Pharmacokinetics of loxoprofen and its active metabolite after dermal application of loxoprofen gel to rats.

This study was conducted to evaluate the pharmacokinetics of loxoprofen (LX) and its active metabolite (trans-OH form) after a single dermal application of LX gel (LX-G) to rats. In the skin at the treated site, generation of the trans-OH form was detected and both LX and the trans-OH form remained at high concentrations for 24 h after dermal application. Furthermore, both LX and the trans-OH form also remained in the skeletal muscle over 24 h after the single dermal application, while they eliminated rapidly after the single oral administration. The area under the curve up to the last measurable point (AUC(0-t)) for plasma concentrations of LX or the trans-OH form after dermal application of LX-G was less than 11% of that after oral administration of LX. In addition, C(max) and AUC(0-t) increased in a saturable manner while increasing the dose. Overall, these results demonstrated that the trans-OH form was generated at the treated site with the process of dermal absorption of LX and it remained at the target site for a long period with low systemic exposure compared to oral administration.

Hepatic capillariasis in children: report of 3 cases in Brazil.

Capillaria hepatica is a helminth that may cause an extremely rare condition of parasitic hepatitis. Only 29 cases have been published, 2 of them in Brazil. We report here 3 cases of children in Brazil with massive hepatic capillariasis who presented the characteristic triad of this type of infection, i.e., persistent fever, hepatomegaly, and eosinophilia. The diagnosis was made by liver biopsy. All children responded well after treatment with thiabendazole (case 1), albendazole (case 3), and albendazole in combination with a corticoid (case 2). Case 1 has been followed-up for 24 years, an event not previously reported in the literature.

DNA strand breaks in mammalian tissues induced by methylarsenics.

DNA damage induced by administration of dimethylarsinic acid (DMAA) to rats and mice was investigated. At 12 h after administration of DMAA, DNA single-strand breaks were induced markedly in lung. The majority of dimethylarsine, one of the main metabolites, in the expired air was excreted within 6-18 h after administration of DMAA to rats. In vitro experiments using nuclei isolated from lung of mice indicated that DNA strand breaks were caused by dimethylarsine. Furthermore, the strand breaks after exposure to dimethylarsine were reduced in the presence of catalase and/or superoxide dismutase. These results strongly suggest that the strand breaks are induced not by dimethylarsine itself but by active oxygen, e.g., O2- and .OH, produced both by dimethylarsine and molecular oxygen. When DNA was exposed to dimethylarsine, thiobarbituric acid (TBA)-reactive intermediates and cis-thymine glycol were produced. Dimethylarsine appears to induce DNA damage by the mechanism similar to the damage produced by ionizing radiation.

[Alterations of intestinal permeability in children]. / Alterações da permeabilidade intestinal em crianças.

The authors present an updated review of intestinal permeability with emphasis on permeability pathways, test substances and the techniques most commonly employed for the study and quantification of this process. They also point out certain pediatric conditions associated with abnormal intestinal permeability.

[Lactose content and beta-galactosidase activity in yogurt, cheeses and curdled milk made in Brazil]. / Conteúdo de lactose e atividade de beta-galactosidade em iogurtes, queijos e coalhadas produzidos no Brasil.

We studied yogurts and industrialized curdled milk in three different storage times, as well as homemade and Syrian curdled milk and cheeses. Lactose content (gm%) and beta-galactosidase activity were determined in these products. Lactose content was elevated in yogurts and curdled milk with a lactose reduction of about 22% compared to the lactose of cow milk, with a mean and standard desviation (M +/- SD) of 3.81 +/- 0.47 gm%. In the cheeses lactose content was low, between 1.91 and 0.03 g%. beta-galactosidase activity was present in yogurts and curdled milk, with values between 0.58 and 3.61 U in time I and M +/- SD of 0.15 +/- 0.23 U. A significant decrease of beta-galactasidase activity was observed during the storage time. By analyzing and comparing these findings with the literature, we conclude that the products studied, by their low content of lactose (cheeses and yakult) or by the presence of beta-galactasidase activity (yogurts and curdled milk at time I) probably would be tolerated by most hipolactasic persons.

[Increased intestinal permeability to 51 Cr-EDTA among children with persistent diarrhea]. / Aumento da permeabilidade intestinal ao 51Cr-EDTA em crianças com diarréia persistente.

Persistent diarrhea, a condition highly prevalent in developing countries, causes different morphological and functional alterations of the mucosa of the small intestine, including increased permeability to different test molecules. In the present study we investigate for the first time the intestinal permeability to 51Cr-EDTA of Brazilian children with persistent diarrhea. The test of 51Cr-EDTA absorption was performed in 13 control children and in 14 children with persistent diarrhea by offering 50 microCi of the test substance by the oral route, with later detection of radioactivity excreted in 24-hour urine. There was a statistically significant difference between the control group (median = 1.26; range = 0.20-3.31%) and the group with persistent diarrhea (median = 4.68; range = 1.40-10.29%). Using the minimum and maximum values detected in the control group as the normal reference standard for the test of urinary 51Cr-EDTA absorption, we observed that 61.5% of the patients with persistent diarrhea showed altered results. Among the patients with persistent diarrhea, 51Cr-EDTA excretion was significantly higher in the group fed a protein hydrolysate diet and/or total parenteral nutrition than in the group that did not receive this diet. In four patients with persistent diarrhea, the test was performed after clinical recovery, with a fall in the excretion levels in all cases. On the basis of these data, we may conclude that: 1) in persistent diarrhea there must be alteration of intestinal permeability that might permit an increased entry of local alimentary antigens, with subsequent sensitization and allergic enteropathy, contributing to the perpetuation of the diarrhea, malabsorption and malnutrition cycle; 2) the 51Cr-EDTA test may be useful as an indicator of severity in persistent diarrhea; 3) alteration of intestinal permeability is a secondary phenomenon in persistent diarrhea, with normalization occurring after reconstruction of the intestinal barrier.

Report of two cases of children with Budd-Chiari syndrome successfully treated with streptokinase.

Two children with Budd-Chiari syndrome were successfully submitted to thrombolytic therapy. This study suggests that streptokinase is safe and effective in the treatment of this syndrome and should be considered as primary treatment in case of early diagnosed acute disease in view of the poor prognosis and the aggressiveness of surgical treatment currently available.

[Neonatal cholestasis and cytomegalovirus infection: clinical and histopathologic forms]. / Colestase neonatal e infecção por citomegalovírus: formas de apresentação clínica e histopatológica.

Cytomegalovirus infection is symptomatic in only 10% of cases. The most frequent findings are cholestasis and hepatosplenomegaly. Ten patients who presented neonatal cholestasis associated with cytomegalovirus infection were studied. The majority had elevation of serum aminotransferases and mild abnormality of hepatic function. The histopathologic findings were: normal, giant cell hepatitis, bile duct proliferation (confused with extrahepatic biliary atresia) and ductopenia. The clinical course of the patients varied from disappearance of the symptoms (2 cases) to death (2 cases). Because of the possibility of confusing the histologic findings with extrahepatic biliary atresia, the etiology of neonatal cholestasis, including cytomegalovirus infection, should be determined as soon as possible.

[Excretion of 99m Tc-DISIDA through the bile ducts in the etiological diagnosis of neonatal cholestasis]. / Excreção de 99mTc-DISIDA pelo trato biliar no diagnóstico etiológico da colestase neonátal.

We evaluated 51 tests of 99mTc-DISIDA excretion by the biliary tree in patients with neonatal cholestasis. The aim of the present study was to verify the value of this test in the differentiation of this syndrome, correlating it to the clinical and laboratory data. The case studied were divided into two groups: extrahepatic biliary atresia, 26 patients (50.9%) and no-extrahepatic biliary atresia, 25 patients (49.1%). Analyzing the results, we concluded that this test had 96% sensitivity, 56% specificity, 69% positive predictive value, 93% negative predictive value and 76.5% accuracy. The accuracy of this test was only lower than that of hepatic biopsy. We conclude that the hepatobiliary scintigraphy was very useful in the definition of extrahepatic biliary atresia, with less value in the group of neonatal hepatitis, perhaps due to the delayed referral of the patients, short time of the scintigraphy study or factors related to the etiology of cholestasis itself.

[Hepatic glycogenosis in childhood: clinical and laboratory findings in 20 patients]. / Glicogenose hepática na infância: achados clínicos e laboratoriais em 20 pacientes.

We studied 20 children with a clinical picture and laboratory study suggestive of hepatic glycogenosis. The age of the beginning of symptoms varied from birth to 24 months and the age at the diagnosis varied from 2 to 81 months. Hepatomegaly was found in all patients, diarrhea in 65% (13/26), "doll-face" in 55% (11/20) and convulsions in 50% (10/20). Nutritional evaluation showed more height deficiency than weight deficiency. Laboratory tests showed elevation of hepatic transaminases (12/19), hypercolesterolemia (8/14), hyperuricemia (6/17) and hypoglycemia (6/20). Liver function was not compromised in most of the cases. The results of glucagon tolerance test were variable. The histoenzymology study performed in 15 patients revealed the following results: Type VI (liver phosphorylase deficiency) in seven, Type I (glucose-6-phosphatase deficiency) in two, Type IV (brancher enzyme) in one and no conclusion could be drawn in five patients. The finding of hypoglycemia in few cases of this study can be justified by the few number of glycogenosis Type I, probably due to the fact that this type is the most easily diagnosed, with less necessity of referring them to specialized centers.

Longitudinal evaluation of hepatic osteodystrophy in children and adolescents with chronic cholestatic liver disease.

Bone mass loss is a major complication of chronic cholestatic liver disease (CCD). However, the long-term impact of CCD on bone mass acquisition is unknown. We longitudinally assessed bone mineral density (BMD) and factors involved in bone remodeling in 9 children and adolescents with CCD Child-Pugh A (5 boys/4 girls) and in 13 controls (6 boys/7 girls). The groups were evaluated twice, at baseline (T0) and after 3 years (T1), when osteocalcin, deoxypyridinoline, 25-hydroxyvitamin-D, parathyroid hormone, insulin-like growth factor-I (IGF-I), and BMD (L1-L4, proximal femur and total body) were determined. Serum levels of receptor activator for nuclear factor kB ligand (RANKL) and osteoprotegerin were measured only at T1. Lumbar spine BMD was reanalyzed twice: after adjustment for bone age and to compensate for the height factor. Volumetric density was also estimated mathematically in L2-L4. The BMD of L1-L4 was lower in the CCD group (Z-score at T0: control = -1.2 ± 0.8 vs CCD = -2.2 ± 1.4, P < 0.05; T1: control = -0.7 ± 0.8 vs CCD = -2.1 ± 1.1, P < 0.05). Osteocalcin and deoxypyridinoline were similar for the two groups. The CCD group presented lower IGF-I (Z-score at T1: control = 1.4 ± 2.8 vs CCD = -1.5 ± 1.0, P < 0.05) and RANKL (control = 0.465 ± 0.275 vs CCD = 0.195 ± 0.250 pM, P < 0.05) than control. Children with compensated CCD Child-Pugh A showed early impairment of bone acquisition, with the impact being more severe in an initial phase and then tapering in a slowly progressive way. Reduction in endocrine IGF-I has a crucial role in this process.

Longitudinal evaluation of hepatic osteodystrophy in children and adolescents with chronic cholestatic liver disease

Bone mass loss is a major complication of chronic cholestatic liver disease (CCD). However, the long-term impact of CCD on bone mass acquisition is unknown. We longitudinally assessed bone mineral density (BMD) and factors involved in bone remodeling in 9 children and adolescents with CCD Child-Pugh A (5 boys/4 girls) and in 13 controls (6 boys/7 girls). The groups were evaluated twice, at baseline (T0) and after 3 years (T1), when osteocalcin, deoxypyridinoline, 25-hydroxyvitamin-D, parathyroid hormone, insulin-like growth factor-I (IGF-I), and BMD (L1-L4, proximal femur and total body) were determined. Serum levels of receptor activator for nuclear factor kB ligand (RANKL) and osteoprotegerin were measured only at T1. Lumbar spine BMD was reanalyzed twice: after adjustment for bone age and to compensate for the height factor. Volumetric density was also estimated mathematically in L2-L4. The BMD of L1-L4 was lower in the CCD group (Z-score at T0: control = -1.2 ± 0.8 vs CCD = -2.2 ± 1.4, P < 0.05; T1: control = -0.7 ± 0.8 vs CCD = -2.1 ± 1.1, P < 0.05). Osteocalcin and deoxypyridinoline were similar for the two groups. The CCD group presented lower IGF-I (Z-score at T1: control = 1.4 ± 2.8 vs CCD = -1.5 ± 1.0, P < 0.05) and RANKL (control = 0.465 ± 0.275 vs CCD = 0.195 ± 0.250 pM, P < 0.05) than control. Children with compensated CCD Child-Pugh A showed early impairment of bone acquisition, with the impact being more severe in an initial phase and then tapering in a slowly progressive way. Reduction in endocrine IGF-I has a crucial role in this process.

Dimethylated arsenics induce DNA strand breaks in lung via the production of active oxygen in mice.

In order to study the genotoxicity of arsenics, we focused our attention on dimethylarsinic acid (DMAA) which was a main metabolite of inorganic arsenics in mammals. ICR mice were orally administered DMAA-Na (1500mg/kg). DNA single-strand breaks occurred specifically in lung at 12h after administration. An in vitro experiment indicated that the breaks were not caused directly by DMAA but by dimethylarsine, a further metabolite of DMAA. Furthermore, the dimethylarsine-induced breaks were diminished by the addition of SOD and catalase, suggesting that active oxygen produced by dimethylarsine was involved in the induction of DNA damage.

Differences between freshwater and seawater killifish (Oryzias latipes) in the accumulation and elimination of pentachlorophenol.

Freshwater and seawater acclimated (FWA and SWA) killifish (Oryzias latipes) were exposed to pentachlorophenol (PCP) for 3-10 days. Uptake and clearance rates of FWA and SWA killifish were determined. The estimated bioaccumulation factors (BCF) of PCP for FWA and SWA killifish were 1680 and 370, respectively. The smaller uptake rate and faster clearance rate resulted in the lower BCF for SWA killifish. Fresh- and seawater killifish excreted the PCP metabolites, the glucuronide and sulfate conjugates of PCP; the major metabolite of freshwater killifish was PCP sulfate; for seawater acclimated fish, it was PCP glucuronide. The greater excretion of PCP glucuronide by seawater killifish may be responsible for the rapid elimination of PCP. PCP accumulation in killifish decreased with higher pH levels in both freshwater and seawater environments, but these differences were less than the effect of salinity. The results indicate that salinity can affect the accumulation and elimination of environmental pollutants in killifish.

Inhibitory effect of azole antifungal agents on the glucuronidation of lorazepam using rabbit liver microsomes in vitro.

Azole antifungal agents (azoles) have inhibitory effects on the cytochrome P450. However, the effect of azoles on conjugative metabolism has not been given much attention. Lorazepam (LZP), a benzodiazepine sedative agent, is known to be metabolized by uridine 5'-diphosphate (UDP)-glucuronyltransferase. Herein we report investigation of the effect of azoles on the enzyme-kinetics of glucuronidation of lorazepam using rabbit liver microsomes in vitro. The Km and Vmax for LZP glucuronidation were determined to be 0.26+/-0.08 mM and 1.25+/-0.21 nmol/min/mg protein, respectively, when evaluated in the presence of a detergent 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate (CHAPS) (0.8 mg/mg protein). Azoles fluconazole, miconazole, and ketoconazole competitively inhibited the glucuronidation of LZP, with Ki values of 7.17+/-4.78 mM, 0.17+/-0.08 mM, and 0.092+/-0.026 mM, respectively. These results are comparable to the previously reported Ki values of azoles with zidovudine (AZT) glucuronidation (1.4, 0.18, and 0.08 mM for fluconazole, miconazole, and ketoconazole, respectively) [Sampol et al., Br. J. Clin. Pharmacol., 40, 83-86, 1995]. Therefore, in order to avoid possible side effects of LZP, the concomitant administration of LZP and azoles should be carefully evaluated.

Cellular response to oxidative damage in lung induced by the administration of dimethylarsinic acid, a major metabolite of inorganic arsenics, in mice.

Oral administration of dimethylarsinic acid (DMAA), a major metabolite of inorganic arsenics, induces DNA damage in the mouse and rat lung due to both active oxygens and dimethylarsenic peroxyl radical produced in the metabolism of DMAA. Our paper describes the cellular response to DMAA in the mouse lung. In male ICR mice given a single po dose (1500 mg/kg) of DMAA-Na, the activities of mitochondrial superoxide dismutase, glutathione peroxidase, and glucose-6-phosphate dehydrogenase significantly increased at 6 hr or longer after dosing, while cytosolic superoxide dismutase and catalase did not. With regard to cellular sulfhydryls after DMAA dosing, levels of reduced glutathione and nonprotein sulfhydryl decreased, while mixed disulfides significantly increased. Further, NADPH markedly decreased at 6-9 hr after DMAA dosing. These cellular variations suggest that the mouse pulmonary cell produced active oxygens, i.e., superoxide anion radical, hydrogen peroxide, and subsequent radicals in the metabolism of DMAA and that these and also the dimethylarsenic peroxyl radical were responsible for pulmonary DNA damage.

Induction of DNA damage by dimethylarsine, a metabolite of inorganic arsenics, is for the major part likely due to its peroxyl radical.

To reveal the mechanisms of previously reported lung-specific DNA strand scissions in murine after oral administration of dimethylarsinic acid (DMAA), a main metabolite of inorganic arsenics in mammals, the ultimate substance causing DNA lesion was investigated using dimethylarsine which was a further metabolite of DMAA. The alkaline elution assay using 3H-labeled DNA showed that a major portion of the strand breaks was not suppressed by SOD and catalase, suggesting an ultimate substance other than active oxygen participated in the DNA damage. By ESR analysis, a radical estimated to be (CH3)2AsOO. was detected as a reaction product of dimethylarsine and molecular oxygen. This peroxyl radical, rather than active oxygen, was assumed to play a major role in DNA damage.