Pseudoirreversible inhibition elicits persistent efficacy of a sphingosine 1-phosphate receptor 1 antagonist.

Sphingosine 1-phosphate receptor 1 (S1PR1), a G protein-coupled receptor, is required for lymphocyte trafficking, and is a promising therapeutic target in inflammatory diseases. Here, we synthesize a competitive S1PR1 antagonist, KSI-6666, that effectively suppresses pathogenic inflammation. Metadynamics simulations suggest that the interaction of KSI-6666 with a methionine residue Met124 in the ligand-binding pocket of S1PR1 may inhibit the dissociation of KSI-6666 from S1PR1. Consistently, in vitro functional and mutational analyses reveal that KSI-6666 causes pseudoirreversible inhibition of S1PR1, dependent on the Met124 of the protein and substituents on the distal benzene ring of KSI-6666. Moreover, in vivo study suggests that this pseudoirreversible inhibition is responsible for the persistent activity of KSI-6666.

Design, synthesis, and structure-activity relationships of a series of 4-benzyl-5-isopropyl-1H-pyrazol-3-yl ß-D-glycopyranosides substituted with novel hydrophilic groups as highly potent inhibitors of sodium glucose co-transporter 1 (SGLT1).

Sodium glucose co-transporter 1 (SGLT1) plays a dominant role in the absorption of glucose in the gut and is considered a promising target in the development of therapeutic options for postprandial hyperglycemia. Previously, we reported potent and selective SGLT1 inhibitors 1 and 2 showing efficacy in oral carbohydrate tolerance tests in diabetic rat models. In a pharmacokinetic (PK) study of 2, excessive systemic exposure to metabolites of 2 was observed, presumably due to the high permeability of its aglycone (2a). To further improve SGLT1 inhibitory activity and reduce aglycone permeability, a series of 4-benzyl-5-isopropyl-1H-pyrazol-3-yl ß-D-glycopyranoside derivatives bearing novel hydrophilic substitution groups on the phenyl ring were synthesized and their inhibitory activity toward SGLTs was evaluated. Optimized compound 14c showed an improved profile satisfying both higher activity and lower permeability of its aglycone (22f) compared with initial leads 1 and 2. Moreover, the superior efficacy of 14c in various carbohydrate tolerance tests in diabetic rat models was confirmed compared with acarbose, an α-glucosidase inhibitor (α-GI) widely used in the clinic.

Structure-activity relationship studies of 4-benzyl-1H-pyrazol-3-yl ß-d-glucopyranoside derivatives as potent and selective sodium glucose co-transporter 1 (SGLT1) inhibitors with therapeutic activity on postprandial hyperglycemia.

Sodium glucose co-transporter 1 (SGLT1) plays a dominant role in the absorption of glucose in the gut and is considered a promising target in the development of treatments for postprandial hyperglycemia. A series of 4-benzyl-1H-pyrazol-3-yl ß-d-glucopyranoside derivatives have been synthesized, and its inhibitory activity toward SGLTs has been evaluated. By altering the substitution groups at the 5-position of the pyrazole ring, and every position of the phenyl ring, we studied the structure-activity relationship (SAR) profiles and identified a series of potent and selective SGLT1 inhibitors. Representative derivatives showed a dose-dependent suppressing effect on the escalation of blood glucose levels in oral mixed carbohydrate tolerance tests (OCTT) in streptozotocin-nicotinamide-induced diabetic rats (NA-STZ rats).

Long-term study of dental implants placed into alveolar cleft sites.

OBJECTIVE: To evaluate the long-term prognosis of dental implants placed into cleft sites after bone grafting in a relatively large number of cases in order to clarify the usefulness of the modality. PATIENTS: Forty-seven patients with unilateral (dental, n=32) or bilateral (n=15) clefts of the alveolar process were included in this study. INTERVENTIONS: A total of 71 implants, including smooth- or rough-surface titanium, and hydroxyapatite (HA)-coated implants, were placed after bone grafting from the anterior iliac crest and/or mandible. The placed implants were 13 to 15 mm in length. MAIN OUTCOME: The follow-up period was from 21 to 120 months (average=60 months). Implant survival rates were calculated as cumulative survival. Marginal bone loss (MBL) from the implant shoulder was examined, with statistical analyses performed on the influence of simultaneous bone graft and surface characteristics. RESULTS: At the end of the clinical follow-up period, all implants except one were in situ and stable. Thus, the overall survival rate was 98.6% at the end of the first year and remained the same until the end of observation. Titanium implants with smooth surfaces had the lowest MBL with almost negligible regression slope, although some implants had relatively high MBL by the end of the first year. CONCLUSIONS: Implant therapy in the cleft site offers a reliable option for patients. Particular attention should be focused preoperatively on whether bone volume can provide primary implant stability.

Alveolar bone graft for patients with cleft lip/palate using bone particles and titanium mesh: A quantitative study.

PURPOSE: This study evaluated the bone volume, height, and width that can be obtained in alveolar ridge augmentation using titanium mesh and autogenous bone particles in patients with cleft lip/palate. PATIENTS AND METHODS: Subjects were 15 patients with cleft lip/palate requiring tertiary bone graft for implant therapy. Computed tomography (CT) scans were taken before removing the mesh, from 1 to 21 months after bone grafting. Forty-three reconstructed images corresponding to the positions for implant placement were selected for this study. The percent defect filled with bone (%BONE), defined as the percentage of newly formed bone in the space created by the mesh, was measured for image analyses. In linear analyses, 4 parameters were used: increased bone height (IBH), percent increased bone height (%IBH), increased bone width (IBW), and percent increased bone width (%IBW). Factors influencing the quantitative data and the clinical courses of placed implants were also explored. RESULTS: The average %BONE was 91.1%. IBH averaged 4.4 mm, whereas %IBH averaged 88.5%. IBW averaged 4.6 mm, whereas %IBW averaged 86.4%. Little correlation was present between the quantitative data and patient age, or time interval. A significant correlation was identified between the data for span of the grafted area and %BONE (correlation coefficient value = -0.36). However, the diminishing rate was very low. No implants were lost postoperatively. CONCLUSIONS: Alveolar ridge augmentation with titanium mesh and autogenous bone particles from the anterior iliac crest has very high predictability as a preimplant procedure in patients with cleft lip/palate.

Effect of intermittent parathyroid hormone (1-34) treatment on the bone response after placement of titanium implants into the tibia of ovariectomized rats.

PURPOSE: This study investigated the effect of parathyroid hormone (1-34) [PTH(1-34)] on bone reactions after tibial placement of titanium screw implants into ovariectomized rats. MATERIALS AND METHODS: Twelve-week-old female Wistar rats were divided into 3 groups of 24. The first group (Sham group) was sham-operated; the second group (OVX group) was ovariectomized only; and the third group (PTH group) was subcutaneously administered 30 microg/kg PTH in the dorsal region 3 days per week starting the fourth week after ovariectomy until the end of the experiment. Titanium screw implants were placed in the proximal metaphysis of the tibia of all 3 groups at 168 days after surgery. The animals were killed 7, 14, 28, and 56 days after implantation. Undecalcified sections were prepared and evaluated by light microscopy. Histomorphometric measurements were obtained using a computer-based image analyzer to quantify the unit bone mass around the implant and the rate of implant-bone contact. RESULTS: When PTH administration was started 21 days after ovariectomy, the volume density of bone around implants in the PTH group was almost the same as that of the Sham group throughout the entire observation period. This finding suggests that not only can intermittent human PTH(1-34) administration prevent resorption of newly generated trabeculae around an implant but also it can aid in the recovery of bone volume lost due to ovariectomy. CONCLUSION: When dental implants are applied to jaw bone showing trabecular bone loss, it may be possible to increase bone density around an implant by intermittent human PTH(1-34) administration and thereby improve clinical results.

Effects of bisphosphonate on bone reaction after placement of titanium implants in tibiae of ovariectomized rats.

PURPOSE: This study was undertaken to investigate the action of bisphosphonate on bone reactions after the placement of titanium screw implants into the tibiae of ovariectomized rats. MATERIALS AND METHODS: Twelve-week-old female Wistar rats were divided into 4 groups of 18 animals each. The first group (Sham) was sham-operated, the second group (OVX) was ovariectomized only, the third group (Estrogen) was ovariectomized and received continuous estrogen with a 17beta-estradiol pellet, and the fourth group (YM-175) was ovariectomized and received bisphosphonate at a dose of 10 microg/kg of body weight. Titanium screw implants were placed in the proximal metaphyses of the tibiae 168 days after surgery. The animals were sacrificed 7, 14, and 56 days after implant placement. Undecalcified sections were prepared and evaluated by light microscopy. Histomorphometric measurements were obtained with a computer-based image analyzer to quantify the unit bone mass around the implant and the rate of implant-bone contact. RESULTS: Ovariectomies significantly reduced implant-bone contact and the bone volume around the implants. However, in the YM-175 group, only slight differences in both bone contact and bone volume were noted compared with the Sham and Estrogen group. The woven structure of new bone in the YM-175 group was also replaced by mature lamellar bone, as in the other groups. DISCUSSION AND CONCLUSION: These results suggested that bisphosphonate preserved the implant-bone contact and bone volume around the implants.

An anatomical study of vascularized iliac bone grafts for dental implantation.

PURPOSE: The purpose of this study was to clarify the anatomical features of vascularized iliac bone grafts used for mandibular reconstruction and dental implantation. MATERIAL AND METHOD: Twenty-six cadavers were dissected to examine vessels and areas of iliac bone that could be used as pedicles and grafts. The length and diameter of vessels of the vascular pedicle were determined, and the length and depths of the iliac bone were measured with respect to points determined by the relative dimensions of the bone. RESULTS: The deep circumflex iliac arteries were classified as double nutrient type (75%), iliac-crest type (19%), or iliacus-muscle type (6%). The mean arterial length was 64+/-15 mm in the double nutrient type. The mean internal diameters at the origin of the deep circumflex iliac artery and vein that could be used for anastomosis were 1.7+/-0.4 mm and 2.1+/-0.7 mm respectively. The greatest mean cross-sectional width and height were 18+/-3 and 42+/-5 mm respectively. The greatest mean cross-sectional cortical thickness at the intermediate line of the iliac crest was 3.4+/-0.8 mm. CONCLUSION: These results should be useful in designing bone grafts for mandibular reconstruction followed by dental implantation.

Relationship of the mandibular canal to the lateral cortex of the mandibular ramus as a factor in the development of neurosensory disturbance after bilateral sagittal split osteotomy.

PURPOSE: This study evaluated the location of the mandibular canal in the ramus of the mandible before bilateral sagittal split ramus osteotomy and examined its relationship with postoperative neurosensory disturbance. PATIENTS AND METHODS: The subjects consisted of 20 patients undergoing bilateral sagittal split ramus osteotomy. Before surgery, the region from a plane containing the lowest point of the mandibular foramen to 22 mm below it was observed on transaxial computed tomograms acquired with a slice thickness of 2 mm and a slice interval of 2 mm. The relationship between the distance from the mandibular canal to the external cortical bone and neurosensory disturbance in the lower lip or mentum more than 1 year after surgery was evaluated. RESULTS: The mandibular canal came into contact with the external cortical bone on 10 sides (25%); neurosensory disturbance occurred on all these sides, an incidence significantly greater than that (20%) on the 30 sides (75%) without contact between the canal and the external cortical bone (P <.05). In patients with mandibular canal/external cortical bone contact, the vertical extent of contact ranged from 2 to 18 mm (mean, 10.6 +/- 4.9 mm). Neurosensory disturbance was significantly more likely to be present 1 year after surgery, when the width of the marrow space between the mandibular canal and the external cortical bone was 0.8 mm or less (P <.002). CONCLUSIONS: The increased risk of neurosensory disturbance associated when there is contact between the mandibular canal and the external cortical bone should be considered when sagittal split ramus osteotomy is performed.

Clinicoanatomic study on the craniofacial bones used for cranio- and maxillofacial implants.

PURPOSE: To clarify basic clinico-anatomic factors associated with cranio-maxillofacial rehabilitation using implants. MATERIALS AND METHODS: Morphometrically evaluated were items such as the length and width of bone and the thickness of cortical bone at important sites for implant placement into cranial and maxillofacial bones in 30 cadavers at autopsy. RESULTS: At sites corresponding to potential placement sites for implants as the fixation source for ocular epitheses, the mean length of bone was 7.8 mm, and the mean width was 8.3 mm. CONCLUSION: Useful data have been obtained for the selection of the placements sites, direction, length, and external diameter of cranio- and maxillofacial implants.