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In our paper Comparative analysis of the activity and content of different streptokinase preparations,1 we only mentioned the results of the chromogenic assay for the activity measurement. However, the respective data were also confirmed by a clot-lysis assay as a second assay, which was performed in accordance with the current European Pharmacopoeia. Furthermore, wherever feasible, we also evaluated an additional sample from a second batch of any given manufacturer of streptokinase. Even with the presented data, a batch-to-batch comparison is possible, taking into account the fact that we were able to prove the identity of several samples from different distributors (e.g. Streptonase and Solustrep or Strek and Unitinase, etc.) and even for different claimed manufacturers (e.g. BBT Biotech and Polamin Werk). Although the gel electrophoreses in Figures 3A and 7 already suggest identity, we, in addition, used isoelectric focusing (data not shown) to demonstrate the identity of samples from different distributors or manufacturers used in this investigation.
The results of our activity tests have also been confirmed by other groups.2,3 We are aware that our results are limited to the investigated batches and that these batches may not be representative of all batches of streptokinase that were manufactured by a certain supplier; however, the results raise at least doubts on the quality control processes installed in some institutes. Our investigation clearly demonstrates some deficiencies in several products; of course this does not allow definite conclusions on the clinical efficacy or safety of these products. Therefore, in our conclusion, we addressed only the potential risk of using deficient preparations, which appears justified considering the severely ill patient population.
We fully agree with Betancourt and his coworkers that the published data for the product heberkinasa are better than for the majority of streptokinase products, with the exception of our reference product streptase. Although in this case only a single sample of the recombinant streptokinase was evaluated, our results are similar to those published by other investigators,3 when using the same assay method. In a newly developed assay, the activity of recombinant streptokinase was almost doubled, an effect that was unique for this recombinant preparation, whereas natural streptokinases showed similar activity results in both assays. The authors concluded: future development of recombinant streptokinase pose even more problems for standardization of dosage during thrombolytic therapy.
Betancourt refers to a randomized clinical trial4 that compared natural and recombinant streptokinase and claims similar results for both agents. This statement, however, is based on only 224 patients, meaning that this comparison is definitely underpowered to demonstrate equal efficacy of these two products (if mortality is used as a clinical endpoint) or safety, considering that some adverse events occur in the range of 15% or even in <1% of patients in case of cerebral bleeding.
With regard to the immunological effects of a recombinant or a natural streptokinase product, the clinical study of Mainet et al.5 highlights that the SK-antibody pattern was similar for both products and that the detected antibodies were also cross-reacting. Although these findings are strongly indicating that the natural and the recombinant streptokinase exhibit similar or even identical epitopes, this does not exclude the alteration of other parts of the molecule or even the formation of neoantigens.
The larger clinical trial that assessed the efficacy and safety of recombinant streptokinase,6 although with the limitation of comparing against a historical conservatively treated control, demonstrates that with the introduction of this product, plus perhaps other factors, a clear improvement in therapy has been achieved, which is definitely a success for cardiology in Cuba. However, this does not alter the results of our investigation and our conclusion that the detected deviations may have an unpredictable, but potentially negatively impact on the clinical outcome of patients with acute myocardial infarction.
References
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