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Biomedical subjects

E M Gordon

Publications and source records attributed to E M Gordon.

At least 109 records · Page 6Linked to original sources
PubMed1985

Oropharyngeal Candida prophylaxis in pediatric bone marrow transplant patients.

The effect of a multi-agent regimen on oropharyngeal candidiasis (OPC) prophylaxis in 16 consecutive pediatric bone marrow transplant patients was assessed. The multi-agent regimen consisted of: 1) debriding all mucous membrane surfaces within the oropharyngeal cavity with povidone-iodine 4 times a day, 2) swabbing all mucous membrane surfaces within the oropharyngeal cavity with nystatin 4 times a day, and 3) Ketoconazole given daily by mouth. Multi-agent regimen therapy was initiated on the day marrow ablative therapy began, and was terminated when the patient's absolute neutrophil count recovered to above 500/mm3. Baseline oropharyngeal fungal cultures indicated that 8 out of 16 (50%) of the patients were Candida carriers. Subsequent surveillance cultures indicated that 13 out of 16 (81.3%) of the patients had negative oropharyngeal fungal cultures during the entire period they were on the multi-agent regimen. The remaining three patients had negative oropharyngeal fungal cultures by the end of the experimental period. None of the patients developed Candida esophagitis or sepsis. The above regimen is an effective and non-toxic method to prevent oropharyngeal candidiasis in pediatric BMT patients.

Adolescent↗
PubMed1985

The influence of estrogen and prolactin on Hageman factor (factor XII) titer in ovariectomized and hypophysectomized rats.

The synthesis of prothrombin in hepatic microsomes is augmented in intact estrogen-treated rats and in hypophysectomized rats treated with purified prolactin. We investigated the influence of these gonadal and pituitary hormones on the titer of Hageman factor (factor XII), reportedly elevated in women using oral contraceptives. Rats were ovariectomized to minimize the influence of endogenous estrogen and progesterone on the Hageman factor titer. The administration of progesterone did not alter the plasma concentration of Hageman factor. In contrast, the infusion of 17 beta-estradiol induced a marked elevation of the plasma Hageman factor titer, as measured functionally and immunologically. The titer of Hageman factor was directly related to both plasma estradiol and prolactin concentrations, indicating that prolactin may play a role in the regulation of plasma Hageman factor titers. In agreement with this, hypophysectomy induced a marked decrease in the Hageman factor level. In hypophysectomized ovariectomized animals, the administration of estradiol restored the Hageman factor titer to normal levels, whereas the infusion of prolactin induced a dramatic rise in the Hageman factor titer to the degree observed in nonhypophysectomized estrogen-treated rats. No further increase in the Hageman factor titer was observed in rats treated with both estradiol and prolactin. These data indicate that estrogens increase the plasma Hageman factor titer both directly and through its release of prolactin and that prolactin may also increase the titer of Hageman factor through estrogen-independent mechanisms.

Animals↗
PubMed1984

Design of conformationally constrained angiotensin-converting enzyme inhibitors.

Modification of alanyl proline by introduction of both zinc coordinating and S1 subsite binding interactions affords potent new carboxy- and mercapto-acyl dipeptide angiotensin-converting enzyme (ACE) inhibitors. Design of these inhibitors was guided by an extension of the hypothetical ACE active site model originally used to derive captopril. Significant increases in ACE inhibitory activity were observed by introduction of conformation constraint into acyclic acyl dipeptides, thus further defining the three dimensional structure of the ACE active site.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1984

Ketomethyldipeptides I. A new class of angiotensin converting enzyme inhibitors.

The design rationale for a new series of angiotensin-converting enzyme (ACE) inhibitors which incorporate a ketone substituent into a peptide backbone is described. Molecular regions which were expected to mimic the binding of an N-acyl tripeptide substrate at secondary binding sites S1 and S1' were systematically varied in order to study the specificity of inhibitor binding and optimize inhibition against ACE. The most effective ketomethyldipeptides inhibit ACE in the 10(-9) M range.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1984

Ketomethyldipeptides II. Effect of modifications of the alpha-aminoketone portion on inhibition of angiotensin converting enzyme.

Results of an investigation aimed at identifying the consequences of chemical modifications of the alpha-aminoketone moiety of ketomethyldipeptides on angiotensin converting enzyme (ACE) inhibition are reported. These studies lead to the conclusion that within this series, the optimal structural backbone formulation for inhibition of ACE is represented by 1. Introduction of a Sar-Pro C-terminal dipeptide in this system, in contrast to other inhibitor classes, is compatible with potent inhibitory activity. Other structure-activity relationships for ketomethyldipeptides and related derivatives are presented, and speculations on possible modes of binding of these inhibitors to ACE, and on the question of ketone rehybridization are offered.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1984

Streptomyces R61 DD-carboxypeptidase: hydrolysis of X-D-alanyl-D-alanine peptides measured by a fluorometric assay.

A fluorometric procedure for measuring the activity of DD-carboxypeptidase is described. The method is based on the reaction of one of the products, D-alanine, with o-phthaldialdehyde to form a highly fluorescent adduct. The method has been applied in examining a series of X-D-alanyl-D-alanine peptides as substrates of the penicillin-sensitive DD-carboxypeptidase from Streptomyces R61. The effect of the third residue, X, on kinetic parameters and its implications on the steric analog model for penicillin action are also discussed.

Alanine↗
PubMed1984

Acute monoblastic leukemia in infancy and early childhood: successful treatment with an epipodophyllotoxin.

Four of five infants and young children with acute monoblastic leukemia, a disease that heretofore has been highly refractory to therapy, were successfully treated with sequential infusions of a podophyllin derivative employed as a single agent over a protracted period of time. In three of the five children, monocytic leukemia cutis was present at birth. Treatment was begun in two of them when the disease had progressed to systemic involvement at a few months of age, and in the third when disease was still localized. The other two children were 11 and 18 months of age at initial presentation with widespread disease. Four children are off therapy 11 months, 26 months, 5 years, and 6 years, respectively.

Alopecia↗
PubMed1983

Purification and characterization of enkephalinase, angiotensin converting enzyme, and a third peptidyldipeptidase from rat brain.

Three distinct peptidyldipeptidases (exopeptidases releasing carboxyl terminal dipeptide residues) can be solubilized from nerve terminal membrane fractions from whole rat brain or striatum, and separated by ion exchange chromatography. Brain angiotensin-converting enzyme (PDP-1) cleaves Hip-His-Leu, but not 80 nM [3H-Tyr1, Leu5]-enkephalin, and is markedly inhibited by several specific inhibitors such as captopril, teprotide, and MK-422. Enkephalinase (PDP-2) cleaves 80 nM [3H-Tyr1, Leu5]-enkephalin, but not Hip-His-Leu; it is not inhibited by any of the standard competitive inhibitors of angiotensin-converting enzyme (all analogs of carboxyl-terminal peptide sequences Phe-Ala-Pro or Ala-Pro), but is strongly inhibited by captopril analogs such as thiorphan (Phe-Gly analog). A third peptidyldipeptidase (PDP-3) cleaves Hip-His-Leu, but not 80 nM [3H-Tyr1, Leu5]-enkephalin; it is inhibited by dipeptide analog inhibitors such as captopril and thiorphan, but not by longer peptides such as teprotide or tripeptide analog inhibitors such as MK-422. Both PDP-2 (enkephalinase) and PDP-3 are apparently present in nerve terminal membranes predominantly as inactive proenzyme precursors, which elute from DEAE-cellulose at high salt concentration, and are activated very slowly by a process involving one or more trypsin-like enzymes. Rechromatography of activated PDP-2 and PDP-3 achieves a nearly complete separation of the two enzymes, both markedly purified, since each is much less acidic than its proenzyme precursor. Purified enkephalinase does not appear to have any significant endopeptidase activity. It cleaves Hip-Phe-Arg 200 times more effectively than Hip-Phe-Arg-NH2, and appears to be quite selective for cleaving the terminal dipeptide residue, Phe-Arg, from bradykinin, with no release of the second dipeptide and no cleavage of the Gly4-Phe5 interior peptide bond.

Animals↗
PubMed1983

Rat brain enkephalinase: characterization of the active site using mercaptopropanoyl amino acid inhibitors, and comparison with angiotensin-converting enzyme.

Over fifty mercaptopropanoyl amino acids and related derivatives were synthesized to define the steric, electronic and stereochemical requirements for binding to the active site of enkephalinase (ENKASE), and also for their ability to inhibit angiotensin-converting enzyme (ACE). In this way the character of ENKASE and ACE active sites were compared.

Amino Acids, Sulfur↗
PubMed1983

Effect of chronic metabolic acidosis on vitamin D metabolism in humans.

Bone disease may occur in disorders associated with chronic metabolic acidosis. This has been attributed, in part, to reduced production of 1,25(OH)2D3. Although metabolic acidosis in the vitamin D deficient animal has been associated with a reduction in the conversion of radiolabeled 25(OH)D3 to 1,25(OH)2D3, studies in D-replete humans have revealed no effect of acidosis on 1,25(OH)2D3 metabolism. To examine this issue further, we measured serum 25(OH)D, 1,25(OH)2D, and 24,25(OH)2D levels in six healthy subjects before and after 9 days of metabolic acidosis induced by the ingestion of ammonium chloride. In four subjects, we measured the increment in serum levels of 1,25(OH)2D in response to the infusion of parathyroid extract both during control and acidosis. Serum levels of 1,25(OH)2D, 13.6 +/- 1.3 and 14.3 +/- 0.9 pg/ml, in control and acidosis, respectively, were not different. The serum 1,25(OH)2D levels in control and acidosis rose to a similar degree with the infusion of PTE. These data provide strong evidence that metabolic acidosis does not have a substantial impact on the synthesis of 1,25(OH)2D3 metabolism in vitamin D-replete humans.

Acidosis↗
PubMed1983

Influence of augmented Hageman factor (Factor XII) titers on the cryoactivation of plasma prorenin in women using oral contraceptive agents.

Prolonged cold storage of plasma may induce the conversion of plasma prorenin (inactive renin) to renin. This phenomenon is exaggerated in oral contraceptive (OC) users; the titer of Hageman factor (HF, Factor XII) in OC users is higher than in nonusers. The present study relates these observations. The increment in plasma renin activity (PRA) during cold storage, as measured by generation of angiotensin I, correlated strongly with the initial plasma titer of HF. Increasing the HF titer of nonusers to that observed in OC users by addition of purified HF increased cold-induced PRA at least twofold, while reducing the plasma HF titer of OC users correspondingly decreased cold-induced PRA. Thus, in OC users, the enhanced conversion of plasma prorenin to renin during cold storage reflects the elevated plasma titer of HF.

Angiotensin I↗
PubMed1983

Intensive melphalan chemotherapy and cryopreserved autologous bone marrow transplantation for the treatment of refractory cancer.

Thirty-three adult and pediatric patients with refractory malignancies were treated with escalating doses of melphalan (120-225 mg/m2 IV over 3 days) followed by reinfusion of previously harvested and cryopreserved autologous marrow. The hematological and nonhematological toxicities and the therapeutic effects of this regimen were evaluated. Increasing doses of melphalan did not alter the rate of decline nor the recovery of peripheral blood counts. Granulocyte (greater than 500/microL) and platelet count (greater than 20,000/microL) recovery occurred in a median of 19 (range 12-54) and 24 (range: 12-54) days after bone marrow transplantation, respectively. Five patients experienced severe infection, three of which were fatal, and one patient died due to thrombocytopenic hemorrhage. Toxicity to the gastrointestinal system was dose limiting. The maximum tolerated dose of melphalan was 180 mg/m2; only three of 24 patients experienced severe stomatitis, esophagitis, and diarrhea at this level or less, while eight of nine patients at 225 mg/m2 were affected (p less than 0.005). Administration of cyclophosphamide (300 mg/m2 IV) 1 week before melphalan therapy did not reduce the incidence of severe gastrointestinal toxicity. Plasma melphalan concentration peaked 30-60 min after infusion (4.8-11.5 micrograms/mL) but declined rapidly. Cerebrospinal fluid concentration was 10% of the corresponding plasma concentration and was undetectable at 3 hours. Antitumor responses occurred in nine of 13 patients with malignant melanoma (five complete and four partial remissions), and ranged 2-12+ months with a median of 5 months. Four of six neuroblastomas demonstrated responses (three complete and one partial remission( lasting a median of 7.5 (range: 5-10) months. Other tumors in which this regimen had activity included breast cancer and Ewing's sarcoma. The overall response rate for the 33 patients was 30% complete remissions (10 patients) and 21% partial remissions (seven patients). High dose melphalan and autologous bone marrow transplantation is a promising therapy for patients with malignancies for which no effective treatment is known or for patients whose cancer is refractory to conventional therapeutic agents.

Adolescent↗
PubMed1983

The effect of chronic metabolic acidosis on the end organ responsiveness to parathyroid hormone in man.

To examine the effect of prolonged metabolic acidosis on the responsiveness of end organs to PTH, we measured the changes in serum ionized calcium and the urinary excretion of calcium and phosphorus in response to a 10-h infusion of parathyroid extract (PTE) before and after 9 days of metabolic acidosis. During the first hours of PTE infusion, the increases in ionized calcium were slower during acidosis, but the maximal increments in ionized calcium (0.5 +/- 0.1 and 0.4 +/- 0.1 mg/dl, respectively) were not different. Moreover, the PTE-induced increments in the fractional excretion of phosphate during acidosis and the control study were not different. Fractional excretion of calcium before the infusion of PTE was higher in acidosis than in control (3.7 +/- 0.3% compared to 0.8 +/- 0.3%; P less than 0.01). However, at 10 h of the infusion, when the maximal effect of PTE was observed, the fractional excretions of calcium in control and acidosis were not significantly different. These data suggest that prolonged metabolic acidosis has little or no effect on bone or renal responsiveness to PTH.

Acidosis↗
PubMed1983

Oral complications associated with bone marrow transplantation in a pediatric population.

The effect of dental evaluation and treatment prior to bone marrow transplantation in 11 pediatric patients was assessed. Oral complications associated with marrow ablative therapy and the immediate posttransplant period (Days 0-35) were also studied. Oral complications during marrow ablative therapy included: xerostomia (2/11 patients) and parotitis (1/11 patients). Oral complications in the immediate post-transplant period (Days 0-35) included: mucositis (11/11 patients); moniliasis (9/11 patients); and stomatitis associated with acute G.V.H.D. (3/9 patients receiving allogenic marrow transplants). The onset of the mucositis in the posttransplant period usually occurred at the nadir of the white blood cell count and resolved when the absolute neutrophil count was approximately 500/m3. The onset of moniliasis in the posttransplant period was usually 1-2 days after the onset of the mucositis. Resolution of the moniliasis usually paralleled resolution of the mucositis. No patient developed an infectious and/or hemorrhagic complication of odontogenic origin.

Adolescent↗
PubMed1982

Bone marrow transplantation with high-dose cytosine arabinoside.

Eleven patients received allogeneic bone marrow from all HCA-identical sibling for the treatment of acute leukemia. The preparative regiment included high-dose cytosine arabinoside (Ara-C), 3 g/m2q 12 h for 12 doses, and 1000 rad single-fraction total body irradiation (5 patients) or 1200 rad fractionated total body irradiation (6 patients). The 5 patients receiving the 1000 rad single-fraction regimen were transplanted in relapse, while the 6 patients receiving the 1200 rad fractionated program were transplanted during remission. Both regimens were well-tolerated, but the single-dose radiation regimen was associated with more severe skin problems. Bone marrow engraftment was documented in 10 of 10 evaluable patients, occurring 2-3 weeks after marrow infusion. No recurrences have been observed during the brief follow-up time.

Bone Marrow Transplantation↗
PubMed1982

The role of parathyroidectomy in the management of hyperparathyroidism in patients on maintenance haemodialysis and after renal transplantation.

Between March 1964 and March 1980, 36 (34 dialysis, 2 transplant) of 327 patients accepted for the maintenance dialysis/transplantation programme at Charing Cross Hospital were submitted to parathyroidectomy. There were four main indications: persistent hypercalcaemia, progressive phalangeal erosions, aseptic necrosis of the femoral head and height loss with abnormal bone biopsy despite normal hand radiographs. At parathyroidectomy, 4 glands were removed in 1 patient, 3 1/2 glands in 24, 3 glands in 7, 2 glands in 3 and a single large gland in 1 patient. The operation was followed by improvement in 28 patients, no change in 5, and progression of hyperparathyroidism in 3.2 of the 28 patients who improved later relapsed and were treated with 1,25-(OH)2 vitamin D3. 4 patients were submitted to a further parathyroidectomy and improved considerably. We would conclude that, although parathyroidectomy is an effective and safe procedure, it is to be hoped that careful monitoring of bone state and early administration of 1,25-(OH)2 vitamin D3 may reduce the need for parathyroidectomy.

Adult↗
PubMed1982

Adenosine deaminase positive, E receptor negative lymphoma.

The measurement of enzymatic activity in the blast cell is a recent investigational technique which seems to complement immunologic measurement of cell membrane receptors in childhood lymphoproliferative malignancies. We have identified a patient with non-Hodgkin's lymphoma, not readily classifiable on the basis of either morphology or cell surface markers, i.e., E rosette and SIg negative, EAC positive. Analysis of enzymatic function, however, revealed markedly elevated ADA activity and essentially normal TdT activity. ADA positive lymphoma can arise from a primitive T-cell line. It is, thus, apparent that the morphological description of malignant lymphoid lines must be accompanied by surface marker and enzymatic data in order to properly classify cell lineage and identify appropriate therapeutic modalities.

Adenosine Deaminase↗