Toxicity in a double-blind, placebo-controlled pilot trial with D-penicillamine and metacycline in secondary progressive multiple sclerosis.

The serine proteinase tissue-type plasminogen activator (t-PA) and the metalloproteinase gelatinase B (MMP-9) have recently been demonstrated in MS lesions. Both enzymes are interconnected in an enzyme cascade which contributes to destruction of the blood brain barrier and demyelination and both enzymes are inhibited by D-penicillamine. Metacycline was shown in in vitro experiments to inhibit gelatinase B. The combination of peroral D-penicillamine plus metacycline was evaluated in a double-blind placebo-controlled way in two groups of 10 patients suffering from secondary progressive multiple sclerosis. The major objectives of this pilot trial were to examine the safety of this combination and the possibility of blinding, while the effect on disease progression was considered as a secondary endpoint. Over a follow-up period of 1 year and in this selected patient group, there was no significant improvement in the Expanded Disability Status Scale score (EDSS) as compared with that of the placebo-control group. Toxicity was too high to consider additional trials with this combination of metalloproteinase inhibitors. Although peroral treatment is by most MS patients acknowledged as a major improvement in treatment compliance, one has to await the development of more selective and efficacious protease inhibitors than those used in the combination therapy described here.

[Comparative toxicity of oxytetracycline and its semisynthetic derivatives, methacycline and doxycycline]. / Sravnitel'naia toksichnost' oksitetratsiklina i ego polusinteticheskikh proizvodnykh metatsiklina i doksitsiklina.

The acute toxicity parameters of oxytetracycline and its semisynthetic derivatives was determined on laboratory animals of various species. The three antibiotics were described as belonging to the group of low toxic compounds according to the classification adopted in industrial toxicology. However, the absolute values of LD50 indicated that doxycycline was 5.6 or 2.8 times more toxic than oxyteyracycline or methacycline respectively. In addition, doxycycline had the most pronounced hepatoxic effect.