RESUMO
Piperine (PIP) was evaluated as a natural coformer in the preparation of multicomponent organic materials for enhancing solubility and dissolution rate of the poorly water-soluble drugs: curcumin (CUR), lovastatin (LOV), and irbesartan (IBS). A screening based on liquid assisted grinding technique was performed using 1:1 drug-PIP molar ratio mixtures, followed by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) analyses. Three eutectic mixtures (EMs) composed of CUR-PIP, LOV-PIP, and IBS-PIP were obtained. Therefore, binary phase and Tamman's diagrams were constructed for each system to obtain the exact eutectic composition, which was 0.41:0.59, 0.29:0.71, and 0.31:0.69 for CUR-PIP, LOV-PIP, and IBS-PIP, respectively. Further, bulk materials of each system were prepared to characterize them through DSC, PXRD fully, Fourier transform infrared spectroscopy (FT-IR), and solution-state nuclear magnetic resonance (NMR) spectroscopy. In addition, the contact angle, solubility, and dissolution rate of each system were evaluated. The preserved characteristic in the PXRD patterns and FT-IR spectra of the bulk material of each system confirmed the formation of EM mixture without molecular interaction in solid-state. The formation of EM resulted in improved aqueous solubility and dissolution rate associated with the increased wettability observed by the decrease in contact angle. In addition, solution NMR analyses of CUR-PIP, LOV-PIP, and IBS-PIP suggested no significant intermolecular interactions in solution between the components of the EM. Hence, this study concludes that PIP could be an effective coformer to improve the solubility and dissolution rate of CUR, LOV, and IBS.
Assuntos
Curcumina , Irbesartana , Lovastatina , Piperidinas , Alcaloides , Benzodioxóis , Doenças Cardiovasculares , Curcumina/química , Irbesartana/química , Piperidinas/química , Alcamidas Poli-Insaturadas/química , Pós/química , Espectroscopia de Infravermelho com Transformada de Fourier , Lovastatina/químicaRESUMO
Background: Statins have extensive hepatic metabolism and can have multiple pharmacological interactions. The aim was to identify the main pharmacokinetic interactions between statins and their comedications in a group of patients from Colombia.Research design and methods: A cross-sectional study of pharmacokinetic interactions in patients treated with statins who were identified from a population database. The interactions were documented using the Lexicomp® database.Results: A total of 123,026 patients with statin prescriptions were identified, with a mean age of 68.4 ± 11.5 years; 57.1% were women, and 81.6% received atorvastatin. A total of 19.4% (n = 23.831) of patients presented pharmacological interactions. Some 15,474 (12.6%) had interactions classified as category C, 7.4% (n = 9077) as category D, and 0.5% (n = 660) as category X. 36.8% of the patients with lovastatin prescriptions had some interaction. Age older than 65 years, male sex, residence in capital cities, comorbidities, endocrine pathologies and HIV were associated with an increase in the probability of having contraindicated or risky interactions.Conclusions: Important interactions between statins and other medications were more common in adults over 65 years of age and those with endocrine comorbidities or HIV infection. This knowledge should help when proposing solutions that reduce the risk of adverse reactions.
Assuntos
Atorvastatina/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Lovastatina/farmacocinética , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Atorvastatina/administração & dosagem , Colômbia , Estudos Transversais , Bases de Dados Factuais , Interações Medicamentosas , Doenças do Sistema Endócrino/epidemiologia , Feminino , Infecções por HIV/epidemiologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Lovastatina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores Sexuais , Adulto JovemRESUMO
Lovastatin is a drug in the statin class which acts as a natural inhibitor of 3-hydroxy-3-methylglutaryl, a coenzyme reductase reported as being a potential therapeutic agent for several diseases: Alzheimer's, multiple sclerosis, osteoporosis and due to its anti-cancer properties. Aspergillus terreus is known for producing a cholesterol reducing drug. This study sets out to evaluate the production of lovastatin by Brazilian wild strains of A. terreus isolated from a biological sample and natural sources. Carbon and nitrogen sources and the best physicochemical conditions using factorial design were also evaluated. The 37 fungal were grown to produce lovastatin by submerged fermentation. A. terreus URM5579 strain was the best lovastatin producer with a level of 13.96 mg/L. Soluble starch and soybean flour were found to be the most suitable substrates for producing lovastatin (41.23 mg/L) and biomass (6.1 mg/mL). The most favorable production conditions were found in run 16 with 60 g/L soluble starch, 15 g/L soybean flour, pH 7.5, 200 rpm and maintaining the solution at 32 °C for 7 days, which led to producing 100.86 mg/L of lovastatin and 17.68 mg/mL of biomass. Using natural strains and economically viable substrates helps to optimize the production of lovastatin and promote its use.
Assuntos
Aspergillus/metabolismo , Biotecnologia/métodos , Lovastatina/biossíntese , Biomassa , Brasil , Carbono , Colesterol/química , Cromatografia Líquida de Alta Pressão , Fermentação , Concentração de Íons de Hidrogênio , Nitrogênio , Glycine max , Espectrofotometria Ultravioleta , Amido/química , Temperatura , Fatores de TempoRESUMO
Neuronal α7 and α4ß2 are the predominant nicotinic acetylcholine receptor (nAChR) subtypes found in the brain, particularly in the hippocampus. The effects of lovastatin, an inhibitor of cholesterol biosynthesis, on these two nAChRs endogenously expressed in rat hippocampal neuronal cells were evaluated in the 0.01-1 µM range. Chronic (14 days) lovastatin treatment augmented cell-surface levels of α7 and α4 nAChRs, as measured by fluorescence microscopy and radioactive ligand binding assays. This was accompanied in both cases by an increase in total protein receptor levels as determined by Western blots. At low lovastatin concentrations (10-100 nM), the increase in α4 nAChR in neurites was higher than in neuronal cell somata; the opposite occurred at higher (0.5-1 µM) lovastatin concentrations. In contrast, neurite α7 nAChRs raised more than somatic α7 nAChRs at all lovastatin concentrations tested. These results indicate that cholesterol levels homeostatically regulate α7 and α4 nAChR levels in a differential manner through mechanisms that depend on statin concentration and receptor localization. The neuroprotective pleomorphic effects of statins may act by reestablishing the homeostatic equilibrium.
Assuntos
Lovastatina/farmacologia , Neurônios/efeitos dos fármacos , Receptores Nicotínicos/genética , Receptor Nicotínico de Acetilcolina alfa7/genética , Animais , Colesterol/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Humanos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , RatosRESUMO
Lovastatin, and its semisynthetic derivative simvastatine, has great medical and economic importance, besides great potential for other uses. In the last years, a deeper and more complex view of secondary metabolism regulation has emerged, with the incorporation of cluster-specific and global transcription factors, and their relation to signaling cascades, as well as the new level of epigenetic regulation. Recently, a new mechanism, which regulates lovastatin biosynthesis, at transcriptional level, has been discovered: reactive oxygen species (ROS) regulation; also new unexpected environmental stimuli have been identified, which induce the synthesis of lovastatin, like quorum sensing-type molecules and support stimuli. The present review describes this new panorama and uses this information, together with the knowledge on lovastatin biosynthesis and genomics, as the foundation to analyze literature on optimization of fermentation parameters and medium composition, and also to fully understand new strategies for strain genetic improvement. This new knowledge has been applied to the development of more effective culture media, with the addition of molecules like butyrolactone I, oxylipins, and spermidine, or with addition of ROS-generating molecules to increase internal ROS levels in the cell. It has also been applied to the development of new strategies to generate overproducing strains of Aspergillus terreus, including engineering of the cluster-specific transcription factor (lovE), global transcription factors like the ones implicated in ROS regulation (or even mitochondrial alternative respiration aox gen), or the global regulator LaeA. Moreover, there is potential to apply some of these findings to the development of novel unconventional production systems. KEY POINTS: ⢠New findings in regulation of lovastatin biosynthesis, like ROS regulation. ⢠Induction by unexpected stimuli: autoinducer molecules and support stimuli. ⢠Recent reports on culture medium and process optimization from this stand point. ⢠Applications to molecular genetic strain improvement methods and production systems.
Assuntos
Epigênese Genética , Lovastatina , Aspergillus/genética , FermentaçãoRESUMO
Filamentous fungi are well known for producing secondary metabolites applied in various industrial segments. Among these, lovastatin and itaconic acid, produced by Aspergillus terreus, have applications in the pharmaceutical and chemical industries. Lovastatin is primarily used for the control of hypercholesterolemia, while itaconic acid is a building block for the production of synthetic fibers, coating adhesives, among others. In this study, for the first time, 35 strains of Aspergillus sp. from four Brazilian culture collections were evaluated for lovastatin and itaconic acid production and compared to a reference strain, ATCC 20542. From an initial screening, the strains ATCC 20542, URM 224, URM1876, URM 5061, URM 5254, URM 5256, URM 5650, and URM 5961 were selected for genomic comparison. Among tested strains, the locus corresponding to the lovastatin genomic cluster was assembled, showing that all genes essential for lovastatin biosynthesis were present in producing URM 5961 and URM 5650 strains, with 100% and 98.5% similarity to ATCC 20542, respectively. However, in the no producing URM 1876, URM 224, URM 5254, URM 5061, and URM 5256 strains, this cluster was either fragmented or missing. Among the 35 strains evaluated for itaconic acid production in this study, only three strains had titers above 0.5 g/L, 16 strains had production below 0.5 g/L, and the remaining 18 strains had no production, with the highest production of itaconic acid observed in the URM 5254 strain with 2.2 g/L. The essential genes for itaconic acid production, mttA, cadA msfA were also mapped, where all three genes linked to itaconic acid production were found in a single contig in the assembly of each strain. In contrast to lovastatin loci, there is no correlation between the level of itaconic acid production and genetic polymorphisms in the genes associated with its biosynthesis.
Assuntos
Aspergillus , Lovastatina , Succinatos , Aspergillus/genética , Aspergillus/metabolismo , Biodiversidade , Brasil , Genes Fúngicos , Variação Genética , Genoma Fúngico , Lovastatina/biossíntese , Lovastatina/genética , Filogenia , Succinatos/metabolismoRESUMO
INTRODUCTION: Lipid-lowering drugs, especially statins, have shown great relevance in preventing and treating cardiovascular diseases. OBJECTIVE: To determine the prescription patterns of lipid-lowering drugs and the variables associated with their use in a Colombian population. MATERIALS AND METHODS: This is a cross-sectional descriptive study. From a drug dispensing database of approximately 4.5 million Colombian health system affiliates, patients of all ages and both sexes treated with lipid-lowering agents (statins, fibrates, ezetimibe) were identified between January and March, 2017. Demographic, pharmacological and co-medication variables were included. RESULTS: In total, 103,624 patients were identified as being treated with lipid-lowering agents. The average age was 67.5 years, and 49.8% were 65 years or older. Women comprised 58.0% of the patients. Statins were the most used (n=96,910; 93.5%), and atorvastatin (n=80,812; 78.0%) and lovastatin (n=12,621; 12.2%) were the most frequent. The mean atorvastatin dose was 30.3 mg/day, and 49.9% of its users received presentations of 40 mg or more. A total of 9,258 (8.9%) patients received fibrates, and only 780 (0.8%) were taking ezetimibe. Of this population, 94.9% were treated with lipid-lowering monotherapy, and 97.3% (n=100,813) had co-medication for their comorbidities, with the most frequent being antihypertensive (89.1%), antiplatelet (57.8%), antidiabetic (31.5%) and antiulcerative agents (34.2%). CONCLUSIONS: Atorvastatin is currently the most frequently used lipid-lowering drug in this group of Colombian patients, especially in monotherapy and at doses close to the defined daily dose. Only half received high-intensity doses. New studies are required to verify the efficacy of these therapies.
Introducción. Los fármacos hipolipemiantes, especialmente las estatinas, han demostrado gran relevancia para la prevención y el tratamiento de las enfermedades cardiovasculares. Objetivo. Determinar los patrones de prescripción de los fármacos hipolipemiantes y las variables asociadas con su uso en una población de Colombia. Materiales y métodos. Se trata de un estudio descriptivo y transversal. A partir de una base de datos de dispensación de medicamentos de 4,5 millones de afiliados al sistema de salud de Colombia, se identificaron los pacientes de cualquier edad y sexo en tratamiento con hipolipemiantes (estatinas, fibratos, ezetimibe), entre enero y marzo de 2017. Se incluyeron variables demográficas, farmacológicas y de comedicaciones. Resultados. Se identificaron 103.624 pacientes en tratamiento con hipolipemiantes. La edad promedio fue de 67,5 años y el 49,8 % tenía 65 o más años. El 58,0 % eran mujeres. Las estatinas fueron los más utilizados (n=96.910; 93,5 %), siendo la atorvastatina (n=80.812; 78,0 %) y la lovastatina (n=12.621; 12,2 %) las más frecuentes. La dosis promedio de atorvastatina fue de 30,3 mg/día y el 49,9 % de sus usuarios recibía presentaciones de 40 mg o más. Un total de 9.258 (8,9 %) pacientes recibían fibratos y solo 780 (0,8 %) tomaban ezetimibe. El 94,9 % de casos recibió tratamiento en monoterapia hipolipemiante y el 97,3 % (n=100.813) tenía comedicaciones para comorbilidades, siendo las más frecuentes antihipertensivos (89,1 %), antiagregantes plaquetarios (57,8 %), antidiabéticos (31,5 %) y antiulcerosos (34,2 %). Conclusiones. La atorvastatina es actualmente el medicamento hipolipemiante más utilizado en este grupo de pacientes de Colombia, especialmente en monoterapia y a dosis cercanas a las definidas, aunque solo la mitad recibían dosis recibían dosis de alta intensidad. Se requieren nuevos estudios que verifiquen la efectividad de estos tratamientos.
Assuntos
Hipolipemiantes/uso terapêutico , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Atorvastatina/administração & dosagem , Atorvastatina/uso terapêutico , Cidades/estatística & dados numéricos , Colômbia , Estudos Transversais , Quimioterapia Combinada , Ezetimiba/administração & dosagem , Ezetimiba/uso terapêutico , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipolipemiantes/administração & dosagem , Lovastatina/administração & dosagem , Lovastatina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Distribuição por Sexo , Adulto JovemRESUMO
CHILD syndrome (Congenital Hemidysplasia, Ichthyosiform erythroderma, Limb Defects) is a rare X-linked dominant disease. The authors report a 2-month-old patient presenting with typical features of CHILD syndrome that was treated with a topical solution containing cholesterol and lovastatin, with complete clearance of her CHILD nevus. The changes in skin lipid metabolism that explain the CHILD ichthyosiform nevus and their correction through topical application of cholesterol and lovastatin are discussed.
Assuntos
Anormalidades Múltiplas/tratamento farmacológico , Anticolesterolemiantes/administração & dosagem , Colesterol/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Eritrodermia Ictiosiforme Congênita/tratamento farmacológico , Deformidades Congênitas dos Membros/tratamento farmacológico , Lovastatina/administração & dosagem , Anormalidades Múltiplas/genética , Administração Tópica , Colesterol/biossíntese , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Eritrodermia Ictiosiforme Congênita/genética , Lactente , Deformidades Congênitas dos Membros/genética , Doenças Metabólicas/genéticaRESUMO
Statins are drugs used for people with abnormal lipid levels (hyperlipidemia) and are among the best-selling medications in the United States. Thus, the aspects related to the production of these drugs are of extreme importance for the pharmaceutical industry. Herein, we provide a non-exhaustive review of fungal species used to produce statin and highlighted the major factors affecting the efficacy of this process. The current biotechnological approaches and the advances of a metabolic engineer to improve statins production are also emphasized. The biotechnological production of the main statins (lovastatin, pravastatin and simvastatin) uses different species of filamentous fungi, for example Aspergillus terreus. The statins production is influenced by different types of nutrients available in the medium such as the carbon and nitrogen sources, and several researches have focused their efforts to find the optimal cultivation conditions. Enzymes belonging to Lov class, play essential roles in statin production and have been targeted to genetic manipulations in order to improve the efficiency for Lovastatin and Simvastatin production. For instance, Escherichia coli strains expressing the LovD have been successfully used for lovastatin production. Other examples include the use of iRNA targeting LovF of A. terreus. Therefore, fungi are important allies in the fight against hyperlipidemias. Although many studies have been conducted, investigations on bioprocess optimization (using both native or genetic- modified strains) still necessary.
Assuntos
Biotecnologia/métodos , Fungos/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lovastatina/biossíntese , Engenharia Metabólica/métodos , Pravastatina/biossíntese , Animais , Fermentação , Fungos/genética , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/toxicidade , Hiperlipidemias/tratamento farmacológico , Lovastatina/farmacologia , Lovastatina/toxicidade , Pravastatina/farmacologia , Pravastatina/toxicidadeRESUMO
Aims: Lipid-core nanocapsules (LNCs) loaded with simvastatin (SV, SV-LNC) or lovastatin (LV, LV-LNC) were formulated for pulmonary administration. Methods: The LNC suspensions were characterized physicochemically, their stability was evaluated, and drug delivery by the pulmonary route was tested in vitro. Results: The loaded LNCs had a particle size close to 200 nm, a low polydispersity index, and a zeta potential around -20 mV. The encapsulation efficiency was high for SV (99.21 ± 0.7%) but low for LV (20.34 ± 1.2%). SV release from nanocapsules was slower than it was from SV in solution, with a monoexponential release profile, and the drug emitted and aerosol output rate was higher for SV-LNCs (1.58 µg/s) than for SV in suspension (0.54 µg/s). Conclusions: SV-LNCs had a median aerodynamic diameter of 3.51 µm and a highly respirable fraction (61.9%), indicating that nanoparticles are a suitable system for efficient delivery of simvastatin to the lung.