Pharmacological effects of darifenacin on human isolated urinary bladder

Darifenacin [(S)-2--2,2-diphenylacetamide] is a novel antimuscarinic drug currently undergoing phase III trials for the treatment of overactive bladder. We investigated the functional antagonist potency of darifenacin, and the antimuscarinic drugs propiverine, oxybutynin and atropine, on human detrusor smooth muscle. Urinary bladder specimens were obtained from 20 patients who underwent total cystectomy for malignant bladder tumor. Using an organ-bath technique, the effects of the compounds on carbachol-, KCl-, CaCl(2)- or electrical field stimulation (EFS)-induced contractions of the tissues were evaluated. The order of antagonist potency (pA(2 )values) at the muscarinic M(3) receptors was: darifenacin (9.34) > atropine (9.26) > oxybutynin (7.74) > propiverine (7.68). Darifenacin and atropine, at concentrations up to 10(-6) mol/l, did not inhibit the KCl- and CaCl(2)-induced contractions (concentrations 80 and 5 mmol/l, respectively), while propiverine and oxybutynin (10(-5) mol/l) significantly inhibited these contractions. Pretreatment with darifenacin (10(-9)-10(-6) mol/l), propiverine (10(-8)- 10(-5) mol/l), oxybutynin (10(-8)-10(-5) mol/l) and atropine (10(-9)-10(-6) mol/l) significantly inhibited maximum EFS-induced contractions. Darifenacin inhibited contractions of human detrusor smooth muscle only through its antimuscarinic action, while propiverine and oxybutynin had both antimuscarinic and Ca(2+) channel antagonist actions. These findings indicate that darifenacin is a potent antagonist at the M(3) receptor and support its use as a treatment for overactive bladder.     

Protective effects of glutathione on 5-fluorouracil-induced myelosuppression in mice

The protective effects of glutathione (GSH) administration on myelosuppression induced by 5-fluorouracil (5-FU) were investigated in female BALB/c mice. Animals were allocated to four groups (16 mice/group). GSH was given orally at a dose of 800 mg/kg to groups 3 and 4 for 21 consecutive days (day 0 to day 20). 5-FU was repeatedly administered at a dose of 40 mg/kg to groups 2 and 3 for 1 week (day 7 to day 13) by gavage. Group 3 served as a combined treatment group and group 1 as a non-treated control group. The total observation period was 3 weeks. Body weight was measured once a week. A decrease in body weight due to 5-FU treatment was observed in groups 2 and 3 on day 14. Although the body weight in group 2 had not increased by 1-week after cessation of 5-FU treatment, the value in group 3 markedly recovered. Hematology, total nucleated myelocyte count and histopathology of bone marrow were carried out on day 14 and day 21. In groups 2 and 3, these examinations showed thrombocytopenia, leukopenia, reticulocytopenia and myelosuppression on day 14. However, platelets and bone marrow were less affected in group 3 than in group 2. On day 21, the thrombocytopenia in groups 2 and 3 was resolved. The myelosuppression, leukopenia and reticulocytopenia resolved in group 3, but not in group 2. Although simple microcytic anemia occurred delayed on day 21, it was less severe in group 3 than in group 2. Therefore, GSH may have preventive effects against 5-FU-induced hematopoietic toxicity, and accelerate recovery after cessation of 5-FU treatment.     

Efficacy of corticosteroids in sarcoidosis presenting with atrioventricular block

BACKGROUND: The usefulness of corticosteroid therapy for cardiac sarcoidosis has not yet been fully clarified. METHODS: Of 40 patients diagnosed with cardiac sarcoidosis, twenty patients complicated by atrioventricular block but normal cardiac function (left ventricular ejection fraction > or = 50%) were divided retrospectively into one group (n = 7) receiving corticosteroids and another (n = 13) not receiving these agents. Over a mean observation period of 79.4 +/- 39.9 months, long-term outcome and laboratory findings were compared between the two groups and side effects also were noted. RESULTS: There were no deaths in the corticosteroid-treated group. In the untreated group, 2 patients died (15.4%). Atrioventricular block resolved in 4 of the 7 patients in the treated group (57.1%), but did not resolve or improve in any of the untreated patients (p < 0.05). Left ventricular ejection fraction did not differ significantly between the treated and untreated groups at the time of initial evaluation (66.7 +/- 6.5% vs. 60.5 +/- 6.4%). In the follow-up period, a marked decline in the ejection fraction had occurred in the untreated group (37.6 +/- 17.3%), but not in the treated group (62.1 +/- 4.4%; p < 0.005). Ventricular tachycardia was not present at the initial assessment in any patient in either group. In the follow-up period, ventricular tachycardia occurred in only 1 of 7 treated patients (14.3%), but was present in 8 of 13 untreated patients (61.5%; p < 0.05). However, side effects of corticosteroid therapy were noted in 6 of the 7 treated patients (85.7%). CONCLUSION: Our findings suggest that corticosteroids are useful in the treatment of cardiac sarcoidosis complicated by atrioventricular block but with normal cardiac function. However, these agents must be used with caution, with the maintenance dose kept as low as possible.     

Nonspecific interstitial pneumonia in collagen vascular diseases: comparison of the clinical characteristics and prognostic significance with usual interstitial pneumonia

BACKGROUND: Nonspecific interstitial pneumonia (NSIP) has recently been described as a distinct clinicopathological entity among idiopathic interstitial pneumonias (IIP), having more favorable prognosis than usual interstitial pneumonia (UIP). Although NSIP was initially reported to also occur in patients with interstitial pneumonia associated with collagen vascular diseases (IP-CVD), the prevalence of NSIP and its prognostic significance in IP-CVD remains to be determined. Thus, we attempted to clarify clinical characteristics and prognostic significance of NSIP in IP-CVD. METHODS: We histologically examined surgical lung biopsies from 43 patients with IP-CVD based on a current classification of interstitial pneumonias, and compared the clinical characteristics and prognostic significance of NSIP with UIP in IP-CVD. We also studied 98 patients with biopsy-proven NSIP and UIP in IIP, and compared the prognostic significance of histopathologic subclassification in IIP with that in IP-CVD. RESULTS: In IP-CVD, twenty-six patients (60%) were classified as NSIP, 17 (40%) as UIP. In contrast, 76 (77%) were categorized into UIP and 22 (23%) into NSIP of the patients with IIP. No significant difference in survival rates was observed between UIP and NSIP in IP-CVD (p = 0.3863), while, in IIP, NSIP has a significant better survival than UIP (p = 0.022). CONCLUSIONS: These results suggest that NSIP is more common histologic pattern than UIP in IP-CVD and, unlike in IIP, the prognosis of NSIP patients may not be different from that of UIP patients in IP-CVD.     

Usefulness of urinary NMP22 to detect tumor recurrence of superficial bladder cancer after transurethral resection

Background In a prospective study we compared the usefulness of urinary nuclear matrix protein 22 (NMP22) with that of urine cytology and other urinary markers in the monitoring of superficial bladder cancer after transurethral resection (TURBT).Methods The subjects were 156 patients, comprising 99 patients with superficial bladder cancer in whom TURBT was planned (untreated group) and 57 patients without tumors in the bladder who had been followed up after TURBT (follow-up group).Results Among the 156 patients, who were monitored for 11–26 months (median, 21 months), recurrence was observed in 51 patients (33.0%). At the time of recurrence, the sensitivities of NMP22, basic fetoprotein (BFP), and bladder tumor antigen (BTA) tests, and urine cytology were 18.6%, 23.3%, 9.3%, and 7.0%, respectively. The factors affecting the sensitivity of NMP22 were tumor size and urinary WBC. The size of recurrent tumors was significantly smaller (P 0.05) than that of the initial tumors. Based on receiver operating characteristic (ROC) curves calculated from the data of patients with recurrence, the ideal cutoff values at recurrence were recommended to be 5.0U/ml for NMP22 and 6.0ng/ml for BFP. Using these cutoff values, the sensitivities of NMP22 and BFP were 48.8% and 44.2%, respectively.Conclusions Because the size of recurrent bladder tumors is usually smaller than that of the initial tumors, the cutoff values of urinary markers should be reduced to detect these tumors. We recommend 5.0U/ml as a cutoff value of NMP22 for detection of recurrence of bladder tumor.     

Different expression patterns of KIT, EGFR, and HER-2 (c-erbB-2) oncoproteins between epithelial and mesenchymal components in uterine carcinosarcoma

Uterine carcinosarcoma histologically comprises the components of epithelial and mesenchymal malignancies, and is known to be clinically highly aggressive. To reveal the significance of the expression of tyrosine-kinase-receptor-type oncoproteins in this tumor type, the incidence and distribution of the KIT, EGFR, and HER-2 (c-erbB-2) oncoproteins were immunohistochemically examined in 16 surgically resected cases. For 6 cases, the EGFR and HER-2 amplifications were also examined by fluorescence in situ hybridization (FISH). In the epithelial component, overexpressions of KIT, EGFR, and HER-2 were detected in 4 (25%), 5 (31%), and 9 (56%) cases, respectively, whereas these overexpressions in the mesenchymal component were detected in 6 (38%), 8 (50%), and 1 (6%) cases, respectively. KIT and EGFR were co-overexpressed in the mesenchymal component of 4 cases and in the epithelial component of 2 cases. However, HER-2 overexpression was mostly detected in the epithelial component only, and tended to occur independently of KIT and/or EGFR overexpression. By FISH, one of the 4 cases with HER-2 overexpression showed low-level gene amplification. In two cases with EGFR overexpression, the gain of EGFR alleles and/or polyploidization of chromosome 7 had occurred. The expression patterns of KIT, EGFR, and HER-2 differed between the epithelial and mesenchymal components, and the regulation of their expression appeared important in the acquisition of mesenchymal metaplasia in uterine carcinosarcoma. Structural and/or numerical alterations of chromosomes might be in part involved in EGFR and/or HER-2 overexpression in this tumor type.     

Modified pharmacokinetic modulating chemotherapy using 5-fluorouracil,UFT, and taxotere (docetaxel) for advanced gastric cancer

The efficacy of neoadjuvant chemotherapy for advanced gastric carcinoma is controversial. Moreover, a standard regimen for such chemotherapy has not been clearly established. Pharmacokinetic modulating chemotherapy (PMC), a combination of infused 5-fluorouracil and oral uracil-tegafur, has been proven to be highly effective for the treatment of colorectal carcinoma. We report two patients with advanced gastric carcinoma successfully treated with PMC and infused taxotere (TXT; docetaxel). Preoperative treatment with PMC and TXT significantly decreased the depth of wall penetration of the tumor in one patient and reduced the size of the tumor in the other patient. In both patients, there were significant chemotherapeutic effects on the primary tumor and on regional lymph nodes pathologically. Preoperative PMC plus TXT produced primary tumor downstaging, leading to improved resectability. The responsiveness of metastatic cancer cells in the regional lymph nodes suggested the possibility of nodal downstaging by this regimen.     

Expression of copper-transporting P-type adenosine triphosphatase (ATP7B) as a chemoresistance marker in human oral squamous cell carcinoma treated with cisplatin

An important clinical problem in the treatment of oral squamous cell carcinoma is the intrinsic/acquired resistance to cisplatin-based chemotherapy. Copper-transporting P-type adenosine triphosphate (ATP7B) has been reported to be associated with cisplatin resistance in vitro (Komatsu et al., Cancer Res 60, 1312-1316,2000). However, the clinical significance of this transporter has not previously been addressed. Our aim of this study was to investigate if ATP7B is expressed in oral squamous cell carcinoma and whether its expression correlates with prognosis and reduced responsiveness to cisplatin treatment. Biopsy tissues were obtained from the tumors of 70 patients with oral SCC, and 51 patients received cisplatin-based preoperative chemotherapy. We performed immunohistochemical analysis of ATP7B using monoclonal antibody against ATP7B in 51 oral SCC and adjacent neoplastic tissues. The significance of ATP7B in the prognosis of patients with oral SCC was also examined in the survival analysis of mortality follow-up data covering the period 1991 through 2000. We retrospectively examined the expression of ATP7B in primary oral SCC carcinoma and its association with chemotherapeutic effect. A variable degree of cytoplasmic staining of tumor cells was observed in 54.9% (28/51 cases) of the analyzed carcinomas. Patients with ATP7B-positive tumors had a significantly inferior response to chemotherapy compared with the patients with ATP7B-negative tumors (P = 0.03). The patients who received cisplatin-based chemotherapy with ATP7B-positive carcinomas had a significantly poorer overall survival than those with ATP7B-negative tumors (P = 0.015). These findings suggest that high levels of ATP7B expression in oral SCC are associated with unfavorable clinical outcome in patients with oral SCCs treated with cisplatin-based chemotherapy. ATP7B expression may be a preoperative indicator for a choice of cisplatin in some patients.     

A new regimen for S-1 therapy aiming at adverse reaction mitigation and prolonged medication by introducing a 1-week drug-free interval after each 2-week dosing session: efficacy and feasibility in clinical practice

Background

The response rate of advanced or recurrent gastric cancer to S-1 (TS-1^®) is 46.5%, which is higher than the response rate of this type of cancer to any other anticancer agent. However, the incidence of adverse reactions to this drug has also been reported to be as high as 83.2%. According to a postmarketing survey, adverse reactions to this drug begin to appear 2–3 weeks after the start of drug administration. With these findings in mind, we recently devised a new dosing regimen for the drug, by which the drug is administered for 2-week periods separated by 1-week drug-free intervals (the 2-week regimen). The aim of this retrospective study was to evaluate the efficacy and feasibility of the 2-week regimen in comparison with a 4-week dosing regimen with a 2-week interval between sessions (the 4-week regimen) as the historical control.

Methods

The subjects were 27 patients with advanced or recurrent gastric cancer who received S-1 therapy at our center between September 1999 and November 2001. Of these patients, 14 who received the 4-week regimen before January 2001 served as historical controls, and the results in these patients were compared with those of the remaining 13 patients, who received the 2-week regimen after February 2001. Patient backgrounds, adverse reactions, compliance, and efficacy were investigated retrospectively.

Results

The incidence of adverse reactions tended to be lower in the 2-week-regimen group (77%) than in the 4-week-regimen group (93%). The percentage of patients who received the drug for 6 months in complete compliance with the dosing schedule, as calculated by the Kaplan-Meier method, was 85% in the 2-week-regimen group and 40% in the 4-week-regimen group. The response rate to the drug was 23% in the 2-week-regimen group and 21% in the 4-week-regimen group.

Conclusion

These results suggest that this 2-week regimen may mitigate adverse reactions and prolong the medication period.

     

Myocardial laser coagulation for free wall rupture following acute infarction

A 73-year-old woman was diagnosed with ventricular free wall rupture following acute myocardial infarction. The lesion was repaired with laser coagulation, fibrinogen-thrombin glue application, and patch reinforcement. Five years after surgery, the patient was in New York Heart Association class I.