Martin W. Edwards

The anabolic effect of estrogen on endosteal bone formation in the mouse is attenuated by ovariohysterectomy: A role for the uterus in the skeletal response to estrogen?

SummaryIn the mouse, the anabolic effect of estrogen on the uterus and its stimulatory effect on endosteal bone formation are well documented. When these observations are coupled with the recent description of uterine-derived bone cell mitogens, it raises the possibility that uterine hypertrophy in response to estrogen might lead to the production and release of factors that participate in the skeletons anabolic response to estrogen. To determine if the stimulatory effects of estrogen on endosteal bone formation and uterine tissue in the mouse are related, we have studied this specific skeletal response to ovariectomy (OVX) and ovariohysterectomy (OHTX), and to two levels of 17β-estradiol (17β-E2). To assess treatment effects, 48 Swiss-webster mice were assigned to six groups: OHTX/oil vehicle, OVX/oil vehicle, OHTX/150 μg 17β-E2, OHTX/300 μg 17β-E2, OVX/150 μg 17β-E2, and OVX/300 μg 17β-E2. Animals were treated once per week with vehicle or the respective 17β-E2 dose. To quantitate bone formation, fluorochrome labels were administered at the beginning and end of the experimental period. At the conclusion of the 5-week study, tibiae were processed undecalcified for embedding in methyl methacrylate plastic. Cross-sectional areal properties and bone formation rates were quantitated from 30 μm mid-diaphyseal sections using a Bioquant Bone Morphometry system. Compared with the vehicle-treated OVX and OHTX mice, 150 μg of 17β-E2 administered once per week significantly increased cortical bone areas (P<0.05) but cortical bone widths and the ratio of cortical bone area to total bone area was increased only in estrogen-treated OVX mice (P<0.01). The attenuation of bone formation in the OHTX mice was even more apparent in animals treated with 300 μg 17β-E2. Endosteal mineral apposition and bone formation, cortical bone widths, and cortical bone ratios were all significantly reduced in OHTX mice compared with OVX animals treated with the same 17β-E2 dose. Indeed, the 17β-E2-induced cortical bone increases in the OVX animals were reduced 50% by OHTX. These results suggest that the anabolic effects of high-dose 17β-E2 on endosteal bone formation in the mouse are modulated by estrogens uterotrophic activity, and are therefore consistent with the hypothesis that the uterus may produce and release factors with the capacity to stimulate bone formation.

Prevention of postoperative intracerebral hemorrhage with topical recombinant factor XIII in the rat.

Factor XIII is an endogenous clotting factor that retards thrombus degradation by cross-linking fibrin. To determine the efficacy of Factor XIII as a topical clot-stabilizing agent in preventing postoperative hemorrhage associated with coagulopathy, a rat model of experimental craniotomy and standardized bilateral frontal corticectomy was developed. In 25 rats (50 lesions), recombinant human Factor XIII or placebo solution was topically applied to corticectomy cavities after hemostasis was achieved; each animal served as its own control. In 20 rats, heparin sulfate (100 U/kg.h) was initiated intraperitoneally 3 days after surgery and was continually administered by an Alzet pump for 7 days, compared with a control group of 5 rats receiving saline intraperitoneally. The volume of intracranial hemorrhage was quantitatively determined from coronal sections by use of automated image analysis. Large (> 50 mm3) intracerebral hemorrhages were significantly more frequent in placebo (60%)- compared with recombinant Factor XIII (15%)-treated lesions (P < 0.01) in animals receiving heparin. The topical application of clot-stabilizing agents such as Factor XIII may reduce the risk of postoperative intracranial hemorrhage, especially in high-risk patients with coagulopathy.

LOGISTICS-BASED APPROACHES TO REDUCING CLINICAL DEVELOPMENT TIMES

Speed in drug development is increasingly recognized as being key to creating and sustaining a competitive advantage within the pharmaceutical industry. The long duration of clinical development and the enormous potential cost of delays indicates that even a small percentage of time savings on activities with a long time-base may translate into substantial revenue gains. Inter-company comparisons suggest that some organizations are faster at development than others, but do not suggest where inefficiencies lie, or how time can be saved. We suggest the use of iterative work study principles to determine the optimum way of performing key medical development processes and show how this can be linked to measures of individual and departmental productivity.