Botulinum neurotoxin type A in urology: antibodies as a cause of therapy failure.

OBJECTIVES: Botulinum toxin type A (BoNT/A) proved very effective in therapy for hyperactive detrusor or sphincter dysfunction of neurogenic and non-neurogenic origin. However, therapy may fail. In a search for possible reasons, we investigated the presence of BoNT/A antibodies (BoNT/A-AB) in patients who were treated more than once and correlated the presence of antibodies with clinical findings. METHODS: In 25 patients (aged 11-75 years; average, 48.3 years) who had experienced at least one previous BoNT/A detrusor and/or sphincter injection, BoNT/A-AB was detected with the mouse diaphragm assay before and within 3 months after the current injection. Clinically, subjective and objective outcomes of this injection session were determined on an efficacy scale. RESULTS: In eight patients, BoNT/A-AB was detected; titers were clearly positive in four patients and were borderline in four patients. The subjective and objective outcomes indicated complete therapy failure in three of four patients who were positive for BoNT/A-AB. In two patients, BoNT/A-AB developed after just one injection session. CONCLUSIONS: Botulinum toxin type A antibodies can develop after injection of BoNT/A for urologic disorders and the antibodies can lead to therapy failure. In patients with clinically complete therapy failure in whom no obvious other causes can be determined (such as a progressive disease in a patient with multiple sclerosis), screening for BoNT/A-AB should be carried out.

Antibodies against botulinum neurotoxin type A as a cause of treatment failure after the first detrusor injection.

Botulinum neurotoxins are increasingly used in treatment for hyperactive detrusor and sphincter function. Although reported results are promising, conditions in some patients are refractory. We report what we believe to be the first urologic case of therapy failure possibly induced by botulinum toxin antibodies after just one injection and discuss treatment alternatives based on experience in other fields.

The immunosuppressive drugs cyclosporin A and tacrolimus inhibit membrane depolarization-induced CREB transcriptional activity at the coactivator level.

Cyclosporin A and tacrolimus are clinically important immunosuppressive drugs directly targeting the transcription factor nuclear factor of activated T cells (NFAT). Through inhibition of calcineurin phosphatase activity they block the dephosphorylation and thus activation of NFAT. Cyclosporin A and tacrolimus also inhibit other calcineurin-dependent transcription factors including the ubiquitously expressed cAMP response element-binding protein (CREB). Membrane depolarization by phosphorylating CREB on Ser119 leads to the recruitment of its coactivator CREB-binding protein (CBP) that stimulates initiation of transcription. It was unknown at what step in CREB-mediated transcription cyclosporin A and tacrolimus interfere. In transient transfection experiments, using GAL4-CREB fusion proteins and a pancreatic islet beta-cell line, cyclosporin A inhibited depolarization-induced activation of CREB proteins which carried various deletions or mutations throughout their sequence providing no evidence for the existence of a distinct CREB domain conferring cyclosporin A sensitivity. In a mammalian two-hybrid assay, cyclosporin A did not inhibit Ser119-dependent interaction of CREB with its coactivator CBP. Using GAL4-CBP fusion proteins, cyclosporin A inhibited depolarization-induced CBP activity, with cyclosporin A-sensitive domains mapped to both the N- (aa 1-451) and C-terminal (aa 2040-2305) ends of CBP. The depolarization-induced transcriptional activity of the CBP C-terminus was enhanced by overexpression of calcineurin and was inhibited by cyclosporin A and tacrolimus in a concentration-dependent manner with IC50 values (10 and 1 nM, respectively) consistent with their known IC50 values for inhibition of calcineurin. These data suggest that, in contrast to NFAT, cyclosporin A and tacrolimus inhibit CREB transcriptional activity at the coactivator level.