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Objective: Fumaric acid is a dicarboxylic acid that belongs to the phenolic class enriched in fruits and vegetables that are traditionally used for the treatment of various ailments. The research was planned to find out the anti-inflammatory and anti-arthritic activities of fumaric acid using in-vitr o and in-vivo assays. Moreover, safety study was also done., Materials and methods: The 0.1 ml complete Freund's adjuvant was injected in left hind paw in all Wistar rats except normal rats at day 1 to induced arthritis. The treatment with fumaric acid at 10, 20, 40, and fumaric acid 40 mg/kg together with methotrexate (MTX) was administered to immunized rats at 8th day via oral gavage and continued till 28th day though, MTX was administered as standard control., Results: The fumaric acid notably ( p  < 0.0001) lessened the paw edema and arthritic scoring, reinstated body and immune organ weight, and oxidation status in treated rats. Fumaric acid notably restored altered C-reactive protein, rheumatoid factor, liver function tests, ESR, WBCs, RBCs and Hb levels in treated rats. The fumaric acid in combination noticeably ( p  < 0.01-0.0001) suppressed the expression of TNF- α, IL-6, IL-1β, NF-kβ, and COX-2, and over expressed IL-4, and IL-10 in contrast to other treated groups. Fumaric acid had presented a dose-dependent antioxidant, anti-inflammatory and anti-arthritic activities while notable activity exhibited by fumaric acid in combination with MTX. The fumaric acid exhibited non-significant clinical signs of toxicity and mortality in acute toxicity study. The LD50 was more than 2000 mg/kg., Conclusion: Fumaric acid in combination can be used as disease-modifying anti-rheumatic drug but it will need extensive pre-clinical and clinical studies.

Dietary methane (CH 4 ) mitigation is in some cases associated with an increased hydrogen (H 2 ) emission. The objective of the present study was to investigate the acute and short-term effects of acceptors for H 2 (fumaric acid, acrylic acid, or phloroglucinol) supplemented via pulse-dosing to dairy cows fed CH 4 mitigating diets (using nitrate or 3-nitrooxypropanol), on gas exchange, rumen gas, and VFA composition. For this purpose, 2 individual 4 × 4 Latin square experiments were conducted with 4 periods of 3 d (nitrate supplementation) and 7 d (3-nitrooxypropanol supplementation), respectively. In each study, 4 rumen-cannulated Danish Holstein cows were used. Each additive for CH 4 mitigation was included in the ad libitum-fed diet within the 2 experiments (exp. 1 and exp. 2), to which the cows were adapted for at least 14 d. Acceptors for H 2 were administered twice daily in equal portions through the rumen fistula immediately after feeding of the individual cow. In exp. 1 (nitrate), the treatments were CON-1 (no H 2 -acceptor), FUM-1 (fumaric acid), ACR-1 (acrylic acid), and FUM+ACR-1 (50% FUM-1 + 50% ACR-1). In exp. 2 (3-nitrooxypropanol), the 3 treatments, CON-2, FUM-2, and ACR-2, were similar to CON-1, FUM-1 and ACR-1 treatments, however the fourth treatment was PHL-2 (phloroglucinol). Gas exchanges were measured in respiration chambers, and samples of rumen liquid and headspace gas were taken in time series relative to feeding and dosing on specific days. Headspace gas was analyzed for gas composition, and rumen liquid was analyzed for VFA composition and dissolved gas concentrations. Headspace gas composition and dissolved gas concentration were only measured in exp. 2. Dry matter intake was reduced upon acrylic acid supplementation. There were no significant effects of any treatments in any experiments on H 2 emission, except for a decrease in hourly H 2 emission rate (g/h) at 1 h after feeding in both experiments. In exp. 2, H 2 headspace proportions increased with ACR-2 supplementation, whereas dissolved concentrations were unaffected. In exp. 1, cows on ACR-1 increased propionate proportion at 1 h after feeding. In exp. 2, both FUM-2 and ACR-2 increased rumen propionate proportion in the hours after feeding and dosing. There was no effect on rumen acetate for cows on PHL-2. There was a strong positive correlation between rumen dissolved CH 4 and headspace CH 4 (r = 0.84), whereas the equivalent correlation was weaker for H 2 (r = 0.41). For the relationship between dissolved concentrations and emissions of CH 4 and H 2 , there was a moderate positive correlation for CH 4 (r = 0.54), whereas it was weak for H 2 (r = 0.28) with zero slope. In conclusion, the results suggested that fumaric acid and acrylic acid to some extent was reduced to propionate without associative effects on measures for H 2 redirection. Furthermore, phloroglucinol seemed not to be metabolized in the rumen in the present study, because no effects on rumen acetate or measures of H 2 were observed. Changes in H 2 headspace and emission may be a poor proxy for actual changes in the rumen fluid concentration of H 2 ., (© 2024, The Authors. Published by Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Background: The anti-interleukin-23 antibody guselkumab (GUS) demonstrated favourable week 24 efficacy and safety over fumaric acid esters (FAE) in systemic treatment-naïve patients with moderate-to-severe plaque psoriasis (study part I)., Objectives: To compare, in study part II, the sustainability of treatment responses (weeks 24-32) in GUS- and FAE-treated patients and treatment responses (weeks 32-56) in patients treated with GUS and FAE and in FAE nonresponders switching to GUS; and, in part III, to investigate the maintenance of response through week 100 in patients withdrawn from GUS at week 56., Methods: At week 0, systemic treatment-naïve patients were randomized 1 : 1 to GUS or FAE as per label. At week 32, patients with a Psoriasis Area and Severity Index (PASI) 75 (≥ 75% improvement in PASI score) response (r) continued assigned treatment (GUSr-GUS; FAEr-FAE), whereas nonresponders (nr) received GUS (FAEnr-GUS; GUSnr-GUS). GUS-treated patients with a week 56 PASI 90 response (≥ 90% improvement in PASI score) were withdrawn (w) and followed until loss of response or week 100., Results: At week 32, 98% (n = 54/55) of GUS- and 41% (n = 14/34) of FAE-treated patients were PASI 75 responders. At week 56, 91%, 50% and 80% of GUSr-GUS, FAEr-FAE and FAEnr-GUS patients, respectively, achieved a PASI 90 response; 72%, 29% and 45%, respectively, achieved a Dermatology Life Quality Index score of 0/1. At week 100, 44 weeks postwithdrawal, 47% (n = 17/36) and 25% (n = 3/12) of GUS-GUSw and FAE-GUSw patients, respectively, maintained a PASI score ≤ 5. Overall, the adverse event and discontinuation rates were lower for GUS than FAE., Conclusions: In these exploratory analyses, GUS, as a first-line systemic treatment or second-line systemic treatment in FAE nonresponders, was associated with long-term clinical efficacy up to week 100, including a withdrawal period., Competing Interests: Conflicts of interest D.T. has received investigator honoraria, honoraria for consultancy and/or has received speakers’ honoraria and/or research grants from AbbVie, Almirall, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Galapagos, Galderma, Janssen, LEO Pharma, Lilly, MSD, Novartis, Pfizer, Regeneron/Sanofi, Samsung and UCB. C.T. has received investigator honoraria and/or has received speakers’ honoraria and/or has received grants from and/or has been an advisor for the following companies: AbbVie, Allergopharma, Almirall, Janssen, LEO Pharma and UCB. A.P. has received investigator honoraria and/or has received speakers’ honoraria and/or has received grants from and/or has been an advisor for the following companies: AbbVie, Almirall-Hermal, Amgen, Biogen Idec, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, GSK, Hexal, Janssen, LEO Pharma, Medac, Merck Serono, Mitsubishi, MSD, Novartis, Pfizer, Regeneron, Roche, Sandoz Biopharmaceuticals, Schering-Plough, Tigercat Pharma and UCB Pharma. M. Sebastian has received investigator honoraria, has received grants from and/or has been an advisor/consultant for the following companies: AbbVie, Almirall, Boehringer Ingelheim, Celgene, Dr. Reddy, Galderma, GSK, Janssen, LEO Pharma, Lilly, MSD, Mundipharma, Novartis, Regeneron and UCB Pharma. M. Sticherling has received investigator and/or speaker honoraria, has received grants from and/or has participated in clinical studies for the following companies: AbbVie, Actelion, Almirall, Amgen, Boehringer Mannheim, Celgene, Galderma, GSK, Hexal, Janssen, LEO Pharma, Lilly, MSD, Mundipharma, Novartis, Pfizer, Sandoz, Sanofi and UCB Pharma. S.G. has been an advisor for and/or has received speakers’ honoraria and/or has received grants and/or has participated in clinical trials for the following companies: AbbVie, Affibody, Akari Therapeutics, Almirall-Hermal, Amgen, Argenx, Aristea Therapeutics, Biogen Idec, Bioskin, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Dermira, Eli Lilly, Galderma, Hexal, Incyte, Janssen-Cilag, Johnson & Johnson, Klinge Pharma, Kymab, LEO Pharma, Medac, MSD, Neubourg Skin Care, Novartis, Pfizer, Pierre Fabre, Principia Biopharma, Regeneron Pharmaceuticals, Sandoz Biopharmaceuticals, Sanofi-Aventis, Trevi Therapeutics and UCB Pharma. K.S. has received investigator and/or speaker honoraria, has received grants from and/or has participated in clinical studies for the following companies: AbbVie, Almirall, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, Janssen-Cilag, LEO Pharma, Novartis, Pfizer and UCB. S.W., S.K., C.R. and H.B. are employees of Janssen-Cilag, Germany. F.T. owns Taut Science and Service, a consultancy specialized in clinical development and medical affairs, and is receiving consultancy fees from the Janssen group. K.E. has received investigator honoraria and/or has received speakers’ honoraria from and/or received grants and/or has been an advisor for the following companies: AbbVie, BMS, Boehringer Ingelheim, Janssen, Lilly, LEO Pharma, Novartis, Pfizer, Sanofi and UCB., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Diroximel fumarate (Vumerity ® ), an orally administered disease-modifying drug (DMD), expands the available treatment options for adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting MS (RRMS), and active secondary progressive MS. It demonstrates bioequivalence to dimethyl fumarate and was developed to provide similar clinical benefits, but with an improved gastrointestinal (GI) tolerability profile. In RRMS patients who are treatment-naïve or were previously treated with interferon-β or glatiramer acetate, diroximel fumarate reduces annualized relapse rates, with most patients experiencing no relapses during treatment, and reduces the formation of new MS-associated brain lesions. Diroximel fumarate has an acceptable tolerability profile that is consistent with that of dimethyl fumarate, albeit with a significantly lower rate of GI adverse events.

Background: Tecfidera ® (dimethyl fumarate [DMF]) is an approved product for the treatment of relapsing forms of multiple sclerosis. Monomethyl fumarate (MMF) is the only active metabolite of DMF and is responsible for its therapeutic efficacy., Objective: The objective of this study was to determine whether two Bafiertam™ capsules each containing 95 mg of MMF is bioequivalent to one Tecfidera ® capsule containing 240 mg of DMF, a prodrug of MMF., Methods: This was a single-dose, open-label, randomized, two-way crossover study evaluating two treatments over two periods with a washout interval between treatments. Fifty healthy subjects were randomized to receive a single dose of the test drug MMF 190 mg as 2 × 95 mg delayed-release capsules or the reference drug DMF 240 mg as a 1 × 240-mg delayed-release capsule. Blood samples were obtained prior to dosing and at prespecified time points through 24 h post-dose to determine plasma concentrations of MMF. The pharmacokinetic parameters of MMF were calculated including maximum observed concentration, time to reach maximum observed concentration, apparent half-life of the drug in plasma, AUC 0-t which is the area under the plasma concentration-time curve (AUC) from time zero (dosing time) to the last time point, t, with measurable analyte concentration, and AUC 0-inf , which is AUC 0-t plus the extrapolated AUC from time t to infinity., Results: The geometric least-squares mean ratios (90% confidence interval) of the test drug MMF vs the reference drug DMF were 96.80% (92.18-101.64), 96.35% (91.81-101.12), and 104.84% (95.54-115.05) for AUC 0-t , AUC 0-inf , and maximum observed concentration, respectively. Two capsules of Bafiertam™ was safe and generally well tolerated. The most common adverse event for both products was flushing, 60% and 51%, for Bafiertam™ and Tecfidera ® , respectively., Conclusions: Based on the statistical analysis results of the pharmacokinetic parameters of MMF, a single oral dose of two Bafiertam™ DR 95 mg capsules is bioequivalent to a single oral dose of one Tecfidera ® DR 240 mg capsule., Clinical Trial Registration: This study was retrospectively registered with ClinicalTrials.gov (NCT04570670) on 30 September, 2020.

Background: Inflammatory bowel disease affects approximately seven million people globally. Iron deficiency anaemia can occur as a common systemic manifestation, with a prevalence of up to 90%, which can significantly affect quality of life, both during periods of active disease or in remission. It is important that iron deficiency anaemia is treated effectively and not be assumed to be a normal finding of inflammatory bowel disease. The various routes of iron administration, doses and preparations present varying advantages and disadvantages, and a significant proportion of people experience adverse effects with current therapies. Currently, no consensus has been reached amongst physicians as to which treatment path is most beneficial., Objectives: The primary objective was to evaluate the efficacy and safety of the interventions for the treatment of iron deficiency anaemia in people with inflammatory bowel disease., Search Methods: We searched CENTRAL, MEDLINE, Embase, and two other databases on 21st November 2019. We also contacted experts in the field and searched references of trials for any additional trials., Selection Criteria: Randomised controlled trials investigating the effectiveness and safety of iron administration interventions compared to other iron administration interventions or placebo in the treatment of iron deficiency anaemia in inflammatory bowel disease. We considered both adults and children, with studies reporting outcomes of clinical, endoscopic, histologic or surgical remission as defined by study authors., Data Collection and Analysis: Two review authors independently conducted data extraction and 'Risk of bias' assessment of included studies. We expressed dichotomous and continuous outcomes as risk ratios and mean differences with 95% confidence intervals. We assessed the certainty of the evidence using the GRADE methodology., Main Results: We included 11 studies (1670 randomised participants) that met the inclusion criteria. The studies compared intravenous iron sucrose vs oral iron sulphate (2 studies); oral iron sulphate vs oral iron hydroxide polymaltose complex (1 study); oral iron fumarate vs intravenous iron sucrose (1 study); intravenous ferric carboxymaltose vs intravenous iron sucrose (1 study); erythropoietin injection + intravenous iron sucrose vs intravenous iron sucrose + injection placebo (1 study); oral ferric maltol vs oral placebo (1 study); oral ferric maltol vs intravenous ferric carboxymaltose (1 study); intravenous ferric carboxymaltose vs oral iron sulphate (1 study); intravenous iron isomaltoside vs oral iron sulphate (1 study); erythropoietin injection vs oral placebo (1 study). All studies compared participants with CD and UC together, as well as considering a range of disease activity states. The primary outcome of number of responders, when defined, was stated to be an increase in haemoglobin of 20 g/L in all but two studies in which an increase in 10g/L was used. In one study comparing intravenous ferric carboxymaltose and intravenous iron sucrose, moderate-certainty evidence was found that intravenous ferric carboxymaltose was probably superior to intravenous iron sucrose, although there were responders in both groups (150/244 versus 118/239, RR 1.25, 95% CI 1.06 to 1.46, number needed to treat for an additional beneficial outcome (NNTB) = 9). In one study comparing oral ferric maltol to placebo, there was low-certainty evidence of superiority of the iron (36/64 versus 0/64, RR 73.00, 95% CI 4.58 to 1164.36). There were no other direct comparisons that found any difference in the primary outcomes, although certainty was low and very low for all outcomes, due to imprecision from sparse data and risk of bias varying between moderate and high risk. The reporting of secondary outcomes was inconsistent. The most common was the occurrence of serious adverse events or those requiring withdrawal of therapy. In no comparisons was there a difference seen between any of the intervention agents being studied, although the certainty was very low for all comparisons made, due to risk of bias and significant imprecision due to the low numbers of events. Time to remission, histological and biochemical outcomes were sparsely reported in the studies. None of the other secondary outcomes were reported in any of the studies. An analysis of all intravenous iron preparations to all oral iron preparations showed that intravenous administration may lead to more responders (368/554 versus 205/373, RR 1.17, 95% CI 1.05 to 1.31, NNTB = 11, low-certainty due to risk of bias and inconsistency). Withdrawals due to adverse events may be greater in oral iron preparations vs intravenous (15/554 versus 31/373, RR 0.39, 95% CI 0.20 to 0.74, low-certainty due to risk of bias, inconsistency and imprecision)., Authors' Conclusions: Intravenous ferric carboxymaltose probably leads to more people having resolution of IDA (iron deficiency anaemia) than intravenous iron sucrose. Oral ferric maltol may lead to more people having resolution of IDA than placebo. We are unable to draw conclusions on which of the other treatments is most effective in IDA with IBD (inflammatory bowel disease) due to low numbers of studies in each comparison area and clinical heterogeneity within the studies. Therefore, there are no other conclusions regarding the treatments that can be made and certainty of all findings are low or very low. Overall, intravenous iron delivery probably leads to greater response in patients compared with oral iron, with a NNTB (number needed to treat) of 11. Whilst no serious adverse events were specifically elicited with any of the treatments studied, the numbers of reported events were low and the certainty of these findings very low for all comparisons, so no conclusions can be drawn. There may be more withdrawals due to such events when oral is compared with intravenous iron delivery. Other outcomes were poorly reported and once again no conclusions can be made as to the impact of IDA on any of these outcomes. Given the widespread use of many of these treatments in practice and the only guideline that exists recommending the use of intravenous iron in favour of oral iron, research to investigate this key issue is clearly needed. Considering the current ongoing trials identified in this review, these are more focussed on the impact in specific patient groups (young people) or on other symptoms (such as fatigue). Therefore, there is a need for studies to be performed to fill this evidence gap., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Aims: To study the effect of direct renin inhibitor (aliskiren) on the renal function during acute and chronic partial ureteral obstruction (PUO) in rat solitary kidney., Main Methods: Sixty male Sprague-Dawley rats were randomly allocated into three groups (20 rats each); sham, PUO and aliskiren groups. Right nephrectomy was performed in all groups. Rats in PUO and aliskiren groups were subjected to left PUO and received no treatment and aliskiren (10 mg/kg, orally, once per day till sacrification), respectively. Blood samples were then collected for biochemical measurements. Ten rats from each group were sacrificed after two weeks, while the remaining rats were sacrificed after four weeks. Left kidneys were harvested for histopathological examination, BCL-2, interleukin (IL)-6, transforming growth factor (TGF)-β1, collagen I and fibronectin relative gene expression and assessment of glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) activity., Key Findings: After two and four weeks of PUO, aliskiren significantly recompensed the rise of serum creatinine (Scr) and blood urea nitrogen (BUN). Aliskiren also revealed significantly better histopathological results regarding cortical and medullary necrosis, regeneration and inflammatory cell infiltration. Aliskiren group showed statistically significant up-regulation of BCL-2 and down-regulation of IL-6, TGF-β1, collagen I and fibronectin relative gene expression. Aliskiren significantly increased GSH and SOD activity and reduced MDA and NO activity. Moreover, aliskiren administration for four weeks after PUO significantly yielded more renoprotective effect compared to its administration for two weeks., Significance: Aliskiren ameliorates the deterioration of the renal function during acute and chronic PUO in a solitary kidney., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: Worldwide, diabetic neuropathy (DN) is a major complication of diabetes mellitus. The direct renin inhibitor aliskiren is recognized as a treatment for cardiovascular disease in diabetic patients, but little is known about its potential benefits in cases of diabetic neuropathy. Accordingly, we investigated the effects of aliskiren (ALIS) and gliclazide (GLZ) and their combination therapy on peripheral neuropathy in streptozotocin-induced diabetic rats., Methods: In total, 112 adult Sprague-Dawley rats were used for this study. Diabetes was induced using streptozotocin (STZ), whereas the control group was treated with an equal volume of citrate buffer. The diabetic rats were divided randomly into six groups according to the proposed treatment regime: diabetic control (DC), gliclazide (GLZ), aliskiren (ALIS), ramipril (RAM), (GLZ + ALIS) and (GLZ + RAM). Behavioural responses to thermal (hot-plate) and mechanical (tail-pinch) pain were evaluated. After eight weeks of daily treatments, the animals were fasted and sacrificed. The blood samples were collected, with the serum separated and subjected to various biochemical and enzyme analyses so as to assess the effect of the treatments on diabetic peripheral neuropathy., Results: After 8 weeks, aliskiren alone and in combination with gliclazide therapy had a significant effect ( P  < .001) in reducing blood glucose levels and showed increased hot-plate and tail-flick latencies compared with the diabetic control group. The threshold of mechanical hyperalgesia was also significantly elevated ( P  < .001)., Conclusions/interpretations: These data suggest that either aliskerin alone or in combination with gliclazide can protect against the development and progression of diabetic neuropathy., (© 2020 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

Background NT-proBNP (N-terminal pro-B-type natriuretic peptide) improves the discriminatory ability of risk-prediction models in type 2 diabetes mellitus (T2DM) but is not yet used in clinical practice. We assessed the discriminatory strength of NT-proBNP by itself for death and cardiovascular events in high-risk patients with T2DM. Methods and Results Cox proportional hazards were used to create a base model formed by 20 variables. The discriminatory ability of the base model was compared with that of NT-proBNP alone and with NT-proBNP added, using C-statistics. We studied 5509 patients (with complete data) of 8561 patients with T2DM and cardiovascular and/or chronic kidney disease who were enrolled in the ALTITUDE (Aliskiren in Type 2 Diabetes Using Cardiorenal Endpoints) trial. During a median 2.6-year follow-up period, 469 patients died and 768 had a cardiovascular composite outcome (cardiovascular death, resuscitated cardiac arrest, nonfatal myocardial infarction, stroke, or heart failure hospitalization). NT-proBNP alone was as discriminatory as the base model for predicting death (C-statistic, 0.745 versus 0.744, P =0.95) and the cardiovascular composite outcome (C-statistic, 0.723 versus 0.731, P =0.37). When NT-proBNP was added, it increased the predictive ability of the base model for death (C-statistic, 0.779 versus 0.744, P <0.001) and for cardiovascular composite outcome (C-statistic, 0.763 versus 0.731, P <0.001). Conclusions In high-risk patients with T2DM, NT-proBNP by itself demonstrated discriminatory ability similar to a multivariable model in predicting both death and cardiovascular events and should be considered for risk stratification. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT00549757.

Background: Renin is the starting point of the renin angiotensin (RA) system cycle. Aliskiren (AL), which is a direct renin inhibitor, suppressed the entire RA cycle. In the present study, the efficacy of add-on of AL treatment in patients with essential hypertension (HT) was investigated., Methods: This study was a multi-center, open-label, prospective, observational study. Study subjects were patients with essential HT and poor blood pressure (BP) control, who had received calcium channel blocker monotherapy or angiotensin II receptor blocker monotherapy or had not received any BP lowering drugs. Following add-on of AL for 12 months, BP and additional laboratory findings were analyzed., Results: A total of 150 subjects were enrolled. There were 50 dropout subjects including discontinuation. Dropouts were the highest in the ARB combination therapy group at 9 subjects due to adverse events, and 3 of them were due to hyperkalemia. A significantly higher number of patients with chronic kidney disease (CKD) dropped out compared to patients without CKD (φ = 0.166, p < .05). BP before add-on of AL was 155/88 mmHg. After add-on of AL, BP was significantly improved and this lowering was sustained for 3 months (136/78 mmHg, p < .001), 6 months (136/77 mmHg, p < .001) and 12 months (134/78 mmHg, p < .001). In contrast, add-on of AL increased the potassium level and decreased the estimated glomerular filtration rate., Conclusion: While add-on AL treatment achieved a favorable and sustained decrease of BP in this study, caution is necessary with regard to elevation of potassium levels and renal impairment.

Purpose: (R,R)-penehyclidine fumarate (R2PHF) is a highly selective muscarinic receptor antagonist used to suppress glandular secretions before general anesthesia or tracheal intubation and to treat organophosphorus poisoning. This is the first-in-human study to evaluate the safety, tolerability, and pharmacokinetics of R2PHF in healthy subjects., Materials and Methods: In this single-center, double-blind, randomized study, 23 subjects received escalation doses of R2PHF (0.0625 mg, 0.25 mg, 0.50 mg, and 1.0 mg), 4 received the parent drug penehyclidine hydrochloride (PHC, 1.0 mg) as a reference, and 4 received a placebo. The pharmacokinetic parameters of R2PHF were determined. Tolerability was assessed based on adverse events and clinical laboratory tests., Results: Single doses of 0.0625 mg, 0.25 mg, and 0.50 mg R2PHF were well-tolerated by healthy subjects. Delirium was set as the termination outcome and appeared in 1 case receiving 1.0 mg. For this reason, the escalation experiment was cut off. The mean half-life (T 1/2 ) ranged from 30.57 to 32.27 hours., Conclusion: R2PHF was safe and well-tolerated at doses ranging from 0.0625 to 0.50 mg. A single administration of 0.50 mg was determined to be the maximum tolerated dose of R2PHF. Further pharmacodynamics, safety, and efficacy testing is required to advance R2PHF to the next stage of clinical development and application.

The significance of switching of the nucleos(t)ide analog used to treat patients with hepatitis B virus (HBV) from entecavir (ETV) to tenofovir alafenamide fumarate (TAF) is uncertain. The subjects of this study were 159 patients with HBV who received treatment with ETV followed by TAF. Among these patients, serial changes in the HBV marker levels were monitored in 92 patients in whom the serum HBsAg levels were ≥100 IU/mL during the 48-week period immediately before and after the switching. A questionnaire survey for medication compliance was performed in 127 patients. The serum HBsAg levels (log IU/mL) decreased by 0.041 during the ETV treatment period and by 0.068 during the TAF administration period. The degree of reduction was higher during the TAF administration period than during the ETV administration period in patients without cirrhosis (P = .030), patients with genotype B HBV (P = .014), and patients with undetectable serum HBcrAg (P = .038). Multivariate analysis revealed the HBV genotype (B vs C; odds ratio, 3.400; P = .025) and serum aspartate aminotransferase level (every 1+; 1.111; P = .015) at the time of switching as factors influencing the treatment efficacy. Thirty-six patients (28%) responded that the number of days that they forgot to take the drug decreased after the drug switching, and 77 patients (61%) reported feeling satisfied with the drug switching. Switching of the nucleos(t)ide analog used from ETV to TAF may be useful in the treatment of patients with HBV infection, as it is associated with both a decrease in the serum HBsAg level and improvement of the medication compliance., (© 2019 Wiley Periodicals, Inc.)

Background: Fumaric acid esters (FAE) represent the most widely-used oral systemic treatment for moderate-to-severe psoriasis in Germany. Not licensed outside Germany, little is known about the demographics of patients receiving FAE. PsoBest is a large national patient registry documenting long-term treatment of psoriasis in Germany., Objectives: To evaluate FAE relative to methotrexate (MTX) in patients from the PsoBest registry., Materials and Methods: Patient demographics, disease severity at baseline and dosing regimen were reported for patients who initiated treatment with either FAE or MTX between 2007 and 2015., Results: Overall, 1,409 patients treated with FAE and 877 with MTX were analysed. At baseline, compared with the MTX cohort, patients receiving FAE were younger (45.4 vs. 50.2 years; p≤0.001) and had a lower BMI (28.0 vs. 28.3 kg/m 2 ; p≤0.023) and less nail involvement (45.4% vs. 50.7%; p≤0.013). The MTX cohort reported a greater mean duration of illness at baseline (18.2 years vs. 14.9 years; p≤0.001). In total, 85.6% and 58.5% patients in the FAE and MTX cohorts, respectively, had not received prior systemic therapy. Cardiovascular disease was the most prevalent comorbidity (FAE: 26.7%; MTX: 31.5%; p≤0.014). Health-related quality of life was similar for both cohorts (mean DLQI: 10.8 [FAE]; 10.5 [MTX]; p≤0.079). Mean FAE dose was 165.0 mg at inclusion and 406.4 mg following up-titration., Conclusion: This study contributes to a better understanding of the usual practices of long-term FAE use, which may also lead to improved treatment strategies not only in Germany, but in other countries where FAE may become available in the near future.

Aliskiren is an oral antihypertensive medication that acts by directly inhibiting renin. High levels of circulating renin and prorenin activate the pathological signaling pathway of fibrosis. This drug also reduces oxidative stress. Thus, the aim of this systematic review is to analyze experimental studies that show the actions of aliskiren on fibrosis. PubMed and LILACS databases were consulted using the keywords aliskiren and fibrosis within the period between 2005 and 2017. Fifty-three articles were analyzed. In the heart, aliskiren attenuated remodeling, hypertrophy, inflammatory cytokines, collagen deposition, and oxidative stress. In the kidneys, there was a reduction in interstitial fibrosis, the infiltration of inflammatory cells, apoptosis, proteinuria, and in the recruitment of macrophages. In diabetic models, an improvement in the albumin/creatinine relationship and in the insulin pathway in skeletal muscles was observed; aliskiren was beneficial to pancreatic function and glucose tolerance. In the liver, aliskiren reduced fibrosis, steatosis, inflammatory cytokines, and collagen deposition. In the lung and peritoneal tissues, there was a reduction in fibrosis. Many studies have reported on the beneficial effects of aliskiren on endothelial function and arterial rigidity. A reduction in fibrosis in different organs is cited by many authors, which complies with the results found in this review. However, studies diverge on the use of the drug in diabetic patients. Aliskiren has antifibrotic potential in several experimental models, interfering with the levels of fibrogenic cytokines and oxidative stress. Therefore, its use in diseases in which fibrosis plays an important pathophysiological role is suggested., (© 2019 Wiley Periodicals, Inc.)

Aliskiren (ALS) is well known for its antihypertensive properties. However, the potential underlying the molecular mechanism and the anti-hypertrophic effect of ALS have not yet been fully elucidated. The aim of the present study was to investigate the role of ALS in mammalian target of rapamycin (mTOR) and apoptosis signaling using in vivo and in vitro models of cardiac hypertrophy. A rat model of cardiac hypertrophy was induced by isoproterenol treatment (5 mg·kg-1·day-1) for 4 weeks, with or without ALS treatment at 20 mg·kg-1·day-1. The expression of hypertrophic, fibrotic, and apoptotic markers was determined by RT-qPCR. The protein expression of apoptotic markers mTOR and p-mTOR was assessed by western blot analysis. The proliferation of H9C2 cells was monitored using the MTS assay. Cell apoptosis was analyzed using flow cytometry. In vivo, isoproterenol-treated rats exhibited worse cardiac function, whereas ALS treatment reversed these dysfunctions, which were associated with changes in p-mTOR, Bcl-2, Bax, and cleaved caspase-3 expression, as well as the number of apoptotic cells. In vitro, H9C2 cardiomyocyte viability was significantly inhibited and cardiac hypertrophy was induced by Ang II administration, but ALS reversed Ang II-induced H9C2 cardiomyocyte hypertrophy and death. Furthermore, Ang II triggered the activation of the mTOR and apoptosis pathways in hypertrophic cardiomyocytes that were inhibited by ALS treatment. These results indicated that ALS alleviated cardiac hypertrophy through inhibition of the mTOR and apoptosis pathways in cardiomyocytes.

Background: Fumaric acid esters (FAEs) are used for systemic therapy of moderate to severe psoriasis. Until recently, only a mixture of dimethyl fumarate (DMF) and three salts of ethyl hydrogen fumarate was available. However, a drug containing DMF as the sole ingredient was registered for the same indication in 2017. This prospective study aimed to investigate the switch from the currently used FAE mixture to DMF alone., Patients and Methods: Forty patients were consecutively recruited, for whom the FAE mixture was switched to DMF alone on the basis of the last DMF-equivalent dose without interrupting treatment. At the first check-up after switching, the efficacy and tolerability of the DMF drug was compared with that of the previous treatment., Results: The data show that the efficacy remained unchanged in the majority of patients. Tolerability (e.g. gastrointestinal complaints and flushing) of the DMF drug was rated equal or better in most patients than with the previous treatment., Conclusions: The results show that it is possible to switch psoriasis patients under stable therapy with the FAE mixture to the DMF drug directly and without interruption., (© 2019 The Authors Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Aliskiren, a renin inhibitor, has been shown to have cardioprotective and blood pressure (BP) lowering effects. We aimed to determine the effects of nanoparticle-loaded aliskiren on BP, nitric oxide synthase activity (NOS) and structural alterations of the heart and aorta developed due to spontaneous hypertension in rats. Twelve week-old male spontaneously hypertensive rats (SHR) were divided into the untreated group, group treated with powdered or nanoparticle-loaded aliskiren (25 mg/kg/day) and group treated with nanoparticles only for 3 weeks by gavage. BP was measured by tail-cuff plethysmography. NOS activity, eNOS and nNOS protein expressions, and collagen content were determined in both the heart and aorta. Vasoactivity of the mesenteric artery and wall thickness, inner diameter, and cross-sectional area (CSA) of the aorta were analyzed. After 3 weeks, BP was lower in both powdered and nanoparticle-loaded aliskiren groups with a more pronounced effect in the latter case. Only nanoparticle-loaded aliskiren increased the expression of nNOS along with increased NOS activity in the heart (by 30%). Moreover, nanoparticle-loaded aliskiren decreased vasoconstriction of the mesenteric artery and collagen content (by 11%), and CSA (by 25%) in the aorta compared to the powdered aliskiren group. In conclusion, nanoparticle-loaded aliskiren represents a promising drug with antihypertensive and cardioprotective effects.

Background: Plaque psoriasis has significant impact on patients' quality of life. Topical therapy is considered the treatment mainstay for mild-to-moderate disease according to guidelines. Calcipotriol/betamethasone dipropionate (Cal/BD) [0.005%/0.05%] aerosol foam is indicated for psoriasis vulgaris treatment in adults. Cal/BD foam trials demonstrated improved efficacy and similar safety in this population. Psoriasis treatment is complicated by the broad range of disease presentation, variability and therapeutic options; particularly decisions on transition from topical to non-biologic systemic treatment are difficult. Assessing comparative effectiveness of treatment options provides meaningful value to treatment decisions., Objective: To compare efficacy of Cal/BD foam individual patient data from pooled trials with efficacy of non-biologic systemic treatments based on aggregated patient characteristics and treatment outcomes., Methods: Individual data from four Cal/BD foam trials in 749 psoriasis patients were pooled to conduct matching-adjusted indirect comparisons. Literature review identified non-biologic systemic treatment trials where methods, populations and outcomes align with Cal/BD foam trials. Of 3090 screened publications, four studies of apremilast, methotrexate, acitretin or fumaric acid esters (FAE) were included., Results: After baseline matching, patients treated with 4 weeks of Cal/BD foam had greater Physician's Global Assessment 0/1 response compared to those treated with 16 weeks of apremilast (52.7% vs. 30.4%; P < 0.001). Patients treated with Cal/BD foam had significantly greater Psoriasis Area and Severity Index (PASI) 75 response at Week 4 compared to 16 weeks of apremilast treatment (51.1% vs. 21.6%; P < 0.001). Cal/BD foam patients demonstrated significantly greater PASI 75 response improvements at Week 4 vs. 12 weeks of methotrexate (50.8% vs. 33.5%; P < 0.001) or acitretin (50.9% vs. 31.7%; P = 0.009), and comparable response to FAE (42.4% vs. 47.0%; P = 0.451)., Conclusions: Despite recent treatment advances, unmet needs for psoriasis patients remain. Cal/BD foam offers improved efficacy in baseline matched psoriasis patients compared to apremilast, methotrexate or acitretin, and comparable efficacy to FAE., (© 2018 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Although anticancer systemic therapy agents clearly lead to improved survival in patients with cancer, these can come at the cost of serious complications including cardiotoxicity. Two types of targeted systemic therapies currently in use for colorectal cancer (CRC) and renal cell cancer (RCC), respectively, include the vascular endothelial growth factor inhibitor bevacizumab (BVZ) and the tyrosine kinase inhibitor sunitinib (SNT). Despite the beneficial effects of BVZ and SNT in improving clinical outcomes in the settings of CRC and RCC, there is an increased risk of cardiac dysfunction. The aim of the present study was to determine whether prophylactic administration of renin-angiotensin system (RAS) inhibitors would attenuate the cardiotoxic side effects of BVZ or SNT in a chronic in vivo murine model. A total of 194 wild-type C57Bl/6 male mice received: 1) 0.9% saline, 2) BVZ (10 mg·kg -1 ·wk -1 ), or 3) SNT (40 mg·kg -1 ·day -1 ) for 4 wk. Within each arm, mice received daily prophylactic treatment with hydralazine (0.05 mg/ml), aliskiren (50 mg/kg), perindopril (4 mg/kg), or valsartan (2 mg/kg). Although hydralazine effectively lowered blood pressure in BVZ- or SNT-treated mice, it did not prevent left ventricular systolic dysfunction. Prophylactic administration of aliskiren, perindopril, or valsartan prevented adverse cardiovascular remodeling in mice treated with either BVZ or SNT. The addition of RAS antagonists also downregulated expression of phosphorylated p38 and Bcl-2-like 19-kDa interacting protein 3 in SNT-treated mice. In our chronic in vivo murine model, RAS antagonists partially attenuated the development of BVZ- or SNT-mediated cardiac dysfunction. Future clinical studies are warranted to investigate the cardioprotective effects of prophylactic treatment with RAS inhibitors in the settings of CRC and RCC. NEW & NOTEWORTHY In the evolving field of cardio-oncology, bevacizumab and sunitinib improve clinical outcomes in the settings of metastatic colorectal cancer and renal cell cancer, respectively. These anticancer drugs, however, are associated with an increased risk of cardiotoxicity. The prophylactic administration of renin-angiotensin system antagonists is partially cardioprotective against bevacizumab- and sunitinib-mediated cardiac dysfunction.

Purpose: To determine whether changing from a tenofovir disoproxil fumarate (TDF)- to a tenofovir alafenamide fumarate (TAF)-containing regimen is correlated with weight changes in a human immunodeficiency virus (HIV)-positive adult cohort., Methods: Retrospective analysis was conducted of data gathered from routine care in a university hospital in Munich, Germany, between July 2015 and June 2017. Data from patients' charts were extracted and a two-step approach was applied. First, weight/BMI progression within 1 year after initiation of either TDF or TAF was compared. Subsequently, weight measurements within subjects changing from a TDF- to a TAF-containing antiretroviral regimen were analyzed by means of a repeated measurements general linear model., Results: After 360 days of initiating TAF, patients showed a mean (± standard deviation) percentual weight increase of 3.17 ± 0.21, whereas after 360 days of initiating TDF, patients only showed a mean (± standard deviation) percentual weight increase of 0.55 ± 0.17. The repeated measurements general linear model for within-subjects design showed a statistically significant correlation in weight after changing from a TDF to a TAF containing antiretroviral regimen. The weight difference between the two measurements while on TDF was not statistically significant, but every measure after switching to TAF was significantly higher than the previous., Conclusion: Changing from a TDF- to a TAF-containing regimen is correlated with weight gain in this retrospectively analyzed real-world cohort in Munich, Germany.

Aim: Vitamin D plays an important role in water and salt homeostasis. The aim of our study was to investigate the underlying relationship of Vitamin D and Aquaporins (AQP)., Methods: The behaviors of 1 α (OH)-ase knockout mice and wild type mice were observed before analysis. The ICR mice were treated with vehicle or paricalcitol, a vitamin D analogue, followed by animals receiving a standard diet and free access to drinking water either with aliskiren (renin blocker; 37.5 mg aliskiren in 100 ml water), or telmisartan (a angiotensin II type I receptor blocker; 40 mg telmisartan in 100 ml water) a week before study. The expressions of AQP-1, AQP-4, and renin in mice kidneys were detected by western bolting, immunohistochemistry, and immunofluorescence., Results: Diuresis and polydipsia were observed in 1 α (OH)-ase knockout mice, and a decreased water intake and urine output in ICR mice was observed after paricalcitol treatment. Compared with wild type, the AQP-1 expressions were increased in renal papilla and AQP-4 expressions were decreased in renal proximal tubule of 1 α (OH) ase knockout mice. In addition, AQP-1 was decreased in renal papilla and AQP-4 expressions were increased in proximal tubule by suppressing renin activity or supplement of Vitamin D analogue. After injecting renin into the lateral ventricle of the 1 α (OH)ase knockout mice, the renin expression level was decreased in the kidney, followed by the decrease of AQP-1 in renal papilla and increase of AQP-4 in proximal tubule., Conclusions: Overall, Vitamin D and renin inhibitors have synergistic effects in regulating water channels in mice kidneys.

This study was aimed to evaluate the effects of organic acid (OA) and medium-chain fatty acid (MCFA) blends on production performance of sows and their litters. A total of 36 sows (Landrace × Yorkshire, average parity is 3.3, SE = 0.2) were randomly allocated to three treatments with 12 replicates. Dietary treatments were as follows: CON, basal diet; MC1, CON + 0.1% OA, and MCFA blends; MC2, CON + 0.2% OA, and MCFA blends. During lactation, no differences were observed in body weight (BW) loss, average daily feed intake, backfat thickness, digestibility of dry matter, nitrogen, or energy of sows. There were linear increase (p < 0.05) in BW and average daily gain of sucking piglets. On parturition and weaning day, there was a linear increase (p < 0.05) in fecal Lactobacillus counts, as well as a linear decrease (p < 0.05) in fecal Escherichia coli counts of sows on weaning day. The sucking piglets also had a linear increase (p < 0.05) in fecal Lactobacillus counts and a linear decrease (p < 0.05) in fecal E. coli counts. In conclusion, dietary supplementation of OA and MCFA blends in sows exerts beneficial effects to sows shifted fecal microbiota by increasing Lactobacillus and decreased E. coli counts. It also improved the performance of piglets., (© 2018 Japanese Society of Animal Science.)

Objectives: The aim of this study was to determine if hyperpolarized [1,4- 13 C 2 ]malate imaging could measure cardiomyocyte necrosis after myocardial infarction (MI)., Background: MI is defined by an acute burst of cellular necrosis and the subsequent cascade of structural and functional adaptations. Quantifying necrosis in the clinic after MI remains challenging. Magnetic resonance-based detection of the conversion of hyperpolarized [1,4- 13 C 2 ]fumarate to [1,4- 13 C 2 ]malate, enabled by disrupted cell membrane integrity, has measured cellular necrosis in vivo in other tissue types. Our aim was to determine whether hyperpolarized [1,4- 13 C 2 ]malate imaging could measure necrosis after MI., Methods: Isolated perfused hearts were given hyperpolarized [1,4- 13 C 2 ]fumarate at baseline, immediately after 20 min of ischemia, and after 45 min of reperfusion. Magnetic resonance spectroscopy measured conversion into [1,4- 13 C 2 ]malate. Left ventricular function and energetics were monitored throughout the protocol, buffer samples were collected and hearts were preserved for further analyses. For in vivo studies, magnetic resonance spectroscopy and a novel spatial-spectral magnetic resonance imaging sequence were implemented to assess cardiomyocyte necrosis in rats, 1 day and 1 week after cryo-induced MI., Results: In isolated hearts, [1,4- 13 C 2 ]malate production became apparent after 45 min of reperfusion, and increased 2.7-fold compared with baseline. Expression of dicarboxylic acid transporter genes were negligible in healthy and reperfused hearts, and lactate dehydrogenase release and infarct size were significantly increased in reperfused hearts. Nonlinear regression revealed that [1,4- 13 C 2 ]malate production was induced when adenosine triphosphate was depleted by >50%, below 5.3 mmol/l (R 2  = 0.904). In vivo, the quantity of [1,4- 13 C 2 ]malate visible increased 82-fold over controls 1 day after infarction, maintaining a 31-fold increase 7 days post-infarct. [1,4- 13 C 2 ]Malate could be resolved using hyperpolarized magnetic resonance imaging in the infarct region one day after MI; [1,4- 13 C 2 ]malate was not visible in control hearts., Conclusions: Malate production in the infarcted heart appears to provide a specific probe of necrosis acutely after MI, and for at least 1 week afterward. This technique could offer an alternative noninvasive method to measure cellular necrosis in heart disease, and warrants further investigation in patients., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction and Objectives: The aim of this study was to evaluate the effect of aliskiren on aortic stiffness in patients with Marfan syndrome (MS)., Methods: Twenty-eight MS patients (mean age ± standard deviation: 32.6 ± 10.6 years) were recruited from November 2009 to October 2014. All patients were receiving atenolol as standard beta-blocker therapy. A prospective randomization process was performed to assign participants to either aliskiren treatment (150-300mg orally per day) or no aliskiren treatment (negative control) in an open-label design. Central aortic distensibility and central pulsed wave velocity (PWV) by magnetic resonance imaging (MRI), peripheral PWV, central aortic blood pressure and augmentation index by peripheral tonometry, and aortic dilatation by echocardiography were examined initially and after 24 weeks. The primary endpoint was central aortic distensibility by MRI., Results: In analyses of differences between baseline and 24 weeks for the aliskiren treatment group vs the negative control group, central distensibility (overall; P = .26) and central PWV (0.2 ± 0.9 vs 0.03 ± 0.7 [m/s]; P = .79) by MRI were not significantly different. Central systolic aortic blood pressure tended to be lower by 14mmHg in patients in the aliskiren treatment group than in the control group (P = .09). A significant decrease in peripheral PWV (brachial-ankle PWV) in the aliskiren treatment group (-1.6 m/s) compared with the control group (+0.28 m/s) was noted (P = .005)., Conclusions: Among patients with MS, the addition of aliskiren to beta-blocker treatment did not significantly improve central aortic stiffness during a 24-week period., (Copyright © 2017 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

The purpose of this study was to investigate if AZD5329, a dual neurokinin NK1/2 receptor antagonist, is a suitable candidate for further development as an oral immediate release (IR) solid dosage form as a final product. The neutral form of AZD5329 has only been isolated as amorphous material. In order to search for a solid material with improved physical and chemical stability and more suitable solid-state properties, a salt screen was performed. Crystalline material of a maleic acid salt and a fumaric acid salt of AZD5329 were obtained. X-ray powder diffractiometry, thermogravimetric analysis, differential scanning calorimetry and dynamic vapor sorption were used to investigate the physicochemical characteristics of the two salts. The fumarate salt of AZD5329 is anhydrous, the crystallization is reproducible and the hygroscopicity is acceptable. Early polymorphism assessment work using slurry technique did not reveal any better crystal modification or crystallinity for the fumarate salt. For the maleate salt, the form isolated originally was found to be a solvate, but an anhydrous form was found in later experiments; by suspension in water or acetone, by drying of the solvate to 100-120 °C or by subjecting the solvate form to conditions of 40 °C/75%RH for 3 months. The dissolution behavior and the chemical stability (in aqueous solutions, formulations and solid-state) of both salts were also studied and found to be satisfactory. The compound displays sensitivity to low pH, and the salt of the maleic acid, which is the stronger acid, shows more degradation during stability studies, in line with this observation. The presented data indicate that the substance fulfils basic requirements for further development of an IR dosage form, based on the characterization on crystalline salts of AZD5329., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Multiple Sclerosis (MS) is an autoimmune-neurodegenerative disorder managed therapeutically by modulating lymphocytes activity which has potential in disease management. Prohibitin 1(PHB) that controls the reactive oxygen species (ROS) and present on the activated lymphocytes have significance in the therapy of MS as esters of fumaric acid that regulates ROS is in phase II/III clinical trials. Thus, we evaluated the expression levels of PHB1 in experimental autoimmune encephalomyelitis (EAE), the animal model of MS and on MS patient's lymphocytes. PHB levels in brain tissue of EAE animals were determined by immunoblotting and on blood lymphocytes from MS relapse, Remission, Optic Neuritis, Neurological controls and Healthy volunteers by FACS using anti-PHB and anti-CD45 antibodies. We observed significant elevation of PHB in EAE brains (91.0 ± 17.59%) vs controls (29.8 ± 12.9%) (p = 0.01) and on lymphocytes of MS patients in acute (73.5 ± 11.20%) or relapsing (69.3 ± 17.33%) phase compared to remission (45.9 ± 8.08%) [p = 0.034 acute vs remission; p = 0.004 relapse vs remission]. Up regulation of PHB in relapsing vs remission MS patients imply the potential use of PHB to clinically evaluate subclinical disease status towards prognosis of an oncoming relapse. Elevated PHB levels in EAE brains signify the role of PHB in regulating ROS and implies PHB's role in oxidative stress., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aims: The direct renin inhibitor, aliskiren, is known to reduce plasma renin activity (PRA), but whether the efficacy of aliskiren varies based on an individual's baseline PRA in patients hospitalized for heart failure (HF) is presently unknown. We characterized the prognostic value of PRA and determined if this risk is modifiable with use of aliskiren., Methods and Results: This pre-specified neurohormonal substudy of ASTRONAUT analysed all patients hospitalized for HF with ejection fraction (EF) ≤40% with available baseline PRA data (n = 1306, 80.9%). Risk associated with baseline PRA and short-term changes in PRA from baseline to 1 month was modelled with respect to 12-month clinical events. Median baseline PRA was 3.0 (interquartile range 0.6-16.4) ng/mL/h. Aliskiren significantly reduced PRA early after treatment initiation through 12-month follow-up compared with placebo (P < 0.001). The lowest baseline PRA quartile (<0.6 ng/mL/h) was independently predictive of lower all-cause mortality [adjusted hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.31-0.81] and the composite of cardiovascular mortality and HF hospitalization (adjusted HR 0.57, 95% CI 0.40-0.79). Delta log-normalized PRA (from baseline to 1 month) was not predictive of either primary endpoint at 12 months (P ≥ 0.43). The prognostic value of baseline PRA and short-term changes in PRA did not vary by randomization to aliskiren or placebo (interaction P ≥ 0.13)., Conclusions: Plasma renin activity is reduced early and durably by aliskiren, but this did not translate into improved clinical outcomes in ASTRONAUT. Baseline PRA or short-term reduction in PRA do not identify a subgroup who may preferentially benefit from direct renin inhibition. Clinical Trial Registration ClinicalTrials.gov Unique Identifier: NCT00894387., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Two experiments (E) were carried out to evaluate the effects of fumaric acid and an acidifier blend [composed by calcium formate, calcium lactate and medium-chain fatty acids (capric and caprylic)] in piglet diets containing colistin (40 ppm) or halquinol (120 ppm) on performance, diarrhea incidence (E1), organs relative weight, pH values, intestinal morphometry and microbiota (E2). In E1, 192 and E2, 24 piglets weaned at 21-day-old were randomly assigned to blocks with 2x2 factorial arrangement of treatments [absence or presence of fumaric acid x absence or presence of acidifier blend], six replicates of eight (E1) and one piglet per pen (E2). For E1, the treatments were control (CD): no acidifier product + 40 ppm of colistin, FA: fumaric acid in absence of acidifier blend, AB: acidifier blend in absence of fumaric acid and, AF+AB: presence of fumaric acid and acidifier blend. For E2, the pre-starter I diet were used and the same treatments as E1 evaluated. No treatment effects (P>0.05) were observed on performance, diarrhea incidence (E1), gut pH values and duodenum morphometry of piglets (E2). However, the addition of AB increased (P<0.05) large intestine relative weight and, FA addition decreased (P<0.05) pancreas relative weight, jejunum villi height and, total coliform and E. coli counts in cecum. The inclusion of FA and AB in diets containing colistin or halquinol did not improve performance, although FA exerted an inhibitory effect on cecum microbiota.

Aims: Because of concerns about the safety of aliskiren in patients with diabetes, study treatment was stopped prematurely in the Aliskiren Trial of Minimizing OutcomeS for Patients with HEart failuRE (ATMOSPHERE). We examined outcomes and treatment effect in these patients compared with those without diabetes., Methods and Results: ATMOSPHERE included 7016 patients with heart failure and a reduced ejection fraction (HFrEF) randomly assigned to enalapril plus aliskiren, aliskiren alone, or enalapril. At baseline, 1944 (27.7%) patients had diabetes. Median follow-up was shorter in patients with diabetes compared with those without (24 months vs. 46 months). Among patients with diabetes, the primary endpoint of cardiovascular death or hospitalization for heart failure occurred in 216 patients (33.1%) in the enalapril group (reference), 172 (27.4%) in the aliskiren group [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.67-1.00; P = 0.053], and 196 (29.5%) in the combination group (HR 0.86, 95% CI 0.71-1.04; P = 0.13). The effects of the treatments studied did not differ significantly compared with patients without diabetes. In patients with diabetes, aliskiren monotherapy was associated with a lower risk of symptomatic hypotension compared to enalapril [42 (6.7%) vs. 65 (10.0%); P = 0.04], whereas other adverse events were generally balanced between the three groups., Conclusion: In patients with HFrEF and diabetes, there was no signal of harm and a trend towards benefit when direct renin inhibition monotherapy was compared with an angiotensin-converting enzyme inhibitor, whereas combined aliskiren and enalapril treatment led to more adverse events with no improvement in outcomes. Treatment effects did not differ in patients with diabetes compared with those without. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00853658., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Dual renin-angiotensin-aldosterone blockade (dRAASb) is purposed in the prevention of the cardiorenal syndrome (CRS). However, all attempts with dRAASb even in patients with moderate impaired chronic kidney disease (CKD) were terminated due to the typical severe adverse events (SAE), e. g., hyperkalemia and rise of serum creatinine. The aim of our study with the direct renin inhibitor aliskiren was to evaluate the effect of dRAASb with a washout phase in patients with severely advanced CKD. We have studied 45 patients (G3b to 4, A2 and >A3; median glomerular filtration rate (GFR) CKD-EPI 31 (23-40) ml/min per 1.73 m² BSA (body surface area), albumin-creatinine-ratio in urine (UACR) (0.413 (0.164 to 1.39) g/g) and proteinuria (0.5 (0.2 to 0.9) g/l) before, with and without aliskiren (150 respectively 300 mg per day) added to an angiotensin-converting enzyme inhibitor (ACEi) or an AT1-receptor blocker (ARB) over 4 ½ years. The dRAASb with aliskiren showed a significant decrease of proteinuria (0.5 to 0.38 g/l), especially in patients with an UACR≥350 mg/g and in the subgroup analysis e. g., in patients with diabetes, but proteinuria increased in the washout phase again. The blood pressure (130/80 mm Hg), serum potassium (4.9 to 5.0 mmol/l) and GFR remained nearly constant (31 to 29.5 ml/min per 1.73 m 2 BSA). A more than 30% increase in serum creatinine was associated with an UACR>300 mg/g. The dRAASb has beneficial effects on proteinuria and is safe in patients with severely advanced CKD. However, in patients with high UACR (>300 mg/g) raise of creatinine and potassium have to be controlled., Competing Interests: Conflicts of Interest: None., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Delayed-release dimethyl fumarate (DMF) is an approved oral treatment for relapsing forms of multiple sclerosis (MS). Preclinical studies demonstrated that DMF activated the nuclear factor E2-related factor 2 (Nrf2) pathway. DMF and its primary metabolite monomethyl fumarate (MMF) were also shown to promote cytoprotection of cultured central nervous system (CNS) cells via the Nrf2 pathway., Objective: To investigate the activation of Nrf2 pathway following ex vivo stimulation of human peripheral blood mononuclear cells (PBMCs) with DMF or MMF, and in DMF-treated patients from two Phase 3 relapsing MS studies DEFINE and CONFIRM., Methods: Transcription of Nrf2 target genes NADPH:quinone oxidoreductase-1 (NQO1) and heme-oxygenase-1 (HO1) was measured using Taqman® assays. RNA samples were isolated from ex vivo-stimulated PBMCs and from whole blood samples of 200 patients each from placebo, twice daily (BID) and three times daily (TID) treatments., Results: DMF and MMF induced NQO1 and HO1 gene expression in ex vivo-stimulated PBMCs, DMF being the more potent inducer. Induction of NQO1 occurred at lower DMF concentrations compared to that of HO1. In DMF-treated patients, a statistically significant induction of NQO1 was observed relative to baseline and compared to placebo. No statistical significance was reached for HO1 induction., Conclusion: These data provide the first evidence of Nrf2 pathway activation from two large pivotal Phase 3 studies of DMF-treated MS patients.

Background: A non-interventional study suggested that use of angiotensin-converting enzyme inhibitors (ACEIs) or aliskiren was associated with an angioedema risk three times that of beta-blockers (BBs)., Objective: The aim was to assess angioedema incidence rates (IRs) and the relative angioedema risk of aliskiren compared to other antihypertensive drugs (AHDs)., Methods: A cohort study in hypertensive patients with an AHD prescription between 2007 and 2012 was conducted using data from the US PharMetrics Plus™ claims database. Angioedema was identified using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9CM) code 995.1. Additionally, a nested case-control analysis was conducted to assess the relative angioedema risk of aliskiren or other AHDs versus BBs., Results: A total of 3,090,114 patients were included (aliskiren n = 30,720). There were 15,744 angioedema events (IR 2.28/1000 person-years; 95% confidence interval (CI) 2.24-2.32). Aliskiren IRs were: any aliskiren 2.58 (2.08-3.17), aliskiren monotherapy 1.71 (0.74-3.37), aliskiren fixed-dose combination (FDC) 1.27 (0.41-2.96), and aliskiren free-standing combination (FSC) 2.93 (2.31-3.66). The case-control analysis included 15,100 angioedema cases and 60,400 controls; the angioedema risk for both aliskiren monotherapy and FDC was not significantly different from BBs [adjusted odds ratio (adjOR) 0.99 (95% CI 0.45-2.20) and 1.06 (0.40-2.76)]; aliskiren FSC was associated with an increased angioedema risk [adjOR 3.29 (2.42-4.48)], mainly driven by concomitant ACEI use [adjOR 7.03 (4.10-12.05)]., Conclusions: The IR and risk of angioedema in patients with aliskiren monotherapy or FDC are comparable to BBs. The higher IR and risk of angioedema identified in the aliskiren FSC group may largely be driven by the concomitant use of ACEIs.

A novel orotic acid salt form of tenofovir disoproxil (DA-2802) was developed and is expected to replace the fumaric acid salt form. The pharmacokinetic (PK) characteristics and tolerability profiles of DA-2802 were compared to those of tenofovir disoproxil fumarate (TDF, Viread ® ) in healthy subjects. A randomized, open-label, single-dose study was conducted in 36 healthy subjects using a two-treatment, two-period, and two-sequence crossover design. Subjects received a single oral dose of 319 mg DA-2802 or 300 mg TDF, during each period, with a 7-day washout. Serial blood samples were collected pre-dosing and up to 72 hours post-dosing in each period, for determination of serum tenofovir concentration, which was measured by ultra-performance liquid chromatography-tandem mass spectrometry. A non-compartmental method was used to obtain PK parameters of tenofovir. For comparison between the two tenofovir disoproxil salts, the 90% confidence intervals (90% CIs) of geometric mean ratios of DA-2802 to TDF for the maximum concentration (C max ) and the area under the concentration-time curve to the last quantifiable concentration (AUC 0-t ) were determined. The tolerability profiles of tenofovir were assessed by evaluation of adverse events and vital signs, physical examination, ECG, and clinical laboratory tests. The serum tenofovir concentration-time profiles of DA-2802 or TDF were comparable in 32 subjects who completed the study. In both profiles, a two-compartmental elimination with first-order elimination kinetics in the terminal phase was reported in a few subjects, showing a secondary peak in the initial phase of elimination. The geometric mean ratio (90% CI) of DA-2802 to TDF was 0.898 (0.815-0.990) for C max and 0.904 (0.836-0.978) for AUC 0-t . There were no clinically significant findings in the tolerability assessments. DA-2802 showed comparable PK characteristics and tolerability profiles to TDF., Competing Interests: Disclosure Ms Mun Ju Choi and Mr Tae Young Oh are employees of Dong-A ST Co., Ltd. None of the authors of this study are involved in financial or personal relationships with agencies, institutions, or organizations that could inappropriately influence the statistical analysis plan or interpretation of this work. The authors report no other conflicts of interest in this work.

Background: Secukinumab is a fully human antibody that neutralizes interleukin-17A. It has significant efficacy and a favourable safety profile in moderate-to-severe plaque psoriasis and psoriatic arthritis., Objectives: To compare secukinumab with fumaric acid esters (FAEs) in a randomized controlled trial., Methods: In this 24-week, randomized, open-label, multicentre study with blinded assessment, patients with moderate-to-severe plaque psoriasis, naive to systemic treatments, were randomized to receive secukinumab 300 mg subcutaneously or oral FAEs. The primary end point was ≥ 75% improvement from baseline Psoriasis Area and Severity Index score (PASI 75 response) at week 24, and missing patients were considered responders if they were responders at the time of dropout., Results: In total 202 patients were randomized and 200 were treated with at least one dose. Outcomes at week 24 were available for 147 and imputed for 53 patients. Discontinuations were mostly due to adverse events, and occurred more frequently in the FAE group (1·9% vs. 40·0%). At week 24, significantly more patients receiving secukinumab compared with FAEs achieved PASI 75 response (89·5% vs. 33·7%, P < 0·001), PASI 90 response (75·2% vs. 18·9%, P < 0·001) and Dermatology Life Quality Index 0 or 1 response (71·4% vs. 25·3%, P < 0·001)., Conclusions: Secukinumab demonstrated superior efficacy to FAEs in patients with psoriasis over a 24-week period., (© 2017 British Association of Dermatologists.)

The accelerated generation of endothelial microparticles (EMPs) and impaired angiogenesis are the markers of vascular pathology during various cardiovascular and inflammatory conditions including hypertension. Because studies comparing the effects of antihypertensive agents on these 2 parameters are limited, this study was designed to compare the effects of 3 antihypertensive agents: aliskiren, nebivolol, and olmesartan, on the EMP generation and angiogenesis. Changes in the hemodynamic parameters and serum EMP count were determined after 3 weeks of the drug treatments [aliskiren (30 mg/kg), nebivolol (10 mg/kg), or olmesartan (5 mg/kg) per orally] in L-NAME-induced rat model of hypertension. The 3 drugs prevented the rise in blood pressure and EMP count to a similar extent. Furthermore, nebivolol was found to possess more potent and concentration-dependent antiangiogenic activity compared with aliskiren, whereas olmesartan was devoid of such an effect. The EMPs generated by virtue of the respective drug treatments were found to be involved in mediating the antiangiogenic effect of nebivolol and aliskiren. In addition, olmesartan treatment also resulted in the increased eNOS expression. The results of this study show that the antihypertensive drugs, viz. aliskiren, nebivolol, and olmesartan, regulate the vascular health by their differential effects on the EMP generation and angiogenesis.

Although garlic oil and nitrate can effectively suppress ruminal methane (CH 4 ) production in vitro, the application of these compounds is associated with suppressed total volatile fatty acid (VFA) concentration. On the other hand, the effectiveness of fumarate as a ruminal CH 4 mitigating agent is variable but its application increases total VFA concentration. We therefore hypothesized that the different characteristics of the compounds can compensate for the shortcomings of the other. The objective of this study was to develop an optimal blend of garlic oil, nitrate and fumarate that can suppress in vitro ruminal CH 4 without affecting total VFA concentration. Three ruminal in vitro fermentation experiments were carried out. The first one, a one factor at a time experiment was employed to investigate the effective concentration of each of the compounds on CH 4 and VFA production by ruminal bacteria. We then applied the fractional factorial design and response surface methodology in the second experiment to determine optimal concentrations of the compounds in the blend. The optimal blending of garlic oil, fumarate and nitrate was determined to be 50 mg/l, 15 mm and 20 mm, respectively. This simulated optimal blend was verified in a 48 h in vitro batch fermentation experiment. The blend achieved the intended goal of suppressing CH 4 whilst maintaining total VFA concentration. The blend and nitrate suppressed archaea populations (p < 0.001) but did not affect the total microbial population (p = 0.945). The observed results could be explained by additive effects of the agents making up the blend. Supplementing a high concentrate diet with the blend can significantly decrease ruminal CH 4 and maintain total VFAin vitro. These findings however, need to be verified in vivo using the optimized ratio of combining the three methane inhibitors as a guide., (Journal of Animal Physiology and Animal Nutrition © 2016 Blackwell Verlag GmbH.)

Nearly 75% of breast tumors express estrogen receptor (ER), and will be treated with endocrine therapy, such as selective estrogen receptor modulator (SERM), tamoxifen, or aromatase inhibitors. Despite their proven success, as many as 40-50% of ER+ tumors fail to respond to endocrine therapy and eventually recur as aggressive, metastatic cancers. Therefore, preventing and/or overcoming endocrine resistance in ER+ tumors remains a major clinical challenge. Deregulation or activation of the nuclear factor κB (NFκB) pathway has been implicated in endocrine resistance and poor patient outcome in ER+ tumors. As a consequence, one option to improve on existing anti-cancer treatment regimens may be to introduce additional anti-NFκB activity to endocrine therapy drugs. Our approach was to design and test SERM-fumarate co-targeting hybrid drugs capable of simultaneously inhibiting both ER, via the SERM, raloxifene, and the NFκB pathway, via fumarate, in breast cancer cells. We find that the hybrid drugs display improved anti-NFκB pathway inhibition compared to either raloxifene or fumarate. Despite some loss in potency against the ER pathway, these hybrid drugs maintain anti-proliferative activity in ER+ breast cancer cells. Furthermore, these drugs prevent clonogenic growth and mammosphere formation of ER+ breast cancer cells. As a proof-of-principle, the simultaneous inhibition of ER and NFκB via a single bifunctional hybrid drug may represent a viable approach to improve the anti-inflammatory activity and prevent therapy resistance of ER-targeted anti-cancer drugs.

Background: Hypertension is a chronic condition associated with an increased risk of mortality and morbidity. Renin is the enzyme responsible for converting angiotensinogen to angiotensin I, which is then converted to angiotensin II. Renin inhibitors are a new class of drugs that decrease blood pressure (BP) by preventing the formation of both angiotensin I and angiotensin II., Objectives: To quantify the dose-related BP lowering efficacy of renin inhibitors compared to placebo in the treatment of primary hypertension.To determine the change in BP variability, pulse pressure, and heart rate and to evaluate adverse events (mortality, non-fatal serious adverse events, total adverse events, withdrawal due to adverse effects and specific adverse events such as dry cough, diarrhoea and angioedema)., Search Methods: The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials (RCTs) up to February 2017: the Cochrane Hypertension Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 2), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. There was no restriction by language or publication status. We also searched the European Medicines Agency (EMA) for clinical study reports, the Novartis Clinical Study Results Database, bibliographic citations from retrieved references, and contacted authors of relevant papers regarding further published and unpublished work., Selection Criteria: We included randomized, double-blinded, placebo-controlled studies evaluating BP lowering efficacy of fixed-dose monotherapy with renin inhibitor compared with placebo for a minimum duration of three to 12 weeks in adult patients with primary hypertension., Data Collection and Analysis: This systematic review is a comprehensive update which includes four additional studies and extensive detail from nine clinical study reports (CSRs) of previously included studies obtained from EMA. The remaining three CSRs are not available.Two review authors independently assessed study eligibility and extracted data. In all cases where there was a difference between the CSR and the published report, data from the CSR was used. Dichotomous outcomes were reported as risk ratio (RR) with 95% confidence intervals (CIs) and continuous outcomes as mean difference (MD) with 95% CIs., Main Results: 12 studies (mean duration of eight weeks) in 7439 mostly Caucasian patients (mean age 54 years) with mild-to-moderate uncomplicated hypertension were eligible for inclusion in the review. Aliskiren was the only renin inhibitor evaluated. All included studies were assessed to have high likelihood of attrition, reporting and funding bias.Aliskiren has a dose-related systolic/diastolic blood pressure (SBP/DBP) lowering effect as compared with placebo MD with 95% CI: aliskiren 75 mg (MD -2.97, 95% CI -4.76 to -1.18)/(MD -2.05, 95% CI -3.13 to -0.96) mm Hg (moderate-quality evidence), aliskiren 150 mg (MD -5.95, 95% CI -6.85 to -5.06)/ (MD -3.16, 95% CI -3.74 to -2.58) mm Hg (moderate-quality evidence), aliskiren 300 mg (MD -7.88, 95% CI -8.94 to -6.82)/ (MD -4.49, 95% CI -5.17 to -3.82) mm Hg (moderate-quality evidence), aliskiren 600 mg (MD -11.35, 95% CI -14.43 to -8.27)/ (MD -5.86, 95% CI -7.73 to -3.99) mm Hg (low-quality evidence). There was a dose-dependent decrease in blood pressure for aliskiren 75 mg, 150 mg and 300 mg. The blood pressure lowering effect of aliskiren 600 mg was not different from 300 mg (MD -0.61, 95% CI -2.78 to 1.56)/(MD -0.68, 95% CI -2.03 to 0.67). Aliskiren had no effect on blood pressure variability. Due to very limited information available regarding change in heart rate and pulse pressure, it was not possible to meta-analyze these outcomes.Mortality and non-fatal serious adverse events were not increased. This review found that in studies of eight week duration aliskiren may not increase withdrawal due to adverse events (low-quality evidence). Diarrhoea was increased in a dose-dependent manner (RR 7.00, 95% CI 2.48 to 19.72) with aliskiren 600 mg (low-quality evidence). The most frequent adverse events reported were headache, nasopharyngitis, diarrhoea, dizziness and fatigue., Authors' Conclusions: Compared to placebo, aliskiren lowered BP and this effect is dose-dependent. This magnitude of BP lowering effect is similar to that for angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). There is no difference in mortality, nonfatal serious adverse events or withdrawal due to adverse effects with short term aliskiren monotherapy. Diarrhoea was considerably increased with aliskiren 600 mg.

Background: Fumaric acid esters (FAE) have been used for over 30 years in the management of psoriasis. There have been a number of case reports linking the use of FAE with nephrotoxicity, including acute renal injury and Fanconi syndrome. However, one large multicentre retrospective trial showed no evidence of renal dysfunction with FAE., Objectives/aims: The aim of this study was to determine the number of patients in our institution being treated with FAE who developed significant proteinuria or renal dysfunction., Methods: This was a single-centre retrospective study assessing all patients on FAE who attended for follow-up during an 18-week period between February and June 2015. Demographics, comorbidities, duration and dose of treatment with FAE, proteinuria, renal function and other biochemical serum abnormalities were recorded., Results: One hundred and twenty-seven patients were included in the study. Eighty-two patients had proteinuria detected at some stage during treatment with FAE, and 18 of these had persistent proteinuria (positive in at least three consecutive specimens, 12 weeks apart). Six patients (five female) developed proximal tubular dysfunction (PTD). The risk factors for the development of PTD appear to be lower bodyweight (P = 0.03), higher dose per weight (P = 0.03) and longer duration of treatment (P = 0.03). Renal dysfunction improved on discontinuation or dose reduction in FAE., Conclusion: Fumaric acid esters are frequently associated with transient or persistent proteinuria. Significant renal dysfunction is rare and usually reversible on dose reduction or discontinuation of FAE. This study highlights the importance of screening for proteinuria. Higher doses per weight of treatment and longer duration of FAE therapy are likely risk factors for PTD., (© 2016 European Academy of Dermatology and Venereology.)

Necrobiosis lipoidica (NL) is a rare granulomatous disease of hitherto unclear etiology frequently seen in patients with diabetes. Characterized by its potential for ulcerations, it often presents a serious burden for those affected. There are currently neither German nor European guidelines for the treatment of NL. At the same time, standard treatment with topical or intralesional corticosteroids does not always show satisfactory results. We therefore set out to evaluate whether the various treatment regimens published since 2000 have actually expanded the therapeutic armamentarium in a relevant manner. Included were all publications that described more than one patient being treated with any given therapeutic modality. Overall, we analyzed data for 16 different treatment regimens reported in 49 publications. The largest amount of data exists for topical PUVA therapy, photodynamic therapy (PDT), and systemic treatment with fumaric acid esters. Remarkably, our analysis showed that with an increase in the number of documented patients treated with a given therapeutic modality, the proportion of those achieving a complete or partial response actually decreased. This was interpreted as publication bias. Thus, no clear recommendation can be given for second-line therapy in case topical or intralesional corticosteroids fail., (© 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

Aliskiren, a direct renin inhibitor, has shown potent ability to attenuate hypertension. Our previous research has found that aliskiren protected against myocardial ischaemia-reperfusion (I/R) injury and enhanced phosphorylation of endothelial nitric oxide synthase (eNOS) in spontaneously hypertensive rats. However, whether the cardioprotective effect of aliskiren against myocardial I/R injury was eNOS-dependent is unknown. In the present study, 12-week-old male eNOS knockout (eNOS -/- ) and wild-type C57BL/6J mice (WT) were orally administrated with the dose of 50 mg/kg per day of aliskiren. After a 4-week treatment, aliskiren decreased blood pressure in eNOS -/- mice, and reduced renin-angiotension II levels in both eNOS -/- and WT mice. Aliskiren also improved left ventricular ejection fraction (EF) and fractional shortening (FS), decreased myocardial infarct size, reduced creatine kinase (CK) and lactate dehydrogenase (LDH) activity in plasma, attenuated dihydroethidium (DHE) fluorescence and levels of malondialdehyde (MDA), enhanced superoxide dismutase (SOD) activity and total antioxidant capacity (T-AOC) in myocardium, increased SOD and thioredoxin (Trx) proteins expression in WT mice subjected to 30 minutes of ischaemia followed by reperfusion for 24 hours. However, aliskiren failed to restore all of the above indices in eNOS -/- mice subjected to the same I/R injury. Our study indicated that aliskiren protected against myocardial I/R injury via an eNOS dependent manner., (© 2016 John Wiley & Sons Australia, Ltd.)

Purpose: The purpose of the study is to analyze the impact of an intervention to disseminate safety alerts on the utilization of Aliskiren added to angiotensin converting enzyme inhibitor (ACEI) or an angiotensin-receptor blocker (ARB)., Methods: Quasi-experimental design (non-randomized intervention) comparing the utilization of Aliskiren + ACEI or ARB in a primary care area-intervention (PCA-I) with a primary care area-control (PCA-C) following a safety alert. All physicians were provided with a list of diabetic patients (DM) on Aliskiren + ACEI or ARB. Physicians in the PCA-I received also a non-DM patients list, a report with recommendations and information on the utilization of Aliskiren + ACEI or ARB in their area. Information was obtained from electronic medical records, period from May 2010 to December 2012. Interrupted time series analysis were used to assess the effect of the intervention on the number of patients on Aliskiren + ACEI or ARB., Results: The number of DM receiving Aliskiren + ACEI or ARB at the time of the alert (23 December 2011) was 106 in the PCA-I (91 non-DM) and 45 in the PCA-C (25 non-DM). After the alert, a decreased in the number of patients on Aliskiren + ACEI or ARB was noted at both PCAs, although the average of daily treatments ended was significantly higher in the PCA-I, both in the DM group (slope after alert: -0.81, 95%CI -0.91 to -0.71 vs. -0.30, 95%CI -0.37 to -0.22) as well as in the non-DM group (-0.56, 95%CI -0.67 to -0.45 vs. -0.10 95%CI -0.17 to -0.04)., Conclusions: The prescription of Aliskiren + ACEI or ARB decreased at both PCAs, albeit such decreased was more significant at the PCA-I. The intervention led to a more expeditious implementation of the safety alert recommendations. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

The article describes some characteristics of temperature homeostasis regulation while intraoperative period and its correction methods by infusions of balanced crystalloid solutions on the basis amino acids and the Krebs cycle substrates., Materials and Methods: 107 children of different ages were included into the study. All of them underwent surgery on thoracic or abdominal organs. The average age was 13 (7-16) years. All the operations were performed with total intravenous anesthesia and artificial lung ventilation. 0,9% sodium chloride solution, "Mafusol" "Infezol-40" and "Reamberin" were used in order to correct perioperative hypothermia. Results of the study. It was found that solutions based onfumarate (mafusol) and succinate (reamberin) have a significant positive effect on the temperature homeostasis. This fact means they can be recommendfor a broad usage in clinical practice for the purpose ofprevention and elimination of intraoperative hypothermia.

Background: The renoprotective effects of the direct renin inhibitor, aliskiren, in renal transplant recipients have been supposed, but not finally proven. We performed an exploratory double-blind, losartan controlled, cross-over study to evaluate the influence of aliskiren, direct renin inhibitor, on albuminuria and other surrogate markers of kidney injury in patients after renal transplantation. The safety of this therapy was also evaluated., Method: 16 of 18 patients (12 M, 4 F), 48.3 ± 9.0 years, 57.7 ± 9.1 months after kidney transplantation, with hypertension and stable serum creatinine 1.4 ± 0.08 mg/dl without proteinuria, completed the protocol. Each patient underwent two 8-week treatment periods (one with 150 mg of aliskiren, and one with 50 mg of losartan) in random order, allowing an 8-week placebo washout between them., Results: There were no differences in albuminuria, transforming growth factor β-1 and 15-F2t-isoprostanes urine excretion between aliskiren and losartan. Creatinine serum level, eGFR, 24 h systolic and 24 h diastolic blood pressure were stable through the study. There were no differences in haemoglobin and potassium serum concentration between studied drugs., Conclusion: Aliskiren decreases albuminuria in renal transplant recipients with clinically minimal side effects. The effect does not differ from that of losartan.

Aliskiren, a direct renin inhibitor is expected to achieve sufficient suppression of renin-angiotensin system. We evaluated the effect of aliskiren on the electrical and structural remodeling in a canine atrial fibrillation (AF) model. Twenty-eight dogs were divided into three groups: (1) pacing control group (n = 12), with continuous atrial rapid pacing for 3 or 6 weeks, (2) pacing + aliskiren group (n = 12), with oral aliskiren (30 mg/kg/day), and (3) sham group (n = 4), no pacing nor drug administration. Electrophysiological properties and AF inducibility were evaluated every week. After the protocol, the left atrial tissue was sampled for the further histological and mRNA analysis. The electrical remodeling, AF inducibility, the left atrial enlargement and interstitial fibrosis were observed in pacing control group and were more prominent in the 6-week protocol (vs. 3 week, p < 0.05). The mRNA expressions of matricellular proteins exhibited upregulation in 3-week pacing control, but these upregulations became insignificant in 6 weeks. In contrast, collagen type 3 exhibited significant upregulation in 6 week but not in 3-week protocol. These changes were suppressed in the pacing + aliskiren group. Aliskiren suppressed the atrial remodeling in a canine AF model. This effect was accompanied by the suppression of tissue fibrosis.

Introduction: Growing resistance of pathogens to antibiotics, including cross-resistance to other antimicrobial classes that are used in the treatment of recurrent infections of the lower urinary system in children demands constant control of issues of regional antibiotic resistance. In the present days, in the empirical treatment of such patients physicians still choose medications with preserved activity in relation to E. coli. The aim of our study was to investigate the regional features of microbial landscape of urine in children with cystitis and study the efficacy of 7-day administration of Furamag medicinal drug for the treatment of recurrent episodes of this disease in children., Material and Methods: 65 children aged 5 to 16 years underwent clinical and laboratory examinations. The patients in Group I (33 children) received Furamag as an antimicrobial therapy; the comparison group consisted of patients (32 children) who received cefuroxime axetil. The both therapies course duration was 7 days., Results: Bacteriological examination results were indicative of prevalence of gram-negative opportunistic microflora; in particular, E. coli prevailed in the structure of isolated causative agents (61.9%). Analysis of detected pathogens susceptibility to antimicrobial agents showed a high level of E.coli resistance to ampicillin, amoxicillin/clavulanate and gentamicin (in 97.4% of cases), and in 50% of cases the E.coli were resistant to cefotaxime, ceftriaxone and cefuroxime. High rates of resistance of Enterococcus spp. (100%) and Enterobacter spp. (96.7%) to cefuroxime, cefotaxime and ceftriaxone were recorded. Furamag demonstrated significantly higher bacteriological efficacy vs. cefuroxime axetil as for eradication of the most clinically significant causative agents of cystitis identified in the Poltava region (93.9% and 68.8%, respectively, p <0.05). During the follow-up study, anti-relapse efficacy of Furamag appeared to be 1.5 times higher as compared to the reference drug in the children examined (p <0.05).

Aims: Sickle retinopathy (SR) is a major cause of blindness in sickle cell disease (SCD). The genetic mutation responsible for SCD is known, however; oxidative stress and inflammation also figure prominently in the development and progression of pathology. Development of therapies for SR is hampered by the lack of (a) animal models that accurately recapitulate human SR and (b) strategies for noninvasive yet effective retinal drug delivery. This study addressed both issues by validating the Townes humanized SCD mouse as a model of SR and demonstrating the efficacy of oral administration of the antioxidant fumaric acid ester monomethyl fumarate (MMF) in the disease., Results: In vivo ophthalmic imaging, electroretinography, and postmortem histological RNA and protein analyses were used to monitor retinal health and function in normal (HbAA) and sickle (HbSS) hemoglobin-producing mice over a one-year period and in additional HbAA and HbSS mice treated with MMF (15 mg/ml) for 5 months. Functional and morphological abnormalities and molecular hallmarks of oxidative stress/inflammation were evident early in HbSS retinas and increased in number and severity with age. Treatment with MMF, a known inducer of Nrf2, induced γ-globin expression and fetal hemoglobin production, improved hematological profiles, and ameliorated SR-related pathology. Innovation and Conclusion: United States Food and Drug Administration-approved formulations in which MMF is the primary bioactive ingredient are currently available to treat multiple sclerosis; such drugs may be effective for treatment of ocular and systemic complications of SCD, and given the pleiotropic effects, other nonsickle-related diseases in which oxidative stress, inflammation, and retinal vascular pathology figure prominently. Antioxid. Redox Signal. 25, 921-935., Competing Interests: Author Disclosure Statement V.G. and P.M.M. are coinventors of US20140171504 A1 patent titled “Methods of treating SCD and related disorders using fumaric acid esters.” The remaining authors have no disclosures or competing financial interests to report.

Aliskiren (Rasilez), a direct renin inhibitor, is indicated for the treatment of essential hypertension. A postmarketing prescription-event monitoring (PEM) study was conducted in England to monitor the safety and utilization of aliskiren. Summary statistics and event incidence densities were calculated. The cohort consisted of 6385 individuals with a median age of 68 years (interquartile range, 59-76). Aliskiren was largely prescribed for its licensed indication of hypertension (93.3%) and was reported as "effective" by the prescriber in 77.4% of individuals. Frequently reported clinical events during treatment were diarrhea (3.1% of on-treatment events), malaise/lassitude (3.0%), and nausea/vomiting (1.2%), which were also common reasons for treatment cessation. Renal events were rare, with 24 cases probably or possibly related to aliskiren use, and four of which were classified as acute renal failure using RIFLE (Risk Injury Failure Loss End-Stage Kidney Disease) criteria. These results should be used in conjunction with other clinical and pharmacoepidemiologic studies to optimize the safe prescribing of aliskiren., (©2016 Wiley Periodicals, Inc.)

Soluble urokinase plasminogen activator receptor (suPAR) is associated with faster decline in kidney function and the pathogenesis of diabetic nephropathy. However, little is known about the impact of treatment on plasma and urinary levels of suPAR. We aimed to investigate the impact of renin angiotensin system (RAS) single and dual blockade on suPAR levels in patients with type 2 diabetes and albuminuria. We conducted a post-hoc analysis of a randomized controlled crossover trial. Urine and plasma samples were analyzed for suPAR levels. The placebo period was considered reference and all treatment periods were compared to placebo. Patients (n = 22) were treated for 2-month periods with either placebo, irbesartan 300 mg once daily, aliskiren 300 mg once daily or irbesartan/aliskiren combination in random order. Placebo geometric mean plasma (SEM) levels of suPAR were 3.3 ng/mL (1.1) and urine levels were 4.0 ng/mL (1.1). None of the treatments had significant effects on plasma levels of suPAR compared to placebo. Compared to placebo, irbesartan and combination treatment decreased urinary levels of suPAR significantly (-1.3 ng/mL), while aliskiren did not. In patients with type 2 diabetes urinary levels of suPAR were reduced during RAS blockade treatment, which may contribute to renoprotection., (Copyright © 2016 Elsevier Inc. All rights reserved.)

To examine the effects of aliskiren, a small-molecule renin inhibitor, on cancer cachexia and to explore the underlying mechanisms. A cancer cachexia model was established by subcutaneously injecting C26 mouse colon carcinoma cells into isogenic BALB/c mice. Aliskiren was administered intragastrically [10 mg/kg body weight (BW)] on day 5 (as a preventive strategy, AP group) or on day 12 (as a therapeutic strategy, AT group) after C26 injection. Mice that received no C26 injection (healthy controls, HC group) or only C26 injection but not aliskiren (cancer, CA group) were used as controls. BW, tumor growth, whole body functions, and survival were monitored daily in half of the mice in each group, whereas serum, tumors, and gastrocnemius muscles were harvested from the other mice after sacrifice on day 20 for further analysis. Aliskiren significantly alleviated multiple cachexia‑associated symptoms, including BW loss, tumor burden, muscle wasting, muscular dysfunction, and shortened survival. On the molecular level, aliskiren antagonized cachexia‑induced activation of the renin‑angiotensin system (RAS), systematic and muscular inflammation, oxidative stress, and autophagy‑lysosome as well as ubiquitin‑proteasome stimulation. In addition, early administration of aliskiren before cachexia development (AP group) resulted in more robust effects in alleviating cachexia or targeting underlying mechanisms than administration after cachexia development (AT group). Aliskiren exhibited potent anti‑cachexia activities. These activities were achieved through the targeting of at least four mechanisms underlying cachexia development: RAS activation, increase in systematic inflammation, upregulation of oxidative stress, and stimulation of autophagy-lysosome pathway (ALP) and ubiquitin-proteasome pathway (UPP).