RESUMO
A series of new tetrasubstituted α-aminophosphonate derivatives with a methylphosphoserine fragment were described. These compounds were synthesized by a three-component (3-CR) "Kabachnik-Fields reaction." The novel α-aminophosphonates were screened for in vivo anti-inflammatory activity through topical and oral administration routes. All compounds decreased TPA-induced ear edema in a dose-dependent fashion. In this test, compounds 2, 5, and 7 showed the same efficacy (≈ 90%) and higher potency than indomethacin and decreased the inflammatory marker neutrophil-to-lymphocyte ratio (NLR). Moreover, oral pretreatment and post-treatment with compounds 2-7 reduced CFA-induced paw edema, as did indomethacin or (S)-naproxen. Based on the promising in vivo anti-inflammatory results, we investigated their physicochemical and pharmacokinetics profiles in silico. The analysis also revealed that the novel tetrasubstituted α-aminophosphonates did not break Lipinski's rule of five and had drug-likeness and favorable ADME properties for oral and transdermal administration.
Assuntos
Edema , Organofosfonatos , Animais , Organofosfonatos/química , Organofosfonatos/síntese química , Organofosfonatos/farmacologia , Organofosfonatos/farmacocinética , Camundongos , Edema/tratamento farmacológico , Edema/induzido quimicamente , Masculino , Administração Oral , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Relação Estrutura-Atividade , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/química , Ratos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismoRESUMO
Crohn's disease (CD) involves immune system interactions with intestinal tissue, driven by pro-inflammatory cytokines like Tumor Necrosis Factor (TNF-α). Adalimumab, targeting TNF-α, regulates associated inflammatory responses. Despite being humanized, it may induce immunogenic processes, affecting treatment effectiveness. Thus, monitoring serum adalimumab and anti-drug antibody (ADA) levels can optimize therapy. Understanding genetic factors influencing adalimumab response can enhance personalized treatment and improve patient quality of life. We aimed to quantify adalimumab serum levels, assess test interchangeability, detect ADA, examine immune complex formation, and investigate genetic phenotypes related to immunogenicity in CD patients. Seventy CD patients in the maintenance phase with adalimumab were classified into active (CDA) and remission (CDR) groups. Adalimumab concentration was determined via enzyme-linked immunosorbent assay (ELISA-Promonitor) and lateral flow assay (Quantum Blue), with assay interchangeability assessed statistically. ADA and immune complex formation were quantified using ELISA assays. DNA was genotyped for the genes ATG16L1, CD96, and CD155. No significant differences in adalimumab serum concentrations were observed between groups, regardless of the assay. However, a statistical difference between the tests indicated measurement disparity (P = 0.003), with moderate agreement (Lin's correlation of 0.247). ADA was detected in 4 of 27 of the patients with infratherapeutic levels, 3 in the CDA group and 1 in the CDR group. Analysis of immune complexes revealed significantly higher concentrations in the CDA group (P = 0.0125). The genotypic evaluation revealed significant associations for the CD96 CC (wild-type) genotype with higher CRP levels, colonic involvement, and infratherapeutic levels of adalimumab. ATG16L1 CC genotype was associated with higher CDEIS and fecal calprotectin values, while the variant (TT) genotype had lower platelet counts. The effectiveness of treatment with adalimumab was not directly related to higher medication levels in this cohort. The disparity between tests indicates the need to use only one test in patient follow-up to ensure accuracy in therapeutic monitoring. Genotypic differences highlight the correlation between the wild genotype for CD96 and ATG16L1 with unfavorable laboratory and endoscopic response to adalimumab. Finally, the more significant levels of immune complexes in the CDA group indicate an association with a worse response to adalimumab.
Assuntos
Adalimumab , Doença de Crohn , Monitoramento de Medicamentos , Humanos , Adalimumab/uso terapêutico , Adalimumab/sangue , Adalimumab/imunologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/genética , Doença de Crohn/imunologia , Doença de Crohn/sangue , Monitoramento de Medicamentos/métodos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/sangue , Anti-Inflamatórios/farmacocinética , Genótipo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Imunogenética/métodos , Proteínas Relacionadas à AutofagiaRESUMO
In vitro release testing (IVRT) serves as a crucial tool to assess the quality, physicochemical behavior, and performance of semisolid formulations already available on the market. In vitro skin permeation studies (IVPT) are widely used to evaluate the safety and efficacy profiles of topical drugs, utilizing biological membranes prepared from ex vivo human and porcine skin tissues. This study aimed to develop and validate a discriminative IVRT method to evaluate various marketed topical benzoyl peroxide formulations. Additionally, IVPT was employed to assess skin permeation and retention profiles of these formulations, comparing porcine skin results with those obtained by using ex vivo human skin tissues. Physicochemical differences among the evaluated benzoyl peroxide formulations were identified, with the poloxamer-based formulation exhibiting a higher release rate. IVPT using both porcine and human skin differentiated retention and skin permeation profiles, with the poloxamer-based formulation demonstrating greater skin retention capacity compared to the other formulations evaluated. Similar conclusions on benzoyl peroxide retention and cutaneous permeation were drawn from both porcine and human skin IVPT tests, confirming the correlation between the two models.
Assuntos
Administração Cutânea , Peróxido de Benzoíla , Absorção Cutânea , Pele , Humanos , Suínos , Peróxido de Benzoíla/farmacocinética , Peróxido de Benzoíla/química , Peróxido de Benzoíla/administração & dosagem , Pele/metabolismo , Absorção Cutânea/efeitos dos fármacos , Animais , Permeabilidade , Liberação Controlada de Fármacos , Poloxâmero/química , Técnicas In Vitro , Química Farmacêutica/métodosRESUMO
Using in-house computational tools, this work focuses on investigating how the combination of the electric field magnitude (E), bloodstream velocity (λinl) and pharmaco-kinetic profile (PK) impacts the reaction and transport mechanisms of drug (RTMs) arising in electro-chemotherapeutic treatments. The first step implies retrieving the ratios between extracellular, free intracellular, and bound intracellular concentrations from numerical simulations, employing a meshless code developed, calibrated and validated in a previous work. Subsequently, a Boolean model is developed to determine the presence, interaction and rates of RTMs based on the comparison of the spatio-temporal evolution of the drug concentration ratios, being this the main contribution of the present work to the comprehension of the phenomena involved in the systemic administration of chemotherapeutic drugs in cancer tumors. Different combinations of E (0 kV/m, 46 kV/m, 70 kV/m), λinl (1x10-4m/s, 1x10-3m/s, 1x10-2m/s) and PK (One-short tri-exponential, mono-exponential) are examined. In general, results show that both the presence and relative importance of RTMs can differ between both PKs for a given combination of E and λinl. Additionally, for a given PK, radial uniformity of transmembrane transport rate is aversively affected by the increase of E and λinl, whereas radial homogeneity of association/dissociation rate is monotonously affected only by E. Regarding the axial uniformity of transmembrane transport rate, this is benefited by the increase of λinl and, in a lower extent, by the reduction of E.
Assuntos
Antineoplásicos , Simulação por Computador , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Humanos , Transporte Biológico , Modelos Biológicos , Cinética , Neoplasias/tratamento farmacológico , Neoplasias/metabolismoRESUMO
Alzheimer's disease (AD) is characterized by a cholinergic deficit, prompting conventional therapies to elevate acetylcholine levels as a compensatory measure. Two main strategies involve the inhibition of acetylcholinesterase (AChE) and/or the stimulation of acetylcholine receptors (AChR). Caffeine (CFF), known as a partial agonist of nAChR and an AChE inhibitor, acts as a cholinergic enhancer. Additionally, it is suggested that CFF may exhibit neuroprotective capabilities through the inhibition of the human adenosine receptor type 2A (hA2AR) in the brain's striatum, potentially preventing cellular apoptosis. This study explores on the design and prediction of the bioactivity of CFF analogues with the aim of enhancing cholinergic signaling and providing neuroprotection to improve their therapeutic potential. We employed tools to predict pharmacokinetic and bioactivity properties, molecular docking, molecular dynamics, and target prediction to identify potential candidates among the designed CFF analogues capable of enhancing neurotransmission and providing cellular protection. In a novel approach, a normalized index is proposed for the combined analysis of the pharmacokinetic parameters and molecular docking binding affinities, which facilitates the systematic evaluation and comparison of the synthesized analogues and minimizes subjectivity in the selection of promising candidates. Results indicated that some analogues show promise in improving cholinergic activity and providing neuroprotection. These findings instill optimism, encouraging further research to corroborate their effects, while also representing a significant step towards the development of new therapeutic agents for AD.
Assuntos
Cafeína , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores , Cafeína/farmacologia , Cafeína/química , Cafeína/análogos & derivados , Cafeína/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Humanos , Simulação de Dinâmica Molecular , Simulação por Computador , Receptor A2A de Adenosina/metabolismo , Receptor A2A de Adenosina/química , Acetilcolinesterase/metabolismo , Acetilcolinesterase/química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacocinética , Neuroproteção/efeitos dos fármacos , Colinérgicos/farmacologia , Colinérgicos/químicaRESUMO
Background: Studies have demonstrated that resveratrol exerts several pharmacological effects. However, the pharmacokinetic parameters are not completely established. Objectives: This study describes the plasma pharmacokinetics and tissue distribution of resveratrol after administration by different routes and doses in rats. Methods: A reliable, simple, and sensitive HPLC method using UV detection for the quantification of resveratrol in rat plasma and tissues was developed and validated. In addition, a pharmacokinetic analysis using non-compartmental and population modeling was performed. Results: The pharmacokinetic parameters of resveratrol after the administration of 5 mg/kg via i.v. bolus calculated by non-compartmental analysis were a constant of elimination (ke) of 0.09 h-1 ± 0.04, a half-life (t1/2) of 9.5 h ± 3.7, an apparent volume of distribution (Vd) of 5.8 L/kg ± 4.7, a clearance (Cl) of 0.39 L/h/Kg ± 0.26, and an area under the curve (AUC) of 6076 ng/h/mL ± 2959. The results obtained after the administration of 100 mg/kg p.o. were an elimination constant (ke) of 0.12 ± 0.07 h-1, a half-life (t1/2) of 7.9 ± 4.2 h, the apparent volume distribution (Vd) of 13.3 ± 3.3 L/kg, a clearance (Cl) of 1.76 ± 0.49 L/h/Kg ± 0.26, and an area under the curve (AUC) of 6519 ± 1592 ng/h/mL. For the tissue distribution analysis, 10 mg/kg of resveratrol was intravenously administered to rats and the molecule was quantified in the liver, lung, kidney, heart, stomach, spleen, adipose tissue, and brain of the animals. Conclusions: The population pharmacokinetic modeling showed that resveratrol has a two-compartment model in both routes of administration and has a higher volume of distribution when it is given orally. In addition, resveratrol showed a high brain concentration after iv administration, which indicates that this molecule is capable of crossing the blood-brain barrier of animals, a crucial capacity for its neuroprotective activity.
Assuntos
Resveratrol , Resveratrol/farmacocinética , Resveratrol/administração & dosagem , Animais , Distribuição Tecidual , Masculino , Ratos , Meia-Vida , Administração Oral , Ratos Wistar , Cromatografia Líquida de Alta Pressão , Modelos Biológicos , Área Sob a CurvaRESUMO
Developing orally administered pediatric formulations presents significant challenges due to the unique characteristics of pediatric patients. Terbinafine hydrochloride (TER), a powerful antifungal agent, is effective against various fungal infections, including Tinea capitis, which is common in children. However, its low aqueous solubility necessitates innovative pharmaceutical strategies to enhance its effectiveness. This study describes a rational approach to selecting suitable carriers, approved for use in children, to increase the apparent solubility of TER and to guide the development of amorphous solid dispersions containing this drug. Assessments of solubility parameters, equilibrium solubility measurements, and calculations of pediatric dose numbers guided formulation development using theoretical and experimental methodologies. Carriers like Plasdone S-360 ULTRA®, HPMCAS L, and Soluplus® demonstrated favorable solubility parameter values with TER, indicating potential for drug solubilization. The solubility of TER was strongly dependent on pH. In buffer pH 6.5 containing 10% (w/v) of Soluplus®, TER presented the highest solubility value. The solid-state characterization techniques employed to assess the precipitate formed after equilibrium solubility studies during preformulation demonstrated that there were no phase transitions and no significant interactions between the drug and the evaluated carriers. Furthermore, the results demonstrate that Soluplus® achieved the lowest dose number (0.23) for pediatric patients over 6 years old. So, it was selected for preparing the amorphous solid dispersion via spray drying, which significantly enhanced the apparent solubility of TER while maintaining prolonged supersaturation, offering a promising alternative for developing solid formulations of this drug, particularly for pediatric patients, as it aims to improve oral bioavailability.
Assuntos
Antifúngicos , Química Farmacêutica , Solubilidade , Terbinafina , Terbinafina/química , Terbinafina/administração & dosagem , Terbinafina/farmacocinética , Antifúngicos/administração & dosagem , Antifúngicos/química , Antifúngicos/farmacocinética , Química Farmacêutica/métodos , Criança , Composição de Medicamentos/métodos , Administração Oral , Humanos , Portadores de Fármacos/química , Concentração de Íons de Hidrogênio , Tecnologia Farmacêutica/métodos , Polietilenoglicóis , PolivinilRESUMO
A huge challenge after the emergence of COVID-19 has been the discovery of effective antiviral drugs. Although remdesivir (RDV) emerged as one of the most promising drugs, its pharmaceutical formulation Veklury® is limited by moderate efficacy, high toxicity and need for parenteral administration. The aim of the present work was to develop a liposomal formulation of RDV for pulmonary administration and evaluate its efficacy in models of COVID-19. Liposomal RDV nanoformulation (LRDV) was selected based on high drug encapsulation efficiency, sustained drug release property and high in vitro selectivity index. A pharmacokinetic study of intranasal LRDV in mice demonstrated effective delivery of the drug to the lungs. LRDV was then evaluated for its efficacy in SARS-CoV-2-infected K18-hACE2 mice after repeated intranasal administration at 10 mg/kg/bid for 5 days. Veklury® given intraperitoneally at 20 mg/kg/bid was used for comparison. Mice receiving LRDV remained alive up to 15 days post-infection (dpi). On the other hand, the control groups receiving PBS and empty liposomes showed 100 % death at 6 dpi and the Veklury® group had 62.5 % death at 8 dpi. Intranasal LRDV also promoted a strong reduction in viral loads in the brain and lungs of mice and prevented the inflammatory response induced by SARS-CoV-2 in the lungs. This is in contrast with Veklury®, which did not significantly reduce the viral titer in the brain and was poorly effective in preventing the inflammatory response in the lungs. Intranasal LRDV emerges as a promising therapeutic strategy for COVID-19, including "Long COVID".
Assuntos
Monofosfato de Adenosina , Administração Intranasal , Alanina , Antivirais , Tratamento Farmacológico da COVID-19 , COVID-19 , Lipossomos , Pulmão , SARS-CoV-2 , Animais , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/farmacocinética , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/farmacocinética , Alanina/administração & dosagem , Alanina/uso terapêutico , Antivirais/administração & dosagem , Antivirais/farmacocinética , Antivirais/uso terapêutico , Antivirais/farmacologia , Camundongos , SARS-CoV-2/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/efeitos dos fármacos , Carga Viral/efeitos dos fármacos , Feminino , Humanos , Camundongos TransgênicosRESUMO
INTRODUCTION: Androgenic alopecia is a multifactorial disease with a high incidence and a great psychological burden on patients. The current FDA-approved treatment is topical minoxidil or oral finasteride. However, both present significant limitations. While the systemic absorption of finasteride causes serious sexual side effects, minoxidil's low solubility imposes a challenge in obtaining a non-irritative and effective formulation. One way to solve such limitations is by using nanocarriers targeting the drug delivery to the hair follicles upon topical application. AREAS COVERED: Here, we review which advancements have been made to achieve a more effective treatment for androgenic alopecia, focusing on nanocarriers for the topical drug delivery systems developed to target hair follicles. EXPERT OPINION: The results from multiple reviewed studies demonstrate the potential of incorporating drugs into different nanocarriers to improve follicular targeting in drug delivery for androgenic alopecia treatment. However, many studies fail to perform the proper controls. Most studies also do not quantify the drug accumulation in all skin layers, especially in hair follicles, which avoids comparisons between different nanocarriers and, hence, reliable conclusions. Future experiments with a broader nanocarrier size range, suitable skin models and controls, and clinical tests to assess the safety of developed formulations will improve the androgenic alopecia treatment.
Assuntos
Alopecia , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Folículo Piloso , Minoxidil , Nanopartículas , Humanos , Alopecia/tratamento farmacológico , Folículo Piloso/metabolismo , Folículo Piloso/efeitos dos fármacos , Portadores de Fármacos/química , Minoxidil/administração & dosagem , Minoxidil/farmacocinética , Animais , Administração Tópica , Finasterida/administração & dosagem , Finasterida/farmacocinética , Administração CutâneaRESUMO
BACKGROUND: Schistosomiasis is a neglected tropical disease caused by Schistosoma sp., and praziquantel (PZQ) is the first-line treatment. However, traditional PZQ formulations have low solubility and fast metabolism, limiting its effectiveness. Thus, nanoparticles have been proposed to improve the bioavailability and efficacy of poorly soluble antischistosomal drugs. AIMS: This systematic review used in vivo preclinical studies to map the available evidence and compare the efficacy of free PZQ and PZQ-based nanostructured formulations (N-PZQ) for schistosomiasis treatment. METHODS: PubMed, Embase, Scopus, and Web of Science were searched, and 1186 experimental studies published between 1974 and 2024 were screened. Parasitological, histopathological, pharmacokinetic, and toxicological outcomes were evaluated. RESULTS: Twelve relevant studies were identified exploring N-PZQ formulations based on liposomes, nanoliposomes, and nanocrystals. N-PZQ demonstrated better therapeutic efficacy than free PZQ, reducing parasite load, modifying oogram profiles, and down-regulating liver granuloma development (number and size). N-PZQ also exhibited improved pharmacokinetic profile, with enhanced bioavailability and longer half-life, as well as reduced toxicity (cytotoxicity, genotoxicity, and hepatotoxicity) compared to free PZQ. CONCLUSION: PZQ-based nanostructured formulations represent a promising strategy to enhance schistosomiasis treatment by improving chemotherapy efficacy, optimizing antiparasitic responses, pharmacokinetics, and reducing drug toxicity.
Assuntos
Disponibilidade Biológica , Praziquantel , Esquistossomose , Praziquantel/farmacologia , Praziquantel/administração & dosagem , Praziquantel/farmacocinética , Animais , Esquistossomose/tratamento farmacológico , Nanopartículas , Nanoestruturas/química , Humanos , Esquistossomicidas/farmacologia , Esquistossomicidas/administração & dosagem , Composição de Medicamentos , Lipossomos , Schistosoma/efeitos dos fármacosRESUMO
OBJECTIVES: Copaiba essential oil (CEO) is obtained through the distillation of copaiba balsam and has been used in the traditional medicine to treat inflammatory conditions. However, the highly lipophilic nature of CEO restricts its pharmaceutical use. This study evaluated the effect of CEO, carried in a self-nanoemulsifying drug delivery system (SNEDDS), on articular and systemic inflammation and liver changes in Holtzman rats with Freund's adjuvant-induced arthritis. METHODS: Healthy and arthritic rats received orally for 18 days the non-formulated CEO and the one carried in a self-nanoemulsifying drug delivery system (FSNEDDS), both at doses of 50 and 100 mg/kg. The oral bioavailability of FSNEDDS was determined in healthy rats by quantifying the levels of ß-caryophyllene in the plasma. KEY FINDINGS: FSNEDDS exhibited more than three times greater oral bioavailability compared to non-formulated CEO. This phenomenon allowed FSNEDDS (100 mg/kg) to effectively reduce adjuvant-induced articular and systemic inflammation and oxidative stress in arthritic rats at a dose four times lower than copaiba balsam and ß-caryophyllene. Furthermore, FSNEDDS did not alter the serum markers of liver damage, hepatic morphometry, and liver gluconeogenesis in healthy rats. CONCLUSION: FSNEDDS was effective against arthritis in rats, and unlike copaiba balsam, it does not exhibit hepatotoxicity, suggesting it could serve as a phytotherapeutic alternative in the treatment of rheumatoid arthritis.
Assuntos
Artrite Experimental , Disponibilidade Biológica , Sistemas de Liberação de Medicamentos , Emulsões , Fabaceae , Óleos Voláteis , Ratos Sprague-Dawley , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Óleos Voláteis/farmacologia , Óleos Voláteis/administração & dosagem , Ratos , Fabaceae/química , Masculino , Sesquiterpenos Policíclicos/farmacologia , Sesquiterpenos Policíclicos/administração & dosagem , Adjuvante de Freund , Estresse Oxidativo/efeitos dos fármacos , Nanopartículas , Administração Oral , Óleos de Plantas/farmacologia , Óleos de Plantas/administração & dosagem , Óleos de Plantas/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacocinética , Fígado/metabolismo , Fígado/efeitos dos fármacosRESUMO
INTRODUCTION: Healthcare systems face several challenges, with microbial infections being one of the main concerns. Therapeutic drug monitoring (TDM) is a strategy that has been encouraged to optimize antimicrobial regimens, particularly those with significant toxicity and narrow therapeutic indices, such as amikacin (AMK). We aimed to evaluate AMK concentrations of patients in a non-routine TDM setting and compare the performance of immunoassay and chromatography methods for routine clinical use. MATERIAL AND METHODS: In this prospective study, peak (Cmax) and trough (Cmin) plasma samples were collected from 39 adult patients and quantified by ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS/MS). Relevant clinical information was collected from medical records. AMK concentrations and clinical data were analyzed to evaluate therapy performance and influencing factors. In addition, fluorescence polarized immunoassay (FPIA) and UPLC-MS/MS were compared with Passing-Bablok regression and Bland-Altman plot analysis. RESULTS: AMK concentrations varied widely, with a median Cmax of 41.40 µg/mL (interquartile range [IQR] 27.60 - 56.75 µg/mL) and a median Cmin of 1.87 µg/mL (IQR 0.7 - 6.19 µg/mL). A high proportion of patients (83.1 %) failed to achieve the Cmax therapeutic target, while 31.7 % failed to achieve the Cmin therapeutic target. Overall, elderly patients and those with reduced renal function had higher Cmax target attainment, while the same groups had lower Cmin target attainment. The method comparison showed a mean difference of 1.54 % (limits of agreement -42.46 % to 45.54 %) in measured concentrations, with good correlation and no constant or proportional differences. CONCLUSION: Many patients failed to reach the Cmax target and were at risk of treatment failure, although adequate Cmin was achieved more often. TDM with dose adjustments could improve AMK therapy, but further research is needed.
Assuntos
Amicacina , Antibacterianos , Países em Desenvolvimento , Monitoramento de Medicamentos , Espectrometria de Massas em Tandem , Humanos , Amicacina/sangue , Amicacina/farmacocinética , Monitoramento de Medicamentos/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Idoso , Estudos Prospectivos , Espectrometria de Massas em Tandem/métodos , Antibacterianos/sangue , Antibacterianos/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Imunoensaio de Fluorescência por Polarização/métodosRESUMO
This study analyzed the residue depletion kinetics of ivermectin (IVM) in Nelore and crossbred (Nelore x Angus) cattle aiming to compare the profiles between the breeds and evaluate the residue levels at the injection site. IVM 1%, at a dose of 0.2 mg/kg, was administered via the subcutaneous route, and tissue samples were collected on different days post administration for analysis by LC-MS/MS. The results revealed that the detection of the marker residue in conventional matrices such as the liver, perirenal fat, and trapezius muscle (injection site) had relatively high residue concentrations. The maximum residue limit (MRL) was exceeded at the injection site at 21- and 35-days post administration in crossbred and Nelore animals, respectively, with significant variations between animals. This study highlighted significant challenges in accurately determining the pharmacokinetic profile and withdrawal periods of IVM in cattle due to high variability in tissue residue data, particularly at injection sites. The comparison of IVM concentrations between cattle breeds was hindered by high standard errors, emphasizing the need for more rigorous sampling protocols. The results suggest that current guidelines may not adequately account for the erratic depletion kinetics of injectable formulations like IVM, especially at injection sites. Therefore, improving sampling techniques and revising guidelines are essential for accurate residue monitoring and withdrawal period determination.
Assuntos
Resíduos de Drogas , Ivermectina , Animais , Ivermectina/análise , Ivermectina/farmacocinética , Bovinos , Resíduos de Drogas/análise , Espectrometria de Massas em Tandem , Fígado/química , Fígado/metabolismo , Contaminação de Alimentos/análise , CruzamentoRESUMO
The pharmacokinetics and pharmacodynamics (PK/PD) of vancomycin change during HD, increasing the risk of subtherapeutic concentrations. The aim of this study was to evaluate during and after the conventional and prolonged hemodialysis sessions to identify the possible risk of the patient remaining without adequate antimicrobial coverage during therapy. Randomized, non-blind clinical trial, including critically ill adults with septic AKI on conventional (4 h) and prolonged HD (6 and 10 h) and using vancomycin for at least 72 h. Sessions were analyzed and randomized into three groups (G): control (C), dose of 15 mg/kg after session), intervention (I) 2 h (dose of 7.5 mg/kg in the second hour and 7.5 mg/kg after) and IG continuous infusion (dose of 30 mg/kg in 24 h). Of the 316 patients recruited, 87 were randomized, and 174 HD sessions were monitored. For the analysis, 28 sessions belonged to the CG, 47 to the 2-hour IG, and 31 to the continuous IG. The groups were similar in age, weight, severity scores, use of nephrotoxins, sérum albumin, Kt/V, HD modality, ultrafiltration, and intradialytic intercurrences. The intervention groups showed a higher therapeutic concentration frequency than the control group (p < 0.002). The initial concentration was identified as a risk factor (OR 1.16, p = 0.001) for a non-therapeutic vancomycin concentration in the logistic regression. In contrast, the 2-hour IG was identified as a protective factor (OR 0.24, p = 0.04). Administration of vancomycin during dialysis proved to be a protective factor against concentrations outside the therapeutic target. Further studies are needed to suggest more appropriate doses of vancomycin for patients with AKI on dialysis therapy and to assess the impact of these results on clinical outcomes.
Assuntos
Injúria Renal Aguda , Antibacterianos , Diálise Renal , Vancomicina , Humanos , Vancomicina/administração & dosagem , Vancomicina/farmacocinética , Masculino , Injúria Renal Aguda/terapia , Feminino , Pessoa de Meia-Idade , Idoso , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Testes de Sensibilidade Microbiana , Área Sob a CurvaRESUMO
Cafestol is an ent-kaurene skeleton diterpene that is present in coffee beans and brews. Although several biological activities have been described in the literature for cafestol, such as hypercholesterolemic, anti-inflammatory, anticerous, and antidiabetic effects, its metabolism within the human body remains poorly understood. Therefore, this study aimed to quantify cafestol in boiled coffee brew, assess its bioaccessibility using a static in vitro digestion model, and investigate the metabolites formed during the digestion process using liquid chromatography coupled to high-resolution mass spectrometry. Cafestol content in the boiled coffee brew ranged from 127.47 to 132.65 mg L-1. The bioaccessibility of cafestol from boiled coffee brew using the in vitro digestion model was 93.65%; additionally, in the intestinal phase, cafestol was mainly found in its alcohol form. Additionally, a novel carboxylic acid derivative metabolite from cafestol with m/z 331.1909 [M + H]+ formed in the oral digestion phase is proposed. This metabolite was also detected in other digestion phases. Thus, this is the first article to investigate the metabolism of cafestol during digestion using an in vitro digestion model. The results indicate that cafestol is bioaccessible, is available to absorption, in its alcohol form, and suffers an oxidation reaction during the oral phase of digestion.
Assuntos
Coffea , Café , Digestão , Espectrometria de Massas , Modelos Biológicos , Humanos , Coffea/química , Coffea/metabolismo , Café/química , Café/metabolismo , Espectrometria de Massas/métodos , Sementes/química , Sementes/metabolismo , Diterpenos/metabolismo , Diterpenos/química , Diterpenos/análise , Diterpenos/farmacocinética , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , CulináriaRESUMO
Intranasal topical administration offers a promising route for local and systemic drug delivery, with in vitro permeation and mucoadhesion studies often using porcine models. However, the impact of storage on mucosal integrity after the procedure remains unaddressed. This study aimed to standardize the preparation process and evaluated whether storage of porcine nasal mucosa impairs its integrity and permeability for experimental comparisons. Additionally, an optimized in vitro mucoadhesion experiment using texture analyzer equipment was investigated. Porcine nasal mucosa was subjected to different storage conditions ("fresh"; refrigerated at 4°C for 24 h and 48 h, and frozen at -20°C for two or three weeks) and assessed using optical and transmission electron microscopy. In vitro permeation assays were performed in a Franz-type vertical diffusion system with lidocaine hydrochloride (LDC). In vitro mucoadhesion assays were conducted using fresh nasal mucosa and a commercial nasal topical formulation using TA.XT. Plus texture analyzer. The variables involved (probe speed, contact time, and application force) in assessing mucoadhesive capacity (maximum mucoadhesive force Fmax and work of mucoadhesion Wmuc) were optimized using a Central Composite Design. Fresh tissues showed no alterations in histological arrangement or in the ultrastructure of adherence junctions. Stored tissues exhibited histological disorganization, reduced thickness, and loss of epithelial integrity. LDC permeability increased in storage tissues (p < 0.05). Contact force had a positive effect on Fmax and Wmuc (p < 0.0001), with a minimum required value of 0.48 N. Variations in contact time and probe speed did not affect the responses (p > 0.05). In conclusion, the preparation technique was adequate to maintain mucosa integrity for permeability studies. However, storing the mucosa at 4 or -20°C overestimated LDC permeation, which could mislead critical data for formulation development. Therefore, the use of fresh mucosa is recommended to ensure more reliable results. For in vitro mucoadhesion assays, a minimum contact force of 0.48N is required for optimal responses.
Assuntos
Administração Intranasal , Lidocaína , Mucosa Nasal , Permeabilidade , Animais , Mucosa Nasal/metabolismo , Suínos , Lidocaína/administração & dosagem , Lidocaína/farmacocinética , Administração Intranasal/métodos , Adesividade , Sistemas de Liberação de Medicamentos/métodos , Química Farmacêutica/métodosRESUMO
Lupin (Lupinus angustifolius L.) proteins are potential sources of bioactive peptides (LBPs) that can inhibit dipeptidyl peptidase IV (DPP-IV) and angiotensin I-converting enzyme (ACE-I) activity. However, the capacity of different enzymes to release LBPs, the pharmacokinetic and bioactivities of the peptides released, and their binding affinities with the active sites of DPP-IV and ECA-I are topics scarcely addressed. Therefore, we used in silico hydrolysis (BIOPEP-UWM platform) with various enzymes to predict the release of LBPs. Among the bioactive peptides identified in lupin proteins (n = 4813), 2062 and 1558 had DPP-IV and ACE-I inhibitory activity, respectively. Ficin, bromelain, and papain released the highest proportion of ACE-I (n = 433, 411, and 379, respectively) and DPP-IV (n = 556, 544, and 596, respectively) inhibitory peptides. LBPs with favorable pharmacokinetics and gastrointestinal stability tightly interacted with the active sites of ACE-I (-5.6 to -8.9 kcal/mol) and DPP-IV (-5.4 to -7.6 kcal/mol). Papain generated the most bioavailable LBPs (n = 459) with ACE-I (n = 223) and DPP-IV (n = 412) inhibitory activity. These peptides were non-toxic and gastrointestinal digestion stable. Notably, papain-based hydrolysis released some LBPs (n = 270) that inhibited both ACE-I and DPP-IV. Plant protease-based hydrolysis is a promising approach for producing lupin hydrolysates with ACE-I and DPP-IV inhibitory activities.
Assuntos
Anti-Hipertensivos , Hipoglicemiantes , Lupinus , Lupinus/química , Hidrólise , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Dipeptidil Peptidase 4/metabolismo , Dipeptidil Peptidase 4/química , Peptídeo Hidrolases/metabolismo , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/farmacocinética , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/química , Proteínas de Plantas/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Humanos , Simulação por Computador , Digestão/efeitos dos fármacosRESUMO
Intravaginal drug administration offers several advantages over other routes, primarily bypassing the initial stages of metabolism. Additionally, this route has demonstrated both local and systemic effects. Mucoadhesive polymeric systems can be utilized to prevent dose loss due to the mucous barriers and the formation of wet cavities. This study employed various techniques to evaluate the performance and characteristics of a mucoadhesive film composed of HPMC-PEG 400 containing retinyl palmitate and ketorolac molecules. Scanning Electron Microscopy (SEM) was employed to analyze the porous structure of the film. Thermogravimetric Analysis (TGA) was conducted at different temperatures to assess thermal stability. Fourier Transform Infrared Spectroscopy (FTIR) was used to analyze the functional groups and intermolecular interactions between the film and the drug. Swelling and weight loss tests indicated that the film disintegrated within 3-4 days. UV-VIS spectroscopy was used for drug release evaluation based on the Higuchi equation. Additionally, the surface wetting properties were assessed through contact angle measurements. The system's biocompatibility was confirmed using the MTT assay. Finally, adhesion and glide tests demonstrated the film's interaction with porcine uterine tissue. This study shows that the HPMC-PEG 400 film containing retinyl palmitate molecules interacts effectively with tissue and could be considered a novel tool for treating damaged epithelial tissues.
Assuntos
Diterpenos , Cetorolaco , Polietilenoglicóis , Ésteres de Retinil , Polietilenoglicóis/química , Animais , Feminino , Suínos , Administração Intravaginal , Cetorolaco/química , Cetorolaco/administração & dosagem , Cetorolaco/farmacocinética , Diterpenos/química , Liberação Controlada de Fármacos , Derivados da Hipromelose/química , Espectroscopia de Infravermelho com Transformada de Fourier , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodosRESUMO
Breast cancer is a public health concern worldwide, characterized by increasing incidence and mortality rates, requiring novel and effective therapeutic strategies. Curcumin is a bioactive compound extracted from turmeric with several pharmacological activities. Curcumin is a multifaceted anticancer agent through mechanisms including the modulation of signaling pathways, inhibition of cell proliferation, induction of apoptosis, and production of reactive oxygen species. However, the poor water solubility and bioavailability of curcumin create important barriers in its clinical application. This review elaborates on the therapeutic potential of curcumin in breast cancer treatment, focusing on the efficacy of different administration routes and synergistic effects with other therapeutic agents. The intravenous administration of curcumin-loaded nanoparticles significantly improves bioavailability and therapeutic outcomes compared to oral routes. Innovative formulations, such as nano-emulsifying drug delivery systems, have shown promise in enhancing oral bioavailability. While intravenous delivery ensures higher bioavailability and direct action on tumor cells, it is more invasive and expensive than oral administration. Advancing research on curcumin in breast cancer treatment is essential for improving therapeutic outcomes and enhancing the quality of life of patients.
Assuntos
Neoplasias da Mama , Curcumina , Curcumina/uso terapêutico , Curcumina/administração & dosagem , Curcumina/farmacologia , Curcumina/farmacocinética , Curcumina/química , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Feminino , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Animais , Disponibilidade Biológica , Vias de Administração de Medicamentos , Nanopartículas/química , Administração Oral , Sistemas de Liberação de Medicamentos/métodosRESUMO
The design and development of nanoparticle- and microparticle-based delivery systems incorporating carotenoids into carrier materials offers multiple advantages, including enhancing the bio-efficacy of these compounds due to improving their bioaccessibility and bioavailability. This study introduced pitanga saponified carotenoid extract (PSCE) and pitanga non-saponified carotenoid extract (PSCE) in a 12 % zein/1 %PEO solution and electrospun for fiber production. Then, the fibers were characterized, and their bioaccessibility and bioavailability were also evaluated. The average mean diameter of carotenoid non-saponified microfiber (CNSM) and saponified (CSM) was 5.76 ± 1.7 µm and 4.92 ± 1.4 µm, respectively, indicating that the saponification process reduces the viscosity of the solution resulting in the development of finer microfibers. Carotenoid encapsulation efficiency ranged between 10.3 % and 8.43 % for saponified and non-saponified extracts, respectively. Surprisingly, no carotenoid release was detected from both microfibers after 72 h. Carotenoid bioaccessibility was higher in pitanga pulp compared to both microfibers. The xanthophylls showed higher bioavailability in pitanga pulp. The study's results suggest that the microfibers' structure significantly influenced carotenoid release and cellular absorption more than the chemical structure of carotenoids themselves.