RESUMO
Previous in vitro work characterized the protease Q8009 isolated from the venom of the Australian brown snake Pseudonaja textilis textilis with Factor Xa-like activity and hemostatic properties. The purpose of the work described here characterizes the in vivo hemostatic properties in a rat model of parenchymatous organ injury. The key parameters of activity included reduction in time-to-hemostasis and total volume of blood loss in spleen, liver and kidney wound models in rats. The surgical protocols involved exposure of the organs via a midline abdominal laparotomy. Using a clean metal template with 6, 6.5, 9 mm holes for spleen, liver and kidney, respectively, a predetermined volume of the organ was gently extruded through the template hole and excised with a razor blade. About 50 to 75 microL of collagen matrix with the different test solutions was applied to the wounds. Blood was collected and at the end of the procedure animals were humanely sacrificed with an anesthetic overdose. Determination of blood was performed using the hematin assay using a standard curve. Blood loss per minute and total blood loss were calculated. Results from the studies demonstrated that the application of Q8009 and collagen matrix to surgical wounds significantly reduced the total amount of blood loss and the time-to-hemostasis. In the spleen wound model, Q8009 at 100, 250 and 1000 microg/ml significantly reduced (p<0.001) the total volume of blood lost relative to thrombin and reduced the time-to-hemostasis by 25-50%, as compared to 7% by thrombin. In the liver wound model, Q8009 at 250 and 1000 microg/ml significantly reduced (p<0.001) the total volume of blood lost relative to thrombin and reduced the time-to-hemostasis from 10.5 min by thrombin to 5.6 min with Q8009. In the kidney wound model, Q8009 at 250 microg/ml significantly reduced (p<0.05) the total volume of blood lost and reduced the time-to-hemostasis by 25% when compared to thrombin. The hemostasis levels were consistent with previous findings in skin wound rat models where Q8009 consistently reduced the total volume of blood lost and shortened time-to-hemostasis. Application of Q8009 plus collagen matrix significantly reduced the volume of total blood loss and time-to-hemostasis in rat surgical organ wound models induced bleeding, as compared to a commercially available hemostat device. The protein Q8009 has greater capacity to reduce blood loss and shorten time-to-hemostasis; highly desirable properties where rapid hemostasis is needed in surgical wounds in parenchymatous organs.
Assuntos
Venenos Elapídicos/enzimologia , Hemorragia/tratamento farmacológico , Hemostáticos/uso terapêutico , Rim/lesões , Fígado/lesões , Proteínas de Répteis/uso terapêutico , Serina Endopeptidases/uso terapêutico , Baço/lesões , Animais , Modelos Animais de Doenças , Hemostasia , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Dyslipoproteinemias represent a group of disorders closely related to alterations of cholesterol and triglycerides. The alterations of these lipids are considered important risk factors in coronary heart disease and indicate the need for clinically effective and safe drugs. Hypolipidemic agent therapy, however, does not appear without risk since the administration of these agents is by necessity, on a long-term basis. In the conduct of animal safety studies with some hypolipidemics, hyperplastic nodules or tumors developed in the liver of rodents. Data from the literature seem to indicate that the tumor response in rodents varies with the type of hypolipidemic drug administered. This paper summarizes the studies with the new lipid-regulating agent gemfibrozil. Aside from conventional long-term studies in rodents, the ultrastructural aspects of the liver were analyzed in several species and genotoxicity assays and short-term tests for hepatocarcinogenicity were conducted. Thus, it was possible to obtain an overview of these biological phenomena in order to allow for safety extrapolations. The biological behavior of these liver nodules showed that gemfibrozil and clofibrate-induced hepatocytes had not undergone malignant transformation. Further, the phenomenon of peroxisome proliferation, a characteristic event that follows hypolipidemic administration in rodents, was not confirmed in primate or human liver. Peroxisome proliferation has been linked to the process of hepatocarcinogenesis in rodents, although genotoxicity assays were negative and initiation/promotion tests failed to elicit tumors or nodules in a system where hepatocarcinogens manifest their activity. Thus, hypolipidemics such as gemfibrozil or clofibrate may possess low tumorigenic potential with low risk due to the lack of correlation between these tests. Nevertheless, these agents are indicated for specific lipoprotein phenotype alteration with the resulting clinical benefits.
RESUMO
The antidiabetic agent troglitazone was given to groups of 4 cynomolgus monkeys per sex at 300, 600, or 1200 mg/kg daily by gavage for 52 weeks. A group of 4 monkeys per sex received vehicle alone and served as controls. Emesis and soft stool or diarrhea occurred sporadically in all troglitazone-treated groups, but did not compromise animal health. There were no effects on body weight or food consumption, or ophthalmologic, electrocardiographic, or echocardiographic parameters. Erythrocyte count, hemoglobin, and hematocrit decreased 8% to 16% in males at all doses and serum cholesterol decreased 30% to 46% in both sexes at all doses. Urinary ketones were increased in several animals at 600 and 1200 mg/kg. Absolute and relative liver weights increased at all doses in both sexes by 40% to 71%. The only microscopic change attributable to troglitazone treatment was minimal to mild bile duct hyperplasia in males at all doses and in females at 600 and 1200 mg/kg. No differences in systemic exposure were apparent between sexes. Over the dose range tested, AUC(0-24) values were 27 to 102 micrograms.hr/ml of troglitazone, 401 to 2060 micrograms.hr/ml of its sulfate conjugate, and 34 to 312 micrograms.hr/ml of its quinone metabolite. Therefore, oral administration of troglitazone to monkeys at 300, 600, and 1200 mg/kg for 52 weeks resulted in significant systemic exposure, with only minimal gastrointestinal, hematologic, and hepatic effects.
Assuntos
Cromanos/toxicidade , Hipoglicemiantes/toxicidade , Macaca fascicularis , Tiazóis/toxicidade , Tiazolidinedionas , Administração Oral , Anemia/induzido quimicamente , Anemia/patologia , Animais , Área Sob a Curva , Ductos Biliares Intra-Hepáticos/efeitos dos fármacos , Ductos Biliares Intra-Hepáticos/patologia , Colesterol/sangue , Cromanos/administração & dosagem , Cromanos/farmacocinética , Relação Dose-Resposta a Droga , Contagem de Eritrócitos , Feminino , Hiperplasia/induzido quimicamente , Hiperplasia/patologia , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Tiazóis/administração & dosagem , Tiazóis/farmacocinética , Testes de Toxicidade , TroglitazonaRESUMO
OBJECTIVES: Analgesic synergy and improved tolerability have been reported for flexible dose morphine and oxycodone combinations. This report describes two studies with similar double-blind, randomized, 7-day crossover designs (up to 7 days per arm) conducted to 1) explore the analgesic and safety benefit offixed ratio of morphine (M) and oxycodone (0) combinations (MOX) and 2) define the optimal ratio for morphine and oxycodone combination. SETTING: Clinical study centers in Australia. PATIENTS: Patients with chronic noncancer pain. INTERVENTION: Eligible patients were randomly assigned to receive flexible doses of either M or fixed ratio of MOX (M3:02 in study A; M1:02 in study B). The starting doses of M or MOX were the morphine equivalent doses (MEDs) converted from the analgesics received before entering double-blind treatment. At each crossover period, the doses were titrated to achieve analgesia at steady state, which was defined as when the same total daily dose (+/-10 percent) had been given consecutively for 3 days. MAIN OUTCOME MEASURE: The primary endpoint was the study medication dose (MED), which produced adequate pain control at steady state. RESULTS: Analgesic synergy in MOX was observed in both studies. On an MED basis, 61.6 percent (study A, M:0 = 3:2) or 46.8 percent (study B, M:0 = 1:2) more MED were needed forM monotherapy to achieve steady-state pain control when compared with MOX. Patient tolerability profiles were also generally better in the MOX groups. CONCLUSION: A 3:2 or 1:2 fixed ratio combination of morphine and oxycodone (MOX) produced analgesic synergy and a tolerability profile improvement in patients with chronic noncancer pain.
Assuntos
Analgésicos/administração & dosagem , Analgésicos/uso terapêutico , Dor Crônica/tratamento farmacológico , Morfina/efeitos adversos , Morfina/uso terapêutico , Oxicodona/efeitos adversos , Oxicodona/uso terapêutico , Adulto , Idoso , Austrália , Estudos Cross-Over , Método Duplo-Cego , Sinergismo Farmacológico , Quimioterapia Combinada/métodos , Tolerância a Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Hemostatic properties of a factor Xa-like protease (Q8009) from the Australian snake Pseudonaja textilis textilis were determined. In tail-tip transection and dermal incision (hind limb) models, reagents were applied with collagen matrix. Blood was collected on filter paper chads for 12 one-minute intervals or until hemostasis. Determination of blood loss was performed using the hematin content and reported as blood loss per minute and total blood lost. Results from the studies demonstrated that the addition of the protease Q8009 and collagen matrix significantly reduced the volume of blood loss and shortened the time-to-hemostasis. In the dermal incision model, Q8009 (100, 250 and 1000 microg/ml) plus collagen matrix significantly reduced (p<0.001) the volume of blood lost relative to Thrombin and shortened the time-to-hemostasis to 2.0 min compared to 4.77 min with Thrombin. In the tail-tip transection model when Q8009 was mixed with a collagen matrix there was no significant reduction in blood loss, when compared to Thrombin plus collagen matrix. However, when injured tail-tips were held in Q8009 (1000 microg/ml) solution, there was a significant reduction (p<0.001) in blood loss (5.88 microl) versus that of Thrombin at 58.0 mul, and time-to-hemostasis was reduced from 11 min with Thrombin to 3 min when the Q8009 solution was used. In these studies, topical application of the venomic protease Q8009 significantly reduced total blood loss with a shorter time-to-hemostasis relative to Thrombin.
Assuntos
Venenos Elapídicos/toxicidade , Hemostasia/efeitos dos fármacos , Animais , Bovinos , Colágeno/farmacologia , Gelatina/farmacologia , Modelos Animais , Ratos , SuínosRESUMO
BACKGROUND AND AIMS: Neonatal necrotizing enterocolitis (NEC) is a common and serious acquired gastrointestinal tract condition. This clinical study assessed the potential clinical efficacy and microscopic effects of recombinant human epidermal growth factor 1-48 (EGF(1-48)) in neonates with NEC. METHODS: This prospective, double-blind, randomized controlled study included 8 neonates with NEC. The study compared the effects of a 6-day continuous intravenous infusion of EGF(1-48) at 100 ng kg(-1) h(-1) against placebo. Clinical outcomes and morphological evaluation of serial rectal mucosal biopsies were assessed at baseline and 4, 7, and 14 days after starting EGF infusions. RESULTS: There was no difference between the clinical safety outcomes recorded for EGF(1-48) or placebo patients. Quantitative morphologic differences in the rectal mucosa biopsies were noted with EGF(1-48) treatment compared with baseline or placebo and included a statistically significant increase in the number of mitoses per mucosal crypt on study day 4, significantly increased thickness of rectal mucosa from baseline on study days 4 and 7, and increased crypt surface area of rectal mucosa in parallel with increased mucosa thickness on day 14. CONCLUSION: This study of EGF(1-48) in neonates with severe NEC showed that growth factor treatment was well tolerated and produced positive and measurable remodeling trophic effects on the gastrointestinal mucosa.