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1.
Int. j. morphol ; 37(4): 1572-1577, Dec. 2019. tab
Artigo em Inglês | LILACS | ID: biblio-1040171

RESUMO

Hypoxia hypobaric (HH) can cause alterations at testicular level, with temperature increase, intrascrotal alteration and deterioration of spermatogenesis. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ketoprofen have anti-angiogenic properties, and can decrease testicular abnormalities. The objective of the study was to evaluate the effect of ketoprofen on spermatogenesis of mice exposed to continuous hypobaric hypoxia. 78 Mus musculus CF-1 male mice 3 to 4 months old were used and subjected to HH in chamber at 4200 m. They were divided into 13 groups (G) of 6 animals: 10 with HH cycles (1, 2, 3, 4 and 8, lasting 8.3 days each cycle, two groups each) and 3 in normoxia (Nx). Intraperitoneal ketoprofen 25 mg/kg was administered every 4 days. Euthanasia of these animals was performed at the end of each cycle and in the case the Nx groups at the end of cycles 1, 4 and 8. Percentage of microhematocrit and reticulocytes were measured in blood smears and a morphometric and histopathological analysis of the height of the epithelium, the tubular diameter and the diameter of the tubular lumen was made. It was shown that hematocrit increases continuously up to 8 cycles, while reticulocytes increase up to 3 cycles. Continuous HH decreases the tubular diameter in a sustained manner and proportional to HH cycles, and the height increased only in the groups subjected to 8 cycles. The groups treated with ketoprofen saw a decrease in angiogenesis, presenting some degree of protection at the testicular level.


La hipoxia hipobárica (HH) puede provocar alteraciones a nivel testicular, con aumento de la temperatura, alteración intraescrotal y deterioro de la espermatogénesis. Los antiinflamatorios no esteroidales (AINEs) como el ketoprofeno tienen propiedades antiangiogénicas, pudiendo disminuir las alteraciones testiculares. El objetivo de estudio fue evaluar el efecto del ketoprofeno en la espermatogénesis de ratones expuestos a hipoxia hipobárica continua. Se utilizaron 78 ratones macho Mus musculus CF-1 de 3 a 4 meses de edad y se sometieron a HH en cámara a 4200 m. Se dividieron en 13 grupos (G) de 6 animales: 10 con ciclos de HH (1, 2, 3, 4 y 8, con duración de 8,3 días cada ciclo, dos grupos cada uno) y 3 en normoxia (Nx). Se administró ketoprofeno intraperitoneal 25 mg/kg cada 4 días. La eutanasia de estos animales se realizó al final de cada ciclo y en el caso los grupos Nx al final de los ciclos 1, 4 y 8. Se midió porcentaje de microhematocrito y reticulocitos en frotis de sangre y se hizo un análisis morfométrico e histopatológico de la altura del epitelio, el diámetro tubular y el diámetro de la luz tubular. Se evidenció que el hematocrito aumenta de manera continua hasta los 8 ciclos, en cambio los reticulocitos aumentan hasta los 3 ciclos. La HH continua disminuye el diámetro tubular de forma sostenida y proporcional a los ciclos de HH, y la altura aumentó sólo en los grupos sometidos a 8 ciclos. Los grupos tratados con ketoprofeno se vio una disminución de la angiogénesis, presentando algún grado de protección a nivel testicular.


Assuntos
Animais , Masculino , Camundongos , Espermatogênese/efeitos dos fármacos , Testículo/efeitos dos fármacos , Anti-Inflamatórios não Esteroides/farmacologia , Cetoprofeno/farmacologia , Hipóxia/fisiopatologia , Reticulócitos/efeitos dos fármacos , Túbulos Seminíferos/efeitos dos fármacos , Testículo/lesões , Anti-Inflamatórios não Esteroides/administração & dosagem , Cetoprofeno/administração & dosagem , Hematócrito , Neovascularização Patológica
2.
Pol J Vet Sci ; 22(3): 609-615, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31560476

RESUMO

Early lactation period in dairy cows could be harmful to their health since it is challenging and demanding. Proinflammatory cytokine concentrations are increased in the early phase of the inflammatory response and during the early lactation period in cows. The aim of this study was to determine if ketoprofen treatment in the first days following parturition would decrease proinflammatory cytokine concentration and their correlation between lipid mobilization, ketogenesis and metabolic parameters in cows. The study was conducted on 30 cows divided into two groups of 15 cows each. The experimental group was treated with 3 mg × kg.bw.-1 ketoprofen for three consecutive days after parturition. The blood samples were collected on the first day of treatment and in the first and second week postpartum and they were analyzed for biochemical parameters such as non-esterified fatty acids (NEFA), beta-hydroxybutyrate (BHBA), glucose, cholesterol and total bilirubine and inflammatory parameters such as tumour necrosis factor-α (TNF-α), interleukin-1α (IL-1α) and interferon-γ (IFN-γ). The results suggested that ketoprofen- treated cows had a significantly lower concentration of TNF-α, IL-1α, IFN-γ, NEFA and BHBA in the first and second postpartum week compared to the control group. Ketoprofen administration increased glucose levels (the first week, p⟨0.05), increased cholesterol levels (the second week, p⟨0.01) and decreased serum total bilirubin levels (second week, p⟨0.01) compared to the control group of cows. A positive correlation was found between TNF-α and NEFA and total bilirubin, significantly more expressed in the control than in experimental group of cows (p⟨0.01) and it was also found between IL-1α and NEFA (p⟨0.01). A negative correlation was found between TNF-α and glucose and cholesterol, significantly more expressed in the control than in experimental group of cows (p⟨0.01). A positive correlation was also found between IL-1α and glucose (p⟨0.01). Ketoprofen given parenterally to Holstein cows immediately after calving could reduce inflammation and decrease the relation between inflammatory response and lipogenesis and ketogenesis in postpartum cows.


Assuntos
Bovinos , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Cetonas/metabolismo , Cetoprofeno/farmacologia , Lipogênese/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Citocinas/genética , Feminino , Cetoprofeno/administração & dosagem , Período Pós-Parto
3.
Molecules ; 24(17)2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31480789

RESUMO

Studies of interactions between pesticides and target mammalian proteins are important steps toward understanding the pesticide's toxicity. Using calorimetric and spectroscopic methods, the interaction between triazole fungicide tebuconazole and human serum albumin has been investigated. The spectroscopic techniques showed that fluorescence quenching of human serum albumin by tebuconazole was the result of the formation of tebuconazole/human serum albumin complex with the static type as the dominant mechanism. The association constant was found to be 8.51 × 103 L/mol. The thermodynamic parameters were obtained as ΔH = -56.964 kJ/mol, ΔS = -115.98 J/mol·K. The main active interactions forming the tebuconazole/human serum albumin complex were identified as the interplay between hydrogen bonds and/or van der Waals forces, based on thermodynamic experiments. These binding modes were corroborated well by the predictions of molecular modeling. Hydrogen bonding of tebuconazole with Arg222, Ala215 and Ala291 of human serum albumin played a relevant role in binding. The conformation changes in secondary structure were characterized by circular dichroism and 3D fluorescence spectra.


Assuntos
Fungicidas Industriais/farmacologia , Albumina Sérica Humana/química , Triazóis/farmacologia , Varredura Diferencial de Calorimetria , Humanos , Ibuprofeno/farmacologia , Cetoprofeno/farmacologia , Simulação de Acoplamento Molecular , Ligação Proteica , Albumina Sérica Humana/metabolismo , Espectrometria de Fluorescência , Termodinâmica , Triazóis/química
4.
Mater Sci Eng C Mater Biol Appl ; 103: 109742, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349429

RESUMO

This study aimed to develop nanocapsules containing ketoprofen using rose hip oil (Keto-NC) as oil core, and to evaluate their anti-inflammatory activity in acute and chronic ear edema models in mice. Physicochemical characterization, drug release, photostability and cytotoxicity assays were performed for the developed Keto-NC formulations and compared to ketoprofen-loaded nanocapsules using medium chain triglycerides as oil core (Keto-MCT-NC). Anti-inflammatory activity of orally delivered KP (Ketoprofen-free; 10 mg.kg-1) or Keto-NC (2.5; 5; 10 mg.kg-1) was assessed in mouse acute and chronic ear edema induced by croton oil (CO). Edema histological characteristics were determined by H&E stain, and redox parameters were analyzed in blood plasma and erythrocytes. Keto-MCT-NC and Keto-NC did not exhibit differences regarding physicochemical parameters, including size diameters, polydispersity index, pH, Ketoprofen content, and encapsulation efficiency. However, Keto-NC, which contains rose hip oil as lipid core, decreased drug photodegradation under UVC radiation when compared to Keto-MCT-NC. KP or Keto-NC were not cytotoxic to keratinocyte cultures and produced equal edema inhibition in the acute protocol. Conversely, in the chronic protocol, Keto-NC was more effective in reducing edema (~60-70% on 7-9th days of treatment) when compared to KP (~40% on 8-9th days of treatment). This result was confirmed by histological analysis, which indicated reduction of edema and inflammatory infiltrate. A sub-therapeutic dose of Keto-NC (5 mg.kg-1) significantly reduced edema when compared to control. Finally, KP and Keto-NC exhibited similar effects on redox parameters, suggesting that the advantages associated with Ketoprofen nanoencapsulation did not involve oxidative stress pathways. The results showed that Keto-NC was more efficient than KP in reducing chronic inflammation. These data may be important for the development of strategies aiming treatment of chronic inflammatory diseases with fewer adverse effects.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inflamação/tratamento farmacológico , Cetoprofeno/farmacologia , Nanocápsulas/química , Óleos Vegetais/química , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacocinética , Linhagem Celular , Doença Crônica , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Edema/tratamento farmacológico , Humanos , Queratinócitos/efeitos dos fármacos , Cetoprofeno/administração & dosagem , Cetoprofeno/farmacocinética , Masculino , Camundongos Endogâmicos C57BL , Nanocápsulas/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Rosa/química
5.
PLoS One ; 14(6): e0218546, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31211805

RESUMO

In veterinary practice pain alleviation plays a part in managing lameness. The aim of this randomized and placebo-controlled clinical study was to evaluate the effect of a single administration of ketoprofen on locomotion characteristics and weight distribution in cattle with foot (located up to and including the fetlock; n = 31) and (proximal to the fetlock; n = 10) pathologies. Cattle were randomly allocated to either the ketoprofen (group K; intravenous 3 mg/kg of body weight; n = 21) or an equivalent volume of isotonic sterile saline solution (group P; n = 20). Two accelerometers (400 Hz; kinematic outcome = stance phase duration; kinetic outcome = foot load and toe-off), a 4-scale weighing platform (weight distribution and SD of the weight) and a subjective locomotion score were measured before (baseline) and after 1 h and 18 h of treatment. All variables were expressed as differences across contralateral limbs, and the measurements at 1 h and 18 h were compared to the baseline. A repeated measures ANOVA was used to determine the differences between groups K and P. A logistic regression model with a binary outcome (0 = no improvement and 1 = improvement of the differences across the contralateral limbs over time) was calculated. Mean (± SD) of locomotion scores at baseline were not significantly different (P = 0.102) in group K (3.10 ± 0.80) as compared to group P (3.48 ± 0.64). Cattle of group K showed significantly lower differences across contralateral limbs at 1 h as compared to group P for the relative stance phase and the weight distribution. Only the treatment (P versus K) remained a significant factor in the model for relative stance phase (odds ratio (OR) = 6.5; 95% CI = 1.38-30.68) and weight distribution (OR = 6.36; 95% CI = 1.30-31.07). The effects of ketoprofen were evident in improving the differences across contralateral limbs-both for stance phase during walking and weight bearing during standing-after 1 h but not after 18 h of administration.


Assuntos
Doenças dos Bovinos/diagnóstico , Doenças dos Bovinos/tratamento farmacológico , Extremidades/fisiopatologia , Cetoprofeno/farmacologia , Locomoção , Dor/veterinária , Suporte de Carga , Análise de Variância , Animais , Bovinos , Doenças dos Bovinos/etiologia , Gerenciamento Clínico , Marcha , Coxeadura Animal/diagnóstico , Coxeadura Animal/etiologia
6.
Int J Mol Sci ; 20(12)2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31238499

RESUMO

Cisplatin and several non-steroidal anti-inflammatory drugs (NSAIDs) have been proven to act synergistically or at least additively on several tumor cell lines. Dual-action cisplatin-based Pt(IV) combos containing ketoprofen and naproxen offer good antiproliferative performance on a panel of human tumor cell lines, including a malignant pleural mesothelioma (MPM) one, a very chemoresistant tumor. The main reason of the increased activity relies on the enhanced lipophilicity of these Pt(IV) conjugates that in turn promotes increased cellular accumulation. A quick Pt(IV)→Pt(II) reduction generates the active cisplatin metabolite. The NSAID adjuvant action seems to be almost independent from cyclooxygenase-2 (COX-2) expression in the tumor cells under investigation (lung A-549, colon HT-29, HCT 116, SW480, ovarian A2780, and biphasic MPM MSTO-211H), but it seems to rely (at least in part) on the activation of the NSAID activated gene, NAG-1 (a member of the transforming growth factor beta, TGF-ß, superfamily), which has been suggested to be involved in NSAID antiproliferative activity.


Assuntos
Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Cetoprofeno/química , Cetoprofeno/farmacologia , Naproxeno/química , Naproxeno/farmacologia , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Pró-Fármacos/química , Pró-Fármacos/farmacologia
7.
Arch Pharm (Weinheim) ; 352(7): e1800339, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31231875

RESUMO

Ketoprofen belongs to one of the most common nonsteroidal anti-inflammatory drugs (NSAIDs) but its clinical usefulness has been restricted due to the high incidence of gastrointestinal complications. The release of reactive oxygen species (ROS) in NSAIDs therapy plays a major role in causing gastric complications. Antioxidants not only prevent gastric ulceration and lipid peroxidation but also preserve glutathione-type peroxidase (GPO) activity. Therefore, the present study investigates the utility of combining anti-inflammatory and antioxidant properties of two different compounds in a single molecule to form a series of 16 ketoprofen-antioxidant mutual codrugs. The free carboxylic group, which is believed to be one of the reasons for gastric toxicity of ketoprofen, was masked temporarily by simple and double esterification with alcoholic/phenolic-OH of natural antioxidants. In simple esterification, ketoprofen is directly linked to natural antioxidants (IIa-h) in the hope to obtain drugs free of gastric side effects. In an attempt to improve the in vivo lability, as well as gastric side effects, the double ester codrugs, that is, ketoprofen-antioxidant through the glycolic acid spacer (-CH2 COO; IIIa-h), have also been designed and synthesized. The synthesized codrugs were characterized by IR, 1 H NMR, 13 C NMR, mass spectroscopy and elemental analysis. The in vitro hydrolysis studies showed the lowest hydrolysis (highest stability) in acidic pH 1.2, whereas moderate hydrolysis was seen at pH 7.4 and significant hydrolysis in 80% human blood plasma, as indicated by their t1/2 . The pharmacological evaluation results indicate that these ketoprofen-antioxidant mutual codrugs showed the retention of anti-inflammatory and analgesic activity with a significant reduction in the ulcer index.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antiulcerosos/farmacologia , Antioxidantes/farmacologia , Inflamação/tratamento farmacológico , Cetoprofeno/farmacologia , Analgésicos/síntese química , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antiulcerosos/síntese química , Antiulcerosos/química , Antioxidantes/química , Compostos de Bifenilo/antagonistas & inibidores , Humanos , Hidrólise , Cetoprofeno/química , Cinética , Estrutura Molecular , Dor/tratamento farmacológico , Picratos/antagonistas & inibidores , Ratos , Úlcera Gástrica/tratamento farmacológico
8.
Colloids Surf B Biointerfaces ; 180: 362-370, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31077864

RESUMO

In this report, novel pH-sensitive interpenetrated network (IPN) polyspheres were developed utilizing polyacrylamide-g-locust bean gum (PAAm-g-LBG) in combination with sodium alginate (SA) to achieve intestinal targeted delivery of ketoprofen. PAAm-g-LBG was synthesized under microwave irradiation wherein ceric ammonium nitrate was used as reaction initiator and then conversion of PAAm-g-LBG as pH-sensitive copolymer was carried out by alkaline hydrolysis. The PAAm-g-LBG copolymer was characterized through 1H-NMR, FTIR and elemental analysis. The IPN polyspheres exhibited pH-depended swelling or de-swelling with the alteration of surrounding pH. The in-vitro release of drug from IPN polyspheres was found to be higher (≈ 90%) in phosphate buffer of pH 7.4 in comparison with that in pH 1.2 buffer (10.6%). The in-vivo pharmacokinetic, anti-inflammatory screening and stomach histopathology studies performed on Wistar rats revealed pH sensitivity of IPN polyspheres where ketoprofen was successfully targeted to small intestine resulting in reduced side effects of ketoprofen like ulcer formation, erosion of gastric mucosa and hemorrhages.


Assuntos
Resinas Acrílicas/química , Alginatos/química , Sistemas de Liberação de Medicamentos , Galactanos/química , Intestinos/efeitos dos fármacos , Cetoprofeno/farmacologia , Mananas/química , Gomas Vegetais/química , Animais , Anti-Inflamatórios/farmacologia , Varredura Diferencial de Calorimetria , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Cetoprofeno/farmacocinética , Tamanho da Partícula , Espectroscopia de Prótons por Ressonância Magnética , Ratos Wistar , Espectroscopia de Infravermelho com Transformada de Fourier , Estômago/patologia , Termogravimetria , Difração de Raios X
9.
J Coll Physicians Surg Pak ; 29(6): 511-515, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31133146

RESUMO

OBJECTIVE: To evaluate the efficacy of dexketoprofene trometamol solution following the administration of contrast agent for Endoscopic Retrograde Cholangiopancreatography (ERCP) in decreasing the rate of pancreatitis, in experimental rat model. STUDY DESIGN: Experimental study. PLACE AND DURATION OF STUDY: Faculty of Medicine, Research and Animal Laboratory of Bezmialem University, Istanbul, Turkey in January 2018. METHODOLOGY: Forty Wistar-Albino® male rats of 250-300g were divided into 4 equal groups. Group I underwent cannulation; group II had cannulation with saline; group III had cannulation and contrast agent; group IV had cannulation with contrast agent and dexketoprofene trometamol intra-muscular (IM). Twenty four hours following the procedure, the rats were sacrified and pancreatic tissues were examined histopathologically, with evaluation of blood levels of leukocyte, glucose, SGOT, LDH, amylase, and C-reactive protein (CRP) level. Histopathological grading of acute pancreatitis was performed using haematoxylin and eosin staining. RESULTS: Mean levels of amylase and leukocyte were found to be significantly higher in groups II, III, IV when compared to group I (p=0.001). CRP level was found to be highest in group III (p=0.001). Histopathological grade of pancreatitis was found to be significantly higher in groups II, III, IV than group I (p: 0.001, 0.001, 0.028, and 0.001, respectively). Scores of edema, acinar necrosis, inflammation and perivascular infiltration of group III were higher than in group IV (p=0.001). CONCLUSION: Intra-muscular administration of dexketoprofen trometamol during ERCP procedure may be beneficial in decreasing the rate of post-ERCP pancreatitis, as shown by histopathological and laboratory profile.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Colangiopancreatografia Retrógrada Endoscópica/efeitos adversos , Cetoprofeno/análogos & derivados , Pancreatite/prevenção & controle , Trometamina/administração & dosagem , Amilases/sangue , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Aspartato Aminotransferases/sangue , Proteína C-Reativa/análise , Cateterismo , Colangiopancreatografia Retrógrada Endoscópica/métodos , Meios de Contraste/efeitos adversos , Feminino , Glucose/análise , Humanos , Cetoprofeno/administração & dosagem , Cetoprofeno/farmacologia , L-Lactato Desidrogenase/sangue , Leucócitos , Masculino , Pessoa de Meia-Idade , Pâncreas/patologia , Pancreatite/etiologia , Pancreatite/patologia , Complicações Pós-Operatórias , Ratos , Ratos Wistar , Trometamina/farmacologia
10.
Drug Dev Res ; 80(5): 556-565, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30901500

RESUMO

The main challenges in treating cancer using chemotherapeutics are insufficient dose at the target site and the development of drug resistance, while higher doses can induce side effects by damaging nontarget tissues. Combinatorial drug therapy may overcome these limitations by permitting lower doses and more specific targeting, thereby mitigating drug resistance and nontarget side effects. Recent reports indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) have anticancer potential and can be used together with conventional chemotherapeutics to improve efficacy and safety. In the present study, imatinib mesylate and dexketoprofen trometamol were selected as model drugs to develop targeted surface-modified liposome and nanocochleate formulations for fibrosarcoma treatment. The physicochemical properties and in vitro efficacy of various formulations were evaluated by measurement of particle size distribution, polydispersity index, zeta potential, encapsulation efficiency, diffusion through Caco-2 cells, and toxicity in culture. Selected formulations were then evaluated in fibrosarcoma-bearing model mice by histopathological observations and tyrosine kinase receptor inhibition assays. The most effective formulation on the fibrosarcoma model was a PEGylated nanocochleate formulation. These findings provide a foundation for developing more effective formulations and chemotherapeutic strategies for the treatment of fibrosarcoma and other types of cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Fibrossarcoma/tratamento farmacológico , Mesilato de Imatinib/administração & dosagem , Cetoprofeno/análogos & derivados , Trometamina/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Composição de Medicamentos , Humanos , Mesilato de Imatinib/farmacologia , Cetoprofeno/administração & dosagem , Cetoprofeno/farmacologia , Lipossomos , Masculino , Camundongos , Nanopartículas , Tamanho da Partícula , Trometamina/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Biomed Pharmacother ; 111: 1458-1466, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30841461

RESUMO

INTRODUCTION: Prostaglandins (PGs) play an important role in corpus cavernosum relaxation, as evidenced by alprostadil being used as a drug for erectile dysfunction. Reports about the effect of cyclooxygenase (COX) inhibitors on erectile function are highly contradictory. AIM: To compare the potential effects of some COX inhibitors with varying COX-1/COX-2 selectivities (indomethacin, ketoprofen and diclofenac) with that of the selective COX-2 inhibitor (DFU) on corpus cavernosal tone in-vitro. The role played by PGE1, PGI2-analogue and PGE4 receptor (EP4)-agonist in controlling corpus cavernosum function and the modulation of their action by sildenafil is also studied. METHODS: Organ bath experiments were performed using isolated rat corpus cavernosum. Direct relaxations and changes to electric field stimulation (EFS, 2-16 Hz, 60 V, 0.8 ms, 10 s train)-induced relaxation by the effect of the selected drugs were studied. Strips were precontracted using phenylephrine (PE, 10-5 M). Results are expressed as mean ± SEM of 5-9 rats. RESULTS: Alprostadil, iloprost and L902688 (selective EP4 agonist) induced direct relaxation where L902688 showed greater relaxant effect. Sildenafil potentiated the Emax of alprostadil and iloprost but not L902688. EFS and acetylcholine (ACh)-induced relaxations were significantly potentiated in presence of indomethacin, ketoprofen and diclofenac (20, 100 µM) but not in presence of selective COX-2 inhibitor (DFU, 1 µM). GR32191B (Thromboxane A2 receptor antagonist, 10-6 M) significantly reduced the potentiatory effect of indomethacin. Only diclofenac succeeded to potentiate sodium nitroprusside (SNP)-induced relaxation. CONCLUSIONS: EP4 receptors may play an important nitric oxide (NO)/cGMP-independent role in corpus cavernosal relaxation. Nonselective COX inhibitors seem of no harm concerning cavernosal tissue relaxation, possibly because they inhibit the synthesis of the highly contracting mediator thromboxane A2.


Assuntos
Inibidores de Ciclo-Oxigenase/farmacologia , Relaxamento Muscular/efeitos dos fármacos , Pênis/efeitos dos fármacos , Prostaglandinas/metabolismo , Alprostadil/farmacologia , Animais , GMP Cíclico/metabolismo , Diclofenaco/farmacologia , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/metabolismo , Iloprosta/farmacologia , Indometacina/farmacologia , Cetoprofeno/farmacologia , Masculino , Óxido Nítrico/metabolismo , Nitroprussiato/farmacologia , Ereção Peniana/efeitos dos fármacos , Pênis/metabolismo , Piperazinas/farmacologia , Ratos , Citrato de Sildenafila/farmacologia , Sulfonas/farmacologia
12.
Vet Anaesth Analg ; 45(6): 820-830, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30316696

RESUMO

OBJECTIVE: To evaluate and compare the analgesic efficacy and adverse effects of dexketoprofen and methadone using a noninferiority trial, during the first 24 postoperative hours in dogs undergoing orthopaedic surgery. STUDY DESIGN: Randomized, blinded clinical study. ANIMALS: A total of 38 healthy dogs undergoing orthopaedic surgery. METHODS: Dogs were premedicated with dexmedetomidine [1 µg kg-1 intravenously (IV)] followed by dexketoprofen (1 mg kg-1 IV; group DK) or methadone (0.2 mg kg-1 IV; group M). Anaesthesia was induced with propofol and maintained with isoflurane in 60% oxygen. Postoperatively, dexketoprofen was administered every 8 hours (group DK) and methadone every 4 hours (group M). Analgesia was assessed at baseline and at 1, 2, 4, 6, 18 and 24 hours after extubation using a dynamic and interactive visual analogue scale (DIVAS), the short form of the Glasgow Composite Measure Pain Scale (CMPS-SF), mechanical wound thresholds (MWTs) and plasma cortisol levels. If CMPS-SF score was ≥5, rescue analgesia was administered. Data were analysed using a general linear mixed model, Mann-Whitney U test and chi-squared test as appropriate; a p value <0.05 was considered significant. RESULTS: The CMPS-SF and DIVAS scores were significantly higher in group M compared with group DK and remained higher for a longer period in group M, although the differences were not clinically significant. No significant differences were found in MWT assessment between groups. Plasma cortisol level significantly increased 2 hours after extubation, without significant differences between treatments. Rescue analgesia was administered to three animals (one in group DK; two in group M). CONCLUSION AND CLINICAL RELEVANCE: We conclude that 1 mg kg-1 IV dexketoprofen administered every 8 hours during the first 24 hours postoperatively is noninferior to methadone in controlling pain after orthopaedic surgery in dog, although frequent pain assessments are recommended to adjust the analgesia plan.


Assuntos
Analgésicos Opioides/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Cães/cirurgia , Cetoprofeno/análogos & derivados , Metadona/farmacologia , Procedimentos Ortopédicos/veterinária , Dor Pós-Operatória/veterinária , Trometamina/farmacologia , Analgesia/veterinária , Animais , Feminino , Cetoprofeno/farmacologia , Masculino , Dor Pós-Operatória/tratamento farmacológico , Período Pós-Operatório , Método Simples-Cego
13.
Georgian Med News ; (280-281): 120-125, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30204109

RESUMO

Pain is characterized as a complex experience, dependent not only on the regulation of nociceptive sensory systems but also on the activation of mechanisms that control emotional processes in limbic brain areas. Non-opioid, non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely used analgesics in the treatment of not-severe pain. We have recently shown that repeated doses result in tolerance to these drugs like opioids. Here we investigated the central brain mechanisms of non-opioid induced antinociception in the non-acute pain models of rats, such as the 'formalin test' and a relation between administration of NSAIDs in the limbic brain area, - the anterior cingulated cortex (ACC), - and the endocannabinoid system. We measured nociceptive thermal paw withdrawal latencies and mechanical thresholds monolaterally in rats following microinjections of NSAIDs (diclofenac, ketoprofen, xefocam), saline or the cannabinoid receptor 1 (CB1) antagonist (AM-251) in the ACC. Five min following intraplantar formalin injection all animals showed a significant reduction in thermal paw withdrawal latency and mechanical withdrawal threshold compared to pre-baseline values. Fifteen minutes after formalin injection, diclofenac, ketoprofen, xefocam clearly showed antinociceptive effects of NSAIDs. When pretreated with AM-251 we found a significant reduction of analgesic effects of NSAIDs. The present data support the notion that endocannabinoids' CB1 receptor contributes in part to antinociceptive effects of NSAIDs and probably involved in activation of the descending opioid modulatory system of pain.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Endocanabinoides/metabolismo , Giro do Cíngulo/metabolismo , Dor/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Diclofenaco/farmacologia , Diclofenaco/uso terapêutico , Tolerância a Medicamentos , Cetoprofeno/farmacologia , Cetoprofeno/uso terapêutico , Masculino , Microinjeções , Nociceptividade/efeitos dos fármacos , Dor/metabolismo , Piperidinas/farmacologia , Piroxicam/análogos & derivados , Piroxicam/farmacologia , Piroxicam/uso terapêutico , Pirazóis/farmacologia , Ratos Wistar , Tempo de Reação , Receptor CB1 de Canabinoide/antagonistas & inibidores
14.
Chemosphere ; 213: 423-433, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30243208

RESUMO

Ketoprofen a nonsteroidal anti-inflammatory drug (NSAID) is widely used in over-the-counter to treat pain, swelling and inflammation. Due to extensive application these drugs has been detected in surface waters which may create a risk to aquatic organisms. The aim of the present study is to assess the ecotoxicity of ketoprofen at different concentrations (1, 10 and 100 µg/ml) on embryos and adult zebrafish (1, 10 and 100 µg L-1) under laboratory conditions. In embryos, concentration dependent developmental changes such as edema, spinal curvature, slow heartbeat, delayed hatching, and mortality rate were observed. In adult zebrafish, biochemical enzymes such as AST, ALT and LDH activities were significantly (P < 0.05) increased whereas a decrease in Na+/K+-ATPase activity was noticed in all the tested concentrations of the drug ketoprofen. Similarly, exposure of ketoprofen caused a significant decrease in antioxidant levels in liver tissue (SOD, CAT, GSH, GPx, and GST). However, lipid peroxidation (LPO) level in liver tissue was found to be increased. The histopathological studies further evidenced the impact of ketoprofen in the liver tissue of zebrafish. The present result concludes that ketoprofen could have an impact on the development and biological endpoints of the zebra fish at above concentrations. The malformation in the development of the embryo and changes in the biological end points may provide integrated evaluation of the toxic effect of ketoprofen on zebrafish in a new perspective.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Cetoprofeno/efeitos adversos , Poluentes Químicos da Água/química , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Cetoprofeno/farmacologia , Peixe-Zebra
15.
J Dairy Sci ; 101(12): 11321-11329, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30243628

RESUMO

Nonsteroidal anti-inflammatory drugs are commonly administered parenterally in addition to antimicrobial mastitis therapy to increase the well-being of the diseased animal. As mastitis is usually a localized infection of mammary tissue, we tested the hypothesis that a local administration of nonsteroidal anti-inflammatory drugs through the teat canal could have anti-inflammatory effects on the affected area. We investigated the effects of intramammarily administered ketoprofen (KET) during an LPS-induced immune response on somatic cell count (SCC) and blood-milk barrier integrity. In addition, we investigated the effects of KET on the mRNA abundance of immune factors and their prostaglandin E2 secretion in primary bovine mammary epithelial cells in vitro. Six cows received 0.2 µg of LPS (serotype O26:B6) together with 50 mg of KET into one quarter and LPS only in the opposing quarter. The increase of SCC and of serum albumin (SA) and IgG concentrations and the increase of lactate dehydrogenase (LDH) activity in milk induced by LPS were lower in quarters that received KET in addition. In 3 cows, intramammary KET (50 mg) without additional LPS did not affect SCC, SA, IgG, and LDH in milk. Effects of KET on the immune response of mammary epithelial cells in vitro were investigated in cells from 3 cows challenged with or without LPS (0.2 µg/mL) and with or without additional KET in 2 concentrations (1.25 or 2.5 mg/mL). Ketoprofen reduced the LPS-induced increase of mRNA abundance of tumor necrosis factor α, IL-8, serum amyloid A, and cyclooxygenase-2. The mRNA abundance of cyclooxygenase-1 and prostaglandin E synthase was reduced in cells without LPS challenge by addition of KET at 2.5 mg/mL. Furthermore, the LPS-induced secretion of prostaglandin E2 of mammary epithelial cells into the supernatant could not be detected if KET was added. The results demonstrate that intramammary KET diminishes the increase of SCC and reduces the impairment of the blood-milk barrier (based on SA and LDH in milk), leading to a reduced IgG concentration in milk during LPS-induced mastitis. In mammary epithelial cells, KET limits the expression of several immune factors that are increased during an immune response. In summary, intramammary administration of KET reduces the inflammatory response in the mammary gland. However, it remains unclear whether the inhibited transfer of immune cells and IgG from blood into milk after KET administration would reduce the success of the immune defense in infectious mastitis.


Assuntos
Anti-Inflamatórios não Esteroides , Imunidade/efeitos dos fármacos , Cetoprofeno/efeitos adversos , Lipopolissacarídeos/farmacologia , Mastite Bovina/imunologia , Animais , Bovinos , Contagem de Células/veterinária , Dinoprostona/metabolismo , Feminino , Imunidade/genética , Imunoglobulina G/análise , Cetoprofeno/farmacologia , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/imunologia , Glândulas Mamárias Animais/metabolismo , Mastite Bovina/tratamento farmacológico , Leite/citologia , Leite/imunologia , Leite/metabolismo , RNA Mensageiro/análise
16.
PLoS One ; 13(6): e0198682, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29924840

RESUMO

In this study, we aimed to evaluate the immunomodulatory effects of crude leaf extracts from Piper gaudichaudianum Kunth, P. arboreum Aub., P. umbellata L., P. fuligineum Kunth, and Peperomia obtusifolia A. Dietr. on an in vitro model of inflammatory response. The crude extracts were previously obtained by maceration of the leaves. The half-maximal inhibitory concentration was determined by the MTT assay using human peripheral blood mononuclear cells. Human monocytes were simultaneously challenged with each crude extract and lipopolysaccharide (LPS), the major component of the outer membrane of Gram-negative bacteria, to induce a strong inflammatory response. After 24 h of incubation, cell-free supernatants were used for evaluating the mediators involved in inflammation: H2O2, TNF-α, IL-8, IL-6, IL-1ß, IL-10, IL-12, FGF-b, and TGF-ß1. We also compared the results with the effects of ketoprofen, a well-known anti-inflammatory drug. The P. gaudichaudianum crude extract downmodulated the production of H2O2, IL-1ß, IL-6, IL-8, and TGF-ß1 by LPS-stimulated monocytes; P. arboreum, IL-1ß, IL-6, IL-8, and TNF-α; P. umbellata and P. fuligineum, H2O2, IL-1ß, IL-6, IL-8, IL-10, and TNF-α; and P. obtusifolia, H2O2, IL-6, IL-8, IL-10, and TNF-α. In general, the crude leaf extracts amplified the anti-inflammatory response when compared with ketoprofen, particularly reducing the production of IL-8, a mediator involved in neutrophil recruitment during tissue damage. Thus, the crude leaf extracts of P. gaudichaudianum, P. arboreum, P. umbellata, P. fuligineum, and Peperomia obtusifolia elicited an anti-inflammatory response against LPS-challenged monocytes. These findings show the anti-inflammatory properties of these crude leaf extracts and offer new perspectives for their use in the treatment of inflammatory diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Monócitos/efeitos dos fármacos , Peperomia/química , Piper/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Acetatos , Anti-Inflamatórios/isolamento & purificação , Brasil , Células Cultivadas , Clorofórmio , Citocinas/metabolismo , Avaliação Pré-Clínica de Medicamentos , Etanol , Hexanos , Humanos , Concentração Inibidora 50 , Cetoprofeno/farmacologia , Lipopolissacarídeos/farmacologia , Monócitos/imunologia , Monócitos/metabolismo , Extratos Vegetais/isolamento & purificação , Especificidade da Espécie
17.
Bioconjug Chem ; 29(6): 1932-1941, 2018 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-29787238

RESUMO

The controlled release of small molecular modulators of the immune response from hydrogel microspheres (MS) used for cell immobilization is an attractive approach to reduce pericapsular fibrotic overgrowth (PFO) after transplantation. Ketoprofen is a well-known nonsteroidal anti-inflammatory drug involved in the early stage inflammation cascade. PEGylated derivatives of ketoprofen, presenting either ester or amide linkage to the drug, were synthesized and conjugated to the hydroxyl groups of sodium alginate (Na-alg). Functionalized cell-free and MIN6 cells containing MS were produced from the resulting modified alginates. In vitro quantification of ketoprofen release indicated regular and sustained drug delivery over 14 days, resulting from the hydrolytic cleavage of the ester bond. The release kinetics was enhanced over the initial 7 days by the presence of MIN6 cells, probably as a result of cell esterase activity. In the presence of amide bond, traces of ketoprofen were released over 14 days due to a much slower hydrolysis kinetics. Cell-free and MIN6 cells containing MS were transplanted in immune-competent mice, either in the peritoneal cavity or under the kidney capsule, with a follow-up period of 30 days. Comparison with nonmodified Ca-alg MS transplanted in the same conditions demonstrated a clear reduction in the severity of PFO for MS functionalized with ketoprofen. Quantification of collagen deposition on MIN6 cells containing MS transplanted under the kidney capsule revealed the significant effect of ketoprofen release to decrease fibrotic tissue formation. The impact was more pronounced when the drug was covalently conjugated by an ester linkage, allowing higher concentration of the anti-inflammatory compound to be delivered at the transplantation site. The functionality of microencapsulated MIN6 cells 30 days after transplantation was confirmed by detection of insulin positive cell content.


Assuntos
Alginatos/química , Anti-Inflamatórios não Esteroides/administração & dosagem , Células Secretoras de Insulina/transplante , Cetoprofeno/administração & dosagem , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/farmacologia , Cápsulas , Linhagem Celular , Células Imobilizadas/citologia , Células Imobilizadas/transplante , Colágeno/análise , Preparações de Ação Retardada/química , Composição de Medicamentos , Fibrose , Células Secretoras de Insulina/citologia , Cetoprofeno/farmacocinética , Cetoprofeno/farmacologia , Rim/efeitos dos fármacos , Rim/patologia , Camundongos Endogâmicos C57BL
18.
Mol Pharm ; 15(3): 1284-1295, 2018 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-29433307

RESUMO

Interindividual variability in warfarin dose requirement demands personalized medicine approaches to balance its therapeutic benefits (anticoagulation) and bleeding risk. Cytochrome P450 2C9 ( CYP2C9) genotype-guided warfarin dosing is recommended in the clinic, given the more potent S-warfarin is primarily metabolized by CYP2C9. However, only about 20-30% of interpatient variability in S-warfarin clearance is associated with CYP2C9 genotype. We evaluated the role of hepatic uptake in the clearance of R- and S-warfarin. Using stably transfected HEK293 cells, both enantiomers were found to be substrates of organic anion transporter (OAT)2 with a Michaelis-Menten constant ( Km) of ∼7-12 µM but did not show substrate affinity for other major hepatic uptake transporters. Uptake of both enantiomers by primary human hepatocytes was saturable ( Km ≈ 7-10 µM) and inhibitable by OAT2 inhibitors (e.g., ketoprofen) but not by OATP1B1/1B3 inhibitors (e.g., cyclosporine). To further evaluate the potential role of hepatic uptake in R- and S-warfarin pharmacokinetics, mechanistic modeling and simulations were conducted. A "bottom-up" PBPK model, developed assuming that OAT2-CYPs interplay, well recovered clinical pharmacokinetics, drug-drug interactions, and CYP2C9 pharmacogenomics of R- and S-warfarin. Clinical data were not available to directly verify the impact of OAT2 modulation on warfarin pharmacokinetics; however, the bottom-up PBPK model simulations suggested a proportional change in clearance of both warfarin enantiomers with inhibition of OAT2 activity. These results suggest that variable hepatic OAT2 function, in conjunction with CYP2C, may contribute to the high population variability in warfarin pharmacokinetics and possibly anticoagulation end points and thus warrant further clinical investigation.


Assuntos
Anticoagulantes/farmacocinética , Hepatócitos/metabolismo , Modelos Biológicos , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Varfarina/farmacocinética , Adulto , Ciclosporina/farmacologia , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2C9/metabolismo , Interações Medicamentosas , Feminino , Células HEK293 , Hepatócitos/efeitos dos fármacos , Humanos , Cetoprofeno/farmacologia , Fígado/citologia , Fígado/metabolismo , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos Sódio-Independentes/antagonistas & inibidores , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/antagonistas & inibidores , Estereoisomerismo
19.
Colloids Surf B Biointerfaces ; 164: 218-223, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29413599

RESUMO

In the present work novel drug delivery systems consisting in highly porous Hyaluronan foams for the administration of a non-steroidal anti-inflammatory drug (NSAID), ketoprofen, have been obtained. A sugar-derived surfactant associated with ketoprofen was prepared and incorporated into the porous hyaluronan materials. The association between a lactose derived surfactant, Lhyd12, and ketoprofen was obtained by acid-base reaction and its physicochemical properties were studied. Tensiometric and dynamic light scattering (DLS) determinations showed the formation of catanionic surfactant aggregates, Lhyd12/ketoprofen, in aqueous solution. Furthermore, the catanionic surfactants allowed greater solubilisation of ketoprofen. Hyaluronan porous materials were developed using butanediol diglycidyl ether as crosslinking agent. The profile release of Lhyd12/ketoprofen from hyaluronan based materials shows differences as a function of the aggregation state of catanionic surfactant.


Assuntos
Sistemas de Liberação de Medicamentos , Ácido Hialurônico/química , Açúcares/química , Tensoativos/química , Ânions , Cátions , Células HeLa , Humanos , Cetoprofeno/farmacologia , Nitrogênio/química , Espectrofotometria Infravermelho , Tensoativos/síntese química , Temperatura
20.
J Biomed Mater Res B Appl Biomater ; 106(7): 2636-2644, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29377599

RESUMO

Herein, we propose the fabrication of a new carrier with core/shell structure-inner core of cellulose acetate (CA) coated by a micrometric layer of chitosan (CS)-fabricated through an integrated process, which combines Electro Dynamic Atomization (EDA) and layer-by-layer (LbL) technique. We demonstrate that CA based microspheres possess a unique capability to relevantly retain the drugs-that is, Ketoprofen Lysinate (KL)-along the gastric tract, while providing a massive release along the intestine. CS shell slightly influences the morphology and water retention under different pH conditions, improving drug encapsulation without compromising drug release kinetics. In vitro studies in simulated gastric and intestine fluids (SGF, SIF) with physiological enzymes, show a moderate release of LSK during the first 2 h (ca. 20% at pH 2), followed by a sustained release during the next 6 h (ca. 80% at pH 7). The obtained results demonstrate that CA-based microspheres hold strong potential to be used as carriers for a delayed oral administration of anti-inflammatory drugs. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2636-2644, 2018.


Assuntos
Celulose/análogos & derivados , Quitosana , Cetoprofeno/análogos & derivados , Lisina/análogos & derivados , Microesferas , Administração Oral , Celulose/química , Celulose/farmacocinética , Celulose/farmacologia , Quitosana/química , Quitosana/farmacocinética , Quitosana/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Concentração de Íons de Hidrogênio , Cetoprofeno/química , Cetoprofeno/farmacocinética , Cetoprofeno/farmacologia , Lisina/química , Lisina/farmacocinética , Lisina/farmacologia
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