Search

Upacicalcet (UPASITA®) is an intravenous calcimimetic agent being developed by Sanwa Kagaku Kenkyusho, under license from EA Pharma, for the treatment of secondary hyperparathyroidism (SHPT), a common and early complication of chronic kidney disease, in patients undergoing haemodialysis. By acting directly on parathyroid cell membrane calcium-sensing receptors, upacicalcet suppresses excessive parathyroid hormone (PTH) secretion, thereby lowering blood PTH levels. Upacicalcet received its first approval on 23 June 2021 for the treatment of SHPT in adults undergoing haemodialysis in Japan. It is administered intravenously three times per week into the venous side of the haemodialysis circuit at the time of blood return at the end of the haemodialysis session. The generally recommended starting dose of upacicalcet is 25 µg, with the dose adjusted within a 25–300 µg range based on PTH and serum calcium levels. This article summarizes the milestones in the development of upacicalcet leading to this first approval for the treatment of SHPT in patients undergoing haemodialysis.

Background and Aims Calcimimetic therapy, including oral cinacalcet and intravenous (IV) etelcalcetide, is often used to control parathyroid hormone (PTH) levels in hemodialysis (HD) patients. In a head-to-head clinical trial, etelcalcetide was superior to cinacalcet on PTH reduction. Given that oral administration of cinacalcet is susceptible to challenges of self-management and adherence, etelcalcetide may be even more effective in the real-world setting. To limit confounding by indication, we used a facility calcimimetic preference approach to investigate the comparative effectiveness of etelcalcetide vs. cinacalcet by estimating effects on PTH and other mineral and bone disorder (MBD) markers in a cohort of US HD patients. Method We used data from the US Dialysis Outcomes and Practice Patterns Study (US-DOPPS), a prospective cohort study of in-center HD patients. During a 6-month run-in period from March to August 2019, we evaluated facility calcimimetic preference by calculating the proportion of calcimimetic users in each facility who were prescribed etelcalcetide (vs. cinacalcet). Among patients with any prescription for a calcimimetic during the 6-month run-in period, we evaluated MBD marker outcomes (PTH, albumin-corrected serum calcium [Ca], serum phosphorus [P]), averaged over the subsequent 6 months, from September 2019 to February 2020. We compared HD facilities that treated >75% of calcimimetic users with etelcalcetide (“Etel-first”) vs. those that treated >75% of calcimimetic users with cinacalcet (“Cina-first”). Linear regression was used to model each continuous outcome. Modified Poisson regression was used to estimate the prevalence ratio (PR) of each MBD marker being out of target (PTH >600 pg/mL, Ca 5.5 mg/dL). All models were adjusted for patient-level and facility-level confounders and accounted for facility clustering using GEE. Results We excluded 38 HD facilities with little-to-no calcimimetic use (600 was lower (PR=0.75; 95% CI: 0.60, 0.94) in adjusted models. The adjusted mean levels of serum Ca and serum P (secondary outcomes) were slightly lower in Etel-first (vs. Cina-first) facilities [Table 1]. Conclusion To our knowledge, this is the first large-scale comparison of IV etelcalcetide with oral cinacalcet in the real-world setting. Our unique approach resembles a natural experiment by leveraging practice variation across the US and isolating HD facilities with a clear preference for one calcimimetic. Thus, the prescribed calcimimetic type for included patients was more likely determined by facility preference than biased by patient indication. Our results indicate better PTH control (mean levels ∼100 pg/mL lower) in US HD facilities using etelcalcetide (vs. cinacalcet) as the primary calcimimetic therapy. Further research is needed to investigate the degree to which the greater real-world effectiveness of IV etelcalcetide (vs. oral cinacalcet) may be driven by adherence to the prescribed therapy, and how clinical outcomes may be affected.

Background and Aims Oral cinacalcet (CIN) and IV-administered etelcalcetide (ETEL) are calcimimetics available for the management of secondary hyperparathyroidism (SHPT) in hemodialysis (HD) patients. This pilot study assessed patient adherence to calcimimetic therapy and calcimimetic preference of nephrologists and nurses based on adapted questionnaires. Method A cross-sectional survey was conducted with HD patients currently using a calcimimetic, and nephrologists and dialysis nurses who prescribed/administered calcimimetic in 7 European countries (Belgium, France, Germany, Italy, Spain, Sweden and the United Kingdom). Patient questionnaires were adapted from the Medication Adherence Report Scale (MARS), the Beliefs about Medicines Questionnaire (BMQ-specific Necessity and Concern), and Treatment Intrusiveness Scale (TIS) to understand patterns of adherence and perceptions of medications; questions about gastrointestinal (GI) symptoms were included. Questionnaires for nephrologists and nurses were adapted from the Treatment Rating Scale (TRS), Health Professional Preference Scale (HPPS), and Prescribing Comparator Scale (PCS) to understand calcimimetic preference. Questionnaires were translated and administered in the local language. Results Sixty HD patients (33 CIN and 27 ETEL), 16 nephrologists and 18 dialysis nurses participated in the survey. ETEL patients were younger than CIN patients (mean age: 57 vs. 59 yrs). ETEL patients also had a lower pill burden (mean no. of pills: 6 vs. 11) and had numerically fewer hospitalizations in the last 6 months (mean no. of days: 1.5 vs 3.9) than CIN patients. Self-reported adherence to CIN was high (mean MARS: 4.7±0.7). ETEL and CIN patients did not perceive medications (excluding dialysis, diet and dietary restrictions) as interfering with their life (mean TIS: 1.5±0.5 vs. 1.6±1.6) and neither calcimimetic group had a specific belief in medicines in terms of necessity (mean BMQ CIN: 2.4±0.6 and ETEL: 2.3±0.4) or concerns about potential side-effects (mean BMQ CIN: 3.1±0.6 and ETEL: 3.5±0.7). ETEL patients were less likely than CIN patients to experience GI symptoms in the prior month: nausea (11% vs. 49%), vomiting (11% vs. 24%), and diarrhea (15% vs. 33%). Overall, the adapted patient questionnaires showed good internal consistency for MARS (Cronbach’s α=0.99) and BMQ-Necessity and BMQ-Concerns scales (CIN: α=0.74 and ETEL: α=0.81) but lower consistency for TIS (α=0.3 for both CIN and ETEL). Nephrologists and nurses had been practicing for a mean of 17 yrs. Nephrologists and nurses viewed ETEL to have more efficacy, lower risk of side effects, lower risk of non-adherence, lower burden for patients compared to CIN according to the TRS. According to HPPS, the top 3 treatment attributes for ETEL preference vs. CIN among nephrologists were encouraging patient adherence (93%; n=14/15), minimizing patient burden (87%; n=13/15) and having fewer side effects (80%; 12/15). Similar for nurses, encouraging patient adherence (88%; n=15/17) and minimizing patient burden (94%; n=16/17) were top attributes for ETEL preference as well as improving patient quality of life (82%; 14/17). Based on PCS, the majority of nephrologists agreed that compared to CIN, ETEL will ensure high adherence (100%), achieve better PTH control (93%; 14/15), reduce treatment burden for patients (87%; 13/15), improve patient’s quality of life (80%; 12/15), and improve effectiveness without increasing side-effects (80%; 12/15); they also agreed that ETEL created more work for nursing staff (80%; 12/15). Two thirds of nephrologists (n=10/15) agreed that ETEL would be more efficacious than CIN. Conclusion In this pilot study, CIN patients self-reported high adherence and both calcimimetic groups did not perceive medications to be concerning or intrusive. Nephrologists and nurses showed preference for ETEL than CIN. The questionnaires were validated and will be administered in a large study.

Background and Aims Vitamin D analogues stimulate the absorption of calcium and phosphorus, while calcimimetics reduce parathyroid hormone (PTH) without calcium and phosphorus elevation, which reduces the risk of vascular calcification. However, the biggest problem of first-generation calcimimetics is the lack of adherence due to abandonment or non-compliance due to side effects and the high load of tablets taken by our patients. Method A prospective and exploratory 24-week study, which included 54 adult patients on chronic hemodialysis (3 times per week) with secondary hyperparathyroidism (PTH >=150 pg/ml). Thirty-three patients were converted from cinacalcet to etelcalcetide, due to the lack of adherence to cinacalcet treatment and the inability to increase the dose due to the side effects of cinacalcet. The remaining 21 patients started etelcalcetide without previously taking cinacalcet. The dose of etelcalcetide was done according to the baseline PTH value. PTH >150 and 300 and 500 and 800 pg/ml with 15mg/week. Results In the first four weeks, calcium decreased significantly, but subsequently remained stable for the rest of the study. From the baseline to the 24-week, serum calcium 8.85 ± 0.85 vs. 8.43 ± 0.83 mg/dl (p 0.05). PTH decreased significantly at the end of the study (718.4 ± 450 vs. 391.3 ± 232.7 pg/ml, p =0.03). PTH was reduced by 42% in the group that changed cinacalcet to etelcalcetide, and 50% in the group that did not take calciomimetics before the study. At the beginning of the study, 61.1% of our sample also maintained paricalcitol as a treatment for secondary hyperparathyroidism. At the end of week 24, 51.8% maintained paricalcitol but with a significant reduction of 36.8% of the dose of paricalcitol (3.22 ± 3.78 mg/week), without significant changes in the dose of etelcalcetide at the end of the study (9.5 ± 1.3 mg/week) . No symptomatic hypocalcaemia was recorded throughout the study. At week 12, the dose of etelcalcetide was reduced in 11% of patients and 7% at the end of week 24 due asymptomatic hypocalcemia. Conclusion Etelcalcetide showed a significant reduction in PTH with the optimization of therapeutic compliance. In our population, the use of paricalcitol was reduced by 30% due to a progressive increase in the dose of etelcalcetide, keeping calcium levels stable and safe. Asymptomatic hypocalcemia was the most observed side effect, but it is claimed that etelcalcetide has an even better safety profile than cinacalcet, with respect to digestive side effects. It is advisable to use Etelcalcetide by individualizing the dose in each patient, depending on their levels of PTH and calcium.

Background and Aims Chronic kidney diseases disrupt normal bone-mineral axis endocrine functions causing the onset of mineral bone disorders (MBDs). The general and hemodialysis (HD) populations have been found to exhibit diurnal rhythms in phosphate (PO4), calcium (Ca), and parathyroid hormone (PTH) regulation (Trivedi et al. J Nephrol. 2015), but reference values for fluctuations have not been established in HD patients and do not consider PO4 binder use. We profiled the diurnal rhythms of MBD labs overall and stratified by PO4 binder use in a large nationally representative HD population in the United States. Method We used prevalent in-center HD patient (vintage >90 days) data on adults (age ≥18 years) treated at a dialysis organization in 2018. Mean annual pre-HD blood PO4, corrected Ca, and intact PTH levels were computed in 2-hour periods through 24 hours for the population and stratified by binder use. HD initiation time was a varying exposure, allowing patients to switch time groups if blood draws occurred in multiple time periods. Mean MBD lab levels with 95% confidence limits were plotted using nonparametric smoothing spline models to fit data and calculate trajectories throughout the day. Results The population of adult HD patients (n=156,873) was: mean age 62.8±14.3 years, 57.1% male, 58.2% white race, 41.9% with diabetes, 19.6% with congestive heart failure, and HD vintage 1510±1289 days. Mean pre-dialysis albumin=3.8±0.4 g/dL, PO4=5.4±1.5 mg/dL, corrected Ca=9.1±0.6 mg/dL, PTH=468±333 pg/dL for the population. Mean PO4, corrected Ca and PTH levels varied remarkably by 0.9 mg/dL, 0.2 mg/dL, and 186 pg/dL throughout the day. For PO4 and PTH, nadir levels occurred from 0900 to 1100 hours (5.3±1.6 mg/dL and 473±340 pg/dL), followed by a rise to a mid-day peak from 1700 to 1900 hours (5.8±1.8 mg/dL and 562±401 pg/dL), and the highest levels had a peak time from 2300 to 0100 hours (6.2±2.1 mg/dL and 659±389 pg/dL) (Figure 1A & C). Corrected Ca showed relatively inverse fluctuations to PO4 and PTH, with peak levels from 1100 to 1300 hours (9.2±0.7 mg/dL) and nadir levels from 1900 to 2100 hours (9.0±0.7 mg/dL) (Figure 1B). Similar fluctuations and levels were observed for PO4 and PTH among patients using any phosphate binder type (90.7%), however, patients not using a phosphate binder exhibited absolute values that were persistently lower at every timepoint (Figure 1D & F). Corrected Ca levels were similar by any binder use (Figure 1E). Conclusion Our results suggest PO4, Ca, and PTH levels have a diurnal variation of 0.9 mg/dL, 0.2 mg/dL, and 186 pg/dL in hemodialysis patients. PO4 and PTH exhibit a nadir in the morning, a mid-day peak and a larger nocturnal peak. Ca exhibits relatively inverse diurnal fluctuations with PO4 and PTH. Patients using any binder exhibit similar fluctuations and levels of PO4 and PTH; while patients not requiring a binder have similar fluctuations, yet persistently lower levels of PO4 and PTH. Given PO4 binder and calcimimetic therapies are commonly used for treatment of MBDs based on pre-dialysis blood levels, these findings provide insights for further research and pose the question if algorithms are warranted to compute daily time-adjusted levels for MBD laboratories.

Background and Aims Active vitamin D analogs and calcimimetics are cornerstones for managing secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). Their direct effects on bone cells remain to be determined. Method Peripheral blood mononuclear cells (PBMCs) of 19 pediatric CKD patients and 6 healthy donors (HD) were differentiated into osteoclasts in presence of M-CSF and RANKL. Effect of combined or single treatment with active vitamin D (1.25-D) and/or the calcimimetic KP2326 were evaluated onto osteoclast differentiation and osteoclast mediated bone resorption. Results 1.25-D inhibited osteoclastic differentiation, a significant resistance to 1.25-D was observed when CKD worsens. A significant albeit less important inhibitory effect of KP2326 on osteoclastic differentiation was also found both in cells derived from HD and CKD patients, through an activation of the Erk pathway. This inhibitory effect was not modified by CKD stage. Combinatorial treatment with 1.25-D and KP2326 did not result in synergistic effects. Last, KP2326 significantly inhibited human osteoclast-mediated bone resorption. Conclusion Both 1.25-D and KP2326 inhibit osteoclastic differentiation, however to a different extent. Whilst 1.25-D has no significant effect on bone resorption, KP2326 inhibits bone resorption. Recent data showed that calcimimetics also have a direct anabolic effect on bone, through the stimulation of osteoblastic differentiation and mineralization in human mesenchymal stem cells in vitro. All these results provide a strong rationale for a global positive effect of calcimimetics on bone remodeling. Calcimimetics also significantly decrease FGF23 levels. In the setting of global systematic deleterious effects of high FGF23 levels in CKD, and keeping in mind that active vitamin D analogs stimulate FGF 23 production, all these data could favor the use of decreased doses of 1.25-D with low-doses of calcimimetics in SHPT in dialysis, the combination of these two therapies already being proposed in the 2017 K-DIGO guidelines.

Objective Secondary hyperparathyroidism (SHPT) is a major complication in patients with chronic kidney disease (CKD). SHPT is related to chronic kidney disease-mineral bone disorder, leading to increased morbidity and mortality. Etelcalcetide is intravenously administered at the end of hemodialysis (HD). Etelcalcetide differs from the oral calcimimetic cinacalcet because it reduces gastrointestinal adverse events, thereby improving therapeutic effects. Etelcalcetide has only been approved by the U.S. Food and Drug Administration for several months. Therefore, there have only been a few reports regarding treatment of SHPT using etelcalcetide. This study aimed to evaluate the efficacy of etelcalcetide in patients on HD with SHPT. Methods Nine patients on HD (four men and five women, aged 58 ± 10 years) were enrolled in this study. All of the patients received etelcalcetide (5–10 mg, three times a week after HD). The observation period was 4.4 ± 1.0 months. Results All of the patients showed a significant reduction in serum parathyroid hormone levels during the observation period (−59% ± 20%). No significant adverse effects were observed. Conclusions Although this study had an uncontrolled small group and a short observation period, our results suggest that etelcalcetide could be a promising agent for SHPT treatment.

During the process development of Cinacalcet hydrochloride, a calcimimetic agent, we encountered an unexpected substantial increase in the content of impurities in the product while scaling up the process in the pilot plant. Detailed investigation led to the conclusion that the agitation speed of the reaction mass impacted the reaction kinetics of Schiff’s base, leading to the formation of the impurities and lowering the product yield to ca. 40%. The present work reports details of an investigation carried out to control the formation of impurities to achieve an efficient and one-pot process for Cinacalcet hydrochloride with an overall yield of ca. 70%.

Etelcalcetide hydrochloride (also known as AMG 416) is a new, second generation, long-acting calcimimetic agent that is administered intravenously. In November 2016 it received its first approval in the UE for the treatment of secondary hyperparathyroidism (SHPT) in adult haemodialysis patients. This article summarizes the results of pre-clinical and clinical studies which demonstrated that Etelcalcetide decreases effectively PTH levels. Although questions about this new compound remain open, and further studies are required to assess clinical hard outcomes as well as long term efficacy and safety, Etelcalcetide represents a new therapeutic option for the challenging treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD).

Etelcalcetide hydrochloride (also known as AMG 416) is a new, second generation, long-acting calcimimetic agent that is administered intravenously. In November 2016 it received its first approval i...

Use of calcimimetics will be influenced not only by assessment of benefits and harms in individual patients but also by cost and by national guidelines. The Japanese Society for Dialysis Therapy has a lower PTH threshold for PTH control than other countries. The current RCT, despite its limitations, provides a rationale for use of evocalcet in the management of secondary hyperPTH.

The main cause of death in patients with parathyroid carcinoma is parathyroid hormone (PTH)-induced hypercalcemia. To date, the management of hypercalcemia has been based on the use of bisphosphonates and calcimimetic agents. In recent reports, the use of denosumab has shown encouraging results in cases of refractory hypercalcemia of malignancy. Our objective is to present a case of successful management of resistant hypercalcemia due to parathyroid carcinoma with denosumab, to review similar cases from the literature, and to propose denosumab's use in the clinical management of PTH-induced refractory hypercalcemia.Presentation of a case report and review of the literature for cases of parathyroid carcinoma-mediated hypercalcemia successfully treated with denosumab.A 71-year-old man with metastatic parathyroid carcinoma was referred to our department for uncontrolled hypercalcemia, resistant to treatment with bisphosphonates and cinacalcet. Treatment with denosumab (120 mg per month) in addition to cinacalcet (180 mg per day) resulted in normalization of calcium levels and maintenance within the normal range for an observation period of 11 months. Review of the literature revealed 4 case reports and a letter to the editor, all of which reported the successful treatment of resistant hypercalcemia associated with parathyroid carcinoma.Based on the above findings of the effectiveness of denosumab in controlling refractory hypercalcemia, its safety in renal failure and the fact that denosumab may reduce PTH-induced bone loss, we endorse its use in the management of hypercalcemia in patients with parathyroid carcinoma and perhaps other conditions with PTH-induced hypercalcemia.

Secondary hyperparathyroidism is almost a constant feature in chronic kidney disease (CKD) patients maintained on hemodialysis (HD). Calcimimetic agents appear to offer an alternative to surgery in controlling secondary hyperparathyroidism in these patients. Recent studies provide conflicting data on the benefits, efficacy and tolerance of cinacalcet as first-line therapy for the treatment of secondary hyperparathyroidism in CKD. This study was designed to investigate the efficacy and tolerance of a low dose of the calcimimetic agent cinacalcet in patients on long-term HD having moderate to severe secondary hyperparathyroidism. Twenty five adult male patients on HD for more than three years were included in the study. All had moderate to severe secondary hyperparathyroidism with serum intact parathyroid hormone (iPTH) >50 pmol/L, resistant to conventional treatment. We used the targets of Chronic Kidney Disease: Outcomes Quality Initiative (K/DOQI) clinical guidelines as optimal target of serum iPTH, calcium and phosphate. Patients were administered cinacalcet as a single oral daily dose of 30 mg and were followed-up for six months. Cinacalcet treatment for six months resulted in a significant reduction in the serum phosphate and iPTH levels while the serum calcium levels remained unchanged. Thirty-six percent of the patients attained the recommended serum iPTH levels, 40% achieved significant reduction of the serum iPTH levels and 24% showed no favorable response. Only one patient dropped out because of severe gastrointestinal symptoms. Our results suggest that treatment of CKD patients, having moderate to severe secondary hyperparathyroidism, with low-dose cinacalcet is effective and well tolerated.

Vascular calcification, both in the coronary and in the peripheral arteries, is associated with increased cardiovascular (CV) risk. However, agents that prevent vascular calcification (e.g. estrogens or calcimimetic agents) might have neutral or detrimental effects on CV events. Moreover, statins and antihypertensive agents do not appear to modify vascular calcification, despite their established benefits on CV disease prevention. On the other hand, recent data suggest that microRNAs play a role in the regulation of vascular calcification. It is therefore possible that modulation of the expression of microRNAs might represent a useful strategy for preventing or delaying the progression of this process.

Purpose of Review The treatment of CKD-MBD (Chronic Kidney Disease-Mineral Bone Disorder) has traditionally focused on improvement in biochemical parameters of the disease. However, studies evaluating hard clinical end points or surrogate end points are limited.

Uncontrolled secondary hyperparathyroidism (sHPT) in patients with ESRD is a risk factor for calcific uremic arteriolopathy (CUA; calciphylaxis).Adverse event reports collected during the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events trial were used to determine the frequency of CUA in patients receiving hemodialysis who had moderate to severe sHPT, as well as the effects of cinacalcet versus placebo. CUA events were collected while patients were receiving the study drug.Among the 3861 trial patients who received at least one dose of the study drug, 18 patients randomly assigned to placebo and six assigned to cinacalcet developed CUA (unadjusted relative hazard, 0.31; 95% confidence interval [95% CI], 0.13 to 0.79; P=0.014). Corresponding cumulative event rates (95% CI) at year 4 were 0.011% (0.006% to 0.018%) and 0.005% (0.002% to 0.010%). By multivariable analysis, other factors associated with CUA included female sex, higher body mass index, higher diastolic BP, and history of dyslipidemia or parathyroidectomy. Median (10%, 90% percentile) plasma parathyroid hormone concentrations proximal to the report of CUA were 796 (225, 2093) pg/ml and 410 (71, 4957) pg/ml in patients randomly assigned to placebo and cinacalcet, respectively. Active use of vitamin K antagonists was recorded in 11 of 24 patients with CUA, nine randomly assigned to placebo, and two to cinacalcet, in contrast to 5%-7% at any one time point in patients in whom CUA was not reported.Cinacalcet appeared to reduce the incidence of CUA in hemodialysis recipients who have moderate to severe sHPT.

This paper reflects the position of the CKD-MBD workgroup, an official working group of ERA-EDTA and of the ERBP advisory board, the official guideline-producing body of ERA-EDTA, on the topic of the use of calcimimetics in patients with CKD stage 5D, as based on two recent meta-analysis.

Chiral rhodium(I)-catalyzed highly enantioselective arylation of aliphatic N-sulfonyl aldimines with arylboronic acids has been developed. This transformation is achieved by the use of a rhodium/bis(phosphoramidite) catalyst to give enantiomerically enriched α-branched amines (up to 99 % ee). In addition, this system enables efficient synthesis of (+)-NPS R-568 and Cinacalcet which are calcimimetic agents.

The authors show that cinacalcet, which mediates allosteric modulation of the calcium-sensing receptor, corrects loss of function of AP2S1 mutations that cause familial hypocalciuric hypercalcemia type 3 and ameliorates symptomatic hypercalcemia.

Chiral rhodium(I)-catalyzed highly enantioselective arylation of aliphatic N-sulfonyl aldimines with arylboronic acids has been developed. This transformation is achieved by the use of a rhodium/bis(phosphoramidite) catalyst to give enantiomerically enriched α-branched amines (up to 99 % ee). In addition, this system enables efficient synthesis of (+)-NPS R-568 and Cinacalcet which are calcimimetic agents.

Resumen Fundamento y objetivo Cinacalcet reduce la hormona paratiroidea (PTH) en el hiperparatiroidismo (HPT) uremico. En el trasplante renal ayuda al manejo del HPT con hipercalcemia. Pretendemos valorar si cinacalcet, administrado en dosis unica diaria, reduce y mantiene descendido el valor de PTH durante 24 horas en el trasplantado renal con HPT e hipercalcemia. Pacientes y metodo Estudiamos la PTH y otros biomarcadores oseos en dos grupos de trasplantados renales: uno con HPT e hipercalcemia (Grupo 1), otro sin alteracion del metabolismo mineral (Grupo 2), y un tercer grupo de voluntarios sanos (Grupo 3). En total se incluyeron 35 sujetos. El Grupo 1 recibio cinacalcet a dosis de 60 mg via oral en dosis unica a las 9 horas. A todos se les extrajeron muestras de sangre a las 8, 10, 11, 12, 13, 19 horas (dia 1) y 9 horas del dia siguiente (dia 2), determinando valores de PTH y biomarcadores oseos. Resultados En el Grupo 1, el valor basal de PTH descendio de forma significativa en los instantes posteriores, observando un valor similar en el dia 2. En el Grupo 2, la PTH basal fue superior respecto al valor 10 h (p Conclusiones Cinacalcet reduce la PTH en trasplantados renales con HPT e hipercalcemia, sin matenerlo durante 24 horas, y no modifica otros biomarcadores oseos.

Objective: Cinacalcet is a calcimimetic agent, recommended for treating refractory secondary hyperparathyroidism in patients undergoing dialysis. The aim of this study was to evaluate the efficacy and safety of cinacalcet, comparing patients with baseline iPTH > 300 pg/ml with those with iPTH 300 pg/ml and 11 with iPTH 30%. The safety was evaluated based on the most frequent adverse effects and the levels of serum calcium 300 had significant differences before and after cinacalcet treatment in iPTH (563.49 + 286.88 pg/ml vs 315.15 + 201.948 pg/ml; P = .017) and serum calcium (9.1 + 1.77 mg/dl vs 8.15 + 1.2 mg/dl; P = .02). There were no significant differences in patients with initial iPTH 300pg/ml, and only in 27.3% of those with basal iPTH 300 pg/ml.

Resume L’etiologie principale de la resistance aux agents stimulants l’erythropoiese (ASE) utilises dans le traitement de l’anemie chez les hemodialyses chroniques (HDC) est la carence martiale absolue ou fonctionnelle. L’hyperparathyroidie secondaire (HPTS) constitue un des facteurs secondaires de resistance. En effet, il a ete rapporte dans la litterature une amelioration des parametres de l’anemie apres parathyroidectomie (PTX). L’objectif de cette etude est d’evaluer, chez des HDC, l’impact de la correction de l’HPTS par un calcimimetique, le cinacalcet (CI), (ce qui est considere comme une PTX pharmacologique) sur la reponse aux ASE evaluee par l’index de resistance a l’erythropoietine (IRE). Vingt-deux HDC presentant une HPTS severe documentee par un taux de parathormone intacte (PTHi) superieur a 800 pg/mL ont ete inclus dans cette etude pilote prospective. Nous avons realise une exploration du metabolisme mineral et osseux, de l’anemie et des parametres nutritionnels avant initiation du CI (M0) et pendant les six mois d’etude. L’effet sur l’anemie est evalue en fin d’etude par l’IRE, la variation des concentrations d’Hb et la proportion des patients presentant un taux d’Hb superieur a 11 g/dL. Resultats En fin d’etude on note une diminution significative (M6 vs M0) de la PTHi (1302 vs 674 pg/mL soit −48 %, p = 0,006), de la calcemie (2,39 vs 2,15 mmol/L soit −10 %), de la phosphoremie (2 vs 1,7 mmol/L soit–15 %), du produit phosphocalcique (CaxP) (4,8 vs 3,8 mmol2/L2 soit − 20 % (p 4,4 mmol2/L2 (64 vs 32 %, p 11 g/dL (50 vs 70 %, p Conclusion Un traitement par calcimimetique ameliore le controle de l’anemie par les ASE chez les HDC et interfere positivement sur l’une des causes de resistance secondaire aux ASE representee par l’HPTS. Le mecanisme des ces effets pourrait etre lie a une diminution de la fibrose medullaire et du processus inflammatoire et au tryptique constitue par la diminution de la PTHi, du CaxP et de la phosphoremie.

Resume L’hyperparathyroidie secondaire est associee a une augmentation du risque fracturaire et de mortalite chez les patients dialyses. Les traitements classiques tels les derives actifs de la vitamine D et la chirurgie s’averent efficaces mais limites. Les calcimimetiques permettent de controler la concentration serique de PTH tout en diminuant le produit phosphocalcique. Cet article revise les bases physiologiques de la regulation de la PTH, le mode d’action des calcimimetiques et les resultats des etudes precliniques et cliniques evaluant les effets des calcimimetiques sur differents parametres cliniques, biochimiques et histologiques.

Background: Calcific uremic arteriolopathy is an uncommon cutaneous ischemic necrotizing disease, most commonly associated with renal disease and hyperparathyroidism, bearing a high mortality rate. Objective and Method: A case of a 57-year-old female renal patient with hyperparathyroidism who was successfully treated with combined paricalcitol and cinacalcet systemically, while autologous growth factors were locally applied, is herein presented. Result and Conclusion: The combination of cinacalcet and paricalcitol is a reliable alternative to parathyroidectomy in patients with calcific uremic arteriolopathy and hyperparathyroidism. Meticulous débridement of necrotic tissues is essential and application of autologous growth factors promotes healing.

An asymmetric synthesis of the calcimimetic agent NPS R-568 using a (1R,2S)-N-benzylephedrine-promoted addition of dimethylzinc to a diphenylphosphinoylimine derived from 3-methoxybenzaldehyde is described. The enantiomeric ratio of the key amine fragment was determined to be 93:7 (86% ee), favoring the (R)-enantiomer by derivatization and chiral stationary phase HPLC analysis. Copyright © 2010 John Wiley & Sons, Ltd.

Resume Introduction Le cinacalcet (CC) a transforme le traitement de l’hyperparathyroidie secondaire (HPTS) et tertiaire (HPTT) des patients dialyses. Le but de cette etude est d’evaluer prospectivement l’efficacite et la tolerance du CC dans le traitement de l’HPTS resistante aux therapeutiques conventionnelles et de l’HPTT chez des patients traites par hemodialyse longue dans un meme centre. Patients et methodes Entre septembre 2004 et septembre 2009, nous avons suivi tous les patients hemodialyses traites par CC. Nous decrivons leurs caracteristiques en comparaison de celles des autres patients du centre. Nous avons compare les parametres biologiques et les traitements des patients avant l’introduction du CC (T-0) et aux dernieres nouvelles (T-fin). Les patients etaient dialyses trois fois par semaine avec une duree moyenne de seance de six heures 20 minutes (cinq heures a huit heures). Les criteres de prescriptions de CC etaient une PTH superieure a 300 pg/ml associee a une calcemie superieure a 2,45 mmol/l et a des phosphatases alcalines osseuses superieures a 20 μg/l, ou associee a une calcemie superieure a 2,55 mmol/l temoignant d’une HPTT. Resultats Quatre-vingt-un patients sur 550 prevalents ont ete traites par CC (14,7 %). Ils etaient plus jeunes, avec un index de masse corporelle (IMC) et des apports proteiques (nPCR) plus eleves que le reste de la population. Parmi les patients traites, 6,1 % ont eu un echec therapeutique, 12,3 % un arret pour intolerance digestive severe, 10 % ont du avoir une parathyroidectomie (PTX) et 81,4 % ont poursuivi le traitement avec une posologie finale de CC de 51 ± 30 mg/j. Entre T-0 et T-fin (18 ± 15 mois), la PTH a diminue de 77 %, la calcemie de 10 % et la phosphatemie de 14 % permettant d’ameliorer significativement la proportion des patients dans les cibles biologiques pour la PTH (150–300 pg/ml : de 0 a 50 %), la calcemie corrigee (2,1–2,37 mmol/l : de 6 a 77 %) et la phosphatemie (1,15–1,78 mol/l : de 58 a 84 %). Un sevrage au long cours a ete possible chez huit patients (10 %). Aucune hypocalcemie inferieure a 2 mmol/l n’a ete observee. Les traitements par alfacalcidol (de 68 a 40 %) et sevelamer (de 72 a 50 %) ont diminue, les traitements par CaCO 3 sont restes stables (20 %), ceux par vitamine D native ont augmente (de 55 a 95 %). Conclusion Meme s’il n’est pas toujours bien tolere et efficace, le traitement par CC, associe aux derives de la vitamine D, permet de traiter la grande majorite des HPTS et HPTT des patients dialyses qui ont resiste aux traitements conventionnels, avec une amelioration spectaculaire du metabolisme mineral.

A method has been developed for the preparation of amines through a process of coupling acyl succinimides derived from commercially available carboxylic acids with amines to afford the corresponding amides. These amides are then reduced in situ with either diisobutylaluminum hydride or lithium aluminum hydride. The reaction tandem of the coupling reaction followed by the reduction affords the amine in fair to good yields after purification by flash chromatography. This one-pot, two reaction tandem process has been successfully applied to the synthesis of the calcimimetic agents cinacalcet, NPS R-467, and NPS R-568.

It is increasingly acknowledged that mineral and bone disorders (MBDs) contribute to the excessively high cardiovascular (CV) disease morbidity and mortality observed in patients with chronic kidney disease (CKD). There is ongoing debate as to whether screening for CV calcification, one of the hallmarks of CKD-MBD, should be implemented in clinical practice in patients with CKD. Issues to be considered in this controversy relate to prevalence, severity, relevance, and last but not least, modifiability and reversibility of vascular and valvular calcifications in the setting of CKD. The recent expansion of the armamentarium to treat CKD-MBD (calcium-free phosphate binders and calcimimetics) creates new opportunities. Mounting experimental and clinical evidence indicates that progression of CV calcification may indeed be attenuated. Whether this will translate into better outcomes remains to be proven. We acknowledge that hard outcome data so far are limited and, overall, yielded inconclusive results. Nevertheless, in an era in which personalized medicine has gained much popularity, we consider it reasonable, awaiting the results of additional studies, to screen for CV calcification in selected individuals. This policy may help to stratify CV risk and to guide therapy. We speculate that such an approach will ultimately improve outcomes and reduce health costs. © © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

La regulation de la calcemie se fait par l’intermediaire du Recepteur Sensible au Calcium (CaSR), dont la decouverte il y a 10 ans a permis d’elucider de nombreux tableaux cliniques. Les pathologies liees aux anomalies du CaSR se manifestent par une hypo ou une hypercalcemie associee a une calciurie inadaptee, d’origine genetique ou auto-immune. Les causes d’hypercalcemie liees a une mutation du CaSR sont l’Hypercalcemie Hypocalciurique Familiale et les hypercalcemies severes neonatales ou plus tardives. Les hypocalcemies d’origine genetique sont representees par les hypocalcemies autosomiques dominantes et leurs formes sporadiques. Une forme voisine du syndrome de Bartter a egalement ete rapportee. Des anticorps bloquants ou stimulants diriges contre ce recepteur, evoluant souvent dans un contexte de pathologies auto-immunes, peuvent mimer ces pathologies. Enfin, les polymorphismes du gene du CaSR modulent le niveau de la calcemie. Le diagnostic de ces differentes affections est important afin d’eviter les therapeutiques deleteres. Par ailleurs, de nouvelles perspectives therapeutiques telles que celles offertes par les calcimimetiques dans l’hyperparathyroidie decoulent de la decouverte de ce recepteur.

Medical therapy is useful in cases of acute primary hyperparathyroidism, patients with recurrent disease, and parathyroid carcinoma. Among the therapeutic agents that have been employed, oral phosphate, bisphosphonates, and estrogens have been successful. The newly described calcimimetic agents directly block secretion of parathyroid hormone from the glands and offer an important new approach to medical therapy of primary hyperparathyroidism.

Secondary hyperparathyroidism is a common complication for patients with end-stage renal disease (ESRD). When it progresses, it is associated with morbidity and mortality [1]. Phosphate binders and vitamin D can be used to prevent the progression of secondary hyperparathyroidism. However, these conservative treatments often fail to control severe hyperparathyroidism. In such cases, parathyroidectomy is required. Despite medical management after parathyroidectomy, persistent or recurrent hyperparathyroidism can occur. One of the causes of recurrent hyperparathyroidism is parathyromatosis, which has been described as multiple nodules or rests of hyperfunctioning parathyroid tissue that become evident following parathyroidectomy. We describe a female haemodialysis patient diagnosed with secondary hyperparathyroidism, which was probably caused by parathyromatosis. Treatment with cinacalcet, a calcimimetic agent, in combination with vitamin D was extremely effective.

A practical synthesis of cinacalcet (Sensipar®, Mimpara®) is described. The synthesis starts from readily available starting materials and relies on safe and practical reaction conditions. The sequence comprises three synthetic steps and only one isolation point. The overall yield for the sequence is 85%.

We present the case of a 61-year- old female patient in long-term hemodialysis who developed calcific uremic arteriolopathy (CUA) upon administration of the oral calcimimetic agent cinacalcet for treatment of secondary hyperparathyroidism. In May 2009, the baseline serum values were parathormone (PTH) 310 pg/ml, calcium 9.1 mg/dl and phosphorous 6.9 mg/dl. Necrotic wounds in the suprapubic fat tissue were successfully treated first, by correcting the calcium phosphorous product; second, through treatment with sodium thiosulfate and third, through intensive wound care with hyperbaric oxygen therapy and vacuum-assisted closure therapy, with no need for parathyroidectomy. Multiple factors have been described to play a role in the development of CUA. Based on the findings of this case, the treatment of CUA should be aimed at correcting different causes simultaneously.