Rat and hamster species differences in susceptibility to elastase-induced pulmonary emphysema relate to differences in elastase inhibitory capacity

Syrian Golden hamsters develop severe emphysema after a single intratracheal dose of elastase, whereas Sprague-Dawley rats exhibit mild emphysema with the same dose per kilogram body weight. We hypothesized that the development of severe emphysema is prevented in rats by the high serum level of alpha1-antitrypsin reported in rats, compared with hamsters, which provides for a high lung elastase inhibitory capacity (EIC). To explore this possibility, we challenged the antiprotease system of the rats by treating them with three similar weekly doses of elastase. Four months after treatment, we evaluated changes in histology, volume, and elastic properties of rat lungs and compared them with those of hamsters receiving a single dose of elastase. We also measured serum alpha1-antitrypsin levels and serum and lung EIC in control rats and hamsters. Results showed that, in association with 40% less serum and lung EIC compared with rats (P < 0.001), hamster lungs had upper-lobe bullae formation, severe microscopic emphysema, a fourfold increase in lung volume (P < 0.01) and a threefold increase in constant k, an index of compliance, of the lung deflation pressure-volume curve (P < 0.01). In contrast, rats developed mild emphysema, with only 50% increase in volume (P < 0.05) and 60% increase in constant k (P < 0.01). In conclusion, two species that differ in serum and lung EIC exhibit significant differences in emphysema development after elastase. Rats with high EIC, despite receiving three doses of elastase, showed significantly less derangement of morphological and physiological parameters than hamsters with low EIC receiving a single dose.     

Inhaled radon-induced genotoxicity in Wistar rat,Syrian hamster,and Chinese hamster deep-lung fibroblasts in vivo

This study was performed (1) to provide a comparison of the genotoxin effects of inhaled radon and radon progeny, referred to as radon in this paper, among three species of rodents: Wistar rats, Syrian hamsters, and Chinese hamsters; (2) to determine if initial chromosome damage was related to the risk of induction of lung cancer; and (3) to evaluate the tissue repair and long-term presence of cytogenetic damage in respiratory tract cells. These species were selected because Syrian hamsters are very resistant to radon induction of lung cancer and Wistar rats are sensitive; no literature is available on the in vivo effects of radon in the Chinese hamster. Exposure-response relationships were established for the rats and Syrian hamsters while the Chinese hamsters received a single exposure of radon. At 4 h (0.2 days), 15 days, and 30 days after the highest WLM exposure to radon, Wistar rats, Chinese hamsters, and Syrian hamsters were killed, and lung fibroblasts were isolated and grown in culture to determine the frequency of induced micronuclei. Animals at each level of exposure showed an increase in the frequency of micronuclei relative to that in controls (P < 0.05). The exposure-response relationship data for rats and Syrian hamsters killed 0.2 days after the end of exposure were fit to linear equations (micronuclei/1000 binucleated cells = 15.5±14.4+0.53±0.06 WLM and 38.3±15.1+0.80±0.08 WLM, respectively). For the single exposure level used (496 WLM) in Chinese hamsters killed at 0.2 days after exposure, the frequency of micronuclei/1000 binucleated cells/WLM was 1.83±0.02. A comparison of the sensitivity for induction of micronuclei/WLM illustrated that Chinese hamsters were three times more sensitive than rats. The Syrian hamsters also showed a significantly elevated response (P < 0.05) relative to rats. These data suggest that initial chromosome damage is not the major factor responsible for the high rate of radon-induced cancer in rats relative to Syrian hamsters. The frequency of micronuclei in radon-exposed rats, Syrian hamsters, and Chinese hamsters significantly decreased (P < 0.05) as a function of time after the exposure. The rate of loss of damaged cells from the lung was greatest in the Chinese hamsters, followed by Wistar rats and Syrian hamsters, respectively. Our experiments demonstrated that the mammalian lung fibroblast/micronucleus method has the potential to (1) detect species differences in the induction of in vivo genotoxic damage in the lungs by inhaled environmentalal agents; (2) evaluate exposure-response relationships for in vivo induction of genetic damage; and (3) determine the persistence in vivo of preclastogenic and premutagenic lesions in cell populations.     

Lung tumor induction in Syrian hamsters with internally deposited particulate Pu: A synthesis based on microscopic dose distribution

Syrian hamsters inhaled a monodisperse aerosol of 238PuO2 and were serially sacrificed to study the microscopic distribution of particles, tissue at risk and dose as a function of time after exposure. The distribution of dose and tissue at risk around single particles in lung and the changes in distribution of particles with time have been reported previously. In the present paper, these measurements are applied to the computation of tissue-at-risk and radiation-dose-rate distributions within the lungs of Syrian hamsters. Based on these results, airway epithelium is irradiated at the same levels as other lung tissue and does not require separate consideration on the basis of dose to tissue. Incorporation of the measured microscopic radiation dose distribution into existing dose-effect models allowed data on lung tumor induction in Syrian hamsters from several laboratories to be adequately described by a model fit to data from a single laboratory.     

Differences in acute lung response to elastase instillation in two rodent species may determine differences in severity of emphysema development

Elastase intratracheal instillation induces early emphysema in rodents. However, Syrian Golden hamsters develop more severe emphysema than Sprague-Dawley rats. We have reported species differences in oxidant/antioxidant balance modulating antiprotease function early after instillation. We now hypothesize that other components of the initial lung response to elastase might also be species-dependent. Sprague-Dawley rats and Syrian Golden hamsters received a single dose of pancreatic elastase (0.55 U/100 g body wt) to study acute lung injury biomarkers. Using serum, lung, and bronchoalveolar lavage fluid (BALF) samples, we evaluated changes in alveolar-capillary permeability, alpha 1-antitrypsin (α(1)-AT) concentration and activity, glutathione content, and proinflammatory cytokines. Rats showed a large increase in alveolar-capillary permeability and few hemorrhagic changes, whereas hamsters exhibited large hemorrhagic changes (P < 0.01) and mild transendothelial passage of proteins. Western blots showed a 30-fold increase in BALF α(1)-AT concentration in rats and only a 7-fold increase in hamsters (P < 0.001), with [α(1)-AT-elastase] complexes only in rats, suggesting differences in antiprotease function. This was confirmed by the α(1)-AT bioassay showing 20-fold increase in α(1)-AT activity in rats and only twofold increase in hamsters (P < 0.001). In rats, results were preceded by a 3-, 60-, and 20-fold increase in IL-6, IL-1β, and TNF-α respectively (P < 0.001). In hamsters, only IL-1β and TNF-α showed mild increases. All parameters studied were back to baseline by 4 days. In conclusion, several components of the initial lung response showed species differences. Cytokine release pattern and functional inhibition of α(1)-AT were the most significant components differing among species and could account for differences in susceptibility to elastase.     

Qualitative and quantitative differences in normal vaginal flora of conventionally reared mice, rats, hamsters, rabbits, and dogs

We examined quantitatively the vaginal flora of conventionally reared mice, rats, hamsters, rabbits and dogs, species that are widely used as laboratory animals. Vaginal specimens were examined according to the method of analyzing intestinal flora (Mitsuoka's procedure). The total number of bacteria (aerobes and anaerobes) and the prevalence of specific bacteria were determined. The total number of bacteria was highest during estrus and lowest during diestrus or anestrus in mice, rats, hamsters, and dogs. The most predominant bacteria during estrus were streptococci in mice; gram-negative rods (GNR), streptococci, and members of the family Bacteroidaceae in rats; GNR, Bacteroidaceae and gram-positive anaerobic cocci in hamsters, and Bacteroidaceae in dogs. The increase in the total number of bacteria during estrus was caused by an increase of predominant bacteria in the vagina. Aerobes were more predominant than anaerobes in mice, and number of aerobes was comparable to that of anaerobes in rats and dogs. On the other hand, in hamsters, anaerobes were more predominant than aerobes and the total number of bacteria was highest among the laboratory animals (mice, rats, hamsters, rabbits, and dogs). However, in rabbits, bacteria were not isolated from about 90% of the vaginal specimens. Rabbits do not have cyclic reproductive stages and are usually in precoital status in the laboratory. In precoital rabbits, vaginal epithelium manifests few signs of secretion. Therefore, we suspect that the vaginal environment in precoital rabbits is comparable to that during diestrus or anestrus in mice, rats, hamsters, and dogs. These results suggest that the vaginal flora of laboratory animals is influenced by the estrous cycle, and probably by mucous secretion. Our data imply that vaginal flora differ among laboratory animals species, and researchers need to take into consideration the estrous cycle of laboratory animals when studying their vaginal flora.     

Impact of lung density on isolated lung tumor dose in VMAT using inline MR-Linac

PurposeThis study investigated the impact of lung density on the isolated lung tumor dose for volumetric modulated arc therapy (VMAT) in an inline magnetic resonance linear accelerator (MR-Linac) using the Monte Carlo (MC) simulation.MethodsCT images of the thorax phantoms with lung tumors of 1, 2, and 3 cm diameters were converted into voxel-base phantoms with lung densities of 0.1, 0.2, and 0.3 g/cm³, respectively. The dose distributions were calculated for partial-arc VMAT. The dose distributions were compared using dose differences, dose volume histograms, and dose volume indices.ResultsIn all cases, the inline magnetic field significantly enhanced the lung tumor dose compared to that at 0 T. For the 1 cm lung tumor, the inline magnetic field of 1 T increased the minimum dose of 95% of the Planning target volume (PTV D₉₅) by 14.0% in 0.1 g/cm³ lung density as compared to that in 0.3 g/cm³ at 0 T. In contrast, at 0 and 0.5 T, the PTV D₉₅ in 0.3 g/cm³ lung density was larger than that in lung density of 0.1 g/cm³. For the 2 cm lung tumor, a similar tendency to 1 cm was observed, whereas the dose impact of lung density was smaller than that for 1 cm. For the 3 cm lung tumor, the lung tumor dose was independent of lung density at 0.5 T and 1.0 T.ConclusionThe inline MR-Linac with the magnetic field over 1 T can enhance the PTV D₉₅ for VMAT regardless of the lung density.     

PBPK models in risk assessment--A focus on chloroprene

Mathematical models are increasingly being used to simulate events in the exposure-response continuum, and to support quantitative predictions of risks to human health. Physiologically based pharmacokinetic (PBPK) models address that portion of the continuum from an external chemical exposure to an internal dose at a target site. Essential data needed to develop a PBPK model include values of key physiological parameters (e.g., tissue volumes, blood flow rates) and chemical specific parameters (rate of chemical absorption, distribution, metabolism, and elimination) for the species of interest. PBPK models are commonly used to: (1) predict concentrations of an internal dose over time at a target site following external exposure via different routes and/or durations; (2) predict human internal concentration at a target site based on animal data by accounting for toxicokinetic and physiological differences; and (3) estimate variability in the internal dose within a human population resulting from differences in individual pharmacokinetics. Himmelstein et al. [M.W. Himmelstein, S.C. Carpenter, P.M. Hinderliter, Kinetic modeling of beta-chloroprene metabolism. I. In vitro rates in liver and lung tissue fractions from mice, rats, hamsters, and humans, Toxicol. Sci. 79 (1) (2004) 18-27; M.W. Himmelstein, S.C. Carpenter, M.V. Evans, P.M. Hinderliter, E.M. Kenyon, Kinetic modeling of beta-chloroprene metabolism. II. The application of physiologically based modeling for cancer dose response analysis, Toxicol. Sci. 79 (1) (2004) 28-37] developed a PBPK model for chloroprene (2-chloro-1,3-butadiene; CD) that simulates chloroprene disposition in rats, mice, hamsters, or humans following an inhalation exposure. Values for the CD-PBPK model metabolic parameters were obtained from in vitro studies, and model simulations compared to data from in vivo gas uptake studies in rats, hamsters, and mice. The model estimate for total amount of metabolite in lung correlated better with rodent tumor incidence than did the external dose. Based on this PBPK model analytical approach, Himmelstein et al. [M.W. Himmelstein, S.C. Carpenter, M.V. Evans, P.M. Hinderliter, E.M. Kenyon, Kinetic modeling of beta-chloroprene metabolism. II. The application of physiologically based modeling for cancer dose response analysis, Toxicol. Sci. 79 (1) (2004) 28-37; M.W. Himmelstein, R. Leonard, R. Valentine, Kinetic modeling of beta-chloroprene metabolism: default and physiologically-based modeling approaches for cancer dose response, in: IISRP Symposium on Evaluation of Butadiene & Chloroprene Health Effects, September 21, 2005, TBD--reference in this proceedings issue of Chemical-Biological Interactions] propose that observed species differences in the lung tumor dose-response result from differences in CD metabolic rates. The CD-PBPK model has not yet been submitted to EPA for use in developing the IRIS assessment for chloroprene, but is sufficiently developed to be considered. The process that EPA uses to evaluate PBPK models is discussed, as well as potential applications for the CD-PBPK model in an IRIS assessment.     

Uptake and retention of3H-estradiol by gonadotrophs and lactotrophs in the pituitary glands of the guinea pig,hamster and gerbil

Summary Nuclear uptake and retention of³H-estradiol by luteinizing hormone (LH) and prolactin (PRL) cells was examined in three species of rodents (guinea pigs, hamsters and gerbils) using the combined techniques of immunocyto-chemistry and autoradiography. Castrated animals were injected with³H-estradiol and decapitated 1.5 h later. The pituitary glands were processed for thaw-mount autoradiography followed by conventional immunocytochemical staining for LH and PRL.³H-estradiol accumulated in more than 80% of the anterior pituitary cells in the gerbils, while only 33 and 22% of the cells accumulated³H-estradiol in the hamsters and guinea pigs, respectively. A varying percentage of immunoreactive LH and PRL cells in all three species were found also to contain binding sites for estradiol. Some LH and PRL cells in hamsters and guinea pigs and only some in PRL cells of gerbils were found to be devoid of grains. Quantitative analysis revealed that the number of grains per nucleus differed considerably from cell to cell. LH cells of guinea pigs accumulated much larger amounts of³H-estradiol than did the PRL cells, while the LH cells in the hamsters and gerbils accumulated only slightly more³H-estradiol than the PRL cells.These results confirm the previous observations in rats and baboons that demonstrated tremendous species differences in percentage of cells in the anterior pituitary gland that accumulated³H-estradiol. Also, these data suggest that there are functionally heterogeneous cell types among the LH and PRL cells in hamsters, guinea pigs and gerbils as has been previously demonstrated in rats and baboons.     

Cytoprotective and antisecretory properties of a non-diarrheogenic and non-uterotonic prostacyclin analog: U-68, 215

U-68,215 [15-Cyclohexyl-9-deoxo-13, 14-dihydro-2′, 9a-methano-4,5,6,16,17,18,19,20-octanor-3-oxa-3,7-(′1,′3-interphenylene)-PGE₁] is a stable prostacyclin analog. When given orally to rats, it is cytoprotective for the stomach (ED₅₀: 0.8 μg/kg) and the intestine (ED₅₀: 22 μg/kg), is gastric antisecretory (ED₅₀: 35 μg/kg) and antiulcer (aspirin) (ED_{50: 5 μg/kg}). The oral antisecretory ED₅₀ in dogs in 50 μg/kg. It has a long duration of gastric cytoprotection: 8–10 hours compared to 3 hours for 16, 16-dimethyl PGE₂ Unlike most prostaglandins of the E type, it is not diarrheogenic (not enteropooling), it does not induced cellular proliferation of the gastroeintestinal mucosa, when given twice a day for eight days, it is not uterotonic (in monkeys), and it does not prevent embryo implantation in hamsters. It ihibits platelet aggregation (ED₅₀: 300 μg/kg), but does not promote bleeding from cut vessels nor from gastric ulcers. U-68,215 lowers blood pressure at a n oral dose correponding to 1–5 time the antisecretory ED₅₀ in rats and dogs, and to 150 times the cytoprotective ED₅₀ in rats. It may be of therapeutic value in the treatment of conditions where inhibition of gastric acid secretion is desirable, e.g., gastric and duodenal ulcer, and in conditions responding to cytoprotection, e.g., stress ulcers, hemorrhagic gastritis and gastric erosions associated with nonsteroidal antiinflammatory drugs.     

RBEs of Thermal Neutron Capture Therapy and 10B(n,α)7 Li Reaction on Melanoma-Bearing Hamsters

Using Greene's melanoma transplanted into Syrian (golden) hamsters, we determined the relative biological effectiveness (RBE) of thermal neutron capture therapy (TNCT) using ¹⁰B-paraboronophenylalanine (¹⁰B-BPA) in comparison with a 9-MeV electron beam. We also obtained the RBE of the ¹⁰B(n,α)⁷Li reaction by calculation based on summed dose data from TNCT. Throughout this study, the Kyoto University Research Reactor was used as the source for thermal neutrons; the reactor was specially altered to attain a low contamination level both for gamma-rays and fast neutrons. ¹⁰B-BPA was administered 8 hours before thermal neutron irradiation to the hamsters with melanoma. The tumor was then irradiated at 5 MW for 90 minutes. The absorbed dose from this TNCT was calculated by the method of Fairchild and Goodman (Phys. Med. Biol. 1966; 2:15–30). The RBEs of the TNCT and the ¹⁰B(n,α)⁷Li reaction obtained by the tumor growth delay time (TGDT) method were 2.22 and 2.51, respectively, at 10.5 days of TGDT. These RBE values varied with TGDT and the absorbed dose. The RBE value of TNCT had a peak at 7.0 days of TGDT; that of the ¹⁰B(n,α)⁷Li reaction was higher at a low absorbed dose level and lower at a high absorbed dose level.     

Distribution of nickel,zinc, and copper in rat organs after oral administration of nickel(II) chloride

The distribution of Ni administered as NiCl₂ · 6H₂O in the drinking water (300 and 1200 ppm Ni for 90 d) was studied using male Wistar rats. Next, the effect of Ni on the concentration of zinc (Zn) and copper (Cu) in selected organs and serum was measured. The metals were analyzed in the liver, kidney, lung, spleen, brain, and serum by electrothermal (Ni) or flame (Zn, Cu) atomic absorption spectrophotometry. The results indicate that exposed rats drank less nickel solutions than the volume of water drunk by controls, but there was no mortality of animals. In comparison to control animals, a very high increase in Ni levels was found in the kidney and then lung and serum of all exposed rats. In the liver, spleen, and brain, the metal accumulation was lower. A directly proportional relation between the nickel intake and its deposition was observed in the collected organs and in the serum. The metal level did not change significantly in the course of exposure (the first analysis was after 30 d). The administration of 300 ppm Ni did not affect the zinc and copper concentration in studied organs, except the serum, where zinc content was significantly reduced. At a dose of 1200 ppm Ni, these metals were found to be depressed in the liver, kidney, serum (zinc), and copper in the kidney.     

Low-Dose Vascular Photodynamic Therapy Decreases Tumor Interstitial Fluid Pressure,which Promotes Liposomal Doxorubicin Distribution in a Murine Sarcoma Metastasis Model

INTRODUCTION: Solid tumors are known to have an abnormal vasculature that limits the distribution of chemotherapy. We have recently shown that tumor vessel modulation by low-dose photodynamic therapy (L-PDT) could improve the uptake of macromolecular chemotherapeutic agents such as liposomal doxorubicin (Liporubicin) administered subsequently. However, how this occurs is unknown. Convection, the main mechanism for drug transport between the intravascular and extravascular spaces, is mostly related to interstitial fluid pressure (IFP) and tumor blood flow (TBF). Here, we determined the changes of tumor and surrounding lung IFP and TBF before, during, and after vascular L-PDT. We also evaluated the effect of these changes on the distribution of Liporubicin administered intravenously (IV) in a lung sarcoma metastasis model. MATERIALS AND METHODS: A syngeneic methylcholanthrene-induced sarcoma cell line was implanted subpleurally in the lung of Fischer rats. Tumor/surrounding lung IFP and TBF changes induced by L-PDT were determined using the wick-in-needle technique and laser Doppler flowmetry, respectively. The spatial distribution of Liporubicin in tumor and lung tissues following IV drug administration was then assessed in L-PDT–pretreated animals and controls (no L-PDT) by epifluorescence microscopy. RESULTS: L-PDT significantly decreased tumor but not lung IFP compared to controls (no L-PDT) without affecting TBF. These conditions were associated with a significant improvement in Liporubicin distribution in tumor tissues compared to controls (P < .05). DISCUSSION: L-PDT specifically enhanced convection in blood vessels of tumor but not of normal lung tissue, which was associated with a significant improvement of Liporubicin distribution in tumors compared to controls.     

孔腔镜肺叶切除及淋巴结清扫术围手术期应用不同剂量氨溴索对肺癌患者的作用研究

摘要 目的：探讨围手术期应用不同剂量氨溴索对行单孔腔镜肺叶切除及淋巴结清扫术的肺癌患者的作用。方法：选取本院2017年1月至2018年12月期间收治的124例肺癌患者作为受试者,结合患者意愿按随机数字表法将受试者分为小剂量组（n=41）、中剂量组（n=41）和大剂量组（n=42）,术前1d开始给予氨溴索静脉滴注,术后持续7d,比较各组患者临床症状、治疗前后的肺功能、炎症因子、T细胞亚群水平变化及不良反应发生率。结果：大剂量组咳痰容易人数所占比例高于小剂量组,痰液稀薄人数所占比例高于中剂量组及小剂量组（P<0.05）。治疗后大剂量组第一秒用力呼吸容积（FEV¹）、FEV¹/用力肺活量（FVC）高于中剂量组、小剂量组（P<0.05）。治疗后各组炎症因子水平均高于治疗前,且随着剂量的升高,C反应蛋白（CRP）、白介素-6（IL-6）、白介素-8（IL-8）水平呈降低的趋势（P<0.05）。随着剂量的升高,治疗后的 CD3⁺、CD4⁺、CD4⁺/CD8⁺均呈升高趋势,CD8⁺呈降低趋势（P<0.05）。各组不良反应发生率比较无统计学差异（P>0.05）。结论：肺癌患者行单孔腔镜肺叶切除及淋巴结清扫术围手术期应用120mg氨溴索,可加快患者术后恢复,保护患者肺功能,抑制炎症反应,改善患者的免疫功能和临床症状。     

Promotion of pulmonary carcinogenesis by plutonium particle aggregation following inhalation of 239PuO2

Promotion of lung tumor formation from inhaled 239PuO2 in rats may be associated with aggregation of plutonium particles near bronchioles. The relationship of plutonium particle aggregation in the lung and the development of lung tumors after inhalation of 239PuO2 was studied in 664 life span rats with mean lung doses ranging from 0.35 to 20 Gy. Plutonium particle concentration and aggregation were determined from autoradiographic sections of the left lung lobe. The increase in particles/cm2 and mean number of particles per aggregate up to 20 Gy were directly proportional to lung dose. Aggregates with greater than 25 particles increased linearly with dose from 0.2% at 1.4 Gy to 8.2% at 20 Gy, in a pattern similar to increasing severity of pulmonary fibrosis and incidence of lung tumors. Lung tumor incidence increased from about 6% at 1.4 Gy to 83% at 8 Gy; no further increase in lung tumors was seen at doses greater than 8 Gy. Maximum lung tumor incidence at 8 Gy corresponded to a particle concentration of 130/cm2 and four particles/aggregate with 4% of aggregates having greater than 25 particles. Aggregation of inhaled plutonium particles in clusters of greater than 25 particles resulted in daily doses of only a few centigray to focal tissue regions containing clustered particles, yet these doses appeared sufficient to cause pulmonary fibrosis and promotion of pulmonary carcinogenesis.     

Antithrombotic effects of LB30870, a potent,orally active,selective and direct thrombin inhibitor,and pharmacokinetics of its prodrug

Antithrombotic activity and bleeding complication of a new potent, selective, and direct thrombin inhibitor, LB30870, were evaluated in comparison with other anticoagulants. In order to improve oral absorption of LB30870, pharmacokinetics of LB30889, which is a double prodrug with blocking groups in both amidine and carboxyl groups, was studied in rats and dogs. LB30870 was more potent than melagatran or argatroban with thrombin inhibition constants of 0.02, 1.3 and 4.5 nM, respectively. All three direct thrombin inhibitors were selective towards other serine proteases with selectivity ratio greater than 1000, except for trypsin. Thrombin binding kinetics of LB30870 showed rapid association and slow dissociation rate constants, demonstrating its potential as anticoagulant. LB30870 was more effective than melagatran or argatroban in plasma clot-bound thrombin inhibition. In the rat venous stasis model of the caval vein, LB30870 reduced wet clot weights in a dose dependent manner after the intravenous bolus with infusion administration. The ED₅₀ of LB30870, melagatran and enoxaparin were 50 μg/kg + 2 μg/kg/min, 35 μg/kg + 1.4 μg/kg/min and 200 μg/kg + 8.3 μg/kg/min, respectively. No significant bleeding problem was observed with LB30870 at the dose up to two times ED₈₀ in rats. LB30889, a double prodrug of LB30870, showed species difference in pharmacokinetics. Its oral bioavailability in rats or dogs was not better than that of LB30870. In conclusion, LB30870 has the potential to be useful as an effective oral anticoagulant for the prevention and treatment of thromboembolic diseases.     

Effects of selenium on chemical carcinogenesis

Chemical carcinogenesis can be characterized by a sequence of events leading to the development of tumors. Selenium (Se) inhibition of colon, liver, and lung carcinogens is demonstrated. Using the male Sprague Dawley rat model Se inhibited the colon tumor incidence in 1,2-dimethylhydrazine (DMH) treated rats and reduced the total number of colon tumors in methylazoxymethanol (MAM) treated rats. Selenium inhibited 2-acetylaminofluorene (AAF) and 3′-methyl-4-dimethylaminoazobenzene (3′-MeDAB) hepatocarcinogenesis. The hepatic tumor incidence induced by 3′-MeDAB was reduced by both inorganic Se (Na₂SeO₃) and by organic Se (Se-yeast) supplements. In vitro systems have been studied in an effort to decipher the inhibitory properties of Se on the multistage origin of tumors induced by chemical carcinogens. Current studies suggest that the protective effect of Se against AAF hepatocarcinogenesis may be correlated with a change in AAF metabolism. The mutagenicity of AAF and AAF metabolites inSalmonella typhimurium TA1538 is decreased by Se. Additionally, Se reduced N-t-OH−AAF induction of sister chromatid exchange (SCE) frequencies in whole blood cultures, and also reduced aryl hydrocarbon hydroxylase activity using benzo(a) pyrene as substrate. The comparative effects of antioxidants on DMH induction of colon tumors are presented in detail. Supplements of 4 ppm Se to the drinking water, 1.2% ascorbic acid (V _c ) to the diet or 0.5% butylated hydroxytoluene (BHT) to the diet of DMH-treated rats reduced the colon tumor incidence of DMH controls from 64 to 31% (Se), 38% (V _c ), and 43% (BHT). The colon tumor incidence in DMH-treated rats receiving a combination of Se+V _c increased to 83%, while the combination of Se+BHT decreased the colon tumor incidence to 55%. The growth and survival of rats provided long-term supplements of 4 ppm Se in the drinking water are compared with untreated controls.     

The distribution of 14C-imipramine in mice bearing Lewis lung carcinoma

The distribution of ¹⁴C-imipramine (10 mg/kg ip) and several of its metabolites in tumor, lung, liver, and kidney was investigated in male BDF₁ mice bearing Lewis lung carcinoma. In contrast to other tissues, the tumor exhibited a pronounced absorption phase of ¹⁴C-imipramine; peak concentrations were reached approximately 2 hours after administration. The lung accumulated more imipramine than other tissues at early time points; however, by 12 hours the lung had the lowest tissue/plasma ratio of ¹⁴C-imipramine-derived radioactivity of the tissues studied. In both lung and tumor, the metabolic profile of imipramine was similar, with unchanged imipramine predominating; 2-hydroxyimipramine was the principle metabolite in liver. The presence of Lewis lung tumor had minimal effects on the distribution and metabolism of imipramine.     

L-tryptophan binding to hepatic nuclei: Age and species differences

Summary The present experiments report differences in in vitro nuclear binding affinity for L-tryptophan 1) between livers of young (6 1/2 weeks old) and older (30 weeks old) NZBWF₁ mice, but not so in similar aged Swiss mice, and also, 2) in livers of hamsters compared to livers of guinea pigs. In vitro hepatic nuclear specific binding affinity after tube-feeding L-tryptophan (520mg/100g body weight) to mice 1 h before killing revealed less in young than in older NZWBF₁ mice, comparable to the above in vitro assay studies. In vitro nuclear binding affinity for L-tryptophan of livers of hamsters was significantly less than that of livers of guinea pigs or Swiss mice. In general, the degree of stimulatory effect on hepatic protein synthesis, as measured by in vitro [¹⁴C]leucine incorporation into protein using microsomes of animals tube-fed L-tryptophan 1 h before killing compared to that of animals tubefed water, correlated with the basal nuclear specific binding affinity to L-tryptophan of the animals (ages and species) used.This study was supported by U.S. Public Health Service Research Grant DK-45353 from the National Institute of Diabetes and Digestive and Kidney Diseases.     

Voxel-by-voxel correlation between radiologically radiation induced lung injury and dose after image-guided,intensity modulated radiotherapy for lung tumors

PurposeTo correlate radiation dose to the risk of severe radiologically-evident radiation-induced lung injury (RRLI) using voxel-by-voxel analysis of the follow-up computed tomography (CT) of patients treated for lung cancer with hypofractionated helical Tomotherapy.Methods and materialsThe follow-up CT scans from 32 lung cancer patients treated with various regimens (5, 8, and 25 fractions) were registered to pre-treatment CT using deformable image registration (DIR). The change in density was calculated for each voxel within the combined lungs minus the planning target volume (PTV). Parameters of a Probit formula were derived by fitting the occurrences of changes of density in voxels greater than 0.361 g cm⁻³ to the radiation dose. The model’s predictive capability was assessed using the area under receiver operating characteristic curve (AUC), the Kolmogorov-Smirnov test for goodness-of-fit, and the permutation test (P_test).ResultsThe best-fit parameters for prediction of RRLI 6 months post RT were D₅₀ of 73.0 (95% CI 59.2.4–85.3.7) Gy, and m of 0.41 (0.39–0.46) for hypofractionated (5 and 8 fractions) and D₅₀ of 96.8 (76.9–123.9) Gy, and m of 0.36 (0.34–0.39) for 25 fractions RT. According to the goodness-of-fit test the null hypothesis of modeled and observed occurrence of RRLI coming from the same distribution could not be rejected. The AUC was 0.581 (0.575–0.583) for fractionated and 0.579 (0.577–0.581) for hypofractionated patients. The predictive models had AUC>upper 95% band of the P_test.ConclusionsThe correlation of voxel-by-voxel density increase with dose can be used as a support tool for differential diagnosis of tumor from benign changes in the follow-up of lung IMRT patients.     

The orally active thia-imino-prostacyclin Hoe 892: Antiaggregatory and cardiovascular activities

The short chemical half-life limits the potential therapeutic value of Prostacyclin (PGI₂). Replacement of the acid-labile enolether structure of PGI₂ by a β-thia-imino group resulted in the orally active and chemically stable analogue Hoe 892. Incubation of rabbit platelet rich plasma with PGI₂ and Hoe 892 caused a dose dependent inhibition of collagen and arachidonic acid (AA) induced platelet aggregation with ID₅₀ of 4.2 and 20.1 ng/ml for PGI₂ respectively 43.3 and 170.2 ng/ml for Hoe 892. These effects could be potentiated by the phosphodiesterase inhibitor theophylline. Single oral administration of Hoe 892 in conscious rabbits inhibited platelet aggregation for more than 3 hrs with an ID₅₀ of 0.2 mg/kg using collagen and 1.5 mg/kg using AA. These doses were without influence on systemic blood pressure (BP) in conscious rabbits. One month oral treatment with a daily dose of 0.3 mg/kg resulted in marked antiaggregatory effects in conscious rabbits. Intravenous injection of Hoe 892 induced a dose dependent decrease of systemic BP in anesthetized rats (ED₂₅ of 2.2 μg/kg) and in the rats with acute renal hypertension. Hoe 892 stimulated renin release in anesthetized rats. The hemodynamic profile in anesthetized dogs (0.5 μg/kg/min i.v.) was characterized by a decrease of systemic BP, left ventricular pressure, pulmonary artery pressure, total peripheral resistance and in increase in heart rate, cardiac output and dp/dt max, thus demonstrating arteriolar vasodilation. In conscious dogs with two kidney, two wrapped hypertension oral treatment for 1 or 5 days resulted in a marked reduction of BP.