Animals ; Biopterin ; analogs & derivatives ; therapeutic use ; Genetic Therapy ; Humans ; Phenylalanine Ammonia-Lyase ; administration & dosage ; Phenylketonurias ; therapy

OBJECTIVES: To retrospectively analyze the variation and characteristics of phenylalanine hydroxylase (PAH) gene, and to observe the long-term treatment effect and follow-up of newborns with PAH deficiency. METHODS: Clinical data, treatment and follow-up results of 198 patients with PAH deficiency diagnosed by newborn screening in Jinan from 1996 to 2021 were collected. The genetic analysis of 55 patients with PAH deficiency diagnosed by newborn screening in Jinan and 213 patients referred from the surrounding areas of Jinan were summarized. Gene variations were checked by a customized Panel gene detection method. Blood phenylalanine-concentration and physical development indicators including height and weight were regularly monitored. Intellectual development was assessed using a neuropsychological development scale for patients aged 0-6 years and academic performance, and brain injury in patients was assessed using brain magnetic resonance imaging. RESULTS: c.728G>A, c.158G>A, c.721C>T, c.1068C>A, c.611A>G variations were common in PAH gene. The genotype of c.158G>A variation is compound heterozygous variation, with mainly a mild hyperpheny-lalaninemia. 168 patients with PAH deficiency who were followed-up regularly had normal physical development without dwarfism or malnutrition. Among the 33 preschool patients who underwent mental development assessment, 2 were mentally retarded and the initial treatment age was older than 6 months. Nine patients with an average age of (17.13±2.42) years completed brain magnetic resonance imaging, one case was normal, and 8 cases were abnormal. There were patchy or patchy hyperintense foci near the bilateral lateral ventricles on T₂WI, and the intellectual development was normal. Compared with the other eight patients, the blood phenylalanine concentration of the normal child was better and stably controlled within the ideal range. CONCLUSIONS c.728G>A, c.158G>A, c.721C>T, c.1068C>A, c.611A>G variations were common in PAH gene. After standardized treatment, most patients with PAH deficiency diagnosed by screening can obtain normal growth and intellectual development in adolescence, but there are different degrees of organic lesions in the cerebral white matter.
Child ; Child, Preschool ; Adolescent ; Humans ; Infant, Newborn ; Young Adult ; Adult ; Neonatal Screening ; Follow-Up Studies ; Retrospective Studies ; Phenylketonurias/genetics* ; Phenylalanine Hydroxylase/genetics* ; Phenylalanine/therapeutic use* ; Mutation

OBJECTIVETetrahydrobiopterin (BH(4)) responsive phenylalanine hydroxylase (PAH) deficiency is one of the forms of phenylketonuria (PKU). The aim of this study was to screen and diagnose BH(4) responsive PAH deficiency, to further understand its clinical characteristics, and to provide evidence for applying BH(4) drug therapy.

METHODSBH(4) 20 mg/kg loading test was performed in 73 patients with hyperphenylalaninemia (HPA) (47 males and 26 females), the mean age was 1.93 months. Combined phenylalanine (100 mg/kg) and BH(4) loading test was performed if patients had a basic blood phenylalanine concentration less than 600 micromol/L. The urine pterin profile analysis and the dihydropteridine reductase (DHPR) activity in dry blood filter spot were analyzed simultaneously. The patients with BH(4) responsive PAH deficiency were treated with BH(4) tablets (10 - 20 mg/kg x d) under normal diet for 6 to 7 days. Their blood phenylalanine concentration was checked.

RESULTS(1) The characteristic curve of phenylalanine level was observed in 73 patients after BH(4) loading test. Twenty-two patients were diagnosed as classic phenylketonuria (PKU), 39 were moderate PKU and 12 were BH(4) deficiency. (2) Twenty-two (56.4%) of 39 moderate PKU patients were found to be responsive to BH(4) and the blood phenylalanine was decreased by at least 30%. (3) Six patients with BH(4) responsive PAH deficiency were treated with BH(4) for 6 to 7 days, 4 patients had a normal phenylalanine concentration after 10 mg/kg BH(4) supplement, while other 2 patients needed a treatment of BH(4) at 20 mg/kg.

CONCLUSIONSome patients with moderate PKU caused by phenylalanine hydroxylase deficiency were responsive to BH(4). Their blood phenylalanine significantly decreased after oral BH(4) loading. The BH(4) loading test is an effective diagnostic method to detect BH(4) sensitivity in PKU patients. BH(4) responsive PAH deficiency patient could be treated with BH(4) to replace low-phenylalanine diet treatment totally or partially, which may provide an optional treatment for the disease and improve the quality of life of the patients.

Biopterin ; analogs & derivatives ; deficiency ; therapeutic use ; Child, Preschool ; Female ; Humans ; Infant ; Male ; Phenylalanine Hydroxylase ; deficiency ; Phenylketonurias ; diagnosis ; drug therapy

Ultra-high-performance liquid chromatography-Q exactive orbitrap tandem mass spectrometry(UHPLC-QEOrbitrap-MS/MS) was used to explore the inhibitory effect and mechanism of ginkgo flavone aglycone(GA) combined with doxorubicin(DOX) on H22 cells. The effects of different concentrations of GA and DOX on the viability of H22 cells were investigated, and combination index(CI) was used to evaluate the effects. In the experiments, control(CON) group, DOX group, GA group, and combined GA and DOX(GDOX) group were constructed. Then the metabolomics strategy was employed to explore the metabolic markers that were significantly changed after combination therapy on the basis of single medication treatment, and by analyzing their biological significance, the effect and mechanism of the anti-tumor effect of GA combined with DOX were explained. The results revealed that when 30 μg·mL~(-1) GA and 0.5 μmol·L~(-1) DOX was determined as the co-administration concentration, the CI value was 0.808, indicating that the combination of GA and DOX had a synergistic anti-tumor effect. Metabolomics analysis identified 23 metabolic markers, including L-arginine, L-tyrosine and L-valine, mostly amino acids. Compared with the CON group, 22 and 17 metabolic markers were significantly down-regulated after DOX treatment and GA treatment, respectively. Compared with the DOX and GA groups, the treatment of GA combined with DOX further down-regulated the levels of these metabolic markers in liver cancer, which might contribute to the synergistic effect of the two. Five key metabolic pathways were found in pathway enrichment analysis, including glutathione metabolism, phenylalanine metabolism, arginine and proline metabolism, β-alanine metabolism, and valine, leucine and isoleucine degradation. These findings demonstrated that the combination of GA and DOX remarkably inhibited the viability of H22 cells and exerted a synergistic anti-tumor effect. The mechanism might be related to the influence of the energy supply of tumor cells by interfering with the metabolism of various amino acids.
Arginine/therapeutic use* ; Doxorubicin/therapeutic use* ; Flavones/therapeutic use* ; Ginkgo biloba/chemistry* ; Glutathione ; Humans ; Isoleucine/therapeutic use* ; Leucine/therapeutic use* ; Liver Neoplasms/drug therapy* ; Metabolomics/methods* ; Phenylalanine/therapeutic use* ; Proline ; Tandem Mass Spectrometry/methods* ; Tyrosine/therapeutic use* ; Valine/therapeutic use* ; beta-Alanine/therapeutic use*

OBJECTIVETo emphasize early differential diagnosis from patients with hyperphenylalaninemia (HPA) and to evaluate the treatment and long-term outcome of patients with tetrahydrobiopterin synthase (BH4) deficiency in Northern Chinese population.

METHODSFrom 1992 to 2005, a total of 618 patients with HPA were diagnosed and/or cared for in our outpatient clinic. Urinary pterin analysis, detection of dihydropteridine reductase (DHPR) activity in blood, and then BH4 loading tests were carried out to differentiate BH4 deficiency in these patients from classical phenylketonuria. BH4 deficient patients were treated with BH4, levodopa and 5-hydroxytryptophane (5-HTP) immediately while the diagnosis was done to disease. Patientso blood phenylalanine levels, psychomotor and intelligence development were followed up.

RESULTSA total of 38 cases were diagnosed as BH4 deficiency, all of them were revealed as 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency from the extremely decreased urine biopterin, normal DHPR activities and drop down of blood phenylalanine level to normal range within 4 to 8 hours after BH4 loading. The most common manifestations were progressively psychomotor and mental retardation to patients even after taking early dietary treatment. The patients were diagnosed and treated with drugs at the ages of 2.1 months to 13 years. With 4 patients died of pneumonia, 7 patients refused to treatment, only 27 patients were under treatment and followed up. The average full scale development or intelligence quotient (DQ/IQ) of patients who were treated within and after 6 months were 86+/- 10 or 66+/- 7 respectively. Development was not even in different aspects. A significant negative correlation was observed between the level of the DQ and the age of treatment commenced (r was -0.714, P< 0.01). Eleven patients experienced the extrapyramidal movement disorders, 3 of them combined with epilepsy. The extrapyramidal disorders were controlled by administration of levodopa.

CONCLUSIONThe differential diagnosis for BH4 deficiency should be carried out in all patients with HPA. PTPS deficiency is the most common form of BH4 deficiency in Northern Chinese population. The long-term outcome of these patients benefits from diagnosis and treatment with BH4, levodopa and 5-HTP as early as possible.

5-Hydroxytryptophan ; therapeutic use ; Asian Continental Ancestry Group ; genetics ; Biopterin ; analogs & derivatives ; deficiency ; therapeutic use ; Child, Preschool ; China ; Dihydropteridine Reductase ; blood ; Humans ; Infant ; Levodopa ; therapeutic use ; Phenylalanine ; blood ; Phenylketonurias ; drug therapy ; genetics ; metabolism ; Phosphorus-Oxygen Lyases ; deficiency ; genetics

OBJECTIVETo analyze characteristics of different hyperphenylalaninemia (HPA) and to discuss the clinical difference between southern and northern Chinese patients with tetrahydrobiopterin (BH4) responsive phenylalanine hydroxylase (PAH) deficiency.

METHODS(1)BH4 (20 mg/kg) loading test was performed in all 108 HPA patients. These patients, 63 males and 45 females, were at a mean age of 7.05 months. A combined phenylalanine (Phe) and BH4 loading test was carried out in the patients who had a basic blood Phe concentration less than 600 micromol/L. The urine pterine profile analysis and the dihydropteridine reductase (DHPR) activity in dry blood filter spot were analyzed simultaneously. (2)BH4 responsive patients were divided to southern and northern groups by their parent's native place and geographic boundary determined by Changjiang River. The change of Phe concentration after BH4 loading test was compared between the two groups.

RESULTS(1)Among the 108 HPA cases, 36 patients (33.3%) were BH4 responsive PAH deficiency, 49 (45.4%) were non-BH4 no responsive phenylketonuria (PKU)and 23(21.3%)were BH4 deficiency (BH4D). The Phe concentration of patients with BH4 responsive PAH deficiency decreased by 49.24% and 65.35% at 8 h and 24 h after oral BH4, 23 in southern group and 13 in northern group among 36 patients. (2)The mean Phe concentration at 24 h after loading test in southern and northern groups were (217.02+/-189.03) micromol/L and 458.75+/-342.54 micromol/L respectively (P<0.05), although the decrease percent of plasma Phe concentration at 2 h, 4 h, 8 h, 24 h was no distinct difference between southern and northern groups (P>0.05).

CONCLUSIONMost of mild and moderate HPA patients affected by PAH deficiency show plasma Phe concentration decrease >30% in 24 h after oral BH4 20 mg/kg, few are classic PKU. The responsiveness to BH4 is no difference between southern and northern Chinese patients with BH4 responsive PAH deficiency according to the decrease percent of plasma Phe concentration, although the Phe concentration is lower in southern patients than that in northern patients.

Biopterin ; analogs & derivatives ; pharmacology ; therapeutic use ; Child, Preschool ; China ; Dihydropteridine Reductase ; blood ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Phenylalanine ; blood ; Phenylketonurias ; blood ; drug therapy ; Time Factors

OBJECTIVETo evaluate the efficacy and safety of nateglinide, a new antidiabetic agent, in the treatment of type 2 diabetes.

METHODSA total of 219 treatment-naïve patients with type 2 diabetes from 6 centers were enrolled in this study and blindly divided into nateglinide group (n = 105) and repaglinide group (n = 114). In all patients, the disease was confirmed for at least three months. The whole observation lasted for 12 weeks. The efficacy indicators measured include glycohemoglobin A1c (HbA1c), fasting blood glucose, and 2 hours postprandial blood glucose, and the safety parameters measured included renal and hepatic function, serum lipids, and blood and urea profiles.

RESULTSSimilar decreases in fasting blood glucose, 2 hours postprandial blood glucose, and HbA1 c were found in both nateglinide group and repaglinide group without significant differences. No severe adverse events were noted. The hypoglycemia event reports were not significantly different between these two groups.

CONCLUSIONNateglinide is an effective and safe drug in treating type 2 diabetes.

Blood Glucose ; drug effects ; Cyclohexanes ; administration & dosage ; adverse effects ; therapeutic use ; Diabetes Mellitus, Type 2 ; drug therapy ; Drug Administration Schedule ; Female ; Humans ; Hypoglycemic Agents ; administration & dosage ; adverse effects ; therapeutic use ; Male ; Middle Aged ; Phenylalanine ; administration & dosage ; adverse effects ; analogs & derivatives ; therapeutic use ; Treatment Outcome