The systemically administered competitive AMPA receptor antagonist, YM872, has analgesic effects on thermal or formalin-induced pain in rats

A new competitive alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist, (2,3-dioxo-7-[1H-imidazol-1-yl]-6-nitro-1,2,3,4-tetrahydro-1-quinoxal inyl) acetic acid (YM872) has analgesic effects on acute thermal- and formalin-induced nociception by intrathecal administration. The purpose of this study was to determine the analgesic effects of systemically administered YM872 in both acute thermal- and irritant-induced pain. Sprague-Dawley rats were tested for tail withdrawal response by the tail flick test and for paw flinches by formalin injection after intraperitoneal administration of YM872. The tail flick latency increased dose-dependently with a 50% effective dose value of 156.3 microg. The number of flinches in both first and second phases of the formalin test decreased with increasing the dose of YM872. The 50% effective dose values were 1.0 microg in the first phase and 38.7 microg in the second phase. Transiently, intraperitoneal administration of 1 and 10 mg of YM872 induced motor disturbance and 10 mg induced loss of pinna reflex. We conclude that intraperitoneal administration of YM872 had analgesic effects on both acute thermal- and formalin-induced nociceptions in rats. Transient motor disturbance and loss of pinna reflex occurred only with large doses. IMPLICATIONS: Intraperitoneally administered YM872, a new alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist, had analgesic effects on thermal- and formalin-induced pain in rats. Larger doses induced transient motor disturbance and loss of pinna reflex mediated in the brain.     

Structure-activity relationships of quaternary protoberberine alkaloids having an antimalarial activity

Seventeen quaternary protoberberine alkaloids related to berberine 1 were tested for antimalarial activity in vitro against Plasmodium falciparum and structure-activity relationships are proposed. The activity of the protoberberine alkaloids was influenced by the type of the oxygen substituents on rings A, C and D and the position of the oxygen functions on ring D. The position of the oxygen functions on ring D and the type of the oxygen substituents at the C-13 position (ring C) strongly influenced the activity. Shifting the oxygen functions at C-9 and C-10 to C-10 and C-11 on ring D resulted in a significant increase in the activity. Compounds bearing a methylenedioxy function at C-2 and C-3 (ring A) or C-9 and C-10 (ring D) showed higher activity than those which have methoxy groups at the same positions. Introduction of a methoxy group into the C-1 position (ring A) decreased the activity. Replacement of a hydroxy group at C-2 or C-3 (ring A) by a methoxy group led to a reduction in the activity. Displacement of a hydroxy function at C-13 (ring C) by the oxygen substituents such as OMe, OEt, OCOOEt, and OCON(Me)₂ reduced the activity. In the same replacement at C-9 (ring D), the activity depended upon the type of the oxygen function. Six protoberberines displayed more potent activity than berberine 1. The activity decreased in the order: 10, 11, 17 and 18 > 7 and 8 > 1.     

Use of YAG laser combined with mucosal suturing for the treatment of polypoid vocal cord]

To improve low-pitched voices in cases with polypoid vocal cords, YAG laser irradiation combined with a mucosal suturing technique was attempted in 9 female cases with severe polypoid changes in their vocal cords. A YAG laser beam (5 to 10 W) was used to irradiate the upper surface of the polypoid vocal cord. The polypoid content of the cord was gradually coagulated, and the free edge of the cord appeared to slide up toward the burned area. The polypoid content was then removed and squeezed through an open wound made in the burned area using a conventional method. Bleeding was successfully controlled using the laser. After the excessive mucosal margin was trimmed and the contour of the vocal cord was adjusted, the wound was closed by 7-0 monofilament absorbable suture. Suturing was relatively easy because the mucosal edge was also coagulated. Postoperative evaluations of voice quality revealed an improvement in the GRBAS scale of voice quality as well as an elevation in voice pitch and an upwards shift in the voice range in all cases.     

The influence of androgen deprivation therapy on dihydrotestosterone levels in the prostatic tissue of patients with prostate cancer.

PURPOSE: The influence of androgen deprivation therapy on dihydrotestosterone levels in the prostatic tissue is not clearly known. Changes in dihydrotestosterone levels in the prostatic tissue during androgen deprivation therapy in the same patients have not been reported. We analyzed dihydrotestosterone levels in prostatic tissue before and after androgen deprivation therapy. EXPERIMENTAL DESIGN: A total of 103 patients who were suspected of having prostate cancer underwent prostatic biopsy. Sixty-nine patients were diagnosed as having prostate cancer whereas the remaining 34 were negative. Serum samples were collected before biopsy or prostatectomy. Dihydrotestosterone levels in prostatic tissue and serum were analyzed using liquid chromatography/electrospray ionization-mass spectrometry after polar derivatization. In 30 of the patients with prostate cancer, dihydrotestosterone levels in prostatic tissue were determined by performing rebiopsy or with prostate tissues excised after 6 months on androgen deprivation therapy with castration and flutamide. RESULTS: Dihydrotestosterone levels in prostate tissue after androgen deprivation therapy remained at approximately 25% of the amount measured before androgen deprivation therapy. Dihydrotestosterone levels in serum decreased to approximately 7.5% after androgen deprivation therapy. The level of dihydrotestosterone in prostatic tissue before androgen deprivation therapy was not correlated with the serum level of testosterone. Serum levels of adrenal androgens were reduced to approximately 60% after androgen deprivation therapy. CONCLUSIONS: The source of dihydrotestosterone in prostatic tissue after androgen deprivation therapy involves intracrine production within the prostate, converting adrenal androgens to dihydrotestosterone. Dihydrotestosterone still remaining in prostate tissue after androgen deprivation therapy may require new therapies such as treatment with a combination of 5alpha-reductase inhibitors and antiandrogens, as well as castration.     

Sleep survey of medical residents at a National University Hospital]

In order to ascertain the workload and lifestyle of medical residents prior to the introduction of a new medical resident training system, 102 residents at a national university hospital were monitored for four consecutive weeks to ascertain their life habits. Valid responses were obtained from 76% of the respondents for a total of 2,722 person days. It was found that the average length of sleep was 5.7 h on weekdays and 6.8 h on weekends. Of the 102 residents, 40% slept less than six hours a night and 17% slept less than five hours a night. The time spent sleeping was particularly short among surgical residents. Given that lack of sleep not only affects the health of the residents negatively, but also compromises the safety of medical care that they provide, the new medical residency training system will need to monitor and analyze the wellbeing, including sleep patterns, of medical residents.     

Simultaneous display of MRA and MPR in detecting vascular compression for trigeminal neuralgia or hemifacial spasm: comparison with oblique sagittal views of MRI

A new technique, simultaneous display of magnetic resonance angiography (MRA) and multiplanar reconstruction (MPR), was performed by a workstation to identify the involved vessels in patients with trigeminal neuralgia (TN) or hemifacial spasm (HFS), and the results were compared with those of oblique sagittal MRI technique. Twelve patients with either HFS or TN were prospectively assessed by simultaneous display of MRA and MPR, and oblique sagittal techniques, to point out the neurovascular compression and to identify the involved vessels. Three-dimensional (3D) time-of-flight (TOF) spoiled gradient-echo (SPGR) images were acquired to create MRA and MPR. Oblique sagittal views were also created and displayed on films. A total of 15 vessels in 12 patients were identified as compressing vessels during surgery. Simultaneous display of MRA and MPR technique pointed out the presence of vessels at and/or around root entry/exit zone (REZ) in all 12 patients, but proper identification by the name of the individual vessel was correct in 13 of 15 cases. However, oblique sagittal technique indicated the presence of vessels at and/or around REZ in 11 patients, but only 8 of 14 vessels were correctly identified. Our new method, simultaneous display of MRA-MPR, facilitated correct identification of the involved vessels compared with the oblique sagittal view method. Received: 30 June 1999; Revised: 9 September 1999; Accepted: 23 November 1999     

Identification of Ki23819, a highly potent inhibitor of kinase activity of mutant FLT3 receptor tyrosine kinase.

Constitutively active internal tandem duplication (ITD) in the juxtamembrane domain of Fms-like tyrosine kinase 3 (FLT3), a type III receptor tyrosine kinase, is the most common molecular defect associated with acute myeloid leukemia. Its presence confers a poor outcome in patients with acute myeloid leukemia who receive conventional chemotherapy. FLT3-ITD has therefore been considered to be an attractive molecular target for a novel therapeutic modality. We describe here the identification and characterization of Ki23819 as a novel FLT3 inhibitor. Ki23819 suppressed proliferation and induced apoptosis of FLT3-ITD-expressing human leukemia cell lines. The growth-inhibitory effect of Ki23819 on MV4-11 cells was superior to that of SU11248, another FLT3 inhibitor (IC(50)<1 vs 3-10 nM). Ki23819 inhibited the autophosphorylation of FLT3-ITD more efficiently than that of wild-type FLT3. FLT3-ITD-dependent activation of the downstream signaling proteins ERK and STAT5 was also inhibited within similar concentration ranges. Thus, Ki23819 is a potent in vitro inhibitor of FLT3.     

Anesthesia for a cervical myelopathy patient with tracheal stenosis

A 71-year-old male with cervical myelopathy was scheduled for C 3-7 laminectomy. Once he had been rejected of general anesthesia in other hospital because of his tracheal stenosis. The diameter of the narrowest part of his trachea was 5 mm probably resulting from tracheostomy at 2 years of age. His cervical myelopathy seemed to be no problem for anesthesia induction because he had no problems in his neck movement and opening mouth. We evaluated his tracheal stenosis carefully using bronchofiberscopy, chest X-ray, computed tomography and pulmonary function tests. After intravenous fentanyl 100 micrograms and midazolam 2.5 mg, it was impossible to ventilate the patient. Therefore, tracheal intubation was performed immediately after lidocaine administration into the trachea. During surgery, tracheal tube dilated the narrowed portion. After surgery, the tracheal tube was removed under bronchofiberscopic observation without any problems. Tracheal stenosis was observed by chest X-ray after surgery, but he had no complaints.     

Combined intercostal nerve block and epidural anesthesia in a patient with severe aortitis syndrome

A 74-year-old woman with aortitis syndrome was scheduled for mastectomy. Her left vertebral artery was totally occluded and left carotid arteries, left subclavia artery and bilateral common renal arteries were occluded. For anesthesia a catheter was inserted into the epidural space between T3 and T4. Lidocaine 80 mg (2%, 4 ml) was administered epidurally. Then intercostal nerve block was performed with bupivacaine 15 mg (0.5%, 3 ml) at T3 and T4 level. Local infiltration of lidocaine 50 mg (1%, 5 ml) was added. During the surgery, hemodynamics were stable and no neurological symptom was observed. Epidural anesthesia alone might be sufficient for anesthesia if higher concentration of local anesthetic was used. However, to avoid hemodynamic change, we used 1% lidocaine and added intercostal nerve block. We conclude that combined intercostal nerve block and epidural anesthesia was useful for a patient with severe aortitis syndrome in oder to monitor consciousness to detect cerebral ischemia and to avoid hemodynamic instability.