Efficacy and Safety of the Natural Killer T Cell-Stimulatory Glycolipid OCH-NCNP1 for Patients With Relapsing Multiple Sclerosis: Protocol for a Randomized Placebo-Controlled Clinical Trial.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system that causes myelin sheath damage and axonal degeneration. The glycolipid (2S, 3S, 4R)-1-O-(α-d-galactosyl)-2-tetracosanoylamino-1,3,4-nonaetriol (OCH-NCNP1 or OCH) exerts an immunoregulatory action that suppresses T helper (Th)1 cell-mediated immune responses through natural killer T cell activation, selective interleukin-4 production, and Th2 bias induction in human CD4-positive natural killer T cells. OBJECTIVE: This trial aims to investigate the efficacy and safety of the immunomodulator OCH in patients with relapsing MS through 24-week repeated administration. METHODS: This protocol describes a double-blind, multicenter, placebo-controlled, randomized phase II clinical trial that was initiated in September 2019. The participants were randomly assigned to either a placebo control group or an OCH-NCNP1 group and the investigational drug (3.0 mg) was orally administered once weekly for the 24-week duration. Major inclusion criteria are as follows: patients had been diagnosed with relapsing MS (relapsing-remitting and/or secondary progressive MS) based on the revised McDonald criteria or were diagnosed with MS by an attending physician as noted in their medical records; patients with at least two medically confirmed clinical exacerbations within 24 months prior to consent or one exacerbation within 12 months prior to consent; patients with at least one lesion suspected to be MS on screening magnetic resonance imaging (MRI); and patients with 7 points or less in the Expanded Disability Status Scale during screening. Major exclusion criteria are as follows: diagnosis of neuromyelitis optica and one of optic neuritis, acute myelitis, and satisfying at least two of the following three items: (1) spinal cord MRI lesion extending across at least three vertebral bodies, (2) no brain MRI lesions during onset (at least four cerebral white matter lesions or three lesions, one of which is around the lateral ventricle), and (3) neuromyelitis optica-immunoglobulin G or antiaquaporin-4 antibody-positive. Outcome measures include the primary outcome of MRI changes (the percentage of subjects with new or newly expanded lesions at 24 weeks on T2-weighted MRI) and the secondary outcomes annual relapse rate (number of recurrences per year), relapse-free period (time to recurrence), sustained reduction in disability (SRD) occurrence rate, period until SRD (time to SRD occurrence), no evidence of disease activity, and exploratory biomarkers from phase I trials (such as gene expression, cell frequency, and intestinal and oral microbiome). RESULTS: We plan to enroll 30 patients in the full analysis set. Enrollment was closed in June 2021 and the study analysis was completed in March 2023. CONCLUSIONS: This randomized controlled trial will determine whether OCH-NCNP1 is effective and safe in patients with MS as well as provide evidence for the potential of OCH-NCNP1 as a therapeutic agent for MS. TRIAL REGISTRATION: ClinicalTrials.gov NCT04211740; https://clinicaltrials.gov/study/NCT04211740. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46709.

Systemic administration of the antisense oligonucleotide NS-089/NCNP-02 for skipping of exon 44 in patients with Duchenne muscular dystrophy: Study protocol for a phase I/II clinical trial.

AIM: The purpose of this study is to evaluate the safety and pharmacokinetics of the novel morpholino oligomer NS-089/NCNP-02 which can induce exon 44 skipping, in patients with DMD. Additionally, we aimed to identify markers predictive of therapeutic efficacy and determine the optimal dosing for future studies. METHODS: This is an open-label, dose-escalation, two-center phase I/II trial in ambulant patients with DMD, presence of an out-of-frame deletion, and a mutation amenable to exon 44 skipping. Part 1 is a stepwise dose-finding stage (4 weeks) during which NS-089/NCNP-02 will be administered intravenously at four dose levels once weekly (1.62, 10, 40, and 80 mg/kg); Part 2 is a 24-week evaluation period based on the dosages determined during Part 1. The primary (safety) endpoints are the results of physical examinations, vital signs, 12-lead electrocardiogram and echocardiography tests, and adverse event reporting. Secondary endpoints include expression of dystrophin protein, motor function assessment, exon 44 skipping efficiency, plasma and urinary NS-089/NCNP-02 concentrations, and changes in blood creatine kinase levels. DISCUSSION: Exon-skipping therapy using ASOs shows promise in selected patients, and this first-in-human study is expected to provide critical information for subsequent clinical development of NS-089/NCNP-02.

Comparison of Drug Use Between Clinical Practice and Regulatory Approval: Results in Older Japanese Patients With Rheumatoid Arthritis, Diabetes, High Blood Pressure, or Depression.

BACKGROUND: In this study, differences in older patients between drug use as reported in clinical practice and in clinical trials for regulatory approval were examined. METHODS: Electronic medical record (EMR) data such as patient background (age, sex), concomitant drugs, data on laboratory tests, and prescribed doses of drugs from outpatients with rheumatoid arthritis, diabetes, high blood pressure, or depression at Chiba University Hospital were obtained for the period from January 2003 to December 2012. These data were compared with data from relevant clinical trials for regulatory approval in order to examine differences in drug use. RESULTS: There were 5134 eligible patients. The prescribed doses of drugs were lower than the standard approved doses for depression and rheumatoid arthritis but were generally within the approved dose range for type 2 diabetes mellitus and hypertension. When comparing the characteristics of older patients taking tacrolimus, 5.6% to 17.0% of those would not be able to participate in clinical trials because of liver or renal abnormality, and the incidence rates of some adverse drug events (ADEs) differed significantly between clinical practice and clinical trials. CONCLUSIONS: Appropriate doses of drugs for older patients may differ from approved doses in certain diseases. Complex situations such as a lot of polypharmacy, comorbidity, and functional impairment in older patients in clinical practice make it difficult to evaluate safety based on data from clinical trials. In the future, utilization of a database created from the EMR of older patients should be considered for assessment of drug safety in older patients in clinical practice.

[Questionnaire survey about NSAIDs use in late pregnancy for pharmacists and physicians].

It has been reported the use of nonsteroid anti-inflammatory drugs (NSAIDs) in late pregnancy was associated with potentially fetal toxicity (contraction of fetal ductus areteriosus). According to the package inserts in Japan, many oral NSAIDs are contraindicated to women in late pregnancy, but several oral and topical NSAIDs with case reports of fetal toxicity are not. In the present study, a web-based questionnaire survey was conducted in pharmacists/physicians to determine their awareness of fetal toxicity caused by NSAIDs, as well as their attitudes regarding the use of NSAIDs in late pregnancy. Responses were obtained from 427 pharmacists, 22 obstetricians, and 160 non-obstetric physicians. Of the non-obstetric respondents, more than 40% had no knowledge of fetal ductus arteriosus contraction caused by oral ibuprofen, and most of them were not aware of the relevant warning statement on the package insert. In contrast, these were familiar to nearly 100% of the obstetricians. As for ketoprofen tape, only 20-40% of the pharmacists/physicians were aware of the warning statement, and nearly all respondents did not confirm whether the patient was in late pregnancy. The majority of the respondents answered that oral ibuprofen, ketoprofen tape and NSAID-containing OTC drugs should not be used in late pregnancy after they knew the warning statements in late pregnancy. This survey suggests that the fetal toxicity of NSAIDs is not well recognized by pharmacists/physicians. It would be necessary to make it thoroughly known to them through such as enrichment of safety information on the package inserts, accompanying with the evidence.

The Roles of Regulatory Science Research in Drug Development at the Pharmaceuticals and Medical Devices Agency of Japan.

Recently, it is becoming increasingly difficult to develop innovative drugs. Thus, the role of regulatory science research in drug development and postmarketing settings has become more important. In this article, the authors discuss the roles of regulatory science research at the Pharmaceuticals and Medical Devices Agency (PMDA), which aims to improve public health in Japan.

Community pharmacists' attitudes relating to patients' use of health products in Japan.

BACKGROUND: There is little information about Japanese pharmacists' perceived facilitators and barriers to communication with patients about orally taken health products, including herbs and dietary supplements. OBJECTIVE: To explore Japanese pharmacists' attitudes relating to patients' use of health products. METHOD: Qualitative study involving focus group interviews with pharmacists was conducted. Data were analyzed using the constant comparative method. SETTING: Focus group interviews with community pharmacists were conducted in Japan. Main outcome measure Pharmacists' views and experiences about patients' health product use and their perceived facilitators and barriers to communication. RESULTS: Sixteen pharmacists participated and were asked to describe their views and experiences about patients' health product use. Some were uncomfortable inquiring about and being asked about patients' health product use, due to lack of scientific evidence for their efficacy and safety, lack of knowledge to advise patients properly, and fear that they could not answer patients' questions. Other pharmacists had similar views or experiences, but those who were proactive in communicating with patients were motivated by certain predisposing factors, such as their professional responsibility for ensuring patients' health and safety. CONCLUSION: This study showed that differences in opinion about their roles might create differences in pharmacists' attitudes toward patients' health product use. This highlights the importance of reconsidering pharmacists' roles in community settings. Further studies and debate are needed in order to clarify the pharmacists' roles and to ensure the design of educational objectives that would enable pharmacists to support their patients in using health products and prescription drugs safely.

Similarities and differences between US and Japan as to pharmacogenomic biomarker information in drug labels.

Pharmacogenomics (PGx) has been utilized as a tool to improve a drug's benefit/risk ratio and the efficiency of drug developments. In order to examine what factors are involved to determine the level of contexts (contents and descriptions) of drug-PGx biomarker information, we graded sections of Japanese package inserts and US drug labels into six levels according to the importance of cautions in regards to clinical practice and compared similarities and differences of the contexts between the two countries. Out of 54 contexts identified, 33 (61%) were graded differently between Japan and the US. The different contexts were mainly related to metabolizing enzymes used in terms of safety, therapeutic areas other than oncology, outcome before 1993, Japan-based companies having marketing authorization and no PGx data on the Japanese population. We describe the potential reasons that could lead to the differences between the two countries such as genetic differences and quantitative evidence in the Japanese population, and also discuss future perspectives to improve PGx utilization in clinical practices in Japan.

Structures of the SEp22 dodecamer, a Dps-like protein from Salmonella enterica subsp. enterica serovar Enteritidis.

The crystal structure of SEp22, a DNA-binding protein from starved cells from Salmonella enterica subsp. enterica serovar Enteritidis, has been determined in two forms: the native state at 1.25 Šresolution and an iron-soaked form at 1.30 Šresolution. The SEp22 protomers form a dodecameric shell with 23 symmetry and a single iron ion per protomer was found at the ferroxidase centre in the iron-soaked form. Along the threefold axes of the 23 symmetry, hydrophilic Asp channels that consist of Asp146 were found. Iron ions may flow into the cavity of the dodecameric shell through the Asp channels.

Understanding of definition and safety of oral health products among patients, physicians and pharmacists.

Our objective was to clarify the current understanding of the definition and safety of oral health products among patients and health professionals, and patients' perception about their communication with physicians and pharmacists regarding those products. Self-administered questionnaires were completed by patients at 17 community pharmacies in 14 prefectures of Japan. For health professionals, we sent a questionnaire to pharmacists and physicians who were registered as members of the Internet-based Medical Doctor's and Pharmacist's Information-Sharing System. The respondents were 242 patients, 158 physicians and 407 pharmacists. Some patients did not categorize dietary supplements as health products, while they did so categorize conventional foods (e.g., fermented soybeans, yogurt). Their understanding of the definition of health products was different from that of health professionals. Less than half of the patients considered that health products might potentiate or attenuate the effects of concomitant drugs, and this view was especially common among the elderly. The percentage of patients who reported that they rarely or never asked for advice from a pharmacist about their use of health products was significantly higher among those who had an incorrect understanding about health products. In conclusion, some patients' recognition of oral health products was different from that of health professionals, and most patients do not discuss their use of such products unless they are asked. Therefore, it is important for health professionals to check a patient's use of health products and be sure what he or she means when using the term 'health product'.

[Safety Assessment regarding use of glucosamine sulfate by patients whose dietary potassium intake is restricted].

Hyperkalemia is common in patients with renal disease, and is sometimes caused by dietary potassium intake. We aimed to determine and compare the content of potassium in nine brands of glucosamine supplements sold in the Japanese market and via the Internet. The potassium content was 0.165-3 mg per daily dose in Japanese products, which contained glucosamine hydrochloride or N-acetylglucosamine, while the content in foreign products, in which glucosamine was sulfated, was 197-280 mg. Our results show that the potassium content in glucosamine sulfate supplements can correspond to 20% of the maximum daily intake of potassium by patients on hemodialysis, because the products sometimes contain glucosamine as glucosamine sulfate potassium chloride for stabilization. Although it is not permitted to sell glucosamine sulfate as food in Japan, consumers can easily buy foreign products that contain glucosamine sulfate via the Internet, and those products rarely indicate the potassium content. Health professionals should pay attention to patients' use of glucosamine supplements, especially when patients' dietary potassium intake needs to be restricted.

[Collecting and sharing information about dietary supplements and functional foods among healthcare professionals using internet-based system].

Since we do not know much about the efficacy and safety of dietary supplements and functional foods (DS), it is important to collect DS-related events and to share the information among healthcare professionals. Therefore, we aimed to develop an internet-based system which would allow medical doctors and pharmacists to report DS-related events. We conducted a questionnaire survey among pharmacists about their experiences and views of DS-related adverse event reporting. Many pharmacists did not report events because they never had any patient who reported an event. This might have been, in part, owing to lack of awareness of an occurrence, so we collected events using our internet-based system, which periodically offers educational DS information. After educational commentaries and elucidation were appended, collected cases were distributed to the registered members via web pages to encourage them to be more concerned about the safety of DS. Additionally, we constructed a simple posting system for members to easily report similar events, because the questionnaire survey revealed that lack of time and uncertainty of causal relation between an event and DS were sometimes reasons not to report. We obtained several DS-related events both via the normal data collecting form and the simple posting system, and subsequently confirmed reports by e-mail contact. Our interactive system enabled us to obtain more detailed information about posted events. In conclusion, this information system for DS was proved to be useful to facilitate reporting of DS-related events by healthcare professionals and to accumulate events similar to already reported cases.

[Development and evaluation of an internet-based educational system about herbs and dietary supplements through periodical distribution of information to health professionals].

Herbs and dietary supplements (HDS) are widely used, and health professionals are in an ideal position to educate patients about them. However, it is sometimes difficult to evaluate their risks and benefits with limited information and what is worse, many health professionals in Japan are unconcerned with HDS. Therefore, we aimed to develop an internet-based educational system to periodically provide information about HDS to medical doctors and pharmacists in order to increase their awareness. Monographs about selected HDS, accompanied with educational quizzes, were prepared to meet pharmacists' needs. Examples of clinical Q&A cases about drug interactions involving HDS were prepared. The material was distributed weekly to registered health professionals by e-mail and via WWW pages. Two hundred and forty-four health professionals evaluated the system by questionnaire. The questionnaire results revealed that 1) more than 75% of responders evaluated the system as useful, 2) compilation of information into educational quizzes and cases encouraged health professionals to learn about HDS with less difficulty, and 3) e-mails led them to learn periodically and to be more concerned about the safety of HDS. In conclusion, the developed information system for HDS was proved to be useful and should serve to improve the understanding of health professionals about this issue.