[Two cases of pulmonary aspergilosis, which deteriorated with generic itraconazole].

We experienced two cases of pulmonary aspergillosis, which deteriorated during treatment with generic itraconazole (ITCZ) because of low plasma concentration. One case was chronic pulmonary aspergillosis and the other was allergic bronchopulmonary aspergillosis (ABPA). Treatment of both cases was started with a brand-name-ITCZ, and changed to a generic ITCZ. Deterioration of pulmonary aspergillosis occurred after 8 months and 9 months from change to generic ITCZ respectively. In the first case, the ITCZ-plasma concentration was 46.9 ng/mL and of OH-ITCZ 96.5 ng/mL with generic ITCZ at the dose of 300 mg/day, but increased to 1,559.7 ng/mL and to 2,485.0 ng/mL with the brand-name-ITCZ 300 mg/day, respectively. In the second case, the ITCZ-plasma concentration was 27.2 ng/mL and of OH-ITCZ 20.1 ng/mL with 150 mg/day for generic ITCZ, but reached 857.3 ng/mL and to 1,144.2 ng/ml with the brand-name-ITCZ 300 mg/day, respectively. After treatment failure, the first case was changed to voriconazole, then brand-name-ITCZ 300 mg/day, and the second case to the brand-name-ITCZ 300 mg/day, with successful clinical course. Plasma concentrations of ITCZ can differ significantly depending on the patient or type of ITCZ. The ITCZ-plasma concentration should be controlled after changing from a brand-name-ITCZ to a generic ITCZ.

[Successful reintroduction of mesylate imatinib after pneumonitis in two patients with gastrointestinal stromal tumor (GIST)].

We report 2 cases of successful reintroduction of mesylate imatinib for gastrointestinal stromal tumor (GIST) after drug-induced pneumonitis. Both of them were women in the fifth decade who had been medicated by mesylate imatinib about for 5 months previously, and had been given a diagnosis of imatinib mesylate-induced pneumonitis. After only cessation of that drug, symptoms and shadows on chest X-ray film improved. However, we had to reintroduce the drug because of the growth of primary tumor, so we gave half the previous dose of imatinib mesylate, with low dose prednisone. There has been no recurrence of drug related pneumonitis and effective control of the primary tumor was obtained. The evidence acquired from our cases suggests that it may be possible to reintroduce imatinib mesylate carefully by adjusting the dose with low dose prednisone in a GIST patient, without causing recurrence of drug-induced pneumonitis.

[Case of severe streptococcus pyogenes pneumonia with streptococcus toxic shock syndrome].

A 30-year-old woman who had until recently been healthy, was transferred to our hospital by ambulance with complaints of dyspnea and pain in both lower limbs. She had 1-week history of sore throat, fever and cough. She had been to a neighboring clinic three days previously, and had been prescribed some medication for bronchitis, but her symptoms had not improved. By the time of admission, she was already in shock and had severe respiratory failure. Laboratory data showed renal dysfunction, disseminated intravascular coagulation, CPK elevation and severe metabolic acidosis. Chest x-ray and CT films revealed consolidation of the entire right lung field. The patient was quickly intubated and we began mechanical ventilation. We immediately initiated broad-spectrum antibiotics, immunogloblin, dopamine hydrochloride and gabexate mesilate, but she died 7 hours later. From cultures of blood and sputum taken from the patient, Streptococcus pyogenes was isolated. On the basis of these clinical and bacteriological findings, we confirmed a diagnosis of pneumonia and toxic shock syndrome caused by Streptococcus pyogenes (STSS). Serologically her M protein was serotyped as M1, and with regard to Streptococcal pyrogenic exotoxin genes were identified as speA and speB. These serological findings were consistent with the most frequent type that causes STSS. In spite of the uncommon cause of community-acquired pneumonia, Streptococcus pyogenes can potentially affect healthy individuals. The pneumonia can be complicated with STSS and so the clinical course may be severe and fulminant. The evidence acquired from this case suggests that in the event of severe pneumonia with shock, we should be aware that this may represent the presence of Streptococcus pyogenes and/or toxic shock syndrome.

Long-term use of corticosteroid eye drops delays the spontaneous remission of pulmonary sarcoidosis.

Topical corticosteroid eye drops are commonly used for ocular sarcoidosis. That systemic absorption of corticosteroids by eye drops may influence the clinical course of sarcoidosis may be speculated because it has been reported that the serum concentration of corticosteroids after drop administration was dose-related. To evaluate the effects of corticosteroid eye drops on the clinical course of patients with stage I pulmonary sarcoidosis, we compared the serum levels of angiotensin converting enzyme (ACE) and bilateral hilar lymphadenopathy (BHL) on chest radiographs of group CS, which is consisted of patients who received topical therapy of betamethasone in the form of eye drops for anterior uveitis, and group CN, which is consisted of patients who did not receive any medications throughout the entire course of the disease. Although the serum ACE level was not significantly different between groups CS and CN at the time of the diagnosis of pulmonary sarcoidosis, the level of serum ACE in group CS was significantly higher than that in group CN 20 months after the topical corticosteroid treatment (24 IU/ml and 16 IU/ml, respectively). Further, the size of BHL on chest radiography in group CS was significantly larger than that in group CN 20 months after the topical treatment (82% and 37% of before control, respectively). These findings suggest the possibility that the topical corticosteroid therapy influenced the clinical course of pulmonary sarcoidosis, inducing some delay in the spontaneous remission in the longterm course.

Cyclic ADP-ribose, a putative Ca2+-mobilizing second messenger, operates in submucosal gland acinar cells.

Cyclic ADP-ribose (cADPR), a putative Ca(2+)-mobilizing second messenger, has been reported to operate in several mammalian cells. To investigate whether cADPR is involved in electrolyte secretion from airway glands, we used a patch-clamp technique, the measurement of microsomal Ca(2+) release, quantification of cellular cADPR, and RT-PCR for CD38 mRNA in human and feline tracheal glands. cADPR (>6 microM), infused into the cell via the patch pipette, caused ionic currents dependent on cellular Ca(2+). Infusions of lower concentrations (2-4 microM) of cADPR or inositol 1,4,5-trisphosphate (IP(3)) alone were without effect on the baseline current, but a combined application of cADPR and IP(3) mimicked the cellular response to low concentrations of acetylcholine (ACh). Microsomes derived from the isolated glands released Ca(2+) in response to both IP(3) and cADPR. cADPR released Ca(2+) from microsomes desensitized to IP(3) or those treated with heparin. The mRNA for CD38, an enzyme protein involved in cADPR metabolism, was detected in human tissues, including tracheal glands, and the cellular content of cADPR was increased with physiologically relevant concentrations of ACh. We conclude that cADPR, in concert with IP(3), operates in airway gland acinar cells to mobilize Ca(2+), resulting in Cl(-) secretion.

Differential effect of epidermal growth factor on serous and mucous cells in porcine airway submucosal gland.

Using a patch-clamp technique, we found that the fresh porcine submucosal gland acinar cells contained two functionally distinct cell populations, i.e. physiologically relevant concentration of acetylcholine (ACh, 30 nM) induced two distinct patterns of electric response in tracheal gland acinar cells. One was characterized by an outstanding oscillatory Cl(-)-current activity, and the other was with poor Cl(-)-current response but with a comparable K(+)-current. We examined the effect of epidermal growth factor (EGF) on the ACh-induced electric responses in these cells. EGF affected only the latter (K(+)-prominent) cell type to potentiate significantly the ACh-induced K(+)-current. An immunohistochemistry revealed that the receptor for EGF was identified preferentially on the mucous, but not serous, cells. Genistein, one of the tyrosine-kinase inhibitors, abolished the augmentation effect of EGF on the ACh-induced current. Thus, we identified the serous cell with a Cl(-)-rich current in response to ACh and the mucous cell with a K(+)-dominant response. Moreover, EGF affected the mucous cells alone to potentiate the ACh-induced electric response. EGF may contribute to the pathophysiological alterations in chronic inflammatory airways both in morphological (mucous cell hypertrophy/hyperplasia) and functional (thick viscous hypersecretion) ways.