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  • 1
    Electronic Resource
    Electronic Resource
    Importance of Preclinical Studies in the Development of Drugs for Treatment of Osteoporosis: A Review Related to the 1998 WHO Guidelines (1999)
    Springer
    Osteoporosis international 9 (1999), S. 379-393 
    Details
    ISSN: 1433-2965
    Keywords: Key words:Animal models – Clinical trials – Drug registration – Guidelines – Osteoporosis – Preclinical program
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract: Osteoporosis, which is defined as a disease characterized by low bone mass and microarchitectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk, is a major health issue worldwide. Among the various strategies to prevent and cure this devastating ailment, an important objective is the development of new efficacious and safe drugs. This situation prompted the World Health Organization (WHO) to provide a comprehensive statement of guiding principles for the design, implementation and interpretation of both preclinical testing and clinical trials in osteoporosis. These guidelines, which are now available, underline the crucial importance of the preclinical evaluation, particularly for assessing the effect of an intervention on bone strength. This concept is heightened by the lack of a validated technique for noninvasively evaluating bone strength in humans and the multiple difficulties and heavy burden inherent in the evaluation of fracture rate in clinical trials. The WHO guidelines emphasize that a comprehensive and adequate preclinical program is expected to provide key information on the relationship between bone mass and strength and thus attenuate the burden of clinical studies. The present report provides a review of experimental evidence in support of the preclinical program as proposed in the WHO guidelines. This program is based on the recent development and refinement of animal models of osteoporosis that mimic the human condition according to the conceptual definition of the disease. Many preclinical studies carried out in appropriate animal models with agents that exert either antiresorbing or anabolic effects on bone indicate that they have been highly predictive of the drug action in humans in terms of both bone mass and remodeling, as well as of bone strength whenever fracture rate has been documented in clinical trials. Based on this evidence the WHO guidelines propose strategies according to which the results of preclinical evaluation will determine the end-points required in the different phases of the clinical development of the drug. Such a distribution of task assignment between preclinical and clinical programs should optimize the progress of research available to patients already suffering from or at risk of osteoporosis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001980050161
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  • 2
    Electronic Resource
    Electronic Resource
    Bone density and shape as determinants of bone strength in IGF-I and/or pamidronate-treated ovariectomized rats (1996)
    Springer
    Osteoporosis international 6 (1996), S. 219-227 
    Details
    ISSN: 1433-2965
    Keywords: Bone mechanical properties ; IGF-I ; Osteoporosis ; Pamidronate ; Rats
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Areal bone mineral density (BMD) is a major determinant of bone strength and thereby of fracture risk. Other factors including trabecular microarchitecture and bone dimensions also contribute to bone strength. To investigate the relative importance for bone strength of BMD and bone dimensions, the relations between strength and the latter variables were evaluated under different experimental conditions in ovariectomized rats. Bone strength was assessed in compression and bending with measurement of BMD by dual-energy X-ray absorptiometry. Interventions were designed to increase trabecular BMD in rats with estrogen deficiency-induced bone loss (OVX) by treatment with pamidronate, an inhibitor of bone resorption, or to modify bone dimensions, particularly diameter, by administration of the growth factor IGF-I. In OVX rats, pamidronate treatment increased BMD with a commensurate increase in bone strength at the level of lumbar vertebrae and femoral neck (r=0.789,p〈0.0001 andr=0.535,p〈0.001, respectively). IGF-I increased the external diameter of midshaft tibia and femoral neck, which also correlated with bone strength (r=0.678,p〈0.0001 andr=0.507,p〈0.0002, respectively). Thus, both bone dimensions and BMD contributed to the determination of bone strength. In conclusion, adult rats with estrogen deficiency-induced bone loss represent a useful experimental model for investigating bone strength and its determinants such as BMD and external bone dimensions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01622738
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  • 3
    Electronic Resource
    Electronic Resource
    The New Selective Estrogen Receptor Modulator MDL 103,323 Increases Bone Mineral Density and Bone Strength in Adult Ovariectomized Rats (1999)
    Springer
    Osteoporosis international 10 (1999), S. 369-376 
    Details
    ISSN: 1433-2965
    Keywords: Key words:Bisphosphonate – Bone mineral density – Bone strength – IGF-I – Osteoporosis – Ovariectomy – SERM
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract: Selective estrogen receptor modulators (SERMs) can prevent the bone loss induced by ovariectomy (OVX), but it is not established whether they can increase bone mass and strength in a curative protocol in ovariectomized osteopenic animals. We investigated the influence of a SERM of the new generation, MDL 103,323, on areal bone mineral density (BMD), as measured by dual-energy X-ray absorptiometry, bone strength and remodeling in OVX osteopenic rats. Nine weeks after OVX, 8-month-old rats were divided into six groups of 10 animals. MDL 103,323 was given by gavage at doses of 0.01, 0.1 or 0.6 mg/kg body weight, 5 days a week. The effect of MDL 103,323 was compared with that of the bisphosphonate pamidronate (APD), which was injected subcutaneously at a dose of 1.6 mmol/kg body weight for 5 days every 4 weeks. Lumbar spine (LS), femoral neck (FN), proximal tibia (PT) and midshaft tibia (MT) BMD, bone strength, and proximal tibia histomorphometry, serum osteocalcin, urinary total deoxypyridinoline and serum insulin-like growth factor I (IGF-I) were measured. After 16 weeks of treatment, BMD changes (means ± SEM) were −11.4 ± 2.2, +4.0 ± 2.1 and +6.4 ± 1.0% respectively in OVX controls, in rats treated with 0.1 mg/kg MDL 103,323 (p〈0.05) and in APD-treated rats (p〈0.02) at the level of LS; −0.4 ± 1.1, +6.7 ± 1.4, +7.2 ± 1.8% (p〈0.01 and NS) at the level of FN; and −2.6 ± 1.2%, +5.8 ± 1.2, +6.9 ± 1.4% (p〈0.03 and 0.01) at the level of PT. MDL 103,323-treated animals had a higher trabecular bone volume, a higher number of trabeculae and smaller intertrabecular spaces compared with OVX controls. Vertebral body ultimate strength was 186 ± 13, 292 ± 16, 249 ± 23 N (p〈0.05) in OVX controls, MDL 103,323-treated rats and APD-treated rats, respectively. The administration of 0.6 mg/kg of MDL 103,323 did not further increase BMD or bone strength, indicating a bell-shaped dose–response curve. MDL 103,323 lowered plasma osteocalcin concentration and urinary deoxypyridinoline excretion. In rats treated with 0.1 mg/kg MDL 103,323, plasma IGF-I was increased as compared with OVX controls (664 ± 36 ng/ml vs 527 ± 39 ng/ml, p〈0.05). In conclusion, these results indicate that this new SERM positively influences BMD and lumbar spine bone strength in estrogen-deficient rats.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001980050242
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  • 4
    Electronic Resource
    Electronic Resource
    Effect of Estrogen Deficiency on Cancellous and Cortical Bone Structure and Strength of the Femoral Neck in Rats (1997)
    Springer
    Calcified tissue international 61 (1997), S. 336-344 
    Details
    ISSN: 1432-0827
    Keywords: Key words: Ovariectomy — Femoral neck — DEXA — Histomorphometry — SEM — Mechanical testing.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Abstract. Eighty mature Sprague-Dawley rats were weight matched before ovariectomy (Ovx) or Sham surgery (Sham). Sham rats had free access to food and water throughout the experiment, whereas Ovx rats were kept on the pair-fed diet. Rats were euthanized at 4, 8, and 12 weeks after surgery, and had received fluorochrome bone markers at 9 and 2 days prior to euthanasia. In addition 10 rats were euthanized at the time of surgery serving as baseline controls. All rats were also scanned for body composition and bone mineral parameters by DEXA before surgery and euthanasia. Left proximal femurs (femoral necks) were used for bone histomorphometry, whereas right femurs were used for in vitro DEXA measurements and mechanical testing. Despite pair-feeding, ovariectomized rats had increased body weights and fat body mass, whereas the percent lean body mass steadily declined throughout the experiment. Mineral density of the whole femur and femoral neck was significantly higher in the Sham rats relative to Ovx animals. Ovariectomy reduced trabecular number and thickness, and increased trabecular separation and bone marrow space at the femoral midneck location. The structure of the remaining trabeculae was dramatically changed toward simpler struts as revealed by nodal analyses. Cortical thickness in Ovx rats was reduced because of the high endocortical resorption, which, in addition to cancellous bone resorption, resulted in fewer endocortico-trabecular connections. Femoral necks obtained from ovariectomized rats had reduced strength and were less stiff relative to controls. Because of the enormous clinical significance of the proximal femur for osteoporosis in humans, and the opportunity for studying bone BMD, mass, structure, and strength at the same skeletal location, the femoral neck appears superior to other skeletal sites routinely used for bone histomorphometry or mechanical testing in the Ovx rat model.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002239900344
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  • 5
    Electronic Resource
    Electronic Resource
    Cor triatriatum dexter bei einem erwachsenen Patienten (1998)
    Springer
    Zeitschrift für Kardiologie 87 (1998), S. 891-893 
    Details
    ISSN: 1435-1285
    Keywords: Schlüsselwörter Cor triatriatum dexter – kongenitale Fehlbildungen – Chiari-Netzwerk – Eustachische Klappe – Thebesische Klappe ; Key words Cor triatriatum dexter – congenital malformation – Chiari network – Eustachian valve – Thebesian valve
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Cor triatriatum dexter is a rare congenital malformation in which a membrane divides the right atrium into two chambers. The membrane represents a persistence of the right sinus venosus valve (RSV). Normally the RSV regresses between the 9th and 15th week of gestation, as the cephalic portion forms the crista terminalis and the caudal portion develops into the Eustachian and Thebesian valve. Any failure in the regression process may result in remnants of RSV as a simple muscle bar, a Chiari-network or a fenestrated or unfenestrated membrane (cor triatriatum dexter). We describe a patient with cor triatriatum dexter in whom diagnosis was made several years after successful valvulotomy procedure for severe congenital valvular pulmonary stenosis.
    Notes: Zusammenfassung Das Cor triatriatum dexter ist eine seltene Fehlbildung, bei der eine Membran den rechten Vorhof in zwei Kammern teilt. Es handelt sich dabei um eine persistierende Sinus-venosus-Klappe, welche sich normalerweise zwischen der 9. bis 15. Gestationswoche zurückbildet. Fehler in dieser physiologischen Regression führen dazu, daß Reste der ehemaligen Sinus-venosus-Klappe als einfacher Muskelstrang, ein Chiari-Netzwerk oder eine fenestrierte oder unfenestrierte Membran persistieren können. Wir beschreiben einen Patienten mit einem Cor triatriatum dexter, bei dem die Diagnose erst einige Jahre nach erfolgreicher Valvulotomie einer schweren kongenitalen, valvulären Pulmonalstenose gestellt wurde.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s003920050245
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  • 6
    Electronic Resource
    Electronic Resource
    Chemical reactions during rapid quenching of oxygen-nitrogen mixtures from very high temperatures (1966)
    Hoboken, NJ : Wiley-Blackwell
    AIChE Journal 12 (1966), S. 956-963 
    Details
    ISSN: 0001-1541
    Keywords: Chemistry ; Chemical Engineering
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: A model has been developed to study chemical reactions which occur in oxygen-nitrogen mixtures during very rapid cooling in small-diameter tubes. The system considers both homogeneous gas phase reactions and surface reactions based upon a simplified mass transfer mechanism. With an energy balance used to determine the rate of quenching, the mole fractions of nitrogen, oxygen, nitric oxide, atomic nitrogen, and atomic oxygen were calculated as a function of temperature. In these studies, air and an equimolal oxygen-nitrogen mixture were cooled from temperatures which ranged between 3,000° and 7,000°K. The calculations showed that when the gases were cooled at rates exceeding ten million degrees per second, the species did not follow a chemical equilibrium path during the quenching process. In cooling from 4,000° to 7,000°K. the computations show that consideration of surface reactions predicts greater nitric oxide yields in the quenched gas than for homogeneous reactions alone. In fact, the heterogeneous reactions must contribute to the overall chemistry of quenching air. The composition of the quenched gas is strongly dependent upon the temperature-time history of the gas in the probe and upon the composition of the hot gas before it is quenched.
    Additional Material: 10 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/aic.690120522
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