Serial pentamidine levels in bronchial epithelial lining fluid after aerosol administration.

BACKGROUND: There is no information on serial pharmacokinetic assessment in the lungs after administration of aerosolized pentamidine. OBJECTIVE: The present study was performed to evaluate the elimination of aerosolized pentamidine from bronchial airways following inhalation. METHODS: We used 4 sheep with tracheotomies in the present study. Pentamidine (300 mg) was administered by inhalation to each animal. Serial bronchial washing to obtain epithelial lining fluid (ELF) was performed 1, 7, 10, 14, 21 and 28 days after administration of aerosolized pentamidine in each animal. The pentamidine concentration in the supernatant of ELF was measured by high-performance liquid chromatography. RESULTS: The maximal pentamidine level on the first day (12 h after inhalation) was 616.5 +/- 238.2 ng/ml (mean +/- SE) in ELF. The pentamidine levels rapidly decreased within 2 weeks (8.9 +/- 1.2 ng/ml at 14 days), followed by slow elimination (8.9 +/- 0.8 ng/ml at 28 days). Thus, inhaled pentamidine showed a rapid clearance from the bronchial wall within the first 2 weeks. CONCLUSIONS: These findings may be useful in designing and interpreting future studies of aerosolized pentamidine in patients who are receiving inhaled pentamidine, especially for those with failure of prophylaxis for Pneumocystis carinii pneumonia.

Gastric sarcoidosis--a single polypoid appearance in the involvement.

We describe a case of gastric sarcoidosis which developed during a 10-year period of observation of generalized sarcoidosis. The patient was asymptomatic, but gastroduodenoscopy revealed a polypoid lesion in the antral region. The specimen obtained by polypectomy showed noncaseating granuloma, suggesting sarcoidosis. Chest radiograph and computed tomographic examination revealed no involvement of the lung or mediastinal lymph nodes, although these findings were present at the initial diagnosis. The present case indicates that gastric involvement should be considered in patients with sarcoidosis, even when no hilar lymphadenopathy is present. Furthermore, the macroscopic appearance of a single polyp in gastric sarcoidosis is extremely rare in gastric sarcoidosis in the literature.

[Two cases of pulmonary disease with perinuclear anti-neutrophil cytoplasmic antibody].

We encountered two cases of perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA). The first was a case of idiopathic interstitial pneumonia diagnosed in a 73-year-old man since 1998. He was admitted to our hospital because of renal failure and anemia. The serum level of p-ANCA on admission was 264 EU, and specimens obtained by percutaneous renal biopsy showed crescentic glomerulonephritis and vasculitis due to p-ANCA. He was treated with prednisolone pulse therapy and prednisolone (PSL), however interstitial pneumonia occurred during PSL tapering. We treated him for pulmonary fibrosis with plasmapheresis, methylprednisolone (mPSL) and cyclophosphamide (CPA), which suppressed the progress of the interstitial pneumonia. The second case was one of massive pulmonary hemorrhage in a 68-year-old man who was admitted to our hospital. Physical examination revealed anemia: the laboratory data, renal failure; and the serum level of p-ANCA was elevated to 611 EU. The specimens obtained by percutaneous renal biopsy showed crescentic glomerulonephritis and vasculitis. The renal failure was not improved by PSL, but, together with the inflammation, responded to the combination of PSL and CPA. However, both patients died of serious infection. They were regarded as compromised patients because of the therapy mentioned above. No standard therapy has been established against p-ANCA positive pulmonary disease with renal failure. The treatment should control the progression of interstitial pneumonitis and pulmonary hemorrhage. It is important to consider the possibility of serious infection.

Effects of lecithinized superoxide dismutase and a neutrophil elastase inhibitor (ONO-5046) on hyperoxic lung injury in rat.

Reactive oxygen and neutrophil metabolites have been implicated in the development of hyperoxic lung injury. We determined the protective effects of either a superoxide dismutase or neutrophil elastase inhibitor and the combination of both agents on the development of hyperoxic lung injury in rats. Two drugs (lecithinized superoxide dismutase and ONO-5046) were used in the present study. Lecithinized superoxide dismutase, a lecithin derivative bound to recombinant CuZn superoxide dismutase, has a higher affinity for cells such as polymorphonuclear leukocytes and endothelial cells than recombinant human superoxide dismutase. N-[2-[4-2,2-dimethylpropionyloxy) phenylsulfonylamino] benzoyl]¿ aminoacetic acid (ONO-5046), a specific neutrophil elastase inhibitor, which was developed as a low-molecular weight inhibitor, showed protective effects against various lung injuries. Rats were exposed to over 90% oxygen for 72 h, and bronchoalveolar lavage was performed to evaluate the permeability and neutrophil accumulation in the lungs. Rats were treated with lecithinized superoxide dismutase (30,000 U/day, intravenously n=7) or ONO-5046 (10 mg/kg, intramuscularly twice a day, n=7) or a combination of both drugs (n=7). Albumin concentration and neutrophil counts in bronchoalveolar lavage fluid were compared between animals with and without drug treatment. Either lecithinized superoxide dismutase or ONO-5046 treatment significantly decreased albumin concentration and neutrophil counts in bronchoalveolar lavage fluid compared to those in the animals of the hyperoxia-alone group (n=9). However, albumin leakage and neutrophil accumulation in the rat lung treated with combined agents were identical to that of either the lecithinized superoxide dismutase or ONO-5046 treatment. These findings suggest that lecithinized superoxide dismutase and ONO-5046 are useful drugs to protect against hyperoxic lung injury in rats. However, there were no additive effects by the combination in preventing hyperoxic lung injury.

Double cancer (lung and colon cancer) that showed complete remission with irinotecan and cisplatin combined chemotherapy.

We report a rare case of double (colon and lung) cancer which showed complete remission with chemotherapy with irinotecan (CPT-11) and cisplatin (CDDP). The patient was a 67-year-old man who was diagnosed as having double cancer (stage IIIb pulmonary adenocarcinoma and stage 0 [or 1] well-differentiated adenocarcinoma of the ascending colon). Two courses of chemotherapy (CPT-11, 60 mg/m2, days 1 and 8; CDDP, 30 mg/m2, days 1 and 8) were performed. The combination therapy of CPT-11 and CDDP was very effective. In Japan, there have been few published reports describing the use of CPT-11 for the treatment of gastrointestinal cancer. We think that the use of CPT-11 in gastrointestinal cancer is promising.

Spontaneous pneumomediastinum in 33 patients: yield of chest computed tomography for the diagnosis of the mild type.

BACKGROUND: Spontaneous pneumomediastinum (SPM) usually occurs in young people without an apparent precipitating factor or disease. Although there have been many studies focused on the clinical features and standard chest X-ray (CXR) findings of SPM, few have reviewed the chest computed-tomographic (CT) findings. OBJECTIVES: We assessed SPM using CXR and CT, and the relation between them. METHODS: We evaluated 33 patients (26 males) diagnosed with SPM on the basis of symptoms and chest radiological findings. RESULTS: Three patients showed normal CXR but a diagnostic CT scan. Seven showed mild pneumomediastinum on CXR. In these 10 patients, pneumomediastinum was easily detected by chest CT. Moderate and severe SPM were easily detected by both CXR and CT. CONCLUSIONS: These findings suggested that CXR alone poorly detected approximately 30% of SPM and that chest CT scan was needed to make the diagnosis in these cases. It seems likely that SPM is underdiagnosed by 30% or more in clinical practice.

Lung lymph response to overinfusion with hydroxyethyl starch in sheep. Comparative studies of high and low molecular weight compounds.

BACKGROUND: Several hydroxyethyl starch (HES) solutions are available clinically. We performed comparative studies of low and high molecular weight HES to evaluate the effects on lung lymph flow in sheep, to see the difference in the types of HES. METHODS: We prepared awake sheep with vascular monitorings and lung lymph fistulas. We measured systemic artery pressure (Psa), pulmonary artery pressure (Ppa), and left atrial pressure (Pla) continuously. Cardiac output (CO) was measured every 30 min. Lung lymph flow (Qlym) was collected every 15 min. After baseline measurements, two HES solutions were infused over 2 h, respectively. Experiment 1 (n=6): low molecular weight HES (MW 70 000, substitution ratio 0.5-0.55), Experiment 2 (n=5): high molecular weight HES (MW 450 000, substitution ratio 0.7). RESULTS: Both low and high molecular HES behaved similarly as a volume expander, increasing Psa, CO, Pla and Ppa, and decreasing hematocrit. In addition, the actual oncotic pressure gradient (plasma - lymph) was widened after the start of either low or high molecular HES, but the value for high molecular HES was significantly higher than that for low molecular HES. Qlym of low molecular HES rose significantly from the baseline and the percent increase in Qlym for low molecular HES was significantly higher than that for high molecular HES. CONCLUSION: These data suggest that low molecular HES is as useful a plasma substitute as high molecular HES, but may increase lung fluid filtration in the overinfused state.

[A case of limited Wegener granulomatosis with hypereosinophilia].

A 51-year-old female was admitted to Nagano Matsushiro General Hospital because of fever, cough and dyspnea on exertion. Her laboratory data revealed leukocytosis with hypereosinophilia, a high erythrocyte sedimentation rate and c-reactive protein. Chest radiography revealed an infiltration shadow with a cavity in the right upper lobe. A lung abscess was diagnosed and antibiotics were administered. Laboratory results showed improvement, but chest radiography continued to show cavities. She was admitted to our hospital because of fever, left pleural effusion and progression of cavities on chest radiographs. She showed no abnormalities of the upper airway or kidney, and was negative for c-antineutrophil cytoplasmic antibody (c-ANCA). Because a positive c-ANCA was seen on day 8 of hospitalization, L-type limited Wegener granulomatosis (WG) was diagnosed according to Gross et al. Prednisolone (PSL) was administered, which improved the anemia, eosinophilia and the cavities. On day 7 of PSL administration, of the left pneumothorax occurred as a complication caused by perforation of the left chest cavity, but her clinical course was good after a cavernectomy was performed. Some studies have reported that limited WG shows a negative c-ANCA, and that antibiotic therapy improves inflammation. The L-type of limited WG revealed a low-grade positive ratio and titer of c-ANCA. Moreover, L-type limited WG responds well to therapy. We therefore selected PSL administration only against L-type limited WG. We have reported L-type limited WG with eosinophilia and the negative effects of c-ANCA at an early clinical stage.

Endothelin receptor blockade attenuates air embolization-induced pulmonary hypertension in sheep.

We investigated the effects of two types of endothelin receptor antagonists on pulmonary hypertension induced by pulmonary air embolization in awake sheep. We prepared awake sheep with indwelling catheters inserted in blood vessels for continuous monitoring of pulmonary artery pressure, left atrial pressure and systemic arterial pressure. Cardiac output was measured every 30 min. The study consisted of two experiments, one with FR139317 (100 microg/kg/min; (R)2-[(R)-2-[(S)-2-[1-(hexahydro-1H-azepinyl)]-carbonyl]amino-4-++ +methy l-pentanoyl]amino-3-[3-(1-methyl-1H-indolyl)]propionyl)amino-3-(2-pyr idyl)propionic acid), a selective endothelin ET(A) receptor antagonist, and the other with TAK-044 (100 microg/kg/h; cyclo[D-alpha-aspartyl-3-[(4-phenylpiperazin-yl)carbonyl]-L-alanyl -L- alpha- aspartyl-D-2-(2-thienyl) glycyl-L-leucyl-D-tryptophyl] disodium salt), an endothelin ET(A) and ET(B) receptor antagonist. In the paired experiments, air was continuously (4.06 ml/min) infused into the main pulmonary artery for 3 h after the baseline pressures were stabilized. Sheep were treated or not treated with FR139317 or TAK-044. Pulmonary artery pressure was significantly higher than the baseline pressure after the start of air infusion. Both FR139317 and TAK-044 significantly attenuated the increase in pulmonary artery pressure during air embolization. Plasma endothelin -1 levels in both pulmonary and systemic arteries were equally and significantly increased after the start of air infusion. The results indicate that endothelin-1 release is attributable to the development of pulmonary hypertension during the course of air embolization in awake sheep.

[Primary ciliary dyskinesia treated with living-donor lobar lung transplantation].

We report a case of primary ciliary dyskinesia in which a living-donor lobar lung transplant was performed. A 24-year-old woman with a diagnosis of primary ciliary dyskinesia and bronchiectasis was admitted to Shinshu University Hospital because of persistent dyspnea and pyrexia over a period of 4 months. Although she was given various antibiotics, neutrophilia, elevated plasma C-reactive protein (CRP) levels, and respiratory failure persisted. Chest roentgenograms and computed tomography disclosed severe bronchiectasis and diffuse infiltrative shadows in both lung fields. Pseudomonas aeruginosa was detected in a sputum culture. Although a variety of conventional therapies were administered, the patient's oxygenation progressively deteriorated. She was intubated and assisted by mechanical ventilation. The patient and her family proposed lung transplantation, and we concluded that a living-donor lobar lung transplant would be a suitable treatment for her disease. We transported the patient to Okayama University Hospital by helicopter 10 days after intubation. A living-donor lobar lung transplant was successfully performed with lung tissues donated by the patient's mother and sister for each transplant site.

A 21-aminosteroid, U-74006F, attenuates endotoxin-induced lung injury in awake sheep.

The purpose of the present study was to examine the efficacy of U-74006F, a 21-aminosteroid, on lung dysfunction induced by endotoxaemia in awake sheep with lung lymph fistula and haemodynamic monitoring. We measured pulmonary haemodynamics, lung lymph balance, circulating leucocyte count, arterial blood gas tensions, and levels of thromboxane (Tx) B2 and 6-keto-prostaglandin (PG) F1 alpha in plasma and lung lymph. We performed two experiments. In experiment 1 (n = 6), we intravenously infused Escherichia coli lipopolysaccharide endotoxin (1 microgram/kg) over 30 min and observed the parameters over 5 h. In experiment 2 (n = 6), we pretreated sheep with an intravenous bolus of U-74006F (2 mg/kg) 30 min before the infusion of endotoxin in the same manner of experiment 1, and continuously infused U-74006F (0.5 mg/kg per h) over 5 h after the bolus during the experiment. The U-74006F significantly suppressed the early pulmonary hypertension, the late increase in pulmonary permeability and the elevations of TxB2 and 6-keto-PGF1 alpha levels in plasma and lung lymph during the early period following endotoxaemia, although the compound did not change the time course of leucocytopenia and hypoxaemia. These findings suggest that the administration of U-74006F attenuates the lung dysfunction induced by endotoxaemia in awake sheep.

Immunoblastic lymphadenopathy-like T-cell lymphoma complicated by multiple gastrointestinal involvement.

We report a rare case of immunoblastic lymphadenopathy (IBL)-like T-cell lymphoma complicated by multiple gastrointestinal involvement, which appeared to be ameliorated by chemotherapy but resulted in perforative peritonitis. A 66-year-old Japanese woman who had generalized lymphadenopathy and eruptions was admitted to our hospital because of bloody stool. Colonoscopic examination revealed hemorrhagic ulcers in the terminal ileum and a saucer-like ulcer in the cecum. Gastrointestinal endoscopy revealed several ulcerative or elevated lesions in stomach and duodenum. Biopsy specimens of these lesions and of a lymph node showed characteristic histological features of IBL-like T-cell lymphoma. The initial treatment with prednisolone (PSL) and cyclophosphamide (CPA) was effective. Six months after the treatment, however, she developed bloody stool again caused by multiple ulcerative lesions in the large intestine. The recurrence of the disease was determined histologically, and four courses of CPA, PSL, vinblastine sulfate and doxorubicin hydrochloride (CHOP) therapy were administered. One month after completing the CHOP therapy, she developed intestinal obstruction and then acute peritonitis resulting from perforation at an ulcer scar in the jejunum. Surgical treatment was successful, and histological examination demonstrated no lymphoma cells in the resected specimen. A gastrointestinal perforation should be recognized as a potential complication of IBL-like T-cell lymphoma, even during remission.

[ADOC regimen for unresectable advanced thymic cancer].

Between 1996 and 1998, we treated 6 patients with unresectable and advanced thymic cancer (stages IVa and IVb). All received 50 mg/m2 of cisplatin and 40 mg/m2 of doxorubicin intravenously (i.v.) on day 1,0.6 mg/m2 of vincristine i.v. on day 3, and 700 mg/m2 of cyclophosphamide i.v. on day 4; ADOC regimen, respectively at 3-4 week intervals. Four patients obtained a partial response (PR) after ADOC chemotherapy and the overall clinical response rate was 67%. No life-threatening side effects were noted. In 2 patients, cisplatin plus VP-16 chemotherapy failed to demonstrate any benefits prior to the ADOC regimen. Radiotherapy was initiated after the achievement of PR in the other 2 patients. ADOC chemotherapy appears to be an effective treatment for thymic cancer.

Pharmacokinetic characteristics of the novel anticancer agent CPT-11 and its active metabolite in plasma and lung lymph fluid following intravenous administration to sheep.

7-Ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (CPT-11, 100286-90-6) is one of the most promising novel anticancer agents, especially for lung cancer. 7-Ethyl-10-hydroxycamptothecin (SN-38), an active metabolic of CPT-11, has much stronger cytotoxicity than CPT-11. The present study was designed to evaluate the distribution and behavior of CPT-11 and SN-38 in lung lymph circulation following intravenous infusion. Awake sheep with chronically instrumented lung lymph fistulas were prepared. The concentrations of CPT-11 and SN-38 in plasma and lung lymph fluid were measured after intravenous infusion of 100 mg/body of CPT-11 for 90 min. SN-38 constantly showed higher lymph to plasma concentration ratios than those of CPT-11, and the % area under the curve (AUC) ratio of SN-38/CPT-11 in lymph fluid was significantly higher than that in plasma. These data indicated that SN-38 distributed in lung tissue moved more easily into lung lymph fluid than CPT-11, and might be more rapidly metabolized in lung tissue than plasma. CPT-11 may have favorable therapeutic effects on intrathoracic malignancies such as lung cancer and lymph metastasis.

Acute pulmonary edema caused by accidental aspiration of sweetened water in two cases of diabetes mellitus.

We treated two cases of diabetes mellitus who developed acute pulmonary edema following accidental aspiration of sweetened water for emergency treatment, when they had fallen into hypoglycemic coma following an overdose of injectable insulin. Although they showed hypoxemia and radiological examinations revealed pulmonary edema, they improved by giving only oxygen and antibiotics in a few days. The osmotic pressure of the sweetened water in each case was approximately 2,600 mOsm and 1,900 mOsm. We suppose that the pathogenesis of the pulmonary edema was due to the sweetened water causing water within the pulmonary vessels to permeate into the alveoli.

Spontaneous pneumomediastinum: origin identified by chest computed tomography.

Spontaneous pneumomediastinum (SPM) is an uncommon disorder. The mechanism of spontaneous pneumomediastinum has been speculated as follows: when air pressure in the alveoli rapidly increases, free air leaks from ruptured alveoli and accumulates along the bronchovascular tissue sheath, and then free air moves toward the mediastinum. In this case report of a 19-year-old man of SPM, a chest computed tomography (CT) revealed air in a tubular shape along the pulmonary artery in the apico-posterior segment of the left lung field. This is the first case in which the process of SPM could be identified by chest CT.

[A case of paragonimiasis westermani].

A 45-year-old man, who had eaten fried fresh water crabs (Geothelphusa dehaani), was admitted to our hospital because of productive cough and bloodysputum. Blood chemistry showed increased levels of white blood cells and C-reactive protein, but peripheral blood eosinophil counts and serum IgE values were not elevated. Chest roentgenogram and chest computed tomographic scan revealed infiltration of the right middle and left upper lung fields. He was diagnosed as having pneumonia, but his symptoms and radiological examination findings did not improve with antibiotics. The diagnosis of paragonimiasis was confirmed by immunoserological examination and detection of ova in sputum, stool and bronchoalveolar lavage fluid samples. Transbronchial lung biopsy showed infiltration and degranulation of eosinophils. The patient was treated with praziquantel for 3 days at a daily dosage of 75 mg/kg. After uneventful completion of treatment all clinical symptoms and radiological abnormalities disappeared. This is the first case in which ova of paragonimiasis westermani were identified in Nagano prefecture.

Pharmacokinetic evaluation of amphotericin B in lung tissue: lung lymph distribution after intravenous injection and airspace distribution after aerosolization and inhalation of amphotericin B.

We have studied the pharmacokinetics of amphotericin B (AmB) in lung lymph circulation and bronchial-wash fluid after intravenous infusion and inhalation, respectively. For two experiments with awake sheep, we used lung lymph fistulas and tracheotomy. In experiment 1, AmB concentrations in plasma and lung lymph after intravenous infusion of AmB (1 mg/kg of body weight) over 1.5 h were measured. The mean peak in plasma level was 756.0 +/- 188.8 ng/ml at 3 h after the start of infusion, and the level then decreased gradually to 194.8 +/- 28.9 ng/ml at 24 h. The stable and maximal levels in lung lymph last 5 to 9 h after the start of AmB infusion. The concentrations in lung lymph after 9 h were slightly higher than those in plasma. Thus, the lung lymph-to-plasma ratio of AmB concentrations increased gradually during infusion, and the ratio was more than 1.0 after the end of infusion, suggesting that AmB could be easily moved from plasma to pulmonary interstitium and/or lung lymph circulation. In another experiment, 5 or 30 mg of aerosol AmB was inhaled, and the concentration of AmB in the bronchial-wash fluid was determined by bronchoalveolar lavage. The peak AmB concentration in the fluid was observed at 0.5 h. After that, AmB was slowly eliminated over 24 h. The area under the concentration-time curve for 30 mg of inhaled AmB was higher than that for 5 mg, but maximum concentrations of AmB in serum for 5 and 30 mg were almost similar. These observations identify the pharmacokinetic characteristics of AmB in the lung and may provide a new insight into the strategy for clinical treatment of fungal pneumonia.

Churg-Strauss syndrome (allergic granulomatous angitis) presenting with ileus caused by ischemic ileal ulcer.

We report a rare case of Churg-Strauss syndrome (CSS) in a 41-year-old Japanese man with a history of middle-age onset of bronchial asthma who had severe abdominal pain. He presented with ileus caused by an annular ulcer of the ileum, attributable to mucosal ischemia resulting from necrotizing vasculitis of the mesenteric artery. He also had marked hypereosinophilia (51.5%), elevated serum IgE levels (34040 IU/ml), and generalized enlargement of the superficial cervical lymph nodes, containing eosinophilic granulomas. A stenotic lesion caused by an annular ulcer in the ileum was found and resected by laparotomy. Microscopic examination of the resected specimen revealed luminal narrowing or occlusion of small arteries in the ulcer base, subserosa, and mesenterium resulting from marked fibrotic intimal thickening with fragmentation or lack of the internal elastic lamina. These findings were diagnosed as vasculitis, scar stage. The postoperative course was uneventful, with the patient receiving a maintenance dose of prednisolone (10-15 mg/day) for 7 years subsequently. We must carefully diagnose and treat patients with middle-age onset asthma, because the symptom may be a lung manifestation of CSS, in which various organs including gastrointestinal tract are involved as a result of systemic necrotizing vasculitis.