Search

Dolphins are characterized by a significant behavioral versatility, which allows them to respond to environmental seasonality. Seasonal variation in dolphin behavior in tropical waters is not well known. Stenella attenuata graffmani is a resident dolphin in the clearly defined seasonal Gulf of Papagayo, Costa Rica, and we studied if dolphin group size, occurrence and behavioral patterns were associated with season and time of day in the gulf. Using strip transects we surveyed two locations for three consecutive years. School size ranged from 1 to 50 individuals, mean group size was 10.16 (SD = 9.61) individuals. Overall, foraging activities were the most frequent, followed by social interactions and travel. From 6:00 AM to 9:00 AM we mostly observed social interactions, followed by feeding-socializing (9:00 AM-12:00 PM) and feeding exclusively (12:00 PM-3:00 PM). Social activities intensified afterwards (3:00 PM-6:00 PM). Behavior and gulf seasonality were associated (chi2 = 90.52, gl = 6, p<0.05, n = 99). In the dry season (December-April) feeding predominated over other activities, but socializing was more frequent in the early rainy season (May-July). Larger groups (mean 12 dolphins) forage actively; smaller groups (mean 6 dolphins 6.51 +/- 5.12) foraged more passively. Seasonal variation in dolphin activities are likely to be associated with food availability, as observed in the high number of groups involved in foraging behaviors, and a high investment in foraging activities during the dry season.

Biological activity of Aconitum alkaloids may be related to their toxicity rather than to a specific pharmacological action. A Quantitative structure-activity relationships (QSAR) analysis was performed on the following two groups of alkaloids: compounds with an aroyl/aroyloxy group at R(14) position (yunaconitine, bulleyaconitine, aconitine, beiwutine, nagarine, 3-acetyl aconitine, and penduline), and compounds with the aroyloxy group at R(4) position (N-deacetyllappaconitine, lappaconitine, ranaconitine, N-deacetylfinaconitine, N-deacetylranaconitine). The LD(50) (micromol/kg) of the 12 alkaloids were obtained from the literature. LD(50) was significantly lower in group 1 than in group 2. The steric and core-core repulsion energies were significantly higher in group 1. The total energy and heat of formation and electronic energies were significantly lower in group 1. The reactivity index of N, C1', C4' and C6' were similar between groups. The reactivity index of C2' was significantly higher and the reactivity index of C3' and C5' were significantly lower in group 1. Log P and pKa were similar between groups. Molecular weight was significantly higher in group 1. A significant linear relationship was observed between log LD(50) and either analgesic log ED(50) or local anesthetic log ED(50). The LD(50)/analgesic ED(50) obtained from average values was 5.9 for group 1 and 5.0 for group 2. However, the LD(50)/local anesthetic ED(50) was 40.4 and 318, respectively. The study supports that the analgesic effects of these alkaloids are secondary to their toxic effects whereas alkaloids from group 2 are susceptible to be further studied as local anesthetic agents.

Alkaloids isolated from Aconitum roots exhibit anesthetic effects at peripheral nerves. We performed the present quantitative structure-activity relationship (QSAR) analysis in order to understand the mechanism of action as local anesthetics of 11 Aconitum alkaloids. The alkaloids with the highest anesthetic activity had an aroyl/aroyloxy group at R14 position while the weaker anesthetic alkaloids had the aroyloxy group at R4. The stable compounds exhibited a higher local anesthetic activity than the unstable compounds. In relation to the reactivity indexes of atoms on the aromatic ring, C2' was more reactive while C3' and C5' were less reactive in the compounds with the highest anesthetic activity. Reactivity of N, C1', C4' and C6' was similar between the two groups of alkaloids. The pKa was approximately 7.3 in both groups. The local anesthetic ED50 of alkaloids was significantly inversely related to molecular weight, core-core repulsion energy, steric energy and RI-C2', and directly related to electronic energy, total energy, RI-C5' and to the heat of formation. In conclusion, we identified a set of structural parameters that are related to the local anesthetic activity of Aconitum alkaloids. Our findings are useful to understand the mechanism of action of these alkaloids and to provide a rational for chemical manipulation of the compounds in order to obtain potent derivates with minor toxicity.

1. Drugs administered into the epidural space by caudal block are cleared by means of a process potentially affected by the lipophilic character of the compounds. 2. In the present study, we examined the relationship between the octanol-water partition coefficient (log Poct) and the time to reach the maximum plasma drug concentration (tmax) of lignocaine, bupivacaine and ropivacaine administered by caudal block in paediatric patients. We also examined the relationship between log Poct and the toxicity of these local anaesthetic agents in experimental models. The tmax and toxicity data were obtained from the literature. 3. Ropivacaine, with a log Poct of 2.9, exhibited a tmax of 61.6 min. The tmax of lignocaine, with a log Poct of 2.4, and bupivacaine, with a log Poct of with 3.4, were approximately 50% shorter than ropivacaine. At log Poct of approximately 3.0, the toxicity of these local anaesthetic agents was substantially increased. The relationship between log Poct and the convulsive effect in dogs was similar to the relationship between log Poct and the lethal dose in sheep. 4. With local anaesthetic agents, it appears that the relationship between log Poct and drug transfer from the epidural space to the blood stream is parabolic, being the slowest rate of transference at log Poct 3.0. Toxicity, due to plasma availability of these local anaesthetic agents, seems to be increased at log Poct equal or higher than 3.0 secondary to the highest transfer from plasma into the central nervous system.

The biotransformation by Flavobacterium sp. of the following organophosphate pesticides was experimentally and theoretically studied: phorate, tetrachlorvinphos, methyl-parathion, terbufos, trichloronate, ethoprophos, phosphamidon, fenitrothion, dimethoate and DEF. The Flavobacterium sp. ATCC 27551 strain bearing the organophosphate-degradation gene was used. Bacteria were incubated in the presence of each pesticide for a duration of 7 days. Parent pesticides were identified and quantified by means of a gas-chromatography mass spectrum system. Activity was considered as the amount (micromol) of each pesticide degraded by Flavobacterium sp. Also, structural parameters obtained by means of the CAChe program package for biomolecules, the reactivity index of phosphorus, of oxygen at the P = O function and of sulfur at the P = S function, and lipophilicity (log Poct) (ALOGPS v. 2.0) were obtained for each pesticide. Pesticides were hydrolyzed at the bond between phosphorous and the heteroatom, producing phosphoric acid and three metabolites. Enzymatic activity was significantly explained by the following multiple linear relationship: Enzymatic activity = 162.2 - 9.5(dihedral angle energy) - 25.0(Total energy) - 0.51(Molecular weight). Finally, a mechanism of Flavobacterium sp. to hydrolyze pesticides was proposed.

Aconitum roots are traditionally prescribed for the management of different types of painful affections in Asiatic countries. A quantitative structure-activity relationship (QSAR) analysis was performed to study the effect of chemical substitutes in the analgesic potency of alkaloids available in Chinese Aconitum roots. Using the CAChe program package for biomolecules, molecular modelling was performed in 12 alkaloids previously tested in a model of acetic acid-induced writhing in rats. The ED50 (micromol/kg) was used as the activity parameter. Structural parameters were compared between alkaloids with an aroyl/aroyloxy group at R14 and alkaloids with the aroyloxy group at R4. Single linear regression analyses were performed in order to find the parameters explaining activity. Alkaloids with an aroyl/aroyloxy group at R14 exhibited the highest potency (significantly less ED50). The stability parameters were different between groups, e.g. total energy was -8.0 +/- 0.4 in the potent analgesic alkaloids and -6.7 +/- 0.3 in the weak analgesic alkaloids (P = 0.001). The reactivity index of C2', C3' and C5' of the aromatic ring was also different between groups, e.g. the reactivity index of C5' was 40.8 +/- 0.6 in potent analgesic alkaloids and 48.1 +/- 0.6 in weaker analgesic alkaloids (P < 0.001). Several structural parameters explained analgesic activity of alkaloids, being the reactivity index of C5' on the aromatic group the most important factor (r = 0.89; P < 0.001).

The in vitro dissolution of albendazole from three different commercially available products (200 mg tablets) was studied using U.S. Pharmacopeia (USP) Apparatus 2 and USP Apparatus 4 in order to compare the release performance of the drug in two essentially different dissolution systems. For both cases, 0.1 N HCl was used as dissolution medium. Only the reference product and one of the generic products studied met the 80% USP 24 specification for albendazole dissolved at 30 min, using USP Apparatus 2. Although the reference product reached 80% of albendazole dissolved at 30 min when Apparatus 4 was used, the generic products' dissolution performance was markedly reduced in this system. Though dissolution rate was slower using Apparatus 4, the total quantity of albendazole dissolved from the reference product, represented by area under the dissolution profile, was practically the same regardless of the system used. Dissolution kinetics of albendazole was adequately described by Weibull's function for all the products. The dissolution time (t(d)) derived from data fitting to this function showed significant differences among the products studied. Data analysis based on analysis of variance (ANOVA) showed nonequivalence among the dissolution profiles of generic products compared with the reference product either with the dissolution vessel system or the flow-through cell, as well as nonequivalence among the dissolution profiles using both apparatuses with the same product. Though differences in the dissolution profiles for generic products against the reference product in both systems were found, USP Apparatus 4 showed higher discriminative capacity in differentiating the release characteristics of the products tested.

Objective: To evaluate the antioxidant effect of selenium on Na+, K(+)-ATPase in rat brain in the presence of nitric oxide., Methods: Male Wistar rats (70 g) were treated as follows: group 1 received 1 microg of i.p. sodium nitroprus-side per kg (SNP), group 2 received 5 microg sodium selenite during 20 days, group 3 received sodium selenite 5 microg + SNP 1 microg and the control group received vehicle 50 microl (0.9% NaCl), same period and route. At the end of treatment, animals were sacrificed and their brain dissected into cortex, hemispheres, cerebellum and brain stem in order to determine lipid peroxidation (TBARS), Na+, K+ ATPase and total ATPase in each section. Blood hemoglobin concentration (Hb) and prostate weight were also assessed., Results: A significant increase of Hb in blood and of proteins in cortex and hemisphere was detected, but TBARS values fell due to the effect of sodium selenite in all examined regions, except for cerebellum. ATPase activity declined in all groups and regions with and without NTP. We conclude that diet supplementary selenium to inhibit NO generation can be a useful treatment in chronic inflammatory diseases.

Objective: To evaluate the efficacy and safety profile of one 30-mg nimodipine oral tablet taken three times per day (one tablet with breakfast, one with lunch, and one with dinner) or one 150-mg cinnarizine verum oral capsule taken once each day with dinner for 12 weeks., Study Design: Comparative in a double-blind, multinational pilot study., Setting: Tertiary referral center., Patients: A total of 221 patients met the study criteria; of that total, 181 adult patients completed the study, including 135 women and 46 men whose ages ranged from 20 to 80 years., Interventions: Two calcium antagonists were used to treat vertigo (nimodipine, 89 patients; cinnarizine, 92 patients), and all patients were maintained on the same dosage regimen until they completed 12 weeks of treatment. Patients were evaluated at 2-and 4-week intervals; an additional evaluation was made at Week 14 to determine vertigo recurrence in the posttreatment period., Main Outcome Measures: The response was evaluated by using the vertigo severity index, a count of vertigo episodes in a given time period. Each episode is weighted according to its intensity., Results: Nimodipine treatment decreased the incidence of moderate vertigo episodes by 78.8% and decreased severe vertigo episodes by 85.0%. Cinnarizine treatment decreased the incidence of moderate vertigo episodes by 65.8% and decreased severe vertigo episodes by 89.8%. Nimodipine and cinnarizine exhibited similar safety profiles. Only two patients withdrew from the study because of adverse events possibly related to the study drug. One patient withdrew from the cinnarizine group because of headache, and one patient withdrew from the nimodipine group because of lipothymia., Conclusion: These data confirm the marked efficacy of both nimodipine and cinnarizine in the treatment of vestibular vertigo.

Purpose: Differences in potency among valproate (VPA) metabolites could be explained by structural properties. Therefore, a quantitative structure-activity relation (QSAR) analysis was performed to study the relation between structural parameters and the effect of the following VPA metabolites: 4-en-VPA, 2-en-VPA, 3-en-VPA, 2,4'-dien-VPA, 4,4'-dien-VPA, 4-hydroxy-VPA, 3-ceto-VPA, 3-hydroxy-VPA, 5-hydroxy-VPA, and propylglutaric acid., Methods: By using the CAChe program package for biomolecules (Oxford Molecular, Ltd), we performed molecular modeling. The anticonvulsant activity determined on the threshold for maximal electroconvulsions in mice was obtained from a study of Löscher and Nau. Structural parameters were compared between metabolites with a double bond and metabolites with oxygen at either side chain (unpaired Student's t test). A single linear regression analysis between each structural parameter and the relative anticonvulsant potency was also performed., Results: Similar parameters were found between the cis and trans and R and S isomers. Biologic activity and most of the structural parameters were significantly different between metabolites with a double bond and metabolites with oxygen at either side chain. Activity was directly related to log P(oct) (r(2) = 0.77) and to reactivity parameters and was inversely related to stability parameters and to molecular weight and surface. The most potent metabolites had a log P(oct) value of higher than 2 units., Conclusions: Similar data were identified between cis and trans, and R and S isomers of VPA metabolites. Anticonvulsant activity was mainly related to log P(oct), probably reflecting the ability of VPA metabolites to cross the blood-brain barrier.

This work evaluates the antinociceptive and constipating effects of the combination of 3.2 mg/kg s.c. morphine with 177.8 mg/kg s.c. metamizol in acutely and chronically treated (once a day for 12 days) rats. On the 13th day, antinociceptive effects were assessed using a model of inflammatory nociception, pain-induced functional impairment model, and the charcoal meal test was used to evaluate the intestinal transit. Simultaneous administration of morphine with metamizol resulted in a markedly antinociceptive potentiation and an increasing of the duration of action after a single (298+/-7 vs. 139+/-36 units area (ua); P<0.001) and repeated administration (280+/-17 vs. 131+/-22 ua; P<0.001). Antinociceptive effect of morphine was reduced in chronically treated rats (39+/-10 vs. 18+/-5 au) while the combination-induced antinociception was remained similar as an acute treatment (298+/-7 vs. 280+/-17 au). Acute antinociceptive effects of the combination were partially prevented by 3.2 mg/kg naloxone s.c. (P<0.05), suggesting the partial involvement of the opioidergic system in the synergism observed. In independent groups, morphine inhibited the intestinal transit in 48+/-4% and 38+/-4% after acute and chronic treatment, respectively, suggesting that tolerance did not develop to the constipating effects. The combination inhibited intestinal transit similar to that produced by morphine regardless of the time of treatment, suggesting that metamizol did not potentiate morphine-induced constipation. These findings show a significant interaction between morphine and metamizol in chronically treated rats, suggesting that this combination could be useful for the treatment of chronic pain.

Background: To assess a possible synergistic antinociceptive interaction, the antinociceptive effects of ketoprofen (KET), and caffeine (CAF) administered either separately or in combinations were determined in a model of arthritic pain., Methods: Antinociceptive activity was assayed using "ellipsis pain-induced functional impairment in the rat" (PIFIR model). The antinociceptive efficacies were evaluated using several dose-response curves and time courses. The antinociceptive effects from the combination that produced the greater effect were compared with the maximal antinociceptive effect of either morphine, acetylsalicylic acid (ASA), or KET alone. The animals were administered with 0.05 mL intra-articular (i.a.) of uric acid to induce nociception. Groups of six rats received orally either ASA, morphine (MOR), KET, CAF, or a combination KET + CAF (24 combinations)., Results: ASA (ED(50) 465.2 +/- 1.5 mg/kg), MOR (ED(50) 71.0 +/- 1.6 mg/kg), and KET (ED(50) 7.2 +/- 1.4 mg/kg) alone induced dose-dependent antinociception, whereas CAF alone showed no activity at the assayed doses. Nine combinations showed various degrees of potentiation (p <0.01), while the remainder exhibited the antinociceptive effect of KET only. Combinations of 17.8 mg/kg CAF with either 1.0, 1.8, 3.2, 5.6, or 10.0 mg/kg KET yielded the highest antinociceptive potentiations. For example, antinociceptive effect was 125.6 +/- 21.4 area units (au) with KET (3.2 mg/kg) alone, but the combination with CAF (17.8 mg/kg) showed 309.5 +/- 10.3 au. The median effective dose (ED(50)) of KET alone was 7.2 +/- 1.4 mg/kg, whereas the ED(50) of KET + CAF 17.8 mg/kg was 0.4 +/- 0.6 mg/kg: KET in the presence of CAF was approximately 18 times more potent than the analgesic drug without CAF., Conclusions: These results showed that CAF was able to potentiate the analgesia of KET, but only at selected dose combinations: CAF in the doses of 10.0 and 17.8 mg/kg was able to potentiate the analgesic effect of KET, the most efficacious drug combination being CAF 17.8 mg/kg + KET 3.2 mg/kg. The combination of analgesic drugs and CAF can produce better antinociceptive effects than the analgesic drug alone. This knowledge will permit the selection of the therapeutically most effective combination ratio of drugs, employing lower doses of each drug.

Organophosphorus pesticides are the most common classes involved in poisonings related to pesticides. We used enzymatic activity of chloroperoxidase on the metabolism of some phosphorothioate pesticides published previously and molecular mechanics methods to perform a theoretical approach of the mechanism of biological oxidation of this class of pesticides. The molecular structure of eight pesticides were optimized by molecular mechanics methods using the CAChe program package for biomolecules, ver. 3.11 (Oxford Molecular Ltd., Campbell, CA). Total energy resulted from the structure optimization process and the partial charges of both phosphorus and sulfur were computed for every pesticide. Phosphorus partial charge and enzymatic activity were significantly related by linear regression analysis (r=0.82, P<0.05). Analyzing our results and using previously reported enzymatic activity of chloroperoxidase on these pesticides, we deduced chemical events involved in activation of the active site of chloroperoxidase and proposed a novel mechanism of oxidation for this class of pesticides. This mechanism will also help to understand the oxidation process of pesticides by cytochrome P450, and production of toxic metabolites.

Some drugs blocking glutamate release produce reduced brain injury in some animal models of cerebral ischemia whereas others lack a clear effect. Meta-analysis is a widely used technique in clinical and epidemiological studies. However, it has never been used in the analysis of preclinical studies. In order to estimate quantitatively the current state of the knowledge concerning the neuroprotective effect of drugs inhibiting glutamate release and to attempt to resolve the apparent controversy in relation to the neuroprotective properties of these drugs, a meta-analysis was performed. It identified a significant difference between drugs blocking glutamate release and controls. Therefore, we hypothesize that inhibition of presynaptic glutamate release could be a major goal in neuroprotection when ischemic brain damage is present and that meta-analysia could be a useful tool for preclinical studies,

Purpose: To investigate in vivo the survival of abducens motoneurons (AMNs) at different periods of time after a single intramuscular injection of the neurotoxin botulinum toxin A (BTxA) or doxorubicin (DXR)., Methods: In Sprague-Dawley rats, the AMNs were labeled with fluorogold (FG), which was applied intramuscularly in the lateral rectus muscle. The numbers of labeled neurons were determined in adult control animals; in young animals that had received intramuscular injections of 0.125, 0.250, 1, or 2 U BTxA; and in adult rats that had received 100 microg, 200 microg, or 300 microg DXR, at various survival times., Results: In control animals, the numbers of FG-labeled motoneurons were similar to the numbers found by other investigators with the use of other retrogradely transported tracers; motoneuron numbers diminished with time after FG application. The numbers of FG-labeled neurons in the animals that had been injected with BTxA were similar to those found in control animals. However, there were fewer FG-labeled neurons in the animals injected with DXR., Conclusions: Fluorogold injected into the lateral rectus muscle can be used to label the AMNs. However, this tracer does not persist within the cytoplasm of the labeled neurons for more than 37 days. The intramuscular injection of 0.125, 0.250, 1, or 2 U BTxA does not induce significant motoneuron death in young rats 30, 60, or 90 days after the injection. Doxorubicin injected intramuscularly causes variable amounts of motoneuron death that is related both to the survival period and to the amount of DXR injected.

Objective: To identify the frequency of health events perceived by the population over 60 years of age in Santiago de Chile, to obtain information for health care programs tailored to needs., Material and Methods: During November and December 1993, a health survey was carried out in a sample of 4,700 individuals in 1,000 households randomly selected within twelve communities of Santiago de Chile. Medical students were trained as interviewers to apply a structured questionnaire to obtain health events occurring in the previous 15 days, including acute and chronic conditions, accidents, medical and dental care., Results: Fifty one per cent of subjects reported health events: acute illness (6.1%), accidents (1.5%), dental care (5.4%), chronic diseases (47.5%), or physical check-up (1.5%). The most frequent chronic diseases were found to be hypertension and diabetes; as for acute illnesses, upper respiratory infections and diarrhea were the most frequent. Accidents commonly reported were falls and burns. The number of episodes was greater in women and in the older age group. Acute illnesses were more frequent in the lower income groups, while dental care and health check-up were common in the highest socioeconomic levels. The proportion of bed-ridden individuals was 0.9% and 1.9% among older individuals., Conclusions: Findings show the frequency of disability in this population by sex and age group and suggest that elderly people are independent and active.

This paper analyzes the problem of quality of medical care and its evolution in various health service institutions. It concludes that quality strategies for countries like Mexico should be of the decentralized/participant type, and that all quality programs in medical care should include five fundamental elements: evaluation, monitoring, design, development, and organizational change.

Esthesioneuroblastoma is a rare tumor that originates in the olfactory epithelium and can invade the orbit. We report a case in which the first symptom was a post-traumatic paralysis of the IV cranial nerve. Whether the tumor itself or the trauma or a combination of the two factors caused the paralysis is discussed.