Discovery of evocalcet, a next-generation calcium-sensing receptor agonist for the treatment of hyperparathyroidism.

The calcium-sensing receptor (CaSR) plays an important role in sensing extracellular calcium ions and regulating parathyroid hormone secretion by parathyroid gland cells, and the receptor is a suitable target for the treatment of hyperparathyroidism. Cinacalcet hydrochloride is a representative CaSR agonist which widely used for the hyperparathyroidism. However, it has several issues to clinical use, such as nausea/vomiting and strong inhibition of CYP2D6. We tried to improve these issues of cinacalcet for a new pharmaceutical agent as a preferable CaSR agonist. Optimization from cinacalcet resulted in the identification of pyrrolidine compounds and successfully led to the discovery of evocalcet as an oral allosteric CaSR agonist. Evocalcet, which exhibited highly favorable profiles such as CaSR agonistic activity and good DMPK profiles, will provide a novel therapeutic option for secondary hyperparathyroidism.

The value of progesterone receptor expression in predicting the Recurrence Score for hormone-receptor positive invasive breast cancer patients.

BACKGROUND: OncotypeDX(®) (ODX) is a well-validated assay for breast cancer treatment planning. We explored whether the conventional pathological factors could pick up high risk patients without the help of the ODX. METHODS: The ODX was performed on 139 hormone receptor-positive invasive breast cancers in a single Japanese institution. The recurrence risk was compared between the ODX and the St. Gallen Consensuses. The correlations were analyzed between the Recurrence Score (RS) measured by ODX and the pathological factors. In addition, we performed a follow-up survey and examined the association of the RS with the confirmed recurrence or death. RESULTS: The ODX classified 68 (49 %) as low RS, 52 (37 %) as intermediate RS, and 19 (14 %) as high RS cases. Correlations were noted between RS and progesterone receptor (PR) (r = -0.53), Ki-67 (r = 0.42), and nuclear grade (NG) (r = 0.41). None had a high RS with PR(3+) or NG1. Only one high RS patient had a Ki-67 (<20 %). The combinations of high RS with PR(0)/Ki-67 (≥20 %) and PR(1+)/Ki-67 (≥20 %) were 70 and 58 %, respectively. The combinations with high RS and PR(0)/NG3, PR(0)/NG2, and PR(1+)/NG3 were 83, 75, and 75 %, respectively. The median follow-up was 39.1 months (range 24.0-67.8). There were one low RS (1 %), four intermediate RS (8 %), and three high RS patients (16 %) who developed local or distant recurrence. CONCLUSION: Hormone receptor-positive invasive breast cancers are stratified with the combinations of PR/Ki-67 or PR/NG. Some of the high recurrence risk cases might be identified without the ODX.

[The usefulness and adverse events of bevacizumab combined with chemotherapy against advanced or recurrent colorectal cancer].

We examined clinical results of 35 patients on bevacizumab(BV)combined with chemotherapy at our hospital. The subjects were 35 patients with advanced or recurrent colorectal cancer who received BV combined with chemotherapy for approximately 2 years. Their median age was 66 years(41 to 86 years), PS was 2 or less for all; it was first-line therapy in 21 patients, second-line in 12 patients and thirdline in 2 patients. The concomitant chemotherapy was mFOLFOX 6 in 24 / patients, 5-FU/LV in 8 patients and FOLFIRI in 3 patients. Therapeutic efficacy was CR in 2 patients, PR in 10 patients, and the overall response rate was 35%. There were 7 adverse events of Grade 3 or higher, among which 4 events were leucopenia. Neither overall survival nor any concomitant chemotherapy reached the median periods. Moreover, the median periods of / progression-free survival in mFOLFOX6/FOLFIRI were 191 days. BV combined with chemotherapy should be actively introduced as first-line therapy against advanced or recurrent colorectal cancer because of its high therapeutic efficacy.

Contrast-enhanced intraoperative ultrasonography equipped with late Kupffer-phase image obtained by sonazoid in patients with colorectal liver metastases.

AIM: To find occult metastases during hepatectomy in patients with colorectal cancer liver metastases (CRCLM), contrast-enhanced intraoperative ultrasonography (CE-IOUS) was performed using a new microbubble agent, sonazoid, which provides a parenchyma-specific contrast image based on its accumulation in the Kupffer cells. METHODS: Eight patients with CRCLM underwent CE-IOUS using sonazoid before hepatectomy. The liver was investigated during a late Kupffer-phase imaging, which is a valuable characteristic of sonazoid. RESULTS: CE-IOUS using sonazoid provided the early vascular- and sinusoidal-phase images for 10 min followed by the late Kupffer-phase image up to 30 min after the injection of sonazoid. IOUS did not provide new findings of metastatic lesion in the 8 patients. However, during the late Kupffer-phase image of sonazoid, a metastatic lesion was newly found in two of the 8 patients. These newly detected lesions were removed by an additional hepatectomy and histopathologically diagnosed as a metastasis. CONCLUSION: CE-IOUS using sonazoid can allow surgeons to investigate the whole liver with enough time and to find new metastases intraoperatively.

Nonprincipal neurons and CA2 pyramidal cells, but not mossy cells are immunoreactive for calcitonin gene-related peptide in the mouse hippocampus.

The distribution and morphological features of calcitonin gene-related peptide (CGRP) positive neurons in the mouse hippocampus were immunohistochemically analyzed, focusing on their differences between mice and rats. In contrast with those in the rat dentate gyrus, the mossy cell somata and their axon terminals in the mouse dentate gyrus were CGRP negative even after intraventricular colchicine injection. In the rat CA1-CA2-CA3 regions, there were two types of CGRP positive neurons, some of the CA3 pyramidal cells and relatively few nonprincipal neurons. In the mouse CA1-CA2-CA3 regions, there were also two types of CGRP positive neurons. The majority were scattered throughout layers and abundant in number when compared with those in the rat hippocampus. They were regarded as nonprincipal neurons by their distribution, structural features and glutamic acid decarboxylase 67 (GAD67) immunoreactivity. The minor group was clustered in the stratum pyramidale of the CA2 region. They extended thick apical dendritic shafts into the stratum radiatum, were GAD67 negative, and thus were regarded as the CA2 pyramidal cells. The CGRP positive nonprincipal neurons were apparently heterogeneous and further characterized immunohistochemically. Although there were significant regional differences in the chemical properties of the CGRP positive nonprincipal neurons, in the whole hippocampus, over 40% of CGRP positive nonprincipal neurons were also positive for parvalbumin, about 15% were positive for somatostatin and about 20% were positive for cholecystokinin, respectively. The present study clearly showed that there were prominent species differences between the mouse and rat hippocampus in the CGRP immunoreactivities.

A New Synthesis of 1beta-Alkylcarbapenems Utilizing Eschenmoser Sulfide Contraction of the Novel Thiazinone Intermediates.

Novel syntheses of the 1beta-alkylcarbapenems were achieved on the basis of Eschenmoser sulfide contraction via the new bicyclic 1,3-thiazinone intermediates. 1,3-Thiazinones 7, 16, and 25 were effectively prepared from thioesters 5 and 22 using a C4-S bond formation process. The sulfide contraction reactions were performed by treatment of 7, 16, and 25 with base (NaH or KO-t-Bu) in the presence of triphenylphosphine to generate the corresponding carbapenem enolate 12, 17, and 26, which were trapped by (PhO)(2)POCl followed by the reaction with mercaptans to afford carbapenems 10a, 10b, 19, and 28, respectively.