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.     

Polymerization contraction stress of resin composite restorations in a model Class I cavity configuration using photoelastic analysis

PURPOSE: An important factor that contributes to deterioration of resin composite restorations is contraction stress that occurs during polymerization. The purpose of this article is to familiarize the clinician with the characteristics of contraction stress by visualizing the stresses associated with this invisible and complex phenomenon. MATERIALS AND METHODS: Internal residual stresses generated during polymerization of resin composite restorations were determined using micro-photoelastic analysis. Butt-joint preparations simulating Class I restorations (2.0 mm x 5.0 mm, 2.0 mm in depth) were prepared in three types of substrates (bovine teeth, posterior composite resin, and transparent composite resin) and were used to examine contraction stress in and around the preparations. Three types of composite materials (a posterior composite, a self-cured transparent composite, and a light-cured transparent composite) were used as the restorative materials. The self-cured composite is an experimental material, and the others are commercial products. After treatment of the preparation walls with a bonding system, the preparations were bulk-filled with composite. Specimens for photoelastic analysis were prepared by cutting sections perpendicular to the long axis of the preparation. Fringe patterns for directions and magnitudes of stresses were obtained using transmitted and reflected polarized light with polarizing microscopes. Then, the photoelastic analysis was performed to examine stresses in and around the preparations. RESULTS: When cavity preparations in bovine teeth were filled with light-cured composite, a gap was formed between the dentinal wall and the composite restorative material, resulting in very low stress within the restoration. When cavity preparations in the posterior composite models were filled with either self-cured or light-cured composite, the stress distribution in the two composites was similar, but the magnitude of the stress was greater in the light-cured material. When preparations in the transparent composite models were filled with posterior composite and light-cured transparent composite material, significant stress was generated in the preparation models simulating tooth structure, owing to the contraction of both restorative materials. CLINICAL SIGNIFICANCE: Polymerization contraction stress is an undesirable and inevitable characteristic of adhesive restorations encountered in clinical dentistry that may compromise restoration success. Clinicians must understand the concept of polymerization contraction stress and realize that the quality of composite resin restorations depends on successful management of these stresses.     

A defect of platelet release reaction in a patient with SLE: impaired platelet aggregation induced by phorbol ester with a normal phosphorylation of 40K protein

A 37-year-old female who suffered from SLE had a bleeding disorder. At the time of initial evaluation, the main disease demonstrated was a delta-storage pool deficiency. After this improved, a marked decrease of aggregation still remained, when induced by either ADP, epinephrine, collagen, A23187, thrombin, or PAF-acether. Although arachidonate-induced aggregation was slightly decreased, thromboxane B2 was produced normally in response to exogenous arachidonate. The patient's endoperoxides and/or thromboxane A2 aggregated aspirin-treated platelets, though her platelets were themselves unresponsive. Impaired aggregability induced by TPA (12-0-tetradecanoylphorbol-13-acetate) or OAG (1-oleoyl-2-acetyl-glycerol) was also found. However, the phosphorylation of P43 and P20 induced by several stimulators including CA++ ionophore was normal, using 32P-labelled platelets. It is suggested that TPA or OAG-induced platelet aggregation requires not only the phosphorylation of those proteins, but also another unknown mechanism after the phosphorylation, and that the platelet dysfunction of this patient was due to a defect of some mechanism involving Ca++ uptake or mobilization of cytoplasmic Ca++ from intracellular storage sites.     

Six-year follow-up of children born from vitrified oocytes

Research questionAre children born from vitrified-warmed oocytes physically or mentally different from naturally conceived children?DesignIntracytoplasmic sperm injection (ICSI) of vitrified-warmed oocytes was performed for 282 patients (307 cycles) from August 2000 to March 2020. Long-term follow-up of children born from vitrified-warmed oocytes was performed via a questionnaire that was sent to the parents at regular intervals from 3 to 72 months after the child's birth. Questionnaires were sent 11 times from birth to the age of 6 years. The development of motor function and mental status was evaluated as the primary outcome, based on the reported data. Subsequently, patients were divided into four groups by age at oocyte retrieval (20–29, 30–34, 35–39, and 40 years or older). Clinical outcomes were calculated as a secondary outcome.ResultsFor the 282 patients, the birth of 116 babies was reported (110 singletons and three sets of twins), and seven cases are, at the time of writing, unconfirmed. The results of the survey found physical parameters in singletons to be equivalent to the nationally reported average data issued by the Ministry of Health, Labor and Welfare of Japan.ConclusionThis is the first follow-up report of children born from vitrified-warmed oocytes followed by ICSI. The data suggested that the responses from the study participants on the mental and physical development of children were comparable to the data reported by the government, although more responses from patients should be collected to allow further study.     

Ultrastructural analysis of enkephalinergic terminals in parasympathetic ganglia innervating the urinary bladder of the cat

Leucine enkephalin immunoreactivity was identified in axons and varicosities in parasympathetic ganglia located in the pelvic plexus and on the surface of the urinary bladder of the cat. Electron microscopic immunohistochemical studies revealed that varicosities containing leucine enkephalin exhibited large dense core vesicles and small, clear, spherical vesicles, which were similar to those found in cholinergic terminals. Leucine enkephalin immunoreactivity was primarily associated with large dense core vesicles. The varicosities formed axodendritic and axosomatic synapses with principal ganglion cells. Axoaxonic synapses were not detected. Some axosomatic enkephalinergic synapses were detected embedded within or invaginating the principal ganglion cells. Varicosities containing flattened and/or small dense core vesicles did not exhibit enkephalin immunoreactivity. Bladder ganglion cells identified by retrograde HRP tracing from the urinary bladder exhibited similar leucine enkephalinergic synapses. These observations, coupled with previous reports that leucine enkephalin is present in sacral preganglionic neurons and released by preganglionic nerve stimulation, suggest that leucine enkephalin and acetylcholine are cotransmitters stored and released from the same nerve terminals in bladder parasympathetic ganglia.     

Activation of the satiety center by auricular acupuncture point stimulation

Stimulation of the rat inner auricular regions that correspond to the human pylorus, lung, trachea, stomach, esophagus, endocrine, and heart acupuncture points evoked potentials in the hypothalamic ventromedial nucleus (HVM), the satiety center. Needle implantation into any of these points reduced the body weight to its initial 290 g after the rat had gained about 410 g in 20 days, and significantly reduced initial 450-g body weights (p less than 0.01, Student's t test) in 14 days. Stimulation of other acupuncture points did not evoke HVM potentials and did not reduce body weight. After the HVM was lesioned, body weight increased and acupuncture point needling had no effect on body weight. Needling of the auricular acupuncture points evoked no potentials in the lateral hypothalamus (LHA), the feeding center, and had almost no influence on weight reduction induced by LHA lesion.     

Unexplained recurrent shock in peripheral T‐cell lymphoma: A case report

Malignant lymphoma sometimes manifests with septic‐like shock symptoms. We report a case of peripheral T‐cell lymphoma presenting with unexplained recurrent shock in absence of apparent lymphadenopathy. The patient also experienced varied symptoms, including severe chest and back pain, respiratory distress due to tracheobronchomalacia, skin rash, and fever.