Long-term treatment of secondary hyperparathyroidism with the calcimimetic cinacalcet HCl.

BACKGROUND: Patients with secondary hyperparathyroidism often require therapy that provides long-term control of parathyroid hormone concentrations without increasing calcium and phosphorus concentrations. Cinacalcet modulates the calcium-sensing receptor on the parathyroid gland to reduce secretion of parathyroid hormone and lower serum calcium, phosphorus and calcium-phosphorus product in haemodialysis patients. METHODS: Dialysis patients with secondary hyperparathyroidism [parathyroid hormone (PTH) level > or =300 pg/ml] who were enrolled in one of four phase 2 placebo-controlled studies were eligible to enroll in an open-label extension study in which all patients received cinacalcet. For this extension study, cinacalcet was initiated at 30 mg in all patients and the dose was escalated to a maximum of 180 mg once daily if PTH concentrations were >250 pg/ml. Use of concomitant vitamin D sterols and phosphate binders was not restricted. RESULTS: The analysis of all patients (n = 59) completing 100 weeks of cinacalcet treatment showed long-term control of PTH and calcium-phosphorus product. Approximately 55% achieved a PTH concentration < or =300 pg/ml at the week-100 study visit, and approximately 60% had at least a 30% reduction in PTH from baseline. Serum calcium, phosphorus and the calcium-phosphorus product did not increase during the study. Concomitant vitamin D sterol and phosphate binder therapy remained stable. Cinacalcet was safe and generally well tolerated at doses up to 180 mg/day. CONCLUSIONS: In this long-term study, cinacalcet effectively sustained reductions in PTH for up to 3 years without increasing concentrations of serum calcium, phosphorus or calcium-phosphorus product.     

Cinacalcet HCl: a novel treatment for secondary hyperparathyroidism in stage 5 chronic kidney disease

BACKGROUND: Chronic kidney disease (CKD) alters the regulation of calcium and phosphate homeostasis, leading to secondary hyperparathyroidism, metabolic bone disease, soft tissue calcifications, and other metabolic derangements that have a significant impact on morbidity and mortality. The parathyroid gland is the central organ responsible for regulating these adaptive responses. Suppression of parathyroid hormone (PTH) secretion, hypertrophy, and hyperplasia are a major goal of treatment of CKD. METHODS: Current literature was reviewed and combined with the author's experience to address a number of issues regarding the optimal treatment of secondary hyperparathyroidism in hemodialysis patients. RESULTS: The calcium sensing receptor (CASR) is the most important factor regulating parathyroid gland function, and allosteric modulators of CASR, called calcimimetics, provide a novel drug therapy to suppress PTH secretion. The current use of active vitamin D analogues to suppress PTH is often limited by hypercalcemia and hyperphosphatemia. Clinical trials of cinacalcet HCl, the first calcimimetic to be approved for treatment of secondary hyperparathyroidism in CKD, have demonstrated suppression of circulating PTH levels without increments in the calcium-phosphorus (Ca x P) product, making it easier to achieve the stringent management guidelines proposed for subjects with CKD by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI). CONCLUSION: The management of disordered calcium and phosphate homeostasis in CKD patients is evolving based on our knowledge of the major importance of the calcium sensing receptor (CASR) in controlling parathyroid gland function and the potent actions of calcimimetics to target CASR. The purpose of this presentation is to provide an overview of the role of the CASR in regulation of parathyroid gland function, to examine the mechanisms whereby calcimimetics target the CASR, and to review the clinical trials that support the use of cinacalcet HCl for the treatment of secondary hyperparathyroidism in stage 5 chronic kidney disease (CKD).     

Cinacalcet HCl: a novel treatment for secondary hyperparathyroidism caused by chronic kidney disease.

Secondary hyperparathyroidism (SHPT) develops as a result of impaired calcium homeostasis when the failing kidneys disturb the complicated interactions between parathyroid hormone (PTH), calcium, phosphorus, and vitamin D. Twelve years ago, the calcium-sensing receptor (CaR) of the parathyroid gland was first cloned and identified as the principal regulator of PTH secretion. The activation of the CaR by small changes in extracellular calcium (ec(Ca2+)) regulates PTH, calcitonin secretion, urinary calcium excretion, and ultimately, bone turnover. The CaR became an ideal target for the development of calcimimetics, which are able to amplify its sensitivity to ec(Ca2+) suppressing PTH secretion. Cinacalcet HCl, a first-in-class calcimimetic, approved in both the United States and the European Union, offers a new therapeutic approach to the treatment of SHPT. The efficacy of cinacalcet HCl in treating SHPT in dialysis patients (n = 1,136) was studied in three similarly designed phase III clinical trials comparing patients receiving standard SHPT therapy plus cinacalcet HCl or plus placebo. Cinacalcet HCl, dosed from 30 to 180 mg/day, significantly reduced PTH while simultaneously lowering calcium, phosphorus, and calcium-phosphorus product in each of the three studies. Respective to the National Kidney Foundation-Kidney Disease Outcomes and Quality Initiative (NKF-K/DOQI) recommended targets for bone and mineral metabolism, 41% of cinacalcet HCl-treated patients achieved both PTH and calcium-phosphorus product targets, compared with only 6% in the placebo group. Results from 2 recent phase IIIb studies (TARGET and CONTROL) conducted in the United States also showed that cinacalcet HCl can significantly reduce or maintain reduction in PTH while simultaneously lowering calcium, phosphorus, and calcium-phosphorus product. In addition, patients taking vitamin D at baseline of these 2 trials were able to see significant mean reductions in vitamin D dose. Further assessment of cinacalcet HCl trial data has shown some important effects in SHPT patient clinical outcomes. A combined post-hoc analysis of clinical events using data from 4 (n = 1,184) cinacalcet HCl phase II and III studies suggests that treatment with cinacalcet HCl has a beneficial effect on relative risks of parathyroidectomy, fracture, and hospitalization for cardiovascular complications. Nausea and vomiting occurred more often in patients taking cinacalcet HCl than in those taking a placebo. There were also transient episodes of hypocalcemia in 5% of cinacalcet HCl patients versus 1% of placebo patients. However, these episodes were rarely associated with symptoms. The development of calcimimetics has already changed the treatment of SHPT in renal patients. Its effectiveness on the control of PTH secretion, along with simultaneous reductions in calcium, phosphorus, and calcium-phosphorus product, give this agent an advantage over traditional therapies in all levels of severity of SHPT.     

Cinacalcet HCl attenuates parathyroid hyperplasia in a rat model of secondary hyperparathyroidism

BACKGROUND: Secondary hyperparathyroidism (HPT) in chronic kidney disease (CKD) is a physiologic response to kidney failure characterized by elevated serum parathyroid hormone (PTH) levels and parathyroid gland enlargement. Calcimimetic agents acting through allosteric modification of the calcium-sensing receptor (CaR) can attenuate parathyroid hyperplasia in rats with secondary HPT. The present study explores the effects of the calcimimetic cinacalcet HCl on parathyroid hyperplasia, apoptosis, and PTH secretion in a rat model of secondary HPT. METHODS: Cinacalcet HCl was gavaged daily (1, 5, or 10 mg/kg) for 4 weeks starting 6 weeks post-5/6 nephrectomy. After dosing, hyperplasia was determined using parathyroid weight and proliferating cell nuclear antigen (PCNA) immunochemistry. Apoptosis was determined using in situ techniques. Serum PTH((1-34)) and blood chemistries were determined throughout the course of the study. RESULTS: Administration of cinacalcet HCl (5 or 10 mg/kg) significantly reduced the number of PCNA-positive cells and decreased parathyroid weight compared with vehicle-treated 5/6 nephrectomized rats. There was no difference in apoptosis from cinacalcet HCl-treated or vehicle-treated animals. Serum PTH and blood ionized calcium levels decreased in cinacalcet HCl-treated animals compared with vehicle-treated controls. CONCLUSION: The results confirm previous work demonstrating that calcimimetic agents attenuate the progression of parathyroid hyperplasia in subtotally nephrectomized rats, extending earlier observations to now include cinacalcet HCl. These results support a role for the CaR in regulating parathyroid cell proliferation. Therefore, cinacalcet HCl may represent a novel therapy for improving the management of secondary HPT.     

Comparisons between oral pulse alfacalcidol therapy and daily therapy in maintenance hemodialysis patients with secondary hyperparathyroidism: a randomized, controlled, and multicenter study

OBJECTIVE: To investigate the efficacy and safety of 1alpha-(OH)-D3 high-dose pulse therapy or daily low-dose therapy in secondary hyperthyroidism in maintenance hemodialysis patients in China. METHODS: Maintenance hemodialysis patients of both gender with intact parathyroid hormone (iPTH) level above 200 pg/mL were randomly divided into a pulse group and a daily group. They were treated for 20 weeks, with 2 microg oral Alfacalcidol twice weekly or thrice weekly in the pulse group, and 0.5 microg oral Alfacalcidol per day in the daily group. The therapeutic end point was parathyroid hormone level < 200 pg/ mL. The iPTH levels during the study were monitored, and parameters representative of calcium and phosphate metabolism and side effects were also observed. RESULTS: One hundred and fifty-eight patients were initially enrolled, 91 in the pulse therapy group and 67 in the daily therapy group. There was no significant difference in age, hemodialysis duration, proportion of diabetic nephropathy and systemic diseases, proportion of patients who had received active vitamin D therapy previously, mean initial iPTH level (pulse group 570.47 +/- 295.86 pg/mL; daily group 498.33 +/- 207.84 pg/mL), serum calcium, serum phosphate, alkaline phosphatase (AKP), and albumin between two groups. In the pulse therapy group there were more patients with iPTH levels of 500 to approximately 1,000 pg/mL and > 1,000 pg/mL, so stratified analysis according to iPTH level was used. In therapeutic end point, iPTH levels in both groups were significantly lower compared with those before therapy (pulse group 261.29 +/- 234.97 pg/mL, P < .01; daily group 262.17 +/- 274.82 pg/mL, P < .01). After 4 weeks, the ratio of reaching end point in the pulse group was 35.2%, which was significantly higher than that (19.4%) in the daily group (P < .05). More obvious change was seen in the 200 to approximately 500 pg/mL subgroup by stratified analysis (P < .05), whereas there was no significant difference between the 500 to approximately 1,000 pg/mL and > 1,000 pg/mL subgroup (P > .05). At therapeutic end point, the total ratio of reaching end point did not differ between the two groups, and there were no obvious differences between each subgroup. In the iPTH 200 to approximately 500 pg/mL subgroup, mean iPTH%/week in the pulse group was significantly higher than that in the daily group, and no obvious difference was seen in other subgroups. AKP levels decreased significantly in both groups at therapeutic end point (pulse group 98.42 +/- 54.52 vs. 74.21 +/- 30.68 IU/L, P < .01; daily group 103.3 +/- 68.04 vs. 75.40 +/- 34.12 IU/L, P < .01). On the 4th week, AKP level in pulse group (82.39 +/- 35.23 IU/L) was significantly lower than the initial level (98.42 +/- 54.52 IU/L, P < .05), whereas in the daily group there was no difference between each week. The mean serum calcium, phosphate, and [Ca2+] x [P3+] levels in both groups did not change greatly. Nine patients in the pulse group (9.9%) and 8 patients in the daily group (11.9%) suffered hypercalcemia at least once. Persistent hypercalcemia occurred in 8 patients in the pulse group (8.8%) and 9 patients in the daily group (13.4%), but the difference in proportion did not show statistical significance. The serum phosphate in the daily group was higher after the therapy (1.74 +/- 0.36 vs. 1.89 +/- 0.36 mmol/L, P < .05), whereas that in the pulse group remained unchanged. At therapeutic end point, [Ca2+] x [P3+] level in the daily group was higher than that before the therapy (48.04 +/- 11.71 vs. 55.46 +/- 12.66, P < .05), whereas in the pulse group there was no significant difference. Side effects for both groups were minimal and well tolerated. CONCLUSIONS: Alfacalcidol [1alpha-(OH)-D3] has good and safe effects on secondary hyperparathyroidism in maintenance hemodialysis patients. The efficacy and early effects of pulse therapy are superior to those of daily therapy in moderate hyperparathyroidism patients.     

Erythropoietin requirements: a comparative multicenter study between peritoneal dialysis and hemodialysis

BACKGROUND: The management of anemia with erythropoietin (EPO) is important in the global treatment of dialysis patients. There is a general impression that anemia control with EPO is obtained more easily in peritoneal dialysis (PD) patients than in hemodialysis (HD) patients. The EPO administration route has to be the same to compare the two techniques adequately. METHODS: To compare EPO action by subcutaneous (SC) route in HD and PD, 132 stable patients were recruited (HD: 69, PD: 63) from six centers, with adequate dialysis criteria (Kt/V in HD >1.3; weekly Kt/V in PD >1.8). In a cross-sectional study, the EPO dose/week, the number of EPO doses/week, hemoglobin (Hb), ferritin, transferrin saturation index (TS), albumin and intact parathyroid hormone (iPTH) were analyzed. Iron treatment, comorbidity and ACE inhibitors (ACEI) and angiotensin II antagonist (AIIA) treatment were recorded. A multivariate regression model was used in the statistical analysis. RESULTS: The mean Hb level was the same in both groups, HD 11.6 (1.3) g/dL, PD 11.4 (1.4) g/dL, p=0.3. The SC, EPO doses required to obtain the Hb levels were higher in HD than in PD patients, with a difference of 64.3 u/Kg/week, statistically significant in the multivariate regression model (p=0.001, 95% CI 42.6-86.0). The number of EPO doses/week was also higher in HD patients (65% of HD patients with > or = 3 doses, 19% of PD patients with three or more doses, p<0.001). TS was similar in both groups, while ferritin was higher in HD patients, with a higher percentage of HD patients using intravenous (i.v.) iron (HD 77% vs. PD 49%, p=0.001). Serum albumin and iPTH were lower in PD patients (p<0.001 and p=0.04, respectively), but the percentage of patients with intact parathyroid hormone (iPTH) >500 pg/mL was similar in both groups (HD 17%, PD 14%). CONCLUSIONS: With the same administration route, PD patients showed a reduced EPO requirement, and less frequent EPO administration than HD patients, to obtain the same Hb level. No other factors, except those involved in better depuration of erythropoiesis inhibitors in PD, seemed responsible for the different EPO requirements.     

Controlled comparison of hemodialysis and peritoneal dialysis: Veterans Administration multicenter study

We measured mortality and morbidity among 114 patients assigned randomly to home hemodialysis (HD) and home intermittent peritoneal dialysis (IPD). Data were collected during the time of home training and for 12 months after initiation of home dialysis. Training time was shorter for the IPD than for the HD patients (P less than 0.001) with median time 1.8 months for IPD and 3.9 months for HD. Switching to the alternative mode of treatment was more frequent for the IPD group (29/59 vs. 5/55, P less than 0.001). Survival time was not different, perhaps because of the modality change. More IPD patients were hospitalized in the first 6 months (20 for IPD vs. 9 for HD, P = 0.02), but they had fewer troublesome cardiovascular events in the first year (0 vs. 12, P less than 0.001). The HD patients maintained better nutritional status as reflected in body weight and arm muscle circumference and possibly in urea appearance rate. Thus, these data suggest that for most patients, IPD is a less satisfactory form of therapy than HD, but certain advantages of IPD did emerge. Applications of this information to the currently more popular mode of CAPD await further study.     

Prospective comparison of the effects of maxacalcitol and calcitriol in chronic hemodialysis patients with secondary hyperparathyroidism: a multicenter, randomized crossover study

BACKGROUND: Maxacalcitol is a vitamin D analogue, which is administered intravenously for secondary hyperparathyroidism in dialysis patients as well as calcitriol. However, few dose-comparison clinical studies have been reported for these drugs. The present multicenter, randomized crossover study was conducted to determine the equivalence of maxacalcitol and calcitriol doses. METHODS: Subjects comprised 31 patients on chronic hemodialysis with secondary hyperparathyroidism who had not received maxacalcitol or calcitriol in the previous 3 months. Patients were randomly divided into two groups, and maxacalcitol or calcitriol was administered in a crossover design for 12 weeks each. Maxacalcitol and calcitriol doses were adjusted based on serum levels of calcium and intact parathyroid hormone. RESULTS: After the 12-week maxacalcitol/calcitriol administration, there were no significant differences in levels of calcium (maxacalcitol 2.40+/-0.22 mmol/1 (9.6+/-0.9 mg/dl), calcitriol 2.42 + 0.25 mmol/l (9.7+/-1.0 mg/dl), p = 0.71), phosphate (maxacalcitol 1.97 + 0.42 mmol/l (6.1+/-1.3 mg/dl), calcitriol 2.00+/-0.48 mmol/l (6.2+/-1.5 mg/dl), p = 0.64), intact parathyroid hormone (maxacalcitol 267+/-169 pg/ml, calcitriol 343+/-195 pg/ml, p = 0.11) in serum or other bone-metabolic parameters such as serum alkaline phosphatase. The doses ofmaxacalcitol and calcitriol were 49.3+/-23.7 microg/month and 9.0+/-3.8 microg/month, respectively, and maxacalcitol : calcitriol dose ratio was 5.5: 1. No severe adverse reactions were seen for either maxacalcitol or calcitriol during the study period. CONCLUSIONS: Comparable therapeutic efficacy can be obtained in the treatment of secondary hyperparathyroidism using either maxacalcitol or calcitriol at a dose ratio of 5.5 : 1.     

Oral doxercalciferol therapy for secondary hyperparathyroidism in a peritoneal dialysis patient

Control of hyperphosphatemia and the administration of vitamin D are the primary treatment modalities for the prevention and management of secondary hyperparathyroidism. Vitamin D therapy for secondary hyperparathyroidism has been limited by the development of hypercalcemia and/or hyperphosphatemia due to increased intestinal absorption of these minerals. Recently, selective vitamin D analogs specifically designed to suppress parathyroid hormone (PTH) without causing hypercalcemia or hyperphosphatemia have shown promise for the treatment of secondary hyperparathyroidism in uremia. This case report describes the successful use of doxercalciferol to treat severe secondary hyperparathyroidism in an adult male patient undergoing chronic peritoneal dialysis, with a follow-up period of 9 months. During this period, the patient's hyperparathyroidism was rapidly and easily controlled. Treatment was complicated by a single incident of over suppression of PTH, with concomitant hypercalcemia. This quickly resolved upon temporary discontinuation of doxercalciferol therapy, after which therapy was resumed without further incident.     

Effects of the calcimimetic cinacalcet HCl on cardiovascular disease, fracture, and health-related quality of life in secondary hyperparathyroidism

BACKGROUND: Secondary hyperparathyroidism (HPT) and abnormal mineral metabolism are thought to play an important role in bone and cardiovascular disease in patients with chronic kidney disease. Cinacalcet, a calcimimetic that modulates the calcium-sensing receptor, reduces parathyroid hormone (PTH) secretion and lowers serum calcium and phosphorus concentrations in patients with end-stage renal disease (ESRD) and secondary HPT. METHODS: We undertook a combined analysis of safety data (parathyroidectomy, fracture, hospitalizations, and mortality) from 4 similarly designed randomized, double-blind, placebo-controlled clinical trials enrolling 1184 subjects (697 cinacalcet, 487 control) with ESRD and uncontrolled secondary HPT (intact PTH > or =300 pg/mL). Cinacalcet or placebo was administered to subjects receiving standard care for hyperphosphatemia and secondary HPT (phosphate binders and vitamin D). Relative risks (RR) and 95% CI were calculated using proportional hazards regression with follow-up times from 6 to 12 months. Health-related quality-of-life (HRQOL) data were obtained from the Medical Outcomes Study Short Form-36 (SF-36), and the Cognitive Functioning scale from the Kidney Disease Quality of Life instrument (KDQOL-CF). RESULTS: Randomization to cinacalcet resulted in significant reductions in the risk of parathyroidectomy (RR 0.07, 95% CI 0.01-0.55), fracture (RR 0.46, 95% CI 0.22-0.95), and cardiovascular hospitalization (RR 0.61, 95% CI 0.43-0.86) compared with placebo. Changes in HRQOL favored cinacalcet, with significant changes observed for the SF-36 Physical Component Summary score and the specific domains of Bodily Pain and General Health Perception. CONCLUSION: Combining results from 4 clinical trials, randomization to cinacalcet led to significant reductions in the risk of parathyroidectomy, fracture, and cardiovascular hospitalization, along with improvements in self-reported physical function and diminished pain. These data suggest that, in addition to its effects on PTH and mineral metabolism, cinacalcet had favorable effects on important clinical outcomes.     

Supplementation with high-dose trans-resveratrol improves ultrafiltration in peritoneal dialysis patients: a prospective,randomized, double-blind study

Background Ultrafiltration (UF) failure mostly contributes to technical failure in peritoneal dialysis (PD) patients, and one of its responsible factors is peritoneal angiogenesis. Resveratrol has been proposed to have an angiogenesis-ameliorating effect on tumor patients. We hypothesize trans-resveratrol has beneficial effects on angiogenesis-related markers in PD patients. Methods In this prospective, randomized, and double-blind trial, 72 patients were randomly assigned to 12-week treatment of low-dose or high-dose (150 or 450?mg/d) trans-resveratrol or a placebo. Visits were scheduled at 0, 4, 8, and 12 weeks after treatment. Clinical indices including 24-hour UF volume, UF rate, 24-hour urine volume, residual renal function, and dialysis adequacy (kt/v) were measured. Angiogenesis markers including vascular endothelial growth factor (VEGF), fetal liver kinase-1 (Flk-1), angiopoietin-2 (Ang-2), tyrosine kinase 2 (Tie-2), and thrombospondin-1 (Tsp-1) in peritoneal effluent were also assessed by enzyme-linked immunosorbent assay. Results Finally, 64 out of 72 patients were analyzed, 18 in the high-dose group, 22 in the low-dose group, and 24 in the placebo group. Over the 12-week period, patients in the high-dose group [mean change from baseline (95% CI): 171.4 (141.3-201.5) (mL), p?=?0.003 (Net UF); 11.3(10.5-12.1) (mL/h), p?=?0.02 (UF rate)] or the low-dose group [mean change from baseline (95% CI: 98.1 (49.5-146.7) (mL), p?=?0.007 (Net UF); 6.5 (4.4-8.6) (mL/h), p?=?0.04 (UF rate)] versus the placebo group had a significantly greater improvement in mean net UF volume and UF rate. The appearance rates of VEGF, Flk-1, and Ang-2 were more significantly reduced (appearance rates of Tie-2 and Tsp-1 increased) in the high-dose group versus the placebo group, but not in the low-dose group. Conclusion Supplementation with trans-resveratrol is beneficial to improve ultrafiltration in PD patients, and high-dose supplementation may improve ultrafiltration by ameliorating angiogenesis induced by conventional lactate-buffered PD solutions.     

Cinacalcet for the treatment of hypercalcemia in renal transplanted patients with secondary hyperparathyroidism

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.     

Intermittent treatment of knee osteoarthritis with oral chondroitin sulfate: a one-year, randomized, double-blind, multicenter study versus placebo

OBJECTIVE: To investigate the efficacy and tolerability of a 3-month duration, twice a-year, intermittent treatment with oral chondroitin sulfate (CS) in knee osteoarthritis (OA) patients. DESIGN: A total of 120 patients with symptomatic knee OA were randomized into two groups receiving either 800mg CS or placebo (PBO) per day for two periods of 3 months during 1 year. Primary efficacy outcome was Lequesne's algo-functional index (AFI); secondary outcome parameters included VAS, walking time, global judgment, and paracetamol consumption. Radiological progression was assessed by automatic measurement of medial femoro-tibial joint space width on weight-bearing X-rays of both knees. Clinical and biological tolerability was assessed. RESULTS: One hundred and ten of 120 patients were included in the ITT analysis. AFI decreased significantly by 36% in the CS group after 1 year as compared to 23% in the PBO group. Similar results were found for the secondary outcomes parameters. Radiological progression at month 12 showed significantly decreased joint space width in the PBO group with no change in the CS group. Tolerability was good with only minor adverse events identically observed in both groups. CONCLUSION: This study provides evidences that oral CS decreased pain and improved knee function. The 3-month intermittent administration of 800mg/day of oral CS twice a year does support the prolonged effect known with symptom-modifying agents for OA. The inhibitory effect of CS on the radiological progression of the medial femoro-tibial joint space narrowing could suggest further evidence of its structure-modifying properties in knee OA.     

阿法迪三冲击和每日治疗对血液透析患者继发性甲旁亢疗效的随机多中心对照临床研究

目的评价阿法迪三(R)[lα-(OH)-D3]每日或冲击治疗血液透析患者继发性甲状旁腺功能亢进(甲旁亢)的有效性和安全性.方法选择158例维持性血透患者,血全段甲状旁腺激素(iPTH)水平＞200 pg/ml,随机分为冲击组和每日组,分别采用阿法迪三(R)2μgbiw～tiw口服和0.5μgqd口服治疗,总观察期为20周,终点指标为iPTH水平＜200ph/ml.分别检测治疗前后血iPTH及钙磷代谢相关指标,并对不良反应进行监测.结果(1)两组患者年龄、透析龄、基础肾病分布、曾接受活性Vit D3治疗比例、平均血iPTH水平[冲击组(570.47±295.86)pg/ml,每日组(498.33±207.84)pg/ml]及血钙血磷等生化指标均无显著性差异.(2)冲击组治疗4周达标率明显高于每日组(35.2%比19.4%,P＜0.05).治疗至终点时两组总达标率相比无明显差异.iPTH%/周水平在iPTH 200～500pg/ml亚组冲击法高于每日法[(10.68±7.32)%比(7.42±7.89)%,P＜0.05].治疗终点时两组患者碱性磷酸酶(AKP)水平均较治疗前明显下降.(3)治疗终点和治疗前相比,每日组血磷、钙磷乘积均上升,而冲击组治疗前后无明显差异.(4)两组患者不良反应轻微.结论 (1)阿法迪三(R)(1α-(OH)-D3)口服和冲击治疗均能有效控制血透患者继发性甲旁亢,安全性良好.(2)早期冲击疗法对于血透患者中度继发性甲旁亢患者疗效更显著,起效更快.     

Chronic peritoneal dialysis in Turkish children: a multicenter study

Chronic peritoneal dialysis (CPD) has been utilized in the treatment of children since 1989 in Turkey. The aims of this study were to summarize our experience with CPD in children and to establish a pediatric registry data system in Turkey. Standard questionnaires were sent to all pediatric CPD centers. 514 patients treated between 1989 and 2002 in 12 pediatric centers were enrolled in the study. Reflux nephropathy was the most common (18.1%) cause of renal failure. Mean age at dialysis initiation was 10.1±4.6 years. Mean duration of dialysis was 24.1±20.5 months. Continuous ambulatory peritoneal dialysis (CAPD) was the first CPD modality for 476 (92.6%) patients, 142 of whom switched to automated peritoneal dialysis (APD) during follow-up. Currently, 47.3% of the patients are still on CPD, 15.4% were transplanted, 13.2% switched to hemodialysis, 16.7% died. The patient and technique survivals were 90% and 95% at one year and 70% and 69% at five years, respectively. The survival was significantly shorter in the youngest age group (0–24 months) compared to those in older age groups (p=0.000). We herein report the first results of the TUPEPD study providing information on demographic data and survival of pediatric CPD patients. As opposed to clear recommendations in favor of APD, there is a clear preponderance of CAPD in our pediatric CPD population. That vesicoureteral reflux (VUR) is still the leading cause of renal failure is a distressing finding. Remarkably lower survival rates and transplantation ratios are as striking and distressing as the high incidence of VUR among the causes of ESRD. We conclude that we must make a great effort to achieve better results and to change these undesirable events.     

The calcimimetic AMG 073 as a potential treatment for secondary hyperparathyroidism of end-stage renal disease

Current treatment of secondary hyperparathyroidism in chronic kidney failure with calcium and active vitamin D is potentially limited by hypercalcemia and hyperphosphatemia. AMG 073 represents a new class of compounds for the treatment of hyperparathyroidism known as calcimimetics, which reduce parathyroid hormone (PTH) synthesis and secretion by increasing the sensitivity of the parathyroid calcium-sensing receptor (CaR) to extracellular calcium. The current study evaluates the efficacy and safety of AMG 073 when added to conventional treatment of secondary hyperparathyroidism in end-stage renal disease (ESRD). Seventy-one hemodialysis patients with uncontrolled secondary hyperparathyroidism, despite standard therapy with calcium, phosphate binders, and active vitamin D sterols, were treated in this 18-wk, dose-titration study with single daily oral doses of AMG 073/placebo up to 100 mg. Changes in plasma PTH, serum calcium, serum phosphorus, and calcium x phosphorus levels were compared between AMG 073 and placebo groups. Mean PTH decreased by 33% in the AMG 073 patients compared with an increase of 3% in placebo patients (P = 0.001). A significantly greater proportion of AMG 073 patients (44%) had a mean PTH < or = 250 pg/ml compared with placebo patients (20%; P = 0.029). Also, a significantly greater proportion of AMG 073 patients (53%) had a decrease in PTH > or =30% compared with placebo patients (23%; P = 0.009). Calcium x phosphorus levels decreased by 7.9% in AMG 073 patients compared with an increase of 11.3% in placebo patients (P = 0.013). Adverse event rates were low and mostly mild to moderate in severity; however, the incidence of vomiting was higher in AMG 073 patients. In this study, the calcimimetic AMG 073 at doses up to 100 mg for 18 wk provided a safe and effective means to attain significant reductions in PTH and calcium x phosphorus levels in ESRD patients. AMG 073 represents a novel and promising therapy to improve the management of secondary hyperparathyroidism.