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.     

MR measurement of visceral fat: assessment of metabolic syndrome.

One diagnostic criterion for metabolic syndrome is obesity from the accumulation of visceral fat; others include abdominal circumference and area of visceral fat as measured by computed tomography (CT) at the umbilical level. We evaluated visceral fat using frequency-selective excitation magnetic resonance (MR) imaging SPAIR (spectral attenuation with inversion recovery) water suppression THRIVE (3D T1-high resolution isotropic volume examination). Fifty of 70 slices with 2-mm interval were used to render and measure volume of visceral fat ranging within 10 cm of the umbilicus; the area of visceral fat at the umbilical level was also measured. Imaging was completed using breath hold within 14 s. Image processing was easier than using CT.     

N-Phenylethyl Amitriptyline in Rat Sciatic Nerve Blockade

Background: The antidepressant amitriptyline is commonly used orally for the treatment of chronic pain, particularly neuropathic pain, which is thought to be caused by high-frequency ectopic discharge. Among its many properties, amitriptyline is a potent Na+ channel blocker in vitro, has local anesthetic properties in vivo, and confers additional blockade at high stimulus-discharge rates (use-dependent blockade). As with other drug modifications, adding a phenylethyl group to obtain a permanently charged quaternary ammonium derivative may improve these advantageous properties.

Methods: The electrophysiologic properties of N-phenylethyl amitriptyline were assessed in cultured neuronal GH3 cells with the whole cell mode of the patch clamp technique, and the therapeutic range and toxicity were evaluated in the rat sciatic nerve model.

Results: In vitro, N-phenylethyl amitriptyline at 10 [mu]m elicits a greater block of Na+ channels than amitriptyline (resting block of approximately 90%vs. approximately 15%). This derivative also retains the attribute of amitriptyline in evoking high-degree use-dependent blockade during repetitive pulses. In vivo, duration to full recovery of nociception in the sciatic nerve model was 1,932 +/- 72 min for N-phenylethyl amitriptyline at 2.5 mm (n = 7) versus 72 +/- 3 min for lidocaine at 37 mm (n = 4; mean +/- SEM). However, there was evidence of neurotoxicity at 5 mm.     

Relationships of plasma viscosity, coagulation and fibrinolysis to coronary risk factors and angina

Plasma viscosity, molecular markers of activated coagulation and fibrinolysis (fibrinopeptides A and B beta 15-42), coagulation factors (fibrinogen and factor VII) and antiplasmins were measured in 529 men aged 35-54 years and related to new angina pectoris (n = 117) and to coronary risk factors in controls without angina (n = 412). Five major risk factors (cigarette-smoking, blood pressure, cholesterol, triglyceride and body mass index) were each associated with increases in plasma viscosity, coagulation factors, and imbalance of coagulation over fibrinolysis (increased ratio of fibrinopeptide A/fibrinopeptide B beta 15-42). Increased viscosity and fibrinogen in smokers were partly reversed in ex-smokers, but the imbalance of coagulation and fibrinolysis persisted. Cholesterol and triglyceride were also associated with increased antiplasmin activity. In men with angina, only fibrinogen was elevated compared to controls. We suggest that increased plasma viscosity and an imbalance of coagulation over fibrinolysis may be mechanisms by which known risk factors promote arterial thrombosis, but are not present in stable angina.     

Comparison of maxillary stability after Le Fort I osteotomy for occlusal cant correction surgery and maxillary advanced surgery.

OBJECTIVE: To compare postoperative maxillary stability following Le Fort I osteotomy for the correction of occlusal cant as compared with conventional Le Fort I osteotomy for maxillary advancement. STUDY DESIGN: The subjects were 40 Japanese adults with jaw deformities. Of these, 20 underwent a Le Fort I osteotomy and intraoral vertical ramus osteotomy (IVRO) to correct asymmetric skeletal morphology and inclined occlusal cant. The other 20 patients underwent a Le Fort I osteotomy and sagittal split ramus osteotomy (SSRO) to advance the maxilla. Lateral and posteroanterior cephalograms were taken postoperatively and assessed statistically. Thereafter, the 2 groups were followed for time-course changes. RESULTS: There was no significant difference between the 2 groups with regard to time-course changes during the immediate postoperative period. CONCLUSION: This suggests that maxillary stability after Le Fort I osteotomy for cant correction does not differ from that after Le Fort I osteotomy for maxillary advancement.     

Effects of medium-chain triglycerides on brush border membrane-bound enzyme activity in rat small intestine

The effects of various types of dietary fat on brush border membrane-bound enzymes in rat intestinal mucosa were examined. Four groups of five rats were pair-fed defined diets for 10 d. The control group was fed a diet containing 57% sucrose and 2% corn oil as a fixed carbohydrate reference; the three experimental groups received diets containing 57% sucrose and 2% corn oil plus 13% fat in the form of medium-chain triglycerides (MCT) or long-chain triglycerides (LCT) (either lard as a highly saturated fat or corn oil as a highly unsaturated fat). Feeding LCT compared to the control diet, decreased sucrase activity in mucosal brush borders of the duodenum and jejunum. In these segments of MCT-fed rats, sucrase activity was similar to that in the control animals. In another experiment, measuring immunoreactive sucrase-isomaltase in jejunal brush border membranes revealed that feeding a high corn oil diet, but not a high MCT diet, led to a reduction in the sucrase catalytic activity per unit weight of enzyme protein, suggesting that the degradation status of sucrase-isomaltase might be altered by the different types of dietary fats. With MCT feeding, jejunal alkaline phosphatase activity was enhanced to a large extent compared to the activity in other groups. Feeding MCT, compared to lard or corn oil, also increased microvillus phospholipids of the jejunal mucosa. These results suggest that MCT, unlike LCT, do not suppress the activity of mucosal microvillus membrane enzymes in rat small intestine.     

Cutaneous eruption with or without ocular complications in patients with herpes zoster involving the trigeminal nerve

We examined 62 patients with acute herpes zoster involving the trigeminal nerve; 13 had eruptions only and 49 (51 eyes) had eruptions with ocular complications. Bilateral involvement was found in two patients. The frequency of the disease appeared to increase with age, and the disease was least active in November. Patients with eruptions only demonstrated affected areas along the first, second, and/or third divisions of the trigeminal nerve. Ocular complications occurred in patients who had eruptions along the first and/or second divisions of the nerve, and they were usually noted in patients with eruptions on the tip and one side of the node. The ocular complications and associated systemic conditions varied.     

Purification, properties, and developmental changes of cellular retinol-binding protein, type II, in chicken intestine

Two distinct cellular retinol-binding proteins were detected in chicken small intestine. A predominant form was purified to homogeneity. The apparent molecular weight of this protein was estimated to be 17,200. This form was larger than a second minor form partially purified (molecular weight of 15,000). The absorption and fluorescence spectra of the bound retinol to the purified proteins were typical for the known cellular retinol-binding proteins. The results suggest that the purified binding protein corresponds to CRBP(II), previously identified in small intestine of rats and humans. To gain an insight into the possible role of CRBP(II) in chicken small intestine, the CRBP(II) contents in cytosols of small intestine of embryonic and post-hatch chicks were determined by enzyme-linked immunosorbent assay. The amount of CRBP(II) per unit DNA in small intestine was low at 15- and 17-day embryonic stage, but rapidly increased around the period of hatching. The increased level was still maintained in 6-week-old chicks, which accounted for 0.9% of total proteins in duodenum. The developmental pattern and the presence of abundant amount of CRBP(II) in chicken small intestine supports the hypothesis that CRBP(II) might play some role in the intestinal absorption of retinoids. Thus the involvement of a tissue-specific cellular retinol-binding protein in the intestinal absorption of retinoids appears to be common in mammalian and avian species.