Discovery of orteronel (TAK-700), a naphthylmethylimidazole derivative, as a highly selective 17,20-lyase inhibitor with potential utility in the treatment of prostate cancer.

A novel naphthylmethylimidazole derivative 1 and its related compounds were identified as 17,20-lyase inhibitors. Based on the structure-activity relationship around the naphthalene scaffold and the results of a docking study of 1a in the homology model of 17,20-lyase, the 6,7-dihydro-5H-pyrrolo[1,2-c]imidazole derivative (+)-3c was synthesized and identified as a potent and highly selective 17,20-lyase inhibitor. Biological evaluation of (+)-3c at a dose of 1mg/kg in a male monkey model revealed marked reductions in both serum testosterone and dehydroepiandrosterone concentrations. Therefore, (+)-3c (termed orteronel [TAK-700]) was selected as a candidate for clinical evaluation and is currently in phase III clinical trials for the treatment of castration-resistant prostate cancer.

Initial airway management skills of senior residents: simulation training compared with traditional training.

BACKGROUND: Scenario-based training (SBT) with a computerized patient simulator (CPS) is effective in teaching physicians to manage high-risk, low-frequency events that are typical of critical care medicine. This study compares the initial airway management skills of a group of senior internal medicine residents trained using SBT with CPS during their first year of postgraduate training (PGY) with a group of senior internal medicine residents trained using the traditional experiential method. METHODS: This was a prospective, controlled trial that compared two groups of PGY3 internal medicine residents at an urban teaching hospital. One group (n = 32) received training in initial airway management skills using SBT with CPS in their PGY1 (ie, the simulation-trained [ST] group). The second group (n = 30) received traditional residency training (ie, the traditionally trained [TT] group). Each group was then tested during PGY3 in initial airway management skills using a standardized respiratory arrest scenario. RESULTS: The ST group performed significantly better than the TT group in 8 of the 11 steps of the respiratory arrest scenario. Notable differences were found in the ability to attach a bag-valve mask (BVM) to high-flow oxygen (ST group, 69%; TT group, 17%; p < 0.001), correct insertion of oral airway (ST group, 88%; TT group, 20%; p < 0.001), and achieving an effective BVM seal (ST group, 97%; TT group, 20%; p < 0.001). CONCLUSIONS: Traditional training consisting of 2 years of clinical experience was not sufficient to achieve proficiency in initial airway management skills, mostly due to inadequate equipment usage. This suggests that SBT with CPS is more effective in training medical residents than the traditional experiential method.

[Clinical study of adenoid cystic carcinoma of the parotid gland].

We report results of a retrospective study of 12 cases of adenoid cystic carcinoma (ACC) in the parotid gland. Local pain was often observed in ACC among other malignant parotid tumors. Although fine-needle aspiration cytology (FNA) was not effective for preoperative diagnosis, frozen section diagnosis (FS) during surgery showed excellent results. Cases with T3 or T4 underwent total or enlarged parotidectomy, but, often showed positive surgical margins. Postoperative radiation therapy seemed useful in these cases and the 5-and 10-year disease-specific survivals in these 12 cases were 90.0% and 80.8%. These compare favorably with other reports in the literature. All 12 cases showed NO and no cervical relapse with or without neck dissection, indicating little effectiveness in prophylactic neck dissection. Tumor size, positive surgical margins, and perineural invasion are risk factors for this tumor as mention previously. Patients with perineural invasion, especially preoperative facial nerve palsy (T4a), are more likely to fail than those with two other factors, so, it seems conceivable for cases of T4a to undergo more positive treatment with surgery and postoperative radiation.

Achieving housestaff competence in emergency airway management using scenario based simulation training: comparison of attending vs housestaff trainers.

STUDY OBJECTIVES: To evaluate a teaching protocol comparing a critical care attending to a housestaff team in training medical interns in initial airway management skills using a computer-controlled patient simulator (CPS) and scenario-based simulation training (SST). DESIGN: Prospective, randomized, controlled, unblinded trial. SETTING: Internal medicine residency training program in an urban teaching hospital. PARTICIPANTS: Forty-nine starting internal medicine interns in July 2003, all of whom had been certified in advanced cardiac life support in June 2003. INTERVENTIONS: All interns were tested and scored with a CPS while responding to a standardized respiratory arrest scenario. Random allocation to either training by a single experienced teaching attending or by a housestaff team occurred immediately following testing. All interns were retested using the same scenario 6 weeks following the initial training, and their clinical performance of airway management was scored during actual patient events throughout the year. MEASUREMENTS: Initial airway management was divided into specific scorable steps. For each intern, individual step scores and total scores were recorded before and after training. For 10 consecutive months following training, intern airway management scores were recorded for actual patient airway events. RESULTS: All starting medical interns demonstrated poor initial airway management skills. SST was effective in improving these skills, both on retesting with the patient simulator and in actual patient situations. Interns trained by a housestaff team performed as well as interns trained by the attending. CONCLUSIONS: SST is effective in training medical interns, and the results are equivalent whether the training is provided by an experienced teaching attending or by a housestaff training team.

Viability and plasma vitamin K levels in the common bile duct-ligated rats.

The common bile duct-ligated (CBDL) rat, which is widely used as a model of human cirrhosis, rapidly develops secondary biliary cirrhosis (SBC) within 4 weeks. The CBDL rat shows poor viability, however, a detailed examination of the causes of its death has not been made. In this study, we investigated the outcome of bile duct ligation in detail and attempted to extend the life span of this model by feeding the animals a diet supplemented with nutrients. Survival rate, blood chemistry, blood cell counts, plasma levels of K vitamins and liver histology were compared among CBDL rats fed a standard diet and an enriched diet. Sham-operated rats were used as a control. Six out of 18 CBDL rats fed the standard diet died within 32 days of operation. The cause of death was massive internal hemorrhage in various organs or body cavities. All CBDL rats fed the enriched diet survived more than 31 days, but the viability of CBDL rats was not significant between those fed the standard diet and the enriched diet. The degree of anemia correlated significantly with the prolongation of prothrombin time. Plasma vitamin K1 levels in CBDL rats were significantly lower than those in sham-operated rats, but vitamin K2 levels were similar. We suggest that massive hemorrhage, which was the direct cause of death, is caused by the impairment of hemostasis resulting from vitamin K deficiency. The enriched diet with vitamin K nutritional supplements seemed to contribute to the prolongation of the life span of CBDL rats.

Secondary shunt procedure for alaryngeal patients in an outpatient clinic.

The shunt procedure used for laryngectomized patients undergoing secondary tracheo-esophageal (T-E) puncture is inconvenient and causes stress to the patient. In order to overcome these problems we developed a novel surgical T-E shunt technique using the Groningen voice prosthesis that does not require esophagoscopy or general anesthesia and can be performed in an outpatient clinic. In this procedure, a shunt is created using a pair of nasal forceps with the patient seated. An endoscope with biopsy forceps is used to insert the Groningen voice prosthesis. The procedure is usually completed within 20 min after inducing local anesthesia. Neither the technique itself nor the time taken to complete the procedure differed for T-E and tracheo-neoesophageal (reconstructed with flap) shunting. We believe that this procedure is suitable for patients who are afraid of esophagoscopy and/or are not considered suitable candidates for esophagoscopy and repeated general anesthesia. The procedure is also beneficial for both patients and surgeons with regard to its duration and the cost-effectiveness of treatment.