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Biomedical subjects

B Morton

Publications and source records attributed to B Morton.

At least 19 recordsLinked to original sources
PubMed1996

Fish oils and low-molecular-weight heparin for the reduction of restenosis after percutaneous transluminal coronary angioplasty. The EMPAR Study.

BACKGROUND: Percutaneous transluminal coronary angioplasty (PTCA) is complicated by restenosis within 6 months in > 40% of patients. Theoretical, animal experimental, and human epidemiological and clinical trial findings have suggested that fish oils (n-3) might reduce restenosis. Low-molecular-weight heparin (LMWH) has reduced cellular proliferation and restenosis in several experimental systems. METHODS AND RESULTS: We randomized 814 patients to fish oils (5.4 g n-3 fatty acids) or placebo a median of 6 days before PTCA and continued for 18 weeks. At the time of sheath removal, 653 patients with at least one successfully dilated lesion were randomized to LMWH (30 mg SC BID) or control for 6 weeks in a 2 x 2 factorial design. Follow-up with quantitative coronary angiography (QCA; target, 18 weeks) was interpretable on 96% of these patients. Restenosis rates per patient were for n-3, 46.5%; placebo, 44.7%; LMWH, 45.8%; and control, 45.4%. Restenosis rates per lesion were for n-3, 39.7%; placebo, 38.7%; LMWH, 38%; and control, 40.4%. At follow-up QCA, mean minimal lumen diameters were (mm) for n-3, 1.12; placebo, 1.10; LMWH, 1.12; and control, 1.10. Fifteen percent of patients permanently discontinued n-3/placebo before study completion, and 21% of patients discontinued LMWH early. There were no significant differences in the occurrences of ischemic events. Bleeding was more common with LMWH, usually was mild, and led to early discontinuation of study medication in only 0.9% of patients. Gastrointestinal side effects were more common in patients receiving n-3 than placebo. CONCLUSIONS: There is no evidence for a clinically important reduction of PTCA restenosis in this trial by either n-3 or LMWH. Evaluation of the results for n-3 in the context of previously published data on the reduction of PTCA restenosis indicates that n-3 is not efficacious and that further trials are unwarranted.

Adult↗
PubMed1996

Merkel cell cancer: is prophylactic lymph node dissection indicated?

Our objective was to determine prognostic factors and the role of prophylactic lymph node dissection in Merkel cell cancer. A retrospective chart review of 15 patients from Loma Linda University Medical Center, Loma Linda, and Kaiser Permanente, Fontana, was used. The most important predictor of survival was presence of lymph node metastasis (P = 0.03). Lymph node metastasis was the first sign of recurrence in 60 per cent of patients and preceded distant metastasis. Age at presentation, tumor size, and location had no influence on survival. Gross presurgical determination of tumor extent was misleading. Microscopically positive margins necessitated reexcision in 60 per cent of patients. Local recurrence occurred in 27 per cent of patients. Recurrence at lymph node basins was lower in patients with elective lymph node dissection (0%) compared with therapeutic node dissection (57%)(P < 0.05). Incidence of micrometastases in patients undergoing prophylactic lymph node dissection was 100 per cent. No difference in survival was seen between prophylactic and therapeutic node dissection. Because Merkel cell cancer spreads in a "cascade" fashion, elective node dissection may provide a chance for a cure. Elective node dissection provides better locoregional control compared with therapeutic node dissection and helps to determine prognosis.

Aged↗
PubMed1995

Synthesis, topoisomerase I inhibitory activity, and in vivo evaluation of 11-azacamptothecin analogs.

A series of analogs based on a novel template, 11-aza-(20S)-camptothecin, were obtained from total synthesis and tested as potential anticancer drugs in the topoisomerase I enzyme cleavable complex assay. The parent compound 11-aza-(20S)-camptothecin (8) was derived from a Friedlander condensation between the known aminopyridine derivative 3-(3-amino-4-picolylidene)-p-toluidine and optically active tricyclic ketone 7. Compound 8 had activity approximately twice that of (20S)-camptothecin in the calf thymus topoisomerase I cleavable complex assay. Compounds were prepared wherein the 11-aza nitrogen atom was quaternized as either the corresponding N-oxide or methyl iodide. Compounds with quaternized N-11 showed improved water solubility and were equipotent to the clinically investigated camptothecin analog topotecan in the cleavable complex assay. These compounds were evaluated in vivo in nude mice bearing HT-29 human colon carcinoma xenografts. The analog 11-aza-(20S)-camptothecin 11-N-oxide was found to significantly retard tumor growth when compared to untreated controls. Finally, 7,10-disubstituted 11-azacamptothecin analogs were synthesized using Pd(0) coupling reactions of 10-bromo-7-alkyl-11-aza-(20S)-camptothecins 19 and 20, which in turn were available from a Friedlander condensation of the novel bromopyridine derivatives 17a and 17b with 7. Among the 10-substituted series, a number of analogs displayed extremely high in vitro potency against topoisomerase I and improved aqueous solubility. A significant number of the compounds were found to be active in whole cell cytotoxicity assays and several were evaluated in nude mice bearing the HT-29 tumor xenografts. The most effective of these proved to be (S)-11-aza-7-ethyl-10-(aminohydroximinomethyl)camptothecin trifluoracetic acid salt (27), a potent topoisomerase I inhibitor which demonstrated excellent efficacy in both short term and in extended in vivo assays. A comparison between in vitro enzyme data and in vivo data from nude mouse studies in other compounds in this series revealed a poor overall correlation between topoisomerase inhibition in vitro and antitumor efficacy in vivo.

Animals↗
PubMed1995

Rigid analogs of camptothecin as DNA topoisomerase I inhibitors.

Substituted 8-ethyl-2-(2-oxo-1,2-dihydroindol-3-ylidene)-8-hydroxy-2,3,5,8- tetrahydro-6-oxa-3a-azacyclopenta[b]naphthalene-1,4,7-triones were synthesized and evaluated as topoisomerase I inhibitors in an in vitro cleavable complex assay. The activity of these compounds may be attributed to their rigid, planar geometry, and an attempt was made to correlate the SAR in this series to known attributes of camptothecin.

Alkaloids↗
PubMed1995

Synthesis and antitumor activity of novel water soluble derivatives of camptothecin as specific inhibitors of topoisomerase I.

The synthesis and antitumor activities of the novel water soluble camptothecin derivatives 7-[(4-methylpiperazino)methyl]-10,11-(methylenedioxy)-(20S)-campto thecin trifluoroacetate (6) and 7-[(4-methylpiperazino)methyl]-10,11-(ethylenedioxy)-(20S)-camptot hecin trifluoroacetate (7) are described. The solubilities of compounds 6 and 7 were measured to be 4.5 and 5.8 mg/mL, respectively, in pH 5 acetate buffer in contrast to < 0.003 mg/mL for camptothecin in the same buffer. In the purified topoisomerase I cleavable complex enzyme assay, compounds 6 and 7 demonstrated potent inhibition of topoisomerase I with IC50's of 300 and 416 nM, respectively, in comparison to 679 nM for camptothecin and 1028 nM for topotecan. In human tumor cell cytotoxicity assays, compounds 6 and 7 demonstrated potent antitumor activity against ovarian (SKOV3), ovarian with upregulated MDRp-glycoprotein (SKVLB), melanoma (LOX), breast (T47D), and colon (HT29) with IC50's ranging from 0.5 to 102 nM. Compounds 6 and 7 induced tumor regressions in the HT29 human colon tumor xenograft model and demonstrated similar rank order of potency compared to in vitro assay results.

Animals↗
PubMed1995

Assessment of agonist- and cell-mediated responses in airway microsections by computerized videomicrometry.

The objective of this investigation was to develop a method for real-time measurement of changes in luminal area in microexplants of airways during pharmacological and physiological interventions. After guinea pigs were killed, tracheal rings (1- to 2-mm thick) were excised and placed in 300-microliters chambers. The area of the airway lumen was calculated as pixel number with the use of computerized videomicrometry. In 29 epithelium-intact airways, 10(-3) M acetylcholine (ACh) caused decrease in luminal area of 38.1 +/- 2.80% (P < 0.001 vs. 10(-9) M). Spontaneous tone also was demonstrated in 34 preparations from 4 guinea pigs; decrease in area of 17.0 +/- 1.45% after 60-min incubation in buffer alone was blocked completely by 10(-5) M indomethacin (P = 0.01). Luminal narrowing caused by < or = 10(-6) M ACh was reversed completely by 10(-6) M albuterol (P = 0.002). Addition of 100,000 activated human eosinophils caused 24.7 +/- 4.41% decrease in luminal area vs. 7.24 +/- 5.51% for nonactivated cells (P = 0.048). We demonstrate a real-time method for the assessment of auxotonic changes in airway caliber that utilizes microsections of explanted airways and permits the use of extremely small numbers of isolated cells to achieve physiological activation. Concentration-response characteristics and spontaneous tone are similar to those of large chamber preparations, and narrowing is reversed by beta 2-adrenoceptor activation.

Acetylcholine↗
PubMed1992

Evidence that changes in hippocampal excitability in vitro are caused by withdrawal from chronic in vivo ethanol administration.

A complex pattern of changes in the field potentials recorded from mouse hippocampal slices, prepared after chronic ethanol treatment in vivo, has previously been demonstrated in this laboratory. In the present study, recordings from slices prepared immediately after 2 weeks of ethanol treatment, showed only an increase in paired pulse potentiation, compared with controls, whereas recordings made immediately after 16 weeks of ethanol administration showed decreases in the thresholds for single and multiple population spikes, increases in paired pulse potentiation and epileptiform activity. In hippocampal slices prepared after 24 hr withdrawal, following 16 weeks of ethanol treatment, there were no signs of hyperexcitability in the field potentials. Ratings of convulsive behaviour were increased in mice during a 12-hr period after withdrawal from 16 weeks of ethanol treatment. Corresponding behaviour ratings for the mice given ethanol for 2 weeks, or those withdrawn for 24 hr after 16 weeks ethanol treatment, were not significantly different from control values. It was concluded that epileptiform activity seen in hippocampal slices after prolonged ethanol administration may contribute to the ethanol withdrawal hyperexcitability seen in vivo.

Alcohol Withdrawal Delirium↗
PubMed1981

Bile salt-enhanced rat jejunal absorption of a macromolecular tracer.

Bile salt deconjugation may occur in the jejunum under conditions of fecal colonic overgrowth of the small intestine. We studied the effects of conjugated and deconjugated bile salts on rat jejunal absorption of a macromolecular tracer, horseradish peroxidase, in an in vivo perfusion system. At a 0.5 mM perfusion concentration, only the deconjugated bile salts, cholate and deoxycholate, produced a significant increase in horseradish peroxidase absorption into serum. At a 0.5 mM concentration of the conjugated salt, taurocholate, horseradish peroxidase-absorption was indistinguishable from that seen in bile salt-free preparations. At a higher 5 mM concentration, both the conjugated and deconjugated salts increased jejunal HRP absorption into serum over that seen in bile salt-free preparations; this absorption wa most marked with the deconjugated salts. At a 0.5 mM level, the bile salts induced minimal sodium and glucose transport alterations but did not produce evidence of morphologic damage to villi or absorptive epithelial cell organelles. At a 5 mM level, the deconjugated salts induced glucose and sodium transport abnormalities and appeared to damage cellular organelles. Our observations suggest that an alteration in the tight junctional barrier to macromolecular absorption may play a role in some of the enhanced horseradish peroxidase absorption seen with deoxycholic acid in these experiments. The process of an increased absorption of intact macromolecules induced by products of bacterial metabolism may be of pathologic significance in the etiology of immunologically related intestinal disease or in toxigenic processes.

Animals↗
PubMed1979

Pineal hydroxyindole-O-methyltransferase: mechanism, and inhibition by scotophobin A.

We had shown that the behaviorally active peptide, scotophobin A, a synthetic analogue of native scotophobin, acted to increase dark avoidance in goldfish by inhibiting pineal hydroxyindole-O-methyltransferase (HIOMT), the enzyme which converts N-acetylserotonin (NAS) to melatonin (MEL). Here we determine the reaction sequence of bovine pineal HIOMT and the mechanism whereby scotophobin A inhibits this enzyme. Initial rate studies in which the substrates NAS and the methyl donor, S-adenosylmethionine SAM), were independently varied indicated the enzyme reacted by a sequential mechanism. With the product, S-adenosylhomocysteine (SAH), included in the reaction mixtures, data were obtained consistent with the following order of substrate addition and product discharge: (see text). The turnover number was 5.7 moles melatonin formed/mole HIOMT/min. The substrate KMs were 4.2 x 10(-4) M for NAS and 4.9 x 10(-5) M for SAM. Further studies showed that scotophobin A is an inhibitor (KI = 7 x 10(-7) M) competitive with NAS, indicating that this peptide combines with the enzyme-SAM complex. The structural similarity of the tyrosinamide end of scotophobin A to NAS and several other HIOMT inhibitors, including two antischizophrenic drugs, is consistent with these observations.

Acetylserotonin O-Methyltransferase↗
PubMed1977

Myocardial infarction following coronary artery bypass: factors influencing its occurrence.

The authors have undertaken a prospective study on postoperative myocardial infarciton (PMI) following coronary artery bypass (CAB) grafting. PMI was diagnosed from electrocardiographic findings by the criteria of the American Heart Association. From Aug. 1, 1975 to Feb. 27, 1976, 198 patients (177 men, 21 women) underwent CAB. Their ages ranged from 31 to 71 years (mean, 49 yr). Of these patients, 18 (9%) sustained a PMI. A number of factors were analyzed to determine their influence on the occurrence rate of PMI. Preoperative factors wuch as the New York Heart Association classification, measurement of left ventricular function and evaluation of the severity of coronary artery disease were not helpful in predicting a predisposition to PMI. Endarterectomy was the only operative intervention associated with a higher inicidence of PMI (18%). Other factors such as the interval of cardiac anoxia and cardiopulmonary bypass and the number of vessels grafted did not seem to be associated with PMI. Low blood flow (less than 40 ml/min) through the graft could be correlated with the area of infarction in only 5 of 18 patients. Among the operated patients, postoperative ventricular arrhythmia was much more common in patients with PMI. The hospital mortality in this group was 11% (two patients).

Adult↗
PubMed1975

The isolation of large polysomes in high yield from unfractionated tissue homogenates.

It was found that if large quantities of both exogenous RNA and Mg-2+ were present during gentle tissue homogenization, the subsequent addition of deoxycholate to the whole homogenate produced a viscous mass from which polysomes could be isolated in large yields. These polysomes were substantially less degraded than those isolated by previous methods. In the case of rat liver, 15 ribosomes per mRNA was the species present in highest concentration. The parameters of this method were investigated and optimized. About 80 percent of the rRNA in the homogenates was recovered in the polysomes. Omission of deoxycholate permitted the isolation of less-degraded free polysomes as well. In the liver of fed rats these represented one-fourth of the total polysomes, in good agreement with results obtained by an independent approach. Using the method to isolate polysomes from the liver of starving rats, it was found that only about one percent of the large amount of monomers and dimers present resulted from polysome breakdown during isolation. It was further shown that random RNAase hydrolysis of polysomes could not produce the patterns of liver polysomes seen during starvation. Polysomes isolated by this procedure were quite stable in solution and were very active in cell-free protein synthesis. Application of this method without adaptation to eight other tissues also permitted the isolation of large polysomes in high yields.

Animals↗