Kazuhiko Teraoka

Characteristics of and Risk Factors for Interstitial Lung Disease Induced by Chemotherapy for Lung Cancer

Background: Drug-induced interstitial lung disease (DILD) is generally a serious adverse effect and almost always necessitates the discontinuation of the offending drug. Cancer pharmacotherapy is strongly associated with DILD, and the risk of DILD has been suggested to be higher in patients with lung cancer because of preexisting pneumonic disease. Objective: The aim of this retrospective study was to identify the risk factors and prognostic factors for early death from interstitial lung disease (ILD) induced by chemotherapy for lung cancer. Methods: The medical records of 459 patients who underwent chemotherapy for lung cancer between April 2007 and March 2013 were analyzed with regard to patient background and DILD development, initial symptoms, and prognosis. Results: A total of 33 patients (7.2%) developed chemotherapy-induced ILD. The most frequently observed initial symptom was dyspnea (94.3%). Preexisting ILD was identified as a risk factor for DILD (odds ratio [OR] = 5.38; 95% CI = 2.47-11.73; P < 0.01). Among the 33 patients who developed DILD, 10 patients suffered an early death despite steroid therapy. Poor prognostic factors included epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) use (OR = 9.26; 95% CI = 1.05-82.0; P < 0.05) and 2 or more prior chemotherapy regimens (OR = 6.95; 95% CI = 1.14-42.3; P < 0.05). Conclusions: Many lung cancer patients have coexisting ILD, and these patients have a high risk of developing chemotherapy-induced ILD. In addition, patients with DILD who underwent EGFR-TKI therapy and 2 or more prior chemotherapy regimens had a higher risk of fatal outcome.

Long-term regulation of catecholamine formation by ouabain in cultured bovine adrenal chromaffin cells.

The long-term effects of ouabain, an inhibitor of Na+/K+ -ATPase, on catecholamine formation in cultured bovine adrenal chromaffin cells were examined. The increase in [14C]catecholamine formation from [14C]tyrosine induced by ouabain was dependent on incubation time, and its maximal effect was observed after incubation for 8 h. The stimulatory effect of ouabain was concentration dependent (10-300 nM), causing maximal stimulation at 300 nM. The formation of [14C]catecholamines induced by ouabain was not increased by incubation with [14C]DOPA instead of [14C]tyrosine. Ouabain-induced [14C]catecholamine formation was influenced by decreases in extracellular Ca2+ concentration, but not by the presence of cycloheximide or actinomycin D. These results suggested that ouabain stimulates continuous activation of hydroxylation of tyrosine through a Ca2+ -dependent mechanism in cultured bovine adrenal chromaffin cells.

Substance P inhibits catecholamine biosynthesis stimulated by carbamylcholine in cultured adrenal chromaffin cells

The effect of substance P on catecholamine biosynthesis was examined using cultured bovine adrenal chromaffin cells as a model for the sympathoadrenergic system. Substance P markedly inhibited the formation of [14C]catecholamines from L-[14C]tyrosine stimulated by cholinergic agonist, but caused no significant effect on the biosynthesis stimulated by depolarizing agent. In addition, this inhibitory action was completely prevented by the addition of substance P antagonists. Under the conditions in which the inhibition of catecholamine biosynthesis was observed, substance P also inhibited the influx of extracellular 45Ca2+ into these cells, and this inhibitory action on Ca2+ influx was almost identical to that on the biosynthesis. These results provide evidence for a possible role of substance P as a putative neuromodulator in the sympathoadrenergic system.

Further studies on the relationship between tyrosine supply and catecholamine production in cultured adrenal chromaffin cells

To elucidate a possible role of tyrosine supply as a factor modulating catecholamine biosynthesis in the adrenergic cell, the transport of [14C]tyrosine into cultured bovine adrenal chromaffin cells was first examined, and the relationship between [14C]tyrosine transport and [14C]catecholamine formation was then investigated. Under the conditions which were routinely employed to determine the rate of catecholamine biosynthesis, tyrosine was taken up into the cells in a manner independent of extracellular Na+ and Ca2+, and this uptake was also insensitive to ouabain and various metabolic inhibitors. The stimulation of these cells with high K+ and other secretagogues caused no significant alteration in the uptake. While, tyrosine transport was markedly inhibited by tyrosine analogues and other L-aromatic amino acids, and this inhibition was accompanied by the reduction of [14C]catecholamine formation. In contrast, tyrosine transport was markedly enhanced by flavone, and this enhancement was also accompanied by the augmentation of catecholamine production under the same experimental conditions. These results seem to indicate that the transport of tyrosine into the cells may be closely related to catecholamine formation within the cells, thus providing an evidence for a possible role of tyrosine supply as one of the factors affecting catecholamine production in the adrenal chromaffin cell.

Effects of bioflavonoids on exocytotic release of catecholamines from digitonin-permeabilized chromaffin cells: A comparison with the effects of other protein kinase C inhibitors.

The effects of bioflavonoids on catecholamine release from permeabilized adrenal chromaffin cells were examined to show their intracellular actions on exocytosis. The release from these permeabilized cells in response to a direct calcium challenge was shown to be markedly inhibited by quercetin in a manner dependent on its concentration. Apigenin was also shown to cause a moderate inhibitory action, but flavone caused no significant effect on the release under the experimental conditions used here. Furthermore, the inhibitory actions of these flavonoids on the phorbol ester-dependent fraction of catecholamine release were shown to be more pronounced than those on the calcium-dependent fraction. The effects of bioflavonoids on the calcium-dependent and the phorbol ester-dependent releases were then compared with those of other protein kinase C inhibitors, and quercetin was shown to cause a potent inhibitory action on the exocytotic secretory process, which was almost equivalent to those caused by polymyxin B and neomycin. Both quercetin and apigenin were clearly shown to inhibit the phorbol ester-dependent as well as the calcium-dependent release of catecholamines from digitonin-permeabilized chromaffin cells. The inhibitory actions of these compounds were therefore thought to be attributed to their inhibitory actions on protein kinase C in the cytoplasmic space of the permeabilized cells. Thus, these results seem to provide further evidence for a possible involvement of protein kinase C as one of the sites for calcium action in the intracellular mechanism of exocytotic secretion.

Modulation by basic polypeptides of ATP-induced activation of tyrosine hydroxylase prepared from bovine adrenal medulla

The effects of basic polypeptides on the activation of adrenal tyrosine hydroxylase by ATP were investigated to show a possible involvement of macromolecular cell components in the regulation of the enzyme activity. Basic polypeptides caused an enhancement of the activation of tyrosine hydroxylase by low concentrations of ATP, and the potentiating effects of these polypeptides were observed to be dependent on their concentrations. Kinetic studies showed that basic polypeptides caused an increase in the Vmax of the ATP-activated enzyme for the cofactor without any change in the Km. These results suggest that basic polypeptides convert the enzyme from a nonsusceptible form to a form susceptible to ATP, thus resulting in the potentiation of the ATP-induced activation. Furthermore, the activation by ATP of tyrosine hydroxylase was not observed after treatment of the enzyme preparation with CM-cellulose, and the responsiveness of the enzyme treated with CM-cellulose to ATP was partially restored by addition of basic polypeptides. These observations suggest the possibility that macromolecular cell components, presumably basic proteins, may be involved in the regulation of the activity of tyrosine hydroxylase through their modulating effects on the sensitivity of the enzyme to ATP within the cell.

Stimulatory actions of bioflavonoids on tyrosine uptake into cultured bovine adrenal chromaffin cells

The effects of flavonoids on L-[14C]tyrosine uptake into cultured adrenal chromaffin cells were examined. Flavone markedly stimulated tyrosine uptake into these cells in a manner dependent on its concentration. Apigenin also caused a moderate stimulatory action, but quercetin had no significant effect on the uptake. Flavone also stimulated the uptake of histidine, but did not affect the uptake of serine, lysine, or glutamic acid. These results are considered to propose the possibility that flavonoids may be able to stimulate the precursor uptake into the cells, resulting in an enhancement of the biogenic amine production.

Clinical Evaluation of Pharmacist Interventions in Patients Treated with Anti-methicillin-Resistant Staphylococcus aureus Agents in a Hematological Ward

The therapeutic effects of anti-methicillin-resistant Staphylococcus aureus (MRSA) agents, vancomycin (VCM), teicoplanin (TEIC), and arbekacin (ABK), depend on their concentrations in blood. Therefore, therapeutic drug monitoring (TDM) is important when these antibiotics are used. In the hematological ward at Tokushima University Hospital, pharmacists have ordered the measurement of blood VCM, TEIC, and ABK concentrations to promote the use of TDM in accordance with an agreed protocol since 2013. Moreover, the infection control team includes several medical disciplines and has advised on the optimal treatment using VCM, TEIC, and ABK since 2013. This study aimed to investigate the clinical effectiveness of these pharmacist interventions. We retrospectively studied 145 cases in which patients were treated with VCM, TEIC, or ABK between January 2012 and December 2013 in the hematological ward at Tokushima University Hospital. The patients were divided into a control group (71 cases) and an intervention group (74 cases), and their clinical outcomes were compared. The rate of achievement of effective drug concentrations significantly increased in the intervention group (74%), compared to the rate in the control group (55%). Moreover, univariate and multivariate Cox proportional hazard regression revealed that pharmacist intervention and appropriate concentrations of anti-MRSA agents were independent factors associated with reduced hospitalization periods in patients with lymphoma. Our study revealed that proactive pharmacist intervention may improve the therapeutic effect of anti-MRSA agents in hematology ward patients.

Possible involvement of intracellular Ca2+ in hyposmosis-evoked catecholamine release from adrenal chromaffin cells

The influence of hyposmotic conditions on catecholamine release was studied using cultured adrenal chromaffin cells. Incubation of the cells in hyposmotic solution led to the enhancement of catecholamine release in a manner dependent on the reduction of osmolarity. Hyposmosis-evoked catecholamine release was similarly observed in the presence or absence of extracellular Ca2+, and was not significantly affected by organic and inorganic Ca2+ entry blockers. These results indicated that the hyposmosis-evoked release might be associated with a rise in the intracellular Ca2+ concentration. Further studies showed that neither ryanodine nor thapsigargin caused any significant effect on hyposmosis-evoked catecholamine release, whereas pretreatment of chromaffin cells with carbonyl cyanide m-chlorophenyl hydrazone significantly enhanced the hyposmosis-evoked release. Catecholamine release evoked by exposure to hyposmotic medium is therefore thought to be mediated through intracellular Ca2+, which may be mainly sequestered by the mitochondrial pools. Neither caffeine- nor inositol 1,4,5-trisphosphate-sensitive Ca2+ pools seems likely to be involved in hyposmosis-evoked catecholamine release, although the Ca2+ pools that contribute to the elevation of intracellular Ca2+ observed under hyposmotic conditions are not yet completely identified.

Effects of bioflavonoids on catecholamine biosynthetic activity in the adrenal gland: In vitro studies using partially purified tyrosine hydroxylase and chromaffin cell cultures

To elucidate the effects of bioflavonoids on catecholamine biosynthetic activity in the sympathoadrenergic system, the direct actions of bioflavonoids on tyrosine hydroxylase activity were first examined in vitro using the enzyme partially purified from bovine adrenal medulla. The enzyme activity was markedly and rapidly inhibited by quercetin, but not significantly affected by either apigenin or flavone. The inhibitory action of quercetin on tyrosine hydroxylase was shown to be accompanied by an alteration in kinetic properties of the enzyme. Furthermore, the effects of these flavonoid compounds on catecholamine biosynthetic activity were examined using cultured bovine adrenal chromaffin cells, and found that quercetin caused a marked decrease in the formation of [(14)C]catecholamines from [(14)C]tyrosine in the cells. In contrast, neither apigenin nor flavone caused any significant effect on the formation of [(14)C]catecholamines under the same conditions. The findings presented here suggest that quercetin may inhibit catecholamine biosynthesis through its direct action on the rate-limiting enzyme in the adrenal chromaffin cell, thus resulting in modulation of the sympathoadrenergic function.