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At least 433 records · Page 24Linked to original sources
PubMed1992

Rapid growth of leiomyoma in patient receiving tamoxifen.

A 49-year-old patient with breast cancer had a leiomyoma that rapidly enlarged shortly after she started therapy with tamoxifen. Exploratory laparotomy was necessary to confirm the diagnosis. The rapid growth may have resulted from the estrogen agonist properties of tamoxifen or alternatively by ovarian stimulation resulting in endogenous estrogen production.

Breast Neoplasms↗
PubMed1977

Choice of operation for acute gastric mucosal hemorrhage. Report of 36 cases and review of literature.

The results of operative treatment of thirty-six patients with acute gastric mucosal hemorrhage are presented. Alcohol and surgery/trauma were the most frequent causes, and renal failure, sepsis, or multisystem disease caused most deaths; overall mortality was 44 per cent. Vagotomy-pyloroplasty and vagotomy-resection are compared, and no statistically significant difference in rebleeding, reoperation for bleeding, or mortality is identified.

Acute Disease↗
PubMed1981

Locally invasive, well-differentiated thyroid cancer. 22 years' experience at Memorial Sloan-Kettering Cancer Center.

Our experience with 32 cases of locally invasive well-differentiated thyroid carcinoma suggests the following: (1) Thyroidectomy may be limited to the area of gross tumor involvement with little risk of recurrence in the normal opposite lobe. (2) Elective neck dissection should be considered in patients with locally invasive tumors since the incidence of nodal metastases is high. As observed in this study, occult metastases were present in five of six patients dissected electively, and nodal metastases developed later in four of eight patients observed. (3) Surgical procedures for the primary tumor should remove all gross disease. This is possible with conservative operations in most patients; the only deaths from uncontrolled local disease occurred in two patients in whom gross disease was left at the first procedure. Most deaths were caused by distant metastases, and the 5, 10 and 15 year survival rates were 86, 64 and 64 percent, respectively.

Adenocarcinoma↗
PubMed1989

Interaction of amiodarone and its analogs with calmodulin.

Benzofurans have important actions on the electrical properties of myocardium; the biochemical basis of those actions is not known. Crystallographic examination of these compounds has revealed that benzofurans share structural homologies with the traditional calmodulin antagonists N-(6-aminohexyl)-5-chloro-1-naphthalene and trifluoperazine. In the present study, the ability of amiodarone, desethylamiodarone, and benziodarone to displace the fluorescent ligand 8-anilino-1-naphthalene sulfonic acid (ANS) from calmodulin, to modulate the fluorescence emission of dansylcalmodulin, and to inhibit the activation by calmodulin of bovine brain cyclic nucleotide phosphodiesterase and human erythrocyte membrane Ca2+-ATPase were investigated at concentrations ranging from 10(-8) to 10(-6) M. These benzofurans displaced ANS from calmodulin with nearly equal efficiency upon forming a 1:1 complex with that protein. Each of these compounds also produced a decreased fluorescence emission of dansylcalmodulin, but with relative efficiencies being desethylamiodarone greater than amiodarone greater than benziodarone. Amiodarone and desethylamiodarone inhibited calmodulin-stimulable phosphodiesterase activity with similar potencies. Amiodarone and benziodarone inhibited calmodulin-stimulable Ca2+-ATPase activity equally, but desethylamiodarone had no effect. The observed differential effects of the amiodarone analogs suggest that calmodulin may possess multiple benzofuran-binding sites that are recognized by specific targets and ligands of this Ca2+-binding protein and that the cellular action of amiodarone and its analogs may reflect calmodulin antagonism.

Amiodarone↗
PubMed1993

Rabbit skeletal muscle sarcoplasmic reticulum Ca(2+)-ATPase activity: stimulation in vitro by thyroid hormone analogues and bipyridines.

Sarcoplasmic reticulum-enriched membranes from rabbit skeletal muscle contained Ca(2+)-ATPase activity which was significantly enhanced (26% increase, P < 0.001) in vitro by physiological concentrations (10(-10) M) of L-thyroxine (T4) and 3,3',5-triiodo-L-thyronine (T3). In contrast, the biologically inactive iodothyronine analogues D-T4 and 3,3',5,5'-tetraiodothyroacetic acid (Tetrac) (10(-10) M) were without effect on enzyme activity. 3,5-Dimethyl-3'-isopropyl-L-thyronine (Dimit), a bioactive analogue, was highly effective as a Ca(2+)-ATPase stimulator, increasing enzyme activity by 43% (P < 0.02 vs. T4 effect). A bipyridine cardiac inotropic agent, milrinone, has been reported to be thyromimetic in a myocardial membrane Ca(2+)-ATPase system, and in concentrations from 10(-10) to 10(-5) M enhanced skeletal muscle SR membrane Ca(2+)-ATPase activity in vitro (P < 0.001). Milrinone analogues which have been previously shown to enhance rabbit myocardial membrane Ca(2+)-ATPase activity, and which have a twist relationship of the pyridine rings, were also striated muscle Ca(2+)-ATPase stimulators. We conclude that (1) striated muscle is a mammalian tissue in which physiological levels of biologically relevant thyroid hormone analogues, particularly Dimit, stimulate Ca(2+)-ATPase activity in vitro by a non-genomic mechanism; (2) cardiac bipyridine analogues which are thyromimetic in vitro in rabbit heart, and which have structural homologies with thyroid hormone, are stimulators of rabbit striated muscle sarcoplasmic reticulum Ca(2+)-ATPase activity.

Animals↗
PubMed1986

Potent and prolonged melanotropic activities of the alpha-MSH fragment analog, Ac-[Nle4,D-Phe7]-alpha-MSH4-9-NH2.

Ac-[Nle4, D-Phe7]-alpha-MSH4-9-NH2 and Ac-[Nle4]-alpha-MSH4-9-NH2, fragment analogs of the tridecapeptide, alpha-melanocyte stimulating hormone (alpha-MSH, alpha-melanotropin), were synthesized. The potency and prolonged activity of the analogs were compared to alpha-MSH in several melanotropin bioassays. The D-Phe-containing hexapeptide was 10 times more active than alpha-MSH in stimulating melanoma tyrosinase activity. This analog was also 10-fold more potent than alpha-MSH in the lizard skin bioassay and about 10-fold less active in the frog skin bioassay. The melanotropic activity of Ac-[Nle4, D-Phe7]-alpha-MSH4-9-NH2 was considerably prolonged compared to alpha-MSH in each of the bioassays. These results demonstrate that the structural requirements for superpotency and prolonged activity of [Nle4, D-Phe7]-substituted analogs reside within this hexapeptide sequence.

Amino Acids↗
PubMed1986

Crystal structure of phlorizin and the iodothyronine deiodinase inhibitory activity of phloretin analogues.

Phloretin, a 7,8-dihydrochalcone of plant origin, and the high molecular weight (less than 15,000) polyphloretinphosphate (PPP) polymers are potent inhibitors of iodothyronine monodeiodinase activity from rat liver microsomal preparations, whereas phlorizin, the 2'-O-glucoside of phloretin, is inactive. The polymers, differing in degree of phosphorylation-dependent polymerization, exhibited a concentration-dependent, and ultimately complete, inhibition of deiodinase activity with an IC50 between 0.2 and 0.5 micrograms PPP/ml. Phloretin inhibition, on the other hand, was cofactor (DTE) competitive, with a Ki = 0.75 microM. 2',4',6',3,4- Pentahydroxychalcone, which has a substitution pattern in the A-ring identical to that of phloretin, was the only active inhibitor (IC50 = 8 microM) among several derivatives tested. The phloretin biodegradation products, phloretic acid and phloroglucinol, and its biosynthetic precursors, monomeric cinnamic acid and cinnamic acid derivatives, were inactive in concentrations up to 100 microM. The X-ray crystal structure analysis of phlorizin dihydrate showed that the molecule is planar and fully extended, similar to the conformation observed in chalcone structures that are characterized by an alpha, beta-unsaturated bond between phenol rings. Comparison of the planar phlorizin crystal structure with a skewed or antiskewed thyroid hormone conformation revealed that the beta-D-glucose moiety does not share any of the thyroid hormone's conformational space, and that the best structural homology is found with the antiskewed conformation of 3',5',3-triiodothyronine, the natural deiodinase substrate that also inhibits further deiodination.

Animals↗
PubMed1987

Competition of milrinone, a non-iodinated cardiac inotropic agent, with thyroid hormone for binding sites on human serum prealbumin (TBPA).

Milrinone [2-methyl-5-cyano-(3,4'-bipyridin)-6(1H)-one] is a positive cardiac inotropic agent recently shown to have thyromimetic activity in vitro in a rabbit myocardial membrane Ca2+-ATPase system [K. M. Mylotte et al., Proc. natn. Acad. Sci. U.S.A. 82, 7974 (1985)]. In the present studies, milrinone was examined for activity as an inhibitor of iodothyronine binding by human serum thyroid hormone transport proteins, thyroxine-binding globulin (TBG), prealbumin (TBPA) and albumin. Polyacrylamide gel electrophoresis at pH 9.0 of sera equilibrated with [125I]thyroxine showed that milrinone competed with L-thyroxine (T4) for binding sites on TBPA (10 and 100 microM milrinone caused 61 and 73% reductions, respectively, in T4 binding to TBPA, P less than 0.01); T4 displaced from TBPA was bound by TBG and albumin. Comparable reductions in T4 binding to TBPA were observed in electrophoretic studies conducted at pH 7.4. Binding of triiodo-L-thyronine (T3) to TBPA was electrophoretically confirmed and shown to be decreased in the presence of milrinone. Electrophoresis of purified TBPA also demonstrated that [14C]milrinone co-migrated with this transport protein and that milrinone displaced tracer T4 from TBPA. Amrinone, the 2-H-5-NH2 analog of milrinone, had less than 5% of the activity of milrinone as an inhibitor of T4 binding in electrophoretic studies. Scatchard analysis of T4 and milrinone binding to purified TBPA, measured by equilibrium dialysis, showed two classes of binding sites, with association constants, respectively, of 6.1 X 10(7) M-1 and 1.6 X 10(6) M-1 for T4, and 1.7 X 10(6) M-1 and 8.9 X 10(2) M-1 for milrinone. Computer graphic modeling of the binding of milrinone to the T4 site in the crystal structure of TBPA showed that milrinone best occupied this site when the substituted bipyridine ring overlapped the phenolic ring of T4. In this orientation the 5-cyano group, which has an electronegativity similar to that of iodine, occupied the same volume as the 5'-iodine of T4. The 5-amino group of amrinone lacks these characteristics. In this orientation, the keto function of milrinone overlapped the T4 4'-hydroxyl and could participate in similar intermolecular interactions. Thus, milrinone, a non-iodinated bipyridine, and thyroid hormone share structural and biochemical homologies and compete for the same binding site on TBPA.

Amrinone↗
PubMed1989

Protein kinase C inhibition by plant flavonoids. Kinetic mechanisms and structure-activity relationships.

Protein kinase C (PKC) from rat brain was inhibited by plant flavonoids in a concentration-dependent manner depending on flavonoid structure. Of the fifteen flavonoids studied, fisetin, quercetin and luteolin were the most potent, while hesperetin, taxifolin and rutin were among the least potent. The flavonol fisetin was almost 100% inhibitory at a concentration of 100 microM. The extent of inhibition was the same whether diacylglycerol or 12-O-tetradecanoylphorbol-13-acetate was used as enzyme activator. Inhibition was independent of Ca2+, phospholipid, and enzyme activator, as shown by inhibition of protamine phosphorylation in the absence of the regulatory components. Fisetin was a competitive inhibitor with respect to ATP binding and noncompetitive with respect to protein substrate. The X-ray crystal structure analysis of hesperetin monohydrate showed that the molecule is essentially planar despite the sofa conformation of the gamma-pyran ring and the 27 degrees twist of the 2-phenyl ring. Comparison of this inactive flavanone with those of the active flavones showed that, although hesperetin can adopt a planar profile similar to those of fisetin and quercetin, the 4'-methoxy substituent blocks an essential structural feature required for inhibitory activity. Analysis of these structure-activity data revealed a model of the minimal essential features required for PKC inhibition by flavonoids: a coplanar flavone structure with free hydroxyl substituents at the 3', 4' and 7-positions.

Animals↗
PubMed1995

Agonist properties of a stable hexapeptide analog of neurotensin, N alpha MeArg-Lys-Pro-Trp-tLeu-Leu (NT1).

The major signal transduction pathway for neurotensin (NT) receptors is the G-protein-dependent stimulation of phospholipase C, leading to the mobilization of intracellular free Ca2+ ([Ca2+]i) and the stimulation of cyclic GMP. We investigated the functional actions of an analog of NT(8-13), N alpha MeArg-Lys-Pro-Trp-tLeu-Leu (NT1), and other NT related analogs by quantitative measurement of the cytosolic free Ca2+ concentration in HT-29 (human colonic adenocarcinoma) cells using the Ca(2+)-sensitive dye fura-2/AM and by effects on cyclic GMP levels in rat cerebellar slices. The NT receptor binding affinities for these analogs to HT-29 cell membranes and newborn (10-day-old) mouse brain membranes were also investigated. Data obtained from HT-29 cell and mouse brain membrane preparations showed saturable single high-affinity sites and binding densities (Bmax) of 130.2 and 87.5 fmol/mg protein, respectively. The respective KD values were 0.47 and 0.39 nM, and the Hill coefficients were 0.99 and 0.92. The low-affinity levocabastine-sensitive site was not present (K1 > 10,000) in either membrane preparation. Although the correlation of binding between HT-29 cell membranes and mouse brain membranes was quite significant (r = 0.92), some of the reference agents had lower binding affinities in the HT-29 cell membranes. The metabolically stable compound NT1 plus other NT analogs and related peptides [NT, NT(8-13), xenopsin, neuromedin N, NT(9-13), kinetensin and (D-Trp11)-NT] increased intracellular Ca2+ levels in HT-29 cells, indicating NT receptor agonist properties. The effect of NT1 in mobilizing [Ca2+]i blocked by SR 48692, a non-peptide NT antagonist. Receptor binding affinities of NT analogs to HT-29 cell membranes were positively correlated with potencies for mobilizing intracellular calcium in the same cells. In addition, NT1 increased cyclic GMP levels in rat cerebellar slices, confirming the latter findings of its NT agonist action. These results substantiate the in vitro NT agonist properties of the hexapeptide NT analog NT1.

Amino Acid Sequence↗
PubMed1991

Smoking and movement disorders in psychiatric patients.

Previous studies have suggested that tardive dyskinesia may occur more frequently in patients who smoke. Further evidence of an interaction between smoking and movement disorders includes the low lifetime exposure to cigarettes found in Parkinson's disease patients. In this study 126 patients with chronic psychiatric illnesses were blindly evaluated for tardive dyskinesia, neuroleptic-induced parkinsonism, and akathisia. Patients who smoked received significantly higher doses of neuroleptics but did not have significantly more frequent or more severe tardive dyskinesia or parkinsonism. Female smokers did have significantly more akathisia. These results are discussed with regard to interactions between smoking, central dopaminergic tone, and the psychopathology of extrapyramidal syndromes. The effect of smoking on neuroleptic blood levels as well as clinical symptomatology is also discussed.

Adult↗