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Biomedical subjects

K D Edwards

Publications and source records attributed to K D Edwards.

At least 19 recordsLinked to original sources
PubMed1990

Pharmacokinetics and disposition of the lipid-lowering drug acifran in normal subjects and in patients with renal failure.

The pharmacokinetics and metabolic fate of the antihyperlipidemic drug acifran were assessed after a single oral dose of the 14C-labeled drug to healthy male volunteers. Peak serum acifran and radioactivity concentrations were attained 1 to 2 hours after dosing, and the drug was eliminated with a half-life of 1.6 hours. Virtually all of the recovered dose was excreted in the urine. All of the serum and urinary radioactivity was caused by unconjugated acifran. In patients with moderate chronic renal failure, the binding of acifran to plasma proteins was decreased, and the plasma concentrations of total and unbound drug were greater than those of healthy subjects. Renal failure substantially reduced the plasma and renal clearance of total and particularly of unbound acifran, moderately reduced its volume of distribution, and increased its elimination half-life from 1.4 to 1.7 hours to 5.7 hours. The results show that acifran is very well absorbed, is rapidly eliminated, is excreted in the urine, and does not undergo any detectable biotransformation in healthy human subjects.

Adult↗
PubMed1987

Acifran: a double-blind, randomized, placebo-controlled efficacy study in type IIa hyperlipoproteinemic patients.

The antihyperlipoproteinemic agent acifran (AY-25,712) was administered double-blind to 14 Type IIa hyperlipoproteinemic patients for 12 weeks in dosages of 100 mg t.i.d. or 300 mg t.i.d. An additional seven patients received placebo. Fasting plasma lipid and lipoprotein concentrations were determined at baseline (mean of 3 values), Week 8 (mean of 6- and 8-Week values), and Week 12 (mean of 10- and 12-Week values). At Week 8, patients receiving acifran 100 mg t.i.d. showed low-density lipoprotein (LDL) cholesterol levels which were 13% lower than pretreatment baseline (p less than 0.01) and 14% lower than patients given placebo (p less than 0.05); high-density lipoprotein (HDL) cholesterol levels were 11% higher compared with either baseline or the placebo group (p less than 0.05); the LDL/HDL ratio was 20% lower than baseline (p less than 0.001) and 21% lower than the placebo group (p less than 0.05); total cholesterol was 8% lower than that of the placebo group (p less than 0.05). There was no apparent relationship between changes in plasma lipid concentrations and acifran dose or treatment duration except for triglycerides, which at Week 12 were 25% lower than baseline (p less than 0.001) and 35% lower than the placebo group (p less than 0.05) only in the acifran 300 mg t.i.d. group, in which HDL-cholesterol was concurrently 18% higher compared with placebo (p less than 0.05). In this 12-week study acifran provided safe and effective treatment for Type IIa hyperlipoproteinemia.

Adult↗
PubMed1985

Controlled trial of acifran in type II hyperlipoproteinemia.

The hypolipidemic effects of acifran were evaluated in a randomized, double-blind, placebo-controlled study of 30 patients with type IIa hyperlipoproteinemia. Plasma lipid and lipoprotein values were determined at baseline (mean of three values), again after a 2-week single-blind period of acifran dosing, and at 2-week intervals during a 10-week period of double-blind drug dosing. At week 8, subjects who received the lower dose of acifran (100 mg t.i.d.) showed significantly lower levels of total and low-density lipoprotein cholesterol and triglycerides compared with their baseline levels (P less than 0.01) or the placebo group (P less than 0.05). At week 12, subjects who received the higher dose of acifran (300 mg t.i.d.) had an increase in high-density lipoprotein levels of 16% (P less than 0.01) and a decrease in the ratio of low- to high-density lipoproteins of 22% compared with their baseline levels (P less than 0.01). There were no significant differences in lipid responses between the two groups receiving acifran. Transient mild flushing and pruritus were experienced by some subjects, but no subject failed to complete the study because of drug intolerance or side effects. The safety and efficacy demonstrated in this short-term therapeutic trial justify additional long-term studies with acifran.

Administration, Oral↗
PubMed1984

Dietary influences on the hepatic mixed-function oxidase system in the rat after portacaval anastomosis.

Studies were undertaken to determine the influence of diet on the hepatic mixed-function oxidase system in rats after portacaval anastomosis. Male rats fed either a cereal-based or purified diet underwent portacaval anastomosis. Weight gain after surgery was highly dependent on the diet. Because rats fed the cereal-based diet weighed 50% less at 4-5 wk after portacaval shunt surgery than unoperated controls fed the same diet, pair-fed unoperated controls were also studied. Rats fed the purified diet grew normally after shunting and therefore studies with this diet did not require pair-fed controls. Shunted rats fed the cereal-based diet had lower liver weights, hepatic microsomal protein concentrations, ethylmorphine N-demethylase, aniline hydroxylase, and cytochromes P450 and b5 when compared with corresponding values in unoperated controls fed the same diet ad libitum; comparisons with pair-fed controls indicated that decreased intake of the cereal-based diet could account for part but not all of the changes seen after portacaval anastomosis. It was shown in rats fed the purified diet that sham operation had no effect on the mixed-function oxidase system, whereas portacaval anastomosis resulted in reduced liver weight, microsomal protein, ethylmorphine N-demethylase, aniline hydroxylase, and cytochrome P450. In comparing shunted rats fed the two types of diet, in contrast with the effects of these diets in normal rats, these hepatic microsomal mixed-function oxidase system components were generally lower in the shunted rats fed the cereal diet. It is concluded that although decreased mixed-function oxidase activity occurs after portacaval anastomosis in the rat, the diet can have an additional substantial influence. Dietary influences on drug oxidations may be an important consideration in drug therapy after portacaval anastomosis.

Aniline Hydroxylase↗
PubMed1982

Cholesterol homeotasis in rats fed a purified diet.

The rate of whole bodyb cholesterol synthesis was measured in male Sprague-Dawley rats fed either a standard chow, cereal-based diet or a semi-synthetic purified diet consisting of casein, sucrose and lard. The purified diet significantly decreased daily fecal excretion of neutral and acidic sterols, the specific acitvity of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase, the bile acid pool size, and total daily cholesterol synthesis in the rat, while increasing plasma cholesterol concentrations and the total body content of cholesterol. The increased body content of cholesterol occurred primarily in muscle and connective tissue and not in the liver. The data demonstrate the importance of quantitating the net tissue accumulatin of cholesterol for accurate measurement of daily sterol synthesis in growing animals when sterol balance measurements are used. Tissue accumulation accounted for 7% of total daily cholesterol synthesis in rats fed the cereal diet, and 20% of daily synthesis in animals fed the purified diet.

Animals↗
PubMed1980

Respiration of 14CO2 by intact animals of various species given L-[1-14C]fucose or D-[1-14C]arabinose.

The production of 14CO2 from L-[1-14C]fucose and D-[1-14C]arabinose been studied in five mammalian species. Cats, guinea pigs, mice, and rabbits respired about 22% of the label of L-[1-14C]fucose or of D-[1-14C]arabinose within 6 h after intraperitoneal injection of the sugar. Rats respired only 1.5% of the L-fucose label and 5% of the D-arabinose label in the same time period. Liver homogenates from cat, guinea pig, and rabbit produced significantly more 14CO2 from L-[1-14C]fucose or D-[1-14C]arabinose than mouse or liver homogenates. Unlike those of the other species, guinea pig liver homogenates had very low L-fucose dehydrogenase activity. The results suggest that substantial catabolism of L-fucose and D-arabinose occurs in the tissues of some animal species. Investigators wishing to employ L-fucose as a tracer of glycoprotein metabolism must, therefore, ensure that the species that they employ does not metabolize L-fucose to products interfering with their studies.

Animals↗
PubMed1979

Cholesterol homeostasis in the rat with a portacaval anastomosis.

Studies were undertaken to determine the effect of portacaval anastomosis on cholesterol homeostasis in rats fed sucrose/lard under conditions of normal body growth. Four to 6 weeks after portacaval shunt surgery, we found decreases in plasma cholesterol and triglyceride concentrations, total liver weight, and hepatic microsomal protein concentration. Measurements oof hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (EC 1.1.1.34) activity showed decreases in specific activity and total liver activity in portacaval shunt rats, but the enzyme diurnal rhythm remained. Decreased reductase activity in shunted rats was not due to an altered Km for D-HMG-COA, nor was an enzyme inhibitor found in the livers of the portacaval shunt animals. Sterol balance measurements in rats with shunts showed a 22% decrease in whole body cholesterol synthesis rate compared to controls. These metabolic studies, coupled with postmortem data, showed diminished bile acid synthesis, unchanged fecal neutral steroid excretion, and decreased net tissue accumulation of cholesterol during growth. The decreased whole body cholesterol synthesis rate ultimately led to a diminished total carcass cholesterol concentration in the rats with shunts.

Animals↗
PubMed1976

Lowering of blood pressure, plasma renin substrate, cholesterol and triglyceride by portacaval anastomosis in rats fed on a 60% sucrose/5% lard diet.

1. Portacaval anastomosis was carried out in ten rats fed on a 60% sucrose/5% lard diet, which induced moderate hypertriglyceridaemia, mild hypercholesterolaemia and normotension. 2. Plasma triglyceride was decreased to 45% of concentrations observed in ten pair-weighed control rats. 3. Plasma cholesterol concentrations were reduced to 58%, renin substrate to 70% and aortic blood pressure to 80% of control values by portacaval shunt surgery. 4. Individual blood pressures were directly related to plasma renin substrate concentrations.

Animals↗
PubMed1976

Increased prevalence of coronary heart disease in analgesic nephropathy: relation to hypertension, hypertriglyceridemia and combined hyperlipidemia.

The prevalence of coronary heart disease (58%) in 43 patients with analgesic nephropathy with moderate to severe chronic renal failure was significantly higher than in the general population of the same age and sex. Mean serum triglyceride concentration and mean diastolic blood pressure were significantly higher in the group with coronary heart disease (214 mg/dl and 102 mm Hg, respectively) than in the group without it (162 and 94). Serum triglyceride values correlated inversely with GFR, indicating that hypertriglyceridemia was largely due to associated chronic renal failure; a specific effect of analgesic abuse on prevalence of heart disease, noted by others, could not be assessed in the absence of GFR-matched controls. The prevalence of coronary heart disease was significantly higher (81%) in the group with combined hyperlipidemia (hypertriglyceridemia and hypercholesteremia) compared to the groups without it or with normal serum triglyceride concentrations (44 and 41%, respectively). Hypotryptophanemia (a possible cause of hyperlipidemia in the nephrotic syndrome) was present in 77% of patients.

Adult↗
PubMed1975

Depression of jejunal dipeptide transport by pyridoxine deficiency in the rat.

Three dipeptides (L-alanyl-L-alanine, beta-alanyl-L-histidine and L-prolylglycine), representative of distinctly different transport groups, and a dicarboxylic acid dipeptide (L-glutamyl-L-glutamic acid) showed a quantitatively equivalent decrease of absorption (mean difference, 12% disappearance 15 min-1 5 cm-1) from jejunal loops in vivo in pyridoxine deficient rats, compared with pyridoxine-repleted controls. Analysis of results for seven dipeptides, including three studied previously, indicated that pyridoxine deficiency caused a general or non-specific reduction in dipeptide transport, similar for all dipeptides. Decrease in dipeptide transport in vitamin deficiency ran parallel to, but was significantly less than, the decrease in amino acid transport, suggesting in theory involvement of pyridoxine in a common cellular efflux mechanism or, less likely, in the energetics of active transport.

Animals↗
PubMed1975

A study of serum and myocardial digitoxin concentrations in man during cardiac arrest.

In 22 digitalized (of a total of 39) patients studied at random by radioimmunoassay during cardiac arrest, the mean serum digoxin concentration was 2.6 (+/- 1.86, range 0.6-8.2) ng/ml, significantly higher (P less than 0.001) than the "eudigitalized" concentration (1.3 +/- 0.52, range 0.5-2.3 ng/ml) determined under carefully standardized conditions in a non-toxic population. Half of the arrest patients had serum digoxin levels in the toxic range (2.4 ng/ml or above), mainly due to significant renal failure (mean serum creatinine concentration 2.9 +/- 2.66 v. 1 +/- 0.26 mg/dl for non-toxic subjects, P less than 0.001), partly due to a higher mean daily digoxin dose (0.40 v 0.31 mg/day, P less than 0.05) and frequently associated with potent diuretic therapy (73 v 54%). A smaller fraction of digitalized patients survived, both short- (27%) and long-term (14%), than did non-digitalized subjects (35% and 26%, respectively). The mean myocardial digoxin concentration was 150 (+/- 63.3, range 52-252) ng/g with an average myocardial/serum ratio of 62.5 (range 38-91). There were significant positive correlations between the serum digoxin and left-ventricular myocardial digoxin concentration (r=0.8107, P less than 0.01) or serum creatinine concentration (r=0.4637, P less than 0.001).

Adult↗
PubMed1975

Efficacy and interactions of oxandrolone, halo-fenate and clofibrate in a factorial study on experimental acute nephrotic hyperlipidemia.

Nephrotic mixed hyperlipidemia may be associated with accelerated coronary artery disease. To investigate the response of experimental nephrotic hyperlipidemia to therapy, a 2(4) factorial study of sodium clofibrate and beta-benzalbutyrate, halofenate and oxandrolone (250, 150, 100 and 10 mg/kg/day, respectively) was carried out. Nephrotic syndrome was induced by a single i.p. injection of puromycin aminonucleoside (90 mg/kg) in 80 female white rats of average weight 160 g. Oxandrolone proved to be significantly hypotriglyceridemic in combined therapy (average fall, 38%; P less than .05), and also lowered serum total cholesterol and phospholipid concentrations (23% and 21% falls, P less than .01) and less than .05), due largely to synergistic interactions with clofibrate-like drugs. Hypocholesteremic effects (23 and 22% average falls) were also significant for halofenate (P less than .01) and clofibrate (P less than .05) . Serum triglyceride levels actually rose significantly (P less than .05) with drug combinations containing beta-benzalbutyrate. Clofibrate and its analogs (halofenate and beta-benzalbutyrate) produced significant hepatomegaly (mean responses of +18, +18 and +10%, respectively) whereas oxandrolone produced significant hepatic shrinkage (-10%)(P less than .05). Secondary effects (drug interactions) were also found; hypotriglyceridemic synergism (effects more than additive) occurred between oxandrolone and clofibrate or its analogs (P less than .05), whereas antagonism (effects less than additive) was observed within the clofibrate-like group (P less than .01 or less .05).

Animals↗
PubMed1974

Comprehensive one-day renal function testing in man.

A comprehensive one-day renal function test consisting of a single outpatient visit lasting nine hours, with a minimum of time off work or away from home, is described in detail. Although a large number of laboratory tests are performed in one day, patients usually appreciate thoroughness, and the cost is more than offset by the saving in occupancy of hospital beds and by the early and precise diagnosis of reversible aspects of renal disease. Some aspects of improved methodology, such as the sequential determination of minimum urinary pH, bicarbonate, titratable acid, ammonium, and total acid on a single sample using an automatic titrator, are given in detail. Clinical application of the comprehensive nine-hour renal function testing system is illustrated by the result sheet of a patient with analgesic nephropathy, who was shown in one day to have secondary severe renal failure (glomerular filtration rate 20% of normal for age and surface area), renal tubular acidosis of the distal gradient type (minimum urinary pH 6.20), increased urinary white cell excretion rate, hyaline casts, and absence of red cell casts, consistent with a diagnosis of analgesic nephropathy and urinary tract inflammation. Normal values with 95% range for this laboratory are also given. This testing system has been found to be very useful in investigating patients with analgesic nephropathy, renal tubular acidosis, and after renal transplantation.

Acidosis, Renal Tubular↗