Wasting in the acquired immune deficiency syndrome is associated with multiple defects in the serum insulin‐like growth factor system

Frost, Robert A.; Fuhrer, Jack; Steigbigel, Roy T.; Mariuz, Peter; Lang, Charles H.; Gelato, Marie C.

doi:10.1046/j.1365-2265.1996.705526.x

Cited by 87 publications

(35 citation statements)

References 26 publications

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“…Candidate hormones with effects on protein catabolism are growth hormone, thyroid hormones, steroids, insulin, and others. Studies have shown that there is a profound dysregulation in some of these systems in patients with advanced HIV disease and especially with AIDS wasting (1,6,7,9,10,19,23). In these patients, lean body mass (proteins and carbohydrates) is being converted into fat, a process which may also impact the degradation of ENF.…”

Section: Resultsmentioning

confidence: 99%

Pharmacokinetics of Enfuvirtide in Patients Treated in Typical Routine Clinical Settings

Stocker

Kloft

Plock

et al. 2006

Antimicrob Agents Chemother

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Therapeutic drug monitoring (TDM) is gaining importance for improving the success of antiretroviral treatment in human immunodeficiency virus-infected patients. However, enfuvirtide (ENF) concentrations are not regularly determined. The objective of this work was to study the pharmacokinetics (PK) of ENF in patients treated in routine clinical settings, to develop a population PK model describing the concentration-time profile, and to establish PK reference values. A liquid chromatography-tandem mass spectrometry method was developed and applied to serum samples submitted for TDM. A two-compartment model with linear absorption and elimination was fitted to 329 concentrations from 131 patients. The PK model was used for simulations resulting in percentile curves for ENF levels for the full dosing interval. The model predicted that a median concentration of 1,968 ng/ml would be reached 12 h after administration of 90 mg of ENF, and 23% and 58% of patients are expected to have concentrations below 1,000 ng/ml and 2,200 ng/ml, respectively. Both values have been proposed as cutoffs for virological efficacy. The median maximum concentration of drug in serum (C max ) of 3,943 ng/ml, predicted for 3 h after drug administration, is lower than the C max reported previously. We found an enormous interpatient variability at every time point, with concentration spectrums covering >1 log and 52% and 123% interindividual variabilities in the typical clearance and volume of distribution, respectively, in contrast to preexisting PK data. In summary, ENF levels are lower and more variable than expected. Many patients may achieve insufficient concentrations. Further covariate analysis in the population PK model might help to identify factors influencing the variability in ENF concentrations.

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Section: Resultsmentioning

confidence: 99%

Pharmacokinetics of Enfuvirtide in Patients Treated in Typical Routine Clinical Settings

Stocker

Kloft

Plock

et al. 2006

Antimicrob Agents Chemother

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“…(38) reported that, in protein-restricted rats, the proportion of IGF-I in smaller molecular mass complexes (ϳ30 kDa), as measured by size-exclusion HPLC, increased from ϳ33% during control to 65% after protein restriction. Certain pathophysiological conditions (i.e., growth hormone deficiency, starvation, tumor hypoglycemia) have also shown that the ratio of IGF-I bound to the ternary vs. binary complexes is decreased (12,16,17). Furthermore, recent studies (29,35) have demonstrated that both acute exercise and chronic physical training can increase circulating concentrations of low molecular mass IGFBPs.…”

mentioning

confidence: 99%

Differential responses of IGF-I molecular complexes to military operational field training

Nindl¹,

Castellani²,

Young³

et al. 2003

Journal of Applied Physiology

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. Differential responses of IGF-I molecular complexes to military operational field training. J Appl Physiol 95: 1083-1089, 2003; 10.1152/japplphysiol. 01148.2002.-Insulin-like growth factor (IGF) I and IGF binding proteins (IGFBPs) modulate metabolic activity and tissue repair and are influenced by nutritional status. IGF-I circulates in free, ternary [IGF-I ϩ IGFBP-3 ϩ acid labile subunit (ALS)], and binary (IGF-I ϩ IGFBP) molecular complexes, and the relative proportions regulate IGF-I extravascular shifting and bioavailability. This study examined the hypothesis that sustained physical activity and sleep deprivation superimposed on a short-term energy deficit would alter the IGFBP concentrations and alter the proportions of IGF-I circulating in ternary vs. binary molecular complexes. Components of the IGF-I system (total and free IGF-I; IGFBP-1, -3, and ALS; nonternary IGF-I and IGFBP-3), biomarkers of metabolic and nutritional status (transferrin, ferritin, prealbumin, glucose, free fatty acids, glycerol, ␤-hydroxybutyrate), and body composition were measured in 12 men (22 Ϯ 3 yr, 87 Ϯ 8 kg, 183 Ϯ 7 cm, 20 Ϯ 5% body fat) on days 1, 3, and 4 during a control and experimental (Exp) period. During Exp, subjects performed prolonged work (energy expenditure of ϳ4,500 kcal/day) with caloric (1,600 kcal/day) and sleep (6.2 h total) restriction. IGF-I and IGFBP-3 were measured by immunoassay before and after immunoaffinity depletion of ALS-based complexes (i.e., ternary complex removal). Exp produced losses in body mass (Ϫ3.0%), lowered total IGF-I (Ϫ24%), free IGF-I (Ϫ42%), IGFBP-3 (Ϫ6%), nonternary IGF-I (Ϫ27%), and IGFBP-3 (Ϫ16%), and increased IGFBP-1 (256%). No Exp effects were observed for ALS. No changes were observed in the proportion of IGF-I circulating in free (ϳ1.2%), ternary (ϳ87.4%), or nonternary (ϳ11.4%) molecular complexes. During Exp, glucose concentrations were lower on day 3, but days 1 and 4 were statistically similar. In conclusion, during a short-term energy deficit in young, healthy men, 1) IGF-I system components differentially respond (both in direction and magnitude) to a given metabolic perturbation and 2) the relative proportion of IGF-I sequestered in ternary vs. nonternary molecular complexes appears to be well maintained.

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“…IGF-I is a GH-dependent anabolic hormone that stimulates protein synthesis and strongly reduces protein breakdown (Fryburg 1994). Decrease in circulating IGF-I has been reported in most catabolic situations (Ross et al 1991, Frost et al 1996, Timmins et al 1996. Furthermore, exogenous GH and IGF-I have also been reported to improve nitrogen balance in some of these situations (Mulligan et al 1993, Berneis et al 1997.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of TNF-alpha production by pentoxifylline does not prevent endotoxin-induced decrease in serum IGF-I

Colson

Willems²,

Thissen

2003

Journal of Endocrinology

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Sepsis and endotoxin (LPS or lipopolysaccharide) injection induce a state of growth hormone (GH) resistance leading to decreased circulating insulin-like growth factor (IGF)-I. Because the proinflammatory cytokines tumor necrosis factor (TNF)-and interleukin (IL)-1 inhibit the GHstimulated IGF-I expression in vitro, it was tempting to speculate that these two cytokines might play an important role in the reduction of circulating IGF-I levels caused by LPS. Pentoxifylline, a methylxanthine usually used in the treatment of peripheral arterial circulatory disorders, has been reported to inhibit TNF-synthesis. The goal of our study was to investigate whether inhibition of TNFproduction by pentoxifylline could prevent the decrease in IGF-I and the GH resistance caused by LPS injection. Because previous studies demonstrated that pentoxifylline can reduce muscle catabolism induced by sepsis, we also assessed whether pentoxifylline could exert its anticatabolic effect by preventing the decrease in circulating IGF-I. LPS injection in rats decreased serum IGF-I ( 45% at 12 h; P,0·01 vs time 0) and its liver mRNA ( 67% at 12 h; P,0·01 vs time 0) while it induced circulating TNF-and IL-1 and their hepatic expression (P,0·01). Pretreatment of LPS-treated animals by pentoxifylline abolished the LPS-induced rise in serum TNF-( 98% at 90 min; P,0·001 vs LPS alone) and to a lesser extent in serum IL-1 ( 44% at 3 h; not significant vs LPS alone). Despite its dramatic inhibitory effect on TNF-induction, however, pentoxifylline failed to suppress both the decrease in IGF-I and the GH resistance induced by LPS in rats. These results suggest that mediators other than TNF-, in particular IL-1 or IL-6, could contribute to the GH resistance induced by LPS. They also suggest that the anticatabolic effect of pentoxifylline is not due to prevention of the decline of circulating IGF-I.

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Wasting in the acquired immune deficiency syndrome is associated with multiple defects in the serum insulin‐like growth factor system

Abstract: AIDS wasting is associated with a GH resistant state that results in low levels of serum IGF-I, IGF-II and IGFBP-3, elevated levels of phosphorylated IGFBP-1, and a reduced ability to form the IGFBP-3 ternary complex.

Cited by 87 publications

References 26 publications

Pharmacokinetics of Enfuvirtide in Patients Treated in Typical Routine Clinical Settings

Pharmacokinetics of Enfuvirtide in Patients Treated in Typical Routine Clinical Settings

Differential responses of IGF-I molecular complexes to military operational field training

Inhibition of TNF-alpha production by pentoxifylline does not prevent endotoxin-induced decrease in serum IGF-I

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