ABSTRACT
Cerebral vasospasm occurs within 4 to 14 days from the onset of aneurysmal subarachnoid hemorrhage (aSAH) in 40 to 70% of patients. Of patients with cerebral vasospasm, 17 to 40% experience delayed ischemic neurological deficits and about half of them develop cerebral infarction. Although the mechanism of the onset of cerebral vasospasm has not been fully elucidated, one of mechanisms is considered that after the onset of aSAH, the level of endothelin, a potent and sustained vasoconstriction substance, increases by production induced by oxyhemoglobin and release from erythrocytes and thus cerebral vasospasm develops via endothelin (ET)A receptor. PIVLAZ I.V. Infusion liquid 150â mg (clazosentan sodium) is an endothelin receptor antagonist with a binding affinity for ETA receptor approximately 1,000 times higher than that for ETB receptor. In the clinical study, the incidence of cerebral vasospasm-related morbidity and all-cause mortality was significantly decreased by clazosentan compared with the placebo. The marketing approval was obtained for the indication of "Prevention of cerebral vasospasm, and vasospasm-related cerebral infarction and cerebral ischemic symptoms after aSAH securing" in January 2022. It is expected to contribute to reducing the risk of sequela and improving quality of life in patients with aSAH.
Subject(s)
Subarachnoid Hemorrhage , Vasospasm, Intracranial , Humans , Cerebral Infarction/etiology , Cerebral Infarction/complications , Endothelin Receptor Antagonists/pharmacology , Endothelin Receptor Antagonists/therapeutic use , Quality of Life , Receptor, Endothelin A , Sodium/therapeutic use , Subarachnoid Hemorrhage/drug therapy , Treatment Outcome , Vasospasm, Intracranial/drug therapy , Vasospasm, Intracranial/etiology , Vasospasm, Intracranial/prevention & controlABSTRACT
BACKGROUND: The Coronavirus disease 2019 pandemic caused the Japanese government to declare a State of Emergency on April 7, 2020. The aim of this study is to provide an overview of the effects of the pandemic on surgical cases at a university hospital trauma center. METHODS: An observational study was performed at a trauma center in a tertiary hospital in Tokyo, Japan. The number of surgeries was compared between two periods: a historical control period (Tuesday April 9 to Monday May 27, 2019) and the period of the Japan State of Emergency due to COVID-19 (Tuesday April 7-Monday May 25, 2020). Information on patient age, gender, and surgical diagnosis, site, and procedure was collected for cases operated on in each period. The number of trauma surgeries was compared between the two periods. Data from the two periods were compared statistically. RESULTS: The total number of surgical cases was 151 in the control period and 83 in the COVID-19 period (including no cases with COVID-19), a decrease of 45.0%. There were significantly more surgeries for patients with hip fractures in the COVID-19 period (9 vs. 19, P < 0.001 by Fisher exact test). CONCLUSIONS: During the State of Emergency in Japan, the number of operations for trauma patients at the trauma center decreased, but surgeries for hip fracture increased.
Subject(s)
COVID-19 , Hip Fractures , Hip Fractures/epidemiology , Hospitals, University , Humans , Japan/epidemiology , Pandemics , SARS-CoV-2 , Trauma CentersSubject(s)
Endothelin Receptor Antagonists/pharmacology , Pyrimidines/pharmacology , Sulfonamides/pharmacology , Animals , Clinical Trials as Topic , Endothelin Receptor Antagonists/chemistry , Endothelin Receptor Antagonists/therapeutic use , Humans , Hypertension, Pulmonary/drug therapy , Pyrimidines/chemistry , Pyrimidines/therapeutic use , Receptor, Endothelin A/metabolism , Receptor, Endothelin B/metabolism , Sulfonamides/chemistry , Sulfonamides/therapeutic useSubject(s)
1-Deoxynojirimycin/analogs & derivatives , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Niemann-Pick Disease, Type C/drug therapy , 1-Deoxynojirimycin/pharmacology , 1-Deoxynojirimycin/therapeutic use , Animals , Calcium/metabolism , Clinical Trials as Topic , Disease Models, Animal , Glucosyltransferases/antagonists & inhibitors , Humans , Lysosomes/metabolism , Mice , Niemann-Pick Disease, Type C/physiopathologyABSTRACT
Lymphocyte-specific protein tyrosine kinase (Lck) plays a critical role in T cell activation. In the present study, the effect of a newly synthesized small molecule compound, 7-[2-(dimethylamino)ethoxy]-2-(4-phenoxyphenyl)-9,10-dihydro-4H- pyrazolo[5,1-b] [1,3]benzodiazepine-3-carboxamide (TKM0150) on Lck activity was investigated. TKM0150 inhibited Lck with an 1C50 value of 0.7 nM. To evaluate if TKM0150 is a specific inhibitor of Lck, the activity against several Src (Proto-oncogene tyrosine-protein kinase Src) and non-Src family kinases were assayed. TKM150 inhibited Src family kinases, Src and Csk (c-Src kinase) (with IC50 values of 0.6 nM and 1.7 nM, respectively) as well as Fyn (p59-Fyn) and Lyn (tyrosine-protein kinase Lyn) at a dose of 1 microM; however, it did not inhibit kinase which is a non-Src family kinase in the tyrosine kinase (TK) group, nor kinases in other groups. Then, the anti-inflammtory potential of TKM0150 was evaluated by known experimental models. TKM0150 inhibited the murine mixed lymphocyte reaction (MLR) in vitro with an IC50 value of 0.7 nM, and 2,4,6-trinitro-1-chlorobenzene-induced contact hypersensitivity in vivo at a dose of 0.3 and 1% w/v administered topically. These results indicate that TKM0150 is a specific inhibitor of Lck/Src kinase and can block T cell-mediated responses in vitro and in vivo. Accordingly, TKM0150 would be expected as a drug candidate for treating T cell-mediated disorders including atopic dermatitis.
Subject(s)
Benzodiazepines/pharmacokinetics , Benzodiazepines/therapeutic use , Dermatitis, Contact/prevention & control , Lymphocyte Culture Test, Mixed , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrazoles/pharmacokinetics , Pyrazoles/therapeutic use , Animals , Female , Immunosuppressive Agents/pharmacology , Indicators and Reagents , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Picryl Chloride/toxicity , Substrate Specificity , T-Lymphocytes/drug effects , Tacrolimus/pharmacologyABSTRACT
We evaluated the effects of NT-702 (parogrelil hydrochloride, NM-702, 4-bromo-6-[3-(4-chlorophenyl) propoxy]-5-[(pyridine-3-ylmethyl) amino] pyridazin-3(2H)-one hydrochloride), a selective phosphodiesterase 3 inhibitor, on the asthmatic response in guinea pigs. NT-702 at a concentration of 1 x 10(-7)M elevated the cyclic adenosine monophosphate content in prostaglandin E(2)-treated guinea pig tracheal smooth muscle cells. Leukotriene (LT) D(4)- and histamine-induced contraction of isolated guinea pig tracheal strips was inhibited by NT-702, with EC(50) values of 3.2 x 10(-7) and 2.5 x 10(-7)M, respectively. In an in vivo study, NT-702 suppressed LTD(4)-induced bronchoconstriction and the ovalbumin-induced immediate asthmatic response in guinea pigs through its bronchodilating effect. Furthermore, NT-702 also suppressed the ovalbumin-induced late asthmatic response, airway hyperresponsiveness, and the accumulation of inflammatory cells in the bronchoalveolar lavage fluid. These results suggest that NT-702 has an anti-inflammatory effect as well as a bronchodilating effect and might be useful as a novel potent therapeutic agent for the treatment of bronchial asthma, a new type of agent with both a bronchodilating and an anti-inflammatory effect.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Asthma/drug therapy , Bronchodilator Agents/pharmacology , Enzyme Inhibitors/pharmacology , Phosphodiesterase 3 Inhibitors , Pyridazines/pharmacology , Animals , Anti-Inflammatory Agents/therapeutic use , Antigens/immunology , Asthma/metabolism , Asthma/pathology , Asthma/physiopathology , Bronchoconstriction/drug effects , Bronchoconstriction/immunology , Bronchodilator Agents/therapeutic use , Cell Movement/drug effects , Cyclic AMP/metabolism , Dinoprostone/pharmacology , Enzyme Inhibitors/therapeutic use , Guinea Pigs , Histamine/pharmacology , In Vitro Techniques , Leukotriene D4/pharmacology , Lung/drug effects , Lung/pathology , Male , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/physiopathology , Pyridazines/therapeutic use , Trachea/drug effectsABSTRACT
NT-702 (parogrelil hydrochloride, NM-702), 4-bromo-6-[3-(4-chlorophenyl)propoxy]-5-[(pyridin-3-ylmethyl)amino]pyridazin-3(2H)-one hydrochloride, a novel phosphodiesterase (PDE) inhibitor synthesized as a potent vasodilatory and antiplatelet agent, is being developed for the treatment of intermittent claudication (IC) in patients with peripheral arterial disease. We assessed the efficacy of NT-702 in an experimental IC model as compared with cilostazol and additionally investigated the pharmacological property in vitro and ex vivo. NT-702 selectively inhibited PDE3 (IC(50)=0.179 and 0.260 nM for PDE3A and 3B) more potently than cilostazol (IC(50)=231 and 237 nM for PDE3A and 3B) among recombinant human PDE1 to PDE6. NT-702 inhibited in vitro human platelet aggregation induced by various agonists (IC(50)=11 to 67 nM) and phenylephrine-induced rat aortic contraction (IC(50)=24 nM). Corresponding results for cilostazol were 4.1 to 17 microM and 1.0 microM, respectively. NT-702 (3 mg/kg or more) significantly inhibited ex vivo rat platelet aggregation after a single oral dose. For cilostazol, 300 mg/kg was effective. In a rat femoral artery ligation model, NT-702 at 5 and 10 mg/kg repeated oral doses twice a day (BID) for 13 days significantly improved the reduced walking distance while the lowered plantar surface temperature was improved at 2.5 mg/kg and more. Cilostazol also improved the walking distance and surface temperature at 300 mg/kg BID but significant difference was only observed for surface temperature on day 8. These results suggest that NT-702 can be expected to have therapeutic advantage for IC.