Clinical implementation of 4-dihydroxyborylphenylalanine synthesised by an asymmetric pathway.
Boron neutron capture therapy (BNCT) is an experimental therapeutic modality combining a boron pharmaceutical with neutron irradiation. 4-Dihydroxyborylphenylalanine (L-BPA) synthesised via the asymmetric pathway by Malan and Morin [Synlett. 167-168 (1996)] was developed to be the boron containing pharmaceutical in the first series of Finnish BNCT clinical trials. The final product was >98.5% chemically pure L-BPA with L-phenylalanine and L-tyrosine as the residual impurities. The solubility of L-BPA was enhanced by complex formation with fructose (BPA-F). The pH and osmolarity of the BPA-F preparation is in the physiological range. Careful attention was given to the pharmaceutical quality of the BPA-F preparations. Prior to starting clinical trials the acute toxicity of L-BPA was studied in male albino Sprague-Dawley rats. In accordance with earlier studies no adverse effects were observed. After completion of the development work L-BPA solution was administered to brain tumour patients in conjunction with clinical studies for development and testing of BPA-based BNCT. No clinically significant adverse events attributable to the L-BPA i.v. infusions were observed. We conclude that our synthesis development, complementary preclinical and clinical observations justify the safe use of L-BPA up to clinical phase III studies with L-BPA produced by the asymmetric pathway, originally presented by Malan and Morin in 1996.
Kulvik
Martti
M
Department of Neurology, Helsinki University Central Hospital, PO Box 220, FIN-00029 HUS, Helsinki, Finland.
Vähätalo
Jyrki
J
Buchar
Evzen
E
Färkkilä
Markus
M
Järviluoma
Eija
E
Jääskeläinen
Juha
J
Kriz
Otomar
O
Laakso
Juha
J
Rasilainen
Merja
M
Ruokonen
Inkeri
I
Kallio
Merja
M
D000328:Adult; D000368:Aged; D000818:Animals; D001896:Boron Compounds / Q000138:chemical synthesis* / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000097:blood / Q000188:drug therapy*; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013678:Technology, Pharmaceutical / Q000379:methods*
C436045:4-dihydroxyborylphenylalanine; D001896:Boron Compounds; D010649:Phenylalanine