ABSTRACT
We investigated the efficacy and potency of Dysport, a botulinum neurotoxin type A complex approved for therapy, under various conditions. Conditions for maximal expression of biological activity were explored in vitro in the phrenic nerve-hemidiaphragm preparation, while conditions for optimal distribution of the toxin were tested in vivo in a double blind trial involving volunteers, using the foot Muscles extensor digitorum brevis. In contrast to the recommendations of the manufacturer, the biological availability of Dysport could be enhanced by (1) lowering its concentration, (2) supplementing with albumin, and (3) increasing the injection volume. On the basis of these experimental findings Dysport was diluted to a final concentration of 50 U/ml for therapeutic purposes. In a blind, single crossover study patients suffering from various forms of dystonia were treated with Dysport, first diluted and dosed as suggested by the manufacturer and then with doses cut by approximately 70% in accordance with the experimental findings. The low-dose treatment was as effective as the treatment with the recommended higher doses, but side effects were considerably less apparent. The benefits to be derived from these adjustments include a low risk of antibody formation, which could preclude continued or future treatment and substantial cost savings.
Subject(s)
Botulinum Toxins, Type A/pharmacokinetics , Botulinum Toxins, Type A/therapeutic use , Action Potentials/drug effects , Adult , Aged , Aged, 80 and over , Animals , Biological Availability , Blepharospasm/drug therapy , Botulinum Toxins, Type A/pharmacology , Cross-Over Studies , Diaphragm/innervation , Double-Blind Method , Dystonia/drug therapy , Electric Stimulation , Female , Hemifacial Spasm/drug therapy , Humans , In Vitro Techniques , Male , Mice , Mice, Inbred Strains , Middle Aged , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Phrenic Nerve/drug effects , Phrenic Nerve/physiology , Time FactorsABSTRACT
Conventionally, the standard test for detection of antibodies against botulinum toxin (BT-A) has been the mouse lethality assay (MLA). Because this test has a number of disadvantages, a novel mouse protection assay (MPA) was recently introduced. We sought to compare the results of both tests. Forty-three samples from 38 patients with cervical dystonia and complete or partial subjective BT-A therapy failure underwent simultaneous MPA and MLA testing. Twenty-seven samples showed concordant results in both tests. Eleven of them were MPA- and MLA-positive and 16 MPA- and MLA-negative, resulting in a significant association of the dichotomous test results (Fisher exact test, p <0.01). Sixteen samples showed discordant results. All of those were MPA-positive and MLA-negative. This excess of MPA-positive results was also significant (Wilcoxon signed-rank test, p <0.001). Of the patients with MPA-positive samples, 62% had complete and 38% had partial therapy failure. Of the patients with MLA-positive samples, 90% had complete and 10% had partial therapy failure. MPA and MLA results show significant association. Statistical analysis and predominance of partial therapy failure in MPA-positive patients demonstrate higher sensitivity of MPA. With its methodologic advantages, its test parameter being more relevant to BT-A therapy, and its higher sensitivity, the MPA appears to be superior to the MLA.
