Cutaneous response to intradermal histamine in lung cancer.

Recent evidence has suggested that human neoplastic patients show decreased blood histamine levels and cutaneous responses to intradermal histamine. In this study we evaluate the skin response to intradermal injections of histamine and IgE levels in 34 male patients with lung cancer (of which 21 had metastasis) and in 16 control subjects. Analysis of our data does not reveal any difference in the areas of wheal and flare between control subjects and lung cancer patients with or without metastasis. Moreover the evaluation of the different histologic cell type of lung cancer provides the same results. In addition, the sensitivity (Histamine Threshold Concentration) and reactivity (slopes) to histamine is not statistically different. No difference is found for IgE levels between controls and cancer patients. In the light of our finding we believe that in lung cancer patients skin response to intradermal histamine is not decreased, and therefore that the hypothesis concerning the existence of H1-histamine receptor antagonist released by tumour is not confirmed.     

Cutaneous reactions to topical NSAIDs

(1) Cutaneous application of nonsteroidal antiinflammatory drugs (NSAIDs) can cause potentially severe skin lesions that may not be restricted to the site of application. Sunlight can be an aggravating factor. (2) Various topical NSAIDs have been implicated. The most frequently mentioned is ketoprofen.     

Cutaneous reactions to non-steroidal anti-inflammatory drugs

We retrospectively reviewed the records of 195 patients with suspected cutaneous reactions from NSAIDs. Two hundred and six different non-steroidal anti-inflammatory drugs (NSAIDs) were suspected of causing cutaneous reactions, and the most frequent suspected causative NSAID was ibuprofen (25.7%). Angioedema and/or urticaria were the most frequent cutaneous reactions (54.4%), and the foremost suspected causative drug for these reactions was ibuprofen. The second most frequently found cutaneous reaction was maculopapular eruption (26.2%), and celecoxib was the most commonly suspected causative NSAID for it. The primary suspected NSAIDs causing fixed drug eruption were in enolic acid group. Furthermore, drug hypersensitivity syndrome was diagnosed in five patients, and Stevens-Johnson syndrome and toxic epidermal necrolysis were detected in five patients.     

Cutaneous drug reactions

Cutaneous drug reactions are the most frequently occurring adverse reactions to drugs. Among hospitalized patients, the incidence of these reactions ranges from 1 to 3%. The frequency of cutaneous reactions to specific drugs may exceed 10%. These reactions may range from mildly discomforting to those that are life-threatening. Anti-infective and anticonvulsant agents are among the drugs most commonly associated with adverse reactions in the skin. We describe and illustrate the clinical morphology of the most common cutaneous drug reactions, as well as drugs that most commonly precipitate specific reactions. The varied nature of the reactions that do occur, even with specific agents, indicates a multiplicity of mechanisms available whereby cutaneous drug reactions may be initiated. Although a variety of terms have been proposed for categorizing cutaneous drug reactions, we propose that reactions are best defined based upon mechanisms, where known. In this review, we assess the current knowledge of four categories of cutaneous drug reactions: immediate-type immune-mediated reactions, delayed-type immune-mediated reactions, photosensitivity reactions, and autoimmune syndromes. Moreover, we describe evidence that viral infection is an important predisposing factor for the development of cutaneous drug reactions upon drug administration. Finally, we review the current knowledge of the type and mechanisms of cutaneous drug reactions to several categories of drugs.     

Cutaneous reactions to epidermal growth factor receptor inhibitors

Cutaneous toxicities are the most common adverse effects of antineoplastic therapy with epidermal growth factor receptor (EGFR) inhibitors. Skin reactions to this class of agents usually present as papular and/or pustular follicular eruptions developing within two weeks of treatment onset. Other manifestations include generalized xerosis and pruritus, as well as abnormalities of the hair and nails. For most EGFR inhibitors, the incidence and severity of cutaneous toxicity are associated with clinical benefit. At the same time, cutaneous toxic effects may detract substantially from health-related quality of life, leading to interruption, discontinuation or dose reduction of EGFR inhibitor therapy in significantly affected patients. Current recommendations for treatment of EGFR inhibitor-induced eruptions are based primarily on anecdotal evidence from published case series and physicians' own experiences, and include antibiotics, corticosteroids and retinoids. Randomized controlled trials are needed to enable the development of evidence-based paradigms for the treatment of EGFR inhibitor-induced skin eruptions.     

Cutaneous drug reactions associated with newer antiretroviral agents

Skin is the most commonly affected organ in patients with HIV, and the incidence of cutaneous adverse reactions in persons infected with HIV versus those who are not infected is significantly higher. Cutaneous drug reactions contribute to increased morbidity and are often the cause of treatment nonadherence. Undoubtedly, the widespread use of highly active antiretroviral therapy has had a positive effect on the natural course of the disease; however, advances in HIV therapy will continue to increase the potential for cutaneous eruptions, further complicating the evaluation of skin manifestations that are so common in this disease. Distinguishing between cutaneous drug reactions and other cutaneous diseases associated with HIV infection can be challenging. Nevertheless, it is important for clinicians to be knowledgeable about the clinical characteristics and presentations of these reactions and to determine whether drug discontinuation is indicated.     

Cutaneous reactions to drugs. An analysis of spontaneous reports in four Italian regions

AIMS: Cutaneous manifestations are frequently reported in association with drug use. The aim of this study was to analyse the skin reactions reported to the spontaneous surveillance systems of four Italian regions (Friuli Venezia Giulia, Lombardy, Sicily and the Veneto), and correlate the reports with estimated drug consumption during the same period, paying particular attention to the reactions to antimicrobial agents and nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: All of the adverse drug reactions (ADRs) reported spontaneously between January 1996 and December 1997 to the surveillance systems of four Italian regions (a total population of about 20 million people) were analysed by a panel of experts including dermatologists. On the basis of the Critical Term List of the World Health Organization (WHO), the reactions were classified as either serious or nonserious events. Drug consumption was expressed as a daily defined dose (DDD)/1000 inhabitants/day. RESULTS: A total of 2224 adverse skin reaction reports (44.7% of all of the reported ADRs) were identified, making a reporting rate of about 5.5 per 100 000 inhabitants/year. The female/male ratio was 1.58, and the reporting rate progressively increased with age. The drug categories with the highest number of cutaneous reactions were antimicrobials, followed by NSAIDs, analgesics and radiology contrast media. There was a total of 372 (16.9%) serious reaction reports, the most frequent being angioedema (171 cases), erythema multiforme (68 cases) and photosensitivity (37 cases). Co-trimoxazole, followed by the cephalosporins and fluoroquinolones, were associated with the highest consumption-related reporting rate among the antimicrobials, and aspirin and dipyrone among the NSAIDs and analgesics. CONCLUSIONS: Spontaneous reports from four Italian regions revealed that the skin was the organ most frequently affected by ADRs. The paper shows the validity of a regional decentralized system in Italy.     

Cutaneous blood flow changes and weal induced by intradermal bradykinin following pretreatment with indomethacin and captopril

Summary The effects of indomethacin and captopril on local cutaneous blood flow changes and weal induced by intradermal injections of bradykinin were assessed in two randomised, double-blind, placebo-controlled studies in healthy volunteers. Alterations in cutaneous blood flow were estimated by laser Doppler flowmetry (LDF) and erythema area.LDF output, erythema area and weal volume increased with incremental bradykinin dose. Single doses of indomethacin 25 mg and 75 mg did not affect these cutaneous responses compared with placebo. Captopril 25 mg significantly potentiated the increase in local cutaneous blood flow measured by LDF, but not erythema area, and weal volume induced by bradykinin. The effects of the combined treatment of indomethacin 75 mg and captopril 25 mg were not significantly different from those due to captopril alone.The enhanced cutaneous effects of bradykinin following administration of captopril are in keeping with effective kininase II inhibition in the tissues. Cyclo-oxygenase products release does not appear to contribute to the cutaneous actions of bradykinin nor the potentiation of these responses by captopril.     

Cutaneous adverse reactions to amoxicillin-clavulanic Acid suspension in children: the role of sodium benzoate

Background: In Europe amoxicillin plus clavulanic acid is the most commonly prescribed antibiotic and sodium benzoate is contained in the suspension formulation as a preservative. Objective: We studied the relevance of sodium benzoate as the culprit agent. In a group of children with a history of adverse reactions to amoxicillin plus clavulanic acid suspension. Study Design: A total of 89 children were enrolled over a period of 3 years (2006 - 2009). Single blind oral provocation tests (OPTs) with amoxicillin plus clavulanic acid, sodium benzoate and placebo were performed. 20 children with recurrent idiopathic urticaria were investigated as a control group. Results: according to personal history: 70% of reactions were late in developing while 23% of reactions were immediate and for 5% of the cases it was not possible to define the timing. 8 children (8/89=9%) resulted positive to the provocation tests with amoxicillin plus clavulanic acid; ten children (10/89=11%) had positive results with sodium benzoate; 3% had a double positivity (i.e. excipient and active drug). The timing of reactions significantly differs between the Amoxicillin plus clavulanic acid and sodium benzoate groups (p=0.002). Conclusion: Sodium benzoate probably acts through a non-immunologic mechanism and care should be given to children allergic to sodium benzoate containing pharmaceutical formulations.     

Role of prostaglandins and nitric oxide in acute inflammatory reactions in guinea-pig skin.

1. Oedema formation in skin is dependent on a synergism between mediators that increase vascular permeability and mediators that enhance local blood flow. Leukocyte accumulation is also enhanced by mediators that increase local blood flow. In this study, we have investigated whether nitric oxide (NO), an important endogenous vasodilator, could modulate oedema formation and leukocyte accumulation in guinea-pig skin. 2. Local administration of the NO synthesis inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), dose-dependently inhibited the oedema formation induced in response to intrademal injection of bradykinin or histamine. L-NAME, but not NG-nitro-D-arginine methyl ester (D-NAME); also inhibited oedema formation in response to i.d. injection of platelet-activating factor (PAF), zymosan-activated plasma (ZAP) and in a passive cutaneous anaphylactic (PCA) reaction. 3. N-iminoethyl-L-ornithine (L-NIO) was less effective and about 100 times less potent than L-NAME in inhibiting bradykinin-induced oedema formation. The cyclo-oxygenase inhibitor, ibuprofen, had little effect on oedema responses induced by bradykinin, PAF and in a PCA reaction. On the other hand, histamine-induced oedema formation was significantly suppressed by ibuprofen. 4. The inhibition by L-NAME of bradykinin-induced oedema formation was reversed by co-injection of sodium nitroprusside (SNP) or prostaglandin E1 (PGE1). 5. L-NAME inhibited 111In-eosinophil and 111In-neutrophil accumulation induced by i.d. injection of ZAP. 111In-eosinophil accumulation induced by PAF and in the PCA reaction was also inhibited by L-NAME but not by D-NAME.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cutaneous vasculitis secondary to ramipril

A 61-year-old patient who had been treated with lisinopril in the past without any problems was commenced on ramipril for left ventricular dysfunction. He developed a painful symmetrical purpuric eruption over both feet after three days. A full vasculitis screen was negative. Ramipril was stopped and he required a course of steroids after which the rash improved slowly. The ACE inhibitors can cause various skin side effects; however, it rarely causes cutaneous vasculitis. Ramipril-induced cutaneous vasculitis is particularly rare and our case was atypical because the patient had tolerated lisinopril before. Previous successful treatment with one ACE inhibitor does not rule out the vasculitis caused by the drug from the same group. Here we report ramipril-induced cutaneous vasculitis in a patient who required steroid therapy to control it.     

Cutaneous allergic drug reactions: update on pathophysiology,diagnostic procedures and differential diagnosic

Important changes in the understanding and management of drug hypersensitivity reactions during the last years result from the increasing importance of biologics in medical practice, which differ in their spectrum of adverse drug reactions (ADRs) from the classical covalent drugs. With regard to covalent drugs, ampicillin and amoxicillin as well as clavulanic acid play an increasing role among ADRs to betalactam antibiotics. Fluoroquinolones are mainly the cause of anaphylactic and photosensitivity reactions. Especially in allergic reactions to NSAIDs, pseudoallergic reactions should be considered in the differential diagnosis. In opposite to the main cutaneous allergic drug reactions such as urticaria or maculopapular skin rash, in which antibiotics are the main culprits, in severe drug allergic reactions such as SJS (Stevens-Johnson Syndrome), TEN (Toxic Epidermal Necrolysis), or DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) Syndrome, compounds like allopurinol and anticonvulsants are the main causes. Similar mutations in the IL36R gene, which were found in both patients with an AGEP (Acute Generalized Exanthematous Pustulosis) and pustular psoriasis, make the differential diagnosis more difficult and raise the question whether there is a difference between these diseases or whether AGEP is not just a drug induced pustular psoriasis. Finally, some special aspects of side effects of biologics and targeted therapies respectively are discussed.