Treating Acne with Octadecenedioic Acid

15 May


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.

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