Absorption, metabolism, and excretion of [14C]imidafenacin, a new compound for treatment of overactive bladder, after oral administration to healthy male subjects.

The absorption, metabolism, and excretion of imidafenacin [KRP-197/ONO-8025, 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide], a new antimuscarinic drug developed for treatment of overactive bladder, were assessed in six healthy male subjects after a single oral administration of 0.25 mg of [(14)C]imidafenacin (approximately 46 microCi). The highest radioactivity in the plasma was observed at 1.5 h after administration. The apparent terminal elimination half-life of the total radioactivity was 72 h. Approximately 65.6 and 29.4% of the administered radioactivity were recovered in the urine and feces, respectively, within 192 h after administration. The metabolite profiling by high-performance liquid chromatography-radiodetector and liquid chromatography/tandem mass spectrometry demonstrated that the main component of radioactivity was unchanged imidafenacin in the 2-h plasma. The N-glucuronide conjugate (M-9) was found as the major metabolite and the oxidized form of the 2-methylimidazole moiety (M-2) and the ring-cleavage form (M-4) were detected as the minor metabolites in the 2-h plasma, but M-4 was found to be the main component in the 12-h plasma. Unchanged imidafenacin, M-9, M-2, and other oxidized metabolites were excreted in the urine, but the unchanged imidafenacin and M-9 were not found in the feces. Two unique metabolites were found in the urine and feces, which were identified as the interchangeable cis- and trans-isomers of 4,5-dihydrodiol forms of the 2-methylimidazole moiety. These findings indicate that imidafenacin is rapidly and well absorbed (at least 65% of dose recovered in urine) after oral administration, circulates in human plasma as the unchanged form, its glucuronide, and other metabolites, and is then excreted in urine and feces as the oxidized metabolites of 2-methylimidazole moiety.

Development and validation of bioanalytical methods for imidafenacin (KRP-197/ONO-8025) and its metabolites in human urine by using liquid chromatography-tandem mass spectrometry.

New bioanalytical methods have been developed for the determination of imidafenacin (KRP-197/ONO-8025, IM), a novel antimuscarinic drug developed for the treatment of overactive bladder, and its metabolites, M-2, M-3, M-4, M-6 and M-8 (method 1), M-5 and M-9 (method 2) in human urine by using liquid chromatography-tandem mass spectrometry. In each method, the urine sample was extracted by solid-phase extraction, separated on a semi-micro high-performance liquid chromatography column using gradient elution and detected by tandem mass spectrometer with an atmospheric pressure chemical ionization or ionspray interface. Extraction recoveries of IM and metabolites were 81.4% or more. Calibration curves had good linearity in the concentration ranges 0.2-50 ng/mL for IM, M-2, M-3, M-4, M-6 and M-8 (method 1) and 1-250 ng/mL for M-5 and M-9 (method 2), respectively. The accuracy and precision in the intra-day and inter-day reproducibility tests were within +/-17.0 and 16.1% at the lowest concentrations, and within +/-12.8 and 11.1% at higher concentrations, respectively. Using these analytical methods, excretion profiles of IM and its metabolites in human urine were successfully determined after oral administration of IM at the therapeutic dosage of 0.1 mg.

Development and validation of bioanalytical methods for Imidafenacin (KRP-197/ONO-8025) and its metabolites in human plasma by liquid chromatography-tandem mass spectrometry.

Imidafenacin (KRP-197/ONO-8025, IM), 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide, is a new antimuscarinic agent currently under application for the indication of treatment of overactive bladder in Japan. We developed and validated the sensitive and selective bioanalytical methods for the extremely low levels of IM and its metabolite, M-2 (Method 1), M-4 (Method 2) and M-9 (Method 3) in human plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In each method, plasma sample was extracted by solid phase extraction, separated on a semi-micro high performance liquid chromatography column and detected by tandem mass spectrometer with an atmospheric pressure chemical ionization or ionspray interface. Selected reaction monitoring mode was used for quantification. Each method was found to have acceptable accuracy, precision, stability, selectivity and linearity over the concentration range of 10-500 pg/mL for IM and M-2, 10-1000 pg/mL for M-4 and 50-5000 pg/mL for M-9. Using these analytical methods, concentration profiles of IM and its metabolites in human plasma were successfully determined even in the low pg/mL levels after oral administration of IM at the therapeutic dosage of 0.1 mg.

Dihydroetorphine: a potent analgesic: pharmacology, toxicology, pharmacokinetics, and clinical effects.

Dihydroetorphine (DHE) is one of the strongest analgesic opioid alkaloids known; it is 1000 to 12000 times more potent than morphine. Several in vitro and in vivo studies have shown that DHE is a selective mu-opioid receptor (OP(3)) agonist that also binds and activates all human recombinant mu-, delta-, and kappa-opioid receptors (OP(3), OP(1), and OP(2)). The onset of the analgesic effect of DHE in rodents is rapid, 5 to 15 min after parenteral administration; the duration of action is short, the analgesic effect disappears within 120 min after administration. By oral administration much higher doses of DHE are required to produce analgesic effects. These characteristics are accounted for by the pharmacokinetic properties of DHE in the rat, namely, by rapid distribution of DHE from the injection site to the brain and rapid metabolism by glucuronidation in the gut and liver followed by elimination into the bile. Continuous infusion and repeated administration of DHE lead to the development of tolerance to analgesia, physical dependence, and a rewarding effect in normal rats but not in animals with formalin-induced inflammation. Although formalin-induced inflammation is only one type of pain stimulus, these findings suggest that DHE addiction would be observed only in the case of pain-free conditions. Clinical reports in China show that sublingual doses of DHE, 20 to 180 microg, produce a potent analgesic effect with only mild side effects, including dizziness, somnolence, nausea, vomiting, constipation, and shortness of breath. To improve the short-lasting effect following sublingual administration, transdermal delivery of DHE via a patch has been investigated. The patch formulation of DHE produces continuous analgesic effect with minimal physical dependence and rewarding effect in rats suffering from chronic pain. This patch formulation, which is very suitable for DHE, may be viable for the treatment of severe pain and is likely to improve patients' quality of life.

Inspired superoxide anions attenuate blood lactate concentrations in postoperative patients.

OBJECTIVE: Low concentrations of superoxide (O(2)(-)) constitute a portion of atmosphere negative ions in the form of O(2)-(H(2)O)(n), which has been reported to have a stimulatory effect on superoxide dismutase activity. If superoxide dismutase is activated by inspired negative ions containing O(2)(-), aerobic metabolism could be improved. To test this hypothesis, we examined blood lactate concentrations in postoperative patients with or without inhalation of air from a home humidifier that generates O(2)-(H(2)O)(n). DESIGN: Prospective, randomized, controlled trial. SETTING: Neurosurgical intensive care unit of a general hospital. PATIENTS: Twenty postneurosurgical patients with arterial blood lactate concentrations >1.5 mmol/L were studied and were divided randomly into two groups. INTERVENTIONS: One group received 40 L/min 40% oxygen flow from a home humidifier as an oxygen therapy for 4 hrs, followed by almost the same flow from a jet nebulizer, which generates positive ions, for 4 hrs. The other group received the reverse combination. MEASUREMENTS AND MAIN RESULTS: During the 8-hr study, arterial blood lactate concentrations were measured every hour. There was a significant difference in the time course of blood lactate concentrations between the groups. In the group in which negative ions were first initiated for 4 hrs and positive ions thereafter, the lactate concentration decreased slightly at 3, 4, and 5 hrs and returned to the baseline concentration thereafter. In the group with the reverse combination, the lactate concentration did not change during the first 4 hrs but decreased thereafter after inhalation of negative ions. CONCLUSIONS: Inspired O(2)(-) attenuates blood lactate concentrations. This may be attributed, in part, to the systemic stimulatory effect on superoxide dismutase activity, which accelerates oxidative phosphorylation in the mitochondria, thus attenuating lactate generation.

[The effect of acupuncture or electro-acupuncture on circulatory parameters].

We examined the effect of acupuncture or electro-acupuncture on circulatory parameters by use of a non-invasive procedure in 10 healthy male adult volunteers. Circulatory parameters measured were systolic blood pressure, pulse rate, total peripheral resistance and cardiac output. Acupuncture and electro-acupuncture significantly increased total peripheral resistance, and electro-acupuncture increased systolic blood pressure further. There was no difference in cardiac output compared with the control. The results suggest that acupuncture or electro-acupuncture has an action of alpha-stimulation but not of beta-stimulation, and that electro-acupuncture has a stronger effect than acupuncture alone.