Stereoselective metabolism of lansoprazole by human liver cytochrome P450 enzymes.

The stereoselective metabolism of lansoprazole enantiomers was evaluated by incubation of human liver microsomes and cDNA-expressed cytochrome p450 (p450) enzymes to understand and predict their stereoselective disposition in humans in vivo. The intrinsic clearances (Clint) of the formation of both hydroxy and sulfone metabolites from S-lansoprazole were 4.9- and 2.4-fold higher than those from the R-form, respectively. The sums of formation Clint of both metabolites were 13.5 and 57.3 microl/min/mg protein for R- and S-lansoprazole, respectively, suggesting that S-lansoprazole would be cleared more rapidly than the R-form. The p450 isoform selective inhibition study in liver microsomes, and the incubation study of cDNA-expressed enzymes, demonstrated that the stereoselective sulfoxidation is mediated by CYP3A4 and that the hydroxylation is mediated by CYP2C9 and CYP3A4 as well as by CYP2C19. Total Clint values of hydroxy and sulfone metabolite formation catalyzed by all these p450 enzymes were consistently higher for S-lansoprazole than for the R-form. The CYP3A4 produced the greatest difference of Clint between S- and R-enantiomers, mainly due to a difference of sulfoxidation metabolism (Clint 76.5 versus 10.8 microl/min/nmol of p450, respectively), whereas CYP2C19-catalyzed hydroxylation resulted in a minor difference of Clint between S- and R-enantiomers (179.6 versus 143.3 microl/min/nmol of p450, respectively). However, the affinity of CYP2C19 on hydroxylation was 5.7-fold higher for S-enantiomer than for the R-form (Km 2.3 versus 13.1 microM), suggesting that the role of CYP2C19 on stereoselective hydroxylation would be more prominent at concentrations around the usual therapeutic level. These findings suggest that both CYP2C19 and CYP3A4 are major enzymes contributing to the stereoselective disposition of lansoprazole, but stereoselective hydroxylation of lansoprazole enantiomers is mainly influenced by CYP2C19, especially at the usual therapeutic doses.     

Temporomandibular joint arthrography following surgical treatment of internal derangements

Arthrograms of the temporomandibular joint were obtained in 20 symptomatic joints that had previous reconstructive arthroplasty with disk repositioning because of internal derangements. Preoperative arthrograms were available for comparison in 18 joints. Symptoms resulting in a postoperative arthrogram included pain, limited ability to open the mouth, and clicking of the joints. Postoperative arthrographic findings included limited anterior translation of the condyle (90%), irregularity in outline of the intraarticular contrast agent (60%), a conical configuration of the posterior recess (25%), decreased size of the joint (28%), anterior displacement of the meniscus (25%), and perforated meniscus (15%). Many of these findings may have resulted from fibrosis and scarring, which may be a response to intraarticular bleeding. The mechanism by which the fibrosis causes the postsurgical arthrographic features is discussed.     

Allograft rejection results from a failed attempt by the immune system to protect foreign tissue

The focus of our research is to understand the immune response to foreign tissue. We believe that adichotomy exists within the immune response to an allograft such that part of the response is dedicated to the protection of the graft. Nevertheless, in a dominantly graft-aggressive environment, rejection typically ensues. In this article, we describe models that have been set up to test directly the ability of potentially protective aspects of the immune response to prevent allograft rejection. We discussour data in the context of a growing body of exciting and often controversial literature.     

Increasing transplant mass results in long-term allograft survival and recovery from transplant vasculopathy

Late allograft rejection due to transplant vasculopathy continues to be a major clinical problem. Increasing the ratio of donor transplant size to recipient weight has been shown to reduce the incidence of late allograft failure. Using a murine pancreas transplant model we have tested the hypothesis that increasing the donor transplant size in a recipient can promote long-term allograft survival by promoting recovery from transplant vasculopathy. Recipients of an allograft that showed extensive vasculopathy were transplanted with a second donor transplant. The effect of the second allograft on the vasculopathy present in the first graft was measured. Transplanting a second allograft reversed all signs of ongoing rejection, including transplant vasculopathy, resulting in long-term survival of the first graft. Vasculopathy was only reversed if the first and second grafts were from the same mouse strain, suggesting an antigen-specific mechanism. However, the recovery of the first graft was not associated with antigen-specific peripheral tolerance.     

Induction of a TC1-mediated experimental autoimmune thyroiditis by deglycosylated porcine thyroglobulin

Contribution of cytotoxic T lymphocytes (CTL) to experimental autoimmune thyroiditis (EAT) was well defined (Speidel et al., Eur. J. Immunol. 1997, 27, 2391-2399, Ref. 7). The native porcine thyroglobulin (pTg) showed high sensitivity to endo-o-N-acetylglucosaminidase F (Endo F) and its molecular weights, corresponding to about 330 kDa as a monomer and 660 kDa as a dimer, were reduced to smaller molecular weight forms by Endo F and trifluoromethanesulfonic acid (TMSF). Deglycosylated porcine Tg (dgpTg) and native pTg were injected i.v. into CBA/J mice, without the aid of adjuvants. Both lymphocytic infiltrations of the thyroid glands and levels of Tg-specific CTL were similar to those found in conventional EAT induced by Tg and adjuvants. In contrast, proliferative responses in native pTg and dgpTg-injected mice could not be detected, and titers of antibodies to pTg and dgpTg were 20 times and 30 times lower than that of pTg and adjuvants, respectively. The EAT-inducer CTL belonged to the CD8+ cell subset and exerted their thyroiditogenic potential through release of IFN-gamma. It was concluded that dgpTg-induced EAT is mediated by type 1 cytotoxic T cells (Tcl). Also, results that EAT induction of the glycosylated pTg (gpTg) was much lower than that of dgpTg, suggested that the abberant and incomplete glycosylation of the thyroglobulin is responsible for the induction of autoimmune thyroiditis.     

Quality of life (QOL) assessment of MIP (mitomycin, ifosfamide and cisplatin) chemotherapy in advanced non-small cell lung cancers (NSCLC)

BACKGROUND: Quality of life (QOL) assessment has emerged to measure and quantify the balance between treatment benefit and toxicity, and has a value in predicting response and overall survival in cancer patients. METHODS: From July 1995 to February 1997, 38 symptomatic patients with advanced non-small cell lung cancer (NSCLC) were treated with MIP chemotherapy (mitomycin 6 mg/m2, ifosfamide 3000 mg/m2 and cisplatin 50 mg/m2 on day 1 every 3 weeks). Patients were assessed for QOL including physical well-being, general symptoms and lung cancer-specific symptoms, as well as objective response. RESULTS: The overall response rate was 38.9% (14/36, all were partial response) and the median duration of response was 3.5 months [95% confidence interval (CI) 2.0-4.0]. The median duration of overall survival was 7 months (95% CI 5.9-8.5). The overall improvement of QOL was 58.3% with 21 patients feeling better on treatment. The toxicity of chemotherapy was mild, mainly nausea/vomiting and minimal alopecia. Using multiple clinical predictors of survival (age, histology, stage, performance status), only change of QOL emerged significantly (P = 0.0007). CONCLUSIONS: MIP had an endurable response and low toxicity profile, and provided good QOL. Integral QOL data in our study provided the strong prediction of survival in advanced NSCLC. Further experienced QOL study will provide greatly enhanced outcome data in clinical trials.      

Ag-exchanged NaY zeolite introduced polyvinyl alcohol/polyacrylic acid mixed matrix membrane for pervaporation separation of water/isopropanol mixture

Ag-exchanged NaY zeolite (Ag-NaZ) particles were prepared by ion exchange and introduced to a polyvinyl alcohol (PVA) membrane cross-linked with polyacrylic acid (PAA) for the pervaporation dehydration of an isopropanol (IPA) aqueous mixture. The Ag-exchanged NaY zeolite particles were characterized by FE-SEM, EDS, BET, and XRD studies. The prepared Ag-NaZ-loaded PVA/PAA composite membrane was characterized by FE-SEM, XRD, a swelling study, and contact angle measurements. Pervaporation characteristics were investigated in terms of Ag-NaZ concentrations within PVA/PAA membranes using diverse feed solution conditions. The preferential sorption of IPA/water mixtures for Ag-NaZ-introduced membranes were also determined by calculating the apparent activation energies of IPA and water permeation, respectively. As a result, flux and selectivity increased with the Ag-NaZ concentration to 5 wt% in the membrane. Optimum pervaporation performance was observed in a 5 wt% Ag-NaZ-incorporated membrane with a flux equal to 0.084 kg m⁻² h⁻¹ and a separation factor of 2717.9 at 40 °C from an 80 wt% IPA aqueous feed solution.

Ag-exchanged NaY zeolite (Ag-NaZ) particles were prepared by ion exchange and introduced to a polyvinyl alcohol (PVA) membrane cross-linked with polyacrylic acid (PAA) for the pervaporation dehydration of an isopropanol (IPA) aqueous mixture.