Pharmacokinetic properties of esomeprazole in children aged 1 to 11 years with symptoms of gastroesophageal reflux disease: a randomized, open-label study

OBJECTIVE: The aim of this study was to assess the overall exposure, other pharmacokinetic (PK) properties, and tolerability of esomeprazole magnesium after repeated oral doses of 5, 10, and 20 mg in pediatric patients who had symptoms of gastroesophageal reflux disease (GERD). METHODS: This randomized, open-label study was conducted at West Coast Clinical Trials, Long Beach, California. Boys and girls aged 1 to 11 years who had a clinical diagnosis of GERD were included and stratified by age (1-5 years [younger group] and 6-11 years [older group]). For this 5-day study, children in the younger group were randomly assigned to receive 1 esomeprazole 5- or 10-mg capsule p.o. QD, and those in the older group were randomly assigned to receive 1 esomeprazole 10- or 20-mg capsule p.o. QD. On days 1 to 4, study medications were administered with the supervision of the study personnel 1 hour before breakfast. Blood samples were collected within 0.5 hour before and 0.5, 1, 1.5, 2, 3, 4, 5, and 6 hours after study drug administration on day 5. Plasma concentrations of esomeprazole were measured using reverse-phase liquid chromatography and mass-spectrometric detection. Tolerability assessments were performed by reviewing the number and severity of adverse events (collected via spontaneous reporting and direct questioning) and findings from the physical examination, which included vital-sign measurements and laboratory analysis (hematology, biochemistry, and urinalysis). Site personnel supervised the administration of the study drug to ensure compliance with treatment. RESULTS: The study included 31 children (17 boys, 14 girls; mean age, 5 years; 18 children in the younger group, 13 in the older group). A total of 27 children were included in the PK analysis. In the younger group, the geometric mean AUC(0-infinity) and Cmax values in the esomeprazole 10-mg group were >2-fold that in the 5-mg group (AUC(0-infinity), 4.83 and 0.74 pmol x h/L [0.32 and 0.04 micromol x h x L(-1)/kg], respectively; Cmax, 2.98 and 0.62 micromol/L [0.19 and 0.03 micromol/L x kg(-1)], respectively). In the older group, the geometric mean AUC(0-infinity) and Cmax values for the 20-mg dose group were approximately 2-fold those for the 10-mg dose group (AUC(0-infinity), 6.28 and 3.70 micromol x h/L [0.21 and 0.12 pmol x h x L(-1)/kg], respectively; Cmax, 3.73 and 1.77 micromol/L [0.13 and 0.06 micromol/L x kg 1], respectively). For the 10-mg esomeprazole dose, the geometric mean body-weight-normalized apparent oral clearance was approximately 50% higher in the younger group compared with the older group (0.40 and 0.25 L/h x kg(-1), respectively). Thirty patients were included in the tolerability analysis. The adverse events that occurred were skin excoriation, discolored feces, and skin laceration (1 [3.3%] patient each); none were considered related to treatment. CONCLUSIONS: The results of this small study suggest that, in children aged 1 to 11 years who had GERD, the PK properties of esomeprazole may be both dose and age dependent and that younger children might have a more rapid metabolism of esomeprazole per kilogram of body weight compared with older children. Esomeprazole was well tolerated at doses of 5, 10, and 20 mg in the pediatric patients studied.     

Serum selenium concentration and disease progress in patients with HIV infection

The selenium concentration in the serum of 67 patients with HIV infection was measured to determine whether selenium deficiency occurred in the different stages of the disease. In the first stage of the study, patients were divided into four groups: symptom-free subjects, PGL (persistent generalized lymphadenopathy), ARC (AIDS related complex), and AIDS (acquired immunodeficiency syndrome). Selenium concentrations were normal in HIV antibody positive symptom-free subjects (1.18 +/- 0.27 mumol/L) and lower than normal in the other three groups (p less than 0.001). There was a significant correlation (p less than 0.001) between selenium levels and values of hemoglobin and erythrocyte sedimentation rate. Selenium deficiency was in no case associated with a lack of zinc in serum (also determined in all patients). In the second stage of the study, 12 patients were treated for a period of two months with low doses of selenium to assess whether such supplementation was able to restore their impaired immunological and hematological functions. The therapy increased serum selenium concentrations (from 0.77 +/- 0.23 to 1.44 +/- 0.41 mumol/L) and symptomatic improvements were noted. However, no changes were observed in the immunological and hematological parameters.     

Elevated levels of plasma homocysteine in postmenopausal women in Burkina Faso.

BACKGROUND: Low levels of plasma homocysteine have been found in children and adult populations living in Burkina Faso in association with a low prevalence of coronary heart disease. METHODS: Based on this finding, the levels of plasma homocysteine and other thiols (cysteine, cysteinylglycine, glutathione) in postmenopausal women living in Burkina Faso were evaluated with the aim of investigating whether age and life conditions influence plasma homocysteine and other thiol levels. RESULTS: It was found that in older postmenopausal women the mean level of homocysteine was higher (16.4+/-6.6 micromol/L) than in fertile women (6.8+/-1.2 micromol/L) and that this increase was correlated with cysteine levels (166.6+/-44.6 micromol/L). While the glutathione level in postmenopausal women was lower (3.6+/-2.3 micromol/L) compared with fertile women (7.0+/-1.7 micromol/L), cysteinylglycine levels were within the normal range (29.9+/-9.3 micromol/L). No correlation was found between homocysteine levels and serum folate, vitamin B(12), vitamin B(6), cystatin C and serum creatinine levels. The older the women were, the higher were their plasma homocysteine levels: levels up to 20.2+/-9.1 micromol/L were found in those >70 years old. CONCLUSIONS: The elevated levels of homocysteine in the postmenopausal women of Burkina Faso must be viewed as a characteristic of older age and its metabolic consequences.     

Cholinesterase (EC 3.1.1.8) with butyrylthiocholine-iodide as substrate: references depending on age and sex with special reference to hormonal effects and pregnancy

Referance values are reported for the assay of cholinesterase (substratae: butyrylthiocholine iodide) in serum at 25 degrees C. There was no evidence of any age-dependency or sex-specific distinction in children (1 to 15 years, N = 309), nor were there any age-dependent changes observed in males (16 to 94 years, N = 718). Compared with the reference range for children, there was no detectable difference in the location and distribution of catalytic cholinesterase concentrations. In females (16 to 99 years, N = 861), an age-dependent difference in cholinesterase values became apparent: Regardless of pregnancy or use of hormonal contraceptives, the catalytic concentrations were found to be lower in younger females (16 to 39 years) than in older ones (greater than or equal to 40 years); the reference values in the older age group (40 to 99 years) did not differ from those of males and children. Therefore the following reference values are proposed (in each case 2.5 to 97.5 percentile: Children, males and females above 40 Years: 3.5 to 8.5 kU/l, Females (16-39 years, nonpregnant, not taking hormonal contraceptives): 2.8 to 7.4 kU/l, Females (18-41 years, pregnant or taking hormonal contraceptives): 2.4 to 6.0 kU/l.     

Inverse association between serum selenium concentrations and parameters of immune activation in patients with cardiac disorders.

BACKGROUND: As a component of the enzyme glutathione peroxidase, the essential trace element selenium contributes to the reduction of peroxides. Disturbed selenium availability may relate to an activated immune response. In humans, immune activation is reflected by increased neopterin production and accelerated tryptophan degradation, expressed as the kynurenine to tryptophan ratio (kyn/trp). Th1-type cytokine interferon-gamma induces both these immunobiological events in human macrophages and they are often activated in patients with cardiac disorders. The aim of this study was to determine the relationship between serum selenium concentrations and neopterin production and tryptophan degradation in patients with cardiac disorders. METHODS: In 56 patients (28 females) with cardiac disorders, serum selenium concentrations were determined by graphite-furnace atomic absorption spectrometry. Serum neopterin concentration was measured by ELISA and tryptophan degradation was examined by HPLC. RESULTS: Selenium concentrations were in the range 0.41-1.90 micromol/L (median 1.02) and were well within the local normal range. Approximately two-thirds of patients presented with higher neopterin concentrations (median 16.4 nmol/L) and tryptophan degradation (median 57 micromol/mmol kyn/trp). There was an inverse correlation between serum selenium and kyn/trp (Spearman's rank correlation, r(s)=-0.431; p<0.001) and neopterin concentrations (r(s)=-0.300; p<0.05). Neopterin concentrations correlated strongly with kyn/trp (r(s)=0.712; p<0.0001). CONCLUSIONS: A higher degree of tryptophan degradation and of neopterin production in patients with cardiac disorders coincides with lower, albeit still normal, serum selenium concentrations. Data show that in these patients immune activation is associated with lower serum selenium concentrations.     

Iron deficiency anemia

The prevalence of iron deficiency anemia is 2 percent in adult men, 9 to 12 percent in non-Hispanic white women, and nearly 20 percent in black and Mexican-American women. Nine percent of patients older than 65 years with iron deficiency anemia have a gastrointestinal cancer when evaluated. The U.S. Preventive Services Task Force currently recommends screening for iron deficiency anemia in pregnant women but not in other groups. Routine iron supplementation is recommended for high-risk infants six to 12 months of age. Iron deficiency anemia is classically described as a microcytic anemia. The differential diagnosis includes thalassemia, sideroblastic anemias, some types of anemia of chronic disease, and lead poisoning. Serum ferritin is the preferred initial diagnostic test. Total iron-binding capacity, transferrin saturation, serum iron, and serum transferrin receptor levels may be helpful if the ferritin level is between 46 and 99 ng per mL (46 and 99 mcg per L); bone marrow biopsy may be necessary in these patients for a definitive diagnosis. In children, adolescents, and women of reproductive age, a trial of iron is a reasonable approach if the review of symptoms, history, and physical examination are negative; however, the hemoglobin should be checked at one month. If there is not a 1 to 2 g per dL (10 to 20 g per L) increase in the hemoglobin level in that time, possibilities include malabsorption of oral iron, continued bleeding, or unknown lesion. For other patients, an endoscopic evaluation is recommended beginning with colonoscopy if the patient is older than 50.     

Selenium, glutathione peroxidase (GSH-Px) and lipid peroxidation products before and after selenium supplementation.

Treated phenylketonuric (PKU) children are at risk of selenium deficiency. We have studied 15 treated PKU children and 30 control children. We observed significantly lower (P less than 0.0005) plasma and erythrocyte selenium, as well as significantly lower (P less than 0.0005) plasma and erythrocyte glutathione peroxidase activities (GSH-Px) in PKU children than in controls. The lipid peroxidation products, evaluated as plasma malondialdehyde (MDA), was higher (P less than 0.0005) in PKU children than in controls. Specific oral sodium selenite supplementation (Selenium: 0.13 mumol/kg/day) resulted in a rapid increase of plasma selenium and GSH-Px activity, and after 10 days and 1 month respectively significant difference is no longer observed between PKU children and controls values. Statistically significant differences in erythrocyte selenium, erythrocyte GSH-Px activity and plasma MDA between PKU and control children disappear after respectively 2 months, 4 months and 6 months of selenium supplementation.     

Evaluation of indicators of cobalamin deficiency defined as cobalamin-induced reduction in increased serum methylmalonic acid

BACKGROUND: Early detection of cobalamin deficiency is clinically important, and there is evidence that such deficiency occurs more frequently than previously anticipated. However, serum cobalamin and other commonly used tests have limited ability to diagnose a deficiency state. METHODS: We investigated the ability of hematological variables, serum cobalamin, plasma total homocysteine (tHcy), serum and erythrocyte folate, gastroscopy, age, and gender to predict cobalamin deficiency. Patients (n = 196; age range, 17-87 years) who had been referred from general practice for determination of serum cobalamin were studied. Cobalamin deficiency was defined as serum methylmalonic acid (MMA) >0.26 micromol/L with at least 50% reduction after cobalamin supplementation. ROC and logistic regression analyses were used. RESULTS: Serum cobalamin and tHcy were the best predictors, with areas under the ROC curve (SE) of 0. 810 (0.034) and 0.768 (0.037), respectively, but age, intrinsic factor antibodies, and gastroscopy gave additional information. CONCLUSIONS: When cobalamin deficiency is suspected in general practice, serum cobalamin should be the first diagnostic test, and the result should be interpreted in relation to the age of the patient. When a definite diagnosis cannot be reached, MMA and tHcy determination will provide additional discriminative information, but MMA, being more specific, is preferable for assessment of cobalamin status.     

Determination of a reference value for N(G), N(G)-dimethyl-L-arginine in 500 subjects

BACKGROUND: Asymmetric dimethylarginine (ADMA) acts as an endogenous inhibitor of NO-synthase. In the last years ADMA has emerged as a cardiovascular risk factor. The aim of this study was to determine a reference value for ADMA. METHODS: Plasma samples of 500 healthy subjects in the 19-75 year age group were analyzed. Exclusion criteria from this study were smoking, any known significant disease, body-mass-index (BMI) above 30 kg m(-2), elevated plasma lipid levels, impaired renal function, hypertension, and intake of any medication. The ADMA levels were determined by ELISA, (DLD Diagnostics, Hamburg, Germany). RESULTS: Mean ADMA plasma concentration of the total population was 0.69 micromol L(-1) (SD 0.20) and 95% of the measured values were in the range from 0.36 micromol L(-1) to 1.17 micromol L(-1). Women below 50 years of age had lower ADMA levels than men below 50 years of age [0.62 (0.17) micromol L(-1) vs. 0.69 (0.19) micromol L(-1); P = 0.001] and woman above 50 years of age had higher ADMA levels than men above 50 years of age [0.80 (0.22) micromol L(-1) vs. 0.73 (0.20) micromol L(-1); P = 0.036]. A regression analysis of ADMA levels and age was performed for each sex. The regression factor was r = 0.444 for women in a squared regression model (P < 0.001) and r = 0.212 for men in a linear regression model (P < 0.001). CONCLUSION: The study was able to define a reference value for ADMA plasma levels with 0.36-1.17 micromol L(-1) and found sex dependent correlations between ADMA and age. Women showed a significant increase in ADMA plasma levels with onset of menopause.     

Cobalamin status and its biochemical markers methylmalonic acid and homocysteine in different age groups from 4 days to 19 years

BACKGROUND: Recent data indicate that cobalamin and folate status, including the metabolic markers methylmalonic acid (MMA) and total homocysteine (tHcy), undergo marked changes during childhood, particularly during the first year. METHODS: Serum cobalamin, serum and whole-blood folate, and plasma MMA and tHcy were determined in a cross-sectional study of 700 children, ages 4 days to 19 years. RESULTS: During the first 6 months, serum cobalamin was lower than and plasma MMA, tHcy, and serum folate were higher than the concentrations detected in the other age groups. In infants 6 weeks to 6 months of age, median MMA and tHcy concentrations were >0.78 and >75 micro mol/L, respectively. In older children (>6 months), serum cobalamin peaked at 3-7 years and then decreased, median plasma MMA remained low (<0.26 micro mol/L), median plasma tHcy was low (<6 micro mol/L) and increased from the age of 7 years on, and serum folate gradually decreased. Plasma MMA was inversely associated with cobalamin (r = -0.4) in both age groups, but across the whole range of cobalamin concentrations, MMA was markedly higher in infants (< or =6 months) than in older children. Plasma tHcy showed a strong negative correlation to cobalamin (r = -0.52) but not to serum folate in infants < or =6 months. In older children, tHcy showed the expected association with both cobalamin (r = -0.48) and folate (r = -0.51). CONCLUSIONS: In infants 6 weeks to 6 months, concentrations of the metabolic markers MMA and tHcy were higher than in the other age groups and strongly correlated to cobalamin, whereas in older children, both makers showed correlations to cobalamin and folate concentrations documented in adults. Whether this metabolic profile in infants is explained by impaired cobalamin status, which in turn may have long-term effects on psychomotor development, remains to be addressed in intervention studies.     

Effect of riboflavin status on the homocysteine-lowering effect of folate in relation to the MTHFR (C677T) genotype

BACKGROUND: Riboflavin (vitamin B(2)) is the precursor for FAD, the cofactor for methylenetetrahydrofolate reductase (MTHFR). MTHFR catalyzes the formation of 5-methyltetrahydrofolate, which acts as a methyl donor for homocysteine remethylation. Individuals with the MTHFR 677C-->T mutation have increased plasma total homocysteine (tHcy) concentrations, particularly in association with low folate status. It has been proposed that riboflavin may act together with folate to lower plasma tHcy, particularly in individuals with the thermolabile MTHFR T variant. METHODS: We measured B-vitamin status and plasma tHcy in 126 healthy individuals 20-63 years of age (42 CC, 42 CT, and 42 TT MTHFR genotypes) at baseline and after three interventions (4 months): placebo plus natural diet; daily 400 microg folic acid supplement plus natural diet; and increased dietary folate to 400 microg/day. RESULTS: At baseline and after nutritional intervention, lower riboflavin status was associated with increased plasma tHcy concentrations. Plasma tHcy was 2.6 micromol/L higher in the lowest plasma riboflavin quartile compared with the highest (P <0.02) and was 4.2 micromol/L higher in the highest erythrocyte glutathione reductase activation coefficient (EGRAC) quartile compared with the lowest (P <0.001). This effect was not restricted to those with the T allele. Folic acid given as a 400 microg/day supplement appeared to exacerbate a tendency toward riboflavin deficiency, as suggested by an increase in the proportion of individuals with EGRAC > or =1.4 from 52% to 65% after supplementation (P <0.05). CONCLUSIONS: Folate and riboflavin interact to lower plasma tHcy, possibly by maximizing the catalytic activity of MTHFR. The effect may be unrelated to MTHFR genotype.     

Direct serum total iron-binding capacity assay suitable for automated analyzers.

BACKGROUND: Present methods for measuring serum total iron-binding capacity (TIBC) involve manipulation of samples or performance of two assays on each sample. We developed a direct automated assay (DTIBC) for TIBC. METHODS: We added to serum a saturating amount of iron bound to an excess of chelating dye at a low pH, recorded a blank reading that represented the sum of the saturating amount of iron plus the serum iron, and then added a strong neutral pH buffer. The decrease in absorbance (as transferrin extracts iron from the iron-dye complex) is directly proportional to the TIBC. TIBC values for 125 patients were determined by DTIBC, alumina column TIBC (AC), magnetic particle TIBC (MTIBC), and the UIBC method (UIBC) on Roche COBAS FARA and Mira chemistry analyzers. In a separate study, TIBC values for 128 patients were determined on an Olympus AU400 by the DTIBC and the MTIBC methods. RESULTS: Methods comparisons on the COBAS analyzers yielded the following results: DTIBC = 1.05(MTIBC) - 1.0 micromol/L (r = 0.987; S(y/x) = 2.6 micromol/L); DTIBC = 1.07(AC) - 1.0 micromol/L (r = 0.982; S(y/x) = 3.0 micromol/L); and DTIBC = 1.14(UIBC) + 3.4 micromol/L (r = 0.982; S(y/x) = 3.0 micromol/L). A similar correlation study using the Olympus AU400 yielded DTIBC = 1.00(MTIBC) - 0.1 micromol/L (r = 0.983; S(y/x) = 2.7 micromol/L). The assay was linear from 12.5 to 125 micromol/L (70-700 microg/dL) TIBC on the COBAS FARA. Within- and between-run imprecision (CV) was 相似文献   

Compound heterozygous hemochromatosis genotype predicts increased iron and erythrocyte indices in women

BACKGROUND: Women who inherit heterozygosity for the C282Y mutation of the HFE gene may have increased serum iron indices and hemoglobin and are less likely to develop iron deficiency compared with women with the wild-type genotype. METHODS: We performed a cross-sectional analysis of 497 women 20-44 years of age and 830 women >51 years of age drawn from the Busselton (Australia) population study to assess the effects of the HFE genotype on serum iron and hematology indices. RESULTS: Heterozygosity for the C282Y mutation occurred in 13.8% of the study population, comprising 11.8% C282Y wild-type heterozygotes and 2.0% C282Y/H63D compound heterozygotes. In the younger age group, C282Y wild-type women did not have significantly increased serum iron, transferrin saturation, or hemoglobin values, and were not protected from developing iron deficiency, compared with women of the same age with the wild-type genotype. Young compound heterozygous women had higher means for serum iron (25.0 vs 16.9 micromol/L; P <0.001), transferrin saturation (42.0% vs 25.6%; P <0. 05), hemoglobin (139.4 vs 132.3 g/L; P <0.05), and corpuscular volume (91.1 vs 87.7 fL; P <0.05), and a higher median ferritin (53 vs 44 microg/L; P <0.05) compared with the wild-type genotype. Similar results were observed for compound heterozygotes in the >51 years age group. CONCLUSIONS: Women with the compound heterozygous HFE genotype C282Y/H63D, but not the C282Y wild-type genotype, had increased values for serum iron and transferrin saturation, and the younger age group also had increased hemoglobin values. We conclude that the compound heterozygous genotype may have a beneficial effect in protecting women from iron deficiency.     

Diagnostic considerations in the measurement of human chorionic gonadotropin in aging women

BACKGROUND: Human chorionic gondadotropin (hCG) screening tests are performed on nearly all female patients of childbearing age before any medical intervention. Although older women usually have negative hCG test results, positive results do occur and may cause clinical confusion. We examined changes with age in serum hCG concentrations in nonpregnant women and investigated the use of serum follicle-stimulating hormone (FSH) measurements as an aid to interpreting higher than expected ("positive") hCG results. METHODS: We used 240 serum specimens for each of 4 female cohorts: pregnant, > or =18 years; nonpregnant, 18-40 years (premenopausal); nonpregnant, 41-55 years (perimenopausal); and nonpregnant, >55 years (postmenopausal). Patients were excluded if they had an ectopic pregnancy, a history of trophoblastic disease or a germ-cell tumor, or if no chart was available for review. Quantitative hCG and FSH tests were performed on each specimen. RESULTS: Serum hCG concentrations in nonpregnant women increased with the age of the women. hCG results were higher and significantly different (P < 0.0001) for nonpregnant women >55 years (<2.0 to 13.1 IU/L) compared with nonpregnant women 18-40 years (<2.0 to 4.6 IU/L) and 41-55 years (<2.0 to 7.7 IU/L). Nineteen nonpregnant women >40 years of age had hCG concentrations > or = 5.0 IU/L, all with an FSH concentration >32.4 IU/L. The highest FSH concentration in pregnancy was 7.3 IU/L. CONCLUSIONS: Serum hCG increases with age in nonpregnant women. A cutoff of 14.0 IU/L should be used when interpreting hCG results in women >55 years of age. Pregnancy is unlikely in perimenopausal women 41-55 years of age with an hCG between 5.0 and 14.0 IU/L if serum FSH is >20.0 IU/L.     

Analysis of guanidinoacetate and creatine by isotope dilution electrospray tandem mass spectrometry.

Guanidinoacetate methyltransferase (GAMT) deficiency is a disorder of creatine metabolism characterized by low plasma creatine concentrations in combination with elevated guanidinoacetate (GAA) concentrations. Although rare, GAMT deficiency has been identified in children with seizures, extrapyramidal movements, developmental delay, myopathies and behavioral abnormalities. Treatment with creatine monohydrate has been proven to be effective. We describe an isotope dilution electrospray tandem mass spectrometry (ES-MS/MS) assay for the simultaneous determination of plasma GAA and creatine using multiple reaction monitoring (MRM), d(3)-creatine as the internal standard and derivatization of GAA and creatine as butyl-esters. We analysed plasma of 16 healthy adults and 20 healthy children as well as three affected children. Plasma GAA concentrations were 5.02+/-1.84 micromol/l (mean+/-S.D.) in adults, 3.91+/-0.76 micromol/l in children age 5-10 years and 11.57, 15.16, 14.36 micromol/l in children with GAMT deficiency. Plasma creatine concentrations were 34.7+/-15.25 micromol/l in adults, 58.96+/-22.30 micromol/l in children and 5.37, 8.15, 403.5 micromol/l in two untreated children and one treated child with GAMT deficiency, respectively. GAA can also be reliably measured from filter cards, which is sufficient to make the correct diagnosis while creatine is consistently falsely elevated probably secondary to liberation of red cell creatine. In nine healthy newborn infants, GAA concentrations from filter cards were 4.83+/-1.43 and 5.04+/-1.84 micromol/l in 16 healthy adults. We conclude that isotope dilution ES-MS/MS is ideal for rapid high-throughput diagnosis of GAMT deficiency both from plasma and filter paper cards. Using this technique neonatal screening is feasible for this treatable inborn error of creatine metabolism.     

Hyperhomocysteinemia and B-vitamin deficiencies in infants and children.

Measurement of total homocysteine (tHcy) in healthy and diseased children has documented the utility of this marker in pediatric research and diagnostics. This article focuses on novel data obtained in infants, children and adolescents, with emphasis on cobalamin status in infants. In children, determinants of plasma tHcy are similar to those established in adults, and include age, gender, nutrition, B-vitamin status, and some drugs interfering with B-vitamin function. In infants (age < 1 year), tHcy is moderately elevated and related to serum cobalamin, whereas in older children and throughout childhood, plasma tHcy is low (about 60% of adult levels), and folate status becomes a strong tHcy determinant. As in adults, hyperhomocysteinemia in childhood is a risk factor for stroke, and folate-responsive hyperhomocysteinemia has been detected in children with renal failure. tHcy seems to be a sensitive indicator of folate deficiency in children on a poor diet, in HIV-infected children, and in children treated with anti-folate drugs. In children at increased risk of cobalamin deficiency, which includes children born to vegetarian mothers or children in developing countries on a poor diet, tHcy and methylmalonic acid are responsive indicators of a deficiency state. In newborns and infants born to mothers with an adequate nutrition, there are consistent observations of low cobalamin, elevated tHcy and methylmalonic acid, and reduction of both metabolites by cobalamin supplementation. These data have raised the question whether cobalamin deficiency may be widespread and undetected in babies born to non-vegetarian women on a Westernized diet.     

The plasma homocysteine concentration is better than that of serum methylmalonic acid as a marker for sociopsychological performance in a psychogeriatric population

BACKGROUND: Cobalamin/folate deficiency in elderly subjects may lead to psychiatric symptoms, but more often it increases the severity of various organic and nonorganic mental diseases. A major clinical problem, however, is the uncertainty and controversy concerning biochemical markers of cobalamin/folate deficiency to be used in the diagnostic evaluation of suspected cobalamin/folate deficiency. METHODS: We measured plasma homocysteine (tHcy), blood folate, serum methylmalonic acid, and serum cobalamin in 80 psychogeriatric patients (age, 77.3 +/- 8.6 years) and 50 controls (age, 76.1 +/- 8. 0 years). We assessed associations of these tests with measures of cognitive and behavior performance by use of regression analyses. RESULTS: Plasma tHcy was increased in 45% of the psychogeriatric population (mean, 20.5 +/- 9.2 micromol/L vs 15.3 +/- 4.7 micromol/L for controls; P <0.01). Plasma tHcy correlated with severity of dementia (r = 0.36; P <0.01), the Katz ADL index (r = 0.29; P <0.05), the Berger scale (r = 0.29; P <0.05), and the score of symptoms (r = 0.39; P <0.001) in the psychogeriatric population. Similarly, blood folate was significantly correlated with these measures, but the concentrations of serum cobalamin and methylmalonic acid were not. In a stepwise multiple regression analysis including the biochemical markers, tHcy was the only significant predictor of the severity of dementia (r(2) = 0.11; P <0.01) and the score of symptoms (r(2) = 0.16; P <0.001). CONCLUSION: Plasma tHcy is the best marker of those measured to investigate suspected tissue deficiency of cobalamin/folate.     

Prediction of methotrexate elimination after high dose infusion in children with acute lymphoblastic leukaemia using a population pharmacokinetic approach

High-dose methotrexate (HD-MTX) with leucovorin rescue is a component of therapy in children with acute lymphoblastic leukaemia. Since MTX toxicity is related to drug exposure, a monitoring of serum MTX concentrations at H24, H48, H72 and until the concentration is less than 0.2 micromol/L is commonly performed. However, a number of patients may reach concentrations of less than 0.2 micromol/L long before the next sampling is scheduled. The aim of our study was to develop a Bayesian method predicting the time at which MTX concentration reaches 0.2 micromol/L in order to decrease the number of samples drawn and to allow for a more rapid patient discharge. Methotrexate population parameters were estimated from a retrospective analysis of 60 infusions in 23 children and MTX concentrations were predicted from an independent set of 20 courses in 14 children with a Bayesian approach using either one (H48) or two (H24 and H48) samples. The following population parameters were obtained using a two-compartment model: CL = 3.51 L/h (inter-individual variability: 66%), Vd = 8.67 L (58%), k12 = 0.0044 h(-1)(105%), k21 = 0.039 h(-1)(25%). Clearance and Vd were found to increase with weight and age respectively. Both sampling schedules tested for the Bayesian estimation enabled accurate prediction of concentrations and provided satisfactory precision despite a small bias. When considering the ability to predict the time at which the threshold was reached, the one-sample (H48) schedule gave the best results. We conclude that a sampling schedule involving only one sample and Bayesian parameter estimation may be able to predict the delay necessary to reach 0.2 micromol/L in each individual.     

Screening for serum total homocysteine in newborn children

BACKGROUND: Newborn screening for total homocysteine (tHcy) in blood may identify babies with vitamin B12 (B12) deficiency or homocystinuria, but data on the causes of increased tHcy in screening samples are sparse. METHODS: Serum concentrations of tHcy, cystathionine, methionine, folate, and B12 and the methylenetetrahydrofolate reductase (MTHFR) 677C > T polymorphism were determined in 4992 capillary blood samples collected as part of the routine screening program in newborn children. Methylmalonic acid (MMA), gender (SRY genotyping), and the frequency of six cystathionine beta-synthase (CBS) mutations were determined in 20-27% of the samples, including all samples with tHcy > 15 micromol/L (n = 127), B12 < 100 pmol/L (n = 159), or methionine > 40 micromol/L (n = 154). RESULTS: The median (5th-95th percentile) tHcy concentration was 6.8 (4.2-12.8) micromol/L. B12 status, as determined by serum concentrations of B12, tHcy, and MMA, was moderately better in boys than in girls. tHcy concentrations between 10 and 20 micromol/L were often associated with low B12, whereas tHcy > 20 micromol/L (n = 43) was nearly always explained by increased methionine. tHcy did not differ according to folate concentrations or MTHFR 677C > T genotypes. None of the babies had definite CBS deficiencies, but heterozygosity led to low cystathionine, increased methionine, but normal tHcy concentrations. CONCLUSION: Increased tHcy is a common but not specific finding in newborns. The metabolite and vitamin profiles will point to the cause of hyperhomocysteinemia. Screening for tHcy and related factors should be further evaluated in regions with high prevalence of homocystinuria and in babies at high risk of B12 deficiency.