Objective: The GH receptor antagonist pegvisomant is a highly effective new treatment option in acromegaly. The German Pegvisomant Observational Study (GPOS) was started to monitor long-term safety and efficacy of pegvisomant as prescribed in clinical practice. Design: GPOS is an observational, multi-center, surveillance study, which comprises noninterventional data collection. Methods: Of the 229 patients included in the study, 90.4% had previous pituitary surgery, 43.2% were treated by radiation therapy, and 94.3% had previous medical therapy for acromegaly that had been discontinued mainly due to persistent IGF-I elevation or side effects. The intention-to-treat population included 177 patients with at least one post-baseline efficacy measurement. Results: IGF-I levels decreased from 1.75G0.91-fold the upper limit of normal at baseline to 1.05G 0.62 at the 6-month visit, 0.96G0.60 at the 12-month visit, and to 0.89G0.41-fold after 24 months (P!0.0001). Mean duration of pegvisomant therapy was 51.8G35.8 weeks (medianZ51.9 weeks). IGF-I was normalized in 64.4% at 6 months with a median dose of 15.0 mg/day, in 70.9% at 12 months, and in 76.3% at 24 months. Fasting glucose levels improved from 114.4G45.9 to 101.5G 42.8 mg/dl after 6 months (P!0.01) and to 100.6G33.2 mg/ml after 12 months (P!0.01). General physical condition measured by specific signs and symptoms score improved significantly. Adverse events occurring in O1% were injection site reactions in 7.4%, elevated liver enzymes (O3 times of normal) in 5.2% (3.1% spontaneously normalized during continued treatment), reported increase of pituitary tumor volume in 5.2% (which was verified in 3.1%), and headache in 1.7%. Conclusions: Pegvisomant is generally well tolerated with a safety profile similar to that reported in clinical trials and can effectively reduce IGF-I in patients with acromegaly refractory to conventional therapy. 156 75-82
European Journal of Endocrinology
Two major forms of cardiac peptides have been established in the last few years: (a) a prohormone of 126 amino acids (CDD/ANP-1-126) in the endocrine heart and (b) the circulating CDD/ANP-99-126 (= alpha ANP) in blood plasma. The method we applied earlier to isolate the circulating form of cardiodilatin from human blood was used to detect and analyze the biologically active, predominant form of the same polypeptide family excreted by the kidneys. Each step of the isolation procedure was followed up by a bioassay using an in vitro vascular smooth muscle relaxation test and a highly specific RIA against cardiodilatin (CDD-99-126) for the initial purification steps. The polypeptides excreted in 1000 l of normal human urine were adsorbed to 2.5 kg of alginic acid, and after elution and lyophilization processed on a G-25 Sephadex column. The obtained crude polypeptide fractions were applied to ion-exchange chromatography. Thereafter four steps of HPLC were carried out to purify the polypeptide which was the suggested form of cardiodilatin (CDD) in human urine. The amino acid analysis and gas phase sequence analysis showed that the main form of urinary cardiodilatin is a 32 amino acid residue containing molecule, cardiodilatin-95-126. The molecule is N-terminally extended compared to the circulating CDD-99-126. This suggests that the analyzed urinary peptide is not the residual plasma form, filtrated and renally cleared from blood, but probably a polypeptide produced and processed in the kidney tubules and cleaved by a different postranslational process. Therefore, this vasorelaxant polypeptide is called urodilatin.
A renal natriuretic peptide and the 'renal urodilatin system' were identified after the observation that immunoassayable ANP in urine may not be identical to the circulating cardiac hormone ANP, which is a peptide of 28 amino acids. Urodilatin (INN: Ularitide) is a natriuretic peptide isolated from human urine and belongs to the family of A-type natriuretic peptides. Urodilatin is differentially processed to a peptide of 32 amino acids from the same precursor as ANP. It is synthesized in kidney tubular cells and secreted luminally. After secretion from epithelial cells of the distal and/or connecting tubules, Urodilatin interacts downstream at distal segments of the nephron with luminally located receptors whereby it regulates Na(+) and water reabsorption. Thus, the physiological function of the renal Urodilatin system can be described as a paracrine intrarenal regulator for Na(+) and water homeostasis, considering Urodilatin as a real diuretic-natriuretic regulatory peptide. However, the regulation upon which the Urodilatin secretion depends is still not clear. Since Urodilatin has been discovered, a great number of pharmacological and clinical investigations have been carried out using Urodilatin as a drug for several indications. So far, clinical phase I and II studies for acute renal failure, congestive heart failure, and bronchial asthma have been performed.
Even in adult severe GHD, GH release appears to be regulated by factors defined to play an important role in normal GH secretion. The impact of very low GH release on IGF-I and lipid parameters indicates a persistent physiological role of low GH concentrations in severely affected patients with GHD.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.