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Biomedical subjects

B R MacDonald

Publications and source records attributed to B R MacDonald.

At least 19 recordsLinked to original sources
PubMed2001

Emerging therapies in osteoporosis.

The approval of alendronate in 1994 marked a watershed in the treatment of osteoporosis. Before that time there was no therapy for which unequivocal proof of efficacy existed. Since then several more agents, all from the anti-resorptive class, have also been approved for use in the treatment of this disease and the range of indications for alendronate has been extended to include the prevention of osteoporosis in women with lesser degrees of bone loss, the treatment of glucocorticoid-induced osteoporosis and, most recently, the treatment of male osteoporosis. Despite this there are still several areas of unmet medical need in this disease, including the availability of well tolerated and convenient therapies and treatments that will go beyond the levels of efficacy offered by current therapies. An intense effort is now being directed towards meeting these unmet needs with the improvement of existing therapies and the development of novel agents that will provide superior long term benefit. Important and exciting drug targets are yielding novel compounds with anti-resorptive activity or anabolic effects to complement current anti-resorptives. Despite this effort considerable obstacles to the successful development of these compounds remain, not least the stringent safety requirements needed to provide an acceptable risk-to-benefit profile and the increasing difficulties of conducting placebo controlled studies in patients at high risk of fracture.

Female↗
PubMed1996

Evaluation of activated protein C on canine infarct size in a nonthrombotic model of myocardial reperfusion injury.

Myocardial infarct size has been measured after 1 hr of mechanical occlusion of the circumflex coronary artery and 5 hr of reperfusion in control dogs infused with saline, and in dogs infused with activated protein C (aPC) (1mg/kg/hr i.v.). Infusion of aPC during reperfusion produced a sustained doubling of activated partial thromboplastin time and no change in thrombin time at a final plasma parent drug concentration of 1.25 +/- 0.11 mug/ml. aPC infusion did not alter systolic arterial pressure, cardiac rate or the rate pressure product when compared to time-related alterations observed in control dogs. ST-segment deviation and the intensity and duration of cardiac arrhythmias associated with reperfusion of ischemic myocardium also were similar between groups. Resultant infarct sizes were 34.8 +/- 3.9 and 33.2 +/- 6.2% of the left ventricular mass placed at risk of necrosis in control and aPC-treated dogs. respectively. aPC infusion was associated with a small reduction in leukocytosis in response to myocardial ischemic injury, but did not alter the localization of leukocytes within ischemic and infarcted myocardium. In vitro concentrations of aPC (0.3, 1 and 3 mug/ml), comparable to the plasma concentration that inhibited blood coagulation in dogs, did not alter superoxide production or CD11b/CD18-mediated adhesion of chemotactic factor f-Met-Leu-Phe-stimulated neutrophils. Present data indicate that aPC lacks cardioprotectant activity at an infusion rate inhibiting coagulation. Apart from inhibition of thrombin generation, no evidence of an anti-inflammatory effect of aPC was observed.

Animals↗
PubMed1993

Proliferative responses to estradiol, IL-1 alpha and TGF beta by cells expressing alkaline phosphatase in human osteoblast-like cell cultures.

The use of primary (nontransformed) bone cell cultures is hampered by their cellular heterogeneity. Primary cultures of osteoblast-like cells have been shown to proliferate in response to several osteotropic agents, but because mixed cell populations are present it is uncertain whether a true osteoblastic response was observed. By combining (1) localization of [3H]-thymidine incorporation into the nuclei of actively dividing cells by autoradiography with (2) subsequent induction of osteoblast differentiation by 1,25(OH)2D3 to optimize the number of cells expressing high alkaline phosphatase activity and (3) its localization by histochemical staining, it is possible to measure the proliferation of cells that are capable of expressing a more mature osteoblastic phenotype in heterogeneous human trabecular bone cell cultures. Over a 72-hour incubation period, rhIL-1 alpha (0.2-2 ng/ml) exerted a dose-dependent stimulation of proliferation of cells expressing alkaline phosphatase. Purified human TGF beta 1 produced a biphasic increase in the proliferation of these cells (0.01-1 ng/ml) but 17 beta and 17 alpha-estradiol (10(-12)-10(-8) M) failed to consistently regulate cell growth. Furthermore, 17 beta-estradiol did not reproducibly modulate proliferation induced by IL-1 alpha or TGF beta when added together in cultures. This procedure represents a more accurate method for the assessment of osteoblast proliferation in primary bone cell cultures and demonstrates that estrogen is not mitogenic for human osteoblasts and does not potentiate the actions of putative local stimulators of osteoblast replication.

Adult↗
PubMed1993

The cell biology of bone.

Bone remodelling and repair are accomplished by the co-ordinated activity of cells of the osteoclast and osteoblast lineages. Small changes in the balance between formation and resorption will, when magnified by repeated cycles, lead to significant reduction in bone mass and strength, ultimately resulting in fracture. This review focuses on the cellular features of bone remodelling and the known regulators of bone cell function. These include systemic and local factors, both soluble and contained within the complex extracellular matrix of bone.

Animals↗
PubMed1992

Evaluation of LY203647 on cardiovascular leukotriene D4 receptors and myocardial reperfusion injury.

In vitro studies have shown LY203647 to be a selective antagonist of contractile responses to leukotriene (LT) D4 and LTE4 in guinea pig ileum, trachea and lung parenchyma. In pithed rat, i.v. injection of LTD4 produced pressor responses that were selectively antagonized by LY203647 in a dose-dependent manner [ED50 7.5 (6.0-9.5) mg/kg, i.v.]. In normal anesthetized rats and dogs, LTD4 reduced aortic blood flow and stroke volume in association with systemic vasoconstriction, variable blood pressure responses and no change in cardiac rate. LTD4 did not alter myocardial contractility corrected for alterations in afterload. Pretreatment of rats and dogs with LY203647 (1-10 mg/kg, i.v.) produced dose-related inhibition of the myocardial and systemic hemodynamic effects of LTD4, whereas coadministration of LY203647 reversed established myocardial depression and systemic and pulmonary vasoconstriction during continuous infusion of LTD4 in dogs. LY203647 (10 mg/kg over 90 min, i.v.) infusion in normal dogs abolished or greatly antagonized hemodynamic responses to LTD4 for 6 hr. In subsequent experiments, myocardial infarct size was measured after 1 hr of occlusion of the circumflex coronary artery and 5 hr of reperfusion. LY203647 (10 mg/kg over 90 min, i.v.) treatment did not alter cardiovascular parameters when compared to time-related alterations observed in control dogs. ST segment deviation and the intensity and duration of cardiac arrhythmias associated with coronary artery occlusion and reperfusion also were similar between groups. Resultant infarct sizes were 46 +/- 1 and 45 +/- 1% of the left ventricular mass placed at risk in control and LY203647-treated dogs, respectively. Present data illustrate the prominent cardiac and systemic hemodynamic effects of LTD4 and indicate that LY203647 produces selective and sustained antagonism of cardiovascular LTD4 receptors. Lack of containment of infarction by LY203647 suggests that endogenous cysteinyl-LT do not contribute to reperfusion injury of ischemic myocardium.

Acetophenones↗
PubMed1991

Characterization of LY233569 on 5-lipoxygenase and reperfusion injury of ischemic myocardium.

LY233569 produced concentration-dependent inhibition of isolated guinea pig 5-lipoxygenase (5-LPO) and 5-LPO activity of human polymorphonuclear leukocytes in vitro; IC50 values were 0.4 and 0.1 microM, respectively. LY233569 also inhibited (IC50 approximately 1.8 microM) zymosan-stimulated production of leukotriene B4 in canine whole blood but had little or no concomitant effect on the production of thromboxane B2. Concentrations of LY233569 as high as 10 microM did not inhibit production or scavenge superoxide from activated human neutrophils. In normal anesthetized dogs, infusion of LY233569 (0.11 mg/kg/min, i.v.) for 6 hr produced persistent inhibition (approximately 80%) of leukotriene B4 production in blood challenged ex vivo with zymosan; the plasma concentration (approximately 4 microM) of LY233569 was consistent with in vitro data illustrating selective and maximal inhibition of 5-LPO. In subsequent experiments, myocardial infarct size was measured after 1 hr of occlusion of the circumflex coronary artery and 5 hr of reperfusion. Continuous infusion of LY233569 (0.11 mg/kg/min, i.v.) had little or no effect on base-line systolic arterial pressure, cardiac rate and the pressure rate product when compared with time-related changes observed in control dogs. LY233569 infusion also did not alter the degree of ST-segment deviation or the intensity and duration of cardiac arrhythmias associated with coronary artery occlusion and reperfusion. Resultant myocardial infarct sizes were 45 +/- 5% of the left ventricle placed at risk in control dogs and 43 +/- 4% in dogs given LY233569. Myeloperoxidase activity of infarcted myocardium did not differ between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Antagonism of leukotriene B4 receptors does not limit canine myocardial infarct size.

Injection of leukotriene (LT)B4 (0.1-3 micrograms/kg i.v.) in normal anesthetized dogs produced dose-related leukopenia that was accompanied by arterial hypotension and tachycardia at higher tested doses. LTD4 (0.1-3 micrograms/kg i.v.), in contrast, increased arterial blood pressure, lowered cardiac rate and produced little change in arterial blood leukocyte count. Continuous infusion of LY255283 [(1-(5-ethyl-2-hydroxy-4-(6-methyl-6-(1H-tetrazol-5-yl)- heptyloxy)phenyl)ethanone] (0.33 mg/kg/min i.v.), a selective LTB4 receptor antagonist, resulted in near complete inhibition of leukopenic, hypotensive and tachycardic responses to LTB4 (3 micrograms/kg i.v.) challenge over a 6-hr test period. Persistent antagonism of canine LTB4 receptors was associated with high circulating levels of LY255283 that were bound extensively to plasma proteins. In subsequent experiments, myocardial infarct size was measured following 1 hr of occlusion of the circumflex coronary artery and 5 hr of reperfusion in control dogs infused with vehicle, and in dogs receiving LY255283 (0.33 mg/kg/min i.v.). Drug and vehicle were infused continuously beginning 15 min before coronary artery occlusion. LY255283 treatment essentially did not alter base-line cardiovascular parameters or myocardial oxygen demand when alterations were compared to time-related changes observed in control dogs. LY255283 infusion also did not alter the degree of myocardial ischemia or the intensity and duration of cardiac arrhythmias associated with coronary artery occlusion and reperfusion. Resultant infarct sizes were 43 +/- 5% of the left ventricle placed at risk in control dogs and 32 +/- 5% in dogs given LY255283; this difference was not statistically significant. The extent of left ventricle placed at risk was similar between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Osteoclast-like cells form in long-term human bone marrow but not in peripheral blood cultures.

Transplantation studies have suggested that peripheral blood mononuclear cells contain precursors for osteoclasts. Thus we tested the capacity of peripheral blood monocytes to form osteoclasts in long-term culture. We have reported previously that mononuclear cells from feline, baboon, and human marrow form osteoclast-like cells in long term cultures. Further, the formation of these cells is increased in response to bone resorption stimulatory agents such as PTH, interleukin 1, and transforming growth factor alpha. We now report that these cells show characteristic cytoplasmic contraction with calcitonin and form resorption lacunae when cultured on sperm whale dentine. Thus, these bone marrow-derived multinucleated cells fulfill the functional criteria for osteoclasts. Although cultured peripheral blood monocytes can be induced to form multinucleated cells with 1,25-dihydroxyvitamin D3, these cells did not show similar responses to the osteotropic factors as multinucleated cells formed in the bone marrow cultures multinucleated cells. These results indicate that osteoclasts or cells closely related to osteoclasts form in long-term human bone marrow cultures. In contrast, few mononuclear cells in the peripheral blood appear capable of forming osteoclasts under the culture conditions used in these experiments.

Bone Marrow↗
PubMed1989

Inhibition of osteoclast-like cell formation by bisphosphonates in long-term cultures of human bone marrow.

Bisphosphonates inhibit bone resorption in vivo and in vitro by unknown mechanisms. The effect of bisphosphonates on the formation of osteoclasts from their mononuclear hematopoietic precursors was investigated using human long-term marrow cultures in which multinucleated cells form that express most of the known features of the osteoclast phenotype (e.g., bone resorption, tartrate-resistant acid phosphatase, calcitonin responsiveness, and reactivity with specific MAbs). The five bisphosphonates that were tested strongly inhibited 1,25-dihydroxyvitamin D3-stimulated formation of these cells with the same relative potencies as they inhibit bone resorption in vivo. Two representative compounds (3-amino-1-hydroxypropylidene-1,1-bisphosphonate and dichloromethylene bisphosphonate) failed to inhibit the proliferation of precursors of the osteoclast-like cells. However, these compounds decreased the proportion of mononuclear and multinucleated cells expressing an osteoclast antigen, thus suggesting a degree of specificity for cells of the osteoclast lineage. We conclude that bisphosphonates are potent inhibitors of osteoclast-like cell formation in long-term human marrow cultures, and that this may be related to their ability to inhibit bone resorption in vivo.

Bone Marrow↗
PubMed1988

Actions of recombinant human gamma-interferon and tumor necrosis factor alpha on the proliferation and osteoblastic characteristics of human trabecular bone cells in vitro.

Using cultured human osteoblast-like cells, we studied the effects of tumor necrosis factor (TNF) and recombinant human gamma-interferon (gamma-IFN) on osteoblast growth and function, and demonstrated that TNF stimulated bone cell proliferation and prostaglandin production while inhibiting 1,25-(OH)2D3-stimulated alkaline phosphatase activity and osteocalcin release. In contrast, gamma-IFN inhibited proliferation and stimulated alkaline phosphatase activity of the cells, while inhibiting 1,25-(OH)2D3-stimulated osteocalcin production and having variable effects on the release of prostaglandins, depending on the presence of other factors. Our results suggest that TNF and gamma-IFN can act directly on bone-forming cells to affect both their proliferation and their differentiated function, and that changes in the ability of cells to produce these factors in disease states may contribute to alterations in the integrity of connective tissue matrices.

Alkaline Phosphatase↗
PubMed1987

Formation of multinucleated cells that respond to osteotropic hormones in long term human bone marrow cultures.

Studies of osteoclasts and their precursors in normal and pathological states have been severely hampered by the lack of an in vitro system for forming osteoclasts. We developed a human marrow culture system in which multinucleated cells with several characteristics of osteoclasts form. Multinucleated cells began to form during the first week of culture, with maximum numbers formed after 3 weeks. PTH (25-50 ng/ml) and 1,25-dihydroxyvitamin D3 (10(-10)-10(-8) M) increased formation of these cells, and these effects were inhibited by calcitonin. These multinucleated cells contained nonspecific esterase and tartrate-resistant acid phosphatase, a marker enzyme of osteoclasts, and had several ultrastructural features of osteoclasts. We used this marrow cell culture technique to study a patient with hyperparathyroidism and markedly increased osteoclasts on bone marrow biopsy. The marrow from this patient formed increased numbers of multinucleated cells in vitro. After parathyroidectomy both multinucleated cell formation in vitro and osteoclast numbers on bone biopsy decreased significantly. This long term marrow culture system represents the first demonstration of human osteoclast-like cell formation in vitro. This system should permit studies to evaluate factors controlling formation of cells with certain osteoclast characteristics in vitro and their precursors as well as to evaluate abnormalities in osteoclast formation in patients with metabolic bone disease.

Bone Marrow Cells↗
PubMed1987

Primate myocardial and systemic hemodynamic responses to leukotriene D4: antagonism by LY171883.

Intravenous infusion of leukotriene D4 (LTD4; 0.1-10 micrograms/kg) produced dose-related depression of myocardial contractility, stroke volume index and mean aortic blood flow index in anesthetized monkeys. These alterations occurred in association with increments in systemic and pulmonary vascular resistances, reductions in calculated left ventricular stroke and minute work indices and relatively little or no dose-dependent change in cardiac rate, mean arterial blood pressure and mean pulmonary arterial blood pressure. Left atrial pressure did not increase in response to LTD4, although cardiac afterload was increased and myocardial contractility and stroke volume index were reduced. LTD4-induced alterations of aortic blood flow index, stroke volume index and systemic and pulmonary vascular resistances were sustained during a 60-min observation period after drug infusion. Pretreatment of monkeys with LY171883 (10 mg/kg i.v.), a selective LTD4-LTE4 receptor antagonist, inhibited the magnitude and duration of hemodynamic responses to LTD4 challenge. For example, LTD4 dose-response curves for depression of mean aortic blood flow index, stroke volume index and left ventricular stroke and minute work indices were shifted to the right approximately 10-fold by LY171883. The plasma concentration of LY171883 effective in this regard was 32 +/- 7 micrograms/ml. Attenuation of LTD4 responses by LY171883 was selective in that antagonist pretreatment did not result in concomitant reduction of vascular and cardiac responses mediated by adrenergic receptors, and LY171883 administration produced little or no change in base-line parameters. The composite data provide evidence of the presence of LT receptors in the primate cardiovascular system and suggest that LY171883 is a selective antagonist of these receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetophenones↗
PubMed1986

Differential sensitivity to trypsin of human bone-derived cells in culture: surface changes detected by partitioning in aqueous two-phase systems.

Human bone-derived cells, grown in monolayer culture, were dissociated by incubations with trypsin/EDTA and subjected to thin-layer counter-current distribution in a 'low potential' aqueous two-phase system. Two major populations of cells were detected. The number of cells in the second (more hydrophobic) population increased with length of trypsinization and time in culture. Cells allowed to 'regain' surface molecules lost by trypsinization did not produce the second population. Cells occupying the second population after a short period of trypsinization had a lower rate of division than peak 1 cells but showed a higher rate of protein synthesis per rate of division than peak 1 cells. These results show that the cells have markedly different sensitivities to trypsin digestion which may be related to cell division rate of growth. The possible relationship between this and osteoblast development are discussed.

Bone and Bones↗
PubMed1986

Effects of human recombinant CSF-GM and highly purified CSF-1 on the formation of multinucleated cells with osteoclast characteristics in long-term bone marrow cultures.

Several studies have suggested that the osteoclast is derived from a mononuclear precursor which is found in bone marrow. We have developed a system for studying the formation of osteoclast-like multinucleated cells in long-term bone marrow culture of baboon cells. Recombinant human CSF-GM and highly purified CSF-1, both of which stimulate the proliferation of monocyte/macrophage precursors, were found to increase the number of osteoclast-like cells formed in long-term bone marrow culture. CSF-GM stimulated multinucleated cell formation more consistently than CSF-1. The subsequent addition of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) to cultures initially treated with CSF-GM or CSF-1 further increased multinucleated cell formation. Autoradiographic studies indicate that CSF stimulated multinucleated cell formation by increasing the proliferation of the precursor cell, and that the potentiating effect of 1,25-(OH)2D3 was caused by fusion of the increased numbers of precursors. These studies suggest that the interaction of locally produced colony-stimulating factors with circulating calcium regulating hormones may be important in the control of osteoclast formation and bone resorption.

Animals↗