New Developments and Future Trends

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After decades of stagnation, research on systemic acne treatment has expanded markedly in the last several years. The results of numerous studies have greatly increased our understanding of both the pathophysiology of the disease and the mechanisms of action for current therapies. New developments occurred including the low-dose long-term isotretinoin regimen, new isotretinoin formulations, understanding of isotretinoin's anti-sebotropic action, new antibiotics, and combination treatments to reduce toxicity and bacterial resistance, and new oral contraceptives. Future trends represent new anti-inflammatory agents, such as 5-lipoxygenase inhibitors, insulin-sen sitizing agents, 5a-reductase type 1 inhibitors, and antisense molecules.

Low-Dose Isotretinoin

Low-dose isotretinoin (0.1-0.3 mg/ml/day daily or intermittent use) can effectively control acne, also being cost-effective. Nevertheless, the daily dose is too low for the cumulative dose obtained to be definitively curative. Although studies have been centered on the use of low doses only in older patients with exceptionally oily skin or in patients with long duration acne [76-80], there is a trend by practicing dermatologists to use low-dose isotre-tinoin in adolescent acne with a tendency to become inflammatory or in moderate acne as replacement of systemic antibiotics. The suggested rationale of such use is the effective control of inflammation with the final objective of preventing inflammation and the resulting scars. The approach taken is that of control and not of absolute resolution, since this resolution will occur in the majority of patients naturally. The simultaneous use of an effective topical therapy is mandatory. Since a large percentage of patients to be treated with mini-doses are women, they should be made to understand that the teratogenesis risk is the same as with the complete dose. Adverse events with these low doses are almost absent.

New Isotretinoin Formulations

A recent study by Strauss et al. [81] using a micronized isotretinoin formulation with higher bioavailability exhibited similar efficacy results of a single daily 0.4 mg/kg dose of micronized isotretinoin and 1.0 mg/kg standard isotretinoin administered in two divided doses after 20 weeks of treatment. Micronized isotretinoin presented a safety profile similar to that of standard isotretinoin with a lower risk of mucocutaneous adverse events and hyper-triglyceridemia [82].

Understanding the Unique Activity of Isotretinoin

The high anti-sebotropic activity of isotretinoin is particularly surprising because of the fact that it has low binding affinities for both cellular retinoic acid-binding proteins I and II as well as for nuclear retinoic acid receptors [83, 84]. Because retinoids are thought to exert most of their effects by modulating gene expression and/or activating nuclear retinoid receptors, it has been suggested that isotretinoin may act as a pro-drug that becomes active after isomerization to tretinoin acid or conversion to alitretinoin [84]. Indeed, current results reported by Tsukada et al. [85] have shown that isotretinoin undergoes significant isomerization to tretinoin in cultured sebocytes, an effect being specific for these cells. In addition, administration of isotretinoin to sebocytes only led to a delayed induction of the cytochrome P450 isoenzymes responsible for tretinoin inactivation. Isotretinoin effects were found to be dependent on the extra-cellular albumin concentration [86]. On the other hand, tretinoin acted via retinoic acid receptors (RAR) to exert its anti-proliferative effect on sebocytes. Therefore, the molecular basis for this anti-sebotrophic activity is probably a selective intracellular isomerization of isotretinoin to tre-tinoin in human sebocytes, with isotretinoin representing a pro-drug for tretinoin in this specific tissue. Newer data indicate that isotretinoin metabolites, such as 4-oxo-iso-tretinoin, may also represent compounds exhibiting direct anti-acne activity.

In addition to the better understanding of isotretinoin activity, new possible adverse events have emerged. The proposed relationship between the compound and depression as well as suicide was reviewed not to be based on a putative molecular mechanism of the compound indicating that there is no evidence to support a casual connection [87]. On the other hand, 38 different signs and symptoms of ocular abnormalities were reported as 'certain' to have resulted from the use of isotretinoin, among them decreased dark adaptation may jeopardize adolescents under the drug who drive in the night [88].

New Antibiotics

Limecycline is a second-generation tetracycline linked to the amino acid lysine, with an efficacy similar to that of doxycycline and minocycline [89]. It is used at a 300 mg initial dose that is lowered to 150 mg after 2 weeks. It exhibits excellent tolerance with scarce risk of hyperpig-mentation, vestibular disorders and photosensitivity, and can be administered together with food.

Roxithromycin, a macrolide antibiotic, is administered in a dose of 150 mg twice daily in the treatment of inflammatory acne. It accumulates at therapeutic levels in the pilosebaceous system [90] and exhibits an interesting spectrum of effects, namely direct anti-inflammatory and anti-androgenic activities. It significantly inhibits the production of lipase and neutrophil chemotactic factor by P. acnes as well as of P. acnes-induced NF-kB activation at concentrations much lower than the MIC at which the growth curve of P. acnes is not affected [34, 91]. In addition, roxithromycin was found to serve as anti-androgen only in the hypersensitive state to androgens, but not in the physiological state through modulating end-organ hypersensitive condition to androgens [92].

Azithromycin, another macrolide antibiotic, was found as effective as doxycycline (100 mg/day) administered in a dose of 500 mg once a day for 4 days per month for a total of 12 weeks on a pure protocol basis and statistically significantly better than doxycycline by intention to treat analysis [93].

In an open study, levofloxacin was found effective for inflammatory acne and achieved high levels in the lesions [94].

Combination Treatments

Combinations of a topical retinoid (adapalene, treti-noin) or azelaic acid with oral antibacterial agents are recommended to induce maximum anti-inflammatory effect in mild to moderate inflammatory acne [45, 46, 93, 95]. Such combinations can lead to a rapid dose reduction and quicker discontinuation of oral antibiotics increasing the effectiveness, improving the compliance, and reducing the development of bacterial resistance to antibiotics.

New Oral Contraceptives

When oral contraceptives are administered in the treatment of acne, it is possible that some women are more sensitive to the androgenic effects of a progestin, but it is more likely that the effect of progestin may be offset by the estrogen. Although some progestins might be more androgenic than others, all oral contraceptives, regardless of the type of progestin each contains, increase SHBG and inhibit serum androgen levels. This is also possible with the marketed combination of ethinyl estradiol (20 |g) and levonorgestrel (100 |g; one of the older and most andro-genic progestins) found to produce a significant decrease in comedones, as well as in papules and pustules [66, 96, 97].

The concentrations of estrogen in oral contraceptives have decreased over the years from 150 to 35 |g, and in the most recent forms to 20 |g, in order to reduce the side effects of estrogen. On the other hand, many progestins have been developed over the years and the third-generation progestins, including desogestrel, drospirenone, ges-todene, and norgestimate, are more selective for the progesterone receptor rather than the androgen receptor. The combinations of ethinyl estradiol (30-40 mg) and deso-gestrel (25-125 |g) [65, 98], ethinyl estradiol (20-35 |g) and norethindrone acetate (1 g) [99], ethinyl estradiol (30 mg) and drospirenone (3 mg) [64], and ethinyl estradiol and norgestimate (180-250 |g) [100, 101] have been marketed as contraceptive pills; among them those including norethindrone acetate and norgestimate have been approved for acne [27].

New Anti-Inflammatory Agents

It is widely accepted that inflammation in acne vulgar-is may be mainly induced by an immunologic reaction to extracellular products of P. acnes [102]. However, it is by no means clear that either bacteria or their products initiate follicular inflammation. Ingham et al. [103] investigated the presence of pro-inflammatory cytokines in open acne comedones from untreated acne patients and found bioactive interleukin(IL)-1a-like material. The majority of open comedones also contained micro-organisms, but there was no significant correlation between levels of any cytokine, in particular IL-1a, and numbers of microorganisms.

Additional results have shown that the sebaceous gland expresses a number of different cytokines at steady state, without the influence of any external factors. Antilla et al. [104] showed that IL-1 is present in normal sebaceous glands and Boehm et al. [105] used in situ hybridization techniques to show that messenger RNA (mRNA) for IL-1a, IL-1P and tumor necrosis factor-a is present at multiple sites in normal skin including the sebaceous glands. Thus, while the presence of bacteria, most notably P. acnes, may stimulate upregulation of cytokine expression in sebaceous glands [106], pro-inflammatory cytokines are expressed in these tissues in the absence of defined external influences.

Guy et al. [107] assessed the action of IL-1 a in the microdissected human pilosebaceous infundibulum preparations in vitro and found an IL-1a-specific induction of hypercornification of the infundibulum similar to that seen in comedones. Follicular keratinocytes and sebocytes in vitro were also found to produce pro-inflammatory cytokines and chemokines [108]. Currently, inflammation has been suggested to occur due to enhancement of IL-8 production in human monocytes and sebocytes through a mechanism requiring transcription factor NF-kB activation [34, 108] and involvement of Toll-like receptor 2 [109, 110]. These results provide logical support for the use of anti-inflammatory regimens in the treatment of acne [13].

The use of anti-inflammatory drugs for the treatment of acne is further supported by recent results indicating a key role for leukotriene B4 (LTB4) in the development of tissue inflammation [111]. LTB4 is a pro-inflammatory mediator synthesized from arachidonic acid. Synthesis of LTB4 is catalyzed by 5-lipoxygenase and leukotriene A4 hydrolase and is increased by inflammatory mediators including endotoxin, complement fragments, tumor necrosis factor-a and interleukins. LTB4 induces recruitment and activation of neutrophils, monocytes and eosin-

Leukotrienes Inflammatory Mediators

Fig. 7. The cascade of eicosanoid synthesis in the skin, as inflammatory signaling pathway possibly involved in the development of acne lesions. IL-1P = Interleukin-1P; TNF-a = tumor necrosis factor-a; LTB4 = leukotriene B4; 15-HETE = 15-hydroxyeicosatetraenoic acid; PPAR = peroxisome proliferator-activated receptor [from ref. 24].

Fig. 7. The cascade of eicosanoid synthesis in the skin, as inflammatory signaling pathway possibly involved in the development of acne lesions. IL-1P = Interleukin-1P; TNF-a = tumor necrosis factor-a; LTB4 = leukotriene B4; 15-HETE = 15-hydroxyeicosatetraenoic acid; PPAR = peroxisome proliferator-activated receptor [from ref. 24].

ophils. It also stimulates the production of a number of pro-inflammatory cytokines and mediators that augment and prolong tissue inflammation (fig. 7). Limited data from pharmacological inhibition studies support a role for LTB4 in the pathogenesis of neutrophil-mediated tissue damage.

The potential importance of this inflammatory pathway for acne treatment was evaluated in a small cohort of patients [112]. A 3-month study of the effectiveness of a specific lipoxygenase inhibitor was performed by systemic administration in 10 patients with inflammatory acne. Clinical evaluation of these patients indicated an approximately 60% decrease in the acne severity index within 3 weeks of the initiation of treatment and a 70% reduction in inflammatory lesions at 3 months. Additional evaluation indicated an approximately 65% reduction in total sebum lipids as well as a substantial decrease in lipoperoxides. Free fatty acids were also decreased by almost 80%. Bivariate analysis indicated that the decrease in total sebum lipids, and especially in pro-inflammatory lipids, was directly correlated with the improvement in inflammatory lesions. Thus, the results of this small-scale clinical trial and associated laboratory analysis strongly support the conclusion that appropriate anti-inflammatory therapy has the potential to effectively treat acne. These results also support the view that sebum lipids induce inflammation in acne, independent of the presence of bacteria or increased systemic levels of pro-inflammatory molecules.

Eleven years ago, Wozel et al. [113] assessed the ability of isotretinoin as well as a number of other agents to inhibit transdermal migration of polymorphonuclear leukocytes stimulated by LTB4. Topical treatment with iso-tretinoin resulted in a marked and statistically significant inhibition of the LTB4-induced migration of polymor-phonuclear leukocytes. Retinoids are nowadays considered to regulate inflammation [114, 115] probably also using the Toll-like receptor 2 pathway [116].

Insulin-Sensitizing Agents

Since insulin has a direct effect on ovarian androgen production in vitro, insulin resistance may play a crucial role in the physiopathology of peripheral hyperandro-genism, including acne [117]. Insulin-sensitizing agents have recently been investigated for their role in the short term treatment of insulin resistance in polycystic ovary syndrome. Controlled studies have shown that metformin administration, by promoting body weight loss, can decrease fasting and stimulated plasma insulin levels. However, other studies have shown metformin 500 mg 3 X daily to decrease insulin secretion and to reduce ovarian production of 17a-hydroxyprogesterone with recovery of spontaneous or clomifene-induced ovulation, independently of weight loss. These findings suggest a new indication for metformin and present insulin-sensitizing agents as a novel approach in the treatment of ovarian hyperan-drogenism.

Peroxisomes play an important role in regulating cellular proliferation and differentiation as well as in the modulation of inflammatory mediators. In addition, peroxi-somes have broad effects on the metabolism of lipids, hormones, and xenobiotics [118]. On the other hand, activation of peroxisome proliferator-activated receptor (PPAR)-y and -a by their respective specific ligands, thia-zolidinedione and clofibrates, was found to induce lipid droplet formation in rat preputial gland cells (resembling sebocytes) but not epidermal cells in vitro [119]. PPAR-y 1 mRNA was also demonstrated in rat preputial gland cells but not in epidermal cells. These findings are compatible with the concepts that PPAR-y1 gene expression plays a unique role in the differentiation of sebocyte-like cells. These findings have implications for the development of new modalities of treatment for acne vulgaris and explain why lipoxygenase inhibitors inhibit lipid synthesis [112]: The lipoxygenase products LTB4 and 15-HETE are natural ligands of PPAR-a and PPAR-y, respectively.

5a-Reductase Type 1 Inhibitors

The inhibitors of 5a-reductase isoenzymes (1 and 2) can be schematically divided in three groups according they substrate specificity: Pure or preferential inhibitors of 5a-reductase 1, pure or preferential inhibitors of 5 a-reductase 2, and dual inhibitors [26, 120]. Despite the fact that several steroidal and non-steroidal inhibitors have been synthesized and experimented in pharmacological models, only finasteride has been extensively used for clinical purposes, namely benign prostate hyperplasia and male baldness with positive results. In women, finasteride has been used in some control trials for treatment of hirsutism with an objective favorable response. On the basis of experimental observations on distribution of 1 and 2 isoenzymes in human skin, scalp and prostate, the pure 5 a-

reductase 1 inhibitors seem the ideal drugs for treatment of acne and hirsutism [121-123] and have been introduced in clinical studies [27].

Antisense Molecules

The androgen receptor is involved in the development of acne and its expression can classically be regulated by androgen receptor blockers. A more elegant way is the transient transfection of skin cells with antisense oligonucleotides against the androgen receptor [124]. The development of thioat- and ribosyl-antisense oligonucleotides against the androgen receptor led with high specificity in a transient diminished protein expression of the receptor and to a strong inhibition of the biological activity of androgens in human sebocytes and keratinocytes in vitro. Such experiments are only in an initial phase. The future clinical use of such highly specific compounds is dependent on several factors, among them being the effective administration pathway and the kind of transfection systems to be applied.

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