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1.
Blood ; 144(10): 1127-1130, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-38917352
2.
Neuroimage ; 301: 120882, 2024 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-39362505

RESUMO

BioLuminescent OptoGenetics ("BL-OG") is a chemogenetic method that can evoke optogenetic reactions in the brain non-invasively. In BL-OG, an enzyme that catalyzes a light producing reaction (i.e., a luciferase) is tethered to an optogenetic element that is activated in response to bioluminescent light. Bioluminescence is generated by injecting a chemical substrate (luciferin, e.g., h-Coelenterazine; h-CTZ) that is catalyzed by the luciferase. By directly injecting the luciferin into the brain, we show that bioluminescent light is proportional to spiking activity, and this relationship scales as a function of luciferin dosage. Here, we build on these previous observations by characterizing the temporal dynamics and dose response curves of bioluminescence generated by luminopsins (LMOs), a proxy of BL-OG effects, to intravenous (IV) injections of the luciferin. We imaged bioluminescence through a thinned skull of mice running on a wheel, while delivering h-CTZ via the tail vein with different dosage concentrations and injection rates. The data reveal a systematic relationship between strength of bioluminescence and h-CTZ dosage, with higher concentration generating stronger bioluminescence. We also found that bioluminescent activity occurs rapidly (< 60 s after IV injection) regardless of concentration dosage. However, as expected, the onset time of bioluminescence is delayed as the injection rate decreases. Notably, the strength and time decay of bioluminescence is invariant to the injection rate of h-CTZ. Taken together, these data show that BL-OG effects are highly consistent across injection parameters of h-CTZ, highlighting the reliability of BL-OG as a minimally invasive neuromodulation method.


Assuntos
Medições Luminescentes , Optogenética , Animais , Optogenética/métodos , Camundongos , Medições Luminescentes/métodos , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem , Pirazinas/administração & dosagem , Pirazinas/farmacocinética , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Imidazóis/farmacocinética , Substâncias Luminescentes , Masculino , Luciferina de Vaga-Lumes/metabolismo , Luciferases/genética , Luciferases/metabolismo , Camundongos Endogâmicos C57BL
3.
Cancer ; 130(10): 1784-1796, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38261444

RESUMO

BACKGROUND: Aberrant PI3K/AKT signaling in BRAF-mutant cancers contributes to resistance to BRAF inhibitors. The authors examined dual MAPK and PI3K pathway inhibition in patients who had BRAF-mutated solid tumors (ClinicalTrials.gov identifier NCT01902173). METHODS: Patients with BRAF V600E/V600K-mutant solid tumors received oral dabrafenib at 150 mg twice daily with dose escalation of oral uprosertib starting at 50 mg daily, or, in the triplet cohorts, with dose escalation of both oral trametinib starting at 1.5 mg daily and oral uprosertib starting at 25 mg daily. Dose-limiting toxicities (DLTs) were assessed within the first 56 days of treatment. Radiographic responses were assessed at 8-week intervals. RESULTS: Twenty-seven patients (22 evaluable) were enrolled in parallel doublet and triplet cohorts. No DLTs were observed in the doublet cohorts (N = 7). One patient had a DLT at the maximum administered dose of triplet therapy (dabrafenib 150 mg twice daily and trametinib 2 mg daily plus uprosertib 75 mg daily). Three patients in the doublet cohorts had partial responses (including one who had BRAF inhibitor-resistant melanoma). Two patients in the triplet cohorts had a partial response, and one patient had an unconfirmed partial response. Pharmacokinetic data suggested reduced dabrafenib and dabrafenib metabolite exposure in patients who were also exposed to both trametinib and uprosertib, but not in whose who were exposed to uprosertib without trametinib. CONCLUSIONS: Concomitant inhibition of both the MAPK and PI3K-AKT pathways for the treatment of BRAF-mutated cancers was well tolerated, leading to objective responses, but higher level drug-drug interactions affected exposure to dabrafenib and its metabolites.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Imidazóis , Mutação , Neoplasias , Oximas , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas B-raf , Proteínas Proto-Oncogênicas c-akt , Piridonas , Pirimidinonas , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Adulto , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Pirimidinonas/administração & dosagem , Pirimidinonas/efeitos adversos , Pirimidinonas/uso terapêutico , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Oximas/administração & dosagem , Oximas/efeitos adversos , Oximas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Idoso de 80 Anos ou mais , Terapia de Alvo Molecular
4.
Br J Cancer ; 131(5): 843-851, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38971952

RESUMO

BACKGROUND: Therapeutic drug monitoring (TDM) - performing dose adjustments based on measured drug levels and established pharmacokinetic (PK) targets - could optimise treatment with drugs that show large interpatient variability in exposure. We evaluated the feasibility of TDM for multiple oral targeted therapies. Here we report on drugs for which routine TDM is not feasible. METHODS: We evaluated drug cohorts from the Dutch Pharmacology Oncology Group - TDM study. Based on PK levels taken at pre-specified time points, PK-guided interventions were performed. Feasibility of TDM was evaluated, and based on the success and practicability of TDM, cohorts could be closed. RESULTS: For 10 out of 24 cohorts TDM was not feasible and inclusion was closed. A high incidence of adverse events resulted in closing the cabozantinib, dabrafenib/trametinib, everolimus, regorafenib and vismodegib cohort. The enzalutamide and erlotinib cohorts were closed because almost all PK levels were above target. Other, non-pharmacological reasons led to closing the palbociclib, olaparib and tamoxifen cohort. CONCLUSIONS: Although TDM could help personalising treatment for many drugs, the above-mentioned reasons can influence its feasibility, usefulness and clinical applicability. Therefore, routine TDM is not advised for cabozantinib, dabrafenib/trametinib, enzalutamide, erlotinib, everolimus, regorafenib and vismodegib. Nonetheless, TDM remains valuable for individual clinical decisions.


Assuntos
Monitoramento de Medicamentos , Neoplasias , Piridinas , Humanos , Monitoramento de Medicamentos/métodos , Estudos Prospectivos , Neoplasias/tratamento farmacológico , Piridinas/farmacocinética , Piridinas/administração & dosagem , Estudos de Viabilidade , Administração Oral , Antineoplásicos/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Terapia de Alvo Molecular , Imidazóis/farmacocinética , Imidazóis/administração & dosagem , Anilidas/farmacocinética , Anilidas/administração & dosagem , Masculino , Everolimo/farmacocinética , Everolimo/administração & dosagem , Feminino , Oximas/farmacocinética , Oximas/administração & dosagem , Feniltioidantoína/análogos & derivados , Feniltioidantoína/farmacocinética , Feniltioidantoína/administração & dosagem , Nitrilas/farmacocinética , Nitrilas/administração & dosagem , Compostos de Fenilureia , Piridonas , Pirimidinonas , Piperazinas , Benzamidas
5.
Drug Metab Dispos ; 52(9): 981-987, 2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-38991780

RESUMO

Two unique metabolites (M18 and M19) were detected in feces of human volunteers dosed orally with [14C]inavolisib with a molecular ion of parent plus 304 Da. They were generated in vitro by incubation with fecal homogenates and we have evidence that they are formed chemically and possibly enzymatically. Structural elucidation by high resolution mass spectrometry and nuclear magnetic resonance spectroscopy showed that the imidazole ring of inavolisib was covalently bound to partial structures derived from stercobilin, an end-product of heme catabolism produced by the gut microbiome. The structural difference between the two metabolites was the position of methyl and ethyl groups on the pyrrolidin-2-one moieties. We propose a mechanism of M18 and M19 generation from inavolisib and stercobilin whereby nucleophilic attack from the imidazole ring of inavolisib occurs to the bridging carbon of a stercobilin molecule. The proposed mechanism was supported by computational calculations of molecular orbitals and transition geometry. SIGNIFICANCE STATEMENT: We report the characterization of two previously undescribed conjugates of the phosphoinositide 3-kinase inhibitor inavolisib, generated by reaction with stercobilin, an end-product of heme catabolism produced by the gut microbiome. These conjugates were confirmed by generating them using in vitro fecal homogenate incubation via nonenzymatic and possibly enzymatic reactions. Given the unique nature of the conjugate, it is plausible that it may have been overlooked with other small molecule drugs in prior studies.


Assuntos
Fezes , Humanos , Fezes/microbiologia , Fezes/química , Masculino , Imidazóis/metabolismo , Imidazóis/farmacocinética , Imidazóis/química , Adulto , Microbioma Gastrointestinal/fisiologia , Feminino , Administração Oral
6.
Pharm Res ; 41(5): 849-861, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38485855

RESUMO

PURPOSE: Olmesartan medoxomil (olmesartan-MX), an ester-type prodrug of the angiotensin II receptor blocker (ARB) olmesartan, is predominantly anionic at intestinal pH. Human organic anion transporting polypeptide 2B1 (OATP2B1) is expressed in the small intestine and is involved in the absorption of various acidic drugs. This study was designed to test the hypothesis that OATP2B1-mediated uptake contributes to the enhanced intestinal absorption of olmesartan-MX, even though olmesartan itself is not a substrate of OATP2B1. METHODS: Tetracycline-inducible human OATP2B1- and rat Oatp2b1-overexpressing HEK 293 cell lines (hOATP2B1/T-REx-293 and rOatp2b1/T-REx-293, respectively) were established to characterize OATP2B1-mediated uptake. Rat jejunal permeability was measured using Ussing chambers. ARBs were quantified by liquid chromatography-tandem mass spectrometry. RESULTS: Significant olmesartan-MX uptake was observed in hOATP2B1/T-REx-293 and rOatp2b1/T-REx-293 cells, whereas olmesartan uptake was undetectable or much lower than olmesartan-MX uptake, respectively. Furthermore, olmesartan-MX exhibited several-fold higher uptake in Caco-2 cells and greater permeability in rat jejunum compared to olmesartan. Olmesartan-MX uptake in hOATP2B1/T-REx-293 cells and in Caco-2 cells was significantly decreased by OATP2B1 substrates/inhibitors such as 1 mM estrone-3-sulfate, 100 µM rifamycin SV, and 100 µM fluvastatin. Rat Oatp2b1-mediated uptake and rat jejunal permeability of olmesartan-MX were significantly decreased by 50 µM naringin, an OATP2B1 inhibitor. Oral administration of olmesartan-MX with 50 µM naringin to rats significantly reduced the area under the plasma concentration-time curve of olmesartan to 76.9%. CONCLUSION: Olmesartan-MX is a substrate for OATP2B1, and the naringin-sensitive transport system contributes to the improved intestinal absorption of olmesartan-MX compared with its parent drug, olmesartan.


Assuntos
Imidazóis , Absorção Intestinal , Olmesartana Medoxomila , Transportadores de Ânions Orgânicos , Pró-Fármacos , Tetrazóis , Animais , Humanos , Absorção Intestinal/efeitos dos fármacos , Olmesartana Medoxomila/metabolismo , Pró-Fármacos/farmacocinética , Pró-Fármacos/metabolismo , Células HEK293 , Tetrazóis/farmacocinética , Tetrazóis/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Masculino , Imidazóis/farmacocinética , Imidazóis/metabolismo , Ratos , Ratos Sprague-Dawley , Jejuno/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacocinética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Permeabilidade/efeitos dos fármacos , Células CACO-2
7.
AAPS PharmSciTech ; 25(8): 252, 2024 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-39443354

RESUMO

Osteoporosis is a metabolic bone disorder with impaired bone microstructure and increased bone fractures, seriously affecting the quality of life of patients. Among various bisphosphonates prescribed for managing osteoporosis, minodronic acid (MA) is the most potent inhibitor of bone context resorption. However, oral MA tablet is the only commercialized dosage form that has extremely low bioavailability, severe adverse reactions, and poor patient compliance. To tackle these issues, we developed MA-loaded dissolving microneedles (MA-MNs) with significantly improved bioavailability for osteoporosis therapy. We investigated the influence of drug loading on the physicochemical properties, transdermal permeation behavior, and pharmacokinetics of MA-MNs. The drug loading of MA-MNs exerted almost no effect on their morphology, mechanical property, and skin insertion ability, but it compromised the transdermal permeability and bioavailability of MA-MNs. Compared with oral MA, MA-MNs with the lowest drug loading (224.9 µg/patch) showed a 9-fold and 25.8-fold increase in peak concentration and bioavailability, respectively. This may be ascribed to the reason that the increased drug loading can generate higher burst release, higher drug residual rate, and drug supersaturation effect in skin tissues, eventually limiting drug absorption into the systemic circulation. Moreover, MA-MNs prolonged the half-life of MA and provided more steady plasma drug concentrations than intravenously injected MA, which helps to reduce dosing frequency and side effects. Therefore, dissolving MNs with optimized drug loading provides a promising alternative for bisphosphonate drug delivery.


Assuntos
Administração Cutânea , Disponibilidade Biológica , Conservadores da Densidade Óssea , Difosfonatos , Sistemas de Liberação de Medicamentos , Imidazóis , Agulhas , Osteoporose , Absorção Cutânea , Animais , Osteoporose/tratamento farmacológico , Imidazóis/administração & dosagem , Imidazóis/farmacocinética , Imidazóis/química , Difosfonatos/administração & dosagem , Difosfonatos/farmacocinética , Ratos , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/farmacocinética , Absorção Cutânea/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Ratos Sprague-Dawley , Pele/metabolismo , Masculino , Solubilidade , Liberação Controlada de Fármacos , Administração Oral
8.
AAPS PharmSciTech ; 25(7): 229, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39354184

RESUMO

The development of effective therapy is necessary because the patients have to contend with long-term therapy as skin fungal infections usually relapse and are hardly treated. Despite being a potent antifungal agent, luliconazole (LCZ) has certain shortcomings such as limited skin penetration, low solubility in aqueous medium, and poor skin retention. Solid Lipid Nanoparticles (SLNs) were developed using biodegradable lipids by solvent injection method and were embodied into the gel base for topical administration. After in-vitro characterizations of the formulations, molecular interactions of the drug with excipients were analyzed using in-silico studies. Ex-vivo release was determined in contrast to the pure LCZ and the commercial formulation followed by in-vivo skin localization, skin irritation index, and antifungal activity. The prepared SLNs have an average particle size of 290.7 nm with no aggregation of particles and homogenous gels containing SLNs with ideal rheology and smooth texture properties were successfully prepared. The ex-vivo LCZ release from the SLN gel was lower than the commercial formulation whereas its skin deposition and skin retention were higher as accessed by CLSM studies. The drug reaching the systemic circulation and the skin irritation potential were found to be negligible. The solubility and drug retention in the skin were both enhanced by the development of SLNs as a carrier. Thus, SLNs offer significant advantages by delivering long lasting concentrations of LCZ at the site of infection for a complete cure of the fungal load together with skin localization of the topical antifungal drug.


Assuntos
Antifúngicos , Géis , Imidazóis , Nanopartículas , Tamanho da Partícula , Pele , Solubilidade , Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Antifúngicos/farmacologia , Nanopartículas/química , Pele/metabolismo , Pele/efeitos dos fármacos , Animais , Imidazóis/administração & dosagem , Imidazóis/farmacocinética , Imidazóis/química , Imidazóis/farmacologia , Administração Tópica , Química Farmacêutica/métodos , Absorção Cutânea/efeitos dos fármacos , Lipídeos/química , Portadores de Fármacos/química , Administração Cutânea , Excipientes/química , Liberação Controlada de Fármacos
9.
Proc Natl Acad Sci U S A ; 117(22): 11987-11994, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32424082

RESUMO

Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis worldwide and kills more Americans than 59 other infections, including HIV and tuberculosis, combined. While direct-acting antiviral (DAA) treatments are effective, limited uptake of therapy, particularly in high-risk groups, remains a substantial barrier to eliminating HCV. We developed a long-acting DAA system (LA-DAAS) capable of prolonged dosing and explored its cost-effectiveness. We designed a retrievable coil-shaped LA-DAAS compatible with nasogastric tube administration and the capacity to encapsulate and release gram levels of drugs while resident in the stomach. We formulated DAAs in drug-polymer pills and studied the release kinetics for 1 mo in vitro and in vivo in a swine model. The LA-DAAS was equipped with ethanol and temperature sensors linked via Bluetooth to a phone application to provide patient engagement. We then performed a cost-effectiveness analysis comparing LA-DAAS to DAA alone in various patient groups, including people who inject drugs. Tunable release kinetics of DAAs was enabled for 1 mo with drug-polymer pills in vitro, and the LA-DAAS safely and successfully provided at least month-long release of sofosbuvir in vivo. Temperature and alcohol sensors could interface with external sources for at least 1 mo. The LA-DAAS was cost-effective compared to DAA therapy alone in all groups considered (base case incremental cost-effectiveness ratio $39,800). We believe that the LA-DAA system can provide a cost-effective and patient-centric method for HCV treatment, including in high-risk populations who are currently undertreated.


Assuntos
Antivirais/administração & dosagem , Sistemas de Liberação de Medicamentos , Hepatite C Crônica/tratamento farmacológico , Animais , Antivirais/farmacocinética , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacocinética , Carbamatos , Análise Custo-Benefício , Modelos Animais de Doenças , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/economia , Sistemas de Liberação de Medicamentos/instrumentação , Sistemas de Liberação de Medicamentos/métodos , Fluorenos/administração & dosagem , Fluorenos/farmacocinética , Hepacivirus/efeitos dos fármacos , Imidazóis/administração & dosagem , Imidazóis/farmacocinética , Cirrose Hepática/tratamento farmacológico , Modelos Animais , Pirrolidinas , Ribavirina/administração & dosagem , Ribavirina/farmacocinética , Sofosbuvir/administração & dosagem , Sofosbuvir/farmacocinética , Suínos , Valina/análogos & derivados
10.
Am J Hum Genet ; 104(3): 484-491, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30803705

RESUMO

Proteus syndrome is a life-threatening segmental overgrowth syndrome caused by a mosaic gain-of-function AKT1 variant. There are no effective treatments for Proteus syndrome. Miransertib is an AKT1 inhibitor that, prior to this study, has been evaluated only in adult oncology trials. We designed a non-randomized, phase 0/1 pilot study of miransertib in adults and children with Proteus syndrome to identify an appropriate dosage starting point for a future efficacy trial using a pharmacodynamic endpoint. The primary endpoint was a 50% reduction in the tissue levels of AKT phosphorylation from biopsies in affected individuals. We also evaluated secondary efficacy endpoints. We found that a dose of 5 mg/m2/day (1/7 the typical dose used in oncology) led to a 50% reduction in phosphorylated AKT (pAKT) in affected tissues from five of six individuals. This dose was well tolerated. Two of the six efficacy endpoints (secondary objectives) suggested that this agent may be efficacious. We observed a decrease in a cerebriform connective tissue nevus and a reduction in pain in children. We conclude that 5 mg/m2/day of miransertib is an appropriate starting point for future efficacy trials and that this agent shows promise of therapeutic efficacy in children with Proteus syndrome.


Assuntos
Aminopiridinas/farmacologia , Imidazóis/farmacologia , Nevo/prevenção & controle , Dor/prevenção & controle , Síndrome de Proteu/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Adolescente , Adulto , Aminopiridinas/farmacocinética , Criança , Feminino , Humanos , Imidazóis/farmacocinética , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Fosforilação , Projetos Piloto , Prognóstico , Síndrome de Proteu/metabolismo , Síndrome de Proteu/patologia , Distribuição Tecidual , Adulto Jovem
11.
Toxicol Appl Pharmacol ; 434: 115797, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34780725

RESUMO

Dabrafenib is a BRAF inhibitor used in combination treatment of malignant melanoma and non-small cell lung carcinoma. In this study, we aimed to characterize its interactions with cytochrome P450 (CYP) isoenzymes and ATP-binding cassette (ABC) efflux transporters that have critical impact on the pharmacokinetics of drugs and play a role in drug resistance development. Using accumulation assays, we showed that dabrafenib inhibited ABCG2 and, less potently, ABCB1 transporter. We also confirmed dabrafenib as a CYP2C8, CYP2C9, CYP3A4, and CYP3A5 inhibitor. Importantly, inhibition of ABCG2 and CYP3A4 by dabrafenib led to the potentiation of cytotoxic effects of mitoxantrone and docetaxel toward respective resistant cell lines in drug combination studies. On the contrary, the synergistic effect was not consistently observed in ABCB1-expressing models. We further demonstrated that mRNA levels of ABCB1, ABCG2, ABCC1, and CYP3A4 were increased after 24 h and 48 h exposure to dabrafenib. Overall, our data confirm dabrafenib as a drug frequently and potently interacting with ABC transporters and CYP isoenzymes. This feature should be addressed with caution when administering dabrafenib to patients with polypharmacy but also could be utilized advantageously when designing new dabrafenib-containing drug combinations to improve the therapeutic outcome in drug-resistant cancer.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Daunorrubicina/farmacologia , Imidazóis/farmacocinética , Mitoxantrona/farmacologia , Oximas/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Inibidores das Enzimas do Citocromo P-450/administração & dosagem , Daunorrubicina/administração & dosagem , Cães , Quimioterapia Combinada , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imidazóis/administração & dosagem , Mitoxantrona/administração & dosagem , Oximas/administração & dosagem , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
12.
J Nanobiotechnology ; 20(1): 34, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-35033089

RESUMO

BACKGROUND: Insufficient radiofrequency ablation (IRFA) can promote the local recurrence and distal metastasis of residual hepatocellular carcinoma (HCC), which makes clinical treatment extremely challenging. In this study, the malignant transition of residual tumors after IRFA was explored. Then, arsenic-loaded zeolitic imidazolate framework-8 nanoparticles (As@ZIF-8 NPs) were constructed, and their therapeutic effect on residual tumors was studied. RESULTS: Our data showed that IRFA can dramatically promote the proliferation, induce the metastasis, activate the epithelial-mesenchymal transition (EMT) and accelerate the angiogenesis of residual tumors. Interestingly, we found, for the first time, that extensive angiogenesis after IRFA can augment the enhanced permeability and retention (EPR) effect and enhance the enrichment of ZIF-8 nanocarriers in residual tumors. Encouraged by this unique finding, we successfully prepared As@ZIF-8 NPs with good biocompatibility and confirmed that they were more effective than free arsenic trioxide (ATO) in sublethal heat-induced cell proliferation suppression, apoptosis induction, cell migration and invasion inhibition, and EMT reversal in vitro. Furthermore, compared with free ATO, As@ZIF-8 NPs exhibited remarkably increased therapeutic effects by repressing residual tumor growth and metastasis in vivo. CONCLUSIONS: This work provides a new paradigm for the treatment of residual HCC after IRFA.


Assuntos
Antineoplásicos , Arsênio , Carcinoma Hepatocelular , Imidazóis , Estruturas Metalorgânicas , Nanopartículas , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Arsênio/química , Arsênio/farmacocinética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacocinética , Camundongos , Nanopartículas/química , Nanopartículas/metabolismo , Ablação por Radiofrequência , Distribuição Tecidual
13.
J Pharmacol Exp Ther ; 377(1): 157-168, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33541889

RESUMO

The metabotropic glutamate receptor 5 (mGlu5) is a recognized central nervous system therapeutic target for which several negative allosteric modulator (NAM) drug candidates have or are continuing to be investigated for various disease indications in clinical development. Direct measurement of target receptor occupancy (RO) is extremely useful to help design and interpret efficacy and safety in nonclinical and clinical studies. In the mGlu5 field, this has been successfully achieved by monitoring displacement of radiolabeled ligands, specifically binding to the mGlu5 receptor, in the presence of an mGlu5 NAM using in vivo and ex vivo binding in rodents and positron emission tomography imaging in cynomolgus monkeys and humans. The aim of this study was to measure the RO of the mGlu5 NAM HTL0014242 in rodents and cynomolgus monkeys and to compare its plasma and brain exposure-RO relationships with those of clinically tested mGlu5 NAMs dipraglurant, mavoglurant, and basimglurant. Potential sources of variability that may contribute to these relationships were explored. Distinct plasma exposure-response relationships were found for each mGlu5 NAM, with >100-fold difference in plasma exposure for a given level of RO. However, a unified exposure-response relationship was observed when both unbound brain concentration and mGlu5 affinity were considered. This relationship showed <10-fold overall difference, was fitted with a Hill slope that was not significantly different from 1, and appeared consistent with a simple Emax model. This is the first time this type of comparison has been conducted, demonstrating a unified brain exposure-RO relationship across several species and mGlu5 NAMs with diverse properties. SIGNIFICANCE STATEMENT: Despite the long history of mGlu5 as a therapeutic target and progression of multiple compounds to the clinic, no formal comparison of exposure-receptor occupancy relationships has been conducted. The data from this study indicate for the first time that a consistent, unified relationship can be observed between exposure and mGlu5 receptor occupancy when unbound brain concentration and receptor affinity are taken into account across a range of species for a diverse set of mGlu5 negative allosteric modulators, including a new drug candidate, HTL0014242.


Assuntos
Fármacos Atuantes sobre Aminoácidos Excitatórios/farmacocinética , Receptor de Glutamato Metabotrópico 5/metabolismo , Administração Oral , Regulação Alostérica , Sítio Alostérico , Animais , Encéfalo/metabolismo , Estudos Clínicos como Assunto , Relação Dose-Resposta a Droga , Fármacos Atuantes sobre Aminoácidos Excitatórios/administração & dosagem , Fármacos Atuantes sobre Aminoácidos Excitatórios/sangue , Imidazóis/administração & dosagem , Imidazóis/sangue , Imidazóis/farmacocinética , Indóis/administração & dosagem , Indóis/sangue , Indóis/farmacocinética , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Piridinas/administração & dosagem , Piridinas/sangue , Piridinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5/química
14.
Drug Metab Dispos ; 49(1): 3-11, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33144341

RESUMO

Understanding the mechanisms of drug transport across the blood-brain barrier (BBB) is an important issue for regulating the pharmacokinetics of drugs in the central nervous system. In this study, we focused on solute carrier family 35, member F2 (SLC35F2), whose mRNA is highly expressed in the BBB. SLC35F2 protein was enriched in isolated mouse and monkey brain capillaries relative to brain homogenates and was localized exclusively on the apical membrane of MDCKII cells and brain microvascular endothelial cells (BMECs) differentiated from human induced pluripotent stem cells (hiPS-BMECs). SLC35F2 activity was assessed using its substrate, YM155, and pharmacological experiments revealed SLC35F2 inhibitors, such as famotidine (half-maximal inhibitory concentration, 160 µM). Uptake of YM155 was decreased by famotidine or SLC35F2 knockdown in immortalized human BMECs (human cerebral microvascular endothelial cell/D3 cells). Furthermore, famotidine significantly inhibited the apical (A)-to-basal (B) transport of YM155 in primary cultured monkey BMECs and hiPS-BMECs. Crucially, SLC35F2 knockout diminished the A-to-B transport and intracellular accumulation of YM155 in hiPS-BMECs. By contrast, in studies using an in situ brain perfusion technique, neither deletion of Slc35f2 nor famotidine reduced brain uptake of YM155, even though YM155 is a substrate of mouse SLC35F2. YM155 uptake was decreased significantly by losartan and naringin, inhibitors for the organic anion transporting polypeptide (OATP) 1A4. These findings suggest SLC35F2 is a functional transporter in various cellular models of the primate BBB that delivers its substrates to the brain and that its relative importance in the BBB is modified by differences in the expression of OATPs between primates and rodents. SIGNIFICANCE STATEMENT: This study demonstrated that SLC35F2 is a functional drug influx transporter in three different cellular models of the primate blood-brain barrier (i.e., human cerebral microvascular endothelial cell/D3 cells, primary cultured monkey BMECs, and human induced pluripotent stem-BMECs) but has limited roles in mouse brain. SLC35F2 facilitates apical-to-basal transport across the tight cell monolayer. These findings will contribute to the development of improved strategies for targeting drugs to the central nervous system.


Assuntos
Transporte Biológico/efeitos dos fármacos , Barreira Hematoencefálica , Famotidina/farmacocinética , Imidazóis/farmacocinética , Proteínas de Membrana Transportadoras/metabolismo , Naftoquinonas/farmacocinética , Transportadores de Ânions Orgânicos/metabolismo , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Células Cultivadas , Fármacos do Sistema Nervoso Central/farmacocinética , Desenvolvimento de Medicamentos/métodos , Células Endoteliais/metabolismo , Haplorrinos , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Modelos Biológicos
15.
Anesthesiology ; 134(1): 35-51, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33064833

RESUMO

BACKGROUND: γ-Aminobutyric acid type A (GABAA) receptor agonists are known to cause involuntary muscle movements. The mechanism of these movements is not known, and its relationship to depth of anesthesia monitoring is unclear. We have explored the effect of involuntary muscle movement on the pharmacokinetic-pharmacodynamic model for the GABAA receptor agonist ABP-700 and its effects on the Bispectral Index (BIS) as well as the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scores. METHODS: Observations from 350 individuals (220 men, 130 women) were analyzed, comprising 6,312 ABP-700 concentrations, 5,658 ABP-700 metabolite (CPM-acid) concentrations, 25,745 filtered BIS values, and 6,249 MOAA/S scores, and a recirculatory model developed. Various subject covariates and pretreatment with an opioid or a benzodiazepine were explored as covariates. Relationships between BIS and MOAA/S models and involuntary muscle movements were examined. RESULTS: The final model shows that the pharmacokinetics of ABP-700 are characterized by small compartmental volumes and rapid clearance. The BIS model incorporates an effect-site for BIS suppression and a secondary excitatory/disinhibitory effect-site associated with a risk of involuntary muscle movements. The secondary effect-site has a threshold that decreases with age. The MOAA/S model did not show excitatory effects. CONCLUSIONS: The GABAA receptor agonist ABP-700 shows the expected suppressive effects for BIS and MOAA/S, but also disinhibitory effects for BIS associated with involuntary muscle movements and reduced by pretreatment. Our model provides information about involuntary muscle movements that may be useful to improve depth of anesthesia monitoring for GABAA receptor agonists.


Assuntos
Anestesia , Monitores de Consciência , Etomidato/análogos & derivados , Agonistas de Receptores de GABA-A/farmacologia , Imidazóis/farmacologia , Adulto , Algoritmos , Analgésicos Opioides , Benzodiazepinas , Sedação Consciente , Etomidato/farmacocinética , Feminino , Agonistas de Receptores de GABA-A/farmacocinética , Humanos , Imidazóis/farmacocinética , Masculino , Monitorização Intraoperatória , Músculo Liso/efeitos dos fármacos , Medicação Pré-Anestésica
16.
Pharm Res ; 38(11): 1821-1838, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34853982

RESUMO

AIMS: Gastric ulcer is a continuous worldwide threat that inquires protective agents. Olmesartan (OLM) has potent anti-oxidant and anti-inflammatory characters, yet having limited bioavailability. We targeted the gastro-protective potential and probable mechanism of OLM and its niosomal form against indomethacin (IND) induced-gastric ulcer in rats. MAIN METHODS: we prepared OLM niosomes (OLM-NIO) with different surfactant: cholesterol molar ratios. We evaluated particle size, zeta-potential, polydispersity, and entrapment efficiency. In-vitro release study, Fourier transform infrared spectroscopy, differential scanning calorimetry, and transmission electron microscopy were performed for selected niosomes. In-vivo, we used oral Omeprazole (30 mg/kg), OLM or OLM-NIO (10 mg/kg) for 3 days before IND (25 mg/kg) ingestion. We assessed gastric lesions, oxidative and inflammatory markers. KEY FINDINGS: OLM-NIO prepared with span 60:cholesterol ratio (1:1) showed high entrapment efficiency 93 ± 2%, small particle size 159.3 ± 6.8 nm, low polydispersity 0.229 ± 0.009, and high zeta-potential -35.3 ± 1.2 mV, with sustained release mechanism by release data. In-vivo macroscopical and histological results showed gastro-protective effects of OLM pretreatment, which improved oxidative stress parameters and enhanced the gastric mucosal cyclooxygenase-1 (COX-1) and prostaglandin E2 (PGE2) contents. OLM pretreatment suppressed interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) contents and translocation of p38 mitogen-activated protein kinase (p38-MAPK). Besides, OLM substantially promoted the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) protective pathway. OLM-NIO furtherly improved all previous outcomes. SIGNIFICANCE: We explored OLM anti-ulcerative effects, implicating oxidative stress and inflammation improvement, mediated by the Nrf2/HO-1 signaling pathway and p38-MAPK translocation. Meanwhile, the more bioavailable OLM-NIO achieved better gastro-protective effects compared to conventional OLM form.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Imidazóis/administração & dosagem , Indometacina/efeitos adversos , Úlcera Gástrica/tratamento farmacológico , Tetrazóis/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacocinética , Animais , Disponibilidade Biológica , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Heme Oxigenase (Desciclizante)/metabolismo , Humanos , Imidazóis/farmacocinética , Lipossomos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologia , Tetrazóis/farmacocinética
17.
Mol Divers ; 25(2): 877-888, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-32189236

RESUMO

Fourteen novel 4,5-diphenyl-imidazol-1,2,3-triazole hybrids 8a-n were synthesized with good yields by performing click reaction between the 4,5-diphenyl-2-(prop-2-yn-1-ylthio)-1H-imidazole and various benzyl azides. The synthesized compounds 8a-n were evaluated against yeast α-glucosidase, and all these compounds exhibited excellent inhibitory activity (IC50 values in the range of 85.6 ± 0.4-231.4 ± 1.0 µM), even much more potent than standard drug acarbose (IC50 = 750.0 µM). Among them, 4,5-diphenyl-imidazol-1,2,3-triazoles possessing 2-chloro and 2-bromo-benzyl moieties (compounds 8g and 8i) demonstrated the most potent inhibitory activities toward α-glucosidase. The kinetic study of the compound 8g revealed that this compound inhibited α-glucosidase in a competitive mode. Furthermore, docking calculations of these compounds were performed to predict the interaction mode of the synthesized compounds in the active site of α-glucosidase. A novel series of 4,5-diphenyl-imidazol-1,2,3-triazole hybrids 8a-n was synthesized with good yields by performing click reaction between the 4,5-diphenyl-2-(prop-2-yn-1-ylthio)-1Himidazole and various benzyl azides. The synthesized compounds 8a-n were evaluated against yeast α-glucosidase and all these compounds exhibited excellent inhibitory activity (IC50 values in the range of 85.6 ± 0.4-231.4 ± 1.0 µM), even much more potent than standard drug acarbose (IC50 = 750.0 µM).


Assuntos
Hipoglicemiantes , Imidazóis , Triazóis , alfa-Glucosidases/química , Desenho de Fármacos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/toxicidade , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacocinética , Imidazóis/toxicidade , Cinética , Modelos Biológicos , Simulação de Acoplamento Molecular , Triazóis/síntese química , Triazóis/química , Triazóis/farmacocinética , Triazóis/toxicidade
18.
J Nanobiotechnology ; 19(1): 330, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34670552

RESUMO

BACKGROUND: Supramolecular theranostics have exhibited promising potentials in disease diagnosis and therapy by taking advantages of the dynamic and reversible nature of non-covalent interactions. It is extremely important to figure out the stability of the driving forces in physiological environment for the preparation of theranostic systems. METHODS: The host-guest complexation between cucurbit[8]uril (CB[8]), 4,4'-bipyridinium, and napththyl guest was fully studied using various characterizations, including nuclear magnetic resonance spectroscopy, ultraviolet-visible (UV-vis) spectroscopy, isothermal titration calorimetry (ITC). The association constants of this ternary complex were determined using isothermal titration calorimetry. The stability of the non-covalent interactions and self-assemblies form from this molecular recognition was confirmed by UV-vis spectroscopy and dynamic light scattering (DLS). A supramolecular nanomedicine was constructed on the basis of this 1:1:1 ternary recognition, and its in vitro and in vivo anticancer efficacy were thoroughly evaluated. Positron emission tomography (PET) imaging was used to monitor the delivery and biodistribution of the supramolecular nanomedicine. RESULTS: Various experiments confirmed that the ternary complexation between 4,4'-bipyridinium, and napththyl derivative and CB[8] was stable in physiological environment, including phosphate buffered solution and cell culture medium. Supramolecular nanomedicine (SNM@DOX) encapsulating a neutral anticancer drug (doxrubincin, DOX) was prepared based on this molecular recognition that linked the hydrophobic poly(ε-caprolactone) chain and hydrophilic polyethylene glycol segment. The non-covalent interactions guaranteed the stability of SNM@DOX during blood circulation and promoted its tumor accumulation by taking advantage of the enhanced permeability and retention effect, thus greatly improving the anti-tumor efficacy as compared with the free drug. CONCLUSION: Arising from the host-enhanced charge-transfer interactions, the CB[8]-based ternary recognition was stable enough in physiological environment, which was suitable for the fabrication of supramolecular nanotheranostics showing promising potentials in precise cancer diagnosis and therapy.


Assuntos
Hidrocarbonetos Aromáticos com Pontes , Sistemas de Liberação de Medicamentos/métodos , Imidazóis , Nanomedicina Teranóstica/métodos , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacocinética , Hidrocarbonetos Aromáticos com Pontes/toxicidade , Caproatos/química , Doxorrubicina/química , Doxorrubicina/farmacocinética , Estabilidade de Medicamentos , Feminino , Células Hep G2 , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Imidazóis/toxicidade , Lactonas/química , Camundongos , Camundongos Nus , Tomografia por Emissão de Pósitrons , Análise Espectral , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
19.
J Clin Pharm Ther ; 46(1): 219-222, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32985698

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Some patients with chronic myeloid leukaemia (CML) cannot continue tyrosine kinase inhibitor (TKI) treatment due to intolerance associated with higher plasma concentration. CASE SUMMARY: A 76-year-old woman with chronic-phase CML who showed resistance/intolerance to pre-TKIs has been treated with ponatinib. A high ponatinib bioavailability was noted; therefore, we administered ponatinib 15 mg/3 d to avoid adverse events due to high exposure. Eventually, the patient achieved a major molecular response. WHAT IS NEW AND CONCLUSION: Monitoring of the ponatinib plasma concentration led to safe and effective CML management in a patient with higher drug bioavailability.


Assuntos
Antineoplásicos/farmacocinética , Imidazóis/farmacocinética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Neutropenia/diagnóstico , Piridazinas/farmacocinética , Administração Oral , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Monitoramento de Medicamentos , Feminino , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Neutropenia/induzido quimicamente , Piridazinas/administração & dosagem , Piridazinas/efeitos adversos
20.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070401

RESUMO

Transition metal coordination compounds play an important role in the treatment of neoplastic diseases. However, due to their low selectivity and bioavailability, as well as the frequently occurring phenomenon of drug resistance, new chemical compounds that could overcome these phenomena are still being sought. The solution seems to be the synthesis of new metal complexes conjugated with drug carriers, e.g., dendrimers. Numerous literature data have shown that dendrimers improve the bioavailability of the obtained metal complexes, solving the problem of their poor solubility and stability in an aqueous environment and also breaking down inborn and acquired drug resistance. Therefore, the aim of this study was to synthesize a novel imidazole platinum(II) complex conjugated with and without the second-generation PAMAM dendrimer (PtMet2-PAMAM and PtMet2, respectively) and to evaluate its antitumor activity. Cell viability studies indicated that PtMet2-PAMAM exhibited higher cytotoxic activity than PtMet2 in MCF-7 and MDA-MB-231 breast cancer cells at relatively low concentrations. Moreover, our results indicated that PtMet2-PAMAM exerted antiproliferative effects in a zebrafish embryo model. Treatment with PtMet2-PAMAM substantially increased apoptosis in a dose-dependent manner via caspase-9 (intrinsic pathway) and caspase-8 (extrinsic pathway) activation along with pro-apoptotic protein expression modulation. Additionally, we showed that apoptosis can be induced by activating POX, which induces ROS production. Furthermore, our results also clearly showed that the tested compounds trigger autophagy through p38 pathway activation and increase Beclin-1, LC3, AMPK, and mTOR inhibition. The high pro-apoptotic activity and the ability to activate autophagy by the imidazole platinum(II) complex conjugated with a dendrimer may be due to its demonstrated ability to reverse multidrug resistance (MDR) and thereby increase cellular accumulation in breast cancer cells.


Assuntos
Antineoplásicos , Neoplasias da Mama , Complexos de Coordenação , Dendrímeros , Imidazóis , Platina , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacocinética , Complexos de Coordenação/farmacologia , Dendrímeros/química , Dendrímeros/farmacocinética , Dendrímeros/farmacologia , Feminino , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Imidazóis/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células MCF-7 , Proteínas de Neoplasias/metabolismo , Platina/química , Platina/farmacocinética , Platina/farmacologia
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