Supporting and advocating for HIV-positive health care workers.
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Acquired Immunodeficiency Syndrome↗
Biomedical subjects
B Schatz
Publications and source records attributed to B Schatz.
Pharmacokinetics and efficacy of a long-acting formulation of the new somatostatin analog BIM 23014 in patients with acromegaly.
The treatment of acromegalics with somatostatin analogs requires continuous sc infusion using pumps or several sc injections daily. Long-acting formulations (BIM-LA) of BIM 23014 (BIM) using delayed microcapsules may provide a more convenient form of therapy. Fourteen acromegalics whose GH secretion had not been normalized by transphenoidal surgery followed, in 10 cases, by pituitary radiotherapy (performed at least 2 yr before the study) were studied. Eight of these patients participated in an initial study of the pharmacokinetics of BIM-LA, after which a 6-month efficacy study was undertaken. The 8 patients in the pharmacokinetic study had an initial blood sample collected for measurements of plasma GH and insulin-like growth factor-I (IGF-I) levels before the im injection of 30 mg BIM-LA, and blood samples were subsequently taken 2, 4, 6, and 8 h after injection and then twice a week for a month. Plasma IGF-I levels were measured on days 4, 14, 20, and 30 after the injection. Assays of plasma GH, IGF-I, and BIM levels were performed by RIAs. The results showed that plasma GH levels were markedly reduced from 26.0 +/- 2.0 to 2.5 +/- 0.2 micrograms/L 2 h after BIM-LA injection and remained lower than 5 micrograms/mL for the 11 following days. Plasma GH levels increased to 5.5 +/- 1.2 micrograms/L on day 14 and returned to basal values 23 days after injection. Similarly, plasma IGF-I decreased from an initial level of 656 +/- 43 to 324 +/- 23 ng/mL on day 4 and remained close to the normal range for the following 10 days. Plasma BIM levels reached a peak 2 h after the injection (7.2 +/- 2.3 ng/mL) and remained higher than or close to 1 ng/mL until the 14th day after injection. This initial study showed that a single injection of 30 mg BIM-LA effectively suppressed GH and IGF-I secretion for at least 14 days, in accordance with the kinetics of the drug in plasma. Based on the results of this initial study, 30 mg BIM-LA were injected twice monthly for 6 months in all 14 patients. All of the subjects had a basal evaluation before treatment with BIM-LA and were then subjected to assessment of clinical, pituitary, and hormonal parameters. Patients were evaluated after 3 and 6 months of treatment on the same basis as that previously used when starting the BIM-LA therapy. Plasma BIM levels were measured monthly. Clinical signs of acromegaly improved during the treatment.(ABSTRACT TRUNCATED AT 400 WORDS)
Acromegaly↗
Pattern discovery in gene regulation; designing an analysis environment.
Interactions that determine cellular fate are exceedingly complex, can take place at different levels of gene regulation and involve a large number of components (such as genes, proteins). 'Wet lab' biology has an inherent difficulty in considering multiple components within one experimental set-up. Thus, the individual experimental results may reflect the behavior of a sub-system and be missing some important information concerning interactions with other components. Computational tools can help in simultaneously analyzing many different pieces of biological knowledge from different data sources. Such tools will aid in comprehending the whole system (cell, organism) as a function of all of its components; this, in turn, will facilitate discovery of the global patterns in genetic regulation. The Worm Community System (WCS) which contains extensive knowledge from many different sources regarding model organism C. elegans, presents a suitable environment for development of the integrated analysis tools. Here we describe a working version of WCS and the strategies employed for the development of the global analysis tools within the System. The present paper deals with the construction of a highly interconnected information space (in the context of the problem) by introducing more sophisticated data objects representing knowledge about genetic regulation. We describe construction of the in-depth objects, development of the analysis tools and discuss the type of analysis feasible within such interconnected space. The analysis tools will serve as an ideal environment for 'dry biology' experimentation and provide a context for 'wet' experiments.
Animals↗
Recent data on estrogen sulfatases and sulfotransferases activities in human breast cancer.
Of the total number of breast cancers approx. 30-50% are hormone-dependent and estradiol is one of the main factors of cancerization. Consequently, the control of this hormone inside the cancer cell is of capital importance because it is well established that the inhibition of estradiol biosynthesis can have a positive effect on the evolution of the disease. The blockage of estradiol can be obtained by the action of anti-aromatases, anti-sulfatases, the control of the 17 beta-hydroxysteroid dehydrogenase activity or by the stimulation of the sulfotransferase which converted the estrogens in their sulfates. In breast cancer tissue estrone sulfate is quantitatively the most important source of estradiol. In the intact cell, estrone sulfatase activity is very intense in the hormone-dependent cell lines (e.g. MCF-7, T-47D) but very small activity is observed in the hormone-independent (e.g. MDA-MB-231, MDA-MB-436) cell lines. However, this activity became very strong after homogenization in the hormone-independent cells, suggesting the presence of repressive factor(s) for this enzyme or its sequestering in an inactive form, in the intact cells of these cell lines. In a series of previous studies it was found that in hormone-dependent cell lines different anti-estrogens: tamoxifen and derivatives, ICI 164,384, very significantly decrease the estradiol concentration originated from estrone sulfate, and recently it was observed that Decapeptyl (D-Trp6-gonadotropin-releasing hormone) in the presence of heparin can also decrease the conversion of estrone sulfate into estradiol. No significant effect was obtained in the presence of heparin or Decapeptyl alone. The estrone sulfatase activity can be inhibited by progesterone, the progestagen R-5020, and testosterone. In another series of recent studies the presence of very strong estrogen sulfotransferase activity has been shown in one breast cancer cell line, the MDA-MB-468. We can conclude that: (1) the control of estradiol concentration can be carried out in the breast cancer tissue itself; (2) estrone sulfate can play an important role in the bioavailability of estradiol in the breast cancer cell; and (3) as is the case for the aromatase, the control of: the estrogen sulfatase, estrogen sulfotransferase, and 17 beta-hydroxysteroid dehydrogenase can be new targets for therapeutic applications in breast cancer.
Breast Neoplasms↗
Effects of the new somatostatin analogue (BIM 23014) on blood glucose homeostasis in normal men.
Changes in blood glucose homeostasis induced by the new somatostatin analogue BIM 23014 (BIM) were studied. Eight normal men (study 1) received either vehicle or 1000, 2000 and 3000 micrograms BIM as a 24 h s.c. infusion. Blood glucose, plasma insulin, C-peptide, glucagon and growth hormone (GH) were measured before treatment and then hourly for 24 h. In five normal men (study 2) an oral glucose tolerance test (OGTT) was performed during vehicle infusion and then on days 1 and 7 of a continuous s.c. infusion of 2000 micrograms BIM daily for 7 days. The same biological parameters as in study 1 were measured before OGTT and then twice-hourly for 5 h. Dose-dependent and transient glucose intolerance was observed in the first half of study 1. Except for glucagon, BIM significantly (P < 0.01) reduced plasma insulin, C-peptide and GH levels. In study 2 BIM infusion induced glucose intolerance and a drop in plasma insulin and C-peptide on day 1 which disappeared on day 7 of infusion. Higher on day 7 than on day 1, plasma GH secretion was significantly (P < 0.01) reduced throughout BIM infusion. In contrast plasma glucagon levels were not modified at any time. Side-effects were abdominal cramps and diarrhoea which were observed in most subjects when increasing BIM daily dose. In conclusion, BIM infusion induced transient changes in glucose homeostasis and insulin secretion in normal men. By contrast, plasma GH levels remained reduced throughout the treatment. BIM appears to be a useful tool to selectively inhibit GH secretion.
Adult↗
[Influence of dose and modalities of administration of BIM 23014 on growth hormone secretion in patients with acromegaly].
Somatostatin analogs, with prolonged half-lives have been proposed for the treatment of acromegalics. The aim of the study was to evaluate the short term efficacy of different doses and modalities of administration of the new somatostatin analog, BIM 23014 (BIM), on GH secretion in acromegalics. Ten acromegalics, with evolutive disease, who previously had had transsphenoidal surgery (and pituitary radiotherapy in 8) were evaluated in a three step study. The first part included four patients who received in a random order either vehicle or 500, 1000 and 1500 micrograms BIM for a day as a continuous s.c. infusion using programmable pumps at one-week interval for 24 hours to measure plasma GH levels. The second part included six patients who received in a random order either vehicle or 1500 micrograms/24h BIM as 500 micrograms x 3 s.c. injections, 750 micrograms x 2 s.c. injections and a continuous s.c. infusion using programmable pumps at one-week interval. During each period of the study blood was sampled at 4 hour intervals for 24 hours in order to measure plasma GH and BIM levels by radioimmunoassays. The third part of the study included the same 6 patients as the second part, who received 30 mg IM of a long acting formulation of BIM. Blood was sampled before and thereafter on days 1, 3, 6, 9, 12, 15, 18 and 21 following the injection for measurement of plasma GH and BIM levels. In first group 500 micrograms BIM slightly decreased plasma GH levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Acromegaly↗
Direct inhibiting effects of [D-Trp6]gonadotropin-releasing hormone on the estrogen-sensitive progression of polyoma virus-induced mammary tumors in athymic mice.
The direct antitumoral effects of gonadotropin-releasing hormone (GnRH) analogues on breast tumors have been surmised from clinical observations and in vitro studies. The present study aimed to determine the effects of the GnRH agonist [D-Trp6]GnRH (Decapeptyl) on steps of experimental mammary carcinogenesis, and the mechanisms, other than the chemical castration, involved. We chose a recent model, i.e., mammary tumors induced by wild-type A2 polyoma (Py) virus in BALB/c female nu/nu mice, which displays the following characteristics. Tumors are mammary adenocarcinomas similar to well differentiated breast carcinomas. Tumor promotion period ends 20 days after Py virus inoculation and is estradiol dependent. The first palpable tumors occur 60 days after Py virus inoculation, and tumor growth is ovarian hormone independent. The effects of Decapeptyl treatment on tumor induction and tumor growth were studied in normal or ovariectomized 6-week-old nude mice inoculated with 10(7) plaque-forming units Py virus (day 0 of experiments). Normal mice and ovariectomized mice percutaneously supplemented with 0.6 micrograms 17 beta-estradiol every other day until day 30 (OvE2 mice) were treated with monthly s.c. injections of the sustained release form of Decapeptyl (5 mg/kg) until the end of 180-day experiments. Overall values for latency periods were included within a day 60 to day 130 time interval. Hormone-independent outgrowth was not affected. We focused on tumor progression before the outgrowth. Incidences on tumor appearance kinetics account for effects at this stage. 17 beta-Estradiol repletion strongly antagonized (P less than 0.001) the slowing effect of ovariectomy on the tumor appearance kinetics, indicating that tumor progression is estradiol sensitive in its early stages. [D-Trp6]GnRH treatment antagonized tumor appearance profiles, inducing similar kinetics in both normal and OvE2 mice. In normal mice, the antagonism (P less than 0.01) was concomitant with significant decreases (P less than 0.05) in serum levels of estradiol and prolactin, which are critical hormones for mammary tumor development in mice, suggesting a pituitary-mediated effect. In OvE2 mice, the antagonism (P less than 0.01) occurs independently of estradiol and prolactin, suggesting a direct effect at the mammary cell level. Because of alterations in kinetics, this effect is exerted at the early stages of tumor progression on Py virus-transformed, ovarian hormone-sensitive cells in the mammary tissue. This new animal model of breast cancer is shown to be useful in characterizing direct antitumoral effects of GnRH analogues and studying the basic mechanisms of mammary carcinogenesis.
Animals↗
Compared effects of GnRH analogs and 4-hydroxytamoxifen on growth and steroid receptors in antiestrogen sensitive and resistant MCF-7 breast cancer cell sublines.
Antiestrogens, such as tamoxifen, have a direct antitumor action and are widely used in cancer therapy. The direct antitumor action of GnRH analogs has been documented in both in vitro and clinical studies. GnRH analog direct action could therefore provide an alternative approach in postmenopausal patients developing antiestrogen resistance, a frequent cause of relapse during hormonal treatment of breast cancer. This study was carried out to compare the effects of two GnRH analogs (the agonist Decapeptyl and the antagonist BIM 21009C) and the antiestrogen 4-hydroxy-tamoxifen (OH-TAM) on proliferation in antiestrogen-responsive or antiestrogen-resistant human breast cancer cell lines (MCF-7, MCF-7 LY2). Ineffective when used without estrogen stimulation, both of the GnRH analogs and OH-TAM inhibit the 17 beta-estradiol-stimulated growth of the estrogen-responsive cell line MCF-7. Compared with parental MCF-7 cell line responsiveness, the antiestrogen-resistant variant MCF-7 LY2 appears to be resistant to GnRH analogs. These findings indicate similarities between the two types of compounds with regard to their antiestrogenic effects on growth observed in vitro. However, since unlike OH-TAM, Decapeptyl displays no effect on steroid receptor levels of sensitive MCF-7 cells, the intracellular inhibitory mechanisms of these drugs are probably in part different. This study suggests that the direct effect of the studied GnRH analogs would not be a potent tool for treating antiestrogen-resistant breast tumors.
Antineoplastic Agents↗
Correlation between follicular fluid content and the results of in vitro fertilization and embryo transfer. III. Proteoglycans.
Using a specific proteoglycan (PG) radioimmunoassay (RIA) in which human cartilage antiserum was directed against the PG protein core, the PG content of follicular fluid (FF) obtained from 42 women undergoing in vitro fertilization (IVF) and embryo transfer (ET) was studied as a function of IVF-ET outcome. Inhibition curves of purified PG cartilage preparations were parallel to those of large and small nonstimulated follicles and follicles that had been stimulated by a luteinizing hormone-releasing hormone (LHRH) agonist, d-tryptophan-6 (Decapeptyl: D-Trp6 analogue, Beaufour Laboratories, IPSEN Biotech, Paris, France), and human menopausal gonadotropin (hMG). While FF levels of immunoreactive PG-like material (Ir-PG) did not differ according to IVF-ET outcome, highly significant negative correlations were obtained between FF 17 beta-estradiol levels and FF Ir-PG levels in oocyte groups where pregnancy was obtained, i.e., oocytes were fertilized and cleaved, and pregnancy followed either for each ET or for one of two embryos reimplanted. The correlation persisted but weakened when all groups were pooled together. No correlation was observed between FF Ir-PG and progesterone. RIA or bioassay showed a positive correlation between FF inhibin and Ir-PG for the group in which each ET led to a pregnancy. Ir-PG concentrations were significantly greater in smaller than in larger follicles collected from untreated women. Upon induction of ovulation with either pure follicle-stimulating hormone (FSH), FSH + human chorionic gonadotropin (hCG), or D-Trp6/hMG + hCG, this difference no longer appeared. These results indicate that the reduction of Ir-PG concentrations constitutes an index of follicular maturation.(ABSTRACT TRUNCATED AT 250 WORDS)
Cartilage↗
Gonadotropin-releasing hormone (GnRH) agonists and GnRH antagonists do not alter endogenous GnRH secretion in short-term castrated rams.
The administration of GnRH agonists and antagonists suppresses pituitary LH secretion. However little is known about their effects on endogenous GnRH secretion. To determine if GnRH analogs act on GnRH secretion through a short or ultrashort loop feedback mechanism, experiments were performed to analyze GnRH secretion in hypophyseal portal blood of conscious short-term castrated rams under both agonist or antagonist treatment. In Study 1, six rams were castrated and surgically prepared for portal blood collection on day -7. Portal and peripheral blood were collected simultaneously every 10 min for 14-15 h on day 0. Five hours after the beginning of the portal blood collection, animals were injected im with 5 mg potent GnRH antagonist (Nal-Glu). In Study 2, six rams were treated daily from day -11 to day 0 with the GnRH agonist D-Trp6 GnRH (0.5 mg im). Castration and surgical preparation for portal blood collection were performed on day -7. On day 0 portal and peripheral blood were collected simultaneously every 10 min for 10-11 h. In both studies, to determine whether an increase in GnRH concentration in hypophyseal portal blood can overcome the inhibitory effect of the GnRH analogs, between 5 and 5.5 h after the injection of the analogs, endogenous GnRH secretion was stimulated by Naloxone administration (3 x 100 mg, iv, at 30-min intervals) followed by a bolus of exogenous GnRH (2 x 10 micrograms, iv at 30-min intervals). In Study 1, Nal-Glu administration led to a rapid cessation of pulsatile LH secretion for the duration of blood collection while GnRH pulse frequency and amplitude were not affected. GnRH and LH pulse frequency before and after Nal-Glu administration were, 6.2 +/- 0.6 vs. 5.7 +/- 0.8 (NS) and 5.3 +/- 0.3 vs. 0.3 +/- 0.2 pulses/6 h (P less than 0.001) respectively. In Study 2, peripheral LH secretion was completely suppressed while GnRH secretion (portal blood) remained pulsatile. GnRH pulses frequency and pulse amplitude were 4.3 +/- 0.3 pulses/6 h and 43.0 +/- 4.7 pg/ml, respectively. In both experiments, neither stimulation of endogenous GnRH secretion by naloxone nor administration of exogenous GnRH allowed reinitiation of LH secretion. However, additional studies in two animals of each treatment group (study-III) showed that this was clearly a dose related effect in antagonist treated but not in agonist-treated animals since higher doses of exogenous GnRH (i.e. 100 micrograms or 1000 micrograms) can increase significantly LH levels.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Correlation between follicular fluid content and the results of in vitro fertilization and embryo transfer. II. Inhibin and aromatase inhibitor activity.
The inhibin content and aromatase inhibitor activity (AIA) of 72 follicular fluids (FF) obtained from 42 women undergoing in vitro fertilization (IVF) and embryo transfer (ET) were studied as a function of IVF ET outcome. Inhibin levels were determined by bioassay (BA) and RIA; AIA was measured by BA. The inhibin content of follicles characterized as immature by their estradiol (E2) levels and E2/progesterone (P) ratios was significantly lower (P less than 0.05) than that of mature follicles (i.e. leading to pregnancy). The mean AIA for mature follicles were significantly lower than AIA in groups where pregnancy was not obtained. AIA for follicles from which a pregnancy was obtained for each ET was also significantly lower than that in FF characterized as immature of hypermature. The highest E2/AIA and inhibin BA/AIA ratios were associated with the highest incidence of successful IVF ET outcome. No correlation was found between AIA and inhibin, on the one hand, and E2, delta 4-androstenedione, E2/P, and PRL, on the other. However, a positive correlation was found between inhibin (RIA and BA) and P, reflecting the production of inhibin by granulosa cells during luteinization. These studies allowed us to conclude that FF inhibin levels do not differ according to IVF ET outcome, but are an index of follicular maturation. AIA not only constitutes an index of follicular maturation and granulosa cell luteinization, but is of predictive value for IVF ET outcome as E2/AIA and inhibin BA/AIA ratios.
Adult↗
Effect of Decapeptyl, an agonistic analog of gonadotropin-releasing hormone on estrogens, estrogen sulfates, and progesterone receptors in leiomyoma and myometrium.
Estrogens (estrone [E1] and estradiol [E2]), their sulfates and progesterone receptor (PR) were evaluated in patients with uterine leiomyomata nontreated and treated with Decapeptyl (D-Trp6-gonadotropin-releasing hormone [GnRH]; Ipsen Biotech, Paris, France). Estrogen concentrations are very high in the leiomyoma (secretory phase, pg/g tissue [mean +/- SEM]: n = 10; E1: 147 +/- 24; E2: 850 +/- 116; E1-sulfate: 1,668 +/- 808; E2-sulfate: 718 +/- 126). Decapeptyl treatment provokes a significant decrease in E2 and particularly in E1 and E2 sulfates. Progesterone receptors were higher in the leiomyoma than in the myometrium; after a long treatment (3 to 4 months) a significant decrease in both tissues is observed. The decrease provoked by D-Trp6-GnRH on estrogens (unconjugated and sulfates) and in PR in the leiomyoma after long treatment, supports the hypothesis that estrogens are implicated in the cause of these tumors.
Adult↗
[Effect of decapeptyl (D-TrpG GnPh) on estrogen receptors, progesterone receptors and tissue levels of estrogens (non-conjugated and sulfate-conjugated) in patients with uterine myoma].
Concentrations of estrogen receptors, progesterone receptors, unconjugated estrogens (estradiol and estrone) and sulfate-conjugated estrogens (estradiol sulfate and estrone sulfate) were determined in patients treated with Decapeptyl and in controls. After prolonged Decapeptyl therapy, a highly significant fall in progesterone receptors was evidenced; estrogen receptors were found to be decreased in the myoma as compared with the secretory phase in controls and in the myometrium as compared with the proliferative phase in controls. Tissue levels of estrone sulfate and estradiol sulfate decreased very substantially. In conclusion, Decapeptyl emerges as a very promising agent for the treatment of uterine myomas.
Antineoplastic Agents↗
Correlation between follicular fluid content and the results of in vitro fertilization and embryo transfer. I. Sex steroids.
The steroid content of 72 follicular fluids (FF) obtained from 42 women subjected to ovulation induction with the luteinizing hormone-releasing hormone analogue D-Trp6 and human menopausal gonadotropin was studied in terms of the evolution of in vitro fertilization (IVF) and embryo transfer (ET) results. The FF were classified into several categories based on oocyte evolution. Individual values of FF estrone and estradiol (E2), as well as androstenedione and testosterone could not be correlated with ET outcome. However, FF progesterone (P) levels for follicles leading to pregnancy were significantly lower when compared with those in the other categories. The correlation between the E2/P ratio and E2 permitted the definition of a band wherein IVF-ET outcome was successful and enabled the characterization of different functional follicular maturational states.
Androstenedione↗
Smectite reduces gastroesophageal reflux in newborn infants.
We assessed the efficacy of a natural clay (smectite) on the frequency and the duration of acid (pH less than 4) and very acid (pH less than 3) gastroesophageal reflux (GER) measured by 24-hour continuous pH recording (CPR). Twenty newborn infants were enrolled in this double-blind controlled study owing to pathological CPR in supine position. After inclusion, all the patients were maintained in the 30-degree elevated prone position and received either smectite (3 g/day; n = 10) or placebo (n = 10) for 7 days. On the 8th day, a second 24-hour CPR was performed in supine position. The postural therapy alone (placebo group) was followed by a significant decrease in the numbers of acid GER (p less than 0.05) during the second CPR. The combination of postural therapy and smectite treatment was followed by a decrease in the number of acid (p less than 0.05) and very acid GER (p = 0.01), the percentages of time spent at pH below 4 (p less than 0.05) and 3 (p less than 0.01) and the maximal duration of acid GER (p less than 0.05).
Clinical Trials as Topic↗
[Efficacy of smectite in gastroesophageal reflux in the newborn infant].
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Clinical Trials as Topic↗
[Spinnability: a new approach to intestinal stress and its therapy].
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Animals↗