Influence of glycemic index/load on glycemic response, appetite, and food intake in healthy humans

OBJECTIVE: High glycemic index (GI)/load (GL) diets reportedly enhance appetite and promote positive energy balance. Support for this hypothesis stems largely from acute feeding trials and longer-term studies lacking control over the macronutrient composition and palatability of test foods. This study evaluated the effects of consuming high- and low-GI/GL meals, matched on macronutrient composition and palatability, plasma glucose and insulin, appetite, and food intake. RESEARCH DESIGN AND METHODS: Thirty-nine healthy adults consumed only low- or only high-GI foods ad libitum in the laboratory for 8 days in either high (three foods per meal)- or low (one food per meal)-variety conditions. Glucose and insulin concentrations as well as appetitive sensations were determined before and for 2 h following breakfast and lunch on days 1 and 8. Energy intake was monitored daily. RESULTS: There were no significant differences in plasma glucose or insulin responses, appetitive ratings, or food intake between treatments. CONCLUSIONS: These data indicate that the differential glycemic response of foods tested in isolation under fixed time are not preserved under conditions of chronic ad libitum consumption of mixed meals.     

Fibrinolytic response to tumor necrosis factor in healthy subjects

Tumor necrosis factor (TNF) may be involved in the disturbance of the procoagulant-fibrinolytic balance in septicemia, leading to microvascular thrombosis. To assess the dynamics of the fibrinolytic response to TNF in humans, we performed a crossover saline-controlled study in six healthy men, investigating the effects of a bolus intravenous injection of recombinant human TNF (50 micrograms/m2) on the stimulation and inhibition of plasminogen activation as well as on plasmin activity and inhibition. TNF induced a brief fourfold increase in the overall plasma plasminogen activator (PA) activity peaking after 1 h (p less than 0.0001), which was associated with rises in the antigenic levels of urokinase-type plasminogen activator (p less than 0.0001) and tissue-type plasminogen activator (p less than 0.0001). Plasminogen activator inhibitor type I antigen remained unchanged in the first hour, but showed a rapid eightfold increase thereafter (p less than 0.0001), which coincided with the decrease in PA activity. Generation of plasmin activity in the first hour was signified by an 11-fold rise in D-dimer levels (p less than 0.0001); inhibition of plasmin was reflected by a 36-fold rise in plasmin-alpha 2 antiplasmin complexes (p less than 0.0001), as well as by a transient 16% decrease in alpha 2-antiplasmin activity (p less than 0.01). In conclusion, TNF induced an early activation of the fibrinolytic system becoming maximal in 1 h, with a rapid inhibition thereafter. Earlier observations in the same subjects showed sustained coagulation activation for 6-12 h. The observed disbalance between the procoagulant and fibrinolytic mechanisms after TNF injection confirms the in vivo relevance of the effects of TNF on vascular endothelium in vitro and may explain the tendency towards microvascular thrombosis in septicemia.     

Enprofylline kinetics in healthy subjects after single doses

The kinetics of enprofylline, a novel antiasthmatic xanthine derivative, were studied. Eight healthy subjects received three different single enprofylline doses, 0.5, 1, and 1.5 mg/kg, injected as an infusion over 10 min. Plasma and urine levels of unchanged enprofylline were observed 3 to 7 and 21 to 24 hr after dosing. Plasma t 1/2 varied among individuals from 1.2 to 1.9 hr. Volume of distribution (V beta or area) and volume of distribution at steady state (V ss) averaged 0.57 and 0.511 X kg-1. Total clearance averaged 0.25 l X hr-1 X kg-1. Renal clearance ranged from 200 to 400 ml X min-1, indicating a large contribution by active tubular secretion. The mean recovery of unchanged drug in the urine was 89%. Thus, unlike theophylline, enprofylline was eliminated mainly by the kidney.     

Intravenous fish oil blunts the physiological response to endotoxin in healthy subjects

Objective To assess the effects of intravenous fish oil fat emulsion on the metabolic alterations induced by lipopolysaccharide (LPS) challenge in healthy volunteers. Design Two groups of eight healthy subjects were randomized to receive either two pharmacological doses of intravenous FO fat emulsion or no treatment. The FO group received twice 0.5 g/kg 10% emulsion (Omegaven) 48 and 24 h before investigation. LPS (2 ng/kg) was injected as a bolus on the investigation day. Systemic parameters, indirect calorimetry, heart rate variability, and platelet membrane phospholipid composition were measured. Results Basal EPA and DHA content in platelet phospholipids was low (0.28% and 2.54%, respectively) and increased significantly after FO to 1.68% and 3.32%. LPS induced reproducible effects in all subjects. Fever was higher in the FO group than in controls; the difference was significant from t ₁₂₀ until t ₃₆₀. FO blunted the neuroendocrine response: the rise in plasma norepinephrine was sevenfold lower at t ₁₂₀ while the ACTH peak was fourfold lower. Tumor necrosis factor α was significantly lower between t ₃₆₀ and t ₁₈₀ in the FO group. Conclusions Two doses of intravenous FO fat emulsion modified the phospholipid composition of platelets in healthy subjects. FO blunted fever and increased the neuroendocrine and the inflammatory responses to LPS.     

Blood metabolite data in response to maximal exercise in healthy subjects

Maximal exercise test with gas exchange measurement evaluates exercise capacities with maximal oxygen uptake (VO(2) max) measurement. Measurements of lactate (L), lactate/pyruvate ratio (L/P) and ammonium (A) during rest, exercise and recovery enhance interpretative power of maximal exercise by incorporating muscular metabolism exploration. Maximal exercise test with gas exchange measurement is standardized in cardiopulmonary evaluations but, no reference data of blood muscular metabolites are available to evaluate the muscular metabolism. We determined normal values of L, L/P and A during a standardized maximal exercise and recovery in 48 healthy sedentary volunteers and compared with results obtained in four patients with exercise intolerance and a mitochondrial disease. In healthy subjects, L, L/P and A rose during exercise. In 98% of them L, L/P or A decreased between the fifth and the fifteenth minutes of recovery. In mitochondrial patients, VO(2) max was normal or low, and L, L/P and A had the same evolution as normal subjects or showed no decrease during recovery. We gave normal L, L/P and A values, which establish references for a maximal exercise test with muscular metabolism exploration. This test is helpful for clinicians in functional evaluation, management and treatment of metabolic myopathy and would be a useful tool in diagnosis of metabolic myopathy.     

Circulatory response to postural change in healthy male subjects in relation to age

The initial heart rate (HR) response evoked by standing up and 70 degrees head-up tilt from the supine resting position, as well as the changes in HR and blood pressure after 1-2 min in the upright position, was analysed in teenage boys (aged 10-15 years) and healthy old men (aged 60-90 years). Standing up induced a characteristic temporary HR increase that lasted 20 s and far exceeded the gradual initial HR rise induced by head-up tilt. The main effect of age on the initial HR transients was a definite diminution of the response. After 1-2 min standing and tilting, young subjects showed a pronounced increase in HR and diastolic pressure with little change in systolic pressure. In contrast, old subjects showed a lesser increase in HR and diastolic pressure and a decrease in systolic pressure. A fall in systolic pressure of greater than 20 mmHg after 1 min of active standing was, however, not observed. It is concluded that the circulatory adjustment to the stress of postural change differs markedly between young and elderly subjects. In healthy old subjects marked postural hypotension appears to be rare.     

Variability of FeNO in healthy subjects at 2240 meters above sea level

Fraction of exhaled nitric oxide (FeNO) is a marker of eosinophilic airway inflammation. Altitude above sea level can affect measurements of this index, but there is only limited information regarding the diurnal variation (ante meridiem vs. post meridiem) and reproducibility of FeNO on consecutive days at moderate altitudes. To evaluate the diurnal variability of FeNO and assess its reproducibility over five consecutive days in healthy individuals living at 2240 m, and to compare the FeNO readings taken with two different analyzers. Healthy non-smoking adults were measured using NIOX MINO^® or NOA 280i^® devices. One group (n = 10) had readings taken morning and afternoon for five consecutive days with the NIOX MINO^® equipment; while the second group (n = 17) was measured on only one morning but by both the electrochemical analyzer (NIOX MINO^®) and the chemiluminescence method (NOA 280i^®). The study group consisted of 27 subjects aged 28.7 ± 6 years. Morning and afternoon FeNO measurements were 15.2 ± 7.5 ppb and 15.2 ± 7.9 ppb (p = 0.9), respectively. The coefficient of variation (CV) of these measurements (a.m. vs. p.m.) was 10.7 %, and the coefficient of repeatability (CR), 4.2 ppb. The concordance correlation coefficient (CCC) between the two measures (morning vs. afternoon) was 0.91. The CV and CR of the five morning readings were 15.4 % and 4.3 ppb, respectively; while those of the five afternoon measures were 13.6 % and 3.5 ppb, respectively. The CCC between the NIOX MINO^® equipment and the NOA-280i^® device was 0.8, with 95 % limits of agreement of ?8.35 to 0.29 ppb. In adults living at 2240 m above sea level, FeNO measurements show minimal diurnal variation, and readings are reproducible (<15 %) over a period of at least five consecutive days; however, the FeNO measurements obtained with the NIOX MINO^® and NOA 280i^® devices are not interchangeable due to the wide limits of agreement recorded.     

Ankle to arm index response to exercise and heat stress in healthy subjects

Summary. Ankle to arm index (AAI) defined as the ratio of ankle systolic blood pressure (ASBP), to brachial systolic blood pressure is largely used in the study of lower extremity arterial disease (LEAD). To study the hypothesis of the shunt of blood away from the skin as the explanation of AAI decrease in exercise, we studied the AAI and ASBP responses to an increase in cardiac output originating from an increase either in muscle blood flow (exercise) or in cutaneous blood flow (thermal stress Brachial systolic pressure, ankle systolic pressure and heart rate (HR) were measured in 9 healthy subjects at rest, during heat thermal stress and following maximal exercise on a cycle ergometer. Compared to resting values, AAI decreased in all subjects from 1.05 ± 0.07 to 0.75 ± 0.07 (P < 0.05) 1 min following exercise and from 1.08 ± 0.07 to 0.94 ± 0.05 (P < 0.05) during heat stress. On the other hand, HR increased from 72.8 ± 12.2 to 112.4±19.6 (P < 0.05) min following exercise and from 75.5 ± 13.6 to 96.8 ± 15.3 (P < 0.05) during heat stress. Since a comparable relation exists between. AAI and HR in thermal stress and exercise, we suggest that the decrease in AAI in normal subjects following exercise is due to turbulences at high flow levels, rather than the shunting of blood to active muscles in exercise.     

法罗培南钠片剂在健康志愿者中药动学研究

目的研究健康志愿者单剂量口服法罗培南钠片剂的药动学特点。方法10名受试者在2个周期内分别空腹单剂量口服法罗培南钠片剂300mg、600mg，以高效液相色谱-紫外线（HPLC—UV）法测定其血液、尿液法罗培南浓度，并用Win-Nonlin专业版计算药动学参数。结果单次口服300mg、600mg法罗培南后的主要药动学参数AUC（0-x）分别为（7．612±3．296）和（15.539±7．395）mg·h／L，AUC（0-∞）分别为（7.737±3．328）和（15．716±7．368）mg·h／l，Cmax分别为（3．815±1．053）和（6.885±2．256）mg／L，Tmax分别为1．00和1．00h，t（1／2）分别为1．006和1．055h，CL／F分别为（46．980±22．247）和（46．996±22．475）L／h，V／F分别为（70．151±38.281）和（73．535±40.439）L。尿药浓度测定结果表明，法罗培南12h尿累积排出率分别为（5．96±3.15）和（4．35±1．48）％。结论法罗培南在300～600mg范围内Cmax和AUC随剂量呈比例增加，单剂量给药在健康人体耐受性良好。     

Effects of food and sucralfate on a single oral dose of 500 milligrams of levofloxacin in healthy subjects.

The effects of food and sucralfate on the pharmacokinetics of levofloxacin following the administration of a single 500-mg oral dose were investigated in a randomized, three-way crossover study with young healthy subjects (12 males and 12 females). Levofloxacin was administered under three conditions: fasting, fed (immediately after a standardized high-fat breakfast), and fasting with sucralfate given 2 h following the administration of levofloxacin. The concentrations of levofloxacin in plasma and urine were determined by high-pressure liquid chromatography. By noncompartmental methods, the maximum concentration of drug in serum (Cmax), the time to Cmax (Tmax), the area under the concentration-time curve (AUC), half-life (t1/2), clearance (CL/F), renal clearance (CLR), and cumulative amount of levofloxacin in urine (Ae) were estimated. The individual profiles of the drug concentration in plasma showed little difference among the three treatments. The only consistent effect of the coadministration of levofloxacin with a high-fat meal for most subjects was that levofloxacin absorption was delayed and Cmax was slightly reduced (Tmax, 1.0 and 2.0 h for fasting and fed conditions, respectively [P = 0.002]; Cmax, 5.9 +/- 1.3 and 5.1 +/- 0.9 microg/ml [90% confidence interval = 0.79 to 0.94] for fasting and fed conditions, respectively). Sucralfate, which was administered 2 h after the administration of levofloxacin, appeared to have no effect on levofloxacin's disposition compared with that under the fasting condition. Mean values of Cmax and AUC from time zero to infinity were 6.7 +/- 3.2 microg/ml and 47.9 +/- 8.4 microg x h/ml, respectively, following the administration of sucralfate compared to values of 5.9 +/- 1.3 microg/ml and 50.5 +/- 8.1 microg x h/ml, respectively, under fasting conditions. The mean t1/2, CL/F, CLR, and Ae values were similar among all three treatment groups. In conclusion, the absorption of levofloxacin was slightly delayed by food, although the overall bioavailability of levofloxacin following a high-fat meal was not altered. Finally, sucralfate did not alter the disposition of levofloxacin when sucralfate was given 2 h after the administration of the antibacterial agent, thus preventing a potential drug-drug interaction.     

Erratum to: Intravenous fish oil blunts the physiological response to endotoxin in healthy subjects

Results second sentence should read: Fever was higher in the control group than in FO group.

     

Urodynamic evaluation of voluntary detrusor response in healthy subjects

The ability of healthy subjects to voluntarily inhibit a bladder detrusor contraction was evaluated using standard urodynamic techniques. Ten healthy subjects (five men and five women) were appraised using trichannel techniques which included measuring bladder volume, bladder pressure, intraabdominal pressure, and electromyographic activity of the anal or external urethral sphincter. Each subject was first evaluated to determine normalcy of urine flow rate. All subjects were assessed in three positions: supine, sitting, and standing. All ten subjects were able to inhibit their detrusor responses without increasing external urethral or anal sphincter activity or raising the tonus pressure limb of the bladder. Three of the subjects were unable to void during any part of the urodynamic evaluation. In one subject, voiding was accomplished by Valsalva maneuver which mimicked detrusor contraction. At least two subjects did not demonstrate their first urge to void until 300 to 400 cc, and one of these individuals was unable to void until his bladder capacity reached 600cc. These results indicated that normal subjects can inhibit their detrusor response during urodynamic studies. Inability to inhibit this response would therefore appear to be an abnormal pattern. Conversely, inability to produce a detrusor response cannot be called an abnormal retention pattern. Bladder volumes in healthy subjects may be higher than the traditional norms, and this must be taken into account during urodynamic evaluations.     

Pharmacokinetics of anti-Pseudomonas hyperimmunoglobulin after single intravenous administration in healthy subjects

This is the first report of the pharmacokinetics of an intravenous hyperimmunoglobulin investigated by assays measuring functional activity. The anti-Pseudomonas hyperimmunoglobulin had previously been shown to be specific and effective in Pseudomonas aeruginosa infectious challenge models when given prophylactically to laboratory animals. In order to facilitate calculation of effective dosage regimes of hyperimmunoglobulin in patients, the pharmacokinetics of 15 g of an anti-Pseudomonas hyperimmunoglobulin was investigated after intravenous administration to six healthy male volunteers. The pharmacokinetics were followed in serum for sixteen days by four assays measuring total IgG, ELISA titre to Pseudomonas serotype 6 or a multivalent Pseudomonas vaccine, and mouse protection against infectious challenge. The increase of ELISA titre and mouse protective ability was modest, being approximately twice that of normal pooled serum. The half-life of the biologically active antibody as measured by the mouse protection assay was about seven days, and the half-life of total anti-Pseudomonas antibodies as measured by ELISA varied greatly between individuals (8–33 days). These results suggest that previous trials of fixed dose hyperimmunoglobulin in patients may have been ineffective owing to inadequate dosage regimens.     

Pharmacokinetics of tigecycline after single and multiple doses in healthy subjects

Tigecycline, a novel glycylcycline antibiotic, exhibits strong activity against gram-positive, gram-negative, aerobic, anaerobic, and atypical bacterial species, including many resistant pathogens, i.e., vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae. The safety and tolerability of tigecycline administered as single or multiple doses or at various infusion rates were explored in three phase 1, randomized, double-blind, placebo-controlled studies in healthy subjects. Full pharmacokinetic profiles of tigecycline were determined in two of these studies. Subjects in the single-dose study received 12.5 to 300 mg of tigecycline, which differed with respect to the duration of infusion, subjects' feeding status, and ondansetron pretreatment. Subjects in the ascending multiple-dose study received 25 to 100-mg doses of tigecycline as a 1-h infusion every 12 h. The variable volume and infusion rate study consisted of administration of 100-mg loading dose of tigecycline, followed by 50 mg every 12 h for 5 days. Serum samples were analyzed for tigecycline by validated high-pressure liquid chromatography or liquid chromatography/tandem mass spectrometry methods. Systemic clearance ranged from 0.2 to 0.3 liters/h/kg, and the tigecycline half-life ranged from 37 to 67 h. Tigecycline had a large volume of distribution (7 to 10 liters/kg), indicating extensive distribution into the tissues. Food increased the maximum tolerated single-dose from 100 to 200 mg, but the duration of infusion did not affect tolerability. Side effects, mainly nausea and vomiting, which are common to the tetracycline class of antimicrobial agents, were seen in these studies. Tigecycline exhibits linear pharmacokinetics and is safe and well tolerated in the dose ranges examined.     

Venous responsiveness to norepinephrine in healthy subjects: effects of single doses of 325 mg aspirin

BACKGROUND: Antithrombotic doses of aspirin, which are widely used in patients with cardiovascular disease, may inhibit prostaglandin synthesis but the physiologic significance with regard to vascular tone is not well defined. We hypothesized that inhibition of vasodilator prostaglandin synthesis by aspirin would significantly increase sympathetic-mediated venoconstriction. METHODS: Twelve healthy volunteers (mean age, 24.5 +/- 0.8 years; age range, 19 to 30 years) were studied on two mornings approximately 7 days apart and not less than 90 minutes after a randomized single dose of 325 mg aspirin or matching placebo. Distension of dorsal hand veins was measured with use of the linear variable differential transformer technique during local infusions of exogenous norepinephrine (0.125 to 1,024 ng/min) and during release of endogenous norepinephrine from sympathetic activation by a forehead cold pressor test. Hemodynamic parameters and venous plasma catecholamine levels were measured. Antiplatelet activity of the dose of aspirin was confirmed in three subjects. RESULTS: Aspirin increased venoconstriction to norepinephrine, causing a significant shift to the left (P < .03) of the norepinephrine dose-response curve and a significant decrease in logED50 (P < .03), representing a decrease in the dose of norepinephrine required to reduce vein distension by 50% from 50 to 25 ng/min. Venoconstriction to the cold pressor test was significantly increased by aspirin (10% +/- 3% versus 3% +/- 1% for placebo; P < .02). Cold pressor-induced increases in mean arterial pressure were significantly larger with aspirin compared with placebo (18 +/- 1 versus 14 +/- 1 mm Hg, respectively; P < .03). Baseline levels and stress-induced increases in plasma norepinephrine were not different between days. CONCLUSIONS: The results suggest that aspirin inhibits the role of vasodilator prostaglandins in modulating peripheral venoconstriction and increases vascular resistance during physiologic stress in young healthy subjects.     

Blunting the response to endotoxin in healthy subjects: effects of various doses of intravenous fish oil

Objective  

To test the dose response effect of infused fish oil (FO) rich in n-3 PUFAs on the inflammatory response to endotoxin (LPS) and on membrane incorporation of fatty acids in healthy subjects.