Perinatal carcinogenicity of isoniazid (INH) in swiss mice

Summary Tumorigenicity of isoniazid (INH) and hydrazine sulfate (HS) was studied in male and virgin Swiss mice. The INH and HS induced 50% und 84% lung tumors in males and 67% and 72% in females, respectively. Both chemicals induced lung tumors in animals of the F₁ generation that were exposed to INH or HS during intrauterine life, lactation, and in the postweaning period. Surprisingly, the F₂ generation from these F₁ animals, which were exposed to INH only during gestation and lactation, showed earlier and much higher tumor incidence than the parent generation.     

A case of acetaminophen-induced pneumonitis]

A 20-year-old woman took 1.2 g of acetaminophen for toothache. She subsequently developed a dry cough, pyrexia, and dyspnea. Chest X-ray revealed diffuse reticulo-nodular shadows in both lung fields. Broncho-alveolar lavage examination showed a marked increase in the total cell number and an increase in the percentage of eosinophils, neutrophils, and lymphocytes. Because drug-induced pneumonitis was suspected, all drugs were stopped and she was administered methylprednisolone. Consequently her symptoms resolved, and pulmonary function and chest X-ray findings improved remarkably. The lymphocyte stimulation test was positive for Norshin and its acetaminophen element. Based on these findings, the diagnosis of acetaminophen-induced pneumonitis was made. Acetaminophen intoxication is well-known, but to our knowledge this is the first reported case of acetaminophen-induced allergic pneumonitis in Japan.     

A case of diphenylhydantoin-induced pneumonitis]

A 60-year-old man had been administered diphenylhydantoin (DPH) for prevention of convulsive seizures following clipping of an aneurysm of the middle cerebral artery. About one month after the commencement of DPH administration, he developed cough and low grade fever. He was treated with various antibiotics, but his condition increasingly worsened. Chest X-ray film revealed bilateral interstitial processes throughout the entire lung fields. Transbronchial lung biopsy was performed and the obtained specimen showed histological findings compatible with drug-induced pneumonitis. Administration of DPH was stopped immediately and 50 mg/day of prednisolone was started. The patient's condition rapidly improved, and the abnormal shadows on chest X-ray film gradually diminished. The lymphocyte stimulation test by DPH was positive with a stimulation index of 282%.     

A case of paclitaxel-induced pneumonitis]

A 79-year-old woman with small-cell lung cancer was treated weekly with paclitaxel after previous treatment with carboplatin and etoposide. Within the first course of paclitaxel, chest radiography and CT revealed thickening of the bronchovascular bundle and interlobular septa, and infiltrates in both lung fields. A marked increase in the number of lymphocytes was found on bronchoalveolar lavage (BAL). Microorganisms such as Cytomegalovirus, Mycobacteria, and Pneumocystis carinii were absent from the BAL fluid. Interstitial infiltration was partially improved simply by stopping paclitaxel administration, without the need for any additional therapy. Drug-induced pneumonitis caused by paclitaxel was diagnosed on the basis of the clinical course and findings, although a drug lymphocyte stimulation test yielded negative results for paclitaxel. Interstitial infiltrates on imaging, symptoms and arterial blood gas results improved with administration of oral prednisolone. The possibility of pneumonitis induced by paclitaxel should be considered even in cases without interstitial lung disease.     

A case of flomoxef-induced pneumonitis]

We report a case of flomoxef-induced pneumonitis. A 22-year-old man was treated with flomoxef following liver biopsy. A few days later he developed a high fever and severe dyspnea, and his chest X-ray film revealed diffuse reticulo-nodular shadows in both lung fields. We suspected interstitial pneumonitis due to flomoxef, and pulse therapy with methylprednisolone was started. He showed rapid recovery of symptoms and marked regression of pulmonary infiltration in his chest X-ray. Lymphocyte stimulation test was positive to flomoxef, which was compatible with the diagnosis of drug-induced pneumonitis. To our knowledge, there has been no previous case of pulmonary hypersensitivity to flomoxef reported in Japan.     

A case of polaprezinc-induced pneumonitis]

A 77-year-old man referred to our hospital three months ago presented with dyspnea on effort and chest radiograph abnormalities. Chest computed tomography showed consolidation and irregular thickening of the peribronchovascular interstitium. Bronchoalveolar lavage fluids showed increases in the percentage of lymphocytes and a decrease of the CD4/8 ratio. Transbronchial lung biopsy specimens showed signs of organizing pneumonia. The patient had been given polaprezinc for the treatment of hypogeusia six months before. A lymphocyte-stimulating test for polaprezinc was positive, and so our diagnosis was polaprezinc-induced pneumonitis.     

A case of rebamipide-induced pneumonitis]

A 75-year-old man who complained of progressive dyspnea was admitted to our hospital. He had been treated with rebamipide at an outpatient clinic for the preceding seven months. Atrial blood gas values obtained on admission indicated hypoxemia. Chest radiographs and CT films revealed diffuse interstitial infiltration and minimal pleural effusion. Bronchoalveolar lavage fluid showed an increase in the total cell number, the percentages of eosinophils and lymphocytes, and a decrease in the CD4/CD8 ratio. Transbronchial lung biopsy specimens had thickened alveolar septa with lymphocyte infiltration within the air spaces. After the discontinuation of rebamipide, oral prednisolone was administered, and the patient's symptoms and pulmonary shadows quickly improved. A lymphocyte stimulating test for rebamipide was positive. A challenge test for rebamipide was not performed because informed consent could not be obtained. On the basis of these findings, our diagnosis was rebamipide-induced pneumonitis.     

A case of Sai-rei-to-induced pneumonitis]

A 77-year-old man was given emergency admission because of fever and dyspnea in October, 2005. He had been treated with Sai-rei-to, a herbal drug, for tinnitus. Laboratory data showed high values of C-reactive protein and liver dysfunction. Chest X-ray and CT films revealed ground-glass attenuation in both lung fields. Bronchoalveolar lavage showed an increase in number of lymphocytes and the lymphocyte-stimulation test was positive for Sai-rei-to. Based on the above findings, we diagnosed this case as Sai-rei-to-induced pneumonitis. The patient recovered after discontinuation of Sai-rei-to and corticosteroid therapy.     

A case of bucillamine-induced pneumonitis]

A 65-year-old woman with rheumatoid arthritis was treated with gold (gold sodium thiomalate), bucillamine, and other drugs. Gold was discontinued because of rash. Consequently she presented with high fever and alopecia, and was admitted with dyspnea. Chest X-ray showed diffuse bilateral reticulolinear infiltrates. The percentage of lymphocytes was increased and OKT4/8 ratio was decreased to 0.22 in bronchoalveolar lavage fluid (BALF). In lung tissue specimens obtained by TBLB, alveolitis with Masson's bodies was seen on light microscopy, and electron micrography showed interstitial edema with desquamated macrophages in the alveolar space and lipid-laden pericytes, secondary to extensive destruction of the alveolar-capillary barrier. After discontinuation of drugs, her symptoms and infiltrates on the chest X-ray resolved. Furthermore, the results of drug lymphocyte stimulation test (DLST) were positive for both drugs. We diagnosed this case as bucillamine-induced pneumonitis, since the symptoms developed after the administration of bucillamine; however, an interaction between bucillamine and gold may have contributed to the occurrence.     

A case of sustained-release theophylline (Theodur)-induced asthma]

Theophylline is used as a prophylactic agent for controlling bronchospasm in patients with asthma. Sustained-release theophylline (Theodur) is widely used for this purpose. In this report, we describe a patient who developed asthma due to administration of Theodur. A 38-year-old man was referred to our hospital for assessment of the relationship between his respiratory symptoms and theophylline. He had been admitted to the hospital several times for dyspneic attacks. Theophylline ethylenediamine (Aminophylline) and hydrocortisone sodium succinate had been administered intravenously for the acute phase, followed by Theodur orally. Following administration of Theodur, he had developed dyspnea, chest tightness and dizziness. An inhalation challenge test with sulpyline showed a negative reaction. Although an oral challenge test with theophylline also showed a negative reaction, that with Theodur evoked an asthmatic response. We were unable to determined any possible cause or the mechanism for this reaction. We concluded that the vehicle or preservative (i.e., inactive ingredients) contained in Theodur were likely to be related to his asthmatic response.     

A case of loxoprofen-induced pneumonitis pathologically resembling hypersensitivity pneumonitis]

A 66-year-old woman was admitted to our hospital because of high fever, general fatigue, hypoxemia and liver dysfunction. Chest radiographs showed diffuse interstitial shadows in both lungs. We suspected drug-induced pneumonitis because of her history of drug administration for upper respiratory infection. Her symptoms and findings were markedly decreased by discontinuation of the drugs. Transbronchial lung biopsy specimens showed infiltration of eosinophils and lymphocytes to the alveolar septa, granuloma with Langhans' giant cells, and Masson bodies in a manner suggestive of hypersensitivity pneumonitis. Drug lymphocyte stimulation tests were negative except for loxoprofen. There was no recurrence of systemic or respiratory symptoms during overnight stays at home. On the basis of these findings, we arrived at a diagnosis of drug-induced pneumonitis caused by loxoprofen.     

A case of pneumonitis induced by Bofu-tsusho-san]

We encountered a patient in whom Bofu-tsusho-san (Chinese herbal drug) had induced pneumonitis. A 65-year-old man was admitted to our hospital because of cough, fever, and dyspnea about one month after treatment with Bofu-tsusho-san. BALF showed an increase in the total cell number and the percentage of lymphocytes. TBLB revealed interstitial pneumonia. The patient recovered after discontinuation of Bofu-tsusho-san alone. We diagnosed Bofu-tsusho-san-induced pneumonitis. Clinicians should be aware of drug-induced pneumonitis in patients receiving herbal drugs.     

A case of drug-induced pneumonitis due to bepridil]

A 66-year-old man had been given bepridil for the treatment of atrial fibrillation since April 28, 2002. The patient developed exertional dyspnea with hypoxemia in the middle of June 2002 and was admitted to our hospital. The chest X-ray and chest CT scans showed diffuse reticulonodular infiltrates in the lower lung fields. Pulmonary function tests revealed depletion of diffusion capacity for carbon monoxide. Bronchoalveolar lavage fluid contained increased percentages of lymphocytes, neutrophils and eosinophils, and a CD4/8 ratio was low. The transbronchial lung biopsy specimens demonstrated alveolar septal thickening with infiltration of mononuclear cells and intraalveolar organization. As drug-induced pneumonitis was suspected, bepridil was discontinued, resulting in improvement of dyspnea and hypoxemia. The patient was then treated with corticosteroid, which led to complete resolution of infiltration on chest X-ray. According to the clinical data consistent with drug-induced pneumonia, the prompt improvement after cessation of bepridil and the absence of other possible causes, we diagnosed this case as bepridil-induce pnemonitis.     

A case of hypersensitivity pneumonitis caused by Strophariaceae]

A 38-year-old woman was admitted to the Iiyama Red Cross Hospital with a non-productive cough. She had been working with Strophariaceae cultures for 4 years, and in January 1999 a cough had developed. On admission, hypoxemia was noted. The serum level of lactate dehydrogenase was slightly elevated. Chest radiography and CT scanning showed diffuse ground glass opacity and small centrilobular nodules in both lower lobes. In the bronchoalveolar lavage fluid, the total cell count was normal, the CD4/CD8 ratio was reduced, and the lymphocyte fraction was very high. A transbronchial lung biopsy revealed alveolitis with lymphocytic infiltration and organizing changes like Masson bodies. The lymphocyte stimulation test was positive for Strophariaceae. Hypersensitivity pneumonitis caused by Strophariaceae was diagnosed. Prednisolone was administered because of persistent symptoms and prolonged abnormal chest radiography findings. These abnormalities disappeared 2 weeks after prednisolone treatment was initiated. There is one previous report of hypersensitivity pneumonitis caused by Strophariaceae. The symptoms are coughing and sputum production as in the common cold. The occupational history must be carefully considered in making a diagnosis.     

Treatment results of rifampicin (RFP) resistant isoniazid (INH) susceptible tuberculosis, a hospital based study

PURPOSE: To evaluate treatment results of Rifampicin (R) resistant Isoniazid (H) susceptible tuberculosis cases. METHOD: Cohort analysis of twenty-three H susceptible R resistant tuberculosis cases started treatment in 1985-2004 at Fukujuji Hospital, by the retrospective review. RESULTS: Three cases became Multi-drug resistant tuberculosis (MDR TB), seventeen cases were cured, two cases died, and one case transferred out. One started treatment with HR became MDR, one of the two started treatment with HR+ Ethambutol (E) became MDR and one of them was cured, eight among ten cases started treatment with HR+Pyrazinamide + (E or Streptomycine (S)) were cured, one among the ten died and one among the ten transferred out, one started treatment with RZE was cured, three among the five cases started treatment with three effective drugs without Z were cured, one among the five died, one among the five became MDR. Three cases started treatment with four effective drugs were cured. Among the nineteen cases continued treatment for more than six months, ten cases treated with four or five effective drugs for at least two months were cured, two cases of nine cases treated with three drugs or less became MDR, seven of the nine cases were cured. Among the same nineteen cases, eleven cases not treated with two or less effective drugs were cured, one case treated with two or less effective drugs for six months became MDR and one of them treated with one or two effective drug for one to three months became MDR and some were cured. The used drugs were H, E, Pyrazinamide, Streptomycin, Kanamycin, Ethionamide and New Quinolones. The duration of treatment of cured cases were eleven to twelve months in 3 cases, twelve to eighteen months in 3 cases, eighteen to twenty-four months in 8 cases and more than two years in 3 cases. CONCLUSION: If the starting regimen is HRZE, we can cure R resistant H susceptible tuberculosis by the use of four effective drugs for more than two months and at least three effective drugs with the total duration of treatment for twelve to twenty-four months.     

A case of hypersensitivity pneumonitis due to isocyanate (TDI)

A 46-year-old man who had worked in a paint processing plast for over 29 years was admitted to our hospital with complaints of nocturnal dyspnea and dry cough. A chest X-ray film showed diffuse granular shadows in bilateral lungs. Pulmonary function tests revealed reduction of diffusing capacity and restrictive impairments. Hypersensitivity pneumonitis (HP) due to isocyanates was speculated from his occupational history and clinical course. Positive skin tests against TDI-HSA and MDI-HSA, precipitating antibody against TDI-HSA, and negative lymphocyte stimulating tests of peripheral blood and bronchoalveolar lavage fluid were also noticed. Environmental provocation test was positive. Histological findings of transbronchial lung biopsy specimens showed diffuse alveolitis and Masson body, but no granulomas. According to these results, the patient was diagnosed as HP due to TDI. Type III allergy of Gell-Coombs seems to participate in this case. The granulomatous lesion is seen less frequently in isocyanate-related HP than in HP induced by organic dusts, which suggests the difference in immunological and histological reactions between both types of HP.     

A case of successful desensitization therapy for isoniazid-induced pneumonitis]

A 65-year-old man was admitted to hospital for treatment of pulmonary tuberculosis. He was treated with isoniazid (INH), rifampicin (RFP), ethambutol (EB), and pyrazinamide (PZA). On the 14th day, he developed a fever and interstitial pneumonia, which improved promptly after discontinuation of the antituberculous drugs. Drug lymphocyte stimulation tests against INH, RFP and PZA were negative. However, the provocation test on INH (only) was positive, leading to a diagnosis of pneumonitis caused by INH. We then tried desensitization of INH over a period of two weeks, which was successful and occurred without any clinical event. In the past, five cases of INH-induced pneumonitis were reported, but desensitization of INH did not occur in any. We conclude that physicians should be aware not only of paradoxical reactions but also of drug-induced pneumonitis when a new pulmonary infiltrate develops in the course of tuberculosis treatment. Furthermore, drug desensitization may be possible in some cases of drug-induced pneumonitis.