Takuma Bando

Aerosolized acetaldehyde, but not ethanol, induces histamine–mediated bronchoconstriction in guinea–pigs

It was reported that ethanol–induced bronchoconstriction was associated with elevated serum levels of aectaldehyde and histamine in Japanese asthmatic patients, but there is no study to investigate the airway response to acetaldehyde. We performed this animal study to test the hypothesis that acctaldehyde has the bronchospastic action via histamine release. First, we investigated the airway response to ascending doses (31.3, 62.5, 125. and 250 MM) of inhaled ethanol or acctaldehyde in guinea–pigs. Secondly, guinea–pigs pretreated with intraperitoneal injection of saline or 20 mg/kg diphenhydramine inhaled acetaldehyde. Finally, guinea–pigs pretreated with intraperitoneal injection of saline or 0–5 mg/kg atropine sulfate inhaled acetaldehyde. Inhalation of acetaldehyde. but not ethanol, caused bronchoconstriction in a dose–dependent manner. The bronchoconstriction induced by inhaled acetaldehyde was completely prevented by pretreatment with diphenhydramine. Atropine had no preventing effect against the acetaldehyde–induced bronchoconstriction. In conclusion, acetaldehyde has the bronchospastic action via histamine release in guinea–pigs. It is suggested that histamine HI–antagonists may be available for preventing alochol–induced asthma.

Tachyphylaxis to capsaicin-induced cough and its reversal by indomethacin, in patients with the sinobronchial syndrome.

Cough reflex testing with capsaicin has been used to study the pathophysiology of the cough reflex and the antitussive effects of various drugs. Although the reproducibility of capsaicin-induced cough has been well established in normal subjects, it is not known if prior challenge with capsaicin reduces the subsequent cough response to inhaled capsaicin in patients with the sinobronchial syndrome, a condition characterized by chronic upper and lower airway inflammation. Measurement of the capsaicin cough threshold, defined as the lowest concentration of capsaicin eliciting five or more coughs, was repeated four times at intervals of 15, 30 and 60 min in eleven patients with the SBS and ten normal subjects. The cough thresholds at 15, 30 and 60 min were greater than the initial value in patients with the SBS but not in normal subjects. In addition, we examined the effect of 4 days treatment with indomethacin (100 mg/day) on the cough thresholds measured twice at an interval of 15 min in eight patients with the SBS. Indomehacin increased the initial cough threshold and reduced the increment in the post-15 min cough threshold from the initial value compared with placebo, thus reducing the tachyphylaxis. These results indicate that chronic airway inflammation may be responsible for the decreased response (tachyphylaxis) to repeated inhalation of capsaicin, and suggest that cyclooxygenase products released by the airway inflammation may be involved in tachyphylaxis, cough receptor sensitivity to inhaled capsaicin, or both, in patients with the SBS.

Analysis of thrombocytopenia due to carboplatin combined with etoposide in elderly patients with lung cancer

Thrombocytopenia induced by carboplatin combined with etoposide for elderly lung cancer patients was analyzed in relation to the predicted thrombocytopenia by the equations advocated by Egorin et al. and Taguchi et al. The thrombocytopenia actually observed was strongly correlated with and significantly more severe than that predicted if carboplatin had been administered as a single agent. The AUC (area under the curve) of carboplatin predicted by Calverts equation significantly affected the degree of thrombocytopenia. These data suggested that dosing of carboplatin should be determined individually on the basis of renal function, as recommended earlier. The reason for the enhancement of thrombocytopenia is yet to be determined in future trials.

Establishment and characterization of non-small cell lung cancer cell lines resistant to mitomycin C under aerobic conditions

To elucidate the mechanisms of acquired resistance to mitomycin C (MMC) in non‐small cell lung cancer (NSCLC), we established two MMC‐resistant NSCLC sublines by continuous exposure to MMC, using PC‐9 as a parent cell line. The sublines, PC‐9/MC2 and PC‐9/MC4, were 6.4‐ and 10‐fold more resistant to MMC than their parent cell line, respectively, at the IC50 value as determined by MTT assay. They exhibited cross‐resistance to EO9, but were not resistant to cisplatin, vindesine, etoposide, carboquone, or KW‐2149, a novel MMC derivative. They were collaterally sensitive to adriamycin and menadione. Accumulation of the drug was decreased in the resistant sublines to about 60% of that in the parent cells. Cytosolic DT‐diaphorase (DTD) activities were decreased to 13.5±3.2 in PC9/MC2 and 1.3±0.6 in PC‐9/MC4 from 261.5±92.7 nmol/min/mg protein in the parent PC‐9. NADH:cytochrome b5 reductase activities in both of the resistant cell lines were significantly decreased as compared to that in the parent cell line. Addition of dicumarol resulted in a two‐fold increase in IC50 value in PC‐9, whereas the IC50 value showed no change in PC‐9/MC4. Moreover, dicumarol did not affect the sensitivities to KW‐2149 but decreased the sensitivities to EO9 in both the parent and the resistant cell lines. Formation of an alkylating metabolite was significantly decreased in the resistant cells, in parallel to the degree of resistance. We concluded that deficient drug activation due to decreased DTD activity was important as a mechanism of resistance to MMC in PC‐9, a relatively DTD‐rich NSCLC cell line.

Interaction of thromboxane A2 and leukotrienes in guinea pig airways in vivo.

Effects of a thromboxane A2 receptor antagonist (S-1452) on bronchoconstriction induced by inhaled leukotriene C4 and a leukotriene receptor antagonist (AS-35) on bronchoconstriction caused by inhalation of a thromboxane A2 mimetic (STA2) were studied in anesthetized, artificially ventilated guinea pigs in order to examine the interaction of thromboxane A2 and leukotrienes in airways. 0.01-1.0 mu g/ml of leukotriene C4 and 0.1-1.0 mu g/ml of STA 2 inhaled from ultrasonic nebulizer developed for small animals caused dose-dependent increase of pressure at the airway opening (Pao) which is considered to be an index representing bronchial response. Pretreatment of the animals with inhaled S-1452 (0.01, 0.033 mg/ml) significantly reduced the airway responses produced by 0.01,0.033,0.1,0.33 and 1.0 mu g/ml of leukotriene C4 in a dose dependent manner. While pretreatment with inhaled AS-35 (1mg) did not affect the STA2 dose-response curve. These findings suggest that leukotriene C4 activates thromboxane A2 generation while thromboxane A2 does not influence 5-lipoxygenase pathway in the airways.

Rhabdomyolysis following Status asthmaticus

A case of rhabdomyolysis following an asthmatic attack is reported. A 71-year-old man was admitted because of wheezing and hypoxemia. Brown urine was present on admission. Although these symptoms completely disappeared with the treatment with aminophylline, salbutamol and corticosteroid, transiently elevated serum creatine phosphokinase and myoglobinuria were present. Rhabdomyolysis has rarely been reported in cases of bronchial asthma. This case represents an extremely rare case of rhabdomyolysis following status asthmaticus.

Modulation of sensitivity to mitomycin C and a dithiol analogue by tempol in non-small-cell lung cancer cell lines under hypoxia

We examined the mechanisms involved in the bioactivation of mitomycin C (MMC) and a newly developed MMC analogue: 7-N-(2-{[2-(γ-l-glutamylamino)ethyl]dithio}ethyl)mitomycin C, KW-2149, in non-small-cell lung cancer (NSCLC) cell lines under aerobic and hypoxic conditions. To investigate these mechanisms, we used MMC-resistant non-small-cell lung cancer cell lines (PC-9/MC4) that had been established in our laboratory from the parent PC-9 cell line by continuous exposure to MMC. We previously reported that the MMC-resistant cell line (PC-9/MC4) was poor in NAD(P)H dehydrogenase (quinone) activity and approximately 6-fold more resistant than the parent cells (PC-9) to MMC on 2-h exposure under aerobic conditions. In this study, the subline PC-9/MC4 was 6.7-fold more resistant to MMC than PC-9, the parent cell line, under aerobic conditions, and 5.2-fold more resistant under hypoxic conditions after 2h exposure to MMC. However, on co-incubation with tempol, an inhibitor of the one-electron reduction pathway, the sensitivity of PC-9/MC4 to MMC was impaired under hypoxic conditions, but the impairment was not evident under aerobic conditions. KW-2149, the newly developed MMC analogue, was cytotoxic for both PC-9/MC4 and PC-9 cells, and the sensitivity of both cell lines to KW-2149 was not changed by exposure to hypoxic conditions or by coincubation with tempol. There were no significant differences in the intracellular uptake of MMC and the activities of cytosolic detoxification enzymes between the PC-9 and PC-9/MC4 cell lines. These results support the hypothesis that the one-electron reduction pathway plays a partial role in the bioactivation of MMC, but not of KW-2149, and that KW-2149 is excellent at circumventing resistance to MMC in NSCLC.

Effect of Fosfomycin on Cisplatin Nephrotoxicity and its Pharmacokinetics.

Cisplatin (CDDP) の腎障害に対するfosfomycin (FOM) の軽減効果とその時のCDDPの血中動態について検討した.対象はCDDP80mg/m2を投与された肺癌患者13例で, 1・3コース目にFOMを1日4-6g, 5日間静脈内投与した.2コース目はNAGの24時間尿中排泄量がCDDP投与2日目から4日目をピークとして上昇を示し, 3日目で1・3コース目と比べて有意に増加した.総Platinum (Pt) 濃度のarea under the curve (AUC) については2コース目は1コース目より有意に高く, 3コース目は1コース目より高い傾向にあり, 最高血中濃度は2コース目は1コース目より高い傾向にあった.非蛋白結合型Ptの血中濃度はいずれのコースでも明らかな差異は認めなかった.蛋白結合型Ptの最高血中濃度については2コース目は1コース目より有意に高かった.また, 総Ptおよび蛋白結合型PtのAUCは尿中NAGのピークと有意な相関関係を認めた.以上よりFOMはCDDPの腎障害の軽減作用を示した.薬物動態学的検討からはFOMが総Ptおよび蛋白結合型Ptに何らかの影響をもたらすことが示唆されたが, 非蛋白結合型Ptに影響はなく抗腫瘍効果に影響を与えないものと考えられた.

136 Thromboxane A2 as a determinant of sensitivity to platinum agents in non-small cell lung cancer cell lines

cis-Diamminedichloroplatinum (II) (CDDP) is one of most active anticancer agents for lung cancer. In this study, we evaluated the role of thromboxane A2 (TXA2), a metabolite of arachidonate, as a determinant of sensitivity to CDDP in non-small cell lung cancer (NSCLC) cell lines in vitro by using selective TXA2 receptor antagonists, S-1452 and BAYu3405. A-549, EBC-1, PC-3, and RERF-LC-MS cell lines which had been derived from human NSCLC were used for these experiments. Drug sensitivity tests were performed with MTT-assay. IC50 values for CDDP and an analogue (CBDCA) of these cell lines by 2-hour exposure were decreased by co-incubation with these TXA2 antagonists. Cellular accumulation of CDDP and CBDCA increased by S-1452. These results indicate the important role of endogenous TXA2 to modulate the cellular accumulation of the platinum agents and to determine intrinsic resistance to these agents in NSCLC cell lines.

A Case of Multiple Myeloma Presenting as Bilateral Chest Wall Tumors and Left Pleural Effusion.

症例は54歳女性, 主訴は左側胸部痛であった. 1990年6月より体動時に左側胸部痛を認めるようになった. 1991年2月胸部X線像で両側胸壁腫瘤と左胸水貯留を指摘された. 胸壁腫瘤の吸引針生検で骨髄腫と診断され, 胸水からも骨髄腫細胞が検出された. 血清, 尿, 胸水の免疫電気泳動でIgG-κ型のMタンパクを認めた. 本例は胸壁腫瘤形成と胸水貯留を呈した多発性骨髄腫としては希な症例と考えられた.