Cytochrome P4502C9: an enzyme of major importance in human drug metabolism

Accumulating evidence indicates that CYP2C9 ranks amongst the most important drug metabolizing enzymes in humans. Substrates for CYP2C9 include fluoxetine, losartan, phenytoin, tolbutamide, torsemide, S-warfarin, and numerous NSAIDs. CYP2C9 activity in vivo is inducible by rifampicin. Evidence suggests that CYP2C9 substrates may also be induced variably by carbamazepine, ethanol and phenobarbitone. Apart from the mutual competitive inhibition which may occur between alternate substrates, numerous other drugs have been shown to inhibit CYP2C9 activity in vivo and/or in vitro. Clinically significant inhibition may occur with coadministration of amiodarone, fluconazole, phenylbutazone, sulphinpyrazone, sulphaphenazole and certain other sulphonamides. Polymorphisms in the coding region of the CYP2C9 gene produce variants at amino acid residues 144 (Arg144Cys) and 359 (Ile359Leu) of the CYP2C9 protein. Individuals homozygous for Leu359 have markedly diminished metabolic capacities for most CYP2C9 substrates, although the frequency of this allele is relatively low. Consistent with the modulation of enzyme activity by genetic and other factors, wide interindividual variability occurs in the elimination and/or dosage requirements of prototypic CYP2C9 substrates. Individualisation of dose is essential for those CYP2C9 substrates with a narrow therapeutic index.     

Fetal assessment based on fetal biophysical profile scoring. VIII. The incidence of cerebral palsy in tested and untested perinates

OBJECTIVE: The intent of this comparative clinical study was fourfold: (1) to determine the incidence of cerebral palsy in a large obstetric population, (2) to compare the incidence of cerebral palsy in patients at high risk referred for and managed according to the fetal biophysical profile score result with the incidence among unreferred and untested patients, (3) to determine the relationship, if any, between the last fetal biophysical profile score and the incidence of cerebral palsy, and (4) to categorize cases of cerebral palsy according to the clinical parameters and the probable time and nature of the damaging insult. STUDY DESIGN: In this retrospective 5-year comparative study (1987 to 1991) the incidence of cerebral palsy was determined by analysis of International Classification of Diseases, Ninth Revision, -coded related medical services. The clinical records were then sought and reviewed in index cases and obstetric, neonatal, and postnatal clinical data were abstracted. Cross-correlation with partial registries was done to confirm completeness of capture of index cases. The population of referred high-risk patients who received serial fetal biophysical profile scoring and were managed according to test results was determined by review of a prospective computer-stored database and by review of patient log books. The population of untested patients was calculated as the residual of total cases minus tested cases. The rate of cerebral palsy for all patients and for the tested and untested population was calculated and compared. The tested and untested perinates were compared for birth age, weight, and assigned timing or etiology of cerebral palsy. In the tested population the distribution of test results by last recorded biophysical profile score was determined and the relationship between the last test result and cerebral palsy and predictive accuracy parameters of the fetal biophysical profile score were calculated. RESULTS: The incidence of cerebral palsy among the 84,947 live births was 3.68 per 1000 live births (313 cases). The rate of cerebral palsy in the 26,290 referred high-risk tested patients was 1.33 per 1000 (35 cases) compared with a rate of 4.74 per 1000 live births in the 58,657 untested mixed low-risk/high-risk patients (278 cases). These differences were highly significant. A significant declining trend in the annual incidence of cerebral palsy was observed in the total population and the untested population, whereas the rate in the tested population remained relatively constant over the 5-year study interval. The differences in the cerebral palsy rate between the tested and untested population were not related to differences in gestational age, birth weight, or assigned timing or etiology category. In the tested population the relationship between the incidence of cerebral palsy and the last test fetal biophysical profile score was inverse, exponential, and highly significant. CONCLUSIONS: Antepartum assessment by fetal biophysical profile scoring is associated with a significant reduction in the incidence of cerebral palsy compared with untested patients. The relationship between the last test score and the incidence of cerebral palsy is inverse and exponential, suggesting that antenatal asphyxia is an important and potentially avoidable cause of cerebral palsy.     

Concomitant treatment with mild hyperthermia, cisplatin and low dose-rate irradiation in human ovarian cancer cells sensitive and resistant to cisplatin

Hyperthermia has been shown to be an effective radiation sensitizer. Cisplatin has also been shown to cause radiosensitization. In part, the sensitization is through the inhibition of repair of radiation damage. In this study we have set out to combine low dose-rate irradiation (during which extensive repair occurs) with both cisplatin and hyperthermia to maximize the radiation sensitizing effect. Two human ovarian carcinoma cell lines, one parental (A2780S) and the other a cisplatin resistant derivative (A2780CP) cell line were used in these experiments. Long duration hyperthermia at 40 degrees C was combined with low concentrations of cisplatin (0.5-3 microg/ml) and low dose-rate irradiation (LDRI). The responses to the individual treatments showed that there was cross resistance in the two cell lines for cisplatin and radiation, but for hyperthermia the opposite effect was found. When all treatments were given concurrently the response was greater than the calculated response of all three individual treatments, indicating a synergistic interaction. The effect was greater in the cisplatin resistant cell line. The combination of mild hyperthermia, low dose cisplatin and LDRI are a good combination for potential clinical application. In addition, this could be a good approach to deal with cisplatin resistance.     

Isolated lung perfusion with tumor necrosis factor for pulmonary metastases

BACKGROUND: A phase I trial was initiated to define the feasibility and safety of single-lung isolation perfusion with tumor necrosis factor-alpha, interferon-gamma, and moderate hyperthermia for patients with unresectable pulmonary metastases. METHODS: Twenty patients with lung metastases (Ewing's, 2; sarcoma, 8; melanoma, 6; other, 4) were considered for single-lung isolation perfusion with 0.3 to 6.0 mg of tumor necrosis factor-alpha and 0.2 mg interferon-gamma delivered through an oxygenated pump circuit. Sixteen perfusions were performed in 15 patients (bilateral in 1). Metastases were completely resected (no single-lung isolation perfusion) in 3 patients, 1 patient had extrapulmonary disease, and one single-lung isolation perfusion was aborted for mechanical reasons. RESULTS: There were no significant changes in systemic arterial blood pressure or cardiac output during perfusion. Systolic pulmonary artery pressure increased with isolation, but returned to pre-single-lung isolation perfusion levels after clamp release. The maximum systemic tumor necrosis factor-alpha level was 8 ng/mL, whereas pump-circuit levels ranged from 200 to 10,976 ng/mL. There were no deaths, and the mean hospitalization period was 9 days (range, 5 to 34 days). A short-term (6 to 9 month) unilateral decrease in perfused nodules was noted in 3 patients (melanoma in 1, adenoid cystic carcinoma in 1, renal cell carcinoma in 1). CONCLUSIONS: Future studies using a combination of biologic modifiers, chemotherapy, and hyperthermia should be pursued to define active cytotoxic agents that will preserve underlying pulmonary function.     

Non-helical perturbations of the flagellar filament: Salmonella typhimurium SJW117 at 9.6 A resolution

Using a liquid-helium-cooled superconducting electron cryo-microscope, we obtained low-dose images of negatively stained preparations at 4 K and collected structural data to 1/9.6 -1 for flagellar filaments from the strain SJW117 of Salmonella typhimurium (serotype gt). The subunits of this left-handed, straight filament are non-helically perturbed in a pairwise manner. The perturbation corresponds to an alternating conformation in every other row of subunits. These are the 5-start rows and, necessarily, the resulting structure has a seam. The perturbation is not confined to the outside but extends into the structure. We separated the non-symmetric and symmetric parts of the structural data and generated a three-dimensional reconstruction from the latter. The resulting density map is a structure similar in domain organization to the left-handed filament of S. typhimurium SJW1660. Filtered images generated from the non-symmetric component show an ordered and polar structure. The nature of the perturbation was analyzed by model building using a sphere to represent the subunit at low resolution. A lateral shift of approximately 10 degrees mimics the perturbation.     

Transcrystalline morphology of nylon 6 on the surface of aramid fibers

In this paper, the isothermal crystallization of nylon 6 in the presence of Kevlar 129 fiber was investigated by polarized optical microscopy (POM). The formation of a transcrystalline domain was found to be mainly controlled by crystallization conditions, such as the temperature of the isothermal crystallization, residual time at melting temperature and the cooling rate of the melt. The nucleation rate of nylon 6 on the fibers was mainly affected by the crystallization temperature. The interfacial transcrystallinity of nylon 6 occurred on the surface of Kevlar 129 fiber in the temperature range 130–190 °C. The reason for the formation of interfacial transcrystalline morphology is discussed from the molecular level, based on the understanding of the packing mode of nylon 6 chains around fibers and the interaction between matrix and fibers. It was found that the lattice matching and hydrogen‐bonding between nylon 6 and poly(p‐phenylene terephthalamide) (PPTA) crystals play an important role in the epitaxial crystallization. Copyright © 2004 Society of Chemical Industry