Severe cutaneous eruptions following the topical use of preparations containing bufexamac: Is it time to reconsider its registration in Australia?

Despite being a well-recognised cause of allergic contact dermatitis with an embargo in many countries around the world, bufexamac is available over the counter in topical preparations in Australia. We present a series of patients who developed severe cutaneous eruptions after the topical application of bufexamac containing preparations to highlight the potential risks of this medication, as well as advocate for the reconsideration of its registration by the Therapeutic Goods Administration in Australia.

Bufexamac ameliorates LPS-induced acute lung injury in mice by targeting LTA4H.

Neutrophils play an important role in the occurrence and development of acute lung injury (ALI). Leukotriene B4 (LTB4), a hydrolysis product of epoxide leukotriene A4 (LTA4) catalyzed by LTA4 hydrolase (LTA4H), is one of the most potent chemoattractants for neutrophil. Bufexamac is a drug widely used as an anti-inflammatory agent on the skin, however, the mechanism of action is still not fully understood. In this study, we found bufexamac was capable of specifically inhibiting LTA4H enzymatic activity and revealed the mode of interaction of bufexamac and LTA4H using X-ray crystallography. Moreover, bufexamac significantly prevented the production of LTB4 in neutrophil and inhibited the fMLP-induced neutrophil migration through inhibition of LTA4H. Finally, bufexamac significantly attenuated lung inflammation as reflected by reduced LTB4 levels and weakened neutrophil infiltration in bronchoalveolar lavage fluid from a lipopolysaccharide-induced ALI mouse model. In summary, our study indicates that bufexamac acts as an inhibitor of LTB4 biosynthesis and may have potential clinical applications for the treatment of ALI.

Allergic contact dermatitis to topical preparations of bufexamac.

In Australia bufexamac is mainly used for pharmacist-initiated local treatment of various dermatoses. The European Medicines Agency's Committee for Medicinal Products for Human Use recently recommended that marketing authorisation for bufexamac-containing preparations be revoked throughout the European Union because of the risk of severe allergic contact dermatitis. We retrospectively reviewed the patch test database at the Skin and Cancer Foundation Inc. and identified 19 cases of positive reactions to bufexamac (5% petrolatum) from 451 people patch tested. The bufexamac reaction was deemed relevant to the presenting dermatitis in 13 of 19 (68%) patients. Bufexamac allergic contact dermatitis is under-reported in the English literature. We wish to emphasise the severity and the unusually polymorphic eruptions observed in some of the cases. Clinicians should consider the possibility of allergic contact dermatitis to bufexamac-containing preparations in all patients where there is a history of exposure, even if used for only a short time.

A systematic review of randomized controlled trials of treatments for inherited forms of epidermolysis bullosa.

BACKGROUND: Many interventions have been described for inherited epidermolysis bullosa (EB), but it is unclear which are beneficial. AIMS: A systematic review of randomized controlled trials (RCTs) was performed to inform practice and highlight research gaps. METHODS: The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and the Cochrane Skin Group specialist library, from inception until 1 April 2007, were searched. Primary outcomes were healing of lesions or prevention of new lesions. Trials were assessed for quality of reporting and data were extracted. RESULTS: Five randomized double-blind placebo-controlled crossover studies were identified (n = 102). Two studies assessed oral tetracyclines in EB simplex (EBS). In one study (n = 12), 4/6 patients improved and 2/6 deteriorated on a dose of 1500 mg of tetracycline daily; only two patients completed the study. In the second study (n = 21), 6/18 and 7/18 improved on oxytetracycline 1 g and placebo, respectively. Two RCTs assessed topical interventions for EBS: aluminium chloride hexahydrate solution 20% (n = 23) and bufexamac cream 5% (n = 8). Neither showed a benefit over placebo. One RCT of 36 patients with recessive dystrophic EB compared phenytoin with placebo and failed to show any difference in mean lesion counts (difference = 0, 95% CI -11 to 4). CONCLUSIONS: There is no reliable trial evidence for interventions in inherited EB. In future, it may be that gene treatment becomes the best treatment approach for these diseases.

Chronic urticaria due to Blastocystis hominis.

A 24-year-old woman had a 9-week history of second to third daily urticaria that began after an episode of contact urticaria to topical bufexamac. She was found to have an underlying gastrointestinal infection with Blastocystis hominis. This was thought to be clinically relevant as she had a history of mild chronic diarrhoea. After treatment of the Blastocystis hominis, her urticaria ceased. This could indicate the importance of performing stool microscopy and culture on all patients with chronic urticaria of unknown aetiology. The relationship of urticaria to intestinal parasites and the possibility that non-steroidal anti-inflammatory medications could act as cofactors that help precipitate an urticarial reaction is discussed.

[A common and insidious side-effect: allergic contact dermatitis caused by bufexamac used in the treatment of dermatitis. Results from the Information Network of Departments of Dermatology (IDVK)]. / Eine heimtückische und häufige Nebenwirkung: Kontaktallergien durch das Ekzemtherapeutikum Bufexamac. Ergebnisse des IVDK.

BACKGROUND AND OBJECTIVE: Bufexamac is a non-steroidal, anti-inflammatory drug used in the topical treatment of atopic dermatitis, stasis dermatitis and perianal eczema. The substance is known to cause severe allergic contact dermatitis (ACD) as an adverse effect (AE), which may be indistinguishable from the eczema which is to be treated. Hence the diagnosis of this AE is often considerably delayed. In order to estimate the quantitative importance of ACD to bufexamac, data of the Information Network of (German) Departments of Dermatology (IVDK) from July 1999 to December 2004 were analysed. PATIENTS AND METHODS: During the study period, 39,392 unselected patients from 40 German departments of the IVDK were patch tested with bufexamac (5 % pet). The results of the reading after 72 hours were analysed. The dichotomized patch test result was further assessed for possible risk factors from the patients' history and clinical diagnosis by Poisson regression analysis. RESULTS: In 560 of 39,392 patients contact allergy to bufexamac was diagnosed, i. e. 1.4 % (95 % confidence interval: 1.3 - 1.5), standardized for sex and age. The Poisson regression analysis revealed a significantly increased risk associated with the following factors: multiple sensitization, perianal eczema, underlying atopic dermatitis, leg dermatitis, female gender and residence in areas of Germany other than Eastern Germany. The latter observation can be explained by low prescription rates in Eastern Germany. CONCLUSION: Bufexamac is an important allergen. Extrapolating the frequency of 1.4 % in our data to the whole German population by the CE-DUR approach yields an estimate of about 6000 cases per year. In view of the high frequency of sensitization, the pitfalls in diagnosis, the severity of the course of disease and the lack of efficacy of this drug, the risk to benefit ratio is obviously critical.

Examinations of the antioxidative properties of the topically administered drug bufexamac reveal new insights into its mechanism of action.

The effect of bufexamac on UV-irradiation-induced lipid peroxidation was investigated. Linolenic acid was used as a model lipid. Bufexamac was shown to be capable of reducing the amount of lipid peroxidation. The quantification was carried out by the thiobarbituric acid assay. Irradiation experiments were also performed using HaCaT keratinocytes as a model system. The oxidative changes were quantified by DNA synthesis measurements and cell viability determinations. Bufexamac was found to act antioxidatively again. To investigate free radical involvement, electron paramagnetic resonance studies were carried out. The influence of bufexamac on the concentration of hydroxyl radicals generated by the Fenton system was examined using the spin trapping technique. Moreover, the hydroxamic acid's ability to react with stable radicals was checked. The quantification assay of 2,2-diphenyl-1-picrylhydrazyl hydrate showed no concentration changes of the stable radical caused by bufexamac. In the Fenton assay antioxidative effects were measured after the addition of the drug. The qualitative changes after irradiating bufexamac were studied at a molecular level by electrospray mass spectrometry. Multiple-stage mass spectrometry experiments enabled the establishment of fragmentation schemes. Phenolic degradation products were detected. The results suggest a new interpretation of the controversially debated mechanism of action of bufexamac and indicate possible reasons for its eczema provoking potential.

[Severe allergic contact dermatitis with generalized spread due to bufexamac presenting as the "baboon" syndrome]. / Schwere allergische Kontaktdermatitis mit generalisierter Streuung auf Bufexamac unter dem Bild eines "Baboon"-Syndroms.

HISTORY AND CLINICAL FINDINGS: A 48-year-old woman presented with acute, pruritic, sharply demarcated, erythematous, maculopapulous exanthem in the anogenital area with disseminated maculae over the back. Several days before, the patient had applied as topical treatment a bufexamac-containing ointment to the anal region. INVESTIGATIONS: The patch test showed an allergic test reaction to bufexamac. DIAGNOSIS: The case presents a serious allergic contact dermatitis with generalization, imitating a baboon syndrome, unequivocally linked to the previous topical treatment. CONCLUSION: During the last 10 years allergic reactions to bufexamac have increasingly been reported, sometimes with erythema multiforme-like reactions. Because of the high rate of sensitization, the serious clinical course of bufexamac allergy and the insidious symptoms of this side effect, sometimes mimicking the disease to be treated, the substance should be used neither for proctological nor for dermatological diseases, even more as these patients are considered to be at high risk of developing allergic contact dermatitis because of the abnormal skin barrier. Considering the data presented, the use of bufexamac should be critically reassessed.

Effects of intra-articular injections of bufexamac suspension in healthy horses.

OBJECTIVE: To evaluate the effects of intra-articular (IA) injections of bufexamac in horses, focusing particularly on the effects of bufexamac on articular cartilage. ANIMALS: 20 Standardbreds. PROCEDURE: Horses were randomly allocated into 4 groups consisting of 5 horses each, and 20, 60, or 100 mg of bufexamac or 1 ml of sterile saline (0.9% NaCl) solution (control) was injected into 1 intercarpal joint at weekly intervals for 6 treatments (days 0, 7, 14, 21, 28, and 35). Clinical signs and results of hematologic, serum biochemical, and synovial fluid (SF) analyses and radiography were used to evaluate treatment effects. On day 49, all horses were euthanatized; gross necropsy and histologic examinations of internal organs and articular tissues were performed. Glycosaminoglycan concentration of the articular cartilage was evaluated in safranin O-stained sections by use of a semiquantitative microspectrophotometric method. RESULTS: No systemic signs were observed. Temporary mild to moderate heat and effusion were the only clinical signs observed in a number of joints after IA injections and more often only in the 100 mg group, compared with controls. The 100 mg dose resulted in significant increases in SF WBC counts, with relative neutrophilia and SF total protein concentration 24 hours after injection (day 1). No lesions suggestive of toxic effects were detected at necropsy or on histologic examination. No changes in articular cartilage glycosaminoglycan concentration were detected. CONCLUSIONS AND CLINICAL RELEVANCE: Six injections of 20, 60, or 100 mg of bufexamac at weekly intervals did not cause any untoward systemic or local effects. These data suggest that bufexamac is a safe nonsteroidal anti-inflammatory drug for IA administration in horses.

[A severe epicutaneous test reaction to the bufexamac in a hemorrhoidal therapeutic preparation]. / Schwere Epikutantestreaktion auf Bufexamac in einem Hämorrhoidal-Therapeutikum.

HISTORY AND FINDINGS: A 49-year-old woman presented with acute perianal vesicular/bullous contact dermatitis. Other areas were over the trunk, face, neck and wrists. She reported occasional application of an ointment (Mastu S) to treat her hemorrhoids. INVESTIGATION: Patch tests (basic series, anal block, own ointment, local anesthetic, cosmetics) provoked strong vesicular and bullous reactions of persisting crescendo type, spreading far beyond the site of application, to Bufexamac, to a derivative of hydroxxamine acid, and to local applied ointment with mild or moderate antiinflammatory action. TREATMENT AND COURSE: A week after the patch tests there was a flare-up of the previous foci of dermatitis. These reactions subsided two days later after intravenous injection of prednisolone. The skin lesions healed after rapid reduction of the systemic treatment and local application of corticosteroids, bathing with tanning substances and basic preparations. CONCLUSION: While Bufexamac is not absorbed when applied rectally, perianal contamination may not be avoidable on intra-anal application and can produce sensitization.

Selective enhancement of production of IgE, IgG4, and Th2-cell cytokine during the rebound phenomenon in atopic dermatitis and prevention by suplatast tosilate.

BACKGROUND: Atopic dermatitis is a chronic inflammatory skin disease, which is commonly treated with topical steroids. It is, however, associated with rebound after therapy has been discontinued. OBJECTIVE: This study was designed to elucidate the mechanisms of the rebound phenomenon, and to test the effect of an oral anti-allergic medication, suplatast tosilate, on atopic dermatitis. METHODS: This is a randomized, placebo controlled study. Patients with atopic dermatitis who had been treated with strong steroid ointment (dexamethasone valerate) for several years were divided into two groups. One group (the control group, n = 15) was treated with a non-steroid anti-inflammatory ointment (bufexamac ointment), while the other group (the suplatast tosilate group, n = 17) was treated with the anti-allergic medications, suplatast tosilate and bufexamac ointment. In each group, in vitro production of immunoglobulins and cytokines before and after 2 weeks of treatment was measured. RESULTS: In the control group, 15 of the 15 patients experienced rebound and mean production of IgE, IgG4, IL-4, IL-5, IL-10, and IL-13 was enhanced after 2 weeks. In contrast, only 2 of the 17 patients in the suplatast tosilate group experienced rebound. There was no enhancement of production of immunoglobulins and cytokines after 2 weeks of treatment. CONCLUSION: Enhanced production of the Th2-cell cytokines, which selectively induces IgE and IgG4 production, may be involved in the pathogenesis of the rebound phenomenon, and that suplatast tosilate may prevent the rebound phenomenon by down-regulating the production of these cytokines.

Effects of intra-articular injections of bufexamac suspension on amphotericin B-induced aseptic arthritis in horses.

OBJECTIVE: To evaluate effects of intra-articular (i.a.) injections of bufexamac on amphotericin B-induced aseptic arthritis in horses. ANIMALS: 24 Standardbred horses. PROCEDURE: Aseptic arthritis was induced in the right intercarpal joint by i.a. injection of amphotericin B (20 mg). One week later (day 0), horses were randomly assigned to four 6-horse treatment groups and treated with i.a. injection of 10, 20, or 40 mg of bufexamac suspension (20 mg/ml) or 2.0 ml of sterile saline (0.9% NaCl) solution (control). The treatment was repeated once after 7 days. Clinical lameness examinations and synovial fluid (SF) analyses were done prior to induction and at weekly intervals for 5 weeks (days 0, 7, 14, 21 and 28). RESULTS: Intra-articular injection of amphotericin B consistently resulted in aseptic arthritis with a lameness index (mean +/- SEM; scale 0 to 5) of 2.7 +/- 0.17 on day 0. Intra-articular injections of 20 and 40 mg of bufexamac significantly reduced the day-28 lameness index, compared with control values. Amphotericin B administration also resulted in a significant increase in SF beta-glucuronidase (BGLUC) activity, and i.a. injections of bufexamac significantly reduced day-28 activity of this enzyme, compared with control values. CONCLUSIONS AND CLINICAL RELEVANCE: 2 i.a. injections of 20 or 40 mg of bufexamac, at weekly intervals, were effective in reducing clinical signs of lameness and SF activity of BGLUC associated with amphotericin B-induced carpal joint arthritis. Bufexamac possesses anti-inflammatory properties useful for i.a. treatment of lameness associated with aseptic arthritis in horses.

[Severe contact dermatitis caused by Parfenac cream]. / Dermite de contact grave à la crème Parfenac.

Bufexamac is an anti-inflammatory agent used as topical treatment of various pruritic diseases. Since it was put on the market, this product has been blamed for the occurrence of contact dermatitis (eczema, urticaria) and, rarely, severe toxicodermia. We report a case of severe contact dermatitis developed after application of bufexamac (Parfenac) cream. Patch-tests performed two months after the acute phase were positive (+ + +) for both Parfenac cream and bufexamac.

[Contact allergies caused by bufexamac]. / Kontaktallergien durch Bufexamac.

Between 1983 and 1987, there were 24 cases of contact allergy due to bufexamac seen at the Dermatological Hospital of the University of Göttingen. Of these patients, 20 were female und four male. It was noticeable, that the course of disease was particularly protracted and refractory: 16 of 22 patients were hospitalized with an average duration of inpatient treatment of 2.9 weeks. Seven patients had a generalized allergic contact dermatitis. Five patients had used topical preparations containing bufexamac for only one week or less. In 15 of 24 patients, further epidermal sensitization could be found. In all forms of eczematous diseases, especially in patients with chronic eczema, contact allergy to bufexamac should be considered, even if bufexamac preparations were used for only a short time.

[Treatment of diaper rash with Parfenac lipid ointment (bufexamac). A study by Austrian pediatricians]. / Behandlung der Windeldermatitis mit Parfenac-Fettsalbe (Bufexamac). Eine Studie Osterreichischer Kinderärzte.

447 children between 0 and 24 months with diaper dermatitis were treated by topical application of Parfenac-Fettsalbe (Bufexamac). This panel was selected out of 844 patients which were originally in the protocol. The Parfenac-Fettsalbe was well tolerated, 7 children presented local side effects. 62.71% of treated girls showed very good results, whereas 59.89% of boys showed this outcome. Good results were obtained in 24.35% of girls and 21.93% of boys. Very good (no efflorescences remaining) and good results (some remaining efflorescences) were thus found in more than 80% of patients treated: with respect to corticosteroid advoidance this can be regarded as an effective antiphlogistic medication for diaper dermatitis. Non responders might have been superinfected with microorganisms as candida and staphylococci. In addition, epidemiological considerations are reported in that study.