Xelaglifam, a novel GPR40/FFAR1 agonist, exhibits enhanced ß-arrestin recruitment and sustained glycemic control for type 2 diabetes.

Xelaglifam, developed as a GPR40/FFAR1 agonist, induces glucose-dependent insulin secretion and reduces circulating glucose levels for Type 2 diabetes treatment. This study investigated the effects of Xelaglifam in comparison with Fasiglifam on the in vitro/in vivo anti-diabetic efficacy and selectivity, and the mechanistic basis. In vitro studies on downstream targets of Xelaglifam were performed in GPR40-expressing cells. Xelaglifam treatment exhibited dose-dependent effects, increasing inositol phosphate-1, Ca2+ mobilization, and ß-arrestin recruitment (EC50: 0.76 nM, 20 nM, 68 nM), supporting its role in Gq protein-dependent and G-protein-independent mechanisms. Despite a lack of change in the cAMP pathway, the Xelaglifam-treated group demonstrated increased insulin secretion compared to Fasiglifam in HIT-T15 ß cells under high glucose conditions. High doses of Xelaglifam (<30 mg/kg) did not induce hypoglycemia in Sprague-Dawley rats. In addition, Xelaglifam lowered glucose and increased insulin levels in diabetic rat models (GK, ZDF, OLETF). In GK rats, 1 mg/kg of Xelaglifam improved glucose tolerance (33.4 % and 15.6 % for the 1 and 5 h) after consecutive glucose challenges. Moreover, repeated dosing in ZDF and OLETF rats resulted in superior glucose tolerance (34 % and 35.1 % in ZDF and OLETF), reducing fasting hyperglycemia (18.3 % and 30 % in ZDF and OLETF) at lower doses; Xelaglifam demonstrated a longer-lasting effect with a greater effect on ß-cells including 3.8-fold enhanced insulin secretion. Co-treatment of Xelaglifam with SGLT-2 inhibitors showed additive or synergistic effects. Collectively, these results demonstrate the therapeutic efficacy and selectivity of Xelaglifam on GPR40, supportive of its potential for the treatment of Type 2 diabetes.

Prediction of Pharmacokinetics of IDP-73152 in Humans Using Physiologically-Based Pharmacokinetics.

IDP-73152, a novel peptide deformylase inhibitor with an antibacterial effect against Gram-positive bacteria, is in phase I development. The objective of this study was to develop a physiologically-based pharmacokinetic model (PBPK) for IDP-73152 in animals, and to extend the model to humans. Biopharmaceutical properties of IDP-73152 are determined using in vitro/in vivo experimentations for the PBPK model. A transit model consisting of gastrointestinal segments is applied for an estimation of the intestinal absorption kinetics. The PBPK model of IDP-73152 in rats is able to appropriately predict the plasma concentration-time profiles after the administration of IDP-73152 at different doses and by different routes (combined absolute average fold error (cAAFE), 1.77). The model is also found to be adequate in predicting the plasma concentration-time profiles of IDP-73152 in mice (cAAFE 1.59) and dogs (cAAFE 1.42). Assuming the oral administration of IDP-73152 to humans at doses of 640 and 1280 mg, the model is able to reproduce the concentration-time profiles obtained in humans (cAAFE 1.38); therefore, these observations indicate that the PBPK model used for IDP-73152 is applicable to animal species and humans. This model may be useful in predicting efficacious doses of IDP-73152 for the management of infectious disease in humans.

Pharmacokinetics and tolerability of IDP-73152 mesylate after a single oral administration under fasted and fed conditions in healthy volunteers.

BACKGROUND AND OBJECTIVE: IDP-73152 mesylate is a peptide deformylase inhibitor under investigation for the treatment of complicated skin and respiratory tract infections. The objective of this study was to investigate the pharmacokinetic (PK) profile and tolerability of IDP-73152 and the effect of food after a single oral administration. METHODS: A dose block-randomized, double-blind, placebo-controlled, dose-escalation study was conducted. A total of 56 healthy volunteers received IDP-73152 mesylate in a single oral dose of 40, 80, 160, 320, 640, or 1280 mg in the fasted and fed (640 mg only) states. Blood and urine samples for PK analysis were collected up to 48 h post dose. RESULTS: The area under the plasma concentration-time curve (AUC0-t) of IDP-73152 increased in a dose-proportional manner in the range of 40-320 mg. The mean terminal half-life decreased from 10.7 to 6.2 hrs as the dose increased. The fraction excreted unchanged in the urine ranged from 0.05 to 0.12. In the 640-mg dose group, food delayed the median time to peak concentration (t max) from 0.9 to 3.5 hrs. Furthermore, the maximum plasma concentration (Cmax) were decreased by 36.2%; however, AUC0-t was not generally affected. No serious adverse event or clinically significant findings were observed. CONCLUSIONS: The systemic exposure of IDP-73152 proportionally increased as the dose increased up to 320 mg. The rate of absorption and extent of exposure were reduced by food intake. IDP-73152 was well tolerated without clinically significant adverse effects after a single oral administration.

Identification of novel aminopiperidine derivatives for antibacterial activity against Gram-positive bacteria.

We have previously reported amidopiperidine derivatives as a novel peptide deformylase (PDF) inhibitor and evaluated its antibacterial activity against Gram-positive bacteria, but poor pharmacokinetic profiles have resulted in low efficacy in in vivo mouse models. In order to overcome these weaknesses, we newly synthesized aminopiperidine derivatives with remarkable antimicrobial properties and oral bioavailability, and also identified their in vivo efficacy against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE) and penicillin-resistant Streptococcus pneumoniae (PRSP).

Comparative histomorphometric analysis of maxillary sinus augmentation with and without bone grafting in rabbit.

PURPOSE: The aim of this animal study was to evaluate, by histomorphometric analysis, new bone formation in rabbit maxillary sinuses with, and without, bone grafting. MATERIALS AND METHODS: Bilateral sinus augmentation procedures were performed in 20 adult male rabbits. Bony windows were made by a saw insert connected with a piezoelectric surgical device in both groups. In the experimental group, the replaceable bony window was repositioned after careful elevation of the sinus mucosa without bone grafting. In the control group, anorganic bovine graft (Bio-Oss; Geistlich AG, Wolhusen, Switzerland) was grafted in the new compartment of the maxillary sinus after elevation of the sinus membrane, and resorbable collagen membrane was used to cover over the bone graft. A mini screw was placed on the bony window to support the elevated sinus membrane. Animals were sacrificed at 1, 2, 4, 6, or 8 weeks after surgical procedure. The augmented sinuses were evaluated by histomorphometric analysis using hematoxylin-eosin and tartrate-resistant acid phosphatase stain. RESULTS: Histologically, new bone was revealed along the elevated sinus membrane, but new bone was not revealed under the collagen membrane or Bio-Oss in the control group after 1 week. In the control group, new bone formation was revealed on the surface of Bio-Oss particles from 2 weeks and continued to 8 weeks. However, new bone formation began from the floor of the replaced bony window and the elevated sinus membrane in the experimental group after 1 week. New bone formation increased under the floor of the repositioned bony window and the elevated sinus membrane, and blood clots appeared in the new compartment of the maxillary sinus throughout the experimental period in the experimental group. Significant higher new bone formation was revealed in the experimental group than in the control group. CONCLUSION: New bone formation in the experimental group was faster and denser than that in the control group. Replaceable bony window, as an autologous barrier, accelerates new bone formation early in the healing phase compared with the collagen membrane over a bone graft in the maxillary sinus. The replaceable bony window and elevated sinus membrane revealed osteoinductive potential.

Piezoelectric internal sinus elevation (PISE) technique: a new method for internal sinus elevation.

This article reports the surgical procedure of a transalveolar approach for sinus floor elevation using piezoelectric surgery without a mallet, called piezoelectric internal sinus elevation (PISE) technique. PISE is the modified technique of the osteotome-mediated sinus floor elevation. Osteotome-mediated sinus floor elevation uses a mallet to break the sinus floor and to push sinus membrane up. Using this technique might possibly bring positional vertigo to the patient. PISE technique does not use a mallet during the procedure to break the sinus floor and to elevate the sinus membrane; therefore, it can reduce the possibility of postoperative positional vertigo.

Efficacy of demineralized bone matrix paste for maxillary sinus augmentation: a histologic and clinical study in humans.

OBJECTIVES: The aim of this study is to report the effect of paste type of demineralized bone matrix (DBM) on augmentation of maxillary sinus using clinical parameters. STUDY DESIGN: Sinus augmentation with DBM was performed on 5 maxillary sinuses. This study included 5 patients, 4 men and 1 woman, aged from 41 to 67 years (mean age 55 years). After an average of 6 months' healing period, a core bone was obtained and stained for histologic analysis. RESULTS: All implants showed favorable osseointegration, and final restorations were completed without failure in all cases. Histologically, new bone formation was active around grafted bone and grafted bone was well integrated to the newly formed bone matrix. In histomorphometric analysis, vital bone volume was 25.2 +/- 11.9%. CONCLUSION: The DBM paste is clinically useful for the increase of bone volume in sinus augmentation, because of its favorable effect of new bone formation and easy handling.

Reconstruction of atrophic anterior mandible using piezoelectric sandwich osteotomy: a case report.

Extensive loss of alveolar bone and teeth in the anterior mandible presents a complex problem for reconstruction. Numerous augmentation techniques are currently in use to create sufficient bone volume for reliable placement of endosseous implants in the case of severely resorbed mandibles. The aim of this report is to assess the efficacy of the piezoelectric sandwich osteotomy for vertical augmentation in the atrophic segment of anterior mandible through clinical and histologic studies. A complete osteotomized segment was made, using the piezoelectric saw, to make a segmented bone in the atrophic edentulous area and the mobile segment was elevated by 10-mm high vertically. Interpositional mineral allograft materials were inserted in the space between the basal bone and the segmented bone. A bone biopsy was performed on the augmented bone region and 3 dental implants were placed simultaneously 6 months later. About 10 mm of vertical gain was achieved by the sandwich technique. Histologic analysis presents new bone formation without inflammatory or foreign body reactions.

Histomorphometric evaluation of mineralized cancellous allograft in the maxillary sinus augmentation: a 4 case report.

PURPOSE: The aim of this article is to report the histomorphometric analysis and clinical study of mineralized cancellous bone allografts in maxillary sinus augmentation procedures in 4 cases. MATERIALS AND METHODS: Sinus bone augmentation, using a piezoelectric device and mineralized cancellous allografts, was performed in 3 patients. After an average of about 8 months of healing, a trephine core sample was gained from the lateral windows area for histomorphometric analysis. The mineralized cancellous allografts demonstrated normal healing of hard tissues. RESULTS: Upon reentry for dental implant placement or secondary surgery, the graft materials showed hard bony structures within the maxillary sinus. Histomorphometric analysis of the cores revealed an average vital new bone content of 17.88%. CONCLUSION: Mineralized cancellous allografts showed favorable bone regeneration histologically and was clinically useful in augmenting bone volume for implant placement in the sinus bone graft.

Erbium, chromium:yttrium-scandium-gallium-garnet laser-assisted sinus graft procedure.

The possibility of using lasers in the field of dentistry has been a subject of investigation. There are few reports that any laser systems have been used for bony window osteotomy by direct sinus grafting. In this study, erbium, chromium:yttrium-scandium-gallium-garnet (Er,Cr:YSGG) laser of various laser systems was used for 12 sinus bone grafts in ten patients, and the efficiency of the laser was evaluated according to the osteotomy time and the rate of sinus membrane perforation in the clinical results; the mechanism is described. Eight of the 12 procedures were performed by direct sinus grafting with the Er,Cr:YSGG laser without membrane perforation (perforation ratio 33.3%). Operating time for bony window osteotomy with laser alone was 2-7 minutes [3 min 24 s on average; 3.4 +/- 1.4 min (mean +/- standard deviation)], and all the implants placed immediately were successful.

Fungal infection as a complication of sinus bone grafting and implants: a case report.

Sinus bone grafts have been used successfully to augment atrophic posterior maxilla for dental implant placement. Even though sinus bone grafting is generally considered to be a safe surgical procedure, postoperative maxillary sinus infections can occur and therefore need to be considered. Bacteria, as well as viruses and fungi, have been identified as causative agents. Because fungal infection of the maxillary sinus after sinus bone grafting is not well known, we report a case of a middle-aged male patient along with the clinical, radiographic, and histologic findings. The patient was referred from his private dentist because of failed sinus bone grafting and osseointegration of implants. The surgical approach to the sinus yielded a friable mass of brownish-red material from the sinus. Review of pathology slides revealed a noninvasive hyphal mass caused by Aspergillus and polypous mucosa. After surgical removal of the mycotic masses, sinus bone grafting, using allograft, was performed. Bone formation after the healing period was favorable and dental implants were placed. There was no recurrence of fungal sinusitis.

Minor tooth movements using microimplant anchorage: case reports.

For the treatment of extruded or tipped molars, various conventional techniques have been used. But those methods may lead to undesirable movement of the anchorage units and lengthen treatment time because of limited tooth-borne anchorage potential. Introduction of microimplants as orthodontic anchorage has expanded treatment possibilities because of their advantages. Some advantages are a less complex surgical procedure, decrease in cost, immediate loading, and their ability to be placed in any area of the alveolar bone. This article will illustrate clinical experiences in patients who were treated with the intrusion of overerupted molars, the up-righting of tilted molars, and other clinical applications for minor tooth movements. Anchorage control was achieved with the surgical insertion of titanium microimplants for immediate loading in the alveolar bone. When needed, minimal fixed appliances were used and orthodontic treatment was completed without any other complications.

Immediate loading with mini dental implants in the fully edentulous mandible.

The use of immediate loaded prostheses is not recommended for at least 2 weeks to prevent implants from premature loading. In addition, immediate removable prostheses are negated for at least 4 weeks at the site of guided bone regeneration or bone graft. However, patients are often not pleased with limited diets and the unaesthetic appearance during the healing period without a denture between implant placement and final prosthesis. Mini dental implants provide stable and esthetic temporary prostheses immediately after implant placement and bone grafts. The use of mini dental implants is simple and cost effective because the patient's old denture is used as a provisional prosthesis. This article shows the success of 27 mini dental implants that were placed for 11 mandibular fully edentulous patients.