Enhancement of the intrinsic defecation reflex by mosapride, a 5-HT4 agonist, in chronically lumbosacral denervated guinea pigs.

The defecation reflex is composed of rectal distension-evoked rectal (R-R) reflex contractions and synchronous internal anal sphincter (R-IAS) reflex relaxations in guinea pigs. These R-R and R-IAS reflexes are controlled via extrinsic sacral excitatory nerve pathway (pelvic nerves), lumbar inhibitory nerve pathways (colonic nerves) and by intrinsic cholinergic excitatory and nitrergic inhibitory nerve pathways. The effect of mosapride (a prokinetic benzamide) on the intrinsic reflexes, mediated via enteric 5-HT(4) receptors, was evaluated by measuring the mechanical activity of the rectum and IAS in anesthetized guinea pigs using an intrinsic R-R and R-IAS reflex model resulting from chronic (two to nine days) lumbosacral denervation (PITH). In this model, the myenteric plexus remains undamaged and the distribution of myenteric and intramuscular interstitial cells of Cajal is unchanged. Although R-R and R-IAS reflex patterns markedly changed, the reflex indices (reflex pressure or force curve-time integral) of both the R-R contractions and the synchronous R-IAS relaxations were unchanged. The frequency of the spontaneous R and IAS motility was also unchanged. Mosapride (0.1-1.0 mg/kg) dose-dependently increased both intrinsic R-R (maximum: 1.82) and R-IAS reflex indices (maximum: 2.76) from that of the control (1.0) 6-9 days following chronic PITH. The dose-response curve was similar to that in the intact guinea pig, and had shifted to the left from that in the guinea pig after acute PITH. A specific 5-HT(4) receptor antagonist, GR 113808 (1.0 mg/kg), decreased both reflex indices by approximately 50% and antagonized the effect of mosapride 1.0 mg/kg. This was quite different from the result in the intact guinea pig where GR 113808 (1.0 mg/kg) did not affect either of the reflex indices. The present results indicate that mosapride enhanced the intrinsic R-R and R-IAS reflexes and functionally compensated for the deprivation of extrinsic innervation. The actions of mosapride were mediated through endogenously active, intrinsic 5-HT(4) receptors which may be post-synaptically located in the myenteric plexus of the anorectum.     

Treatment outcome for systemic chemotherapy for recurrent pancreatic cancer after postoperative adjuvant chemotherapy

ObjectivesA global consensus on how to treat recurrent pancreatic cancer after adjuvant chemotherapy with gemcitabine (ADJ-GEM) does not exist.MethodsWe retrospectively reviewed the clinical data of 41 patients with recurrences who were subsequently treated with chemotherapy.ResultsThe patients were divided into two groups according to the time until recurrence after the completion of ADJ-GEM (ADJ-Rec): patients with an ADJ-Rec < 6 months (n = 25) and those with an ADJ-Rec ≥ 6 months (n = 16). The disease control rate, the progression-free survival after treatment for recurrence and the overall survival after recurrence for these two groups were 68 and 94% (P = 0.066), 5.5 and 8.2 months (P = 0.186), and 13.7 and 19.8 months (P = 0.009), respectively. Furthermore, we divided the patients with an ADJ-Rec < 6 months into two groups: patients treated with gemcitabine (n = 6) and those treated with alternative regimens including fluoropyrimidine-containing regimens (n = 19) for recurrent disease. Patients treated with the alternative regimens had a better outcome than those treated with gemcitabine.ConclusionsFluoropyrimidine-containing regimens may be a reasonable strategy for recurrent disease after ADJ-GEM and an ADJ-Rec < 6 months.     

Myopathy phenotype of transgenic mice expressing active site-mutated inactive p94 skeletal muscle-specific calpain, the gene product responsible for limb girdle muscular dystrophy type 2A

A defect of the gene for p94 (calpain 3), a skeletal muscle-specific calpain, is responsible for limb girdle muscular dystrophy type 2A (LGMD2A), or 'calpainopathy', which is an autosomal recessive and progressive neuromuscular disorder. To study the relationships between the physiological functions of p94 and the etiology of LGMD2A, we created transgenic mice that express an inactive mutant of p94, in which the active site Cys129 is replaced by Ser (p94:C129S). Three lines of transgenic mice expressing p94:C129S mRNA at various levels showed significantly decreased grip strength. Sections of soleus and extensor digitorum longus (EDL) muscles of the aged transgenic mice showed increased numbers of lobulated and split fibers, respectively, which are often observed in limb girdle muscular dystrophy muscles. Centrally placed nuclei were also frequently found in the EDL muscle of the transgenic mice, whereas wild-type mice of the same age had almost none. There was more p94 protein produced in aged transgenic mice muscles and it showed significantly less autolytic degradation activity than that of wild-type mice. Although no necrotic-regenerative fibers were observed, the age and p94:C129S expression dependence of the phenotypes strongly suggest that accumulation of p94:C129S protein causes these myopathy phenotypes. The p94:C129S transgenic mice could provide us with crucial information on the molecular mech-anism of LGMD2A.     

Biological functions of mouse seminal vesicle fluid. I. Suppression of blastogenic responses of lymphocytes

The effect of mouse seminal vesicle fluid (SVF) on blastogenic response of splenocytes to mitogens was investigated. SVF significantly suppressed blastogenic response of splenocytes to concanavalin A and phytohemagglutinin in a dose-dependent manner, but blastogenic response to lipopolysaccharide was suppressed only at low, although significant, levels, even at high concentrations of SVF. Extensive dialysis did not reduce the capacity of SVF to inhibit blastogenesis of splenocytes. For elucidation of the mechanisms of suppression of blastogenic response, interleukin-2 (IL-2)-dependent cells were cultured in the presence of IL-2 and various concentrations of SVF. The presence of SVF did not inhibit the proliferative response of IL-2-dependent cells to IL-2. These results suggest that the suppression of blastogenic response of T lymphocytes to mitogens in seminal plasma is caused by an undialyzable component (or components) derived from seminal vesicle and is attributable to the alteration of receptors for mitogens or of IL-2 receptors that are expressed on stimulation by mitogens.     

Radiotherapy with concurrent docetaxel for advanced and recurrent breast cancer

BACKGROUND: Docetaxel has shown remarkable radiosensitizing properties in vitro. In this study we investigated whether the addition of docetaxel to radiotherapy enhanced tumor response in patients with advanced or recurrent breast cancer. METHODS: A total of 35 patients were enrolled in this study. Docetaxel was administered concurrently during radiotherapy. Radiation doses were 54 to 69 Gy (median 60 Gy). In those enrolled through January 2000, docetaxel 40 mg/m2 was administered biweekly (once every two weeks), with subsequent dose adjustments based on tolerance and bone marrow and liver function. Beginning in February 2000, a weekly docetaxel schedule was used instead. This new regimen was based on data suggesting reduced myelosuppression with this regimen. The weekly dose rate was 20 mg/m2, with dose reductions for impaired organ function. RESULTS: All patients were evaluated for toxicity and response and a total of 40 irradiated sites were evaluated for local response. The overall response rate of irradiated sites was 95% and the CR rate was 68%. CR and PR were achieved in 40%, 37% of patients, respectively. Acute toxicities were tolerated by most patients: 17% had Grade 3-4 neutropenia, 6% had Grade 3-4 radiation dermatitis, and 3% had Grade 3-4 pneumonitis. CONCLUSION: The combination of docetaxel with radiotherapy is an active and safe regimen in patients with inoperable advanced or recurrent breast cancer. We determined the recommended dose of docetaxel with concomitant radiotherapy to be 20 mg/m2 weekly for a Phase II study. Further study is necessary to assess the impact of this treatment on long-term outcome.     

Effectiveness of 3 ways method in intra-arterial infusion chemotherapy for advanced or recurrent cervical cancer with or without radiotherapy

We analyzed 58 cases of advanced or recurrent cervical cancer treated with intra-arterial infusion chemotherapy (IAIC) with or without radiotherapy. Two separate IAIC regimens were administered since 1985: group I consisted of 5-FU + MMC +/- ADR (30 patients) and group II consisted of CDDP + MMC +/- 5-FU (28 patients). The tip of a catheter was placed in the bifurcation of the abdominal aorta (1 way method: 45 patients regimen II: 15) between 1977-1984. We have used selective catheterization (2 ways method: 9) since 1995 in order to get good drug distribution. However we experienced grade 4 toxic effect of cutaneous and pain with this method, so we have used a 3 ways method (4 patients) since 1998. The two-year survival rete was 60% with the 1 way method, and 67% with the 2 ways method and regimen II. Severe adverse effects (grade 3 + 4) were found in 53, 56, 0%, respectively, by each of the three methods (1, 2, 3 ways) hematologically, 13, 22, 0% in gastrointestinally, 0, 44, 0% in cutaneously and 0, 56, 0% in pain or neurotoxicity. These data suggest that IAIC by the 3 ways method is a useful treatment for advanced or recurrent cervical cancer. However, one should check the blood flow distribution periodically, and control concentration of drugs.