S-1, a new oral antitumor agent, is composed of 1-(2-tetrahydrofuryl)-5-fluorouracil (Tegafur, FT), 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1. FT which is a masked compound of 5-fluorouracil (5-FU) acts as an effector, while both CDHP and Oxo which do not have antitumor activity themselves act as modulators. In this study, the antitumor activity and intestinal toxicity of S-1 were investigated using experimental tumor models in rats, and compared with those of other oral fluoropyrimidines, namely 5-FU, FT, FCD (1 M FT/0.4 M CDHP) and UFT (combination of FT and uracil). In rats bearing subcutaneous Yoshida sarcoma, S-1 inhibited tumor growth at the lowest dose (ED50 value: S-1 5, UFT 22, FT 82, FCD 5, and 5-FU 19 mg/kg per day), and induced the least host body weight suppression, leading to the highest therapeutic index (TI) (S-1 4.5, UFT 1.4, FT 1.8, FCD 2.0, and 5-FU 1.4). S-1 also showed a higher therapeutic effect than UFT against AH-130 and Sato lung carcinoma. After administration of S-1 and UFT at equitoxic doses, S-1 showed a higher and more prolonged concentration of 5-FU than UFT both in plasma (AUC0-infinity: S-1 28 nmolh/ml, UFT 15 nmol.h/ml) and in tumor tissue (AUC0-infinity: S-1 95 nmolh/g tissue, UFT 52 nmolh/g tissue), leading to a higher 5-FU level incorporated into the RNA fraction (F-RNA level) in tumor tissue (AUC0-24: S-1 7.0 nmolh/mg RNA, UFT 4.3 nmolh/mg RNA) and 5-8% higher thymidylate synthase (TS) inhibition in tumor tissue at every time-point through 24 h. Compared with other oral fluoropyrimidines after administration of the maximal tolerable dose (MTD), S-1 caused the lowest rates of intestinal toxicities, such as diarrhea and occult blood in feces. S-1 also showed a higher antitumor effect on Yoshida sarcoma implanted intracolonically than UFT at an equitoxic dose (tumor weight: S-1 64 +/- 30 mg, UFT 133 +/- 52 mg; P < 0.05). These results suggest that CDHP, which is a potent inhibitor of 5-FU degradation, increases the antitumor activity of FT, and that Oxo, which is an inhibitor of 5-FU phosphorylation, locally protects the gastrointestinal tract from 5-FU-induced toxicity without decreasing the antitumor activity.

Hayashi Y, Takimoto K, Chancellor MB, Erickson KA, Erickson VL, Kirimoto T, Nakano K, de Groat WC, Yoshimura N. Bladder hyperactivity and increased excitability of bladder afferent neurons associated with reduced expression of Kv1.4 ␣-subunit in rats with cystitis. Am J Physiol Regul Integr Comp Physiol 296: R1661-R1670, 2009. First published March 11, 2009 doi:10.1152/ajpregu.91054.2008.-Hyperexcitability of C-fiber bladder afferent pathways has been proposed to contribute to urinary frequency and bladder pain in chronic bladder inflammation including interstitial cystitis. However, the detailed mechanisms inducing afferent hyperexcitability after bladder inflammation are not fully understood. Thus, we investigated changes in the properties of bladder afferent neurons in rats with bladder inflammation induced by intravesical application of hydrochloric acid. Eight days after the treatment, bladder function and bladder sensation were analyzed using cystometry and an electrodiagnostic device of sensory function (Neurometer), respectively. Whole cell patch-clamp recordings and immunohistochemical staining were also performed in dissociated bladder afferent neurons identified by a retrograde tracing dye, Fast Blue, injected into the bladder wall. Cystitis rats showed urinary frequency that was inhibited by pretreatment with capsaicin and bladder hyperalgesia mediated by C-fibers. Capsaicin-sensitive bladder afferent neurons from sham rats exhibited high thresholds for spike activation and a phasic firing pattern, whereas those from cystitis rats showed lower thresholds for spike activation and a tonic firing pattern. Transient A-type K ϩ current density in capsaicinsensitive bladder afferent neurons was significantly smaller in cystitis rats than in sham rats, although sustained delayed-rectifier K ϩ current density was not altered after cystitis. The expression of voltage-gated K ϩ Kv1.4 ␣-subunits, which can form A-type K ϩ channels, was reduced in bladder afferent neurons from cystitis rats. These data suggest that bladder inflammation increases bladder afferent neuron excitability by decreasing expression of Kv1.4 ␣-subunits. Similar changes in capsaicin-sensitive C-fiber afferent terminals may contribute to bladder hyperactivity and hyperalgesia due to acid-induced bladder inflammation. urinary bladder; hyperalgesia; inflammation; C-fiber afferent; potassium channel IT HAS BEEN DEMONSTRATED THAT afferent pathways innervating the urinary bladder consist of myelinated A␦-fibers and unmyelinated C-fibers and that hyperexcitability of C-fibers in bladder afferent pathways contributes to bladder overactivity and/or bladder pain under pathological conditions such as painful bladder syndrome/interstitial cystitis (PBS/IC) (60, 61).Voltage-gated K ϩ (Kv) currents are major determinants of neuronal excitability. Kv currents in sensory neurons are divided into two major categories; i.e., sustained delayed rectifier-type K ϩ (K DR ) and transient A-type K ϩ (K A ) currents (19,21,30,57). K A currents in sensory neurons ...

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or prednisolone (5 mg/kg) for 7 days, cystometry was performed under urethane anaesthesia. The bladder from HCl-induced cystitis rats was also assessed histopathologically. RESULTSOn cystometrography there was frequent voiding in cystitis rats. Administration of IPD-1151T for 7 days after intravesical HCl instillation dose-dependently increased the micturition volume and intercontraction intervals. Treatment with prednisolone had similar therapeutic effects. Histological analyses in the bladder from cystitis rats revealed oedema and infiltration of inflammatory cells such as mast cells and eosinophils in the lamina propria and the transitional epithelial thickening. These histological changes and the number of mast cells and eosinophils were reduced by administration of IPD-1151T or prednisolone. CONCLUSIONThe present results indicate that IPD-1151T improves bladder function and pathological changes in HCl-induced cystitis rats, as previously observed in patients with IC. The rat cystitis model induced by HCl could provide useful information for studying proposed therapies for IC which might involve T cell-dependent inflammatory responses as one of its potential pathophysiologies.

ABSTRACT-Recent studies indicate a risk of learning and memory impairments when patients with senile dementia are treated with antimuscarinic drugs. In this study, we compared the effectiveness of propiverine hydrochloride (propiverine) and oxybutynin chloride (oxybutynin) on the increased urinary frequency and cognitive impairment induced by nucleus basalis magnocellularis (nBM) lesioning in conscious and nonrestrained rats. For examination of bladder function, nBM-lesioned rats were given total parenteral nutrition regimens for 8 days. Propiverine administered orally at 0.3, 3 and 30 mg/kg on the postoperative day 7 significantly lessened the increase in the frequency of voiding caused by the nBM lesion, whereas oxybutynin administration did not show any improvement at 0.1 or 1 mg/kg but did so at 10 mg / kg. To examine the memory impairment, we trained nBM-lesioned rats in an 8-arm radial maze task for 20 days and then evaluated the effectiveness of oral drug administration on 19th and 20th radial maze performance. The higher rate of errors caused by nBM lesioning was significantly aggravated by oxybutynin at 30 and 100 mg/ kg. Propiverine showed slight aggravation of errors, but with no statistical significance at any dose, 30, 100 or 300 mg/ kg. These results suggest that propiverine has comparatively less effect on the cognitive impairment than oxybutynin.Keywords: Antimuscarinic, Propiverine, Oxybutynin, Dementia, Urinary frequency Recently, the number of patients with abnormally high urinary frequency and/ or urinary incontinence attributed to neurogenic or unstable bladder has been increasing. In particular, the number of patients with neurogenic bladder that results from functional disturbance of the brain (for example, dementia and cerebrovascular disease) is expected to increase concomitantly with the aging of society and the increase in the frequency of traffic accidents. As urinary bladder contraction is controlled largely by parasympathetic nerves, a peripherally active anticholinergic (antimuscarinic) drug, for example, oxybutynin or propiverine (1, 2), is generally used for the treatment of urinary frequency and incontinence. On the other hand, scopolamine, a centrally active anticholinergic agent, has been found to create transient memory impairments more frequently in the Alzheimer-type dementia patients than in age-matched elderly control subjects (3 -5). Depending on the situation, antimuscarinic therapeutic drugs given for the treatment of increased urinary frequency and incontinence would also thus have the potential to create transient memory impairment in patients with senile dementia. However, there have been no clinical or animal studies reported to show whether these drugs affect the memory impairment in dementia or not.Furthermore, under conscious and nonrestrained conditions, there have been few animal studies that have examined the effects of antimuscarinic therapeutic drugs on urinary frequency. These conditions are considered to be essential to assess the clinical efficacy of ora...