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1.
AAPS PharmSciTech ; 22(3): 107, 2021 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-33719019

RESUMO

Ophthalmic diseases represent a significant problem as over 2 billion people worldwide suffer from vison impairment and blindness. Eye drops account for around 90% of ophthalmic medications but are limited in success due to poor patient compliance and low bioavailability. Low bioavailability can be attributed to short retention times in the eye caused by rapid tear turnover and the difficulty of drug diffusion through the multi-layered structure of the eye that includes lipid-rich endothelial and epithelial layers as well as the stroma which is high in water content. In addition, there are barriers such as tight junctional complexes in the corneal epithelium, lacrimal turnover, nasolacrimal drainage, blinking reflexes, efflux transporters, drug metabolism by ocular enzymes, and drug binding to or repulsion from conjunctival mucins, tear proteins, and melanin. In order to maximize transport through the cornea while minimizing drug loss through other pathways, researchers have developed numerous methods to improve eye drop formulations including the addition of viscosity enhancers, permeability enhancers, mucoadhesives, and vasoconstrictors, or using formulations that include puncta occlusion, nanocarriers, or prodrugs. This review explains the mechanism behind each of these methods, examines their history, analyzes previous and current research, evaluates future applications, and discusses the pros and cons of each technique.


Assuntos
Administração Oftálmica , Composição de Medicamentos/métodos , Soluções Oftálmicas/síntese química , Soluções Oftálmicas/farmacocinética , Animais , Disponibilidade Biológica , Córnea/efeitos dos fármacos , Córnea/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Oftalmopatias/tratamento farmacológico , Oftalmopatias/metabolismo , Humanos , Soluções Oftálmicas/administração & dosagem , Pró-Fármacos/administração & dosagem , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Viscosidade
2.
J Med Chem ; 64(3): 1725-1732, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33529029

RESUMO

A pyridone-derived phosphate prodrug of an enhancer of zeste homolog 2 (EZH2) inhibitor was designed and synthesized to improve the inhibitor's aqueous solubility. This prodrug (compound 5) was profiled in pharmacokinetic experiments to assess its ability to deliver the corresponding parent compound (compound 2) to animals in vivo following oral administration. Results from these studies showed that the prodrug was efficiently converted to its parent compound in vivo. In separate experiments, the prodrug demonstrated impressive in vivo tumor growth inhibition in a diffuse large B-cell lymphoma Karpas-422 cell line-derived xenograft model. The described prodrug strategy is expected to be generally applicable to poorly soluble pyridone-containing EZH2 inhibitors and provides a new option to enable such compounds to achieve sufficiently high exposures in vivo.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Piridonas/síntese química , Piridonas/farmacologia , Animais , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Linfoma de Células B/tratamento farmacológico , Camundongos , Modelos Moleculares , Pró-Fármacos/farmacocinética , Piridonas/farmacocinética , Ratos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Nature ; 589(7843): 597-602, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33361818

RESUMO

Isoprenoids are vital for all organisms, in which they maintain membrane stability and support core functions such as respiration1. IspH, an enzyme in the methyl erythritol phosphate pathway of isoprenoid synthesis, is essential for Gram-negative bacteria, mycobacteria and apicomplexans2,3. Its substrate, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), is not produced in metazoans, and in humans and other primates it activates cytotoxic Vγ9Vδ2 T cells at extremely low concentrations4-6. Here we describe a class of IspH inhibitors and refine their potency to nanomolar levels through structure-guided analogue design. After modification of these compounds into prodrugs for delivery into bacteria, we show that they kill clinical isolates of several multidrug-resistant bacteria-including those from the genera Acinetobacter, Pseudomonas, Klebsiella, Enterobacter, Vibrio, Shigella, Salmonella, Yersinia, Mycobacterium and Bacillus-yet are relatively non-toxic to mammalian cells. Proteomic analysis reveals that bacteria treated with these prodrugs resemble those after conditional IspH knockdown. Notably, these prodrugs also induce the expansion and activation of human Vγ9Vδ2 T cells in a humanized mouse model of bacterial infection. The prodrugs we describe here synergize the direct killing of bacteria with a simultaneous rapid immune response by cytotoxic γδ T cells, which may limit the increase of antibiotic-resistant bacterial populations.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Proteínas de Escherichia coli/antagonistas & inibidores , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/imunologia , Ativação Linfocitária/efeitos dos fármacos , Viabilidade Microbiana/efeitos dos fármacos , Oxirredutases/antagonistas & inibidores , Linfócitos T Citotóxicos/efeitos dos fármacos , Animais , Resistência Microbiana a Medicamentos , Resistência a Múltiplos Medicamentos , Inibidores Enzimáticos/química , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Feminino , Meia-Vida , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Oxirredutases/deficiência , Oxirredutases/genética , Oxirredutases/metabolismo , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Especificidade por Substrato , Suínos/sangue , Linfócitos T Citotóxicos/imunologia
4.
Int J Nanomedicine ; 15: 4825-4845, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32753868

RESUMO

Background: Nanosized drug delivery systems (NDDSs) have shown excellent prospects in tumor therapy. However, insufficient penetration of NDDSs has significantly impeded their development due to physiological instability and low passive penetration efficiency. Methods: Herein, we prepared a core cross-linked pullulan-modified nanosized system, fabricated by visible-light-induced diselenide bond cross-linked method for transporting ß-Lapachone and doxorubicin prodrug (boronate-DOX, BDOX), to improve the physiological stability of the NDDSs for efficient passive accumulation in tumor blood vessels (ß-Lapachone/BDOX-CCS). Additionally, ultrasound (US) was utilized to transfer ß-Lapachone/BDOX-CCS around the tumor vessel in a relay style to penetrate the tumor interstitium. Subsequently, ß-Lapachone enhanced ROS levels by overexpressing NQO1, resulting in the transformation of BDOX into DOX. DOX, together with abundant levels of ROS, achieved synergistic tumor therapy. Results: In vivo experiments demonstrated that ultrasound (US) + cross-linked nanosized drug delivery systems (ß-Lapachone/BDOX-CCS) group showed ten times higher DOX accumulation in the tumor interstitium than the non-cross-linked (ß-Lapachone/BDOX-NCS) group. Conclusion: Thus, this strategy could be a promising method to achieve deep penetration of NDDSs into the tumor.


Assuntos
Doxorrubicina/uso terapêutico , Nanopartículas/química , Naftoquinonas/uso terapêutico , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Pró-Fármacos/uso terapêutico , Ultrassonografia , Animais , Ácidos Borônicos/química , Permeabilidade Capilar/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Reagentes para Ligações Cruzadas/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Endocitose/efeitos dos fármacos , Feminino , Glucanos/química , Células Hep G2 , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Naftoquinonas/farmacocinética , Tamanho da Partícula , Pró-Fármacos/farmacocinética , Espécies Reativas de Oxigênio/metabolismo , Distribuição Tecidual/efeitos dos fármacos
5.
Int J Nanomedicine ; 15: 2921-2933, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32425524

RESUMO

Background: Targeted prodrug has various applications as drug formulation for tumor therapy. Therefore, amphoteric small-molecule prodrug combined with nanoscale characteristics for the self-assembly of the nano-drug delivery system (DDS) is a highly interesting research topic. Methods and Results: In this study, we developed a prodrug self-assembled nanoplatform, 2-glucosamine-fluorescein-5(6)-isothiocyanate-glutamic acid-paclitaxel (2DA-FITC-PTX NPs) by integration of targeted small molecule and nano-DDS with regular structure and perfect targeting ability. 2-glucosamine (DA) and paclitaxel were conjugated as the targeted ligand and anti-tumor chemotherapy drug by amino acid group. 2-DA molecular structure can enhance the targeting ability of prodrug-based 2DA-FITC-PTX NPs and prolong retention time, thereby reducing the toxicity of normal cell/tissue. The fluorescent dye FITC or near-infrared fluorescent dye ICG in prodrug-based DDS was attractive for in vivo optical imaging to study the behavior of 2DA-FITC-PTX NPs. In vitro and in vivo results proved that 2DA-FITC-PTX NPs exhibited excellent targeting ability, anticancer activity, and weak side effects. Conclusion: This work demonstrates a new combination of nanomaterials for chemotherapy and may promote prodrug-based DDS clinical applications in the future.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Paclitaxel/administração & dosagem , Pró-Fármacos/química , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Fluoresceína-5-Isotiocianato/química , Glucosamina/química , Ácido Glutâmico/química , Humanos , Camundongos Endogâmicos BALB C , Nanopartículas/administração & dosagem , Paclitaxel/química , Paclitaxel/farmacocinética , Pró-Fármacos/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Eur J Med Chem ; 197: 112280, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32361286

RESUMO

Herein, we demonstrate that butein (1) can prevent swelling in a murine lymphedema model by suppressing tumor necrosis factor α (TNF-α) production. Butein derivatives were synthesized and evaluated to identify compounds with in vitro anti-inflammatory activity. Among them, 20 µM of compounds 7j, 7m, and 14a showed 50% suppression of TNF-α production in mouse peritoneal macrophages after lipopolysaccharide stimulation. Compound 14a, exhibited the strongest potency with an in vitro IC50 of 14.6 µM and suppressed limb volume by 70% in a murine lymphedema model. The prodrug strategy enabled a six-fold increase in kinetic solubility of compound 1 and five-fold higher levels of active metabolite in the blood for compound 14a via oral administration in the pharmacokinetics study. We suggest that the compound 14a could be developed as a potential therapeutic agent targeting anti-inflammatory activity to alleviate lymphedema progression.


Assuntos
Anti-Inflamatórios/uso terapêutico , Chalconas/uso terapêutico , Linfedema/tratamento farmacológico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Chalconas/síntese química , Chalconas/farmacocinética , Humanos , Lipopolissacarídeos/farmacologia , Linfedema/patologia , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos , Microssomos Hepáticos/metabolismo , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Pró-Fármacos/uso terapêutico , Ratos , Fator de Necrose Tumoral alfa/metabolismo
7.
PLoS One ; 15(4): e0231841, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32298376

RESUMO

Elevated intraocular pressure is the only treatable risk factor for glaucoma, an eye disease that is the leading cause of irreversible blindness worldwide. We have identified cromakalim prodrug 1 (CKLP1), a novel water-soluble ATP-sensitive potassium channel opener, as a new ocular hypotensive agent. To evaluate the pharmacokinetic and safety profile of CKLP1 and its parent compound levcromakalim, Dutch-belted pigmented rabbits were treated intravenously (0.25 mg/kg) or topically (10 mM; 4.1 mg/ml) with CKLP1. Body fluids (blood, aqueous and vitreous humor) were collected at multiple time points and evaluated for the presence of CKLP1 and levcromakalim using a liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) based assay. Histology of tissues isolated from Dutch-belted pigmented rabbits treated once daily for 90 days was evaluated in a masked manner by a certified veterinary pathologist. The estimated plasma parameters following intravenous administration of 0.25 mg/kg of CKLP1 showed CKLP1 had a terminal half-life of 61.8 ± 55.2 min, Tmax of 19.8 ± 23.0 min and Cmax of 1968.5 ± 831.0 ng/ml. Levcromakalim had a plasma terminal half-life of 85.0 ± 37.0 min, Tmax of 61.0 ± 32.0 min and Cmax of 10.6 ± 1.2 ng/ml. Topical CKLP1 treatment in the eye showed low levels (<0.3 ng/mL) of levcromakalim in aqueous and vitreous humor, and trace amounts of CKLP1 and levcromakalim in the plasma. No observable histological changes were noted in selected tissues that were examined following topical application of CKLP1 for 90 consecutive days. These results suggest that CKPL1 is converted to levcromakalim in the eye and likely to some extent in the systemic circulation.


Assuntos
Cromakalim/farmacologia , Cromakalim/farmacocinética , Pró-Fármacos/farmacologia , Pró-Fármacos/farmacocinética , Administração Intravenosa , Administração Tópica , Animais , Humor Aquoso/efeitos dos fármacos , Humor Aquoso/metabolismo , Cromatografia Líquida , Córnea/citologia , Córnea/efeitos dos fármacos , Cromakalim/administração & dosagem , Cromakalim/sangue , Olho/citologia , Olho/efeitos dos fármacos , Olho/metabolismo , Feminino , Espectrometria de Massas , Pró-Fármacos/uso terapêutico , Coelhos , Corpo Vítreo/efeitos dos fármacos , Corpo Vítreo/metabolismo
8.
Arterioscler Thromb Vasc Biol ; 40(6): 1533-1542, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32268786

RESUMO

OBJECTIVE: Clopidogrel is a commonly used P2Y12 inhibitor to treat and prevent arterial thrombotic events. Clopidogrel is a prodrug that requires bioactivation by CYP (cytochrome P450) enzymes to exert antiplatelet activity. Diabetes mellitus is associated with an increased risk of ischemic events, and impaired ability to generate the active metabolite (AM) from clopidogrel. The objective of this study is to identify the mechanism of clopidogrel resistance in a murine model of diet-induced obesity (DIO). Approach and Results: C57BL/6J mice and IL-1R-/- mice were given high-fat diet for 10 weeks to generate a murine model of diet-induced obesity. Platelet aggregation and carotid arterial thrombosis were assessed in response to clopidogrel treatment. Wild-type DIO mice exhibited resistance to antiplatelet and antithrombotic effects of clopidogrel that was associated with reduced hepatic expression of CYP genes and reduced generation of the AM. IL (Interleukin)-1 receptor-deficient DIO (IL1R-/- DIO) mice showed no resistance to clopidogrel. Lack of resistance was accompanied by increased exposure of the clopidogrel AM. This resistance was also absent when wild-type DIO mice were treated with the conjugate of the clopidogrel AM, DT-678. CONCLUSIONS: These findings indicate that antiplatelet effects of clopidogrel may be impaired in the setting of diabetes mellitus due to reduced prodrug bioactivation related to IL-1 receptor signaling. Therapeutic targeting of P2Y12 in patients with diabetes mellitus using the conjugate of clopidogrel AM may lead to improved outcomes.


Assuntos
Clopidogrel/farmacocinética , Clopidogrel/uso terapêutico , Resistência a Medicamentos , Obesidade/complicações , Receptores de Interleucina-1/fisiologia , Animais , Trombose das Artérias Carótidas/prevenção & controle , Clopidogrel/farmacologia , Sistema Enzimático do Citocromo P-450/genética , Diabetes Mellitus , Dieta Hiperlipídica , Modelos Animais de Doenças , Fibrinolíticos , Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/enzimologia , Obesidade/etiologia , Obesidade/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas , Pró-Fármacos/farmacocinética , Pró-Fármacos/uso terapêutico , Receptores de Interleucina-1/deficiência
9.
J Pharmacol Exp Ther ; 374(1): 1-5, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32269168

RESUMO

Stimulant abuse is a persistent public health problem with no Food and Drug Administration-approved pharmacotherapy. Although monoamine-releasing drugs such as d-amphetamine can decrease cocaine self-administration in human and animal laboratory studies, their potential for abuse limits clinical utility. "Abuse-deterrent" formulations of monoamine releasers, such as prodrugs, hold greater clinical promise if their abuse potential is, as theorized, lower than that of cocaine. In these studies, we determined the reinforcing strength of phendimetrazine (PDM), a prodrug for the amphetamine-like monoamine releaser phenmetrazine; both drugs have been shown to decrease cocaine self-administration in laboratory animals. To date, no study has directly compared PDM (Schedule III) with cocaine (Schedule II) under progressive-ratio (PR) schedules of reinforcement, which are better suited than fixed-ratio schedules to directly compare reinforcing strength of drugs. Dose-response curves for cocaine (saline, 0.001-0.3 mg/kg per injection) and PDM (0.1-1.0 mg/kg per injection) were generated in six cocaine-experienced male rhesus monkeys during 4-hour sessions with a 20-minute limited hold (LH). Under these conditions, the maximum number of injections was not significantly different between cocaine and PDM. The reinforcing strength of doses situated on the peaks of the cocaine and PDM dose-effect curves were redetermined with a 60-minute LH. The mean number of injections increased for both drugs, but not for saline. Cocaine presentations resulted in significantly higher peak injections than PDM with a 60-minute LH, which is consistent with the lower scheduling of PDM. These results support PDM as Schedule III and highlight the importance of schedule parameters when comparing reinforcing strength of drugs using a PR schedule of reinforcement. SIGNIFICANCE STATEMENT: One strategy for reducing cocaine use is to identify a treatment that substitutes for cocaine but has lower abuse potential. In a rhesus monkey model of drug abuse, this study compared the reinforcing strength of cocaine and phendimetrazine, a drug that has been shown to decrease cocaine use in some studies.


Assuntos
Morfolinas/administração & dosagem , Morfolinas/farmacologia , Reforço Psicológico , Animais , Relação Dose-Resposta a Droga , Esquema de Medicação , Macaca mulatta , Masculino , Morfolinas/farmacocinética , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Autoadministração
10.
PLoS One ; 15(4): e0231173, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32251487

RESUMO

Acetaminophen is one of the most common over-the-counter pain medications used worldwide and is considered safe at therapeutic dose. However, intentional and unintentional overdose accounts for up to 70% of acute liver failure cases in the western world. Extensive research has demonstrated that the induction of oxidative stress and mitochondrial dysfunction are central to the development of acetaminophen-induced liver injury. Despite the insight gained on the mechanism of acetaminophen toxicity, there still is only one clinically approved pharmacological treatment option, N-acetylcysteine. N-acetylcysteine increases the cell's antioxidant defense and protects liver cells from further acetaminophen-induced oxidative damage. Because it primarily protects healthy liver cells rather than rescuing the already injured cells alternative treatment strategies that target the latter cell population are warranted. In this study, we investigated mitochondria as therapeutic target for the development of novel treatment strategies for acetaminophen-induced liver injury. Characterization of the mitochondrial toxicity due to acute acetaminophen overdose in vitro in human cells using detailed respirometric analysis revealed that complex I-linked (NADH-dependent) but not complex II-linked (succinate-dependent) mitochondrial respiration is inhibited by acetaminophen. Treatment with a novel cell-permeable succinate prodrug rescues acetaminophen-induced impaired mitochondrial respiration. This suggests cell-permeable succinate prodrugs as a potential alternative treatment strategy to counteract acetaminophen-induced liver injury.


Assuntos
Acetaminofen/efeitos adversos , Analgésicos não Entorpecentes/efeitos adversos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Respiração Celular/efeitos dos fármacos , Overdose de Drogas/tratamento farmacológico , Mitocôndrias/metabolismo , Pró-Fármacos/farmacocinética , Ácido Succínico/farmacocinética , Acetaminofen/administração & dosagem , Acetaminofen/farmacologia , Idoso , Analgésicos não Entorpecentes/administração & dosagem , Analgésicos não Entorpecentes/farmacologia , Plaquetas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Overdose de Drogas/metabolismo , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Masculino , Mitocôndrias/efeitos dos fármacos
11.
Cancer Chemother Pharmacol ; 85(5): 869-880, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32240335

RESUMO

PURPOSE: Capecitabine is a prodrug of 5-fluorouracil (5-FU) used for the treatment of colorectal cancer, with a two-week course of administration. However, the variance in plasma concentration and metabolic enzyme activities after multiple administration of capecitabine and its metabolites is unknown. The aim of this study was to identify the variance and predict the plasma concentration profile of capecitabine and its metabolites, using metabolic enzyme activities, to develop a more effective and safer medication. METHODS: Rats orally received 180 mg/kg of capecitabine once a day for two weeks. Blood samples were collected nine times, and plasma concentration was measured on day 1, 7, and 14. The liver and small intestine were removed after blood sampling and were used in vitro to evaluate metabolic enzyme activities of carboxylesterase, cytidine deaminase, and thymidine phosphorylase. A physiologically based pharmacokinetic (PBPK) model was developed using in vitro results. RESULTS: Area under the plasma concentration-time curve from 0 h to infinity of 5-FU on day 7 and day 14 was significantly lower than that on day 1. Intrinsic clearance of thymidine phosphorylase in the liver on day 7 and day 14 was 1.4 and 1.3 times lower than that on day 1, respectively. The PBPK model described the observed plasma concentration of capecitabine and its metabolites. CONCLUSION: The decreased plasma concentration of capecitabine was caused by decreased metabolic enzyme activity. Efficacy can be improved by dose adjustment of capecitabine based on metabolic enzyme activities, using the PBPK model.


Assuntos
Capecitabina/farmacocinética , Carboxilesterase/metabolismo , Neoplasias Colorretais , Citidina Desaminase/metabolismo , Fluoruracila/farmacocinética , Timidina Fosforilase/metabolismo , Animais , Antimetabólitos Antineoplásicos/farmacocinética , Biomarcadores Farmacológicos/metabolismo , Neoplasias Colorretais/sangue , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Relação Dose-Resposta a Droga , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Pró-Fármacos/farmacocinética , Ratos , Distribuição Tecidual
12.
AAPS PharmSciTech ; 21(3): 98, 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32128656

RESUMO

Oseltamivir is a neuraminidase inhibitor widely used to treat and prevent influenza A and B infections, although its safety and pharmacokinetics have not been evaluated in patients with severe hepatic impairment. A physiologically based pharmacokinetic (PBPK) model of the prodrug oseltamivir and its active metabolite, oseltamivir carboxylate (OC), was established and validated to simulate their disposition in adults and predict the exposure in patients with Child-Pugh C cirrhosis (CP-C). The simulated results from PBPK modeling and the observed data after oral administration of various oseltamivir regimens were consistent according to the fold error values of less than 2. Furthermore, the clinical observations published in the literature were comparable with our pharmacokinetic predictions. In patients with CP-C, the oseltamivir Cmax was approximately 2-fold increased, and its AUC was approximately 6-fold higher compared with those in normal subjects. In contrast, the AUC of OC in CP-C patients did not differ significantly from that in normal subjects, whereas its Cmax was reduced by approximately 30% in the patients. Examination of drug exposure in different health conditions indicated that the oseltamivir exposure was significantly increased in conditions with elevated cirrhosis severity, which might be associated with a higher risk of adverse drug effects, e.g., neuropsychiatric adverse events (NPAEs). In conclusion, the pharmacokinetics of oseltamivir and OC were correctly predicted by PBPK modeling. The model further predicted that the pharmacokinetics of oseltamivir might be altered in liver cirrhosis, depending on the degree of severity.


Assuntos
Antivirais/farmacocinética , Simulação por Computador , Cirrose Hepática/metabolismo , Modelos Biológicos , Oseltamivir/análogos & derivados , Oseltamivir/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Antivirais/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Cirrose Hepática/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Oseltamivir/administração & dosagem , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Adulto Jovem
13.
Pharm Res ; 37(3): 66, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32166420

RESUMO

PURPOSE: TXA9, a novel cardiac glycoside, has a potent anti-proliferative effect against A549 human lung cancer cells, however, possesses a poor water-solubility and a rapid metabolic rate in vivo which limited the further development of TXA9. To overcome the shortcomings of TXA9, four polymer prodrugs of TXA9 were designed and synthesized. METHODS: Poly (ethylene glycol) monomethyl ether (mPEG) and α-tocopherol polyethylene glycol succinate (TPGS) were applied to modify TXA9 via carbonate ester and glycine linkers respectively to obtain four polymer prodrugs. The water-solubility and stability of prodrugs were studied in vitro while their pharmacokinetic behaviors and antitumor activity were investigated in vivo. RESULTS: The water-solubility of TXA9 was obviously increased and prodrugs with glycine linkers showed a better stability in rat plasma. Their pharmacokinetic investigation found that the t1/2 and AUC0-∞ of TPGS-Gly-TXA9 was increased by 80- and 9.6-fold compared with that of TXA9, which was more superior than the other three prodrugs. More importantly, the tumor inhibition rate of TPGS-Gly-TXA9 (43.81%) on A549 xenograft nude mice was significantly increased compared with that of TXA9 (25.26%). CONCLUSION: The above results suggested that TPGS-Gly-TXA9 possessed better antitumor efficiency than TXA9 and could be further investigated as an anti-cancer agent.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Glicosídeos Cardíacos/química , Glicosídeos Cardíacos/farmacologia , Polímeros/química , Polímeros/farmacologia , Células A549 , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Glicosídeos Cardíacos/farmacocinética , Glicosídeos Cardíacos/uso terapêutico , Desenho de Fármacos , Esterificação , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos Endogâmicos BALB C , Camundongos Nus , Polímeros/farmacocinética , Polímeros/uso terapêutico , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Ratos Sprague-Dawley , Solubilidade , Água/química
14.
Proc Natl Acad Sci U S A ; 117(13): 7021-7029, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32179677

RESUMO

Described here is the development of gadolinium(III) texaphyrin-platinum(IV) conjugates capable of overcoming platinum resistance by 1) localizing to solid tumors, 2) promoting enhanced cancer cell uptake, and 3) reactivating p53 in platinum-resistant models. Side by side comparative studies of these Pt(IV) conjugates to clinically approved platinum(II) agents and previously reported platinum(II)-texaphyrin conjugates demonstrate that the present Pt(IV) conjugates are more stable against hydrolysis and nucleophilic attack. Moreover, they display high potent antiproliferative activity in vitro against human and mouse cell cancer lines. Relative to the current platinum clinical standard of care (SOC), a lead Gd(III) texaphyrin-Pt(IV) prodrug conjugate emerging from this development effort was found to be more efficacious in subcutaneous (s.c.) mouse models involving both cell-derived xenografts and platinum-resistant patient-derived xenografts. Comparative pathology studies in mice treated with equimolar doses of the lead Gd texaphyrin-Pt(IV) conjugate or the US Food and Drug Administration (FDA)-approved agent oxaliplatin revealed that the conjugate was better tolerated. Specifically, the lead could be dosed at more than three times (i.e., 70 mg/kg per dose) the tolerable dose of oxaliplatin (i.e., 4 to 6 mg/kg per dose depending on the animal model) with little to no observable adverse effects. A combination of tumor localization, redox cycling, and reversible protein binding is invoked to explain the relatively increased tolerability and enhanced anticancer activity seen in vivo. On the basis of the present studies, we conclude that metallotexaphyrin-Pt conjugates may have substantial clinical potential as antitumor agents.


Assuntos
Antineoplásicos/administração & dosagem , Metaloporfirinas/administração & dosagem , Oxaliplatina/administração & dosagem , Células A549 , Animais , Antineoplásicos/farmacocinética , Resistencia a Medicamentos Antineoplásicos , Feminino , Células HCT116 , Humanos , Metaloporfirinas/farmacocinética , Camundongos Nus , Oxaliplatina/farmacocinética , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacocinética , Distribuição Tecidual , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Proc Natl Acad Sci U S A ; 117(9): 4518-4526, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32071209

RESUMO

The inception and development of supramolecular chemistry have provided a vast library of supramolecular structures and materials for improved practice of medicine. In the context of therapeutic delivery, while supramolecular nanostructures offer a wide variety of morphologies as drug carriers for optimized targeting and controlled release, concerns are often raised as to how their morphological stability and structural integrity impact their in vivo performance. After intravenous (i.v.) administration, the intrinsic reversible and dynamic feature of supramolecular assemblies may lead them to dissociate upon plasma dilution to a concentration below their critical micellization concentration (CMC). As such, CMC represents an important characteristic for supramolecular biomaterials design, but its pharmaceutical role remains elusive. Here, we report the design of a series of self-assembling prodrugs (SAPDs) that spontaneously associate in aqueous solution into supramolecular polymers (SPs) with varying CMCs. Two hydrophobic camptothecin (CPT) molecules were conjugated onto oligoethylene-glycol (OEG)-decorated segments with various OEG repeat numbers (2, 4, 6, 8). Our studies show that the lower the CMC, the lower the maximum tolerated dose (MTD) in rodents. When administrated at the same dosage of 10 mg/kg (CPT equivalent), SAPD 1, the one with the lowest CMC, shows the best efficacy in tumor suppression. These observations can be explained by the circulation and dissociation of SAPD SPs and the difference in molecular and supramolecular distribution between excretion and organ uptake. We believe these findings offer important insight into the role of supramolecular stability in determining their therapeutic index and in vivo efficacy.


Assuntos
Portadores de Fármacos/química , Micelas , Pró-Fármacos/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Camptotecina/administração & dosagem , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , Portadores de Fármacos/toxicidade , Feminino , Células HT29 , Humanos , Dose Máxima Tolerável , Camundongos , Camundongos Nus , Polietilenoglicóis/química , Polimerização , Pró-Fármacos/farmacocinética , Pró-Fármacos/uso terapêutico , Ratos , Ratos Sprague-Dawley
16.
J Med Chem ; 63(7): 3552-3562, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32073266

RESUMO

We report the discovery of a novel indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor class through the affinity selection of a previously unreported indole-based DNA-encoded library (DEL). The DEL exemplar, spiro-chromane 1, had moderate IDO1 potency but high in vivo clearance. Series optimization quickly afforded a potent, low in vivo clearance lead 11. Although amorphous 11 was highly bio-available, crystalline 11 was poorly soluble and suffered disappointingly low bio-availability because of solubility-limited absorption. A prodrug approach was deployed and proved effective in discovering the highly bio-available phosphonooxymethyl 31, which rapidly converted to 11 in vivo. Obtaining crystalline 31 proved problematic, however; thus salt screening was performed in an attempt to circumvent this obstacle and successfully delivered greatly soluble and bio-available crystalline tris-salt 32. IDO1 inhibitor 32 is characterized by a low calculated human dose, best-in-class potential, and an unusual inhibition mode by binding the IDO1 heme-free (apo) form.


Assuntos
DNA/química , Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Pró-Fármacos/farmacologia , Compostos de Espiro/farmacologia , Animais , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Eutérios , Masculino , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Compostos de Espiro/síntese química , Compostos de Espiro/farmacocinética , Relação Estrutura-Atividade
17.
ACS Appl Mater Interfaces ; 12(10): 12143-12154, 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32078286

RESUMO

The development of valuable theranostic agents for overcoming the blood-brain barrier (BBB) to achieve efficient imaging-guided glioma-targeting delivery of therapeutics remains a great challenge for personalized glioma therapy. We herein developed a novel functional star-shaped polyprodrug amphiphile (denoted as CPP-2) via a combination of successive reversible addition-fragmentation chain transfer (RAFT) polymerization and click functionalization. In a diluted solution, the star amphiphile existed as structurally stable unimolecular micelles, containing hydrophobic cores conjugated with reduction-responsive camptothecin prodrugs Camptothecin (CPT) prodrug monomer (CPTM) and a tertiary amine monomer (2-(diethylamine) ethyl methacrylate, DEA) and hydrophilic oligo-(ethylene glycol) monomethyl ether methacrylat (OEGMA) outer coronas covalently decorated with dual-targeting moieties Angiopep2 (ANG) and small magnetic resonance imaging (MRI) contrast agents DOTA-Gd. In vitro and in vivo data in this study demonstrated that the ANG-modified micelles were capable of efficiently penetrating the BBB and delivering loaded cargoes such as CPT and Gd3+ contrast agents to glioma cells, leading to a considerably enhanced t1 relaxivity as well as antiglioma efficacy. Simultaneously, the targeted antiglioma efficacy and noninvasive MR imaging for a visualized therapy were realized. These collective findings augured well for the star polyprodrug amphiphiles to be utilized as a novel theranostic platform for clinical application in glioma therapy.


Assuntos
Antineoplásicos , Glioma , Peptídeos , Pró-Fármacos , Nanomedicina Teranóstica/métodos , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Camptotecina/química , Camptotecina/farmacocinética , Camptotecina/farmacologia , Portadores de Fármacos/química , Glioma/diagnóstico por imagem , Glioma/metabolismo , Imagem por Ressonância Magnética , Micelas , Peptídeos/química , Peptídeos/farmacocinética , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Ratos , Ratos Sprague-Dawley
18.
Int J Nanomedicine ; 15: 65-80, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021165

RESUMO

Introduction: Poor cell uptake and incomplete intracellular drug release are the two major challenges for polymeric prodrug-based drug delivery systems (PPDDSs) in cancer treatment. Methods: Herein, a PPDDS with pH-induced surface charge-reversal and reactive oxygen species (ROS) amplification for ROS-triggered self-accelerating drug release was developed, which was formed by encapsulating a ROS generation agent (vitamin K3 (VK3)) in pH/ROS dual-sensitive polymetric prodrug (PEG-b-P(LL-g-TK-PTX)-(LL-g-DMA)) based micelle nanoparticles (denoted as PVD-NPs). Results: The surface charge of the PVD-NPs can change from negative to positive for enhanced cell uptake in response to tumor extracellular acidity pH. After internalization by cancer cells, PVD-NPs demonstrate dual drug release in response to intracellular ROS-rich conditions. In addition, the released VK3 can produce ROS under the catalysis by NAD(P)H:quinone oxidoreductase-1, which facilitates tumor-specific ROS amplification and drug release selectively in cancer cells to enhance chemotherapy. Conclusion: Both in vitro and in vivo experiments demonstrated that the PVD-NPs showed significant antitumor activity in human prostate cancer.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Pró-Fármacos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Animais , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Micelas , NAD(P)H Desidrogenase (Quinona)/metabolismo , Células NIH 3T3 , Nanopartículas/administração & dosagem , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinética , Polímeros/síntese química , Polímeros/química , Pró-Fármacos/farmacocinética , Vitamina K 3/administração & dosagem , Vitamina K 3/farmacocinética
19.
PLoS One ; 15(1): e0227104, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31914458

RESUMO

Despite the availability of highly effective direct-acting antiviral (DAA) regimens for the treatment of hepatitis C virus (HCV) infections, sustained viral response (SVR) rates remain suboptimal for difficult-to-treat patient populations such as those with HCV genotype 3, cirrhosis or prior treatment experience, warranting development of more potent HCV replication antivirals. AT-527 is the hemi-sulfate salt of AT-511, a novel phosphoramidate prodrug of 2'-fluoro-2'-C-methylguanosine-5'-monophosphate that has potent in vitro activity against HCV. The EC50 of AT-511, determined using HCV laboratory strains and clinical isolates with genotypes 1-5, ranged from 5-28 nM. The active 5'-triphosphate metabolite, AT-9010, specifically inhibited the HCV RNA-dependent RNA polymerase. AT-511 did not inhibit the replication of other selected RNA or DNA viruses in vitro. AT-511 was approximately 10-fold more active than sofosbuvir (SOF) against a panel of laboratory strains and clinical isolates of HCV genotypes 1-5 and remained fully active against S282T resistance-associated variants, with up to 58-fold more potency than SOF. In vitro, AT-511 did not inhibit human DNA polymerases or elicit cytotoxicity or mitochondrial toxicity at concentrations up to 100 µM. Unlike the other potent guanosine analogs PSI-938 and PSI-661, no mutagenic O6-alkylguanine bases were formed when incubated with cytochrome P450 (CYP) 3A4, and AT-511 had IC50 values ≥25 µM against a panel of CYP enzymes. In hepatocytes from multiple species, the active triphosphate was the predominant metabolite produced from the prodrug, with a half-life of 10 h in human hepatocytes. When given orally to rats and monkeys, AT-527 preferentially delivered high levels of AT-9010 in the liver in vivo. These favorable preclinical attributes support the ongoing clinical development of AT-527 and suggest that, when used in combination with an HCV DAA from a different class, AT-527 may increase SVR rates, especially for difficult-to-treat patient populations, and could potentially shorten treatment duration for all patients.


Assuntos
Antivirais/farmacologia , Guanosina/farmacologia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Pró-Fármacos/farmacologia , Animais , Antivirais/química , Antivirais/metabolismo , Antivirais/farmacocinética , Linhagem Celular , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Feminino , Guanosina/análogos & derivados , Guanosina/metabolismo , Guanosina/farmacocinética , Haplorrinos , Hepacivirus/genética , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/virologia , Humanos , Masculino , Camundongos , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacocinética , Ratos
20.
PLoS Biol ; 18(1): e3000612, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31986134

RESUMO

Antibiotic resistance increasingly limits the success of antibiotic treatments, and physicians require new ways to achieve efficient treatment despite resistance. Resistance mechanisms against a specific antibiotic class frequently confer increased susceptibility to other antibiotic classes, a phenomenon designated collateral sensitivity (CS). An informed switch of antibiotic may thus enable the efficient treatment of resistant strains. CS occurs in many pathogens, but the mechanisms that generate hypersusceptibility are largely unknown. We identified several molecular mechanisms of CS against the antibiotic nitrofurantoin (NIT). Mutants that are resistant against tigecycline (tetracycline), mecillinam (ß-lactam), and protamine (antimicrobial peptide) all show CS against NIT. Their hypersusceptibility is explained by the overexpression of nitroreductase enzymes combined with increased drug uptake rates, or increased drug toxicity. Increased toxicity occurs through interference of the native drug-response system for NIT, the SOS response, with growth. A mechanistic understanding of CS will help to develop drug switches that combat resistance.


Assuntos
Sensibilidade Colateral a Medicamentos/genética , Nitrofurantoína/farmacologia , Ativação Metabólica/efeitos dos fármacos , Ativação Metabólica/genética , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Farmacorresistência Bacteriana/genética , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Escherichia coli/metabolismo , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Mutação/efeitos dos fármacos , Nitrofurantoína/farmacocinética , Organismos Geneticamente Modificados , Pró-Fármacos/farmacocinética , Salmonella enterica/efeitos dos fármacos , Salmonella enterica/genética , Salmonella enterica/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
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