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2.
Life Sci Alliance ; 4(10)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34353886

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic caused by the new coronavirus (SARS-CoV-2) is currently responsible for more than 3 million deaths in 219 countries across the world and with more than 140 million cases. The absence of FDA-approved drugs against SARS-CoV-2 has highlighted an urgent need to design new drugs. We developed an integrated model of the human cell and SARS-CoV-2 to provide insight into the virus' pathogenic mechanism and support current therapeutic strategies. We show the biochemical reactions required for the growth and general maintenance of the human cell, first, in its healthy state. We then demonstrate how the entry of SARS-CoV-2 into the human cell causes biochemical and structural changes, leading to a change of cell functions or cell death. A new computational method that predicts 20 unique reactions as drug targets from our models and provides a platform for future studies on viral entry inhibition, immune regulation, and drug optimisation strategies. The model is available in BioModels (https://www.ebi.ac.uk/biomodels/MODEL2007210001) and the software tool, findCPcli, that implements the computational method is available at https://github.com/findCP/findCPcli.


Assuntos
COVID-19/tratamento farmacológico , COVID-19/metabolismo , Desenvolvimento de Medicamentos/métodos , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/metabolismo , COVID-19/epidemiologia , Biologia Computacional/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Modelos Biológicos , Pandemias
3.
J Clin Lab Anal ; 35(9): e23937, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34396586

RESUMO

OBJECTIVE: To deal with COVID-19, various countries have made many efforts, including the research and development of vaccines. The purpose of this manuscript was to summarize the development, application, and problems of COVID-19 vaccines. METHODS: This article reviewed the existing literature to see the development of the COVID-19 vaccine. RESULTS: We found that different types of vaccines had their own advantages and disadvantages. At the same time, the side effects of the vaccine, the dose of vaccination, the evaluation of the efficacy, and the application of the vaccine were all things worth studying. CONCLUSION: The successful development of the COVID-19 vaccine concerns almost all countries and people in the world. We must do an excellent job of researching the immunogenicity and immune reactivity of the vaccines. We hope this review can help colleagues at home and abroad.


Assuntos
Vacinas contra COVID-19 , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/classificação , Relação Dose-Resposta a Droga , Desenvolvimento de Medicamentos/métodos , Humanos
4.
Biomolecules ; 11(6)2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208760

RESUMO

Parkinson's disease is a progressive neurodegenerative disorder characterized by the death of nerve cells in the substantia nigra of the brain. The treatment options for this disease are very limited as currently the treatment is mainly symptomatic, and the available drugs are not able to completely stop the progression of the disease but only to slow it down. There is still a need to search for new compounds with the most optimal pharmacological profile that would stop the rapidly progressing disease. An increasing understanding of Parkinson's pathogenesis and the discovery of new molecular targets pave the way to develop new therapeutic agents. The use and selection of appropriate cell and animal models that better reflect pathogenic changes in the brain is a key aspect of the research. In addition, computer-assisted drug design methods are a promising approach to developing effective compounds with potential therapeutic effects. In light of the above, in this review, we present current approaches for developing new drugs for Parkinson's disease.


Assuntos
Desenvolvimento de Medicamentos/métodos , Desenvolvimento de Medicamentos/tendências , Doença de Parkinson/tratamento farmacológico , Animais , Encéfalo/patologia , Humanos , Neurônios/patologia , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/patologia , Substância Negra/patologia
5.
Int J Mol Sci ; 22(12)2021 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-34202954

RESUMO

Backgroud: The prediction of drug-target interactions (DTIs) is of great significance in drug development. It is time-consuming and expensive in traditional experimental methods. Machine learning can reduce the cost of prediction and is limited by the characteristics of imbalanced datasets and problems of essential feature selection. METHODS: The prediction method based on the Ensemble model of Multiple Feature Pairs (Ensemble-MFP) is introduced. Firstly, three negative sets are generated according to the Euclidean distance of three feature pairs. Then, the negative samples of the validation set/test set are randomly selected from the union set of the three negative sets in the validation set/test set. At the same time, the ensemble model with weight is optimized and applied to the test set. RESULTS: The area under the receiver operating characteristic curve (area under ROC, AUC) in three out of four sub-datasets in gold standard datasets was more than 94.0% in the prediction of new drugs. The effectiveness of the proposed method is also shown with the comparison of state-of-the-art methods and demonstration of predicted drug-target pairs. CONCLUSION: The Ensemble-MFP can weigh the existing feature pairs and has a good prediction effect for general prediction on new drugs.


Assuntos
Algoritmos , Desenvolvimento de Medicamentos/métodos , Modelos Teóricos , Área Sob a Curva , Desenvolvimento de Medicamentos/normas , Aprendizado de Máquina , Reprodutibilidade dos Testes , Máquina de Vetores de Suporte
6.
Bioanalysis ; 13(15): 1205-1211, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34275332

RESUMO

The COVID-19 pandemic challenged pharmaceutical and bioanalytical communities at large, in the development of vaccines and therapeutics as well as supporting ongoing drug development efforts. Existing processes were challenged to manage loss of staffing at facilities along with added workloads for COVID-19-related study support including conducting preclinical testing, initiating clinical trials, conducting bioanalysis and interactions with regulatory agencies, all in an ultra-rapid timeframes. A key factor of success was creative rethinking of processes and removing barriers - some of which hitherto had been considered immovable. This article describes how bioanalysis was crippled at the onset of the pandemic but how innovative and highly collaborative efforts across teams within and outside of both pharma, bioanalytical labs and regulatory agencies worked together remarkably well.


Assuntos
Bioensaio/métodos , COVID-19/epidemiologia , Desenvolvimento de Medicamentos/métodos , Humanos , Pandemias , SARS-CoV-2
7.
Gene ; 801: 145856, 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34293449

RESUMO

Epidemiological studies have established that untreated hypertension (HTN) is a major independent risk factor for developing cardiovascular diseases (CVD), stroke, renal failure, and other conditions. Several important studies have been published to prevent and manage HTN; however, antihypertensive agents' optimal choice remains controversial. Therefore, the present study is undertaken to update our knowledge in the primary treatment of HTN, specifically in the setting of other three important diseases. MicroRNAs (miRNAs) are remarkably stable short endogenous conserved non-coding RNAs that bind to the mRNA at its (3' UTR) to regulate its gene expression by causing translational repression or mRNA degradation. Through their coordinated activities on different pathways and networks, individual miRNAs control normal and pathological cellular processes. Therefore, to identify the critical miRNA-mRNA-TF interactions, we performed systematic bioinformatics analysis. We have also employed the molecular modelling and docking approach to identify the therapeutic target that delivers novel empathies into Food and Drug Administration approved and herbal drug response physiology. Gene Expression Omnibus (GEO) was employed to identify the differentially expressed genes (DEGs) and hub genes- KNG1, HLA-DPB1, CXCL8, IL1B, and BCL2. The HTN associated feed-forward loop (FFL) network included miR-9-5p, KNG1 and AR. We employed high throughput screening to get the best interacting compounds, telmisartan and limonin, that provided a significant docking score (-13.3 and -12.0 kcal/mol) and a potential protective effect that may help to combat the impact of HTN. The present study provides novel insight into HTN etiology through the identification of mRNAs and miRNAs and associated pathways.


Assuntos
Anti-Hipertensivos/farmacologia , Redes Reguladoras de Genes , Hipertensão/genética , Mapas de Interação de Proteínas/genética , Desenvolvimento de Medicamentos/métodos , Perfilação da Expressão Gênica , Ensaios de Triagem em Larga Escala/métodos , Humanos , Hipertensão/tratamento farmacológico , Cininogênios/química , Cininogênios/genética , Limoninas/química , Limoninas/farmacologia , MicroRNAs/genética , Modelos Moleculares , Simulação de Acoplamento Molecular , Telmisartan/química , Telmisartan/farmacologia , Fatores de Transcrição/genética
8.
Front Immunol ; 12: 648250, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248936

RESUMO

Background: The newly identified betacoronavirus SARS-CoV-2 is the causative pathogen of the coronavirus disease of 2019 (COVID-19) that killed more than 3.5 million people till now. The cytokine storm induced in severe COVID-19 patients causes hyper-inflammation, is the primary reason for respiratory and multi-organ failure and fatality. This work uses a rational computational strategy to identify the existing drug molecules to target host pathways to reduce the cytokine storm. Results: We used a "host response signature network" consist of 36 genes induced by SARS-CoV-2 infection and associated with cytokine storm. In order to attenuate the cytokine storm, potential drug molecules were searched against "host response signature network". Our study identified that drug molecule andrographolide, naturally present in a medicinal plant Andrographis paniculata, has the potential to bind with crucial proteins to block the TNF-induced NFkB1 signaling pathway responsible for cytokine storm in COVID-19 patients. The molecular docking method showed the binding of andrographolide with TNF and covalent binding with NFkB1 proteins of the TNF signaling pathway. Conclusion: We used a rational computational approach to repurpose existing drugs targeting host immunomodulating pathways. Our study suggests that andrographolide could bind with TNF and NFkB1 proteins, block TNF-induced cytokine storm in COVID-19 patients, and warrant further experimental validation.


Assuntos
Antivirais/farmacologia , COVID-19/imunologia , Síndrome da Liberação de Citocina/imunologia , Diterpenos/farmacologia , Desenvolvimento de Medicamentos/métodos , SARS-CoV-2/fisiologia , Andrographis/imunologia , COVID-19/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Humanos , Simulação de Acoplamento Molecular , Subunidade p50 de NF-kappa B/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
9.
Expert Opin Drug Metab Toxicol ; 17(9): 1103-1124, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34253134

RESUMO

Introduction: Physiological pH and chemical pKa are two sides of the same coin in defining the ionization of a drug in the human body. The Henderson-Hasselbalch equation and pH-partition hypothesis form the theoretical base to define the impact of pH-pKa crosstalk on drug ionization and thence its absorption, distribution, metabolism, excretion, and toxicity (ADMET).Areas covered: Human physiological pH is not constant, but a diverse, dynamic state regulated by various biological mechanisms, while the chemical pKa is generally a constant defining the acidic dissociation of the drug at various environmental pH. Works on pH-pKa crosstalk are scattered in the literature, despite its significant contributions to drug pharmacokinetics, pharmacodynamics, safety, and toxicity. In particular, its impacts on drug ADMET have not been effectively linked to the physiologically based pharmacokinetic (PBPK) modeling and simulation, a powerful tool increasingly used in model-informed drug development (MIDD).Expert opinion: Lacking a full consideration of the interactions of physiological pH and chemical pKa in a PBPK model limits scientists' capability in mechanistically describing the drug ADMET. This mini-review compiled literature knowledge on pH-pKa crosstalk and its impacts on drug ADMET, from the viewpoint of PBPK modeling, to pave the way to a systematic incorporation of pH-pKa crosstalk into PBPK modeling and simulation.


Assuntos
Desenvolvimento de Medicamentos/métodos , Modelos Biológicos , Preparações Farmacêuticas/metabolismo , Animais , Simulação por Computador , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Humanos , Concentração de Íons de Hidrogênio , Farmacocinética
10.
Med Sci (Paris) ; 37(8-9): 759-772, 2021.
Artigo em Francês | MEDLINE | ID: mdl-34080537

RESUMO

A vaccine is required to effectively control the COVID-19 pandemic in the mid and long term. The development of vaccines against SARS-CoV-2 was initiated as soon as the genetic sequence of the virus was published, and has evolved at an unprecedented speed, with a first clinical trial launched in March 2020. One year later, more than a dozen of vaccines based on different concepts, with some having been evaluated only in clinical trials so far, are authorized under emergency procedures. Here, we review these vaccines, compare their properties and discuss the challenges they face, including the emergence of viral variants of concern.


Assuntos
Vacinas contra COVID-19/uso terapêutico , COVID-19/prevenção & controle , Desenvolvimento de Medicamentos , SARS-CoV-2/imunologia , Aceleração , Pesquisa Biomédica/métodos , Pesquisa Biomédica/tendências , COVID-19/epidemiologia , Desenvolvimento de Medicamentos/métodos , Desenvolvimento de Medicamentos/organização & administração , Desenvolvimento de Medicamentos/normas , Emergências , História do Século XXI , Humanos , Pandemias/prevenção & controle , Saúde Pública/métodos , Saúde Pública/tendências , Vacinação/métodos , Vacinação/estatística & dados numéricos
11.
Biosensors (Basel) ; 11(5)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069382

RESUMO

The perfusion culture of primary hepatocytes has been widely adopted to build bioreactors for various applications. As a drug testing platform, a unique vertical-flow bioreactor (VfB) array was found to create the compaction culture of hepatocytes which mimicked the mechanic microenvironment in vivo while maintaining the 3D cell morphology in a 2D culture setup and enhancing the hepatic functions for a sustained culture. Here, we report the methodology in designing and fabricating the VfB to reach ideal bioreactor requirements, optimizing the VfB as a prototype for drug testing, and to demonstrate the enhanced hepatic function so as to demonstrate the performance of the bioreactor. This device enables the modular, scalable, and manufacturable construction of a functional drug testing platform through the sustained maintenance of model cells.


Assuntos
Reatores Biológicos , Hepatócitos/citologia , Sobrevivência Celular , Células Cultivadas , Desenvolvimento de Medicamentos/métodos , Preparações Farmacêuticas
12.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071206

RESUMO

Therapeutic agents with novel mechanisms of action are urgently needed to counter the emergence of drug-resistant infections. Several decades of research into proteases of disease agents have revealed enzymes well suited for target-based drug development. Among them are the three recently validated proteolytic targets: proteasomes of the malarial parasite Plasmodium falciparum, aspartyl proteases of P. falciparum (plasmepsins) and the Sars-CoV-2 viral proteases. Despite some unfulfilled expectations over previous decades, the three reviewed targets clearly demonstrate that selective protease inhibitors provide effective therapeutic solutions for the two most impacting infectious diseases nowadays-malaria and COVID-19.


Assuntos
COVID-19/tratamento farmacológico , Desenvolvimento de Medicamentos/métodos , Malária/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , Ácido Aspártico Endopeptidases/metabolismo , COVID-19/enzimologia , COVID-19/metabolismo , Humanos , Malária/enzimologia , Malária/metabolismo , Plasmodium falciparum/patogenicidade , SARS-CoV-2/patogenicidade
13.
Paediatr Drugs ; 23(4): 381-394, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34173206

RESUMO

Regulatory changes have been enacted in the United States (US) and European Union (EU) to encourage the development of new treatments for pediatric cancer. Here, we review some of the factors that have hampered the development of pediatric cancer treatments and provide a comparison of the US and EU regulations implemented to address this clinical need. We then provide some recommendations for each stage of the oncology drug development pathway to help researchers maximize their chance of successful drug development while complying with regulations. A key recommendation is the engagement of key stakeholders such as regulatory authorities, pediatric oncologists, academic researchers, patient advocacy groups, and a Pediatric Expert Group early in the drug development process. During drug target selection, sponsors are encouraged to consult the Food and Drug Administration (FDA), European Medicines Agency (EMA), and the FDA target list, in addition to relevant US and European consortia that have been established to characterize and prioritize oncology drug targets. Sponsors also need to carefully consider the resourcing requirements for preclinical testing, which include ensuring appropriate access to the most relevant databases, clinical samples, and preclinical models (cell lines and animal models). During clinical development, sponsors can account for the pharmacodynamic (PD)/pharmacokinetic (PK) considerations specific to a pediatric population by developing pediatric formulations, selecting suitable PD endpoints, and employing sparse PK sampling or modeling/simulation of drug exposures where appropriate. Additional clinical considerations include the specific design of the clinical trial, the potential inclusion of children in adult trials, and the value of cooperative group trials.


Assuntos
Antineoplásicos/uso terapêutico , Desenvolvimento de Medicamentos/legislação & jurisprudência , Prova Pericial/legislação & jurisprudência , Oncologia/legislação & jurisprudência , Neoplasias/tratamento farmacológico , Antineoplásicos/síntese química , Criança , Ensaios Clínicos como Assunto/legislação & jurisprudência , Ensaios Clínicos como Assunto/métodos , Sistemas de Liberação de Medicamentos/métodos , Desenvolvimento de Medicamentos/métodos , União Europeia , Prova Pericial/métodos , Humanos , Oncologia/métodos , Neoplasias/epidemiologia , Estados Unidos , United States Food and Drug Administration/legislação & jurisprudência
14.
IEEE/ACM Trans Comput Biol Bioinform ; 18(4): 1290-1298, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34081583

RESUMO

An outbreak of COVID-19 that began in late 2019 was caused by a novel coronavirus(SARS-CoV-2). It has become a global pandemic. As of June 9, 2020, it has infected nearly 7 million people and killed more than 400,000, but there is no specific drug. Therefore, there is an urgent need to find or develop more drugs to suppress the virus. Here, we propose a new nonlinear end-to-end model called LUNAR. It uses graph convolutional neural networks to automatically learn the neighborhood information of complex heterogeneous relational networks and combines the attention mechanism to reflect the importance of the sum of different types of neighborhood information to obtain the representation characteristics of each node. Finally, through the topology reconstruction process, the feature representations of drugs and targets are forcibly extracted to match the observed network as much as possible. Through this reconstruction process, we obtain the strength of the relationship between different nodes and predict drug candidates that may affect the treatment of COVID-19 based on the known targets of COVID-19. These selected candidate drugs can be used as a reference for experimental scientists and accelerate the speed of drug development. LUNAR can well integrate various topological structure information in heterogeneous networks, and skillfully combine attention mechanisms to reflect the importance of neighborhood information of different types of nodes, improving the interpretability of the model. The area under the curve(AUC) of the model is 0.949 and the accurate recall curve (AUPR) is 0.866 using 10-fold cross-validation. These two performance indexes show that the model has superior predictive performance. Besides, some of the drugs screened out by our model have appeared in some clinical studies to further illustrate the effectiveness of the model.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , COVID-19/virologia , Avaliação Pré-Clínica de Medicamentos/métodos , Redes Neurais de Computação , SARS-CoV-2/efeitos dos fármacos , COVID-19/epidemiologia , Biologia Computacional , Bases de Dados de Produtos Farmacêuticos/estatística & dados numéricos , Desenvolvimento de Medicamentos/métodos , Desenvolvimento de Medicamentos/estatística & dados numéricos , Avaliação Pré-Clínica de Medicamentos/estatística & dados numéricos , Reposicionamento de Medicamentos/métodos , Reposicionamento de Medicamentos/estatística & dados numéricos , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Humanos , Dinâmica não Linear , Pandemias
15.
AAPS PharmSciTech ; 22(5): 168, 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34080070

RESUMO

Formulation development of KO-947-K mesylate injectable drug products was described. Solution formulations were initially attempted, and key parameters such as drug concentration, buffer, pH, complexing agent, and tonicity modifying agent were carefully evaluated in the lab setting, mainly focusing on solubility and chemical stability. A lead solution formulation was advanced to a scaleup campaign. An unexpected stability issue was encountered, and the root cause was attributed to the heterogeneous liquid freezing process of the formulated solution at -20°C, which had not been captured in the lab setting. A lyophilized product was then designed to overcome the issue and supplied to the phase I clinical trial.


Assuntos
Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Desenvolvimento de Medicamentos/métodos , Inibidores Enzimáticos/síntese química , Estabilidade de Medicamentos , Inibidores Enzimáticos/administração & dosagem , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Liofilização , Congelamento , Injeções , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/síntese química , Solubilidade
16.
Int J Mol Sci ; 22(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34064287

RESUMO

Therapeutics and vaccines against the COVID-19 pandemic need to be developed rapidly and efficiently, given its severity. To maximize the efficiency and productivity of drug development, the world has adopted disruptive technologies and approaches in various drug development areas. Telehealth, characterized by the heavy use of digital technologies; drug repositioning strategies, aided by computational breakthroughs; and data tracking tool hubs, enabling real-time information sharing, have received much attention. Moreover, drug developers have engaged in open innovation by establishing various types of collaborations, many of which have been carried out across nations and enterprises. Finally, regulatory agencies have attempted to operate on a more flexible review basis than before. Although such disruptive approaches have partly reshaped drug development practices, issues and challenges remain before the completion of this paradigm shift in conventional drug development practices for the post-pandemic era. In this review, we have highlighted the role of a collaborative community of experts in order to figure out how disruptive technologies can be fully integrated into the current drug development practices and improve drug development efficiency for the post-pandemic era.


Assuntos
COVID-19/tratamento farmacológico , Desenvolvimento de Medicamentos/métodos , Reposicionamento de Medicamentos/métodos , Informática Médica/métodos , Telemedicina/métodos , Humanos , Pandemias , SARS-CoV-2
17.
AAPS PharmSciTech ; 22(5): 192, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34184160

RESUMO

Neurodegenerative diseases like Alzheimer's disease require treatment where it is essential for drug to reach brain. Nose to brain delivery of drugs enables direct transport to brain bypassing blood brain barrier. Imatinib mesylate, an anti-cancer agent, was found to have potential anti-Alzheimer's activity and thus repurposed for the same. However, the drug has severe side effects, poor brain bioavailability which may hinder effective treatment of Alzheimer's disease. In the current work, imatinib mesylate-loaded liposomes were prepared with particle size below 150 nm with sustained drug release up to 96 h. The liposomal drug formulation was compared with plain drug solution for cytotoxicity on N2a cells and did not show any kind of toxicity at concentrations up to 25 µg/mL. The nanocarrier formulation was then evaluated for brain deposition by nose to brain administration in comparison with drug solution in rats. The liposomes effectively improved the brain deposition of drug in brain from formulation compared to pure drug solution as indicated by AUC from in vivo experiments. These results indicate that the nose to brain delivery of liposomal imatinib mesylate improved the drug deposition and residence time in brain compared to drug solution administered through oral and intranasal routes.


Assuntos
Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Desenvolvimento de Medicamentos/métodos , Mesilato de Imatinib/administração & dosagem , Mesilato de Imatinib/farmacocinética , Administração Intranasal , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Avaliação Pré-Clínica de Medicamentos/métodos , Mesilato de Imatinib/síntese química , Lipossomos , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley
18.
AAPS PharmSciTech ; 22(5): 193, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34184163

RESUMO

The human immunodeficiency virus (HIV) impacts up to 37 million people globally, of which 1.8 million are children. To date, there is no cure for HIV, although treatment options such as antiretroviral therapy (ART) are available. ART, which involves a patient taking a combination of antiretrovirals, is being used to treat HIV clinically. Despite the effectiveness of ART, there is currently no palatable pediatric formulation to treat HIV in children, which has hindered patient compliance and overall treatment efficacy. In addition, anti-HIV therapeutics are often poorly water-soluble, and hence have poor bioavailability. In the present study, we developed a pediatric-friendly formulation for anti-HIV therapeutics with improved dissolution characteristics of the therapeutic agents. Lopinavir (LPV) and ritonavir (RTV), available as FDA-approved fixed-dose combination products, were chosen as model ART drugs, and the formulation and processing parameters of spray-dried cyclodextrin (CD)-based LPV and RTV complexes were studied. Results showed that the spray-dried complexes exhibited enhanced dissolution profiles in comparison to pure drugs, particularly spray-dried ß-CD complexes, which showed the most favorable dissolution profiles. This current formulation with enhanced dissolution and taste-masking ability through the use of cyclodextrin has the potential to address the unmet need for the development of suitable pediatric formulations.


Assuntos
Fármacos Anti-HIV/análise , Fármacos Anti-HIV/síntese química , Ciclodextrinas/análise , Ciclodextrinas/síntese química , Desenvolvimento de Medicamentos/métodos , Secagem por Atomização , Fármacos Anti-HIV/uso terapêutico , Criança , Ciclodextrinas/uso terapêutico , Composição de Medicamentos/métodos , Infecções por HIV/tratamento farmacológico , Humanos , Espectroscopia de Ressonância Magnética/métodos , Pediatria/métodos , Difração de Raios X/métodos
19.
AAPS PharmSciTech ; 22(5): 184, 2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34142250

RESUMO

Hot-melt extrusion has found extensive application as a feasible pharmaceutical technological option over recent years. HME applications include solubility enhancement, taste masking, and sustained drug release. As bioavailability enhancement is a hot topic of today's science, one of the main applications of HME is centered on amorphous solid dispersions. This review describes the most significant aspects of HME technology and its use to prepare solid dispersions as a drug formulation strategy to enhance the solubility of poorly soluble drugs. It also addresses molecular and thermodynamic features critical for the physicochemical properties of these systems, mainly in what concerns miscibility and physical stability. Moreover, the importance of applying the Quality by Design philosophy in drug development is also discussed, as well as process analytical technologies in pharmaceutical HME monitoring, under the current standards of product development and regulatory guidance. Graphical Abstract.


Assuntos
Química Farmacêutica/métodos , Portadores de Fármacos/síntese química , Desenvolvimento de Medicamentos/métodos , Tecnologia de Extrusão por Fusão a Quente/métodos , Disponibilidade Biológica , Composição de Medicamentos/métodos , Composição de Medicamentos/tendências , Tecnologia de Extrusão por Fusão a Quente/tendências , Temperatura Alta , Solubilidade , Tecnologia Farmacêutica/métodos , Tecnologia Farmacêutica/tendências , Termodinâmica
20.
AAPS PharmSciTech ; 22(5): 195, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34184117

RESUMO

Microbial keratitis (MK) is a vision-threatening disease and the fourth leading cause of blindness worldwide. In this work, we aim to develop moxifloxacin (MXN)-loaded chitosan-based cationic mucoadhesive polyelectrolyte nanocapsules (PENs) for the effective treatment of MK. PENs were formulated by polyelectrolyte complex coacervation method and characterized for their particle size, surface charge, morphology, mucoadhesive property, in-vitro and ex-vivo release, ocular tolerance, and antimicrobial efficacy studies. The pharmacodynamic study was conducted on rabbit eye model of induced keratitis and it is compared with marketed formulation (MF). Developed PENs showed the size range from 230.7 ± 0.64 to 249.0 ± 0.49 nm and positive surface charge, spherical shape along with appropriate physico-chemical parameters. Both in-vitro and ex-vivo examination concludes that PENs having more efficiency in sustained release of MXN compared to MF. Ocular irritation studies demonstrated that no corneal damage or ocular irritation. The in-vivo study proved that the anti-bacterial efficacy of PENs was improved when compared with MF. These results suggested that PENs are a feasible choice for MK therapy because of their ability to enhance ocular retention of loaded MXN through interaction with the corneal surface of the mucous membrane.


Assuntos
Desenvolvimento de Medicamentos/métodos , Ceratite/tratamento farmacológico , Moxifloxacina/síntese química , Nanocápsulas/química , Polieletrólitos/síntese química , Animais , Antibacterianos/administração & dosagem , Antibacterianos/síntese química , Antibacterianos/farmacocinética , Embrião de Galinha , Córnea/efeitos dos fármacos , Córnea/metabolismo , Córnea/microbiologia , Cabras , Ceratite/metabolismo , Ceratite/microbiologia , Moxifloxacina/administração & dosagem , Moxifloxacina/farmacocinética , Nanocápsulas/administração & dosagem , Polieletrólitos/administração & dosagem , Polieletrólitos/farmacocinética , Coelhos
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