A novel calcimimetic evocalcet for the management of secondary hyperparathyroidism with little effect on the gastrointestinal tract and cyp isozymes in vivo and in vitro

In the treatment of secondary hyperparathyroidism of end-stage chronic kidney disease, vitamin D receptor activation and allosteric modulators of the calcium-sensing receptor - inhibit glandular hyperplasia; reduce parathyroid hormone levels, impact on bone turnover and mineral density. Cinacalcet, an oral calcimimetic agent has been widely used for the management of secondary hyperparathyroidism in chronic kidney disease. Nevertheless, some patients remain refractory to the treatment, as the dose of cinacalcet cannot be sufficiently increased due to gastrointestinal symptoms and it strong inhibits of cytochrome P450 (CYP) 2D6. In order to resolve this issue, was develop a newly synthesized calcimimetic agent, evocalcet (MT-4580/KHK7580). In a rat model of chronic kidney disease induced by 5/6 nephrectomy, and in multicenter, open-label study phase 3, and in clinical practice oral administration of evocalcet efficiently suppressed the secretion of parathyroid hormone. Evocalcet also demonstrated the less induction of emesis and gastro-intestinal effects, and its pharmacological effects were observed at lower doses because of its higher bioavailability than cinacalcet. In addition, evocalcet showed no substantial direct inhibition of any CYP isozymes in in vitro. These findings suggest that evocalcet can be a better alternative to cinacalcet with a wider safety margin

The effectiveness of nutritional vitamin D supplementation and selective vitamin D receptor agonists treatment on secondary hyperparathyroidism in chronic kidney diseases patients

Background: secondary hyperparathyroidism (SHPT) is an early complication of chronic kidney disease (CKD). Maintaining the level of 25(OH)D and parathyroid hormone concentrations in the target range reduce its associated complications (fractures and cardiovascular calcification). Aims: to examine the effectiveness of vitamin D supplementation and selective vitamin D receptor agonists treatment on SHPT in CKD. Material and methods: prospective observational study to evaluate the efficacy and safety of vitamin D therapy SHPT in 54 in patients with CKD. The first phase (24 weeks) treatment of suboptimal 25-hydroxycalciferol (25(OH)D) levels. The second (16 weeks) treatment colecalciferol-resistant SHPT by combination of cholecalciferol with paricalcitol. Blood samples were taken to assess parathyroid hormone (PTH), 25(OH)D, creatinine, calcium, phosphorus levels and calcium excretion. Results: After 8 weeks of cholecalciferol treatment all patients achieved 25(OH)D levels above 20 ng/ml, however 78% of patients still had SHPT. After 16 weeks, the decrease of PTH was achieved in all patients, but significantly only in patients with CKD 2 (19.2%, p 0.01) and 3 (31%, p 0.05), compared with CKD 4 (17%, p 0.05). After 24 weeks of therapy, PTH normalized in all patients with CKD 2, in 15 (79%) with CKD 3 and in 9 (50%) patients with CKD 4. Cholecalciferol treatment resulted in a substantial increase in 25(OH)D levels with minimal or no impact on calcium, phosphorus levels and kidney function. After 24 weeks we initiated combination therapy (cholecalciferol and paricalcitol) for patients with colecalciferol-resistant SHPT (n=13). PTH levels decreased from 149.113.4 to 118.214.1 pg/ml at 8 weeks, and to 93.19.7 pg/ml (p 0.05) at 16 weeks of treatment. No significant differences in serum calcium, phosphorus or urinary calcium levels. Normalization of PTH was achieved in all patients with CKD 3 and in 8 patients with stage 4. One patient with CKD 4 needed an increase in paricalcitol dose. Conclusion: Cholecalciferol can be used in correcting vitamin D deficiency in patients with all stages of CKD, however, its effectiveness in reducing PTH in stage 4 is limited. Selective analogs, such as paricalcitol, were well-tolerated and effectively decreased PTH levels

Secondary hyperparathyroidism in patient with type 2 diabetes and stages 3–4 chronic kidney disease

Secondary hyperparathyroidism is an early complication of chronic kidney disease, with increasing severity as the glomerular filtration rate decreases and characterized by a progressive increase in parathyroid hormone and growth of the parathyroid glands. It is generally accepted that a deficiency in active form of vitamin D or calcitriol levels seems to play a relevant role in its development and progression of secondary hyperparathyroidism. A reduction in plasma calcitriol levels occurs early in renal disease. Major renal guidelines recommend use of vitamin D for secondary hyperparathyroidism in chronic kidney disease. In the treatment vitamin D receptor activation inhibit glandular hyperplasia; reduce parathyroid hormone levels impact on bone turnover and mineral density. Treatment with calcitriol can occasionally result in hypercalcemia and hyperphosphatemia in renal patients due promotes intestinal calcium and phosphorus absorption. This limits its suitability for the treatment. But next generation vitamin-D analogs such as paricalcitol have lower intestinal absorption of calcium, phosphorous and significantly lowers renin levels, albuminuria and blood pressure. In this article, we present the case of a Caucasian male with type 2 diabetes and secondary hyperparathyroidism in stages 34 chronic kidney disease. Our case study shows that in treating for secondary hyperparathyroidisms selective vitamin D receptor activation with paricalcitol reduction of levels parathyroid hormone, albuminuria, offering low chance hypercalcemia, hyperphosphatemia and other side effects

Non-classical effects of vitamin D

Some studies support the involvement of vitamin D in modulating the inflammatory response and developing diabetes. Since the activation of inflammatory biomarkers, cytokines and pathways interferes with normal metabolism and disrupts proper insulin signaling and insulin resistance, it is hypothesized that vitamin D could influence lipid and glucose homeostasis by modulating inflammatory response and renin-angiotensin system. In this review discussed the mechanisms of the influence of vitamin D on metabolic disease

Functional hypoparathyroidism secondary to magnesium deficiency in long-term users of proton pump inhibitor

Gastroesophageal reflux disease (GERD) is a gastrointestinal motility disorder that results from the reflux of stomach contents into the esophagus resulting in symptoms or complications. GERD is now widely prevalent around the world, with clear evidence of increasing prevalence in many developing countries. Treatment for most people with GERD includes lifestyle changes and medication. Proton pump inhibitors (PPIs) are a mainstay therapy for all gastric acid-related diseases. Long-term use of PPIs is associated with hypomagnesaemia, hypokalemia, hypocalcaemia, osteoporosis and bone fractures, chronic renal disease, acute renal disease, and other. Clinical concerns arise from a small but growing number of case reports presenting PPI-induced hypomagnesaemia. In 2011 the U.S. Food and Drug Administration is informing the public that prescription PPI may cause low serum magnesium levels if taken for prolonged periods of time. In this article, we present the case of a 56-year-old patient with muscle cramps, violation of cardiac rhythm, lethargy and other caused by hypomagnesaemia, hypocalcaemia and hypokalemia with a low parathyroid hormone level while using a PPI. After magnesium repletion abnormalities resolved. A causal relation with PPI use was supported by the recurrence of hypomagnesaemia after re-challenge

Influence of androgen deficiency on carbohydrate metabolism in men

The article provides an overview of the current literature integrating clinical data on the role of androgen deficiency in pathogenesis of metabolic malfunctions and diabetes mellitus. The combination of androgen deficiency and diabetes mellitus is a risk factor of cardiovascular diseases. Due to the fact that general physicians, endocrinologist don’t have knowledge of this problem most of androgen deficiency cases are not only remained without treatment but also not revealed

Secondary and tertiary hyperparathyroidism in chronic kidney disease

In the treatment of secondary hyperparathyroidism of end-stage chronic kidney disease, vitamin D receptor activation and allosteric modulators of the calcium-sensing receptor inhibit glandular hyperplasia, reduce parathyroid hormone levels, impact on bone turnover and mineral density. But the use of calcimimetic and vitamin D analogs or mimetics did not reduce the need for parathyroidectomy for refractory hyperparathyroidism. The enlarged parathyroid gland and gland nodular transformation became refractory to medical therapy and patient need for parathyroidectomy. Tertiary hyperparathyroidism is a state of excessive secretion of parathyroid hormone after a long period of secondary hyperparathyroidism and renal transplantation. In this article, we present the case of a Caucasian male with chronic kidney disease (end-stage on chronic hemodialysis and after kidney transplantation) and different forms of hyperparathyroidism (secondary and tertiary). Our case study shows that only a multi-interventional strategy is likely to be more effective treatment in cases of severe and refractory to medical therapy hyperparathyroidism