Chronic Oral Therapy Research Articles

CONTINUOUS LEFT STELLATE GANGLION BLOCK DURING VT ABLATION TO SLOW VT AND IMPROVE ABLATION OUTCOME

Abstract Introduction Perioperative management of advanced patients with indication to ventricular tachycardia (VT) ablation is complex. A PAINESD score ≥ 15 was proposed to identify those who might benefit from pre–emptive mechanical cardiopulmonary support (MCS). We present a case successfully managed with continuous percutaneous left stellate ganglion block (C–PLSGB). Case A 71–year–old diabetic man with severe post–ischemic cardiomyopathy (LVEF 24%, NYHA Class III) and chronic pulmonary disease was admitted for electrical storm with multiple ICD shocks due to poorly tolerated monomorphic VT (MMVT) at 176 bpm resistant to anti–tachycardia pacing (ATP), despite ongoing chronic oral therapy with amiodarone and carvedilol. Poorly tolerated and ATP–resistant MMVTs at 170–180 bpm recurred despite intravenous (iv) amiodarone and lidocaine (20 mcg/kg/min) and oral propranolol. Ultrasound guided C–PLSGB was therefore started; lidocaine was chosen for the continuous infusion due to the short half–life, at the initial dose of 10 mg/h; 6 hours later, his poorly tolerated MMVT recurred at 167 bpm. Therefore, at first we increased iv lidocaine to 30 mcg/kg/min, without benefit, then we increased C–PLSGB at 37.5 mg/h and decreased iv lidocaine to 20 mcg/kg/min due to neurological symptoms. With this regimen, the patient stayed VT free for 2 hours, then the clinical VT recurred at 130 bpm, with good hemodynamic tolerability and ATP–response. C–PLSGB infusion was than increased to 75 mg/h, with no more VT. Endocardial VT ablation was planned. Despite a very high PAINESD score (31) we decided to avoid pre–emptive MCS. We stopped lidocaine (both iv and as C–PLSGB) 2 hours before ablation. As soon as the patient came in the EP room (before instrumentation), the clinical MMVT recurred at 133 bpm. C–PLSGB was then resumed (initially at 100 mg/h for 30 minutes, then at 37.5 mg/h). The MMVT then spontaneously recurred at 133 bpm: it was mapped and ablated in the medio–apical anterior wall, with acute VT interruption. A second VT morphology then appeared, that was mapped and ablated at a more basal site, despite a partial epicardial component of the circuit was identified. C–PLSGB was then stopped and no more VT occurred nor were induced 1 hour later. At 8 months the patient is still alive with no more VT. Conclusion C–PLSGB with individually tailored infusion rates could be used during VT ablation as a mean to reduce VT cycle length and allow for mapping without MCS.

Safety, tolerability, and pharmacokinetics of AZD5462, a small molecule agonist of the RXFP1 relaxin receptor

Abstract Introduction Despite multiple new drug advancements for patients with heart failure in recent years (specifically, sodium-glucose co-transporter-2 and sacubitril/valsartan), morbidity and mortality remain high. AZD5462 is a selective RXFP1 agonist which mimics the pregnancy hormone relaxin and its actions on systemic hemodynamics and kidney function. Purpose To assess the safety, tolerability, and pharmacokinetics (PK) of AZD5462 in a first-in-human study following single ascending dose (SAD) and multiple ascending dose (MAD) administration in healthy participants. Methods This was a phase 1 randomized, double-blind, placebo-controlled study. The SAD evaluated doses of 20, 80, 400, 750, and 1000 mg across 7 cohorts, with 2 cohorts comprising solely participants of Japanese descent. The MAD evaluated doses of 40, 120, 250, and 500 mg BID for 10 days across 5 cohorts, with 1 cohort of Japanese descent. There were approximately 8 participants in each cohort, randomized 6:2 to AZD5462 or placebo. AZD5462 was administered as an oral liquid solution. Results Overall, 98 participants were randomized and 92 completed the study (56 of 56 in SAD; 36 of 42 in MAD). The majority of participants randomized were male, and the median age was 39 years in the SAD and 36 years in the MAD. There were no major safety and tolerability concerns up to the highest dose administered (1000 mg SAD; 500 mg BID MAD). Pre-specified study stopping criteria were not met. There were no deaths or other serious adverse events. AEs were more common in the pooled AZD5462 group than placebo (approximately 40% for AZD5462 and 20% for placebo). The most common AEs were GI disorders (nausea, abdominal pain, vomiting), headache, medical device site dermatitis, and orthostatic heart rate response increase, but without clear relationship to dose. Three participants discontinued the MAD due to dizziness, supraventricular tachycardia, and positive COVID-19 test. There was no clear pattern in the effect on SBP with 120 mg and higher doses in the MAD. There was a trend for DBP decrease but no signs of hypotension. HR increased in all cohorts, which was dose-dependent in SAD but without clear relationship to dose in MAD. Treatment with AZD5462 led to a dose-dependent increase in plasma renin in all but the lowest SAD dose. AZD5462 was rapidly absorbed with a median Tmax between 0.53 hr and 1.75 hr. Plasma concentrations declined in a biphasic manner, with a geometric mean terminal half-life after a single dose between 3 h and 6 h. The exposure to AZD5462 increased more than proportionately with dose. Conclusions AZD5462 was generally well tolerated at all dose levels in this phase 1 study. These data pave the way for development of a chronic oral relaxin therapy for patients with heart failure.

Understanding the Link Between Adult Asthma and Coronary Artery Disease: A Narrative Review.

Asthma is a common pathology worldwide that occurs due to chronic inflammation of the respiratory airways. Persistent pulmonary inflammation leads to low-grade systemic inflammation, influencing blood vessels and triggering coronary artery disease (CAD) events. This review's objectives include discussing the susceptible population for CAD, the mechanism underlying CAD creation in asthma patients, the characteristics of asthma, and the influence of anti-asthmatic medications on CAD development. Adult-onset asthma is strongly linked to CAD and stroke. Future research may shed light on these disparities. Atherosclerosis and asthma are linked through both intrinsic and extrinsic pathways, with inflammation being the intrinsic pathway and hypoxia and tachyarrhythmia being the extrinsic pathways. The most probable mechanisms for increased coronary vasospastic angina (CVsA) incidence in asthmatic patients are vascular smooth muscle cell hypercontraction and endothelial dysfunction. Studies have shown a dose-response relationship between asthma control and myocardial infarction (MI) risk, with uncontrolled asthma at the highest risk. Impairment of ventilatory function is a distinct risk factor for lethal MI and cardiovascular death (CVD). The use of beta-2-agonists and chronic oral glucocorticoid therapy in severe asthmatics has been linked to increasing the risk for CAD. However, some studies have shown that the risk of MI among patients with active asthma is not related to the use of asthma medications. Further research is needed to determine the involvement of adult asthma features and their treatments in the development of CAD.

Prosthetic Joint Infection Due to Mycobacterium goodii/smegmatis

Total hip arthroplasty is among the most frequently performed elective surgical procedures in the United States. Infection of the implant is a rare but catastrophic complication. Generally, patients require multiple surgical procedures and intravenous antibiotics to eradicate the infection. We present the case of a patient diagnosed with a strain of rapidly growing mycobacteria not frequently encountered. He was successfully treated with retention of implants and chronic oral antibiotic therapy. A literature review was performed to identify similar cases, and the results showed that most of the patients underwent successful revision of the implant along with antibiotic therapy. We present this case to illustrate an alternative method of management for appropriate patients who may not be an adequate surgical candidate for prosthesis removal.

Safety and efficacy of continuous subcutaneous foslevodopa-foscarbidopa in patients with advanced Parkinson's disease: a randomised, double-blind, active-controlled, phase 3 trial

Levodopa is the most effective symptomatic therapy for Parkinson's disease, but patients with advanced Parkinson's disease develop motor fluctuations with chronic oral levodopa therapy. Foslevodopa-foscarbidopa is a soluble formulation of levodopa and carbidopa prodrugs that is delivered as a 24-h/day continuous subcutaneous infusion, and we aimed to assess the safety and efficacy of this formulation in patients with advanced Parkinson's disease. A 12-week randomised, double-blind, double-dummy, active-controlled study was done at 65 academic and community study centres in the USA and Australia. Patients with levodopa-responsive advanced Parkinson's disease inadequately controlled on current therapy, including at least 2·5 h of average daily off time, were randomly assigned (1:1) to continuous subcutaneous infusion of foslevodopa-foscarbidopa plus oral placebo or to oral immediate-release levodopa-carbidopa plus continuous subcutaneous infusion of placebo solution. Randomisation was stratified by site by means of a permutated-block schedule with a block size of two. The participants, treating investigators, study site personnel, and sponsor were masked to treatment group allocation. The primary and first key secondary endpoint in the hierarchical testing strategy were change from baseline to week 12 in on time without troublesome dyskinesia and off time, respectively; both endpoints were evaluated by an intention-to-treat analysis applying a mixed model for repeated measures analysis. Safety and tolerability were assessed throughout the study. The study is completed and is listed on ClinicalTrials.gov, NCT04380142. Between Oct 19, 2020, and Sept 29, 2021, of 270 participants screened and 174 enrolled, 141 were randomly assigned and received continuous subcutaneous infusion of foslevodopa-foscarbidopa plus oral placebo capsules (n=74) or oral encapsulated immediate-release levodopa-carbidopa plus continuous subcutaneous infusion of placebo solution (n=67). Compared with levodopa-carbidopa, foslevodopa-foscarbidopa showed a significantly greater increase in on time without troublesome dyskinesia (model-based mean [SE] 2·72 [0·52] vs 0·97 [0·50] h; difference 1·75 h, 95% CI 0·46 to 3·05; p=0·0083) and a significantly greater reduction in off time (-2·75 [0·50] vs -0·96 [0·49] h; difference -1·79 h, -3·03 to -0·54; p=0·0054). Hierarchical testing ended after the first secondary endpoint. Adverse events were reported in 63 (85%) of 74 patients in the foslevodopa-foscarbidopa group versus 42 (63%) of 67 in the levodopa-carbidopa group, and incidences of serious adverse events were similar between the groups (six [8%] of 74 vs four [6%] of 67, respectively). The most frequent adverse events in the foslevodopa-foscarbidopa group were infusion site adverse events (erythema 20 [27%]), pain 19 [26%]), cellulitis (14 [19%]), and oedema (nine [12%]), most of which were non-serious and mild-moderate in severity. The only system organ class that had more than one serious adverse event in the foslevodopa-foscarbidopa group was infections and infestations (catheter site cellulitis [one [1%]] and infusion site cellulitis [one [1%]). Adverse events led to premature discontinuation of study drug in 16 (22%) of 74 participants in the foslevodopa-foscarbidopa group versus one (1%) of 67 participants in the oral levodopa-carbidopa group. Foslevodopa-foscarbidopa improved motor fluctuations, with benefits in both on time without troublesome dyskinesia and off time. Foslevodopa-foscarbidopa has a favourable benefit-risk profile and represents a potential non-surgical alternative for patients with advanced Parkinson's disease. AbbVie.

The pharmacokinetics of continuous subcutaneous levodopa/carbidopa infusion: Findings from the ND0612 clinical development program.

While treatment with levodopa remains the cornerstone of Parkinson's disease (PD) management, chronic oral therapy is often associated with the development of motor complications, that correlate to fluctuating levodopa plasma concentrations, limiting its clinical utility. Continuous infusion is considered to be the optimal delivery route for treating PD patients with motor fluctuations, but current infusion systems require invasive surgery. Subcutaneous infusion of (SC) levodopa has the potential to provide a better tolerated and more convenient route of continuous levodopa delivery. ND0612 is in development as a combination product providing continuous levodopa/carbidopa via a minimally invasive, subcutaneous delivery system for PD patients experiencing motor response fluctuations. We present pharmacokinetic results from a series of studies that analyzed plasma concentrations after SC levodopa delivery with ND0612 to inform the clinical development program. We performed a series of six Phase I and II studies to characterize the pharmacokinetics of levodopa and carbidopa derived from ND0612 infusion with/without adjunct oral therapy of the same ingredients. These studies were conducted in healthy volunteers and in PD patients experiencing motor response fluctuations while on their current levodopa therapy regimen. Taken together, the results demonstrate dose-proportionality dependent on rate of subcutaneous levodopa infusion leading to stable and sustained plasma concentrations of levodopa. Subcutaneous infusion of ND0612 administered with oral levodopa/carbidopa maintained near-constant, therapeutic levodopa plasma concentrations, thereby avoiding the troughs in levodopa plasma concentrations that are associated with OFF time in PD. The data generated in this series of studies also confirmed that a levodopa/carbidopa dose ratio of 8:1 would be the most reasonable choice for ND0612 development. This series of clinical pharmacokinetic studies have demonstrated that ND0612, administered continuously with a levodopa concentration of 60 mg/ml combined with carbidopa 7.5 mg/ml, and complemented with oral levodopa/carbidopa, is suitable for 24 h continuous administration in patients with PD. The stable plasma concentrations of levodopa achieved predict utility of ND0612 as a parenteral formulation for achieving clinically useful delivery of levodopa for PD patients.

Abstract 15337: Chronic Oral Finerenone Treatment Does Not Improve Left Ventricular Diastolic Compliance in Swine With Repetitive Pressure Overload-Induced HFpEF

Introduction: The non-steroidal mineralocorticoid receptor antagonist finerenone has emerged as a potential treatment for heart failure with preserved ejection fraction (HFpEF) based, in part, on initial evidence of its anti-fibrotic properties. However, it is unclear whether chronic oral finerenone therapy can reverse established cardiac fibrosis. Accordingly, we tested the efficacy of chronic oral finerenone in a porcine model of HFpEF characterized by interstitial fibrosis and reduced left ventricular (LV) diastolic compliance in the absence of co-morbidities or anatomic LV hypertrophy. Methods: Swine (n=12) were subjected to daily (1 hr) episodes of repetitive LV pressure overload (RPO) for 2 weeks using phenylephrine (24 mg/hr) to transiently elevate LVEDP to ~30 mm Hg. After 2 weeks, RPO was discontinued and animals were followed for an additional 4 weeks, during which a subset received oral finerenone (20 mg/day; n=6). LV end-diastolic volume (EDV) and pressure (EDP) were measured at normal and elevated preload to assess LV compliance (ΔLVEDV/ΔLVEDP) and post-mortem picrosirius red staining was performed to quantify interstitial fibrosis vs. normal controls (n=8). Results: Four-weeks after cessation of RPO, untreated animals exhibited a significant increase in interstitial fibrosis vs. normal controls that was attenuated in finerenone-treated animals ( Figure A ). Despite this regression of interstitial collagen, a persistent reduction in LV diastolic compliance was observed after finerenone treatment (1.18 ± 0.33 mL/mmHg vs. 2.11 ± 0.22 mL/mmHg in normal controls; p=0.04) that was comparable to that of untreated animals after RPO (0.97 ± 0.22 mL/mmHg; p=0.61; Figure B ). Conclusion: Four weeks of chronic oral finerenone treatment does not restore LV diastolic compliance in swine with RPO-induced HFpEF despite regression of interstitial collagen content, suggesting that other factors may contribute to diastolic stiffening in this model.

Современные подходы к лечению хронического бактериального простатита.

Introduction. The main treatment option for chronic bacterial prostatitis (CBP) is antimicrobial therapy. However, in connection with the steady increase in resistance to antimicrobial drugs and the high rate of failure in the treatment of such patients, it seems relevant to study new approaches to the treatment of this disease. Materials and methods. The review is based on articles published over the past 10 years (2011-2021) in scientific peer-reviewed journals included in the PubMed databases (https://www.ncbi.nlm.nih.gov/pubmed/) and the Scientific Electronic Library Elibrary.ru (https://elibrary.ru/). The search was carried out for the following keywords: «prostatitis», «chronic prostatitis», «chronic bactrial prostatitis», «chronic infectious prostatitis». At the first stage, 477 sources were found that were relevant to the topic of the review, of which 70 articles were selected for the final version of the review. Results. Oral antibiotic therapy remains the mainstay of treatment for CBP. There is a tendency towards an increase in resistance to traditionally used antimicrobial agents (fluoroquinolones, trimethoprim-sulfamethoxazole, etc.). In this regard, the possibilities of alternative antibacterial drugs (fosfomycin, etc.) and other methods of treatment are actively used and are being studied: direct administration of antimicrobial drugs into the prostate gland, chronic oral antibiotic prophylaxis, phage therapy and surgical interventions. An important role in the treatment of CBP is assigned to other pharmacological groups of drugs and non-drug methods of treatment (primarily physiotherapeutic methods). Conclusion. Many therapies that are used in addition to or instead of oral antibiotic therapy still cannot be recommended for use in general clinical practice, since there is currently a lack of sufficient evidence of their effectiveness and safety. Therefore, considering the existing problems of treating such patients, the need to continue studies to assess the possibilities of new promising approaches to the treatment of CBP remains relevant.

818-P: Chronic Oral Polymeric Duodenal Exclusion Therapy Has Profound Metabolic Benefits in a T2D Rat Model and Affects Duodenal Morphological Enteroplasticity Similar to RYGB surgery: Implications for T2D Therapy

Background: RYGB surgery has significant weight loss and improvement in glycemia, attributed predominantly to duodenal exclusion. To mimic this effect non-invasively, we developed oral, gut-restricted, inert polymer (GLY-POL) that interacts with mucus in the proximal small intestine to form a dynamic barrier excluding the duodenal lining from luminal contents. We hypothesized that such treatment would result in significant metabolic improvement and affect morphologic enteroplasticity similar to RYGB. Methods: Goto-kakizaki (GK) rats were gavaged with GLY-POL daily for 8-weeks (n=7 per group) . Metabolic responses were evaluated weekly (BW, food intake, oGTT, mMTT, HOMA-IR) . Duodenal morphometric analysis (villus height and crypt depth) was performed in excised duodenum after study completion. Results: There was profound metabolic improvement with chronic GLY-POL therapy; oGTT (iAUC ↓ = 60 - 70%, p<0.0005) , mMTT (iAUC ↓ > 55%, p < 0.005) , HOMA-IR improvement (p<0.005) , 6% weight loss (p<0.005) . There was no difference in food intake between the groups. There was a significant reduction in the duodenal villus height (p<0.0001) and crypt depth (p<0.0001) in treated rats compared to controls. Conclusion: Our results confirm a key role for chronic duodenal exclusion oral GLY-POL therapy in improving the systemic metabolic milieu with profound reduction in FPG, PPG, insulin resistance and weight loss. Duodenal villus morphological changes are likely due to nutritional depletion from the GLY-POL lining. Similar cellular structural changes have been reported in the bypassed portion of the small intestine after RYGB surgery. GLY-POL therapy offers the potential for a novel non-invasive approach for glycemic and weight control in T2D patients that mimics the effects of gastric bypass without the adverse effects associated with this surgery. Disclosure A.Nimgaonkar: Employee; Glyscend Inc. M.Fineman: None. T.H.Jozefiak: Employee; Glyscend Inc., Stock/Shareholder; Glycologix, LLC. F.Guerina: Employee; Glyscend Inc. S.L.Kelleher: Research Support; Glyscend Inc. T.Carlson: Employee; Glyscend Inc. K.Colbert: Stock/Shareholder; Glyscend Inc., LifeSprout. S.Polomoscanik: None. J.S.Petersen: None. K.M.Habegger: Consultant; Glyscend Inc., Research Support; Eli Lilly and Company, Novo Nordisk, Stock/Shareholder; Glyscend Inc. P.J.Pasricha: Consultant; Vanda, Other Relationship; Teva Pharmaceutical Industries Ltd., Stock/Shareholder; Glyscend Inc., Neurogastrx, P4M.

Computer-Assisted Analysis of Oral Antifungal Therapy in Chronic Rhinosinusitis with Airway Mycosis: a Retrospective Cohort Analysis.

Environmental fungi are etiologically related to chronic rhinosinusitis (CRS) with airway mycosis, but their infectious role remains uncertain, in part because of potentially inadequate methods of disease quantitation. Our objective was to determine objective radiographic and symptomatic outcomes of oral antifungal therapy in adult patients with CRS and airway mycosis by using computer-assisted analysis. We conducted a retrospective study of 65 patients with CRS and culture-proven airway mycosis in a single-center referral-based academic practice, comparing paired sinus computed tomography (CT) scans and symptom scores prior to and during chronic oral antifungal therapy using computer-assisted analysis of sino-mucosal area (CAASMA). A comparator group received standard therapy without antifungals. Administration of antifungals was associated with significantly reduced sinus mucosal thickening as assessed by CAASMA (-6.85% absolute reduction; 95% confidence interval [CI], -11.8283 to -1.8717; P < 0.005), but not by Lund-Mackay score. In contrast, standard care alone was linked by CAASMA to enhanced mucosal thickening (4.14% absolute increase; 95% CI, -1.8066 to 10.0866; P < 0.005). Thirty of the 41 antifungal-treated patients (73%) showed decreased sinus mucosal burdens, while only 21 patients (43%) receiving standard therapy showed improved imaging (odds ratio [OR], 11.65; 95% CI, 3.2 to 42.2; P < 0.05). Nineteen patients (50%) noted improved symptoms at the time of a follow-up CT scan, while only 8 patients (20%) on standard therapy improved (OR, 6.21; 95% CI, 1.7 to 22.7; P < 0.05). These retrospective findings indicate that oral antifungals can reduce mucosal thickening and improve symptoms in CRS with airway mycosis. Randomized clinical trials are warranted to verify these findings.

Inotropes in Chronic Beta-Blocker Therapy

The increasing rate of cardiovascular disorders contributes to rising hospitalized patients receive chronic oral beta-blocker therapy. Beta-blockers remain one of the fundamental therapy for chronic heart failure. Still, their role in decompensated heart failure and severe sepsis during hospitalization is often debated and inconsistent in clinical practice. In recent years, evidence of the efficacy and clinical outcomes of beta-blockers in acute heart failure (AHF) have accumulated. Clinical research indicates that chronic beta-blockade withdrawals should be prevented, or as soon as hemodynamic stabilization and euvolemic condition are reached, it should be reinstituted. As a subset of AHF patients with low cardiac output required inotropes, the choice of proper agent is fundamental. Different inotropic agents such as inhibitors of the phosphodiesterase, levosimendan, and dobutamine also their associations with beta-blockers are discussed.

Novel Machine Learning Can Predict Acute Asthma Exacerbation

Asthma exacerbations result in significant health and economic burden, but are difficult to predict. Can machine learning (ML) models with large-scale outpatient data predict asthma exacerbations? We analyzed data extracted from electronic health records (EHRs) of asthma patients treated at the Cleveland Clinic from 2010 through 2018. Demographic information, comorbidities, laboratory values, and asthma medications were included as covariates. Three different models were built with logistic regression, random forests, and a gradient boosting decision tree to predict: (1) nonsevere asthma exacerbation requiring oral glucocorticoid burst, (2) ED visits, and (3) hospitalizations. Of 60,302 patients, 19,772 (32.8%) had at least one nonsevere exacerbation requiring oral glucocorticoid burst, 1,748 (2.9%) requiring and ED visit and 902 (1.5%) requiring hospitalization. Nonsevere exacerbation, ED visit, and hospitalization were predicted best by light gradient boosting machine, an algorithm used in ML to fit predictive analytic models, and had an area under the receiver operating characteristic curve of 0.71 (95%CI, 0.70-0.72), 0.88 (95%CI, 0.86-0.89), and 0.85 (95%CI, 0.82-0.88), respectively. Risk factors for all three outcomes included age, long-acting β agonist, high-dose inhaled glucocorticoid, or chronic oral glucocorticoid therapy. In subgroup analysis of 9,448 patients with spirometry data, low FEV1 and FEV1 to FVC ratio were identified as top risk factors for asthma exacerbation, ED visits, and hospitalization. However, adding pulmonary function tests did not improve models' prediction performance. Models built with an ML algorithm from real-world outpatient EHR data accurately predicted asthma exacerbation and can be incorporated into clinical decision tools to enhance outpatient care and to prevent adverse outcomes.

Non-steroidal anti-inflammatory drugs (NSAIDs) – exacerbated respiratory disease: epidemiology, pathogenesis, clinical findings and management

Non-steroidal anti-inflammatory drugs (NSAIDs) exacerbated respiratory disease (N-ERD) are characterized by non-allergic hypersensitivity (intolerance) to NSAIDs and aspirin in patients with asthma and/or eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP). Asthma in N-ERD patients is usually characterized by eosinophilic inflammation, tends to become severe and intractable, and needs chronic oral corticosteroid therapy. For some patients recurrent CSwNP is more significant problem due to nasal congestion, anosmia, and multiple repeated surgeries. Intolerance to aspirin and other NSAIDs limits the choice of pain relievers and antipyretics. Accidental use of these medications can lead to dangerous consequences, including anaphylaxis. This review presents the current understanding of the N-ERD pathogenesis and perspective trends in therapy.

MON-157 The Effect of Exogenous Cushing’s Syndrome on All-Cause and Cause-Specific Mortality: A Systematic Review

Chronic oral glucocorticoid (GC) exposure from therapeutic anti-inflammatory or immunosuppressive use is the most common cause of Cushing’s syndrome (CS). Previous studies of glucocorticoid therapy and mortality have produced inconsistent results and systematic reviews have only focused on endogenous CS. This is the first study that aimed to investigate all-cause and cause-specific mortality in association with exogenous CS from chronic oral GC therapy. The protocol was designed according to the principles of the PRISMA statement and registered in PROSPERO reference CRD42017067530. A literature review was performed in PubMed/MEDLINE (1966 to 31 Mar 2019), EMBASE (1974 to 31 Mar 2019), web of science (1900 to 31 Mar 2019), CINAHL (1981 to 31 Mar 2019) and reference lists within selected articles. Of 104,064 studies, 127 met the inclusion criteria, encompassing 51,380 patients. The Risk Of Bias In Non-randomized Studies of Interventions (ROBIN-I) tool was chosen and modified for evaluation of quality. The weighted percentage mortality by 5 groups of diseases including vasculitis, connective tissue diseases, inflammatory diseases, haematologic diseases and respiratory tract diseases, was 18.1, 12.7, 16.1, 28.2 and 5.7, respectively. The leading causes of death were cardiovascular disease (25.6%), malignancy (15.6 %), infection (13.4) and respiratory failure (10.8%). Although these studies showed high mortality in patients exposed to GC, estimates were not adjusted for known confounders and available data do not allow disentangling the relative contribution of CS vs. the underlying disease or non-GC immunosuppressive therapies. More extensive, high quality, prospective studies are needed to evaluate these associations and to identify modifiable risk factors.

Utilization of COMT inhibitors, dopamine agonists, and MAO-B inhibitors with levodopa-carbidopa instestinal gel in advanced Parkinson's disease patients: Summary of phase 3 and real-world studies

Levodopa remains the most effective treatment for Parkinson's disease (PD); however, as disease evolves, uncontrolled motor and non-motor symptoms with chronic oral therapy may necessitate the use of advanced therapies. Continuous levodopa delivery with levodopa-carbidopa intestinal gel (LCIG) improves motor fluctuations and may reduce the need for concomitant dopamine replacement therapies (DRT). This analysis summarizes add-on medication use in advanced PD patients before and after LCIG treatment from a phase 3 study and real-world observations. Add-on PD medication use including catechol-O-methyl transferase (COMT) inhibitors, dopamine agonists (DAs), and monoamine oxidase (MAO)-B inhibitors was determined at baseline (recent use before LCIG) and after approximately 1 year of LCIG treatment from a phase 3 study (NCT00335153), UK-based retrospective chart review (IRAS ID: 135453), and GLORIA observational registry. The phase 3 trial required LCIG monotherapy (no concomitant PD medications) from LCIG initiation to treatment week 4, after which adjunctive medication use was permitted. In the phase 3 study, patients using COMT inhibitors decreased from 28% to 1%, representing a 96% reduction. Under real-world conditions, patients using COMT inhibitors decreased from 23% to 2% in the retrospective chart review and from 57% to 9% in the GLORIA registry, representing 91% and 84% reductions, respectively. Decreased DA and MAO-B inhibitor use after LCIG therapy were observed in all three studies (Fig. 1). This summary of 840 advanced PD patients treated in a controlled clinical trial setting or during routine clinical care highlights reductions in add-on DRT use following 12 months of LCIG treatment.

A randomized, double-blind, placebo-controlled trial of lamotrigine for prescription corticosteroid effects on the human hippocampus

In animals, stress and corticosteroid excess are associated with decreases in memory performance and hippocampal volume that may be prevented with agents that decrease glutamate release. Humans also demonstrate changes in memory and hippocampus with corticosteroids. In this report the effects of glutamate-release inhibitor lamotrigine on hippocampal structure and memory were examined in people receiving medically needed prescription corticosteroid therapy. A total of 54 outpatient adults (n = 28 women) receiving chronic (≥ 6 months) oral corticosteroid therapy were randomized to lamotrigine or placebo for 48 weeks. Declarative memory was assessed using the Rey Auditory Verbal Learning Test (RAVLT); structural magnetic resonance imaging (MRI) as well as single-voxel proton MR spectroscopy (1HMRS) focused on hippocampus were obtained at baseline and week 48. Utilizing a mixed-model approach, structural and biochemical data were examined by separate ANOVAs, and memory was assessed with a multi-level longitudinal model. RAVLT total scores demonstrated significantly better declarative memory performance with lamotrigine than placebo (p = 0.047). Hippocampal subfield volumes were not significantly different between the treatment groups. In summary, lamotrigine was associated with less decline in declarative memory performance than placebo in corticosteroid-treated patients. Findings suggest that, in humans as well as in animal models, glutamate release inhibitors may attenuate some of the effects on the human memory associated with corticosteroids.

Impact of Nitrite Therapy on Change in Steady State Submaximal Exercise in Older

PURPOSE: The population of older adults is growing, with increasing prevalence of detrimental geriatric risks, particularly sedentariness and downstream risks of cardiovascular disease, disability, and frailty. Nitrate therapy may enable physiological efficiency such that oxygen demands for submaximal workloads are reduced, and daily activity more easily tolerated. We explored the impact of chronic oral nitrite therapy in a cohort of older healthy adults. Nitrites (40 mg) were administered as capsules 3 times daily over one month. Changes in oxygen uptake (VO2) during steady state walking in association with rate of perceived exertion (RPE [10-20 scale]) were analyzed. METHODS: 9 adults (5 male, 4 female) aged ≥70 (mean 77.7±6.3 years, range 70-88) were studied. Functional capacity was assessed at baseline and 4 weeks based on steady state VO2 and RPE during a 5 minute treadmill walk (1.5 mph). RESULTS: Steady state VO2 decreased significantly in the older adults using nitrite therapy (Table 1). RPE also trended downward.Table: No title available.CONCLUSION: This promising pilot work in older adults showed that chronic nitrite was well-tolerated and was associated with increased walking efficiency. Further study is needed to better understand the impact on physical activity and health in this large and growing patient demographic.

N-Acetyl-l-Cysteine treatment efficiently prevented pre-diabetes and inflamed-dysmetabolic liver development in hypothalamic obese rats

AimHypothalamic obese rats are characterized by pre-diabetes, dyslipidemia, hyperadiposity, inflammation and, liver dysmetabolism with oxidative stress (OS), among others. We studied endocrine-metabolic dysfunctions and, liver OS and inflammation in both monosodium l-glutamate (MSG)-neonatally damaged and control litter-mate (C) adult male rats, either chronically treated with N-Acetyl-l-Cysteine since weaned (C-NAC and MSG-NAC) or not. MethodologyWe evaluated circulating TBARS, glucose, insulin, triglycerides, uric acid (UA) and, aspartate and alanine amino-transferase; insulin sensitivity markers (HOMA indexes, Liver Index of Insulin Sensitivity –LISI-) were calculated and liver steps of the insulin-signaling pathway were investigated. Additionally, we monitored liver OS (protein carbonyl groups, GSH and iNOS level) and inflammation-related markers (COX-2 and TNFα protein content; gene expression level of Il1b, Tnfα and Pai-1); and carbohydrate and lipid metabolic functions (glucokinase/fructokinase activities and, mRNA levels of Srebp1c, Fas and Gpat). Key FindingsChronic NAC treatment in MSG rats efficiently decreased the high circulating levels of triglycerides, UA, transaminases and TBARS, as well as peripheral (high insulinemia and HOMA indexes) and liver (LISI and the P-AKT:AKT and P-eNOS:eNOS protein ratio values) insulin-resistance. Moreover, NAC therapy in MSG rats prevented liver dysmetabolism by decreasing local levels of OS and inflammation markers. Finally, NAC-treated MSG rats retained normal liver glucokinase and fructokinase activities, and Srebp1c, Fas and Gpat (lipogenic genes) expression levels. SignificanceOur study strongly supports that chronic oral antioxidant therapy (NAC administration) prevented the development of pre-diabetes, dyslipidemia, and inflamed-dysmetabolic liver in hypothalamic obese rats by efficiently decreasing high endogenous OS.

P241 Anti-IL5 monoclonal antibodies may provide benefit in asthmatics on chronic oral steroid therapy masking eosinophilia

P241 Anti-IL5 monoclonal antibodies may provide benefit in asthmatics on chronic oral steroid therapy masking eosinophilia

Effectiveness of Oral Bisphosphonates in Reducing Fracture Risk Among Oral Glucocorticoid Users: Three Matched Cohort Analyses.

The benefit of oral bisphosphonates in reducing fracture risk in glucocorticoid-induced osteoporosis is controversial. We aimed to estimate the effectiveness of oral bisphosphonates in reducing fracture risk in a cohort of new chronic oral glucocorticoid users. We created three matched cohorts using health care administrative data from Ontario, Canada. We included residents aged 66 years and older initiating chronic oral glucocorticoids (≥450 mg prednisone equivalent and ≥2 glucocorticoid prescriptions within a 6-month window) between January 1998 and September 2014. Exposed patients were those who initiated an oral bisphosphonate (alendronate, etidronate, or risedronate) within the first 6 months of starting chronic oral glucocorticoid therapy. Exposed cohorts (3945 alendronate, 5825 risedronate, and 8464 etidronate) were each matched 1:1 to unexposed patients on glucocorticoid exposure, fracture risk factors, and propensity score. We examined incident hip (primary outcome), vertebral, forearm, and humerus fractures using Cox proportional hazard models. Alendronate (hazard ratio [HR] = 0.46, 95% confidence interval [CI] 0.25-0.80) and risedronate (HR = 0.58, 95% CI 0.36-0.90) were associated with reduced hip fracture risk. Alendronate (HR = 0.52, 95% CI 0.39-0.68), etidronate (HR = 0.59, 95% CI 0.48-0.73) and risedronate (HR = 0.47 95% CI 0.36-0.60) were associated with reduced vertebral fracture risk. No risk reduction in forearm or humerus fractures was apparent for any bisphosphonate. Among older chronic glucocorticoid initiators, all oral bisphosphonates reduced vertebral fracture risk, yet only alendronate and risedronate reduced hip fracture risk. Results were similar between men and women. We provided compelling evidence that early initiation of oral bisphosphonates during chronic oral glucocorticoid therapy is beneficial to prevent osteoporotic fractures. © 2017 American Society for Bone and Mineral Research.