Kyung Koo Kang

Erectogenic effect of the selective phosphodiesterase type 5 inhibitor, DA-8159

DA-8159, a new phosphodiesterase 5 inhibitor, was assessed for its erectogenic potential by a penile erection test in rats, the relaxation of isolated rabbit corpus cavernosum (CC), and estimation of the intracavernous pressure (ICP) in the anesthetized dog. Oral administration of DA-8159 (0.3 to 1 mg/kg) increased the number of erections in rats with increasing dosage, with the highest penile erection index at 10 mg/kg. DA-8159 induced the relaxation of phenylephrine (PHE)-induced contractions in the rabbit CC and decreased the IC50 of the nitric oxide donor sodium nitroprusside (SNP) in a dose-dependent fashion. In pentobarbital-anesthetized dogs, the intravenous administration of DA-8159 (1≈300 μg/kg) potentiated the increase in ICP induced by the intracavernosal SNP in a dose-related manner. These findings suggest that DA-8159 has significant therapeutic potential in the treatment of erectile dysfunction.

Safety Evaluation of GX-12, a New HIV Therapeutic Vaccine: Investigation of Integration into the Host Genome and Expression in the Reproductive Organs

AIDS is one of the greatest infectious disease threats to human health despite the extensive efforts made since the discovery of HIV in 1983. The use of plasmid DNA vaccination to elicit humoral and cell-mediated immune responses against HIV infection has produced promising results in animal and in human trials. However, there are several safety concerns about the use of a DNA vaccine, which include the possibility of integration into the host genome, adverse immunopathology, and anti-DNA autoantibody induction. In this study, we examined the potential integration and distribution of GX-12, a new therapeutic vaccine for HIV infection, at various times in muscles and reproductive organs of rats. Animals of both sexes were injected with GX-12 at the dose of 400 µg/animal i.m. once a week for 4 weeks, and host genome integration and tissue distribution were examined on day 1, 5, 15, 30 and 45 days after the final injection. A PCR-based assay revealed that GX-12 was not integrated into the host genome, nor expressed in reproductive organs at any time. These findings suggest that the risk of mutation or germline transmission due to GX-12 injection is negligible.

Safety evaluation of GX-12. A new DNA vaccine for HIV infection in rodents.

Abstract Toxicity studies for the evaluation of the safety of GX-12, a naked DNA vaccine for the treatment of human immunodeficiency virus (HIV) infection, were performed in rodents. In a single dose intramuscular or intravenous toxicity study, animals were treated with up to 4000 µg/kg of GX-12. During the experimental period, no abnormalities in mortality, clinical finding, or body weight change were observed. For subacute toxicity study, GX-12 was administered intramuscularly once a week for thirteen weeks to rats at dosages of 0, 250, 1000, or 4000 µg/kg. Throughout the experimental period, no dead animals, notable clinical signs, changes in body weight gain, or food and water consumptions were observed. Ophthalmic examination, urinalysis, hematology, and serum chemistry, revealed no abnormalities. In addition, there were no changes in gross findings, organ weight, and histological findings. Based on these results, the NOAEL was estimated to be excess of 4000 µg/kg. To assess the possible effects on the immune system, we investigated the induction of anti-DNA or anti-myosin autoantibodies in mice immunized and boosted with GX-12, and anti-GX-12 antibodies in rat serum obtained from the subacute toxicity study. GX-12 neither stimulated the production of anti-DNA or myosin autoantibodies nor induced the development of myositis or glomerulonephritis. Therefore, we concluded that GX-12 has no toxicity up to 4000 µg/kg in this rat model, which is 60 times higher than the expected human dose. Furthermore, given the limitations of this study, GX-12 neither initiated nor accelerated the development of systemic autoimmune responses.