Chapter 19
Zinc and Other Experimental Medical Treatments
Brigitte Dreno, Anabelle Brocard
19
Key points
Q New drugs are being studied for the medical therapy of hidradenitis suppurativa (HS)
Q Zinc salt may have an anti-inflamma- tory effect in HS
Q Botulinum toxin may play a role in the treatment of HS
#ONTENTS
19.1 Introduction . . . 141
19.2 Zinc Salts . . . 141
19.2.1 Mechanisms of Action: Modulation of the Proliferation and Differentiation of Keratinocytes and Cell Apoptosis . . . . 141
19.2.2 Anti-Inflammatory Activity . . . 142
19.2.3 Activity Against 5A-Reductase . . . .142
19.2.4 Healing . . . 142
19.3 Zinc Salts in Verneuil’s Disease . . . 142
19.4 Other Experimental Drugs . . . 143
References . . . .144
19.1 Introduction
Zinc salts have been used for a long time in the treatment of mild and moderate acne. The usual dose is between 30 mg and 60 mg zinc metal daily (corresponding to two – and four respec- tively – capsules of 15 mg zinc gluconate per day in France). Clinical studies have shown a sig- nificant effect of zinc salts mainly on inflamma-
tory lesions (superficial and deep lesions). Zinc gluconate was about 15% less effective than minocycline in a randomized trial [12].
In Verneuil’s disease, the drugs usually pre- scribed in acne (cyclines, isotretinoin) are poor- ly effective, and a need for additional therapy exists. So, owing to the in vitro anti-inflamma- tory effect of zinc and its clinical efficacy against inflammatory, even nodular, acne lesions, zinc gluconate has been used in Verneuil’ s disease.
19.2 Zinc Salts
19.2.1 Mechanisms of Action:
Modulation of the Proliferation and Differentiation of Keratino- cytes and Cell Apoptosis
Zinc is a cofactor of many metallo-enzymes [1]
implicated in the replication of DNA, gene tran- scription, RNA and proteomic synthesis. Thus, it increases the proliferation of keratinocytes and modulates their differentiation. This physi- ological role is altered by a severe shortage of zinc [2] (congenital or acquired). At the clinical level, it induces an ichtyosiform aspect of the skin, which is, moreover, atrophic. At the histo- logical level, a parakeratosis aspect is noted, with necrosis of keratinocytes, and at the elec- tron microscopy level a decrease of keratohyalin granules and tonofilaments in the keratinocytes is observed.
In the dermis, zinc also stimulates the prolif- eration of fibroblasts, increasing collagen and elastin production. This is mainly related to its action on lysyl oxidase. In addition, it is a co- enzyme of several metallo-enzymes of the der- mis.
142 Brigitte Dreno, Anabelle Brocard
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Zinc also has a role in the apoptosis of kerati- nocytes. In vitro, the addition of a chelator of zinc to the culture medium decreases the nucle- ar concentration of zinc in keratinocytes, induc- ing cell apoptosis. This activity is related mainly to its role as a co-enzyme of different transcrip- tional factors implicated in apoptosis, such as P53 or FP1 (ferroportin 1). In addition, zinc, as an antagonist of calcium, inhibits the activation of “endonucleases”, which have an anti-apop- totic activity. Recently it has been shown that zinc salts stimulate the production of insulin- like growth factor, which induces the prolifera- tion of keratinocytes in the epidermis.
19.2.2 Anti-Inflammatory Activity
Zinc’s efficacy in Verneuil’s disease is probably due to its anti-inflammatory activity. It has ac- tivity against various targets implicated in the cutaneous inflammatory reaction and the mechanism of action is still only partially un- derstood.
As for non-specific immunity, 30 mg zinc metal [3] inhibits the chemotactic migration of granulocytes, both in vitro and in vivo. It acti- vates natural killer cells and the phagocytic function of granulocytes [4].
Zinc also inhibits the expression of integrins by keratinocytes in inflammatory lesions, i.e.
ICAM 1 and LFA 3, which play an important role in the interactions between keratinocytes and lymphocytes [5].
The production of two main inflammatory cytokines produced by keratinocytes in inflam- matory lesions, namely tumour necrosis factor alpha (TNFA) and interleukin-6 (IL-6), is inhib- ited by zinc salts [6]. In addition, zinc has an anti-oxidant activity, by inducing the expres- sion of the enzyme Zn-Cu superoxide dismutase, which is present in keratinocytes and fibro- blasts; thus, it increases the elimination of free radicals. As for T-cell-mediated immunity, zinc is a cofactor of thymulin, which is a thymic cyto- kine implicated in the maturation of T lympho- cytes.
19.2.3 Activity Against 5A-Reductase
Zinc salts have anti-androgenic activity, by in- hibiting the activity of 5A-reductase type I and II (mainly I in vitro [7]). This enzyme induces the transformation of testosterone to dihy- drotestosterone, which binds to androgenic re- ceptors expressed by sebaceous glands stimulat- ing the production of sebum. This activity remains to be demonstrated in vivo.
19.2.4 Healing
Zinc stimulates the migration of keratinocytes, which play an important role in the healing of cutaneous wounds, by stimulating _3, _5 and
`1 integrin functions [8, 9].
19.3 Zinc Salts
in Verneuil’s Disease
Until now there have been no reports on zinc’s efficacy in HS. At the Department of Dermatol- ogy of Nantes (France), we have treated 22 pa- tients with Verneuil’s disease with zinc gluco- nate (Rubozinc·) [10].
In total, 15 women and 7 men were included in the study. The mean age was 38.3 years, the mean age at the onset of lesions was 24. 6 years and the mean duration between the beginning of the illness and diagnosis was 6.5 years. Eleven patients were at Hurley’s grade I, 10 at grade II, and 1 at grade III. Zinc gluconate was used at a dose of six capsules of 15 mg zinc gluconate per day (Rubozinc·). The mean follow-up was 23.7 months. Results were assessed depending on the degree of remission.
Of the included patients 8/22 (36%) experi- enced complete remission. Complete remission was defined as no new lesions for 6 months or more (Figs. 19.1, 19.2). For these patients an at- tempt to decrease the doses of zinc was made but relapses were seen at a dose of between two and four capsules. Recurrences disappeared when the dosage of zinc salts was increased again. Thus, the treatment appears clearly to be suppressive rather than curative. A dose–re- sponse relationship may be present, as it would
Zinc and Other Experimental Medical Treatments Chapter 19 143
appear that a clinically suppressive effect only occurred at high doses.
Partial remissions were seen in 4/22 (18%) patients. Partial remission was defined as a de- crease in the number of nodules and a shorter cycle of each inflammatory lesion, based solely on the patient’s opinion. For an outcome to be classified as a partial remission, the patients’ as- sessments should remain stable for 1 year.
Stabilization was defined as no progression under treatment, and categorized as the lesser of the positive outcomes. Almost half (10/22, 45%) of the included patients experienced stabiliza- tion. None of the patients experienced deterio- ration of their HS during treatment. Gastro- intestinal side-effects (diarrhoea, gastralgia, nausea, abdominal pains) were noted in four pa- tients. One patient had to stop the treatment.
The efficacy of zinc salts in Verneuil’s disease probably relies mainly on its anti-inflammatory activity. A similar effect is seen in acne, where zinc salts are used at a lower dose (30 mg metal zinc) and treatment appears to be brought about essentially by action on inflammatory lesions [11, 12]. A prospective study is now ongoing to confirm this preliminary result.
19.4 Other Experimental Drugs
Apocrine glands produce sweat, which becomes smelly after bacterial degradation. Heckmann et al. [13] reported that botulinum toxin may decrease the production of sweat by apocrine glands, similarly to the effect on eccrine glands.
The mechanism is related to the cholinergic stimulation of apocrine glands, which is inhib- ited by the botulinum toxin. Although based on an erroneous concept of apocrine gland involve- ment, botulinum toxin has been tried in the treatment of HS. Two cases of treatment of Ver- neuil’s disease (HS) with botulinum toxin have been reported [14].
The first patient was a 29-year-old woman with recalcitrant HS, who experienced relapses after isotretinoin, zinc gluconate and antian- drogen therapy. The lesions were located in the axillary regions and mammary folds. Botuli- num toxin A (Botox®) was injected at a dose of 50 units in each axillary region and 10 units in each of the mammary folds. A complete remis- sion was observed after 1 month. The duration of the effect was 6 months, with a disappearance of the lesions after new injections.
The second patient was a 24-year-old woman who had experienced a minor therapeutic effect of antiandrogen and isotretinoin treatment. In her case botulinum toxin (100 units) was inject- ed in the left axillary region, allowing a left–
right comparison of the effect. A clinical effect was observed as soon as 15 days after the injec- tion. The right side was subsequently injected with 100 units 1 month later, when the differ- ence between the two sides was dramatic. The nodules recurred after 6 months, disappearing after a new injection of botulinum toxin. Later, the same treatment was successfully used in the pubic region of the patient.
Fig. 19.1. Before treatment
Fig. 19.2. After 6 months of zinc gluconate, six capsules/
day
144 Brigitte Dreno, Anabelle Brocard
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Although based on an erroneous understand- ing of the tissues involved in HS, these seren- dipitous observations appear promising, and need confirmation in more structured trials.
The possible mechanism may also be interpret- ed to be a reflection of reduced eccrine sweat gland activity, which leads to reduced sweating and thereby indirectly to a reduction of the shear forces on the surface of the skin and the hair follicles. The appropriate doses must also be identified more precisely. Finally, the poten- tial side-effects after several injections should be studied, as the treatment appears only to be suppressive, with a 6 months duration of effect.
References
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2. Stephan F, Revuz J. Sels de zinc en dermatologie. Ann Dermatol Vener 2004; 131: 455–60.
3. Dréno B, Trossaert M, Boiteau HL, Litoux P. Zinc salts effects on granulocyte zinc concentration and chemotaxis in acne patients. Acta Derm Venereol 1992; 72: 250–2.
4. Chvapil M, Stankova L, Zukoski C IV, Zukoski C III.
Inhibition of some functions of polymorphonuclear leukocytes by in vitro zinc. J Lab Clin Med 1977; 89:
135–46.
5. Guéniche A, Viac J, Lizard G et al. Protective effect of zinc on keratinocyte activation markers induced by interferon or nickel. Acta Derm Venereol 1995; 75:
19–23.
6. Sainte Marie I, Jumbou O, Tenaud I, Dréno B. Com- parative study of the in vitro inflammatory activity of three nickels salts on keratinocyte. Acta Derm Venereol 1998; 78: 169 –72.
7. Sugimoto Y, Lopez-Solachez I, Labrie F, Van-Luu- The. Cations inhibit specifically type I 5 alpha re- ductase found in human skin. J Invest Dermatol 1995; 104: 775–8.
8. Tenaud I, Sainte Marie I, Jumbou O, Litoux P, Dreno B. In vitro modulation of keratinocyte integrins involved in cutaneous wound heal- ing by means of trace elements (zinc, copper and manganese). Br J Dermatol 1999; 140: 26–34.
9. Tenaud I, Leroy S, Chebassier N, Dreno B. Zinc, copper and manganese enhanced keratinocyte mi- gration through a functional modulation of kerati- nocyte integrins. Exp Dermatol 2000; 9: 407–16.
9. Brocard A. Maladie de Verneuil et zinc: une nou- velle approche thérapeutique. Thèse Médecine, April 2005.
10. Dreno B, Amblard P, Agache P, Sirot S, Litoux P.
Low doses of zinc gluconate for inflammatory acne.
Acta Derm Venereol 1989; 69: 541–3.
11. Dreno B, Moyse D, Alirezai M, Amblard P, Auffret N, Beylot C, Bodokh I, Chivot M, Daniel F, Hum- bert P, Meynadier J, Poli F and private practice Dermatologists coordinated by the Acne Research and Study Group (GREA). Multicenter randomized comp gluconate versus minocycline hydrochloride in the treatment of inflammatory acne vulgaris.
Dermatology 2001; 203: 135–40.
12. Heckmann M, Teichmann B, Pause BM. Ameliora- tion of body odor after intracutaneous axillary in- jections of botulinium toxine. Arch Dermatol 2003;
139: 57–9.
13. Bodokh I. Traitement de la maladie de Verneuil par injection de toxine botulique A. Poster Journées de Paris, December 2004.
