Pharmacokinetic study of the oral fluorouracil antitumor agent S‐1 in patients with impaired renal function

Although dose reduction of S‐1 is recommended for patients with impaired renal function, dose modification for such patients has not been prospectively evaluated. The aim of the present study was to investigate the pharmacokinetic parameters of 5‐fluorouracil, 5‐chloro‐2,4 dihydroxypyridine and oteracil potassium, and to review the recommended dose modification of S‐1 in patients with renal impairment. We classified patients receiving S‐1 into 4 groups according to their renal function, as measured using the Japanese estimated glomerular filtration rate (eGFR) equation. The daily S‐1 dose was adjusted based on the patient's eGFR and body surface area. Blood samples were collected for pharmacokinetic analysis. A total of 33 patients were enrolled and classified into 4 groups as follows: 10 patients in cohort 1 (eGFR ≥ 80 mL/min/1.73 m²), 10 patients in cohort 2 (eGFR = 50‐79 mL/min/1.73 m²), 10 patients in cohort 3 (eGFR = 30‐49 mL/min/1.73 m²), and 3 patients in cohort 4 (eGFR < 30 mL/min/1.73 m²). Those in cohorts 3 and 4 treated with an adjusted dose of S‐1 showed a similar area under the curve for 5‐fluorouracil (941.9 ± 275.6 and 1043.5 ± 224.8 ng/mL, respectively) compared with cohort 2 (1034.9 ± 414.3 ng/mL). Notably, while there was a statistically significant difference between cohort 1 (689.6 ± 208.8 ng/mL) and 2 (P = 0.0474) treated with an equal dose of S‐1, there was no significant difference observed in the toxicity profiles of the cohorts. In conclusion, dose adjustment of S‐1 in patients with impaired renal function using eGFR is appropriate and safe.     

Recurrent mediastinal liposarcoma twenty years after the initial operation: case report

We report a case of mediastinal liposarcoma, recurrent after 20 years. A 58-year-old man who presented with dyspnea on exertion was found to have a large mediastinal tumor in chest computed tomography (CT), and he was referred to our hospital. He had undergone an extirpation of a mediastinal liposarcoma about 20 years earlier, and we suspected its recurrence. Because the tumor was very large, it was removed in two stages. Histologically it was diagnosed as a recurrence of the previous well-differentiated liposarcoma. Although liposarcoma is one of the most common soft-tissue sarcomas in adults, a mediastinal liposarcoma is rare. Because the recurrence rate is very high, it is necessary to follow up carefully over a long term.     

Activation of hyaluronidase by 8-methoxypsoralen-polyamine photoproducts.

Ultraviolet radiation of 8-methoxypsoralen (8-MOP) in the presence of various polyamines resulted in stable photoproducts that were very soluble in water and showed hyaluronidase-activating properties. Among them, the photoproducts obtained from the reaction systems of 8-MOP-spermine and 8-MOP-spermidine markedly activated hyaluronidase. The enzyme activity was not affected by 8-MOP alone and the photoproduct of 8-MOP (8-MOP-P). From these facts, it was suggested that the photoproducts with hyaluronidase-activating properties might play an important role in the onset of 8-MOP-induced photosensitivity.     

Augmented production of granulocyte-macrophage colony-stimulating factor and alpha/beta interferon in mice inoculated with heat-killed Corynebacterium liquefaciens.

We demonstrated that heat-killed Corynebacterium liquefaciens bacteria, as a known potent host immune activity modulator, stimulate spleen cells to produce granulocyte-macrophage (GM) colony-stimulating factor (CSF) and another CSF with similar activity, as well as alpha/beta interferon, when injected intravenously into mice. Alpha/beta interferon was shown to be produced by C. liquefaciens-activated plastic-G-10 column-adherent cells (A cells) in a thymus-independent manner. In contrast, augmented production of GM-CSF required the action of C. liquefaciens-activated T lymphocytes that collaborated with normal A cells. Non-T spleen cells from C. liquefaciens-stimulated athymic mice, however, produced an alternative CSF that partially replaced GM-CSF. Correspondingly, the numbers of GM-producing CFU developing in cultures of spleen cells from C. liquefaciens-treated euthymic or athymic mice were 10 to 30 times higher than those in cultures of spleen cells from untreated mice. These results suggest that gram-positive rods such as C. liquefaciens activate T and A cells for production of multiple cytokines and that potential cooperative actions of these cytokines underlie the known immunomodulatory action of coryneforms.     

Absence of donor-type major histocompatibility complex class I antigen-bearing microglia in the rat central nervous system of radiation bone marrow chimeras

Localization of bone marrow-originated cells in the central nervous system (CNS) of the rat was investigated by using bone marrow chimeras. In order to do this, Lewis rats which carry major histocompatibility complex (MHC) class I antigens haplotype 1 (RT1.Al) were reconstituted with (Lew X PVG)F1 (RT1.Al/c) bone marrow cells after lethal irradiation. Transferred bone marrow cells were detected by immunohistochemical staining using a monoclonal antibody, OX27, specific for haplotype c of rat MHC class I antigens (RT1.Ac). The spleen and thymus of chimeric rats were fully reconstituted with transferred F1 cells 4 weeks after bone marrow transplantation. At this stage, mononuclear cells in the subarachnoid space of the CNS expressed OX27 antigen indicating that they were of bone marrow origin. A few OX27-positive blood cells were scattered in the CNS parenchyma 4-12 weeks after reconstitution. Ramified microglia, however, remained OX27-negative. Bone marrow-derived microglia were not observed throughout the period of examination until 24 weeks. In addition, experimental allergic encephalomyelitis (EAE) was induced in chimeric rats in order to augment the expression of MHC class I antigens on microglia. Even under this condition, no OX27-positive microglia were observed. Taken together, ramified microglia might be of neuroectodermal origin and there is little possibility that the microglia are derived from the bone marrow. However, if the ramified microglia are derived from blood cells, the microglia may be expected to have characteristic cell kinetics from the following points: (1) the precursor cells of the microglia may enter the CNS only at the perinatal stage; and (2) even under the condition in which lymphocytes and macrophages enter the CNS as observed in EAE, the precursor cells of the microglia are not supplied from the blood.     

A case of middle-aged onset sialidosis type I]

We reported a patient with middle-aged onset sialidosis type I. A 52-year-old Japanese man was referred to our hospital because of dysarthria, involuntary movement of his extremities and gait disturbance since the age of 46 years. On admission, neurological examination revealed scanning speech, action myoclonus, cerebellar ataxia and cherry-red spots. Vacuolated lymphocytes were found in peripheral blood. Brain 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET) showed decreased glucose metabolism in the cerebellum. Enzymological analysis using his skin fibroblasts revealed primary deficiency of sialidase activity. Sialidase gene analysis identified compound heterozygotes for base substitusions of 239T-to-C and 649G-to-A, which resulted in amino acid alterations of P80L and V217M, respectively. These mutations have been reported in Japanese sialidosis type II (P80L) and I (V217M). Further studies are required to reveal effects of gene mutations on residual enzyme activities and phenotypes.     

Successful arterial embolization of arteriovenous fistula in the portal circulation.

We successfully performed arterial embolization of an arteriovenous fistula between the left gastric artery and vein. The increased blood flow in the portal vein via the left gastric vein and the arteriovenous fistula induced severe portal hypertension. After obliteration of the left gastric artery, the arteriovenous fistula was not opacified on angiography and the portal hypertension improved.     

Increase of oxidized/total coenzyme Q-10 ratio in cerebrospinal fluid in patients with Parkinson's disease.

The concentrations of oxidized coenzyme Q-10 (CoQ-10) and reduced CoQ-10 in the cerebrospinal fluid (CSF) of patients with Parkinson's disease (PD) was examined in order to determine whether the balance in oxidized and reduced CoQ-10 is related to the pathogenesis of PD. The percentage of oxidized/total CoQ-10 (%CoQ-10) in the CSF was significantly higher in the untreated PD group (80.3+/-17.9%) compared to the normal control group (68.2+/-20.4%) (p<0.05). The %CoQ-10 in the CSF of PD patients showed significant negative correlation with the duration of illness. These findings in living patients provide in vivo evidence for a possible role for %CoQ-10 in the pathogenesis in the early stages of PD development.