H1抗组胺药物研究进展

人体内组胺受体主要有H1、H2、H3和H4四种受体类型,组胺主要通过受体发挥生物学作用。目前H1抗组胺药物主要用于治疗荨麻疹及其他过敏性疾病,中枢神经系统疾病和前庭疾病。第一代H1抗组胺药物用于治疗过敏性疾病并无规范的研究,多数临床试验不符合当前随机双盲对照试验的标准。与之相比,第二代H1抗组胺药物均有大量充分的试验支持。临床上大部分H1抗组胺药物安全有效,但其中枢神经系统及心脏的不良反应不容忽视。     

Insektengifthyposensibilisierung

Venom immunotherapy (VIT) protects patients with Hymenoptera venom anaphylaxis from subsequent potentially life-threatening reactions. The most important side effect are systemic anaphylactic reactions (SAR). Compared to the administration of aqueous extracts according to a rush protocol, the frequency of systemic and also local side effects will be lower if depot extracts are used and a slow conventional dose schedule is used, as compared to rush desensitization with aqueous extracts. However, protection often has to be achieved rapidly, and adequate surveillance of sufficient duration is hardly feasible in outpatients. Therefore, VIT according to rush schedules in inpatients remains indispensable. Pre-treatment with H(1)-blocking antihistamines reduces frequency and intensity of local and mild systemic adverse reactions during VIT. Up to 25% of patients again develop a SAR when re-stung while on VIT with the usual maintenance dose of 100 microg venom. Patients with honeybee venom allergy or with mastocytosis are at a higher risk for treatment failure. Almost all of them will become fully protected by increasing the maintenance dose, 200 microg venom being sufficient in most cases. Patients with significant risk factors may be treated from the beginning with an elevated maintenance dose, particularly when they are allergic to honeybee venom.     

Second-Generation H1-Antihistamines in Chronic Urticaria

The effects of urticaria are predominantly mediated by histamine release; therefore, H1-antihistamines are the mainstay of treatment. Second-generation H1-antihistamines, compared with their first-generation counterparts, have demonstrated improved peripheral H1-receptor selectivity and decreased lipophilicity (which minimizes CNS adverse effects), and antiallergic properties in addition to being histamine inverse agonists. Evidence of clinical efficacy and tolerability of second-generation H1-antihistamines available in the US for the treatment of chronic urticaria (CU) was analyzed using the GRADE system to develop the strength of recommendations for particular therapies. The evidence for the safety and efficacy of the majority of second-generation H1-antihistamines available in the US is of high quality and leads to a strong recommendation for their use in CU. There is a limited amount of data of variable quality comparing the efficacy between various second-generation H1-antihistamines in CU leading to weak recommendations for using cetirizine over fexofenadine and levocetirizine over desloratadine. Limited data of variable quality exist for the efficacy of higher doses of second-generation H1-antihistamines in CU patients not responsive to standard doses. These limited data lead to a strong recommendation that higher than recommended doses of fexofenadine do not offer greater efficacy in control of CU and a weak recommendation that higher doses of levocetirizine and desloratadine are more effective in CU unresponsive to standard doses. More studies of higher quality are required to make any firm recommendations regarding second-generation H1-antihistamines in the treatment of physical urticarias. All second-generation H1-antihistamines appear to be very well tolerated in CU patients, with rare reports of adverse effects. Due to the relatively large gaps in the quantity and quality of evidence, particularly for choice of H1-antihistamines, use of higher doses, and use in physical urticarias, greater emphasis in management decisions should be based on the risk/benefit ratio and the patient's personal values and preferences (including cost) in clinical decision making.     

EAACI/GA2LEN/EDF/WAO荨麻疹指南:治疗

本指南经2008年第三次国际荨麻疹共识会议讨论达成,由EAACI、GA2LEN、EDF和WAO联合倡议。荨麻疹的一线治疗建议使用非镇静的H1受体拮抗剂。如果标准治疗剂量不起效,建议可将剂量增加到标准治疗剂量的四倍。如果仍无效果,建议采用二线治疗。选择二线治疗时,应权衡利弊和综合考虑治疗的费用。由于糖皮质激素具有不可避免的不良反应,故不推荐长期使用。     

Adverse mucocutaneous reactions to chemotherapeutic agents: part I

The local and systemic treatment of tumors can cause changes in the skin, mucous membranes, hair and nails. Accurate diagnosis and appropriate treatment of side effects require knowledge about the patterns of the most common adverse reactions to drugs the patient may be using. The dermatologist must be familiar with the manifestations of certain soft tissue neoplasms, as well as with the adverse mucocutaneous forms of cancer treatment.     

Cutaneous lupus erythematosus

Cutaneous lupus erythematosus is a heterogeneous autoimmune condition that can significantly impact quality of life. Treatment is focused on reducing clinical inflammation and preventing scarring. The choice of treatment should be guided based on the severity of disease. Mild or localized disease can be treated with sun protection and topical agents. Antimalarials are the initial treatment of choice if systemic therapy is required. Patients with severe or unresponsive disease can also be treated with a number of other immunomodulating or immunosuppressive agents. Clinicians should be aware of their potential adverse effects and appropriate dosing.     

The life-threatening complications of dermatologic therapies

Dermatologists use a variety of systemic drugs, some of which can cause severe adverse reactions and even fatalities. Ivermectin, a well-tolerated drug, can cause severe neurological side effects, whereas metronidazole, in high cumulative doses, has been associated with convulsions and rarely with hepatotoxicity. Dapsone is associated with frequent hematologic side effects, such as methemoglobinemia, hemolysis, and anemia. Although hepatotoxicity is rare and usually mild and reversible with the new antifungal agents, severe cutaneous reactions (such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and anaphylaxis) have been reported. Even a relatively safe drug such as acyclovir has been reported to be the cause of renal failure and neurotoxicity. Retinoids can cause not so benign "benign" intracranial hypertension. Methotrexate can cause not only liver toxicity, but also myelosuppression and pancytopenia, which may be acute and life threatening. Nephrotoxicity is a well-recognized side effect of cyclosporine, whereas thrombotic thrombocytopenic purpura, which is associated with high morbidity and mortality, is less well known. Dermatologists should be familiar with these and other severe adverse reactions of the most popular and most used systemic medications of our trade.     

Spezifische Immuntherapie (SIT) bei atopischer Dermatitis und Nahrungsmittelallergie

Atopic dermatitis (AD) is one of the most frequent chronic inflammatory skin diseases with an increasing prevalence. About 80% of adult AD patients are sensitized against seasonal or perennial aeroallergens and/or food allergens which may play a pivotal role in triggering or maintaining eczema. In addition to local and systemic therapy adjusted to the stage of the disease, the search for relevant trigger factors and then their avoidance plays a crucial role in managing AD. While the effectiveness of SIT is best established in allergic rhinitis, bronchial asthma and insect venom allergy, its use in AD is still controversial. Double-blind, placebo-controlled clinical studies are now available showing good efficacy of SIT in patients with AD. For food allergies there are clues from case reports and small clinical studies suggesting effectiveness of SIT both for food allergies and associated aeroallergens. Double-blind, placebo-controlled studies involving larger numbers of patients are needed to establish the clinical effectiveness and immunologic mechanisms of SIT in food allergies.     

Standards und Fallstricke der In-vitro-Diagnostik der Insektengiftallergie

In patients with a history of anaphylactic sting reactions, in-vitro tests are performed in order to demonstrate venom sensitization to the causative venom. Measurement of specific IgE-antibodies (sIgE) to the natural composite venom represents the standard in-vitro method to demonstrate venom sensitization. If sensitization to the composite venom cannot be demonstrated, one may determine sIgE to recombinant allergen compounds, in order to demonstrate sensitization to molecular venom allergens. Moreover, several cellular tests are available to confirm venom sensitization. Herein basophils, which carry cell-bound sIgE, can be used to produce a confirmatory response upon incubation with venom allergens. Reactions to both honey bee and vespid venom may either indicate true double sensitization or cross sensitization. The identification of antibodies cross-reacting to venoms and to other allergen sources does not exclude clinical relevance. Elevated baseline serum tryptase is a risk factor for severe systemic reactions after a field sting and during venom immunotherapy (VIT), the latter in particular for VIT with vespid venom. Serum tryptase measurement should, therefore, be included into routine diagnostics of venom allergy. The measurement of IgG-antibodies specific to venom is not recommended for routine work-up. None of the mentioned in-vitro tests, which may be used before, during or after VIT, allow, however, a precise prognosis with respect to future sting reactions, or to side effects and to the efficacy of VIT, respectively. To validate the reason for a VIT, one should also consider patient history and results of other tests.     

A systematic review of adverse effects associated with topical treatments for psoriasis

Mild to moderate psoriasis is a disease that can often be treated with topical medications. The diversity of topical therapies and their disparate side effects complicates treatment planning. Our purpose is to compare the rates of adverse events associated with different topical psoriasis treatments. A review of medical literature from 1996 to March, 2002 was conducted using guidelines set by QUORUM statement criteria. In monotherapy studies, corticosteriods caused fewer adverse reactions compared to vitamin D analogues and tazarotene. In combination studies adverse event rates were higher than in monotherapy studies, except for the combination of topical steroid and calcipotriene which decreased irritation. Irritant contact dermatitis was the main side effect with vitamin D analogues, tazarotene, dithranol or coal tar, while side effects of topical corticosteriods included headache, viral infection and skin atrophy. Topical agents for psoriasis are usually well-tolerated without severe side effects. Formulating a patient's medication regimen should take into account the needs for short-term management and long-term control of psoriasis. Since clearance is not a realistic expectation, reasonable goals should be set as excessive use of topical treatments may increase the risk of both cutaneous and systemic side effects.     

Systemic Side-Effects of Topical Corticosteroids

With the introduction of topical corticosteroids, a milestone has been achieved in dermatologic therapy; owing to its potent anti-inflammatory and ant proliferative effects, it became possible to treat some hitherto resistant dermatoses. But this magic drug can cause enough mischief if used inappropriately. Children are more susceptible to the systemic adverse effects because of enhanced percutaneous absorption through their tender skin. So, systemic side effects should be kept in mind while prescribing this therapeutically valuable topical medicament.     

Anaphylaxie im Kindes- und Jugendalter

Anaphylaxis represents a severe, systemic and potentially fatal hypersensitivity reaction that severely impairs the life of affected children and their caregivers. With an estimated life time prevalence of 0.05% to 2%, it is not a rare disease. Therefore every physician caring for children at risk for anaphylaxis should be familiar with this disease pattern. Foods are the most frequent triggers in children; less frequent causes include drugs and insect venom. Particularly in case of idiopathic anaphylaxis, systemic mastocytosis should be ruled out as a potential differential diagnosis in this age group as well. First line emergency treatment consists of parenteral epinephrine in a weight-adjusted dosage, and after cardiovascular stabilization systemic antihistamines and corticosteroids as well as inhaled beta-mimetics can be administered. Affected patients, their relatives and other caregivers should receive extensive training in order to guarantee an adequate emergency management of anaphylactic children.     

Atenolol-induced cutaneous vasculitis

We present a case of cutaneous vasculitis apparently due to an adverse reaction to atenolol. The causal relationship between the drug and the eruption was based mainly on circumstantial evidence. It has been further strengthened by positive results of the indirect rat mast cell degranulation test. The number of published cases of reaction to atenolol is limited. Cutaneous vasculitis has, to the best of our knowledge, never been reported as an adverse reaction to atenolol, although it is not a rare side effect of other beta blocker drugs including propranolol and practolol. Atenolol should be added to the list of beta blocker medications that may produce cutaneous vasculitis.     

Contact dermatitis to topical acne drugs: a review of the literature

Acne vulgaris is a chronic dermatological disorder that affects the majority of teenagers in the Western world. Topical therapy is widely used to treat mild‐moderate acne and is known as well‐tolerated thanks to its low systemic toxicity, although associated to skin adverse effects. Acne seems to be associated also to an intrinsic alteration of the epidermal barrier, regarding both the upper and the follicular stratum corneum that promotes the onset of such local side effects. The commonest one is irritant contact dermatitis, an event of frequent observation occurring with erythema, burning, dryness, scaling, and itching, usually characterized by low severity and limited duration. Among topical acne drugs, retinoids are the most irritating ones. Another side effect is allergic contact dermatitis: it is rare and mainly associated to benzoyl peroxide.     

Mucosal (oral and vulval) lichen planus in women: are angiotensin‐converting enzyme inhibitors protective,and beta‐blockers and non‐steroidal anti‐inflammatory drugs associated with the condition?

Aim. To determine whether there is an association between the use of angiotensin‐converting enzyme (ACE) inhibitors, beta‐blockers and nonsteroidal anti‐inflammatory drugs (NSAIDS) in women with mucosal (oral and vulval) lichen planus (LP) compared with a control population. Methods. This was a retrospective review of medical records in dedicated vulval and oral clinics in hospitals. The study population comprised 141 women with vulval LP and 106 women with oral LP. Medications taken at the time of diagnosis were recorded. Results. Patients with mucosal LP were more likely to be on NSAIDS and beta‐blockers, but less likely to be on ACE inhibitors compared with controls. All three groups were found to have an inverse relationship with ACE inhibitors, but no association was found between patients with oral LP and beta‐blockers. Conclusions. Beta‐blockers and NSAIDS are associated with LP, suggesting that withdrawal of these drugs should be considered. Further studies are needed to confirm or refute the inverse relationship between mucosal LP and use of ACE inhibitors.     

Systemic Glucocorticosteroid Therapy of Skin Disease in Children

The role of systemic glucocorticosteroid therapy in the management of dermatologic disorders in children is limited. Most skin diseases requiring the antiinflammatory or antiproliferative effects of steroids are best managed with topical preparations, because they exert local effects almost exclusively and cause few if any systemic side effects when used properly. There are, however, certain skin diseases, which because of their severity or their intrinsic nature, do not respond adequately to these agents. We propose the indications for pharmacologic doses of systemic glucocorticosteroids in dermatologic disease, the preferred route of administration, the most common as well as the more rare side effects of this therapy. Withdrawal of patients from chronic use of these drugs is also discussed.     

Side effects of drugs on male fertility

Side effects of drugs on male fertility occur more often than they are expected to. In general, they are not recognized till during andrological examination on account of a barren marriage. A transient or permanent inhibition of male fertility by drugs is possible, if one of the following functions interferes: spermatogenesis, sperm maturation within the epididymis, sperm transport, sperm metabolism and motility, semen liquefaction, capacitation, acrosomal reaction, or ovum penetration. Best known is the impairment of spermatogenesis by direct inhibition of the germinal epithelium (antispermatogenic agents: cytostatics, immunosuppressive agents, psychopharmacological compounds, antibiotics) or indirectly by influencing the axis between hypothalamus, pituitary gland, and gonads (hormones: estrogens, gestagens, androgens, anabolics, antiandrogens). Sperm transport may be impaired by neuroleptic drugs, tricyclic antidepressants, antihypertensive drugs like guanethidine, and ganglionic blocking agents. Inhibition of sperm motility is possible by antibiotics, psychopharmacological agents, anthelmintics, and beta receptor blockers. In future, it will therefore be necessary to pay more attention to side effects of drugs on male fertility, particularly with regard to patients at the age of reproductiveness.     

Chronic urticaria: a role for newer immunomodulatory drugs?

Chronic urticaria is now recognized as an autoreactive disorder in a substantial fraction of patients. A serologic mediator of whealing has been demonstrated in 50-60% of patients with chronic urticaria, and autoantibodies against the high affinity IgE receptor or IgE have been detected in about half of these patients. The demonstration that chronic urticaria is frequently autoimmune has encouraged a more aggressive therapeutic approach, with the use of immunomodulatory drugs.A step-by-step approach to the management of chronic urticaria is proposed, based on our personal experience and review of current medical literature, identified through Medline research and hand searching in medical journals. The non- or low-sedating H(1) receptor antagonists (antihistamines), such as cetirizine, fexofenadine, loratadine, mizolastine and, more recently, levocetirizine, desloratadine and ebastine, represent the basic therapy for all chronic urticaria patients. Older sedating antihistamines, such as hydroxyzine and diphenhydramine, may be indicated if symptoms are severe, are associated with angioedema, and if the patient is anxious and disturbed at night.Corticosteroid therapy with prednisone or methylprednisolone can be administered for a few days (7-14) if urticarial symptoms are not controlled by antihistamines and a rapid clinical response is needed. In cases of relapse after corticosteroid suspension, leukotriene receptor antagonists, such as montelukast and zafirlukast, should be tried. In our experience, remission of urticarial symptoms can be achieved in 20-50% of chronic urticaria patients unresponsive to antihistamines alone. When urticaria is unremitting and is not controlled by combined therapy with antihistamines and leukotriene receptor antagonists, prolonged corticosteroid therapy may be needed. Long-term corticosteroid therapy should be administered at the lowest dose able to control urticarial symptoms, in order to minimize adverse effects. In a few patients, however, high-dose corticosteroid therapy may have to be administered for long periods. In these patients, immunosuppressive treatment with low-dose cyclosporine can be started. This type of treatment has a corticosteroid-sparing effect and is also generally effective in patients with severe, unremitting urticaria, but requires careful monitoring of cyclosporine plasma concentration and possible adverse effects. Other immunomodulating drugs that have been tried in chronic urticaria patients include hydroxychloroquine, dapsone, sulfasalazine and methotrexate, but their efficacy has not been proven in large controlled studies. Warfarin therapy may also be considered in some patients with chronic urticaria and angioedema unresponsive to antihistamines.     

Antihistamine update

Antihistamines are a diverse group of drugs, each possessing the ability to inhibit various actions of histamine. Because they act principally through competitive inhibition of the histamine receptor, they are helpful as a means of preventing rather than reversing these actions. As a result of a resurgence of interest in antihistamine therapy during the past decade, a new class of H1 blockers, clinically devoid of sedative and anticholinergic effects, has evolved. Thus, the choice of antihistamine can now be based on the side effects profile as well as the clinical profile. As we continue to develop a better understanding of these newer agents, we will be able to select more rationally the antihistaminic agent most appropriate to the specific disorder. Used judiciously, the antihistamines available today have a broad application of therapeutic uses, with few significant side effects.     

Adjuvant drugs in autoimmune bullous diseases,efficacy versus safety: Facts and controversies

During the last decades, the conventional therapy for autoimmune blistering diseases has been high-dose, long-term systemic corticosteroid and immunosuppressive agents or adjuvant drugs. Long-term, high-dose steroid therapy can result in serious adverse effects. The rationale for using adjuvant drugs is that concerns reducing the need for corticosteroids, and hence, their side effects, or it may result in better control of the disease, or both. Immunosuppressive agents are not free of adverse effects, however. Prolonged immune suppression may account for high rates of morbidity, disability, and possible death. There is no consensus about the first-choice adjuvant drug for the management of blistering autoimmune diseases. This contribution evaluates six adjuvant drugs—cyclophosphamide, azathioprine, cyclosporine, mycophenolate mofetil, intravenous immunoglobulin, and rituximab—and discusses the choice of a “winning drug” that is effective and safe.