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We report the case of a 46-year-old Japanese woman diagnosed with Stage Ⅳ right breast cancer, cT1cN1M1(ovarian and peritoneal metastases). We administered bevacizumab+paclitaxel as the first-line treatment. In the 13th course, the peritoneal dissemination progressed, and the regimen was changed to eribulin(1.4 mg/m2)as the second-line treatment. During the second course, abdominal distension developed and was resolved during follow-up. However, abdominal distension and pain were observed from day 9 of the fourth course. Based on the results of blood chemistry and CT scans, she was diagnosed with acute pancreatitis(CT Grade 1)and was admitted to the hospital. After fasting and fluid replacement therapy, her clinical symptoms and laboratory data improved, and was discharged from the hospital 8 days later. She had no history of excessive alcohol consumption and no evidence of biliary disease, and was considered having eribulin-induced pancreatitis.

Parkinson's disease is a neurodegenerative disorder characterized by the degenerative loss of dopaminergic neurons in the substantia nigra. Dopamine deficiency is thought to disrupt motor control of the basal ganglia and cause characteristic motor symptoms in Parkinson's disease such as bradykinesia, akinesia, and tremor. Therefore, dopamine replacement therapy is widely used in the clinical setting. Safinamide is a novel, selective, and reversible inhibitor of monoamine oxidase B expected to increase dopamine levels in the brain and improve the symptoms of Parkinson's disease. In addition, safinamide shows non-dopaminergic actions such as sodium channel blockade and inhibition of glutamate release. Preclinical studies have demonstrated that safinamide ameliorates "wearing off" symptoms after administration in rat and monkey models with selectively destroyed dopaminergic neurons. In the monkeys, safinamide concurrently inhibited levodopa-induced dyskinesia. These findings suggest that safinamide not only increases the dopaminergic effect of levodopa, but also reduces levodopa-induced adverse events via its non-dopaminergic effects. In clinical trials of patients with Parkinson's disease with the "wearing off" phenomenon, safinamide has been found to prolong the "on time" and improve motor function as assessed by Unified Parkinson's Disease Rating Scale Part III. In Japan, safinamide was approved in September 2019 as a levodopa combination drug for Parkinson's disease with "wearing off" phenomenon. Safinamide is therefore expected to be a new treatment option for patients with Parkinson's disease.

It is often necessary to modify the dose or schedule of eribulin mesilate (Eri) because of adverse events. Therefore, we retrospectively investigated the optimal approach for Eri dose adjustment and/or dosage interval adjustment. Patients who received Eri at the institutions affiliated with the Division of Oncology of the Aichi Prefectural Society of Hospital Pharmacists between July 2011 and November 2013 were enrolled in this study. We compared the group that underwent dose reduction without changes to their dosage interval (dose reduction group) with the group that had a change in their dosage interval (dose-interval prolongation group). The primary end-point was time to treatment failure (TTF), and the secondary end-points were overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), and adverse events. The TTF and OS of the dose reduction group were approximately two times longer than those of the dose-interval prolongation group. In addition, the dose reduction group had significantly improved ORR and CBR, which together indicate an antitumor effect (p=0.013 and 0.002, respectively). Although peripheral neuropathy occurred significantly more frequently in the patients in the dose reduction group (p=0.026), it was grade 1 and controllable in most of the cases. There were no differences in the occurrence of other adverse effects between the two groups. Therefore, we suggest that dose reduction with maintenance of the dosage interval is the preferred treatment approach in cases where Eri dose or schedule modification is necessary.

Recombinant human soluble thrombomodulin (rTM) is a new drug for the treatment of disseminated intravascular coagulation (DIC), although the effects on obstetric DIC have not yet been fully elucidated. We report herein three patients with obstetric DIC caused by placental abruption, hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, and atonic bleeding, respectively. In all three cases, treatment with rTM proved successful, suggesting that rTM is an efficient method for treating obstetric DIC.

We present a 53-year-old man who underwent proximal gastrectomy for gastric gastrointestinal stromal tumor (GIST) in August 2005. Imatinib mesilate (imatinib) 400 mg/day was started in February 2006 for left adrenal metastasis. Tumor size markedly decreased by April 2006, but medication had to be discontinued due to a pruritic rash. A distal pancreatectomy, splenectomy, and left adrenectomy were performed in August for recurrent adrenal metastases. Imatinib 200 mg/day started postoperatively was discontinued immediately due to fever and pruritus. Local recurrence with peritoneal dissemination was found in February 2007. Imatinib 100 mg/day with prednisolone (PDL) 5 mg/day was discontinued in two days due to pruritic dermatitis. Imatinib 200 mg/day with PDL 40 mg/day was restarted in April due to an increase in tumor size. Treatment continued without obvious side effects, and PDL dosage was tapered to 10 mg/day. The tumor was no longer visible on CT in May 2008, and complete response is being maintained as of August 2009.

We calculated achievement rates of target attainment of AUC/MIC using Monte Carlo simulation (MCS). Two doses of pazufloxacin mesilate (PZFX) between q.d. and b.i.d. were compared for each species of bacterium. Concentrations for AUC of PZFX of 8 patients were measured at this hospital, and those from a phase I clinical study (phase I, 6 healthy volunteers) were used. MICs of PZFX were determined for each species of bacterium of respiratory organ origin (Pseudomonas aeruginosa, Haemophilus influenzae, Streptococcus pneumoniae, and Klebsiella pneumoniae). AUC per day of 500 mg b.i.d. used twice AUC (PZFX 500 mg x 2/day by patient, PZFX 500 mg x 2/day by phase I). Target attainment of AUC/MIC was AUC/MIC > or = 30 in S. pneumoniae and AUC/MIC > or = 125 in the other species of bacteria (P. aeruginosa, H. influenzae, and K. pneumoniae). As a result, patients showed an about 3 times higher AUC than the phase I subjects (67.9/21.9 microg/mL). In addition, the target attainment of AUC/MIC showed the highest rate in PZFX 500 mg x 2/day in patients with each type of bacteria: H. influenzae (98%), K. pneumoniae (89%), S. pneumoniae (66%), and P aeruginosa (41%). Target attainment of AUC/MIC was H. influenzae (91%), K. pneumoniae (81%), P. aeruginosa (5%), and S. pneumoniae (0%) in phase I. Therefore, the effectiveness of PZFX was estimated to be low using the MCS method with the phase I data.

We report a case of hyperkalemia in a recipient of living-related liver transplantation. The patient received a continuous infusion of gabexate mesilate at 60 mg x hr(-1) starting about 1 hr after the induction of anesthesia. The serum potassium concentration (K+) was increased from 4.53 mEq x l-(1) to 5.08 mEq x l(-1) within about 1 hr. Thereafter, a massive blood loss caused by an accidental damage of the portal vein necessitated rapid fluid therapy to maintain blood pressure. We observed an abnormal ECG recording including a wide QRS complex and a high T wave when about 30 units of leukocytes-reduced red cell concentrates had been transfused. Blood gas analysis showed high K+ (7.52 mEq x l(-1)) and metabolic acidosis (pH 7.167, base excess-12.5 mmol x l(-1)). We successfully controlled K+ with combination of therapies before causing any cardiac events to the patient. Gabexate mesilate is one possible cause of hyperkalemia in the present case because an increase in K+ was observed before transfusion, and transfusion might have augmented the effect. Gabexate mesilate is one of the protease inhibitors. Naphamostat mesilate, another protease inhibitor, is known to cause hyperkalemia by limiting potassium excretion from the kidney through an inhibition of Na/K-ATPase at the cortical collecting ducts. Although the mechanism by which gabexate mesilate causes hyperkalemia is unclear, it would be of benefit to use this drug cautiously, as it may cause hyperkalemia.

We report a patient who long had a complete response by chemotherapy with imatinib mesilate(IM)for locally recurrent gastrointestinal stromal tumor(GIST)of the stomach. On July 2000, a 58-year-old woman was pointed out to have anemia in the course of surveillance for malignant melanoma of skin. Endoscopic examination revealed continuous bleeding from a submucosal tumor with ulceration on the posterior wall of the stomach. After endoscopic homeostasis failed, emergency laparotomy was performed and a biopsy was also done. The diagnosis made was GIST from immunohistological findings of positive c-kit, positive CD34, negative HMB45, and negative S100. After diagnosis, total gastrectomy, distal pancreatectomy, and splenectomy were performed. On September 2003, a local recurrence was recognized, and then chemotherapy by 400 mg IM daily was started. After beginning with a dose of IM 400 mg daily, the reduction of the tumor was monitored. The IM dose then had to be reduced to 300 mg daily. Because of the adverse side effects of IM, systemic edema and body weight increased. After reduction of IM, the adverse reactions resolved promptly, and a complete response of the primary tumor has been maintained for 4 years 3 months.

Patients with chronic respiratory disease have increased susceptibility to infection, because of impairment of the local immunologic defense mechanism in the airway system, which often results in acute exacerbation. Acute exacerbation of chronic respiratory disease is one of the most important predictors of increased morbidity and mortality, and thus the management in the acute phase is essential for better prognosis. Although the clinical guidelines for the management of respiratory tract infections published by the Japanese Respiratory Society recommend administering fluoroquinolones intravenously in case of hospitalized patients, the clinical evidence is still limited. In this study, we evaluated the efficacy of Pazufloxacin Mesilate (PZFX). an intravenous fluoroquinolone. in patients with chronic respiratory diseases complicated with acute exacerbation caused by acute respiratory infections. As a result, 16 out of 18 cases were successfully treated with PZFX. No adverse event was observed during this study. These results may support the validity of administering intravenous fluoroquinolone in hospitalized patients with acute exacerbation caused by infections, as recommended by the Japanese Respiratory Society.

Restless legs syndrome (RLS) is one of the common nocturnal disturbance seen in Parkinson's disease (PD) patients. The prevalence of RLS with PD is greater than that of general populations; however, etiology of RLS in patients with PD is still controversial. We report a 63-year-old man with PD, who was admitted to our hospital with uncontrollable unpleasant feeling in both legs leading to sleep disturbance. At age 59, he experienced numbness and nocturnal myoclonus in his right foot. One year later, he developed resting tremor and bradykinesia in his right hand, and was diagnosed as PD. Levodopa was initiated with favorable response for his resting tremor and bradykinesia, however, his dysesthesia of the legs spread to both side and associated with an urge to move which occurs at rest and was ameliorated by walking. On admission, his parkinsonism was well controlled by 400 mg/ day of levodopa/benserazide. Polysomnography (PSG) revealed periodic limb movements in sleep (PLMS). Secondary RLS such as drug-induced, iron deficiency and uraemia, was excluded in this patient. Because levodopa did not improve his RLS, additional symptomatic RLS treatment was initiated. Oral dosage with 150 microg pergolide did not have any effect on his RLS symptoms. An increase up to 750 microg pergolide led to a marked reduction of symptoms. Repeated PSG showed significant reduction of PLMS and improved sleep efficacy. Usually, low dose of dopamine agonist is enough to treat RLS occurred in general populations. However, moderate to high dose of dopamine agonists were needed for our patient with RLS, indicating that pharmacological responses might be different between RLS in general and that associated with PD. It is important to consider that PD-related RLS can be treated with high dose dopamine agonist to obtain favorable management of nocturnal disturbances.

Middle and lower esophagectomy was performed in a 68-year-old man in 1997 for the local recurrence of esophageal submucosal tumor after enucleation of the tumor. We subsequently performed partial hepatectomy for multiple liver metastases in 2001. The tumor was first diagnosed as GIST in the histological examinations of the liver metastases. However, 12 months after the hepatectomy, further recurrent lesions were found in multiple lymph nodes, in the remnant liver, and in the pancreas, as well as in the subcutaneous tissue. The lesions were initially considered unresectable, and we thus started an internal use of Glivec (400 mg/day) since July 2004. Within 2 months,all detected recurrent lesions changed into liquid forms,and the size of the subcutaneous tumor was also remarkably reduced. Accumulation of FDG was not seen on FDG-PET examination, suggesting the complete response of the tumor to Glivec. We still continue internal use of Glivec, and new recurrent lesions have not been detected up to now. Furthermore, the sizes of the liquid-regenerated lesions are gradually reducing.

A 65-year-old man is presented here with a huge mass of 13 cm in diameter in the left upper abdomen. Histopathologic assessment of endoscopic forceps biopsy revealed a c-kit positive gastrointestinal storomal tumor (GIST) of the stomach. Abdominal computed tomography (CT) showed a direct invasion to the pancreas. Imatinib mesilate was administered as neoadjuvant therapy according to the NCCN Guidelines. Imatinib mesilate therapy was stopped within 2 weeks because of adverse events such as Grade 2 of facial edema and dizziness. However, no hematological adverse event was shown. After three months of treatment (relative dose intensity was 87.5%), CT revealed a reduction in tumor diameter of 35.6% and showed no longer a direct invasion to the pancreas. The radical operation was considered feasible and partial gastrectomy was performed. The tumor was well encapsulated and radical surgery was possible without rupture. Adjuvant therapy was not performed. The patient has now been in good health without a recurrence for three months after the surgery.

A 78-year-old woman was admitted to our hospital because of tarry stools. A gastric stromal tumor with liver metastasis was diagnosed. Treatment with imatinib mesilate was begun in a dose of 400 mg daily. After 1 month, the primary tumor showed a partial response; the response of the liver metastasis was stable disease. However, grade 2 edema, leukocytopenia, and anemia developed, and the dose of imatinib mesilate was reduced to 200 mg daily. The adverse reactions resolved promptly, and a partial response of both the primary tumor and liver metastasis to imatinib mesilate has been maintained for 28 months. Strategies for lowering the dose of imatinib mesilate are reviewed.

A 75-year-old man underwent partial resection of the small intestine for GIST in January 2000. A recurrent tumor revealed in the intra pelvic space was removed by two operations, and imatinib (400 mg/day) was given after the third operation. As successive administration was not able to be continued due to side effects such as anorexia and fatigue, the recurrent tumor enlarged. After imatinib was given at 200 mg/day, the defecation trouble was improved and the tumor decreased partially on CT image. His partial response has continued over one year. Mutation analysis revealed deletion and point mutation in exon 11 of c-kit gene. Low-dose imatinib administration should be considered in case of side effects at the standard dose.

A 66-year-old woman underwent total gastrectomy. On the first postoperative day, acute pulmonary thromboembolism (PTE) with occlusion of the pulmonary trunk occurred, and the cardiovascular state became unstable. We used urokinase and heparin at lower doses. However, massive bleeding as a result of these drugs made it difficult to continue thrombolytic and anticoagulative therapies. We stopped urokinase on the second postoperative day, and started nafamostat mesilate instead of heparin on the third postoperative day. We found that the targeted activated coagulation time value (180 sec) was more easily attained by nafamostat mesilate than by heparin. We could continue anticoagulation therapy with minimal bleeding thereafter, and the patient recovered smoothly. On CT of the 19 th postoperative day, a small thrombus was observed in the right pulmonary artery.

The potential for QT interval prolongation of pazufloxacin mesilate (PZFX mesilate), a new quinolone antibacterial agent for intravenous use, was investigated by in vitro and in vivo electrophysiology studies. Following results were obtained. In vitro electrophysiology study using guinea pig papillary muscles: PZFX mesilate (30-300 microM) had no effects on resting membrane potential (RMP), action potential amplitude (APA) and action potential duration (APD). Reference quinolones, sparfloxacin (3-30 microM) and moxifloxacin (10-100 microM), had no effects on RMP and APA, but significantly prolonged APD at more than 3 and 10 microM, respectively, while ciprofloxacin (10-100 microM) had no effect on each parameter. In vivo electrophysiology study using anesthetized dogs: PZFX mesilate had no effects on electrocardiograph parameter (PR interval, QRS interval, QT interval and QTc) after intravenous administration of 3-30 mg/kg. These results suggest that PZFX mesilate has low potential for QT interval prolongation.

Pazufloxacin mesilate (PZFX: Pasil INJECTION, Pazucross INJECTION) is a novel injectable quinolone antibiotic that was discovered by Toyama Chemical Co., Ltd. and codeveloped by Toyama Chemical Co. Ltd. and Mitsubishi Pharma Corporation. Laboratory studies indicated that PZFX reached high plasma levels quickly after intravenous administration, and it exhibited weak convulsion inducing activity, low local irritant effect, and less hypotensive activity, all of which are generally recognized as side effects associated with other injectable quinolones. PZFX has potent antibacterial and bactericidal activities against cephalosporin-, carbapenem-, and aminoglycoside-resistant strains. These favorable antibacterial and bactericidal activities gave PZFX superior therapeutic effects, compared to injectable cephalosporin antibiotics, on experimental animal infection models caused by those resistant strains. Clinical studies also revealed PZFX was as safe and effective as the injectable cephalosporin, ceftazidime, against various moderate to severe infections. Furthermore, PZFX showed good clinical effects on the infections resistant to chemotherapy by the other antimicrobial agents. These results indicate that PZFX is a viable choice for various bacterial infections. In this review, results of laboratory and clinical studies are summarized and the clinical role of PZFX among the injectable antimicrobials is discussed.

We report a patient with chronic myelogenous leukemia that responded to imatinib mesilate after relapse of blastic crisis following allogeneic bone marrow transplantation. The patient received an unrelated bone marrow transplantation in the 3rd chronic phase, after which the 3rd blastic crisis occurred 5 months later. Since the case was refractory to chemotherapy at that time, imatinib mesilate (600 mg/day) was given, which resulted in a complete cytogenetical remission (CCR). The CCR has maintained for 11 months.

Imatinib mesilate (Glivec) is a protein-tyrosine kinase inhibitor that potently inhibits the Bcr-Abl tyrosine kinase as well as the receptors for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, at in vitro and cellular kinase assay levels. Since Bcr-Abl tyrosine kinase plays a key role in chronic myelogenous leukemia (CML) patients, treatment with imatinib mesilate that potently inhibits Bcr-Abl tyrosine kinase could be a promising therapeutic approach to CML. Imatinib mesilate was shown to inhibit proliferation of bcr-abl-positive cell lines and suppress the formation of bcr-abl-positive colonies in cells derived from bone marrow of CML patients. This compound induced apoptosis in a variety of bcr-abl-positive cells. Moreover, in vivo data indicated that imatinib mesilate suppress growth and formation of bcr-abl-positive tumors in mice. As the profile expected from the preclinical studies, imatinib mesilate showed impressive hematological and cytogenic responses in the clinical trials, including interferon-alpha-resistant or intolerant patients.

The protective effect of pazufloxacin (PZFX) mesilate, a parenteral quinolone antimicrobial agent, on arbekacin (ABK)-induced nephrotoxicity was evaluated with 8-week-old male Sprague-Dawley rats. Animals were injected with ABK at a dose of 32 mg/kg intramuscularly, or a combination of ABK in the same manner with PZFX mesilate at a dose of 208 mg/kg (160 mg/kg convert to PZFX, active principle of PZFX mesilate) intravenously once a day for 4 days. In consequent, ABK induced increases in protein, beta 2-microglobulin and N-acetyl-beta-(D)-glucosaminidase in urine, and histopathological phospholipidosis in kidneys. The extent of these changes was reduced when ABK was given in a combination with PZFX mesilate. Renal cortex level of ABK increased after an administration of ABK 1 hour to 4 hours; however, the increase was suppressed by coadministration of PZFX mesilate. Taken together, these results suggest that PZFX mesilate has the protective effect on ABK-induced nephrotoxicity, and that this was attributable to a suppression of uptake of ABK in cortical renal tubules.

We investigated the in vitro and in vivo antibacterial activities of pazufloxacin mesilate (PZFX mesilate), a new injectable quinolone, and obtained the following results. 1) The MIC50 and MIC90 values of PZFX against clinically isolated Gram-positive and -negative bacteria, ranged from 0.0125 to 12.5 micrograms/ml and 0.025 to 100 micrograms/ml, respectively. PZFX showed broad spectrum activity. The antibacterial activities of PZFX against quinolone-susceptible, methicillin-resistant Staphylococcus aureus, beta-lactamase-negative, ampicillin-resistant Haemophilus influenzae, extended spectrum beta-lactamase possessing Klebsiella pneumoniae and imipenem/cilastatine (IPM/CS)-resistant Pseudomonas aeruginosa were superior to those of ceftazidime (CAZ), ceftriaxone, IPM/CS, meropenem and panipenem/betamipron. 2) PZFX showed superior bactericidal activity against S. aureus, Escherichia coli, Proteus mirabilis, Serratia marcescens and P. aeruginosa to those of CAZ and IPM/CS after treatment for 15 minutes at the drug concentration equivalent to that in human serum at clinical dose to be continued for 15 minutes. 3) CAZ and IPM/CS had no bactericidal activity at the 16 times of MIC against P. aeruginosa in human polymorphonuclear leucocytes, while PZFX exhibited potent bactericidal activity in a dose-dependent manner against such bacteria. 4) PZFX inhibited both DNA gyrase and topoisomerase IV from S. aureus at nearly the same level. PZFX showed poor inhibitory activity against topoisomerase II from human placenta and showed high selectivity to bacterial topoisomerase. 5) PZFX mesilate showed superior therapeutic activity to that of CAZ with following infection model caused by S. aureus and P. aeruginosa or each; systemic infection with cyclophosphamide-treated mice, systemic infection in mice with high challenge doses, CMC pouch infection in rat, and calculus infection in rat bladder. 6) Intravenous administration of PZFX with high plasma concentration just after administration, showed more excellent therapeutic effect against the rat intraperitoneal infection, than p.o. and s.c. administration.

Phototoxicity of pazufloxacin mesilate (PZFX mesilate), a novel parenteral quinolone antimicrobial agent, were evaluated in vitro and in vivo studies. In vitro, phototoxicity for cultured cells of PZFX, which is active principle of PZFX mesilate, was studied, and stability for long-wavelength ultraviolet (UVA) was examined. In vivo, phototoxicity tests in guinea pigs and rats, and photoallergenicity tests in guinea pigs were conducted. In the phototoxicity test on cultured cells, CHL/IU cells were irradiated UVA of 300-3000 mJ/cm2 in the presence of PZFX, ofloxacin (OFLX), lomefloxacin (LFLX) or sparfloxacin (SPFX) at 10 micrograms/mL. Phototoxic potencies for cultured cells of the quinolones tested were SPFX > LFLX > OFLX > PZFX. In addition, changes in ultraviolet absorption spectrum and residual rate of PZFX, OFLX, LFLX and SPFX were examined after UVA irradiation of 300-3000 mJ/cm2 to each solution. PZFX was stable for UVA compared with OFLX and LFLX. In the phototoxicity test of guinea pigs, each quinolone was administered intraperitoneally daily for 7 days, and UVA of about 11 J/cm2 was irradiated at 30 minutes after the last administration. Dose levels of each quinolone were 65 and 130 mg/kg of PZFX mesilate (dose levels converted to PZFX: 50 and 100 mg/kg), 50 and 100 mg/kg of nalidixic acid (NA), 100 mg/kg of OFLX, enoxacin (ENX), ciprofloxacin (CPFX), LFLX and SPFX. Grade of skin reaction (erythema) at 24 hours after UVA irradiation decreased in the order: SPFX > CPFX > NA > ENX = OFLX > LFLX > PZFX mesilate. Thus, PZFX mesilate was found to have the weakest phototoxicity. In the maximum plasma concentration of quinolones from 0.5 to 2.5 hours after administration, corresponding to the time of UVA irradiation, the concentration of the group administered PZFX mesilate was about 4.1 times higher than that of CPFX group, and about 1.3 times higher than that of SPFX group. The area under the blood concentration-time curve (AUC0.5-2.5) of the group administered PZFX mesilate was the same as that of SPFX group, and about 3.2 times larger than that of CPFX group. These data showed that phototoxicity of PZFX mesilate was also weaker than that of CPFX or SPFX in consideration of AUC0.5-2.5. In the phototoxicity test of rats injected intravenously, no phototoxicity was observed at 130 mg/kg of PZFX mesilate. In the photoallergenicity test of guinea pigs, no photoallergenicity was observed by PZFX mesilate. As mentioned above, from in vitro studies PZFX was found to be stable for UVA irradiation compared with OFLX and LFLX, and phototoxicity for cultured cells of PZFX was weaker than that of SPFX, LFLX or OFLX. In addition, from in vivo studies phototoxicity of PZFX mesilate was found to be weaker than that of NA, OFLX, ENX, CPFX, LFLX or SPFX, and no photoallergenicity was observed. Therefore, photosensitive potency of PZFX mesilate might be less than that of other quinolones.

Convulsant activity of pazufloxacin mesilate (PZFX mesilate), a new quinolone antibacterial agent for intravenous use, in combination with nonsteroidal anti-inflammatory drug (NSAID) was investigated in mice after intravenous or intracerebroventricular administration. Following results were obtained. 1. In combination with 4-biphenylacetic acid (BPAA) at an oral dose of 100 mg/kg, PZFX mesilate did not induce any convulsions at intravenous doses up to 200 mg/kg. Reference quinolones induced convulsions at the following intravenous doses: Enoxacin (ENX), 3.13 mg/kg or more; norfloxacin (NFLX) and lomefloxacin (LFLX), 6.25 mg/kg or more; ciprofloxacin (CPFX), 50 mg/kg or more; sparfloxacin (SPFX) and temafloxacin (TMFX), 100 mg/kg or more; fleroxacin (FLRX), 200 mg/kg. 2. PZFX mesilate at an intravenous dose of 50 mg/kg did not induce convulsions in mice after oral administration of any of 14 kinds of NSAIDs. It induced convulsions at 200 mg/kg in combination with aspirin at an oral dose of 600 mg/kg, while it did not with the other 13 kinds of NSAIDs. 3. Convulsion-inducing dose of PZFX mesilate after intracerebroventricular administration was 100 mg/body, which was higher than those of reference quinolones (NFLX, CPFX, ENX, LFLX, TMFX, levofloxacin, ofloxacin, FLRX and SPFX) and beta-lactam antibiotics (penicillin G, cefazoline, imipenem/cilastatin and panipenem/betamipron). In addition, concurrent dosing of BPAA (1 microgram/body) did not reduce the convulsion-inducing dose of PZFX mesilate. These results suggest that PZFX mesilate has remarkably weak convulsant activity.

We describe a case of thoracic aortic aneurysm complicated by chronic disseminated intravascular coagulation (DIC). Initially the DIC was controlled successfully by administration of gabexate mesilate and dalteparin. However, because these drugs were given intravenously, the patient could not be discharged. Subsequently, the DIC was treated successfully by changing to orally administered camostat mesilate, warfarin and aspirin, which allowed the patient to leave hospital.

The efficacy and safety of the proteolytic enzyme inhibitor FUT-187 were evaluated in postgastrectomy reflux esophagitis and gastric remnant inflammation. FUT-187 was administered orally in a dose of 50 mg four times daily, after meals and bedtime, for periods of 4 to 8 weeks. The subjects consisted of 4 patients with postgastrectomy reflux esophagitis and 9 patients with gastric remnant inflammation. In the endoscopic classification of lesions, postgastrectomy reflux esophagitis was classified as erosive or ulcerative and gastric remnant inflammation as superficial. The general improvement rating, general improvement rating of endoscopic findings, and final global improvement rating were 85% (11/13), 82% (9/11), and 85% (11/13), respectively. Neither adverse reactions nor abnormal laboratory findings due to the test drug were noted. Based on the results of this study, it may be concluded that FUT-187 is an effective drug with a wide margin of safety for postgastrectomy reflux esophagitis and gastric remnant inflammation.

Inhibitory activities of FUT-187 on trypsin-like serine proteases were compared using camostat mesilate (camostat), and 4-(4-guanidino benzoyloxy)-phenyl acetic acid methanesulfonate (GBPA) known as an active metabolite of camostat in the blood. Ki values of FUT-187 on the competitive inhibition mechanism were 0.097 microM for trypsin, 0.029 microM for pancreatic kallikrein, 0.61 microM for plasma kallikrein, 0.57 microM for plasmin, 2.5 microM for thrombin, 20.4 microM for factor Xa and 6.4 microM for C1r. However, FUT-187 acted as a noncompetitive inhibitor for factor XIIa and an uncompetitive inhibitor for C1s, and Ki values for these proteases were 0.021 and 0.18 microM, respectively. Ki values of camostat for these proteases were in the range of 0.037 to 96.4 microM, and those of GBPA for the above proteases except trypsin and plasma kallikrein were higher than those of FUT-187. The inhibitory activity of FUT-187 on trypsin was not reduced by the addition of the serum at 10%, whereas, that of GBPA was reduced (4.3 fold) in terms of IC50 values. The concentration of FUT-187 required to double APTT (activated partial thromboplastin time) was 1.09 microM, while GBPA, by concentrations up to 1 mM failed to double APTT. The kinin formation by glandular kallikrein in the rat plasma was inhibited by FUT-187 with IC50 value of 0.024 microM, while camostat revealed no inhibition by concentrations up to 1 microM. The complement-mediated hemolyses in the classical and alternative pathways were also inhibited by FUT-187 with IC50 values of 0.17 and 3.5 microM, respectively, the corresponding values for camostat being 350 and 150 microM, respectively. It is concluded that FUT-187 is a potent and selective inhibitor of trypsin-like serine proteases, and its inhibitory activities are stronger than those of camostat on glandular kallikrein, factor XIIa and C1s in complement pathway.

Pharmacokinetic studies of nafamostat mesilate (FUT) were reviewed in the previous report (Jpn J Cancer Chemother 27 (5): 767-774, 2000). In this report, the molecular specificity of FUT for these pharmacological behaviors were reviewed. In this study, it became clear that benzene ring inserted between ester-bond and guanidino group of the molecule and amidino group introduced in the opposite chain of guanidino group were found important for eliciting the molecular specificity of FUT.

Unlabelled: During extracorporeal cardiopulmonary bypass (ECB), the activated coagulation and fibrinogenolysis system causes bleeding and postoperative multiple organ failures. We studied the effect of an anti-bleeding agent, nafamostat mesilate (NM) during the surgery of thoracic ascending aorta to decrease a side effect of bleeding. From March 1980 to January 1998, for thoracic ascending aorta operations in our department (true aneurysm, 16-, psudoaneurysm, 2-, and dissection, 11 cases, in 29 cases, respectively), age from 16 to 79 (mean 62.9 +/- 9.5 year of age), we classified the objects in two groups, NM group (intraoperative infusion with NM of 60 mg/hr and with heparin 300 IU/kg) and C group (only with heparin treated, 500 IU/kg). We investigated the preoperative factors (age and aneurysmal diameter), the intraoperative factors (ACT, hematcrit, platelet, aorta clamping time, operative time, ECB time, bleeding volume, and blood transfusion), and the postoperative factors (bleeding and blood transfusion) after the administration of NM., Results: There was no significance for the protection effect of NM infusion on the preoperative and the postoperative factors. However, intraoperative bleeding and blood transfusion volume in NM group were significantly lesser than those in group C., Conclusions: It might be useful for NM infusion during the surgery of thoracic ascending aorta due to the decrease of volume of intraoperative bleeding and blood transfusion amount with the remarkable anti-bleeding effect.

A 73-year-old man who had been receiving treatment for hypertension and angina pectoris was admitted to hospital following a transient ischemic attack. He was diagnosed as having chronic disseminated intravascular coagulation (DIC) complicated by a thoracoabdominal aortic aneurysm, and was treated with heparin sodium and a protease inhibitor. Although the DIC was controlled, the patient had to remain hospitalized in order to receive the medication by continuous infusion. Therefore, the heparin sodium and protease inhibitor were replaced by camostat mesilate, a drug suitable for oral administration and widely used for treatment of chronic pancreatitis. The drug proved effective for the chronic DIC, thus allowing the patient to receive regular treatment on an outpatient basis, and improving his quality of life.

An early phase II clinical study with the proteolysis inhibitor FUT-187 was carried out on patients with reflux esophagitis. FUT-187 was administered orally at the dose of 300 mg/day or 400 mg/day four times daily, after meals and at bedtime, for 4 consecutive weeks. The total number of patients admitted to this study was 40, of whom 9 were assigned to 300 mg/day group and 31 to 400 mg/day group. The rate of effectiveness on postgastrectomy reflux esophagitis was 88% (7/8) in 300 mg/day group and 85%(22/26) in 400 mg/day group when "improved" or better final general improvement ratings were taken into consideration, and 75% (6/8) in 300 mg/day group and 69% (9/13) in 400 mg/day group when "improved" or better endoscopic general improvement ratings were used. The overall safety rating "no problem as to the drug safety" was 89% (8/9) in 300 mg/day group and 71% (22/31) in 400 mg/day group. The main side effect was diarrhea, which was experienced in 6 patients in 400 mg/day group. However, it was resolved by discontinuation of the drug treatment. Other symptoms of gastrointestinal upsets, such as nausea and anorexia, were also induced. Based on these results, it may be concluded that FUT-187 can be a drug with clinical utility that benefits postgastrectomy reflux esophagitis at the dose level of 300 mg/day or less.

Nafamostat mesilate (FUT) was first reported by Fujii et al, in 1981 as a synthetic protease inhibitor. FUT has been reported as a drug for the treatments of DIC (disseminated intravascular coagulation) and acute pancreatitis and as an anticoagulant in extracorporeal circulation. FUT has a structure of ester conjugate of p-guanidinobenzoic acid and 6-amidino-2-naphthol. In in vivo, this ester site was found as the reaction center as well as the site for the catabolic changes. Plasma half life (t1/2 beta) of FUT was about 23.1 min, compared to about 55 seconds of the related compound, FOY. The inhibitory activity of FUT on the protease was found to be due to the mis-reading of serine protease in vivo.

We investigated the possibility of ototoxicity induced by deferoxamine mesilate (DFO). DFO was administered to guinea pigs intraperitoneally at 200 or 400 mg/kg body weight/day, 6 days/week for 5 weeks, or 600 mg/kg body weight/day, 6 days/week for 4 weeks. Physiological saline instead of DFO was given to animals as a control. After the course of administration was completed, we measured the threshold of the compound action potential (CAP) and the endocochlear potential (EP). We also examined the cochlear histology by scanning electron microscopy. The CAP threshold of animals treated with 200 or 400 mg of DFO per kg was not elevated. In the animals treated with 600 mg/kg , however, the CAP threshold was clearly elevated when compared with that of control animals. The EP values of animals treated with 200 or 400 mg of DFO per kg were comparable to those of control animals. In some animals treated with 600 mg of DFO per kg, however, the EP values were decreased. Histological examination revealed that the outer hair cells of the cochlea were missing. DFO presumably acts on hair cells, resulting in elevation of the CAP threshold. We concluded that hair cell damage is one of the contributing factors to CAP threshold elevation.

Cisplatin (CDDP) is an antitumor agent against several types of neoplasms. It has, however, various side effects such as nephrotoxicity and ototoxicity. Several efforts have been made to prevent these toxic side effects. On the other hand, deferoxiamine mesilate (DFO), an iron-chelating agent, has been used for iron-overloaded patients. Since the 1980s, many authors have reported DFO-associated hearing impairment. Some experimental data suggest that DFO itself was responsible for ototoxicity. In addition, it has also been recognized that DFO can act as a free radical scavenger. Experimental trials using DFO are also expected to prevent CDDP-induced toxicity because its generation mechanism is thought to be associated with free radical formation. The present study was planned to investigate whether DFO, which might be an ototoxic agent, had a protective effect against various CDDP-induced toxicities including ototoxicity. Fisher rats were used in this study and were divided into four groups: 1) Group I, a vehicle control, 2) Group II, animals receiving 100 mg of DFO per kg, 3) Group III, animals administered 0.9 mg of CDDP per kg alone and 4) Group IV, animals receiving 100 mg of DFO per kg 60 min before 0.9 mg of CDDP per kg for 10 days. First, the protective effect of DFO against CDDP-induced ototoxicity was studied. The auditory threshold was determined by using the compound action potential (CAP) from the round window membrane. CAPs were recorded on the 5th day after completion of drug administration. Then CAPs recording, cochlear sensory epithelia were observed over all the turns of the cochlea by scanning electron microscopy. There were no significant differences in CAP thresholds between Group I and IV, though the thresholds in Group III were significantly higher at 16 kHz and 20 kHz than those in Group IV. The rate of missing outer hair cells in Group IV was significantly lower than that in Group III. The results clearly demonstrated that DFO had a protective effect against CDDP-induced ototoxicity. Second, the protective effect of DFO against CDDP-induced nephrotoxicity was studied. Renal function was evaluated by measuring blood urea nitrogen (BUN) and serum creatinine (Cr) levels. Both BUN and Cr levels in Group IV were significantly lower than those in Group III. The data suggested that DFO preadministration prevented CDDP-induced nephrotoxicity. Third, the influence of DFO on the antitumor activity of CDDP was investigated in rats inoculated with squamous cell carcinoma cells (SCC-131) subcutaneously. The influence of drugs was determined by measuring the tumor growth rate. There was no difference in the tumor growth rate between Group III and IV. The result revealed that DFO had no influence on CDDP antitumor activity. In conclusion, the above results demonstrating that DFO preadministration can prevent both CDDP-induced ototoxicity and nephrotoxicity without attenuation of CDDP antitumor activity, suggest the usefulness of CDDP antitumor chemotherapy.

A 47-year-old woman was admitted to our hospital complaining of subcutaneous hemorrhages. She had taken medicine because of a common cold one month before admission, and two weeks after that, she noticed the hemorrhagic diathesis. Laboratory data on admission were as follows; 1,000/microliters of platelet count (PLT), normal myelogram, normal coagulation tests, positive PAIgG and anti-platelet antibody. She was diagnosed as idiopathic thrombocytopenic purpura and a standard dose of prednisolone was started immediately. However, on the 3rd hospital day (HD), frequent hematemesis from submucosal hematomas developed. Pulse therapy of methylprednisolone and immunoglobulin therapy were ineffective. From the 15th HD slow drip infusion of vincristine and continuous drip infusion of 1, 500 mg/day of gabexate mesilate (GM) were started. Because PLT increased to 85,000/microliters and hematemesis disappeared on the 22nd HD, GM was discontinued. However on the 25th HD, PLT decreased to 1,000/microliters again. After re-starting GM, PLT was maintained at over 100,000/microliters. Subsequent examinations ruled out collagen diseases but revealed that she had Hashimoto's thyroiditis. We concluded that the complement inhibitory action of gabexate mesilate might have contributed to PLT increase in this case, as has been previously reported in three other cases.

We investigated whether the combination of a new synthetic protease inhibitor, nafamostat mesilate (FUT-175), and heparin-coated cardiopulmonary bypass (CPB) circuit can achieve heparin-free CPB in rabbits. Nine rabbits underwent 2 hours of CPB with heparin-coated circuits. In 4 rabbits (FUT-Group), FUT was administered before (2 mg/kg in bolus) and during (5 mg/kg/hr continuously) CPB. In 5 rabbits (Heparin-Group), heparin was given before (4 mg/kg) and at 1 hour (2 mg/kg) of CPB. Activated clotting time, activated partial thromboplastin time and fibrin degradation products showed no significant differences between the two groups during CPB. However, prothrombin time was significantly (p < 0.05) shorter in FUT-Group than in Heparin-Group. Platelet counts in FUT-Group was significantly lower than Heparin-Group. Massive clots were observed in all of the venous reservoirs of FUT-Group after CPB, whereas there were no major clots in Heparin-Group. The occlusion rate of hollow fibers of the oxygenators was significantly higher in FUT-Group (55 +/- 25%, mean +/- SD) than in Heparin-Group (14 +/- 12%). We concluded that heparin-free CPB with FUT and heparin-coated circuit is difficult in rabbits because activation of the extrinsic coagulation cascade cannot be sufficiently suppressed by FUT.

Basic investigation of inhibitory effect on metastasis of nafamostat mesilate (FUT-175) which is a kind of serine protease inhibitors, was performed. Colon 26 cells were injected to the portal vein of CDF1 mice. FUT-175 at doses of 0.3, 1.0, 3.0, 10.0 mg/kg was injected intravenously every 7 day. Mice were sacrificed on day 21, and metastasis of liver surface were measured. The dose dependent reduction of metastasis was observed and reduction of metastasis of mice treated at a dose of 10.0 mg/kg was significant. FUT-175 showed no cytotoxicity at doses of 10(-5) M or less in vitro, and blood concentration of mice, treated at a dose of 10.0 mg/kg, was 2.67 x 10(-7) M. The results showed that inhibitory effect of FUT-175 on metastasis was not caused by direct cytotoxicity. FUT-175 at 2.67 x 10(-7) M in vitro can inhibit only thrombin and plasmin at nearly 50%, and can not inhibit platelet aggregation and collagenase directly. Possible mechanism of inhibition of metastasis is that FUT-175 inhibited both thrombin-mediated platelet aggregation and plasmin-mediated collagenase activation, that arrest and extravasation in cancer cells were inhibited. If protease inhibitor is administered continuously and immediately after surgery, liver metastasis may be prevented.

To explore the changes of exorine pancreas in the early stage after ligation of pancreatico-biliary duct (PBD) in rat, we evaluated the changes of serum amylase levels, pancreatic water content as well as the changes of subcellular distribution of cathepsin B in the acinar cells. We also evaluated the lactic dehydrogenase (LDH) discharge from dispersed acini as an index of cellular fragility and cathepsin B leakage from lysosomes as an index lysosomal fragility in vitro study as well as the protective effects of a new synthetic protease inhibitor, nafamostat mesilate (FUT 175) in this model. After ligation of PBD, the serum amylase levels and pancreatic water content, increased significantly compared with those of the control group, but returning to the normal levels at 18 hours. The redistribution of cathepsin B in acinar cells was found and both the cellular and lysosomal fragility increased significantly compared with those of the control groups, shown their peak changes at 12 hours after ligation of PBD. But continuous intravenous administration of FUT 175 (2mg/mg.hr) remarkably attenuated all the parameters. These results indicate the important roles of lysosomal enzyme and lysosomal fragility in the pathogenesis of acute pancreatic injuries in this modes, and the clinical usefulness of FUT 175 in the treatment acute pancreatitis.