Long-term sustained delivery of 3'-azido-2',3'-dideoxythymidine in vivo by means of HA and TCP delivery devices.
This study will attempt to determine the amount of circulating drug, when provided at sustained levels over an extended period of time, which provides efficacy and reduces the toxic side effects seen with the use of AZT in vivo. Two ceramic delivery systems were selected for this investigation namely tricalcium-phosphate (TCP) and hydroxyapatite (HA) ceramic implants. Three different dosages were selected (60, 90, 180 mg AZT). A total of 105 rats were used in this study and they were further divided into seven equal groups (n = 15 per group, 250-300 gm BW). Rats in groups I, II and III were implanted with TCP ceramic capsules containing 30, 60, and 90 mg AZT powder, respectively. Each rat in groups IV, V, and VI were implanted with HA capsules containing 30, 60, and 90 mg AZT powder, respectively. Rats in group VII were unimplanted and served as controls. The standard aseptic surgical techniques were performed in this investigation. Rats were anesthetized with a mixture of Zylazine/Ketamine, and their hind limbs shaved and scrubbed with providone iodine. The sterilized ceramics (gas/24 hours) were inserted under the skin using standard surgical techniques. After implantation, the site was sealed with wound clips, and the animals were injected with 0.1 ml of 200,000 units of Penicillin. At the end of 2, 4, and 6 weeks after implantation, five rats from each group were euthanized and the ceramic capsules, reproductive, and vital organs were removed and examined by following standard laboratory protocols. Results obtained from this study revealed that the rates of AZT released from TCP ceramic implants (30 mg = 2.38 +/- 0.23 ng/ml, 60 = 4.64 +/- 1.03 ng/ml, and 90 mg = 11.92 +/- 2.36 ng/ml serum AZT) were significantly higher than the rates of AZT released from HA ceramic implants (30 mg = 0.84 +/- 0.05 ng/ml, 60 = 2.40 +/- 0.83 ng/ml, and 90 mg = 6.41 +/- 1.24 ng/ml serum AZT). Data obtained from this investigation suggest that: (I) TCP and HA ceramic implants can be used effectively to deliver AZT in amounts capable of eliciting physiological responses in vivo, and (II) large fluctuations of AZT concentrations in the blood stream and tissues due to the conventional routes of administration could be eliminated by using ceramic sustained delivery system.
Benghuzzi
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Department of Health Sciences, School of Health Related Professions, University of Mississippi Medical Center, Jackson, USA.
D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002130:Calcium Phosphates; D002516:Ceramics; D016503:Drug Delivery Systems; D004343:Drug Implants; D017886:Durapatite; D051381:Rats; D015215:Zidovudine / Q000008:administration & dosage* / Q000493:pharmacokinetics
D019380:Anti-HIV Agents; D002130:Calcium Phosphates; D004343:Drug Implants; C485828:alpha-tricalcium phosphate; C485830:tetracalcium phosphate; D015215:Zidovudine; C485838:calcium phosphate, monobasic, anhydrous; D017886:Durapatite; C020243:calcium phosphate; C485829:calcium phosphate, dibasic, anhydrous