maxacalcitol and Chronic-Disease

The 'classical' effects of vitamin D receptor activator or agonist (VDRA) therapy for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease primarily involves suppressive effects on the parathyroid gland, and regulation of calcium and phosphorus absorption in the intestine and mobilisation in bone. Observational studies in haemodialysis patients report improved cardiovascular and all-cause survival among those receiving VDRA therapy compared with those not on VDRA therapy. Among VDRAs, the selective VDRA paricalcitol has been associated with greater survival than nonselective VDRAs, such as calcitriol (1,25-dihydroxyvitamin D(3)). The survival benefits of paricalcitol appear to be linked, at least in part, to 'nonclassical' actions of VDRAs, possibly through VDRA-mediated modulation of gene expression. In cardiovascular tissues, VDRAs are reported to have beneficial effects such as anti-inflammatory and antithrombotic effects, inhibition of vascular smooth muscle cell proliferation, inhibition of vascular calcification and stiffening, and regression of left ventricular hypertrophy. VDRAs are also reported to negatively regulate the renin-angiotensin system, which plays a key role in hypertension, myocardial infarction and stroke. The selective VDRAs, paricalcitol and maxacalcitol, are associated with direct protective effects on glomerular architecture and antiproteinuric effects in response to renal damage. Paricalcitol regulates several cardiovascular and renal parameters more favourably than nonselective VDRAs. Complex nonclassical effects, which are not clearly understood, possibly contribute to the improved survival seen with VDRAs, especially paricalcitol.

Topics: Animals; Bone Density Conservation Agents; Calcitriol; Cardiovascular Diseases; Chronic Disease; Ergocalciferols; Humans; Hydroxycholecalciferols; Hyperparathyroidism, Secondary; Kidney Diseases; Receptors, Calcitriol; Survival Rate

Recent evidence suggests that 1α,25-dihydroxyvitamin D3 (calcitriol, VD3), the active form of vitamin D (VD), can inhibit the proliferation of microorganisms. In the present study, we conducted in vitro experiments and utilized in vivo murine models to investigate the antimalarial activity of VD3 and its analog, 22-oxacalcitriol (22-OCT), which was designed to cause less hypercalcemia than VD3. VD3 and 22-OCT treatments effectively resolved a Plasmodium chabaudi (Pc) infection in wild-type mice. Reduced parasitemia was observed during the acute phase of infection in the presence of VD3 and 22-OCT, followed by a delayed peak during the chronic stage of infection. Some anti-Pc activity was observed in VD receptor knockout (KO) mice. VD3 and 22-OCT also completely inhibited the proliferation of P. falciparum (Pf) in human red blood cells in vitro. Plasma levels of interferon (IFN)-γ in VD3-treated B10 and B6 mice were lower than those in vehicle-treated animals, and VD3 resolved a Pc infection in IFN-γ-KO mice, which greatly improved survival. These data suggest that the protective effects of VD3 are elicited through an IFN-γ-independent mechanism. Effective antiplasmodial doses of VD3 and 22-OCT resulted in a loss of body weight in mice. This loss in body weight occurred concomitantly with the development of hypercalcemia. Zoledronic acid partially attenuated VD3-induced hypercalcemia and abrogated the antiparasitic effects of VD3. This study highlights a potential therapeutic role for VD3 in the treatment of malarial infections and shows that hypercalcemia is excellent indicator of the antiplasmodial activity of VD3.

Topics: Acute Disease; Animals; Antimalarials; Body Weight; Calcitriol; Cholecalciferol; Chronic Disease; Diphosphonates; Erythrocytes; Humans; Hypercalcemia; Imidazoles; Interferon-gamma; Malaria; Mice; Mice, Inbred BALB C; Mice, Knockout; Parasitemia; Plasmodium chabaudi; Receptors, Calcitriol; Zoledronic Acid

22-Oxacalcitriol ameliorates high-turnover bone and marked osteitis fibrosa in rats with slowly progressive nephritis.. 22-Oxacalcitriol (OCT) is a unique vitamin D analogue with less calcemic activity than calcitriol, and it effectively suppresses parathyroid hormone (PTH) secretion in uremic rats. This study was performed to examine the long-term effect of intravenously administered OCT on high-turnover bone disease in model rats of slowly progressive renal failure.. Slowly progressive renal failure rats were made by a single injection of glycopeptide isolated from rat renal cortical tissues. At 250 days, glycopeptide-induced nephritis (GN) rats were divided into three groups with the same levels of serum creatinine and PTH, and they received either OCT (0.03 or 0.15 microg/kg body wt) or vehicle given intravenously three times per week for 15 weeks.. Renal function of GN rats deteriorated very slowly but progressively, as assessed by the increase of serum creatinine concentration. At sacrifice, serum PTH levels, bone formation markers, bone resorption markers, and fibrosis volume were significantly elevated in vehicle-treated GN rats compared with those of sham-operated rats, suggesting the development of high-turnover bone disease with osteitis fibrosa. In contrast, in the GN-OCT 0.15 microg/kg group, these high PTH levels and high-turnover bone and fibrosis were significantly decreased. Such amelioration of bone abnormalities by OCT was not accompanied by either hypercalcemia or further deterioration of renal function.. These data indicate that OCT may be a useful and safe agent not only for the suppression of PTH, but also for the amelioration of osteitis fibrosa and high-turnover bone without causing hypercalcemia in chronic dialysis patients.

Topics: Animals; Antineoplastic Agents; Bone Remodeling; Calcitriol; Chronic Disease; Chronic Kidney Disease-Mineral and Bone Disorder; Disease Progression; Feedback; Fibrosis; Glycopeptides; Hyperparathyroidism, Secondary; Male; Nephritis; Osteitis; Rats; Rats, Wistar; Renal Insufficiency; Uremia