TCPL drug delivery system: the effects of synthetic DHEA and Diosgenin using an ovariectomized rat model.
Dehydroepiandrosterone (DHEA) has been shown in numerous studies to exhibit a host of benefits at the vital and reproductive organ levels. However, the use of naturally occurring DHEA is hindered by its inability to survive the first-pass metabolic process of the liver. One possible alternative means that deserves consideration is the administration of DHEA's precursor, namely, Diosgenin (DG). The specific objectives of this investigation were: 1) to deliver DHEA and DG at sustained levels by Tri-Calcium Phosphate Lysine (TCPL) drug delivery systems using ovariectomized (OVX) adult rats as a model, and 2) to evaluate the biochemical and histopathological changes associated with the sustained delivery of DHEA and DG. A total of 30 adult female rats were used in this investigation. The animals were further divided into 8 groups. Groups 1 and 2 animals served as intact control groups while each rat in groups 3-8 was ovariectomized (sham (33), n = 3 [group 3], sham (47), n = 4 [group 4]). Groups 5 and 6 were implanted with DHEA (group 5) and DG (group 6) loaded TCPL capsules immediately following the OVX procedure. Groups 7 and 8 were implanted with DHEA (group 7) and DG (group 8) loaded capsules 14 days following OVX. Surgical aseptic technique was employed according to standard laboratory protocols. Maliondialdehyde (MDA) and hormonal levels were measured from serum, collected semi-weekly, during the entire investigation (for 47 days) and X-rays were performed weekly. Pap smears were collected daily for 47 days to assess endometrial changes associated with DHEA and DG treatment. Following sacrifice (at day 33 for groups 1, 3, 5, and 6 and at day 47 for groups 2, 4, 7, and 8), routine H and E staining was conducted for histopathological evaluation of the reproductive and vital organs. Results of this investigation demonstrated: 1) OVX resulted in an increase in total body weight, and the use of DHEA and DG returned the body weight to near normal levels as compared to the intact control groups, 2) TCPL capsules delivered DHEA and DG at a sustained level during the 47 day study, 3) serum levels of MDA are as follows: DG > DHEA = OVX > control for the 33 day phase and OVX > DG > DHEA > control for the 47 day phase, 4) no significant changes were observed in total wet weights, as well as the morphology of the spleen, kidney, adrenal, heart, liver, and lung tissues, 5) OVX resulted in an atrophy and non-keratinization trend in the reproductive tissues, and sustained delivery of DHEA and DG showed no remarkable change in these tissues, 6) the use of sustained delivery of DHEA and DG resulted in higher weights of uteri compared to the OVX group. In conclusion, this study provided more information regarding the interrelationship between DHEA and DG, and the physiological responses encountered when they are administered continuously using the adult OVX rat as a model.
Scott
A
A
University of Mississippi Medical Center, Jackson 39216, USA.
Higdon
K
K
Benghuzzi
H
H
Tucci
M
M
Cason
Z
Z
England
B
B
Tsao
A
A
Hughes
J
J
D000818:Animals; D002130:Calcium Phosphates; D002516:Ceramics; D003687:Dehydroepiandrosterone / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D004144:Diosgenin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D016503:Drug Delivery Systems; D004343:Drug Implants; D005260:Female; D005836:Genitalia, Female / Q000187:drug effects; D008239:Lysine; D010052:Ovariectomy; D010710:Phosphates; D051381:Rats; D017207:Rats, Sprague-Dawley
D002130:Calcium Phosphates; D004343:Drug Implants; D010710:Phosphates; C112656:tricalcium phosphate lysine; D003687:Dehydroepiandrosterone; D008239:Lysine; D004144:Diosgenin