Therapeutics dermal toxicity

Kenneth A. Walters, PhD, is director of An-eX Analytical Services Ltd and an honorary lecturer in pharmaceutical chemistry at the Welsh School of Pharmacy. His research interests are biological membrane penetration enhancement and retardation, particularly with respect to skin. He has experience at Fisons Pharmaceuticals, Eastman Pharmaceuticals (a division of Eastman Kodak Company) and Controlled Therapeutics Ltd. (Scotland). Dr. Walters has published many articles and reviews and has co-edited two volumes on skin penetration enhancement and dermal toxicity. He is a charter member of the American Association of Pharmaceutical Scientists and also a member of the Society of Investigative Dermatology, the Controlled Release Society, the Society of Toxicology and the Society of Cosmetic Scientists. 

With chronic exposure, side effects may include rash, thrombocytopenia, leukopenia, and a lupus-like disorder. Chronic therapy is likely to result in tolerance, and withdrawal symptoms if primidone therapy is abruptly stopped. Doses in excess of 1500 mg (twice the maximum recommended daily dose) should be considered toxic. Less common side effects are hypotension, hypothermia, and dermal bullae. Encephalopathy has been observed in an epileptic patient with high plasma levels and poor renal function. With plasma concentrations exceeding 80pgml primidone may precipitate and cause crystalluria. Plasma levels >10 rgpml are associated with toxic effects. The therapeutic range is reportedly 5-10pgml , but clinical effects correlate more closely with phenobarbital blood levels. 

Figure 5. Theoretical representation of the toxicokinetics of a nerve agent (following dermal exposure) and pharmacokinetics of the corresponding antidote (i.m. administration). Effective concentration refers to the threshold toxic or therapeutic blood concentrations of antidote, respectively...

Misuse of various chemicals including industrial pesticides, toxic substances, and chemical warfare agents (CWAs) requires adequate personal protective equipment and immediate skin decontamination [151]. Since the time of World War 11, scientists have made a concerted effort to improve prophylactic and therapeutic interventions to counteract cutaneous exposure to CWAs [147]. To curtail dermal systemic exposure to environmental contaminants, most material safety data sheets (MSDSs) recommend either water rinsing or soap-and-water decontamination to remove chemicals from the skin surface [152, 153]. However, it is vital that the skin be washed in such a way that does not elicit the wash-in (W-I) effect [154], The W-1 effect is defined as an enhancement of percutaneous absorption elicited specifically by skin decontamination, particularly with water. It simply means that as some chemical contaminants are washed off the skin, the chemical substance may also wash into the skin and thus become more systemically bioavailable. 

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