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Biomedical subjects

L Demers

Publications and source records attributed to L Demers.

At least 55 records · Page 3Linked to original sources
PubMed1990

The pharmacodynamic inhibition of estrogen synthesis by fadrozole, an aromatase inhibitor, and its pharmacokinetic disposition.

In this dose-ranging phase I study, the relationship between in vivo androgen to estrogen conversion kinetics and plasma concentrations of fadrozole was investigated in postmenopausal women receiving therapy with this aromatase inhibitor. Patients received ascending doses, ranging from 0.3-8 mg fadrozole twice daily, each for a period of 2 weeks. Drug kinetics and endocrine effects were evaluated specifically for the 2- and 8-mg twice daily treatment regimens. The in vivo activity of the drug was demonstrated by the suppression of estrone and estradiol biosynthesis from testosterone and androstenedione, respectively. The drug inhibitory constant, KI, for the estrone synthetic pathway, was 3.0 ng/mL (13.4 nmol/L) and was of similar magnitude as that determined under in vitro conditions. The KI for the estradiol synthetic pathway was 5.3 ng/mL (23.7 nmol/L). The disparity between KI values may indicate that the two pathways are not equivalent in terms of their inhibition by fadrozole. Pharmacokinetic data demonstrated tha the drug was rapidly absorbed after oral dosing, with peak plasma concentrations achieved in median times of 1 and 2 h, respectively, for the 2- and 8-mg twice daily treatment regimens. The average half-life and oral clearance values were 10.5 h and 621 mL/min, respectively. Oral clearance was independent of dose.

Aged↗
PubMed1989

Individual and combined effects of alpha-difluoromethylornithine and ovariectomy on the growth and polyamine milieu of experimental breast cancer in rats.

Despite considerable evidence suggesting a critical role of polyamines in the hormonal control of breast cancer growth in vitro, their role in in vivo tumor growth is not established. In these experiments, we evaluated the individual and combined effects of the polyamine biosynthesis inhibitor alpha-difluoromethylornithine (DFMO) and ovariectomy on the growth and cellular levels of ornithine decarboxylase (ODC) and polyamines of N-nitrosomethylurea-induced rat mammary tumors. Despite a similar suppressive effect on ODC activity, the two treatments had a different effect on polyamine levels. As expected, DFMO selectively suppressed putrescine, whereas spermidine and spermine levels were minimally or not affected at all. Since quantitatively putrescine contributes the least to overall polyamine pools, the DFMO effect on this latter parameter was modest. In contrast, ovariectomy, by suppressing the more abundant spermidine and spermine, produced a more profound suppression of total polyamine pools. This finding is in agreement with the notion that hormones not only control ODC activity, but also other enzymes involved in the synthesis of the distal polyamines. Ovariectomy was also more potent than DFMO administration in inhibiting N-nitrosomethylurea-induced mammary tumor growth. No major additive/synergistic effects were observed between DFMO and ovariectomy on tumor growth and cellular levels of ODC activity and polyamines. DFMO administration lowered the tumor level of progesterone receptors and appeared to potentiate the suppressive effect of ovariectomy. In contrast, neither treatment, alone or in combination, altered tumor levels of estrogen receptors. DFMO administration did not affect circulating levels of estradiol and prolactin or uterine and ovarian weights, thus suggesting that its effects were not indirectly mediated through alterations of the endocrine milieu of the host.

Animals↗
PubMed1989

Polyamine involvement in the growth of hormone-responsive and -resistant human breast cancer cells in culture.

Recent evidence indicates that hormone-responsive but not -resistant human breast cancer cells in culture are sensitive to the antiproliferative effect of the polyamine (PA) biosynthetic inhibitor alpha-difluoromethylornithine (DFMO). The present experiments were designed to investigate the potential differential involvement of the PA pathway in the growth of these different biological subtypes of human breast cancer. Thus, we evaluated the effect of DFMO on proliferation, ornithine decarboxylase (ODC) activity, and PA levels of the hormone-dependent MCF-7 and -independent MDA-MB-231 breast cancer cell lines. When tested at comparable cell density, the two cell lines had similar levels of ODC activity and PA. Administration of DFMO (0.01, 0.1, 1, 4 mM) for 6 days caused a similar dose-dependent inhibition of proliferation (up to approximately 15% of control) associated with suppression of ODC activity to undetectable levels at the highest dose. In both cell lines, putrescine and spermidine levels were maximally suppressed by doses of DFMO greater than 0.1 mM. Higher doses of DFMO (1 and 4 mM) also suppressed spermine levels to approximately 60% of control. In detailed time-course studies, DFMO administration (0.1 mM) similarly suppressed by 80% the rise in ODC observed in both cell lines following a medium change. At all time points, putrescine and spermidine levels were likewise suppressed to a similar extent. Addition of putrescine (0.1-2.5 mM) to DFMO-treated cells repleted cellular PA levels and restored growth to approximately 80% of control in both cell lines. We conclude that, under these experimental conditions, PA are similarly involved in the growth of the hormone-responsive MCF-7 and -resistant MDA-MB-231 human breast cancer cell lines.

Biogenic Polyamines↗
PubMed1989

Hormonal control of polyamine pools in experimental breast cancer in vivo: correlation with estrogen and progesterone receptor levels.

The present experiments were designed to test whether, in the hormone responsive N-nitrosomethyl-urea (NMU)-induced rat mammary tumor, polyamine levels are under hormonal control and whether they correlate with estrogen (ER) and progesterone (PgR) receptor content. We observed that tumor regression induced by ovariectomy was associated with a decline in putrescine (Pu), spermidine (Sd) and spermine (Sm). Administration of estradiol and perphenazine (to stimulate endogenous prolactin release) to castrated rats restored tumor growth and contents of Pu and Sd to control values in a time dependent fashion while Sm levels were only modestly raised. The hormonal modulation of tumor polyamine levels was particularly obvious when the treatment effects on total pools (i.e. Pu + Sd + Sm) were analyzed. No significant correlation was observed between ER and PgR and polyamines in the tumors of intact rats as well as most of the treated groups. In contrast, a highly significant correlation was observed between ER and PgR levels. We conclude that in this experimental system cellular polyamine levels are hormonally regulated but are not correlated with the ER and PgR content of the tumor.

Animals↗
PubMed1989

Central neurotensin inhibits gastric acid secretion: an adrenergic mechanism in rats.

Although parenteral neurotensin (NT) inhibits stimulated gastric acid secretion, published reports on the effect of centrally administered NT on gastric acid secretion are conflicting. This study provides evidence suggesting that, in chronic gastric fistula rats, intracerebroventricularly administered NT (15-60 micrograms) significantly reduces both basal and pentagastrin-, 2-deoxy-D-glucose-, and carbachol-but not histamine-stimulated gastric acid secretion. Using radioimmunoassay, the concentration of plasma immunoreactive NT increased from 30 to 200 pg/ml at 30 and 60 min, respectively after a single intracerebroventricular (i.c.v.) administration of NT at a dose of 60 micrograms. These serum NT concentrations can be reproduced by a constant NT i.v. infusion at 2 micrograms/kg.h. This parenteral infusion dose does not inhibit acid secretion as does i.c.v. NT. Pretreatment with the i.c.v. dopamine-2 receptor antagonists haloperidol or domperidone totally abolishes the inhibitory effect of i.c.v. NT on pentagastrin-stimulated gastric acid secretion. In contrast, pretreatment with the specific dopamine-1 receptor antagonist SCH 23900 or the specific dopamine-2 receptor antagonist sulpiride does not affect i.c.v. NT-induced inhibition of pentagastrin-stimulated gastric acid secretion. Pretreatment (intracerebroventricularly) with the alpha-adrenergic antagonist phentolamine blocks the antisecretory effect of i.c.v. NT. Administration of 3.0 micrograms NT per side directly into nucleus accumbens (NACB), using a stereotaxic technique, significantly reduces basal gastric acid secretion. This effect of central NT is blocked by pretreatment with intra-NACB haloperidol (0.5 microgram per side). These findings suggest that NT acts centrally to inhibit gastric acid secretion, an effect that may occur within NACB and be mediated by central nervous system alpha-adrenergic receptor activation.

Animals↗
PubMed1988

Involvement of the polyamine pathway in antiestrogen-induced growth inhibition of human breast cancer.

Recent evidence indicates that the antiestrogen tamoxifen (TAM) may inhibit breast cancer cell proliferation, at least in part, through suppression of the polyamine (PA) pathway. To directly test this hypothesis, we evaluated the effect of TAM administration on ornithine decarboxylase (ODC) activity, the rate-limiting enzyme in PA synthesis, as well as cellular PA levels in the hormone-responsive MCF-7 breast cancer cell line in culture. In detailed time course studies, we observed that TAM significantly inhibited the rise in ODC activity observed in control cells following a medium change. Chronic treatment with escalating amounts of TAM caused a dose-related decrease in tumor pools of putrescine and spermidine, while spermine levels were unaffected. The TAM effects on ODC activity and PA pools were reversible with exogenous estradiol administration. However, addition of putrescine to TAM-treated cells did not result in a reversal of the antiproliferative effect of TAM, despite repletion of cellular PA pools. Administration of TAM to the hormone-independent MDA-MB-231 breast cancer cell line did not suppress ODC activity or cellular PA levels despite induction, at high concentrations, of an estradiol-irreversible inhibition of proliferation. We conclude that, in the hormone-responsive MCF-7 breast cancer cell line, TAM causes a significant suppression of the PA pathway, the relation of which, if any, to its antiproliferative action remains obscure. This effect seems to be mediated through the estrogen receptor and does not appear to be a nonspecific consequence of inhibition of cell proliferation.

Biogenic Polyamines↗
PubMed1988

Polyamines and autocrine control of N-nitrosomethylurea-induced rat mammary tumor growth in vitro by progesterone.

These experiments were designed to test whether autocrine/paracrine mechanisms are involved in the growth-promoting action of progesterone (Pg) in the N-nitrosomethylurea-induced rat mammary tumor cultured in vitro in soft agar clonogenic assay. In support of our hypothesis, we observed that conditioned media obtained from Pg-treated tumors (Pg-CM), consistently stimulated colony formation in our system to the same degree as Pg itself (approximately 140% of control). Treatment with heat, trypsin, and concanavalin A abolished the colony-stimulating effect of Pg-CM, thus suggesting the possible glycoprotein nature of the Pg-inducible growth factor(s). The growth-promoting action of Pg-CM was rather specific since CMs obtained from tumors exposed to a variety of other steroid hormones rarely stimulated colony formation and usually only to a modest degree. Administration of the polyamine biosynthetic inhibitor, alpha-difluoromethylornithine, abolished the colony-stimulating effect of Pg-CM. The inhibitory effect of alpha-difluoromethylornithine was reversed in a dose-dependent fashion by exogenous administration of spermidine, which entirely restored the growth-promoting action of Pg-CM. Addition of increasing amounts of spermidine, however, did not potentiate Pg-CM action under our experimental conditions. Our results indicate that autocrine/paracrine mechanisms may mediate, at least in part, the colony-stimulating effect of Pg in our system. The polyamine pathway plays an essential role in the expression of such control of tumor growth by Pg.

Animals↗
PubMed1988

Menstrual status in female athletes: correlation with reproductive hormones and bone density.

To determine whether the changes induced in serum hormone levels by strenuous exercise are accompanied by changes in bone density, we obtained medical, sports, and dietary histories, trabecular bone density, percentage body fat, and serum hormone concentrations in collegiate athletes for comparison with those of college students not involved in organized strenuous exercise. Several important observations emerged from this study of collegiate athletes. First, the eumenorrheic athletes began sports training earlier than the oligomenorrheic athletes. Second, oligomenorrheic athletes displayed significantly lower serum estradiol concentrations during cycle weeks 2 and 3 but had a rise in this hormone concentration during cycle week 4. Significant differences in serum gonadotropin concentrations during week 4 were found in the oligomenorrheic athletes. Finally, no significant difference in spinal mineral density values was found in the three groups.

Adolescent↗
PubMed1986

Autocrine stimulation by estradiol-regulated growth factors of rat hormone-responsive mammary cancer: interaction with the polyamine pathway.

We have recently shown that the integrity of the polyamine pathway is essential but not sufficient for expression of the mitogenic effect of estradiol (E2) in the N-nitrosomethylurea-induced rat mammary tumor grown in vitro in the soft agar clonogenic assay. To elucidate the mechanism of E2 action in this system, we tested whether E2 may stimulate tumor growth through induction of secretory growth factor(s), as already proposed for human breast cancer cell lines in culture. Furthermore, we investigated the potential interaction between such "autocrine" control of tumor growth by E2 and the polyamine pathway. Conditioned medium obtained from E2-treated tumors (E2-CM) but not from control tumors (C-CM) consistently stimulated colony formation when added to N-nitrosomethylurea-mammary tumors plated in soft agar under serum-free media conditions. Such growth-promoting effects of the E2-CM was found to increase with increasing protein concentrations of the medium and was abolished by pretreatment of the medium with concanavalin A, heat, and trypsin. The addition of the polyamine biosynthetic inhibitor alpha-difluoromethylornithine (1 mM) totally abolished the colony-stimulating effect of the E2-CM. Exogenous administration of spermidine (0.1 mM) reversed the inhibitory effect of alpha-difluoromethylornithine on colony formation and restored the action of the E2-CM. Although the addition of polyamines alone did not affect the number of colonies formed, the administration of spermidine was found to significantly enhance in a dose-dependent fashion the colony-stimulating effect of suboptimal concentrations of E2-CM. Attempts to identify the E2-inducible growth factor in the E2-CM and in N-nitrosomethylurea-mammary tumor specimens using monoclonal antibodies raised against the Mr 52,000 E2-inducible protein gave negative results. We conclude that autocrine stimulation of tumor growth by E2 is not limited to human breast cancer cell lines but also occurs in individual experimental mammary tumors grown in soft agar. Our results show that the polyamines must be present for the expression of this "autocrine" control of tumor growth by E2. Finally, the identity of the E2-induced growth factor operating in our system remains to be determined.

Animals↗
PubMed1986

Polyamines and hormonal regulation of N-nitrosomethylurea-induced rat mammary tumor growth in vivo.

We have observed that polyamines play an essential role in the expression of hormonal action on the growth of the N-nitrosomethylurea-induced mammary tumor cultured in soft agar. Since polyamine levels cannot be measured in this system, we could not determine whether tumor polyamine pools are under endocrine control. To test this hypothesis, the following experiments were conducted in N-nitrosomethylurea tumor-bearing rats in vivo. Both tamoxifen administration (200 micrograms/day) and ovariectomy produced dramatic reductions in tumor growth but neither treatment significantly altered tumor polyamine levels after either 7 or 21 days of treatment. Some decrease in tumor level of putrescine, spermidine, and spermine was observed 21 days after ovariectomy but it was not statistically significant. Exogenous administration of putrescine (300 mg/kg/day) reversed the antitumor effect of tamoxifen but did not prevent tumor regression induced by ovariectomy. This effect of putrescine was, however, variable in magnitude from experiment to experiment. To test whether the reversal of tamoxifen effect by putrescine might simply be due to interference with tamoxifen uptake by the tumor cells, we measured estrogen and progesterone receptors in the tumors of rats chronically treated with tamoxifen and tamoxifen plus putrescine. In both groups estrogen receptors are virtually undetectable, thus suggesting that putrescine had not inhibited tamoxifen entry into the cells and binding to estrogen receptors. Progesterone receptor levels were similarly high in both groups and not significantly different from control. These results indicate that at least under these experimental conditions N-nitrosomethylurea mammary tumor polyamine pools are not under ovarian hormone control. The mechanism by which putrescine reverses tamoxifen's effect remains unclear.

Animals↗
PubMed1985

Alexithymia. The development of a valid and reliable projective measure (the objectively scored Archetypal9 Test).

The aim of this study was to examine whether the Archetypal9 Test (AT9) could meet the need for a valid and reliable test with which to measure the alexithymic trait cluster. Participants in this study included 61 patients drawn from pain clinics in Montreal (Royal Victoria Hospital) and Detroit (Henry Ford Hospital) and 30 patients undergoing minor surgery at the Royal Victoria Hospital in Montreal. All 91 subjects took both the AT9 Test and the Clarke Vocabulary Scale. The results of the attempts at validation reveal that the objectively scored AT9 Test (SAT9) is a highly internally consistent instrument, that it has demonstrated construct validity, and that it can significantly discriminate between patient groups (pain patients and medical patients). The SAT9 is positively related to age, inversely related to occupational level, and uncorrelated with IQ (as measured by the Clarke Vocabulary Scale). The authors concluded that thus far, the SAT9 has proven to be a valid instrument which can be used to measure a central feature of alexithymia.

Adult↗
PubMed1984

[Youth and family in Québec : demographic aspects.].

The following text presents a description of the principal demographic statistics available on young Quebeckers and the family. The character of transition and heterogeouness of youth is underlined : although the majority of young people still live as children at home, many have already made the transition to the adult "independent" stage, with some of them having become parents themselves. An attempt has been made to bring out modifications in the behaviour of young Quebeckers relative to the family, where a decline in marriage and fertility rate is apparent, and where also appear relatively recent changes in life styles : single parent families, out of wedlock unions, living alone. The statistics also reveal that young Quebeckers differ from the whole of Canadian youth in several aspects. For example, the transition to "adult" life, if measured in terms of shouldering of family responsibilities, is made more slowly by young people from Quebec than by the rest of young Canadians.

English Abstract↗
PubMed1983

Effect of very high dose D-leucine6-gonadotropin-releasing hormone proethylamide on the hypothalamic-pituitary testicular axis in patients with prostatic cancer.

Potent synthetic analogs of gonadotropin-releasing hormone produce parodoxical antireproductive effects when administered chronically. These compounds are minimally toxic and may exhibit no plateau of the dose-response curve even at very high doses. These considerations served as the basis for our systematic evaluation of [D-leucine6-desarginine-glycine-NH2(10)]gonadotropin-releasing hormone (GnRH-A) proethylamide in the very high dose range (i.e., 10-fold larger amounts than previously used). In rats given the analog for 12 wk, prostate, testis, and seminal vesicle weights were suppressed to a greater extent with 200 micrograms q.d. than with 40 micrograms q.d. (P less than 0.01 prostate, less than 0.01 testis, less than 0.01 seminal vesicles), indicating dose-response effects in the very high dose range. 200 micrograms of [D-Leu6-des-Gly-NH2(10]-GnRH-A consistently suppressed leutinizing hormone (LH) values at 6 and 12 wk (basal 71 +/- 9.5; 6 wk 34 +/- 3.8; 12 wk 28 +/- 5 ng/ml) whereas 40 micrograms suppressed LH variably (basal 33 +/- 3.8; 6 wk 17 +/- 3.9; 12 wk 32 +/- 5.2). Testosterone fell to 15 +/- 2.4 and 19 +/- 2.0 ng/100 ml in response to 200 micrograms q.d. and to 27 +/- 6.4 and 22 +/- 7.4 ng/100 ml with the 40-micrograms dose. These findings in the rodent prompted treatment of stage D prostate cancer patients with similarly high doses of [D-Leu6-des-Gly-NH2(10)]-GnRH-A. After treatment for 11 wk with 1,000 or 10,000 micrograms/d of the analog, testosterone and dihydrotestosterone levels transiently rose and then fell into the surgically castrate range (testosterone 19 +/- 4.4 ng/100 ml [D-Leu6-des-Gly-NH2(10)]-GnRH-A vs. surgically castrate 11 +/- 0.9 ng/100 ml, P = NS; dihydrotestosterone 15 +/- 1.7 ng/100 ml GnRH-A vs. surgically castrate 15 +/- 4.1 ng/100 ml. P = NS). However, unlike the chronic stimulatory effect on the pituitary at lower doses, very high dose therapy resulted in profound suppression of plasma and urine LH. Plasma levels fell to the limit of assay detectability, whereas the more sensitive urinary assay detected prepubertal levels of excretion (i.e., 64 +/- 8.4 mlU/h). The highly sensitive rat interstitial cell testosterone bioassay for LH also demonstrated a marked decline in LH to undetectable levels in 17/19 subjects. Clinical results with [D-Leu6-des-Gly-NH2(10)]-GnRH-A simulate those achieved by surgical castration in men with prostatic cancer as suggested by available preliminary data.

Adenocarcinoma↗
PubMed1983

[Somnambulism].

Explore the source record for details and available documents.

Adult↗
PubMed1982

A study of prostaglandin E2, parathormone, and response to indomethacin in patients with hypercalcemia of malignancy.

In order to evaluate the relationship of PGE2 to hypercalcemia in cancer patients, 101 patients were screened with a radioimmunoassay for plasma prostaglandin E2 (PGE2) (NL less than 100 pg/ml). Of the 101 patients, 31 were hypercalcemia. Mean PGE2 (+/- SEM) of the 31 patients was 199 +/- 36 pg/ml. Among the 70 normocalcemic patients, mean +/- SEM PGE2 was 85 +/- 12 pg/ml (range = less than 25--225 pg/ml) (P less than 0.001). Seventeen hypercalcemic patients were initially treated with saline and furosemide, then were prospectively screened for serum parathormone (iPTH) and PGE2. Fourteen of 17 patients were then treated empirically with indomethacin (25 mg b.i.d.) for 72 hours and the PGE2 assay was repeated. Prior to therapy with indomethacin (mean +/- SEM), Ca++ = 12.2 +/- 1.5 mg/dl (NL 8.4--10.6 mg/dl), PGE2 = 87.1 +/- 36.8 pg/ml, (range = less than 25--209 pg/ml), and iPTH = 406 +/- 266 pg/ml (NL less than 400 pg/ml) (range = less than 100--825 pg/ml). PGE2 was elevated before treatment in 6/14 patients (breast, colon, renal, lung, neck tumors, and myeloma). Following treatment with indomethacin, PGE2 and calcium fell to normal levels in three patients (breast, colon, renal carcinomas). These results suggest: (1) A bimodal distribution of PGEs exists in hypercalcemic cancer patients. (2). There was some evidence of lack of whole molecule iPTH suppression in these patients. (3) Multiple stimuli of calcium mobilization may play an important etiologic role in a few hyercalcemic cancer patients and may explain the failure of indomethacin to control serum Ca++ in some patients with elevated PGE2.

Humans↗
PubMed1981

Bioavailability, efficacy, and tolerance of two sustained-release theophylline dosage forms in adult patients with bronchial asthma.

Twenty otherwise health adults with a diagnosis of reversible obstructive airways disease were treated for one month in a single-blind crossover study with approximately equivalent doses of Elixophyllin SR capsules or Theo-Dur tablets. Both products provided evidence of efficacy by improvement in pulmonary function tests, and both were well tolerated. There were no significant differences between the two products with regard to bioavailability, efficacy, or tolerance. Both dosage forms appeared to have similar kinetic properties within the context of the study.

Adolescent↗
PubMed1980

Adrenal of male dog secretes androgens and estrogens.

In the absence of functioning gonads, the adrenal is an important source of androgens and estrogens. In order to precisely quantitate the adrenal secretion rates of the sex steroids, we cannulated the adrenal veins and measured venous blood flow and arterial venous steroid gradients in adult male beagle dogs under pentobarbital anesthesia. Celite chromatography and specific radioimmunoassays were utilized to measure steroid levels. During basal conditions, the adrenal produced larger amounts of the androgens (667 ng/min of androstenedione, 5.45 ng/min of testosterone, and 3.43 ng/ min of dihydrotestosterone) than of the estrogens (1.245 ng/min of estradiol and 0.239 ng/min of estrone. These secretion rates were 20- to 50,000-fold less than that of cortisol (12,360 ng/min). Studies were also carried out during adrenal suppression with hydrocortisone to block ACTH release and with the adrenal steroidogenesis inhibitor, aminoglutethimide, plus hydrocortisone. The secretion rates of each androgen measured fell during ACTH inhibition. Significant suppression of estrone and estradiol, however, required addition of aminoglutethimide. This study provides direct evidence that the adrenal in the male dog can secrete estrogens, a previously controversial issue.

Adrenal Glands↗