Risk Factors for Infusion Reactions in Patients with Breast Cancer Administered Trastuzumab Therapy.

Trastuzumab is a humanized monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2) that is indicated for the treatment of HER2-positive breast cancer. The administration of biologics, such as trastuzumab, frequently causes infusion reactions (IRs) with fever and chills. This study aimed to clarify the risk factors for IRs in trastuzumab therapy. Between March 2013 and July 2022, 227 patients with breast cancer who started trastuzumab therapy were included in this study. The severity of IRs was graded according to the Common Terminology Criteria for Adverse Events, Version 5.0. The incidence of IRs in trastuzumab therapy was 27.3% (62/227). Dexamethasone administration was significantly different between the IR and non-IR groups in patients receiving trastuzumab therapy (univariate analysis, p < 0.001; multivariate analysis, p = 0.0002). Without dexamethasone, the severity of IRs in the pertuzumab combination group (Grade 1, 8/65; Grade 2, 23/65) was significantly higher than that in the non-pertuzumab group (Grade 1, 9/37; Grade 2, 3/37; p < 0.05). Our findings suggest that the risk of IRs is significantly higher in patients not premedicated with dexamethasone in trastuzumab therapy and that the concomitant use of pertuzumab without dexamethasone increases the severity of IRs caused by trastuzumab.

Incidence and risk factors of infusion reactions in patients with breast cancer administered trastuzumab plus pertuzumab-based regimen.

PURPOSE: Pertuzumab (Per) is a humanized monoclonal antibody used in combination with trastuzumab (Tra) in the treatment of human epidermal growth factor receptor-2 (HER2)-positive breast cancer. The administration of biologics, such as Tra and Per, frequently causes infusion reactions (IRs) with fever and chills. This study aimed to clarify the characteristics of and risk factors for IRs in Tra + Per combination therapy. METHODS: Between March 2013 and December 2019, 64 patients with breast cancer who started Tra + Per combination therapy were included in the study. The severity of IRs was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: The incidence of IRs in the Tra + Per combination therapy was 48.4% (31/64). The severity of IRs in the Tra + Per combination therapy was Grade 1 (9 patients) and Grade 2 (22 patients). Lymphocyte counts were significantly different between the IR and non-IR groups in patients receiving Tra + Per combination therapy (univariate analysis, p = 0.006; multivariate analysis, p = 0.050). ROC curve analysis found the cutoff value of lymphocyte counts were 1.60 (× 103/µL). The incidence of IRs in the lymphocyte counts ≥ 1.60 group was significantly higher than that in the lymphocyte counts < 1.60 group (p < 0.001). CONCLUSION: Our study indicates that the severity of IRs in most patients is moderate or less and the risk of IRs is higher in patients with higher lymphocyte counts (≥ 1.60 × 103/µL).

Pathological and Clinical Pathological Changes Induced by Four-week, Repeated-dose, Oral Administration of the Wood Preservative Chromated Copper Arsenate in Wistar Rats.

Chromated copper arsenate (CCA) is used as a wood preservative worldwide. Exposure to it may adversely affect human health. Some events have increased human exposure to CCA, including the Great East Japan Earthquake, which generated a large amount of lumber debris from CCA-treated woods. We elucidated the toxicity due to daily exposure to CCA over a 4-week period at doses of 0, 8, 40, and 80 mg/kg/day in Wistar Hannover rats. Chromium (Cr) and arsenic (As), but not copper, were detected in the plasma samples of rats treated with various doses of CCA. Males and females showed sedation, and males had poor body weight gain. The clinical pathologies observed in both sexes included hypochromic and microcytic anemia, hepatic and renal dysfunction, and changes in lipid and glucose levels. Histopathologically, males and females showed forestomach hyperkeratosis, mucosal epithelial hyperplasia in the small intestine, rectal goblet cell hypertrophy, and lipofuscin deposition in the proximal renal tubule. Females showed diffuse hepatocellular hypertrophy with increased 8-hydroxydeoxyguanosine levels. These results indicated that oral administration of CCA mainly affected hematopoietic, gastrointestinal, hepatic, and renal systems owing to the toxic effects of As and/or Cr. Major toxic effects were observed in both sexes receiving 40 and 80 mg/kg/day.

p,p'-DDT induces microcytic anemia in rats.

Emerging evidence suggests that chronic exposure to DDT and its derivatives is associated with a variety of human disorders such as anemia. The present study demonstrated that p,p'-DDT caused microcystic anemia in a dose-dependent manner (0, 5, 50, and 500 ppm) in the long-term study up to 2 years. To elucidate the mechanism(s) by which p,p'-DDT induces anemia, certain hematological parameters were assessed in rats fed specific doses of p,p'-DDT for 2 weeks, and the effect of lipopolysaccharide on anemia of inflammation was also examined in p,p'-DDT-treated rats. The parameters included the content of hemoglobin per reticulocyte, mean corpuscular volume of reticulocytes and mature erythrocytes, corpuscular hemoglobin concentration mean of mature erythrocytes, and saturation levels of transferrin and iron. During the 2-week treatment period, hypochromic microcytic reticulocytes and hypochromic normocytic mature erythrocytes were observed in p,p'-DDT-treated rats, with no evidence of alteration in plasma iron levels. p,p'-DDT enhanced microcytosis of reticulocytes, as well as mature erythrocytes, which occurred due to severe hypoferremia resulting from anemia of inflammation; however, plasma iron levels were attenuated probably through the inhibition of interleukin-6. Our data suggests that long-term treatment with p,p'-DDT induces microcytic anemia, possibly because of the impairment of iron utility in erythrocytes.

Efficacy and tolerability of oral budesonide in Japanese patients with active Crohn's disease: a multicentre, double-blind, randomized, parallel-group Phase II study.

BACKGROUND AND AIMS: Current treatments for Japanese patients with active Crohn's disease have not proved optimal, and new treatment options are required. The present study therefore evaluated the efficacy and tolerability of oral budesonide in Japanese patients with mild-to-moderate active Crohn's disease. METHODS: In this multicentre, double-blind, randomized, parallel-group, Phase II study, patients (18-65 years) with baseline Crohn's Disease Activity Index (CDAI) score≥200 were randomized to once-daily (od) oral budesonide 9 mg or 15 mg, or matching placebo, for 8 weeks. Concomitant therapy with sulfasalazine or 5-aminosalicylic acid, and nutritional therapy, was allowed. The rate of remission (defined as CDAI score≤150) after 8 weeks' treatment (primary variable), health-related quality of life (assessed using the Inflammatory Bowel Disease Questionnaire [IBDQ]), and tolerability were assessed. RESULTS: 77 patients were randomized and 63 completed the study. The proportion of budesonide-treated patients with remission after 8 weeks' treatment was higher compared with placebo (23.1%, 28.0%, and 11.5% for budesonide 9 mg, 15 mg, and placebo, respectively; no significant difference). The mean change from baseline to week 8 in CDAI total score (-48.0, -58.2, and -27.2, respectively) and IBDQ total score (10.8, 23.2, and 6.5, respectively) was greater for budesonide-treated patients than placebo recipients. While budesonide 9 mg and 15 mg demonstrated similar efficacy, budesonide 9 mg caused fewer drug- and glucocorticosteroid-related adverse events and less adrenal suppression. CONCLUSIONS: Oral budesonide 9 mg od (for up to 8 weeks) may offer a new treatment option for Japanese patients with mild-to-moderate active Crohn's disease.

Immunotoxicity in mice induced by short-term exposure to methoxychlor, parathion, or piperonyl butoxide.

Exposure to environmental agents can compromise numerous immunological functions. Immunotoxicology focuses on the evaluation of the potential adverse effects of xenobiotics on immune mechanisms that can lead to harmful changes in host responses such as: increased susceptibility to infectious diseases and tumorigenesis; the induction of hypersensitivity reactions; or an increased incidence of autoimmune disease. In order to assess the immunosuppressive response to short-term exposure to some commonly used pesticides, the studies here focused on the response of mice after exposures to the organochlorine pesticide methoxychlor, the organophosphorus pesticide parathion, or the agricultural insecticide synergist piperonyl butoxide. In these studies, 7-week-old mice were orally administered (by gavage) methoxychlor, parathion, or piperonyl butoxide daily for five consecutive days. On Day 2, all mice in each group were immunized with sheep red blood cells (SRBC), and their SRBC-specific IgM responses were subsequently assessed. In addition, levels of B-cells in the spleen of each mouse were also analyzed via surface antigen expression. The results of these studies indicated that treatments with these various pesticides induced marked decreases in the production of SRBC-specific IgM antibodies as well as in the expression of surface antigens in IgM- and germinal center-positive B-cells. Based on these outcomes, it is concluded that the short-term exposure protocol was able to detect potential immunosuppressive responses to methoxychlor, parathion, and piperonyl butoxide in situ, and, as a result, may be useful for detecting other environmental chemical-related immunotoxicities.

Induction of hyperchromic microcytic anaemia by repeated oral administration of methotrexate in rats.

Anaemia is a significant prognostic factor in cancer patients receiving anticancer drugs such as methotrexate (MTX). This study focuses on the effects of toxicological changes on the hematopoietic systems in male and female Wistar Hannover rats when MTX is orally administered at a dose of 0, 0.05, 0.15, or 0.45 mg/(kg·day) for a period of 28 days. Both male and female rats receiving 0.45 mg/kg MTX showed a decrease in the haemoglobin concentration (Hb), haematocrit, and erythrocyte count. Female rats showed a decrease in mean corpuscular volume (MCV) and an increase in cell mean Hb (CHCM) in total erythrocytes, including the mature erythrocytes. These results indicate that MTX causes the production of small, mature erythrocytes that contain a high concentration of Hb. MTX reduced the number of peripheral reticulocytes but produced the cells with a large size and a high concentration of Hb, as demonstrated by the reticulocyte MCV and CHCM as well as the content of haemoglobin per reticulocyte (CHr). Consistent with these findings, bone marrow haematopoiesis was impaired by MTX, as there was a reduction in erythroid count in rats of both sexes. The number of cells of the myeloid lineage reduced in female rats, followed by a reduction in the total leukocyte and neutrophil counts in peripheral blood. Thrombocytopenia was detected in a small population of rats. These results indicate that MTX induces hyperchromic microcytic anaemia and pancytopenia, and the use of MCV and CHCM in mature erythrocytes and reticulocytes, along with the CHr, gives a better understanding of the development and nature of anaemia.

Altered pulmonary defense system in lung injury induced by didecyldimethylammonium chloride in mice.

Didecyldimethylammonium chloride (DDAC), a representative dialkyl-quaternary ammonium compound (QAC), could contaminate working atmospheres when used in disinfectant operation and adversely affect human health. Furthermore, the development of bacteria resistant to DDAC might become public health concern. We postulated that DDAC instillation in the lungs alters pulmonary antioxidant and antimicrobial responses and increases susceptibility to systemic administration of a bacterial component lipopolysaccharide (LPS). Mice were intratracheally instilled with DDAC and sacrificed 1, 3, or 7 days after treatment. Pulmonary cytotoxicity in recovered bronchoalveolar lavage was evident on Days 1 and 7, and inflammatory cell influx and interleukin-6 expression peaked on Day 7, in association with altered antioxidant and antimicrobial responses, as demonstrated by measuring heme oxygenase-1, glutathione peroxidase 2, lactoferrin, and mouse ß-defensin-2 and -3 mRNA in the lung samples. The impaired defense system tended to enhance the inflammatory reaction caused by a systemic administration of LPS; the effect was in association with increased expression of toll-like receptor-4 mRNA. The results suggest that DDAC alters pulmonary defense system, which may contribute to susceptibility to an exogenous infectious agent.

Prior exposure to organophosphorus and organochlorine pesticides increases the allergic potential of environmental chemical allergens in a local lymph node assay.

The dysregulation of immune functions by some pesticides leads to various immune disorders, including immunodeficiency, tumorigenesis, allergies, and autoimmunity. This study's primary objective was to examine the relationship between immune disorders and the immunosuppression induced by immunosuppressive pesticides. We focused on the modulation of allergic potential by the organophosphorus pesticide parathion, organochlorine pesticide methoxychlor, phenoxyacetic acid herbicide 2,4-d-butyl, and benzoic acid fungicide eugenol, as detected by a local lymph node assay (LLNA), which was developed initially for hazard identification of skin sensitization. Parathion and methoxychlor are immunosuppressive chemicals, and 2,4-d-butyl and eugenol are contact allergens. After the immunosuppressive characteristics of parathion and methoxychlor were confirmed in a pilot study, 4-week-old mice were orally administered parathion (0, 0.4, 1.2mg/kg) or methoxychlor (0, 100, 300 mg/kg). Four weeks after the last administration, an LLNA was conducted using 2,4-d-butyl (0%, 2.5%, 5%, and 10%) and eugenol (0%, 5%, 10%, and 25%). In addition, detailed analysis of their auricular lymph nodes for number of surface antigen expression of T cells and local cytokine production were performed using 5% 2,4-d-butyl and 5% eugenol treatment groups. EC3 values (estimated concentration to yield a stimulation index of 3) of 2,4-d-butyl and eugenol decreased markedly in parathion- and methoxychlor-pretreated groups. Parathion- and methoxychlor-pretreated groups induced marked increase in number of surface antigen expression of T cells and levels of Th1 cytokines (IFN-γ, TNF-α, and IL-17) produced by ex vivo restimulated lymph node cells. According to our results, the allergic potentials of 2,4-d-butyl and eugenol are increased by prior exposure to parathion and methoxychlor.

Apoptosis in immunocytes induced by several types of pesticides.

Several types of pesticides, such as organophosphates and organochlorines, can induce thymocyte apoptosis, resulting in thymic atrophy and predisposing the highly sensitive fetal immune system to loss of tolerance to self-antigens and subsequent increased risk for autoimmune disease and allergies. In the studies here, mouse primary thymocytes and a human acute T-cell leukemia cell line (J45.01) were employed to examine potential thymocyte apoptosis induced by several types of chemicals, including several commonly-used pesticides. Thymocytes and J45.01 cells were treated for 4 or 8 hr with varying doses of metamidophos, parathion, PNMC, or methoxychlor; dexamethasone was used as a positive control. Apoptosis, cell viability, the proportion of Annexin-V+ cells, the activities of caspases 3/7, 8, and 9, and the levels of DNA fragmentation in both the J45.01 cells and thymocytes were then examined. The results here show that with both cell types, there was an increase in the proportion of annexin-V+ cells and levels of DNA fragmentation following exposure to parathion, PNMC, methoxychlor, or dexamethasone (positive control); however, the levels of sensitivity appeared to differ between the cell types. Furthermore, caspase-7 and -8 activities also differed between the J45.01 cells and thymocytes when treated with PNMC, methoxychlor, or dexamethasone. A more precise characterization of these inter-cellular differences is the logical next step in our studies of the effects of these (and other) pesticides on immune cell integrity. These specific types of follow-on mechanistic experiments are currently underway in our laboratories.

Pulmonary injury and antioxidant response in mice exposed to arsenate and hexavalent chromium and their combination.

Chromated copper arsenate, which is used worldwide as a wood preservative, can adversely affect human health. Accumulating evidence suggests that chromium (Cr) and arsenic (As) can potentially disrupt the redox balance and cause respiratory diseases and cancer in humans. The present study was designed to determine the combined toxic effects of these metals in the lungs and to clarify the specific molecules that are stimulated by combined exposure to both metals. Male C57BL/6J mice were intratracheally instilled with arsenate [As(V)], hexavalent chromium [Cr(VI)], or a combination of both metals. Mice were sacrificed 2 days after treatment to collect bronchoalveolar lavage fluid and lung tissue samples. Inflammation, cytotoxicity, apoptosis, and oxidative stress markers were measured. Our results indicated that administration of Cr(VI) alone or in combination with As(V) induced neutrophil-dominant inflammation as well as phosphorylation of mitogen-activated protein kinases; effects of treatment with As(V) alone were comparatively less potent. By analyzing the production of interleukin-6 and activity of lactate dehydrogenase and caspase, we confirmed that co-treatment intensified pulmonary injury and that it was accompanied by oxidative stress, as confirmed by marked increases in the production of reactive oxygen species, reduced glutathione content, and thioredoxin reductase (TRXRD) activity. Expressed mRNA levels of heme oxygenase-1, glutamylcysteine ligase, glutathione peroxidase 2, thioredoxin (TRX) 1, and TRXRD1 were also enhanced by co-treatment, whereas treatment with As(V) alone reduced the mRNA expression level of TRX2. Our data suggest that co-treatment with As(V) exacerbated Cr(VI)-induced pulmonary injury and that this effect may be exerted through a disruption in the balance among several antioxidant genes.

Multiple organ toxicity, including hypochromic anemia, following repeated dose oral administration of phenobarbital (PB) in rats.

A 4-week repeated dose oral toxicity study of phenobarbital (PB) sodium was conducted in F344 rats of both sexes at PB doses of 0.8, 8, and 80 mg/kg/day to fully elucidate its general toxicity including hematological changes. Both sexes in the 80 mg/kg/day group showed staggering gait, lacrimation, and/or sedation, which were more evident in the early stage of treatment. The body weight gain and food consumption were greater in these animals than in controls. Hematology revealed a significant reduction in the hematocrit (Ht), hemoglobin concentration (Hb), and erythrocyte count (RBC) in both sexes at 80 mg/kg/day, which was accompanied by a decrease in the cell mean Hb (CHCM) in mature erythrocytes with an increase in unsaturated iron binding capacity. Female rats also showed reduction in the CHCM in reticulocytes, content of hemoglobin per reticulocyte, and transferrin saturation. PB prolonged the activated partial thromboplastin time and inversely increased the platelet count with no evidence of platelet activation. Well-known toxic effects of PB on the liver and thyroid were observed in a dose-dependent manner, along with altered lipid, glucose, and electrolyte metabolism. The serum levels of PB increased dose-dependently, when examined in females received 8 and 80 mg/kg/day on day 1 and 28; there were no difference in C(max) and AUC(0-24) values between day 1 and day 28. These results indicated that PB has the potential to elicit multiple organ toxicity including an effect on the hematopoietic system. The hematological analysis provided evidence for hypochromic anemia, plausibly caused by the impairment of iron utility.

Investigation of the chemical-induced selective type II (T(H)2) allergic response in mice: effect of the length of the sensitizing phase.

Allergies are immune system disorders characterized by abnormal, acquired sensitivity to various environmental chemicals. We investigated the mechanism of chemical-induced selective type II (T(H)2) allergy by using three different sensitization protocols and the well-known respiratory sensitizer trimellitic anhydride (TMA). Mice were sensitized for either 1, 2, or 3 weeks. For each sensitization schedule, the mice were allocated into 3 or 4 groups: -/- group, both sensitized and challenged with vehicle; -/+ group, sensitized with vehicle and challenged with 0.1% TMA; +/- group, sensitized with 1% TMA and challenged with vehicle; and +/+ group, both sensitized and challenged with 0.1% TMA. After challenge, we assayed the auricular lymph nodes of all mice for number of lymphocytes, surface antigen expression of B-cells, and local cytokine production, and we measured TMA-specific serum IgE levels. Some parameters in mice sensitized for 1 or 2 wk showed, at most, mild changes. In contrast, all parameters in animals receiving 3-wk sensitization showed marked increases, as well as marked increases in the IgE/major histocompatibility complex (MHC) Class II-positive B-cell population and T(H)2 cell production of IL-10 and IL-13. These results indicate that 3 wk of sensitization according to our protocol led to overt respiratory allergic reactions. While these studies showed that using the approach here, positive reactions were elicited using a typical allergen; whether the same events occur after sensitization by other chemicals that are found in the environment remains uncertain. These findings here should be regarded moreover as preliminary in scope and that additional studies with irritants, dermal sensitizers and other respiratory sensitizers are needed to further evaluate the overall sensitivity and selectivity of this novel protocol.

Allergic reaction induced by dermal and/or respiratory exposure to low-dose phenoxyacetic acid, organophosphorus, and carbamate pesticides.

Several types of pesticides, such as organophosphates, phenoxyacetic acid, and carbamate have a high risk of affecting human health, causing allergic rhinitis and bronchial asthma-like diseases. We used our long-term sensitization method and a local lymph node assay to examine the allergic reactions caused by several types of pesticides. BALB/c mice were topically sensitized (9 times in 3 weeks), then challenged dermally or intratracheally with 2,4-D, BRP, or furathiocarb. One day post-challenge, the mice were processed to obtain biologic materials for use in assays of total IgE levels in serum and bronchoalveolar lavage fluid (BALF); differential cell counts and chemokine levels in BALF; lymphocyte counts and surface antigen expression on B-cells within regional lymph nodes (LNs); and, ex situ cytokine production by cells from these LNs. 2,4-D-induced immune responses characteristic of immediate-type respiratory reactions, as evidenced by increased total IgE levels in both serum and BALF; an influx of eosinophils, neutrophils, and chemokines (MCP-1, eotaxin, and MIP-1beta) in BALF; increased surface antigen expression on B-cells IgE and MHC class II production) in both auricular and the lung-associated LNs; and increased Th2 cytokine production (IL-4, IL-5, IL-10, and IL-13) in both auricular and the lung-associated LN cells. In contrast, BRP and furathiocarb treatment yielded, at most, non-significant increases in all respiratory allergic parameters. BRP and furathiocarb induced marked proliferation of MHC Class II-positive B-cells and Th1 cytokines (IL-2, TNF-alpha, and IFN-gamma) in only auricular LN cells. These results suggest that 2,4-D is a respiratory allergen and BRP and furathiocarb are contact allergens. As our protocol detected classified allergic responses to low-molecular-weight chemicals, it thus may be useful for detecting environmental chemical-related allergy.

Pharmacokinetics and tolerance of linezolid for meticillin-resistant Staphylococcus aureus mediastinitis in paediatric patients.

Here we report our experience with four paediatric patients with mediastinitis due to meticillin-resistant Staphylococcus aureus (MRSA) following cardiac surgery refractory to glycopeptide treatment and treated by linezolid. The pharmacokinetics and tolerance of linezolid administered orally or intravenously were analysed. Linezolid was administered intravenously at a dosage of 10 mg/kg every 8 h and then orally. In oral administration, 10 mg/kg or 15 mg/kg was given every 8 h as a powder made by crushing tablets. The linezolid serum trough concentration was >or=3.5 mg/L in patients treated by intravenous administration. However, with oral administration lower trough levels were detected, including patients with an undetectable level (<0.1 mg/L). No significant intolerance or drug-related haematological events were reported. We conclude that linezolid, with a switch from intravenous to oral administration, could be an effective and safe option in paediatric mediastinitis refractory to conventional glycopeptides, whilst care must be taken to maintain an adequate dose by monitoring the trough concentration.

Interlaboratory validation of the modified murine local lymph node assay based on adenosine triphosphate measurement.

INTRODUCTION: The murine local lymph node assay (LLNA) is a well-established alternative to the guinea pig maximization test (GPMT) or Buehler test (BT) for the assessment of the skin sensitizing ability of drugs and chemicals. Daicel Chemical Industries Ltd. has developed a modified LLNA based on the adenosine triphosphate (ATP) content (LLNA-DA). We conducted 2 interlaboratory validation studies to evaluate the reliability and relevance of LLNA-DA. METHODS: The experiment involved 17 laboratories, wherein 14 chemicals were examined under blinded conditions. In the first study, 3 chemicals were examined in 10 laboratories and the remaining 9 were examined in 3 laboratories. In the second study, 1 chemical was examined in 7 laboratories and the remaining 4 chemicals were examined in 4 laboratories. The data were expressed as the ATP content for each chemical-treated group, and the stimulation index (SI) for each chemical-treated group was determined as the increase in the ATP content relative to the concurrent vehicle control group. An SI of 3 was set as the cut-off value for exhibiting skin sensitization activity. RESULTS: The results of the first study obtained in the experiments conducted for the 3 chemicals that were examined in all the 10 laboratories and for 5 of the remaining 9 chemicals were sufficiently consistent with small variations in their SI values. The sensitivity, specificity, and accuracy of LLNA-DA against those of GPMT/BT were 7/8 (87.5%), 3/3 (100%), and 10/11 (90.9%), respectively. In the second study, all the 5 chemicals studied demonstrated acceptably small interlaboratory variations. DISCUSSION: In the first study, a large variation was observed for 2 chemicals; in the second study, this variation was small. It was attributed to the application of dimethylsulfoxide as the solvent for the metallic salts. In conclusion, these 2 studies provide good evidence for the reliability of the LLNA-DA.

Oral spherical adsorptive carbon for the treatment of intractable anal fistulas in Crohn's disease: a multicenter, randomized, double-blind, placebo-controlled trial.

OBJECTIVES: Anal fistulas are common in individuals with Crohn's disease (CD). We sought to evaluate the efficacy of oral spherical adsorptive carbon (AST-120) (Kremezin; Kureha Corporation, Tokyo, Japan) for the treatment of intractable anal fistulas in patients with CD. METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, patients with CD and at least one active anal fistula under treatment were assigned to receive either AST-120 or placebo for 8 wk. Improvement was defined as a reduction of 50% or more from baseline in the number of draining fistulas observed at both 4 and 8 wk. Remission was defined by closure of all draining fistulas at both 4 and 8 wk. The Perianal Disease Activity Index (PDAI) and Crohn's Disease Activity Index (CDAI) were also assessed. RESULTS: In total, 62 patients were randomized, of whom 57 received AST-120 (N = 27) or placebo (N = 30). The improvement rate in the AST-120 group (37.0%) was significantly greater than that in the placebo group (10.0%) (P= 0.025). The corresponding remission rates were 29.6% and 6.7%, respectively (P= 0.035). PDAI significantly improved at both 4 and 8 wk with AST-120, compared to placebo (P= 0.004 and P= 0.005, respectively). CDAI was also significantly improved at both 4 and 8 wk in the AST-120 group, compared to the placebo group (P= 0.007 and P= 0.001, respectively). AST-120 treatment was well tolerated and no life-threatening adverse events were observed. CONCLUSION: AST-120 is useful for the control of intractable anal fistulas in CD patients.

Glycopeptide pharmacokinetics in current paediatric cardiac surgery practice.

OBJECTIVE: To examine the evolution of serum concentrations of prophylactic glycopeptides administered during state-of-the-art cardiopulmonary bypass (CPB) and vigorous haemodiafiltration in paediatric patients undergoing cardiac surgery. METHODS: We enrolled infants and children <3 years of age who, based on the preoperative microbiological screening, age and surgical complexity, were at high risk of methicillin-resistant Staphylococcus aureus (MRSA) infection. Antimicrobial prophylaxis with glycopeptides was administered to 22 patients, randomly assigned to vancomycin (VAN; n=11) versus teicoplanin (TEC; n=11). Fixed doses of each drug (15 mg/kg for VAN and 8 mg/kg for TEC) were administered immediately before the operation, at the time of priming of the extracorporeal circuit, upon admission to the intensive care unit and for 48 h thereafter, q. 8 h for VAN, and once daily for TEC. Vigorous haemodiafiltration was applied during and briefly after CPB. RESULTS: The second dose of drug added to the prime prevented a fall in serum drug concentrations at the onset of CPB in both groups. A 77% decrease in VAN, versus 53% in TEC concentrations, was observed after the conclusion of CPB. Serum concentrations of TEC>10 microg/ml were observed throughout the treatment period in 91% of patients, while 55% of patients assigned to VAN had serum concentrations consistently >5 microg/ml (p=0.08). Therapeutic serum concentrations were maintained throughout the intraoperative period, particularly with TEC, administered before the first surgical incision, followed by a supplemental bolus in the priming fluid of CPB. Postoperative surgical wound infections occurred in neither group. CONCLUSIONS: The prophylactic use of glycopeptides in paediatric patients at high risk of MRSA infection undergoing cardiac surgery was safe and effective. TEC might be the drug of choice, since stable, therapeutic serum concentrations were easily maintained throughout the treatment period.

Effects of hepatocyte growth factor on rat inflammatory bowel disease models.

Hepatocyte growth factor (HGF) is a hepatotrophic factor and, also, functions as an epithelial growth factor. We examined the therapeutic effects of HGF on rat inflammatory bowel disease models induced by trinitrobenzensulfonic acid or dextran sulfate sodium. Recombinant human HGF was continuously administered at 50 microg/body/day using an intraperitoneally implanted pump for 7 days. Treatment of HGF reduced the ulcerated area, histological damage score, mucosal myeloperoxidase activity, and epithelial apoptotic rate but did not increase epithelial mitotic rate and immunohistochemical labeling indexes of proliferating cell nuclear antigen, Ki-67, and bromodeoxyuridine as indexes of epithelial cell proliferation in either model. We then examined the epithelial localization of the HGF receptor c-met and identified it on the surface epithelia, where apoptosis was observed, but did not find it in the proliferative zone. These results suggest that HGF exhibits therapeutic effects via anti-inflammation including antiapoptosis rather than epithelial cell proliferation in these inflammatory bowel disease models.

Adsorptive Monocyte-granulocytapheresis (M-GCAP) for refractory Crohn's disease.

Six patients with active Crohn's disease (CD) unresponsive to conventional medications (CM) were treated with Monocyte-granulocytapheresis (M-GCAP). CD patients who scored 200-400 points in Crohn's disease activity index (CDAI) in spite of receiving CM, including enteral nutrition, for at least 2 weeks were enrolled in our double series trial. Each series had 5 weekly M-GCAP and 2 follow-up weeks, and each M-GCAP treated 1,800 ml of patient's peripheral blood. After the 1st series, patients who decreased more than 50 points on the CDAI were deemed responders and enrolled in the second series. Patients with a CDAI score less than 150 points were considered in remission. The patients' quality of life was evaluated using an index (IBDQ) before and after the 1st series. The CDAI was significantly decreased comparing before and after the 1st series (258.2 +/- 36.2 vs. 166.5 +/- 16.6; P < 0.02). 50% of patients (3/6) responded to the therapy, and one case (16.7%) could be induced to remission. Significant removal was revealed only for white blood cells (25.6 +/- 16.9%; P < 0.05), especially granulocytes (29.5 +/- 22.5%; P < 0.05). A statistically significant improvement of IBDQ was revealed in the responders' group (162.3 +/- 17.2 vs. 189.3 +/- 11.5; P < 0.03). M-GCAP could be an effective adjunctive therapy for active CD patients unresponsive to CM allowing them to maintain a high QOL. However, it might be difficult to improve patients who could not be induced to remission after the 1st series by applying another series.