Modulation by epidermal growth factor of the basal 1,25(OH)2D3 receptor level and the heterologous up-regulation of the 1,25(OH)2D3 receptor in clonal osteoblast-like cells

Summary The effects of epidermal growth factor (EGF) on basal 1,25-dihydroxyvitamin D₃ (1,25-(OH)₂D₃) receptor level and on parathyroid hormone (PTH)-induced 1,25-(OH)₂D₃ (OH)₂D₃ receptor up-regulation were studied in the phenotypically osteoblastic cell line UMR 106. EGF in concentrations exceeding 0.1 ng/ml reduced the number of 1,25(OH)₂D₃ binding sites without changing the binding affinity. Maximal reduction was 30% at about 1 ng/ml. This reduction was independent of a change in cAMP content. EGF dose-dependently attenuated both PTH-induced 1,25(OH)₂D₃ receptor up-regulation and PTH-stimulated cAMP production without and effect on the ED₅₀ of the PTH effects. For both PTH responses the IC₅₀ and the maximal effective dose were similar, 0.1 ng/ml an 1 ng/ml EGF, respectively. Reduction was first seen at 0.01 ng/ml EGF. At this concentration. EGF reduced PTH-stimulated 1,25-(OH)₂D₃ receptor binding without an inhibition of the cAMP response. Time-course studies with 1 ng/ml EGF revealed that at 2 h preincubation EGF reduced the heterologous up regulation by PTH, and maximal inhibition was seen after 4 h. In contrast, PTH-stimulated cAMP production was just significantly inhibited only after 6 h, with 60% inhibition after 24 h preincubation. The effects of prostaglandin E₂ and forskolin on both 1,25(OH)₂D₃ binding and cAMP production were inhibited in a similar fashion. On the other hand, dibutyryl cAMP- and 3-isobutyl-1-methylxanthinestimulated 1,25(OH)₂D₃ binding were not affected by EGF. Taken together, our results demonstrate that EGF reduces both the basal number of 1,25(OH)₂D₃ binding sites and the heterologous up-regulation of the 1,25(OH)₂D₃ receptor. The current data suggest that EGF reduces heterologous upregulation of the 1,25(OH)₂D₃ receptor independent of as well as dependent on the cAMP messenger system. The EGF effect is not primarily located at the PTH receptor, at cAMP phosphodiesterase, or at protein kinase A level.     

Mitt-C-regionales Parathormon in der klinischen Routine: Diagnostische Wertigkeit beim extrarenalen (primären) und renalen (sekundären) Hyperparathyreodismus

Summary The selective determination of mid-C-regional parathyroid hormone (mid-C-PTH) in combination with other laboratory parameters is a reliable tool for diagnosis and treatment of extrarenal (primary) and renal (secondary) hyperparathyroidism. Early stages, which show either high-to-normal serum calcium and elevated mid-C-PTH or increased serum calcium but normal mid-C-PTH, can be distinguished from overt hyperparathyroidism. Alkaline phosphatase (AP) activity and mid-C-regional PTH provide biochemical confirmation of histologically classified renal osteodystrophy. Since the index AP×PTH signifies osseous changes in dialysis patients at an early stage, therapeutic regimens may be altered without additional invasive procedures. After renal transplantation mid-C-PTH normalizes and serum creatinine decreases. Increased mid-C-PTH in patients with normal renal graft function reflects autonomous PTH secretion, which requires careful monitoring to prevent PTH-induced hypercalciuria.

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Abkürzungsverzeichnis AP Alkalische Phosphatase - Ca Gesamtcalcium - DFO Desferrioxamin - HPT Hyperparathyreodismus - Index (AP×PTH) Produkt aus Mitt-C-PTH und AP - Mitt-C-PTH Mitt-C-regionales PTH - MW Molekulargewicht - NTX Nierentransplantation - PTH Parathormon - PTX Parathyreoidektomie mit Reimplantation in den Unterarm - PO₄ Phosphat - RIA Radioimmunoassay Mit Unterstützung der Deutschen Forschungsgemeinschaft (DFG) Ju 177/1-1     

Hypocalcaemic Effect of WR-2721, S-2 (3-Aminopropylamino) Ethyl-phosphorothioic Acid in an Anuric Haemodialysis Patient

The radio- and chemoprotective agent, S-2 (3-aminopropylamino)ethyl-phosphorothioic acid (WR 2721) has been reported to lowerhypercalcaemia in patients with cancer, probably by increasedrenal calcium excretion and decreased parathyroid hormone (PTH)secretion and bone calcium resorption. The present study reportsthe first clinical use of WR-2721 in an anuric haemodialysispatient with severe secondary hyperparathyroidism. The drugwas administered intravenously at different doses, i.e. 150,300, and 500 mg/m². The infusion was followed by a strikingdecrease of plasma immunoreactive (i) PTH within 30 min. Thenadir of the iPTH decrease was reached at 60 min and was followedby a steady return to previous values. Serum ionised calciumdecreased more progressively from 1.55 mmol/l initially to 1.30mmol/l at 4 h after the 300-mg dose, remained at that levelat 24 h, but rose again to pre-infusion values after 48 h. Theextent and duration of the decrease in plasma iPTH and ionisedcalcium were dose-dependent. The circulating iPTH at 24 h wasinversely related to the corresponding plasma ionised calciumconcentration and had risen above preinfusion values at thattime. Plasma concentrations of three other hormones, i.e. renin,insulin, and prolactin, were not affected by the administrationof WR-2721. In conclusion, WR-2721 can induce a decrease in serum ionisedcalcium in the absence of any excretory kidney function. Therapid effect of the drug on circulating iPTH supports the notionof an interference with PTH secretion or catabolism.     

Monoliths with chiral surface functionalization for enantioselective capillary electrochromatography

The state-of-the-art in CEC enantiomer separations with monolithic capillary columns is comprehensively reviewed. The various types of monolithic columns comprising in situ organic polymer monoliths, molecularly imprinted polymer (MIP) monoliths, silica monoliths and monoliths made from particles are discussed with a focus on materials’ synthesis, chemistry and properties as well as column aspects. Monolithic MIP-type porous layer open-tubular (PLOT) columns are treated herein as well. From this survey of the literature, the authors come to the conclusion that monolithic silica capillaries appear to become the preferred column type for CEC enantiomer separations of low-molecular drugs and other chiral pharmaceuticals or chemicals.     

Effects of Growth Hormone Administration on Bone Mineral Metabolism,PTH Sensitivity and PTH Secretory Rhythm in Postmenopausal Women With Established Osteoporosis

Introduction : Growth hormone (GH) replacement improves target organ sensitivity to PTH, PTH circadian rhythm, calcium and phosphate metabolism, bone turnover, and BMD in adult GH‐deficient (AGHD) patients. In postmenopausal women with established osteoporosis, GH and insulin like growth factor‐1 (IGF‐1) concentrations are low, and administration of GH has been shown to increase bone turnover and BMD, but the mechanisms remain unclear. We studied the effects of GH administration on PTH sensitivity, PTH circadian rhythm, and bone mineral metabolism in postmenopausal women with established osteoporosis. Materials and Methods : Fourteen postmenopausal women with osteoporosis were compared with 14 healthy premenopausal controls at baseline that then received GH for a period of 12 mo. Patients were hospitalized for 24 h before and 1, 3, 6, and 12 mo after GH administration and half‐hourly blood and 3‐h urine samples were collected. PTH, calcium (Ca), phosphate (PO₄), nephrogenous cyclic AMP (NcAMP), β C‐telopeptide of type 1 collagen (βCTX), procollagen type I amino‐terminal propeptide (PINP), and 1,25‐dihydroxyvitamin D [1,25(OH)₂D] were measured. Circadian rhythm analysis was performed using Chronolab 3.0 and Student's t‐test and general linear model ANOVAs for repeated measures were used where appropriate. Results : IGF‐1 concentration was significantly lower in the women with established osteoporosis compared with controls (101.5 ± 8.9 versus 140.9 ± 10.8 μg/liter; p < 0.05) and increased significantly after 1, 3, 6, and 12 mo of GH administration (p < 0.001). Twenty‐four‐hour mean PTH concentration was higher in the osteoporotic women (5.4 ± 0.1 pM) than in healthy controls (4.4 ± 0.1 pM, p < 0.001) and decreased after 1 (5.2 ± 0.1 pM, p < 0.001), 3 (5.0 ± 0.1 pM, p < 0.001), 6 (4.7 ± 0.1 pM, p < 0.001), and 12 mo (4.9 ± 0.1 pM, p < 0.05) of GH administration compared with baseline. NcAMP was significantly lower in osteoporotic women (17.2 ± 1.2 nM glomerular filtration rate [GFR]) compared with controls (21.4 ± 1.4 nM GFR, p < 0.05) and increased after 1 (24.2 ± 2.5 nM GFR, p < 0.05), 3 (27.3 ± 1.5 nM GFR, p < 0.001), and 6 mo (32.4 ± 2.5 nM GFR, p < 0.001) compared with baseline. PTH secretion was characterized by two peaks in premenopausal women and was altered in postmenopausal women with a sustained increase in PTH concentration. GH administration also restored a normal PTH secretory pattern in the osteoporotic women. The 24‐h mean adjusted serum calcium (ACa) concentration increased at 1 and 3 mo (p < 0.001) and PO₄ at 1, 3, 6, and 12 mo (p < 0.001). 1,25(OH)₂D concentration increased after 3, 6, and 12 mo of GH (p < 0.05). An increase in urine Ca excretion was observed at 3 and 6 mo (p < 0.05), and the renal threshold for maximum tubular phosphate reabsorption rate (TmPO4/GFR) increased after 1, 3, 6, and 12 mo (p < 0.05). βCTX concentration increased progressively from 0.74 ± 0.07 μg/liter at baseline to 0.83 ± 0.07 μg/liter (p < 0.05) at 1 mo and 1.07 ± 0.09 μg/liter (p < 0.01) at 3 mo, with no further increase at 6 or 12 mo. PINP concentration increased progressively from baseline (60 ± 5 μg/liter) to 6 mo (126 ± 11 μg/liter, p < 0.001), with no further increase at 12 mo. The percentage increase in PINP concentration was significantly higher than βCTX (p < 0.05). Conclusions : Our study shows that GH has a regulatory role in bone mineral metabolism. GH administration to postmenopausal osteoporotic women improves target organ sensitivity to PTH and bone mineral metabolism and alters PTH secretory pattern with greater increases in bone formation than resorption. These changes, resulting in a net positive bone balance, may partly explain the mechanism causing the increase in BMD after long‐term administration of GH in postmenopausal women with osteoporosis shown in previous studies and proposes a further component in the development of age‐related postmenopausal osteoporosis.     

Cinacalcet (KRN1493) effectively decreases the serum intact PTH level with favorable control of the serum phosphorus and calcium levels in Japanese dialysis patients.

BACKGROUND: Cinacalcet hydrochloride (KRN1493) acts on the parathyroid calcium receptors to suppress parathyroid hormone (PTH) secretion, and is already in wide use in the United States and the European countries. In this study, we examined the efficacy and safety of cinacalcet in Japanese patients on maintenance haemodialysis. METHODS: One hundred forty-four patients with serum intact PTH (iPTH) levels >or=300 pg/ml were enrolled and randomly allocated to two groups assigned to receive either cinacalcet or placebo for 14 weeks. Cinacalcet was started at the dose of 25 mg/day and titrated up to 100 mg/day to achieve the target iPTH level of <250 pg/ml. RESULTS: Cinacalcet significantly decreased the median iPTH level from 606.5 pg/ml to 241.0 pg/ml, despite the mean dialysis vintage being 2.4 times longer (14.3+/-7.1 years) and the proportion of patients receiving vitamin D sterols being higher, than in the phase 3 studies conducted in the US/EU. The target iPTH level was achieved in 51.4% of the patients in the cinacalcet group, in sharp contrast to only 2.8% in the placebo group. Furthermore, the percentage of patients with both the serum calcium and phosphorus levels within the target range in the K/DOQI guidelines increased from 4.2% to 26.4% by cinacalcet. CONCLUSIONS: These results suggest that lower dose levels of cinacalcet, as compared to those in US/EU studies, may be sufficient effectively suppress the serum iPTH levels and allow favourable management of the serum calcium and phosphorus levels in Japanese patients, having a longer average dialysis vintage.     

钙、镁及甲状旁腺激素在心肺转流期间的动态变化

目的 观察心肺转流（CPB）期间钙、镁及甲状旁腺激素（PTH）的变化。方法 静脉血标本取自16例心内直视手术病人，采用原子吸收光谱法、离子选择电极法及化学发光分析方法于CPB期间不同时间点检测总钙、离子钙、总镁及PTH的含量。结果 CPB开始后钙、镁及PTH均降低（P＜0.05），至CPB结束时降至最低点（P＜0.01）。钙离子于术后第1天回复至术前水平，而总钙及总镁含量于术后第1天仍低于术前水平（P＜0.05）。PTH于CPB后2小时升高，于术后第1天升术前的2.6倍（P＜0.01）。结论 CPB期间发生了明显的低钙、低镁血症。钙－镁－甲状旁腺轴反应基本正常，但呈滞后现象。     

Percutaneous Sclerotherapy for Treatment of Tumoral Calcinosis

Massive tumoral calcinosis developed in a 29-year-old woman with type 1 diabetes and failed pancreas and kidney transplant on peritoneal dialysis. The patient had a symptomatic calcified, fluid-filled posterior thigh mass. After percutaneous drainage of 260 mL of milky fluid, she had rapid recurrence of the collection. She underwent catheter-based sclerotherapy first with 110 mL of povidone-iodine followed 2 days later by 40 mL of 3% sodium tetradecyl sulfate foam. At 5.5 months after the procedure, the patient remained asymptomatic, and computed tomography imaging showed complete resolution of the collection.     

脑瘫患儿血骨钙素甲状旁腺素降钙素水平的观察

目的：研究脑瘫患儿血骨钙素（BGP）、甲状旁腺素（PTH）、降钙素（CT）的含量变化,分析它们与脑瘫病情、分型的关系。方法：应用放射免疫法测定37例脑瘫患儿和28例正常儿血清中的BGP、PTH、CT浓度。结果脑瘫组血清BGP明显高于正常组（P＜0．01）;重度脑瘫患儿PTH与正常组比较明显升高（P＜0．01）,而CT则低于正常组（P＜0．05）;同时发现痉挛型脑瘫患儿PTH含量高于手足徐动型,而CT则低于手足徐动型（P＜0．05）。结论：脑瘫患儿血清PTH、CT异常,其异常程度与脑瘫类型、病情轻重有关;血清BGP升高提示脑瘫患儿骨形成活跃。     

甲亢和甲减患者血清PTH、CT水平的变化

目的：探讨了甲亢和甲减患者血清甲状旁腺素（PTH）和降钙素（CT）水平的变化。方法：应用放射免疫分析法测定了62例甲亢患者和32例原发性甲减患者血清中PTH、CT含量,并以35名健康人作对照。结果：甲亢组血清PTH水平低于正常人组（P＜0．05）、甲减组高于正常人组（P＜0．01）,CT水平两组均低于正常人组（P＜0．01）。结论：测定甲亢和甲减病人血清中PTH、CT水平的变化对了解病情,指导临床实践均有重要的临床意义 。