RESUMO
BACKGROUND & AIM: PTC923 (formerly CNSA-001), an oral formulation of sepiapterin, a natural precursor of intracellular tetrahydrobiopterin (BH4), has been shown in humans to induce larger increases in circulating BH4 vs. sapropterin dihydrochloride. Sapropterin reduces blood phenylalanine (Phe) by ≥20-30% in a minority of subjects with PKU. This was a Phase 2 randomized, multicenter, three-period crossover, open-label, active controlled, all-comers [regardless of phenylalanine hydroxylase (PAH) variants] comparison of PTC923 60â¯mg/kg, PTC923 20â¯mg/kg and sapropterin 20â¯mg/kg in 24 adults with phenylketonuria (PKU) and hyperphenylalaninemia. METHODS: Eligible subjects were adult men or women (18-60 y) with PKU. Subjects enrolled received 7â¯days of once-daily oral treatment with PTC923 20â¯mg/kg/day, PTC923 60â¯mg/kg/day and sapropterin dihydrochloride 20â¯mg/kg/day each in a random order. Treatments were separated by a 7-day washout. Subjects maintained their usual pre-study diet, including consumption of amino acid mixtures. Blood Phe was measured on Day 1 (predose baseline), Day 3, Day 5, and Day 7 of each treatment period. RESULTS: Least squares mean changes (SE) from baseline in blood Phe were: -206.4 (41.8) µmol/L for PTC923 60â¯mg/kg (pâ¯<â¯0.0001); -146.9 (41.8) µmol/L for PTC923 20â¯mg/kg (pâ¯=â¯0.0010); andâ¯-â¯91.5 (41.7) µmol/L for sapropterin (pâ¯=â¯0.0339). Effects of PTC923 60â¯mg/kg on blood Phe vs. sapropterin were significantly larger (pâ¯=â¯0.0098) and faster in onset with a significantly larger mean reduction in blood Phe at day 3 of treatment, pâ¯=â¯0.0135 (20â¯mg/kg) and pâ¯=â¯0.0007 (60â¯mg/kg). Only PTC923 60â¯mg/kg reduced blood Phe in classical PKU subjects (nâ¯=â¯11, pâ¯=â¯0.0287). The mean blood Phe reduction (PTC923 60â¯mg/kg) in a cofactor responder analysis (nâ¯=â¯8; baseline Phe ≥300⯵mol/L and blood Phe reduction ≥30%) was -463.3⯵mol/L (SE 51.5) from baseline. Adverse events were mostly mild to moderate, transient, and similar across treatment groups with no serious adverse events or discontinuations. CONCLUSIONS: The substantially significantly better effect of PTC923 60â¯mg/kg on blood Phe reduction vs. sapropterin supports further clinical development of PTC923 for PKU; ANZCTR number, ACTRN12618001031257.
Assuntos
Fenilalanina/sangue , Fenilcetonúrias/tratamento farmacológico , Pterinas/uso terapêutico , Adolescente , Adulto , Biopterinas/análogos & derivados , Biopterinas/líquido cefalorraquidiano , Estudos Cross-Over , Feminino , Humanos , Masculino , Fenilalanina/administração & dosagem , Fenilcetonúrias/sangue , Pterinas/efeitos adversos , Adulto JovemRESUMO
We summarize the pediatric health care system in Georgia. In the 1990s, the socialist health insurance system was abandoned and replaced by a private health insurance system. In general, Georgia has a relatively high number of physicians per capita, and there are 3 times as many physicians per unit of population in Tbilisi than in other region. Furthermore, the country's universities produce far more physicians than needed. Currently, there are approximately 3000 pediatricians. The Georgian National Center of Disease Control provides guidelines for early detection and screening of diseases, immunization, and mother and child health care. Although Georgia has a limited health budget, it has performed major health reforms. It aims at achieving the highest possible standard of care for children with chronic and disabling conditions, however, future development will depend on the access to more advanced diagnostic and therapeutic technologies.