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Background: Systemic atopic dermatitis treatments that have acceptable safety are needed. Objective: To evaluate the safety of the oral Janus kinase inhibitor upadacitinib in combination with topical corticosteroids (TCSs) for the treatment of atopic dermatitis. Methods: In this phase 3, double-blind study (Rising Up), Japanese patients (12-75 years) with moderate-to-severe atopic dermatitis were randomized in a 1:1:1 ratio to receive 15 mg of upadacitinib + TCS, 30 mg of upadacitinib + TCS, or a placebo + TCS (rerandomized in a 1:1 ratio to receive either 15 or 30 mg of upadacitinib + TCS at week 16). Adverse events and laboratory data were assessed for safety. Results: In 272 treated patients, the serious adverse event rates were similar for 15- and 30-mg upadacitinib + TCS at week 24 (15 mg, 56%; 30 mg, 64%) but greater than those for placebo + TCS (42%). Acne (all mild or moderate; none leading to discontinuation) occurred more frequently with upadacitinib + TCS (15 mg, 13.2%; 30 mg, 19.8%) than with placebo + TCS (5.6%). Furthermore, herpes zoster infection (4.4% vs 0%), anemia (1.1% vs 0%), neutropenia (4.4% vs 1.1%), and creatine phosphokinase elevations (2.2% vs 1.1%) occurred more frequently with 30-mg upadacitinib + TCS than with 15-mg upadacitinib + TCS; none of these events were reported with placebo + TCS. No thromboembolic events, malignancies, gastrointestinal perforations, active tuberculosis, or deaths occurred. Limitations: The limitations included a small sample size and short observation period as well as nongeneralizability of the results beyond Japanese populations. Conclusions: The results were generally consistent with those of previous reports; no new safety risks were detected.

PURPOSE: Neutralizing antibodies can reduce SARS-CoV-2 cellular entry, viral titers, and pathologic damage. CT-P59 (regdanvimab), a SARS-CoV-2 neutralizing monoclonal antibody, was examined in 2 randomized, double-blind, placebo-controlled, single ascending dose, Phase I studies. METHODS: In study 1.1, healthy adults were sequentially enrolled to receive CT-P59 10, 20, 40, or 80 mg/kg or placebo. In study 1.2, adult patients with mild SARS-CoV-2 infection were enrolled to receive CT-P59 20, 40, or 80 mg/kg or placebo. Primary objectives of both studies were safety and tolerability up to day 14 after infusion. Secondary end points included pharmacokinetic properties. Study 1.2 also measured virology and clinical efficacy. FINDINGS: Thirty-two individuals were randomized to study 1.1 (6 per CT-P59 dose cohort and 8 in the placebo cohort). By day 14 after infusion, adverse events (AEs) were reported in 2 individuals receiving CT-P59 20 mg/kg (headache and elevated C-reactive protein levels) and 1 receiving CT-P59 40 mg/kg (pyrexia) (all Common Terminology Criteria for Adverse Events grade 1). In study 1.2, 18 patients were randomized (5 per dose cohort and 3 in the placebo cohort). Sixteen AEs were reported in 10 patients receiving CT-P59. No AEs in either study led to study discontinuation. Greater reductions in viral titers were reported with CT-P59 than placebo in those with maximum titers >105 copies/mL. Mean time to recovery was 3.39 versus 5.25 days. IMPLICATIONS: CT-P59 exhibited a promising safety profile in healthy individuals and patients with mild SARS-CoV-2 infection, with potential antiviral and clinical efficacy in patients with mild SARS-CoV-2 infection. ClinicalTrials.gov identifier: NCT04525079 (study 1.1) and NCT04593641 (study 1.2).

Made available in DSpace on 2022-04-29T08:39:25Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-03-01 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Background: It is not clear whether previous thyroid diseases influence the course and outcomes of COVID-19. Methods: The study is a part of a multicentric cohort of patients with confirmed COVID-19 diagnosis from 37 hospitals. Matching for age, sex, number of comorbidities, and hospital was performed for the paired analysis. Results: Of 7,762 patients with COVID-19, 526 had previously diagnosed hypothyroidism and 526 were matched controls. The median age was 70 years, and 68.3% were females. The prevalence of comorbidities was similar, except for coronary and chronic kidney diseases that were higher in the hypothyroidism group (p=0.015 and p=0.001). D-dimer levels were lower in patients with hypothyroid (p=0.037). In-hospital management was similar, but hospital length-of-stay (p=0.029) and mechanical ventilation requirement (p=0.006) were lower for patients with hypothyroidism. There was a trend of lower in-hospital mortality in patients with hypothyroidism (22.1% vs 27.0%; p=0.062). Conclusion: Patients with hypothyroidism had a lower requirement of mechanical ventilation and showed a trend of lower in-hospital mortality. Therefore, hypothyroidism does not seem to be associated with a worse prognosis. Undergrad uate Medical Student. Universidade Federal de Minas Gerais. Avenida Professor Alfredo Balena 190 Endocrinology Unit Department of Internal Medicine Faculdade de Medicina da Universidade Federal de Minas Gerais. Avenida Professor Alfredo Balena 190 Professor and Physician. Internal Medicine Department Universidade Federal do Rio Grande do Sul. Coordinator of the Institute for Health Technology Assessment (IATS/CNPq). Rua Ramiro Barcelos, 2359. Prédio 21 | Sala 507 Physician. Hospital Unimed-BH, Av do Contorno, 3097 Hospitais da Rede Mater Dei Internal Medicine Resident. Hospital Risoleta Tolentino Neves. Rua das Gabirobas 01 Physician. Hospital Santa Rosália Hospital João XXIII. Av. Professor Alfredo Balena 400 Physician. Hospital das Clínicas da Faculdade de Medicina de Botucatu Hospital de Clínicas de Porto Alegre, Av. Ramiro Barcellos, 2350 Hospital Mãe de Deus Hospital Santo Antônio Pharmaceutical. Hospital de Clínicas de Porto Alegre, Av. Ramiro Barcellos, 2350 Coordinator of the Research Sector of Grupo Hospitalar Conceição. Professor of the Graduation Program on Evaluation and Production of Technologies for the Brazilian National Health System Hospital Nossa Senhora da Conceição and Hospital Cristo Redentor, Av. Francisco Trein, 326 Hospital SOS Cárdio Professor and Infectious Diseases Physician. Internal Medicine Department University Hospital Universidade Federal de Minas Gerais, Av. Prof Alfredo Balena, 110 Nephrologist. Hospital Universitário Ciências Médicas Hospital Márcio Cunha Hospital Regional do Oeste, Santa Catarina PhD Departamento de Pneumologia Faculdade de Medicina Universidade Católica do Rio Grande do Sul (RGS) Porto Alegre Brasil. Hospital São Lucas PUCRS PhD. Hospital Mãe de Deus Hospital Universitário de Canoas Universidade Federal do Rio Grande do Sul e Instituto de Avaliação de Tecnologia em Saúde (IATS/CNPQ) Undergraduate Medical Student. Universidade Federal dos Vales do Jequitinhonha e Mucuri. R. Cruzeiro 1 Hospital Luxemburgo Hospital Nossa Senhora da Conceição, Av. Francisco Trein, 326 Hospital Bruno Born, Av. Benjamin Constant, 881 Hospital Moinhos de Vento, Rio Grande do Sul Hospital Metropolitano Odilon Behrens Hospital Santa Cruz Hospital Julia Kubitschek. Avenida Professor Alfredo Balena 190 Hospital São Lucas PUCRS Physician. Hospital Eduardo de Menezes. R. Dr. Cristiano Rezende 2213 Physician. Hospital Metropolitano Doutor Célio de Castro. Rua Dona Luiza 311 Hospital São João de Deus Hospital Semper. Alameda Ezequiel Dias 389 Hospital Universitário Canoas, Rio Grande do Sul Hospital Universitário de Santa Maria, Rio Grande do Sul Hospital Tacchini Associate Professor and Statistician Department of Statistics Universidade Federal de Minas Gerais. Av. Presidente Antônio Carlos, 6627, ICEx, sala 4071 Associate Professor and Internal Medicine Physician. Department of Internal Medicine Medical School; and Telehealth Center University Hospital Universidade Federal de Minas Gerais, Avenida Professor Alfredo Balena 190 sala 246 Researcher. Institute for Health Technology Assessment (IATS/ CNPq). Rua Ramiro Barcelos, 2359. Prédio 21 | Sala 507 Physician. Hospital das Clínicas da Faculdade de Medicina de Botucatu

Statin-induced necrotizing autoimmune myopathy (SINAM) is an exceptionally rare yet devastating complication of statin therapy that can occur at any time after initiation. It should be considered in patients who develop proximal muscle weakness and marked elevated creatine phosphokinase while taking statin therapy. (Level of Difficulty: Beginner.), Graphical abstract, Statin-induced necrotizing autoimmune myopathy (SINAM) is an exceptionally rare yet devastating complication of statin therapy that can occur at any…

Introduction Amyotrophic lateral sclerosis (ALS) is an intractable and incurable neurological disease. It is a progressive disease characterized by muscle atrophy and weakness caused by selective vulnerability of upper and lower motor neurons. In disease research, it has been common to use mouse models carrying mutations in responsible genes for familial ALS as pathological models of ALS. However, there is no model that has reproduced the actual conditions of human spinal cord pathology. Thus, we developed a method of producing human spinal motor neurons using human induced pluripotent stem cells (iPSCs) and an innovative experimental technique for drug screening. As a result, ropinirole hydrochloride was eventually discovered after considering such results as its preferable transitivity in the brain and tolerability, including possible adverse reactions. Therefore, we explore the safety, tolerability and efficacy of ropinirole hydrochloride as an ALS treatment in this clinical trial. Methods The ROPALS trial is a single-center double-blind randomized parallel group-controlled trial of the safety, tolerability, and efficacy of the ropinirole hydrochloride extended-release tablet (Requip CR) at 2- to 16-mg doses in patients with ALS. Twenty patients will be recruited for the active drug group (fifteen patients) and placebo group (five patients). All patients will be able to receive the standard ALS treatment of riluzole if not changed the dosage during this trial. The primary outcome will be safety and tolerability at 24 weeks, defined from the date of randomization. Secondary outcome will be the efficacy, including any change in the ALS Functional Rating Scale-Revised (ALSFRS-R), change in the Combined Assessment of Function and Survival (CAFS), and the composite endpoint as a sum of Z-transformed scores on various clinical items. Notably, we will perform an explorative search for a drug effect evaluation using the patient-derived iPSCs to prove this trial concept. Eligible patients will have El Escorial Possible, clinically possible and laboratory-supported, clinically probable, or clinically definite amyotrophic lateral sclerosis with disease duration less than 60 months (inclusive), an ALSFRS-R score ≥2 points on all items and age from 20 to 80 years. Conclusion Patient recruitment began in December 2018 and the last patient is expected to complete the trial protocol in November 2020. Trial registration Current controlled trials UMIN000034954 and JMA-IIA00397 Protocol version version 1.6 (Date; 5/Apr/2019)., Highlights • ALS is a progressive neurodegenerative disease caused by selective vulnerability of upper and lower motor neurons. • ALS patients have no radical treatment. • The ROPALS trial reveals the safety, tolerability, and efficacy of the ropinirole hydrochloride in patients with ALS. • This trial is the pioneering clinical trial for ALS based on iPSCs-drug discovery in Japan.

A 60-year-old man with a history of 4 cycles of atezolizumab treatment for non-small cell lung cancer presented to our hospital with a chief complaint of proximal muscle-dominant spasms. Blood tests showed elevated creatine phosphokinase (CPK) of 8450 U/L and hypothyroidism. There was little improvement even after stopping levetiracetam and pregabalin, and no subspinous physical findings of myositis. After levothyroxine was started for hypothyroidism, his muscle cramps and serum CPK level improved. Hypothyroidism as an immune-related adverse event can cause muscle spasms and is important in the differential diagnosis of muscle spasms in patients treated with immune checkpoint inhibitors.

Ipilimumab plus nivolumab (Ipi/Nivo) has revolutionized advanced renal cell carcinoma (RCC) treatment. However, it encompassed fatal immune-related adverse events (irAEs). Myocarditis with concomitant myasthenia gravis (MG) has a mortality rate of 50%, and a high dose of methylprednisolone (mPSL) should be administered with careful attention to MG exacerbation. We present the case of a 59-year-old man with progressing lung metastasis of RCC. After one cycle of Ipi/Nivo, he experienced myocarditis and MG, managed by mPSL pulse therapy, plasma exchange, and high-dose intravenous immunoglobulin. We share the therapeutic course, aiming to contribute to the limited literature on rare but aggressive irAEs., Highlights • Ipilimumab plus nivolumab is associated with fatal immune-related adverse events. • Myocarditis concomitant with myasthenia gravis (MG) is rare, but has a high mortality rate. • In the comorbid condition, prompt intervention for myocarditis is essential for survival. • Although high-dose methylprednisolone may worsen MG, myocarditis should be prioritized.

Graphical abstract Thinned Irwin mango fruits were collected at the immature stage and lyophilized. Hot-water extract from thinned immature mango (TIMEx) had no toxic effect on SD rats given daily oral doses of 500, 1000 or 2500 mg/kg for 90 days. No significant alterations in hematological and serum chemical parameters, urinalysis, food consumption, body weight gain, or absolute and relative organ weights were noted in any group. In both sexes, a daily dose up to 2500 mg/kg body weight indicates a NOAEL., Highlights • Thinned immature mango fruits are usually handled as waste. • Information is limited about the safety of its daily consumption. • A 90-days toxicity study of its hot-water extract (TIMEx) was conducted in rats. • TIMEx is safe for daily consumption and its NOAEL is 2500 mg/kg/day. • Thinned immature mango fruits will be candidate for functional food., Thinned immature fruit of the mango tree (Mangifera indica ‘Irwin’) are handled as waste. In this study, we conducted a 90-days toxicity study in male and female Sprague Dawley rats to evaluate the safety of a hot-water extract of thinned immature mango fruits (TIMEx) administered by oral gavage at doses of 500, 1000 and 2500 mg/kg body weight/day. Treatment did not result in death or changes in the behavior or external appearance of the animals. No alterations were observed in hematological or serum chemical parameters, urinalysis, food consumption, body weight gain or organ weights at the end of the treatment period, with the exception of higher mean corpuscular volume in male rats that received high doses and lower serum creatine phosphokinase levels in female rats that received medium doses. Under the conditions of this study and based on the toxicological endpoints evaluated, the no-observed-adverse-effect level (NOAEL) for TIMEx was 2500 mg/kg/day. The findings indicate that TIMEx is safe for consumption and should be investigated as a candidate food.

Introduction A deficiency of glycogen debrancher enzyme in patients with glycogen storage disease type III (GSD III) manifests with hepatic, cardiac, and muscle involvement in the most common subtype (type a), or with only hepatic involvement in patients with GSD IIIb. Objective and methods To describe longitudinal biochemical, radiological, muscle strength and ambulation, liver histopathological findings, and clinical outcomes in adults (≥18 years) with glycogen storage disease type III, by a retrospective review of medical records. Results Twenty-one adults with GSD IIIa (14 F & 7 M) and four with GSD IIIb (1 F & 3 M) were included in this natural history study. At the most recent visit, the median (range) age and follow-up time were 36 (19–68) and 16 years (0–41), respectively. For the entire cohort: 40% had documented hypoglycemic episodes in adulthood; hepatomegaly and cirrhosis were the most common radiological findings; and 28% developed decompensated liver disease and portal hypertension, the latter being more prevalent in older patients. In the GSD IIIa group, muscle weakness was a major feature, noted in 89% of the GSD IIIa cohort, a third of whom depended on a wheelchair or an assistive walking device. Older individuals tended to show more severe muscle weakness and mobility limitations, compared with younger adults. Asymptomatic left ventricular hypertrophy (LVH) was the most common cardiac manifestation, present in 43%. Symptomatic cardiomyopathy and reduced ejection fraction was evident in 10%. Finally, a urinary biomarker of glycogen storage (Glc4) was significantly associated with AST, ALT and CK. Conclusion GSD III is a multisystem disorder in which a multidisciplinary approach with regular clinical, biochemical, radiological and functional (physical therapy assessment) follow-up is required. Despite dietary modification, hepatic and myopathic disease progression is evident in adults, with muscle weakness as the major cause of morbidity. Consequently, definitive therapies that address the underlying cause of the disease to correct both liver and muscle are needed.

We present a 78-year-old male with renal cell carcinoma who developed myasthenia gravis complicated by myositis after nivolumab administration, which was verified by the presence of antibodies against the acetylcholine receptor. The initial symptom was posterior neck pain, and biochemical examination of blood showed elevated levels of hepatic enzymes and creatine phosphokinase. The level of antibody against the acetylcholine receptor increased 4.1-fold. His condition progressed rapidly resulting in respiratory failure 15 days after conservative therapy., 論文

Hydroxytyrosol (HT) is a main phenolic component of olive oil. In this study, we investigated the safety and effects produced by HT purified (99.5%) from olive mill waste. HT was administered at a daily dosage of 45 mg for 8 weeks to volunteers with mild hyperlipidemia (n=14). We measured markers of cardiovascular disease risk, enzyme markers of several clinical conditions, hematology, antioxidant parameters, vitamins and minerals at baseline (T0), 4 weeks (T4) and 8 weeks (T8). The values obtained at T4 and T8 were compared with baseline. We found that the HT dose administered was safe and mostly did not influence markers of cardiovascular disease, blood lipids, inflammatory markers, liver or kidney functions and the electrolyte balance. Serum iron levels remained constant but a significant (P, The authors wish to thank Puleva Biotech SA and the Spanish Ministry of Economy and Competitiveness (formerly Ministry of Science and Innovation) [the ERDF-cofinanced grant AGL2011-24428], for funding. The authors wish to thank Maria González-Santiago, Carlos Rodríguez and Antonio D. Valero for their valuable technical assistance, Dr Luis Perez for the purification of the HT used in the study, Alberto Zafra for his help with the HPLC and GC-MS analytical procedures, Dr Arjan Geerlings for fruitful discussions and Ruth Wilson for revising the manuscript.

The primary goal was to investigate the effects of l-carnitine on fuel efficiency, as an antioxidant, and for muscle recovery in Labrador retrievers. Dogs were split into two groups, with one group being supplemented with 250 mg/d of Carniking™ l-carnitine powder. Two experiments (Expt 1 and Expt 2) were performed over a 2-year period which included running programmes, activity monitoring, body composition scans and evaluation of recovery using biomarkers. Each experiment differed slightly in dog number and design: fifty-six v. forty dogs; one endurance and two sprint runs per week v. two endurance runs; and differing blood collection time points. All dogs were fed a low-carnitine diet in which a fixed amount was offered based on maintaining the minimum starting weight. Results from Expt 1 found that the carnitine dogs produced approximately 4000 more activity points per km compared with the control group during sprint (P = 0·052) and endurance runs (P = 0·0001). Male carnitine dogs produced half the creatine phosphokinase (CPK) following exercise compared with male control dogs (P = 0·05). Carnitine dogs had lower myoglobin at 6·69 ng/ml following intensive exercise compared with controls at 24·02 ng/ml (P = 0·0295). Total antioxidant capacity (TAC) and thiobarbituric acid reactive substance (TBARS) results were not considered significant. In Expt 2, body composition scans indicated that the carnitine group gained more total tissue mass while controls lost tissue mass (P = 0·0006) and also gained lean mass while the control group lost lean mass (P v. control at 28·37 mU/ml 24 h after post-run (P = 0·003). Myoglobin levels were lower in carnitine v. control dogs both 1 h post-run (P = 0·0157; 23·83 v. 37·91 ng/ml) and 24 h post-run (P = 0·0189; 6·25 v.13·5 ng/ml). TAC indicated more antioxidant activity in carnitine dogs at 0·16 mmv. control at 0·13 mm (P = 0·0496). TBARS were also significantly lower in carnitine dogs both pre-run (P = 0·0013; 15·36 v. 23·42 µm) and 1 h post-run (P = 0·056; 16·45 v. 20·65 µm). Supplementing l-carnitine in the form of Carniking™ had positive benefits in Labrador retrievers for activity intensity, body composition, muscle recovery and oxidative capacity.