The first medical cure of Acanthamoeba keratitis was obtained by use of propamidine isethionate. Since then, it has been the basic drug recommended for use in treatment. Because some Acanthamoeba strains have been reported to be resistant to propamidine and propamidine was found to be only weakly cysticidal, superior homologs such as butamidine, pentamidine, hexamidine, heptamidine, octamidine, and nonamidine were tested for their amoebicidal effects on two Acanthamoeba strains isolated from patients with keratitis. Trophozoicidal and cysticidal efficiencies were found to be increased from propamidine to nonamidine; i.e., when the alkyl chain connecting the two benzene rings in their molecular structures was elongated, in comparison with propamidine, hexamidine and octamidine were the most amoebicidal molecules. As a result of these data, a kinetic study carried out on propamidine, hexamidine, and octamidine demonstrated that the amoebicidal effects resulted from two events: the diffusion of molecules through the plasma membrane or the double wall of trophozoites or cysts, respectively, and the lethal effects of molecules on amoebic protoplasm. The diffusion kinetics were increased when the alkyl chain was elongated, i.e., with an increase in the lipophilic properties of molecules. In contrast, the lethal effect kinetics were found to be unchanged by this elongation, indicating that they originated from the cationic surface-active properties induced by the protonated amidine groups attached to each benzene ring, which themselves remained unchanged from one molecule to the other. These results strongly advocate the immediate replacement of propamidine by hexamidine in the medical treatment of Acanthamoeba keratitis; in France, 0.1% hexamidine eyedrops are available (Desomedine). The results also advocate clinical investigations on the efficiency and toxicity of octamidine, which appears to be the most amoebicidal diamidine in vitro.Acanthamoeba keratitis is a serious and potentially devastating corneal infection generally seen in soft contact lens wearers. The responsible amoeba has been detected in the human cornea in two forms: as fragile trophozoites and as resistant dormant cysts. The medical treatment of this ocular infection remains very difficult because of the lack of antiamoebic drugs effective against cysts, which are responsible for frequent and serious recurrences.Since the first medical cure reported in 1985 (16), propamidine isethionate, an antimicrobial agent belonging to the diamidine family, has been the basic drug recommended for use in treatment, which includes the use of topical neomycin sulfate and various imidazoles (2,5,7,8,15). Unfortunately, propamidine is poorly cysticidal and the resistance of some Acanthamoeba strains has been reported (6, 10). In the present study, superior homologs of propamidine were tested for their amoebicidal effects both on trophozoites and cysts with the intent of finding whether some of them are more amoebicidal and, especially, cysticidal than propamidine. At...
A one-pot synthesis of (±)-2-(t-butylamino)-3'-chloropropiophenone (bupropion) as its hydrochloride salt (Zyban, Wellbutrin), an important antidepressant drug used in the treatment of nicotine addiction, is described. The procedure, suitable for students in their first year of organic chemistry, can be carried out in less than two hours and provides material of high purity in overall yield of 75-85%. A solution of m-chloropropiophenone in CH2Cl2 is treated with Br2. After removal of the solvent, t-butylamine and N-methylpyrrolidinone are added and the mixture is warmed briefly, quenched with water, and extracted with ether. Concentrated HCl is added to the ether solution to precipitate the product.
Acanthamoeba keratitis remains very difficult to treat because of the lack of antiamoebic agents completely effective against cysts. Currently, the recommended treatment includes the use of topical neomycin sulfate, various imidazoles, and propamidine isethionate (Brolene) 0.1% eye drops, a compound of the diamidine family. In the present article, we describe the successful management of two patients with an Acanthamoeba keratitis, treated with hexamidine diisethionate (Desomedine) 0.1% eye drops, another diamidine derivative, which was found amoebicidal in vitro on the isolated Acanthamoeba strains. This is to our knowledge the first report on the amoebicidal effectiveness of hexamidine, simultaneously in vitro and in vivo.
The DNA sequences targeted by a complete homologous series of aromatic diamidines have been determined at single-nucleotide resolution via protection from cutting by the endonucleases DNase I, DNase II and micrococcal nuclease. Propamidine, pentamidine and to a lesser extent hexamidine bind selectively to nucleotide sequences composed of at least four consecutive A-T base pairs. In contrast, the binding to DNA of butamidine, heptamidine, octamidine and nonamidine is poorly sequence-selective. Sequences composed of only three consecutive A-T base pairs do not afford a potential binding site for propamidine or the longer homologues, and none of the drugs tolerate the presence of a G-C base pair within the binding site. Experiments with DNA molecules containing inosine in place of guanosine and 2,6-diaminopurine in place of adenine reveal that the lack of binding of propamidine to GC-containing sites is attributable to an obstructive effect of the exocyclic 2-amino group of guanosine. The present data support the view that the local conformation of the double helix (in particular the width of the minor groove) plays a dominant role in the binding reaction and that the capacity of diamidines to recognize AT-rich sequences selectively varies considerably depending on the length of the alkyl chain. The evidence indicates that binding to AT-tracts in DNA must play a role in the biological activity of these diamidines, but there is no simple correlation between binding and pharmacological efficacy.
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