Effect of DPC 333 [(2R)-2-{(3R)-3-amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide], a human tumor necrosis factor alpha-converting enzyme inhibitor, on the disposition of methotrexate: a transporter-based drug-drug interaction case study.

DPC 333 [(2R)-2-{(3R)-3-amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide] is a potent human tumor necrosis factor alpha-converting enzyme inhibitor with potential therapeutic implications for rheumatoid arthritis. Methotrexate (MTX), a drug for the treatment of rheumatoid arthritis, is eliminated primarily unchanged via renal and biliary excretion in humans as well as in rats and dogs. The objective of the present study was to investigate the potential effect of DPC 333 on the disposition of MTX. In dogs, DPC 333 administered orally at 1.7 mg/kg 15 min before the intravenous administration of [14C]MTX (0.5 mg/kg) did not alter the plasma concentration-time profile of MTX; however, the total amount of radioactivity excreted in urine increased from 58.7% to 92.2% of the dose, and the renal clearance increased from 1.8 ml/min/kg to 2.9 ml/min/kg, suggesting a decrease in MTX disposition via biliary excretion. The biliary excretion of MTX was investigated in isolated perfused livers prepared from wild-type and TR(-) [multidrug resistance-associated protein 2 (Mrp2)-deficient] Wistar rats in the absence and presence of DPC 333. Mrp2-mediated biliary excretion of MTX was confirmed with 95.8% and 5.1% of MTX recovered in the bile of wild-type and TR(-) Wistar rats, respectively. DPC 333 at an initial perfusate concentration of 50 microM completely blocked the biliary excretion of MTX, but not the clearance from perfusate, in both wild-type and TR(-) rats. These results suggest that the enhanced renal elimination of MTX may be due to the potent inhibition of biliary excretion and active renal reabsorption by DPC 333 and/or its metabolites.     

Comparative 13-week cigarette smoke inhalation study in Sprague-Dawley rats: evaluation of cigarettes with two banded cigarette paper technologies.

This study compared the toxicological responses of Sprague-Dawley rats exposed nose-only to mainstream smoke (MS) from Test cigarettes (1, 2, and 3) to those of Control cigarettes without banded cigarette paper technologies (BCPT). Test cigarettes 1 and 2 had bands based on one technology (different band weight application) while Test cigarette 3 had bands based on another technology. The banded papers are representative of current marketed technologies. Rats were exposed to humidified HEPA filtered air (Sham) or to MS at concentrations of 0.06, 0.20, or 0.80 mg wet total particulate matter per liter air. Each exposure group contained 30 animals/sex (sentinel had 20 animals/sex). The study had two phases (13 weeks each): MS exposure (1 h/day, 5 days/week) and recovery without smoke exposure. Endpoints included clinical observations, respiratory physiology, hematology, serum chemistry, blood carboxyhemoglobin (COHb), serum nicotine, body/organ weights, gross pathology, and histopathology. Comparisons conducted were: Sham exposed vs. all cigarettes, Control cigarette vs. all Test cigarettes, and Test 1 vs. Test 2. Control and Test MS had comparable effects on respiratory physiology, COHb, serum nicotine, serum chemistry, and hematology. While some minor differences were observed, Control and Test MS had comparable effects on clinical signs, body/organ weights, and gross pathology/histopathology. Consequently, exposure of rats to equivalent MS concentrations from the four cigarettes induced similar toxicological responses in this study.     

Promoting contraceptive use among unmarried female migrants in one factory in Shanghai: a pilot workplace intervention

Background  

In urban China, more single women are becoming pregnant and resorting to induced abortion, despite the wide availability of temporary methods of contraception. We developed and piloted a workplace-based intervention to promote contraceptive use in unmarried female migrants working in privately owned factories.     

Treating lung cancer

Practice profiles are reflective pieces written by nurses in practice and based on continuing professional development articles. This week Ruth Garner discusses the role of the lung cancer nurse.     

The detection of adducts in human cervix tissue DNA using 32 P-postlabelling: a study of the relationship with smoking history and oral contraceptive use

³² was used to measure DNA adducts in the human cervix. Adductlevels were compared with patient smoking histories and contraceptiveuse. DNA adducts were found in 43 out of 58 samples. The numberof adducts ranged from 0.2 to 59.5 adducts/10⁸ nucleotides,though no significant difference was found to exist betweenthe number of DNA adducts detected and the smoking history ofeach patient. In contrast, a significant difference at the 1%probability level was found between the adduct levels obtainedfrom the cervical DNA of smokers who had used oral contraceptivesand smokers who did not. Autoradiograms revealed a variety ofadduct patterns. Some were found to have a diagonal zone ofradioactivity which migrated from the origin of the TLC plate.Other autoradiograms revealed the presence of additional adductspots located in the upper regions of the TLC plate, whereasothers revealed the presence of these adduct spots alone. Theorigin of the adduct spots located in the upper regions of theTLC plate is unknown.     

A case-control study of unexplained antepartum stillbirths.

OBJECTIVE: To ascertain factors that will identify women who are at increased risk of unexplained antepartum stillbirth. DESIGN: Matched case-control study. The cases and controls were initially analysed as a whole group and again after dichotomizing into those of low birthweight (< 2500 g) and those of normal birthweight (> or = 2500 g). SETTING: Western Australia 1980-1983. SUBJECTS: Unexplained antepartum stillbirths of > or = 1000 g birthweight (cases) and liveborn infants individually matched for year of birth, plurality, sex and birthweight of infant and race of mother (controls). RESULTS: The case pregnancies had more polyhydramnios (OR 10.83, 95% CI 2.41-48.69) and cord problems (OR 6.57 95% CI 1.36-31.75) than the controls but, paradoxically, other obstetric and medical complications were less common in the cases. The association with polyhydramnios persisted when the analysis was confined to those with low birthweight. With normal birthweight fetal distress was more frequent in the cases (OR 3.65 95% CI 1.36-9.80) but there were few other differences. CONCLUSIONS: The clinical and diagnostic systems currently in use are unable to identify many fetuses at risk of death. Decreases in the rate of unexplained antepartum stillbirths await the discovery of new preventable causes, or of innovations in clinical or laboratory aspects of obstetric care.     

An exploratory study of the structure and validity of pediatric examination of educational readiness (PEER) factors

The Pediatric Examination of Educational Readiness (PEER) is an assessment instrument specifically designed for use by pediatricians in assessing the development of preschool children. The present study investigated the psychometric properties of the PEER. Specifically, factor analyses of items from the Developmental Attainment and Associated Observation components of the test were performed. The PEER was administered to 69 preschool children. Three major factors were identified as making up the Developmental Attainment portion of the test: perceptual-motor, verbal-cognitive, and gross motor. The Associated Observations component was found to be composed of only one factor, attention. Children's performance on only two of these four factors was associated with their performance on the McCarthy Scales, the Woodcock-Johnson skills cluster, and the Minnesota Child Development Inventory. Discussion focused on the validity and utility of the PEER.     

Formation of hydroxyl radicals in the human lens is related to the severity of nuclear cataract

Recent studies have identified specific hydroxylated amino acid oxidation products which strongly suggest the presence of hydroxyl radical (HO.)-damaged proteins in human cataractous lenses. In the present study, the ability of early stage (type II) and advanced (type IV) nuclear cataractous lens homogenates to catalyse HO. production in the presence of H(2)O(2)was investigated using electron paramagnetic resonance (EPR) spectroscopy with the free radical trap, 5,5-dimethyl-1-pyrroline- N -oxide (DMPO). Cataractous lens homogenates incubated with 1 m m H(2)O(2)generated a distinct HO. signal, which was significantly more intense in the nuclear region of the type IV compared to the type II lenses. The ability of individual lens nuclei and cortices to stimulate HO. production was positively correlated. The DMPO-HO. signal was competitively inhibited by ethanol, confirming that the DMPO-HO. signal was due to HO. formation and not DMPO-OOH degradation. The metal ion chelator, diethylenetriaminepentaacetic acid, also inhibited HO. formation, indicating that lenticular metal ions play a key role in HO. formation. Cataractous lens homogenates also stimulated ascorbyl radical production, further suggesting the presence of redox-active metal ions in the tissue. Analysis of lenses for total Fe and Cu (using atomic absorption spectrometry) showed that the more advanced type IV lenses tended to have higher Fe, but similar Cu, levels compared to the type II lenses. The levels of both metals were lower in non-cataractous lenses. These data support the hypothesis that transition metal-mediated HO. production may play a role in the aetiology of age-related nuclear cataract.     

Distribution of ferritin and redox-active transition metals in normal and cataractous human lenses

Previous studies have shown that lenticular levels of Fe and Cu are elevated in age-related cataract. However, it is not known if these metals are present in a state that is permissive for redox reactions that may lead to the formation of free radicals. In addition, there is little data available concerning the concentration and lenticular distribution of ferritin, the major intracellular Fe-sequestering protein, in the lens. The aim of the present work was therefore to determine the distribution of ferritin and the redox-availability of Fe and Cu in healthy and cataractous lenses. Lens ferritin distribution was assessed by ELISA and immunohistochemistry. A modified ELISA detected ferritin in an 'insoluble' lens protein fraction. Ferritin levels were not significantly different in the cortex vs nucleus of healthy lenses. In contrast, ferritin levels in the cataractous lens nuclei appeared to be 70% lower compared to the cortex. This was at least partially due to the presence of ferritin within an insoluble protein fraction of the homogenized lenses. In normal lenses, ferritin staining was most intense in the epithelium, with diffuse staining observed throughout the cortex and nucleus. The redox-availability of lenticular metals was determined using: (1) autometallography; (2) Ferene-S as a chromogenic Fe chelator; and (3) NO release from nitrosocysteine to probe for redox-active Cu. The autometallography studies showed that the cataractous lenses stained more heavily for redox-active metals in both the nucleus and cortex when compared to age-matched control lenses. Chelatable Fe was detected in homogenized control lenses after incubation with Ferene-S, with almost three-fold higher levels detected in the cataractous lenses on average. The Cu-catalysed liberation of NO from added nitrosocysteine was not demonstrated in any lens sample. When exogenous Cu (50 n M) was added to the lenses, it was rapidly chelated. The cataractous samples were approximately twice as effective at redox-inactivation of added Cu. These studies provide evidence that a chelatable pool of potentially redox-active Fe is present at increased concentrations in human cataractous lenses. In contrast, it seems that lenticular Cu may not be readily available for participation in redox reactions.