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Molecular Genetics and Metabolism Apr 2000It has been postulated that the significant incidence of learning disabilities in well-treated patients with phenylketonuria (PKU) may be due, in part, to reduced...
It has been postulated that the significant incidence of learning disabilities in well-treated patients with phenylketonuria (PKU) may be due, in part, to reduced production of neurotransmitters as a result of deficient tyrosine transport across the neuronal cell membrane. Hypotyrosinemia has been reported in treated and untreated PKU but virtually no data are available. We decided to examine this in our patient population and to compare it with the published norms, patient data from our hospital clinical biochemical laboratory database, and a group of normal children and adolescents in a private pediatric practice. We found that the mean nonfasting plasma tyrosine in 99 classical PKU patients was 41.1 micromol/L, in 26 mild (atypical) PKU patients 53.3 micromol/L, and in 35 non-PKU mild hyperphenylalaninemia patients 66.6 micromol/L. This compared to nonfasting plasma tyrosine levels in 102 non-PKU subjects of 64.0 micromol/L in our hospital biochemistry database, 69.1 micromol/L in 58 volunteers in the private office practice, and 64-78.8 micromol/L in infants, children, and adolescents in the literature review. Our data support the previously undocumented statements in the literature that plasma tyrosine levels are low in PKU.
Topics: Adolescent; Adult; Analysis of Variance; Child; Humans; Infant; Infant, Newborn; Phenylalanine; Phenylketonurias; Review Literature as Topic; Severity of Illness Index; Tyrosine
PubMed: 10870846
DOI: 10.1006/mgme.2000.2985 -
Analytical Chemistry Sep 2001The discovery of a mass-independent isotopic composition (delta17O = (delta17O - 0.512 * delta18O) no equal to 0) in aerosol sulfate and the identification of its origin...
The discovery of a mass-independent isotopic composition (delta17O = (delta17O - 0.512 * delta18O) no equal to 0) in aerosol sulfate and the identification of its origin (aqueous-phase oxidation by 03 and H2O2) have renewed interest in measuring the oxygen isotopic content of sulfate. In this paper, we present a new method to measure both delta17O and delta18O in SO4, with the possibility of sulfur isotope analysis on the same sample. The technique takes advantage of the easy pyrolysis of Ag2SO4 to SO2, O2, and Ag metal in a continuous flow system. Because the technique is not quantitative in oxygen (yield approximately 45% for O2), a calibration is needed. Correction factors of +0.87 and +0.44% were obtained for delta18O and delta17O, respectively. A technique to convert micromole levels of sulfate in any form to silver sulfate is described. To reach this goal, a solid electrolyte (Nafion membrane) is used in an electrolysis apparatus. Reproducibilities for micromole sample sizes are (1sigma) 0.5, 0.3, and 0.1% for delta18O, delta17O, and delta17O, respectively. No memory effects or isotopic exchange during the treatment of the sample is observed. The main advantages of this new method over the existing ones are no fluorinating agent is needed, both oxygen and sulfur isotopes can be measured on the same sample, only very small amounts of sulfate are needed (down to 100 microg (1 micromol)), it is relatively fast and inexpensive, and the possibility exists to couple this technique to an on-line analysis.
PubMed: 11575793
DOI: 10.1021/ac010017f -
Therapeutic Drug Monitoring Jun 2003The aim of the present review is to discuss the potential value of therapeutic drug monitoring (TDM) of the newer antiepileptic drugs (AEDs) felbamate, gabapentin,... (Review)
Review
The aim of the present review is to discuss the potential value of therapeutic drug monitoring (TDM) of the newer antiepileptic drugs (AEDs) felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin, and zonisamide. Studies of the relationship between serum concentrations and clinical efficacy of these drugs are reviewed, and the potential value of TDM of the drugs is discussed based on their pharmacokinetic properties and mode of action. Analytical methods for the determination of the serum concentrations of these drugs are also briefly described. There are only some prospective data on the serum concentration-effect relationships, and few studies have been designed primarily to study these relationships. As TDM is not widely practiced for the newer AEDs, there are no generally accepted target ranges for any of these drugs, and for most a wide range in serum concentration is associated with clinical efficacy. Furthermore, a considerable overlap in drug concentrations related to toxicity and nonresponse is reported. Nevertheless, the current tentative target ranges for felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine (10-hydroxy-carbazepine metabolite), tiagabine, topiramate, vigabatrin, and zonisamide are 125 to 250 micromol/L, 70 to 120 micromol/L, 10 to 60 micromol/L, 35 to 120 micromol/L, 50 to 140 micomol/L, 50 to 250 nmol/L, 15 to 60 micromol/L, 6 to 278 micromol/L, and 45 to 180 micromol/L, respectively. Further systematic studies designed specifically to evaluate concentration-effect relationships of the new AEDs are urgently needed. Although routine monitoring in general cannot be recommended at present, measurements of some of the drugs is undoubtedly of help with individualization of treatment in selected cases in a particular clinical setting.
Topics: Anticonvulsants; Clinical Trials as Topic; Drug Interactions; Drug Monitoring; Epilepsy; Humans
PubMed: 12766564
DOI: 10.1097/00007691-200306000-00016 -
Bratislavske Lekarske Listy 2002Homocysteine has a pro-oxidative activity. This amino acid, a lipid-independent vascular disease risk factor, might cause atherosclerosis by damaging the endothellium...
Homocysteine has a pro-oxidative activity. This amino acid, a lipid-independent vascular disease risk factor, might cause atherosclerosis by damaging the endothellium either directly or by altering the oxidative status. Levels of plasma homocysteine and vitamin C concentrations were determined in the adult majority population of Southern Slovakia (n=146) and in the ethnic Romany minority (n=119) in this region. Average homocysteine and vitamin C values in Romanies are similar to those in the majority group (non-significantly changed) with an equal finding of hyperhomocysteinemia, as well as with similar frequency of deficient, suboptimal and optimal vitamin C values. Under the condition of suboptimal (23-50 micromol/l) and optimal (>50 micromol/l) vitamin C levels, homocysteine values in connected groups are significantly lower with comparison to the value at deficient vitamin C level (<11.5 micromol/l), reduction from 10.74 micromol/l to 9.35 and 9.17 micromol/l. Multiple regression showed a negative linear correlation of homocysteine and folic acid, vitamin B12 (determinants of homocysteine metabolism), vitamin C (antioxidative effect) together (n=265, r=-0.282, p<0.00008). The significance for vitamin B12 alone, was p=0.0199, for folic acid p=0.0046, for vitamin C p=0.0499. The results express a significant effect of vitamin C in prevention of vascular damage. (Tab. 1, Fig. 1, Ref; 19.).
Topics: Adult; Ascorbic Acid; Female; Homocysteine; Humans; Male; Middle Aged; Roma; Slovakia
PubMed: 12413206
DOI: No ID Found -
The American Journal of Clinical... Apr 1980Plasma carnitine and urinary carnitine levels were measured in Thai adults living in Bangkok city and Ubol villages. The mean plasma carnitine and urinary carnitine...
Plasma carnitine and urinary carnitine levels were measured in Thai adults living in Bangkok city and Ubol villages. The mean plasma carnitine and urinary carnitine levels expressed in micromoles per liter in Bangkok adults were higher than those in Ubol adults. Their mean plasma carnitine levels were 56.6 +/- 1.8 and 50.3 +/- 1.7 whereas urinary carnitine levels were 161 +/- 19 and 127 +/- 18 micromole/liter, respectively. The nutritional status in Ubol adults was inadequate. This was evidenced by the significant decrease in urinary creatinine excretion, serum albumin, and hematocrit levels. The dietary assessment agreed with the biochemical findings. Since rice, limiting in carnitine, was the main protein and energy source consumed by Ubol adults their inadequate carnitine status could be due to the low carnitine intake. Sex affects plasma carnitine levels in Bangkok adults and urinary carnitine excretion in both groups. This could be related to the lean body mass in which most of the body carnitine resides. This is supported by the higher urinary creatinine excretion in males and the significant positive correlation between carnitine excretion and creatinine-height index.
Topics: Adult; Blood Proteins; Carnitine; Creatinine; Female; Food Analysis; Hematocrit; Humans; Male; Rural Population; Sex Factors; Thailand; Urban Population
PubMed: 7361706
DOI: 10.1093/ajcn/33.4.876 -
Clinical Pediatrics Apr 2006This study was undertaken to determine the frequency and investigate the etiology of extreme hyperbilirubinemia (total serum bilirubin [TSB]>or=25 mg/dL [428...
This study was undertaken to determine the frequency and investigate the etiology of extreme hyperbilirubinemia (total serum bilirubin [TSB]>or=25 mg/dL [428 micromol/L]) in newborns admitted to a neonatal intensive care unit in southern Turkey. The charts of 93 term and near-term infants admitted with TSB levels of 25 mg/dL (428 micromol/L) or greater in the first 30 days after birth were retrospectively reviewed. During the 4.5-year study period, 774 infants were admitted to our unit with neonatal jaundice. Ninety-three (12%) of these infants had TSB levels of 25 mg/dL (428 micromol/L) or greater. The mean TSB level in the 93 cases was 30.1+/-5.7 mg/dL (514.7+/-97.5 micromol/L), and the peak levels ranged from 25.0 to 57.4 mg/dL (428-981.5 micromol/L). Thirty-three (35.5%) of the 93 babies had TSB levels of 30 mg/dL (513 micromol/L) or greater. Eighty-nine of 93 infants were being exclusively breast-fed. Nineteen babies were isoimmunized, 7 were bacteremic, 2 of the 39 babies tested for glucose-6-phosphate dehydrogenase had this enzyme deficiency, and 1 of the 71 infants tested for thyroid function had hypothyroidism. No cause for extreme hyperbilirubinemia was found in 61 (65.6%) cases.
Topics: Bilirubin; Blood Group Incompatibility; Female; Gestational Age; Glucosephosphate Dehydrogenase Deficiency; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Jaundice, Neonatal; Male; Medical Records; Phototherapy; Retrospective Studies; Turkey
PubMed: 16708139
DOI: 10.1177/000992280604500308 -
The Journal of Clinical Endocrinology... Apr 1999Sulfation is an important pathway of thyroid hormone metabolism that facilitates the degradation of the hormone by the type I iodothyronine deiodinase, but little is...
Sulfation is an important pathway of thyroid hormone metabolism that facilitates the degradation of the hormone by the type I iodothyronine deiodinase, but little is known about which human sulfotransferase isoenzymes are involved. We have investigated the sulfation of the prohormone T4, the active hormone T3, and the metabolites rT3 and 3,3'-diiodothyronine (3,3'-T2) by human liver and kidney cytosol as well as by recombinant human SULT1A1 and SULT1A3, previously known as phenol-preferring and monoamine-preferring phenol sulfotransferase, respectively. In all cases, the substrate preference was 3,3'-T2 >> rT3 > T3 > T4. The apparent Km values of 3,3'-T2 and T3 [at 50 micromol/L 3'-phosphoadenosine-5'-phosphosulfate (PAPS)] were 1.02 and 54.9 micromol/L for liver cytosol, 0.64 and 27.8 micromol/L for kidney cytosol, 0.14 and 29.1 micromol/L for SULT1A1, and 33 and 112 micromol/L for SULT1A3, respectively. The apparent Km of PAPS (at 0.1 micromol/L 3,3'-T2) was 6.0 micromol/L for liver cytosol, 9.0 micromol/L for kidney cytosol, 0.65 micromol/L for SULT1A1, and 2.7 micromol/L for SULT1A3. The sulfation of 3,3'-T2 was inhibited by the other iodothyronines in a concentration-dependent manner. The inhibition profiles of the 3,3'-T2 sulfotransferase activities of liver and kidney cytosol obtained by addition of 10 micromol/L of the various analogs were better correlated with the inhibition profile of SULT1A1 than with that of SULT1A3. These results indicate similar substrate specificities for iodothyronine sulfation by native human liver and kidney sulfotransferases and recombinant SULT1A1 and SULT1A3. Of the latter, SULT1A1 clearly shows the highest affinity for both iodothyronines and PAPS, but it remains to be established whether it is the prominent isoenzyme for sulfation of thyroid hormone in human liver and kidney.
Topics: Adult; Humans; Isoenzymes; Kinetics; Substrate Specificity; Sulfotransferases
PubMed: 10199779
DOI: 10.1210/jcem.84.4.5590 -
Hypertension (Dallas, Tex. : 1979) Jan 1998Angiotensin converting enzyme (ACE) inhibitors augment circulating levels of the vasodilator peptide angiotensin-(1-7) [Ang-(1-7)] in man and animals. Increased...
Angiotensin converting enzyme (ACE) inhibitors augment circulating levels of the vasodilator peptide angiotensin-(1-7) [Ang-(1-7)] in man and animals. Increased concentrations of the peptide may contribute to the antihypertensive effects associated with ACE inhibitors. The rise in Ang-(1-7) following ACE inhibition may result from increased production of the peptide or inhibition of the metabolism of Ang-(1-7)-similar to that observed for bradykinin. To address the latter possibility, we determined whether Ang-(1-7) is a substrate for ACE in vitro. In a pulmonary membrane preparation, the ACE inhibitor lisinopril attenuated the metabolism of low concentrations of 125I-Ang-(1-7). The primary product of 125I-Ang-(1-7) metabolism was identified as Ang-(1-5). Using affinity-purified ACE from canine lung, HPLC separation and amino acid analysis revealed that ACE functioned as a dipeptidyl carboxypeptidase cleaving Ang-(1-7) to the pentapeptide Ang-(1-5). The ACE inhibitors lisinopril and enalaprilat (1 micromol/L), as well as the chelating agents EDTA, o-phenanthroline, and DTT (0.1-1 mmol/L) abolished the generation of Ang-(1-5) and did not yield other metabolic products. Ang-(1-5) was not further hydrolyzed by ACE. Kinetic analysis of the hydrolysis of Ang-(1-7) by ACE revealed a substrate affinity of 0.81 micromol/L and maximal velocity of 0.65 micromols min(-1) mg(-1). The calculated turnover constant for the peptide was 1.8 sec(-1) with a catalytic efficiency (Kcat/Km) of 2200 sec(-1) mmol/L(-1). These findings suggest that increased levels of Ang-(1-7) following ACE inhibition may be due, in part, to decreased metabolism of the peptide.
Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Cell Membrane; Dogs; Humans; Kinetics; Lisinopril; Lung; Models, Chemical; Peptide Fragments; Peptidyl-Dipeptidase A
PubMed: 9453329
DOI: 10.1161/01.hyp.31.1.362 -
The Journal of Clinical Endocrinology... May 1997Benign prostatic hyperplasia (BPH) is a common disease of aging men. Current medical treatment for this condition is only partially effective, therefore many patients...
Benign prostatic hyperplasia (BPH) is a common disease of aging men. Current medical treatment for this condition is only partially effective, therefore many patients must undergo surgery for symptomatic relief. BPH is caused by an increase in prostate epithelial and stromal cells, especially the latter. Since BPH stromal cells have a long life span and are not very responsive to androgen withdrawal, cultured BPH stromal cells were used to explore the feasibility of pharmacologically inducing apoptosis in these cells. We obtained BPH tissue during surgery, and stromal cells were isolated and maintained in culture. After cells achieved confluence, we induced apoptosis with the HMGCoA reductase inhibitor, lovastatin (30 micromol/L). The effects of testosterone (100 micromol/L), dihydrotestosterone (DHT; 100 micromol/L) and finasteride (100 micromol/L) on lovastatin-induced apoptosis were studied on cells grown in media containing charcoal stripped serum. Similarly, we examined the effect of the cholesterol pathway metabolites, mevalonic acid (30 micromol/L), geranyl geraniol (30 micromol/L), farnesol (10 micromol/L), squalene (30 micromol/L) and 7-ketocholesterol (3 micromol/L) on lovastatin-induced apoptosis. We demonstrated apoptosis by DNA laddering in agarose gels, by fluorescence microscopy following acridine orange staining, and by flow cytometry after end-labeling of DNA strand breaks with biotin-16-dUTP using deoxynucleotidyl exotransferase (TdT). Lovastatin at 30 micromol/L, but not at lower concentrations, induced apoptosis in BPH prostate stromal cells. This was seen (by flow cytometry) in 16.6 +/- 7.3% (mean +/- SD) of BPH cells treated with lovastatin at 72 h vs. 2.5 +/- 1.2% of cells treated with ethanol. Lovastatin-induced apoptosis was not increased in stripped serum or by the addition finasteride, and was not inhibited by testosterone or DHT. Only mevalonate and geranyl geraniol, prevented lovastatin-induced apoptosis whereas farnesol, squalene, or 7-ketocholesterol did not. We conclude that lovastatin can induce apoptosis in BPH stromal cells in vitro, and this is not affected by androgen withdrawal or stimulation. It is unlikely that lovastatin, per se, will be an effective treatment for BPH in vivo, but it does provide a means for inducing apoptosis in vitro. Understanding the apoptotic process in BPH stromal cells ultimately may lead to new therapeutic strategies for BPH.
Topics: Apoptosis; Cholesterol; DNA; Dihydrotestosterone; Diterpenes; Enzyme Inhibitors; Finasteride; Flow Cytometry; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kinetics; Lovastatin; Male; Mevalonic Acid; Prostate; Prostatic Hyperplasia; Stromal Cells; Testosterone
PubMed: 9141529
DOI: 10.1210/jcem.82.5.3960