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A Corrigan

Publications and source records attributed to A Corrigan.

At least 19 recordsLinked to original sources
PubMed1992

Gonadotropin-releasing hormone antagonists with N omega-triazolylornithine, -lysine, or -p-aminophenylalanine residues at positions 5 and 6.

In order to be used as fertility regulators in humans, gonadotropin releasing hormone (GnRH) antagonists must be extremely potent and long acting and exhibit negligible side effects such as stimulating histamine release. To this aim, we have recently synthesized a series of analogues with the standard Ac-DNal1-DCpa2-DPal3 substitutions, where the N omega-amino function of ornithine, lysine, or p-aminophenylalanine (Aph) was converted to the aminotriazolyl (atz) derivatives at positions 5 and 6 with further modifications at positions 7 and 10. The analogues were tested for their ability to bind to pituitary cell membranes, to release histamine in a mast cell assay, to inhibit luteinizing hormone (LH) secretion by castrated male rats or cultured pituitary cells, and to interfere with the ovulation in intact female rats. While the subcutaneous (sc) injection of 50 micrograms of Azaline A (7, [Ac-DNal1,DCpa2,DPal3,Lys5(atz),DLys6++ +(atz),ILys8,DAla10]GnRH) dissolved in 0.2 mL of an aqueous media significantly inhibited LH release in the castrated male rat for 24 h, the same dose of Azaline B (11), [Ac-DNal1,DCpa2,DPal3,Aph5(atz),DAph6++ +(atz),ILys8,DAla10]GnRH, inhibited LH release for 72 h. A similar long duration of action was observed for Antide ([Ac-DNal1,DCpa2,DPal3,Lys5(Nic),DLys6(Nic ),ILys8,DAla10]GnRH) but not for Nal-Glu ([Ac-DNal1,DCpa2,DPal3,Arg5,4-(pmethoxybenzoy l)-D-2-Abu6,DAla10]GnRH). In the same paradigm, a 5-fold dilution of the peptide (50 micrograms in 1 mL) and the use of three injection sites rather than one resulted in significantly shorter duration of action for most of the peptides tested. This suggested that long duration of action might be the result of slow release from the injection site(s). In order to investigate this possibility, Nal-Glu and Azaline B were injected intravenously (i.v.) at three doses (10, 50, 250 micrograms) to castrated male rats. At all doses, both peptides significantly lowered LH levels for 8 h. By 24 h, Nal-Glu (250 micrograms) and Azaline B (50 and 250 micrograms) still measurably inhibited LH secretion. Finally, only Azaline B (250 micrograms) was still active at 48 h. These findings demonstrate that subtle structural modifications will yield peptides with different half-lives after iv administration. These findings led us to investigate the effects of other structural modifications on duration of action. We observed that systematic substitutions at positions 7 (NMeLeu) and 10 (Pro9-NHEt, and Gly-NH2) were found to be deleterious. Of interest was the observation that only the DAla10-NH2 substitution led to long duration of action and enzymatic stability under the conditions tested.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Novel gonadotropin-releasing hormone antagonists: peptides incorporating modified N omega-cyanoguanidino moieties.

In order to minimize the deleterious effects of histamine release resulting from the administration to rats and humans of some potent gonadotropin-releasing hormone (GnRH) antagonists, various arginine residues were replaced with the less basic N omega-cyano-N omega-alkyl- or -arylhomoarginine, -arginine, or -p-aminophenylalanine and N omega-triazolyllysine, -ornithine or -p-aminophenylalanine residues in active analogues. These novel analogues were synthesized on a solid-phase support via a two-step modification of the N omega-NH2 of lysine, ornithine, or p-aminophenylalanine residues in otherwise protected resin bound peptides. Most analogues were tested in the rat antiovulatory assay (AOA) and three in vitro assays; a pituitary cell culture assay, a binding assay to pituitary cell membranes, and a histamine release assay. Introduction of the cyanoguanidino and N omega-triazolyl moieties into GnRH analogues yielded several water-soluble antagonists which showed a desirable therapeutic ratio (low histamine release activity to high in vivo potency). Among them, "Azaline" (10, [Ac-DNal1,DCpa2,DPal3,Lys5(atz), DLys6(atz),ILys8,DAla10]GnRH), inhibited ovulation in the rat by 90% at 2 micrograms/rat with an ED50 in the in vitro histamine release assay comparable to that of GnRH itself.

Animals↗
PubMed1991

Effect of recombinant human inhibin on gonadotropin secretion by the male rat.

We have examined the effect of recombinant human inhibin-A on basal and GnRH-induced gonadotropin secretion by male rats or cultured anterior pituitary cells. Inhibin, administered sc 6 h before the experiment, induced dose- and time-related decreases in plasma FSH, but not LH, levels in both intact and castrated male rats. Inhibin also significantly interfered with the in vivo stimulatory effect of 20-500 ng GnRH on FSH release, but had inconsistent and usually modest effects on the LH response. While exposure of cultured pituitary cells to inhibin for 72 h has been reported to interfere with GnRH-induced gonadotropin release, we examined here the effects of shorter exposure periods relevant to in vivo experiments. Exposure of the cells to inhibin (31.3-312.5 pM) for 2-6 h measurably (P less than or equal to 0.01) decreased the ability of 10 nM GnRH to stimulate both FSH and LH released by cultured cells. In contrast, lower (3.1 and 9.4 pM) doses of inhibin had little or no effect. Longer exposures to inhibin (10, 24, and 72 h) increased the inhibitory effect of 31.3-312.5 pM inhibin, while 3.1 and 9.4 pM remained ineffective at all times. These results indicate that exposure of the male rat to inhibin for 6 h decreases FSH secretion, and that this effect is at least partially mediated through blunting of the pituitary response to GnRH. In contrast, the ability of inhibin to interfere with LH release, which is readily apparent in cultured pituitary cells, appears to be of lesser importance in the intact male rat.

Animals↗
PubMed1988

Design of potent cyclic gonadotropin releasing hormone antagonists.

In order to improve the biological potency of cyclic gonadotropin releasing hormone (GnRH) antagonists, we have synthesized analogues, the conformations of which were restrained through internal side chain/side chain amide bridges linking aspartic acid or glutamic acid and L-2,3-diaminopropionic acid or L-ornithine. A disulfide bridge linking L-cysteine residues was also introduced. Residues belonging to the bridge spanned from position 4 to positions 9 or 10. Two series of analogues were synthesized and are characterized by residues at positions 1 [Ac-D-3-(2'-naphthyl)alanine], 2 [D-(4-chlorophenyl)alanine or D-(4-fluorophenyl)alanine], 3 [D-3-(3'-pyridyl)alanine or D-tryptophan], 5 (arginine or tyrosine), and 6 [D-3-(3'-pyridyl)alanine or D-arginine], respectively. These substitutions were selected in an effort to optimize high biopotency for inhibition of luteinizing hormone secretion, minimization of histamine release activity, and high (relative) hydrophilicity. The most potent analogues in the antiovulatory assay were cyclo(4-10) [Ac-DNal1,DCpa2,DPal3,(Asp4 or Glu4),Arg5,DPal]6,Dpr10]GnRH (compounds 5 and 7), which were fully active at ca. 12.5 micrograms/rat in the first series, and cyclo(4-10)[Ac-DNal1,DFpa2,DTrp3,Asp4,DArg6++ +,Dpr10]GnRH (compound 12), which was fully active at 2.5 micrograms/rat in the second.

Amino Acid Sequence↗
PubMed1987

Brain distribution of radioimmunoassayable gonadotropin-releasing hormone in female goldfish: seasonal variation and periovulatory changes.

A radioimmunoassay (RIA) for [Trp7, Leu8]gonadotropin-releasing hormone (sGnRH) was developed to determine the gonadotropin-releasing hormone (GnRH) content in discrete brain areas of female goldfish at different stages of ovarian development. Temporal changes in serum gonadotropin (GtH) and GnRH concentrations in discrete brain areas were measured during spontaneous ovulation. There were no clear parallel changes in brain GnRH with seasonal ovarian development in goldfish. However, under a 10 degrees temperature acclimation regimen, the GnRH content in the hypothalamus and pituitary decreased as the ovary progressed from the regressed to the mature condition; on the other hand. GnRH content in the spinal cord increased in sexually mature fish compared with that in regressed fish. Significant decreases in GnRH concentration were observed in certain brain areas (olfactory bulbs, telencephalon, hypothalamus, and pituitary) of fish undergoing spontaneous ovulation compared with those of nonovulatory fish. The simultaneous changes of GnRH concentration in these brain areas suggested that the GnRH neuronal system may function as an integrated unit for the activation of GtH secretion during ovulation in goldfish.

Animals↗
PubMed1986

A reinvestigation of the Gn-RH (gonadotrophin-releasing hormone) systems in the goldfish brain using antibodies to salmon Gn-RH.

The organization of Gn-RH systems in the brain of teleosts has been investigated previously by immunohistochemistry using antibodies against the mammalian decapeptide which differs from the teleostean factor. Here, we report the distribution of immunoreactive Gn-RH in the brain of goldfish using antibodies against synthetic teleost peptide. Immunoreactive structures are found along a column extending from the rostral olfactory bulbs to the pituitary stalk. Cell bodies are observed within the olfactory nerves and bulbs, along the ventromedial telencephalon, the ventrolateral preoptic area and the latero-basal hypothalamus. Large perikarya are detected in the dorsal midbrain tegmentum, immediately caudal to the posterior commissure. A prominent pathway was traced from the cells located in the olfactory nerves through the medial olfactory tract and along all the perikarya described above to the pituitary stalk. In the pituitary, projections are restricted to the proximal pars distalis. A second immunoreactive pathway ascends more dorsally in the telencephalon and arches to the periventricular regions of the diencephalon. Part of this pathway forms a periventricular network in the dorsal and posterior hypothalamus, whereas other projections continue caudally to the medulla oblongata and the spinal cord. Lesions of the ventral preoptic area demonstrate that most of the fibers detected in the pituitary originate from the preoptic region.

Animals↗
PubMed1986

New effective gonadotropin releasing hormone antagonists with minimal potency for histamine release in vitro.

In order to minimize the adverse effect of histamine release in the rat of some gonadotropin releasing hormone (GnRH) antagonists, such as [Ac-D2Nal1,D4FPhe2,DTrp3,DArg6]-GnRH, new structures with modifications at positions 1, 2, 3, 5, 6, 7, and 10 were synthesized and tested in several biological systems. In vitro: the affinity for the pituitary GnRH receptor was measured as was the ability of the analogues to inhibit GnRH-stimulated release of luteinizing hormone (LH) by dispersed anterior pituitary cells in culture and to release histamine from rat mast cells. In vivo: inhibition of ovulation in the cycling rat was determined after subcutaneous (sc) injection of the peptides at noon on the day of proestrus; the duration of action of the peptides was evaluated by measuring LH levels in the castrated male rat after sc injection of some selected analogues. [Ac-D2Nal1,D4ClPhe2,D3Pal3,Arg5,D-4-p-methoxy benzoyl-2-aminobutyric acid6,DAla10]-GnRH was found to be one of the most potent analogues of this series, causing a 100% inhibition of ovulation at 5 micrograms/kg or less. Release of histamine was observed at doses 10-25 times that required for [Ac-D2Nal1,D4FPhe2,DTrp3,DArg6]-GnRH. Thus, introduction of arginine in position 5 with a hydrophobic amino acid in position 6 is compatible with high potency in several biological systems and results in compounds with lowered potency to release histamine compared to homologous peptides with tyrosine in position 5 and D-arginine in position 6.

Animals↗
PubMed1984

Thymic hormone-containing cells. V. Immunohistological detection of metallothionein within the cells bearing thymulin (a zinc-containing hormone) in human and mouse thymuses.

Using an immunofluorescence (IF) assay, the presence of metallothionein (MT) was investigated in sections of normal and pathologic human thymuses as well as in cultures of thymic epithelial cells. This protein, known to have a high binding affinity for class II B transitional metals, such as zinc, was detected in the epithelial component of the thymus. Moreover, double labeling experiments with the anti-MT and an anti-thymulin monoclonal antibody showed that all cells containing thymulin, a thymic hormone whose active structure is known to contain zinc, also exhibited large amounts of metallothionein. These results, together with the fact that zinc and thymulin have been detected in the same type of cell organelles, lead to the conclusion that the MT present in thymic epithelial cells might be involved in the mechanism of zinc storage in these cells, thus favoring the secretion of thymulin in its biologically active, zinc-containing form.

Animals↗
PubMed1984

Home ventilation.

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Home Nursing↗
PubMed1983

Pneumonectomy.

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Humans↗
PubMed1982

Total and surface-located sialic acid levels in normal and leukaemic lymphocytes: relationship to T and B cell nature and to location in vivo.

Unfractionated normal blood lymphocytes (predominantly T lymphocytes) showed significantly elevated total and neuraminidase-susceptible sialic acid compared with CLL lymphocytes (predominantly B lymphocytes). T-enriched fractions from normal blood contained about three-fold the sialic acid content of the corresponding T-depleted fractions, and similarly low values were also obtained for T-depleted fractions from tonsils. Thus the reduced sialic acid levels in CLL lymphocytes appear to be due to their B cell nature. In contrast to the situation in normal peripheral venous blood, tonsillar T and B cells did not differ markedly in sialic acid content, suggesting that for T cells maturity and/or location in vivo are important determinants of this parameters. Results with calf thymocytes were in agreement with this. Sialic acid was estimated in malignant B and T lymphoblasts. Shedding of sialic acid-containing moieties from lymphocytes was also examined.

B-Lymphocytes↗
PubMed1980

Separation of viable from nonviable cells using a discontinuous density gradient.

When a suspension containing a mixture of viable and nonviable cells is layered over a dense ficoll-metrizoate solution and centrifuged, most of the viable cells are retained at the interface above the dense solution; whereas most of the nonviable cells are distributed in other fractions. The cells recovered from the interface are capable of subsequent growth in culture.

Animals↗
PubMed1979

Lymphocyte membrane alterations caused by nylon wool column separation.

Use of the nylon wool column method to separate lymphocytes results in preparations which, while fully viable, have grossly depleted cellular levels of phospholipid, cholesterol and sialic acid. These membrane effects, which relate mainly to T cells, indicate that the method is unsuitable for use in biochemical analysis of lymphocytes.

B-Lymphocytes↗
PubMed1979

Three-year growth of a pastoral care department.

Three years ago, setting up a pastoral care department combining tradition with a contemporary thrust was an administrative dream at St. Mary's Hospital, Streator, IL. Now such a department is in full operation, offering a variety of services to patients, their families, hospital staff, clergy, and the community.

Chaplaincy Service, Hospital↗