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1.
Rev. neurol. (Ed. impr.) ; 76(1): 31-34, Ene. 2023. ilus
Artigo em Inglês, Espanhol | IBECS | ID: ibc-214334

RESUMO

Introducción: Las estatinas son de los medicamentos más recetados. Aunque las estatinas generalmente se toleran bien, pueden provocar efectos secundarios musculoesqueléticos. La miopatía autoinmune necrotizante inducida por estatinas (SINAM) es una afección rara y la prevalencia sólo es de 1 de cada 100.000 personas. Este trastorno se caracteriza por debilidad muscular simétrica progresiva y grave, elevación marcada de la creatincinasa y síntomas persistentes a pesar de la interrupción de la estatina. La electromiografía suele mostrar un patrón de miopatía irritable inespecífico, indistinguible de otras miopatías inflamatorias. La biopsia muscular muestra la presencia de fibras necróticas, fibras en regeneración sin células inflamatorias significativas y una regulación positiva difusa o focal de la expresión del complejo mayor de histocompatibilidad de clase I. Los anticuerpos anti-3-hidroxi-3-metilglutaril-coenzima A (anti-HMG-CoA) reductasa representan un rasgo serológico característico de la SINAM.Caso clínico: Presentamos a un paciente que desarrolló debilidad muscular progresiva después de tomar simvastatina durante los últimos siete años. En la presentación inicial, su nivel de creatincinasa fue de 2.954 U/L y los anticuerpos anti-HMG-CoA reductasa fueron positivos. La biopsia mostró rasgos miopáticos profundos con numerosas fibras necróticas, algunas fibras en regeneración e infiltrado de células inflamatorias perimisial, combinado con una sobreexpresión difusa del complejo mayor de histocompatibilidad de clase I. Se le diagnosticó SINAM, se suspendió la estatina y se inició una dosis alta de corticoides sistémicos, inmunoglobulina intravenosa y metotrexato. Después de tres meses de seguimiento, tuvo una mejora significativa en la fuerza muscular y el nivel de creatincinasa volvió a la normalidad.(AU)


Introduction: Statins are some of the most widely prescribed medications. Although statins are generally well tolerated, they can lead to musculoskeletal side effects. Statin-induced necrotizing autoimmune myositis (SINAM) is a rare condition and the prevalence is only 1 per 100,000 people. This disorder is characterized by progressive and severe symmetric muscle weakness, marked elevation of creatine kinase and persistent symptoms despite statin discontinuation. Electromyography commonly shows a nonspecific irritable myopathy pattern indistinguishable from other inflammatory myopathies. Muscle biopsy shows the presence of necrotic fibers, regenerating fibers without significant inflammatory cells and diffuse or focal upregulation of major histocompatibility complex class I expression. The anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibodies represent a characteristic serological feature of SINAM. Case report: We present a patient who developed progressive muscle weakness after taking simvastatin for the last seven years. At initial presentation, her creatine kinase level was 2,954 U/L and anti-HMGCR antibodies were positive. The biopsy showed a profound myopathic features with numerous necrotic fibers, some regenerating fibers and perimysial inflammatory cell infiltrate, combined with a diffuse overexpression of major histocompatibility complex class I products. She was diagnosed with SINAM, statin was suspended and a high dose of systemic corticosteroids, intravenous immunoglobulin therapy and methotrexate was started. At three-month follow-up, she had significant improvement in muscle strength and creatine kinase level returned to normal...(AU)


Assuntos
Humanos , Feminino , Idoso , Inibidores de Hidroximetilglutaril-CoA Redutases , Debilidade Muscular , Sinvastatina , Miopia , Neurologia , Doenças do Sistema Nervoso
2.
J Immunother Cancer ; 11(1)2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36650022

RESUMO

BACKGROUND: Anti-PD-1 immune checkpoint blockade is approved for first-line treatment of recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but few patients respond. Statin drugs (HMG-CoA reductase inhibitors) are associated with superior survival in several cancer types, including HNSCC. Emerging data suggest that manipulation of cholesterol may enhance some aspects of antitumor immunity. METHODS: We used syngeneic murine models (mouse oral cancer, MOC1 and TC-1) to investigate our hypothesis that a subset of statin drugs would enhance antitumor immunity and delay tumor growth. RESULTS: Using an ex vivo coculture assay of murine cancer cells and tumor infiltrating lymphocytes, we discovered that all seven statin drugs inhibited tumor cell proliferation. Simvastatin and lovastatin also enhanced T-cell killing of tumor cells. In mice, daily oral simvastatin or lovastatin enhanced tumor control and extended survival when combined with PD-1 blockade, with rejection of MOC1 tumors in 30% of mice treated with lovastatin plus anti-PD-1. Results from flow cytometry of tumors and tumor-draining lymph nodes suggested T cell activation and shifts from M2 to M1 macrophage predominance as potential mechanisms of combination therapy. CONCLUSIONS: These results suggest that statins deserve further study as well-tolerated, inexpensive drugs that may enhance responses to PD-1 checkpoint blockade and other immunotherapies for HNSCC.


Assuntos
Neoplasias de Cabeça e Pescoço , Inibidores de Hidroximetilglutaril-CoA Redutases , Animais , Camundongos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inibidores de Checkpoint Imunológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Lovastatina/farmacologia , Lovastatina/uso terapêutico , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico
3.
J Pharm Biomed Anal ; 225: 115218, 2023 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-36608427

RESUMO

For a more comprehensive characterization of a drug substance and its impurities, multidetector approaches are a helpful tool in liquid chromatography. In particular, the relatively inexpensive hyphenation of the ultraviolet (UV) with the charged aerosol detector (CAD) extends the scope from UV-active to non- or weak chromophore analytes, respectively. In this study, the chromatographic methods of the test for related substances of simvastatin and lovastatin in the European Pharmacopoeia were adapted to UV-CAD and thus allowing a more sophisticated detection of the weak chromophore dihydro impurity besides the other UV-active impurities. The compendial gradient program for simvastatin had to be modified (lowered initial acetonitrile percentage and increased gradient slope) because an additional critical peak pair emerged with the Hypersil C18 BDS column used here. Therefore, a Plackett-Burman design with 11 factors (including 4 dummy factors) was chosen to evaluate robustness of the adapted method. The flow rate, initial acetonitrile percentage, and column temperature were identified as three critical parameters that had to be carefully observed. Finally, the validity of the method for simultaneous detection of dihydrosimvastatin with CAD and of lovastatin and simvastatin as examples of UV detection was verified according to ICH Q2 (R1). In the case of lovastatin, the direct comparison with the pharmacopoeial method reveal that a determination with CAD is the more sensitive method.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Sinvastatina , Lovastatina/análise , Aerossóis/química
4.
Biomed Mater ; 18(2)2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36603225

RESUMO

Since wound dressing has been considered a promising strategy to improve wound healing, recent attention has been focused on the development of modern wound dressings based on synthetic and bioactive polymers. In this study, we prepared a multifunctional wound dressing based on carboxymethyl chitosan (CMC)/sodium alginate (Alg) hydrogel containing a nanostructured lipid carrier (NLC) in which simvastatin (SIM) has been encapsulated. This dressing aimed to act as a barrier against pathogens, eliminate excess exudates, and accelerate wound healing. Among various fabricated composites of dressing, the hydrogel composite with a CMC/sodium Alg ratio of 1:2 had an average pore size of about 98.44 ± 26.9 µm and showed 707 ± 31.9% swelling and a 2116 ± 79.2 g m-2per day water vapor transfer rate (WVTR), demonstrating appropriate properties for absorbing exudates and maintaining wound moisture. The NLC with optimum composition and properties had a spherical shape and uniform particle size distribution (74.46 ± 7.9 nm). The prepared nanocomposite hydrogel displayed excellent antibacterial activity againstEscherichia coliandStaphylococcus aureusas well as high biocompatibility on L929 mouse fibroblast cells. It can release the loaded SIM drug slowly and over a prolonged period of time. The highest drug release occurred (80%) within 14 d. The results showed that this novel nanocomposite could be a promising candidate as a wound dressing for treating various chronic wounds in skin tissues.


Assuntos
Quitosana , Hidrogéis , Camundongos , Animais , Alginatos , Sinvastatina , Cicatrização , Antibacterianos
5.
Respir Physiol Neurobiol ; 309: 104002, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36566004

RESUMO

Acute lung injury (ALI) is a disease of high prevalence and is characterized by the excessive production of inflammatory mediators in the lungs of people sick. Inflammation is the major characteristic of ALI and studies report that inhibition of inflammatory cytokines could be an alternative treatment. Statins such as Simvastatin (SV) are known to their use for cholesterol reduction but also for inflammatory and immunoregulatory processes. In this study, we evaluated the effects of SV on LPS-induced alveolar macrophages and in ALI mice model. Our study has demonstrated the protective effects of SV on LPS-activated alveolar macrophages RAW 264.7 and LPS-induced ALI in mice. SV treatment significantly inhibited the alveolar macrophages activation by decreasing the iNOS, IL-1ß, and IL-6 gene expression in vitro and in vivo. The treatment also decreased the inflammatory cells migration and the cytokines gene expression. Our findings suggest that SV can act as an anti-inflammatory agent for acute lung injury.


Assuntos
Lesão Pulmonar Aguda , Lipopolissacarídeos , Animais , Camundongos , Lipopolissacarídeos/toxicidade , Lipopolissacarídeos/metabolismo , Sinvastatina/efeitos adversos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Pulmão/metabolismo , Citocinas/metabolismo
6.
Ultrastruct Pathol ; 47(1): 1-11, 2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36520527

RESUMO

Type 2 diabetes is a major health burden to the society. Macrophages and liver inflammation emerged as important factors in its development. We investigated ultrastructural changes in the liver, with a special emphasis on macrophages in high fat diet (HFD) fed C57BL/6 J mice treated with metformin or simvastatin, two drugs that are used frequently in diabetes. Both metformin and simvastatin reduced the liver damage in HFD fed animals, manifested as the prevention of nonalcoholic steatohepatitis development and reduced activation and number of macrophages in the liver, as well as the percentage of these cells with lipid droplets in the cytoplasm compared to untreated HFD animals. In contrast with untreated HFD-fed animals, lipid droplets were not observed in lysosomes of macrophages in HFD animals treated with metformin and simvastatin. These findings provide new insight into the effects of metformin and simvastatin on the liver in this experimental model of type 2 diabetes and provide further rationale for implementation of statins in the therapeutic regimens in this disease.


Assuntos
Diabetes Mellitus Tipo 2 , Metformina , Hepatopatia Gordurosa não Alcoólica , Animais , Camundongos , Metformina/farmacologia , Sinvastatina/farmacologia , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BL , Fígado , Macrófagos
7.
J Pharmacol Sci ; 151(1): 17-27, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36522119

RESUMO

Hsp90 is a molecular chaperone that contributes to the activation and stabilization of client proteins. In our previous studies, we found that inhibition of Hsp90 delayed cardiac remodeling during the development of chronic heart failure in animal models. Simvastatin, an inhibitor of HMG-CoA reductase, has been shown to inhibit Hsp90. However, it is unclear whether simvastatin can prevent cardiac remodeling by inhibiting Hsp90. Therefore, the effects of simvastatin were examined in a rat model of chronic heart failure following myocardial infarction. The results showed that simvastatin reduced cardiac remodeling by inhibiting cardiac fibrosis. Furthermore, simvastatin decreased the expression of c-Raf and calcineurin, which are involved in intracellular signaling during the development of myocardial remodeling. In vitro, we found that the interaction of Hsp90 with c-Raf and calcineurin was reduced and the expression levels these client proteins were decreased in fibroblasts cultured in the presence of simvastatin. In addition, simvastatin also reduced proliferation, migration, and collagen production of fibroblasts. These results suggest that Hsp90 inhibition is partly responsible for the inhibitory effect of simvastatin on the development of myocardial remodeling.


Assuntos
Insuficiência Cardíaca , Inibidores de Hidroximetilglutaril-CoA Redutases , Ratos , Animais , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico , Calcineurina , Remodelação Ventricular , Proteínas de Choque Térmico HSP90/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico
8.
Biomed Pharmacother ; 158: 114089, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36538862

RESUMO

BACKGROUND: Combining mouse experiments with big data analysis of the Austrian population, we investigated the association between high-dose statin treatment and bone quality. METHODS: The bone microarchitecture of the femur and vertebral body L4 was measured in male and ovariectomized female mice on a high-fat diet containing simvastatin (1.2 g/kg). A sex-specific matched big data analysis of Austrian health insurance claims using multiple logistic regression models was conducted (simvastatin 60-80 mg/day vs. controls; males: n = 138,666; females: n = 155,055). RESULTS: High-dose simvastatin impaired bone quality in male and ovariectomized mice. In the trabecular femur, simvastatin reduced bone volume (µm3: ♂, 213 ± 15 vs. 131 ± 7, p < 0.0001; ♀, 66 ± 7 vs. 44 ± 5, p = 0.02) and trabecular number (1/mm: ♂, 1.88 ± 0.09 vs. 1.27 ± 0.06, p < 0.0001; ♀, 0.60 ± 0.05 vs. 0.43 ± 0.04, p = 0.01). In the cortical femur, bone volume (mm3: ♂, 1.44 ± 0.03 vs. 1.34 ± 0.03, p = 0.009; ♀, 1.33 ± 0.03 vs. 1.12 ± 0.03, p = 0.0002) and cortical thickness were impaired (µm: ♂, 211 ± 4 vs. 189 ± 4, p = 0.0004; ♀, 193 ± 3 vs. 169 ± 3, p < 0.0001). Similar impairments were found in vertebral body L4. Simvastatin-induced changes in weight or glucose metabolism were excluded as mediators of deteriorations in bone quality. Results from mice were supported by a matched cohort analysis showing an association between high-dose simvastatin and increased risk of osteoporosis in patients (♂, OR: 5.91, CI: 3.17-10.99, p < 0.001; ♀, OR: 4.16, CI: 2.92-5.92, p < 0.001). CONCLUSION: High-dose simvastatin dramatically reduces bone quality in obese male and ovariectomized female mice, suggesting that direct drug action accounts for the association between high dosage and increased risk of osteoporosis as observed in comparable human cohorts. The underlying pathophysiological mechanisms behind this relationship are presently unknown and require further investigation.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Osteoporose , Humanos , Masculino , Feminino , Camundongos , Animais , Sinvastatina/farmacologia , Densidade Óssea , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Osteoporose/tratamento farmacológico , Osteoporose/etiologia , Osso e Ossos , Ovariectomia/efeitos adversos
9.
Environ Res ; 216(Pt 1): 114437, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36181898

RESUMO

Pharmaceutical compounds being able to alter, retard, and enhance metabolism has gained attention in recent time as emerging pollutant. However, hospitals which are part of every urban landscape have yet to gain attention in terms of its hospital wastewater treatment to inhibit pharmaceutical compounds from reaching environment. Hence this study evaluated performance of constructed wetland in combination with tubesettler and aeration based on removal efficiency and ecological risk assessment (HQ). The removal efficiency of constructed wetland with plantation was higher by 31% (paracetamol), 102% (ibuprofen), 46%, (carbamazepine), 57% (lorazepam), 54% (erythromycin), 31% (ciprofloxacin) and 20% (simvastatin) against constructed wetland without plantation. Constructed wetland with aeration efficiency increased for paracetamol, ibuprofen, carbamazepine, lorazepam, erythromycin, ciprofloxacin, and simvastatin removal efficiency were higher by 58%, 130%, 52%, 79%, 107%, 57%, and 29% respectively. In constructed wetland with plantation, removal efficiency was higher by 20% (paracetamol), 13% (ibuprofen), 4% (carbamazepine), 14% (lorazepam), 34% (erythromycin), 19% (ciprofloxacin) and 7% (simvastatin). High ecological risk was observed for algae, invertebrate and fish with hazard quotient values in range of 2.5-484, 10-631 and 1-78 respectively. This study concludes that if space is the limitation at hospitals aeration with constructed wetland can be adopted. If space is available, constructed wetland with tubesettler is suitable, economic and environmentally friendly option. Future research works can focus on evaluating other processes combination with constructed wetland.


Assuntos
Áreas Alagadas , Animais , Eliminação de Resíduos Líquidos , Ibuprofeno , Acetaminofen , Lorazepam , Carbamazepina , Hospitais , Ciprofloxacina , Eritromicina , Sinvastatina , Preparações Farmacêuticas
10.
Cells ; 11(24)2022 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-36552711

RESUMO

Steroid-induced osteonecrosis of femoral head (SONFH) is one of the most common bone disorders in humans. Statin treatment is beneficial in preventing the development of SONFH through anti-inflammation effects and inhibition of the glucocorticoid receptor (GR). However, potential mechanisms of statin action remain to be determined. In this study, pulse methylprednisolone (MP) treatment was used to induce SONFH in broilers, and then MP-treated birds were administrated with simvastatin simultaneously to investigate the changes in cartilage homeostasis. Meanwhile, chondrocytes were isolated, cultured, and treated with MP, simvastatin, or GR inhibitor in vitro. The changes in serum homeostasis factors, cell viability, and expression of GR were analyzed. The results showed that the morbidity of SONFH in the MP-treated group increased significantly compared with the simvastatin-treated and control group. Furthermore, MP treatment induced apoptosis and high-level catabolism and low-level anabolism in vitro and vivo, while simvastatin significantly decreased catabolism and slightly recovered anabolism via inhibiting GR and the hypoxia-inducible factor (HIF) pathway. The GR inhibitor or its siRNA mainly affected the catabolism of cartilage homeostasis in vitro. In conclusion, the occurrence of SONFH in broilers was related to the activation of GR and HIF pathway, and imbalance of cartilage homeostasis. Simvastatin and GR inhibitor maintained cartilage homeostasis via GR and the HIF pathway.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Osteonecrose , Humanos , Animais , Receptores de Glucocorticoides/metabolismo , Sinvastatina/farmacologia , Cabeça do Fêmur/metabolismo , Galinhas , Osteonecrose/metabolismo , Metilprednisolona/farmacologia , Homeostase , Cartilagem
11.
J Indian Prosthodont Soc ; 22(2): 152-160, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36511026

RESUMO

Aim: The purpose of this study was to compare the effects of autologous platelet-rich fibrin (PRF) alone and PRF loaded with SIM on peri-implant bone changes and implant stability in patients undergoing implant rehabilitation. Settings and Design: This was a nonrandomized controlled split-mouth study. Materials and Methods: The study included 8 males between the ages of 45 and 60 years. Each patient received two implants, one on each side of the arch. One side was treated with PRF alone and the other side with PRF loaded with SIM at the time of osteotomy. A cone-beam computed tomography was used to evaluate bone changes around the insertion of implant sites at 3, 6, and 12 months postoperatively. The secondary outcome included measuring implant stability using Osstell device at baseline and 3 months postinsertion. To compare groups at different time periods, data were examined using a two-way analysis of variance. Statistical Analysis Used: The results were compared between the groups using a two-way analysis of variance, followed by a post hoc Bonferroni test. To examine total bone changes and stability comparisons between the two groups at the end of the trial, an unpaired t-test was utilized. Results: The mean crestal bone-level changes in the SIM/PRF group were significantly lower than the PRF group, with a mean shift of 0.9788 ± 0.04853 versus 1.356 ± 0.0434, respectively (P < 0.0001). There was no significant difference between the two groups in implant stability. Conclusion: Peri-implant application of SIM/PRF resulted in less bone changes than PRF alone, which may prove to be beneficial for the long-term success of implants. SIM showed promising results in limiting peri-implant bone resorption providing new clinical application for SIM in dental implant rehabilitation.


Assuntos
Implantes Dentários , Fibrina Rica em Plaquetas , Masculino , Humanos , Pessoa de Meia-Idade , Implantes Dentários/efeitos adversos , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico , Implantação Dentária Endóssea , Transplante Ósseo
12.
Molecules ; 27(23)2022 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-36500698

RESUMO

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 , Oxirredutases
13.
Molecules ; 27(21)2022 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-36363985

RESUMO

Simvastatin (SIM) particles are liposoluble drugs with large particle sizes, resulting in poor compatibility with electrospun polycaprolactone (PCL)/polyethylene glycol (PEG) nanofibers, so that part of them will be exposed to the electrospun nanofiber surface, which is easy to cause the burst release of drugs. Therefore, in this paper, stearic acid (SA) with good biocompatibility was innovatively added to increase the dispersion uniformity of SIM in the spinning solution, thus improving the performances of SIM-loaded PCL/PEG nanofiber membranes (NFMs). Accordingly, the effects of SA addition on the morphologies, mechanical properties, wettability, and drug release properties of the SIM-loaded NFMs were studied. The results showed that after SIM was dissolved in SA solution, the particle size of SIM was significantly reduced and could be evenly dispersed in the polymer spinning solution, thus obtaining the SIM-loaded composite NFMs with the best morphology and performance.


Assuntos
Nanofibras , Polietilenoglicóis , Sinvastatina , Preparações de Ação Retardada , Poliésteres , Liberação Controlada de Fármacos
14.
J Clin Neuromuscul Dis ; 24(2): 75-79, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36409337

RESUMO

ABSTRACT: Patients with HIV have a higher incidence of rhabdomyolysis compared with the HIV negative population because of medication-related myotoxicity and drug-drug interactions. Statins and antiretroviral therapy have been previously reported to cause myopathy in patients with HIV when used alone or in combination. In this study, we describe a case of biopsy-proven noninflammatory and nonautoimmune myopathy associated with the use of simvastatin and Genvoya (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate) and review 3 previously reported similar cases. Our patient presented with acute proximal limb weakness and significantly elevated serum creatine kinase. Muscle biopsy revealed scattered degenerating and regenerating muscle fibers without evidence for an inflammatory process. She did not respond to empiric treatment with high-dose intravenous steroids and intravenous immunoglobulin. Her creatine kinase only began to downtrend after discontinuation of both simvastatin and Genvoya, and she returned to baseline function at 2-month follow-up. Our case highlights the importance of recognizing drug-drug interactions between HIV and statin medications in causing significant noninflammatory myopathy. In these patients, both categories of medications need to be discontinued for recovery.


Assuntos
Infecções por HIV , Doenças Musculares , Feminino , Humanos , Combinação Elvitegravir, Cobicistat, Emtricitabina e Fumarato de Tenofovir Desoproxila/uso terapêutico , Sinvastatina/efeitos adversos , Doenças Musculares/induzido quimicamente , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Creatina Quinase
15.
Int J Pharm ; 629: 122379, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36370997

RESUMO

Anthracyclines such as doxorubicin (Dox) are the preferred chemotherapeutics for several cancers. However, Dox-induced cardiotoxicity limits its therapeutic potential. Liposomal encapsulation of Dox has been used for patients with risk to develop Dox induced cardiotoxicity but does not surpass the efficacy of the unencapsulated drug. Statins are widely used as cholesterol lowering drugs and have also demonstrated cardioprotective activity in cancer patients undergoing Dox therapy. We developed a liposome loaded with Dox and simvastatin (Sim) and investigated their effect on cardiomyocytes and zebrafish larvae. Furthermore, we investigated if the doses required for cardioprotection compromised the cytotoxicity of Dox in mammary and prostate cancer cells. Combination of Sim and Dox reduced ROS generation in cardiomyocytes, both given as free drugs, or co-encapsulated in liposomes. In contrast, Sim potentiated ROS-generation and cytotoxic activity of Dox towards cancer cells also when co-encapsulated in liposomes. In zebrafish larvae, Sim treatment reduced Dox-induced cardiac affection, and the liposomes did not induce any sign of Dox-induced cardiotoxicity. Our results show that liposomal co-encapsulation of Sim and Dox can be an efficient way of further reducing the risk of cardiotoxic events of liposomal Dox, while retaining, or even potentiating the anti-cancer effect of Dox.


Assuntos
Lipossomos , Neoplasias , Masculino , Animais , Peixe-Zebra , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/prevenção & controle , Sinvastatina/farmacologia , Espécies Reativas de Oxigênio , Doxorrubicina/efeitos adversos , Neoplasias/tratamento farmacológico
16.
Redox Biol ; 58: 102539, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36401888

RESUMO

Statins have manifold protective effects on the cardiovascular system. In addition to lowering LDL cholesterol levels, statins also have antioxidant effects on cardiovascular tissues involving intracellular redox pathways that are incompletely understood. Inhibition of HMG-CoA reductase by statins not only modulates cholesterol synthesis, but also blocks the synthesis of lipids necessary for the post-translational modification of signaling proteins, including the GTPase Rac1. Here we studied the mechanisms whereby Rac1 and statins modulate the intracellular oxidant hydrogen peroxide (H2O2) via NADPH oxidase (Nox) isoforms. In live-cell imaging experiments using the H2O2 biosensor HyPer7, we observed robust H2O2 generation in human umbilical vein endothelial cells (HUVEC) following activation of cell surface receptors for histamine or vascular endothelial growth factor (VEGF). Both VEGF- and histamine-stimulated H2O2 responses were abrogated by siRNA-mediated knockdown of Rac1. VEGF responses required the Nox isoforms Nox2 and Nox4, while histamine-stimulated H2O2 signals are independent of Nox4 but still required Nox2. Endothelial H2O2 responses to both histamine and VEGF were completely inhibited by simvastatin. In resting endothelial cells, Rac1 is targeted to the cell membrane and cytoplasm, but simvastatin treatment promotes translocation of Rac1 to the cell nucleus. The effects of simvastatin both on receptor-dependent H2O2 production and Rac1 translocation are rescued by treatment of cells with mevalonic acid, which is the enzymatic product of the HMG-CoA reductase that is inhibited by statins. Taken together, these studies establish that receptor-modulated H2O2 responses to histamine and VEGF involve distinct Nox isoforms, both of which are completely dependent on Rac1 prenylation.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , NADPH Oxidases , Humanos , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Peróxido de Hidrogênio/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Histamina/farmacologia , Sinvastatina/farmacologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Isoformas de Proteínas/metabolismo , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismo
17.
Int Immunopharmacol ; 113(Pt A): 109347, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36332451

RESUMO

Lymphocytes infiltration is a key mechanism that drives asthma lung inflammation. Our previous results demonstrated a significant increase in the frequency and persistence of central memory T (TCM) cells in inflamed lung tissue. This could be due to an increase in the infiltration of TCM in the lung tissue, or the possible differentiation of lung effector memory T (TEM) cells into TCM during lung inflammation. Thus, targeting the accumulation of memory T cells provides a potential approach for asthma treatment. Simvastatin and other statins were shown to impact both the structural and immune lung cells, presenting a distinct immunomodulatory effect on T lymphocyte activation, infiltration, and function. Therefore, we sought to evaluate the effect of simvastatin on the frequency and function of CD4 and CD8 TEM and TCM cells in an ovalbumin (OVA)-induced mouse model of asthma. Simvastatin treatment significantly attenuated the infiltration of both TEM and TCM memory subtypes, along with their production of IL-4 and IL-13 cytokines in a T helper 2 (Th2) OVA-sensitized mouse model. Furthermore, we detected a reduction in ICAM-1 and VCAM-1 levels in the lung homogenate of OVA-sensitized and challenged mice, as well as in human umbilical vein endothelial cells (HUVECs) following treatment with simvastatin. The reduction in leucocyte homing receptors following simvastatin treatment might have contributed to the observed decrease in infiltrated memory T cell numbers. In conclusion, this study demonstrated how statin drug may attenuate allergic asthma lung inflammation by targeting memory T cells and reducing their numbers, whilst limiting their cytokine production at the site of inflammation. Longer clinical trials are required to assess the effectiveness and safety of statin treatment in different asthma phenotypes.


Assuntos
Asma , Inibidores de Hidroximetilglutaril-CoA Redutases , Camundongos , Humanos , Animais , Ovalbumina/uso terapêutico , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Células Endoteliais , Camundongos Endogâmicos BALB C , Pulmão , Inflamação/tratamento farmacológico , Modelos Animais de Doenças , Células Th2 , Líquido da Lavagem Broncoalveolar
18.
Skelet Muscle ; 12(1): 25, 2022 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-36447272

RESUMO

Limb-girdle muscular dystrophy (MD) type 2B (LGMD2B) and Duchenne MD (DMD) are caused by mutations to the Dysferlin and Dystrophin genes, respectively. We have recently demonstrated in typically mild dysferlin- and dystrophin-deficient mouse models that increased plasma cholesterol levels severely exacerbate muscle wasting, and that DMD patients display primary dyslipidemia characterized by elevated plasma cholesterol and triglycerides. Herein, we investigate lipoprotein abnormalities in LGMD2B and if statin therapy protects dysferlin-deficient mice (Dysf) from muscle damage. Herein, lipoproteins and liver enzymes from LGMD2B patients and dysferlin-null (Dysf) mice were analyzed. Simvastatin, which exhibits anti-muscle wasting effects in mouse models of DMD and corrects aberrant expression of key markers of lipid metabolism and endogenous cholesterol synthesis, was tested in Dysf mice. Muscle damage and fibrosis were assessed by immunohistochemistry and cholesterol signalling pathways via Western blot. LGMD2B patients show reduced serum high-density lipoprotein cholesterol (HDL-C) levels compared to healthy controls and exhibit a greater prevalence of abnormal total cholesterol (CHOL)/HDL-C ratios despite an absence of liver dysfunction. While Dysf mice presented with reduced CHOL and associated HDL-C and LDL-C-associated fractions, simvastatin treatment did not prevent muscle wasting in quadriceps and triceps muscle groups or correct aberrant low-density lipoprotein receptor (LDLR) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) protein expression. LGMD2B patients present with reduced serum concentrations of HDL-C, a major metabolic comorbidity, and as a result, statin therapy is unlikely to prevent muscle wasting in this population. We propose that like DMD, LGMD2B should be considered as a new type of genetic dyslipidemia.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Distrofia Muscular do Cíngulo dos Membros , Camundongos , Animais , Disferlina/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Distrofina , HDL-Colesterol , Distrofia Muscular do Cíngulo dos Membros/tratamento farmacológico , Distrofia Muscular do Cíngulo dos Membros/genética , Atrofia Muscular , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico
19.
Cell Physiol Biochem ; 56(6): 685-691, 2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36426391

RESUMO

BACKGROUND/AIMS: Corona virus disease 2019 (COVID-19) has become a deadly infectious disease, especially for those with co-morbidities such as diabetes. People with diabetes developing a viral infection, seem to have harder treatments due to fluctuations in blood glucose levels therefore, effective therapeutic approaches need to be considered for them. Statins are well-known lipid-lowering drugs; they also have anti-inflammatory and immunomodulatory effects and can impact on expression of microRNAs (miRNAs). METHODS: In this study we investigate the effects of simvastatin on the expression of miR-150-5p as a famous regulator of inflammation and its association with multiple cancers in 30 patients with Type 2 diabetes mellitus (T2DM) and COVID-19 compared to the COVID-19 hospitalized patients before and after treatment with simvastatin with real-time-PCR after 2month, and evaluate its targets gens and functions with the help of bioinformatics and GO enrichment analysis respectively. RESULTS: Our results showed that simvastatin can increase miR-150-5p and therefore down regulate expression of its target genes involving in immune stimulation and decrease lipid profile including LDL-C, total cholesterol, and ApoB, especially in the group with type 2 diabetes mellitus (T2DM) and COVID-19 compared to the patients with only COVID-19. CONCLUSION: Simvastatin as an anti-inflammatory agent can modulate miRNAs expression; it can be suggested as an adjunct therapy especially for T2DM patients with COVID-19. Further studies may help us for developing better treatments about therapeutic manipulation of miRNAs in vivo.


Assuntos
Diabetes Mellitus Tipo 2 , MicroRNAs , Humanos , Sinvastatina/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , MicroRNAs/metabolismo , Lipídeos
20.
Nutrients ; 14(19)2022 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-36235772

RESUMO

Obesity causes progressive lipid accumulation and insulin resistance within muscle cells and affects skeletal muscle fibres and muscle mass that demonstrates atrophy and dysfunction. This study investigated the effects of naringin on the metabolic processes of skeletal muscle in obese rats. Male Sprague Dawley rats were divided into five groups: the control group with normal diet and the obese groups, which were induced with a high-fat diet (HFD) for the first 4 weeks and then treated with 40 mg/kg of simvastatin and 50 and 100 mg/kg of naringin from week 4 to 8. The naringin-treated group showed reduced body weight, biochemical parameters, and the mRNA expressions of protein degradation. Moreover, increased levels of antioxidant enzymes, glycogen, glucose uptake, the expression of the insulin receptor substrate 1 (IRS-1), the glucose transporter type 4 (GLUT4), and the mRNA expressions of protein synthesis led to improved muscle mass in the naringin-treated groups. The in vitro part showed the inhibitory effects of naringin on digestive enzymes related to lipid and glucose homeostasis. This study demonstrates the potential benefits of naringin as a supplement for treating muscle abnormalities in obese rats by modulating the antioxidative status, regulating protein metabolism, and improved insulin resistance in skeletal muscle of HFD-induced insulin resistance in obese rats.


Assuntos
Dieta Hiperlipídica , Flavanonas , Resistência à Insulina , Atrofia Muscular , Animais , Antioxidantes/metabolismo , Dieta Hiperlipídica/efeitos adversos , Flavanonas/farmacologia , Glucose/metabolismo , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Glicogênio/metabolismo , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , Músculo Esquelético/metabolismo , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/etiologia , Obesidade/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Sinvastatina/farmacologia
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