Identification of new drug compounds active against Pediculus humanus capitis, and incorporation of the compounds into a safe and potentially effective drug product formulation
Ping, Jeffrey Harold
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Individual citronella oil constituents were screened for in vitro activity against lice and their ova using ASTM methods. The screening studies revealed that all compounds tested possessed pediculicidal activity, but none possessed ovicidal activity. Citronellyl acetate emerged as the target drug compound based on its preferred physiochemical and efficacy properties.|Initial vehicle development efforts produced a vehicle (2-component, "add-mix" system) that maximized the in vitro efficacy profiles of citronellyl acetate. An in vitro dose response study identified the requirements of 3.94% and 8.38% citronellyl acetate for 50% and 100% activity, respectively. Increasing exposure time from 10 to 20 or 30 minutes did not increase activity. Pre-clinical toxicity was assessed using a 12.5% strength product. In vitro assessment of possible dermal penetration revealed that no transdermal absorption of citronellyl acetate occurred after a 10-miunte topical exposure. Acute oral and dermal toxicity testing demonstrated extremely low toxicity (LD50 in mice greater than 5000 mg/kg and between 2000 to 5000mg/kg in rats and dermal LD50 greater than 2000 mg/kg in rabbits). The add-mix formulation was a severe irritant to both the skin (PII = 6.75) and eyes of rabbits. Subsequent human clinical trials failed to identify a product that possessed any ovicidal activity or a 95% or greater clinical cure rate, documented instances of contact site irritation, and demonstrated poor correlation with in vitro results.|Additional efforts to optimize the delivery system resulted in a clear gel formulation and modified in vitro assessment methods with improved correlation and prediction. An in vitro dose response study with the gel identified the requirement of 3.3% and 9.0% citronellyl acetate for 50% and 100% pediculicidal activity, respectively, and 3.0% and 8.3% for 50% and 100% ovicidal activity, respectively. Also, a minimum of 11.1% was required to inhibit all embryonic development. A 12.5% strength gel was only moderately irritating to the skin (PII = 4.54) but severely irritating to eyes.|Extensive literature research uncovered two possible modes of action, isoprenylation inhibition and cuticle destruction. Results of an efficient and cost effective experiment with chirally pure actives and SEM inspection indicated a combination of both possible modes.