[Six patients with pneumonitis related to blended Chinese traditional medicines].

We encountered six patients with pneumonitis related to blended chinese traditional medicine (Kampo). The duration of treatment with kampo ranged from 14 to 110 days (mean: 38 days). The most common complaints were dyspnea, fever, and dry coughing. Fine crackles were heard at the bases of both lungs. Abnormal laboratory findings included high values of C-reactive protein and glutamic-oxaloacetic transaminase in all patients, lactate dehydrogenase in 5 patients, and eosinophil count in 1 patient. Chest X-ray films and CT films revealed diffuse reticulo-nodular interstitial shadows with consolidation in both lung fields in 3 patients and pleural effusion in 1 patient. Bronchoalveolar lavage was done in 4 patients; examination of the lavage fluid showed lymphocyte alveolitis, either pure or associated with neutrophilia and eosinophilia in 3 patients. Inverted CD4/CD8 lymphocyte ratios were found in 3 patients. Transbronchial lung biopsy was done in 4 patients and specimens from 3 of those 4 showed organizing pneumonitis with thickening of alveolar septa. Lymphocyte stimulation tests were positive in 4 patients. Discontinuation of the drug (2 patients) or administration of corticosteroids (4 patients) was followed by rapid improvement. Patients being treated with kampo preparations should be observed for signs and symptoms of drug-induced pneumonitis.

Effect of saiboku-to, an antiasthmatic herbal medicine, on nitric oxide generation from cultured canine airway epithelial cells.

The effect of Saiboku-to (TJ-96), an antiasthmatic Kampo medicine, on the generation of nitric oxide (NO) from cultured canine tracheal epithelium was investigated using a highly specific amperometric sensor for this molecule in vitro. Immersion of the NO-selective electrode in the medium containing tracheal epithelial cells detected the baseline current of 16.8-57.0 pA, which corresponded to an NO concentration ([NO]) of 39.7 +/- 8.1 nM. Addition of TJ-96 increased [NO] in a concentration-dependent manner, the maximal increase from the baseline level and the concentration of TJ-96 required to produce a half-maximal effect (EC50) being 127.5 +/- 20.1 nM (P < 0.001) and 86 +/- 9 micrograms/ml, respectively. Pretreatment of cells with NG-nitro-L-arginine methylester (L-NAME) greatly inhibited the TJ-96-induced increase in [NO], whereas NG-nitro-D-arginine methylester (D-NAME) had no effect, and this inhibition was reversed by L-arginine but not by D-arginine. Cytochemical staining of the epithelial cells showed marked reactivity of NADPH diaphorase activity. These results suggest that NO is spontaneously released by the airway epithelium and that TJ-96 stimulates the epithelial NO generation.

Effect of TJ-96, an anti-allergic herbal medicine, on tracheal transepithelial potential difference in vivo.

We studied the effect of Saiboku-to (TJ-96), an anti-allergic herbal medicine, on transepithelial potential difference of rabbit trachea and possible involvement of nitric oxide (NO) generation in vivo. Perfusion of TJ-96 on the tracheal mucosal surface increased PD in a concentration-dependent manner, the maximal increase from the baseline level and the concentration of TJ-96 required to produce a half-maximal effect (EC50) being 8.1 +/- 1.4 mV (mean +/- SE, P < 0.001) and 47 micrograms/ml. This effect was abolished by pretreatment with the Na channel blocker amiloride. NG-nitro-L-arginine methylester (L-NAME) but not NG-nitro-D-arginine methylester (D-NAME) inhibited TJ-96-induced increase in PD, and this inhibition was selectively reversed by L-arginine. These results suggest that TJ-96 stimulates Na absorption by airway epithelial cells probably through NO generation.

[Effect of Sei-hai-to on ion transport in airway epithelial cells].

The effect of Sei-hai-to on ion transport in airway epithelial cells and its mechanism of action were investigated. Measurement of short-circuit current (Isc) using cultured epithelial cells from canine tracheal mucosa under short-circuit conditions showed that Isc was dose-dependently increased by the submucosal administration of Sei-hai-to. The response of Isc to this drug was not affected by pretreatment the cells with amiloride, but abolished by furosemide, or Cl-free condition. These results suggest that Sei-hai-to stimulates Cl ion transport selectively and may affect the subsequent movement of water across the airway mucosa to the lumen.

Potentiation of beta-adrenergic function by saiboku-to and bakumondo-to in canine bronchial smooth muscle.

To determine the effects of the Kampo drugs Saiboku-to, Bakumondo-to and Orengedoku-to on beta-adrenergic function in airway smooth muscle, we studied isolated canine bronchial segments under isometric conditions in vitro. Incubation of tissues with these drugs did not alter the contractile responses to acetylcholine and histamine. The relaxation of tissues precontracted with acetylcholine induced by isoproterenol was augmented by Saiboku-to and Bakumondo-to, so that the concentration of isoproterenol required to produce a half-maximal effect (IC50) was decreased from 4.6 +/- 0.5 x 10(-8) M to 1.9 +/- 1.0 x 10(-8) M (P < 0.05) and to 1.0 +/- 0.8 x 10(-8) M (P < 0.01), respectively, whereas Orengedoku-to had no effect. These effects were concentration-dependent with the threshold concentrations being 0.3 mg/ml for Saiboku-to and 0.1 mg/ml for Bakumondo-to. Saiboku-to and Bakumondo-to did not affect cyclic AMP levels in airway smooth muscle per se but potentiated the isoproterenol-induced cyclic AMP accumulation. These results suggest that Saiboku-to and Bakumondo-to but not Orengedoku-to potentiate beta-adrenergic function in airway smooth muscle, which may reflect the efficacy of these drugs on airway hyperresponsiveness and asthma.

Angiotensin II-1 receptor-mediated Cl secretion by canine tracheal epithelium.

To elucidate the effect of angiotensin II (AII) on ion transport function of airway epithelium, we studied the bioelectrical properties of canine cultured tracheal epithelium under short-circuit conditions in vitro. Addition of AII to submucosal solution in Ussing chambers increased the short-circuit current (ISC) in a dose-dependent fashion, the maximal increase from the baseline value and the concentration required to produce a half-maximal effect being 5.2 +/- 0.5 microA/cm2 (p < 0.001) and 10(-6) M, respectively. In contrast, mucosal AII had little effect. The AII-induced increase in ISC was not altered by the AII-2 receptor antagonist EXP655 but was depressed by the AII-1 receptor antagonist DuP 753. Diphenylamine-2-carboxylate, Cl-free medium, indomethacin, the phospholipase A2 inhibitor mepacrine, and the methyltransferase inhibitor 3-deazaadenosine reduced the change in ISC, whereas amiloride and the lipoxygenase inhibitor AA-861 did not. Addition of AII to the submucosal but not the mucosal side increased the release of prostaglandin E2, an effect that was abolished by DuP 753. These results suggest that AII may interact with the submucosal AII-1 receptor and stimulate Cl secretion across tracheal epithelium through the mobilization of arachidonic acid and the release of prostaglandin E2.

Stimulation of Na absorption by the antiasthmatic kampo drug Saiboku-to in cultured airway epithelium.

To study the effect of the Kampo drug Saiboku-to (TJ-96) on ion transport function of airway epithelial cells, we studied bioelectric properties of cultured tracheal epithelium from dogs under short-circuit conditions in vitro. Addition of TJ-96 (1 mg/ml) to the mucosal solution of the Ussing chamber increased the epithelial short-circuit current (SCC) from 6.5 +/- 0.7 to 11.4 +/- 1.6 microA/cm2 (P less than 0.001). This effect was dose-dependent, with the maximal increase from the baseline value and the concentration required to produce a half-maximal effect (EC50) being 70.5 +/- 12.6% (P less than 0.001) and 3 micrograms/ml, respectively; and there were corresponding increases in transepithelial potential difference and cell conductance. Submucosal addition of TJ-96 likewise increased SCC, although the magnitude of the response was smaller as compared with the response to the mucosal addition. The TJ-96-induced increase in SCC was not affected by diphenylamine-2-carboxylate or furosemide but abolished by amiloride. Intracellular cyclic AMP levels were dose-dependently increased by TJ-96. These results indicate that TJ-96 may selectively stimulate Na absorption across the tracheal epithelium, probably through intracellular accumulation of cyclic AMP.

[Effect of saibokuto on mucociliary transport system in the airway--basic and clinical assessments].

We studied the effects of Saibokuto, an antiasthmatic agent, on the airway mucociliary transport system. The addition of Saibokuto to a Rose chamber containing rabbit cultured tracheal epithelium dose-dependently increased ciliary beat frequency (CBF) as assessed by a photoelectric method: the maximal increase from the baseline value was 31.5 +/- 5.2% (p less than 0.001) and the concentration of Saibokuto required to produce a half-maximal effect (EC50) was 10(-4) mg/ml. This effect was not affected by the beta-adrenergic receptor antagonist propranolol or Ca(2+)-free medium, but was inhibited by the cyclooxygenase inhibitor indomethacin. Intracellular cyclic AMP levels were increased from 45.6 +/- 8.2 to 72.1 +/- 12.6 pmole/mg protein by 1.0 mg/ml Saibokuto (p less than 0.05). Thus, Saibokuto enhances ciliary motility probably through the synthesis of cyclooxygenase products and cyclic AMP. Additionally, administration of this drug to patients with chronic bronchitis, asthma and bronchiectasis improved their problems with sputum expectoration and reduced the amount of daily sputum (p less than 0.001). Therefore, Saibokuto may be of value in the treatment of patients with impaired mucociliary transport function in the airway.