Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although animal studies suggest that there may be major differences between the effects of bisphosphonates and ovarian hormones on skeletal metabolism, whether this also holds for their actions in patients is unknown. To address this question, we compared the effects of 12 weeks treatment with HRT on bone turnover markers in osteopenic postmenopausal women with those of an amino-bisphosphonate. Women within 15 yr of the menopause, with a lumbar and/or femoral neck bone mineral density 1 S.D. below the predicted value, received either oestradiol valerate 2 mg and dydrogesterone 5 mg (E/D; n = 16) or aminohexane bisphosphonate 400 mg (AHBP; n = 9). Urine and serum samples were collected on two separate occasions before starting treatment, and 1, 2, 4, 8 and 12 weeks afterwards. To assess bone resorption, we measured the urinary deoxypyridinoline/creatinine ratio (DPD/crea), while serum alkaline phosphatase (ALP), osteocalcin and C-terminal propeptide of type I collagen (CICP) were analysed to assess bone formation. Repeated measures analysis of variance revealed a highly significant decrease in DPD/crea over the treatment period. Furthermore, this pattern of response differed significantly between the two treatment groups, since DPD/crea was maximally suppressed within 2 weeks of starting AHBP, while E/D showed little decrease until 8 weeks. AHBP was also found to suppress ALP, osteocalcin and CICP more rapidly than E/D, the former reducing these markers by 8 weeks, while E/D caused little inhibition even by 12 weeks. We conclude that, in the doses used in this study, AHBP appears to suppress bone turnover significantly more rapidly than E/D, suggesting that clinically important differences may exist in the effects of bisphosphonates and ovarian hormones on bone metabolism.
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PMID:Aminohexane bisphosphonate suppresses bone turnover in postmenopausal women more rapidly than oestrogen-gestagen therapy. 867 May 96

Renal osteodystrophy has become a frequent complication in patients with chronic renal failure (CRF), and various histologic forms such as high turnover, low turnover and mixed bone disease have been demonstrated. The only reliable method for distinguishing patients with high turnover from those with low turnover bone disease is bone histomorphometric study, but its clinical utility is restricted. Because of its invasive nature, efforts have been made to predict indirectly the type and severity of this metabolic bone disease by serum assays. In this cross-sectional study, we measured total and regional (head, arms, trunk, ribs, legs, spine and pelvis) bone mineral densities (BMD) by dual X-ray absorptiometry (DXA) in patients with variable degrees of CRF and correlated them with various bone markers. Decreased BMDs were detected in various skeletal sites (trunk and pelvis) in the patients' group. Total BMD Z score was lower in predialysis CRF patients than in the control subjects. Decreased BMD Z scores on weight-bearing bone were pronounced at L1 lumbar vertebra, femur trochanter, femur neck and Ward's triangle. Positive linear correlations were found between creatinine clearance and trunk, ribs, pelvis, and spine BMDs. There were inverse linear correlations between total BMD and total BMD Z score and alkaline phosphatase (AP), urine deoxypyridinoline (U-DPD) in the patients' group. There were no correlations between regional and total BMD, total BMD Z score and serum calcium, ionized calcium, and serum phosphate. There were inverse linear correlations between BUN, creatinine and bone-specific alkaline phosphatase in the predialysis CRF group. We evaluated the correlations between intact parathyroid hormone (i-PTH) and biochemical and other bone markers. There was statistically significant linear correlation between i-PTH and AP. Other bone markers have no significant correlations with i-PTH. Our results demonstrated that there is significant bone loss in patients with CRF before the start of dialysis and also regional variations of BMDs in predialysis CRF patients. DXA is a useful method for evaluating regional and total BMDs and provides information about diverse regional skeletal changes. AP, i-PTH and U-DPD can predict BMD of predialysis CRF patients.
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PMID:Studies on bone markers and bone mineral density in patients with chronic renal failure. 899 67

We examined associations of biochemical markers of bone turnover with rapid bone loss, as measured by changes in bone mineral density (BMD). To improve the precision of bone loss estimates, calcaneal BMD was measured up to eight times over a long interval (13 years) among postmenopausal women (mean age = 62 years at baseline). Women with fractures during the previous year, and users of corticosteroids, active vitamin D, bisphosphonates or calcitonin were excluded to avoid potential transient effects on marker levels. Among the remaining 354 women, markers were measured for 100 women with the fastest BMD loss (rapid loss group; mean = 2.2%/year) and 100 with the slowest loss (mean = 0.4%/year). Two markers of bone formation, serum bone alkaline phosphatase (Alkphase-B; BAP) and osteocalcin (NovoCalcin; OC), and two markers of bone resorption, urinary creatinine-corrected free deoxypyridinoline (Pyrilinks-D; DPD) and free pyridinolines (Pyrilinks; PYD), were measured. In separate logistic regression models, each of the markers was strongly associated with rapid loss: the odds of rapid loss increased by 1.8 to 2.0 times for each 1.0 standard deviation (SD) increase of the marker. For BAP levels 2 SD above the mean, the probability of rapid bone loss was 80%; in contrast, the probability was only 20% at 2 SD below the mean. The other markers yielded similar results. We conclude that these markers are associated with rapid bone loss; this relationship appears to be continuous, with progressively greater risk of rapid bone loss with increasing levels of biomarkers. Prospective studies that include the entire distribution of bone loss rates are warranted to confirm these findings.
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PMID:Rapid bone loss is associated with increased levels of biochemical markers. 949 24

The objective of this study was to attempt to identify patient co-variables which could influence interpatient variability in 5-fluorouracil (5-FU) clearance during a 5-day continuous venous infusion (CVI, cisplatin 100 mg/m2 day 1 then 5-FU 1 g/m2/day days 2-6). The analysis was performed using a NONMEM program according to a linear one-compartment model. A total of 186 cycles (2 samples per day, 8 a.m. and 5 p.m.) were analysed from 104 patients with various cancers (the majority of head and neck and oesophagus). The study co-variables were age, sex, body surface area, hepatic metastases, peripheral mononuclear cell dihydropyrimidine dehydrogenase activity (PMNC-DPD), liver enzymes, clock-time (8 a.m. versus 5 p.m.), elapsed time during CVI. The data showed that 5-FU clearance was significantly reduced by increased age, low PMNC-DPD, high serum alkaline phosphatase and elapsed time during infusion. These data may be useful for improving knowledge of predictive factors which can influence 5-FU exposure and thus predispose to toxic manifestations.
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PMID:Co-variables influencing 5-fluorouracil clearance during continuous venous infusion. A NONMEM analysis. 962 44

Nowadays, bisphosphonates are considered the drugs of choice for the treatment of several bone disorders. Their exact mechanism of action is not clear but recently it has been reported that the aminobisphosphonates inhibit cholesterol biosynthesis and that this might be relevant for their actions on bone osteoclasts. The study includes 87 postmenopausal women with moderate to severe osteoporosis. The patients were randomly assigned to intravenous (iv) infusion of 50 mg of the aminobisphosphonate Neridronate dissolved in 100 ml of saline solution every 2 months for a year (44 patients). The remaining 43 served as controls. At the time of each infusion blood samples were obtained for the evaluation of total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), apolipoprotein A-I (Apo A-I), apolipoprotein B (Apo B), and total and bone alkaline phosphatase (AP). Free deoxypyridinoline (f-DPD) was measured in fasting urine specimens. In the control group no significant changes were observed throughout the study period for any of the biochemical variables. In the Neridronate-treated patients both bone AP and f-DPD excretion fell significantly by 15-20%. In these patients serum total cholesterol and serum triglycerides showed marginal decreases, which were occasionally significant. LDL-C and Apo B fell by 5-6% and these changes were statistically significant at most time points. Apo A-I and HDL-C rose progressively with time. At the 12th month, HDL-C rose 17-18% (p < 0.0001) above the baseline values. Similar findings were obtained in four postmenopausal women given high iv doses of Pamidronate or Alendronate. In conclusion aminobisphophonates, at least when given iv, induce remarkable and unexpected effects on lipid metabolism with a final profile that might be clinically relevant.
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PMID:Chronic intravenous aminobisphosphonate therapy increases high-density lipoprotein cholesterol and decreases low-density lipoprotein cholesterol. 1075 May 76

Advanced tumor osteopathy is characterized by abnormal bone turnover. Using a rat model of parathyroid hormone-related peptide (PTHrP)-mediated tumor osteolysis, the aim of the present study was to define the sequential changes in, and the association between, biochemical and histomorphometric indices of bone metabolism during the early stages of developing tumor osteopathy. Eight-month-old Wistar rats (n = 48) were subcutaneously inoculated with either 2 x 10(6) cells of the Walker carcinosarcoma 256, or saline on day 0, and treated with either saline or the bisphosphonate ibandronate until killing on day 8. Serum calcium (sCa), alkaline phosphatase (sTAP), and osteocalcin (sOC) and urinary calcium (uCa), deoxypyridinoline (uDPD), and pyridinoline (uPYD) were measured daily. In a second semilongitudinal experiment (n = 70), the number of osteoclasts and osteoblasts (N.Oc, N.Ob), trabecular bone volume (BV/TV), and osteoid volume (O.Ar) were assessed by histomorphometry. In untreated tumor-bearing animals, osteoclast numbers increased by 74% on day 3 (5.4 +/- 2.4 vs. 3.1 +/- 1.5/mm(2), p < 0.05), and trabecular bone volume fell by 24% on day 4 (12.5 +/- 2.0 vs. 15.8 +/- 1.2%, p < 0.05). Both time course and magnitude of these changes were closely reflected by an increase in uDPD (0.46 +/- 0.14 vs. 0. 31 +/- 0.15 nmol/12 h, p < 0.05) and uPYD on day 4 (1.44 +/- 0.25 vs. 1.03 +/- 0.3 nmol/12 h, p < 0.05), sCa (3.8 +/- 0.52 vs. 3.0 +/- 0. 13 mmol/L, p < 0.01), and uCa (0.13 +/- 0.08 vs. 0.03 +/- 0.01 mmol/12 h, p < 0.001) on day 6, and sTAP (254 +/- 127 vs. 120 +/- 40 U/L, p < 0.001) on day 7 (mean +/- SD), whereas sOC remained unchanged until day 8. When combining the results of the two experiments, a high correlation was found between the number of osteoclasts and the urinary excretion of PYD (r = 0.91) and DPD (r = 0.89). Treatment with ibandronate delayed hypercalcemia, abolished hypercalciuria, and accelerated bone resorption. We conclude that osteoclast activation is an early event in PTHrP-mediated osteolysis, which is closely reflected by the renal excretion of pyridinium cross-links of type I collagen. Therefore, specific biochemical markers of collagen breakdown may be useful as early indicators of developing tumor osteopathy.
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PMID:Association between histomorphometry and biochemical markers of bone turnover in a longitudinal rat model of parathyroid hormone-related peptide (PTHrP)-mediated tumor osteolysis. 1077 87

Hyperthyroid patients exhibit accelerated bone loss by increased bone turnover, and normalization of thyroid function is associated with a significant attenuation of increased bone turnover, followed by an increase in bone mineral density. However, of patients with Graves' disease (GD) maintained on antithyroid drug (ATD) treatment, some exhibit persistent suppression of TSH long after normalization of their serum free T3 (FT3) and free T4 (FT4) levels. The aim of this study was to examine whether bone metabolism is still enhanced in TSH-suppressed premenopausal GD patients with normal FT3 and FT4 levels after ATD therapy (n = 19) compared with that in TSH-normal premenopausal GD patients (n = 30), and to evaluate the relationship between serum TSH receptor antibody (TRAb), an indicator of disease activity of GD, and various biochemical markers of bone metabolism. No difference was found between the two groups in serum Ca, phosphorus, or intact PTH, or in urinary Ca excretion. Serum bone alkaline phosphatase (B-ALP), bone formation markers, and urinary excretions of pyridinoline (U-PYD) and deoxypyridinoline (U-DPD), which are bone resorption markers, were significantly higher in the TSH-suppression group than in the TSH-normal group (B-ALP, P < 0.05; U-PYD, P < 0.001; U-DPD, P < 0.001). For the group of all GD patients enrolled in this study, TSH, but neither FT3 nor FT4, exhibited a significant negative correlation with B-ALP (r = -0.300; P < 0.05), U-PYD (r = -0.389; P < 0.05), and U-DPD (r = -0.446; P < 0.05), whereas TRAb exhibited a highly positive and significant correlation with B-ALP (r = 0.566; P < 0.0001), U-PYD (r = 0.491; P < 0.001), and U-DPD (r = 0.549; P < 0.0001). Even in GD patients with normal TSH, serum TRAb was positively correlated with B-ALP (r = 0.638; P < 0.001), U-PYD (r = 0.638; P < 0.001), and U-DPD (r = 0.641; P < 0.001). In conclusion, it is important to achieve normal TSH levels during ATD therapy to normalize bone turnover. TRAb was not only a useful marker for GD activity, but was also a very sensitive marker for bone metabolism in GD patients during ATD treatment.
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PMID:Persistent increase in bone turnover in Graves' patients with subclinical hyperthyroidism. 1109 47

Biochemical markers of resorption and formation of bone tissue (piridinoline-PD, desoxypiridinoline-DPD and alkaline phosphatase-AP, respectively) were measured in blood serum and urine of 41 prostatic cancer (PC) patients with metastases to the bones and 24 PC patients free of such metastases as well as of 40 healthy males and 11 males with benign prostatic hyperplasia (BPH). It was found that PD, DPD levels, general AP activity and activity of its bone fraction were significantly higher in PC patients with bone metastases than in the others (p < 0.001). The former had a significantly higher percent of peptide-bound and lower percent of free forms of PD and DPD (p < 0.001) vs patients without metastases and controls. Higher biochemical serum and urine indices in PC patients with bone metastases reflect enhanced intensity of both formation and resorption of bone tissue in PC with bone metastatic lesions. Therefore, it is possible to use PD, DPD and AP values in diagnosis and monitoring of metastatic skeletal destruction in PC.
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PMID:[Role of biochemical indices as metastatic markers in patients with prostatic cancer invading skeleton]. 1118 86

In a 12-month randomized, double-blind, placebo-controlled trial, we have studied the effects of intranasal salmon calcitonin (SCT) on bone mineral density (BMD) and biochemical markers of bone turnover. Twenty-eight men with idiopathic osteoporosis aged 27-74 years (mean, 52.4 years) were randomized to receive either nasal SCT (200 IU) or a nasal placebo daily for a period of 1 year. All the men received a daily supplement of 0.5 g of calcium. The men who received SCT had a mean (+/-SEM) increase in BMD of 7.1 +/- 1.7% at the lumbar spine. In contrast, the men who received the placebo had an increase of 2.4 +/- 1.5% (p > 0.05) for the comparison with baseline. The increase in lumbar BMD in the calcitonin group was significantly greater than that in the placebo group (p < 0.05). There were no significant changes in the femoral neck, trochanter, or Ward's triangle relative to both baseline and placebo after 12 months. Treatment with nasal SCT resulted in a significantly pronounced suppression of bone resorption markers (urinary deoxypyridinoline [DPD], type I cross-linked N-telopeptide [NTX], and type I cross-linked C-telopeptide [CTX]) and to a lesser extent in bone formation markers (serum bone-specific alkaline phosphatase [BALP], osteocalcin [OC], serum C-terminal procollagen type I extension peptides [PICP], and serum N-termnal procollagen type I extension peptides [PINP]), whereas the placebo did not. Therapy was tolerated well and there were no treatment-related adverse events. We conclude that intranasal SCT (200 IU daily) is safe and effective in increasing lumbar BMD and reducing bone turnover in men with idiopathic osteoporosis.
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PMID:A randomized trial of nasal spray salmon calcitonin in men with idiopathic osteoporosis: effects on bone mineral density and bone markers. 1187 43

Even though 5-fluorouracil (FU) is one of the oldest anticancer drugs, its use in cancer chemotherapy continues to increase. Fluorouracil is a pro-drug that requires intracellular activation to exert its effects. This makes it difficult to associate blood drug concentration with cell toxicity directly, although data from the literature show the existence of such a relationship. The relationship between FU pharmacokinetics and patient response has been explored extensively and reports attest a link between systemic drug exposure and response and survival. This has led to the concept of maximal tolerated exposure, and strategies to achieve this rely on pharmacokinetic follow-up and individual dose adjustment. More than 80% of the administered FU dose is eliminated by catabolism through dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme. Dihydropyrimidine dehydrogenase activity is found in most tissues but is highest in the liver. Peripheral blood mononuclear cells (PBMC) are used to monitor clinically DPD activity. A significant, but weak correlation between PBMC and liver DPD activity has been observed. The relationship between PBMC-DPD activity and FU systemic clearance is weak (r2 = 0.10); thus, simply determining PBMC-DPD is not sufficient to predict accurately FU clearance. Population pharmacokinetic analysis identified patient co-variables that influence FU clearance; drug kinetics is significantly reduced by increased age, high serum alkaline phosphatase, length of drug infusion, and low PBMC-DPD. Autoregulation of FU metabolism also is suggested; inhibition of DPD activity was observed after FU administration in both colorectal cancer patients and an animal model. Circadian rhythmicity in DPD activity is suggested from both human and animal investigations. In patients receiving protracted low dose 5-FU infusion, the circadian rhythm in FU plasma concentration peaks at 11:00h and is lowest at 23:00h, on average. The inverse relationship observed between the circadian profile of FU plasma concentration and PBMC-DP activity in these same patients suggests a link between DPD activity and FU pharmacokinetics. The impact of the biological time of drug administration was also studied with short venous infusions; clearance was 70% greater at 13:00h than at 01:00h. Similarly, peak drug concentration occurred in the first half of the night in patients receiving constant rate 5-FU infusion for 2-5d. Several studies describe wide interindividual variation in the timing of the peak and trough of the 24h rhythm in DPD activity. The rational for FU chronomodulated therapy has been the circadian rhythm in host drug tolerance, which is greatest during the night time when the proliferation of normal target tissue is least. A randomized study of chronomodulated FU therapy with maximal delivery rate at 04:00h was shown clearly to be significantly more effective and less toxic than control flat FU therapy. Future research must focus on easy-to-obtain markers of specific rhythms to individualize the chronomodulated FU delivery.
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PMID:Clinical pharmacokinetics of 5-fluorouracil with consideration of chronopharmacokinetics. 1196 74


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