Rituximab combined with a small dose of melphalan for a refractory follicular lymphoma patient

A 48-year-old male patient with follicular lymphoma, grade II, stage IV, was treated with CHOP, ESHAP and MACOP-B, resulting in partial remission. After 9 months, the disease progressed and several chemotherapy agents, including three courses of rituximab combined with etoposide, sobuzoxane or methotrexate, only resulted in a stable disease response. However, the fourth course of rituximab combined with a small dose of melphalan produced excellent results and the complete response continued for more than 15 months. It is possible that these two drugs may act synergistically.     

Toxicokinetics of bisphenol A in rats, monkeys and chimpanzees by the LC-MS/MS method

We examined the toxicokinetics of bisphenol A (BPA) in F344 rats, cynomolgus monkeys and chimpanzees. Serum BPA levels were quantified using the LC-MS/MS method. After oral administration at 10 mg/kg, the maximum concentration in the serum (C(max)) and the area under the serum concentration curve (AUC) of BPA in cynomolgus monkeys and chimpanzees were greater than in rats. After oral administration at 100 mg/kg, AUC during the first 4h (AUC(0-->4h)) in cynomolgus monkeys was greater than in rats. In rats, the serum BPA levels were increased again 6h or later after oral administration at each dose, which suggested the enterohepatic circulation of BPA in rats. After subcutaneous administration at 10 mg/kg, the AUCs were ranked in the following order: cynomolgus monkeys>chimpanzees>rats, and C(max) in cynomolgus monkeys was greater than in rats and chimpanzees. After subcutaneous administration at 100 mg/kg to cynomolgus monkeys and rats, both the C(max) and AUCs in cynomolgus monkeys were greater than in rats. In all species, the oral administration of BPA resulted in much lower C(max) and AUCs than subcutaneous administration at the corresponding doses, indicating the low bioavailability of oral administration. This result suggests that BPA undergoes an extensive first-pass metabolism in these animal species. AUCs of subcutaneous administration and the AUC (0-->4h) of oral administration in the two primates were greater than that in rats. Because the systemic clearance for BPA is assumed to be dependent on the hepatic blood flow-rate, the high AUCs in primates are considered to be due to the lower systemic clearance by a lower hepatic blood flow-rate in primates than in rats. In addition, the toxicokinetics of the metabolites of BPA were examined. After the oral administration of 10 mg/kg BPA, both C(max) and AUCs of BPA metabolites were ranked in the following order: cynomolgus monkeys>chimpanzees>rats, and the terminal elimination half-life (T(1/2)) in rats was greater than that in cynomolgus monkeys and chimpanzees, suggesting the enterohepatic circulation of BPA in rats. From these results, the systemic clearance of BPA in primates is considered to be close to that in humans due to the similarity of the hepatic blood flow-rate. Furthermore, the major elimination route of BPA metabolites in primates is assumed to be renal excretion, as in humans, because the enterohepatic circulation that was observed in rats was not observed. In conclusion, primates are thought to be served as a valuable surrogate model for the toxicokinetics of BPA in humans.     

Familial acanthosis nigricans with p.K650T FGFR3 mutation

Acanthosis nigricans (AN) is a pigmentary skin disorder, which may present in association with clinical disorders such as obesity and malignancy. Occasionally, this unique skin manifestation is seen in alliance with several skeletal disorders, such Crouzon syndrome, achondroplasia and hypochondroplasia (HCH). These orthopedic disorders are known to have genetic changes in FGFR3. Recently, AN was reported in HCH with p.K650T mutation in FGFR3, and to date, there are only three reports, comprising 18 cases, describing AN harboring this specific gene mutation. Herein, we detail three new cases of AN with p.K650T FGFR3 mutation, and review the 21 known cases.     

The impact of pre-dialytic endurance training on nutritional status and quality of life in stable hemodialysis patients (Sawada study)

BACKGROUND: Protein-energy malnutrition and decreased quality of life (QOL) are common in hemodialysis (HD) patients. Although several studies have proved that regular exercise has beneficial effects, few control studies have shown the effects of exercise training on the nutritional status and QOL in HD patients. METHODS: Fifty-five HD patients were recruited, and 22 of them were trained to exercise on an ergometer prior to dialysis three times a week for one year. Serum albumin levels, creatinine generation rate (CGR), and the Short Form 36 were assessed as outcome measures. RESULTS: The serum albumin levels and CGR increased in the training group compared with baseline. The QOL scores also increased in half of the physical health and mental health dimensions in the training group. CONCLUSION: These observations suggest that low-dose, long-term pre-dialytic endurance training might reverse the poor clinical outcome by improving the nutritional status and QOL in HD patients.     

Structure and function of eritadenine and its 3-deaza analogues: potent inhibitors of S-adenosylhomocysteine hydrolase and hypocholesterolemic agents

d-Eritadenine (DEA) is a potent inhibitor of S-adenosyl-l-homocysteine hydrolase (SAHH) and has hypocholesterolemic activity. We have hypothesized that 3-deaza-DEA (C3-DEA) and its analogues retain high level of SAHH inhibitory activity and have resistance to deamination and glycosidic bond hydrolysis in vivo. Such C3-DEA analogues would have much higher hypocholesterolemic activity. C3-DEA, and its methyl ester (C3-OMeDEA) and its methyl amido (C3-NMeDEA) were synthesized to examine their SAHH inhibitory and hypocholesterolemic activities. A crystal structure of SAHH containing C3-DEA was determined and confirmed that DEA and C3-DEA bound to the same site of SAHH with the same binding mode. The SAHH inhibitory activities of C3-DEA (K(I)=1.5 microM) and C3-OMeDEA (K(I)=1.5 microM) are significantly lower than that of DEA (K(I)=30 nM), while rats fed by C3-DEA and C3-OMeDEA decrease the total plasma cholesterol and phospholipids by 36-40% and 23%, respectively, which is similar to the level of reductions (42% and 27%) by DEA. C3-NMeDEA lost most of the SAHH inhibitory activity (K(I)=30 microM) and dietary C3-NMeDEA does not decrease cholesterol and phospholipid in plasma but decreases the triacylglycerol level by 16%. DEA and C3-DEA analogues are neither substrates nor inhibitors of adenosine deaminase.