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At least 613 records · Page 34Linked to original sources

PubMed2004

Chronopharmacology of oxacalcitriol in 5/6 nephrectomized rats.

We previously reported on the merits of the chronopharmacological effects of 1,25(OH) 2 vitaminD3 in 5/6 nephrectomized rats (Tsuruoka et al, Life Scineces 2002; 71: 1809-1820). In this study, the chronopharmacological effect of 22-oxacalcitriol (OCT), a newly developed active vitaminD3 analogue with less calcemic activity, was evaluated by a single and repeated dosing of the drug. The 5/6 nephrectomized animals were kept in rooms with a 12-h light/dark cycle. Single (12.5 microg/kg, i.v.) and repeated (5 microg/kg, i.v. three times a week for 12 weeks) dosing of OCT or vehicle was given at either 2 hours after lights on (2HALO) or 14 hours after lights on (14HALO). The severity of hypercalcemia and hyperphosphatemia was significantly milder when the drug was given at 14HALO. Serum concentrations of total OCT and albumin of the 2HALO and 14HALO trials did not differ significantly. The decrease of parathyroid hormone concentration was greater in the 14HALO trial while the increase in urinary ratio of Ca to creatinine was greater in the 2HALO trial. The suppression of urinary deoxypyridinoline excretion, an index of bone resorption capacity of osteoclast, and the increase in bone density of both femurs were greater in the 14HALO trial. These results suggest that the adverse reactions of OCT were ameliorated and its efficacy was enhanced after dosing of the drug at 14HALO. Chronopharmacological differences of OCT were more prominent than those seen with other vitamin D analogues. Dosing-time-dependent variation in the sensitivity of the drug to osteoclast were involved in the mechanisms of these events.

Amino Acids↗

PubMed2006

Ablation of vitamin D signaling rescues bone, mineral, and glucose homeostasis in Fgf-23 deficient mice.

To explore further the role of the vitamin D axis for fibroblast growth factor-23 (FGF23) signaling, we mated Fgf-23 deficient (Fgf-23(-/-)) mice and vitamin D receptor (VDR) mutant mice with a non-functioning VDR. To prevent secondary hyperparathyroidism in VDR and compound mutant mice, all mice were kept on a rescue diet enriched with calcium, phosphorus, and lactose. Consistent with previous findings, Fgf-23(-/-) animals showed hypercalcemia, hyperphosphatemia, growth retardation, ectopic calcifications, severe osteoidosis, skin atrophy, and renal dysfunction. In addition, here we describe that Fgf-23(-/-) mice are hypoglycemic, and have profoundly increased peripheral insulin sensitivity and improved subcutaneous glucose tolerance, but normal renal expression of the aging suppressor gene Klotho. Although VDR and double mutants on the rescue diet still had moderately elevated parathyroid hormone serum levels and lower bone mineral density compared to wild-type mice, double mutant mice were normocalcemic and normophosphatemic, and had normal body weight, normal renal function, and no ectopic calcifications. Ablation of vitamin D signaling in compound mutants also normalized subcutaneous glucose tolerance tests and insulin secretory response. In conclusion, our results indicate that the alterations in mineral and carbohydrate metabolism present in Fgf-23(-/-) mice require an intact vitamin D signaling pathway.

Analysis of Variance↗

PubMed2006

A common structural mechanism underlying GCMB mutations that cause hypoparathyroidism.

Hypoparathyroidism, either of acquired or inherited origin, is a heterogenous group of human disorders caused by a defective calcium homeostasis clinically known as hypocalcemia and hyperphosphatemia. Two mutations (R47L, G63S) in the DNA binding domain of the parathyroid-specific transcription factor GCMB have been reported to be linked to hypoparathyroidism. Both mutations cause a loss of transactivation either with (R47L) or without (G63S) a concomitant loss of DNA binding. Despite these differences with respect to their DNA binding ability, molecular modeling of the wild type and mutant GCMB-DNA complexes reveals a common regular pattern of molecular interactions which is apparently crucial for the integrity of the GCM DNA binding domain and is altered by the respective mutations. The significance of this model is substantiated from an investigation of all biochemically known mutations of the DNA binding domain of GCM proteins that impede transactivation. All of them share the proposed molecular mechanism and thus can be predicted correctly by our model. This mechanistic commonness allows the prediction of 21 additional residues of which mutation might critically affect the transactivating ability of GCMB and thus might be linked to disease when present in patients.

Amino Acid Sequence↗

PubMedDate not supplied

Failure to gain weight on long-term parenteral nutrition attributed to tri-iodothyronine thyrotoxicosis.

We describe the case of a 49-y-old female patient on long-term parenteral nutrition after abdominal surgery who failed to gain weight despite nutritional provision in excess of theoretical requirements. On investigation, she was found to have a negative nitrogen balance (-5.9 g) and to have a tri-iodothyronine thyrotoxicosis but without many of the typical clinical features of hyperthyroidism. The patient also had mild hypercalcemia and hyperphosphatemia, which resolved fully after mobilization and treatment of the thyrotoxicosis. A derangement of the liver function tests was observed, which worsened progressively during parenteral nutrition but resolved promptly at its discontinuation. This case illustrates the importance of carrying out appropriate investigations including all thyroid function tests on patients who fail to gain weight on nutritional support.

Diagnosis, Differential↗

PubMed2006

New clinical syndromes in dermatology.

Dermatologists are in the unique position to be able to diagnose serious systemic diseases through skin findings; in addition, cutaneous manifestations can be associated with internal symptoms and clarify the pathogenesis and treatment of challenging new syndromes. Calciphylaxix, now renamed Calcific Uremic Arteriolopathy, primarily affects patients with end-stage renal disease with concomitant hyperphosphatemia, increased calcium-phosphate product and hyperparathyroidism, skin biopsy and wound care are crucial parts of the diagnosis and treatment. Hyperhomocysteinemia may play a very important role in many cutaneous and systemic diseases including, chronic cutaneous wounds, systemic lupus erythematosus, Behcet's disease and psoriasis. Through a skin biopsy and biochemical analysis of the proteoglycans accumulation it may be possible to diagnose a new systemic mucinosis and prevent sudden death in patients with severe mitral valve prolapse. Nephrogenic Fibrosing Dermopathy is a newly described fibrosing disorder occurring in patients with end stage renal disease, the etiology and pathogenesis are still unknown, and the ultimate course of this disease has not been defined.

Fibrosis↗

PubMed2004

Mechanisms of vascular calcification in uremia.

Vascular calcification and cardiovascular disease mortality are highly correlated with increased serum phosphate levels in end-stage renal disease patients. Mechanistic studies in cultured human smooth muscle cells (SMCs) indicate that increased phosphate levels induces both calcification and phenotypic transition through a pathway requiring a sodium-dependent phosphate cotransporter. Thus, in addition to contributing to increased calcium x phosphate product (Ca x P), hyperphosphatemia may have direct effects on SMCs that predispose these cells to calcium deposition in end-stage renal disease patients.

Calcinosis↗

PubMed2004

Disturbances of purine nucleotide metabolism in uremia.

The increased concentration of adenosine triphosphate (ATP) in erythrocytes from patients with chronic renal failure (CRF) has been observed in many studies but the mechanism leading to these abnormalities still is controversial. It is believed that hyperphosphatemia and metabolic acidosis triggering enhanced reutilization of purine bases are the factors responsible for changes in erythrocyte nucleotide concentration. During the past decade we have performed several studies. A summary of the obtained results is presented. A high-performance liquid chromatography technique was used for the determination of plasma and intraerythrocyte nucleotide concentrations. Labeled adenine and adenosine were used for measuring adenine incorporation. In CRF patients treated conservatively increased concentrations of ATP levels and other nucleotides such as adenosine diphosphate were found. Adenosine monophosphate and hypoxanthine levels were lower than in controls. In hemodialyzed patients both ATP and adenosine monophosphate intraerythrocyte concentrations were higher than in controls. At the same time, adenosine monophosphate and hypoxantine level were comparable with levels in healthy people. The main pattern of nucleotides during hemodialysis remained unchanged, independent from the mode of therapy. The only exception was a decreased level of hypoxantine. Results of a consecutive study have suggested that the increased rate of adenine incorporation into the adenine nucleotide pool could be partially responsible for the increased ATP concentration in uremic erythrocytes. Last but not least, trying to elucidate the pathomechanism of adenine nucleotide disturbances in uremia, we have found that the concentration of N-methyl-2-pyridone-5-carboxamide (2PY), one of the end products of nicotinamide-adenine dinucleotide degradation, were enhanced in CRF patients to values that are potentially toxic. Our findings suggest that 2PY could be a novel uremic toxin. Disturbances of nucleotide metabolism are one of the important components of uremic syndrome.

Adenosine Triphosphate↗

PubMedDate not supplied

Effectiveness of surgical parathyroidectomy for secondary hyperparathyroidism in renal dialysis patients in Qatar.

Pharmacologic interventions designed to control hyperparathyroidism (HPT) in uremic patients have limitations and potentially serious adverse clinical consequences. Hence, one still has to resort to surgical parathyroidectomy (PTX) in a considerable number of dialysis patients. The aim of the present study was to illustrate our experience with 26 renal dialysis patients who underwent surgical PTX. The main indications for PTX included iPTH > 1000 pg/mL associated with severe osteitis fibrosa, debilitating pruritus, marked soft tissue calcification, or hypercalcemia with hyperphosphatemia, which sometimes complicated vitamin D therapy. All patients were resistant to more conservative measures, including control of serum phosphate, attention to oral intake and dialysate calcium levels, and oral/intravenous administration of active vitamin-D-pulse therapy. Ultrasound and technetium 99-sestamibi scan were used to image the thyroid and the parathyroid glands. Total PTX with autotransplantation was performed in 23 patients; subtotal PTX was performed in 3 patients. Histology of frozen sections taken intraoperatively showed nodular changes in 14 and diffuse hyperplasia in 12 cases. During the 2-year follow-up period significant reductions in parathyroid hormone, alkaline phospatase blood levels, skeletal changes, and soft tissue calcifications were observed. Pruritus improved in half the cases. Some improvement in hemoglobin and hematocrit was also noticed. The complication rate after PTX was low. Transient postoperative hypocalcemia requiring intensification of calcium and vitamin D therapy was seen in cases with high preoperative alkaline phosphatase levels. Recurrence was observed in two cases. Hypoparathyroidism was not recorded. We conclude that surgical reduction of parathyroid mass is a safe and effective treatment for symptomatic disease not suppressible by pharmacologic means.

Adolescent↗

PubMed2005

Vascular calcification in dialysis patients.

UNLABELLED: The risk factors for vascular calcification (VC) in dialysis patients include duration of dialysis, diabetes mellitus, aging, hyperphosphatemia, hyperparathyroidism, and calcium or vitamin D supplementation. This study was performed to evaluate the prevalence of and risk factors for VC in our dialysis population. METHODS: One hundred twenty-nine chronic dialysis patients underwent plain x-rays of the hands for VC. Patients were grouped as either positive (PVC) or negative (NVC) for VC. Age, gender, duration of dialysis, presence of non-insulin-dependent diabetes mellitus (NIDDM), oral calcium, and 1alpha-hydroxyvitamin D3 supplement, serum levels of calcium (Ca), phosphorus (P), calcium phosphorus product (CaxP), alkaline phosphates (ALP) and intact parathyroid hormone (iPTH) were compared between the two groups. RESULTS: Thirty-four patients (26.35%) showed VC. There were no differences between PVC and NVC patients for duration of dialysis (38.4 +/- 27.7 for PVC and 34.6 +/- 31.2 months for NVC, P = .80), levels of serum Ca (P = .26), P (P = .19), CaxP (P = .33), ALP (P = .89), or iPTH (P = .24). Similarly, oral calcium and 1alpha-hydroxyvitamin D3 intake were not different between the two groups (P = .971 and P = .3710 respectively). Compared to NVC patients, PVC patients were older (56.3 +/- 10.4 versus 47.5 +/- 16.1 years, P = .008) and had a greater incidence of NIDDM (17/34 PVC and diabetic versus 20/95 NVC, P = .001). In conclusion, for patients with a medium length of dialysis, the duration of dialysis as well as the doses of calcium salts and of 1alpha-hydroxyvitamin D3 were not significantly associated with vascular calcifications, but it was not possible to exclude a role for these and other factors in patients with longer dialysis.

Alkaline Phosphatase↗

PubMed1997

Tumor lysis syndrome in small cell carcinoma and other solid tumors.

OBJECTIVE: To review the risk factors and clinical findings associated with tumor lysis syndrome (TLS) in patients with small cell carcinomas and other solid tumors. METHODS: Reports of TLS in the English-language literature were identified by searching MEDLINE and the bibliographies of relevant case reports, journal articles, and book chapters. All reports identified through these searches, including abstracts from national meetings, were reviewed and included in this analysis. Data regarding clinical and biochemical parameters relevant to the occurrence of TLS were extracted from each report. RESULTS: Of the 25 reported solid tumor patients who developed TLS, 7 had small cell carcinoma, 5 breast cancer, and 4 neuroblastoma. TLS was associated with a variety of treatment regimens, including chemotherapy, immunotherapy, hormonal therapy, radiation therapy, and surgery. Common risk factors for TLS in this population included pretreatment renal insufficiency, elevated serum lactate dehydrogenase (LDH), and hyperuricemia. Among the typical biochemical findings of TLS, acute renal insufficiency and hyperuricemia were identified in nearly all patients and hyperkalemia, hyperphosphatemia, hypocalcemia, and increased serum LDH were reported in over 75% of patients. In addition, seven patients, including the current case, presented with profound metabolic acidosis. Nine of 25 patients died during the acute episode of TLS. CONCLUSIONS: Although TLS occurs infrequently in patients with solid tumors, the risk factors and biochemical abnormalities associated with this potentially fatal complication of therapy must be recognized to allow for adequate monitoring and early initiation of appropriate therapeutic measures.

Aged↗

PubMed1996

Crystal-induced arthritis: an overview.

The most common crystal-related arthropathies-gout, calcium pyrophosphate dihydrate disease or "pseudogout," and calcific periarthritis/tendinitis-may be appropriately diagnosed and managed by the primary care physician. Definitive diagnosis via synovial tap is recommended, as the clinical picture may not identify some cases. The acute pain and swelling of attacks, regardless of etiology, generally respond to treatment with nonsteroidal anti-inflammatory drugs and local or occasionally systemic corticosteroids. Once a causative crystal has been identified and a diagnosis established, a plan for long-term management and prevention of recurrences may be devised. Thus, uric-acid-lowering therapy may be indicated in a patient who has experienced recurrent attacks of gout, whereas control of serum phosphate levels might be effective in some individuals with hyperphosphatemia and hydroxyapatite-associated periarthritis or arthritis. Crystal deposits in joints can be destructive as well as painful. Treatment, therefore, has two objectives: To relieve the pain of the acute attack, thus restoring normal function, and to prevent the accumulation of crystals that can lead to degenerative disease. Identification and subsequent treatment of preventable or correctable underlying disorders may be one of the most gratifying aspects of managing crystal-induced arthropathies.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2003

Inhibition of human intestinal brush border membrane vesicle Na+-dependent phosphate uptake by phosphophloretin derivatives.

Hyperphosphatemia and II(o) hyperparathyroidism are common and severe complications of chronic renal failure. Reduced dietary phosphorus has been shown to be an effective treatment in reducing serum phosphate and serum PTH. 2(')-Phosphophloretin inhibited small intestine apical membrane Na(+)/phosphate cotransport and reduced serum phosphate in adult rats. 2(')-PP and phosphoesters of phloretin were tested for inhibition of human small intestine brush border membrane alkaline phosphatase activity and for inhibition of Na(+)-dependent phosphate uptake. The IC(50)'s for inhibition of alkaline phosphatase suggested an order of inhibitory potency of 4-PP > phloretin > 4(')-PP > 2(')-PP. Inhibition of Na(+)-dependent phosphate uptake followed the sequence 2(')-PPz.Gt;4(')-PP > 4-PP > phloretin. These results are consistent with 2(')-PP being a specific inhibitor of human intestinal brush border membrane Na(+)/phosphate cotransport.

Animals↗

PubMed2003

A review of clinical and laboratory findings and treatment of tumor lysis syndrome.

Acute tumor lysis syndrome (TLS) has started to be considered a separate entity or condition associated with bulk tumor treatment. TLS is described as the biochemical disturbances associated with rapid destruction of tumor cells with subsequent synchronised massive release of cellular breakdown products sufficient to overwhelm excretory mechanisms and the body's normal reutilization capacity. The cardinal signs of TLS are: hyperkalemia, hyperphosphatemia, hypocalcemia and hyperuricemia. This review comprehensively discusses the differential diagnosis, pathophysiology and clinical features, possible causal indications for laboratory monitoring and treatment options of TLS.

Diagnosis, Differential↗

PubMed1999

Chronotherapy of high-dose 1,25-dihydroxyvitamin D3 in hemodialysis patients with secondary hyperparathyroidism: a single-dose study.

BACKGROUND: A high-dose oral intermittent vitamin D (pulse therapy) is widely used for the treatment of secondary hyperparathyroidism associated with kidney failure. However, hypercalcemia by vitamin D sometimes interrupts this treatment. Because serum calcium concentration possesses a circadian rhythm, a chronopharmacologic approach of vitamin D may have merit for avoidance of adverse reactions. METHODS: Six female secondary hyperparathyroidism patients receiving maintenance hemodialysis received a single oral dose of 2 microg 1,25-dihydroxyvitamin D3 at either 8 AM or 8 PM in a crossover design. Serum concentrations of ionized and total calcium, phosphate, and vitamin D3 were determined for a 48-hour period after administration. We also measured serum intact parathyroid hormone before and 48 hours after dosing as an index for efficacy. RESULTS: A single oral administration of the drug caused an increase in concentration of ionized calcium, serum calcium, and phosphate. However, the area under concentration-time curve from zero to 48 hours [AUC(0-48)] and peak concentration of these variables were markedly lower after dosing at 8 PM. Pre-dose concentrations of these variables were lower at night. The AUC(0-48) of serum vitamin D3 of the morning and night trials did not differ significantly. Reduction of intact parathyroid hormone concentration was also similar between the two trials. CONCLUSION: The administration of vitamin D3 at night may reduce the occurrence of hypercalcemia and hyperphosphatemia in patients with secondary hyperparathyroidism, whereas the pharmacokinetics and intact parathyroid hormone-lowering effect of the drug does not vary with dosing time.

Area Under Curve↗

PubMed2001

Chronotherapy with active vitamin D3 in aged stroke-prone spontaneously hypertensive rats, a model of osteoporosis.

The chronotherapeutic effects of 1-alpha-(OH) vitamin D3, a pro-drug of 1,25(OH)2 vitamin D3 (1,25(OH)2D3), were evaluated by repeated dosing of the drug in aged stroke-prone spontaneously hypertensive male rats, a model of osteoporosis. Animals (7 months old) were kept in rooms with a 12-h light/dark cycle. Drug (0.5 microg/kg) or vehicle was given once daily at 2 or 14 h after lights on for 3 months. The severity of adverse effects such as body weight loss, hypercalcemia and hyperphosphatemia was significantly less when the drug was given at 14 h after lights on (14 HALO). Serum 1,25(OH)2 vitamin D3 concentrations of 2 h after lights on (2 HALO) group and 14 HALO group did not differ significantly after dosing. The decrease in parathyroid hormone (PTH) level 12 weeks after the start of the study was greater in the 14 HALO group than in the 2 HALO group. Urinary excretion of inorganic Ca and P in the 2 HALO group was greater than that in the 14 HALO group. Urinary excretion of deoxypyridiniline, an index of the bone resorption capacity of osteoclasts, was much suppressed in the 14 HALO group, suggesting that the efficacy of vitamin D3 for suppressing bone resorption might vary with the dosing time. The increase in bone density of both femurs, determined by dual-energy X-ray absorption at the end of the study, was greater in the 14 HALO group than in the 2 HALO group. This is the first study to show the dosing time-dependent efficacy and toxicity of active vitamin D3 in an animal model of osteoporosis. These results indicate that a chronopharmacological approach is beneficial for establishing a more effective and/or safer regimen of active vitamin D3 for the treatment of osteoporosis.

Aging↗

PubMed2004

Safety, efficacy, and patient tolerance of a three-dose regimen of orally administered aqueous sodium phosphate for colonic cleansing before colonoscopy.

BACKGROUND: Sodium phosphate, administered orally, is an effective, well-tolerated colonic cleansing agent. However, colonoscopic visualization is suboptimal in many patients after a conventional 2-dose regimen. This study assessed the safety, the efficacy, and patient tolerance of a 3-dose regimen of sodium phosphate. METHODS: Patients without cardiac, renal, or hepatic insufficiency were randomized to precolonoscopy purgation with 3 (45 mL) doses vs. two doses of aqueous sodium phosphate administered orally. Hemodynamic measurements and serum and urine biochemical tests were obtained at baseline and after purgation. Tolerance of the bowel preparation and colonoscopic visualization were assessed via questionnaires. RESULTS: Quality of colonic cleansing was significantly better with the 3-dose regimen compared with the 2-dose regimen (p < 0.0001). No clinically significant adverse event was detected in either group. Subclinical orthostasis was observed in 5% of patients given the 2-dose regimen vs. 3% of those who took the 3-dose regimen. Post-purgation hyperphosphatemia was greater in the 3-dose group vs. the 2-dose group (p = 0.0003). No other significant differences in biochemistry were noted between the groups. Patient tolerance of the 2-dose regimen was better than the 3-dose regimen (p = 0.0379). CONCLUSIONS: A 3-dose regimen of orally administered sodium phosphate provides superior colonic cleansing without compromising volume status or serum biochemistry but is associated with poorer overall patient tolerance compared with a conventional 2-dose regimen.

Administration, Oral↗

PubMed1984

Total parathyroidectomy and autotransplantation for tertiary hyperparathyroidism in children with chronic renal failure.

An association between chronic renal failure and skeletal deformities in the adolescent patient was first documented by Lucas in 1883. Since then it has been established that the kidneys play a major role in the regulation of calcium, phosphate, and parathyroid hormone, and that chronic renal failure is characterized by profound alterations in the normal metabolic homeostasis of the human body. With the hyperphosphatemia of uremia, compensatory hyperparathyroidism is also a well known complication. Due to these factors, loss of normal renal function ultimately leads to derangement in mineral and bone metabolism resulting in severe skeletal deformities. Reports in the English literature suggest that the changes of renal osteodystrophy are much more pronounced in the pediatric patient, as compared to those in the adult. In the last two decades, renal transplantation has come to be recognized as a satisfactory modality for controlling renal failure and its complications. This procedure is often not available as an option, however, in small patients, especially those under three years of age. The pediatric nephrologist is often forced to manage these patients for long periods with conservative therapy, in an attempt to control the ravages of renal osteodystrophy. The problem becomes unmanageable when the compensatory hyperparathyroidism proceeds to autonomy. When this occurs, despite maintenance of normal serum calcium levels, the renal osteodystrophy progresses rapidly, producing pain, deformities and growth retardation. At this point, the condition is often refractory to medical management and resection of parathyroid tissue remains the only satisfactory modality for control.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic Kidney Disease-Mineral and Bone Disorder↗

PubMed1975

Parathyroid function in infants of diabetic mothers.

Serum parathyroid hormone and total and ionized Ca, Mg, and P levels were determined serially from birth to 96 hr of age in 28 infants of diabetic mothers (IDM, 15 Class A, 13 Class B, C, D) and their respective mothers at the time of delivery. In spite of marked decreases in concentrations of serum total and ionized Ca from birth to 24 to 48 hr, there was an insignificant increase in serum PTH values over this period in infants of insulin-dependent mothers. Infants of Class A diabetic mothers had an equivocal PTH response. Nineteen term control infants were similarly examined and had a significant increase in serum PTH postnatally. Relatively higher values of serum ionized Ca at birth in IDM were followed by greater decreases in ionized Ca from birth to 24-48 hr of age, and by decreased neonatal parathyroid function. The data support functional hypoparathyroidism as a basis for the hypocalcemia and hyperphosphatemia of IDM. It is speculated that increased concentrations of serum ionized Ca in utero and suppression of activity in the fetal parathyroid glands may be a cause for the functional hypoparathyroidism.

Blood↗