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Phenylbutyrate improves nitrogen disposal via an alternative pathway without eliciting an increase in protein breakdown and catabolism in control and ornithine transcarbamylase-deficient patients.
Marini, JC, Lanpher, BC, Scaglia, F, O'Brien, WE, Sun, Q, Garlick, PJ, Jahoor, F, Lee, B
The American journal of clinical nutrition. 2011;(6):1248-54
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Abstract
BACKGROUND Phenylbutyrate is a drug used in patients with urea cycle disorder to elicit alternative pathways for nitrogen disposal. However, phenylbutyrate administration decreases plasma branched-chain amino acid (BCAA) concentrations, and previous research suggests that phenylbutyrate administration may increase leucine oxidation, which would indicate increased protein degradation and net protein loss. OBJECTIVE We investigated the effects of phenylbutyrate administration on whole-body protein metabolism, glutamine, leucine, and urea kinetics in healthy and ornithine transcarbamylase-deficient (OTCD) subjects and the possible benefits of BCAA supplementation during phenylbutyrate therapy. DESIGN Seven healthy control and 7 partial-OTCD subjects received either phenylbutyrate or no treatment in a crossover design. In addition, the partial-OTCD and 3 null-OTCD subjects received phenylbutyrate and phenylbutyrate plus BCAA supplementation. A multitracer protocol was used to determine the whole-body fluxes of urea and amino acids of interest. RESULTS Phenylbutyrate administration reduced ureagenesis by ≈15% without affecting the fluxes of leucine, tyrosine, phenylalanine, or glutamine and the oxidation of leucine or phenylalanine. The transfer of (15)N from glutamine to urea was reduced by 35%. However, a reduction in plasma concentrations of BCAAs due to phenylbutyrate treatment was observed. BCAA supplementation did not alter the respective baseline fluxes. CONCLUSIONS Prolonged phenylbutyrate administration reduced ureagenesis and the transfer of (15)N from glutamine to urea without parallel reductions in glutamine flux and concentration. There were no changes in total-body protein breakdown and amino acid catabolism, which suggests that phenylbutyrate can be used to dispose of nitrogen effectively without adverse effects on body protein economy.
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Prophylaxis with a cream containing urea reduces the incidence and severity of radio-induced dermatitis.
Pardo Masferrer, J, Murcia Mejía, M, Vidal Fernández, M, Alvarado Astudillo, A, Hernández Armenteros, ML, Macías Hernández, V, Soto Pérez, R, Mirada Ferre, A
Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico. 2010;(1):43-8
Abstract
INTRODUCTION Radio-induced dermatitis is one of the most frequent side effects of radiotherapy. Among the commercially available products for the care of irradiated skin is a hydrating lotion containing 3% urea, polidocanol and hyaluronic acid. Its effectiveness for preventing the appearance of radiodermatitis or reducing its severity has been studied on a number of occasions. OBJECTIVE To evaluate the effectiveness of "intensive use" of the lotion containing 3% urea, polidocanol and hyaluronic acid for preventing the appearance of acute radiodermatitis and controlling its severity. MATERIAL AND METHODS Prospective observational study in 98 patients with breast cancer with a 10-week follow-up period. Skin toxicity (RTOG/EORTC scale) was evaluated weekly. To study the effectiveness we compared incidence and grade of toxicity with a sample of 174 breast cancer patients (control sample) treated in our centre during 2006 who used skin-support measures at the start of the radiotherapy or the occurrence of radiodermatitis. RESULTS The proportion of patients who did not develop radiodermatitis was significantly higher in the intensive use group (27.6% vs. 15.5%; p<0.05; OR: 2.07). Compared with the same lotion in standard conditions, the intensive use group showed lower incidence of radiodermatitis (p<0.01), lower grade of toxicity (p<0.001) and lower proportion of radiodermatitis grade 2 or higher (p<0.01). CONCLUSIONS Intensive use of the lotion doubles the likelihood that breast cancer patients will not develop radiodermatitis during radiotherapy. Furthermore, compared with standard use, intensive use is more effective in reducing the incidence of skin toxicity and skin toxicity grade 2 or higher.
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[Urea plus ceramides and vitamins: improving the efficacy of a topical urea preparation by addition of ceramides and vitamins].
Grether-Beck, S, Mühlberg, K, Brenden, H, Krutmann, J
Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete. 2008;(9):717-8, 720-3
Abstract
Topical urea preparations containing urea have been used successfully to improve the barrier function of the skin. We investigated whether the efficacy of an urea-containing topical preparation could be improved by the addition of vitamins and ceramides. For this an intra-individual comparative study was conducted on 10 subjects with healthy skin. The application of the combination preparation containing urea, vitamins and ceramides for 2 weeks was significantly superior to the urea-only preparation in respect to reduction of transepidermal water loss and skin hydration levels. This improved efficacy was associated with a stronger up-regulation of the transcriptional expression of differentiation genes in keratinocytes in the treated skin areas. While both preparations caused an increased expression of the genes encoding transglutaminase-1, involucrin, loricrin and filaggrin, this increase was significantly greater in those skin areas treated with the combination preparation. This study indicates that the efficacy of topical preparations containing urea can be enhanced by the incorporation of ceramides and vitamins.
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Effect of protein restriction on (15)N transfer from dietary [(15)N]alanine and [(15)N]Spirulina platensis into urea.
Hamadeh, MJ, Hoffer, LJ
American journal of physiology. Endocrinology and metabolism. 2001;(2):E349-56
Abstract
Six normal men consumed a mixed test meal while adapted to high (1.5 g. kg(-1) x day(-1)) and low (0.3 g. kg(-1) x day(-1)) protein intakes. They completed this protocol twice: when the test meals included 3 mg/kg of [(15)N]alanine ([(15)N]Ala) and when they included 30 mg/kg of intrinsically labeled [(15)N]Spirulina platensis ([(15)N]SPI). Six subjects with insulin-dependent diabetes mellitus (IDDM) receiving conventional insulin therapy consumed the test meal with added [(15)N]Ala while adapted to their customary high-protein diet. Protein restriction increased serum alanine, glycine, glutamine, and methionine concentrations and reduced those of leucine. Whether the previous diet was high or low in protein, there was a similar increase in serum alanine, methionine, and branched-chain amino acid concentrations after the test meal and a similar pattern of (15)N enrichment in serum amino acids for a given tracer. When [(15)N]Ala was included in the test meal, (15)N appeared rapidly in serum alanine and glutamine, to a minor degree in leucine and isoleucine, and not at all in other circulating amino acids. With [(15)N]SPI, there was a slow appearance of the label in all serum amino acids analyzed. Despite the different serum amino acid labeling, protein restriction reduced the postmeal transfer of dietary (15)N in [(15)N]Ala or [(15)N]SPI into [(15)N]urea by similar amounts (38 and 43%, respectively, not significant). The response of the subjects with IDDM was similar to that of the normal subjects. Information about adaptive reductions in dietary amino acid catabolism obtained by adding [(15)N]Ala to a test meal appears to be equivalent to that obtained using an intrinsically labeled protein tracer.
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Effects of budesonide and prednisolone on hepatic kinetics for urea synthesis.
Wolthers, T, Hamberg, O, Grøfte, T, Vilstrup, H
Journal of hepatology. 2000;(4):549-54
Abstract
BACKGROUND/AIMS: Glucocorticoids upregulate hepatic urea synthesis and cause protein breakdown to prevail over synthesis, releasing amino acids into the blood stream and increasing the substrate supply for hepatic urea synthesis. Budesonide is a new generation glucocorticoid that may be used for treatment of inflammatory diseases, e.g. Crohn's disease and autoimmune hepatitis. Due to its extensive first-pass metabolism in the liver, it has a potential adverse effect profile superior to that of prednisolone. Little attention has been directed towards differences in nitrogen catabolic properties between budesonide and prednisolone. METHODS Eight normal male subjects (age 20-44 years; BMI 21.6-28.2 kg/m2) were randomly studied 3 times: 1) At baseline, 2) after 6 days of prednisolone (50 mg/day), and 3) after 6 days of budesonide (9 mg/ day). We measured urea nitrogen synthesis rates (UNSR) and blood alpha-amino-nitrogen (N) levels before, during, and after a 3-h constant infusion of alanine (2 mmol/(kg BW x h)). UNSR was estimated hourly as urinary excretion corrected for gut hydrolysis and accumulation in body water. The slope of the linear relationship between UNSR and amino-N concentration represents the hepatic kinetics of conversion of amino- to urea-N, and is denoted the functional hepatic nitrogen clearance (FHNC). RESULTS Prenisolone, but not budesonide, administration increased basal blood and amino nitrogen concentrations (3.5 +/- 0.1 mmol/l (control) vs 3.8 +/- 0.1 mmol/l (prednisolone) (p<0.05) and 3.6 +/- 0.1 mmol/l (budesonide) (NS). Basal UNSR values were significantly increased following prednisolone (23.3 +/- 6.5 (control) vs 51.2 +/- 6.3 (prednisolone) (p<0.05)), while budesonide had no effect on basal UNSR (33.7 +/- 4.2 (budesonide) (NS)). Prednisolone administration increased FHNC (from 24.6 +/- 4.7 l/h (control) to 47.3 +/- 5.9 l/h (prednisolone) (p<0.05). Budesonide administration did not significantly increase FHNC (33.7 +/- 4.2 l/h (budesonide), (vs control; p=0.12, vs prednisolone: p<0.05)). CONCLUSIONS Prednisolone administration led to increased levels of amino acids in blood and loss of N as urea, the latter in part due to a specific hepatic mechanism as shown by the increased FHNC. Budesonide led to unaltered levels of amino acids in blood, no changes in loss of N as urea, and unaltered hepatic kinetics for urea synthesis. Thus, oral budesonide administration had very limited effects on the hepatic contribution to nitrogen homeostasis and metabolism via urea synthesis, making treatment with budesonide superior to that of conventional glucocorticoids in this respect.