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.     

A case of diaphragmatic hernia incarceration after a heart transplant operation

We report a case of a diaphragmatic hernia after a heart transplant operation. A 43-year-old woman, who underwent orthotropic heart transplantation for hypertrophic cadiomyopathy two year earlier, presented with vomiting and epigastric pain. A computed tomography scan showed that the stomach and transverse colon were dislocated in the left thoracic cavity. We diagnosed left diaphragmatic hernia incarceration and performed laparoscopic repair of the diaphragmatic hernia. A 12 × 8 cm diaphragmatic defect was found intraoperatively on the ventrolateral aspect of the left diaphragm, and the stomach with volvulus had herniated into the thorax through the defect. The hernia was considered to be iatrogenic. The diaphragmatic defect was large, and the diaphragm was thinning. We closed the defect by mesh repair. Laparoscopic mesh repair of the diaphragmatic hernia could be performed safely and with minimal invasiveness.     

Biological activity of partially purified digitalis-like substance and Na-K-ATPase inhibitor in rats

In order to study the biological activity of endogenous digitalis-like substance (DLS) and Na-K-ATPase inhibitor (ATPI), human urine was partially purified and administered to rats, and its effects on the urinary volume, urinary Na excretion and blood pressure (BP) were determined. In addition, the effect on myocardial Na-K-ATPase activity was also measured. After the extraction of 40L of urine with a reversed phase cartridge column (S-fraction), 20 ml of chloroform was added and extraction was repeated. The chloroform layer was applied to an open silica gel column, and at a fraction with ethylacetate: methanol (60: 40, T-1 fraction), DLS and ATPI were eluted at the highest concentration. The water layer was treated with charcoal (D-1 fraction). The acute administration of K-1, T-1 fraction to rats in vivo caused significant rises in urinary volume, urinary Na excretion and BP. In chronic administration of K-1 fraction, urinary Na excretion was significantly elevated and myocardial Na-K-ATPase activity was also significantly suppressed. These results suggest that DLS and ATPI cause increase in the urinary volume and urinary Na excretion and also possess a hypertensive action; and moreover, these substance may affect the heart like cardiotonic steroids and regulate BP by increasing cardiac contractility.     

Induction of immunoreactive proliferating cell nuclear antigen (PCNA) in goldfish retina following intravitreal injection with tunicamycin.

Effects of a photoreceptor-specific biotoxin, tunicamycin (TM), injected intravitreally into the goldfish eye at one side, were explored on electroretinograms (ERGs) and proliferating cell nuclear antigen-immunoreactive (PCNA-ir) nuclei, representing the mitotic activity of rod precursors, in the retina at both sides. The eye-cup preparations were made for ERG recording, and the retinas were isolated and processed as cryosections or wholemounts by a routine immunohistochemical method for visinin (cones), opsin (rods), tyrosine hydroxylase (dopaminergic cells) and proliferating cell nuclear antigen (PCNA), at various intervals after intravitreal injection with TM (1.0 micrograms/eye). On some thin sections, autoradiographic study was combined following intravitreal injection with [3H]thymidine (TdR, 0.1 microCi/eye). The dose of TM used heavily destroyed cones and rods only in the treated retinas 2-15 days after injection, the photoreceptors being renewed for further 15-20 days. Approximately in parallel, ERGs were largely impaired 2-10 days after TM injection and recovered for 10-20 days. However, intravitreal TM altered the distribution and density of PCNA-ir nuclei in both treated and untreated retinas. The density of PCNA-ir nuclei reduced at first (on days 1 and 2), and then clustered and rapidly increased on days 3-5 and maintained at high levels with diffuse distribution over the whole area, particularly in the treated retinas, up to 60 days after TM injection; the maximum peak of 3.7 and 20 times the initial level was seen on day 20 in the outer nuclear layer (ONL) and inner nuclear layer (INL), respectively. PCNA-ir nuclei were found to be abundant in the ONL even after the photoreceptors and ERGs had been restored in the treated retinas on day 20, suggesting a kind of overproduction of retinal cells. The autoradiographic study provided comparable results to those obtained with PCNA immunohistochemistry. The mechanism by which damage to the treated retina causes rod precursor cells to proliferate in the untreated retina remains unresolved.     

Vasodilator effects of sarafotoxins and endothelin-1 in spontaneously hypertensive rats and rat isolated perfused mesentery

Sarafotoxins (SRTa, SRTb and SRTc) and ET-1 produced a potent vasodilator effect in spontaneously hypertensive rats in vivo and in rat isolated perfused mesenteries in vitro. Among these peptides SRTc demonstrated the most potent vasodilator activity, and was three times more active than SRTa in both preparations. These peptides induced endothelium-dependent vasodilatation in vitro and pretreatment with methylene blue inhibited this effect, while exposure to the antagonists of other vasodilators did not. In contrast, [nitrophenylsulfenylated Trp21]SRTc, SRTc(1-18) and reduced and S-carboxymethylated SRTc caused no vasodilatation in either animal model; the vasodilator effect of acetylated SRTc was less potent than that of SRTc. These results suggest that (i) the vasodilatations of these peptides may be exerted through the release of endothelium derived relaxing factor; (ii) the C-terminal Trp21 and disulfide bonds are essential; and (iii) the N-terminal amino group plays an important role in vasodilator activity.     

Successful Treatment of Adult T-cell Leukemia/Lymphoma with MACOP-B,M-FEPA and VEPP-B Combination Chemotherapy

A 45-year-old man was referred to our department in March of 1989. Physical examination showed erythroderma, palmo-plantar hyperkeratosis, generalized lymphadenopathy, hepatosplenomegaly, and leukemic manifestation. The lymphocyte count in the peripheral blood before treatment was 1.7 × 10⁴ cells/mm³. Atypical lymphocytes such as flower cells and lobulated cells were seen in the peripheral blood. A sample excised from a lymph node showed immunoblastic, pleomorphic T cells by a modified classification scheme of the Working Formulation. A high level of serum LDH was detected (2.1 times the upper normal limit). Anti HTLV-1 antibody was also detected in the serum. The atypical lymphocytes were positive for CD3, CD4, CD5, CD7 and HLA-DR, and negative for CD8. Thus, the clinical, pathologic and immunologic features were those of typical acute-type ATL. The patient was treated with VEPA-M for three months starting in March of 1989. Because of poor response, the patient was then treated with MACOP-B, M-FEPA, and VEPP-B for about one year from June of 1989 and has been free of disease up to the time of writing, March of 1993.     

Lidocaine Increases Intracellular Sodium Concentration through Voltage-dependent Sodium Channels in an Identified Lymnaea Neuron

Background: The local anesthetic lidocaine affects neuronal excitability in the central nervous system; however, the mechanisms of such action remain unclear. The intracellular sodium concentration ([Na+]i) and sodium currents (INa) are related to membrane potential and excitability. Using an identifiable respiratory pacemaker neuron from Lymnaea stagnalis, the authors sought to determine whether lidocaine changes [Na+]i and membrane potential and whether INa is related to these changes.

Methods: Intracellular recording and sodium imaging were used simultaneously to measure membrane potentials and [Na+]i, respectively. Measurements for [Na+]i were made in normal, high-Na+, and Na+-free salines, with membrane hyperpolarization, and with tetrodotoxin pretreatment trials. Furthermore, changes of INa were measured by whole cell patch clamp configuration.

Results: Lidocaine increased [Na+]i in a dose-dependent manner concurrent with a depolarization of the membrane potential. In the presence of high-Na+ saline, [Na+]i increased and the membrane potential was depolarized; the addition of lidocaine further increased [Na+]i, and the membrane potential was further depolarized. In Na+-free saline or in the presence of tetrodotoxin, lidocaine did not change [Na+]i. Similarly, hyperpolarization of the membrane by current injections also prevented the lidocaine-induced increase of [Na+]i. In the patch clamp configuration, membrane depolarization by lidocaine led to an inward sodium influx. A persistent reduction in membrane potential, resulting from lidocaine, brings the cell within the window current of INa where sodium channel activation occurs.