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Biomedical subjects

E M Gordon

Publications and source records attributed to E M Gordon.

At least 91 records · Page 5Linked to original sources
PubMed1988

Design of novel inhibitors of aminopeptidases. Synthesis of peptide-derived diamino thiols and sulfur replacement analogues of bestatin.

Investigations were directed toward inhibition of an aminopeptidase, isolated from rat brain, which has been implicated in the metabolic inactivation of enkephalins. The design rationale and synthesis of novel peptidyl diamino thiol inhibitors of rat brain aminopeptidase are presented, along with accompanying structure-activity analysis. Some of the reported compounds are highly active aminopeptidase inhibitors and possess enzyme inhibitory potency in the nanomolar range (62; I50 = 1 nM). Analysis of the data permits speculations on possible modes of binding of diamino thiols to aminopeptidase. Other investigations were directed toward understanding the mode of enzyme binding of the naturally occurring aminopeptidase inhibitor bestatin. On the basis of published models of enzyme binding, replacement of the C-2 hydroxyl group of bestatin by a sulfhydryl group was anticipated to lead to enhanced inhibition due to a strengthened interaction of this group with enzymic zinc. Contrary to expectations, "thiobestatin" inhibited rat brain aminopeptidase with only the same degree of effectiveness as the corresponding alcohol. Speculations on the possible mode of enzyme-inhibitor binding of bestatin are offered.

Aminopeptidases↗
PubMed1988

Ketomethylureas. A new class of angiotensin converting enzyme inhibitors.

The design rationale for a new series of tripeptide derived angiotensin converting enzyme (ACE) inhibitors, which we term "ketomethylureas", is described. Analogs of tripeptide substrates (i.e. N-benzoyl-Phe-Ala-Pro) in which the nitrogen atom of the scissile amide bond and the adjacent asymmetric carbon atom of the penultimate amino acid residue are formally transposed give rise to this novel class of inhibitors. The most potent ketomethylureas inhibit ACE with I50 values in the nM range.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1988

High-dose cytosine arabinoside and fractionated total-body irradiation: an improved preparative regimen for bone marrow transplantation of children with acute lymphoblastic leukemia in remission.

Twenty children with acute lymphoblastic leukemia in second (18 patients) or third (two patients) complete remission after bone marrow relapse received allogeneic bone marrow transplants from histocompatible sibling donors. The preparative regimen for marrow transplantation consisted of 12 doses of 3,000 mg/m2 cytosine arabinoside twice daily for six days followed by 1,200 cGy total-body irradiation (six doses of 200 cGy twice daily for three days). The preparative regimen was well tolerated, and all patients showed marrow engraftment promptly. Twelve patients are alive in complete remission 12+ to 79+ months posttransplant; eight patients are over 48 months posttransplant. Six patients died 1 to 9 months posttransplant of nonleukemic causes: (two each of graft-v-host disease, interstitial pneumonitis, and infection). Two patients developed recurrent leukemia at 15 and 30 months posttransplant. Both have died at 19 and 36 months posttransplant. Life table analysis reveals an actuarial survival and event-free survival rate of 58% and a marrow relapse rate of 17%. These results suggest that high-dose cytosine arabinoside and fractionated total-body irradiation is a relatively nontoxic and highly effective preparative regimen for allogeneic bone marrow transplantation for acute lymphoblastic leukemia that deserves further evaluation.

Adolescent↗
PubMed1988

Dose-dependent effects of postmenopausal estrogen and progestin on antithrombin III and factor XII.

The frequent use of estrogen and progestin replacement for treatment in postmenopausal women makes assessment of its effect on the coagulation system of interest. Although the amount of estrogen used to achieve the desired therapeutic effect is lower than the lowest doses in oral contraception, the age and medical condition of this population may amplify any hormone-induced risk. The common impression is that postmenopausal replacement therapy does not increase risk for thromboembolic disease, but no large epidemiologic studies of estrogen replacement have addressed that question. In this randomized prospective study, we examined the effects of varying low doses of an estrogen-progestin preparation on the titers of clotting factors in postmenopausal women. The coagulation factors selected for investigation were among those that have been reported to be significantly altered in the plasma samples of high-dose estrogen users. There were no changes in prothrombin time, factor X, fibrinogen, factor VII, or fibrinopeptide A in any of the hormone-treated groups. Mild but significant shortening of the partial thromboplastin time and elevation of factor XII titer were noted in all treatment groups. The titer of antithrombin III was reduced in the group given 20 micrograms ethinyl estradiol, but not in the groups given 5 or 10 micrograms. The clinical significance of these changes is difficult to determine in postmenopausal women receiving sex hormone replacement. However, we have not noted any thromboembolic episodes in our volunteers after a 1-year follow-up period.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Rational design and biochemical utility of specific inhibitors of angiotensin-converting enzyme.

Angiotensin-converting enzyme (ACE), the receptor for an important new class of antihypertensive drugs, is now one of the better studied zinc metallopeptidases. The development of several classes of tightly binding competitive inhibitors of ACE has led to increased understanding of the structure and function of this enzyme while also yielding important new drugs for the diagnosis and treatment of hypertensive disease. Peptides from snake venom provided the first proof of the therapeutic utility of ACE inhibitors, and a tripeptide sequence, Phe-Ala-Pro, was used as a model for sidechain interactions with ACE in the rational design of simpler nonpeptidic inhibitors such as captopril and enalapril. These and more recently developed ACE inhibitors can be classified according to their structural analogy to dipeptides or tripeptides and according to the nature of their zinc-binding ligands, such as sulfhydryl, ketone, carboxylate, or hydroxyphosphinyl, that contribute greatly to their binding to ACE. Several newer ACE inhibitors have increased potency and/or improved pharmacokinetic properties due to modifications such as substitution of the proline ring or replacement of the methyl side chain analogous to Ala by an aminobutyl residue analogous to Lys. The availability of structurally diverse ACE inhibitors with great potency and specificity provides a powerful biochemical tool for purification, localization, and characterization of ACE in different tissues, and for distinguishing related zinc metallopeptidases with similar properties.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1987

Augmented Hageman factor and prolactin titers, enhanced cold activation of factor VII, and spontaneous shortening of prothrombin time in survivors of myocardial infarction.

Hyperestrogenemia has been implicated in the pathophysiology of myocardial infarction. Because marked augmentation of the titer of Hageman factor is brought about by the administration of estrogens in humans and by prolactin or estrogen infusion in hypophysectomized rats, we measured the plasma concentrations of estradiol, prolactin, and clotting factors participating in surface-mediated reactions of coagulation in survivors of myocardial infarction. We observed higher titers of Hageman factor, prolactin, and high molecular weight kininogen but no significant change in estradiol or prekallikrein in survivors of myocardial infarction compared with controls. The titer of Hageman factor tended to be directly associated with the prolactin titer. We also report an increase in factor VII activity and spontaneous shortening of prothrombin time in the cold-stored plasma of survivors of myocardial infarction. In such individuals as well as in the control group, the titer of Hageman factor appeared to be responsible for half of the observed increase in factor VII activity and two thirds of the observed shortening of prothrombin time. These data indicate that although the titer of Hageman factor strongly influences the cold activation of factor VII, other factors may affect these phenomena.

Aged↗
PubMed1987

Hyperprolactinemia and reduction in plasma titers of Hageman factor, prekallikrein, and high molecular weight kininogen in patients with acute myocardial infarction.

Hemostatic changes and hyperestrogenemia have been reported in men during myocardial ischemia and acute myocardial infarction. Because marked augmentation of Hageman factor (factor XII) titer is induced by estrogen intake in humans, we studied the factors participating in the surface-mediated reactions of clotting in patients with documented acute myocardial infarction. We report lower coagulant titers of Hageman factor, prekallikrein, high molecular weight kininogen, and plasma thromboplastin antecedent (factor XI) in the plasma samples of patients with acute myocardial infarction than in control samples. Further, the plasma estradiol titers of patients with acute myocardial infarction were not significantly different from those of controls. In contrast, the prolactin concentration of patients with acute myocardial infarction was elevated. These data suggest that other nonhormonal factors such as excessive consumption may influence the observed reduction in the titers of surface-mediated clotting factors in acute myocardial infarction.

Aged↗
PubMed1985

Design of peptide derived amino alcohols as transition-state analog inhibitors of angiotensin converting enzyme.

A new amino alcohol modification designed to mimic the putative transition-state of amide bond cleavage by proteolytic enzymes has been incorporated into the scissile bond position of N-benzoyl-Phe-Ala-Pro, a known substrate of angiotensin converting enzyme (ACE). The resulting modified tripeptides (i.e. 4) are shown to be a new class of potent inhibitors of converting enzyme.

Amino Alcohols↗
PubMed1985

Red cell superoxide dismutase and sickle cell anemia symptom severity.

Patients with sickle cell anemia vary in the severity of their symptoms but the basis of this variability is unknown. We have tested the hypothesis that this variability is related to differences in the activity of the antioxidant superoxide dismutase (SOD). The amount of superoxide dismutase I (SOD) enzyme activity in red cells of patients with different degrees of symptom severity and healthy black and white controls was measured and correlated with symptom severity in SCA patients. Blacks with normal (AA) hemoglobin had significantly (p less than .001) more SOD activity (1.82 U/mg Hb) than white controls (1.44 U/mg Hb). Patients with moderate or severe symptoms had less SOD activity (1.16 and 0.95 U/mg Hb, respectively) than control blacks or SCA patients with mild symptoms (1.62 U/mg Hb). The correlation of SOD activity and symptom severity was not a function of age or sex and was unrelated to reticulocyte count or fetal hemoglobin level.

Adolescent↗
PubMed1985

Reduction of contact factors in sickle cell disease.

Surface-mediated reactions of clotting were compared in 21 black children with homozygous sickle cell disease, 12 age-matched controls, and 15 adults. Both the coagulant and antigen titers of Hageman factor (factor XII) were decreased in asymptomatic patients compared with those in the control groups. These findings were associated with slight but significant reductions in the plasma titers of prekallikrein and high molecular weight kininogen. A further decrease from the initially low titers of these contact factors was observed during vaso-occlusive crises. Additionally, we observed a disparate relationship between Hageman factor coagulant activity and its antigen titers. These data provide evidence for reduction of the contact factors in patients with homozygous sickle cell disease.

Adolescent↗
PubMed1985

Psychogenic purpura in adolescent patients.

The occurrence of psychogenic purpura has been documented in adults. The authors present their experience with nine adolescent and young adult patients observed since 1981. The age of eight of these patients ranged from 13 to 18 years. One patient with cystic fibrosis was 23-years-old. All patients presented with painful inflammatory lesions followed by bruising. There was no evidence of an infectious process or a hematologic, immunologic, or renal abnormality. Integral to the diagnosis was the existence of an underlying emotional disorder. In all patients, bruising decreased after diagnosis was explained to the patient and family. Four patients required psychotherapy. Results of 2-year follow-up suggest that early intervention may produce a favorable outcome in this age group.

Adolescent↗