An Exploratory Study on the Contractile Effects of Hydroxy-α-Sanshool and Hydroxy-ß-Sanshool, the Active Ingredients of Daikenchuto, on the Internal Anal Sphincter.

Objectives: Daikenchuto (DKT) enhances the contraction of the internal anal sphincter (IAS) in patients with constipation and fecal incontinence; however, the mechanism of its action is unknown. We investigated the effects of the active ingredients of DKT (hydroxy-α-sanshool (HAS) and hydroxy-ß-sanshool (HBS)) on the contractile activity of the canine rectum and IAS. Methods: Three male beagle dogs were prepared for each of the HAS, HBS, and control groups. Force transducers were attached to the rectal and IAS surfaces of the dogs, and the contractile responses were measured by telemetry under conscious conditions. HAS (10 mg/body) and HBS (2.5 mg/body) were administered intrarectally at doses previously identified from an effective dose of DKT extract (1.5 g/body), and contractile responses were recorded up to 6 h after administration. Contractile activity of the rectum and IAS was evaluated by observing the area under the curve (AUC) of the recorded contraction waveform. Plasma concentrations of HAS and HBS were measured before and after administration to confirm IAS exposure to both ingredients. Results: The mean AUC values of the IAS for the control, HAS, and HBS groups at 10 min after administration were 115, 87, and 220 (g-min), respectively, indicating a higher contraction in the HBS group, which was maintained for approximately 3 h. As for the rectum, no contractile response was observed in either the HAS or HBS groups. Plasma concentrations of both ingredients peaked at 20 min after administration. Conclusions: HBS could be involved in the contractile action of DKT on the IAS.

Antianginal effects of lercanidipine on the vasopressin or methacholine induced anginal model in rats.

The antianginal effects of lercanidipine, a newly synthesized 1,4-dihydropyridine derivative calcium channel antagonist, were evaluated in experimental angina model rats and the effects were compared with those of nifedipine, benidipine and amlodipine. In the vasopressin-induced angina model, intravenous administration of lercanidipine dose-dependently suppressed vasopressin-induced ST-depression. Amlodipine barely suppressed it, while benidipine, at the same dose, completely suppressed it. Nifedipine had a potency between that of amlodipine and benidipine. Oral administration of lercanidipine showed similar effects to the intravenous administration test on ST change. High doses of amlodipine, benidipine and nifedipine suppressed ST-depression by almost 100%. In the methacholine-induced angina model, lercanidipine suppressed the ST elevation dose dependently. Amlodipine barely suppressed it, while benidipine at 30 microg/kg effected almost total suppression. Nifedipine had a potency between that of amlodipine and benidipine. Intraduodenal administration of lercanidipine also suppressed the ST-elevation dose dependently. Nifedipine, benidipine and amlodipine at 10 mg/kg all markedly suppressed the elevation. Lercanidipine was more potent than the other calcium channel antagonists tested. In conclusion, it was explicitly demonstrated that lercanidipine exerts potent protective effects on the ischemic electrocardiography (ECG) changes in a variety of putative angina pectoris models in rats. An antispasmolytic coronary vasodilating action may be involved in the mechanism. It is expected that lercanidipine will be useful as an antianginal agent.

Possible involvement of P-glycoprotein in renal excretion of pazufloxacin in rats.

The present study aims to investigate whether pazufloxacin, a new quinolone antimicrobial agent, is a substrate for P-glycoprotein in vitro, and whether it is excreted from kidney by P-glycoprotein and/or multidrug resistance-associated protein (Mrp2) in vivo. The in vitro experiments showed that the intracellular accumulation of pazufloxacin in adriamycin-resistant human chronic myelogenous leukemia cells (K562/ADR) overexpressing P-glycoprotein was significantly lower than that in human chronic myelogenous leukemia cells (K562/S) not expressing P-glycoprotein. When rats received an intravenous injection of pazufloxacin in combination with or without cyclosporine, cyclosporine significantly delayed the disappearance of pazufloxacin from plasma and decreased the systemic clearance and volume of distribution at steady state of pazufloxacin to 50% and 70% of the corresponding control values, respectively. Renal handling experiments revealed that the renal clearance of pazufloxacin was 75% of that corresponding to the systemic clearance, suggesting that the main route of pazufloxacin elimination is the kidney. Cyclosporine significantly increased the steady-state concentration of pazufloxacin in plasma by decreasing the tubular secretion clearance and glomerular filtration rate. These results suggest the possibility that pazufloxacin is excreted into the urine via P-glycoprotein. No significant differences in the renal and tubular secretion clearances of pazufloxacin were observed between normal rats and Eisai hyperbilirubinemic rats (EHBR), which have a hereditary deficiency in Mrp2, indicating the lack of the involvement of Mrp2 in the renal excretion of pazufloxacin. Sparfloxacin, a P-glycoprotein substrate, also significantly decreased the renal and tubular secretion clearances of pazufloxacin, suggesting that pazufloxacin and sparfloxacin share the same transporters, including P-glycoprotein. The present study at least suggests that pazufloxacin is excreted into the urine via P-glycoprotein and some active drug transporters other than Mrp2.

Studies for the emetic mechanisms of ipecac syrup (TJN-119) and its active components in ferrets: involvement of 5-hydroxytryptamine receptors.

Ipecac syrup, prepared from a galentical ipecac, contains the nauseant alkaloids cephaeline and emetine. The involvement of receptors and serotonin- and dopamine-metabolizing enzymes in the emesis induced by ipecac syrup and these components was investigated. 1) In ferrets, the selective 5-HT3-receptor antagonist ondansetron (0.5 mg/kg, p.o.) prevented each emesis induced by TJN-119 (0.5 mL/kg, p.o.), cephaeline (0.5 mg/kg, p.o.) and emetine (5.0 mg/kg, p.o.), but the intraperitoneal administration of the selective dopamine D2-receptor antagonist sulpiride failed to significantly suppress the TJN-119, cephaeline and emetine-induced emesis at a dose of 0.1 mg/kg that blocked apomorphine-induced emesis. 2) In the receptor binding assays, cephaeline and emetine had a distinct affinity to 5-HT4 receptor, but no or weak affinity to 5-HT1A, 5-HT3, nicotine, M3, beta1, NK1, and D2 receptors. 3) Cephaeline and emetine did not affect activities of metabolic enzymes of 5-HT and dopamine (MAO-A, MAO-B, tryptophan 5-hydroxylase and tyrosine hydroxylase) in vitro. These results suggest that 5-HT3 receptor plays an important role in the emetic action of TJN-119, cephaeline and emetine, and the 5-HT4 receptor may be involved in their mechanisms.