OBJECTIVE: The aim of this study was to clarify the effect of genetic polymorphisms of CYP2C19 on the pharmacokinetics of phenobarbitone (PB) using a nonlinear mixed-effects model (NONMEM) analysis in Japanese adults with epilepsy. METHODS: A total of 144 serum PB concentrations were obtained from 74 subjects treated with both PB and phenytoin but without valproic acid. All patients were classified into three groups by CYP2C19 genotyping: G1, G2 and G3 were homozygous for the wild type of CYP2C19 (*1/*1), heterozygous extensive metabolizers (EMs), (*1/*2 or *1/*3), and poor metabolizers (PMs), (*2/*2, *2/*3), respectively. All data were analyzed using NONMEM to estimate pharmacokinetic parameters of PB with respect to the CYP2C19 genotype. RESULTS: Thirty-three patients belonged to G1 (44.6%), 35 to G2 (47.3%), and 6 to G3 (8.1%). The total clearance (CL) of PB significantly decreased by 18.8% in PMs (G3) relative to EMs (G1 and G2). The CL tended to be lower in G2 than in G1. CONCLUSION: In this study, we first demonstrated the effect of the CYP2C19 polymorphism on pharmacokinetics of PB by genotyping. The contribution of other metabolic enzymes in the metabolism of PB in humans remains to be elucidated; however, it appears that the disposition of PB is mediated in part by this enzyme. The estimated population clearance values in the three genotype groups can be used to predict the PB dose required to achieve an appropriate serum concentration in an individual patient.

Adolescent↗

PubMedDate not supplied

NPC1 gene mutations in Japanese patients with Niemann-Pick disease type C.

Complementary and genomic DNAs isolated from the fibroblasts of 10 Japanese (7 late infantile, 2 juvenile, and 1 adult form of the disease) and one Caucasian patient with Niemann-Pick disease type C were analyzed for mutations in the NPC1 gene. Fourteen novel mutations were found including small deletions and point mutations. A one-base deletion and a point mutation caused splicing errors. The mutations were not clustered in any particular region of the gene and were found both in and out of the transmembrane domains. Three patients were homozygous, five were compound heterozygous, and the remaining three were suspected of being compound hetrozygous with an unknown error in one of their NPC1 alleles. Of the 14 mutations, the G1553A substitution that caused a splicing error of exon 9 appeared to be relatively common in Japanese patients, because two patients were homozygous and one patient was compound heterozygous for this mutation.

Adolescent↗

PubMedDate not supplied

Studies on vitrectomy cases associated with complicated branch retinal vein occlusion.

PURPOSE: To study the preoperative factors leading to vitrectomy, and to demonstrate the postoperative conditions causing the decreased visual acuity that results from branch retinal vein occlusion (BRVO). METHODS: In 113 patients (114 eyes) with BRVO, the following data were analyzed: age, general complications, distribution of occluding vessels, location of retinal breaks, classification of vitreoretinal pathology, and the number of cases, period from onset of BRVO to vitreous hemorrhage and from vitreous hemorrhage to vitrectomy, number of operations, relationship between posterior vitreous detachment (PVD) and number of operations, preoperative photocoagulations, pre- and postoperative visual acuity, and cases with poor visual outcome. RESULTS: The visual prognosis was much better in cases with vitreous hemorrhage only than in those with proliferative membrane and retinal detachment (P =.0023). Repeated surgeries were needed in the cases where there was only partial PVD (P =.0029). Macular disorders and optic nerve atrophy were the main causes of postoperative visual acuity < 0.1. CONCLUSIONS: Early vitrectomy before development of vitreo retinal proliferation and retinal detachment, especially in cases where there is only partial PVD, seems to be essential for case management and treatment to attain better visual acuity for the patient.

Aged↗

PubMedDate not supplied

Effects of the Na+/H+ exchange inhibitor cariporide (HOE 642) on cardiac function and cardiomyocyte cell death in rat ischaemic-reperfused heart.

1. Na+/H+ exchange has been implicated in the mechanism of reperfusion injury. We examined the effects of the cardiac-specific Na+/H+ exchange inhibitor cariporide (HOE 642) on postischaemic recovery of cardiac function and cardiomyocyte cell death (i.e. necrosis and apoptosis). 2. Rat isolated and buffer-perfused hearts were subjected to 25 min normothermic global ischaemia followed by 120 min reperfusion. Cariporide (10 micromol/L) or its vehicle (0.01% dimethylsulphoxide) was administered for 15 min before ischaemia and for the first 30 min after reperfusion. 3. Cariporide significantly improved the recovery of isovolumic left ventricular function (heart rate, left ventricular developed pressure and left ventricular end-diastolic pressure) and coronary flow throughout reperfusion. Creatine kinase release during reperfusion was significantly less in the cariporide-treated heart. In situ terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL)-positive cardiomyocytes were also significantly less in the cariporide-treated heart after 120 min reperfusion. Electron microscopy showed necrotic changes without typical apoptotic features in cardiomyocytes after reperfusion. Such necrotic changes were mitigated by cariporide. Simultaneous detection of necrotic and apoptotic cardiomyocytes using propidium iodide (PI) and Annexin V revealed that cardiomyocytes in the infarct area were stained with only PI or both PI and Annexin V. Cariporide did not alter the pattern of cardiomyocyte staining with PI and Annexin V, although the number of cardiomyocytes stained with PI or PI plus Annexin V was less than that in vehicle-treated hearts. 4. These results suggest that apoptosis is not a major manifestation of cardiomyocyte cell death in the ischaemic-reperfused myocardium and a cariporide-sensitive mechanism of reperfusion injury promotes both necrotic and apoptotic processes of cell death.

Animals↗

PubMedDate not supplied

Selective IgG2,4 subclass and IgE deficiencies in an adult patient with recurrent pneumonia.

A 28-year-old woman with recurrent pneumonia was found to have selective IgG2, 4 subclass and IgE deficiencies. She had a history of repeated episodes of otitis media and sinusitis in childhood. Her total immunoglobulin level was slightly below the normal range, and selective deficiencies of IgG2, 4 and IgE were found. Although lymphocyte responses to several mitogens were within the normal ranges, peripheral blood mononuclear cells produced only IgM when stimulated by Staphylococcus aureus Cowan 1 and interleukin-2. Gene deletion of the IgG2, 4 subclass was not found, but polymorphism of the IgG gene was detected by DNA analysis of the patient's lymphocytes.

Adult↗

PubMedDate not supplied

Chromosome 17 allelic loss in astrocytic tumors and its clinico-pathologic implications.

To prognosticate the implications of various allelic losses on chromosome 17 in the morphology and biology of astrocytic tumors, we have examined loss of heterozygosity (LOH) at 14 microsatellite loci on chromosome 17 in a series of 19 astrocytic tumors (3 astrocytomas, 5 anaplastic astrocytomas, and 11 glioblastomas). The DNA samples extracted from tumor and matched normal brain tissue were amplified by polymerase chain reaction (PCR) followed by polyacrylamide gel electrophoresis and photography under UV transillumination. The molecular genetic data were compared with immunohistochemistry performed with antibodies to glial fibrillary acidic protein (GFAP), MIB-1 and p53 protein. LOH was observed in 11/19 (58%) instances with frequent involvement of TP53, NF1, and D17S795 loci, LOH at D17S578 and D17S520 occurred in recurrent tumors exclusively. Allelic status of D17S795 in all 12 informative instances were concordant with GFAP immunoreactivity (p < 0.01, Fisher's test). p53 immunopositivity (> 25% of tumor cell nuclei) was seen in 11 (58%) tumors, of which 6 were informative of TP53 locus with 2 (33%) demonstrating LOH. The MIB-1 staining indexes in astrocytomas, anaplastic astrocytomas, and glioblastomas were 1.9 +/- 0.9, 8.4 +/- 4.0, and 17.1 +/- 7.1% (mean +/- SD), respectively, and their differences were statistically significant (p < 0.05, Student's t test). A trend of inverse relationship between patient survival and the number of tumor cell nuclei with immunohistochemically detectable p53 protein was seen in glioblastoma cases: 20.5 +/- 12.7 versus 13.7 +/- 6.3 months (mean +/- SD) in instances with > or > or = 25% positive cells, respectively. We conclude, the intriguing correlation between allelic status of D17S795 microsatellite locus and GFAP immunoreactivity suggests the possible involvement of q21.2 segment of chromosome 17 in the morphology and biology of astrocytic tumors.

Alleles↗