Soon-Hoe Kim

Percutaneous absorption and histopathology of a poloxamer-based formulation of capsaicin analog

A new synthetic capsaicin analog (CA) modified with 4-hydroxyl and alkyl chain of capsaicin was synthesized as a potent anti-inflammatory analgesic drug and is now on clinical trial in Korea. The purpose of this study was to investigate the percutaneous absorption and histopathology of a poloxamer-based formulation of CA. A poloxamer-based gel was prepared by cold method using poloxamer 407. Vertical Franz type diffusion cells were used for skin penetration of drug against receptor phase filled with about 10 ml of 0.9% isotonic saline at 32°C. The concentration of drug was determined by the reverse phased HPLC (C18, Symmetry®) with fluorometeric detector. Total amount of CA free base permeated was higher than that of the CA salt form. Percutaneous absorption of CA was greatly enhanced in ethanol and PG than that in water, 2-hydroxypropy-β-cyclodextrin and PEG400. As ethanol concentration increased, percutaneous absorption greatly increased. The flux rate of CA increased slightly when PG was added to ethanol solution. The marked enhancing effect of the 5% fatty acid IPM in cosolvents was also noted on the percutaneous absorption of a poloxamer-based formulation of CA. Addition of 5% OA and 5% LA into the gel containing 5% IPM resulted in a slight increase in skin permeation. No significant difference in skin permeation was observed as a function of poloxamer content (20, 25 and 30%). The buffer system of 30% poloxamer-based gel slightly changed the cumulative amounts of CA penetrated for 24 h. The flux of poloxamer-based gels increased linearly as the drug concentration increased. There was a variation of percutaneous absorption of the drug, depending on the species used. The flux of a poloxamer-based formulation of CA was the highest in case of hairless mice but the lowest in hamsters. No skin erythema and histopathologic changes were observed on the dorsal site of hairless mice in six groups after a week or two months application, suggesting no skin toxicity of the poloxamer-based gel. Based on these findings, the current poloxamer-based formulation appears useful in the systemic delivery of CA as topical or transdermal patch formulations.

Candidate Molecule for Premature Ejaculation, DA-8031: In Vivo and In Vitro Characterization of DA-8031

OBJECTIVES To evaluate the efficacy of DA-8031 against premature ejaculation, we performed in vitro and in vivo pharmacologic studies. METHODS We used a monoamine transporter binding affinity assay, receptor binding affinity assay, monoamine reuptake inhibition assay, and serotonin uptake inhibition assay in platelets and chemically induced ejaculation models in rats. RESULTS The present study reports on the pharmacologic profile of the putative antipremature ejaculation drug, DA-8031. DA-8031 exhibits high affinity and selectivity to the serotonin transporter (Ki value 1.94 nM for 5-hydroxytryptamine transporter, 22 020 nM for norepinephrine transporter, and 77 679 nM for dopamine transporter) and potency to inhibit serotonin reuptake into the rat brain synaptosome in vitro (half maximal inhibitory concentration 6.52 nM for 5-hydroxytryptamine, 30.2 μM for norepinephrine, and 136.9 μM for dopamine). In the platelet serotonin uptake study, DA-8031 exhibited significant inhibition at oral doses of 10 and 30 mg/kg in a dose-dependent manner. In the sexual response studies, after oral and intravenous administration of DA-8031, ejaculation was significantly inhibited in both para-chloroamphetamine- and meta-chlorophenylpiperazine-mediated ejaculation models in rats. CONCLUSIONS The pharmacologic profiles observed in the present study suggest the potential for DA-8031 as a therapeutic agent useful in the treatment of premature ejaculation.

Protective effects of acetyl-L-carnitine on neurodegenarative changes in chronic cerebral ischemia models and learning-memory impairment in aged rats

This study investigated the effects of acetyl-L-carnitine (ALC) in secondarily-induced cerebral chronic ischemia models using rats with permanent ligation of bilateral common carotid arteries (BCCL) and spontaneously hypertensive rats (SHR). Additionally, we used normal aged rats as a primary dementia model. Chronic ALC administration at 100 mg/kg (p.o.) for 4 weeks significantly attenuated neurodegenerative changes. In groups receiving 50 mg/kg or 100 mg/kg, ALC inhibited the active astrocyte increase in cerebral tissues of both BCCL and SHR models. In BCCL rats, ALC administration (50 mg/kg or 100 mg/kg, p.o.) resulted in significant promotion of glutathione levels in brain tissues. We also confirmed behavioral improvement after ALC treatment (100 mg/kg for 8 weeks, p.o.) on learning-memory function using aged rats (18 months old) in a passive avoidance task and preservation of CA1 pyramidal neurons was coincided on histopathological observation. In conclusion, chronic ALC administration may ameliorate cerebral ischemia progress after a cerebrovascular disorder as well as spontaneous ageing-related cerebral dysfunction via hippocampal protection.