Reduction of enantioselectivity in the kinetic disposition and metabolism of verapamil in rats exposed to toluene

Toluene and verapamil are subject to extensive oxidative metabolism mediated by CYP enzymes, and their interaction can be stereoselective. In the present study we investigated the influence of toluene inhalation on the enantioselective kinetic disposition of verapamil and its metabolite, norverapamil, in rats. Male Wistar rats (n = 6 per group) received a single dose of racemic verapamil (10 mg/kg) orally at the fifth day of nose-only toluene or air (control group) inhalation for 6 h/day (25, 50, and 100 ppm). Serial blood samples were collected from the tail up to 6 h after verapamil administration. The plasma concentrations of verapamil and norverapamil enantiomers were analyzed by LC-MS/MS by using a Chiralpak AD column. Toluene inhalation did not influence the kinetic disposition of verapamil or norverapamil enantiomers (p > 0.05, Kruskal-Wallis test) in rats. The pharmacokinetics of verapamil was enantioselective in the control group, with a higher plasma proportion of the S-verapamil (AUC 250.8 versus 120.4 ng.h.mL(-1); p <= 0.05, Wilcoxon test) and S-norverapamil (AUC 72.3 versus 52.3 ng.h.mL(-1); p <= 0.05, Wilcoxon test). Nose-only exposure to toluene at 25, 50, or 100 ppm resulted in a lack of enantioselectivity for both verapamil and norverapamil. The study demonstrates the importance of the application of enantioselective methods in studies on the interaction between solvents and chiral drugs.

Reduction of podocytes number in late diabetic alloxan nephropathy: prevention by glycemic control

OBJETIVO: Avaliar o número de podócitos e espessamento da membrana basal glomerular (MBG) em ratos diabéticos com e sem controle glicêmico com 6 e 12 meses da indução. MÉTODOS: 100 ratos Wistar com 200-300g compuseram 6 grupos: Normal (N6, N12 - 25 animais) Diabético (D6,D12 - 25 animais) e diabético tratado com insulina 1,8 a 3,0 U/Kg e acarbose misturada a ração (50g para cada 100g de ração) (DT6 e DT12 - 25 animais). Aloxana foi ministrada via endovenosa na dose de 42mg/Kg. Peso, ingestão hídrica e diurese de 24 horas e glicemia e glicosúria foram determinados antes da inoculação, 7 e 14 dias após e mensalmente. No 14ª dia foi iniciado o tratamento. Três grupos de animais (N6, D6 e DT6) foram sacrificados no 6° mês e três grupos (N12, D12 e DT12), no 12ª mês sendo o tecido renal processado para estudo à microscopia eletrônica. RESULTADOS: A glicemia dos animais DT6 e DT12 diferiram significativamente, dos ratos D6 e D12, e não diferiram dos grupos N6 e N12. O número de podócitos do grupo DT6 não diferiu de N6 e D6 (mediana=11); o número de podócitos de DT12 (mediana=11) diferiu de D12 (mediana=8) e não diferiu de N12 (mediana=11). O espessamento da MBG de D6 (0,18 micrômetros) foi menor que D12 (0,29 micrômetros); de DT6 (0,16 micrômetros) foi menor que D6 (0,18 micrômetros) e de DT12 (0,26 micrômetros) foi menor que D12 (0,29 micrômetros). CONCLUSÃO: O controle da hiperglicemia preveniu o espessamento da MBG na nefropatia diabética aloxânica precoce (6 meses) e tardia (12 meses), e a diminuição do número de podócitos.

Cholesterol reduction and lack of genotoxic or toxic effects in mice after repeated 21-day oral intake of lemongrass (Cymbopogon citratus) essential oil

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

Thermoluminescence measurements of entrance surface skin dose in exams of dog's chest in veterinary radiology

This study aims to determine the entrance surface skin doses in dogs (with suspected pulmonary metastasis) submitted to chest X-rays using the technique of thermoluminescence (TL) dosimetry. Twenty seven radiologic exams of dogs of different breed and sizes were performed. The radiation doses were assessed using thermoluminescent dosimeters of calcium sulphate doped with dysprosium (CaSO(4):Dy) produced at Instituto de Pesquisas Energeticas e Nucleares (IPEN-CNEN). The entrance surface skin dose range evaluated in this type of procedure was between 0.43 mGy to small size dogs and 4.22 mGy to big size dogs with repeated exams. The obtained results indicate that is extremely important the assessment of radiation doses involved in veterinary diagnostic radiology procedures, to evaluate the delivered doses to the animals, to be used as a parameter in the individual monitoring of pet's owners, who assist the animal positioning, and to protect occupationally exposed workers at the Veterinary Radiology Clinics. (C) 2010 Elsevier Ltd. All rights reserved.

Dose de exposição radiométrica e composição das rochas sedimentares e ígneas na bacia do Rio Corumbataí (SP)

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

Radionuclide concentrations in raw and purified phosphoric acids from Brazil and their processing wastes: implications for radiation exposures

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

Redução da dose e do volume de calda nas aplicações noturnas de herbicidas em pós-emergência na cultura de soja

O objetivo deste trabalho foi avaliar o efeito de reduções da dose e do volume de calda nas aplicações noturnas de herbicidas em pós-emergência sobre o controle de plantas daninhas e a seletividade para a cultura da soja. Dois experimentos foram conduzidos na Fazenda de Ensino e Pesquisa da FCAV/UNESP - Campus de Jaboticabal, durante os anos agrícolas de 94/95 e 95/96. As aplicações foram realizadas às 5, 9, 14, 17 e 22h e o volume de calda de 300 l/ha foi reduzido para 75 e 150l/ha. No primeiro experimento foram aplicadas as doses de 432 g de bentazon/ha e 90 g de lactofen/ha, correspondentes a 60% das recomendações de rótulo desses herbicidas, e no segundo, 60 g lactofen/ha e 157,5 g de fomesafen/ha + 2 % de adjuvante (v/v), correspondentes a 40% e 70% das recomendações. Também foram incluídos nos experimentos tratamentos com as recomendações dos rótulos e testemunhas com e sem capina das plantas daninhas durante todo o ciclo da cultura. As aplicações noturnas, realizadas às 5 e 22h, favoreceram significativamente a ação do lactofen com 60% da dose recomendada e desfavoreceram a do fomesafen no controle das plantas daninhas. Não ocorreram diferenças significativas entre os volumes de aplicação estudados, possibilitando o uso de 75 ou 150 l de calda/ha aplicados nos horários mais favoráveis a cada um dos herbicidas. A maior eficiência das aplicações dos herbicidas bentazon, lactofen e fomesafen depende, além das condições ambientais favoráveis no período noturno, das interações específicas entre os herbicidas e as plantas daninhas.

Growth and physiological responses of sunflower plants exposed to ultraviolet-B radiation

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

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.

REDUCTION OF URINE VOLUME AMELIORATES ADRIAMYCIN-INDUCED NEPHROPATHY

1. Adriamycin, a commonly used antineoplastic antibiotic, induces glomerular lesions in rats, resulting in persistent proteinuria and glomerulosclerosis.2. The effect of urine volume on the progression of adriamycin-induced nephropathy was studied in 70 male Wistar rats (180-200 g) observed for 30 weeks and separated into 4 groups: healthy control group (HCG, N = 10) inoculated iv with 1 ml of saline, and nephrotic groups inoculated iv with a single dose of adriamycin of 3 mg/kg body weight. The nephrotic rats were separated into 3 groups (N = 20): nephrotic control group (NCG) receiving only adriamycin; dehydrated nephrotic group (DNG) water deprived for 36 h within each 48-h period, and furosemide nephrotic group (FNG) treated with 12 mg/dl furosemide, and 0.9 g/dl NaCl in the drinking water.3. The 30-week survival rates of the DNG (100%) and HCG (100%) were significantly higher than those of the NCG (85%) and FNG (55%).4. The proteinuria observed in the HCG (range, 7.38 +/- 0.7 to 13.6 +/- 1.27 mg/24 h) was significantly lower than that observed for all the nephrotic groups throughout the experiment. The DNG presented significantly less proteinuria (range, 42.71 +/- 6.83 to 140.10 +/- 19.22 mg/24 h) than the NCG (range, 35.32 +/- 7.64 to 250.00 +/- 25.91 mg/24 h) from week 10 on. There was no significant difference between the mean 24-h proteinuria of the NCG (range, 35.32 +/- 7.64 to 250.00 +/- 25.91 mg/24 h) and the FNG (range, 35.82 +/- 7.91 to 221.54 +/- 26.74).5. The mean frequency of damaged glomeruli was 0.3% +/- 0.3 for HCG, 42% +/- 6% for CNG, 40.8% +/- 8% for DNG, and 47% +/- 14% for FNG. The median value of the tubulointerstitial lesion, evaluated by a semiquantitative method, was 0 in HCG, 10 in CNG, 8.5 in DNG and 9.5 in FNG(P<0.05 for all groups compared to HCG).6. The data indicate that reduction of urine volume has a protective effect on adriamycin-induced nephropathy.

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.

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.

Developing new radiotherapy techniques using linac based gamma radiation sources

A major challenge in cancer radiotherapy is to deliver a lethal dose of radiation to the target volume while minimizing damage to the surrounding normal tissue. We have proposed a model on how treatment efficacy might be improved by interfering with biological responses to DNA damage using exogenous electric fields as a strategy to drastically reduce radiation doses in cancer therapy. This approach is demonstrated at this Laboratory through case studies with prokaryotes (bacteria) and eukaryotes (yeast) cells, in which cellkilling rates induced by both gamma radiation and exogenous electric fields were measured. It was found that when cells exposed to gamma radiation are immediately submitted to a weak electric field, cell death increases more than an order of magnitude compared to the effect of radiation alone. This finding suggests, although does not prove, that DNA damage sites are reached and recognized by means of long-range electric DNA-protein interaction, and that exogenous electric fields could destructively interfere with this process. As a consequence, DNA repair is avoided leading to massive cell death. Here we are proposing the use this new technique for the design and construction of novel radiotherapy facilities associated with linac generated gamma beams under controlled conditions of dose and beam intensity.

Induction of mitotic crossing-over in diploid strains of Aspergillus nidulans using low-dose X-rays

As a contribution towards detecting the genetic effects of low doses of genotoxic physical agents, this paper deals with the consequences of low-dose X-rays in the Aspergillus nidulans genome. The irradiation doses studied were those commonly used in dental clinics (1-5 cGy). Even very low doses promoted increased mitotic crossing-over frequencies in diploid strains heterozygous for several genetic markers including the ones involved in DNA repair and recombination mechanisms. Genetic markers of several heterozygous strains were individually analyzed disclosing that some markers were especially sensitive to the treatments. These markers should be chosen as bio-indicators in the homozygotization index assay to better detect the recombinogenic/ carcinogenic genomic effects of low-dose X-rays. ©FUNPEC-RP.

Dose de exposição radiométrica de granitos do estado de Rondônia, Brasil

This work evaluated the activity concentration of the radioelements K, eU and eTh in samples of granites from Rondônia State, Brazil. The statistical analysis of the data indicated that they fit lognormal distributions. The modal values correspond to about 11% for K, 29 ppm for eU and 85 ppm for eTh. Directsignificant correlations were found among the concentrations of the three radioelements, i.e. r = 0.71 (between K and eU), r = 0.72 (between K and eTh), andr = 0.72 (between eU and eTh), suggesting congruency of their accumulation in minerals occurring in the rocks analyzed. The activity concentration data allowed estimate the absorbed dose rate in air at 1 m above the ground, which also fits a lognormal distribution characterized by a mode of 2.7 mSv/y that is slightly higher than the average worldwide exposure of 2.4 mSv/y. The results obtained also allowed evaluate if the granites analyzed are radiometrically suitable as building and ornamental materials. © 2009 Sociedade Brasileira de Geofísica.