BACKGROUND: GH receptors exist in the hippocampus, cerebral cortex, and hypothalamus, possibly influencing mood, cortical blood flow, and neuronal growth and mediating negative feedback. RATIONALE: Pegvisomant is a recombinant mutated GH molecule with high affinity, but little or no activating capability, for the GH receptor. It is used clinically as a GH antagonist. HYPOTHESIS: Systemic pegvisomant enters brain interstitial fluid via putative choroid-plexus GH receptors, thereby allowing for antagonism of central actions of GH. SUBJECTS AND LOCATION: Six adults requiring a cerebrospinal fluid (CSF) examination for nonneoplastic and noninflammatory syndromes participated at a tertiary medical center. METHODS: Direct assays were conducted of serum and CSF pegvisomant concentrations 18-24 h after sc injection of pegvisomant (20 mg). OUTCOMES: Median (range) concentrations of pegvisomant in serum were 215 (74-539) microg/liter and in CSF 0.035 (0.010-0.28) microg/liter (P=0.016). CSF drug levels were indistinguishable from assay threshold. Corresponding GH values were 0.29 (0.010-1.3) in serum and 0.075 microg/liter (0.01-0.13) in CSF. The geometric mean ratios of serum/CSF pegvisomant and GH concentrations were 5116:1 and 3.5:1, respectively, thus defining a more than 1400-fold difference between mutated and natural GH. CONCLUSIONS: Based upon CSF measurements, a pegylated GH-receptor antagonist does not cross the human blood-brain barrier, thereby sparing inhibition of central nervous system GH actions. Thus, the capability of this antagonist to stimulate GH secretion predominantly reflects its actions outside the blood-brain barrier, such as via the median eminence and/or via suppression of IGF-I concentrations.
BACKGROUND: GH receptors exist in the hippocampus, cerebral cortex, and hypothalamus, possibly influencing mood, cortical blood flow, and neuronal growth and mediating negative feedback. RATIONALE: Pegvisomant is a recombinant mutated GH molecule with high affinity, but little or no activating capability, for the GH receptor. It is used clinically as a GH antagonist. HYPOTHESIS: Systemic pegvisomant enters brain interstitial fluid via putative choroid-plexus GH receptors, thereby allowing for antagonism of central actions of GH. SUBJECTS AND LOCATION: Six adults requiring a cerebrospinal fluid (CSF) examination for nonneoplastic and noninflammatory syndromes participated at a tertiary medical center. METHODS: Direct assays were conducted of serum and CSF pegvisomant concentrations 18-24 h after sc injection of pegvisomant (20 mg). OUTCOMES: Median (range) concentrations of pegvisomant in serum were 215 (74-539) microg/liter and in CSF 0.035 (0.010-0.28) microg/liter (P=0.016). CSF drug levels were indistinguishable from assay threshold. Corresponding GH values were 0.29 (0.010-1.3) in serum and 0.075 microg/liter (0.01-0.13) in CSF. The geometric mean ratios of serum/CSF pegvisomant and GH concentrations were 5116:1 and 3.5:1, respectively, thus defining a more than 1400-fold difference between mutated and natural GH. CONCLUSIONS: Based upon CSF measurements, a pegylated GH-receptor antagonist does not cross the human blood-brain barrier, thereby sparing inhibition of central nervous system GH actions. Thus, the capability of this antagonist to stimulate GH secretion predominantly reflects its actions outside the blood-brain barrier, such as via the median eminence and/or via suppression of IGF-I concentrations.
Authors: J D Veldhuis; M Bidlingmaier; S M Anderson; W S Evans; Z Wu; C J Strasburger Journal: J Clin Endocrinol Metab Date: 2002-12 Impact factor: 5.958
Authors: P J Trainer; W M Drake; L Katznelson; P U Freda; V Herman-Bonert; A J van der Lely; E V Dimaraki; P M Stewart; K E Friend; M L Vance; G M Besser; J A Scarlett; M O Thorner; C Parkinson; A Klibanski; J S Powell; A L Barkan; M C Sheppard; M Malsonado; D R Rose; D R Clemmons; G Johannsson; B A Bengtsson; S Stavrou; D L Kleinberg; D M Cook; L S Phillips; M Bidlingmaier; C J Strasburger; S Hackett; K Zib; W F Bennett; R J Davis Journal: N Engl J Med Date: 2000-04-20 Impact factor: 91.245
Authors: Weihong Pan; Yongmei Yu; Courtney M Cain; Fred Nyberg; Pierre O Couraud; Abba J Kastin Journal: Endocrinology Date: 2005-08-11 Impact factor: 4.736
Authors: Maximilian Bielohuby; Sayyed Hamid Zarkesh-Esfahani; Jenny Manolopoulou; Elisa Wirthgen; Katja Walpurgis; Mohaddeseh Toghiany Khorasgani; Zahra Sadat Aghili; Ian Robert Wilkinson; Andreas Hoeflich; Mario Thevis; Richard J Ross; Martin Bidlingmaier Journal: Dis Model Mech Date: 2014-09-19 Impact factor: 5.758