4 Regulace mineralového metabolismu Ca2+Ca2+ reabsorpcePO43– exkreceledvinaPTHkalcitriolnormální Ca2+příštítná tělískaThere is a complex homeostatic system that exists to maintain serum calcium levels within 2% of normal.The system comprises sensing tissues such as the parathyroid glands, calciotropic hormones (e.g. parathyroid hormone [PTH] and vitamin D [calcitriol]) and effector tissues upon which the hormones act (e.g. kidney, bone and intestine).PTH is the most important calciotropic hormone.Build 1For example, suppression of serum calcium leads to the release of PTH from parathyroid glands.A decrease in calcitriol level also leads to the release of PTH from parathyroid glands.Build 2PTH acts on the kidneys to increase reabsorption of calcium from urine and increase excretion of phosphorus.PTH induces the release of calcium and phosphorus from bone.Build 3Renal retention of calcium and its release from bone stores result in the normalization of serum calcium levels.Build 4PTH also induces production of active vitamin D (calcitriol; 1,25 dihydroxy vitamin D3) in the kidney. Calcitriol facilitates absorption of calcium from the gastrointestinal tract, thus helping to normalize serum calcium levels.Calcitriol also acts on the parathyroid gland to decrease hormone synthesis.Brown EM. In: The Parathyroids – Basic and Clinical Concepts 2nd ed Bilezikian JP et al. (eds) pp. 167–82Ca2+PO43–bonevýdejBrown EM. In: The Parathyroids – Basic and Clinical Concepts 2nd ed Bilezikian JP et al. (eds)PTH, parathyroid hormone
5 Vztah mezi kalciem a PTH v CasR CaRCa2+VDRPTHCa2+Ca2+secretion PTHproduction PTHproliferation of cellssekrece PTHtvorba PTHproliferace buňkyHypercalcaemia (Build 1)Activation of the CaR leads to a rapid inhibition of PTH secretion.1Calcium ions interact with the extracellular domain of the receptor and induce a conformational change in the CaR.G-protein activates phosphatidylinositol-phospholipase C (PI-PLC), which leads to activation of protein-kinase C (PKC).2Activation of PKC initiates the mitogen-activating protein kinase (MAPK) cascade through which phospholipase A2 is phosphorylated and activated, ultimately leading to the release of free arachidonic acid (AA).2,3AA is then metabolized to biologically active leukotriene metabolites that inhibit PTH secretion.2,3In normocalcaemic conditions, the CaR is partially activated, acting as a brake on PTH production.4Hypocalcaemia (Build 2)When extracellular calcium levels are low, the CaR is relaxed and PTH secretion and synthesis are unrestrained.Serum PTH levels begin to rise with the aim of correcting serum calcium.1Parathyroid cells exhibit a progressive response to hypocalcaemia (see next slide).1. Brown EM. Rev Endocrine Met Disorders 2000;1:307–152. Kifor O et al. J Bone Miner Res 1997;12:715–253. Kifor O et al. Am J Physiol Renal Physiol 2001;280:F291–3024. Silver J et al. Am J Physiol Renal Physiol 2002;283:F367–76Brown EM. Rev Endocrine Met Disorders 2000;1:307–15Kifor O et al. J Bone Miner Res 1997;12:715–25Kifor O et al. Am J Physiol Renal Physiol 2001;280:F291–302
9 Klinický obraz hyperkalcémie Snížení koncentrační funkce ledvinpolyurie,polydipsie,dehydrataceNausea,zvraceníSvalová slabost, hyporeflexiedeprese, somnolence, kómaZkrácení ST intervalu, arytmie
10 90% všech hyperkalcémií je způsobeno tumorem nebo endokrinopathií Endokrinní nemoci spojené s hyperkalcémiíSe zvýšenou produkcí PTHPHPT sporadickáPHPT familiárníMEN I a MEN IITerapie LithiemBez zvýšené produkce PTHhypertyreóza, hypokortikalismus20 PHPT / ob150 operací pro PHPT na III . chirurgickéklinice za rok
31 Účinek cinacalcetu na plasmatické hladiny iPTH controls (n = 165)cinacalcet (n = 166)800700600iPTH (pg/mL)500400In humans, cinacalcet has been undergoing an extensive clinical trials programme.Cinacalcet has been shown to induce rapid and sustained reductions in serum iPTH, Ca x P, calcium and phosphorus in Phase I and Phase II studies.The above data are from a large-scale Phase III clinical trial conducted in Europe and Australia.1To enter the study, haemodialysis patients were required to have uncontrolled PTH (i.e. > 300 pg/mL [32 pmol/L]).Patients were randomized, double-blind, to receive cinacalcet (30 mg/day orally) or placebo. They were then titrated to optimal dose during the first 12 weeks of the study (maximum dose 180 mg/day).Efficacy was then assessed over the following 14 weeks.All patients were allowed to receive standard care with phosphate binders and/or vitamin D (vitamin D dose was kept as constant as possible throughout).During the efficacy assessment period, plasma iPTH was significantly lower in patients receiving cinacalcet compared with those receiving placebo.1. de Francisco ALM et al. J Am Soc Nephrol 2003;14:461A(SA-PO742)3002468101214161820222426weeksde Francisco ALM et al. J Am Soc Nephrol 2003;14:461A (SA-PO742)
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