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Biomedical subjects

L M Demers

Publications and source records attributed to L M Demers.

At least 73 records · Page 4Linked to original sources
PubMed1995

Biochemical markers of bone turnover in patients with metastatic bone disease.

Several biochemical markers of bone formation and bone resorption have recently been developed. These markers have been evaluated for clinical utility in patients with metabolic bone disease, including Paget disease and osteoporosis, and for their potential use in cancer patients whose disease has metastasized to bone. We have evaluated seven markers of bone turnover in the plasma and urine of 94 patients with newly diagnosed or progressive malignancy with and without clinical evidence of bone metastases. As determined by a positive bone scan and (or) bone survey, 30 patients had metastases to bone; 51 patients had metastatic cancer without overt bony involvement; and 13 patients had local disease without bone metastases. To evaluate the predictive value of these markers in the metastatic population, we utilized a "Z-score" and logistic regression analysis to distinguish patients with documented bone metastatic disease from those patients without clinical evidence of bone metastases. The higher the Z-score, the better the marker predicts the presence of bone metastases. With this statistical approach, urine N-telopeptide measurements had the highest Z-score and the most significant association with the probability of bone metastases. Urine deoxypyridinoline was the second most predictive marker of bone metastases. Thus, biochemical markers of bone resorption might be of use to predict the presence of bone metastases in cancer patients and to monitor the efficacy of antiresorptive therapy in patients treated for metastatic bone disease.

Alkaline Phosphatase↗
PubMed1995

Clinical and analytical evaluation of an immunoradiometric assay for corticotropin.

We evaluated a new IRMA developed commercially for the measurement of corticotropin (ACTH) in human plasma. The assay involves purified polyclonal goat capture antibodies specific for ACTH 26-39 and an 125I-labeled monoclonal signal antibody specific for ACTH 1-17. CVs for intraassay and total precision at ACTH concentrations between 9 and 801 ng/L ranged from 2.5% to 4.7% and from 3.3% to 9.3%, respectively, with an assay detection limit of 1.7 ng/L. The reference interval determined for adults with the new method (16-52 ng/L) differed significantly (P < 0.05) from that for an established ACTH IRMA (9-54 ng/L). Method comparison with clinical samples (n = 179) revealed a correlation coefficient of 0.970 and a best-fit equation of y (new IRMA) = (1.011 +/- 0.019)x + (4.17 +/- 3.31) with Sylx = 40.2. Both methods showed equivalent clinical sensitivity in evaluating Cushing disease, adrenal tumors, ectopic ACTH-producing tumors, hypopituitarism, steroid suppression, surgical adrenalectomy, Nelson syndrome, Addison disease, and corticotropin-releasing hormone stimulation. We conclude that the new IRMA is technically simple to perform and provides a specific and sensitive method for evaluating of adrenocortical function.

Adrenal Cortex Diseases↗
PubMed1995

Bone markers in osteoporosis and malignancy.

Normal bone turnover is characterized by a balance (coupling) between the formation of new bone by osteoblasts and the resorption of old bone by osteoclasts. This bone remodeling takes place at discrete sites in the skeleton called bone remodeling units. Initially, the cells that line bone are replaced by osteoclasts that bring about resorption of the surface of bone. Next, osteoclasts are replaced by osteoblasts that gradually refill this space. This balance between bone formation and bone resorption is altered in most metabolic bone diseases (uncoupling). Over the past two decades many investigators have attempted to develop both sensitive and specific assays for the noninvasive assessment of bone turnover. Biochemical markers of bone formation include total and bone-specific alkaline phosphatase, serum osteocalcin (bone gla protein), and more recently procollagen I extension peptides. During the extracellular processing of type I collagen, there is a cleavage of the aminoterminal (p-coll-I-N) and carboxyterminal (p-coll-I-C) extension peptides prior to fibril formation. These peptides circulate in blood and could be useful markers of bone formation.

Alkaline Phosphatase↗
PubMed1994

Pyrazinoylguanidine downregulates the glucose fatty-acid cycle in hypertensive, hyperinsulinemic diabetic patients.

Eight hypertensive patients with noninsulin dependent diabetes mellitus (NIDDM) were administered the experimental drug pyrazinoylguanidine (PZG) either alone or in combination with calcium-channel or beta-blockers. This treatment appeared to "downregulate" the glucose fatty acid cycle and reduced both systolic and diastolic blood pressures and mean body weight. Patients served as their own controls in this dose-escalation study, which included placebo treatment (baseline) 3 weeks, 300 mg PZG for 3 weeks and 600 mg for 3 weeks. PZG reduced increased serum concentrations of free fatty acids (FFA), glucose, and triglycerides (TG). TG concentrations correlated inversely with serum HDL-cholesterol concentrations. The beta-blockers used by several patients increased their FFA, glucose, insulin and TG concentrations, as well as blunting their response to PZG. The calcium-channel blockers exerted these effects to a much lesser extent. PZG reduced or abolished glycosuria, related to PZG's capacity to decrease hyperglycemia. Withdrawal of PZG restored glycosuria, as blood sugar increased. PZG was well tolerated. No patient reported any adverse effect or missed a weekly clinic visit (12 weeks). PZG deserves further study as supplementary and/or replacement therapy in NIDDM patients who are hypertensive and hyperlipidemic.

Adult↗
PubMed1994

Effects of Fadrozole (CGS 16949A) and Letrozole (CGS 20267) on the inhibition of aromatase activity in breast cancer patients.

Fadrozole Hydrochloride (CGS 16949A) and Letrozole (CGS 20267), are two of the newest non-steroidal, orally active aromatase inhibitors currently being evaluated as second line treatment of patients with hormone dependent forms of metastatic breast cancer. In a phase I clinical efficacy study, we examined the ability of these two imidazole derivatives to suppress the synthesis of estrogen in a cohort of postmenopausal patients with metastatic breast cancer. Both medications at relatively low doses were potent and rapid inhibitors of aromatase activity as evidenced by their ability to suppress the level of blood and urine estradiol and estrone as well as blood estrone sulfate in these patients. Letrozole appeared to be the more potent of the two, with over 95% suppression of both plasma and urinary estrogens observed within 2 weeks of therapy. Letrozole appeared to be more selective than Fadrozole in inhibiting aromatase activity in that no compromise in cortisol and aldosterone output was evident with Letrozole therapy at all of the doses tested, a compromise clearly seen with Fadrozole. The inhibition of aromatase activity by these imidazole derivatives as second line therapy for patients with hormone dependent breast cancer appears to be a favorable alternative form of hormone ablative therapy and holds considerable promise for the treatment of this malignancy.

Aromatase Inhibitors↗
PubMed1994

Clinical tests explain blunted cortisol responsiveness but not mild hypercortisolism in amenorrheic runners.

To investigate mechanisms of blunted adrenocortical responsiveness to exercise and mild hypercortisolism in amenorrheic runners, adrenocorticotropic hormone [ACTH-(1-24) 0.25 mg Cortrosyn] stimulation tests were performed in the presence and absence of overnight dexamethasone (1 mg) suppression (DX and NDX condition, respectively) in six eumenorrheic sedentary women (ES), nine eumenorrheic runners (ER), and nine amenorrheic runners (AR). Before the NDX stimulation test, plasma cortisol was higher (P < 0.001) in AR than in ER and ES. The cortisol response to the NDX stimulation test was blunted (P < 0.001) in AR but reached similar (P > 0.7) peak levels in all groups. Dexamethasone suppressed (P < 0.001) cortisol to similar (P > 0.5) levels (approximately 20 nmol/l) in all groups. In AR, cortisol responses to the DX test were larger (P < 0.03) than to the NDX test and similar (P > 0.6) in the three groups, again reaching comparable (P > 0.8) peak levels. The blunted cortisol response to stimulation in AR in the presence of their mild hypercortisolism appears to be due to a normal limitation in maximal adrenal secretory capacity. Extrapituitary modulators of adrenal responsiveness to ACTH may explain the mild hypercortisolism observed in AR, but limitations of these tests prevent a central negative-feedback defect or an intrinsic adrenal abnormality from being excluded until results of additional studies with even lower doses of dexamethasone and submaximal doses of ACTH-(1-24) are available.

Adolescent↗
PubMed1994

Influence of mineral dusts on metabolism of arachidonic acid by alveolar macrophage.

The alveolar macrophage (AM) responds to stimuli such as coal mine dust by releasing inflammatory mediators such as cytokines, growth factors, reactive oxygen species, and eicosanoids. Eicosanoids are synthesized by AM through the action of cyclooxygenase and lipoxygenase enzymes and serve to modulate the proinflammatory function of this cell as part of the lungs' host defense mechanism. Reactive oxygen species can be generated by AM as a by-product in the biosynthetic pathway of the prostaglandins. AM produces primarily prostaglandin E2, thromboxane A2, and leukotriene B4 as part of the cellular response to an inflammatory stimulus. There is evidence to suggest that eicosanoid production by AM is functionally linked to both surface interaction with mine dust particles like silica and by the phagocytosis of the dust particle itself. In this report, we examined the effects of an antioxidant, vitamin E, on dust-induced synthesis of PGE2 and TXB2 in vitro and in vivo by AM obtained by bronchoalveolar lavage from rats. We also looked at the effects of the surface of silica particles on AM eicosanoid biosynthesis under conditions of calcination, a process that removes exposed hydroxyl groups from the surface of silica particles, thus reducing the likelihood of soluble hydroxyl radical formation. Treatment of AM with vitamin E in vivo and in vitro reduced the augmentation in eicosanoid production usually observed when AM are exposed to mine dusts. These results suggest that vitamin E may effectively reduce the inflammatory and fibrotic response produced by inhalation of mineral dust through an antioxidant mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Arachidonic Acid↗
PubMed1993

Evidence for progesterone receptors in human osteoblast-like cells.

We report on the presence of progesterone receptor and its mRNA in a human osteoblast-like cell line (HOS TE85) using recombinant DNA methods, saturation analysis, specific immunoprecipitation with an anti-progesterone receptor antibody, and Northern blot analysis. These osteoblast-like cells were also found to be responsive to progesterone in a dose-dependent fashion through an augmentation in cellular alkaline phosphatase activity. These results support the presence of progesterone receptors in bone cells and suggest a direct effort of progesterone and/or antiprogestins on osteoblast cell function.

Alkaline Phosphatase↗
PubMed1993

Calcium supplementation and bone mineral density in adolescent girls.

OBJECTIVE: To evaluate the effect of calcium supplementation on bone acquisition in adolescent white girls. DESIGN: A randomized, double-blind, placebo-controlled trial of the effect of 18 months of calcium supplementation on bone density and bone mass. SUBJECTS: Ninety-four girls with a mean age of 11.9 + 0.5 years at study entry. SETTING: University hospital in a small town. INTERVENTIONS: Calcium supplementation, 500 mg/d calcium as calcium citrate malate; controls received placebo pills. MAIN OUTCOME MEASURES: Bone mineral density and bone mineral content of the lumbar spine and total body were measured by dual-energy x-ray absorptiometry and calcium excretion from 24-hour urine specimens. RESULTS: Calcium intake from dietary sources averaged 960 mg/d for the entire study group. The supplemented group received, on average, an additional 354 mg/d of calcium. The supplemented group compared with the placebo group had greater increases of lumbar spine bone density (18.7% vs 15.8%; P = .03), lumbar spine bone mineral content (39.4% vs 34.7%; P = .06), total body bone mineral density (9.6% vs 8.3%; P = .05), and 24-hour urinary calcium excretion (90.4 vs 72.9 mg/d; P = .02), respectively. CONCLUSIONS: Increasing daily calcium intake from 80% of the recommended daily allowance to 110% via supplementation with calcium citrate malate resulted in significant increases in total body and spinal bone density in adolescent girls. The increase of 24 g of bone gain per year among the supplemented group translates to an additional 1.3% skeletal mass per year during adolescent growth, which may provide protection against future osteoporotic fracture.

Absorptiometry, Photon↗
PubMed1993

Effects of pyrazinoylguanidine on the glucose-fatty acid cycle in normal subjects and patients with non-insulin-dependent diabetes mellitus.

Pyrazinoylguanidine (PZG) reduced the hyperglycemia, hyperinsulinemia, and hyperlipidemia of patients with non-insulin-dependent diabetes mellitus (NIDDM) as well as of normal subjects receiving hydrochlorothiazide (HCTZ). Mechanisms are proposed by which PZG downregulated the elevated glucose-fatty acid cycle toward a more normal level in NIDDM patients and in non-diabetic subjects maintained on HCTZ. Despite maintenance of these NIDDM patients on their current antihypertensive medication, PZG reduced further their systolic and diastolic pressures. PZG was well tolerated by both normal and NIDDM patients.

Adult↗
PubMed1993

Effects of gastrin and difluoromethylornithine on growth of human colon cancer.

The effect of difluoromethylornithine (DFMO), a specific inhibitor of ornithine decarboxylase activity, was evaluated in vivo and in vitro on the growth of a gastrin-sensitive human colon carcinoma (WiDr). In vivo, mice bearing the tumor treated with pentagastrin had larger tumors with higher ornithine decarboxylase activity and polyamine content (P < 0.05) than mice not treated with pentagastrin. Difluoromethylornithine treatment significantly decreased ornithine decarboxylase in both the pentagastrin-treated and the untreated animals; however, DFMO had no effect on tumor volume, weight, protein, or DNA content. In cell culture, gastrin treatment increased WiDr cell number and [3H]thymidine incorporation in the presence or absence of serum. In serum-free conditions, however, gastrin stimulated cell growth without concomitantly increasing ODC activity. DFMO, on the other hand, decreased both ODC activity and growth. These studies suggest that the trophic effect of gastrin on WiDr human colon cancer is independent of ODC activity. Since gastrin treatment increased ODC activity in vivo, gastrin may interact in vitro with other factors present in serum that can alter ODC activity.

Animals↗
PubMed1993

Neutrophil attractant/activating peptide-1/interleukin-8: association with histologic chorioamnionitis, preterm delivery, and bioactive amniotic fluid leukoattractants.

OBJECTIVES: The goals of this study were (1) to determine immunoreactive neutrophil attractant/activating peptide-1/interleukin-8 levels in amniotic fluid from patients with preterm labor and (2) to compare neutrophil attractant/activating peptide-1/interleukin-8 levels, amniotic fluid culture, Gram stain, and the leukotaxis bioassay for their ability to predict histologic chorioamnionitis and clinical outcome. STUDY DESIGN: Amniotic fluid was collected by amniocentesis from 55 patients with idiopathic preterm labor and three patients with preterm labor and clinical chorioamnionitis. Gram stain, culture (aerobic, anaerobic, and Mycoplasma species), leukotaxis bioassay, and a commercially available neutrophil attractant/activating peptide-1/interleukin-8 enzyme-linked immunosorbent assay (sensitivity 1 ng/ml) were performed on the amniotic fluid samples. Placentas and chorionic membranes were evaluated for evidence of histologic chorioamnionitis in patients delivered preterm. RESULTS: All patients with detectable leukoattractants by the leukotaxis bioassay had neutrophil attractant/activating peptide-1/interleukin-8 levels above the threshold of the assay. The presence of amniotic fluid neutrophil attractant/activating peptide-1/interleukin-8 is a more sensitive marker for histologic chorioamnionitis and delivery before 34 weeks than is amniotic fluid culture (100% vs 59%, p < 0.01; and 95% vs 56%, p < 0.01, respectively). Also, of patients in idiopathic preterm labor those without amniotic fluid leukoattractants (group 1) had the lowest amniotic fluid levels, followed by patients with amniotic fluid leukoattractants and a negative culture (group 2) and patients with amniotic fluid leukoattractants and a positive culture (group 3) who had the highest levels (group 1 vs group 2, p < 0.001; group 2 vs group 3, p < 0.01). CONCLUSIONS: Amniotic fluid neutrophil attractant/activating peptide-1/interleukin-8, like the leukotaxis assay, is an accurate antepartum predictor of histologic chorioamnionitis and subsequent early delivery in patients with preterm onset of labor. This study supports the role of neutrophil attractant/activating peptide-1/interleukin-8 in the recruitment of neutrophils into chorionic membranes and placenta during developing intrauterine infection.

Amniocentesis↗
PubMed1993

An inhibitor of thromboxane production attenuates tumor necrosis factor release by activated human alveolar macrophages.

Tumor necrosis factor alpha (TNF alpha) and thromboxane A2 (TXA2) are major products of the activated alveolar macrophage and serve as key mediators of lung injury. In order to determine if the synthesis of TXA2 and the release of TNF alpha are associated, the production of these inflammatory agents by the human alveolar macrophage (AM), as a result of activation by lipopolysaccharide (LPS), was assessed in the absence and presence of the thromboxane synthase inhibitors UK 38,485 (Dazmegrel) and OKY 046. UK 38,485 and OKY 046 inhibited both LPS-stimulated TXA2 production and TNF alpha release in a dose-dependent manner. Prostaglandin E2 (PGE2) production was not increased by UK 38,485 or OKY 046. Neither LPS nor UK 38,485 had any effect on LTB4 production by AM. Neither UK 38,485 or OKY 046 had any effect on LPS-stimulated interleukin-1 beta release. However, the TXA2 mimetic, U46619, did not stimulate TNF alpha release by AM either in the absence or presence of UK 38,485. These findings suggest that 1) UK 38,485 and OKY 046 are inhibitors of both TXA2 production and TNF alpha release by activated human AM, 2) UK 38,485 probably does not exert its inhibitory action on TNF alpha release through effects on eicosanoid production and 3) the possibility that TNF alpha- and TXA2-induced lung injury may be subject to amelioration by imidazole-based compounds should be further evaluated.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1993

Characterization of alveolar macrophage eicosanoid production in a non-human primate model of mineral dust exposure.

The relative activation of eicosanoid production which results from the exposure of the alveolar macrophage (AM) to mineral dusts is thought to be a key factor in the pathophysiology of occupational lung disease. We compared in vitro basal and silica-stimulated production of prostaglandin E2 (PGE2) and thromboxane A2 (TXA2) by AM from normal humans and non-human primates (Macaca nemestrina). In addition, we instilled mineral dusts directly into one lung of the non-human primate and evaluated AM eicosanoid production at two week intervals following dust instillation. Unstimulated AM from humans produce more PGE2 and TXA2 than do AM from M. nemestrina. However, in vitro exposure of AM from both species to silica dust produced a qualitatively similar increase in TXA2 production accompanied by no change in PGE2 production. Sequential analysis of AM eicosanoid production following a single bolus exposure to bituminous or anthracite coal dusts, titanium dioxide (TiO2) dust or crystalline silica showed marked variability among individual non-human primates in qualitative and quantitative aspects of dust-induced eicosanoid production. However, the rank order of potency of the different dusts (silica > anthracite > bituminous) correlated with epidemiological evidence relating the type of dust mined to the incidence of pneumoconiosis. These studies suggest that the non-human primate may serve as a model for the study of both the role of eicosanoids in the etiology of dust-induced occupational lung disease and the biochemical basis for individual variability in the response of lung cells to mineral dust exposure.

Adult↗
PubMed1993

The effects of long term fadrozole hydrochloride treatment in patients with advanced stage breast cancer.

Fadrozole hydrochloride at a dose of 2 mg b.i.d. has been shown to be an effective aromatase inhibitor in advanced stage breast cancer patients as determined by its ability to significantly suppress endogenous estrogen biosynthesis over a 12-week period. Continued suppression of circulating estrogen levels over a prolonged period has not yet been examined in published reports. In this study, we report the extended use of fadrozole hydrochloride at a maintenance dose of 2 mg b.i.d. in a cohort of 11 patients extending to 973 days of therapy. Results show that the degree of suppression of plasma and urinary estrogens was maintained in all patients throughout the extended period of drug use. Continued estradiol suppression of over 50% or greater from baseline was observed, as was continued suppression of estrone to over 80% from baseline. Cortisol determinations after 9 months of treatment showed no suppression from baseline. The aldosterone values and responses to cortrosyn stimulation continued to be suppressed as first noted following the initial 3 months of the core clinical trial. Objective tumor response noted in the core clinical trial did not change until disease progression. These findings suggest that fadrozole hydrochloride maintains its ability to suppress the aromatase enzyme during long term use. No observable escape from suppression of plasma and urinary estrogens occurred during prolonged treatment.

Adrenocorticotropic Hormone↗
PubMed1993

The efficacy of CGS 20267 in suppressing estrogen biosynthesis in patients with advanced stage breast cancer.

The pharmacologic inhibition of aromatase activity has been the focus of clinical trials in patients with advanced stage breast cancer. Recent developments with imidazole compounds that inhibit aromatase activity suggest their clinical use as potent inhibitors of estrogen biosynthesis in postmenopausal breast cancer patients. In this Phase I, open-label, dose-range finding study, we examined the inhibitory potency of CGS 20267 on blood and urine levels of estradiol, estrone and estrone sulfate in 8 patients with metastatic breast cancer. Studies included evaluation of adrenal and thyroid function to look for evidence of general hydroxylase inhibition at dose levels effective for aromatase blockade. Patients were administered CGS 20267 at doses of 0.1 and 0.25 mg, once a day in ascending doses over a 12-week period. Preliminary data reveal that CGS 20267 elicits a striking suppression in plasma estradiol, estrone and estrone sulphate which was observed in some patients as quickly as within 24 h of the first dose. Estrogen suppression of over 90% was achieved within 2 weeks of therapy. No alterations in either baseline or ACTH (cortrosyn) stimulated cortisol and aldosterone levels were observed through the 12 weeks of therapy. In addition, 24 h urine sodium and potassium values were not appreciably altered during therapy. We conclude that CGS 20267 is a potent, specific inhibitor of estrogen biosynthesis in postmenopausal patients with metastatic breast cancer and effectively reduces blood and urine estrogens to undetectable levels.

Aldosterone↗