PHARMACOLOGICAL REACTIVITY OF RAT VAS-DEFERENS IN CHRONIC AND SUBACUTE LEAD-INTOXICATION

The influence of subacute and chronic lead intoxication on the responsiveness of the rat vas deferens was investigated by determining pD2 and relative responsiveness ratio (p) values for noradrenaline and for acetylcholine. Thus, the pD2 values of noradrenaline and acetylcholine from vas deferens of lead-treated rats were greater than those from normal rats, indicating that lead, in the dose and periods of treatment utilized, provoked a rise in vas deferens sensibility to noradrenaline and acetylcholine. Since it is known that the cirurgical or chemical denervation of the sexual ducts also provokes hypersensitivity, it may be suggested that this would be a possible mechanism for the observed alterations. A local lead toxic effect on the smooth muscle or at the level of androgen receptors should also be considered.

Pharmacological and toxicological studies of Drimys angustifolia Miers. (Winteraceae)

Drimys angustifolia Miers. (Winteraceae) is a Brazilian medicinal plant used as analgesic, antiulcer and anti-inflammatory without studies to assure its efficacy and safety Leaf and stem bark extracts were evaluated to determine the antiulcer, analgesic, antiinflammatory and antioxidant activities. Preliminary toxic effects and qualitative phytochemical profile were also performed. The antiulcer activity was detected in both extracts. Administration of the leaf extract at 250 mg/kg inhibited total lesion area by 76.50% (p < 0.01 in ethanol/HCl method), while carbenoxolone at 250 mg/kg reduced lesions by 69.48%. Stem bark extract (250 mg/kg) inhibited lesion by 81.42%, while carbenoxolone by 74.10%. Similar effects were observed in the ethanol-induced ulcer method, but no activity was observed in piroxican model. The effects involve nitric oxide in gastric protection, since the L-NAME treatment reversed the protection given by the extracts. Antioxidant effects suggest an involvement against oxidative stress. In the pain (writhing, tail-flick and hot-plate tests) and inflammation (carrageenan-induced paw edema) models, the extracts did not present any effect. The phytochemical studies demonstrated that both extracts contain flavonoids, saponins, glycosilated triterpenoids, fixed acids, cyanogenic glycosides, quinones, tannins, xanthone and steroidal aglycones. Toxicological studies showed that the extracts are safe at the effective antiulcer doses. (c) 2006 Elsevier B.V.. All rights reserved.

Sufentanil-2-hydroxypropyl-beta-cyclodextrin inclusion complex for pain treatment: Physicochemical, cytotoxicity, and pharmacological evaluation

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Proteome analysis of snake venom toxins: pharmacological insights

Snake venoms are an extremely rich source of pharmacologically active proteins with a considerable clinical and medical potential. To date, this potential has not been fully explored, mainly because of our incomplete knowledge of the venom proteome and the pharmacological properties of its components, in particular those devoid of enzymatic activity. This review summarizes the latest achievements in the determination of snake venom proteome, based primarily on the development of new strategies and techniques. Detailed knowledge of the venom toxin composition and biological properties of the protein constituents should provide the scaffold for the design of new more effective drugs for the treatment of the hemostatic system and heart disorders, inflammation, cancer and consequences of snake bites, as well as new tools for clinical diagnostic and assays of hemostatic parameters.

Energy Expenditure and Oxygen Consumption as Novel Biomarkers of Obesity-induced Cardiac Disease in Rats

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Modulation of the Pharmacological Activities of Secretory Phospholipase A2 from Crotalus durissus cascavella Induced by Naringin

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Pharmacological antagonism of Anchietia salutaris extracts on the contraction induced by prostaglandin D2 and U46619 in guinea-pig lung parenchymal strips

Anchietia salutaris tea is traditionally used in Brazil to treat allergies, suggesting it contains compounds with antagonistic activity on the allergic mediators. We have evaluated extracts and semi-purified fractions of Anchietia salutaris as a source of compounds having this type of antagonism on the contraction induced in guinea-pig lung parenchymal strips and on platelet aggregation and shape change. After 10 min pre-incubation dichloromethane extracts containing 30 or 100 μg mL-1 inhibited the contraction induced by prostaglandin D2 (PGD2) in guinea-pig lung parenchymal strips with dose ratios (DR) of 0.76 ± 0.14 and 0.93 ± 0.19, respectively; the amount of inhibition depended both on the concentration and on the time of preincubation (DR after 30 min pre-incubation was 1.21 ± 0.51). The dichloromethane extract and its semi-purified fractions also inhibited the contractions induced by U46619, a more potent, stable, synthetic agonist of thromboxane A2 (TxA2) prostanoid (TP) receptors, the receptors acted upon by PGD2 to produce lung contractions. The dichloromethane extract did not inhibit the lung parenchymal contractions induced by histamine, leukotriene D4 (LTD4) or platelet-activating factor (PAF). Platelet aggregation induced by U46619, adenosine 5'-diphosphate (ADP) or PAF was not inhibited by the dichloromethane extract. Indeed, the extract potentiated platelet aggregation induced by low concentrations of these agonists and also potentiated the shape change induced by U46619. These results imply that the dichloromethane extract of Anchietia salutaris and its semipurified fractions contain an active principle that competitively inhibits TxA2 TP receptors, the stimulation of which causes lung parenchymal contraction. The inhibition seems to be selective for this receptor subtype, because the extract fails to inhibit platelet aggregation or shape change. This provides additional support of earlier reports suggesting the occurrence of TP receptor subtypes.

Pharmacological evidence for β2-adrenoceptor in right atria from stressed female rats

The purpose of the present study was to demonstrate a physiological response to TA2005, a potent β2-adrenoceptor (β2-AR) selective agonist, in right atria isolated from stressed female rats under the influence of the estrous cycle. We obtained concentration-response curves to the agonist in the presence and in the absence of selective antagonists in right atria isolated from female rats submitted to three daily foot-shock sessions (30 min duration, 120 pulses of 1.0 mA, 1.0 s, applied at random intervals of 5- 25 s) and sacrificed at estrus or diestrus. Our results showed that the pD2 values of TA2005 were not influenced by estrous cycle phase or foot-shock stress. However, in right atria from stressed rats sacrificed during diestins, the concentration-response curve to TA2005 was biphasic, with a response being obtained at concentrations of 0.1 nM, whereas during estrus no response was observed at doses lower than 3 nM. ICI118,551, a β2-AR antagonist, abolished the response to nanomolar concentrations of TA2005 in right atria from stressed rats at diestrus, with no changes in agonist pD2 values in right atria from control rats (7.47 ± 0.09, p > 0.05) but a 3-fold decrease in pD2 values of TA2005 in right atria from foot shock stressed rats (7.90 ± 0.07, p ≤ 0.05). Concentration-response curves to TA2005 in the presence of ICI118,551 were best fitted by a one-site model equation. The β1-AR antagonist, CGP20712A, shifted to the right only the second part of the concentration-response curves to the agonist, unmasking the putative β2-AR-mediated response to the agonist in tissues isolated from stressed rats at diestrus. Under this condition, concentration-response curves to the agonist were best fitted by a two-site model equation, pD2 and maximum response of TA2005 interaction with β1- and putative β2-adrenoceptor components were calculated. Schild analyses gave a pK(B) value for CGP20712A that was typical for the interaction with β1-AR in each experimental group, pK(B) values for ICI118,551 could not be obtained in stressed rats sacrificed at diestins since Schild plot slopes were lower than 1.0. In right atria from control rats, ICI118,551 pK(B) values were similar to reported values for the interaction of the antagonist with β1-AR. These results confirm that a heterogenous β1-AR population mediating the chronotropic response to catecholamines can be demonstrated in right atria from foot shock stressed female rats sacrificed at diestins. The stress-induced response seems to be mediated by the β2-AR subtype. Right atria from rats sacrificed during estrus are protected against stress-induced alterations on the homogeneity of β-AR population.

Evaluation of a protein deficient diet in rats through blood oxidative stress biomarkers

Protein malnutrition leads to functional impairment in several organs, which is not fully restored with nutritional recovery. Little is known about the role of oxidative stress in the genesis of these alterations. This study was designed to assess the sensitivity of blood oxidative stress biomarkers to a dietary protein restriction. Male Wistar rats were divided into two groups, according to the diet fed from weaning (21 days) to 60 day old: normal protein (17% protein) and low protein (6% protein). Serum protein, albumin, free fatty acid and liver glycogen and lipids were evaluated to assess the nutritional status. Blood glutathione reductase (GR) and catalase (CAT) activities, plasma total sulfhydryl groups concentration (TSG) as well as plasma thiobarbituric acid reactive substances (TBARs) and reactive carbonyl derivatives (RCD) were measured as biomarkers of the antioxidant system and oxidative damage, respectively. The glucose metabolism in soleus muscle was also evaluated as an index of stress severity imposed to muscular mass by protein malnutrition. No difference was observed in muscle glucose metabolism or plasma RCD concentration between both groups. However, our results showed that the low protein group had higher plasma TBARs (62%) concentration and lower TSG (44%) concentration than control group, indicating increased reactive oxygen species production in low protein group. The enhancement of erythrocyte GR (29%) and CAT (28%) activities in this group also suggest an adaptation to the stress generated by the protein deficiency. Taken together, the results presented here show that the biomarkers used were able to reflect the oxidative stress level induced by this specific protein deficient diet.

The frequency of pharmacological pain relief in university neonatal intensive care units

Objective: To evaluate the use of drugs to relieve the pain of invasive procedures newborn infants cared for at a university hospital NICU. Methods: A prospective cohort study of all newborn infants hospitalized in four NICU during October 2001. The following data were collected: demographic data of the hospitalized newborn infants; clinical morbidity; number of potentially painful procedures and frequency of analgesic administration. Factors associated with the use of analgesia in this cohort of patients were studied by multiple linear regression using SPSS 8.0. Results: Ninety-one newborn infants were admitted to the NICU during the study period (1,025 patient-days). Only 25% of the 1,025 patient-days received systemic analgesia. No specific drugs were administered to relieve acute pain during any of the following painful events: arterial punctures, venous, capillary and lumbar punctures or intubations. For chest tube insertion, 100% of newborn infants received specific analgesia. For the insertion of central catheters 8% of the newborn infants received painkillers. Only nine of the 17 newborn infants that underwent surgical procedures received any analgesic dosage during the postoperative period. For 93% of patients under analgesia the drug of choice was fentanyl. The presence of mechanical ventilation increased the chance of newborn infants receiving painkillers by 6.9 times and the presence of chest tube increased this chance by five times. Conclusion: It is necessary to train health professionals in order to bridge the gap between scientific knowledge regarding newborn infant pain and clinical practice. Copyright © 2005 by Sociedade Brasileira de Pediatria.

Different stress biomarkers sensitivity during acute treadmill running exercise in rats

The level of stress during acute or chronic exercise is important since higher levels of stress may impair homeostasis. The adrenal gland is an essential stress-responsive organ involved in the hypothalamic-pituitary-adrenal axis. The aim of the study was to analyze the sensitivity of different stress biomarkers of the adrenal gland during acute treadmill running at different intensities. Adult rats performed three 25 min running tests at velocities of 15, 20 and 25 m/min, for determination of maximum lactate steady state (MLSS). After obtaining individual MLSS animals were assigned to two groups: M, sacrificed after 25 minutes of exercise at MLSS, and AM, sacrificed after exercise at 25% above MLSS. For comparison, a control group C was sacrificed at rest. Blood corticosterone concentrations, as well, adrenal gland cholesterol and ascorbic acid concentrations were used as biomarkers. Serum corticosterone concentrations were higher after exercise in both M (1802,74±700,42) and AM (2027,96±724,94) groups when compared C group (467,11±262,12), but were not different as a function of exercise intensity. No difference in adrenal ascorbic acid (M=2,37±0,66; AM=2,11±0,50 and C=2,54±0,53) and cholesterol (M=1,04±0,12; AM=0,91±0,31 and C=1,15±0,40) levels were observed when the three groups were compared. Serum corticosterone concentrations showed to be sensitive to acute treadmill exercise intensity. On the other hand, ascorbic acid and cholesterol concentrations in adrenal were biomarkers not adequate to evaluate exercise stress in rats.