Acne is and will always remain a disturbing disease because it is highly visible as well as manifesting itself at an age when young teenagers are very concerned about their looks. However, to state that acne is only limited to adolescents (where males tend to show the more severe forms of the disease) is wrong, as especially postado- lescent women are also affected by the disease (1). The primary cause of acne is an obstruction of the pilosebaceous canal. This is due to at least four pathogenic factors: (i) increased proliferation, cornification, and shedding of follicular epi- thelium (i.e., hyperkeratinization); (ii) increased sebum production (i.e., hyper- seborrhea); (iii) colonization of the follicle with Propionibacterium acnes and Staphylococcus aureus (i.e., microbes); (iv) induction of inflammatory responses by bacterial antigens and cell signals (i.e., inflammation) (2). Earlier chapters of this book will have dealt extensively with these etiological and pathogenetical aspects of acne.
Topical treatments improving acne all affect one or more of these four main causes of acne (3). For instance, topical retinoids, of which tretinoin, isotretinoin, and adapalene are probably the most well-known examples, cause an expulsion of mature comedones, an inhibition of the formation and number of microcome- dones, and an inhibition of inflammation. Benzoyl peroxide (BPO), erythromycin, clindamycin, and azelaic acid (AZA) are examples of topical antimicrobials and antibiotics, although due to the increasing development of bacterial resistance, the concentrations of the topical antibiotics clindamycin and erythromycin have been raised from 1% to 4%. AZA is a C9:0 dicarboxylic acid with efficacy on follicular keratinization and on P. acnes. It seems to have some inflammatory efficacy via effects on neutrophilic granulocytes. It is used at very high concen- trations (20%), although somewhat lower concentrations (15%) have recently
also been shown to be effective (4). Salicylic acid, finally, has mainly a keratolytic effect. It has also a slight anti-inflammatory effect and is bacteriostatic and fungi- static at low concentrations by competitive inhibition of pantothenic acid, which is important for micro-organisms (3).
Very recently, advances in fundamental sebaceous gland research have suggested that the peroxisome proliferator-activated receptor (PPAR) might also be implicated in sebogenesis (5). PPARs are members of the nuclear hormone recep- tor superfamily and have been shown to be important in the regulation and catabo- lism of dietary fats (6), stimulation of epidermal differentiation (7,8), reduction in inflammation (9,10), and reduction in melanocyte proliferation (11,12). These activi- ties are regulated through one or more of the three isoforms of PPARs: PPARa, PPARd, and PPARg. In human skin, epidermal differentiation is predominantly regulated by PPARa and to a lesser extent by PPARd, inflammation by PPARa and some PPARg, and melanocyte proliferation mainly via PPARg. Using human chest sebaceous glands as seven-day cultured whole organs, Downie et al. were able to demonstrate that activators of PPARa and PPARg inhibited the rate of sebac- eous lipogenesis and reduced the synthesis of the sebum-specific lipids squalane and triacylglycerol in human sebaceous glands. They concluded that, “As suppres- sion of sebum secretion is associated with reduced acne activity, the nuclear hormone receptors involved may open new avenues in the development of novel acne treatments” (5).
The C18:1 dicarboxylic acid octadecenedioic acid (DCA) was recently devel- oped as a novel building block for synthetic polymers. But the resulting polymers did not have the desired novel properties and the molecule was, therefore, tested for its antimicrobial activity against P. acnes because of its structural similarity to AZA. When it was found to be more active than AZA, formulations were devel- oped with which clinical trials were performed to assess its clinical activity. Activity against acne could be demonstrated. At a later date, DCA was found to be a pan- PPAR agonist with a preference for PPARg (13). In this chapter, the antimicrobial efficacy tests, the skin delivery of DCA-containing formulations, the results of two clinical trials, and the binding experiments to PPAR will be described, wher- ever possible compared with AZA. Finally, based on all the evidence collected, a rationale for the mechanism of DCA as a novel topical acne treatment as suggested by Downie et al. (5) will be presented.
DCA is the dicarboxylic version of oleic acid. Its structural formula is given in Figure 1. It cannot be made by traditional oxidative chemistry because of the pre- sence of the double bond in the middle of the molecule, but is made via biotrans- formation. Normal yeasts rely on glucose and hydrocarbons such as alkanes, fatty acids, and triglycerides for their energy consumption. The hydrocarbons are taken up into the microsomes within the cells and oxidized on one end to form a fatty acid and then at the other end to form a dicarboxylic acid, generally known as dioic acid. These dioic acids are excreted from the microsome and taken up in
FIGURE 1 Structural formula of octadecenedioic acid.
the peroxisome in which b-oxidation takes place, yielding acetyl-CoA. This acetyl- CoA is transferred to the mitochondria in which it is inserted into the tricarboxylic acid cycle, yielding water, carbon dioxide, and energy in the form of ATP (Fig. 2A). A natural mutant of this specific yeast was identified, which follows the earlier- described biological pathway but in which the peroxisome is inactive. This yeast
FIGURE 2 General biochemical pathways in normal yeasts (A) and specific mutant yeasts (B).
Abbreviation : TCA, tricarboxylic acid.
will start the bioconversion of alkanes, fatty acids, and triglycerides, but cannot produce beyond the dicarboxylic acid phase (Fig. 2B). Such natural mutants can survive in nature because they can still obtain their energy via the conversion of glucose. When one feeds this natural mutant with only a very small amount of glucose to prevent it from dying and a relatively large amount of oleic acid as the fatty acid, it will convert oleic acid to DCA.
Because oleic acid is a natural product with its own distribution of chain lengths, DCA will also, similar to all other oleochemicals, have its own typical chain length distribution. DCA consists predominantly of C18:1, C18:2, and some C16 dicarboxylic acids. It is a solid with a melting point of approximately 64 to 688C, typi- cally in the form of flakes of a yellowish-white color. The chemical has a limited solu- bility in lipids such as hexane, an even lower aqueous solubility but a reasonable solubility in polar lipids such as ethyl acetate and acetone. Adding polar lipids such as propylene glycol and dipropylene glycol can enhance its solubility in aqueous media, whereas cosmetic emollients such as isostearyl alcohol and propylene glycol isostearate are typically used to dissolve it in the oil phase of formulations.