Cimetidine: A review of the recent developments and reports in cutaneous medicine
Department of Dermatology, St. Luke's-Roosevelt Hospital Center, New York. Scheinfeld@rcn.com
Noah Scheinfeld, MD
Dermatology Online Journal 9(2): 4
Cimetidine, approved by the FDA for inhibition of gastric acid secretion, has been advocated for a number of dermatological diseases. The cutaneous uses and immunological effects of cimetidine have been actively studied over the past few years, and this review summarizes the literature accumulated since 1997.
Several reviews have assessed the use of cimetidine in dermatology in the last decade. Since the last review was published in 2000, over 500 articles have been published on cimetidine. In fact, cimetidine is a most actively researched medication, and more than 1,000 articles concerning it have been published in the last 5 years. To allow dermatologists to keep abreast of developments in the use of this medication, this review summarizes the literature since 1997 on the cutaneous benefits and side effects of cimetidine and its immunological effects.
Cimetidine-approved uses, side effects, and drug interactions
Cimetidine is approved by the FDA for the reduction of the secretion of gastric acid. It is used to alleviate the symptoms of peptic ulcer disease, erosive gastroesophageal reflux disease, and hypersecretory conditions including Zollinger-Ellison syndrome and multiple endocrine adenomas. It is available over the counter and by prescription. In dermatology it is most commonly used to treat warts, urticaria, and mastocytosis.
Cimetidine is generally taken without ill effect. Its side effects include dizziness and mild somnolence (at doses of 800–1600 mg/day), a reversible state of confusion (especially in the elderly with preexisting renal or hepatic disease), gastrointestinal upset, gynecomastia (may occur if treatment period is greater than 1 month), reversible dose-related increase in serum transaminases, and dose-related elevations in plasma creatinine.
Cimetidine can produce significant inhibition of cytochrome P450 (CYP) 1A2, 2C9, 2D6, and 3A4 P450 isoforms. Of these isoforms, clinically significant inhibition is most important with CYP 3A4 and 1A2. It does not affect CYP 1A1 in rat models. Clinically relevant interactions include theophylline, aminophylline, metoprolol, nifedipine and quinidine. The interaction involving the beta-blockers, metoprolol and propranolol, results in significant sinus bradycardia and hypotension. It does not interact with atenolol and nadolol. It can inhibit the metabolism of hydroxyzine and the conversion of dapsone to its toxic hydroxylamine, effects which are beneficial in dermatologic therapy. Oral cimetidine prolongs clarithromycin absorption. Cimetidine has been examined for its antimalarial properties in the presence or absence of chloroquine or pyrimethamine and was found to be synergistic with them. It appears that cimetidine is safe in pregnancy.
Cimetidine has immunomodulatory effects that include blocking suppressor T cells and facilitating cell-mediated immunity (CMI). The histamine-induced upregulation of IL-6 and IL-8 production, however, may be completely abrogated by a combination of pyrilamine and cimetidine. In patients with allergic rhinitis, cimetidine decreases the number of CD4+ and increases the number of CD8+ lymphocytes. Cimetidine and famotidine slightly reduce the O2- or H2O2 production of neutrophils in a dose-dependent manner, although ranitidine fails to do so. Cimetidine inhibits nitric-oxide-associated nitrate production in a horse soft-tissue inflammation model. It decreases interleukin 6 production by human keratinocytes. It can block cell proliferation and c-fox gene transcription. It also might have a role in suppressing delayed hypersensitivity reactions. The exact role that these immunological effects play in the treatment of clinical disease has yet to be defined.
Common warts in adults
In the last 5 years, double-blind, placebo-controlled studies have finally been performed on cimetidine in the treatment of common warts. These studies have shown it to be ineffective; this ineffectiveness is shown most clearly in adults. Some still advocate consideration of its use at a dose of 40 mg/kg/day, but most reviewers do not.
The role of cimetidine in children is a more open question. In a 3-month open-label study of 47 patients with multiple, nongenital, viral warts who were treated with oral cimetidine, 56% of children cleared and 44% of adults cleared. However, in a placebo-controlled study, its efficacy was not statistically superior to that of placebo, although a trend toward efficacy was suggested for younger subjects. Moreover, a prospective, randomized, controlled trial of 40 patients (62% less than 15 years old) yielded negative results. Thus, in cases where the use of topical medications is not possible, cimetidine might still have a role in the treatment of warts in children. Interestingly, however, a recently reported case described marked improvement in a 16 year old boy with epidermodysplasia after three months of oral cimetidine at 40mg/kg/day. No relapse occurred over a six month follow up period.
One promising avenue for the use of cimetidine for treating warts is in conjunction with other therapies. Parsad et al. have reported that a combination regimen of cimetidine and levamisole is superior to cimetidine alone in treating warts in adults and in children. Levamisole is an immunomodulator that is approved by the FDA for use with 5-fluorouracil in the treatment of colon cancer. The original use of levamisole was as an antihelminthic.
Genital warts and papillomatosis
Cimetidine has been shown to be useful in the treatment of condylomata acuminata and papillomatosis. Four children treated with extensive condylomata acuminata of the genital and perigenital areas were treated with cimetidine 30–40 mg/kg; clearing of their condylomata was noted at 24 months following treatment. Cimetidine was effective in the treatment of recurrent respiratory papillomatosis and recalcitrant, diffuse conjunctival papillomatosis.
Molluscum contagiosum, a common illness in children, caused by a pox virus, has been treated with cimetidine. At a dose of 30–40 mg/kg/day, it has been used as a treatment for children and adults. In two patients, one with 60 lesions and the other with 200 lesions, cimetidine at 40 mg/kg/day in four divided doses for six weeks cleared all lesions. However, other studies find it ineffective. There is no evidence from double-blind, placebo-controlled studies that cimetidine clears molluscum contagiosum.
Urticaria and other mast-cell-mediated diseases
Cimetidine appears to have a role in the treatment of chronic idopathic urticaria and some other types of urticaria when used in combination with various H1 blockers.[35,36] For symptomatic dermatographism, the combination of an antihistamine and an H2 antagonist, such as chlorpheniramine and cimetidine, appears to be effective. Cimetidine might also increase the latency time of heat-induced urticaria. It appears that a combination regimen of H1 blockers, H2 blockers, and mast-cell stabilizers gives partial relief to the patients with mastocytosis. Scombroid fish poisoning has been successfully treated with cimetidine.
Because of its function as an immunomodulator, researchers have used cimetidine in research on melanoma. In horses, it has been used to treat melanoma, although no benefit has been found. In immunodeficient mice with transplanted melanoma cell lines, administration of cimetidine combined with tamoxifen seems to decrease melanoma growth. It should be noted that levamisole, mentioned above, has been extensively evaluated as an immunomodulator to ameliorate melanoma without significant effect.
Several eosinophilic dermatoses have responded to cimeditine. It was successful when used for eosinophilic fascitis (however, after a 5-month course it was discontinued because of side effects). It has been used to treat eosinophilic pustular folliculitis in children. The beneficial effects might be a result of the interrelation of histamine, mast cells and eosinophils in allergy and allergic disease.
Cutaneous effects: pruritus and skin integrity
Cimetidine was useful in treating pruritus after a burn injury. In a study controlling for the effect of topical medications, a cetirizine-cimetidine combination demonstrated a dramatic improvement at 1 and 6 hours, and a moderate improvement at 12 hours after the initial administration of the medication when compared with a diphenhydramine-placebo combination. Oral cimetidine accelerated the recovery of skin barrier function after disruption in a dry environment, but histamine and the histamine H2 receptor agonist, dimaprit, delayed barrier repair.
Periodic fever, apthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome
Cimetidine has a valuable role in treating of PFAPA syndrome. In one study, it was as an effective first-line therapy for PFAPA at 20 mg/kg/day, curing 49 of 83 patients. Alternatively, other authorities state that glucocorticoids are the most highly effective in controlling symptoms. Tonsillectomy and cimetidine treatment were associated with remission in a small number of patients. In another study of 8 children, cimetidine was effective with no side effects.
Acute intermittent porphyria
Cimetidine has been suggested as a treatment for acute intermittent porphyria. Its role seems to be as a second-line treatment to intravenous hemin, which is expensive but appears to be more effective than increased carbohydrate intake. At a dose of 800 mg/day, cimetidine may also have a role in the prophylaxis of acute episodes by maintaining a baseline suppression of ALA-synthase activity.
Inhibition of Dapsone Toxicity
One of the most important uses of cimetidine in dermatological therapy is to reduce the dapsone induction of methemoglobinemia. Cimetidine reduces the hepatic oxidation of dapsone to the hydroxylamine, thereby limiting methemoglobinemia formation. This strategy allows maintenance of higher daily dosages of dapsone, sometimes even in excess of 200 mg. In one study, co-administration of cimetidine with dapsone kept methemoglobin levels at 30% below the control values for nearly three months. Eight patients with dermatitis herpetiformis, linear IgA disease, or folliculitis decalvans, who were on long term dapsone therapy (50-100 mg daily), added cimetidine, 1.6 g daily, for three months. Their mean methemoglobin level fell from a baseline of 5.5 g/dl to 3.9 g/dl in the third week. The values remained low until week 12 when there was a return to baseline. There was no alteration in hemoglobin level from baseline (mean 12.7 g/dl) during the cimetidine therapy. However, there was a significant fall in the visual analogue score for headache. The patients also reported a significant decrease in lethargy. These improvements were not associated with any deterioration in the control of the various skin disorders. Similar findings were obtained in an earlier study in dermatitis herpetiformis patients.
In rats, cimetidine has been shown to be more effective than ranitidine or famotidine in the reversible inhibition of the toxic metabolic pathway which produces dapsone's hydroxylamine metabolite. Cimetidine also did not appear to inhibit the detoxification pathways of dapsone or cytosolic acetylation because of its greater affinity for cytochrome P-450.
Cutaneous side effects
Despite its common use, cimetidine has few cutaneous side effects. It can cause a delayed hypersensitivy reaction and fixed drug eruption. It has been reported to precipitate erythema multiforme and toxic epidermal necrolysis. Cross-reaction with famotidine to induce erythema multiforme has been reported in cases where cimetidine-related erythema multiforme has already occurred.
Cimetidine has yet to be proven to be an effective monotherapy for dermatological diseases. It seems that cimetidine is probably most effective when used in conjunction with other medications. In the same fashion that levamisole eventually was proven to be an effective secondary medication along with 5-fluorouracil in the treatment of cancer of the colon, cimetidine will probably be proven useful outside of its use as an antacid. Promising uses include treating urticaria in conjunction with other antihistamines, and treating warts in conjunction with levamisole. In addition, cimetidine's inhibitory effect on the metabolism of dapsone, chloroquine, and pyrimethamine can aid dermatological therapy by maintaining medication levels and decreasing toxicity. The multiple immunomodulating effects of cimetidine are significant but poorly understood. As its immunological effects are elucidated, new uses will emerge.
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