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1.
Clin Transl Sci ; 14(5): 1967-1976, 2021 09.
Article in English | MEDLINE | ID: covidwho-1226667

ABSTRACT

Camostat mesylate, an oral serine protease inhibitor, is used to treat chronic pancreatitis and reflux esophagitis. Recently, camostat mesylate and its active metabolite 4-(4-guanidinobenzoyloxy)phenylacetic acid (GBPA) were reported to inhibit the infection of cells by severe acute respiratory syndrome coronavirus 2 by inhibiting type II transmembrane serine protease. We conducted a phase I study to investigate high-dose camostat mesylate as a treatment for coronavirus disease 2019. Camostat mesylate was orally administered to healthy adults at 600 mg 4 times daily under either of the following conditions: fasted state, after a meal, 30 min before a meal, or 1 h before a meal, and the pharmacokinetics and safety profiles were evaluated. In addition, the time of plasma GBPA concentration exceeding the effective concentration was estimated as the time above half-maximal effective concentration (EC50 ) by using pharmacokinetic/pharmacodynamic modeling and simulation. Camostat mesylate was safe and tolerated at all dosages. Compared with the fasted state, the exposure of GBPA after a meal and 30 min before a meal was significantly lower; however, no significant difference was observed at 1 h before a meal. The time above EC50 was 11.5 h when camostat mesylate 600 mg was administered 4 times daily in the fasted state or 1 h before a meal. Based on the results of this phase I study, we are currently conducting a phase III study.


Subject(s)
COVID-19/drug therapy , Drug Repositioning , Esters/adverse effects , Guanidines/adverse effects , Serine Proteinase Inhibitors/administration & dosage , Administration, Oral , Adolescent , Adult , Computer Simulation , Dose-Response Relationship, Drug , Drug Administration Schedule , Esters/administration & dosage , Esters/pharmacokinetics , Food-Drug Interactions , Guanidines/administration & dosage , Guanidines/pharmacokinetics , Healthy Volunteers , Humans , Male , Middle Aged , Models, Biological , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/adverse effects , Young Adult
2.
Endocr J ; 68(4): 477-484, 2021 Apr 28.
Article in English | MEDLINE | ID: covidwho-1204140

ABSTRACT

We provide the details of the successful management of a patient with active Cushing's disease complicated with coronavirus disease 2019 (COVID-19) pneumonia. The patient was a 27-year-old Japanese female healthcare worker who was scheduled to undergo pituitary surgery for Cushing's disease. She had been in close contact with an undiagnosed patient infected with COVID-19 and then developed COVID-19 pneumonia. Despite a lack of known risk factors associated with severe COVID-19 infection, the patient's dyspnea worsened and her respiratory condition deteriorated, as indicated by the need for 7 L/min oxygen supply by mask to maintain her oxygen saturation at >90%. Medical treatment was initiated to control hypercortisolism by the 'block and replace' regimen using steroidogenesis inhibitors and hydrocortisone. The COVID-19 pneumonia improved with multi-modal treatment including antiviral therapy. One month later, after a negative severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) test result and with appropriate protection against virus transmission to medical staff in the operating room and daily medical care nurses, trans-sphenoidal surgery was performed by our highly experienced pituitary surgeon. One month after the surgery, the patient's basal ACTH and cortisol levels and urinary free cortisol were all under the detection limit. Surgical remission was expected. Since hypercortisolism due to active Cushing's disease may worsen a COVID-19 infection, multi-disciplinary management that includes appropriate and prompt treatment strategies is mandatory in such cases.


Subject(s)
Amides/administration & dosage , Benzamidines/administration & dosage , COVID-19/therapy , Guanidines/administration & dosage , Metyrapone/administration & dosage , Pituitary ACTH Hypersecretion/therapy , Pregnenediones/administration & dosage , Pyrazines/administration & dosage , ACTH-Secreting Pituitary Adenoma/complications , ACTH-Secreting Pituitary Adenoma/drug therapy , Adenoma/complications , Adenoma/drug therapy , Adult , COVID-19/complications , COVID-19/pathology , Combined Modality Therapy , Dihydrotestosterone/administration & dosage , Dihydrotestosterone/analogs & derivatives , Disease Progression , Female , Health Personnel , Heparin/administration & dosage , Humans , Japan , Neurosurgical Procedures , Pituitary ACTH Hypersecretion/blood , Pituitary ACTH Hypersecretion/complications , Pituitary ACTH Hypersecretion/pathology , SARS-CoV-2/physiology , Treatment Outcome , Trimethoprim, Sulfamethoxazole Drug Combination/administration & dosage
3.
Basic Clin Pharmacol Toxicol ; 128(2): 204-212, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-919229

ABSTRACT

The coronavirus responsible for COVID-19, SARS-CoV-2, utilizes a viral membrane spike protein for host cell entry. For the virus to engage in host membrane fusion, SARS-CoV-2 utilizes the human transmembrane surface protease, TMPRSS2, to cleave and activate the spike protein. Camostat mesylate, an orally available well-known serine protease inhibitor, is a potent inhibitor of TMPRSS2 and has been hypothesized as a potential antiviral drug against COVID-19. In vitro human cell and animal studies have shown that camostat mesylate inhibits virus-cell membrane fusion and hence viral replication. In mice, camostat mesylate treatment during acute infection with influenza, also dependent on TMPRSS2, leads to a reduced viral load. The decreased viral load may be associated with an improved patient outcome. Because camostat mesylate is administered as an oral drug, it may be used in outpatients as well as inpatients at all disease stages of SARS-CoV-2 infection if it is shown to be an effective antiviral agent. Clinical trials are currently ongoing to test whether this well-known drug could be repurposed and utilized to combat the current pandemic. In the following, we will review current knowledge on camostat mesylate mode of action, potential benefits as an antiviral agent and ongoing clinical trials.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Esters/therapeutic use , Guanidines/therapeutic use , Serine Proteinase Inhibitors/therapeutic use , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Drug Repositioning , Esters/administration & dosage , Esters/adverse effects , Guanidines/administration & dosage , Guanidines/adverse effects , Humans , Mice , Patient Safety , Serine Endopeptidases/drug effects , Serine Proteinase Inhibitors/administration & dosage , Serine Proteinase Inhibitors/adverse effects
4.
Int J Infect Dis ; 102: 529-531, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-898988

ABSTRACT

Nafamostat, a serine proteinase inhibitor with various actions including antithrombin, antiplasmin, and antitrypsin effects, has been used in clinical practice to treat disseminated intravascular coagulation (DIC) and pancreatitis. This case report describes the clinical course of a patient with COVID-19 pneumonia whose severe hypoxemia, probably caused by DIC and pulmonary embolism, showed remarkable improvement with combination heparin and nafamostat therapy. In addition, beneficial mechanisms of nafamostat against COVID-19 and the necessity of attention to hyperkalemia as an adverse effect are discussed.


Subject(s)
Anticoagulants/administration & dosage , COVID-19/complications , Disseminated Intravascular Coagulation/drug therapy , Guanidines/administration & dosage , Aged , Benzamidines , Blood Coagulation/drug effects , COVID-19/blood , COVID-19/virology , Disseminated Intravascular Coagulation/blood , Disseminated Intravascular Coagulation/etiology , Disseminated Intravascular Coagulation/virology , Humans , Male , SARS-CoV-2/physiology
5.
J Infect Chemother ; 26(12): 1319-1323, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-695890

ABSTRACT

The number of people infected with severe acute respiratory syndrome coronavirus 2 is increasing globally, and some patients have a fatal clinical course. In light of this situation, the World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) a pandemic on March 11, 2020. While clinical studies and basic research on a treatment for COVID-19 are ongoing around the world, no treatment has yet been proven to be effective. Several clinical studies have demonstrated the efficacy of chloroquine phosphate and nafamostat mesylate with COVID-19. Here, we report the case of a Japanese patient with COVID-19 with severe respiratory failure who improved following the administration of hydroxychloroquine and continuous hemodiafiltlation with nafamostat mesylate. Hence, hydroxychloroquine with nafamostat mesylate might be a treatment option for severe COVID-19.


Subject(s)
Coronavirus Infections/drug therapy , Guanidines/administration & dosage , Hemodiafiltration/methods , Hydroxychloroquine/administration & dosage , Pneumonia, Viral/drug therapy , Aged , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Antiviral Agents/administration & dosage , Benzamidines , Betacoronavirus , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/therapy , Drug Combinations , Humans , Japan , Lopinavir/administration & dosage , Male , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/therapy , Respiratory Insufficiency/complications , Ritonavir/administration & dosage , SARS-CoV-2 , Treatment Outcome
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