Functions of retinoic acid receptors (RARs) in adult CNS have been poorly characterized. Here we investigated potential neuroprotective action of tamibarotene (Am80), an RARα/β agonist available for the treatment of acute promyelocytic leukemia, on midbrain dopaminergic neurons. Am80 protected dopaminergic neurons in rat midbrain slice culture from injury mediated by lipopolysaccharide‐activated microglia, without affecting production of nitric oxide, a key mediator of cell injury. The effect of Am80 was mimicked by another RAR agonist, TAC‐101, but not by a retinoid X receptor agonist, HX630, and HX630 did not synergize with Am80. We observed neuronal expression of RARα and RARβ in midbrain slice culture and also found that Am80 increased tissue level of brain‐derived neurotrophic factor (BDNF) mRNA. Exogenous BDNF prevented dopaminergic neurodegeneration, and the neuroprotective effect of Am80 was suppressed by a TrkB inhibitor, K252a, or by anti‐BDNF neutralizing antibody. These results reveal a novel action of RARs mediated by enhancement of BDNF expression. Finally, oral administration of Am80 prevented dopaminergic cell loss in the substantia nigra induced by local injection of lipopolysaccharide in mice, indicating that RARs are a promising target of therapeutics for neurodegenerative disorders.

Objectives The aim of this trial is to evaluate the antiviral efficacy, clinical efficacy, and safety of nelfinavir in patients with asymptomatic and mild COVID-19. Trial design The study is designed as a multicenter, open-label, blinded outcome assessment, parallel group, investigator-initiated, exploratory, randomized (1:1 ratio) controlled clinical trial. Participants Asymptomatic and mild COVID-19 patients will be enrolled in 10 university and teaching hospitals in Japan. The inclusion and exclusion criteria are as follows: Inclusion criteria: Japanese male or female patients aged ≥ 20 years SARS-CoV-2 detected from a respiratory tract specimen (e.g., nasopharyngeal swab or saliva) using PCR, LAMP, or an antigen test within 3 days before obtaining the informed consent Provide informed consent Exclusion criteria: Symptoms developed ≥ 8 days prior to enrolment SpO2 < 96 % (room air) Any of the following screening criteria: ALT or AST ≥ 5 × upper limit of the reference range Child-Pugh class B or C Serum creatinine ≥ 2 × upper limit of the reference range and creatinine clearance < 30 mL/min Poorly controlled diabetes (random blood glucose ≥ 200 mg/dL or HbA1c ≥ 7.0%, despite treatment) Unsuitable serious complications based on the assessment of either the principal investigator or the sub-investigator Hemophiliac or patients with a marked hemorrhagic tendency Severe diarrhea Hypersensitivity to the investigational drug Breastfeeding or pregnancy With childbearing potential and rejecting contraceptive methods during the study period from the initial administration of the investigational drug Receiving rifampicin within the previous 2 weeks Participated in other clinical trials and received drugs within the previous 12 weeks Undergoing treatment for HIV infection History of SARS-CoV-2 vaccination or wishes to be vaccinated against SARS-CoV-2 Deemed inappropriate (for miscellaneous reasons) based on the assessment of either the principal investigator or the sub-investigator Intervention and comparator Patients who meet the inclusion criteria and do not meet any of the exclusion criteria will be randomized to either the nelfinavir group or the symptomatic treatment group. The nelfinavir group will be administered 750 mg of nelfinavir orally, three times daily for 14 days (treatment period). However, if a participant tests negative on two consecutive PCR tests of saliva samples, administration of the investigational drug for that participant can be discontinued at the discretion of the investigators. The symptomatic treatment group will not be administered the investigational drug, but all other study procedures and conditions will be the same for both groups for the duration of the treatment period. After the treatment period of 14 days, each group will be followed up for 14 days (observational period). Main outcomes The primary endpoint is the time to negative conversion of SARS-CoV-2. During the study period from Day 1 to Day 28, two consecutive negative PCR results of saliva samples will be considered as the negative conversion of the virus. The secondary efficacy endpoints are as follows: For patients with both asymptomatic and mild disease: area under the curve of viral load, half decay period of viral load, body temperature at each time point, all-cause mortality, incidence rate of pneumonia, percentage of patients with newly developed pneumonia, rate of oxygen administration, and the percentage of patients who require oxygen administration. For asymptomatic patients: incidence of symptomatic COVID-19, incidence of fever (≥ 37.0 °C for two consecutive days), incidence of cough For patients with mild disease: incidence of defervescence (< 37.0 °C), incidence of recovery from clinical symptoms, incidence of improvement of each symptom The secondary safety endpoints are adverse events and clinical examinations. Randomization Patients will be randomized to either the nelfinavir group or the symptomatic treatment group using the electric data capture system (1:1 ratio, dynamic allocation based on severity [asymptomatic], and age [< 60 years]). Blinding (masking) Only the assessors of the primary outcome will be blinded (blinded outcome assessment). Numbers to be randomized (sample size) The sample size was determined based on our power analysis to reject the null hypothesis, S (t | z =1) = S (t | z = 0) where S is a survival function, t is time to negative conversion, and z denotes randomization group, by the log-rank test with a two-sided p value of 0.05. We estimated viral dynamic parameters by fitting a nonlinear mixed-effects model to reported viral load data, and simulated our primary endpoint from viral-load time-courses that were realized from sets of viral dynamics parameters sampled from the estimated probability distribution of the parameters (sample size: 2000; 1000 each for randomization group). From this estimation of the hazard ratio between the randomization groups for the event of negative conversion using this simulation dataset, the required number of events for rejecting our null hypothesis with a power of 0.80 felled 97.345 by plugging the estimated hazard ratio, 1.79, in Freedman’s equation. Therefore, we decided the required number of randomizations to be 120 after consideration of the frequency of censoring and the anticipated rate of withdrawal caused by factors such as withdrawal of consent. Trial Status Protocol version 6.0 of February 12, 2021. Recruitment started on July 22, 2020 and is anticipated to be completed by March 31, 2022. Trial registration This trial was registered in Japan Registry of Clinical Trials (jRCT) (jRCT2071200023) on 21 July 21, 2020. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Background: Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder of unknown etiology with systemic symptoms that include fever, night sweats, weight loss, and fatigue. Although tocilizumab (TCZ), which is a recombinant, humanized, anti-human interleukin 6 receptor monoclonal antibody, has been recommended to treat patients with iMCD, 40% of patients with iMCD do not achieve complete remission with TCZ treatment. Methods/Design: In this phase II, investigator-initiated, multicenter, double-blind, randomized, parallel-group trial, the efficacy and safety of sirolimus will be compared with placebo in patients with TCZ-resistant iMCD. The study will be conducted in 8 centers in Japan. Participants (n = 20) will be randomly assigned to receive 2 mg of oral sirolimus (n = 10) or placebo (n = 10) once daily for 16 weeks. The primary endpoint is a decrease in CHAP score by ≥1 from baseline at 16 weeks. Secondary endpoints include levels of hemoglobin, albumin, and C-reactive protein; change in CHAP score; SF-36 Health Survey Questionnaire; physician global assessment (100 mm visual analog scale); patient global assessment (100 mm visual analog scale) at 2, 4, 8, 12, and 16 weeks; change in lymphadenopathy at 16 weeks; and pharmacodynamic assessment, including the measurement of whole blood sirolimus level. Discussion: This clinical trial will provide evidence of efficacy and safety of sirolimus as a potential new therapeutic agent for patients with TCZ-resistant iMCD. Trial Registration: This study was registered with the Japan Registry of Clinical Trials as jRCT2071190029 on October 8, 2019.

The anti-HIV drug nelfinavir suppresses the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro . However, its efficacy in patients with COVID-19 has not been studied.

Background: Interleukin 6 (IL-6) inhibitors are the first-line treatment for idiopathic multicentric Castleman disease (iMCD); however, there is no established treatment for cases that are resistant to IL-6 inhibitors. Although sirolimus, a mammalian target of rapamycin inhibitor, has been suggested to be effective in patients with iMCD, the long-term safety and efficacy of sirolimus on individuals with IL-6 inhibitor-resistant iMCD have not been evaluated. Methods/Design: In this investigator-initiated, multicenter, open-label trial, the long-term safety of sirolimus will be evaluated in patients participating in a placebo-controlled, randomized, double-blind, parallel-group trial on tocilizumab (TCZ)-resistant iMCD. The study will be conducted in 7 centers in Japan. This trial will be promptly started after the evaluation and examination for 16 weeks in the preceding study. The trial will be completed by the time the drug is approved for iMCD treatment in Japan. The primary endpoint is the incidence of adverse events. The secondary endpoints include the following: the levels of hemoglobin, albumin, and C-reactive protein; change in CHAP score; physician global assessment (100-mm visual analog scale); patient global assessment (100-mm visual analog scale); and lymph node changes in subjects with lymphadenopathy. Discussion: This clinical trial will provide evidence regarding the long-term safety of sirolimus as a potential novel therapeutic agent for patients with tocilizumab-resistant iMCD. Trial Registration number: jRCT2051200050

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