Effects of epinastine on the antitussive and rewarding effects of dihydrocodeine in mice

The effects of chlorpheniramine and epinastine on dihydrocodeine were examined in mice. Orally administered dihydrocodeine (3-30 mg/kg) dose-dependently inhibited the number of capsaicin-induced coughs. The dose-dependent antitussive effects of dihydrocodeine were enhanced by each corresponding dose of chlorpheniramine or epinastine delivered at a ratio generally similar to that found in over-the-counter antitussive preparations (dihydrocodeine:histamine H1 antagonist = 3:1). The ED50 value of dihydrocodeine in combination with chlorpheniramine was nearly the same as that for dihydrocodeine in combination with epinastine. On the other hand, while combination treatment with dihydrocodeine (3 mg/kg i.p.) and chlorpheniramine (1 mg/kg s.c.) significantly potentiated place preference, no potentiation was observed with the combination of dihydrocodeine (3 mg/kg i.p.) and epinastine (1 mg/kg s.c.). These results suggest that epinastine may be a useful constituent opioid-containing antitussive preparation that would not enhance the potential for psychological dependence.     

Dietary therapy in two patients with vitamin B12-unresponsive methylmalonic acidemia

The biochemical and therapeutic responses to dietary therapy were studied in a 25-month-old girl and a 1-month-old girl with methylmalonic acidemia (MMA-emia), which was unresponsive to vitamin B₁₂.The minimum daily intake of protein which patients could tolerate and display a good development was between 1.0 and 1.2 g per kg body weight. Supplementation with amino acid mixture devoid of toxic amino acids was required to prevent protein malnutrition when daily protein intake was restricted to 0.6 g per kg body weight. Caloric intake should be sufficient, not only to promote growth but also to prevent a rise in MMA level, especially when a patient has ketoacidosis.It was found that MMA excretion per mg creatinine in random urine specimens correlated significantly with serum MMA and twenty four-hour output of MMA per kg body weight. Therefore measurement of MMA in a single urine specimen is useful for evaluating the in vivo accumulation of MMA.     

The 1999 domestic state of development of anti-asthma

According to the "Guideline for Diagnosis and Treatment of Asthma" established by the Japanese Society of Allergy in 1998, inhaled adrenergic beta 2 agonists and inhaled corticosteroids are recommended for treatment of asthma. Thereafter, the development of new drugs for the treatment of asthma has begun changing. The concepts upon which the development of investigational drugs for asthma are based include improvements of drug delivery systems (ease of use, long-acting preparations, fewer side-effects), device design and appropriate auxiliary instrumentation. Moreover, chronic asthma has come to be recognized as an inflammatory disease of airway mucosa. At present, various antiallergic compounds such as tachykinin, leucotrien, PAF antagonists and others are under investigation thanks to the identification of new chemical mediators of airway inflammation and studies have progressed to the synthesis and manufacturing of new pharmaceuticals with antagonistic action. Thus, this review classified and introduced various new investigational anti-asthma and further describes the structure-activity relationships of beta 2 agonists and inhaled corticosteroids.     

Differential involvement of opioid receptors in stress-induced antinociception caused by repeated exposure to forced walking stress in mice

We examined the effects of repeated exposure to forced walking stress for 6 h once a day for 0, 6 and 9 consecutive days on formalin-induced paw licking in mice. In each observation period, stress-induced antinociception (SIA) was observed only in the late phase (from 10 to 30 min), but not in the early phase (from 0 to 10 min) of formalin-induced paw licking in mice. Moreover, it was hard to develop tolerance even by daily exposure to stress for 6 days, although SIA for 9 days decreased compared with those for 0 and 6 days. Naloxone (10 mg/kg), an opioid-receptor antagonist, was effective in reducing the SIA induced by forced walking stress for 6 days and/or 9 days, but not for 0 days. Furthermore, the experiments with selective opioid-receptor antagonists, beta-funaltrexamine (mu) naltrindol (delta), or nor-binaltorphimine (kappa) demonstrated that SIA induced by forced walking stress for 9 successive days may be mediated through opioid delta- and kappa-receptors. Finally, although SIA seemed to be a unitary phenomenon, the present results strengthened the idea that SIA is induced by exposure to forced walking stress with characteristics dependent on the duration of exposure.     

Lysyl oxidase secreted by tumour endothelial cells promotes angiogenesis and metastasis

Background:

Molecules that are highly expressed in tumour endothelial cells (TECs) may be candidates for specifically targeting TECs. Using DNA microarray analysis, we found that the lysyl oxidase (LOX) gene was upregulated in TECs compared with its expression in normal endothelial cells (NECs). LOX is an enzyme that enhances invasion and metastasis of tumour cells. However, there are no reports on the function of LOX in isolated TECs.

Methods:

TECs and NECs were isolated to investigate LOX function in TECs. LOX inhibition of in vivo tumour growth was also assessed using β-aminopropionitrile (BAPN).

Results:

LOX expression was higher in TECs than in NECs. LOX knockdown inhibited cell migration and tube formation by TECs, which was associated with decreased phosphorylation of focal adhesion kinase (Tyr 397). Immunostaining showed high LOX expression in human tumour vessels in vivo. Tumour angiogenesis and micrometastasis were inhibited by BAPN in an in vivo tumour model.

Conclusion:

LOX may be a TEC marker and a possible therapeutic target for novel antiangiogenic therapy.     

Relationship Between Diffusion-Weighted Magnetic Resonance Imaging and Histological Tumor Grading of Hepatocellular Carcinoma

Background

Intrahepatic and extrahepatic recurrence remains a significant problem for hepatocellular carcinoma (HCC). The aim of this study was to determine the usefulness of diffusion-weighted magnetic resonance imaging (DWI) for histological tumor grading and preoperative prediction of early HCC recurrence within 6 months of operation.

Methods

A total of 44 patients who had undergone hepatic resection for HCC (50 nodules) were reviewed retrospectively. DWI was performed within 30 days before hepatectomy, and apparent diffusion coefficients (ADCs) were measured using 2 methods: mean ADC and minimum-spot ADC. Relationships between ADCs and histological differentiation and between ADCs and early recurrence of HCC were analyzed.

Results

Mean ADC was significantly lower in poorly differentiated HCC (n = 18, 1.07 ± 0.15 × 10^?3 mm²/s) than in moderately differentiated HCC (n = 29, 1.29 ± 0.21 × 10^?3 mm²/s; P < .05). Minimum-spot ADC was significantly lower in poorly differentiated HCC (n = 18, 0.69 ± 0.19 × 10^?3 mm²/s) than in well-differentiated HCC (n = 3, 1.15 ± 0.10 × 10^?3 mm²; P < .01) or in moderately differentiated HCC (n = 29, 0.98 ± 0.18 × 10^?3 mm²/s; P < .0001). Of 34 patients who were able to be observed for >6 months after resection, 9 showed early recurrence. Minimum-spot ADC was significantly lower in patients with early recurrence (n = 9, 0.64 ± 0.24 × 10^?3 mm²/s) than in patients without early recurrence (n = 25, 0.88 ± 0.19 × 10^?3 mm²/s; P < .05). On multivariate analysis, minimum-spot ADC was a significant risk factor for early recurrence (P < .05).

Conclusion

Quantitative measurement of ADC of HCC with magnetic resonance diffusion weighted imaging is a promising functional imaging tool in the prediction of histological grade and early recurrence before treatment.     

Silibinin activated p53 and induced autophagic death in human fibrosarcoma HT1080 cells via reactive oxygen species-p38 and c-Jun N-terminal kinase pathways

Our previous research demonstrated that hepatic-protectant silibinin induced autophagy in human fibro-sarcoma HT1080 cells through reactive oxygen species (ROS) pathway. Pifithrin-α (PFT-α), a specific inhibitor of p53, reduced autophagy and reversed silibinin's growth-inhibitory effect; besides, PFT-α decreased the activation of caspase-3, a crucial executor of apoptosis. Silibinin upregulated expression of p53/phosphorylated-p53 (p-p53) in a time-dependent manner. Catalase (scavenger of H(2)O(2)), superoxide dismutase (SOD) (scavenger of O(2)(?-)), and SB203580 (inhibitor of p38) attenuated upregulation of p53 expression, suggesting that p53 might be partially regulated by ROS-p38 pathway. On the other hand, c-Jun N-terminal kinase (JNK) increased autophagic death in silibinin-treated cells, and JNK/p-JNK expression was upregulated by silibinin time-dependently. Inhibition of JNK by SP600125 did not influence generation of ROS. Scavengers of H(2)O(2) or O(2)(?-) showed no effect on expression of JNK/p-JNK, indicating that JNK might not correlate with ROS in this process. However, activation of p53 was suppressed by SP600125; therefore the function of p53 was possibly controlled by JNK as well. Western blotting analysis showed that PFT-α reduced activation of extracellular regulated kinase1/2 (ERK1/2) and expression of protein kinase B (PKB, or Akt)/p-Akt. PD98059 (inhibitor of mitogen-activated protein kinase kinase (MEK)/ERK) and wortmannin (inhibitor of phosphoinositide 3-kinase (PI3K)/Akt) enhanced silibinin's cytotoxicity. Wortmannin augmented silibinin-induced autophagy, while PD98059 did not affect autophagic ratio. These results suggest that silibinin might induce p53-mediated autophagic cell death by activating ROS-p38 and JNK pathways, as well as inhibiting MEK/ERK and PI3K/Akt pathways.     

Staurosporine, a novel protein kinase C inhibitor, prevents postischemic neuronal damage in the gerbil and rat

The protective effects of protein kinase inhibitors and a calmodulin kinase inhibitor (W-7) against ischemic neuronal damage were examined in the CA1 subfield of the hippocampus. Staurosporine, KT5720, and KT5822 were used as inhibitors of protein kinase C (PKC), cyclic AMP-dependent protein kinase, and cyclic GMP-dependent protein kinase, respectively. All test compounds were injected topically into the CA1 subfield of the hippocampus. In the gerbil ischemia model, staurosporine (0.1-10 ng) administered 30 min before ischemia prevented neuronal damage in a dose-dependent manner. However, KT5720, KT5822, and W-7 were ineffective, even at a dose of 10 ng. In the rat ischemia model, staurosporine (10 ng) also prevented neuronal damage when administered before ischemic insult, although staurosporine administered 10 or 180 min after recirculation was ineffective. These results suggest the involvement of PKC in CA1 pyramidal cell death after ischemia and that the fate of vulnerable CA1 pyramidal cells through PKC-mediated processes could be determined during the early recirculation period.     

Correlation of tensile strength with bursting pressure in the evaluation of intestinal anastomosis

BACKGROUND: Although bursting pressure and tensile strength have long been measured to evaluate anastomotic techniques, it has yet to be clarified whether or not they are correlated, what implications they have, and which should be used as a gold standard. MATERIAL AND METHODS: Using an experimental model to estimate pressure and tension in the same colonic anastomosis, the following variables were measured in 48 rats between days 0 and 14: bursting pressure (BP); minimal tensile strength (MITS) necessary to break a part of the anastomosis, and maximal tensile strength (MATS) needed to disrupt the whole anastomosis. Also, circulatory wall tension (CWT) was derived from BP and the anastomotic circumference (AC), and longitudinal wall tension (LWT) from MITS and AC. These variables were compared using correlation and regression analysis. RESULTS: During the lag phase (days < or = 4) there was poor correlation between pressure-related and tension-related variables whereas highly significant correlations were noted in the subsequent fibroplastic phase (day > or = 5). It was shown by regression lines that positive MITS and MATS were expected when BP was zero. CONCLUSION: Contrary to the previous assumption, no correlation was found between BP and tensile strength in the critical postoperative period. Based on our present and previous studies, measurement of MITS is recommended to evaluate the healing of colonic anastomosis.