EFFICACY AND SAFETY OF BISPHOSPHONATE THERAPY IN MCCUNE-ALBRIGHT SYNDROME-RELATED POLYOSTOTIC FIBROUS DYSPLASIA: A SINGLE-CENTER EXPERIENCE.

OBJECTIVE: Fibrous dysplasia (FD) is a rare disorder characterized by pain, deformity, and pathologic fractures. McCune-Albright syndrome (MAS) includes a combination of FD, hyperfunctional endocrinopathy, and/or café-au-lait pigmentation. Surgery is generally ineffective in treating FD. This study aimed to evaluate the efficacy and safety of bisphosphonates (BPs) and compare the efficacy of different BPs in FD patients. METHODS: In this retrospective clinical study, laboratory and clinical findings of 22 polyostotic FD cases all associated with MAS were recorded before and after therapy with BPs. RESULTS: Within the first year of therapy with BPs, the level of alkaline phosphatase (ALP) decreased by 30.3% of baseline in the alendronate cases and by 22.7 ± 16.9% and 34.1 ± 26.3% in the pamidronate (PAM) (n = 10) and zoledronic acid (ZA) (n = 11) groups, respectively. There was no significant difference ( P = .256) between the PAM and ZA groups in the rate of change in ALP levels. Bone pain was alleviated in 64% of the cases. Number of affected bones was positively correlated with baseline serum ALP levels ( r = 0.533; P = .011), which was the only significant factor affecting efficacy of BPs. BP treatment was safe and caused no obvious impairment on children's linear growth. CONCLUSION: Our results suggest that BPs may suppress high bone turnover to partially control the activity of the disease and are well tolerated in most patients. ZA has similar effects as PAM in controlling disease activity. ABBREVIATIONS: ALP = alkaline phosphatase; ß-CTX = C-terminal telopeptide of type I collagen; BP = bisphosphonate; BTM = bone turnover marker; FD = fibrous dysplasia; MAS = McCune-Albright syndrome; ONJ = osteonecrosis of the jaw; PAM = pamidronate; PFD = polyostotic fibrous dysplasia; ULN = upper limit of normal; ZA = zoledronic acid.

Drug-coated balloon for vertebral artery origin stenosis: a pilot study.

BACKGROUND: Drug-coated balloon (DCB) is a potential treatment for patients with low restenosis risk in vertebral artery origin stenosis (VAOS). However, the clinical data of long-term outcome are limited. OBJECTIVE: To evaluate the safety and efficacy of a DCB in patients with severe VAOS. METHODS: A prospective, non-randomized, single-center pilot study enrolled 30 patients with severe VAOS treated with DCB between 2017 and 2018. The first 20 patients were treated with a balloon-to-vessel ratio of predilation (pBVR)＜0.8 (small-size balloon predilation) and the following 10 patients were treated with a pBVR 0.8-1.0 (large-size balloon predilation). Primary safety endpoints included 30-day death, stroke, and transient ischemic attack (TIA). The main efficacy outcome was restenosis at 6 months, defined as a peak systolic velocity >140 cm/s measured by Doppler ultrasound. Long-term outcomes, including TIAs, stroke, death, and modified Rankin Scale score, were followed up to 2 years. RESULTS: Technical success (<50% residual stenosis) was achieved in 26 patients (mean age 66.2±7.0; seven women). Four patients received bailout stenting and were excluded. Ultrasound confirmed restenosis at 6 months in 10 (38.5%) of 26, which was significantly less frequent in LSBP (LSBP vs SSBP=10% vs 56.3%, p<0.05). No adverse events occurred within 30 days of treatment. 19 patients were followed up for 2 years, with two deaths due to cancer. CONCLUSION: This pilot study suggests that DCB is a safe approach for VAOS. The relatively low restenosis rate indicates the its potential long-term efficacy for VAOS. Future randomized controlled trials to confirm its efficacy are warranted.

One-step treatment of periodontitis based on a core-shell micelle-in-nanofiber membrane with time-programmed drug release.

As a chronic inflammatory disease, periodontitis is responsible for irreversible soft tissue damage and severe alveolar bone resorption. However, curative effects of current therapies are largely confined by the difficulty to simultaneously achieve anti-inflammation and bone regeneration. Also, the dynamic environment in oral cavity easily causes the drugs swallowed or rinsed away by saliva. We report here a one-step treatment based on a core-shell nanofiber membrane fabricated by coaxial electrospinning. Polymeric micelles containing SP600125 were distributed in the shell, while BMP-2 was incorporated in the core. After crosslinking, the nanofiber membrane displayed a prolonged degradation and release period up to 4 weeks. The release of SP600125 was detected at beginning, whereas BMP-2 was not released until day 12. Such a time-programmed release behavior was proved desirable for suppressing the expression of pro-inflammatory factors and enhancing the osteogenic induction in vitro. Further in vivo investigation confirmed that, by simply covering the periodontitis site with our nanofiber membrane, alveolar destruction was largely avoided and bone defects recovered within 2 month. Taken together, we believe that the use of our membrane with sequential release of SP600125 and BMP-2 may become a convenient and highly comprehensive therapy for periodontitis.

Nobiletin-loaded micelles reduce ovariectomy-induced bone loss by suppressing osteoclastogenesis.

BACKGROUND: Nobiletin (NOB), a polymethoxy flavonoid, possesses anti-cancer and anti-inflammatory activities, has been reported that it played role in anti-osteoporosis treatment. However, previous research did not focus on practical use due to lack of hydrophilicity and cytotoxicity at high concentrations. The aim of this study was to develop a therapeutic formulation for osteoporosis based on the utilization of NOB. METHODS: In this study, NOB-loaded poly(ethylene glycol)-block-poly(e-caprolactone) (NOB-PEG-PCL) was prepared by dialysis method. The effects on osteoclasts and anti-osteoporosis functions were investigated in a RANKL-induced cell model and ovariectomized (OVX) mice. RESULTS: Dynamic light scattering and transmission electron microscopy examination results revealed that the NOB-PEG-PCL had a round shape, with a mean diameter around 124 nm. The encapsulation efficiency and drug loading were 76.34±3.25% and 7.60±0.48%, respectively. The in vitro release of NOB from NOB-PEG-PCL showed a remarkably sustained releasing characteristic and could be retained at least 48 hrs in pH 7.4 PBS. Anti-osteoclasts effects demonstrated that the NOB-PEG-PCL significantly inhibited the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells stimulated by RANKL. Furthermore, the NOB-PEG-PCL did not produce cytotoxicity on bone marrow-derived macrophages (BMMs). The mRNA expressions of genetic markers of osteoclasts including TRAP and cathepsin K were significantly decreased in the presence of NOB-PEG-PCL. In addition, the NOB-PEG-PCL inhibited OC differentiation of BMMs through RANKL-induced MAPK signal pathway. After administration of the NOB-PEG-PCL, NOB-PEG-PCL prevented bone loss and improved bone density in OVX mice. These findings suggest that NOB-PEG-PCL might have great potential in the treatment of osteoporosis. CONCLUSION: The results suggested that NOB-PEG-PCL micelles could effectively prevent NOB fast release from micelles and extend circulation time. The NOB-PEG-PCL delivery system may be a promising way to prevent and treat osteoporosis.

Dual micelles-loaded gelatin nanofibers and their application in lipopolysaccharide-induced periodontal disease.

INTRODUCTION: Combined therapies utilizing inhibitors to remove pathogens are needed to suppress lipopolysaccharide (LPS)-induced periodontal disease. We prepared a novel, multi-agent delivery scaffold for periodontal treatment. METHODS: In this study, we synthesized SP600125 (a JNK inhibitor) and SB203580 (a p38 inhibitor) drug-loaded poly(ethylene glycol)-block-caprolactone copolymer via dialysis method. The physical property of micelles was characterized through dynamic light scattering and transmission electron microscopy. The cell growth and LPS-induced MMP-2 and MMP-13 expression were evaluated through CCK-8, real-time PCR and Western blot assay. The release of SP600125 and SB203580 from different scaffolds was estimated. Microcomputed tomography and histology were used for evaluating the effect of the micelles-loaded nanofibers on the treatment of class II furcation defects in dogs. RESULTS: The drug was then successfully incorporated into gelatin fibers during electrospinning process. We confirmed that the micelles had spherical structure and an average particle size of 160 nm for SP600125-micelles (SP-Ms) and 150 nm for SB203580-micelles (SB-Ms). The nanofiber scaffold showed excellent encapsulation capability, in vitro drug-release behavior, and cell compatibility. Real-time PCR and Western blot assay further indicated that LPS-induced MMP-2 and MMP-13 expression was significantly inhibited by the scaffold. CONCLUSION: The results suggested that the dual drug-loaded system developed in this study might become a highly effective therapy for periodontal disease.

Partition of calibrated tris-acryl gelatin microspheres in the arterial vasculature of embolized nasopharyngeal angiofibromas and paragangliomas.

PURPOSE: To determine the location of calibrated tris-acryl gelatin microspheres (TGMs) in the arterial vasculature of nasopharyngeal angiofibromas (NAFs) and paragangliomas (PGs). MATERIALS AND METHODS: Forty-nine specimens (25 PGs and 24 NAFs) treated operatively after embolization with TGMs of various sizes (100-300 microm to 900-1200 microm) were stained with hematoxylin and eosin saffron and analyzed at an objective magnification of 10 or 20 with a micrometric eyepiece (magnification, x12.5). The diameter of occluded vessels, their localization (intra- or extratumoral), and the number and diameter of TGMs they contained were determined. RESULTS: Embolized vessels (N = 1125) were measured: 440 in PGs and 685 in NAFs. Vessels were 89% intratumoral and 11% extratumoral. The diameter of the occluded vessels increased significantly with the size range of TGMs used for embolization for each tumor type (P < .0001). Intratumoral occluded vessels were significantly smaller than extratumoral vessels (P < .0001). Distribution of TGMs within the vascular network (intratumoral or extratumoral location) were similar for NAFs and PGs. The intratumoral and extratumoral dissemination of TGMs was different when comparing 100-300-microm TGMs versus 500-700-microm TGMs (P = .0006) as well as 300-500-microm TGMs versus 500-700-microm TGMs (P = .0001). CONCLUSIONS: The size of the vessels occluded by TGMs and their intra- or extratumoral location directly depend on the size of the injected TGMs. The vessels located inside the tumors were smaller than those located outside the tumors. A threshold for the intratumoral penetration of TGMs in the vasculature can be proposed from these data. There was no evidence of different behavior of TGMs in NAFs versus PGs.