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1.
Ann Hematol ; 99(9): 2193-2195, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32621180
2.
EMBO Mol Med ; 12(8): e12697, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32473600

RESUMO

Baricitinib is an oral Janus kinase (JAK)1/JAK2 inhibitor approved for the treatment of rheumatoid arthritis (RA) that was independently predicted, using artificial intelligence (AI) algorithms, to be useful for COVID-19 infection via proposed anti-cytokine effects and as an inhibitor of host cell viral propagation. We evaluated the in vitro pharmacology of baricitinib across relevant leukocyte subpopulations coupled to its in vivo pharmacokinetics and showed it inhibited signaling of cytokines implicated in COVID-19 infection. We validated the AI-predicted biochemical inhibitory effects of baricitinib on human numb-associated kinase (hNAK) members measuring nanomolar affinities for AAK1, BIKE, and GAK. Inhibition of NAKs led to reduced viral infectivity with baricitinib using human primary liver spheroids. These effects occurred at exposure levels seen clinically. In a case series of patients with bilateral COVID-19 pneumonia, baricitinib treatment was associated with clinical and radiologic recovery, a rapid decline in SARS-CoV-2 viral load, inflammatory markers, and IL-6 levels. Collectively, these data support further evaluation of the anti-cytokine and anti-viral activity of baricitinib and support its assessment in randomized trials in hospitalized COVID-19 patients.


Assuntos
Antivirais/farmacologia , Inteligência Artificial , Azetidinas/farmacologia , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Pandemias , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Sulfonamidas/farmacologia , Adulto , Idoso , Antivirais/farmacocinética , Antivirais/uso terapêutico , Azetidinas/farmacocinética , Azetidinas/uso terapêutico , Citocinas/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Leucócitos/efeitos dos fármacos , Fígado , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/virologia , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico
3.
J Pharmacol Exp Ther ; 373(2): 261-268, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32127372

RESUMO

In vitro approaches for predicting drug-drug interactions (DDIs) caused by alterations in transporter protein regulation are not well established. However, reports of transporter regulation via nuclear receptor (NR) modulation by drugs are increasing. This study examined alterations in transporter protein levels in sandwich-cultured human hepatocytes (SCHH; n = 3 donors) measured by liquid chromatography-tandem mass spectrometry-based proteomic analysis after treatment with N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-N-(2,2,2-trifluoroethyl)benzenesulfonamide (T0901317), the first described synthetic liver X receptor agonist. T0901317 treatment (10 µM, 48 hours) decreased the levels of organic cation transporter (OCT) 1 (0.22-, 0.43-, and 0.71-fold of control) and organic anion transporter (OAT) 2 (0.38-, 0.38-, and 0.53-fold of control) and increased multidrug resistance protein (MDR) 1 (1.37-, 1.48-, and 1.59-fold of control). The induction of NR downstream gene expression supports the hypothesis that T0901317 off-target effects on farnesoid X receptor and pregnane X receptor activation are responsible for the unexpected changes in OCT1, OAT2, and MDR1. Uptake of the OCT1 substrate metformin in SCHH was decreased by T0901317 treatment. Effects of decreased OCT1 levels on metformin were simulated using a physiologically-based pharmacokinetic (PBPK) model. Simulations showed a clear decrease in metformin hepatic exposure resulting in a decreased pharmacodynamic effect. This DDI would not be predicted by the modest changes in simulated metformin plasma concentrations. Altogether, the current study demonstrated that an approach combining SCHH, proteomic analysis, and PBPK modeling is useful for revealing tissue concentration-based DDIs caused by unexpected regulation of hepatic transporters by NR modulators. SIGNIFICANCE STATEMENT: This study utilized an approach combining sandwich-cultured human hepatocytes, proteomic analysis, and physiologically based pharmacokinetic modeling to evaluate alterations in pharmacokinetics (PK) and pharmacodynamics (PD) caused by transporter regulation by nuclear receptor modulators. The importance of this approach from a mechanistic and clinically relevant perspective is that it can reveal drug-drug interactions (DDIs) caused by unexpected regulation of hepatic transporters and enable prediction of altered PK and PD changes, especially for tissue concentration-based DDIs.


Assuntos
Hepatócitos/efeitos dos fármacos , Hidrocarbonetos Fluorados/farmacologia , Receptores X do Fígado/agonistas , Proteômica/métodos , Sulfonamidas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/análise , Adulto , Células Cultivadas , Interações Medicamentosas , Feminino , Hepatócitos/metabolismo , Humanos , Hidrocarbonetos Fluorados/farmacocinética , Pessoa de Meia-Idade , Modelos Biológicos , Fator 1 de Transcrição de Octâmero/análise , Transportadores de Ânions Orgânicos Sódio-Independentes/análise , Sulfonamidas/farmacocinética
4.
Toxicol Lett ; 324: 38-45, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32062017

RESUMO

Tolylfluanid (TF) is a sensitizing biocide used in antifouling products and wood preservatives. Paint application is associated with skin exposure; however, the importance of this exposure route is uncertain as TF skin permeation rates are lacking in the peer-reviewed scientific literature. TF is a lipophilic powder that hydrolyses rapidly in contact with water to dimethylamino sulfotoluidid (DMST). DMST is also a TF metabolite. We characterized TF and DMST skin permeation using an ex vivo flow-through diffusion system with viable and frozen human skin. TF permeated as DMST with a low permeation rate (0.18 ± 0.05 µg/cm2/h) and a moderate time lag (7.1 ± 1.4 h) in viable human skin. Applying DMST gave a 3.5-fold lower permeation rate (0.05 ± 0.01 µg/cm2/h) compared to TF under a similar experimental setting. We simulated paint activities in an exposure chamber to understand a possible skin exposure from airborne TF concentrations. Although, paint can deposit onto the skin during work activities, TF permeation when paint was applied to human skin ex vivo was very low (as TF: 0.004 ± 0.005 µg/cm2/h, and as DMST: 0.02 ± 0.001 µg/cm2/h). Our results show that TF can permeate skin, and consequently, can contribute to sensitization, which support previous reports on sensitization in TF exposed workers.


Assuntos
Pele/metabolismo , Sulfonamidas/farmacocinética , Toluidinas/farmacocinética , Poluentes Atmosféricos/análise , Humanos , Hidrólise , Exposição Ocupacional , Pintura , Permeabilidade , Solubilidade , Sulfonamidas/análise , Sulfonamidas/química , Toluidinas/análise , Toluidinas/química
5.
AAPS PharmSciTech ; 21(3): 87, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32016607

RESUMO

This study aims to evaluate the effect of different formulation variables (surfactant type and HLB value) adopting full factorial design (51. 21) using coacervation phase technique on in vitro characterization of dorzolamide hydrochloride (DZ)-loaded proniosomal gels, namely, entrapment efficiency percentage (EE%), vesicle size distribution, polydispersion index (PDI), and in vitro DZ release. The optimum formula F2 with a desirability value of 0.937 composed of 40 mg DZ, 500 mg span 60, 500 mg of L-α-Lethicin, and 55.5 mg cholesterol showing EE% of 84.5 ± 1.5%, PS of 189.5 ± 35.76 nm with PDI 0.8 ± 0.28 and 58.51% ± 1.00 of DZ released after 8 h was further evaluated using differential scanning calorimetry (DSC) and transmission electron microscopy (TEM). The effect of gamma sterilization on transcorneal permeation and stability of DZ from the selected formulation (F2) revealed that F2 was significantly tolerable, stable, and competent to corneal permeation confirmed by histological examination, confocal laser microscopy, and intraocular pressure (IOP) measurement. Significant corneal bioavailability was attained from formula F2 (370.6 mg. h/m) compared to the market product Trusopt® eye drops (92.59 mg. h/ml) following IOP measurement, thereby proniosomal gels could be considered as tolerable and competent ocular platforms for improving the transcorneal permeation of DZ.


Assuntos
Córnea/metabolismo , Glaucoma/tratamento farmacológico , Sulfonamidas/administração & dosagem , Tiofenos/administração & dosagem , Animais , Composição de Medicamentos , Estabilidade de Medicamentos , Raios gama , Géis/química , Lipossomos/química , Masculino , Permeabilidade , Coelhos , Esterilização , Sulfonamidas/farmacocinética , Tiofenos/farmacocinética
6.
J Med Chem ; 63(3): 1281-1297, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31935086

RESUMO

Cell division cycle 37 (Cdc37) is known to work as a kinase-specific cochaperone, which selectively regulates the maturation of kinases through protein-protein interaction (PPI) with Hsp90. Directly disrupting the Hsp90-Cdc37 PPI is emerging as an alternative strategy to develop anticancer agents through a specific inhibition manner of kinase clients of Hsp90. Based on a first specific small-molecule inhibitor targeting Hsp90-Cdc37 PPI (DDO-5936), which was previously reported by our group, we conducted a preliminary investigation of the structure-activity relationships and pharmacodynamic evaluations to improve the potency and drug-like properties. Here, our efforts resulted in the currently best inhibitor 18h with improved binding affinity (Kd = 0.5 µM) and cellular inhibitory activity (IC50 = 1.73 µM). Both in vitro and in vivo assays revealed that 18h could efficiently block the Hsp90-Cdc37 interaction to specifically inhibit kinase clients of Hsp90. Furthermore, 18h showed ideal physiochemical properties with favorable stability, leading to an oral efficacy in vivo.


Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Ciclo Celular/antagonistas & inibidores , Chaperoninas/antagonistas & inibidores , Neoplasias Colorretais/tratamento farmacológico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Ligação Proteica/efeitos dos fármacos , Sulfonamidas/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Sítios de Ligação , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chaperoninas/química , Chaperoninas/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/química , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética
7.
Breast Cancer Res ; 22(1): 4, 2020 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924241

RESUMO

BACKGROUND: Cancer stem cells (CSCs) are purported to be responsible for tumor initiation, treatment resistance, disease recurrence, and metastasis. CXCR1, one of the receptors for CXCL8, was identified on breast cancer (BC) CSCs. Reparixin, an investigational allosteric inhibitor of CXCR1, reduced the CSC content of human BC xenograft in mice. METHODS: In this multicenter, single-arm trial, women with HER-2-negative operable BC received reparixin oral tablets 1000 mg three times daily for 21 days before surgery. Primary objectives evaluated the safety of reparixin and the effects of reparixin on CSC and tumor microenvironment in core biopsies taken at baseline and at treatment completion. Signal of activity was defined as a reduction of ≥ 20% in ALDH+ or CD24-/CD44+ CSC by flow cytometry, with consistent reduction by immunohistochemistry. RESULTS: Twenty patients were enrolled and completed the study. There were no serious adverse reactions. CSC markers ALDH+ and CD24-/CD44+ measured by flow cytometry decreased by ≥ 20% in 4/17 and 9/17 evaluable patients, respectively. However, these results could not be confirmed by immunofluorescence due to the very low number of CSC. CONCLUSIONS: Reparixin appeared safe and well-tolerated. CSCs were reduced in several patients as measured by flow cytometry, suggesting targeting of CXCR1 on CSC. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT01861054. Registered on April 18, 2013.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Células-Tronco Neoplásicas/patologia , Receptor ErbB-2/metabolismo , Receptores de Interleucina-8A/antagonistas & inibidores , Receptores de Interleucina-8B/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Adulto , Idoso , Animais , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Feminino , Humanos , Camundongos , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/efeitos dos fármacos , Segurança do Paciente , Sulfonamidas/farmacocinética , Distribuição Tecidual
8.
FASEB J ; 34(2): 1996-2010, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31907999

RESUMO

Despite the use of antiretroviral therapy for the treatment of HIV-1 infection, cognitive impairments, that is, HIV-1-associated neurocognitive disorders remain prevalent potentially due to persistent viral replication, production of viral proteins, associated brain inflammation or in certain instances, antiretroviral neurotoxicity. Cellular targets in the brain include microglia which in response to infection release inflammatory markers and viral proteins. Evidence suggests that PPARγ agonists exert anti-inflammatory properties in neurological disorders. However, these agonists namely, thiazolidinediones have limited use in the clinic due to reported adverse side effects. INT131 is a novel non-thiazolidinedione compound that belongs to a new class of drugs known as selective PPARγ modulators. INT131 is considered to have a safer profile; however, its neuroprotective role in vivo is not known.The goal of this study was to examine the effect of INT131 in the context of EcoHIV-induced inflammation in vitro, in primary cultures of mouse glial cells and in vivo, in a mouse model of EcoHIV-associated brain inflammation, as well as characterize its pharmacokinetic properties and brain penetration. In primary cultures of glial cells and in the in vivo mouse model, EcoHIV exposure resulted in a significant elevation of inflammatory markers such as TNFα, IL-1ß, CCL3, and C3 which were attenuated with INT131 treatment. Pharmacokinetic analyses revealed that INT131 penetrates into the brain with a brain to blood partition ratio Kp value of 8.5%. Overall, this is the first report to demonstrate that INT131 could be a potential candidate for the treatment of HIV-1-associated brain inflammation.


Assuntos
Anti-Inflamatórios , Infecções por HIV/tratamento farmacológico , HIV-1/metabolismo , Transtornos Neurocognitivos/tratamento farmacológico , PPAR gama/agonistas , Quinolinas , Sulfonamidas , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Infecções por HIV/genética , Infecções por HIV/metabolismo , Infecções por HIV/patologia , HIV-1/genética , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Transtornos Neurocognitivos/genética , Transtornos Neurocognitivos/metabolismo , Transtornos Neurocognitivos/patologia , Neuroglia/patologia , PPAR gama/genética , PPAR gama/metabolismo , Quinolinas/farmacocinética , Quinolinas/farmacologia , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia
9.
Toxicol Lett ; 319: 225-236, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760063

RESUMO

N-Butylbenzenesulfonamide (NBBS) is a plasticizer detected in the environment suggesting potential human exposure. These studies investigated the in vitro hepatic clearance and disposition of [14C]NBBS in rodents following a single gavage (2, 20 or 200 mg/kg) or intravenous (IV) administration (20 mg/kg). NBBS was cleared slower in hepatocytes from humans compared to rodents. [14C]NBBS was well-absorbed in male rats following gavage administration and excreted extensively in urine (70-76 %) and feces (11-15 %) 72 h following administration. Following a 20 mg/kg gavage dose in male rats, 25 % of the dose was excreted in bile by 24 h suggesting that observed fecal excretion was due to biliary excretion. The radioactivity was distributed to tissues with 14 % and 8 % of the administered dose remaining in tissues at 24 and 72 h, respectively. There was no apparent dose-dependent effect in disposition in male rats. Disposition patterns were similar in female rats (urine, 83 %; feces, 14 %) and male (urine, 69 %; feces, 11 %) and female (urine, 72 %; feces, 9 %) mice following gavage administration of 20 mg/kg. The disposition following IV administration was similar to that of gavage. Urinary radiochemical profiles were similar between doses, routes, species, and sexes. Among numerous metabolites identified, oxidative metabolites of NBBS predominated.


Assuntos
Hepatócitos/metabolismo , Plastificantes/farmacocinética , Sulfonamidas/farmacocinética , Administração Intravenosa , Animais , Bile/metabolismo , Células Cultivadas , Fezes/química , Feminino , Humanos , Intubação Gastrointestinal , Masculino , Camundongos , Camundongos Endogâmicos , Plastificantes/metabolismo , Plastificantes/toxicidade , Ratos , Ratos Sprague-Dawley , Sulfonamidas/administração & dosagem , Sulfonamidas/metabolismo , Distribuição Tecidual
10.
Bioanalysis ; 12(1): 11-22, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31849262

RESUMO

Aim: A sensitive and reliable LC-MS/MS method has been established and validated to the quantitation of rivaroxaban (RIV) and TAK-438 in rat plasma using carbamazepine as internal standard. Results: The procedure of method validation was conducted according to the guidelines of EMA and US FDA. At the same time, the method was applied to pharmacokinetic interactions study between RIV and TAK-438 for the first time. When RIV and TAK-438 co-administration to rats, main pharmacokinetic parameters of TAK-438 like AUC(0-t), AUC(0-∞) and Cmax had statistically significant increase. The main pharmacokinetic parameters of RIV have no statistically significant difference (p > 0.05) when co-administered except for t1/2 (p < 0.01). Conclusion: The results indicated that drug-drug interactions occurred between RIV and TAK-438 when co-administered to rats.


Assuntos
Cromatografia Líquida de Alta Pressão , Pirróis/sangue , Rivaroxabana/sangue , Sulfonamidas/sangue , Espectrometria de Massas em Tandem , Animais , Cromatografia Líquida de Alta Pressão/normas , Interações Medicamentosas , Meia-Vida , Masculino , Pirróis/administração & dosagem , Pirróis/farmacocinética , Controle de Qualidade , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Rivaroxabana/administração & dosagem , Rivaroxabana/farmacocinética , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Espectrometria de Massas em Tandem/normas
11.
Pharm Res ; 37(1): 2, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31823033

RESUMO

PURPOSE: Bosentan, clazosentan, and tezosentan are three small-molecule endothelin receptor antagonists (ERAs), displacing endothelin-1 (ET-1) from its binding site. A target-mediated drug disposition (TMDD) pharmacokinetic (PK) model described the non-linearity in the PK of bosentan caused by its high receptor binding affinity with time-dependent varying receptor expression or reappearance. The aim of this analysis was to investigate the presence of TMDD for clazosentan and tezosentan and to corroborate the hypothesis of a diurnal receptor synthesis. METHODS: PK data from healthy subjects after intravenous (i.v.) administration of single ascending doses of bosentan, clazosentan, and tezosentan were analyzed. Frequent blood samples for PK measurements were collected. Population analyses, simulations, and evaluations were performed using a non-linear mixed-effects modeling approach. RESULTS: Two-compartment TMDD models were successfully developed describing the PK of all three ERAs with different receptor-complex internalization properties. The observed multiple peaks in the concentration-time profiles were captured with cosine functions on the receptor synthesis rate mimicking a diurnal receptor expression or reappearance. The results strongly suggest that TMDD is a class effect of ERAs. CONCLUSION: The developed TMDD PK models are a next step towards understanding the complex PK of ERAs and further support the hypothesis that TMDD is a class effect of ERAs.


Assuntos
Bosentana/farmacocinética , Dioxanos/farmacocinética , Antagonistas dos Receptores de Endotelina/farmacocinética , Modelos Biológicos , Piridinas/farmacocinética , Pirimidinas/farmacocinética , Receptores de Endotelina/metabolismo , Sulfonamidas/farmacocinética , Tetrazóis/farmacocinética , Bosentana/administração & dosagem , Dioxanos/administração & dosagem , Relação Dose-Resposta a Droga , Antagonistas dos Receptores de Endotelina/administração & dosagem , Humanos , Infusões Intravenosas , Masculino , Dinâmica não Linear , Piridinas/administração & dosagem , Pirimidinas/administração & dosagem , Sulfonamidas/administração & dosagem , Espectrometria de Massas em Tandem , Tetrazóis/administração & dosagem
12.
Int J Nanomedicine ; 14: 8725-8738, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31806967

RESUMO

Background: Iguratimod (IGUR) is a novel disease-modifying antirheumatic drug used for treating rheumatoid arthritis (RA). To improve its bioavailability and to alleviate gastrointestinal side effects, we changed the formulation into nanoiguratimod-loaded hydrogel (NanoIGUR-loaded hydrogel) composites for sustained release of therapeutics. Methods: IGUR was first encapsulated in biodegradable polyvinyl alcohol micelle by liquid antisolvent precipitation (LAP) technology, and then loaded into an in situ injectable hyaluronic acid hydrogel, which was cross-linked by PEG (Thiol)2 (HS-PEG-SH) through Michael addition reaction. In vitro, the biological effects (proliferation, migration, and invasion) of NanoIGUR-loaded hydrogel on fibroblast-like synoviocytes (RA-FLS) from RA patients were evaluated. In vivo, the pharmacokinetics of NanoIGUR-loaded hydrogel was assessed and the efficacy of NanoIGUR-loaded hydrogel in treating collagen-induced arthritis (CIA) rats was evaluated. Results: By the LAP technique, we acquired the amorphous form nanoiguratimod, with an average size of 458 nm, which had higher dissolution rates and higher stability. The release of IGUR from hydrogel composite in PBS was gradual and sustained for up to 72 hrs compared with nanoiguratimod. Different concentrations of NanoIGUR-loaded hydrogel inhibited the proliferation, migration, and invasion of RA-FLS. The pharmacokinetic parameters showed better bioavailability and longer half-life time with NanoIGUR-loaded hydrogel by subcutaneous administration than oral raw iguratimod. Animal experiments confirmed that subcutaneous injection of NanoIGUR-loaded hydrogel (10 mg/kg every 3 days) and oral raw iguratimod (10mg/kg daily) showed similar efficacy in decreasing arthritis index score, pathological score, and expression of inflammatory cytokines. Conclusion: Overall, we demonstrate that NanoIGUR-loaded hydrogel provides a new route of administration and extends the administration interval. It could be a promising drug-delivery approach in the management of RA.


Assuntos
Antirreumáticos/farmacocinética , Cromonas/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Hidrogéis/administração & dosagem , Hidrogéis/química , Sulfonamidas/farmacocinética , Animais , Antirreumáticos/administração & dosagem , Antirreumáticos/química , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Proliferação de Células/efeitos dos fármacos , Cromonas/administração & dosagem , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Liberação Controlada de Fármacos , Feminino , Humanos , Ácido Hialurônico/química , Micelas , Nanoestruturas/química , Álcool de Polivinil/química , Ratos Endogâmicos Lew , Sulfonamidas/administração & dosagem , Sinoviócitos/efeitos dos fármacos
13.
Clin Drug Investig ; 39(11): 1117-1123, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31435905

RESUMO

BACKGROUND: The orally active dual endothelin receptor antagonist aprocitentan targets a novel pathway in the treatment of hypertension and could be a key player in the treatment of salt/volume-dependent hypertension. Its pharmacokinetic profile supports a once-daily dosing strategy. OBJECTIVE: As hypertensive patients may also experience concomitant renal disease, the objectives of this study were to evaluate the pharmacokinetics and tolerability of aprocitentan in subjects with severe renal function impairment (SRFI) and compare these with matched healthy subjects. DESIGN, SETTING, PARTICIPANTS: In this open-label, single-center, phase 1 study (NCT03165071) eight subjects with SRFI (mean estimated glomerular filtration rate [eGFR] 21.9 mL/min/1.73 m2) and eight healthy subjects (mean eGFR 94.9 mL/min/1.73 m2) received a single dose of 50 mg of aprocitentan followed by an observation period of up to 17 days. Plasma pharmacokinetic parameters of aprocitentan were derived by noncompartmental analysis of the plasma concentration-time profiles. Differences in pharmacokinetic parameters were explored using geometric means ratio (GMR) and 90% confidence intervals (CIs) with SRFI subjects as test group and healthy subjects as reference group. Safety and tolerability evaluations included adverse events (AEs), electrocardiograms, vital signs, and clinical laboratory tests. RESULTS: All 16 subjects received aprocitentan and completed the study. The pharmacokinetics of aprocitentan were similar in SRFI and healthy subjects with maximum plasma concentrations reached at 7.6 h and 5.0 h, respectively. Maximum plasma concentrations did not differ as indicated by a GMR (90% CI) of 1.04 (0.85-1.28). Due to a slightly lower observed clearance in SRFI subjects, half-life was longer (53.2 h compared to 47.4 h in healthy subjects), while exposure expressed as area under the curve was 34% higher (GMR 90% CI 1.13-1.58). There were no differences in plasma protein binding (> 99% bound). Aprocitentan was well tolerated in subjects with SRFI with no notable difference compared to healthy subjects. CONCLUSIONS: Based on these single-dose results, subjects with mild, moderate, or severe renal function can be included in clinical studies without the need for dose adjustment.


Assuntos
Antagonistas dos Receptores de Endotelina/farmacocinética , Rim/efeitos dos fármacos , Pirimidinas/farmacocinética , Insuficiência Renal/metabolismo , Sulfonamidas/farmacocinética , Adulto , Antagonistas dos Receptores de Endotelina/uso terapêutico , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/fisiologia , Humanos , Rim/fisiologia , Masculino , Pessoa de Meia-Idade , Pirimidinas/uso terapêutico , Insuficiência Renal/tratamento farmacológico , Sulfonamidas/uso terapêutico
14.
Cancer Chemother Pharmacol ; 84(4): 891-898, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31444617

RESUMO

PURPOSE: Fedratinib (SAR302503, TG101348) is an orally administered Janus kinase (JAK) 2-selective inhibitor that is being developed for the treatment of patients with myelofibrosis (MF). The objectives of this analysis were to develop a population pharmacokinetic (PK) model to characterize fedratinib concentration-time profiles in patients with MF, polycythemia vera (PV) and essential thrombocythemia (ET) following oral fedratinib administration; and to investigate the effects of selected covariates on fedratinib PK parameters. METHODS: Nonlinear mixed effects modeling was employed in developing a population PK model for fedratinib. Intensive or sparse fedratinib concentration data collected in adult subjects with MF, PV or ET from six studies were pooled, and a total of 452 subjects and 3442 plasma concentration observations were included in the final model. RESULTS: Fedratinib PK in patients with MF/PV/ET was adequately described by a two-compartment structural PK model with first-order absorption incorporating a lag time and first-order elimination. Following oral administration, fedratinib undergoes biphasic disposition and exhibits linear, time-invariant PK at doses of 200 mg and above. Compared to MF/ET patients, PV patients had higher apparent clearance (CL/F) and apparent central volume of distribution. Creatinine clearance was a statistically significant covariate on CL/F, and patients with mild and moderate renal impairment had 10% and 37% increases in fedratinib exposure as compared to patients with normal renal function. No clinically meaningful effect on fedratinib exposure was observed regarding age, body weight, sex, race and liver function. CONCLUSIONS: These results should serve as the basis for dose adjustment of fedratinib for special populations.


Assuntos
Janus Quinase 2/metabolismo , Policitemia Vera , Mielofibrose Primária , Pirrolidinas , Sulfonamidas , Trombocitemia Essencial , Administração Oral , Adulto , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Testes de Função Renal/métodos , Testes de Função Renal/estatística & dados numéricos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Policitemia Vera/sangue , Policitemia Vera/tratamento farmacológico , Mielofibrose Primária/sangue , Mielofibrose Primária/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Pirrolidinas/administração & dosagem , Pirrolidinas/sangue , Pirrolidinas/farmacocinética , Sulfonamidas/administração & dosagem , Sulfonamidas/sangue , Sulfonamidas/farmacocinética , Trombocitemia Essencial/sangue , Trombocitemia Essencial/tratamento farmacológico
15.
Arch Pharm (Weinheim) ; 352(9): e1900099, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31381192

RESUMO

Optimization of a modified Grimmel's method for N-heterocyclization of a leucine-linked sulfonamide side-arm at position 2 leading to 2,3-disustituted-4-quinazolin-(3H)-ones was accomplished. Further, 22 hybrid quinazolinone motifs (4a-v) were synthesized by N-heterocyclization reaction under microwave irradiation using the ionic liquid [Bmim][BF4 ]-H2 O as green solvent as well as the catalyst. The in vitro screening of the hybrid entities against the malarial species Plasmodium falciparum yielded five potent molecules 4l, 4n, 4o, 4t, and 4u owning antimalarial activity comparable to those of the reference drugs. In continuation, an in silico study was carried out to obtain a pharmacophoric model and quantitative structure-activity relationship. We also built a 3D-QSAR model to procure more information that could be applied to design new molecules with more potent Pf-DHFR inhibitory activity. The designed pharmacophore was recognized to be more potent for the selected molecules, exhibiting five pharmacophoric features. The active scaffolds were further evaluated for enzyme inhibition efficacy against alleged receptor Pf-DHFR computationally and in vitro, proving their candidature as lead dihydrofolate reductase inhibitors, and the selectivity of the test candidates was ascertained by toxicity study against Vero cells. Good oral bioavailability was also proved by studying pharmacokinetic properties.


Assuntos
Antimaláricos/síntese química , Desenho de Fármacos , Antagonistas do Ácido Fólico/síntese química , Ácido Fólico/metabolismo , Leucina/química , Quinazolinas/química , Sulfonamidas/síntese química , Animais , Antimaláricos/farmacocinética , Antimaláricos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Antagonistas do Ácido Fólico/farmacocinética , Antagonistas do Ácido Fólico/farmacologia , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Estrutura Molecular , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Relação Quantitativa Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Células Vero
16.
ACS Chem Biol ; 14(9): 1990-1997, 2019 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-31407891

RESUMO

Here, we report the design, synthesis, and evaluation of a series of inhibitors of Staphylococcus aureus BPL (SaBPL), where the central acyl phosphate of the natural intermediate biotinyl-5'-AMP (1) is replaced by a sulfonamide isostere. Acylsulfamide (6) and amino sulfonylurea (7) showed potent in vitro inhibitory activity (Ki = 0.007 ± 0.003 and 0.065 ± 0.03 µM, respectively) and antibacterial activity against S. aureus ATCC49775 with minimum inhibitory concentrations of 0.25 and 4 µg/mL, respectively. Additionally, the bimolecular interactions between the BPL and inhibitors 6 and 7 were defined by X-ray crystallography and molecular dynamics simulations. The high acidity of the sulfonamide linkers of 6 and 7 likely contributes to the enhanced in vitro inhibitory activities by promoting interaction with SaBPL Lys187. Analogues with alkylsulfamide (8), ß-ketosulfonamide (9), and ß-hydroxysulfonamide (10) isosteres were devoid of significant activity. Binding free energy estimation using computational methods suggests deprotonated 6 and 7 to be the best binders, which is consistent with enzyme assay results. Compound 6 was unstable in whole blood, leading to poor pharmacokinetics. Importantly, 7 has a vastly improved pharmacokinetic profile compared to that of 6 presumably due to the enhanced metabolic stability of the sulfonamide linker moiety.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Carbono-Nitrogênio Ligases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Sulfonamidas/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/farmacocinética , Proteínas de Bactérias/química , Carbono-Nitrogênio Ligases/química , Cristalografia por Raios X , Desenho de Fármacos , Estabilidade de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Dinâmica Molecular , Ratos , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/enzimologia , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética
17.
PLoS One ; 14(7): e0219022, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31291311

RESUMO

AIMS: Drug-induced liver damage characterized by serum alanine aminotransferase (ALT) elevation often occurs in direct-acting antiviral (DAA) combination therapy for chronic hepatitis C virus (HCV) infection. This study explored single nucleotide polymorphisms (SNPs) at drug metabolism- or transport-related genes that were associated with ALT elevation in asunaprevir plus daclatasvir therapy. METHODS: Subjects were 185 Japanese patients with chronic HCV genotype 1b infection who received asunaprevir plus daclatasvir therapy. Tag SNPs at possible metabolizing enzyme and transporter genes, which were involved in the pharmacokinetics of asunaprevir and daclatasvir, were selected. RESULTS: Among the tag SNPs analyzed, CYP3A4 rs4646437 was significantly associated with ALT elevation (p = 0.013): maximum ALT values in patients with genotype CC were higher than those in patients with genotype non-CC (allele T). The proportion of grades 2-4 in genotype CC patients were significantly greater than those in genotype non-CC patients (p = 0.028). No patients with genotype non-CC showed grade ≥2 ALT elevation. In multivariate analysis, rs4646437 genotype CC and cirrhosis were significant, independent factors associated with grade ≥1 ALT elevation (odds ratio, 2.83 and 1.88; p = 0.040 and 0.045, respectively). In exploratory analyses, although serum concentrations of asunaprevir and daclatasvir were not correlated with maximum ALT values or rs4646437 genotypes, asunaprevir concentrations in patients with grade ≥1 ALT elevation were significantly higher than those in patients with grade <1 ALT elevation (P = 0.023). CONCLUSIONS: CYP3A4 rs4646437 was found to be significantly and independently associated with ALT elevation in Japanese patients receiving ASV plus DCV therapy. Notably, none of the patients with rs4646437 genotype non-CC (allele T) had grade ≥2 ALT elevation. SNP genotyping prior to treatment might be useful for carefully monitoring patients to complete treatment safely.


Assuntos
Alanina Transaminase/sangue , Doença Hepática Induzida por Substâncias e Drogas/genética , Citocromo P-450 CYP3A/genética , Hepatite C Crônica/tratamento farmacológico , Imidazóis/administração & dosagem , Isoquinolinas/administração & dosagem , Sulfonamidas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Hepática Induzida por Substâncias e Drogas/sangue , Quimioterapia Combinada/efeitos adversos , Feminino , Genótipo , Hepacivirus/genética , Hepatite C Crônica/sangue , Hepatite C Crônica/genética , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Imidazóis/uso terapêutico , Isoquinolinas/efeitos adversos , Isoquinolinas/farmacocinética , Japão , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Polimorfismo de Nucleotídeo Único , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Regulação para Cima
18.
Hematol Oncol ; 37(4): 464-473, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31251400

RESUMO

The objective of this research was to characterize the venetoclax exposure-efficacy and exposure-safety relationships and determine its optimal dose in elderly patients with newly diagnosed acute myeloid leukemia (AML) receiving venetoclax in combination with low intensity therapies (hypomethylating agent [HMA; azacitidine or decitabine] or low-dose cytarabine [LDAC]). A total of 212 patients from the HMA study and 92 patients from the LDAC study were included in the exposure-safety analyses. Those who received at least one dose of venetoclax and had at least one measurable response (201 and 83 in the HMA and LDAC studies, respectively) were included in the exposure-efficacy analyses. The probability of response based on International Working Group (IWG) for AML response criteria, adverse events of grade 3 or worse neutropenia or infection or a serious adverse event was modeled using logistic regression analyses to characterize the venetoclax exposure-response relationships. In combination with an HMA, increasing concentrations of venetoclax, up to those associated with a less than or equal to 400-mg once daily (QD) dose, were associated with a higher probability of response, with a trend for flat or decreasing probabilities of response thereafter. In combination with LDAC, increasing concentrations of venetoclax were associated with higher probabilities of response, with no plateau observed. Increasing concentrations of venetoclax were not associated with increasing probability of any safety event except for a slight increase in grade 3 or worse infections with HMAs; however, tolerability issues were observed at doses of greater than or equal to 800 mg QD in each study. Exposure-response analyses support the use of venetoclax 400 mg QD in combination with an HMA and 600 mg QD in combination with LDAC (ie, the next highest dose evaluated below 800 mg in each combination) to safely maximize the probability of response in elderly patients with newly diagnosed AML.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Sulfonamidas/administração & dosagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Ensaios Clínicos Fase I como Assunto/estatística & dados numéricos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Metilação de DNA/efeitos dos fármacos , Decitabina/administração & dosagem , Decitabina/efeitos adversos , Relação Dose-Resposta a Droga , Humanos , Terapia de Alvo Molecular , Indução de Remissão , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Resultado do Tratamento
19.
AAPS PharmSciTech ; 20(5): 210, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31161269

RESUMO

Dorzolamide HCl (DRZ) ophthalmic drop is one of the most common glaucoma medications which rapidly eliminates after instillation leading to short residence time of the drug on cornea. The purpose of the present study is to develop a pH-triggered in situ gel system for ophthalmic delivery of DRZ for treatment of ocular hypertension. In this study, a 32 full factorial design was used for preparation of in situ gel formulations using different levels of Carbopol® and hydroxyl propyl methyl cellulose (HPMC). Rheological behavior, in vitro drug release, ex vivo corneal permeability, and IOP-lowering activity were investigated. DRZ solution (2% w/v) containing of 0.1% (w/v) Carbopol® and 0.1% (w/v) HPMC was selected as the optimal formulation considering its free flow under non-physiological conditions (initial pH and 25 ± 2°C) and transition to appropriate gel form under physiological circumstance (pH 7.4 and 34°C). This in situ gel presented the mucoadhesive property. Ex vivo corneal permeability of this combined solution was similar to those of DRZ solution. The developed formulation compared to the marketed drop (Biosopt®) and DRZ 2% solution had a better performance in intraocular pressure activity. The efficiency and long duration of IOP reduction could be due to the prolonged residence time of the in situ gel. The presence of Carbopol® as a pH triggered and mucoadhesive polymer causes to attach to the ocular mucosal surface for a long term.


Assuntos
Resinas Acrílicas/farmacocinética , Anti-Hipertensivos/farmacocinética , Portadores de Fármacos/farmacocinética , Derivados da Hipromelose/farmacocinética , Sulfonamidas/farmacocinética , Tiofenos/farmacocinética , Resinas Acrílicas/administração & dosagem , Resinas Acrílicas/síntese química , Administração Oftálmica , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/síntese química , Córnea/efeitos dos fármacos , Córnea/metabolismo , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Avaliação Pré-Clínica de Medicamentos/métodos , Liberação Controlada de Fármacos , Géis , Glaucoma/tratamento farmacológico , Glaucoma/metabolismo , Concentração de Íons de Hidrogênio , Derivados da Hipromelose/administração & dosagem , Derivados da Hipromelose/síntese química , Pressão Intraocular/efeitos dos fármacos , Pressão Intraocular/fisiologia , Masculino , Soluções Oftálmicas/administração & dosagem , Soluções Oftálmicas/síntese química , Soluções Oftálmicas/farmacocinética , Coelhos , Sulfonamidas/administração & dosagem , Sulfonamidas/síntese química , Suínos , Tiofenos/administração & dosagem , Tiofenos/síntese química
20.
Lancet Respir Med ; 7(7): 594-604, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31178422

RESUMO

BACKGROUND: No dedicated randomised clinical trials have evaluated therapies for pulmonary arterial hypertension in patients with portopulmonary hypertension. The endothelin receptor antagonist macitentan has demonstrated long-term efficacy in pulmonary arterial hypertension with a good hepatic safety profile. We aimed to evaluate efficacy and safety of macitentan in patients with portopulmonary hypertension. METHODS: PORTICO was a phase 4 study done in 36 centres in seven countries, consisting of a 12-week double-blind period (randomly assigned 1:1 to macitentan 10 mg or placebo once daily) followed by a 12-week open-label period. Adults (≥18 years) with portopulmonary hypertension, a 6-minute walk distance of 50 m or more, and with pulmonary vascular resistance of 320 dyn·s·cm-5 or more without severe hepatic impairment (Child-Pugh class C or model for end-stage liver disease score ≥19) were eligible. The primary endpoint was pulmonary vascular resistance at week 12, expressed as ratio of baseline in the full analysis set. Safety was assessed throughout. This trial is registered at ClinicalTrials.gov, number NCT02382016. FINDINGS: Between June 23, 2015, and July 28, 2017, 85 patients were randomly assigned to macitentan (n=43) or placebo (n=42). At baseline, 54 (64%) were receiving background therapy for pulmonary arterial hypertension. Most patients were WHO functional class II (50, 59%) or III (33, 39%) with a mean 6-minute walk distance of 384·5 m (SD 103·9). At week 12, the geometric mean ratio of baseline pulmonary vascular resistance was 0·63 (95% CI 0·58-0·67) in the macitentan group and 0·98 (95% CI 0·91-1·05) in the placebo group, corresponding to a ratio of geometric mean for pulmonary vascular resistance of 0·65 (95% CI 0·59-0·72, p<0·0001), which in turn represented a 35% (95% CI 28-41) reduction in pulmonary vascular resistance with macitentan versus placebo. During the double-blind period, 36 (84%) macitentan-treated and 33 (79%) placebo-treated patients had adverse events, and nine (21%) and six (14%), had serious adverse events. Four (9%) macitentan-treated patients had an adverse event leading to discontinuation versus none in the placebo group. The most frequent adverse event during the double-blind period was peripheral oedema (11 [26%] in the macitentan group and five [12%] in the placebo group). INTERPRETATION: Macitentan significantly improved pulmonary vascular resistance in portopulmonary hypertension patients, with no hepatic safety concerns. FUNDING: Actelion Pharmaceuticals Ltd.


Assuntos
Antagonistas dos Receptores de Endotelina/uso terapêutico , Hipertensão Portal/tratamento farmacológico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Idoso , Método Duplo-Cego , Antagonistas dos Receptores de Endotelina/farmacocinética , Feminino , Humanos , Hipertensão Portal/complicações , Masculino , Pessoa de Meia-Idade , Hipertensão Arterial Pulmonar/complicações , Pirimidinas/farmacocinética , Sulfonamidas/farmacocinética , Resultado do Tratamento , Resistência Vascular
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