The effects of ropivacaine at clinically relevant doses on myocardial ischemia in pigs

A major risk associated with bupivacaine during myocardial ischemia is ventricular fibrillation. We investigated the influence of ropivacaine on cardiac contractility and the propensity to ventricular fibrillation before and after myocardial ischemia in a placebo-controlled pig study. Anesthetized domestic pigs were administered 1 mg·kg⁻¹ of ropivacaine intravenously over 1 min and then 0.03 mg·kg⁻¹·min⁻¹ as a 30-min infusion, or saline. The following endpoints were measured before and after ropivacaine administration: (1) the ventricular fibrillation threshold (VFT) before and during myocardial ischemia induced by total transient ligation of the anterior interventricular artery and (2) electrophysiological (sinus heart rate, duration of QRS and QT intervals) and hemodynamic (blood pressure, the time derivative of left ventricular pressure [peak LV dP/dt]) parameters. Ropivacaine induced no changes in sinus heart rate, QRS, and or QT before or during ischemia. In contrast, there was a mild increase in the VFT before ischemia, which was drastically and significantly reduced during ischemia. The reduction of peak LV dP/dt during ischemia was further increased by ropivacaine. We also found that the effect of ropivacaine on the VFT was coronary blood flow-dependent, with a markedly decreased threshold in the presence of ischemia. Similar effects have been observed in humans with several other local anesthetics, as well as with class I antiarrhythmic drugs. The results of this study should be taken into account by anesthesiologists when administering ropivacaine to coronary patients.     

Haemodynamic effects of oral aminorex and amphetamine in unanaesthetized beagle dogs

The haemodynamic effects of four daily oral doses of 1·5 mg/kg of aminorex (as fumarate) were measured in unanaesthetized beagle dogs. A similar study was performed in another group of related animals using d-amphetamine sulphate (1 mg/kg). Both agents produced similar sympathomimetic effects consisting of transient rises in systemic and pulmonary arterial blood pressures over an eight-hour period after administration of either drug. Heart rate remained unchanged in the dogs receiving aminorex whereas it decreased in those receiving amphetamine.     

The effects of continuous estradiol therapy on cortical bone remodeling activity in the spayed beagle

Summary Ribs from 6 oophorectomized and 4 17β-estradiol-supplemented spayed, 4-year-old Beagle dams were subjected to histomorphometric analyses to determine what effects continuous estradiol treatment of 9 months duration had on the Basic Multicellular Unit (BMU) of cortical bone remodeling. The findings of this study suggest that 17β-estradiol has a two-step mode of action. First, this estrogen directly suppresses the formation of new BMUs. Secondly, it causes uncoupling of the Resorption/Formation (R/F) mechanism within each BMU, together with the creation of an approximate 1∶1 balance between bone resorption and bone formation. This balance is probably responsible for the preservation of cortical bone mass seen to occur with continuous estrogen replacement therapy.     

Oophorectomy and cortical bone remodeling in the beagle

Cortical bone remodeling measurements were carried out on the ribs of 6 spayed and five control Beagle dams which had been subjected to a period of observation equal to more than one sigma of cortical bone remodeling activity. The results of the measurements of static and dynamic parameters indicate that the lack of ovarian hormones does not produce a major alteration in the rates of cortical bone remodeling, but does result in an increase in the number of resorption spaces per mm2 of cortical bone without altering the parameters of bone function. This latter fact supports the hypothesis that decreased levels of circulatory ovarian hormones may influence the duration of the resorption activity as well as possibly uncoupling the resorption/formation (R/F) mechanism of the bone remodeling unit.     

Oophorectomy and cortical bone remodeling in the beagle

Summary Cortical bone remodeling measurements were carried out on the ribs of 6 spayed and five control Beagle dams which had been subjected to a period of observation equal to more than one sigma of cortical bone remodeling activity. The results of the measurements of static and dynamic parameters indicate that the lack of ovarian hormones does not produce a major alteration in the rates of cortical bone remodeling, but does result in an increase in the number of resorption spaces per mm² of cortical bone without altering the parameters of bone function. This latter fact supports the hypothesis that decreased levels of circulatory ovarian hormones may influence the duration of the resorption activity as well as possibly uncoupling the resorption/formation (R/F) mechanism of the bone remodeling unit.     

Effect of alendronate on fracture healing and bone remodeling in dogs

To examine the effect of alendronate (4-amino-1-hydroxybutylidene bisphosphonate) on fracture repair, the drug was given to mature beagle dogs orogastrically at 2 mg/kg/day for 9 weeks preceding fracture, 16 weeks after fracture, or both before and after fracture (25 weeks). A transverse mid-diaphyseal fracture of the right radius was surgically induced and was stabilized by external coaptation splinting. Fracture healing and bone remodeling were evaluated by radiography, gross and histological examination, and bone histomorphometry. The mechanical properties of the fracture callus were determined by a four-point bending test. Radiographs and gross and microscopic examination demonstrated normal bone healing at the fracture site in all dogs. In dogs that received alendronate during the fracture healing period, at 16 weeks the calluses were approximately 2–3 times larger than those in dogs that received a placebo during the healing period. This is consistent with slower callus bone remodeling, an expected pharmacological effect of the compound. Bone histomorphometry demonstrated that treatment with alendronate did not inhibit bone formation or mineralization. Mechanical testing showed that the ultimate load at failure and the flexural rigidity of both the fractured and contralateral intact bone were unaffected by treatment with alendronate. Therefore, in this study, treatment with alendronate before or during fracture healing, or both, resulted in no adverse effects on the union, strength, or mineralization of bone in mature beagle dogs.     

Re-evaluating the toughness of human cortical bone

Data for fracture in human humeral cortical bone are re-analyzed to assess the validity for this material of linear-elastic fracture mechanics (LEFM), which is the standard method of analyzing toughness and one basis for analyzing clinical data relating to bone quality. A nonlinear fracture model, which is based on representing the damage zone in the bone by a cohesive model, is calibrated against a number of sets of test data for normal (not diseased or aged) human cortical bone taken from cadavers. The data consist of load vs. load-point displacement measurements from standard compact–tension fracture tests. Conventional LEFM is unable to account for the shape of the load–displacement curves, but the nonlinear model overcomes this deficiency. Calibration of the nonlinear model against one data curve leads to predictions of the peak load and the displacement to peak load for two other data curves that are, for this limited test set, more accurate than those made using LEFM. Furthermore, prior observations of damage mechanisms in bone are incompatible with the modeling assumption of LEFM that all nonlinearity is confined to a zone much smaller than the specimen and the crack length. The predictions of the cohesive model and the prior observations concur that the length of the nonlinear zone in human cortical bone varies in the range 3–10 mm, which is comparable to or larger than naturally-occurring bones and the specimens used to test them. We infer that LEFM is not an accurate model for cortical bone. The fracture toughness of bone deduced via LEFM from test data will not generally be a material constant, but will take different values for different crack lengths and test configurations. The accuracy of using LEFM or single-parameter fracture toughness for analyzing the significance of data from clinical studies is called into question. The nonlinear cohesive zone model is proposed to be a more accurate model of bone and the traction-displacement or cohesive law is hypothesized to be a material property. The cohesive law contains a more complete representation of the mechanics of material failure than the single-parameter fracture toughness and may therefore provide a superior measure of bone quality, e.g., for assessing the efficacy of therapy for osteoporosis.     

Microarchitectural deterioration of cortical and trabecular bone: Differing effects of denosumab and alendronate

The intensity of bone remodeling is a critical determinant of the decay of cortical and trabecular microstructure after menopause. Denosumab suppresses remodeling more than alendronate, leading to greater gains in areal bone mineral density (aBMD). These greater gains may reflect differing effects of each drug on bone microarchitecture and strength. In a phase 2 double‐blind pilot study, 247 postmenopausal women were randomized to denosumab (60 mg subcutaneous 6 monthly), alendronate (70 mg oral weekly), or placebo for 12 months. All received daily calcium and vitamin D. Morphologic changes were assessed using high‐resolution peripheral quantitative computed tomography (HR‐pQCT) at the distal radius and distal tibia and QCT at the distal radius. Denosumab decreased serum C‐telopeptide more rapidly and markedly than alendronate. In the placebo arm, total, cortical, and trabecular BMD and cortical thickness decreased (?2.1% to ?0.8%) at the distal radius after 12 months. Alendronate prevented the decline (?0.6% to 2.4%, p = .051 to <.001 versus placebo), whereas denosumab prevented the decline or improved these variables (0.3% to 3.4%, p < .001 versus placebo). Changes in total and cortical BMD were greater with denosumab than with alendronate (p ≤ .024). Similar changes in these parameters were observed at the tibia. The polar moment of inertia also increased more in the denosumab than alendronate or placebo groups (p < .001). Adverse events did not differ by group. These data suggest that structural decay owing to bone remodeling and progression of bone fragility may be prevented more effectively with denosumab. © 2010 American Society for Bone and Mineral Research     

米非司酮单次和多次给药在Beagle犬体内的药代动力学研究

目的研究米非司酮单次和多次给药在Beagle(比格)犬体内的药动学特征。方法选用雌性8～12kg大小比格犬,根据给药次数分为单次给药组和多次给药组,单次给药采用静脉和灌胃两种方式给药,单次灌胃给药又分为低、中、高3个剂量组,分别是1、3、10mg/kg米非司酮,多次给药采用口服灌胃法给药。每组各3只比格犬。单次给药组:给药前和给药后15、30min,1、2、4、8、12、24、48、72、96h采集血浆样本。多次给药组:分别于第1、3、5、7、9、11、13、15天灌胃10mg/kg米非司酮,给药前、后2h取血,第15天给药前及给药后15、30min,1、2、4、8、12、24、48、72、96h取血。用LC-MS/MS法检测各组血浆中米非司酮的浓度,并采用Phoenix WinNonlin软件处理各组血药浓度测定数据,采用非房室模型估算药代动力学参数,绘制药-时曲线,计算主要药代动力学参数。结果单次灌胃给药1 mg/kg组的t_(1/2)值和MRT与3 mg/kg组和10mg/kg组相比较,差异具有统计学意义(P0.05),3mg/kg组和10mg/kg之间差异无统计学意义(P0.05);AUC_(last)、AUC_(Inf)值的增长比值与给药剂量不成比例,呈现非线性药代动力学特征;单次灌胃给药3个剂量组的tmax值相比,差异无统计学意义(P0.05)。10mg/kg组生物利用度为52.6%。单次灌胃10mg给药组和多次给药组的t_(max)、C_(max)、AUC_(last)、AUC_(Inf)、MRT等主要药动学参数相比较,差异无统计学意义(P0.05);多次灌胃给米非司酮10mg/kg后,比格犬体内的血药浓度保持稳定。结论米非司酮单次与多次给药后的主要药动学参数差异不显著,呈现非线性药代动力学特征,药物在体内有蓄积。     

Transient effects of subcutaneously administered prostaglandin E2 on cancellous and cortical bone in young adult dogs

The transient effects of prostaglandin E2 (PGE2) on cancellous and cortical bone in iliac crests and mid-tibial shafts of nine intact young adult dogs were evaluated following 31 days of treatment. Histomorphometric bone changes were characterized from in vivo fluorescent double-labeled undecalcified bone specimens. PGE2 caused an increase in cancellous bone remodeling evidence by increased in activation frequency; increased percent eroded and formation surfaces; increased mineral apposition and bone formation rates; and shortened resorption, formation, and total bone remodeling periods. Activated cancellous bone remodeling did not lead to decreased cancellous bone mass, indicating an imbalance between bone resorption and formation in favor of formation (activation----resorption----stimulated formation; A----R----F increases) at remodeling sites. The PGE2 treatment activated bone modeling in the formation mode (activation----formation; A----F) at the periosteal and endocortical surfaces and increased activation frequency of intracortical bone remodeling in the tibial shaft. Increased modeling activation converted quiescent bone surfaces to formation surfaces with stimulated osteoblastic activity (i.e., increased percent labeled periosteal and endocortical surfaces, mineral apposition rates, and woven and lamellar trabecular bone formation) leading to 9- to 26-fold increases in newly formed bone mass in subperiosteal, subendosteal, and marrow regions, compared to controls. However, increased intracortical bone remodelling elevated remodeling space (i.e., increased cortical porosity), producing a bone loss that partially offsets the bone gain. The combined events lead to a positive bone balance in PGE2-treated cortical bone, compared to a negative bone balance in control bones. Collectively our data suggest that in vivo PGE2 is a powerful activator of cancellous and cortical bone formation, which may be able to build a peak bone mass to prevent and/or correct the skeletal defects to cure osteoporosis.     

Effect of oral alendronate on net bone ingrowth into canine cementless total hips

Alendronate has been shown to prevent osteolysis in a canine total hip arthroplasty (THA) model. However, the effect of alendronate on bone ingrowth and remodeling around canine cementless hip replacement components remains unclear. We hypothesized that oral alendronate would increase net bone ingrowth into the porous surface of THA components when intimate bone/implant contact exists. To test this hypothesis, six mature dogs received unilateral cementless THA and were treated with five milligrams of oral alendronate daily from day seven to day eighty-four postoperatively. Six comparable dogs served as controls. Quantitative analysis of net bone ingrowth into the porous surface did not show a significant difference between the two groups, (control 7.9 +/- 1.5, alendronate 7.5 +/- 1.4, P < 0.6). These results did not support the hypothesis that oral alendronate would increase net new bone formation into the porous surface of THA components. Key words: alendronate, bone ingrowth, total hip arthroplasty.     

Some clinically relevant variables affecting the mechanical behaviour of bone cement

Summary The effects of 12 clinically relevant variables upon the basic mechanical properties of acrylic cement are reported. Attention is drawn to the facts that these variables may at times coexist to lead to serious reductions in the strength of the cement, and that the operating surgeon may exercise a substantial influence on the effective mechanical properties of the cement he is using.

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Zusammenfassung Es wird über die Wirkung von 12 klinisch relevanten Größen mit Einfluß auf die grundliegenden mechanischen Eigenschaften von Knochenzement berichtet.Die Aufmerksamkeit wird auf die Tatsache gelenkt, daß these Größen gelegentlich zusammentreffen und damit zu ausgeprägter Schwächung des Knochen zementes führen sowie die Tatsache, daß der Operateur einen erheblichen Einfluß auf die wirksamen mechanischen Eigenschaften des Zementes, den er benutzt, ausüben kann.

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This investigation was supported by: Howmedica International Ltd., North Hill Plastics Division, 622 Western Avenue, Park Royal, London, W3 OTF     

Intermittent and continuous administration of the bisphosphonate ibandronate in ovariohysterectomized beagle dogs: effects on bone morphometry and mineral properties.

Bisphosphonates have emerged as a valuable treatment for postmenopausal osteoporosis. Bisphosphonate treatment is usually accompanied by a 3-6% gain in bone mineral density (BMD) during the first year of treatment and by a decrease in bone turnover. Despite low bone turnover, BMD continues to increase slowly beyond the first year of treatment. There is evidence that bisphosphonates not only increase bone volume but also enhance secondary mineralization. The present study was conducted to address this issue and to compare the effects of continuous and intermittent bisphosphonate therapy on static and dynamic parameters of bone structure, formation, and resorption and on mineral properties of bone. Sixty dogs were ovariohysterectomized (OHX) and 10 animals were sham-operated (Sham). Four months after surgery, OHX dogs were divided in six groups (n = 10 each). They received for 1 year ibandronate daily (5 out of 7 days) at a dose of 0, 0.8, 1.2, 4.1, and 14 microg/kg/day or intermittently (65 microg/kg/day, 2 weeks on, 11 weeks off). Sham dogs received vehicle daily. At month 4, there was a significant decrease in bone volume in OHX animals (p < 0.05). Doses of ibandronate >/= 4.1 microg/kg/day stopped or completely reversed bone loss. Bone turnover (activation frequency) was significantly depressed in OHX dogs given ibandronate at the dose of 14 microg/kg/day. This was accompanied by significantly higher crystal size, a higher mineral-to-matrix ratio, and a more uniformly mineralized bone matrix than in control dogs. This finding lends support to the hypothesis that an increase in secondary mineralization plays a role in gain in BMD associated with bisphosphonate treatment. Moreover, intermittent and continuous therapies had a similar effect on bone volume. However, intermittent therapy was more sparing on bone turnover and bone mineral properties. Intermittent therapy could therefore represent an attractive alternative approach to continuous therapy.     

Effects of ovariectomy in beagle dogs

Beagle dogs 3-7 years old were ovariectomized (n = 9) or sham operated (n = 6) and followed for 48 weeks with measurements of body weight, tibial shaft bone mineral content (BMC), and serum biochemistry. Following killing, measurements were made of bone strength and histomorphometry. Ovariectomy (OX) significantly reduced serum estrone and estradiol concentrations and their variability from month to month. There was a transient decrease in cortical BMC of the OX dogs during the first 12 postoperative weeks but no difference between the groups after 48 weeks. Serum osteocalcin was elevated, but there was little effect on serum alkaline phosphatase, Ca, P, or calcitonin. OX increased the number of tetracycline-labeled osteons in cortical bone but reduced the percent trabecular surface labeled with tetracycline. OX produced no significant changes in the composition of the bones or loss of cortical area, but a statistically significant 15% trabecular bone loss occurred in the spine. However, bone strength had not been significantly affected at the time of sacrifice.     

Treatment of lung cancer using clinically relevant oral doses of the cyclooxygenase-2 inhibitor rofecoxib: potential value as adjuvant therapy after surgery

OBJECTIVE: To investigate the uses and limitations of cyclooxygenase- (COX) 2 inhibition using clinically relevant doses of oral rofecoxib in the treatment of murine models of non-small-cell lung cancer (NSCLC). SUMMARY BACKGROUND DATA: Overexpression of COX-2 has been reported in lung cancer. Several studies have demonstrated that high doses of COX-2 inhibitors could inhibit the growth of rodent and human lung cancer cell lines. The potential uses and limitations of COX-2 inhibition at doses equivalent to those currently approved for use in humans have not been well studied. METHODS: Three murine NSCLC cell lines were injected into the flanks of mice to establish tumor xenografts. Mice were treated orally with low doses of a COX-2 inhibitor (rofecoxib chow, 0.0075%). Mechanisms were evaluated by analysis of tumor-infiltrating lymphocytes. To study rofecoxib as adjuvant therapy, large established tumors (14-18 days after tumor inoculation) were surgically debulked and animals were treated with rofecoxib starting 3 days before surgery. Recurrence of the tumor after debulking was monitored. RESULTS: Rofecoxib significantly slowed the growth of small (0-120 mm) tumors (P < 0.01-0.05) in all 3 cell lines, with higher efficacy in the more immunogenic tumors. Minimal responses were noted in larger tumors. Rofecoxib appeared to augment CD8 T cell infiltration in immunogenic tumors. Rofecoxib significantly reduced the recurrence rate after debulking (P < 0.01). CONCLUSIONS: Clinically relevant doses of the COX-2 inhibitor rofecoxib given orally were effective in inhibiting the growth of small (but not large) tumors in 3 murine NSCLC cell lines tested and in preventing recurrences after surgical debulking. Depending on the immunogenicity of human tumors, COX-2 inhibition might be useful as adjuvant therapy for surgically resectable NSCLC.     

Effect of aging on the toughness of human cortical bone: evaluation by R-curves

Age-related deterioration of the fracture properties of bone, coupled with increased life expectancy, is responsible for increasing incidence of bone fracture in the elderly, and hence, an understanding of how its fracture properties degrade with age is essential. The present study describes ex vivo fracture experiments to quantitatively assess the effect of aging on the fracture toughness properties of human cortical bone in the longitudinal direction. Because cortical bone exhibits rising crack-growth resistance with crack extension, unlike most previous studies, the toughness is evaluated in terms of resistance-curve (R-curve) behavior, measured for bone taken from wide range of age groups (34–99 years). Using this approach, both the ex vivo crack-initiation and crack-growth toughness are determined and are found to deteriorate with age; the initiation toughness decreases some 40% over 6 decades from 40 to 100 years, while the growth toughness is effectively eliminated over the same age range. The reduction in crack-growth toughness is considered to be associated primarily with a degradation in the degree of extrinsic toughening, in particular, involving crack bridging in the wake of the crack.