fumarates and Chronic-Disease

Psoriasis is a chronic skin disease associated with increased morbidity and mortality. Effective and safe long term treatment options are required to manage the illness successfully. A number of systemic agents are available, however, each of them has potentially significant side effects. Fumaric acid esters (FAE) are used first line in Germany for the management of moderate to severe psoriasis, however, their use in Ireland is on an unlicensed basis (Clinical and Experimental Dermatology 37:786-801, 2012).. The purpose of this literature review is to evaluate the efficacy and safety of FAEs in the management of moderate to severe psoriasis in adult patients. The reviewer intends to systematically review all available literature on the efficacy and/or safety of fumaric acid esters in the management of moderate to severe psoriasis in adult patients.. A systematic review of the literature was performed by one reviewer. The PubMed, TRIP, Embase, and Cochrane Collaboration databases were systematically interrogated to include randomised controlled trials, cohort studies and case studies evaluating the efficacy and/or safety of FAEs in the management of moderate to severe psoriasis in adult patients. Inclusion criteria were studies which included adults over 18 years of age, with a diagnosis of moderate to severe chronic plaque psoriasis, who were treated with FAEs and no other systemic anti-psoriatic agents concurrently. Exclusion criteria were studies involving children, mild psoriasis, studies which did not include patients with chronic plaque psoriasis, the use of FAE for the management of illnesses other than psoriasis, and patients treated with more than one systemic anti-psoriatic agent concurrently.. In total 19 articles were selected for review including 2 randomised placebo controlled trials, 1 non-randomised comparative study, 7 retrospective cohort studies, 2 prospective cohort studies and 7 case studies. The findings suggest that FAEs are a safe and effective treatment option for the management of moderate to severe psoriasis in adult patients. Gastrointestinal side effects may occur on treatment initiation and may be minimised by slow dose titration. Lymphocytopenia and eosinophilia are common, however, they are rarely of significance and there is no high level of evidence available to suggest a resultant increased risk of infection or malignancy. Rarely alterations of renal and hepatic function may occur, however, these are largely reversible on treatment withdrawal.. In conclusion, the use of FAE in the management of moderate to severe psoriasis is a promising treatment option, especially for those patients intolerant of, or unresponsive to other agents. If blood parameters are closely monitored during treatment as per the European Medicine Agencies guidelines (European Medicines Agency, 'Updated recommendations to minimise the risk of the rare brain infection PML with Tecfidera', http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2015/10/WC500196017.pdf , 2015) they may be safely used in practice. The licensing of FAEs in Ireland for the treatment of moderate to severe psoriasis would be desirable, increasing available treatment options.

Topics: Adult; Chronic Disease; Dermatologic Agents; Fumarates; Germany; Humans; Ireland; Psoriasis; Treatment Outcome

There have been few major breakthroughs in heart failure (HF) drug therapies in recent years yet HF morbidity and mortality remain high, and there is a clear need for further research. Several newer agents that appear promising in Phase I and II trials do not progress to show clinical benefit in later trials. Part of the failure to find new therapies may lie in flawed trial design compounded by the need for ever-increasing patient numbers in order to prove outcome benefit. We summarize some of the most recent and promising medical therapies for HF.

Topics: Amides; Cardiotonic Agents; Chronic Disease; Diuretics; Forecasting; Fumarates; Heart Failure; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Myocardial Contraction; Naphthyridines; Oligopeptides; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Vasodilator Agents

Topics: Albuminuria; Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Calcium Channel Agonists; Catheter Ablation; Cerebrovascular Circulation; Chronic Disease; Diabetic Nephropathies; Drug Therapy, Combination; Evidence-Based Medicine; Fumarates; Humans; Hypertension; Imidazoles; Kidney; Kidney Diseases; Randomized Controlled Trials as Topic; Tetrazoles; Valine; Valsartan

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Fumarates; Humans; Hypertension; Kidney Diseases; Prorenin Receptor; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptor, Angiotensin, Type 1; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Renin; Renin-Angiotensin System

Topics: Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Chronic Disease; Clinical Trials as Topic; Drug Therapy, Combination; Evidence-Based Medicine; Fumarates; Kidney Diseases; Losartan; Tetrazoles; Valine; Valsartan

Interruption of the Renin-Angiotensin-Aldosterone System (RAAS) with Angiotensin-Converting Enzyme (ACE) inhibitors and Angiotensin-Receptor Blockers (ARBs), alone or in combination, has become a leading therapeutic strategy to slow down the progression of chronic kidney disease. Nevertheless, a considerable proportion of patients progress despite this therapy. New alternative arms are available today to treat hypertension in uncontrolled patients that might have a role in renoprotection. The role of aliskiren, the recently available renin inhibitor may be assumed, based on the pathophysiology of RAAS related renal damage and from data derived on experimental and clinical studies in-patient with type 2 diabetes related nephropathy. The review focuses on the potential consequences of (pro)renin blockade in glomerular hypertension and renal scarring along with some patented treatment methods. The benefit of this additional therapy is still only hypothetical. Ad hoc clinical trials have been conducted to confirm the expected results. Finding that prolonged inhibition of renin vasoconstrictor effect, suppression of plasma renin activity and a more effective RAAS blockade, in patients with chronic RAAS inhibition may help to achieve a sustained reduction of proteinuria, would suggest that renin inhibitors may represent a new weapon to fight progressive nephropathies.

Topics: Amides; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Chronic Disease; Fumarates; Humans; Kidney Diseases; Rats; Receptors, Angiotensin; Renin; Renin-Angiotensin System; Treatment Outcome

Chronic kidney failure remains a major health problem worldwide. Although current treatment is focused on the renin-angiotensin system, it is essential that new treatments targeted toward novel pathophysiological mechanisms are developed if we are to make significant progress in this area. In this review, we have outlined several promising new areas while emphasizing that large, randomized, well-controlled clinical trials are essential to reach a meaningful conclusion about the efficacy and safety of novel treatment.

Topics: Amides; Anticoagulants; Antihypertensive Agents; Bicarbonates; Chronic Disease; Enzyme Inhibitors; Fumarates; Glycosaminoglycans; Humans; Indoles; Iron Chelating Agents; Kidney Diseases; Kidney Failure, Chronic; Maleimides; Pentoxifylline; Phosphodiesterase Inhibitors; Protein Kinase C; Pyridones; Renin; Renin-Angiotensin System

Activation of the renin-angiotensin system (RAS) plays an important role in the pathogenesis of heart failure. Thus, strategies for the treatment of heart failure have focused on agents that block the RAS. More recently, the role of angiotensin receptor blockers (ARBs) in heart failure therapy has been better defined. This article examines the rationale and role of ARBs in the treatment of patients with heart failure on the basis of evidence from clinical trials.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Fumarates; Heart Failure; Humans; Losartan; Randomized Controlled Trials as Topic; Renin; Tetrazoles; Treatment Outcome; Valine; Valsartan

Psoriasis is a chronic, recurrent disease that affects between 1% and 3% of the population. Patients with moderate to severe disease generally require phototherapy (e.g. narrowband ultraviolet B radiation), photochemotherapy (oral psoralen plus ultraviolet A radiation) or systemic agents (e.g. ciclosporin, methotrexate, oral retinoids, fumaric acid esters) to control their disease adequately. In general, these therapeutic modalities have proven to be highly effective in the treatment of psoriasis. However, potentially serious toxicities can limit their long-term use. Given that there is no standard therapeutic approach for patients with moderate to severe psoriasis, the benefits and risks of phototherapy, photochemotherapy and systemic therapy must be weighed carefully for each patient, and treatment individualized accordingly. This review summarizes the benefits and risks of traditional, nonbiological therapies for moderate to severe chronic plaque psoriasis.

Topics: Administration, Oral; Chronic Disease; Cyclosporine; Dermatologic Agents; Ficusin; Fumarates; Humans; Immunosuppressive Agents; Methotrexate; Photosensitizing Agents; Psoriasis; PUVA Therapy; Retinoids; Risk Assessment; Ultraviolet Therapy

Among patients with chronic heart failure, angiotensin-converting-enzyme (ACE) inhibitors reduce mortality and hospitalization, but the role of a renin inhibitor in such patients is unknown. We compared the ACE inhibitor enalapril with the renin inhibitor aliskiren (to test superiority or at least noninferiority) and with the combination of the two treatments (to test superiority) in patients with heart failure and a reduced ejection fraction.. After a single-blind run-in period, we assigned patients, in a double-blind fashion, to one of three groups: 2336 patients were assigned to receive enalapril at a dose of 5 or 10 mg twice daily, 2340 to receive aliskiren at a dose of 300 mg once daily, and 2340 to receive both treatments (combination therapy). The primary composite outcome was death from cardiovascular causes or hospitalization for heart failure.. After a median follow-up of 36.6 months, the primary outcome occurred in 770 patients (32.9%) in the combination-therapy group and in 808 (34.6%) in the enalapril group (hazard ratio, 0.93; 95% confidence interval [CI], 0.85 to 1.03). The primary outcome occurred in 791 patients (33.8%) in the aliskiren group (hazard ratio vs. enalapril, 0.99; 95% CI, 0.90 to 1.10); the prespecified test for noninferiority was not met. There was a higher risk of hypotensive symptoms in the combination-therapy group than in the enalapril group (13.8% vs. 11.0%, P=0.005), as well as higher risks of an elevated serum creatinine level (4.1% vs. 2.7%, P=0.009) and an elevated potassium level (17.1% vs. 12.5%, P<0.001).. In patients with chronic heart failure, the addition of aliskiren to enalapril led to more adverse events without an increase in benefit. Noninferiority was not shown for aliskiren as compared with enalapril. (Funded by Novartis; ATMOSPHERE ClinicalTrials.gov number, NCT00853658.).

Topics: Aged; Amides; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Follow-Up Studies; Fumarates; Heart Failure; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Renin; Stroke Volume; Treatment Failure

Various methods of combination renin-angiotensin-aldosterone system blockade help achieve more potent antiproteinuric effects, but may be associated with higher risk of side effects. Therapies involving direct renin inhibitor, aliskiren, may promote renal fibrosis by stimulating (pro)renin receptor due to increased renin levels.. The aim of the study was to compare the effects of combination treatment with angiotensin receptor blockers, telmisartan (80 mg/d) and aliskiren (300 mg/d) with those of combination treatment with 80 mg/d telmisartan and mineralocorticoid receptor blocker (50 mg/d eplerenone) and telmisartan (160 mg/d) alone on the urinary excretion of transforming growth factor β1 (TGF‑β1), renal function, and serum potassium levels.. A randomized open-label controlled cross-over study was performed in 18 white patients (7 women and 11 men; mean age, 42.4 ±1.9 years) with proteinuric nondiabetic chronic kidney disease and estimated glomerular filtration rate of 85.2 ±4.6 ml/min.. The urinary excretion of TGF‑β1 was stable despite a significant increase in plasma renin levels after treatment with telmisartan and aliskiren. There were no differences in renal function and serum potassium levels between the compared treatments. Moreover, there were no episodes of hypotension or acute renal impairment.. Combination therapy with telmisartan and aliskiren may be safe in young nondiabetic patients with normal renal function at low vascular risk. This treatment may be an alternative for a subset of patients in whom standard RAA system blockade is ineffective.

Topics: Adult; Amides; Angiotensin II Type 1 Receptor Blockers; Benzimidazoles; Benzoates; Chronic Disease; Diuretics; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fumarates; Humans; Kidney Diseases; Male; Middle Aged; Patient Safety; Renin-Angiotensin System; Severity of Illness Index; Telmisartan; Treatment Outcome

To evaluate the efficacy of nitrofurans in children and adolescents with pyelonephritis in the presence of crystalluria.. The study included 50 patients aged 4-14 years with chronic pyelonephritis in the presence of dysmetabolism. The patients underwent general blood test, general urinalysis with an urocytogram, bacteriological examination of urine, biochemical test of serum (uric acid, calcium, phosphorus, magnesium, urea, and creatinine) and 24-hour urinary excretion (uric acid, oxalates, calcium, phosphorus, and magnesium) at hospital admission and over time. The treatment regimen for Group 1 patients after antibiotic therapy involved furamag, Group 2 received furagin. The drugs were used in a dosage of 2 mg/kg/day in 2 divided doses for 14 days. Complaints, major clinical manifestations, crystalluria patterns, and a number of laboratory findings were analyzed over time.. The urinary sediment showed leukocyturia and bacteriuria in all the patients, oxaluria in 70% of the patients, uraturia in 10%, and mixed crystalluria in 20%. The main etiological agent of pyelonephritis was Escherichia coli (48.4%). Increased serum uric acid concentrations were revealed in 14% of the patients. Daily urine tests revealed hyperoxaluria, hyperuricosuria, and hypercalciuria in 86, 18, and 8% of the patients, respectively; urinary magnesium excretion was reduced in 86%. After treatment, Group 1 patients showed a more marked therapeutic effect in terms of a number of indicators (leukocyturia, crystalluria, uricosuria, magnesuria).. The results of the study showed that the antibacterial therapy involving antibiotics and nitrofurans for an exacerbation of chronic pyelonephritis in the presence of crystalluria not only provides an anti-inflammatory effect, but also leads to reductions in the level of crystalluria and the urinary content of uric acid and calcium. There was a significantly marked reduction in crystalluria, serum uric acid, and urinary oxalates and calcium in the children taking furamag. Out of nitrofurans, furamag may be recommended as the drug of choice to treat urinary tract infections in the presence of crystalluria.

Topics: Adolescent; Anti-Bacterial Agents; Child; Child, Preschool; Chronic Disease; Crystallization; Female; Fumarates; Furagin; Humans; Male; Pyelonephritis; Treatment Outcome; Urinary Calculi

It is highly likely that the rise in plasma prorenin and plasma renin during renin inhibitor treatment is induced at least as much by the fall in blood pressure (BP) as it is by the negative feedback of angiotensin II. This could potentially be harmful because high levels of renin and prorenin may stimulate the (pro)renin receptor, thus inducing profibrotic effects. To further understand this relationship, the influence of aliskiren on the urinary excretion of transforming growth factor-β1 (TGF-β1) and procollagen III N-terminal propeptide (PIIINP) was evaluated in patients with nondiabetic kidney diseases.. Aliskiren 300 mg and perindopril 10 mg, were each individually administered for 12 weeks separated by a placebo period in a cross-over, randomized, double-blinded pilot study.. A 1,131% (P < 0.001) and 628% (P < 0.001) increase in plasma renin concentration was observed after the aliskiren and perindopril therapies, respectively, as compared to the placebo. Aliskiren and perindopril increased prorenin concentrations as compared to the placebo by 100% (P < 0.01) and 52.4% (P = 0.53), respectively. The TGF-β1 excretion was lower after tested therapies compared to the placebo (55.0 ± 7.56 vs. 56.21 ± 8.56 vs. 85.79 ± 14.11 pg/mg creatinine; P = 0.016); without differences between aliskiren and perindopril. PIIINP excretion did not differ between treatments.. The study shows that both aliskiren and perindopril suppress TGF-β1 in patients with chronic kidney diseases. This effect was observed despite significant increases in the renin and prorenin concentrations. Further studies involving histological assessments are required to elucidate the exact impact of these agents on renal fibrosis.

Topics: Adult; Amides; Antihypertensive Agents; Chronic Disease; Creatinine; Cross-Over Studies; Double-Blind Method; Female; Fibrosis; Fumarates; Humans; Kidney; Kidney Diseases; Male; Peptide Fragments; Perindopril; Pilot Projects; Procollagen; Renin; Transforming Growth Factor beta; Treatment Outcome

Technosphere® [Bis-3,6(4-fumarylaminobutyl)-2,5-diketopiperazine (FDKP)] microparticles, the integral component of the Technosphere inhalation system, deliver drugs to the deep lung and have been used to administer insulin and glucagon-like peptide-1 via inhalation in clinical studies. Three studies were conducted to characterize FDKP pharmacokinetics, including assessments in subjects with diabetic nephropathy (DNP), in subjects with chronic liver disease (CLD), and in healthy subjects.. An open-label, nonrandomized, two-period, fixed-sequence crossover absorption, distribution, metabolism, and excretion (ADME) study was conducted in six healthy nonsmoking men who received single intravenous and oral doses of [(14)C]FDKP solution, with serial sampling of blood, urine, feces, and expired air. Additionally, two single-dose, open-label, parallel-design studies with 20 mg of inhaled FDKP were conducted in (1) 12 diabetic subjects with normal renal function and 24 DNP subjects and (2) 12 healthy subjects and 21 CLD subjects.. In the ADME study, >95% of the intravenous dose and <3% of the oral dose were recovered in urine, with no evidence of metabolism. No significant pharmacokinetic differences were observed between healthy subjects and CLD subjects [geometric mean (% coefficient of variation) area under the curve from time 0 to 480 minutes (AUC(0-480)): 26,710 (34.8) and 31,477 (28.8) ng/ml·min, respectively]. Maximum observed drug concentration (C(max)) and AUC(0-480) were higher in DNP subjects than in subjects with normal renal function [C(max): 159.9 (59.4) ng/ml versus 147.0 (44.3) ng/ml; AUC(0-480): 36,869 (47.2) ng/ml·min versus 30,474 (31.8) ng/ml·min]. None of the differences observed were considered clinically significant.. Fumaryl diketopiperazine is predominantly cleared unchanged by the kidney with essentially no oral bioavailability. Technosphere is a safe delivery vehicle for medications administered via inhalation.

Topics: Administration, Inhalation; Adult; Aged; Chronic Disease; Diabetic Neuropathies; Drug Delivery Systems; Excipients; Female; Fumarates; Humans; Injections, Intravenous; Kidney; Liver Diseases; Male; Microspheres; Middle Aged; Piperazines

Suppression of the renin-angiotensin-aldosterone system (RAAS) is therapeutically valuable in chronic heart failure (CHF). RAAS inhibition can be achieved in a number of ways though an orally active renin inhibitor (RI) has never been studied before. We describe the neurohumoral effects of an RI.. 27 patients with NYHA class II or III CHF and an ejection fraction

Topics: Aged; Aldosterone; Amides; Analysis of Variance; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Female; Fumarates; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Ramipril; Renin; Statistics, Nonparametric; Treatment Outcome

Calcipotriol is an established topical therapy for psoriasis vulgaris.. This study aimed to investigate whether the addition of calcipotriol to fumaric acid ester (FAE) monotherapy had an additive efficacy and an FAE-sparing effect in patients with severe plaque psoriasis.. This multicentre, randomised, double-blind, vehicle-controlled study included 143 patients for up to 13 weeks treatment. Group A received FAE tablets (Fumaderm) with an increasing daily dosage from 105 to 1,075 mg + ointment vehicle. Group B received FAE tablets + calcipotriol ointment (50 microg/g). Ointments were applied twice daily. Clinical response was assessed using percentage changes in the Psoriasis Area and Severity Index (PASI), from baseline to treatment end.. The mean percentage change in the PASI was -76.1% in group B and -51.9% in group A, the difference between treatments was -24.2% (95% CI from -34.2 to -14.2%; p < 0.001). Group B responded more rapidly to treatment. Investigators' and patients' overall efficacy assessments were significantly more favourable for group B (p < or = 0.001). Group B was prescribed less FAE than group A. This difference was greatest at the last visit (mean daily dose 529 and 685 mg, respectively; p = 0.006). Overall adverse events in the two groups were similar.. This study shows that the combination of calcipotriol and FAEs is significantly more effective and faster acting than FAE monotherapy in the treatment of severe plaque psoriasis. The combination has a slight FEA-sparing effect and therefore a superior benefit/risk ratio.

Topics: Administration, Oral; Administration, Topical; Adult; Calcitriol; Chronic Disease; Dermatologic Agents; Dimethyl Fumarate; Double-Blind Method; Drug Therapy, Combination; Female; Fumarates; Humans; Male; Prospective Studies; Psoriasis

The new antihistamine, HC20-511 (Sandoz), was compared with Dimetinden (Fenistil retard) in a single-blind comparative study in 42 patients with dermatoses, 28 of whom suffered from chronic urticaria. HC20-511 had a better effect, especially in chronic urticaria, where pruritus, erythema and papules quickly disappeared. The effect appeared somewhat faster than and lasted as long as that of Dimetinden, although HC20-511 is not a retard-preparation unlike the Dimetinden preparation used for comparison. HC20-511 also caused less side effects.

Topics: Adolescent; Adult; Aged; Chronic Disease; Clinical Trials as Topic; Dimethindene; Drug Therapy, Combination; Female; Fumarates; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines; Pruritus; Skin Diseases; Thiophenes; Urticaria; Vomiting

Degradable materials that can support cell infiltration and remodeling are the basis of tissue engineered approaches to vascular repair. In addition, to replace or close a large area of the vasculature, a patch material or scaffold must also withstand high pressure over time. Extracellular matrix-based (ECM-based) scaffolds offer a biological substrate with environmental cues that can support the formation of appropriate vascular tissue. However, scaffolds made from pure natural materials can degrade rapidly, resulting in reduced mechanical integrity of the implant and possible chronic inflammation in the site. A hybrid biomaterial, combining the matrix-dense tissue pericardium with a layer of the degradable polymer poly(propylene fumarate) (PPF), is suited to withstand rapid enzymatic degradation and control the presentation of an unaltered natural tissue matrix for remodeling activity. In this study, we show that the polymer reinforced hybrid supports cellular infiltration, but has fewer macrophages in the vicinity of the implant after 6 weeks in vivo than an untreated tissue control in both athymic and immunocompetent rat models. This result is supported by changes seen in other inflammatory cell populations. Based on significant differences in the inflammatory response to untreated pericardium and PPF-reinforced pericardium, we conclude that the polymer reinforcement layer can be used as a tool to leverage presentation of the ECM molecules in ECM-based scaffolds. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 494-504, 2019.

Topics: Animals; Chronic Disease; Coated Materials, Biocompatible; Extracellular Matrix; Fumarates; Inflammation; Male; Pericarditis; Pericardium; Polypropylenes; Rats; Rats, Nude; Rats, Sprague-Dawley; Tissue Scaffolds

Pulmonary fibrosis, which influences lung function and exacerbates a patient's condition, is the ultimate stage of many lung diseases. Vitamin D deficiency is associated with pulmonary fibrosis and impaired lung function, but the underlying mechanism has not yet been fully elucidated. Moreover, vitamin D deficiency may cause over-activation of the renin-angiotensin system (RAS), which aggravates extracellular matrix (ECM) deposition and lung fibrosis. This study aims to investigate the effect of chronic vitamin D deficiency on lung fibrosis in otherwise healthy mice and to explore the role of RAS in this process. Mice were depleted of vitamin D through diet control and were compared with healthy subjects. Chronic vitamin D deficiency destructs lung structures, impairs lung development and stimulates ECM deposition. RAS components are also found to increase. These effects seem to worsen with prolonged vitamin D deficiency. By giving RAS blockers, these changes can be largely rescued. However, a smooth muscle relaxant whose regulatory effect on blood pressure is independent of RAS does not show similar effects. This study demonstrated that chronic vitamin D deficiency may induce RAS activation, which subsequently stimulates the expression of profibrotic factors and activates the fibrotic cascade. This profibrotic effect of RAS is independent of elevated blood pressure.

Topics: Amides; Animals; Blood Pressure; Chronic Disease; Extracellular Matrix; Female; Fumarates; Losartan; Lung; Mice; Pulmonary Fibrosis; Renin-Angiotensin System; Vitamin D Deficiency

Fumaric acid esters (FAEs) have proven efficacy in the treatment of psoriasis and have been in use for decades. More recently, as their mechanism of action and abundant immunomodulatory effects become clearer, the potential benefits of treating other inflammatory skin conditions using FAEs are increasingly being recognized. The use of FAEs as combination systemic therapy has not been well studied and data are lacking regarding the safety and efficacy of this type of therapy. In this case report, three patients with severe, extensive and recalcitrant cutaneous manifestations of systemic lupus erythematosus (SLE) (one case of disseminated discoid lesions and two with severe chilblain lesions) were treated with Fumaderm

Topics: Adult; Chronic Disease; Dermatologic Agents; Facial Dermatoses; Female; Fumarates; Hand Dermatoses; Humans; Lupus Erythematosus, Cutaneous; Middle Aged; Treatment Outcome

Results of the very first experiments conducted to evaluate therapeutic potentials of a fumarate containing Fumaria indica extract and of fairly low daily oral doses of monomethyl fumarate for prevention of chronic unavoidable foot-shock stress-induced gastric ulcers, and possible involvement of diverse neuro-hormonal and oxidative process in their stress response desensitizing effects are reported and discussed in this article. Preventive effects of 21 daily oral 60, 120, and 240 mg/kg doses of a standardized 50 % methanolic F. indica extract (MFI) and 1.25, 2.50, and 5.00 mg/kg/day of pure monomethyl fumarate (MMF) were compared in rats subjected to one hour daily unavoidable foot-shocks. A pharmaceutically well-standardized Withania somnifera (WS) root extract was used as a reference herbal anti-stress agent in all experiments. Effects of the treatments on stress-induced alterations in body weight, adrenal and spleen weights, gastric ulcer and ulcer index, weight of glandular stomach, protective mucosal glycoprotein content, cellular proliferation, oxidative stress on stomach fundus, and brain tissues of male rats were quantified. Other parameters quantified were plasma corticosterone levels, brain monoamine levels, and expressions of the cytokines TNF-α, IL-10, and IL-1β in blood and brain of stressed and treated rats. Most but not every observed stress-induced anomalies were suppressed or completely prevented by both MFI and pure MMF treatments in dose-dependent manner. Qualitatively, the observed activity profiles of both of them were similar to those of WS dose tested. These results reveal that both MFI and MMF are potent gastro-protective agents against chronic unavoidable stress-induced ulcers and strongly suggest that they act as regulators or modulators of monoamine, corticosterone, and cytokine homeostasis.

Topics: Animals; Body Weight; Brain; Chronic Disease; Corticosterone; Cytokines; Fumarates; Fumaria; Male; Maleates; Methanol; Organ Size; Plant Extracts; Protective Agents; Rats; Real-Time Polymerase Chain Reaction; Stomach; Stomach Ulcer; Stress, Psychological

The purpose of this study was to determine the prognostic significance and associated clinical profile of early post-discharge N-terminal pro-B-type natriuretic peptide (NT-proBNP) trajectory among patients hospitalized for worsening chronic heart failure (HHF).. This post-hoc analysis of the Aliskiren Trial in Acute Heart Failure Outcomes (ASTRONAUT) included 1351 HHF patients with ejection fraction (EF) ≤40%, elevated B-type natriuretic peptide ≥400 pg/mL or NT-proBNP ≥1600 pg/mL at admission, and available NT-proBNP measurements (from a central core laboratory) at baseline (median 5 days after admission) and 1-month follow-up. The co-primary endpoints were all-cause mortality and cardiovascular mortality or HHF within 12 months. Median follow-up was 11.3 months. Patients with decreasing post-discharge NT-proBNP trajectory tended to be younger and have non-ischaemic HF aetiology. The presence of baseline atrial fibrillation was associated with high NT-proBNP at 1 month (i.e. above the median), regardless of the baseline value. After adjustment for patient characteristics and 1-month NT-proBNP level, every twofold increase in continuous NT-proBNP change from baseline to 1 month was predictive of increased cardiovascular mortality or HHF (hazard ratio 1.14; 95% confidence interval 1.02-1.26), but not all-cause mortality (hazard ratio 0.95; 95% confidence interval 0.81-1.11).. In this cohort of HHF patients with reduced EF, early post-discharge NT-proBNP trajectory was associated with a distinct clinical profile and carried independent prognostic value after adjustment for patient characteristics and absolute NT-proBNP level. Future prospective study of serial NT-proBNP measurement during the hospital and early post-discharge periods is warranted to validate these findings and evaluate post-discharge NT-proBNP trajectory as a therapeutic target.

Topics: Aged; Amides; Chronic Disease; Cohort Studies; Disease Progression; Female; Fumarates; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Proportional Hazards Models; Renin

To compare the clinical efficacy of methotrexate (MTX) vs. fumaric acid esters (FAE) in psoriasis treated under daily life conditions.. Data were extracted from a registry (http://www.psoriasisregistry.at) of 272 adult patients with moderate-to-severe chronic plaque psoriasis treated primarily with MTX (n = 72) or FAE (n = 200) between 2004 and 2011. Data from all patients, including those who did not complete at least 3 months of monotherapy, were included in an intention-to-treat (ITT) worst-case analysis.. Thirty of 72 (41.7%) patients treated with MTX and 85 of 200 (42.5%) patients treated with FAE discontinued early, mainly due to side-effects or lack of response. Among patients who completed at least 3 months of treatment, the response to primary treatment with MTX vs. FAE did not differ significantly at any time point. In the ITT worst-case analysis at month 3, complete remission rate, PASI90, PASI75 and PASI50 rates were 6%, 7%, 24% and 39% in MTX-treated patients vs. 1%, 5%, 27% and 44% in FAE-treated patients. Overall mean PASI reduction score improved significantly in response to primary MTX and FAE treatment (by 10.6% and 12.6%, respectively) between 3 and 6 months (P = 0.0005; exact Wilcoxon test), but not between 6 and 12 months (P = 0.16). A subset of 32 patients who did not respond satisfactorily to primary treatment with FAE responded better to subsequent MTX therapy (P < 0.0001; paired Wilcoxon test).. As shown by retrospective analysis, the primary efficacy of FAE was similar to that of MTX under daily life conditions.

Topics: Adult; Chronic Disease; Fumarates; Humans; Immunosuppressive Agents; Methotrexate; Middle Aged; Psoriasis; Registries; Retrospective Studies; Severity of Illness Index

Doxorubicin (DXR) is one of the most effective antineoplastic agents. However, the optimal clinical use of this agent is limited because of marked cardiomyopathy and congestive heart failure. Renin angiotensin system (RAS) plays an important role in the development of cardiac hypertrophy, reperfusion injury and congestive heart failure. Aliskiren (ALK) is a direct inhibitor of renin and does not affect other systems involved in cardiovascular regulation. This study was designed to explore the possible protective effects of ALK (30 and 100 mg/kg, per oral [p.o.] respectively for 42 days) in chronic model of DXR (1.25 mg/kg, intraperitoneally (i.p.) sixteen equal cumulative doses) induced cardiomyopathy in rats. DXR treatment significantly (P<0.01) increased the activities of serum creatine kinase (CK-MB), lactate dehydrogenase (LDH), cardiomyocyte caspase-3 and catalase (CAT). ALK (100 mg/kg) treatment prevented the animals significantly (P<0.01) from rise in the above indices. Furthermore ALK (100 mg/kg) significantly restores the DXR-induced decrease in antioxidant defense, reduced glutathione (GSH) and superoxide dismutase (SOD). Transmission electron microscopic studies showed that DXR caused apoptosis in myocardium, manifested as condensation of chromatin network at the margins and rupture of nuclear membrane which was well protected by ALK (100 mg/kg) treatment. The present study indicates that ALK protected rats from DXR-induced cardiomyopathy.

Topics: Amides; Animals; Antibiotics, Antineoplastic; Antioxidants; Apoptosis; Cardiomyopathies; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Doxorubicin; Fumarates; Microscopy, Electron, Transmission; Myocardium; Oxidative Stress; Rats; Rats, Wistar; Renin; Renin-Angiotensin System

Despite significant advances in pharmacological and non-pharmacological therapy, epidemiological data from European and US hospitals show that the prevalence of heart failure (HF) hospitalization, especially for patients >65 years, continues to rise. Hospitalization for worsening HF is one of the most important predictors of short- and long-term outcomes in patients with chronic HF. There is therefore a clear need for new therapies that can work synergistically with standard medications to reverse the progression of the disease and improve myocardial efficiency. In the last years, researches in chronic HF focused on drugs that can exert a greater attenuation of neurohormonal activation and that can improve cardiac energy and substrate utilization.

Topics: Algorithms; Amides; Benzazepines; Chronic Disease; Fumarates; Heart Failure; Heart Rate; Humans; Ivabradine

Data on a protective role of fumarate in acute ischemia of the rat heart led to the obvious hypothesis that addition of fumarate to the preservation solution for kidney transplantation may have beneficial value. This study was designed to test this hypothesis. Kidneys of Lewis or Fischer 344 rats were flushed with University of Wisconsin (UW) solution or UW solution containing 5 mM fumarate. Grafts were immediately transplanted to Lewis recipients or stored at 4 °C for 5 h before transplantation. Renal function was assessed on d 10 and monthly for 6 mo. One group of isografts was removed on d 10 post-transplantation, the other groups of isografts and allografts after 6 mo. We detected a modest protective effect regarding proteinuria 10 d after isogeneic transplantation, and exclude the possibility that fumarate exerts acute nephrotoxicity. Surprisingly, fumarate strongly promoted intimal hyperplasia of allograft arteries, thickening of the arterial media of isografts and allografts, tubulo-interstitial allograft damage, and allograft infiltration by macrophages on the long run. To date, we do not know the mechanism resulting in fumarate-induced chronic graft damage. We suggest, however, that addition of fumarate to the conservation fluid does not improve graft outcome.

Topics: Acute Disease; Animals; Chronic Disease; Fumarates; Hyperplasia; Kidney; Kidney Transplantation; Lactates; Leukocytes; Male; Organ Preservation Solutions; Primary Graft Dysfunction; Rats; Rats, Inbred F344; Rats, Inbred Lew; Renal Artery; Transplantation, Homologous

The objective of this case series was to review the safety and efficacy of aliskiren in combination with losartan in pediatric chronic kidney disease (CKD) patients. This was a retrospective study in which the medical files of all patients who had received aliskiren were reviewed. Four patients were identified between 5 and 18 years of age who had received aliskiren and losartan for the reduction of refractory proteinuria. While proteinuria was reduced in all four of these patients by 45, 96, 53, and 64%, respectively, three patients experienced side effects requiring changes in the aliskiren dose. A significant side effect occurred in the patient with CKD stage 3 who suffered accelerated loss of kidney function leading to dialysis after only a short course of therapy. The data from this preliminary trial strongly suggest that clinicians should exercise caution when prescribing aliskiren in combination with losartan until appropriate pediatric trials establish dosing, efficacy, and safety.

Topics: Adolescent; Age Factors; Amides; Angiotensin II Type 1 Receptor Blockers; Child, Preschool; Chronic Disease; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fumarates; Humans; Kidney Diseases; Losartan; Male; Off-Label Use; Patient Selection; Proteinuria; Renin; Renin-Angiotensin System; Risk Assessment; Risk Factors; Treatment Outcome

Fumaric acid esters (FAE) are used in Germany as a first-line systemic treatment for chronic plaque psoriasis, with proven efficacy and low toxicity. Their use in the U.K. is variable, and they remain unlicensed. Consequently, efficacy and safety data from U.K. patients is limited and their place in the psoriasis treatment armamentarium is unclear.. To examine the efficacy and safety of FAE in a prospective cohort of U.K. patients with severe, treatment-recalcitrant, chronic plaque psoriasis.. A single-centre, open, nonrandomized, prospective study was performed in a regional referral centre for patients with severe psoriasis. Outcomes were measured by the Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI), blood investigations and adverse events monitoring.. Eighty patients were recruited. Fifty-nine per cent were taking a concomitant oral antipsoriatic agent; 20% achieved a PASI-50, 8% a PASI-75 and 4% a PASI-90 on intention-to-treat analysis at 3 months with an overall, statistically significant, reduction in PASI from 13.9 + or - 9.0 to 11.3 + or - 9.2 (P < 0.0001). At 3 months, lymphopenia was seen in 33% of the cohort with significantly lower counts in patients responsive to FAE (P = 0.008). In addition, by 3 months, 36% of concomitant antipsoriatic medication had been stopped and 25% of doses had been reduced without loss of disease control. Side-effects (most commonly diarrhoea, abdominal pain and flushing) were reported by 74% of patients resulting in cessation of FAE in 36%.. FAE is a useful alternative treatment option in patients with severe, treatment-resistant, chronic plaque psoriasis and can allow dose reduction, and subsequent cessation, of other, potentially more toxic agents.

Topics: Adult; Aged; Chronic Disease; Cohort Studies; Dermatologic Agents; Dimethyl Fumarate; Female; Fumarates; Humans; Male; Middle Aged; Prospective Studies; Psoriasis; Severity of Illness Index; Treatment Outcome; Young Adult

The antipsoriatic dimethylfumarate (DMF) has been anecdotically reported to reduce asthma symptoms and to improve quality of life of asthma patients. DMF decreases the expression of proinflammatory mediators by inhibiting the transcription factor NF-kappaB and might therefore be of interest for the therapy of inflammatory lung diseases. In this study, we determined the effect of DMF on platelet-derived growth factor (PDGF)-BB- and TNFalpha-induced asthma-relevant cytokines and NF-kappaB activation by primary human asthmatic and nonasthmatic airway smooth muscle cells (ASMC). Confluent nonasthmatic and asthmatic ASMC were incubated with DMF (0.1-100 microM) and/or dexamethasone (0.0001-0.1 microM), NF-kappaB p65 siRNA (100 nM), the NF-kappaB inhibitor helenalin (1 microM) before stimulation with PDGF-BB or TNFalpha (10 ng/ml). Cytokine release was measured by ELISA. NF-kappaB, mitogen and stress-activated kinase (MSK-1), and CREB activation was determined by immunoblotting and EMSA. TNFalpha-induced eotaxin, RANTES, and IL-6 as well as PDGF-BB-induced IL-6 expression was inhibited by DMF and by dexamethasone from asthmatic and nonasthmatic ASMC, but the combination of both drugs showed no glucocorticoid sparing effect in either of the two groups. NF-kappaB p65 siRNA and/or the NF-kappaB inhibitor helenalin reduced PDGF-BB- and TNFalpha-induced cytokine expression, suggesting the involvement of NF-kappaB signaling. DMF inhibited TNFalpha-induced NF-kappaB p65 phosphorylation, NF-kappaB nuclear entry, and NF-kappaB-DNA complex formation, whereas PDGF-BB appeared not to activate NF-kappaB within 60 min. Both stimuli induced the phosphorylation of MSK-1, NF-kappaB p65 at Ser276, and CREB, and all were inhibited by DMF. These data suggest that DMF downregulates cytokine secretion not only by inhibiting NF-kappaB but a wider range of NF-kappaB-linked signaling proteins, which may explain its potential beneficial effect in asthma.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Becaplermin; Bronchi; Cells, Cultured; Chemokine CCL11; Chemokine CCL5; Chronic Disease; Cyclic AMP Response Element-Binding Protein; Cytokines; Dexamethasone; Dimethyl Fumarate; Enzyme Inhibitors; Fumarates; Glucocorticoids; Humans; I-kappa B Proteins; Immunosuppressive Agents; Interleukin-6; Isoquinolines; Myocytes, Smooth Muscle; NF-KappaB Inhibitor alpha; Platelet-Derived Growth Factor; Pneumonia; Proto-Oncogene Proteins c-sis; Ribosomal Protein S6 Kinases, 90-kDa; RNA, Small Interfering; Sesquiterpenes; Sesquiterpenes, Guaiane; Sulfonamides; Transcription Factor RelA; Tumor Necrosis Factor-alpha

YM-393059 is a novel phosphodiesterase (PDE) 7A and PDE4 dual inhibitor that inhibits both Th1 [interleukin (IL)-2 and interferon-gamma] and Th2 (IL-4) cytokines in vitro [Yamamoto, S., Sugahara, S., Naito, R., Ichikawa, A., Ikeda, K., Yamada, T., Shimizu, Y., 2006. The effects of a novel phosphodiesterase 7A and -4 dual inhibitor, YM-393059, on T-cell-related cytokine production in vitro and in vivo. Eur. J. Pharmacol. 541, 106-114]. To characterize the pharmacological profile of YM-393059, its effects on several acute and chronic inflammation models were examined. In acute inflammation models, YM-393059 significantly suppressed the delayed-type hypersensitivity reaction to sheep red blood cells in mice with an ED(50) value of 17.1 mg/kg. YM-393059 failed to suppress paw edema in the carrageenin-induced edema model in rats. These pharmacological effects were similar to those of cyclosporine, a typical T-cell immunosuppressant. However, YM-393059, but not cyclosporine, significantly inhibited zymosan-induced neutrophil accumulation in mice with an ED(50) value of 25.7 mg/kg. In mouse toluene-2,4-diisocyanate-induced contact dermatitis, a chronic inflammation model, YM-393059 and cyclosporine significantly suppressed ear edema at doses of 30 and 20 mg/kg, respectively. In this model, YM-393059 also tended to reduce the serum immunoglobulin E antibody level, whereas cyclosporine dramatically potentiated it. These results suggest that YM-393059 inhibits both Th1- and Th2-cell-dependent reactions and also the function of neutrophils.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Acute Disease; Animals; Anti-Inflammatory Agents; Carrageenan; Chronic Disease; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclic Nucleotide Phosphodiesterases, Type 7; Cyclosporine; Dermatitis, Contact; Edema; Erythrocytes; Fumarates; Hypersensitivity, Delayed; Immunosuppressive Agents; Indoles; Inflammation; Male; Mice; Mice, Inbred BALB C; Peritonitis; Phosphodiesterase Inhibitors; Rats; Rats, Sprague-Dawley; Sheep; Sulfonamides; Toluene 2,4-Diisocyanate; Zymosan

The effectiveness and safety of fumaric acid esters (FAEs) for the treatment of psoriasis has been demonstrated. Their mode of action, however, is poorly understood. To determine the immunomodulatory potential of calcium methyl hydrogen fumarate (CaMHF) in transplant models, we tested the compound in rat transplantation models of acute rejection (AR) and chronic rejection (CR). Orthotopic kidney transplantation was combined with contralateral nephrectomy using the strain combinations WF to BDIX (AR) and F344 to LEW (CR). Recipients were treated orally prophylactically (day -28 to day +28, AR and CR model) or therapeutically (day +30 to day +60, CR model). CaMHF significantly prolonged the time to onset of AR in the WF/BDIX model. The half-lives of the grafts were 14 days in the CaMHF group, 7 days in the placebo-treated control group and 9 days in the untreated control group ( P<0.01). Three of ten CaMHF-treated rats showed permanent graft acceptance (defined as survival for >100 days) resulting in a mean survival time of >42.3+/-41.0 ( P<0.01) in comparison with >28.3+/-38.3 days in the placebo-treated group and 9.4+/-2.6 days in the untreated control group. In the F344/LEW model of chronic graft injury, only prophylactic CaMHF treatment significantly inhibited the development of CR ( P=0.001; mean survival times >28.4+/-2.0 weeks, >23.9+/-6.0 weeks and >21.1+/-5.4 weeks in the prophylactic CaMHF, therapeutic CaMHF, and placebo group, respectively). By 30 weeks six of ten prophylactically treated animals were still alive, but only three of nine and one of ten were alive in the therapeutically treated and placebo-treated groups, respectively ( P<0.05). These findings indicate that CaMHF treatment effectively inhibits AR and CR, and demonstrates marked in vivo immunomodulatory efficacy. Thus, FAEs should be considered as drugs showing considerable immunosuppressive efficacy. This might have implications with regard to safety issues (e.g. immune monitoring) and novel potentially suitable indications (e.g. transplantation and other immune diseases).

Topics: Acute Disease; Animals; Chronic Disease; Creatinine; Fumarates; Graft Rejection; Graft Survival; Immunosuppressive Agents; Kidney Transplantation; Male; Rats; Rats, Inbred Strains

We studied the electrophysiological effects of LU111995 (1-15 mg/kg p.o.) in conscious dogs with chronic atrioventricular block and ventricular pacing at 50 to 130 beats/min. LU111995 had no effects on idioventricular rhythm, QRS duration, and ventricular conduction time. It significantly prolonged Q-T interval (by 5-8%) and effective refractory period (ERP) (by 5-12%) with the maximal effect at 4 h after a 10 mg/kg dose. At 10 and 15 mg/kg, it increased the ERP/Q-T ratio. In vitro, the effects of LU111995 (1 x 10(-7) to 1 x 10(-5) M) on action potentials of Purkinje fibers (PFs) and M cells were studied at cycle lengths (CL) of 300 to 2000 ms. It had no effects on maximum diastolic potential and action potential amplitude in either tissue. High concentrations induced a moderate, rate-independent decrease of Vmax in M cells. In PFs and M cells, it produced reverse use-dependent lengthening of action potential duration (APD). In PFs at long CL, the drug exhibited a biphasic concentration-dependent effect on APD: maximum prolongation (by 26% at a CL of 2000 ms) was attained at 1 x 10(-6) M, and a decrease of APD occurred at higher concentrations. In M cells, the maximum effect on APD occurred at 3 x 10(-6) M. Early afterdepolarizations were seen in 50% of M cell preparations but only at CL of 2000 ms. Triggered activity did not occur. In summary, LU111995 prolongs the Q-T interval to a limited degree and is not arrhythmogenic over the physiological range of CLs.

Topics: Action Potentials; Animals; Antipsychotic Agents; Chronic Disease; Dogs; Electrocardiography; Electrophysiology; Female; Fumarates; Heart; Heart Block; Heart Rate; In Vitro Techniques; Male; Myocardial Contraction; Myocardium; Purkinje Fibers; Quinazolines; Refractory Period, Electrophysiological

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.

Topics: Acute Kidney Injury; Adult; Biopsy; Chronic Disease; Drug Combinations; Drug Therapy, Combination; Female; Fumarates; Humans; Kidney; Powders; Psoriasis

Topics: Chronic Disease; Fumarates; Gluconeogenesis; Humans; Hyperventilation; Infant; Intellectual Disability; Ketoglutaric Acids; Lactates; Malates; Muscle Tonus; Psychomotor Disorders; Pyruvate Carboxylase Deficiency Disease; Succinates; Vitamins

Topics: Acute Disease; Amides; Analgesics; Chronic Disease; Drug Combinations; Drug Evaluation; Female; Fumarates; Humans; Male; Nerve Compression Syndromes; Neuralgia; Pain; Piperidines; Propionates; Pyridines

Topics: Benzene Derivatives; Chronic Disease; Ethers; Fumarates; Histamine; Histamine H1 Antagonists; Humans; Pyrrolidines; Skin Tests; Urticaria

Topics: Alanine Transaminase; Alkaline Phosphatase; Arginine; Aspartate Aminotransferases; Bilirubin; Biopsy; Blood Proteins; Cholesterol; Chronic Disease; Clinical Enzyme Tests; Creatine Kinase; Fumarates; Hepatitis; Hepatitis A; Humans; L-Lactate Dehydrogenase; Liver; Liver Diseases; Liver Neoplasms; Lyases; Methods; Neoplasm Metastasis; Succinates