Hypersensitivity reactions to trimetrexate

Summary Trimetrexate is a nonclassical antifol currently being tested for efficacy in cancer patients and as an antiparasitic agent against Pneumocystis carinii pneumonia in AIDS patients. We have now received the first reports of hypersensitivity reactions in Phase II cancer trials. Two types of reactions were noted. The most severe reaction, immediate hypotension with loss of consciousness, occurred in only one patient. Four other patients exhibited an immediate systemic effect with one or more of the following symptoms: facial flushing, fever, shaking, pruritus, bronchospasm, periorbital edema, and difficulty in swallowing. Immediate hypersensitivity should now be considered a known side effect of trimetrexate therapy, occurring in < 2% of patients.     

Hypersensitivity reactions to quinolones

Quinolones are one of the most important classes of antimicrobial agents discovered in the recent years and one of the most widely used classes of antibiotics in clinical medicine. Their broad spectrum of activity and pharmacokinetic properties make them ideal agents for treating a variety of infections. Their clinical importance is further demonstrated by their activity against a wide range of diseases of public health importance such as anthrax, tuberculosis, bacterial pneumonia, and sexually transmitted diseases. Like other antibiotics, quinolones can cause various, sometimes dangerous hypersensitivity reactions. The underlying pathomechanisms are only poorly understood. Some are thought to be partly non-immune mediated reactions, others are considered to be IgE- or T cell-mediated reactions. This review gives an insight into the different immunological mechanisms leading to the diverse symptoms of quinolone-induced hypersensitivity reactions, with special emphasis on the role of T cells in such reactions.     

Hypersensitivity reactions to anticoagulant drugs

Drugs with anticoagulant activity, including heparins, hirudins, coumarins, and platelet aggregation inhibitors belong to the most widely used drugs. Hypersensitivity reactions from these agents are rare. However, due to their widespread use, they may have a considerable impact on patient safety and treatment. Accurate diagnosis of potentially life-threatening adverse events and identification of alternatives is mandatory. We review hypersensitivity reactions caused by the different groups of anticoagulant agents and discuss the pathophysiological mechanisms, diagnostic possibilities and management options. According to patients histories the most common hypersensitivity reaction is intolerance to acetylsalicylic acid (ASA). Also localized erythematous plaques, occurring to subcutaneous application of heparins are rather common. Other hypersensitivity reactions are rare but may be life-threatening, e.g. skin necrosis due to heparin-induced thrombocytopenia. Rarely anaphylactoid reactions have been observed to ASA, heparin, and hirudin. Skin and provocation tests with immediate and late readings are the most reliable diagnostic tools for heparin- or hirudin-induced urticaria/anaphylaxis or heparin-induced delayed plaques. Provocation tests may be used to identify safe alternatives. In cases of necrosis from heparins or coumarins, all in vivo tests are contraindicated. Most in vitro tests are not universally available, and with the exception of platelet aggregation tests, they have a low sensitivity. In some anticoagulant-associated hypersensitivity reactions detailed allergologic investigation may help to identify safe treatment alternatives. Typically, several tests are needed, and therefore the test procedures are time consuming.     

Hypersensitivity reactions to ophthalmic products

Adverse reactions after administration of ophthalmic products have frequently been observed. These reactions can be provoked by both active principles and excipients. Different pathogenic mechanisms have been suggested for such reactions, including immunologic ones. Basophils and mast cells participate in IgE-mediated reactions through the release of mediators like histamine and tryptase, whereas a T-cell-mediated pathogenic mechanism is involved in most delayed reactions, particularly conjunctival ones and eyelid dermatitis. Prick tests and immediate-reading intradermal tests are carried out to diagnose immediate hypersensitivity reactions, while patch tests are usually performed to evaluate delayed reactions. Other diagnostic tests, such as serum-specific IgE assays in immediate reactions, as well as delayed-reading intradermal tests and/or lymphocyte transformation tests in delayed ones, are rarely performed. In this review, particular attention is addressed to the clinical and practical aspects of both cell-mediated and IgE-mediated hypersensitivity reactions to ophthalmic products.     

Hypersensitivity reactions to neuromuscular blocking agents

Neuromuscular blocking agents are the leading drugs responsible for immediate hypersensitivity reactions during anaesthesia. Most hypersensitivity reactions represent IgE-mediated allergic reactions. Their incidence is estimated to be between 1 in 3,000 to 1 in 110,000 general anaesthetics. However striking variations have been reported among countries. The mechanism of sensitisation seems to implicate the presence of a substituted ammonium ion in the molecule. Due to lack of exposure prior to the reaction in a large number of reactors, it has been hypothesised that sensitisation may involve other, as yet undefined, substituted (quaternary and tertiary) ammonium ion containing compounds such as pholcodine, present in the environment of the patient. This hypothesis is still under investigation. The mechanism of non-IgE mediated hypersensitivity reactions is less well known. Identified mechanisms correspond to direct histamine release or interactions with muscarinic and nicotinic receptors. Allergic reactions cannot be clinically distinguished from non-IgE-mediated reactions. Therefore, any suspected hypersensitivity reaction must be investigated using combined pre and postoperative testing. Because of the frequent but not systematic cross-reactivity observed with muscle relaxants, every available neuromuscular blocking agent should be tested, using intradermal tests to confirm the responsibility of the suspected drug which should be definitely excluded. Cross-sensitivity investigation will also try to identify the safety of drugs that can be potentially used in future anaesthesia. The determination of basophil activation investigations using direct leukocyte histamine release test or flow cytometry would be of particular interest to investigate cross sensitisation in complement to skin tests. There is no demonstrated evidence supporting systematic pre-operative screening in the general population at this time. However, since no specific treatment has been shown to reliably prevent anaphylaxis, allergy assessment must be performed in all high-risk patients. In view of the relative complexity of allergy investigation, and of the differences between countries, an active policy to identify patients at risk and to provide any necessary support from expert advice to anaesthetists and allergologists through the constitution of allergo-anaesthesia centres in every country should be promoted.     

Hypersensitivity reactions to iodinated contrast media

Adverse reactions after iodinate contrast media (ICM) administration have been observed, which can be classified as immediate (i.e., occurring within one hour after administration) and delayed or non-immediate (i.e., occurring more than one hour after administration). Even though the incidence of ICM adverse reactions has been significantly reduced by the introduction of non-ionic compounds, immediate reactions still occur in about 3% of administrations. Different pathogenic mechanisms have been suggested for ICM reactions, including immunologic ones. Basophils and mast cells participate in immediate reactions through the release of mediators like histamine and tryptase, whereas a T-cell-mediated pathogenic mechanism is involved in most non-immediate reactions, particularly maculopapular rashes. Skin tests and specific IgE assays are carried out to diagnose immediate hypersensitivity reactions, while both delayed-reading intradermal tests and patch tests are usually performed to evaluate non-immediate reactions. However, in vitro specific IgE assays are not commercially available. As far as in vitro tests are concerned, a response involving ICM-related T-cell activity may be assessed by the lymphocyte transformation test. Allergologic evaluation appears to be indicated in hypersensitivity reactions to ICM, although the sensitivity, specificity, and predictive values of allergologic tests have not yet been established. This paper summarizes the current state of the art and addresses the research that is still needed on the pathogenic mechanisms, diagnosis, and prevention of ICM-induced hypersensitivity reactions.     

Hypersensitivity reactions to complementary and alternative medicine products

Complementary and alternative medicine (CAM) is becoming increasingly popular, and is often used for treating hypersensitivity diseases. Virtually all alternative remedies can cause hypersensitivity reactions, but the most frequently involved ones are tea tree oil, members of the Compositae family, propolis, oils used in aromatherapy, substances responsible for photosensitization, and metal-containing compounds. The main target organ is skin, with manifestations ranging from contact dermatitis (the most common) to urticaria-angioedema, maculopapular eruptions, photosensitivity reactions, and the Stevens-Johnson syndrome. Other types of reactions are possible, including respiratory and anaphylactic ones. Different pathogenic mechanisms have been suggested for CAM product reactions, including immunologic ones. Basophils and mast cells participate in IgE-mediated reactions through the release of mediators like histamine and tryptase, whereas a T-cell-mediated pathogenic mechanism is involved in most delayed reactions, particularly contact dermatitis and maculopapular eruptions. Skin tests and serum specific IgE assays are carried out to diagnose immediate hypersensitivity reactions, while patch tests and lymphocyte transformation tests are usually performed to evaluate delayed hypersensitivity reactions. Thus clinicians should know about the potential of CAM products for causing adverse reactions. Our study is aimed at highlighting the risk of hypersensitive reactions to CAM remedies on the basis of the numerous cases reported in the literature. Because little is known about adverse reactions to CAM products, further systematic studies and an appropriate regulation by heath authorities are necessary.     

Hypersensitivity reactions to drugs: evaluation and management

Most hypersensitivity reactions to drugs occur within several weeks of administration; signs and symptoms are often consistent with known immune-mediated reactions, including anaphylaxis, rashes, fever, cytopenias and vasculitis. The culprit immune mechanisms range from immunoglobulin E antibody to T cells inducing apoptosis of keratinocytes, in the case of bullous exfoliative rashes. Many drugs induce reactions via altered hepatic metabolism, with production of reactive intermediates which induce a common syndrome of rash and fever plus variable types of other signs. Examples of this reactive metabolite syndrome include the rash and fever in HIV-positive patients given sulfamethoxazole and reactions to the aromatic anticonvulsants. With the notable exception of anaphylaxis and severe bullous exfoliative rashes, most immune reactions to drugs are not life-threatening and generally resolve once the drug is discontinued. The key is prevention. Specific immune testing is standardized only for penicillin. If test results are negative, however, the patient can tolerate all beta-lactam antibiotics. Of those patients with a positive penicillin skin test, only 2% develop reactions when given cephalosporins. Sulfa and quinolone antibiotics, and muscle relaxants, also frequently induce reactions. If there is a history of bullous rash, the patient should never again receive sulfa or quinolone, or related drugs. In other cases, a cautious graded challenge or desensitization can be done. Vancomycin, protamine, and radiocontrast media induce non-immune reactions secondary to their irritant effects on vascular endothelium. Narcotic pain medications cause histamine release by binding to a specific receptor on mast cells in sensitive patients. In contrast to true immune reactions, most patients can receive these medications again, if they are pretreated and the drugs are given slowly. Angiotensin-converting enzymes, aspirin, and non-steroidal anti-inflammatory drugs induce adverse reactions by their effect on enzymes. Readministration usually results in repeat symptoms. It is possible to desensitize patients to aspirin. Some patients appear to develop similar adverse symptoms with multiple unrelated drugs. Although these cases present management problems, most patients can complete a therapeutic course of a vital drug, after careful review of the history, immune testing when possible, and graded challenge or desensitization.     

Hypersensitivity reactions associated with oxaliplatin

The reported incidence of hypersensitivity reactions (HSRs) associated with oxaliplatin in patients with colorectal cancer (CRC) is approximately 12%, with 1 - 2% of patients developing grade 3 or 4 in severity. However, the recent rising incidence of HSR to oxaliplatin observed is the result of increasing clinical use. HSR to oxaliplatin may manifest as facial flushing, rash/hives, tachycardia, dyspnoea, erythema, pruritus, fever, tongue swelling, headache, chills, weakness, vomiting, burning sensations, dizziness and oedema. Anaphylactic shock is rare but serious, and must be considered in the event of hypotension. No definitive approaches to prevent and treat HSR associated with oxaliplatin are available; however, few successful strategies have been reported. Such strategies include: slowing the infusion rate, use of steroids and antagonists of type 1 and 2 histamine receptors, and desensitisation. Successful implementation of oxaliplatin desensitisation protocols based on other platinum-containing compounds have been reported, which could enable a small number of patients who experience severe HSR to further receive an effective therapy for CRC. However, reintroductions have only been reported as single case studies or small cohorts. Large-scale validation on desensitisation strategies are still missing. Recently, subcutaneous adrenaline has also been utilised as an alternative approach to manage HSR to oxaliplatin. Knowledge of this rare but real toxicity of oxaliplatin is paramount because the use of this drug continues to increase not only for the treatment of patients with stage II-IV CRC, but also other solid malignancies. In this article, the author discusses the incidence, clinical presentation, pathogenesis, risk factors and current strategies of management of HSR associated with oxaliplatin.     

碘普罗胺注射液致过敏反应3例

例1男,64岁,既往无任何药物过敏史,曾使用过碘海醇(欧乃派克)造影无不适主诉。因右下肺小细胞未分化癌于2004年12月28日行CT增强扫描。上午11:00静脉注射碘普罗胺注射液300mg/100m(l优维显)。20min后,患者主诉全身发痒,发热,大汗,头晕目眩面色苍白,脉搏细弱,血压测未及,先后肌内注射地塞米松注射液5mg,静脉滴注肾上腺素注射液0.5mg,后又静脉推注地塞米松5mg,吸氧。11:40症状缓解,P90次/min,BP86/50mmH(g1mmHg=0.133Kpa)。心电监测,12:30示窦性心率。1h后患者诉喉头阻塞感,全身皮疹。将氟美松注射液10mg,呋塞米注射液20mg,分别入液静脉滴…     

386例头孢菌素类药物不良反应文献分析

目的探讨头孢菌素类药物不良反应的规律及特点,指导合理用药.方法采用文献计量学方法对近10年国内公开报道的386例头孢菌素类药物所致的不良反应进行分析.结果A型45例,B型341例,引起的器官系统损害以过敏反应(35.49%)和泌尿系统损害(29.02%)最多.反应程度绝大多数为轻、中度反应,重度反应93例,其中死亡7例.药物以头孢哌酮(97例)、头孢拉定(78例)和头孢唑啉(69例)不良反应报道较多,比例分别占25.13%、20.21%、17.88%.结论临床应加强对头孢菌素类药物的合理应用,避免和减少不良反应的发生.     

第三代头孢菌素类药物的不良反应分析

目的：观察第三代头孢菌素类药物在临床应用中的不良反应情况。方法随机选择我院进行常规静脉注射治疗的患者1900例,对他们使用第三代头孢菌素类药物进行临床治疗,并就患者的不良反应情况进行统计、比较和分析。结果临床分析显示,第三代头孢菌素类药物在临床应用中的不良反应发生率为2.89%,且以过敏反应（56.34%）为主。头孢他啶产生的不良反应最少,且所有不良反应的发生同患者的性别、年龄均无明显的关联性（P＞0.05）。结论在进行第三代头孢菌素类药物的临床应用时,要在关注抗菌效应的同时,注重患者用药的不良反应,从而确保药物应用的正确性,提高患者的临床治疗效果,避免出现药物滥用现象。     

Hypersensitivity reactions associated with oxaliplatin and their clinical management

Introduction: Oxaliplatin, has become an integral part of the medical treatment of colorectal cancer and other malignancies. Increased use of the drug during the last decade, has led to increased occurrence of oxaliplatin-induced hypersensitivity reactions (HSRs), posing a significant challenge for clinicians. This article aims to review the existing literature regarding the incidence, clinical presentation, pathophysiology, risk factors and current management of oxaliplatin-induced HSRs.

Areas covered: A systematic review of the English literature published in PubMed and Medline was undertaken. The clinical manifestations of HSRs were found to be variable and unpredictable. These reactions should be an important concern, as their potential life-threatening risks can force doctors to stop treatment and seek alternatives, which may be less effective, not as well tolerated and/or more expensive. There are a few strategies to prevent these reactions so that patients can still benefit from oxaliplatin. Such strategies include the use of premedication (steroid and antagonists of type I and II histamine receptors), prolonged infusion time and desensitization.

Expert opinion: The presented management strategies as well as novel diagnostic tools including skin/intradermal tests and specific IgE have shown promising results. However, future research and validation are warranted in bigger clinical trials.     

IgE-mediated hypersensitivity to cephalosporins

Like penicillins, cephalosporins may cause IgE-mediated reactions such as urticaria, angioedema, and anaphylactic shock, which occur because of sensitization to determinants shared with penicillins or to unique cephalosporin haptens. In particular, side-chain structures may be responsible for selective sensitization or cross-reactivity. For this reason, individual free cephalosporins are usually employed in skin testing, in addition to the classic penicillin reagents. Cephalosporin skin tests are sensitive in diagnosing immediate hypersensitivity to these betalactams. As far as in vitro tests are concerned, IgE assays for cephalosporins, specifically sepharose-radioimmunoassays, are a potentially useful tool in evaluating immediate reactions and could be used as complementary tests. In selected cases displaying negative results in both skin tests and IgE assays, a graded challenge with the implicated cephalosporin can be performed. Cephalosporin IgE-mediated hypersensitivity may be a transient condition; therefore, allergologic exams should be repeated in patients with negative initial allergologic work-ups, including challenges. Performing allergologic tests with cephalosporins other than the culprit, as well as with penicillin reagents, allows the identification of cross-reactivity with penicillins, selective responses, or cross-reactivity among cephalosporins. In the latter group, cross-reactivity is more frequently related to R1 than to R2 side-chain recognition. In assessing the selectivity of the response, negative results in skin testing with cephalosporins other than the responsible one appear to be a reliable indicator of tolerability.     

350例头孢菌素类抗生素不良反应报告分析

目的 了解该院头孢菌素类抗生素不良反应发生特点与一般规律,为临床合理用药提供参考.方法 采用回顾性调查方法对2005～2009年该院ADR监测中心收集到的350例头孢菌素类抗生素ADR报表进行统计分析.结果 350例ADR报表中涉及21种头孢菌素类抗生素,ADR累及皮肤及其附件损害最多,发生ADR头孢菌素类抗生素以头...     

头孢菌素类药物79例不良反应的回顾性分析

目的了解头孢菌素类药物不良反应的发生情况，提高其用药合理性。方法对本院2010～2011年采集的头孢菌素类药物79例不良反应进行回顾性分析。结果头孢菌素类药物不良反应在新生儿和老年患者中较多。与给药途径、给药剂型和给药浓度相关，主要为变态反应。结论医生应该充分了解各种头孢菌素类药物的特性，根据患者的病情和个体差异制定给药方案，提高其临床合理应用水平。     

头孢菌素类药物不良反应机制与化学结构的关系

目的:了解头孢菌素类药物不良反应发生机制与化学结构的关联。方法:根据临床病例分析和实验研究结果,对常用头孢菌素与化学结构相关的不良反应文献进行归类与分析。结果:头孢菌素不良反应的发生与其化学结构密切关联,其结构中的β-内酰胺环、β-内酰胺环胼合的杂环及环上的侧链取代基均与不良反应相关,可与多种生物分子如γ-氨基丁酸,Na⁺-K⁺-ATP酶等相互作用引起不良反应。结论:了解头孢菌素类药物不良反应机制与化学结构的关联,可以合理促进选用头孢菌素,将可能的不良反应降至最低,维护头孢菌素类药物持久的抗感染作用。