Treatment of onychomycosis with oral antifungal agents

Onychomycosis is the most common nail disease and describes the invasion of the nail by fungi. Different clinical patterns of infection depend on the way and the extent by which fungi colonise the nail: distal subungual onychomycosis, proximal subungual onychomycosis, white superficial onychomycosis, endonyx onychomycosis and total dystropic onychomycosis. The type of nail invasion depends on both the fungus responsible and on host susceptibility. Treatment of onychomycosis depends on the clinical type of the onychomycosis, the number of affected nails and the severity of nail involvement. The goals for antifungal therapy are mycological cure and a normal looking nail. In this paper the treatment of onychomycosis with oral antifungal agents will be reviewed.     

伊曲康唑治疗甲癣

目的 :观察伊曲康唑治疗甲癣的疗效。方法 :选择临床症状典型 ,经真菌学检查确诊的甲癣病人 4 7例 (男性 30例 ,女性 17例 ,年龄 4 6a±s 15a) ,服用伊曲康唑 2 0 0mg ,每日 2次 ,连用 7d ,停药2 1d为一个疗程 ,2～ 3个疗程。结果 :近期疗效总痊愈率 13% ,总有效率 2 6 % ,真菌学总治愈率5 7%。远期疗效总痊愈率 92 % ,总有效率 96 % ,真菌学总治愈率 96 %。结论 :伊曲康唑短程间歇冲击疗法治疗甲癣疗效佳 ,不良反应少     

抗真菌药物的应用与发展

真菌感染既可累及浅部组织,也可侵犯深部各器官,易复发。临床上抗真菌药物治疗真菌感染易出现不良反应。本文简要综述抗真菌药物的临床应用及未来发展方向。     

New antifungal therapies for the treatment of onychomycosis

Onychomycosis is a common disorder of nails caused by diverse spectrum of fungi ranging from dermatophytes to nondermatophyte molds and yeasts. Presently, oral and topical therapies are the mainstay of treatment with oral therapies yielding somewhat better results. Though various treatment options are available to treat onychomycosis, search for a convenient, cost effective agent with high and long-lasting cure rates is continuing. Currently, many new therapies for onychomycosis are under investigation which includes new formulations of azoles, improvement of existing topical treatments through addition of ungual enhancers and new drugs with better nail permeation.     

Novel investigational therapies for onychomycosis: an update

Introduction: Onychomycosis is an infection of the nail plate that is prevalent among the ageing population. Onychomycosis is difficult to treat with low initial cure rates, high rates of relapse, and reinfection. Present treatment options include oral and topical therapies, with oral therapies yielding better results. However, there has been a greater emphasis on the development of topical antifungal therapies as they have fewer side effects and drug interactions.

Areas Covered: This review summarizes new and reformulated drugs. Results from in vitro studies to Phase III clinical trials are discussed. Novel drugs include: the oral azole VT-1161, the topical azole efinaconazole, the benzoxaborole tavaborole, reformulations of terbinafine P-3058 and LI-P, novel inhibitor of succinate dehydrogenase ME1111, and off-label use of tazarotene. Enhanced permeation of the morpholine amorolfine through the nail plate is also discussed using ultraviolet (UV) curable gels, and a fractional CO₂ laser.

Expert opinion: Novel topical antifungals and the reformulation of current antifungals have demonstrated marked improvement in nail penetration. Current research has an emphasis on topical therapies due to their minimized risk for adverse effects and higher patient demand. Nevertheless, few topical agents have surfaced in the past few years and the investigation of efficacious combination therapies may become more important.     

Emerging therapeutic agents for onychomycosis

Onychomycosis is a frequent disorder that represents the most prevalent fungal infection, particularly among older individuals. Diverse fungi of the dermatophyte, non-dermatophyte mold and yeast families have been reported to be responsible for onychomycosis. The output from the pharmaceutical industry of new antifungals to treat onychomycosis has been limited over the last decade. Present treatment options include both oral and topical drugs, with oral therapies giving better outcomes. However, neither of these treatment options provides high cure rates that are durable. At present, azoles and allylamines are keeping the pivotal roles. New derivatives with a favorable risk-benefit ratio and new formulations of older azoles seem to be promising. Thus, ongoing drug development activities have focused on novel delivery technologies to facilitate incorporation of existing antifungal drugs inside the nail plate and the discovery of new active antifungals.     

Synthesis of isotopically labelled [3-14C]- and [3,3-2H2]-5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2690), a new antifungal agent for the potential treatment of onychomycosis

5-Fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2690) is a new antifungal agent for the potential treatment of onychomycosis. During the preclinical development phase, it was necessary to synthesize the radioisotope [3-¹⁴C]-5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole and the deuterium isotope [3,3-²H₂]-5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole for in vitro studies. We report the synthesis of these two isotopically labelled derivatives. Copyright © 2007 John Wiley & Sons, Ltd.     

Risk of oral antifungal agent-induced liver injury in Taiwanese

Aim

Oral antifungal agent-induced liver injury is a common safety concern that may lead to patients'' hesitation in treating fungal infections such as onychomycosis. This study evaluated risk of drug-induced liver injury (DILI) caused by oral antifungal agents in Taiwanese populations.

Methods

A population-based study was conducted by analyzing who used oral antifungal agents from 2002 to 2008 from the Taiwan National Health Insurance Database. A comparison control group was randomly extracted from the remainder of the original cohort.

Results

Of the 90 847 oral antifungal agents users, 52 patients had DILI. Twenty-eight DILI cases used ketoconazole, 12 fluconazole, eight griseofulvin, three itraconazole and two terbinafine. The incidence rates (IR) of DILI per 10 000 persons were 31.6, 4.9, 4.3, 3.6 and 1.6 for fluconazole, ketoconazole, griseofulvin, itraconazole and terbinafine, respectively. Longer exposure duration increased the risk of DILI, with IR for exposure duration ≥ 60 defined daily dose (DDD) of 170.9, 62.5, and 36.1 per 10 000 persons for ketoconazole, itraconazole and terbinafine, respectively. Patients taking antifungal agents had higher incidences of developing DILI compared with those in the control group after adjusting for age, gender and co-morbidities (relative risk 2.38, P < 0.001). All of the six patients with fatal DILI used fluconazole. Old age and fluconazole increased the risk of oral antifungal-induced fatal DILI.

Conclusions

Oral antifungal agents are associated with low incidence of acute liver injury, but which may be fatal, especially for the elderly. Longer treatment duration may increase the risk of antifungal agent-induced liver injury, especially ketoconazole.     

New pharmacotherapy for the treatment of onychomycosis: an update

Introduction: Onychomycosis is an infection of the nail plate that is an important priority area for the development of antifungal drugs. The high incidence of relapse and reinfection often makes onychomycosis a chronic condition. The current gold standard is oral therapy, but the development of effective topical agents remains a priority as they have fewer systemic interactions.

Areas covered: This review summarizes development of antifungals from early phase development through Phase III clinical trials for onychomycosis. The oral molecules in development are azole molecules. Topical drugs in development include azoles, allylamines, benzoxaboroles and nanoemulsions. Photosensitizers for photodynamic therapy and new laser systems are also emerging therapeutic options. There is a diverse array of antifungal drugs in the early phases of development.

Expert opinion: The goals of onychomycosis therapy are a mycological cure and a normal appearing nail. The recent development of topical antifungals has been successful at improving the nail permeation and efficacy. The diversification of molecular targets is the next primary goal of antifungal development. Incomplete treatment of onychomycosis provides an environment conducive to the development of antifungal resistance. New topical agents and device-based therapies expand the therapeutic options. Combination therapy using multiple drug classes may improve the overall efficacy of antifungal treatment in onychomycosis.     

新型口服抗凝药和唑类抗真菌药相互作用及其机制研究进展

新型口服抗凝药(new oral anticoagulants,NOACs)已广泛用于防治静脉血栓栓塞以及预防非瓣膜性房颤患者的系统性栓塞.NOACs是细胞色素P4503A4(CYP3A4)和/或P糖蛋白的底物,NOACs的暴露量易受CYP3A4和/或P糖蛋白抑制剂的影响.唑类抗真菌药是CYP3A4和/或P糖蛋白抑制剂...     

A risk-benefit assessment of the newer oral antifungal agents used to treat onychomycosis.

The newer antifungal agents itraconazole, terbinafine and fluconazole have become available to treat onychomycosis over the last 10 years. During this time period these agents have superseded griseofulvin as the agent of choice for onychomycosis. Unlike griseofulvin, the new agents have a broad spectrum of action that includes dermatophytes, Candida species and nondermatophyte moulds. Each of the 3 oral antifungal agents, terbinafine, itraconazole and fluconazole, is effective against dermatophytes with relatively fewer data being available for the treatment of Candida species and nondermatophyte moulds. Itraconazole is effective against Candida onychomycosis. Terbinafine may be more effective against C. parapsilosis compared with C. albicans; furthermore with Candida species a higher dose of terbinafine or a longer duration of therapy may be required compared with the regimen for dermatophytes. The least amount of experience in treating onychomycosis is with fluconazole. Griseofulvin is not effective against Candida species or the nondermatophyte moulds. The main use of griseo-fulvin currently is to treat tinea capitis. Ketoconazole may be used by some to treat tinea versicolor with the dosage regimens being short and requiring the use of only a few doses. The preferred regimens for the 3 oral antimycotic agents are as follows: itraconazole - pulse therapy with the drug being administered for 1 week with 3 weeks off treatment between successive pulses; terbinafine - continuous once daily therapy; and fluconazole - once weekly treatment. The regimen for the treatment of dermatophyte onychomycosis is: itraconazole - 200mg twice daily for I week per month x 3 pulses; terbinafine - 250 mg/day for 12 weeks; or, fluconazole - 150 mg/wk until the abnormal-appearing nail plate has grown out, typically over a period of 9 to 18 months. For the 3 oral antifungal agents the more common adverse reactions pertain to the following systems, gastrointestinal (for example, nausea, gastrointestinal distress, diarrhoea, abdominal pain), cutaneous eruption, and CNS (for example, headache and malaise). Each of the new antifungal agents is more cost-effective than griseofulvin for the treatment of onychomycosis and is associated with high compliance, in part because of the shorter duration of therapy. The newer antifungal agents are generally well tolerated with drug interactions that are usually predictable.     

3种抗真菌药治疗甲真菌病的成本-效果比较

目的　探讨不同抗真菌药治疗甲真菌病的经济效果。方法　选择 12 0例甲真菌病患者 ,随机分成A、B、C3组 ,分别给予伊曲康唑、特比萘芬、氟康唑口服治疗 ,运用药物经济学的成本 效果分析方法进行评价。结果　A、B、C 3组方案中治疗指甲真菌病 /趾甲真菌病的成本 效果比分别为 10 2 3/ 15 0 7,9 2 1/ 12 .5 6 ,10 6 1/ 15 99;敏感度分析后分别为 9.17/ 13 32、8 2 7/11 14、9 5 8/ 14 2 4。结论　B组方案为治疗甲真菌病的最经济有效方案     

新型三唑类化合物的合成及抗真菌活性

目的寻找广谱、高效、低毒的新一代三唑类抗真菌药物。方法根据靶酶活性位点的空间特征、各种力场和关键残基分布，设计并合成了21个1-(1,2,4-三唑-1H -1-基)-2-(2,4-二氟苯基)-3-(4-取代-1-哌嗪基)-2-丙醇类化合物，并测定了体外抑菌活性。结果体外抑菌测试结果表明，所有化合物对8种致病真菌均有一定程度的抗真菌活性，对深部真菌的活性明显优于浅部真菌。在哌嗪的各种取代基中，苯基和杂环取代的抗真菌活性明显优于苯甲酰基取代。结论有多个化合物的体外抗真菌活性明显高于氟康唑和特比萘芬，其中化合物VIII-1,4,5和IX-3具有广谱、高活性的优点，值得进一步研究。     

抗真菌药物研究进展

综述近年来抗真菌药物的研究进展,包括抗真菌抗生素与合成抗真菌药.还概述了开发中的新药.     

Treatment of onychomycosis: an update

Fungal infections of skin are one of the most common infections in human beings. The areas which are likely to get infected include the scalp, the hands and the feet. Dermatophytes, yeasts and moulds are the three major fungi responsible for skin infections. Earlier oral antifungal agents were used for treatment of fungal infection in finger and toe nails. The disadvantages of oral antifungal agents are toxicity and longer treatment period. Now medicated nail lacquers have been developed for the treatment of fungal infections i.e. onychomycosis, which has less toxicity and shorter treatment period.     

Topical delivery of antifungal agents

Importance of the field: Superficial fungal infections of skin, hair, nails and the eye are among the most widespread diseases known to man. Topical therapy is the most favored form of treatment for these infections because it lends itself to self-administration, patient compliance, and absence of systemic adverse effects.

Areas covered in this review: The clinical efficacy of antifungal drugs depends on the concentration achieved in cutaneous/ocular tissue, which in turn depends on the molecular mass, route of administration, duration of contact and ability of the compound to penetrate the tissue. Several of these agents have a high molecular mass > 500 Da (such as amphotericin B, natamycin, or ketoconazole), resulting in their poor penetration (even if they are lipophilic in nature). The latter causes relapse infections and requires frequent administration. Packaging these agents into suitable delivery systems can improve the effectiveness of these agents. The usefulness of liposomes/niosomes, lipid emulsions, nanoparticles including solid lipid nanoparticles and microemulsions for development of these agents is discussed.

What the reader will gain: This article aims to discuss limitations to the topical therapy of antifungal agents, and delivery approaches used to enhance their effectiveness.

Take home message: A physicochemical and pharmacokinetic guided approach can help to tailor-make therapeutically effective systems for existing antifungal agents, thus doing away with the need for newer agents, which will save on time, money and manpower.     

抗真菌药的不良反应

目前临床上许多疾病导致机体免疫力下降,真菌感染的发生率大大增加,使抗真菌药在临床得到越来越广泛的应用.大多数抗真菌药的特异性不强,作用于真菌的同时也易对宿主细胞产生毒性作用,不良反应成为限制抗真菌药在临床应用的重要因素.现概括介绍目前临床常用抗真菌药的不良反应.     

Recent progress on the topical therapy of onychomycosis

Onychomycosis is a fungal infection of the fingernails and toenails that results in thickening, discoloration, splitting of the nails and lifting of the nail from the nail bed. The disease is caused by dermatophytes and has a high incidence within the general population, especially among older individuals. Present treatment options include both oral and topical drugs, with oral therapies giving better outcomes; however, neither of these treatment options provides high cure rates that are durable. The difficulty in treating onychomycosis results from the deep-seated nature of the infection within the nail unit (nail plate, nail bed and surrounding tissue) and the inability of drugs to effectively reach all sites. Ongoing drug development activities have focused on novel delivery technologies to facilitate penetration of existing antifungal drugs through the nail plate and on the discovery of inherently penetrable antifungals. AN-2690 represents an oxaborole antifungal that is designed to penetrate the nail plate and is showing promising results in clinical trials.     

国外治疗念珠菌阴道炎外用药物研究进展

通过Medline等文献检索,综述了国外治疗念珠菌阴道炎外用药物的发展概况、各类药物的主要特点、选用药物时考虑的主要因素以及美国1997年治疗念珠菌阴道炎的15种常用处方,包括3种口服药处方及12种外用药处方.     

Novel triazole antifungal agents

The risk of opportunistic infections is greatly increased in patients who are immunocompromised due to AIDS, cancer chemotherapy and organ or bone marrow transplantation. Candida albicans is often associated with serious systemic fungal infections, however other Candida species such as Candida krusei, Candida tropicalis and Candida glabrata, as well as Cryptococcus neoformans and filamentous fungi such as Aspergillus, have also emerged as clinically significant fungal pathogens. Two triazole antifungal agents, fluconazole and itraconazole, were introduced over a decade ago and since then have been used extensively for the prophylaxis and treatment of a variety of fungal infections. Although both drugs are effective and have their place in therapy, limitations regarding the utility of these agents do exist. For example, fluconazole is not effective for the prophylaxis or treatment of Aspergillus species and has limited activity against C. krusei and C. glabrata. The use of itraconazole has been limited secondary to concerns regarding unpredictable bioavailability. The rising incidence of fungal infections and the reported increase of non-albicans candidal infections noted over the past two decades highlight the need for new antifungal agents with improved spectra of activity. Several new triazole agents are in various phases of preclinical and clinical trials and may be available for human use in the near future. Three such agents voriconazole, posaconazole and ravuconazole are reviewed and compared with existing agents.