Hisamitsu Pharmaceutical (Japan)

Since the revised Animal Welfare and Management Law in Japan became effective on June 1st, 2022, it became mandatory for pet dogs and cats to have microchips implanted and registered prior to be sold. Two cases of spinal cord injury as the result of inappropriate microchip implantation in puppies were referred to our facility, of which were diagnosed by cervical spinal radiography and computed tomography (CT). While adverse reactions following microchip implantation are rare, the possibility of iatrogenic spinal cord injury remains a serious complication. This is the first report of adverse reactions following microchip implantation in Japan, and it alerts the possibility of iatrogenic spinal cord injury secondary to inappropriate microchip implantation, where adequate training and extra caution is crucial especially in small light-weight animals.

This phase III multicenter randomized double-blind placebo-controlled comparative study evaluated the efficacy and safety of diclofenac sodium patches for the treatment of cancer pain. The study consisted of a 2-week to 4-week open-label dose-titration phase and a 4-week double-blind phase. In the double-blind phase, patients who were expected to continue treatment of cancer pain with nonopioid analgesics alone were randomized to the diclofenac sodium patch or placebo group. Once-daily diclofenac sodium patches were started at 150 mg/day (2 patches) and could be increased up to 225 mg/day (3 patches). The primary efficacy endpoint was the time to insufficient analgesic response. Statistical analysis of the double-blind phase included data from 120 patients of the diclofenac sodium patch group and 118 patients of the placebo group. Time to insufficient analgesic response was significantly longer with diclofenac sodium patches than with placebo (P = 0.0016). The hazard ratio for insufficient response for diclofenac sodium patch vs placebo was 0.459 (95% confidence interval, 0.275-0.768). Regarding sleep quality during the double-blind phase, the proportion of patients with "very good sleep" or "good sleep" in the diclofenac sodium patch and placebo groups was 90.8% and 88.1% at the start of the double-blind phase and 81.4% and 78.6% at the final assessment, respectively. The incidence of adverse events was 60.8% (73/120) in the diclofenac sodium patch group and 60.2% (71/118) in the placebo group. Once-daily diclofenac sodium patches are effective in treating cancer pain and are well tolerated.

The asenapine transdermal system (HP-3070) is the first antipsychotic patch approved in the United States for treatment of adults with schizophrenia. Three phase 1, open-label, randomized studies characterized the pharmacokinetic (PK) profile of HP-3070 by assessing its relative bioavailability compared with sublingual asenapine, its single-/multiple-dose PK and dose proportionality, and the effects of application site, ethnicity, and external heat on bioavailability. Two studies were conducted in healthy subjects, and 1 was conducted in adults with schizophrenia. During single HP-3070 administration, asenapine concentrations increased gradually over approximately 12 hours and remained steady until the patch was removed 24 hours after application. Asenapine area under the curve values at HP-3070 3.8 and 7.6 mg/24 hours doses were similar to those for sublingual asenapine 5 and 10 mg twice-daily doses, respectively, whereas peak exposure (maximum observed plasma concentration) was significantly lower. During daily application of HP-3070, steady-state PK was reached within approximately 72 hours after initiating daily dosing and was characterized by peak-to-trough asenapine plasma concentration ratio of approximately 1.5. HP-3070 PK was dose proportional in the dose range studied, not affected by administration site, and similar across the studied ethnic groups. Application of external heat increased the rate of asenapine absorption (time to reach maximum observed plasma concentration) but did not significantly affect peak and total exposure. HP-3070 exhibited a dose-dependent PK profile unaffected by site of administration or ethnicity. HP-3070 showed a predictable absorption profile with limited variability, with an area under the curve similar to that of sublingual asenapine. Based on these PK metrics, HP-3070 steadily delivers asenapine with lower peaks and troughs than sublingual administration of asenapine.

The use of transdermal fentanyl for opioid-naïve patients is restricted, however, transdermal fentanyl is a useful opioid analgesic for patients in whom oral administration is difficult or for those with renal failure. In this study, the efficacy and safety of fentanyl citrate patches was evaluated in opioid-naïve patients suffering from cancer pain. An open-label uncontrolled study was conducted in opioid-naïve patients with cancer pain unable to be controlled by non-opioid analgesics. Fentanyl citrate patches starting at a low dose (0.5mg/patch, corresponding to 6.25μg/h fentanyl delivered) were applied once/day for up to 14days. The analgesic effect was assessed every day from the visual analogue scale pain score and the number of doses of rescue medication. When improvement of the analgesic effect was "significant" or "moderate" at a certain dose for three consecutive days, the patient was classified as a "responder" and was considered to have "completed" the study. A fentanyl citrate patch was administered to 208 of 209 enrolled patients. In the full-analysis set, 87.0% of the patients were "responders" (95% confidence interval 81.7-91.3%). In 148 patients, the optimum dose was low (0.5mg in 99, and 1mg in 49), with patients finishing the study on days 4-8. Following dose escalation to 4mg, respiratory depression occurred in one patient; however, this was considered a mild adverse event. A low-dose fentanyl citrate patch was effective in the management of cancer pain in opioid-naïve patients and was well tolerated. JPRN-JapicCTI-173717.

A dopamine agonist patch is an important treatment option for PD. A randomized, double-blind, parallel-group, placebo-controlled trial was conducted to evaluate superiority of ropinirole hydrochloride patch over placebo and noninferiority to ropinirole hydrochloride extended-release tablet. PD patients using levodopa received ropinirole patch (up to 64 mg/d), ropinirole tablets (up to 16 mg/d), or placebo once-daily (double-dummy technique). The primary endpoint was the change from baseline in the total score for the UPDRS Part III (on state) at week 16. The change of the least squares mean (95% confidence interval) in the UPDRS Part III total score was -9.8 (-10.8 to -8.7) with ropinirole patch, -4.3 (-5.8 to -2.8) with placebo, and -10.1 (-11.2 to -9.1) with ropinirole tablet. The difference between the ropinirole patch and placebo groups was -5.4 (-7.3 to -3.6), demonstrating superiority of the patch over placebo. The difference between the ropinirole patch and tablet groups was 0.3 (-1.2 to 1.8). The upper limit of the 95% confidence interval was smaller than the noninferiority limit of 2.5, demonstrating noninferiority of ropinirole patch to ropinirole tablet. In all three groups, most adverse events were mild or moderate and there were no serious safety concerns. Once-daily ropinirole patch was effective in advanced PD patients, having demonstrated superiority over placebo and noninferiority to ropinirole tablet, without causing serious safety problems. Ropinirole patch can be an alternative option for PD patients. © 2020 International Parkinson and Movement Disorder Society.

Introduction: Tissue plasminogen activator (tPA) is the standard treatment for acute stroke but its widespread use is constrained by its narrow therapeutic window: better treatments are needed. Clinical stroke is heterogeneous in presentation and responsiveness to therapeutics. There are several methods of inducing acute cerebral ischemia in NHP and each model induces a differential pathology following occlusion. The goal of the current study was to characterize the PIT model of acute stroke in nonhuman primates. Methods: First, the time course of brain infarction between PIT and permanent middle cerebral artery (pMCA) occlusion was compared. PIT and pMCA occlusion were performed in cynomolgus macaques (n = 3/procedure). Total brain infarction volume and the volume of viable tissue surrounding the ischemic core that eventually becomes necrotic (“penumbra”) over time was measured using FLAIR MR imaging, 3, 6, 24 hours, 3, 5 and 7 days post-occlusion. In addition, functionality (Neurologic Deficit Score; NDS) was assessed 24 hours, 3, 5 and 7 days post-occlusion. Second, tPA’s (n = 7) therapeutic time window was determined. tPA (0.9 mg/kg) was i.v. infused 1, 3 and 4.5 hours post-occlusion. Control animals (n = 7) received a saline infusion 3 hours post-occlusion. Total brain infarction volume and presence of intracerebral hemorrhage 24 hours post-occlusion were measured. NDS was also determined. Results: First, significant brain infarction was observed 6 hours post-occlusion with FLAIR MR imaging in both models. Significant penumbral tissue was observed up to 6 hours post-occlusion. The brain infarction volume plateaued 5-7 days post-occlusion. In the second stage, tPA showed robust efficacy when it was infused 1 hour after occlusion. However, when tPA was infused either 3 or 4.5 hours post-occlusion, infarct volume and NDS were not different compared to saline treatment. Furthermore, significant intracranial hemorrhaging was observed when tPA was infused 3 or 4.5 hours post-occlusion. Conclusion: The current study suggests that the PIT model mimics human thrombotic stroke. In addition, since significant risks associated with tPA can also observed, the PIT model can be used to compare novel treatments with tPA in terms of intracranial hemorrhaging.

ATP-binding cassette transporter A1 (ABCA1) exerts an atheroprotective action through the biogenesis of high-density lipoprotein in hepatocytes and prevents the formation of foam cells from macrophages. Controlling ABCA1 is a rational approach to improving atherosclerotic cardiovascular disease. Although much is known about the regulatory mechanism of ABCA1 synthesis, the molecular mechanism underpinning its degradation remains to be clearly described. ABCA1 possesses potential sites of phosphorylation by serine/threonine-protein kinase Pim-1 (Pim-1). Pim-1 depletion decreased the expression of cell surface-resident ABCA1 (csABCA1) and apolipoprotein A-I-mediated [3H]cholesterol efflux in the human hepatoma cell line HepG2, but not in peritoneal macrophages from mice. In vitro kinase assay, immunoprecipitation, and immunocytochemistry suggested phosphorylation of csABCA1 by the long form of Pim-1 (Pim-1L). Cell surface biotinylation indicated that Pim-1L inhibited lysosomal degradation of csABCA1 involving the liver X receptor β, which interacts with csABCA1 and thereby protects it from ubiquitination and subsequent lysosomal degradation. Cell surface coimmunoprecipitation with COS-1 cells expressing extracellularly hemagglutinin-tagged ABCA1 showed that Pim-1L-mediated phosphorylation of csABCA1 facilitated the interaction between csABCA1 and liver X receptor β and thereby stabilized the csABCA1-Pim-1L complex. Mice deficient in Pim-1 kinase activity showed lower expression of ABCA1 in liver plasma membranes and lower plasma high-density lipoprotein levels than control mice. Pim-1L protects hepatic csABCA1 from lysosomal degradation by facilitating the physical interaction between csABCA1 and liver X receptor β and subsequent stabilization of the csABCA1-Pim-1L complex and thereby regulates the circulating level of high-density lipoprotein. Our findings may aid the development of high-density lipoprotein-targeted therapy.

In response to DNA damage, p73 plays a critical role in cell fate determination. In this study, we have found that Plk1 (polo-like kinase 1) associates with p73, phosphorylates p73 at Thr-27, and thereby inhibits its pro-apoptotic activity. During cisplatin-mediated apoptosis in COS7 cells in which the endogenous p53 is inactivated by SV40 large T antigen, p73 was induced to accumulate in association with a significant down-regulation of Plk1. Consistent with these observations, Plk1 reduced the stability of the endogenous p73. Immunoprecipitation and in vitro pulldown assay demonstrated that p73 binds to the kinase domain of Plk1 through its NH(2)-terminal region. Luciferase reporter assay and reverse transcription-PCR analysis revealed that Plk1 is able to block the p73-mediated transcriptional activation. Of note, kinase-deficient Plk1 mutant (Plk1(K82M)) retained an ability to interact with p73; however, it failed to inactivate the p73-mediated transcriptional activation, suggesting that kinase activity of Plk1 is required for the inhibition of p73. Indeed, in vitro kinase assay indicated that p73 is phosphorylated at Thr-27 by Plk1. Furthermore, small interference RNA-mediated knockdown of the endogenous Plk1 in p53-deficient H1299 cells resulted in a significant increase in the number of cells with sub-G(1) DNA content accompanied by the up-regulation of p73 and pro-apoptotic p53(AIP1) as well as the proteolytic cleavage of poly(ADP-ribose) polymerase. Thus, our present results suggest that Plk1-mediated dysfunction of p73 is one of the novel molecular mechanisms to inhibit the p53-independent apoptosis, and the inhibition of Plk1 might provide an attractive therapeutic strategy for cancer treatment.