Administration of gentamicin does not increase factor levels in severe hemophilia-B due to premature termination codons

Abstract number: CD043

Srivastava A., Viswabandya A., Baidya S., Jayandharan G., George B., Shaji R. V., Chandy M.

Christian Medical College, India

Premature termination codons (PTC) result in the synthesis of truncated proteins. Recently, it was shown that aminoglycosides can partially overcome the effect of such PTCs by inducing translational misreading at these sites leading to synthesis of some intact wild-type protein (Wagner KR et al. Ann Neurol 2001). About 10% patients with hemophilia B (HB) have PTCs due to nonsense or frameshift mutations. To evaluate whether a similar response can be obtained in patients with HB and PTCs, we studied the response to gentamicin in four patients with severe HB (FIX:C <1%). None of these patients had inhibitors. Two of them had Arg338FS mutations and two had Arg333Stop mutations. Gentamicin was administered as an infusion over 1 h at the following doses: 5 mg kg^-1 day^-1 on days 1–7, 7.5 mg kg^-1 day^-1 on days 8–14 to children (<15 years) and 3 mg kg^-1 day^-1 on days 1–7, 5 mg kg^-1 day^-1 on days 8–14 to adults. Fix:C was assayed by the one-stage method (CA1500, Sysmex) and FIX antigen levels (FIX:Ag) were determined by an ELISA method (Asserachrom^® FIX:Ag, Diagnostica Stago) on days 0, 7 and 14. Factor assays were repeated on the 8th and 15th days after initiation of therapy. Serum gentamicin levels were monitored. Audiometry and renal function tests were done before, during and after the study on all patients. There were two children (11 and 13 years) and two adults (18 and 31 years). Fix:C and FIX:Ag was <1% in all of them. No increase in either of these two parameters was noted after 7 and 14 days of gentamicin therapy in any of the patients. Serum gentamicin levels were in the therapeutic range in all these patients and no drug related toxicity was occurred. This preliminary data suggests that gentamicin at the usual therapeutic doses does not increase FIX levels in patients with HB due to PTCs.