Physiologically based pharmacokinetic modelling of oxycodone drug–drug interactions

Oxycodone is an opioid analgesic with several pharmacologically active metabolites and relatively narrow therapeutic index. Cytochrome P450 (CYP) 3A4 and CYP2D6 play major roles in the metabolism of oxycodone and its metabolites. Thus, inhibition and induction of these enzymes may result in substantial changes in the exposure of both oxycodone and its metabolites. In this study, a physiologically based pharmacokinetic (PBPK) model was built using GastroPlus™ software for oxycodone, two primary metabolites (noroxycodone, oxymorphone) and one secondary metabolite (noroxymorphone). The model was built based on literature and in house in vitro and in silico data. The model was refined and verified against literature clinical data after oxycodone administration in the absence of drug–drug interactions (DDI). The model was further challenged with simulations of oxycodone DDI with CYP3A4 inhibitors ketoconazole and itraconazole, CYP3A4 inducer rifampicin and CYP2D6 inhibitor quinidine. The magnitude of DDI (AUC ratio) was predicted within 1.5-fold error for oxycodone, within 1.8-fold and 1.3–4.5-fold error for the primary metabolites noroxycodone and oxymorphone, respectively, and within 1.4–4.5-fold error for the secondary metabolite noroxymorphone, when compared to the mean observed AUC ratios. This work demonstrated the capability of PBPK model to simulate DDI of the administered compounds and the formed metabolites of both DDI victim and perpetrator. However, the predictions for the formed metabolites tend to be associated with higher uncertainty than the predictions for the administered compound. The oxycodone model provides a tool for forecasting oxycodone DDI with other CYP3A4 and CYP2D6 DDI perpetrators that may be co-administered with oxycodone.     

Effect of pregnancy on periodontal and dental health

Clinical studies have shown that oral tissues can be affected by pregnancy. Pregnancy-related changes are most frequent and most marked in gingival tissue. Pregnancy does not cause gingivitis, but may aggravate pre-existing disease. The most marked changes are seen in gingival vasculature. Characteristic of pregnancy gingivitis is that the gingiva is dark red, swollen, smooth and bleeds easily. Women with pregnancy gingivitis may sometimes develop localized gingival enlargements. The gingival changes usually resolve within a few months of delivery if local irritants are eliminated. The inflammatory changes are usually restricted to the gingiva and probably do not cause permanent changes in periodontal tissues more often than those in the non-pregnant state. Although it is widely believed that pregnancy is harmful to the teeth, the effect of pregnancy on the initiation or progression of caries is not clear. Previous studies, however, indicate that the teeth do not soften, i.e. no significant withdrawal of calcium or other minerals occurs in the teeth. It is mainly the environment of the tooth that is affected. The number of certain salivary cariogenic microorganisms may increase in pregnancy, concurrently with a decrease in salivary pH and buffer effect. Changes in salivary composition in late pregnancy and during lactation may temporarily predispose to dental caries and erosion. Although their underlying mechanisms of action are not fully understood, pregnancy-related changes in the oral environment may have some untoward temporary or permanent effects on oral health. Most of these effects could be avoided by practising good oral hygiene.     

Matrix metalloproteinase-8 (MMP-8) is the major collagenase in human dentin

Objective

Previously an unidentified collagenolytic metalloprotease together with gelatinase (matrix metalloproteinase-2, MMP-2), and enamelysin (MMP-20) have been detected in human dentin. The aim of the study was to characterize dentinal collagenolytic enzymes. Furthermore, we hypothesized that the dentinal MMPs are protected by the mineral phase, and studied the stability of dentinal MMPs.

Design

To characterize dentinal collagenolytic enzymes, we used Western blotting with specific antibodies against MMP collagenases (MMP-1, -8, and -13) and cathepsin K. MMP-8 immunofluorometric assay (IFMA) was also used for MMP-8 detection, and functional collagenase activity was examined with type I collagen degradation assay. The stability of dentinal MMPs was examined by autoclaving dentin blocks before protein extraction and subsequent examination of protein levels and the activities of dentin collagenase and gelatinases.

Results

MMP-8 (collagenase-2) was detected in dentin both with Western blot and IFMA, and dentinal samples also cleaved the intact type I collagen into characteristic 3/4(αA)-cleavage products in vitro. No other collagenases or cathepsin K were detected. In autoclaved samples no MMP-8 was found, but gelatinase activity was observed in protein fractions of mineralized dentin.

Conclusions

MMP-8 represents the major collagenase in human dentin. Unlike MMP-8, dentinal gelatinases can be detected after autoclave treatment of dentin, indicating their high resistance to external sample treatment procedures.     

Pregnancy-related changes in human whole saliva

Flow rate, pH, buffer capacity, viscosity, sialic acid, selected proteins (amylase, lysozyme, peroxidase, lactoferrin) and anions (thiocyanate, hypothiocyanite) were analysed in paraffin-stimulated whole saliva of 16 women during the three trimesters of pregnancy and post partum. Salivary pH and buffer capacity decreased towards late pregnancy, followed by a rapid and significant (p < 0.01) increase after delivery. The specific activity of salivary peroxidase increased significantly (p < 0.05) during the third trimester, thus supporting the concept of oestrogen-dependency of this enzyme. None of the other parameters changed significantly during pregnancy or lactation. The results suggest that the composition of human saliva is influenced by female sex steroids during pregnancy.     

Protein Kinase C-β Dictates B Cell Fate by Regulating Mitochondrial Remodeling,Metabolic Reprogramming,and Heme Biosynthesis

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Bacterial ghosts as vaccine candidates for veterinary applications.

The application of new strategies to develop effective vaccines is essential in modern veterinary medicine. The bacterial ghost system is a novel vaccine delivery system endowed with intrinsic adjuvant properties. Bacterial ghosts are nonliving Gram-negative bacterial cell envelopes devoid of cytoplasmic contents while maintaining their cellular morphology and native surface antigenic structures including bioadhesive properties. They are produced by PhiX174 protein E-mediated lysis of Gram-negative bacteria. The intrinsic adjuvant properties of bacterial ghost preparations enhance immune responses against envelope bound antigens, including T-cell activation and mucosal immunity. Since native and foreign antigens can be expressed in the envelope complex of ghosts before E-mediated lysis, multiple antigens of various origins can be presented to the immune system simultaneously. The advantages of bacterial ghosts include the simplicity of the production method, safety, independence from the cold chain, and versatility as a combination vaccine.     

Antimicrobial resistance of invasive pneumococci in Finland in 1999-2000

The resistance patterns and macrolide resistance mechanisms of 910 Finnish invasive pneumococci isolated during 1999 and 2000 were studied. Macrolide resistance was detected in 6.9% of isolates. Penicillin resistance was detected in 1.5% of isolates, and penicillin intermediate resistance was detected in 4.0% of isolates. Active macrolide efflux, mediated by the mef(A) gene, was the most common macrolide resistance mechanism. Four macrolide-resistant isolates had mutations in rRNA or ribosomal protein L22.