Increased Blood Calcium Research Articles

Systemic review of Jintiange Capsules in treatment of postmenopausal osteoporosis

To systemically evaluate the efficacy and safety of Jintiange Capsules in the treatment of postmenopausal osteoporosis(PMOP).Seven literature databases were retrieved systematically,and two reviewers independently searched and screened studies,extracted data,and included all the randomized controlled trials on Jintiange Capsules in the treatment of PMOP.Interventions included comparison of Jintiange Capsules with placebo and routine treatment,and the studies on Jintiange Capsules combined with routine treatment versus conventional treatment were also included.The evaluation indicators of the study included at least one of the followings:fracture,quality of life,daily living ability,clinical symptoms,death,adverse events/adverse reactions,bone density,and bone metabolism indexes.The original study quality evaluation was conducted by following the Cochrane Handbook standard and statistical analysis was performed by using Rev Man 5.2.A total of 7 randomized controlled trials were included and the study quality was low.Meta-analysis showed that as compared with conventional treatment alone,Jintiange Capsules combined with conventional treatment showed more obvious effects in pain relief(MD=-0.98,95% CI[-1.55,-0.41],P=0.000 8),increasing blood calcium levels(MD=0.05,95% CI[0.02,0.09],P=0.003) and lowering serum alkaline phosphatase levels(MD=-12.92,95% CI[-24.09,-1.75],P=0.02).In addition,the Chinese patent medicine alone or in combination with conventional treatment was relatively safe.In conclusion,Jintiange Capsules has a certain effect in treating PMOP,but the quality of evidence is low.It is necessary to conduct well designed randomized controlled trials and select recognized evaluation indicators,especially the end outcomes in order to further improve the clinical evidence.

Metabolism of 2α-[2-(tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D3 by CYP24A1 and biological activity of its 24R-hydroxylated metabolite

Our previous study revealed that the 2α-substituted vitamin D analog 2α-[2-(tetrazol-2-yl)ethyl]-1α,25(OH)2D3 (AH-1) exhibited a higher osteocalcin promoter transactivation activity in human osteosarcoma cells and a greater effect on bone mineral density in a rat model of osteoporosis than 1α,25(OH)2D3 without increasing blood calcium concentration. Thus, we hypothesized that AH-1 could be a promising therapeutic agent for osteoporosis without any serious side effects. In this study, we compared the CYP24A1-dependent metabolism of AH-1 with that of 1α,25(OH)2D3. The resistance to CYP24A1-dependent metabolism could be an important property of vitamin D analogs in prolonging their biological effects. A kinetic analysis was performed using a membrane fraction prepared from recombinant E. coli expressing human CYP24A1. The kcat/Km (μM−1 min−1) value for AH-1 was 31% of that for 1α,25(OH)2D3, suggesting that AH-1 is not as resistant to CYP24A1-dependent metabolism as the other C2-substituted vitamin D analogs such as eldecalcitol [2β-hydroxypropoxy-1α,25(OH)2D3]. The major metabolite of AH-1 was the 24R-hydroxylated metabolite, which had high vitamin D receptor (VDR) binding affinity and high HL-60 cell differentiation activity similar to AH-1 itself. In contrast, 1α,25(OH)2D3 was metabolized by multistep monooxygenation reactions, which led to the loss of affinity for VDR. Thus, the greater therapeutic effects of AH-1 than those of 1α,25(OH)2D3 in in vivo studies using osteoporosis rat models may be due to 24R-hydroxy-AH-1 whose VDR affinity was 91% of that of AH-1.

EFFECT OF EGGSHELL FLOUR ON BLOOD CALCIUM LEVELS IN PREGNANT MICE

Objective: To examine the effect of eggshell flour on blood calcium levels in pregnant mice.
 Methods: This was a true experimental study with pretest and posttest control group design. The research was conducted at the Nutrition Laboratory of the Center for Food and Nutrition Studies, Gadjah Mada University on December 1, 2017 to December 31, 2017. There were 30 pregnant rats included using simple random sampling, which assigned in five groups. Spectrophotometer was used to measure blood calcium levels. Paired t-test and One-way ANOVA were used for data analysis.
 Results: There were significant differences in blood calcium levels before and after treatment with eggshell flour dose 5.4 mg/dl (p= 0.000), 10.8mg/dl (p = 0.000), and 21.6 mg/dl (p = 0.000). There was also significant difference in blood calcium levels in control group with generic tablet of calcium powder of 21.6 mg/dl (p = 0.000).
 Conclusion: There was a significant effect of given eggshell flour for 7 days with dose 5.4 mg/dl, 10.8 mg/dl, and 21.6 mg/l as well as generic tablet of calcium powder of 21.6 mg/dl in increasing blood calcium levels. Thus, eggshell can be used as alternative for calcium supplement.

The efficacy of using exogenous enzymes cocktail on production, egg quality, egg nutrients and blood metabolites of laying hens fed distiller's dried grains with solubles.

An experiment was performed using 120 Hisex Brown laying hens for evaluating the effects of different inclusion levels of corn distiller's dried grains with solubles (DDGS) as a replacement of soybean meal (SBM) with or without enzyme cocktail on performance, egg quality, egg nutrients and blood metabolites in laying hens through 22-42weeks of age. A 4×2 factorial design experiment was performed including four substitution levels of DDGS (0, 250, 500 and 750g/kg respectively) and two enzyme cocktail levels (0 and 250mg/kg diet). The used enzyme in this study "Gallazyme" composed of xylanase, Trichoderma longibrachiatum (600units/g), protease, Bacillus subtilis (8,000units/g) and amylase and Bacillus amyloliquofaciens (800units/g). The control diet showed the best feed efficiency followed by the intermediate levels of DDGS. The lowest value of feed efficiency was found in the group fed the highest level of DDGS. Enzyme addition improved feed efficiency and decreased laying rate. Increasing DDGS levels was associated with albumin and shell thickness increases. Dietary DDGS depressed all egg components except the organic matter which maximised in enzyme-treated groups. Increasing DDGS level was accompanied by increase in yolk cholesterol and total lipids. No significant impacts were detected with enzymes supplementation on yolk lipids profile. Excepting serum calcium and phosphorous, all serum constituents increased with increasing level of DDGS. Using enzyme markedly depressed serum ammonia by 15.02% and increased calcium by 6.44% compared with enzyme-free diets. Interaction between DDGS and enzyme was significant on most of studied parameters. It could be concluded that using enzyme cocktail in DDGS-based diets may improve feed efficiency and egg quality, in addition to lowering blood ammonia and increasing blood calcium. It is recommended to substitute SBM by DDGS up to 500g/kg diet.

Knockin mouse with mutant Gα11 mimics human inherited hypocalcemia and is rescued by pharmacologic inhibitors.

Heterotrimeric G proteins play critical roles in transducing extracellular signals generated by 7-transmembrane domain receptors. Somatic gain-of-function mutations in G protein α subunits are associated with a variety of diseases. Recently, we identified gain-of-function mutations in Gα11 in patients with autosomal-dominant hypocalcemia type 2 (ADH2), an inherited disorder of hypocalcemia, low parathyroid hormone (PTH), and hyperphosphatemia. We have generated knockin mice harboring the point mutation GNA11 c.C178T (p.Arg60Cys) identified in ADH2 patients. The mutant mice faithfully replicated human ADH2. They also exhibited low bone mineral density and increased skin pigmentation. Treatment with NPS 2143, a negative allosteric modulator of the calcium-sensing receptor (CASR), increased PTH and calcium concentrations in WT and mutant mice, suggesting that the gain-of-function effect of GNA11R6OC is partly dependent on coupling to the CASR. Treatment with the Gα11/q-specific inhibitor YM-254890 increased blood calcium in heterozygous but not in homozygous GNA11R60C mice, consistent with published crystal structure data showing that Arg60 forms a critical contact with YM-254890. This animal model of ADH2 provides insights into molecular mechanism of this G protein-related disease and potential paths toward new lines of therapy.

AMPK Expressed By Multiple Myeloma Cells Inhibited Metformin-Induced Myeloma Cells Proliferation

BackgroundMultiple myeloma(MM) is a malignant plasma cells proliferative disease which is characterized by increased blood calcium level, renal insufficiency, anemia, and bone lesions(CRAB). MM is still uncured disease. To further explore the mechanisms of MM was an urgent problem needs to be solved. AMPK is an "energy sensor". Studies had demonstrated that metformin could activate AMPK and exert anti-tumor effect in many tumors. However, a paradoxical phenomenon was found that knockdown AMPK could enhance the anti-tumor effect of metformin. Recent studies had revealed that AMPK maybe a double-edged sword in tumors. Our previous study had discovered that metformin exert anti-myeloma effect without activating AMPK. In this study, we mainly focus on the expression of AMPK in MM cells and to explore whether the expression of AMPK in MM cells could block the anti-myeloma effect of metformin.MethodsThe expression of AMPK in MM cells was detected by Western blotting. Small interfering RNA(siRNA) was used to knockdown the expression of AMPK. Apoptotic cells of MM cells were detected by Annexin V-FITC/PI using flow cytometry analysis. Western blotting was used to elucidate the apoptotic protein of MM cells induced by metformin with or without knockdown AMPK.ResultsOur study revealed that AMPK was obviously expressed by MM cells(Fig.1). Metformin could not activate AMPK signaling pathway. Knockdown AMPK with siRNA could enhance the anti-myeloma effect of metformin(Fig.2 and Fig.3).ConclusionsTaken together, our data indicated that AMPK was expressed by MM cells. Inhibit AMPK could enhance the anti-myeloma effect of metformin. AMPK maybe a new therapy target. DisclosuresNo relevant conflicts of interest to declare.

The safety and effectiveness profile of eldecalcitol in a prospective, post-marketing observational study in Japanese patients with osteoporosis: interim report.

This large-scale post-marketing surveillance study was conducted to assess the safety and effectiveness of eldecalcitol treatment in patients with osteoporosis in a Japanese clinical setting. A total of 3567 patients with osteoporosis were enrolled and received eldecalcitol 0.75μg/day for 12months. For this interim report, 3285 patients were eligible for analysis. Mean age was 74.9±8.7years; 86.8% (2854/3285) were women. There were 142 reported adverse drug reactions (ADRs) in 129 patients (3.92% of the total 3285 patients): the most common were hypercalcemia and increased blood calcium (0.88%), renal impairment (0.27%), abdominal discomfort (0.24%), constipation (0.24%), and pruritus (0.24%). The incidence of ADRs was 5.10% in men and 3.74% in women. Although 10 serious ADRs were reported in 9 patients (0.27%), no clinically significant safety issues were identified. Incidence of hypercalcemia or increased blood calcium was 8.47% in patients with renal impairment and only 0.74% in patients without renal impairment. At last observation, the incidence of new vertebral and nonvertebral fractures was 2.44% and 1.70%, respectively. There was a significant increase in bone mineral density at the lumbar spine and distal radius. The bone turnover markers BAP, serum NTX, urinary NTX, and TRACP-5b were suppressed by eldecalcitol treatment in both sexes. In conclusion, consistent with the findings of the phase III pivotal clinical trial, eldecalcitol was shown to have a favorable safety profile and effectiveness in Japanese patients with osteoporosis. However, periodic measurements of serum calcium were required to prevent occurrence of hypercalcemia during eldecalcitol treatment, especially in patients with renal impairment.

Pengaruh Pemberian Kalsium Vitamin D dan Zat Besi terhadap Kadar Kalsium Serum Tikus Putih (Rattus novergicus) Galur Wistar

Osteoporosis is a bone systemic disease marked with the lessen of bone mass density and then bone will become fragile and breakable. The calcium imbalance disorder can cause osteoporosis. Vitamin D has strong effect on calcium absorbtion and keeping calcium plasma, but vitamin D must be change become active form 1,25 dihydroxyvitamin D through hydroxylation reaction in liver and kidney. The hydroxylation process requires enzyme of ferrum; iron protein sulphur and cytocrom P-450. This research was aimed to know the influent of combining calcium, vitamin D and iron to blood calcium rate compared with the control group. Research type was experimental static group comparison with pretest and posttest design. Samples were divided in to 5 group iron deficient. Two group for control group and 3 group for treatment that giving combining calcium- vitamin D, calcium-iron and calsium-vitamin D-iron for 14 days. The result showed the significant different (p>0,05) of calcium blood rate before an after the treatment in calcium-vitamin D group and calcium-vitamin D-iron group, but calcium blood rate is higher in calcium-vitamin D-iron group. The giving of calcium-vitamin D-iron combination can increase blood calcium rate significantly

Profil toxique du lithium : revue exhaustive de la littérature avec méta-analyse des résultats

ObjectivesLithium is a widely used and effective treatment for mood disorders. There has been concern about the safety of lithium but no adequate recent synthesis of the evidence on adverse effects was published in French language. The objective of this study was to produce a clinically informative, systematic toxicity profile of lithium. Materials and methodsWe up-to-dated the systematic review and meta-analysis of randomized controlled trials and observational studies investigating the association between lithium and all reported major adverse effects that we previously published. We searched electronic databases specialist journals, reference lists, textbooks and conference abstracts. We used a hierarchy of evidence which considered RCTs, cohorts, case-control studies and case reports including patients with mood disorders treated with lithium. Outcome measures were renal, thyroid and parathyroid function; weight change, skin disorders, hair disorders and teratogenicity. ResultsFive thousand nine hundred and eighty-eight abstracts were screened for eligibility and 390 studies included in the analysis. On average, glomerular filtration rate was reduced by –9.30mls/min [95 % CI –12.15 to –6.44, P<0.001] and urinary concentrating ability was reduced by 15 % of normal maximum. Lithium use may increase rates of renal failure but absolute risk appears to be of the order of 0.3 %. The prevalence of clinical hypothyroidism was increased in patients taking lithium [OR 5.78, 95 % CI 2.00 to 16.67, P=0.001], whilst thyroid stimulating hormone was increased on average by 4.00 iU/mL [95 % CI 3.90 to 4.10, P=<0.001]. Lithium treatment was associated with increased blood calcium [+0.09 mmol/L, 95 % CI 0.02 to 0.09; P=0.009], and parathyroid hormone [+7.32 pg/mL, 95 % CI 3.42 to 11.23; P<0.001]. Lithium was associated with more weight gain than placebo [OR 1.89 (1.27 to 2.82) P=0.002], but not olanzapine [OR 0.32 (0.21 to 0.49) P≤0.001]. There was no statistically significant increased risk of congenital malformations, alopecia, or skin disorders despite many suggesting such associations. ConclusionsLithium is associated with increased risk of reduced urinary concentrating ability, hypothyroidism, hyperparathyroidism and weight gain. There is little evidence for a clinically significant reduction in renal function in the majority of patients and the risk of end-stage renal failure is low. The risk of congenital malformations is uncertain; the balance of risks should be considered before lithium is withdrawn during pregnancy. The consistent finding of a high prevalence of hyperparathyroidism means calcium levels should be checked before and during treatment.

Fibroblast Activation Protein Protects Bortezomib Induced Apoptosis In Multiple Myeloma Cells Through β-Catenin Signaling Pathway

BackgroundMultiple myeloma(MM) is a malignant plasma cells proliferative disease which is characterized by increased blood calcium level, renal insufficiency, anemia, and bone lesions(CRAB). The intricate cross-talk with the bone marrow microenvironment plays an important role in facilitating the growth and survival of myeloma cells. Fibroblast activation protein(FAP) is a vital transmembrane protein expressed in 90% epithelial tumor stroma, which is reported to be involved in mediating drug resistance, tumorigenesis, neoplastic progression, angiogenesis, invasion and metastasis of tumor cells. The present study is aimed to investigate the roles of FAP may play in regulation of apoptosis in MM cells induced by bortezomib and the potential signaling pathway that FAP may be participated in. MethodsBone marrow mesenchymal stem cells(hBMMSCs) from MM patients and normal donors and the cell line of hBMMSCs were analyzed for expression of the FAP protein by semiquantitative real time-polymerase chain(qRT-PCR), flow cytometry(FCM) and immunofluorescence(IF). Tumor cell-conditioned medium (TCCM) from supernatant of MM cell lines were added to hBMMSCs to observe the effect of TCCM for the expression of FAP. We further studied the function and mechanism of FAP in bortezomib induced apoptosis of myeloma cells by silencing FAP with small interfering RNA(siRNA). Apoptotic cells of MM cells were detected by APC-CD138/annexin V-FITC using flow cytometry analysis. Western blotting was used to elucidate the signaling pathway that FAP may be involved in mediating apoptosis of MM cells induced by bortezomib. ResultsThere was no significant difference in the expression of FAP in hBMMSCs isolated from MM patients and normal donors(p>0.05) as determined by qRT-PCR, FCM and immunofluorescence. hBMMSCs stimulated by TCCM for 7 days displayed an elevated expression of FAP as detected by qRT-PCR(p<0.05). In the presence of 30nM bortezomib, MM cell lines RPMI8226 or CAG cells co-cultured with hBMMSCs in which FAP was knockdown or not by siRNA for 48h demonstrated that FAP is capable of protecting RPMI8226 and CAG cells induced by bortezomib from apoptosis as determined by FCM(NC siRNA vs FAP siRNA, p<0.05). Further study showed that the activity of β-catenin was significantly elevated in RPMI8226 cells after co-cultured with hBMMSC in the presence of bortezomib. Knockdown FAP can reduce the expression of β-catenin and its downstream target proteins, such as c-myc, survivin, cyclin D1 in RPMI8226 cells detected by western blot. ConclusionsTaken together, our data indicated that the expression level of FAP was no difference between the hBMMSCs isolated from MM patients and normal donors. The expression of FAP can be increased by TCCM stimulation. Further study demonstrated that FAP can protect MM cells from apoptosis induced by bortizomib, which is likely through β-catenin signaling pathway. Disclosures:No relevant conflicts of interest to declare.

Effect of a prebiotic on performance of partridge

An experiment was conducted to investigate the effect of a prebiotic on performance of partridge. The experiment was carried out with a total of eighty-day-old male Chukar partridge (Alectoris chukar chukar) chicks in a completely randomized design. The dietary treatments consisted of a control and an experimental treatment, and each treatment was replicated four times with 10 chicks per replicate. The experimental period lasted 16 weeks with a starter period (0-8 weeks) and a grower period (9-16 weeks). The control group was fed the basal diet, while the experimental group was fed the basal diet supplemented with 0.18% prebiotic Aspergillus meal in each period. Performance parameters included body weight gain, cumulative feed consumption and cumulative FCR and were recorded at biweekly intervals. Carcass characteristics and blood parameters were measured at the end of the experiment (week 16). Although the results showed that prebiotic had no significant effect on body weight gain and cumulative feed conversion ratio; however, the supplementation of Aspergillus meal significantly (p < 0.05) decreased cumulative feed consumption. Also prebiotic significantly increased percentages of breast and gastrointestinal tract, decreased percentage of back-neck, decreased blood triglyceride and total cholesterol content and increased blood calcium content. From this study, it was concluded that dietary supplementation of 0.18% Aspergillus meal might offer beneficial effects on partridge feed consumption, carcass quality and blood cholesterol.

Effects of dietary clinoptilolite and calcium levels on uric acid and calcium blood concentrations and bone quality of commercial layers

The objective of the present study was to evaluate the effect of clinoptilolite and calcium levels on uric acid and calcium blood profile and bone quality of commercial layers. A total of 576 birds were distributed according to a completely randomized experimental design in a 3x4 factorial arrangement (calcium levels of 2.5, 3.1, or 3.7% and clinoptilolite levels of 0.0, 0.15, 0.25, or 0.50%), into 12 treatments with six replicates of eight birds per cage (experimental unit). The experimental period was 112 days. The experimental diets were based on corn and soybean meal. Results were submitted to analysis of variance and means were compared by the test of Tukey at 5% significance level using SISVAR statistical package. Blood uric acid was significantly influenced by the interaction of the evaluated factors. Clinoptilolite levels significantly increased blood calcium levels. There was no effect of dietary calcium levels on any of the evaluated characteristics. It was concluded that feeding layers with up to 0.50% clinoptilolite does not benefit blood uric acid and calcium concentrations and does not affect their bone quality. When layers at the end of the first laying cycle are fed ad libitum and present 119.50g/hen/day average feed intake, 3.1% dietary calcium promotes 3.7g/hen/day calcium intake, which is sufficient to maintain adequate calcium blood levels and bone quality.

Eldecalcitol for the treatment of osteoporosis

Eldecalcitol (1α, 25-dihydroxy-2β-[3-hydroxypropyloxy] vitamin D3; ED-71) is a new analog of the active form of vitamin D. Eldecalcitol has recently been approved for the treatment of osteoporosis in Japan. In addition to regulation of calcium metabolism carried out by conventional vitamin D analogs, eldecalcitol possesses a strong inhibitory effect on bone resorption and causes a significant increase in bone mineral density. A Phase III clinical trial on osteoporosis showed that eldecalcitol reduced the incidence of new vertebral fractures over 3 years by 26% compared with alfacalcidol. Although the overall risk of nonvertebral fractures was not reduced by eldecalcitol, the risk of wrist fracture was decreased significantly in the eldecalcitol group (71%) compared with the alfacalcidol group. The serum level of 25-hydroxyvitamin D (25[OH]D) was normalized by supplementation of native vitamin D in this trial, so the desirable effects on bone by eldecalcitol were considered to be derived from its distinctive pharmacological action. Increased blood calcium was observed in 21% of patients treated with eldecalcitol, and hypercalcemia (>11.5 mg/dL) occurred in 0.4% of eldecalcitol recipients, so serum calcium concentration should be monitored after starting eldecalcitol treatment. Eldecalcitol has dual effects on the metabolism of bone and calcium and is useful for the treatment of osteoporosis, especially for elderly patients (who frequently suffer from vitamin D deficiency). This article reviews the clinical efficacy and safety of eldecalcitol in the treatment of osteoporosis.

PTH-independent regulation of blood calcium concentration by the calcium-sensing receptor

Tight regulation of calcium levels is required for many critical biological functions. The Ca2+-sensing receptor (CaSR) expressed by parathyroid cells controls blood calcium concentration by regulating parathyroid hormone (PTH) secretion. However, CaSR is also expressed in other organs, such as the kidney, but the importance of extraparathyroid CaSR in calcium metabolism remains unknown. Here, we investigated the role of extraparathyroid CaSR using thyroparathyroidectomized, PTH-supplemented rats. Chronic inhibition of CaSR selectively increased renal tubular calcium absorption and blood calcium concentration independent of PTH secretion change and without altering intestinal calcium absorption. CaSR inhibition increased blood calcium concentration in animals pretreated with a bisphosphonate, indicating that the increase did not result from release of bone calcium. Kidney CaSR was expressed primarily in the thick ascending limb of the loop of Henle (TAL). As measured by in vitro microperfusion of cortical TAL, CaSR inhibitors increased calcium reabsorption and paracellular pathway permeability but did not change NaCl reabsorption. We conclude that CaSR is a direct determinant of blood calcium concentration, independent of PTH, and modulates renal tubular calcium transport in the TAL via the permeability of the paracellular pathway. These findings suggest that CaSR inhibitors may provide a new specific treatment for disorders related to impaired PTH secretion, such as primary hypoparathyroidism.

Lithium toxicity profile: a systematic review and meta-analysis

Lithium is a widely used and effective treatment for mood disorders. There has been concern about its safety but no adequate synthesis of the evidence for adverse effects. We aimed to undertake a clinically informative, systematic toxicity profile of lithium. We undertook a systematic review and meta-analysis of randomised controlled trials and observational studies. We searched electronic databases, specialist journals, reference lists, textbooks, and conference abstracts. We used a hierarchy of evidence which considered randomised controlled trials, cohort studies, case-control studies, and case reports that included patients with mood disorders given lithium. Outcome measures were renal, thyroid, and parathyroid function; weight change; skin disorders; hair disorders; and teratogenicity. We screened 5988 abstracts for eligibility and included 385 studies in the analysis. On average, glomerular filtration rate was reduced by -6·22 mL/min (95% CI -14·65 to 2·20, p=0·148) and urinary concentrating ability by 15% of normal maximum (weighted mean difference -158·43 mOsm/kg, 95% CI -229·78 to -87·07, p<0·0001). Lithium might increase risk of renal failure, but the absolute risk was small (18 of 3369 [0·5%] patients received renal replacement therapy). The prevalence of clinical hypothyroidism was increased in patients taking lithium compared with those given placebo (odds ratio [OR] 5·78, 95% CI 2·00-16·67; p=0·001), and thyroid stimulating hormone was increased on average by 4·00 iU/mL (95% CI 3·90-4·10, p<0·0001). Lithium treatment was associated with increased blood calcium (+0·09 mmol/L, 95% CI 0·02-0·17, p=0·009), and parathyroid hormone (+7·32 pg/mL, 3·42-11·23, p<0·0001). Patients receiving lithium gained more weight than did those receiving placebo (OR 1·89, 1·27-2·82, p=0·002), but not those receiving olanzapine (0·32, 0·21-0·49, p<0·0001). We recorded no significant increased risk of congenital malformations, alopecia, or skin disorders. Lithium is associated with increased risk of reduced urinary concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain. There is little evidence for a clinically significant reduction in renal function in most patients, and the risk of end-stage renal failure is low. The risk of congenital malformations is uncertain; the balance of risks should be considered before lithium is withdrawn during pregnancy. Because of the consistent finding of a high prevalence of hyperparathyroidism, calcium concentrations should be checked before and during treatment. National Institute for Health Research Programme Grant for Applied Research.

Spotlight on Eldecalcitol in Osteoporosis†

Eldecalcitol (1α,25[OH](2)-2β-(3-hydroxypropyloxy)vitamin D(3); ED-71; Edirol®) is an orally administered analogue of active vitamin D (calcitriol) that is available in Japan for the treatment of osteoporosis at a dosage of 0.75 μg/day. In a randomized, double-blind, placebo-controlled, dose-ranging trial, eldecalcitol reduced markers of bone turnover significantly more than placebo. Similarly, in a randomized, double-blind comparison with the calcitriol prodrug, alfacalcidol 1.0 μg/day, eldecalcitol 0.75 μg/day produced significantly greater reductions in markers of bone turnover and had a positive effect on femoral biomechanical properties. In both trials, eldecalcitol treatment was associated with an increase in bone mineral density (BMD), whereas patients who received the comparators generally had a reduction in BMD. In the comparison with alfacalcidol, eldecalcitol significantly reduced the 3-year incidence of vertebral fractures (primary endpoint), with an absolute risk reduction of 4.1% over this period, representing a relative risk reduction of 26%. There was no significant difference in the rate of non-vertebral fractures. In both trials, increases in blood calcium (to >2.6 mmol/L) and urinary calcium (to >0.1 mmol/L glomerular filtrate) were the most clinically important treatment-emergent adverse events. In the comparison with alfacalcidol over 36 months of treatment, 21.0% and 13.5% of eldecalcitol 0.75 μg/day and alfacalcidol 1.0 μg/day recipients had increased blood calcium, whereas hypercalcaemia (defined as a serum calcium >2.9 mmol/L) occurred in 0.4% and urolithiasis in 1.3% of eldecalcitol recipients. Eldecalcitol is an efficacious treatment for patients with osteoporosis that should be further investigated in head-to-head trials with other recommended first-line pharmacological treatments.

Eldecalcitol

Eldecalcitol (1α,25[OH](2)-2β-(3-hydroxypropyloxy)vitamin D(3); ED-71; Edirol®) is an orally administered analogue of active vitamin D (calcitriol) that is available in Japan for the treatment of osteoporosis. Two randomized, double-blind, multicentre trials were conducted in patients with osteoporosis. In a placebo-controlled, dose-ranging trial, eldecalcitol significantly reduced serum bone-specific alkaline phosphatase (BALP) and serum osteocalcin, markers of bone formation, more than placebo. Eldecalcitol at a 1.0 μg/day dosage, but not at lower dosages, also significantly reduced urinary type I collagen N-telopeptide (NTX), a marker of bone resorption, more than placebo. In a comparison with alfacalcidol (a prodrug of calcitriol), eldecalcitol produced significantly greater reductions in serum BALP and urinary NTX, and had a positive effect on CT markers of femoral biomechanical properties. In the comparison with alfacalcidol, eldecalcitol 0.75 μg/day significantly reduced the 3-year incidence of vertebral fractures, with an absolute risk reduction of 4.1% over this period, representing a relative risk reduction of 26%. There was no significant difference in the rate of non-vertebral fractures. In both trials, eldecalcitol treatment was also associated with an increase in bone mineral density, whereas patients who received the comparators generally had a reduction in bone mineral density. Increases in blood calcium (to >2.6 mmol/L) and urinary calcium (to >0.1 mmol/L glomerular filtrate) were the most clinically important treatment-emergent adverse events. In the placebo-controlled, dose-ranging trial, 23% and 25% of patients in the eldecalcitol 1 μg/day group had increased blood and urinary calcium compared with 7% and 7%, 6% [corrected] and 9%, and 0% and 1.9% in the eldecalcitol 0.5 and 0.75 μg/day, and placebo groups, respectively. In the comparison with alfacalcidol, 21.0% and 13.5% of eldecalcitol 0.75 μg/day and alfacalcidol 1.0 μg/day recipients had increased blood calcium, whereas hypercalcaemia (defined as a serum calcium >2.9 mmol/L) occurred in 0.4% and urolithiasis in 1.3% of eldecalcitol recipients over 36 months of treatment. Eldecalcitol is an efficacious treatment for patients with osteoporosis that should be further investigated in head-to-head trials with other recommended first-line pharmacological treatments.

Studies on preparation of haddock calcium tablet and its biological utilization

With China’s increasing development of fisheries and aquaculture,there is an annual increase in the manufacture of aquatic products. Processing of aquatic products is associated with a large amount of waste products,in which fishbone and fishhead account for 45%. The waste products had been used as material of fish sauce and hydrolyzed protein,with high cost and complicated processes. How to efficiently utilize this kind of calcium source becomes focus in fish deep processing. Not only in China calcium deficiency is a prevalent nutritional disease,it has attracted the attention of the world because of its serious result. The lack of calcium intake leads to great interest in demand of calcium supplement and calcium fortification. Fishbone is a kind of natural calcium source. Until recently,researches on utilization of fishbone almost focused on freshwater fish,while no research on seawater fish was conducted to study biological effects on calcium supplement and bone fortification. So,investigating the possible use of waste products obtained after processing haddock,the present study prepared haddock bone calcium powder by NaOH and ethanol soaking (alkaline-alcohol method) and prepared haddock bone calcium tablets using the powder in combination with appropriate excipients. The biological efficacy of the haddock bone calcium tablets was investigated using Wistar rats as an experiment model. Results showed that the optimal parameters for the alkaline-alcohol method are as follows: NaOH concentration 1 mol/L,immersion time 30 h,ethanol concentration 60%,immersion time 15 h. The fish powder processed in this way has high quality in color and odor compared with that prepared in acid method. Contents of fishbone powder are as follows: calcium 27.8%,phosphors 12.2%,protein 3.67%,fat 0.44%. A mixture of 4% polyvinylpyrrolidone in ethanol was used as an excipient,and the ratio between full-cream milk powder and filler was 1∶2. Under these conditions,there is no necessity of the use of a disintegrating agent because disintegrating time is less than 12 min. This process provided satisfactory characters for tablets in terms of rigidity and taste. Animal studies showed that the haddock bone calcium tablets at a dose of 2 g/kg·d or 5 g/kg·d significantly increased blood calcium and phosphorus levels and bone calcium content in Wistar rats. Therefore,the haddock bone calcium tablets have a better biological efficacy than the traditional calcium carbonate formulation,promote bone growth,increase bone density and prevent osteoporosis. The absorption rate is crucial for nutrients. High absorption rates are usually directly related to the bioactivity of the nutrient. Although the reasons of high absorption in the rats fed with haddock bone calcium tablets are still unclear,it is suggested that some factors,such as treatment with method of alkaline-alcohol or the vitamin D in the added milk,may play positive roles in increasing absorption ratio. Some natural trace elements such as magnesium,iron and phosphorus may also be responsible for the high bioavailability of calcium derived from haddock fishbone relative to calcium carbonate. These researches provide a more effective way for economic utilization of fish bone derived from marine fish processing.

Preparation and biological efficacy of haddock bone calcium tablets

To investigate the possible use of waste products obtained after processing haddock, the present study prepared haddock bone calcium powder by NaOH and ethanol soaking (alkalinealcohol method) and prepared haddock bone calcium tablets using the powder in combination with appropriate excipients. The biological efficacy of the haddock bone calcium tablets was investigated using Wistar rats as an experiment model. Results show that the optimal parameters for the alkalinealcohol method are: NaOH concentration 1 mol/L, immersion time 30 h; ethanol concentration 60%, immersion time 15 h. A mixture of 2% polyvinylpyrrolidone in ethanol was used as an excipient at a ratio of 1:2 to full-cream milk powder, without the use of a disintegrating agent. This process provided satisfactory tablets in terms of rigidity and taste. Animal studies showed that the haddock bone calcium tablets at a dose of 2 g·kg−1·d−1 or 5g·kg−1·d−1 significantly increased blood calcium and phosphorus levels and bone calcium content in rats. Therefore, these tablets could be used for calcium supplementation and prevent osteoporosis. Although the reasons of high absorption in the rats fed with haddock bone calcium tablets are unclear, it is suggested that there are some factors, such as treatment with method of alkaline-alcohol or the added milk, may play positive roles in increasing absorption ratio.

Calcitriol Derivatives with Two Different Side Chains at C-20. II. Diastereoselective Syntheses of the Metabolically Produced 24(R)-Hydroxygemini

Vitamin D derivatives containing two side chains emanating at C-20 are known as gemini. We have recently synthesized two gemini which are related to calcitriol and 19-norcalcitriol containing two identical side chains. The metabolism of these species involves 24(R)-hydroxylation on one of the side chains. To determine the outcome of this diastereospecific transformation, we synthesized both C-20 epimeric pairs containing the 24(R)-hydroxy group in the gemini and 19-norgemini series. On the basis of the availability of these reference compounds, it was shown that the metabolic hydroxylation occurred at the pro-R side chain in both gemini compounds. In comparison to the parent compounds, the 24-hydroxygemini required higher doses to increase blood calcium levels in mice and to suppress INF-gamma release in MLR.