Platelet activating factor antagonists: synthesis and structure-activity studies of novel PAF analogues modified in the phosphorylcholine moiety.

New analogues of platelet activating factor (PAF), in which the phosphate and trimethylammonium moieties were replaced with an acylcarbamoyl moiety and a quaternary cyclic ammonium group, were synthesized. Their biological activities as PAF antagonists were evaluated by the inhibition of PAF-induced rabbit platelet aggregation in vitro and protective effects on PAF-induced hypotension in rats and PAF-induced death in mice. Investigation of structure-activity relationships revealed that PAF antagonist activity is strongly influenced by the acyl substituent of the nitrogen atom on the carbamoyl group and the nature of the polar head group at the 3-position of the glycerin backbone. Among the compounds tested, 2-[[N-acetyl-N-[[2-methoxy-3-[ (octadecylcarbamoyl)oxy]propoxy]-carbonyl]amino] methyl]-1-ethylpyridinium chloride (21, CV-6209) was one of the most potent compounds in the in vitro assay (IC50 = 7.5 X 10(-8) M) and the most potent and long-lasting in the in vivo assays. (R)-(-)-21 and (S)-(+)-21 were also synthesized, and no significant differences were observed in PAF antagonist activity in vitro and an inhibitory effect on PAF induced hypotension in vivo between (RS)-21 and its enantiomers.

Synergistic antithrombotic properties of G4120, a RGD-containing synthetic peptide, and argatroban, a synthetic thrombin inhibitor, in a hamster femoral vein platelet-rich thrombosis model.

The synergistic antithrombotic properties of G4120, a synthetic Arg-Gly-Asp (RGD) containing peptide which strongly inhibits platelet aggregation, and of Argatroban, a synthetic thrombin inhibitor, were examined in a reproducible quantitative hamster femoral vein platelet-rich mural thrombosis model. Bolus injections of G4120 and Argatroban inhibit thrombus formation in a dose-dependent way; 50% inhibition (ID50) is obtained with 11 micrograms/kg G4120 and with 2 mg/kg Argatroban. Combined bolus injections of 3 micrograms/kg G4120 with 0.5, 0.75 or 1 mg/kg Argatroban and of 1 mg/kg Argatroban with 1.5 or 3 micrograms/kg G4120 caused linear dose-dependent inhibition of thrombus formation, whereas 3 micrograms/kg G4120 or 1 mg/kg Argatroban alone had very little effect (less than 20% inhibition). ID50 was obtained with the combination of 3 micrograms/kg G4120 and 0.5 mg/kg Argatroban, corresponding to an equi-effective fractional combination of 0.62 with a 95% confidence interval of 0.50 to 0.74. Alternatively the ID50 was obtained with the combination of 1 mg/kg Argatroban and 1.3 micrograms/kg G4120, corresponding to an equi-effective fractional combination of 0.52 with a 95% confidence interval of 0.18 to 0.86. In both instances these results are indicative of a significant synergistic interaction. Bolus injection of 10 mg/kg aspirin, 100 U/kg heparin or the combination did not inhibit thrombus formation. The synergistic effect of the combination of platelet inhibiting RGD-peptides and synthetic thrombin inhibitors could be useful in the prevention of arterial occlusion with platelet-rich thrombus in patients with ischemic heart disease following thrombolytic therapy or angioplasty, although this combination is not expected to reverse platelet thrombus formation.

Inhibition by CV-3988 of the binding of [3H]-platelet activating factor (PAF) to the platelet.

The inhibitory effects of CV-3988, a specific antagonist of PAF, on the binding of [3H]-PAF to washed platelets of various species including human were examined. The dissociation constant (Kd), binding capacity (Bmax), and the number of receptor/platelet for the specific binding site of rabbit platelets were 2.2 +/- 0.2 nM, 93.7 +/- 8.3 fmoles/10(8) platelets, and 568 +/- 50, respectively. CV-3988 selectively inhibited the specific binding of [3H]-PAF to rabbit platelets with an IC50 of 7.9 X 10(-8) M, and it slightly increased the Kd value (2.5 +/- 0.8 nM) and decreased the binding capacity for PAF (Bmax: 54.3 +/- 16.3 fmoles/10(8) platelets). The Ki value of CV-3988 for the specific binding of [3H]-PAF to rabbit platelets was 1.2 X 10(-7) M. CV-3988 had no effects on the binding of [3H]-5-hydroxytryptamine (5-HT) to rabbit platelets and on the shape change of the platelet induced by 5-HT. CV-3988 also inhibited the specific binding of [3H]-PAF to human and guinea-pig platelets with IC50 values of 1.6 X 10(-7) and 1.8 X 10(-7) M, respectively. CV-3988 inhibited the PAF-induced aggregation in rabbit, guinea-pig, and human platelets. These findings show that CV-3988 is a specific antagonist of PAF at the receptor site(s) of platelets and, in these species, inhibits PAF-induced platelet aggregation by inhibiting the binding of PAF to the "PAF receptor". No specific binding of [3H]-PAF to the platelet of rats and mice was observed, indicating that these species lack a PAF receptor.

Effects of candesartan cilexetil (TCV-116) and enalapril in 5/6 nephrectomized rats.

The renal protective properties of candesartan cilexetil (TCV-116), an angiotensin II type 1 receptor antagonist (AT1A), and enalapril, an angiotensin I converting enzyme inhibitor (ACEI), were investigated in 5/6 nephrectomized (NX) rats. Candesartan cilexetil (1 mg/kg/day) and enalapril (10 mg/kg/day) were administered orally to 5/6 NX rats for four weeks (during the early phase of disease development) or 16 weeks (through the late phase). In vehicle-treated rats, proteinuria, glomerulosclerosis, interstitial mononuclear cell (MNC) infiltration and interstitial fibrosis developed. Moreover, immunohistological studies showed enhanced expression of transforming growth factor-beta 1 (TGF-beta 1) in the injured glomeruli. Both drugs inhibited these adverse changes in the early phase. In the late phase, the progressive proteinuria, interstitial MNC infiltration were attenuated by both drugs. However, candesartan cilexetil significantly inhibited the progression of glomerulosclerosis, the expression of TGF-beta 1 and the interstitial fibrosis, while enalapril did not. Candesartan cilexetil and enalapril showed comparable hypotensive effects after the 16-week administration. These results indicate that candesartan cilexetil shows a more potent protective effect than enalapril against the progression of renal injury in the late phase. Thus, an AT1A might be more useful than an ACEI for the treatment of patients with chronic renal failure.

The thromboxane A2/prostaglandin endoperoxide receptor antagonist activity of CV-4151, a thromboxane A2 synthetase inhibitor.

The thromboxane A2/prostaglandin endoperoxide (TXA2/PGH2) receptor antagonist activity of CV-4151, a potent TXA2 synthetase inhibitor, was examined. CV-4151 inhibited guinea pig and human platelet aggregation induced by U-44069 with IC50 values of 1.2 +/- 0.3 X 10(-5) and 1.9 +/- 0.4 X 10(-5) M, respectively, and inhibited the specific binding of [3H]U-46619 to washed guinea pig and human platelets with IC50 values of 1.2 +/- 0.3 X 10(-6) and 5.1 +/- 1.0 X 10(-6) M, respectively. CV-4151 competitively inhibited the contraction of rabbit aortic strips induced by U-44069 with a pA2 value of 5.90. In experiments in mice in vivo, CV-4151 (1 and 10 mg/kg i.v.) significantly inhibited the thrombocytopenia induced by U-44069 in a dose-dependent manner. These results show that CV-4151 has a distinct TXA2/PGH2 receptor antagonist effect, and that this effect together with its inhibition of TXA2 synthetase could be important for the pharmacological action of this compound.

Is platelet activating factor (PAF) a mediator of endotoxin shock?

To determine whether endogenous PAF contributes to the pathogenesis of endotoxin shock, CV-3988, a specific PAF antagonist, was injected i.v. to rats before, simultaneously with or after endotoxin. CV-3988 (5 mg/kg i.v.) injected 5 min before the endotoxin completely inhibited endotoxin (15 mg/kg i.v.)-induced hypotension, and CV-3988 (0.05-1 mg/kg i.v.) injected 7-10 min after the endotoxin rapidly reversed endotoxin-induced hypotension. A combination of CV-3988 (10 mg/kg) with endotoxin (5 mg/kg) administered i.v. improved the survival rate for 20 h or more. CV-3988 (0.05-1 mg/kg i.v.) rapidly reversed the PAF (1 microgram/kg i.v.)-induced hypotension. These findings strongly suggest that endogenous PAF may play a pivotal role in the pathogenesis of endotoxin shock.

The role of thromboxane (TX) A2 in rabbit arterial thrombosis induced by endothelial damage.

To clarify the role of thromboxane (TX) A2 in arterial thrombus formation, we examined the antithrombotic effects of both a TXA2 synthetase inhibitor (CV-4151) and a TXA2 receptor antagonist (AA-2414) on the rabbit common carotid artery thrombosis which was induced by injury of the endothelium by treatment with 0.25% pronase solution. CV-4151 (1,10 mg/kg, p.o.) and AA-2414 (10 mg/kg, p.o.) significantly inhibited thrombus formation. Furthermore, the combined use of CV-4151 and AA-2414 (0.1 mg/kg, p.o. each) significantly inhibited thrombus formation, though these drugs at the same doses had no effect when administered singly. The plasma level of 11-dehydro TXB2 increased significantly during thrombus formation, and CV-4151 (10 mg/kg) markedly inhibited this increase. There was a significant correlation between the in vivo antithrombotic effects of these drugs and their ex vivo inhibitory effects on arachidonic acid-induced platelet aggregation. The antithrombotic effect of CV-4151 also correlated significantly with its ability to inhibit the production of serum TXA2. These results show that TXA2 may play an important role in the thrombus formation in arterial thrombosis.

Inhibitory effect of TCV-309, a novel platelet activating factor (PAF) antagonist, on endotoxin-induced disseminated intravascular coagulation in rats: possible role of PAF in tissue factor generation.

The possible involvement of platelet activating factor (PAF) in the pathogenesis of endotoxin-induced disseminated intravascular coagulation (DIC) was investigated in rats using a novel potent PAF antagonist, TCV-309. TCV-309 (> 1 mg/kg, i.v.) showed beneficial effects in rats with experimental DIC induced by a 4-hour sustained infusion of endotoxin (1 mg/kg) in a dose-dependent manner. TCV-309 (1 mg/kg) significantly ameliorated the decrease in platelet count and plasma fibrinogen, the prolongation of prothrombin time (PT) and activated partial thromboplastin time (APTT) and the increase in fibrin and fibrinogen degradation products (FDP) and inhibited glomerular fibrin deposition. Furthermore, plasma tissue factor (TF) activity was greatly increased in the DIC rats, and this was also significantly decreased by TCV-309 (1 mg/kg). TCV-309 (1 mg/kg) did not affect these parameters in normal rats. A 4-hour sustained infusion of PAF (60 micrograms/kg) caused mild but significant changes in some DIC parameters such as PT, fibrinogen and FDP concentration and increased the plasma TF activity. TCV-309 (1 mg/kg) inhibited all these PAF-induced changes. TCV-309 (0.1 mM) itself had no direct in vitro effects on the blood coagulation system including TF activity. These results strongly suggest that PAF plays a role in the pathogenesis of endotoxin-induced DIC via the generation of TF. Prophylactic use of PAF antagonists may therefore be useful for the treatment of DIC with sepsis.

Effects of thromboxane A2 synthase inhibitors (CV-4151 and ozagrel), aspirin, and ticlopidine on the thrombosis caused by endothelial cell injury.

The antiplatelet and antithrombotic effects of CV-4151 (isbogrel), a potent selective thromboxane A2 (TXA2) synthase inhibitor, were compared with those of ozagrel (OKY-046), aspirin, and ticlopidine in rats. Two hours after oral administration, CV-4151, ozagrel and aspirin inhibited blood TXA2 generation with ID50 values of 0.04, 0.3 and 6.4 mg/kg, respectively. These values were similar to the oral ID50 values of CV-4151 (0.06 mg/kg), ozagrel (0.92 mg/kg) and aspirin (7.0 mg/kg) for arachidonic acid (AA)-induced platelet aggregation ex vivo. Two hours after p.o. administration, CV-4151 and ozagrel inhibited femoral vein platelet-rich thrombosis caused by endothelial injury with ID50 values of 2.46 and 13.7 mg/kg, respectively. However, aspirin (100 mg/kg, p.o.) only slightly inhibited the thrombosis. Ticlopidine (300 mg/kg, p.o.) slightly but significantly inhibited AA-induced and ADP-induced platelet aggregation, however, it potently inhibited the thrombosis. CV-4151 and ozagrel given by i.v. injection showed therapeutic effects on the thrombosis with ED50 values of 0.026 and 0.066 mg/kg, respectively. These values were similar to the i.v. ED50 values of CV-4151 (0.0056 mg/kg) and ozagrel (0.042 mg/kg) for blood TXA2 generation. However, aspirin (30 mg/kg, i.v.) only moderately reduced the thrombosis. CV-4151 (> 0.3 mg/kg, p.o.), ozagrel (> 3 mg/kg, p.o.) and ticlopidine (300 mg/kg, p.o.) all significantly prolonged tail bleeding time. Aspirin (100 mg/kg, p.o.) tended to prolong the bleeding time. The antiplatelet and antithrombotic effects of CV-4151 are more potent than those of ozagrel, aspirin and ticlopidine in rats. CV-4151 may therefore be a useful drug for the treatment of thrombotic diseases.

Beneficial effect of CV-4151 (Isbogrel), a thromboxane A2 synthase inhibitor, in a rat middle cerebral artery thrombosis model.

Effects of thromboxane A2 (TXA2) synthase inhibitors (CV-4151 and ozagrel) on cerebral thrombosis and cerebral damage were examined in a rat middle cerebral artery (MCA) thrombosis model and their potencies were compared with the conventional antithrombotic agents, aspirin and ticlopidine. CV-4151 significantly inhibited photochemically induced MCA thrombosis by oral (1 and 10 mg/kg) and intravenous (1 mg/kg) administration. Ozagrel (10 mg/kg, p.o.) also inhibited it. The potency of CV-4151 was about 10 times stronger than that of ozagrel, being comparable with the inhibition of blood TXA2 generation. Aspirin (100 mg/kg, p.o.) and ticlopidine (300 mg/kg, p.o.) showed an inhibitory tendency on MCA thrombosis. Twenty-four h after photochemical stimulation, cerebral edema and cerebral infarction were observed, and the lactate content in the brain increased. CV-4151 and ozagrel prevented this edema, and the antiedema effects of the drugs were correlated with the antithrombotic effect on thrombotic MCA occlusion. CV-4151 (10 mg/kg, p.o.), furthermore, significantly reduced the infarct size and inhibited the increase in lactate content. These results indicate that TXA2 synthase inhibitors inhibit cerebral damage by inhibition of MCA occlusion with thrombosis, probably resulting from the inhibition of TXA2 generation, and their effects are superior to those of aspirin and ticlopidine. TXA2 might play an important role in cerebral damage in the MCA thrombosis model. CV-4151 might be a useful drug for the treatment of cerebral thrombosis and for the prevention of cerebral infarction.

CV-4151--a potent, selective thromboxane A2 synthetase inhibitor.

(E)-7-Phenyl-7-(3-pyridyl)-6-heptenoic acid (CV-4151) inhibited horse platelet microsomal thromboxane (TX) A2 synthetase with an IC50 of 2.6 X 10(-8) M, but even at a high concentration of 10(-4) M it had little effect on cyclooxygenase, PGI2 synthetase and 5-lipoxygenase in in vitro enzymatic assays. CV-4151 did not affect PGI2 release from rat and rabbit aortic tissues in in vitro (10(-4) M) and ex vivo (10 and 100 mg/kg, p.o.) experiments, whereas aspirin (10(-4) M or 10 and 100 mg/kg, p.o.) markedly inhibited PGI2 release in these preparations. When given orally to rats and dogs, CV-4151 markedly inhibited blood TXA2 synthetase activity: the ID50 values (mg/kg, 2 hr later) were 0.05 in rats and 0.17 in dogs. The inhibitory effects at an oral dose of 1 mg/kg lasted more than 24 hr in both species; the inhibition was 41% in rats and 32% in dogs 24 hr after the administration. When injected i.v. to rats and dogs, CV-4151 caused inhibitory effects on TXA2 synthetase equipotent to those observed with the oral administration. In both species, CV-4151 given orally increased concentration of serum immunoreactive 6-keto-PGF1 alpha concomitant with a decrease of serum TXB2-8 concentration. CV-4151 was equipotent to OKY-1580 (IC50: 2.3 X 10 M), a well documented TXA2 synthetase inhibitor, in an in vitro TXA2 synthetase assay. However, CV-4151, given orally or i.v. to rats and dogs, was much more potent and longer acting in inhibition of blood TXA2 production than OKY-1580. Dazoxiben was less potent than these compounds in vitro. In rats, serial oral administration of CV-4151 (10 mg/kg) once daily for 14 days produced a constant and marked reduction of serum TXB2 concentration with concomitant increase of serum immunoreactive 6-keto-PGF1 alpha concentration. No rebound phenomenon in inhibition of TXA2 synthetase was observed after the dosing was stopped. These findings indicate that CV-4151 is a potent and long acting selective inhibitor of TXA2 synthetase and may reorient the metabolism of PG endoperoxides to PGI2.

Possible role of platelet activating factor (PAF) in disseminated intravascular coagulation (DIC), evidenced by use of a PAF antagonist, CV-3988.

The i.v. infusion of endotoxin (ET) (0.25 mg/kg/hr for 4 hr) induced disseminated intravascular coagulation (DIC) in rats; thrombocytopenia, prolongation of prothrombin time (PT) and partial thromboplastin time (PTT), hypofibrinogenemia and elevated levels of fibrinogen/fibrin degradation products (FDP) were observed. Platelet activating factor (PAF) (8 micrograms/kg/hr for 4 hr) also induced DIC-like changes, except in platelets. A specific PAF antagonist, CV-3988 (2 mg/kg bolus 5 min before ET + 1 or 2 mg/kg/hr for 4 hr of ET infusion) improved all the parameters that had been altered by both ET and PAF. CV-3988 (2 mg/kg bolus 2 hr after ET + 2 mg/kg/hr for 2 hr of ET infusion) also had beneficial effects on DIC. CV-3988 itself had no effects on the parameters of DIC. These results strongly suggest that PAF may play a role in the pathogenesis of DIC and CV-3988 may prove to be useful for the treatment of DIC.

Endothelin-induced sudden death and the possible involvement of platelet activating factor (PAF).

Endothelin (5 nmol/kg, i.v.) caused a transient hypotension followed by a lasting hypertension in rats. However, an abrupt fall in the blood pressure was observed in most rats 6 to 30 min after the injection of endothelin and sudden death followed with lethality noted over 60 min. An abnormal electrocardiogram (ECG) (ventricular arrhythmias) was observed in rats injected with endothelin. Endothelin (i.v.) also caused sudden death in mice. Pretreatment (5 or 60 min) with specific PAF antagonists, CV-6209 (0.1-3 mg/kg, i.v.) and WEB 2086 (30 mg/kg, p.o.), and a calcium channel blocker, diltiazem (60 mg/kg, p.o.) prevented death and attenuated the ECG changes induced by endothelin, but CV-6209 did not prevent the blood pressure changes induced by endothelin. CV-6209 (0.5-3 mg/kg, i.v.), WEB 2086, diltiazem and dexamethasone (5 mg/kg, i.v.) protected mice against the death induced by endothelin. On the other hand, aspirin (cyclooxygenase inhibitor, 100 mg/kg, p.o.) did not protect mice from the death. Thus, endothelin is a highly toxic peptide with cardiotoxic effects, and PAF may be involved in the pathogenesis of the sudden death.

Microchimerism in female renal transplant recipients from male donors.

Microchimerism in 23 female renal transplant recipients from male donors was studied using nested polymerase chain reaction (nPCR) and fluorescence in situ hybridization (FISH) to detect Y-chromosome. nPCR was a sensitive and specific assay enabling a detection rate of 1/10(6) male/female cells, compared with a sensitivity of 1/10(2) by standard PCR (sPCR). None of the 23 patients with a male allograft demonstrated Y-chromosome using sPCR. In contrast, 1 3 (56.5%) patients demonstrated Y-chromosome with nPCR. Of 9 patients proven to have microchimerism by nPCR, only 3 also demonstrated Y-chromosome using FISH. The existence of B cells and CD8 cells in donor chimeric cells were proved by separation with Dynabeads class I and class II. Dynamic changes of microchimerism occurred in 4 of 5 patients. Four patients were proven to have microchimerism within a year of transplantation and the microchimerism later disappeared in 3, although the sequential change was variable in individual patients. There was no correlation between microchimerism and patients'clinical factors such as donor-specific blood transfusion, HLA matching, immunosuppression, past history of acute rejection and chronic rejection. The degree of microchimerism in renal transplant recipients was relatively low, and its existence did not seem to be compatible with long-term graft acceptance. However, further studies are required to elucidate the immunological mechanism of microchimerism, and it might be an important clue to immunological tolerance.

Pulmonary multiple metastases of ovarian granulosa cell tumor 15 years after initial diagnosis.

We report a case of multiple pulmonary metastases occurring 15 years after an ovarian granulosa cell tumor was initially diagnosed. A 62-year-old woman undergoing left salpingo-oophorectomy for a granulosa cell tumor of the left ovary 15 years earlier presented with abnormal chest shadows. Computed tomography of the chest confirmed the presence of 3 well-defined nodular lesions, and Computed tomography of the abdomen and pelvis revealed a 3.5 x 2.5 cm partially solid, cystic pelvic mass. Left thoracotomy was conducted and tumors diagnosed a pulmonary metastases of a granulosa cell tumor. The pelvic mass was resected and infracolic omentectomy then conducted with total hysterectomy and right salpingo-oophorectomy including the adherent rectal segment. The pelvic mass proved to be a granulosa cell tumor. Adjuvant combination chemotherapy was started every 3 weeks and the woman has remained disease-free for 9 months.

[Cavernoplasty for pulmonary aspergillosis associated with restrictive ventilatory impairment].

Nine patients were diagnosed as suffering from localized pulmonary aspergillosis associated with restrictive ventilatory impairment. Eight cases reportedly received a combination of thoracoplasty and cavernoplasty, while one case received only cavernoplasty. The following postoperative courses were observed in these nine patients: of the eight patients having combined thoracoplasty and cavernoplasty, seven patients were cured as the result of successful cavity closures. Cavernotomy was required for the remaining patient whose cavity failed to close. An attempt was made to close the cavity of the one patient reported to have only cavernoplasty, but the cavity failed to close on the first attempt. The cavity was successfully closed in a later attempt using thoracoplasty. Although the application of thoracoplasty and cavernoplasty is useful and safe to the treatment of patients being unable to undergo resection and/or having pulmonary dysfunction, it is very important to reduce the number of ribs being resected because pulmonary function may be more worsened after operation. A combination of extraperiosteal detachment and cavernoplasty seems to be a useful alternative. A lower limitation of the postoperative ventilation function, evaluated as a ratio of FEV1.0/VCpr is thought to be 20%.

[Surgical treatment of pulmonary aspergilloma--with modified conservative operation].

During the past 10 years 26 patients were operated on for pulmonary aspergilloma (20 males and six females, mean age of 55.8 years). Lung resections were performed on 13 cases (Group 1). Conservative operations were performed on the remaining cases, including one bilateral operation case (Group 2). New paragraph. The operative techniques in Group 1 were: lobectomy 11 cases of lobectomy, one case of partial resection; and one case of segmental resection. The operative techniques for Group 2 were; five cases of thoracoplasty and cavernoplasty; three cases of thoracoplasty plus cavernoplasty and muscle flap; three cases of thoracoplasty and muscle flap; one case of thoracoplasty and air-plombage; and two cases of cavernoplasty. A second operation was required in four and seven cases in Groups 1 and 2, respectively, and a third operation in two and four cases respectively. The conservative technique was used in all of additional operations required. The mean operation time and amount of blood loss were 262 min and 1,943 ml for Group 1 and 170 min and 918 ml for Group 2-being shorter and lesser for Group 2. Both the operation time and blood loss were reduced during the second and third operations. Reduction of %VC after the first operation was also less remarkable for Group 2 (-9.6%, No = 9). The advantage of using a conservative technique is that successful results can be expected without insult to the hilus and mediastinal surface in cases with compromised pulmonary functions, or in those cases which pneumonectomy or resection is difficult because of the risk of massive bleeding.(ABSTRACT TRUNCATED AT 250 WORDS)

[One case of chronic pyothorax with MRSA infection cured by air-plombage method].

It is very difficult to cure a chronic pyothorax with MRSA infection. We experienced one such case with low pulmonary function (VC 1700 ml, %VC 50.7%), 73 years old man, who had a history of esophageal cancer and was operated two years ago. As the control of bacteria and the surgical intervention are both important in the treatment of pyothorax cases, we tried to reduce MRSA by washing with Povidone-Iodine solution through the drain. Then, we selected Air-plombage method as it is expected to maintain or to increase the pulmonary function after operation. We could easily close the bronchial fistula with a muscle flap, as it was located at the centre of the cavity. During the operation we frequently used acidic electrolyzed NaCl solution against MRSA. For one month after the operation, we used Vancomycin which is effective against MRSA, however, rather severe side effects were seen, and finally and MRSA vanished. Pulmonary function has improved from the initial VC 1700 ml, %VC 50.7% to VC 2120 ml, %VC 63.6% one year later. We recommend Air-plombage method for such cases with low pulmonary function under the control of MRSA by using acidic solution.

[A case of pulmonary aspergillosis complicated with perforated empyema--indication of thoracoplasty, cavernoplasty and extraperiosteal detachment].

We reported one case of pulmonary aspergillosis secondary to pulmonary tuberculosis, which perforated to the pleural space and was complicated with chronic empyema. We performed thoracoplasty, cavernoplasty and extraperiosteal detachment. The type and indications of cavernoplasty we use are also described.

[A case of empyema after plastic ball plombage cured by air-plombage method].

Conventionally, thoracoplasty has been conducted for empyema space after removal of plastic ball for empyema cases after plastic ball plombage. We applied air-plombage method for empyema as a new operative technique. The patient was a 56-year-old man who had had 37 plastic balls implanted for the treatment of pulmonary tuberculosis 39 years ago. In April 1988 he was admitted to our department complaining bloody sputum and high fever. Roentogenographic findings revealed residual middle lobe with normal size and plastic balls some with niveau. From these findings, the case was diagnosed as partial empyema after plastic ball plombage. In June 1988 air-plombage method was performed. At 5 months after operation, reinflation of the residual pulmonary lobe was seen accompanying improvement of pulmonary functions; FVC increased from 1780 ml to 1910 ml and blood gas PaO2 from 75.0 mmHg to 88.3 mmHg. Blood loss during operation was about 2,000 ml, which was smaller than the conventionally experienced amount of blood loss. Because of residual right middle lobe, pulmonary decortication was impossible and significant reinflation of the collapsed pulmonary lobe could not be expected. We selected air-plombage method rather than thoracoplasty as postoperative worsening of pulmonary functions was anticipated by the latter. Postoperative improvement of pulmonary functions could be explained by reinflation of the residual lobe due to removal of plastic balls and the capsule. When conventional thoracoplasty is carried out to obtain satisfying closure of the empyema cavity, pulmonary functions are always deteriorated, while air-plombage method is followed by slight improvement of pulmonary functions.(ABSTRACT TRUNCATED AT 250 WORDS)