Determination of NTBC in serum samples from patients with hereditary tyrosinemia type I by capillary electrophoresis.

Hereditary tyrosinemia type I is a serious metabolic disorder leading to liver failure. 2-(2-Nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) is a relatively new drug which is used to prevent the accumulation of toxic metabolites in patients with hereditary tyrosinemia type I. In the present study, we have developed a new, simple, fast, and cost-effective capillary electrophoresis method for the quantitative monitoring of this drug in serum samples. Micellar electrochromatographic separation of NTBC was performed using 20 mmol/L phosphate and 40 mmol/L sodium dodecylsulfate (SDS) at pH 12 as running electrolyte. Separation of NTBC was achieved in around 4 min. Reproducibilities of migration times and corrected peak areas of NTBC (as R.S.D.%) were found as 0.73 and 1.99, respectively. The detection limit was 3.17 and the quantification limit was 10.6 micromol/L for NTBC using UV detection at 278 nm. The utility of the method was demonstrated by the detection of NTBC in serum samples from patients with hereditary tyrosinemia type I using this drug.

Clinical practice. NTBC therapy for tyrosinemia type 1: how much is enough?

UNLABELLED: Four patients with tyrosinemia type 1 (ages 6-32 months) were treated with 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexandion (NTBC) at Cairo University Children's Hospital, Egypt and followed up for 12-27 months. The recommended average dose of NTBC is 1 mg/kg/day. They were started on the following doses: 0.8, 0.58, 0.5, and 0.625 mg/kg/day, respectively. Two months after start of therapy, succinylacetone was undetectable in patients 1, 2, and 4, while in case 3, it was 5.4 microM. Her NTBC dose was increased from 0.5 to 0.65 mg/kg/day, and succinylacetone was undetectable 1 month later. They were kept on NTBC doses ranging from 0.55 to 0.65 mg/kg/day. These doses allowed catch up growth, normalization of synthetic liver functions, steep drop in serum alpha fetoprotein, reduction in phosphate loss in urine, normalization of serum calcium, phosphate, and alkaline phosphatase, and healing of active rickets. Succinylacetone was undetectable in urine on these doses. IN CONCLUSION: Doses of NTBC, lower than recommended, may be helpful in treatment of tyrosinemia, on condition that succinylacetone production is suppressed, and AFP is maintained normal or showing a progressive decrease. This cost-effective dose may allow treatment of affected children from economically underprivileged countries, but longer follow up periods are needed.

Nitisinone: new drug. Type 1 tyrosinemia: an effective drug.

(1) Type 1 hereditary tyrosinemia is a rare disease due to an enzyme deficiency. It is associated with life-threatening liver disorders, starting during the very first months of life. If left untreated (other than with a diet low in tyrosine and phenylalanine), most patients die during childhood. Liver transplantation is currently the only treatment to have an effect on survival. (2) Nitisinone is the first drug to be approved in Europe for the treatment of type 1 hereditary tyrosinemia. (3) An international non comparative trial included 207 patients treated with nitisinone in addition to a diet low in tyrosine and phenylalanine. Children treated before the age of 6 months had a far better four-year survival rate than patients treated previously with dietary measures alone (94% versus 60%). The difference was even greater in the subgroups treated before the age of two months (88% versus 29%). When disease onset occurred after the age of 6 months, the ten-year survival rate was about 85% with nitisinone, compared to 60% with dietary measures alone. Only one patient had a neurological crisis during nitisinone therapy. Early nitisinone treatment also reduced the incidence of liver transplantation (13%, compared to 25% with dietary measures alone). (4) Nitisinone seems to have few adverse effects, mainly consisting of thrombocytopenia, leukopenia, cutaneous disorders, and various visual disorders (most of which resolve spontaneously). There may also be a risk of seizures. (5) In practice, nitisinone seems to provide a major benefit for children with type 1 tyrosinemia, provided they are diagnosed and treated during the first 6 months of life. Adverse effects appear to be acceptable but need to be monitored.