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1.
Cancer Metastasis Rev ; 38(3): 507-524, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31471691

RESUMO

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.


Assuntos
Neoplasias/tratamento farmacológico , Serina Endopeptidases/metabolismo , Inibidores de Serino Proteinase/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular , Metástase Neoplásica , Neoplasias/enzimologia , Neoplasias/patologia , Serina Endopeptidases/química , Inibidores de Serino Proteinase/administração & dosagem , Bibliotecas de Moléculas Pequenas/farmacologia
2.
Med Mycol ; 57(8): 1024-1037, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30753649

RESUMO

Candida parapsilosis sensu stricto (C. parapsilosis) has emerged as the second/third commonest Candida species isolated from hospitals worldwide. Candida spp. possess numerous virulence attributes, including peptidases that play multiple roles in both physiological and pathological events. So, fungal peptidases are valid targets for new drugs development. With this premise in mind, we have evaluated the effect of serine peptidase inhibitors (SPIs) on both cell biology and virulence aspects of C. parapsilosis. First, five different SPIs, phenylmethylsulfonyl fluoride, benzamidine, 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride, N-α-tosyl-L-lysine chloromethyl ketone hydrochloride, and N-tosyl-L-phenylalanine chloromethyl ketone (TPCK) were tested, and TPCK showed the best efficacy to arrest fungal growth. Subsequently, the ability of TPCK to modulate physiopathological processes was investigated. Overall, TPCK was able to (i) inhibit the cell-associated serine peptidase activities, (ii) promote morphometric and ultrastructural alterations, (iii) induce an increase in the intracellular oxidation level, which culminates in a vigorous lipid peroxidation and accumulation of neutral lipids in cytoplasmic inclusions, (iv) modulate the expression/exposition of surface structures, such as mannose/glucose-rich glycoconjugates, N-acetylglucosamine-containing molecules, chitin, polypeptides and surface aspartic peptidases, (v) reduce the adhesion to either polystyrene or glass surfaces as well as to partially disarticulate the mature biofilm, (vi) block the fungal interaction with macrophages, and (vii) protect Galleria mellonella from fungal infection, enhancing larvae survivability. Altogether, these results demonstrated that TPCK induced several changes over fungal biology besides the interference with aspects associated to C. parapsilosis virulence and pathogenesis, which indicates that SPIs could be novel promising therapeutic agents in dealing with candidiasis.


Assuntos
Antifúngicos/farmacologia , Candida parapsilosis/efeitos dos fármacos , Candidíase/prevenção & controle , Inibidores de Serino Proteinase/farmacologia , Tosilfenilalanil Clorometil Cetona/farmacologia , Animais , Antifúngicos/administração & dosagem , Candida parapsilosis/citologia , Candida parapsilosis/crescimento & desenvolvimento , Adesão Celular/efeitos dos fármacos , Modelos Animais de Doenças , Larva/microbiologia , Lepidópteros/microbiologia , Estresse Oxidativo , Inibidores de Serino Proteinase/administração & dosagem , Análise de Sobrevida , Tosilfenilalanil Clorometil Cetona/administração & dosagem , Resultado do Tratamento , Virulência/efeitos dos fármacos
3.
Respir Investig ; 57(1): 89-96, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30416054

RESUMO

BACKGROUND: Alpha1-Proteinase Inhibitor, Modified Process (Alpha-1 MP) is used for augmentation therapy in alpha1-antitrypsin deficiency (AATD), an extremely rare disease in Japan. Weekly doses of 60 mg/kg Alpha-1 MP have been shown to be safe and well tolerated in non-Japanese subjects, but the safety and pharmacokinetics (PK) have not been evaluated in Japanese subjects. The objectives of this study were to evaluate the safety and PK of 60 mg/kg Alpha-1 MP administered by weekly IV infusions over 8 weeks in Japanese subjects with AATD. METHODS: This was a multicenter, open-label trial in Japanese adults aged ≥20 years with AATD. Samples for evaluation of serum alpha1-PI concentration and PK parameters were collected at 10 time points until the seventh day after the last dose at Week 8: immediately before dosing, immediately after dosing (time 0), and 0.25, 2, 4, 8, 24, 48, 120, and 168 hours after dosing. RESULTS: Four subjects were analyzed. The median tmax was 0.534 h. Mean ± SD values for t½, Cmax, and AUC0-7days were 150.4 ± 36.18 h, 174.2 ± 30.51 mg/dL, and 14,913.2 ± 1633.45 mg*h/dL, respectively. Mean trough concentration at week 8 was 55.4 ± 7.23 mg/dL. Alpha-1 MP therapy was safe, with no serious adverse events or deaths reported. Two treatment-emergent adverse events of fatigue in one subject were considered to be possibly related. CONCLUSIONS: The PK and safety of Alpha-1 MP in Japanese subjects with AATD were consistent with the Alpha-1 MP profile in non-Japanese subjects (ClinicalTrials.gov: NCT02870309; JAPIC CTI: JapicCTI-163160).


Assuntos
Inibidores de Serino Proteinase/administração & dosagem , Inibidores de Serino Proteinase/farmacocinética , Deficiência de alfa 1-Antitripsina/tratamento farmacológico , alfa 1-Antitripsina/administração & dosagem , alfa 1-Antitripsina/farmacocinética , Idoso , Grupo com Ancestrais do Continente Asiático , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Segurança , Fatores de Tempo , Deficiência de alfa 1-Antitripsina/metabolismo
4.
Vasc Health Risk Manag ; 14: 409-418, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30573963

RESUMO

Purpose: To describe patient characteristics and treatment patterns among early initiators of proprotein convertase subtilisin/kexin type nine inhibitors (PCSK9is) who initiated treatment within the first 6 months of market availability. Patients and methods: This retrospective cohort study used IQVIA's longitudinal open-source point-of-sale pharmacy claims database (LRx) and PharMetrics Plus (P+) health plan claims database to identify patients initiating a PCSK9i between January 1, 2016 and June 30, 2016. The index date was defined as the date of the first PCSK9i prescription (index claim) during the enrollment window; patients were followed for ≥6 months postindex. Patient characteristics including use of baseline lipid-lowering therapy (LLT) and measures such as persistence and adherence to PCSK9i therapy were evaluated with respect to health plan type (commercial vs Medicare). Results: Overall, patients initiating PCSK9i (n=13,151) had a mean age of 66 years, and 51% were male. Approximately 67.4% of patients used some form of LLT (statin and/or ezetimibe) in the 24 months prior to initiating PCSK9i therapy. The proportion of patients covered by a commercial health plan (51.2%) was similar to that covered by Medicare (48.8%). Persistence on PCSK9i was marginally longer for patients with commercial insurance than Medicare (mean days on therapy 202.2 vs 198.5). Overall, 42.6% of patients discontinued their PCSK9i during the 180 days of follow-up. Conclusion: This study demonstrates that a large proportion of patients discontinue PCSK9i therapy at 30 and 90 days, which are the time frames for which many health plans require recertification to continue access to PCSK9i. Future studies looking at treatment patterns among patients who initiate PCSK9i therapy after the first 180 days once health plan formularies and utilization management criteria were finalized are needed to understand more comprehensively real-world PCSK9i usage patterns.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Aterosclerose/prevenção & controle , LDL-Colesterol/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Padrões de Prática Médica/tendências , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/administração & dosagem , Demandas Administrativas em Assistência à Saúde , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/efeitos adversos , Aterosclerose/sangue , Aterosclerose/diagnóstico , Aterosclerose/enzimologia , Biomarcadores/sangue , Bases de Dados Factuais , Esquema de Medicação , Quimioterapia Combinada , Feminino , Formulários Farmacêuticos como Assunto , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/enzimologia , Masculino , Medicare/tendências , Pessoa de Meia-Idade , Pró-Proteína Convertase 9/metabolismo , Estudos Retrospectivos , Inibidores de Serino Proteinase/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Adulto Jovem
5.
Rev Cardiovasc Med ; 19(S1): S20-S24, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30207554

RESUMO

Cardiovascular disease mortality rates have begun to rise in the United States. Based on the large body of supportive evidence, we propose a proof-of-concept, first-in-human trial to cure atherosclerosis: CURing Early ATHEROsclerosis (CURE ATHERO). This trial is based on a model of intensive induction therapy for extensive, if not complete, plaque regression, followed by intermittent maintenance therapy. An extensive body of evidence has demonstrated the causal role of apolipoprotein B lipoproteins in atherosclerosis progression and data suggest intensive low-density lipoprotein cholesterol (LDL-C) lowering may have a substantial impact on earlier stages of atherosclerosis. Compared with lifetime treatment to prevent atherosclerosis progression, this induction-intermittent treatment model will minimize costs and maximize adherence and safety.


Assuntos
Anticolesterolemiantes/administração & dosagem , Aterosclerose/tratamento farmacológico , LDL-Colesterol/sangue , Dislipidemias/tratamento farmacológico , Anticolesterolemiantes/efeitos adversos , Apolipoproteína B-100/sangue , Aterosclerose/sangue , Aterosclerose/diagnóstico , Aterosclerose/epidemiologia , Biomarcadores/sangue , Esquema de Medicação , Quimioterapia Combinada , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Placa Aterosclerótica , Pró-Proteína Convertase 9/antagonistas & inibidores , Pró-Proteína Convertase 9/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Inibidores de Serino Proteinase/administração & dosagem , Fatores de Tempo , Resultado do Tratamento
6.
Parasit Vectors ; 11(1): 499, 2018 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-30189888

RESUMO

BACKGROUND: Trichinella spiralis serine protease inhibitor (TsSPI) was identified in ES proteins of adult worms (AW), the TsSPI gene was highly expressed at enteral stage worms (AW and newborn larvae), distributed mainly in the cuticle and stichosome of this nematode. Vaccination of mice with rTsSPI exhibited a 62.2% reduction of intestinal AW and a 57.25% reduction of muscle larvae after larval challenge. The aim of this study was to investigate the biological characteristics of TsSPI and its roles in the process of T. spiralis invasion of host's intestinal epithelium cells (IECs). METHODS: The rTsSPI inhibition on trypsin enzymatic activity was detected by SDS-PAGE and spectrophotometry. The binding of rTsSPI with intestinal epithelium from normal mice and the primary cultured mouse intestinal epithelium cells (IECs) was examined by indirect immunofluorescent (IIF), the cellular localization of rTsSPI binding to IECs was observed by confocal microscopy. The inhibition of anti-rTsSPI serum on T. spiralis invasion of IECs was determined by an in vitro invasion assay. Anti-rTsSPI antibody cytotoxicity on the newborn larvae (NBL) was also determined. RESULTS: The rTsSPI had the inhibitory activity against porcine trypsin. The rTsSPI specifically bound to the intestinal epithelium from normal mice and primary cultured mouse IECs, and the binding sites were located in IEC membrane and cytoplasm. Anti-rTsSPI antibodies depressed the larval invasion of IECs with a dose-dependent mode. Anti-rTsSPI antibodies also participated in the destruction of T. spiralis NBL via an ADCC-mediated manner. CONCLUSIONS: TsSPI might participate in the T. spiralis larval invasion of IECs and it is likely the potential vaccine target against T. spiralis enteral stages.


Assuntos
Interações Hospedeiro-Parasita , Mucosa Intestinal/parasitologia , Larva/fisiologia , Inibidores de Serino Proteinase/genética , Trichinella spiralis/química , Triquinelose/prevenção & controle , Animais , Anticorpos Anti-Helmínticos/sangue , Contagem de Células , Linhagem Celular , Feminino , Proteínas de Helminto/administração & dosagem , Proteínas de Helminto/imunologia , Intestino Delgado/citologia , Intestino Delgado/parasitologia , Larva/genética , Camundongos , Camundongos Endogâmicos BALB C , Carga Parasitária , Inibidores de Serino Proteinase/administração & dosagem , Inibidores de Serino Proteinase/imunologia , Inibidores de Serino Proteinase/metabolismo , Trichinella spiralis/imunologia , Trichinella spiralis/metabolismo , Triquinelose/imunologia , Vacinas/administração & dosagem , Vacinas/imunologia
7.
J Cardiovasc Med (Hagerstown) ; 19(9): 485-490, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29917002

RESUMO

AIMS: The analysis evaluated the contemporary percentage of patients with established coronary heart disease (CHD) reaching the European guidelines recommended LDL-cholesterol (LDL-C) levels of less than 70 mg/dl and the threshold required for proprotein convertase subtlisin/kexin type 9 reimbursement in Italy (100 mg/dl). It also assessed how these percentages would change in case of diffuse use of ezetimibe. METHODS: The Dyslipidemia International Study II enrolled CHD patients aged at least 18 either on lipid-lowering therapy (LLT) for at least 3 months or not on LLT at the time of the lipid profile. Distribution of LLTs and LDL-C target attainment were assessed. Multivariate logistic regression evaluated predictors of LDL-C target attainment. A 24% LDL-C lowering was modeled in patients not taking ezetimibe to assess its potential effects. RESULTS: Among 676 Italian CHD patients enrolled, LDL-C concentrations were lower among the 631 patients (93.3%) who were on LLT (82 versus 118 mg/dl; P < 0.001). The LDL-C target was attained by 35.4% of patients. Statin dose (median atorvastatin dose 40 mg/day) was the sole significant predictor of LDL-C target attainment. The simple addition of ezetimibe in the model reduced the percentage of patients more than 70 and 100 mg/dl from 64.6 to 37.9% and from 25.1 to 11.8%, respectively. CONCLUSION: Despite treatment in more than 90%, only one-third of Italian stable CHD patients attained the recommended LDL-C target. Statin dose was the sole predictor of the target achievement. The addition of ezetimibe would almost double patients at target and halve the potential candidates for reimbursement of more expensive agents such as proprotein convertase subtlisin/kexin type 9 inhibitors.


Assuntos
Anticolesterolemiantes/administração & dosagem , LDL-Colesterol/sangue , Doença das Coronárias/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Ezetimiba/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Serino Proteinase/administração & dosagem , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , Tomada de Decisão Clínica , Doença das Coronárias/sangue , Doença das Coronárias/diagnóstico , Doença das Coronárias/epidemiologia , Regulação para Baixo , Quimioterapia Combinada , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Ezetimiba/efeitos adversos , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Pró-Proteína Convertase 9/antagonistas & inibidores , Sistema de Registros , Medição de Risco , Fatores de Risco , Inibidores de Serino Proteinase/efeitos adversos , Resultado do Tratamento
8.
Arterioscler Thromb Vasc Biol ; 38(7): 1644-1655, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29880491

RESUMO

OBJECTIVE: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) and statins are known to lower plasma LDL (low-density lipoprotein)-cholesterol concentrations. However, the comparative effects of these treatments on the postprandial metabolism of TRLs (triglyceride-rich lipoproteins) remain to be investigated. APPROACH AND RESULTS: We performed a 2-by-2 factorial trial of the effects of 8 weeks of subcutaneous evolocumab (420 mg every 2 weeks) and atorvastatin (80 mg daily) on postprandial TRL metabolism in 80 healthy, normolipidemic men after ingestion of an oral fat load. We evaluated plasma total and incremental area under the curves for triglycerides, apo (apolipoprotein)B-48, and VLDL (very-LDL)-apoB-100. We also examined the kinetics of apoB-48 using intravenous D3-leucine administration, mass spectrometry, and multicompartmental modeling. Atorvastatin and evolocumab independently lowered postprandial VLDL-apoB-100 total area under the curves (P<0.001). Atorvastatin, but not evolocumab, reduced fasting plasma apoB-48, apoC-III, and angiopoietin-like 3 concentrations (P<0.01), as well as postprandial triglyceride and apoB-48 total area under the curves (P<0.001) and the incremental area under the curves for plasma triglycerides, apoB-48, and VLDL-apoB-100 (P<0.01). Atorvastatin also independently increased TRL apoB-48 fractional catabolic rate (P<0.001) and reduced the number of apoB-48-containing particles secreted in response to the fat load (P<0.01). In contrast, evolocumab did not significantly alter the kinetics of apoB-48. CONCLUSIONS: In healthy, normolipidemic men, atorvastatin decreased fasting and postprandial apoB-48 concentration by accelerating the catabolism of apoB-48 particles and reducing apoB-48 particle secretion in response to a fat load. Inhibition of PCSK9 with evolocumab had no significant effect on apoB-48 metabolism.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Atorvastatina/administração & dosagem , Gorduras na Dieta/sangue , Lipoproteínas/sangue , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/administração & dosagem , Triglicerídeos/sangue , Administração Oral , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Apolipoproteína B-100/sangue , Apolipoproteína B-48/sangue , Apolipoproteína C-III/sangue , Gorduras na Dieta/administração & dosagem , Método Duplo-Cego , Esquema de Medicação , Humanos , Injeções Subcutâneas , Lipoproteínas VLDL/sangue , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Pró-Proteína Convertase 9/metabolismo , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
9.
J Cardiovasc Pharmacol Ther ; 23(5): 423-432, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29768954

RESUMO

BACKGROUND: The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab reduces low-density lipoprotein cholesterol (LDL-C) and the risk of cardiovascular events. OBJECTIVES: To compare LDL-C reduction using evolocumab 140 mg once every 2 weeks (Q2W) or 420 mg monthly (QM) versus lower doses (70 mg Q2W or 280 mg QM) or placebo. METHODS: Patients received evolocumab 70 or 140 mg Q2W, 280 or 420 mg QM, or placebo Q2W or QM in two 12-week phase 2 studies: one with and one without statins. Changes from baseline in LDL-C were compared across Q2W doses and across QM doses. RESULTS: The analysis included 741 patients. Mean (95% confidence interval [CI]) reduction in LDL-C across Q2W visits through week 12 was 63.0% (60.3% to 65.7%) for evolocumab 140 mg Q2W, compared to 41.3% (38.6% to 44.0%) for 70 mg Q2W and 1.9% (4.6% reduction to 0.8% increase) for placebo Q2W (each P < .001 vs 140 mg Q2W), and 62.7% (60.1% to 65.3%) for 420 mg QM, compared to 55.5% (52.9% to 58.0%) for 280 mg QM and 2.5% (5.1% reduction to 0.1% increase) for placebo QM (each P < .001 vs 420 mg QM). Similar results were observed at the mean of weeks 10 and 12. In a subgroup (n = 151) with weekly assessments from weeks 8 to 12, mean (95% CI) peak effect on LDL-C reduction was 72.8% (67.7% to 77.9%) for 140 mg Q2W and 69.0% (63.6% to 74.3%) for 420 mg QM. Trough effect at week 12 underestimated LDL-C reduction. Median peak-trough variability was 20.5%, 21.1%, 31.9%, and 35.1% for evolocumab 140 mg Q2W, 420 mg QM, 70 mg Q2W, and 280 mg QM, respectively. CONCLUSION: Evolocumab 140 mg Q2W and 420 mg QM yielded similar LDL-C reduction. These doses sustained maximal LDL-C reduction, resulting in greater stability in LDL-C reduction over the dosing interval compared to lower doses. These results support evolocumab doses of either 140 mg Q2W or 420 mg QM.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticolesterolemiantes/administração & dosagem , LDL-Colesterol/sangue , Dislipidemias/tratamento farmacológico , Inibidores de Serino Proteinase/administração & dosagem , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Controlados como Assunto , Regulação para Baixo , Esquema de Medicação , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/enzimologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9/antagonistas & inibidores , Pró-Proteína Convertase 9/metabolismo , Inibidores de Serino Proteinase/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
10.
Clin Pharmacol Ther ; 104(6): 1155-1164, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29484635

RESUMO

Neutrophil serine proteases (NSPs), such as neutrophil elastase (NE), are activated by dipeptidyl peptidase 1 (DPP1) during neutrophil maturation. High NSP levels can be detrimental, particularly in lung tissue, and inhibition of NSPs is therefore an interesting therapeutic opportunity in multiple lung diseases, including chronic obstructive pulmonary disease (COPD) and bronchiectasis. We conducted a randomized, placebo-controlled, first-in-human study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of the DPP1 inhibitor AZD7986 in healthy subjects. Pharmacokinetic and pharmacodynamic data were analyzed using nonlinear mixed effects modeling and showed that AZD7986 inhibits whole blood NE activity in an exposure-dependent, indirect manner-consistent with in vitro and preclinical predictions. Several dose-dependent, possibly DPP1-related, nonserious skin findings were observed, but these were not considered to prevent further clinical development. Overall, the study results provided confidence to progress AZD7986 to phase II and supported selection of a clinically relevant dose.


Assuntos
Benzoxazóis/administração & dosagem , Catepsina C/antagonistas & inibidores , Inibidores de Cisteína Proteinase/administração & dosagem , Elastase de Leucócito/antagonistas & inibidores , Neutrófilos/efeitos dos fármacos , Oxazepinas/administração & dosagem , Inibidores de Serino Proteinase/administração & dosagem , Administração Oral , Benzoxazóis/efeitos adversos , Benzoxazóis/farmacocinética , Inibidores de Cisteína Proteinase/efeitos adversos , Inibidores de Cisteína Proteinase/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Voluntários Saudáveis , Humanos , Elastase de Leucócito/sangue , Masculino , Modelos Biológicos , Neutrófilos/enzimologia , Dinâmica não Linear , Oxazepinas/efeitos adversos , Oxazepinas/farmacocinética , Inibidores de Serino Proteinase/farmacocinética
11.
Int J Biol Macromol ; 111: 1214-1221, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29339284

RESUMO

Protease/anti-protease imbalance is the main pathogenic mechanism of emphysema and protease inhibitors have been recognized as potential molecules to treat the disease conditions. In this work the rBmTI-6 first domain (rBmTI-6-D1), a recombinant Kunitz-type serine proteinase inhibitor, was used to verify its effect in prevention or minimization of PPE-induced emphysema in mice. C57BL/6 mice were submitted to a PPE-induced emphysema model and treated with rBmTI-6-D1 before the emphysema development. We showed that the rBmTI-6-D1 treatment was sufficient to avoid the loss of elastic recoil, an effective decrease in alveolar enlargement and in the number of macrophages and lymphocytes in bronchoalveolar lavage fluid. Proteolytic analysis showed a significant increase in elastase activity in PPE-VE (induced emphysema) group that is controlled by rBmTI-6-D1. Kallikrein activity was decreased in the PPE-rBmTI6 (induced emphysema and inhibitor treated) group when compared to PPE-VE group. Although rBmTI-6-D1, did not present a neutrophil elastase (NE) inhibitory activity, the results show that the inhibitor interfered in the pathway of NE secretion in PPE-emphysema mice model. The role of rBmTI-6-D1 in the prevention of emphysema development in the mice model, apparently, is related with a control of inflammatory response due the trypsin/kallikrein inhibitory activity of rBmTI-6-D1.


Assuntos
Inflamação/tratamento farmacológico , Pulmão/efeitos dos fármacos , Enfisema Pulmonar/tratamento farmacológico , Inibidores de Serino Proteinase/química , Animais , Líquido da Lavagem Broncoalveolar/química , Modelos Animais de Doenças , Humanos , Inflamação/induzido quimicamente , Inflamação/fisiopatologia , Pulmão/fisiopatologia , Camundongos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Polímeros/toxicidade , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/fisiopatologia , Rhipicephalus/química , Inibidores de Serino Proteinase/administração & dosagem , Inibidores de Serino Proteinase/genética
13.
Exp Biol Med (Maywood) ; 243(1): 87-95, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29096562

RESUMO

Mechanical ventilation is extensively used to treat patients with lung injury but may result in ventilator-induced lung injury (VILI). The present study investigated the protective effect of alpha 1-antitrypsin (AAT) on VILI. Adult male rats were subjected to sham, ventilation + saline, or ventilation + AAT treatment and lung injuries were evaluated. Peripheral blood and bronchoalveolar lavage fluid (BALF) were obtained to assess systemic and local inflammatory responses, respectively. Mechanical ventilation resulted in lung injury, as evidenced by histological abnormalities as well as elevations in PaO2/FiO2 ratio, the wet-to-dry weight ratio, and the BALF level of proteins. The intravenous administration of AAT significantly improved these parameters of lung function, suggesting a protective role of AAT in VILI. Mechanistically, ventilator-induced inflammation was effectively reduced by AAT, as evidenced by decreases in BALF neutrophil counts, BALF cytokines, and serum adhesion factors. In contrast, anti-inflammatory interleukin-10 in BALF was increased in response to AAT. AAT treatment also inhibited the expression of nuclear factor-κB, Bax, and cleaved caspase-3 while promoting Bcl-2 expression in ventilator-injured lung tissues. AAT treatment can ameliorate VILI by inhibiting inflammatory mediator production and apoptosis. Impact statement Mechanical ventilation has been commonly used to treat patients with lung injury but may result in ventilator-induced lung injury (VILI). Few effective treatment options are currently available to reduce VILI. Alpha 1-antitrypsin (AAT) is an inhibitor of serine protease with anti-inflammatory and antiapoptotic properties, suggesting a possible role in attenuating lung injury. The present study demonstrates that AAT inhibits the development of VILI by modulating inflammation- and apoptosis-related protein expression. Therefore, AAT may be a novel therapeutic agent for acute respiratory distress syndrome patients undergoing mechanical ventilation.


Assuntos
Anti-Inflamatórios/administração & dosagem , Apoptose , Inflamação/patologia , Inibidores de Serino Proteinase/administração & dosagem , Lesão Pulmonar Induzida por Ventilação Mecânica/patologia , alfa 1-Antitripsina/administração & dosagem , Administração Intravenosa , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Moléculas de Adesão Celular/análise , Citocinas/análise , Contagem de Leucócitos , Pulmão/patologia , Masculino , Ratos , Soro/química , Resultado do Tratamento
14.
Cardiovasc Ther ; 36(1)2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29078037

RESUMO

AIMS: Three single-dose and one multiple-dose phase I studies were conducted in subjects with primary hypercholesterolemia to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of bococizumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. METHODS: The dosing schedules for hypercholesterolemic subjects randomized in the four phase I studies were (1) ascending, single, intravenous (IV) bococizumab (0.3, 1, 3, 6, 12, or 18 mg/kg), or placebo (N = 48; baseline low-density lipoprotein cholesterol [LDL-C] ≥130 mg/dL); (2) single, IV bococizumab (0.5 or 4 mg/kg; no placebo) added to ongoing atorvastatin 40 mg/day (N = 24); (3) single, fixed, subcutaneous (SC) bococizumab (100 or 200 mg), or IV bococizumab (200 mg; no placebo; N = 49; baseline LDL-C ≥130 mg/dL); and (4) weekly IV bococizumab (0.25, 0.5, 1, or 1.5 mg/kg) or placebo for 4 weeks (N = 67; baseline LDL-C ≥130 mg/dL). RESULTS: Bococizumab pharmacokinetics were well characterized following single IV or SC doses and following multiple IV doses. Exposure to single-dose bococizumab increased slightly greater than dose-proportionally and clearance decreased with increasing dose. In the single-dose studies, maximal mean percent reductions from baseline in LDL-C ranged from 43% (0.3 mg/kg) to 84% (18 mg/kg) in bococizumab-treated subjects, compared with 2% for placebo. For the multiple-dose study, maximal reductions in LDL-C ranged from 55% (0.25 mg/kg) to 66% (1 mg/kg) in bococizumab-treated subjects, compared with 9% for placebo. In all studies, adverse events were infrequent, transient, and not dose-related. CONCLUSIONS: Bococizumab was generally safe and well tolerated. Bococizumab lowered LDL-C levels substantially in all four studies.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Atorvastatina/administração & dosagem , LDL-Colesterol/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/administração & dosagem , Administração Intravenosa , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacocinética , Atorvastatina/efeitos adversos , Biomarcadores/sangue , Regulação para Baixo , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hipercolesterolemia/sangue , Hipercolesterolemia/enzimologia , Hipercolesterolemia/genética , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9/metabolismo , Inibidores de Serino Proteinase/efeitos adversos , Inibidores de Serino Proteinase/farmacocinética , Fatores de Tempo , Resultado do Tratamento
15.
Ann Thorac Cardiovasc Surg ; 24(1): 32-39, 2018 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-29118307

RESUMO

PURPOSE: Unilateral re-expansion pulmonary edema (RPE) is a rare but one of the most critical complications that may occur after re-expansion of a collapsed lung after minimally invasive cardiac surgery (MICS) with mini-thoracotomy. METHODS: We performed a total of 40 consecutive patients with MICS by right mini-thoracotomy with single-lung ventilation between January 2013 and June 2016. We divided the patients into control group (n = 13) and neutrophil elastase inhibitor group (n = 27). Neutrophil elastase inhibitor group received continuous intravenous infusion of neutrophil elastase inhibitor at 0.2-0.25 mg/kg per hour from the start of anesthesia until extubation during the perioperative period. RESULTS: There were no relations with operative time, cardiopulmonary bypass (CPB) time, aortic clamp time, and intraoperative water valances for postoperative mechanical ventilation support time. Compared with the neutrophil elastase inhibitor group, the control group had significantly higher initial alveolar-arterial oxygen gradient and significantly lower initial ratio of partial pressure of arterial oxygen to fraction of inspired oxygen at the intensive care unit (ICU). The control group had significantly longer postoperative mechanical ventilation support time and hospital stay compared with the neutrophil elastase inhibitor group. CONCLUSIONS: Neutrophil elastase inhibitor may have beneficial effects against RPE after MICS with mini-thoracotomy.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Glicina/análogos & derivados , Elastase de Leucócito/antagonistas & inibidores , Edema Pulmonar/prevenção & controle , Inibidores de Serino Proteinase/administração & dosagem , Sulfonamidas/administração & dosagem , Toracotomia , Adulto , Idoso , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Procedimentos Cirúrgicos Cardíacos/métodos , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Humanos , Infusões Intravenosas , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Ventilação Monopulmonar , Edema Pulmonar/diagnóstico por imagem , Edema Pulmonar/etiologia , Estudos Retrospectivos , Fatores de Risco , Inibidores de Serino Proteinase/efeitos adversos , Sulfonamidas/efeitos adversos , Toracotomia/efeitos adversos , Toracotomia/métodos , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento
16.
Cardiovasc Ther ; 36(1)2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29057618

RESUMO

AIMS: Two multiple-dose phase II studies were conducted in subjects with primary hypercholesterolemia to evaluate the LDL-C lowering efficacy, safety, and tolerability of bococizumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. METHODS: The results from the two phase II, double-blinded, randomized, placebo-controlled, multicenter studies conducted in the USA and Canada were combined. In Study 1, 90 subjects with LDL-C ≥100 mg/dL received intravenous (IV) placebo or bococizumab 0.25, 1, 3, or 6 mg/kg. In Study 2, 45 subjects with LDL-C ≥80 mg/dL received IV placebo or bococizumab 1 or 3 mg/kg. Subjects were treated every 4 weeks for 12 weeks. Dosing was interrupted if LDL-C dipped to ≤25 mg/dL and resumed if LDL-C returned to ≥40 mg/dL. The primary endpoint was percent LDL-C reduction from baseline at Week 12. RESULTS: At Week 12, the reductions from baseline in LDL-C vs placebo in the bococizumab 0.25, 1, 3, and 6 mg/kg groups were 9.3%, 10.2%, 41.6%, and 52.0%, respectively (P < .001 vs placebo for all). LDL-C reductions were greater (69.9%) in subjects who received all three doses of bococizumab 6 mg/kg (P < .001 vs placebo). Pharmacogenomic analysis revealed that 15% of hyperlipidemic subjects carried polymorphisms associated with familial hypercholesterolemia, with maximal LDL-C reductions being similar between carriers and noncarriers. Adverse events were mild, unrelated to bococizumab, and resolved by Week 12. CONCLUSIONS: These studies demonstrated that bococizumab safely and effectively lowered LDL-C in hypercholesterolemic subjects on high doses of statin.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticolesterolemiantes/administração & dosagem , LDL-Colesterol/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/administração & dosagem , Administração Intravenosa , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacocinética , Biomarcadores/sangue , Canadá , Método Duplo-Cego , Regulação para Baixo , Quimioterapia Combinada , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hipercolesterolemia/sangue , Hipercolesterolemia/enzimologia , Hipercolesterolemia/genética , Masculino , Pessoa de Meia-Idade , Farmacogenética , Pró-Proteína Convertase 9/metabolismo , Inibidores de Serino Proteinase/efeitos adversos , Inibidores de Serino Proteinase/farmacocinética , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
17.
Eur Rev Med Pharmacol Sci ; 21(22): 5268-5274, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29228444

RESUMO

OBJECTIVE: We aimed to evaluate the results in our case series of AP ERCP over the last three years. The prophylaxis for acute pancreatitis (AP) post-endoscopic retrograde cholangiopancreatography (ERCP) consists of rectal indomethacin, but some studies are not concordant. PATIENTS AND METHODS: We compared 241 ERCP performed from January 2014 to February 2015 with intravenous gabexate mesylate (Group A), with the 387 ERCP performed from March 2015 to December 2016 with rectal indomethacin (Group B) as prophylaxis for AP post-ERCP. RESULTS: There were 8 (3.31%) AP post-ERCP in Group A vs. 4 (1.03%) in Group B. CONCLUSIONS: Rectal indomethacin shows a better statistically significant performance than intravenous gabexate mesylate in the prophylaxis of AP post-ERCP, besides being cheaper.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/uso terapêutico , Colangiopancreatografia Retrógrada Endoscópica/efeitos adversos , Gabexato/administração & dosagem , Gabexato/uso terapêutico , Indometacina/administração & dosagem , Indometacina/uso terapêutico , Pancreatite/etiologia , Pancreatite/prevenção & controle , Inibidores de Serino Proteinase/administração & dosagem , Inibidores de Serino Proteinase/uso terapêutico , Doença Aguda , Administração Intravenosa , Administração Retal , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios não Esteroides/economia , Colangiopancreatografia Retrógrada Endoscópica/economia , Custos e Análise de Custo , Feminino , Gabexato/economia , Humanos , Indometacina/economia , Masculino , Pessoa de Meia-Idade , Pancreatite/economia , Estudos Retrospectivos , Inibidores de Serino Proteinase/economia
18.
Early Hum Dev ; 115: 71-76, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28950234

RESUMO

BACKGROUND: Chorioamnionitis, or infiltration of the chorioamnion by neutrophils, is a risk factor associated with the development of bronchopulmonary dysplasia. Increased neutrophil elastase levels are observed in the tracheal aspirates of these patients. AIMS: To examine the effects of early administration of the selective neutrophil elastase inhibitor sivelestat, which is used to treat acute lung injury in adults, on bronchopulmonary dysplasia in extremely premature infants. STUDY DESIGN: Retrospective cohort study. SUBJECTS: This study included extremely low-birth-weight infants born at a gestational age<28weeks. Patients were divided into groups based on the receipt of sivelestat. OUTCOME MEASURES: The primary outcome was the rate of bronchopulmonary dysplasia-free survival at a postmenstrual age of 36weeks, and the secondary outcomes included various clinically significant factors of neonatal mortality and morbidity and adverse events. RESULTS: Of the 1031 included neonates, 124 (12.0%) were treated with sivelestat. Significant differences between the groups were noted for gestational age, delivery method, fetal number, the frequency of chorioamnionitis, immunoglobulin M levels, and WBC counts. No differences were identified concerning the bronchopulmonary dysplasia-free survival rate at a postmenstrual age of 36weeks (adjusted odds ratio for sivelestat to control, 0.83; 95% confidence interval=0.53-1.30). Secondary outcomes did not significantly differ between the groups. CONCLUSIONS: In extremely premature infants, early sivelestat use was not associated with an improved rate of survival without bronchopulmonary dysplasia at a postmenstrual age of 36weeks.


Assuntos
Displasia Broncopulmonar/tratamento farmacológico , Glicina/análogos & derivados , Inibidores de Serino Proteinase/uso terapêutico , Sulfonamidas/uso terapêutico , Esquema de Medicação , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/uso terapêutico , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Recém-Nascido Pequeno para a Idade Gestacional , Masculino , Inibidores de Serino Proteinase/administração & dosagem , Inibidores de Serino Proteinase/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos
19.
J Neuroinflammation ; 14(1): 168, 2017 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-28835277

RESUMO

BACKGROUND: A subset of osteoarthritis (OA) patients experience joint pain with neuropathic characteristics. Mediators such as neutrophil elastase, a serine proteinase, may be released during acute OA inflammatory flares. We have previously shown that local administration of neutrophil elastase causes joint inflammation and pain via activation of proteinase-activated receptor-2 (PAR2). The aim of this study was to examine the contribution of endogenous neutrophil elastase and PAR2 to the development of joint inflammation, pain, and neuropathy associated with monoiodoacetate (MIA)-induced experimental OA. METHODS: MIA (0.3 mg/10 µl) was injected into the right knee joint of male C57BL/6 mice (20-34 g). Joint inflammation (edema, leukocyte kinetics), neutrophil elastase proteolytic activity, tactile allodynia, and saphenous nerve demyelination were assessed over 14 days post-injection. The effects of inhibiting neutrophil elastase during the early inflammatory phase of MIA (days 0 to 3) were determined using sivelestat (50 mg/kg i.p.) and serpinA1 (10 µg i.p.). Involvement of PAR2 in the development of MIA-induced joint inflammation and pain was studied using the PAR2 antagonist GB83 (5 µg i.p. days 0 to 1) and PAR2 knockout animals. RESULTS: MIA caused an increase in neutrophil elastase proteolytic activity on day 1 (P < 0.0001), but not on day 14. MIA also generated a transient inflammatory response which peaked on day 1 (P < 0.01) then subsided over the 2-week time course. Joint pain appeared on day 1 and persisted to day 14 (P < 0.0001). By day 14, the saphenous nerve showed signs of demyelination. Early treatment with sivelestat and serpinA1 blocked the proteolytic activity of neutrophil elastase on day 1 (P < 0.001), and caused lasting improvements in joint inflammation, pain, and saphenous nerve damage (P < 0.05). MIA-induced synovitis was reversed by early treatment with GB83 and attenuated in PAR2 knockout mice (P < 0.05). PAR2 knockout mice also showed reduced MIA-induced joint pain (P < 0.0001) and less nerve demyelination (P = 0.81 compared to saline control). CONCLUSIONS: Neutrophil elastase and PAR2 contribute significantly to the development of joint inflammation, pain, and peripheral neuropathy associated with experimental OA, suggesting their potential as therapeutic targets.


Assuntos
Dor Crônica/enzimologia , Elastase de Leucócito/antagonistas & inibidores , Neuralgia/enzimologia , Osteoartrite/enzimologia , Profilaxia Pré-Exposição/métodos , Inibidores de Serino Proteinase/administração & dosagem , Animais , Dor Crônica/diagnóstico por imagem , Dor Crônica/prevenção & controle , Glicina/administração & dosagem , Glicina/análogos & derivados , Elastase de Leucócito/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuralgia/diagnóstico por imagem , Neuralgia/prevenção & controle , Osteoartrite/diagnóstico por imagem , Osteoartrite/tratamento farmacológico , Sulfonamidas/administração & dosagem
20.
Expert Opin Ther Pat ; 27(8): 919-928, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28425830

RESUMO

INTRODUCTION: Tryptase is one of the main serine-proteinases located in the secretory granules of mast cells, and is released through degranulation, which is involved in the pathogenesis of allergic inflammatory disease, cardiovascular diseases, lung fibrosis and tumor. Therefore, inhibitors targeting tryptase may represent a new direction for the treatment of allergic inflammatory disease and other diseases. Areas covered: In this article, we discussed the history and development of tryptase inhibitors and described a variety of tryptase inhibitors via their structures and biological importance in clinical studies and drug development for tryptase-related diseases. Expert opinion: Initial tryptase inhibitors based on indole structure as the hydrophobic substituent on a benzylamine-piperidine template have low specificity and poor bioavailability. Therefore, designing new and specific inhibitors targeting tryptase should be involved in future clinical studies. Modifications toward indoles with varying N-substitution, introducing an amide bond, and growing the chain length contribute to an increase in the specific selectivity and potency of tryptase inhibitors. Tryptase has become the research hotspot to explore many related diseases. Therefore, there has been growing appreciation for the potential importance of the tryptase inhibitors as a target for treating these diseases.


Assuntos
Desenho de Fármacos , Inibidores de Serino Proteinase/farmacologia , Triptases/antagonistas & inibidores , Animais , Humanos , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/enzimologia , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Mastócitos/enzimologia , Mastócitos/metabolismo , Patentes como Assunto , Inibidores de Serino Proteinase/administração & dosagem , Triptases/metabolismo
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