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.     

Marmoset cytochrome P450 2B6, a propofol hydroxylase expressed in liver

1. The common marmoset (Callithrix jacchus) is a useful experimental animal to evaluate the pharmacokinetics of drug candidates. Cytochrome P450 (P450) 2B enzyme in marmoset livers has been identified; however, only limited information on the enzymatic properties and distribution has been available.

2. Marmoset P450 2B6 amino acids showed high sequence identities (>86%) with those of primates including humans and cynomolgus monkeys. Phylogenetic analysis using amino acid sequences indicated that marmoset P450 2B6 was closer to human and cynomolgus monkey P450 2B6 than to P450 2B orthologs of other species, including pigs, dogs, rabbits and rodents.

3. Quantitative polymerase chain reaction analysis using specific primers showed P450 2B6 mRNA predominantly expressed in livers among the five marmoset tissues, similar to those of humans and cynomolgus monkeys.

4. Marmoset P450 2B6 heterologously expressed in Escherichia coli membranes oxidized 7-ethoxycoumarin, pentoxyresorufin, propofol and testosterone, at roughly similar rates to those of humans and/or cynomolgus monkeys. A high capacity of marmoset P450 2B6 with propofol 4-hydroxylation (at low ionic strength conditions) with a low K_m value was relatively comparable to that for marmoset livers.

5. These results collectively indicated a high propofol 4-hydroxylation activity of P450 2B6 expressed in marmoset livers.

     

A novel procedure combining transoral resection and set-back tongue flap for oropharyngeal cancer

Seven patients with advanced lateral oropharyngeal cancer (T3N2bM0, or T4N2bM0) underwent transoral lateral oropharyngectomy (TLO) with reconstruction performed through set-back tongue flap and polyglycolic acid (PGA) sheet. TLO was performed following en bloc resection of tumors using endoscopy. To cover the resulting defect in the lateral oropharyngeal wall, the set-back tongue flap was moved posteriorly and laterally to the area of the tongue base and lateral pharyngeal wall. The tip of the set-back tongue flap was sutured to the lateral pharynx to reconstruct the elevated tongue base and altered anterior pillar. The defect on the floor of the mouth was reconstructed using a PGA sheet. Following surgery, the mean observation period was 24 months. The mean operating time was 4 h and 2 min, with an average blood loss of 68.1 ml. All oral intake resumed on the first postoperative day via gastric tube. The mean gastric tube removal time was 1.6 postoperative days as a result of sufficient oral intake. None of the patients received postoperative radiotherapy or displayed evidence of tumor recurrence. We conclude that this novel procedure is highly effective for treating advanced oropharyngeal cancer as it demonstrates good prognostic and functional outcomes.     

Identification and evaluation of antioxidants in Japanese parsley

Two cultivars of Japanese parsley were harvested in different seasons; their antioxidant capacities were evaluated by oxygen radical absorbance capacity (ORAC) methods, and the contents of hydrophilic and lipophilic antioxidants were compared. Japanese parsley possessed potent antioxidant capacities both in hydrophilic and lipophilic extracts when evaluated by ORAC methods. LC/MS/MS analyses revealed that chlorogenic acid and four kinds of quercetin glycosides were major antioxidants in the hydrophilic extract. Lutein was the main contributor to the antioxidant capacity of the lipophilic extract. Antioxidant capacities of the hydrophilic extracts of both cultivars tended to be higher in winter because of the increase in the contents of chlorogenic acid and quercetin glycosides. An obvious trend in the lipophilic antioxidant capacities or lutein contents was not observed irrespective of the cultivar.     

Population Pharmacokinetic and Exposure-Response Analyses of Baloxavir Marboxil in Adults and Adolescents Including Patients With Influenza

Baloxavir marboxil, a prodrug that is metabolized to baloxavir acid, suppresses viral replication by inhibiting cap-dependent endonuclease. Our aim is to characterize its pharmacokinetics and exposure-response relationships. Population pharmacokinetic analysis of the baloxavir acid was performed using 8310 plasma concentration data points from 1109 subjects. Exposure-response analyses were performed regarding the time to alleviation of symptoms and the reduction in the influenza virus titer. A 2-compartment model with first-order absorption and lag time well described the plasma concentration data for baloxavir acid, and body weight and race were found to be the most important factors influencing the clearance and distribution volume. A dose regimen based on the body weight (40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg) could provide sufficient exposures for expecting efficacy irrespective of body weight or race; however, the exposures were dependent on the body weight and race. Exposure-response analyses suggested that the reduction in the influenza virus titer was greater in any exposure-based groups in baloxavir marboxil treatment than in the oseltamivir phosphate treatment and placebo groups. In conclusion, the population pharmacokinetic model and exposure-response relationships would be useful for understanding the pharmacokinetic and pharmacodynamic characteristics of baloxavir acid.     

Stereotyped behaviors and compulsive complaints of pain improved by fluvoxamine in two cases of frontotemporal dementia]

There have been no systematic efforts to manage and treat patients with frontotemporal dementia (FTD), but Perry described pharmacologic interventions for some behavioral syndromes in 2001. In Perry's report, selective serotonin reuptake inhibitors (SSRI) were recommended as first choice drugs because they were well tolerated and might have an effect on some symptoms such as compulsive symptoms and eating abnormalities. Some reports were presented concerning Japanese FTD patients which showed the effect of SSRI on stereotyped behaviors and eating abnormalities by Nishikawa, et al. (2001), Ikeda, et al. (2004), and others. We describe two FTD patients with compulsive complaints of pain, one mainly on abdomen and the other on lumbar region. Fluvoxamine markedly improved their complaints of pain as well as stereotyped symptoms. Fluvoxamine might be effective for behavioral disturbances due to improvement of serotoninergic dysfunction in frontal medial and cingulated cortices, as previously described. Moreover, it has been reported that an altered response to pain stimuli, either via a loss of awareness of pain or exaggerated reaction to pain, is a specific feature of FTD, but there have been only a few reports on this feature. Fluvoxamine might be effective for compulsive complaints of pain due to improvements of compulsive symptoms and exaggerated reactions to pain in FTD, or due to the analgesic effect of SSRI. SSRI may improve compulsive complaints of pain in FTD patients.     

Severe Graves' ophthalmopathy accompanied by myasthenia gravis]

We report a 53-year-old woman with severe Graves' ophthalmopathy accompanied by uncontrolled myasthenia gravis. She presented remarkable exophthalmos, chemosis, and restriction of eye movement. Despite plasma exchange, steroid pulse therapy, local injection of steroid, and irradiation, ocular symptoms did not ameliorate. Since optic neuropathy was seen, orbital decompression surgery was performed in the left eye. Bilateral chemosis was improved after the surgery. Five years after surgery, there was no ocular palsy in the operated left eye, but in the contralateral eye. For the good prognosis of the eye movement, orbital decompression might be recommended in the severe Graves' ophthalmopathy accompanied by the optic neuropathy and/or ophthalmoplegia with proptosis.