Metabolism In Healthy Volunteers Research Articles

Exercise metabolism in healthy volunteers taking celiprolol, atenolol, and placebo.

OBJECTIVE: Previous studies have shown that beta 1 selective agents have fewer adverse effects on exercise metabolism than nonselective beta blockers, and this has been attributed to their reduced blockade...

Influence of low dose prednisone on bone metabolism in healthy volunteers

Influence of low dose prednisone on bone metabolism in healthy volunteers

Physiologic hyperinsulinemia stimulates protein synthesis and enhances transport of selected amino acids in human skeletal muscle.

We have investigated the mechanisms of the anabolic effect of insulin on muscle protein metabolism in healthy volunteers, using stable isotopic tracers of amino acids. Calculations of muscle protein synthesis, breakdown, and amino acid transport were based on data obtained with the leg arteriovenous catheterization and muscle biopsy. Insulin was infused (0.15 mU/min per 100 ml leg) into the femoral artery to increase femoral venous insulin concentration (from 10 +/- 2 to 77 +/- 9 microU/ml) with minimal systemic perturbations. Tissue concentrations of free essential amino acids decreased (P < 0.05) after insulin. The fractional synthesis rate of muscle protein (precursor-product approach) increased (P < 0.01) after insulin from 0.0401 +/- 0.0072 to 0.0677 +/- 0.0101%/h. Consistent with this observation, rates of utilization for protein synthesis of intracellular phenylalanine and lysine (arteriovenous balance approach) also increased from 40 +/- 8 to 59 +/- 8 (P < 0.05) and from 219 +/- 21 to 298 +/- 37 (P < 0.08) nmol/min per 100 ml leg, respectively. Release from protein breakdown of phenylalanine, leucine, and lysine was not significantly modified by insulin. Local hyperinsulinemia increased (P < 0.05) the rates of inward transport of leucine, lysine, and alanine, from 164 +/- 22 to 200 +/- 25, from 126 +/- 11 to 221 +/- 30, and from 403 +/- 64 to 595 +/- 106 nmol/min per 100 ml leg, respectively. Transport of phenylalanine did not change significantly. We conclude that insulin promoted muscle anabolism, primarily by stimulating protein synthesis independently of any effect on transmembrane transport.

Lack of effect of phenobarbital on ex vivo leukocyte oxidative metabolism in healthy volunteers.

Oxidative metabolism in activated human polymorphonuclears catabolizes leukotriene B4 by a cytochrome P450 omega-hydroxylase and procainamide by a myeloperoxidase. The percentage of leukotriene B4 metabolized by activated human polymorphonuclears and the apparent enzymatic parameters of procainamide metabolism were studied ex vivo in six healthy volunteers before and after phenobarbital intake (100 mg/day) for 10 days and in six healthy control volunteers. No differences were found between groups for the difference in percentage of leukotriene B4 metabolized between day 11 and day 1. The apparent enzymatic parameters, Km and Vm, of procainamide oxidation did not differ significantly between the groups both on day 1 and day 11. These results do not show any evidence of inducibility of leukotriene B4 and procainamide metabolism in human polymorphonuclears. However, a positive correlation between 6 beta OH-cortisol excretion and percentage of leukotriene B4 metabolized was observed on day 11. This study suggests that human polymorphonuclears cytochrome P450 leukotriene B4 omega-hydroxylase and procainamide metabolism is not a useful method to study cytochrome P450 induction in clinical pharmacology.

The effect of ketanserin on cerebral blood flow and oxygen metabolism in healthy volunteers.

The effect of the anti-hypertensive agent ketanserin on average global cerebral blood flow (CBF) and average global cerebral oxygen metabolism (CMRO2) was examined in 8 healthy volunteers. CBF and CMRO2 were measured with the Kety-Schmidt technique before ketanserin administration (baseline) and after administration of 2 different doses of ketanserin intravenously (dose I: 10 mg bolus and an infusion of 6 mg/h; dose II: 20 mg bolus and an infusion of 20 mg/h). Baseline CBF and CMRO2 were 60 and 3.6 ml/100 g/min, respectively, and were not changed by administration of ketanserin dose I. During administration of dose II, however, CBF fell to 52 ml/100 g/min (p = 0.05) and CMRO2 was reduced to 3.2 ml/100 g/min (p < 0.05). We conclude that when administered in a high dose, ketanserin has the ability to depress cerebral oxygen metabolism, but when administered in a clinically relevant dose ketanserin does not influence average global CBF or average global CMRO2. Ketanserin could be a safe antihypertensive drug in neuroanaesthesia or in the neuro-intensive care unit.

The effect of human growth hormone on metabolism in healthy volunteers given a normal diet

The effect of human growth hormone on metabolism in healthy volunteers given a normal diet

Differential Effects of Inhaled Budesonide and Oral Prednisolone on Serum Osteocalcin*

Inhaled glucocorticosteroids have been developed for the treatment of asthma in an attempt to minimize the suppression of endogenous adrenal function that complicates oral or injected steroid usage, but it is unclear whether this strategy leads to reduced systemic complications in other areas, such as the skeleton. In this study we evaluated serum osteocalcin levels as a marker of skeletal metabolism in healthy volunteers treated with oral and inhaled steroids alone and in response to an oral calcitriol stimulation test. Forty subjects, aged 33 +/- 9 (mean +/- SD) yr were randomized to receive either high or low dose oral prednisolone (40 vs. 10 mg/day) or inhaled budesonide (3.2 vs. 0.8 mg/day). Each dose of budesonide is known to have a greater antiasthmatic potency than the dose of prednisolone with which it was compared. In addition 10 control subjects received placebos containing no active steroid drugs. During the second week of treatment, half of the subjects in each of the 4 steroid-treated groups and all subjects in the control group received oral calcitriol (2.0 micrograms/day). There was a marked dose-dependent reduction in serum cortisol levels, but this reduction was significantly less pronounced during budesonide treatment, such that low dose budesonide was without effect. During the first week of steroid therapy there were significant dose-dependent reductions in serum osteocalcin (P = 0.003), but this reduction was not significantly different between budesonide and prednisolone treatments. In response to calcitriol, serum osteocalcin increased by 35% in the control group (P = 0.06). Osteocalcin levels increased by 56% and 50% in the low dose budesonide and prednisolone groups and by 106% in the high dose budesonide group, but did not change in the high dose prednisolone group. The osteocalcin response to calcitriol was significantly higher in the budesonide groups (P = 0.03, by analysis of variance). High dose prednisolone caused increases in serum 1,25-dihydroxyvitamin D3 (P less than 0.02), urinary calcium excretion (P = 0.07), and urinary hydroxyproline (P less than 0.01). None of these changes was seen during budesonide therapy. There are as yet no data for these variables after long term use of inhaled budesonide in asthmatic patients, but our acute studies suggest that this potent topical glucocorticoid may have considerably less impact on the skeleton than oral prednisolone, even if used at doses high enough to suppress endogenous adrenal function.

Effect of a Single Infusion of Aminohydroxypropylidene on Calcium and Bone Metabolism in Healthy Volunteers Monitored during 2 Months

Recently, bisphosphonates have been used to prevent postmenopausal bone loss. As the effects of bisphosphonates on normal bone metabolism are unknown, 3-amino-1-hydroxypropylidene-1,1-diphosphonate (APD) was studied in healthy subjects. The effects of a single 20-mg APD infusion on biochemical parameters of calcium and bone metabolism were investigated during 2 months in 10 healthy male volunteers. This single moderate dose of APD reduced biochemical parameters of bone resorption during the time of follow-up. After 2 months, urinary hydroxyproline excretion was still below the basal level. The decreased serum calcium levels did not return to basal values. Biochemical parameters of bone formation, serum alkaline phosphatase and osteocalcin, showed a slight increase during the first month after stimulation of the parathyroids and a corresponding increase in serum 1,25-dihydroxyvitamin D. These formation parameters decreased thereafter, probably representing coupling between bone resorption and bone formation.

Physiological variations in blood ethanol measurements during the post–absorptive state

Specimens of arterial plasma and venous whole blood were obtained at 3-10 min intervals during the post-peak phase of ethanol metabolism in healthy volunteers. The concentrations of ethanol in blood and plasma were determined by headspace gas chromatography. This method had a standard deviation of 0.28 mg/dl for whole blood and 0.26 mg/dl for plasma and the coefficients of variation were 0.43% and 0.79% respectively. The physiological variation from time-to-time, expressed as the residual standard deviation after fitting the ethanol concentration-time regression relationships, ranged from 0.43-3.7 mg/dl (0.65-16%). The time-to-time variations in concentrations of ethanol were maximum when there were problems in getting an unimpeded flow of blood through the indwelling catheters. The results do not support the existence of sporadic fluctuations or spiking in the blood alcohol concentration-time profile during the post-absorptive state. Instead, this study underscores the need to control carefully the method of sampling blood and in this way keep pre-analytical sources of variation to a minimum.

Comparative effects of quinine and quinidine on glucose metabolism in healthy volunteers.

1. To investigate the relative effects of quinine and quinidine on glucose metabolism, 11 healthy males aged 17-32 years were given three separate 1 h intravenous infusions; normal saline alone, quinine dihydrochloride 10 mg base kg-1 body weight (BW) in normal saline, and quinidine dihydrochloride 10 mg base kg-1 BW in normal saline. A constant infusion of 5 mg glucose kg-1 ideal BW min-1 was given for 1 h before and during each study. 2. Assessment of pancreatic beta cell function and tissue insulin sensitivity from plasma glucose and insulin concentrations at the end of the first hour using the Continuous Infusion of Glucose with Model Assessment (CIGMA) technique confirmed normal glucose tolerance for each subject on each test day. 3. Plasma glucose concentrations at 1 h were similar to those at 2 h. There was no significant difference between the plasma glucose profiles during the three infusion regimes (P greater than 0.05). Plasma insulin rose significantly during the second hour (P less than 0.0001); increments after quinine (geometric mean [-1 s.d- +1 s.d.]; 47.0 [27.8-79.4] mu l-1) were significantly greater than those after quinidine (19.8 [6.1-65.2] mu l-1) and saline (7.5 [0-21.5] mu l-1; P less than 0.05). Plasma quinine concentrations at the end of the infusion (6.5 +/- 4.4 mg l-1) correlated with insulin increments during the second hour (r = 0.662, P = 0.028) and were significantly greater than those of quinidine (3.0 +/- 0.8 mg l-1; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of acute and prolonged treatment with propranolol on cerebral blood flow and cerebral oxygen metabolism in healthy volunteers

The effect of acute and long-term treatment with propranolol on cerebral blood flow (CBF) and the cerebral metabolic rate of oxygen (CMRO2) has been studied in 8 young healthy volunteers. CBF was measured by 133Xe-inhalation and single photon emission computer tomography, and CMRO2 was calculated from the arterio-venous oxygen difference and CBF. Studies were done before and 1 h after i.v. injection of 5 mg propranolol and after three weeks on oral propranolol 80 mg/d for 1 week and 160 mg/d for 2 weeks. Cerebrovascular CO2 reactivity in terms of the A-V oxygen difference was tested on all three occasions during hypercapnia and hyperventilation. CBF, CMRO2 and cerebrovascular CO2 reactivity remained stable both after acute and after 3 weeks of treatment with propranolol.

Effects of taprostene, a stable prostacyclin analogue, on haemodynamics, platelet function and arachidonate metabolism in healthy volunteers

In order to assess the effect of taprostene on haemodynamics, platelet function and arachidonate metabolism in 4 healthy volunteers an intravenous infusion of 25 ng.kg-1.min-1 was given for 6 h. During the infusion period systolic blood pressure dropped from 130 to 111 mm Hg and diastolic blood pressure from 77 to 69 mm Hg. The heart rate rose from 77 to 84 beats/min. During the taprostene infusion the slope and height of the ADP and collagen induced platelet aggregation curves were significantly inhibited and the sensitivity of platelets to PGI2 and PGE1 was increased. Plasma and serum thromboxane B2, conversion of exogenous radiolabelled arachidonic acid, WU-test, circulating endothelial cell count, concentration of platelet factor 4, beta-thromboglobulin, malondialdehyde and the PGI2-synthesis stimulating plasma factor did not show any clear drug-related alteration. It is concluded that infusion of taprostene 25 ng.kg-1.min-1 caused measurable inhibition of platelet function ex vivo.

Nicotine gum and theophylline metabolism

When cigarette smokers with chronic lung disease stop smoking, they may do so with the aid of chewing nicotine gum. Smoking is known to accelerate the metabolism of theophylline, but the effects of nicotine gum on theophylline metabolism have not been determined. We studied the effects of nicotine and placebo gum on theophylline metabolism in healthy volunteers. Clearance of theophylline decreased by 32 % after cessation of smoking in comparison to while chewing placebo gum. Clearance while chewing nicotine gum was similar to that measured while chewing placebo gum. Nicotine gum appears to have no effect on theophylline metabolism. For smokers who are chronically taking theophylline, the dose of theophylline will need to be reduced by one-fourth to one-third after smoking cessation and initiation of nicotine gum use.

Reduction of postprandial triglyceridemia in humans by dietary n-3 fatty acids

Long chain n-3 fatty acids present in fish oils have been shown to reduce fasting plasma triglyceride and very low density lipoprotein levels in normal and hyperlipidemic human subjects. The present studies were designed to examine whether dietary n-3 fatty acids influence chylomicron formation and metabolism in healthy volunteers. In the first study seven subjects were fed either saturated fat, vegetable oil, or fish oil-based diets for 4 weeks each, and test meals containing 50 g of the background fat were administered after the second week of each diet. The postprandial rise in triglyceride levels was significantly lower following the fish oil test meal as compared to the saturated fat or vegetable oil test meals. In the second study, six subjects eating their usual home diets were given two fat tolerance tests. The first contained saturated fat and the second, given 1 week later, contained fish oil. There was no difference in the postprandial triglyceride response between the fish oil and the saturated fat meals. A third study was then conducted with eight volunteers in which saturated fat and fish oil test meals were administered during saturated fat and fish oil background diets in a crossover design. The presence of fish oil in the background diet reduced postprandial lipemia regardless of the type of fat in the test meal. Although there was no effect of the fish oil diet on the lipoprotein lipase and hepatic lipase activity of postheparin plasma measured in vitro, stimulation of in vivo lipolysis was not ruled out. Our results suggest that chronic (but not acute) intake of fish oil may inhibit the synthesis or secretion of chylomicrons from the gut. However, accelerated clearance due to decreased VLDL competition cannot be excluded.

Effect of alcohol intake on high and low density lipoprotein metabolism in healthy volunteers

To determine the effect of moderate doses of ethanol on lipoprotein metabolism, the kinetics of [ 115I]high density apolipoprotein (Apo) A-I and [ 131I]low density Apo B were examined in 9 normal volunteers before and after regular intake of 60–70 g of ethanol/day. Plasma levels of Apo B and Apo A-I were significantly increased but remained in the normal range. Mean synthesis of Apo A-I and B were increased, respectively, from 12.6 and 13.7 mg/kg per day in the absence of ethanol to 18.8 and 17.1 mg/kg/day after 2 wk of ethanol intake. Fractional catabolic rates for Apo A-I and B increased respectively from 0.204 and 0.340 in the period without ethanol to 0.266 and 0.372 after ethanol. These findings indicate that despite rather moderate increase in both Apo plasma levels, ethanol produced profound alterations in their metabolism, namely increased turnovers.

Distribution and metabolism in healthy volunteers of disodium azodisalicylate, a potential therapeutic agent for ulcerative colitis.

A series of experiments has been performed in healthy male volunteers to investigate the disposition of orally administered disodium azodisalicylate, a potentially useful drug for the treatment of ulcerative colitis. The drug was given by mouth in doses of up to 2 g a day for six weeks and there were no adverse effects. Serum concentrations of the intact compound were low and the serum half-time was 4-12.8 days, probably because of a combination of a low clearance rate and a high apparent volume of distribution. Less than 5% of the ingested dose was excreted unchanged in the urine. Circulating concentrations of 5-ASA and N-acetyl-5-ASA were low and 30% of the equivalent daily dose was excreted in the urine, predominantly as N-acetyl-5-ASA. In most subjects more than 30% of the equivalent daily dose of 5-ASA was recovered from the faeces, either as 5-ASA itself or as the acetylated derivative. As 5-ASA has been shown to be the active therapeutic moiety of sulphasalazine, disodium azodisalicylate appears to be suitable for therapeutic trial in ulcerative colitis.

Study on Effect of 30 μg Ethinylestradiol (Ee)+150 μg Desogestrel on Lipid and Lipoprotein Metabolism in Healthy Volunteers, Also in Comparison with 30 μg Ee + 150 μg Levonorgestrel

Abstract. In a cross‐over design study, 15 healthy young volunteers were randomly allocated an oral contraceptive containing 30 μg EE. Preparation A contained in addition 150 μg of a new progestogenic compound, desogestrel, and preparation B 150 μg levonorgestrel. Subjective side effects were few during use of any of the preparations.Preparations A and B induced similar changes in most of the serum lipid and lipoprotein‐lipid parameters. Body weight, triglycerides, VLDL‐triglycerides and LDL‐free cholesterol, total cholesterol and triglycerides were significantly lower and HDL‐total cholesterol and triglycerides significantly higher with preparation A than preparation B.The relative fatty acid composition of lecithin revealed with preparation B (as compared with preparation A), higher levels of palmitic and linoleic acids which could be interpreted as an enhancement of pathway I for liver lecithin synthesis which in turn is usually coupled to a reduced capacity of liver excretory function.The present data regarding preparation B are in agreement with those reported by others, while preparation A has not been studied before. The differences observed between preparation A and B are ascribed to the more marked androgen‐like effects of preparation B.

Alterations of lipid metabolism in healthy volunteers during long-term ethanol intake.

Nine young, healthy male volunteers were given ethanol (75 g/day) for 5 weeks. The ethanol was divided into five daily doses and taken so that blood ethanol levels never exceeded 0.04% (w/v). During the latter part of the ethanol intake period, there was a significant, transient increase of plasma triglyceride (TG) concentrations followed by reduction to normal levels. A three-fold increase of lipoprotein lipase activity (LLA) occurred in biopsy specimens of adipose tissue. An increase of alpha-lipoprotein concentrations, which correlated significantly with the decrease in plasma TG levels and the increase in adipose LLA, was also observed during the ethanol intake period. No changes were observed in plasma cholesterol and beta-lipoprotein levels. A transient, three-fold increase of TG concentrations occurred in liver biopsy specimens. Ultrastructural and cytochemical examinations of the biopsy specimens showed hyperplasia of the smooth endoplasmic reticulum, and increased canallicular activity of gamma-glutamyl transferase (gamma-GT) activity in most subjects towards the end of and after the ethanol intake period. Serum gamma-GT levels also increased significantly.