Background: Replacement therapy with plasma-derived C1-inhibitor (C1-INH) has been used for decades to treat patients with hereditary angioedema (HAE) with C1-INH deficiency. Objective: This article reviewed the rationale for using C1-INH replacement therapy in patients with HAE and the process of manufacturing plasma-derived C1-INH. Methods: The manufacture of C1-INH is an involved and carefully monitored process that includes screening and selection of prospective donors, the collection of source plasma, and purification with dedicated pathogen reduction steps. Donor eligibility is determined by restrictive criteria established and monitored by regulatory agencies as well as voluntary standards implemented by plasma collection centers that exceed government regulations. Individual and pooled donations are tested for transfusion-transmissible infections, including hepatitis B virus, hepatitis C virus, human immunodeficiency virus, parvovirus B19, and hepatitis A virus, by using enzyme-linked immunosorbent assays or nucleic acid amplification technologies. Frozen plasma that is cleared for manufacturing undergoes controlled thawing and centrifugation, and the resulting supernatant (i.e., cryoprecipitate-depleted plasma) is used to manufacture several plasma-derived therapies, including C1-INH. In addition to chromatography steps, the manufacturing process consists of dedicated and effective pathogen reduction steps, including pasteurization, hydrophobic interaction chromatography or polyethylene glycol precipitation, and virus filtration. Manufacturers continuously monitor the safety profile of C1-INH products by robust pharmacovigilance processes that enable systematic collection and evaluation of all suspected adverse drug reaction reports as well as evaluation of safety information from all other sources. Results and Conclusion: These procedures used in donor screening, donation and manufacturing pool testing, manufacturing, and pharmacovigilance ensure that plasma-derived C1-INH products have the safety, quality, identity, potency, and purity that is necessary to provide the intended therapeutic effect.

The antimycobacterial effects of benzylamines are not related to an inhibition of aminoacyl-tRNA synthetases.

Experiments on the P 388 D1 cell line (48 h exposure) demonstrate that [1,2-bis-(fluorophenyl)ethylenediamine]platinum(II) complexes are comparably active on the cell number and 3H-thymidine incorporation, irrespective of the position of the fluorine atom (ortho, meta, or para) and the nature of the "leaving group" (Cl- or H2O). However, the compounds of the R,R/S,S series are more active than those of the R,S series and comparable to cisplatin. In the "tumor colony forming assay" the R,R/S,S configurated compounds are about ten times as active as cisplatin. The R,R/S,S configurated diaqua[1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) salts reach their half maximum effect more readily (t1/2 approximately equal to 1.6 h) than their R,S configurated analogues (t1/2 approximately equal to 20 h). A time limited contact of the cells with R,R/S,S configurated diaqua[1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) salts (-1h) leads to a similar inhibition like a permanent drug exposure indicating a fast uptake of the complex by the tumor cell. In experiments on the Ehrlich ascites tumor of the mouse and on the L 1210 leukemia cell line R,R/S,S-[1,2-bis(4-fluorophenyl)ethylenediamine]dichloroplatinum(II) turns out to be equipotent with cisplatin.

The synthesis of the diastereomeric 1,2-bis(2-,3-and 4-fluorophenyl)ethylenediamines 4-6, lo-12 from meso-1,2-bis(2-hydroxyphenyl)ethylenediamine and 2-, 3-and 4-fluorobenzaldehyde by a diaza-Cope-rearrangement and their conversion into the [1,2-bis(2-, 3-and 4-fluorophenyl)ethylenediamine]dihaloplatinum (II) complexes (Hal = Cl, 13-M; Hal = I, 19-24) with K,PtHal, is described. From the diiodoplatinum(I1) complexes (19-24) the better water soluble diaqua[l,Zbis(2-, 3-and 4-fluorophenyl)ethylenediamine]platinum(II) sulfates (25-30) and [1,2-bis(4fluorophenyl)ethylenediamine]dinitratoplatinum (II) complexes (31 and 32) are obtained by reacting with Ag2S04 or AgNOs. On the P388Di leukemia cell line the racemic platinum (II) complexes are more active than their meso-analogues and equiactive with cis-platin. The position of the fluorine atom and the kind of the leaving group do not influence the activity. RbumC-Synthese des diastCrkoisomi%res 1,2-bis(2-,3-et 4-fluoroph&yl)6thyl&nediamines 4-6, lo-12 g partir de m&o 1,2-bis(2-hydroxyphCnyl)&hyl&nediamine et de 2-,3-et 4-fluorobenzaldbhyde par la transposition de diaza-Cope et leur transformation en complexes [1,2-bis(2-,3-et 4-fluorophCnyl)6thylkwdi~e]dihaIoplatine (II) (Hal = Cl: 13-18; Hal = I: 19-24) g I'aide de K,PtH&. A partir des complexes de diiodoplatine (ZZ) (19-24), on obtient des composes plus hydrosolubles tels des sulfates de diaquaplatine (ZZ) [I,2-bis(Juoro-2,-3 et 4 phenyl)tthylenediamine] (25-30) et des [1,2-bis(4-fluorophenyl) tthylenediamine]dinitratoplatine (ZZ) complexes (31 et 32) par reaction avec Ag2S04 et AgN03 respectivement. Dans les cellules en lignees de leucemie P388Dt, les complexes racemiques de platine (ZZ) sont plus actifs que leurs analogues meso et aussi actifs que le cis-platine. La position du jluor et la nature du groupe partant n'influencent pas l'activite. diastereomeric l,%bis(2-,3-and 4-fluorophenyl)ethylenediamines / d&a-Cope-rearrangement / [1,2-bis(2-,3-and 4luoropbenyl)ethylenediamine] dihaIopIatinum(I1) complexes / diaqua[l,Zbis(2-,3-and 4-fluorophenyl)ethylenediamine] platinum(II) spits / P388D1 leukemia cell line/structure activity-relationship

Amino acid antagonists with proven or potentially inhibitory activities on aminoacyl-tRNA synthetases were tested for their antiproliferative effect against E. coli B. The compounds 4- and 6-fluoro-tryptophan, 5-methyltryptophan, selenocystine and beta-(2-thienyl)alanine gave strong growth inhibition in minimal medium, which disappeared after addition of structurally related natural amino acids or in an enriched broth. The inhibitory effect on amino-acyl-tRNA synthetases and the minimal inhibitory concentration for growth inhibition in minimal medium could not be correlated.