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Naunyn Schmiedebergs Arch Pharmacol ; 394(11): 2273-2287, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34468816


Morbidity and mortality risks are enhanced in preeclamptic (PE) mothers and their offspring. Here, we asked if sexual dimorphism exists in (i) cardiovascular and renal damage evolved in offspring of PE mothers, and (ii) offspring responsiveness to antenatal therapies. PE was induced by administering NG-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg/day, oral gavage) to pregnant rats for 7 days starting from gestational day 14. Three therapies were co-administered orally with L-NAME, atrasentan (endothelin ETA receptor antagonist), terutroban (thromboxane A2 receptor antagonist, TXA2), or α-methyldopa (α-MD, central sympatholytic drug). Cardiovascular and renal profiles were assessed in 3-month-old offspring. Compared with offspring of non-PE rats, PE offspring exhibited elevated systolic blood pressure and proteinuria and reduced heart rate and creatinine clearance (CrCl). Apart from a greater bradycardia in male offspring, similar PE effects were noted in male and female offspring. While terutroban, atrasentan, or α-MD partially and similarly blunted the PE-evoked changes in CrCl and proteinuria, terutroban was the only drug that virtually abolished PE hypertension. Rises in cardiorenal inflammatory (tumor necrosis factor alpha, TNFα) and oxidative (isoprostane) markers were mostly and equally eliminated by all therapies in the two sexes, except for a greater dampening action of atrasentan, compared with α-MD, on tissue TNFα in female offspring only. Histopathologically, antenatal terutroban or atrasentan was more effective than α-MD in rectifying cardiac structural damage, myofiber separation, and cytoplasmic alterations, in PE offspring. The repair by antenatal terutroban or atrasentan of cardiovascular and renal anomalies in PE offspring is mostly sex-independent and surpasses the protection offered by α-MD, the conventional PE therapy.

Inflamm Res ; 70(9): 981-992, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34382102


OBJECTIVE AND DESIGN: Montelukast, a cysteinyl leukotriene receptor antagonist, exhibits antiinflammatory action. We tested whether exposure to montelukast plus nonsteroidal antiinflammatory drugs (NSAIDs) elicits better control of paw inflammation in the rat formalin test and improves associated gastric damage. MATERIALS: A total of 46 adult male rats were used in the study. TREATMENTS: We evaluated separate and combined effects of montelukast (20 mg/kg), celecoxib (COX2 inhibitor, 10 mg/kg), and diclofenac (nonselective COX1/COX2 inhibitor, 10 mg/kg) on paw and gastric damage in the rat formalin test. RESULTS: Individual pretreatments of rats with montelukast, diclofenac, or celecoxib partly reduced formalin-induced increases in (i) paw edema, fibrosis, and inflammatory cells, (iii) serum interleukin-6 (IL-6) and leukotrienes (LTB4 and LTD4), and (iv) paw expressions of inducible nitric oxide synthase (iNOS) and COX2. These effects were accentuated in rats treated with montelukast plus diclofenac or montelukast plus celecoxib. Alternatively, montelukast or celecoxib, but not diclofenac, alleviated formalin-evoked gastric damage and increments in tumor necrosis factor-α and decrements in prostaglandin-E2. These advantageous gastric influences were potentiated in rats treated with montelukast plus celecoxib. CONCLUSIONS: While montelukast equally enhances antiinflammatory action of diclofenac or celecoxib via downregulating iNOS/COX2/LTs/IL-6 signaling, its gastroprotective action is preferentially potentiated by celecoxib.

Toxicol Appl Pharmacol ; 426: 115615, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34102242


Current therapies for preeclampsia (PE) and its complications are limited and defective. Considering the importance of endothelin (ET) and thromboxane A2 (TXA2) signaling in PE pathophysiology, we tested the hypothesis that prenatal blockade of endothelin ETA or thromboxane TXA2 receptors favorably reprograms preeclamptic cardiovascular and renal insults. PE was induced by daily oral administration of L-NAME (50 mg/kg) to pregnant rats for 7 consecutive days starting from gestational day 14. The effects of co-exposure to atrasentan (ETA receptor blocker, 10 mg/kg/day) or terutroban (TXA2 receptor blocker, 10 mg/kg/day) on cardiovascular and renal anomalies induced by PE were assessed on gestational day 20 (GD20) and at weaning time and compared with those evoked by the sympatholytic drug α-methyldopa (α-MD, 100 mg/kg/day), a prototypic therapy for PE management. Among all drugs, terutroban was basically the most potent in ameliorating PE-evoked increments in blood pressure and decrements in creatinine clearance. Cardiorenal tissues of PE rats exhibited significant increases in ETA and TXA2 receptor expressions and these effects disappeared after treatment with atrasentan and to a lesser extent by terutroban or α-MD. Atrasentan was also the most effective in reversing the reduced ETB receptor expression in renal tissues of PE rats. Signs of histopathological damage in cardiac and renal tissues of PE rats were mostly improved by all therapies. Together, pharmacologic elimination of ETA or TXA2 receptors offers a relatively better prospect than α-MD in controlling perinatal cardiorenal irregularities sparked by PE.

Atrasentana/uso terapêutico , Antagonistas do Receptor de Endotelina A/uso terapêutico , Cardiopatias/prevenção & controle , Nefropatias/prevenção & controle , Naftalenos/uso terapêutico , Pré-Eclâmpsia/tratamento farmacológico , Propionatos/uso terapêutico , Receptores de Tromboxano A2 e Prostaglandina H2/antagonistas & inibidores , Animais , Atrasentana/farmacologia , Antagonistas do Receptor de Endotelina A/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Cardiopatias/genética , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Nefropatias/genética , Nefropatias/patologia , Nefropatias/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Naftalenos/farmacologia , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/patologia , Pré-Eclâmpsia/fisiopatologia , Gravidez , Propionatos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A/genética , Receptores de Tromboxano A2 e Prostaglandina H2/genética
J Chem Neuroanat ; 110: 101878, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33144183


Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a multifactorial etiology and significantly increasing incidence during the last decade. Hence, developing an effective therapy is crucial for public health. The current study aimed to examine the dual prophylactic/therapeutic potential of a nutraceutical formula based on aqueous extract of roasted date seeds, and nigella and virgin-olive oils against experimentally-induced Alzheimer's disease in rats. Alzheimer's disease-like pathology was induced in male Wistar rats using oral CuSO4 (200 mg/Kg/day for two months). The nutraceutical formula was given orally to experimental animals (10 mL/kg/d) for 14 days before (as prophylaxis) and after Alzheimer's disease induction and its therapeutic effect in both cases is tested in comparison to donepezil (0.5 mg/kg/d). The nutraceutical formula was found to ameliorate the CuSO4-induced neuronal damage and regenerate the affected hippocampus tissue and significantly improvemed in learning ability. The formula was also effective in decreasing brain amyloid-ß, tau protein, TNF-α level, iNOS level in hippocampus, oxidative stress level, and inhibiting acetylcholinesterase activity and expression in brain and hippocampus, respectively. Further, an increase in GSH levels, activities of SOD, and GST and levels of hippocampus ADAM 17 and brain phospholipids was observed. In conclusion, the studied nutraceutical formula is proved to be effective in ameliorating Alzheimer's neurodegenerative progression with added-prophylactic potential.

Doença de Alzheimer/tratamento farmacológico , Suplementos Nutricionais , Donepezila/uso terapêutico , Nigella , Azeite de Oliva/uso terapêutico , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Modelos Animais de Doenças , Donepezila/administração & dosagem , Glutationa/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Azeite de Oliva/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fosfolipídeos/metabolismo , Ratos , Ratos Wistar , Proteínas tau/metabolismo
Drug Dev Ind Pharm ; 46(6): 996-1004, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32378971


Rheumatoid arthritis (RA) is a chronic autoimmune disease of idiopathic etiology that triggers inflammatory cytokines compromising the joint mobility. Epidemiological evidences recommend the utilization of galantamine (GH) to reverse the anti-inflammatory reactions induced RA. Oral administration of GH is non-selectivity due to its association with serious gastrointestinal symptoms which, could hinder its therapeutic success. Therefore, the present study aimed to validate the therapeutic potential of GH transdermal patches as a novel application to constitute an effective and tolerable delivery system for managing RA in adjuvant arthritis model. RA was induced in Sprague-Dawley rats intradermally by Heat-killed M (0.12 ml/day). Oral GH (1.25 mg/kg/day) and GH transdermal patch (2.5 mg/kg/2 days) were administrated for 14 days, during which the hind paw and body weight (BW) were assessed. Effects of C-reactive protein (CRP), inflammatory cytokines (TNF-α, IL-10 and IL-1ß) and Janus kinase (JAK-2) were evaluated. Oral- and transdermal GH significantly improved the hind paw edema in arthritis animal model and offered a protective impact against RA. Oral GH group showed marked decrease in BW than that of transdermal patches group. Transdermal patch group showed a significant decrease in the level of IL-1ß more than the oral group. However, no significant difference was detected in the levels of TNF-α and IL-10 between the two groups. It is concluded that GH transdermal patch can be a promising drug delivery system that copes with side effects better than oral GH consequently represents novel strategy in management of RA.

Artrite Experimental , Artrite Reumatoide , Galantamina/química , Animais , Artrite Reumatoide/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Adesivo Transdérmico
Expert Opin Drug Deliv ; 17(1): 111-122, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31782320


Background: Atopic dermatitis is a chronic inflammatory skin disease that remarkably affects the quality-of-life of patients. Chamomile oil is used to treat skin inflammations. We evaluated the efficacy of chamomile oil and nanoemulgel formulations as a natural alternative therapeutic option for atopic dermatitis.Research design and methods: Formulations were developed comprising chamomile oil: olive oil (1:1), Tween 20/80 or Gelucire 44/14 as surfactant-cosurfactant mixtures, propylene glycol (10%w/w), water and hydroxypropyl methylcellulose (3%w/w). In-vitro physicochemical characterization, stability testing and in-vivo assessment of inflammatory biomarkers and histopathological examination of skin lesions were conducted in rats induced with atopic dermatitis.Results: Nanoemulgels G1 and X1 which displayed the smallest particle size of 137.5 ± 2.04 and 207.1 ± 5.44 nm, good homogeneity and high zeta-potential values of -26.4 and -32.7 mV were selected as the optimized emulgel. Nanoemulgels were nonirritating of pH value 5.56, readily spreadable, and were physically stable following 10 heating-cooling cycles. Treatment with nanoemulgels showed a two-fold decrease in duration of skin healing and no spongiosis compared to chamomile oil. Levels of biomarkers were reduced after topical application of both nanoemulgels and chamomile oil.Conclusion: Nanoemulgels are a potential cost effective, safe topical carrier system for chamomile in treating atopic dermatitis.

Camomila/química , Dermatite Atópica/tratamento farmacológico , Modelos Animais de Doenças , Nanopartículas/química , Extratos Vegetais/administração & dosagem , Tensoativos/química , Administração Tópica , Animais , Animais Recém-Nascidos , Dermatite Atópica/patologia , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Feminino , Concentração de Íons de Hidrogênio , Masculino , Microscopia Eletrônica de Transmissão , Tamanho da Partícula , Gravidez , Prenhez , Ratos , Ratos Sprague-Dawley