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Sample records for alemtuzumab aliskiren fumarate

  1. Aliskiren

    MedlinePlus

    ... day. Aliskiren should be taken either always with food or always without food. Take aliskiren at around the same time every ... try to avoid eating a high fat meal (foods such as fried foods or fast foods) when ...

  2. Dimethyl Fumarate

    MedlinePlus

    ... course of disease where symptoms flare up from time to time) of multiple sclerosis (MS; a condition in which ... day. Take dimethyl fumarate at around the same times every day. Follow the directions on your prescription ...

  3. Aldosterone breakthrough during aliskiren, valsartan, and combination (aliskiren + valsartan) therapy.

    PubMed

    Bomback, Andrew S; Rekhtman, Yelena; Klemmer, Philip J; Canetta, Pietro A; Radhakrishnan, Jai; Appel, Gerald B

    2012-01-01

    Aldosterone levels increase in 30%-40% of patients on angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers over the long term. This "aldosterone breakthrough" may carry important clinical consequences given aldosterone's nonepithelial, pro-fibrotic actions. The renin inhibitor, aliskiren, by suppressing the renin-angiotensin-aldosterone system (RAAS) proximally, may limit breakthrough compared to conventional RAAS blockade. This open-label study (NCT01129557) randomized subjects to aliskiren 300 mg daily (A), valsartan 320 mg daily (V), or aliskiren 150 mg + valsartan 160 mg daily (A+V) for 9 months. Eligible subjects had proteinuria >300 mg/day, estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m(2), and systolic blood pressure (BP) >130 or diastolic BP >80 mm Hg. Serum and 24-hour urine aldosterone (indexed to 24-hour urine Na) were checked before initiation of therapy and at 3, 6, and 9 months. Aldosterone breakthrough was defined as a sustained increase from baseline aldosterone by study end. The study was intended to enroll 120 subjects but was terminated early by the sponsor. We present here the results of 33 subjects who completed the protocol, of which 12 were randomized to A, 11 were randomized to V, and 10 were randomized to A+V. Mean baseline eGFR was 75.5 (±23.3) mL/min/1.73 m(2); baseline proteinuria was 3104 (±2943) mg/day; and baseline BP was 134.7 (±10.5)/84.8 (±8.4) mm Hg. Three (27%) subjects on V, three (25%) subjects on A, and three (30%) subjects on A+V had aldosterone breakthrough. Mean proteinuria reduction was 31% from baseline in all subjects: 30% in subjects with breakthrough vs. 32% in subjects without breakthrough. Mean BP reduction was 11.0/8.8 mm Hg in all subjects: 8.4/6.1 mm Hg in subjects with breakthrough vs. 12.0/9.8 mm Hg in subjects without breakthrough. Aliskiren, alone or in combination with valsartan, did not reduce the incidence of aldosterone breakthrough in subjects with hypertension

  4. Alemtuzumab long-term immunologic effect

    PubMed Central

    De Mercanti, Stefania; Rolla, Simona; Cucci, Angele; Bardina, Valentina; Cocco, Eleonora; Vladic, Anton; Soldo-Butkovic, Silva; Habek, Mario; Adamec, Ivan; Horakova, Dana; Annovazzi, Pietro; Novelli, Francesco; Clerico, Marinella

    2016-01-01

    Objective: To analyze changes in T-helper (Th) subsets, T-regulatory (Treg) cell percentages and function, and mRNA levels of immunologically relevant molecules during a 24-month follow-up after alemtuzumab treatment in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: Multicenter follow-up of 29 alemtuzumab-treated patients with RRMS in the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) I and CARE-MS II trials. Peripheral blood (PB) samples were obtained at months 0, 6, 12, 18, and 24. We evaluated (1) mRNA levels of 26 immunologic molecules (cytokines, chemokines, chemokine receptors, and transcriptional factors); (2) Th1, Th17, and Treg cell percentages; and (3) myelin basic protein (MBP)–specific Treg suppressor activity. Results: We observed 12 relapses in 9 patients. mRNA levels of the anti-inflammatory cytokines interleukin (IL)–10, IL-27, and transforming growth factor–β persistently increased whereas those of proinflammatory molecules related to the Th1 or Th17 subsets persistently decreased after alemtuzumab administration throughout the follow-up period. PB CD4+ cell percentage remained significantly lower than baseline while that of Th1 and Th17 cells did not significantly change. A significant increase in Treg cell percentage was observed at month 24 and was accompanied by an increase in Treg cell suppressive activity against MBP-specific Th1 and Th17 cells. Conclusions: The long-lasting therapeutic benefit of alemtuzumab in RRMS may involve a shift in the cytokine balance towards inhibition of inflammation associated with a reconstitution of the PB CD4+ T-cell subsets that includes expansion of Treg cells with increased suppressive function. PMID:26819963

  5. Aliskiren-associated acute renal failure with hyperkalemia.

    PubMed

    Venzin, R M; Cohen, C D; Maggiorini, M; Wüthrich, R P

    2009-03-01

    We report the first case of acute renal failure with hyperkalemia associated with the recently marketed direct renin inhibitor aliskiren. To optimize blood pressure control, the antihypertensive medication of a 76-year-old hypertensive female patient was changed from the angiotensin II receptor antagonist irbesartan to aliskiren. Spironolactone was continued, as serum creatinine and potassium levels were initially normal. Two weeks later the patient presented with acute oliguric renal failure, symptomatic hyperkalemia and metabolic acidosis, necessitating emergency dialytic treatment. Unrecognized pre-existing renal insufficiency (CKD Stage 2 - 3) and the continuation of spironolactone were identified as predisposing risk factors.

  6. Alemtuzumab in refractory Sézary syndrome*

    PubMed Central

    Reifs, Carmen María Alcántara; Salido-Vallejo, Rafael; Garnacho-Saucedo, Gloria María; la Corte-Sánchez, Sofía De; González-Menchen, Alberto; García-Nieto, Antonio Vélez

    2016-01-01

    Sézary syndrome is a primary cutaneous T-cell lymphoma characterized by the triad of erythroderma, lymphadenopathy and circulating atypical cells. The emergence of new molecular targets has enabled the development of drugs such as alemtuzumab, an anti-CD52 monoclonal antibody, which has shown promising results in the treatment of this entity. We report the case of a 70-year-old male with refractory Sézary syndrome in whom treatment with alemtuzumab achieved an 80% skin lesion clearance with complete haematologic and radiologic response. The treatment was discontinued after 4 months due to adverse effects, with the patient showing a sustained response without disease progression after 13 months of follow-up. PMID:27828640

  7. Handle region peptide counteracts the beneficial effects of the Renin inhibitor aliskiren in spontaneously hypertensive rats.

    PubMed

    van Esch, Joep H M; van Veghel, Richard; Garrelds, Ingrid M; Leijten, Frank; Bouhuizen, Angelique M; Danser, A H Jan

    2011-04-01

    To investigate whether the putative (pro)renin receptor blocker, the handle region peptide (HRP), exerts effects on top of the blood pressure-lowering and cardioprotective effects of the renin inhibitor aliskiren, spontaneously hypertensive rats were implanted with telemetry transmitters to monitor heart rate and mean arterial pressure (MAP). After a 2-week recovery period, vehicle, aliskiren, HRP (100 and 1 mg/kg per day, respectively), and HRP+aliskiren were infused for 3 weeks using osmotic minipumps. Subsequently, the heart was removed to study coronary function according to Langendorff. Baseline MAP and heart rate in vehicle-treated rats were 146±3 mm Hg and 326±4 bpm. HRP did not affect MAP, whereas aliskiren and HRP+aliskiren lowered MAP (by maximally 29±2 and 20±1 mm Hg, respectively) without affecting heart rate. Aliskiren significantly reduced MAP throughout the 3-week infusion period, whereas the blood pressure-lowering effect of HRP+aliskiren returned to baseline within 2 weeks of treatment. In comparison with vehicle, aliskiren increased the endothelium-dependent response to bradykinin and decreased the response to angiotensin II in the coronary circulation, whereas these responses were not altered after treatment with HRP or HRP+aliskiren. HRP did not alter plasma renin activity, plasma angiotensin levels, or the renal angiotensin content, either alone or on top of aliskiren, nor did it alter the aliskiren-induced decrease in renal Ang II type 1 receptor expression. Yet, it did reverse the aliskiren-induced reduction in cardiomyocyte area, without affecting this area when given alone. In conclusion, HRP counteracts the beneficial effects of aliskiren on blood pressure, coronary function, and cardiac hypertrophy in an angiotensin-independent manner.

  8. An observational study of alemtuzumab following fingolimod for multiple sclerosis

    PubMed Central

    Willis, Mark; Pearson, Owen; Illes, Zsolt; Sejbaek, Tobias; Nielsen, Christian; Duddy, Martin; Petheram, Kate; van Munster, Caspar; Killestein, Joep; Malmeström, Clas; Tallantyre, Emma

    2017-01-01

    Objective: To describe a series of patients with relapsing multiple sclerosis (MS) who experienced significant and unexpected disease activity within the first 12 months after switching from fingolimod to alemtuzumab. Methods: Patients with relapsing MS treated sequentially with fingolimod then alemtuzumab who experienced significant subsequent disease activity were identified by personal communication with 6 different European neuroscience centers. Results: Nine patients were identified. Median disease duration to alemtuzumab treatment was 94 (39–215) months and follow-up from time of first alemtuzumab cycle 20 (14–21) months. Following first alemtuzumab infusion cycle, 8 patients were identified by at least 1 clinical relapse and radiologic disease activity and 1 by significant radiologic disease activity alone. Conclusions: We acknowledge the potential for ascertainment bias; however, these cases may illustrate an important cause of reduced efficacy of alemtuzumab in a vulnerable group of patients with MS most in need of disease control. We suggest that significant and unexpected subsequent disease activity after alemtuzumab induction results from prolonged sequestration of autoreactive lymphocytes following fingolimod withdrawal, allowing these cells to be concealed from the usual biological effect of alemtuzumab. Subsequent lymphocyte egress then provokes disease reactivation. Further animal studies and clinical trials are required to confirm these phenomena and in the meantime careful consideration should be given to mode of action of individual therapies and sequential treatment effects in MS when designing personalized treatment regimens. PMID:28101520

  9. 21 CFR 172.350 - Fumaric acid and salts of fumaric acid.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Fumaric acid and salts of fumaric acid. 172.350... Nutritional Additives § 172.350 Fumaric acid and salts of fumaric acid. Fumaric acid and its calcium, ferrous... prescribed conditions: (a) The additives meet the following specifications: (1) Fumaric acid contains...

  10. Aliskiren in the treatment of hypertension and organ damage.

    PubMed

    Riccioni, Graziano

    2011-02-01

    Hypertension is one of the most important risk factor and cause of cardiovascular diseases (CVD). Chronic activation of the renin-angiotensin-aldosterone system (RAAS) plays a key role in the development of hypertension, cardiac and renal diseases. RAAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs), improve cardiovascular and renal outcomes. However, studies have shown that residual morbidity and mortality remains high, despite current optimal treatment. More comprehensive control of the RAAS might provide additional reductions in morbidity and mortality. Direct renin inhibitors such aliskiren offer the potential for enhanced RAAS control as they target the system at the point of activation, thereby reducing plasma renin activity; by contrast, ACEI and ARBs increase plasma renin activity. The efficacy of aliskiren in the reduction of major clinical events is being tested in large ongoing clinical trials. This review examines the efficacy, safety, and tolerability of aliskiren, and considers the evidence for the potential organ protection benefits of this treatment.

  11. Magnetic poly(D,L-lactide) nanoparticles loaded with aliskiren: A promising tool for hypertension treatment

    NASA Astrophysics Data System (ADS)

    Antal, Iryna; Kubovcikova, Martina; Zavisova, Vlasta; Koneracka, Martina; Pechanova, Olga; Barta, Andrej; Cebova, Martina; Antal, Vitaliy; Diko, Pavel; Zduriencikova, Martina; Pudlak, Michal; Kopcansky, Peter

    2015-04-01

    In this study anti-hypertensive drug called aliskiren was encapsulated in magnetic poly(D,L-lactide) nanoparticles by the modified nanoprecipitation method. The effect of magnetite and drug concentrations on the size distribution and zeta potential of polymer nanoparticles was investigated. The optimized loadings were as follows: theoretical magnetite loading was 20 mg/100 mg polymer nanoparticles and aliskiren was encapsulated in magnetic poly(D,L-lactide) nanoparticles at theoretical loading 0.6 mg aliskiren/100 mg magnetic polymer nanoparticles. The physicochemical characteristics of nanoparticles were studied, with spherical shape of nanoparticles sized between 58 and 227 nm being one of the observed results. Differential scanning calorimetry and infrared spectroscopy confirmed that aliskiren was successfully identified in the magnetic poly(D,L-lactide) nanoparticles. The in vivo experiments indicated that encapsulated aliskiren decreased blood pressure of the studied male spontaneously hypertensive rat even more significantly than common administered drug.

  12. Alemtuzumab treatment alters circulating innate immune cells in multiple sclerosis

    PubMed Central

    Ahmetspahic, Diana; Ruck, Tobias; Schulte-Mecklenbeck, Andreas; Schwarte, Kathrin; Jörgens, Silke; Scheu, Stefanie; Windhagen, Susanne; Graefe, Bettina; Melzer, Nico; Klotz, Luisa; Arolt, Volker; Wiendl, Heinz; Meuth, Sven G.

    2016-01-01

    Objective: To characterize changes in myeloid and lymphoid innate immune cells in patients with relapsing-remitting multiple sclerosis (MS) during a 6-month follow-up after alemtuzumab treatment. Methods: Circulating innate immune cells including myeloid cells and innate lymphoid cells (ILCs) were analyzed before and 6 and 12 months after onset of alemtuzumab treatment. Furthermore, a potential effect on granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)–23 production by myeloid cells and natural killer (NK) cell cytolytic activity was determined. Results: In comparison to CD4+ T lymphocytes, myeloid and lymphoid innate cell subsets of patients with MS expressed significantly lower amounts of CD52 on their cell surface. Six months after CD52 depletion, numbers of circulating plasmacytoid dendritic cells (DCs) and conventional DCs were reduced compared to baseline. GM-CSF and IL-23 production in DCs remained unchanged. Within the ILC compartment, the subset of CD56bright NK cells specifically expanded under alemtuzumab treatment, but their cytolytic activity did not change. Conclusions: Our findings demonstrate that 6 months after alemtuzumab treatment, specific DC subsets are reduced, while CD56bright NK cells expanded in patients with MS. Thus, alemtuzumab specifically restricts the DC compartment and expands the CD56bright NK cell subset with potential immunoregulatory properties in MS. We suggest that remodeling of the innate immune compartment may promote long-term efficacy of alemtuzumab and preserve immunocompetence in patients with MS. PMID:27766281

  13. Fumaric acid production by fermentation

    PubMed Central

    Roa Engel, Carol A.; Zijlmans, Tiemen W.; van Gulik, Walter M.; van der Wielen, Luuk A. M.

    2008-01-01

    The potential of fumaric acid as a raw material in the polymer industry and the increment of cost of petroleum-based fumaric acid raises interest in fermentation processes for production of this compound from renewable resources. Although the chemical process yields 112% w/w fumaric acid from maleic anhydride and the fermentation process yields only 85% w/w from glucose, the latter raw material is three times cheaper. Besides, the fermentation fixes CO2. Production of fumaric acid by Rhizopus species and the involved metabolic pathways are reviewed. Submerged fermentation systems coupled with product recovery techniques seem to have achieved economically attractive yields and productivities. Future prospects for improvement of fumaric acid production include metabolic engineering approaches to achieve low pH fermentations. PMID:18214471

  14. 21 CFR 172.350 - Fumaric acid and salts of fumaric acid.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Fumaric acid and salts of fumaric acid. 172.350... HUMAN CONSUMPTION Special Dietary and Nutritional Additives § 172.350 Fumaric acid and salts of fumaric acid. Fumaric acid and its calcium, ferrous, magnesium, potassium, and sodium salts may be safely...

  15. 21 CFR 172.350 - Fumaric acid and salts of fumaric acid.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Fumaric acid and salts of fumaric acid. 172.350... HUMAN CONSUMPTION Special Dietary and Nutritional Additives § 172.350 Fumaric acid and salts of fumaric acid. Fumaric acid and its calcium, ferrous, magnesium, potassium, and sodium salts may be safely...

  16. 21 CFR 172.350 - Fumaric acid and salts of fumaric acid.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Fumaric acid and salts of fumaric acid. 172.350... HUMAN CONSUMPTION Special Dietary and Nutritional Additives § 172.350 Fumaric acid and salts of fumaric acid. Fumaric acid and its calcium, ferrous, magnesium, potassium, and sodium salts may be safely...

  17. 21 CFR 172.350 - Fumaric acid and salts of fumaric acid.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Fumaric acid and salts of fumaric acid. 172.350... HUMAN CONSUMPTION Special Dietary and Nutritional Additives § 172.350 Fumaric acid and salts of fumaric acid. Fumaric acid and its calcium, ferrous, magnesium, potassium, and sodium salts may be safely...

  18. Renoprotective effects of aliskiren on adenine-induced tubulointerstitial nephropathy: possible underlying mechanisms.

    PubMed

    Hussein, Abdelaziz M; Malek, Hala Abdel; Saad, Mohamed-Ahdy

    2016-08-01

    The present study investigated the possible renoprotective effect of direct renin inhibitor (aliskiren) on renal dysfunctions, as well as its underlying mechanisms in rat model of adenine-induced tubulointerstitial nephropathy. Forty male Sprague-Dawley rats were randomized into 4 groups; normal group, aliskiren group (normal rats received 10 mg/kg aliskiren), adenine group (animals received high-adenine diet for 4 weeks and saline for 12 weeks), and adenine + aliskiren group (animals received adenine for 4 weeks and aliskiren 10 mg/kg for 12 weeks). It was found that adenine caused significant decrease in body mass, Hb, HR, serum Ca(2+), eNOS and nrf2 expression, GSH, and catalase in kidney tissues with significant increase in arterial blood pressure (ABP), serum creatinine, BUN, plasma renin activity (PRA), K(+) and P, urinary albumin excretion (UAE), caspase-3, and MDA (lipid peroxidation marker) in kidney tissues compared to normal group (p < 0.05). Administration of aliskiren caused significant improvement in all studied parameters compared to adenine group (p < 0.05). We concluded that aliskiren has renoprotective effect against adenine-induced nephropathy. This might be due to inhibition of PRA, attenuation of oxidative stress, activation of Nrf2 and eNOS genes, and suppression of caspase-3.

  19. Aliskiren toxicity in juvenile rats is determined by ontogenic regulation of intestinal P-glycoprotein expression

    SciTech Connect

    Hoffmann, Peter; Beckman, David; McLean, Lee Anne; Yan, Jing-He

    2014-02-15

    Juvenile rat toxicity studies with the direct renin inhibitor aliskiren were initiated to support treatment in the pediatric population. In Study 1, aliskiren was administered orally to juvenile rats at doses of 0, 30, 100 or 300 mg/kg/day with repeated dosing from postpartum day (PPD) 8 to PPD 35/36. In-life, clinical pathology, anatomic pathology, and toxicokinetics evaluations were performed. In Study 2, single oral doses of aliskiren (0, 100 or 300 mg/kg) were given to 14-, 21-, 24-, 28-, 31- or 36-day-old rats; in-life data and toxicokinetics were evaluated. Study 3 was a single dose (3 mg/kg i.v.) pharmacokinetic study in juvenile rats on PPD 8, 14, 21 and 28. In Study 4, naïve rats were used to investigate ontogenic changes of the multidrug-resistant protein 1 (MDR1) and the organic anion transporting polypeptide (OATP) mRNA in several organs. Oral administration of aliskiren at 100 and 300 mg/kg caused unexpected mortality and severe morbidity in 8-day-old rats. Aliskiren plasma and tissue concentrations were increased in rats aged 21 days and younger. Expression of MDR1 and OATP mRNA in the intestine, liver and brain was significantly lower in very young rats. In conclusion, severe toxicity and increased exposure in very young rats after oral administration of aliskiren are considered to be the result of immature drug transporter systems. Immaturity of MDR1 in enterocytes appears to be the most important mechanism responsible for the high exposure. - Highlights: • Aliskiren was orally administered to juvenile rats. • Unexpected severe toxicity and acute mortality occurred in rats aged 8 days. • Toxicity was associated with increased aliskiren plasma and tissue exposure. • Developmental changes of exposure correlated with ontogeny of transporters. • Immaturity of MDR1 in enterocytes causes increased exposure in very young rats.

  20. The Role of RAAS Inhibition by Aliskiren on Paracetamol-Induced Hepatotoxicity Model in Rats.

    PubMed

    Karcioglu, Saliha Sena; Palabiyik, Saziye Sezin; Bayir, Yasin; Karakus, Emre; Mercantepe, Tolga; Halici, Zekai; Albayrak, Abdulmecit

    2016-03-01

    Paracetamol is one of the most popular and widely used analgesic and antipyretic agents, but an overdose can cause hepatotoxicity and lead to acute liver failure. Aliskiren directly inhibits renin which downregulates the renin-angiotensin-aldosterone system (RAAS). Recent findings suggest that RAAS system takes part in the pathogenesis of liver fibrosis. We aimed to reveal the relationship between hepatotoxicity and the RAAS by examining paracetamol induced hepatotoxicity. Rats were separated into five groups as follows: control, 100 mg/kg aliskiren (p.o.), 2 g/kg paracetamol (per os (p.o.)), 2 g/kg paracetamol + 50mg/kg aliskiren (p.o.), and 2 g/kg paracetamol + 100 mg/kg aliskiren(p.o.). Samples were analyzed at the biochemical, molecular, and histopathological levels. Paracetamol toxicity increased alanine aminotransferases (ALT), aspartate aminotransferases (AST), renin, and angiotensin II levels in the serum samples. In addition, the SOD activity and glutathione (GSH) levels decreased while Lipid Peroxidation (MDA) levels increased in the livers of the rats treated with paracetamol. Paracetamol toxicity caused a significant increase in TNF-α and TGF-β. Both aliskiren doses showed an improvement in ALT, AST, oxidative parameters, angiotensin II, and inflammatory cytokines. Only renin levels increased in aliskiren treatment groups due to its pharmacological effect. A histopathological examination of the liver showed that aliskiren administration ameliorated the paracetamol-induced liver damage. In immunohistochemical staining, the expression of TNF-α in the cytoplasm of the hepatocytes was increased in the paracetamol group but not in other treatment groups when compared to the control group. In light of these observations, we suggest that the therapeutic administration of aliskiren prevented oxidative stress and cytokine changes and also protected liver tissues during paracetamol toxicity by inhibiting the RAAS.

  1. Aliskiren restores renal AQP2 expression during unilateral ureteral obstruction by inhibiting the inflammasome

    PubMed Central

    Wang, Weidong; Luo, Renfei; Lin, Yu; Wang, Feifei; Zheng, Peili; Levi, Moshe; Yang, Tianxin

    2015-01-01

    Ureteral obstruction is associated with reduced expression of renal aquaporins (AQPs), urinary concentrating defects, and an enhanced inflammatory response, in which the renin-angiotensin system (RAS) may play an important role. We evaluated whether RAS blockade by a direct renin inhibitor, aliskiren, would prevent the decreased renal protein expression of AQPs in a unilateral ureteral obstruction (UUO) model and what potential mechanisms may be involved. UUO was performed for 3 days (3UUO) and 7 days (7UUO) in C57BL/6 mice with or without aliskiren injection. In 3UUO and 7UUO mice, aliskiren abolished the reduction of AQP2 protein expression but not AQP1, AQP3, and AQP4. mRNA levels of renal AQP2 and vasopressin type 2 receptor were decreased in obstructed kidneys of 7UUO mice, which were prevented by aliskiren treatment. Aliskiren treatment was also associated with a reduced inflammatory response in obstructed kidneys of UUO mice. Aliskiren significantly decreased mRNA levels of several proinflammatory factors, such as transforming growth factor-β and tumor necrosis factor-α, seen in obstructed kidneys of UUO mice. Interestingly, mRNA and protein levels of the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome components apoptosis-associated speck-like protein containing a caspase recruitment domain, caspase-1, and IL-1β were dramatically increased in obstructed kidneys of 7UUO mice, which were significantly suppressed by aliskiren. In primary cultured inner medullary collecting duct cells, IL-1β significantly decreased AQP2 expression. In conclusions, RAS blockade with the direct renin inhibitor aliskiren increased water channel AQP2 expression in obstructed kidneys of UUO mice, at least partially by preventing NLRP3 inflammasome activation in association with ureteral obstruction. PMID:25694485

  2. Aliskiren Increases Aquaporin-2 Expression and Attenuates Lithium-induced Nephrogenic Diabetes Insipidus.

    PubMed

    Lin, Yu; Zhang, Tiezheng; Feng, Pinning; Qiu, Miaojuan; Liu, Qiaojuan; Li, Suchun; Zheng, Peili; Kong, Yonglun; Levi, Moshe; Li, Chunling; Wang, Weidong

    2017-02-22

    The direct renin inhibitor aliskiren has been shown to retain and persist in medullary collecting ducts even after treatment was discontinued, suggesting a new mechanism of action for this drug. The purpose of the present study was to investigate whether aliskiren regulates renal aquaporin expression in the collecting ducts and improves urinary concentrating defect induced by lithium in mice. The mice were either fed with normal chow or LiCl diet (40mM/kg dry food/day for 4 days and 20mM/kg dry food/day for last 3 days) for seven days. Some mice were intraperitoneally injected with aliskiren (50mg/kg BW/day in saline). Aliskiren significantly increased protein abundance of AQP2 in the kidney inner medulla in mice. In inner medulla collecting duct cell suspension, aliskiren markedly increased AQP2 and pS256-AQP2 protein abundance which was significantly inhibited either by adenylyl cyclase inhibitor MDL-12330A or by PKA inhibitor H89, indicating an involvement of the cAMP-PKA signaling pathway in aliskiren-induced increased AQP2 expression. Aliskiren treatment improved urinary concentrating defect in lithium-treated mice, and partially prevented the decrease of AQP2 and pS256-AQP2 protein abundance in inner medulla of the kidney. In conclusion, the direct renin inhibitor aliskiren upregulates AQP2 protein expression in inner medullary collecting duct principal cells and prevents lithium-induced nephrogenic diabetes insipidus (NDI) likely via cAMP-PKA pathways.

  3. Successful treatment of cancer-associated retinopathy with alemtuzumab.

    PubMed

    Espandar, Ladan; O'Brien, Susan; Thirkill, Charles; Lubecki, Linda A; Esmaeli, Bita

    2007-07-01

    We herein report a patient with cancer-associated retinopathy who experienced multiple bouts of paraneoplastic retinopathy and optic neuropathy but responded to treatments with alemtuzumab and was able to maintain useful vision over the course of 8 years of follow-up.

  4. The effects of direct renin inhibitor, aliskiren, on arterial hypertension, chronic kidney disease and cardiovascular disease: optimal pharmacotherapy.

    PubMed

    Morishita, Yoshiyuki; Kusano, Eiji

    2013-03-01

    The renin-angiotensin-aldosterone system (RAAS) plays pivotal roles in the pathogenesis of progression of arterial hypertension, chronic kidney disease (CKD) and cardiovascular disease (CVD). Previous studies suggested that a direct renin inhibitor, aliskiren, may be effective for blood pressure lowering, renoprotection and cardiovascular protection. This review focuses on the effects of aliskiren for arterial hypertension, CKD and CVD.

  5. Pilot experience with continuous infusion alemtuzumab in patients with fludarabine-refractory chronic lymphocytic leukemia.

    PubMed

    Ferrajoli, Alessandra; Wierda, William G; LaPushin, Ruth; O'Brien, Susan M; Faderl, Stefan; Browning, Mary L; Keating, Michael J

    2008-04-01

    We evaluated the activity and tolerability of alemtuzumab given as a continuous infusion for 7 d followed by subcutaneous administration for 11 wk as salvage therapy for 10 patients with fludarabine-refractory chronic lymphocytic leukemia. The continuous infusion of alemtuzumab was well tolerated. The typical infusion reaction seen with intravenous alemtuzumab was abolished. Two patients achieved a partial response with an overall response rate of 20%. Alemtuzumab levels were measured in four patients and detectable levels were obtained in three. Clinical activity needs to be confirmed in a larger patient population.

  6. Azilsartan, aliskiren, and combination antihypertensives utilizing renin-angiotensin-aldosterone system antagonists.

    PubMed

    Lanier, Gregg; Sankholkar, Kedar; Aronow, Wilbert S

    2014-01-01

    Health care providers managing hypertension (HTN) have a large selection of pharmacologic agents to choose from, including several different classes of drugs and many similar drugs within each class. Antagonism of the renin-angiotensin-aldosterone system has been shown to be very effective for HTN, especially in patients with cardiovascular disease, diabetes, and heart failure. Within this group, there have been 2 new agents recently introduced to the US market and approved by the Food and Drug Administration. It is important for the HTN specialist to be familiar with the merits of these 2 drugs: the angiotensin receptor blocker Edarbi (azilsartan) and the renin inhibitor Tekturna (aliskiren). Additionally, there have been several new, fixed-dose combination antihypertensives introduced to the market since 2006 that use a renin-angiotensin-aldosterone antagonist. Seven of these combine 2 drugs together in a single pill: Edarbyclor (azilsartan/chlorthalidone), Exforge (amlodipine/valsartan), Azor (olmesartan/amlodipine), Twynsta (amlodipine/telmisartan), Tekturna HCT [aliskiren/hydrochlorothiazide (HCTZ)], Valturna (aliskiren/valsartan), Tekamlo (aliskiren/amlodipine). Three triple-drug combination medications have also been introduced recently: Exforge HCT (amlodipine/valsartan/HCTZ), Tribenzor (olmesartan/amlodipine/HCTZ), and Amturnide (aliskiren/amlodipine/hydrocholorothiazide). This review will summarize the trial data and important pharmacologic merits of these 2 new renin-angiotensin-aldosterone antagonists and the advantages of initiating treatment with one of the new fixed-dose, combination drugs approved over the last 5 years.

  7. Pharmacokinetics of alemtuzumab after haploidentical HLA-mismatched hematopoietic stem cell transplantation using in vivo alemtuzumab with or without CD52-positive malignancies.

    PubMed

    Oshima, Kumi; Kanda, Yoshinobu; Nakahara, Fumio; Shoda, Eriko; Suzuki, Takahiro; Imai, Yoichi; Watanabe, Takuro; Asai, Takashi; Izutsu, Koji; Ogawa, Seishi; Motokura, Toru; Chiba, Shigeru; Kurokawa, Mineo

    2006-11-01

    We recently reported that the addition of in vivo alemtuzumab to the conditioning regimen enables 2- or 3-locus-mismatched hematopoietic stem cell transplantation without an excessive risk of graft rejection or graft-versus-host disease. In a later series of patients, however, one patient with refractory chronic lymphocytic leukemia with large residual tumors at transplantation developed graft rejection. While the peak alemtuzumab concentration in the previous patients without graft rejection was higher than 5 micro g/ml, the peak alemtuzumab concentration in this patient was only 1.44 micro g/ml. We considered that alemtuzumab was bound to the large residual tumors, which resulted in a low blood concentration of alemtuzumab. Therefore, it is important to debulk tumors before the conditioning regimen for patients with refractory CD52-positive hematological malignancies, or the dose of alemtuzumab should be adjusted by monitoring the blood concentration, when alemtuzumab is used for in vivo T-cell depletion in 2- or 3-locus-mismatched transplantation.

  8. Refractory Adult Primary Autoimmune Neutropenia that Responded to Alemtuzumab.

    PubMed

    Neerukonda, Anu R; Lan, Fengshuo; Gabig, Theodore; Saraya, Takeshi

    2016-01-01

    Primary autoimmune neutropenia (P-AIN) is an extremely rare disease. The most effective treatment for primary P-AIN is a granulocyte colony-stimulating factor; however, no curative treatment has been reported. We herein report a case of an adult P-AIN patient with a relatively mild medical history (irrespective of the severe neutropenia) who showed a sustained hematological response over seventeen months after the initiation of treatment with subcutaneous Alemtuzumab.

  9. Aliskiren attenuates proteinuria in mice with lupus nephritis by a blood pressure-independent mechanism.

    PubMed

    Yen, T-H; Yang, H-Y; Yeh, Y-H; Chu, P-H; Wen, C-J; Fu, J-F; Wang, I-K; Liang, C-C; Chang, C-T; Chen, K-H; Tian, Y-C; Hung, C-C; Lin, J-L; Yang, C-W

    2013-02-01

    This study revealed that low-dose aliskiren treatment could attenuate proteinuria by interrupting the renin-angiotensin system in mice with lupus nephritis, and the beneficial effect was beyond blood pressure control. An in and ex vivo fluorescence imaging (using a non-invasion in vivo imaging system) showed intense labeling of renin in the kidneys of female MRL/lpr mice. In the study, Alzet mini-osmotic pumps were implanted into 6-week-old female MRL/lpr mice. Pumps were filled with either phosphate-buffered saline or a solution of aliskiren dissolved in phosphate-buffered saline (20 mg/kg/day) and replaced at 28-day intervals. Mice were sacrificed at four and eight weeks. To label cells for DNA synthesis, bromodeoxyuridine (BrdU) (50 mg/kg) was injected intraperitoneally an hour prior to sacrifice. The level of renin inhibition was adequate, as aliskiren-treated mice demonstrated higher renal renin mRNA expression than controls (p < 0.05). Although there were no significant differences in the systolic blood pressure (control versus aliskiren-treated: 127.20 ± 4.44 mmHg versus 103.80 ± 7.40 mmHg, p > 0.05) and heart rate (control versus aliskiren-treated: 680.50 ± 11.71 versus 647.80 ± 13.90, p > 0.05) of both groups after eight weeks, there was significant reduction of inflammatory cytokines (transforming growth factor-beta1, regulated on activation normal T cell expressed, monocyte chemoattractant protein-1 and osteopontin, p < 0.05), reduction of innate immunity (toll-like receptor 7, p < 0.05), as well as a reduction of glomerular proliferation and inflammation (BrdU-, CD45-, CD3- and F4/80-positive glomerular cells, p < 0.01) after aliskiren infusion, which might translate into an improvement in proteinuria (control versus aliskiren-treated: 493.7 versus 843.7 mg/g, p < 0.01) or weight gain (control versus aliskiren-treated: 5.65 ± 1.61 versus 8.67 ± 0.97%, p < 0.05).

  10. Alemtuzumab Induction and Delayed Acute Rejection in Steroid-Free Simultaneous Pancreas-Kidney Transplant Recipients

    PubMed Central

    Bank, Jonna R.; Heidt, Sebastiaan; Moes, Dirk Jan A. R.; Roelen, Dave L.; Mallat, Marko J. K.; van der Boog, Paul J.M.; Vergunst, Manon; Jol-van der Zijde, Cornelia M.; Bredius, Robbert G. M.; Braat, Andries E.; Ringers, Jan; van Tol, Maarten J. D.; Claas, Frans H. J.; Reinders, Marlies E. J.; de Fijter, Johannes W.

    2017-01-01

    Background The optimal immunosuppressive regimen in simultaneous pancreas-kidney transplant (SPKT) recipients that prevents acute rejection episodes (AREs) and allows optimal outcome remains elusive. Methods This cohort study assessed incidence and time to AREs in 73 consecutive SPKT recipients receiving alemtuzumab induction and steroid-free maintenance with tacrolimus and mycophenolate mofetil. A cohort with single high-dose antithymocyte globulin (ATG; n = 85) and triple therapy served as controls. In addition, we provided mechanistic insights in AREs after alemtuzumab depletion, including composition and alloreactivity of lymphocytes (flow cytometry and mixed lymphocyte reaction) plasma alemtuzumab levels (enzyme-linked immunosorbent assay), and maintenance drug exposure. Results Overall number of AREs at 3 years was significantly lower with alemtuzumab versus ATG induction (26.0% vs 43.5%; adjusted hazard ratio, 0.38; P = 0.029). Most AREs (94.6%) with ATG occurred within the first month, whereas 84.2% of AREs with alemtuzumab occurred beyond 3 months. Patients with and without an ARE in the steroid-free alemtuzumab group showed no differences in composition of lymphocytes, or in alemtuzumab levels. Of note, more than two thirds of these AREs were preceded by empiric tacrolimus and/or mycophenolate mofetil dose adjustments due to viral infections, leukopenia, or gastrointestinal symptoms. Conclusions Alemtuzumab induction resulted in a significant lower incidence of AREs. Empiric dose adjustments beyond 3 months in the absence of steroids carry a significant risk for subsequent rejection in SPKT recipients. PMID:28349124

  11. Spectrofluorimetric determination of aliskiren in dosage forms and urine.

    PubMed

    Aydoğmuş, Zeynep

    2012-01-01

    A new, simple and sensitive spectrofluorimetric method has been developed for the determination of aliskiren (ALS) in dosage forms and human urine. The method is based on the reaction between ALS and fluorescamine in borate buffer solution, pH 9, to give a highly fluorescent derivative which is measured at 482 nm after excitation at 382 nm. The factors affecting the reaction were carefully studied. The fluorescence intensity concentration plots were rectilinear over the range 140-1400 ng/mL with a limit of detection 13.47 ng/mL and limit of quantitation 40.81 ng/mL. The developed method was successfully applied to the analysis of the drug in tablets and human urine; the average recoveries (n = 6) were 99.88 ± 0.38% and 99.57 ± 0.44%, respectively. The analytical performance of the method was fully validated and the results were satisfactory. The stability of the drug was studied by subjecting it to acidic, basic, oxidative and thermal degradation.

  12. Aliskiren in Patients Failing to Achieve Blood Pressure Targets With Angiotensin Converting Enzyme Inhibitors or Angiotensin Receptor Blockers

    PubMed Central

    Hawkins, Elizabeth B.; Ling, Hua; Burns, Tammy L.; Mooss, Aryan N.; Hilleman, Daniel E.

    2012-01-01

    Background To assess the efficacy of aliskiren in patients failing to reach blood pressure (BP) goals with angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). Methods A total of 107 patients who failed to reach BP goals on ACEI or ARB were switched to aliskiren. Changes in BP were determined during maximal ACEI, ARB, or aliskiren therapy. Results Mean reduction in sBP and dBP with ACEI was 8.5 ± 6.3 mmHg and 6.0 ± 4.7 mmHg, respectively. Mean reduction in sBP and dBP with ARB was 8.3 ± 6.7 mmHg and 5.0 ± 5.2 mmHg, respectively. Mean reduction in sBP and dBP with aliskiren 150 mg/d was 6.7 ± 5.4 mmHg and 5.4 ± 4.8 mmHg, respectively. Mean reduction in sBP and dBP with aliskiren 300 mg/d was 8.6 ± 6.3 mmHg and 6.0 ± 4.9 mmHg, respectively. BP reductions between ACEI, ARB, and aliskiren were not significantly different. Conclusions Aliskiren is ineffective in patients failing ACEI or ARB therapy. Given the label changes restricting the use of aliskiren in combination with ACEI and ARB, excess cost compared to ACEI and ARB, and a paucity of outcome data, there is a limited role for aliskiren in practice.

  13. Alemtuzumab improves preexisting disability in active relapsing-remitting MS patients

    PubMed Central

    Cohen, Jeffrey A.; Coles, Alasdair J.; Hartung, Hans-Peter; Havrdova, Eva; Selmaj, Krzysztof W.; Margolin, David H.; Lake, Stephen L.; Kaup, Susan M.; Panzara, Michael A.; Compston, D. Alastair S.

    2016-01-01

    Objective: To characterize effects of alemtuzumab treatment on measures of disability improvement in patients with relapsing-remitting multiple sclerosis (RRMS) with inadequate response (≥1 relapse) to prior therapy. Methods: Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) II, a 2-year randomized, rater-blinded, active-controlled, head-to-head, phase 3 trial, compared efficacy and safety of alemtuzumab 12 mg with subcutaneous interferon-β-1a (SC IFN-β-1a) 44 μg in patients with RRMS. Prespecified and post hoc disability outcomes based on Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), and Sloan low-contrast letter acuity (SLCLA) are reported, focusing on improvement of preexisting disability in addition to slowing of disability accumulation. Results: Alemtuzumab-treated patients were more likely than SC IFN-β-1a–treated patients to show improvement in EDSS scores (p < 0.0001) on all 7 functional systems. Significantly more alemtuzumab patients demonstrated 6-month confirmed disability improvement. The likelihood of improved vs stable/worsening MSFC scores was greater with alemtuzumab than SC IFN-β-1a (p = 0.0300); improvement in MSFC scores with alemtuzumab was primarily driven by the upper limb coordination and dexterity domain. Alemtuzumab-treated patients had more favorable changes from baseline in SLCLA (2.5% contrast) scores (p = 0.0014) and MSFC + SLCLA composite scores (p = 0.0097) than SC IFN-β-1a–treated patients. Conclusions: In patients with RRMS and inadequate response to prior disease-modifying therapies, alemtuzumab provides greater benefits than SC IFN-β-1a across several disability outcomes, reflecting improvement of preexisting disabilities. Classification of evidence: This study provides Class I evidence (based on rater blinding and a balance in baseline characteristics between arms) that alemtuzumab modifies disability measures favorably compared with SC IFN-β-1a

  14. Acute effects of alemtuzumab infusion in patients with active relapsing-remitting MS

    PubMed Central

    Thomas, Katja; Eisele, Judith; Rodriguez-Leal, Francisco Alejandro; Hainke, Undine

    2016-01-01

    Objective: Alemtuzumab exerts its clinical efficacy by its specific pattern of depletion and repopulation of different immune cells. Beyond long-term immunologic and clinical data, little is known about acute changes in immunologic and routine laboratory parameters and their clinical relevance during the initial alemtuzumab infusion. Methods: Fifteen patients with highly active MS were recruited. In addition to parameters including heart rate, blood pressure, body temperature, and monitoring of adverse events, complete blood cell count, liver enzymes, kidney function, acute-phase proteins, serum cytokine profile, complement activation, peripheral immune cell distribution, and their potential of cytokine release were investigated prior to and after methylprednisolone and after alemtuzumab on each day of alemtuzumab infusion. Results: After the first alemtuzumab infusion, both the total leukocyte and granulocyte counts markedly increased, whereas lymphocyte counts dramatically decreased. In addition to lymphocyte depletion, cell subtypes important for innate immunity also decreased within the first week after alemtuzumab infusion. Although patients reported feeling well, C-reactive protein and procalcitonin peaked at serum levels consistent with septic conditions. Increases in liver enzymes were detected, although kidney function remained stable. Proinflammatory serum cytokine levels clearly rose after the first alemtuzumab infusion. Alemtuzumab led to impaired cytokine release ex vivo in nondepleted cells. Normal clinical parameters and mild adverse events were presented. Conclusions: Dramatic immunologic effects were observed. Standardized infusion procedure and pretreatment management attenuated infusion-related reactions. Alemtuzumab-mediated effects led to artificially altered parameters in standard blood testing. We recommend clinical decision-making based on primarily clinical symptoms within the first alemtuzumab treatment week. PMID:27213173

  15. Aliskiren Administration during Early Postnatal Life Sex-Specifically Alleviates Hypertension Programmed by Maternal High Fructose Consumption

    PubMed Central

    Hsu, Chien-Ning; Wu, Kay L. H.; Lee, Wei-Chia; Leu, Steve; Chan, Julie Y. H.; Tain, You-Lin

    2016-01-01

    Key points summary Maternal high-fructose (HF) induces programmed hypertension in adult offspring.Early aliskiren administration prevents HF-induced hypertension in both sexes of adult offspring.HF regulates RAS components in the offspring kidney in a sex-specific manner.HF alters renal transcriptome, with female offspring being more sensitive.Deprogramming strategy to prevent hypertension might be sex-specific. Background: Maternal high fructose (HF) intake induced renal programming and hypertension in male adult offspring. We examined whether maternal HF intake causes programmed hypertension and whether aliskiren administration confers protection against the process in a sex-specific manner, with a focus on the transcriptome changes in the kidney using next-generation RNA sequencing (NGS) technology and renin-angiotensin system (RAS). Methods: Pregnant Sprague—Dawley rats received regular chow or chow supplemented with 60% fructose throughout pregnancy and lactation. Offspring were assigned to six groups: male control, male HF (MHF), MHF+Aliskiren, female control, female HF (FHF), and FHF+Aliskiren. Oral aliskiren 10 mg/kg/day was administered via gastric gavage between 2 and 4 weeks of age. Rats were sacrificed at 12 weeks of age. Results: Maternal HF intake induced programmed hypertension in 12-week-old offspring of both sexes. HF regulated renal transcriptome and RAS components in the offspring kidney in a sex-specific manner. Aliskiren administration prevented HF-induced programmed hypertension in both sexes of adult offspring. Aliskiren administration increased ACE2 and MAS protein levels in female kidneys exposed to maternal HF intake. Conclusion: Maternal HF induced programmed hypertension in both sexes of adult offspring, which was sex-specifically mitigated by early aliskiren administration. Better understanding of the sex-dependent mechanisms that underlie maternal HF-induced renal programming will help develop a novel sex-specific strategy to prevent

  16. Itraconazole, a P-glycoprotein and CYP3A4 inhibitor, markedly raises the plasma concentrations and enhances the renin-inhibiting effect of aliskiren.

    PubMed

    Tapaninen, Tuija; Backman, Janne T; Kurkinen, Kaisa J; Neuvonen, Pertti J; Niemi, Mikko

    2011-03-01

    In a randomized crossover study, 11 healthy volunteers took 100 mg (first dose 200 mg) of the antifungal drug itraconazole, a P-glycoprotein and CYP3A4 inhibitor, or placebo twice daily for 5 days. On day 3, they ingested a single 150-mg dose of aliskiren, a renin inhibitor used in the treatment of hypertension. Itraconazole raised the peak plasma aliskiren concentration 5.8-fold (range, 1.1- to 24.3-fold; P < .001) and the area under the plasma aliskiren concentration-time curve 6.5-fold (range, 2.6- to 20.5-fold; P < .001) but had no significant effect on aliskiren elimination half-life. Itraconazole increased the amount of aliskiren excreted into the urine during 12 hours 8.0-fold (P < .001) and its renal clearance 1.2-fold (P = .042). Plasma renin activity 24 hours after aliskiren intake was 68% lower during the itraconazole phase than during the placebo phase (P = .011). In conclusion, itraconazole markedly raises the plasma concentrations and enhances the renin-inhibiting effect of aliskiren. The interaction is probably mainly explained by inhibition of the P-glycoprotein-mediated efflux of aliskiren in the small intestine, with a minor contribution from inhibition of CYP3A4. Concomitant use of aliskiren and itraconazole is best avoided.

  17. 21 CFR 184.1307d - Ferrous fumarate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... ferrous sulfate and sodium fumarate. (b) The ingredient meets the specifications of the Food Chemicals... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Ferrous fumarate. 184.1307d Section 184.1307d Food... Specific Substances Affirmed as GRAS § 184.1307d Ferrous fumarate. (a) Ferrous fumarate (iron (II)...

  18. 21 CFR 184.1307d - Ferrous fumarate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... ferrous sulfate and sodium fumarate. (b) The ingredient meets the specifications of the Food Chemicals... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Ferrous fumarate. 184.1307d Section 184.1307d Food... Specific Substances Affirmed as GRAS § 184.1307d Ferrous fumarate. (a) Ferrous fumarate (iron (II)...

  19. 21 CFR 184.1307d - Ferrous fumarate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... ferrous sulfate and sodium fumarate. (b) The ingredient meets the specifications of the Food Chemicals... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Ferrous fumarate. 184.1307d Section 184.1307d Food... Specific Substances Affirmed as GRAS § 184.1307d Ferrous fumarate. (a) Ferrous fumarate (iron (II)...

  20. 21 CFR 184.1307d - Ferrous fumarate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... ferrous sulfate and sodium fumarate. (b) The ingredient meets the specifications of the Food Chemicals... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Ferrous fumarate. 184.1307d Section 184.1307d Food... Specific Substances Affirmed as GRAS § 184.1307d Ferrous fumarate. (a) Ferrous fumarate (iron (II)...

  1. 21 CFR 172.826 - Sodium stearyl fumarate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Sodium stearyl fumarate. 172.826 Section 172.826... Sodium stearyl fumarate. Sodium stearyl fumarate may be safely used in food in accordance with the following conditions: (a) It contains not less than 99 percent sodium stearyl fumarate calculated on...

  2. 21 CFR 172.826 - Sodium stearyl fumarate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Sodium stearyl fumarate. 172.826 Section 172.826... CONSUMPTION Multipurpose Additives § 172.826 Sodium stearyl fumarate. Sodium stearyl fumarate may be safely... sodium stearyl fumarate calculated on the anhydrous basis, and not more than 0.25 percent sodium...

  3. Efficacy and Safety of Alemtuzumab in Multiple Sclerosis and Impact on Nursing Role

    PubMed Central

    Meyer, Cathy; Mayer, Lori; Smith, M. Shelton

    2013-01-01

    Alemtuzumab, a humanized monoclonal antibody, has shown efficacy for relapsing-remitting multiple sclerosis (MS) in phase 2 and phase 3 trials. Compared with subcutaneous interferon beta-1a, alemtuzumab significantly reduced the risk for accumulation of disability and the rate of relapse, and improved mean disability level from baseline. Notable safety and tolerability concerns include infusion-associated reactions, infections of predominantly mild-to-moderate severity, and autoimmune adverse events, principally thyroid disorders and immune thrombocytopenia. As emerging therapies such as alemtuzumab are approved for the treatment of MS, nurses specializing in the care of MS patients will make increasingly significant contributions to the education of patients, caregivers, and other health-care providers about these therapies' efficacy, tolerability, safety, and administration. This article reviews the phase 2 and phase 3 efficacy and safety results for alemtuzumab, with an emphasis on the role of nurses in communication about this treatment option for those with MS. PMID:24453779

  4. Cardiac complications after haploidentical HLA-mismatched hematopoietic stem cell transplantation using in vivo alemtuzumab.

    PubMed

    Oshima, K; Sakata-Yanagimoto, M; Asano-Mori, Y; Izutsu, K; Watanabe, T; Shoda, E; Ogawa, S; Motokura, T; Chiba, S; Kurokawa, M; Hirai, H; Kanda, Y

    2005-11-01

    Alemtuzumab is a humanized monoclonal antibody directed against human CD52 with a strong lympholytic effect. We have performed unmanipulated hematopoietic stem cell transplantation (HSCT) from 2- or 3-locus-mismatched family donors in 14 patients using in vivo alemtuzumab. All achieved complete donor cell engraftment and grade III-IV acute graft-versus-host disease was observed in only one patient. However, eight of the 14 patients developed grade II-IV cardiac complications according to Bearman's criteria. Next, we retrospectively analyzed the records of 142 adult patients who underwent allogeneic HSCT from 1995 to 2004 to evaluate whether the use of alemtuzumab was an independent risk factor for cardiac complications. Among several factors that increased the incidence of grade II-IV cardiac complications with at least borderline significance, a multivariate analysis identified the cumulative dose of anthracyclines (P=0.0016) and the use of alemtuzumab (P=0.0001) as independent significant risk factors. All of the cardiac complications in the alemtuzumab group were successfully treated with diuretics and/or catecholamines. Patient selection and close monitoring of cardiac function may be important in HLA-mismatched HSCT using in vivo alemtuzumab.

  5. Anti-diabetic and renoprotective effects of aliskiren in streptozotocin-induced diabetic nephropathy in female rats.

    PubMed

    Mahfoz, Amal M; El-Latif, Hekma A Abd; Ahmed, Lamiaa A; Hassanein, Nahed M; Shoka, Afaf A

    2016-12-01

    Since chronic kidney disease due to diabetic nephropathy (DN) is becoming an ever larger health burden worldwide, more effective therapies are desperately needed. In the present study, the anti-diabetic and renoprotective effects of aliskiren have been evaluated in streptozotocin (STZ)-induced DN in rats. DN was induced by a single intraperitoneal injection of STZ (65 mg/kg). Three weeks after STZ, rats were divided into four groups; normal, diabetic, diabetic treated with gliclazide (10 mg/kg/day) for 1 month, and diabetic treated with aliskiren (50 mg/kg/day) for 1 month. At the end of the experiment, mean arterial blood pressure and heart rate were recorded. Rats were then euthanized and serum was separated for determination of glucose, insulin, kidney function tests, superoxide dismutase activity (SOD), adiponectin, and tumor necrosis factor-alpha (TNF-α). One kidney was used for estimation of malondialdehyde (MDA), reduced glutathione (GSH), and nitric oxide (NO) contents. Other kidney was used for histopathological study and immunohistochemical measurement of caspase-3 and transforming growth factor beta (TGF-β). In addition, islets of Langerhans were isolated from normal rats by collagenase digestion technique for in vitro study. Aliskiren normalized STZ-induced hyperglycemia, increased insulin level both in vivo and in vitro, normalized kidney function tests and blood pressure, and alleviated STZ-induced kidney histopathological changes. This could be related to the ability of aliskiren toward preserving hemodynamic changes and alleviating oxidative stress and inflammatory and apoptotic markers induced by STZ in rats. However, aliskiren was more effective than gliclazide in relieving STZ-induced DN. These findings support the beneficial effect of aliskiren treatment in DN which could be attributed to its anti-diabetic, renoprotective, antioxidant, anti-inflammatory, and anti-apoptotic effects. Moreover, clinical studies are required to establish the

  6. Renoprotection, renin inhibition, and blood pressure control: the impact of aliskiren on integrated blood pressure control.

    PubMed

    Rashid, Haroon-Ur

    2010-01-01

    Hypertension (HTN) is an important factor in progressive loss of renal function. The kidney can be both a contributor to and a target of HTN. The functional integrity of the kidney is vital for the maintenance of cardiovascular homeostasis. Chronic activation of the renin system causes HTN and, ultimately, end-organ damage. Direct renin inhibitors (DRIs) inhibit plasma renin activity (PRA), thereby preventing the conversion of angiotensinogen to angiotensin I; consequently, the levels of both Ang I and Ang II are reduced. There is no compensatory increase in PRA activity with DRIs as seen with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). There are reasons to speculate that renin inhibition might prove to be a superior strategy for blocking the renin-angiotensin-aldosterone system compared with ACEIs or ARBs. Evidence for the efficacy of aliskiren (a DRI) is considered to be relatively strong, based on published, short-term, double-blind, randomized, controlled trials showing that aliskiren is as effective as other antihypertensive agents in reducing blood pressure (BP), with no rebound effects on BP after treatment withdrawal. When combined with diuretics, fully additive BP reduction is seen. When given with an ACEI or ARB, aliskiren produces significant additional BP reduction indicative of complimentary pharmacology and more complete renin-angiotensin system blockade.

  7. Superior MRI outcomes with alemtuzumab compared with subcutaneous interferon β-1a in MS

    PubMed Central

    Fisher, Elizabeth; Brinar, Vesna V.; Cohen, Jeffrey A.; Coles, Alasdair J.; Giovannoni, Gavin; Hartung, Hans-Peter; Havrdova, Eva; Selmaj, Krzysztof W.; Stojanovic, Miroslav; Weiner, Howard L.; Lake, Stephen L.; Margolin, David H.; Thomas, David R.; Panzara, Michael A.; Compston, D. Alastair S.

    2016-01-01

    Objective: To describe detailed MRI results from 2 head-to-head phase III trials, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis Study I (CARE-MS I; NCT00530348) and Study II (CARE-MS II; NCT00548405), of alemtuzumab vs subcutaneous interferon β-1a (SC IFN-β-1a) in patients with active relapsing-remitting multiple sclerosis (RRMS). Methods: The impact of alemtuzumab 12 mg vs SC IFN-β-1a 44 μg on MRI measures was evaluated in patients with RRMS who were treatment-naive (CARE-MS I) or who had an inadequate response, defined as at least one relapse, to prior therapy (CARE-MS II). Results: Both treatments prevented T2-hyperintense lesion volume increases from baseline. Alemtuzumab was more effective than SC IFN-β-1a on most lesion-based endpoints in both studies (p < 0.05), including decreased risk of new/enlarging T2 lesions over 2 years and gadolinium-enhancing lesions at year 2. Reduced risk of new T1 lesions (p < 0.0001) and gadolinium-enhancing lesion conversion to T1-hypointense black holes (p = 0.0078) were observed with alemtuzumab vs SC IFN-β-1a in CARE-MS II. Alemtuzumab slowed brain volume loss over 2 years in CARE-MS I (p < 0.0001) and II (p = 0.012) vs SC IFN-β-1a. Conclusions: Alemtuzumab demonstrated greater efficacy than SC IFN-β-1a on MRI endpoints in active RRMS. The superiority of alemtuzumab was more prominent during the second year of both studies. These findings complement the superior clinical efficacy of alemtuzumab over SC IFN-β-1a in RRMS. ClinicalTrials.gov identifier: NCT00530348 and NCT00548405. Classification of evidence: The results reported here provide Class I evidence that, for patients with active RRMS, alemtuzumab is superior to SC IFN-β-1a on multiple MRI endpoints. PMID:27590291

  8. Bis-(2-amino-5-methyl-pyridinium) fumarate-fumaric acid (1/1).

    PubMed

    Hemamalini, Madhukar; Fun, Hoong-Kun

    2010-07-24

    In the crystal structure of the title compound, C(6)H(9)N(2) (+)·0.5C(4)H(2)O(4) (2-)·0.5C(4)H(6)O(4), the fumarate dianion and fumaric acid mol-ecule are located on inversion centres. The 2-amino-5-methyl-pyrimidinium cation inter-acts with the carboxyl-ate group of the fumarate anion through a pair of N-H⋯O hydrogen bonds, forming an R(2) (2)(8) ring motif. These motifs are centrosymmetrically paired via N-H⋯O hydrogen bonds, forming a complementary DDAA array. The carboxyl groups of the fumaric acid mol-ecules and the carboxyl-ate groups of the fumarate anions are hydrogen bonded through O-H⋯O hydrogen bonds, leading to a supra-molecular chain along [101]. The crystal structure is further stabilized by weak C-H⋯O hydrogen bonds.

  9. Fumarate Reductase Activity of Streptococcus faecalis

    PubMed Central

    Aue, B. J.; Diebel, R. H.

    1967-01-01

    Some characteristics of a fumarate reductase from Streptococcus faecalis are described. The enzyme had a pH optimum of 7.4; optimal activity was observed when the ionic strength of the phosphate buffer was adjusted to 0.088. The Km value of the enzyme for reduced flavin mononucleotide was 2 × 10−4 m as determined with a 26-fold preparation. In addition to fumarate, the enzyme reduced maleate and mesaconate. No succinate dehydrogenase activity was detected, but succinate did act as an inhibitor of the fumarate reductase activity. Other inhibitors were malonate, citraconate, and trans-, trans-muconate. Metal-chelating agents did not inhibit the enzyme. A limited inhibition by sulfhydryl-binding agents was observed, and the preparations were sensitive to air oxidation and storage. Glycine, alanine, histidine, and possibly lysine stimulated fumarate reductase activity in the cell-free extracts. However, growth in media supplemented with glycine did not enhance fumarate reductase activity. The enzymatic activity appears to be constitutive. PMID:4960892

  10. Signal transduction in Halobacterium depends on fumarate.

    PubMed Central

    Marwan, W; Schäfer, W; Oesterhelt, D

    1990-01-01

    The isolation of a straight-swimming mutant of Halobacterium halobium is reported which has a defect in switching the rotational sense of its flagellar motor. Cells of this mutant strain could be complemented with an extract from wild-type cells by mild sonication and resealing of the cells in fresh medium. The switch factor responsible for restoration of wild-type behaviour was isolated from membrane vesicle preparations. Its chemical nature is proposed to be that of fumarate on the basis of chemical, chromatographic and mass spectrometric analysis. Since the switch factor (fumarate) was released from a membrane-bound state by heat and was accumulated into mutant cells that lack this compound, it is proposed that a membrane-bound protein exists which specifically binds the switch factor. Both the switch factor and fumarate cause stimulus-induced responses in cells at the level of one or few molecules. PMID:2303030

  11. 21 CFR 184.1307d - Ferrous fumarate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... produce a yellow streak when crushed. It is prepared by admixing hot solutions of ferrous sulfate and... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Ferrous fumarate. 184.1307d Section 184.1307d Food... GRAS § 184.1307d Ferrous fumarate. (a) Ferrous fumarate (iron (II) fumarate, (C4H2FeO4), CAS Reg....

  12. The effect of aliskiren on the renal dysfunction following unilateral ureteral obstruction in the rat

    PubMed Central

    Hammad, Fayez T; Lubbad, Loay

    2016-01-01

    Purpose: To investigate the effect of blocking renin-angiotensin system by direct renin inhibition using aliskiren on the renal dysfunction following reversible unilateral ureteral obstruction (UO). Methods: Wistar rats underwent reversible left UO for 72 hours. Group-Alsk (n=12) received aliskiren (30 mg/kg/day) dissolved in water starting one day before creating UO and continued until the terminal experiment five days post reversal when renal functions were measured using clearance techniques. Group-Vx (n=12) underwent similar protocol but had water only. Gene expression analysis of some markers of kidney injury was measured using PCR technique. Results: In Group-Vx, renal blood flow (RBF) and glomerular filtration rate (GFR) in the left kidney were significantly lower than the right kidney (1.82±0.12 vs. 3.19±0.40, P=0.001 and 0.81±0.08 vs. 1.44±0.09, P=0.004, respectively). However, left fractional excretion of sodium (FENa) was higher than the right FENa (0.80±0.15 vs. 0.55±0.04, P=0.05). Comparing the left obstructed kidney in Group-Alsk vs. Group-Vx, RBF and GFR were higher in Group-Alsk (2.44±0.30 vs. 1.82±0.12, P=0.049 and 1.02±0.11 vs. 0.81±0.08, P=0.07, respectively). The left renal FENa was lower in Group-Alsk but did not reach statistical significance (0.54±0.07 vs. 0.80±0.15, P=0.07). Aliskiren also decreased the gene expressions of NGAL, KIM-1 and p53. Conclusion: Direct renin inhibition by aliskiren appears to have protective effect on the renal dysfunction and on the markers of renal injury following UO indicating a potential clinical benefit of this agent. Further, this data and the previous studies indicate that blocking renin-angiotensin system at any level has a protective effect in obstructive nephropathy. PMID:27570581

  13. Lymphocytes as an Indicator for Initial Kidney Function: A Single Center Analysis of Outcome after Alemtuzumab or Basiliximab Induction

    PubMed Central

    Weissenbacher, Annemarie; Hautz, Theresa; Kimelman, Michael; Oberhuber, Rupert; Ulmer, Hanno; Bösmüller, Claudia; Maglione, Manuel; Schneeberger, Stefan

    2015-01-01

    Alemtuzumab, an anti-CD52 T-cell and B-cell depleting monoclonal antibody, is established for induction therapy in renal transplantation (KTx). We herein provide a comparative analysis between alemtuzumab and basiliximab induction therapy and correlate lymphocyte depletion and recovery with the clinical course after KTx. This is a single center retrospective analysis of 225 patients/consecutive kidney transplantations treated with alemtuzumab for lymphocyte depletion and 205 recipients treated with basiliximab. Mean lymphocyte counts were 22.8 ± 9.41% before Tx and 2.61 ± 3.11% between week 1 and week 3 in the alemtuzumab group and 23.77 ± 10.42% before Tx and 13.92 ± 8.20% in the basiliximab group. Delayed graft function (DGF), cytomegalovirus (CMV) status, and recipient age showed a significant correlation with lymphocyte counts in the alemtuzumab group only. The outcome was read in reference to the velocity of lymphocyte recovery and in comparison to the control group. Lymphocyte counts early after transplantation, following alemtuzumab treatment, could be identified as a predictive factor for kidney function early after transplantation. A detailed analysis of phenotype and function of lymphocytes after alemtuzumab induction together with a correlation with the clinical course is warranted. PMID:26171403

  14. Lymphocytes as an Indicator for Initial Kidney Function: A Single Center Analysis of Outcome after Alemtuzumab or Basiliximab Induction.

    PubMed

    Weissenbacher, Annemarie; Hautz, Theresa; Kimelman, Michael; Oberhuber, Rupert; Ulmer, Hanno; Bösmüller, Claudia; Maglione, Manuel; Schneeberger, Stefan

    2015-01-01

    Alemtuzumab, an anti-CD52 T-cell and B-cell depleting monoclonal antibody, is established for induction therapy in renal transplantation (KTx). We herein provide a comparative analysis between alemtuzumab and basiliximab induction therapy and correlate lymphocyte depletion and recovery with the clinical course after KTx. This is a single center retrospective analysis of 225 patients/consecutive kidney transplantations treated with alemtuzumab for lymphocyte depletion and 205 recipients treated with basiliximab. Mean lymphocyte counts were 22.8 ± 9.41% before Tx and 2.61 ± 3.11% between week 1 and week 3 in the alemtuzumab group and 23.77 ± 10.42% before Tx and 13.92 ± 8.20% in the basiliximab group. Delayed graft function (DGF), cytomegalovirus (CMV) status, and recipient age showed a significant correlation with lymphocyte counts in the alemtuzumab group only. The outcome was read in reference to the velocity of lymphocyte recovery and in comparison to the control group. Lymphocyte counts early after transplantation, following alemtuzumab treatment, could be identified as a predictive factor for kidney function early after transplantation. A detailed analysis of phenotype and function of lymphocytes after alemtuzumab induction together with a correlation with the clinical course is warranted.

  15. Role of aliskiren in cardio-renal protection and use in hypertensives with multiple risk factors

    PubMed Central

    Pimenta, Eduardo; Oparil, Suzanne

    2009-01-01

    The renin-angiotensin-aldosterone system (RAAS) is an important mediator of blood pressure (BP) and volume regulation in both normotensive and hypertensive persons and is a major contributor to hypertension-related target organ damage. The concept of renin inhibition for managing hypertension by blocking the RAAS pathway at its point of activation is very attractive since the renin-angiotensinogen reaction is the first and rate-limiting step in the generation of angiotensin II (Ang II). Aliskiren, the first in a new class of orally effective direct renin inhibitors (DRIs), is approved for the treatment of hypertension. It is effective in reducing BP in the general population of hypertensive patients and in special patient groups such as obese persons, and has a tolerability and safety profile similar to placebo. Aliskiren has renoprotective, cardioprotective and anti-atherosclerotic effects in animal models that appear to be independent of BP lowering. It reduces proteinuria in diabetic patients and has favorable neurohumoral effects in patients with symptomatic heart failure. Additional outcome trials are needed to establish the role of this novel class of antihypertensive medication in the therapeutic armamentarium. PMID:19475781

  16. Role of aliskiren in cardio-renal protection and use in hypertensives with multiple risk factors

    PubMed Central

    Pimenta, Eduardo; Oparil, Suzanne

    2009-01-01

    The renin–angiotensin–aldosterone system (RAAS) is a key mediator of blood pressure (BP) and volume regulation in both normotensive and hypertensive persons. Stimulation of RAAS also contributes to hypertension-related target organ damage. The renin–angiotensinogen reaction is the first and rate-limiting step in the generation of angiotensin II (Ang II) and has been a target of antihypertensive drug development for decades. Aliskiren is the first in a new class of orally effective direct renin inhibitors (DRIs) and is approved for the treatment of hypertension in humans. It effectively reduces BP in the general population of hypertensive patients and has a tolerability and safety profile similar to placebo. Aliskiren has favorable effects on vascular inflammation and remodeling, on neurohumoral mediators of various forms of cardiovascular disease, including heart failure, and on proteinuria in diabetic patients. Additional outcome trials are needed to establish the role of this novel class of antihypertensive medication in preventing cardiovascular disease morbidity and mortality. PMID:19707255

  17. A Trial of Alemtuzumab Adjunctive Therapy in Allogeneic Hematopoietic Cell Transplantation with Minimal Conditioning for Severe Combined Immunodeficiency

    PubMed Central

    Dvorak, Christopher C.; Horn, Biljana N.; Puck, Jennifer M.; Adams, Stuart; Veys, Paul; Czechowicz, Agnieszka; Cowan, Morton J.

    2014-01-01

    For infants with severe combined immunodeficiency (SCID) the ideal conditioning regimen before allogeneic hematopoietic cell transplantation (HCT) would omit cytotoxic chemotherapy to minimize short- and long-term complications. We performed a prospective pilot trial with alemtuzumab monotherapy to overcome NK-cell mediated immunologic barriers to engraftment. We enrolled 4 patients who received CD34-selected haploidentical cells, two of whom failed to engraft donor T cells. The 2 patients who engrafted had delayed T cell reconstitution, despite rapid clearance of circulating alemtuzumab. Although well-tolerated, alemtuzumab failed to overcome immunologic barriers to donor engraftment. Furthermore, alemtuzumab may slow T cell development in patients with SCID in the setting of a T-cell depleted graft. PMID:24977928

  18. A trial of alemtuzumab adjunctive therapy in allogeneic hematopoietic cell transplantation with minimal conditioning for severe combined immunodeficiency.

    PubMed

    Dvorak, Christopher C; Horn, Biljana N; Puck, Jennifer M; Adams, Stuart; Veys, Paul; Czechowicz, Agnieszka; Cowan, Morton J

    2014-09-01

    For infants with SCID the ideal conditioning regimen before allogeneic HCT would omit cytotoxic chemotherapy to minimize short- and long-term complications. We performed a prospective pilot trial with alemtuzumab monotherapy to overcome NK-cell mediated immunologic barriers to engraftment. We enrolled four patients who received CD34-selected haploidentical cells, two of whom failed to engraft donor T cells. The two patients who engrafted had delayed T-cell reconstitution, despite rapid clearance of circulating alemtuzumab. Although well-tolerated, alemtuzumab failed to overcome immunologic barriers to donor engraftment. Furthermore, alemtuzumab may slow T-cell development in patients with SCID in the setting of a T-cell depleted graft.

  19. Mitochondrial engineering of the TCA cycle for fumarate production.

    PubMed

    Chen, Xiulai; Dong, Xiaoxiang; Wang, Yuancai; Zhao, Zihao; Liu, Liming

    2015-09-01

    Microbial fumarate production from renewable feedstock is a promising and sustainable alternative to petroleum-based chemical synthesis. Here, mitochondrial engineering was used to construct the oxidative pathway for fumarate production starting from the TCA cycle intermediate α-ketoglutarate in Candida glabrata. Accordingly, α-ketoglutarate dehydrogenase complex (KGD), succinyl-CoA synthetase (SUCLG), and succinate dehydrogenase (SDH) were selected to be manipulated for strengthening the oxidative pathway, and the engineered strain T.G-K-S-S exhibited increased fumarate biosynthesis (1.81 g L(-1)). To further improve fumarate production, the oxidative route was optimized. First, three fusion proteins KGD2-SUCLG2, SUCLG2-SDH1 and KGD2-SDH1 were constructed, and KGD2-SUCLG2 led to improved fumarate production (4.24 g L(-1)). In addition, various strengths of KGD2-SUCLG2 and SDH1 expression cassettes were designed by combinations of promoter strengths and copy numbers, resulting in a large increase in fumarate production (from 4.24 g L(-1) to 8.24 g L(-1)). Then, through determining intracellular amino acids and its related gene expression levels, argininosuccinate lyase in the urea cycle was identified as the key factor for restricting higher fumarate production. Correspondingly, after overexpression of it, the fumarate production was further increased to 9.96 g L(-1). Next, two dicarboxylic acids transporters facilitated an improvement of fumarate production, and, as a result, the final strain T.G-KS(H)-S(M)-A-2S reached fumarate titer of 15.76 g L(-1). This strategy described here paves the way to the development of an efficient pathway for microbial production of fumarate.

  20. Aliskiren Prevents the Toxic Effects of Peritoneal Dialysis Fluids during Chronic Dialysis in Rats

    PubMed Central

    Pérez-Martínez, Juan; Pérez-Martínez, Francisco C.; Carrión, Blanca; Masiá, Jesús; Ortega, Agustín; Simarro, Esther; Nam-Cha, Syong H.; Ceña, Valentín

    2012-01-01

    The benefits of long-term peritoneal dialysis (PD) in patients with end-stage renal failure are short-lived due to structural and functional changes in the peritoneal membrane. In this report, we provide evidence for the in vitro and in vivo participation of the renin-angiotensin-aldosterone system (RAAS) in the signaling pathway leading to peritoneal fibrosis during PD. Exposure to high-glucose PD fluids (PDFs) increases damage and fibrosis markers in both isolated rat peritoneal mesothelial cells and in the peritoneum of rats after chronic dialysis. In both cases, the addition of the RAAS inhibitor aliskiren markedly improved damage and fibrosis markers, and prevented functional modifications in the peritoneal transport, as measured by the peritoneal equilibrium test. These data suggest that inhibition of the RAAS may be a novel way to improve the efficacy of PD by preventing inflammation and fibrosis following peritoneal exposure to high-glucose PDFs. PMID:22558414

  1. Can Aliskiren be Considered as a New Novel Drug for Hypertension?

    PubMed Central

    Gazali, Zarine Anwar

    2015-01-01

    Hypertension is one of the most common causes of death across the globe. Many trials and drugs have been used for controlling the debilitating effects of hypertension. One such new class of drug is direct renin inhibitors (DRI), e.g., aliskiren, which block the renin-angiotensin system (RAS). It blocks the very first step in the RAS system. Multiple trials have been carried out debating the outcome of monotherapy and combination therapy with other classes of hypertensive drugs. Focus on compliance, adverse effects, and the cost have also been in the news. Extensive studies are still needed to justify the clinical use of a DRI in the effective treatment of hypertension. PMID:26677425

  2. Comparative effects of Aliskiren and Telmisartan in high fructose diet-induced metabolic syndrome in rats.

    PubMed

    Rabie, Esraa M; Heeba, Gehan H; Abouzied, Mekky M; Khalifa, Mohamed M A

    2015-08-05

    Fructose is a commonly used sweetener associated with diets that increase the prevalence of metabolic syndrome (MS). Inhibition of the renin-angiotensin system (RAS) has been consistently demonstrated to reduce MS. However, there has been no direct comparison among different pharmacological modes of inhibiting the RAS concerning their effects on MS. This study investigated the effect of aliskiren, a direct renin inhibitor, versus telmisartan, an angiotensin II-receptor blocker, in the treatment of fructose-induced MS in rats. MS was induced by high fructose (FRC) diet feeding for 12 weeks. Oral administrations of telmisartan (TEL, 5 mg/kg), aliskiren (ALS, 30 mg/kg) or vehicle were started in the last 4 weeks. Results showed that administration of either TEL or ALS with FRC diet equally ameliorated the metabolic parameters (glucose level, oral glucose tolerance test, insulin resistance and serum lipids profile), systolic blood pressure and oxidative stress markers (malondialdehyde, nitric oxide, reduced glutathione levels and catalase activity). Additionally, the effects of TEL and ALS were associated with a decrease in body composition index and attenuation of liver index, serum liver enzyme activities and hepatic expressions of inflammatory and fibrotic markers (tumor necrosis factor-α, nuclear factor kappa-B and transforming growth factor-β) with a significant increase in hepatic glucose transporter-2 and peroxisome proliferator-activated receptors-alpha and gamma expressions. The results suggested that, at indicated dosage, ALS has ameliorative effect equal to that of TEL against FRC-induced metabolic and hepatic disorders; implying that drugs which inhibit the RAS, by different mode of inhibition, profoundly affect fructose-induced MS in rats.

  3. Production of Fumaric Acid in 20-Liter Fermentors

    PubMed Central

    Rhodes, R. A.; Lagoda, A. A.; Misenheimer, T. J.; Smith, M. L.; Anderson, R. F.; Jackson, R. W.

    1962-01-01

    The conditions necessary for the production of fumaric acid in 20-liter fermentors by fermentation of glucose with Rhizopus arrhizus strain NRRL 2582 were determined. Continuous neutralization of fumaric acid was necessary for optimal yields. Yields of the calcium salt were in excess of 65 g of fumaric acid from 100 g of sugar consumed during fermentation of sugar concentrations of 10 to 16%. Conditions established for calcium fumarate production include a simple mineral salts medium, 0.5 v:v:min aeration rate, 300 rev/min agitation rate in a baffled tank, 33 C incubation temperature, CaCO3 to neutralize the acid formed, and a 4 to 5% (v/v) vegetative inoculum. A suitable procedure and medium for the preparation of a vigorous vegetative inoculum were established. The tendency for calcium fumarate fermentations to foam excessively was controlled with a proper antifoam agent added prior to sterilization of the medium and again at daily intervals during fermentation. The production of soluble sodium or potassium fumarates was inhibited when the concentration of fumarates reached 3.5 to 4.0%. No means of overcoming this inhibition was found. Starches and certain other grain-derived carbohydrates were fermented to form calcium fumarate in flask experiments with approximately the same efficiency as was glucose. PMID:16349614

  4. 21 CFR 520.82a - Aminopropazine fumarate tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ....600(c) of this chapter. (c) Conditions of use. (1) The drug is used in dogs and cats for reducing... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Aminopropazine fumarate tablets. 520.82a Section... Aminopropazine fumarate tablets. (a) Specifications. The drug is in tablet form. Each tablet...

  5. 21 CFR 520.82a - Aminopropazine fumarate tablets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ....600(c) of this chapter. (c) Conditions of use. (1) The drug is used in dogs and cats for reducing... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Aminopropazine fumarate tablets. 520.82a Section... Aminopropazine fumarate tablets. (a) Specifications. The drug is in tablet form. Each tablet...

  6. 21 CFR 520.82a - Aminopropazine fumarate tablets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ....600(c) of this chapter. (c) Conditions of use. (1) The drug is used in dogs and cats for reducing... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Aminopropazine fumarate tablets. 520.82a Section... Aminopropazine fumarate tablets. (a) Specifications. The drug is in tablet form. Each tablet...

  7. 21 CFR 520.82a - Aminopropazine fumarate tablets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ....600(c) of this chapter. (c) Conditions of use. (1) The drug is used in dogs and cats for reducing... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Aminopropazine fumarate tablets. 520.82a Section... Aminopropazine fumarate tablets. (a) Specifications. The drug is in tablet form. Each tablet...

  8. Production of Fumaric Acid in 20-Liter Fermentors.

    PubMed

    Rhodes, R A; Lagoda, A A; Misenheimer, T J; Smith, M L; Anderson, R F; Jackson, R W

    1962-01-01

    The conditions necessary for the production of fumaric acid in 20-liter fermentors by fermentation of glucose with Rhizopus arrhizus strain NRRL 2582 were determined. Continuous neutralization of fumaric acid was necessary for optimal yields. Yields of the calcium salt were in excess of 65 g of fumaric acid from 100 g of sugar consumed during fermentation of sugar concentrations of 10 to 16%. Conditions established for calcium fumarate production include a simple mineral salts medium, 0.5 v:v:min aeration rate, 300 rev/min agitation rate in a baffled tank, 33 C incubation temperature, CaCO(3) to neutralize the acid formed, and a 4 to 5% (v/v) vegetative inoculum. A suitable procedure and medium for the preparation of a vigorous vegetative inoculum were established. The tendency for calcium fumarate fermentations to foam excessively was controlled with a proper antifoam agent added prior to sterilization of the medium and again at daily intervals during fermentation. The production of soluble sodium or potassium fumarates was inhibited when the concentration of fumarates reached 3.5 to 4.0%. No means of overcoming this inhibition was found. Starches and certain other grain-derived carbohydrates were fermented to form calcium fumarate in flask experiments with approximately the same efficiency as was glucose.

  9. Los LGBT y fumar | Smokefree Español

    Cancer.gov

    En Estados Unidos, las personas lesbianas, gays, bisexuales y transexuales (LGBT) tienen el doble de probabilidades de empezar a fumar que los heterosexuales. Sepa por qué los miembros de la comunidad LGBT fuman y aprenda estrategias para dejar de fumar definitivamente.

  10. Fumarate induces redox-dependent senescence by modifying glutathione metabolism.

    PubMed

    Zheng, Liang; Cardaci, Simone; Jerby, Livnat; MacKenzie, Elaine D; Sciacovelli, Marco; Johnson, T Isaac; Gaude, Edoardo; King, Ayala; Leach, Joshua D G; Edrada-Ebel, RuAngelie; Hedley, Ann; Morrice, Nicholas A; Kalna, Gabriela; Blyth, Karen; Ruppin, Eytan; Frezza, Christian; Gottlieb, Eyal

    2015-01-23

    Mutations in the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase (FH) are associated with a highly malignant form of renal cancer. We combined analytical chemistry and metabolic computational modelling to investigate the metabolic implications of FH loss in immortalized and primary mouse kidney cells. Here, we show that the accumulation of fumarate caused by the inactivation of FH leads to oxidative stress that is mediated by the formation of succinicGSH, a covalent adduct between fumarate and glutathione. Chronic succination of GSH, caused by the loss of FH, or by exogenous fumarate, leads to persistent oxidative stress and cellular senescence in vitro and in vivo. Importantly, the ablation of p21, a key mediator of senescence, in Fh1-deficient mice resulted in the transformation of benign renal cysts into a hyperplastic lesion, suggesting that fumarate-induced senescence needs to be bypassed for the initiation of renal cancers.

  11. Effect of add-on aliskiren to type 1 angiotensin receptor blocker therapy on endothelial function and autonomic nervous system in hypertensive patients with ischemic heart disease.

    PubMed

    Ozeki, Atsuko; Amiya, Eisuke; Watanabe, Masafumi; Hosoya, Yumiko; Takata, Munenori; Watanabe, Aya; Kawarasaki, Shuichi; Nakao, Tomoko; Watanabe, Shogo; Omori, Kazuko; Yamada, Namie; Tahara, Yukiko; Hirata, Yasunobu; Nagai, Ryozo

    2014-08-01

    The aim of this study was to evaluate the add-on effect of aliskiren to valsartan on endothelial-dependent vasodilation in hypertensive patients with ischemic heart disease (IHD). After 4 weeks of treatment with 80 mg of valsartan, 28 patients were allocated to either continued treatment with valsartan or an add-on treatment with valsartan plus 150 mg of aliskiren. Aliskiren significantly decreased plasma renin activity, whereas endothelium-dependent vasodilation measured by flow-mediated dilation (FMD) did not change. In contrast, heart rate significantly decreased (73.1 ± 9.8 to 66.3 ± 7.0 beats per minute at baseline and 24 weeks, respectively [P = .009]) and the standard deviation of the R-R intervals (SDNN) significantly increased in the aliskiren group. The add-on aliskiren to valsartan therapy may not improve endothelial functions, although it significantly reduced resting heart rate via regulation of the autonomic nervous system in hypertensive patients with IHD.

  12. Alemtuzumab in T-cell large granular lymphocytic leukaemia: a phase 2 study

    PubMed Central

    Dumitriu, Bogdan; Ito, Sawa; Feng, Xingmin; Stephens, Nicole; Yunce, Muharrem; Kajigaya, Sachiko; Melenhorst, Joseph J.; Rios, Olga; Scheinberg, Priscila; Chinian, Fariba; Keyvanfar, Keyvan; Battiwalla, Minoo; Wu, Colin O.; Maric, Irina; Xi, Liqiang; Raffeld, Mark; Muranski, Pawel; Townsley, Danielle M.; Young, Neal S.; Barrett, Austin John; Scheinberg, Phillip

    2016-01-01

    Background T-cell large granular lymphocytic leukemia (T-LGL) is a lymphoproliferative disease presenting with immune-mediated cytopenias and characterized by clonal expansion of cytotoxic CD3+CD8+ lymphocytes. Methotrexate, cyclosporine, or cyclophosphamide improve cytopenias in 50% of patients as first therapy, but the activity of an anti-CD52 monoclonal antibody, alemtuzumab, is not defined in T-LGL. Methods Twenty-five consecutive subjects with T-LGL were enrolled from October 2006 to March 2015 at the National Institutes of Health (www.clinicaltrials.gov-NCT00345345). Alemtuzumab was administered at 10 mg/day intravenously for 10 days. The primary endpoint was haematologic response at 3 months. Analysis was intention to treat. Here we report the protocol specified interim benchmark of a phase II clinical trial using alemtuzumab in T-LGL. Findings In this heterogeneous, previously treated cohort, 14/25 (56%; 95% CI, 37–73%) subjects had a haematological response at 3 months. In T-LGL cases not associated with myelodysplasia or marrow transplantation, the response rate was 14/19 (74%; 95% CI, 51–86%). First dose infusion reactions were common which improved with symptomatic therapy. EBV and CMV reactivations were common and subclinical. In only 2 patients pre-emptive anti-CMV therapy was instituted. There were no cases of EBV or CMV disease. Alemtuzumab induced sustained reduction of absolute clonal population of T-cytotoxic lymphocytes, as identified by TCRBV-receptor phenotype, but the abnormal clone serendipitously persisted in responders. STAT3 mutations in the SH2 domain, identified in ten subjects, did not correlate with response. When compared with healthy volunteers, T-LGL subjects showed a distinct plasma cytokine and JAK-STAT signature prior to treatment, but neither correlated to response. Interpretation This is the largest and only prospective cohort of T-LGL subjects treated with alemtuzumab yet reported. The high activity with a single course

  13. Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: insights from the ASTRONAUT trial

    PubMed Central

    Maggioni, Aldo P.; Greene, Stephen J.; Fonarow, Gregg C.; Böhm, Michael; Zannad, Faiez; Solomon, Scott D.; Lewis, Eldrin F.; Baschiera, Fabio; Hua, Tsushung A.; Gimpelewicz, Claudio R.; Lesogor, Anastasia; Gheorghiade, Mihai; Ramos, Silvina; Luna, Alejandra; Miriuka, Santiago; Diez, Mirta; Perna, Eduardo; Luquez, Hugo; Pinna, Jorge Garcia; Castagnino, Jorge; Alvarenga, Pablo; Ibañez, Julio; Blumberg, Eduardo Salmon; Dizeo, Claudio; Guerrero, Rodolfo Ahuad; Schygiel, Pablo; Milesi, Rodolfo; Sosa, Carlos; Hominal, Miguel; Marquez, Lilia Lobo; Poy, Carlos; Hasbani, Eduardo; Vico, Marisa; Fernandez, Alberto; Vita, Nestor; Vanhaecke, Johan; De Keulenaer, Gilles; Striekwold, Harry; Vervoort, Geert; Vrolix, Mathias; Henry, Philippe; Dendale, Paul; Smolders, Walter; Marechal, Patrick; Vandekerckhove, Hans; Oliveira, Mucio; Neuenschwande, Fernando; Reis, Gilmar; Saraiva, Jose; Bodanese, Luiz; Canesin, Manoel; Greco, Oswaldo; Bassan, Roberto; Marino, Roberto Luis; Giannetti, Nadia; Moe, Gordon; Sussex, Bruce; Sheppard, Richard; Huynh, Thao; Stewart, Robert; Haddad, Haissam; Echeverria, Luis; Quintero, Adalberto; Torres, Adriana; Jaramillo, Mónica; Lopez, Mónica; Mendoza, Fernan; Florez, Noel; Cotes, Carlos; Garcia, Magali; Belohlavek, Jan; Hradec, Jaromir; Peterka, Martin; Gregor, Pavel; Monhart, Zdenek; Jansky, Petr; Kettner, Jiri; Reichert, Petr; Spinar, Jindrich; Brabec, Tomas; Hutyra, Martin; Solar, Miroslav; Pietilä, Mikko; Nyman, Kai; Pajari, Risto; Cohen, Ariel; Galinier, Michel; Gosse, Philippe; Livarek, Bernard; Neuder, Yannick; Jourdain, Patrick; Picard, François; Isnard, Richard; Hoppe, Uta; Kaeaeb, Stefan; Rosocha, Stefan; Prondzinsky, Roland; Felix, Stephan; Duengen, Hans-Dirk; Figulla, Hans-Reiner; Fischer, Sven; Behrens, Steffen; Stawowy, Philipp; Kruells-Muench, Juergen; Knebel, Fabian; Nienaber, Christoph; Werner, Dierk; Aron, Wilma; Remppis, Bjoern; Hambrecht, Rainer; Kisters, Klaus; Werner, Nikos; Hoffmann, Stefan; Rossol, Siegbert; Geiss, Ernst; Graf, Kristof; Hamann, Frank; von Scheidt, Wolfgang; Schwinger, Robert; Tebbe, Ulrich; Costard-Jaeckle, Angelika; Lueders, Stephan; Heitzer, Thomas; Leutermann-Oei, Marie-Louise; Braun-Dullaeus, Ruediger; Roehnisch, Jens-Uwe; Muth, Gerhard; Goette, Andreas; Rotter, Achim; Ebelt, Henning; Olbrich, Hans-Georg; Mitrovic, Veselin; Hengstenberg, Christian; Schellong, Sebastian; Zamolyi, Karoly; Vertes, Andras; Matoltsy, Andras; Palinkas, Attila; Herczeg, Bela; Apro, Dezso; Lupkovics, Geza; Tomcsanyi, Janos; Toth, Kalman; Mathur, Atul; Banker, Darshan; Bharani, Anil; Arneja, Jaspal; Khan, Aziz; Gadkari, Milind; Hiremath, Jagdish; Patki, Nitin; Kumbla, Makund; Santosh, M.J.; Ravikishore, A.G.; Abhaichand, Rajpal; Maniyal, Vijayakukmar; Nanjappa, Manjunath; Reddy, P. Naveen; Chockalingam, Kulasekaran; Premchand, Rajendra; Mahajan, Vijay; Lewis, Basil; Wexler, Dov; Shochat, Michael; Keren, Andre; Omary, Muhamad; Katz, Amos; Marmor, Alon; Lembo, Giuseppe; Di Somma, Salvatore; Boccanelli, Alessandro; Barbiero, Mario; Pajes, Giuseppe; De Servi, Stefano; Greco, Dott Cosimo; De Santis, Fernando; Floresta, Agata; Visconti, Luigi Oltrona; Piovaccari, Giancarlo; Cavallini, Claudio; Di Biase, Matteo; Masini, Dott Franco; Vassanelli, Corrado; Viecca, Maurizio; Cangemi, Dott Francesco; Pirelli, Salvatore; Borghi, Claudio; Volpe, Massimo; Branzi, Angelo; Percoco, Dott Giovanni; Severi, Silvia; Santini, Alberto; De Lorenzi, Ettore; Metra, Marco; Zacà, Valerio; Mortara, Andrea; Tranquilino, Francisco P.; Babilonia, Noe A.; Ferrolino, Arthur M.; Manlutac, Benjamin; Dluzniewski, Miroslaw; Dzielinska, Zofia; Nowalany-Kozie, Ewa; Mazurek, Walentyna; Wierzchowiecki, Jerzy; Wysokinski, Andrzej; Szachniewicz, Joanna; Romanowski, Witold; Krauze-Wielicka, Magdalena; Jankowski, Piotr; Berkowski, Piotr; Szelemej, Roman; Kleinrok, Andrzej; Kornacewicz-Jac, Zdzislawa; Vintila, Marius; Vladoianu, Mircea; Militaru, Constantin; Dan, Gheorghe; Dorobantu, Maria; Dragulescu, Stefan; Kostenko, Victor; Vishnevsky, Alexandr; Goloschekin, Boris; Tyrenko, Vadim; Gordienko, Alexander; Kislyak, Oxana; Martsevich, Sergey; Kuchmin, Alexey; Karpov, Yurii; Fomin, Igor; Shvarts, Yury; Orlikova, Olga; Ershova, Olga; Berkovich, Olga; Sitnikova, Maria; Pakhomova, Inna; Boldueva, Svetlana; Tyurina, Tatiana; Simanenkov, Vladimir; Boyarkin, Mikhail; Novikova, Nina; Tereschenko, Sergey; Zadionchenko, Vladimir; Shogenov, Zaur; Gordeev, Ivan; Moiseev, Valentin; Wong, Raymond; Ong, Hean Yee; Le Tan, Ju; Goncalvesova, Eva; Kovar, Frantisek; Skalina, Ivan; Kasperova, Viera; Hojerova, Silvia; Szentivanyi, Miroslav; Stancak, Branislav; Babcak, Marian; Kycina, Peter; Poliacik, Pavol; Toth, Peter; Sirotiakova, Jana; de Sa, Esteban Lopez; Bueno, Manuel Gomez; Selles, Manuel Martinez; Cabrera, Jose Angel; Freire, Ramon Bover; Gonzalez Juanatey, Jose Ramon; Comin, Josep; Soriano, FranciscoRidocci; Lopez, Alejandro; Vicho, Raul; Lama, Manuel Geraldia; Schaufelberger, Maria; Brunotte, Richard; Ullman, Bengt; Hagerman, Inger; Cizinsky, Stella; Cherng, Wen-Jin; Yu, Wen-Chung; Kuo, Chi-Tai; Chang, Kuan-Cheng; Lai, Wen-Ter; Kuo, Jen-Yuan; Ural, Dilek; Badak, Ozer; Akin, Mustafa; Yigit, Zerrin; Yokusoglu, Mehmet; Yilmaz, Mehmet; Abaci, Adnan; Ebinc, Haksun; Perlman, Richard; Parish, David; Bergin, James; Burnham, Kenneth; Brown, Christopher; Lundbye, Justin; Williams, Celeste; Eisen, Howard; Juneman, Elizabeth; Joseph, Susan; Peberdy, Mary Ann; Peura, Jennifer; Gupta, Vishal; Habet, Kalim; French, William; Mody, Freny; Graham, Susan; Hazelrigg, Monica; Chung, Eugene; Dunlap, Stephanie; Nikolaidis, Lazaros; Najjar, Samer; Katz, Richard; Murali, Srinivas; Izzo, Joseph L.; Callister, Tracy; Phillips, Roland; Lippolis, Nicholas; Winterton, John; Meymandi, Sheba; Heilman, Karl; Oren, Ron; Zolty, Ronald; Brottman, Michael; Gunawardena, D.R.; Adams, Kirkwood; Barnard, Denise; Klapholz, Marc; Fulmer, James

    2013-01-01

    Aims The objective of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) was to determine whether aliskiren, a direct renin inhibitor, would improve post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction. Pre-specified subgroup analyses suggested potential heterogeneity in post-discharge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM). Methods and results ASTRONAUT included 953 patients without DM (aliskiren 489; placebo 464) and 662 patients with DM (aliskiren 319; placebo 343) (as reported by study investigators). Study endpoints included the first occurrence of cardiovascular death or HHF within 6 and 12 months, all-cause death within 6 and 12 months, and change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 1, 6, and 12 months. Data regarding risk of hyperkalaemia, renal impairment, and hypotension, and changes in additional serum biomarkers were collected. The effect of aliskiren on cardiovascular death or HHF within 6 months (primary endpoint) did not significantly differ by baseline DM status (P = 0.08 for interaction), but reached statistical significance at 12 months (non-DM: HR: 0.80, 95% CI: 0.64–0.99; DM: HR: 1.16, 95% CI: 0.91–1.47; P = 0.03 for interaction). Risk of 12-month all-cause death with aliskiren significantly differed by the presence of baseline DM (non-DM: HR: 0.69, 95% CI: 0.50–0.94; DM: HR: 1.64, 95% CI: 1.15–2.33; P < 0.01 for interaction). Among non-diabetics, aliskiren significantly reduced NT-proBNP through 6 months and plasma troponin I and aldosterone through 12 months, as compared to placebo. Among diabetic patients, aliskiren reduced plasma troponin I and aldosterone relative to placebo through 1 month only. There was a trend towards differing risk of post-baseline potassium ≥6 mmol/L with aliskiren by underlying DM status (non-DM: HR: 1.17, 95% CI: 0.71–1.93; DM: HR: 2.39, 95% CI: 1.30

  14. Branch retinal vein occlusion associated with quetiapine fumarate

    PubMed Central

    2011-01-01

    Background To report a case of branch retinal vein occlusion in a young adult with bipolar mood disorder treated with quetiapine fumarate. Case Presentation A 29 years old gentleman who was taking quetiapine fumarate for 3 years for bipolar mood disorder, presented with sudden vision loss. He was found to have a superior temporal branch retinal vein occlusion associated with hypercholesterolemia. Conclusion Atypical antipsychotic drugs have metabolic side effects which require regular monitoring and prompt treatment. PMID:21867521

  15. Tailored Assays for Pharmacokinetic and Pharmacodynamic Investigations of Aliskiren and Enalapril in Children: An Application in Serum, Urine, and Saliva

    PubMed Central

    Tins, Jutta; Ramusovic, Sergej; Läer, Stephanie

    2015-01-01

    OBJECTIVES: Drugs that are effectively used to treat hypertension in adults (e.g., enalapril) have not been sufficiently investigated in children. Studies required for pediatric approval require special consideration regarding ethics, study design, and conduct and are also associated with special demands for the bioanalytic method. Pediatric-appropriate assays can overcome these burdens and enable systematic investigations of pharmacokinetics and pharmacodynamic in all pediatric age groups. METHODS: Tailored assays were developed for pharmacokinetic investigation of a drug in 100 μL of serum, saliva, and urine. All assays were applied in a proof-of-concept study to 22 healthy volunteers who had been given 300 mg aliskiren hemifumarate or 20 mg enalapril maleate and allowed for dense sampling. Changes in humoral parameters of the renin-angiotensin-aldosterone system were also evaluated with 6 parameters in 2.1 mL blood per time point. RESULTS: The pharmacokinetic results of aliskiren and enalapril obtained by low-volume assays in serum and urine were comparable to that noted in the literature. The dense sampling enabled very detailed concentration-time profiles that showed high intersubject variability and biphasic absorption behavior of aliskiren. The replacement of invasive sampling by saliva collection appears inappropriate for both drugs because the correlations of drug concentrations in both fluids were low. A low-volume assay was also used to determine values for in the renin-angiotensin-aldosterone system and to compare those results with the published literature. CONCLUSION: These results support both the use of low-volume assays in pediatric research and the systematic investigation of their use in neonates and infants. Use of this assay methodology will increase information about drug pharmacokinetics and pharmacodynamics in this vulnerable population and might contribute to safe and effective use of pharmacotherapy. PMID:26766933

  16. Alemtuzumab as graft-versus-host disease (GVHD) prophylaxis strategy in a developing country: lower rate of acute GVHD, increased risk of cytomegalovirus reactivation

    PubMed Central

    Resende, C.B.; Rezende, B.M.; Bernardes, P.T.T.; Teixeira, G.M.; Teixeira, M.M.; Pinho, V.; Bittencourt, H.

    2017-01-01

    Acute graft-versus-host disease (aGVHD) and cytomegalovirus reactivation are important complications after allogeneic stem cell transplantation (alloHSCT). Here, we evaluated the impact of treatment with alemtuzumab on the occurrence of aGVHD, cytomegalovirus reactivation and survival after alloHSCT. This was a prospective cohort study conducted at the allo-HSCT unit of Hospital das Clínicas, Universidade Federal de Minas Gerais, Brazil, from January 2009 to December 2011. Fifty-seven patients who underwent alloHSCT were included. Forty-five (79%) patients had a malignant disease. Alemtuzumab was administered before the conditioning regimen at a dose of 1 mg/kg in children and 30 mg/day for 2 days in adults or children weighing more than 40 kg (a total dose of 60 mg) with a non-malignant disease or patients with a malignant disease and high-risk for GVHD mortality. Alemtuzumab was used in 23 (40%) patients, of whom 17 received a reduced-intensity conditioning. Eleven patients presented aGVHD (grade 2–4) and only 1 of them received alemtuzumab. Cumulative incidence of aGVHD (grade 2–4) at day 100 after transplantation (D+100) was 4 for patients receiving alemtuzumab and 29% for patients not receiving alemtuzumab. Cumulative incidence of cytomegalovirus reactivation for patients receiving or not alemtuzumab was 62 and 38%, respectively. Sixteen patients died in the first 100 days after alloHSCT, most of them due to bacterial sepsis. Only 2 patients died of aGVHD until D+100. Overall survival was 50% without any impact of alemtuzumab. Alemtuzumab effectively controlled aGVHD but increased the risk of cytomegalovirus reactivation without improving survival. PMID:28198910

  17. Alemtuzumab as graft-versus-host disease (GVHD) prophylaxis strategy in a developing country: lower rate of acute GVHD, increased risk of cytomegalovirus reactivation.

    PubMed

    Resende, C B; Rezende, B M; Bernardes, P T T; Teixeira, G M; Teixeira, M M; Pinho, V; Bittencourt, H

    2017-02-09

    Acute graft-versus-host disease (aGVHD) and cytomegalovirus reactivation are important complications after allogeneic stem cell transplantation (alloHSCT). Here, we evaluated the impact of treatment with alemtuzumab on the occurrence of aGVHD, cytomegalovirus reactivation and survival after alloHSCT. This was a prospective cohort study conducted at the allo-HSCT unit of Hospital das Clínicas, Universidade Federal de Minas Gerais, Brazil, from January 2009 to December 2011. Fifty-seven patients who underwent alloHSCT were included. Forty-five (79%) patients had a malignant disease. Alemtuzumab was administered before the conditioning regimen at a dose of 1 mg/kg in children and 30 mg/day for 2 days in adults or children weighing more than 40 kg (a total dose of 60 mg) with a non-malignant disease or patients with a malignant disease and high-risk for GVHD mortality. Alemtuzumab was used in 23 (40%) patients, of whom 17 received a reduced-intensity conditioning. Eleven patients presented aGVHD (grade 2-4) and only 1 of them received alemtuzumab. Cumulative incidence of aGVHD (grade 2-4) at day 100 after transplantation (D+100) was 4 for patients receiving alemtuzumab and 29% for patients not receiving alemtuzumab. Cumulative incidence of cytomegalovirus reactivation for patients receiving or not alemtuzumab was 62 and 38%, respectively. Sixteen patients died in the first 100 days after alloHSCT, most of them due to bacterial sepsis. Only 2 patients died of aGVHD until D+100. Overall survival was 50% without any impact of alemtuzumab. Alemtuzumab effectively controlled aGVHD but increased the risk of cytomegalovirus reactivation without improving survival.

  18. Effect of the Direct Renin Inhibitor Aliskiren on Urinary Albumin Excretion in Spontaneous Type 2 Diabetic KK-A (y) Mouse.

    PubMed

    Furukawa, Masako; Gohda, Tomohito; Hagiwara, Shinji; Tanimoto, Mitsuo; Horikoshi, Satoshi; Funabiki, Kazuhiko; Tomino, Yasuhiko

    2013-01-01

    Objective. Although angiotensin II-mediated inflammation and extracellular matrix accumulation are considered to be associated with the progression of diabetic nephropathy, these processes have not yet been sufficiently clarified. The objective of this study was to determine whether the correction of the abnormal renal expression of MMPs and its inhibitors (MMPs/TIMPs) and cytokines following the administration of aliskiren to KK-A (y) mice results in a renoprotective effect. Methods. KK-A (y) mice were divided into two groups, that is, untreated (saline) and treated (aliskiren) groups. Systolic BP, HbA1c levels, and the albumin-creatinine ratio (ACR) were measured. The renal expression of MMPs/TIMPs, fibronectin, type IV collagen, MCP-1, and (pro)renin receptor ((P)RR) was examined using real-time PCR and/or immunohistochemical staining. Renal MAPK and NF- κ B activity were also examined by Western blot analyses and ELISA, respectively. Results. Significant decreases in systolic BP and ACR levels were observed in treated KK-A (y) mice compared with the findings in untreated KK-A (y) mice. Furthermore, increases in MMPs/TIMPs, fibronectin, type IV collagen, MCP-1, and (P)RR expression, in addition to MAPK and NF- κ B activity, were significantly attenuated by aliskiren administration. Conclusions. It appears that aliskiren improves albuminuria and renal fibrosis by regulating inflammation and the alteration of collagen synthesis and degradation.

  19. A comparative study of reduced dose alemtuzumab in matched unrelated donor and related donor reduced intensity transplants.

    PubMed

    Jardine, Laura; Publicover, Amy; Bigley, Venetia; Hale, Geoff; Pearce, Kim; Dickinson, Anne; Jackson, Graham; Collin, Matthew

    2015-03-01

    In vivo T cell depletion with 100 mg alemtuzumab prevents graft-versus-host disease (GVHD) in reduced intensity conditioned transplants but is associated with delayed immune reconstitution, a higher risk of infection and relapse. De-escalation studies have shown that a reduced dose of 30 mg is as effective as 100 mg in preventing GVHD in matched related donor (MRD) transplants. Dose reduction in matched unrelated donor (MUD) transplants is feasible but the comparative efficacy of alemtuzumab in this setting is not known and opinions vary widely concerning the optimal level of GVHD prophylaxis that should be achieved. Through retrospective analysis we made an objective comparison of MUD transplants receiving an empirically reduced dose of 60 mg, with MRD transplants receiving a 30 mg dose. We observed proportionate levels of alemtuzumab according to dose but an inverse relationship with body surface area particularly in MRD transplants. MUD transplants experienced more acute and chronic GVHD, higher T cell chimerism, more sustained use of ciclosporin and less need for donor lymphocyte infusion than MRD transplants. Thus, doubling the dose of alemtuzumab to 60 mg did not provide equivalent prevention of GVHD after MUD transplant although there was no difference in non-relapse mortality or survival compared with MRD transplants.

  20. Cyclophosphamide, fludarabine, alemtuzumab, and rituximab as salvage therapy for heavily pretreated patients with chronic lymphocytic leukemia

    PubMed Central

    Badoux, Xavier C.; Keating, Michael J.; Wang, Xuemei; O'Brien, Susan M.; Ferrajoli, Alessandra; Faderl, Stefan; Burger, Jan; Koller, Charles; Lerner, Susan; Kantarjian, Hagop

    2011-01-01

    Patients with relapsed chronic lymphocytic leukemia (CLL) and high-risk features, such as fludarabine refractoriness, complex karyotype, or abnormalities of chromosome 17p, experience poor outcomes after standard fludaradine-based regimens. Alemtuzumab is a chimeric CD52 monoclonal antibody with activity in CLL patients with fludarabine-refractory disease and 17p deletion. We report the outcome for 80 relapsed or refractory patients with CLL enrolled in a phase 2 study of cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR). All patients were assessed for response and progression according to the 1996 CLL-working group criteria. For the intention-to-treat analysis, the overall response rate was 65%, including 29% complete response. The estimated progression-free survival was 10.6 months and median overall survival was 16.7 months. Although we noted higher complete response in high-risk patients after CFAR compared with a similar population who had received fludarabine, cyclophosphamide, and rituximab as salvage therapy, there was no significant improvement in progression-free survival and overall survival appeared worse. CFAR was associated with a high rate of infectious complications with 37 patients (46%) experiencing a serious infection during therapy and 28% of evaluable patients experiencing late serious infections. Although CFAR produced good response rates in this highly pretreated high-risk group of patients, there was no benefit in survival outcomes. PMID:21670470

  1. Reconstruction of cytosolic fumaric acid biosynthetic pathways in Saccharomyces cerevisiae

    PubMed Central

    2012-01-01

    Background Fumaric acid is a commercially important component of foodstuffs, pharmaceuticals and industrial materials, yet the current methods of production are unsustainable and ecologically destructive. Results In this study, the fumarate biosynthetic pathway involving reductive reactions of the tricarboxylic acid cycle was exogenously introduced in S. cerevisiae by a series of simple genetic modifications. First, the Rhizopus oryzae genes for malate dehydrogenase (RoMDH) and fumarase (RoFUM1) were heterologously expressed. Then, expression of the endogenous pyruvate carboxylase (PYC2) was up-regulated. The resultant yeast strain, FMME-001 ↑PYC2 + ↑RoMDH, was capable of producing significantly higher yields of fumarate in the glucose medium (3.18 ± 0.15 g liter-1) than the control strain FMME-001 empty vector. Conclusions The results presented here provide a novel strategy for fumarate biosynthesis, which represents an important advancement in producing high yields of fumarate in a sustainable and ecologically-friendly manner. PMID:22335940

  2. Fumarate-Mediated Persistence of Escherichia coli against Antibiotics.

    PubMed

    Kim, Jun-Seob; Cho, Da-Hyeong; Heo, Paul; Jung, Suk-Chae; Park, Myungseo; Oh, Eun-Joong; Sung, Jaeyun; Kim, Pan-Jun; Lee, Suk-Chan; Lee, Dae-Hee; Lee, Sarah; Lee, Choong Hwan; Shin, Dongwoo; Jin, Yong-Su; Kweon, Dae-Hyuk

    2016-04-01

    Bacterial persisters are a small fraction of quiescent cells that survive in the presence of lethal concentrations of antibiotics. They can regrow to give rise to a new population that has the same vulnerability to the antibiotics as did the parental population. Although formation of bacterial persisters in the presence of various antibiotics has been documented, the molecular mechanisms by which these persisters tolerate the antibiotics are still controversial. We found that amplification of the fumarate reductase operon (FRD) inEscherichia coliled to a higher frequency of persister formation. The persister frequency ofE. coliwas increased when the cells contained elevated levels of intracellular fumarate. Genetic perturbations of the electron transport chain (ETC), a metabolite supplementation assay, and even the toxin-antitoxin-relatedhipA7mutation indicated that surplus fumarate markedly elevated theE. colipersister frequency. AnE. colistrain lacking succinate dehydrogenase (SDH), thereby showing a lower intracellular fumarate concentration, was killed ∼1,000-fold more effectively than the wild-type strain in the stationary phase. It appears thatSDHandFRDrepresent a paired system that gives rise to and maintainsE. colipersisters by producing and utilizing fumarate, respectively.

  3. Fumarate-Mediated Persistence of Escherichia coli against Antibiotics

    PubMed Central

    Kim, Jun-Seob; Cho, Da-Hyeong; Heo, Paul; Jung, Suk-Chae; Park, Myungseo; Oh, Eun-Joong; Sung, Jaeyun; Kim, Pan-Jun; Lee, Suk-Chan; Lee, Dae-Hee; Lee, Sarah; Lee, Choong Hwan; Shin, Dongwoo

    2016-01-01

    Bacterial persisters are a small fraction of quiescent cells that survive in the presence of lethal concentrations of antibiotics. They can regrow to give rise to a new population that has the same vulnerability to the antibiotics as did the parental population. Although formation of bacterial persisters in the presence of various antibiotics has been documented, the molecular mechanisms by which these persisters tolerate the antibiotics are still controversial. We found that amplification of the fumarate reductase operon (FRD) in Escherichia coli led to a higher frequency of persister formation. The persister frequency of E. coli was increased when the cells contained elevated levels of intracellular fumarate. Genetic perturbations of the electron transport chain (ETC), a metabolite supplementation assay, and even the toxin-antitoxin-related hipA7 mutation indicated that surplus fumarate markedly elevated the E. coli persister frequency. An E. coli strain lacking succinate dehydrogenase (SDH), thereby showing a lower intracellular fumarate concentration, was killed ∼1,000-fold more effectively than the wild-type strain in the stationary phase. It appears that SDH and FRD represent a paired system that gives rise to and maintains E. coli persisters by producing and utilizing fumarate, respectively. PMID:26810657

  4. Alternative respiration and fumaric acid production of Rhizopus oryzae.

    PubMed

    Gu, Shuai; Xu, Qing; Huang, He; Li, Shuang

    2014-06-01

    Under the conditions of fumaric acid fermentation, Rhizopus oryzae ME-F14 possessed at least two respiratory systems. The respiration of mycelia was partially inhibited by the cytochrome respiration inhibitor antimycin A or the alternative respiration inhibitor salicylhydroxamic acid and was completely inhibited in the presence of both antimycin A and salicylhydroxamic acid. During fumaric acid fermentation process, the activity of alternative respiration had a great correlation with fumaric acid productivity; both of them reached peak at the same time. The alternative oxidase gene, which encoded the mitochondrial alternative oxidase responsible for alternative respiration in R. oryzae ME-F14, was cloned and characterized in Escherichia coli. The activity of alternative respiration, the alternative oxidase gene transcription level, as well as the fumaric acid titer were measured under different carbon sources and different carbon-nitrogen ratios. The activity of alternative respiration was found to be comparable to the transcription level of the alternative oxidase gene and the fumaric acid titer. These results indicated that the activity of the alternative oxidase was regulated at the transcription stage under the conditions tested for R. oryzae ME-F14.

  5. Effects of a long-term treatment with aliskiren or ramipril on structural alterations of subcutaneous small-resistance arteries of diabetic hypertensive patients.

    PubMed

    De Ciuceis, Carolina; Savoia, Carmine; Arrabito, Emanuele; Porteri, Enzo; Mazza, Monica; Rossini, Claudia; Duse, Sarah; Semeraro, Francesco; Agabiti Rosei, Claudia; Alonzo, Alessandro; Sada, Lidia; La Boria, Elisa; Sarkar, Annamaria; Petroboni, Beatrice; Mercantini, Paolo; Volpe, Massimo; Rizzoni, Damiano; Agabiti Rosei, Enrico

    2014-10-01

    Structural alterations of subcutaneous small-resistance arteries are associated with a worse clinical prognosis in hypertension and non-insulin-dependent diabetes mellitus. The effects of the direct renin inhibitor aliskiren on microvascular structure were never previously evaluated. Therefore, we investigated the effects of aliskiren in comparison with those of an extensively used angiotensin-converting enzyme inhibitor, ramipril, on peripheral subcutaneous small-resistance artery morphology, retinal arteriolar structure, and capillary density in a population of patients with non-insulin-dependent diabetes mellitus. Sixteen patients with mild essential hypertension and with a previous diagnosis of non-insulin-dependent diabetes mellitus were included in the study. Patients were then randomized to 1 of the 2 active treatments (aliskiren 150 mg once daily, n=9; or ramipril 5 mg once daily, n=7). Each patient underwent a biopsy of the subcutaneous fat from the gluteal region, an evaluation of retinal artery morphology (scanning laser Doppler flowmetry), and capillary density (capillaroscopy), at baseline and after 1 year of treatment. Subcutaneous small arteries were dissected and mounted on a pressurized micromyograph, and the media-to-lumen ratio was evaluated. A similar office blood pressure-lowering effect and a similar reduction of the wall-to-lumen ratio of retinal arterioles were observed with the 2 drugs. Aliskiren significantly reduced media-to-lumen ratio of subcutaneous small-resistance arteries, whereas ramipril-induced reduction of media to lumen ratio was not statistically significant. No relevant effect on capillary density was observed. In conclusion, treatment with aliskiren or ramipril was associated with a correction of microvascular structural alterations in patients with non-insulin-dependent diabetes mellitus.

  6. Effect of aliskiren, telmisartan and torsemide on cardiac dysfunction in l-nitro arginine methyl ester (l-NAME) induced hypertension in rats

    PubMed Central

    Sadek, Sawsan A.; Rashed, Laila A.; Bassam, Amira M.; Said, Eman S.

    2014-01-01

    Comparative study of cardio protective effect of aliskiren, telmisartan, and torsemide was carried out on l-nitro arginine methyl ester (l-NAME) induced hypertension in rats. The three drugs were given daily for 8 weeks simultaneously with l-NAME, with a control group for each drug and l-NAME. The degree of protection was assessed by measurement of systolic blood pressure and heart rate of animals every two weeks. At the end of the experimental period blood sampling was carried out for estimation of the level of NO2−/NO3−. After which animals were sacrificed for heart dissection to detect collagen types I and III gene expression. Histopathological study was done to evaluate the extension of collagen deposits. The study revealed that the three drugs decreased blood pressure significantly compared to l-NAME. There was no significant difference between aliskiren and telmisartan in all measurements, but there was significant decrease in measurements of both aliskiren and telmisartan treated groups compared to torsemide starting from 4th week. There were insignificant changes in pulse rate values between the three l-NAME treated groups through the experiment. The three drugs significantly increased NO compared to l-NAME. Collagen I and III gene expression was significantly decreased by the three drugs but the highest percentage of inhibition was with telmisartan compared to l-NAME. Comparing the percentage inhibition of cardiac fibrosis, there was insignificant difference between telmisartan and torsemide treated groups while both were superior to aliskiren. In conclusion, further experimental studies are required to elucidate the potential cardioprotective mechanisms of aliskiren, telmisartan and torsemide, and assess their efficacy in treatment of heart failure. PMID:26644935

  7. Comparison of Aerosol Formulations of Formoterol Fumarate and Budesonide

    PubMed Central

    Nirale, N. M.; Nagarsenker, M. S.; Mendon, S. B.; Chanagare, R.; Katkurwar, A.; Lugade, V.

    2011-01-01

    The aerodynamic diameter of pharmaceutical aerosols is the main factor governing their deposition in the human respiratory tract. Particle size of the pharmaceutical aerosols is characterized by liquid impingers and Andersen Cascade Impactors. The present study was aimed at comparing two metered dose inhaler formulation containing formoterol fumarate (6 μg) and budesonide (200 μg). These two formulations were evaluated by using Twin Stage Impinger and Andersen Cascade Impactor. Study revealed that developed metered dose inhaler I formulation of the formoterol fumarate and budesonide had lower mass median aerodynamic diameter and higher fine particle fraction than marketed formulation. PMID:22457551

  8. Photocrosslinking characteristics and mechanical properties of diethyl fumarate/poly(propylene fumarate) biomaterials.

    PubMed

    Fisher, John P; Dean, David; Mikos, Antonios G

    2002-11-01

    The development of tissue engineered materials for the treatment of large bone defects would provide attractive alternatives to the autografts, allografts, non-degradable polymers, ceramics, and metals that are currently used in clinical settings. To this end, poly(propylene fumarate) (PPF), a viscous polyester synthesized from diethyl fumarate (DEF), has been studied for use as an engineered bone graft. We have investigated the photocrosslinking of PPF dissolved in its precursor, DEF, using the photoinitiator bis(2,4,6-trimethylbenzoyl) phenylphosphine oxide (BAPO) and low levels of ultraviolet light exposure. A three factor, 2 x 2 x 4 factorial design was developed, studying the effects of PPF number average molecular weight, BAPO initiator content, and DEF content upon photocrosslinking characteristics and mechanical properties. Uncured DEF/PPF solution viscosity fell over three orders of magnitude as DEF content was increased from 0% to 75%. The exothermic photocrosslinking reaction released low levels of heat, with no more than 160J/g released from any formulation tested. As a result, the maximum photocrosslinking temperature remained below 47 degrees C for all samples. Both sol fraction and swelling degree generally increased with increasing DEF content. Compressive mechanical properties were within the range of trabecular bone, with the strongest samples possessing an elastic modulus of 195.3 +/- 17.5 MPa and a fracture strength of 68.8 +/- 9.4MPa. Finally, the results indicate that PPF crosslinking was facilitated at low DEF precursor concentrations, but hindered at higher precursor concentrations. These novel DEF/PPF solutions may be preferred over pure PPF as the basis for an engineered bone graft because they (1) exhibit reduced viscosity and thus are easily handled, (2) form polymer networks with compressive strength at fracture suitable for consideration for trabecular bone replacement, and (3) may be readily fabricated into solids with a wide range of

  9. Aliskiren/amlodipine as a single-pill combination in hypertensive patients: subgroup analysis of elderly patients, with metabolic risk factors or high body mass index

    PubMed Central

    Axthelm, Christoph; Sieder, Christian; Meister, Franziska; Pittrow, David; Kaiser, Edelgard

    2013-01-01

    Aims Blood pressure (BP) reduction in hypertensive patients is more difficult to achieve in the elderly or in the presence of comorbidities. We aimed to investigate the efficacy of the single-pill combination (SPC) aliskiren/amlodipine in hypertensive elderly patients, patients with high body mass index (BMI), with at least one metabolic risk factor, and/or type 2 diabetes mellitus (DM). Methods In an open-label non-randomized study, patients not adequately controlled by previous treatment with the SPC olmesarten 40/amlodipine 10 (phase 1) were switched to the SPC aliskiren 300/amlodipine 10 (phase 2). The present post-hoc analysis investigated BP reduction in phase 2 in the named subgroups. The EudraCT identifier was 2009-016693-33, ClinicalTrials.gov identifier NCT01113047. Results Of the 187 patients not adequately controlled in phase 1 and thus treated with the SPC aliskiren 300/amlodipine 10 in phase 2, 69 were of advanced age (≥65 years), 74 or 89 were overweight or obese (BMI 25.0–29.9 kg/m2 or ≥30 kg/m2, respectively), 91 had metabolic risk factors (without DM) and 41 had DM. At the beginning of phase 2, depending on the subgroup, baseline SBP was 168–169 mmHg and DBP 103–104 mmHg. After 4 weeks of treatment with aliskiren 300/amlodipine 10, SBP/DBP was lowered by −5.1/−4.8 mmHg in the total cohort, by −5.5/−5.1 mmHg in elderly patients, by −6.7/−5.5 in overweight and by −4.2/−4.5 mmHg in obese patients, by −6.4/−4.7 mmHg in patients with metabolic risk factors without DM, and by −3.3/−5.0 mmHg in DM patients. Limitations include low sample size, limited treatment duration and the fact that the post-hoc defined groups were not mutually exclusive. Conclusions In this study reflecting clinical practice, the aliskiren/amlodipine combination achieved effective BP reduction in elderly patients or with metabolic comorbidities, including DM that might be more difficult to treat. This consistent BP lowering

  10. Enhanced acid tolerance of Rhizopus oryzae during fumaric acid production.

    PubMed

    Liu, Ying; Lv, Chunwei; Xu, Qing; Li, Shuang; Huang, He; Ouyang, Pingkai

    2015-02-01

    Ensuring a suitable pH in the culture broth is a major problem in microorganism-assisted industrial fermentation of organic acids. To address this issue, we investigated the physiological changes in Rhizopus oryzae at different extracellular pH levels and attempted to solve the issue of cell shortage under low pH conditions. We compared various parameters, such as membrane fatty acids' composition, intracellular pH, and adenosine triphosphate (ATP) concentration. It was found that the shortage of intracellular ATP might be the main reason for the low rate of fumaric acid production by R. oryzae under low pH conditions. When 1 g/l citrate was added to the culture medium at pH 3.0, the intracellular ATP concentration increased from 0.4 to 0.7 µmol/mg, and the fumaric acid titer was enhanced by 63% compared with the control (pH 3.0 without citrate addition). The final fumaric acid concentration at pH 3.0 reached 21.9 g/l after 96 h of fermentation. This strategy is simple and feasible for industrial fumaric acid production under low pH conditions.

  11. 21 CFR 520.82 - Aminopropazine fumarate oral dosage forms.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Aminopropazine fumarate oral dosage forms. 520.82 Section 520.82 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS §...

  12. 21 CFR 520.82a - Aminopropazine fumarate tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Aminopropazine fumarate tablets. 520.82a Section 520.82a Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS §...

  13. 21 CFR 522.82 - Aminopropazine fumarate sterile solution injection.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Aminopropazine fumarate sterile solution injection. 522.82 Section 522.82 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM...

  14. 21 CFR 522.82 - Aminopropazine fumarate sterile solution injection.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Aminopropazine fumarate sterile solution injection. 522.82 Section 522.82 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM...

  15. 21 CFR 522.84 - Beta-aminopropionitrile fumarate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Beta-aminopropionitrile fumarate. 522.84 Section 522.84 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM NEW ANIMAL DRUGS §...

  16. 21 CFR 522.82 - Aminopropazine fumarate sterile solution injection.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Aminopropazine fumarate sterile solution injection. 522.82 Section 522.82 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM...

  17. 21 CFR 522.84 - Beta-aminopropionitrile fumarate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Beta-aminopropionitrile fumarate. 522.84 Section 522.84 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM NEW ANIMAL DRUGS §...

  18. 21 CFR 522.84 - Beta-aminopropionitrile fumarate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Beta-aminopropionitrile fumarate. 522.84 Section 522.84 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM NEW ANIMAL DRUGS §...

  19. 21 CFR 522.82 - Aminopropazine fumarate sterile solution injection.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Aminopropazine fumarate sterile solution injection. 522.82 Section 522.82 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM...

  20. 21 CFR 522.84 - Beta-aminopropionitrile fumarate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Beta-aminopropionitrile fumarate. 522.84 Section 522.84 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM NEW ANIMAL DRUGS §...

  1. Definition of the variables affecting efficacy of immunodepletion ex vivo of peripheral blood progenitor cell grafts by alemtuzumab (Campath in the bag).

    PubMed

    Novitzky, Nicolas; Davison, Glenda; Abdulla, Rygana; Mowla, Shaheen

    2013-12-01

    The immunodepleting effects of alemtuzumab on peripheral blood progenitor cell (PBPC) grafts for stem cell transplantation need to be better defined. The optimal graft cell concentration, antibody dose, need for complement, and whether alemtuzumab is infused with the graft during transplantation remain unclear. PBPC from 6 normal allogeneic stem cell donors harvested by apheresis were first quantitated and the cellular content defined by flow cytometry. Mononuclear cells were then incubated with incremental concentrations of alemtuzumab (.00001, .0001, .001, and .01 mg/mL) for 30 minutes at 20°C or in cell dose responses with 1, 5, and 10 × 10(6) mononuclear cells/mL added to a fixed dose of .001 mg/mL of alemtuzumab with or without a source of complement. Cells were enumerated and analyzed by flow cytometry before and after exposure to alemtuzumab. To determine the presence of unbound anti-CD52, the supernatant of the cell dose responses were tested using the ELISA assay. Selected CD34+ lineage-negative cells were incubated with antibody at the same working concentrations and conditions and cultured in granulocyte-macrophage colony-forming unit assay. The colony numbers were compared with control cultures devoid of the antibody. Incremental concentrations of alemtuzumab led to a significant (2 log) reduction in CD3, CD4, and CD8 populations, which plateaued at .001 mg/mL. Addition of complement led to a further significant reduction in the CD4 and CD8 cells. The maximum CD4 (3 log) and CD8 (2 log) cell death was obtained at 10 × 10(6) cells/mL. Analysis of supernatants for soluble alemtuzumab by ELISA showed a significant reduction in the free antibody concentration when the cell number was increased from 1 to 10 × 10(6) cells/mL implying utilization/binding of the antibody by target cells. Incremental concentrations of alemtuzumab did not affect the number of granulocyte-macrophage colony-forming units. Alemtuzumab depletes all cells expressing the CD52

  2. Unrelated donor hematopoietic stem cell transplantation for the treatment of non-malignant genetic diseases: An alemtuzumab based regimen is associated with cure of clinical disease; earlier clearance of alemtuzumab may be associated with graft rejection.

    PubMed

    Abdel-Azim, Hisham; Mahadeo, Kris Michael; Zhao, Quan; Khazal, Sajad; Kohn, Donald B; Crooks, Gay M; Shah, Ami J; Kapoor, Neena

    2015-11-01

    Hematopoietic stem cell transplantation (HSCT) with matched unrelated donors (MUD), offers potentially curative therapy for patients with non-malignant genetic diseases. In this pilot study conducted from 2006 to 2014, we report the outcomes of 15 patients with non-malignant genetic diseases who received a myeloablative regimen with a reduced cyclophosphamide dose, adjunctive serotherapy and MUD HSCT [intravenous alemtuzumab (52 mg/m(2) ), busulfan (16 mg/kg), fludarabine (140mg/m(2) ), and cyclophosphamide (105 mg/kg)]. Graft-versus-host-disease (GVHD) prophylaxis consisted of tacrolimus/cyclosporine and methylprednisolone. Median (range) time to neutrophil engraftment (>500 cells/µL) and platelet engraftment (>20,000/mm(3) ) were 15 (12-28) and 25 (17-30) days, respectively. At a median follow-up of 2 (0.2-5.4) years, the overall survival (OS) was 93.3% (95% CI: 0.61-0.99) and disease-free survival (DFS) was 73.3% (95% CI: 0.44-0.89). Among this small sample, earlier alemtuzumab clearance was significantly associated with graft rejection (P = 0.047), earlier PHA response (P = 0.009) and a trend toward earlier recovery of recent thymic emigrants (RTE) (P = 0.06). This regimen was associated with durable donor engraftment and relatively low rates of regimen related toxicity (RRT); future alemtuzumab pharmacokinetic studies may improve outcomes, by allowing targeted alemtuzumab clearance to reduce graft rejection and promote more rapid immune reconstitution.

  3. Chronic renin inhibition with aliskiren improves glucose tolerance, insulin sensitivity, and skeletal muscle glucose transport activity in obese Zucker rats.

    PubMed

    Marchionne, Elizabeth M; Diamond-Stanic, Maggie K; Prasonnarong, Mujalin; Henriksen, Erik J

    2012-01-01

    We have demonstrated previously that overactivity of the renin-angiotensin system (RAS) is associated with whole body and skeletal muscle insulin resistance in obese Zucker (fa/fa) rats. Moreover, this obesity-associated insulin resistance is reduced by treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor (type 1) blockers. However, it is currently unknown whether specific inhibition of renin itself, the rate-limiting step in RAS functionality, improves insulin action in obesity-associated insulin resistance. Therefore, the present study assessed the effect of chronic, selective renin inhibition using aliskiren on glucose tolerance, whole body insulin sensitivity, and insulin action on the glucose transport system in skeletal muscle of obese Zucker rats. Obese Zucker rats were treated for 21 days with either vehicle or aliskiren (50 mg/kg body wt ip). Renin inhibition was associated with a significant lowering (10%, P < 0.05) of resting systolic blood pressure and induced reductions in fasting plasma glucose (11%) and free fatty acids (46%) and homeostatic model assessment for insulin resistance (13%). Glucose tolerance (glucose area under the curve) and whole body insulin sensitivity (inverse of the glucose-insulin index) during an oral glucose tolerance test were improved by 15% and 16%, respectively, following chronic renin inhibition. Moreover, insulin-stimulated glucose transport activity in isolated soleus muscle of renin inhibitor-treated animals was increased by 36% and was associated with a 2.2-fold greater Akt Ser(473) phosphorylation. These data provide evidence that chronic selective inhibition of renin activity leads to improvements in glucose tolerance and whole body insulin sensitivity in the insulin-resistant obese Zucker rat. Importantly, chronic renin inhibition is associated with upregulation of insulin action on skeletal muscle glucose transport, and it may involve improved Akt signaling. These data support the

  4. Determination of aliskiren in tablet dosage forms by a validated stability-indicating RP-LC method.

    PubMed

    Wrasse-Sangoi, M; Sangoi, M S; Oliveira, P R; Secretti, L T; Rolim, C M B

    2011-02-01

    A reversed-phase liquid chromatography (RP-LC) method is validated for the determination of aliskiren in tablet dosage form. The LC method is carried out on a Waters XBridge C(18) column (150 × 4.6 mm i.d.), maintained at 25°C. The mobile phase consisted of acetonitrile:water (95:5, v/v)/phosphoric acid (25 mM, pH 3.0) (40:60, v/v), run at a flow rate of 1.0 mL/min, with photodiode array detector set at 229 nm. The chromatographic separation is obtained with aliskiren retention time of 3.68 min, and it is linear in the range of 10-300 μg/mL (r = 0.9999). The limits of detection and quantitation are 2.38 and 7.93 μg/mL, respectively. The specificity and stability-indicating capability of the method are proven through degradation studies, which also showed that there is no interference of the formulation excipients, showing that peak is free from any coeluting peak. The method showed adequate precision, with a relative standard deviation (RSD) values lower than 0.92%. Good values of accuracy were also obtained, with a mean value of 99.55%. Experimental design is used during validation to calculate method robustness. The proposed method is applied for the analysis of the tablet dosage forms, contributing to improve the quality control and to assure the therapeutic efficacy.

  5. Successful treatment of refractory Guillain-Barré syndrome with alemtuzumab in a patient with chronic lymphocytic leukemia.

    PubMed

    Tzachanis, Dimitrios; Hamdan, Ayad; Uhlmann, Erik J; Joyce, Robin M

    2014-01-01

    This is the case of a 79-year-old man with chronic lymphocytic leukemia who presented with Guillain-Barré syndrome with features overlapping with the Miller Fisher syndrome and Bickerstaff brainstem encephalitis and positive antiganglioside GQ1b antibody about 6 months after treatment with bendamustine and rituximab. His clinical and neurologic condition continued to deteriorate despite sequential treatment with corticosteroids, intravenous immunoglobulin and plasmapheresis, but in the end, he had a complete and durable response to treatment with alemtuzumab.

  6. The Impact of Alemtuzumab and Basiliximab Induction on Patient Survival and Time to Bronchiolitis Obliterans Syndrome in Double Lung Transplantation Recipients.

    PubMed

    Furuya, Y; Jayarajan, S N; Taghavi, S; Cordova, F C; Patel, N; Shiose, A; Leotta, E; Criner, G J; Guy, T S; Wheatley, G H; Kaiser, L R; Toyoda, Y

    2016-08-01

    We examined the effect of alemtuzumab and basiliximab induction therapy on patient survival and freedom from bronchiolitis obliterans syndrome (BOS) in double lung transplantation. The United Network for Organ Sharing database was reviewed for adult double lung transplant recipients from 2006 to 2013. The primary outcome was risk-adjusted all-cause mortality. Secondary outcomes included time to BOS. There were 6117 patients were identified, of whom 738 received alemtuzumab, 2804 received basiliximab, and 2575 received no induction. Alemtuzumab recipients had higher lung allocation scores compared with basiliximab and no-induction recipients (41.4 versus 37.9 versus 40.7, p < 0.001) and were more likely to require mechanical ventilation before to transplantation (21.7% versus 6.5% versus 6.2%, p < 0.001). Median survival was longer for alemtuzumab and basiliximab recipients compared with patients who received no induction (2321 versus 2352 versus 1967 days, p = 0.001). Alemtuzumab (hazard ratio 0.80, 95% confidence interval 0.67-0.95, p = 0.009) and basiliximab induction (0.88, 0.80-0.98, p = 0.015) were independently associated with survival on multivariate analysis. At 5 years, alemtuzumab recipients had a lower incidence of BOS (22.7% versus 55.4 versus 55.9%), and its use was independently associated with lower risk of developing BOS on multivariate analysis. While both induction therapies were associated with improved survival, patients who received alemtuzumab had greater median freedom from BOS.

  7. Alemtuzumab Injection

    MedlinePlus

    ... injection, the medication is usually given three times weekly on alternate days (usually Monday, Wednesday, and Friday) ... that you eat foods that are rich in iron such as meats, leafy green vegetables, and fortified ...

  8. A Phase I Study of Alemtuzumab for Therapy of Steroid-Refractory Chronic Graft-versus-Host Disease

    PubMed Central

    Nikiforow, Sarah; Kim, Haesook T.; Bindra, Bhavjot; McDonough, Sean; Glotzbecker, Brett; Armand, Philippe; Koreth, John; Ho, Vincent T.; Alyea, Edwin P.; Blazar, Bruce R.; Ritz, Jerome; Soiffer, Robert J.; Antin, Joseph H.; Cutler, Corey S.

    2013-01-01

    Steroid-refractory chronic graft-versus-host disease (cGvHD) carries a poor prognosis with no agreed-upon algorithm for treatment. Since both B and T cells contribute to the pathophysiology of cGvHD, we conducted a Phase 1 study in subjects with steroid-refractory cGvHD using the anti-CD52 antibody alemtuzumab to transiently deplete most mononuclear subsets. Three regimens were investigated in a 3+3 dose-escalation design: 3 mg×6 (Dose level 1); 3 mg×1, then 10 mg×5 (Dose level 2); and 3 mg×1, 10 mg×1, then 30mg×4 (Dose level 3) administered over 4 weeks. The maximum tolerated dose of alemtuzumab was Dose level 2. Thirteen patients were evaluable for toxicities, which were primarily infectious and hematologic. Rates of infectious complications in the first 12 weeks were 0% at Dose level 1 (n=3), 50% at Dose Level 2 (1 death, n=6), and 75% at Dose Level 3 (2 deaths, n=4). Of 10 patients evaluable for response, seven (70%) responded at 12 weeks, with a 30% complete response rate. Four subjects reduced steroid dose or discontinued an immunosuppressant at 12 weeks. The median decrease in steroid dose at 1 year was 61.6%. Infectious complications occurred predominantly in the first 3 months after therapy, but full B and T cell recovery took well over 12 months. Immunophenotypic profiling revealed early recovery by NK cells and relative sparing of CD4+ and CD8+ central memory T cell subsets. Our study indicates that therapy with alemtuzumab for steroid-refractory chronic GvHD is tolerable with close attention to dosing and may be active in subjects who have failed multiple therapies. The pattern of lymphocyte recovery after alemtuzumab will inform the biology and future therapy of cGvHD. The use of alemtuzumab in the context of therapy for cGvHD deserves study in larger Phase 2 trials. PMID:23416855

  9. Bis(adamantan-1-aminium) hydrogen phosphate fumaric acid sesquisolvate

    PubMed Central

    Mrad, Mohamed Lahbib; Zeller, Matthias; Hernandez, Kristen J.; Rzaigui, Mohamed; Ben Nasr, Cherif

    2012-01-01

    The asymmetric unit of the title compound, 2C10H18N+·HPO4 2−·1.5C4H4O4, contains two adamantan-1-aminium cations, one hydrogen phosphate anion, and one and a half mol­ecules of fumaric acid, one of which exhibits crystallographic inversion symmetry. Each HPO4 2− anion is hydrogen bonded, via all of its O atoms, to four NH3 + groups of the adamantan-1-aminium cations, forming chains along [100]. These chains are, in turn, inter­connected via a set of O—H⋯O hydrogen bonds involving the fumaric acid solvent mol­ecules, forming layers parallel to (001). Weak C—H⋯O inter­actions lead to a consolidation of the three-dimensional set-up. PMID:22904965

  10. Alemtuzumab for relapsed and refractory erythrodermic cutaneous T-cell lymphoma: a single institution experience from the Robert H. Lurie Comprehensive Cancer Center.

    PubMed

    Querfeld, Christiane; Mehta, Neha; Rosen, Steven T; Guitart, Joan; Rademaker, Alfred; Gerami, Pedram; Kuzel, Timothy M

    2009-12-01

    We present the results of an open-label clinical trial and the clinical use of alemtuzumab in 19 heavily pretreated patients with advanced erythrodermic cutaneous T-cell lymphomas (CTCL) (erythrodermic mycosis fungoides and Sézary syndrome). Ten patients received alemtuzumab intravenously using an escalating dose regimen with a final dose of 30 mg three times weekly for 4 weeks followed by subcutaneous administration for 8 weeks. Nine patients were treated with only the SQ or IV dosing. The overall response rate was 84%, with 9 (47%) complete and 7 (37%) partial remissions. The median follow-up was 24 months (range, 6 to 62+ months). Median overall survival was 41 months whereas median progression free survival was 6 months. Minimal residual disease by T-cell gene rearrangement studies was detected in 11 patients who achieved complete response and partial response. Toxicities included myelosuppression and infections; however, the majority of side effects were of Grade 2 in severity and transient. One patient was diagnosed with a concurrent lymphoma (mantle cell lymphoma) 6 months after completing alemtuzumab therapy. Alemtuzumab is particularly effective in patients with erythrodermic CTCL with acceptable toxicities. Combined strategies with alemtuzumab may achieve molecular remissions with longer response durations.

  11. A phase I study of escalated dose subcutaneous alemtuzumab given weekly with rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma.

    PubMed

    Brown, Jennifer R; Messmer, Bradley; Werner, Lillian; Davids, Matthew S; Mikler, Evgeny; Supko, Jeffrey G; Fisher, David C; LaCasce, Ann S; Armand, Philippe; Jacobsen, Eric; Dalton, Virginia; Tesar, Bethany; Fernandes, Stacey M; McDonough, Sean; Ritz, Jerome; Rassenti, Laura; Kipps, Thomas J; Neuberg, Donna; Freedman, Arnold S

    2013-06-01

    This study assessed the safety and preliminary efficacy of escalated dose subcutaneous alemtuzumab in combination with rituximab in chronic lymphocytic leukemia. Twenty-eight patients with relapsed refractory chronic lymphocytic leukemia were treated on four dosing cohorts of weekly rituximab at 375 mg/m(2) and alemtuzumab doses that started at 30 mg three times per week and escalated to weekly dosing over four weeks, culminating with 90 mg weekly. One dose limiting toxicity of a rituximab infusion reaction was seen in cohort 2, but the regimen was otherwise well tolerated without evidence of differential toxicity by cohort. The overall response rate by National Cancer Institute-Working Group criteria was 61%, and the rate of complete bone marrow response was 43%, most of whom were negative for minimal residual disease. The addition of CT scan evaluation per International Workshop on Chronic Lymphocytic Leukemia 2008 criteria reduced the overall response rate to 14%. Median overall survival was 35 months, with 12 patients able to proceed to stem cell transplantation. Pharmacokinetic studies showed that chronic lymphocytic leukemia involving more than 80% of the bone marrow at study start was associated with lower trough concentrations of alemtuzumab and rituximab, and that higher trough serum concentrations of alemtuzumab were associated with complete bone marrow clearance. We conclude that escalated subcutaneous doses of alemtuzumab given weekly are well tolerated and result in excellent bone marrow clearance of chronic lymphocytic leukemia, helping patients to proceed to stem cell transplantation. This study is registered at ClinicalTrials.gov (Identifier:00330252).

  12. Microwave-assisted radical polymerization of dialkyl fumarates

    NASA Astrophysics Data System (ADS)

    Cortizo, M. Susana; Laurella, Sergio; Alessandrini, José Luis

    2007-07-01

    Free radical polymerization of dialkyl fumarates (R:isopropyl, cyclohexyl, 2-ethylhexyl, 2-phenylethyl) under microwave irradiation was investigated. The polymerizations were carried out at different powers of irradiation and initiator concentrations (benzoyl peroxide, BP) and the effect of the monomer structure on the conversion, average molecular weights and the polydispersity index ( Mw/ Mn) was analyzed. A significant enhancement of the rates of polymerization was found, as compared with those obtained under thermal conditions.

  13. Fumaric and sorbic acid as additives in broiler feed.

    PubMed

    Pirgozliev, V; Murphy, T C; Owens, B; George, J; McCann, M E E

    2008-06-01

    The aim of the experiment was to study the effect of dietary organic acids, fumaric and sorbic, on nitrogen corrected apparent metabolisable energy (AME(N)), metabolisability of nutrients, endogenous losses and performance on young broiler chickens. A total of 56 male Ross broilers were used in a growing experiment from 14 to 30d age. Seven experimental wheat-based (655g/kg) diets were formulated. The control diet did not contain organic acids. The other six diets were produced with the addition of fumaric or sorbic acids, replacing 0.5% , 1.0% or 1.5% of the wheat. The organic acid supplemented diets contained higher levels of AME(N) compared to the control diet. Overall, birds offered organic acids had lower feed intake. Dietary organic acids did not significantly affect weight gain or feed efficiency, however, birds offered supplemented diets had lower numbers of Lactic acid bacteria and Coliforms in the ileum and caeca. Birds offered organic acids had lower levels of endogenous losses compared to control fed birds. There was a negative relationship between AME(N) of the diets and excreted endogenous losses, measured as sialic acid. It can be concluded that the decrease in secretions from the gastrointestinal tract in the presence of fumaric and sorbic acids may be a mechanism involved in the mode of action of dietary organic acids.

  14. Nanofiltration, bipolar electrodialysis and reactive extraction hybrid system for separation of fumaric acid from fermentation broth.

    PubMed

    Prochaska, Krystyna; Staszak, Katarzyna; Woźniak-Budych, Marta Joanna; Regel-Rosocka, Magdalena; Adamczak, Michalina; Wiśniewski, Maciej; Staniewski, Jacek

    2014-09-01

    A novel approach based on a hybrid system allowing nanofiltration, bipolar electrodialysis and reactive extraction, was proposed to remove fumaric acid from fermentation broth left after bioconversion of glycerol. The fumaric salts can be concentrated in the nanofiltration process to a high yield (80-95% depending on pressure), fumaric acid can be selectively separated from other fermentation components, as well as sodium fumarate can be conversed into the acid form in bipolar electrodialysis process (stack consists of bipolar and anion-exchange membranes). Reactive extraction with quaternary ammonium chloride (Aliquat 336) or alkylphosphine oxides (Cyanex 923) solutions (yield between 60% and 98%) was applied as the final step for fumaric acid recovery from aqueous streams after the membrane techniques. The hybrid system permitting nanofiltration, bipolar electrodialysis and reactive extraction was found effective for recovery of fumaric acid from the fermentation broth.

  15. Metabolic engineering of Escherichia coli for the production of fumaric acid.

    PubMed

    Song, Chan Woo; Kim, Dong In; Choi, Sol; Jang, Jae Won; Lee, Sang Yup

    2013-07-01

    Fumaric acid is a naturally occurring organic acid that is an intermediate of the tricarboxylic acid cycle. Fungal species belonging to Rhizopus have traditionally been employed for the production of fumaric acid. In this study, Escherichia coli was metabolically engineered for the production of fumaric acid under aerobic condition. For the aerobic production of fumaric acid, the iclR gene was deleted to redirect the carbon flux through the glyoxylate shunt. In addition, the fumA, fumB, and fumC genes were also deleted to enhance fumaric acid formation. The resulting strain was able to produce 1.45 g/L of fumaric acid from 15 g/L of glucose in flask culture. Based on in silico flux response analysis, this base strain was further engineered by plasmid-based overexpression of the native ppc gene, encoding phosphoenolpyruvate carboxylase (PPC), from the strong tac promoter, which resulted in the production of 4.09 g/L of fumaric acid. Additionally, the arcA and ptsG genes were deleted to reinforce the oxidative TCA cycle flux, and the aspA gene was deleted to block the conversion of fumaric acid into L-aspartic acid. Since it is desirable to avoid the use of inducer, the lacI gene was also deleted. To increase glucose uptake rate and fumaric acid productivity, the native promoter of the galP gene was replaced with the strong trc promoter. Fed-batch culture of the final strain CWF812 allowed production of 28.2 g/L fumaric acid in 63 h with the overall yield and productivity of 0.389 g fumaric acid/g glucose and 0.448 g/L/h, respectively. This study demonstrates the possibility for the efficient production of fumaric acid by metabolically engineered E. coli.

  16. Adipocyte protein modification by Krebs cycle intermediates and fumarate ester-derived succination.

    PubMed

    Manuel, Allison M; Frizzell, Norma

    2013-11-01

    Protein succination, the non-enzymatic modification of cysteine residues by fumarate, is distinguishable from succinylation, an enzymatic reaction forming an amide bond between lysine residues and succinyl-CoA. Treatment of adipocytes with 30 mM glucose significantly increases protein succination with only a small change in succinylation. Protein succination may be significantly increased intracellularly after treatment with fumaric acid esters, however, the ester must be removed by saponification to permit 2SC-antibody detection of the fumarate adduct.

  17. Comparative proteomics of Rhizopus delemar ATCC 20344 unravels the role of amino acid catabolism in fumarate accumulation

    PubMed Central

    Sloothaak, Jasper; van Heck, Ruben G.A.; Martins dos Santos, Vitor A.P.; Suarez-Diez, Maria

    2017-01-01

    The filamentous fungus Rhizopus delemar naturally accumulates relatively high amounts of fumarate. Although the culture conditions that increase fumarate yields are well established, the network underlying the accumulation of fumarate is not yet fully understood. We set out to increase the knowledge about fumarate accumulation in R. delemar. To this end, we combined a transcriptomics and proteomics approach to identify key metabolic pathways involved in fumarate production in R. delemar, and propose that a substantial part of the fumarate accumulated in R. delemar during nitrogen starvation results from the urea cycle due to amino acid catabolism. PMID:28382234

  18. Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia

    PubMed Central

    Parikh, Sameer A.; Keating, Michael J.; O'Brien, Susan; Wang, Xuemei; Ferrajoli, Alessandra; Faderl, Stefan; Burger, Jan; Koller, Charles; Estrov, Zeev; Badoux, Xavier; Lerner, Susan

    2011-01-01

    Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) is associated with superior overall survival (OS) for patients with chronic lymphocytic leukemia (CLL). Alemtuzumab (A) was added to FCR (CFAR) in a phase 2 trial for high-risk untreated patients < 70 years with serum β-2 microglobulin (β2M) ≥ 4 mg/L. Sixty patients were enrolled; median age was 59 years (range, 42-69); 75% were male; median β2M was 5.1 mg/L (range, 4-11.6); and 51% were Rai III-IV. Complete remission (CR) was achieved in 70%, partial remission (PR) in 18%, nodular PR in 3%, for an overall response of 92%. Of 14 patients with 17p deletion, CR was achieved by 8 (57%). Of 57 BM samples evaluated by 3-color flow cytometry at the end of treatment, 41 (72%) were negative for residual disease. Grade 3-4 neutropenia and thrombocytopenia occurred with 33% and 13% courses, respectively. The median progression-free survival was 38 months and median OS was not reached. In conclusion, CFAR is an active frontline regimen for high-risk CLL. Response rates and survival are comparable with historic high-risk FCR-treated patients. CFAR may be a useful frontline regimen to achieve CR in patients with 17p deletion before allogeneic stem cell transplantation. PMID:21750315

  19. Impact of ABO blood group mismatch in alemtuzumab-based reduced-intensity conditioned haematopoietic SCT.

    PubMed

    Brierley, C K; Littlewood, T J; Peniket, A J; Gregg, R; Ward, J; Clark, A; Parker, A; Malladi, R; Medd, P

    2015-07-01

    The impact of ABO incompatibility on clinical outcomes following haematopoietic SCT (HSCT) remains controversial. This retrospective study assessed the effect of ABO mismatch on transplant outcomes and transfusion requirements in 594 patients undergoing reduced-intensity conditioned (RIC) HSCT with alemtuzumab in three UK transplant centres. We found no significant effects of minor, major or bidirectional ABO mismatch on overall survival, relapse-free survival, nonrelapse mortality or relapse incidence. Although the rate of acute GVHD was unaffected by ABO mismatch, the incidence of extensive chronic GVHD was higher in patients with minor and major mismatch compared with those who were ABO matched (hazard ratio (HR) 1.74, P=0.032 for minor, HR 1.69 P=0.0036 for major mismatch). Red cell and platelet transfusion requirements in the first 100 days post transplant did not differ by ABO mismatch. In this large UK series, ABO mismatch in RIC HSCT has no clinically significant effect on survival outcomes but appears to modify susceptibility to extensive chronic GVHD.

  20. Transport and metabolism of fumaric acid in Saccharomyces cerevisiae in aerobic glucose-limited chemostat culture.

    PubMed

    Shah, Mihir V; van Mastrigt, Oscar; Heijnen, Joseph J; van Gulik, Walter M

    2016-04-01

    Currently, research is being focused on the industrial-scale production of fumaric acid and other relevant organic acids from renewable feedstocks via fermentation, preferably at low pH for better product recovery. However, at low pH a large fraction of the extracellular acid is present in the undissociated form, which is lipophilic and can diffuse into the cell. There have been no studies done on the impact of high extracellular concentrations of fumaric acid under aerobic conditions in S. cerevisiae, which is a relevant issue to study for industrial-scale production. In this work we studied the uptake and metabolism of fumaric acid in S. cerevisiae in glucose-limited chemostat cultures at a cultivation pH of 3.0 (pH < pK). Steady states were achieved with different extracellular levels of fumaric acid, obtained by adding different amounts of fumaric acid to the feed medium. The experiments were carried out with the wild-type S. cerevisiae CEN.PK 113-7D and an engineered S. cerevisiae ADIS 244 expressing a heterologous dicarboxylic acid transporter (DCT-02) from Aspergillus niger, to examine whether it would be capable of exporting fumaric acid. We observed that fumaric acid entered the cells most likely via passive diffusion of the undissociated form. Approximately two-thirds of the fumaric acid in the feed was metabolized together with glucose. From metabolic flux analysis, an increased ATP dissipation was observed only at high intracellular concentrations of fumarate, possibly due to the export of fumarate via an ABC transporter. The implications of our results for the industrial-scale production of fumaric acid are discussed.

  1. Treatment of simultaneous acute antibody-mediated rejection and acute cellular rejection with alemtuzumab in kidney transplantation: a case report.

    PubMed

    Jirasiritham, S; Khunprakant, R; Techawathanawanna, N; Jirasiritham, Si; Mavichak, V

    2010-04-01

    This is a case report of a living related donor kidney transplantation using basiliximab induction and maintenance immunosuppression with cyclosporine, mycophenolate sodium, and steroid. On the second posttransplant day, the patient developed acute antibody-mediated rejection, which was treated with plasmapheresis and intravenous immunoglobulin (IVIG). Five days later, the graft had still not responded to the treatment. Another biopsy revealed additional acute cellular rejection (Banff IIA). As alemtuzumab can rapidly deplete T and B lymphocytes, monocytes, and natural killer cells, the patient was treated with alemtuzumab (30 mg subcutaneously) together with methylprednisolone (500 mg) and two more plasmaphereses. The kidney graft responded within 48 hours, producing more than 4 L of urine per day. The total lymphocyte decreased from 530/microL to 50/microL remaining in the 50 to 220/microL range. The patient received valgancyclovir and cotrimoxazole as infection prophylaxis. The kidney graft responded well to the rescue treatment and the patient was discharged with a serum creatinine of 1.1 mg/mL and has been uneventfully followed in the outpatient clinic for 8 months. Today, with the potent, effective, and selective immunosuppressive regimens, the rate and severity of acute cellular rejection in kidney transplantation has decreased in most centers. However, the rate of acute antibody-mediated rejection has increased to levels greater than those of acute cellular rejection in many centers. Acute antibody-mediated rejection is more difficult and expensive to treat successfully. The treatment of acute antibody-mediated rejection included plasmapheresis and IVIG. Herein we have reported a case of kidney transplantation simultaneously developing acute antibody-mediated and acute cellular rejection; the patient was successfully treated with alemtuzumab.

  2. Highly sensitive HPLC method for assay of aliskiren in human plasma through derivatization with 1-naphthyl isocyanate using UV detection.

    PubMed

    Belal, F; Walash, M; El-Enany, N; Zayed, S

    2013-08-15

    A simple and sensitive HPLC method has been developed for the determination of aliskiren in human plasma through derivatization with 1-naphthyl isocyanate. The separation was achieved on a C18 column using a mobile phase consisting of acetonitrile/water/phosphoric acid (45:55:0.01, v/v/v, pH 3.2) in a flow rate of 1mL/min with UV detection at 230nm. Caffeine was used as an internal standard. The factors influencing the derivatization reaction yields were carefully studied and optimized. The method was linear over the concentration range of 5-400ng/mL with a detection limit of 0.5ng/mL and a limit of quantification of 1.0ng/mL. The relative standard deviation was less than 4.2% for both intra-day assay and inter-day assay results. No interferences from endogenous compounds were encountered. The percentage recovery was in the range 97.1-98.6%. The method is suitable for routine therapeutic drug monitoring and for pharmacokinetic studies.

  3. Simultaneous determination of aliskiren and hydrochlorothiazide from their pharmaceutical preparations using a validated stability-indicating MEKC method.

    PubMed

    Sangoi, Maximiliano S; Wrasse-Sangoi, Micheli; Oliveira, Paulo R; Rolim, Clarice M B; Steppe, Martin

    2011-08-01

    A stability-indicating MEKC method was developed and validated for the simultaneous determination of aliskiren (ALI) and hydrochlorothiazide (HCTZ) in pharmaceutical formulations using ranitidine as an internal standard (IS). Optimal conditions for the separation of ALI, HCTZ and its major impurity chlorothiazide (CTZ), IS and degradation products were investigated. The method employed 47 mM Tris buffer and 47 mM anionic detergent SDS solution at pH 10.2 as the background electrolyte. MEKC method was performed on a fused-silica capillary (40 cm) at 28°C. Applied voltage was 26 kV (positive polarity) and photodiode array (PDA) detector was set at 217 nm. The method was validated in accordance with the ICH requirements. The method was linear over the concentration range of 5-100 and 60-1200 μg/mL for HCTZ and ALI, respectively (r(2) >0.9997). The stability-indicating capability of the method was established by enforced degradation studies combined with peak purity assessment using the PDA detection. Precision and accuracy evaluated by RSD were lower than 2%. The method proved to be robust by a fractional factorial design evaluation. The proposed MEKC method was successfully applied for the quantitative analysis of ALI and HCTZ both individually and in a combined dosage tablet formulation to support the quality control.

  4. 21 CFR 520.82b - Aminopropazine fumarate, neomycin sulfate tablets.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... chapter. (c) Conditions of use. (1) The drug is used in dogs to control bacterial diarrhea caused by... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Aminopropazine fumarate, neomycin sulfate tablets... Aminopropazine fumarate, neomycin sulfate tablets. (a) Specifications. The drug is in tablet form. Each...

  5. 21 CFR 520.82b - Aminopropazine fumarate, neomycin sulfate tablets.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... chapter. (c) Conditions of use. (1) The drug is used in dogs to control bacterial diarrhea caused by... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Aminopropazine fumarate, neomycin sulfate tablets... Aminopropazine fumarate, neomycin sulfate tablets. (a) Specifications. The drug is in tablet form. Each...

  6. 21 CFR 520.82b - Aminopropazine fumarate, neomycin sulfate tablets.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... chapter. (c) Conditions of use. (1) The drug is used in dogs to control bacterial diarrhea caused by... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Aminopropazine fumarate, neomycin sulfate tablets... Aminopropazine fumarate, neomycin sulfate tablets. (a) Specifications. The drug is in tablet form. Each...

  7. Orange but not apple juice enhances ferrous fumarate absorption in small children

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ferrous fumarate is a common, inexpensive iron form increasingly used instead of ferrous sulfate as a food iron supplement. However, few data exist as to whether juices enhance iron absorption from ferrous fumarate. We studied 21 children, ages 4.0 to 7.9 years using a randomized crossover design. S...

  8. Study of Vitamins and Dietary Supplements Containing Ferrous Fumarate and Ferrous Sulfate Using Moessbauer Spectroscopy

    SciTech Connect

    Oshtrakh, M. I.; Novikov, E. G.; Semionkin, V. A.; Dubiel, S. M.

    2010-07-13

    A study of several samples of vitamins and dietary supplements containing ferrous fumarate and ferrous sulfate was carried out using Moessbauer spectroscopy with a high velocity resolution. A presence of ferrous and ferric impurities was revealed. Small variations of Moessbauer hyperfine parameters were found for both ferrous fumarates and ferrous sulfates in the investigated medicines.

  9. Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition

    PubMed Central

    Sciacovelli, Marco; Gonçalves, Emanuel; Isaac Johnson, Timothy; Roberto Zecchini, Vincent; da Costa, Ana Sofia Henriques; Gaude, Edoardo; Vercauteren Drubbel, Alizee; Julian Theobald, Sebastian; Abbo, Sandra; Tran, Maxine; Rajeeve, Vinothini; Cardaci, Simone; Foster, Sarah; Yun, Haiyang; Cutillas, Pedro; Warren, Anne; Gnanapragasam, Vincent; Gottlieb, Eyal; Franze, Kristian; Huntly, Brian; Richard Maher, Eamonn; Henry Maxwell, Patrick; Saez-Rodriguez, Julio; Frezza, Christian

    2016-01-01

    Mutations of the tricarboxylic acid cycle (TCA cycle) enzyme fumarate hydratase (FH) cause Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC)1. FH-deficient renal cancers are highly aggressive and metastasise even when small, leading to an abysmal clinical outcome2. Fumarate, a small molecule metabolite that accumulates in FH-deficient cells, plays a key role in cell transformation, making it a bona fide oncometabolite3. Fumarate was shown to inhibit α-ketoglutarate (aKG)-dependent dioxygenases involved in DNA and histone demethylation4,5. However, the link between fumarate accumulation, epigenetic changes, and tumorigenesis is unclear. Here we show that loss of FH and the subsequent accumulation of fumarate elicits an epithelial-to-mesenchymal-transition (EMT), a phenotypic switch associated with cancer initiation, invasion, and metastasis6. We demonstrate that fumarate inhibits Tet-mediated demethylation of a regulatory region of the antimetastatic miRNA cluster6 miR-200ba429, leading to the expression of EMT-related transcription factors and enhanced migratory properties. These epigenetic and phenotypic changes are recapitulated by the incubation of FH-proficient cells with cell-permeable fumarate. Loss of FH is associated with suppression of miR-200 and EMT signature in renal cancer patients, and is associated with poor clinical outcome. These results imply that loss of FH and fumarate accumulation contribute to the aggressive features of FH-deficient tumours. PMID:27580029

  10. Effect of bicarbonate concentration on aerobic growth of campylobacter in a fumarate-pyruvate medium

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The purpose of the present study was to examine the effect of sodium bicarbonate (NaHCO3) concentration on aerobic growth of Campylobacter in a fumarate-pyruvate medium. Fumarate-pyruvate broth medium was supplemented with 0.00 to 0.10% NaHCO3 and inoculated with Campylobacter coli 33559, Campyloba...

  11. Comparable effect of aliskiren or a diuretic added on an angiotensin II receptor blocker on augmentation index in hypertension: a multicentre, prospective, randomised study

    PubMed Central

    Miyoshi, Toru; Murakami, Takashi; Sakuragi, Satoru; Doi, Masayuki; Nanba, Seiji; Mima, Atsushi; Tominaga, Youkou; Oka, Takafumi; Kajikawa, Yutaka; Nakamura, Kazufumi; Ito, Hiroshi

    2017-01-01

    Background The effects of antihypertensive drug combination therapy on central blood pressure (BP) and augmentation index (AI) have not been fully elucidated. We investigated the effects of the direct renin inhibitor, aliskiren, or a diuretic added to an angiotensin II receptor blocker on AI in patients with essential hypertension. Methods A 24-week, prospective, multicentre, randomised, open-label study enrolled 103 patients already treated with valsartan. Participants were randomly allocated to receive either valsartan with aliskiren (V+A), or valsartan with trichlormethiazide (V+T). The primary outcome was the change in AI derived from radial artery tonometry. Secondary outcome measures included systolic and diastolic BP, cardio-ankle vascular index (CAVI, which reflects arterial stiffness) and urinary 8-hydroxydeoxyguanosine concentration. Results After 24 weeks, systolic and diastolic BP were significantly reduced in both groups to a broadly comparable extent. There was no significant difference in AI at the end of the study between the V+A group and the V+T group (between-group difference: −2.3%, 95% CI −6.9% to 2.2%, p=0.31). Central BP at the end of the study also did not differ between the two groups (p=0.62). There was no significant difference in the CAVI between the groups at the end of the study. Urinary 8-hydroxydeoxyguanosine concentration was significantly lower in the V+A group than in the V+T group (p<0.01), suggesting that V+A attenuated oxidative stress more than V+T. Conclusion The combination of valsartan and aliskiren had an effect on AI comparable with that of the combination of valsartan and trichlormethiazide. UMIN Clinical Trial Registration number UMIN000005726.

  12. Metabolic engineering of Rhizopus oryzae: Effects of overexpressing pyc and pepc genes on fumaric acid biosynthesis from glucose

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fumaric acid, a dicarboxylic acid used as a food acidulant and in manufacturing synthetic resins, can be produced from glucose in fermentation by Rhizopus oryzae. However, the fumaric acid yield is limited by the co-production of ethanol and other byproducts. To increase fumaric acid production, ove...

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

    PubMed Central

    Sreelatha, M

    2016-01-01

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

  14. Growth and characterization of terbium fumarate heptahydrate single crystals

    NASA Astrophysics Data System (ADS)

    Want, B.; Shah, M. D.

    2014-03-01

    The growth of terbium fumarate heptahydrate single crystals was achieved by single gel diffusion technique using silica gel as a medium of growth. The effect of various growth parameters on the nucleation rate of these crystals was studied. The crystals were characterized by different physico-chemical techniques of characterization. Powder X-ray diffraction pattern showed that terbium fumarate is a crystalline compound. Fourier transform infrared spectroscopy was performed for the identification of water and other functional groups present in the compound. UV-vis and photoluminescence spectrophotometric experiments were carried out to study the optical properties of the grown crystals. Elemental analysis suggested the chemical formula of the crystals to be Tb2(C4H2O4)3·7H2O. The presence of seven molecules of water was also supported by the thermogravimetric analysis. The hydrated compound was found to be thermally stable upto a temperature of about 110 °C and its anhydrous form up to the temperature of 410 °C. The thermal decomposition of the compound in the nitrogen atmosphere leads to the formation of terbium oxide as the final product. An attempt was made to relate the experimental results with the classical nucleation theory.

  15. Metabolically Labile Fumarate Esters Impart Kinetic Selectivity to Irreversible Inhibitors.

    PubMed

    Zaro, Balyn W; Whitby, Landon R; Lum, Kenneth M; Cravatt, Benjamin F

    2016-12-14

    Electrophilic small molecules are an important class of chemical probes and drugs that produce biological effects by irreversibly modifying proteins. Examples of electrophilic drugs include covalent kinase inhibitors that are used to treat cancer and the multiple sclerosis drug dimethyl fumarate. Optimized covalent drugs typically inactivate their protein targets rapidly in cells, but ensuing time-dependent, off-target protein modification can erode selectivity and diminish the utility of reactive small molecules as chemical probes and therapeutics. Here, we describe an approach to confer kinetic selectivity to electrophilic drugs. We show that an analogue of the covalent Bruton's tyrosine kinase (BTK) inhibitor Ibrutinib bearing a fumarate ester electrophile is vulnerable to enzymatic metabolism on a time-scale that preserves rapid and sustained BTK inhibition, while thwarting more slowly accumulating off-target reactivity in cell and animal models. These findings demonstrate that metabolically labile electrophilic groups can endow covalent drugs with kinetic selectivity to enable perturbation of proteins and biochemical pathways with greater precision.

  16. Comparison of Subcutaneous versus Intravenous Alemtuzumab for Graft-versus-Host Disease Prophylaxis with Fludarabine/Melphalan-Based Conditioning in Matched Unrelated Donor Allogeneic Stem Cell Transplantation.

    PubMed

    Patel, Khilna; Parmar, Sapna; Shah, Shreya; Shore, Tsiporah; Gergis, Usama; Mayer, Sebastian; van Besien, Koen

    2016-03-01

    The objective of this study was to compare infusion-related reactions and outcomes of using subcutaneous (subQ) alemtuzumab versus intravenous (i.v.) alemtuzumab as graft-versus-host disease (GVHD) prophylaxis for matched unrelated donor stem cell transplantations. Outcomes include incidence of cytomegalovirus (CMV)/Epstein-Barr (EBV) viremia, development of CMV disease or post-transplantation lymphoproliferative disorder, fatal infections, acute and chronic GVHD, time to engraftment, relapse rate, and survival. We conducted a retrospective study of all adult matched unrelated donor stem cell transplantations patients who received fludarabine/melphalan with subQ or i.v. alemtuzumab in combination with tacrolimus as part of their conditioning for unrelated donor transplantation at New York-Presbyterian/Weill Cornell Medical Center from January 1, 2012 to March 21, 2014. Alemtuzumab was administered at a total cumulative dose of 100 mg (divided over days -7 to -3). Forty-six patients received an unrelated donor stem cell transplantation with fludarabine/melphalan and either subQ (n = 26) or i.v. (n = 20) alemtuzumab in combination with tacrolimus. Within the evaluable population, 130 subQ and 100 i.v. alemtuzumab doses were administered. For the primary outcome, ≥grade 2 infusion-related reactions occurred in 11 (8%) versus 25 (25%) infusions in the subQ and i.v. cohorts, respectively (P = .001). Overall, 12 injections (9%) in the subQ arm versus 26 infusions (26%) in the i.v. arm experienced an infusion-related reaction of any grade (P = .001). There were no significant differences between the subQ and i.v. arms in rates of reactivation of CMV/EBV, development of CMV disease or post-transplantation lymphoproliferative disorder, fatal infections, acute and chronic GVHD, relapse, or survival. Subcutaneous administration of alemtuzumab for GVHD prophylaxis was associated with fewer infusion-related reactions compared with i.v. administration in the SCT setting

  17. Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions

    PubMed Central

    Vukovic, Milica; van de Lagemaat, Louie N.; Morgan, Marcos; Gonzalez, Marta Vila; Paris, Jasmin; Gezer, Deniz; Wills, Jimi; Coman, David; So, Chi Wai Eric; O’Carroll, Donal; Vernimmen, Douglas; Rodrigues, Neil P.; Pollard, Patrick J.; Morton, Nicholas M.

    2017-01-01

    Strict regulation of stem cell metabolism is essential for tissue functions and tumor suppression. In this study, we investigated the role of fumarate hydratase (Fh1), a key component of the mitochondrial tricarboxylic acid (TCA) cycle and cytosolic fumarate metabolism, in normal and leukemic hematopoiesis. Hematopoiesis-specific Fh1 deletion (resulting in endogenous fumarate accumulation and a genetic TCA cycle block reflected by decreased maximal mitochondrial respiration) caused lethal fetal liver hematopoietic defects and hematopoietic stem cell (HSC) failure. Reexpression of extramitochondrial Fh1 (which normalized fumarate levels but not maximal mitochondrial respiration) rescued these phenotypes, indicating the causal role of cellular fumarate accumulation. However, HSCs lacking mitochondrial Fh1 (which had normal fumarate levels but defective maximal mitochondrial respiration) failed to self-renew and displayed lymphoid differentiation defects. In contrast, leukemia-initiating cells lacking mitochondrial Fh1 efficiently propagated Meis1/Hoxa9-driven leukemia. Thus, we identify novel roles for fumarate metabolism in HSC maintenance and hematopoietic differentiation and reveal a differential requirement for mitochondrial Fh1 in normal hematopoiesis and leukemia propagation. PMID:28202494

  18. KRT6 interacting with notch1 contributes to progression of renal cell carcinoma, and aliskiren inhibits renal carcinoma cell lines proliferation in vitro.

    PubMed

    Hu, Jing; Zhang, Li-Chao; Song, Xu; Lu, Jian-Rao; Jin, Zhu

    2015-01-01

    Notch signaling is a conserved and widely expressed signaling pathway, which mediates various physiological processes including tumorigenesis. This study aims to explore the potential role and mechanism of notch1 interacting with KRT6B in the progression of RCC. The results indicated that the mRNA and protein expression of notch1 and KRT6 were significantly increased in tumor tissues, and highly positive correlation existed between notch1 and KRT6. Moreover, the patients with high notch1 expression had a significantly poorer prognosis than those of low expression patients. In vitro, KRT6 loss-of-function could inhibit the expression of notch1 and induce renal carcinoma cell death. Eventually, we found that renin inhibitor, aliskiren, could inhibit cell proliferation and decrease the expression of notch1 and KRT6 as well as regulate apoptosis-related protein expression in 786-O and ACHN renal carcinoma cell lines. These results suggested that the upregulation of notch1 and KRT6B might be involved in the development, progression and prognosis of human RCC, and aliskiren could suppress renal carcinoma cell proliferation, at least partially, through downregulation the expression of notch1 and KRT6.

  19. The Epi-TAF for Tenofovir Disoproxil Fumarate?

    PubMed

    Walensky, Rochelle P; Horn, Tim H; Paltiel, A David

    2016-04-01

    Approximately 84% of human immunodeficiency virus (HIV)-infected US residents on antiretroviral therapy currently receive some form of tenofovir disoproxil fumarate (TDF) as part of their HIV treatment regimen. The TDF analogue tenofovir alafenamide (TAF) has demonstrated equal efficacy but with decreased renal injury and bone mineral density loss compared with TDF. We examine how much more society ought to be willing to pay for TAF over TDF, in exchange for its improved toxicity profile. Using cost-effectiveness methods, we find that current conditions warrant an annual premium of up to $1000 over the average wholesale price (AWP) of TDF. Once generic coformulations of tenofovir/lamivudine become accessible, however, the appropriate premium for TAF will likely merit a downward adjustment, using generic TDF-based costs as the benchmark.

  20. [Acute kidney failure during psoriasis therapy with fumaric acid derivatives].

    PubMed

    Dalhoff, K; Faerber, P; Arnholdt, H; Sack, K; Strubelt, O

    1990-06-29

    24 days after starting treatment of psoriasis with fumaric acid derivatives (0.8-1.0 g orally, plus unknown quantities locally) a 21-year-old woman developed acute oliguric renal failure with a rise of serum creatinine levels to 1094 mumol/l (12.4 mg/dl). Deterioration of renal function had been preceded by severe abdominal symptoms with nausea, vomiting and colicky pain. On admission to hospital she was dehydrated with hyponatraemia and hypokalaemia. There was glomerular microhaematuria, increased excretion of renal epithelia, and tubular proteinuria. Renal biopsy demonstrated acute tubular damage with vacuolization of proximal epithelia, dilated tubules and scattered necroses. After intermittent haemodialysis (13 courses over two weeks) renal function gradually recovered, as demonstrated at a follow-up examination four months after discharge.

  1. The Maillard reaction of bisoprolol fumarate with various reducing carbohydrates.

    PubMed

    Szalka, Mateusz; Lubczak, Jacek; Naróg, Dorota; Laskowski, Marek; Kaczmarski, Krzysztof

    2014-08-01

    HPLC analysis of drug products containing bisoprolol fumarate and lactose revealed the presence of N-formylbisoprolol, which is a final product of the Maillard reaction. Formulations containing secondary amines and reducing carbohydrates are prone to the condensation of amine and carbonyl functional groups and formation of glycosylamines in pharmaceutically relevant conditions. Further rearrangement occurs in the presence of a nucleophile and leads to the formation of 1-deoxy-1-amino-2-ketose also known as the Amadori Rearrangement Product (ARP). The influence of water content, carbohydrate, and lubricant types on the reaction rate was tested. The reaction progress was monitored by HPLC and UV-Vis spectrophotometry. The structures of intermediates were confirmed by the LC/MS(2) analysis. N-formylbisoprolol - the final reaction product - was synthesised and characterised by LC/MS(2), H(1) and C(13) NMR.

  2. Progressive Neurologic Dysfunction in a Psoriasis Patient Treated With Dimethyl Fumarate

    PubMed Central

    Bartsch, Thorsten; Rempe, Torge; Wrede, Arne; Leypoldt, Frank; Brück, Wolfgang; Adams, Ortwin; Rohr, Axel; Jansen, Olav; Wüthrich, Christian; Deuschl, Günther; Koralnik, Igor J.

    2016-01-01

    Progressive multifocal leukoencephalopathy (PML) has recently been described in psoriasis or multiple sclerosis patients treated with fumaric acid esters (fumarates), who had developed severe and long-standing lymphocytopenia (<500/mm3). We report a psoriasis patient who presented with progressive neurologic dysfunction and seizures after 2.5 years of fumarate therapy. Despite absolute lymphocyte counts remaining between 500–1000/mm3, his CD4+ and CD8+ T-cell counts were markedly low. MRI showed right hemispheric and brainstem lesions and JC virus DNA was undetectable in his cerebrospinal fluid. Brain biopsy revealed typical features of PML as well as JC virus-infected neurons. Clinicians should consider PML in the differential diagnosis of fumarate-treated patients presenting with brain lesions or seizures even in the absence of severe lymphocytopenia. PMID:26150206

  3. El estrés y fumar | Smokefree Español

    Cancer.gov

    Muchas personas fuman cuando se sienten estresadas. Una parte importante de dejar de fumar es encontrar maneras de manejar el estrés. Reciba recomendaciones sobre formas de disminuir el estrés en su vida.

  4. Early primary graft failure after a pediatric heart transplant and successful rescue with plasmapheresis, immunoglobulins, and alemtuzumab

    PubMed Central

    Raj, Shashi; Ruiz, Phillip; Rusconi, Paolo

    2017-01-01

    Early primary graft failure after pediatric orthotopic heart transplantation (OHT) has a high mortality rate and can occur due to several causes including but not limited to prolonged graft ischemia time, suboptimal preimplant myocardial preservation, hyperacute rejection, and maladaptation of the graft to the host's hemodynamic status. Mechanical circulatory support with either extracorporeal membrane oxygenation (ECMO) or ventricular assist device has been used for the rescue of primary graft failure in pediatric patients after heart transplant. Cardiac arrest before ECMO initiation in these patients is associated with adverse neurologic outcome although those surviving to hospital discharge generally have excellent long-term outcome. We report a case of early primary graft failure after OHT who required ECMO support and successful rescue with plasmapheresis, immunoglobulins, and alemtuzumab. PMID:28163432

  5. Allosteric substrate inhibition of Arabidopsis NAD-dependent malic enzyme 1 is released by fumarate.

    PubMed

    Tronconi, Marcos Ariel; Wheeler, Mariel Claudia Gerrard; Martinatto, Andrea; Zubimendi, Juan Pablo; Andreo, Carlos Santiago; Drincovich, María Fabiana

    2015-03-01

    Plant mitochondria can use L-malate and fumarate, which accumulate in large levels, as respiratory substrates. In part, this property is due to the presence of NAD-dependent malic enzymes (NAD-ME) with particular biochemical characteristics. Arabidopsis NAD-ME1 exhibits a non-hyperbolic behavior for the substrate L-malate, and its activity is strongly stimulated by fumarate. Here, the possible structural connection between these properties was explored through mutagenesis, kinetics, and fluorescence studies. The results indicated that NAD-ME1 has a regulatory site for L-malate that can also bind fumarate. L-Malate binding to this site elicits a sigmoidal and low substrate-affinity response, whereas fumarate binding turns NAD-ME1 into a hyperbolic and high substrate affinity enzyme. This effect was also observed when the allosteric site was either removed or altered. Hence, fumarate is not really an activator, but suppresses the inhibitory effect of l-malate. In addition, residues Arg50, Arg80 and Arg84 showed different roles in organic acid binding. These residues form a triad, which is the basis of the homo and heterotrophic effects that characterize NAD-ME1. The binding of L-malate and fumarate at the same allosteric site is herein reported for a malic enzyme and clearly indicates an important role of NAD-ME1 in processes that control flow of C4 organic acids in Arabidopsis mitochondrial metabolism.

  6. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2007-11-01

    1-Octanol, 9vPnC-MnCc; Abiraterone acetate, Adalimumab, Adefovir dipivoxil, Alemtuzumab, Aliskiren fumarate, Aminolevulinic acid hexyl ester, Amlodipine besylate/atorvastatin calcium, Amrubicin hydrochloride, Anakinra, Aripiprazole, ARRY-520, AS-1404, Asimadoline, Atazanavir sulfate, AVE-0277, Azelnidipine; Bevacizumab, Bimatoprost, Boceprevir, Bortezomib, Bosentan, Botulinum toxin type B; Certolizumab pegol, Cetuximab, Clevudine, Contusugene ladenovec, CP-751871, Crofelemer, Cypher, CYT006-AngQb; Darbepoetin alfa, Desmopressin, Dexlansoprazole, DG-041; E-5555, Ecogramostim, Entecavir, Erlotinib hydrochloride, Escitalopram oxalate, Eszopiclone, Everolimus, Ezetimibe, Ezetimibe/simvastatin; Falecalcitriol, Fampridine, Fesoterodine fumarate, Fingolimod hydrochloride; Gefitinib, Ghrelin (human), GS-7904L, GV-1001; HT-1001; Insulin detemir, ISIS-112989, Istradefylline; Laquinimod sodium, Latanoprost/timolol maleate, Lenalidomide, Levobetaxolol hydrochloride, Liposomal doxorubicin, Liposomal morphine sulfate, Lubiprostone, Lumiracoxib, LY-518674; MEM-1003, Mesna disulfide, Mipomersen sodium, MM-093, Mycophenolic acid sodium salt; Naptumomab estafenatox, Natalizumab; Olmesartan medoxomil, Olmesartan medoxomil/hydrochlorothiazide; Paclitaxel nanoparticles, Paclitaxel poliglumex, Pasireotide, Pazufloxacin mesilate, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Peginterferon alfa-2b/ribavirin, Pegvisomant, Pemetrexed disodium, Pimagedine, Pimecrolimus, Pramlintide acetate, Prasterone, Pregabalin, Prulifloxacin; QAE-397; Rec-15/2615, RFB4(dsFv)-PE38, rhGAD65, Roflumilast, Romiplostim, Rosuvastatin calcium, Rotigotine, Rupatadine fumarate; Safinamide mesilate, SIR-Spheres, Sitagliptin phosphate, Sodium phenylacetate, Sodium phenylacetate/Sodium benzoate, Sorafenib, SSR-244738; Taribavirin hydrochloride, Taxus, Teduglutide, Tegaserod maleate, Telaprevir, Telbivudine, Tenofovir disoproxil fumarate, Tigecycline, Tiotropium bromide, Trabectedin, Travoprost

  7. Transformation of Sézary syndrome into CD30+ anaplastic large T-cell lymphoma after alemtuzumab therapy with evidence of clonal unity.

    PubMed

    Nevet, Mariela Judith; Zuckerman, Tsila; Sahar, Dvora; Bergman, Reuven

    2015-01-01

    Alemtuzumab is a humanized mouse antibody targeting the CD52 cell surface, which has been effective in patients with advanced stage mycosis fungoides (MF) including erythrodermic MF and Sézary syndrome. There are a few descriptions of large cell transformation after its administration. A young patient with an acute onset of Sézary syndrome treated initially unsuccessfully with fludarabine and cyclophosphamide and later on successfully with alemtuzumab has been described. Three weeks after the beginning of therapy, however, she developed transformed T-cell lymphoma indistinguishable from CD30 anaplastic large-cell lymphoma. After bone marrow transplantation, the transformed CD30 cutaneous T-cell lymphoma recurred as a transformed CD30 plaque MF. All 3 types of lesions showed the same T-cell receptor clonal gene rearrangement, which supports the notion that Sézary syndrome, CD30 anaplastic large-cell lymphoma, and MF are interrelated.

  8. A Prospective Study of an Alemtuzumab Containing Reduced-intensity Allogeneic Stem Cell Transplantation Program in Patients with Poor-Risk and Advanced Lymphoid Malignancies

    PubMed Central

    Sauter, Craig S.; Chou, Joanne F.; Papadopoulos, Esperanza B.; Perales, Miguel-Angel; Jakubowski, Ann A.; Young, James W.; Scordo, Michael; Giralt, Sergio; Castro-Malaspina, Hugo

    2015-01-01

    Reduced-intensity conditioning (RIC) regimens for allogeneic stem cell transplantation (allo-SCT) have used alemtuzumab to abrogate the risk of graft-versus-host disease (GVHD). Thirty-eight advanced lymphoma patients underwent a prospective phase II study of melphalan, fludarabine and alemtuzumab containing RIC allo-SCT from 20 matched related and 18 unrelated donors with cyclosporin-A as GVHD prophylaxis. The cumulative incidence of grade II-IV acute GVHD at 3 months was 10.5% and three evaluable patients experienced chronic GVHD. Progression-free (PFS) and overall (OS) survival at 5 years is 25% (95% CI: 13-40) and 44% (95% CI: 28-59%) respectively. Previous high-dose therapy and autologous stem cell transplantation (HDT-ASCT) and elevated LDH at the time of allo-SCT resulted in inferior OS. Within this cohort of high-risk lymphoma patients, alemtuzumab containing RIC resulted in a low risk of GVHD and a high incidence of POD, especially in those with poor-risk features defined by elevated LDH pre-allo-SCT and previous HDT-ASCT. PMID:24528216

  9. Characterisation of the fumarate hydratase repertoire in Trypanosoma cruzi.

    PubMed

    de Pádua, Ricardo A P; Kia, Ali Martin; Filho, Antonio José Costa; Wilkinson, Shane R; Nonato, M Cristina

    2017-03-27

    Nifurtimox and benznidazole represent the only treatments options available targeting Chagas disease, the most important parasitic infection in the Americas. However, use of these is problematic as they are toxic and ineffective against the more severe stages of the disease. In this work, we used a multidisciplinary approach to characterise the fumarases from Trypanosoma cruzi, the causative agent of Chagas Disease. We showed this trypanosome expresses cytosolic and mitochondrial fumarases that via an iron-sulfur cluster mediate the reversible conversion of fumarate to S-malate. Based on sequence, biochemical properties and co-factor binding, both T. cruzi proteins share characteristics with class I fumarases, enzymes found in bacteria and some other protozoa but absent from humans, that possess class II isoforms instead. Gene disruption suggested that although the cytosolic or mitochondrial fumarase activities are individually dispensable their combined activity is essential for parasite viability. Finally, based on the mechanistic differences with the human (host) fumarase, we designed and validated a selective inhibitor targeting the parasite enzyme. This study showed that T. cruzi fumarases should be exploited as targets for the development of new chemotherapeutic interventions against Chagas disease.

  10. Dimethyl Fumarate Induces Glutathione Recycling by Upregulation of Glutathione Reductase

    PubMed Central

    Hoffmann, Christina; Dietrich, Michael; Herrmann, Ann-Kathrin; Schacht, Teresa

    2017-01-01

    Neuronal degeneration in multiple sclerosis has been linked to oxidative stress. Dimethyl fumarate (DMF) is an effective oral therapeutic option shown to reduce disease activity and progression in patients with relapsing-remitting multiple sclerosis. DMF activates the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) leading to increased synthesis of the major cellular antioxidant glutathione (GSH) and prominent neuroprotection in vitro. We previously demonstrated that DMF is capable of raising GSH levels even when glutathione synthesis is inhibited, suggesting enhanced GSH recycling. Here, we found that DMF indeed induces glutathione reductase (GSR), a homodimeric flavoprotein that catalyzes GSSG reduction to GSH by using NADPH as a reducing cofactor. Knockdown of GSR using a pool of E. coli RNase III-digested siRNAs or pharmacological inhibition of GSR, however, also induced the antioxidant response rendering it impossible to verify the suspected attenuation of DMF-mediated neuroprotection. However, in cystine-free medium, where GSH synthesis is abolished, pharmacological inhibition of GSR drastically reduced the effect of DMF on glutathione recycling. We conclude that DMF increases glutathione recycling through induction of glutathione reductase. PMID:28116039

  11. Bioelectrocatalysts: engineered oxidoreductase system for utilization of fumarate reductase in chemical synthesis, detection, and fuel cells.

    PubMed

    Park, Doo Hyun; Vieille, C; Zeikus, J G

    2003-10-01

    Fumarate reductase was used as a model oxidoreductase to demonstrate continuous electrical cofactor reduction-oxidation during the bioelectrochemical synthesis and detection of chemicals. The enzyme preparation was immobilized onto a graphite felt electrode that was modified with carboxymethylcellulose (CMC). Nicotinamide adenine dinucleotide (NAD), neutral red, and fumarate reductase (which contained menaquinone) were covalently linked by peptide bonds to the CMC. The electron mediator neutral red allowed NAD and menaquinone to be recycled electrically during enzymatic chemical synthesis. Succinate detection by the bioelectrocatalyst was linear from 5 microM to 10 mM succinate. Fumarate synthesis using this bioelectrode was dependent on succinate utilization and resulted in proportional production of electricity and fumarate. Succinate synthesis using this bioelectrocatalyst was dependent on current and fumarate concentration. This bioelectrocatalyst system may enhance the utility of menaquinone- and/or pyridine nucleotide-linked oxidoreductases in diverse enzymatic fuel cells and sensors. It may also enhance the utility of oxidoreductase-based chemical synthesis systems because it eliminates the problem of cofactor recycling.

  12. Fumarate hydratase gene mutation in two young patients with sporadic uterine fibroids.

    PubMed

    Kubinova, Kristyna; Tesarova, Marketa; Hansikova, Hana; Vesela, Kamila; Kuzel, David; Mara, Michal

    2013-01-01

    Fumarate hydratase (FH) is a key enzyme of the Krebs cycle. Germline mutations in the FH gene encoding fumarate hydratase cause autosomal dominant syndromes multiple cutaneous and uterine leiomyomata and hereditary leiomyomatosis and renal cell cancer (HLRCC). Few data have been published on the role of FH gene mutation in development of uterine fibroids outside the context of multiple cutaneous and uterine leiomyomata /HLRCC. We report two FH gene mutations, one novel and one previously described, in two young patients with sporadic uterine fibroids and decreased fumarate hydratase activity in lymphocytes. In patient 1, a novel heterozygous mutation c.892G>C was found. In patient 2 we detected heterozygous mutation c.584T>C. Both the patients had a negative family history for renal cancer and cutaneous leiomyomatosis. None of the relatives, however, underwent renal imaging at the time of writing. FH mutation carriers may be easily identified by analysis of fumarate hydratase activity in blood lymphocytes. We suggest performing fumarate hydratase activity or FH mutation screening in women with onset of uterine fibroids in their 20s and family history of uterine fibroids or other HLRCC-associated malignancies.

  13. Treatment with Dimethyl Fumarate attenuates calcineurin inhibitor-induced Nephrotoxicity

    PubMed Central

    Takasu, Chie; Vaziri, Nosratola D.; Li, Shiri; Robles, Lourdes; Vo, Kelly; Takasu, Mizuki; Pham, Christine; Liu, Shuman; Farzaneh, Seyed H.; Foster, Clarence E; Stamos, Michael J; Ichii, Hirohito

    2014-01-01

    Background Cyclosporine A (CsA) is an immunosuppressive drug which has been widely used to prevent rejection following organ transplantation. However, its therapeutic use is limited by nephrotoxicity, in part mediated by oxidative stress. The present study aims to investigate the protective effects of Dimethyl Fumarate (DMF) on CsA-induced nephrotoxicity by enhancing the antioxidant defense system. Methods Male Sprague-Dawley rats were treated with CsA (n=8, 20 mg/kg/day i.p.) orCsA + DMF (n=7, 50 mg/kg/day p.o.) for 28 days. Renal function, histopathology, malondialdehyde (MDA), myeloperoxidase (MPO) levels and anti-oxidant enzyme expression were determined. Results DMF co-treatment ameliorated CsA-induced renal dysfunction as evidenced by significant decrease in serum creatinine (CsA 0.79 ± 0.02 mg/dl vs. CsA + DMF 0.62 ± 0.04 mg/dl, P=0.001) and urea (CsA 66.9 ± 0.4 mg/dl vs. CsA + DMF 53.3 ± 2.6 mg/dl, P<0.0001) levels, as well as improvement of creatinine clearance. DMF also significantly decreased serum MDA and renal tissue MDA and MPO contents. The protein expression of NQO-1, a major cellular anti-oxidant and detoxifying enzyme was significantly enhanced by DMF administration in kidney. Conclusions Administration of DMF has a protective potential against CsA nephrotoxicity. The protection afforded by DMF is mediated in part through inhibiting oxidative stress and inflammation and enhancing the antioxidant capacity. PMID:25710612

  14. Dimethyl Fumarate Reduces Inflammatory Responses in Experimental Colitis

    PubMed Central

    Casili, Giovanna; Cordaro, Marika; Impellizzeri, Daniela; Bruschetta, Giuseppe; Paterniti, Irene; Cuzzocrea, Salvatore

    2016-01-01

    Background and Aims: Fumaric acid esters have been proven to be effective for the systemic treatment of psoriasis and multiple sclerosis. We aimed to develop a new treatment for colitis. Methods: We investigated the effect of dimethylfumarate [DMF, 10-30-100mg/kg] on an experimental model of colitis induced by dinitrobenzene sulphuric acid [DNBS]. We also evaluated the therapeutic activity of 7 weeks’ treatment with DMF [30mg/kg] on 9-week-old IL-10KO mice that spontaneously develop a T helper-1 [Th1]-dependent chronic enterocolitis after birth, that is fully established at 8–10 weeks of age. The mechanism of this pharmacological potential of DMF [10 μM] was investigated in colonic epithelial cell monolayers [Caco-2] exposed to H2O2. The barrier function was evaluated by the tight junction proteins. Results: The treatment with DMF significantly reduced the degree of haemorrhagic diarrhoea and weight loss caused by administration of DNBS. DMF [30 and 100mg/kg] also caused a substantial reduction in the degree of colon injury, in the rise in myeloperoxidase [MPO] activity, and in the increase in tumour necrosis factor [TNF]-α expression, as well as in the up-regulation of ICAM-1 caused by DNBS in the colon. Molecular studies demonstrated that DMF impaired NF-κB signalling via reduced p65 nuclear translocalisation. DMF induced a stronger antioxidant response as evidenced by a higher expression of Mn-superoxide dismutase. Moreover, DMF protected human intestinal epithelial cells against H2O2-induced barrier dysfunction, restoring ZO-1 occludin expression, via the HO-1 pathway. Conclusions: DMF treatment reduces the degree of colitis caused by DNBS. We propose that DMF treatment may be useful in the treatment of inflammatory bowel disease. PMID:26690241

  15. Bioconversion of fumaric acid to L-malic acid by the bacteria of the genus Nocardia.

    PubMed

    Hronská, Helena; Tokošová, Silvia; Pilniková, Anna; Krištofíková, Ľudmila; Rosenberg, Michal

    2015-01-01

    The bacterial strains of the genus Nocardia were used for the bioconversion of fumaric acid to L-malic acid. The ability of the bacterial strain Nocardia sp. CCM 4837/A to produce L-malic acid from fumaric acid was investigated under various conditions. The optimal temperature for the bioconversion was approximately 37 °C, and the optimal pH was around 8.0. The addition of an inductor (fumarate salt) to the fermentation medium was necessary to enhance enzyme activity. The presence of detergent Triton X-100 (0.02-0.1 %) in the reaction mixture rapidly increased the enzyme activity of fumarase. The specific fumarase activity of intact cells Nocardia sp. CCM 4837/A increased from 2.8 to 75 U/mg after optimising the experimental conditions described here. Pretreatment of the Nocardia cells with malonate was not necessary because succinate was not detected as a by-product under our experimental conditions.

  16. Structure and Function of Benzylsuccinate Synthase and Related Fumarate-Adding Glycyl Radical Enzymes.

    PubMed

    Heider, Johann; Szaleniec, Maciej; Martins, Berta M; Seyhan, Deniz; Buckel, Wolfgang; Golding, Bernard T

    2016-01-01

    The pathway of anaerobic toluene degradation is initiated by a remarkable radical-type enantiospecific addition of the chemically inert methyl group to the double bond of a fumarate cosubstrate to yield (R)-benzylsuccinate as the first intermediate, as catalyzed by the glycyl radical enzyme benzylsuccinate synthase. In recent years, it has become clear that benzylsuccinate synthase is the prototype enzyme of a much larger family of fumarate-adding enzymes, which play important roles in the anaerobic metabolism of further aromatic and even aliphatic hydrocarbons. We present an overview on the biochemical properties of benzylsuccinate synthase, as well as its recently solved structure, and present the results of an initial structure-based modeling study on the reaction mechanism. Moreover, we compare the structure of benzylsuccinate synthase with those predicted for different clades of fumarate-adding enzymes, in particular the paralogous enzymes converting p-cresol, 2-methylnaphthalene or n-alkanes.

  17. Preservation of acidified cucumbers with a combination of fumaric acid and cinnamaldehyde that target lactic acid bacteria and yeasts

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The naturally occurring compound, fumaric acid, was evaluated as a potential preservative for the long-term storage of cucumbers. Fumaric acid inhibited growth of lactic acid bacteria (LAB) in an acidified cucumber juice medium model system resembling conditions that could allow preservation of cucu...

  18. Study of Vitamins and Dietary Supplements Containing Ferrous Fumarate and Ferrous Sulfate Using Mössbauer Spectroscopy

    NASA Astrophysics Data System (ADS)

    Oshtrakh, M. I.; Novikov, E. G.; Dubiel, S. M.; Semionkin, V. A.

    2010-07-01

    A study of several samples of vitamins and dietary supplements containing ferrous fumarate and ferrous sulfate was carried out using Mössbauer spectroscopy with a high velocity resolution. A presence of ferrous and ferric impurities was revealed. Small variations of Mössbauer hyperfine parameters were found for both ferrous fumarates and ferrous sulfates in the investigated medicines.

  19. pH-Dependent Uptake of Fumaric Acid in Saccharomyces cerevisiae under Anaerobic Conditions

    PubMed Central

    Jamalzadeh, Elaheh; Verheijen, Peter J. T.; Heijnen, Joseph J.

    2012-01-01

    Microbial production of C4 dicarboxylic acids from renewable resources has gained renewed interest. The yeast Saccharomyces cerevisiae is known as a robust microorganism and is able to grow at low pH, which makes it a suitable candidate for biological production of organic acids. However, a successful metabolic engineering approach for overproduction of organic acids requires an incorporation of a proper exporter to increase the productivity. Moreover, low-pH fermentations, which are desirable for facilitating the downstream processing, may cause back diffusion of the undissociated acid into the cells with simultaneous active export, thereby creating an ATP-dissipating futile cycle. In this work, we have studied the uptake of fumaric acid in S. cerevisiae in carbon-limited chemostat cultures under anaerobic conditions. The effect of the presence of fumaric acid at different pH values (3 to 5) has been investigated in order to obtain more knowledge about possible uptake mechanisms. The experimental results showed that at a cultivation pH of 5.0 and an external fumaric acid concentration of approximately 0.8 mmol · liter−1, the fumaric acid uptake rate was unexpectedly high and could not be explained by diffusion of the undissociated form across the plasma membrane alone. This could indicate the presence of protein-mediated import. At decreasing pH levels, the fumaric acid uptake rate was found to increase asymptotically to a maximum level. Although this observation is in accordance with protein-mediated import, the presence of a metabolic bottleneck for fumaric acid conversion under anaerobic conditions could not be excluded. PMID:22113915

  20. Fumaric acid microenvironment tablet formulation and process development for crystalline cenicriviroc mesylate, a BCS IV compound.

    PubMed

    Menning, Mark M; Dalziel, Sean M

    2013-11-04

    Cenicriviroc mesylate (CVC) is a potent dual antagonist of C-C chemokine receptor type 5 (CCR5) and C-C chemokine receptor type 2 (CCR2) in phase 2b development as an entry inhibitor for HIV-1 infection treatment.1,2 CVC is a weak base exhibiting BCS IV characteristics with a highly pH dependent solubility profile (>100 mg/mL for pH < 2 and <0.2 μg/mL for pH > 4) and low Caco-2 cell line permeability. Previous tablet formulations of CVC, including spray-dried dispersion and a wet granulation with citric acid, had been found unacceptable for commercial use due to chemical and physical instability or unacceptably high excipient loading precluding fixed-dose combinability. A high drug loading, 26% (w/w), acidic microenvironment tablet formulation with fumaric acid solubilizer (1:1 CVC/fumaric acid) and a dry granulation process was developed iteratively through a sequence of prototypes characterized by beagle dog absorption studies, focused beam reflectance measurement (FBRM), dynamic vapor sorption (DVS), and accelerated stability testing. The fumaric acid based dry granulated product demonstrated a mean bioavailability comparable to an oral solution dose in a dog model. Stability and moisture sensitivity of the formulation were improved via the dry granulation process technique and the use of fumaric acid. It is hypothesized that the observed slow dissolution kinetics of fumaric acid prolongs an acidic microenvironment around the agglomerated CVC crystals and excipients leading to increased CVC dissolution and thereby absorption. The fumaric acid formulation also demonstrated absorption resilience to gastric pH extremes in a dog model. This optimized formulation and process enables CVC to be a viable candidate for current HIV treatment paradigms of single once daily fixed-dose combination products.

  1. Use of Response Surface Methodology in the Formulation and Optimization of Bisoprolol Fumarate Matrix Tablets for Sustained Drug Release

    PubMed Central

    Malakar, Jadupati; Nayak, Amit Kumar; Goswami, Soumita

    2012-01-01

    The aim of this investigation was to develop and optimize bisoprolol fumarate matrix tablets for sustained release application by response surface methodology based on 23 factorial design. The effects of the amounts of calcium alginate, HPMC K4M, and Carbopol 943 in bisoprolol fumarate matrix tablets on the properties of bisoprolol fumarate sustained release matrix tablets like drug release and hardness were analyzed and optimized. The observed responses were coincided well with the predicted values by the experimental design. The optimized bisoprolol fumarate matrix tablets showed prolonged sustained release of bisoprolol fumarate over 6 hours. These matrix tablets followed the first-order model with anomalous (non-Fickian) diffusion mechanism. PMID:23378933

  2. Effects of fumarate on ruminal ammonia accumulation and fiber digestion in vitro and nutrient utilization in dairy does.

    PubMed

    Yu, C-W; Chen, Y-S; Cheng, Y-H; Cheng, Y-S; Yang, C-M J; Chang, C-T

    2010-02-01

    The objective of this study was to evaluate effects of fumarate on ruminal ammonia accumulation and fiber digestion in vitro and on feed intake and nutrient utilization in dairy does. Batch cultures of mixed rumen microorganisms were used to study effects of different concentrations of fumarate on fermentation with various N sources (ammonia as ammonium bicarbonate, casein amino acids, casein peptides, gelatin peptides) and feeds (bermudagrass hay, mixed diet of 60% bermudagrass hay plus 40% concentrate) for 6 and 24h, respectively. Substrates were grouped into pairs for separate incubations. Monosodium fumarate was added to incubation tubes to achieve final concentrations of 0, 5, and 10mM fumarate. More ammonia accumulated at the end of incubation with added ammonium bicarbonate. Ammonia concentration was higher for peptide compared with amino acid incubation, and for casein peptide compared with gelatin peptide. Addition of fumarate linearly decreased ammonia for all N sources and for feed substrates. For all substrate types, fumarate treatment increased acetate, propionate, and total volatile fatty acids (VFA), decreased acetate to propionate ratio, and tended to reduce branched-chain VFA. Digestion of feed neutral detergent fiber (NDF) by rumen microorganisms was improved by fumarate along with elevated endoglucanase and xylanase activities. In an animal metabolism experiment, 8 dairy does (4 per treatment) were used in a completely randomized design for 21 d. Does were fed a hay plus concentrate diet without (control) or with fumarate (6 g/head per day) supplementation to determine feed intake, whole-tract nutrient digestibility, and N utilization. Fumarate treatment did not affect weight change or feed intake but increased whole-tract digestion of gross energy, crude protein, and cellulose. Digested N was increased by fumarate supplementation; however, N retention was unaffected. Plasma glucose concentration was elevated with fumarate but urea N

  3. Reduced-intensity conditioning for allogeneic haematopoietic stem cell transplantation in relapsed and refractory Hodgkin lymphoma: impact of alemtuzumab and donor lymphocyte infusions on long-term outcomes.

    PubMed

    Peggs, Karl S; Sureda, Anna; Qian, Wendi; Caballero, Dolores; Hunter, Ann; Urbano-Ispizua, Alvaro; Cavet, James; Ribera, Josep M; Parker, Anne; Canales, Miguel; Mahendra, Premini; Garcia-Conde, Javier; Milligan, Donald; Sanz, Guillermo; Thomson, Kirsty; Arranz, Reyes; Goldstone, Anthony H; Alvarez, Ivan; Linch, David C; Sierra, Jorge; Mackinnon, Stephen

    2007-10-01

    The introduction of reduced-intensity conditioning (RIC) has enabled the role of allogeneic transplantation to be re-evaluated in Hodgkin lymphoma (HL). While T-cell depletion reduces graft-versus-host disease (GvHD), it potentially abrogates graft-versus-tumour activity and increases infective complications. We compared the results in 67 sibling donor transplantations following RIC in multiply relapsed patients from two national phase II studies conditioned with fludarabine/melphalan. One used cyclosporine/alemtuzumab (MF-A, n = 31), the other used cyclosporine/methotrexate (MF, n = 36) as GvHD prophylaxis. There was a small excess of chemorefractory cases in the MF cohort (P = NS). MF-A resulted in significantly lower incidences of non-relapse mortality, acute and chronic GvHD, but no significant excess of relapse/progression. Post donor lymphocyte infusion (DLI) disease responses occurred in 8/14 (57%) and 6/11 (55%) patients in the MF-A and MF groups, respectively. Current progression-free survival (CPFS) was superior with MF-A (univariate analysis), with durable responses to DLI contributing to the favourable outcome (43% vs. 25%, P = 0.0356). Disease status at transplantation significantly influenced overall survival (P = 0.0038) and CPFS (P = 0.0014), retaining significance in multivariate analyses, which demonstrated a trend towards improved CPFS with T-cell depletion (P = 0.0939). These data suggest that alemtuzumab significantly reduced GvHD without resulting in a deleterious impact on survival outcomes following RIC in HL, and that durable responses to DLI may be more common following the inclusion of alemtuzumab in the conditioning protocol.

  4. Fumarate Production by Torulopsis glabrata: Engineering Heterologous Fumarase Expression and Improving Acid Tolerance

    PubMed Central

    Chen, Xiulai; Song, Wei; Gao, Cong; Qin, Wen; Luo, Qiuling; Liu, Jia; Liu, Liming

    2016-01-01

    Fumarate is a well-known biomass building block compound. However, the poor catalytic efficiency of fumarase is one of the major factors preventing its widespread production. To address this issue, we selected residues 159HPND162 of fumarase from Rhizopus oryzae as targets for site-directed mutagenesis based on molecular docking analysis. Twelve mutants were generated and characterized in detail. Kinetic studies showed that the Km values of the P160A, P160T, P160H, N161E, and D162W mutants were decreased, whereas Km values of H159Y, H159V, H159S, N161R, N161F, D162K, and D162M mutants were increased. In addition, all mutants displayed decreased catalytic efficiency except for the P160A mutant, whose kcat/Km was increased by 33.2%. Moreover, by overexpressing the P160A mutant, the engineered strain T.G-PMS-P160A was able to produce 5.2 g/L fumarate. To further enhance fumarate production, the acid tolerance of T.G-PMS-P160A was improved by deleting ade12, a component of the purine nucleotide cycle, and the resulting strain T.G(△ade12)-PMS-P160A produced 9.2 g/L fumarate. The strategy generated in this study opens up new avenues for pathway optimization and efficient production of natural products. PMID:27711153

  5. 21 CFR 520.82b - Aminopropazine fumarate, neomycin sulfate tablets.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... contains both aminopropazine fumarate equivalent to 25 milligrams of aminopropazine base and neomycin sulfate equivalent to 50 milligrams of neomycin base. (b) Sponsor. See No. 000061 in § 510.600(c) of this... administered at a dosage level of one to two tablets per 10 pounds of body weight twice daily for 3 days.1...

  6. Total synthesis of (−)-dihydroprotolichesterenic acid via diastereoselective conjugate addition to chiral fumarates

    PubMed Central

    Hethcox, J. Caleb; Shanahan, Charles S.; Martin, Stephen F.

    2013-01-01

    A diastereoselective conjugate addition of a variety of monoorganocuprates, Li[RCuI], to chiral fumarates to provide funtionalized succinates has been developed. The utility of this reaction is demonstrated in a concise total synthesis of (−)-dihydroprotolichesterenic acid that required only four steps and proceeded in an overall 31% yield. PMID:23539490

  7. Diastereoselective addition of monoorganocuprates to a chiral fumarate: reaction development and synthesis of (-)-dihydroprotolichesterinic acid.

    PubMed

    Hethcox, J Caleb; Shanahan, Charles S; Martin, Stephen F

    2015-09-16

    Recent studies of diastereoselective conjugate additions of monoorganocuprates, Li[RCuI], to chiral γ-alkoxycrotonates and fumarates are disclosed. This methodology was applied to the shortest total synthesis of (-)-dihydroprotolichesterinic acid to date, but several attempts to prepare other succinate-derived natural products, such as pilocarpine and antrodin E, were unsuccessful.

  8. Food Waste Fermentation to Fumaric Acid by Rhizopus arrhizus RH7-13.

    PubMed

    Liu, Huan; Ma, Jingyuan; Wang, Meng; Wang, Weinan; Deng, Li; Nie, Kaili; Yue, Xuemin; Wang, Fang; Tan, Tianwei

    2016-12-01

    Fumaric acid as a four-carbon unsaturated dicarboxylic acid is widely used in the food and chemical industries. Food waste (FW), rich in carbohydrates and protein, is a promising potential feedstock for renewable bio-based chemicals. In this research, we investigated the capability of Rhizopus arrhizus RH7-13 in producing fumaric acid from FW. The liquid fraction of the FW (L-FW) was proven to be the best seed culture medium in our research. When it was however used to be fermentation medium, the yield of fumaric acid reached 32.68 g/L, at a volumetric production of 0.34 g/L h. The solid fraction of FW mixed with water (S-FW) could also be used as fermentation medium when a certain amount of glucose was added, and the yield of fumaric acid reached 31.26 g/L. The results indicated that both fractions of FW could be well utilized in fermentation process and it could replace a part of common carbon, nitrogen, and nutrient. The process has an application potential since reducing the costs of raw materials.

  9. The Campylobacter jejuni RacRS system regulates fumarate utilization in a low oxygen environment

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The natural environment of the human pathogen Campylobacter jejuni is the gastrointestinal tract of warm blooded animals. In the gut, the availability of oxygen is limited; therefore, less efficient electron acceptors such as nitrate or fumarate are used by C. jejuni. C. jejuni has a highly branched...

  10. Production of fumaric acid from biodiesel-derived crude glycerol by Rhizopus arrhizus.

    PubMed

    Zhou, Yuqing; Nie, Kaili; Zhang, Xin; Liu, Shihong; Wang, Meng; Deng, Li; Wang, Fang; Tan, Tianwei

    2014-07-01

    This work investigated the capability of Rhizopus arrhizus to assimilate biodiesel-derived crude glycerol and convert it into fumaric acid. After optimizing the initial glycerol concentration, spore inoculum and yeast extract concentration, smaller pellets (0.7 mm) and higher biomass (3.11 g/L) were obtained when R. arrhizus grew on crude glycerol. It was found that crude glycerol was more suitable than glucose for smaller R. arrhizus pellet forming. When 80 g/L crude glycerol was used as carbon source, the fumaric acid production of 4.37 g/L was obtained at 192 h. With a highest concentration of 22.81 g/L achieved in the co-fermentation of crude glycerol (40 g/L) and glucose (40 g/L) at 144 h, the fumaric acid production was enhanced by 553.6%, compared to the fermentation using glycerol (80 g/L) as sole carbon source. Moreover, the production cost of fumaric acid in co-fermentation was reduced by approximately 14% compared to glucose fermentation.

  11. 21 CFR 520.82b - Aminopropazine fumarate, neomycin sulfate tablets.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Aminopropazine fumarate, neomycin sulfate tablets. 520.82b Section 520.82b Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS §...

  12. Hydro-thermal synthesis and crystal structure of a new lanthanum(III) coordination polymer with fumaric acid.

    PubMed

    Anana, Hayet; Trifa, Chahrazed; Bouacida, Sofiane; Boudaren, Chaouki; Merazig, Hocine

    2015-05-01

    The title compound, poly[di-aqua-tris-(μ4-but-2-enedioato)(μ2-but-2-enedioic acid)dilanthanum(III)], [La2(C4H2O4)3(C4H4O4)(H2O)2] n , was synthesized by the reaction of lanthanum chloride penta-hydrate with fumaric acid under hydro-thermal conditions. The asymmetric unit comprises an La(III) cation, one and a half fumarate dianions (L (2-)), one a half-mol-ecule of fumaric acid (H2 L) and one coordinated water mol-ecule. Each La(III) cation has the same nine-coordinate environment and is surrounded by eight O atoms from seven distinct fumarate moieties, including one proton-ated fumarate unit and one water mol-ecule in a distorted tricapped trigonal-prismatic environment. The LaO8(H2O) polyhedra centres are edge-shared through three carboxyl-ate bridges of the fumarate ligand, forming chains in three dimensions to construct the MOF. The crystal structure is stabilized by O-H⋯O hydrogen-bond inter-actions between the coordin-ated water mol-ecule and the carboxyl-ate O atoms, and also between oxygen atoms of fumaric acid.

  13. Phase II study of alemtuzumab-rituximab therapy in previously untreated patients with chronic lymphocytic leukemia: short- and long-term outcomes.

    PubMed

    Frankfurt, Olga; Ma, Shuo; Gordon, Leo; Winter, Jane N; Horowitz, Jeanne M; Rademaker, Alfred; Weitner, Bing Bing; Peterson, LoAnn C; Altman, Jessica K; Tallman, Martin S; Petrich, Adam; Rosen, Steven T

    2015-02-01

    We investigated the safety, efficacy, and long-term outcomes of alemtuzumab and rituximab (AR) combination therapy in previously untreated patients with CLL. Thirty patients, ages 28-80 years, 47% older than 60 years, 90% Rai clinical stages II-IV, and 67% without favorable cytogenetics received AR. Based on the NCI-WG 1996 criteria, OR was 100%, with 60% CR. With CT scans OR was 70%, with 23% CR, 47% PR, and 30% SD. Sixty-seven percent of patients showed no evidence of MRD in the bone marrow by 6-color flow cytometry. Median PFS, TFS, and 5-year OS were 24.4, 50.7 months, and 80%, respectively. Grade 3/4 neutropenia and thrombocytopenia were reported in 30% and 7% of patients, respectively. CMV reactivation, asymptomatic in all but one patient, occurred in 8 patients. Immunotherapy with alemtuzumab and rituximab results in robust responses and long asymptomatic therapy-free intervals. It is well tolerated with infrequent, predictable, and easily managed complications.

  14. Anaerobic energy-yielding reaction associated with transhydrogenation from glycerol 3-phosphate to fumarate by an Escherichia coli system.

    PubMed

    Miki, K; Lin, E C

    1975-12-01

    A particulate subcellular fraction from Escherichia coli K-12 induced in anaerobic sn-glycerol 3-phosphate (G3P) dehydrogenase and fumarate reductase can catalyze under anaerobic conditions the transfer of hydrogens from G3P to fumarate, with attendant generation of high-energy phosphate. The phsophorylation process is more sensitive than the transhydrogenation process to inhibition by the detergent Triton X-100. The same is true with respect to sensitivity to sodium azide, carbonyl cyanide m-chlorophenylhydrazone and N,N'-dicyclohexylcarbodiimide. Such a preparation derived from cells with beta-galactoside permease can accumulate thiomethyl beta-D-galactoside anaerobically, and the accumulation can be stimulated twofold by adding G3P and fumarate. Mutants lacking the membrane-associated Mg2+-dependent adenosine triphosphatase cannot grow anaerobically on glycerol with fumarate as the hydrogen acceptor, although they can grow aerobically on glycerol alone.

  15. Anaerobic energy-yielding reaction associated with transhydrogenation from glycerol 3-phosphate to fumarate by an Escherichia coli system.

    PubMed Central

    Miki, K; Lin, E C

    1975-01-01

    A particulate subcellular fraction from Escherichia coli K-12 induced in anaerobic sn-glycerol 3-phosphate (G3P) dehydrogenase and fumarate reductase can catalyze under anaerobic conditions the transfer of hydrogens from G3P to fumarate, with attendant generation of high-energy phosphate. The phsophorylation process is more sensitive than the transhydrogenation process to inhibition by the detergent Triton X-100. The same is true with respect to sensitivity to sodium azide, carbonyl cyanide m-chlorophenylhydrazone and N,N'-dicyclohexylcarbodiimide. Such a preparation derived from cells with beta-galactoside permease can accumulate thiomethyl beta-D-galactoside anaerobically, and the accumulation can be stimulated twofold by adding G3P and fumarate. Mutants lacking the membrane-associated Mg2+-dependent adenosine triphosphatase cannot grow anaerobically on glycerol with fumarate as the hydrogen acceptor, although they can grow aerobically on glycerol alone. PMID:127785

  16. [Atypical leiomyoma in a patient with cutaneous leiomyomatosis and mutation of the enzyme fumarate hydratase].

    PubMed

    Calderón-Komáromy, Angélica; Arias-Palomo, Dolores; Tardío, Juan C; Freites-Martínez, Azael; Borbujo, Jesús

    2016-03-01

    We report the case of a 56 year-old male with an atypical leiomyoma in the context of a cutaneous leiomyomatosis and a family history of uterine leiomyomatosis. The genetic study revealed a mutation in the gene for the enzyme fumarate hydratase, but he has not had any renal malignancy so far. Atypical leiomyoma is a rare tumor that usually presents as a single lesion and is exceptional in patients with cutaneous leiomyomatosis. The relation between fumarate hydratase enzyme mutations with multiple leiomyomas, uterine leiomyomatosis and an increased risk of developing kidney cancer is widely known. However, the role of these mutations in the development of atypical leiomyomas is still impossible to clarify given the few cases reported in the literature.

  17. Direct fungal fermentation of lignocellulosic biomass into itaconic, fumaric, and malic acids: current and future prospects.

    PubMed

    Mondala, Andro H

    2015-04-01

    Various economic and environmental sustainability concerns as well as consumer preference for bio-based products from natural sources have paved the way for the development and expansion of biorefining technologies. These involve the conversion of renewable biomass feedstock to fuels and chemicals using biological systems as alternatives to petroleum-based products. Filamentous fungi possess an expansive portfolio of products including the multifunctional organic acids itaconic, fumaric, and malic acids that have wide-ranging current applications and potentially addressable markets as platform chemicals. However, current bioprocessing technologies for the production of these compounds are mostly based on submerged fermentation, which necessitates physicochemical pretreatment and hydrolysis of lignocellulose biomass to soluble fermentable sugars in liquid media. This review will focus on current research work on fungal production of itaconic, fumaric, and malic acids and perspectives on the potential application of solid-state fungal cultivation techniques for the consolidated hydrolysis and organic acid fermentation of lignocellulosic biomass.

  18. Application of acetate, lactate, and fumarate as electron donors in microbial fuel cell

    NASA Astrophysics Data System (ADS)

    Vasyliv, Oresta M.; Bilyy, Oleksandr I.; Ferensovych, Yaroslav P.; Hnatush, Svitlana O.

    2013-09-01

    Microbial fuel cells (MFCs) are devices that use bacteria as the catalysts to oxidize organic and inorganic matter and generate current. Up to now, several classes of extracellular electron transfer mechanisms have been elucidated for various microorganisms. Shewanellaceae and Geobacteraceae families include the most of model exoelectrogenic microorganisms. Desulfuromonas acetoxidans bacterium inhabits aquatic sedimental sulfur-containing environments and is philogenetically close to representatives of Geobacteraceae family. Two chamber microbial fuel cell (0.3 l volume) was constructed with application of D. acetoxidans IMV B-7384 as anode biocatalyst. Acetic, lactic and fumaric acids were separately applied as organic electron donors for bacterial growth in constructed MFC. Bacterial cultivation in MFC was held during twenty days. Lactate oxidation caused electric power production with the highest value up to 0.071 mW on 64 hour of D. acetoxidans IMV B-7384 growth. Addition of acetic and fumaric acids into bacterial growth medium caused maximal power production up to 0.075 and 0.074 mW respectively on the 40 hour of their growth. Increasing of incubation time up to twentieth day caused decrease of generated electric power till 0.018 mW, 0.042 mW and 0.047 mW under usage of lactic, acetic and fumaric acids respectively by investigated bacteria. Power generation by D. acetoxidans IMV B-7384 was more stabile and durable under application of acetic and fumaric acids as electron donors in constructed MFC, than under addition of lactic acid in the same concentration into the growth medium.

  19. Fumarate and Succinate Regulate Expression of Hypoxia-inducible Genes via TET Enzymes*

    PubMed Central

    Laukka, Tuomas; Mariani, Christopher J.; Ihantola, Tuukka; Cao, John Z.; Hokkanen, Juho; Kaelin, William G.; Godley, Lucy A.; Koivunen, Peppi

    2016-01-01

    The TET enzymes are members of the 2-oxoglutarate-dependent dioxygenase family and comprise three isoenzymes in humans: TETs 1–3. These TETs convert 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC) in DNA, and high 5-hmC levels are associated with active transcription. The importance of the balance in these modified cytosines is emphasized by the fact that TET2 is mutated in several human cancers, including myeloid malignancies such as acute myeloid leukemia (AML). We characterize here the kinetic and inhibitory properties of Tets and show that the Km value of Tets 1 and 2 for O2 is 30 μm, indicating that they retain high activity even under hypoxic conditions. The AML-associated mutations in the Fe2+ and 2-oxoglutarate-binding residues increased the Km values for these factors 30–80-fold and reduced the Vmax values. Fumarate and succinate, which can accumulate to millimolar levels in succinate dehydrogenase and fumarate hydratase-mutant tumors, were identified as potent Tet inhibitors in vitro, with IC50 values ∼400–500 μm. Fumarate and succinate also down-regulated global 5-hmC levels in neuroblastoma cells and the expression levels of some hypoxia-inducible factor (HIF) target genes via TET inhibition, despite simultaneous HIFα stabilization. The combination of fumarate or succinate treatment with TET1 or TET3 silencing caused differential effects on the expression of specific HIF target genes. Altogether these data show that hypoxia-inducible genes are regulated in a multilayered manner that includes epigenetic regulation via TETs and 5-hmC levels in addition to HIF stabilization. PMID:26703470

  20. Glatiramer Acetate, Dimethyl Fumarate, and Monomethyl Fumarate Upregulate the Expression of CCR10 on the Surface of Natural Killer Cells and Enhance Their Chemotaxis and Cytotoxicity

    PubMed Central

    Maghazachi, Azzam A.; Sand, Kristin L.; Al-Jaderi, Zaidoon

    2016-01-01

    In vitro harnessing of immune cells is the most important advance in the field of cancer immunotherapy. Results shown in the current paper may be used to harness natural killer (NK) cells in vitro. It is observed that drugs used to treat multiple sclerosis such as glatiramer acetate, dimethyl fumarate, and monomethyl fumarate upregulate the expression of chemokines receptor 10 (CCR10) on the surface of human IL-2-activated NK cells. This is corroborated with increased chemotaxis of these cells toward the concentration gradients of the ligands for CCR10, namely CCL27 and CCL28. It is also demonstrated that these three drugs enhance NK cell cytotoxicity against tumor target cells, an activity that is abrogated by prior incubation of the cells with anti-CCR10 antibody. Because CCL27 and CCL28 are secreted by selective tumor types such as malignant melanoma, squamous cell carcinomas, and colorectal cancer, respectively, it is hypothesized that activated NK cells may be harnessed in vitro with any of these drugs before utilizing them as a therapeutic modality for cancer. PMID:27807435

  1. In vitro degradation of polymeric networks of poly(propylene fumarate) and the crosslinking macromer poly(propylene fumarate)-diacrylate.

    PubMed

    Timmer, Mark D; Ambrose, Catherine G; Mikos, Antonios G

    2003-02-01

    Polymeric networks of poly(propylene fumarate) (PPF) crosslinked with poly(propylene fumarate)-diacrylate (PPF-DA) are currently being investigated as an injectable, biodegradable bone cement. This study examined the effect of crosslinking density, medium pH, and the incorporation of a beta-tricalcium phosphate (beta-TCP) filler on the in vitro degradation of PPF/PPF-DA. Cylindrical specimens were submerged in buffered saline at 37 degrees C and the change in weight, geometry, and compressive mechanical properties were monitored over a 52-week period. All formulations showed an initial increase in modulus and yield strength over the first 12 weeks, achieving maxima of 1307+/-101 and 51+/-3MPa, respectively, for the beta-TCP composite. PPF/PPF-DA networks with the lower crosslinking density demonstrated the greatest degradation with a 17% mass loss. Samples in the lower buffer pH 5.0 compared to physiological pH 7.4 did not show any differences in mass loss, but exhibited a faster decrease in the compressive strength over time. The beta-TCP composites maintained their mechanical properties at the level following their initial increase. These results show that the degradation of PPF/PPF-DA networks can be controlled by the crosslinking density, accelerated at a lower pH, and prolonged with the incorporation of the beta-TCP filler.

  2. Spectroscopic investigation on cocrystal formation between adenine and fumaric acid based on infrared and Raman techniques.

    PubMed

    Du, Yong; Fang, Hong Xia; Zhang, Qi; Zhang, Hui Li; Hong, Zhi

    2016-01-15

    As an important component of double-stranded DNA, adenine has powerful hydrogen-bond capability, due to rich hydrogen bond donors and acceptors existing within its molecular structure. Therefore, it is easy to form cocrystal between adenine and other small molecules with intermolecular hydrogen-bond effect. In this work, cocrystal of adenine and fumaric acid has been characterized as model system by FT-IR and FT-Raman spectral techniques. The experimental results show that the cocrystal formed between adenine and fumaric acid possesses unique spectroscopical characteristic compared with that of starting materials. Density functional theory (DFT) calculation has been performed to optimize the molecular structures and simulate vibrational modes of adenine, fumaric acid and the corresponding cocrystal. Combining the theoretical and experimental vibrational results, the characteristic bands corresponding to bending and stretching vibrations of amino and carbonyl groups within cocrystal are shifted into lower frequencies upon cocrystal formation, and the corresponding bond lengths show some increase due to the effect of intermolecular hydrogen bonding. Different vibrational modes shown in the experimental spectra have been assigned based on the simulation DFT results. The study could provide experimental and theoretical benchmarks to characterize cocrystal formed between active ingredients and cocrystal formers and also the intermolecular hydrogen-bond effect within cocrystal formation process by vibrational spectroscopic techniques.

  3. Spectroscopic investigation on cocrystal formation between adenine and fumaric acid based on infrared and Raman techniques

    NASA Astrophysics Data System (ADS)

    Du, Yong; Fang, Hong Xia; Zhang, Qi; Zhang, Hui Li; Hong, Zhi

    2016-01-01

    As an important component of double-stranded DNA, adenine has powerful hydrogen-bond capability, due to rich hydrogen bond donors and acceptors existing within its molecular structure. Therefore, it is easy to form cocrystal between adenine and other small molecules with intermolecular hydrogen-bond effect. In this work, cocrystal of adenine and fumaric acid has been characterized as model system by FT-IR and FT-Raman spectral techniques. The experimental results show that the cocrystal formed between adenine and fumaric acid possesses unique spectroscopical characteristic compared with that of starting materials. Density functional theory (DFT) calculation has been performed to optimize the molecular structures and simulate vibrational modes of adenine, fumaric acid and the corresponding cocrystal. Combining the theoretical and experimental vibrational results, the characteristic bands corresponding to bending and stretching vibrations of amino and carbonyl groups within cocrystal are shifted into lower frequencies upon cocrystal formation, and the corresponding bond lengths show some increase due to the effect of intermolecular hydrogen bonding. Different vibrational modes shown in the experimental spectra have been assigned based on the simulation DFT results. The study could provide experimental and theoretical benchmarks to characterize cocrystal formed between active ingredients and cocrystal formers and also the intermolecular hydrogen-bond effect within cocrystal formation process by vibrational spectroscopic techniques.

  4. Fumarate-Mediated Inhibition of Erythrose Reductase, a Key Enzyme for Erythritol Production by Torula corallina

    PubMed Central

    Lee, Jung-Kul; Koo, Bong-Seong; Kim, Sang-Yong

    2002-01-01

    Torula corallina, a strain presently being used for the industrial production of erythritol, has the highest erythritol yield ever reported for an erythritol-producing microorganism. The increased production of erythritol by Torula corallina with trace elements such as Cu2+ has been thoroughly reported, but the mechanism by which Cu2+ increases the production of erythritol has not been studied. This study demonstrated that supplemental Cu2+ enhanced the production of erythritol, while it significantly decreased the production of a major by-product that accumulates during erythritol fermentation, which was identified as fumarate by instrumental analyses. Erythrose reductase, a key enzyme that converts erythrose to erythritol in T. corallina, was purified to homogeneity by chromatographic methods, including ion-exchange and affinity chromatography. In vitro, purified erythrose reductase was significantly inhibited noncompetitively by increasing the fumarate concentration. In contrast, the enzyme activity remained almost constant regardless of Cu2+ concentration. This suggests that supplemental Cu2+ reduced the production of fumarate, a strong inhibitor of erythrose reductase, which led to less inhibition of erythrose reductase and a high yield of erythritol. This is the first report that suggests catabolite repression by a tricarboxylic acid cycle intermediate in T. corallina. PMID:12200310

  5. Molecular characterization of potato fumarate hydratase and functional expression in Escherichia coli.

    PubMed Central

    Nast, G; Müller-Röber, B

    1996-01-01

    The tricarboxylic acid cycle enzyme fumarase (fumarate hydratase; EC 4.2.1.2) catalyzes the reversible hydration of fumarate to L-malate. We report the molecular cloning of a cDNA (StFum-1) that encodes fumarase from potato (Solanum tuberosum L.). RNA blot analysis demonstrated that StFum-1 is most strongly expressed in flowers, immature leaves, and tubers. The deduced protein contains a typical mitochondrial targeting peptide and has a calculated molecular mass of 50.1 kD (processed form). Potato fumarase complemented a fumarase-deficient Escherichia coli mutation for growth on minimal medium that contains acetate or fumarate as the sole carbon source, indicating that functional plant protein was produced in the bacterium. Antiserum raised against the recombinant plant enzyme recognized a 50-kD protein in wild-type but not in StFum-1 antisense plants, indicating specificity of the immunoreaction. A protein of identical size was also detected in isolated potato tuber mitochondria. Although elevated activity of fumarase was previously reported for guard cells (as compared with mesophyll cells), additional screening and genomic hybridization data reported here do not support the hypothesis that a second fumarase gene is expressed in potato guard cells. PMID:8938419

  6. Fumaric acid: an overlooked form of fixed carbon in Arabidopsis and other plant species

    SciTech Connect

    Chia, D.W.; Yoder, T.J.; Reiter, W.D.; Gibson, S.I.

    2000-10-01

    Photoassimilates are used by plants for production of energy, as carbon skeletons and in transport of fixed carbon between different plant organs. Many studies have been devoted to characterizing the factors that. regulate photoassimilate concentrations in different plant species. Most studies examining photoassimilate concentrations in C{sub 3} plants have focused on analyzing starch and soluble sugars. However, work presented here demonstrates that a number of C{sub 3} plants, including the popular model organism Arabidopsis thaliana (L.) Heynh., and agriculturally important plants, such as soybean [Glycine ma (L.) Merr.], contain significant quantities of furnaric acid. In fact, furnaric acid can accumulate to levels of several mg per g fresh weight in A-abidopsis leaves, often exceeding starch and soluble sugar levels. Furnaric acid is a component of the tricarboxylic acid cycle and, like starch and soluble sugars, can be metabolized to yield energy and carbon skeletons for production of other compounds. Fumaric acid concentrations increase with plant age and light intensity in Arabidopsis leaves. Arabidopsis phloem exudates contain significant quantities of fumaric acid, raising the possibility that fumaric acid may function in carbon transport.

  7. Dimethyl fumarate in the management of multiple sclerosis: appropriate patient selection and special considerations.

    PubMed

    Prosperini, Luca; Pontecorvo, Simona

    2016-01-01

    Delayed-release dimethyl fumarate (DMF), also known as gastroresistant DMF, is the most recently approved oral disease-modifying treatment (DMT) for relapsing multiple sclerosis. Two randomized clinical trials (Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS [DEFINE] and Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis [CONFIRM]) demonstrated significant efficacy in reducing relapse rate and radiological signs of disease activity, as seen on magnetic resonance imaging. The DEFINE study also indicated a significant effect of DMF on disability worsening, while the low incidence of confirmed disability worsening in the CONFIRM trial rendered an insignificant reduction among the DMF-treated groups when compared to placebo. DMF also demonstrated a good safety profile and acceptable tolerability, since the most common side effects (gastrointestinal events and flushing reactions) are usually transient and mild to moderate in severity. Here, we discuss the place in therapy of DMF for individuals with relapsing multiple sclerosis, providing a tentative therapeutic algorithm to manage newly diagnosed patients and those who do not adequately respond to self-injectable DMTs. Literature data supporting the potential role of DMF as a first-line therapy are presented. The possibility of using DMF as switching treatment or even as an add-on strategy in patients with breakthrough disease despite self-injectable DMTs will also be discussed. Lastly, we argue about the role of DMF as an exit strategy from natalizumab-treated patients who are considered at risk for developing multifocal progressive leukoencephalopathy.

  8. Aliskiren attenuates bleomycin-induced pulmonary fibrosis in rats: focus on oxidative stress, advanced glycation end products, and matrix metalloproteinase-9.

    PubMed

    Abuelezz, Sally A; Hendawy, Nevien; Osman, Wesam M

    2016-08-01

    Pulmonary fibrosis is a progressive lung disorder with high mortality rate and limited successful treatment. This study was designed to assess the potential anti-oxidant and anti-fibrotic effects of aliskiren (Alsk) during bleomycin (BLM)-induced pulmonary fibrosis. Male Wistar rats were used as control untreated or treated with the following: a single dose of 2.5 mg/kg of BLM endotracheally and BLM and Alsk (either low dose 30 mg/kg/day or high dose 60 mg/kg/day), and another group was given Alsk 60 mg/kg/day alone. Alsk was given by gavage. Alsk anti-oxidant and anti-fibrotic effects were assessed. BLM significantly increased relative lung weight and the levels of lactate dehydrogenase and total and differential leucocytic count in bronchoalveolar lavage that was significantly ameliorated by high-dose Alsk treatment. As markers of oxidative stress, BLM caused a significant increase in the levels of lipid peroxides and nitric oxide accompanied with a significant decrease of superoxide dismutase and glutathione transferase enzymes. High-dose Alsk treatment restored these markers toward normal values. Alsk counteracted the overexpression of advanced glycation end products, matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinases-1 in lung tissue induced by BLM. Fibrosis assessed by measuring hydroxyproline content, which markedly increased in the BLM group, was also significantly reduced by Alsk. These were confirmed by histopathological and immunohistochemical examination which revealed that Alsk attenuates signs of pulmonary fibrosis and decreased the overexpressed MMP-9 and transforming growth factor β1. Collectively, these findings indicate that Alsk has a potential anti-fibrotic effect beside its anti-oxidant activity.

  9. Phase I-II study of lenalidomide and alemtuzumab in refractory chronic lymphocytic leukemia (CLL): effects on T cells and immune checkpoints.

    PubMed

    Winqvist, Maria; Mozaffari, Fariba; Palma, Marzia; Eketorp Sylvan, Sandra; Hansson, Lotta; Mellstedt, Håkan; Österborg, Anders; Lundin, Jeanette

    2017-01-01

    This phase I-II study explored safety, immunomodulatory and clinical effects of lenalidomide (weeks 1-16) and alemtuzumab (weeks 5-16) in 23 patients with refractory chronic lymphocytic leukemia. Most patients had Rai stage III/IV disease and were heavily pretreated (median 4 prior therapies), and 61% had del(17p)/del(11q). Eleven of 19 evaluable patients (58%) responded, with a median response duration of 12 months (1-29+); time to progression was short in non-responders. Lenalidomide had a narrow therapeutic dose range, 2.5 mg/day was not efficient, and maximum tolerated dose was 5 mg/day. Grade 3-4 neutropenia and thrombocytopenia occurred in 84 and 55%, 30% had febrile neutropenia, and CMV-reactivation requiring valganciclovir occurred in 30% of patients. The frequency of proliferating (Ki67(+)) CD8(+) T cells was increased at week 4, with further increase in both the CD4(+) and CD8(+) subsets (p < 0.01 and <0.05), which was accompanied by significant upregulation of HLA-DR after addition of alemtuzumab. Antigen-experienced cells increased at week 4 as the frequency of effector memory cells increased in the CD8(+) subset (p < 0.003), while effector cells decreased in both the CD8(+) and CD4(+) subsets (p < 0.0001 and p < 0.01). The Th1/Th2 balance was unchanged at week 4 but shifted toward a Th2 profile after combination therapy. At end of treatment, the frequency of Th17 and regulatory T cells was reduced (p < 0.01), naïve T cells decreased, and effector memory T cells increased (p < 0.05 and p < 0.01). Granzyme B(+) T cells increased at 30-week follow-up (p < 0.05). PD-1 expression was unaffected. In conclusion, low-dose lenalidomide and alemtuzumab induced major perturbations of T cells, including increased proliferative activity and cytotoxic potential.

  10. Role of dimethyl fumarate in oxidative stress of multiple sclerosis: A review.

    PubMed

    Suneetha, A; Raja Rajeswari, K

    2016-04-15

    Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS affecting both white and grey matter. Inflammation and oxidative stress are also thought to promote tissue damage in multiple sclerosis. Recent data point at an important role of anti-oxidative pathways for tissue protection in chronic MS, particularly involving the transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2). Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for MS treatment. Oxidative stress and anti-oxidative pathways are important players in MS pathophysiology and constitute a promising target for future MS therapy with dimethyl fumarate. The clinical utility of DMF in multiple sclerosis is being explored through phase III trials with BG-12, which is an oral therapeutic agent. Currently a wide research is going on to find out the exact mechanism of DMF, till date it is not clear. Based on strong signals of nephrotoxicity in non-humans and the theoretical risk of renal cell cancer from intracellular accumulation of fumarate, post-marketing study of a large population of patients will be necessary to fully assess the long-term safety of dimethyl fumarate. The current treatment goals are to shorten the duration and severity of relapses, prolong the time between relapses, and delay progression of disability. In this regard, dimethyl fumarate offers a promising alternative to orally administered fingolimod (GILENYA) or teriflunomide (AUBAGIO), which are currently marketed in the United States under FDA-mandated Risk Evaluation and Mitigation Strategy (REMS) programs because of serious safety concerns. More clinical experience with all three agents will be necessary to differentiate the tolerability of long-term therapy for patients diagnosed with multiple sclerosis. This write-up provides the detailed information of dimethyl fumarate in treating the neuro disease, multiple sclerosis and its mechanism involved via

  11. Long term follow-up of BEAM-autologous and BEAM-alemtuzumab allogeneic stem cell transplantation in relapsed advanced stage follicular lymphoma.

    PubMed

    Noriega, Victor; Kaur, Harpreet; Devereux, Stephen; Byrne, Jennifer; Marcus, Robert; Haynes, Andrew; Yallop, Deborah; McMillan, Andrew; Ingram, Wendy; Khan, Anjum; Kenyon, Michelle; Potter, Victoria; Russell, Nigel; Mufti, Ghulam J; Pagliuca, Antonio

    2014-07-01

    This is an analysis in 171 patients comparing BEAM-Auto and BEAM-Allo (alemtuzumab)-hematopoietic stem cell transplantation in relapsed follicular lymphoma. BEAM-Allo group had a lower 10 years cumulative incidence of relapse(31.4% vs 55.1%, p=0.042), a trend to a plateau in survival but no statistical differences in OS or DFS, and a TRM of 24%. When transplanted in CR BEAM-Allo patients had better OS and DFS. Incidence of acute and chronic GVHD was 16.6% and 22%. 29% of BEAM-Allo patients received DLI (all but two remain in CR and alive). Our data supports Allo-HSCT as a potential curative treatment for selected patients with FL.

  12. Late onset of autoimmune hemolytic anemia and pure red cell aplasia after allogeneic hematopoietic stem cell transplantation using in vivo alemtuzumab.

    PubMed

    Kako, Shinichi; Kanda, Yoshinobu; Oshima, Kumi; Nishimoto, Nahoko; Sato, Hiroyuki; Watanabe, Takuro; Hosoya, Noriko; Motokura, Toru; Miyakoshi, Shigesaburo; Taniguchi, Shuichi; Kamijo, Aki; Takahashi, Koki; Chiba, Shigeru; Kurokawa, Mineo

    2008-03-01

    Hemolytic anemia and pure red cell aplasia (PRCA) after allogeneic hematopoietic stem cell transplantation (HSCT) have been reported to be mainly related to ABO-incompatibility between donor and recipient. Autoimmune hemolytic anemia (AIHA) without ABO-incompatibility has been also reported after allogeneic HSCT, especially with T-cell depletion. However, optimal management of AIHA or PRCA remains unclear. A 54-year-old male with myelodysplastic syndrome (MDS) underwent haploidentical human leukocyte antigen-mismatched HSCT using in vivo alemtuzumab and developed AIHA and PRCA simultaneously 15 months after transplantation, following the administration of cidofovir and probenecid for persistent cytomegalovirus (CMV) antigenemia and retinitis. AIHA was successfully treated with rituximab, and subsequently PRCA with cyclosporine without relapse of MDS or recurrence of CMV infection. The clinical course suggested that AIHA was mainly caused by humoral immune response, while PRCA was mainly caused by cell-mediated immune response in this patient, although these immune responses might be related to each other.

  13. Effectiveness of subcutaneous low-dose alemtuzumab and rituximab combination therapy for steroid-resistant chronic graft-versus-host disease

    PubMed Central

    Gutiérrez-Aguirre, Cesar Homero; Cantú-Rodríguez, Olga Graciela; Borjas-Almaguer, Omar David; González-Llano, Oscar; Jaime-Pérez, José Carlos; Solano-Genesta, Manuel; Gómez-Guijosa, Miguel; Mancias-Guerra, Consuelo; Tarin, Luz; Gómez-Almaguer, David

    2012-01-01

    Background Chronic graft-versus-host disease is a common late complication of allogeneic hematopoietic stem cell transplantation. Corticosteroids are the standard initial treatment. Second-line treatment has not been well defined. We evaluated the effectiveness and safety of low doses of alemtuzumab plus low doses of rituximab in the treatment of steroid-refractory chronic graft-versus-host disease. Design and Methods Ten men and 5 women were prospectively included in the study. All patients received one cycle of subcutaneous alemtuzumab 10 mg/day/3 days and intravenous rituximab 100 mg on Days +4, +11, +18 and +25. The therapeutic response was measured on Days +30, +90 and +365 of the protocol. Results Median age was 41 years. The main site involved was the oral mucosa (86.7%) followed by the eyes (66.7%), liver (60%), skin (53%), lungs (13.3%) and intestinal tract (6.7%). The overall response was 100% at Day +30 evaluation: 10 patients (67%) had partial remission, 5 (33%) had complete remission. At Day +90 evaluation, 7 (50%) patients had partial remission, 4 (28%) had complete remission; 3 (21%) had relapsed chronic graft-versus-host disease and one patient did not reach the evaluation time point. So far, 5 patients have reached the Day +365 follow-up evaluation; 2 (40%) had partial remission, 2 had complete remission and one experienced chronic graft-versus-host disease progression. Adverse effects were mainly infections in 67% of patients; these were all quickly solved, except for one patient who died from pneumonia. Conclusions This combination therapy appears to be an efficacious and safe treatment for steroid-refractory chronic graft-versus-host disease. Longer follow up to determine the durability of response and survival is required. PMID:22133770

  14. Bis­(2-amino-5-methyl­pyridinium) fumarate–fumaric acid (1/1)

    PubMed Central

    Hemamalini, Madhukar; Fun, Hoong-Kun

    2010-01-01

    In the crystal structure of the title compound, C6H9N2 +·0.5C4H2O4 2−·0.5C4H6O4, the fumarate dianion and fumaric acid mol­ecule are located on inversion centres. The 2-amino-5-methyl­pyrimidinium cation inter­acts with the carboxyl­ate group of the fumarate anion through a pair of N—H⋯O hydrogen bonds, forming an R 2 2(8) ring motif. These motifs are centrosymmetrically paired via N—H⋯O hydrogen bonds, forming a complementary DDAA array. The carboxyl groups of the fumaric acid mol­ecules and the carboxyl­ate groups of the fumarate anions are hydrogen bonded through O—H⋯O hydrogen bonds, leading to a supra­molecular chain along [101]. The crystal structure is further stabilized by weak C—H⋯O hydrogen bonds. PMID:21588388

  15. Results of a phase I/II British Society of Bone Marrow Transplantation study on PCR-based pre-emptive therapy with valganciclovir or ganciclovir for active CMV infection following alemtuzumab-based reduced intensity allogeneic stem cell transplantation.

    PubMed

    Lim, Z Y; Cook, G; Johnson, P R; Parker, Anne; Zuckerman, M; Marks, D; Wiltshire, H; Mufti, G J; Pagliuca, A

    2009-02-01

    This multi-centre randomized study assessed the bioavailability of ganciclovir in patients undergoing alemtuzumab-based reduced intensity conditioning (RIC) haematopoietic stem cell transplantation (HSCT) after oral administration of valganciclovir. Patients were randomized to 2 groups receiving either oral valganciclovir (900 mg twice daily) or intravenous ganciclovir (5mg/kg twice daily) for 14 days. Twenty-seven patients were recruited and 18 patients (67%) completed allocated treatment resulting in clearance of cytomegolovirus (CMV) DNA load at a median of 14 days. The bioavailability of ganciclovir from valganciclovir was 73% (95% CI: 34-112%). The average exposure in the valganciclovir group (36.9+/-14.9 microg h/ml) was higher than the ganciclovir cohort (27.9+/-7.5 microg h/ml). When compared with intravenous ganciclovir, oral valganciclovir had high bioavailability in patients undergoing alemtuzumab-based RIC HSCT.

  16. [Ketotifen fumarate (Zaditen) eye drops in the treatment of seasonal allergic conjunctivitis].

    PubMed

    Haicl, P; Cerná, H

    2004-09-01

    A group of 25 patients with signs of seasonal allergic conjunctivitis treated during the period of 2 to 6 month with ketotifen fumarate 0.05% eye drops 2-3 times daily (Zaditen eye drops, Novartis Ophthalmic, AG, Switzerland) is described here. As subjective symptoms of itching, stinging, tearing, and mucous discharge were observed and evaluated, as well as objective signs of hyperemia of the conjunctiva and hypertrophy of the tarsal papillae. Similarly the onset of action, duration time, and toleration of the drug were assessed. Subjective symptoms disappeared after 10 days of treatment duration in 60% to 80% patients, after two months of treatment were present in the range 0% to 20%. Objective signs diminished after 10 days of treatment in 60%-72% patients, and after 2 months in 72% to 96% of patients. Hypertrophy of papillae of the tarsal conjunctiva did not totally disappear even after 6 month of treatment with ketotifen fumarate eye drops. Onset of action in all patients was 20 minutes or less, the duration of action was in the range of 8-13 hours. The drug was found as a good tolerable by all patients. Sixteen per cent of patients felt some burning following the instillation. The study states that ketotifen fumarate 0.05% eye drops are effective in a monotherapy of seasonal allergic conjunctivitis. Due to its multiple action, the drug prevents the allergic reaction as well. Subjective symptoms are influenced faster and more effective than the objective signs. The treatment of objective signs needs prolonged use of these drops.

  17. Combination Therapy of Etanercept and Fumarates versus Etanercept Monotherapy in Psoriasis: A Randomized Exploratory Study

    PubMed Central

    van Bezooijen, Ji Sun; Balak, Deepak M.W.; van Doorn, Martijn B.A.; Looman, Caspar W.N.; Schreurs, Marco W.J.; Koch, Birgit C.P.; van Gelder, Teun; Prens, Errol P.

    2016-01-01

    Background Biologics are a safe and efficacious therapy for psoriasis. The drug survival of biologics may be disappointing, primarily due to loss of efficacy. Therefore, safe combination treatments are sought to improve their clinical response. Objective To assess the efficacy, safety and tolerability of the combination therapy of etanercept with fumarates versus etanercept monotherapy. Methods Thirty-three patients with psoriasis were randomized 1:1 to receive etanercept combined with fumarates or etanercept monotherapy. The primary outcome measure was the difference in PASI-75 response after 24 weeks; additionally, a longitudinal analysis was performed. An important secondary outcome measure was the proportion of patients with a Physician Global Assessment (PGA) of clear or almost clear. Adverse events were collected throughout the study. Results In the combination therapy group, 78% (14 out of 18 patients) reached PASI-75 at week 24 versus 57% (8 out of 14 patients) in the monotherapy group (p = 0.27). The longitudinal analysis showed a PASI reduction of 5.97% per week for the combination therapy group and of 4.76% for the monotherapy group (p = 0.11). In the combination therapy group, 94% (17 out of 18 patients) of patients had a PGA of clear/almost clear versus 64% (9 out of 14 patients) in the monotherapy group (p = 0.064). The incidence of mild gastrointestinal complaints was higher in the combination group than in the monotherapy group. Conclusion Using the PGA, combination therapy showed a trend towards faster improvement in the first 24 weeks. The difference in the PASI score between the two groups was not statistically significant. Addition of fumarates to etanercept for 48 weeks appeared safe with an acceptable tolerability. PMID:27576483

  18. Studies on potential effects of fumaric acid on rumen microbial fermentation, methane production and microbial community.

    PubMed

    Riede, Susanne; Boguhn, Jeannette; Breves, Gerhard

    2013-01-01

    The greenhouse gas methane (CH4) contributes substantially to global climate change. As a potential approach to decrease ruminal methanogenesis, the effects of different dosages of fumaric acid (FA) on ruminal microbial metabolism and on the microbial community (archaea, bacteria) were studied using a rumen simulation technique (RUSITEC). FA acts as alternative hydrogen acceptor diverting 2H from methanogenesis of archaea towards propionate formation of bacteria. Three identical trials were conducted with 12 fermentation vessels over a period of 14 days. In each trial, four fermentation vessels were assigned to one of the three treatment groups differing in FA dosage: low fumaric acid (LFA), high fumaric acid (HFA) and without FA (control). FA was continuously infused with the buffer. Grass silage and concentrate served as substrate. FA led to decreases in pH and to higher production rates of total short chain fatty acids (SCFA) mediated by increases in propionate for LFA of 1.69 mmol d(-1) and in propionate and acetate production for HFA of 4.49 and 1.10 mmol d(-1), respectively. Concentrations of NH3-N, microbial crude protein synthesis, their efficiency, degradation of crude nutrients and detergent fibre fraction were unchanged. Total gas and CH4 production were not affected by FA. Effects of FA on structure of microbial community by means of single strand conformation polymorphism (SSCP) analyses could not be detected. Given the observed increase in propionate production and the unaffected CH4 production it can be supposed that the availability of reduction equivalents like 2H was not limited by the addition of FA in this study. It has to be concluded from the present study that the application of FA is not an appropriate approach to decrease the ruminal CH4 production.

  19. Clemastine fumarate as an antipruritic agent in pruritic cats: results of an open clinical trial.

    PubMed Central

    Miller, W H; Scott, D W

    1994-01-01

    Clemastine fumarate was administered to 10 presumed or proven atopic cats to determine its efficacy in controlling their pruritus. Initially, each cat received 0.34 mg orally every twelve hours for 14 days. When none responded satisfactorily, the dosage was increased to 0.68 mg/cat every twelve hours. At that dosage, the pruritus in five cats (50%) was eliminated. Diarrhea was seen in one cat. Under the conditions of the study, clemastine was a useful antipruritic agent for the cat. PMID:7954223

  20. Effects of irradiation and fumaric acid treatment on the inactivation of Listeria monocytogenes and Salmonella typhimurium inoculated on sliced ham

    NASA Astrophysics Data System (ADS)

    Song, Hyeon-Jeong; Lee, Ji-Hye; Song, Kyung Bin

    2011-11-01

    To examine the effects of fumaric acid and electron beam irradiation on the inactivation of foodborne pathogens in ready-to-eat meat products, sliced ham was inoculated with Listeria monocytogenes and Salmonella typhimurium. The inoculated ham slices were treated with 0.5% fumaric acid or electron beam irradiation at 2 kGy. Fumaric acid treatment reduced the populations of L. monocytogenes and S. typhimurium by approximately 1 log CFU/g compared to control populations. In contrast, electron beam irradiation decreased the populations of S. typhimurium and L. monocytogenes by 3.78 and 2.42 log CFU/g, respectively. These results suggest that electron beam irradiation is a better and appropriate technique for improving the microbial safety of sliced ham.

  1. Synthesis of a Moldable Biodegradable Bone Repair Material: Characterization and In Vivo Evaluation of Cross-Linked Poly(Propylene Fumarate)

    DTIC Science & Technology

    1987-09-01

    Synthesis of a Moldable Biodegradable Bone Repair Material: Characterization and in Vivo Evaluation of Cross-Linked Poly (Propylene Fumarate) 12. PERSONAL... Bone Repair ; Biodegradable Polymers; Poly (Propylene 161(Cntnu o reere f ncesay ndFumarate); Moldable Polymer. 19. 8BSTRACT...demonstrate degradation rates conducive to mediating bone repair . In vivo studies were also negative. However, the data suggest that poly (propylene

  2. Determination of fumaric and maleic acids with stacking analytes by transient moving chemical reaction boundary method in capillary electrophoresis.

    PubMed

    He, Jian-Feng; Yang, Wei-Ying; Yao, Fu-Jun; Zhao, Hong; Li, Xiang-Jun; Yuan, Zhuo-Bin

    2011-06-17

    The paper presents an on-line transient moving chemical reaction boundary (MCRB) method for simply but efficiently stacking analytes in capillary electrophoresis (CE). The CE technique was developed for a rapid determination of fumaric and maleic acid. Based on the theory of MCRB, Effects of several important factors such as the pH and concentration of running buffer and the conditions of stacking analytes were investigated to acquire the optimum conditions. The optimized separations were carried out in a 20 mmol/L sulphate neutralized with ethylenediamine to pH 6.0 electrolytes using a capillary coated with poly (diallyldimethylammonium chloride) and direct UV detection at 214 nm. The optimized preconcentrations were carried out in 50 mmol/L borax (pH 9.0). The calibration curves were linear in the concentration range of 1.0×10⁻⁷-1.0×10⁻⁴ mol/L and 5.0×10⁻⁷-1.0×10⁻⁴ mol/L for fumaric and maleic acid with correlation coefficients higher than 0.9991. The detection limits were 5.34×10⁻⁸ mol/L for fumaric acid and 1.92×10⁻⁷ mol/L for maleic acid. This method was applied for determination of fumaric acid in apple juice and of fumaric and maleic acid in dl-malic, the recovery tests established for real samples were within the range 95-105%. This work provided a valid and simple approach to detect fumaric and maleic acid.

  3. Fumaric Acid Production from Alkali-Pretreated Corncob by Fed-Batch Simultaneous Saccharification and Fermentation Combined with Separated Hydrolysis and Fermentation at High Solids Loading.

    PubMed

    Li, Xin; Zhou, Jin; Ouyang, Shuiping; Ouyang, Jia; Yong, Qiang

    2017-02-01

    Production of fumaric acid from alkali-pretreated corncob (APC) at high solids loading was investigated using a combination of separated hydrolysis and fermentation (SHF) and fed-batch simultaneous saccharification and fermentation (SSF) by Rhizopus oryzae. Four different fermentation modes were tested to maximize fumaric acid concentration at high solids loading. The highest concentration of 41.32 g/L fumaric acid was obtained from 20 % (w/v) APC at 38 °C in the combined SHF and fed-batch SSF process, compared with 19.13 g/L fumaric acid in batch SSF alone. The results indicated that a combination of SHF and fed-batch SSF significantly improved production of fumaric acid from lignocellulose by R. oryzae than that achieved with batch SSF at high solids loading.

  4. Fumarate hydratase isoforms of Leishmania major: subcellular localization, structural and kinetic properties.

    PubMed

    Feliciano, Patrícia R; Gupta, Shreedhara; Dyszy, Fabio; Dias-Baruffi, Marcelo; Costa-Filho, Antonio J; Michels, Paul A M; Nonato, M Cristina

    2012-01-01

    Fumarate hydratases (FHs; EC 4.2.1.2) are enzymes that catalyze the reversible hydration of fumarate to S-malate. Parasitic protists that belong to the genus Leishmania and are responsible for a complex of vector-borne diseases named leishmaniases possess two genes that encode distinct putative FH enzymes. Genome sequence analysis of Leishmania major Friedlin reveals the existence of genes LmjF24.0320 and LmjF29.1960 encoding the putative enzymes LmFH-1 and LmFH-2, respectively. In the present work, the FH activity of both L. major enzymes has been confirmed. Circular dichroism studies suggest important differences in terms of secondary structure content when comparing LmFH isoforms and even larger differences when comparing them to the homologous human enzyme. CD melting experiments revealed that both LmFH isoforms are thermolabile enzymes. The catalytic efficiency under aerobic and anaerobic environments suggests that they are both highly sensitive to oxidation and damaged by oxygen. Intracellular localization studies located LmFH-1 in the mitochondrion, whereas LmFH-2 was found predominantly in the cytosol with possibly also some in glycosomes. The high degree of sequence conservation in different Leishmania species, together with the relevance of FH activity for the energy metabolism in these parasites suggest that FHs might be exploited as targets for broad-spectrum antileishmanial drugs.

  5. Formulation Design and Optimization of Orodispersible Tablets of Quetiapine Fumarate by Sublimation Method

    PubMed Central

    Kalyankar, P.; Panzade, P.; Lahoti, S.

    2015-01-01

    The objective of present study was to formulate directly compressible orodispersible tablets of quetiapine fumarate by sublimation method with a view to enhance patient compliance. A full 32 factorial design was used to investigate the effect of two variables viz., concentration of Indion 414 and camphor. Indion 414 (3-5 % w/w) was used as superdisintegrant and camphor (5-15 % w/w) as subliming agent. The tablets were evaluated for thickness, weight variation, hardness, friability, content uniformity, wetting time, porosity, in vitro disintegration time and in vitro drug release. The formulation containing 5% w/w of Indion 414 and 5% w/w camphor was emerged as promising based on evaluation parameters. The disintegration time for optimized formulation was 18.66 s. The tablet surface was evaluated for presence of pores by scanning electron microscopy before and after sublimation. Differential scanning colorimetric study did not indicate any drug excipient incompatibility, either during mixing or after compression. The effect of independent variables on disintegration time, % drug release and friability is presented graphically by surface response plots. Short-term stability studies on the optimized formulation indicated no significant changes in drug content and in vitro disintegration time. The directly compressible orodispersible tablets of quetiapine fumarate with lower friability, greater drug release and shorter disintegration times were obtained using Indion 414 and camphor at optimum concentrations. PMID:26180271

  6. Selective small molecule inhibitor of the Mycobacterium tuberculosis fumarate hydratase reveals an allosteric regulatory site

    PubMed Central

    Kasbekar, Monica; Fischer, Gerhard; Mott, Bryan T.; Yasgar, Adam; Hyvönen, Marko; Boshoff, Helena I. M.; Abell, Chris; Barry, Clifton E.; Thomas, Craig J.

    2016-01-01

    Enzymes in essential metabolic pathways are attractive targets for the treatment of bacterial diseases, but in many cases, the presence of homologous human enzymes makes them impractical candidates for drug development. Fumarate hydratase, an essential enzyme in the tricarboxylic acid (TCA) cycle, has been identified as one such potential therapeutic target in tuberculosis. We report the discovery of the first small molecule inhibitor, to our knowledge, of the Mycobacterium tuberculosis fumarate hydratase. A crystal structure at 2.0-Å resolution of the compound in complex with the protein establishes the existence of a previously unidentified allosteric regulatory site. This allosteric site allows for selective inhibition with respect to the homologous human enzyme. We observe a unique binding mode in which two inhibitor molecules interact within the allosteric site, driving significant conformational changes that preclude simultaneous substrate and inhibitor binding. Our results demonstrate the selective inhibition of a highly conserved metabolic enzyme that contains identical active site residues in both the host and the pathogen. PMID:27325754

  7. Evaluation of chronic toxicity and carcinogenesis in rodents with the synthetic analgesic, tilidine fumarate.

    PubMed

    McGuire, E J; DiFonzo, C J; Martin, R A; de la Iglesia, F A

    1986-05-01

    The carcinogenic potential of tilidine fumarate, a synthetic analgesic, was studied for 80 and 104 weeks in mice and rats, respectively. Groups of 50 albino CF1 mice and 65 albino Wistar rats of each sex received tilidine fumarate-lactose blend (1:1) at doses of 100, 40 and 16 mg/kg. The control groups consisted of 100 mice and 115 rats of each sex and received the lactose vehicle only. Treatment-related non-neoplastic changes consisted of reversible, increased cytoplasmic eosinophilia of hepatocytes in high and mid dose rats corresponding to areas of proliferating smooth endoplasmic reticulum; and an increased incidence in high dose rats of proliferative or cystic lesions of the biliary epithelium. Adequate survival rates allowed stringent statistical analysis of neoplasia. Tilidine did not evoke increased tumor incidences or changes in the average latency or onset of tumors in either species. The most frequent tumors represented spontaneous neoplasia characteristic of historical background incidence in these strains. In mice, the only statistically significant (P less than 0.01) variation in tumor incidence was an increased rate of lung alveologenic adenocarcinomas in females at 100 mg/kg (24%), compared with the concurrent untreated controls (10%), but without a statistically significant difference from historical control data (27%). Female rats given 100 mg/kg showed statistically significant (P less than 0.01) decreased incidences of mammary fibroadenoma and pituitary adenoma. From these data, it was concluded that the synthetic analgesic tilidine does not possess tumorigenic potential in rodents.

  8. Formulation Design and Optimization of Orodispersible Tablets of Quetiapine Fumarate by Sublimation Method.

    PubMed

    Kalyankar, P; Panzade, P; Lahoti, S

    2015-01-01

    The objective of present study was to formulate directly compressible orodispersible tablets of quetiapine fumarate by sublimation method with a view to enhance patient compliance. A full 3(2) factorial design was used to investigate the effect of two variables viz., concentration of Indion 414 and camphor. Indion 414 (3-5 % w/w) was used as superdisintegrant and camphor (5-15 % w/w) as subliming agent. The tablets were evaluated for thickness, weight variation, hardness, friability, content uniformity, wetting time, porosity, in vitro disintegration time and in vitro drug release. The formulation containing 5% w/w of Indion 414 and 5% w/w camphor was emerged as promising based on evaluation parameters. The disintegration time for optimized formulation was 18.66 s. The tablet surface was evaluated for presence of pores by scanning electron microscopy before and after sublimation. Differential scanning colorimetric study did not indicate any drug excipient incompatibility, either during mixing or after compression. The effect of independent variables on disintegration time, % drug release and friability is presented graphically by surface response plots. Short-term stability studies on the optimized formulation indicated no significant changes in drug content and in vitro disintegration time. The directly compressible orodispersible tablets of quetiapine fumarate with lower friability, greater drug release and shorter disintegration times were obtained using Indion 414 and camphor at optimum concentrations.

  9. Transcriptome analysis of Rhizopus oryzae in response to xylose during fumaric acid production.

    PubMed

    Xu, Qing; Liu, Ying; Li, Shuang; Jiang, Ling; Huang, He; Wen, Jianping

    2016-08-01

    Xylose is one of the most abundant lignocellulosic components, but it cannot be used by R. oryzae for fumaric acid production. Here, we applied high-throughput RNA sequencing to generate two transcriptional maps of R. oryzae following fermentation in glucose or xylose. The differential expression analysis showed that, genes involved in amino acid metabolism, fatty acid metabolism, and gluconeogenesis, were up-regulated in response to xylose. Moreover, we discovered the potential presence of oxidative stress in R. oryzae during xylose fermentation. To adapt to this unfavorable condition, R. oryzae displayed reduced growth and induce of a number of antioxidant enzymes, including genes involved in glutathione, trehalose synthesis, and the proteasomal pathway. These responses might divert the flow of carbon required for the accumulation of fumaric acid. Furthermore, using high-throughput RNA sequencing, we identified a large number of novel transcripts and a substantial number of genes that underwent alternative splicing. Our analysis provides remarkable insight into the mechanisms underlying xylose fermentation by R. oryzae. These results may reveal potential target genes or strategies to improve xylose fermentation.

  10. Cell adhesion on poly(propylene fumarate-co-ethylene glycol) hydrogels.

    PubMed

    Tanahashi, Kazuhiro; Mikos, Antonios G

    2002-12-15

    We synthesized poly(propylene fumarate-co-ethylene glycol) block copolymers [P(PF-co-EG)] that were crosslinked to form hydrogels and investigated the effect of copolymer composition on cell adhesion to the hydrogels. These copolymers were water soluble when the molar ratio of ethylene glycol repeating unit to propylene fumarate repeating unit was higher than 4.4. The water content of swollen hydrogels increased from 29 to 63% and the water contact angle decreased from 38 to 21 degrees as the molar ratio increased from 0.6 to 4.4. No significant change in either property was observed for ratios higher than 4.4. In a cell adhesion assay under serum-free conditions, the number of adherent platelets and smooth muscle cells decreased from 21 to 2% and from 78 to 20% of the initial seeding density, respectively, as the molar ratio increased from 0.6 to 7.8. Adherent smooth muscle cells did not spread on the hydrogels of the compositions tested. Adherent platelets did not show any filopodia. These results suggest that the hydrophilicity of P(PF-co-EG) hydrogels is one of the factors affecting cell adhesion, and that copolymer modification may be required for enhancing cell adhesion for an application involving the copolymers as in situ crosslinkable cell carriers.

  11. Overexpression of NADH-dependent fumarate reductase improves D-xylose fermentation in recombinant Saccharomyces cerevisiae.

    PubMed

    Salusjärvi, Laura; Kaunisto, Sanna; Holmström, Sami; Vehkomäki, Maija-Leena; Koivuranta, Kari; Pitkänen, Juha-Pekka; Ruohonen, Laura

    2013-12-01

    Deviation from optimal levels and ratios of redox cofactors NAD(H) and NADP(H) is common when microbes are metabolically engineered. The resulting redox imbalance often reduces the rate of substrate utilization as well as biomass and product formation. An example is the metabolism of D-xylose by recombinant Saccharomyces cerevisiae strains expressing xylose reductase and xylitol dehydrogenase encoding genes from Scheffersomyces stipitis. This pathway requires both NADPH and NAD(+). The effect of overexpressing the glycosomal NADH-dependent fumarate reductase (FRD) of Trypanosoma brucei in D-xylose-utilizing S. cerevisiae alone and together with an endogenous, cytosol directed NADH-kinase (POS5Δ17) was studied as one possible solution to overcome this imbalance. Expression of FRD and FRD + POS5Δ17 resulted in 60 and 23 % increase in ethanol yield, respectively, on D-xylose under anaerobic conditions. At the same time, xylitol yield decreased in the FRD strain suggesting an improvement in redox balance. We show that fumarate reductase of T. brucei can provide an important source of NAD(+) in yeast under anaerobic conditions, and can be useful for metabolic engineering strategies where the redox cofactors need to be balanced. The effects of FRD and NADH-kinase on aerobic and anaerobic D-xylose and D-glucose metabolism are discussed.

  12. Identification, characterization, and high-performance liquid chromatography quantification of process-related impurities in vonoprazan fumarate.

    PubMed

    Liu, Lei; Cao, Na; Ma, Xingling; Xiong, Kaihe; Sun, Lili; Zou, Qiaogen

    2016-04-01

    High-performance liquid chromatography analysis of vonoprazan fumarate, a novel proton pump inhibitor drug revealed six impurities. These were identified by liquid chromatography with mass spectrometry. Further, the structures of the impurities were confirmed by synthesis followed by characterization by mass spectrometry, NMR spectroscopy, and infrared spectroscopy. On the basis of these data and knowledge of the synthetic scheme of vonoprazan fumarate, the previously unknown impurity was identified as 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methyldimethylamine, which is a new compound. The possible mechanisms by which these impurities were formed were also discussed. A high-performance liquid chromatography method was optimized in order to separate, selectively detect, and quantify all process-related impurities of vonoprazan fumarate. The presented method has been validated in terms of linearity, limits of detection, and quantification, and response factors and, therefore, is highly suitable for routine analysis of vonoprazan fumarate related substances as well as stability studies.

  13. Recent advances in the biomedical applications of fumaric acid and its ester derivatives: The multifaceted alternative therapeutics.

    PubMed

    Das, Ratul Kumar; Brar, Satinder Kaur; Verma, Mausam

    2016-04-01

    Several lines of evidence have demonstrated the potential biomedical applications of fumaric acid (FA) and its ester derivatives against many human disease conditions. Fumaric acid esters (FAEs) have been licensed for the systemic treatment of the immune-mediated disease psoriasis. Biogen Idec Inc. announced about the safety and efficacy of the formulation FAE (BG-12) for treating RRMS (relapsing-remitting multiple sclerosis). Another FAE formulation DMF (dimethyl fumarate) was found to be capable of reduction in inflammatory cardiac conditions, such as autoimmune myocarditis and ischemia and reperfusion. DMF has also been reported to be effective as a potential neuroprotectant against the HIV-associated neurocognitive disorders (HAND). Many in vivo studies carried out on rat and mice models indicated inhibitory effects of fumaric acid on carcinogenesis of different origins. Moreover, FAEs has emerged as an important matrix ingredient in the fabrication of biodegradable scaffolds for tissue engineering applications. Drug delivery vehicles composed of FAEs have shown promising results in delivering some leading drug molecules. Apart from these specific applications and findings, many more studies on FAEs have revealed new therapeutic potentials with the scope of clinical applications. However, until now, this scattered vital information has not been written into a collective account and analyzed for minute details. The aim of this paper is to review the advancement made in the biomedical application of FA and FAEs and to focus on the clinical investigation and molecular interpretation of the beneficial effects of FA and FAEs.

  14. The effect of dimethyl fumarate (Tecfidera™) on lymphocyte counts: A potential contributor to progressive multifocal leukoencephalopathy risk.

    PubMed

    Khatri, Bhupendra O; Garland, Jeffery; Berger, Joseph; Kramer, John; Sershon, Lisa; Olapo, Tayo; Sesing, Jean; Dukic, Mary; Rehn, Eileen

    2015-07-01

    Dimethyl fumarate (Tecfidera™) is an effective therapy for relapsing forms of multiple sclerosis (MS). Our study suggests that this drug may have immunosuppressive properties evidenced by significant sustained reduction in CD8 lymphocyte counts and, to a lesser extent, CD4 lymphocyte counts. This observation is relevant in light of the recent case of progressive multifocal leukoencephalopathy in a patient receiving this drug.

  15. Geometric Restraint Drives On- and Off-pathway Catalysis by the Escherichia coli Menaquinol:Fumarate Reductase

    SciTech Connect

    Tomasiak, Thomas M.; Archuleta, Tara L.; Andréll, Juni; Luna-Chávez, César; Davis, Tyler A.; Sarwar, Maruf; Ham, Amy J.; McDonald, W. Hayes; Yankovskaya, Victoria; Stern, Harry A.; Johnston, Jeffrey N.; Maklashina, Elena; Cecchini, Gary; Iverson, Tina M.

    2012-01-05

    Complex II superfamily members catalyze the kinetically difficult interconversion of succinate and fumarate. Due to the relative simplicity of complex II substrates and their similarity to other biologically abundant small molecules, substrate specificity presents a challenge in this system. In order to identify determinants for on-pathway catalysis, off-pathway catalysis, and enzyme inhibition, crystal structures of Escherichia coli menaquinol:fumarate reductase (QFR), a complex II superfamily member, were determined bound to the substrate, fumarate, and the inhibitors oxaloacetate, glutarate, and 3-nitropropionate. Optical difference spectroscopy and computational modeling support a model where QFR twists the dicarboxylate, activating it for catalysis. Orientation of the C2-C3 double bond of activated fumarate parallel to the C(4a)-N5 bond of FAD allows orbital overlap between the substrate and the cofactor, priming the substrate for nucleophilic attack. Off-pathway catalysis, such as the conversion of malate to oxaloacetate or the activation of the toxin 3-nitropropionate may occur when inhibitors bind with a similarly activated bond in the same position. Conversely, inhibitors that do not orient an activatable bond in this manner, such as glutarate and citrate, are excluded from catalysis and act as inhibitors of substrate binding. These results support a model where electronic interactions via geometric constraint and orbital steering underlie catalysis by QFR.

  16. Study of metabolic profile of Rhizopus oryzae to enhance fumaric acid production under low pH condition.

    PubMed

    Liu, Ying; Xu, Qing; Lv, Chunwei; Yan, Caixia; Li, Shuang; Jiang, Ling; Huang, He; Ouyang, Pingkai

    2015-12-01

    Ensuring a suitable pH is a major problem in industrial organic acid fermentation. To circumvent this problem, we used a metabolic profiling approach to analyze metabolite changes in Rhizopus oryzae under different pH conditions. A correlation between fumaric acid production and intracellular metabolic characteristics of R. oryzae was revealed by principal component analysis. The results showed that to help cell survival in the presence of low pH, R. oryzae altered amino acid and fatty acid metabolism and promoted sugar or sugar alcohol synthesis, corresponding with a suppressing of energy metabolism, phenylalanine, and tyrosine synthesis and finally resulting in the low performance of fumaric acid production. Based on this observation, 1 % linoleic acid was added to the culture medium in pH 3.0 to decrease the carbon demand for cell survival, and the fumaric acid titer was enhanced by 39.7 % compared with the control (pH 3.0 without linoleic acid addition), reaching 18.3 g/L after 84 h of fermentation. These findings provide new insights into the mechanism by which R. oryzae responds to acidic stress and would be helpful for the development of efficient strategies for fumaric acid production at low pH.

  17. High production of fumaric acid from xylose by newly selected strain Rhizopus arrhizus RH 7-13-9#.

    PubMed

    Liu, Huan; Wang, Weinan; Deng, Li; Wang, Fang; Tan, Tianwei

    2015-06-01

    Fumaric acid, as an important material for polymerization, is highly expected to be produced by fermentation of lignocellulosic biomass which is composed of cellulose, hemicellulose and lignin. Xylose as the main component of hemicellulose cannot be efficiently utilized by most of the common fermentation. In this study, a new strain Rhizopus arrhizus RH 7-13-9# was selected from the R. arrhizus RH 7-13 through a novel convenient and efficient selection method. Efficient production of fumaric acid (45.31 g/L) from xylose was achieved by the new strain, and the volumetric productivity was still 0.472 g/L h. Moreover, the conversion of xylose reached 73% which is close to the theoretic yield (77%). The production of fumaric acid was increased approximate by 172%, compared with the initial strain counterpart. These results indicated that xylose, as the main component of hemicellulose, has a promising application for the production of fumaric acid on an industrial-scale.

  18. Activation of glycerol metabolic pathway by evolutionary engineering of Rhizopus oryzae to strengthen the fumaric acid biosynthesis from crude glycerol.

    PubMed

    Huang, Di; Wang, Ru; Du, Wenjie; Wang, Guanyi; Xia, Menglei

    2015-11-01

    Rhizopus oryzae is strictly inhibited by biodiesel-based by-product crude glycerol, which results in low fumaric acid production. In this study, evolutionary engineering was employed to activate the glycerol utilization pathway for fumaric acid production. An evolved strain G80 was selected, which could tolerate and utilize high concentrations of crude glycerol to produce 14.9g/L fumaric acid with a yield of 0.248g/g glycerol. Key enzymes activity analysis revealed that the evolved strain displayed a significant upregulation in glycerol dissimilation, pyruvate consumption and reductive tricarboxylic acid pathways, compared with the parent strain. Subsequently, intracellular metabolic profiling analysis showed that amino acid biosynthesis, tricarboxylic acid cycle, fatty acid and stress response metabolites accounted for metabolic difference between two strains. Moreover, a glycerol fed-batch strategy was optimized to obtain the highest fumaric acid production of 25.5g/L, significantly increased by 20.9-fold than that of the parent strain of 1.2g/L.

  19. Evaluation of the binding interaction between bovine serum albumin and dimethyl fumarate, an anti-inflammatory drug by multispectroscopic methods

    NASA Astrophysics Data System (ADS)

    Jattinagoudar, Laxmi; Meti, Manjunath; Nandibewoor, Sharanappa; Chimatadar, Shivamurti

    2016-03-01

    The information of the quenching reaction of bovine serum albumin with dimethyl fumarate is obtained by multi-spectroscopic methods. The number of binding sites, n and binding constants, KA were determined at different temperatures. The effect of increasing temperature on Stern-Volmer quenching constants (KD) indicates that a dynamic quenching mechanism is involved in the interaction. The analysis of thermodynamic quantities namely, ∆H° and ∆S° suggested hydrophobic forces playing a major role in the interaction between dimethyl fumarate and bovine serum albumin. The binding site of dimethyl fumarate on bovine serum albumin was determined by displacement studies, using the site probes viz., warfarin, ibuprofen and digitoxin. The determination of magnitude of the distance of approach for molecular interactions between dimethyl fumarate and bovine serum albumin is calculated according to the theory of Förster energy transfer. The CD, 3D fluorescence spectra, synchronous fluorescence measurements and FT-IR spectral results were indicative of the change in secondary structure of the protein. The influence of some of the metal ions on the binding interaction was also studied.

  20. Shewanella spp. Use Acetate as an Electron Donor for Denitrification but Not Ferric Iron or Fumarate Reduction

    PubMed Central

    Yoon, Sukhwan; Sanford, Robert A.

    2013-01-01

    Lactate but not acetate oxidation was reported to support electron acceptor reduction by Shewanella spp. under anoxic conditions. We demonstrate that the denitrifiers Shewanella loihica strain PV-4 and Shewanella denitrificans OS217 utilize acetate as an electron donor for denitrification but not for fumarate or ferric iron reduction. PMID:23396327

  1. Comparative Meta-Analysis of Tenofovir Disoproxil Fumarate versus Emtricitabine and Tenofovir Disoproxil Fumarate as Treatments for Patients with Chronic Hepatitis B.

    PubMed

    Cui, Guangying; Xu, Xuejun; Diao, Hongyan

    2015-07-13

    Tenofovir disoproxil fumarate (TDF) monotherapy has proven superior antiviral efficacy in chronic hepatitis B (CHB) patients; however, whether the combination of TDF and emtricitabine (FTC) exerts a significant advantage remains controversial. A meta-analysis was performed to comprehensively compare the therapeutic effects of FTC/TDF combination with TDF alone in CHB patients. Five studies involving 614 patients were identified, and subgroup analysis was performed based on the nucleos(t)ide treatment history. Our results revealed that in patients with nucleos(t)ide-naïve treatment, there were no significant differences between the treatment groups with TDF alone and FTC/TDF combination after 12 and 24 weeks; however, the FTC/TDF combination showed better viral suppression efficacy versus TDF alone after 48 (OR = 2.16, 95% CI = 1.06-4.41, P = 0.03), 96 (OR = 2.76, 95% CI = 1.29-5.92, P = 0.009) and 192 weeks (OR = 2.60, 95% CI = 1.21-5.56, P = 0.01). In patients with nucleos(t)ide treatment history, no differences were noted between the two treatment groups after 12, 24, 48 and 96 weeks. Our results indicated that FTC/TDF combination showed better viral suppression efficacy versus TDF alone in CHB patients with nucleos(t)ide-naïve treatment, while both treatments provided similar viral suppression efficacy in CHB patients with nucleos(t)ide treatment history.

  2. [In vitro incubation of lenses. Model for testing substrate utilization of substances of the energy metabolism, demonstrated with bencyclane-hydrogen-fumarate (author's transl)].

    PubMed

    Hockwin, O; Korte, I; Breuer, R; Schmidt, G; Rast-Czyborra, F

    1978-08-16

    When bovine lens homogenate was treated with bencyclane-hydrogen-fumarate, the carbohydrate metabolism was activated. This may chiefly be due to the fumarate part of the substance. A 24 H In vitro incubation of whole bovine lenses in TC-199 with and without bencyclane-hydrogen-fumarate did not show the above effect. On the model of former investigations by J.E. Harris et al. we modified the test procedure by selecting the medium and the time of incubation so that the endogenous carbohydrates of the lens were consumed, thus creating new metabolic balances. This metabolic condition allows investigations intended to activate metabolic processes and to restore the steady state of metabolic parameters. We investigated the effect of bencyclane-hydrogen-fumarate using the same method and found that given certain conditions the lens recovers when incubated for 2 h in TC-199 (containing 1 g glucose/1) with addition of a 10(-4) M solution of bencyclane-hydrogen-fumarate. The ATP-content of these lenses in particular gives proof of this result. As already observed in former investigations on homogenates, this effect is probably due to metabolization of the fumarate part of the bencyclane-hydrogen-fumarate by the citric acid cycle. The method used explains the differences observed when using lens homogenates or whole lenses under the same experimental conditions.

  3. Essential role of Glu-C66 for menaquinol oxidation indicates transmembrane electrochemical potential generation by Wolinella succinogenes fumarate reductase

    PubMed Central

    Lancaster, C. Roy D.; Groß, Roland; Haas, Alexander; Ritter, Michaela; Mäntele, Werner; Simon, Jörg; Kröger, Achim

    2000-01-01

    Quinol:fumarate reductase (QFR) is a membrane protein complex that couples the reduction of fumarate to succinate to the oxidation of quinol to quinone, in a reaction opposite to that catalyzed by the related enzyme succinate:quinone reductase (succinate dehydrogenase). In the previously determined structure of QFR from Wolinella succinogenes, the site of fumarate reduction in the flavoprotein subunit A of the enzyme was identified, but the site of menaquinol oxidation was not. In the crystal structure, the acidic residue Glu-66 of the membrane spanning, diheme-containing subunit C lines a cavity that could be occupied by the substrate menaquinol. Here we describe that, after replacement of Glu-C66 with Gln by site-directed mutagenesis, the resulting mutant is unable to grow on fumarate and the purified enzyme lacks quinol oxidation activity. X-ray crystal structure analysis of the Glu-C66 → Gln variant enzyme at 3.1-Å resolution rules out any major structural changes compared with the wild-type enzyme. The oxidation-reduction potentials of the heme groups are not significantly affected. We conclude that Glu-C66 is an essential constituent of the menaquinol oxidation site. Because Glu-C66 is oriented toward a cavity leading to the periplasm, the release of two protons on menaquinol oxidation is expected to occur to the periplasm, whereas the uptake of two protons on fumarate reduction occurs from the cytoplasm. Thus our results indicate that the reaction catalyzed by W. succinogenes QFR generates a transmembrane electrochemical potential. PMID:11186225

  4. Nonmyeloablative Stem Cell Transplantation with Alemtuzumab/Low-Dose Irradiation to Cure and Improve the Quality of Life of Adults with Sickle Cell Disease.

    PubMed

    Saraf, Santosh L; Oh, Annie L; Patel, Pritesh R; Jalundhwala, Yash; Sweiss, Karen; Koshy, Matthew; Campbell-Lee, Sally; Gowhari, Michel; Hassan, Johara; Peace, David; Quigley, John G; Khan, Irum; Molokie, Robert E; Hsu, Lewis L; Mahmud, Nadim; Levinson, Dennis J; Pickard, A Simon; Garcia, Joe G N; Gordeuk, Victor R; Rondelli, Damiano

    2016-03-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is rarely performed in adult patients with sickle cell disease (SCD). We utilized the chemotherapy-free, alemtuzumab/total body irradiation 300 cGy regimen with sirolimus as post-transplantation immunosuppression in 13 high-risk SCD adult patients between November 2011 and June 2014. Patients received matched related donor (MRD) granulocyte colony-stimulating factor-mobilized peripheral blood stem cells, including 2 cases that were ABO incompatible. Quality-of-life (QoL) measurements were performed at different time points after HSCT. All 13 patients initially engrafted. A stable mixed donor/recipient chimerism was maintained in 12 patients (92%), whereas 1 patient not compliant with sirolimus experienced secondary graft failure. With a median follow-up of 22 months (range, 12 to 44 months) there was no mortality, no acute or chronic graft-versus-host disease (GVHD), and no grades 3 or 4 extramedullary toxicities. At 1 year after transplantation, patients with stable donor chimerism have normalized hemoglobin concentrations and improved cardiopulmonary and QoL parameters including bodily pain, general health, and vitality. In 4 patients, sirolimus was stopped without rejection or SCD-related complications. These results underscore the successful use of a chemotherapy-free regimen in MRD HSCT for high-risk adult SCD patients and demonstrates a high cure rate, absence of GVHD or mortality, and improvement in QoL including the applicability of this regimen in ABO mismatched cases (NCT number 01499888).

  5. Reduced-intensity allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome and acute myeloid leukemia with multilineage dysplasia using fludarabine, busulphan, and alemtuzumab (FBC) conditioning.

    PubMed

    Ho, Aloysius Y L; Pagliuca, Antonio; Kenyon, Michelle; Parker, Jane E; Mijovic, Aleksandar; Devereux, Stephen; Mufti, Ghulam J

    2004-09-15

    Reduced-intensity conditioned (RIC) hematopoietic stem cell transplantation (HSCT) has improved the accessibility of transplantation in patients previously ineligible. We report the results of allografting following conditioning with fludarabine, busulphan, and alemtuzumab in 62 patients with myelodysplastic syndromes (MDSs) (matched sibling donors [24] or volunteer unrelated donors [VUDs, 38]). The median age for sibling recipients was 56 years (range, 41-70 years) and for VUD recipients, 52 years (range, 22-65 years), with a median follow-up (survivors) of 524 days (range, 93-1392 days) and 420 days (range, 53-1495 days), respectively. The nonrelapse mortality (NRM) at days 100, 200, and 360 was 0%, 5%, and 5%, respectively, for siblings and 11%, 17%, and 21%, respectively, for VUD. The overall survival at one year was 73% for siblings and 71% for VUDs, with a disease-free survival (DFS) of 61% and 59%, respectively. The prognostic significance of the International Prognostic Scoring System (IPSS) was preserved. Of recipients, 86% achieved full-donor chimerism. The cumulative incidence at day 100 of grades III to IV graft-versus-host disease (GVHD) for VUD recipients was 9% and for sibling recipients, 0%. There were 26 patients (16 sibling and 10 VUD) who received donor lymphocyte infusion (DLI) at a median of 273 days (range, 126-1323 days). RIC allogeneic HSCT using this protocol appears to be safe and permits durable donor engraftment. Longer follow-up is required to confirm any potential survival advantage.

  6. Succination of proteins by fumarate: mechanism of inactivation of glyceraldehyde-3-phosphate dehydrogenase in diabetes.

    PubMed

    Blatnik, Matthew; Thorpe, Suzanne R; Baynes, John W

    2008-04-01

    S-(2-succinyl)cysteine (2SC) is a chemical modification of proteins formed by a Michael addition reaction between the Krebs cycle intermediate, fumarate, and thiol groups in protein--a process known as succination of protein. Succination causes irreversible inactivation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in vitro. GAPDH was immunoprecipitated from muscle of diabetic rats, then analyzed by ultra-performance liquid chromatography-electrospray ionization-mass spectroscopy. Succination of GAPDH was increased in muscle of diabetic rats, and the extent of succination correlated strongly with the decrease in specific activity of the enzyme. We propose that 2SC is a biomarker of mitochondrial and oxidative stress in diabetes and that succination of GAPDH and other thiol proteins may provide the chemical link between glucotoxicity and the pathogenesis of diabetic complications.

  7. A Role for Cytosolic Fumarate Hydratase in Urea Cycle Metabolism and Renal Neoplasia

    PubMed Central

    Adam, Julie; Yang, Ming; Bauerschmidt, Christina; Kitagawa, Mitsuhiro; O’Flaherty, Linda; Maheswaran, Pratheesh; Özkan, Gizem; Sahgal, Natasha; Baban, Dilair; Kato, Keiko; Saito, Kaori; Iino, Keiko; Igarashi, Kaori; Stratford, Michael; Pugh, Christopher; Tennant, Daniel A.; Ludwig, Christian; Davies, Benjamin; Ratcliffe, Peter J.; El-Bahrawy, Mona; Ashrafian, Houman; Soga, Tomoyoshi; Pollard, Patrick J.

    2013-01-01

    Summary The identification of mutated metabolic enzymes in hereditary cancer syndromes has established a direct link between metabolic dysregulation and cancer. Mutations in the Krebs cycle enzyme, fumarate hydratase (FH), predispose affected individuals to leiomyomas, renal cysts, and cancers, though the respective pathogenic roles of mitochondrial and cytosolic FH isoforms remain undefined. On the basis of comprehensive metabolomic analyses, we demonstrate that FH1-deficient cells and tissues exhibit defects in the urea cycle/arginine metabolism. Remarkably, transgenic re-expression of cytosolic FH ameliorated both renal cyst development and urea cycle defects associated with renal-specific FH1 deletion in mice. Furthermore, acute arginine depletion significantly reduced the viability of FH1-deficient cells in comparison to controls. Our findings highlight the importance of extramitochondrial metabolic pathways in FH-associated oncogenesis and the urea cycle/arginine metabolism as a potential therapeutic target. PMID:23643539

  8. Unsuspected task for an old team: succinate, fumarate and other Krebs cycle acids in metabolic remodeling.

    PubMed

    Bénit, Paule; Letouzé, Eric; Rak, Malgorzata; Aubry, Laetitia; Burnichon, Nelly; Favier, Judith; Gimenez-Roqueplo, Anne-Paule; Rustin, Pierre

    2014-08-01

    Seventy years from the formalization of the Krebs cycle as the central metabolic turntable sustaining the cell respiratory process, key functions of several of its intermediates, especially succinate and fumarate, have been recently uncovered. The presumably immutable organization of the cycle has been challenged by a number of observations, and the variable subcellular location of a number of its constitutive protein components is now well recognized, although yet unexplained. Nonetheless, the most striking observations have been made in the recent period while investigating human diseases, especially a set of specific cancers, revealing the crucial role of Krebs cycle intermediates as factors affecting genes methylation and thus cell remodeling. We review here the recent advances and persisting incognita about the role of Krebs cycle acids in diverse aspects of cellular life and human pathology.

  9. Breastfeeding while taking lamivudine or tenofovir disoproxil fumarate: a review of the evidence.

    PubMed

    Ehrhardt, Stephan; Xie, Chan; Guo, Nan; Nelson, Kenrad; Thio, Chloe L

    2015-01-15

    Lamivudine and tenofovir disoproxil fumarate (TDF) are both active against hepatitis B virus (HBV). Due to its potency, high genetic barrier to resistance, and safety during pregnancy, TDF may be useful to prevent HBV transmission from mother to child, which is the leading cause of transmission globally. Despite the safety record of lamivudine and TDF in pregnancy, the labels for both of these drugs recommend against their use during breastfeeding. In this review, we discuss the data regarding lamivudine and TDF use during pregnancy and breastfeeding and find that the exposure to the drug is lower from breastfeeding than from in utero exposure. Thus, the data do not support the contraindication to their use during breastfeeding.

  10. Dielectric and conducting behavior of gadolinium-terbium fumarate heptahydrate crystals

    NASA Astrophysics Data System (ADS)

    Shah, M. D.; Want, B.

    2015-07-01

    Gadolinium-terbium fumarate heptahydrate crystals were grown in silica gel by using single gel diffusion technique. The crystals were characterized by different physico-chemical techniques of characterization. Powder X-ray diffraction results showed that the grown material is purely crystalline in nature. Elemental analyses suggested the chemical formula of the compound to be Gd Tb (C4H2O4)3ṡ7H2O. Energy dispersive X-ray analysis confirmed the presence of Gd and Tb in the title compound. The dielectric and conductivity studies of the grown compound were carried as function of frequency of applied field and the temperature. The grown material showed a dielectric anomaly which was correlated with its thermal behavior. The ac conductivity of the material showed Jonscher's power law behavior: σ(ω)=σo+Aωs, with a temperature-dependent power exponent s(<1). The conductivity was found to be a function of temperature and frequency.

  11. Molecular pathways: Fumarate hydratase-deficient kidney cancer--targeting the Warburg effect in cancer.

    PubMed

    Linehan, W Marston; Rouault, Tracey A

    2013-07-01

    Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a hereditary cancer syndrome in which affected individuals are at risk for development of cutaneous and uterine leiomyomas and an aggressive form of type II papillary kidney cancer. HLRCC is characterized by germline mutation of the tricarboxylic acid (TCA) cycle enzyme, fumarate hydratase (FH). FH-deficient kidney cancer is characterized by impaired oxidative phosphorylation and a metabolic shift to aerobic glycolysis, a form of metabolic reprogramming referred to as the Warburg effect. Increased glycolysis generates ATP needed for increased cell proliferation. In FH-deficient kidney cancer, levels of AMP-activated protein kinase (AMPK), a cellular energy sensor, are decreased resulting in diminished p53 levels, decreased expression of the iron importer, DMT1, leading to low cellular iron levels, and to enhanced fatty acid synthesis by diminishing phosphorylation of acetyl CoA carboxylase, a rate-limiting step for fatty acid synthesis. Increased fumarate and decreased iron levels in FH-deficient kidney cancer cells inactivate prolyl hydroxylases, leading to stabilization of hypoxia-inducible factor (HIF)-1α and increased expression of genes such as VEGF and glucose transporter 1 (GLUT1) to provide fuel needed for rapid growth demands. Several therapeutic approaches for targeting the metabolic basis of FH-deficient kidney cancer are under development or are being evaluated in clinical trials, including the use of agents such as metformin, which would reverse the inactivation of AMPK, approaches to inhibit glucose transport, lactate dehydrogenase A (LDHA), the antioxidant response pathway, the heme oxygenase pathway, and approaches to target the tumor vasculature and glucose transport with agents such as bevacizumab and erlotinib. These same types of metabolic shifts, to aerobic glycolysis with decreased oxidative phosphorylation, have been found in a wide variety of other cancer types. Targeting the

  12. Molybdenum effector of fumarate reductase repression and nitrate reductase induction in Escherichia coli.

    PubMed Central

    Iuchi, S; Lin, E C

    1987-01-01

    In Escherichia coli the presence of nitrate prevents the utilization of fumarate as an anaerobic electron acceptor. The induction of the narC operon encoding the nitrate reductase is coupled to the repression of the frd operon encoding the fumarate reductase. This coupling is mediated by nitrate as an effector and the narL product as the regulatory protein (S. Iuchi and E. C. C. Lin, Proc. Natl. Acad. Sci. USA 84:3901-3905, 1987). The protein-ligand complex appears to control narC positively but frd negatively. In the present study we found that a molybdenum coeffector acted synergistically with nitrate in the regulation of frd and narC. In chlD mutants believed to be impaired in molybdate transport (or processing), full repression of phi(frd-lac) and full induction of phi(narC-lac) by nitrate did not occur unless the growth medium was directly supplemented with molybdate (1 microM). This requirement was not clearly manifested in wild-type cells, apparently because it was met by the trace quantities of molybdate present as a contaminant in the mineral medium. In chlB mutants, which are known to accumulate the Mo cofactor because of its failure to be inserted as a prosthetic group into proteins such as nitrate reductase, nitrate repression of frd and induction of narC were also intensified by molybdate supplementation. In this case a deficiency of the molybdenum coeffector might have resulted from enhanced feedback inhibition of molybdate transport (or processing) by the elevated level of the unutilized Mo cofactor. In addition, mutations in chlE, which are known to block the synthesis of the organic moiety of the Mo cofactor, lowered the threshold concentration of nitrate (< 1 micromole) necessary for frd repression and narC induction. These changes could be explained simply by the higher intracellular nitrate attainable in cells lacking the ability to destroy the effector. PMID:3301812

  13. Preparation and characterization of poly(propylene fumarate-co-ethylene glycol) hydrogels.

    PubMed

    Suggs, L J; Kao, E Y; Palombo, L L; Krishnan, R S; Widmer, M S; Mikos, A G

    1998-01-01

    We describe the preparation and bulk characterization of a cross-linked poly(propylene fumarate-co-ethylene glycol), p(PF-co-EG), hydrogel. Eight block copolymer formulations were made varying four different design parameters including: poly(ethylene glycol) (PEG) molecular weight, poly(propylene fumarate) (PPF) molecular weight, copolymer molecular weight, and ratio of PEG to PPF. Two different cross-linking formulations were also tested, one with a cross-linking monomer and one without. The extent of the cross-linking reaction and the degree of swelling in aqueous solution were determined on copolymer formulations made without a cross-linking monomer. The values of molecular weight between cross-links, Mc ranged from 300 +/- 120 to 1190 +/- 320 as determined from swelling data (n = 3). The equilibrium volume swelling ratios, Q, varied from 1.5 +/- 0.1 to 3.0 +/- 0.1. This ratio was found to increase with increasing PEG content in the copolymer and decrease with increasing PPF molecular weight. The values for complex dynamic elastic moduli magnitudes of E*, ranged from 0.9 +/- 0.2 to 13.1 +/- 1.1 MPa for the formulations with the cross-linking monomer, N-vinyl pyrrolidinone (VP) (n = 3). The ultimate tensile stresses on the formulations made with VP ranged from 0.15 +/- 0.03 to 1.44 +/- 1.06 MPa, and tensile moduli ranged from 1.11 +/- 0.20 to 20.66 +/- 2.42 MPa (n = 5). All of the mechanical properties increased with increasing PPF molecular weight and decreased with increasing PEG content in the copolymer. These data show that the physical properties of p(PF-co-EG) hydrogels can be tailored for specific applications by altering the material composition.

  14. Emtricitabine/rilpivirine/tenofovir disoproxil fumarate for the treatment of HIV-1 infection in adults.

    PubMed

    Kabbara, Wissam K; Ramadan, Wijdan H

    2015-01-01

    This paper reviews the current literature and information on the combination drug Complera(™) (rilpivirine/emtricitabine/tenofovir disoproxil fumarate) that was approved by the Food and Drug Administration (FDA) in August 2011. PubMed, Cochrane and Embase (2001-2014) were searched for primary and review articles on rilpivirine, emtricitabine, and tenofovir disoproxil fumarate, individually or in combination. Data from drug manufacturer and product label was also used. Clinical trial reports were selected, extracted and analyzed to include relevant and recent ones. Selected English-language trials were limited to those with human subjects and included both safety and efficacy outcomes. Results from two phase 3 randomized double blind trials (ECHO and THRIVE) showed that rilpivirine is non-inferior to efavirenz in suppressing viral load below 50 copies/mL in anti-retroviral therapy (ART) naïve human immunodeficiency virus (HIV) infected patients. In addition, psychiatric disturbances, rash and increase in lipid levels occurred less frequently with rilpivirine when compared to efavirenz. However, virological failure and drug resistance were higher with rilpivirine in patients with baseline viral load >100,000 copies/mL. Rilpivirine showed cross resistance to efavirenz and etravirine. Efavirenz, on the other hand, did not demonstrate cross resistance to rilpivirine and etravirine, leaving the latter drugs as options for use in case of virological failure with efavirenz. Complera(™) remains an acceptable alternative treatment to Atripla(™) in ART naïve patients who have a pre-ART plasma HIV RNA <100,000 copies/mL and CD4 count >200 cells/mm(3) with non-inferior efficacy and better safety and tolerability.

  15. Co-fermentation of a mixture of glucose and xylose to fumaric acid by Rhizopus arrhizus RH 7-13-9.

    PubMed

    Liu, Huan; Hu, Huirong; Jin, Yuhan; Yue, Xuemin; Deng, Li; Wang, Fang; Tan, Tianwei

    2017-02-11

    Lignocellulose is the most abundant biomass, composed of cellulose, hemicellulose and lignin. It can be converted into glucose and xylose, which could be utilized as carbon source to produce fumaric acid. But glucose and xylose were commonly used separately to produce fumaric acid, while the co-fermentation of glucose and xylose process was not studied so far. In this work, the co-fermentation process was researched through a new strain R. arrhizus RH 7-13-9# isolated from high concentration xylose. It was firstly proven to utilize glucose efficiently and 37.52g/L fumaric acid was obtained from 80g/L glucose. Furthermore, the effect of different ratios of glucose/xylose and carbon/nitrogen in the co-fermentation process was investigated and the best ratios were 75/25 (w/w) and 800/1 (w/w), where the yield of fumaric acid reached 46.78g/L.

  16. A randomized double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: analysis of week 96 results.

    PubMed

    Zolopa, Andrew; Sax, Paul E; DeJesus, Edwin; Mills, Anthony; Cohen, Calvin; Wohl, David; Gallant, Joel E; Liu, Hui C; Plummer, Andrew; White, Kirsten L; Cheng, Andrew K; Rhee, Martin S; Szwarcberg, Javier

    2013-05-01

    We report week 96 results from a phase 3 trial of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF, n = 348) vs efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF, n = 352). At week 48, EVG/COBI/FTC/TDF was noninferior to EFV/FTC/TDF (88% vs 84%, difference +3.6%, 95% confidence interval: -1.6% to 8.8%). Virologic success (HIV-1 RNA <50 copies/mL) was maintained at week 96 (84% vs 82%, difference +2.7%, 95% CI: -2.9% to 8.3%). Discontinuation due to adverse events was low (5% vs 7%). Median changes in serum creatinine (mg/dL) at week 96 were similar to week 48. These results support the durable efficacy and long-term safety of EVG/COBI/FTC/TDF.

  17. Utilization of Electrically Reduced Neutral Red by Actinobacillus succinogenes: Physiological Function of Neutral Red in Membrane-Driven Fumarate Reduction and Energy Conservation

    PubMed Central

    Park, D. H.; Zeikus, J. G.

    1999-01-01

    Neutral red (NR) functioned as an electronophore or electron channel enabling either cells or membranes purified from Actinobacillus succinogenes to drive electron transfer and proton translocation by coupling fumarate reduction to succinate production. Electrically reduced NR, unlike methyl or benzyl viologen, bound to cell membranes, was not toxic, and chemically reduced NAD. The cell membrane of A. succinogenes contained high levels of benzyl viologen-linked hydrogenase (12.2 U), fumarate reductase (13.1 U), and diaphorase (109.7 U) activities. Fumarate reductase (24.5 U) displayed the highest activity with NR as the electron carrier, whereas hydrogenase (1.1 U) and diaphorase (0.8 U) did not. Proton translocation by whole cells was dependent on either electrically reduced NR or H2 as the electron donor and on the fumarate concentration. During the growth of Actinobacillus on glucose plus electrically reduced NR in an electrochemical bioreactor system versus on glucose alone, electrically reduced NR enhanced glucose consumption, growth, and succinate production by about 20% while it decreased acetate production by about 50%. The rate of fumarate reduction to succinate by purified membranes was twofold higher with electrically reduced NR than with hydrogen as the electron donor. The addition of 2-(n-heptyl)-4-hydroxyquinoline N-oxide to whole cells or purified membranes inhibited succinate production from H2 plus fumarate but not from electrically reduced NR plus fumarate. Thus, NR appears to replace the function of menaquinone in the fumarate reductase complex, and it enables A. succinogenes to utilize electricity as a significant source of metabolic reducing power. PMID:10198002

  18. Fumarate and cytosolic pH as modulators of the synthesis or consumption of C(4) organic acids through NADP-malic enzyme in Arabidopsis thaliana.

    PubMed

    Arias, Cintia Lucía; Andreo, Carlos Santiago; Drincovich, María Fabiana; Gerrard Wheeler, Mariel Claudia

    2013-02-01

    Arabidopsis thaliana is a plant species that accumulates high levels of organic acids and uses them as carbon, energy and reducing power sources. Among the enzymes that metabolize these compounds, one of the most important ones is malic enzyme (ME). A. thaliana contains four malic enzymes (NADP-ME 1-4) to catalyze the reversible oxidative decarboxylation of malate in the presence of NADP. NADP-ME2 is the only one located in the cell cytosol of all Arabidopsis organs providing most of the total NADP-ME activity. In the present work, the regulation of this key enzyme by fumarate was investigated by kinetic assays, structural analysis and a site-directed mutagenesis approach. The final effect of this metabolite on NADP-ME2 forward activity not only depends on fumarate and substrate concentrations but also on the pH of the reaction medium. Fumarate produced an increase in NADP-ME2 activity by binding to an allosteric site. However at higher concentrations, fumarate caused a competitive inhibition, excluding the substrate malate from binding to the active site. The characterization of ME2-R115A mutant, which is not activated by fumarate, confirms this hypothesis. In addition, the reverse reaction (reductive carboxylation of pyruvate) is also modulated by fumarate, but in a different way. The results indicate pH-dependence of the fumarate modulation with opposite behavior on the two activities analyzed. Thereby, the coordinated action of fumarate over the direct and reverse reactions would allow a precise and specific modulation of the metabolic flux through this enzyme, leading to the synthesis or degradation of C(4) compounds under certain conditions. Thus, the physiological context might be exerting an accurate control of ME activity in planta, through changes in metabolite and substrate concentrations and cytosolic pH.

  19. Co-production of fumaric acid and chitin from a nitrogen-rich lignocellulosic material - dairy manure - using a pelletized filamentous fungus Rhizopus oryzae ATCC 20344.

    PubMed

    Liao, Wei; Liu, Yan; Frear, Craig; Chen, Shulin

    2008-09-01

    Fumaric acid is widely used as a food additive for flavor and preservation. Rhizopus oryzae ATCC 20344 is a fungus known for good fumaric acid production. It also has been reported that the fungal biomass has high chitin content. This study investigated the possibility of producing both fumaric acid and chitin via R. oryzae fermentation of dairy manure. Co-production of valuable bio-based chemicals such as fumaric acid and chitin could make the utilization of manure more efficient and more profitable. A three step fermentation process was developed which effectively utilized the nitrogen as well as the carbohydrate sources within the manure. These steps were: the culturing of pellet seed; biomass cultivation on liquid manure to produce both biomass and chitin; and fumaric acid production on the hydrolysate from the manure fiber. Under the identified optimal conditions, the fermentation system had a fumaric acid yield of 31%, and a biomass concentration of 11.5 g/L that contained 0.21 g chitin/g biomass.

  20. Production of fumaric acid from L-malic acid by solvent engineering using a recombinant thermostable fumarase from Thermus thermophilus HB8.

    PubMed

    Liu, Yanhui; Song, Jianing; Tan, Tianwei; Liu, Luo

    2015-03-01

    Currently, fumaric acid is produced by catalytic isomerization of maleic acid in aqueous solutions at low pH. Being petroleum based, requiring catalyst, and producing vast amounts of by-products and wastewater, the production of fumaric acid from renewable resources by a "green" process is increasingly attractive. In an aqueous solution, the reaction equilibrium constant of the fumarase-mediated conversion of L-malic acid to fumaric acid is 1:4.2 (fumaric acid to L-malic acid). To shift the reaction equilibrium to fumaric acid, solvent engineering was carried out by varying hydrophilic solvents and their concentrations. Generally, organic solvents may denature fumarase. Therefore, fumarase from Thermus thermophilus was employed to overcome this problem. Ethylene glycol was found more suitable than other solvents. This fumarase was shown to be more stable in 50% than in 70% ethylene glycol. Therefore, a preparation was carried out in 50% ethylene glycol. Under this condition, 54.7% conversion was observed using fumarase for transforming 1 mmol L-malic acid. After precipitation by adapting the pH, and washing to remove residual solvent and substrate, 27% total yield was obtained with 99% purity. The results demonstrated that the alternative green route to produce bio-based fumaric acid via L-malic acid is feasible and viable.

  1. The antiproliferative activity of all-trans-retinoic acid catabolites and isomers is differentially modulated by liarozole-fumarate in MCF-7 human breast cancer cells.

    PubMed

    Van heusden, J; Wouters, W; Ramaekers, F C; Krekels, M D; Dillen, L; Borgers, M; Smets, G

    1998-04-01

    The clinical use of all-trans-retinoic acid (ATRA) in the treatment of cancer is significantly hampered by the prompt emergence of resistance, believed to be caused by increased ATRA catabolism. Inhibitors of ATRA catabolism may therefore prove valuable for cancer therapy. Liarozole-fumarate is an anti-tumour drug that inhibits the cytochrome P450-dependent catabolism of ATRA. ATRA, but also its naturally occurring catabolites, 4-oxo-ATRA and 5,6-epoxy-ATRA, as well as its stereoisomers, 9-cis-RA and 13-cis-RA, show significant antiproliferative activity in MCF-7 human breast cancer cells. To further elucidate its mechanism of action, we investigated whether liarozole-fumarate was able to enhance the antiproliferative activity of ATRA catabolites and isomers. Liarozole-fumarate alone up to a concentration of 10(-6) M had no effect on MCF-7 cell proliferation. However, in combination with ATRA or the ATRA catabolites, liarozole-fumarate (10(-6) M) significantly enhanced their antiproliferative activity. On the contrary, liarozole-fumarate (10(-6) M) was not able to potentiate the antiproliferative activity of the ATRA stereoisomers, most probably because of the absence of cytochrome P450-dependent catabolism. Together, these findings show that liarozole-fumarate acts as a versatile inhibitor of retinoid catabolism in that it not only blocks the breakdown of ATRA, but also inhibits the catabolic pathway of 4-oxo-ATRA and 5,6-epoxy-ATRA, thereby enhancing their antiproliferative activity.

  2. Simultaneous Production and Recovery of Fumaric Acid from Immobilized Rhizopus oryzae with a Rotary Biofilm Contactor and an Adsorption Column

    PubMed Central

    Cao, N.; Du, J.; Gong, C. S.; Tsao, G. T.

    1996-01-01

    An integrated system of simultaneous fermentation-adsorption for the production and recovery of fumaric acid from glucose by Rhizopus oryzae was investigated. The system was constructed such that growing Rhizopus mycelia were self-immobilized on the plastic discs of a rotary biofilm contactor during the nitrogen-rich growth phase. During the nongrowth, production phase, the biofilm was alternately exposed to liquid medium and air upon rotation of the discs in the horizontal fermentation vessel. The product of fermentation, fumaric acid, was removed simultaneously and continuously by a coupled adsorption column, thereby moderating inhibition, enhancing the fermentation rate, and sustaining cell viability. Another beneficial effect of the removal of fumaric acid is release of hydroxyl ions from a polyvinyl pyridine adsorbent into the circulating fermentation broth. This moderates the decrease in pH that would otherwise occur. Polyvinyl pyridine and IRA-900 gave the highest loading for this type of fermentation. This fermentation system is capable of producing fumaric acid with an average yield of 85 g/liter from 100 g of glucose per liter within 20 h under repetitive fed-batch cycles. On a weight yield basis, 91% of the theoretical maximum was obtained with a productivity of 4.25 g/liter/h. This is in contrast to stirred-tank fermentation supplemented with calcium carbonate, whose average weight yield was 65% after 72 h with a productivity of 0.9 g/liter/h. The immobilized reactor was operated repetitively for 2 weeks without loss of biological activity. PMID:16535381

  3. Identification of Pseudomonas fluorescens Chemotaxis Sensory Proteins for Malate, Succinate, and Fumarate, and Their Involvement in Root Colonization

    PubMed Central

    Oku, Shota; Komatsu, Ayaka; Nakashimada, Yutaka; Tajima, Takahisa; Kato, Junichi

    2014-01-01

    Pseudomonas fluorescens Pf0-1 exhibited chemotactic responses to l-malate, succinate, and fumarate. We constructed a plasmid library of 37 methyl-accepting chemotaxis protein (MCP) genes of P. fluorescens Pf0-1. To identify a MCP for l-malate, the plasmid library was screened using the PA2652 mutant of Pseudomonas aeruginosa PAO1, a mutant defective in chemotaxis to l-malate. The introduction of Pfl01_0728 and Pfl01_3768 genes restored the ability of the PA2652 mutant to respond to l-malate. The Pfl01_0728 and Pfl01_3768 double mutant of P. fluorescens Pf0-1 showed no response to l-malate or succinate, while the Pfl01_0728 single mutant did not respond to fumarate. These results indicated that Pfl01_0728 and Pfl01_3768 were the major MCPs for l-malate and succinate, and Pfl01_0728 was also a major MCP for fumarate. The Pfl01_0728 and Pfl01_3768 double mutant unexpectedly exhibited stronger responses toward the tomato root exudate and amino acids such as proline, asparagine, methionine, and phenylalanine than those of the wild-type strain. The ctaA, ctaB, ctaC (genes of the major MCPs for amino acids), Pfl01_0728, and Pfl01_3768 quintuple mutant of P. fluorescens Pf0-1 was less competitive than the ctaA ctaB ctaC triple mutant in competitive root colonization, suggesting that chemotaxis to l-malate, succinate, and/or fumarate was involved in tomato root colonization by P. fluorescens Pf0-1. PMID:25491753

  4. Unravelling the impact of hydrocarbon structure on the fumarate addition mechanism--a gas-phase ab initio study.

    PubMed

    Bharadwaj, Vivek S; Vyas, Shubham; Villano, Stephanie M; Maupin, C Mark; Dean, Anthony M

    2015-02-14

    The fumarate addition reaction mechanism is central to the anaerobic biodegradation pathway of various hydrocarbons, both aromatic (e.g., toluene, ethyl benzene) and aliphatic (e.g., n-hexane, dodecane). Succinate synthase enzymes, which belong to the glycyl radical enzyme family, are the main facilitators of these biochemical reactions. The overall catalytic mechanism that converts hydrocarbons to a succinate molecule involves three steps: (1) initial H-abstraction from the hydrocarbon by the radical enzyme, (2) addition of the resulting hydrocarbon radical to fumarate, and (3) hydrogen abstraction by the addition product to regenerate the radical enzyme. Since the biodegradation of hydrocarbon fuels via the fumarate addition mechanism is linked to bio-corrosion, an improved understanding of this reaction is imperative to our efforts of predicting the susceptibility of proposed alternative fuels to biodegradation. An improved understanding of the fuel biodegradation process also has the potential to benefit bioremediation. In this study, we consider model aromatic (toluene) and aliphatic (butane) compounds to evaluate the impact of hydrocarbon structure on the energetics and kinetics of the fumarate addition mechanism by means of high level ab initio gas-phase calculations. We predict that the rate of toluene degradation is ∼100 times faster than butane at 298 K, and that the first abstraction step is kinetically significant for both hydrocarbons, which is consistent with deuterium isotope effect studies on toluene degradation. The detailed computations also show that the predicted stereo-chemical preference of the succinate products for both toluene and butane are due to the differences in the radical addition rate constants for the various isomers. The computational and kinetic modeling work presented here demonstrates the importance of considering pre-reaction and product complexes in order to accurately treat gas phase systems that involve intra and inter

  5. Influence of dietary phosphorus deficiency with or without addition of fumaric acid to a diet in pigs on bone parameters.

    PubMed

    Liesegang, A; Ursprung, R; Gasser, J; Sassi, M-L; Risteli, J; Riond, J-L; Wanner, M

    2002-02-01

    The purpose of this study was to examine if substantial bone loss occurs in weaned pigs by feeding a phosphorus-deficient diet with or without fumaric acid. Eighteen weaned pigs were used. The animals were assigned to three groups: group C (control; 0.65% P on DM basis), group LP (low phosphorus; 0.37% P on DM basis) and group LPF (low phosphorus plus fumaric acid; 0.35% P on DM basis plus 2% fumaric acid). These three diets were fed to the groups for a period of four weeks after a two-week adaptation period. Blood samples were collected once a week. Carboxyterminal telopeptide of type I collagen (ICTP) in serum was used as a bone resorption marker. Osteocalcin (OC) and bone-specific alkaline phosphatase (bAP) were used as bone formation markers. Bone mineral density (BMD) and content (BMC) were determined by peripheral quantitative computer tomography. BAP activities significantly increased (24%) in group LPF, and at the last sampling day group LPF had significantly increased activities in comparison to group C. In contrast, ICTP concentrations significantly increased with time in group LP and LPF, and at the last sampling day group LPF had significantly increased activities in comparison to group C. BMD and BMC in femur and tibia significantly decreased in group LP and LPF. The results show that P-deficient diets induce a bone loss. Fumaric acid did not influence the degree of bone loss. With a better understanding of its effect on bone, dietary phosphorus requirements in pigs could be more precisely defined.

  6. Advances in Nucleotide Antiviral Development from Scientific Discovery to Clinical Applications: Tenofovir Disoproxil Fumarate for Hepatitis B

    PubMed Central

    2013-01-01

    Exploration of naturally occurring chemical structures for medicinal uses has received significant interest in drug discovery and development research in the past few decades. None have had more success or products of greater clinical efficacy than synthetic analogs of nucleosides and nucleotides, especially as antiviral drugs. Nucleos(t)ide antivirals are synthetic analogs of the natural building blocks of DNA or RNA. This review focuses on the developmental path of tenofovir disoproxil fumarate (TDF), a prodrug of a nucleotide analog and its clinical applications as a first-line antiviral for chronic hepatitis B (CHB). Tenofovir is a potent antiviral compound, but has poor oral availability. The disoproxil fumarate (DF) prodrug moiety greatly enhances intestinal absorption allowing it to become an oral medication. Tenofovir is activated intracellularly, and the incorporation into HBV DNA prevents further elongation thus terminating replication. In patients with CHB, TDF has demonstrated broad, potent and sustained virologic response. Maintenance of viral suppression for up to 5 years resulted in regression of fibrosis and cirrhosis. No tenofovir-resistant HBV variants have been detected in patients after long-term use. The efficacy and safety profiles reported from cohort studies of clinical practices were consistent with those observed in registration trials. Continuous development includes a new oral prodrug, tenofovir alafenamide fumarate (TAF), which has enhanced delivery of tenofovir to target cells compared to TDF. PMID:26357604

  7. Anaerobic alkane biodegradation by cultures enriched from oil sands tailings ponds involves multiple species capable of fumarate addition.

    PubMed

    Tan, BoonFei; Semple, Kathleen; Foght, Julia

    2015-05-01

    A methanogenic short-chain alkane-degrading culture (SCADC) was enriched from oil sands tailings and transferred several times with a mixture of C6, C7, C8 and C10 n-alkanes as the predominant organic carbon source, plus 2-methylpentane, 3-methylpentane and methylcyclopentane as minor components. Cultures produced ∼40% of the maximum theoretical methane during 18 months incubation while depleting the n-alkanes, 2-methylpentane and methylcyclopentane. Substrate depletion correlated with detection of metabolites characteristic of fumarate activation of 2-methylpentane and methylcyclopentane, but not n-alkane metabolites. During active methanogenesis with the mixed alkanes, reverse-transcription PCR confirmed the expression of functional genes (assA and bssA) associated with hydrocarbon addition to fumarate. Pyrosequencing of 16S rRNA genes amplified during active alkane degradation revealed enrichment of Clostridia (particularly Peptococcaceae) and methanogenic Archaea (Methanosaetaceae and Methanomicrobiaceae). Methanogenic cultures transferred into medium containing sulphate produced sulphide, depleted n-alkanes and produced the corresponding succinylated alkane metabolites, but were slow to degrade 2-methylpentane and methylcyclopentane; these cultures were enriched in Deltaproteobacteria rather than Clostridia. 3-Methylpentane was not degraded by any cultures. Thus, nominally methanogenic oil sands tailings harbour dynamic and versatile hydrocarbon-degrading fermentative syntrophs and sulphate reducers capable of degrading n-, iso- and cyclo-alkanes by addition to fumarate.

  8. In vitro and in vivo evaluation of ketotifen fumarate-loaded silicone hydrogel contact lenses for ocular drug delivery.

    PubMed

    Xu, Jinku; Li, Xinsong; Sun, Fuqian

    2011-02-01

    The purpose of this work was to evaluate the usefulness of silicone hydrogel contact lenses loaded with ketotifen fumarate for ocular drug delivery. First, silicone contact lenses were prepared by photopolymerization of bitelechelic methacrylated polydimethylsiloxanes macromonomer, 3-methacryloxypropyltris(trimethylsiloxy)silane, and N,N-dimethylacrylamide using ethylene glycol dimethacrylate as a cross-linker and Darocur 1173 as an initiator followed by surface plasma treatment. Then, the silicone hydrogel matrices of the contact lenses were characterized by equilibrium swelling ratio (ESR), tensile tests, ion permeability, and surface contact angle. Finally, the contact lenses were loaded with ketotifen fumarate by pre-soaking in drug solution to evaluate drug loading capacity, in vitro and in vivo release behavior of the silicone contact lenses. The results showed that ESR and ion permeability increase, and the surface contact angle and tensile strength decreased with the increase of DMA component in the silicone hydrogel. The drug loading and in vitro releases were dependent on the hydrogel composition of hydrophilic/hydrophobic phase of the contact lenses. In rabbit eyes, the pre-soaked contact lenses sustained ketotifen fumarate release for more than 24 h, which leads to a more stable drug concentration and a longer mean retention time in tear fluid than that of eye drops of 0.05%.

  9. Anaerobic α-amylase production and secretion with fumarate as the final electron acceptor in Saccharomyces cerevisiae.

    PubMed

    Liu, Zihe; Österlund, Tobias; Hou, Jin; Petranovic, Dina; Nielsen, Jens

    2013-05-01

    In this study, we focus on production of heterologous α-amylase in the yeast Saccharomyces cerevisiae under anaerobic conditions. We compare the metabolic fluxes and transcriptional regulation under aerobic and anaerobic conditions, with the objective of identifying the final electron acceptor for protein folding under anaerobic conditions. We find that yeast produces more amylase under anaerobic conditions than under aerobic conditions, and we propose a model for electron transfer under anaerobic conditions. According to our model, during protein folding the electrons from the endoplasmic reticulum are transferred to fumarate as the final electron acceptor. This model is supported by findings that the addition of fumarate under anaerobic (but not aerobic) conditions improves cell growth, specifically in the α-amylase-producing strain, in which it is not used as a carbon source. Our results provide a model for the molecular mechanism of anaerobic protein secretion using fumarate as the final electron acceptor, which may allow for further engineering of yeast for improved protein secretion under anaerobic growth conditions.

  10. Opposite variations in fumarate and malate dominate metabolic phenotypes of Arabidopsis salicylate mutants with abnormal biomass under chilling.

    PubMed

    Scott, Ian M; Ward, Jane L; Miller, Sonia J; Beale, Michael H

    2014-12-01

    In chilling conditions (5°C), salicylic acid (SA)-deficient mutants (sid2, eds5 and NahG) of Arabidopsis thaliana produced more biomass than wild type (Col-0), whereas the SA overproducer cpr1 was extremely stunted. The hypothesis that these phenotypes were reflected in metabolism was explored using 600 MHz (1) H nuclear magnetic resonance (NMR) analysis of unfractionated polar shoot extracts. Biomass-related metabolic phenotypes were identified as multivariate data models of these NMR 'fingerprints'. These included principal components that correlated with biomass. Also, partial least squares-regression models were found to predict the relative size of plants in previously unseen experiments in different light intensities, or relative size of one genotype from the others. The dominant signal in these models was fumarate, which was high in SA-deficient mutants, intermediate in Col-0 and low in cpr1 at 5°C. Among signals negatively correlated with biomass, malate was prominent. Abundance of transcripts of the FUM2 cytosolic fumarase (At5g50950) showed strong positive correlation with fumarate levels and with biomass, whereas no significant differences were found for the FUM1 mitochondrial fumarase (At2g47510). It was confirmed that the morphological effects of SA under chilling find expression in the metabolome, with a role of fumarate highlighted.

  11. Biomimetic synthesis of poly(propylene-fumarate)-calcium phosphate composites for tissue engineering

    NASA Astrophysics Data System (ADS)

    Hakimi Mehr, Dorna

    A novel in-situ co-precipitation process for the synthesis of poly(propylene-fumarate)-calcium phosphate composites was developed. In this process the calcium phosphate phase nucleates and grows in the presence of poly(propylene-fumarate) (PPF), in a novel two-solvent system including tetrahydrofuran (THF) and water. It was found that the presence of the organic solvent (THF) does not affect the phase evolution of the calcium phosphate. Both in the presence and absence of THF crystalline dicalcium phosphate dihydrate (DCPD, brushite) and poorly crystalline hydroxyapatite (HAp) form, and transform to crystalline HAp after 24 hours of synthesis time. Contrary to the organic solvent, PPF has a significant influence on the calcium phosphate phase that forms in its presence. It is found that PPF provides a template for the formation of the calcium phosphate phase through a coordination bond between the calcium ion and the carbonyl group of the polymer. As a result of this templating, hydroxyapatite can form in a significantly shorter period of time (˜1 hr) compared to the system where PPF is not present (24 hrs). The nature of the calcium phosphate phase that forms in the presence of PPF depends on the molecular weight and concentration of PPF. High concentration of PPF in the composite (e.g. 80%) stabilizes an amorphous calcium phosphate (ACP) phase and hinders its transformation to crystalline apatite, while low concentration of PPF (e.g. 5%) promotes the formation of crystalline apatite. Higher molecular weight PPF (Mw = 4500) is found to be more efficient in stabilizing the amorphous phase compared to lower molecular weight PPF (Mw = 1800). While high molecular weight PPF stabilizes ACP, low molecular weight PPF promotes its conversion to crystalline apatite. TEM observations revealed that flake-like hydroxyapatite crystals form in the absence of PPF while spherical ACP particles form in a composite containing 80% PPF. The ACP nano-particles (50-100 nm in diameter

  12. Extrusion-based 3D printing of poly(propylene fumarate) scaffolds with hydroxyapatite gradients.

    PubMed

    Trachtenberg, Jordan E; Placone, Jesse K; Smith, Brandon T; Fisher, John P; Mikos, Antonios G

    2017-04-01

    The primary focus of this work is to present the current challenges of printing scaffolds with concentration gradients of nanoparticles with an aim to improve the processing of these scaffolds. Furthermore, we address how print fidelity is related to material composition and emphasize the importance of considering this relationship when developing complex scaffolds for bone implants. The ability to create complex tissues is becoming increasingly relevant in the tissue engineering community. For bone tissue engineering applications, this work demonstrates the ability to use extrusion-based printing techniques to control the spatial deposition of hydroxyapatite (HA) nanoparticles in a 3D composite scaffold. In doing so, we combined the benefits of synthetic, degradable polymers, such as poly(propylene fumarate) (PPF), with osteoconductive HA nanoparticles that provide robust compressive mechanical properties. Furthermore, the final 3D printed scaffolds consisted of well-defined layers with interconnected pores, two critical features for a successful bone implant. To demonstrate a controlled gradient of HA, thermogravimetric analysis was carried out to quantify HA on a per-layer basis. Moreover, we non-destructively evaluated the tendency of HA particles to aggregate within PPF using micro-computed tomography (μCT). This work provides insight for proper fabrication and characterization of composite scaffolds containing particle gradients and has broad applicability for future efforts in fabricating complex scaffolds for tissue engineering applications.

  13. Selenite reduction by Shewanella oneidensis MR-1 is mediated by fumarate reductase in periplasm

    PubMed Central

    Li, Dao-Bo; Cheng, Yuan-Yuan; Wu, Chao; Li, Wen-Wei; Li, Na; Yang, Zong-Chuang; Tong, Zhong-Hua; Yu, Han-Qing

    2014-01-01

    In situ reduction of selenite to elemental selenium (Se(0)), by microorganisms in sediments and soils is an important process and greatly affects the environmental distribution and the biological effects of selenium. However, the mechanism behind such a biological process remains unrevealed yet. Here we use Shewanella oneidensis MR-1, a widely-distributed dissimilatory metal-reducing bacterium with a powerful and diverse respiration capability, to evaluate the involvement of anaerobic respiration system in the microbial selenite reduction. With mutants analysis, we identify fumarate reductase FccA as the terminal reductase of selenite in periplasm. Moreover, we find that such a reduction is dependent on central respiration c-type cytochrome CymA. In contrast, nitrate reductase, nitrite reductase, and the Mtr electron transfer pathway do not work as selenite reductases. These findings reveal a previously unrecognized role of anaerobic respiration reductases of S. oneidensis MR-1 in selenite reduction and geochemical cycles of selenium in sediments and soils. PMID:24435070

  14. Single dose of ketotifen fumarate .025% vs 2 weeks of cromolyn sodium 4% for allergic conjunctivitis.

    PubMed

    Greiner, Jack V; Michaelson, Clifford; McWhirter, Cecilia L; Shams, Naveed B K

    2002-01-01

    This single-masked, contralateral-eye, active-controlled allergen-challenge study compared ketotifen fumarate .025% and cromolyn sodium 4% ophthalmic solutions in the prevention of ocular itching, tearing, and redness induced by allergen challenge. After a confirmatory conjunctival provocation test (CPT), 56 patients randomly received masked study medication (placebo in one eye, cromolyn in the other eye) four times daily for 2 weeks. At visit 3, patients received one drop of ketotifen in the eye previously treated with placebo and cromolyn in the other eye. Ocular comfort was assessed 30 seconds postinstillation, and a CPT was conducted 15 minutes and 4 hours postinstillation to evaluate ocular itching, tearing, and redness. Forty-seven patients were analyzed for efficacy. At the 15-minute and 4-hour challenges, ketotifen was superior to cromolyn in preventing itching (P < .001) at all assessments and redness (ciliary, conjunctival, and episcleral) (P < or = .001) at most assessments. Tearing scores were higher in cromolyn-treated eyes than in ketotifen-treated eyes. Patients reported greater comfort in the ketotifen-treated than in the cromolyn-treated eye (P = .066). The most common adverse event was burning/stinging with cromolyn. A single dose of ketotifen was superior to a 2-week four-times-daily regimen of cromolyn in alleviating symptoms of allergic conjunctivitis in the conjunctival allergen-challenge model.

  15. Dual bronchodilator therapy with aclidinium bromide/formoterol fumarate for chronic obstructive pulmonary disease.

    PubMed

    D'Urzo, Tony; Donohue, James F; Price, David; Miravitlles, Marc; Kerwin, Edward

    2015-10-01

    Inhaled bronchodilator therapy is a mainstay of treatment for chronic obstructive pulmonary disease (COPD). Despite the number and types of treatments available, the control of symptoms and exacerbations remains suboptimal, and adherence to, and persistence with, inhaled therapy is generally poor. Results from clinical studies suggest that dual bronchodilator therapy with long-acting muscarinic receptor antagonists (LAMAs) and long-acting β2 adrenergic receptor agonists (LABAs) may provide additional benefit over LAMA or LABA monotherapy without additive effects on safety and tolerability. Several combinations of a LAMA plus a LABA have recently become available in a single inhaler for maintenance therapy for adults with moderate-to-severe COPD, including aclidinium bromide/formoterol fumarate, glycopyrronium/indacaterol and umeclidinium/vilanterol. Here, we review clinical data demonstrating significant improvements in bronchodilation, 24-h symptoms, and health status with aclidinium/formoterol twice daily, and discuss how this treatment can be implemented in clinical practice as part of a patient-focused approach to disease control.

  16. Oral delivery of insulin loaded poly(fumaric-co-sebacic) anhydride microspheres.

    PubMed

    Furtado, Stacia; Abramson, Danielle; Burrill, Roxanne; Olivier, Gloria; Gourd, Celinda; Bubbers, Emily; Mathiowitz, Edith

    2008-01-22

    The bioadhesive polymer, poly(fumaric-co-sebacic) anhydride, p(FASA), was used to fabricate small diameter insulin microspheres and evaluate their in vivo performance in a type 1 diabetic rat as well as a type 1 diabetic dog model. The process of phase inversion nanoencapsulation was used to fabricate p(FASA) microspheres containing insulin. Using laser diffraction spectrometry, 90% of the microspheres used in the fed double dose rat experiments were found to have a volumetric diameter of 5.9 microm or smaller. In comparison, 90% of the microspheres used in fed single dose rat experiments were found to have a volumetric diameter of 2.6 microm or smaller while the microspheres used in the diabetic dog experiments were found to have a volumetric diameter of 1.2 microm or smaller. Insulin microspheres administered to diabetic rats in the fed double dose experiment produced a relative bioavailability (RB) of 23.3% while insulin microspheres administered to diabetic rats in the fed single dose experiment produced a RB of 5.5+/-1.7%. Insulin microspheres administered to fasted diabetic dogs produced a RB of 5.5+/-3.4%.

  17. Effects of fumaric acid esters on blood-brain barrier tight junction proteins.

    PubMed

    Bénardais, Karelle; Pul, Refik; Singh, Vikramjeet; Skripuletz, Thomas; Lee, De-Hyung; Linker, Ralf A; Gudi, Viktoria; Stangel, Martin

    2013-10-25

    The blood-brain barrier (BBB) is composed of a network of tight junctions (TJ) which interconnect cerebral endothelial cells (EC). Alterations in the TJ proteins are common in inflammatory diseases of the central nervous system (CNS) like multiple sclerosis (MS). Modulation of the BBB could thus represent a therapeutic mechanism. One pathway to modulate BBB integrity could be the induction of nuclear-factor (erythroid derived 2) related factor-2 (Nrf2) mediated oxidative stress responses which are targeted by fumaric acid esters (FAE). Here we analyze effects of FAE on the expression of TJ proteins in the human cerebral endothelial cell line hCMEC/D3 and experimental autoimmune encephalomyelitis (EAE). We show that dimethylfumarate (DMF) and its primary metabolite monomethylfumarate (MMF) induce the expression of the Nrf2/NQO1 pathway in endothelial cells. Neither MMF nor DMF had a consistent modulatory effect on the expression of TJ molecules in hCMEC/D3 cells. Tumor necrosis factor (TNFα)-induced downregulation of TJ proteins was at least partially reversed by treatment with FAE. However, DMF had no effect on claudin-5 expression in EAE, despite its effect on the clinical score and infiltration of immune cells. These data suggest that the modulation of the BBB is not a major mechanism of action of FAE in inflammatory demyelinating diseases of the CNS.

  18. Tenofovir Disoproxil Fumarate: Toxicity, Toxicokinetics, and Toxicogenomics Analysis After 13 Weeks of Oral Administration in Mice

    PubMed Central

    Ng, Hanna H.; Stock, Howard; Rausch, Linda; Bunin, Deborah; Wang, Abraham; Brill, Shirley; Gow, Jason; Mirsalis, Jon C.

    2014-01-01

    Tenofovir disoproxil fumarate (TDF) is a prodrug of tenofovir that exhibits activity against human immunodeficiency virus (HIV) and hepatitis B. The goals of this study were to evaluate the molecular mechanism of TDF-induced toxicity in mice after 13 weeks of daily oral administration (50–1000 mg/kg) by correlating transcriptional changes with plasma drug levels and traditional toxicology endpoints. Plasma levels and systemic exposure of tenofovir increased less than dose-proportionally, and were similar on Days 1 and 91. No overt toxicity was observed following the completion of TDF administration. The kidneys of TDF-treated mice were histopathologically normal. This result is consistent with the genomic microarray results, which showed no significant differences in kidney transcriptional levels between TDF-treated animals and controls. In liver, cytomegaly was observed in mice treated with 1000 mg/kg of TDF after 4 and 13 weeks of TDF-treatment, but mice recovered from this effect following cessation of administration. Analysis of liver transcripts on Day 91 reported elevated levels of Cdkn1a in TDF-treated animals compared with controls, which may have contributed to the inhibition of liver cell cycle progression. PMID:25568137

  19. Fumaric Acid and Slightly Acidic Electrolyzed Water Inactivate Gram Positive and Gram Negative Foodborne Pathogens.

    PubMed

    Tango, Charles Nkufi; Mansur, Ahmad Rois; Oh, Deog-Hwan

    2015-02-12

    Sanitizing effectiveness of slightly acidic electrolyzed water (SAEW) and fumaric acid (FA) at different dipping temperatures (25-60 °C), times (1-5 min), and concentrations (5-30 ppm for SAEW and 0.125%-0.5% for FA) on pure cultures of two Gram positive pathogens Staphylococcus aureus (SA) and Listeria monocytogenes (LM) and two Gram negative pathogens Escherichia coli O157:H7 (EC) and Salmonella Typhimurium (ST) was evaluated. FA (0.25%) showed the strongest sanitizing effect, demonstrating complete inactivation of EC, ST, and LM, while SA was reduced by 3.95-5.76 log CFU/mL at 25-60 °C, respectively, after 1 min of treatment. For SAEW, the complete inactivation was obtained when available chlorine concentration was increased to 20 ppm at 40 °C for 3 and 5 min. Moreover, Gram positive pathogens have been shown to resist to all treatment trends more than Gram negative pathogens throughout this experiment. Regardless of the different dipping temperatures, concentrations, and times, FA treatment was more effective than treatment with SAEW for reduction of foodborne pathogens. This study demonstrated that application of FA in food systems may be useful as a method for inactivation of foodborne pathogens.

  20. Chitosan/polyethylene glycol fumarate blend film: physical and antibacterial properties.

    PubMed

    Hashemi Doulabi, Azadehsadat; Mirzadeh, Hamid; Imani, Mohammad; Samadi, Nasrin

    2013-01-30

    The objective of this work was to prepare chitosan/polyethylene glycol fumarate (chitosan/PEGF) blend films as wound dressings and to evaluate the influence of composition ratio on the blending properties of the films. Blending chitosan with PEGF obviated the brittleness of neat chitosan film. Film topography performed by atomic force microscopy illustrated that blending could increase and control the surface roughness of the neat film. Their water vapor transmission rates were close to the range of 904-1447 g(-2)day(-1) found to be proper candidates for dressing the wounds with moderate exudates. Controlled water solubility, swelling, wettability and surface tension of the blend films were also evaluated. The blend films showed a powerful antibacterial activity against Pseudomonas aeruginosa and Staphylococcus aureus (Kill%>99.76 ± 0.16%). Physical properties as well as antibacterial activity assessments showed that among different compositions, the film comprising 80 wt% chitosan and 20 wt% PEGF is a suitable candidate for biomedical applications as a wound dressing material.

  1. Poly(propylene fumarate)/Polyethylene Glycol-Modified Graphene Oxide Nanocomposites for Tissue Engineering.

    PubMed

    Díez-Pascual, Ana M; Díez-Vicente, Angel L

    2016-07-20

    Poly(propylene fumarate) (PPF)-based nanocomposites incorporating different amounts of polyethylene glycol-functionalized graphene oxide (PEG-GO) have been prepared via sonication and thermal curing, and their surface morphology, structure, thermal stability, hydrophilicity, water absorption, biodegradation, cytotoxicity, mechanical, viscoelastic and antibacterial properties have been investigated. SEM and TEM images corroborated that the noncovalent functionalization with PEG caused the exfoliation of GO into thinner flakes. IR spectra suggested the presence of strong hydrogen-bonding interactions between the nanocomposite components. A gradual rise in the level of hydrophilicity, water uptake, biodegradation rate, surface roughness, protein absorption capability and thermal stability was found upon increasing GO concentration in the composites. Tensile tests revealed improved stiffness, strength and toughness for the composites compared to unfilled PPF, ascribed to a homogeneous GO dispersion within the matrix along with a strong PPF/PEG-GO interfacial adhesion via polar and hydrogen bonding interactions. Further, the nanocomposites retained enough stiffness and strength under a biological state to provide effective support for bone tissue formation. The antibacterial activity was investigated against Gram-positive Staphylococcus aureus and Staphylococcus epidermidis as well as Gram-negative Pseudomonas aeruginosa and Escherichia coli microorganisms, and it rose sharply upon increasing GO concentration; systematically, the biocide effect was stronger versus Gram-positive bacteria. Cell viability data demonstrated that PPF/PEG-GO composites do not induce toxicity over human dermal fibroblasts. These novel materials show great potential to be applied in the bone tissue engineering field.

  2. Effect of Prevascularization on In Vivo Vascularization of Poly(Propylene fumarate)/Fibrin Scaffolds

    PubMed Central

    Mishra, Ruchi; Roux, Brianna M.; Posukonis, Megan; Bodamer, Emily; Brey, Eric M.; Fisher, John P.; Dean, David

    2016-01-01

    The importance of vascularization in the field of bone tissue engineering has been established by previous studies. The present work proposes a novel poly(propylene fumarate) (PPF)/fibrin composite scaffold for the development of vascularized neobone tissue. The effect of prevascularization (i.e., in vitro pre-culture prior to implantation) with human mesenchymal stem cells (hMSCs) and human umbilical vein endothelial cells (HUVECs) on in vivo vascularization of scaffolds was determined. Five conditions were studied: no pre-culture (NP), 1 week preculture (1P), 2 week pre-culture (2P), 3 week pre-culture (3P), and scaffolds without cells (control, C). Scaffolds were implanted subcutaneously in a severe combined immunodeficiency (SCID) mice model for 9 days. During in vitro studies, CD31 staining showed a significant increase in vascular network area over 3 weeks of culture. Vascular density was significantly higher in vivo when comparing NP to 3P groups. Immunohistochemical staining of human CD-31 expression indicated spreading of vascular networks with increasing pre-culture time. These vascular networks were perfused with mouse blood indicated by perfused lectin staining in human CD-31 positive vessels. Our results demonstrate that in vitro prevascularization supports in vivo vascularization in PPF/fibrin scaffolds. PMID:26606451

  3. Dimethyl fumarate attenuates cerebral edema formation by protecting the blood-brain barrier integrity.

    PubMed

    Kunze, Reiner; Urrutia, Andrés; Hoffmann, Angelika; Liu, Hui; Helluy, Xavier; Pham, Mirko; Reischl, Stefan; Korff, Thomas; Marti, Hugo H

    2015-04-01

    Brain edema is a hallmark of various neuropathologies, but the underlying mechanisms are poorly understood. We aim to characterize how tissue hypoxia, together with oxidative stress and inflammation, leads to capillary dysfunction and breakdown of the blood-brain barrier (BBB). In a mouse stroke model we show that systemic treatment with dimethyl fumarate (DMF), an antioxidant drug clinically used for psoriasis and multiple sclerosis, significantly prevented edema formation in vivo. Indeed, DMF stabilized the BBB by preventing disruption of interendothelial tight junctions and gap formation, and decreased matrix metalloproteinase activity in brain tissue. In vitro, DMF directly sustained endothelial tight junctions, inhibited inflammatory cytokine expression, and attenuated leukocyte transmigration. We also demonstrate that these effects are mediated via activation of the redox sensitive transcription factor NF-E2 related factor 2 (Nrf2). DMF activated the Nrf2 pathway as shown by up-regulation of several Nrf2 target genes in the brain in vivo, as well as in cerebral endothelial cells and astrocytes in vitro, where DMF also increased protein abundance of nuclear Nrf2. Finally, Nrf2 knockdown in endothelial cells aggravated subcellular delocalization of tight junction proteins during ischemic conditions, and attenuated the protective effect exerted by DMF. Overall, our data suggest that DMF protects from cerebral edema formation during ischemic stroke by targeting interendothelial junctions in an Nrf2-dependent manner, and provide the basis for a completely new approach to treat brain edema.

  4. Structural Insights into the Molecular Design of Flutolanil Derivatives Targeted for Fumarate Respiration of Parasite Mitochondria

    PubMed Central

    Inaoka, Daniel Ken; Shiba, Tomoo; Sato, Dan; Balogun, Emmanuel Oluwadare; Sasaki, Tsuyoshi; Nagahama, Madoka; Oda, Masatsugu; Matsuoka, Shigeru; Ohmori, Junko; Honma, Teruki; Inoue, Masayuki; Kita, Kiyoshi; Harada, Shigeharu

    2015-01-01

    Recent studies on the respiratory chain of Ascaris suum showed that the mitochondrial NADH-fumarate reductase system composed of complex I, rhodoquinone and complex II plays an important role in the anaerobic energy metabolism of adult A. suum. The system is the major pathway of energy metabolism for adaptation to a hypoxic environment not only in parasitic organisms, but also in some types of human cancer cells. Thus, enzymes of the pathway are potential targets for chemotherapy. We found that flutolanil is an excellent inhibitor for A. suum complex II (IC50 = 0.058 μM) but less effectively inhibits homologous porcine complex II (IC50 = 45.9 μM). In order to account for the specificity of flutolanil to A. suum complex II from the standpoint of structural biology, we determined the crystal structures of A. suum and porcine complex IIs binding flutolanil and its derivative compounds. The structures clearly demonstrated key interactions responsible for its high specificity to A. suum complex II and enabled us to find analogue compounds, which surpass flutolanil in both potency and specificity to A. suum complex II. Structures of complex IIs binding these compounds will be helpful to accelerate structure-based drug design targeted for complex IIs. PMID:26198225

  5. In vivo degradation of a poly(propylene fumarate)/beta-tricalcium phosphate injectable composite scaffold.

    PubMed

    Peter, S J; Miller, S T; Zhu, G; Yasko, A W; Mikos, A G

    1998-07-01

    This study was designed to investigate the in vivo biodegration and biocompatibility of a poly(propylene fumarate) (PPF)-based orthopedic biomaterial. The effects of varying the PPF to N-vinyl pyrrolidinone ratio and PPF to beta-tricalcium phosphate content were studied. The composite mechanical properties and local tissue interactions were analyzed over 12 weeks. An initial increase in both compressive modulus and strength was seen for composite formulations that incorporated beta-tricalcium phosphate. The samples incorporating a higher PPF to N-vinyl pyrrolidinone ratio reached a maximal compressive strength of 7.7 MPa and a maximal compressive modulus of 191.4 MPa at 3 weeks. The lower PPF to N-vinyl pyrrolidinone ratio samples gained a maximum compressive strength of 7.5 MPa initially and a compressive modulus of 134.0 MPa at 1 week. At 6 weeks, all samples for formulations incorporating beta-tricalcium phosphate crumbled upon removal and were not mechanically tested. Samples that did not incorporate beta-tricalcium phosphate were very weak and insufficient for bone replacement at the 4-day time point and beyond. Tissue interactions resulted in a mild inflammatory response at the initial time points and mature fibrous encapsulation by 12 weeks.

  6. Comparison of Different Nanosuspensions as Potential Ophthalmic Delivery Systems for Ketotifen Fumarate

    PubMed Central

    Soltani, Saieede; Zakeri-Milani, Parvin; Barzegar-Jalali, Mohammad; Jelvehgari, Mitra

    2016-01-01

    Purpose: The objective of this study was to develop, characterize, and comparatively investigate the ketotifen fumarate (KF) nanosuspensions (NSS) to enhance the permeability of KF. Methods: In the present work, the NSP and NSE were prepared by double-emulsion solvent evaporation/nanoprecipitation methods with poly (D,Llactide-co-glycolide) and Eudragit RL100 polymers, respectively. The loading efficiency, particle size, and polydispersity index of prepared different NSs were evaluated with scanning electron microscopy (SEM), X-ray diffraction, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and in vitro release and transcorneal permeation . NSs were also compared on the basis of particle size and polydispersity index. Results: Particle size, polydispersity index, and loading efficiency of NSP1 and NSE3 showed the best value (158 nm, 117 nm, 0.21, 0.43 and 43%, 95.23%, respectively). SEM showed spherical globules and DSC results showed the reduction in crystallinity. The NSE3 formulations demonstrated significantly (p<0.05) higher drug release rates than the NSP1 due to increases in the surface area. Comparative studies showed that NSE release and permeability are higher than NSP. Conclusion: It is concluded that both NSP and NSE provide a useful dosage form for the ocular drug delivery which can enhance the permeability of KF. PMID:27766218

  7. Structural Insights into the Molecular Design of Flutolanil Derivatives Targeted for Fumarate Respiration of Parasite Mitochondria.

    PubMed

    Inaoka, Daniel Ken; Shiba, Tomoo; Sato, Dan; Balogun, Emmanuel Oluwadare; Sasaki, Tsuyoshi; Nagahama, Madoka; Oda, Masatsugu; Matsuoka, Shigeru; Ohmori, Junko; Honma, Teruki; Inoue, Masayuki; Kita, Kiyoshi; Harada, Shigeharu

    2015-07-07

    Recent studies on the respiratory chain of Ascaris suum showed that the mitochondrial NADH-fumarate reductase system composed of complex I, rhodoquinone and complex II plays an important role in the anaerobic energy metabolism of adult A. suum. The system is the major pathway of energy metabolism for adaptation to a hypoxic environment not only in parasitic organisms, but also in some types of human cancer cells. Thus, enzymes of the pathway are potential targets for chemotherapy. We found that flutolanil is an excellent inhibitor for A. suum complex II (IC50 = 0.058 μM) but less effectively inhibits homologous porcine complex II (IC50 = 45.9 μM). In order to account for the specificity of flutolanil to A. suum complex II from the standpoint of structural biology, we determined the crystal structures of A. suum and porcine complex IIs binding flutolanil and its derivative compounds. The structures clearly demonstrated key interactions responsible for its high specificity to A. suum complex II and enabled us to find analogue compounds, which surpass flutolanil in both potency and specificity to A. suum complex II. Structures of complex IIs binding these compounds will be helpful to accelerate structure-based drug design targeted for complex IIs.

  8. The Development of Electrically Conductive Polycaprolactone Fumarate-Polypyrrole Composite Materials for Nerve Regeneration

    PubMed Central

    Runge, M. Brett; Dadsetan, Mahrokh; Baltrusaitis, Jonas; Knight, Andrew M.; Ruesink, Terry; Lazcano, Eric; Lu, Lichun; Windebank, Anthony J.; Yaszemski, Michael J.

    2010-01-01

    Electrically conductive polymer composites composed of polycaprolactone fumarate and polypyrrole (PCLF-PPy) have been developed for nerve regeneration applications. Here we report the synthesis and characterization of PCLF-PPy and in vitro studies showing PCLF-PPy materials support both PC12 cell and dorsal root ganglia (DRG) neurite extension. PCLF-PPy composite materials were synthesized by polymerizing pyrrole in pre-formed PCLF scaffolds (Mn 7,000 or 18,000 g mol−1) resulting in interpenetrating networks of PCLF-PPy. Chemical compositions and thermal properties were characterized by ATR-FTIR, XPS, DSC, and TGA. PCLF-PPy materials were synthesized with five different anions (naphthalene-2-sulfonic acid sodium salt (NSA), dodecylbenzenesulfonic acid sodium salt (DBSA), dioctyl sulfosuccinate sodium salt (DOSS), potassium iodide (I), and lysine) to investigate effects on electrical conductivity and to optimize chemical composition for cellular compatibility. PCLF-PPy materials have variable electrical conductivity up to 6 mS cm−1 with bulk compositions ranging from 5 to 13.5 percent polypyrrole. AFM and SEM characterization show microstructures with a root mean squared (RMS) roughness of 1195 nm and nanostructures with RMS roughness of 8 nm. In vitro studies using PC12 cells and DRG show PCLF-PPy materials synthesized with NSA or DBSA support cell attachment, proliferation, neurite extension, and are promising materials for future studies involving electrical stimulation. PMID:20483452

  9. Fumaric Acid and Slightly Acidic Electrolyzed Water Inactivate Gram Positive and Gram Negative Foodborne Pathogens

    PubMed Central

    Tango, Charles Nkufi; Mansur, Ahmad Rois; Oh, Deog-Hwan

    2015-01-01

    Sanitizing effectiveness of slightly acidic electrolyzed water (SAEW) and fumaric acid (FA) at different dipping temperatures (25–60 °C), times (1–5 min), and concentrations (5–30 ppm for SAEW and 0.125%–0.5% for FA) on pure cultures of two Gram positive pathogens Staphylococcus aureus (SA) and Listeria monocytogenes (LM) and two Gram negative pathogens Escherichia coli O157:H7 (EC) and Salmonella Typhimurium (ST) was evaluated. FA (0.25%) showed the strongest sanitizing effect, demonstrating complete inactivation of EC, ST, and LM, while SA was reduced by 3.95–5.76 log CFU/mL at 25–60 °C, respectively, after 1 min of treatment. For SAEW, the complete inactivation was obtained when available chlorine concentration was increased to 20 ppm at 40 °C for 3 and 5 min. Moreover, Gram positive pathogens have been shown to resist to all treatment trends more than Gram negative pathogens throughout this experiment. Regardless of the different dipping temperatures, concentrations, and times, FA treatment was more effective than treatment with SAEW for reduction of foodborne pathogens. This study demonstrated that application of FA in food systems may be useful as a method for inactivation of foodborne pathogens. PMID:27682077

  10. Extrafine beclometasone diproprionate/formoterol fumarate: a review of its effects in chronic obstructive pulmonary disease.

    PubMed

    Singh, Dave; Corradi, Massimo; Spinola, Monica; Petruzzelli, Stefano; Papi, Alberto

    2016-06-16

    A fixed-dose inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) combination of extrafine beclometasone dipropionate and formoterol fumarate (BDP/FF) has been recently approved for use in chronic obstructive pulmonary disease (COPD). Small airway inflammation and remodelling are cardinal features of COPD; therefore, the ability of this extrafine formulation to reach the small, as well as the large, airways is likely to be therapeutically important by enabling treatment of inflammatory processes in the whole bronchial tree. The clinical development of extrafine BDP/FF has demonstrated significant benefits over extrafine FF in terms of lung function improvement and reduction of the exacerbation rate, thus supporting the beneficial effect of an ICS combined to a LABA in COPD patients. Head-to-head comparison studies versus other ICS/LABA combinations have shown that the extrafine formulation enables the clinical benefits to be achieved with a lower dose of ICS. Extrafine BDP/FF showed lung function and dyspnoea improvements comparable to other ICS/LABAs, and a significantly faster onset of action was observed when compared with a salmeterol-containing fixed-dose combination. This review summarises the clinical evidence supporting the efficacy of extrafine BDP/FF in COPD and confirming that extrafine BDP/FF achieves the type of health benefit expected from such a targeted ICS/LABA combination in COPD.

  11. Extrafine beclometasone diproprionate/formoterol fumarate: a review of its effects in chronic obstructive pulmonary disease

    PubMed Central

    Singh, Dave; Corradi, Massimo; Spinola, Monica; Petruzzelli, Stefano; Papi, Alberto

    2016-01-01

    A fixed-dose inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) combination of extrafine beclometasone dipropionate and formoterol fumarate (BDP/FF) has been recently approved for use in chronic obstructive pulmonary disease (COPD). Small airway inflammation and remodelling are cardinal features of COPD; therefore, the ability of this extrafine formulation to reach the small, as well as the large, airways is likely to be therapeutically important by enabling treatment of inflammatory processes in the whole bronchial tree. The clinical development of extrafine BDP/FF has demonstrated significant benefits over extrafine FF in terms of lung function improvement and reduction of the exacerbation rate, thus supporting the beneficial effect of an ICS combined to a LABA in COPD patients. Head-to-head comparison studies versus other ICS/LABA combinations have shown that the extrafine formulation enables the clinical benefits to be achieved with a lower dose of ICS. Extrafine BDP/FF showed lung function and dyspnoea improvements comparable to other ICS/LABAs, and a significantly faster onset of action was observed when compared with a salmeterol-containing fixed-dose combination. This review summarises the clinical evidence supporting the efficacy of extrafine BDP/FF in COPD and confirming that extrafine BDP/FF achieves the type of health benefit expected from such a targeted ICS/LABA combination in COPD. PMID:27309985

  12. Safety of Oral Tenofovir Disoproxil Fumarate-Based Pre-Exposure Prophylaxis for HIV Prevention

    PubMed Central

    Mugwanya, Kenneth K.; Baeten, Jared M.

    2016-01-01

    Introduction Tenofovir disoproxil fumarate (TDF)-based pre-exposure prophylaxis is a novel HIV prevention strategy for individuals at increased sexual risk for HIV infection. For any biomedical prevention intervention, the bar for tolerating adverse effects in healthy persons is high compared to therapeutic interventions. Areas covered We provide a concise summary of the clinical safety of TDF-based pre-exposure prophylaxis with focus on TDF-related effects on tolerability and side effects, kidney function, bone density, HIV resistance, sexual and reproductive health. The evidence base for this review is derived from a literature search of both randomized and observational studies evaluating efficacy and safety of TDF-based PrEP, TDF alone or in combination with emtricitabine, identified from PUBMED and EMBASE electronic databases, clinicaltrials.gov and major HIV conferences. Expert opinion TDF-based pre-exposure prophylaxis is a potent intervention against HIV acquisition when taken which is generally safe and well tolerated. The risk of the small, non-progressive, and reversible decline in glomerular filtration rate and bone mineral density as well as the potential selection for drug resistance associated with PrEP are outweighed, at the population level and broadly for individuals, by PrEP’s substantial reduction in the risk of HIV infection. PMID:26634852

  13. Dimethyl Fumarate ameliorates pulmonary arterial hypertension and lung fibrosis by targeting multiple pathways

    PubMed Central

    Grzegorzewska, Agnieszka P.; Seta, Francesca; Han, Rong; Czajka, Caitlin A.; Makino, Katsunari; Stawski, Lukasz; Isenberg, Jeffrey S.; Browning, Jeffrey L.; Trojanowska, Maria

    2017-01-01

    Pulmonary arterial hypertension (PAH) is a fatal condition for which there is no cure. Dimethyl Fumarate (DMF) is an FDA approved anti-oxidative and anti-inflammatory agent with a favorable safety record. The goal of this study was to assess the effectiveness of DMF as a therapy for PAH using patient-derived cells and murine models. We show that DMF treatment is effective in reversing hemodynamic changes, reducing inflammation, oxidative damage, and fibrosis in the experimental models of PAH and lung fibrosis. Our findings indicate that effects of DMF are facilitated by inhibiting pro-inflammatory NFκB, STAT3 and cJUN signaling, as well as βTRCP-dependent degradation of the pro-fibrogenic mediators Sp1, TAZ and β-catenin. These results provide a novel insight into the mechanism of its action. Collectively, preclinical results demonstrate beneficial effects of DMF on key molecular pathways contributing to PAH, and support its testing in PAH treatment in patients. PMID:28150703

  14. Comparison of Different Nanosuspensions as Potential Ophthalmic Delivery Systems for Ketotifen Fumarate.

    PubMed

    Soltani, Saieede; Zakeri-Milani, Parvin; Barzegar-Jalali, Mohammad; Jelvehgari, Mitra

    2016-09-01

    Purpose: The objective of this study was to develop, characterize, and comparatively investigate the ketotifen fumarate (KF) nanosuspensions (NSS) to enhance the permeability of KF. Methods: In the present work, the NSP and NSE were prepared by double-emulsion solvent evaporation/nanoprecipitation methods with poly (D,Llactide-co-glycolide) and Eudragit RL100 polymers, respectively. The loading efficiency, particle size, and polydispersity index of prepared different NSs were evaluated with scanning electron microscopy (SEM), X-ray diffraction, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and in vitro release and transcorneal permeation . NSs were also compared on the basis of particle size and polydispersity index. Results: Particle size, polydispersity index, and loading efficiency of NSP1 and NSE3 showed the best value (158 nm, 117 nm, 0.21, 0.43 and 43%, 95.23%, respectively). SEM showed spherical globules and DSC results showed the reduction in crystallinity. The NSE3 formulations demonstrated significantly (p<0.05) higher drug release rates than the NSP1 due to increases in the surface area. Comparative studies showed that NSE release and permeability are higher than NSP. Conclusion: It is concluded that both NSP and NSE provide a useful dosage form for the ocular drug delivery which can enhance the permeability of KF.

  15. Multimodal imaging of sustained drug release from 3-D poly(propylene fumarate) (PPF) scaffolds.

    PubMed

    Choi, Jonghoon; Kim, Kyobum; Kim, Taeho; Liu, Guanshu; Bar-Shir, Amnon; Hyeon, Taeghwan; McMahon, Michael T; Bulte, Jeff W M; Fisher, John P; Gilad, Assaf A

    2011-12-10

    The potential of poly(propylene fumarate) (PPF) scaffolds as drug carriers was investigated and the kinetics of the drug release quantified using magnetic resonance imaging (MRI) and optical imaging. Three different MR contrast agents were used for coating PPF scaffolds. Initially, iron oxide (IONP) or manganese oxide nanoparticles (MONP) carrying the anti-cancer drug doxorubicin were absorbed or mixed with the scaffold and their release into solution at physiological conditions was measured with MRI and optical imaging. A slow (hours to days) and functional release of the drug molecules into the surrounding solution was observed. In order to examine the release properties of proteins and polypeptides, protamine sulfate, a chemical exchange saturation transfer (CEST) MR contrast agent, was attached to the scaffold. Protamine sulfate showed a steady release rate for the first 24h. Due to its biocompatibility, versatile drug-loading capability and constant release rate, the porous PPF scaffold has potential in various biomedical applications, including MR-guided implantation of drug-dispensing materials, development of drug carrying vehicles, and drug delivery for tumor treatment.

  16. Importance of fumarate and nitrate reduction regulatory protein for intestinal proliferation of Vibrio vulnificus.

    PubMed

    Kado, Takehiro; Kashimoto, Takashige; Yamazaki, Kohei; Ueno, Shunji

    2017-01-01

    The sepsis caused by Vibrio vulnificus is characterized by an average incubation period of 26 h and a high mortality rate exceeding 50%. The fast growth and dissemination of V. vulnificus in vivo lead to poor clinical outcomes in patients. Therefore, elucidation of the proliferation mechanisms of this organism in vivo may lead to the development of an effective therapeutic strategy. In this study, we focused on the low oxygen concentration in the intestinal milieu because of its drastic difference from that in air. Fumarate and nitrate reduction regulatory protein (FNR) is known to be a global transcriptional regulator for adaptation to anaerobic conditions in various bacteria. We generated a strain of V. vulnificus in which the fnr gene was replaced with an erythromycin resistance gene (fnr::erm mutant). When the fnr::erm mutant was tested in a growth competition assay against the wild-type (WT) in vivo, the competitive index of fnr::erm mutant to WT in the intestinal loop and liver was 0.378 ± 0.192 (mean ± SD) and 0.243 ± 0.123, respectively. These data suggested that FNR is important for the proliferation of V. vulnificus in the intestine to achieve a critical mass to be able to invade the systemic circulation.

  17. Liquid chromatography-tandem mass spectrometric assay for aliskiren, a novel renin inhibitor in micro-volumes of human plasma: a pharmacokinetic application in healthy South Indian male subjects.

    PubMed

    Adireddy, Vinayender; Pilli, Nageswara Rao; Derangula, Venkata Ramu; Satla, Shobha Rani; Ganguri, Chinna Veera Badraiah; Ponneri, Venkateswarlu

    2013-08-01

    This paper describes a simple, rapid and sensitive liquid chromatography/tandem mass spectrometry assay for the determination of aliskiren in human plasma using nevirapine as an internal standard. Analyte and the internal standard were extracted from 100 μL of human plasma via liquid-liquid extraction using tert-butyl methyl ether. The chromatographic separation was achieved on a C18 column using a mixture of acetonitrile and 0.1% formic acid (90:10, v/v) as the mobile phase at a flow rate of 0.9 mL/min. The calibration curve obtained was linear (r(2) ≥ 0.99) over the concentration range of 0.10-1013 ng/mL. Method validation was performed as per US Food and Drug Administration guidelines and the results met the acceptance criteria. A run time of 2.2 min for each sample made it possible to analyze a greater number of samples in a short time, thus increasing the productivity. The proposed method was found to be applicable to clinical studies.

  18. Growth of Campylobacter incubated aerobically in fumarate-pyruvate media or media supplemented with dairy, meat, or soy extracts and peptones.

    PubMed

    Hinton, Arthur

    2016-09-01

    The ability of Campylobacter to grow aerobically in media supplemented with fumarate-pyruvate or with dairy, meat, or soy extracts or peptones was examined. Optical densities (OD) of Campylobacter cultured in basal media, media supplemented with fumarate-pyruvate or with 1.0, 2.5, 5.0, or 7.5% beef extract was measured. Growth was also compared in media supplemented with other extracts or peptones. Finally, cfu/mL of Campylobacter recovered from basal media or media supplemented with fumarate-pyruvate, casamino acids, beef extract, soytone, or beef extract and soytone was determined. Results indicated that OD of cultures grown in media supplemented with fumarate-pyruvate or with 5.0 or 7.5% beef extract were higher than OD of isolates grown in basal media or media supplemented with lower concentrations of beef extract. Highest OD were produced by isolates grown in media supplemented with beef extract, peptone from meat, polypeptone, proteose peptone, or soytone. Also, more cfu/mL were recovered from media with fumarate-pyruvate, beef extract, soytone, or beef extract-soytone than from basal media or media with casamino acids. Findings indicate that media supplemented with organic acids, vitamins, and minerals and media supplemented with extracts or peptones containing these metabolites can support aerobic growth of Campylobacter.

  19. Poly(propylene fumarate) reinforced dicalcium phosphate dihydrate cement composites for bone tissue engineering.

    PubMed

    Alge, Daniel L; Bennett, Jeffrey; Treasure, Trevor; Voytik-Harbin, Sherry; Goebel, W Scott; Chu, Tien-Min Gabriel

    2012-07-01

    Calcium phosphate cements have many desirable properties for bone tissue engineering, including osteoconductivity, resorbability, and amenability to rapid prototyping-based methods for scaffold fabrication. In this study, we show that dicalcium phosphate dihydrate (DCPD) cements, which are highly resorbable but also inherently weak and brittle, can be reinforced with poly(propylene fumarate) (PPF) to produce strong composites with mechanical properties suitable for bone tissue engineering. Characterization of DCPD-PPF composites revealed significant improvements in mechanical properties for cements with a 1.0 powder to liquid ratio. Compared with nonreinforced controls, flexural strength improved from 1.80 ± 0.19 MPa to 16.14 ± 1.70 MPa, flexural modulus increased from 1073.01 ± 158.40 MPa to 1303.91 ± 110.41 MPa, maximum displacement during testing increased from 0.11 ± 0.04 mm to 0.51 ± 0.09 mm, and work of fracture improved from 2.74 ± 0.78 J/m(2) to 249.21 ± 81.64 J/m(2) . To demonstrate the utility of our approach for scaffold fabrication, 3D macroporous scaffolds were prepared with rapid prototyping technology. Compressive testing revealed that PPF reinforcement increased scaffold strength from 0.31 ± 0.06 MPa to 7.48 ± 0.77 MPa. Finally, 3D PPF-DCPD scaffolds were implanted into calvarial defects in rabbits for 6 weeks. Although the addition of mesenchymal stem cells to the scaffolds did not significantly improve the extent of regeneration, numerous bone nodules with active osteoblasts were observed within the scaffold pores, especially in the peripheral regions. Overall, the results of this study suggest that PPF-DCPD composites may be promising scaffold materials for bone tissue engineering.

  20. Mechanisms of Oxidative Damage in Multiple Sclerosis and Neurodegenerative Diseases: Therapeutic Modulation via Fumaric Acid Esters

    PubMed Central

    Lee, De-Hyung; Gold, Ralf; Linker, Ralf A.

    2012-01-01

    Oxidative stress plays a crucial role in many neurodegenerative conditions such as Alzheimer’s disease, amyotrophic lateral sclerosis and Parkinson’s as well as Huntington’s disease. Inflammation and oxidative stress are also thought to promote tissue damage in multiple sclerosis (MS). Recent data point at an important role of anti-oxidative pathways for tissue protection in chronic-progressive MS, particularly involving the transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2). Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for MS treatment. Here, fumaric acid esters (FAE) are a new, orally available treatment option which had already been tested in phase II/III MS trials demonstrating beneficial effects on relapse rates and magnetic resonance imaging markers. In vitro, application of dimethylfumarate (DMF) leads to stabilization of Nrf2, activation of Nrf2-dependent transcriptional activity and abundant synthesis of detoxifying proteins. Furthermore, application of FAE involves direct modification of the inhibitor of Nrf2, Kelch-like ECH-associated protein 1. On cellular levels, the application of FAE enhances neuronal survival and protects astrocytes against oxidative stress. Increased levels of Nrf2 are detected in the central nervous system of DMF treated mice suffering from experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In EAE, DMF ameliorates the disease course and improves preservation of myelin, axons and neurons. Finally, Nrf2 is also up-regulated in the spinal cord of autopsy specimens from untreated patients with MS, probably as part of a naturally occurring anti-oxidative response. In summary, oxidative stress and anti-oxidative pathways are important players in MS pathophysiology and constitute a promising target for future MS therapies like FAE. PMID:23109883

  1. Drug-induced Fanconi syndrome associated with fumaric acid esters treatment for psoriasis: a case series

    PubMed Central

    Balak, Deepak M.W.; Bouwes Bavinck, Jan Nico; de Vries, Aiko P.J.; Hartman, Jenny; Neumann, Hendrik A. Martino; Zietse, Robert; Thio, Hok Bing

    2016-01-01

    Background Fumaric acid esters (FAEs), an oral immunomodulating treatment for psoriasis and multiple sclerosis, have been anecdotally associated with proximal renal tubular dysfunction due to a drug-induced Fanconi syndrome. Few data are available on clinical outcomes of FAE-induced Fanconi syndrome. Methods Descriptive case series with two cases of Fanconi syndrome associated with FAE treatment diagnosed at two Dutch university nephrology departments, three cases reported at the Dutch and German national pharmacovigilance databases and six previously reported cases. Results All 11 cases involved female patients with psoriasis. The median age at the time of onset was 38 years [interquartile range (IQR) 37–46]. Patients received long-term FAEs treatment with a median treatment duration of 60 months (IQR 28–111). Laboratory tests were typically significant for low serum levels of phosphate and uric acid, while urinalysis showed glycosuria and proteinuria. Eight (73%) patients had developed a hypophosphataemic osteomalacia and three (27%) had pathological bone fractures. All patients discontinued FAEs, while four (36%) patients were treated with supplementation of phosphate and/or vitamin D. Five (45%) patients had persisting symptoms despite FAEs discontinuation. Conclusions FAEs treatment can cause drug-induced Fanconi syndrome, but the association has been reported infrequently. Female patients with psoriasis treated long term with FAEs seem to be particularly at risk. Physicians treating patients with FAEs should be vigilant and monitor for the potential occurrence of Fanconi syndrome. Measurement of the urinary albumin:total protein ratio is a suggested screening tool for tubular proteinuria in Fanconi syndrome. PMID:26798466

  2. Differential Mechanisms of Tenofovir and Tenofovir Disoproxil Fumarate Cellular Transport and Implications for Topical Preexposure Prophylaxis

    PubMed Central

    Crooker, Kerry; Park, Sung Hyun; Su, Jonathan T.; Ott, Adina; Cheshenko, Natalia; Szleifer, Igal; Kiser, Patrick F.; Frank, Bruce; Mesquita, Pedro M. M.

    2015-01-01

    Intravaginal rings releasing tenofovir (TFV) or its prodrug, tenofovir disoproxil fumarate (TDF), are being evaluated for HIV and herpes simplex virus (HSV) prevention. The current studies were designed to determine the mechanisms of drug accumulation in human vaginal and immune cells. The exposure of vaginal epithelial or T cells to equimolar concentrations of radiolabeled TDF resulted in over 10-fold higher intracellular drug levels than exposure to TFV. Permeability studies demonstrated that TDF, but not TFV, entered cells by passive diffusion. TDF uptake was energy independent but its accumulation followed nonlinear kinetics, and excess unlabeled TDF inhibited radiolabeled TDF uptake in competition studies. The carboxylesterase inhibitor bis-nitrophenyl phosphate reduced TDF uptake, suggesting saturability of intracellular carboxylesterases. In contrast, although TFV uptake was energy dependent, no competition between unlabeled and radiolabeled TFV was observed, and the previously identified transporters, organic anion transporters (OATs) 1 and 3, were not expressed in human vaginal or T cells. The intracellular accumulation of TFV was reduced by the addition of endocytosis inhibitors, and this resulted in the loss of TFV antiviral activity. Kinetics of drug transport and metabolism were monitored by quantifying the parent drugs and their metabolites by high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). Results were consistent with the identified mechanisms of transport, and the exposure of vaginal epithelial cells to equimolar concentrations of TDF compared to TFV resulted in ∼40-fold higher levels of the active metabolite, tenofovir diphosphate. Together, these findings indicate that substantially lower concentrations of TDF than TFV are needed to protect cells from HIV and HSV-2. PMID:26711762

  3. Dimethyl fumarate treatment of relapsing-remitting multiple sclerosis influences B-cell subsets

    PubMed Central

    Lundy, Steven K.; Wu, Qi; Wang, Qin; Dowling, Catherine A.; Taitano, Sophina H.; Mao, Guangmei

    2016-01-01

    Objective: To test the hypothesis that dimethyl fumarate (Tecfidera, BG-12) affects B-cell subsets in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: Peripheral blood B cells were compared for surface marker expression in patients with RRMS prior to initiation of treatment, after 4–6 months, and at more than 1 year of treatment with BG-12. Production of interleukin (IL)–10 by RRMS patient B cells was also analyzed. Results: Total numbers of peripheral blood B lymphocytes declined after 4–6 months of BG-12 treatment, due to losses in both the CD27+ memory B cells and CD27neg B-cell subsets. Some interpatient variability was observed. In contrast, circulating CD24highCD38high (T2-MZP) B cells increased in percentage in the majority of patients with RRMS after 4–6 months and were present in higher numbers in all of the patients after 12 months of treatment. The CD43+CD27+ B-1 B cells also increased at the later time point in most patients but were unchanged at 4–6 months compared to pretreatment levels. Purified B cells from 7 of the 9 patients with RRMS tested after 4–6 months of treatment were able to produce IL-10 following CD40 ligand stimulation, and the amount corresponded with the combined levels of T2-MZP and B-1 B cells in the sample. None of the patients with RRMS in this study have had a relapse while taking BG-12. Conclusions: These data suggest that BG-12 differentially affects B-cell subsets in patients with RRMS, resulting in increased numbers of circulating B lymphocytes with regulatory capacity. PMID:27006972

  4. Intravaginal ring eluting tenofovir disoproxil fumarate completely protects macaques from multiple vaginal simian-HIV challenges.

    PubMed

    Smith, James M; Rastogi, Rachna; Teller, Ryan S; Srinivasan, Priya; Mesquita, Pedro M M; Nagaraja, Umadevi; McNicholl, Janet M; Hendry, R Michael; Dinh, Chuong T; Martin, Amy; Herold, Betsy C; Kiser, Patrick F

    2013-10-01

    Topical preexposure prophylaxis interrupts HIV transmission at the site of mucosal exposure. Intermittently dosed vaginal gels containing the HIV-1 reverse transcriptase inhibitor tenofovir protected pigtailed macaques depending on the timing of viral challenge relative to gel application. However, modest or no protection was observed in clinical trials. Intravaginal rings (IVRs) may improve efficacy by providing long-term sustained drug delivery leading to constant mucosal antiretroviral concentrations and enhancing adherence. Although a few IVRs have entered the clinical pipeline, 100% efficacy in a repeated macaque vaginal challenge model has not been achieved. Here we describe a reservoir IVR technology that delivers the tenofovir prodrug tenofovir disoproxil fumarate (TDF) continuously over 28 d. With four monthly ring changes in this repeated challenge model, TDF IVRs generated reproducible and protective drug levels. All TDF IVR-treated macaques (n = 6) remained seronegative and simian-HIV RNA negative after 16 weekly vaginal exposures to 50 tissue culture infectious dose SHIV162p3. In contrast, 11/12 control macaques became infected, with a median of four exposures assuming an eclipse of 7 d from infection to virus RNA detection. Protection was associated with tenofovir levels in vaginal fluid [mean 1.8 × 10(5) ng/mL (range 1.1 × 10(4) to 6.6 × 10(5) ng/mL)] and ex vivo antiviral activity of cervicovaginal lavage samples. These observations support further advancement of TDF IVRs as well as the concept that extended duration drug delivery devices delivering topical antiretrovirals could be effective tools in preventing the sexual transmission of HIV in humans.

  5. Single and mixed chemically modified carbon paste ion-selective electrodes for determination of ketotifen fumarate.

    PubMed

    Khater, M M; Issa, Y M; Mohamed, S H

    2013-02-01

    New modified carbon paste electrodes for determination of ketotifen fumarate in its pure and pharmaceutical preparations were constructed. The used modifiers are ketotifen phosphotungestate (Keto(3) PT), and ketotifen tetraphenylborate (Keto-TPB). Single and mixed ion-associate electrodes were prepared. Both Keto-TPB and mixed (Keto-TPB and Keto(3) PT) electrodes have a linearity range of 1.00 × 10(-5) -1.00 × 10(-2) mol L(-1) . The slopes were 58.30 and 54.20 mV/decade for Keto-TPB and mixed chemically modified carbon paste electrodes (CMCPE), respectively. The limits of detection were 1.42 × 10(-6) and 1.00 × 10(-5) mol L(-1) for Keto-TPB and mixed CMCPEs, respectively. The potential variation due to pH change is considered acceptable in the pH ranges 4.44-9.11 and 2.50-9.00 for Keto-TPB and mixed ion-exchanger CMCPE, respectively. The response time was ≤10 s for both electrodes. Selectivity coefficients values towards different inorganic cations, sugars, and amino acids reflect high selectivity of the prepared electrodes. Potentiometric titrations and standard addition methods were applied for the determination of ketotifen ion in its pure samples and pharmaceutical formulations (Zaditen tablet and syrup) using proposed electrodes. The electrodes were also tested in flow injection analysis (FIA). The results obtained from both methods were statistically treated by F- and t-tests. The carbon paste electrodes have the advantages of being more easily prepared and longer life span compared to the plastic membrane electrodes previously reported.

  6. Digital micromirror device (DMD)-based 3D printing of poly(propylene fumarate) scaffolds.

    PubMed

    Mott, Eric J; Busso, Mallory; Luo, Xinyi; Dolder, Courtney; Wang, Martha O; Fisher, John P; Dean, David

    2016-04-01

    Our recent investigations into the 3D printing of poly(propylene fumarate) (PPF), a linear polyester, using a DMD-based system brought us to a resin that used titanium dioxide (TiO2) as an ultraviolet (UV) filter for controlling cure depth. However, this material hindered the 3D printing process due to undesirable lateral or "dark" curing (i.e., in areas not exposed to light from the DMD chip). Well known from its use in sunscreen, another UV filter, oxybenzone, has previously been used in conjunction with TiO2. In this study we hypothesize that combining these two UV filters will result in a synergistic effect that controls cure depth and avoids dark cure. A resin mixture (i.e., polymer, initiator, UV filters) was identified that worked well. The resin was then further characterized through mechanical testing, cure testing, and cytotoxicity testing to investigate its use as a material for bone tissue engineering scaffolds. Results show that the final resin eliminated dark cure as shown through image analysis. Mechanically the new scaffolds proved to be far weaker than those printed from previous resins, with compressive strengths of 7.8 ± 0.5 MPa vs. 36.5 ± 1.6 MPa, respectively. The new scaffolds showed a 90% reduction in elastic modulus and a 74% increase in max strain. These properties may be useful in tissue engineering applications where resorption is required. Initial cytotoxicity evaluation was negative. As hypothesized, the use of TiO2 and oxybenzone showed synergistic effects in the 3D printing of PPF tissue engineering scaffolds.

  7. Dimethyl fumarate attenuates intracerebroventricular streptozotocin-induced spatial memory impairment and hippocampal neurodegeneration in rats.

    PubMed

    Majkutewicz, Irena; Kurowska, Ewelina; Podlacha, Magdalena; Myślińska, Dorota; Grembecka, Beata; Ruciński, Jan; Plucińska, Karolina; Jerzemowska, Grażyna; Wrona, Danuta

    2016-07-15

    Intracerebroventricular (ICV) injection of streptozotocin (STZ) is a widely-accepted animal model of sporadic Alzheimer's disease (sAD). The present study evaluated the ability of dimethyl fumarate (DMF), an agent with antioxidant and anti-inflammatory properties, to prevent spatial memory impairments and hippocampal neurodegeneration mediated by ICV injection of STZ in 4-month-old rats. Rodent chow containing DMF (0.4%) or standard rodent chow was made available on day 0. Rat body weight and food intake were measured daily for whole the experiment (21days). STZ or vehicle (SHAM) ICV injections were performed on days 2 and 4. Spatial reference and working memory were evaluated using the Morris water maze on days 14-21. Cells containing Fluoro-Jade B (neurodegeneration marker), IL-6, IL-10 were quantified in the hippocampus and choline acetyltransferase (ChAT) in the basal forebrain. The disruption of spatial memory and a high density of hippocampal CA1-3 cells labeled with Fluoro-Jade B or containing IL-6 or IL-10 were observed in the STZ group but not in the STZ+DMF group, as compared to the SHAM or SHAM+DMF groups. STZ vs. STZ+DMF differences were found: worse reference memory acquisition, fewer ChAT-positive neurons in the medial septum (Ch1), more Fluoro-Jade-positive CA1 hippocampal cells in STZ rats. DMF therapy in a rodent model of sAD prevented the disruption of spatial reference and working memory, loss of Ch1 cholinergic cells and hippocampal neurodegeneration as well as the induction of IL-6 and IL-10 in CA1. These beneficial cognitive and molecular effects validate the anti-inflammatory and neuroprotective properties of DMF in the hippocampus.

  8. Bone formation in transforming growth factor beta-1-coated porous poly(propylene fumarate) scaffolds.

    PubMed

    Vehof, Johan W M; Fisher, John P; Dean, David; van der Waerden, Jan-Paul C M; Spauwen, Paul H M; Mikos, Antonios G; Jansen, John A

    2002-05-01

    This study determined the bone growth into pretreated poly(propylene fumarate) (PPF) scaffolds implanted into a subcritical size, rabbit cranial defect. PPF scaffolds were constructed by using a photocrosslinking-porogen leaching technique. These scaffolds were then either prewetted (PPF-Pw), treated with RF glow-discharge (PPF-Gd), coated with fibronectin (PPF-Fn), or coated with rhTGF-beta1 (PPF-TGF-beta1). One of each scaffold type was then placed into the cranium of nine rabbits. The rabbits were sacrificed after 8 weeks, and the scaffolds were retrieved for histological analysis. The most bone formation was present in the PPF-TGF-beta1 implants; the newly formed bone had a trabecular appearance together with bone marrow-like tissue. Little or no bone formation was observed in implants without rhTGF-beta1. These histological findings were confirmed by image analysis. Bone surface area, bone area percentage, pore fill percentage, and pore area percentage were significantly higher in the rhTGF-beta1-coated implants than in the noncoated implants. No statistical difference was seen between the PPF-Fn, PPF-Pw, or PPF-Gd scaffolds for these parameters. Quadruple fluorochrome labeling showed that in PPF-TGF-beta1 implants bone formation mainly started in the interior of a pore and proceeded toward the scaffold. We conclude that (a) PPF-TGF-beta1 scaffolds can indeed adequately induce bone formation in porous PPF, and (b) PPF scaffolds prepared by the photocrosslinking-porogen leaching technique are good candidates for the creation of bone graft substitutes.

  9. Prevention of Schizophrenia Relapse with Extended Release Quetiapine Fumarate Dosed Once Daily

    PubMed Central

    Trivedi, Jitendra; Malyarov, Sergiy; Brecher, Martin; Svensson, Ola; Miller, Frank; Persson, Inger; Meulien, Didier

    2007-01-01

    Introduction: This long-term, randomized, double-blind, placebo-controlled study examined the efficacy of extended release quetiapine fumarate (quetiapine XR) in preventing psychotic relapse in schizophrenia. Methods: Three hundred twenty-seven clinically stable patients with schizophrenia were switched to open-label quetiapine XR (300mg on Day 1, 600mg on Day 2, followed by flexible dosing [400–800mg/day]) for a 16-week stabilization phase. Thereafter, patients who were clinically stable for four months were randomized to flexible doses of quetiapine XR (400–800mg/day) or placebo. Primary endpoint was time to first schizophrenia relapse after randomization. Secondary endpoints included risk of relapse at six months. Interim analyses were planned after 45 and 60 relapses and final analysis after 90 relapses. Maximal treatment time was one year. Results: The study was terminated after the first interim analysis showed a significant difference between randomized treatment groups. Time to relapse was significantly longer in quetiapine XR-treated patients versus placebo (hazard ratio 0.16 [95% confidence interval 0.08, 0.34]; p=0.001). Fewer quetiapine XR-treated patients relapsed versus those receiving placebo (10.7% vs. 41.4%, respectively). Estimated risk of relapse at six months was significantly lower with quetiapine XR (14.3%) compared with placebo (68.2%; p=0.0001). The incidence of treatment-related adverse events (AEs) was similar between quetiapine XR and placebo groups (18% and 21% of patients, respectively) and only one percent of patients in each group withdrew because of AEs. Conclusion: Once-daily quetiapine XR (400–800mg/day) was effective in preventing relapse in patients with clinically stable schizophrenia. Quetiapine XR was well tolerated during longer-term use. PMID:20428302

  10. Repurposing the NRF2 Activator Dimethyl Fumarate as Therapy Against Synucleinopathy in Parkinson's Disease

    PubMed Central

    García-Yagüe, Angel J.; Scannevin, Robert H.; Casarejos, María J.; Kügler, Sebastian; Rábano, Alberto

    2016-01-01

    Abstract Aims: This preclinical study was aimed at determining whether pharmacological targeting of transcription factor NRF2, a master controller of many homeostatic genes, might provide a disease-modifying therapy in the animal model of Parkinson's disease (PD) that best reproduces the main hallmark of this pathology, that is, α-synucleinopathy, and associated events, including nigral dopaminergic cell death, oxidative stress, and neuroinflammation. Results: Pharmacological activation of NRF2 was achieved at the basal ganglia by repurposing dimethyl fumarate (DMF), a drug already in use for the treatment of multiple sclerosis. Daily oral gavage of DMF protected nigral dopaminergic neurons against α-SYN toxicity and decreased astrocytosis and microgliosis after 1, 3, and 8 weeks from stereotaxic delivery to the ventral midbrain of recombinant adeno-associated viral vector expressing human α-synuclein. This protective effect was not observed in Nrf2-knockout mice. In vitro studies indicated that this neuroprotective effect was correlated with altered regulation of autophagy markers SQTSM1/p62 and LC3 in MN9D, BV2, and IMA 2.1 and with a shift in microglial dynamics toward a less pro-inflammatory and a more wound-healing phenotype. In postmortem samples of PD patients, the cytoprotective proteins associated with NRF2 expression, NQO1 and p62, were partly sequestered in Lewy bodies, suggesting impaired neuroprotective capacity of the NRF2 signature. Innovation: These experiments provide a compelling rationale for targeting NRF2 with DMF as a therapeutic strategy to reinforce endogenous brain defense mechanisms against PD-associated synucleinopathy. Conclusion: DMF is ready for clinical validation in PD. Antioxid. Redox Signal. 25, 61–77. PMID:27009601

  11. Binding to DNA protects Neisseria meningitidis fumarate and nitrate reductase regulator (FNR) from oxygen.

    PubMed

    Edwards, James; Cole, Lindsay J; Green, Jasper B; Thomson, Melanie J; Wood, A Jamie; Whittingham, Jean L; Moir, James W B

    2010-01-08

    Here, we report the overexpression, purification, and characterization of the transcriptional activator fumarate and nitrate reductase regulator from the pathogenic bacterium Neisseria meningitidis (NmFNR). Like its homologue from Escherichia coli (EcFNR), NmFNR binds a 4Fe-4S cluster, which breaks down in the presence of oxygen to a 2Fe-2S cluster and subsequently to apo-FNR. The kinetics of NmFNR cluster disassembly in the presence of oxygen are 2-3x slower than those previously reported for wild-type EcFNR, but similar to constitutively active EcFNR* mutants, consistent with earlier work in which we reported that the activity of FNR-dependent promoters in N. meningitidis is only weakly inhibited by the presence of oxygen (Rock, J. D., Thomson, M. J., Read, R. C., and Moir, J. W. (2007) J. Bacteriol. 189, 1138-1144). NmFNR binds to DNA containing a consensus FNR box sequence, and this binding stabilizes the iron-sulfur cluster in the presence of oxygen. Partial degradation of the 4Fe-4S cluster to a 3Fe-4S occurs, and this form remains bound to the DNA. The 3Fe-4S cluster is converted spontaneously back to a 4Fe-4S cluster under subsequent anaerobic reducing conditions in the presence of ferrous iron. The finding that binding to DNA stabilizes FNR in the presence of oxygen such that it has a half-life of approximately 30 min on the DNA has implications for our appreciation of how oxygen switches off FNR activatable genes in vivo.

  12. Foamed oligo(poly(ethylene glycol)fumarate) hydrogels as versatile prefabricated scaffolds for tissue engineering.

    PubMed

    Henke, Matthias; Baumer, Julia; Blunk, Torsten; Tessmar, Joerg

    2014-03-01

    Radically cross-linked hydrogels are frequently used as cell carriers due to their excellent biocompatibility and their tissue-like mechanical properties. Through frequent investigation, PEG-based polymers such as oligo(poly(ethylene glycol)fumarate [OPF] have proven to be especially suitable as cell carriers by encapsulating cells during hydrogel formation. In some cases, NaCl or biodegradable gelatin microparticles were added prior to cross-linking in order to provide space for the proliferating cells, which would otherwise stay embedded in the hydrogel matrix. However, all of these immediate cross-linking procedures involve time consuming sample preparation and sterilization directly before cell culture and often show notable swelling after their preparation. In this study, ready to use OPF-hydrogel scaffolds were prepared by gas foaming, freeze drying, individual packing into bags and subsequent γ-sterilization. The scaffolds could be stored and used "off-the-shelf" without any need for further processing prior to cell culture. Thus the handling was simplified and the sterility of the cell carrier was assured. Further improvement of the gel system was achieved using a two component injectable system, which may be used for homogenous injection molding in order to create individually shaped three dimensional scaffolds. In order to evaluate the suitability of the scaffolds for tissue engineering, constructs were seeded with juvenile bovine chondrocytes and cultured for 28 days. Cross-sections of the respective constructs showed an intense and homogenous red staining of GAG with safranin O, indicating a homogenous cell distribution within the scaffolds and the production of substantial amounts of GAG-rich matrix.

  13. Determination of dimethyl fumarate and other potential allergens in desiccant and antimould sachets.

    PubMed

    Lamas, J Pablo; Sanchez-Prado, Lucia; Regueiro, Jorge; Llompart, Maria; Garcia-Jares, Carmen

    2009-08-01

    A method for the determination of dimethyl fumarate (DMF), benzothiazole (BT) and tert-butylphenol (TBP) in desiccant and antimould agents employed for protecting consumer products from humidity and mould has been developed. The method is based on ultrasound-assisted extraction (UAE) followed by GC-MS analysis. Parameters that could affect the extraction of the compounds have been optimised using a multivariate approach. In the final conditions, the extraction is performed using only 0.5 or 1 mL ethyl acetate and applying ultrasound energy for 5 min. Simultaneous extractions could also be carried out in 5 min without losing efficiency. The method was validated showing good linearity (R2 >0.995). Both intra- and inter-day precisions were studied at several concentration levels, being satisfactory in all cases (RSD <10%). Recovery was evaluated in four real desiccant samples at different compound concentrations, ranging between 87% and 109%. Limits of detection and quantification were in the low nanogramme per gramme level, thus allowing the determination of DMF at concentrations well below the limit established by the recent EU Directive (0.1 microg/g). The proposed procedure was applied to the determination of the target compounds in several desiccant and antimould samples. Although most of them were simply labelled as "silica gel", more than 70% of the tested samples contained high amounts of DMF, many of them at the high microgram per gramme level. Many samples also showed the presence of the other two potential allergens. These results demonstrate that the content of the "desiccant" sachets and tablets in consumer products does not usually belong with the label of the desiccant, and hence, the high risk of exposition to the powerful allergen DMF and other potentially harmful chemicals through consumer goods should be a matter of concern.

  14. Design of oral agents for the management of multiple sclerosis: benefit and risk assessment for dimethyl fumarate.

    PubMed

    Nicholas, Jacqueline Ann; Boster, Aaron Lee; Imitola, Jaime; O'Connell, Colleen; Racke, Michael Karl

    2014-01-01

    Dimethyl fumarate (DMF) is the most recent oral disease-modifying therapy approved by the US Food and Drug Administration and is indicated for the treatment of relapsing forms of multiple sclerosis (MS). Prior to approval for use in MS, DMF and its active metabolite, monomethyl fumarate, had been used for decades as two of the fumaric acid esters in Fumaderm, a medication used in Europe for the treatment of psoriasis. The unique mechanism of action of DMF remains under evaluation; however, it has been shown to act through multiple pathways leading to shifts away from the Th1 proinflammatory response to the less inflammatory Th2 response. Preliminary data suggest that DMF may induce neuroprotective effects in central nervous system white matter, although further studies are needed to demonstrate these effects on inflammatory demyelination. The DMF Phase III clinical trials demonstrated its efficacy with regard to a reduction in the annualized relapse rate and reductions in new or enlarging T2 lesions and numbers of gadolinium-enhancing lesions on magnetic resonance imaging. DMF has a well-defined safety profile, given the experience with its use in the treatment of psoriasis, and more recently from the DMF clinical trials program and post-marketing era for treatment of MS. The safety profile and oral mode of administration of DMF place it as an attractive first-line therapy option for the treatment of relapsing forms of MS. Long-term observational studies will be needed to determine the effects of DMF on progression of disability in MS.

  15. Metabolic reprogramming for producing energy and reducing power in fumarate hydratase null cells from hereditary leiomyomatosis renal cell carcinoma.

    PubMed

    Yang, Youfeng; Lane, Andrew N; Ricketts, Christopher J; Sourbier, Carole; Wei, Ming-Hui; Shuch, Brian; Pike, Lisa; Wu, Min; Rouault, Tracey A; Boros, Laszlo G; Fan, Teresa W-M; Linehan, W Marston

    2013-01-01

    Fumarate hydratase (FH)-deficient kidney cancer undergoes metabolic remodeling, with changes in mitochondrial respiration, glucose, and glutamine metabolism. These changes represent multiple biochemical adaptations in glucose and fatty acid metabolism that supports malignant proliferation. However, the metabolic linkages between altered mitochondrial function, nucleotide biosynthesis and NADPH production required for proliferation and survival have not been elucidated. To characterize the alterations in glycolysis, the Krebs cycle and the pentose phosphate pathways (PPP) that either generate NADPH (oxidative) or do not (non-oxidative), we utilized [U-(13)C]-glucose, [U-(13)C,(15)N]-glutamine, and [1,2- (13)C2]-glucose tracers with mass spectrometry and NMR detection to track these pathways, and measured the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of growing cell lines. This metabolic reprogramming in the FH null cells was compared to cells in which FH has been restored. The FH null cells showed a substantial metabolic reorganization of their intracellular metabolic fluxes to fulfill their high ATP demand, as observed by a high rate of glucose uptake, increased glucose turnover via glycolysis, high production of glucose-derived lactate, and low entry of glucose carbon into the Krebs cycle. Despite the truncation of the Krebs cycle associated with inactivation of fumarate hydratase, there was a small but persistent level of mitochondrial respiration, which was coupled to ATP production from oxidation of glutamine-derived α-ketoglutarate through to fumarate. [1,2- (13)C2]-glucose tracer experiments demonstrated that the oxidative branch of PPP initiated by glucose-6-phosphate dehydrogenase activity is preferentially utilized for ribose production (56-66%) that produces increased amounts of ribose necessary for growth and NADPH. Increased NADPH is required to drive reductive carboxylation of α-ketoglutarate and fatty acid synthesis

  16. Tenofovir disoproxil fumarate intravaginal ring protects high-dose depot medroxyprogesterone acetate-treated macaques from multiple SHIV exposures.

    PubMed

    Smith, James M; Srinivasan, Priya; Teller, Ryan S; Lo, Yungtai; Dinh, Chuong T; Kiser, Patrick F; Herold, Betsy C

    2015-01-01

    Preclinical HIV prevention models use either a single high-dose viral challenge in depot medroxyprogesterone acetate-treated macaques or repeated viral challenges in cycling macaques. We tested the efficacy of an intravaginal tenofovir disoproxil fumarate (TDF) ring in a model combining repeated 30-mg injections of depot medroxyprogesterone acetate every 6 weeks with vaginal viral challenges weekly for 12 weeks. Twelve macaques were randomized to TDF or placebo rings. All placebo macaques became infected after a median of 2 exposures, whereas only 1 TDF macaque became infected at the eighth exposure (P = 0.0012). The TDF ring provides durable protection in a stringent challenge model.

  17. Characterization of the hyperline of D1/D0 conical intersections between the maleic acid and fumaric acid anion radicals

    NASA Astrophysics Data System (ADS)

    Takahashi, Ohgi; Sumita, Masato

    2004-10-01

    The cation and anion radicals of symmetrical 1,2-disubstituted ethylenes are expected to have a symmetry-allowed conical intersection (CI) between the ground doublet state (D0) and the lowest excited doublet state (D1) near a 90°-twisted geometry. By the complete active space self-consistent field method, we characterized the hyperline formed by D1/D0 CIs between the anion radicals of maleic acid (cis) and fumaric acid (trans). An implication of the results for the known one-way cis→trans photoisomerization of the maleic acid anion radical and other related ion radicals is presented.

  18. Influence of various amounts of fumaric acid on performance and parameters of the acid-base balance of growing bulls fed with grass or maize silage.

    PubMed

    Remling, Nicole; Hachenberg, Sabrina; Meyer, Ulrich; Höltershinken, Martin; Flachowsky, Gerhard; Dänicke, Sven

    2011-10-01

    The aim of the present study was to determine the effects of the potential methane reducer fumaric acid on the fattening performance and acid-base balance of growing bulls fed two different silage types as roughage (maize and grass silage). A total of 62 fattening bulls (German Holstein breed, initial body weight: 266 +/- 42 kg), randomly assigned to eight feeding groups, received four levels of fumaric acid (0, 100, 200 or 300 g/d) at each silage type. The daily feed and water intake and the live weight were measured over the whole testing period of 280 days. In blood samples, blood cells and blood gases as a parameter of acid-base status were analysed. Feed and faeces were collected to determine the apparent nutrient digestibility. Five animals from each group fed maize or grass silage, supplemented with 0 g or 300 g fumaric acid, were slaughtered at 580 kg body weight. After slaughter, rumen fluid pH was measured and dressing percentage was calculated. Neither the total feed intake (8.81 +/- 0.07 kg/d) nor the daily weight gain (1277 +/- 24 g/d) was influenced significantly by treatments. Fumaric acid supplementation did not influence the erythrocyte count or the blood gas concentration. The silage type significantly influenced the apparent digestibility of the whole diet. The dressing percentage was slightly higher (p < 0.1) after fumaric acid supplementation. No signs of an incompatibility to fumaric acid on the animals were observed over the whole experimental period. However, it seems to be necessary to conduct more long-term studies with different silage types and addition of organic acids combined with direct measurements of methane.

  19. The antiproliferative activity of all-trans-retinoic acid catabolites and isomers is differentially modulated by liarozole-fumarate in MCF-7 human breast cancer cells.

    PubMed Central

    Van heusden, J.; Wouters, W.; Ramaekers, F. C.; Krekels, M. D.; Dillen, L.; Borgers, M.; Smets, G.

    1998-01-01

    The clinical use of all-trans-retinoic acid (ATRA) in the treatment of cancer is significantly hampered by the prompt emergence of resistance, believed to be caused by increased ATRA catabolism. Inhibitors of ATRA catabolism may therefore prove valuable for cancer therapy. Liarozole-fumarate is an anti-tumour drug that inhibits the cytochrome P450-dependent catabolism of ATRA. ATRA, but also its naturally occurring catabolites, 4-oxo-ATRA and 5,6-epoxy-ATRA, as well as its stereoisomers, 9-cis-RA and 13-cis-RA, show significant antiproliferative activity in MCF-7 human breast cancer cells. To further elucidate its mechanism of action, we investigated whether liarozole-fumarate was able to enhance the antiproliferative activity of ATRA catabolites and isomers. Liarozole-fumarate alone up to a concentration of 10(-6) M had no effect on MCF-7 cell proliferation. However, in combination with ATRA or the ATRA catabolites, liarozole-fumarate (10(-6) M) significantly enhanced their antiproliferative activity. On the contrary, liarozole-fumarate (10(-6) M) was not able to potentiate the antiproliferative activity of the ATRA stereoisomers, most probably because of the absence of cytochrome P450-dependent catabolism. Together, these findings show that liarozole-fumarate acts as a versatile inhibitor of retinoid catabolism in that it not only blocks the breakdown of ATRA, but also inhibits the catabolic pathway of 4-oxo-ATRA and 5,6-epoxy-ATRA, thereby enhancing their antiproliferative activity. PMID:9579827

  20. Wortmannilactones I-L, new NADH-fumarate reductase inhibitors, induced by adding suberoylanilide hydroxamic acid to the culture medium of Talaromyces wortmannii.

    PubMed

    Liu, Wen-Cai; Wang, Yi-Yu; Liu, Jun-Hui; Ke, Ai-Bing; Zheng, Zhi-Hui; Lu, Xin-Hua; Luan, Yu-Shi; Xiu, Zhi-Long; Dong, Yue-Sheng

    2016-11-01

    With the aim of finding more potential inhibitors against NADH-fumarate reductase (specific target for treating helminthiasis and cancer) from natural resources, Talaromyces wortmannii was treated with the epigenome regulatory agent suberoylanilide hydroxamic acid, which resulted in the isolation of four new wortmannilactones derivatives (wortmannilactones I-L, 1-4). The structures of these new compounds were elucidated based on IR, HRESIMS and NMR spectroscopic data analyses. These four new compounds showed potent inhibitory activity against NADH-fumarate reductase with the IC50 values ranging from 0.84 to 1.35μM.

  1. Early Fesoterodine Fumarate Administration Prevents Neurogenic Detrusor Overactivity in a Spinal Cord Transected Rat Model

    PubMed Central

    Biardeau, Xavier; Przydacz, Mikolaj; Aharony, Shachar; Loutochin, George; Campeau, Lysanne; Kyheng, Maeva; Corcos, Jacques

    2017-01-01

    Background In spinal cord injury, onset of detrusor overactivity (DO) is detrimental for quality of life (incontinence) and renal risk. Prevention has only been achieved with complex sophisticated electrical neuromodulation techniques. Purpose To assess the efficacy of early fesoterodine fumarate (FF) administration in preventing bladder overactivity in a spinal cord transected (SCT) rat model. Methods 33 Sprague-Dawley rats were allocated to 6 groups–Group 1: 3 normal controls; Group 2: 6 SCT controls; Group 3: 6 SCT rats + FF 0.18 mg/kg/d; Group 4: 6 SCT rats + FF 0.12 mg/kg/d; Group 5: 6 SCT rats + FF 0.18 mg/kg/d + 72-h wash-out period; Group 6: 6 SCT rats + FF 0.12 mg/kg/d + 72-h wash-out period. SCT was performed at T10. FF was continuously administered. Cystometry was undertaken 6 weeks after SCT in awake rats recording intermicturition pressure (IMP), baseline pressure, threshold pressure (Pthres) and maximum pressure (Pmax). Normal controls and SCT controls were initially compared using the Mann-Whitney U tests in order to confirm the SCT effect on cystometric parameters. The comparisons in cystometric and metabolic cage parameters between SCT controls and treated rats were done using post-hoc Dunn’s tests for Kruskal-Wallis analysis. Statistical testing was conducted at the two-tailed α-level of 0.05. Results Pressure parameters were significantly higher in SCT control group compared to normal controls. Six weeks after SCT, IMP was significantly lower in low dose treated group than in SCT controls. Pmax was significantly lower in 3 treated groups compared to SCT controls. Pthres was significantly lower in full time treated groups than in SCT controls. Conclusion Early administration of FF modulates bladder overactivity in a SCT rat model. Whereas short-term prevention has been demonstrated, the long-term should be further analyzed. Clinical application of these results should confirm this finding through randomized research protocols. PMID:28060912

  2. The anti-inflammatory effects of dimethyl fumarate in astrocytes involve glutathione and haem oxygenase-1

    PubMed Central

    Lin, Shao Xia; Lisi, Lucia; Dello Russo, Cinzia; Polak, Paul E; Sharp, Anthony; Weinberg, Guy; Kalinin, Sergey; Feinstein, Douglas L

    2011-01-01

    DMF (dimethyl fumarate) exerts anti-inflammatory and pro-metabolic effects in a variety of cell types, and a formulation (BG-12) is being evaluated for monotherapy in multiple sclerosis patients. DMF modifies glutathione (GSH) levels that can induce expression of the anti-inflammatory protein HO-1 (haem oxygenase-1). In primary astrocytes and C6 glioma cells, BG-12 dose-dependently suppressed nitrite production induced by either LI [LPS (lipopolysaccharide) at 1 μg/ml plus IFNγ (interferon γ) at 20 units/ml] or a mixture of pro-inflammatory cytokines, with greater efficacy in C6 cells. BG-12 reduced NOS2 (nitric oxide synthase 2) mRNA levels and activation of a NOS2 promoter, reduced nuclear levels of NF-κB (nuclear factor κB) p65 subunit and attenuated loss of IκBα (inhibitory κBα) in both cell types, although with greater effects in astrocytes. In astrocytes, LI decreased mRNA levels for GSHr (GSH reductase) and GCL (c-glutamylcysteine synthetase), and slightly suppressed GSHs (GSH synthetase) mRNAs. Co-treatment with BG-12 prevented those decreased and increased levels above control values. In contrast, LI reduced GSHp (GSH peroxidase) and GCL in C6 cells, and BG-12 had no effect on those levels. BG-12 increased nuclear levels of Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2), an inducer of GSH-related enzymes, in astrocytes but not C6 cells. In astrocytes, GSH was decreased by BG-12 at 2 h and increased at 24 h. Prior depletion of GSH using buthionine-sulfoximine increased the ability of BG-12 to reduce nitrites. In astrocytes, BG-12 increased HO-1 mRNA levels and effects on nitrite levels were blocked by an HO-1 inhibitor. These results demonstrate that BG-12 suppresses inflammatory activation in astrocytes and C6 glioma cells, but with distinct mechanisms, different dependence on GSH and different effects on transcription factor activation. PMID:21382015

  3. The anti-inflammatory effects of dimethyl fumarate in astrocytes involve glutathione and haem oxygenase-1.

    PubMed

    Lin, Shao Xia; Lisi, Lucia; Dello Russo, Cinzia; Polak, Paul E; Sharp, Anthony; Weinberg, Guy; Kalinin, Sergey; Feinstein, Douglas L

    2011-04-07

    DMF (dimethyl fumarate) exerts anti-inflammatory and pro-metabolic effects in a variety of cell types, and a formulation (BG-12) is being evaluated for monotherapy in multiple sclerosis patients. DMF modifies glutathione (GSH) levels that can induce expression of the anti-inflammatory protein HO-1 (haem oxygenase-1). In primary astrocytes and C6 glioma cells, BG-12 dose-dependently suppressed nitrite production induced by either LI [LPS (lipopolysaccharide) at 1 μg/ml plus IFNγ (interferon γ) at 20 units/ml] or a mixture of pro-inflammatory cytokines, with greater efficacy in C6 cells. BG-12 reduced NOS2 (nitric oxide synthase 2) mRNA levels and activation of a NOS2 promoter, reduced nuclear levels of NF-κB (nuclear factor κB) p65 subunit and attenuated loss of IκBα (inhibitory κBα) in both cell types, although with greater effects in astrocytes. In astrocytes, LI decreased mRNA levels for GSHr (GSH reductase) and GCL (c-glutamylcysteine synthetase), and slightly suppressed GSHs (GSH synthetase) mRNAs. Co-treatment with BG-12 prevented those decreased and increased levels above control values. In contrast, LI reduced GSHp (GSH peroxidase) and GCL in C6 cells, and BG-12 had no effect on those levels. BG-12 increased nuclear levels of Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2), an inducer of GSH-related enzymes, in astrocytes but not C6 cells. In astrocytes, GSH was decreased by BG-12 at 2 h and increased at 24 h. Prior depletion of GSH using buthionine-sulfoximine increased the ability of BG-12 to reduce nitrites. In astrocytes, BG-12 increased HO-1 mRNA levels and effects on nitrite levels were blocked by an HO-1 inhibitor. These results demonstrate that BG-12 suppresses inflammatory activation in astrocytes and C6 glioma cells, but with distinct mechanisms, different dependence on GSH and different effects on transcription factor activation.

  4. Preparation and evaluation of poly (caprolactone fumarate) nanoparticles containing doxorubicin HCI

    PubMed Central

    Shokri, N.; Akbari Javar, H.; Fouladdel, Sh.; Khalaj, A.; Khoshayand, MR.; Dinarvand, R.; Atyabi, F.; Nomani, A.; Azizi, E.

    2011-01-01

    Background and the purpose of the study Biodegradable Poly(caprolactone fumarate) (PCLF) has been used as bioresorbable sutures. In this study, doxorubicin HCl (Dox) loaded PCLF nanoparticles were prepared and characterized. Material and methods PCLFs were synthesized by polycondensation of PCL diols (Mws of 530, 1250 and 2000) with fumaryl chloride. The degradation of PCLF in NaOH, water and phosphate buffer saline (PBS), was determined in terms of changes in Mw. Nanoparticles (NPs) were prepared by two methods. In microemulsion polymerization method, dichloromethane containing PCLF and photoinitiator were combined with the water containing surfactants and then the mixture was placed under light for crosslinking. In nanoprecipitation method, the organic solvent containing PCLF was poured into the stirring water. The effect of several variables including concentration of PCLF, polyvinyl alcohol (PVA), Dox and Trypan blue (Trb) and the Mw of PCLF and PVA on NP size and loading were evaluated. Result PCLF 530, 1250 and 2000 in PBS or water were not degraded over 28 days. Nanoprecipitaion method gave spherical (revealed by SEM images) stable NPs of about 225 with narrow size distribution and a zeta potential of −43 mV. The size of NP increased significantly by increase in Mw or concentration of PCLF. Although PVA was not necessary for formation of NPs, but it decreased with NP size. Dox loading and EE were 2.5–6.8% and 15–20%, respectively. Increasing the drug concentration increased the drug loading (DL) and NP size. The entrapment efficiency (EE) for Trb ranged from 1% for PCLF530 to 6% for PCLF2000. An increase in PCLF concentration resulted in an increase in EE. Dox and Trb release showed a burst followed by 80% and 78% release during 3 and 4 days respectively. Conclusion PCLF possessed suitable characteristics for preparation of nanoparticulate drug delivery system such as desired NP size, stability and degradation time. Although PCLF530 NPs were the

  5. In vitro study of a new biodegradable nanocomposite based on poly propylene fumarate as bone glue.

    PubMed

    Shahbazi, S; Moztarzadeh, F; Sadeghi, G Mir Mohamad; Jafari, Y

    2016-12-01

    A novel poly propylene fumarate (PPF)-based glue which is reinforced by nanobioactive glass (NBG) particles and promoted by hydroxyethyl methacrylate (HEMA) as crosslinker agent, was developed and investigated for bone-to-bone bonding applications. In-vitro bioactivity, biodegradability, biocompatibility, and bone adhesion were tested and the results have verified that it can be used as bone glue. In an in-vitro condition, the prepared nanocomposite (PPF/HEMA/NBG) showed improved adhesion to wet bone surfaces. The combined tension and shear resistance between two wet bone surfaces was measured, and its maximum value was 9±59MPa. To investigate the bioactivity and biodegradability of the nanocomposite, it has been immersed in simulated body fluid (SBF). After 14days exposure to SBF, a hydroxyapatite (HA) layer formed on the surface of the composite confirms the bioactivity of this material. In the XRD pattern of the nanocomposite surface, the HA characteristic diffraction peak at θ=26 and 31.8 were observed. Also, by monitoring the weight change after 8weeks immersion in SBF, the mass loss was about 16.46wt%. It has been confirmed that this nanocomposite is a biodegradable material. Also, bioactivity and biodegradability of nanocomposite have been proved by SEM images. It has been showed that by using NBG particles and HEMA precursor, mechanical properties increased significantly. The ultimate tensile strength (UTS) of nanocomposite which contains 20% NBG and the ratio of 70/30wt% PPF/HEMA (PHB.732) was approximately 62MPa, while the UTS in the pure PPF/HEMA was about 32MPa. High cell viability in this nanocomposite (MTT assays, 85-95%) can be attributed to the NBG nature which contains calcium phosphate and is similar to physiological environment. Furthermore, it possesses biomineralization and biodegradation which significantly affected by impregnation of hydrophilic HEMA in the PPF-based polymeric matrix. The results indicated that the new synthesized

  6. Topical Tenofovir Disoproxil Fumarate Nanoparticles Prevent HIV-1 Vaginal Transmission in a Humanized Mouse Model

    PubMed Central

    Mandal, Subhra; Yuan, Zhe; Kang, Guobin; Date, Abhijit A.; Lu, Wuxun; Shibata, Annemarie; Pham, Rachel; Bruck, Patrick; Rezich, Michael; Zhou, You; Vivekanandan, Renuga; Fletcher, Courtney V.; Li, Qingsheng

    2016-01-01

    Preexposure prophylaxis (PrEP) with 1% tenofovir (TFV) vaginal gel has failed in clinical trials. To improve TFV efficacy in vaginal gel, we formulated tenofovir disoproxil fumarate nanoparticles in a thermosensitive (TMS) gel (TDF-NP-TMS gel). TDF-NPs were fabricated using poly(lactic-co-glycolic acid) (PLGA) polymer and an ion-pairing agent by oil-in-water emulsification. The efficacy of TDF-NP-TMS gel was tested in humanized bone marrow-liver-thymus (hu-BLT) mice. Hu-BLT mice in the treatment group (Rx; n = 15) were administered TDF-NP-TMS gel intravaginally, having TDF at 0.1%, 0.5%, and 1% (wt/vol) concentrations, whereas the control (Ctr; n = 8) group received a blank TMS gel. All Rx mice (0.1% [n = 4], 0.5% [n = 6], and 1% [n = 5]) were vaginally challenged with two transmitted/founder (T/F) HIV-1 strains (2.5 × 105 50% tissue culture infectious doses). Rx mice were challenged at 4 h (0.1%), 24 h (0.5%), and 7 days (1%) posttreatment (p.t.) and Ctr mice were challenged at 4 h p.t. Blood was drawn weekly for 4 weeks postinoculation (p.i.) for plasma viral load (pVL) using reverse transcription-quantitative PCR. Ctr mice had positive pVL within 2 weeks p.i. Rx mice challenged at 4 h and 24 h showed 100% protection and no detectable pVL throughout the 4 weeks of follow-up (P = 0.009; Mantel-Cox test). Mice challenged at 7 days were HIV-1 positive at 14 days p.i. Further, HIV-1 viral RNA (vRNA) in vaginal and spleen tissues of Rx group mice with negative pVL were examined using an in situ hybridization (ISH) technique. The detection of vRNA was negative in all Rx mice studied. The present studies elucidate TDF-NP-TMS gel as a long-acting, coitus-independent HIV-1 vaginal protection modality. PMID:27044548

  7. Fabrication of poly(propylene fumarate)-based orthopaedic implants by photo-crosslinking through transparent silicone molds.

    PubMed

    Timmer, Mark D; Carter, Cory; Ambrose, Catherine G; Mikos, Antonios G

    2003-11-01

    This work presents a new molding process for photo-crosslinked, degradable polymeric networks of poly(propylene fumarate) (PPF) and the crosslinking agent poly(propylene fumarate)-diacrylate (PPF-DA). Transparent room temperature vulcanizing silicone molds were fabricated for parts ranging from simple test coupons to orthopaedic implants. The PPF/PPF-DA resin blend was injected into the cavity and photo-crosslinked as light was transmitted through the mold wall. The volumetric shrinkage, mechanical properties, and the effects of gamma sterilization were reported for molded PPF/PPF-DA networks prepared with varying compositions of the two polymer components. The shrinkage decreased while the mechanical properties displayed a general increasing trend when more of the crosslinking agent was incorporated into the network. Gamma irradiation resulted in an improvement of the mechanical properties. In addition, PPF/PPF-DA replicates of a 70:30 poly(L/DL-lactide) biodegradable fixation plate and a bone allograft interbody fusion spacer were produced to evaluate the performance of PPF/PPF-DA as an orthopaedic implant and allow for a comparison to be made with materials that have been established for clinical use.

  8. Angiogenic Rg1 /Sr-Doped TiO2 Nanowire/Poly(Propylene Fumarate) Bone Cement Composites.

    PubMed

    Salarian, Mehrnaz; Xu, William Z; Bohay, Richard; Lui, Edmund M K; Charpentier, Paul A

    2017-02-01

    A new approach is provided for preparing radiopaque and angiogenic poly(propylene fumarate) (PPF) bone cements by integrating Sr-doped n-TiO2 nanowires and ginsenoside Rg1 suitable for treating osteonecrosis. High aspect ratio radiopaque TiO2 -nanowires are synthesized by strontium doping in supercritical CO2 for the first time, showing a new phase, SrTiO3 . PPF is synthesized using a transesterification method by reacting diethyl fumarate and propylene glycol, then functionalized using maleic anhydride to produce terminal carboxyl groups, which are subsequently linked to the nanowires. The strong interfacial adhesion between functionalized PPF and nanowires is examined by scanning electron microscopy, Fourier transform infrared, X-ray photoelectron spectroscopy, thermal analysis, and mechanical testing. An angiogenic modulator, ginsenoside Rg1 , is integrated into the bone cement formulation with the mechanical properties, radiopacity, drug release, and angiogenesis behavior of the formed composites explored. The results show superior radiopacity and excellent release of ginsenoside Rg1 in vitro, as well as a dose-dependent increase in the branching point numbers. The present study suggests this new methodology provides sufficient mechanical properties, radiopacity, and angiogenic activity to be suitable for cementation of necrotic bone.

  9. Heterologous production in Wolinella succinogenes and characterization of the quinol:fumarate reductase enzymes from Helicobacter pylori and Campylobacter jejuni

    PubMed Central

    Mileni, Mauro; MacMillan, Fraser; Tziatzios, Christos; Zwicker, Klaus; Haas, Alexander H.; Mäntele, Werner; Simon, Jörg; Lancaster, C. Roy D.

    2005-01-01

    The ϵ-proteobacteria Helicobacter pylori and Campylobacter jejuni are both human pathogens. They colonize mucosal surfaces causing severe diseases. The membrane protein complex QFR (quinol:fumarate reductase) from H. pylori has previously been established as a potential drug target, and the same is likely for the QFR from C. jejuni. In the present paper, we describe the cloning of the QFR operons from the two pathogenic bacteria H. pylori and C. jejuni and their expression in Wolinella succinogenes, a non-pathogenic ϵ-proteobacterium. To our knowledge, this is the first documentation of heterologous membrane protein production in W. succinogenes. We demonstrate that the replacement of the homologous enzyme from W. succinogenes with the heterologous enzymes yields mutants where fumarate respiration is fully functional. We have isolated and characterized the heterologous QFR enzymes. The high quality of the enzyme preparation enabled us to determine unequivocally by analytical ultracentrifugation the homodimeric state of the three detergent-solubilized heterotrimeric QFR enzymes, to accurately determine the different oxidation–reduction (‘redox’) midpoint potentials of the six prosthetic groups, the Michaelis constants for the quinol substrate, maximal enzymatic activities and the characterization of three different anti-helminths previously suggested to be inhibitors of the QFR enzymes from H. pylori and C. jejuni. This characterization allows, for the first time, a detailed comparison of the QFR enzymes from C. jejuni and H. pylori with that of W. succinogenes. PMID:16367742

  10. The NRF2 transcriptional target, OSGIN1, contributes to monomethyl fumarate-mediated cytoprotection in human astrocytes

    PubMed Central

    Brennan, Melanie S.; Matos, Maria F.; Richter, Karl E.; Li, Bing; Scannevin, Robert H.

    2017-01-01

    Dimethyl fumarate (DMF) is indicated for the treatment of relapsing multiple sclerosis and may exert therapeutic effects via activation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway. Following oral DMF administration, central nervous system (CNS) tissue is predominantly exposed to monomethyl fumarate (MMF), the bioactive metabolite of DMF, which can stabilize NRF2 and induce antioxidant gene expression; however, the detailed NRF2-dependent mechanisms modulated by MMF that lead to cytoprotection are unknown. Our data identify a mechanism for MMF-mediated cytoprotection in human astrocytes that functions in an OSGIN1-dependent manner, specifically via upregulation of the OSGIN1-61 kDa isoform. NRF2-dependent OSGIN1 expression induced P53 nuclear translocation following MMF administration, leading to cell-cycle inhibition and cell protection against oxidative challenge. This study provides mechanistic insight into MMF-mediated cytoprotection via NRF2, OSGIN1, and P53 in human CNS-derived cells and contributes to our understanding of how DMF may act clinically to ameliorate pathological processes in neurodegenerative disease. PMID:28181536

  11. Adapting biodegradable oligo(poly(ethylene glycol) fumarate) hydrogels for pigment epithelial cell encapsulation and lens regeneration.

    PubMed

    Zhang, Mimi W; Park, Hansoo; Guo, Xuan; Nakamura, Kenta; Raphael, Robert M; Kasper, F Kurtis; Mikos, Antonios G; Tsonis, Panagiotis A

    2010-04-01

    This study investigated the encapsulation of newt iris pigment epithelial cells (PECs), which have the ability to regenerate a lens by trans-differentiation in vivo, within a biodegradable hydrogel of oligo(poly(ethylene glycol) fumarate) crosslinked with poly(ethylene glycol)-diacrylate. Hydrogel beads of initial diameter of 1 mm were fabricated by a molding technique. The swelling ratio and degradation rate of the hydrogel beads decreased with increasing crosslinking ratios. Confocal microscopy confirmed the cytocompatibility of crosslinking hydrogel formulations as evidenced by the viability of an encapsulated model cell line within a crosslinked hydrogel bead. Hydrogel beads encapsulating iris PECs were also implanted into lentectomized newts in vivo; histological evaluation of explants after 30 days revealed a regenerated lens, thus demonstrating that the presence of degrading hydrogel did not adversely affect lens regeneration. The results of this study suggest the potential of a method for lens regeneration involving oligo(poly(ethylene glycol) fumarate) hydrogels for iris PEC encapsulation and transplantation.

  12. Studies on Poly(propylene fumarate-co-caprolactone diol) Thermoset Composites towards the Development of Biodegradable Bone Fixation Devices

    PubMed Central

    Jayabalan, M.

    2009-01-01

    The effect of reinforcement in the cross-linked poly(propylene fumarate-co-caprolactone diol) thermoset composites based on Kevlar fibres and hydroxyapatite was studied. Cross-linked poly(propylene fumarate-co-caprolactone diol) was also studied without any reinforcement for comparison. The reinforcing fibre acts as a barrier for the curing reaction leading to longer setting time and lesser cross-link density. The fibre and HA reinforced composites have almost the same compressive strength. Nonreinforced material undergoes greater degree of swelling. Among the reinforced materials, the hydroxyapatite reinforced composite has a much higher swelling percentage than the fibre reinforced one. The studies on in vitro degradation of the cured materials reveal hydrolytic degradation in Ringer's solution and PBS medium during aging. All the three materials are found to swell initially in Ringer's solution and PBS medium during aging and then undergo gradual degradation. Compression properties of these cross-linked composites increase with aging; HA reinforced composite has the highest compressive strength and compressive modulus, whereas the aged fibre-reinforced composite has the least compressive strength and modulus. PMID:20126578

  13. Gateways to clinical trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2004-01-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Know- ledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: ABI-007, Ad.Egr.TNF.11D, adefovir dipivoxil, AdPEDF.11, AES-14, albumex, alefacept, alemtuzumab, aliskiren fumarate, alvimopan hydrate, aAminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, anakinra, anti-IL-12 MAb, aprepitant, atazanavir sulfate, atrasentan, avanafil; Banoxantrone, BG-12, bimatoprost, bortezomib, bosentan; Calcipotriol/betamethasone dipropionate, caspofungin acetate, CBT-1, ciclesonide, clofarabine, conivaptan hydrochloride, CpG-7909, C-Vax, Cypher; DA-8159, DAC:GLP-1, darbepoetin alfa, darifenacin, duloxetine hydrochloride; Eculizumab, efalizumab, efaproxiral sodium, EGF vaccine, eletriptan, epratuzumab, erlotinib hydrochloride, escitalopram oxalate, ETC-642, etoricoxib, everolimus, exenatide; Gefitinib, IV gamma-globulin; Human insulin, gamma-hydroxybutyrate sodium; IDN-6556, iguratimod, imatinib mesylate, indiplon, ixabepilone; Laquinimod, LB-80380, lidocaine/prilocaineliraglutide, lopinavir, lopinavir/ritonavir, lucinactant; MAb-14.18, melatonin, MLN-591-DM1; NC-531, neridronic acid, nesiritide, neutrophil-inhibitory factor, niacin/lovastatin; Oblimersen sodium, olcegepant, oral Insulin, ORV-105; Palonosetron hydrochloride, PAmAb, pegaptanib sodium, peginterferon alfa-2a, pegvisomant, perifosine, pexelizumab, phenoxodiol, phenserine tartrate, pimecrolimus, pramlintide acetate, pregabalin, PRO-542, prostate cancer vaccine, PT-141; Ramelteon, rasagiline mesilate, rDNA insulin, reslizumab, rh-Lactoferrin, ribamidine hydrochloride, rosuvastatin calcium; S-8184l, SC-1, sorafenib, St. John's Wort extract, SU-11248; Taxus, telbivudine, tenofovir disoproxil fumarate, teriparatide

  14. Omics-based approaches reveal phospholipids remodeling of Rhizopus oryzae responding to furfural stress for fumaric acid-production from xylose.

    PubMed

    Pan, Xinrong; Liu, Huanhuan; Liu, Jiao; Wang, Cheng; Wen, Jianping

    2016-12-01

    In order to relieve the toxicity of furfural on Rhizopus oryzae fermentation, the molecular mechanism of R. oryzae responding to furfural stress for fumaric acid-production was investigated by omics-based approaches. In metabolomics analysis, 29 metabolites including amino acid, sugars, polyols and fatty acids showed significant changes for maintaining the basic cell metabolism at the cost of lowering fumaric acid production. To further uncover the survival mechanism, lipidomics was carried out, revealing that phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol and polyunsaturated acyl chains might be closely correlated with R. oryzae's adapting to furfural stress. Based on the above omics analysis, lecithin, inositol and soybean oil were exogenously supplemented separately with an optimized concentration in the presence of furfural, which increased fumaric acid titer from 5.78g/L to 10.03g/L, 10.05g/L and 12.13g/L (increased by 73.5%, 73.8% and 110%, respectively). These findings provide a methodological guidance for hemicellulose-fumaric acid development.

  15. Preservation of acidified cucumbers with a natural preservative combination of fumaric acid and allyl isothiocyanate that target lactic acid bacteria and yeasts

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Without the addition of preservative compounds cucumbers acidified with 150 mM acetic acid with pH adjusted to 3.5 typically undergo fermentation by lactic acid bacteria. Fumaric acid (20 mM) inhibited growth of Lactobacillus plantarum and the lactic acid bacteria present on fresh cucumbers, but sp...

  16. Rumen microbial response in production of CLA and methane to safflower oil in association with fish oil or/and fumarate.

    PubMed

    Li, Xiang Z; Long, Rui J; Yan, Chang G; Lee, Hong G; Kim, Young J; Song, Man K

    2011-06-01

    Supplementation effect of fish oil and/or fumarate on production of conjugated linoleic acid (CLA) and methane by rumen microbes was examined when incubated with safflower oil. One hundred and twenty milligrams of safflower oil (SO), safflower oil with 24 mg fish oil (SOFO), safflower oil with 24 mmol/L fumarate (SOFA), or safflower oil with 24 mg fish oil and 24 mmol/L fumarate (SOFOFA) were added to the 90 mL culture solution. The culture solution was also made without any supplements (control). The SOFA and SOFOFA increased pH and propionate (C3) compared to other treatments from 3 h incubation time. An accumulated amount of total methane (CH(4) ) for 12 h incubation was decreased by all the supplements compared to control. The concentrations of c9,t11CLA for all the incubation times were increased in the treatments of SOFO, SOFA and SOFOFA compared to SO. The highest concentration of c9,t11CLA was observed from SOFOFA among all the treatments at all incubation times. Overall data indicate that supplementation of combined fumarate and/or fish oil when incubated with safflower oil could depress CH(4) generation and increase production of C(3) and CLA under the condition of current in vitro study.

  17. Arabidopsis has a cytosolic fumarase required for the massive allocation of photosynthate into fumaric acid and for rapid plant growth on high nitrogen.

    PubMed

    Pracharoenwattana, Itsara; Zhou, Wenxu; Keech, Olivier; Francisco, Perigio B; Udomchalothorn, Thanikan; Tschoep, Hendrik; Stitt, Mark; Gibon, Yves; Smith, Steven M

    2010-06-01

    The Arabidopsis genome has two fumarase genes, one of which encodes a protein with mitochondrial targeting information (FUM1) while the other (FUM2) does not. We show that a FUM1-green fluorescent protein fusion is directed to mitochondria while FUM2-red fluorescent protein remains in the cytosol. While mitochondrial FUM1 is an essential gene, cytosolic FUM2 is not required for plant growth. However FUM2 is required for the massive accumulation of carbon into fumarate that occurs in Arabidopsis leaves during the day. In fum2 knock-out mutants, fumarate levels remain low while malate increases, and these changes can be reversed with a FUM2 transgene. The fum2 mutant has lower levels of many amino acids in leaves during the day compared with the wild type, but higher levels at night, consistent with a link between fumarate and amino acid metabolism. To further test this relationship we grew plants in the absence or presence of nitrogen fertilizer. The amount of fumarate in leaves increased several fold in response to nitrogen in wild-type plants, but not in fum2. Malate increased to a small extent in the wild type but to a greater extent in fum2. Growth of fum2 plants was similar to that of the wild type in low nitrogen but much slower in the presence of high nitrogen. Activities of key enzymes of nitrogen assimilation were similar in both genotypes. We conclude that FUM2 is required for the accumulation of fumarate in leaves, which is in turn required for rapid nitrogen assimilation and growth on high nitrogen.

  18. A tricarboxylic acid cycle intermediate regulating transcription of a chloroaromatic biodegradative pathway: fumarate-mediated repression of the clcABD operon.

    PubMed

    McFall, S M; Abraham, B; Narsolis, C G; Chakrabarty, A M

    1997-11-01

    The ortho-cleavage pathways of catechol and 3-chlorocatechol are central catabolic pathways of Pseudomonas putida that convert aromatic and chloroaromatic compounds to tricarboxylic acid (TCA) cycle intermediates. They are encoded by the evolutionarily related catBCA and clcABD operons, respectively. Expression of the cat and clc operons requires the LysR-type transcriptional activators CatR and ClcR, respectively, and the inducer molecules cis,cis-muconate and 2-chloro-cis,cis-muconate, respectively. The regulation of the cat and clc promoters has been well studied, but the extent to which these operons are repressed by growth in TCA cycle intermediates has not been explored. We demonstrate by transcriptional fusion studies that the expression from the clc promoter is repressed when the cells are grown on succinate, citrate, or fumarate and that this repression is ClcR dependent and occurs at the transcriptional level. The presence of these organic acids did not affect the expression from the cat promoter. In vitro transcription assays demonstrate that the TCA cycle intermediate fumarate directly and specifically inhibits the formation of the clcA transcript. No such inhibition was observed when CatR was used as the activator on either the cat or clc template. Titration studies of fumarate and 2-chloromuconate show that the fumarate effect is concentration dependent and reversible, indicating that fumarate and 2-chloromuconate most probably compete for the same binding site on ClcR. This is an interesting example of the transcriptional regulation of a biodegradative pathway by the intracellular sensing of the state of the TCA cycle.

  19. Inactivation of Glyceraldehyde-3-Phosphate Dehydrogenase by Fumarate in Diabetes: Formation of S-(2-Succinyl)Cysteine, a Novel Chemical Modification of Protein and Possible Biomarker of Mitochondrial Stress

    PubMed Central

    Blatnik, Matthew; Frizzell, Norma; Thorpe, Suzanne R.; Baynes, John W.

    2008-01-01

    OBJECTIVE S-(2-succinyl)cysteine (2SC) is formed by a Michael addition reaction of the Krebs cycle intermediate, fumarate, with cysteine residues in protein. We investigated the role of fumarate in chemical modification and inhibition of the sulfhydryl enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), in vitro and in tissues of diabetic rats. RESEARCH DESIGN AND METHODS GAPDH was incubated with fumarate in PBS to assess effects of fumarate on enzyme activity in vitro. Sites of 2SC formation were determined by analysis of tryptic peptides by high-performance liquid chromatography–quadrupole/time-of-flight mass spectrometry. 2SC and fumarate in gastrocnemius muscle of control and streptozotocin-induced diabetic rats were measured by liquid chromatography/tandem mass spectrometry and by gas chromatography/mass spectrometry, respectively. GAPDH was isolated from muscle by immunoprecipitation, and sites of modification of GAPDH were determined by mass spectrometry analysis. RESULTS 2SC was found, both in vitro and in vivo, about equally at active-site Cys-149 and nucleophilic Cys-244. Inactivation of GAPDH by fumarate in vitro correlated with formation of 2SC. In diabetic compared with control rats, fumarate and 2SC concentration increased approximately fivefold, accompanied by an ~25% decrease in GAPDH specific activity. The fractional modification of GAPDH by 2SC was significantly increased in diabetic versus control animals, consistent with the decreased specific activity of GAPDH in muscle of diabetic animals. CONCLUSIONS Fumarate contributes to inactivation of GAPDH in diabetes. 2SC may be a useful biomarker of mitochondrial stress in diabetes. Modification of GAPDH and other enzymes and proteins by fumarate may contribute to the metabolic changes underlying the development of diabetes complications. PMID:17934141

  20. H2 S Sensors: Fumarate-Based fcu-MOF Thin Film Grown on a Capacitive Interdigitated Electrode.

    PubMed

    Yassine, Omar; Shekhah, Osama; Assen, Ayalew H; Belmabkhout, Youssef; Salama, Khaled N; Eddaoudi, Mohamed

    2016-12-19

    Herein we report the fabrication of an advanced sensor for the detection of hydrogen sulfide (H2 S) at room temperature, using thin films of rare-earth metal (RE)-based metal-organic framework (MOF) with underlying fcu topology. This unique MOF-based sensor is made via the in situ growth of fumarate-based fcu-MOF (fum-fcu-MOF) thin film on a capacitive interdigitated electrode. The sensor showed a remarkable detection sensitivity for H2 S at concentrations down to 100 ppb, with the lower detection limit around 5 ppb. The fum-fcu-MOF sensor exhibits a highly desirable detection selectivity towards H2 S vs. CH4 , NO2 , H2 , and C7 H8 as well as an outstanding H2 S sensing stability as compared to other reported MOFs.

  1. Development of poly(propylene fumarate-co-ethylene glycol) as an injectable carrier for endothelial cells.

    PubMed

    Suggs, L J; Mikos, A G

    1999-01-01

    Poly(propylene fumarate-co-ethylene glycol) [P(PF-co-EG)] hydrogels were examined as in situ polymerizable carriers for endothelial cells. The temperature increase from 37 degrees C during cross-linking was measured. The maximum temperature did not increase above 38.3 degrees C for any copolymer formulation. The temperature profiles also appeared to be independent of the amount or molecular weight of poly(ethylene glycol). These materials were polymerized in situ in a subcutaneous rat model and evaluated for initial biocompatibility. A normal wound-healing response was seen with formation and subsequent maturity of a fibrous capsule. Endothelial cells were embedded in vitro during the cross-linking process and their proliferation was assessed over the first 24 h. There was significant DNA synthesis by the embedded endothelial cells during this time period. These data suggest that P(PF-co-EG) hydrogels could be developed for use as injectable cell carriers.

  2. Gene dosage effect for fumarate hydratase (FH; E.C. 4.2.1.2) in partial trisomy 1.

    PubMed

    Braunger, R; Kling, H; Krone, W; Schmid, M; Olert, J

    1977-08-31

    A strain of fibroblasts partially trisomic for the larger part of 1q (Norwood and Hoehn, 1974) contains about 1.5 times as much fumarate hydratase (FH) as various control-strains. This gene dosage effect was ascertained by (1) comparative measurements of the specific activity; (2) relating the specific activity of FH to that of reference enzymes, not influenced by the chromosomal anomaly; and (3) by immunoprecipitation methods, using a rabbit antiserum against pig heart FH which cross-reacts with the human enzyme. Among others, this gene dosage effect can be demonstrated numerically by the following parameters: Ratio of the average specific activity of FH in the trisomic strain to that of the control strains: 1.53. Corresponding ratio after dividing FH activity by that of reference enzymes; for acid phosphatase: 1.58, for glutamate dehydrogenase: 1.53. Average ratio of the immunoprecipitation areas obtained upon radial immunodiffusion according to Mancini et al. (1965): 1.56.

  3. Photo-Crosslinked Poly(ε-caprolactone fumarate) Networks: Roles of Crystallinity and Crosslinking Density in Determining Mechanical Properties

    PubMed Central

    Wang, Shanfeng; Yaszemski, Michael J.; Gruetzmacher, James A.; Lu, Lichun

    2010-01-01

    We present a material design strategy of combining crystallinity and crosslinking to control the mechanical properties of polymeric biomaterials. Three polycaprolactone fumarates (PCLF530, PCLF1250, and PCLF2000) synthesized from the precursor polycaprolactone (PCL) diols with nominal molecular weights of 530, 1250, and 2000 g.mol-1, respectively, were employed to fabricate polymer networks via photo-crosslinking process. Five different amounts of photo-crosslinking initiator were applied during fabrication in order to understand the role of photoinitiator in modulating the crosslinking characteristics and physical properties of PCLF networks. Thermal properties such as glass transition temperature (Tg), melting temperature (Tm), and degradation temperature (Td) of photo-crosslinked PCLFs were examined and correlated with their rheological and mechanical properties. PMID:20936057

  4. Effects of baffle configuration and tank size on spherical agglomerates of dimethyl fumarate in a common stirred tank.

    PubMed

    Lin, Po Yen; Lee, Hung Lin; Chen, Chih Wei; Lee, Tu

    2015-11-30

    To pave the way for technology transfer and scale up of the spherical agglomeration (SA) process for dimethyl fumarate, effects of the US, European and Kawashima type baffles and 0.5, 2.0 and 10 L-sized common stirred tank were studied. It was found that the particle size distribution varied significantly. However, the size-related properties such as dissolution profile and flowability of agglomerates from the same size cut after sieving could remain unchanged. The interior structure-related properties such as particle density and mechanical property of agglomerates upon baffle change and scale up from the same size cut were decayed and the agglomerates could become denser and stronger by prolonged maturation time. To maintain the same size distribution, agglomerates from any batch could have been separated and classified by sieving and then blended back together artificially by the desired weight% of each cut.

  5. Potentiometric determination of ketotifen fumarate in pharmaceutical preparations and urine using carbon paste and PVC membrane selective electrodes.

    PubMed

    Frag, Eman Y Z; Mohamed, Gehad G; Khalil, Mohamed M; Hwehy, Mohammad M A

    2011-01-01

    This study compares between unmodified carbon paste (CPE; the paste has no ion pair) and polyvinyl chloride (PVC) membrane selective electrodes that were used in potentiometric determination of ketotifen fumarate (KTF), where sodium tetraphenylborate (NaTPB) was used as titrant. The performance characteristics of these sensors were evaluated according to IUPAC recommendations which reveal a fast, stable, and linear response for KTF over the concentration range of 10(-7) to 10(-2) mol L(-1). The electrodes show Nernstian slope value of 52.51 ± 0.20 and 51.51 ± 0.25 mV decade(-1) for CPE and PVC membrane electrodes at 30°C, respectively. The potential is nearly stable over the pH range 3.0-6.0 and 2.0-7.0 for CPE and PVC membrane electrodes, respectively. Selectivity coefficient values towards different inorganic cations, sugars, and amino acids reflect high selectivity of the prepared electrodes. The electrodes responses at different temperatures were also studied, and long operational lifetime of 12 and 5 weeks for CPE and PVC membrane electrodes, respectively, were found. These are used for determination of ketotifen fumarate using potentiometric titration, calibration, and standard addition methods in pure samples, its pharmaceutical preparations (Zaditen tablets), and biological fluid (urine). The direct potentiometric determination of KTF using the proposed sensors gave recoveries % of 98.97 ± 0.53 and 98.62 ± 0.74 with RSD 1.42 and 0.63% for CPE and PVC membrane selective electrodes, respectively. Validation of the method shows suitability of the proposed sensors for use in quality control assessment of KTF. The obtained results were in a good agreement with those obtained using the reported spectrophotometric method.

  6. Pharmacokinetics of fixed-dose combination of tenofovir disoproxil fumarate, lamivudine, and efavirenz: results of a randomized, crossover, bioequivalence study.

    PubMed

    Abhyankar, Dhiraj; Shedage, Ashish; Gole, Milind; Raut, Preeti

    2016-06-17

    The objective of this study was to assess the bioequivalence between a fixed-dose combination of tenofovir disoproxil fumarate/lamivudine/efavirenz 300/300/600 mg and the individual innovator products. A randomized, balanced, open-label, two-sequence, two-treatment, two-period, single dose, crossover study in 48 healthy adults was conducted. Dosing was separated by a washout period of 32 days. Twenty-seven blood samples were collected in each period from pre-dose to 72 h post-dose. The data of 45 subjects were analyzed for pharmacokinetics and safety. Ninety percent CIs of geometric mean ratio on Cmax, AUC0-t, and AUC0-inf for tenofovir and lamivudine and on Cmax and AUC0-72 for efavirenz were within the acceptance criteria (80-125%). For tenofovir disoproxil fumarate, the Tmax, Kel, and t1/2 values for the test and reference products were 1.02 versus 0.91 h, 0.04 versus 0.04/h, 18.67 versus 18.46 h, respectively. For lamivudine, the Tmax, Kel, and t1/2 values were: 1.38 versus 1.30 h, 0.21 versus 0.19/h, 3.44 versus 3.91 h, respectively. For efavirenz, the Tmax values for the test and reference products were 3.71 and 3.65 h, respectively. Both the treatments were well tolerated. Our findings suggest that the tested formulation is bioequivalent to the innovators' formulations, and both treatments were well tolerated.

  7. Photo-crosslinked poly(epsilon-caprolactone fumarate) networks for guided peripheral nerve regeneration: material properties and preliminary biological evaluations.

    PubMed

    Wang, Shanfeng; Yaszemski, Michael J; Knight, Andrew M; Gruetzmacher, James A; Windebank, Anthony J; Lu, Lichun

    2009-06-01

    In an effort to achieve suitable biomaterials for peripheral nerve regeneration, we present a material design strategy of combining a crystallite-based physical network and a crosslink-based chemical network. Biodegradable polymer disks and conduits have been fabricated by photo-crosslinking three poly(epsilon-caprolactone fumarate)s (PCLF530, PCLF1250, and PCLF2000), which were synthesized from the precursor poly(epsilon-caprolactone) (PCL) diols with nominal molecular weights of 530, 1250, and 2000 g mol(-1), respectively. Thermal properties such as glass transition temperature (T(g)), melting temperature (T(m)), and crystallinity of photo-crosslinked PCLFs were examined and correlated with their rheological and mechanical properties. Furthermore, in vitro degradation of uncrosslinked and crosslinked PCLFs in PBS crosslinked PCLFs in 1 N NaOH aqueous solution at 37 degrees C was studied. In vitro cytocompatibility, attachment, and proliferation of Schwann cell precursor line SPL201 cells on three PCLF networks were investigated. Crosslinked PCLF2000 with the highest crystallinity and mechanical properties was found to best support cell attachment and proliferation. Using a new photo-crosslinking method, single-lumen crosslinked PCLF nerve conduits without defects were fabricated in a glass mold. Crosslinked PCLF2000 nerve conduits were selected for evaluation in a 1cm gap rat sciatic nerve model. Histological evaluation demonstrated that the material was biocompatible with sufficient strength to hold sutures in place after 6 and 17 weeks of implantation. Nerve cable with myelinated axons was found in the crosslinked PCLF2000 nerve conduit.

  8. Pyruvate and Lactate Metabolism by Shewanella oneidensis MR-1 under Fermentation, Oxygen Limitation, and Fumarate Respiration Conditions

    SciTech Connect

    Pinchuk, Grigoriy E.; Geydebrekht, Oleg V.; Hill, Eric A.; Reed, Jennifer L.; Konopka, Allan; Beliaev, Alex S.; Fredrickson, Jim K.

    2011-12-30

    Shewanella oneidensis MR-1 is a facultative anaerobe growing by coupling organic matter oxidation to reduction of wide range of electron acceptors. Here we quantitatively assessed lactate and pyruvate metabolism of these bacteria under three distinct conditions: electron acceptor limited growth on lactate with O2 and fumarate, and pyruvate fermentation, which does not sustain growth but allows cells to survive for prolonged period. Using physiological and genetic approaches combined with flux balance analysis, we showed that the proportion of ATP produced by substrate-level phosphorylation varied from 33% to 72.5% of all ATP needed for growth depending on the electron acceptor nature and availability. While being indispensible for growth, respiration of fumarate does not contribute much to ATP generation and likely serves to remove formate, a product of pyruvate formate-lyase-catalyzed pyruvate disproportionation. Under both tested respiratory conditions S. oneidensis MR-1 carried out incomplete substrate oxidation, and TCA cycle did not contribute significantly to substrate oxidation. Pyruvate dehydrogenase reaction was not involved in lactate metabolism under O2 limitation, however was important for anaerobic growth probably supplying reducing equivalents for biosynthesis. Unexpectedly, obtained results suggest that pyruvate fermentation by S. oneidensis MR-1 cells represents a combination between substrate-level phosphorylation and a respiratory process, where pyruvate serves as electron donor and electron acceptor. Pyruvate reduction to lactate at the expense of formate oxidation is catalyzed by recently described new type of oxidative NAD(P)H independent D-lactate dehydrogenase (Dld-II). Based on involved enzymes localization we hypothesize that pyruvate reduction coupled to formate oxidation may be accompanied by proton motive force generation.

  9. Pyruvate and lactate metabolism by Shewanella oneidensis MR-1 under fermentation, oxygen limitation, and fumarate respiration conditions.

    PubMed

    Pinchuk, Grigoriy E; Geydebrekht, Oleg V; Hill, Eric A; Reed, Jennifer L; Konopka, Allan E; Beliaev, Alexander S; Fredrickson, Jim K

    2011-12-01

    Shewanella oneidensis MR-1 is a facultative anaerobe that derives energy by coupling organic matter oxidation to the reduction of a wide range of electron acceptors. Here, we quantitatively assessed the lactate and pyruvate metabolism of MR-1 under three distinct conditions: electron acceptor-limited growth on lactate with O(2), lactate with fumarate, and pyruvate fermentation. The latter does not support growth but provides energy for cell survival. Using physiological and genetic approaches combined with flux balance analysis, we showed that the proportion of ATP produced by substrate-level phosphorylation varied from 33% to 72.5% of that needed for growth depending on the electron acceptor nature and availability. While being indispensable for growth, the respiration of fumarate does not contribute significantly to ATP generation and likely serves to remove formate, a product of pyruvate formate-lyase-catalyzed pyruvate disproportionation. Under both tested respiratory conditions, S. oneidensis MR-1 carried out incomplete substrate oxidation, whereby the tricarboxylic acid (TCA) cycle did not contribute significantly. Pyruvate dehydrogenase was not involved in lactate metabolism under conditions of O(2) limitation but was required for anaerobic growth, likely by supplying reducing equivalents for biosynthesis. The results suggest that pyruvate fermentation by S. oneidensis MR-1 cells represents a combination of substrate-level phosphorylation and respiration, where pyruvate serves as an electron donor and an electron acceptor. Pyruvate reduction to lactate at the expense of formate oxidation is catalyzed by a recently described new type of oxidative NAD(P)H-independent d-lactate dehydrogenase (Dld-II). The results further indicate that pyruvate reduction coupled to formate oxidation may be accompanied by the generation of proton motive force.

  10. Pyruvate and Lactate Metabolism by Shewanella oneidensis MR-1 under Fermentation, Oxygen Limitation, and Fumarate Respiration Conditions

    SciTech Connect

    Pinchuk, Grigoriy E.; Geydebrekht, Oleg V.; Hill, Eric A.; Reed, Jennifer L.; Konopka, Allan; Beliaev, Alex S.; Fredrickson, Jim K.

    2011-12-01

    Shewanella oneidensis MR-1 is a facultative anaerobe that derives energy by coupling organic matter oxidation to the reduction of wide range of electron acceptors. Here, we quantitatively assessed lactate and pyruvate metabolism of MR-1 under three distinct conditions: electron acceptor limited growth on lactate with O2; lactate with fumarate; and pyruvate fermentation. The latter does not support growth but provides energy for cell survival. Using physiological and genetic approaches combined with flux balance analysis, we showed that the proportion of ATP produced by substrate-level phosphorylation varied from 33% to 72.5% of that needed for growth depending on the electron acceptor nature and availability. While being indispensible for growth, respiration of fumarate does not contribute significantly to ATP generation and likely serves to remove formate, a product of pyruvate formate-lyase-catalyzed pyruvate disproportionation. Under both tested respiratory conditions S. oneidensis MR-1 carried out incomplete substrate oxidation, whereby the TCA cycle did not contribute significantly. Pyruvate dehydrogenase was not involved in lactate metabolism under O2 limitation but was required for anaerobic growth likely by supplying reducing equivalents for biosynthesis. The results suggest that pyruvate fermentation by S. oneidensis MR-1 cells represents a combination of substrate-level phosphorylation and respiration, where pyruvate serves as electron donor and electron acceptor. Pyruvate reduction to lactate at the expense of formate oxidation is catalyzed by recently described new type of oxidative NAD(P)H independent D-lactate dehydrogenase (Dld-II). The results further indicate that pyruvate reduction coupled to formate oxidation may be accompanied by proton motive force generation.

  11. The NMR structure of the sensory domain of the membranous two-component fumarate sensor (histidine protein kinase) DcuS of Escherichia coli.

    PubMed

    Pappalardo, Lucia; Janausch, Ingo G; Vijayan, Vinesh; Zientz, Eva; Junker, Jochen; Peti, Wolfgang; Zweckstetter, Markus; Unden, Gottfried; Griesinger, Christian

    2003-10-03

    The structure of the water-soluble, periplasmic domain of the fumarate sensor DcuS (DcuS-pd) has been determined by NMR spectroscopy in solution. DcuS is a prototype for a sensory histidine kinase with transmembrane signal transfer. DcuS belongs to the CitA family of sensors that are specific for sensing di- and tricarboxylates. The periplasmic domain is folded autonomously and shows helices at the N and the C terminus, suggesting direct linking or connection to helices in the two transmembrane regions. The structure constitutes a novel fold. The nearest structural neighbor is the Per-Arnt-Sim domain of the photoactive yellow protein that binds small molecules covalently. Residues Arg107, His110, and Arg147 are essential for fumarate sensing and are found clustered together. The structure constitutes the first periplasmic domain of a two component sensory system and is distinctly different from the aspartate sensory domain of the Tar chemotaxis sensor.

  12. Case report: persistent cytomegalovirus (CMV) infection after haploidentical hematopoietic stem cell transplantation using in vivo alemtuzumab: emergence of resistant CMV due to mutations in the UL97 and UL54 genes.

    PubMed

    Oshima, Kumi; Kanda, Yoshinobu; Kako, Shinichi; Asano-Mori, Yuki; Watanabe, Takuro; Motokura, Toru; Chiba, Shigeru; Shiraki, Kimiyasu; Kurokawa, Mineo

    2008-10-01

    Addition of in vivo alemtuzumab to the conditioning regimen enabled 2- or 3-locus-mismatched hematopoietic stem cell transplantation with an acceptable incidence of graft-versus-host-disease. However, the procedure was associated with a high incidence of cytomegalovirus (CMV) reactivation. Although preemptive therapy with ganciclovir prevented successfully severe CMV diseases and CMV-related mortality, a patient developed persistent positive CMV antigenemia for more than 1 year after transplantation and CMV disease, despite the use of ganciclovir and foscarnet. The in vitro susceptibility assay showed that the clinical isolate was resistant to foscarnet, moderately resistant to ganciclovir, but sensitive to cidofovir. Therefore, cidofovir was administered. CMV antigenemia became negative within 2 weeks and never developed again. Nucleotide sequence of the UL54 and UL97 of the clinical isolate showed 4 amino acid substitutions (V11L, Q578H, S655L, and G874R) in UL54 and 2 mutations (A140V and A594V) in UL97 compared with the Towne and AD169 strains. Ganciclovir resistance was suspected to be caused by both A594V of UL97 and Q578H of UL54, whereas foscarnet resistance was due mainly to Q578H of UL54. In conclusion, the in vitro susceptibility assay as well as nucleotide sequence of clinical isolate is important to choose appropriate antiviral agents for patients who have persistent CMV reactivation after stem cell transplantation.

  13. A metabolic-based approach to improve xylose utilization for fumaric acid production from acid pretreated wheat bran by Rhizopus oryzae.

    PubMed

    Wang, Guanyi; Huang, Di; Li, Yong; Wen, Jianping; Jia, Xiaoqiang

    2015-03-01

    In this work, wheat bran (WB) was utilized as feedstock to synthesize fumaric acid by Rhizopus oryzae. Firstly, the pretreatment process of WB by dilute sulfuric acid hydrolysis undertaken at 100°C for 30min offered the best performance for fumaric acid production. Subsequently, through optimizing the seed culture medium, a suitable morphology (0.55mm pellets diameter) of R. oryzae was obtained. Furthermore, a metabolic-based approach was developed to profile the differences of intracellular metabolites concentration of R. oryzae between xylose (the abundant sugar in wheat bran hydrolysate (WBH)) and glucose metabolism. The xylitol, sedoheptulose 7-phosphate, ribulose 5-phosphate, glucose 6-phosphate, proline and serine were responsible for fumaric acid biosynthesis limitation in xylose fermentation. Consequently, regulation strategies were proposed, leading to a 149% increase in titer (up to 15.4g/L). Finally, by combinatorial regulation strategies the highest production was 20.2g/L from WBH, 477% higher than that of initial medium.

  14. Diaqua­(1,4,8,11-tetra­aza­cyclo­tetra­deca­ne)nickel(II) fumarate tetra­hydrate

    PubMed Central

    Lim, Shao Liang; Ng, Chew Hee; Teoh, Siang Guan; Loh, Wan-Sin; Fun, Hoong-Kun

    2010-01-01

    The asymmetric unit of the title complex salt, [Ni(C10H24N4)(H2O)2](C4H2O4)·4H2O, comprises half of a nickel(II) complex dication, half of a fumarate dianion and two water mol­ecules. Both the NiII cation and fumarate anion lie on a crystallographic inversion center. The NiII ion in the cyclam complex is six-coordinated within a distorted N4O2 octa­hedral geometry, with the four cyclam N atoms in the equatorial plane and the two water mol­ecules in apical positions. The six-membered metalla ring adopts a chair conformation, whereas the five-membered ring exists in a twisted form. In the crystal packing, inter­molecular O—H⋯O hydrogen bonds between the water molecules and the carboxyl groups of the fumarate anions lead to the formation of layers with R 4 2(8) ring motifs. NiII complex cations are sandwiched between two such layers, being held in place by O—H⋯O, N—H⋯O and C—H⋯O hydrogen bonds, consolidating a three-dimensional network. PMID:21587678

  15. Stability of salt double-fortified with ferrous fumarate and potassium iodate or iodide under storage and distribution conditions in Kenya.

    PubMed

    Oshinowo, Toks; Diosady, Levente; Yusufali, Rizwan; Laleye, Louis

    2004-09-01

    The stability of table salt double-fortified with iron as ferrous fumarate, and with iodine as potassium iodide or potassium iodate, has been investigated under actual field conditions of storage and distribution in the coastal and highland regions of Kenya. Seven 200-g sample packets of double-fortified salt in sealed polyethylene bags and a similar packet containing a datalogger for monitoring temperature and humidity were packaged with 21 sample bags of salt from another study into a bundle, which then entered the distribution network from a salt manufacturer's facility to the consumer. Iodine retention values of up to 90% or more were obtained during the three-month study. Double-fortified salt was prepared using ferrous fumarate microencapsulated with a combination of binders and coloring agents and coated with soy stearine, in combination with either iodated salt or salt iodized with potassium iodide microencapsulated with dextrin and coated with soy stearine. Most of the ferrous iron was retained, with less than 17% being oxidized to the ferric state. The polyethylene film overwrap of salt packs in the bundles provided significant protection from ambient humidity. Salt double-fortified with iodine and microencapsulated iron ferrous fumarate premix was generally quite stable, because both iodine and ferrous iron were protected during distribution and retail in typical tropical conditions in Kenya's highlands and humid lowlands.

  16. RP-HPLC method for simultaneous estimation of tenofovir disoproxil fumarate, lamivudine, and efavirenz in combined tablet dosage form

    PubMed Central

    Bhavsar, Dhara S.; Patel, Bhavini N.; Patel, Chhaganbhai N.

    2012-01-01

    Background: A simple, precise, accurate, and rapid reverse phase-high performance liquid chromatography (RP-HPLC) method with UV-Visible detector has been developed and subsequently validated for the simultaneous determination of tenofovir disoproxil fumarate (TDF), lamivudine (LAMI), and efavirenz (EFV) in their combined tablet dosage form. Materials and Methods: The separation was based on the use of a Kromasil C18 analytical column (150 × 4.6 mm, i.d., 5 μm). The mobile phase consisted of a mixture of 70 volumes of methanol and 30 volumes of 10 mM phosphate buffer (pH 5.0). The separation was carried out at 40°C temperature with a flow rate of 1 ml/min. Results: Quantitation was achieved with UV detection at 254 nm, with linear calibration curves at concentration ranges of 1–6 μg/ml for TDF and LAMI and 2–12 μg/ml for EFV. The recoveries obtained were 99.46–101.36% for LAMI, 99.57–101.42% for TDF, and 99.96–100.87 for EFV. Conclusion: The method was validated according to International conference of harmonisation guidelines in terms of accuracy, precision, specificity, robustness, limits of detection and quantitation, and other aspects of analytical validation. PMID:23781482

  17. [Determination of dimethyl fumarate in leather and textiles by gas chromatography-tandem mass spectrometry with solid phase extraction].

    PubMed

    Zhao, Yang; Qi, Xiaoxia

    2010-01-01

    An effective method for the determination of dimethyl fumarate (DMF) in leather and textiles by gas chromatography-tandem mass spectrometry (GC-MS/MS) was developed. Samples of leather or textiles were extracted with ethyl acetate and concentrated, DMF was separated on a VF-5 ms column and analyzed by GC-MS/MS after solid phase extraction (SPE) process. The result shows that this method is sensitive, accurate and reliable. The linear relationship was perfect and the interference with background signal was further eliminated after pretreatment, SPE and GC-MS/MS analytical conditions were optimized. The average recoveries of DMF in leather and textiles at three levels ranged from 84% to 93%, the relative standard deviations (n = 6) were lower than 7.2%, the limits of detection in the range from 0.012 to 0.039 mg/kg (S/N = 3) , the correlation coefficient was 0.999 0 over the range 0.05 - 100 mg/L. It has been applied to routine determination of DMF in leather and textiles with satisfactory results.

  18. Reformulating Polycaprolactone Fumarate to Eliminate Toxic Diethylene Glycol: Effects of Polymeric Branching and Autoclave Sterilization on Material Properties

    PubMed Central

    Runge, M. Brett; Wang, Huan; Spinner, Robert J; Windebank, Anthony J; Yaszemski, Michael J.

    2011-01-01

    Polycaprolactone fumarate (PCLF) is a cross-linkable derivate of polycaprolactone diol that has been shown to be an effective nerve conduit material that supports regeneration across segmental nerve defects and has warranted future clinical trials. Degradation of the previously studied PCLF (PCLFDEG) releases toxic small molecules of diethylene glycol used as the initiator for the synthesis of polycaprolactone diol. In an effort to eliminate this toxic degradation product we present a strategy for the synthesis of PCLF from either propylene glycol (PCLFPPD) or glycerol (PCLFGLY). PCLFPPD is linear and resembles the previously studied PCLFDEG, while PCLFGLY is branched and exhibits dramatically different material properties. The synthesis and characterization of their thermal, rheological, and mechanical properties are reported. The results show that the linear PCLFPPD has material properties similar to the previously studied PCLFDEG. The branched PCLFGLY exhibits dramatically lower crystalline properties resulting in lower rheological and mechanical moduli, and is therefore a more compliant material. In addition, the question of an appropriate FDA approvable sterilization method is addressed. This study shows that autoclave sterilization on PCLF materials is an acceptable sterilization method for cross-linked PCLF and has minimal effect on the PCLF thermal and mechanical properties. PMID:21911087

  19. High-dose beclometasone dipropionate/formoterol fumarate in fixed-dose combination for the treatment of asthma.

    PubMed

    Corradi, Massimo; Spinola, Monica; Petruzzelli, Stefano; Kuna, Piotr

    2016-10-01

    The high-strength formulation of extrafine beclometasone dipropionate/formoterol fumarate (BDP/Form) 200/6 µg has been developed to step up inhaled corticosteroid treatment, without increasing the dose of the bronchodilator, in patients who are not controlled with previous therapies. Two clinical studies have evaluated efficacy of high-strength BDP/Form as compared with another high-dose fixed combination and BDP monotherapy. Overall, data show that BDP/Form 200/6 μg improves lung function and has beneficial effects on symptoms, use of rescue medication and asthma control, with an acceptable safety profile comparable with that of high-dose fluticasone propionate/salmeterol. Therefore, BDP/Form 200/6 μg could be considered as an effective and safe treatment for patients with asthma who are not adequately controlled with high doses of inhaled corticosteroid monotherapy or medium doses of inhaled corticosteroid/long-acting β2-agonist combinations.

  20. Dimethyl Fumarate Therapy Significantly Improves the Responsiveness of T Cells in Multiple Sclerosis Patients for Immunoregulation by Regulatory T Cells

    PubMed Central

    Schlöder, Janine; Berges, Carsten; Luessi, Felix; Jonuleit, Helmut

    2017-01-01

    Multiple sclerosis (MS) is a chronic autoimmune disease caused by an insufficient suppression of autoreactive T lymphocytes. One reason for the lack of immunological control is the reduced responsiveness of T effector cells (Teff) for the suppressive properties of regulatory T cells (Treg), a process termed Treg resistance. Here we investigated whether the disease-modifying therapy of relapsing-remitting MS (RRMS) with dimethyl fumarate (DMF) influences the sensitivity of T cells in the peripheral blood of patients towards Treg-mediated suppression. We demonstrated that DMF restores responsiveness of Teff to the suppressive function of Treg in vitro, presumably by down-regulation of interleukin-6R (IL-6R) expression on T cells. Transfer of human immune cells into immunodeficient mice resulted in a lethal graft-versus-host reaction triggered by human CD4+ Teff. This systemic inflammation can be prevented by activated Treg after transfer of immune cells from DMF-treated MS patients, but not after injection of Treg-resistant Teff from therapy-naïve MS patients. Furthermore, after DMF therapy, proliferation and expansion of T cells and the immigration into the spleen of the animals is reduced and modulated by activated Treg. In summary, our data reveals that DMF therapy significantly improves the responsiveness of Teff in MS patients to immunoregulation. PMID:28134847

  1. Enhanced Gene Detection Assays for Fumarate-Adding Enzymes Allow Uncovering of Anaerobic Hydrocarbon Degraders in Terrestrial and Marine Systems

    PubMed Central

    von Netzer, Frederick; Pilloni, Giovanni; Kleindienst, Sara; Krüger, Martin; Knittel, Katrin; Gründger, Friederike

    2013-01-01

    The detection of anaerobic hydrocarbon degrader populations via catabolic gene markers is important for the understanding of processes at contaminated sites. Fumarate-adding enzymes (FAEs; i.e., benzylsuccinate and alkylsuccinate synthases) have already been established as specific functional marker genes for anaerobic hydrocarbon degraders. Several recent studies based on pure cultures and laboratory enrichments have shown the existence of new and deeply branching FAE gene lineages, such as clostridial benzylsuccinate synthases and homologues, as well as naphthylmethylsuccinate synthases. However, established FAE gene detection assays were not designed to target these novel lineages, and consequently, their detectability in different environments remains obscure. Here, we present a new suite of parallel primer sets for detecting the comprehensive range of FAE markers known to date, including clostridial benzylsuccinate, naphthylmethylsuccinate, and alkylsuccinate synthases. It was not possible to develop one single assay spanning the complete diversity of FAE genes alone. The enhanced assays were tested with a range of hydrocarbon-degrading pure cultures, enrichments, and environmental samples of marine and terrestrial origin. They revealed the presence of several, partially unexpected FAE gene lineages not detected in these environments before: distinct deltaproteobacterial and also clostridial bssA homologues as well as environmental nmsA homologues. These findings were backed up by dual-digest terminal restriction fragment length polymorphism diagnostics to identify FAE gene populations independently of sequencing. This allows rapid insights into intrinsic degrader populations and degradation potentials established in aromatic and aliphatic hydrocarbon-impacted environmental systems. PMID:23124238

  2. Spray drying of budesonide, formoterol fumarate and their composites-II. Statistical factorial design and in vitro deposition properties.

    PubMed

    Tajber, L; Corrigan, O I; Healy, A M

    2009-02-09

    The aim of this study was to investigate the effect of changing spray drying parameters on the production of a budesonide/formoterol fumarate 100:6 (w/w) composite. The systems were spray dried as solutions from 95% ethanol/5% water (v/v) using a Büchi 191-Mini Spray Dryer. A 2(5-1) factorial design study was undertaken to assess the consequence of altering spray drying processing variables on particle characteristics. The processing parameters that were studied were inlet temperature, spray drier airflow rate, pump rate, aspirator setting and feed concentration. Each batch of the resulting powder was characterised in terms of thermal and micromeritic properties as well as an in vitro deposition by twin impinger analysis. Overall, the parameter that had the greatest influence on each response investigated was production yield - airflow (higher airflow giving greater yields), median particle size - airflow (higher airflow giving smaller particle sizes) and Carr's compressibility index - feed concentration (lower feed concentration giving smaller Carr's indices). A six- to seven-fold difference in respirable fraction can be observed by changing the spray drying process parameters. The co-spray dried composite system which displayed best in vitro deposition characteristics, showed a 2.6-fold increase in respirable fraction in the twin impinger experiments and better dose uniformity compared with the physical mix of micronised powders.

  3. Topical Delivery of Tenofovir Disoproxil Fumarate and Emtricitabine from Pod-Intravaginal Rings Protects Macaques from Multiple SHIV Exposures

    PubMed Central

    Gunawardana, Manjula; Churchman, Scott A.; Yang, Flora; Dinh, Chuong T.; Mitchell, James M.; Zhang, Jining; Fanter, Rob; Miller, Christine S.; Butkyavichene, Irina; McNicholl, Janet M.; Smith, Thomas J.; Baum, Marc M.; Smith, James M.

    2016-01-01

    Topical preexposure prophylaxis (PrEP) against HIV has been marginally successful in recent clinical trials with low adherence rates being a primary factor for failure. Controlled, sustained release of antiretroviral (ARV) drugs may help overcome these low adherence rates if the product is protective for extended periods of time. The oral combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) is currently the only FDA-approved ARV drug for HIV PrEP. A novel pod-intravaginal ring (IVR) delivering TDF and FTC at independently controlled rates was evaluated for efficacy at preventing SHIV162p3 infection in a rigorous, repeat low-dose vaginal exposure model using normally cycling female pigtailed macaques. Six macaques received pod-IVRs containing TDF (65 mg) and FTC (68 mg) every two weeks, and weekly vaginal exposures to 50 TCID50 of SHIV162p3 began one week after the first pod-IVR insertion. All pod-IVR-treated macaques were fully protected throughout the study (P = 0.0002, Log-rank test), whereas all control animals became infected with a median of 4 exposures to infection. The topical, sustained release of TDF and FTC from the pod-IVR maintained protective drug levels in macaques over four months of virus exposures. This novel and versatile delivery system has the capacity to deliver and maintain protective levels of multiple drugs and the protection observed here warrants clinical evaluation of this pod-IVR design. PMID:27275923

  4. Incorporation of phosphate group modulates bone cell attachment and differentiation on oligo(polyethylene glycol) fumarate hydrogel

    PubMed Central

    Dadsetan, Mahrokh; Giuliani, Melissa; Wanivenhaus, Florian; Runge, M. Brett; Charlesworth, Jon E.; Yaszemski, Michael J.

    2014-01-01

    In this work, we have investigated the development of a synthetic hydrogel that contains a negatively charged phosphate group for use as a substrate for bone cell attachment and differentiation in culture. The photoreactive, phosphate-containing molecule, bis(2-(methacryloyloxy)ethyl)phosphate (BP), was incorporated into oligo(polyethylene glycol) fumarate hydrogel and the mechanical, rheological and thermal properties of the resulting hydrogels were characterized. Our results showed changes in hydrogel compression and storage moduli with incorporation of BP. The modification also resulted in decreased crystallinity as recorded by differential scanning calorimetry. Our data revealed that incorporation of BP improved attachment and differentiation of human fetal osteoblast (hFOB) cells in a dose-dependent manner. A change in surface chemistry and mineralization of the phosphate-containing surfaces verified by scanning electron microscopy and energy dispersive X-ray analysis was found to be important for hFOB cell attachment and differentiation. We also demonstrated that phosphate-containing hydrogels support attachment and differentiation of primary bone marrow stromal cells. These findings suggest that BP-modified hydrogels are capable of sustaining attachment and differentiation of both bone marrow stromal cells and osteoblasts that are critical for bone regeneration. PMID:22277774

  5. Effects of crosslinking on the thermal stability of hemoglobin. I. The use of bis(3,5-dibromosalicyl) fumarate.

    PubMed

    White, F L; Olsen, K W

    1987-10-01

    The double-headed aspirin, bis(3,5-dibromosalicyl) fumarate, has been used to crosslink hemoglobin A between Lys 82 beta 1 and Lys 82 beta 2 (J. A. Walder et al. (1979) Biochemistry 18,4265). Denaturation experiments were used to compare the stability of this crosslinked protein to that of hemoglobin A. Thermal denaturations, done in 0.01 M 4-morpholine-propanesulfonic acid, pH 7, containing 0.9 M guanidine to prevent precipitation at high temperatures, were monitored by changes in absorbance between 190 and 650 nm using a diode array spectrophotometer. The sample was heated from 25 to 70 degrees C at 0.3 degrees C/min. The data were analyzed by using both a two-state model and a novel first derivative method. As expected, methemoglobin A had a single, broad transition with a midpoint of 40.7 degrees C. The crosslinked methemoglobin showed a transition at 57.1 degrees C. Two minor transitions, one of which was apparently due to residual unmodified hemoglobin, were also observed in the crosslinked sample. Thus, a single crosslink between only two of the four subunits can lead to a significantly more stable molecule. These results can be explained by Le Chatelier's principle, since crosslinking prevents dissociation of the beta-subunits and, thereby, holds the entire tetramer together.

  6. Material properties and electrical stimulation regimens through polycaprolactone fumarate-polypyrrole scaffolds as potential conductive nerve conduits

    PubMed Central

    Moroder, Philipp; Wang, Huan; Ruesink, Terry; Lu, Lichun; Windebank, Anthony J.; Yaszemski, Michael J.; Runge, M. Brett

    2010-01-01

    Mechanical and electrical properties of polycaprolactone fumarate-polypyrrole (PCLF-PPy) scaffolds were studied under physiological conditions to evaluate their ability to maintain material properties necessary for application as conductive nerve conduits. PC12 cells cultured on PCLF-PPy scaffolds were stimulated with regimens of 10 μA of constant or 20 Hz frequency current passed through the scaffolds for 1 h/day. PC12 cellular morphologies were analyzed by fluorescence microscopy after 48 h. PCLF-PPy scaffolds exhibited excellent mechanical properties at 37°C which would allow suturing and flexibility. The surface resistivity of the scaffolds was 2kΩ and the scaffolds were electrically stable during application of electrical stimulation (ES). In vitro studies showed significant increases in percentage of neurite bearing cells, number of neurites per cell and neurite length in the presence of ES compared to no ES. Additionally, extending neurites were observed to align in the direction of the applied current. This study shows that electrically conductive PCLF-PPy scaffolds possess material properties necessary for application as nerve conduits. Additionally, the capability to significantly enhance and direct neurite extension by passing electrical current through PCLF-PPy scaffolds renders them even more promising as future therapeutic treatments for severe nerve injuries. PMID:20965280

  7. A fermentative approach towards optimizing directed biosynthesis of fumaric acid by Rhizopus oryzae 1526 utilizing apple industry waste biomass.

    PubMed

    Das, Ratul Kumar; Brar, Satinder Kaur; Verma, Mausam

    2015-12-01

    The present research account deals with the bioproduction of fumaric acid (FA) from apple pomace ultrafiltration sludge (APUS) and apple pomace (AP) through fermentation. The filamentous fungus Rhizopus oryzae 1526 was used as a biocatalyst and its morphological impact on FA production was analysed in detail. For submerged fermentation, 40 g L(-1) of total solids concentration of APUS, pH 6.0, 30 °C, 200 rpm flask shaking speed and 72 h of incubation were found to be optimum for FA production (25.2 ± 1.0 g L(-1), 0.350 g (L(-1) h(-1))). Broth viscosity (cP), residual reducing sugar (g L(-1)) and ethanol (g L(-1)) produced as by-product, were also analysed. Plastic trays were used for solid state fermentation and at optimized level of moisture and incubation period, 52 ± 2.67 g FA per kg dry weight of AP was obtained. Changes in the total phenolic content (mg g(-1) dry weight of AP) were monitored at regular intervals. Utilization of APUS and AP for the directed synthesis of the high-value platform chemical FA by the fungal strain R. oryzae 1526 was an excellent display of fungal physiological and morphological control over a fermentative product.

  8. Preparation and brain delivery of nasal solid lipid nanoparticles of quetiapine fumarate in situ gel in rat model of schizophrenia

    PubMed Central

    Li, Jian-Chun; Zhang, Wen-Jing; Zhu, Jin-Xiu; Zhu, Na; Zhang, Hong-Min; Wang, Xiu; Zhang, Jin; Wang, Qing-Qing

    2015-01-01

    To investigate the brain delivery in rat by nasal Quetiapine fumarate (QF) loaded with solid lipid nanoparticles in situ gel (QF-SLN-gel). QF-SLN-gel was prepared through micro-emulsion technique. The rat model of schizophrenia was established by intraperitoneal injection of (+)-MK-801, evaluated by stereotypic behavior, Mori’s Water Maze (MWM) test and hematoxylin and eosin (HE) staining of hippocampus. The animals were administrated with QF via oral, nasal or tail vein approach and the concentration of QF in blood and brain was determined using high performance liquid chromatography (HPLC). The QF-SLN-gel was even and transparent, having size of 117.8±2.67 d.nm, potential of 57.2±0.24 mV and EF of 97.6±0.58%. After administration of QF-SLN-gel, the concentration of QF in blood and brain of rats in nasal QF-SLN-gel group was similar with that of rats in tail vein QF group, but significantly higher than that of rats in oral QF group. The hippocampal morphology changes induced by (+)-MK-801 were ameliorated by QF, with advantage of nasal QF-SLN-gel over tail vein QF. The nasal QF-SLN-gel had stable and good brain delivery and could ameliorate the damages in rat model of schizophrenia induced by (+)-MK-801. PMID:26770349

  9. Mixed T Cell Chimerism After Allogeneic Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia Using an Alemtuzumab-Containing Regimen Is Shaped by Persistence of Recipient CD8 T Cells.

    PubMed

    Grimaldi, Francesco; Potter, Victoria; Perez-Abellan, Pilar; Veluchamy, John P; Atif, Muhammad; Grain, Rosemary; Sen, Monica; Best, Steven; Lea, Nicholas; Rice, Carmel; Pagliuca, Antonio; Mufti, Ghulam J; Marsh, Judith C W; Barber, Linda D

    2017-02-01

    Prevention of graft-versus-host disease (GVHD) is paramount for allogeneic hematopoietic stem cell transplantation (HSCT) to treat nonmalignant diseases. We previously reported that allogeneic HSCT for severe aplastic anemia (SAA) using the fludarabine, cyclophosphamide, and alemtuzumab (Campath-1H) (FCC) regimen is associated with a very low risk of GVHD and excellent clinical outcomes. We now report a single-center study of 45 patients with longer follow-up and investigation of lymphocyte recovery. Overall survival (OS) was 93%, and event-free survival (EFS) was 90.7%. Acute and chronic GVHD each occurred in 6 patients (13.3%), and only 1 case was severe. Mixed T cell chimerism was frequent and persisted after cessation of immunosuppression. T cells were extensively depleted, representing only 11.3% of lymphocytes at day 30 and rising to 43.8% by 1 year, but still significantly below normal levels (67.2%; P = .018), and deficiency persisted after immunosuppressive therapy (IST) withdrawal. Depletion of CD4 T cells was particularly profound, causing inversion of the normal CD4:CD8 T cell ratio. T cell subset composition was also abnormal, with memory and effector T cells predominating for at least 6 months after FCC HSCT. Analysis of T cell subset chimerism showed that CD4 T cells were predominantly donor-derived at 1 year, whereas recipient-derived CD8 T cells shaped mixed chimerism with a notable contribution of recipient effector CD8 T cells. The prolonged mixed T cell chimerism after IST withdrawal and low incidence of GVHD indicates the establishment of mutual tolerance, but the low incidence of viral disease suggests maintenance of antiviral immunity. Our study shows that despite the abnormal T cell profile after allogeneic HSCT for SAA using the FCC regimen, this regimen is conducive to an excellent clinical outcome.

  10. Injectable biodegradable polymer composites based on poly(propylene fumarate) crosslinked with poly(ethylene glycol)-dimethacrylate.

    PubMed

    He, S; Yaszemski, M J; Yasko, A W; Engel, P S; Mikos, A G

    2000-12-01

    New injectable, in situ crosslinkable biodegradable polymer composites were investigated consisting of poly(propylene fumarate) (PPF), poly(ethylene glycol)-dimethacrylate (PEG-DMA), and beta-tricalcium phosphate (beta-TCP). We examined the effects of the PEG-DMA/PPF double-bond ratio and beta-TCP content on the crosslinking characteristics of the composites including the maximum crosslinking temperature and the gel point, as well as the properties of the crosslinked composites such as the compressive strength and modulus, and the water-holding capacity. The maximum crosslinking temperature was constant averaging 39.7 degrees C for the composite formulations tested. The gel points varied from 8.0 +/- 1.0 to 12.6 +/- 2.5 min and were not affected by the relative amounts of PEG-DMA. The compressive strength at yield of PEG-DMA/PPF composites without beta-TCP increased from 5.9 +/- 1.0 to 11.2 +/- 2.2 MPa as the double-bond ratio of PEG-DMA/PPF increased from 0.38 to 1.88. An increase in compressive modulus was also observed from 30.2 +/- 3.5 to 58.4 +/- 6.2 MPa for the same range of the PEG-DMA/PPF double-bond ratio. Also, the addition of beta-TCP (33 wt%) enhanced the mechanical properties of all composites. The equilibrium water content of networks without beta-TCP increased from 21.7 +/- 0.2 to 30.6 +/- 0.2% for a double-bond ratio of PEG-DMA/PPF ranging from 0.38 to 1.88. However, the mechanical properties of the swollen composites under compression were smaller than the dry ones. These data demonstrate the feasibility of fabricating injectable biodegradable polymer composites with engineered mechanical properties for orthopedic tissue engineering.

  11. Poly(propylene fumarate)/(calcium sulphate/beta-tricalcium phosphate) composites: preparation, characterization and in vitro degradation.

    PubMed

    Cai, Zhong-Yu; Yang, De-An; Zhang, Na; Ji, Cheng-Guang; Zhu, Lei; Zhang, Tao

    2009-02-01

    This study aimed to prepare a poly(propylene fumarate)/(calcium sulphate/beta-tricalcium phosphate) (PPF/(CaSO(4)/beta-TCP)) composite. We first examined the effects of varying the molecular weight of PPF and the N-vinyl pyrrolidinone (NVP) to PPF ratio on the maximum cross-linking temperature and the composite compressive strength and modulus. Then the in vitro biodegradation behaviour of PPF/(CaSO(4)/beta-TCP) composites was investigated. The effects of varying the molecular weight of PPF, the NVP/PPF ratio and the CaSO(4)/beta-TCP molar ratio on the weight loss and the composite compressive strength and modulus were examined. The cross-linking temperature, which increased with increasing molecular weight of PPF and NVP/PPF ratio, ranged from 41 to 43 degrees C for all formulations. The mechanical properties were increased by a decrease in the NVP/PPF ratio. For all formulations, the compressive strength values fell between 12 and 62 MPa, while the compressive modulus values fell between 290 and 1149 MPa. The weight loss decreased either with increasing molecular weight of PPF or with decreasing NVP/PPF ratio and CaSO(4)/beta-TCP molar ratio during degradation. The compressive strength and modulus increased with decreasing NVP/PPF ratio or decreasing CaSO(4)/beta-TCP ratio. The greatest weight loss over 6 weeks was 14.72%. For all formulations, the compressive modulus values fell between 57 and 712 MPa and the compressive strength fell between 0.5 and 21 MPa throughout 6 weeks degradation. Scanning electron microscopy and X-ray diffraction analysis of the PPF/(CaSO(4)/beta-TCP) composites demonstrated that hydroxyapatite was deposited on the surface of CaSO(4)/beta-TCP granules during degradation.

  12. Effects of iron polymaltose complex, ferrous fumarate and ferrous sulfate treatments in anemic pregnant rats, their fetuses and placentas.

    PubMed

    Toblli, Jorge E; Cao, Gabriel; Oliveri, Leda; Angerosa, Margarita

    2013-06-01

    Although oral iron preparations are widely prescribed to prevent and to treat iron deficiency anemia in pregnancy, comparative data on their effects to the mother, fetus and placenta are limited. In this study, the effects of oral iron polymaltose complex (IPC), ferrous fumarate (FF) and ferrous sulfate (FS) were compared in anemic pregnant rats, their fetuses and placentas. Hematological variables and oxidative stress markers in the liver, heart and kidneys of the dams and fetuses as well as the markers for oxidative stress, inflammation and hypoxia in placentas were assessed. Pregnancy outcome was measured by number of fetuses, and by neonate and placental weight. All therapies were comparably effective in correcting anemia. FS and FF, but not IPC, resulted in liver damage in dams and oxidative stress in dams, fetuses and placentas. FS group presented the highest catalase and GPx levels in dams, fetuses and placentas. IPC, but not FF or FS, restored normal TNF-α and IL6 expression levels in placentas whereas FS-treated animals presented the highest cytokine levels, suggesting a local inflammatory reaction. Anemia-induced high levels of HIF-1α were partially lowered by IPC and FF but further elevated by FS. Most of the negative effects associated with IDA were resolved by IPC treatment. Especially FS treatment was found to elicit hepatic damage in the dams, oxidative stress in the dams, fetuses and placenta as well as inflammation and high levels of HIF-1α in the placenta. Pregnancy outcome of FFand FS-treated animals was worse than that of IPC-treated animals.

  13. Effects of composite formulation on the mechanical properties of biodegradable poly(propylene fumarate)/bone fiber scaffolds

    PubMed Central

    Zhu, Xun; Liu, Nathan; Yaszemski, Michael J.; Lu, Lichun

    2010-01-01

    The objective of our study was to determine the effects of composite formulation on the compressive modulus and ultimate strength of a biodegradable, in situ polymerizable poly(propylene fumarate) (PPF) and bone fiber scaffold. The following parameters were investigated: the incorporation of bone fibers (either mineralized or demineralized), PPF molecular weight, N-vinyl pyrrolidinone (NVP) crosslinker amount, benzoyl peroxide (BP) initiator amount, and sodium chloride porogen amount. Eight formulations were chosen based on a resolution III two level fractional factorial design. The compressive modulus and ultimate strength of these formulations were measured on a materials testing machine. Absolute values for compressive modulus varied from 21.3 to 271 MPa and 2.8 to 358 MPa for dry and wet samples, respectively. The ultimate strength of the crosslinked composites varied from 2.1 to 20.3 MPa for dry samples and from 0.4 to 16.6 MPa for wet samples. Main effects of each parameter on the measured property were calculated. The incorporation of mineralized bone fibers and an increase in PPF molecular weight resulted in higher compressive modulus and ultimate strength. Both mechanical properties also increased as the amount of benzoyl peroxide increased or the NVP amount decreased in the formulation. Sodium chloride had a dominating effect on the increase of mechanical properties in dry samples but showed little effects in wet samples. Demineralization of bone fibers led to a decrease in the compressive modulus and ultimate strength. Our results suggest that bone fibers are appropriate as structural enforcement components in PPF scaffolds. The desired orthopaedic PPF scaffold might be obtained by changing a variety of composite formulation parameters. PMID:22034584

  14. In vivo release of plasmid DNA from composites of oligo(poly(ethylene glycol)fumarate) and cationized gelatin microspheres.

    PubMed

    Kasper, F Kurtis; Kushibiki, Toshihiro; Kimura, Yu; Mikos, Antonios G; Tabata, Yasuhiko

    2005-10-20

    Composites of cationized gelatin microspheres (CGMS), crosslinked with either 3 mM or 6 mM glutaraldehyde solution, and a novel hydrogel material, oligo(poly(ethylene glycol)fumarate) (OPF) were fabricated and investigated toward prolonging the release of plasmid DNA in vivo relative to the constituent materials. The composites and constituent materials were investigated in a subcutaneous murine model to assess the release of 125I-labeled plasmid DNA and 125I-labeled cationized gelatin in vivo. The time profiles of the radioactivity remaining were employed to compare the profiles of DNA release and cationized gelatin degradation. Both composite formulations (incorporating either 3 mM or 6 mM CGMS) prolonged the bioavailability of plasmid DNA relative to both injected plasmid DNA solution and the respective non-embedded cationized gelatin microspheres. Injected plasmid DNA solution persisted in the subject for only 7-10 days, whereas the persistence of DNA from composites of OPF and either 3 mM or 6 mM CGMS extended to at least day 42. The 3 mM and 6 mM CGMS each increased the persistence of DNA slightly, relative to injection of DNA solution, to between 28 and 35 days. Interestingly, the release profile of plasmid DNA from composites was not significantly different from the release of DNA from OPF alone. The release of plasmid DNA from the composites was in accord with the degradation of the microspheres within the OPF. These results show that composites of OPF and cationized gelatin microspheres are able to prolong the availability of plasmid DNA in vivo relative to cationized gelatin microspheres alone and provide a promising candidate material for the sustained, controlled release of plasmid DNA.

  15. Dimethyl fumarate restores apoptosis sensitivity and inhibits tumor growth and metastasis in CTCL by targeting NF-κB

    PubMed Central

    Müller-Decker, Karin; Schroeder, Anne; Brechmann, Markus; Möbs, Markus; Géraud, Cyrill; Assaf, Chalid; Goerdt, Sergij; Krammer, Peter H.; Gülow, Karsten

    2016-01-01

    Despite intensive efforts in recent years, a curative therapy for cutaneous T-cell lymphoma (CTCL) has not yet been developed. Therefore, the establishment of new therapeutic approaches with higher efficacy rates and milder side effects is strongly desired. A characteristic feature of the malignant T-cell population in CTCL is resistance toward cell death resulting from constitutive NF-κB activation. Therefore, NF-κB–dependent cell death resistance represents an interesting therapeutic target in CTCL because an NF-κB–directed therapy would leave bystander T cells widely unaffected. We investigated the effects of dimethyl fumarate (DMF) on CTCL cells in vitro and in vivo. DMF induced cell death in primary patient-derived CD4+ cells and CTCL cell lines, but hardly in T cells from healthy donors. DMF-induced cell death was linked specifically to NF-κB inhibition. To study the impact of DMF in vivo, we developed 2 CTCL xenograft mouse models with different cutaneous localizations of the T-cell infiltrate. DMF treatment delayed the growth of CTCL tumors and prevented formation of distant metastases. In addition, DMF induced increased cell death in primary CTCL tumors and in liver metastases. In summary, DMF treatment represents a remarkable therapeutic option in CTCL because it restores CTCL apoptosis in vitro and in preclinical models in vivo and prevents spreading of the disease to distant sites. DMF treatment is of particular promise in CTCL because DMF is already in successful clinical use in the treatment of psoriasis and multiple sclerosis allowing fast translation into clinical studies in CTCL. PMID:27268084

  16. Non-invasive intranasal delivery of quetiapine fumarate loaded microemulsion for brain targeting: Formulation, physicochemical and pharmacokinetic consideration.

    PubMed

    Shah, Brijesh; Khunt, Dignesh; Misra, Manju; Padh, Harish

    2016-08-25

    Systemic drug delivery in schizophrenia is a major challenge due to presence of obstacles like, blood-brain barrier and P-glycoprotein, which prohibit entry of drugs into the brain. Quetiapine fumarate (QF), a substrate to P-glycoprotein under goes extensive first pass metabolism leading to limited absorption thus necessitating frequent oral administration. The aim of this study was to develop QF based microemulsion (ME) with and without chitosan (CH) to investigate its potential use in improving the bioavailability and brain targeting efficiency following non-invasive intranasal administration. QF loaded ME and mucoadhesive ME (MME) showed globule size, pH and viscosity in the range of 29-47nm, 5.5-6.5 and 17-40cP respectively. CH-ME with spherical globules having mean size of 35.31±1.71nm, pH value of 5.61±0.16 showed highest ex-vivo nasal diffusion (78.26±3.29%) in 8h with no sign of structural damage upon histopathological examination. Circular plume with an ovality ratio closer to 1.3 for CH-ME depicted ideal spray pattern. Significantly higher brain/blood ratio of CH-ME in comparison to QF-ME and drug solution following intranasal administration revealed prolonged retention of QF at site of action suggesting superiority of CH as permeability enhancer. Following intranasal administration, 2.7 and 3.8 folds higher nasal bioavailability in brain with CH-ME compared to QF-ME and drug solution respectively is indicative of preferential nose to brain transport (80.51±6.46%) bypassing blood-brain barrier. Overall, the above finding shows promising results in the area of developing non-invasive intranasal route as an alternative to oral route for brain delivery.

  17. Synthesis and characterization of triblock copolymers of methoxy poly(ethylene glycol) and poly(propylene fumarate).

    PubMed

    Behravesh, Esfandiar; Shung, Albert K; Jo, Seongbong; Mikos, Antonios G

    2002-01-01

    Amphiphilic block copolymers were synthesized by transesterification of hydrophilic methoxy poly(ethylene glycol) (mPEG) and hydrophobic poly(propylene fumarate) (PPF) and characterized. Four block copolymers were synthesized with a 2:1 mPEG:PPF molar ratio and mPEGs of molecular weights 570, 800, 1960, and 5190 and PPF of molecular weight 1570 as determined by NMR. The copolymers synthesized with mPEG of molecular weights 570 and 800 had 1.9 and 1.8 mPEG blocks per copolymer, respectively, as measured by NMR, representing an ABA-type block copolymer. The number of mPEG blocks of the copolymer decreased with increasing mPEG block length to as low as 1.5 mPEG blocks for copolymer synthesized with mPEG of molecular weight 5190. At a concentration range of 5-25 wt % in phosphate-buffered saline, copolymers synthesized with mPEG molecular weights of 570 and 800 possessed lower critical solution temperatures (LCST) between 40 and 45 degrees C and between 55 and 60 degrees C, respectively. Aqueous solutions of copolymer synthesized with mPEG 570 and 800 also experienced thermoreversible gelation. The sol-gel transition temperature was dependent on the sodium chloride concentration as well as the mPEG block length. The copolymer synthesized from mPEG 570 had a transition temperature between 40 and 20 degrees C with salt concentrations between 1 and 10 wt %, while the sol-gel transition temperatures of the copolymer synthesized from mPEG molecular weight 800 were higher in the range 75-30 degrees C with salt concentrations between 1 and 15 wt %. These novel thermoreversible copolymers are the first biodegradable copolymers with unsaturated double bonds along their macromolecular chain that can undergo both physical and chemical gelation and hold great promise for drug delivery and tissue engineering applications.

  18. Marrow stromal osteoblast function on a poly(propylene fumarate)/beta-tricalcium phosphate biodegradable orthopaedic composite.

    PubMed

    Peter, S J; Lu, L; Kim, D J; Mikos, A G

    2000-06-01

    The objective of this study was to assess the osteoconductivity of a poly(propylene fumarate)/beta-tricalcium phosphate (PPF/beta-TCP) composite in vitro. We examined whether primary rat marrow stromal cells would attach, proliferate, and express differentiated osteoblastic function when seeded on PPF/beta-TCP substrates. Attachment studies showed that a confluent monolayer of cells had adhered to the substrates within an 8 h time frame for marrow stromal cells seeded at confluent numbers. Proliferation and differentiated function of the cells were then investigated for a period of 4 weeks for an initial seeding density of 42,000 cells/cm2. Rapid proliferation during the first 24 h as determined by 3H-thymidine incorporation was mirrored by an initial rapid increase in total cell number by DNA assay. A lower proliferation rate and a gradual increase in cell number persisted for the remainder of the study, resulting in a final cell number of 128,000 cells/cm2. Differentiated cell function was assessed by measuring alkaline phosphatase (ALP) activity and osteocalcin (OC) production throughout the time course. Both markers of osteoblastic differentiation increased significantly over a 4-week period. By day 28, cells grown on PPF/beta-TCP reached a maximal ALP activity of 11 (+/- 1) x 10(-7) micromol/min/cell, while the OC production reached 40 (+/- 1) x 10(-6) ng/cell. These data show that a PPF/beta-TCP composite exhibits in vitro osteoconductivity similar to or better than that of control tissue culture polystyrene.

  19. In vivo bone and soft tissue response to injectable, biodegradable oligo(poly(ethylene glycol) fumarate) hydrogels.

    PubMed

    Shin, Heungsoo; Quinten Ruhé, P; Mikos, Antonios G; Jansen, John A

    2003-08-01

    This study was designed to assess in vivo bone and soft tissue behavior of novel oligo(poly(ethylene glycol) fumarate) (OPF) hydrogels using a rabbit model. In vitro degradation of the OPF hydrogels was also investigated in order to compare with in vivo characteristics. Four groups of OPF hydrogel implants were synthesized by alternation of crosslinking density, poly(ethylene glycol) (PEG) block length of OPF, and cell-binding peptide content. The in vitro degradation rate of OPF hydrogels increased with decreasing crosslinking density of hydrogels, which was characterized by measuring weight loss and swelling ratio of hydrogels and medium pH change. Examination of histological sections of the subcutaneous and cranial implants showed that an uniform thin circumferential fibrous capsule was formed around the OPF hydrogel implants. Quantitative evaluation of the tissue response revealed that no statistical difference existed in capsule quality or thickness between implant groups, implantation sites or implantation times. At 4 weeks, there was a very limited number of inflammatory and multinuclear cells at the implant-fibrous capsule interface for all implants. However, at 12 weeks, OPF hydrogels with PEG block length of number average molecular weight 6090+/-90 showed extensive surface erosion and superficial fragmentation that was surrounded by a number of inflammatory cells, while OPF hydrogels with PEG block length of number average molecular weight 930+/-10 elicited minimal degradation. Constant fibrous capsule layers and number of inflammatory cells were observed regardless of the incorporation of cell-binding peptide and crosslinking density of OPF hydrogels with PEG block length of number average molecular weight 930+/-90. These results confirm that the degradation of implants can be controlled by tailoring the macromolecular structure of OPF hydrogels. Additionally, histological evaluation of implants proved that the OPF hydrogel is a promising material for

  20. Design of eudragit RL nanoparticles by nanoemulsion method as carriers for ophthalmic drug delivery of ketotifen fumarate

    PubMed Central

    Soltani, Saieede; Zakeri-Milani, Parvin; Barzegar-Jalali, Mohammad; Jelvehgari, Mitra

    2016-01-01

    Objective(s): Ketotifen fumarate (KF) is a selective and noncompetitive histamine antagonist (H1-receptor) that is used topically in the treatment of allergic conditions of rhinitis and conjunctivitis. The aim of this study was to formulate and improve an ophthalmic delivery system of KF. Ocular nanoparticles were prepared with the objective of reducing the frequency of administration and obtaining controlled release to improve the anti-inflammatory drug delivery. Materials and Methods: In the present study, ocular KF loaded Eudragit RL 100 nanoparticles were prepared using O/W solvent diffusion method. The nanoparticles were evaluated for particle size, entrapment efficiency, surface morphology, X-ray diffraction (XRD), Fourier transform spectroscopy (FTIR), and differential scanning calorimetry (DSC). In vitro release and permeation studies were also carried out on nanoparticles. Results: An average size range of 182 to 314.30 nm in diameter was obtained and encapsulation efficiency up to 95.0% was observed for all the formulations. Drug release for all formulations after 24 hr was between 65.51% and 88.82% indicating effective controlled release property of KF. The mechanism of drug release for best formulation was found to be fickian diffusion mechanism. KF nanoparticles containing high polymer concentration (1:15) presented a faster drug release and a higher drug penetration; on the contrary, nanoparticles containing low polymer concentration (1:7.5) were able to give a more sustained release of the drug and thus a slower KF permeation through the cornea. Conclusion: The study revealed that KF NPs were capable of releasing the drug for a prolonged period of time and increasing the ocular bioavailability. PMID:27403262

  1. Controlled drug release from a novel injectable biodegradable microsphere/scaffold composite based on poly(propylene fumarate).

    PubMed

    Kempen, Diederik H R; Lu, Lichun; Kim, Choll; Zhu, Xun; Dhert, Wouter J A; Currier, Bradford L; Yaszemski, Michael J

    2006-04-01

    The ideal biomaterial for the repair of bone defects is expected to have good mechanical properties, be fabricated easily into a desired shape, support cell attachment, allow controlled release of bioactive factors to induce bone formation, and biodegrade into nontoxic products to permit natural bone formation and remodeling. The synthetic polymer poly(propylene fumarate) (PPF) holds great promise as such a biomaterial. In previous work we developed poly(DL-lactic-co-glycolic acid) (PLGA) and PPF microspheres for the controlled delivery of bioactive molecules. This study presents an approach to incorporate these microspheres into an injectable, porous PPF scaffold. Model drug Texas red dextran (TRD) was encapsulated into biodegradable PLGA and PPF microspheres at 2 microg/mg microsphere. Five porous composite formulations were fabricated via a gas foaming technique by combining the injectable PPF paste with the PLGA or PPF microspheres at 100 or 250 mg microsphere per composite formulation, or a control aqueous TRD solution (200 microg per composite). All scaffolds had an interconnected pore network with an average porosity of 64.8 +/- 3.6%. The presence of microspheres in the composite scaffolds was confirmed by scanning electron microscopy and confocal microscopy. The composite scaffolds exhibited a sustained release of the model drug for at least 28 days and had minimal burst release during the initial phase of release, as compared to drug release from microspheres alone. The compressive moduli of the scaffolds were between 2.4 and 26.2 MPa after fabrication, and between 14.9 and 62.8 MPa after 28 days in PBS. The scaffolds containing PPF microspheres exhibited a significantly higher initial compressive modulus than those containing PLGA microspheres. Increasing the amount of microspheres in the composites was found to significantly decrease the initial compressive modulus. The novel injectable PPF-based microsphere/scaffold composites developed in this study

  2. Effects of composite formulation on the mechanical properties of biodegradable poly(propylene fumarate)/bone fiber scaffolds.

    PubMed

    Zhu, Xun; Liu, Nathan; Yaszemski, Michael J; Lu, Lichun

    2010-01-01

    The objective of our study was to determine the effects of composite formulation on the compressive modulus and ultimate strength of a biodegradable, in situ polymerizable poly(propylene fumarate) (PPF) and bone fiber scaffold. The following parameters were investigated: the incorporation of bone fibers (either mineralized or demineralized), PPF molecular weight, N-vinyl pyrrolidinone (NVP) crosslinker amount, benzoyl peroxide (BP) initiator amount, and sodium chloride porogen amount. Eight formulations were chosen based on a resolution III two level fractional factorial design. The compressive modulus and ultimate strength of these formulations were measured on a materials testing machine. Absolute values for compressive modulus varied from 21.3 to 271 MPa and 2.8 to 358 MPa for dry and wet samples, respectively. The ultimate strength of the crosslinked composites varied from 2.1 to 20.3 MPa for dry samples and from 0.4 to 16.6 MPa for wet samples. Main effects of each parameter on the measured property were calculated. The incorporation of mineralized bone fibers and an increase in PPF molecular weight resulted in higher compressive modulus and ultimate strength. Both mechanical properties also increased as the amount of benzoyl peroxide increased or the NVP amount decreased in the formulation. Sodium chloride had a dominating effect on the increase of mechanical properties in dry samples but showed little effects in wet samples. Demineralization of bone fibers led to a decrease in the compressive modulus and ultimate strength. Our results suggest that bone fibers are appropriate as structural enforcement components in PPF scaffolds. The desired orthopaedic PPF scaffold might be obtained by changing a variety of composite formulation parameters.

  3. A comprehensive smoking cessation program for the San Francisco Bay Area Latino community: Programa Latino Para Dejar de Fumar.

    PubMed

    Pérez-Stable, E J; Marín, B V; Marín, G

    1993-01-01

    Background. Prevalence of cigarette smoking among Latinos compared to whites is higher among men (30.9% versus 27.9%), but lower among women (16.3% versus 23.5%). More acculturated Latina women, however, smoke more. Compared to other smokers, Latinos report consuming about half the average number of cigarettes per day. Up to a quarter of Latino smokers of less than 10 cigarettes per day may be underreporting consumption. The association between smoking and depression has also been found in Latinos. Program Goals. The Programa Latino Para Dejar de Fumar (Programa) goals are: 1) to evaluate attitudinal, behavioral, and cultural differences between Latino and white smokers; 2) to integrate these findings into a comprehensive, culturally-appropriate smoking cessation intervention; and 3) to implement the intervention in a defined community in order to decrease cigarette smoking prevalence, increase behaviors that may lead smokers to quit, and promote a nonsmoking environment. Program Components. Heightened concern about health effects of smoking, the importance of social smoking, and the influence of the family on behavior are integrated in the Programa components: 1) the promotion of a full-color, Spanish-language, self-help, smoking cessation guide (Guia), distributed at no charge; 2) an anti-smoking, Spanish-language, electronic media campaign; 3) community involvement; 4) quit smoking contests; 5) smoking cessation, individual, telephone consultations (consultas); and 6) collaboration with health care personnel. Results. Effectiveness of the Programa is being evaluated by annual, cross-sectional, random digit dialing telephone surveys compared to two baseline surveys. After 19 months of intervention, the proportion who had heard of the Programa increased from 18.5% to 44.0%, and over one third of less acculturated smokers had the Guia. Future directions will emphasize smoking prevention among youth, prevention of relapse among quitters, and depression prevention.

  4. A Phase 1 Randomized Placebo-Controlled Safety and Pharmacokinetic Trial of a Tenofovir Disoproxil Fumarate Vaginal Ring

    PubMed Central

    Keller, Marla J.; Mesquita, Pedro M.; Marzinke, Mark A.; Teller, Ryan; Espinoza, Lilia; Atrio, Jessica M.; Lo, Yungtai; Frank, Bruce; Srinivasan, Sujatha; Fredricks, David N.; Rabe, Lorna; Anderson, Peter L.; Hendrix, Craig W.; Kiser, Patrick F.; Herold, Betsy C.

    2015-01-01

    Background Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir (TFV), may be ideal for topical HIV preexposure prophylaxis because it has higher tissue and cell permeability than TFV, is not adversely impacted by seminal proteins, and its active metabolite, TFV-diphosphate (TFV-DP), has a long intracellular half-life. We engineered a TDF eluting polyurethane reservoir intravaginal ring (IVR) to provide near constant mucosal antiretroviral concentrations. Methods A first-in-human randomized placebo-controlled trial was conducted to assess the safety and pharmacokinetics of the TDF IVR in healthy, sexually abstinent women (15 TDF and 15 placebo). Drug concentrations were measured in cervicovaginal fluid (CVF) obtained by swab, cervical tissue, plasma, and dried blood spots (DBS) over 14 days of continuous ring use. Results There were 43 total, 23 reproductive tract, and 8 product-related Grade 1 adverse events. Steady state CVF TFV concentrations were achieved proximal (vagina, ectocervix) and distal (introitus) to the TDF IVR one day after ring insertion. Median tissue TFV-DP concentrations 14 days after TDF IVR placement were 120 fmol/mg (interquartile range 90, 550). CVF collected from the cervix one week and two weeks after TDF IVR insertion provided significant protection against ex vivo HIV challenge. Eleven of 14 (78%) participants had detectable TFV-DP DBS concentrations 14 days after TDF IVR placement, suggesting that DBS may provide a surrogate marker of adherence in future clinical trials. Conclusions A TDF IVR is safe, well tolerated, and results in mucosal TFV concentrations that exceed those associated with HIV protection. The findings support further clinical evaluation of this TDF IVR. PMID:26605514

  5. Design of sustained release pellets of ferrous fumarate using cow ghee as hot-melt coating agent

    PubMed Central

    Sakarkar, Dinesh M; Dorle, Avinash K; Mahajan, Nilesh Manoharrao; Sudke, Suresh Gendappa

    2013-01-01

    Introduction: The objective of the present study was to design ferrous fumarate (FF) sustained release (SR) pellets using of cow ghee (CG) as an important hot-melt coating (HMC) agent. Materials and Methods: The pellets were coated by HMC technique using CG and ethyl cellulose composition by conventional coating pan without the use of spray system. FF formulated as pellets and characterized with regard to the drug content and physico-chemical properties. Stability studies were carried out on the optimized formulation for a period of 6 months at 40 ± 2°C and 75 ± 5% relative humidity. Results: Pellets with good surface morphology and smooth texture confirmed by stereo micrographs. HMC is easy, efficient, rapid and simple method since virtually no agglomeration seen during coating. In-vitro release from pellets at a given level of coating and for present pellet size was dependent upon the physico-chemical property of the drug and mostly aqueous solubility of the drug. The selection of optimized FF formulation was confirmed by comparing percent cumulative drug release with theoretical release profile. Formulation F2 had difference factor (f1) and similarity factor (f2) values was found to be 5 and 66 respectively. F2 showed SR of drug for 8 h with cumulative per cent release of 98.03 ± 4.49%. Release kinetics indicates approximately zero order release pattern. HMC pellets were stable during the course of stability study. Conclusions: By means of HMC using CG and ethyl cellulose, SR pellets containing FF were successfully prepared. PMID:24167787

  6. Use of microencapsulated iron(II) fumarate sprinkles to prevent recurrence of anaemia in infants and young children at high risk.

    PubMed Central

    Zlotkin, Stanley; Antwi, Kojo Yeboah; Schauer, Claudia; Yeung, George

    2003-01-01

    OBJECTIVE: To compare the effectiveness of microencapsulated iron(II) fumarate sprinkles (with and without vitamin A), iron(II) sulfate drops, and placebo sprinkles in preventing recurrence of anaemia and to determine the long-term haematological outcomes in children at high risk of recurrence of anaemia 12 months after the end of supplementation. METHODS: A prospective, randomized, placebo-controlled design was used to study 437 Ghanaian children aged 8-20 months who were not anaemic (haemoglobin > or = 100 g/l). Four groups were given microencapsulated iron(II) fumarate sprinkles, microencapsulated iron(II) fumarate sprinkles with vitamin A, iron(II) sulfate drops or placebo sprinkles daily for six months. Primary outcome measures were change in haemoglobin and anaemic status at baseline and study end. Non-anaemic children at the end of the supplementation period were reassessed 12 months after supplementation ended. FINDINGS: Overall, 324 children completed the supplementation period. Among the four groups, no significant changes were seen in mean haemoglobin, ferritin or serum retinol values from baseline to the end of the supplementation period. During the trial, 82.4% (267/324) of children maintained their non-anaemic status. Sprinkles were well accepted without complications. At 12 months post-supplementation, 77.1% (162/210) of children with no intervention remained non-anaemic. This proportion was similar for children among the four groups. CONCLUSION: In most children previously treated for anaemia, further supplementation was not needed to maintain their non-anaemic status. These results may have important implications for community intervention programmes in which initial high-dose treatment is needed because of a high prevalence of anaemia. PMID:12756979

  7. The Dual-Functioning Fumarate Reductase Is the Sole Succinate:Quinone Reductase in Campylobacter jejuni and Is Required for Full Host Colonization▿

    PubMed Central

    Weingarten, Rebecca A.; Taveirne, Michael E.; Olson, Jonathan W.

    2009-01-01

    Campylobacter jejuni encodes all the enzymes necessary for a complete oxidative tricarboxylic acid (TCA) cycle. Because of its inability to utilize glucose, C. jejuni relies exclusively on amino acids as the source of reduced carbon, and they are incorporated into central carbon metabolism. The oxidation of succinate to fumarate is a key step in the oxidative TCA cycle. C. jejuni encodes enzymes annotated as a fumarate reductase (Cj0408 to Cj0410) and a succinate dehydrogenase (Cj0437 to Cj0439). Null alleles in the genes encoding each enzyme were constructed. Both enzymes contributed to the total fumarate reductase activity in vitro. The frdA::cat+ strain was completely deficient in succinate dehydrogenase activity in vitro and was unable to perform whole-cell succinate-dependent respiration. The sdhA::cat+ strain exhibited wild-type levels of succinate dehydrogenase activity both in vivo and in vitro. These data indicate that Frd is the only succinate dehydrogenase in C. jejuni and that the protein annotated as a succinate dehydrogenase has been misannotated. The frdA::cat+ strain was also unable to grow with the characteristic wild-type biphasic growth pattern and exhibited only the first growth phase, which is marked by the consumption of aspartate, serine, and associated organic acids. Substrates consumed in the second growth phase (glutamate, proline, and associated organic acids) were not catabolized by the the frdA::cat+ strain, indicating that the oxidation of succinate is a crucial step in metabolism of these substrates. Chicken colonization trials confirmed the in vivo importance of succinate oxidation, as the frdA::cat+ strain colonized chickens at significantly lower levels than the wild type, while the sdhA::cat+ strain colonized chickens at wild-type levels. PMID:19525346

  8. Addition of fumaric acid and sodium benzoate as an alternative method to achieve a 5-log reduction of Escherichia coli O157:H7 populations in apple cider.

    PubMed

    Comes, Justin E; Beelman, Robert B

    2002-03-01

    A study was conducted to develop a preservative treatment capable of the Food and Drug Administration-mandated 5-log reduction of Escherichia coli O157:H7 populations in apple cider. Unpreserved apple cider was treated with generally recognized as safe acidulants and preservatives before inoculation with E. coli O157:H7 in test tubes and subjected to mild heat treatments (25, 35, and 45 degrees C) followed by refrigerated storage (4 degrees C). Fumaric acid had significant (P < 0.05) bactericidal effect when added to cider at 0.10% (wt/vol) and adjusted to pH 3.3, but citric and malic acid had no effect. Strong linear correlation (R2 = 0.96) between increasing undissociated fumaric acid concentrations and increasing log reductions of E. coli O157:H7 in apple cider indicated the undissociated acid to be the bactericidal form. The treatment that achieved the 5-log reduction in three commercial ciders was the addition of fumaric acid (0.15%, wt/vol) and sodium benzoate (0.05%, wt/vol) followed by holding at 25 degrees C for 6 h before 24 h of refrigeration at 4 degrees C. Subsequent experiments revealed that the same preservatives added to cider in flasks resulted in a more than 5-log reduction in less than 5 and 2 h when held at 25 and 35 degrees C, respectively. The treatment also significantly (P < 0.05) reduced total aerobic counts in commercial ciders to populations less than those of pasteurized and raw ciders from the same source (after 5 and 21 days of refrigerated storage at 4 degrees C, respectively). Sensory evaluation of the same ciders revealed that consumers found the preservative-treated cider to be acceptable.

  9. Inducible overexpression of the FUM1 gene in saccharomyces cerevisiae: Localization of fumarase and efficient fumaric acid bioconversion to L-Malic acid

    SciTech Connect

    Peleg, Y.; Rokem, J.S.; Goldberg, I.; Pines, O. )

    1990-09-01

    Cloning of the Saccharomyces cerevisiae FUM1 gene downstream of the strong GAL10 promoter resulted in inducible overexpression of fumarase in the yeast. The overproducing strain exhibited efficient bioconversion of fumaric acid to L-malic acid with an apparent conversion value of 88% and a conversion rate of 80.4 mmol of fumaric acid/h per g of cell wet weight, both of which are much higher than parameters known for industrial bacterial strains. The only product of the conversion reaction was L-malic acid, which was essentially free of the unwanted by-product succinic acid. The GAL10 promoter situated upstream of a promoterless FUM1 gene led to production and correct distribution of the two fumarase isoenzyme activities between cytosolic and mitochondrial subcellular fractions. The amino-terminal sequence of fumarase contains the mitochondrial signal sequence since (i) 92 of 463 amino acid residues from the amino terminus of fumarase are sufficient to localize fumarase-lacZ fusions to mitochondria and (ii) fumarase and fumarase-lacZ fusions lacking the amino-terminal sequence are localized exclusively in the cytosol. The possibility that both mitochondrial and cytosolic fumarases are derived from the same initial translation product is discussed.

  10. Anaerobic respiratory growth of Vibrio harveyi, Vibrio fischeri and Photobacterium leiognathi with trimethylamine N-oxide, nitrate and fumarate: ecological implications.

    PubMed

    Proctor, L M; Gunsalus, R P

    2000-08-01

    Two symbiotic species, Photobacterium leiognathi and Vibrio fischeri, and one non-symbiotic species, Vibrio harveyi, of the Vibrionaceae were tested for their ability to grow by anaerobic respiration on various electron acceptors, including trimethylamine N-oxide (TMAO) and dimethylsulphoxide (DMSO), compounds common in the marine environment. Each species was able to grow anaerobically with TMAO, nitrate or fumarate, but not with DMSO, as an electron acceptor. Cell growth under microaerophilic growth conditions resulted in elevated levels of TMAO reductase, nitrate reductase and fumarate reductase activity in each strain, whereas growth in the presence of the respective substrate for each enzyme further elevated enzyme activity. TMAO reductase specific activity was the highest of all the reductases. Interestingly, the bacteria-colonized light organs from the two squids, Euprymna scolopes and Euprymna morsei, and the light organ of the ponyfish, Leiognathus equus, also had high levels of TMAO reductase enzyme activity, in contrast to non-symbiotic tissues. The ability of these bacterial symbionts to support cell growth by respiration with TMAO may conceivably eliminate the competition for oxygen needed for both bioluminescence and metabolism.

  11. Crosslinking characteristics of and cell adhesion to an injectable poly(propylene fumarate-co-ethylene glycol) hydrogel using a water-soluble crosslinking system.

    PubMed

    Shung, Albert K; Behravesh, Esfandiar; Jo, Seongbong; Mikos, Antonios G

    2003-04-01

    The crosslinking characteristics of an injectable poly(propylene fumarate-co-ethylene glycol) [P(PF-co-EG)]-based hydrogel were investigated. A water-soluble crosslinking system was used, consisting of poly(ethylene glycol) diacrylate (PEG-DA), ammonium persulfate (APS), and ascorbic acid (AA). The effects of PEG block length of the P(PF-co-EG), APS concentration, AA concentration, and PEG-DA concentration on equilibrium water content, sol fraction, onset of gelation, mechanical properties, and endothelial cell adhesion were studied. The equilibrium water content of the hydrogels ranged from 57.1 +/- 0.3 to 79.7 +/- 0.2% whereas the sol fraction ranged from 2.5 +/- 0.0 to 3.33 +/- 5.4%. The onset of gelation times varied from 1.1 +/- 0.1 to 4.3 +/- 0.2 min. For all hydrogel formulations, the tensile strength fell between 61.7 +/- 18.2 and 401.3 +/- 67.5 kPa and tensile moduli ranged from 0.4 +/- 0.0 to 3.3 +/- 0.3 MPa. Endothelial cells attached to the hydrogels in a range of 3.9 +/- 1.4 to 31.1 +/- 14.1% of cells seeded. These findings suggest that injectable poly(propylene fumarate-co-ethylene glycol) hydrogel formulations in conjunction with a novel water-soluble crosslinking system may be useful for in situ crosslinkable tissue-engineering applications.

  12. Fumaric Acid Esters Do Not Reduce Inflammatory NF-κB/p65 Nuclear Translocation, ICAM-1 Expression and T-Cell Adhesiveness of Human Brain Microvascular Endothelial Cells.

    PubMed

    Haarmann, Axel; Nehen, Mathias; Deiß, Annika; Buttmann, Mathias

    2015-08-13

    Dimethyl fumarate (DMF) is approved for disease-modifying treatment of patients with relapsing-remitting multiple sclerosis. Animal experiments suggested that part of its therapeutic effect is due to a reduction of T-cell infiltration of the central nervous system (CNS) by uncertain mechanisms. Here we evaluated whether DMF and its primary metabolite monomethyl fumarate (MMF) modulate pro-inflammatory intracellular signaling and T-cell adhesiveness of nonimmortalized single donor human brain microvascular endothelial cells at low passages. Neither DMF nor MMF at concentrations of 10 or 50 µM blocked the IL-1β-induced nuclear translocation of NF-κB/p65, whereas the higher concentration of DMF inhibited the nuclear entry of p65 in human umbilical vein endothelium cultured in parallel. DMF and MMF also did not alter the IL-1β-stimulated activation of p38 MAPK in brain endothelium. Furthermore, neither DMF nor MMF reduced the basal or IL-1β-inducible expression of ICAM-1. In accordance, both fumaric acid esters did not reduce the adhesion of activated Jurkat T cells to brain endothelium under basal or inflammatory conditions. Therefore, brain endothelial cells probably do not directly mediate a potential blocking effect of fumaric acid esters on the inflammatory infiltration of the CNS by T cells.

  13. Long-term (96-week) Efficacy and Safety After Switching from Tenofovir Disoproxil Fumarate (TDF) to Tenofovir Alafenamide (TAF) in HIV-infected, Virologically Suppressed Adults.

    PubMed

    Raffi, Francois; Orkin, Chloe; Clarke, Amanda; Slama, Laurence; Gallant, Joel; Daar, Eric; Henry, Keith; Santana-Bagur, Jorge; Stein, David K; Bellos, Nicholaos; Scarsella, Anthony; Yan, Mingjin; Abram, Michael E; Cheng, Andrew; Rhee, Martin S

    2017-03-06

    In a double-blind, phase 3 trial, 663 HIV-infected, virologically suppressed adults were randomized to switch to tenofovir alafenamide (TAF; n=333) vs. remain on tenofovir disoproxil fumarate (TDF; n=330), each coformulated with emtricitabine (FTC), while continuing their third agent (boosted protease inhibitor or unboosted third agent). At week 96, 88.6% on FTC/TAF and 89.1% on FTC/TDF had HIV-1 RNA <50 copies/mL (adjusted difference -0.5%; 95%CI [-5.3%, 4.4%]). Proteinuria, albuminuria, proximal renal tubular function, and bone mineral density improved after switching to TAF- from TDF-containing regimens. These longer-term data support FTC/TAF as a safe, well tolerated, and durable nucleotide reverse transcriptase inhibitor backbone.

  14. Crystal structure of an Fe-S cluster-containing fumarate hydratase enzyme from Leishmania major reveals a unique protein fold.

    PubMed

    Feliciano, Patricia R; Drennan, Catherine L; Nonato, M Cristina

    2016-08-30

    Fumarate hydratases (FHs) are essential metabolic enzymes grouped into two classes. Here, we present the crystal structure of a class I FH, the cytosolic FH from Leishmania major, which reveals a previously undiscovered protein fold that coordinates a catalytically essential [4Fe-4S] cluster. Our 2.05 Å resolution data further reveal a dimeric architecture for this FH that resembles a heart, with each lobe comprised of two domains that are arranged around the active site. Besides the active site, where the substrate S-malate is bound bidentate to the unique iron of the [4Fe-4S] cluster, other binding pockets are found near the dimeric enzyme interface, some of which are occupied by malonate, shown here to be a weak inhibitor of this enzyme. Taken together, these data provide a framework both for investigations of the class I FH catalytic mechanism and for drug design aimed at fighting neglected tropical diseases.

  15. Combination Emtricitabine and Tenofovir Disoproxil Fumarate Prevents Vaginal Simian/Human Immunodeficiency Virus Infection in Macaques Harboring Chlamydia trachomatis and Trichomonas vaginalis.

    PubMed

    Radzio, Jessica; Henning, Tara; Jenkins, Leecresia; Ellis, Shanon; Farshy, Carol; Phillips, Christi; Holder, Angela; Kuklenyik, Susan; Dinh, Chuong; Hanson, Debra; McNicholl, Janet; Heneine, Walid; Papp, John; Kersh, Ellen N; García-Lerma, J Gerardo

    2016-05-15

    Genital inflammation associated with sexually transmitted infections increases susceptibility to human immunodeficiency virus (HIV), but it is unclear whether the increased risk can reduce the efficacy of pre-exposure prophylaxis (PrEP). We investigated whether coinfection of macaques with Chlamydia trachomatis and Trichomonas vaginalis decreases the prophylactic efficacy of oral emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF). Macaques were exposed to simian/human immunodeficiency virus (SHIV) vaginally each week for up to 16 weeks and received placebo or FTC/TDF pericoitally. All animals in the placebo group were infected with SHIV, while 4 of 6 PrEP recipients remained uninfected (P= .03). Oral FTC/TDF maintains efficacy in a macaque model of sexually transmitted coinfection, although the infection of 2 macaques signals a modest loss of PrEP activity.

  16. Effect of Chemical and Physical Properties on the In Vitro Degradation of 3D Printed High Resolution Poly(propylene fumarate) Scaffolds.

    PubMed

    Walker, Jason M; Bodamer, Emily; Krebs, Olivia; Luo, Yuanyuan; Kleinfehn, Alex; Becker, Matthew L; Dean, David

    2017-04-10

    Two distinct molecular masses of poly(propylene fumarate) (PPF) are combined with an additive manufacturing process to fabricate highly complex scaffolds possessing controlled chemical properties and porous architecture. Scaffolds were manufactured with two polymer molecular masses and two architecture styles. Degradation was assessed in an accelerated in vitro environment. The purpose of the degradation study is not to model or mimic in vivo degradation, but to efficiently compare the effect of modulating scaffold properties. This is the first study addressing degradation of chain-growth synthesized PPF, a process that allows for considerably more control over molecular mass distribution. It demonstrates that, with greater process control, not only is scaffold fabrication reproducible, but the mechanical properties and degradation kinetics can be tailored by altering the physical properties of the scaffold. This is a clear step forward in using PPF to address unmet medical needs while meeting regulatory demands and ultimately obtaining clinical relevancy.

  17. Crystal structure of an Fe-S cluster-containing fumarate hydratase enzyme from Leishmania major reveals a unique protein fold

    PubMed Central

    Drennan, Catherine L.; Nonato, M. Cristina

    2016-01-01

    Fumarate hydratases (FHs) are essential metabolic enzymes grouped into two classes. Here, we present the crystal structure of a class I FH, the cytosolic FH from Leishmania major, which reveals a previously undiscovered protein fold that coordinates a catalytically essential [4Fe-4S] cluster. Our 2.05 Å resolution data further reveal a dimeric architecture for this FH that resembles a heart, with each lobe comprised of two domains that are arranged around the active site. Besides the active site, where the substrate S-malate is bound bidentate to the unique iron of the [4Fe-4S] cluster, other binding pockets are found near the dimeric enzyme interface, some of which are occupied by malonate, shown here to be a weak inhibitor of this enzyme. Taken together, these data provide a framework both for investigations of the class I FH catalytic mechanism and for drug design aimed at fighting neglected tropical diseases. PMID:27528683

  18. Ligament Tissue Engineering Using a Novel Porous Polycaprolactone Fumarate Scaffold and Adipose Tissue-Derived Mesenchymal Stem Cells Grown in Platelet Lysate

    PubMed Central

    Wagner, Eric R.; Bravo, Dalibel; Dadsetan, Mahrokh; Riester, Scott M.; Chase, Steven; Westendorf, Jennifer J.; Dietz, Allan B.; van Wijnen, Andre J.; Yaszemski, Michael J.

    2015-01-01

    Purpose: Surgical reconstruction of intra-articular ligament injuries is hampered by the poor regenerative potential of the tissue. We hypothesized that a novel composite polymer “neoligament” seeded with progenitor cells and growth factors would be effective in regenerating native ligamentous tissue. Methods: We synthesized a fumarate-derivative of polycaprolactone fumarate (PCLF) to create macro-porous scaffolds to allow cell–cell communication and nutrient flow. Clinical grade human adipose tissue-derived human mesenchymal stem cells (AMSCs) were cultured in 5% human platelet lysate (PL) and seeded on scaffolds using a dynamic bioreactor. Cell growth, viability, and differentiation were examined using metabolic assays and immunostaining for ligament-related markers (e.g., glycosaminoglycans [GAGs], alkaline phosphatase [ALP], collagens, and tenascin-C). Results: AMSCs seeded on three-dimensional (3D) PCLF scaffolds remain viable for at least 2 weeks with proliferating cells filling the pores. AMSC proliferation rates increased in PL compared to fetal bovine serum (FBS) (p < 0.05). Cells had a low baseline expression of ALP and GAG, but increased expression of total collagen when induced by the ligament and tenogenic growth factor fibroblast growth factor 2 (FGF-2), especially when cultured in the presence of PL (p < 0.01) instead of FBS (p < 0.05). FGF-2 and PL also significantly increased immunostaining of tenascin-C and collagen at 2 and 4 weeks compared with human fibroblasts. Summary: Our results demonstrate that AMSCs proliferate and eventually produce a collagen-rich extracellular matrix on porous PCLF scaffolds. This novel scaffold has potential in stem cell engineering and ligament regeneration. PMID:26413793

  19. A Randomized Switch From Nevirapine-Based Antiretroviral Therapy to Single Tablet Rilpivirine/Emtricitabine/Tenofovir Disoproxil Fumarate in Virologically Suppressed Human Immunodeficiency Virus-1-Infected Rwandans.

    PubMed

    Collins, Sean E; Grant, Philip M; Uwinkindi, Francois; Talbot, Annie; Seruyange, Eric; Slamowitz, Deborah; Mugeni, Adeline; Remera, Eric; Niyonsenga, Simon Pierre; Nyirimigabo, Josbert; Uwizihiwe, Jean Paul; Dongier, Pierre; Muhayimpundu, Ribakare; Mazarati, Jean-Baptiste; Zolopa, Andrew; Nsanzimana, Sabin

    2016-09-01

    Background.  Many human immunodeficiency virus (HIV)-infected patients remain on nevirapine-based antiretroviral therapy (ART) despite safety and efficacy concerns. Switching to a rilpivirine-based regimen is an alternative, but there is little experience with rilpivirine in sub-Saharan Africa where induction of rilpivirine metabolism by nevirapine, HIV subtype, and dietary differences could potentially impact efficacy. Methods.  We conducted an open-label noninferiority study of virologically suppressed (HIV-1 ribonucleic acid [RNA] < 50 copies/mL) HIV-1-infected Rwandan adults taking nevirapine plus 2 nucleos(t)ide reverse-transcriptase inhibitors. One hundred fifty participants were randomized 2:1 to switch to coformulated rilpivirine-emtricitabine-tenofovir disoproxil fumarate (referenced as the Switch Arm) or continue current therapy. The primary efficacy endpoint was HIV-1 RNA < 200 copies/mL at week 24 assessed by the US Food and Drug Administration Snapshot algorithm with a noninferiority margin of 12%. Results.  Between April and September 2014, 184 patients were screened, and 150 patients were enrolled; 99 patients switched to rilpivirine-emtricitabine-tenofovir, and 51 patients continued their nevirapine-based ART. The mean age was 42 years and 43% of participants were women. At week 24, virologic suppression (HIV-1 RNA level <200 copies/mL) was maintained in 93% and 92% in the Switch Arm versus the continuation arm, respectively. The Switch Arm was noninferior to continued nevirapine-based ART (efficacy difference 0.8%; 95% confidence interval, -7.5% to +12.0%). Both regimens were generally safe and well tolerated, although 2 deaths, neither attributed to study medications, occurred in participants in the Switch Arm. Conclusions.  A switch from nevirapine-based ART to rilpivirine-emtricitabine-tenofovir disoproxil fumarate had similar virologic efficacy to continued nevirapine-based ART after 24 weeks with few adverse events.

  20. The effect of electron transport (ET) inhibitors and thiabendazole on the fumarate reductase (FR) and succinate dehydrogenase (SDH) of Strongyloides ratti infective (L3) larvae.

    PubMed

    Armson, A; Grubb, W B; Mendis, A H

    1995-02-01

    The fumarate reductase (FR) and succinate dehydrogenase (SDH) activities of isolated submitochondrial particles (SMPs) prepared from axenised L3 larvae of S. ratti were characterised with respect to their response to a selected range of inhibitors. Rotenone (a specific inhibitor of electron transport Complex I) inhibited the S. ratti FR (EC50 = 3.0 x 10(-7) M) but not SDH. This strongly suggests that the S. ratti FR is functionally linked with the S. ratti ET-Complex I. 2-Thenoyltrifluoroacetone (TTFA, an inhibitor of ET-Complex II) inhibited FR (EC50 = 2.6 x 10(-5) M) and SDH (EC50 = 2.8 x 10(-5) M) with similar effectiveness. Sodium malonate (substrate analogue of succinate) had a greater affinity for SDH (EC50 = 6.8 x 10(-4) M), than FR (EC50 = 1.9 x 10(-2) M). Sodium fumarate was ca. 8-fold more effective in inhibiting the S. ratti FR (EC50 = 6.0 x 10(-4) M) than SDH (EC50 = 4.8 x 10(-3) M). The S. ratti FR was more sensitive to inhibition by thiabendazole (TBZ; EC50 = 4.6 x 10(-4) M) than SDH (EC50 > 1.0 x 10(-3) M), suggesting that one of the sites-of-action of TBZ to be the FR of S. ratti mitochondria. More potent inhibitors of S. ratti FR, if developed, may prove to be effective chemotherapeutic agents in the management of human strongloidiasis.

  1. Synthesis and characterization of biodegradable cationic poly(propylene fumarate-co-ethylene glycol) copolymer hydrogels modified with agmatine for enhanced cell adhesion.

    PubMed

    Tanahashi, Kazuhiro; Jo, Seongbong; Mikos, Antonios G

    2002-01-01

    We synthesized positively charged biodegradable hydrogels by cross-linking of agmatine-modified poly(ethylene glycol)-tethered fumarate (Agm-PEGF) and poly(propylene fumarate-co-ethylene glycol) (P(PF-co-EG)) to investigate the effect of the guanidino groups of the agmatine on hydrogel swelling behavior and smooth muscle cell adhesion to the hydrogels. The weight swelling ratio of these hydrogels at pH 7.0 increased from 279 +/- 4 to 306 +/- 7% as the initial Agm-PEGF content increased from 0 to 200 mg/g of P(PF-co-EG), respectively. The diffusional exponents, n, during the initial phase of water uptake were independent of the initial Agm-PEGF content and were determined to be 0.66 +/- 0.08, 0.71 +/- 0.07, and 0.60 +/- 0.05 for respective initial Agm-PEGF contents of 0, 100, and 200 mg/g. The heat of fusion of water present in the hydrogels increased from 214 +/- 11 to 254 +/- 4 J/g as the initial Agm-PEGF content increased from 0 to 200 mg/g. The number of adherent smooth muscle cells increased dose-dependently from 15 +/- 6 to 75 +/- 7% of the initial seeding density as the initial Agm-PEGF content increased from 0 to 200 mg/g. These results suggest that the incorporation of the guanidino groups of agmatine into P(PF-co-EG) hydrogels increases the hydrogel free water content and the total water content of the hydrogels and also enhances cell adhesion to the hydrogels.

  2. A Randomized Switch From Nevirapine-Based Antiretroviral Therapy to Single Tablet Rilpivirine/Emtricitabine/Tenofovir Disoproxil Fumarate in Virologically Suppressed Human Immunodeficiency Virus-1-Infected Rwandans

    PubMed Central

    Collins, Sean E.; Grant, Philip M.; Uwinkindi, Francois; Talbot, Annie; Seruyange, Eric; Slamowitz, Deborah; Mugeni, Adeline; Remera, Eric; Niyonsenga, Simon Pierre; Nyirimigabo, Josbert; Uwizihiwe, Jean Paul; Dongier, Pierre; Muhayimpundu, Ribakare; Mazarati, Jean-Baptiste; Zolopa, Andrew; Nsanzimana, Sabin

    2016-01-01

    Background. Many human immunodeficiency virus (HIV)-infected patients remain on nevirapine-based antiretroviral therapy (ART) despite safety and efficacy concerns. Switching to a rilpivirine-based regimen is an alternative, but there is little experience with rilpivirine in sub-Saharan Africa where induction of rilpivirine metabolism by nevirapine, HIV subtype, and dietary differences could potentially impact efficacy. Methods. We conducted an open-label noninferiority study of virologically suppressed (HIV-1 ribonucleic acid [RNA] < 50 copies/mL) HIV-1-infected Rwandan adults taking nevirapine plus 2 nucleos(t)ide reverse-transcriptase inhibitors. One hundred fifty participants were randomized 2:1 to switch to coformulated rilpivirine-emtricitabine-tenofovir disoproxil fumarate (referenced as the Switch Arm) or continue current therapy. The primary efficacy endpoint was HIV-1 RNA < 200 copies/mL at week 24 assessed by the US Food and Drug Administration Snapshot algorithm with a noninferiority margin of 12%. Results. Between April and September 2014, 184 patients were screened, and 150 patients were enrolled; 99 patients switched to rilpivirine-emtricitabine-tenofovir, and 51 patients continued their nevirapine-based ART. The mean age was 42 years and 43% of participants were women. At week 24, virologic suppression (HIV-1 RNA level <200 copies/mL) was maintained in 93% and 92% in the Switch Arm versus the continuation arm, respectively. The Switch Arm was noninferior to continued nevirapine-based ART (efficacy difference 0.8%; 95% confidence interval, −7.5% to +12.0%). Both regimens were generally safe and well tolerated, although 2 deaths, neither attributed to study medications, occurred in participants in the Switch Arm. Conclusions. A switch from nevirapine-based ART to rilpivirine-emtricitabine-tenofovir disoproxil fumarate had similar virologic efficacy to continued nevirapine-based ART after 24 weeks with few adverse events. PMID:27704000

  3. Shape selective properties of the Al-fumarate metal-organic framework in the adsorption and separation of n-alkanes, iso-alkanes, cyclo-alkanes and aromatic hydrocarbons.

    PubMed

    Bozbiyik, Belgin; Lannoeye, Jeroen; De Vos, Dirk E; Baron, Gino V; Denayer, Joeri F M

    2016-01-28

    The primary goal of this work is to study the adsorption of a wide range of hydrocarbon adsorbates in the Al-fumarate metal-organic framework in order to identify and explore trends in adsorption behaviour that can be related to the sorbate's molecular properties and as well as the properties of this MOF. The pulse chromatographic technique was used to study the adsorption properties of C5-C8 linear, branched, cyclic and aromatic hydrocarbons in vapour phase at low coverage and at high temperatures (150-250 °C). Chromatograms of alkanes having the same number of carbon atoms (C5-C8) clearly show that the linear alkane is retained the longest over its branched and cyclic isomers. Moreover, xylene isomers are also clearly separated by Al-fumarate, with retention times increasing in the order: ortho-xylene < meta-xylene < para-xylene. Differences in adsorption enthalpy of more than 10 kJ mol(-1) between linear alkanes and their di/tri-branched or cyclo-alkane isomers were observed, clearly showing that steric effects imposed by the pore structure of the adsorbent cause the difference in adsorption between linear alkanes and their isomers. In conclusion, Al-fumarate behaves as a shape selective material with respect to structural isomers of linear alkanes, with properties resembling those of medium pore size zeolites.

  4. Multi-micronutrient Sprinkles including a low dose of iron provided as microencapsulated ferrous fumarate improves haematologic indices in anaemic children: a randomized clinical trial.

    PubMed

    Christofides, Anna; Asante, Kwaku Poku; Schauer, Claudia; Sharieff, Waseem; Owusu-Agyei, Seth; Zlotkin, Stanley

    2006-07-01

    Home-fortification of complementary foods with micronutrients (including iron) as Sprinkles is a new strategy to control iron deficiency and anaemia in developing countries. However, the most effective dose and form of iron is not known. The purpose of this study was to compare the efficacy of various doses (12.5, 20 or 30 mg) and treatment methods (multi-micronutrient Sprinkles vs. ferrous sulphate drops) on haemoglobin (Hb) concentration after 8 weeks of treatment in anaemic children. In total, 133 anaemic Ghanaian children (Hb 70-99 g L(-1)) aged 6-18 months were randomly assigned to one of five daily interventions for 8 weeks. Out of the five interventions, four used Sprinkles, and one used iron drops. Of the four Sprinkles groups, three included 12.5, 20 or 30 mg of iron as ferrous fumarate, and one included 20 mg of iron as ferric pyrophosphate. The iron drops group included 12.5 mg of iron as liquid ferrous sulphate. Hb concentrations were measured at baseline, week 3 and week 8. The primary outcome measure was Hb concentration at 8 weeks after treatment. We compared differences in Hb and ferritin concentrations and prevalence of iron deficiency anaemia (Hb < 100 g L(-1) and soluble transferrin receptor concentrations >8.5 mg L(-1)) from baseline to 8 weeks within and between groups. Adherence and reporting of side effects (staining of the teeth, ease of use, diarrhoea and darkening of stools) were compared between groups. Mean change in Hb was 1.4 g L(-1) (SD = 1.8) (P = 0.0001). Change in Hb concentrations from baseline to 8 weeks was significant in all groups (P = 0.0001-0.0007), with no differences across groups. Geometric means of serum ferritin varied from 18.6 to 44.0 microg L(-1) at baseline. At week 8, these means were in the interval of 48.0-78.3 microg L(-1), with no group differences. Prevalence of iron deficiency anaemia decreased significantly from baseline to 8 weeks in all groups with the exception of the iron drops group, with no group

  5. "Application of Box-Behnken design for optimization and development of quetiapine fumarate loaded chitosan nanoparticles for brain delivery via intranasal route* ".

    PubMed

    Shah, Brijesh; Khunt, Dignesh; Misra, Manju; Padh, Harish

    2016-08-01

    The objective of the present investigation was to optimize and develop quetiapine fumarate (QF) loaded chitosan nanoparticles (QF-NP) by ionic gelation method using Box-Behnken design. Three independent variables viz., X1-Concentration of chitosan, X2-Concentration of sodium tripolyphosphate and X3-Volume of sodium tripolyphosphate were taken to investigate their effect on dependent variables (Y1-Size, Y2-PDI and Y3-%EE). Optimized formula of QF-NP was selected from the design space which was further evaluated for physicochemical, morphological, solid state characterization, nasal diffusion and in-vivo distribution for brain targeting following non-invasive intranasal administration. The average particle size, PDI, %EE and nasal diffusion were found to be 131.08±7.45nm, 0.252±0.064, 89.93±3.85% and 65.24±5.26% respectively. Neither toxicity nor structural damage on nasal mucosa was observed upon histopathological examination. Significantly higher brain/blood ratio and 2 folds higher nasal bioavailability in brain with QF-NP in comparison to drug solution following intranasal administration revealed preferential nose to brain transport bypassing blood-brain barrier and prolonged retention of QF at site of action suggesting superiority of chitosan as permeability enhancer. Overall, the above finding shows promising results in the area of developing non-invasive intranasal route as an alternative to oral route for brain delivery.

  6. Generic selection criteria for safety and patient benefit [V]: Comparing the pharmaceutical properties and patient usability of original and generic nasal spray containing ketotifen fumarate.

    PubMed

    Wada, Yuko; Ami, Shyoko; Nozawa, Mitsuru; Goto, Miho; Shimokawa, Ken-Ichi; Ishii, Fumiyoshi

    The pH, osmotic pressure (cryoscopy), viscosity, squeeze force, spray angle, and spraying frequency of nasal spray containing ketotifen fumarate (1 brand-name product and 8 generic products) were measured. Based on the results of pH measurement, all products were weakly acidic (4.0 to 5.1). For all products, the osmotic pressure ratio to physiological saline was approximately 1. The viscosity of various products ranged from approximately 1.0 to 1.5 mPa·s. The spray angle of drug solution differed among the products: minimum, 46 degrees (Sawai and Fusachol); and maximum, 68.7 degrees (Sekiton). In particular, TOA, Sawai, Fusachol, and TYK showed significantly smaller angles compared to Zaditen (brand-name product). Container properties varied among the products: minimum squeeze force, 19.0 N (Sekiton); and maximum squeeze force, 43.1 N (Sawai). Based on these results, although all the above products are identical in dosage form and active ingredient, the differences in pharmaceutical properties, such as container operations and drug-solution spraying/attachment, may markedly influence patients' subjective opinions.

  7. Safety and Tolerability of Delayed-Release Dimethyl Fumarate Administered with Interferon Beta or Glatiramer Acetate in Relapsing-Remitting Multiple Sclerosis

    PubMed Central

    Calkwood, Jonathan; Vollmer, Timothy; Fox, Robert J.; Zhang, Ray; Novas, Mark; Sheikh, Sarah I.

    2016-01-01

    Background: Delayed-release dimethyl fumarate (DMF; also known as gastroresistant DMF) is indicated for relapsing multiple sclerosis (MS). The objective of this study was to explore the safety and tolerability of DMF when administered with interferon beta (IFNβ) or glatiramer acetate (GA). Methods: Patients with relapsing-remitting MS receiving established therapy with the same dose of IFNβ or GA for at least 12 months continued their prescribed therapy for 2 months (monotherapy period) and then received DMF 240 mg three times daily in addition to their prescribed MS therapy for 6 months (add-on therapy period). Safety and magnetic resonance imaging outcomes were monitored monthly. Results: During the add-on therapy period, in the DMF+IFNβ (n = 57) and DMF+GA (n = 47) groups, the overall incidence of adverse events was 95% and 100%, respectively; the most common adverse events were flushing, diarrhea, and abdominal pain. In both groups, mean lymphocyte counts decreased but remained within normal limits, and hepatic transaminase levels increased transiently; no case met Hy's law criteria. There was no overall increased risk of infection. In both groups, gadolinium-enhancing lesion activity and new/enlarging T2 lesions decreased compared with the monotherapy period (exploratory endpoints). Conclusions: The safety profile of DMF taken with IFNβ or GA was acceptable and consistent with the known safety profile of DMF monotherapy. PMID:27252601

  8. Positively Charged Oligo[Poly(Ethylene Glycol) Fumarate] Scaffold Implantation Results in a Permissive Lesion Environment after Spinal Cord Injury in Rat

    PubMed Central

    Hakim, Jeffrey S.; Esmaeili Rad, Melika; Grahn, Peter J.; Chen, Bingkun K.; Knight, Andrew M.; Schmeichel, Ann M.; Isaq, Nasro A.; Dadsetan, Mahrokh; Yaszemski, Michael J.

    2015-01-01

    Positively charged oligo[poly(ethylene glycol) fumarate] (OPF+) scaffolds loaded with Schwann cells bridge spinal cord injury (SCI) lesions and support axonal regeneration in rat. The regeneration achieved is not sufficient for inducing functional recovery. Attempts to increase regeneration would benefit from understanding the effects of the scaffold and transplanted cells on lesion environment. We conducted morphometric and stereological analysis of lesions in rats implanted with OPF+ scaffolds with or without loaded Schwann cells 1, 2, 3, 4, and 8 weeks after thoracic spinal cord transection. No differences were found in collagen scarring, cyst formation, astrocyte reactivity, myelin debris, or chondroitin sulfate proteoglycan (CSPG) accumulation. However, when scaffold-implanted animals were compared with animals with transection injuries only, these barriers to regeneration were significantly reduced, accompanied by increased activated macrophages/microglia. This distinctive and regeneration permissive tissue reaction to scaffold implantation was independent of Schwann cell transplantation. Although the tissue reaction was beneficial in the short term, we observed a chronic fibrotic host response, resulting in scaffolds surrounded by collagen at 8 weeks. This study demonstrates that an appropriate biomaterial scaffold improves the environment for regeneration. Future targeting of the host fibrotic response may allow increased axonal regeneration and functional recovery. PMID:25891264

  9. The Fumarate Reductase of Bacteroides thetaiotaomicron, unlike That of Escherichia coli, Is Configured so that It Does Not Generate Reactive Oxygen Species

    PubMed Central

    Lu, Zheng

    2017-01-01

    ABSTRACT The impact of oxidative stress upon organismal fitness is most apparent in the phenomenon of obligate anaerobiosis. The root cause may be multifaceted, but the intracellular generation of reactive oxygen species (ROS) likely plays a key role. ROS are formed when redox enzymes accidentally transfer electrons to oxygen rather than to their physiological substrates. In this study, we confirm that the predominant intestinal anaerobe Bacteroides thetaiotaomicron generates intracellular ROS at a very high rate when it is aerated. Fumarate reductase (Frd) is a prominent enzyme in the anaerobic metabolism of many bacteria, including B. thetaiotaomicron, and prior studies of Escherichia coli Frd showed that the enzyme is unusually prone to ROS generation. Surprisingly, in this study biochemical analysis demonstrated that the B. thetaiotaomicron Frd does not react with oxygen at all: neither superoxide nor hydrogen peroxide is formed. Subunit-swapping experiments indicated that this difference does not derive from the flavoprotein subunit at which ROS normally arise. Experiments with the related enzyme succinate dehydrogenase discouraged the hypothesis that heme moieties are responsible. Thus, resistance to oxidation may reflect a shift of electron density away from the flavin moiety toward the iron-sulfur clusters. This study shows that the autoxidizability of a redox enzyme can be suppressed by subtle modifications that do not compromise its physiological function. One implication is that selective pressures might enhance the oxygen tolerance of an organism by manipulating the electronic properties of its redox enzymes so they do not generate ROS. PMID:28049145

  10. Dimethyl fumarate blocks pro-inflammatory cytokine production via inhibition of TLR induced M1 and K63 ubiquitin chain formation

    PubMed Central

    McGuire, Victoria A.; Ruiz-Zorrilla Diez, Tamara; Emmerich, Christoph H.; Strickson, Sam; Ritorto, Maria Stella; Sutavani, Ruhcha V.; Weiβ, Anne; Houslay, Kirsty F.; Knebel, Axel; Meakin, Paul J.; Phair, Iain R.; Ashford, Michael L. J.; Trost, Matthias; Arthur, J. Simon C.

    2016-01-01

    Dimethyl fumarate (DMF) possesses anti-inflammatory properties and is approved for the treatment of psoriasis and multiple sclerosis. While clinically effective, its molecular target has remained elusive - although it is known to activate anti-oxidant pathways. We find that DMF inhibits pro-inflammatory cytokine production in response to TLR agonists independently of the Nrf2-Keap1 anti-oxidant pathway. Instead we show that DMF can inhibit the E2 conjugating enzymes involved in K63 and M1 polyubiquitin chain formation both in vitro and in cells. The formation of K63 and M1 chains is required to link TLR activation to downstream signaling, and consistent with the block in K63 and/or M1 chain formation, DMF inhibits NFκB and ERK1/2 activation, resulting in a loss of pro-inflammatory cytokine production. Together these results reveal a new molecular target for DMF and show that a clinically approved drug inhibits M1 and K63 chain formation in TLR induced signaling complexes. Selective targeting of E2s may therefore be a viable strategy for autoimmunity. PMID:27498693

  11. In vitro cytotoxicity of injectable and biodegradable poly(propylene fumarate)-based networks: unreacted macromers, cross-linked networks, and degradation products.

    PubMed

    Timmer, Mark D; Shin, Heungsoo; Horch, R Adam; Ambrose, Catherine G; Mikos, Antonios G

    2003-01-01

    This study evaluates the in vitro biocompatibility of an injectable and biodegradable polymeric network based on poly(propylene fumarate) (PPF) and the cross-linking agent PPF-diacrylate (PPF-DA). Using a methyl tetrazolium (MTT) assay, the effect of the concentrations of PPF and PPF-DA on the cytotoxicity of its unreacted macromers, cross-linked networks, and degradation products was examined. The influence of network structure properties on cell viability and attachment to the cross-linked material was also investigated. The unreacted macromers exhibited a time- and dose-dependent cytotoxic response that increased with more PPF-DA in the mixture. Conversely, the cross-linked networks formed with more PPF-DA did not demonstrate an adverse response because increases in conversion and cross-linking density prevented the extraction of toxic products. Fibroblast attachment was observed on the PPF/PPF-DA networks with the highest double bond conversions. The degradation products, obtained from the complete breakdown of the networks in basic conditions, displayed a dose-dependent cytotoxic response. These results show that there are concerns regarding the biocompatibility of injectable, biodegradable PPF/PPF-DA networks but also sheds light onto potential mechanisms to reduce the cytotoxic effects.

  12. Stability-Indicating HPLC Method for the Simultaneous Determination of HIV Tablet Containing Emtricitabine, Tenofovir Disoproxil Fumarate, and Rilpivirine Hydrochloride in Pharmaceutical Dosage Forms.

    PubMed

    Venkatesan, S; Kannappan, N; Mannemala, Sai Sandeep

    2014-01-01

    A simple, accurate, rapid, and stability-indicating RP-HPLC method for a combination of tenofovir disoproxil fumarate, emtricitabine, and rilpivirine has been developed and subsequently validated in commercial tablets. The proposed HPLC method utilizes Phenomenex Gemini C18 column (150 mm × 4.6 mm i.d., 5 µm) and mobile phase consisting of MeCN, potassium dihydrogen phosphate buffer (20 mM, pH 3.3), and triethylamine 58.72 : 41.23 : 0.05 (v/v) at a flow rate of 1.7 mL/min. Quantitation was achieved with UV detection at 270 nm. The method was validated in terms of accuracy, precision, linearity, limits of detection, limits of quantitation, and robustness. This optimized method has been successively applied to pharmaceutical formulation and no interference from the tablet excipients was found. TDF, EMT, and RPV and their combination drug product were subjected to acid, base, neutral hydrolysis, oxidation, dry heat, and photolytic stress conditions and the stressed samples were analyzed by the proposed method. As the proposed LC method could effectively separate the drugs from its degradation products, it can be employed as stability-indicating method for the determination of instability of these drugs in bulk and commercial tablets.

  13. A factorial analysis of the combined effects of hydrogel fabrication parameters on the in vitro swelling and degradation of oligo(poly(ethylene glycol) fumarate) hydrogels.

    PubMed

    Lam, Johnny; Kim, Kyobum; Lu, Steven; Tabata, Yasuhiko; Scott, David W; Mikos, Antonios G; Kasper, F Kurtis

    2014-10-01

    In this study, a full factorial approach was used to investigate the effects of poly(ethylene glycol) (PEG) molecular weight (MW; 10,000 vs. 35,000 nominal MW), crosslinker-to-macromer carbon-carbon double bond ratio (DBR; 40 vs. 60), crosslinker type (PEG-diacrylate (PEGDA) vs. N,N'-methylene bisacrylamide (MB)), crosslinking extent of incorporated gelatin microparticles (low vs. high), and incubation medium composition (with or without collagenase) on the swelling and degradation characteristics of oligo[(poly(ethylene glycol) fumarate)] (OPF) hydrogel composites as indicated by the swelling ratio and the percentage of mass remaining, respectively. Each factor consisted of two levels, which were selected based on previous in vitro and in vivo studies utilizing these hydrogels for various tissue engineering applications. Fractional factorial analyses of the main effects indicated that the mean swelling ratio and the mean percentage of mass remaining of OPF composite hydrogels were significantly affected by every factor. In particular, increasing the PEG chain MW of OPF macromers significantly increased the mean swelling ratio and decreased the mean percentage of mass remaining by 5.7 ± 0.3 and 17.2 ± 0.6%, respectively. However, changing the crosslinker from MB to PEGDA reduced the mean swelling ratio and increased the mean percentage of mass remaining of OPF composite hydrogels by 4.9 ± 0.2 and 9.4 ± 0.9%, respectively. Additionally, it was found that the swelling characteristics of hydrogels fabricated with higher PEG chain MW or with MB were more sensitive to increases in DBR. Collectively, the main and cross effects observed between factors enables informed tuning of the swelling and degradation properties of OPF-based hydrogels for various tissue engineering applications. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 3477-3487, 2014.

  14. Extended release quetiapine fumarate (quetiapine XR) monotherapy as maintenance treatment for generalized anxiety disorder: a long-term, randomized, placebo-controlled trial.

    PubMed

    Katzman, Martin A; Brawman-Mintzer, Olga; Reyes, Efren B; Olausson, Bengt; Liu, Sherry; Eriksson, Hans

    2011-01-01

    The objective of this study was to evaluate the efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) as maintenance monotherapy for patients with generalized anxiety disorder (GAD). Time-to-event (anxiety symptom recurrence; maximum 52 weeks) multicenter, randomized-withdrawal, parallel-group, double-blind, placebo-controlled study of quetiapine XR (50-300 mg/day) following open-label run-in (4-8 weeks) and open-label stabilization (≥ 12 weeks). Primary variable: time from randomization to anxiety event. Secondary variables included: Hamilton Anxiety Rating Scale (HAM-A) total, HAM-A psychic/somatic anxiety factors, Clinical Global Impression-Severity of Illness (CGI-S), and Quality of Life, Enjoyment and Satisfaction Questionnaire (Q-LES-Q) scores; adverse events (AE) reporting. Four hundred and thirty-two patients, stabilized on quetiapine XR, were randomized to continue quetiapine XR (N=216) or switch to placebo (N=216). Risk of anxiety symptom recurrence was significantly reduced by 81% for quetiapine XR versus placebo: hazard ratio=0.19 (95% confidence interval 0.12-0.31; P<0.001). Fewer patients receiving quetiapine XR (N=22, 10.2%) than placebo (N=84, 38.9%) experienced anxiety symptom recurrence. Significant differences were observed between quetiapine XR and placebo in: HAM-A total, psychic/somatic, CGI-S (all P<0.001) and Q-LES-Q (P<0.05) scores. AEs (>10%) during open-label treatment were dry mouth, sedation, somnolence, dizziness, fatigue, and constipation. During randomized treatment, the most common AEs for quetiapine XR were headache and nasopharyngitis. Quetiapine XR monotherapy reduced the risk of anxiety symptom recurrence in patients with GAD stabilized on quetiapine XR, with tolerability results consistent with the known profile of quetiapine.

  15. Pooled analysis of adjunct extended-release quetiapine fumarate in patients with major depressive disorder according to ongoing SSRI or SNRI treatment.

    PubMed

    Bauer, Michael; Demyttenaere, Koen; El-Khalili, Nizar; Thase, Michael E; Papakostas, George I; Szamosi, Johan; Earley, Willie R; Eriksson, Hans

    2014-01-01

    This pooled analysis evaluated the efficacy of extended-release quetiapine fumarate (quetiapine XR) adjunct to selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) in patients with major depressive disorder (MDD). Pooled data were analyzed from two 6-week, double-blind, randomized, placebo-controlled trials of adjunct quetiapine XR (150 and 300 mg/day) in patients with MDD and inadequate response to initial antidepressant monotherapy. This post-hoc analysis included evaluation of change from randomization at week 6 in Montgomery Åsberg Depression Rating Scale (MADRS) total scores (primary endpoint), and week 6 MADRS response and remission rates for quetiapine XR as an adjunct to ongoing SSRI or SNRI. In total, 189, 178, and 202 patients received quetiapine XR 150 mg/day+SSRI, 300 mg/day+SSRI, and placebo+SSRI, respectively, whereas 82, 90, and 76 patients, respectively, received quetiapine XR 150 mg/day+SNRI, 300 mg/day+SNRI, and placebo+SNRI. At week 6, quetiapine XR 150 mg/day+SSRI and 300 mg/day+SSRI reduced the MADRS total score from randomization versus placebo+SSRI [least squares mean (LSM) change, -14.70 (P<0.05) -14.72 (P<0.05) vs. -12.59, respectively]. Quetiapine XR 150 mg/day+SNRI (LSM change, -14.68, P<0.01) and 300 mg/day+SNRI (LSM change, -14.99, P<0.01) also reduced the MADRS total score from randomization at week 6 versus placebo+SNRI (-10.77). In conclusion, in patients with MDD and inadequate response to ongoing antidepressant, adjunct quetiapine XR (150 and 300 mg/day) was effective in both SSRI and SNRI subgroups.

  16. Dimethyl fumarate attenuates 6-OHDA-induced neurotoxicity in SH-SY5Y cells and in animal model of Parkinson's disease by enhancing Nrf2 activity.

    PubMed

    Jing, X; Shi, H; Zhang, C; Ren, M; Han, M; Wei, X; Zhang, X; Lou, H

    2015-02-12

    Oxidative stress is central to the pathology of several neurodegenerative diseases, including Parkinson's disease (PD), and therapeutics designed to enhance antioxidant potential could have clinical value. In this study, we investigated whether dimethyl fumarate (DMF) has therapeutic effects in cellular and animal model of PD, and explore the role of nuclear transcription factor related to NF-E2 (Nrf2) in this process. Treatment of animals and dopaminergic SH-SY5Y cells with DMF resulted in increased nuclear levels of active Nrf2, with subsequent upregulation of antioxidant target genes. The cytotoxicity of 6-hydroxydopamine (6-OHDA) was reduced by pre-treatment with DMF in SH-SY5Y cells. The increase in the reactive oxygen species caused by 6-OHDA treatment was also attenuated by DMF in SH-SY5Y cells. The neuroprotective effects of DMF against 6-OHDA neurotoxicity were dependent on Nrf2, since treatment with Nrf2 siRNA failed to block against 6-OHDA neurotoxicity and induce Nrf2-dependent cytoprotective genes in SH-SY5Y cells. In vivo, DMF oral administration was shown to upregulate mRNA and protein levels of Nrf2 and Nrf2-regulated cytoprotective genes, attenuate 6-OHDA induced striatal oxidative stress and inflammation in C57BL/6 mice. Moreover, DMF ameliorated dopaminergic neurotoxicity in 6-OHDA-induced PD animal models as evidenced by amelioration of locomotor dysfunction, loss in striatal dopamine, and reductions in dopaminergic neurons in the substantia nigra and striatum. Taken together, these data strongly suggest that DMF may be beneficial for the treatment of neurodegenerative diseases like PD.

  17. Formulation development and optimization of Lamivudine 300 mg and Tenofovir Disoproxil Fumarate (TDF) 300 mg FDC tablets by D-optimal mixture design.

    PubMed

    Tibalinda, Prosper; Sempombe, Joseph; Shedafa, Raphael; Masota, Nelson; Pius, Dickson; Temu, Mary; Kaale, Eliangiringa

    2016-12-01

    The usage of fixed dose combination (FDC) tablets of Lamivudine and Tenofovir Disoproxil Fumarate (TDF) is increasing due to increased incidences of HIV/Hepatitis B and HIV/TB co-infections. This is likely to increase the financial crisis due to limited resources for funding procurement of ready-made products from the pharmaceuticals manufacturing leading countries. Therefore, production of local oral tablets containing Lamivudine and TDF FDC is inevitable. Lamivudine 300 mg/TDF 300 mg tablets were developed and optimized by D-optimal mixture design and produced by direct compression technique. Twenty trial formulations with independent variables, including PVP-CL 1-12.00%, PVP-K30 1-10.00%, starch-1500 2.5-12.5% and Avicel-PH102 2-19.25% were prepared by direct compression technique. The formulations were assessed on assay, dissolution, friability, weight variation and disintegration time. It was found that assay ranged from 98.13-101.95% for Lamivudine, 98.25-102.84 for TDF, both were within the in-house assay specification of 95 to 105%. Dissolution at single point was above 80% for Lamivudine 93.96-100.55% and 95.85-103.15% for TDF, disintegration time was between 1.92-66.33 min and friability 0.06-12.56%. Out of twenty formulation trials, eight formulations had all parameters in proven acceptable range. On optimization, one formulation with independent variables, PVP-CL 5.67%, PVP-K30 1.00%, Starch-1500 5.76% was selected. The optimized formulation was comparable to the reference product on the market with similarity factor (f2) and difference factor (f1) within the acceptable range for both Lamivudine and TDF.

  18. Is Emtricitabine-Tenofovir Disoproxil Fumarate Pre-exposure Prophylaxis for the Prevention of Human Immunodeficiency Virus Infection Safer Than Aspirin?

    PubMed Central

    Kojima, Noah; Klausner, Jeffrey D.

    2016-01-01

    Background. The safety and effectiveness studies of emtricitabine-tenofovir disoproxil fumarate (FTC-TDF) for human immunodeficiency virus (HIV) infection pre-exposure prophylaxis (PrEP) in men and women showed that daily use reduced the risk of HIV acquisition, but there still may concerns about safety. Methods. A narrative review was done in September 2015 comparing the 5 major studies on PrEP for HIV infection—Preexposure Prophylaxis Initiative (N = 2499; 3324 person-years), Partners Preexposure Prophylaxis (N = 4747; 7830 person-years), TDF2 (N = 1219; 1563 person-years), Preexposure Prophylaxis Trial for HIV Prevention among African Women (N = 2056; 1407 person-years), and Vaginal and Oral Interventions to Control the Epidemic (N = 4969; 5509 person-years)—and the 2 major studies on aspirin safety—Physicians' Health Study (N = 22 071; over 110 000 person-years) and the Women's Health Study (N = 39 876; approximately 400 000 person-years). The numbers needed to harm (NNH) were calculated for FTC-TDF for HIV infection PrEP and aspirin. Results. The NNH for FTC-TDF in men who have sex with men and transgender women was 114 for nausea and 96 for unintentional weight loss; in heterosexual couples, the NNH was 68 for moderate decreased absolute neutrophil count. For aspirin, the NNH was 909 for major gastrointestinal bleeding, 123 for any gastrointestinal bleeding, and 15 for any bleeding problems in men. In women, the NNH for easy bruising was 10. Conclusions. We conclude that FTC-TDF for PrEP for HIV infection favorably compares with aspirin in terms of user safety. Although long-term studies are needed, providers should feel reassured about the safety of short- and medium-term PrEP for HIV infection with FTC-TDF. PMID:26949714

  19. A Randomized, Double-blind Study of the Efficacy and Tolerability of Extended Release Quetiapine Fumarate (Quetiapine XR) Monotherapy in Patients with Major Depressive Disorder

    PubMed Central

    Wang, Gang; McIntyre, Alexander; Earley, Willie R.; Raines, Shane; Eriksson, Hans

    2012-01-01

    Objectives Evaluate the efficacy and tolerability of once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in patients with major depressive disorder (MDD). Methods 10-week (8-week active-treatment/2-week post-treatment), randomized, double-blind, placebo- and active-controlled study (D1448C00004). Patients received quetiapine XR 150 mg/day, escitalopram 10 mg/day, or placebo; patients with an inadequate response (<20% improvement in MADRS total score) at Week 2 received double-treatment dose. Primary endpoint: Week 8 change from randomization in MADRS total score. Secondary endpoints included: MADRS response (≥50% improvement) and remission (score ≤8), HAM-D total and Item 1, HAM-A total, psychic and somatic, CGI-S total, PSQI global, and Q-LES-Q-SF% maximum total scores; tolerability was assessed throughout. Results 471 patients were randomized. No significant improvements in MADRS total score were observed at Week 8 (LOCF) with either active treatment (quetiapine XR, −17.21 [p=0.174]; escitalopram, −16.73 [p=0.346]) versus placebo (−15.61). There were no significant differences in secondary endpoints versus placebo, with the exception of Week 8 change in PSQI global score (quetiapine XR, −4.96 [p < 0.01] versus placebo, −3.37). MMRM analysis of observed cases data suggested that the primary analysis may not be robust. Most commonly reported AEs included: dry mouth, somnolence, and dizziness for quetiapine XR; headache and nausea for escitalopram. Conclusions In this study, neither quetiapine XR (150/300 mg/day) nor escitalopram (10/20 mg/day) showed significant separation from placebo. Both compounds have been shown previously to be effective in the treatment of MDD; possible reasons for this failed study are discussed. Quetiapine XR was generally well tolerated with a profile similar to that reported previously. PMID:27738365

  20. Extended Release Quetiapine Fumarate (Quetiapine XR) as Adjunct Therapy in Patients with Generalized Anxiety Disorder and a History of Inadequate Treatment Response: A Randomized, Double-Blind Study

    PubMed Central

    Khan, Arifulla; Atkinson, Sarah; Mezhebovsky, Irina; She, Fahua; Leathers, Todd; Pathak, Sanjeev

    2011-01-01

    Objective To evaluate the efficacy and tolerability of adjunct extended release quetiapine fumarate (quetiapine XR) in patients with generalized anxiety disorder (GAD) and inadequate response to selective serotonin reuptake inhibitors/ serotonin norepinephrine reuptake inhibitors (SSRI/SNRIs). Methods 11-week (1-week single-blind placebo run-in; 8-week randomized treatment; 2-week post-treatment period), double-blind, placebo-controlled study. Patients were randomized to quetiapine XR or placebo adjunct to SSRI/SNRI. 50 mg initial dose; 150 mg/day, Day 3; 300 mg/day, Weeks × and 4 if indicated (Clinical Global Impressions-Severity of Illness [CGI-S] ≥ 4; 150 mg/day tolerated). Primary endpoint: change from randomization to Week 8 in HAM-A total score. Secondary variables: Hamilton Rating Scale for Anxiety (HAM-A) psychic/somatic clusters, response and remission; and CGI-S. Results 409 patients were randomized to quetiapine XR (n = 209) or placebo (n = 200); 41% and 55% of patients, respectively, had dose increases (300 mg/day). Week 8 mean change in HAM-A total score was not statistically significant for quetiapine XR (–10.74; p = 0.079) versus placebo (–9.61). Secondary variables were generally consistent with the primary analysis, except a significant reduction in HAM-A total score at Week 1 (–6.45, quetiapine XR versus –4.47, placebo; p < 0.001); significant improvements in HAM-A psychic cluster (p < 0.05) and CGI-S total (p < 0.05) scores at Week 8. Adverse events (.10% either group) were dry mouth, somnolence, sedation, headache, and dizziness. Conclusions In patients with GAD and inadequate response to SSRI/SNRI, adjunct quetiapine XR did not show a statistically significant effect for the primary endpoint at Week 8, although some secondary endpoints were statistically significant versus placebo. Quetiapine XR was generally well tolerated. PMID:27738353

  1. Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: subgroup analyses of the CONFIRM study.

    PubMed

    Hutchinson, Michael; Fox, Robert J; Miller, David H; Phillips, J Theodore; Kita, Mariko; Havrdova, Eva; O'Gorman, John; Zhang, Ray; Novas, Mark; Viglietta, Vissia; Dawson, Katherine T

    2013-09-01

    In the phase 3, randomized, placebo-controlled and active reference (glatiramer acetate) comparator CONFIRM study in patients with relapsing-remitting multiple sclerosis, oral BG-12 (dimethyl fumarate) reduced the annualized relapse rate (ARR; primary endpoint), as well as the proportion of patients relapsed, magnetic resonance imaging lesion activity, and confirmed disability progression, compared with placebo. We investigated the clinical efficacy of BG-12 240 mg twice daily (BID) and three times daily (TID) in patient subgroups stratified according to baseline demographic and disease characteristics including gender, age, relapse history, McDonald criteria, treatment history, Expanded Disability Status Scale score, T2 lesion volume, and gadolinium-enhancing lesions. BG-12 treatment demonstrated generally consistent benefits on relapse-related outcomes across patient subgroups, reflecting the positive findings in the overall CONFIRM study population. Treatment with BG-12 BID and TID reduced the ARR and the proportion of patients relapsed at 2 years compared with placebo in all subgroups analyzed. Reductions in ARR with BG-12 BID versus placebo ranged from 34% [rate ratio 0.664 (95% confidence interval 0.422-1.043)] to 53% [0.466 (0.313-0.694)] and from 13% [0.870 (0.551-1.373)] to 67% [0.334 (0.226-0.493)] with BG-12 TID versus placebo. Treatment with glatiramer acetate reduced the ARR and the proportion of patients relapsed at 2 years compared with placebo in most patient subgroups. The results of these analyses indicate that treatment with BG-12 is effective on relapses across a broad range of patients with relapsing-remitting multiple sclerosis with varied demographic and disease characteristics.

  2. Effects of crosslinking on the thermal stability of hemoglobins. II. The stabilization of met-, cyanomet-, and carbonmonoxyhemoglobins A and S with bis(3,5-dibromosalicyl) fumarate.

    PubMed

    Yang, T; Olsen, K W

    1988-03-01

    Hemoglobins A and S were crosslinked between Lys 82 beta 1 and Lys 82 beta 2 using bis (3,5-dibromosalicyl) fumarate (J. A. Walder et al. (1979) Biochemistry 18, 4265). Thermal denaturation experiments were used to compare the stabilities of the met, cyanomet, and carbonmonoxy forms of these crosslinked hemoglobins to the corresponding uncrosslinked proteins. Uncrosslinked carbonmonoxy- and cyanomethemoglobins had transition temperatures about 11 degrees C higher than the corresponding met samples. The increase in denaturation temperature (Tm) due to crosslinking was 15 degrees C for the methemoglobins, 10 degrees C for the cyanomethemoglobins, and 4 degrees C for the carbonmonoxy ones. There was no significant difference in stability between the met and carbonmonoxy crosslinked proteins. In order of increasing stability the samples were: met Hb S less than met Hb A less than CO Hb S less than CO Hb A = CN-met Hb A less than met XL-Hb S = CO XL-Hb S less than met XL-Hb A = CO XL-Hb A less than CN-met XL-Hb A. The slight decrease in the stability of Hb S (beta 6 Glu----Val) compared to Hb A can be explained by the replacement of an external ionic group by a hydrophobic residue in Hb S. In mixtures of crosslinked and normal Hb A, the Tm of the uncrosslinked material was slightly increased by the presence of the more stable crosslinked hemoglobin. The effects of both crosslinking and cyanide or carbon monoxide binding can be explained by Le Chatelier's principle since both would favor the native form of the protein.

  3. Novel biodegradable poly(propylene fumarate)-co-poly(l-lactic acid) porous scaffolds fabricated by phase separation for tissue engineering applications

    PubMed Central

    Liu, Xifeng; Miller, A. Lee; Waletzki, Brian E.; Yaszemski, Michael J.

    2015-01-01

    Scaffolds with intrinsically interconnected porous structures are highly desirable in tissue engineering and regenerative medicine. In this study, three-dimensional polymer scaffolds with highly interconnected porous structures were fabricated by thermally induced phase separation of novel synthesized biodegradable poly(propylene fumarate)-co-poly(l-lactic acid) in a dioxane/water binary system. Defined porous scaffolds were achieved by optimizing conditions to attain interconnected porous structures. The effect of phase separation parameters on scaffold morphology were investigated, including polymer concentration (1, 3, 5, 7, and 9%), quench time (1, 4, and 8 min), dioxane/water ratio (83/17, 85/15, and 87/13 wt/wt), and freeze temperature (−20, −80, and −196 °C). Interesting pore morphologies were created by adjusting these processing parameters, e.g., flower-shaped (5%; 85/15; 1 min; −80 °C), spherulite-like (5%; 85/15; 8 min; −80 °C), and bead-like (5%; 87/13; 1 min; −80 °C) morphology. Modulation of phase separation conditions also resulted in remarkable differences in scaffold porosities (81% to 91%) and thermal properties. Furthermore, scaffolds with varied mechanic strengths, degradation rates, and protein adsorption capabilities could be fabricated using the phase separation method. In summary, this work provides an effective route to generate multi-dimensional porous scaffolds that can be applied to a variety of hydrophobic polymers and copolymers. The generated scaffolds could potentially be useful for various tissue engineering applications including bone tissue engineering. PMID:26989483

  4. Modulation of marrow stromal osteoblast adhesion on biomimetic oligo[poly(ethylene glycol) fumarate] hydrogels modified with Arg-Gly-Asp peptides and a poly(ethyleneglycol) spacer.

    PubMed

    Shin, Heungsoo; Jo, Seongbong; Mikos, Antonios G

    2002-08-01

    Novel oligo[poly(ethylene glycol) fumarate] (OPF) hydrogels functionalized with cell adhesion peptides were prepared, and the effects of incorporated peptide density and macromolecular structure of hydrogels on attachment and morphology of marrow stromal cells (MSCs) were evaluated. Poly(ethylene glycol) (PEG; number average molecular weight of 930, 2860, and 6090) was used to synthesize OPF. A model peptide, Gly-Arg-Gly-Asp (GRGD), was incorporated into OPF hydrogels after being coupled to acrylated PEG of molecular weight 3400. The increase of incorporated peptide concentration enhanced MSC attachment to OPF hydrogels of PEG of molecular weight of 930 and 2860. However, the number of attached MSCs to OPF hydrogels of PEG (molecular weight 6090) remained constant regardless of the peptide density. The length of PEG in OPF also influenced cell attachment. When 1 micromole peptide/g hydrogel was incorporated into the OPF hydrogels, the degree of cell attachment at 12 h relative to the initial seeding density was 93.9 +/- 5.9%, 64.7 +/- 8.2%, and 9.3 +/- 6.6% for OPF hydrogels prepared with PEG of molecular weights of 930, 2860, and 6090, respectively. However, the crosslinking density of hydrogels did not significantly affect cell attachment. The interaction was sequence specific, in that MSC attachment to GRGD-modified hydrogels was competitively inhibited when cells were incubated in the presence of 0.5 mM soluble GRGD before cell seeding. These results suggest that we can modulate MSC attachment to OPF hydrogels by altering the peptide density and the molecular structure of OPF hydrogels.

  5. Effect of poly(ethylene glycol) molecular weight on tensile and swelling properties of oligo(poly(ethylene glycol) fumarate) hydrogels for cartilage tissue engineering.

    PubMed

    Temenoff, Johnna S; Athanasiou, Kyriacos A; LeBaron, Richard G; Mikos, Antonios G

    2002-03-05

    This study was designed to determine the effect of changes in poly(ethylene glycol) (PEG) molecular weight on swelling and mechanical properties of hydrogels made from a novel polymer, oligo(poly(ethylene glycol) fumarate) (OPF), recently developed in our laboratory. Properties of hydrogels made from OPF with initial PEG molecular weights of 860, 3900, and 9300 were examined. The PEG 3900 formulation had a tensile modulus of 23.1 +/- 12.4 kPa and percent elongation at fracture of 53.2 +/- 13.7%; the PEG 9300 formulation had similar tensile properties (modulus: 16.5 +/- 4.6 kPa, elongation: 76.0 +/- 26.4%). However, the PEG 860 gels had a significantly higher modulus (89.5 +/- 50.7 kPa) and a significantly smaller percent elongation at fracture (30.1 +/- 6.4%), when compared with other formulations. Additionally, there were significant differences in percent swelling between each of the formulations. Molecular weight between crosslinks (M(c)) and mesh size were calculated for each OPF formulation. M(c) increased from 2010 +/- 116 g/mol with PEG 860 to 6250 +/- 280 g/mol with PEG 9300. Mesh size calculations showed a similar trend (76 +/- 2 A for PEG 860 to 160 +/- 6 A for PEG 9300). It was also found that these hydrogels could be laminated if a second layer was added before the first had completely crosslinked. Mechanical testing of these laminated gels revealed that the presence of an interfacial area did not significantly alter their tensile properties. These results suggest that the material properties of OPF-based hydrogels can be altered by changing the molecular weight of PEG used in synthesis and that multilayered OPF hydrogel constructs can be produced, with each layer having distinct mechanical properties.

  6. Changes in Proteinuria and Albuminuria with Initiation of Antiretroviral Therapy: Data from a Randomized Trial Comparing Tenofovir Disoproxil Fumarate/Emtricitabine versus Abacavir/Lamivudine

    PubMed Central

    Wyatt, Christina M; Kitch, Douglas; Gupta, Samir K; Tierney, Camlin; Daar, Eric S; Sax, Paul E; Ha, Belinda; Melbourne, Kathleen; McComsey, Grace A

    2014-01-01

    Antiretroviral therapy (ART) is associated with improved kidney function; however, the nucleotide reverse transcriptase inhibitor (NRTI) tenofovir disoproxil fumarate (TDF) has been associated with decreased kidney function and proteinuria. Methods We examined changes in urine protein:creatinine (UPCR) and albumin:creatinine (UACR) ratios in 245 ART-naïve participants in A5202 randomized in a substudy to blinded NRTI (abacavir/lamivudine, ABC/3TC, n=124 or TDF/emtricitabine, TDF/FTC, n=121) with open-label protease inhibitor (PI) atazanavir/ritonavir (ATV/r) or non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (EFV). Results At baseline, 18% of participants had clinically significant proteinuria (UPCR ≥ 200 mg/g) and 11% had clinically significant albuminuria (UACR ≥ 30 mg/g). The prevalence of clinically significant proteinuria and albuminuria decreased from baseline to week 96 in all treatment groups. In intention-to-treat analyses, there was a significant effect of NRTI component on fold-change in UPCR (p=0.011) and UACR (p=0.018) from baseline to week 96, with greater improvements in participants randomized to ABC/3TC. There was no significant effect of NNRTI/PI component on fold-change in UPCR (p=0.23) or UACR (p=0.88), and no significant interactions between NRTI and NNRTI/PI components. Conclusion In this pre-specified secondary analysis, ART initiation was associated with improvements in proteinuria and albuminuria, with significantly greater improvements in participants randomized to ABC/3TC versus TDF/FTC. These are the first data from a randomized trial to suggest that initiation of TDF/FTC may not be associated with the same degree of improvement in proteinuria and albuminuria that have been reported with other regimens. Future studies should consider the long-term clinical significance of these findings. PMID:25117929

  7. Greater change in bone turnover markers for efavirenz/emtricitabine/tenofovir disoproxil fumarate versus dolutegravir + abacavir/lamivudine in antiretroviral therapy-naive adults over 144 weeks

    PubMed Central

    Tebas, Pablo; Kumar, Princy; Hicks, Charles; Granier, Catherine; Wynne, Brian; Min, Sherene; Pappa, Keith

    2015-01-01

    Objective: Antiretroviral therapy initiation has been linked to bone mineral density and bone biomarker changes. We assessed long-term bone turnover biomarker effects over 144 weeks in patients initiating dolutegravir (DTG) + abacavir/lamivudine (ABC/3TC) versus efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF). Methods: Patients randomized in SINGLE received DTG (50 mg once daily) + ABC/3TC or fixed-dose combination EFV/FTC/TDF. We evaluated vitamin D serum levels and bone turnover markers (BTMs), including type 1 collagen cross-linked C-telopeptide (CTx), osteocalcin, bone-specific alkaline phosphatase (BSAP), and procollagen type 1 N-terminal propeptide (P1NP), at baseline and weeks 48, 96, and 144. Results: Among the 833 enrolled patients (68% white, 85% men), baseline median age was 35 years (range 18–85), median CD4+ was 338 cells/μl, and median BMI was 24 kg/m2. Fifty-three percent of patients smoked, and 6% reported baseline vitamin D use, with no meaningful differences between groups. Relative to baseline, CTx, osteocalcin, BSAP, and P1NP increased; vitamin D decreased in both groups at weeks 48, 96, and 144. Changes from baseline typically peaked at weeks 48 or 96 and for the four analytes, excluding vitamin D, with the EFV/FTC/TDF group having significantly greater changes from baseline at all time points. Conclusion: DTG + ABC/3TC in antiretroviral therapy-naive patients resulted in significantly lower increases in BTMs (CTx, osteocalcin, BSAP, P1NP) compared with EFV/FTC/TDF over 144 weeks. The observed changes are consistent with results from other smaller, randomized trials. These differences in BTMs likely correlate with changes in bone mineral density over time. PMID:26355674

  8. Vaginally delivered tenofovir disoproxil fumarate provides greater protection than tenofovir against genital herpes in a murine model of efficacy and safety.

    PubMed

    Nixon, Briana; Jandl, Thomas; Teller, Ryan S; Taneva, Ekaterina; Wang, Yanhua; Nagaraja, Umadevi; Kiser, Patrick F; Herold, Betsy C

    2014-01-01

    Increased susceptibility to genital herpes in medroxyprogesterone-treated mice may provide a surrogate of increased HIV risk and a preclinical biomarker of topical preexposure prophylaxis safety. We evaluated tenofovir disoproxil fumarate (TDF) in this murine model because an intravaginal ring eluting this drug is being advanced into clinical trials. To avoid the complications of surgically inserting a ring, hydroxyethylcellulose (HEC)-stable formulations of TDF were prepared. One week of twice-daily 0.3% TDF gel was well tolerated and did not result in any increase in HSV-2 susceptibility but protected mice from herpes simplex virus 2 (HSV-2) disease compared to mice treated with the HEC placebo gel. No significant increase in inflammatory cytokines or chemokines in vaginal washes or change in cytokine, chemokine, or mitochondrial gene expression in RNA extracted from genital tract tissue was detected. To further evaluate efficacy, mice were treated with gel once daily beginning 12 h prior to high-dose HSV-2 challenge or 2 h before and after viral challenge (BAT24 dosing). The 0.3% TDF gel provided significant protection compared to the HEC gel following either daily (in 9/10 versus 1/10 mice, P < 0.01) or BAT24 (in 14/20 versus 4/20 mice, P < 0.01) dosing. In contrast, 1% tenofovir (TFV) gel protected only 4/10 mice treated with either regimen. Significant protection was also observed with daily 0.03% TDF compared to HEC. Protection was associated with greater murine cellular permeability of radiolabeled TDF than of TFV. Together, these findings suggest that TDF is safe, may provide substantially greater protection against HSV than TFV, and support the further clinical development of a TDF ring.

  9. Effect of Autologous Bone Marrow Stromal Cell Seeding and Bone Morphogenetic Protein-2 Delivery on Ectopic Bone Formation in a Microsphere/Poly(Propylene Fumarate) Composite

    PubMed Central

    Kempen, Diederik H.R.; Kruyt, Moyo C.; Lu, Lichun; Wilson, Clayton E.; Florschutz, Anthony V.; Yaszemski, Michael J.; Dhert, Wouter J.A.

    2009-01-01

    A biodegradable microsphere/scaffold composite based on the synthetic polymer poly(propylene fumarate) (PPF) holds promise as a scaffold for cell growth and sustained delivery vehicle for growth factors for bone regeneration. The objective of the current work was to investigate the in vitro release and in vivo bone forming capacity of this microsphere/scaffold composite containing bone morphogenetic protein-2 (BMP-2) in combination with autologous bone marrow stromal cells (BMSCs) in a goat ectopic implantation model. Three composites consisting of 0, 0.08, or 8 μg BMP-2 per mg of poly(lactic-co-glycolic acid) microspheres, embedded in a porous PPF scaffold, were combined with either plasma (no cells) or culture-expanded BMSCs. PPF scaffolds impregnated with a BMP-2 solution and combined with BMSCs as well as empty PPF scaffolds were also tested. The eight different composites were implanted subcutaneously in the dorsal thoracolumbar area of goats. Incorporation of BMP-2–loaded microspheres in the PPF scaffold resulted in a more sustained in vitro release with a lower burst phase, as compared to BMP-2–impregnated scaffolds. Histological analysis after 9 weeks of implantation showed bone formation in the pores of 11/16 composites containing 8 μg/mg BMP-2–loaded microspheres with no significant difference between composites with or without BMSCs (6/8 and 5/8, respectively). Bone formation was also observed in 1/8 of the BMP-2–impregnated scaffolds. No bone formation was observed in the other conditions. Overall, this study shows the feasibility of bone induction by BMP-2 release from microspheres/scaffold composites. PMID:18925831

  10. The energy-conserving electron transfer system used by Desulfovibrio alaskensis strain G20 during pyruvate fermentation involves reduction of endogenously formed fumarate and cytoplasmic and membrane-bound complexes, Hdr-Flox and Rnf.

    PubMed

    Meyer, Birte; Kuehl, Jennifer V; Price, Morgan N; Ray, Jayashree; Deutschbauer, Adam M; Arkin, Adam P; Stahl, David A

    2014-11-01

    The adaptation capability of Desulfovibrio to natural fluctuations in electron acceptor availability was evaluated by studying Desulfovibrio alaskensis strain G20 under varying respiratory, fermentative and methanogenic coculture conditions in chemostats. Transition from lactate to pyruvate in coculture resulted in a dramatic shift in the population structure and closer interspecies cell-to-cell interactions. Lower methane production rates in coculture than predicted from pyruvate input was attributed to redirection of electron flow to fumarate reduction. Without a methanogenic partner, accumulation of H₂and formate resulted in greater succinate production. Comparative transcript and gene fitness analysis in concert with physiological data of G20 wildtype and mutants demonstrated that pyruvate fermentation involves respiration of cytoplasmically formed fumarate using cytoplasmic and membrane-bound energy-conserving complexes, Rnf, Hdr-Flox-1 and Hmc. At the low H₂/formate levels maintained in coculture, Rnf likely functions as proton-pumping ferredoxin (Fd): type-I cytochrome c oxidoreductase, which transitions to a proton-pumping Fd(red):  nicotinamide adenine dinucleotide (NAD⁺) oxidoreductase at high H₂/formate levels during fermentation in monoculture. Hdr-Flox-1 is postulated to recycle Fd(red) via a flavin-based electron bifurcation involving NADH, Fdox and the thiol/disulphide-containing DsrC. In a menaquinone (MQ)-based electron confurcation reaction, the high-molecular-weight cytochrome-c₃complex, Hmc, is proposed to then couple DsrC(red) and periplasmic H₂/formate oxidation using the MQ pool to fuel a membrane-bound fumarate reductase.

  11. Reversibility of Glomerular Renal Function Decline in HIV Uninfected Men and Women Discontinuing Emtricitabine-Tenofovir Disoproxil Fumarate Pre-exposure Prophylaxis

    PubMed Central

    Mugwanya, Kenneth K.; Wyatt, Christina; Celum, Connie; Donnell, Deborah; Kiarie, James; Ronald, Allan; Baeten, Jared M.

    2015-01-01

    Background Tenofovir disoproxil fumarate (TDF) pre-exposure prophylaxis (PrEP) use is associated with a small but statistically significant decline in estimated glomerular filtration rate (eGFR). We investigated the reversibility of eGFR decline among HIV-uninfected adults discontinuing PrEP. Methods Data were from the Partners PrEP Study, a randomized trial of daily oral TDF and emtricitabine (FTC)-TDF PrEP among African HIV-uninfected men and women with baseline creatinine clearance ≥60mL/min. Serum creatinine was measured quarterly while on study medication and at month 1 and 2 after discontinuation. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration Equation. Results A total of 3924 individuals had a post-study drug serum creatinine measurement after the scheduled drug discontinuation (1271 for TDF, 1308 for FTC-TDF, and 1345 for placebo); 65% were male, median age was 35 (range 18–64) years. Median time on study drug was 33 (IQR 25–36) months overall, and 36 months (IQR 30–36) for TDF and FTC-TDF. Mean eGFR at the last on-treatment visit was 129 mL/min/1.73 m2 for TDF and 128 mL/min/1.73 m2 for FTC-TDF versus 131 mL/min/1.73 m2 for placebo (2-3 mL/min/1.73 m2 mean decline for PrEP versus placebo, p ≤0.01) and this difference reversed by 4 weeks after drug discontinuation (mean eGFR at the first post-drug visit: 130 mL/min/1.73 m2 in all groups). More than 96% of participants had a confirmed >75% eGFR rebound to baseline eGFR level by 8 weeks after drug discontinuation, with similar proportions across treatment groups. Conclusions In this large, placebo-controlled study of TDF-based PrEP, the small reduction in mean eGFR associated with PrEP reversed within weeks after discontinuation. PMID:26914909

  12. The Mast Cell Stabilizer Ketotifen Fumarate Lessens Contracture Severity and Myofibroblast Hyperplasia: A Study of a Rabbit Model of Posttraumatic Joint Contractures

    PubMed Central

    Monument, Michael J.; Hart, David A.; Befus, A. Dean; Salo, Paul T.; Zhang, Mei; Hildebrand, Kevin A.

    2010-01-01

    Background The propensity of the elbow to become stiff after trauma is widely appreciated and in this setting, the joint capsule is commonly recognized as the major motion-limiting anatomical structure. Affected joint capsules become fibrotic, characterized by myofibroblast hyperplasia and excessive collagen deposition. Mast cell hyperplasia is common within fibrotic tissue and mast cells are known to synthesize many profibrotic mediators. We have hypothesized that mast cell inhibition after skeletal injury will lessen the degree of contracture severity and will reduce myofibroblast hyperplasia within the joint capsule. Methods Posttraumatic contractures of the knee were created using a combination of intra-articular injury coupled to internal immobilization in skeletally mature, New Zealand white rabbits. Four groups of animals were studied: a non-operative control group (CON), an operative contracture group (ORC) and two-operative groups treated with a mast cell stabilizer, Ketotifen fumarate at doses of 0.5mg/kg (KF0.5) and 1.0mg/kg (KF1.0) twice daily, respectively. After 8 weeks of immobilization, flexion contractures were measured biomechanically and the posterior joint capsule was harvested for quantification of myofibroblast and mast cell numbers. Results Flexion contractures developed in the ORC group (58 ± 14°) and the severity of contracture was significantly reduced in both groups treated with Ketotifen (KF0.5: 42 ± 17° and KF1.0: 45 ± 10°, p<0.02). Joint capsule myofibroblast and mast cell numbers were significantly increased within the operative contracture group (p<0.001). In both surgical groups treated with Ketotifen, myofibroblast and mast cell numbers were significantly reduced (p<0.001). Conclusions The use of a mast cell stabilizer, Ketotifen was effective in reducing the biomechanical and cellular manifestations of joint capsule fibrosis in a rabbit model of posttraumatic joint contracture. This is suggestive that an inflammatory pathway

  13. Dietary inclusion of diallyl disulfide, yucca powder, calcium fumarate, an extruded linseed product, or medium-chain fatty acids does not affect methane production in lactating dairy cows.

    PubMed

    van Zijderveld, S M; Dijkstra, J; Perdok, H B; Newbold, J R; Gerrits, W J J

    2011-06-01

    Two similar experiments were conducted to assess the effect of diallyl disulfide (DADS), yucca powder (YP), calcium fumarate (CAFU), an extruded linseed product (UNSAT), or a mixture of capric and caprylic acid (MCFA) on methane production, energy balance, and dairy cow performance. In experiment 1, a control diet (CON1) and diets supplemented with 56 mg of DADS/kg of dry matter (DM), 3g of YP/kg of DM, or 25 g of CAFU/kg of DM were evaluated. In experiment 2, an inert saturated fat source in the control diet (CON2) was exchanged isolipidically for an extruded linseed source (100g/kg of DM; UNSAT) or a mixture of C8:0 and C10:0 (MCFA; 20.3g/kg of DM). In experiment 2, a higher inclusion level of DADS (200mg/kg of DM) was also tested. Both experiments were conducted using 40 lactating Holstein-Friesian dairy cows. Cows were adapted to the diet for 12 d and were subsequently kept in respiration chambers for 5 d to evaluate methane production, diet digestibility, energy balance, and animal performance. Feed intake was restricted to avoid confounding effects of possible differences in ad libitum feed intake on methane production. Feed intake was, on average, 17.5 and 16.6 kg of DM/d in experiments 1 and 2, respectively. None of the additives reduced methane production in vivo. Methane production in experiment 1 was 450, 453, 446, and 423 g/d for CON1 and the diets supplemented with DADS, YP, and CAFU, respectively. In experiment 2, methane production was 371, 394, 388, and 386 g/d for CON2 and the diets supplemented with UNSAT, MCFA, and DADS, respectively. No effects of the additives on energy balance or neutral detergent fiber digestibility were observed. The addition of MCFA increased milk fat content (5.38% vs. 4.82% for control) and fat digestibility (78.5% vs. 59.8% for control), but did not affect milk yield or other milk components. The other products did not affect milk yield or composition. Results from these experiments emphasize the need to confirm methane

  14. Transforming growth factor-beta 1 release from oligo(poly(ethylene glycol) fumarate) hydrogels in conditions that model the cartilage wound healing environment.

    PubMed

    Holland, Theresa A; Tessmar, Joerg K V; Tabata, Yasuhiko; Mikos, Antonios G

    2004-01-08

    This research demonstrates that controlled material degradation and transforming growth factor-beta1 (TGF-beta1) release can be achieved by encapsulation of TGF-beta1-loaded gelatin microparticles within the biodegradable polymer oligo(poly(ethylene glycol) fumarate) (OPF), so that these microparticles function as both a digestible porogen and a delivery vehicle. Release studies performed with non-encapsulated microparticles confirmed that at normal physiological pH, TGF-beta1 complexes with acidic gelatin, resulting in slow release rates. At pH 4.0, this complexation no longer persists, and TGF-beta1 release is enhanced. However, by encapsulating TGF-beta1-loaded microparticles in a network of OPF, release at either pH can be diffusionally controlled. For instance, after 28 days of incubation at pH 4.0, final cumulative release from non-encapsulated microparticles crosslinked in 10 and 40 mM glutaraldehyde (GA) was 75.4+/-1.6% and 76.6+/-1.1%, respectively. However, when either microparticle formulation was encapsulated in an OPF hydrogel (noted as OPF-10 mM and OPF-40 mM, respectively), these values were reduced to 44.7+/-14.6% and 47.4+/-4.7%. More interestingly, release studies, in conditions that model the expected collagenase concentration of injured cartilage, demonstrated that by altering the microparticle crosslinking extent and loading within OPF hydrogels, TGF-beta1 release, composite swelling, and polymer loss could be systematically altered. Composites encapsulating less crosslinked microparticles (OPF-10 mM) exhibited 100% release after only 18 days and were completely degraded by day 24 in collagenase-containing phosphate-buffered saline (PBS). Hydrogels encapsulating 40 mM GA microparticles did not exhibit 100% release or polymer loss until day 28. Hydrogels with no microparticle component demonstrated only 79.3+/-9.2% release and 89.2+/-3.4% polymer loss after 28 days in enzyme-containing PBS. Accordingly, these studies confirm that the rate of TGF

  15. Pharmacokinetics and Safety of Single-Dose Tenofovir Disoproxil Fumarate and Emtricitabine in HIV-1-Infected Pregnant Women and Their Infants▿

    PubMed Central

    Flynn, Patricia M.; Mirochnick, Mark; Shapiro, David E.; Bardeguez, Arlene; Rodman, John; Robbins, Brian; Huang, Sharon; Fiscus, Susan A.; Van Rompay, Koen K. A.; Rooney, James F.; Kearney, Brian; Mofenson, Lynne M.; Watts, D. Heather; Jean-Philippe, Patrick; Heckman, Barbara; Thorpe, Edwin; Cotter, Amanda; Purswani, Murli

    2011-01-01

    Tenofovir (TFV) is effective in preventing simian immunodeficiency virus (SIV) transmission in a macaque model, is available as the oral agent tenofovir disoproxil fumarate (TDF), and may be useful in the prevention of mother-to-child transmission of human immunodeficiency virus (HIV). We conducted a trial of TDF and TDF-emtricitabine (FTC) in HIV-infected pregnant women and their infants. Women received a single dose of either 600 mg TDF, 900 mg TDF, or 900 mg TDF-600 mg FTC at labor onset or prior to a cesarean section. Infants received no drug or a single dose of TDF at 4 mg/kg of body weight or of TDF at 4 mg/kg plus FTC at 3 mg/kg as soon as possible after birth. All regimens were safe and well tolerated. Maternal areas under the serum concentration-time curve (AUC) and concentrations at the end of sampling after 24 h (C24) were similar between the two doses of TDF; the maximum concentrations of the drugs in serum (Cmax) and cord blood concentrations were higher in women delivering via cesarean section than in those who delivered vaginally (P = 0.04 and 0.046, respectively). The median ratio of the TFV concentration in cord blood to that in the maternal plasma at delivery was 0.73 (range, 0.26 to 1.95). Without TDF administration, infants had a median TFV concentration of 12 ng/ml 12 h after birth. Following administration of a single dose of TDF at 4 mg/kg, infant TFV concentrations fell below the targeted level, 50 ng/ml, by 24 h postdose. In HIV-infected pregnant women and their infants, 600 mg of TDF is acceptable as a single dose during labor. Low concentrations at birth support infant dosing as soon after birth as possible. Rapidly decreasing TFV levels in infants suggest that multiple or higher doses of TDF will be necessary to maintain concentrations that are effective for viral suppression. PMID:21896911

  16. A randomized, double-blind study of the efficacy and tolerability of extended-release quetiapine fumarate (quetiapine XR) monotherapy in patients with major depressive disorder

    PubMed Central

    Wang, Gang; McIntyre, Alexander; Earley, Willie R; Raines, Shane R; Eriksson, Hans

    2014-01-01

    Objectives To evaluate the efficacy and tolerability of once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in patients with major depressive disorder (MDD). Patients and methods This was a 10-week (8-week active treatment/2-week post-treatment) randomized, double-blind, placebo- and active-controlled study (D1448C00004). Patients received quetiapine XR 150 mg/day, escitalopram 10 mg/day, or placebo; patients with an inadequate response (<20% improvement in Montgomery–Åsberg Depression Rating Scale [MADRS] total score) at week two received double-dose treatment. The primary end point was week eight change from randomization in MADRS total score. Secondary end points included MADRS response (≥50% improvement) and remission (score ≤8); Hamilton Rating Scale for Depression total and item 1; Hamilton Rating Scale for Anxiety total, psychic, and somatic; Clinical Global Impressions – Severity of Illness total; Pittsburgh Sleep Quality Index (PSQI) global; and Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form percentage maximum total scores. Tolerability was assessed throughout. Results A total of 471 patients was randomized. No significant improvements in MADRS total score were observed at week eight (last observation carried forward) with either active treatment (quetiapine XR, −17.21 [P=0.174]; escitalopram, −16.73 [P=0.346]) versus placebo (−15.61). There were no significant differences in secondary end points versus placebo, with the exception of week-eight change in PSQI global score (quetiapine XR, −4.96 [P<0.01] versus placebo, −3.37). Mixed-model repeated-measures analysis of observed-case data suggested that the primary analysis may not be robust. Most commonly reported adverse events included dry mouth, somnolence, and dizziness for quetiapine XR, and headache and nausea for escitalopram. Conclusion In this study, neither quetiapine XR (150/300 mg/day) nor escitalopram (10/20 mg/day) showed

  17. Effects of transforming growth factor beta1 released from biodegradable polymer microparticles on marrow stromal osteoblasts cultured on poly(propylene fumarate) substrates.

    PubMed

    Peter, S J; Lu, L; Kim, D J; Stamatas, G N; Miller, M J; Yaszemski, M J; Mikos, A G

    2000-06-05

    Recombinant human transforming growth factor beta1 (TGF-beta1) was incorporated into microparticles of blends of poly(DL-lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) to create a delivery vehicle for the growth factor. The entrapment efficiency of TGF-beta1 in the microparticles containing 5% PEG was 40.3 +/- 1.2% for a TGF-beta1 loading density of 6.0 ng/1 mg of microparticles. For the same loading, 17.9 +/- 0.6 and 32.1 +/- 2.5% of the loaded TGF-beta1 was released after 1 and 8 days, respectively, followed by a plateau for the remaining 3 weeks. Rat marrow stromal cells showed a dose response to TGF-beta1 released from the microparticles similar to that of added TGF-beta1, indicating the activity of TGF-beta1 was retained during microparticle fabrication and after TGF-beta1 release. An optimal TGF-beta1 dosage of 1.0 ng/mL was determined through a 3-day dose response study for maximal alkaline phosphatase (ALP) activity. The TGF-beta1 released from the microparticles loaded with 6.0 ng TGF-beta1/1 mg of microparticles for the optimal dosage of TGF-beta1 enhanced the proliferation and osteoblastic differentiation of marrow stromal cells cultured on poly(propylene fumarate) substrates. The cells showed significantly increased total cell number, ALP activity, and osteocalcin production with values reaching 138,700 +/- 3300 cells/cm(2), 22.8 +/- 1.5 x 10(-7) micromol/min/cell, and 15.9 +/- 1.5 x 10(-6) ng/cell, respectively, after 21 days as compared to cells cultured under control conditions without TGF-beta1. These results suggest that controlled release of TGF-beta1 from the PLGA/PEG blend microparticles may find applications in modulating cellular response during bone healing at a skeletal defect site.

  18. Effect of drying history on swelling properties and cell attachment to oligo(poly(ethylene glycol) fumarate) hydrogels for guided tissue regeneration applications.

    PubMed

    Temenoff, Johnna S; Steinbis, Emily S; Mikos, Antonios G

    2003-01-01

    In these experiments, the effects of the drying history of hydrogels made from a novel polymer, oligo(poly(ethylene glycol) fumarate) (OPF) with two different poly(ethylene glycol) (PEG) molecular weights (approximately 920 (1K) and 9110 (10K) g/mol), were investigated. The hydrogels were either formed, dried and then swelled, representing what may occur in the case of a pre-formed membrane for guided tissue regeneration, or were formed and swelled immediately, as may occur with an injectable material for such applications. Subsequently, swelling properties, sol fraction and polymer network structure (as indicated by differential scanning calorimetry), as well as attachment of human dermal fibroblasts to these hydrogels at 4 and 24 h was examined. It was found that drying before swelling caused a significant reduction in final fold swelling of OPF hydrogels, regardless of OPF formulation or method of drying (air-dried or vacuum-dried) (e.g. PEG 10K swollen first: 13.94 +/- 0.35 vs. vacuum first: 6.53 +/- 0.12; PEG 1K swollen first: 8.99 +/- 0.47 vs. vacuum first: 2.26 +/- 0.08). This decreased swelling correlated to significantly higher cell attachment (% seeded) to these hydrogels at 24 h (PEG 10K vacuum first: 21.1 +/- 4.7% vs. swollen first: 7.1 +/- 5.5%; PEG 1K vacuum first: 58.2 +/- 2% vs. swollen first: 7.4 +/- 2.2%). LIVE/DEAD staining followed by microscopic analysis revealed attached cells were viable, yet rounded, and that, in the case of the PEG 1K dried-first samples, undulations in the surface visible in the hydrated state may have affected cell adhesion. Regardless of treatment, all hydrogels showed significantly less cell attachment than the tissue culture polystyrene control after 24 h (104.9 +/- 4.4%). These results suggest that, by altering the PEG molecular weight used in synthesis, OPF hydrogels may be tailored to produce desired swelling properties and reduce non-specific cell adhesion for either injectable or pre-formed applications, thus

  19. Real-World Assessment of Renal and Bone Safety among Patients with HIV Infection Exposed to Tenofovir Disoproxil Fumarate-Containing Single-Tablet Regimens

    PubMed Central

    Nkhoma, Ella T.; Rosenblatt, Lisa; Myers, Joel; Villasis-Keever, Angelina; Coumbis, John

    2016-01-01

    Objectives Tenofovir disoproxil fumarate (TDF)-containing antiretroviral regimens have been associated with an increased incidence of renal and bone adverse outcomes. Here, we estimated the real-world incidence of renal and bone adverse outcomes among patients with HIV infection receiving different TDF-containing single-tablet regimens (STRs). Methods This cohort study used US health insurance data spanning the years 2008–2014. We identified HIV-infected patients aged ≥18 years (all HIV patients) and those with ≥6 months of continuous enrollment prior to initiating efavirenz/emtricitabine/TDF (EFV/FTC/TDF), rilpivirine/FTC/TDF (RPV/FTC/TDF) or elvitegravir/cobicistat/FTC/TDF (EVG/COBI/FTC/TDF). Renal adverse outcomes were identified using renal International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes. Bone adverse outcomes were identified using ICD-9-CM diagnosis codes for fracture. Incidence rates (IRs) and associated 95% confidence intervals (CIs) were estimated assuming a Poisson distribution, and outcomes between STRs were compared using IR ratios (IRRs) and IR differences (IRDs). Results We identified 9876 and 10,383 eligible patients for the renal and fracture analyses, respectively. Observed IRs for renal adverse outcomes were 9.7, 10.5, 13.6, and 18.0 per 1000 person-years among those receiving EFV/FTC/TDF, RPV/FTC/TDF, or EVG/COBI/FTC/TDF, or all HIV patients, respectively. Corresponding values for IRs of fracture were 3.4, 3.6, 7.2, and 4.4 per 1000 person-years, respectively. Renal adverse outcomes with EFV/FTC/TDF were significantly less frequent than with EVG/COBI/FTC/TDF (IRD −3.96; 95% CI: −7.31, −1.06). No IRR differences were identified for the renal analysis. Fractures with EFV/FTC/TDF were significantly less frequent than with EVG/COBI/FTC/TDF (IRR 0.47; 95% CI: 0.27, 0.81 and IRD −3.85; 95% CI: −5.02, −2.78). Conclusions In this large real-world database, observed IRs for renal

  20. Cloning and sequence of cymA, a gene encoding a tetraheme cytochrome c required for reduction of iron(III), fumarate, and nitrate by Shewanella putrefaciens MR-1.

    PubMed Central

    Myers, C R; Myers, J M

    1997-01-01

    The cymA gene, which encodes a tetraheme cytochrome c, was cloned from Shewanella putrefaciens MR-1. This gene complemented a mutant which had a TnphoA insertion in cymA and which was deficient in the respiratory reduction of iron(III), nitrate, fumarate, and manganese(IV). The 561-bp nucleotide sequence of cymA encodes a protein of 187 amino acids with a predicted molecular mass of 20.8 kDa. No N-terminal signal sequence was readily apparent; consistent with this, a cytochrome with a size of 21 kDa was detected in the wild type but was absent in the insertional mutant. The cymA gene is transcribed into an mRNA; the major transcript was approximately 790 bases, suggesting that it is not part of a multicistronic operon. This RNA transcript was not detected in the cymA mutant. The CymA protein was found in the cytoplasmic membrane and soluble fraction of MR-1, and it shares partial amino acid sequence homology with multiheme c-type cytochromes from other bacteria. These cytochromes are ostensibly involved in the transfer of electrons from the cytoplasmic membrane to acceptors in the periplasm. The localization of the fumarate and iron(III) reductases to the periplasm and outer membrane of MR-1, respectively, suggests the possibility of a similar electron transfer role for CymA. PMID:9023196

  1. Combination of accelerated solvent extraction and vortex-assisted liquid-liquid microextraction for the determination of dimethyl fumarate in textiles and leathers by gas chromatography-mass spectrometry.

    PubMed

    Lu, Yang; Zhu, Yan

    2014-02-01

    A simple and environmentally friendly sample preparation procedure coupled with gas chromatography-mass spectrometry was developed to assay dimethyl fumarate in textiles and leathers. The sample preparation procedure involved an accelerated solvent extraction (ASE) using water as the extract solvent, followed by the extraction and concentration of dimethyl fumarate from the aqueous solution using vortex-assisted liquid-liquid microextraction (VALLME). The parameters affecting the ASE and VALLME were optimized to achieve the maximum extraction efficiency, and the performance of the developed method was evaluated. Good linearity was observed over the range assayed (0.01-1mg/kg) with a regression coefficient of 0.998. The limit of detection and enrichment factor for the VALLME step were 0.001 mg/kg and 53, respectively. The intra- and inter-day precision were below 8.9%, and the recovery was approximately 84-103%. The as-developed method was successfully applied to textiles and leather samples.

  2. Spectrophotometric simultaneous determination of Tenofovir disoproxil fumarate and Emtricitabine in combined tablet dosage form by ratio derivative, first order derivative and absorbance corrected methods and its application to dissolution study.

    PubMed

    Choudhari, Vishnu P; Ingale, Snehal; Gite, Sacchidanand R; Tajane, Dipali D; Modak, Vikram G; Ambekar, Archana

    2011-01-01

    Three simple, economical, precise, and accurate methods are described for the simultaneous determination of Tenofovir disoproxil fumarate (TE) and Emtricitabine (EM) in combined tablet dosage form. The first method is ratio derivative spectra, second is first-order derivative spectrophotometry and third is absorption corrected method. The amplitudes at 271.07 and 302.17 nm in the ratio derivative method, 224.38 and 306.88 nm in the first order derivative method were selected to determine Tenofovir disoproxil fumarate (TE) and Emtricitabine (EM), respectively, in combined formulation. Beer's law is obeyed in the concentration range of 3-21 μg/ml for TE and 2-14 μg/ml for EM for first two methods and range for third method was 6-30 μg/ml of TE and 4-20 μg/ml of EM. The percent assay for commercial formulation was found to be in the range 98.91%-101.72% for both the analytes by the proposed three methods. Absorption corrected method was successfully applied to carry out dissolution study of commercial tablet formulation by using USP II dissolution test apparatus. The methods were validated with respect to linearity, precision, and accuracy. Recoveries by proposed methods were found in the range of 99.06 %-101.34 % for both the analytes.

  3. Efficiency of sodium hypochlorite, fumaric acid, and mild heat in killing native microflora and Escherichia coli O157:H7, Salmonella typhimurium DT104, and Staphylococcus aureus attached to fresh-cut lettuce.

    PubMed

    Kondo, Nozomi; Murata, Masatsune; Isshiki, Kenji

    2006-02-01

    The effect of the disinfectant sodium hypochlorite (NaClO), with or without mild heat (50 degrees C) and fumaric acid, on native bacteria and the foodborne pathogens Staphylococcus aureus, Escherichia coli O157:H7, and Salmonella Typhimurium DT104 attached to iceberg lettuce leaves was examined. The retail lettuce examined consistently harbored 6 to 7 log CFU/g of native bacteria throughout the study period. Inner leaves supported 1 to 2 log CFU/g fewer bacteria than outer leaves. About 70% of the native bacterial flora was removed by washing five times with 0.85% NaCl. S. aureus, E. coli, and Salmonella allowed to attach to lettuce leaves for 5 min were more easily removed by washing than when allowed to attach for 1 h or 2 days, with more S. aureus being removed than E. coli or Salmonella Typhimurium. An increase of time for attachment of pathogens from 5 min to 2 days leads to decreased efficiency of the washing and sanitizing treatment. Treatment with fumaric acid (50 mM for 10 min at room temperature) was the most effective, although it caused browning of the lettuce, with up to a 2-log reduction observed. The combination of 200 ppm of sodium hypochlorite and mild heat treatment at 50 degrees C for 1 min reduced the pathogen populations by 94 to 98% (1.2- to 1.7-log reduction) without increasing browning.

  4. Provisional CDC guidelines for the use and safety monitoring of bedaquiline fumarate (Sirturo) for the treatment of multidrug-resistant tuberculosis.

    PubMed

    2013-10-25

    Multidrug-resistant tuberculosis (MDR TB) is caused by Mycobacterium tuberculosis that is resistant to at least isoniazid and rifampin, the two most effective of the four first-line TB drugs (the other two drugs being ethambutol and pyrazinamide). MDR TB includes the subcategory of extensively drug-resistant TB (XDR TB), which is MDR TB with additional resistance to any fluoroquinolone and to at least one of three injectable anti-TB drugs (i.e., kanamycin, capreomycin, or amikacin). MDR TB is difficult to cure, requiring 18-24 months of treatment after sputum culture conversion with a regimen that consists of four to six medications with toxic side effects, and carries a mortality risk greater than that of drug-susceptible TB. Bedaquiline fumarate (Sirturo or bedaquiline) is an oral diarylquinoline. On December 28, 2012, on the basis of data from two Phase IIb trials (i.e., well-controlled trials to evaluate the efficacy and safety of drugs in patients with a disease or condition to be treated, diagnosed, or prevented), the Food and Drug Administration (FDA) approved use of bedaquiline under the provisions of the accelerated approval regulations for "serious or life-threatening illnesses" (21CFR314.500) (Cox EM. FDA accelerated approval letter to Janssen Research and Development. Available at http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/204384Orig1s000ltr.pdf). This report provides provisional CDC guidelines for FDA-approved and unapproved, or off-label, uses of bedaquiline in certain populations, such as children, pregnant women, or persons with extrapulmonary MDR TB who were not included in the clinical trials for the drug. CDC's Division of TB Elimination developed these guidelines on the basis of expert opinion informed by data from systematic reviews and literature searches. This approach is different from the statutory standards that FDA uses when approving drugs and drug labeling. These guidelines are intended for health-care professionals

  5. Virological Response to Tenofovir Disoproxil Fumarate in HIV-Positive Patients with Lamivudine-Resistant Hepatitis B Virus Coinfection in an Area Hyperendemic for Hepatitis B Virus Infection

    PubMed Central

    Huang, Yu-Shan; Chang, Sui-Yuan; Sheng, Wang-Huei; Sun, Hsin-Yun; Lee, Kuan-Yeh; Chuang, Yu-Chung; Su, Yi-Ching; Liu, Wen-Chun; Hung, Chien-Ching; Chang, Shan-Chwen

    2016-01-01

    Background Sequential addition of tenofovir disoproxil fumarate (TDF) is often needed for patients coinfected with HIV and hepatitis B virus (HBV) who develop HBV resistance to lamivudine after combination antiretroviral therapy (cART) containing only lamivudine for HBV. We aimed to assess the virological response of HBV to add-on TDF in patients coinfected with lamivudine-resistant HBV. Methods Between November 2010 and December 2014, 33 HIV/HBV-coinfected patients with lamivudine-resistant HBV and 56 with lamivudine-susceptible HBV were prospectively included. TDF plus lamivudine was used to substitute zidovudine or abacavir plus lamivudine contained in cART in patients with lamivudine-resistant HBV infection, while patients with lamivudine-susceptible HBV infection received TDF plus lamivudine as backbone of cART. Serial determinations of plasma HBV DNA load, HBV serologic markers, and liver and renal functions were performed after initiation of TDF-containing cART. Results Of 89 patients included, 38.6% tested positive for HBV envelope antigen (HBeAg) at baseline. The plasma HBV DNA level at enrollment of lamivudine-resistant and lamivudine-susceptible group were 6.1 ± 2.2 log10 and 6.0 ± 2.2 log10 copies/mL, respectively (p = 0.895). The cumulative percentage of HBV viral suppression in lamivudine-resistant and lamivudine-susceptible group was 81.8% and 91.1% at 48 weeks, respectively (p = 0.317), which increased to 86.7% and 96.2% at 96 weeks, respectively (p = 0.185). At 48 weeks, 11 patients testing HBeAg-positive at baseline failed to achieve viral suppression. In multivariate analysis, the only factor associated with failure to achieve viral suppression at 48 weeks was higher HBV DNA load at baseline (odds ratio, per 1-log10 copies/mL increase, 1.861; 95% CI, 1.204–2.878). At 48 weeks, HBeAg seroconversion was observed in 5 patients (1 in the lamivudine-resistant group and 4 in the lamivudine-susceptible group; p = 0.166). During the study period, HBs

  6. Brief Report: A Randomized, Double-Blind Comparison of Tenofovir Alafenamide Versus Tenofovir Disoproxil Fumarate, Each Coformulated With Elvitegravir, Cobicistat, and Emtricitabine for Initial HIV-1 Treatment: Week 96 Results.

    PubMed

    Wohl, David; Oka, Shinichi; Clumeck, Nathan; Clarke, Amanda; Brinson, Cynthia; Stephens, Jeffrey; Tashima, Karen; Arribas, Jose R; Rashbaum, Bruce; Cheret, Antoine; Brunetta, Jason; Mussini, Cristina; Tebas, Pablo; Sax, Paul E; Cheng, Andrew; Zhong, Lijie; Callebaut, Christian; Das, Moupali; Fordyce, Marshall

    2016-05-01

    In 2 double-blinded Phase 3 trials, 1733 antiretroviral-naive participants were randomized to tenofovir alafenamide (TAF), a tenofovir prodrug versus tenofovir disoproxil fumarate (TDF), each coformulated with elvitegravir/cobicistat/emtricitabine (E/C/F). At 96 weeks, 86.6% in the TAF arm and 85.2% in the TDF arm had HIV-1 RNA <50 c/mL [difference 1.5%; (95% CI: -1.8% to 4.8%)]. With TAF, there are smaller declines in bone mineral density and more favorable changes in proteinuria, albuminuria, and tubular proteinuria, and no cases of proximal tubulopathy compared with 2 for TDF. These longer-term data support E/C/F/TAF as a safe, well-tolerated, and durable regimen for initial HIV-1 treatment.

  7. Preparation of yolk-shell structured copper oxide@silica oxide spheres and their application in high performance electrochemical sensing of Formoterol fumarate residues in swine feed and tissues.

    PubMed

    Gan, Tian; Shi, Zhaoxia; Hu, Danyang; Lv, Zhen; Sun, Junyong; Liu, Yanming

    2016-01-01

    In this paper, we report a facile route to synthesize yolk-shell structured copper oxide@silica oxide (CuO@SiO2) spheres and their application to construct an electrochemical Formoterol fumarate (FF) sensor. The CuO@SiO2 was characterized by means of Fourier transform infrared spectroscopy, X-ray powder diffraction, Raman spectroscopy, scanning electron microscopy, and transmission electron microscopy. Further, FF was electrocatalytically oxidized at the CuO@SiO2 film modified glassy carbon electrode (GCE), which led to a sensitive determination of FF. The oxidation current of FF was linear with concentration in the range of 0.030-10 μM and the detection limit was found to be 5.0 nM (S/N = 3). The observed analytical parameters such as wide linear range, low detection limit and short response time were superior to previously reported FF sensors. Finally, it was demonstrated that the proposed sensor could be used for the selective determination of FF present in swine feed and tissues.

  8. A Randomized, Double-Blind Comparison of Tenofovir Alafenamide (TAF) vs. Tenofovir Disoproxil fumarate (TDF), Each Coformulated with Elvitegravir, Cobicistat, and Emtricitabine (E/C/F) for Initial HIV-1 Treatment: Week 144 Results.

    PubMed

    Arribas, José R; Thompson, Melanie; Sax, Paul E; Haas, Bernhard; McDonald, Cheryl; Wohl, David A; DeJesus, Edwin; Clarke, Amanda E; Guo, Susan; Wang, Hui; Callebaut, Christian; Plummer, Andrew; Cheng, Andrew; Das, Moupali; McCallister, Scott

    2017-03-09

    In two double-blind Phase 3 trials, 1733 antiretroviral-naïve adults were randomized to tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF), each coformulated with elvitegravir/cobicistat/emtricitabine (E/C/F). At 144 weeks, TAF was superior to TDF in virologic efficacy, with 84.2% vs. 80.0% having HIV-1 RNA <50 copies/mL (difference 4.2%; 95%CI 0.6% to 7.8%). TAF had less impact than TDF on bone mineral density and renal biomarkers. No participants on TAF had renal-related discontinuations vs 12 on TDF (P<0.001), with no cases of proximal tubulopathy for TAF vs 4 for TDF. There were greater increases in lipids with TAF vs. TDF, with no difference in the total cholesterol to high density lipoprotein ratio. For initial HIV therapy, E/C/F/TAF is superior to E/C/F/TDF in efficacy and bone and renal safety.

  9. Efficacy and Safety of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate in Asian Subjects with Human Immunodeficiency Virus 1 Infection: A Sub-Analysis of Phase 3 Clinical Trials.

    PubMed

    Choi, Jun Yong; Sungkanuparph, Somnuek; Anekthananon, Thanomsak; Sax, Paul; DeJesus, Edwin; Edelstein, Howard; Nelson, Mark; DeMorin, Jennifer; Liu, Hui C; Swamy, Raji; Bahn, Joonwoo; Hwang, Sunjin; Yang, Sang Youn; Ng, Christopher; Piontkowsky, David

    2016-09-01

    The efficacy and safety of a single tablet regimen (STR) of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF) were analyzed in Phase 3 clinical trials in antiretroviral therapy (ART)-naïve and ART-experienced Asian subjects infected with human immunodeficiency virus (HIV)-1. Studies GS-US-236-102 and GS-US-236-103 were randomized, double-blind, placebo-controlled, 144-week studies conducted in ART-naïve subjects, comparing E/C/F/TDF versus efavirenz (EFV)/F/TDF or ritonavir-boosted atazanavir (ATV+RTV) plus emtricitabine/tenofovir DF (F/TDF), respectively. Studies GS-US-236-115 and GS-US-236-121 were randomized, open-label, 96-week long conducted in ART-experienced subjects, who switched to E/C/F/TDF from ritonavir-boosted protease inhibitors (PI+RTV)+F/TDF, or non-nucleoside reverse transcriptase inhibitors (NNRTI)+F/TDF regimens. The E/C/F/TDF appeared to have sustained efficacy and safety and was well tolerated in the small number of ART-naïve and ART-experienced Asian subjects.

  10. Development of an injectable, in situ crosslinkable, degradable polymeric carrier for osteogenic cell populations. Part 2. Viability of encapsulated marrow stromal osteoblasts cultured on crosslinking poly(propylene fumarate).

    PubMed

    Payne, Richard G; McGonigle, Joseph S; Yaszemski, Michael J; Yasko, Alan W; Mikos, Antonios G

    2002-11-01

    The effect of temporary encapsulation of rat marrow stromal osteoblasts in crosslinked gelatin microparticles on cell viability and proliferation was investigated in this study for microparticles placed on a crosslinking poly(propylene fumarate) (PPF) composite over a 7 day time period. Encapsulated cells were seeded on crosslinking PPF composites at times up to 10 min following initiation of the crosslinking reaction, and also on fully crosslinked PPF composites and tissue culture polystyrene controls, with a cell seeding density of 5.3 x 10(4) cells/cm2. The crosslinked PPF composite exhibited an average gel point of 10.3 min and an average maximum crosslinking temperature of 47.5 degrees C. Cell viability and proliferation were assessed by DNA and 3H-thymidine assays and the results were compared with those for nonencapsulated cells. The results showed that the addition time of cells to a crosslinking PPF composite had a large effect on cell viability and proliferation for both encapsulated and nonencapsulated cells with more surviving cells added at later time points. Most importantly, the temporary encapsulation of cells significantly enhanced cell viability at earlier time points. The data indicate that the presence of gelatin microparticles does not affect the crosslinking of a PPF composite. They further suggest that the temporary encapsulation of cells in crosslinked gelatin microparticles may preserve the viability of cells contained in an actively crosslinking PPF composite used as an injectable polymeric scaffold serving also as a carrier for osteogenic cell populations.

  11. Adhesion and migration of marrow-derived osteoblasts on injectable in situ crosslinkable poly(propylene fumarate-co-ethylene glycol)-based hydrogels with a covalently linked RGDS peptide.

    PubMed

    Behravesh, Esfandiar; Zygourakis, Kyriacos; Mikos, Antonios G

    2003-05-01

    Marrow-derived osteoblasts were cultured on poly(propylene fumarate-co-ethylene glycol) (P(PF-co-EG)) based hydrogels modified in bulk with a covalently linked RGDS model peptide. A poly(ethylene glycol) spacer arm was utilized to covalently link the peptide to the hydrogel. Three P(PF-co-EG) block copolymers were synthesized with varying poly(ethylene glycol) block lengths relative to poly(ethylene glycol) spacer arm. A poly(ethylene glycol) block length of nominal molecular weight 2000 and spacer arm of nominal molecular weight 3400 were found to reduce nonspecific cell adhesion and show RGDS concentration dependent marrow-derived osteoblast adhesion. A concentration of 100 nmol/mL RGDS was sufficient to promote adhesion of 84 +/- 17% of the initial seeded marrow-derived osteoblasts compared with 9 +/- 1% for the unmodified hydrogel after 12 h. Cell spreading was quantified as a method for evaluating adhesivity of cells to the hydrogel. A megacolony migration assay was utilized to assess the migration characteristics of the marrow-derived osteoblasts on RGDS modified hydrogels. Marrow-stromal osteoblasts migration was greater on hydrogels modified with 100 nmol/mL linked RGDS when compared with hydrogels modified with 1000 nmol/mL linked RGDS, while proliferation was not affected. These P(PF-co-EG) hydrogels modified in the bulk with RGDS peptide are potential candidates as in situ forming scaffolds for bone tissue engineering applications.

  12. Development of an injectable, in situ crosslinkable, degradable polymeric carrier for osteogenic cell populations. Part 3. Proliferation and differentiation of encapsulated marrow stromal osteoblasts cultured on crosslinking poly(propylene fumarate).

    PubMed

    Payne, Richard G; McGonigle, Joseph S; Yaszemski, Michael J; Yasko, Alan W; Mikos, Antonios G

    2002-11-01

    This study investigated the effect of temporary encapsulation of rat marrow stromal osteoblasts in crosslinked gelatin microparticles on long-term cell proliferation and phenotypic expression for microparticles placed on crosslinking poly(propylene fumarate) (PPF) composites using N-vinyl pyrollidinone (N-VP) as a crosslinking agent over a 28 day time period. Encapsulated cells (ECs) were seeded on actively crosslinking PPF composites 6 min after initiation of the crosslinking reaction, and also on fully crosslinked PPF composites and tissue culture polystyrene controls, with a cell seeding density of 5.3 x 10(4) cells/cm2. Composites prepared with three PPF:N-VP ratios were examined: 1:0.5, 1:0.1, and 1:0.05. Samples were taken at specified time points and analyzed by DNA, 3H-thymidine, alkaline phosphatase, osteocalcin, and calcium assays, and the measurements were compared with those for nonencapsulated cells (NCs). The results showed that encapsulated marrow stromal cells exhibited much higher viability, proliferation, and phenotypic expression when placed on crosslinking PPF composites than NCs. The assay results for ECs on crosslinking PPF composites were also similar to those on fully crosslinked PPF composites. The data further demonstrated that the PPF:N-VP ratio had no effect on the viability, proliferation, or phenotypic expression of the ECs. These results suggest that cells encapsulated in crosslinked gelatin microparticles may be part of an injectable, in situ crosslinkable, biodegradable polymeric composite for bone tissue engineering applications.

  13. Poly(propylene fumarate) and poly(DL-lactic-co-glycolic acid) as scaffold materials for solid and foam-coated composite tissue-engineered constructs for cranial reconstruction.

    PubMed

    Dean, David; Topham, Neal S; Meneghetti, S Cristina; Wolfe, Michael S; Jepsen, Karl; He, Shulin; Chen, Jeffrey E-K; Fisher, John P; Cooke, Malcolm; Rimnac, Clare; Mikos, Antonios G

    2003-06-01

    This pilot study investigates the osseointegration of four types of critical-size (1.5-cm diameter) rabbit cranial defect (n = 35) bone graft scaffolds. The first is a solid poly(propylene fumarate)/beta-tricalcium phosphate(PPF/beta-TCP) disk; the three remaining constructs contain a PPF/beta-TCP core coated with a 1-mm resorptive porous foam layer of PPF or PLGA [poly(DL-lactic-co-glycolic acid)], and bone marrow. Animals were killed at 6, 12, and 20 weeks. There was no evidence of a foreign body inflammatory response at any time during the study. Histomorphometric analyses of new bone formation sorted lineal and areal measures of new bone into three cranial layers (i.e., external, middle, and internal). Statistical analyses revealed significantly more bone in the PLGA foam-coated constructs than in the PPF foam-coated constructs (p < 0.03). No implant fixation was used; there is no strength at time 0. Twenty percent of all explants were tested for incorporation strength with a one-point "push-in" test, and failure ranged from 8.3 to 34.7 lb. The results of this study support the use of PPF as a biocompatible material that provides both a structural and osteogenic substrate for the repair of cranial defects.

  14. An understanding of modified release matrix tablets behavior during drug dissolution as the key for prediction of pharmaceutical product performance - case study of multimodal characterization of quetiapine fumarate tablets.

    PubMed

    Kulinowski, Piotr; Woyna-Orlewicz, Krzysztof; Rappen, Gerd-Martin; Haznar-Garbacz, Dorota; Węglarz, Władysław P; Dorożyński, Przemysław P

    2015-04-30

    Motivation for the study was the lack of dedicated and effective research and development (R&D) in vitro methods for oral, generic, modified release formulations. The purpose of the research was to assess multimodal in vitro methodology for further bioequivalence study risk minimization. Principal results of the study are as follows: (i) Pharmaceutically equivalent quetiapine fumarate extended release dosage form of Seroquel XR was developed using a quality by design/design of experiment (QbD/DoE) paradigm. (ii) The developed formulation was then compared with originator using X-ray microtomography, magnetic resonance imaging and texture analysis. Despite similarity in terms of compendial dissolution test, developed and original dosage forms differed in micro/meso structure and consequently in mechanical properties. (iii) These differences were found to be the key factors of failure of biorelevant dissolution test using the stress dissolution apparatus. Major conclusions are as follows: (i) Imaging methods allow to assess internal features of the hydrating extended release matrix and together with the stress dissolution test allow to rationalize the design of generic formulations at the in vitro level. (ii) Technological impact on formulation properties e.g., on pore formation in hydrating matrices cannot be overlooked when designing modified release dosage forms.

  15. Tenofovir disoproxil fumarate therapy for chronic hepatitis B in human immunodeficiency virus/hepatitis B virus-coinfected individuals for whom interferon-alpha and lamivudine therapy have failed.

    PubMed

    Ristig, Maria B; Crippin, Jeffrey; Aberg, Judith A; Powderly, William G; Lisker-Melman, Mauricio; Kessels, Lisa; Tebas, Pablo

    2002-12-15

    A significant proportion of human immunodeficiency virus (HIV) infected patients are coinfected with hepatitis B virus (HBV). Currently available treatments for chronic hepatitis B (interferon [IFN]-alpha and lamivudine [3TC]) have limited long-term utility because of side effects or of the development of resistance. Tenofovir disoproxil fumarate (TDF) is a nucleotide analog with excellent activity in vitro against HBV, which is also active against 3TC-resistant HBV variants. In this 24-week pilot study, the anti-HBV activity of TDF was prospectively evaluated in a cohort of 6 HIV coinfected subjects for whom 3TC and IFN therapy had previously failed. At baseline, all patients were taking 3TC or FTC and were hepatitis B surface antigen and hepatitis B e antigen positive; 4 had cirrhosis. Baseline HBV load was 7.95 log(10) copies/mL. By weeks 12 and 24, HBV load had decreased by 3.1 log(10) copies/mL and 4.3 log(10) copies/mL, respectively. There was a transient increase of transaminases after the initiation of treatment. No patient developed HBe antibodies. TDF is a very promising drug for the treatment of chronic hepatitis B in HIV-infected individuals.

  16. Tenofovir disoproxil fumarate monotherapy for nucleos(t)ide-naïve chronic hepatitis B patients in Korea: data from the clinical practice setting in a single-center cohort

    PubMed Central

    Ahn, Sung Soo; Chon, Young Eun; Kim, Beom Kyung; Kim, Seung Up; Kim, Do Young; Ahn, Sang Hoon; Han, Kwang-Hyub

    2014-01-01

    Background/Aims This study assessed the antiviral efficacy and safety of tenofovir disoproxil fumarate (TDF) for up to 12 months in Korean treatment-naïve chronic hepatitis B (CHB) patients. Methods A total of 411 treatment-naïve CHB patients who had been treated with TDF for at least 3 months (median 5.6) were consecutively enrolled. Clinical, biochemical, virological parameters and treatment adherence were routinely assessed every 3 months. Results The median age was 51.3 years, 63.0% of the patients were male, 49.6% were HBeAg (+), and 210 patients had liver cirrhosis. The median baseline HBV DNA was 5.98 (SD 1.68) log10 IU/mL. Among the patients completing week 48, 83.3% had a complete virologic response (CVR, <12 IU/mL by HBV PCR assay), and 88.2% had normalized levels of alanine aminotransferase (ALT). The cumulative probabilities of CVR at 3, 6, 9 and 12 months were 22.8%, 53.1%, 69.3% and 85.0%. During the follow-up period, 9.8% patients achieved HBeAg loss and 7.8% patients achieved HBeAg seroconversion. There was no virological breakthrough after initiating TDF. The most common TDF-related adverse event was gastrointestinal upset, and three patients discontinued TDF therapy. However, no serious life-threatening side effect was noted. Conclusions In a clinical practice setting, TDF was safe and highly effective when administered for 12 months to Korean treatment-naïve CHB patients. PMID:25320729

  17. Association of Higher Plasma Vitamin D Binding Protein and Lower Free Calcitriol Levels with Tenofovir Disoproxil Fumarate Use and Plasma and Intracellular Tenofovir Pharmacokinetics: Cause of a Functional Vitamin D Deficiency?

    PubMed Central

    Kiser, Jennifer J.; Stephensen, Charles B.; Hazra, Rohan; Flynn, Patricia M.; Wilson, Craig M.; Rutledge, Brandy; Bethel, James; Pan, Cynthia G.; Woodhouse, Leslie R.; Van Loan, Marta D.; Liu, Nancy; Lujan-Zilbermann, Jorge; Baker, Alyne; Kapogiannis, Bill G.; Gordon, Catherine M.

    2013-01-01

    Tenofovir disoproxil fumarate (TDF) causes bone, endocrine, and renal changes by an unknown mechanism(s). Data are limited on tenofovir pharmacokinetics and these effects. Using baseline data from a multicenter study of HIV-infected youth on stable treatment with regimens containing TDF (n = 118) or lacking TDF (n = 85), we measured cross-sectional associations of TDF use with markers of renal function, vitamin D-calcium-parathyroid hormone balance, phosphate metabolism (tubular reabsorption of phosphate and fibroblast growth factor 23 [FGF23]), and bone turnover. Pharmacokinetic-pharmacodynamic associations with plasma tenofovir and intracellular tenofovir diphosphate concentrations were explored among those receiving TDF. The mean age was 20.9 (standard deviation [SD], 2.0) years; 63% were male; and 52% were African American. Compared to the no-TDF group, the TDF group showed lower mean estimated glomerular filtration rates and tubular reabsorption of phosphate, as well as higher parathyroid hormone and 1,25-dihydroxy vitamin D [1,25-OH(2)D] levels. The highest quintile of plasma tenofovir concentrations was associated with higher vitamin D binding protein, lower free 1,25-OH(2)D, higher 25-OH vitamin D, and higher serum calcium. The highest quintile of intracellular tenofovir diphosphate concentration was associated with lower FGF23. Higher plasma tenofovir concentrations were associated with higher vitamin D binding protein and lower free 1,25-OH(2)D, suggesting a functional vitamin D deficiency explaining TDF-associated increased parathyroid hormone. The finding of lower FGF23 accompanying higher intracellular tenofovir diphosphate suggests that different mechanisms mediate TDF-associated changes in phosphate handling. Separate pharmacokinetic properties may be associated with distinct TDF toxicities: tenofovir with parathyroid hormone and altered calcium balance and tenofovir diphosphate with hypophosphatemia and FGF23 regulation. (The clinical trial

  18. Efficacy of extended release quetiapine fumarate monotherapy in elderly patients with major depressive disorder: secondary analyses in subgroups of patients according to baseline anxiety, sleep disturbance, and pain levels.

    PubMed

    Montgomery, Stuart A; Altamura, A Carlo; Katila, Heikki; Datto, Catherine; Szamosi, Johan; Eriksson, Hans

    2014-03-01

    This study evaluated extended release quetiapine fumarate (quetiapine XR) monotherapy in elderly patients with major depressive disorder (MDD) according to baseline levels of anxiety, sleep disturbance, and pain. Post-hoc analyses of data from an 11-week (9-week randomized-treatment, 2-week post-treatment phase), double-blind, placebo-controlled study of quetiapine XR (50-300 mg/day) monotherapy in elderly (≥66 years) patients (n=338) with MDD were carried out. Outcomes included randomization to week 9 change in Montgomery Åsberg Depression Rating Scale (MADRS) score and week 9 response (≥50% MADRS score reduction) rates. Post-hoc analyses were carried out to assess subgroups of patients with MDD according to baseline levels in terms of the following: higher or lower anxiety (Hamilton Rating Scale for Anxiety total score≥20 or < 20, respectively); high or low sleep disturbance [Hamilton Rating Scale for Depression sleep disturbance factor (items 4+5+6) score≥5 or <5, respectively]; and pain visual analog scale total score 40 mm or higher or less than 40 mm. At week 9, quetiapine XR reduced the MADRS total score compared with placebo in the higher anxiety (least squares mean change -17.8 vs. -8.5; P<0.001) and lower anxiety (-14.8 vs. -8.8; P<0.001) subgroups. MADRS total score was also reduced with quetiapine XR compared with placebo in the high (-17.6 vs. -8.7; P<0.001) and low (-14.4 vs. -9.2; P<0.001) sleep disturbance subgroups, as well as in the pain visual analog scale subgroups [≥40 mm (-16.6 vs. -8.9; P<0.001) and <40 mm (-15.7 vs. -8.7; P<0.001)]. Quetiapine XR response rates were higher than those of placebo in all subgroups analyzed. In this study, quetiapine XR (50-300 mg/day) monotherapy was shown to be effective against depressive symptoms in elderly patients with MDD, irrespective of baseline levels of anxiety, sleep disturbance, and pain.

  19. Effects of mometasone furoate/formoterol fumarate fixed-dose combination formulation on chronic obstructive pulmonary disease (COPD): results from a 52-week Phase III trial in subjects with moderate-to-very severe COPD

    PubMed Central

    Doherty, Dennis E; Tashkin, Donald P; Kerwin, Edward; Knorr, Barbara A; Shekar, Tulin; Banerjee, Sibabrata; Staudinger, Heribert

    2012-01-01

    Rationale The purpose of this study was to investigate the clinical efficacy and safety of a fixed-dose combination of mometasone furoate/formoterol fumarate (MF/F) administered via a metered-dose inhaler in subjects with moderate-to-very severe chronic obstructive pulmonary disease (COPD). Methods This multicenter, double-blind, placebo-controlled trial had a 26-week treatment period and a 26-week safety extension. Subjects (n = 1196), at least 40 years old, were current or ex-smokers randomized to twice-daily inhaled MF/F 400/10 μg, MF/F 200/10 μg, MF 400 μg, F 10 μg, or placebo. The trial’s co-primary endpoints were mean changes from baseline, as area under the curve (AUC), in forced expiratory volume (FEV1) over 0–12 hours (AUC0–12 h FEV1) with MF/F versus MF, and in morning (AM) pre-dose (trough) FEV1 with MF/F versus F after 13 weeks of treatment. Key secondary endpoints were the effects of MF/F on respiratory health status using the Saint George’s Respiratory Questionnaire (SGRQ), symptom-free nights, partly stable COPD at 26 weeks, and time to first COPD exacerbation. Results The largest improvements in AUC0–12 h FEV1 were observed with MF/F 400/10 μg and MF/F 200/10 μg. Serial spirometry results demonstrated that bronchodilator effects with MF/F occurred rapidly (within 5 minutes), persisted for 12 hours after dosing, and were sustained over the 26-week treatment period. Similar findings were observed for AM pre-dose FEV1, for which effects were further investigated, excluding subjects whose AM FEV1 data were incorrectly collected after 2 days from the last dose of study treatment. Improvements in SGRQ scores surpassed the minimum clinically important difference of more than four units with both MF/F treatments. At 26 weeks, no notable between-treatment differences in the occurrence and nature of adverse events (AEs) were reported. No unexpected AEs were observed. Overall, 90 subjects reported AEs considered to be treatment-related, the

  20. Rilpivirine versus efavirenz with emtricitabine/tenofovir disoproxil fumarate in treatment-naïve HIV-1-infected patients with HIV-1 RNA ≤100,000 copies/mL: week 96 pooled ECHO/THRIVE subanalysis.

    PubMed

    Behrens, Georg; Rijnders, Bart; Nelson, Mark; Orkin, Chloe; Cohen, Calvin; Mills, Anthony; Elion, Richard A; Vanveggel, Simon; Stevens, Marita; Rimsky, Laurence; Thorpe, David; Bosse, Matthew; White, Kirsten; Zhong, Lijie; DeMorin, Jennifer; Chuck, Susan K

    2014-04-01

    The once daily, single-tablet regimen (STR) combining rilpivirine (RPV), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) provides a simplified treatment option for antiretroviral therapy (ART)-naïve patients with baseline HIV-1 RNA (BLVL) of ≤100,000 copies/mL. The aim of this analysis is to compare long-term efficacy, safety, and tolerability of RPV+FTC/TDF vs. efavirenz (EFV)+FTC/TDF as individual components in subjects with BLVL ≤100,000 copies/mL. Week 96 efficacy and safety data from subjects with BLVL ≤100,000 copies/mL, who received daily RPV 25 mg or EFV 600 mg with FTC/TDF in the phase 3, randomized, double-blind, double-dummy, active-controlled, registrational trials ECHO and THRIVE, were analyzed. Virologic response was evaluated by intent-to-treat, time to loss of virological response (ITT-TLOVR), and Snapshot algorithms. Through Week 96, RPV+FTC/TDF demonstrated non-inferior efficacy to EFV+FTC/TDF (84% vs. 81%, respectively; ITT-TLOVR) in 543 subjects with BLVL ≤100,000 copies/mL, and overall rates of virologic failure (VF) were 5.9% vs. 2.4%, respectively. Resistance development was lower in Year 2 than Year 1. Subjects in both arms with suboptimal adherence (≤95%) had lower virologic responses (63% vs. 62%, respectively). Treatment with RPV+FTC/TDF was associated with significantly fewer treatment-related adverse events (AEs), grade 2-4 AEs, neurological and psychiatric AEs (including dizziness and abnormal dreams/nightmares), and rash. Additionally, grade 2-4 treatment-emergent laboratory abnormalities and grade 1-3 lipid abnormalities were significantly less common with RPV+FTC/TDF than EFV+FTC/TDF. RPV+FTC/TDF demonstrated non-inferior efficacy to EFV+FTC/TDF in ART-naïve subjects with BLVL ≤100,000 copies/mL and was associated with a higher rate of VF but a more favorable safety and tolerability profile through Week 96.

  1. Alemtuzumab and Combination Chemotherapy in Treating Patients With Untreated Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2014-03-20

    Acute Undifferentiated Leukemia; B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; L1 Adult Acute Lymphoblastic Leukemia; L1 Childhood Acute Lymphoblastic Leukemia; L2 Adult Acute Lymphoblastic Leukemia; L2 Childhood Acute Lymphoblastic Leukemia; Philadelphia Chromosome Negative Adult Precursor Acute Lymphoblastic Leukemia; Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia; Philadelphia Chromosome Positive Childhood Precursor Acute Lymphoblastic Leukemia; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Childhood Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

  2. 21 CFR 172.826 - Sodium stearyl fumarate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... products in an amount not to exceed 0.5 percent by weight of the flour used. (2) As a conditioning agent in... nonyeast-leavened bakery products in an amount not to exceed 1 percent by weight of the flour used. (4) As... conditioning agent in starch-thickened or flour-thickened foods in an amount not to exceed 0.2 percent...

  3. 21 CFR 172.826 - Sodium stearyl fumarate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... a conditioning agent in processed cereals for cooking in an amount not to exceed 1 percent by weight of the dry cereal, except for foods for which standards of identity preclude such use. (5) As...

  4. 21 CFR 172.826 - Sodium stearyl fumarate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... a conditioning agent in processed cereals for cooking in an amount not to exceed 1 percent by weight of the dry cereal, except for foods for which standards of identity preclude such use. (5) As...

  5. Gateways to clinical trials.

    PubMed

    Tomillero, A; Moral, M A

    2009-12-01

    [Methoxy-(11)C]PD-153035, 2-Methoxyestradiol; Adalimumab, Adecatumumab, Adefovir dipivoxil, ADH-1, ADX-10059, Aflibercept, AIR-human growth hormone, Aliskiren fumarate, AMG-221, Amlodipine besylate/olmesartan medoxomil, Aprepitant; Bavituximab, Bevacizumab, Bexarotene, BIBW-2992, BMS-690514, Bortezomib, Bosentan, Briakinumab; Capecitabine, Certolizumab pegol, Cetuximab, Cholecalciferol, Choline fenofibrate, Chorionic gonadotropin (human), Cixutumumab, Clopidogrel, CP-690550 citrate; Dabigatran, Dacetuzumab, Daclizumab, Dapagliflozin, Darbepoetin alfa, Dasatinib, Denosumab; Efavirenz, Elisidepsin, Enoxaparin, Enzastaurin hydrochloride, Eribulin mesilate, Erlotinib hydrochloride, Everolimus, Exenatide; Fenobam, Figitumumab, Filibuvir, Fondaparinux sodium, Fresolimumab; Gefitinib, Golimumab, Golnerminogene pradenovec; Ifosfamide, Imatinib mesylate, Ipilimumab, Ivabradine hydrochloride, Ixabepilone; Lapatinib ditosylate, Lenalidomide, Levocetirizine dihydrochloride, Liposomal vincristine, Liraglutide; M-118, Masitinib mesylate, Metformin hydrochloride, Micafungin sodium, Moxifloxacin hydrochloride; Neratinib; Oblimersen sodium, Ofatumumab, Olmesartan medoxomil; Paclitaxel nanoparticles, Palifosfamide lysine, Panobacumab, Panobinostat, Patupilone, Peginterferon alfa-2a, Pegylated arginine deiminase 20000, Piclozotan hydrochloride hydrate, Pixantrone maleate, Prasterone, Prasugrel, Prednisone, Progesterone, Prucalopride, pVGI.1 (VEGF-2); Retigabine, rhFSH, Rituximab, Rivaroxaban, Rosuvastatin calcium; Salinosporamide A, Selumetinib, Sipuleucel-T, Somatropin, Sorafenib, SSR-244738, Sunitinib malate; Tamoxifen citrate, Teduglutide, Telavancin hydrochloride, Telmisartan, Telmisartan/amlodipine, Telmisartan/hydrochlorothiazide, Temsirolimus, Tenofovir disoproxil fumarate, Tipifarnib, Tolvaptan, Trastuzumab, Trastuzumab-MCC-DM1, Travoprost, Tremelimumab; Valsartan/amlodipine besylate, Valsartan/amlodipine besylate/hydrochlorothiazide, Valsartan/hydrochlorothiazide, Vandetanib

  6. New and emerging immune-targeted drugs for the treatment of multiple sclerosis

    PubMed Central

    Palmer, Alan M

    2014-01-01

    Multiple sclerosis (MS) is a neurodegenerative disease with a major inflammatory component that constitutes the most common progressive and disabling neurological condition in young adults. Injectable immunomodulatory medicines such as interferon drugs and glatiramer acetate have dominated the MS market for over the past two decades but this situation is set to change. This is because of: (i) patent expirations, (ii) the introduction of natalizumab, which targets the interaction between leukocytes and the blood–CNS barrier, (iii) the launch of three oral immunomodulatory drugs (fingolimod, dimethyl fumarate and teriflunomide), with another (laquinimod) under regulatory review and (iv) a number of immunomodulatory monoclonal antibodies (alemtuzumab, daclizumab and ocrelizumab) about to enter the market. Current and emerging medicines are reviewed and their impact on people with MS considered. PMID:24251808

  7. Gateways to clinical trials.

    PubMed

    Tomillero, A; Moral, M A

    2008-09-01

    Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com.This issue focuses on the following selection of drugs: ABT-263, AC-2307, Aclidinium bromide, Adefovir dipivoxil, ADH-1, Agatolimod sodium, Alefacept, Aliskiren fumarate, Aminolevulinic acid methyl ester, Anakinra, Apaziquone, Aprepitant, Aripiprazole, ASM-8, Atiprimod hydrochloride, AVE-0277, AVE-1642, AVE-8062, Axitinib, Azacitidine, AZD-0530; Bazedoxifene acetate, Bevacizumab, Bexarotene, BI-2536, Biphasic insulin aspart, BMS-387032, BMS-663513, Bortezomib, BQ-123, Brivanib alaninate, BSI-201; Caspofungin acetate, CDX-110, Cetuximab, Ciclesonide, CR-011, Cypher; Daptomycin, Darbepoetin alfa, Dasatinib, Decitabine, Deferasirox, Denosumab, Dexlansoprazole, Dexmethylphenidate hydrochloride, DNA-Hsp65 vaccine, Dovitinib, Drotrecogin alfa (activated), DTaP-HBV-IPV/Hibvaccine, DTaP-IPV-HB-PRP-T, Duloxetine hydrochloride, Dutasteride; Ecogramostim, Elacytarabine, Emtricitabine, Endothelin, Entecavir, Eplivanserin fumarate, Escitalopram oxalate, Everolimus, Ezetimibe, Ezetimibe/simvastatin; Farletuzumab, Fesoterodine fumarate, Fibrin sealant (human), Fulvestrant; Gefitinib, Gemtuzumab ozogamicin, Glufosfamide, GSK-1562902A; Hib-TT; Imatinib mesylate, IMC-11F8, Imidazoacridinone, IMP-321, INCB-18424, Indiplon, Indisulam, INNO-406, Irinotecan hydrochloride/Floxuridine, ITF-2357, Ixabepilone; KRN-951; Lasofoxifene tartrate; Lenalidomide, LGD-4665, Lonafarnib, Lubiprostone, Lumiliximab; MDX-1100, Melan-A/MART-1/gp100/IFN-alfa, Methyl-CDDO, Metreleptin, MLN-2704, Mycophenolic acid sodium salt; Na-ASP-2, Naproxcinod, Nilotinib hydrochloride monohydrate, NPI-2358; Oblimersen sodium, Odanacatib; Paclitaxel nanoparticles, PAN-811, Panobinostat, PBI-1402, PC-515, Peginterferon alfa

  8. Safety concerns and risk management of multiple sclerosis therapies.

    PubMed

    Soelberg Sorensen, P

    2016-11-27

    Currently, more than ten drugs have been approved for treatment of relapsing-remitting multiple sclerosis (MS). Newer treatments may be more effective, but have less favorable safety record. Interferon-β preparations and glatiramer acetate treatment require frequent subcutaneous or intramuscular injections and are only moderately effective, but have very rarely life-threatening adverse effects, whereas teriflunomide and dimethyl fumarate are administered orally and have equal or better efficacy, but have more potentially severe adverse effects. The highly effective therapies fingolimod, natalizumab, daclizumab, and alemtuzumab have more serious adverse effects, some of which may be life-threatening. The choice between drugs should be based on a benefit-risk evaluation and tailored to the individual patient's requirements in a dialogue between the patient and treating neurologist. Patients with average disease activity can choose between dimethyl fumarate and teriflunomide or the "old injectable." Patients with very active MS may choose a more effective drug as the initial treatment. In case of side effects on one drug, switch to another drug can be tried. Suboptimal effect of the first drug indicates escalation to a highly efficacious drug. A favorable benefit-risk balance can be maintained by appropriate patient selection and appropriate risk management on therapy. New treatments will within the coming 1-2 years change our current treatment algorithm for relapsing-remitting MS.

  9. Gateways to clinical trials.

    PubMed

    Bayés, M; Rabasseda, X; Prous, J R

    2005-04-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity. prous.com. This issue focuses on the following selection of drugs: ABX-IL-8, Acclaim, adalimumab, AGI-1067, alagebrium chloride, alemtuzumab, Alequel, Androgel, anti-IL-12 MAb, AOD-9604, aripiprazole, atomoxetine hydrochloride; Biphasic insulin aspart, bosentan, botulinum toxin type B, bovine lactoferrin, brivudine; Cantuzumab mertansine, CB-1954, CDB-4124, CEA-TRICOM, choriogonadotropin alfa, cilansetron, CpG-10101, CpG-7909, CTL-102, CTL-102/CB-1954; DAC:GRF, darbepoetin alfa, davanat-1, decitabine, del-1 Genemedicine, dexanabinol, dextofisopam, dnaJP1, dronedarone hydrochloride, dutasteride; Ecogramostim, eletriptan, emtricitabine, EPI-hNE-4, eplerenone, eplivanserin fumarate, erlotinib hydrochloride, ertapenem sodium, escitalopram oxalate, esomeprazole magnesium, etoricoxib, ezetimibe; Falecalcitriol, fingolimod hydrochloride; Gepirone hydrochloride; HBV-ISS, HSV-2 theracine, human insulin; Imatinib mesylate, Indiplon, insulin glargine, ISAtx-247; L612 HuMAb, levodopa/carbidopa/entacapone, lidocaine/prilocaine, LL-2113AD, lucinactant, LY-156735; Meclinertant, metelimumab, morphine hydrochloride, morphine-6-glucuronide; Natalizumab, nimotuzumab, NX-1207, NYVAC-HIV C; Omalizumab, onercept, osanetant; PABA, palosuran sulfate, parathyroid hormone (human recombinant), parecoxib sodium, PBI-1402, PCK-3145, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, pemetrexed disodium, pimecrolimus, PINC, pregabalin; Ramelteon, rasagiline mesilate, rasburicase, rimonabant hydrochloride, RO-0098557, rofecoxib, rosiglitazone maleate/metformin hydrochloride; Safinamide mesilate, SHL-749, sitaxsentan sodium, sparfosic acid, SprayGel, squalamine, St. John's Wort

  10. Disease-modifying therapy in multiple sclerosis and chronic inflammatory demyelinating polyradiculoneuropathy: common and divergent current and future strategies

    PubMed Central

    Melzer, N; Meuth, S G

    2014-01-01

    Multiple sclerosis (MS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) represent chronic, autoimmune demyelinating disorders of the central and peripheral nervous system. Although both disorders share some fundamental pathogenic elements, treatments do not provide uniform effects across both disorders. We aim at providing an overview of current and future disease-modifying strategies in these disorders to demonstrate communalities and distinctions. Intravenous immunoglobulins (IVIG) have demonstrated short-and long-term beneficial effects in CIDP but are not effective in MS. Dimethyl fumarate (BG-12), teriflunomide and laquinimod are orally administered immunomodulatory drugs that are already approved or likely to be approved in the near future for the basic therapy of patients with relapsing–remitting MS (RRMS) due to positive results in Phase III clinical trials. However, clinical trials with these drugs in CIDP have not (yet) been initiated. Natalizumab and fingolimod are approved for the treatment of RRMS, and trials to evaluate their safety and efficacy in CIDP are now planned. Alemtuzumab, ocrelizumab and daclizumab respresent monoclonal antibodies in advanced stages of clinical development for their use in RRMS patients. Attempts to study the safety and efficacy of alemtuzumab and B cell-depleting anti-CD20 antibodies, i.e. rituximab, ocrelizumab or ofatumumab, in CIDP patients are currently under way. We provide an overview of the mechanism of action and clinical data available on disease-modifying immunotherapy options for MS and CIDP. Enhanced understanding of the relative effects of therapies in these two disorders may aid rational treatment selection and the development of innovative treatment approaches in the future. PMID:24032475

  11. Anaerobic Activation of p-Cymene in Denitrifying Betaproteobacteria: Methyl Group Hydroxylation versus Addition to Fumarate

    PubMed Central

    Strijkstra, Annemieke; Trautwein, Kathleen; Jarling, René; Wöhlbrand, Lars; Dörries, Marvin; Reinhardt, Richard; Drozdowska, Marta; Golding, Bernard T.; Wilkes, Heinz

    2014-01-01

    The betaproteobacteria “Aromatoleum aromaticum” pCyN1 and “Thauera” sp. strain pCyN2 anaerobically degrade the plant-derived aromatic hydrocarbon p-cymene (4-isopropyltoluene) under nitrate-reducing conditions. Metabolite analysis of p-cymene-adapted “A. aromaticum” pCyN1 cells demonstrated the specific formation of 4-isopropylbenzyl alcohol and 4-isopropylbenzaldehyde, whereas with “Thauera” sp. pCyN2, exclusively 4-isopropylbenzylsuccinate and tentatively identified (4-isopropylphenyl)itaconate were observed. 4-Isopropylbenzoate in contrast was detected with both strains. Proteogenomic investigation of p-cymene- versus succinate-adapted cells of the two strains revealed distinct protein profiles agreeing with the different metabolites formed from p-cymene. “A. aromaticum” pCyN1 specifically produced (i) a putative p-cymene dehydrogenase (CmdABC) expected to hydroxylate the benzylic methyl group of p-cymene, (ii) two dehydrogenases putatively oxidizing 4-isopropylbenzyl alcohol (Iod) and 4-isopropylbenzaldehyde (Iad), and (iii) the putative 4-isopropylbenzoate-coenzyme A (CoA) ligase (Ibl). The p-cymene-specific protein profile of “Thauera” sp. pCyN2, on the other hand, encompassed proteins homologous to subunits of toluene-activating benzylsuccinate synthase (termed [4-isopropylbenzyl]succinate synthase IbsABCDEF; identified subunits, IbsAE) and protein homologs of the benzylsuccinate β-oxidation (Bbs) pathway (termed BisABCDEFGH; all identified except for BisEF). This study reveals that two related denitrifying bacteria employ fundamentally different peripheral degradation routes for one and the same substrate, p-cymene, with the two pathways apparently converging at the level of 4-isopropylbenzoyl-CoA. PMID:25261521

  12. Targeting Thioredoxin-1 by dimethyl fumarate induces ripoptosome-mediated cell death

    PubMed Central

    Schroeder, Anne; Warnken, Uwe; Röth, Daniel; Klika, Karel D.; Vobis, Diana; Barnert, Andrea; Bujupi, Fatmire; Oberacker, Tina; Schnölzer, Martina; Nicolay, Jan P.; Krammer, Peter H.; Gülow, Karsten

    2017-01-01

    Constitutively active NFκB promotes survival of many cancers, especially T-cell lymphomas and leukemias by upregulating antiapoptotic proteins such as inhibitors of apoptosis (IAPs) and FLICE-like inhibitory proteins (cFLIPs). IAPs and cFLIPs negatively regulate the ripoptosome, which mediates cell death in an apoptotic or necroptotic manner. Here, we demonstrate for the first time, that DMF antagonizes NFκB by suppressing Thioredoxin-1 (Trx1), a major regulator of NFκB transcriptional activity. DMF-mediated inhibition of NFκB causes ripoptosome formation via downregulation of IAPs and cFLIPs. In addition, DMF promotes mitochondrial Smac release and subsequent degradation of IAPs, further enhancing cell death in tumor cells displaying constitutive NFκB activity. Significantly, CTCL patients treated with DMF display substantial ripoptosome formation and caspase-3 cleavage in T-cells. DMF induces cell death predominantly in malignant or activated T-cells. Further, we show that malignant T-cells can die by both apoptosis and necroptosis, in contrast to resting T-cells, which are restricted to apoptosis upon DMF administration. In summary, our data provide new mechanistic insight in the regulation of cell death by targeting NFκB via Trx1 in cancer. Thus, interference with Trx1 activity is a novel approach for treatment of NFκB-dependent tumors. PMID:28233787

  13. [ACCEPTANCE OF PULP FRUIT BEVERAGES FORTIFIED WITH FERROUS FUMARATE; AN ALTERNATIVE SUPPLEMENT FOR A HEALTH PROGRAM].

    PubMed

    Morales Guerrero, Josefina Consuelo; García Zepeda, Rodrigo Antonio; Sánchez Vargas, Elena

    2015-07-01

    Introducción: la desnutrición y la deficiencia de hierro son problemas de salud pública en varios países, México no es la excepción, y la mayor prevalencia se presenta en el medio rural. Una forma de atenderla es a través de la suplementación. El suplemento que se seleccione debe ser aceptado sensorialmente por el consumidor final para que la intervención sea exitosa. Objetivos: elaborar un suplemento multivitamínico para el programa “Salud y Nutrición para Pueblos Indígenas” y evaluar su aceptación en la población infantil urbana y rural. Métodos: se determinaron las características fisicoquímicas del producto a desarrollar y el método de elaboración y de preparación para su consumo. La aceptación se evaluó en niños de entre 6 a 24 meses de edad, con una prueba de caritas, y en los infantes de 6 a 12 meses se corroboró con el registro del volumen consumido. Para determinar las diferencias en la aceptación por edad y género en la misma población y para establecer diferencias entre poblaciones se aplicó una Ji cuadrada. Resultados: los suplementos, en los tres sabores evaluados, cumplieron con la concentración de vitaminas y nutrimentos inorgánicos establecidos en el programa citado. El 80% de los niños aceptaron los suplementos multivitamínicos (SM) en sus tres sabores. La edad de los niños fue el factor que más influyó en la aceptación. Conclusión: los SM desarrollados en este estudio son una alternativa al suplemento que actualmente proporciona el PSNPI, para los niños mayores a seis meses.

  14. Ability of lactate and pyruvate to stimulate aerobic growth of campylobacter in media supplemented with fumarate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Campylobacter spp. are human, foodborne, and bacterial pathogens that are frequently isolated from live poultry and processed poultry products. These pathogens are classified as microaerophiles; therefore, Campylobacter cultures are generally grown in atmospheres with reduced oxygen levels and elev...

  15. Alemtuzumab, Fludarabine Phosphate, and Low-Dose Total Body Irradiation Before Donor Stem Cell Transplantation in Treating Patients With Hematological Malignancies

    ClinicalTrials.gov

    2017-01-26

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Contiguous Stage II Grade 1 Follicular Lymphoma; Contiguous Stage II Grade 2 Follicular Lymphoma; Contiguous Stage II Marginal Zone Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Peripheral T-cell Lymphoma; Previously Treated Myelodysplastic Syndromes; Progressive Hairy Cell Leukemia, Initial Treatment; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Splenic Marginal Zone Lymphoma; Stage I Adult Diffuse Small Cleaved Cell Lymphoma; Stage I Childhood Anaplastic Large Cell Lymphoma; Stage I Childhood Large Cell Lymphoma; Stage I Cutaneous T-cell Non-Hodgkin Lymphoma; Stage I Grade 1 Follicular Lymphoma; Stage I Grade 2 Follicular Lymphoma; Stage I Mantle Cell Lymphoma; Stage I Marginal Zone Lymphoma; Stage I Mycosis Fungoides/Sezary Syndrome; Stage I Small Lymphocytic Lymphoma; Stage II Childhood Anaplastic Large Cell Lymphoma; Stage II Childhood Large Cell Lymphoma; Stage II Cutaneous T-cell Non-Hodgkin Lymphoma; Stage II Mycosis Fungoides/Sezary Syndrome; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Childhood Anaplastic Large Cell Lymphoma; Stage III Childhood Large Cell Lymphoma; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Childhood Anaplastic Large Cell Lymphoma; Stage IV Childhood Large Cell Lymphoma; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage IV Small Lymphocytic Lymphoma; T-cell Large Granular Lymphocyte Leukemia; Waldenström Macroglobulinemia

  16. Alemtuzumab and Glucocorticoids in Treating Newly Diagnosed Acute Graft-Versus-Host Disease in Patients Who Have Undergone a Donor Stem Cell Transplant

    ClinicalTrials.gov

    2010-05-12

    Breast Cancer; Chronic Myeloproliferative Disorders; Gestational Trophoblastic Tumor; Graft Versus Host Disease; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases; Neuroblastoma; Ovarian Cancer; Testicular Germ Cell Tumor

  17. Alemtuzumab, Fludarabine Phosphate, and Total-Body Irradiation Followed by Cyclosporine and Mycophenolate Mofetil in Treating Patients Who Are Undergoing Donor Stem Cell Transplant for Hematologic Cancer

    ClinicalTrials.gov

    2016-06-13

    Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Juvenile Myelomonocytic Leukemia; Mast Cell Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Myelodysplastic Syndromes; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenström Macroglobulinemia

  18. Requirement for safety monitoring for approved multiple sclerosis therapies: an overview

    PubMed Central

    Rommer, P S; Zettl, U K; Kieseier, B; Hartung, H-P; Menge, T; Frohman, E; Greenberg, B M; Hemmer, B; Stüve, O

    2014-01-01

    During the last two decades, treatment options for patients with multiple sclerosis (MS) have broadened tremendously. All agents that are currently approved for clinical use have potential side effects, and a careful risk–benefit evaluation is part of a decision algorithm to identify the optimal treatment choice for an individual patient. Whereas glatiramer acetate and interferon beta preparations have been used in MS for decades and have a proven safety record, more recently approved drugs appear to be more effective, but potential risks might be more severe. The potential complications of some novel therapies might not even have been identified to their full extent. This review is aimed at the clinical neurologist in that it offers insights into potential adverse events of each of the approved MS therapeutics: interferon beta, glatiramer acetate, mitoxantrone, natalizumab, fingolimod and teriflunomide, as well as recently approved therapeutics such as dimethyl fumarate and alemtuzumab. It also provides recommendations for monitoring the different drugs during therapy in order to avoid common side effects. PMID:24102425

  19. The use of immune modulating drugs for the treatment of multiple sclerosis

    PubMed Central

    Al-Khamis, Fahd A.

    2016-01-01

    This review discusses the mechanisms of action of 4 immune modulating drugs currently used in the treatment of multiple sclerosis (MS), including Alemtuzumab, a humanized monoclonal antibody that functions by targeting CD52, an antigen primarily expressed on T and B lymphocytes and monocytes/macrophages, resulting in their depletion and subsequent repopulation; Dimethyl fumarate that switches cytokine production toward a T helper 2 profile and enhances cytosolic levels of nuclear factor erythroid 2–related factor 2, which has immune regulatory and cytoprotective effects on oligodendrocytes, neurons, and glial cells; Fingolimod functions by blocking the release of activated lymphocytes from lymph nodes by targeting sphingosin-1-phosphate receptors; Natalizumab a humanized monoclonal antibody binds a4b1-integrin resulting in reduced migration of immune cells from blood across the blood-brain barrier into the CNS. This review presents the most up to date information on mechanisms of action, safety, and efficacy of these immune modulators and provides future perspectives for the treatment of MS. PMID:26818160

  20. The use of immune modulating drugs for the treatment of multiple sclerosis.

    PubMed

    Al-Khamis, Fahd A

    2016-01-01

    This review discusses the mechanisms of action of 4 immune modulating drugs currently used in the treatment of multiple sclerosis (MS), including Alemtuzumab, a humanized monoclonal antibody that functions by targeting CD52, an antigen primarily expressed on T and B lymphocytes and monocytes/macrophages, resulting in their depletion and subsequent repopulation; Dimethyl fumarate that switches cytokine production toward a T helper 2 profile and enhances cytosolic levels of nuclear factor erythroid 2-related factor 2, which has immune regulatory and cytoprotective effects on oligodendrocytes, neurons, and glial cells; Fingolimod functions by blocking the release of activated lymphocytes from lymph nodes by targeting sphingosin-1-phosphate receptors; Natalizumab a humanized monoclonal antibody binds α4β1-integrin resulting in reduced migration of immune cells from blood across the blood-brain barrier into the CNS. This review presents the most up to date information on mechanisms of action, safety, and efficacy of these immune modulators and provides future perspectives for the treatment of MS.

  1. New approaches in the management of multiple sclerosis

    PubMed Central

    Barten, Laurie J; Allington, Douglas R; Procacci, Kendra A; Rivey, Michael P

    2010-01-01

    Multiple sclerosis (MS) is a central nervous system chronic inflammatory disease that is characterized by an extensive and complex immune response. Scientific advances have occurred in immunology, pathophysiology, and diagnostic and clinical assessment tools, and recent discovery of unique therapeutic targets has spurred numerous Phase II and Phase III clinical trials. Reductions in MS relapse rates and improvements in T2 or gadolinium-enhancing lesion burdens have been reported from Phase III trials that include fingolimod, alemtuzumab, cladribine, and rituximab. Promising Phase II trial data exist for teriflunomide, daclizumab, laquinimod, and fumarate. The optimism created by these favorable findings must be tempered with evaluation of the adverse effect profile produced by these new agents. Given the discovery of progressive multifocal leukoencephalopathy with the use of natalizumab, ongoing vigilance for rare and life-threatening reactions due to new agents should be paramount. Patients with MS often experience difficulty with ambulation, spasticity, and cognition. Recent clinical trial data from two Phase III dalfampridine-SR trials indicate certain patients receive benefits in ambulation. This article provides an overview of data from clinical trials of newer agents of potential benefit in MS. PMID:21151622

  2. Direct renin inhibitor ameliorates insulin resistance by improving insulin signaling and oxidative stress in the skeletal muscle from post-infarct heart failure in mice.

    PubMed

    Fukushima, Arata; Kinugawa, Shintaro; Takada, Shingo; Matsumoto, Junichi; Furihata, Takaaki; Mizushima, Wataru; Tsuda, Masaya; Yokota, Takashi; Matsushima, Shouji; Okita, Koichi; Tsutsui, Hiroyuki

    2016-05-15

    Insulin resistance can occur as a consequence of heart failure (HF). Activation of the renin-angiotensin system (RAS) may play a crucial role in this phenomenon. We thus investigated the effect of a direct renin inhibitor, aliskiren, on insulin resistance in HF after myocardial infarction (MI). MI and sham operation were performed in male C57BL/6J mice. The mice were divided into 4 groups and treated with sham-operation (Sham, n=10), sham-operation and aliskiren (Sham+Aliskiren; 10mg/kg/day, n=10), MI (n=11), or MI and aliskiren (MI+Aliskiren, n=11). After 4 weeks, MI mice showed left ventricular dilation and dysfunction, which were not affected by aliskiren. The percent decrease of blood glucose after insulin load was significantly smaller in MI than in Sham (14±5% vs. 36±2%), and was ameliorated in MI+Aliskiren (34±5%) mice. Insulin-stimulated serine-phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle of MI compared to Sham by 57% and 69%, and both changes were ameliorated in the MI+Aliskiren group (91% and 94%). Aliskiren administration in MI mice significantly inhibited plasma renin activity and angiotensin II (Ang II) levels. Moreover, (pro)renin receptor expression and local Ang II production were upregulated in skeletal muscle from MI and were attenuated in MI+Aliskiren mice, in tandem with a decrease in superoxide production and NAD(P)H oxidase activities. In conclusion, aliskiren ameliorated insulin resistance in HF by improving insulin signaling in the skeletal muscle, at least partly by inhibiting systemic and (pro)renin receptor-mediated local RAS activation, and subsequent NAD(P)H oxidase-induced oxidative stress.

  3. Vitamin D3 supplementation increases fibroblast growth factor-23 in HIV-infected youth treated with tenofovir disoproxil fumarate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Tenofovir (TDF) is associated with phosphaturia and elevated 1,25 dihydroxy vitamin D (1,25-OH(2)D). Fibroblast growth factor-23 causes phosphaturia and increases in response to elevated 1,25-OH(2)D. Vitamin D binding proetin (VDBP) binds to 1,25-OH(2)D, decreasing biologic activity, and is elevated...

  4. Vitamin D Supplementation increases fibroblast growth factor-23 in HIV-infected youth treated with tenofovir disoproxil fumarate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    BACKGROUND: Tenofovir (TDF) is associated with phosphaturia and elevated 1,25 dihydroxy vitamin D (1,25-OH(2)D). Fibroblast growth factor 23 (FGF23) causes phosphaturia and increases in response to elevated 1,25-OH(2)D. Vitamin D binding protein (VDBP) binds to 1,25-OH(2)D, decreasing its biologic...

  5. Original research paper. Formulation and pharmaceutical development of quetiapine fumarate sustained release matrix tablets using a QbD approach.

    PubMed

    Gavan, Alexandru; Porfire, Alina; Marina, Cristina; Tomuta, Ioan

    2017-03-01

    The main objective of the present study was to apply QbD methodology in the development of once-a-day sustained release quetiapine tablets. The quality target product profile (QTPP) was defined after the pharmaceutical properties and kinetic release of the innovator product, Seroquel XR 200 mg. For the D-optimal experimental design, the level and ratio of matrix forming agents and the type of extragranular diluent were chosen as independent inputs, which represented critical formulation factors. The critical quality attributes (CQAs) studied were the cumulative percentages of quetiapine released after certain time intervals. After the analysis of the experimental design, optimal formulas and the design space were defined. Optimal formulas demonstrated zero-order release kinetics and a dissolution profile similar to the innovator product, with f2 values of 74.53 and 83.74. It was concluded that the QbD approach allowed fast development of sustained release tablets with similar dissolution behavior as the innovator product.

  6. Acceptance and Effect of Ferrous Fumarate Containing Micronutrient Sprinkles on Anemia, Iron Deficiency and Anthropometrics in Honduran Children

    DTIC Science & Technology

    2012-02-01

    two years after birth such as improved maternal nutrition and care, breastfeeding within one hour of birth, exclusive breastfeeding for the first 6...after birth (United Nations, 2011). These measures should incorporate improved maternal nutrition and care, breastfeeding within one hour of birth...exclusive breastfeeding for the first 6 months of life, and timely, adequate, safe, and appropriate complementary feeding and micronutrient intake

  7. Analysis of potentially predictive factors of efficacy of adjunct extended-release quetiapine fumarate in patients with major depressive disorder.

    PubMed

    Bauer, Michael; Thase, Michael E; Liu, Sherry; Earley, Willie; Eriksson, Hans

    2015-05-01

    Identification of predictors of treatment response in patients with major depressive disorder (MDD) may facilitate improved disease management. Data were pooled from two 6-week, double-blind, placebo-controlled studies of extended-release quetiapine (quetiapine XR; 150 or 300 mg/day) as adjunct to ongoing antidepressant therapy. Effects of psychiatric history and baseline demographic and disease characteristics on efficacy outcomes (Week 6 Montgomery Åsberg Depression Rating Scale [MADRS] total score reduction) were evaluated in population subgroups (quetiapine XR both doses pooled, n = 616; placebo, n = 303). Baseline Clinical Global Impressions-Severity (CGI-S) score and previous depressive episodes on Week 6 MADRS total score change, and baseline MADRS individual item scores on Week 6 change in CGI-Improvement score, were also evaluated. No major differences between responders and non-responders to quetiapine XR were observed for patient characteristics or demographic and disease characteristics. No suggestion of a predictive association was found between baseline CGI-S score, number of depressive episodes, and baseline MADRS item scores and efficacy outcomes. These analyses showed no major differences between responders and non-responders, and no predictive association between the parameters assessed and efficacy outcomes for adjunct quetiapine XR in patients with MDD and an inadequate response to prior antidepressant therapy.

  8. Long-Term Fluticasone Propionate/Formoterol Fumarate Combination Therapy Is Associated with a Low Incidence of Severe Asthma Exacerbations

    PubMed Central

    Mansur, Adel H.; Pertseva, Tetyana; Kaiser, Kirsten; McIver, Tammy; Grothe, Birgit; Dissanayake, Sanjeeva

    2016-01-01

    Abstract Background: A primary goal of asthma management is the reduction of exacerbation risk. We assessed the occurrence of oral corticosteroid-requiring exacerbations (OCS exacerbations) with long-term fluticasone/formoterol therapy, and compared it with the occurrence of similar events reported with other inhaled corticosteroid/long acting β2-agonist (ICS/LABA) combinations. Methods: The occurrence of OCS exacerbations was assessed in two open-label trials of fixed-dose fluticasone/formoterol administered for between 26 to 60 weeks in adults and adolescents with asthma. The incidence of OCS exacerbations with fluticasone/formoterol was compared with those reported in three recent Cochrane meta-analyses of other ICS/LABAs. Results: The pooled incidence of OCS exacerbations with long-term fluticasone/formoterol was 2.1% (95% CI: 1.1, 3.2%, n/N = 16/752). In only two of the nineteen treatment arms summarized by Cochrane did OCS exacerbation incidence approximate that seen in the two fluticasone/formoterol trials (single-inhaler fluticasone/salmeterol [2.9%]; separate inhaler budesonide, beclometasone, or flunisolide plus formoterol [3.4%]). In Lasserson's review the pooled incidence of OCS exacerbations for single-inhaler combinations was 9.5% (95% CI: 8.4, 10.6%; n/N = 239/2516) for fluticasone/salmeterol, and 10.6% (95% CI: 9.3, 11.8%; n/N = 257/2433) for budesonide/formoterol. In Ducharme's and Chauhan's meta-analyses (primarily incorporating separate inhaler combinations [fluticasone, budesonide, beclometasone, or flunisolide plus salmeterol or formoterol]), the pooled incidences of OCS exacerbations were 16.0% (95% CI: 14.2, 17.8%, n/N = 258/1615) and 16.7% (95% CI: 14.9, 18.5, n/N = 275/1643), respectively. Conclusions: The incidence of exacerbations in two fixed-dose fluticasone/formoterol studies was low and less than in the majority of comparable published studies involving other ICS/LABA combinations. This difference could not be readily explained by differences in features of the respective studies and may be related to the favorable pharmacological/mechanistic characteristics of the constituent components fluticasone and formoterol compared to other drugs in their respective classes. PMID:27104231

  9. Gateways to clinical trials.

    PubMed

    Tomillero, A; Moral, M A

    2009-03-01

    ABT-869, Acadesine, Acetylsalicylic acid/omeprazole, Adefovir, Adefovir dipivoxil, AEG-35156, Agatolimod sodium, Albiglutide, Alemtuzumab, Alipogene tiparvovec, Alogliptin benzoate, AMG-386, Amrubicin hydrochloride, Apremilast, Aripiprazole, Asoprisnil, Atorvastatin/fenofibrate, AVN-944, Axitinib; Belinostat, Bevacizumab, BHT-3021, BI-2536, Biapenem, Bilastine, Biphasic insulin aspart, Blinatumomab, Bortezomib, Bosentan; Catumaxomab, CD-NP, Cediranib, Certolizumab pegol, Cetuximab, Choline fenofibrate, Ciclesonide, CK-1827452,Clevudine, Clofarabine, CSL-360, CYT-997; Dapagliflozin, Darinaparsin, Denosumab, Densiron 68, Desloratadine, Dulanermin; Edoxaban tosilate, Emtricitabine, Entecavir, Erlotinib hydrochloride, Everolimus, Exenatide, Ezetimibe, Ezetimibe/simvastatin; Fidaxomicintiacumiv, Fulvestrant; G-207, GCR-8015, Gefitinib, Ghrelin (human), Glufosfamide; HPV16L1E7CVLP; Ibutamoren mesilate, Imatinib mesylate, Insulin detemir, Insulin glargine, Iodine (I131) tositumomab, Istaroxime, ITMN-191, Ixabepilone; JZP-4, Lenalidomide; Levetiracetam, Linaclotide acetate, Liposomal cytarabine/daunorubicin, Liposomal doxorubicin, Liraglutide, LY-518674; Milatuzumab, MMR-V, Motesanib diphosphate, Mycophenolic acid sodium salt; Niacin/simvastatin; Obatoclax mesylate, Odanacatib; Paclitaxel nanoparticles, Paclitaxel-eluting stent, Pazufloxacin, PBT-2, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Peginterferon alfa-2b/ribavirin, Pemetrexed disodium, Perampanel, PfCP2.9, Pitavastatin calcium, Poly I:CLC, Pomalidomide, Pralatrexate, Pramlintide acetate, Prucalopride; rhGAD65, Roflumilast; RTS,S/AS02D; SCH-530348, Semagacestat, Sirolimus-eluting coronary stent, Sirolimus-Eluting Stent, SIR-Spheres, Sivelestat sodium hydrate, Sorafenib, Sunitinib malate; Tadalafil, Tafluprost, Tanespimycin, Teduglutide, Telaprevir, Telbivudine, Tenofovir disoproxil fumarate, Tiotropium bromide, TMC-435350, Tositumomab/iodine (I131) tositumomab, Travoprost/timolol, Triciribine

  10. Gateways to Clinical Trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2002-04-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the world's first drug discovery and development portal, and provides information on study design, treatments, conclusions and references. This issue focuses on the following selection of drugs: Abiciximab, acetylcholine chloride, acetylcysteine, alefacept, alemtuzumab, alicaforsen, alteplase, aminopterin, amoxicillin sodium, amphotericin B, anastrozole, argatroban monohydrate, arsenic trioxide, aspirin, atazanavir, atorvastatin, augmerosen, azathioprine; Benzylpenicillin, BMS-284756, botulinum toxin type A, botulinum toxin type B, BQ-123, budesonide, BXT-51072; Calcium folinate, carbamazepine, carboplatin, carmustine, ceftriaxone sodium, cefuroxime axetil, chorionic gonadotropin (human), cimetidine, ciprofloxacin hydrochloride, cisplatin, citalopram hydrobromide, cladribine, clarithromycin, clavulanic acid, clofarabine, clopidogrel hydrogensulfate, clotrimazole, CNI-1493, colesevelam hydrochloride, cyclophosphamide, cytarabine; Dalteparin sodium, daptomycin, darbepoetin alfa, debrisoquine sulfate, dexrazoxane, diaziquone, didanosine, docetaxel, donezepil, doxorubicin hydrochloride liposome injection, DX-9065a; Eberconazole, ecogramostim, eletriptan, enoxaparin sodium, epoetin, epoprostenol sodium, erlizumab, ertapenem sodium, ezetimibe; Fampridine, fenofibrate, filgrastim, fluconazole, fludarabine phosphate, fluorouracil, 5-fluorouracil/epinephrine, fondaparinux sodium, formoterol fumarate; Gabapentin, gemcitabine, gemfibrozil, glatiramer; Heparin sodium, homoharringtonine; Ibuprofen, iloprost, imatinib mesilate, imiquimod, interferon alpha-2b, interferon alpha-2c, interferon-beta; KW-6002; Lamotrigine, lanoteplase, metoprolol tartrate, mitoxantrone hydrochloride; Naproxen sodium, naratriptan, Natalizumab, nelfinavir mesilate

  11. Gateways to clinical trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2005-10-01

    Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: (-)-Epigallocatechin gallate, (Z)-4-hydroxytamoxifen; Ad.muIFN-beta AD-237, adalimumab, adefovir dipivoxil, agalsidase alfa, alemtuzumab, almotriptan, ALVAC vCP1452, alvimopan hydrate, ambrisentan, anakinra, anti-IFN-gamma MAb; Bimatoprost, BMS-188797, BMS-214662, bortezomib, bosentan, bovine lactoferrin; Caffeine, canertinib dihydrochloride, canfosfamide hydrochloride, cannabidiol, caspofungin acetate, cetuximab, cH36, ChimeriVax-JE, ciclesonide, cilansetron, cinacalcet hydrochloride, clopidogrel, CpG-7909, Cypher; Daptomycin, darbepoetin alfa, darifenacin hydrobromide, decitabine, denufosol tetrasodium, Dexamet, diindolemethane, drotrecogin alfa (activated), duloxetine hydrochloride, DX-9065a; E-7010, edaravone, efalizumab, eicosapentaenoic acid/docosahexaenoic acid, elacridar, eletriptan, emtricitabine, epratuzumab, erlotinib hydrochloride, ertapenem sodium, eszopiclone, everolimus, ezetimibe; Fludarabine, fondaparinux sodium; gamma-Hydroxybutyrate sodium, gavestinel sodium, gefitinib, granisetron-Biochronomer; Human Albumin, human insulin; Imatinib mesylate, indiplon, interleukin-2 XL, isatoribine, ISS-1018, i.v. gamma-globulin, ivabradine hydrochloride, ixabepilone; Lanthanum carbonate, L-arginine hydrochloride, liposomal doxorubicin, LY-450139; Magnesium sulfate, melatonin, motexafin gadolinium, mycophenolic acid sodium salt; Natalizumab, nesiritide, niacin/lovastatin; OGX-011, olmesartan medoxomil, omalizumab, ospemifene; PACAP38, panitumumab, parathyroid hormone (human recombinant), parecoxib sodium, patupilone, pegfilgrastim, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b

  12. Gateways to clinical trials.

    PubMed

    Bayes, M; Rabasseda, X; Prous, J R

    2006-03-01

    Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 131I-labetuzumab; Abacavir sulf