Oral Protein Drug Delivery - Some Additional  Thoughts
I had a short conversation with a colleague at the gym earlier today as we both engaged in our respective continuing battles against mother nature and father time.  The topic of conversation was health care costs  and concluded that as long as profit trumps treatment in the United States,  our healthcare system will be less effective than other countries ( http://www.numbeo.com/health-care/rankings_by_country.jsp ).  Another conversation with a different colleague concerned the difficulty in bringing a new therapeutic or diagnostic forward unless it could be demonstrated to produce a large profit.   An excellent example is the use of transexamic acid to prevent bleeding in trauma patients as discussed by Dr. Janice Boughten (March 17, 2014)  in KevinMD Today (http://www.kevinmd.com/blog) .   Experimental work also tended to be reproducible  since reproducibility of research results seems to be an increasing problem (http://protomag.ticsnetwork.com/assets/replication-in-research-problem).  The issue is that there is no reward for reproducing someone's else results - a bit of a change from when I started at the University of Washington in 1961.   Finally, going back a number of years to my conversations with scientists from "the greatest generation," it was clear that their success was based on wanting to solve problems rather than accruing fame and fortune.

 Having now purged myself, I want to spend some time on oral protein drug delivery - specifically for hemophilia A.  Elsewhere I have described early work on oral therapeutics for hemophilia a (Oral protein drug delivery and hemophilia A).  I continue to be surprised that there is no interest in following on these early observations.  The assay methods, while antiquated, provide solid information (it helps a bit that I have been working on and around factor VIII for more than fifty years and do understand the assay systems).   So, if this work is so interesting, why was there no further work?   It is my understanding that work in both Netherlands and the United States fell victim to the more immediate needs of WWII.    The blood programs developed during WWII provided the basis for plasma fractionation (1) providing an approach to the treatment of hemophilia A which was not available in early 1930.   


I have had a variety of research interests other than factor VIII including tissue kallikrein (glandular kallikrein, KLK1).  In the course of work on tissue kallikrein, I become aware of the therapeutic use of porcine pancreatic kallikrein.  A therapeutic product, Padutin®, was developed by Bayer and, to the best of my knowledge is still available.   The early use (1930-1935) considered the pancreatic product to be a hormone or coenzyme.  The active component was later identified as pancreatic kallikrein. There has been continuing interest in the use of Padutin® in male reproductive biology (2,3).   There are two studies on absorption and distribution of the orally administered material (4,5).   The sum of the data, while not as quantitative as one would like, it that orally administered kallikrein can have a systemic therapeutic action.  It is noted that two members of the kallikrein-related peptidase family, PSA and KLK2, have been suggested to have a role in seminal plasma (6).

In conclusion, it would be somewhat satisfying to see if the results of oral hemophilia therapy published in the 1930's could be repeated. The wealth of animal model systems available in 2014 should permit a more sophisticated approach.


References


1.  Kendrick, D.B., Blood Program in World War II, Office of the Surgeon General, Washington, DC, USA, 1989.
2.  Schill, W.B., Krizic, A. and Rjosk, H., Determination of various semen parameters and sex hormone levels in subfertile men during kallikrein therapy, Adv.Exp.Med.Biol. 120A, 537-546, 1979.
3.  Schill, W.B. and Miska, W., Possible effects of the kallikrein-kinin system on male reproductive functions, Andrologia  24, 69-75, 1992.
4. Miska, W., Geiger, R., and Schill, W.B., Absorption studies with porcine pancreatic kallikrein in man, Agents Actions Suppl, 38, 136-143, 1992.
5.  Yasuda,Y., Lu, Z., Kato, N., and Jomori, T., Change in blood kinin and plasma porcine pancreatic kallikrein concentrations after oral administration of kallikrein formulation, Biol.Pharm.Bull. 34, 1518-1521, 2011.
6.  Sävblom, C., Halldén, C., Cronin, A.M., et al., Genetic variation in KLK2 and KLK3 is associated with concentrations of hK2 and PSA in serum and seminal plasma in young men, Clin.Chem. 60, 490-499, 2014.