1 / 34

NeoPhe in the Treatment of Phenylketonuria New Formulation of LNAA

NeoPhe in the Treatment of Phenylketonuria New Formulation of LNAA. 2 nd Ukraine Congress On Clinical Genetics October 2005. Ukraine Elena Grechanina Russia Peter Novikov Denmark Jytte Bieber Nielsen Leah Brammer Kirstin Ahring USA Reuben Matalon, M.D., Ph.D. Kim Matalon.

edan-stevens
Download Presentation

NeoPhe in the Treatment of Phenylketonuria New Formulation of LNAA

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. NeoPhe in the Treatment of PhenylketonuriaNew Formulation of LNAA 2nd Ukraine Congress On Clinical Genetics October 2005

  2. UkraineElena GrechaninaRussiaPeter Novikov DenmarkJytte Bieber NielsenLeah BrammerKirstin AhringUSAReuben Matalon, M.D., Ph.D.Kim Matalon

  3. Large Neutral Amino Acids (LNAA) • Phenylalanine (Phe) • Leucine • Tyrosine • Tryptophan • Methionine • Histidine • Isoleucine • Valine • Threonine

  4. Transport of LNAA to the Brain Km mmol/L Km app • Phenylalanine (Phe) 0.12 0.45 • Leucine 0.15 0.53 • Tyrosine 0.16 0.58 • Tryptophan 0.19 0.71 • Methionine 0.19 0.77 • Histidine 0.28 1.10 • Isoleucine 0.33 1.30 • Valine 0.63 2.50 • Threonine 0.73 3.00 Pardridge, Inborn Errors of Metabolism in Humans. MTP Press, 1980.

  5. Andersen AE, Avins L • LNAA injected to rat pups • Phenylalanine hydroxylase was ihibited by parachlorophenylalanine • Brain phenylalanine decreased 1976 Arch Neurology 33:684

  6. Tyrosine in The Treatment of PKU Lou et al used Tyr 160 mg/kg in treated patients with PKU • Increased attention span • Increased dopamine synthesis 1987 Acta Paediatr Scand 76:560

  7. Tyrosine in Treatment of PKU • Pietz et al. used high dose tyrosine in adults with PKU and high blood Phe • No difference in treated group vs placebo 1995 J Pediatr 127:936

  8. Tryptophan in Treated PKU • Nielsen et al used tryptophan 4.5 gm/day to treated PKU for 3 weeks • Showed a 3 fold increase in 5-HIAA in CSF despite high blood Phe 1988 Dietary Phenylalanine and Brain Function. Birkhauser

  9. LNAA Supplementation in PKU • Dotremont et al. used LNAA and a low protein diet 0.6 gm/kg on 4 patients with PKU • After 1 month subjects found with negative nitrogen balance • Lysine was limiting amino acid 1995 J Inherit Metab Dis 18:127

  10. Km (app) – Km (1 + ∑[aa]/Km] This predicts that, if the plasma level of an LNAA is much less than its value of Km, then that amino acid will not compete effectively for the carrier protein

  11. LNAA Transport in Intestinal Mucosa Km mmol/L • Phenylalanine 1.0 • Leucine 2.0 • Valine 3.0 • Methionine 5.0 • Histidine 6.0 • Competition effect is not likely to occur in tissue other than brain unless high concentration of amino acids is used Pardridge, Inborn Errors of Metabolism in Humans. MTP Press, 1980.

  12. Hidalgo Biochem Biophys. Acta 1008: 5-30a (1990)

  13. PKU Mice on NeoPhe phe mg/dl Mice Control NeoPhe

  14. PKU Mice on NeoPhe phe mg/dl Mice Control NeoPhe

  15. Denmark LNAA STUDY1 tablet/kg/day

  16. Denmark LNAA STUDY2 tablets/kg/day

  17. Russia LNAA STUDY

  18. Russia LNAA STUDY

  19. Russia LNAA Study

  20. USA LNAA STUDY

  21. USA LNAA STUDY

  22. µmol/l1260 870 960 474 762 426 780

  23. µmol/l1200 828 765 624

  24. US Blood Phe and TyrNeoPhe Patient K 1 Weekµmol/L (mg)

  25. US Blood Phe and TyrNeoPhe Patient G 1 Weekµmol/L (mg)

  26. NeoPhe 0.5 g/kg in PKU Subjects • 13 subjects • Mean age 26.6 years • 7 males, 6 females • Mean decrease in blood Phe after one week 243 µmol/L • Average decrease in blood Phe 22 %.

  27. NeoPhe 1.0 g/kg in PKU Subjects • 7 subjects • Mean age 25.2 years • 5 males, 2 females • Mean decrease in blood Phe after one week 377 µmol/L • Average decrease in blood Phe 25 %.

  28. Figure 1. Blood Phe Response to 0.5g/kg NeoPhe in Patients withPKU Paired t-test: p=0.001

  29. Figure 2. Blood Phe Response to 1.0 g/kg NeoPhe in Patients withPKU Paired t-test: p=0.006

  30. CONCLUSIONS • For the first time mixture of LNAA can lower blood phenylalanine • Using NeoPhe avoids lysine deficiency and negative nitrogen balance • NeoPhe offers new options to treat PKU • Diet can be more liberal with NeoPhe • Still blood phe levels need to be controlled

  31. Acknowledgement Participants in the study Professor Elena Grechanina Kharkiv, Ukraine Professor Peter Novikov Moscow, Russia Dr. Jytte Bieber Nielsen Glostrup, Denmark

More Related