药物成瘾的病理生理学基础

药物成瘾使社会继续付出巨大的人力和财力,而当前可采用的治疗手段对大多数药物成瘾者仍然达不到预期的效果.与其他医学专业一样,治疗上的进展是来自对特殊疾病的病理生理学机制的分子和细胞基础研究的逐步深入.药物成瘾是慢性、复发性脑疾病.对成瘾发生过程的脑神经组织的适应性变化的研究将导致更为有效的治疗方法和策略的出现.     

Pustular drug hypersensitivity syndrome due to allopurinol

Allopurinol hypersensitivity syndrome (AHS) is a severe drug reaction. It is characterized by rash, fever, and internal organ involvement. It may present in different clinical forms. We present a case of acute generalized exanthematous pustulosis occurring as a manifestation of AHS.KEY WORDS: Allopurinol, hypersensitivity syndrome, pustulosis     

Use of transgenic animals to investigate drug hypersensitivity

Hypersensitivity reactions to drugs and environmental agents are often due to exaggerated humoral (Th(2)) or cell mediated (Th(1)) immune responses with typical cytokine profiles. Overexpression of Th(2) cytokines, such as IL-4, IL-5 or IL-13 in mice, enhances an IgE antibody mediated response, while deletion of these cytokines attenuates and/or prevents allergic responses. Conversely, modulation of Th(1) cytokine gene expression may affect cell-mediated immune responses. Therefore, cytokine transgenic mice are used as investigative tools to study potential chemicals and/or drug allergies. In addition to cytokines and chemokines, other factors are important for the development of allergic responses, such as IgE, Fc receptors, vasopressin and several other factors, which can be tested in transgenic mice.     

The pharmacological activity of tribenoside

Ethyl-3,5,6-tri-O-benzyl-D-glucofuranoside (RBGF) the active substance of Glyvenol displays a unique spectrum of activities. It possesses anti-inflammatory, mild analgesic, antitoxic, wound-healing, fibrinolysis-promoting, anti-arthrotic, amine-release-inhibitory, membrane-stabilizing and venotropic properties. Unlike corticosteroids or nonsteroidal anti-inflammatory agents, TBGF dose not exert untoward effects on the gastrointestinal system, the connective tissue or the body's defence systems. In addition, TBGF does not affect the prostaglandin-synthetase system. TBGF thus seems to share the positive pharmacological properties ascribed to glucocorticoids and non-steroidal anti-inflammatory agents, yet is free from the undesirable effects of both.     

Clinical heterogeneity of drug hypersensitivity

Skin is the most frequent target of drug reactions that are reported, may be because they are easily detected. Most (probably more than 90%) are related to drug hypersensitivity, i.e. an individually tailored, unexpected effect mediated by a drug specific activation of the immune response. The clinical presentation of "drug eruptions" is highly variable, from the most common transient and benign erythema that occurs 6-9 days after the introduction of a new drug in 1 to 3 % of users to the most severe forms, that fortunately affect less than 1/10,000 users. Even though there are some overlapping or unclassifiable cases, it is important for clinicians to recognize and categorize severe cutaneous adverse reactions/SCAR (bullous fixed drug eruptions/bFDE, acute generalized exanthematous pustulosis/AGEP, drug reaction with eosinophilia and systemic symptoms/DRESS, Stevens-Johnson syndrome/SJS, toxic epidermal necrolysis/TEN). First they must suspect rapidly that an unusual eruption with high fever and severe constitutional symptoms is caused by a medication and not by an infection. Second they have to look for involvement of organs that differ according to the type of reaction. Third they can determine a prognosis, the mortality rate being virtually 0 for bFDE, 5% for AGEP, 10% for "hypersensitivity syndrome"/DRESS and 25% for SJS or TEN. In addition if some medications are "usual suspects" for all types (e.g. anticonvulsants), some other are more specific of a given pattern (pristinamycine, hydroxychloroquine, diltiazem for AGEP, minocycline for DRESS, anti-infectious sulfonamides, allopurinol for epidermal necrolysis). The "phenotypic" diversity of the final expression drug reactions can be explained by the engagement of a variety of cytokines and inflammatory cells and by regulatory mechanisms. For example, memory cytotoxic T-Cells are key effectors in both localized blisters of bFDE and in extensive blisters of epidermal necrolysis.     

HLA and pharmacogenetics of drug hypersensitivity

Immunologically mediated drug reactions have been traditionally classified as unpredictable based on the fact that they cannot be predicted strictly on the pharmacological action of the drug. Such adverse drug reactions are associated with considerable morbidity and include severe cutaneous adverse reactions such as Stevens-Johnson syndrome/toxic epidermal necrolysis and the drug hypersensitivity syndromes (drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome). Over the last decade there have been many associations between these syndromes and Class I and II HLA alleles of the MHC, which have enriched and driven our knowledge of their immunopathogenesis. Significant translation has also occurred in the case of HLA-B*5701 screening being used to exclude at risk patients from abacavir and prevent abacavir hypersensitivity. The ultimate translation of the knowledge of how drugs interact with HLA would be applicable to preclinical drug screening programs to improve the safety and cost-effectiveness of drug design and development.     

Definitions and mechanisms of drug hypersensitivity

Adverse drug reactions are a difficult problem faced by clinicians in everyday practice. The mechanisms of drug hypersensitivity are not well understood. This is reflected by difficulties in their classification, which is mainly based upon the current knowledge of immunologic and nonimmunologic mechanisms, onset of symptoms (immediate or nonimmediate) and morphology. For the individual patient, the correct diagnosis and classification is important because strict avoidance of the offending drug might be of vital importance. Considerable experience is required to guide management, to interpret results of investigations and to undertake drug challenges. This article summarizes the current knowledge regarding definitions and mechanisms. However, the field of drug hypersensitivity is rapidly expanding. Modern drugs such as biological agents bare hypersensitivity risks that are potentially mediated by, so far, unknown mechanisms.     

Definitions and mechanisms of drug hypersensitivity

Adverse drug reactions are a difficult problem faced by clinicians in everyday practice. The mechanisms of drug hypersensitivity are not well understood. This is reflected by difficulties in their classification, which is mainly based upon the current knowledge of immunologic and nonimmunologic mechanisms, onset of symptoms (immediate or nonimmediate) and morphology. For the individual patient, the correct diagnosis and classification is important because strict avoidance of the offending drug might be of vital importance. Considerable experience is required to guide management, to interpret results of investigations and to undertake drug challenges. This article summarizes the current knowledge regarding definitions and mechanisms. However, the field of drug hypersensitivity is rapidly expanding. Modern drugs such as biological agents bare hypersensitivity risks that are potentially mediated by, so far, unknown mechanisms.     

Provocation tests in diagnosing drug hypersensitivity

A position paper by the European Network for Drug Allergy (ENDA), the European Academy of Allergology and Clinical Immunology (EAACI) interest group on drug hypersensitivity, defines drug provocation tests (DPTs) as "the controlled administration of a drug in order to diagnose drug hypersensitivity reactions". The DPT is widely considered to be the "gold standard" to establish or exclude the diagnosis of hypersensitivity to a certain substance, as it not only reproduces hypersensitivity symptoms, but also any other adverse clinical manifestation, irrespective of the mechanism. The DPT can be harmful and thus should only be considered after balancing the risk-benefit ratio in the individual patient. The ENDA position paper specifies two main indications for DPTs with the suspected compounds: 1. to exclude hypersensitivity in non-suggestive histories of drug hypersensitivity and in patients with non-specific symptoms, such as vagal symptoms under local anesthesia; 2. to establish a firm diagnosis in suggestive histories of drug hypersensitivity with negative, non-conclusive, or non-available allergologic tests. A positive DPT result optimizes allergen avoidance, while a negative one allows a false label of drug hypersensitivity to be removed. For these reasons, DPTs are often carried out to exclude a diagnosis of hypersensitivity to beta-lactams when other allergologic tests are negative. DPTs are also performed when the sensitivity of allergologic tests for evaluating allergic reactions to certain drugs, such as non-beta-lactam antibiotics, heparins, and glucocorticoids, is limited. On the other hand, DPTs are also performed to diagnose hypersensitivity reactions to nonsteroidal anti-inflammatory drugs in subjects with the cross-reactive pattern, because both skin tests and in vitro diagnostic methods are ineffective in such patients.     

Pathophysiological response to hypoxia - from the molecular mechanisms of malady to drug discovery: drug discovery for targeting the tumor microenvironment

The tumor microenvironment, characterized by regions of hypoxia, low nutrition, and acidosis due to incomplete blood vessel networks, has been recognized as a major factor that influences not only the response to conventional anti-cancer therapies but also malignant progression and metastasis. However, exploiting such a cumbersome tumor microenvironment for cancer treatment could provide tumor-specific therapeutic approaches. In particular, hypoxia is now considered a fundamentally important characteristic of the tumor microenvironment in which hypoxia inducible factor (HIF)-1-mediated gene regulation is considered essential for angiogenesis and tumor development. Additional oxygen sensitive signaling pathways including mammalian target of rapamycin (mTOR) signaling and signaling through activation of the unfolded protein response (UPR) also contribute to the adaptation in the tumor microenvironment. This in turn has led to the current extensive interest in the signal molecules related to adaptive responses in the tumor microenvironment as potential molecular targets for cancer therapy against refractory cancer and recurrence in preparation for the aging society. Therefore, we should focus on the drug discovery for targeting the tumor microenvironment to develop tumor-specific cytostatic agents including angiogenesis inhibitors. In this paper, the development of hypoxia-selective prodrugs, HIF-1 inhibitors, and modulators of the tumor microenvironment will be discussed.     

药物过敏动物模型研究进展

药物过敏是药物临床应用和临床前研究面临的一个严重问题,预测性差,发生机制尚未明确,主要分为系统综合征和药物性皮肤反应2类。目前认为,其发生机制可能是药物通过直接或间接途径引发机体免疫病理反应。制备理想的动物模型是研究其作用机制的关键环节,最常用的模型动物有豚鼠、大鼠、小鼠和兔,在一些特殊药物实验中也使用猫、犬和猪。不同药物过敏动物模型的制备方法不同,评价方法和检测指标也不尽相同。结合相应的超敏反应病理学检测指标,探索建立适当的动物模型和合理评价体系,有助于提高对药物过敏的预测性。     

Teratogenic potential of tribenoside, a drug for the treatment of haemorrhoids and varicose veins--a population-based case--control study

Tribenoside is used for the treatment of haemorrhoids and varicose veins, frequently in pregnant women as well, but published data regarding its possible teratogenic effect are not available. Thus the risk of congenital abnormalities (CAs) was estimated in cases of pregnant women with oral tribenoside treatment (TT) in the Hungarian Case-Control Surveillance System of Congenital Abnormalities. Of 22,843 cases with CA, 174 (0.76%), while of 38,151 matched controls without CA, 285 (0.75%) were born to mothers with TT. There was no higher risk for total CAs after TT during any time of pregnancy but congenital hydrocephaly had a higher risk after medically recorded TT in the second and/or third month of pregnancy, i.e. critical period of this CA. In conclusion TT in pregnant women associated with a higher risk of congenital hydrocephalus in their children, however, this finding is based on only 4 cases therefore requires further confirmation in future studies.     

Drug-induced hypersensitivity: role in drug development

Drug-induced hypersensitivity is an adverse reaction, characterised by damaging immune-mediated responses, initiated by medicine given at therapeutic doses for prevention, diagnosis or treatment. Immune-mediated drug hypersensitivity accounts for 6-10% of the adverse drug reactions, which rank between the fourth and sixth leading causes of death in the US. With <10% of all adverse drug reactions reported, the magnitude of the problem is significant, with estimates of costs >$US30 billion annually in the US (1995 value). In addition, the costs of not determining the potential of a drug to produce hypersensitivity in the pre-clinical phase of drug development can be substantial. It has been estimated that the pre-clinical phase and clinical phase I, phase II and phase III costs are approximately $US6 million, $US12 million, $US12 million and $US100 million per drug, respectively (1999 values). It is important that investigational drugs with the potential to produce hypersensitivity reactions be identified as early in the development process as possible. Some adverse reactions to drugs can be avoided if drug-drug interactions are known or if there is a structure-activity relationship established. However, these methods are inadequate. Appropriate animal models of drug-induced hypersensitivity are needed, especially because hypersensitivity has been cited as the leading reason for taking drugs off the market.It is of critical importance to be able to predict hypersensitivity reactions to drugs. Most anaphylactic reactions occur in atopic individuals. Similarly, patients who have experienced other hypersensitivity reactions are more likely to have recurrent reactions. Therefore, animal models should be considered that predispose the animal to the reaction, such as the use of appropriate adjuvants and species. Using known positive controls of varying strengths, the investigator can rank the reaction against the positive controls as standards. This approach might yield greater results in a shorter period of time than using novel models. For the greatest safety, use of well understood models that have been thoroughly validated is imperative.     

Comparison of pharmacovigilance algorithms in drug hypersensitivity reactions

Background A firm diagnosis of drug hypersensitivity, because it may re-induce the reaction, is seldom confirmed. Causality assessment algorithms are therefore of interest.Aims The objective of this work was to compare three algorithms in the diagnosis of drug hypersensitivity.Methods Evaluation of 120 clinical histories of drug hypersensitivity was carried out: 60 involving -lactams (50%) and 60 involving non-steroidal anti-inflammatory drugs (50%). Each of these groups of patients underwent a standardised allergy diagnosis, which included a detailed anamnesis, skin tests and, often, provocation tests under strict hospital surveillance. Unaware of the final allergy diagnosis, scores were established for all of the cases and compared using algorithms suggested by Begaud and coworkers [2, 20], Jones [13] and Naranjo et al. [21].Results Although the methods of Jones [13] and Naranjo et al. [21] were perfectly concordant (k=1), no concordance was noted using the Begaud and coworkers [2, 20] method.Conclusions All three algorithms are dissimilar regarding the diagnosis of drug hypersensitivity.     

Delayed drug hypersensitivity: models of T-cell stimulation

Drug-induced hypersensitivity reactions can cause a variety of serious diseases by involving drug-specific T-cells. Many of these reactions have been explained by the hapten concept, which postulates that small chemical compounds need to bind covalently to proteins to be recognized by the immune system. Due to their chemical reactivity, haptens stimulate the innate immunity by binding covalently to endogenous proteins and form so called hapten-carrier complexes, which are antigenic and induce T-cell responses. In recent years, a new concept has been developed since drug-induced hypersensitivity reactions were also observed with chemically unreactive drugs. This concept implies direct and reversible interactions of the drug between T-cell receptors (TCR) and major histocompatability complex (MHC) molecules. Therefore it was termed pharmacological interactions with immune receptors (p-i concept). Early observations on drug reacting T-cell clones (TCC) let believe that drugs bind first to the T-cell receptor since HLA molecules could be exchanged without affecting the drug reactivity. However, MHC molecules were always required for full activation of TCC. According to its strong HLA-B*5701 association, recent data on abacavir suggest that a drug could first bind to the peptide binding groove of the MHC molecule. The thereby modified HLA molecule can then be recognized by specific T-cells. Consequently, two types of reactions based on the p-i mechanism may occur: on the one hand, drugs might preferentially bind directly to the TCR, whereas in defined cases with strong HLA association, drugs might bind directly to the MHC molecule.     

Cellular tests in the diagnosis of drug hypersensitivity

The application of flowcytometry in the study of basophil activation for the diagnosis of allergic diseases has given interesting results in recent years. The quantification of basophil activation by flowcytometry has been proven to be a useful tool for the assessment of the immediate-type response to allergens mediated by IgE or by other mechanisms in drug allergic patients. Up to now, most basophil activation test studies reported in the literature have used CD69 or CD203c as markers to quantify basophil activation after antigen-specific stimulation. Some technical variations such as the use of whole blood or isolated leukocytes, the addition of IL-3, the conditions of storage of the blood sample, the time of incubation with allergens and their concentration can affect the results of the basophil activation tests. The basophil activation test is more sensitive and specific than other in vitro diagnostic techniques in drug allergy. In various studies, its sensitivity in allergy to muscle relaxant drugs ranges between 36 and 97.7%, with a specificity around 95%. For betalactam antibiotics, basophil activation test sensitivity is 50% and its specificity 90%. For NSAIDs, sensitivity varies between 66% and 75%; specificity is about 93%. Basophil activation test reproduces in vitro hypersensitivity mechanisms involved in immediate-type allergic reactions, allows the diagnosis of allergic and pseudo-allergic reactions particularly for drugs, which are often not detectable by serological techniques, such as determination of specific IgE.