Simultaneous determination of serum trimethadione and its metabolite by gas chromatography.
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Biomedical subjects
Publications and source records attributed to S Misawa.
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A 37-year-old Japanese male patient with acute myelomonocytic leukemia subtype M4 (according to FAB classification) associated with bone marrow eosinophilia and specific chromosome abnormalities: a pericentric inversion of chromosome 16, inv(16)(p13q22); a long arm deletion of chromosome #7, del(7)(q22q34); and a gain of chromosomes #8 and #22 is reported. In addition to the modal karyotype, 47,XY,7q-,inv(16),+22, there were three other clones whose karyotypes were 46,XY,inv(16); 47,XY,inv(16),+22; and 48,XY,+8,inv(16),+22. As these karyotypes were related to each other, the presence of multiple clones indicated that karyotypic evolution had occurred. The karyotypic evolution associated with 7q- has not been reported previously in patients with M4Eo with inv(16).
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Two sublines of HL-60 human promyelocytic leukemia cells were examined cytogenetically with banding techniques. The karyotype of one subline was 44,X,-X,-5,-9,-10,-15,-17,+18,8q+,14q-,16q+,16q+,+mar1,+mar2 ,+mar3. The defective chromosome #8 contained an expanded chromosomal segment at the end of the long arm at band q24. The segment appeared to be a homogeneously staining region on the basis of quinacrine fluorescence banding. Using G-banding technique, this segment showed some evidence of indistinct aberrant bands and, thus, was designated an abnormally banded region (ABR). Double minute chromosomes (DM) were not seen in these cells. The second subline showed a similar karyotype; however, these cells lacked the 8q+ marker and contained one to 37 DM in approximately 90% of the cells examined. Because HL-60 cells are known to contain multiple copies of the c-myc oncogene, in situ chromosomal hybridization of a c-myc probe to HL-60 metaphase cells was performed to localize the amplified genes. The hybridization studies revealed localization to the ABR, as well as to DM, which is consistent with amplification of c-myc within these novel interchangeable chromosomal aberrations.
The metabolism of trimethadione (TMO) following oral administration (4 mg kg-1) has been studied in 11 young male and 11 elderly male patients. The elimination half-life (h) of TMO was 11.8 +/- 1.4 (mean +/- s.e. mean) in the young and 23.5 +/- 2.17 in the elderly (P less than 0.01). Total body clearance (1 h-1 kg-1) was 41.4 +/- 2.8 in the young and 29.0 +/- 2.4 in the elderly (P less than 0.01). The apparent volume of distribution (1 kg-1) was 0.67 +/- 0.03 in the young and 0.65 +/- 0.04 in the elderly. Serum dimethadione (DMO)/TMO ratios at 4 h were 0.65 +/- 0.03 in the young and 0.46 +/- 0.03 in the elderly (P less than 0.01). These results suggest that N-demethylation of TMO is inversely related to age.
A family is described in which six members developed acute nonlymphocytic leukaemia (ANLL) over the past 15 years, all morphologically FAB M6. Five affected individuals (ages 54-73) are members of a single sibship, the sixth (age 31) was the son of one of the affected sibs. The family lives in a rural area, and no environmental hazard has been identified. One of the six patients never resided in the same geographic area as the others. Three patients with leukaemia died without chemotherapy, two died shortly after the initiation of chemotherapy and the most recent patient never achieved remission, surviving 10 months. Bone marrow specimens from the two most recent patients were analysed for cytogenetic abnormalities using chromosome banding techniques. In addition, skin fibroblasts were examined in a single patient. The fibroblasts had a normal karyotype. Bone marrow cells from both patients had complex abnormalities. Some similarities were observed, including: hypodiploidy; loss of one chromosome 20; the presence of multiple marker chromosomes. In each case one marker appeared to involve the 'missing' no. 20 with an alteration of the long arm--loss (20q-) in one patient and gain (20q+) in the other. Peripheral blood lymphocytes were grown in folate deficient medium, but no evidence for folate sensitive fragile sites was found. Marrow chromosomes from a third leukaemic sibling were examined without banding techniques in 1976 and the karyotype was 45,XY,-18,-F(19 or 20), +marker. No specific cytogenetic finding was common to the three patients studied except for the loss of an F group chromosome. This family is unique in the literature with six cases of familial leukaemia of the same morphologic subtype, and the cytogenetic findings suggest that loss or rearrangement of part of the long arm of a single chromosome 20 may have occurred in each of the three patients examined.
Serum dimethadione (DMO)/trimethadione (TMO) ratios after oral administration of TMO have been investigated in 10 patients with normal livers, 8 patients with hepatoma and 8 patients with hepatoma and cirrhosis. Serum concentration ratios of DMO to TMO at 4 h after oral administration of TMO in patients with chronic liver disease were significantly decreased by 27% for those with hepatoma and 52% for those with hepatoma and cirrhosis. Serum DMO/TMO ratios at 4 h correlated well with liver function characteristics (total protein r = 0.741, plasma albumin r = 0.826, total bilirubin r = -0.725, cholinesterase r = 0.853) as well as with pharmacokinetic parameters (total body clearance r = 0.852, half-life r = -0.636) in both patients with normal livers and patients with chronic liver disease. This study suggests that serum DMO/TMO ratios in a blood sample obtained by a single collection after an oral administration of TMO might provide a clinically useful index of the hepatic drug-oxidizing capacity in an individual patient with chronic liver disease without determining the liver function characteristics or the pharmacokinetic parameters.
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A 49-year-old nursery school teacher noticed epigastric discomfort and loss of appetite, and was hospitalized for diagnosis and treatment on Dec. 19, 1984. She was diagnosed to have Borrmann type 4 gastric cancer with Schnitzler's metastasis. After one month's administration of UFTM-O (UFT, mitomycin C, OK-432) subjective symptoms disappeared and improvement of the gastric lesion was demonstrated 2 months later. On Apr. 4, 1985 she was able to return to work, receiving UFTM-O therapy for one year as an outpatient. When ascites appeared in October, UFTM-O was discontinued and a single intraperitoneal administration of cis-platinum was done for peritoneal effusion. Another combination chemotherapy consisting of MTX, 5-FU and OK-432 was started, but she died 3 months later. In consequence, she had been able to live 18 months from the initial diagnosis. Moreover, she was able to enjoy a high quality of life, which meant she was able to return to her work and travel abroad, during the initial two-thirds of the disease period.
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Trimethadione (TMO) is exclusively metabolized to dimethadione (DMO) by cytochrome P-450 dependent mono-oxygenase in liver microsomes. We have chosen TMO as an indicator compound for estimating the microsomal function of the liver. TMO tolerance test was performed in the CCl4 intoxicated injury or 68% partial-hepatectomized rats. Serum DMO/TMO ratios in 2 hours following oral administration of TMO in these rats in vivo were well correlated with changes in content of hepatic cytochrome P-450 and activity of TMO N-demethylase in vitro. TMO tolerance test could also determine quantitatively the changes of the functional capacity of the liver in the 68% partial hepatectomy. These results suggest that TMO tolerance test is a useful tool for the surgical indication in the hepatectomy.
Cytogenetic studies were performed on a group of 32 patients with myelodysplastic syndrome (MDS). Five patients had refractory anemia (RA), four RA with ring sideroblasts (RARS), nine RA with excess blasts (RAEB), eight RAEB 'in transformation' (RAEB-T), three chronic myelomonocytic leukemia (CMML) and three secondary MDS (SMDS). Two patients in the SMDS group had been treated with alkylating agents for lung cancer and polycythemia vera, respectively. The other had been exposed to thorotrast. Chromosome analyses were performed with Q and G bandings on bone marrow cells incubated for 24 hr. A clonal chromosomal abnormality was observed in the marrow cells from 19 of the 32 patients (59%). Chromosomal abnormalities of nos. 5 and/or 7 were found in five patients, and were probably specific for RAEB-T and SMDS. Among the twelve patients with solely abnormal metaphases (AA), eight (67%) progressed to acute leukemia, a higher proportion than the three from the 13 patients (23%) with solely normal metaphases (NN) (P less than 0.05). One of the seven patients (14%) with both normal and abnormal metaphases (AN) developed acute leukemia (AA v. AN, P less than 0.03). In only two of the 12 patients who progressed to acute leukemia (17%), was complete remission achieved. The median survival time was only 4.0 months for patients with karyotype AA compared with 18.0 months for AN and 24.0 months for NN (AA v. AN, P less than 0.05, AA v. NN, P less than 0.05). The absence of cytogenetically normal cells indicated a poor prognosis with frequent progression to acute leukemia which is resistant to chemotherapy. Progression to acute leukemia depended not only on chromosomal abnormalities but also on morphological subtype classified according to French-American-British co-operative group criteria. Morphological findings and karyotype combined gave a good indication of the outcome for patients with MDS.
Unusual cytogenetic findings are described in two patients with acute leukemia and rearrangements involving chromosomes 4 and 11. Both patients had clinical and phenotypic features often found in leukemia with t(4;11)(q21;q23). At initial diagnosis, one patient showed a standard t(4;11) with duplication of the 4q-translocation derivative. The latter finding has been described previously in a few patients with t(4;11) in association with disease progression. By analogy with the Ph1 chromosome in chronic myelogenous leukemia, duplication of the 4q-suggests that this derivative is the critical recombinant in the t(4;11). The second patient has a novel complex translocation, t(4;11;15)(q21;q23;q21). Analysis of this variant translocation implies that the 11q+ is the consistent chromosome rearrangement in this type of leukemia. The apparent contradiction of the findings in these and other relevant reported cases reviewed here suggests that genes on both the 11q+ and 4q- recombinant chromosomes are important, in either the etiology or the progression of this disease.