Short-term High Dose Research Articles

Efficacy of bepridil as a periprocedural support drug in atrial fibrillation patients with left ventricular systolic dysfunction undergoing catheter ablation

Abstract We previously reported that sinus restoration either with drugs or DC cardioversion prior to catheter ablation (CA) was associated with a better outcome in persistent atrial fibrillation (AF). As an antiarrhythmic agent for persistent AF, amiodarone is recommended for patients with structural heart disease. Bepridil, a unique multichannel inhibitor, has a comparable defibrillation efficacy and fewer extracardiac complications than amiodarone, although safety and efficacy of bepridil has not been established in those with left ventricular (LV) systolic dysfunction. We compared the safety and efficacy of bepridil and amiodarone as periprocedural support drugs for CA in patients with persistent AF with LV systolic dysfunction. Method and result: Persistent AF patients with LVEF ≤50% taking bepridil or amiodarone as periprocedural support drugs for CA were retrospectively analyzed; 51 patients in the bepridil group and 17 patients in the amiodarone group. There were 20 (39%) in the bepridil group and 17 (100%) in the amiodarone group with LVEF less than 40%. The amiodarone group had more history of heart failure hospitalizations, higher BNP, and lower LVEF than the bepridil group (HF; Bep 35.8% vs Amio 94.1% [p<0.01], BNP; Bep 306.4±422.8 pg/ml vs Amio 645.2±456.3 [p<0.01], LVEF; Bep 39.9±8.4% vs Amio 26.7±7.9% [p<0.01]). Bepridil was used at a dose of 126±39 mg and amiodarone at 153±60 mg before CA. Successful pharmacological defibrillation before CA was more prevalent in the bepridil group (Bep; 15:29.4% vs Amio; 2:11.8%, p=0.14). The time from drug induction to CA was 41±38 days in the bepridil group and 66±59 days in the amiodarone group. At 1-year after CA, doses of both drugs could be reduced (Bep: 72±53mg, Amio: 67±49mg), and 12 (23.5%) in the bepridil group and 3 (17.6%) in the amiodarone group were able to discontinue the drug. AF recurred in 6 (11%) in the bepridil group, and 2 (11%) in the amiodarone group. QTc was the longest immediately before CA in the both groups (Bep: 462±36ms, Amio: 462±32ms), but was shortened at 1-year with the drug dose reduction (Bep: 435±40ms, Amio: 444±29ms). LVEF significantly improved following maintenance of sinus rhythm in the both groups (Bep: 39.9±8.4% to 52.6±10.2% [p<0.01], Amio: 26.7±7.9% to 49.5±14.5% [p<0.01]), which was comparable between the 2 groups. Fatal ventricular arrhythmia occurred in 1 (5%) in the amiodarone group but not in the bepridil group. Hospitalization for heart failure occurred in 2 (3.9%) in the bepridil group. Discussion: Bepridil could be used safely at a short-term high dose before ablation and then reducing the dose after ablation. There is also a trend toward selecting bepridil in patients with relatively preserved cardiac function and less severe conditions. Conclusion: Bepridil can be used rather safely in AF patients with LV systolic dysfunction undergoing CA as a periprocedural support drug.

Short-Term High Dose Inulin Supplementation Does Not Improve Cognitive Function In Healthy And Diseased Participants

Short-Term High Dose Inulin Supplementation Does Not Improve Cognitive Function In Healthy And Diseased Participants

Efficacy of Short-Term High Dose Pulsed Dapsone Combination Therapy in the Treatment of Chronic Lyme Disease/Post-Treatment Lyme Disease Syndrome (PTLDS) and Associated Co-Infections: A Report of Three Cases and Literature Review.

Lyme disease and associated co-infections are increasing worldwide and approximately 20% of individuals develop chronic Lyme disease (CLD)/Post-Treatment Lyme Disease Syndrome (PTLDS) despite early antibiotics. A seven- to eight-week protocol of double dose dapsone combination therapy (DDDCT) for CLD/PTLDS results in symptom remission in approximately 50% of patients for one year or longer, with published culture studies indicating higher doses of dapsone demonstrate efficacy against resistant biofilm forms of Borrelia burgdorferi. The purpose of this study was, therefore, to evaluate higher doses of dapsone in the treatment of resistant CLD/PTLDS and associated co-infections. A total of 25 patients with a history of Lyme and associated co-infections, most of whom had ongoing symptoms despite several courses of DDDCT, took one or more courses of high dose pulsed dapsone combination therapy (200 mg dapsone × 3–4 days and/or 200 mg BID × 4 days), depending on persistent symptoms. The majority of patients noticed sustained improvement in eight major Lyme symptoms, including fatigue, pain, headaches, neuropathy, insomnia, cognition, and sweating, where dapsone dosage, not just the treatment length, positively affected outcomes. High dose pulsed dapsone combination therapy may represent a novel therapeutic approach for the treatment of resistant CLD/PTLDS, and should be confirmed in randomized, controlled clinical trials.

Effect of Short Term High Dose Oral Vitamin D Therapy on the Inflammatory Markers in Patients with COVID 19 Disease

Effect of Short Term High Dose Oral Vitamin D Therapy on the Inflammatory Markers in Patients with COVID 19 Disease

Relation between the vitaminD status and the occurrence and severity of thyroid malignancy

Background. In spite of large volume of data linking vitaminD with cardiovascular morbidity, autoimmunity, cancer, and virtually every organ system, vitaminD and thyroid is a lesser-known aspect of vitaminD in clinical practice. The association between vitaminD deficiency and thyroid cancer is controversial. Some studies have demonstrated that higher serum vitaminD levels might protect against thyroid cancer, whereas others have not, or have even indicated the opposite to to be the case. This review intends to highlight the current literature on the impact of vitaminD status on thyroid cancer. Materials and methods. References for this review were identified through searches of PubMed for articles published to from 2005 to June 2021 using the terms “thyroid cancer” and “vitaminD”. Results. A large volume of medical literature is available from observational studies linking vitaminD with thyroid cancer. Data from interventional studies documenting beneficial effects of vitaminD on thyroid autoimmunity is also available, but lesser than that from observational studies. Short-term high dose oral vitaminD supplementation reduces TPOAb titers. Certain vitaminD receptor (VDR) gene polymorphism have been linked to increased occurrence of autoimmune thyroid disorders. VitaminD deficiency, decreased circulating calcitriol has been linked to increased thyroid cancer. Certain VDR gene polymorphisms have been linked with increased as well as decreased occurrence of thyroid cancer. Data is scant on use of vitaminD and its analogues for treating thyroid cancer. The results suggest that VitaminD deficiency may have value as a negative prognostic indicator in papillary thyroid cancer and that pre-operative laboratory evaluation may be less useful. This is important because VitaminD deficiency is modifiable. Conclusions. In spite of large volume of medical literature from observational studies linking vitaminD with thyroid cancer, meaningful concrete clinical data on impact of vitaminD supplementation on hard clinical end points in these disorders is lacking, and should be the primary area of research in the next decade.

Влияние обеспечения витамином D на аутоиммунное состояние щитовидной железы

Актуальность. Несмотря на большой объем данных, связывающих витамин D с сердечно-сосудистой заболеваемостью, аутоиммунитетом, раком и практически каждой системой органов, взаимосвязь между витамином D и щитовидной железой остается менее известным аспектом в клинической практике. Причиной активного влияния витамина D является тот факт, что рецепторы витамина D (VDR) размещены практически в каждой ткани и системе органов организма. Цель: осветить данные современной литературы о влиянии витамина D и его обеспечения на аутоиммунитет щитовидной железы. Материалы и методы. Источники этого обзора были определены с помощью поиска в PubMed по статьям, опубликованным с 2015 года по сентябрь 2020 года, с использованием терминов «щитовидная железа» и «витамин D». Результаты. Зарегистрирована достоверная обратная корреляция между антителами к тиреоидной пероксидазе (АТ-ТПО) и содержанием 25-гидроксивитамина D (25(OH)D) в сыворотке крови. Наличие положительных титров АТ-ТПО более распространено у лиц с дефицитом витамина D. В большом объеме медицинской литературы приводятся результаты наблюдательных исследований, связывающих витамин D с аутоиммунитетом щитовидной железы. Также приводятся данные интервенционных исследований, подтверждающих положительное влияние витамина D на аутоиммунитет щитовидной железы. Краткосрочный прием высоких доз пероральных добавок витамина D содействует уменьшению титров АТ-ТПО. Некоторые полиморфизмы гена VDR связаны с увеличением случаев аутоиммунных расстройств щитовидной железы. Данные о том, приводит ли коррекция дефицита витамина D при аутоиммунных расстройствах щитовидной железы к снижению потребности в левотироксине или карбимазоле соответственно при гипотиреозе или болезни Грейвса, отсутствуют. Выводы. Несмотря на большой объем медицинской литературы по обсервационным исследованиям, в которых связывают витамин D с аутоиммунитетом щитовидной железы, отсутствуют важные конкретные клинические данные о влиянии дополнительного назначения витамина D на основные клинические конечные точки при этих расстройствах. Это должно быть основной сферой исследований в следующем десятилетии.

Abstract 1725: Short-term administration of high dose mIL-2/CD25 fusion protein elicits CD8+ T cell-driven anti-tumor immunity and memory

Abstract Recombinant IL-2 (rIL-2) promotes the differentiation, proliferation, and survival of antigen-activated T cells and induces potent anti-tumor activity. High dose (HD) rIL-2 broadly targets T effector (Teff) and NK cells. However, rIL-2 cancer therapy requires long-term infusions of high doses due to its short half-life and is associated with severe toxicities which limit efficacy. To circumvent these limitations, our lab has developed and is testing a new IL-2-based biologic, mIL-2/CD25, which can be used at high doses to promote anti-tumor immunity. mIL-2/CD25 is a fusion protein (FP) composed of mouse IL-2 fused to the mouse CD25 extracellular domain via a non-cleavable glycine-serine linker with selectivity toward the high affinity IL-2R. This FP has a much longer half-life (16 hr) than rIL-2 (15 min). At a low dose, mIL-2/CD25 selectively expands Tregs, but at a HD, Teff cells are also engaged. These properties allow for HD FP to readily expand activated endogenous tumor-reactive Teff cells, but not memory-phenotypic CD8+ T cells and NK cells. In the current study, we tested the extent short-term HD FP therapy activated tumor-reactive Teff cells to elicit efficacious anti-tumor immunity responses despite Treg stimulation. HD FP prolonged survival in mice bearing B16.F10 melanoma, MC-38 colon adenocarcinoma, or CT26 colon carcinoma. In the CT26 model, a significant increase in both the number and the frequency of CD8+ T cells was detected in the tumor microenvironment (TME) of treated mice. FP-dependent Treg expansion was observed in secondary lymphoid tissues but not the TME. This therapeutic approach, therefore, led to a higher CD8+ Teff to Treg ratio specifically in the TME. After FP treatment, CD8+ T cells isolated from the TME expressed lower levels of TOX, PD-1, and LAG-3, suggesting that they were less exhausted. T cell depletion studies using anti-CD8 revealed that CD8+ T cells are the major driver of the FP-induced anti-tumor response. Rechallenge of animals that had previously cleared CT26 due to FP treatment led to successful tumor rejection, showing that the FP supported anti-tumor memory. These findings demonstrate that mIL-2/CD25 amplifies recently activated tumor-reactive CD8+ Teff cells to generate efficacious anti-tumor responses that limit Treg-dependent negative regulation in the TME and lead to anti-tumor memory. Citation Format: Kathryn LaPorte, Rosmely Hernandez, Thomas Malek. Short-term administration of high dose mIL-2/CD25 fusion protein elicits CD8+ T cell-driven anti-tumor immunity and memory [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1725.

Inflammatory Bowel Disease Patients Hospitalized for Flares Are at Risk for Chronic Steroid Use Due to Lack of Clear Instructions at Discharge: A 15-Month Retrospective Study at a Private, Not-For-Profit Academic Hospital

Patients with inflammatory bowel disease (IBD) who are hospitalized with an IBD flare can be managed acutely with short-term (4-6 weeks) high dose glucocorticoid taper. Corticosteroid use beyond 3-4 months can cause serious and significant side effects. Thus, it is imperative for patients to be discharged with a prednisone tapering plan and steroid-sparing treatment strategy. This quality assessment project examines the rate at which IBD patients remain on high dose steroids 3 months after hospital discharge.

Characterization of a potential host-directed therapy against TB in non-human primates

Abstract An estimated 558,000 cases of drug-resistant tuberculosis (TB) occurred in 2017, emphasizing a need for new treatment strategies. We assessed a host-directed therapy (HDT) for TB using two FDA-approved drugs. Linezolid (LZD) is a potent antibiotic for antibiotic-resistant Gram-positive infections and is an effective treatment for TB. However, lengthy antibiotic regiments (>4 weeks) may lead to LZD-associated host toxicities, most commonly bone marrow (BM) suppression. LZD toxicities are mediated by IL-1, a pathway important for early immunity during Mtb infection that later contributes to pathological TB disease. We hypothesized LZD efficacy could be enhanced by addition of Anakinra, a recombinant IL-1R antagonist (rIL-1RA), by reducing BM toxicity and TB-associated inflammation. We tested this HDT in a non-human primate (NHP) model which emulates the spectrum of human TB, combined with PET/CT to monitor disease progression. NHPs with active TB were treated with LZD or LZD+rIL-1RA and tracked by PET/CT to monitor granuloma formation and inflammation. Analysis of BM erythroid progenitor cells determined little evidence of BM suppression associated with short-term high dose LZD. However, we observed sterilization of the majority of granulomas and a trend of enhanced bacterial clearance with rIL-1RA. Addition of rIL-1RA decreased granuloma inflammation (measured by PET/CT) compared to LZD alone, however few differences in immune cell populations were observed. Together, these data indicate LZD as a promising addition to treatment of drug resistant TB and the potential of HDTs in improving therapy.

Vitamin D, Thyroid Autoimmunity and Cancer: An Interplay of Different Factors.

Background and Aims:In spite of large volume of data linking Vitamin D with cardiovascular morbidity, autoimmunity, cancer, and virtually every organ system, Vitamin D and thyroid is a lesser-known aspect of Vitamin D in clinical practice. This article intends to highlight the current literature on the impact of Vitamin D status and supplementation on thyroid autoimmunity and cancer.Methods:References for this review were identified through searches of PubMed for articles published to from 1950 to August 2019 using the terms “thyroid” [MeSH Terms] AND “Vitamin D” [MeSH Terms] OR “thyroid” [All Fields] AND “Vitamin D” [All Fields].Results:Significant inverse correlation was documented between anti-thyroid peroxidase antibody (TPOAb) and serum 25-hydroxy-Vitamin D (25OHD). TPOAb positivity is more prevalent in Vitamin D deficient individuals. A large volume of medical literature is available from observational studies linking Vitamin D with thyroid autoimmunity. Data from interventional studies documenting beneficial effects of Vitamin D on thyroid autoimmunity is also available, but lesser than that from observational studies. Short-term high dose oral Vitamin D supplementation reduces TPOAb titers. Certain Vitamin D receptor (VDR) gene polymorphism have been linked to increased occurrence of autoimmune thyroid disorders (AITD). Vitamin D deficiency, decreased circulating calcitriol has been linked to increased thyroid cancer. Certain VDR gene polymorphisms have been linked with increased as well as decreased occurrence of thyroid cancer. Data is scant on use of Vitamin D and its analogues for treating thyroid cancer.Conclusion:In spite of large volume of medical literature from observational studies linking Vitamin D with thyroid autoimmunity and cancer, meaningful concrete clinical data on impact of Vitamin D supplementation on hard clinical end points in these disorders is lacking, and should be the primary area of research in the next decade.

The Effect of High Dose Isoflavone Supplementation on Serum Reverse T3 in Euthyroid Men With Type 2 Diabetes and Post-menopausal Women.

Background: The health benefits of soy are widely reported but there are queries on the effect of soy isoflavones on thyroid function and the underlying mechanism of action.Materials and Methods: We examined the effect of soy isoflavones on reverse tri-iodothyronine (or 3,3′,5′-tri-iodothyronine; rT3) in two studies comprising 400 patients: 200 men (study 1; 3 months) and 200 post-menopausal women (study 2; 6 months) who were randomized to consume 15 g soy protein with 66 mg of isoflavones (SPI) daily, or 15 g soy protein alone without isoflavones (SP) daily.Results: SPI supplementation increased rT3 serum concentration in both men 0.41 (0.12) vs. 0.45 (0.14) nmol/L and women 0.33 (0.12) vs. 0.37 (0.09) nmol/L at 3 months compared to SP that was not seen at 6 months. Thyroid stimulating hormone (TSH) serum concentrations increased while free thyroxine (fT4) concentrations decreased with 3 months of SPI compared to SP supplementation for both men and women. rT3 correlated with TSH in both studies (p = 0.03) but not with either fT3 or fT4. fT3 levels did not differ between the SPI and SP preparations.Conclusion: Soy isoflavones transiently increased rT3 levels within 3 months though reverted to baseline at 6 months. The mechanism for this would be either rT3 degrading deiodinase 1 and/or deiodinase 2 activities are transiently inhibited at 3 months, or inhibition of deiodinase 3, which generates rT3 from T4 is induced at 6 months. These changes were mirrored in the TSH concentrations, suggesting that short-term high dose isoflavone transiently impairs thyroid function in the first 3 months and may impact on general health during this period.ISRCTN Registry: ISRCTN 90604927; ISRCTN34051237.

Short-Term Effect of High-Dose Pantoprazol on Serum and Urinary Magnesium Levels.

Proton pump inhibitor (PPI) induced hypomagnesemia is a completely unexplained issue and cases are still being reported. Long-term use is the main factor, but there are a few articles stating that it may also emerge with short-term use. We aimed to evaluate the changes of serum and urine magnesium levels during shortterm high dose pantoprazol treatment. The serum and 24-hour urine magnesium levels of 58 patients were evaluated during the course of 2 days. Of 58 patients, 25 were allowed oral intake on the 3rd day of hospitalization and thus, 24-hour urine for 3 days was collected from 33 patients. There were no significant differences in the mean levels of serum magnesium and the median levels of urine magnesium. When the magnesium levels were evaluated by age over and under 60 years, the baseline serum magnesium level was significantly higher than the 1st level in patients aged ≥ 60 years (p = 0.029). The 3rd day serum magnesium level was significantly higher than the baseline and 1st day levels in those aged < 60 years (p = 0.049). We showed that plasma levels and urinary excretion of magnesium did not change significantly during high-dose pantoprazol treatment. It can be hypothesized that magnesium levels are not affected by PPIs in short-term usage. Age and other contributing factors may have more impact on PPI induced hypomagnesemia. Patients aged over 60 years might be handled carefully under proton pump inhibitors treatment.

Effect of Erythropoietin in patients with acute myocardial infarction: five-year results of the REVIVAL-3 trial

BackgroundErythropoietin (EPO) has been suggested to promote cardiac repair after MI. However, the randomized, double-blind, placebo controlled REVIVAL-3 trial showed that short term high dose EPO in timely reperfused myocardium does not improve left ventricular ejection fraction after 6 months. Moreover, the study raised safety concerns due to a trend towards a higher incidence of adverse clinical events as well as a increase in neointima formation after treatment with EPO. The present study therefore aimed to assess the 5-year clinical outcomes.MethodsAfter successful reperfusion 138 patients with STEMI were randomly assigned to receive epoetin beta (3.33×104 U, n = 68) or placebo (n = 70) immediately, 24 and 48 h after percutaneous coronary intervention. The primary outcome of the present study- the combined incidence of MACE 5 years after randomization - occurred in 25% of the patients assigned to epoetin beta and 17% of the patients assigned to placebo (RR 1.5; 95% CI 0.8-3.5; p = 0.26). Target lesion revascularization was required in 15 patients (22.1%) treated with epoetin-ß and 9 patients (12.9%) treated with placebo (p = 0.15). Analysis of patients in the upper and lower quartile of baseline hemoglobin as an indirect estimate of endogenous erythropoietin levels revealed no significant impact of endogenous erythropoietin on efficiency of exogen administered epoetin-ß in terms of death and MACE.ConclusionThese long-term follow-up data show that epoetin beta does not improve clinical outcomes of patients with acute myocardial infarction.Trial registrationURL www.clinicaltrials.gov; Unique identifier NCT00390832; trial registration date October 19th 2006

Short-term High Dose of Quercetin and Resveratrol Alters Aging Markers in Human Kidney Cells.

Background:Hyperglycemia-mediated oxidative stress implicates in etiology of kidney cell aging and diabetic nephropathy. We evaluated the effects of different doses of resveratrol and quercetin and their combination therapy on aging marker in human kidney cell culture under hyperglycemia condition.Methods:Human embryonic kidney cell (HEK-293) was cultured in Dulbecco's Modified Eagle Medium (DMEM) containing 100 mM (18 mg/L) for 24 h. The cells were treated with resveratrol (2.5, 5, 10 μm), quercetin (3, 6, 12 μm), and combination of these (R 2.5 μm, Q 3 μm) and (R 5 μm, Q 6 μm) and (R 10 μm, Q 12 μm) for 48 h, and then, cells were lysed to access RNA and lysate.Results:The analysis of data showed that beta-galactosidase enzyme gene expression as an aging marker in all treatment groups has reduced in a dose-dependent manner. Gene expression of Sirtuin1 and thioredoxin (Trx) in all treated groups in comparison to control group increased in a dose-dependent fashion. Trx interacting protein (TXNIP) gene expression decreased in a dose-dependent manner in all treated groups, especially in resveratrol and combination therapy.Conclusions:According to the results of this research, quercetin, resveratrol, and especially combination treatments with increased expression levels of antioxidants, can reduce aging markers in HEK cell line in hyperglycemia conditions. These results lead us to use flavonoids such as resveratrol for anti-aging potential.

Response and Defense Mechanisms of Taxus chinensis Leaves Under UV-A Radiation are Revealed Using Comparative Proteomics and Metabolomics Analyses.

Taxus chinensis var. mairei is a species endemic to south-eastern China and one of the natural sources for the anticancer medicine paclitaxel. To investigate the molecular response and defense mechanisms of T. chinensis leaves to enhanced ultraviolet-A (UV-A) radiation, gel-free/label-free and gel-based proteomics and gas chromatography-mass spectrometry (GC-MS) analyses were performed. The transmission electron microscopy results indicated damage to the chloroplast under UV-A radiation. Proteomics analyses in leaves and chloroplasts showed that photosynthesis-, glycolysis-, secondary metabolism-, stress-, and protein synthesis-, degradation- and activation-related systems were mainly changed under UV-A radiation. Forty-seven PSII proteins and six PSI proteins were identified as being changed in leaves and chloroplasts under UV-A treatment. This indicated that PSII was more sensitive to UV-A than PSI as the target of UV-A light. Enhanced glycolysis, with four glycolysis-related key enzymes increased, provided precursors for secondary metabolism. The 1-deoxy-d-xylulose-5-phosphate reductoisomerase and 4-hydroxy-3-methylbut-2-enyl diphosphate reductase were identified as being significantly increased during UV-A radiation, which resulted in paclitaxel enhancement. Additionally, mRNA expression levels of genes involved in the paclitaxel biosynthetic pathway indicated a down-regulation under UV-A irradiation and up-regulation in dark incubation. These results reveal that a short-term high dose of UV-A radiation could stimulate the plant stress defense system and paclitaxel production.

Does Short-Term High Dose Probiotic Supplementation Containing Lactobacillus casei Attenuate Exertional-Heat Stress Induced Endotoxaemia and Cytokinaemia?

The study aimed to determine if short-term high dose probiotic supplementation containing Lactobacillus casei (L.casei) attenuates the commonly reported exertional-heat stress (EHS) induced endotoxinaemia and cytokinaemia. Eight endurance trained male volunteers (mean± SD: age 26 ± 6 y, nude body mass 70.2 ± 8.8 kg, height 1.75 ± 0.05 m, VO2max 59 ± 5 ml·kg-1·min-1) completed a blinded randomized cross-over design, whereby oral ingestion of a commercially available probiotic beverage containing L.casei (volume equivalent for ×1011 colony forming units·day-1) (PRO) or placebo (PLA) was consumed for 7 consecutive days before exposure to EHS, which comprised of 2h running exercise at 60% VO2max in hot ambient conditions (34.0 °C and 32% RH). Blood samples were collected at baseline (7 days before EHS), pre-EHS, post-EHS (1 hr, 2 hr, 4 hr, and at 24 hr). Plasma samples were analyzed for gram-negative bacterial endotoxin, cytokine profile (IL-6, IL-1β, TNF-α, IFN-γ, IL-8, and IL-10) and plasma osmolality. Plasma osmolality did not differ between trials. Seven days of L.casei supplementation did not show significant changes in resting circulatory endotoxin concentration or plasma cytokine profile compared with PLA. A main effect of time was observed for IL-6, TNF-α, IL-10 and IL-8; whereby levels increased in response to EHS (p < .05). Relative to pre-EHS concentrations, higher plasma concentrations of endotoxin (p = .05), and a trend for higher plasma TNF-α concentration (p = .09) was observed on PRO compared with PLA throughout recovery. Short-term high dose supplementation of a probiotic beverage containing L.casei before EHS did not attenuate EHS induced endotoxaemia and cytokinaemia; nor is it more positively favorable over a placebo.

Abstract 13502: Statins Buffer the Vasoconstricting, Pro-Inflammatory and Pro-Oxidant Effects of Experimental Venous Congestion in Patients With Systolic Heart Failure on Stable Medical Regimen

Background: In heart failure (HF), statins decrease hospitalizations for acute decompensation, which are primarily due to venous congestion (VC). The reason is unknown. We tested whether statins buffer the vasoconstricting, pro-inflammatory and pro-oxidant effects of VC in an established human model of this condition. Methods: We studied 41 pts, NYHA class II-III, LVEF &lt;40%, euvolemic and on stable medical therapy. To experimentally model VC, venous arm pressure was increased to 30 mmHg above baseline by inflating a pressure cuff around the dominant arm. Blood was sampled from test and control arm (lacking an inflated cuff) before and after 90 minutes of VC. Plasma endothelin-1 (ET-1), interleukin-6 (IL-6), and vascular cell adhesion molecule 1 (VCAM-1) were measured by ELISA; isoprostane by LC-MS. Results: Age was 53±2 years, 32% were female, 29% had an ischemic etiology, LVEF was 22±1%, 56% were treated with a statin. Experimental VC increased plasma isoprostane, ET-1, VCAM-1 and IL-6. However, the use of a statin greatly influenced the rate of this response: the increase in isoprostane (marker of oxidative stress) was four-fold higher among nonstatin vs statin users (62.3±11 vs 15.4±11.2 pg/ml, p=0.01); ET-1 (marker of vasoconstriction and inflammation) increased 50% more among nonstatin users (1.83±0.23 vs 1.21±0.21 pg/ml, p=0.05); VCAM-1 (marker of endothelial activation) increased 80% more among non-statin users (62.5±15.1 vs 33.6±13.3 pg/ml, p=0.16). Changes in IL-6 (marker of inflammation) did not differ in the two groups (1.2±.08 vs 1.1±0.08 pg/ml, p=0.78). Of note, the effects of statins on ET-1 was dose-dependent. Conclusions: We provide the first evidence that statins (particularly at high dose) partially buffer the vasoconstricting, pro-inflammatory and pro-oxidant effects of experimental VC. Future studies are warranted to address whether short-term high dose statins have an adjunctive role in the treatment of acute decompensation in HF pts.

Statins Against Drug-Induced Nephrotoxicity

Drug-induced nephrotoxicity (DIN) accounts for up to 60% of hospital acquired acute kidney injury with considerable morbidity and mortality. Several efforts have been made to reduce drug-induced nephrotoxicity; however, DIN remains a matter of concern. Statins with their antioxidant, anti-inflammatory and anti-apoptotic effects may have the potential to protect kidney against DIN. The present review evaluated all of the available in vitro and in vivo studies that examined the use of statins as renoprotective agents against nephrotoxic drugs. Materials for this review were obtained by searching Medline, PubMed, Scopus, Cochrane central register of controlled trials, and Cochrane database of systematic reviews. Key words used as search terms included "statin", "3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, "HMG-CoA reductase inhibitors", "nephroprotective", "renoprotective", "drug-induced renal diseases", "drug-induced nephrotoxicity", "drug-induced renal toxicity", "drug-induced nephropathy", "drug-induced renal side effects", and "contrast-induced nephropathy". This search was performed without time limitation. Only English language articles were included in this review. This review concluded that chronic statin user may be less prone to contrast-induced nephropathy (CIN) compared with statin non-users. Short-term high dose statin administration may also reduce the incidence of CIN in statin naïve patients. This renoprotective effect of statins against CIN is seen in low risk patients with normal kidney function or mild kidney dysfunction, but probably not in patients with moderate to severe renal dysfunction. Based on available animal data, statins may protect kidney against gentamicin-, cisplatin- and cyclosporine-induced nephrotoxicity, however, theses animal results have not yet been confirmed by human data. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Evidence for oral agmatine sulfate safety – A 95-day high dosage pilot study with rats

Agmatine, decarboxylated arginine, exerts beneficial effects in various experimental disease models. Clinical trials indicate the safety and effectiveness of short-term (up to 21days) high dose regimens of oral agmatine sulfate, but longer term studies are lacking. This pilot study undertook to assess the safety of a longer term high dosage oral agmatine sulfate in laboratory rats. Adult Wistar rats consumed 5.3g/l agmatine sulfate in their drinking water for 95days, a regimen estimated to result in a daily dosage of absorbed agmatine of about 100mg/kg. Animals’ body weight, water consumption and blood pressure were periodically measured, and general cage behavior, fur appearance, urination and feces appearance monitored. These parameters were also determined at 20days after treatment cessation (day 115). On days 95 and 115, animals were euthanized for gross necropsy assessment. Agmatine-treated rats showed slight, but significant reductions in body weight and blood pressure, and reduced water consumption during treatment, which recovered completely within 20days after treatment cessation. Otherwise, no abnormal behaviors or organ pathologies were observed. These findings are first to suggest apparent safety of sub-chronic high dosage dietary agmatine sulfate in laboratory rats, thus lending further support to the therapeutic applications of agmatine.

Impact of oral omega-3 fatty acids supplementation in early sepsis on clinical outcome and immunomodulation

IntroductionSepsis is a systemic inflammatory response that is usually aggravated by inappropriate immune responses, which can be inhibited by omega-3 fatty acids and antioxidants. ObjectivesTo determine the efficacy and safety of omega-3 fatty acid plus antioxidants in early sepsis. Methods75 patients with sepsis were divided equally into: (group A) who received high dose omega-3 fatty acids plus fixed dose antioxidants for consecutive 7 days besides conventional sepsis treatment, (group B) who received the same treatment as group A but a lower dose of omega-3 fatty acids and the control group who received only conventional sepsis treatment. All groups were followed up by: Inflammatory markers, SOFA score monitoring, need for organ supportive measures, length of ICU stay, 28 day mortality, final outcome and complications. ResultsCompared to the control group, the high dose omega-3 fatty acid exhibited significantly lower levels of CRP, IL6 and PCT at day 7 (P = 0.047, 0.05, 0.041 respectively). Compared to the control group, group A patients showed significantly lesser need and shorter duration of mechanical ventilation (P = 0.044, 0.038 respectively), significantly reduced development of severe sepsis indicated by mean and highest SOFA score; (P = 0.040 and 0.046 respectively), with insignificant difference in the need for vasopressors and hemodialysis (P = 0.12, 0.6 respectively). Comparing low dose omega-3 fatty acids plus antioxidants group to control group using same parameters, no significant results were found. ConclusionThe use of a short term high dose omega-3 therapy is safe and associated with promising effects on inflammatory cascade and may play a role in treatment of these patients.