Combination antifungal therapy: From bench to bedside

Invasive fungal infections are major causes of mortality in immunocompromised patients. Despite improved outcomes with new antifungals, there remains a pressing need to further improve outcomes, especially with invasive aspergillosis and other invasive mold infections. Combination antifungal therapy is an attractive option that offers the prospect for improved efficacy, decreased toxicity, reduced likelihood for the emergence of resistance, and shorter courses of therapy. The current available evidence regarding the role of combination antifungal therapy for invasive fungal infections is discussed in this article, including data from in vitro studies, animal models, and human clinical trials to try to clarify this important issue. Randomized, prospective clinical trials are urgently needed, especially for invasive aspergillosis.     

Ginkgo biloba extract for essential hypertension: A systemic review

BackgroundGinkgo biloba extract (GBE), a traditional natural herbal product, is often used in the treatment of essential hypertension (EH) as complementary therapy in China and European countries.AimTo critically assess the current clinical evidence of efficacy and safety of GBE for EH.Methods7 electronic databases (Cochrane Library, PubMed, EMBASE, VIP, CBM, Wanfang data, and CNKI) were searched to identify randomized controlled trials (RCTs) of GBE for EH. Methodological quality was assessed independently using the Cochrane Handbook for Systematic Reviews of Interventions.ResultsA total of 9 RCTs with 1012 hypertensive patients were identified and reviewed. Most RCTs were of high risk of bias with flawed study design and poor methodological quality. 6 trials demonstrated potential positive effect of GBE as complementary therapy on BP reduction when compared with antihypertensive drug therapy; however, it was not associated with a statistically significant effect on both SBP and DBP reduction in 3 other trials. Despite the positive findings, there were so many methodological limitations and significant clinical heterogeneity. Most of the trials did not report adverse effects, and the safety of GBE is still uncertain.ConclusionNo confirmative conclusions on the efficacy and safety of GBE for EH could be drawn. More rigorous trials are warranted to support their clinical use.     

Effect of statins in stroke prevention

PURPOSE OF REVIEW: This paper reviews recent studies into the outcomes of clinical trials in which statin therapy has been used in the prevention and treatment of strokes. RECENT DEVELOPMENTS: Epidemiologic studies found no or little association between blood cholesterol levels and stroke. Randomized trials have confirmed that LDL lowering decreased the risk of stroke, in diabetic or hypertensive patients with 'normal' LDL cholesterol at baseline, and in patients with coronary artery disease, with respectively 48, 27 and 25% reduction in stroke incidence. A meta-analysis of trials showed that the greater the LDL cholesterol reduction, the greater the intima-media thickness and stroke risk reductions. Even if statins also have 'pleiotropic' effects, their main action seems to be through LDL reduction. The Heart Protection Study only included strokes that occurred 4.6 years before--a time when the stroke event rate is low and the cardiac event rate is high, and so may not have had the power to find a true effect of LDL cholesterol lowering in preventing recurrent stroke. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial may give a definite answer because SPARCL investigators included 4732 patients with brain infarction or transient ischemic attacks and no history of myocardial infarction within 6 months of their stroke event, at a time when the expected stroke rate is very high and the myocardial infarction rate is very low. The results should be announced by mid-2006. SUMMARY: The positive effect of statins on stroke observed in trials of patients with coronary heart disease depended mainly on between-group LDL reduction, but other mechanisms could be involved. Though effective in prevention of major coronary events after a first stroke, statins have not yet been proven effective in prevention of recurrent stroke.     

Antifungal activity of immunosuppressants used alone or in combination with fluconazole

Fungal infections remain a challenge to clinicians due to the limited available antifungals. With the increasing use of antifungals in clinical practice, drug resistance has been emerging continuously, especially to fluconazole (FLC). Thus, a search for new antifungals and approaches to overcome antifungal resistance is needed. However, the development of new antifungals is usually costly and time consuming; discovering the antifungal activity of non-antifungal agents is one way to address these problems. Interestingly, some researchers have demonstrated that several classes of immunosuppressants (calcineurin inhibitors, glucocorticoids, etc) also displayed potent antifungal activity when used alone or in combination with antifungals, especially with FLC. Some of them could increase FLC's susceptibility against resistant Candida albicans significantly reversing fungal resistance to FLC. This article reviews the antifungal activities of immunosuppressants used alone or in combination with antifungals and their potential antifungal mechanisms that have been discovered so far. Although immunosuppressive agents have been identified as risk factors for fungal infection, we believe these findings are very important for overcoming drug resistance and developing new antifungals.     

Antifungal Resistance Mechanisms in Dermatophytes

Although fungi do not cause outbreaks or pandemics, the incidence of severe systemic fungal infections has increased significantly, mainly because of the explosive growth in the number of patients with compromised immune system. Thus, drug resistance in pathogenic fungi, including dermatophytes, is gaining importance. The molecular aspects involved in the resistance of dermatophytes to marketed antifungals and other cytotoxic drugs, such as modifications of target enzymes, over-expression of genes encoding ATP-binding cassette (ABC) transporters and stress-response-related proteins are reviewed. Emphasis is placed on the mechanisms used by dermatophytes to overcome the inhibitory action of terbinafine and survival in the host environment. The relevance of identifying new molecular targets, of expanding the understanding about the molecular mechanisms of resistance and of using this information to design new drugs or to modify those that have become ineffective is also discussed.     

Invasive Candidiasis in the Neutropenic Cancer Patient

Invasive candidiasis (IC) is an important complication among cancer patients with neutropenia, as it is associated with significant mortality. Despite the introduction of the new antifungals in clinical practice and their widespread use as treatment or prophylaxis, the incidence of IC and the predominance of non-albicans Candida species remain unchanged, and mortality rates remain as high as in previous periods. New techniques have been developed to decrease the time to Candida species identification from blood cultures. Nonculture diagnostic methods and molecular diagnostic tests for detection of Candida are promising but have not been validated in neutropenic patients. Recently, voriconazole was proved to be as effective as fluconazole for prophylaxis in neutropenic recipients of hematopoietic stem cell transplants and in patients with graft-versus-host disease. Despite the lack of randomized studies of the treatment of IC among neutropenic patients, it seems that the success rates of antifungal therapy do not differ from those in non-neutropenic patients.     

Hydroxyurea in the treatment of HIV-1 infection: toxicity and side effects

Hydroxyurea has been used in numerous clinical trials for the treatment of HIV-1 infection, almost always in combination with didanosine with or without other antiretrovirals. Due to its inhibition of DNA synthesis, the main side effect of hydroxyurea is myelosuppression. When administered at the dosage of 1000 mg/day in asymptomatic, moderately-immunosuppressed HIV-1 infected patients, its tolerability profile appears to be quite favourable, with rare, reversible episodes of peripheral blood cytopenia that seldom require therapy discontinuation. Higher dosages of hydroxyurea and its use in advanced, heavily-pretreated patients may increase the likelihood of more severe side effects or newer toxicities developing. So far hydroxyurea-containing long therapy courses, up to 3 years, have not elicited any significant toxicity and appear to be safe as in onco-hematologic patients.     

Gene therapy in The Netherlands: highlights from the Low Countries

Gene therapy is an active research area in The Netherlands and Dutch scientists involved in fundamental and clinical gene therapy research significantly contribute to the progresses made in this field. This ranges from the establishment of the 293, 911 and PER.C6 cell lines, which are used worldwide for the production of replication-defective adenoviral vectors, to the development of targeted viral vectors and T lymphocytes as well as of non-viral vectors. Several milestones have been achieved in Dutch clinical gene therapy trials, including the first treatment worldwide of patients with adenosine deaminase deficiency with genetically corrected hematopoietic stem cells in collaboration with French and British scientists. Until now, about 230 patients with various diseases have been treated with viral and non-viral gene therapy in this country. Ongoing and upcoming Dutch clinical trials focus on the translation of new developments in gene therapy research, including the restoration of genetic defects other than SCID, and the use of oncolytic adenoviruses and targeted T cells for the treatment of cancer. The growing commercial interest in Dutch clinical gene therapy is reflected by the involvement of two Dutch companies in ongoing trials as well as the participation of Dutch clinical centres in large phase III international multicenter immuno-gene therapy trials on prostate cancer sponsored by an American company. Translational gene therapy research in The Netherlands is boosted at a governmental level by the Dutch Ministry of Health via a dedicated funding programme. This paper presents an overview on milestones in Dutch basic gene therapy research as well as on past, present and future clinical gene therapy trials in The Netherlands.     

Mycological view of dermatophytes in humans.

Dermatophytes are a group of closely related fungi that have the capacity to invade keratinized tissue (skin, hair, and nails) of humans and animals to produce an infection, dermatophytosis, commonly referred to as ringworm. Dermatophytoses are common of world wide: in the United States, Microsporum audouinii and Microsporum canis, once the major agents of tinea capitis, have been superseded by Trichophyton tonsurans. Since the 1950s, T. tonsuranshas advanced from Mexico and the Caribbean and is now the prevalent cause of tinea capitisin North America. M. canisis the prevalent agent of tinea capitis in many regions of the world, including Spain, at this moment. This could be related to close association of humans with their pets. M. canis is more prevalent in urban areas and Trichophyton mentagrophytes in rural ones. The superficial dermatophyte infections of the skin do not represent a single disease, their clinical appearance is dependent largely on the region of the body affected. There are more antifungal preparations available today than at any other time in medical history. Oral antifungals are indicated or required to treat hyperkeratotic areas such as nails, palms, soles and tinea capitis, patients with disabling or extensive disease, patients intolerant to or who have failed topical therapy, tose with chronic infection, those with granulomatous lesions and patients immunosuppressed by disease or by therapy. A successfull eradication of the fungi is now possible with relatively short treatment regimens.     

Antibiotic treatment of atherosclerosis

PURPOSE OF REVIEW: Several lines of evidence have demonstrated an association between a variety of chronic bacterial infections and atherosclerotic cardiovascular disease. This has led to the proposal that antibiotic therapy might be helpful in the secondary prevention of atherosclerosis. A variety of smaller pilot studies have been reported testing this hypothesis and several large multicenter trials are also underway. The purpose of this review is to summarize the results of these studies and comment on their implications for the treatment of atherosclerosis. RECENT FINDINGS: Most of the antibiotic studies to date have been secondary prevention studies that have targeted patients exposed to Chlamydia pneumoniae. Most have used either azithromycin or roxithromycin with treatment courses ranging from a few days to 3 months. Several small studies of coronary artery disease patients have shown significant promise for reducing cardiovascular events such as death, myocardial infarction, or admission for unstable angina. However, other studies have not been so positive. Weekly Intervention with Zithromax for Atherosclerosis and its Related Disorders, WIZARD, the largest study to date, in which stable post-myocardial infarction patients were randomized to receive a 3-month course of azithromycin or placebo, demonstrated a significant reduction in death and myocardial infarction by 6 months, but this benefit was not sustained throughout the remaining course of follow-up. The Azithromycin and Coronary Events (ACES) and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trials are ongoing and are testing the effect of more prolonged treatment duration. SUMMARY: A variety of antibiotic trials for the secondary prevention of atherosclerosis have been performed. Several pilot studies have shown significant positive clinical effects, but, thus far, no large randomized trial has confirmed those findings. Some concerns over the antibiotics chosen and the duration of treatment have been raised. Other trials are underway to address some of those concerns. In the meantime, no recommendation for the use of antibiotic therapy for the secondary prevention of atherosclerosis can yet be made.     

Natural products targeting the synthesis of β(1,3)-D-glucan and chitin of the fungal cell wall. Existing drugs and recent findings

Background: During the last three decades systemic fungal infections associated to immunosuppressive therapies have become a serious healthcare problem. Clinical development of new antifungals is an urgent requirement. Since fungal but not mammalian cells are encased in a carbohydrate-containing cell wall, which is required for the growth and viability of fungi, the inhibition of cell wall synthesizing machinery, such as β(1,3)-D-glucan synthases (GS) and chitin synthases (CS) that catalyze the synthesis of β(1-3)-D-glucan and chitin, respectively, represent an ideal mode of action of antifungal agents. Although the echinocandins anidulafungin, caspofungin and micafungin are clinically well-established GS inhibitors for the treatment of invasive fungal infections, much effort must still be made to identify inhibitors of other enzymes and processes involved in the synthesis of the fungal cell wall.Purpose: Since natural products (NPs) have been the source of several antifungals in clinical use and also have provided important scaffolds for the development of semisynthetic analogues, this review was devoted to investigate the advances made to date in the discovery of NPs from plants that showed capacity of inhibiting cell wall synthesis targets. The chemical characterization, specific target, discovery process, along with the stage of development are provided here.Methods: An extensive systematic search for NPs against the cell wall was performed considering all the articles published until the end of 2020 through the following scientific databases: NCBI PubMed, Scopus and Google Scholar and using the combination of the terms “natural antifungals” and “plant extracts” with “fungal cell wall”.Results: The first part of this review introduces the state of the art of the structure and biosynthesis of the fungal cell wall and considers exclusively those naturally produced GS antifungals that have given rise to both existing semisynthetic approved drugs and those derivatives currently in clinical trials. According to their chemical structure, natural GS inhibitors can be classified as 1) cyclic lipopeptides, 2) glycolipids and 3) acidic terpenoids. We also included nikkomycins and polyoxins, NPs that inhibit the CS, which have traditionally been considered good candidates for antifungal drug development but have finally been discarded after enduring unsuccessful clinical trials. Finally, the review focuses in the most recent findings about the growing field of plant-derived molecules and extracts that exhibit activity against the fungal cell wall. Thus, this search yielded sixteen articles, nine of which deal with pure compounds and seven with plant extracts or fractions with proven activity against the fungal cell wall. Regarding the mechanism of action, seven (44%) produced GS inhibition while five (31%) inhibited CS. Some of them (56%) interfered with other components of the cell wall. Most of the analyzed articles refer to tests carried out in vitro and therefore are in early stages of development.Conclusion: This report delivers an overview about both existing natural antifungals targeting GS and CS activities and their mechanisms of action. It also presents recent discoveries on natural products that may be used as starting points for the development of potential selective and non-toxic antifungal drugs.     

Do anti-TNF agents have equal efficacy in patients with rheumatoid arthritis?

Tumor necrosis factor (TNF) antagonists have dramatically improved the outcomes of rheumatoid arthritis (RA). Three agents currently available in the USA--infliximab, etanercept, and adalimumab--have been designed to modify the biologic effects of TNF. Infliximab and adalimumab are monoclonal antibodies, and etanercept is a soluble protein. The pharmacokinetic and pharmacodynamic properties of each differs significantly from those of the others. All three agents are effective and safe, and can improve the quality of life in patients with RA. Although no direct comparisons are available, clinical trials provide evidence that can be used to evaluate the comparative efficacy of these agents. Infliximab, in combination with methotrexate, has been shown to relieve the signs and symptoms of RA, decrease total joint score progression, prevent joint erosions and joint-space narrowing, and improve physical function for up to 2 years. Etanercept has been shown to relieve the signs and symptoms of RA, decrease total joint score progression, and slow the rate of joint destruction, and might improve physical function. Etanercept is approved with and without methotrexate for patients who have demonstrated an incomplete response to therapy with methotrexate and other disease-modifying anti-rheumatic drugs (DMARDs), as well as for first-line therapy in early RA, psoriatic arthritis, and juvenile RA. Adalimumab relieves the signs and symptoms of RA with and without methotrexate and other DMARDs, decreases total joint score progression, prevents joint erosions and joint-space narrowing in combination with methotrexate, and might improve physical function. When selecting a TNF antagonist, rheumatologists should weigh evidence and experience with specific agents before a decision is made for use in therapy.     

黑升麻对围绝经期综合征治疗作用的研究进展

黑升麻是一种植物药,目前已广泛应用于缓解围绝经期综合征的相关症状。近些年来,大量临床研究证明,黑升麻能有效缓解低雌激素相关的血管舒缩症状(潮热出汗)、精神心理症状(失眠、抑郁、易激惹)、泌尿生殖症状(阴道萎缩、干涩)等,并能预防绝经后妇女的骨质疏松。与激素疗法相比,黑升麻的不良反应少且轻,暂未发现妇科恶性肿瘤增加的风险。其安全性远远高于激素,且对身体还有其它的潜在益处。黑升麻的作用机制目前还未明确,目前发现黑升麻的作用机制类似于雌激素受体调节剂,且黑升麻还与神经递质5-羟色胺、γ-氨基丁酸及阿片受体有关。本文主要综述黑升麻在缓解围绝经期综合征中的作用机制、有效性及安全性,并与其它治疗围绝经期综合征的药物的疗效进行比较。     

集落刺激因子治疗重型再生障碍性贫血疗效和安全性的Meta 分析

目的:通过Meta分析评价粒系或粒单系集落刺激因子(G-CSF或GM-CSF)对接受免疫抑制治疗(IST)的重型再生障碍性贫血(SAA)患者的疗效和安全性。方法:使用相关检索词检索MEDLINE、Cochrane Library、EMBASE、CNKI及CBM数据库,检索时间1990年1月～2011年12月。纳入G-CSF或GM-CSF治疗SAA的随机对照研究。用Review Manager4.2统计软件对数据进行Meta分析。结果:共纳入4篇文献,共466例SAA患者。Meta分析结果显示:①IST疗效:G-CSF/GM-CSF组与对照组的SAA患者对比,近远期疗效与生存率均无显著差异:总体生存率[OR=1.15,95%C(I0.73,1.82),P=0.54]、完全缓解率[OR=1.20,95%CI(0.71,2.02),P=0.50]、早期总体有效率[OR=1.61,95%CI(0.85,3.03),P=0.14]、远期总体有效率[OR=1.17,95%CI(0.78,1.74),P=0.45];②IST相关感染:IST治疗早期感染发生率、严重感染发生率、感染相关死亡率方面均未优于对照组;③G-CSF/GM-CSF组的复发率低于对照组,差异显著[OR=0.57,95%C(I0.35,0.93),P=0.02];④G-CSF/GM-CSF组远期随访发生克隆性病变的发生率与对照组无统计学差异,恶性肿瘤(MDS/AML)发生率[OR=0.90,95%CI(0.41,1.99),P=0.79]、PNH发生率[OR=1.48,95%CI(0.65,3.33),P=0.35]。结论:G-CSF/GM-CSF应用于接受IST治疗的SAA患者,尚不能证明具有提高总体生存率、完全缓解率、总体有效率、减少感染和感染相关死亡率等优势。虽然有可能降低复发率,也不增加远期克隆性病变发生率,但还需要更严格设计的大样本双盲随机对照试验,并进行更为长期的随访研究。     

Therapeutic efficacy of anidulafungin for the treatment of oesophageal candidiasis, candidemia and invasive candidiasis

Anidulafungin is a new echinocandin that appears to have several advantages over existing antifungals. It is unique because it slowly degrades in humans, undergoing a process of biotransformation rather than being metabolized. It exhibits high in vitro and in vivo activities against Candida spp. and Aspergillus spp. In several clinical studies investigating Candida esophagitis; candidemia and invasive candidiasis, the clinical efficacy of this echinocandin was similar, or even superior, to that of established antifungals in candidemia. Antifungal activity against strains no longer susceptible to conventional antifungal agents, such as fluconazole and amphotericin B suggests that anidulafungin can be used as salvage therapy in life-threatening fungal infections. The limited toxicity profile, minimal drug-drug interactions and the fact that does not require dosage adjustment in subjects with hepatic or renal impairment, establishes this echinocandin as an attractive new option for the treatment of invasive fungal infections.     

New Antifungal Agents and New Formulations Against Dermatophytes

A variety of oral and topical antifungal agents are available for the treatment of superficial fungal infections caused by dermatophytes. This review builds on the antifungal therapy update published in this journal for the first special issue on Dermatophytosis (Gupta and Cooper 2008;166:353–67). Since 2008, there have not been additions to the oral antifungal armamentarium, with terbinafine, itraconazole, and fluconazole still in widespread use, albeit for generally more severe or recalcitrant infections. Griseofulvin is used in the treatment of tinea capitis. Oral ketoconazole has fallen out of favor in many jurisdictions due to risks of hepatotoxicity. Topical antifungals, applied once or twice daily, are the primary treatment for tinea pedis, tinea corporis/tinea cruris, and mild cases of tinea unguium. Newer topical antifungal agents introduced include the azoles, efinaconazole, luliconazole, and sertaconazole, and the oxaborole, tavaborole. Research is focused on developing formulations of existing topical antifungals that utilize novel delivery systems in order to enhance treatment efficacy and compliance.     

Oxidative stress: the special case of diabetes

The implication of oxidative stress (OS) in diabetes is a major concern for the development of therapeutics aimed at improving the metabolic and/or vascular dysfunctions of this burdening disease. Ample evidence is available suggesting that OS is present in essentially all tissues and can even be observed in prediabetic states. This raises the question of the origin of OS and suggests that, although hyperglycemia is largely linked with free radical production, its role may mainly be the aggravation of a preexisting state. Indeed other factors are also causally linked to OS, such as hormones and lipids. The main debate is about the pertinence of antioxidant therapy since the large scale clinical trials performed recently have essentially failed to show any significant improvement in metabolic or vascular disturbances of diabetic patients. However this conclusion must be tempered by the fact that they have mainly been using vitamin E +/-C; indeed many arguments suggest that either the choice or the application modalities of these substances may have been inadequate. Potential reasons for the actual failure of antioxidant therapy in diabetes are discussed; the indisputable involvement of OS in this disease still leaves hope for alternative therapeutic approaches.     

Management of allergic aspergillosis

Treatment of allergic bronchopulmonary aspergillosis depends on accurate diagnosis, which is difficult because of multiple clinical, radiographic, and immunologic criteria; unstandardized immunoassays; and its similarity to cystic fibrosis. Advances in chest CT interpretation, measuring serum Aspergillus fumigatus-specific antibodies and the T_H2 chemokine thymusactivated-and-regulated chemokine, recognizing risk factors, should improve diagnostic accuracy. Oral glucocorticosteroids remain the mainstay of treatment. Dose regimen and duration are not standardized, so expert recommendations are used. Inhaled steroids have not been proven to be effective. Due to relapse and toxicity, itraconazole has been added as second-tier therapy, supported by randomized, placebo-controlled trials in asthma and open-label trials in cystic fibrosis. Itraconazole is steroid sparing with anti-inflammatory aspects and poor bioavailability. Despite combination steroid-itraconazole therapy, relapses and steroid toxicity have led to open-label use of voriconazole, nebulized amphotericin B, monthly high-dose intravenous methylprednisolone, and omalizumab. Controlled trials are needed to evaluate these and other antifungal or immunomodulatory interventions.