[|I areee completely with
the views in this chapter.|auteur193]
Topical treatments may be used alone or in association. They are useful in limited and stable psoriasis. They may also be of great help combined with systemic treatments to reduce the dosage, cope with a transient attack or increase their efficacy in certain sites. Some topical treatments are especially useful for coping with a crisis situation and will be used for a relatively short time, while others only develop their efficacy over a longer period and can be used as maintenance treatment. The same topical treatment may be used daily in the clearing phase and progressively spaced out over time as maintenance therapy. Only very few topical treatments (vitamin D analogues, Dithranol) are suitable for maintenance therapy. With regards to extensive psoriasis, convenient topical treatments for maintenance therapy are sorely lacking.
Topical treatments are hydration of the skin, tars, dithranol, topical corticotherapy, vitamin D derivatives, topical retinoids and spa cures.
1.2. Hydration of the skin
Applying Vaseline to normal skin slows down epidermal renewal of the basal layer, and it has been shown by Eugène Farber that the occlusive effect of hydrating the skin was able to halve epidermal renewal in a psoriasis plaque. This is not enough to eliminate the lesions, but is far from being negligible. A good excipient may result in a 60% improvement in PASI, like certain studies of topical treatments versus placebo have shown. Cosmetics (and thus excipients) perform a variety of biological activities on the epidermis, which differ according to the cosmetic. The biological activity of cosmetics is still very poorly understood, and excipients are not all equally effective on psoriasis. The excipient my patients prefer the most has the following formula: Hydrocerin 70g, methyl parahydroxybenzoate 1g, water 30g. The high concentration of preservative brings out its mild, but interesting, anti-proliferative activity. Hydrating the skin just before phototherapy increases the transparency of the corneal layer and thus its efficacy, but also the risk of a phototoxic incident.
These are mixtures of more than 10,000 molecules, 6,000 of which have been barely identified. Tars slow down skin renewal by unidentified mechanisms. They have been in use for more than 60 years in combination with ultraviolet B’s in the treatment of psoriasis, particularly in England. No epidemiological study has been carried out to assess whether any relation exists between this treatment and an increase in the incidence of skin cancers or deep-seated organs.
They have been practically removed from therapy in France because of their messy, smelly nature, because of a theoretical carcinogenic risk and, above all, due to the existence of dithranol, which ranks closely in effectiveness. Tars still perform some services associated with corticosteroids according to the varied formulations suggested by Charles Gruper and by combining coal-tar between 2 and 6%, salicylic acid between 1 and 2%, Diprosone ointment (a class 2 steroid ointment) between 30 and 60%, with Vaseline to make it up.
Some patients are still pleased with cade oil, which is far less active but more convenient to use.
1.4. Dithranol or anthraline
Anthraline does not interact with DNA. Neither mutagenic nor carcinogenic, it acts by blocking mitochondrial respiration and inhibiting the pentoses pathway. This occasions a drastic decrease in the energy available to the cell, with selective action on the cells displaying intense mitochondrial activity, as is the case of the psoriatic keratinocytes and the activated T lymphocytes.
Unlike many other European countries, we, in France, have no satisfactory commercial dithranol preparations and must use magistral preparations, which must be clearly marked ”Refundable magistral preparation for therapeutic use,” otherwise the price asked of the patient may be exorbitant and a refund refused. The quality of the magistral preparation must be checked, which is easy enough to do simply by observing the colour of the preparation that must be of a very light yellow. Any trace of brown indicates that the dithranol has oxidized and transformed into dimers, which are messy and ineffective. This sensitivity to inactivation by oxidization and dimerization means that dithranol must be prescribed in a hydrophobic excipient in order to reduce the rate of oxidization and combined with an antioxidant. The classically used antioxidant was salicylic acid in a concentration equal to that of dithranol. Salicylic acid actually heightens the irritant properties of dithranol and it is better to replace it with ascorbic acid.
Applied to the skin, dithranol is an irritant, especially in a delicate skin zone: the genital area, folds, neck and face. In these regions, dithranol is contraindicated. Dithranol stains underwear, as it becomes progressively oxidized on contact with air, and in a few hours brown stains, difficult to get rid of, will appear.
Used in accordance with a proper strategy, the clearance rate is 70%. Its efficacy is equivalent to that of the PUVA, making dithranol the most effective topical treatment.
Dithranol can be used according to two different strategies:
a) Short contact therapy
This technique exploits the fact that the lesional skin is much more permeable than the normal skin. Strong concentrations of the topical drug are therefore applied for a short time. This makes for considerable penetration on damaged skin and weak penetration on normal skin. This application is followed by careful washing and the application of moisturizing cream. Of course, this strategy can only be taken into service for psoriasis involving relatively few stable plaques. If the psoriasis is in flare mode and new plaques are appearing, this technique is no longer possible. The concentration of the preparation is chosen from 0.5 to 3%, and the application time will range from 10 minutes to one hour, according to the tolerance and the efficacy.
[|I agree with this procedure but I would like to
underline that the lowest concentration of Dithranol we use in our preparation
for a short contact therapy is 0.2 % (increased to a concentration of 0.4 % after one week); a treatment initiation
at this concentration has the advantage to minimize local adverse events
b) Low concentrations
0.05% dithranol can be applied to the whole body as a moisturizing cream, avoiding the face, neck, folds and genitalia. It can be left for between 1 and 12 hours. This strategy is therefore well suited to extensive psoriasis, even in the acute phase. It is particularly convenient for extensive paediatric psoriasis. The preparation is applied to the child’s whole body when they come home from school, then left for an hour or two, putting on an old tracksuit, then taking a shower and applying moisturizing cream. This strategy, suggested by Odile Enjolras, comes in most handy. If it proves ineffective after a month, the concentration can be doubled, increasing it every month in this way until an effective concentration is found that is not too irritating. When a result has been obtained, the applications are spaced out. Here again, the antioxidant must be ascorbic acid. An excellent dithranol formulation exists in England, called Dithrocream, making several concentrations available to patients in a particularly pleasant and mostly non-irritating excipient. Let us hope that we shall have this kind of formulation in France one day.
Applications are done every day until the lesions disappear; then it is either possible to stop the treatment or move on to maintenance therapy once or twice a week. Anthralin is therefore used for the clearing phase therapy and as a maintenance therapy.
Dithranol has been combined with UVB therapy for more than 60 years in the USA, where this treatment is given in day care centres. Dithranol may also be combined with topical corticotherapy, akin to the strategy developed by Charles Gruper with tars. It is clear, however, that nothing is known about the stability of the corticosteroid molecules placed in contact with a molecule with such a violent oxidizing nature.
Dithranol is contraindicated on erythrodermic and/or pustular psoriasis.
Dithranol must be applied following the direction of body hair to avoid chemical folliculitis.
[|I am glad that dithranol treatment is still going strong. However, we should not forget that an adequate treatment setting is needed for successful dithranol treatment: In patient department or daycare clinic. Although dermatologists regard these treatments as old-fashioned, the efficacy of dithranol treatment at in patient department or day care unit is remarkable and can be comparable to PUVA treatment. What to do if a patient is covered with squamous-cell carcinomata by combinations of photo(chemo)therapy and systemic treatments? It is important to reach clearance for optimal inspection, should we do that, in a patient who is cancer prone with an immuno-suppressive treatment? Dithranol and also systemic retinoids are of major importance here, for the fast induction of clearance and maintenance resp.|auteur197]
1.5. Topical corticosteroids
[|In the area of topical corticosteroid therapy, it has interested me that clobetasol propionate was developed in the early 1970’s by Glaxo in England. Why have we not had any further advances in pure topical steroid therapy since? Also, are there better methodologies of delivering topical steroids of different strengths, eg vehicles and occlusive dressings? I do believe there is a role for a broad-ranging use of dressings of various shapes and sizes to more easily adapt to bony areas, including joints, hairy areas, that will allow patients to go about their daily work while accomplishing clearing of their psoriasis within days rather than weeks. Even with our potent new systemic biological agents plus ciclosporin and methotrexate, localized areas remain that fail to clear completely, necessitating intensive topical therapy for these residual plaques.|auteur215]
Topical corticotherapy remains the benchmark topical treatment for psoriasis in numerous countries. It is still the benchmark topical treatment for the majority of therapeutic trials when compared to new topical therapies on the clearing phase. This paradoxical situation is the outcome of topical corticotherapy having long been the only topical treatment available and of this treatment being relatively inexpensive.
Resuming the development of the relationship between corticosteroids and psoriasis, everything starts after the Second World War with systemic corticotherapy. It was spotted very soon that some patients, very few in number, are highly sensitive to general corticotherapy that can be stopped without giving rise to rapid relapse. The vast majority of patients, however, become cortico-dependent to doses of corticosteroids unacceptable in terms of side effects. Finally, numerous patients witness the onset of a vigorous psoriasis attack on discontinuing general corticotherapy. These rebound effects may extend as far as a pustular or erythrodermic psoriasis attack. These findings have caused general corticotherapy to be contraindicated in psoriasis.
The main difference between topical corticotherapy and general corticotherapy is that the systemic effects of the former are less significant. Everyone has noted that with topical corticotherapy, done properly, a small number of patients benefited from prolonged remissions, allowing topical treatment to be stopped progressively, but that most patients become corticodependent and an indisputable rebound effect may follow a sudden halt in topical corticotherapy.
Equally, everyone knows that in any chronic inflammatory disease, like systemic lupus erythematosus, for example, a too fast decrease in general corticotherapy can bring about a relapse and a rebound in the disease. Since the use of strong topical corticotherapy in the treatment of bullous pemphigoid, it has been clearly observed that a too rapid fall-off in treatment will also end in a relapse of the illness. These observations need to be taken into account when using the topical corticotherapy of psoriasis. It must be strong to begin with, then reduced very gradually, and pursued despite the disappearance of the lesions. The most usual time-frame for the elbows and knees, for example, is the use of strength 1 corticotherapy (Clobetasol), every day for one month, one day out of two for two months, two days a week for three months, one day a week for one year. Stopping too quickly will often be followed by a relapse, frequently with the appearance of corticoresistance. If the improvement is incomplete, the patient’s corticodependence needs to be realized fairly quickly. Moreover, topical long-term corticotherapy is not only relatively ineffective in some patients but it seems to maintain the disease: out of a series of one hundred patients monitored for a year, 30 saw their psoriasis present a mild attack for a month or two and then disappear completely after stopping long-term topical corticotherapy. Cortico-maintained psoriasis does exist, then.
Interestingly, different areas of the body do not respond to topical corticotherapy in the same way. Hairy areas are generally cortico-sensitive, and so are the folds. However, in these areas a reduction in corticosteroid strength is necessary because of the occlusive effect, and we must prefer the use of lotions to reduce maceration risks. Topical corticotherapy in psoriasis, as in all chronic disorders, is contraindicated for the facial area.
[|I feel that the use of topical
corticoids should be more strict about the fact that they always should be used
only over short periods of time, that areas with thin skin should be spared,
and there are practically no side effects even in long term use in the scalp.
Furthermore, low potency corticosteroids are generally ineffective (and thus
useless) in psoriasis.|auteur195]
Topical corticotherapy in psoriasis is essentially used to cope with urgent situations where clearance must be achieved quickly without having to take long-term effectiveness into account (hospitalization, erythroderma, getting married, going away on holiday etc). When topical corticotherapy is undertaken in psoriasis, some thought must be given to whatever topical or systemic treatment that may be suggested as its successor and it should be set in motion before the end of the topical corticotherapy. Topical corticotherapy may be used initially in conjuction with calcipotriol or other vitamin D analogues to improve tolerability and efficacy. This association is proposed according to different strategies:
- topical steroids in the morning, vitamin D derivatives by night,
- topical steroids the weekend, vitamin D derivatives the week days,
- in the same tube (Daivobet?) once a day.
This association can be used during the clearing phase and the maintenance phase.
[|We introduced a “WE strategy” as a maintenance
therapy for topical steroid treatment: this approach is consistent
in an every day application during saturdays and sundays (easy to
remember for the patients). This strategy avoids short and long term adverse
events of continuous topical steroid application but prevents an early relapse
of psoriasis on recalcitrant localisations.|auteur194]
Topical corticotherapy is contraindicated in combination with phototherapy due to the risk of rebound on halting the topical corticotherapy despite the phototherapy. Topical corticotherapy remains a virtually constantly effective treatment on the scalp. The side-effects of topical corticotherapy are well known. It is necessary to underline the risk of stretch marks, especially on teenagers. The possibility must be stressed of inducing or disclosing suprarenal insufficiency in a few patients with a very special sensitivity that is poorly understood at present.
1.6. Vitamin D derivatives
Their antipsoriatic activity was discovered by chance and, of their numerous biological properties, the reason for their antipsoriatic powers is yet speculated about: effects on differentiation of the epidermis, anti-proliferative effect, inhibition of cytokine production. The available molecules, in the order they are made available to patients, are Calcipotriol (Daivonex®), Tacalcitol (Apsor®) and Calcitriol (Silkis®).
All vitamin D derivatives have antipsoriatic activity, equal or slightly inferior to class 2 corticosteroids over two-three months of treatment (acute phase) (photos 68 and 69). No comparative studies have been carried out between topical corticosteroids and vitamin D derivatives in situations resembling more closely to real life, i.e. over one year. The major advantage of vitamin D derivatives is their absence of corticosteroid-type side effects, though they may have an irritative potential for some patients. Topical vitamin D derivatives do not induce tachyphylaxis or rebound and are quite adapted to poorly compliant patients.
At the moment, the most effective product is Daivonex® ointment, used mornings and evenings. Due to its irritative potential, however, usage in sensitive regions, skin folds, genitalia and face should be carried out with care. Apsor® has the advantage of a single application a day. Its irritant potential has not been compared with that of Daivonex®. Silkis® has the distinctive feature of being well tolerated in the sensitive regions, folds and face. Oddly, on other areas of the body, it is as irritating as Daivonex® and slightly less effective, though some studies consider it just as efficacious. The option of using it on the face would make it an excellent candidate for treating seborrheic dermatitis.
The risk of hypocalcaemia is negligible with Vitamin D derivatives for topical use as long as the recommended weekly dosages are not exceeded. These molecules improve the quality of life on 30 to 40% of patients. Nonetheless, efforts remain to be made towards the improvement of galenic forms enhancing efficacy and tolerability, forms showing similar effectiveness whether applied once or twice a day, and a better knowledge of the possibilities of combination.
The combination of vitamin D derivatives with topical corticotherapy seems particularly interesting and is being put available in the same tube, in the combined form of calcipotriol/betamethasone dipropionate (Daivobet®). Applied once a day, it is well tolerated and has superior efficacy than both of its components used once daily as monotherapy. The combination of vitamin D derivatives with topical retinoids has not been studied but entails a risk of potentiating the irritant effects of these two molecules.
[|In a multicentrestudy no indication of increased calcipotriol irritancy during acitretin
treatment was observed.1 In contrast to the "heightening of the
irritant nature of vitamin D derivatives" as described in this book. van de Kerkhof PCM,
Cambazard F, Hutchinson PE et al. The effect of the addition of
calcipotriol ointment to acitretin therapy. BJ Dermatol 1998;138:84-9|auteur197]
Vitamin D derivatives can be combined, in a highly beneficial manner, with phototherapy (post-treatment application to avoid photodestruction), with retinoid treatment (subject to good cutaneous tolerability), with methotrexate and with cyclosporine.
Vitamin D derivatives used as monotherapy in the clearing phase present an average effectiveness, slightly below class 2 topical corticosteroids. The association between vitamin D derivatives and topical steroids is a huge progress for the clearing phase as well as for the maintenance phase of the treatment. Vitamin D derivatives, used as monotherapy, are the most convenient topical form of maintenance treatment for psoriasis as long as tolerability is good and the regular application restrictions are not too onerous for the patient. Vitamin D derivatives are the most interesting molecules in conjunction with other available treatment options. These associations should be more widely studied in psoriasis maintenance therapy. Ideally, it should be possible to assess them alone or in association at a low concentration in an excipient sufficiently pleasant to be used on the whole body as long-term maintenance therapy, after psoriasis has been cleared up by any other clearing phase therapy.
1.7. Topical retinoids
Of their numerous biological properties, the reasons for the antipsoriatic action of retinoids are not known. They have long been used via oral administration. Their topical use in the treatment of psoriasis has been severely set back by the irritant nature of these molecules and hence the risk of inducing Köebner’s phenomenon. Recently, the systematic study of a new retinoid derivative, tazarotene (Zorac®), has demonstrated that retinoids can be effective in psoriasis if administered topically and has qualified the ways and means of using them. Improvements in psoriasis plaques are less rapid than with a topical corticosteroid but seem to be longer lasting, although we lack sufficiently extended studies. The combination Zorac®/topical corticotherapy is particularly interesting because these topical corticosteroids cut down the irritation caused by Zorac®, while Zorac® reduces the atrophogenic effect of the corticosteroids and suppresses the rebound effect associated with stopping strong topical corticotherapy. The major problem, as with all topical retinoids, is skin irritation. The solution is the same as for all topical retinoids: patients must be educated, trained to apply as little product as possible and to adjust the frequency of applications according to tolerability. Some patients start off on a once a week regimen. As with the other retinoids, there is some progressive habituation of the skin which allows the application frequency to be increased after a few weeks, ending up with one application every day. This requires strict discipline, and underlines the interest of the combination of topical corticotherapy and tazarotene.
It is still too early to know what position tazarotene will take in the topical treatment of psoriasis or what will be the best strategy for use, the best indications (palmoplantar psoriasis?) and the best combinations with topical or general treatments. Controlled long-term studies are needed to pinpoint this molecule’s position in psoriasis treatment strategy.
[|I agree with the
statement that tazarotene is a good treatment alternative for palmoplantar
psoriasis in association with topical steroids, especially for palmoplantar
pustulosis. Local irritation is less frequently observed on this localisation.
A combination therapy with a topical steroid minimizes this local adverse
[|Likewise with the topical retinoids, with only one molecule currently available, ie tazarotene, it would be hoped that other topical retinoid molecules under development will prove more effective and less irritating, particularly as monotherapy, as I do believe that new retinoids, both topically as well as systemically, may hold promise in the future for psoriasis therapy.|auteur215]
1.8. Topical Calcineurin Inhibitors
Tacrolimus (Protopic?) is very effective in face and folds psoriasis. Its effectiveness on the other body areas is weak.
Some dermatologists have obtained good results with Tacrolimus under occlusive on Acrodermatitis continua of Hallopeau. Pimecrolimus (Elidel?) could also be useful but is less effective. These molecules are very helpful for treating seborrheic dermatitis resistant to classical treatments.
1.9. Spa treatments
Sun and sea improve 70% and aggravate 10% of psoriatics. We have no rigorous assessment of the benefits of “spa cures” and it would be very interesting to have this therapeutic approach evaluated. It is not known what proportion of their effectiveness is linked to the psychological relaxation and group therapy they encompass, to the ritual of using thermal springs or to the intrinsic qualities of any particular spa water. A certain number of patients (25%?) derive real benefit from such cures in terms of their quality of life. Nor is it known the benefits of a cure compared to those of a stay at the seaside in the sunshine. Finally, there is no information available that would lead us to suppose that a specific and expensive cure not funded by the national health service, like those at the Dead Sea, might be of special and of greater interest than others.
- 2019/08/12 Focus on...Latin American Clinical Practice Guidelines on the Systemic Treatment of Psoriasis
- 2019/06/03 Focus on...News from our SPIN Columbian members
- 2019/05/21 Focus on...SPIN2019 is now available on your screen!
- 2019/04/18 Focus on...SPIN Congress 2019 in Paris coming soon
- 2019/04/17 Focus on...Do not miss Spin Congress 2019 highlights
News from the web office
- 2017/06/05PIN becomes SPIN - Skin Inflammation & Psoriasis International Network
- 2016/10/29PSO 2016 Congress - Webcasts Available!
- 2016/05/26PIN Survey on Phototherapy
- 2016/02/20PIN Study on Therapeutic Patient Education
- 2016/02/19World Directory of Psoriasis Medical Resources - February 2016 Update
- 2019/04/18 Focus on...SPIN Congress 2019 in Paris coming soon
- 2018/07/16SPIN Symposium at the Spring continental meeting - Tehran, 25-27 April 2018
- 2018/02/222nd National Meeting of the Egyptian Society for Psoriasis
- 2018/02/211st Psoriasis Symposium - Sarajevo 2017
- 2017/06/2815th São Paulo Meeting of Psoriasis and Vitiligo
News from medical groups
- 2018/04/183rd Turkish National Psoriasis Symposium
- 2017/06/21Brazilian Center for Psoriasis Studies joins SPIN!
- 2017/06/21Costa Rica Psoriasis Group - Meet them!
- 2017/02/02Works of the 1st Senegalese Psoriasis Day published!
- 2016/07/29Swiss S1 Guidelines for Systemic treatment of psoriasis vulgaris
News from patients associations
- 2017/02/08France Psoriasis - 2016 World Psoriasis Day
- 2016/05/26Senegal Patients Association joins PIN!
- 2015/08/04Epidermia Greece: a new partner association of PIN
- 2015/08/01Canadian Association of Psoriasis Patients joins PIN!
- 2015/04/09AEPSO Argentina launches digital map to find people with psoriasis in the country
Recent publications on Psoriasis and Atopic Dermatitis
JAK-inhibitors in dermatology: current evidence and future applications.
J Dermatolog Treat. 2019 Nov , 30, (7):648-658.
The Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway is a ubiquitous intracellular signaling network. Selective JAK-inhibitors have anti-inflammatory properties and have been approved in many countries for the treatment of rheumatoid arthritis (tofacitinib, baricitinib) and myelofibrosis or polycythemia vera (ruxolitinib). The aim of the publication was to summarize and critically analyze the efficacy and safety of JAK-inhibitors in skin diseases, such (...)see on pubmed
Patient preferences for attributes of topical anti-psoriatic medicines.
J Dermatolog Treat. 2019 Nov , 30, (7):659-663.
Patient preferences should be considered when prescribing topical treatments to drive up adherence and improve clinical outcomes. The aim of this work was to identify the most important attributes of topical medicines for psoriasis treatment in the patients' view, and explore the sociodemographic and clinical determinants of these preferences. A questionnaire for the evaluation of the relevancy given to specific attributes of topical medicines used for psoriasis treatment was developed (...)see on pubmed
Salidroside inhibits MAPK, NF-κB, and STAT3 pathways in psoriasis-associated oxidative stress via SIRT1 activation.
Redox Rep.. 2019 Dec , 24, (1):70-74.
To unveil the role of SIRT1 in limiting oxidative stress in psoriasis and to further discuss the therapeutic prospects of salidroside in psoriasis. Literature from 2002 to 2019 was searched with "psoriasis", "oxidative stress", "SIRT1", "salidroside" as the key words. Then, Oxidative stress in psoriasis and the role of SIRT1 were summarized and the potential role of salidroside in the disease was speculated. Oxidative stress might contribute to the pathogenesis of psoriasis. High levels (...)see on pubmed
A case of infective endocarditis associated with atopic dermatitis perioperatively treated with dupilumab.
J Dermatolog Treat. 2019 Nov , 30, (7):674-676.
Several case reports and reviews support a relationship between atopic dermatitis (AD) and infective endocarditis (IE). Here, we present a case of severe AD suspected of causing IE. A 21-year-old man with severe AD was admitted to our hospital due to unidentified fever, syncope, and headache. He was diagnosed with IE with cerebral embolism and mitral regurgitation. Before elective cardiac surgery, he was subcutaneously administered dupilumab for 2 months to control AD. Dupilumab improved (...)see on pubmed
Effect of cinnamamides on atopic dermatitis through regulation of IL-4 in CD4 cells.
J Enzyme Inhib Med Chem. 2019 Dec , 34, (1):613-619.
This study aimed to evaluate the effects of cinnamamides on atopic dermatitis (AD) and the mechanisms underlying these effects. To this end, the actions of two cinnamamides, (E)-3-(4-hydroxyphenyl)-N-phenylethyl acrylamide (NCT) and N-trans-coumaroyltyramine (NCPA), were determined on AD by orally administering them to mice. Oral administration of the cinnamamides ameliorated the increase in epidermal and dermal thickness as well as mast cell infiltration. Cinnamamides suppressed serum (...)see on pubmed
Sublingual immunotherapy of atopic dermatitis in mite-sensitized patients: a multi-centre, randomized, double-blind, placebo-controlled study.
Artif Cells Nanomed Biotechnol. 2019 Dec , 47, (1):3540-3547.
Allergen-specific immunotherapy is widely used for allergic rhinitis and asthma treatment worldwide. This study explored the efficacy and safety of sublingual immunotherapy (SLIT) with the extracts of ( Drops) on house dust mites (HDM)-induced atopic dermatitis (AD). 239 patients with HDM-induced AD were recruited and exposure to a multi-centre, randomized, double-blind, and placebo-controlled clinical trials for 36 weeks, which were randomly divided into placebo and sublingual Drops (...)see on pubmed