Cysteinylprolyl ester-mediated drug release from a lipid-drug conjugate.

For small-molecule drugs, lipidation via a cleavable linkage can extend half-life in circulation through interaction with albumin. Here we modified the cysteinylprolyl ester (CPE) system used in peptide thioester synthesis, which normally requires basic conditions, for use as an self-immolative linker and release device for a lipid-gemcitabine conjugate. To improve release under physiological conditions for medical application, a methyl group at the α-position of cysteine on the CPE unit was incorporated in anticipation of the Thorpe-Ingold effect. As a result, Ac-Gly-(α-Me)Cys(SH)-Pro-gemcitabine 11 drastically promoted the release of gemcitabine in comparison with Ac-Gly-Cys(SH)-Pro-gemcitabine 10. Furthermore, in the presence of bovine serum albumin and/or 2-mercaptoethanesulfonic acid, the gentle and continuous release of gemcitabine from the lipid-gemcitabine conjugate 16 was achieved. In addition to gemcitabine, this method could allow high clearance drugs, including nucleic acid and prostacyclin derivatives, to maintain their biological activity long enough to become effective.

Discovery of DS44470011: An oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of renal anemia.

Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We identified a pyrimidine core with HIF-PHD inhibitory activity based on scaffold hopping of FG-2216 using crystal structures of HIF-PHD2 in complex with compound. By optimizing the substituents at the 2- and 6- positions of the pyrimidine core, we discovered DS44470011, which improves the effectiveness of erythropoietin (EPO) release in cells. Oral administration of DS44470011 to cynomolgus monkeys increased plasma EPO levels.

Discovery of DS-1093a: An oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of renal anemia.

Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We discovered DS44470011 in our previous study, which showed potent in vitro activity and in vivo efficacy based on HIF-PHD inhibition. However, DS44470011 was also found to exert genotoxic effects. By converting the biphenyl structure, which is suspected to be the cause of this genotoxicity, to a 1-phenylpiperidine structure, we were able to avoid genotoxicity and further improve the in vitro activity and in vivo efficacy. Furthermore, through the optimization of pyrimidine derivatives, we discovered DS-1093a, which has a wide safety margin with potent in vitro activity and an optimal pharmacokinetic profile. DS-1093a achieved an increase in hemoglobin levels in an adenine-induced rat model of chronic kidney disease after its continuous administration for 4 days.

Does the presence of preoperative neck pain impact clinical outcomes after posterior decompression in patients with cervical ossification of the posterior longitudinal ligament?: Retrospective multicenter cohort study.

STUDY DESIGN: Retrospective multicenter study. OBJECTIVES: To evaluate how preoperative neck pain influences clinical outcomes following posterior decompression for cervical ossification of the posterior longitudinal ligament (OPLL). SETTING: Fourteen medical institutions in Japan. METHODS: We enrolled 90 patients with cervical OPLL who underwent posterior decompression and were followed for a minimum of two years. We collected demographic data, medical history, and imaging findings. Patients were divided into two groups based on preoperative neck pain presence (Pre-op. neck pain (-) and (+) groups), and their outcomes were compared. RESULTS: There were no significant differences in patient demographics between the Pre-op. neck pain (-) and (+) groups. Both groups showed similar distributions of ossification types and K-line positivity. Perioperative complications were comparable between the two groups. Radiographic analysis revealed no significant differences in C2-7 angles or cervical range of motion, pre- and postoperatively. Both groups demonstrated significant improvement in postoperative Japanese orthopedic association (JOA) scores, but there were no significant differences in scores or recovery rates. In the Pre-op. neck pain (-) group, factors associated with appearance of postoperative neck pain included pre- and postoperative lower JOA scores and larger C2-7 angles in neutral and extension positions. CONCLUSIONS: It emerges that lower pre- and postoperative JOA scores or larger C2-7 angles in neutral and extension positions predispose to postoperative neck pain even in those patients without preoperative neck pain. Therefore, this is worth discussing at the time of consenting patients for surgical decompression and fixation.

Enhanced tumor specific drug release by hypoxia sensitive dual-prodrugs based on 2-nitroimidazole.

Hypoxia in cancer is important in the development of cancer-selective medicines. Here, a novel hypoxia-responsible dual-prodrug is described. We designed and synthesized 2-nitroimidazole derivatives which spontaneously release both a PYG inhibitor and gemcitabine under hypoxic conditions. One such derivative, a prodrug 9 was found to be stable against chemical and enzymatic hydrolysis, and upon chemical reduction of the nitro group on imidazole, successfully releases both drugs. In an in vitro proliferation assay using human pancreatic cells, compound 9 exhibited significant anti-proliferative effects in hypoxia but fewer effects in normoxia. Consequently, prodrug 9 should be useful for cancer treatment due to its improved cancer selectivity and potential to overcome drug resistance.

Japanese Orthopaedic Association (JOA) clinical practice guidelines on the management of lumbar spinal stenosis, 2021 - Secondary publication.

BACKGROUND: The Japanese Orthopaedic Association (JOA) guideline for the management of lumbar spinal stenosis (LSS) was first published in 2011. Since then, the medical care system for LSS has changed and many new articles regarding the epidemiology and diagnostics of LSS, conservative treatments such as new pharmacotherapy and physical therapy, and surgical treatments including minimally invasive surgery have been published. In addition, various issues need to be examined, such as verification of patient-reported outcome measures, and the economic effect of revised medical management of patients with lumbar spinal disorders. Accordingly, in 2019 the JOA clinical guidelines committee decided to update the guideline and consequently established a formulation committee. The purpose of this study was to describe the formulation we implemented for the revision of the guideline, incorporating the recent advances of evidence-based medicine. METHODS: The JOA LSS guideline formulation committee revised the previous guideline based on the method for preparing clinical guidelines in Japan proposed by the Medical Information Network Distribution Service in 2017. Background and clinical questions were determined followed by a literature search related to each question. Appropriate articles based on keywords were selected from all the searched literature. Using prepared structured abstracts, systematic reviews and meta-analyses were performed. The strength of evidence and recommendations for each clinical question was decided by the committee members. RESULTS: Eight background and 15 clinical questions were determined. Answers and explanations were described for the background questions. For each clinical question, the strength of evidence and the recommendation were both decided, and an explanation was provided. CONCLUSIONS: The 2021 clinical practice guideline for the management of LSS was completed according to the latest evidence-based medicine. We expect that this guideline will be useful for all medical providers as an index in daily medical care, as well as for patients with LSS.

Formulation of Japanese Orthopaedic Association (JOA) clinical practice guideline for the management of low back pain- the revised 2019 edition.

BACKGROUND: The latest clinical guidelines are mandatory for physicians to follow when practicing evidence-based medicine in the treatment of low back pain. Those guidelines should target not only Japanese board-certified orthopaedic surgeons, but also primary physicians, and they should be prepared based entirely on evidence-based medicine. The Japanese Orthopaedic Association Low Back Pain guideline committee decided to update the guideline and launched the formulation committee. The purpose of this study was to describe the formulation we implemented for the revision of the guideline with the latest data of evidence-based medicine. METHODS: The Japanese Orthopaedic Association Low Back Pain guideline formulation committee revised the previous guideline based on a method for preparing clinical guidelines in Japan proposed by Medical Information Network Distribution Service Handbook for Clinical Practice Guideline Development 2014. Two key phrases, "body of evidence" and "benefit and harm balance" were focused on in the revised version. Background and clinical questions were determined, followed by literature search related to each question. Appropriate articles were selected from all the searched literature. Structured abstracts were prepared, and then meta-analyses were performed. The strength of both the body of evidence and the recommendation was decided by the committee members. RESULTS: Nine background and nine clinical qvuestions were determined. For each clinical question, outcomes from the literature were collected and meta-analysis was performed. Answers and explanations were described for each clinical question, and the strength of the recommendation was decided. For background questions, the recommendations were described based on previous literature. CONCLUSIONS: The 2019 clinical practice guideline for the management of low back pain was completed according to the latest evidence-based medicine. We strongly hope that this guideline serves as a benchmark for all physicians, as well as patients, in the management of low back pain.

The impact of diabetes mellitus on spinal fracture with diffuse idiopathic skeletal hyperostosis: A multicenter retrospective study.

BACKGROUND: Patients with diffuse idiopathic skeletal hyperostosis (DISH) are susceptible to spinal column injuries with neurological deterioration. Previous studies indicated that the prevalence of diabetes mellitus (DM) in patients with DISH was higher than that in patients without DISH. This study investigates the impact of DM on surgical outcomes for spinal fractures in patients with DISH. METHODS: We retrospectively evaluated 177 spinal fractures in patients with DISH (132 men and 45 women; mean age, 75 ± 10 years) who underwent surgery from a multicenter database. The subjects were classified into two groups according to the presence of DM. Perioperative complications, neurological status by Frankel grade, mortality rate, and status of surgical site infection (SSI) were compared between the two groups. RESULTS: DM was present in 28.2% (50/177) of the patients. The proportion of men was significantly higher in the DM group (DM group: 86.0% vs. non-DM group: 70.1%) (p = 0.03). The overall complication rate was 22.0% in the DM group and 19.7% in the non-DM group (p = 0.60). Poisson regression model revealed that SSI was significantly associated with DM (DM group: 10.0% vs. non-DM group: 2.4%, Relative risk: 4.5) (p = 0.048). Change in neurological status, mortality rate, instrumentation failure, and nonunion were similar between both groups. HbA1c and fasting blood glucose level (SSI group: 7.2% ± 1.2%, 201 ± 67 mg/dL vs. non-SSI group: 6.6% ± 1.1%, 167 ± 47 mg/dL) tended to be higher in patients with SSI; however, there was no significant difference. CONCLUSIONS: In spinal fracture in patients with DISH, although DM was an associated factor for SSI with a relative risk of 4.5, DM did not negatively impact neurological recovery. Perioperative glycemic control may be useful for preventing SSI because fasting blood glucose level was high in patients with SSI.

OPN4 belongs to the photosensitive system of the human skin.

The human skin has previously been described to be affected by light; however, the underlying mechanism remains unknown. OPN4 (melanopsin) expression was first identified in the skin of amphibians; however, whether it is also expressed and functioned in the human skin has not yet been identified. Here, we show that OPN4 was expressed in the human skin tissue and cultures of isolated keratinocytes, melanocytes and fibroblasts. Additionally, Ca2+ influx in vitro and ex vivo and phosphorylation of extracellular signal-regulated kinases 1/2 in human fibroblasts were observed by stimulation of blue light irradiation. Notably, our findings showed that this Ca2+ influx and phosphorylation of extracellular signal-regulated kinases 1/2 are promoted in an intensity-dependent manner, indicating that the light signal is converted to an intracellular signal via OPN4 in the human skin. Overall, in this study we showed that the human skin functions as a photoreceptor by demonstrating that in human skin, the photoreceptive protein was expressed, and photoreception was conducted via photoreceptive protein.

Discovery of 1-[2-(1-methyl-1H-pyrazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-3-(pyridin-4-ylmethyl)urea as a potent NAMPT (nicotinamide phosphoribosyltransferase) activator with attenuated CYP inhibition.

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step of the NAD+ salvage pathway. Since NAD+ plays a pivotal role in many biological processes including metabolism and aging, activation of NAMPT is an attractive therapeutic target for treatment of diverse array of diseases. Herein, we report the continued optimization of novel urea-containing derivatives which were identified as potent NAMPT activators. Early optimization of HTS hits afforded compound 12, with a triazolopyridine core, as a lead compound. CYP direct inhibition (DI) was identified as an issue of concern, and was resolved through modulation of lipophilicity to culminate in 1-[2-(1-methyl-1H-pyrazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-3-(pyridin-4-ylmethyl)urea (21), which showed potent NAMPT activity accompanied with attenuated CYP DI towards multiple CYP isoforms.