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.     

Hepatic conversion of 1-(tetrahydro-2-furanyl)-5-fluorouracil into 5-fluorouracil in patients with hepatocellular carcinoma

The pharmacokinetics of 1-(tetrahydro-2-furanyl)-5-fluorouracil (FT) and its conversion into 5-fluorouracil (FUra) in liver tissue were studied in ten patients with hepatocellular carcinoma (HCC). The plasma concentration of FT after its intravenous injection (dosage: 800 mg) was computerfitted to a bi-exponential function (C = Ae-alpha t + Be-beta t), indicating a two-compartment disposition. The pharmacokinetic parameters did not significantly differ between the five patients with, and the five without cirrhosis of the liver. The plasma concentrations of FUra likewise showed no significant difference between the two groups. The rates of FT degradation in the liver tissue homogenate were similar for four of the patients with cirrhosis (0.10 +/- 0.05 mumol/g liver protein/30 min) and four of those without it (0.13 +/- 0.05). The rates of cytochrome P-450-dependent FUra formation in the microsomal fraction of liver tissue from two patients (1.1 and 1.3 nmol/mg microsomal protein/30 min) were dramatically reduced to less than half of those of two control subjects (2.4 and 2.7). The estimated rates of FUra formation in the soluble fraction (105,000 X g supernatant fraction) from the two patients (0.1 and 0.13 nmol/mg protein/30 min) were almost identical to those from the controls (0.12 and 0.14), suggesting that the rate in the soluble fraction from HCC patients may not be as strongly affected as the rate in the microsomal fraction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Case of acute urinary retention as a result of non-steroidal anti-inflammatory drugs

Abstract:   A 19-year-old woman presented at our hospital with acute urinary retention in September 2005. She had experienced the same chief complaint twice previously. She had used non-steroidal anti-inflammatory drugs before acute urinary retention. The results of physical examinations were unremarkable, and her neurologic signs were not remarkable. The basic laboratory test values were all normal and a psychiatric assessment indicated that her symptoms were not psychogenic. Magnetic resonance imaging was carried out, but revealed only a slight bulging in the L3/L4/L5 disk. Water cystometry showed acontractile detrusor. We made a diagnosis of acute urinary retention as a result of non-steroidal anti-inflammatory drugs because of her use of such drugs before the development of symptoms on multiple occasions. This patient was regularly followed up as an outpatient, and she could void smoothly in February 2006. This is the first report which acute urinary retention associated with non-steroidal anti-inflammatory drugs in Japan.     

The effect of intraosseous graft length on tendon-bone healing in anterior cruciate ligament reconstruction using flexor tendon

The current study was performed to understand the relationship between graft length placed within the bone tunnel and intraosseous graft healing in anterior cruciate ligament (ACL) reconstruction. Twenty-four adult beagle dogs were divided into two groups of 12 animals each. In each animal, ACL reconstruction using a 4-mm diameter autogenous flexor tendon graft was done in the left knee. In groups I and II, the graft having a length of 15 and 5 mm, respectively, was placed within the tibial tunnel. The proximal end of the graft was placed through the over-the-top route in all animals. In each group, five animals were sacrificed immediately after surgery, and the remaining seven were sacrificed at 6 weeks postoperatively. Biomechanical and histologic evaluations were performed. In pull out testing, the ultimate failure load and the linear stiffness of the graft-tibia complex harvested at 6 weeks were significantly greater than those harvested at the time-zero period. There were no significant differences in those parameters between groups I and II at 6 weeks. In each group, the perpendicular collagen fibers connecting the tendon to the bone tunnel wall were observed only in the narrow area located close to the intra-articular tunnel outlet. In conclusion, excessively long placement of the flexor graft within the bone tunnel does not result in an additional increase of anchoring strength and stiffness of the graft in ACL reconstruction.     

Progressive supranuclear palsy with asymmetric lesions in the thalamus and cerebellum,with special reference to the unilateral predominance of many torpedoes

This report concerns a notable case of progressive supranuclear palsy exhibiting asymmetric dentate nucleus and thalamic degeneration with numerous torpedoes. The neuronal loss in the ventral lateral nucleus of the thalamus was predominant on the right side, while in the cerebellum, a quantitative study revealed the contralateral predominance of the neuronal loss in the dentate nuclei and torpedo formation, with preserved Purkinje cells. The abnormal tau-protein-related profiles in the two nuclei did not show any laterality in their distribution, indicating that the dentatothalamic tract may have been affected in a non-specific way in this case. In addition, the fact that the prominent sites of torpedo formation and loss of dentate nucleus neurons are identical supports the hypothesis that the torpedoes may be formed in association with neuronal loss in the dentate nucleus because of a plausible metabolic change in Purkinje cells through synaptic detachment of their axon terminals. Received: 4 January 1996 / Revised: 27 March 1996 / Accepted: 5 April 1996     

Collagen synthesis activities of chondrocytes from histologically distinct zones of chick embryo tibia

Monolayer cultures of 12-day chick embryo chondrocytes from the regions of dividing (zone 1), elongated (zone 2), and hypertrophied (zone 3) chondrocytes in the tibial cpiphyseal growth plate were analyzed for their capacity to synthesize types II, IX, X, and XI collagens. Synthesis of types II and IX collagens was markedly elevated in the zone 2 culture, while type X collagen synthesis was maximal in zone 3. Type XI collagen was synthesized at low rates in all cultures, with some elevation of its rate in zones 2 and 3. In terms of mol percent of total collagen synthesis, types II and IX collagens decreased from zone 1 to zone 3, while type X collagen increased progressively. Thus, the composition of the extracellular collagens produced by the different zones changed markedly during chondrocyte differentiation. In addition, type X collagen was released exclusively into the culture medium, whereas type XI collagen was retained in the extracellular cell-associated matrix. In contrast, types II and IX collagens were found in both the culture medium and the cell matrix pools. Although types II and IX collagens showed similar changes during differentiation, the synthetic molar ratios of these two collagens varied from 3 to 18 in different cultures, suggesting that the synthesis of these two products is not tightly coupled in these cells.     

Successful heart-lung transplantation in a patient with kyphoscoliosis.

The association is well established between congenital heart disease and spinal deformities such as scoliosis or kyphosis, but data are not available for risks and the outcome of heart surgery in patients with spinal deformities. We report a case of successful orthotopic heart lung transplantation in a patient with complex congenital heart disease and severe chest deformity who had undergone previous spinal fusion surgery for progressive right convex thoracic kyphoscoliosis.