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1.
Int J Nanomedicine ; 14: 9763-9776, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31849467

RESUMO

Background: Photoreceptor degeneration is one of the most refractory oculopathy in the world, leading to vision loss in severe cases. Methyprednisolone is one of the most commonly prescribed medications for the treatment of retinal degenerative diseases, either by oral administration or repeated intraocular injections. However, the efficacy was unsatisfactory due to its systemic or local side effects and short retention time within the retina. Methods: Nanoscale zirconium-porphyrin metal-organic framework (NPMOF) was synthesized and characterized. The biotoxicity and imaging capability of NPMOF were evaluated using zebrafish embryos and larvae. NPMOF was then used as a skeleton and loaded with methylprednisolone (MPS) to prepare a novel kind of nanoparticle, MPS-NPMOF. Photoreceptor degeneration was induced by high-intensity light exposure in adult zebrafish. MPS-NPMOF was delivered to the injured retina by intraocular injection. The photoreceptor regeneration and its underlying mechanism were explored by immunohistochemistry, quantitative real-time polymerase chain reaction and behavioral test. Results: NPMOF not only had low biotoxicity but also emitted bright fluorescence. Following a single MPS-NPMOF intraocular injection, the injured retina exhibited the faster photoreceptor regeneration with better visual function by promoting the cell proliferation. Conclusion: NPMOF is an ideal carrier and could be applied in tracking and delivering medications. By intraocular injection, the novel drug delivery system, MPS-NPMOF, accomplishes the sustained release of drug and plays a therapeutic role in photoreceptor degeneration.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Estruturas Metalorgânicas/química , Metilprednisolona/administração & dosagem , Porfirinas/química , Degeneração Retiniana/tratamento farmacológico , Zircônio/química , Animais , Animais Geneticamente Modificados , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Embrião não Mamífero/efeitos dos fármacos , Fluorescência , Injeções Intraoculares , Estruturas Metalorgânicas/administração & dosagem , Estruturas Metalorgânicas/farmacologia , Metilprednisolona/farmacologia , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Células Fotorreceptoras de Vertebrados/metabolismo , Retina/efeitos dos fármacos , Retina/lesões , Degeneração Retiniana/etiologia , Peixe-Zebra/embriologia
2.
Biomed Res Int ; 2019: 6539050, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31309111

RESUMO

Objective: To determine whether the administration of intra-arrest cyclosporine (CCY) and methylprednisolone (MP) preserves left ventricular ejection fraction (LVEF) and cardiac output (CO) after return of spontaneous circulation (ROSC). Methods: Eleven, 25-30kg female swine were randomized to receive 10mg/kg CCY + 40mg MP or placebo, anesthetized and given a transthoracic shock to induce ventricular fibrillation. After 8 minutes, standard CPR was started. After two additional minutes, the experimental agent was administered. Animals with ROSC were supported for up to 12h with norepinephrine as needed. Echocardiography was performed at baseline, and 1, 2, 6 and 12h post-ROSC. Analysis was performed using generalized estimating equations (GEE) after downsampling continuously sampled data to 5 minute epochs. Results: Eight animals (64%) achieved ROSC after a median of 7 [IQR 5-13] min of CPR, 2 [ IQR 1-3] doses of epinephrine and 2 [IQR 1-5] defibrillation shocks. Animals receiving CCY+MP had higher post ROSC MAP (GEE coefficient -10.2, P = <0.01), but reduced cardiac output (GEE coefficient 0.8, P = <0.01) compared to placebo. There was no difference in LVEF or vasopressor use between arms. Conclusions: Intra-arrest cyclosporine and methylprednisolone decreased post-arrest cardiac output and increased mean arterial pressure without affecting left ventricular ejection fraction.


Assuntos
Cardiomiopatias/tratamento farmacológico , Ciclosporina/farmacologia , Parada Cardíaca/tratamento farmacológico , Metilprednisolona/farmacologia , Animais , Débito Cardíaco/efeitos dos fármacos , Reanimação Cardiopulmonar/métodos , Ecocardiografia/métodos , Cardioversão Elétrica/métodos , Epinefrina/farmacologia , Feminino , Ventrículos do Coração/efeitos dos fármacos , Suínos , Vasoconstritores/farmacologia , Fibrilação Ventricular/tratamento farmacológico
3.
Ann Surg Oncol ; 26(9): 2831-2838, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31286307

RESUMO

BACKGROUND: Surgery often introduce inflammatory response, which may promote tumor growth and metastasis of residual cancer cells. We investigated the impacts of methylprednisolone on the tumor growth and peritoneal seedings in mice treated with lipopolysaccharide (LPS), which mimics systemic inflammation induced by surgical stress and postoperative complications. METHODS: The serum interleukin-6 (IL-6) levels, tumor volume, tumor weight, and the number of peritoneal nodules were investigated in tumor growth model and peritoneal seeding model using BALB/c mice and murine CT26 cancer cell lines in vivo. We conducted functional analyses of IL-6 in Western blotting and proliferation assays in vitro. We also investigated whether preoperative administration of methylprednisolone decreased postoperative serum IL-6 levels in cancer patients in a randomized clinical study. RESULTS: In the in vivo study, methylprednisolone inhibited the LPS-induced increase of serum IL-6 levels (mean, 33,756 pg/ml vs. 5917 pg/ml; P < 0.001), tumor volume (mean, 397 mm3 vs. 274 mm3; P = 0.019), tumor weight (mean, 0.38 g vs. 0.15 g; P = 0.020), and the number of peritoneal nodules (mean, 112 vs. 47; P = 0.002). In the in vitro study, IL-6 enhanced JAK/STAT signaling and increased the cell proliferation, and IL-6R-neutralizing antibody attenuated these effects. In the clinical study, serum IL-6 levels were significantly decreased by methylprednisolone (median, 97.5 pg/ml vs. 18.0 pg/ml; P = 0.030). CONCLUSIONS: Surgical stress and postoperative complications may enhance tumor growth due to the increase of IL-6. However, methylprednisolone can decrease serum IL-6 levels, thus inhibiting tumor growth and peritoneal seeding.


Assuntos
Metilprednisolona/farmacologia , Recidiva Local de Neoplasia/tratamento farmacológico , Inoculação de Neoplasia , Neoplasias Peritoneais/tratamento farmacológico , Complicações Pós-Operatórias , Neoplasias Gástricas/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Apoptose , Biomarcadores Tumorais/sangue , Proliferação de Células , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Interleucina-6/sangue , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/cirurgia , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Transdução de Sinais , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Pharmacol Exp Ther ; 370(2): 337-349, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31197018

RESUMO

Our previous report examined the pharmacokinetics (PK) of methylprednisolone (MPL) and adrenal suppression after a 50 mg/kg IM bolus in male and female rats, and we described in detail the development of a minimal physiologically based pharmacokinetic/pharmacodynamic (mPBPK/PD) model. In continuation of such assessments, we investigated sex differences in genomic MPL responses (PD). Message expression of the glucocorticoid-induced leucine zipper (GILZ) was chosen as a multitissue biomarker of glucocorticoid receptor (GR)-mediated drug response. Potential time-dependent interplay between sex hormone and glucocorticoid signaling in vivo was assessed by comparing the enhancement of GILZ by MPL in the uterus [high estrogen receptor (ER) density] and in liver (lower ER density) from male and female rats dosed within the proestrus (high estradiol/progesterone) and estrus (low estradiol/progesterone) phases of the rodent estrous cycle. An expanded-systems PD model of MPL considering circadian rhythms, multireceptor (ER and GR) control, and estrous variations delineated the determinants controlling receptor/gene-mediated steroid responses. Hepatic GILZ response was ∼3-fold greater in females, regardless of estrous stage, compared with males, driven predominantly by increased MPL exposure in females and a negligible influence of estrogen interaction. In contrast, GILZ response in the uterus during proestrus in females was 60% of that observed in estrus-phased females, despite no PK or receptor differences, providing in vivo support to the hypothesis of estrogen-mediated antagonism of glucocorticoid signaling. The developed model offers a mechanistic platform to assess the determinants of sex and tissue specificity in corticosteroid actions and, in turn, reveals a unique PD drug-hormone interaction occurring in vivo. SIGNIFICANCE STATEMENT: Mechanisms relating to sex-based pharmacodynamic variability in genomic responses to corticosteroids have been unclear. Using combined experimental and systems pharmacology modeling approaches, sex differences in both pharmacokinetic and pharmacodynamic mechanisms controlling the enhancement of a sensitive corticosteroid-regulated biomarker, the glucocorticoid-induced leucine zipper (GILZ), were clarified in vivo. The multiscale minimal physiologically based pharmacokinetics/pharmacodynamic model successfully captured the experimental observations and quantitatively discerned the roles of the rodent estrous cycle (hormonal variation) and tissue specificity in mediating the antagonistic coregulation of GILZ gene synthesis. These findings collectively support the hypothesis that estrogens antagonize pharmacodynamic signaling of genomic corticosteroid actions in vivo in a time- and estrogen receptor-dependent manner.


Assuntos
Ciclo Estral/efeitos dos fármacos , Metilprednisolona/farmacologia , Metilprednisolona/farmacocinética , Modelos Biológicos , Receptores Estrogênicos/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Animais , Estradiol/sangue , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Metilprednisolona/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Caracteres Sexuais , Fatores de Transcrição/genética
5.
J Pharmacol Exp Ther ; 370(2): 327-336, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31197019

RESUMO

Methylprednisolone (MPL), a corticosteroid of intermediate potency, remains an important immunomodulatory agent for autoimmune diseases. Although sex differences in corticosteroid pharmacokinetics/pharmacodynamics (PK/PD) have been documented in humans, comprehensive preclinical assessments of such differences have not been conducted. Limited in vitro evidence indicates possible sex differences in corticosteroid PK and PD. Therefore, it is hypothesized that comparative PK/PD assessments of MPL disposition and selected PD actions in both sexes will provide insights into factors controlling sex differences in steroid responses. This report focused on the plasma and tissue pharmacokinetics of MPL and its adrenal suppressive effects. Because time-dependent (estrous) regulation of sex hormones in females can influence drug responses, female rats were studied in the proestrus (high estradiol/progesterone) and estrus (low estradiol/progesterone) phases of the reproductive cycle. Cohorts of male and female rats were given a 50 mg/kg bolus dose of MPL intramuscularly. Plasma and liver concentrations of MPL as well as plasma corticosterone concentrations were assayed using high-performance liquid chromatography. An enhanced minimal physiologically-based PK/PD model was developed to characterize MPL kinetics and corticosterone dynamics. The clearance of MPL was ∼3-fold higher in males compared with females, regardless of estrous phase, likely attributable to sex-specific hepatic metabolism in males. Strong inhibitory effects on adrenal suppression were observed in all animals. These temporal steroid profiles in plasma and tissues will be used to drive receptor/gene-mediated PD effects of MPL in both sexes, as described in a companion article (Part III). SIGNIFICANCE STATEMENT: Sex is a relevant factor influencing the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs. Few preclinical PK/PD studies, however, include sex as a variable. Sex differences in the PK and adrenal suppressive effects of the synthetic corticosteroid, methylprednisolone, were assessed in male and female rats as a function of the 4-day rodent reproductive cycle. Drug exposure was 3-fold higher in females, regardless of estrous stage, compared with males. An extended minimal physiologically-based PK/PD model utilizing in vitro and in vivo measurements was developed and applied. These studies provide a framework to account for sex-dependent variability in drug and endogenous agonist (corticosterone) exposures, serving as a prelude to more intricate assessments of sex-related variability in receptor/gene-mediated PD corticosteroid actions.


Assuntos
Corticosterona/farmacologia , Corticosterona/farmacocinética , Metilprednisolona/farmacologia , Metilprednisolona/farmacocinética , Modelos Biológicos , Caracteres Sexuais , Animais , Feminino , Masculino , Ratos , Ratos Wistar
6.
J Pharmacol Exp Ther ; 370(2): 318-326, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31197020

RESUMO

The plasma and tissue binding properties of two corticosteroids, dexamethasone (DEX) and methylprednisolone (MPL), were assessed in the rat in anticipation of developing physiologically based pharmacokinetic and pharmacokinetic/pharmacodynamic models. The tissue-to-plasma partition coefficients (K P) of DEX and MPL were measured in liver, muscle, and lung in vivo after steady-state infusion and bolus injection in rats. Since K P is often governed by reversible binding to macromolecules in blood and tissue, an attempt was made to assess K P values of DEX and MPL by in vitro binding studies using rat tissue homogenates and to compare these estimates to those obtained from in vivo kinetics after dosing. The K P values of both steroids were also calculated in rat tissues using mechanistic tissue composition-based equations. The plasma binding of DEX and MPL was linear with moderate binding (60.5% and 82.5%) in male and female rats. In vivo estimates of steroid uptake appeared linear across the tested concentrations and K P was highest in liver and lowest in muscle for both steroids. Assessment of hepatic binding of MPL in vitro was severely affected by drug loss at 37°C in male liver homogenates, whereas DEX was stable in both male and female liver homogenates. With the exception of MPL in liver, in vitro-derived K P estimates reasonably agreed with in vivo values. The mechanistic equations modestly underpredicted K P for both drugs. Tissue metabolism, saturable tissue binding, and active uptake are possible factors that can complicate assessments of in vivo tissue binding of steroids when using tissue homogenates. SIGNIFICANCE STATEMENT: Assuming the free hormone hypothesis, the ratio of the unbound drug fraction in plasma and in tissues defines the tissue-to-plasma partition coefficient (K P), an important parameter in physiologically based pharmacokinetic modeling that determines total drug concentrations within tissues and the steady-state volume of distribution. This study assessed the plasma and tissue binding properties of the synthetic corticosteroids, dexamethasone and methylprednisolone, in rats using ultrafiltration and tissue homogenate techniques. In vitro-in vivo and in silico-in vivo extrapolation of K P was assessed for both drugs in liver, muscle, and lung. Although the extrapolation was fairly successful across the tissues, in vitro homogenate studies severely underpredicted the K P of methylprednisolone in liver, partly attributable to the extensive hepatic metabolism.


Assuntos
Dexametasona/farmacologia , Dexametasona/farmacocinética , Metilprednisolona/farmacologia , Metilprednisolona/farmacocinética , Modelos Biológicos , Animais , Proteínas Sanguíneas/metabolismo , Simulação por Computador , Dexametasona/metabolismo , Estabilidade de Medicamentos , Feminino , Masculino , Metilprednisolona/metabolismo , Ratos , Ratos Wistar , Distribuição Tecidual
7.
Cornea ; 38(8): 1017-1022, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31090593

RESUMO

PURPOSE: To determine in-use stability and sterility of fortified cefazolin, ceftazidime, vancomycin, amphotericin B, and methylprednisolone eye drops in a simulated inpatient setting with and without a mobile refrigerated container (MR). METHODS: Each drug was prepared and divided into 4 groups: 1) simulated patient use with the MR group: stored at 4°C and kept in the MR during drug administration, 2) simulated patient use without the MR (NoMR) group: stored at 4°C and no MR, 3) refrigerated control group: stored at 4°C, and 4) room temperature control group: stored at room temperature. Stability and sterility data were evaluated at days 0, 4, 7, 14, 21, and 28. Linear mixed-effects model and survival analysis were performed. RESULTS: Median time to 10% loss of concentration for in-use medications (MR/NoMR groups) was >28/27.9, 22.2/22.2, 19.4/19.4, 10.18/<4, and >28/>28 days for cefazolin, ceftazidime, vancomycin, amphotericin B, and methylprednisolone, respectively. There was no significant difference in the predicted concentration loss per day among all groups for vancomycin and methylprednisolone (all P > 0.05). For the other study medications, all room temperature control groups, the cefazolin NoMR group, and the ceftazidime NoMR group had significantly greater predicted concentration loss per day compared with the refrigerated control groups (all P ≤ 0.02). Culture results were negative for all drugs throughout the study. CONCLUSIONS: The NoMR group showed that the drug significantly degraded rapidly for cefazolin, ceftazidime, and amphotericin B. Implementation of MR could decrease the predicted loss of concentration per day for cefazolin and ceftazidime. In vitro antimicrobial activity and sterility were retained for 28 days.


Assuntos
Antibacterianos/análise , Estabilidade de Medicamentos , Glucocorticoides/análise , Preparações Farmacêuticas/análise , Esterilização , Anfotericina B/análise , Anfotericina B/farmacologia , Antibacterianos/farmacologia , Cefazolina/análise , Cefazolina/farmacologia , Ceftazidima/análise , Ceftazidima/farmacologia , Armazenamento de Medicamentos , Glucocorticoides/farmacologia , Metilprednisolona/análise , Metilprednisolona/farmacologia , Soluções Oftálmicas , Conservantes Farmacêuticos , Estudos Prospectivos , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Vancomicina/análise , Vancomicina/farmacologia
8.
Cells ; 8(5)2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31052442

RESUMO

Glucocorticoids represent some of the most prescribed drugs that are widely used in the treatment of neuromuscular diseases, but their usage leads to side effects such as muscle atrophy. However, different synthetic glucocorticoids can lead to different muscle effects, depending upon its chemical formulation. Here, we intended to demonstrate the muscle histologic and molecular effects of administering different glucocorticoids in equivalency and different dosages. Methods: Seventy male Wistar rats distributed into seven groups received different glucocorticoids in equivalency for ten days or saline solution. The study groups were: Control group (CT) saline solution; dexamethasone (DX) 1.25 or 2.5 mg/kg/day; methylprednisolone (MP) 6.7 or 13.3mg/kg/day; and deflazacort (DC) 10 or 20 mg/kg/day. At the end of the study, the animals were euthanized, and the tibialis anterior and gastrocnemius muscles were collected for metachromatic ATPase (Cross-sectional area (CSA) measurement), Western blotting (protein expression of IGF-1 and Ras/Raf/MEK/ERK pathways) and RT-PCR (MYOSTATIN, MuRF-1, Atrogin-1, REDD-1, REDD-2, MYOD, MYOG and IRS1/2 genes expression) experiments. Results: Muscle atrophy occurred preferentially in type 2B fibers in all glucocorticoid treated groups. DC on 10 mg/kg/day was less harmful to type 2B fibers CSA than other doses and types of synthetic glucocorticoids. In type 1 fibers CSA, lower doses of DC and DX were more harmful than high doses. DX had a greater effect on the IGF-1 pathway than other glucocorticoids. MP more significantly affected P-ERK1/2 expression, muscle fiber switching (fast-to-slow), and expression of REDD1 and MyoD genes than other glucocorticoids. Compared to DX and MP, DC had less of an effect on the expression of atrogenes (MURF-1 and Atrogin-1) despite increased MYOSTATIN and decreased IRS-2 genes expression. Conclusions: Different glucocorticoids appears to cause muscle atrophy affecting secondarily different signaling mechanisms. MP is more likely to affect body/muscles mass, MEK/ERK pathway and fiber type transition, DX the IGF-1 pathway and IRS1/2 expression. DC had the smallest effect on muscle atrophic response possibly due a delayed timing on atrogenes response.


Assuntos
Dexametasona/farmacologia , Metilprednisolona/farmacologia , Músculo Esquelético/efeitos dos fármacos , Pregnenodionas/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Dexametasona/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/administração & dosagem , Glucocorticoides/farmacologia , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Metilprednisolona/administração & dosagem , Desenvolvimento Muscular/efeitos dos fármacos , Desenvolvimento Muscular/genética , Fibras Musculares Esqueléticas/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Pregnenodionas/administração & dosagem , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar
9.
Inflammation ; 42(5): 1585-1594, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31081527

RESUMO

Acute respiratory distress syndrome (ARDS) is a fatal disease that includes inflammation formed by septic and non-septic causes. Reactive oxygen radicals (ROS) play a key role in ARDS pathophysiology and constitute the base of damage process. Antioxidant vitamins are used for inhibiting hazardous effects of radicals. Therefore, effects of antioxidant vitamins such as α-lipoic acid (ALA), vitamin E (VITE), and C (VITC) were investigated on oleic acid (OA)-induced ARDS rat model. Furthermore, high and low dose of methylprednisolone (HDMP, LDMP) was used for comparing effects of the vitamins. In this study, 42 male rats were divided to seven groups named control, OA, ALA, VITE, VITC, LDMP, and HDMP. OA was intravenously administered to all groups except control group and other compounds were orally administered (ALA, VITE, and VITC: 100 mg/kg, LDMP: 5 mg/kg, HDMP: 50 mg/kg) after OA injections. OA increased MDA level in lung tissue and TNF-α and IL-1ß cytokine levels in serum. ALA, VITE, VITC, and both dose of MP significantly decreased the cytokine levels. Although OA reduced SOD, CAT, and GSH levels in lung tissue, the vitamins and LDMP markedly enhanced the levels except for HDMP. Furthermore, OA showed thickening in bronchi and alveolar septum, hyperemia in vessels, and inflammatory cell infiltrations in lung tissue histopathological examinations. Antioxidant vitamins may be useful for premedication of ARDS and similar disorders. However, methylprednisolone was not found sufficient for being a therapeutic agent for ARDS.


Assuntos
Antioxidantes/uso terapêutico , Substâncias Protetoras/uso terapêutico , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Vitaminas/uso terapêutico , Animais , Masculino , Metilprednisolona/farmacologia , Metilprednisolona/uso terapêutico , Ácido Oleico , Pré-Medicação/métodos , Ratos , Síndrome Respiratória Aguda Grave/induzido quimicamente
10.
Int J Nanomedicine ; 14: 1953-1968, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30936696

RESUMO

Introduction and aim: Olmesartan medoxomil (OLM) is an antihypertensive drug with low oral bioavailability due to extensive first-pass metabolism. This study aimed to prepare transetho somes (TEs) for enhancing the transdermal delivery of OLM to avoid its oral problems. Methods: TE formulae were prepared utilizing 51.31 full factorial design using various surfactants (SAAs) and different phospholipid-to-SAA ratios. The formulae were characterized regarding their entrapment efficiency percentage (EE%), particle size (PS), polydispersity index (PDI), zeta potential (ZP), and the amount of drug released after 6 hours (Q6h). Design Expert® software was employed to select the optimum formula. Results: The optimum formula (TE14) had an EE% of 58.50%±1.30%, PS of 222.60±2.50 nm, PDI of 0.11±0.06, ZP of -20.80±0.30 mV, and Q6h of 67.40%±0.20%. In addition, TE14 was compared to transferosomes (TFs) in terms of elasticity and was found to show higher deformability index. Further, evaluation of ex vivo permeation using both rat and shed snake skin showed higher permeability of TE14 compared to TFs and OLM suspension. Confocal laser scanning microscopy confirmed the capability of the fluorolabeled TE14 to penetrate deep within the skin, while the histopathological study confirmed its safety. TE14 successfully maintained normal blood pressure values of rats up to 24 hours. Moreover, TE14 showed superiority in dermatokinetic study when compared with drug suspension. Conclusion: Taken together, the obtained results confirmed the potential of employing TEs as a successful carrier for the transdermal delivery of OLM.


Assuntos
Sistemas de Liberação de Medicamentos , Olmesartana Medoxomila/administração & dosagem , Olmesartana Medoxomila/farmacologia , Administração Cutânea , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Varredura Diferencial de Calorimetria , Estabilidade de Medicamentos , Elasticidade , Análise Fatorial , Lipossomos , Masculino , Metilprednisolona/administração & dosagem , Metilprednisolona/farmacologia , Olmesartana Medoxomila/farmacocinética , Ratos Wistar , Pele/efeitos dos fármacos , Serpentes
11.
Bratisl Lek Listy ; 120(3): 207-211, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31023039

RESUMO

In this study, we aimed to investigate the effectiveness of etofenamate and compare it with methyl prednisolone in the experimental spinal cord trauma model. A total of 31 Wistar Albino rats weighed between 220 and 270 gr were used in this study. The rats were divided into three groups as the control; posttraumatic normal saline (NS), trauma + E; posttraumatic etofenamate; and trauma + methylprednisolone, posttraumatic methylprednisolone. All medications were given into the peritoneum. Six hours after trauma and drug administration, approximately 2 cm of cord segment in the area subjected to dorsal laminectomy was dissected from the dura spinal cord and removed. The samples were histopathologically examined. In this study, significant differences were found both between trauma + NS and trauma + methylprednisolone, and between trauma NS and trauma + etofenamate, and trauma + methylprednisolone and trauma + etofenamate groups according to the Ivan Damjanov criteria and in terms of petechial hemorrhage, diffuse bleeding, loss in the regulation of grey and white matters, edema, necrosis, and cystic degeneration findings. According to the Ivan Damjanov criteria, trauma + NS group was found as Grades 2-3, trauma + etofenamate group as Grade 1, and trauma + methylprednisolone as Grades 1-2. Neuroprotective effect of etofenamate was found to be stronger than that of methyl prednisolone in rats with induced posttraumatic spinal cord damage (Tab. 4, Ref. 24). Keywords: etofenamate, methylprednisolone, spinal trauma, rats.


Assuntos
Anti-Inflamatórios , Metilprednisolona , Fármacos Neuroprotetores , Traumatismos da Medula Espinal , Animais , Anti-Inflamatórios/farmacologia , Modelos Animais de Doenças , Metilprednisolona/farmacologia , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Wistar , Medula Espinal , Traumatismos da Medula Espinal/tratamento farmacológico
12.
Brain Dev ; 41(6): 531-537, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30833092

RESUMO

The detailed clinical time course in acute disseminated encephalomyelitis (ADEM) from initial symptoms, through exacerbation, to remission has not been widely reported. Hence, this study aimed to investigate the clinical time course of pediatric ADEM. This was a multicenter retrospective study based on registry data from medical chart reviews. The study included children who met the international consensus diagnostic criteria for ADEM. The patients comprised 18 boys and 6 girls, with a mean age of 5.5 ±â€¯3.3 years at onset. From onset, the time until peak neurological symptoms, time until initial improvement, and time until full recovery was 3.1 ±â€¯3.7 days, 6.0 ±â€¯4.5 days, and 26 ±â€¯34 days, respectively. Twenty-three (96%) patients were treated with high-dose methylprednisolone (mPSL) with a mean duration of 4.1 ±â€¯4.0 days from onset. The condition of 15 patients (65%) improved within 3 days of high-dose mPSL initiation, whereas, that of four patients began to improve after >5 days of high-dose mPSL initiation. Only one patient (4%) did not achieve full recovery despite treatment with high-dose mPSL, intravenous immunoglobulin, and plasma exchange. This study presents the detailed clinical time course in pediatric ADEM in Japan. Progression of neurologic deficits typically lasts a few days, with initial improvement in 1 week leading to full recovery within 1 month.


Assuntos
Encefalomielite Aguda Disseminada/diagnóstico , Encefalomielite Aguda Disseminada/fisiopatologia , Criança , Pré-Escolar , Encefalomielite Aguda Disseminada/classificação , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Japão , Imagem por Ressonância Magnética , Masculino , Metilprednisolona/farmacologia , Troca Plasmática , Plasmaferese , Sistema de Registros , Estudos Retrospectivos
13.
J Thorac Cardiovasc Surg ; 157(5): 2109-2117, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30827536

RESUMO

OBJECTIVE: Surfactant proteins A and D are important molecules involved in lung allograft innate immunity. Genetic polymorphisms of surfactant proteins A and D are associated with various lung diseases. In this study, surfactant protein A and D expression responses were investigated during pharmacogenetics upon methylprednisolone treatment as observed during lung transplantation. METHODS: A human cell line (NCI-H441) and precision-cut lung slices from 16 human donors were incubated with methylprednisolone, and surfactant protein A1, surfactant protein A2, and surfactant protein D messenger RNA and surfactant protein A protein expression were assayed. Surfactant protein A1, A2, and D polymorphisms and surfactant protein A gene and protein expressions were determined. RESULTS: In NCI-H441 cells, methylprednisolone treatment at 10-5 M and 10-6 M reduced surfactant protein A1 and surfactant protein A2 messenger RNA and surfactant protein A protein expression (P < .05). A pharmacogenetic relationship was observed in human donor precision-cut lung slices between the surfactant protein A2 (1Ax) variants: Surfactant protein A1, A2, and D messenger RNA expression were greater for 1A0 versus 1A1 (P < .05); surfactant protein A1/surfactant protein A2 genotype 6A26A2/1A01A0 (n = 5) showed greater surfactant protein A1, A2, and D messenger RNA expression and surfactant protein A protein expression compared with the other surfactant protein A1/surfactant protein A2 genotypes (n = 11) (P < .05). CONCLUSIONS: The surfactant protein A genotype and methylprednisolone stimuli influence donor lung surfactant protein A and D expression. Lungs carrying the surfactant protein A2 variant 1A0 have a greater expression of surfactant protein A when treated with methylprednisolone. Surfactant protein A polymorphisms could be used to personalize immunosuppressive regimens.


Assuntos
Glucocorticoides/farmacologia , Imunossupressores/farmacologia , Transplante de Pulmão , Pulmão/efeitos dos fármacos , Metilprednisolona/farmacologia , Variantes Farmacogenômicos , Polimorfismo Genético , Proteína A Associada a Surfactante Pulmonar/genética , Proteína D Associada a Surfactante Pulmonar/genética , Doadores de Tecidos , Linhagem Celular , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica , Frequência do Gene , Genótipo , Humanos , Técnicas In Vitro , Pulmão/metabolismo , Proteína A Associada a Surfactante Pulmonar/metabolismo , Proteína D Associada a Surfactante Pulmonar/metabolismo
14.
J Bone Miner Metab ; 37(5): 805-814, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30706148

RESUMO

This study evaluated the preventative effects of metformin (Met) on glucocorticoid (GC)-induced osteoporosis in a rat model, compared with alendronate (Aln). Twenty-eight 3-month-old female Sprague-Dawley rats were randomly assigned into four groups: normal control (Ctr), methylprednisolone (MP, 13 mg/kg/day, sc, 5 days per week), MP plus Aln orally (1 mg/kg/day), and MP plus Met orally (200 mg/kg/day). After 9 weeks, serum bone metabolic biochemistry, bone densitometry and histomorphometry were performed. The GC-induced osteoporosis model was characterized by decreased osteocalcin, increased tartrate-resistant acid phosphatase-5b (TRAP-5b), and decreased bone mineral density (BMD) in the femur and fifth lumbar vertebra (L5). Histomorphometrically, MP significantly decreased trabecular bone volume, decreased bone formation and increased bone resorption in proximal metaphysis, compared with the controls. Aln and Met increased the BMDs of femur (0.305 ± 0.011 vs. 0.280 ± 0.012, P < 0.05; 0.304 ± 0.019 vs. 0.280 ± 0.012, P < 0.05) and L5 (0.399 ± 0.029 vs. 0.358 ± 0.022, P < 0.05; 0.397 ± 0.022 vs. 0.358 ± 0.022, P < 0.05), compared with the model group. Met increased osteocalcin and decreased TRAP-5b, but Aln only decreased TRAP-5b, compared with model group. In histomorphometry of tibial proximal metaphysis, Aln and Met increased trabecular bone volume (39.21 ± 2.46 vs. 30.98 ± 5.83, P < 0.05; 38.97 ± 5.56 vs. 30.98 ± 5.83, P < 0.05), while Met increased the bone formation dynamic parameters and decreased bone resorption dynamic parameters, but Aln just decreased bone resorption dynamic parameters, compared with model group significantly. These findings suggest that metformin prevents GC-induced bone loss by suppressing bone resorption and stimulating bone formation in trabecular bone. The action mode of metformin was different from alendronate, which only suppressed bone resorption.


Assuntos
Glucocorticoides/efeitos adversos , Metformina/uso terapêutico , Osteoporose/induzido quimicamente , Osteoporose/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Alendronato/farmacologia , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Feminino , Fêmur/efeitos dos fármacos , Fêmur/fisiologia , Fêmur/fisiopatologia , Lipídeos/sangue , Vértebras Lombares/efeitos dos fármacos , Vértebras Lombares/patologia , Vértebras Lombares/fisiopatologia , Metformina/farmacologia , Metilprednisolona/farmacologia , Osteocalcina/sangue , Osteoporose/sangue , Osteoporose/fisiopatologia , Substâncias Protetoras/farmacologia , Ratos Sprague-Dawley , Fosfatase Ácida Resistente a Tartarato/sangue
16.
Turk Neurosurg ; 29(2): 247-253, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30649798

RESUMO

AIM: To determine the neuroprotective functions of quercetin and compare them with methylprednisolone in an experimental spinal cord injury model in rats. MATERIAL AND METHODS: Thirty male, Wistar rats were assigned to five experimental groups: sham (n=6), trauma (n=6), methylprednisolone (n=6), single dose quercetin (n=6), and multiple doses of quercetin (n=6). An aneurysm clip compression method was used to produce spinal cord injury at level T7-9 after performing a laminectomy. In the sham group, only a laminectomy was performed. Clip compression was performed to the spinal cord after laminectomy in the trauma group. For Group 3, a single dose of intraperitoneal (ip) methylprednisolone (30mg/kg) was administered after laminectomy and trauma. A single dose of ip quercet in (100mg/kg) was administered after laminectomy and trauma in Group 4. For Group 5, multiple doses of ip quercetin (100 mg/kg) were administered on the first, second, and third days after laminectomy and trauma. Spinal cord and serum samples were obtained to measure the levels of malondialdehyde (MDA), nitric oxide (NO), total antioxidant levels (TAL) at the 72nd hour. Neurofunctional examinations of all the rats according to Drummond and Moore criteria and inclined-plane tests to evaluate functional healing were performed. All rats were sacrificed via intracardiac blood depletion after the procedure. RESULTS: Quercetin and methylprednisolone both increased plasma and tissue levels of NO and MDA, and decreased TAL, with a statistically significant difference (p < 0.05). NO and MDA levels in plasma and tissue were significantly higher in the trauma group (Group 2) when compared to the sham group (Group 1), and TAL levels were significantly lower (p < 0.05). There was a statistically significant increase in the treatment group's inclined-plane test (p < 0.05), while there was no difference in motor examination evaluations. CONCLUSION: The results of this experimental study suggest that quercetin can be thought as an option of treatment in spinal cord injury.


Assuntos
Metilprednisolona/farmacologia , Fármacos Neuroprotetores/farmacologia , Quercetina/farmacologia , Traumatismos da Medula Espinal/patologia , Medula Espinal/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Masculino , Malondialdeído/sangue , Óxido Nítrico/sangue , Ratos , Ratos Wistar
17.
Mult Scler Relat Disord ; 29: 7-14, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30654246

RESUMO

BACKGROUND: Alemtuzumab is a humanized IgG monoclonal antibody approved in more than 60 countries for patients with relapsing remitting multiple sclerosis (RRMS). In phase 2 and 3 clinical trials (CAMMS223 (NCT00050778), CARE-MS I (NCT00530348), and CARE-MS II (NCT00548405)), patients receiving alemtuzumab demonstrated significantly greater improvements on clinical and MRI outcomes versus SC IFNß-1a; mild to moderate infusion-associated reactions (IARs) were the most frequently reported adverse events (AEs) associated with alemtuzumab. EMERALD (NCT02205489) was a phase 4, multicenter, multinational, single-arm study designed to assess an algorithm for the prevention and management of IARs in RRMS patients treated with alemtuzumab. METHODS: Patients were treated with a study regimen of enhanced IAR prophylaxis relative to phase 2 and 3 studies. H1 and/or H2 antagonists or equivalent gastroprotection (proton pump inhibitors) were given 1 day before alemtuzumab infusion, 1 h prior to the infusion, and post-infusion. Methylprednisolone was given orally 1 day before infusion, 1 h prior to the infusion, and as needed post-infusion. Antipyretics were given 1 h before infusion and as needed post-infusion. Anti-emetics and normal saline were given as needed during and post-infusion. RESULTS: Of the 61 patients screened, 58 (95.1%) were enrolled into the study. Of the 58 patients who received the first infusion of Period 1, 57 (98.3%) completed the 5 days of Course 1. A total of 54 patients received the first infusion of Period 2 and 53 completed the 3-day course. All patients (n = 58) completed the Month 6 visit and 54 the Month 12 visit. 93.1% of patients had at least one IAR (91.4% in Period 1 and 81.5% in Period 2), the majority of which were grade 1 (69.1%) or grade 2 (28.0%). The three most common IARs of headache, pyrexia, and rash occurred in 48.8%, 40.7%, and 24.1% of patients during the first course and 14.8%, 17.2%, and 5.6% of patients during the second course, respectively. The majority of IARs occurred within 6 h after the start of alemtuzumab infusion, with a peak during the first 2 h. The types and overall incidence of IARs were consistent with phase 2 and 3 trials. Frequency and distribution of rash were reduced in the EMERALD study compared with previous clinical trials. Serious IARs occurred in 15.5%, a higher rate than reported in clinical trials of alemtuzumab. CONCLUSION: Although most alemtuzumab-treated patients experienced IARs as in previous controlled clinical studies, there was an improvement in the frequency and distribution of alemtuzumab-associated rash, which may have been associated with this study's prophylaxis regimen.


Assuntos
Alemtuzumab/efeitos adversos , Anti-Inflamatórios/farmacologia , Anticorpos Monoclonais Humanizados/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Exantema , Fatores Imunológicos/efeitos adversos , Infusões Intravenosas/efeitos adversos , Metilprednisolona/farmacologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adulto , Alemtuzumab/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Antipiréticos/farmacologia , Quimioterapia Combinada , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Exantema/induzido quimicamente , Exantema/tratamento farmacológico , Exantema/epidemiologia , Exantema/prevenção & controle , Feminino , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Fatores Imunológicos/administração & dosagem , Incidência , Masculino , Metilprednisolona/administração & dosagem , Pessoa de Meia-Idade , Inibidores da Bomba de Prótons/farmacologia
18.
Biol Blood Marrow Transplant ; 25(3): 529-537, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30481596

RESUMO

This long-term follow-up study evaluated the effects of corticosteroid prophylaxis on graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) based on a controlled open-label randomized trial in which 228 allotransplant recipients were categorized as low risk (n = 83, group A) or high risk; patients at high risk were randomly assigned to receive (n = 72, group B) or not receive (n = 73, group C) low-dose methylprednisolone prophylaxis. The cumulative incidences of chronic GVHD, relapse, nonrelapse mortality, leukemia-free survival, overall survival, and GRFS were 60%, 19%, 16%, 68%, 73%, and 46%, respectively, in all cases. Compared with the patients in group C, the cases in group B experienced a lower cumulative incidence of moderate to severe chronic GVHD (42% versus 20%; P = .010), herpes zoster infection (28% versus 12%; P = .010), pulmonary infections (42% versus 21%; P = .040), and osteonecrosis of the femoral head (ONFH; 16% versus 6%; P = .045) as well as better GRFS (59% versus 33%; P = .017). Factors associated with GRFS included total dose of corticosteroid used in the first 100days after transplantation (hazard ratio, 1.547; P = .015) and platelet recovery (hazard ratio, 1.456; P = .037). Our results suggest that low-dose glucocorticoid prophylaxis reduces GVHD and thus reduces the total dose of steroids, which might contribute to lower incidence of infections and ONFH and a superior GRFS, indicating that higher steroid doses are harmful. Reducing the total dose is of course beneficial. (ClinicalTrials.gov number, NCT01607580.).


Assuntos
Intervalo Livre de Doença , Glucocorticoides/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Metilprednisolona/uso terapêutico , Pré-Medicação/métodos , Transplante Haploidêntico , Adulto , Feminino , Necrose da Cabeça do Fêmur/induzido quimicamente , Necrose da Cabeça do Fêmur/etiologia , Seguimentos , Glucocorticoides/farmacologia , Humanos , /etiologia , Masculino , Metilprednisolona/farmacologia , Pessoa de Meia-Idade , Transplante Haploidêntico/métodos , Transplante Haploidêntico/mortalidade , Transplante Homólogo
19.
Poult Sci ; 98(3): 1111-1120, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30285155

RESUMO

In our previous study, chondrocyte apoptosis in femoral head necrosis (FHN)-affected broilers was found to be associated with the endoplasmic reticulum stress (ERS) signaling pathway. In the present study, we further explored the role of ERS-induced chondrocyte apoptosis in FHN-affected broilers and the parallel test was carried out with articular chondrocytes cultivated in vitro. The broilers and chondrocytes were treated with methylprednisolone (MP). The main pathological changes in FHN-affected broilers included the proximal femoral head separated from its articular cartilage and growth plate lesions. MP-treated chondrocytes demonstrated morphology changes, cell viability reduction, secretory capacity dysfunction, and apoptosis. The mRNA expressions of pro-apoptotic genes controlled by ERS signaling pathway were up-regulated both in vivo and in vitro experiments. It showed that MP induced FHN in broilers, activated apoptosis-related genes on ERS signaling pathway, and affected the survival and apoptosis of chondrocytes, and bone growth.


Assuntos
Apoptose/fisiologia , Galinhas , Estresse do Retículo Endoplasmático/fisiologia , Necrose da Cabeça do Fêmur/fisiopatologia , Glucocorticoides/farmacologia , Metilprednisolona/farmacologia , Doenças das Aves Domésticas/fisiopatologia , Animais , Apoptose/efeitos dos fármacos , Cartilagem Articular/fisiopatologia , Condrócitos/efeitos dos fármacos , Condrócitos/fisiologia , Feminino , Necrose da Cabeça do Fêmur/induzido quimicamente , Glucocorticoides/administração & dosagem , Lâmina de Crescimento/fisiopatologia , Masculino , Metilprednisolona/administração & dosagem , Doenças das Aves Domésticas/etiologia , Tunicamicina/administração & dosagem
20.
Neurochem Res ; 44(1): 200-213, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29290040

RESUMO

Any spinal cord injury carries the potential for persistent disability affecting motor, sensory and autonomic functions. To prevent this outcome, it is highly desirable to block a chain of deleterious reactions developing in the spinal areas immediately around the primary lesion. Thus, early timing of pharmacological neuroprotection should be one major strategy whose impact may be first studied with preclinical models. Using a simple in vitro model of the rat spinal cord it is possible to mimic pathological processes like excitotoxicity that damages neurons because of excessive glutamate receptor activation due to injury, or hypoxic/dysmetabolic insult that preferentially affects glia following vascular dysfunction. While ongoing research is exploring the various components of pathways leading to cell death, current treatment principally relies on the off-label use of riluzole (RLZ) or methylprednisolone sodium succinate (MPSS). The mechanism of action of these drugs is diverse as RLZ targets mainly neurons and MPSS targets glia. Even when applied after a transient excitotoxic stimulus, RLZ can provide effective prevention of secondary excitotoxic damage to premotoneurons, although not to motoneurons that remain very vulnerable. This observation indicates persistent inability to express locomotor activity despite pharmacological treatment conferring some histological protection. MPSS can protect glia from dysmetabolic insult, yet it remains poorly effective to prevent neuronal death. In summary, it appears that these pharmacological agents can produce delayed protection for certain cell types only, and that their combined administration does not provide additional benefit. The search should continue for better, mechanism-based neuroprotective agents.


Assuntos
Anti-Inflamatórios/uso terapêutico , Metilprednisolona/uso terapêutico , Neuroproteção/fisiologia , Fármacos Neuroprotetores/uso terapêutico , Riluzol/uso terapêutico , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Humanos , Metilprednisolona/farmacologia , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Riluzol/farmacologia , Traumatismos da Medula Espinal/metabolismo
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