub 2}CrO{sub 4} (Lithium Chromate) at concentrations of 5, 20 and 50 ppm. Electrochemical techniques included potentiodynamic polarization curves, electrochemical noise resistance (EN) and electrochemical impedance spectroscopy (EIS) measurements. Additionally, adsorption isotherms were calculated. The results obtained showed that both, the corrosion rate and the passive current density decreased with inhibitors, and, in general terms, inhibitors efficiency increased with inhibitor concentration, except in the case of Li{sub 2}CrO{sub 4,} where the highest efficiency was obtained with 20 ppm of inhibitor. Pitting potential with 5 ppm of inhibitor, regardless its chemical composition, was more active than in absence of inhibitor, increased at 20 ppm, especially with Li{sub 2}CrO{sub 4}, and remained unaltered with 50 ppm. EN measurements showed that at 5 ppm of inhibitor, the number of film rupture/repassivation events was higher than that obtained at 20 or 50 ppm. Adsorption isotherms suggested a different adsorption mechanism for each inhibitor, whereas EIS results suggested that the corrosion process when nitrates were added was under charge transfer control, but in the case of molybdates or chromates was under diffusion control.

  20. Synergistic Malaria Parasite Killing by Two Types of Plasmodial Surface Anion Channel Inhibitors.

    Directory of Open Access Journals (Sweden)

    Margaret Pain

    Full Text Available Malaria parasites increase their host erythrocyte's permeability to a broad range of ions and organic solutes. The plasmodial surface anion channel (PSAC mediates this uptake and is an established drug target. Development of therapies targeting this channel is limited by several problems including interactions between known inhibitors and permeating solutes that lead to incomplete channel block. Here, we designed and executed a high-throughput screen to identify a novel class of PSAC inhibitors that overcome this solute-inhibitor interaction. These new inhibitors differ from existing blockers and have distinct effects on channel-mediated transport, supporting a model of two separate routes for solute permeation though PSAC. Combinations of inhibitors specific for the two routes had strong synergistic action against in vitro parasite propagation, whereas combinations acting on a single route produced only additive effects. The magnitude of synergism depended on external nutrient concentrations, consistent with an essential role of the channel in parasite nutrient acquisition. The identified inhibitors will enable a better understanding of the channel's structure-function and may be starting points for novel combination therapies that produce synergistic parasite killing.

  1. 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.

  2. A specific pharmacophore model of sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors.

    Science.gov (United States)

    Tang, Chunlei; Zhu, Xiaoyun; Huang, Dandan; Zan, Xin; Yang, Baowei; Li, Ying; Du, Xiaoyong; Qian, Hai; Huang, Wenlong

    2012-06-01

    Sodium-dependent glucose co-transporter 2 (SGLT2) plays a pivotal role in maintaining glucose equilibrium in the human body, emerging as one of the most promising targets for the treatment of diabetes mellitus type 2. Pharmacophore models of SGLT2 inhibitors have been generated with a training set of 25 SGLT2 inhibitors using Discovery Studio V2.1. The best hypothesis (Hypo1(SGLT2)) contains one hydrogen bond donor, five excluded volumes, one ring aromatic and three hydrophobic features, and has a correlation coefficient of 0.955, cost difference of 68.76, RMSD of 0.85. This model was validated by test set, Fischer randomization test and decoy set methods. The specificity of Hypo1(SGLT2) was evaluated. The pharmacophore features of Hypo1(SGLT2) were different from the best pharmacophore model (Hypo1(SGLT1)) of SGLT1 inhibitors we developed. Moreover, Hypo1(SGLT2) could effectively distinguish selective inhibitors of SGLT2 from those of SGLT1. These results indicate that a highly predictive and specific pharmacophore model of SGLT2 inhibitors has been successfully obtained. Then Hypo1(SGLT2) was used as a 3D query to screen databases including NCI and Maybridge for identifying new inhibitors of SGLT2. The hit compounds were subsequently subjected to filtering by Lipinski's rule of five. And several compounds selected from the top ranked hits have been suggested for further experimental assay studies.

  3. ACE Inhibitor-Induced Angioedema of the Intestine: Case Report, Incidence, Pathophysiology, Diagnosis and Management

    Directory of Open Access Journals (Sweden)

    Gavin Oudit

    2001-01-01

    Full Text Available A case report of fosinopril-induced angioedema of the intestine with a chronic course accompanied by multiple acute exacerbations is described. Angiotensin-converting enzyme (ACE inhibitor-induced angioedema of the intestine (AIAI occurs in a minority of patients taking an ACE inhibitor. The clinical presentation encompasses acute abdominal symptoms, pronounced bowel edema and ascites with occasional facial and/or oropharyngeal swelling. AIAI is diagnosed based on the temporal relationship between the symptomatic presentation and drug use, absence of alternative diagnoses including other causes of angioedema, and the prompt resolution of symptoms upon discontinuation of the ACE inhibitor. Prompt radiological investigation (abdominal computerized tomography and/or ultrasound is critical in making an early diagnosis and in preventing unnecessary surgical intervention. There is a female predominance of AIAI, which may reflect the interaction of estradiol with the various pathways involved in the pathophysiology of AIAI. Management of AIAI consists mainly of conservative measures and discontinuation of the ACE inhibitor. Angiotensin II receptor antagonists should not be considered as appropriate alternatives. Awareness and knowledge of AIAI are important because of the increasing use of ACE inhibitors, current delays in making the diagnosis, obvious management strategies once the diagnosis is made and the dysutility of alternative diagnoses, which may lead to considerable morbidity. AIAI must be considered in patients taking ACE inhibitors who develop gastrointestinal complaints irrespective of the duration of the therapy.

  4. Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors activate the aryl hydrocarbon receptor

    Energy Technology Data Exchange (ETDEWEB)

    Moyer, Benjamin J. [Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756 (United States); Rojas, Itzel Y. [Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756 (United States); Murray, Iain A. [Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802 (United States); Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802 (United States); Lee, Seokwon; Hazlett, Haley F. [Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756 (United States); Perdew, Gary H. [Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802 (United States); Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802 (United States); Tomlinson, Craig R., E-mail: Craig.R.Tomlinson@Dartmouth.edu [Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756 (United States); Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756 (United States)

    2017-05-15

    Indoleamine 2,3-dioxygenase 1 (IDO1) plays a key role in the immune system by regulating tryptophan levels and T cell differentiation. Several tumor types overexpress IDO1 to avoid immune surveillance making IDO1 of interest as a target for therapeutic intervention. As a result, several IDO1 inhibitors are currently being tested in clinical trials for cancer treatment as well as several other diseases. Many of the IDO1 inhibitors in clinical trials naturally bear structural similarities to the IDO1 substrate tryptophan, as such, they fulfill many of the structural and functional criteria as potential AHR ligands. Using mouse and human cell-based luciferase gene reporter assays, qPCR confirmation experiments, and CYP1A1 enzyme activity assays, we report that some of the promising clinical IDO1 inhibitors also act as agonists for the aryl hydrocarbon receptor (AHR), best known for its roles in xenobiotic metabolism and as another key regulator of the immune response. The dual role as IDO antagonist and AHR agonist for many of these IDO target drugs should be considered for full interrogation of their biological mechanisms and clinical outcomes. - Highlights: • Indoleamine-2,3-dioxygenase 1 (IDO1) inhibitors are in cancer clinical trials. • Some IDO1 inhibitors also potently activate AHR signaling. • The dual role of the IDO1 inhibitors may explain some past paradoxical findings. • AHR induction studies must be included in assessing clinical suitability.

  5. Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a German expert opinion.

    Science.gov (United States)

    Potthoff, K; Hofheinz, R; Hassel, J C; Volkenandt, M; Lordick, F; Hartmann, J T; Karthaus, M; Riess, H; Lipp, H P; Hauschild, A; Trarbach, T; Wollenberg, A

    2011-03-01

    Anti-epidermal growth factor receptor treatment strategies, i.e. monoclonal antibodies such as cetuximab and panitumumab, or epidermal growth factor receptor (EGFR) small molecule tyrosine kinase inhibitors, such as erlotinib and gefitinib, have expanded the treatment options for different tumor types. Dermatologic toxic effects are the most common side-effects of EGFR inhibitor therapy. They can profoundly affect the patient's quality of life. The aim of this study was to provide interdisciplinary expert recommendations on how to treat patients with skin reactions undergoing anti-EGFR treatment. An expert panel from Germany with expertise in medical oncology, dermatology or clinical pharmacology was convened to develop expert recommendations based on published peer-reviewed literature. The expert recommendations for the state-of-the-art treatment of skin reactions induced by EGFR inhibitor therapy include recommendations for diagnostics and grading as well as grade-specific and stage-adapted treatment approaches and preventive measures. It was concluded that EGFR-inhibitor-related dermatologic reactions should always be treated combining basic care of the skin and a specific therapy adapted to stage and grade of skin reaction. For grade 2 and above, specific treatment recommendations for early- and later-stage skin reactions induced by EGFR-inhibitor therapy were proposed. This paper presents a German national expert opinion for the treatment of skin reactions in patients receiving EGFR inhibitor therapy.

  6. Modulation of the epithelial sodium channel (ENaC by bacterial metalloproteases and protease inhibitors.

    Directory of Open Access Journals (Sweden)

    Michael B Butterworth

    Full Text Available The serralysin family of metalloproteases is associated with the virulence of multiple gram-negative human pathogens, including Pseudomonas aeruginosa and Serratia marcescens. The serralysin proteases share highly conserved catalytic domains and show evolutionary similarity to the mammalian matrix metalloproteases. Our previous studies demonstrated that alkaline protease (AP from Pseudomonas aeruginosa is capable of activating the epithelial sodium channel (ENaC, leading to an increase in sodium absorption in airway epithelia. The serralysin proteases are often co-expressed with endogenous, intracellular or periplasmic inhibitors, which putatively protect the bacterium from unwanted or unregulated protease activities. To evaluate the potential use of these small protein inhibitors in regulating the serralysin induced activation of ENaC, proteases from Pseudomonas aeruginosa and Serratia marcescens were purified for characterization along with a high affinity inhibitor from Pseudomonas. Both proteases showed activity against in vitro substrates and could be blocked by near stoichiometric concentrations of the inhibitor. In addition, both proteases were capable of activating ENaC when added to the apical surfaces of multiple epithelial cells with similar slow activation kinetics. The high-affinity periplasmic inhibitor from Pseudomonas effectively blocked this activation. These data suggest that multiple metalloproteases are capable of activating ENaC. Further, the endogenous, periplasmic bacterial inhibitors may be useful for modulating the downstream effects of the serralysin virulence factors under physiological conditions.

  7. Structure-based virtual screening of molecular libraries as cdk2 inhibitors

    International Nuclear Information System (INIS)

    Riaz, U.; Khaleeq, M.

    2011-01-01

    CDK2 inhibitor is an important target in multiple processes associated with tumor growth and development, including proliferation, neovascularization, and metastasis. In this study, hit identification was performed by virtual screening of commercial and in-house compound libraries. Docking studies for the hits were performed, and scoring functions were used to evaluate the docking results and to rank ligand-binding affinities. Subsequently, hit optimization for potent and selective candidate CDK2 inhibitors was performed through focused library design and docking analyses. Consequently, we report that a novel compound with an IC50 value of 89 nM, representing 2-Amino-4,6-di-(4',6'-dibromophenyl)pyrimidine 1, is highly selective for CDK2 inhibitors. The docking structure of compound 1 with CDK2 inhibitor disclosed that the NH moiety and pyrimidine ring appeared to fit tightly into the hydrophobic pocket of CDK2 inhibitor. Additionally, the pyrimidine NH forms a hydrogen bond with the carboxyl group of Asp348. These results confirm the successful application of virtual screening studies in the lead discovery process, and suggest that our novel compound can be an effective CDK2 inhibitor candidate for further lead optimization. (author)

  8. Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Aβ Levels Mediated by Brain Shuttle Transport

    Directory of Open Access Journals (Sweden)

    Nadine Ruderisch

    2017-10-01

    Full Text Available Therapeutic approaches to fight Alzheimer's disease include anti-Amyloidβ (Aβ antibodies and secretase inhibitors. However, the blood-brain barrier (BBB limits the brain exposure of biologics and the chemical space for small molecules to be BBB permeable. The Brain Shuttle (BS technology is capable of shuttling large molecules into the brain. This allows for new types of therapeutic modalities engineered for optimal efficacy on the molecular target in the brain independent of brain penetrating properties. To this end, we designed BACE1 peptide inhibitors with varying lipid modifications with single-digit picomolar cellular potency. Secondly, we generated active-exosite peptides with structurally confirmed dual binding mode and improved potency. When fused to the BS via sortase coupling, these BACE1 inhibitors significantly reduced brain Aβ levels in mice after intravenous administration. In plasma, both BS and non-BS BACE1 inhibitor peptides induced a significant time- and dose-dependent decrease of Aβ. Our results demonstrate that the BS is essential for BACE1 peptide inhibitors to be efficacious in the brain and active-exosite design of BACE1 peptide inhibitors together with lipid modification may be of therapeutic relevance.

  9. Repigmentation in vitiligo using the Janus kinase inhibitor tofacitinib may require concomitant light exposure.

    Science.gov (United States)

    Liu, Lucy Y; Strassner, James P; Refat, Maggi A; Harris, John E; King, Brett A

    2017-10-01

    Vitiligo is an autoimmune disease in which cutaneous depigmentation occurs. Existing therapies are often inadequate. Prior reports have shown benefit of the Janus kinase (JAK) inhibitors. To evaluate the efficacy of the JAK 1/3 inhibitor tofacitinib in the treatment of vitiligo. This is a retrospective case series of 10 consecutive patients with vitiligo treated with tofacitinib. Severity of disease was assessed by body surface area of depigmentation. Ten consecutive patients were treated with tofacitinib. Five patients achieved some repigmentation at sites of either sunlight exposure or low-dose narrowband ultraviolet B phototherapy. Suction blister sampling revealed that the autoimmune response was inhibited during treatment in both responding and nonresponding lesions, suggesting that light rather than immunosuppression was primarily required for melanocyte regeneration. Limitations include the small size of the study population, retrospective nature of the study, and lack of a control group. Treatment of vitiligo with JAK inhibitors appears to require light exposure. In contrast to treatment with phototherapy alone, repigmentation during treatment with JAK inhibitors may require only low-level light. Maintenance of repigmentation may be achieved with JAK inhibitor monotherapy. These results support a model wherein JAK inhibitors suppress T cell mediators of vitiligo and light exposure is necessary for stimulation of melanocyte regeneration. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  10. Histone deacetylase inhibitors improve the replication of oncolytic herpes simplex virus in breast cancer cells.

    Directory of Open Access Journals (Sweden)

    James J Cody

    Full Text Available New therapies are needed for metastatic breast cancer patients. Oncolytic herpes simplex virus (oHSV is an exciting therapy being developed for use against aggressive tumors and established metastases. Although oHSV have been demonstrated safe in clinical trials, a lack of sufficient potency has slowed the clinical application of this approach. We utilized histone deacetylase (HDAC inhibitors, which have been noted to impair the innate antiviral response and improve gene transcription from viral vectors, to enhance the replication of oHSV in breast cancer cells. A panel of chemically diverse HDAC inhibitors were tested at three different doses (LD50 for their ability to modulate the replication of oHSV in breast cancer cells. Several of the tested HDAC inhibitors enhanced oHSV replication at low multiplicity of infection (MOI following pre-treatment of the metastatic breast cancer cell line MDA-MB-231 and the oHSV-resistant cell line 4T1, but not in the normal breast epithelial cell line MCF10A. Inhibitors of class I HDACs, including pan-selective compounds, were more effective for increasing oHSV replication compared to inhibitors that selectively target class II HDACs. These studies demonstrate that select HDAC inhibitors increase oHSV replication in breast cancer cells and provides support for pre-clinical evaluation of this combination strategy.

  11. Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors activate the aryl hydrocarbon receptor

    International Nuclear Information System (INIS)

    Moyer, Benjamin J.; Rojas, Itzel Y.; Murray, Iain A.; Lee, Seokwon; Hazlett, Haley F.; Perdew, Gary H.; Tomlinson, Craig R.

    2017-01-01

    Indoleamine 2,3-dioxygenase 1 (IDO1) plays a key role in the immune system by regulating tryptophan levels and T cell differentiation. Several tumor types overexpress IDO1 to avoid immune surveillance making IDO1 of interest as a target for therapeutic intervention. As a result, several IDO1 inhibitors are currently being tested in clinical trials for cancer treatment as well as several other diseases. Many of the IDO1 inhibitors in clinical trials naturally bear structural similarities to the IDO1 substrate tryptophan, as such, they fulfill many of the structural and functional criteria as potential AHR ligands. Using mouse and human cell-based luciferase gene reporter assays, qPCR confirmation experiments, and CYP1A1 enzyme activity assays, we report that some of the promising clinical IDO1 inhibitors also act as agonists for the aryl hydrocarbon receptor (AHR), best known for its roles in xenobiotic metabolism and as another key regulator of the immune response. The dual role as IDO antagonist and AHR agonist for many of these IDO target drugs should be considered for full interrogation of their biological mechanisms and clinical outcomes. - Highlights: • Indoleamine-2,3-dioxygenase 1 (IDO1) inhibitors are in cancer clinical trials. • Some IDO1 inhibitors also potently activate AHR signaling. • The dual role of the IDO1 inhibitors may explain some past paradoxical findings. • AHR induction studies must be included in assessing clinical suitability.

  12. Effect of kinase inhibitors on the therapeutic properties of monoclonal antibodies.

    Science.gov (United States)

    Duong, Minh Ngoc; Matera, Eva-Laure; Mathé, Doriane; Evesque, Anne; Valsesia-Wittmann, Sandrine; Clémenceau, Béatrice; Dumontet, Charles

    2015-01-01

    Targeted therapies of malignancies currently consist of therapeutic monoclonal antibodies and small molecule kinase inhibitors. The combination of these novel agents raises the issue of potential antagonisms. We evaluated the potential effect of 4 kinase inhibitors, including the Bruton tyrosine kinase inhibitor ibrutinib, and 3 PI3K inhibitors idelalisib, NVP-BEZ235 and LY294002, on the effects of the 3 monoclonal antibodies, rituximab and obinutuzumab (directed against CD20) and trastuzumab (directed against HER2). We found that ibrutinib potently inhibits antibody-dependent cell-mediated cytotoxicity exerted by all antibodies, with a 50% inhibitory concentration of 0.2 microM for trastuzumab, 0.5 microM for rituximab and 2 microM for obinutuzumab, suggesting a lesser effect in combination with obinutuzumab than with rituximab. The 4 kinase inhibitors were found to inhibit phagocytosis by fresh human neutrophils, as well as antibody-dependent cellular phagocytosis induced by the 3 antibodies. Conversely co-administration of ibrutinib with rituximab, obinutuzumab or trastuzumab did not demonstrate any inhibitory effect of ibrutinib in vivo in murine xenograft models. In conclusion, some kinase inhibitors, in particular, ibrutinib, are likely to exert inhibitory effects on innate immune cells. However, these effects do not compromise the antitumor activity of monoclonal antibodies in vivo in the models that were evaluated.

  13. 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.

  14. Births and deaths including fetal deaths

    Data.gov (United States)

    U.S. Department of Health & Human Services — Access to a variety of United States birth and death files including fetal deaths: Birth Files, 1968-2009; 1995-2005; Fetal death file, 1982-2005; Mortality files,...

  15. General amyloid inhibitors? A critical examination of the inhibition of IAPP amyloid formation by inositol stereoisomers.

    Directory of Open Access Journals (Sweden)

    Hui Wang

    Full Text Available Islet amyloid polypeptide (IAPP or amylin forms amyloid deposits in the islets of Langerhans; a process that is believed to contribute to the progression of type 2 diabetes and to the failure of islet transplants. An emerging theme in amyloid research is the hypothesis that the toxic species produced during amyloid formation by different polypeptides share common features and exert their effects by common mechanisms. If correct, this suggests that inhibitors of amyloid formation by one polypeptide might be effective against other amyloidogenic sequences. IAPP and Aβ, the peptide responsible for amyloid formation in Alzheimer's disease, are particularly interesting in this regard as they are both natively unfolded in their monomeric states and share some common characteristics. Comparatively little effort has been expended on the design of IAPP amyloid inhibitors, thus it is natural to inquire if Aβ inhibitors are effective against IAPP, especially since no IAPP inhibitors have been clinically approved. A range of compounds inhibit Aβ amyloid formation, including various stereoisomers of inositol. Myo-, scyllo-, and epi-inositol have been shown to induce conformational changes in Aβ and prevent Aβ amyloid fibril formation by stabilizing non-fibrillar β-sheet structures. We investigate the ability of inositol stereoisomers to inhibit amyloid formation by IAPP. The compounds do not induce a conformational change in IAPP and are ineffective inhibitors of IAPP amyloid formation, although some do lead to modest apparent changes in IAPP amyloid fibril morphology. Thus not all classes of Aβ inhibitors are effective against IAPP. This work provides a basis of comparison to work on polyphenol based inhibitors of IAPP amyloid formation and helps provide clues as to the features which render them effective. The study also helps provide information for further efforts in rational inhibitor design.

  16. PENGHAMBAT α AMILASE: JENIS, SUMBER, DAN POTENSI PEMANFAATANNYA DALAM KESEHATAN [α Amylase Inhibitors: Types, Sources, and Their Potential Utilization for Health Purposes

    Directory of Open Access Journals (Sweden)

    Budiasih Wahyuntari

    2011-12-01

    Full Text Available SUMMARYAlpha amylase inhibitors affect carbohydrate metabolism in digestive system. The inhibitors induce carbohydrate tolerance, fullness and prolonging gastric emptying that might be used to aid in diabetic and obesity treatment. There are two types of α- amylase inhibitors, proteinaceous and non-proteinaceous ones. Proteinaceous inhibitor is classified into seven classes including legumes, lectin, knottin, cereal, Kunitz, -thionin and thaumatin types. Plant proteinaceous inhibitors are present in cereals and legumes. Some non-proteinaceous inhibitors include flavonid, polyphenols, organic acid that might be produced by microbes or extracted from plants such as acarbose, saponin dan cardiac glycoside, gallic acid, proto-catechuic acid, caffeic acid, ellagic acid, ferulic acid, quercetin hibiscus acid and α-, β- and γ-cyclodextrin.

  17. Tea Contains Potent Inhibitors of Tyrosine Phosphatase PTP1B

    OpenAIRE

    Ma, Junfeng; Li, Zhe; Xing, Shu; Ho, Wanting Tina; Fu, Xueqi; Zhao, Zhizhuang Joe

    2011-01-01

    Tea is widely consumed all over the world. Studies have demonstrated the role of tea in prevention and treatment of various chronic diseases including diabetes and obesity, but the underlying mechanism is unclear. PTP1B is a widely expressed tyrosine phosphatase which has been defined as a target for therapeutic drug development to treat diabetes and obesity. In screening for inhibitors of PTP1B, we found that aqueous extracts of teas exhibited potent PTP1B inhibitory effects with an IC50 val...

  18. Discovery of a potent, dual serotonin and norepinephrine reuptake inhibitor.

    Science.gov (United States)

    Dreyfus, Nicolas; Myers, Jason K; Badescu, Valentina O; de Frutos, Oscar; de la Puente, Maria Luz; Ding, Chunjin; Filla, Sandra A; Fynboe, Karsten; Gernert, Douglas L; Heinz, Beverly A; Hemrick-Luecke, Susan K; Johnson, Kirk W; Johnson, Michael P; López, Pilar; Love, Patrick L; Martin, Laura J; Masquelin, Thierry; McCoy, Michael J; Mendiola, Javier; Morrow, Denise; Muhlhauser, Mark; Pascual, Gustavo; Perun, Thomas J; Pfeifer, Lance A; Phebus, Lee A; Richards, Simon J; Rincón, Juan Antonio; Seest, Eric P; Shah, Jikesh; Shaojuan, Jia; Simmons, Rosa Maria A; Stephenson, Gregory A; Tromiczak, Eric G; Thompson, Linda K; Walter, Magnus W; Weber, Wayne W; Zarrinmayeh, Hamideh; Thomas, Craig E; Joshi, Elizabeth; Iyengar, Smriti; Johansson, Anette M

    2013-06-13

    The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug-drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions.

  19. Fatty acid synthase inhibitors isolated from Punica granatum L

    Energy Technology Data Exchange (ETDEWEB)

    Jiang, He-Zhong [School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, (China); Ma, Qing-Yun; Liang, Wen-Juan; Huang, Sheng-Zhuo; Dai, Hao-Fu; Wang, Peng-Cheng; Zhao, You-Xing, E-mail: zhaoyx1011@163.com [Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences, Haikou (China); Fan, Hui-Jin; Ma, Xiao-Feng, E-mail: maxiaofeng@gucas.ac.cn [College of Life Sciences, Graduate University of Chinese Academy of Sciences, Beijing (China)

    2012-05-15

    The aim of this work is the isolation of fatty acid synthase (FAS) inhibitors from the ethyl acetate extracts of fruit peels of Punica granatum L. Bioassay-guided chemical investigation of the fruit peels resulted in the isolation of seventeen compounds mainly including triterpenoids and phenolic compounds, from which one new oleanane-type triterpene (punicaone) along with fourteen known compounds were isolated for the first time from this plant. Seven isolates were evaluated for inhibitory activities of FAS and two compounds showed to be active. Particularly, flavogallonic acid exhibited strong FAS inhibitory activity with IC{sub 50} value of 10.3 {mu}mol L{sup -1}. (author)

  20. Antiretroviral activity of protease inhibitors against Toxoplasma gondii

    Directory of Open Access Journals (Sweden)

    Lianet Monzote

    2013-02-01

    Full Text Available The introduction of highly active antiretroviral therapy (HAART has caused a marked reduction in the occurrence and severity of parasitic infections, including the toxoplasmic encephalitis (TE. These changes have been attributed to the restoration of cell-mediated immunity. This study was developed to examine the activity of six antiretroviral protease inhibitors (API on Toxoplasma gondii tachyzoites. The six API showed anti-Toxoplasma activity, with IC50 value between 1.4 and 6.6 µg/mL. Further studies at the molecular level should be performed to clarify if the use of API could be beneficial or not for AIDS patients with TE.

  1. Fatty acid synthase inhibitors isolated from Punica granatum L

    International Nuclear Information System (INIS)

    Jiang, He-Zhong; Ma, Qing-Yun; Liang, Wen-Juan; Huang, Sheng-Zhuo; Dai, Hao-Fu; Wang, Peng-Cheng; Zhao, You-Xing; Fan, Hui-Jin; Ma, Xiao-Feng

    2012-01-01

    The aim of this work is the isolation of fatty acid synthase (FAS) inhibitors from the ethyl acetate extracts of fruit peels of Punica granatum L. Bioassay-guided chemical investigation of the fruit peels resulted in the isolation of seventeen compounds mainly including triterpenoids and phenolic compounds, from which one new oleanane-type triterpene (punicaone) along with fourteen known compounds were isolated for the first time from this plant. Seven isolates were evaluated for inhibitory activities of FAS and two compounds showed to be active. Particularly, flavogallonic acid exhibited strong FAS inhibitory activity with IC 50 value of 10.3 μmol L -1 . (author)

  2. Including Indigenous Minorities in Decision-Making

    DEFF Research Database (Denmark)

    Pristed Nielsen, Helene

    Based on theories of public sphere participation and deliberative democracy, this book presents empirical results from a study of experiences with including Aboriginal and Maori groups in political decision-making in respectively Western Australia and New Zealand......Based on theories of public sphere participation and deliberative democracy, this book presents empirical results from a study of experiences with including Aboriginal and Maori groups in political decision-making in respectively Western Australia and New Zealand...

  3. Gas storage materials, including hydrogen storage materials

    Science.gov (United States)

    Mohtadi, Rana F; Wicks, George G; Heung, Leung K; Nakamura, Kenji

    2013-02-19

    A material for the storage and release of gases comprises a plurality of hollow elements, each hollow element comprising a porous wall enclosing an interior cavity, the interior cavity including structures of a solid-state storage material. In particular examples, the storage material is a hydrogen storage material such as a solid state hydride. An improved method for forming such materials includes the solution diffusion of a storage material solution through a porous wall of a hollow element into an interior cavity.

  4. New halogenated phenylcoumarins as tyrosinase inhibitors.

    Science.gov (United States)

    Matos, Maria João; Santana, Lourdes; Uriarte, Eugenio; Delogu, Giovanna; Corda, Marcella; Fadda, Maria Benedetta; Era, Benedetta; Fais, Antonella

    2011-06-01

    With the aim to find out structural features for the tyrosinase inhibitory activity, in the present communication we report the synthesis and pharmacological evaluation of a new series of phenylcoumarin derivatives with different number of hydroxyl or ether groups and bromo substituent in the scaffold. The synthesized compounds 5-12 were evaluated as mushroom tyrosinase inhibitors showing, two of them, lower IC(50) than the umbelliferone. Compound 12 (IC(50)=215 μM) is the best tyrosinase inhibitor of this series. Copyright © 2011 Elsevier Ltd. All rights reserved.

  5. Green inhibitors. Rare Earth based systems

    International Nuclear Information System (INIS)

    Aballe, A.; Bethencourt, M.; Botana, F.J.; Perez, J.; Rodriguez, M.A.; Marcos, M.

    1997-01-01

    Lanthanum, Cerium and Samarium chlorides have been investigated as uniform and pitting corrosion inhibitors of AISI 434 and AISI 304 stainless steels and AA 5083 Al-Mg alloy in 3.5% Na Cl aerated aqueous solutions. Their inhibitor power was evaluated by using electrochemical techniques such as Linear and Cyclic Polarisation. In each case, the highest protection degree was found in the solution dropped with 500 ppm of CeCl 3 . Similar results were obtained for additions of 500 ppm of LaCl 3 . Scanning Electron Microscopy and Energy Dispersive Spectroscopy allowed us to confirm the cathodic nature of the inhibition process. (Author) 27 refs

  6. 2-Aminobenzimidazoles as potent Aurora kinase inhibitors.

    Science.gov (United States)

    Zhong, Min; Bui, Minna; Shen, Wang; Baskaran, Subramanian; Allen, Darin A; Elling, Robert A; Flanagan, W Michael; Fung, Amy D; Hanan, Emily J; Harris, Shannon O; Heumann, Stacey A; Hoch, Ute; Ivy, Sheryl N; Jacobs, Jeffrey W; Lam, Stuart; Lee, Heman; McDowell, Robert S; Oslob, Johan D; Purkey, Hans E; Romanowski, Michael J; Silverman, Jeffrey A; Tangonan, Bradley T; Taverna, Pietro; Yang, Wenjin; Yoburn, Josh C; Yu, Chul H; Zimmerman, Kristin M; O'Brien, Tom; Lew, Willard

    2009-09-01

    This Letter describes the discovery and key structure-activity relationship (SAR) of a series of 2-aminobenzimidazoles as potent Aurora kinase inhibitors. 2-Aminobenzimidazole serves as a bioisostere of the biaryl urea residue of SNS-314 (1c), which is a potent Aurora kinase inhibitor and entered clinical testing in patients with solid tumors. Compared to SNS-314, this series of compounds offers better aqueous solubility while retaining comparable in vitro potency in biochemical and cell-based assays; in particular, 6m has also demonstrated a comparable mouse iv PK profile to SNS-314.

  7. Impact of the clinical use of ROCK inhibitor on the pathogenesis and treatment of glaucoma.

    Science.gov (United States)

    Honjo, Megumi; Tanihara, Hidenobu

    2018-03-01

    Rho-associated protein kinase (ROCK), a ubiquitously expressed signaling messenger and downstream effector of Rho, is activated by several bioactive factors in the aqueous humor (AH). Rho-ROCK signaling regulates a wide spectrum of fundamental cellular events, including cell adhesion, motility, proliferation, differentiation, and apoptosis. Previous studies, including our own, found that ROCK inhibitor lowers intraocular pressure (IOP) via a direct effect on the conventional AH outflow pathway, by regulation of contractile properties, fibrotic activity, and permeability of the trabecular meshwork (TM) and Schlemm's canal (SC) tissues, influencing extracellular matrix (ECM) production. Recently, a novel ROCK inhibitor, ripasudil, has been introduced in Japan. Other ROCK inhibitors are now in clinical trials as new IOP-lowering drugs for glaucoma patients. To date, ripasudil, administered together with other glaucoma medications, has proved safe and efficient in lowering IOP as well as additional effects such as prostaglandin analogs, beta-blockers, and carbonic anhydrase inhibitors, all of which help lower IOP by different mechanisms. In addition, we found that long-term treatment with ripasudil exerted an additional IOP-lowering effect, especially in eyes with high IOP, suggesting that late-onset remodeling of the ECM in glaucomatous eyes may elicit mild and delayed changes in IOP levels. ROCK inhibitors have also shown several additional effects, including increased retinal blood flow, direct protection of neurons against various types of stress, and regulation of wound healing; these benefits may potentially be useful in glaucoma treatment.

  8. Research Advances and Detection Methodologies for Microbe-Derived Acetylcholinesterase Inhibitors: A Systemic Review

    Directory of Open Access Journals (Sweden)

    Jingqian Su

    2017-01-01

    Full Text Available Acetylcholinesterase inhibitors (AChEIs are an attractive research subject owing to their potential applications in the treatment of neurodegenerative diseases. Fungi and bacteria are major producers of AChEIs. Their active ingredients of fermentation products include alkaloids, terpenoids, phenylpropanoids, and steroids. A variety of in vitro acetylcholinesterase inhibitor assays have been developed and used to measure the activity of acetylcholinesterases, including modified Ellman’s method, thin layer chromatography bioautography, and the combined liquid chromatography-mass spectrometry/modified Ellman’s method. In this review, we provide an overview of the different detection methodologies, the microbe-derived AChEIs, and their producing strains.

  9. Discovery of amido-benzisoxazoles as potent c-Kit inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Kunz, Roxanne K.; Rumfelt, Shannon; Chen, Ning; Zhang, Dawei; Tasker, Andrew S.; Bürli, Roland; Hungate, Randall; Yu, Violeta; Nguyen, Yen; Whittington, Douglas A.; Meagher, Kristin L.; Plant, Matthew; Tudor, Yanyan; Schrag, Michael; Xu, Yang; Ng, Gordon Y.; Hu, Essa (Amgen)

    2010-01-12

    Deregulation of the receptor tyrosine kinase c-Kit is associated with an increasing number of human diseases, including certain cancers and mast cell diseases. Interference of c-Kit signaling with multi-kinase inhibitors has been shown clinically to successfully treat gastrointestinal stromal tumors and mastocytosis. Targeted therapy of c-Kit activity may provide therapeutic advantages against off-target effects for non-oncology applications. A new structural class of c-Kit inhibitors is described, including in vitro c-Kit potency, kinase selectivity, and the observed binding mode.

  10. Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease.

    Science.gov (United States)

    Chong, Jimmy; Leung, Bonnie; Poole, Phillippa

    2017-09-19

    Chronic obstructive pulmonary disease (COPD) is associated with cough, sputum production or dyspnoea and a reduction in lung function, quality of life and life expectancy. Apart from smoking cessation, there are no other treatments that slow lung function decline. Roflumilast and cilomilast are oral phosphodiesterase 4 (PDE 4 ) inhibitors proposed to reduce the airway inflammation and bronchoconstriction seen in COPD. This is an update of a Cochrane review first published in 2011 and updated in 2013. To evaluate the efficacy and safety of oral PDE 4 inhibitors in the management of stable COPD. We identified randomised controlled trials (RCTs) from the Cochrane Airways Trials Register (date of last search October 2016). We found other trials from web-based clinical trials registers. We included RCTs if they compared oral PDE 4 inhibitors with placebo in people with COPD. We allowed co-administration of standard COPD therapy. One review author extracted data and a second review author checked the data. We reported pooled data in Review Manager as mean differences (MD), standardised mean differences (SMD) or odds ratios (OR). We converted the odds ratios into absolute treatment effects in a 'Summary of findings' table. Thirty-four separate RCTs studying roflumilast (20 trials with 17,627 participants) or cilomilast (14 trials with 6457 participants) met the inclusion criteria, with a duration of between six weeks and one year. These included people across international study centres with moderate to very severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades II-IV), with a mean age of 64 years.We considered that the methodological quality of the 34 published and unpublished trials was acceptable overall. Treatment with a PDE 4 inhibitor was associated with a significant improvement in forced expiratory volume in one second (FEV 1 ) over the trial period compared with placebo (MD 51.53 mL, 95% confidence interval (CI) 43.17 to 59.90, 27

  11. Electric Power Monthly, August 1990. [Glossary included

    Energy Technology Data Exchange (ETDEWEB)

    1990-11-29

    The Electric Power Monthly (EPM) presents monthly summaries of electric utility statistics at the national, Census division, and State level. The purpose of this publication is to provide energy decisionmakers with accurate and timely information that may be used in forming various perspectives on electric issues that lie ahead. Data includes generation by energy source (coal, oil, gas, hydroelectric, and nuclear); generation by region; consumption of fossil fuels for power generation; sales of electric power, cost data; and unusual occurrences. A glossary is included.

  12. Electrochemical cell structure including an ionomeric barrier

    Science.gov (United States)

    Lambert, Timothy N.; Hibbs, Michael

    2017-06-20

    An apparatus includes an electrochemical half-cell comprising: an electrolyte, an anode; and an ionomeric barrier positioned between the electrolyte and the anode. The anode may comprise a multi-electron vanadium phosphorous alloy, such as VP.sub.x, wherein x is 1-5. The electrochemical half-cell is configured to oxidize the vanadium and phosphorous alloy to release electrons. A method of mitigating corrosion in an electrochemical cell includes disposing an ionomeric barrier in a path of electrolyte or ion flow to an anode and mitigating anion accumulation on the surface of the anode.

  13. Isolators Including Main Spring Linear Guide Systems

    Science.gov (United States)

    Goold, Ryan (Inventor); Buchele, Paul (Inventor); Hindle, Timothy (Inventor); Ruebsamen, Dale Thomas (Inventor)

    2017-01-01

    Embodiments of isolators, such as three parameter isolators, including a main spring linear guide system are provided. In one embodiment, the isolator includes first and second opposing end portions, a main spring mechanically coupled between the first and second end portions, and a linear guide system extending from the first end portion, across the main spring, and toward the second end portion. The linear guide system expands and contracts in conjunction with deflection of the main spring along the working axis, while restricting displacement and rotation of the main spring along first and second axes orthogonal to the working axis.

  14. Synergistic apoptosis induction in leukemic cells by the phosphatase inhibitor salubrinal and proteasome inhibitors.

    Directory of Open Access Journals (Sweden)

    Hannes C A Drexler

    Full Text Available Cells adapt to endoplasmic reticulum (ER-stress by arresting global protein synthesis while simultaneously activating specific transcription factors and their downstream targets. These processes are mediated in part by the phosphorylation-dependent inactivation of the translation initiation factor eIF2alpha. Following restoration of homeostasis protein synthesis is resumed when the serine/threonine-protein phosphatase PP1 dephosphorylates and reactivates eIF2alpha. Proteasome inhibitors, used to treat multiple myeloma patients evoke ER-stress and apoptosis by blocking the ER-associated degradation of misfolded proteins (ERAD, however, the role of eIF2alpha phosphorylation in leukemic cells under conditions of proteasome inhibitor-mediated ER stress is currently unclear.Bcr-Abl-positive and negative leukemic cell lines were used to investigate the functional implications of PP1-related phosphatase activities on eIF2alpha phosphorylation in proteasome inhibitor-mediated ER stress and apoptosis. Rather unexpectedly, salubrinal, a recently identified PP1 inhibitor capable to protect against ER stress in various model systems, strongly synergized with proteasome inhibitors to augment apoptotic death of different leukemic cell lines. Salubrinal treatment did not affect the phosphorlyation status of eIF2alpha. Furthermore, the proapoptotic effect of salubrinal occurred independently from the chemical nature of the proteasome inhibitor, was recapitulated by a second unrelated phosphatase inhibitor and was unaffected by overexpression of a dominant negative eIF2alpha S51A variant that can not be phosphorylated. Salubrinal further aggravated ER-stress and proteotoxicity inflicted by the proteasome inhibitors on the leukemic cells since characteristic ER stress responses, such as ATF4 and CHOP synthesis, XBP1 splicing, activation of MAP kinases and eventually apoptosis were efficiently abrogated by the translational inhibitor cycloheximide.Although PP1

  15. 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.

  16. Current treatment of dyslipidaemia: PCSK9 inhibitors and statin intolerance.

    Science.gov (United States)

    Koskinas, Konstantinos; Wilhelm, Matthias; Windecker, Stephan

    2016-01-01

    Statins are the cornerstone of the management of dyslipidaemias and prevention of cardiovascular disease. Although statins are, overall, safe and well tolerated, adverse events can occur and constitute an important barrier to maintaining long-term adherence to statin treatment. In patients who cannot tolerate statins, alternative treatments include switch to another statin, intermittent-dosage regimens and non-statin lipid-lowering medications. Nonetheless, a high proportion of statin-intolerant patients are unable to achieve recommended low-density lipoprotein (LDL) cholesterol goals, thereby resulting in substantial residual cardiovascular risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease implicated in LDL receptor degradation and plays a central role in cholesterol metabolism. In recent studies, PCSK9 inhibition by means of monoclonal antibodies achieved LDL cholesterol reductions of 50% to 70% across various patient populations and background lipid-lowering therapies, while maintaining a favourable safety profile. The efficacy and safety of the monoclonal antibodies alirocumab and evolocumab were confirmed in statin-intolerant patients, indicating that PCSK9 inhibitors represent an attractive treatment option in this challenging clinical setting. PCSK9 inhibitors recently received regulatory approval for clinical use and may be considered in properly selected patients according to current consensus documents, including patients with statin intolerance. In this review we summarise current evidence regarding diagnostic evaluation of statin-related adverse events, particularly statin-associated muscle symptoms, and we discuss current recommendations on the management of statin-intolerant patients. In view of emerging evidence of the efficacy and safety of PCSK9 inhibitors, we further discuss the role of monoclonal PCSK9 antibodies in the management of statin-intolerant hypercholesterolaemic patients.

  17. PCSK9 inhibitors in the current management of atherosclerosis.

    Science.gov (United States)

    Whayne, Thomas F

    The history of proprotein convertase subtilisin/kexin type 9 (PCSK9) in medical science is fascinating and the evolution of knowledge of its function has resulted in new medications of major importance for the cardiovascular (CV) patient. PCSK9 functions as a negative control or feedback for the cell surface receptors for low-density lipoprotein including its component of cholesterol (LDL-C). The initial and key findings were that different abnormalities of PCSK9 can result in an increase or a decrease of LDL-C because of more or less suppression of cell surface receptors. These observations gave hints and awoke interest that it might be possible to prepare monoclonal antibodies to PCSK9 and decrease its activity, after which there should be more active LDL-C cell receptors. The rest is a fascinating story that currently has resulted in two PCSK9 inhibitors, alirocumab and evolocumab, which, on average, decrease LDL-C approximately 50%. Nevertheless, if there are no contraindications, statins remain the standard of prevention for the high-risk CV patient and this includes both secondary and primary prevention. The new inhibitors are for the patient that does not attain the desired target for LDL-C reduction while taking a maximum statin dose or who does not tolerate any statin dose whatsoever. Atherosclerosis can be considered a metabolic disease and the clinician needs to realize this and think more and more of CV prevention. These inhibitors can contribute to both the stabilization and regression of atherosclerotic plaques and thereby avoid or delay major adverse cardiac events. (United States). Copyright © 2016 Instituto Nacional de Cardiología Ignacio Chávez. Publicado por Masson Doyma México S.A. All rights reserved.

  18. 28 CFR 20.32 - Includable offenses.

    Science.gov (United States)

    2010-07-01

    ... Exchange of Criminal History Record Information § 20.32 Includable offenses. (a) Criminal history record... vehicular manslaughter, driving under the influence of drugs or liquor, and hit and run), when unaccompanied by a § 20.32(a) offense. These exclusions may not be applicable to criminal history records...

  19. Including Students with Visual Impairments: Softball

    Science.gov (United States)

    Brian, Ali; Haegele, Justin A.

    2014-01-01

    Research has shown that while students with visual impairments are likely to be included in general physical education programs, they may not be as active as their typically developing peers. This article provides ideas for equipment modifications and game-like progressions for one popular physical education unit, softball. The purpose of these…

  20. Extending flood damage assessment methodology to include ...

    African Journals Online (AJOL)

    Optimal and sustainable flood plain management, including flood control, can only be achieved when the impacts of flood control measures are considered for both the man-made and natural environments, and the sociological aspects are fully considered. Until now, methods/models developed to determine the influences ...

  1. BIOLOGIC AND ECONOMIC EFFECTS OF INCLUDING DIFFERENT ...

    African Journals Online (AJOL)

    The biologic and economic effects of including three agro-industrial by-products as ingredients in turkey poult diets were investigated using 48 turkey poults in a completely randomised design experiment. Diets were formulated to contain the three by-products – wheat offal, rice husk and palm kernel meal, each at 20% level ...

  2. Including Children Dependent on Ventilators in School.

    Science.gov (United States)

    Levine, Jack M.

    1996-01-01

    Guidelines for including ventilator-dependent children in school are offered, based on experience with six such students at a New York State school. Guidelines stress adherence to the medical management plan, the school-family partnership, roles of the social worker and psychologist, orientation, transportation, classroom issues, and steps toward…

  3. Preoperative renin-angiotensin system inhibitors protect renal function in aging patients undergoing cardiac surgery.

    Science.gov (United States)

    Barodka, Viachaslau; Silvestry, Scott; Zhao, Ning; Jiao, Xiangyin; Whellan, David J; Diehl, James; Sun, Jian-Zhong

    2011-05-15

    Renal failure (RF) represents a major postoperative complication for elderly patients undergoing cardiac surgery. This observational cohort study examines effects of preoperative use of renin-angiotensin system (RAS) inhibitors on postoperative renal failure in aging patients undergoing cardiac surgery. We retrospectively analyzed a cohort of 1287 patients who underwent cardiac surgery at this institution (2003-2007). The patients included were ≥65 years old, scheduled for elective cardiac surgery, and without preexisting RF (defined by the criteria of the Society of Thoracic Surgeons as described in Method). Of all patients evaluated, 346 patients met the inclusion criteria and were divided into two groups: using (n = 122) or not using (n = 224) preoperative RAS inhibitors. A comparison of the two groups showed no significant differences in baseline parameters, including creatinine clearance, body mass index, history of diabetes and smoking, preoperative medicines (except that more patients with RAS inhibitors had a history of hypertension or congestive heart failure, fewer RAS inhibitor patients had chronic lung disease), in intraoperative perfusion and aortic cross-clamp time, and in postoperative complications and 30-d mortality. Multivariate logistic regression analysis demonstrated, however, that preoperative RAS inhibitors significantly and independently reduced the incidence of postoperative RF in the patients undergoing cardiac surgery compared with those not taking RAS inhibitors: 1.6% versus 7.6%, yielding an odds ratio of 0.19 (95 % CI 0.04-0.84, P = 0.029). Preoperative RAS inhibitors may have significant renoprotective effects for aging patients undergoing elective cardiac surgery. Copyright © 2011 Elsevier Inc. All rights reserved.

  4. Structural Characterization of LRRK2 Inhibitors

    NARCIS (Netherlands)

    Gilsbach, Bernd K; Messias, Ana C; Ito, Genta; Sattler, Michael; Alessi, Dario R; Wittinghofer, Alfred; Kortholt, Arjan

    2015-01-01

    Kinase inhibition is considered to be an important therapeutic target for LRRK2 mediated Parkinson's disease (PD). Many LRRK2 kinase inhibitors have been reported but have yet to be optimized in order to qualify as drug candidates for the treatment of the disease. In order to start a

  5. Rational Design of Rho Protein Inhibitors

    National Research Council Canada - National Science Library

    Rojas, Rafael J

    2006-01-01

    ... nucleotide exchange factors (RhoGEFs). We have developed a high throughput screening strategy identify novel inhibitors of Rho activation are currently following up on several compounds which appear to selectively inhibit Rho activation. These compounds may form the basis of future drug development strategies for the treatment of metastatic breast cancer.

  6. Rational Design of Rho Protein Inhibitors

    National Research Council Canada - National Science Library

    Rojas, Rafael J

    2005-01-01

    ... nucleotide exchange factors (RhoGEFs). We have developed a high throughput screening strategy identify novel inhibitors of Rho activation are currently following up on several compounds which appear to selectively inhibit Rho activation. These compounds may form the basis of future drug development strategies for the treatment of metastatic breast cancer.

  7. [Mechanisms and efficacy of SGLT2 inhibitors].

    Science.gov (United States)

    Shiba, Teruo

    2015-03-01

    SGLT2 is a low affinity, high capacity glucose co-transporter, almost exclusively expressed in the kidney cortex. Inhibition of SGLT2 has been shown to increase the daily 50g or more urinary glucose excretion, as compared to placebo, leading to a reduction in blood glucose levels and indicated only for the treatment of type 2 diabetes. In Japan 6 species of SGLT2 inhibitors have already been sold and reported to results in a decrease of FPG by 14.4 to 45.8 (mg/dL), in a reduction of HbA1c by 0.35 to 1.24% and in loss of body weight by 1.29 to 2.50(kg). There is less effect of the SGLT2 inhibitor in diabetic subjects with renal impairment and the reduction in HbA1c and FPG will be approximately half of the average in those with 30 ≤ eGFR ≤ 59. The position of SGLT2 inhibitors would be considered as the drug administered in combination or add-on therapy when the young obese type 2 diabetics without renal impairment has not yet reached to the glycemic target with other drugs although in AACE consensus statement of 2013, it has been shelved for inexperienced use with respect to the positioning of the SGLT2 inhibitors.

  8. Th17 Inhibitors in Active Psoriatic Arthritis

    DEFF Research Database (Denmark)

    Naik, Girish S; Ming, Wai K; Magodoro, Itai M

    2018-01-01

    BACKGROUND: Several biologics targeting the Th17 pathway have been developed for the treatment of psoriatic arthritis (PsA), a disabling disease with moderate response and an increased incidence of serious infections to first-line biologics (TNF-α antagonists). Th17 inhibitors could replace TNF-α...

  9. Vildagliptin: the first innovative DDP-4 inhibitor

    Directory of Open Access Journals (Sweden)

    Edvin Villkhauer

    2010-09-01

    Full Text Available A review of the main stages of investigation undertaken by Novartis Pharmaceuticals in search of a new molecule for the treatment of type 2 diabetesmellitus, dipeptidyl peptidase-4 (DPP-4 inhibitor (Vildaglyptin. The data on specificity and selectivity of the action of this molecule are presentedalong with the results of its comparison with another agent of this group (sitagliptin.

  10. Curcumin derivatives as HIV-1 protease inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Sui, Z.; Li, J.; Craik, C.S.; Ortiz de Montellano, P.R. [Univ. of California, San Francisco, CA (United States)

    1993-12-31

    Curcumin, a non-toxic natural compound from Curcuma longa, has been found to be an HIV-1 protease inhibitor. Some of its derivatives were synthesized and their inhibitory activity against the HIV-1 protease was tested. Curcumin analogues containing boron enhanced the inhibitory activity. At least of the the synthesized compounds irreversibly inhibits the HIV-1 protease.

  11. Dissolution properties of cerium dibutylphosphate corrosion inhibitors

    NARCIS (Netherlands)

    Soestbergen, van M.; Erich, S.J.F.; Huinink, H.P.; Adan, O.C.G.

    2013-01-01

    The corrosion inhibitor cerium dibutylphosphate, Ce(dbp)3, prevents corrosion by cerium and dbp deposition at the alkaline cathode and acidic anode respectively. The pH dependent Ce(dbp)3 solubility seems to play an essential role in the inhibition degree. We found that Ce(dbp)3 scarcely dissolves

  12. Peptide aldehyde inhibitors of bacterial peptide deformylases.

    Science.gov (United States)

    Durand, D J; Gordon Green, B; O'Connell, J F; Grant, S K

    1999-07-15

    Bacterial peptide deformylases (PDF, EC 3.5.1.27) are metalloenzymes that cleave the N-formyl groups from N-blocked methionine polypeptides. Peptide aldehydes containing a methional or norleucinal inhibited recombinant peptide deformylase from gram-negative Escherichia coli and gram-positive Bacillus subtilis. The most potent inhibitor was calpeptin, N-CBZ-Leu-norleucinal, which was a competitive inhibitor of the zinc-containing metalloenzymes, E. coli and B. subtilis PDF with Ki values of 26.0 and 55.6 microM, respectively. Cobalt-substituted E. coli and B. subtilis deformylases were also inhibited by these aldehydes with Ki values for calpeptin of 9.5 and 12.4 microM, respectively. Distinct spectral changes were observed upon binding of calpeptin to the Co(II)-deformylases, consistent with the noncovalent binding of the inhibitor rather than the formation of a covalent complex. In contrast, the chelator 1,10-phenanthroline caused the time-dependent inhibition of B. subtilis Co(II)-PDF activity with the loss of the active site metal. The fact that calpeptin was nearly equipotent against deformylases from both gram-negative and gram-positive bacterial sources lends further support to the idea that a single deformylase inhibitor might have broad-spectrum antibacterial activity. Copyright 1999 Academic Press.

  13. Immune checkpoint inhibitors for metastatic bladder cancer.

    Science.gov (United States)

    Massari, Francesco; Di Nunno, Vincenzo; Cubelli, Marta; Santoni, Matteo; Fiorentino, Michelangelo; Montironi, Rodolfo; Cheng, Liang; Lopez-Beltran, Anto; Battelli, Nicola; Ardizzoni, Andrea

    2018-03-01

    Chemotherapy has represented the standard therapy for unresectable or metastatic urothelial carcinoma for more than 20 years. The growing knowledge of the interaction between tumour and immune system has led to the advent of new classes of drugs, the immune-checkpoints inhibitors, which are intended to change the current scenario. To date, immunotherapy is able to improve the overall responses and survival. Moreover, thanks to its safety profile immune-checkpoint inhibitors could be proposed also to patients unfit for standard chemotherapy. No doubts that these agents have started a revolution expected for years, but despite this encouraging results it appears clear that not all subjects respond to these agents and requiring the development of reliable predictive response factors able to isolate patients who can more benefit from these treatments as well as new strategies aimed to improve immunotherapy clinical outcome. In this review we describe the active or ongoing clinical trials involving Programmed Death Ligand 1 (PD-L1), Programmed Death receptor 1 (PD-1) and Cytotoxic-T Lymphocyte Antigen 4 (CTLA 4) inhibitors in urothelial carcinoma focusing our attention on the developing new immune-agents and combination strategies with immune-checkpoint inhibitors. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Current and Novel Inhibitors of HIV Protease

    Czech Academy of Sciences Publication Activity Database

    Pokorná, Jana; Machala, L.; Řezáčová, Pavlína; Konvalinka, Jan

    2009-01-01

    Roč. 1, č. 3 (2009), s. 1209-1239 ISSN 1999-4915 R&D Projects: GA MŠk 1M0508 Grant - others:GA AV ČR(CZ) IAAX00320901 Program:IA Institutional research plan: CEZ:AV0Z40550506 Keywords : HIV protease * protease inhibitor * HAART Subject RIV: CE - Biochemistry

  15. Proton pump inhibitors affect the gut microbiome

    NARCIS (Netherlands)

    Imhann, Floris; Bonder, Marc Jan; Vich Vila, Arnau; Fu, Jingyuan; Mujagic, Zlatan; Vork, Lisa; Feenstra, Ettje T.; Jankipersadsing, Soesma A; Cenit, Maria Carmen; Harmsen, Hermie J M; Dijkstra, Gerard; Franke, Lude; Xavier, Ramnik J; Jonkers, Daisy; Wijmenga, Cisca; Weersma, Rinse K; Zhernakova, Alexandra

    BACKGROUND AND AIMS: Proton pump inhibitors (PPIs) are among the top 10 most widely used drugs in the world. PPI use has been associated with an increased risk of enteric infections, most notably Clostridium difficile. The gut microbiome plays an important role in enteric infections, by resisting or

  16. Pharmacological caspase inhibitors: Research towards therapeutic perspectives

    Czech Academy of Sciences Publication Activity Database

    Kudělová, J.; Fleischmannová, J.; Adamová, E.; Matalová, Eva

    2015-01-01

    Roč. 66, č. 4 (2015), s. 473-482 ISSN 0867-5910 R&D Projects: GA ČR(CZ) GA14-28254S Institutional support: RVO:68081715 Keywords : caspase * caspase inhibitor * apoptosis Subject RIV: CB - Analytical Chemistry, Separation Impact factor: 2.804, year: 2015

  17. Pharmacological caspase inhibitors: Research towards therapeutic perspectives

    Czech Academy of Sciences Publication Activity Database

    Kudělová, J.; Fleischmannová, Jana; Adamová, Eva; Matalová, Eva

    2015-01-01

    Roč. 66, č. 4 (2015), s. 473-482 ISSN 0867-5910 R&D Projects: GA ČR GB14-37368G Institutional support: RVO:67985904 Keywords : caspase * caspase inhibitor * apoptosis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.804, year: 2015

  18. Discovery of inhibitors of bacterial histidine kinases

    NARCIS (Netherlands)

    Velikova, N.R.

    2014-01-01

    Discovery of Inhibitors of Bacterial Histidine Kinases Summary

    The thesis is on novel antibacterial drug discovery (http://youtu.be/NRMWOGgeysM). Using structure-based and fragment-based drug discovery approach, we have identified small-molecule histidine-kinase

  19. Novel peptide-based protease inhibitors

    DEFF Research Database (Denmark)

    Roodbeen, Renée

    of novel peptide-based protease inhibitors, efforts were made towards improved methods for peptide synthesis. The coupling of Fmoc-amino acids onto N-methylated peptidyl resins was investigated. These couplings can be low yielding and the effect of the use of microwave heating combined with the coupling...

  20. Oestrogen, testosterone, cytotoxin and cholinesterase inhibitor ...

    African Journals Online (AJOL)

    Oestrogen, testosterone, cytotoxin and cholinesterase inhibitor removal during reclamation of sewage to drinking water. ... Risks associated with sewage effluent and reclaimed sewage should be closely monitored; therefore water at the Gammams Sewage Treatment Plant (GSTP) inlet and outlet, as well as reclaimed water ...