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Biomedical subjects

C D Mitchell

Publications and source records attributed to C D Mitchell.

At least 55 records · Page 3Linked to original sources
PubMed1986

Does cyclophosphamide (CPM) improve survival rates in patients with solid tumors?

Cyclophosphamide (CPM) was first synthesized in 1958 by Arnold and Bourseaux as part of a program to develop new anticancer agents with fewer side effects and greater efficacy than those in existence. There are now many reports of good response rates obtained with CPM in patients with both hematological and solid malignant conditions, and it has been widely accepted as an important component of multi-drug regimens. What remains to be proven, however, is whether CPM significantly improves survival expectancy when used either alone or in combination with other agents. It should be remembered that evidence of efficacy as a single agent in terms of response rate or even complete remission may not be translated into improved survival when that agent is incorporated into a multi-drug regimen. Before a chemotherapeutic agent is evaluated as part of a multi-drug regimen there should be adequate evidence of efficacy against the relevant tumor. In addition, the agent must be used at a dosage that has been established as adequate. Despite these safeguards, it is not necessarily true that the addition of the drug either alone or as part of a multi-drug regimen will improve survival. Further use of the agent alone or in combination would then be illogical, just as it would be to use agents that have been shown to be ineffective, or to use an agent at too low a dose. The purpose of this article is to review the accumulated experience with CPM in both adult and pediatric oncology in the treatment of solid tumors with the above considerations in mind.

Adult↗
PubMed1982

Multicenter collaborative trial of intravenous acyclovir for treatment of mucocutaneous herpes simplex virus infection in the immunocompromised host.

Intravenous acyclovir was evaluated in the treatment of 97 immunocompromised patients with mucocutaneous herpes simplex virus infection in a randomized, double-blind, placebo-controlled trial. Acyclovir recipients had significantly shorter periods of virus shedding (p less than 0.0002) and lesion pain (p less than 0.01), and more rapid lesion scabbing (p less than 0.004) and lesion healing (p less than 0.04). The most common adverse reaction was a low incidence of peripheral vein irritation; no serious toxicity could be definitely attributed to acyclovir treatment even in these seriously ill patients. Intravenous acyclovir offers both safe and effective treatment for mucocutaneous herpes simplex virus infection in the immunocompromised host.

Acyclovir↗
PubMed1981

Early changes in phosphatidylinositol and arachidonic acid metabolism in quiescent swiss 3T3 cells stimulated to divide by platelet-derived growth factor.

We added platelet-derived growth factor to cultures of quiescent Swiss 3T3 cells to investigate early changes in lipid metabolism related to initiation of cell cycle traverse. In a series of experiments that focused on lipid degradation we added the growth factor to cells that had been prelabeled with myoinositol, glycerol, or arachidonic acid. We observed the following mitogen-dependent effects: a decline of radioactivity in cell phosphatidylinositol within 2 to 5 min that progressed to 25 to 50% during the 1st h, a transient rise of radioactivity in cell diacylglycerol that peaked at 10 min, a gradual increase of radioactivity in monoacylglycerol in the medium, and a concomitant increase of radioactivity in medium-free fatty acid. In experiments that focused on lipid biosynthesis, we added the growth factor to cells and pulse-labeled them with radioactive precursors. We observed increased incorporation within 60 min of myoinositol into phosphatidylinositol, arachidonic acid into phosphatidylinositol, diacylglycerol, and phosphatidylethanolamine, and choline into phosphatidylcholine. These results support the possibility that action of platelet-derived growth factor on Swiss 3T3 cells leads to release of diacylglycerol from phosphatidylinositol, that some of the released diacylglycerol is hydrolyzed to monoacylglycerol and arachidonic acid, and that these lipid products are in part reconverted to phosphatidylinositol and other lipids.

Animals↗
PubMed1981

Studies of the interaction between apolipoproteins A and C and triacylglycerol-rich particles.

We studied the interaction of apolipoproteins A-I, C, and HDL2 with phospholipid-stabilized, triacylglycerol-rich particles to learn more about the molecular mechanisms that underlie the metabolism of chylomicrons. Apolipoproteins A-I, C-I, C-III1 and C-III2 all bound to and destabilized triacylglycerol-rich particles, apparently by removing phospholipids from the particle surface. None of the apolipoprotein C tested, at any concentration, was, however, able to equal the disruptive effect of apolipoprotein A-I. The destabilizing effects of apolipoproteins A-I and C were not additive. Apolipoprotein C-III1 seemed to lessen the disruptive effect of apolipoprotein A-I by binding competitively to triacylglycerol-rich particles. Unexpectedly, previous binding of apolipoprotein A-I to triacylglycerol-rich particles nearly tripled the ability of these particles to bind apolipoprotein C. Destabilization of triacylglycerol-rich particles by apolipoprotein A-I was prevented by HDL2. The protective effect of HDL2 seemed to depend partly on transfer of unesterified cholesterol from HDL2, since the amounts of unesterified cholesterol and apolipoprotein A-I bound to the particles surface showed a strong negative correlation.

Apolipoproteins↗
PubMed1981

Acyclovir therapy for mucocutaneous herpes simplex infections in immunocompromised patients.

11 of 24 immunocompromised patients with mucocutaneous herpes simplex virus (HSV) infections were given intravenous acyclovir in a randomised double-blind placebo-controlled study. Patients receiving acyclovir experienced no major adverse effects. The median times to cessation of new lesion formation, lesion crusting, lesion healing, cessation of pain, and termination of viral shedding were shorter in the acyclovir-treated group than in the placebo group. The time-to-event probability curves for the acyclovir and placebo groups were significantly different for cessation of pain (p=0.032) and termination of viral shedding (p=0.004). The median times to termination of viral shedding were also statistically different (p=0.045). Acyclovir seems to be a non-toxic and effective treatment for mucocutaneous HSV infections in immunocompromised patients.

Acyclovir↗
PubMed1980

In vitro effects of lecithin:cholesterol acyltransferase on apolipoprotein distribution in familial lecithin:cholesterol acyltransferase deficiency.

Action of LCAT on the plasma of patients afflicted with familial LCAT deficiency shifts the distribution of C apolipoproteins from lipoproteins of d less than 1.019 g/ml to lipoproteins of d greater than 1.109 g/ml, and causes an opposite shift in the distribution of apolipoprotein E. The altered distribution of apolipoprotein E appears to depend primarily on enzyme-related effects on HDL. Loss of apolipoprotein E from HDL occurs as cholesteryl esters are formed and transfer to other lipoproteins; disc-shaped HDL, rich in apolipoprotein E, are converted into spherical particles; and the population of HDL as a whole is converted first into particles the size of HDL2 and HDL3 and then into intermediate-sized particles. Transfer of apolipoprotein E to artificially prepared triglyceride-rich particles occurs at a nearly linear rate that is slow than the rates of formation and transfer of cholesteryl esters or the rate of formation of "HDL2" and "HDL3." Transfer of apolipoprotein E is faster, however, when the patients' disc-shaped HDL are incubated with triglyceride-rich particles in the presence of normal plasma lipoproteins of d greater than 1.063 g/ml. Since the disc-shaped HDL, rich in apolipoprotein E, resemble particles reported to be released from perfused rat livers, they may be nascent lipoproteins of hepatic origin. If so, it appears that action of LCAT on these lipoproteins may be one of the factors that regulates the content of apolipoprotein E in VLDL.

Apolipoproteins↗
PubMed1980

Characterization of apolipoprotein E-rich high density lipoproteins in familial lecithin:cholesterol acyltransferase deficiency.

We have isolated and charachterized a subfraction of high density lipoproteins, rich in apolipoprotein E, from the plasma of patients afflicted with familial lecithin:cholesterol acyltransferase deficiency. Prepared by successive ultracentrifugal flotation, affinity chromatography on heparin-agarose, and affinity chromatography on conconavalin A-agarose, the subfraction contained disc-shaped lipoproteins that measured 14--40 nm in diameter and 4.4--4.5 nm in thickness. The major components were apolipoprotein E, phosphatidylcholine, and unesterified cholesterol, though other apolipoproteins and lipids were present in small amounts. A second subfraction of high density lipoproteins, isolated during the chromatography, contained apolipoproteins A-I and A-II, but no apolipoprotein E. This subfraction included disc-shaped lipoproteins, 13--24 nm in diameter, as well as small round particles, 5.7 nm in diameter. Both subfractions contained similar proportions of total protein relative to lipid, similar amounts of unesterified cholesterol relative to phosphatidylcholine, and a similar distribution of phosphatidylcholine fatty acid.

Adult↗
PubMed1980

Abnormalities in lipoproteins of d < 1.006 g/ml in familial lecithin:cholesterol acyltransferase deficiency.

Studies of different sized lipoproteins of d < 1.006 g/ml from patients with familial lecithin:cholesterol acyltransferase deficiency have yielded new evidence of abnormalities in this lipoprotein class. Lipoproteins of all sizes contain high amounts of unesterified cholesterol, low amounts of total protein, and particularly low amounts of apolipoproteins C-II and C-III. Lipoproteins 60 nm in diameter or larger include particles that show a notched appearance upon electron microscopy, and contain a) a high combined volume of phospholipid, unesterified cholesterol, and protein; b) high amounts of cholesteryl ester and apolipoproteins C-I and E, and c) two major tetramethylurea-insoluble proteins that can be separated by electrophoresis in the presence of sodium dodecylsulfate. In contrast, lipoproteins that are 40 nm in diameter or less appear to contain low amounts of cholesteryl ester, normal amounts of apolipoproteins C-I and E, and a single tetramethylurea-insoluble protein the size of that in control lipoproteins. Since these abnormalities occur in the lipoproteins of four different patients from four different families, they are probably effects of the enzyme deficiency. Most, however, appear to arise indirectly because in vitro experiments published earlier indicate that few are reversed by incubation in the presence of the enzyme and patient high density lipoproteins.

Adult↗
PubMed1975

Plasma lipoproteins in familial lecithin: cholesterol acyltransferase deficiency: effects of dietary manipulation.

To study the metabolism of the abnormal plasma lipoproteins in familial lecithin:cholesterol acyltransferase deficiency we performed five dietary experiments designed to perturb their distribution and composition. Four patients with the disease were given successive diets that differed in triglyceride, carbohydrate, or cholestrol content, and after each dietary period the lipoproteins were analyzed by combinations of preparative and analytical ultracentrifugation, gel filtration, chromatography, and disc gel electrophorsis. Lowering the intake of long chain, dietary triglyceride descreased the concentrations of the large very low density lipoproteins, the large and intermediate low density lipoproteins, and the small high density lipoproteins by as much ad 79 %, but either increased or did not change the concentrations of the small very low and low density lipoproteins. Re-adding long chain triglycerdine to the diet generally reversed these effects, but increasing the dietary cholesterol without lowering the dietary triglyceride only decreased the concentration of plasma cholesteryl ester. We conclude that the concentrations of the large very low and low sensity lipoproteins, the intermediate-sized low density lipoproteins, and the small high density lipoproteins are related to the absorption and subsequent transport of long chain dietary fatty acids. Since these lipoproteins are rich in unesterified cholesterol and lecithin, two polar lipids that form a substantial part of the surfaces of chylomicrons, components of chylomicron surfaces may accumulate in the patient's plasma following enzymic removal of chylomicron triglyceride and contribute to several of the abnormal lipoproteins.

Acyltransferases↗
PubMed1975

Plasma lipoproteins in familial lecithin: cholesterol acyltransferase deficiency: effects of incubation with lecithin: cholesterol acyltransferase in vitro.

To study the effect of lecithin: cholesterol acyltransferase (LCAT) on the plasma lipoproteins of patients with familial LCAT deficiency, whole plasma or the lipoprotein fraction of d smaller than 1.006 g/ml (VLDL) was incubated in the presence of LCAT and subsequently examined by chemical, physical, and immunological techniques. The following occured upon incubating either hyperlipemic or nonlipemic plasma: The concentrations of polar lipids decreased, particulary in the large molecular weight lipoprotein subfraction of d 1.019-1.063 g/ml (LDL2) and in the lipoprotein fraction of 1.06301.25 g/ml (HDL). The concentration of cholesteryl ester (CE) increased, particularly in the VLDL and in the lipoprotein fractions of d 1.006-1.019 g/ml (LDL1) and LDL2. The concentration of arginine-rich apolipoprotein decreased in the HDL and increased in the VLDL and LDL1. The concentrations of the C-apoliproteins appeared to change in the opposite direction. The concentration of apolipoprotein B in the LDL increased concomitantly with an increase in the concentration and flotation rsate of the small LDL2. The concentration apolipoprotein A-I in the HDL increased; and a major component in the HDL fraction became identical in apperance to normal HDL. Upon incubating a patient's isolated VLDL in the presence of LCAT, lipoproteins with properties similar to normal LDL2 were formed. These experiments show that the LCAT reaction can alter the apolipoprotein content and physical properties as well as the lipid content of the patient's lipoproteins.

Acyltransferases↗