Single Administration of the T-Type Calcium Channel Enhancer SAK3 Reduces Oxidative Stress and Improves Cognition in Olfactory Bulbectomized Mice.

Alzheimer's disease (AD), characterized by cognitive impairments, is considered to be one of the most widespread chronic neurodegenerative diseases worldwide. We recently introduced a novel therapeutic agent for AD treatment, the T-type calcium channel enhancer ethyl-8-methyl-2,4-dioxo-2-(piperidin-1-yl)-2H-spiro[cyclopentane-1,3-imidazo[1,2-a]pyridin]-2-ene-3-carboxylate (SAK3). SAK3 enhances calcium/calmodulin-dependent protein kinase II and proteasome activity, thereby promoting amyloid beta degradation in mice with AD. However, the antioxidative effects of SAK3 remain unclear. We investigated the antioxidative effects of SAK3 in olfactory bulbectomized mice (OBX mice), compared with the effects of donepezil as a positive control. As previously reported, single oral administration of both SAK3 (0.5 mg/kg, p.o.) and donepezil (1.0 mg/kg, p.o.) significantly improved cognitive and depressive behaviors in OBX mice. Single oral SAK3 administration markedly reduced 4-hydroxy-2-nonenal and nitrotyrosine protein levels in the hippocampus of OBX mice, which persisted until 1 week after administration. These effects are similar to those observed with donepezil therapy. Increased protein levels of oxidative stress markers were observed in the microglial cells, which were significantly rescued by SAK3 and donepezil. SAK3 could ameliorate oxidative stress in OBX mice, like donepezil, suggesting that the antioxidative effects of SAK3 and donepezil are among the neuroprotective mechanisms in AD pathogenesis.

T-type calcium channel enhancer SAK3 produces anti-depressant-like effects by promoting adult hippocampal neurogenesis in olfactory bulbectomized mice.

T-type calcium channels are involved in the pathophysiology of epilepsy, pain, and sleep. Recently, we developed a novel spiroimidazopyridine compound, SAK3 (ethyl 8'-methyl-2',4-dioxo-2-(piperidin-1-yl)-2'H-spiro[cyclopentane-1,3'-imidazo[1,2-a]pyridine]-2-ene-3-carboxylate), which enhances T-type calcium channel currents and improves memory deficits in olfactory bulbectomized (OBX) mice. Here, we demonstrated the anti-depressant effects of SAK3 in OBX mice. Chronic SAK3 administration (0.5 or 1.0 mg/kg, p.o.) improved depressive-like behaviors in OBX mice. The impaired adult neurogenesis in the hippocampal dentate gyrus (DG) that occurred 4 weeks after OBX administration was significantly restored by chronic SAK3 administration (0.5 or 1.0 mg/kg, p.o.). Additionally, SAK3 (0.5 mg/kg, p.o.) promoted the proliferation and survival of newborn cells in the naïve DG. Moreover, SAK3 administration (0.5 mg/kg, p.o.) antagonized the reduction of calcium/calmodulin-dependent protein kinase II (CaMKII) and CaMKIV phosphorylation levels, thereby rescuing the decreased levels of cAMP response element-binding protein (CREB)/brain derived neurotrophic factor (BDNF) signaling in the OBX DG. The effects of SAK3 were completely blocked by the T-type calcium channel selective blocker NNC 55-0396 (12.5 mg/kg, i.p.). Altogether, these results suggest that SAK3 improves depressive-like behaviors by promoting adult neurogenesis via T-type calcium channel stimulation in the hippocampus.

Methylglyoxal Impairs ß2-Adrenoceptor-Mediated Vasodilatory Mechanisms in Rat Retinal Arterioles.

Methylglyoxal, a highly reactive dicarbonyl compound, is formed as a by-product of glycolysis and plays an important role in the pathogenesis of diabetic complications, including diabetic retinopathy. However, it remains to be determined how methylglyoxal affects the regulatory mechanisms of retinal blood flow. In this study, we examined the effects of methylglyoxal on ß2-adrenoceptor-mediated vasodilatory mechanisms in rat retinal arterioles. The retinal vasodilator responses were assessed by measuring the diameter of retinal arterioles in the fundus images. Intravitreal injection of methylglyoxal significantly diminished the vasodilation of retinal arterioles induced by the ß2-adrenoceptor agonist salbutamol. The vasodilator effect of BMS-191011, a large-conductance Ca2+-activated K+ (BKCa) channel opener, on retinal arterioles was also attenuated by methylglyoxal. In contrast, methylglyoxal had no significant effect on retinal vasodilator response to forskolin. Methylglyoxal attenuated retinal vasodilator response to salbutamol under blockade of BKCa channels with iberiotoxin, an inhibitor of the channels. These results suggest that methylglyoxal attenuates ß2-adrenoceptor-mediated retinal vasodilation by impairing the coupling of the ß2-adrenoceptor to the guanine nucleotide-binding protein (Gs protein) and the function of the BKCa channel. Increased methylglyoxal in the eyes may contribute to the impairment of regulatory mechanisms of retinal blood flow in patients with diabetic retinopathy.

Store-Operated Calcium Channel Complex in Postsynaptic Spines: A New Therapeutic Target for Alzheimer's Disease Treatment.

Mushroom dendritic spine structures are essential for memory storage and the loss of mushroom spines may explain memory defects in aging and Alzheimer's disease (AD). The stability of mushroom spines depends on stromal interaction molecule 2 (STIM2)-mediated neuronal-store-operated Ca2+ influx (nSOC) pathway, which is compromised in AD mouse models, in aging neurons, and in sporadic AD patients. Here, we demonstrate that the Transient Receptor Potential Canonical 6 (TRPC6) and Orai2 channels form a STIM2-regulated nSOC Ca2+ channel complex in hippocampal mushroom spines. We further demonstrate that a known TRPC6 activator, hyperforin, and a novel nSOC positive modulator, NSN21778 (NSN), can stimulate activity of nSOC pathway in the spines and rescue mushroom spine loss in both presenilin and APP knock-in mouse models of AD. We further show that NSN rescues hippocampal long-term potentiation impairment in APP knock-in mouse model. We conclude that the STIM2-regulated TRPC6/Orai2 nSOC channel complex in dendritic mushroom spines is a new therapeutic target for the treatment of memory loss in aging and AD and that NSN is a potential candidate molecule for therapeutic intervention in brain aging and AD. SIGNIFICANCE STATEMENT: Mushroom dendritic spine structures are essential for memory storage and the loss of mushroom spines may explain memory defects in Alzheimer's disease (AD). This study demonstrated that Transient Receptor Potential Canonical 6 (TRPC6) and Orai2 form stromal interaction molecule 2 (STIM2)-regulated neuronal-store-operated Ca2+ influx (nSOC) channel complex in hippocampal synapse and the resulting Ca2+ influx is critical for long-term maintenance of mushroom spines in hippocampal neurons. A novel nSOC-positive modulator, NSN21778 (NSN), rescues mushroom spine loss and synaptic plasticity impairment in AD mice models. The TRPC6/Orai2 nSOC channel complex is a new therapeutic target and NSN is a potential candidate molecule for therapeutic intervention in brain aging and AD.

Synthesis, pharmacological evaluation and molecular docking of pyranopyrazole-linked 1,4-dihydropyridines as potent positive inotropes.

1,4-Dihydropyridines are well-known calcium channel blockers, but variations in the substituents attached to the ring have resulted in their role reversal making them calcium channel activators in some cases. We describe the microwave-assisted eco-friendly approach for the synthesis of pyranopyrazole-1,4-dihydropyridines, a new class of 1,4-DHPs, under solvent-free conditions in good yield, and screen them for various in silico, in vitro and in vivo activities. The in vivo experimentation results show that the compounds possess positive inotropic effect, and the docking results validate their good binding with calcium channels. Compounds 7c, 7g and 7i appear to be the most effective positive inotropes, even at low doses, and bind with the calcium channels even more strongly than Bay K 8644, a well-known calcium channel activator. The chronotropic effect for the new compounds was also studied. The target and off-target affinity profiling supported the in vivo results and revealed that the hybridized pyranopyrazole dihydropyridine scaffold has delivered new moderate hits, to be optimized, for the cytochrome P450 3A4 enzymes, opening avenues for combined pharmacological activity through standard structural modification.

Use of calcitriol to maintain postpartum blood calcium and improve immune function in dairy cows.

Our objectives were to determine the effects of an injectable formulation of calcitriol on mineral metabolism and immune function in postpartum Holstein cows that received an acidogenic diet prepartum to minimize hypocalcemia. In experiment 1, cows within 6 h of calving received calcitriol (0, 200, or 300 µg) to determine the dose needed to increase plasma concentrations of Ca; 300 µg was sufficient to sustain Ca for at least 3 d. In experiment 2, multiparous cows were assigned randomly to receive only vehicle (control, n = 25) or 300 µg of calcitriol (n = 25) subcutaneously within the first 6 h after calving. Blood was sampled before treatment and 12 h later, then daily until 15 d in milk (DIM), and analyzed for concentrations of ionized Ca (iCa), total Ca (tCa), total Mg (tMg), and total P (tP), metabolites, and hormones. Urine was sampled in the first 7 DIM and analyzed for concentrations of tCa, tMg, and creatinine. Neutrophil function was evaluated in the first week postpartum. Dry matter intake and production performance were evaluated for the first 36 DIM. Calcitriol administration increased concentrations of calcitriol in plasma within 12 h of application from 51 to 427 pg/mL, which returned to baseline within 5 d. Concentrations of iCa and tCa increased 24 h after treatment with calcitriol. Concentrations of iCa (control = 1.08 vs. calcitriol = 1.20 mM), tCa (control = 2.23 vs. calcitriol = 2.33 mM), and tP (control = 1.47 vs. calcitriol = 1.81 mM) remained elevated in cows treated with calcitriol until 3, 5, and 7 DIM, respectively, whereas concentration of tMg (control = 0.76 vs. calcitriol = 0.67 mM) was less in calcitriol cows than control cows until 3 DIM. Concentrations of parathyroid hormone decreased in calcitriol cows compared with control cows (control = 441 vs. calcitriol = 336 pg/mL). Calcitriol tended to increase plasma concentrations of ß-hydroxybutyrate and serotonin, but concentrations of glucose, nonesterified fatty acids, and C-telopeptide of type I collagen in plasma did not differ between treatments. Cows treated with calcitriol excreted more urinary tCa (control = 0.5 vs. calcitriol = 2.1 g/d) and tMg (control = 4.5 vs. calcitriol = 5.0 g/d) in the first 7 and 2 DIM, respectively, than control cows. Compared with control, calcitriol improved the proportion of neutrophils with oxidative burst (control = 31.9 vs. calcitriol = 40.6%), mean fluorescence intensity for oxidative burst (control = 90,900 vs. calcitriol = 99,746), and mean fluorescence intensity for phagocytosis (control = 23,887 vs. calcitriol = 28,080). Dry matter intake, yields of milk, and milk components did not differ between treatments. Administration of 300 µg of calcitriol at calving was safe and effective in increasing blood concentration of iCa and plasma concentrations of calcitriol, tCa, and tP for the first 6 d after treatment, and improved measures of innate immune function in early-lactation Holstein cows.

Effects of pamidronate and calcitriol on the set point of the parathyroid gland in postmenopausal hemodialysis patients with secondary hyperparathyroidism.

BACKGROUND/AIMS: Secondary hyperparathyroidism may worsen after the administration of pamidronate in postmenopausal hemodialysis (HD) patients. The aim of this study was to evaluate the short-term effect of coadministration of calcitriol and pamidronate on dynamic parathyroid hormone (PTH) secretion. METHODS: Fifteen postmenopausal women undergoing regular HD with serum intact PTH levels of >200 pg/ml were enrolled. The PTH-ionized calcium (iCa) curve was evaluated by the response to hypo- and hypercalcemia induced with 1 and 4 mEq/l of dialysate calcium, respectively. Parameters were compared after pamidronate was administered and after coadministration of pamidronate and calcitriol. Changes in serum levels of maximal serum PTH (PTHmax), basal PTH (PTHbase) and minimal PTH (PTHmin) were evaluated. RESULTS: Pamidronate therapy resulted in a decrease in predialysis basal plasma iCa (p < 0.05) and an increase in PTHmax (p < 0.01), PTHbase (p < 0.01) and PTHmin (p < 0.01). The change in serum iCa and PTH was reversed after the coadministration of calcitriol and pamidronate. CONCLUSION: Our study demonstrated that pamidronate therapy is associated with a reduced plasma iCa and increased PTH secretion. These adverse effects may be reversed by calcitriol. These findings suggest that in considering pamidronate treatment in postmenopausal patients with osteoporosis receiving HD, it might be safer to add calcitriol to prevent the increased PTH secretion.

Trifluoperazine: a rynodine receptor agonist.

Trifluoperazine (TFP), a phenothiazine, is a commonly used antipsychotic drug whose therapeutic effects are attributed to its central anti-adrenergic and anti-dopaminergic actions. However, TFP is also a calmodulin (CaM) antagonist and alters the Ca(2+) binding properties of calsequestrin (CSQ). The CaM and CSQ proteins are known modulators of sarcoplasmic reticulum (SR) Ca(2+) release in ventricular myocytes. We explored TFP actions on cardiac SR Ca(2+) release in cells and single type-2 ryanodine receptor (RyR2) channel activity in bilayers. In intact and permeabilized ventricular myocytes, TFP produced an initial activation of RyR2-mediated SR Ca(2+) release and over time depleted SR Ca(2+) content. At the single channel level, TFP or nortryptiline (NRT; a tricyclic antidepressant also known to modify CSQ Ca(2+) binding) increased the open probability (Po) of CSQ-free channels with an EC(50) of 5.2 microM or 8.9 microM (respectively). This Po increase was due to elevated open event frequency at low drug concentrations while longer mean open events sustained Po at higher drug concentrations. Activation of RyR2 by TFP occurred in the presence or absence of CaM. TFP may also inhibit SR Ca uptake as well as increase RyR2 opening. Our results suggest TFP and NRT can alter RyR2 function by interacting with the channel protein directly, independent of its actions on CSQ or CaM. This direct action may contribute to the clinical adverse cardiac side effects associated with these drugs.

L-type calcium channels and calcium/calmodulin-dependent kinase II differentially mediate behaviors associated with nicotine withdrawal in mice.

Smoking is a widespread health problem. Because the nicotine withdrawal syndrome is a major contributor to continued smoking and relapse, it is important to understand the molecular and behavioral mechanisms of nicotine withdrawal to generate more effective smoking cessation therapies. Studies suggest a role for calcium-dependent mechanisms, such as L-type calcium channels and calcium/calmodulin-dependent protein kinase II (CaMKII), in the effects of nicotine dependence; however, the role of these mechanisms in nicotine-mediated behaviors is unclear. Thus, the goal of this study was to elucidate the role of L-type calcium channels and CaMKII in nicotine withdrawal behaviors. Using both pharmacological and genetic methods, our results show that L-type calcium channels are involved in physical, but not affective, nicotine withdrawal behaviors. Although our data do provide evidence of a role for CaMKII in nicotine withdrawal behaviors, our pharmacological and genetic assessments yielded different results concerning the specific role of the kinase. Pharmacological data suggest that CaMKII is involved in somatic signs and affective nicotine withdrawal, and activity level is decreased after nicotine withdrawal, whereas the genetic assessments yielded results suggesting that CaMKII is involved only in the anxiety-related response, yet the kinase activity may be increased after nicotine withdrawal; thus, future studies are necessary to clarify the precise behavioral specifics of the relevance of CaMKII in nicotine withdrawal behaviors. Overall, our data show that L-type calcium channels and CaMKII are relevant in nicotine withdrawal and differentially mediate nicotine withdrawal behaviors.

Phase II study of calcitriol-enhanced docetaxel in patients with previously untreated metastatic or locally advanced pancreatic cancer.

PURPOSE: To determine the safety and efficacy of weekly high-dose oral calcitriol and docetaxel, given to patients with non-resectable, incurable pancreatic cancer. PATIENTS AND METHODS: Twenty-five patients were enrolled onto this phase II study. Patients were treated with oral calcitriol 0.5 microg/kg on day 1, followed by docetaxel 36 mg/m(2) IV on day 2, administered weekly for three consecutive weeks, followed by 1 week without treatment. Patients followed a low-calcium diet and increased their hydration. The primary end-point of the trial was time-to-progression. RESULTS: Three of 25 patients attained a partial response (12%, 95% CI 3 to 31) and seven (28%) achieved stable disease. Median time-to-progression was 15 weeks, and median overall survival was 24 weeks. Toxicities observed (hyperglycemia, fatigue) were mostly attributable to the docetaxel or its pre-treatment. CONCLUSIONS: This regimen of high-dose calcitriol with docetaxel may have activity in incurable pancreatic cancer, with a modest increase in TTP when compared to historical findings using single-agent docetaxel. However, results do not appear superior to those seen with gemcitabine, with or without erlotinib.

Metabolic acidosis inhibits soft tissue calcification in uremic rats.

Metabolic acidosis is common in patients with chronic kidney disease, which is known to affect bone metabolism. We examined the effect of metabolic acidosis on the development of vascular and other soft-tissue calcifications in uremic rats treated with calcitriol. Extraskeletal calcification was measured in vivo, in control rats and rats with a remnant kidney model of uremia with or without ammonium chloride-induced acidosis. Soft-tissue calcification was assessed histologically, by measurement of the expression of the sodium-dependent phosphate cotransporter Pit-1 and by quantification of tissue calcium and phosphorus. Calcitriol administration to uremic rats resulted in significant deposition of material positive for von Kossa stain in the aorta, stomach, and kidney, elevated aortic calcium and phosphorus, increased aortic Pit-1 expression, and high mortality. Calcitriol-treated uremic rats with acidosis did not develop aortic or soft-tissue calcification, did not increase aortic Pit-1 expression, and had significantly lower mortality. Additionally, an acidotic environment prevented calcification of vascular smooth muscle cells in vitro. Our study shows that metabolic acidosis inhibits extraskeletal calcification.

Cinacalcet does not affect the activity of cytochrome P450 3A enzymes, a metabolic pathway for common immunosuppressive agents : a randomized, open-label, crossover, single-centre study in healthy volunteers.

BACKGROUND AND OBJECTIVE: Cinacalcet HCl (cinacalcet) is approved for the treatment of secondary hyperparathyroidism in subjects receiving dialysis and for the reduction of hypercalcaemia in patients with parathyroid carcinoma. The drug may also be co-administered with medications used in the renal transplantation setting, such as immunosuppressants. Cinacalcet, as well as some immunosuppressants such as ciclosporin, tacrolimus and sirolimus, is partially metabolized by the cytochrome P450 3A enzymes (CYP3A). This study aimed to evaluate the potential inhibitory effects of cinacalcet on CYP3A activity using midazolam as a probe substrate in healthy volunteers. METHODS: In this randomized, open-label, crossover, two-treatment, two-period, single-centre study, 12 healthy volunteers received either oral cinacalcet 90 mg once daily for 5 days plus a single oral dose of midazolam 2 mg on day 5, or a single oral dose of midazolam 2 mg on day 1. Following a 10-day washout period, subjects received the alternate treatment. Blood samples were collected predose and at selected time points up to 24 hours after dosing with midazolam for measurement of midazolam pharmacokinetic parameters. RESULTS: Eleven subjects completed the study. Mean (standard deviation) midazolam maximum plasma concentrations (C(max)) and area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) were 9.31 (3.09) ng/mL and 24.1 (7.7) ng . h/mL, respectively, when administered in combination with cinacalcet, compared with 9.76 (2.81) ng/mL and 22.8 (6.1) ng . h/mL when administered alone. The mean geometric ratios (90% confidence interval) were 0.95 (0.84, 1.06) and 1.05 (0.95, 1.16) for C(max) and AUC(infinity), respectively. All adverse events were mild to moderate in severity, and consistent with the safety profile of cinacalcet. CONCLUSION: Once-daily administration of cinacalcet did not alter the pharmacokinetics of midazolam relative to administration of midazolam alone. These data suggest that cinacalcet administration does not affect CYP3A activity, and thus would not have an effect on any drug eliminated via CYP3A, including some commonly used immunosuppressant therapies.

The critical role of voltage-dependent calcium channel in axonal repair following mechanical trauma.

Membrane disruption following mechanical injury likely plays a critical role in the pathology of spinal cord trauma. It is known that intracellular calcium is a key factor that is essential to membrane resealing. However, the differential role of calcium influx through the injury site and through voltage dependent calcium channels (VDCC) has not been examined in detail. Using a well-established ex vivo guinea-pig spinal cord white matter preparation, we have found that axonal membrane resealing was significantly inhibited following transection or compression in the presence of cadmium, a non-specific calcium channel blocker, or nimodipine, a specific L-type calcium channel blocker. Membrane resealing was assessed by the changes of membrane potential and compound action potential (CAP), and exclusion of horseradish peroxidase 60 min following trauma. Furthermore, 1 microM BayK 8644, a VDCC agonist, significantly enhanced membrane resealing. Interestingly, this effect was completely abolished when the concentration of BayK 8644 was increased to 30 microM. These data suggest that VDCC play a critical role in membrane resealing. Further, there is likely an appropriate range of calcium influx through VDCC which ensures effective axonal membrane resealing. Since elevated intracellular calcium has also been linked to axonal deterioration, blockage of VDCC is proposed to be a clinical treatment for various injuries. The knowledge gained in this study will likely help us better understand the role of calcium in various CNS trauma, which is critical for designing new approaches or perhaps optimizing the effectiveness of existing methods in the treatment of CNS trauma.

Apolipoprotein A-1-related amyloidosis 2 case reports and review of the literature.

RATIONALE: Apolipoprotein A-1 (ApoA-1)-related amyloidosis is characterized by the deposition of ApoA-1 in various organs and can be either hereditary or nonhereditary. It is rare and easily misdiagnosed. Renal involvement is common in hereditary ApoA-1 amyloidosis, but rare in the nonhereditary form. PATIENT CONCERNS: We reported two cases with ApoA-1 amyloidosis, a 64-year-old man suffering from nephrotic syndrome and a 40-year-old man with nephrotic syndrome and splenomegaly. Renal biopsies revealed glomerular, interstitial and vascular amyloid deposits and positive phospholipase A2 receptor staining in the glomerular capillary loop in case 1, and mesangial amyloid deposits in case 2. DIAGNOSES: After immunostaining failed to determine the specific amyloid protein, proteomic analysis of amyloid deposits by mass spectrometry was performed and demonstrated the ApoA-1 origin of the amyloid. Genetic testing revealed no mutation of the APOA1 gene in case 1 but a heterozygous mutation, Trp74Arg, in case 2. Case 1 was thus diagnosed as nonhereditary ApoA-1 associated renal amyloidosis with membranous nephropathy, and case 2 as hereditary ApoA-1 amyloidosis with multiorgan injuries (kidney and spleen) and a positive family history. INTERVENTIONS: Case 1 was treated with glucocorticoid combined with cyclosporine. Case 2 was treated with calcitriol and angiotensin converting enzyme inhibitors. OUTCOMES: Two cases were followed up for 5 months and 2 years, respectively; and case 1 was found to have attenuated proteinuria while case 2 had an elevation of cholestasis indices along with renal insufficiency. LESSONS: Proteomic analysis by mass spectrometry of the amyloid deposits combined with genetic analysis can provide accurate diagnosis of ApoA-1 amyloidosis. Besides, these 2 cases expand our knowledge of ApoA-1-related renal amyloidosis.

Calcitriol regresses cardiac hypertrophy and QT dispersion in secondary hyperparathyroidism on hemodialysis.

BACKGROUND: Sudden cardiac death is common in patients on hemodialysis (HD), and its rate is as high as 25% of all cardiac deaths associated with left ventricular hypertrophy (LVH) and secondary hyperparathyroidism. A prolonged QT interval on standard electrocardiography is related to an increase in sudden death in various patient groups. It is also well known that LVH has been noted in uremic patients with high parathyroid hormone levels. METHODS: To evaluate the response of intravenous calcitriol treatment on the QT interval and LVH in HD patients with secondary hyperparathyroidism (intact parathyroid hormone, iPTH, > 450 ng/ml), echocardiographic, electrocardiographic (ECG), and biochemical assessments were performed over a 15-week period in 25 HD patients before and after intravenous calcitriol treatment. We also evaluated 25 age-, sex-, HD duration-, and BMI-matched HD control patients with secondary hyperparathyroidism. RESULTS: In patients receiving intravenous calcitriol, a significant reduction in iPTH levels (p < 0.05) and alkaline phosphatase levels (p < 0.01) was found without changes in values of serum calcium and ionized Ca2+, phosphorus, Na+, K+, Mg2+, hematocrit, blood pressure, or other hemodynamic changes. Echocardiograms showed significant decreases in the thickness of the interventricular septum (p < 0.05), left posterior wall thickness (p < 0.05), and left ventricle mass index (LVMi, p < 0.01). In addition, sequential ECG measurement in patients with calcitriol treatment showed significant reductions in QTcmax (QTmax interval corrected for heart rates, p < 0.01) and QTc dispersion (QT dispersion corrected for heart rates, p < 0.01). However, in the control patients, biochemical, hemodynamic, and ECG changes, as well as myocardial structural and functional changes were not seen. Multiple regression analysis in all patients indicated that iPTH and LVMi levels were independent predictors of QTcmax while the LVMi level was the only independent predictor of QTc dispersion (p < 0.05). CONCLUSIONS: Our study showed a significant correlation between LVMi and QT dispersion in HD patients with secondary hyperparathyroidism. Intravenous calcitriol treatment, to be used for the control of secondary hyperparathyroidism, was found to cause regression of myocardial hypertrophy and a reduction in the QTc interval and dispersion, without biochemical and hemodynamic changes. These findings suggest that an active vitamin D metabolite has a cardioprotective action in HD patients.

Comparison of the effects of daily and intermittent-dose calcitriol on serum parathyroid hormone and ionized calcium concentrations in normal cats and cats with chronic renal failure.

BACKGROUND: Chronic renal failure is complicated by secondary hyperparathyroidism, which traditionally has been controlled by dietary restriction of phosphorus and administration of phosphorus binders. Early treatment of patients with chronic renal failure with calcitriol may be indicated because once established, parathyroid gland hyperplasia does not readily resolve with therapy. HYPOTHESIS: Daily and intermittent dosing of calcitriol will decrease plasma parathyroid hormone concentration in normal cats and cats with chronic renal failure without causing ionized hypercalcemia. ANIMALS: Ten normal cats; 10 cats with chronic renal failure. METHODS: Phase 1 was daily calcitriol administration (2.5 ng/kg PO q24h) for 14 days. Phase 2 was intermittent calcitriol administration (8.75 ng/kg PO q84h) for 14 days. A 7-day washout period separated phases 1 and 2. Before each phase, calcitriol, parathyroid hormone, and ionized calcium concentrations were measured. On days 1, 2, and 3 of both phases, serum ionized calcium concentrations were measured. On the last day of both phases, calcitriol, parathyroid hormone, and ionized calcium concentrations were measured 0, 2, 4, and 6 hours after calcitriol administration. RESULTS: Overall, serum parathyroid hormone concentrations were significantly higher in cats with chronic renal failure than in normal cats (P = .022), but serum parathyroid hormone concentrations for both normal cats and cats with chronic renal failure were not significantly different before and after 14 days of treatment with calcitriol, regardless of whether calcitriol was administered daily or intermittently. Adverse effects of calcitriol administration (specifically ionized hypercalcemia) were not seen in either feline group during either phase of the study over the 3-day evaluation after calcitriol administration was initiated. CONCLUSIONS AND CLINICAL IMPORTANCE: At the dosages used, calcitriol treatment did not result in significant differences in serum parathyroid hormone concentrations before and after treatment in both normal cats and cats with chronic renal failure. With these dosages, adverse affects of calcitriol administration were not seen. Potential reasons for lack of apparent effect include small sample size, insufficient duration of study, insufficient dosage of calcitriol, problems with formulation or administration of calcitriol, and variable gastrointestinal absorption of calcitriol.

Elderly patients on chronic hemodialysis with hyperparathyroidism: increase of hemoglobin level after intravenous calcitriol.

In patients on chronic hemodialysis (CHD), hyperparathyroidism (HPTH) is associated with anemia and resistance to erythropoietin (EPO). In the last few years, calcitriol intravenously (IV) has been used with success in the treatment of the HPTH, secondary to chronic renal failure. However, the effects of calcitriol on the hematological parameters of these patients have never been well evaluated. This study included 11 elderly CHD patients (f = 6, m = 5; mean age = 73.6 years, mean time on CHD = 42.8 months) with HPTH under EPO therapy (IV). They were treated for 12 months with calcitriol IV (mean dose = 2.33 mcg/pt/week). Patients with iron deficiency anemia (ferritin < 200 ng/ml) were excluded. The patients were compared before and after 12 months of calcitriol treatment, with respect to several laboratory parameters and with respect to EPO dose. A paired t-test was used. After treatment, we found a decrease of PTH (634 vs. 418 pg/ml, P = 0.029); the serum calcium increased (8.8 vs. 9.9 mg/dl, P = 0.002); no differences were noted in the plasma levels of alkaline phosphatase, phosphorous, BUN, creatinine, Na and K. Mean levels of Hb (10.2 vs. 11.4 g/dl, P = 0.004) and the Hct (30 vs. 34.3, P = 0.004) increased after 12 months of calcitriol; the levels of serum iron (70 vs. 78 microg/dl, P = ns) and ferritin (531 vs. 785 ng/ml, P = ns) and the EPO dose (105 vs. 100 U/kg/week, P = ns) were similar before and after treatment. Our data show that the treatment of HPTH in CHD elderly patients with calcitriol can increase Hb level without increasing EPO dose.

[Therapy of acute decompensated heart failure with levosimendan]. / Akute hämodynamische und klinische Effekte von Levosimendan in der Therapie des kardiogenen Schocks.

PURPOSE: To determine the short-term hemodynamic and clinical effects of levosimendan, a calcium-sensitizing agent, in patients with decompensated heart failure. PATIENTS AND METHODS: Seven patients with cardiogenic shock requiring catecholamines (two patients with acute myocardial infarction, two patients with decompensated hypertensive heart disease, one patient with low cardiac output with ischemic cardiomyopathy, two patients with dilated cardiomyopathy [ethyl-toxic, polymyositis] with a cardiac index < or = 2.5 ) 1 x min(-1) x m(-2) and a pulmonary wedge pressure > or = 15 mmHg received levosimendan with an initial loading dose of 12 microg/kg over 10 min followed by a continuous infusion of 0.1 microg/kg/min for 24 h. RESULTS: During levosimendan infusion an increase in cardiac index (30% after 6 h and 24 h), a decrease in heart rate (4% after 6 h and 10% after 24 h, respectively), and a decrease in systemic vascular resistance (27% after 6 h and 41% after 24 h, respectively) appeared. In combination with volume resuscitation the pulmonary capillary wedge pressure increased. Under therapy with levosimendan no relevant adverse events occurred; there was no increase in severe cardiac arrhythmias and QT interval duration. CONCLUSION: Levosimendan causes rapid improvement in hemodynamic function in patients with cardiogenic shock. These hemodynamic effects are not associated with relevant adverse events. Levosimendan may be of value in the short-term management of patients with cardiogenic shock.

An open label pilot study of supraerythemogenic excimer laser in combination with clobetasol spray and calcitriol ointment for the treatment of generalized plaque psoriasis.

A common therapeutic modality for psoriasis includes the combination of phototherapy with topical treatments. The recent development of targeted phototherapy with the excimer laser and spray formulations for topical treatments has increased the efficacy and convenience of these combinational therapies. Herein, we aim to assess the efficacy of a novel combination of therapies using the 308 nm excimer laser, clobetasol propionate spray and calcitriol ointment for the treatment of moderate to severe generalized psoriasis. In this 12-week study, patients with moderate to severe psoriasis received twice weekly treatments with a 308-nm excimer laser combined with clobetasol proprionate twice daily for a month followed by calcitriol ointment twice daily for the next month. Of the 30 patients enrolled, 83% of patients (25/30) achieved PASI-75 [65-94%, 95% confidence interval (CI)] at week 12. For PGA, there was an estimated decrease of 3.6 points (3.1-4.1, 95% CI, p < 0.0005) by week 12. In conclusion, the combination of excimer laser with alternating clobetasol and calcitriol application has shown to be a promising combination of therapies for the treatment of moderate to severe generalized psoriasis. Further evaluation may be conducted with a larger study inclusive of control groups and head-to-head comparisons against topical steroid and UVB therapy as monotherapies.