Biotransformation, tissue distribution, and persistence of 4-nonylphenol residues in juvenile rainbow trout (Oncorhynchus mykiss)

Alkylphenols are weak oestrogenic environmental contaminants and have been implicated in the disruption of endocrine function in wildlife. The influence of biotransformation, tissue distribution, and elimination on biological activity was investigated in juvenile rainbow trout following a single iv dose of [3H]4-nonylphenol. Distribution and elimination of [3H]4-nonylphenol residues in tissues sampled 1, 2, 4, 24, 48, 72, and 144 hr after dosing was determined by sample combustion and liquid scintillation counting (LSC). Total 3H-labeled residue concentrations in trout 144 hr after dosing were in order: bile >> faeces >> liver > pyloric caecae > kidney > brain, gill, gonad, heart, plasma, skeletal muscle, and skin. The depletion kinetics of [3H] residues from tissues and plasma was biphasic with prolonged b-phase half-lives in muscle and liver of 99 hr. Radio-HPLC analysis of metabolites in bile, liver, pyloric caecae, and faeces samples demonstrated similar profiles and contrasted with muscle where only parent compound was found. The predominant metabolite in bile was a glucuronide conjugate of 4-nonylphenol. Other metabolites included glucuronide conjugates of ring or side chain hydroxylated 4-nonylphenol. Liver contained a low level (1.7%) of covalently bound residues. Metabolism studies using isolated trout hepatocytes produced a similar range of metabolites and a sulfate conjugate of hydroxylated 4-nonylphenol. Despite rapid metabolism and excretion, a substantial depot of parent compound remained in muscle which will have implications for the maintenance of 4-nonylphenol residues and associated biological activity

LC/MS study of benzydamine metabolites in bovine liver slices

Benzydamine hydrochloride (BZ) is a nonsteroidal anti-inflammatory drug widely used in human and veterinary therapy. It is metabolized by cattle liver microsomes to benzydamine N-oxide (BZ-NO), Nor-benzydamine (Nor-BZ), and to a more polar metabolite. Its biotransformation in cattle has been studied by using precision-cut liver slices, an alternative in vitro model that is increasingly utilised. Bovine liver slices (Krumdieck Tissue Slicer, 200 \uf06dm thick, 8 mm diameter) were incubated for 0, 2, 4, 6, 8 and 24 hours with BZ (100, 500 and 1000 \uf06dM). The incubation mixtures, containing RPMI 1640 W/Glutamax II with 25 mM HEPES (Gibco), and supplements, were maintained at 37\ub0C with 95%O2/5% CO2. The medium obtained from incubated slices was analysed by LC-MS. Nine new metabolites were found besides Nor-BZ and BZ-NO and tentatively identified on the basis of their daughter and grand-daughter ion mass spectra. Three proposed pathways can explain the formation of these metabolites in cattle: benzyl or benzene hydroxylation, dephenylation and conjugation with glucuronic acid to form N+-glucuronides. BZ-NO was the most important derivative and reached at 24 h the highest levels. Previous studies in rats (1) demonstrated that BZ-NO is reduced back to BZ both in vitro and in vivo. Actually, it can act as a reservoir of the parent compound, continually being oxidised and reduced while other metabolites are excreted. References: (1) Kataoka et al. (1973) Chem. Pharm. Bull. 21, 358-365 Work supported by a MURST grant (ex 40% 1998)

Mutagenic activation and detoxification of benzo[a]pyrene in vitro by hepatic cytochrome P450 1A1 and phase II enzymes in three meat-producing animals

The mutagenic activation activity of hepatic microsomes from three meat-producing animals (cattle, deer and horses) was compared with those of rats as a reference species. In the Ames Salmonella typhimurium TA98 assay, the liver microsomes of all examined animals mutagenically activated benzo[a]pyrene, an ideal promutagens, in terms of production of histidine-independent revertant colonies. The microsomes of horses had the highest ability to produce revertant colonies of the examined animals under both low and high substrate concentrations. Inhibition of this mutagenic activity using α-naphthoflavone, anti-rat CYP1A1, CYP3A2 and CYP2E1 antibodies suggests that this activity was mainly because of CYP1A1 in these animals as well as in rats. The addition of co-factors for two phase II enzymes, microsomal UDP glucoronosyl transferase and cytosolic glutathione-S-transferase, reduced the production of the revertant colonies in a concentration-dependent manner. Interestingly, horses had the highest reduction rate among the examined animals, suggesting that phase II enzymes play a great role in producing a state of balance between the bioactivation and detoxification of xenobiotics in these meat-producing animals. This report is the first to investigate the mutagenic activation activity of the hepatic microsomes and the role of phase II enzymes against this activity in meat-producing animals

Intra-articular Hyaluronic Acid (HA) and Platelet Rich Plasma (PRP) injection versus Hyaluronic acid (HA) injection alone in Patients with Grade III and IV Knee Osteoarthritis (OA): A Retrospective Study on Functional Outcome

Introduction: Intra-articular hyaluronic acid (HA) is widely utilized in the treatment of knee osteoarthritis whereas platelet rich plasma (PRP) enhances the regeneration of articular cartilage. This study analyses the efficacy of HA and PRP in grade III and IV knee osteoarthritis. Methodology: This is a cross sectional study with retrospective review of 64 patients (101 knees) which includes 56 knees injected with HA+ PRP, and 45 knees with HA only. Results: During the post six months International Knee Documentation Committee (IKDC) evaluation, HA+PRP group showed marked improvement of 24.33 compared to 12.15 in HA group. Decrement in visual analogue score (VAS) in HA+PRP was 1.9 compared to 0.8 in HA group. Conclusion: We propose intra-articular HA and PRP injections as an optional treatment modality in Grade III and IV knee osteoarthritis in terms of functional outcome and pain control for up to six months when arthroplasty is not an option

Late preterm birth and growth trajectories during childhood: a linked retrospective cohort study

Abstract Background Evidence suggests that accelerated postnatal growth in children is detrimental for adult cardiovascular health. It is unclear whether children born late preterm (34–36 weeks) compared to full term (≥ 39 weeks), have different growth trajectories. Our objective was to evaluate the association between gestational age groups and growth trajectories of children born between 2006–2014 and followed to 2021 in Ontario, Canada. Methods We conducted a retrospective cohort study of children from singleton births in TARGet Kids! primary care network with repeated measures of weight and height/length from birth to 14 years, who were linked to health administrative databases. Piecewise linear mixed models were used to model weight (kg/month) and height (cm/month) trajectories with knots at 3, 12, and 84 months. Analyses were conducted based on chronological age. Results There were 4423 children included with a mean of 11 weight and height measures per child. The mean age at the last visit was 5.9 years (Standard Deviation: 3.1). Generally, the more preterm, the lower the mean value of weight and height until early adolescence. Differences in mean weight and height for very/moderate preterm and late preterm compared to full term were evident until 12 months of age. Weight trajectories were similar between children born late preterm and full term with small differences from 84–168 months (mean difference (MD) -0.04 kg/month, 95% CI -0.06, -0.03). Children born late preterm had faster height gain from 0–3 months (MD 0.70 cm/month, 95% CI 0.42, 0.97) and 3–12 months (MD 0.17 cm/month, 95% CI 0.11, 0.22). Conclusions Compared to full term, children born late preterm had lower average weight and height from birth to 14 years, had a slightly slower rate of weight gain after 84 months and a faster rate of height gain from 0–12 months. Follow-up is needed to determine if growth differences are associated with long-term disease risk