title: Clinical implementation of 4-dihydroxyborylphenylalanine synthesised by an asymmetric pathway.
abstract: 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.
authors.affiliation: Department of Neurology, Helsinki University Central Hospital, PO Box 220, FIN-00029 HUS, Helsinki, Finland.
authors.forename: Martti
authors.initials: M
authors.lastname: Kulvik
authors.forename: Jyrki
authors.initials: J
authors.lastname: Vähätalo
authors.forename: Evzen
authors.initials: E
authors.lastname: Buchar
authors.forename: Markus
authors.initials: M
authors.lastname: Färkkilä
authors.forename: Eija
authors.initials: E
authors.lastname: Järviluoma
authors.forename: Juha
authors.initials: J
authors.lastname: Jääskeläinen
authors.forename: Otomar
authors.initials: O
authors.lastname: Kriz
authors.forename: Juha
authors.initials: J
authors.lastname: Laakso
authors.forename: Merja
authors.initials: M
authors.lastname: Rasilainen
authors.forename: Inkeri
authors.initials: I
authors.lastname: Ruokonen
authors.forename: Merja
authors.initials: M
authors.lastname: Kallio
mesh_terms: 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*
chemical_list: C436045:4-dihydroxyborylphenylalanine; D001896:Boron Compounds; D010649:Phenylalanine