Dose- and sex-related carcinogenesis by N-bis(2-hydroxypropyl)nitrosamine in Wistar rats

An initiation-promotion medium-term bioassay for detection of chemical carcinogens, developed in the male F344 rat, uses 0.1% N-bis(2-hydroxypropyl)nitrosamine (DHPN) among five genotoxic chemicals for the initiation of carcinogenesis in multiple organs. To establish this bioassay in the Wistar strain, the effects of two dose levels of DHPN were evaluated on the main DHPN rat target organs: lung, thyroid gland, kidneys and liver. Four groups of male and female animals were studied: Control--untreated group; Multi-organ initiated group (also referred to as DMBDD, based on the initials of the five initiators)-treated sequentially with N-diethylnitrosamine (DEN, i.p.), N-methyl-N-nitrosourea (MNU, i.p.), N-butyl-N-(4-hydroxy butyl)nitrosamine (BBN, drinking water), N, N'-dimethylhydrazine (DMH, s.c.) and DHPN (drinking water) for 4 weeks; a third group treated with 0.1% DHPN in drinking water for 2 weeks and the last group treated with 0.2% DHPN in drinking water for 4 weeks. The animals were sacrificed after 30 weeks. DHPN at 0.2% induced preneoplasia in the liver and kidneys of rats of both sexes, the number and area of the putative preneoplastic liver glutathione S-transferase-positive hepatocyte foci being significantly increased in these animals. It also induced benign and malignant tumors in female and in male rats. However, there was no relationship between the increased incidence of preneoplastic lesions and tumor development in the 0.2% DHPN-exposed groups of both sexes. DHPN at 0.1% induced only a few preneoplastic lesions in the liver and kidney and no tumors in both male and female rats. A clear dose and sex-related carcinogenic activity of DHPN was registered, although Wistar rats of both sexes showed a relative resistance to the carcinogenic activity of this compound.

Fluoride dose response in pH-cycling models using bovine enamel

The aim of this study was to establish methodologies for verification of the fluoride solution dose-response relationship using bovine enamel and pH-cycling models. Six models of the cariogenic challenge were performed, varying the time of demineralization and pH, time of remineralization, composition of de- and remineralization solutions, frequency and time of application of treatment solutions and pH-cycling duration. For the evaluation of the fluoride effect on caries dynamics, two proposed models provided for improvement in standardization of methods leading to a higher level of precision, demonstrating a dose response between treatments with regard to surface microhardness and Delta Z. For the evaluation of the fluoride effect on enamel remineralization, the addition of fluoride to the de- and remineralization solutions and the reduction of frequency and time of application of fluoride solutions led to a more suitable pH-cycling model. Copyright (C) 2005 S. Karger AG, Basel.

Single dose of a vaccine based on DNA encoding mycobacterial hsp65 protein plus TDM-loaded PLGA microspheres protects mice against a virulent strain of Mycobacterium tuberculosis

The high incidence of tuberculosis around the world and the inability of BCG to protect certain populations clearly indicate that an improved vaccine against tuberculosis is needed. A single antigen, the mycobacterial heat shock protein hsp65, is sufficient to protect BALB/c mice against challenge infection when administered as DNA vaccine in a three-dose-based schedule. In order to simplify the vaccination schedule, we coencapsulated hsp65-DNA and trehalose dimicolate (TDM) into biodegradable poly(DL-lactide-co-glycolide) (PLGA) microspheres. BALB/c mice immunized with a single dose of DNA-hsp65/TDM-1oaded microspheres produced high levels of IgG2a subtype antibody and high amounts of IFN-gamma in the supernatant of spleen cell cultures. DNA-hsp65/TDM-loaded microspheres were also able to induce high IFN-gamma production in bulk lung cells from challenged mice and confer protection as effective as that attained after three doses of naked DNA administration. This new formulation also allowed a ten-fold reduction in the DNA dose when compared to naked DNA. Thus, this combination of DNA vaccine and adjuvants with immunomodulatory and carrier properties holds the potential for an improved vaccine against tuberculosis.

Variable dose rate application of herbicides using optical sensors

The aim of this study was to develop and evaluate a variable dose rate application of herbicides using an online electronic control based system with optical sensors for weed detection in forested areas. The proposed concept was to apply a basic dose on 100% of the area (aiming to control small weeds) and to apply a complementary patch-spraying dose only on areas with higher weed infestation. For that purpose, a conventional spray boom was adjusted to apply 40% of the herbicide dose on the full area and the optical sensors were used to control the application of the complementary dose (60%) only on areas with higher infestation. The results showed that the system performed adequately. Field applications presented herbicide savings around 20 to 30%, with a similar weed control performance as compared to the full dose application on 100% of the area.

An open-label, comparative study of the efficacy and safety of once-daily dose of enoxaparin versus unfractionated heparin in the treatment of proximal lower limb deep-vein thrombosis

Background: Treatment of deep-vein thrombosis (DVT) with a once-daily regimen of enoxaparin, rather than a continuous infusion of unfractionated heparin (UFH) is more convenient and allows for home care in some patients. This study was designed to compare the efficacy and safety of these two regimens for the treatment of patients with proximal lower limb DVT. Methods: 201 patients with proximal lower limb DVT from 13 centers in Brazil were randomized in an open manner to receive either enoxaparin [1.5 mg/kg subcutaneous (s.c.) OD] or intravenous (i.v.) UFH (adjusted to aPTT 1.5-2.5 times control) for 5-10 days. All patients also received warfarin (INR 2-3) for at least 3 months. The primary efficacy endpoint Was recurrent DVT (confirmed by venography or ultrasonography), and safety endpoints included bleeding and serious adverse events. The rate of pulmonary embolism (PE) was also collected. Hospitalization was at the physician's discretion. Results: Baseline patient characteristics were comparable between groups. The duration of hospital stay was significantly shorter with enoxaparin than with UFH (3 versus 7 days). In addition, 36% of patients receiving enoxaparin did not need to be hospitalized, whereas all of the patients receiving UFH were! hospitalized. The treatment duration was slightly longer with enoxaparin (8 versus 7 days). There was a nonsignificant trend toward a reduction in the rate of recurrent DVT with enoxaparin versus UFH, and similar safety. Conclusions: A once-daily regimen of enoxaparin 1.5 mg/kg subcutaneous is at least as effective and safe as conventional treatment with a continuous intravenous infusion of UFH. However, the once daily enoxaparin regimen is easier to administer (subcutaneous versus intravenous), does not require aPTT monitoring, and leads to both a reduced number of hospital admissions and an average 4-day-shorter hospital stay. (C) 2004 Elsevier Ltd. All rights reserved.

Dose-related antinociceptive effects of intravenous buprenorphine in cats

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

Autoradiographic investigation of effects of high-dose colchicine on dentinogenesis in rat incisors

Twelve female Wistar rats received 1.5 mg/kg of colchicine (CLC) intravenously. Control animals were similarly injected with isotonic saline solution. The animals were killed 5 h, 24 h, 3 days and 7 days after injection. Ninety minutes prior to sacrifice, all animals received an intraperitoneal injection of 3H-proline. Autoradiograms of maxillary incisors showed that CLC increased the retention of the labeled precursor in the odontoblasts. It was also shown that the odontoblasts in the different sectors of the rat incisor present different sensitivities to the CLC action.

Associacao de opioides lipofilicos a bupivacaina na anestesia peridural. Ha vantagem no aumento da dose do opioide?

Background and Objectives: - The effects of associating lipophilic opioids to local anesthetics in epidural anesthesia are not well defined. There are still questions and controversies about opioid doses to be used and their major effects in the epidural block. This study aimed at evaluating the epidural block effects in humans of the association of different fentanyl and sufentanil doses to bupivacaine with 1:200.000 epinephrine. Methods: - A double-blind randomized study was performed in 94 patients of both genders, physical status ASA I, aged between 18 and 60 years, submitted to lower abdomen, perineal or lower limb surgery. Patients without preanesthetic medication were epidurally injected with 100 mg (20 ml) 0.5% bupivacaine, 0.1 mg (0.1 ml) 1%o epinephrine plus a combination of the following drugs: BUPI Group (15 patients): 2 ml of 0.9% saline solution (SS); FENT50 Group (19 patients): 50 μg (1 ml) fentanyl + 1 ml SS; FENT100 Group (20 patients): 100 μg (2 ml) fentanyl; SUF30 Group (20 patients): 30 μg (0.6 ml) sufentanil + SS (1.4 ml); SUF100 Group (20 patients): 50 μg (1 ml) sufentanil + SS (1 ml). The following parameters were studied: onset of sensory block, analgesic block (onset time) in T12, T10 and T8, analgesic block duration in T10 and T12, motor block degree, consciousness degree, need for supplemental perioperative sedation and analgesia, hypotension, bradycardia and peri and post operative side-effects, analgesia duration, proportion of patients needing supplemental analgesia and evaluation of postoperative pain (pain analog visual scale). Results: Groups were demographically uniform. The addition of fentanyl or sufentanil did not alter major characteristics of perioperative epidural block and has not significantly increased postoperative analgesia duration as compared to the use of bupivacaine only. However, the addition of lipophilic opioids has increased the quality of perioperative anesthetic block, translated into a lesser need for supplemental analgesia (p < 0.02). The increased dose of fentanyl and especially of sufentanil has increased the incidence of perioperative drowsiness (p < 0.001) without significant increase in other side effects. Conclusions: In the conditions and doses used, the addition of lipophilic opioids to bupivacaine and the increased dose of lipophilic opioids have improved anesthetic block quality without changes in the epidural block characteristics or a significant increase in side effects, with the exception of drowsiness mainly caused by sufentanil. However, they were not able to provide a significant increase in postoperative analgesia duration.

Efeito dose-resposta de uma formulação de dentifrício com concentração reduzida de fluoreto - estudo in vitro.

The utilization of dentifrices with low fluorine concentration, for children under 6 years of age, has been suggested to reduce the risks of dental fluorosis. However, in order to have anticariogenic potential, the dentifrice should form loosely-bound fluorine (CaF2) on dental enamel. Considering that the formation of CaF2 is a function inversely related to pH, dentifrices with pH 5.5, with 275, 550 and 1,100 ppm F (NaF/silica) were developed in order to assess dose-response effects. A comparison between those dentifrices, a placebo product and the Crest toothpaste (positive control - standard) was carried out. Furthermore, the bioavailability of dentifrices, in terms of formation of total fluorine (TF), CaF2, and fluorapatite (FA) on human dental enamel, was evaluated. An ion-specific electrode was utilized for the determination of the dosage of fluorine. The results revealed that the dentifrice with 550 ppm F was more effective than both the placebo and the dentifrice with 275 ppm, presenting no difference in relation to the positive control (p > 0.05). A dose-effect correlation was observed as to the CaF2 formed. In conclusion, the modified formulation with 550 ppm F can be considered as effective as the standard dentifrice with 1,100 ppm, and its utilization would be safer with regard to dental fluorosis.

Tissue distribution of a plasmid DNA encoding Hsp65 gene is dependent on the dose administered through intramuscular delivery

In order to assess a new strategy of DNA vaccine for a more complete understanding of its action in immune response, it is important to determine the in vivo biodistribution fate and antigen expression. In previous studies, our group focused on the prophylactic and therapeutic use of a plasmid DNA encoding the Mycobacterium leprae 65-kDa heat shock protein (Hsp65) and achieved an efficient immune response induction as well as protection against virulent M. tuberculosis challenge. In the present study, we examined in vivo tissue distribution of naked DNA-Hsp65 vaccine, the Hsp65 message, genome integration and methylation status of plasmid DNA. The DNA-Hsp65 was detectable in several tissue types, indicating that DNA-Hsp65 disseminates widely throughout the body. The biodistribution was dose-dependent. In contrast, RT-PCR detected the Hsp65 message for at least 15 days in muscle or liver tissue from immunized mice. We also analyzed the methylation status and integration of the injected plasmid DNA into the host cellular genome. The bacterial methylation pattern persisted for at least 6 months, indicating that the plasmid DNA-Hsp65 does not replicate in mammalian tissue, and Southern blot analysis showed that plasmid DNA was not integrated. These results have important implications for the use of DNA-Hsp65 vaccine in a clinical setting and open new perspectives for DNA vaccines and new considerations about the inoculation site and delivery system. © 2006 Coelho-Castelo et al; licensee BioMed Central Ltd.

Interval between first dose and booster affected antibody production in cattle vaccinated against rabies

In this study, we compared the levels of neutralizing antibodies induced by inactivated rabies vaccine in cattle by using three alternative immunization procedures. Forty-five bovines (breed nelore) were then organized in three groups (A, B and C, with 15 animals/group). Group A received only one vaccine dose at day zero and Group B received the first dose at day zero and then another dose at day 30 (early booster). Group C was also immunized with two doses; however, the booster was postponed until day 180 after the first dose (delayed booster). Blood samples were withdrawn at days zero (before the first dose) and 30, 210, 390, and 540 after the beginning of immunization and the antibody titers were evaluated by mouse neutralization test. The protocol used to immunize Group C (booster at day 180) was clearly more efficient. In this group, antibody levels were higher and also remained higher for longer periods in comparison with the other two groups. These results show that booster timing significantly affected antibody levels. Therefore, programs addressed to control this disease in cattle should consider not only the use of a booster but also its administration time.