The role of growth hormone in glucocorticoid-induced osteoporosis.

Glucocorticoid-induced osteoporosis (GIO) is the most common form of secondary osteoporosis. GC influence bone metabolism via a modulation of different components of the GH/IGF-I system. GH has multiple anabolic effects on bone, either direct or mediated by IGF-I. GH-deficient subjects have significant reduction in bone mineralization, bone turnover markers, and increased fracture risk when compared with healthy age-matched controls. The increase of bone remodeling achieved by recombinant human GH (rhGH) therapy may be helpful in both males and females with decreased bone turnover and impaired osteoblastic function such as subjects with GC excess. rhGH treatment may improve lean body mass and skeletal muscle mass that may further reduce fracture risk in GIO patients. Nevertheless, the real efficacy of rhGH and IGF-I treatment in GIO and during aging is still controversial and further well-designed prospective controlled studies are necessary in order to clarify this issue, thus identifying who could potentially benefit from GH treatment.

[Methimazole versus methimazole and diphosphonates in hyperthyroid and osteoporotic patients]. / Metimazolo versus metimazolo e bifosfonatiin pazienti ipertiroidei con osteoporosi.

AIM: It is well-know that hyperthyroidism is one of the key causes of secondary osteoporosis. High values of thyroid hormones increase the bone mineral turnover speed by promoting osteoclastic and osteoblastic activities. The aim of our study is to evaluate the increase of bone mineral density (BMD) in osteoporotic and hyperthyroid patients treated with only antithyroid drugs versus patients treated with antithyroid drugs and diphosphonates. METHODS: Twenty-six elderly male patients, 65-75 years, were selected. In all these patients, thyroid function (FT3, FT4, TSH, Tg, AbTg, AbTPO) was evaluated at baseline and after 6 and 12 months from the start of medical treatment; the following were evaluated: BMD, calcium serum, phosphorus serum, alkaline phosphatase, PTH and 24 hours urinary calcium, phosphorus and hydroxyprolin. Thirteen patients (group 1) were treated with antithyroid drugs (methimazole 5-20 mg/die/os) and diphosphonates (alendronate 10 mg/die/os). The control group of 13 patients (group 2) was treated with antithyroid drugs only. RESULTS: After 6 months of treatment, the patients of group 1 showed a mean increase of 2.5% in lumbar spine BMD compared with a mean increase of 0.3% in group 2 (p<0.01). After 12 months, group 1 showed a mean increase of 6.2% in lumbar spine BMD, compared with a mean increase of 2% in group (p<0.001). CONCLUSIONS: The combination of antithyroid and diphosphonates drugs appears to be more efficacious than antithyroid therapy alone for the treatment of osteoporosis in male hyperthyroid patients.

Inhibition of the hepatitis C virus NS3/4A protease. The crystal structures of two protease-inhibitor complexes.

The hepatitis C virus NS3 protein contains a serine protease domain with a chymotrypsin-like fold, which is a target for development of therapeutics. We report the crystal structures of this domain complexed with NS4A cofactor and with two potent, reversible covalent inhibitors spanning the P1-P4 residues. Both inhibitors bind in an extended backbone conformation, forming an anti-parallel beta-sheet with one enzyme beta-strand. The P1 residue contributes most to the binding energy, whereas P2-P4 side chains are partially solvent exposed. The structures do not show notable rearrangements of the active site upon inhibitor binding. These results are significant for the development of antivirals.

Alpha-ketoacids are potent slow binding inhibitors of the hepatitis C virus NS3 protease.

The replication of the hepatitis C virus (HCV), an important human pathogen, crucially depends on the proteolytic maturation of a large viral polyprotein precursor. The viral nonstructural protein 3 (NS3) harbors a serine protease domain that plays a pivotal role in this process, being responsible for four out of the five cleavage events that occur in the nonstructural region of the HCV polyprotein. We here show that hexapeptide, tetrapeptide, and tripeptide alpha-ketoacids are potent, slow binding inhibitors of this enzyme. Their mechanism of inhibition involves the rapid formation of a noncovalent collision complex in a diffusion-limited, electrostatically driven association reaction followed by a slow isomerization step resulting in a very tight complex. pH dependence experiments point to the protonated catalytic His 57 as an important determinant for formation of the collision complex. K(i) values of the collision complexes vary between 3 nM and 18.5 microM and largely depend on contacts made by the peptide moiety of the inhibitors. Site-directed mutagenesis indicates that Lys 136 selectively participates in stabilization of the tight complex but not of the collision complex. A significant solvent isotope effect on the isomerization rate constant is suggestive of a chemical step being rate limiting for tight complex formation. The potency of these compounds is dominated by their slow dissociation rate constants, leading to complex half-lives of 11-48 h and overall K(i) values between 10 pM and 67 nM. The rate constants describing the formation and the dissociation of the tight complex are relatively independent of the peptide moiety and appear to predominantly reflect the intrinsic chemical reactivity of the ketoacid function.