Efeito do flunixin meglumine na duração da fase luteal e na taxa de prenhez de receptoras de embriões bovinos

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Inibição e reversão da agregação plaquetária de eqüinos in vitro com o uso de ketoprofeno, fenilbutazona e flunixim meglumine

Como são várias as enfermidades e os distúrbios que induzem à hipercoagulabilidade e à pré-ativação de plaquetas em eqüinos. A atividade de medicamentos utilizados para controle dessas enfermidades sobre a agregação de plaquetas pode, não apenas servir para avaliar sua evolução, como também a resposta terapêutica. Com o objetivo de avaliar a prevenção e a reversão da agregação plaquetária de eqüinos in vitro foram utilizados os antiinflamatórios não esteroidais (AINES): ketoprofeno, fenilbutazona e flunixim meglumine. A comparação demonstrou que a fenilbutazona e o ketoprofeno previnem a agregação de plaquetas de eqüinos induzida pelo ADP, de forma mais eficaz do que o flunixim-meglumine e, superior ao fragmento monoclonal de anticorpo Reopro, sendo semelhante a dos bloqueadores de receptores de membrana Ro-438857 e RGDS. Quanto a reverão da agregação plaquetária tanto a fenilbutazona quanto o ketoprofeno demonstraram efeitos dose-dependente.

Characterization, inclusion mode, phase-solubility and in vitro release studies of inclusion binary complexes with cyclodextrins and meglumine using sulfamerazine as model drug

In order to investigate the effect on the aqueous solubility and release rate of sulfamerazine (SMR) as model drug, inclusion complexes with beta-cyclodextrin (beta CD), methyl-beta-cyclodextrin (M beta CD) and hydroxypropyl-beta-cyclodextrin (HP beta CD) and a binary system with meglumine (MEG) were developed. The formation of 1: 1 inclusion complexes of SMR with the CDs and a SMR: MEG binary system in solution and in solid state was revealed by phase solubility studies (PSS), nuclear magnetic resonance (NMR), Fourier-transform infrared spectroscopy (FT-IR), thermal analysis and X-Ray diffractometry (XRD) studies. The CDs solubilization of SMR could be improved by ionization of the drug molecule through pH adjustments. The higher apparent stability constants of SMR:CDs complexes were obtained in pH 2.00, demonstrating that CDs present more affinity for the unionized drug. The best approach for SMR solubility enhancement results from the combination of MEG and pH adjustment, with a 34-fold increment and a S-max of 54.8 mg/ml. The permeability of the drug was reduced due to the presence of beta CD, M beta CD, HP beta CD and MEG when used as solubilizers. The study then suggests interesting applications of CD or MEG complexes for modulating the release rate of SMR through semipermeable membranes.

Effects of flunixin meglumine administration on physiological and performance responses of transported feeder cattle

The objective was to evaluate the effects of flunixin meglumine administration on physiological and performance responses of transported cattle during feedlot receiving. Forty-five Angus x Hereford steers were ranked by BW on d 0 and assigned to 1 of 3 treatments:1) transport for 1,280 km in a commercial livestock trailer and administration of flunixin meglumine (1.1 mg/kg BW; intravenous) at loading (d 0) and unloading (d 1; FM), 2) transport for 1,280 km in a commercial livestock trailer and administration of 0.9% saline (0.022 mL/kg BW; intravenous) at loading (d 0) and unloading (d 1; TRANS), or 3) no transport and administration of 0.9% saline (0.022 mL/kg BW; intravenous) concurrently with loading (d 0) and unloading (d 1) of FM and TRANS cohorts (CON). Upon arrival and processing for treatment administration on d 1, steers within each treatment were ranked by BW and assigned to 15 feedlot pens (5 pens/treatment, 3 steers/pen). Full BW was recorded before (d -1 and 0) treatment application and at the end of experiment (d 28 and 29) for ADG calculation. Total DMI was evaluated daily from d 1 to 28. Blood samples were collected on d 0 (before treatment administration), 1 (after unloading but before treatment administration), 4, 7, 10, 14, 21, and 28. Body weight shrink from d 0 to 1 was less (P < 0.01) in CON vs. FM and TRANS but similar (P = 0.94) between TRANS and FM. Mean ADG was greater (P <= 0.04) in CON vs. FM and TRANS but similar (P = 0.69) between TRANS and FM. No treatment effects were detected on DMI, but CON had greater G:F vs. TRANS (P = 0.08) and FM (P = 0.02), whereas G:F was similar (P = 0.68) between TRANS and FM. Mean plasma cortisol concentrations tended (P <= 0.09) to be greater in TRANS vs. FM and CON but was similar (P = 0.87) between CON and FM. Plasma NEFA concentrations were greater (P <= 0.02) for TRANS and FM vs. CON on d 1 and greater (P <= 0.04) for FM vs. TRANS and CON on d 4. Plasma ceruloplasmin concentrations were greater (P <= 0.03) for TRANS vs. CON on d 1, 4, and 7, greater (P <= 0.05) for TRANS vs. FM on d 4 and 7, and greater (P <= 0.04) for FM vs. CON on d 1 and 4. Plasma haptoglobin concentrations were greater (P < 0.01) for TRANS vs. CON and FM on d 1 and 4 and greater (P <= 0.05) for FM vs. CON on d 1 and 4. In conclusion, flunixin meglumine reduced the cortisol and acute-phase protein responses elicited by road transport but did not improve receiving performance of feeder cattle.

Solubility and release modulation effect of sulfamerazine ternary complexes with cyclodextrins and meglumine

This study investigated the effect on solubility and release of ternary complexes of sulfamerazine (SMR) with beta-(beta CD), methyl-(M beta CD) and hydroxypropyl-P-cyclodextrin (HP beta CD) using meglumine (MEG) as the ternary component. The combination of MEG with M beta CD resulted the best approach, with an increased effect (29-fold) of the aqueous solubility of SMR. The mode of inclusion was supported by 2D NMR, which indicated that real ternary complexes were formed between SMR, MEG and M beta CD or HP beta CD. Solid state analysis was performed using Fourier-transform infrared spectroscopy (FT IR), differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD), which demonstrated that different interactions occurred among SMR, MEG and M beta CD or HP beta CD in the ternary lyophilized systems. The ternary complexes with beta CD and M beta CD produced an additional retention effect on the release of SMR compared to the corresponding binary complexes, implying that they were clearly superior in terms of solubility and release modulation. (C) 2014 Elsevier B.V. All rights reserved.

Lethal effect of high concentrations of Parecoxib and Flunixin meglumine on the in vitro culture of bovine embryos

Since cyclooxygenase (COX) inhibitors have been pointed out as potential treatments to increase pregnancy rates after embryo transfer, the present experiment aimed to evaluate the effects of flunixin meglumine (FM) and parecoxib (P), a COX-1 and 2 or COX-2 specific inhibitor, respectively, on the development of bovine embryos until the hatched blastocyst stage. In vitro produced bovine embryos were cultured in media with different concentrations of FM (0.14; 1.4; 14; 140 or 1400 mu g/ml) or P (0.09; 0.9; 9; 90 or 900 mu g/ml) and the production rates were evaluated. Concentrations of FM <= 14 mu g/ml and P <= 90 mu g/ml did not impair embryo development, although compiled data from non-lethal FM concentrations (<= 14 mu g/ml) indicated a toxic effect enough to decrease the hatching rate of blastocysts. Concentrations of FM at 140 and 1400 mu g/ml and P at 900 mu g/ml were lethal as no cleavage was detected on presumptive zygotes.

Hydration and N-acetylcysteine in acute renal failure caused by iodinated contrast medium: an experiment with rats

Background: The involvement of nephrotoxic agents in acute renal failure (ARF) has increased over the last few decades. Among the drugs associated with nephrotoxic ARF are the radiologic contrast media whose nephrotoxic effects have grown, following the increasing diagnostic use of these agents. Methods: We evaluated the effect of iodinated contrast (IC) medium, administered in combination, or not, with hyperhydration or N-acetylcysteine (NAC), on creatinine clearance, production of urinary peroxides and renal histology of rats. Adult Wistar rats treated for 5 days were divided into the following groups: control (saline, 3 ml/kg/day, intraperitoneally [i.p.]), IC (sodium iothalamate meglumine, 3 ml/kg/day i.p.), IC + water (12 mL water, orally + IC, 3 ml/kg/day i.p. after 1 hour), IC + NAC (NAC, 150 mg/kg/day, orally + IC, 3 ml/kg/day i.p. after 1 hour) and IC + water + NAC. Results: IC medium reduced renal function, with maintenance of urinary flow. Hyperhydration did not reduce the nephrotoxic effect of the IC agent, which was observed in the group IC + NAC. The combination of hyperhydration and NAC had no superior protective effect compared with NAC alone. An increase in urinary peroxides was observed in the IC group, with NAC or water or the combination of both reducing this parameter. Histopathologic analysis revealed no significant alterations. Conclusions: In summary, given 5 days previously, NAC was found to be more effective than hyperhydration alone in the prevention of contrast-induced acute renal failure.

Mechanisms of Action of Eicosapentaenoic Acid in Bladder Cancer Cells In Vitro: Alterations in Mitochondrial Metabolism, Reactive Oxygen Species Generation and Apoptosis Induction

Purpose: Eicosapentaenoic acid has been tested in bladder cancer as a synergistic cytotoxic agent in the form of meglumine-eicosapentaenoic acid, although its mechanism of action is poorly understood in this cancer. The current study analyzed the mechanisms by which eicosapentaenoic acid alters T24/83 human bladder cancer metabolism in vitro. Materials and Methods: T24/83 human bladder cancer cells were exposed to eicosapentaenoic acid for 6 to 24 hours in vitro and incorporation profiles were determined. Effects on membrane phospholipid incorporation, energy metabolism, mitochondrial activity, cell proliferation and apoptosis were analyzed Reactive oxygen species and lipid peroxide production were also determined. Results: Eicosapentaenoic acid was readily incorporated into membrane phospholipids with a considerable amount present in mitochondrial cardiolipin. Energy metabolism was significantly altered by eicosapentaenoic acid, accompanied by decreased mitochondrial membrane potential, and increased lipid peroxide and reactive oxygen species generation. Subsequently caspase-3 activation and apoptosis were detected in eicosapentaenoic acid exposed cells, leading to decreased cell numbers. Conclusions: These findings confirm that eicosapentaenoic acid is a potent cytotoxic agent in bladder cancer cells and provide important insight into the mechanisms by which eicosapentaenoic acid causes these changes. The changes in membrane composition that can occur with eicosapentaenoic acid likely contribute to the enhanced drug cytotoxicity reported previously in meglumine-eicosapentaenoic acid/epirubicin/mitomycin studies. Dietary manipulation of the cardiolipin fatty acid composition may provide an additional method for stimulating cell death in bladder cancer. In vivo studies using intravesical and dietary manipulation of fatty acid metabolism in bladder cancer merit further attention.

Função renal em pacientes com leishmaniose muco-cutânea tratados com antimoniais pentavalentes

Avaliou-se a função renal em 10 pacientes com leishmaniose muco-cutânea tratados com glucantime (antimoniato de Meglumine, Rhodia) ou Pentostam (estibogluconato de sólio, Wellcome). Durante o uso das drogas, verificou-se a existência de um defeito na capacidade concentrante do rim, obtendo-se menores valores da osmolaridade urinária máxima e de depuração negativa máxima de água livre, neste período, em relação aos testes efetuados antes do tratamento. A capacidade de concentração urinária normalizou-se em 5, de 8 pacientes estudados no período de 15 a 30 dias, após a suspensão dos medicamentos, embora com valores de osmolaridade urinária máxima inferiores aos obtidos antes do tratamento. Em dois pacientes surgiu proteínúria, acima de 150 mg/dia, com o uso dos antimoniais, normalizando-se posteriormente. A depuração de creatinina endógena não se alterou significativamente com o uso das drogas. Os resultados sugerem que os antimoniais pentavalentes podem levar a uma disfunção tubular renal, caracterizada por um defeito na capacidade de concentrar a urina, reversível após a retirada dos medicamentos.

Failure of both azithromycin and antimony to treat cutaneous leishmaniasis in Manaus, AM, Brazil

A non-randomized controlled clinical trial was carried outin order to evaluate both azithromycin and antimony efficacy in cutaneous leishmaniasis in Manaus, AM, Brazil. Forty nine patients from both genders, aged 14 to 70, with cutaneous ulcers for less than three months and a positive imprint for Leishmania spp. amastigotes were recruited into two groups. Group I (26 patients) received a daily-single oral dose of 500 mg of azithromycin for 20 days and Group II (23 patients) received a daily-single intramuscular dose of 20 mg/kg of meglumine antimony, also for 20 days. Azithromycin cured three of 24 (12.5%) patients on days 60, 90 and 120 respectively whereas therapeutic failure was considered in 21 of 24 (87.5%) cases. In group II, antimony cured eight of 19 (42.1%) cases as follows: three on day 30, one each on day 60 and day 90, and three on day 120. Therapeutic failure occurred in 11 of 19 (57.9%) individuals. The efficacy of antimony for leishmaniasis was better than azithromycin but analysis for the intention-to-treat response rate did not show statistical difference between them. Although azithromycin was better tolerated, it showed a very low efficacy to treat cutaneous leishmaniasis in Manaus.

AMERICAN CUTANEOUS LEISHMANIASIS WITH UNUSUAL CLINICAL PRESENTATION AND RESPONSE TO TREATMENT

The clinical manifestations and prognosis of cutaneous leishmaniasis (CL) can be influenced by the immune response of the patient and the species of the parasite. A case of atypical clinical presentation of CL, with development of non-characteristic lesions, poor response to therapy, and a long time to resolution is reported. Confirmatory laboratory tests included parasite detection, indirect immunofluorescence, Montenegro skin test, polymerase chain reaction, and parasite identification by multilocus enzyme electrophoresis. The parasite was identified as Leishmaniabraziliensis. The lesion was unresponsive to three complete courses of N-methylglucamine antimoniate intramuscular, and to treatment with pentamidine. The patient did not tolerate amphotericin B. The lesion finally receded after treatment with intravenous N-methylglucamine antimoniate. It is essential to ensure the accuracy of diagnosis and the appropriate treatment, which can include the use a second choice drug or a different route of administration.

AA-amyloidosis caused by visceral leishmaniasis in a human immunodeficiency virus-infected patient.

AA-amyloidosis in the setting of chronic visceral leishmaniasis (VL) has been reported in animal models but documentation in humans is unavailable. Here, we report on a Portuguese man who in 1996 was diagnosed with both human immunodeficiency virus (HIV)-infection and VL. Antiretroviral treatment led to sustained suppression of HIV viremia but CD4+ lymphocytes rose from 8 to only 160 cells/mL. Several courses of antimony treatment did not prevent VL relapses. Renal failure developed in 2006 and renal biopsy revealed AA-amyloidosis. The patient had cryoglobulinemia and serum immune complexes containing antibodies directed against seven leishmanial antigens. Antimony plus amphotericin B, followed by oral miltefosine resulted in a sustained VL treatment response with elimination of circulating Leishmania infantum DNA and CD4+ recovery. The concomitant reduction of serum AA levels and disappearance of circulating leishmanial immune complexes suggests that prolonged VL may lead to AA-amyloidosis in immunocompromised humans.

Profile order and time-dependent artifacts in contrast-enhanced coronary MR angiography at 3T: origin and prevention.

To enhance the clinical value of coronary magnetic resonance angiography (MRA), high-relaxivity contrast agents have recently been used at 3T. Here we examine a uniform bilateral shadowing artifact observed along the coronary arteries in MRA images collected using such a contrast agent. Simulations were performed to characterize this artifact, including its origin, to determine how best to mitigate this effect, and to optimize a data acquisition/injection scheme. An intraluminal contrast agent concentration model was used to simulate various acquisition strategies with two profile orders for a slow-infusion of a high-relaxivity contrast agent. Filtering effects from temporally variable weighting in k-space are prominent when a centric, radial (CR) profile order is applied during contrast infusion, resulting in decreased signal enhancement and underestimation of vessel width, while both pre- and postinfusion steady-state acquisitions result in overestimation of the vessel width. Acquisition during the brief postinfusion steady-state produces the greatest signal enhancement and minimizes k-space filtering artifacts.

Concentrações plasmáticas de triptamina, tiramina e feniletilamina em eqüinos sob efeitos de sobrecarga de carboidratos e antiinflamatórios não esteroidais

As concentrações plasmáticas das aminas triptamina (TRP), tyramina (TYR) e pheniletilamina (PEA) foram determinadas por cromatografia gasosa (CG) de 20 eqüinos sob efeito de sobrecarga por carboidratos (SC). Após 36h da SC os animais foram aleatoriamente divididos em quatro grupos (n=5) e receberam a cada 12h por via iv: solução salina 10mL (GC), ketoprofeno 2,2mg/kg (GK), fenilbutazona 4,4mg/kg (GF) e flunixin meglumine 1,1mg/kg (GFM). As concentrações das aminas TYR e PEA variaram de 0,18 a 164,2mg/L, com diferenças nos tempos avaliados, mas não entre os tratamentos (p<0,01). A concentração plasmática de TRP apresentou diferenças entre os tempos e também entre os tratamentos. O GC diferiu dos demais nos momentos 48h e 60h e as concentrações nos grupos GK e GFM foram menores que nos grupos GF e GC às 72h (P= 0,0012). Conclui-se que nas doses utilizadas os antiinflamatórios não esteroidais avaliados não interferem nas concentrações de TYR e PEA. Entretanto, o ketoprofeno e o flunixin meglumine foram efetivos em diminuir a concentração plasmática de TRP.

Correlação entre os métodos de concepção, ocorrência e formas de tratamento das onfalopatias em bovinos: estudo retrospectivo

Alguns problemas têm sido observados nos bezerros produtos da técnica fertilização in vitro, dentre esses a elevada casuística de onfalopatias. A partir dessa observação, objetivou-se com este trabalho realizar um estudo retrospectivo da correlação entre os métodos de concepção e a ocorrência de onfalopatias em bovinos e descrever os resultados obtidos a partir dos tratamentos conservativo e cirúrgico. Foram utilizados 44 bovinos atendidos no Hospital Veterinário da Unesp, Campus de Araçatuba, com idade variando de um dia a 12 meses entre os anos de 2003 e 2007. Desses bovinos 27 eram provenientes de fertilização in vitro (FIV), 12 de inseminação artificial (IA), dois de monta natural (MN) e três de transferência de embriões (TE). O diagnóstico clínico-cirúrgico revelou que todos apresentavam afecções umbilicais, sendo 22 casos de persistência de úraco, oito de onfaloflebite, oito de hérnias umbilicais, cinco de onfalites e um de fibrose umbilical. Inicialmente e no pós-operatório administrou-se em todos os animais, uma vez ao dia, durante dez dias, 3mg/kg de ceftiofur sódico pela via intravenosa (IV). Nos casos de infecção grave ou irresponsiva a terapia antimicrobiana inicial, acrescentou-se 6,6mg/kg, durante sete dias de sulfato de gentamicina IV. A antissepsia do umbigo, com tintura de iodo a 2%, foi instituída duas vezes ao dia, nos casos tratados conservativamente, enquanto que os bovinos submetidos à cirurgia receberam 1,1mg/kg de flunixin meglumine IV, uma vez ao dia, por cinco dias consecutivos. Dos 22 animais diagnosticados com persistência de úraco, 10 apresentavam drenagem de urina pelo umbigo e receberam 2mL de tintura de iodo 10% no interior do úraco, sendo 15 tratados com a excisão cirúrgica, especialmente, devido à formação de divertículo vésico-uracal. Todos os animais que apresentavam onfaloflebite e hérnia umbilical foram submetidos à cirurgia. Já dos cinco casos de onfalite, três foram tratados conservativamente. A análise dos diferentes métodos de concepção, correlacionados à ocorrência de onfalopatias, sugere que os animais provenientes de FIV, apresentam maior frequência de persistência de úraco (66,7%), e aqueles concebidos por IA, maior frequência de hérnia umbilical (58,4%), O tratamento cirúrgico foi mais eficiente que a terapia conservativa. Essa última apresentou melhores resultados nos casos descomplicados e precocemente diagnosticados.