ABSTRACT
BACKGROUND: High-intensity statin therapy is currently recommended initial guideline therapy in ACS treatment. However, only a minority of patients are achieving LDL-C attainment goal at 6 months. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are on recommended guideline therapy post-ACS if LDL-C goal attainment is not achieved after high-intensity statin (4-6 weeks) and after the addition of ezetimibe if guideline goal attainment is not achieved after an additional 4-6 weeks. Thus, it has been recommended that PCSK9 inhibitors be considered earlier post-ACS. However, the efficacy of early PCSK9 inhibitors initiation in ACS patients remains uncertain. METHODS: This systematic review and meta-analysis was conducted following PRISMA guidelines. Randomized controlled trials (RCTs) and observational studies involving ACS patients who received PCSK9 inhibitors within 48 h of hospitalization were included. Common and random effects models were used to evaluate the pooled effect of early PCSK9 inhibitor administration. Nine RCTs and three cohort studies were included. RESULTS: Early PCSK9 inhibitor administration reduced the incidence of MI, ACS hospitalization, and revascularization at 6-18 months post-ACS. Although there was a drift towards reduced stroke, all-cause mortality, and cardiovascular death, no statistically significant reduction was observed. Additionally, PCSK9 inhibitors significantly enhanced lipid control at 4-12 weeks after index hospitalization. CONCLUSION: Early PCSK9 inhibitors initiation in ACS patients reduces MACE and improves lipid profiles. While the results propose promising benefits in terms of stroke and mortality, further research with longer follow-up is required for more decisive evidence.
Subject(s)
Acute Coronary Syndrome , Biomarkers , PCSK9 Inhibitors , Humans , Acute Coronary Syndrome/drug therapy , Acute Coronary Syndrome/mortality , Acute Coronary Syndrome/blood , Acute Coronary Syndrome/diagnosis , Anticholesteremic Agents/adverse effects , Anticholesteremic Agents/administration & dosage , Anticholesteremic Agents/therapeutic use , Biomarkers/blood , Cholesterol, LDL/blood , Drug Administration Schedule , Dyslipidemias/drug therapy , Dyslipidemias/blood , Dyslipidemias/diagnosis , Dyslipidemias/mortality , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Myocardial Infarction/mortality , Myocardial Infarction/drug therapy , Myocardial Infarction/diagnosis , Myocardial Revascularization , Observational Studies as Topic , Randomized Controlled Trials as Topic , Risk Factors , Serine Proteinase Inhibitors/adverse effects , Serine Proteinase Inhibitors/therapeutic use , Serine Proteinase Inhibitors/administration & dosage , Time Factors , Treatment OutcomeABSTRACT
Aprotinin is a broad-spectrum inhibitor of human proteases that has been approved for the treatment of bleeding in single coronary artery bypass surgery because of its potent antifibrinolytic actions. Following the outbreak of the COVID-19 pandemic, there was an urgent need to find new antiviral drugs. Aprotinin is a good candidate for therapeutic repositioning as a broad-spectrum antiviral drug and for treating the symptomatic processes that characterise viral respiratory diseases, including COVID-19. This is due to its strong pharmacological ability to inhibit a plethora of host proteases used by respiratory viruses in their infective mechanisms. The proteases allow the cleavage and conformational change of proteins that make up their viral capsid, and thus enable them to anchor themselves by recognition of their target in the epithelial cell. In addition, the activation of these proteases initiates the inflammatory process that triggers the infection. The attraction of the drug is not only its pharmacodynamic characteristics but also the possibility of administration by the inhalation route, avoiding unwanted systemic effects. This, together with the low cost of treatment (≈2 Euro/dose), makes it a good candidate to reach countries with lower economic means. In this article, we will discuss the pharmacodynamic, pharmacokinetic, and toxicological characteristics of aprotinin administered by the inhalation route; analyse the main advances in our knowledge of this medication; and the future directions that should be taken in research in order to reposition this medication in therapeutics.
Subject(s)
Antiviral Agents , Aprotinin , COVID-19 Drug Treatment , SARS-CoV-2 , Aprotinin/therapeutic use , Aprotinin/pharmacology , Aprotinin/chemistry , Humans , Antiviral Agents/therapeutic use , Antiviral Agents/pharmacology , Antiviral Agents/administration & dosage , Administration, Inhalation , SARS-CoV-2/drug effects , COVID-19/virology , Animals , Drug Repositioning/methods , Serine Proteinase Inhibitors/therapeutic use , Serine Proteinase Inhibitors/pharmacology , Serine Proteinase Inhibitors/administration & dosageABSTRACT
BACKGROUND: There are limited effective prophylactic/early treatments for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Viral entry requires spike protein binding to the angiotensin-converting enzyme-2 receptor and cleavage by transmembrane serine protease 2 (TMPRSS2), a cell surface serine protease. Targeting of TMPRSS2 by either androgen blockade or direct inhibition is in clinical trials in early SARS-CoV-2 infection. METHODS: We used differentiated primary human airway epithelial cells at the air-liquid interface to test the impact of targeting TMPRSS2 on the prevention of SARS-CoV-2 infection. RESULTS: We first modelled the systemic delivery of compounds. Enzalutamide, an oral androgen receptor antagonist, had no impact on SARS-CoV-2 infection. By contrast, camostat mesylate, an orally available serine protease inhibitor, blocked SARS-CoV-2 entry. However, oral camostat is rapidly metabolised in the circulation, with poor airway bioavailability. We therefore modelled local airway administration by applying camostat to the apical surface of differentiated airway cultures. We demonstrated that a brief exposure to topical camostat effectively restricts SARS-CoV-2 infection. CONCLUSION: These experiments demonstrate a potential therapeutic role for topical camostat for pre- or post-exposure prophylaxis of SARS-CoV-2, which can now be evaluated in a clinical trial.
Subject(s)
Respiratory Mucosa/drug effects , Respiratory Mucosa/metabolism , Respiratory Mucosa/virology , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/administration & dosage , Administration, Topical , Androgens/metabolism , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , COVID-19/prevention & control , COVID-19/virology , Cells, Cultured , Epithelial Cells , Esters/pharmacology , Gene Expression , Goblet Cells/immunology , Goblet Cells/metabolism , Guanidines/pharmacology , Host-Pathogen Interactions/drug effects , Humans , Serine Endopeptidases/genetics , Signal Transduction , Virus Internalization/drug effects , Virus Replication/drug effectsABSTRACT
This study aimed to evaluate the effects of nafamostat, a serin protease inhibitor, in the management of subarachnoid hemorrhage (SAH). SAH was induced by endovascular perforation in male mice. Nafamostat was administered intraperitoneally four times immediately after SAH induction. Cerebral blood flow, neurological behavior tests, SAH grade and protein expression were evaluated at 24 h after SAH induction. In the in vitro model, human brain microvascular endothelial cells (HBMVECs), HBVECs were exposed to thrombin and hypoxia for 24 h; nafamostat was administered and the protein expression was evaluated. Eighty-eight mice were included in the in vivo study. Fifteen mice (17%) were excluded because of death or procedure failure. Nafamostat exerted no significant effect on the SAH grade or cerebral blood flow; however, it improved the neurological behavior and suppressed the thrombin and MMP-9 expression. In addition, nafamostat suppressed the ICAM-1 expression and p38 phosphorylation in the in vitro study. Nafamostat has a protective effect against HBMVEC after exposure to thrombin and hypoxia, suggesting its role in improving the neurological outcomes after SAH. These findings indicate that nafamostat has the potential to be a novel therapeutic drug in the management of SAH.
Subject(s)
Benzamidines/administration & dosage , Brain Injuries/etiology , Brain Injuries/prevention & control , Guanidines/administration & dosage , Serine Proteinase Inhibitors/administration & dosage , Subarachnoid Hemorrhage/complications , Subarachnoid Hemorrhage/drug therapy , Animals , Benzamidines/pharmacology , Brain/cytology , Brain Injuries/genetics , Cells, Cultured , Cerebrovascular Circulation , Disease Models, Animal , Endothelial Cells/metabolism , Gene Expression/drug effects , Gene Expression/genetics , Guanidines/pharmacology , Humans , Infusions, Parenteral , Intercellular Adhesion Molecule-1/genetics , Intercellular Adhesion Molecule-1/metabolism , Male , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , Mice, Inbred Strains , Serine Proteinase Inhibitors/pharmacology , Subarachnoid Hemorrhage/genetics , Thrombin/genetics , Thrombin/metabolismABSTRACT
Treatment with aprotinin, a broad-spectrum serine protease inhibitor with a molecular weight of 6512 Da, was associated with acute kidney injury, which was one of the reasons for withdrawal from the market in 2007. Inhibition of renal serine proteases regulating the epithelial sodium channel ENaC could be a possible mechanism. Herein, we studied the effect of aprotinin in wild-type 129S1/SvImJ mice on sodium handling, tubular function, and integrity under a control and low-salt diet. Mice were studied in metabolic cages, and aprotinin was delivered by subcutaneously implanted sustained release pellets (2 mg/day over 10 days). Mean urinary aprotinin concentration ranged between 642 ± 135 (day 2) and 127 ± 16 (day 8) µg/mL . Aprotinin caused impaired sodium preservation under a low-salt diet while stimulating excessive hyperaldosteronism and unexpectedly, proteolytic activation of ENaC. Aprotinin inhibited proximal tubular function leading to glucosuria and proteinuria. Plasma urea and cystatin C concentration increased significantly under aprotinin treatment. Kidney tissues from aprotinin-treated mice showed accumulation of intracellular aprotinin and expression of the kidney injury molecule 1 (KIM-1). In electron microscopy, electron-dense deposits were observed. There was no evidence for kidney injury in mice treated with a lower aprotinin dose (0.5 mg/day). In conclusion, high doses of aprotinin exert nephrotoxic effects by accumulation in the tubular system of healthy mice, leading to inhibition of proximal tubular function and counterregulatory stimulation of ENaC-mediated sodium transport.
Subject(s)
Aprotinin/metabolism , Kidney Tubules/metabolism , Serine Proteinase Inhibitors/metabolism , Animals , Aprotinin/administration & dosage , Aprotinin/adverse effects , Dose-Response Relationship, Drug , Female , Injections, Subcutaneous , Kidney Tubules/pathology , Male , Mice , Mice, Transgenic , Molecular Structure , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/administration & dosage , Serine Proteinase Inhibitors/adverse effects , Structure-Activity RelationshipABSTRACT
Purpose: Traumatic brain injury (TBI) remains a major public health problem and cause of death. Ulinastatin (UTI), a serine protease inhibitor, has been reported to have an anti-inflammatory effect and play a role in immunoregulation and organ protection by reducing reactive oxygen species (ROS) production, oxidative stress and inflammation. However, the neuroprotective of UTI in TBI has not been confirmed. Therefore, this study aimed to investigate the neuroprotection and potential molecular mechanisms of UTI in TBI-induced EBI in a C57BL/6 mouse model. Methods: The neurological score and brain water content were evaluated. Enzyme-linked immunosorbent assay was used to detect neuroinflammatory cytokine levels, ROS and malondialdehyde detection to evaluate oxidative stress levels, and TUNEL staining and western blotting to examine neuronal damages and their related mechanisms. Results: Treatment with UTI markedly increased the neurological score; alleviated brain oedema; decreased the inflammatory cytokine tumour necrosis factor a, interleukin-1ß (IL-1ß), IL-6 and nuclear factor kappa B (NF-kB) levels; inhibited oxidative stress; decreased caspase-3 and Bax protein expressions; and increased the Bcl-2 levels, indicating that UTI-mediated inhibition of neuroinflammation, oxidative stress and apoptosis ameliorated neuronal death after TBI. The neuroprotective capacity of UTI is partly dependent on the TLR4/NF-kB/p65 signalling pathway. Conclusions: Therefore, this study reveals that UTI improves neurological outcomes in mice and reduces neuronal death by protecting against neural neuroinflammation, oxidative stress and apoptosis.
Subject(s)
Animals , Mice , Brain Injuries/therapy , Serine Proteinase Inhibitors/administration & dosage , Serine Proteinase Inhibitors/therapeutic use , Apoptosis , Oxidative StressABSTRACT
Background: Hereditary angioedema (HAE) is a rare genetic disorder characterized by unpredictable and potentially life-threatening episodes of swelling in various parts of the body. These attacks can be painful and debilitating, and affect a patient's quality of life. Every patient who experiences an attack should be treated with on-demand medication to mitigate attack severity and duration. Many patients with HAE also receive long-term prophylaxis to reduce the frequency and severity of edema episodes. Although long-term prophylaxis reduces the disease burden for patients with HAE, available intravenous and subcutaneous treatments are accompanied by a significant treatment burden because of the logistical, emotional, and physical challenges posed by their long-term parenteral nature. Androgens are an effective oral prophylactic treatment; however, they are associated with significant adverse events and are not suitable for all patients. Thus, the HAE community has expressed interest in the development of alternative oral prophylactic therapies for preventing HAE attacks. Objective: Here, we review the phase II and III clinical data of berotralstat (BCX7353), which was approved by the U.S. Food and Drug Administration in December 2020. Results: Berotralstat is an oral, second-generation, synthetic, small-molecule plasma kallikrein inhibitor taken once daily for the prevention of HAE attacks in patients ages ≥ 12 years. Results from the APeX studies (APeX-1 NCT02870972, APeX-2 NCT03485911, APeX-S NCT03472040, APex-J NCT03873116) demonstrated the efficacy of berotralstat as long-term prophylaxis for patients with HAE, which showed a reduction in the attack rate and on-demand medication usage. Berotralstat was well tolerated, and gastrointestinal treatment-emergent adverse events were generally mild and self-limited. Conclusion: Oral berotralstat is an effective and safe long-term prophylactic treatment for patients with HAE that will provide patients unable to tolerate parenteral therapies with the option of disease control. Berotralstat may be associated with reduced treatment burden compared with injectable therapies, highlighting the importance of patient preference with regard to the administration route of their HAE prophylactic treatment.
Subject(s)
Angioedemas, Hereditary/prevention & control , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Pyrazoles/administration & dosage , Serine Proteinase Inhibitors/administration & dosage , Administration, Oral , Humans , Treatment OutcomeABSTRACT
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 Treatment , 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 AdultABSTRACT
BACKGROUND: While circulating levels of alpha1 -proteinase inhibitor (alpha1 -PI) are typically normal, antiprotease activity appears to be compromised in patients with Type 1 diabetes mellitus (T1DM). Because alpha1 -PI [human] (alpha1 -PI[h]) therapy can inhibit pro-inflammatory mediators associated with ß-cell destruction and reduced insulin production, it has been proposed for T1DM disease prevention. The aim of this study was to evaluate safety, tolerability, and efficacy of intravenous (IV) alpha1 -PI[h] in preserving C-peptide production in newly diagnosed T1DM patients. PARTICIPANTS: Seventy-six participants (aged 6-35 years) were randomized at 25 centers within 3 months of T1DM diagnosis. METHODS: A Phase II, multicenter, partially blinded, placebo-controlled, proof-of-concept study evaluating four dosing regimens of alpha1 -PI[h] (NCT02093221, GTI1302): weekly IV infusions of either 90 or 180 mg/kg, each for either 13 or 26 weeks. Safety and efficacy were monitored over 52 weeks with an efficacy evaluation planned at 104 weeks. The primary efficacy endpoint was change from baseline in the 2-h area-under-the-curve C-peptide level from a mixed-meal tolerance test at 52 weeks. A battery of laboratory tests, including inflammatory biomarkers, constituted exploratory efficacy variables. RESULTS: Infusions were well tolerated with no new safety signals. All groups exhibited highly variable declines in the primary outcome measure at 52 weeks with no statistically significant difference from placebo. Interleukin-6 (IL-6) was reduced from baseline in all alpha1 -PI treatment groups but not the placebo group. CONCLUSION: Pharmacologic therapy with alpha1 -PI[h] is safe, well tolerated, and able to reduce IL-6 levels; however, due to variability in the efficacy endpoint, its effects on preservation of C-peptide production were inconclusive.
Subject(s)
Diabetes Mellitus, Type 1/drug therapy , Serine Proteinase Inhibitors/administration & dosage , alpha 1-Antitrypsin/administration & dosage , Adolescent , Adult , C-Peptide/blood , Child , Diabetes Mellitus, Type 1/blood , Drug Administration Schedule , Female , Humans , Infusions, Intravenous , Interleukin-6/blood , Male , Proof of Concept Study , Serine Proteinase Inhibitors/pharmacokinetics , Treatment Outcome , Young Adult , alpha 1-Antitrypsin/pharmacokineticsABSTRACT
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 Treatment , 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 effectsABSTRACT
To date, no effective vaccines or therapies are available against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pandemic agent of the coronavirus disease 2019 (COVID-19). Due to their safety, efficacy and specificity, peptide inhibitors hold great promise for the treatment of newly emerging viral pathogens. Based on the known structures of viral proteins and their cellular targets, antiviral peptides can be rationally designed and optimized. The resulting peptides may be highly specific for their respective targets and particular viral pathogens or exert broad antiviral activity. Here, we summarize the current status of peptides inhibiting SARS-CoV-2 entry and outline the strategies used to design peptides targeting the ACE2 receptor or the viral spike protein and its activating proteases furin, transmembrane serine protease 2 (TMPRSS2), or cathepsin L. In addition, we present approaches used against related viruses such as SARS-CoV-1 that might be implemented for inhibition of SARS-CoV-2 infection.
Subject(s)
Antiviral Agents/administration & dosage , COVID-19 Drug Treatment , COVID-19/metabolism , Peptide Fragments/administration & dosage , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Amino Acid Sequence , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Drug Delivery Systems/methods , Humans , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Protein Binding/drug effects , Protein Binding/physiology , Protein Structure, Secondary , Protein Structure, Tertiary , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/administration & dosage , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/metabolismABSTRACT
Dry eye syndrome (DES), a multifactorial disorder which leads to ocular discomfort, visual disturbance and tear film instability, has a rising prevalence and limited treatment options. In this study, a newly developed trypsin-like serine protease inhibitor (UAMC-00050) in a tear drop formulation was evaluated to treat ocular inflammation. A surgical animal model of dry eye was employed to investigate the potential of UAMC-00050 on dry eye pathology. Animals treated with UAMC-00050 displayed a significant reduction in ocular surface damage after evaluation with sodium fluorescein, compared to untreated, vehicle treated and cyclosporine-treated animals. The concentrations of IL-1α and TNF-α were also significantly reduced in tear fluid from UAMC-00050-treated rats. Additionally, inflammatory cell infiltration in the palpebral conjunctiva (CD3 and CD45), was substantially reduced. An accumulation of pro-MMP-9 and a decrease in active MMP-9 were found in tear fluid from animals treated with UAMC-00050, suggesting that trypsin-like serine proteases play a role in activating MMP-9 in ocular inflammation in this animal model. Comparative qRT-PCR analyses on ocular tissue indicated the upregulation of tryptase, urokinase plasminogen activator receptor (uPAR) and protease-activated receptor 2 (PAR2). The developed UAMC-00050 formulation was stable up to 6 months at room temperature in the absence of light, non-irritating and sterile with compatible pH and osmolarity. These results provide a proof-of-concept for the in vivo modifying potential of UAMC-00050 on dry eye pathology and suggest a central role of trypsin-like serine proteases and PAR2 in dry eye derived ocular inflammation.
Subject(s)
Dry Eye Syndromes/drug therapy , Dry Eye Syndromes/immunology , Serine Proteinase Inhibitors/administration & dosage , Animals , Conjunctiva/drug effects , Conjunctiva/immunology , Disease Models, Animal , Dry Eye Syndromes/genetics , Humans , Interleukin-1alpha/genetics , Interleukin-1alpha/immunology , Male , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/immunology , Rats , Rats, Wistar , Serine Proteinase Inhibitors/chemistry , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunologyABSTRACT
COVID-19 emerged in December 2019 in China, and since then, has disrupted global public health and changed economic paradigms. In dealing with the new Coronavirus, SARS-CoV-2, the world has not faced such extreme global fragility since the "Spanish flu" pandemic in 1918. Researchers globally are dedicating efforts to the search for an effective treatment for COVID-19. Drugs already used in a clinical setting for other pathologies have been tested as a new therapeutic approach against SARS-CoV-2, setting off a frenzy over the preliminary data of different studies. This work aims to compile and discuss the data published thus far. Despite the potential effects of some antivirals and antiparasitic against COVID-19, clinical studies must confirm real effectiveness. However, non-pharmacological approaches have proven to be the most efficient strategy to date.
Subject(s)
Anti-Bacterial Agents/administration & dosage , Antiparasitic Agents/administration & dosage , Antiviral Agents/administration & dosage , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Macrolides/administration & dosage , Pneumonia, Viral/drug therapy , Serine Proteinase Inhibitors/administration & dosage , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antiparasitic Agents/chemistry , Antiparasitic Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19 , Humans , Macrolides/chemistry , Macrolides/pharmacology , Pandemics , SARS-CoV-2 , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacologyABSTRACT
PURPOSE: During the alirocumab open-label extension study ODYSSEY OLE (open-label extension; NCT01954394), physicians could adjust alirocumab dosing for enrolled patients, who were diagnosed with heterozygous familial hypercholesterolemia (HeFH) and who had completed previous phase III clinical trials with alirocumab. This post hoc analysis evaluated the differences in physician-patient dosing decisions between the regions of Western Europe, Eastern Europe, North America, and the rest of the world (ROW). METHODS: Patients (n = 909) who received starting dose alirocumab 75 mg every 2 weeks (Q2W) during ODYSSEY OLE (patients from FH I, FH II, and LONG TERM parent studies) were included. Low-density lipoprotein cholesterol (LDL-C) levels were blinded until week 8; subsequently, LDL-C values were communicated to physicians. From week 12, dose adjustment from 75 to 150 mg Q2W, or vice versa, was possible. RESULTS: Mean LDL-C values used for the decision to increase dose from 75 to 150 mg Q2W were higher in Eastern Europe (3.7 mmol/L; 144.0 mg/dL) and ROW (3.8 mmol/L; 145.2 mg/dL) compared with Western Europe (3.1 mmol/L; 118.6 mg/dL) and North America (3.3 mmol/L; 126.6 mg/dL). Irrespective of region, the mean LDL-C at the time of decision to maintain at 75 mg Q2W was approximately 1.8 mmol/L (70 mg/dL). During ODYSSEY OLE (median treatment duration of 131.7 weeks), alirocumab was shown to have no unexpected long-term safety concerns. CONCLUSIONS: In this OLE study, the observed variations in clinical treatment decisions suggest that physicians may perceive the severity of HeFH and/or the treatment of HeFH differently depending on their region.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Anticholesteremic Agents/administration & dosage , Healthcare Disparities/trends , Hyperlipoproteinemia Type II/drug therapy , Practice Patterns, Physicians'/trends , Serine Proteinase Inhibitors/administration & dosage , Adult , Aged , Antibodies, Monoclonal, Humanized/adverse effects , Anticholesteremic Agents/adverse effects , Biomarkers/blood , Cholesterol, LDL/blood , Drug Dosage Calculations , Drug Utilization/trends , Female , Genetic Predisposition to Disease , Heterozygote , Humans , Hyperlipoproteinemia Type II/blood , Hyperlipoproteinemia Type II/diagnosis , Hyperlipoproteinemia Type II/genetics , Male , Middle Aged , PCSK9 Inhibitors , Phenotype , Serine Proteinase Inhibitors/adverse effectsSubject(s)
Angioedemas, Hereditary , Bradykinin/blood , Kallikreins , Serine Proteinase Inhibitors/administration & dosage , Administration, Oral , Adult , Angioedemas, Hereditary/blood , Angioedemas, Hereditary/drug therapy , Double-Blind Method , Humans , Kallikreins/antagonists & inhibitors , Kallikreins/blood , Male , Serine Proteinase Inhibitors/adverse effectsSubject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Coronary Artery Disease/therapy , Dyslipidemias/drug therapy , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Percutaneous Coronary Intervention , Plaque, Atherosclerotic , Rosuvastatin Calcium/administration & dosage , Serine Proteinase Inhibitors/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Biomarkers/blood , Cholesterol, LDL/blood , Coronary Artery Disease/diagnostic imaging , Drug Therapy, Combination , Dyslipidemias/blood , Dyslipidemias/diagnosis , Fibrosis , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , PCSK9 Inhibitors , Percutaneous Coronary Intervention/adverse effects , Percutaneous Coronary Intervention/instrumentation , Prospective Studies , Rosuvastatin Calcium/adverse effects , Serine Proteinase Inhibitors/adverse effects , Stents , Time Factors , Tomography, Optical Coherence , Treatment OutcomeABSTRACT
Matriptase is a type II transmembrane serine protease, which has been suggested to play critical roles in numerous pathways of biological developments. Matriptase is the activator of several oncogenic proteins, including urokinase-type plasminogen activator (uPA), hepatocyte growth factor (HGF) and protease-activated receptor 2 (PAR-2). The activations of these matriptase substrates subsequently lead to the generation of plasmin, matrix metalloproteases (MMPs), and the triggers for many other signaling pathways related to cancer proliferation and metastasis. Accordingly, matriptase is considered an emerging target for the treatments of cancer. Thus far, inhibitors of matriptase have been developed as potential anti-cancer agents, which include small-molecule inhibitors, peptide-based inhibitors, and monoclonal antibodies. This review covers established literature to summarize the chemical and biochemical aspects, especially the inhibitory mechanisms and structure-activity relationships (SARs) of matriptase inhibitors with the goal of proposing the strategies for their future developments in anti-cancer therapy.
Subject(s)
Neoplasms/drug therapy , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/pharmacology , Animals , Cell Proliferation/drug effects , Humans , Molecular Targeted Therapy , Neoplasm Metastasis , Neoplasms/enzymology , Neoplasms/pathology , Serine Endopeptidases/chemistry , Serine Proteinase Inhibitors/administration & dosage , Small Molecule Libraries/pharmacologyABSTRACT
This manuscript describes the discovery of a series of macrocyclic inhibitors of FXIa with oral bioavailability. Assisted by structure based drug design and ligand bound X-ray crystal structures, the group linking the P1 moiety to the macrocyclic core was modified with the goal of reducing H-bond donors to improve pharmacokinetic performance versus 9. This effort resulted in the discovery of several cyclic P1 linkers, exemplified by 10, that are constrained mimics of the bioactive conformation displayed by the acrylamide linker of 9. These cyclic P1 linkers demonstrated enhanced bioavailability and improved potency.
Subject(s)
Drug Design , Drug Discovery , Factor XIa/antagonists & inhibitors , Macrocyclic Compounds/administration & dosage , Macrocyclic Compounds/chemistry , Serine Proteinase Inhibitors/administration & dosage , Serine Proteinase Inhibitors/chemistry , Administration, Oral , Biological Availability , Humans , Ligands , Macrocyclic Compounds/pharmacology , Models, Molecular , Molecular Structure , Serine Proteinase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
Elevated expression of transmembrane serine protease 4 (TMPRSS4) correlates with poor prognosis in non-small cell lung cancer, gastric cancer, colorectal cancer, prostate cancer, and other cancer patients. Previously, we demonstrated that TMPRSS4 mediates tumor cell invasion, migration, proliferation, and metastasis. In addition, we reported novel 2-hydroxydiarylamide derivatives, IMD-0354 and KRT1853, as TMPRSS4 serine protease inhibitors. Here, we further evaluated the effects of the representative derivatives on TMPRSS4-mediated cellular function and signaling. IMD-0354 and KRT1853 inhibited cancer cell invasion, migration, and proliferation in TMPRSS4-expressing prostate, colon, and lung cancer cells. Both compounds suppressed TMPRSS4-mediated induction of Sp1/3, AP-1, and NF-κB transcription factors. Furthermore, TMPRSS4 promoted cancer cell survival and drug resistance, and both compounds enhanced anoikis sensitivity as well as reduced bcl-2 and survivin levels. Importantly, KRT1853 efficiently reduced tumor growth in prostate and colon cancer xenograft models. These results strongly recommend KRT1853 for further development as a novel anti-cancer agent.
Subject(s)
Benzamides/administration & dosage , Colorectal Neoplasms/drug therapy , Lung Neoplasms/drug therapy , Prostatic Neoplasms/drug therapy , Serine Proteinase Inhibitors/administration & dosage , Animals , Benzamides/chemistry , Benzamides/pharmacology , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Colorectal Neoplasms/metabolism , Female , HCT116 Cells , HeLa Cells , Humans , Lung Neoplasms/metabolism , Male , Membrane Proteins/antagonists & inhibitors , Prostatic Neoplasms/metabolism , Serine Endopeptidases , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Signal Transduction/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) reduce cardiovascular events in coronary artery disease (CAD). Their costs exceed that of established oral lipid-lowering agents. Previous cost-effectiveness assessments have been inconsistent. Markov cohort state transitions models for stable CAD patients were calculated using information from 1530 participants of the Ludwigshafen Risk and Cardiovascular Health Study (LURIC) with known causes of deaths. Non-fatal to fatal event rates, drug prices, direct treatment costs, and utility weights were from public sources. At an assumed relative risk reduction of 32.5% and an annual drug price of 8500 Euros, QALYs gained were 1.23 and 1.20, savings were 2390 and 2410 Euros, and ICERs were 112,530 and 108,660 Euros in women and men, respectively. When the annual cost of this medication was set at 1600 Euros, corresponding ICERs were 21,180 and 20,450 Euros. PCSK9i treatment is cost-effective in stable CAD at a threshold of 150,000 Euro and annual costs of 8500 Euros. As the broad use of PCSK9i therapy in CAD would have a disruptive impact on the healthcare budget, treatment should be focused on very high risk patients (≥3 comorbidities, annual risk of 10%); alternatively, and for lower risk, significant cost reductions would be needed.