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Cholinergic Urticaria

Cholinergic urticaria is a form of physical, non-allergic urticaria due to excitement or due to heat, for instance pyrexia, hot baths, sun exposure, physical exertion or exposure to a warm room. The distinctive lesions are pruritic areas of 1-2 mm diameter and are surrounded by bright red macules.


Presentation

The presentation of urticaria is elevated, erythematous, pruritic weals or serpiginous exanthem, which are usually surrounded by an area of erythema, appearing transiently. Additionally, there may also be macular erythema or erythematous papule areas present. After etiological exposure skin lesions occur and within minutes to hours they peak, with the disappearance of individual lesions happening usually within 24 hours. The trunk and extremities are usually where urticarial lesions are found, but any epidermal or mucosal surface can be involved. An angioedema is a large weal formation where an edema from the dermis extends into the subcutaneous tissue. More distensible tissues, such as the eyelids, lips, ear lobes, external genitalia, and mucous membranes, are where this condition is normally seen. 

History

Normally, during the first few minutes of onset of sweating, cholinergic urticaria appears rapidly and has a duration of half hour to an hour or more averaging about 80 minutes. The most typical precipitating event is exercise, although an urticarial attack can be caused in some people by any stimulus that causes sweating, including an environmental temperature that has been elevated, hot food, sauna baths, hot water immersion, gustatory stimuli, emotional stress and hemodialysis [14]. Pruritus can be exacerbated and lesions provoked in areas that were unaffected previously by hot baths and exercise.

Symptoms

The onset of many small (1 to 4 millimeters in diameter), pruritic weals with large, surrounding flares are frequently preceded by burning, tingling, irritation, warmth, irritation, or itching in cholinergic urticaria. The appearance of cholinergic urticaria may occur anywhere in the body, although not in the palms of the hands or the soles of the feet, and it rarely occurs in the axillae. Sometimes, the only presentation is flares. Patient may experience systemic symptomatology if cholinergic urticaria affects them more severely including:

Duration

Cholinergic urticaria is a condition that returns for several years. A tendency to continue developing it for a number of years is retained by the majority of patients. The injection of botulinum toxin used for axillary hyperhidrosis may improve the disease [15]. However, a study showed that from its onset until the time it reaches 50% remission (roughly 34 months), the shortest course belongs to cholinergic urticaria [16].

Physical examination

Causing the patient to sweat through a stimulus such as walking or running on a treadmill, most reliably reproduces cholinergic urticaria. Cholinergic dermographism may be noted in some patients. Cholinergic urticaria may occur in a localized form with urticarial lesions induced by cold [17]. Patients with this condition experienced a generalized reaction when exposed to cold ambient air and to cold water, but the response to the ice-cube test was negative. About 1% of cold urticaria patients may be seen to have cholinergic urticaria induced by cold, and cold urticaria. Pressure urticaria, cold urticaria, and even aquagenic urticaria may accompany cholinergic urticaria.

Mucosal Edema
  • Distribution on the face and scalp was observed in 20 (21.7%) patients, on the lower limb in 18 (19.6%), and one (1.1%) had mucosal edema ( Table 2 ).[ncbi.nlm.nih.gov]
Hepatosplenomegaly
  • The clinical picture was identical: urticaria, hepatosplenomegaly, lymphadenopathy and elevation of liver enzymes. The causative agent was never identified and recovery was complete, with or without antibiotic therapy.[ncbi.nlm.nih.gov]
Urticaria
  • About 1% of cold urticaria patients may be seen to have cholinergic urticaria induced by cold, and cold urticaria. Pressure urticaria, cold urticaria, and even aquagenic urticaria may accompany cholinergic urticaria.[symptoma.com]
  • Other associated factors The prevalence of cholinergic urticaria is definitely higher in persons with urticaria; cholinergic urticaria affected 11% of a population with chronic urticaria in one study and 5.1% of persons with urticaria in another.[emedicine.com]
  • These conditions include urticaria factitia/symptomatic dermographism, delayed pressure urticaria, cold contact urticaria, heat contact urticaria, solar urticaria, and vibratory urticaria/angioedema.[ncbi.nlm.nih.gov]
  • Cholinergic Urticaria Pictures What does cholinergic urticaria look like? Like many diseases, cholinergic urticaria may have a slightly different appearance for each person.[cholinergicurticaria.net]
  • RESULTS: Fifty-nine adults participated in the study: 30 patients with cholinergic urticaria, 15 with chronic urticaria, and 14 healthy volunteers.[ncbi.nlm.nih.gov]
Chronic Urticaria
  • RESULTS: Fifty-nine adults participated in the study: 30 patients with cholinergic urticaria, 15 with chronic urticaria, and 14 healthy volunteers.[ncbi.nlm.nih.gov]
  • Karsten Weller and Marcus Maurer, Chronic Urticaria, Evidence‐Based Dermatology, (210-222), (2014).[doi.org]
  • Karsten Weller and Marcus Maurer, Chronic Urticaria, Evidence‐Based Dermatology, (210-222), (2014). David M.[doi.org]
  • Abstract Twenty patients with cholinergic urticaria, 11 sex- and age-unmatched patients with acute or chronic urticaria and 20 sex- and age-matched non-atopic control subjects were skin tested with autologous sweat.[ncbi.nlm.nih.gov]
  • The chronic urticaria prognosis in primary care is not known.[symptoma.com]
Anhidrosis
  • […] autonomic dysfunction other than generalized anhidrosis, raised serum IgE level, and marked response to steroid.[ncbi.nlm.nih.gov]
  • Kay DM, Maibach HI: Pruritus and acquired anhidrosis. Arch Dermatol 1969;100:291–293.[doi.org]
  • CU patients are occasionally complicated by anhidrosis and/or hypohidrosis. This reduced-sweat type should be included in the classification because the therapeutic approaches are different from the ordinary CU.[ncbi.nlm.nih.gov]
  • "Acquired idiopathic generalized anhidrosis: A rare cause of heat intolerance". Clinical and Experimental Dermatology. 28 (3): 262–264. doi : 10.1046/j.1365-2230.2003.01208.x.[en.wikipedia.org]
  • Acquired generalized hypohidrosis/anhidrosis is a rare condition of unknown pathogenesis, while idiopathic cholinergic urticaria is relatively common.[ncbi.nlm.nih.gov]
Eczema
  • The prevalence is also higher in persons with atopic conditions (eg, asthma, rhinitis, atopic eczema), but this is by no means exclusive. A rare, familial form of cholinergic urticaria has also been reported.[emedicine.com]
  • Abstract Autonomic function in patients with cholinergic urticaria and atopic eczema was compared with that in patients with chronic idiopathic urticaria and non-atopic allergic contact dermatitis, respectively. Forty-nine patients were studied.[ncbi.nlm.nih.gov]
  • Urticaria differs from eczema (atopic dermatitis) in that eczema is characterized by dryness, crusting, blistering, cracking, oozing, or bleeding. Hives are not typically described in these ways.[allergies.about.com]
  • People who are more likely to suffer from cholinergic urticaria include: Those who already suffer from generalised chronic urticaria People with asthma, rhinitis, and atopic dermatitis ( eczema ).[dermnetnz.org]
Decreased Sweating
  • History taking included symptom duration, association with atopy, decreased sweat secretions, seasonal variation, and response to treatment.[ncbi.nlm.nih.gov]
  • In particular, most patients who complained of winter exacerbations also complained of decreased sweat secretion. The patients had been treated with first and second-generation antihistamines, but their responses were poor.[ncbi.nlm.nih.gov]
Suggestibility
  • Four patients with symptoms suggestive of either cold urticaria or a combination of cold and cholinergic urticaria were studied.[ncbi.nlm.nih.gov]
  • The results suggest that histamine is the major mediator of urticaria and hypotension in cold urticaria.[ncbi.nlm.nih.gov]
  • A variety of pathogeneses has been proposed, which suggests that there exists several clinical subtypes.[ncbi.nlm.nih.gov]
  • Possible allergy-based etiology Several factors, including an increased incidence in patients with atopic dermatitis (AD), a marked sensitivity in some patients with anaphylactic and anaphylactoid reactions, and an immediate reactivity in some patients, suggest[emedicine.com]
  • This findings suggest a threshold dependency for the induction of CU. SVL measurement may be a useful method for the evaluation of sweating tests in CU patients.[ncbi.nlm.nih.gov]
Neglect
  • It is often true that when we are experiencing stress in life we tend to neglect things that seem less important. Skin care is probably pretty low on many peoples list of important things in life.[cholinergicurticariasite.com]

Workup

Urticarial lesions specimens that are biopsied may only show subtle microscopic changes. Subcutaneous or dermal edema, increased mast cell numbers, and a modest perivascular lymphocytic infiltrate, that might have cosinophils intermingled, may be evident. Mast cell and eosinophilic degranulation are revealed by electron microscopy. A 0.05mL of 0.02% (0.01mg) methacholine or 0.05mL of 0.002% carbamylcholine chloride (carbachol) intradermal injection has been traditionally used to cause a flare-up of the characteristic weals, often with satellites, of cholinergic urticaria. About 51% of patients have this outcome occur. People without this condition may experience the same flare-up, but in a smaller scale and the wealing is absent. A nicotinic acid dilution of 1:100,000 or 1:500,000 has also been used. Even curare derivatives (e.g. D-tubocurarine) have reproduced cholinergic urticaria lesions.

The reproduction of cholinergic demographism is possible by using methyl acetylcholine, stroking the skin, or using other stimuli known to result in sweating. Sweat-specific immunoglobulin E demonstrations can be facilitated by using iontophoresis and pilocarpine nitrate for those patients with cholinergic urticaria who cannot provide the sufficient sweat needed [18].

Skin Test Positive
  • The skin test-positive patient, who was not hypotensive when initially challenged, was strenuously exercised for 15 min/day.[ncbi.nlm.nih.gov]
Sinus Arrhythmia
Colitis
  • We describe a 25-year-old man with ulcerative colitis who developed cholinergic urticaria diagnosed by a metacholine test.[ncbi.nlm.nih.gov]
Lymphocytic Infiltrate
  • Subcutaneous or dermal edema, increased mast cell numbers, and a modest perivascular lymphocytic infiltrate, that might have cosinophils intermingled, may be evident. Mast cell and eosinophilic degranulation are revealed by electron microscopy.[symptoma.com]

Treatment

Traditionally for cholinergic urticaria, immunosuppressives, leukotriene inhibitors, and antihistimines have been used as treatment options [18]. However, some patients may have refractory cholinergic urticaria. At times, rapid cooling can abort a cholinergic urticaria attack. In some patients, ultraviolet (UV) light has helped the condition, but caution must be taken regarding contraindications to UV light.

Cholinergic urticaria attacks can sometimes result from hot foods and beverages, highly spiced foods, and alcohol, and so modifying one’s diet may be helpful. Cholinergic urticaria can be helped by antihistamines, including cetirizine. Cetirizine response is important as antimuscarinic activity can attribute to some of the antihistaminic effect. Some data suggests that combining different H1 blockers is less effective than combining H1 and H2 blockers [19]. A suggested therapeutic option has been the antimuscarinic cholinergic methanthelinium bromide [20].

Ketotifen (where available) me be helpful for those patients with cholinergic urticaria as well as cold urticaria. Another agent beneficial to cholinergic urticaria patients is danazol, as it apparently leads to the elevation of antichymotrypsin levels. Beta-blockers are reportedly useful in the treatment, such as propranolol [21]. Blocking cholinergic urticaria lesion appearance after challenge may be helped, where available, by the topical application of benzoyl scopolamine and oral scopolamine butylbromide [22].

Prognosis

Acute urticaria prognosis is excellent, with the resolution of most cases occurring within days. Symptomatic treatment with antihistamines can control acute urticaria. The chronic urticaria prognosis in primary care is not known. The study of dermatology clinics in numerous countries reported idiopathic chronic urticaria resolved completely in about one-third of patients over the course of 1 to 5 years and that another third were reported to have partial improvement. Sufferers fared less well if they were younger than 30 and suffered more severe symptoms, or had symptoms with causes that were physical.

Etiology

In cholinergic urticaria, autonomic functions are normal. One study found that binding of muscarinic receptors was normal, but the number was reduced. The areas of involvement are shown presumably through thermography. In cholinergic urticaria sufferers, detection of histamine level elevation is possible 5 minutes after exercise, peaking at 25 ng/mL after 30 minutes. Generalized skin warmth can be felt after exercise on a treadmill and is followed by urticaria, erythema, pruritus, and transient symptoms of the respiratory tract including wheezing, shortness of breath, or both. Observations have been made of decreases that are significant statistically in specific conductance, forced expiratory volumes of 1 second duration, and maximal mid-expiratory flow rates. There may also be a detected increase in residual volume.

Possible allergy-based etiology

A number of factors have suggested that cholinergic urticaria might have an allergic basis, such as a greater occurrence in atopic dermatitis patients, some patients showing an immediate reaction, and a noticeable sensitivity in those patients who have reactions of an anaphylactic and anaphylactoid nature [2]. One report demonstrated an immediate and positive result of sweat sensitivity accompanied by passive transfer [3]. Cholinergic urticaria’s follicular pattern has been delineated by another group in patients sensitive to sweat, but such a pattern was not noted in patients lacking prominent sensitivity.

Responding to autologous sweat, individuals with atopic dermatitis and cholinergic urticaria develop reactions to the skin and the release of histamine by basophils [4] [5]. Following injection of acetylcholine, immediate-type responses to their own sweat and satellite weals are demonstrated on the skin in majority of patients. Autologous serum skin tests return positive results for the rest [6]. Disordered immune responses of the skin flora to soluble products found in human sweat may be involved in the pathogenesis. Against the fungal protein MGL 1304 produced by Malassezia globosa, those with cholinergic urticaria and atopic dermatitis demonstrate immunoglobulin E elevations [7].

Body temperature

In cholinergic urticaria, an increase or a decrease in the average temperature of the body is a crucial point, rather than the actual temperature of the skin surface, the average temperature of the skin, or even the temperature of the core. Cholinergic urticaria may be triggered by the increase of core temperature in the body, but there are patients who do not appear affected by exercise or other activities during the summertime [8].

Seasonal temperature

Two conditions have been suggested as being requirements for the provocation of seasonally occurring cholinergic urticaria, there must be heat induction by various cholinergic stimuli and there must be a low ambient temperature. Apparently those people who only report cholinergic urticaria symptoms during the winter months, only have a reaction during heat exposure, or to exercise that produces heat, while not heat-acclimatized. Whether provocation of skin lesions is at a low ambient temperature by active heating, or by the resting body through passive heating (e.g. sauna-like conditions), the thermoregulatory process is related to basically by cholinergic urticaria.

Other associated factors

Cholinergic urticaria has a high prevalence in those with urticaria. It was shown in one study that 11% of a chronic urticaria population were affected by cholinergic urticaria and in another it was 5.1% of urticaria patients. People with atopic conditions (such as asthma, allergic rhinitis and atopic dermatitis) were shown to have a higher prevalence as well, but this is not an exclusive fact. There have been reports of rare cholinergic urticaria of a familial form.

Conditions where generalized decrease or absence of sweat has been acquired may give rise to cholinergic urticaria. It is theorized that a defect of the nerve-sweat gland junction may exist in patients who have acquired idiopathic generalized hypohidrosis [9]. Acquired generalized hypohidrosis is sometimes associated with a superficial obstruction of the acrosyringium [10]. Like other urticaria forms, Aspirin aggravated the hives of 52% of cholinergic urticaria patients.

Epidemiology

Cholinergic urticaria prevalence varies. Moore-Robinson and Warin discovered about 0.2% of those in a dermatologic clinic for outpatients had cholinergic urticaria [11]. However, it has been shown by numerous published series that cholinergic urticaria is common. A survey in western India of 600 medical and engineering students showed that 4% was the overall prevalence [12].

Although both sexes can experience the disorder, it appears to be less common in females than in males. Almost 96% cholinergic urticaria patients were shown to be men in one study. Cholinergic urticaria is normally developed first by those aged between 10 and 30 years. The average age of onset was 16 within one study and the mean age in a different survey was 22.

Sex distribution
Age distribution

Pathophysiology

Urticaria is caused when bradykinin, histamine, kallikrein, and other vasoactive substances are released by mast cells and basophils found within the superficial layer of the dermis. This results in capillary and venous vasodilation which in turn causes intradermal edema, which leukocyte infiltration may also cause on occasion. It may be an immune-mediated or non-immune-mediated process.

Immune-mediated activation of the mast cell includes:

  • Type I hypersensitivity reactions, where high-affinity cell surface receptors of mast cells and basophils are bound to IgE antibodies that are allergen-bound.
  • Autoimmune disorders, where the binding of antibodies to IgE receptors cross-links them functionally and causes the degranulation of the mast cell.

Non-immune mediated activation of the mast cell includes:

  • Certain drugs causing direct non-allergic mast cell activation.
  • Inhibition of cyclooxygenase induced by drugs causes mast cell activation through mechanisms that are poorly understood.
  • Physical or emotional stimuli activation, a mechanism that is not well understood and may involve neuropeptide release to facilitate interaction with mast cells.

Mast cell activity has been studied using cholinergic urticaria [13]. The concentration of principal mediator serum histamine rises during exercise induced experimentally. Tryptase, and eosinophil and neutrophil chemotactic factors also accompany this mediator rise. It has been seen in urticaria, in some other forms, that reduced alpha1-antichymotrypsin levels are present. Danazol improves the eruption. Due to these findings, some have argued that proteases cause the release of histamine. While cholinergic urticaria seems to involve mast cell release, when compared to other urticaria forms, there is a lower presence of eosinophilic major basic protein.

The lesions are normally tiny, histaminic weals of two to four millimeters and bright erythema typically surround them. The release of acetylcholine at the skin of cholinergic nerve endings produces them in cholinergic urticaria. Heat, exercise, or emotional tension are typical stimuli that cause such a release; sweating is initiated by these same stimuli. Under physiological conditions, acetylcholine is released at the nerve endings supplying sweat glands and this causes sweating. Regardless of the pathogenic mechanism that leads to the release of histamine in cholinergic urticaria, it is expected that an abnormal acetylcholine reaction would occur at sudoriferous nerve endings.

Prevention

Precipitating factors should be avoided by cholinergic urticaria patients. In some people these factors include exercise and any other activity that may cause sweating, such as elevation of the environmental temperature, hot food, sauna baths, hot water immersion, gustatory stimuli, emotional stress, and hemodialysis.

Summary

Physical urticarias are disorders where urticarias are triggered by environmental stimuli. These stimuli include cold, pressure, heat, sunlight, exercise, vibration, and water. Probably resulting from the mast cell’s heightened sensitivity to conditions in the environment. The exact pathogenesis of these conditions is unknown.

The physical urticarias are seen as chronic urticaria subclasses. For certain patients, the sole activator for hives is a specific physical stimulus, whereas a physical stimulus in other patients is a factor that identifies an idiopathic chronic urticaria case, alternatively known as chronic spontaneous urticaria. Multiple physical stimuli trigger the disorder in a small number of patients. The presence of urticaria during most days in a week for six weeks or longer defines chronic urticaria. Several theories have been put forward, although not established conclusively, for the pathogenesis of idiopathic chronic urticaria. In most patients, the disorder is self-limited, and has a two to five year duration on average. Chronic urticaria is a term used to describe patients that have isolated chronic idiopathic urticaria, plus those who have angioedema along with urticaria.

Cholinergic urticaria is a subtype of physical urticarias caused by a physical stimulus. Heat is mostly considered the stimulus, but the actual precipitating factor is sweating. The topic of diagnostic testing and definition of cholingergic urticaria is subjected to consensus panel recommendations.

The following 4 subtypes are divisions of cholinergic urticaria [1]:

  • Cholinergic urticaria plus poral occlusion
  • Cholinergic urticaria accompanied by generalized hypohidrosis, which has been acquired
  • Cholinergic urticaria alongside a sweat allergy
  • Idiopathic cholinergic urticaria

Patient Information

Although more common in children rather than in adults, nonallergic urticaria is more common than allergic urticaria is. An overreaction by the immune system to infections, drugs, foods, and various substances causes it. Cholinergic urticaria is a physical urticaria that is provoked by a physical stimulus. Although heat may be considered to be this stimulus, sweating is the actual precipitating cause. Urticaria (hives) will, in many cases, go away after a few days on its own. However, symptoms can be eased by medications (for example, antihistamines or corticosteroids). An EpiPen may be needed if you have a severe reaction, such as breathing difficulties, to recurring urticaria. You can inject yourself with an EpiPen to provide an emergency adrenaline dose, which will counteract a reaction.

References

Article

  1. Nakamizo S, Egawa G, Miyachi Y, Kabashima K. Cholinergic urticaria: pathogenesis-based categorization and its treatment options. J Eur Acad Dermatol Venereol. 2012 Jan. 26(1):114-6.
  2. Montgomery SL. Cholinergic urticaria and exercise-induced anaphylaxis. Curr Sports Med Rep. 2015 Jan. 14(1):61-3.
  3. Nakazato Y, Tamura N, Ohkuma A, Yoshimaru K, Shimazu K. Idiopathic pure sudomotor failure: anhidrosis due to deficits in cholinergic transmission. Neurology. 2004 Oct 26. 63(8):1476-80.
  4. Takahagi S, Tanaka T, Ishii K, et al. Sweat antigen induces histamine release from basophils of patients with cholinergic urticaria associated with atopic diathesis. Br J Dermatol. 2009 Feb. 160(2):426-8.
  5. Fukunaga A, Bito T, Tsuru K, et al. Responsiveness to autologous sweat and serum in cholinergic urticaria classifies its clinical subtypes. J Allergy Clin Immunol. 2005 Aug. 116(2):397-402.
  6. Horikawa T, Fukunaga A, Nishigori C. New concepts of hive formation in cholinergic urticaria. Curr Allergy Asthma Rep. 2009 Jul. 9(4):273-9.
  7. Hiragun M, Hiragun T, Ishii K, et al. Elevated serum IgE against MGL_1304 in patients with atopic dermatitis and cholinergic urticaria. Allergol Int. 2014 Mar. 63(1):83-93.
  8. Ramam M, Pahwa P. Is cholinergic urticaria a seasonal disorder in some patients?. Indian J Dermatol Venereol Leprol. 2012 Mar. 78(2):190-1.
  9. Kobayashi H, Aiba S, Yamagishi T, et al. Cholinergic urticaria, a new pathogenic concept: hypohidrosis due to interference with the delivery of sweat to the skin surface. Dermatology. 2002. 204(3):173-8.
  10. Itakura E, Urabe K, Yasumoto S, Nakayama J, Furue M. Cholinergic urticaria associated with acquired generalized hypohidrosis: report of a case and review of the literature. Br J Dermatol. 2000 Nov. 143(5):1064-6.
  11. Moore-Robinson M, Warin RP. Some clinical aspects of cholinergic urticaria. Br J Dermatol. 1968 Dec. 80(12):794-9.
  12. Godse K, Farooqui S, Nadkarni N, Patil S. Prevalence of cholinergic urticaria in Indian adults. Indian Dermatol Online J. 2013 Jan. 4(1):62-3.
  13. Soter NA, Wasserman SI. Physical urticaria/angioedema: an experimental model of mast cell activation in humans. J Allergy Clin Immunol. 1980 Nov. 66(5):358-65.
  14. Confino-Cohen R, Goldberg A, Magen E, Mekori YA. Hemodialysis-induced rash: a unique case of cholinergic urticaria. J Allergy Clin Immunol. 1995 Dec. 96(6 Pt 1):1002-4.
  15. Sheraz A, Halpern S. Cholinergic Urticaria Responding to Botulinum Toxin injection for Axillary Hyperhidrosis. Br J Dermatol. 2013 Jan 10.
  16. Silpa-Archa N, Kulthanan K, Pinkaew S. Physical urticaria: prevalence, type and natural course in a tropical country. J Eur Acad Dermatol Venereol. 2010 Dec 22.
  17. Torabi B, Ben-Shoshan M. The association of cholinergic and cold-induced urticaria: diagnosis and management. BMJ Case Rep. 2015 Feb 18. 2015.
  18. Otto HF, Calabria CW. A case of severe refractory chronic urticaria: a novel method for evaluation and treatment. Allergy Asthma Proc. 2009 May-Jun. 30(3):333-7.
  19. Alsamarai AM, Hasan AA, Alobaidi AH. Evaluation of different combined regimens in the treatment of cholinergic urticaria. World Allergy Organ J. 2012 Aug. 5(8):88-93.
  20. Altrichter S, Wosny K, Maurer M. Successful treatment of cholinergic urticaria with methantheliniumbromide. J Dermatol. 2015 Jan 9.
  21. Ammann P, Surber E, Bertel O. Beta blocker therapy in cholinergic urticaria. Am J Med. 1999 Aug. 107(2):191.
  22. Tsunemi Y, Ihn H, Saeki H, Tamaki K. Cholinergic urticaria successfully treated with scopolamine butylbromide. Int J Dermatol. 2003 Oct. 42(10):850.

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Last updated: 2019-07-11 20:57