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.     

Different types of relationship between beta-adrenergic relaxation and activation of cyclic AMP-dependent protein kinase in canine saphenous and portal veins

We examined the relationships between the relaxation mediated by beta-adrenoceptor and either the associated cyclic AMP production or the activation of cyclic AMP-dependent protein kinase (A-PK) in canine saphenous and portal veins. In the saphenous vein constricted with methoxamine, isoproterenol caused concentration-dependent relaxation (maximum relaxation 92.7%), and concomitant increases in cyclic AMP and A-PK activity ratio (from 52.8 to 73.5%). The portal vein was only slightly relaxed by isoproterenol (14.7% in the longitudinal strips) after constriction with methoxamine, while cyclic AMP and A-PK activation increased significantly. Isoproterenol markedly activated A-PK of the portal vein after KCl constriction (from 52.6 to 74.6%) but the maximum relaxation was only slight (13.3%). The portal vein also showed a smaller relaxation response to either forskolin or dibutyryl cyclic AMP than the saphenous vein. These results indicated that the relationship between the relaxation response to isoproterenol and either cyclic AMP production or A-PK activation was different in the saphenous and portal veins.     

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.     

Pigmented squamous cell carcinoma of the uterine cervix.

A 57-year-old female presented with an abnormal Pap smear. Colposcopic examination of the cervix revealed white mucosa with erosion and several areas of black pigmentation. After a colposcopically directed biopsy and loop conization, radical hysterectomy and bilateral salpingo-oophorectomy with pelvic and paraaortic lymphadenectomy were performed. Pathological examination disclosed an invasive squamous cell carcinoma admixed with many dendritic melanocytes. Melanin granules were present within the melanocytes and tumor cells. Although similar tumors have been reported in other sites, this is the first report to our knowledge of a pigmented squamous cell carcinoma of the uterine cervix.     

Protein adsorption on ex vivo catheters and polymers exposed to peritoneal dialysis effluent.

BACKGROUND: Deposition of proteins on surfaces of medical devices has been recognized to putatively relate to the process of regulation of biomaterial-associated complications by attachment of fibrin clots, eukaryotic cells, and microbes. The molecules adsorb to a varying extent, depending not only on the physicochemical properties of the biomaterial, but also on the composition of the host fluid. OBJECTIVE: Adsorption of proteins on catheters exposed both ex vivo and in vitro to dialysate of patients on peritoneal dialysis (PD) was studied. METHODS: Peritoneal dialysis effluent was collected from 5 patients with end-stage renal disease on continuous ambulatory PD. Tenckhoff catheters were obtained from 16 patients. Deposition of proteins on excised Tenckhoff catheters and tubing of different materials exposed to PD effluent in vitro was studied using 125iodine-labeled antibodies. Adhesion of Staphylococcus aureus and Staphylococcus epidermidis strains was quantified on tubing exposed to PD effluent in vitro. RESULTS: The presence of albumin, transferrin, immunoglobulin G, fibrinogen, fibronectin, von Willebrand factor, vitronectin, and thrombospondin was determined at various concentrations in PD effluent. All proteins analyzed were detected on PD catheters removed from patients. The extent of protein deposition on Tenckhoff catheters exposed to PD effluent, in vitro, rapidly reached a plateau and remained constant, as it did on polyvinyl chloride and polyethylene tubing. Adhesion of staphylococci was enhanced on Tenckhoff catheters exposed to PD effluent compared to unused PD solution. CONCLUSIONS: The data identify surface exposed proteins that may serve as adhesion sites for microbes on peritoneal catheters indwelled in patients undergoing PD.     

Direct injections of calcitriol into enlarged parathyroid glands in chronic dialysis patients with severe parathyroid hyperfunction

Summary: Severe secondary hyperparathyroidism in chronic dialysis patients has been recently treated by supraphysiological concentration of calcitriol achieved through pulse therapy. However, there are many patients resistant to this therapy, who usually have larger parathyroid gland(s). to overcome this resistance, calcitriol was injected directly into the enlarged glands under ultrasonographic guidance. We injected 70–90% of the calculated gland volume of calcitriol solution (1 μg/mL) into the glands of 7 patients three times per week for 2 weeks. the parathyroid hormone (PTH) levels decreased significantly after 2 weeks of direct injections of calcitriol. Following a further 4 weeks of calcitriol pulse therapy, PTH levels remained suppressed and serum alkaline phosphatase activity and the volume of parathyroid glands also decreased. During the long-term follow up, five patients remained well controlled with calcitriol pulse therapy, while two patients needed ethanol injections to control hyperparathyroidism. Although we could not completely rule out a toxic effect of the vehicle, direct injection of calcitriol into parathyroid glands may be another treatment option for chronic dialysis patients. Our data further support the important role of resistance of parathyroid cells to calcitriol in the pathogenesis of parathyroid hyper function in uraemic patients.