Efficacy and Use of Benzoyl Peroxide

15 May

BPO is still  the  gold  standard for  mild-to-moderate acne.  It is the  leading OTC antiacne agent  (in  the  United States)  and  it  is  available in  several   formulation types  including gels, creams,  lotions,  soap  bars,  and  liquid cleansers, at a concen- tration ranging from 2.5% to 10% in strength.

Why Is Benzoyl Peroxide So Successful in Acne Therapy?

Antibacterial formulations that suppress P. acnes are a mainstay in the treatment of acne.  As BPO’s activity  is primarily antibacterial against P. acnes, its use  in acne therapy is corollary. The mechanism of action  is presumably due  to its strong  oxi- dizing action,  as explained further in Figure  2. The release  of free radical oxygen causes  oxidation of bacterial proteins and  the  development of oxygen  creates  a milieu  in the follicle, where anaerobic bacteria like P. acnes cannot  survive. The anti- bacterial efficacy is reported in a large  body  of literature (13,33 – 36) and  is proven in  numerous studies. BPO has  a broad-spectrum activity  and  rapid bactericidal effects.  It  is  active   against  gram-positive  and   gram-negative  bacteria,   yeasts, and  various fungi  (34). In  vitro  investigations using  the  agar  diffusion method demonstrated   strong     antibacterial   efficacy    against   gram-positive   bacteria

(Table 3). The minimal inhibitory concentration (MIC) of BPO was found to be about

100 mg/mL (35,36).

In  addition to  this  in  vitro  data,  antibacterial action  within the  sebaceous follicle  was   also   shown  in  vivo   using   the   cyanoacrylate  technique.  After   a seven-week treatment  with   a  5%  BPO-gel,  reduction of  propionibacteria was demonstrated (37). Further studies have  revealed a very  fast  antibacterial action that,  however, does  not increase with  the continued use of BPO. After application of 5% BPO in an aqueous gel (daily  use  on the face), mean  numbers of propioni- bacteria   recovered from  the  skin  surface   and  follicular   casts  were  significantly reduced after  two  days  of treatment. In the  following days,  the  population was maintained, but  no  further decrease was  observed (38). The  same  rapid effects could   be  observed in  another study  where the  effect  of  BPO  against P.  acnes after   only   three   days   was   proven,  but   no  further  decrease was   observed at day  7 (39).

One major advantage of BPO over common antibiotics, used  in acne therapy, is its full activity  against antibiotic-resistant propionibacteria as well  as sensitive strains (36). This might  be due  to its mechanism of antibacterial action,  which  is probably mediated by its powerful oxidizing property. This nonspecific mode  of antibacterial action  means that  BPO  does  not  induce resistance like  antibiotics during long-term therapeutic use (38). Therefore, in order to preserve the efficacy of antibiotics in the  therapy of acne,  one  obvious way  could  be to treat  patients either   concomitantly or  sequentially with  a  broad-spectrum antibacterial agent such  as BPO.

As acne is not only caused by bacterial colonization, efficacy of BPO against other   factors   is  also   of  interest  and   has   been   investigated.  One   question  is whether BPO has  any  impact on  sebum production or  secretion. It was  found that  BPO has  a lack  of direct  effect  on  sebum production per  se  and  does  not reduce skin  surface   lipids,   but  it  is  effective   in  reducing the  free  fatty  acids, known as comedogenic agents, and  triggers of inflammation, in sebum. It inhibits hydrolysis of fatty  esters  and  dramatically lowers  the  free  fatty  acid  content in

sebum, concomitantly leading to an  increase of triglycerides (Table  4) (37,40,41). This  was  also  found in  a further study (42). The  same  study revealed contrary results in  the  way  that  a  sebo-suppressive effect  was  demonstrated by  investi- gations on  cell kinetics.  A prolongation of the  S-phase  of sebaceous follicle  cells and  a diminution of the sebum glands were  observed, which  would be regarded as  a direct  sebo-suppressive effect  and,  therefore, the  skin  surface  lipids  would need  to be reduced in consequence. As this, however, was not observed, the prac- tical  relevance of these  data  remains uncertain. Therefore, due  to these  contrary results, the  impact of  BPO  on  sebo-suppression in  acne  therapy is  still  under discussion.

Having discussed the questions of antibacterial and sebo-suppressive activity of BPO, it is still open  whether BPO can also act against another factor of acne—the comedolytic activity.  Before going on, it is necessary to define  the terms  comedoly- tic, keratolytic, or corneodesmolytic. Although these  terms  are  often  used  for the same  action,  they  are, strictly  speaking, not identical. Comedolytic means lysis of a  comedo caused  by  loosening  of  sticked   corneocytes, whereas  keratolytic  is defined as lyses of superficial corneocytes, nails, or hair due to lyses of keratin. Cor- neodesmolytic is a newer terminology, which  expresses nearly  the same action, as it results in desquamation due  to degradation of corneodesmosomes, which  are pro- teinaceous complexes that  effectively  rivet  corneocytes together. As a keratolytic action,  however, can  be  defined as  reducing cohesion between corneocytes in  a broader sense,  the  terms  comedolytic, corneodesmolytic,  and  keratolytic will  be used  for the same  action  from here on.

The keratolytic efficacy of BPO has widely been  investigated in the past.  On the  one  hand, this  drug was  considered to  be  moderately  comedolytic in  the rabbit  ear model, whereas it looked  rather inactive  in the human assay.  Using  the rabbit  ear model, which  is used  for comedonegicity assessment, BPO was  shown to moderately reduce the  development of comedones (24). Recent  studies, using a new  technique for  quantifying the  number and  size  of microcomedones, also demonstrated  comedolytic activity   of  BPO  (43).  However, using   the  follicular biopsy  technique, the anticomedogenic effect is only  comparatively slight  in con- trast  to tretinoin or  SA (4,22). One  explanation for  this  mismatch may  reside  in

TABLE 4    Thin-Layer Chromatographic and Densitometric Analysis of Skin Surface Lipids (Volunteers n ¼ 5) Before  and After Application of 5% Benzoyl Peroxide and Placebo (Half-Faced Comparison). Ratio of Triglycerides to Free  Fatty Acids

the nature of comedones. In the follicular  biopsy  technique, native  microcomedones were studied, which  may well be different from the tar- or azetulen-induced come- dones used  in the rabbit  studies (43). Overall,  a weak  comedolytic activity  of BPO can be stated.

Another  supplementary   benefit   of   BPO   in   acne   therapy  is   its   anti- inflammatory  action.   BPO,  however,  does   not  have   significant  direct   in  vivo anti-inflammatory potency. It  had  been  suggested that  protein kinase  C  might serve  as  an  additional  pharmacological target   of BPO.  Therefore, the  effects  of BPO  were  investigated on  the  release  of  reactive   oxygen  species,  regulated by protein kinase  C and  calmodulin, from  human neutrophils, a potential important step  in  acne  inflammation.  Micromolar concentrations  of  BPO  were   found  to inhibit  the release  of reactive oxygen  species  from  human neutrophils but  associ- ated   with   a  marked  drug-induced  cytotoxicity. When,   in  cell-free  assays,   the effects of BPO on protein kinase  C and  calmodulin as regulators of the release  of reactive oxygen  species  were  investigated, there  was  only  a marginal inhibition of protein kinase C and no detectable inhibition of calmodulin. Thus, the inflamma- tory  activity  of BPO is unlikely to be mediated by protein kinase  C or calmodulin (44,45). A potential explanation for the anti-inflammatory effects of BPO could  be the  mediation by  the  antibacterial  or  oxidizing action   of  BPO.  Following  the decrease in  the  population of P.  acnes in  the  follicles  and  the  reduction of free oxygen radicals, one source of inflammation is cut and therefore inflammatory reac- tions  are suppressed (4,22).

The anti-inflammatory benefit of BPO, regardless of being direct or indirect, is reflected in  several   studies (37,46,47). BPO  products are  indicated for  mild-to- moderate acne with  occurrence of predominantly inflamed lesions.

One study tested gel formulations with  different concentrations of BPO (3, 5, or 10%) depending on the skin condition. After four weeks  of treatment, the differ- ent BPO formulations were proven to be effective in the treatment of moderate acne. BPO was shown to decrease the number of papules and  pustules and,  to a smaller degree, the number of comedones (48).

Interestingly, not  only  efficacy  in  mild-to-moderate acne  but  also  a  quick onset  of action  can  be  observed after  BPO application, which   accompanies the quick  antibacterial action.  A  double-blind study showed that  a  5% BPO lotion used  topically for  only  five  days  significantly reduced the  number of inflamed lesions  (49). Since  acne  usually responds slowly  to  treatment, these  results are

very  surprising. Another study  also  demonstrated the  effect  of  short-duration treatment with  a BPO aqueous gel. Compared to baseline, a statistically signifi- cant   reduction  of  inflamed-lesions  was   determined  after   nine   days   and   a reduction of noninflamed lesions  after  four  days  of treatment. Over  the  whole study period (28 days),  improvement in the  reduction of inflamed lesions  could be observed (50).

Is There  a Difference  in Efficacy Between Various Benzoyl Peroxide Levels?

As mentioned earlier,  BPO products are not  only  available in a variety of formu- lations  such  as gel, cleanser, or emulsion but  also  in a variety of concentrations. But  is  a  higher  level  of  active   really   more   efficacious   than   a  lower   one?  In general, one would expect superior efficacy from a product with the higher concen- tration. Surprisingly, a 2.5% gel formulation of BPO was proven to be equivalent in

reducing the number of inflammatory lesions  to 5% or 10% BPO gel preparations. With  respect to the side  effects, however, a difference could  be observed. Desqua- mation, erythema, and  symptoms of burning with  the 2.5% gel were  less frequent than  with  the 10% preparation but equivalent to the 5% gel. The 2.5% formulation also  significantly reduced P.  acnes and  the  percentage of free  fatty  acids  in  the surface   lipids   after  two  weeks   of  topical   application (51). So why  are  not  the lowest  strengths in favor?  The answer is probably consumer psychology. Folklore has  established the  belief that  products with  higher levels  of active  are generally better  and more efficacious  than those with a lower concentration (52). Which prep- aration should be used  then?  In practical use, people with  delicate or irritable skin should start  with  preparations of lower  strength and,  when this  preparation  is tolerated, can continue with  higher strength formulations.

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