RESUMO
Statins are cholesterol-lowering drugs with a mechanism of inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase, but long-term use can cause side effects. An example of a plant capable of reducing cholesterol levels is Angelica keiskei (ashitaba). Therefore, this study aimed to obtain suitable compounds with inhibitory activity against the HMG-CoA reductase enzyme from ashitaba through in silico tests. The experiment began with screening and pharmacophore modeling, followed by molecular docking on ashitaba's compounds, statins groups, and the native ligand was (3R,5R)-7-[4-(benzyl carbamoyl)-2-(4-fluorophenyl)-5-(1-methylethyl)-1H-imidazole-1-yl]-3,5-dihydroxyheptanoic acid (4HI). Based on the results of the molecular docking simulations, 15 hit compounds had a small binding energy (ΔG). Pitavastatin, as the comparator drug (ΔG = -8.24 kcal/mol; Ki = 2.11 µM), had a lower ΔG and inhibition constant (Ki) than the native ligand 4HI (ΔG = -7.84 kcal/mol; Ki = 7.96µM). From ashitaba's compounds, it was found that 4'-O-geranylnaringenin, luteolin, isobavachalcone, dorsmannin A, and 3'-carboxymethyl-4,2'-dihydroxy-4'-methoxychalcone have low ΔG of below -6 kcal/mol. The lowest ΔG value was found in 3'-carboxymethyl-4,2'-dihydroxy-4'-methoxy chalcone with a ΔG of -6.67 kcal/mol and Ki value of 16.66 µM, which was lower than the ΔG value of the other comparator drugs, atorvastatin (ΔG = -5.49 kcal/mol; Ki = 1148.17 µM) and simvastatin (ΔG = -6.50 kcal/mol; Ki = 22.34 µM). This compound also binds to the important amino acid residues, including ASN755D, ASP690C, GLU559D, LYS735D, LYS691C, and SER684C, through hydrogen bonds. Based on the results, the compound effectively binds to six important amino acids with good binding affinity and only requires a small concentration to reduce half of the enzyme activity.
Assuntos
Angelica , Hidroximetilglutaril-CoA Redutases , Simulação de Acoplamento Molecular , Angelica/química , Hidroximetilglutaril-CoA Redutases/metabolismo , Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Metabolismo Secundário , Ligação Proteica , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ligantes , FarmacóforoRESUMO
Statins are widely used to treat hyperlipidemia; however, their mechanism-inhibiting cholesterol production without promoting its utilization-causes problems, such as inducing diabetes. In our research, we develop, for the first time, a chemically engineered statin conjugate that not only inhibits cholesterol production but also enhances its consumption through its multifunctional properties. The novel rosuvastatin (RO) and ursodeoxycholic acid (UDCA) conjugate (ROUA) is designed to bind to and inhibit the core of the apical sodium-dependent bile acid transporter (ASBT), effectively blocking ASBT's function in the small intestine, maintaining the effect of rosuvastatin. Consequently, ROUA not only preserves the cholesterol-lowering function of statins but also prevents the reabsorption of bile acids, thereby increasing cholesterol consumption. Additionally, ROUA's ability to self-assemble into nanoparticles in saline-attributable to its multiple hydroxyl groups and hydrophobic nature-suggests its potential for a prolonged presence in the body. The oral administration of ROUA nanoparticles in animal models using a high-fat or high-fat/high-fructose diet shows remarkable therapeutic efficacy in fatty liver, with low systemic toxicity. This innovative self-assembling multifunctional molecule design approach, which boosts a variety of therapeutic effects while minimizing toxicity, offers a significant contribution to the advancement of drug development.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Nanopartículas , Transportadores de Ânions Orgânicos Dependentes de Sódio , Rosuvastatina Cálcica , Simportadores , Animais , Nanopartículas/química , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Simportadores/antagonistas & inibidores , Simportadores/metabolismo , Masculino , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Rosuvastatina Cálcica/administração & dosagem , Humanos , Camundongos Endogâmicos C57BL , Ácidos e Sais Biliares/metabolismo , Ácidos e Sais Biliares/química , Colesterol/química , Ratos Sprague-Dawley , CamundongosRESUMO
Three new monacolin analogues, 3,6-dihydroxy-monacolin P (1), 6-methoxy monacolin S (2), and 6-methoxy dehydromonacolin S (3), were isolated from a fraction that strongly inhibited 3-hydroxy-3-methylglutaryl-CoA reductase from the ethyl acetate portion of red yeast rice ethanol extract. Their structures were determined through a combination of 1D and 2D NMR experiments, mass spectrometry analysis, and known literature reports.
Assuntos
Espectroscopia de Ressonância Magnética , Monascus , Monascus/química , Estrutura Molecular , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Hidroximetilglutaril-CoA Redutases/química , Hidroximetilglutaril-CoA Redutases/metabolismo , Produtos BiológicosRESUMO
HMG-CoA reductase (HMGR), a rate-limiting enzyme of the mevalonate pathway in Gram-positive pathogenic bacteria, is an attractive target for development of novel antibiotics. In this study, we report the crystal structures of HMGR from Enterococcus faecalis (efHMGR) in the apo and liganded forms, highlighting several unique features of this enzyme. Statins, which inhibit the human enzyme with nanomolar affinity, perform poorly against the bacterial HMGR homologs. We also report a potent competitive inhibitor (Chembridge2 ID 7828315 or compound 315) of the efHMGR enzyme identified by a high-throughput, in-vitro screening. The X-ray crystal structure of efHMGR in complex with 315 was determined to 1.27 Å resolution revealing that the inhibitor occupies the mevalonate-binding site and interacts with several key active site residues conserved among bacterial homologs. Importantly, 315 does not inhibit the human HMGR. Our identification of a selective, non-statin inhibitor of bacterial HMG-CoA reductases will be instrumental in lead optimization and development of novel antibacterial drug candidates.
Assuntos
Enterococcus faecalis , Inibidores de Hidroximetilglutaril-CoA Redutases , Humanos , Acil Coenzima A/metabolismo , Enterococcus faecalis/enzimologia , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Ácido MevalônicoRESUMO
Tacca leontopetaloides (T. leontopetaloides) contain a number of active compounds such as flavonoids, tannins, phenolics, steroids, and alkaloids. The active compounds from plants have been shown to reduce the risk of cardiovascular disease by lowering cholesterol levels by inhibiting the enzyme 3-hydroxy-3-methylglutaryl-coenzym A (HMG-CoA) reductase activity. This study aims to investigate the potential active compounds in the ethanolic extract of Tacca tubers (T. leontopetaloides) from the Banyak Islands, Aceh Singkil Regency, Aceh Province both in vitro and in silico. Tacca tubers contain secondary metabolites including flavonoids, phenolics, tannins, steroids and saponins, according to phytochemical screening. In vitro investigation of ethanolic extract of Tacca tuber revealed inhibitory activity of HMG Co-A reductase with an IC50 value of 4.92 ppm. Based on the in silico study, active compound from the extract, namely Stigmasterol with the highest binding affinities with HMG Co-A reductase (-7.2 kcal/mol). As a comparison, the inhibition of HMG Co-A reductase activity by simvastatin with an IC50 4.62 ppm and binding affinity -8.0 Kcal/mol. Our findings suggest that the ethanolic extract of Tacca tuber (T. leontopetaloides) from Banyak Islands, Aceh Province has the potential to inhibit the activity of HMG Co-A reductase.
Assuntos
Dioscoreaceae , Inibidores de Hidroximetilglutaril-CoA Redutases , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Sinvastatina , Esteroides , Extratos Vegetais/farmacologia , Extratos Vegetais/química , OxirredutasesRESUMO
BACKGROUND: Fixed-dose combinations can simplify prescribing, and numerous combination products exist for hypertension and dyslipidemia in South Korea. This study's aim was to compare trends in the consumption of single products versus fixed-dose combinations for hypertension and hyperlipidemia. METHODS AND FINDINGS: We analyzed the Korean national health insurance claims database from January 2015 through December 2019. Consumption of medicines was calculated using the defined daily dose per 1,000 inhabitants per day (DIDs) and expenditures over time. During 2015-2019, the use of antihypertensive drugs increased with an annual growth rate (AGR) of 0.9% for single products and with an AGR of 35.6% for fixed-dose combinations. A notable increase was observed for antihyperlipidemic combination drugs with an AGR of 268.1% compared to single products with 35.7%. For older adults (65+ years), the consumption of drugs for hypertension and hyperlipidemia was 3-4.5 and about 3 times higher, respectively, than in adults aged 20-64 years, and a sharp increase was found in antihyperlipidemic fixed-dose combinations among older adults. A large increase was seen for C09 (agents acting on the renin-angiotensin system) with an AGR of 36.5%, especially C09DB (angiotensin II receptor blockers + calcium channel blockers) was widely used and steeply increased with 114.2%. For antihyperlipidemic drugs, C10AA (HMG CoA reductase inhibitors) accounted for a large share and sharply increased, with 52.1 DIDs in 2019 and with an AGR of 78.4%, whereas C10BA (combinations of various lipid modifying agents) increased 9.6 times from 2.9 DIDs (96 million USD) in 2015 to 27.7 DIDs (912 million USD) in 2019. CONCLUSION: The findings of increased consumption and drug spending among older adults underscores the need for real-world evidence about health outcomes of fixed-dose combinations in this population.
Assuntos
Anti-Hipertensivos/química , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Hiperlipidemias/tratamento farmacológico , Hipertensão/tratamento farmacológico , Adulto , Idoso , Anti-Hipertensivos/uso terapêutico , Bases de Dados Factuais , Quimioterapia Combinada/economia , Quimioterapia Combinada/estatística & dados numéricos , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , República da Coreia , Estudos Retrospectivos , Adulto JovemRESUMO
SIGNIFICANCE: Statins are an important class of drugs that help to control hyperlipidemia, and one of these statins recently used is pitavastatin calcium (PITA). Nevertheless, the most reported adverse effect of statins is myopathy. Therefore, combining statins with non-steroidal anti-inflammatory drugs (NSAIDs) as Lornoxicam (LORNO) can help in the management of statin-induced myopathy. PURPOSE: This study aimed to formulate and evaluate different oral disintegrating tablets (ODTs) containing PITA using different co-processed excipients. The best PITA-ODT was selected and reformulated with the addition of LORNO, forming a single ODT comprising both drugs. The pharmacokinetic parameters of PITA and LORNO in a single ODT were compared to those of the marketed products (Lipidalon® and Lornoxicam®). METHODS: Eight PITA-ODTs were prepared via direct compression. The prepared PITA-ODTs were evaluated for their weight variation, thickness, breaking force, friability, drug content, and wetting time (WT). In-vitro disintegration time (DT) and dissolution were also evaluated and taken as parameters for selection of the best formula based on the criteria of scoring the fastest DT and highest Q10 min. LORNO was added to the selected PITA-ODT, forming a single ODT (M1) comprising both drugs, which was subjected to an in-vivo pharmacokinetic study using rats as an animal model and liquid chromatography-mass spectrometry (LC-MS/MS) for analysis of both drugs in rat plasma. RESULTS: Results showed that all PITA-ODTs had acceptable physical properties in accordance with pharmacospecial standards. PITA-ODT prepared with Pharmaburst® (F2) had significantly (p<0.05) the fastest DT (6.66±1.52 s) and highest Q10 min (79.07±2.02%) and was chosen as the best formula. The in-vivo pharmacokinetic study of M1 formula showed higher percent relative bioavailability (%RB) of 286.7% and 169.73% for PITA and LORNO, respectively, compared with the marketed products. CONCLUSION: The single ODT comprising PITA and LORNO was promising for instant co-delivery of both drugs with higher %RB when compared with the marketed products.
Assuntos
Sistemas de Liberação de Medicamentos , Piroxicam/análogos & derivados , Quinolinas/administração & dosagem , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacocinética , Disponibilidade Biológica , Química Farmacêutica/métodos , Cromatografia Líquida , Combinação de Medicamentos , Liberação Controlada de Fármacos , Excipientes/química , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Masculino , Piroxicam/administração & dosagem , Piroxicam/química , Piroxicam/farmacocinética , Quinolinas/química , Quinolinas/farmacocinética , Ratos , Ratos Wistar , Solubilidade , Comprimidos , Espectrometria de Massas em TandemRESUMO
In this study, in silico approaches are employed to investigate the binding mechanism of peptides derived from cowpea ß-vignin and HMG-CoA reductase. With the obtained information, we designed synthetic peptides to evaluate their in vitro enzyme inhibitory activity. In vitro, the total protein extract and <3 kDa fraction, at 5000 µg, support this hypothesis (95% and 90% inhibition of HMG-CoA reductase, respectively). Ile-Ala-Phe, Gln-Gly-Phe, and Gln-Asp-Phe peptides were predicted to bind to the substrate binding site of HMGCR via HMG-CoAR. In silico, it was established that the mechanism of HMG-CoA reductase inhibition largely entailed mimicking the interactions of the decalin ring of simvastatin and via H-bonding; in vitro studies corroborated the predictions, whereby the HMG-CoA reductase activity was decreased by 69%, 77%, and 78%, respectively. Our results suggest that Ile-Ala-Phe, Gln-Gly-Phe, and Gln-Asp-Phe peptides derived from cowpea ß-vignin have the potential to lower cholesterol synthesis through a statin-like regulation mechanism.
Assuntos
Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo , Peptídeos/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação , Domínio Catalítico , Meia-Vida , Ligação de Hidrogênio , Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Simulação de Acoplamento Molecular , Peptídeos/química , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Sinvastatina/química , Sinvastatina/metabolismo , Vigna/metabolismoRESUMO
BACKGROUND: The neurocognitive effect of statins in older adults remain uncertain. OBJECTIVES: The aim of this study was to investigate the associations of statin use with cognitive decline and incident dementia among older adults. METHODS: This analysis included 18,846 participants ≥65 years of age in a randomized trial of aspirin, who had no prior cardiovascular events, major physical disability, or dementia initially and were followed for 4.7 years. Outcome measures included incident dementia and its subclassifications (probable Alzheimer's disease, mixed presentations); mild cognitive impairment (MCI) and its subclassifications (MCI consistent with Alzheimer's disease, other MCI); and changes in domain-specific cognition, including global cognition, memory, language and executive function, psychomotor speed, and the composite of these domains. Associations of baseline statin use versus nonuse with dementia and MCI outcomes were examined using Cox proportional hazards models and with cognitive change using linear mixed-effects models, adjusting for potential confounders. The impact of statin lipophilicity on these associations was further examined, and effect modifiers were identified. RESULTS: Statin use versus nonuse was not associated with dementia, MCI, or their subclassifications or with changes in cognitive function scores over time (p > 0.05 for all). No differences were found in any outcomes between hydrophilic and lipophilic statin users. Baseline neurocognitive ability was an effect modifier for the associations of statins with dementia (p for interaction < 0.001) and memory change (p for interaction = 0.02). CONCLUSIONS: In adults ≥65 years of age, statin therapy was not associated with incident dementia, MCI, or declines in individual cognition domains. These findings await confirmation from ongoing randomized trials.
Assuntos
Cognição/efeitos dos fármacos , Disfunção Cognitiva/induzido quimicamente , Demência/induzido quimicamente , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Idoso , Estudos de Coortes , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Inibidores de Hidroximetilglutaril-CoA Redutases/química , MasculinoRESUMO
Statins are among the most widely used drug classes in the world. Apart from their basic mechanism of action, which is lowering cholesterol levels, many pleiotropic effects have been described so far, such as anti-inflammatory and antiatherosclerotic effects. A growing number of scientific reports have proven that these drugs have a beneficial effect on the functioning of the nervous system. The first reports proving that lipid-lowering therapy can influence the development of neurological and psychiatric diseases appeared in the 1990s. Despite numerous studies about the mechanisms by which statins may affect the functioning of the central nervous system (CNS), there are still no clear data explaining this effect. Most studies have focused on the metabolic effects of this group of drugs, however authors have also described the pleiotropic effects of statins, pointing to their probable impact on the neurotransmitter system and neuroprotective effects. The aim of this paper was to review the literature describing the impacts of statins on dopamine, serotonin, acetylcholine, and glutamate neurotransmission, as well as their neuroprotective role. This paper focuses on the mechanisms by which statins affect neurotransmission, as well as on their impacts on neurological and psychiatric diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), vascular dementia (VD), stroke, and depression. The pleiotropic effects of statin usage could potentially open floodgates for research in these treatment domains, catching the attention of researchers and clinicians across the globe.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/fisiopatologia , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/fisiopatologia , Fármacos Neuroprotetores/uso terapêutico , Transmissão Sináptica , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Fármacos Neuroprotetores/farmacologia , Neurotransmissores/metabolismo , Transmissão Sináptica/efeitos dos fármacosRESUMO
Statins are the most effective cholesterol-lowering drugs. They also exert many pleiotropic effects, including anti-cancer and cardio- and neuro-protective. Numerous nano-sized drug delivery systems were developed to enhance the therapeutic potential of statins. Studies on possible interactions between statins and human proteins could provide a deeper insight into the pleiotropic and adverse effects of these drugs. Adenylate kinase (AK) was found to regulate HDL endocytosis, cellular metabolism, cardiovascular function and neurodegeneration. In this work, we investigated interactions between human adenylate kinase isoenzyme 1 (hAK1) and atorvastatin (AVS), fluvastatin (FVS), pravastatin (PVS), rosuvastatin (RVS) and simvastatin (SVS) with fluorescence spectroscopy. The tested statins quenched the intrinsic fluorescence of hAK1 by creating stable hAK1-statin complexes with the binding constants of the order of 104 M-1. The enzyme kinetic studies revealed that statins inhibited hAK1 with significantly different efficiencies, in a noncompetitive manner. Simvastatin inhibited hAK1 with the highest yield comparable to that reported for diadenosine pentaphosphate, the only known hAK1 inhibitor. The determined AK sensitivity to statins differed markedly between short and long type AKs, suggesting an essential role of the LID domain in the AK inhibition. Our studies might open new horizons for the development of new modulators of short type AKs.
Assuntos
Adenilato Quinase/química , Geobacillus stearothermophilus/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Adenilato Quinase/metabolismo , Sequência de Aminoácidos , Atorvastatina/química , Dicroísmo Circular , Fluvastatina/química , Geobacillus stearothermophilus/química , Geobacillus stearothermophilus/enzimologia , Geobacillus stearothermophilus/genética , Humanos , Concentração Inibidora 50 , Isoenzimas/química , Cinética , Ligantes , Simulação de Acoplamento Molecular , Pravastatina/química , Ligação Proteica , Proteínas Recombinantes , Rosuvastatina Cálcica/química , Alinhamento de Sequência , Sinvastatina/química , Espectrometria de Fluorescência , Espectrofotometria , Eletricidade Estática , TemperaturaRESUMO
Enzymes are highly specific biological catalysts that accelerate the rate of chemical reactions within the cell. Our knowledge of how enzymes work remains incomplete. Computational methodologies such as molecular mechanics (MM) and quantum mechanical (QM) methods play an important role in elucidating the detailed mechanisms of enzymatic reactions where experimental research measurements are not possible. Theories invoked by a variety of scientists indicate that enzymes work as structural scaffolds that serve to bring together and orient the reactants so that the reaction can proceed with minimum energy. Enzyme models can be utilized for mimicking enzyme catalysis and the development of novel prodrugs. Prodrugs are used to enhance the pharmacokinetics of drugs; classical prodrug approaches focus on alternating the physicochemical properties, while chemical modern approaches are based on the knowledge gained from the chemistry of enzyme models and correlations between experimental and calculated rate values of intramolecular processes (enzyme models). A large number of prodrugs have been designed and developed to improve the effectiveness and pharmacokinetics of commonly used drugs, such as anti-Parkinson (dopamine), antiviral (acyclovir), antimalarial (atovaquone), anticancer (azanucleosides), antifibrinolytic (tranexamic acid), antihyperlipidemia (statins), vasoconstrictors (phenylephrine), antihypertension (atenolol), antibacterial agents (amoxicillin, cephalexin, and cefuroxime axetil), paracetamol, and guaifenesin. This article describes the works done on enzyme models and the computational methods used to understand enzyme catalysis and to help in the development of efficient prodrugs.
Assuntos
Enzimas/química , Pró-Fármacos/química , Aciclovir/química , Atenolol/química , Atovaquona/química , Catálise , Química Farmacêutica/métodos , Decitabina/química , Dopamina/química , Concentração de Íons de Hidrogênio , Hidrólise , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Conformação Molecular , Nucleosídeos/química , Fenilefrina/química , Prótons , Teoria Quântica , Software , Tecnologia Farmacêutica/métodos , Temperatura , Ácido Tranexâmico/químicaRESUMO
BACKGROUND: Statin is biologically plausible in cataract development, but inconclusive associations between statin and cataract are presented in human studies. Given most early onset cataract (EOC) occurs in regions with high cholesterol composition, we therefore aimed to assess the association between statin and EOC. METHODS: A population based case-control study was performed using the Taiwan National Health Insurance Research Database (NHIRD). The case involved patients aged 20-55 years with EOC. Controls were 1:1 matched by age, gender, year of index date, and propensity score estimated from comorbidities and comedications. Statin exposure, including intensity, properties and cumulative exposure one year before the index date were tracked. The odds ratios (ORs) of EOC associated with statin were estimated by conditional logistic regression. RESULTS: A total of 4213 cases and 4213 controls were included. Statins were associated with EOC (OR = 3.257, 95% CI 2.519-4.211). The ORs of cataract was positively associated with cumulative exposure. Subgroup analysis indicated that the ORs of cataract were significant both in lipophilic (OR = 3.485, 95% CI 2.606-4.659) and hydrophilic (OR = 3.241, 95% CI 1.975-5.321) statin users. CONCLUSIONS: Statins were associated with an increased risk of cataract in young populations.
Assuntos
Catarata/epidemiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Adulto , Idade de Início , Estudos de Casos e Controles , Catarata/induzido quimicamente , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Masculino , Pessoa de Meia-Idade , Razão de Chances , Prevalência , Medição de Risco/estatística & dados numéricos , Fatores de Risco , Taiwan/epidemiologia , Adulto JovemRESUMO
Atorvastatin (ATV) is a poorly water-soluble drug that exhibits poor oral bioavailability. Therefore, present research was designed to develop ATV solid dispersions (SDs) to enhance the solubility, drug release, and oral bioavailability. Various SDs of ATV were formulated by conventional and microwave-induced melting methods using Gelucire®48/16 as a carrier. The formulated SDs were characterized for different physicochemical characterizations, drug release, and oral bioavailability studies. The results obtained from the different physicochemical characterization indicate the molecular dispersion of ATV within various SDs. The drug polymer interaction results showed no interaction between ATV and used carrier. There was marked enhancement in the solubility (1.95-9.32 folds) was observed for ATV in prepared SDs as compare to pure ATV. The drug content was found to be in the range of 96.19% ± 2.14% to 98.34% ± 1.32%. The drug release results revealed significant enhancement in ATV release from prepared SDs compared to the pure drug and the marketed tablets. The formulation F8 showed high dissolution performance (% DE30 value of 80.65 ± 3.05) among the other formulations. Optimized Gelucire®48/16-based SDs formulation suggested improved oral absorption of atorvastatin as evidenced with improved pharmacokinetic parameters (Cmax 2864.33 ± 573.86 ng/ml; AUC0-t 5594.95 ± 623.3 ng/h ml) as compared to ATV suspension (Cmax 317.82 ± 63.56 ng/ml; AUC0-t 573.94 ± 398.9 ng/h ml) and marketed tablets (Cmax 852.72 ± 42.63 ng/ml; 4837.4 ± 174.7 ng/h ml). Conclusively, solid dispersion-based oral formulation of atorvastatin could be a promising approach for enhanced drug solubilization, dissolution, and subsequently improved absorption.
Assuntos
Atorvastatina/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Administração Oral , Animais , Atorvastatina/sangue , Atorvastatina/química , Disponibilidade Biológica , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Técnicas In Vitro , Ratos , Solubilidade , ComprimidosRESUMO
This study aimed to comprehensively investigate the in vitro metabolism of statins. The metabolism of clinically relevant concentrations of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and their metabolites were investigated using human liver microsomes (HLMs), human intestine microsomes (HIMs), liver cytosol, and recombinant cytochrome P450 enzymes. We also determined the inhibitory effects of statin acids on their pharmacological target, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. In HLMs, statin lactones were metabolized to a much higher extent than their acid forms. Atorvastatin lactone and simvastatin (lactone) showed extensive metabolism [intrinsic clearance (CLint) values of 3700 and 7400 µl/min per milligram], whereas the metabolism of the lactones of 2-hydroxyatorvastatin, 4-hydroxyatorvastatin, and pitavastatin was slower (CLint 20-840 µl/min per milligram). The acids had CLint values in the range <0.1-80 µl/min per milligram. In HIMs, only atorvastatin lactone and simvastatin (lactone) exhibited notable metabolism, with CLint values corresponding to 20% of those observed in HLMs. CYP3A4/5 and CYP2C9 were the main statin-metabolizing enzymes. The majority of the acids inhibited HMG-CoA reductase, with 50% inhibitory concentrations of 4-20 nM. The present comparison of the metabolism and pharmacodynamics of the various statins using identical methods provides a strong basis for further application, e.g., comparative systems pharmacology modeling. SIGNIFICANCE STATEMENT: The present comparison of the in vitro metabolic and pharmacodynamic properties of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin and their metabolites using unified methodology provides a strong basis for further application. Together with in vitro drug transporter and clinical data, the present findings are applicable for use in comparative systems pharmacology modeling to predict the pharmacokinetics and pharmacological effects of statins at different dosages.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Intestinos/metabolismo , Fígado/metabolismo , Microssomos/fisiologia , Biotransformação , Sistema Enzimático do Citocromo P-450/metabolismo , Citosol/metabolismo , Desenho de Fármacos/métodos , Desenvolvimento de Medicamentos/métodos , Eliminação Hepatobiliar , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/classificação , Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Concentração Inibidora 50 , Taxa de Depuração Metabólica/efeitos dos fármacos , Farmacologia em RedeRESUMO
Rupture of the rotator cuff is a common injury of the shoulder joint in sports professionals. In addition, research on repair of the rotator cuff has gained popularity over the recent years. Given the high rate of re-tear after surgery, it is necessary to design and prepare biodegradable materials with good mechanical properties, for the management of the condition. Consequently, the present study conducted surface modification of the simvastatin factor-loaded silk fibroin for the repair of chronic rotator cuff injury in SD rats. The in vitro experiments were analyzed through scanning electron microscopy and the water contact angle. Additionally, the CCK-8 assay was used to observe the effect of the intervention on the proliferation of BMSCs. Moreover, the osteogenic differentiation of BMSCs was detected through the ALP and ARS assays while the expression of osteogenic genes was examined using qRT-PCR and Western blot analysis. Furthermore, a model for repairing chronic rotator cuff tears in SD rats was established in vivo. Thereafter, rotator cuff repair and healing were evaluated through HE staining while Masson and Sirius staining was used to detect the collagen formation ratio. Additionally, the study analyzed the mechanism underlying the effect of simvastatin-loaded silk fibroin. The results showed that the simvastatin-loaded silk fibroin membrane had better biocompatibility and the in vitro experiments confirmed that it could promote the proliferation and osteogenic differentiation of BMSCs. In addition, the in vivo HE staining experiments similarly confirmed that it could enhance tendon bone healing and alleviate inflammation in chronic rotator cuff injuries. On the other hand, Masson and Sirius staining showed that the simvastatin-loaded silk fibroin could promote the formation of collagen. Further analysis also revealed that it could promote the osteogenic differentiation of BMSCs by activating the ß-catenin signaling pathway. In general, these findings suggested that surface modification of the simvastatin factor-loaded silk fibroin was a potential means of improving the healing of rotator cuff injuries and can be implemented in clinical practice in future.
Assuntos
Fibroínas/química , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sinvastatina/química , Cicatrização/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Osteogênese/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Lesões do Manguito Rotador/tratamento farmacológico , Lesões do Manguito Rotador/patologia , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico , Propriedades de Superfície , beta Catenina/metabolismoRESUMO
Myocarditis refers to the clinical and histological characteristics of a diverse range of inflammatory cellular pathophysiological conditions which result in cardiac dysfunction. Myocarditis is a major cause of mortality in individuals less than 40 years of age and accounts for approximately 20% of cardiovascular disease (CVD) events. Myocarditis contributes to dilated cardiomyopathy in 30% of patients and can progress to cardiac arrest, which has a poor prognosis of <40% survival over 10 years. Myocarditis has also been documented after infection with SARS-CoV-2. The most commonly used lipid-lowering therapies, HMG-CoA reductase inhibitors (statins), decrease CVD-related morbidity and mortality. In addition to their lipid-lowering effects, increasing evidence supports the existence of several additional beneficial, 'pleiotropic' effects of statins. Recently, several studies have indicated that statins may attenuate myocarditis. Statins modify the lipid oxidation, inflammation, immunomodulation, and endothelial activity of the pathophysiology and have been recommended as adjuvant treatment. In this review, we focus on the mechanisms of action of statins and their effects on myocarditis, SARS-CoV-2 and CVD.
Assuntos
Tratamento Farmacológico da COVID-19 , Doenças Cardiovasculares/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Miocardite/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , COVID-19/complicações , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Estrutura Molecular , Miocardite/etiologiaRESUMO
Disruption of the intracellular lipid balance leading to cholesterol accumulation is one of the features of cells that participate in the development of atherosclerotic lesions. Evidence form our laboratory indicates that anti-inflammatory cyclopentenone prostaglandins (cyPGs) of A- and J-family deviate lipid metabolism from the synthesis of cholesterol and cholesteryl esters to the synthesis of phospholipids in foam-cell macrophages. cyPGs possessing an α,ß-unsaturated cyclopentane ring are highly electrophilic substances able to promptly react with reactive cysteines of intracellular molecules through Michael addition. On the other hand, HMG-CoA reductase (HMGCR), the enzyme responsible for the rate-limiting step in cholesterol biosynthesis, presents critically reactive cysteines at the entry of catalytic domain, particularly Cys561, that could be target of cyPG inhibition. In the present study, we showed that cyPGs (but not other non-α,ß-unsaturated PGs) physically interact with HMGCR, in a dithiothreitol- and ß-mercaptoethanol-sensitive way, and block the activity of the catalytic subunit of the enzyme (IC50 for PGA2 = 0.17 µM). PGA2 inhibits HMGCR activity in cultured rat and human macrophages/macrophage-foam cells and leads to enhanced expression of HMGCR protein, as observed with statins. In cell culture models, PGA2 effectively inhibits the reductase at non-toxic doses (e.g., 1 µM) that block cell proliferation thus suggesting that part of the well-known antiproliferative effect of PGA2 may be due to its ability of blocking HMGCR activity, as cells cannot proliferate without a robust cholesterogenesis. Therefore, besides the powerfully anti-inflammatory and antiproliferative effects, the anticholesterogenic effects of PGA2 should be exploited in atherosclerosis therapeutics.
Assuntos
Anti-Inflamatórios , Células Espumosas/enzimologia , Hidroximetilglutaril-CoA Redutases , Inibidores de Hidroximetilglutaril-CoA Redutases , Prostaglandinas A , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Humanos , Hidroximetilglutaril-CoA Redutases/química , Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Masculino , Prostaglandinas A/química , Prostaglandinas A/farmacologia , Ratos , Ratos WistarRESUMO
The inhibition of CYP2C9-mediated warfarin metabolism by acid or lactone forms of statin converted in the body and effects of CYP2C9 genetic variants on their inhibition are not fully understood. Here, the effects of acid and lactone forms of statins on S-warfarin 7-hydroxylation were investigated in vitro. S-Warfarin 7-hydroxylase activities of human liver microsomes (HLMs), recombinant CYP2C9.1 (rCYP2C9.1), and rCYP2C9.3 (Ile359Leu variant) in the presence of statins were determined by high-performance liquid chromatography. Lactone forms of atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin inhibited the activity of HLMs more potently than the corresponding acid forms, whereas fluvastatin acid showed stronger inhibition than fluvastatin lactone. When the effects of statins on rCYP2C9 variants were examined, inhibition profiles of acid versus lactone forms of statins except for fluvastatin were similar between rCYP2C9.1 and rCYP2C9.3. However, the degrees of inhibition by atorvastatin lactone, fluvastatin acid, fluvastatin lactone, lovastatin lactone, and pitavastatin lactone (Ki values) were significantly different between these variants. These results indicated that lactone forms of statins other than fluvastatin showed more potent inhibition of CYP2C9-catalyzed S-warfarin 7-hydroxylation than the corresponding acid forms. Furthermore, our results indicated that Ile359Leu substitution in CYP2C9 affected the inhibitory potencies of statins.
Assuntos
Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2C9/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo , Microssomos Hepáticos/metabolismo , Variantes Farmacogenômicos/fisiologia , Varfarina/metabolismo , Ácidos/metabolismo , Catálise , Relação Dose-Resposta a Droga , Interações Medicamentosas/fisiologia , Feminino , Humanos , Hidroxilação/fisiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Lactonas/metabolismo , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Varfarina/farmacologiaRESUMO
Inflammation and oxidative stress are two major factors that are involved in the pathogenesis of atherosclerosis. A smart drug delivery system that responds to the oxidative microenvironment of atherosclerotic plaques was constructed in the present study. Simvastatin (SIM)-loaded biodegradable polymeric micelles were constructed from hyaluronic acid (HA)-coated poly(ethylene glycol)-poly(tyrosine-ethyl oxalyl) (PEG-Ptyr-EO) for the purpose of simultaneously inhibiting macrophages and decreasing the level of reactive oxygen species (ROS) to treat atherosclerosis. HA coating endows the micelle system the ability of targeting CD44-positive inflammatory macrophages. Owing to the ROS-responsive nature of PEG-Ptyr-EO, the micelles can not only be degraded by enzymes, but also consumes ROS by itself at the pathologic sites, upon which the accumulation of pro-inflammatory macrophages is effectively suppressed and oxidative stress is alleviated. Consequently, the cellular uptake experiment demonstrated that SIM-loaded HA-coated micelles can be effectively internalized by LPS-induced RAW264.7 cells and showed high cytotoxicity against the cells, but low cytotoxicity against LO2 cells. In mouse models of atherosclerosis, intravenously SIM-loaded HA-coated micelles can effectively reduce plaque content of cholesterol, resulting in remarkable therapeutic effects. In conclusion, the SIM-loaded micelle system provides a promising and innovative option against atherosclerosis.