Folia Pharmacologica Japonica最新文献

Parkinson's disease (PD), which has characteristic motor symptoms such as tremor, muscle rigidity, and akinesia, and as the disease progresses, Lewy bodies spread throughout the brain, eventually causing Parkinson disease dementia (PDD). The clinical picture of PDD is similar to Dementia with Lewy bodies (DLB) and their pathological features are indistinguishable from each other. More than 80% of PD cases will eventually develop dementia and their prognosis are generally 3 to 4 years from the onset of dementia, regardless of disease duration or age of onset. We found that patients with severe olfactory impairment had lower cognitive function scores, more frequent onset of dementia, brain atrophy, and prominent cerebral metabolic abnormalities in a 3-year longitudinal study (Brain 135:161-169, 2012). This study demonstrated for the first time in the world that olfaction tests are useful in predicting dementia in PD, and similar results have been followed up worldwide. Based on these results, a randomized, double-blind, multicenter comparative study of donepezil in PD with severe olfactory dysfunction (DASH-PD study) was conducted and completed a 4-year follow-up period. The results were recently published showing the efficacy and safety of cholinesterase inhibitors for PD without dementia (eClinicalMedicine 51: 101571, 2022).

Tezepelumab (TEZSPIRE^® Subcutaneous Injection 210 ‍mg), a biologic medicine with a novel mechanism, was approved in Japan in September 2022 for the treatment of bronchial asthma. Tezespire auto-injector was approved in Japan in August 2023 as an additional dosage. It is indicated for severe or refractory patients whose asthmatic symptoms cannot be controlled by currently available treatment. Tezepelumab binds to the epithelial cytokine thymic stromal lymphopoietin (TSLP) and disrupts TSLP signaling via the heterodimeric receptor. In the Phase 3 NAVIGATOR trial, the annual asthma exacerbation rate was significantly reduced by tezepelumab when administered subcutaneously every 4 weeks over a 52-week period to patients with uncontrolled, severe asthma who had received medium- or high-dose inhaled glucocorticoids. Its efficacy in reducing asthma exacerbations was observed regardless of blood eosinophil (bEOS) count, fractional exhaled nitric oxide (FeNO) levels, or serum total IgE at baseline. Significant improvements were noted in lung function, health-related quality of life, and change from baseline in asthma control. Reductions in the levels of inflammatory biomarkers (bEOS, FeNO, and IgE) was also noted. Clinical pharmacology trials demonstrated the efficacy of tezepelumab in improving airway hyperresponsiveness. In this article, we reviewed pharmacological characteristics, pharmacokinetics, clinical efficacy, and the safety profile of tezepelumab.

The prognosis of patients with B-cell non-Hodgkin lymphoma (B-NHL) has improved with the use of anti-CD20 based immunochemotherapy. However, management of relapsed or refractory disease remains a challenge, indicating a high unmet need for novel treatments. Epcoritamab (recombinant) is a humanized immunoglobulin G1 (IgG1) bispecific antibody that simultaneously binds to CD3 on T cells and CD20 on B cells or tumor cells inducing T-cell mediated cytotoxicity against CD20-positive B cells. It demonstrated consistent cytotoxic effects in B-cell lymphoma cell line-derived xenograft models, patient-derived xenograft models, and cynomolgus monkey studies. Pharmacological studies in cynomolgus monkeys showed peak plasma concentrations of cytokines were lower with subcutaneous versus intravenous administration. To reduce the risk of cytokine release syndrome (CRS) and improve convenience, Epcoritamab has been developed as a subcutaneous formulation.To further reduce the risk of CRS, clinical trials utilized a priming dose and incremental dose increases. In Phase I/II overseas trials with relapsed, progressive, or refractory B-NHL patients, the recommended Phase II trial dose was determined based on safety, efficacy, and pharmacokinetic model simulation results. The Phase II dose-expansion part demonstrated the efficacy and high tolerability of epcoritamab monotherapy at the recommended dose. Similar efficacy and tolerability were observed in Japanese Phase I/II trials in relapsed or refractory B-NHL patients. Based on these results, epcoritamab received the approval in September 2023 for the treatment of "relapsed or refractory large B-cell lymphoma (DLBCL, HGBCL, PMBCL)" and "relapsed or refractory follicular lymphoma (Grade 3B)" in Japan.

We have reported on two Catalytides (Catalytic peptides), JAL-TA9 (YKGSGFRMI) and ANA-TA9 (SKGQAYRMI). Both peptides belong to the Tob/BTG family proteins and cleave Aβ42. Although Catalytides must be delivered to the brain parenchyma to treat Alzheimer's disease, the blood-brain barrier (BBB) limits their entry into the brain from the systemic circulation. Thus, we evaluated the direct route of ANA-TA9 from the nasal cavity to the brain to bypass the BBB. In this study, we present our findings on JAL-TA9. Animal studies using rats and mice clarified that the plasma clearance of JAL-TA9 was more rapid than its in vitro degradation in plasma, whole blood, and cerebrospinal fluid (CSF). After nasal administration of JAL-TA9, brain concentrations were significantly higher than after intraperitoneal administration, despite much lower plasma concentration. This observation strongly suggests direct delivery of JAL-TA9 to the brain from the nasal cavity. Similar findings were observed for its transport to CSF after nasal and intravenous administration. The concentration of JAL-TA9 in the olfactory bulb peaked at 5 ‍min, while those in the frontal brain peaked at 30 ‍min and in the occipital brain at 60 ‍min. In conclusion, JAL-TA9 was efficiently delivered to the brain by nasal application compared to other routes.

The mainstay of treatment for endometriosis is hormonal therapy, which suppresses ovulation; therefore, patients cannot conceive during treatment. There is a dilemma with ovarian-sparing surgery, known as laparoscopic cystectomy, as it can potentially damage the ovaries. Therefore, there is a need for non-hormonal drug therapies. We addressed these challenges in endometriosis treatment, aiming to maintain ovarian function while achieving effective treatment through basic research. Herein, we present two studies using different mouse models of endometriosis. The first study investigates the effects of a nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing (NLRP) 3 inhibitor in a mouse model of ovarian endometriotic cysts. We confirmed the increased expression of NLRP in ovarian endometriotic cysts compared with that in the uterine endometrium in both patient-derived samples and mouse model lesions. Administering an NLRP3 inhibitor to model mice resulted in lesion reduction. The second study used a peritoneal lesion mouse model to examine bacterial infection in the endometrium and its association with endometriosis development. Using existing databases and patient-derived samples, we identified that Fusobacterium was involved in the development of endometriosis and lesion enlargement when infecting the endometrium in the model. Furthermore, antibiotic treatment led to a reduction in the lesions. These studies highlight the potential of repositioning existing drugs with NLRP3 inhibitory effects or antibiotics as new non-hormonal treatments for endometriosis.

APOHIDE_® Lotion 20% is a topical agent for treating primary palmar hyperhidrosis that contains the active ingredient oxybutynin hydrochloride. Oxybutynin hydrochloride has anticholinergic effects and inhibits sweating by binding to the M₃ receptor, a subtype of the muscarinic acetylcholine receptor, in eccrine sweat glands. The clinical response to oxybutynin hydrochloride treatment also involves N-desethyloxybutynin, an active metabolite of oxybutynin. A clinical study in Japanese patients with primary palmar hyperhidrosis showed superiority of APOHIDE_® Lotion 20% over placebo, i.e., there were significantly more responders (i.e., patients with a reduction in sweat volume ≥50% from baseline) in the APOHIDE_® Lotion 20% group (APOHIDE_® Lotion 20% group: 52.8%, placebo group: 24.3%; treatment difference: 28.5%; P < 0.001, Fisher's exact test). This and other clinical studies reported some adverse events (AEs) associated with the drug's anticholinergic effects and some application site AEs, but most of the AEs were mild. Clinical response did not decrease with long-term (52-week) treatment, and only a few patients (2 of 125) discontinued treatment because of AEs. Taken together, study results indicate that APOHIDE_® Lotion 20% may be an effective and safe new treatment option for patients with primary palmar hyperhidrosis.

Pertuzumab and trastuzumab are anti-HER2 humanized monoclonal antibodies with different mechanisms of action. Their combination is expected to suppress intracellular HER2 signaling additively or synergistically. Their combination is widely recommended worldwide and has been established as a standard of care for HER2-positive breast cancer. However, improvement is required because of the prolonged time of intravenous infusion. Vorhyaluronidase alfa (rHuPH20) depolymerizes hyaluronan in the subcutaneous connective tissue. It's reported to increase the permeability and absorption levels of drugs. PHESGO^® combination for subcutaneous injection MA/IN (PHESGO^®) is a fixed-dose combination of pertuzumab, trastuzumab, and rHuPH20. A confirmatory phase III study (FeDeriCa) was conducted following a dose-finding phase I study (BO30185). Patients with HER2-positive early breast cancer were randomly assigned to receive either intravenous infusion of pertuzumab and trastuzumab or subcutaneous injection of PHESGO^®, in combination with chemotherapy, to compare the pharmacokinetics (PK), efficacy and safety. A phase II study (PHranceSCa) was also conducted to assess patients' preference and satisfaction. Based on these results, population PK analysis, and other data, PHESGO^® obtained marketing approval in Japan in September 2023 with indications for "HER2-positive breast cancer" and "advanced or recurrent HER2-positive colorectal cancer that has progressed following cancer chemotherapy and is not amenable to curative resection". By reducing the administration time, PHESGO^® is expected to contribute to various needs of patients and improvement of their daily lives. Since drug preparation is not required, it can provide convenience to healthcare professionals, leading to stress reduction of medical resources as well.