Comment on activity of commercial streptokinase preparations: issue of sub-standard life-saving drugs

Prasanta K. Ghosh

Cadila Pharmaceuticals Ltd
Sarkhej-Dholka Highway
Bhat
Ahmedabad 382210
India
E-mail address: pghosh{at}cadilapharma.co.in

Bakulesh M. Khamar

Cadila Pharmaceuticals Ltd
Sarkhej-Dholka Highway
Bhat
Ahmedabad 382210
India

We read the pre-clinical research paper of Hermentin et al.1 with interest. The paper compares the potency and purity of different commercial streptokinase (SK) preparations.

The paper, inter alia, analyses STPase Batches 2008 and 2009 manufactured by Cadila Pharmaceuticals Ltd (CPL), India.

STPase is a natural SK produced by Streptococcus ATCC 12449 and is not a recombinant product as has been mentioned in the paper. Amino acid sequence of STPase is well characterized and matches with authentic SK. Results of N-terminal sequence analysis of the STPase carried out in four different experiments are shown in Table 1.


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Table 1 N-terminal sequencing analysis performed on STPase
 
The STPase was also analysed by trypsin digestion followed by RP-HPLC for mapping. N-terminal sequences of six tryptic-digests peptides match completely with the natural SK protein sequence.2

The euglobulin assay carried out in February 2004 with the earlier mentioned batches gave the potency of 14.75x105 and 14.32x105 IU per vial, which was 98.3 and 95.5% of the declared potency, respectively. In India, Streptase and STPase are sold as per Indian Pharmacopeia (IP). Estimation of SK potency is carried out by euglobulin clot lysis assay instead of chromogenic method. By chromogenic assay, the potency was >100%. The latter method gives higher potency than that obtained from euglobulin assay.

The details of the procedures adopted for preparing STPase samples for activity determination have not been elaborated by Hermentin et al.1 On reconstitution, all SK samples lose activity with time. Samples prepared and left for long time even at –15 to –25°C preservation on thawing have shown large difference in the activity.3 Reconstituted Streptase lost substantial activity (>60% after 24 h) when preserved3 at 4°C.

Lyophilized SK requires storage at 2–8°C and cold chain integrity maintenance is essential to preserve the quality of the product. The history of transport and handling the STPase batches is not mentioned. It is not unlikely that improper conditions of exposure of STPase batches has led to the observed results and this has also been recognized by the authors in the paper.

STPase is manufactured by CPL based on the technology developed by the Institute of Microbial Technology, Chandigarh, a national institute under the Indian Council for Scientific and Industrial Research, New Delhi, a research organization of the government of India.

References

  1. Hermentin P, Cuesta-Linker T, Weisse J, Schmidt KH, Knorst M, Scheld M, Thimme M. Comparative analysis of the activity and content of different streptokinase preparations. Eur Heart J 2005;26:933–940.[Abstract/Free Full Text]
  2. Costa CS, Torres FAG, Filho SA. Streptokinase precursor. www.ncbi.nlm.nih.gov/entrez. Accession no. AAQ73571.
  3. Couto LT, Donato JL, de Nucci G. Analysis of five streptokinase formulations using the euglobulin lysis test and the plasminogen activation assay. Braz J Med Biol Res 2004;37:1889–1894.[ISI][Medline]




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