THE LABORATORY OF CHEMOTHERAPY FOR PARASITIC DISEASES

In the Rockefeller University’s laboratory of chemotherapy for parasitic diseases,
Professor Ernst A. H. Friedheim, M.D., Ph.D., doctor of tropical medicine and hygiene, is
working to develop safe, effective drugs against parasites that cause debilitating diseases
throughout the world.

Over the years, Dr. Friedheim has synthesized chemical compounds against
several major parasitic diseases, including schistosomiasis, filariasis, onchocerciasis, and
African trypanosomiasis (or sleeping sickness). After testing the compounds in laboratory
animals, he has evaluated the most promising of these drugs in clinical studies conducted in
Africa, Asia, Central and South America, and the Pacific islands.

Melarsoprol, the drug Dr. Friedheim developed for African trypanosomiasis, is the
main drug used to treat the encephalitic stage of this disease, when the trypanosome parasites
have entered and damaged the brain. Today, melarsoprol cures approximately 95 percent of
lethal cases of encephalitic African trypanosomiasis and saves an estimated 15,000 lives a
year. Before melarsoprol was developed, advanced cases of the East African form of this
disease were incurable.

In an effort to combat parasites that invade the brain, Dr. Friedheim is studying
the components of the blood-brain barrier and the relationship between the structure of various
chemicals and their ability to penetrate this barrier. Much of this research focuses on a
network of blood vessels known as the choroid plexus. Found in the innermost membrane of
the brain, the choroid plexus secretes cerebrospinal fluid. Studies in the Friedheim laboratory
have shown that the choroid plexus retains and accumulates arsenic and lead, and that
concentrations of lead increase with age in at least one part of this network. These
investigations suggest that the choroid plexus may serve as a kind of protective "sink" for lead
and possibly other heavy metals.

Building on his extensive experience with parasitic diseases, Dr. Friedheim has
recently addressed the urgent need for new drugs to fight the parasites that cause opportunistic
infections in AIDS patients. Pneumocystis carinii, one of the parasites currently studied in the
Friedheim laboratory, is responsible for a pneumonia that strikes nearly all AIDS patients
during the course of their disease, often fatally.

This single-celled parasite is normally found in the lungs of healthy human
beings. P. carinii causes no ill effects in these individuals because their immune systems are
able to hold the organism in check. When the immune system is compromised by AIDS,
however, the parasites are free to multiply rapidly, and pneumonia results.

The main drugs currently used for Pneumocystis pneumonia are
trimethoprim/sulfamethoxazole and pentamidine. These drugs are helpful in treating this
pneumonia, but their therapeutic use is limited by adverse side effects. Pentamidine is also
the standard drug treatment for first stage African trypanosomiasis, when trypanosome
parasites circulate in the blood but have not yet penetrated the brain.
Since pentamidine is less than satisfactory as a treatment for Pneumocystis
pneumonia, Dr. Friedheim synthesized several other compounds, chemically different from
pentamidine, that kill trypanosomes. In collaboration with Dr. Friedheim, Dr. Marilyn Bartlett
of the Indiana University School of Medicine in Indianapolis investigated the effect of these
drugs on P. carinii grown in culture (that is, outside of a living organism).

In these studies, three of Dr. Friedheim’s trypanocidal drugs were highly active--
in very low concentrations--against P. carinii. These concentrations were on the order of one
part per million, lower than the concentrations of pentamidine needed to kill P. carinii. Dr.
Friedheim has now begun to test the compounds in rats infected with P. carinii.

Dr. Friedheim has also focused his research on Acanthamoeba, which has recently
been shown to cause opportunistic infections in AIDS patients. Free-living parasites found in
soil and fresh water, Acanthamoebas cause lethal meningitis and blinding keratitis, or
inflammation of the cornea, and have afflicted many contact lens wearers. As with P. carinii,
pentamidine kills Acanthamoeba, but it also causes severe side effects in many patients.

Dr. Friedheim has synthesized four chemical compounds that are highly active
against Acanthamoeba parasites grown in culture. One of these drugs kills 99 percent of three
strains of the parasite, in a concentration 10,000 times smaller than the dosage tolerated in a
rabbit’s eye.

In collaboration with Drs. David Podell and David Gorman, ophthalmologists at
Lenox Hill Hospital in New York, Dr. Friedheim has begun experiments to study the effect of
these drugs on keratitis in rats. Dr. Friedheim also has studies under way to test two of the
. drugs in mice with amoeba meningitis.

In future studies of P. carinii and Acanthamoeba, Dr. Friedheim plans to evaluate
the effect of various doses of these drugs in an increased number of laboratory animals. The
expanded experiments will make it possible for Dr. Friedheim to refine the chemistry of these
compounds and determine the optimum dosage needed to treat Pneumocystis pneumonia and
Acanthamoeba infections.