Theobromine, the active ingredient in chocolate, means"God's food," in Greek. Theophylline, the comparablecompound in tea, means "God's leaf." Caffeine, thechemical zinger in coffee, owes its name not to Greek butto the Arabic word for _ simply _ "coffee."
All three of these age-old, licit drugs are derivatives ofthe same mother molecule, xanthine. "They act asphysiological stimulants," explained medicinal chemistKenneth Jacobson, "by blocking a chemical signal in thebody that normally depresses the action of heart, brain,kidneys and immune system, among others. That signal ismediated by the ubiquitous modulator, adenosine."
Now a new xanthine derivative takes on a novel task _nothing less than therapeutically reversing the effects ofcystic fibrosis. This synthetic molecule carries thechemical name, 8-cyclopentyl-1,3-dipropylxanthine(CPX).
The man who made that molecule, Kenneth Jacobson, ischief of the molecular recognition section at the NationalInstitute of Diabetes and Digestive and Kidney Diseases,(NIDDK), in Bethesda, Md.
Hustling Build-Up Out Of Cystic Fibrosis Cells
"CPX is one of several xanthine-class molecules,"Jacobson told BioWorld Today, "that were previouslyknown only as adenosine antagonists." (See BioWorldToday, Sept. 13, 1993, p. 1.) "CPX acts at a novel site,and causes an action predictive of therapeutic utility incystic fibrosis. "That action," he added, "consists ofstimulating the export of chlorine ions from epithelialcells that contain the principal genetic defect occurring incystic fibrosis patients."
CPX, he said, "has an effect only on the cells that havethe genetic defect, which is caused by a mutant cysticfibrosis transmembrane conductance regulator (CFTR)gene. In cells that have the normal CFTR," Jacobsonadded, "CPX has no effect, because the chloride transportis so robust that you don't even see the difference."
Last month in Dallas, Jacobson's partner in developingCPX, biochemist Harvey Pollard, described their newdrug to the 9th annual North American Cystic FibrosisConference. "I characterized CPX as a chemical repairsystem," Pollard told BioWorld Today, "because it seemsto reactivate the impaired chloride-ion conductancechannels of the non-functional mutant protein, butdoesn't touch the normal, wild-type protein."
Pollard is chief of NIDDK's Laboratory of Cell Biologyand Genetics. "Cystic fibrosis," he observed, "is a whole-body disease. Wherever there's epithelium, there areproblems." But the most problematic organ of all, headded, is the lung.
"So the focus of therapy for cystic fibrosis, especiallygene therapy, has been on the lungs," Pollard pointed out."That's the one place we haven't been able to impact onas much as we'd like. So this CPX medicine should havean effect on the lung, but also everywhere else in the bodywhere cystic fibrosis creates problems."
He and Jacobson "made this discovery some years ago,"Pollard went on, "and we've been trying ever since to getpeople interested. But with the strong interest in genetherapy, as opposed to pharmacological therapy, it wasn'treally all that interesting."
Stop-Gap Pill Until Gene Therapy Comes Of Age
"We continue to work on CPX because I'm of theopinion that until the next generation of gene therapy _vectors, vehicles, and so on _ comes on line, we needsomething now," Pollard said.
That "something," CPX, would be taken by mouth, like apill. "This compound has similar physical properties tocaffeine," Pollard said. "It's a xanthine." He pictures it asthe cystic fibrosis therapeutic equivalent of insulin fordiabetes, a maintenance medicine to be taken regularlyfor life.
"To test out this point," he said, "we are licensing CPX,and other analogs, to SciClone Pharmaceuticals Inc., ofSan Mateo, Calif. Our collaboration with that company isstill gearing up. I'm hoping that under the license,SciClone will undertake clinical trials of CPX for cysticfibrosis."
So far, the only human studies Pollard and Jacobson haveconducted at the NIDDK consist of exposing explantedtissues from the respiratory tracts of cystic fibrosispatients to CPX. "It seems to actually make those cellsfunctional," Pollard said.
CPX has potential for treating a range of other diseases,Jacobson said. "Because the patent we are licensingcovers only cystic fibrosis, SciClone would have no rightto apply the compound to other diseases."
Jacobson added, "We have shown that chronicallyadministered CPX can be useful in depressing seizures,so it has possibilities as an anti-epileptic drug. It may alsohave utility in memory disorders, in asthma, and as aprophylactic treatment of stroke conditions."
A notice in the Oct. 30, 1995, Federal Register announcedthat the National Institutes of Health (NIH) "iscontemplating the grant of a worldwide, limited field ofuse, exclusive, royalty-bearing license" to SciClone.Those who take exception to this proposed award have 60days, expiring Dec. 29, 1995, to enter their objections.
The license covers U.S. patent 5,336,997, issued Nov. 22,1994, titled "Method of treating cystic fibrosis using[CPX] or xanthine amino congeners." Jacobson andPollard are its co-inventors.
Editor's note: For patent licensing information, consult J.Peter Kim, NIH Office of Technology Transfer, (301)496-7056 ext. 264; for technical questions concerningthis invention, Kenneth Jacobson, (301) 496-9024, orHarvey Pollard, (301) 496-3435. n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.