BACKGROUND & AIMS: :The objective of this study was to prepare a 72 h-release formulation of silybin (72 h-SLB) using a combination of solid dispersion, gel matrix and porous silica nanoparticles (PSNs) and to investigate the in vitro/in vivo correlations (IVIVCs). The results of scanning electron microscopy and N(2) adsorption demonstrated that empty PSNs possessed a spherical shape, a highly porous structure, a large specific surface area (385.89 ± 1.12 m(2)/g) and a small pore size (2.74 nm on average). The in vitro dissolution profiles of both 72 h-SLB and silybin-loaded PSNs in different concentrations (0.01, 0.06 and 0.08M) of Na(2)CO(3) solutions revealed that 0.06 M Na(2)CO(3) solution was the optimal medium in which silybin could be released from 72 h-SLB with first-order release kinetics and from PSNs with Higuchi kinetics. Furthermore, the IVIVCs of 72 h-SLB and silybin-loaded PSNs in beagle dogs were also established. Using 0.06 M Na(2)CO(3) solution as the in vitro dissolution medium, a good linear relationship could be achieved for both 72 h-SLB and silybin-loaded PSNs. The findings support the fact that the 72 h-SLB (consisting of solid dispersion, regular gel matrix and PSNs) together with Na(2)CO(3) solution as an in vitro dissolution medium can be developed into a promising formulation for poorly soluble drugs, which enjoys a good IVIVC.

背景与目标： : 本研究的目的是使用固体分散体，凝胶基质和多孔二氧化硅纳米颗粒 (psn) 的组合制备水飞蓟宾 (72 h-SLB) 的72 h释放制剂，并研究体外/体内相关性 (IVIVCs)。扫描电子显微镜和N(2) 吸附结果表明，空psn具有球形，高度多孔结构，大的比表面积 (385.89 ± 1.12 m(2)/g) 和小的孔径 (平均2.74 nm)。72 h-SLB和水飞蓟宾负载的psn在不同浓度 (0.01，0.06和0.08M) 的Na(2)CO(3) 溶液表明，0.06 M Na(2)CO(3) 溶液是最佳介质，其中水飞蓟宾可以从72 h-SLB中释放，具有一级释放动力学和psn。具有Higuchi动力学。此外，还建立了beagle犬中72 h-SLB和水飞蓟宾psn的ivvc。使用0.06 M Na(2)CO(3) 溶液作为体外溶出介质，对于72 h-SLB和水飞蓟宾负载的psn都可以实现良好的线性关系。研究结果支持以下事实: 72 h-SLB (由固体分散体，规则凝胶基质和psn组成) 与Na(2)CO(3) 溶液一起作为体外溶出介质，可以开发为具有良好的IVIVC可溶性药物的有希望的制剂。

BACKGROUND & AIMS: :The present study aimed to evaluate the mechanical and degradative properties of poly(L-co-D,L-lactic acid)/silicate bioactive glass fibers (PLDLA/SGFs) composite pins in vivo. Both PLDLA and PLDLA/SGFs pins were inserted into the erector spinae muscles and femurs of beagle dogs and were harvested 6, 12, 16, 26, 52, 78, and 104 weeks after insertion. Bone formation around the pins was evaluated by micro-computed tomography. Mechanical properties were measured by the shear strength test. Thermogravimetric analysis, differential scanning calorimetry, and gel permeation chromatography were used to assess the degradation of these materials. The surface and cross-sectional morphology of both pins were observed using a scanning electron microscope. The experimental data demonstrated that PLDLA/SGFs pins can support new bone formation due to the influence of bioactive glass fibers. PLDLA/SGFs composite pins had higher initial shear strength and were relatively stable for at least 26 weeks. The addition of bioactive glass fibers accelerated the degradation rate of the composite pins. Thus, PLDLA/SGFs composite pins have promising potential for bone fixation applications.

背景与目标： : 本研究旨在评估体内聚 (L-co-D，L-乳酸)/硅酸盐生物活性玻璃纤维 (PLDLA/SGFs) 复合销钉的机械和降解性能。将PLDLA和PLDLA/SGFs针都插入比格犬的竖脊肌和股骨中，并在插入后6、12、16、26、52、78和104周收获。通过微计算机断层扫描评估引脚周围的骨形成。通过剪切强度测试测量机械性能。使用热重分析，差示扫描量热法和凝胶渗透色谱法评估这些材料的降解。使用扫描电子显微镜观察两个销钉的表面和横截面形态。实验数据表明，由于生物活性玻璃纤维的影响，PLDLA/SGFs引脚可以支持新的骨形成。PLDLA/SGFs复合销钉具有较高的初始剪切强度，并且在至少26周内相对稳定。生物活性玻璃纤维的加入加快了复合销钉的降解速度。因此，PLDLA/SGFs复合销钉在骨固定应用中具有广阔的潜力。

BACKGROUND & AIMS: :The aim of this study was to evaluate the healing of class III furcation defects following transplantation of autogenous periosteal cells combined with beta-tricalcium phosphate (beta-TCP). Periosteal cells obtained from Beagle dogs' periosteum explant cultures, were inoculated onto the surface of beta-TCP. Class III furcation defects were created in the mandibular premolars. Three experimental groups were used to test the defects' healing: group A, beta-TCP seeded with periosteal cells were transplanted into the defects; group B, beta-TCP alone was used for defect filling; and group C, the defect was without filling materials. Twelve weeks post surgery, the tissue samples were collected for histology, immunohistology and X-ray examination. It was found that both the length of newly formed periodontal ligament and the area of newly formed alveolar bone in group A, were significantly increased compared with both group B and C. Furthermore, both the proportion of newly formed periodontal ligament and newly formed alveolar bone in group A were much higher than those of group B and C. The quantity of cementum and its percentage in the defects (group A) were also significantly higher than those of group C. These results indicate that autogenous periosteal cells combined with beta-TCP application can improve periodontal tissue regeneration in class III furcation defects.

背景与目标： : 这项研究的目的是评估自体骨膜细胞联合 β-磷酸三钙 (β-TCP) 移植后III类分叉缺损的愈合情况。将从Beagle犬的骨膜外植体培养物中获得的骨膜细胞接种到beta-TCP的表面。在下颌前磨牙中产生了III类分叉缺损。三个实验组用于测试缺陷的愈合: A组，用骨膜细胞接种的 β-TCP移植到缺损中; B组，单独使用 β-TCP进行缺损填充; C组，缺损没有填充材料。术后12周，收集组织样本进行组织学，免疫组织学和x线检查。发现与B组和C组相比，A组新形成的牙周膜长度和新形成的牙槽骨面积均显着增加。此外，A组新形成的牙周膜和新形成的牙槽骨的比例均远高于B组和C组。牙骨质的数量及其在缺陷中的百分比 (A组) 也明显高于C组。这些结果表明，自体骨膜细胞结合 β-TCP应用可以改善III类分叉缺损的牙周组织再生。

BACKGROUND & AIMS: OBJECTIVES:This study was undertaken to evaluate the influences of concave, machined and concave-roughened profiles of transmucosal implant designs on early peri-implant tissue responses. MATERIALS AND METHODS:Implants were used and classified by transmucosal profile and surface type as straight-machined implants (SM), concave-machined implants (CM), or concave-roughened implants (CR). A total of 30 implants (10 per each type) with matching transmucosal profiles were placed directly on alveolar crests in randomized order in the edentulous mandibular ridges of three beagle dogs. Healing abutments were connected 4 weeks after implant placement, and prostheses were connected 8 weeks after implant placement and functionally loaded. All animals were sacrificed at 16 weeks. Peri-apical radiographs were obtained and measured to evaluate peri-implant marginal bone levels. Histological specimens were prepared to measure bone resorption, connective tissue contact, epithelial tissue height, biological width, and length of implant-abutment junction to the apical portion of junctional epithelium. RESULTS:Radiographic and histometric analysis showed that least bone resorption occurred around CM implants and greatest bone resorption around SM implants (P < 0.05). Histometric analysis showed that highest connective tissue attachment and shortest biological width had formed around CM implants. CONCLUSION:Concave-machined profiled implants with a transmucosal design may induce less bone resorption and better connective tissue attachment around implants than the straight-machined profiled implants during the early healing phase.

背景与目标：

BACKGROUND & AIMS: :Aging is an inevitable process that occurs in the whole body system accompanying with many functional and morphological changes. Inflammation is known as one of age-related factors, and inflammatory changes could enhance mortality risk. In this study, we compared immunoreactivities of inflammatory cytokines, such as interleukin (IL)-2 (a pro-inflammatory cytokine), its receptor (IL-2R), IL-4 (an anti-inflammatory cytokine), and its receptor (IL-4R) in the cervical and lumbar spinal cord of young adult (2-3 years old) and aged (10-12 years old) beagle dogs using immunohistochemistry and western blotting. IL-2 and IL-2R-immunoreactive nerve cells were found throughout the gray matter of the cervical and lumbar spinal cord of young adult and aged dogs. In the spinal cord neurons of the aged dog, immunoreactivity and protein levels were apparently increased compared with those in the young adult dog. Change patterns of IL-4- and IL-4R-immunoreactive cells and their protein levels were also similar to those in IL-2 and IL-2R; however, IL-4 and IL-4R immunoreactivity in the periphery of the neuronal cytoplasm in the aged dog was much stronger than that in the young adult dog. These results indicate that the increase of inflammatory cytokines and their receptors in the aged spinal cord might be related to maintaining a balance of inflammatory reaction in the spinal cord during normal aging.

背景与目标： : 衰老是一个不可避免的过程，发生在整个身体系统中，伴随着许多功能和形态变化。炎症是与年龄相关的因素之一，炎症改变会增加死亡风险。在这项研究中，我们比较了炎性细胞因子的免疫反应性，例如白介素 (IL)-2 (促炎性细胞因子)，其受体 (IL-2R)，IL-4 (抗炎性细胞因子)，其受体 (IL-4R) 在青壮年 (2-3岁) 和高龄 (10-12岁) 比格犬的颈椎和腰椎脊髓中应用免疫组织化学和western blotting。在年轻成年和老年狗的颈和腰脊髓的灰质中发现了IL-2和IL-2R-immunoreactive神经细胞。与成年成年犬相比，在老年犬的脊髓神经元中，免疫反应性和蛋白质水平明显增加。IL-4和IL-4R-immunoreactive细胞的变化模式及其蛋白质水平也与IL-2和IL-2R相似; 然而，老年狗神经元细胞质外围的IL-4和IL-4R免疫反应性比年轻成年狗强得多。这些结果表明，衰老脊髓中炎症细胞因子及其受体的增加可能与正常衰老过程中维持脊髓炎症反应的平衡有关。

BACKGROUND & AIMS: :Tenofovir disoproxil (TD) is very unstable in the solid state under storage conditions. Moreover, tenofovir disoproxil fumarate (TDF), a commercial salt, is chemically unstable in alkaline solution. In this study, a novel tenofovir disoproxil phosphate (TDP), with stability enhancement and bioequivalence to commercial TDF in rats and beagle dogs, has been developed as an alternative. The TDP and its tablets were easily manufactured, and its physicochemical properties, such as morphology, crystallinity, solubility, lipophilicity and stability were investigated and compared to TD and TDF. Its dissolution and pharmacokinetics were investigated in rats and beagle dogs in comparison to TD and TDF. TDP appeared as an irregularly-shaped crystalline powder with a rough surface, like TDF. However, TDP significantly improved the solubility (7.4 ± 1.3 vs. 28.6 ± 1.0 mg/ml), hydrophilicity (Log P, 0.58 ± 0.03 vs. 0.47 ± 0.04), and aqueous stability (drug concentration over 12 h at pH 6.8 84.0 ± 2.0% vs. 88.2 ± 1.5%) of TD compared to TDF. The TDP gave no significant different plasma concentrations, AUC and Cmax compared to TDF in rats (AUC, 1242.1 ± 584.9 vs. 825.9 ± 79.5 h·ng/ml; Cmax, 154.8 ± 25.4 vs. 210.9 ± 70.3 ng/ml). Moreover, the TDP-loaded tablets were stable for at least six months and provided similar dissolution and bioequivalence to the TDF-loaded commercial product in beagle dogs (AUC, 26,832.7 ± 4093.0 vs. 26,605.3 ± 2530.1 h·ng/ml; Cmax, 4364.0 ± 2061.9 vs. 4186.3 ± 2616.5 ng/ml). Therefore, as an alternative salt, the TDP would be a recommendable candidate with stability enhancement and bioequivalence to the commercial TDF.

背景与目标： : 替诺福韦酯 (TD) 在储存条件下固态非常不稳定。此外，富马酸替诺福韦酯 (TDF) 是一种商业盐，在碱性溶液中化学不稳定。在这项研究中，已经开发出一种新型的替诺福韦磷酸二丙氧酯 (TDP)，其稳定性增强并与大鼠和比格犬的商业TDF具有生物等效性。TDP及其片剂易于制造，并研究了其理化性质，例如形态，结晶度，溶解度，亲脂性和稳定性，并与TD和TDF进行了比较。与TD和TDF相比，在大鼠和比格犬中研究了其溶出度和药代动力学。TDP表现为不规则形状的结晶粉末，具有粗糙的表面，如TDF。然而，TDP显著提高了溶解度 (7.4   ±   1.3 vs. 28.6   ±   1.0  mg/ml) 、亲水性 (Log P，0.58   ±   0.03 vs. 0.47   ±   0.04)，与TDF相比，TD的水性稳定性 (在pH 6.8 84.0   ±   2.0% 对88.2   ±   1.5% 时药物浓度超过12  h)。与TDF相比，TDP的血浆浓度，AUC和Cmax无显着差异 (AUC，1242.1   ±   584.9 vs. 825.9   ±   79.5  ng/ml; Cmax，154.8   ±   25.4 vs. 210.9   ±   70.3  ng/ml)。此外，负载TDP的片剂稳定至少六个月，并提供与负载TDF的商业产品相似的溶出度和生物等效性 (AUC，26,832.7   ±   4093.0 vs. 26,605.3 ± ±   2530.1  h·ng/ml; Cmax，4364.0   ±   2061.9 vs. 4186.3   ±   2616.5  ng/ml)。因此，作为替代盐，TDP将是推荐的候选物，具有增强稳定性和与商业TDF的生物等效性。

BACKGROUND & AIMS: :The toxicity of Prednisolone farnesylate (PNF) gel, a synthetic glucocorticoid, was investigated in the Beagle dog. PNF gel was administered percutaneously at doses of 0.2, 0.8 and 3.2 mg/kg/day for 13 weeks, then the drug was withdrawn for 5 weeks to evaluate the reversibility. In addition, 2 mg/kg/day prednisolone gel (PN gel), which is approximate to 3.2 mg/kg/day PNF gel in prednisolone molarity, was also administered for comparison. The results are summarized as follows: 1. No deaths were observed in any of the PNF gel test groups or the PN gel group, nor were there any abnormal findings in the clinical signs of the animals. 2. In the hematology, a tendency toward a decrease in the lymphocyte ratio was observed in males from the PNF gel 0.8 mg/kg/day and above groups. In the PN gel group, a significant decrease or a tendency toward a decrease in the lymphocyte ratio was observed, as well as an increase in the white blood cell count in some animals. 3. In the blood biochemistry, a significant decrease or a tendency toward a decrease in total cholesterol and phospholipid was observed in males from the PNF gel 3.2 mg/kg/day group and a tendency toward an increase in triglyceride in females from the PNF gel 3.2 mg/kg/day group was observed. In the PN gel group, a tendency toward an increase in AIP activity, a tendency toward an increase in triglyceride were observed. 4. In the histological examinations, a decrease in the weight of the thymus and adrenal glands, vacuolation of hepatocytes in the middle zone of the liver, atrophy of zona fasciculata of the adrenal glands, hypertrophy of zona glomeruli, swelling of cortical cells of zona faciculate and atrophy of the thymus were observed in the PNF gel 0.8 mg/kg/day and above groups. In the PN gel group, atrophy of submandibular lymph nodes and mesenteric lymph nodes was observed in addition to the same changes as observed in the PNF gel groups. Furthermore, thinning, atrophy or a decrease in the weight of the adrenal glands was also observed both in the PNF gel 3.2 mg/kg/day group and the PN gel group at the end of the 5-week recovery period. 5. As described above, a decrease in the lymphocyte ratio, in the weight of the thymus and adrenal glands and vacuolation of hepatocytes were observed in the PNF gel 0.8 mg/kg/day and above groups.(ABSTRACT TRUNCATED AT 400 WORDS)

背景与目标： : 在Beagle犬中研究了合成糖皮质激素法呢酸泼尼松龙 (PNF) 凝胶的毒性。PNF凝胶以0.2、0.8和3.2 mg/kg/天的剂量经皮给药13周，然后撤回药物5周以评估可逆性。此外，还施用2 mg/kg/天的泼尼松龙凝胶 (PN凝胶)，其在泼尼松龙摩尔浓度中约为3.2 mg/kg/天的PNF凝胶，以进行比较。研究结果总结如下: 1.在任何PNF凝胶测试组或PN凝胶组中均未观察到死亡，动物的临床体征也没有任何异常发现。2.在血液学中，从PNF凝胶0.8 mg/kg/天及以上组的男性中观察到淋巴细胞比率下降的趋势。在PN凝胶组中，观察到淋巴细胞比率显着降低或趋于降低，并且某些动物的白细胞计数增加。3.在血液生物化学中，在PNF凝胶3.2 mg/kg/天组的男性中观察到总胆固醇和磷脂的显着降低或趋于降低，而在PNF凝胶3.2 mg/kg/天组的女性中观察到甘油三酯的增加趋势。在PN凝胶组中，观察到AIP活性增加的趋势，甘油三酸酯增加的趋势。4.在组织学检查中，胸腺和肾上腺的重量减少，肝脏中间区域的肝细胞空泡化，肾上腺束状带萎缩，肾小球带肥大，在0.8 mg/kg/天及以上的PNF凝胶中观察到透明带皮质细胞肿胀和胸腺萎缩。在PN凝胶组中，除了与PNF凝胶组相同的变化外，还观察到下颌下淋巴结和肠系膜淋巴结的萎缩。此外，在5周恢复期结束时，在PNF凝胶3.2 mg/kg/天组和PN凝胶组中也观察到肾上腺变薄、萎缩或重量减少。5.如上所述，在0.8毫克/千克/天及以上的PNF凝胶中观察到淋巴细胞比率、胸腺和肾上腺重量的降低以及肝细胞的空泡化。(摘要截短于400字)

BACKGROUND & AIMS: :Guided bone regeneration (GBR) is a principle adopted from guided tissue regeneration (GTR). Wherein, GBR is used for the healing of peri-implant bony dehiscences, for the immediate placement of implants into extraction sockets and for the augmentation of atrophic alveolar ridges. This procedure is done by the placement of a resorbable or non-resorbable membrane that will exclude undesirable types of tissue growth between the extraction socket and the soft tissue to allow only bone cells to regenerate in the surgically treated lesion. Here, we investigated the biodegradable effect of polylactic-co-glycolic acid (PLGA) membrane in the alveolar bone on Beagle dogs. Results show that both collagen and PLGA membrane had been fully resorbed, biodegraded, at four weeks post-operative reentry into the alveolar bone. Histological results under light microscopy revealed formation of new bone trabeculae in the extraction sites on both collagen and PLGA membrane. In conclusion, PLGA membrane could be a potential biomaterials for use on GBR and GTR. Nevertheless, further studies will be necessary to elucidate the efficiency and cost effectiveness of PLGA as GBR membrane in clinical.

背景与目标： 引导骨再生 (GBR) 是引导组织再生 (GTR) 的原则。其中，GBR用于修复种植体周围的骨开裂，将植入物立即放置到拔牙窝中以及增加萎缩性牙槽脊。此过程是通过放置可吸收或不可吸收的膜来完成的，该膜将排除拔牙窝和软组织之间不希望的组织生长类型，从而仅允许骨细胞在手术治疗的病变中再生。在这里，我们研究了聚乳酸-乙醇酸 (PLGA) 膜在比格犬牙槽骨中的可生物降解作用。结果表明，胶原蛋白和PLGA膜在术后四周均被完全吸收，生物降解，再次进入牙槽骨。光学显微镜下的组织学结果显示，在胶原蛋白和PLGA膜的提取部位均形成了新的骨小梁。总之，PLGA膜可能是用于GBR和GTR的潜在生物材料。然而，需要进一步的研究来阐明PLGA作为GBR膜在临床中的效率和成本效益。

BACKGROUND & AIMS: -2

背景与目标： -2

BACKGROUND & AIMS: :Male and female dogs, aged 17--21 months, were administered orall M 73101 (0, 60, 120 and 240 mg/kg/day), a new analgesic and antiinflammatory drug, for 27 weeks, and following recovery test was carried out for 5 weeks. Dead animals were not found throughout the experimental period. Body weight gain, and food and water consumption were not affected due to M 73101 administration. Except for a slight increase of vomitting in the highest dose, there were no abnormal symptoms. Biochemical examination showed the slight increase in serum alkaline phosphatase activity and free cholesterol level. Pathological examination revealed a dose-dependent increase of liver weight and hypertrophy of hepatocytes due to proliferation of smooth endoplasmic reticulum. In addition, mitochondria became irregularly large in the highest dose. There were no abnormal findings in the gastro-intestinal tracts except for an erosion of gastric mucosa, which was noted in a female dog treated 240 mg/kg/day of M 73101. From these results, it was suggested that the maximum non-toxic dose was 60 mg/kg/day or less, and the greatest safety dose was 120 mg/kg/day in beagle dogs.

背景与目标： : 雄性和雌性犬，年龄17-21个月，给予或所有M 73101 (0、60、120和240 mg/kg/天) (一种新的止痛和抗炎药物) 27周，然后进行5周的恢复试验。在整个实验期间都没有发现死动物。由于M 73101给药，体重增加以及食物和水的消耗没有受到影响。除了最高剂量的呕吐物略有增加外，没有异常症状。生化检查显示血清碱性磷酸酶活性和游离胆固醇水平略有增加。病理检查显示，由于光滑内质网的增殖，肝脏重量和肝细胞肥大呈剂量依赖性增加。此外，线粒体在最高剂量下不规则地变大。除了胃黏膜的侵蚀外，在胃肠道中没有异常发现，这在240 mg/kg/天的M 73101中被发现。从这些结果表明，在beagle犬中，最大无毒剂量为60 mg/kg/天或更少，最大安全剂量为120 mg/kg/天。

BACKGROUND & AIMS: :The aim of the present study was to find a method to increase oral bioavailability of silymarin, that is to say, by the preparation of silymarin proliposome and to compare the pharmacokinetic characteristics and bioavailability after oral administration of silymarin proliposome and silymarin in beagle dogs. Silymarin proliposome was prepared by the film-deposition on carriers. After the proliposome was contacted with water, the silymarin liposome suspensions formed automatically. The tests of physicochemical properties including SEM, TEM, encapsulation efficiency, dissolution studies, particle size of the reconstituted liposome and stability of the silymarin proliposome were determined by laser-particle-sizer, HPLC, etc. The concentrations of silymarin in plasma of beagle dogs and its pharmacokinetic behaviors after oral administration of silymarin liposome suspensions and silymarin were studied by RP-HPLC. The pharmacokinetic parameters were computed by software program 3p97. The encapsulation efficiency of silymarin liposome could be more than 90%, with an average particle size of about 196.4 nm and the proliposome appeared a very stability at 40 degrees C during 3 months. It was found that mean plasma concentration-time curves of silymarin after oral administration of liposome suspensions and silymarin in beagle dogs were both in accordance with open two-compartments model and first-order absorption. Pharmacokinetic parameters of silymarin proliposome and silymarin in beagle dogs were Tmax both 30 min; Cmax 472.62 and 89.78 ng mL(-1); and AUC0-infinity 2606.21 and 697 ng mL(-1)h, respectively. The high bioavailability of silymarin proliposome could be obtained by oral administration. Silymarin proliposome was stable and did enchance the gastrointestinal absorption of silymarin.

背景与目标： 本研究的目的是找到一种提高水飞蓟素口服生物利用度的方法，即通过制备水飞蓟素前脂质体，并比较口服水飞蓟素前脂质体和水飞蓟素后的药代动力学特征和生物利用度。比格犬。水飞蓟素前体脂质体是通过在载体上沉积膜来制备的。前脂质体与水接触后，水飞蓟素脂质体悬浮液自动形成。通过激光-颗粒-sizer，HPLC等方法测定了水飞蓟素前体脂质体的理化性质，包括SEM，TEM，包封率，溶出度研究，重组脂质体的粒径和稳定性。通过rp-hplc研究了口服水飞蓟素脂质体悬浮液和水飞蓟素后，比格犬血浆中水飞蓟素的浓度及其药代动力学行为。药代动力学参数由软件程序3p97计算。水飞蓟素脂质体的包封效率可以超过90%，平均粒径约为196.4 nm，并且前脂质体在40 ℃ 下在3个月内表现出非常稳定。发现在beagle犬中口服脂质体悬浮液和水飞蓟素后，水飞蓟素的平均血浆浓度-时间曲线均符合开放的两室模型和一阶吸收。水飞蓟素前脂质体和水飞蓟素在比格犬中的药代动力学参数为Tmax均为30分钟; Cmax 472.62和89.78 ng mL(-1); 和AUC0-infinity 2606.21和697 ng mL(-1)h。水飞蓟素前脂质体的高生物利用度可通过口服获得。水飞蓟素前脂质体稳定，并能促进水飞蓟素的胃肠道吸收。

BACKGROUND & AIMS: BACKGROUND:MicroRNAs (miRNA) are varied in length, under 25 nucleotides, single-stranded noncoding RNA that regulate post-transcriptional gene expression via translational repression or mRNA degradation. Elevated levels of miRNAs can be detected in systemic circulation after tissue injury, suggesting that miRNAs are released following cellular damage. Because of their remarkable stability, ease of detection in biofluids, and tissue specific expression patterns, miRNAs have the potential to be specific biomarkers of organ injury. The identification of miRNA biomarkers requires a systematic approach: 1) determine the miRNA tissue expression profiles within a mammalian species via next generation sequencing; 2) identify enriched and/or specific miRNA expression within organs of toxicologic interest, and 3) in vivo validation with tissue-specific toxicants. While miRNA tissue expression has been reported in rodents and humans, little data exists on miRNA tissue expression in the dog, a relevant toxicology species. The generation and evaluation of the first dog miRNA tissue atlas is described here. RESULTS:Analysis of 16 tissues from five male beagle dogs identified 106 tissue enriched miRNAs, 60 of which were highly enriched in a single organ, and thus may serve as biomarkers of organ injury. A proof of concept study in dogs dosed with hepatotoxicants evaluated a qPCR panel of 15 tissue enriched miRNAs specific to liver, heart, skeletal muscle, pancreas, testes, and brain. Dogs with elevated serum levels of miR-122 and miR-885 had a correlative increase of alanine aminotransferase, and microscopic analysis confirmed liver damage. Other non-liver enriched miRNAs included in the screening panel were unaffected. Eli Lilly authors created a complimentary Sprague Dawely rat miRNA tissue atlas and demonstrated increased pancreas enriched miRNA levels in circulation, following caerulein administration in rat and dog. CONCLUSION:The dog miRNA tissue atlas provides a resource for biomarker discovery and can be further mined with refinement of dog genome annotation. The 60 highly enriched tissue miRNAs identified within the dog miRNA tissue atlas could serve as diagnostic biomarkers and will require further validation by in vivo correlation to histopathology. Once validated, these tissue enriched miRNAs could be combined into a powerful qPCR screening panel to identify organ toxicity during early drug development.

背景与目标：

BACKGROUND & AIMS: :The absorption characteristics of vitamin E acetate (VEA) formulated into a dry emulsion system after its oral administration to beagle dogs were determined and compared to those of two different dosage forms (an oily mixture of the drug with cottonseed oil and an oil (drug)-in-water emulsion). The three dosage forms were administered in a crossover fashion to six nonfasting subjects, and the drug absorption was assessed from the plasma concentration of the major metabolite (free vitamin E). VEA formulated in the dry emulsion was rapidly absorbed, which suggested that a considerable amount was released as reformed emulsion droplets in the gastrointestinal tract as well as in water in vitro. Based on the analysis of variance, no significant differences in bioavailability parameters (AUC, Cmax or Tmax) were observed among the three dosage forms.

背景与目标： : 测定了口服给比格犬后配制成干乳液系统的维生素e乙酸酯 (VEA) 的吸收特性，并将其与两种不同剂型 (药物与棉籽油和油 (药物) 的油性混合物) 的吸收特性进行了比较。-水包乳液)。以交叉方式向六名非禁食受试者施用三种剂型，并根据主要代谢物 (游离维生素e) 的血浆浓度评估药物吸收。配制在干燥乳剂中的VEA被迅速吸收，这表明在胃肠道以及体外水中以重整乳剂液滴的形式释放了大量。根据方差分析，在三种剂型之间未观察到生物利用度参数 (AUC，Cmax或Tmax) 的显着差异。

BACKGROUND & AIMS: :The placement of oral implants into jaw bone has a high predictability provided an adequate bone volume surrounding the implant is present to ensure primary stability and resistance to functional loading forces after completion of osseointegration. In the distal area of the maxilla, an adequate bone volume is often lacking because of the proximity of the sinus cavities. The aim of this study was to evaluate histologically the simultaneous placement of endosseous implants into the sinus cavity and the surgical elevation of the sinus floor including filling the cavity with different grafting materials. In 9 sinus areas of 5 beagle dogs, 9 titanium implants (ITI Dental Implant System) were placed, and the void space of the sinus cavity was filled simultaneously with either demineralized freeze-dried human cortical bone (Musculoskeletal Transplant Foundation), resorbable hydroxyapatite (Osteogen) or natural cancelleous bovine bone mineral (Bio-Oss). To study bone formation, fluorochrome markers (tetracycline HCl and calcein green) were used at 2 and 8 weeks. Clinically, all implants healed uneventfully, and 5 months after implant placement the dogs were killed for histologic evaluation. All implants exhibited osseointegration within the pre-existing cortical bone of the sinus floor. The implants surrounded by freeze-dried bone xenografts yielded no formation of new bone, whereas the sites with hydroxyapatite or natural bovine bone mineral demonstrated newly formed bone with direct contact at the implant surface. The average extent of bone to implant contact was 25% (SD = 10.6%) and 27% (SD = 8.8%), respectively in relation to the length of the originally denuded implant surface.(ABSTRACT TRUNCATED AT 250 WORDS)

背景与目标： : 口腔植入物在颌骨中的放置具有很高的可预测性，前提是植入物周围存在足够的骨体积，以确保在完成骨整合后的主要稳定性和对功能加载力的抵抗力。在上颌骨的远端区域，由于窦腔的接近，通常缺乏足够的骨骼体积。这项研究的目的是从组织学上评估将骨内植入物同时放置到窦腔中以及窦底的手术抬高，包括用不同的移植材料填充腔。在5只beagle犬的9个窦区，放置9个钛植入物 (ITI牙科植入物系统)，同时用脱矿质冻干的人皮质骨 (肌肉骨骼移植基础) 填充窦腔的空隙，可吸收的羟基磷灰石 (骨原) 或天然的非天然牛骨矿物质 (Bio-Oss)。为了研究骨形成，在第2周和第8周使用了荧光染料标记物 (四环素HCl和钙绿素)。临床上，所有植入物均顺利愈合，植入后5个月，将狗杀死以进行组织学评估。所有植入物均在窦底预先存在的皮质骨内表现出骨整合。被冻干的异种骨所包围的植入物没有形成新的骨，而羟基磷灰石或天然牛骨矿物质的部位显示出新形成的骨，并在植入物表面直接接触。骨与植入物接触的平均程度分别为25% (SD = 10.6%) 和27% (SD = 8.8%)，与最初剥去的植入物表面的长度有关。(摘要截断为250字)

BACKGROUND & AIMS: :We isolated and purified 35 kDa protein from the myocardium of the beagle dog and identified it to be annexin V from partial amino acid sequence determination. It was confirmed that anticanine cardiac annexin V rabbit polyclonal antibody, which was produced using the 35 kDa protein, cross-reacts with annexin V of the myocardium, lung, liver, kidney, and brain of the rat. The localization of cardiac annexin V and the effect of ischemia for 30-180 min in the rat were immunohistochemically studied with the use of the Langendorff perfusion heart. In the normal myocardium, annexin V, accompanied by cross-striation, was observed throughout the cell. In ischemia of 30 min, extracellular leakage of annexin V was observed with uneven staining in the cytoplasm. When the ischemic time exceeded 60 min, annexin V was observed in the cell membrane with a decrease of annexin V in the cytoplasm. Also, extracellular leakage of annexin V was observed prominently. In ischemia for 180 min, almost all the annexin V in the cytoplasm disappeared. These results suggest that the level of ischemia can be estimated from the changes in localization of annexin V.

背景与目标： : 我们从beagle犬的心肌中分离并纯化了35 kDa蛋白，并通过部分氨基酸序列测定将其鉴定为膜联蛋白V。已证实，使用35 kDa蛋白产生的抗ancine心脏膜联蛋白V兔多克隆抗体与大鼠心肌，肺，肝，肾和脑的膜联蛋白V发生交叉反应。使用Langendorff灌注心脏免疫组织化学研究了大鼠心脏膜联蛋白V的定位和缺血30-180分钟的作用。在正常心肌中，在整个细胞中观察到膜联蛋白V伴有横纹。在缺血30分钟时，观察到膜联蛋白V的细胞外渗漏，细胞质染色不均匀。当缺血时间超过60分钟时，在细胞膜中观察到膜联蛋白V，胞浆中膜联蛋白V减少。此外，显着观察到膜联蛋白V的细胞外渗漏。在缺血180分钟时，细胞质中的膜联蛋白V几乎全部消失。这些结果表明，可以从膜联蛋白V的定位变化来估计缺血水平。