Clinical study on SM-4300 in the field of internal medicine

A new human gamma-globulin for intravenous use, SM-4300, was administered to 13 patients with infectious diseases. Five grams of SM-4300 was drip infused to each patient whose infection was not controlled by previous administered antibiotics. All of 13 patients had primary diseases besides infections. Thirteen patients were composed of 4 with pyelonephritis, 2 with pneumonia, 1 with bronchopneumonia, 1 with bronchitis, 1 with pyothorax, 2 with sepsis and 2 with cholecystitis. The results obtained were good in 3 cases, fair in 2 cases and poor in 7 cases. The results of a patient was not determined. No side effect was found including in laboratory findings.     

Gene expression analysis on the dicyclanil-induced hepatocellular tumors in mice

Our previous studies showed the possibility that oxidative stress, including oxidative DNA damage, is involved in the mechanism of dicyclanil (DC)-induced hepatocarcinogenesis at the preneoplastic stage in mice. In this study, the expression analyses of genes, including oxidative stress-related genes, were performed on the tissues of hepatocellular tumors in a two-stage liver carcinogenesis model in mice. After partial hepatectomy, male ICR mice were injected with N-diethylnitrosamine (DEN) and given a diet containing 0 or 1500 ppm of DC for 20 weeks. Histopathological examinations revealed that the incidence of hepatocellular tumors (adenomas and carcinomas) significantly increased in the DEN + DC group. Gene expression analysis on the microdissected liver tissues of the mice in the DEN + DC group showed the highest expression levels of oxidative stress-related genes, such as Cyp1a1 and Txnrd1, in the tumor areas. However, no remarkable up-regulation of Ogg1-an oxidative DNA damage repair gene-was observed in the tumor areas, but the expression of Trail-an apoptosis-signaling ligand gene-was significantly down-regulated in the tumor tissues. These results suggest the possibility that the inhibition of apoptosis and a failure in the ability to repair oxidative DNA damage occur in the hepatocellular DC-induced tumors in mice.     

Enhancing effects of carbon tetrachloride on in vivo mutagenicity in the liver of mice fed 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)

Chronic stimulus subsequent to cell injury plays an important role in cancer development, but the precise mechanisms remain unknown partly because appropriate animal models are lacking. In the present study, the effects of hepatotoxicant carbon tetrachloride (CCl(4)) on in vivo mutagenicity were investigated using gpt delta mice with or without p53. Female B6C3F(1) p53-proficient or -deficient gpt delta mice were given a diet containing 300 ppm of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) for 13 weeks, concurrently with intraperitoneal injection of 1 ml/kg CCl(4) solution once a week. Mutant frequencies of gpt and red/gam in p53-proficient mice fed MeIQx were both significantly elevated by CCl(4)co-treatment. Enhancing effects of CCl(4) treatment were also noted in p53-deficient mice. In the mutation spectra analysis of gpt mutant colonies, G:C to T:A transversions were predominantly observed regardless of CCl(4) injection, and clonal expansion of gpt colonies were increased in the co-treated group as compared with MeIQx alone group. The present data showing no significant changes in mRNA expression levels of CYP1A2 and GSTa4 between MeIQx-treated groups with and without CCl(4). In the Western blotting analysis, CYP1A2 protein levels were significantly decreased in the co-treated group as compared to MeIQx alone group, and GSTα protein levels were not changed among any groups. It is suggested that the mutant frequency by co-treatment with CCl(4) might result from some factors other than p53 or MeIQx metabolism/excretion. Thus, our data clearly demonstrate that this model could be a powerful tool for identifying the mechanisms underlying combinatorial effects on carcinogenesis.     

Effects of co-treatment of dextran sulfate sodium and MeIQx on genotoxicity and possible carcinogenicity in the colon of p53-deficient mice

To investigate the effects of dextran sulfate sodium (DSS) and/or 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) on in vivo genotoxicity in the colon, male C57BL/6 p53 (+/+), p53 (+/-) or p53 (-/-) gpt delta mice were twice given 1-week treatment with DSS, 2 weeks apart, and then sacrificed after 2 and 14 weeks. Although colon length was significantly shortened after DSS treatment in all genotypes at each time point, no significant difference in gpt mutant frequency (MF) and tumorigenicity was found between DSS and control groups regardless of genotype. Then, male B6C3F(1) p53 (+/+) or p53 (+/-) gpt delta mice were given DSS as described above and/or fed 300 ppm MeIQx for 7 weeks. Colon length was significantly shortened with DSS in either genotype at weeks 7 and 26, but no effects of co-treatment with MeIQx or p53 deficiency were evident. MeIQx showed a tendency to increase gpt MF in the colon of mice with either genotype, but co-treatment with DSS did not affect these increments. Appreciable incidences of colonic aberrant crypt foci (ACFs) were reported in DSS as well as co-treatment groups of each genotype. Colonic adenomas were observed in co-treatment groups of both genotypes as well as the DSS-only group of p53 (+/+). No effects of the combination of DSS and MeIQx on colon pre- and neoplastic lesions were reported. Our results indicate that MeIQx may take more than 7 weeks to induce genotoxicity in the colon and that the co-treatment of mice did not enhance colon tumorigenicity even in p53-deficient mice.     

Direct progression of capsular invasive carcinomas from subcapsular focal hyperplasias induced by hypothyroidism-mediated tumor promotion in a rat two-stage thyroid carcinogenesis model

Purpose

Some goitrogens promote thyroid carcinogenesis in rats in an initiation-promotion model; this model frequently produces carcinomas that invade fibrously thickened capsules, termed capsular invasive carcinomas (CICs). The present study tested a hypothesis that CICs originate from parenchymal proliferative lesions located beneath the capsule.

Methods

Cell proliferation activity, cell-cycle kinetics and cellular invasion were immunohistochemically examined in subcapsular proliferative lesions in male F344 rats treated with an anti-thyroid agent, propylthiouracil or sulfadimethoxine, during the tumor-promotion phase after initiation with N-bis(2-hydroxypropyl)nitrosamine.

Results

Focal follicular cell hyperplasias (FFCHs) were the most commonly observed parenchymal proliferative lesions. Subcapsular FFCHs located near CICs showed more Ki-67⁺ cells in the capsular side than the contrary parenchymal center side. Most of these FFCHs located near CICs showed accumulated immunoreactivity for cyclin A, cyclin D, cyclin E and cyclin-dependent kinase-2, whereas most subcapsular FFCHs located elsewhere did not show such accumulated expression of cell-cycle molecules. Subcapsular FFCHs immunoreactive at the capsular front for tenascin-C, a tumor invasion marker of extracellular matrix protein, showed high proliferation activity.

Conclusions

Subcapsular FFCH-forming cells can potentially spread directly into the fibrously thickened capsule to form CICs by accelerating cell-cycle activity.     

Differential activation of the μ-opioid receptor by oxycodone and morphine in pain-related brain regions in a bone cancer pain model

Background and Purpose

Bone cancer pain is chronic and often difficult to control with opioids. However, recent studies have shown that several opioids have distinct analgesic profiles in chronic pain.

Experimental Approach

To clarify the mechanisms underlying these distinct analgesic profiles, functional changes in the μ-opioid receptor were examined using a mouse femur bone cancer (FBC) model.

Key Results

In the FBC model, the B_max of [³H]-DAMGO binding was reduced by 15–45% in the periaqueductal grey matter (PAG), region ventral to the PAG (vPAG), mediodorsal thalamus (mTH), ventral thalamus and spinal cord. Oxycodone (10⁻⁸–10⁻⁵ M) and morphine (10⁻⁸–10⁻⁵ M) activated [³⁵S]-GTPγS binding, but the activation was significantly attenuated in the PAG, vPAG, mTH and spinal cord in the FBC model. Interestingly, the attenuation of oxycodone-induced [³⁵S]-GTPγS binding was quite limited (9–26%) in comparison with that of morphine (46–65%) in the PAG, vPAG and mTH, but not in the spinal cord. Furthermore, i.c.v. oxycodone at doses of 0.02–1.0 μg per mouse clearly inhibited pain-related behaviours, such as guarding, limb-use abnormalities and allodynia-like behaviour in the FBC model mice, while i.c.v. morphine (0.05–2.0 μg per mouse) had only partial or little analgesic effect on limb-use abnormalities and allodynia-like behaviour.

Conclusion and Implications

These results show that μ-opioid receptor functions are attenuated in several pain-related regions in bone cancer in an agonist-dependent manner, and suggest that modification of the μ-opioid receptor is responsible for the distinct analgesic effect of oxycodone and morphine.     

Fluorine Scanning by Nonselective Fluorination: Enhancing Raf/MEK Inhibition while Keeping Physicochemical Properties

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