Phase 1 study of TAS-102 administered once daily on a 5-day-per-week schedule in patients with solid tumors

This study was designed to determine the safety and optimal dosing of TAS-102, a novel oral combination of alphaalphaalpha-trifluorothymidine (FTD) and an inhibitor of thymidine phoshorylase, in patients with solid tumors. Patients who met the eligibility criteria were treated with one of two different TAS-102 regimens: once per day on either days 1-5 and 8-12 every 4 weeks (schedule A) or days 1-5 every 3 weeks (schedule B). The primary objectives were the determination of the maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended phase II dose. Pharmacokinetic analysis was conducted during courses 1 and 2. Sixty-three patients received a total of 172 courses of therapy with the median number of courses delivered on both schedules being 2. DLTs were observed in three patients on schedule A, 70 mg/m(2)/day (1) and 110 mg/m(2)/day (2); and in five patients on schedule B, 120 mg/m(2)/day (1), 170 mg/m(2)/day (2), 180 mg/m(2)/day (2). Granulocytopenia was the DLT in seven of the eight cases. The most frequent toxicities were nausea, fatigue, granulocytopenia, anemia, diarrhea, and abdominal pain. Twelve patients, 6 on schedule A and 6 on schedule B, were treated at the recommended phase II dose, with good tolerance. No objective responses were seen in this heavily pretreated, 5-FU-refractory population. The pharmacokinetic parameters of FTD are a T (max) of 0.53 to 3.15 h, t (1/2) of 1.46 to 4.20 h, volume of distribution of 0.0526 to 0.483 l/kg, and clearance of 0.0194 to 0.197 1/h/kg. The recommended phase II doses for TAS-102 are 100 mg/m(2)/day on schedule A and 160 mg/m(2)/day on schedule B. Future development of TAS-102 should focus upon multiple daily dosing schedules.     

Eye-concentrated distribution of dexamethasone carried by sugar-chain modified liposome in experimental autoimmune uveoretinitis mice

Corticosteroid is generally accepted as a standard therapeutic agent for active inflammatory (and) autoimmune eye diseases. In an attempt to develop a system to deliver corticosteroid most efficiently to the target eye, a sialyl-Lewis X (sLe(x))-conjugated liposome was adopted as a candidate for a carrier of dexamethasone (Dexa) and tissue distribution of intravenous Dexa with the modified liposome as well as Dexa alone as control was studied in normal and experimental autoimmune uveoretinitis (EAU) mice. Intravenous Dexa (1 mg) was widely distributed in all the tissues (eye, brain, heart, lung, liver, kidney, spleen and intestine) examined in similar manner in both mice and Dexa concentration was lowest in the eye except the brain. The tissue concentrations of Dexa in EAU group were all significantly lower than those in the corresponding tissues in normal group. Intravenous Dexa (2 microg) in the modified liposome was almost concentrated to the eye in EAU mice, reaching 13.84 ng/mg tissue in contrast to 2.34 ng/mg tissue in Dexa (1 mg) alone administered EAU mice. In normal mice, Dexa was undetectable in any tissues examined and thus the effect of the modified liposome was not observed. The result supported the potentiality of sLe(x)-conjugated liposome for target-delivering of corticosteroid to inflamed eye.     

The effects of age on insulin sensitivity and insulin secretion in Japanese subjects with normal glucose tolerance

The prevalence of impaired glucose tolerance and type 2 diabetes increases with age. However, controversial results have been reported in regard to which has a greater influence on the deterioration of glucose tolerance with age, namely impaired insulin sensitivity or impaired insulin secretion. The conflicting results may arise mainly from differences in the evaluation of insulin secretion and insulin sensitivity, and from differences in the physical composition and the ethnicity of the study subjects. We therefore selected Japanese subjects, between 20 and 80 years of age, with normal glucose tolerance (NGT) and with a body mass index (BMI) below 25.0 kg/m2, and then examined the subject's insulin sensitivity based on the indices of a homeostasis model assessment-insulin resistance index (HOMA-IR) and ISI composite (ISI), and beta-cell function by these of HOMA-beta, AUC I/G(0-120), an insulinogenic index (deltaI30/deltaG30), and then (deltaI30/deltaG30)/HOMA-IR derived from a 75 g-oral glucose tolerance test (OGTT). The subjects were divided into the six subgroups according to sex and age, below age 30, between ages 30 and 49, and equal to and over age 50. Both HOMA-IR and the ISI showed no differences across the range of age and sex. HOMA-beta decreased with age, and AUC I/G(0-120) decreased in the elderly. No change was observed in deltaI30/deltaG30 across the age range in men, however deltaI30/deltaG30/HOMA-IR, the index of the early phase insulin secretion adjusted for insulin sensitivity, decreased with age in both men and women. These data indicated that aging itself had no effect on insulin sensitivity, while insulin secretion in both the early and late phase during the OGTT deteriorated with age even within the NGT subjects.     

Significance of fistulography findings to the healing time of postoperative pancreatic fistula after pancreaticoduodenectomy

Pancreatic fistula (PF) is a common and serious complications after pancreaticoduodenectomy (PD). However, few studies have discussed the time required for PF healing in patients with this complication. This study investigates the PF healing time (PF-HT) and its association with findings of postoperative fistulography performed via the drainage tubes. The subjects of this study were 35 patients with PF among a total of 144 patients who underwent PD for periampullary diseases in our hospital. PF-HT, which was defined as the duration from the first postoperative fistulography to removal of the drainage tubes, was assessed in the enrolled patients. Fistulography findings were classified into four types based on fluid collection and communication with the jejunal loop. We investigated the factors affecting the PF-HT, including the fistulography findings. The average PF-HT was 22 ± 20 days. Multivariate analysis revealed that the fistulography type was the only independent factor that affected PF-HT significantly. The PF-HT was significantly shorter in patients without fluid collection than in those with fluid collection. Moreover, those patients with fluid collection and a communication had a significantly shorter PF-HT than those without a communication. We found that fistulography findings were significantly associated with the PF-HT. This suggests that fistulography findings could help to predict the time needed for PF healing.     

Clinical investigation of the cystic duct variation based on the anatomy of the hepatic vasculature

Surgery Today - Anatomical variation of the cystic duct (CD) is rare but can result in misunderstanding of the CD anatomy during laparoscopic cholecystectomy, potentially leading to bile duct...     

Identification of VanB-type vancomycin resistance inEnterococcus gallinarum from Japan

In late January 1996, pus obtained from a periproctal abscess on an acute myeloid leukemia patient in Toho University Omori Hospital yieldedEnterococcus gallinarum strain TUH327. Antimicrobial susceptibility testing by the agar dilution method showed that this strain was resistant to low levels of vancomycin but remained susceptible to teicoplanin, indicating resistance of the VanC type that is, the intrisic glycopeptide resistance of motile enterococci such asEnterococcus. casseliflavus andE. gallinarum. Subsequently, to confirm the existence of theVanC inE. gallinarum TUH 327, we carried out PCR using primer sets specific tovanA, vanB andvanC. Unexpectedly, results showed the coexistence ofvanB andvanC inE. gallinarum TUH327. This appears to be the first reported isolation anywhere in the world of motile enterococci harboringvanB, and also the first report ofvanB in any enterococci from Japan.     

Cloning and Sequencing of the Gene Encoding Toho-2, a Class A β-Lactamase Preferentially Inhibited by Tazobactam

Escherichia coli TUM1083, which is resistant to ampicillin, carbenicillin, cephaloridine, cephalothin, piperacillin, cefuzonam, and aztreonam while being sensitive to cefoxitin, moxalactam, cefmetazole, ceftazidime, and imipenem, was isolated from the urine of a patient treated with β-lactam antibiotics. The β-lactamase (Toho-2) purified from the bacteria hydrolyzed β-lactam antibiotics such as penicillin G, carbenicillin, cephaloridine, cefoxitin, cefotaxime, ceftazidime, and aztreonam and especially had increased relative hydrolysis rates for cephalothin, cephaloridine, cefotaxime, and ceftizoxime. Different from other extended-spectrum β-lactamases, Toho-2 was inhibited 16-fold better by the β-lactamase inhibitor tazobactam than by clavulanic acid. Resistance to β-lactams was transferred by conjugation from E. coli TUM1083 to E. coli ML4909, and the transferred plasmid was about 54.4 kbp, belonging to the incompatibility group IncFII. The cefotaxime resistance gene for Toho-2 was subcloned from the 54.4-kbp plasmid. The sequence of the gene was determined, and the open reading frame of the gene was found to consist of 981 bases. The nucleotide sequence of the gene (DDBJ accession no. {"type":"entrez-nucleotide","attrs":{"text":"D89862","term_id":"3142148","term_text":"D89862"}}D89862) designated as bla_toho was found to have 76.3% identity to class A β-lactamase CTX-M-2 and 76.2% identity to Toho-1. It has 55.9% identity to SHV-1 β-lactamase and 47.5% identity to TEM-1 β-lactamase. Therefore, the newly isolated β-lactamase designated as Toho-2 produced by E. coli TUM1083 is categorized as an enzyme similar to Toho-1 group β-lactamases rather than to mutants of TEM or SHV enzymes. According to the amino acid sequence deduced from the DNA sequence, the precursor consisted of 327 amino acid residues. Comparison of Toho-2 with other β-lactamase (non-Toho-1 group) suggests that the substitutions of threonine for Arg-244 and arginine for Asn-276 are important for the extension of the substrate specificity.β-Lactam antibiotics are widely used as front line agents in the clinical field. In the early 1980s, expanded-spectrum β-lactams, with stability for β-lactamase and good activity against gram-negative bacteria, were first used in the clinical setting. Not long after the beginning of wide use of the expanded-spectrum β-lactams, extended-spectrum β-lactamases were isolated in Europe and the United States and now have become a serious problem in the clinical field (29). In the late 1980s and early 1990s, those enzymes hydrolyzing the expanded-spectrum β-lactams were generally derived from TEM- or SHV-type β-lactamases through several mutations (6, 24). The mutations of Glu-104, Arg-164, and Glu-240 have been suggested to be important for the spectrum expansion (16, 24). In more recent years, non-TEM- or non-SHV-type β-lactamases such as Toho-1 (13), CTX-M-2 (5), and MEN-1 (3) have been identified. Those β-lactamases have high homology to the chromosomally encoded β-lactamase of Proteus vulgaris or Klebsiella oxytoca (2, 9, 23). In most cases, the β-lactamase-producing organisms show resistance to expanded-spectrum β-lactams such as cefotaxime and ceftazidime (6, 24). On the other hand, they are susceptible to carbapenems such as imipenem (6, 24). The main characteristic of those class A β-lactamases, except TEM-30 to TEM-40, is that they are sensitive to β-lactamase inhibitors such as clavulanic acid, sulbactam, and tazobactam (6). The reaction mechanism and the amino acid residues associated with the spectrum expansion of β-lactamases are still under investigation. Ishii et al. (13) proposed that mutations at positions 244 and 276 are important for the substrate extension after performing sequence alignment of Toho-1 and other β-lactamases.The expanded-spectrum β-lactam-resistant strains isolated from several hospitals were surveyed and collected. We investigated those strains by enzymological and molecular biological methods and focused upon Escherichia coli TUM1083, a cefotaxime-resistant clinical isolate.In this report, we discuss a correlation between the mutation and the substrate specificity of the β-lactamase from E. coli TUM1083 based on the sequence alignment and a three-dimensional structure of a related β-lactamase of Bacillus licheniformis (17).     

In Vivo Antibacterial Activities of Sanfetrinem Cilexetil, a New Oral Tricyclic Antibiotic

The in vivo antibacterial activities of a new oral trinem, sanfetrinem cilexetil (a prodrug of sanfetrinem), were evaluated in comparison with those of cefdinir and amoxicillin. Sanfetrinem cilexetil showed potent efficacy against experimental murine septicemia caused by Staphylococcus aureus, Streptococcus pyogenes, and Escherichia coli and against murine respiratory infections caused by Streptococcus pneumoniae. Likewise, in murine models of respiratory infection by penicillin-susceptible and penicillin-resistant S. pneumoniae, sanfetrinem cilexetil was more effective than amoxicillin in reducing the number of bacteria in infected lungs. These results were reflected in its potent in vitro activity and high levels in plasma.     

Association of autoantibodies to muscarinic acetylcholine receptors with gastrointestinal symptoms and disease severity in patients with postural orthostatic tachycardia syndrome

Previous studies have reported a relationship between postural orthostatic tachycardia syndrome (POTS) and positivity for serum autoantibodies against G-protein-coupled receptors (GPCRs). However, the role of these autoantibodies in POTS is unclear. The present retrospective study analyzed the autoimmune etiology of POTS in 24 patients using a head-up tilt test to assess for any correlation between the clinical features of POTS and serum levels of autoantibodies against diverse GPCRs. In total, ten assessment items, including autonomic function tests, were analyzed. Of these, persistent, gastrointestinal symptoms and disease severity showed a significant association with the serum level of anti-muscarinic acetylcholine receptor (mAChRs) antibodies (gastrointestinal symptoms, M1, M2, M5; disease severity, M1, M3, M4, M5) [P <0.05]), while no significant association was found between the clinical features and autoantibodies against adrenergic receptors (α1, α2, β1, β2), angiotensin receptor 1, or endothelin receptor A. The patients were further divided into two groups based on the presence or absence of persistent gastrointestinal symptoms and then were characterized by the ten assessment items and neuropsychological tests, including the Wechsler Adult Intelligence Scale score and Self-Rating Depression Scale score. The results demonstrated a clear difference between the two groups in terms of disease severity, age at onset (older or younger than 20 years), and processing speed index (P <0.05), which were highly consistent with the association between these clinical features and the levels of serum anti-mAChR antibodies, particularly the anti-M5 receptor antibody. These findings suggested that anti-mAChR antibodies may play an important role in a subgroup of POTS patients with persistent gastrointestinal symptoms.