Maxacalcitol,a medicine for secondary hyperparathyroidism (2 degrees HPT)

Maxacalcitol (Oxarol) is a derivative of vitamin D compounds applied for the secondary hyperparathyroidism (2 degrees HPT) of hemodialysis (HD) patients as an injection and psoriasis as an ointment. 2 degrees HPT is one of the complications in HD patients with hyperplasia of parathyroid glands and elevated serum parathyroid hormone (PTH) levels. On the other hand, vitamin D compounds are known to have multiple actions in many organs (promotion of calcium absorption from the small intestine, induction of differentiation of leukemia cells, differentiation and proliferation of the chondrocyte, muscle cells and epidermal cells, immunosuppressive activities) and their activities on parathyroid glands seem to be mediated by the vitamin D receptor (genomic action). It was reported that both serum PTH and PTH mRNA levels were suppressed by Maxacalcitol with less calcemic action and also Maxacalcitol could ameliorate high-turnover bone and marked osteitis fibrosa in uremic rats. Here I review many reports focused on the effects of Maxacalcitol on the 2 degrees HPT.     

The calcimimetic agent KRN 1493 lowers plasma parathyroid hormone and ionized calcium concentrations in patients with chronic renal failure on haemodialysis both on the day of haemodialysis and on the day without haemodialysis

AIMS: Treatment with vitamin D sterols can lower plasma parathyroid hormone (PTH) in patients with secondary hyperparathyroidism; however, hypercalcaemia, hyperphosphataemia, or both, often develop. Calcimimetic agents, employed in alternative therapeutic approaches, directly inhibit PTH secretion by activating the calcium-sensing receptor in the parathyroid glands. METHODS: In this study, patients were given orally 25, 50, and 100 mg doses of the calcimimetic agent KRN 1493 each on two occasions, on the day of haemodialysis and on the day without haemodialysis. RESULTS: In the pharmacokinetic results, because the clearance of KRN 1493 by haemodialysis was much smaller than the systemic clearance, the influence of haemodialysis was not remarkable. In the pharmacodynamic study, on both the days with or without haemodialysis, plasma PTH concentrations decreased in a dose-dependent manner. Serum calcium concentrations decreased in association with the decrease in plasma PTH concentrations. Mild dose-dependent adverse effects (mainly nausea) were seen after the administration of KRN 1493 on both the day of haemodialysis and the day without haemodialysis. CONCLUSIONS: We conclude that the pharmacokinetics of KRN 1493 after a single administration were similar on the day of haemodialysis and the day without haemodialysis. KRN 1493 is safe and effective in suppressing PTH secretion and serum calcium concentrations on the day of haemodialysis and on the day without haemodialysis in patients with secondary hyperparathyroidism.     

Parathyroid gland regulation: contribution of the in vivo and in vitro models

Importance of the field: The current regulation of parathyroid hormone (PTH) and the development of parathyroid disorders in chronic kidney disease involve complex mechanisms. Factors such as calcium, phosphorous, calcitriol, vitamin D receptor, calcium-sensing receptor and fibroblast growth factor 23 play a key role in the regulatory process in the pathogenesis of secondary hyperparathyroidism. Areas covered in this review: This review provides an analysis of published results related to the different models and approaches used to study the mechanisms involved in the pathogenesis of secondary hyperparathyroidism. The review includes clinical studies, animal and ex vivo/in vitro models which have been extensively used in this area. What the reader will gain: Readers will have an overview of the main findings and progress achieved in the knowledge of the parathyroid function combining the results obtained from the different models used to understand the parathyroid gland regulation. Take home message: Each of the available models used to study the complex system of parathyroid regulation has advantages and limitations; therefore, it is necessary to combine the information obtained from more than one model in order to have a more complete knowledge of the mechanisms involved in PTH regulation.     

Secondary hyperparathyroidism in children with chronic renal failure: pathogenesis and treatment

Despite advances in the management of patients with chronic renal failure, histologic features associated with secondary hyperparathyroidism remain the predominant skeletal findings; however, over the last decade the prevalence of adynamic bone has increased in both adult and pediatric patients with chronic renal failure. The management of children with secondary hyperparathyroidism and mild to moderate chronic renal failure should be started early, and should include correction of hypocalcemia and metabolic acidosis, maintenance of age-appropriate serum phosphorus levels, and institution of vitamin D therapy when serum intact parathyroid hormone (PTH) measurements are elevated to maintain the blood levels within normal limits; however, in children undergoing chronic dialysis therapy, the current recommendation is to maintain the serum intact PTH levels at least 2-4 times the upper limits of normal to prevent the development of low bone turnover disease. Serum calcium, phosphorus, alkaline phosphatase, and PTH levels should be monitored frequently, especially in infants and very young children. Discontinuation or reduction of vitamin D should be considered when there is a rapid decline in PTH levels, persistent elevation in serum calcium and serum phosphorus levels, and a significant diminution in alkaline phosphatase levels. In addition, a reduction in the calcium concentration of the dialysis fluid, and judicious use of calcium-containing salts as phosphate binding agents should also be performed in these patients. Although not yet extensively used in pediatric patients with secondary hyperparathyroidism, several therapeutic alternatives, such as the less calcemic vitamin D analogs, including paricalcitol [19-nor-1,25-(OH)(2)D(2)] and doxercalciferol [1-alpha-(OH)(2)D(2)], calcimimetics, and the availability of a calcium-free, aluminum-free phosphate binder such as sevelamer hydrochloride and lanthanum carbonate, may play significant roles in the future management of children with secondary hyperparathyroidism to promote linear growth, prevent parathyroid gland hyperplasia, avoid calciphylaxis and, in the long run, avert vascular calcifications.     

Pharmacological regulation of parathyroid hormone secretion

Parathyroid hormone (PTH) is the key endocrine factor regulating systemic Ca(2+) homeostasis. Elevated levels of circulating PTH increase bone turnover and, depending on the duration of elevation, will result in net anabolic or catabolic effects on the skeleton. Secretion of PTH from the parathyroid glands is regulated by small changes in circulating levels of Ca(2+) which are detected by a Ca(2+) receptor on the surface of parathyroid cells. This G protein-coupled receptor is the primary molecular entity used by parathyroid cells to regulate secretion of PTH. As such, the Ca(2+) receptor is a unique molecular target for new drugs capable of increasing or decreasing circulating levels of PTH. Compounds which activate the Ca(2+) receptor are termed calcimimetics and they inhibit the secretion of PTH; a calcimimetic compound is in late stage clinical trials for the treatment of both primary and secondary hyperparathyroidism. Conversely, calcilytic compounds, which are Ca(2+) receptor antagonists, stimulate secretion of PTH; a calcilytic compound is in early clinical development for the treatment of osteoporosis.     

Paricalcitol: a review of its use in the management of secondary hyperparathyroidism

Paricalcitol (Zemplar) is a synthetic vitamin D(2) analogue that inhibits the secretion of parathyroid hormone (PTH) through binding to the vitamin D receptor. It is approved in the US and in most European nations for intravenous use in the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure in adult, and in the US paediatric, patients.Paricalcitol effectively reduced elevated serum PTH levels and was generally well tolerated in children and adults with secondary hyperparathyroidism associated with chronic renal failure. In well designed clinical trials, paricalcitol was as effective as calcitriol and as well tolerated in terms of the incidence of prolonged hypercalcaemia and/or elevated calcium-phosphorus product (Ca x P). Thus, paricalcitol is a useful option for the management of secondary hyperparathyroidism in adults and children with chronic renal failure.     

Animal models of hyperfunctioning parathyroid diseases for drug development

Background: Disorders of mineral and bone metabolism have been implicated as a risk factor in the high mortality in patients with chronic kidney disease (CKD). Hyperphosphatemia, disorders of vitamin D metabolism and secondary hyperparathyroidism of uremia (SHPT) are therapeutic targets in these patients to improve the mortality. Animal models for CKD are indispensable and uremic rats produced by 5/6-nephrectomies are one of the most useful animal models for the development of new therapeutic agents. As there are limitations of uremic rats such as short lifespan and less severity of secondary hyperparathyroidism distinct from CKD patients on maintenance hemodialysis, the development of new model animals is expected. Objective: This review discusses the molecular pathogenesis of hyperfunctioning parathyroid diseases and the applications of animal models exhibiting hyperparathyroidisms in the aspect of the development of new therapeutics. Conclusion: PTH–cyclin D1 transgenic mice, with parathyroid-targeted overexpression of cyclin D1 oncogene, not only developed abnormal parathyroid cell proliferation but, notably, also developed biochemical hyperparathyroidism with characteristic abnormalities in bone. The mice exhibit age-dependent development of biochemical hyperparathyroidism, which enables testing of the drug precisely. In addition, the mice develop parathyroid cell hyperplasia, followed by monoclonal expansion, which is observed in refractory SHPT patients.     

Calcitriol in the Management of Secondary Hyperparathyroidism of Renal Failure

Secondary hyperparathyroidism (HPT) is characterized by persistent hypersecretion of parathyroid hormone (PTH), and produces characteristics of hyperparathyroid bone disease and a variety of biochemical and hormonal derangements. Management of uremic secondary HPT involves both prevention and treatment. Among preventive measures are attempts to control serum phosphate and serum calcium concentrations through dietary restriction, administration of phosphate binders, and calcium supplementation. Treatment with a vitamin D analog such as calcitriol returns plasma calcium concentrations toward normal and suppresses PTH secretion. The availability of a parenteral formulation of calcitriol, and new information regarding alternative routes of administration and regimens employing oral pulse dosing have renewed interest in calcitriol for the management of uremic secondary HPT.     

Parathyroid gland regulation: contribution of the in vivo and in vitro models

Importance of the field: The current regulation of parathyroid hormone (PTH) and the development of parathyroid disorders in chronic kidney disease involve complex mechanisms. Factors such as calcium, phosphorous, calcitriol, vitamin D receptor, calcium-sensing receptor and fibroblast growth factor 23 play a key role in the regulatory process in the pathogenesis of secondary hyperparathyroidism.

Areas covered in this review: This review provides an analysis of published results related to the different models and approaches used to study the mechanisms involved in the pathogenesis of secondary hyperparathyroidism. The review includes clinical studies, animal and ex vivo/in vitro models which have been extensively used in this area.

What the reader will gain: Readers will have an overview of the main findings and progress achieved in the knowledge of the parathyroid function combining the results obtained from the different models used to understand the parathyroid gland regulation.

Take home message: Each of the available models used to study the complex system of parathyroid regulation has advantages and limitations; therefore, it is necessary to combine the information obtained from more than one model in order to have a more complete knowledge of the mechanisms involved in PTH regulation.     

The calcium-sensing receptor and calcimimetics in blood pressure modulation

Calcium is a crucial second messenger in the cardiovascular system. However, calcium may also be an extracellular first messenger through a G-protein-coupled receptor that senses extracellular concentration (Ca(2+)(o)), the calcium-sensing receptor (CaR). The most prominent physiological function of the CaR is to maintain the extracellular Ca(2+) level in a very tight range by regulating the circulating levels of parathyroid hormone (PTH). This control over PTH and Ca(2+) levels is partially lost in patients suffering from primary and secondary hyperparathyroidism. Allosteric modulators of the CaR (calcimimetics) are the first drugs in their class to become available for clinical use and have been shown to successfully treat certain forms of primary and secondary hyperparathyroidism. In addition, several studies suggest beneficial effects of calcimimetics on cardiovascular risk factors associated with hyperparathyroidism. Although a plethora of studies demonstrated the CaR in heart and blood vessels, exact roles of the receptor in the cardiovascular system still remain to be elucidated. However, several studies point toward a possibility that the CaR might be involved in the regulation of vascular tone. This review will summarize the current knowledge on the possible functions of the CaR and calcimimetics on blood pressure regulation.     

Current pharmacological options for the management of primary hyperparathyroidism

Drugs for treating primary hyperparathyroidism can be divided into two main groups: (i) antiresorptive drugs that inhibit the increased bone turnover, which can be divided into estrogen-like compounds (estrogen, oral contraceptives and selective estrogen receptor modulators [SERMs]), bisphosphonates and calcitonin; and (ii) drugs that interfere with parathyroid hormone (PTH) secretion (currently only cinacalcet is available). No drugs that interfere with PTH action are currently available. Available studies suggest that all classes of drugs are able to lower serum calcium levels. However, calcitonin does so only temporarily. Estrogen-containing compounds (hormone replacement therapy) may be less attractive because of the potential risk of breast cancer, cardiovascular disease and deep vein thromboembolism. Oral contraceptives have not been shown to be able to prevent fractures in the general population, and no data are available on their effect in women with primary hyperparathyroidism. The only SERM marketed for hyperparathyroidism is raloxifene and this has not been associated with an increased risk of breast cancer and cardiovascular diseases, and has been shown to be able to prevent vertebral fractures in postmenopausal women with osteoporosis. Two small trials suggest that raloxifene may increase bone mineral density (BMD) and decrease serum calcium levels in patients with primary hyperparathyroidism. Bisphosphonates have been shown to decrease serum calcium and increase BMD in patients with primary hyperparathyroidism, but PTH levels may increase. Cinacalcet effectively induces a sustained decrease in serum calcium and PTH for up to 1 year. However, BMD does not seem to increase. No data on hard endpoints such as fractures, kidney stones, cardiovascular disease etc. are available for any of the drugs available for the treatment of primary hyperparathyroidism.     

骨化三醇冲击治疗尿毒症继发性甲状旁腺功能亢进的效果分析

目的分析骨化三醇冲击治疗尿毒症继发性甲状旁腺功能亢进的疗效。方法将2011年2月-2013年1月本院尿毒症继发性甲状旁腺功能亢进患者83例纳入研究,根据患者意愿分为A、B组,均接受低钙透析治疗,在此基础上A组患者接受骨化三醇常规治疗,B组患者接受骨化三醇冲击治疗。连续治疗8周,对比两组患者血清钙（Ca）、磷（P）和甲状旁腺激素（trrH）指标和不良反应的差异性。结果与A组比较,B组患者血清Ca、P、PTH水平较低,不良反应发生率较低,差异有统计学意义（P〈0．05）。结论采用骨化三醇冲击治疗尿毒症继发性甲状旁腺功能亢进的疗效和安全性具有一定的优越性,值得临床推广应用。     

Clinical utilization of cinacalcet in hypercalcemic conditions

INTRODUCTION: Cinacalcet has recently been introduced as a treatment for secondary hyperparathyroidism in dialysis patients and for parathyroid carcinoma. However, there has been an increasing interest in finding out whether cinacalcet can be used as a treatment for other parathyroid hormone (PTH)-dependent hypercalcemic conditions also. AREAS COVERED: The article reports the most relevant recent contributions dealing with calcium sensing receptor (CaSR) physiology as well as cinacalcet pharmacokinetics and pharmacodynamics. It also looks at the different hypercalcemic conditions where the use of cinacalcet has been proposed. This article was researched using clinical trials, case reports and outstanding basic research published in the last 3 years (MEDLINE database up to 31 November 2010). It provides the reader with an insight into the many unaddressed issues regarding cinacalcet that need to be resolved before it can be used in newly proposed fields. EXPERT OPINION: Since cinacalcet may not only have an effect on parathyroid CaSR but also on CaSR expressed at bone and renal levels, it can currently only be considered a good alternative to parathyroidectomy in PTH-dependent hypercalcemic conditions when surgical intervention is burdened by a high failure rate or when it can be considered a risky procedure. At present, cinacalcet cannot be considered the first choice treatment in asymptomatic primary hyperparathyroidism or in mild-to-moderate forms of familial hypocalciuric hypocalcemia.     

Pathogenesis and treatment of secondary hyperparathyroidism in dialysis patients: the role of paricalcitol

Hemodialysis (HD) patients are commonly affected by secondary hyperparathyroidism (SHPT), in which 3 well-known factors are usually involved: hypocalcemia, hyperphosphatemia and calcitriol deficiency. Classically, high parathyroid hormone (PTH) levels cause bone-associated diseases, such as osteitis fibrosa and renal osteodystrophy, but more recently it has been demonstrated the link between SHPT and a systemic toxicity, with a major role in determining cardio-vascular disease, including arterial calcification, endocrine disturbances, compromised immune system, neurobehavioral changes, and altered erythropoiesis. Treatment with calcitriol (CT), the active form of vitamin D, reduces parathyroid hormone (PTH) levels, but may result in elevations in serum calcium (Ca) and phosphorus (P), increasing the risk of cardio-vascular calcification in the HD population. Several new vitamin D analogs have been developed and investigated with the rationale to treat SHPT with a reduced risk of hypercalcemia and hyperphosphatemia in HD patients. Paricalcitol (1,25-dihydroxy-19-nor-vitamin D(2), 19-Nor-D(2)) is a vitamin D analog that suppresses PTH secretion with minimal increases on serum calcium and phosphate levels. It was demonstrated that paricalcitol prevents vascular calcification in experimental models of renal failure, compared with calcitriol. Furthermore, 19-Nor-D(2) is the first analog approved for use in HD patients and is available for i.v. and oral administration, commonly 3 times weekly after HD. The purpose of the present review is to analyze the pathogenesis and treatment of SHPT in HD patients, and the role of paricalcitol in the prevention of arterial calcification.     

Regulation of renal calbindin-D28K

Calbindin-D28k is an intracellular protein with high affinity for calcium. In the kidney, this protein is exclusively localized in the distal tubule and in the proximal part of the collecting ducts. Functionally, calbindin-D28k is supposed to be involved in the regulation of the reabsorption of calcium and possibly magnesium in the distal nephron though the exact regulatory mechanisms are not yet known. Thus, several theories regarding the functional role of calbindin-D28k have been proposed: The carrier theory describes calbindin-D28k as a transport protein which binds calcium and then transports it from the luminal to the basolateralcell membrane. The buffer theory assumes that calbindin-D28k functions by binding calcium ions to prevent intracellular calcium concentrations from reaching toxic levels. The activator theory describes that calbindin-D28k increases the activity of calcium channels or the enzymatic activity of the Ca++-Mg++-ATPase in the luminal membrane and thereby increases the tubular reabsorption of calcium. The renal calbindin-D28k is dependent upon vitamin D. Pharmacological doses of the active vitamin D metabolite 1,25-(OH)2D increases the concentrations of renal calbindin-D28k, whereas the concentration of calbindin-D28k is low in conditions with reduced levels of circulating 1,25-(OH)2D. Likewise, plasma calcium concentrations, uremia and hypertension affect calbindin-D28k expression. However, several studies have rendered probable the effect of additional factors in the regulation of renal calbindin-D28k. The aim of the present dissertation therefore was to examine the regulation of renal calbindin-D28k in a series of physiological and pathophysiological conditions established in vivo in the rat. A possible correlation between hypertension and calbindin-D28k was examined in three models of experimental hypertension: the genetically defined spontaneous hypertensive rat, the salt-sensitive Dahl rat and the renovascular hypertensive rat. These three models clearly demonstrated three separate patterns in the calcium metabolism, but the studies were unable to support a role for calbindin-D28k in the development of hypertension. In all three models the development of hypertension caused an increased plasma 1,25-(OH)2D. This increase was accompanied by either unaltered or reduced levels of renal calbindin-D28k possibly secondary to a cellular resistance against 1,25-(OH)2D. Magnesium binds to calbindin-D28k with a relatively high affinity. The regulation of urinary magnesium excretion takes place in the distal tubule where calbindin-D28k is found in high concentrations. Therefore, a possible relation between magnesium and calbindin-D28k was examined. The studies demonstrated not previously known connections between magnesium intake, urinary magnesium excretion and renal calbindin-D28k which suggests that this protein is involved in the regulation of magnesium homeostasis by the kidney. Calcitonin increases the reabsorption of calcium in the distal tubule. Therefore, the effect ofcalcitonin on renal calbindin-D28k was examined both by eliminating the endogeneous calcitonin production by a selective thyroidectomy followed by an autotransplantation of the parathyroid glands and further by infusion of calcitonin. These studies demonstrated unchanged concentrations of renal calbindin-D28k. It was concluded that the increased calcium reabsorption induced by calcitonin in the distal tubule is not mediated by calbindin-D28k. Urinary calcium excretion is in part regulated by the action of PTH on calcium reabsorption in the distal nephron. Previous reports of increased expression of renal calbindin-D28k in uremic rats led us to suggest that secondary hyperparathyroidism associated with uremia induced the synthesis of renal calbindin-D28k. Therefore, the effect of PTH was examined in a study comprising selective parathyroidectomy and infusions of PTH, PTHrP, 1,25-(OH)2D and calcium. (ABSTRACT TRUNCATED)     

Outcomes of secondary hyperparathyroidism in chronic kidney disease and the direct costs of treatment

BACKGROUND: There has been an emphasis over the last several years to identify and treat chronic kidney disease (CKD) and its complications as they evolve rather than waiting until the patient reaches end-stage renal disease (ESRD), also known as CKD stage 5. The number of patients who will be identified and prescribed therapies for complications such as secondary hyperparathyroidism (SHPT) is greater than initially proposed. OBJECTIVE: To review the pathways, complications, management, and estimated treatment costs of CKD-related SHPT. METHODS: An electronic literature search of MEDLINE (January 1980 through January 2007) was conducted for English-language publications using the base search term secondary hyperparathyroidism. To refine subsequent searches, the authors added Boolean operators to the following secondary and tertiary search terms: parathyroid hormone, chronic kidney disease, renal osteodystrophy, adynamic bone disease, vascular calcification, cardiovascular disease, vitamin D, vitamin D analogs, hypercalcemia, hyperphosphatemia, calcimimetics, costs, prevalence, and economics. RESULTS: The initial MEDLINE search produced 278 relevant articles. After refining the search terms, the authors triaged the results for English-language publications relevant to the discussion of SHPT and its complications in CKD, eliminating 149 publications. The remaining 129 publications were accepted for review. These articles represent a growing body of primarily observational evidence that demonstrates that elevated intact parathyroid hormone (PTH) levels cause deleterious physiological results across a variety of organ systems, including the cardiovascular and skeletal systems. Specific complications associated with SHPT are left ventricular hypertrophy (LVH), renal osteodystrophy (ROD), and extraskeletal calcification. Medical management of the PTH/vitamin D/calcium and phosphorus imbalances in SHPT focus on regulating PTH levels via vitamin D therapy. The class of calcimimetics is a newer treatment modality that has favorable effects on biochemical laboratory values, such as serum calcium and phosphorus levels, but current data do not show differences on hard endpoint patient-oriented outcomes compared with standard generic agents. The direct drug costs in April 2007 U.S. dollars of treating CKD-associated elevations in PTH in predialysis patients range from $8.40 per patient per week ($437 per year) for oral generic calcitriol to $88.90 per patient per week ($4,623 per year) for oral paricalcitol (expressed as 85% of average wholesale price [AWP] for brand drugs or 70% of AWP for generic drugs). The direct drug costs of treating SHPT in hemodialysis patients range from $80.20 per patient per week ($4,170 per year) for generic calcitriol (IV) to $278.46 per patient per week ($14,480 per year) for oral cinacalcet. CONCLUSIONS: SHPT causes skeletal and cardiovascular complications in CKD patients. Calcitriol therapy is effective in managing PTH levels, but efforts to reduce the associated hypercalcemia and hyperphosphatemia have led to the development of newer, yet more expensive, vitamin D analogs. With the lack of evidence to support comparative superior outcomes in end-organ disease among SHPT therapy alternatives, future research is still needed to clearly identify which newer agents are most competitive with the historical gold standard of calcitriol therapy.     

Cardiovascular disease in chronic kidney failure: is there a role for vitamin D analogs?

Vitamin D3 is modified by vitamin D3-25-hydroxylase in the liver, and 25-hydroxyvitamin D3-1alpha-hydroxylase in the kidney, to form the active metabolite, 1,25-dihydroxyvitamin D3. Chronic kidney disease (CKD) is characterized by reduced synthesis of 1,25-dibydroxyvitamin D3, inadequate renal phosphate clearance and calcium imbalance, secondary hyperparathyroidism (SHPT) and bone disease. CKD patients encounter a much higher risk of cardiovascular disease (CVD) than the general public. The cardiovascular risk factors for CKD patients include conventional factors such as age, gender, hypertension, diabetes, dyslipidemia and smoking, and non-conventional factors, such as anemia, uremia, reduced vascular compliance, inflammation and various hormonal factors. Several vitamin D analogs are currently available for the treatment of SHPT, and recent clinical data show that these analogs provide survival benefit for CKD patients in the order of paricalcitol > calcitriol > no vitamin D analog, independent of parathyroid hormone and calcium. Moreover, the survival benefit seems to be associated with cardiovascular causes. The observations made from these clinical studies raised intriguing questions about the involvement of the vitamin D receptor locus (VDR) in the cardiovascular system. This review discusses recent data regarding the role of vitamin D and its analogs in the CVD associated with CKD.     

Cinacalcet hydrochloride

Oral cinacalcet hydrochloride (HCl) [Sensipar, Mimpara] is the first in a new class of therapeutic agents, the calcimimetics, and has a novel mechanism of action. It directly modulates the principal regulator of parathyroid hormone (PTH) secretion, namely the calcium-sensing receptor (CaR) on the chief cells in the parathyroid gland. Cinacalcet HCl reduces circulating PTH levels by increasing the sensitivity of the CaR to extracellular calcium. In three pivotal phase III, 26-week, randomised, double-blind, multicentre trials in chronic kidney disease (CKD) patients (n = 1136) on dialysis with uncontrolled secondary hyperparathyroidism (HPT), a significantly higher proportion of oral cinacalcet HCl 30-180 mg/day than placebo recipients achieved a reduction in intact PTH levels to < or =250 pg/mL. Cinacalcet HCl treatment also simultaneously lowered serum calcium and phosphorus, and calcium-phosphorous product levels. Notably, cinacalcet HCl proved effective in a broad range of CKD patients on dialysis with uncontrolled secondary HPT, regardless of disease severity, duration of dialysis treatment, dialysis modality, race, age, gender, or concurrent phosphate binder or vitamin D sterol use. Cinacalcet HCl (60-360 mg/day) also reduced elevated serum calcium levels by > or =1 mg/dL in 15 of 21 (71%) patients with parathyroid carcinoma in an open-label, multicentre, dose-titration trial. Cinacalcet HCl was generally well tolerated in clinical trials. Most treatment-emergent adverse events were mild to moderate in severity.     

Cinacalcet HCl: a novel therapeutic for hyperparathyroidism

Hyperparathyroidism (HPT) is a significant clinical concern for patients with a variety of diseases, notably the secondary HPT associated with chronic kidney disease requiring dialysis. Secondary HPT is associated with elevated para-thyroid hormone (PTH) levels, decreased levels of 1,25 dihydroxyvitamin D, and disordered mineral levels (usually high calcium and phosphorus). If not controlled, secondary HPT can result in bone disease, vascular calcification, and ultimately, patient mortality. Established, conventional therapies, such as 1,25dihydroxyvitamin D analogues (vitamin D analogues) and phosphate binders, have proven to be inadequate in enabling patients to meet the National Kidney Foundation's-Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) treatment goals for PTH, calcium and phosphorus levels. A novel therapeutic, cinacalcet HCl (formerly AMG 073; Sensipar in the US and Mimpara in Europe; Amgen, Inc.), binds directly to the calcium-sensing receptor (CaR) on the cells of the parathyroid gland, increasing the receptor's sensitivity to calcium and reducing PTH, serum calcium and phosphorus levels. Treatment with cinacalcet in clinical trials has safely and effectively improved achievement of the NKF-K/DOQI goals. Cinacalcet has also reduced serum calcium levels in patients with primary HPT, including parathyroid carcinoma, in the clinical trial setting. Evidence suggesting the utility of cinacalcet in these diseases and the potential for additional therapeutic applications will be discussed.