维甲酸类药物在皮肤科疾病治疗中的应用

维甲酸类药物（retinoic acids,RAs）是一组与维生素A结构相似的化合物,包括维生素A的各种天然及人工合成衍生物,是维持生长和发育必不可少的物质。1960年,德国皮肤病学家Stuttgen成功地将维甲酸类药物外用于各种角化不良及角化过度性皮肤病治疗。     

Recent development of new drugs for the treatment of allergic diseases

Due to the prevalence of allergic diseases such as bronchial asthma, allergic rhinoconjunctivitis and dermallergosis, efforts at the discovery of novel and effective medications for prevention and treatment of these conditions have been reinforced. Recently, it has been recognized that these allergic diseases are a chronic inflammatory disorder of the lower and upper airways and skin. In this article, we reviewed the recent development of the following new antiallergic therapies: anti-Th2 cytokine antibodies, decoy receptors, receptor antibodies, anti-IgE antibodies, anti-cell adhesion molecules antibodies, antisense oligonucleotides, keratinocyte modulators, inhibitors of phosphodiesterase 4, tachykinin receptor antagonists, and anti-histaminic drugs. Most of these new agents are aimed to inhibit various components of allergic inflammation. The future use of allergic disease therapies hold great promise and excitement.     

抗组胺药在皮肤科疾病治疗中的应用

1分类及药理作用 抗组胺药是一类能通过与组胺竞争性地结合组胺受体,从而拈抗组胺作用的药物。     

Drug discovery for a new generation of covalent drugs

INTRODUCTION: The design of target-specific covalent inhibitors is conceptually attractive because of increased biochemical efficiency through covalency and increased duration of action that outlasts the pharmacokinetics of the agent. Although many covalent inhibitors have been approved or are in advanced clinical trials to treat indications such as cancer and hepatitis C, there is a general tendency to avoid them as drug candidates because of concerns regarding immune-mediated toxicity that can arise from indiscriminate reactivity with off-target proteins. AREAS COVERED: The review examines potential reason(s) for the excellent safety record of marketed covalent agents and advanced clinical candidates for emerging therapeutic targets. A significant emphasis is placed on proteomic techniques and chemical/biochemical reactivity assays that aim to provide a systematic rank ordering of pharmacologic selectivity relative to off-target protein reactivity of covalent inhibitors. EXPERT OPINION: While tactics to examine selective covalent modification of the pharmacologic target are broadly applicable in drug discovery, it is unclear whether the output from such studies can prospectively predict idiosyncratic immune-mediated drug toxicity. Opinions regarding an acceptable threshold of protein reactivity/body burden for a toxic electrophile and a non-toxic electrophilic covalent drug have not been defined. Increasing confidence in proteomic and chemical/biochemical reactivity screens will require a retrospective side-by-side profiling of marketed covalent drugs and electrophiles known to cause deleterious toxic effects via non-selective covalent binding.     

Drug discovery for a new generation of covalent drugs

Introduction: The design of target-specific covalent inhibitors is conceptually attractive because of increased biochemical efficiency through covalency and increased duration of action that outlasts the pharmacokinetics of the agent. Although many covalent inhibitors have been approved or are in advanced clinical trials to treat indications such as cancer and hepatitis C, there is a general tendency to avoid them as drug candidates because of concerns regarding immune-mediated toxicity that can arise from indiscriminate reactivity with off-target proteins.

Areas covered: The review examines potential reason(s) for the excellent safety record of marketed covalent agents and advanced clinical candidates for emerging therapeutic targets. A significant emphasis is placed on proteomic techniques and chemical/biochemical reactivity assays that aim to provide a systematic rank ordering of pharmacologic selectivity relative to off-target protein reactivity of covalent inhibitors.

Expert opinion: While tactics to examine selective covalent modification of the pharmacologic target are broadly applicable in drug discovery, it is unclear whether the output from such studies can prospectively predict idiosyncratic immune-mediated drug toxicity. Opinions regarding an acceptable threshold of protein reactivity/body burden for a toxic electrophile and a non-toxic electrophilic covalent drug have not been defined. Increasing confidence in proteomic and chemical/biochemical reactivity screens will require a retrospective side-by-side profiling of marketed covalent drugs and electrophiles known to cause deleterious toxic effects via non-selective covalent binding.     

他克莫司软膏在皮肤科的应用进展

他克莫司（taerolimus）是从链霉菌产物中提取得到的一种具有免疫调节活性的钙调神经磷酸酶抑制剂,其分子量较环孢素（CsA）小,但免疫活性是CsA的10～100倍。他克莫司最早用于器官移植,后来发现它对多种免疫相关疾病有效,且局部外用较CsA具有更好的透皮性。     

The brain as a target for development of new class of drugs for the treatment of somatic diseases

Usually, drugs are designed to modulate at cellular level the activity of peripheral tissues and organs affected by pathological processes. Despite unprecedented investment, the number of newly developed drugs remains low. Therefore, potent new drugs that directly influence and restore activity of peripheral tissues and organs altered by somatic diseases are being released into clinical use at the same rate as seen in the past. The brain has long been known to regulate the function of all tissues and organs in the body. This regulatory influence has also been shown to play an important role during pathological conditions, when the brain triggers protective and adaptive reactions modulating the development and progression of somatic diseases affecting peripheral tissues and organs. Importantly, several drugs recently used for the treatment of somatic diseases (e.g., beta-blockers, sartans, statins) also act at the level of the CNS, where they modulate the protective and adaptive reactions of the brain. Pharmacological modulation of brain structures activities may represent the basis for a new approach towards the treatment of various somatic diseases (e.g., cardiovascular and gastrointestinal diseases). Therefore, brain-targeted therapy of somatic diseases may significantly extend the area for development of new drugs.     

New nitric oxide-donating drugs for the treatment of airway diseases

Nitric oxide (NO) is involved in many pathological and physiological processes in mammals, providing a possible biological basis for the use of NO replacement therapy in many conditions. A series of compounds have been synthesized in which an NO-releasing group has been linked to well-established parent molecules. This strategy has resulted in novel molecules with an improved profile of pharmacological activity, either in terms of enhanced therapeutic efficacy or reduced side effects. This review examines the biological significance, mechanism(s) of action and therapeutic potential of such compounds in respiratory disease.     

A comprehensive review of imatinib mesylate (Gleevec) for dermatological diseases

Imatinib mesylate (Gleevec, also known as STI-571), is an approved oral treatment for patients with chronic myeloid leukemia (CML). It blocks the activity of Abelson cytoplasmic tyrosine kinase (ABL), c-Kit and the platelet-derived growth factor receptor (PDGFR). As an inhibitor of PDGFR, imatinib mesylate appears to have utility in the treatment of a variety of dermatological diseases. Imatinib has been reported to be an effective treatment for FIP1L1-PDGFRalpha+ mast cell disease, hypereosinophilic syndrome, and dermatofibrosarcoma protuberans. One report notes its effectiveness for treating HIV related Kaposi's sarcoma; imatinib has not been effective for the treatment of melanoma.     

Synthetic investigational new drugs for the treatment of tuberculosis

Introduction: Tuberculosis (TB) is a major global health concern. And while there are treatments already on the market, there is a demand for new drugs that are effective and safe against Mycobacterium tuberculosis, which reduce the number of drugs and the duration of treatment in both drug-susceptible TB and multidrug-resistant TB (MDR-TB).

Area covered: This review covers promising novel investigational TB drugs that are currently under development. Specifically, the authors review the efficacy of novel agents for the treatment of TB in preclinical, phase I and phase II clinical trials. The authors also review the safety and tolerability profiles of these drugs.

Expert opinion: Bedaquiline and delamanid are the most promising novel drugs for the treatment of MDR-TB, each having high efficacy and tolerability. However, the best regimen for achieving better outcomes and reducing adverse drug reactions remains to be determined, with safety concerns regarding cardiac events due to QT prolongation still to be addressed. Pretomanid is a novel drug that potentially shortens the duration of treatment in both drug-susceptible and drug-resistant TB in combination with moxifloxacin and pyrazinamide. Linezolid shows marked efficacy in the treatment of MDR-TB and extensively drug-resistant TB (XDR-TB), but the drug is known to cause significant adverse drug reactions, including peripheral neuropathy, optic neuropathy and myelosuppression. These adverse reactions must be considered prior to prescribing long-term usage of this drug.     

Drug dosage in the elderly: dermatological drugs

Drug pharmacokinetics and pharmacodynamics may be altered in the elderly. An important contribution is made by decreased renal function, but biotransformation in the liver may also play a role. Commonly prescribed dermatological drugs such as methotrexate and cetirizine are likely to be eliminated more slowly in the elderly and potentially hepatotoxic drugs such as itraconazole and acitretin should be used with caution. Altered drug distribution as a result of body composition changes can lead to prolonged half-life or higher plasma concentrations of many drugs. Higher prevalence of adverse drug reactions and multidrug regimens, and large interindividual variability in drug response make drug dosage and administration in the elderly challenging. New immunobiological agents such as alefacept, efalizumab and etanercept, which are approved for treatment of psoriasis, seem to be as well tolerated in the elderly as in younger patients. A recommended approach when prescribing drugs to the elderly would be to start with a small initial dose and to reduce the number of drugs administered simultaneously. It is crucial to simplify the drug regimen as much as possible in order to enhance drug management in the elderly. To improve pharmacotherapy in the elderly, we review age-related changes in pharmacokinetics that are likely to play a role in dermatological practice.