Efficacy, safety and tolerability of topical terbinafine nail solution in patients with mild-to-moderate toenail onychomycosis: results from three randomized studies using double-blind vehicle-controlled and open-label active-controlled designs.

BACKGROUND: Terbinafine nail solution (TNS) was developed for the treatment of onychomycosis. OBJECTIVE: To assess the efficacy of TNS vs. vehicle and amorolfine 5% nail lacquer. METHODS: Subjects with mild-to-moderate toe onychomycosis (25% to ≤75% nail-involvement, matrix uninvolved) were randomized to receive either TNS or vehicle in two double-blind studies, and to TNS or amorolfine in an active-controlled, open-label study. Primary endpoint was complete cure (no residual clinical involvement and negative mycology) at week 52. Secondary endpoints were mycological cure (negative mycology defined as negative KOH microscopy and negative culture) and clinical effectiveness (≤10% residual-involvement and negative mycology) at week 52. RESULTS: Complete cure was not different between TNS vs. vehicle and amorolfine. Mycological cure was higher with TNS vs. vehicle, as was clinical effectiveness with TNS vs. vehicle, and TNS and amorolfine were not different for secondary efficacy endpoints. Patients achieving mycological cure had a better clinical outcome, and efficacy was improved in subjects with milder disease. Post hoc analysis suggests that nail thickness is an important prognostic factor. Moreover, mycological cure may require 6 months of treatment regimen while complete cure and clinical effectiveness may be achievable only after 10 months. A simulation study suggests that longer treatment duration would have resulted in higher complete cure with TNS vs. vehicle. Study treatments were well-tolerated. CONCLUSION: Primary efficacy objectives were not met in the studies reported herein. Possible reasons for failure to achieve significant outcomes include insufficient length of treatment; stringency of primary endpoint and severity of nail involvement of study population.

Thiol WR-1065 and disulphide WR-33278, two metabolites of the drug ethyol (WR-2721), protect DNA against fast neutron-induced strand breakage.

The main metabolites of the cytoprotective drug Ethyol (Amifostine, WR-2721) are the thiol WR-1065 and the disulphide WR-33278 (formed by the oxidation of WR-1065). Both metabolites are well-known protectors against DNA damage induced by gamma-rays. Using supercoiled plasmid DNA and restriction fragments we show that they protect efficiently also in the case of fast neutrons. In anoxic conditions WR-1065 (Z = +2) protects by scavenging of OH. and by 'chemical repair' (by H donation from its SH function). WR-33278 (Z = +4) protects by scavenging of OH. and, in the case of the supercoiled plasmid DNA, by reducing the accessibility of radiolytic attack sites via the induction of packaging of DNA in liquid-crystalline condensates (observed by circular dichroism). Because of this second mechanism, the plasmid DNA is more efficiently protected by WR-33278 than by WR-1065, at concentration ratios > 1 drug/4 nucleotides. Moreover, using sequencing gel electrophoresis of irradiated fragments of known sequence, we show that the protection by the two metabolites is non-homogeneously distributed along the DNA sequence, with 'hot spots' of protection and with unprotected regions. Based on presented molecular modelling results we explain the sequence dependence of radioprotection by structural variations induced by the binding of the drugs.

Radioprotection of DNA by spermine: a molecular modelling approach.

PURPOSE: To observe and explain the sequence-dependence of DNA radioprotection by spermine. MATERIALS AND METHODS: Sequencing gel electrophoresis was used to analyse the probability of frank strand break (FSB) induction at each nucleotide site. Molecular modelling of complexes of DNA with spermine molecules and of a curved electrically null DNA has been performed. RESULTS: The effect of spermine on radiation-induced strand breakage varied significantly along the studied fragment. At low spermine concentration, some sequences were protected while others were unprotected. Molecular modelling calculations show that the most electro-negative sites are located in the minor or in the major groove of DNA. The positively charged spermine (Z=+4) should preferentially bind to such sites. When bound in the minor groove, spermine triggers a reduction of the accessibility of radiolytic attack sites to OH* radicals. This is due to induced structural modifications and to the masking of attack sites. In the case of major groove binding, no reduction of accessibility occurs. This type of binding can explain the lack of protection of sequences with electro-negative sites in the major groove. At high spermine concentration, the fragment is strongly protected. A nucleosome-like pattern of breakage with periodically distributed regions of protection was observed. Molecular modelling calculations show that the accessibility of the attack sites in a curved electrically null DNA is also periodically reduced. CONCLUSIONS: Molecular modelling of DNA-spermine complexes that takes into account the electrostatic properties of DNA, allows an explanation of the experimentally observed effects of spermine on DNA radiosensitivity.