Pharmacokinetic and pharmacodynamic analysis of bis-acetato-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) administered once a day for five consecutive days: a phase I study

BACKGROUND: Bis-acetato-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) is the first orally given platinum complex that shows in vitro cytotoxicity comparable to that of cisplatin and in vivo cytotoxicity superior to those of cisplatin and carboplatin. METHODS: We conducted an escalating-dose (50, 75, 100, 120 mg/m2) phase I study of JM216 administered orally once a day for five consecutive days in patients with solid tumors to establish the toxicity profile, maximum tolerated dose (MTD) and pharmacokinetic profile. Twenty-three patients were enrolled and all were assessable for toxicity. RESULTS: The MTD was 120 mg/m2/day and the dose-limiting toxicities were leukopenia, thrombocytopenia, anemia and diarrhea. Because of the delayed hematological toxicities, it was difficult to repeat cycles every 26 days in some patients. Tumor shrinkage was observed in two patients with breast cancer, both of whom were resistant to doxorubicin. A pharmacokinetic study showed that the areas under the concentration-time curve (AUC) and peak plasma concentrations (Cmax) for total platinum (Pt) on days 1 and 5 and ultrafiltered Pt (UF-Pt) on day 1 increased in proportion to the dose of JM216. The AUCs for both total and UF-Pt on day 5 were higher than the AUCs on day 1. The AUC for UF-Pt on day 5 showed the best correlation with percentage reduction in leukocyte count and in absolute neutrophil count. CONCLUSION: The recommended dose for phase II studies is 100 mg/m2/day every 4-6 weeks. The observation of tumor shrinkage in previously heavily treated breast cancer patients supports a phase II investigation.     

Effects of Oral Clonidine Premedication on Plasma Glucose and Lipid Homeostasis Associated with Exogenous Glucose Infusion in Children

Background: Oral clonidine may influence plasma glucose and lipid homeostasis by modulating endocrinologic responses to surgical stress. The effect of oral clonidine premedication on plasma glucose and lipid homeostasis associated with exogenous glucose infusion were investigated in children undergoing minor surgery.

Methods: Otherwise healthy children (n, 120; aged 3-13 yr) were assigned randomly to six groups according to the glucose concentration of the intravenous solution (0%, 2%, or 5%, at a rate of 6 ml [center dot] kg sup -1 [center dot] h sup -1) and the preoperative medications (4 micro gram/kg clonidine or placebo given 100 min before anesthesia) they were to receive. The plasma concentrations of glucose, nonesterified fatty acid, ketone bodies, epinephrine, norepinephrine, and cortisol were determined.

Results: Infusion of 5% glucose caused hyperglycemia (mean glucose concentration > 200 mg/dl) in six children receiving placebo and two receiving clonidine. Although the mean plasma glucose concentration increased in three placebo groups, it was unchanged and the plasma concentrations of total ketone bodies and nonesterified fatty acid were increased in children receiving clonidine and glucose-free solution. The plasma epinephrine, norepinephrine, and cortisol levels in children receiving placebo increased in response to surgery. Clonidine attenuated the increase in catecholamines and cortisol.     

The beneficial effects of microflora, especially obligate anaerobes, and their products on the colonic environment in inflammatory bowel disease

Because intestinal microflora play a pivotal role in the development of inflammatory bowel disease (IBD), there is currently some interest in alternating the composition of the microflora toward a potentially more remedial community. This paper summarizes the clinical and experimental efficacy of the manipulation of microflora by the use of antibiotics, probiotics, and prebiotics in IBD. Germinated barley foodstuff (GBF) is a prebiotic whose unique characteristics make it highly suitable for applications in IBD. It also helps prolong remission in remissive ulcerative colitis (UC) patients and also attenuates clinical activity in non-remissive UC patients. GBF has shown to be converted into a preferential nutrient, butyrate, for colonocytes through the action of Eubacterium and Bifidobacterium, and this bacterial butyrate can provide anti-inflammatory effects. The probiotic approaches for IBD include VSL#3, Nissle1917, Clostridium butyricum, and Bifidobacterium-fermented milk. In this paper, we summarize the distinctive role of another probiotic, Eubacterium limosum (E. limosum), which is a commensal microorganism that is promoted by GBF administration. The metabolites of E. limosum included butyrate, which can accelerate intestinal epithelial growth and inhibit IL-6 production. This new probiotic approach may be useful as an adjunctive IBD treatment in the future. Although these strategies hold great promise and appear to be useful in some settings, more experimental and clinical studies are needed to firmly establish their relevance.     

Subdural hyperintense band on diffusion-weighted imaging of chronic subdural hematoma indicates bleeding from the outer membrane

The diffusion-weighted magnetic resonance (MR) imaging characteristics of chronic subdural hematoma and the correlation between hematoma liquidity and apparent diffusion coefficient (ADC) were investigated in 26 consecutive patients, 16 males and 10 females aged 42 to 92 years (mean +/- SD 73.3 +/- 13.1 years), with 31 chronic subdural hematomas. The chronic subdural hematomas were divided into homogeneous, separate, and trabecular types based on diffusion-weighted MR imaging findings. Almost all hematomas were low intensity on diffusion-weighted imaging, and the mean ADC value was 1.81 +/- 0.79 x 10(-3) mm2/sec. The high intensity areas in the subdural hematomas consisted of several types: high intensity line along the dura mater (subdural hyperintense band), high intensity along the intrahematoma septum, and laminar shape along the inner membrane. The subdural hyperintense bands accounted for almost all high intensity areas in the subdural hematomas. The mean ADC value of the high intensity areas was 0.76 +/- 0.24 x 10(-3) mm2/sec, close to that of the normal brain. The subdural hyperintense bands were considered to be intracellular and/or extracellular methemoglobin based on the T1- and T2-weighted imaging and intraoperative findings. The subdural hyperintense band is an important finding indicating relatively fresh bleeding from the outer membrane. Diffusion-weighted imaging shows liquid subdural hematoma as low intensity, and measurement of the ADC values can differentiate between liquid and solid components of the chronic subdural hematoma.     

Peribronchiolar metaplasia: a common histologic lesion in diffuse lung disease and a rare cause of interstitial lung disease: clinicopathologic features of 15 cases

Peribronchiolar metaplasia (PBM) is a histologic lesion consisting of peribronchiolar metaplasia (PBM) of bronchiolar-type epithelium. Although widely recognized, PBM has received little attention in the pathologic literature and is not known to have clinical significance. We identified 15 cases in which PBM was the only major histologic finding in surgical lung biopsies from patients with interstitial lung disease (PBM-ILD), and we reviewed the clinical, imaging, and pathologic findings. The mean age was 57 years (range, 44-74 years) with 13 females and 2 males. One patient had been a welder with fume and asbestos exposure; another had pigeon exposure. Smoking history was available for 13 patients: three current smokers, one cocaine user, two former smokers, and seven never smokers. Three patients had collagen vascular disease. One had elevated serum antinuclear antibody titers. Pulmonary function data were available for 10 patients: one obstructive, five restrictive, two mixed obstructive and restrictive, and two normal. Computerized tomography in 7 patients showed mosaic attenuation in 3 patients and air trapping in 1 patient; no bronchiectasis, septal lines, or honeycombing were seen in any cases. All 11 patients with available follow-up are alive; 4 of them have experienced symptomatic improvement (follow-up, 0.6-6.9 years; mean, 2.4 years). PBM was found focally in other interstitial lung diseases, which were assessed for this lesion: 59% of usual interstitial pneumonia (17 of 29), 50% of nonspecific interstitial pneumonia (10 of 20), desquamative interstitial pneumonia (3 of 6), hypersensitivity pneumonitis (9 of 18), and 11% of respiratory bronchiolitis (2 of 18). In summary, PBM is a common histologic finding in various interstitial lung disorders. It is rarely the sole major lung biopsy finding in patients presenting with interstitial lung disease (PBM-ILD). Patients are mostly older women, with mild symptoms and CT findings. Survival appears to be favorable.     

Multidimensional structure of anxiety-related behavior in early-weaned rats

Early environmental stimuli affect various aspects of physical and behavioral development. Weaning is one of the most important events in the early stage of life, and recently we have found that precocious weaning augments anxiety and aggressiveness in mice. Here, we report the presence of virtually identical phenomena in rats. To understand the multidimensional structure of anxiety-related behavior, the influence of early weaning upon behavior in adulthood was investigated using three behavioral tests: the elevated plus-maze test, the hole-board test and the open-field test. Two groups of rats were prepared. One was weaned from the dam at 16 days of age (early-weaned group) and the other at 30 days (normally weaned group) as a control. Both groups were subjected to the three tests at 8-10 weeks of age. The elevated plus-maze test revealed lower frequency of entry to and shorter duration of stay in the open arms in the early-weaned animals. In the hole-board test, the early-weaned rats showed lower frequency and shorter duration of head dipping into the holes. And in the open-field test, the early-weaned rats tended to stay at the central square for a shorter period and to defecate more frequently. The behavioral parameters of the three tests were combined and subjected to principal component analysis (PCA). The factorial scores for six extracted factors were compared between the early-weaned and normally weaned groups, and it was revealed that the early-weaned rats had a lower score in Factor 1 (non-anxious exploration) and Factor 5 (risk assessment behavior). Taken together, these results suggest that the time of weaning had a considerable impact on behavioral development, particularly with respect to anxiety-related behaviors.     

Anti-angiogenic therapy and chemotherapy affect 99mTc sestamibi and 99mTc-HL91 accumulation differently in tumour xenografts

BACKGROUND: Favourable effects of cytotoxic chemotherapy for tumours are characterized by the reduced accumulation of radiotracers such as 99mTc sestamibi (MIBI). Anti-angiogenic therapy is primarily cytostatic; consequently, its influence on tracer accumulation may differ from that of cytotoxic treatments. METHODS: Anti-angiogenic therapy employing 2-methoxyestradiol was administered in mice bearing subcutaneous xenografts of LS180 colon cancer cells. The effects of chemotherapy with 5-fluorouracil were examined as a cytotoxic counterpart. Treatments were conducted for 4 days from day 8. Distribution of 99mTc-MIBI and Tc-HL91, a hypoxic marker, was observed on days 8 and 12. Oxygen tension (PO2) in tumours was measured by a microelectrode. Cellular uptake of tracers was examined in vitro in normoxic and hypoxic conditions. RESULTS: 99mTc-MIBI accumulation decreased with increasing tumour weight when no treatment was conducted. Tumour growth was suppressed by anti-angiogenic therapy and chemotherapy. 99mTc-MIBI accumulation in tumours decreased after chemotherapy as compared to pre-therapeutic values, whereas accumulation of 99mTc-HL91 increased. In contrast, accumulation of tracers did not significantly change after anti-angiogenic therapy as compared to that observed pre-therapeutically. Tumour PO2 decreased with increasing tumour volume when no treatment was conducted. Chemotherapy reduced PO2 in tumours. PO2 in tumours treated with anti-angiogenic therapy was as high as that observed before treatment. 2-Methoxyestradiol or 5-fluorouracil did not significantly affect tracer accumulation in cells under both normoxic and hypoxic conditions in vitro. CONCLUSION: These findings indicate that scintigraphic assessment of therapeutic efficacy of anti-angiogenic therapy should be performed from a perspective distinct from that of cytotoxic treatment.     

Intratracheal application of recombinant surfactant protein-C surfactant to rabbits attenuates acute lung injury induced by intratracheal acidified infant formula

Our aim in the current study was to determine whether recombinant surfactant protein-C (rSP-C) surfactant improves acute lung injury (ALI) induced by intratracheal acidified milk products. Twenty-eight rabbits were randomly divided into four groups. ALI was induced with intratracheal acidified infant formula (0.8 mL/kg, pH 1.8) in 3 groups. The control group received intratracheal acidified saline. Therapy groups received 1 of 2 doses of intratracheal rSP-C surfactant (0.5 or 2 SP-C mg/kg) 30 min after the acidified infant formula. The lungs were ventilated with 100% oxygen for 4 h after induction of ALI. Acidified infant formula dramatically reduced oxygenation and lung compliance, and increased resistance. Both doses of rSP-C improved the variables [mean PaO(2) (mm Hg) and compliance (mL/cm H(2)O) at 4 h: 61 and 0.4 for infant formula, 162 and 1.0 for small-dose rSP-C, and 152 and 1.2 for large-dose rSP-C, respectively; P < 0.05]. Pulmonary leukosequestration and edema, and severe morphological changes were attenuated by rSP-C treatment (ALI score: 14, 7, 7 in infant formula, small-dose rSP-C, and large-dose rSP-C; P < 0.05). The efficacy was similar for the two doses of rSP-C. These findings suggest that intratracheal administration of rSP-C ameliorates ALI induced by aspiration of acidified milk products. IMPLICATIONS: Small or large doses of recombinant surfactant protein-C surfactant given 30 min after intratracheal acidified infant formula attenuated physiological, biochemical, and morphological lung damage.