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.     

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.     

Severe malabsorption in autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy syndrome successfully treated with immunosuppression

A 15 year old boy with autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy syndrome suffered recurrent episodes of severe intractable diarrhoea, steatorrhoea, and hypocalcaemia. The only treatment modality, which controlled the malabsorption syndrome, was immunosuppression with intravenous high dose methylprednisolone and oral methotrexate maintenance therapy.     

Toxic cardiogenic shock in a patient receiving weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin

A 54-year-old man was treated with weekly 24-h infusion of high-dose 5-fluorouracil (2600 mg/m2) and leucovorin (100 mg/m2) for metastatic colon cancer. At first, he tolerated the treatment well and no significant toxicity was identified. After a total of eight courses of treatment, a stable disease was observed, but mild shortness of breath was found on occasion. The patient had no previous history of cardiac disease and the heart performance assessed by left ventricular ejection fraction before treatment was normal. Unfortunately, acute pulmonary edema with lethal cardiogenic shock occurred during the ninth course of treatment, in spite of intensive medical treatment. The chest X-ray showed extreme cardiomegaly. Repeated assessment of his heart function by echocardiogram and ventricular ejection fraction revealed a very poor cardiac performance. Toxic cardiogenic shock during weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin is extremely rare. To the best of our knowledge, no case has been reported in the English literature. We report a case and the relevant literature about the incidence, clinical picture and possible pathophysiology on 5-fluorouracil-related cardioxicity is reviewed.      

Differentiation between malignant and benign pathologic fractures with F-18-fluoro-2-deoxy-<Emphasis Type="SmallCaps">D</Emphasis>-glucose positron emission tomography/computed tomography

Objective To evaluate the efficacy of F-18-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG PET/CT) in differentiating malignant from benign pathologic fractures. Materials and methods F-18 FDG PET/CT was performed on 34 patients with pathologic fractures between May 2004 and June 2007. Fractures were located in tubular bones (26), in the pelvis (six), in the spine (one) and in a rib (one). The FDG uptake pattern at the fracture site was described, whether FDG uptake occurred in the marrow or cortex and soft tissue. Maximum standardized uptake values (SUVmax, the largest value at the region of interest) were measured at the fracture site, including cortical bone, bone marrow and soft tissue. As a reference standard, biopsy was used for 12 patients and clinical follow-up for 22 patients. Sensitivity, specificity and diagnostic accuracy of PET/CT were calculated. Results There were 19 malignant and 15 benign fractures. In the malignant fractures, PET/CT demonstrated high (mean SUVmax 12.0, range 4.3 to 45.7) F-18 FDG uptake in bone marrow in most cases (17 of 19). In benign fractures, there was low FDG uptake (mean SUVmax 2.9, range 0.6 to 5.5) within cortical bone or adjacent soft tissue around the fracture, rarely in the marrow. There were significant differences in the pattern of intramedullary FDG uptake (P < 0.001) and in the mean SUVmax (P < 0.01) between malignant and benign fractures. The sensitivity, specificity and diagnostic accuracy of F-18 FDG PET/CT were 89.5%, 86.7% and 88.2%, respectively, with a cut-off SUVmax set at 4.7. The time interval between fracture and PET/CT did not significantly influence FDG uptake at the fracture site. Conclusion F-18 FDG PET/CT reliably differentiated between malignant and benign fractures based on the SUVmax and based on medullary uptake, which was characteristic for malignant fractures. This research was supported by the Yeungnam University research grants in 2007.     

Femoral head stress fracture: an unknown complication following Sugioka's transtrochanteric rotational osteotomy

Sugioka's transtrochanteric rotational osteotomy, as a treatment of osteonecrosis of the femoral head, has variable success rates. Its known complications include: progressive varus deformity, femoral neck fracture, and femoral head collapse. However, femoral head stress fracture has not been described as a complication of Sugioka's transtrochanteric rotational osteotomy. This article presents cases of 2 of 64 patients who underwent Sugioka's transtrochanteric rotational osteotomy between 1994 and 2006 and experienced femoral head stress fractures. Both patients were young and active. They presented with acute inability to bear weight and pain on the operated hip after mountain climbing 1 and a half to 3 years following the index surgery. Diagnosis of femoral head stress fracture was established by the presence of an inferolaterally-directed vertical fracture line from the superolateral aspect of the femoral head on computed tomography scans for both patients. One patient was successfully managed with conservative measures, whereas the other underwent total hip replacement after failed conservative treatment. We hypothesize that the direction alteration of the trabecular system due to proximal femoral segment rotation, varus positioning of the proximal femur, and inadequate placement of the screw into the necrotic femoral head may have caused the femoral head stress fractures after transtrochanteric rotational osteotomies. Stress fracture of the femoral head is a potential complication following Sugioka's transtrochanteric rotational osteotomy for osteonecrosis of the femoral head, which may be prevented by avoiding heavy exercises such as mountain climbing, until adequate remodeling of the trabecular system is gained and screws can be inserted into the femoral head subchondral bone as deeply as possible with avoidance of the necrotic area.     

Racial variations in Department of Veterans Affairs ambulatory care use and unmet health care needs

Our objective was to describe racial/ethnic variations in Department of Veterans Affairs (VA) ambulatory care use and its association with the presence of unmet health care needs. Using the 1992 National Survey of Veterans, we examined race/ethnicity and unmet health care need for ambulatory care users of VA and non-VA facilities. Black and Hispanic veterans were more likely to report any VA use. In unadjusted analyses, American Indian/Eskimo, Hispanic, and black veterans were 4.4, 2.5, and 1.9 times more likely, respectively, than white veterans to report an inability to get needed care. Adjusting for VA ambulatory care use diminished the disparity in inability to get needed care between American Indian/Eskimo or Hispanic veterans and white veterans and eliminated the disparity between black and white veterans. Our findings support the VA's role as a medical safety net provider and suggest that VA ambulatory care use is effective in mitigating health-related racial disparities for some veterans. Additional facilitators for reducing unmet need should be explored.