Latest industry information on the safety profile of levofloxacin in Japan.

This paper focuses on the development of four major adverse drug reactions (ADRs) associated with some fluoroquinolones: convulsions, phototoxicity, cardiac effects, and hepatotoxicity. CNS adverse events have been linked to fluoroquinolone administration, including seizures, which are more likely with co-administration of NSAIDs. Only 61 cases of convulsions have been reported with levofloxacin, with 33 of those affected having received NSAIDs. The assumed rate of serious convulsions was as low as 1/65,000 with NSAIDs and 1/260,000 without NSAIDs. Levofloxacin has a very low phototoxicity-inducing potential confirmed by pre-clinical animal studies and the results of post-marketing surveillance (PMS). Pre-clinical results demonstrated that levofloxacin was 20 times less phototoxic than sparfloxacin and PMS data show that serious phototoxicity develops in only 1 in 1.8 million cases treated with levofloxacin. While many fluoroquinolones are associated with cardiac effects, pre-clinical data has shown that compared with sparfloxacin and grepafloxacin, levofloxacin has no effect on myocardial conduction. PMS data further support the safety of levofloxacin in this regard. While trovafloxacin is associated with serious hepatic problems, PMS data demonstrates that levofloxacin has a very low incidence of 1/100,000 hepatic effects. These results were confirmed in a prospective study that confirmed a low 1.3% incidence rate for all ADRs associated with levofloxacin.

HLA DPB1*0201 gene confers disease susceptibility in japanese with childhood onset type I diabetes, independent of HLA-DR and DQ genotypes.

HLA is an important etiologic genetic factor in Type I diabetes and specific HLA-class II genes are closely related to the onset of the disease. Many differences in the patterns of susceptible and resistant DRB1, DQA1, and DQB1 genes have been observed among various ethnic groups. We have previously shown that DRB1*0405, DRB1*0901 and DQA1*0301-DQB1*0302 were the major susceptible alleles or haplotype to Type I diabetes while DR-DQ haplotype studies suggested the important role of DR and DQ alleles in susceptibility and resistance in Japanese patients. Based on the analysis of 90 Japanese patients with childhood onset Type I diabetes and 136 unrelated healthy Japanese controls by polymerase chain reaction-restriction fragment polymorphism method (PCR-RFLP), we report here the association of Type I diabetes with DPB1*0201 (relative risk = 2.29; Pc = 0.027) in this population. Comparison of linkage disequilibrium patterns between patients and controls showed that the significantly high prevalence of DPB1*0201 among patients cannot be attributed simply to linkage disequilibrium with susceptible DRB1 alleles and DQA1-DQB1 haplotypes. Our results suggest that in addition to alleles at the DRB1, DQA1, DQB1 loci, polymorphism at DPB1 locus also influences the risk of Type I diabetes.

Interferon-related bronchiolitis obliterans organizing pneumonia.

We present an unusual case of a patient with chronic hepatitis C who experienced dyspnea, fever, and cough after 2 1/2 months' treatment with interferon. His radiograph demonstrated diffuse pulmonary infiltrates and bronchoalveolar lavage fluid showed an increase in lymphocytes, especially CD8-positive cells. The lung biopsy findings were bronchiolitis obliterans organizing pneumonia (BOOP). The pulmonary symptoms disappeared and the chest radiograph became normal after interferon therapy was discontinued and corticosteroid therapy was given. Interferon is suspected to be responsible for the BOOP.

Extracellular ATP regulates the proliferation of alveolar macrophages.

We examined the effects of extracellular ATP on the proliferation and synthesis of DNA by guinea pig alveolar macrophages (AM). AM proliferated spontaneously in vitro, their number doubling in 72 h. Such proliferation was completely inhibited by adding 1 mM ATP to the culture. The inhibition was dose dependent. ATP also suppressed the spontaneous synthesis of DNA by AM. The inhibitory effect of ATP was not related to cell damage, as the viability and the superoxide anion-generating activity of these cells were unaffected by treatment with ATP for 24 h. The order of potency of the adenosine nucleotides (ATP > ADP > AMP) reflected the character of the P2 purinoceptor. Theophylline inhibited the effect of ATP on the synthesis of DNA by AM to a level produced by the nonhydrolyzable analogue, ATP gamma S, but did not influence the effect of ATP gamma S. These data suggest that the effect of ATP on the synthesis of DNA was exerted mainly via the P2 purinoceptor (82.0%) and to a lesser extent via the P1 purinoceptor (12.6%). We found that small molecules in the lavage fluid inhibited the synthesis of DNA by AM. Thus, the extracellular ATP present in the alveolar lining fluid may participate in controlling the proliferation of AM.

Tyrosine-specific protein kinase participates in the pathogenesis of acute immune complex alveolitis in rats.

Rabbit IgG antibodies against ovalbumin (OA) was injected intravenously into Wistar rats. When the animals were challenged with OA aerosolized by ultrasonic nebulization, acute lung injury occurred as reflected by increased recovery of bronchoalveolar cells, especially polymorphonuclear leukocytes (PMN) in bronchoalveolar lavage fluid (BALF). Lung morphology demonstrated cellular infiltration in the alveolar septa and intra-alveolar hemorrhage. When the rats were administered ST-638, a novel tyrosine kinase inhibitor, intraperitoneally prior to nebulization, the number of PMN in BALF decreased in a dose-dependent manner and superoxide anion (O2-)-producing activity in peripheral leukocytes was significantly suppressed. Furthermore, the reagent inhibited migration of human peripheral blood neutrophils induced by the chemotactic peptide f-met-leu-phe in vitro. These studies strongly indicate that tyrosine kinase plays an important role in immune complex-triggered neutrophil-related lung disorders, and the novel tyrosine kinase inhibitor ST-638 attenuates lung injury by preventing superoxide production and neutrophil migration.

Hypotonic cisplatin treatment for carcinomatous pleuritis found at thoracotomy in patients with lung cancer. In vitro experiments and preliminary clinical results.

We have developed an intraoperative intrapleural treatment with the use of distilled water combined with cisplatin for carcinomatous pleuritis found at thoracotomy in patients with non-small-cell lung cancer. In the in vitro experiment, three different cell lines were used as a model of malignant pleural effusion. Cell growth was examined after a 3-day culture, which was preceded by exposure of the cells to cisplatin in either phosphate-buffered saline solution or distilled water for 1/2 to 5 minutes. The growth inhibition of tumor cells after hypotonic cisplatin treatment was significantly greater than after treatment with saline solution and cisplatin. Tumor that was obtained by resection of non-small-cell lung cancer was used as a model to demonstrate decreased viability of the tumor after exposure to hypotonic cisplatin. The viability of the tumor in a 6-day culture, preceded by exposure to hypotonic cisplatin (50 micrograms/ml) for 10 minutes, was markedly decreased. Intraoperative intrapleural hypotonic cisplatin was instilled in seven patients with pleural carcinomatosis without side effects and with control of pleural dissemination and pleural effusion for 6 to 29 months.

Thrombosis-inducing activity--a factor which appears in plasma of patients with allergic asthma during attack.

Thrombosis-inducing activity (TIA) is a factor which was recently identified in plasma from patients with advanced lung cancer and acute respiratory tract infection. In the present study, TIA was measured during periods of attack and nonattack in patients with the allergic and nonallergic type of asthma and pulmonary emphysema with an asthmatic component. In the allergic type of asthma, the attack was accompanied by the appearance of TIA, but when the attack ended it disappeared from plasma. In the nonallergic type of asthma and emphysema with an asthmatic component, TIA remained negative even during the attack. These observations indicate that TIA has some correlations with allergic asthma.

[Thrombosis-inducing activity (TIA) in plasma of a patient with lung cancer, which disappeared after radiotherapy].

A 58-year-old man had been suffering from persistent right shoulder pain was admitted following detection of a Pancoast tumor in the right lung. On admission, there was elevation of peripheral platelet count, plasma FDP and fibrinogen levels and thrombosis-inducing activity (TIA) was detected in his plasma. After receiving 30 Gy of Liniack, the mass shadow and the shoulder pain disappeared, which was accompanied by the normalization of laboratory data and the disappearance of TIA from plasma. However, plasma TIA became positive again one month later, in association with reappearance of shoulder pain and elevation of FDP and fibrinogen levels, which were considered due to recurrence of the tumor, 30 Gy of Liniack together with thermotherapy was again given. There was no subsequent recurrence of tumor, nor TIA has been detected for more than 3 years.

Simultaneous measurements of adenosine deaminase activity and tuberculostearic acid in pleural effusions for the diagnosis of tuberculous pleuritis.

Adenosine deaminase (ADA) activity and tuberculostearic acid (TSA) levels in pleural effusions were measured in 18 patients with active tuberculous pleuritis, 16 patients suspected of having tuberculous pleuritis, 14 patients with carcinomatous pleuritis, and 19 patients suffering from pleuritis of non-malignant and non-tuberculous etiology. In the patients with active tuberculous pleuritis, ADA was elevated in 56% and TSA was positive in 78%. In 83% of these patients, either ADA was elevated or TSA was positive. ADA was elevated together with a positive TSA in 50%. In contrast, TSA was positive in only 6% and ADA was elevated in 24% of the patients with non-tuberculous pleuritis, and none of these patients showed the combination of an elevation of ADA and a positive TSA. These results suggest that simultaneous measurements of both ADA and TSA in pleural effusions are useful for the diagnosis of tuberculous pleuritis.

A case of pulmonary tuberculosis with bilateral hilar lymphadenopathy diagnosed by sputum culture subsequent to open thoracic biopsy.

We report a case of pulmonary tuberculosis with bilateral hilar lymphadenopathy. Open thoracic lymph nodes and lung biopsy revealed findings consistent with sarcoidosis. Culture and special staining of the biopsied specimen for mycobacteria were negative. Culture of the postoperative sputum grew Mycobacterium tuberculosis and antituberculous therapy resulted in a decrease in sizes of the lymphadenopathy. A review of the literature, with emphasis on the differential diagnosis between tuberculosis and sarcoidosis, is discussed.

Species dependency of in vitro macrophage activation by bacterial peptidoglycans.

The effect of various bacterial cell wall components on in vitro biological function of murine peritoneal exudate macrophages was evaluated. We examined four different parameters of metabolic activity and monokine secretion. Peritoneal exudate macrophages from rats and guinea pigs, all of the strains tested, were stimulated by whole bacterial cell wall preparations, purified bacterial cell wall peptidoglucans, its water-soluble peptidolglycan fragments, muramyl dipeptides and amphipathic substances. Murine peritoneal exudate macrophages were activated by amphipathic substances of gram-positive bacteria. However, macrophages from mice, irrespective of strains, were not stimulated in the in vitro assay systems by purified bacterial cell wall peptidoglycan, water-soluble bacterial peptidoglycan fragments or muramyl dipeptides. These results suggest that macrophage activation by bacterial peptidoglycan in vitro is animal species specific.

Herpes zoster in patients with sarcoidosis.

108 patients with sarcoidosis were retrospectively studied for the development of herpes zoster. Five of these patients (4.6%), 2 of whom were in their twenties, developed herpes zoster. Only 1 patient had been treated with an oral steroid. All 5 had extrathoracic lesions. Zoster tended to occur during the inactive stage of sarcoidosis and did not exacerbate the activity of the sarcoidosis. The clinical course of their zoster infection was typically benign. There have been few reports of herpes zoster in patients with sarcoidosis. Further studies are required to determine whether sarcoidosis predisposes to herpes zoster infection.

Hypercoagulopathy induced by chemotherapy in a patient with lung cancer. A possible role for a factor with thrombosis-inducing activity (TIA).

We treated a patient with lung cancer in whom a hypercoagulopathy was induced acutely by chemotherapy. He received systemic chemotherapy twice and in both instances developed disseminated intravascular coagulopathy (DIC), accompanied by acute decrements of the peripheral platelet count and plasma fibrinogen, an increment of the fibrin degradation products (FDP), and bleeding tendency with the appearance of skin purpura. In each instance, the plasma thrombosis-inducing activity (TIA) appeared one to three days after chemotherapy and subsided subsequently.

Appearance of thrombosis-inducing activity in the plasma of patients undergoing pulmonary resection.

Thrombosis-inducing activity (TIA) was detected in the peripheral blood of patients with lung cancer who had undergone pulmonary resection. TIA was examined by intravenously injecting plasma from the patients into BALB/c mice. The plasma containing TIA induced multiple thromboses in the lung and caused the mice to die 3 to 30 minutes after injection. The subjects were 19 patients whose plasma contained no TIA before operation. TIA was detected in 5.3 percent (1/19) on the first postoperative day (POD), 47.4 percent (9/19) on the seventh POD, 47.1 percent (8/17) on the 14th POD, 26.7 percent (4/15) on the 21st POD, and 20 percent (2/10) on the 28th POD. Plasma fibrinogen levels and peripheral platelet counts increased postoperatively and reached a maximum on the seventh and 14th POD, respectively. Peripheral blood with TIA had a significant elevation of plasma fibrinogen levels and platelet counts as compared to that without TIA. These observations suggest that TIA is present in blood in a hypercoagulable state in patients after pulmonary resection. Since tumor necrosis factor and interleukin 1 are known to induce hypercoagulable states both in vitro and in vivo, we tried to determine whether it was possible to detect both cytokines in blood indicated as hypercoagulable state by the presence of TIA. They did not, however, reach detectable levels in the blood.

Extracellular ATP itself elicits superoxide generation in guinea pig peritoneal macrophages.

Extracellular ATP itself elicited the generation of superoxide (O2-) in guinea pig peritoneal macrophages associated with an increase in cytosolic calcium ([Ca2+]i). The ATP-induced O2- generation was completely inhibited by pretreatment with pertussis toxin (PT) accompanied by the suppression of [Ca2+]i mobilization. Pre-exposure to a small amount of phorbol myristate acetate (PMA) primed the ATP-induced generation of O2- without a change of [Ca2+]i. The results suggest that ATP-induced O2- generation is mediated by [Ca2+]i mobilization and by PT-sensitive G protein.

Plasma thrombosis-inducing activity in 120 patients with primary lung cancer.

One hundred and twenty patients with primary lung cancer were examined for the presence of thrombosis-inducing activity (TIA) in their plasma. TIA was identified in plasma from 16 of 38 patients with stage 3 (42%) and 31 of 65 patients with stage 4 (48%) disease. On the other hand, only 1 of 17 patients with stages 1 and 2 (6%) showed TIA in their plasma. Cell type did not seem to correlate with the presence of plasma TIA, since TIA was identified in plasma from patients with all cell types. Survival of 32 patients with inoperable non-small cell lung cancer, all stage 4, was studied. The mean survival time was 7.2 months in the TIA-positive group and 10.3 months in the TIA-negative group. This difference was statistically significant.

Thrombosis-inducing activity in plasma of patients with acute respiratory tract infection disappears after treatment.

Thrombosis-inducing activity (TIA) was identified in plasma from 16 of 27 patients (59%) with acute respiratory tract infections. On the other hand, it was present in only 9 of 79 subjects (11%) with chronic lung diseases and 4 of 49 healthy volunteers (8%). In the patients with acute respiratory tract infections, there were significant elevations in plasma fibrinogen, C-reactive protein and erythrocyte sedimentation rate in the TIA-positive group compared with the negative group. Plasma TIA disappeared in all of the 8 patients who were retested for TIA 2-5 weeks after they became disease free. Pneumonia was induced in rabbits by transbronchial injection of viable Escherichia coli. TIA was not present in plasma from normal rabbits, but it appeared in plasma collected 3 days after injection. It then disappeared after 1-2 weeks of treatment with antibiotics. TIA may serve as a marker for inflammatory responses and be a factor responsible for elevated blood coagulation activity in patients with acute infectious diseases.

The in vivo and in vitro use of monoclonal antibody for the deletion of phagocytic cells in guinea pigs.

A monoclonal antibody (MAb) was raised against guinea pig macrophages and its reactivity to bone marrow derived cells was tested. The Ab selectively reacted to phagocytic cells such as polymorphonuclear leukocytes (PMNL) and macrophages, but not to erythrocytes, lymphocytes, hepatocytes and platelets, as determined by the binding and complement-dependent cytolytic activity. In vivo effect of the Ab on peripheral leukocytes was tested. More than 90% of PMNL were deleted 3 hours after the intravenous administration of the antibody. The cells started to reappear in peripheral blood on the 3rd day and returned to the level before the administration on the 6-7th day. Erythrocytes in peripheral blood were not affected. Phytohemagglutinin (PHA) and muramyl dipeptide(MDP) induced proliferation of thymocytes were tested after removal of macrophages by the selective binding of the MAb reactive cells to the plastic dish. Proliferation of the macrophage-deleted thymocytes was significantly suppressed, however, it was restored by addition of a small number of peritoneal macrophages. Those results strongly indicate that the MAb presented here is directed selectively to phagocytic cells of guinea pigs and should prove useful to study both in vivo and in vitro functions of the cells.

[Immunohistochemical studies of collagen types I, III and IV distribution and the expression of procollagen III peptide in papillary carcinomas of the thyroid].

Collagen types I, III and IV and procollagen III peptide (P III P) were examined immunohistochemically in 38 papillary carcinomas of the thyroid. The immunoreactivity to both type I and type III collagen was diffuse and abundantly observed in the fibrous stroma, where it displayed a fibrillar and/or granular pattern with little difference in the intensity of the staining. The immunoreactivity to collagen type IV was localized in the basement membrane of the vessels and partly in the tumor cell nests. A distinctive cytoplasmic immunoreactivity to P III P was observed in the cancer cells and the fibroblasts in all of the 38 papillary carcinomas, specifically an intense and extensive immunoreactivity by the cancer cells present in tumors having fibrosclerosing stroma and/or showing an extensive local invasion. Thus, it is conceivable that stromal collagen in a papillary carcinoma can be produced by not only the fibroblasts but also by tumor cells and its productivity could be affected by the degree of the tumoral invasion.