Successful antidote of multiple lethal infections using sustained delivery of difluoromethylornithine by means of ceramic drug delivery devices.
The objectives of this study were (1) to cure multiple infections of trypanosomiasis in rats by the sustained release of DFMO from biodegradable tricalcium phosphate (TCP) and aluminum-calcium-phosphorous oxide (ALCAP) delivery systems, and (2) to determine if the side effects associated with oral administration of DFMO can be avoided by using TCP and ALCAP capsules.  Sixty-eight SD male albino rats (235-270 g) were divided randomly into five groups.  Each rat in group I (n = 16) was implanted subcutaneously (s.c.) with four TCP capsules (two large TCP (L-TCP), one PLA-impregnated large TCP (IL-TCP) and one thin TCP capsule (TN-TCP)).  Rats in group II (n = 16) were implanted s.c. with four ALCAP ceramics (two large ALCAP (L-ALCAP), one PLA-impregnated large ALCAP (IL-ALCAP) and one thin ALCAP capsule (TN-ALCAP)).  Rats in groups III (n = 16), IV (n = 4) and V (n = 16) were left without implants.  Rats in group III (n = 16) were given 4% (w/v) DFMO (pH 7) in drinking water at the day of inoculation and continued up to 7 days postinoculation.  Rats in group IV (n = 4) served as a nontreated group.  Rats in group V (n = 16) served as normal controls.  The results showed that all rats implanted with with TCP or ALCAP implants had no intoxications symptoms or side effects such as diarrhea during the treatment period.  In contrast, rats given DFMO in drinking water exhibited foul-smelling diarrhea during the treatment period. Microscopic evaluation of blood smears collected from rats receiving DFMO chemotherapy showed an occasional or limited number of stumpy shape (SS) trypanosomes.  This study suggests that (1) ceramic drug delivery systems are capable of delivering DFMO in a sustained manner for two months, and were able to cure repeated infections of trypanosomiasis; (2) the use of ceramic implants avoided widely fluctuating, irregular levels of DFMO in the body by keeping sustained levels above minimal effective concentrations; (3) ceramic drug delivery systems provide a pharmacological potentiality for drugs such as DFMO which have been withheld from the market because of severe side effects when administered using conventional methods of drug administration; and (4) DFMO-filled ceramic devices can be implanted subcutaneously in animals that face a threat of lethal protozoal infections in highly infested areas of the world.
Department of Health Science and Department of Pathology, University of Mississippi Medical Center, Jackson 39216.
H A
HA
Benghuzzi
B G
BG
England
P K
PK
Bajpai
B F
BF
Giffin
D000284:Administration, Oral; D000537:Aluminum Oxide / Q000627:therapeutic use; D000818:Animals; D002130:Calcium Phosphates / Q000627:therapeutic use; D002516:Ceramics / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods*; D004343:Drug Implants; D000518:Eflornithine / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008422:Materials Testing; D011474:Prosthesis Design; D051381:Rats; D017207:Rats, Sprague-Dawley; D014352:Trypanosomiasis / Q000188:drug therapy*