Investigation of the cause of polyurethane catheter cracking during constant infusion of etoposide (VP-16) injection (2)--Analysis of ethanol eluting materials from catheter

We studied the cause of cracking of clinically used polyurethane (PU) catheters during the constant infusion of etoposide (VP-16) injection (Lastet inj.) without dilution. After the vehicles used for VP-16 injection, ethanol or polyethylene glycol 400 (PEG400), were infused into the PU catheters at a constant infusion rate (30 ml/h) for 24 h, obvious degradation of the internal wall of the catheter was observed under an electron microscope. When the PU catheter was immersed in ethanol for 24 h, condensed polymers of 1,4-butanediol (BD), contained in PU catheters as an elasticizer, were detected in the ethanol elute using the ESI/MS method. Moreover, time-dependent elution of BD from PU catheters with the infusion of ethanol into the catheter for 24 h at 30 ml/h was observed using the GC/MS method. The cumulative amount of BD eluted from the PU catheter with ethanol vehicle for 24 h was 130 micrograms. In conclusion, degradation and subsequent cracking of PU catheters during the infusion of VP-16 injection were caused by ethanol and PEG400 contained in the injection solution. Furthermore, to prevent the elution of BD from PU catheters, we suggest that PU catheters should not be used for the administration of VP-16 injection without dilution in consideration of safety and efficacy.     

International Union of Pharmacology XXXVII. Nomenclature for leukotriene and lipoxin receptors

The leukotrienes and lipoxins are biologically active metabolites derived from arachidonic acid. Their diverse and potent actions are associated with specific receptors. Recent molecular techniques have established the nucleotide and amino acid sequences and confirmed the evidence that suggested the existence of different G-protein-coupled receptors for these lipid mediators. The nomenclature for these receptors has now been established for the leukotrienes. BLT receptors are activated by leukotriene B(4) and related hydroxyacids and this class of receptors can be subdivided into BLT(1) and BLT(2). The cysteinyl-leukotrienes (LT) activate another group called CysLT receptors, which are referred to as CysLT(1) and CysLT(2). A provisional nomenclature for the lipoxin receptor has also been proposed. LXA(4) and LXB(4) activate the ALX receptor and LXB(4) may also activate another putative receptor. However this latter receptor has not been cloned. The aim of this review is to provide the molecular evidence as well as the properties and significance of the leukotriene and lipoxin receptors, which has lead to the present nomenclature.     

WF-536 inhibits metastatic invasion by enhancing the host cell barrier and inhibiting tumour cell motility

1. Rho-associated coiled-coil forming protein serine/threonine kinase (ROCK) is involved in the development of tumour metastasis. Wf-536, (+)-(R)-4-(1-Aminoethyl)-N-(4-pyridyl) benzamide monohydrochloride, a novel inhibitor of ROCK, inhibits tumour metastasis in some animal models. To metastasise, tumour cells have to disturb the tight intercellular junctions and the basement membrane matrix of the host tissue, which, respectively, create an intercellular barrier and the extracellular membrane. To clarify the mechanism of Wf-536 in inhibition of tumour metastasis, we analysed the effect of Wf-536 on the transition of tumour cells through the host cell layer and the basement membrane in in vitro systems. 2. In a coculture system of human fibrosarcoma HT1080 cells plated on a monolayer of human ECV304 cells, Wf-536 (0.3-3 micromol/L) inhibited the paracellular infiltration of tumour cells. 3. Wf-536 (3-30 micromol/L) inhibited the invasion of tumour cells through the reconstituted basement membrane (Matrigel) layer. 4. Wf-536 (10-30 micromol/L) inhibited the migration of tumour cells. At 0.3-3 micromol/L, Wf-536 also restrained hepatocyte growth factor/scatter factor (HGF)-induced increases in paracellular permeability of the ECV304 cell layer. 5. These results suggest that Wf-536 suppresses tumour metastasis by both enhancing the barrier function of host cell layers and inhibiting tumour cell motility at the stage of host tissue penetration by metastatic tumour cells.     

Thirteen-week repeated dose toxicity study of wormwood (Artemisia absinthium) extract in rats

Wormwood, Artemisia absinthium, is a very bitter plant, and its extract has been used as food additives such as seasonings for food and drinks. A 13-week repeated dose toxicity study of wormwood extract was performed in both sexes of Wistar Hannover (GALAS) rats. Rats were divided into 4 groups consisting of 10 males and 10 females each, and were given water containing 0, 0.125, 0.5, or 2% wormwood extract. All rats had survived at the end of the study, and no changes indicating obvious toxicities that are attributable to the treatment of wormwood extract were observed in the body weights, hematological and serum biochemical examinations, organ weights, and histopathological examinations. Based on the results of the present study, the NOAEL (no-observed-adverse-effect-level) of wormwood extract of Wistar Hannover rats was estimated to be 2% (equivalent to 1.27 g/kg/day in males and 2.06 g/kg/day in females) or more.     

Carcinogenetic process in gallbladder mucosa with pancreaticobiliary maljunction (Review)

Pancreaticobiliary maljunction (PBM) is a congenital anomaly with a high incidence of biliary tract carcinoma. Pathological findings strongly suggest that there is a hyperplasia-dysplasia-carcinoma sequence in carcinogenesis of PBM. A molecular biological analysis revealed high incidence of cellular proliferation activating factors such as TGF-alpha, COX-2 from the hyperplasia stage. In addition, cellular proliferative activity including BrdU, AgNOR, PCNA, and Ki-67 was significantly higher in regular gallbladder mucosa without PBM. Furthermore, a high incidence of K-ras gene mutation could be seen in hyperplasia (13-63%) and microsatellite instability could be observed in 60% of all cases in dysplasia. In cancerous lesions, a high rate of overexpression of cyclin D1, beta-catenin, p53, as well as p53 gene mutation has been recognized. These results suggest that a multistep carcinogenetic process contributes to the carcinogenesis of PBM, similar to that of other cancers. In addition, after preventive operation with resection of the extrahepatic bile duct is performed, carcinogenesis in the remnant biliary tract or pancreatic duct is rarely found. Whether the carcinogenesis is a result of the accumulation of genetic alteration from shortly after birth, or a result of regurgitation of gastrointestinal juice due to hepaticoenterostomy, remains unknown. Since a high frequency of COX-2 is positive in PBM, COX-2 inhibitors such as NSAIDs may play an important role in preventing carcinogenesis.     

Protective effects of a protein-bound polysaccharide, PSK, against Candida albicans infection in syngeneic tumor-bearing mice via Th1 cell functions

We investigated the effects of a protein-bound polysaccharide, PSK, on the resistance of tumor-bearing mice against Candida albicans infection. In BALB/c mice that had received subcutaneous (sc) transplantation of fibrosarcoma Meth A, viable fungal counts were increased in the kidney and the mean survival period was shortened after challenge with C. albicans, compared with healthy mice. Oral administration of PSK to such mice resulted in a significant decrease of viable fungal counts and a prolongation of the mean survival period. The ratio of CD4-positive T cells in the spleen was decreased in noninfected tumor-bearing mice and the decrease was prevented by PSK, although in vitro anticandida activities of phagocytes were not significantly affected by tumor burden or PSK. Further, intracellular interferon (IFN)-gamma productivity was enhanced and the number of IFN-gamma-producing CD4-positive T cells was enhanced by PSK. PSK enhanced the gene expression of interleukin (IL)-12 and IFN-gamma in the spleen of tumor-bearing mice inoculated with C. albicans. Treatments with anti-IL-12 or anti-IFN-gamma antibody reduced the anti-infectious effects of PSK. These findings suggest that the protective effect of PSK on sublethal inoculation with C. albicans in tumor-bearing mice is possibly mediated by Th1 cell functions.     

Nonspecific interstitial pneumonia in collagen vascular diseases: comparison of the clinical characteristics and prognostic significance with usual interstitial pneumonia

BACKGROUND: Nonspecific interstitial pneumonia (NSIP) has recently been described as a distinct clinicopathological entity among idiopathic interstitial pneumonias (IIP), having more favorable prognosis than usual interstitial pneumonia (UIP). Although NSIP was initially reported to also occur in patients with interstitial pneumonia associated with collagen vascular diseases (IP-CVD), the prevalence of NSIP and its prognostic significance in IP-CVD remains to be determined. Thus, we attempted to clarify clinical characteristics and prognostic significance of NSIP in IP-CVD. METHODS: We histologically examined surgical lung biopsies from 43 patients with IP-CVD based on a current classification of interstitial pneumonias, and compared the clinical characteristics and prognostic significance of NSIP with UIP in IP-CVD. We also studied 98 patients with biopsy-proven NSIP and UIP in IIP, and compared the prognostic significance of histopathologic subclassification in IIP with that in IP-CVD. RESULTS: In IP-CVD, twenty-six patients (60%) were classified as NSIP, 17 (40%) as UIP. In contrast, 76 (77%) were categorized into UIP and 22 (23%) into NSIP of the patients with IIP. No significant difference in survival rates was observed between UIP and NSIP in IP-CVD (p = 0.3863), while, in IIP, NSIP has a significant better survival than UIP (p = 0.022). CONCLUSIONS: These results suggest that NSIP is more common histologic pattern than UIP in IP-CVD and, unlike in IIP, the prognosis of NSIP patients may not be different from that of UIP patients in IP-CVD.     

A case of breast cancer metastasizing to cervix after resection of pancreatic metastasis

A case of breast cancer that metastasized to the cervix 10 years and 8 months after mastectomy is reported. The patient had undergone pancreaticoduodenectomy due to solitary metastasis to the head of the pancreas 4 years previously. The cervical metastasis was associated with abnormal genital bleeding. After pancreaticoduodenectomy the serum levels of CEA, CA15-3 and NCC-ST-439, which are markers of breast cancer, were within normal limits, but the serum level of CA15-3 had increased month by month. The patient had abnormal genital bleeding and presented to the department of gynecology at our hospital. The tumor was in the cervix, bled easily and 2.5x2.0 cm in size on ultrasonography. It was thought to be carcinoma of the cervix, but biopsy revealed the tumor to be an adenocarcinoma pathologically and CA15-3 was immunohistochemically demonstrated in the resected specimen, similar to lobular carcinoma of the breast. Abdominal CT scan revealed involvement of the ovaries and uterus, prompting hysterectomy with bilateral oophorectomy. After discharge, she received chemoendocrine therapy. However, she subsequently died due to peritoneal carcinomatosis.     

Mirimostim (macrophage colony-stimulating factor; M-CSF) improves chemotherapy-induced impaired natural killer cell activity,Th1/Th2 balance,and granulocyte function

The purpose of this study was to clarify the effects of mirimostim (macrophage colony-stimulating factor; M-CSF) on immunological functions after chemotherapy. The percentage of natural killer (NK) cells in peripheral blood mononuclear cells (PBMCs), NK cell activity, T-helper cell 1/T-helper cell 2 (Th1/Th2) ratio, and superoxide anion production by granulocytes (granulocyte function) were measured as immunological parameters before and after chemotherapy in 44 patients with primary ovarian cancer who received at least three consecutive courses of postoperative chemotherapy. Patients were observed during the first course of chemotherapy, and 39 patients who presented grade III or IV neutropenia were entered into this study and randomly allocated to an M-CSF-administered group (group 1; 19 patients) and a non-M-CSF-administered group (group 2; 20 patients) for the second course. For the third course, a crossover trial was conducted. In the observation period, chemotherapy significantly impaired the immunological parameters. In particular, those parameters were significantly decreased at day 14 compared to the level before chemotherapy. The values of the parameters of group 1 were significantly higher than those of group 2. In the course of chemotherapy during which M-CSF was administered, 19 of the 39 patients presented grade IV neutropenia, and received granulocyte colony-stimulating factor (G-CSF) between days 7 and 14. We compared the changes of those immunological parameters in the M-CSF alone group and the M-CSF+G-CSF group, and found that the concomitant use of G-CSF did not further improve the parameters. These results indicate that chemotherapy markedly impaired the immunological functions, and that the administration of M-CSF significantly improved the impaired immunological functions.