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.     

Basic fibroblast growth factor and epidermal growth factor reverse impaired ulcer healing of the rabbit oral mucosa

BACKGROUND: The therapies for refractory ulcers on the oral mucosa are symptomatic and very unsatisfactory. We hypothesized that application of growth factors might be able to achieve successful remission of the lesion. We evaluated the effects of systemic administration and topical application of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) on impaired wound healing of ulcers in the rabbit gingiva. METHODS: Almost uniform round ulcers could be created on the gingiva of the rabbits by chemical injury with acetic acid. When the submandibular glands were removed or i.v. injection of cisplatin (CDDP) and peplomycin sulfate was performed before ulcer formation, healing of the ulcers took longer than in untreated rabbits. To ascertain whether or not human EGF and bFGF affect rabbit cells, we first examined the effects of EGF and bFGF on the proliferation of the cells derived from rabbit gingiva. We then applied EGF or bFGF in these impaired healing models. RESULTS: EGF and bFGF promoted proliferation of the fibroblasts, and EGF also promoted proliferation of the keratinocytes isolated from gingival tissue of rabbits in vitro. Systemic injections of EGF and bFGF in rabbits, which had their submandibular glands removed, and topical application of bFGF accelerated healing of ulcers created in rabbits injected with CDDP and peplomycin sulfate. The ability of bFGF to promote the healing of ulcers was much greater than that of EGF. CONCLUSION: Basic FGF may be effective for refractory oral mucosal lesions.     

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)     

Surgical outcomes of partial nephrectomy for renal cell carcinoma: A joint study by the Japanese Society of Renal Cancer

OBJECTIVE: A joint study was undertaken by the Japanese Society of Renal Cancer to investigate the present status of partial nephrectomy in Japan and to speculate about what may be the indications for partial nephrectomy in patients with renal cell carcinoma. METHODS: Data were tabulated for 469 patients from participating medical institutions and various clinical factors were investigated with regard to disease progression (local recurrence and distant metastasis). RESULTS: Disease progression was observed in 21 patients (4.5%). No significant relation to disease progression was observed for sex, laterality, tumor histology, grade and tumor size. Although patients with solitary tumors displayed excellent prognosis irrespective of tumor diameter, patients with multiple tumors displayed a high likelihood of disease progression. Patients older than 77 years old and patients with imperative indication were found to have a poorer prognosis. CONCLUSION: In patients with solitary tumors, partial nephrectomy can be actively performed, even if the patient displays elective indications and the tumor is >4 cm in diameter. In patients displaying multiple tumors with imperative indications, the decision whether to perform partial nephrectomy should be made by the patients and their physicians after considering the impact on curability and the quality of life.     

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.     

Resetting of the arterial baroreflex increases orthostatic sympathetic activation and prevents postural hypotension in rabbits

Since humans are under ceaseless orthostatic stress, the mechanism to maintain arterial pressure (AP) under orthostatic stress against gravitational fluid shift is of great importance. We hypothesized that (1) orthostatic stress resets the arterial baroreflex control of sympathetic nerve activity (SNA) to a higher SNA, and (2) resetting of the arterial baroreflex contributes to preventing postural hypotension. Renal SNA and AP were recorded in eight anaesthetized, vagotomized and aortic-denervated rabbits. Isolated intracarotid sinus pressure (CSP) was increased stepwise from 40 to 160 mmHg with increments of 20 mmHg (60 s for each CSP level) while the animal was placed supine and at 60 deg upright tilt. Upright tilt shifted the CSP–SNA relationship (the baroreflex neural arc) to a higher SNA, shifted the SNA–AP relationship (the baroreflex peripheral arc) to a lower AP, and consequently moved the operating point to marked high SNA while maintaining AP. A simulation study suggests that resetting in the neural arc would double the orthostatic activation of SNA and increase the operating AP in upright tilt by 10 mmHg, compared with the absence of resetting. In addition, upright tilt did not change the CSP–AP relationship (the baroreflex total arc). A simulation study suggests that although a downward shift of the peripheral arc could shift the total arc downward, resetting in the neural arc would compensate this fall and prevent the total arc from shifting downward to a lower AP. In conclusion, upright tilt increases SNA by resetting the baroreflex neural arc. This resetting may compensate for the reduced pressor responses to SNA in the peripheral cardiovascular system and contribute to preventing postural hypotension.