RESUMO
N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA) is a novel valproic acid derivative that has shown anti-proliferative activity against epitheloid cervix carcinoma (HeLa), rhabdomyosarcoma (A204), and several breast cancer cell lines. The aim of this research was to evaluate the pharmacokinetic profile and tissue distribution of HO-AAVPA in Wistar rats, as well as its human serum albumin binding potential by experimental and in silico methods. A single dose of HO-AAVPA was given to male rats by intravenous, intragastric or intraperitoneal routes at doses of 25, 100, and 100 mg/kg, respectively. Then, blood samples were drawn at predetermined intervals of time, and the HO-AAVPA concentration in the plasma was quantified with a validated HPLC method. The elimination half-life (t1/2) was approximately 222 min, and the systemic clearance (CL) and apparent volume of distribution (Vd) were 2.20 mL/min/kg and 0.70 L/kg, respectively. The absolute oral bioavailability of HO-AAVPA was 33.8%, and the binding rate of HO-AAVPA with rat plasma proteins was between 66.2% and 83.0%. Additionally, in silico, UV and Raman spectroscopy data showed weak interactions between the test compound and human serum albumin. Thus, the results that were obtained demonstrated that despite its low oral bioavailability, the potential anticancer agent HO-AAVPA exhibits acceptable pharmacokinetic properties that would allow it to reach its site of action and exert its pharmacological effect in Wistar Rats, and it has a convenient profile for future assays to evaluate its human applications.
Assuntos
Amidas/farmacocinética , Antineoplásicos/farmacocinética , Pentanos/farmacocinética , Albumina Sérica Humana/metabolismo , Ácido Valproico/farmacocinética , Administração Oral , Amidas/administração & dosagem , Amidas/sangue , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Sítios de Ligação , Disponibilidade Biológica , Injeções Intraperitoneais , Injeções Intravenosas , Masculino , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pentanos/administração & dosagem , Pentanos/sangue , Ligação Proteica , Ratos Wistar , Distribuição Tecidual , Ácido Valproico/administração & dosagem , Ácido Valproico/sangueRESUMO
The purpose of the present study was to develop and assess a novel sustained-release drug delivery system of Bimatoprost (BIM). Chitosan polymeric inserts were prepared using the solvent casting method and characterized by swelling studies, infrared spectroscopy, differential scanning calorimetry, drug content, scanning electron microscopy and in vitro drug release. Biodistribution of 99mTc-BIM eye drops and 99mTc-BIM-loaded inserts, after ocular administration in Wistar rats, was accessed by ex vivo radiation counting. The inserts were evaluated for their therapeutic efficacy in glaucomatous Wistar rats. Glaucoma was induced by weekly intracameral injection of hyaluronic acid. BIM-loaded inserts (equivalent to 9.0 µg BIM) were administered once into conjunctival sac, after ocular hypertension confirmation. BIM eye drop was topically instilled in a second group of glaucomatous rats for 15 days days, while placebo inserts were administered once in a third group. An untreated glaucomatous group was used as control. Intraocular pressure (IOP) was monitored for four consecutive weeks after treatment began. At the end of the experiment, retinal ganglion cells and optic nerve head cupping were evaluated in the histological eye sections. Characterization results revealed that the drug physically interacted, but did not chemically react with the polymeric matrix. Inserts sustainedly released BIM in vitro during 8 hours. Biodistribution studies showed that the amount of 99mTc-BIM that remained in the eye was significantly lower after eye drop instillation than after chitosan insert implantation. BIM-loaded inserts lowered IOP for 4 weeks, after one application, while IOP values remained significantly high for the placebo and untreated groups. Eye drops were only effective during the daily treatment period. IOP results were reflected in RGC counting and optic nerve head cupping damage. BIM-loaded inserts provided sustained release of BIM and seem to be a promising system for glaucoma management.
Assuntos
Amidas/administração & dosagem , Cloprostenol/análogos & derivados , Glaucoma/tratamento farmacológico , Administração Oftálmica , Amidas/farmacocinética , Amidas/uso terapêutico , Animais , Bimatoprost , Varredura Diferencial de Calorimetria , Cloprostenol/administração & dosagem , Cloprostenol/farmacocinética , Cloprostenol/uso terapêutico , Preparações de Ação Retardada , Sistemas de Liberação de Medicamentos , Glaucoma/fisiopatologia , Humanos , Técnicas In Vitro , Pressão Intraocular , Masculino , Microscopia Eletrônica de Varredura , Ratos , Ratos Wistar , Espectroscopia de Infravermelho com Transformada de Fourier , Distribuição TecidualRESUMO
BACKGROUND: Junín virus (JUNV), the etiologic agent of Argentine hemorrhagic fever (AHF), is classified by the NIAID and CDC as a Category A priority pathogen. Presently, antiviral therapy for AHF is limited to immune plasma, which is readily available only in the endemic regions of Argentina. T-705 (favipiravir) is a broadly active small molecule RNA-dependent RNA polymerase inhibitor presently in clinical evaluation for the treatment of influenza. We have previously reported on the in vitro activity of favipiravir against several strains of JUNV and other pathogenic New World arenaviruses. METHODOLOGY/PRINCIPAL FINDINGS: To evaluate the efficacy of favipiravir in vivo, guinea pigs were challenged with the pathogenic Romero strain of JUNV, and then treated twice daily for two weeks with oral or intraperitoneal (i.p.) favipiravir (300 mg/kg/day) starting 1-2 days post-infection. Although only 20% of animals treated orally with favipiravir survived the lethal challenge dose, those that succumbed survived considerably longer than guinea pigs treated with placebo. Consistent with pharmacokinetic analysis that showed greater plasma levels of favipiravir in animals dosed by i.p. injection, i.p. treatment resulted in a substantially higher level of protection (78% survival). Survival in guinea pigs treated with ribavirin was in the range of 33-40%. Favipiravir treatment resulted in undetectable levels of serum and tissue viral titers and prevented the prominent thrombocytopenia and leucopenia observed in placebo-treated animals during the acute phase of infection. CONCLUSIONS/SIGNIFICANCE: The remarkable protection afforded by i.p. favipiravir intervention beginning 2 days after challenge is the highest ever reported for a small molecule antiviral in the difficult to treat guinea pig JUNV challenge model. These findings support the continued development of favipiravir as a promising antiviral against JUNV and other related arenaviruses.
Assuntos
Amidas/uso terapêutico , Antivirais/uso terapêutico , Febre Hemorrágica Americana/tratamento farmacológico , Vírus Junin/efeitos dos fármacos , Pirazinas/uso terapêutico , Administração Oral , Amidas/farmacocinética , Animais , Antivirais/farmacocinética , Modelos Animais de Doenças , Cobaias , Febre Hemorrágica Americana/virologia , Injeções Intraperitoneais , Masculino , Plasma/química , Pirazinas/farmacocinética , Análise de Sobrevida , Viremia/prevenção & controleRESUMO
Aliskiren, the first in a new class of orally effective direct renin inhibitors (DRIs) was recently approved for the treatment of hypertension. In this review, we discuss the history of the development of DRIs and available data regarding the effects of DRIs in the treatment of hypertension and related target organ damage.
Assuntos
Amidas/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Fumaratos/uso terapêutico , Hipertensão/tratamento farmacológico , Renina/antagonistas & inibidores , Amidas/farmacocinética , Amidas/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/farmacologia , Fumaratos/farmacocinética , Fumaratos/farmacologia , Humanos , Hipertensão/fisiopatologiaRESUMO
Ropivacaine (RVC) is an enantiomerically pure local anesthetic (LA) largely used in surgical procedures, which presents physico-chemical and therapeutic properties similar to those of bupivacaine (BPV), but associated to less systemic toxicity. This study focuses on the development and pharmacological evaluation of a RVC in 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) inclusion complex. Phase-solubility diagrams allowed the determination of the association constant between RVC and HP-beta-CD (9.46 M(-1)) and showed an increase on RVC solubility upon complexation. Release kinetics revealed a decrease on RVC release rate and reduced hemolytic effects after complexation (onset at 3.7 mM and 11.2mM for RVC and RVC HP-beta-CD, respectively) were observed. Differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and X-ray analysis (X-ray) showed the formation and the morphology of the complex. Nuclear magnetic resonance (NMR) and job-plot experiments afforded data regarding inclusion complex stoichiometry (1:1) and topology. Sciatic nerve blockade studies showed that RVC HP-beta-CD was able to reduce the latency without increasing the duration of motor blockade, but prolonging the duration and intensity of the sensory blockade (p<0.001) induced by the LA in mice. These results identify the RVC HP-beta-CD complex as an effective novel approach to enhance the pharmacological effects of RVC, presenting it as a promising new anesthetic formulation.
Assuntos
Amidas/farmacologia , Composição de Medicamentos/métodos , beta-Ciclodextrinas/farmacologia , 2-Hidroxipropil-beta-Ciclodextrina , Amidas/química , Amidas/farmacocinética , Anestésicos Locais/química , Anestésicos Locais/farmacocinética , Anestésicos Locais/farmacologia , Animais , Varredura Diferencial de Calorimetria/métodos , Relação Dose-Resposta a Droga , Hemólise/efeitos dos fármacos , Temperatura Alta , Humanos , Cinética , Espectroscopia de Ressonância Magnética/métodos , Masculino , Camundongos , Microscopia Eletrônica de Varredura/métodos , Estrutura Molecular , Bloqueio Nervoso , Limiar da Dor/efeitos dos fármacos , Ropivacaina , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/fisiopatologia , Solubilidade , Estereoisomerismo , Fatores de Tempo , Difração de Raios X/métodos , beta-Ciclodextrinas/química , beta-Ciclodextrinas/farmacocinéticaRESUMO
Foi realizada uma revisäo crítica da literatura a respeito da estabilidade de fármacos em presença de surfactantes. Os grupos funcionais envolvidos nas reaçöes de decomposiçäo dos fármacos foram usados para o desenvolvimento da discussäo. A análise global desses estudos indicou que o efeito de surfactantes pode ser usado no controle de velocidades e mecanismos de decomposiçäo de fármacos e para obter informaçöes específicas de características da reatividade desses compostos em seus sítios de açäo farmacológica