Proceedings of the Western Pharmacology Society最新文献

Neonatal administration of monosodium glutamate (MSG) to mice causes neurotoxicity of the CNS resulting in endocrine, metabolic and behavioral abnormalities. Aminooxyacetic acid (AOAA) is a potent inhibitor of GABA-transaminase and increases GABA levels in the brain. In this work, we studied the effect of neonatal treatment of CFW mice with MSG (2 mg/g sc on the 2nd and 4th days after birth followed by 4 mg/g on days 6, 8 and 10) on AOAA- (100 to 250 mg/kg ip) induced hypothermia, hypnosis and lethality after six months of treatment. The control group was vehicle-treated only. MSG treatment significantly increased susceptibility to the hypothermic, hypnotic and lethal effect of AOAA acutely administered. The increased susceptibility to the depressor effects of AOAA may occur as a consequence of changes in neural excitability, up regulation of GABA-receptors or might be related to pharmacokinetic modifications induced by neonatal treatment with MSG.

The renal renin angiotensin system modulates blood pressure via the action of angiotensin II at type 1 (AT1) and type 2 (AT2) angiotensin receptors. It has been proposed that there is an increased pressor response to angiotensin II (ANG II) in the hypertensive rat kidney. We determined the role of the AT1 receptor in L-NAME-induced hypertension. Male Wistar rats (250-300 g) were divided into control (tap water) and L-NAME (50 mg/kg/day/2 weeks) treated groups. Concentration-response curves to ANG II were constructed in isolated perfused kidneys and AT1 receptor expression was determined by Western blot in the renal cortex, medulla and papilla. ANG II evoked an increase in perfusion pressure in kidneys of both control and L-NAME-treated rats in a concentration-related manner. In L-NAME-treated rats, a greater maximal effect was observed compared to control rats (160 +/- 13 vs. 138 +/- 8 mmHg; p<0.05, respectively), suggesting that L-NAME promoted ANG II hypersensitivity. In both, control and L-NAME groups, the response to ANG II was blocked by the selective AT1 receptor antagonist losartan (1 x 10(-8) and 3.16 x 10(-8) M). AT1 receptor expression in kidney cortex, medulla and papilla did not show significant differences between groups. Our results demonstrate that AT1 receptor stimulation is related to renal vasculature hypersensitivity in L-NAME-induced hypertension.

Heparin is the most commonly used anticoagulant drug for prevention and treatment of thromboembolic diseases. Heparin-induced thrombocytopenia (HIT) is a well-known and potentially fatal side-effect of heparin therapy. HIT type 1 (HIT-1) is transient and relatively common; it usually develops within 1-7 days of initial heparin exposure. Type 2 HIT (HIT-2) is more severe and is associated with thrombocytopenia and thrombosis. HIT-2 usually develops 5 or more days after initial heparin exposure. It is an immune-mediated disorder that is presumably caused by development of platelet activating antibody against platelet factor 4 (PF4)/heparin complex. Fondaparinux (Arixtra) is a fast-acting selective inhibitor of factor Xa believed to be non-reactive to HIT sera and therefore may be used as prophylaxis for thrombosis in patients with a history of HIT-1 or HIT-2. Development of HIT-2 in patients currently taking fondaparinux prophylaxis is rare. Here we present a fatal case of delayed-onset HIT-2 (1 year after heparin exposure) manifesting while on fondaparinux prophylaxis.

Uterine leiomyosarcoma (ULMS) is an uncommon malignant tumor that accounts for less than one-third of uterine sarcomas and approximately 1% of uterine malignancies. Cases of local and distant ULMS metastasis have been widely reported, especially to the lungs. There have been very few cases, however, of ULMS metastasis to the upper gastrointestinal (GI) tract published in the peer-reviewed literature. Here we describe a case of biopsy-proven ULMS metastasis to the first part of the duodenum, representing the third reported case of its kind. Theories regarding presentation, treatment, clinical course, and outcome of patients with ULMS metastasis to the duodenum are presented.

Heliopsis longipes is an herbaceous plant found in Mexico. Heliopsis longipes is traditionally used for its analgesic and anesthetic properties. Plant extracts may represent a therapeutic advantage for the clinical treatment of pain. Therefore, the main objective of this study was to determine the possible antihyperalgesic effect produced by the Heliopsis longipes ethanolic extract (HLEE) in the Hargreaves model of thermal hyperalgesia in the mouse. HLEE was administrated systemically to mice and the antihyperalgesic effect was evaluated using the thermal hyperalgesia test. Oral Administration of HLEE produced a dose-dependent antihyperalgesic effect. Previously, it was reported that Heliopsis longipes extract was able to release GABA in mice temporal cortex slices. Therefore, it is likely that the antihyperalgesic effect observed in our study could result from GABA liberation and its inhibition of excessive excitation of nociceptive circuits in the thalamus and cortex evoked by tissue injury. Our results suggest that HLEE may represent a therapeutic advantage for the clinical treatment of inflammatory pain.

Ibervillea sonorae Greene, Cucurbita ficifolia Bouché, Tagetes lucida Cav and Justicia spicigera Scheltdd are Mexican native plants used in the treatment of different illnesses. The ethanolic extract of J. spicigera and T. lucida as well as aqueous extracts from I. sonorae, C. ficifolia, T. lucida and J. spicigera were investigated using sulforhodamine B assay. These extracts were assessed using two cell line: T47D (Human Breast cancer) and HeLa (Human cervix cancer). Colchicine was used as the positive control. Data are presented as the dose that inhibited 50% control growth (ED50). All of the assessed extracts were cytotoxic (ED50 < 20 microg/ml) against T47D cell line, meanwhile only the aqueous extract from T. lucida and the ethanolic extract from J. spicigera were cytotoxic to HeLa cell line. Ethanolic extract from J. spicigera presented the best cytotoxic effect. The cytotoxic activity of J. spicigera correlated with one of the popular uses, the treatment of cancer.

This work describes the sub-acute treatment of male Wistar rats with estradiol (E2) and the 17beta-aminoestrogen pentolame (AEP) on the hemostatic screening tests: blood clotting time (BCT), prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT) and fibrinogen concentrations (FIB). Animals received five consecutive subcutaneous (s.c.) doses of E2 (1 and 10 mg/kg) and AEP (5, 10 and 20 mg/kg) and the course of blood clotting times (BTC) was followed 24, 48, 72 and 96 hr after finishing treatment. Five injections of equivalent doses (0.1, 1, 10, 100 or 1000 microg/kg) of both steroids were performed. In all experiments a control group (propylenglycol 1 ml/kg) was included. Individual blood samples were obtained (under anesthesia) from the iliac artery and PT, aPTT, TT, and FIB were determined according to previous reported techniques. Forty-eight hr after treatment, E2 decreased BCT (10%) while AEP increased BCT 87% in a dose dependent manner. Only E2 significantly decreased FIB concentration (p<0.5; 25%) while AEP induced a dose dependent increase in FIB from 18 to 88%, (p < 0.05). AEP produced biphasic responses on aPTT (+24 % and -15%; p<0.05) and decreased TT from 11 to 14%, (p<0.01). AEP aPTT vs. FIB showed a r2=-0.99, (p < 0.05). Pentolame showed disparate effects compared with E2 on the blood clotting parameters and exerts its most important effects on the common coagulation pathway.

In an attempt to provide more direct evidence concerning the possible antinociceptive effect of resveratrol-benfotiamine combination on neurogenic pain, we investigated whether resveratrol and benfotiamine administered alone or in combination decrease capsaicin induced nociception in mice. Before testing, the animals were placed individually in transparent glass cylinders, 20 cm in diameter, serving as observation chambers. After the adaptation period, 20 microL of capsaicin (1.6 microg/paw) were injected under the skin of the dorsal of the right hind paw. Animals were observed individually for 5 min after capsaicin injection. The amount of time spent licking the injected paw was timed with a chronometer and was considered as indicative of nociception. Animals were pretreated with resveratrol (56.2-177 mg/kg, i.p.), benfotiamine (100-1000 mg/kg, p.o.) and their combinations (11:1, 22:2, 44:4; 88:8 mg/kg benfotiamine:resveratrol). It was observed that resveratrol (ED50 = 104 +/- 8.2 mg/kg) was able to produce more important decrement of capsaicin-induced licking than benfotiamine (ED50 = 529.4 +/- 85.2 mg/kg). In addition, a synergistic interaction was observed between benfotiamine and resveratrol, suggesting that this combination could be useful in neurogenic nociception.

We have previously reported the effect of a compound derived from estradiol containing a radical amino butyl at the 17-beta position which has shown anticoagulant effects in whole blood and antiplatelet effects in light transmission aggregometry where platelets are isolated from other blood cells. In contrast, whole blood aggregometry includes the platelet interactions with blood elements such as erythrocytes and leukocytes. We examined the cooperative effect between leukocytes, erythrocytes and platelets and the antiplatelet effect of Buame in whole blood aggregometry, a tool to assess platelet function in its physiological environment. Buame (5-500 microM) dissolved in DMSO was tested in platelet aggregation induced by ADP (1.25 microM) or collagen (1 microg/mL) and the response recorded over 5 min. Controls were run with DMSO and the average control aggregation was taken as 100%. Results were obtained in both whole blood and platelet aggregometry. Buame was able to inhibit the secondary aggregation induced with ADP suggesting impairment in thromboxane A2 production. Also the first and second aggregation phases were inhibited when collagen-induced platelet activation was employed. This concentration-dependent pattern was shown in both whole blood and platelet aggregometry assays. When tested in light transmission aggregometry, a higher concentration of Buame was required in order to inhibit to the same degree ADP- or collagen-induced platelet aggregation (30 microM ,114 microM) than that required in the whole blood assay (IC50 84 microM, 191 microM). Interactions among different cell types in whole blood may modify the response of Buame-treated platelets to agonists suggesting a cooperative mechanism.

A dengue epidemic is one of the most important public health problems in the tropical and subtropical areas of the World. In 2005, 7,062 dengue cases were reported in Tamaulipas on Mexico's eastern coast, including 1,832 (26%) cases classified as Dengue Hemorrhagic Fever (DHF). Dengue fever (DF) is characterized by fever, intense headache, myalgias, arthralgias, rash, nausea and vomiting. A proportion of infected persons may develop DHF characterized by prominent hemorrhagic manifestations associated with thrombocytopenia. An immune mechanism of thrombocytopenia due to increased platelet destruction appears to be operative in patients with DHF. Excessive capillary permeability may lead to Dengue Shock Syndrome (DSS). Patients with DHF/DSS who also have prolonged fever (> 5 days) are at high risk for concurrent bacteremia. Standard treatment is limited to electrolytic solutions, rest, measurements of body temperature, blood pressure, hematocrit, platelet count, and administration of antipyretics like paracetamol when fever is too high. Extracellular calcium plays a key role in platelet aggregation and for the regulation of the immune response in personsinfected with Dengue Virus (DV), and dihydroxy-vitamin D has recently been found to alter IL-12 expression anddendritic cell maturation. We report the cases of five patients who received oral calcium carbonate plus Vitamin D3, who improved overall clinical condition and reduced the duration of signs and symptoms of DF.