Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Therapy with i.v. calcitriol (CLT), that had been the mainstay of the cure of severe secondary hyperparathyroidism (SHPT) for many years, is often hindered by the occurrence of hypercalcemia, that requires discontinuation of the drug with consequent rebounding of the parathyroid hormone (PTH) oversecretion. To circumvent this shortcoming, CLT-analogs with less calcemic effects with respect to CLT have been developed. One of these analogs, paracalcitol (PCLT), proved to be at least as powerful as CLT in decreasing serum PTH, but it still remains endowed with some calcemic effect as the parent compound. Meanwhile, calcimimetics (CaMs) drugs targeting the calcium-sensing receptors on the PTG, have been marketed woldwide. Cinacalcet (CNC) is a CaM endowed with the unique prerogative to significantly decrease serum PTH while also decreasing serum calcium. Thus, one may attempt to speculate that CaMs may completely replace vitamin D derivatives from the therapeutic arena. Uremic patients, however, suffer from severe deprivation of biological vitamin D effects, that puts them in need of highly dosed vitamin D in order to both ameliorate their bone status and to preserve their general and cardiovascular health. Thus, a combination therapy with PCLT, which has a significant patient-survival advantage over CLT, and CNC seems to be more appropriate than only-one-drug based therapy for SHPT. Such a combination will hopefully result in a better control of SHPT, avoidance of cumbersome hypercalcemia and higher life expectancy for uremic patients than ever before.
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PMID:Therapy of secondary hyperparathyroidism to date: vitamin D analogs, calcimimetics or both? 1704 95

Cinacalcet, a calcimimetic, was evaluated in persistent hyperparathyroidism after kidney transplantation (Tx). Ten kidney transplant recipients and one kidney-pancreas recipient with persistent post-Tx hypercalcemia (serum calcium [SCa] > 10.2 mg/dl), stable graft function, and intact parathyroid hormone (iPTH) > or = 2 times normal received 30 mg/d cinacalcet between 2 mo and 5 yr after Tx. SCa, serum phosphorus (SP), and iPTH were measured before and after cinacalcet. Mean pre-cinacalcet SCa was 10.9 mg/dl (8.6 to 11.9 mg/dl). Average pre-cinacalcet SP was 2.9 mg/dl (1.8 to 4.0 mg/dl). Mean pre-cinacalcet iPTH was 267.0 pg/ml (99 to 723 pg/ml). After cinacalcet, SCa decreased on average by 1.6 mg/dl (95% confidence interval 1.2 to 2.1; P < 0.0001). Post-cinacalcet SP increased on average 0.45 mg/dl (P = 0.046). Post-cinacalcet iPTH averaged 156.9 mg/dl (P = 0.10). Graft function remained stable. Cinacalcet lowers SCa and raises SP in the short term in patients with persistent post-Tx hyperparathyroidism; long-term bone effects and persistent hyperparathyroidism merit further study.
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PMID:Improvement in hypercalcemia with cinacalcet after kidney transplantation. 1769 5

Persistent hyperparathyroidism is the most frequent cause of hypercalcemia after renal transplantation, namely, hypercalcemia is observed in about 10% of patients at 1 year. This prospective study evaluated the effect of cinacalcet, a second-generation calcimimetic, on serum calcium and parathyroid hormone (PTH) blood levels among recipients with hypercalcemia due to persistent hyperparathyroidism. Thirteen renal transplanted patients (10 women and 3 men) were included based upon: a total serum calcium >10.5 mg/dL; intact PTH (iPTH) blood levels >65 pg/mL; graft function >6 months, and stable maintenance immunosuppressive therapy. After inclusion, patients initially received 30 mg of cinacalcet once daily. The mean time of initiation was 64 +/- 7 months after transplantation. The follow-up was 6 months. The median dose of cinacalcet was 30 mg/d (5 patients received 60 mg/d). During the study period, renal function remained stable. Serum calcium levels decreased significantly from 11.7 +/- 0.39 to 10.35 +/- 0.8 mg/dL (P < .001). Serum phosphate levels increased from 2.82 +/- 0.34 mg/dL to 3.2 +/- 0.41 mg/dL (P < .05). The mean iPTH levels significantly decreased from 308 +/- 120 to 210 +/- 80 pg/mL (P < .05). There were no significant change in 25-hydroxyvitamin D3 blood levels (from 17.7 +/- 9 to 17.4 +/- 6 ng/mL), but the 1,25-dihydroxyvitamin D3 blood levels decreased from 53.8 +/- 18.2 to 32.6 +/- 9.2 pg/mL (P < .01). There were no significant changes in blood levels of alkaline phosphatase, magnesium, bicarbonate, calciuria, phosphaturia, and immunosuppressive drugs. Cinacalcet was well tolerated in all patients except one who had gastrointestinal discomfort. In summary, cinacalcet corrected hypercalcemia and improved phosphatemia in patients with persistent hyperparathyroidism after transplantation with no negative effects on renal function.
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PMID:Cinacalcet for the treatment of hypercalcemia in renal transplanted patients with secondary hyperparathyroidism. 1788 55

The successful use of cinacalcet in dialysis patients and in patients with primary hyperparathyroidism has prompted transplant physicians to use it to treat renal-transplant patients with persisting hyperparathyroidism. However, in the setting of kidney transplantation, many questions remain unanswered, i.e. the time of initiation of cinacalcet after transplantation, its dosage and the side effects on kidney function all remain unknown. Herein, we report on a kidney-transplant recipient with persisting hyperparathyroidism who developed hypercalciuria afterreceiving high doses of cinacalcet. Cinacalcet was started 3 months after transplantation at a once-daily dose of 60 mg. Thereafter, the dosage was increased progressively because of persistant hyperparathyroidism and hypercalcemia. At a dose of 90 mg b.i.d, hypercalciuria occurred. The latter disappeared after reduction of cinacalcet dosage. Cinacalcet might be responsible for urinary calcium excretion, either by reduction of tubular calcium reabsorption via the reduction of PTH level, or by its direct effect on the calcium sensor receptor located in the upper thick ascending limb of the loop of Henle. We conclude that cinacalcet should be used with caution in renal-transplant patients. Further investigations are required to determine the best way to use this drug in this setting.
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PMID:Hypercalciuria induced by a high dose of cinacalcet in a renal-transplant recipient. 1796 93

Secondary hyperparathyroidism has a significant impact on morbidity and mortality due to skeletal and extraskeletal manifestations. Cinacalcet, a newly developed calcimimetic, is reported to decrease parathyroidism, as well as serum levels of phosphorus (P) and calcium (Ca) and therefore Ca x P product. Available evidence has shown that cinacalcet decreases the rate of parathyroidectomy and bone fracture in hemodialysis patients, but the death rate remains the same. Although, it is not yet available in Japan, cinacalcet is expected to be available as a possible drug for patients undergoing hemodialysis due to secondary hyperparathyroidism associated with refractory hyperphosphatemia and hypercalcemia. Except for the high cost, cinacalcet will be a welcome therapeutic option for end-stage renal disease and probably also for pre-end-stage renal disease patients. Dietary phosphate restriction and adequate hemodialysis, however, are still the main strategy for the control of hyperphosphatemia and secondary hyperparathyroidism.
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PMID:Pharmacological control of secondary hyperparathyroidism in chronic hemodialysis patients: cinacalcet is coming to Japan. 1831 61

Primary hyperparathyroidism (HPT) is the leading cause of hypercalcemia in the outpatient setting, and it is treated primarily by parathyroidectomy. There are few nonsurgical treatment options for patients who do not wish to have surgery, who have failed surgery, or who have contraindications to surgery. Cinacalcet increases the sensitivity of parathyroid calcium-sensing receptors to extracellular calcium, thereby reducing serum calcium levels. We conducted a retrospective chart review from 2004 to 2006 to investigate the efficacy of cinacalcet in reducing serum total calcium, ionized calcium, and parathyroid hormone (PTH) in patients with primary HPT. Patients were started on cinacalcet if they met at least one indication for parathyroidectomy, which includes T score less than -2.5 standard deviations from the mean, serum calcium 1 mg/dL above the upper limit of normal, 24-hour urine calcium above 400 mg/dL, age less than 50 years, or a creatinine clearance that is 30% below age- and sex-matched controls. The primary outcome was normalization of serum calcium. A total of 18 patients with primary HPT were started on cinacalcet: 16 men and 2 women with a mean age of 70 years. Mean baseline serum calcium was 10.60 +/- .53 mg/dL; ionized serum calcium, 1.45 +/- .07 mmol/L; and serum PTH, 141 +/- 78 pg/mL. After treatment with cinacalcet, the mean serum calcium decreased to 9.46 +/- .34 mg/dL, ionized calcium decreased to 1.26 +/- .06 mmol/L, and PTH decreased to 108 +/- 64.5 pg/mL. Ninety-four percent of the patients on cinacalcet had normal total serum calcium, 81% had normal serum ionized calcium, whereas only 25% had a normal serum PTH level. Cinacalcet normalizes serum calcium in most patients while only modestly reducing serum PTH levels.
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PMID:Cinacalcet for the treatment of primary hyperparathyroidism. 1832 54

Cinacalcet is a type II calcimimetic agent which is an allosteric modulator of the calcium-sensing receptor (CaR) located on the surface of the parathyroid cells. Cinacalcet increases the sensitivity of CaR via binding to the transmembrane region of CaR. Increasing sensitivity of CaR causes reduced secretion of parathyroid hormone (PTH) and suppression of serum calcium levels. Cinacalcet has recently been approved by Federal Drug Administration (FDA) for the treatment of patients with secondary hyperparathyroidism on maintenance dialysis and hypercalcemia in patients with parathyroid cancer. It is used also in Europe for both indications. Several controlled studies have shown that cinacalcet is effective in normalizing serum calcium levels also in primary hyperparathyroidism. Cinacalcet is metabolized primarily in the liver by N-dealkylation leading to carboxylic acid and oxidation of naphthalene ring to form dihydrodiols. The safety and optimal dosage of the drug in hypercalcemic patients with liver impairment remains unclear. We present a patient with Child-Pugh B class primary biliary cirrhosis who presented with moderate hypercalcemia and was diagnosed as primary hyperparathyroidism. As she refused having parathyroid surgery for her parathyroid adenoma at first, her hypercalcemia was treated successfully with 30 mg/day cinacalcet for 6 months. Cinacalcet was discontinued after 6 months. Her calcium level increased gradually. As she accepted surgery this time, her parathyroid adenoma was removed by minimally invasive parathyroidectomy. Parathyroid adenoma was confirmed pathologically. Her calcium levels maintained within the normal ranges after surgery.
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PMID:Hypercalcemia of primary hyperparathyroidism was treated by cinacalcet in a patient with liver cirrhosis. 1856 Oct 96

Cinacalcet (trade name: Mimpara) enhances allosterically the action of Ca (2+)-ions at the parathyroid gland Ca (2+)-receptor which belongs to the superfamily of G protein-coupled receptors. As a consequence blood levels of Ca (2+) and parathyroid hormone decline. Cinacalcet is orally administered and approved for a) the treatment of secondary hyperparathyroidism in patients with end stage renal disease receiving hemodialysis and b) to lower hypercalcemia in patients with parathyroid carcinoma. Therapeutic monitoring includes measurement of blood levels of Ca (2+) and parathyroid hormone. The stable suppression of parathyroid hormone levels under chronic treatment was shown in clinical trials. Clinically relevant outcome parameters, such as bone mass and fracture risk, remain to be evaluated.
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PMID:[Cinacalcet - an allosteric enhancer at the Ca2+-receptor]. 1866 62

An 80-year-old woman on maintenance hemodialysis therapy developed severe hypercalcemia under vitamin D treatment for secondary hyperparathyroidism. To avoid the toxic calcemic effects, cinacalcet was introduced and the dose of vitamin D was substantially decreased. Cinacalcet targets the calcium-sensing receptor and decreases parathyroid hormone levels without increasing calcium and phosphorus levels. Three days after starting cinacalcet therapy, the patient developed palpable purpura on both upper and lower extremities that resolved after discontinuation of cinacalcet and administration of steroids. Skin biopsy of the initial eruption showed leukocytoclastic vasculitis. According to the Naranjo adverse drug reaction probability scale, leukocytoclastic vasculitis probably was caused by cinacalcet introduction. Drug-induced vasculitis is a poorly defined disorder, and, in most cases, no pathogenetic mechanism can be described. An idiosyncratic reaction to the agent often is proposed. Cinacalcet should be considered a causative agent of cutaneous leukocytoclastic vasculitis, and although this is the result of only a clinical observation, further attention is required in the future because cinacalcet recently has been introduced in the treatment of secondary hyperparathyroidism in patients on long-term hemodialysis therapy.
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PMID:Cinacalcet-induced leukocytoclastic vasculitis. 1956 Aug 49

Cinacalcet hydrochloride (cinacalcet) is a calcimimetic approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) receiving dialysis and for the treatment of hypercalcaemia in patients with parathyroid carcinoma. Following oral administration, peak plasma concentrations of cinacalcet occur within 2-6 hours. The absolute bioavailability is 20-25%, and administration of cinacalcet with low- or high-fat meals increases exposure (area under the plasma concentration-time curve from time zero to infinity [AUC(infinity)]) 1.5- to 1.8-fold. Cinacalcet has no significant interaction with calcium carbonate or sevelamer hydrochloride, phosphate binders commonly used in the treatment of patients with CKD receiving dialysis. The terminal elimination half-life is 30-40 hours, and steady-state concentrations are achieved within 7 days. The pharmacokinetics of cinacalcet are dose proportional over the dose range of 30-180 mg. The pharmacokinetic profile of cinacalcet is not notably affected by varying degrees of renal impairment. The pharmacokinetics of cinacalcet are comparable between healthy subjects, patients with primary hyperparathyroidism and patients with secondary hyperparathyroidism with reduced renal function (including those patients with secondary hyperparathyroidism receiving dialysis). Additionally, the pharmacokinetics of cinacalcet are similar in patients with secondary hyperparathyroidism receiving haemodialysis and patients with secondary hyperparathyroidism receiving peritoneal dialysis. Mild hepatic impairment does not affect the pharmacokinetics of cinacalcet, whereas moderate or severe hepatic impairment increases the exposure (AUC(infinity)) by approximately 2- and 4-fold, respectively. Age, sex, bodyweight and race do not notably affect the pharmacokinetics of cinacalcet. Cinacalcet is extensively metabolized by multiple hepatic cytochrome P450 (CYP) enzymes (primarily 3A4, 2D6 and 1A2) with <1% of the parent drug excreted in the urine. Dose adjustments of cinacalcet may be necessary, and parathyroid hormone (PTH) and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor (e.g. ketoconazole, erythromycin, itraconazole). Cinacalcet is a strong inhibitor of CYP2D6; therefore, dose adjustment of concomitant medications that are predominantly metabolized by CYP2D6 and have a narrow therapeutic index (e.g. flecainide, vinblastine, thioridazine and most tricyclic antidepressants) may be required. Cinacalcet does not appreciably inhibit or induce the activities of CYP3A4, 1A2, 2C9 or 2C19. An inverse relationship exists between plasma PTH and cinacalcet concentrations. PTH concentrations are greatest before dose administration when the cinacalcet concentration is lowest (24 hours after the previous day's dose). Nadir PTH levels occur approximately 2-3 hours after dosing.
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PMID:Clinical pharmacokinetic and pharmacodynamic profile of cinacalcet hydrochloride. 1956 13


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