Teaching old drugs new tricks: reincarnating immunosuppressants as antifungal drugs

Invasive fungal infections are rising worldwide as the number of immunocompromised patients increases. Unfortunately, our armamentarium of antifungal drugs is limited. Although current therapies are effective in treating some of the most prevalent infections, the development of novel treatments is vital because of emerging drug-resistant strains and species and because of the toxicity of certain current therapies. The immunosuppressive drugs CsA (cyclosporin A), FK-506 (tacrolimus) and rapamycin (sirolimus) exert potent antifungal effects against a variety of pathogenic fungi. These compounds are all currently in clinical use as immunosuppressive therapy to treat and prevent rejection of transplanted organs. Rapamycin is also in clinical trials as an antiproliferative agent for chemotherapy and invasive cardiology. Recent studies reveal a potent fungicidal synergism between azoles and the calcineurin inhibitors CsA and FK-506, and animal studies demonstrate that the CsA-fluconazole synergistic combination has therapeutic benefit. Less immunosuppressive analogs have been identified with potential to enhance current therapies, or as monotherapy without deleterious effects on the immune system. In summary, these highly successful pharmaceutical agents may find an even broader clinical application in combating infectious diseases.     

Antiparkinsonian drugs and their neuroprotective effects

In Parkinson's disease, while dopamine (DA) replacement therapy, such as with L-DOPA (levodopa), improves the symptoms, it does not inhibit the degeneration of DA neurons in the substantia nigra. Numerous studies have suggested that both endogenous and environmental neurotoxins and oxidative stress may participate in this disease, but the detailed mechanisms are still unclear. Recent genetic studies in familial Parkinson's disease and parkinsonism have shown several gene mutations. This new information regarding its pathogenesis offers novel prospects for effective strategies involving the neuroprotection of vulnerable DA neurons. This review summarizes current findings regarding the pathogenesis and antiparkinsonian drugs, and discusses their possibilities of targets to develop novel neuroprotective drugs.     

Astrocytes as targets for neuroprotective drugs

Astrocytes have long been considered as merely structural support for neurons in the central nervous system (CNS). However, more recent evidence has demonstrated roles for astrocytes in both neuroprotection and neurodegeneration. One major role is in the modulation of glutamatergic neurotransmission. Astrocytes can also modulate inflammatory responses in the CNS; they contain high levels of antioxidants and mediate neuronal protection after physiological assault, as well as releasing neurotrophic factors and being important to neuronal plasticity in the hippocampus. Targeting astrocytes as mediators for neuroprotective drugs may be a promising strategy.     

Neuroimmunophilin ligands: the development of novel neuroregenerative/ neuroprotective compounds

FK506 (tacrolimus), initially developed as an immunosuppressant drug, represents a class of compounds with potential high impact for the treatment of human neurological disorders. While immunosuppression is mediated by the 12-kD FK506-binding-protein (FKBP-12), the neurite elongation activity of FK506 involves FKBP-52 (also known as FKBP-59 or Hsp-56), a component of mature steroid receptor complexes: FKBP-52 binds to Hsp-90, which bind to p23 and the steroid receptor protein to form the complex. The brief review focuses on how three classes of compounds (FK506 derivatives, steroid hormones, and ansamycin anti-cancer drugs, e.g., geldanamycin) increase neurite elongation/nerve regeneration (axonal elongation). A model is presented whereby neurite elongation is elicited by compounds that bind to steroid receptor chaperone proteins (e.g., FKBP-52 and Hsp-90) and thereby disrupt mature steroid receptor complexes (comprising FKBP-52, Hsp-90 and p23 in addition to the steroid receptor binding protein). Disruption of the complex leads to a "gain-of-function" whereby one or more of these steroid receptor chaperone proteins (i.e, FKBP-52, Hsp-90 or p23) activates mitogen-associated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) pathway. Thus, the neurotrophic actions of these distinct classes of compounds can be understood from their ability to bind steroid receptor chaperones, thereby providing a unique receptor-mediated means to activate the ERK pathway. These studies thereby shed new light on the intrinsic mechanism regulating axonal elongation. Furthermore, this mechanism may also underlie calcineurin-independent neuroprotective actions of FK506. We suggest that components of steroid receptor complexes are novel targets for the design of neuroregenerative/neuroprotective drugs.     

Cortical focal stroke model to evaluate neuroprotective action of drugs

The experimental central nervous system (CNS) stroke model of cerebral cortical focal isch- emia in the rat is detailed to produce consistent and reproducible ischemic injuries, and is discussed for its adequacy to investigate the molecular mechanisms of ischemic injuries and to evaluate the neuroprotective efficacy of drugs. The model involves the permanent occlusion of ipsilateral (left) common carotid artery (CCAo) and middle cerebral artery (MCAod), and 1 hr occlusion of contralateral (right) CCAo. It is relatively easy to perform, highly reproducible, and does not result in mortality, and therefore is most suitable to delineate the time-dependent changes in biochemical processes associated with various CNS injuries to anatomically distinct regions of the brain initiated after ischemia. These injuries include primary and peri-ischemic injuries due to direct interruption of blood supply, and secondary non-ischemic injuries in brain areas with intact blood circulation. The consistency, reproducibility, and reliability are based on the analyses of several physiological (tissue levels of edema, Na⁺, K⁺, and Ca⁺⁺) and biochemical (membrane levels of fatty acids, [Na⁺ + K⁺]-ATPases, Ca⁺⁺-ATPase, and levels of enzymes of oxy-radical metabolism) indices of plasma membrane dysfunction which paralleled the functional deficits. These characteristics of the model make it possible for us to investigate the temporal relationship of a cascade of these acute physiological and biochemical processes in addition to loss of energy and nutrition, alterations in membrane lipid metabolism, increased lipid peroxidation, and alterations in receptor-mediated transfer of information. These processes, if not attenuated in time, can lead to cellular death. Since the ischemic injury affects several neurotransmitter systems simultaneously in anatomically distinct areas of the brain, probably through generalized alterations of cellular plasma membrane physicochemical properties, the MCA_o model is also well suited to compare efficacy of drugs with a wide range of physiological actions using a large number of the same biochemical and behavioral param- eters. In summary, a highly reproducible and consistent MCAo model of ischemia is adequate, if not identical to human ischemic stroke, to study several relevant variables of human stroke which include transient ischemia, reperfusion, different degree of ischemia due to varying lengths of occlusion or site of occlusion, hemorrhage, hypoglycemia, and hypothermia, and to evaluate the efficacy of a drug to stop the most acute injury process(es) before injury reaches the “point of no return.” © 1992 Wiley-Liss, Inc.     

Pharmacogenetics and individualized therapy in children: immunosuppressants, antidepressants, anticancer and anti-inflammatory drugs

Pharmacogenetic polymorphisms that change the amino acid sequences in coding regions only account for part of the interindividual differences in disease susceptibility and drug response. Additional pharmacogenomic and epigenetic factors are also involved. In children, pharmacogenetic studies are limited, although it has been clear for many years that the interactions between developmental patterns of drug-metabolizing enzymes and transporters have a major impact on dose exposure with age-specific dosage requirements. This article will analyze the factors affecting variability in drug response in children and focus on the pharmacogenetic polymorphisms of immunosuppressants, antidepressants, anticancer and anti-inflammatory drugs. Additional pharmacogenetic and epigenetic studies should be performed to allow the individualization of therapy in children.     

Important drug interactions in patients with rheumatic disorders: interactions of glucocorticoids, immunosuppressants and antimalarial drugs

Despite the fact that biological treatments are very promising, classical immunosuppressants, antimalarial drugs and glucocorticosteroids are still very important and widely used in practice. Although drug interactions can have fatal consequences, few studies have reviewed drug interactions of these classical drugs used in rheumatology, and very few guidelines are available on this subject. Therefore, this report summarizes important interactions of immunosuppressants, antimalarial drugs and glucocorticosteroids with drugs commonly used in internal medicine. In the present study, more than 300 interactions were retrieved from the Micromedex ? database. The selection was reduced to the interactions rated as moderate, major or contraindicated. The selected interactions were further checked against PubMed ?, MEDLINE ?, InfoPharm Compendium of Drug Interactions and Summaries of Product Characteristics. For each interaction, its nature, mechanism, onset and clinical severity were indicated, documentation quality was rated and recommendations for clinical practice were formulated. Twenty significant interactions that we rated as moderate, severe and very severe were identified. Interacting drugs were warfarin, fluoroquinolones, azole antifungals, co-trimoxazole, proton pump inhibitors, amiodarone, cholestyramine, activated carbon, allopurinol, angiotensin-converting enzyme inhibitors, statins, digoxin, iron, aluminium and magnesium salts, and hepatotoxic and nephrotoxic agents.     

DNA-intercalating ligands as anti-cancer drugs: prospects for future design

Interest in DNA-intercalating ligands as anti-cancer drugs has developed greatly since the clinical success of doxorubicin. However, despite a great deal of 'rational design' of synthetic DNA-intercalators, only a few such compounds have proved clinically useful. This review briefly surveys the history of DNA-intercalators as clinically-used anti-cancer drugs, summarizes the known structure-experimental activity relationships and modes of action, and concludes that a factor in the slow progress is that much of the work on these compounds has been carried out by chemists, who were generally more interested in ligand/DNA interactions than drug development. Future development of the class rests on a careful consideration of the biochemical reasons behind the common limitations of the present drugs. The most important are: the inherent resistance of non-cycling cells, the rapid development (even by cycling cells) of resistance by the expression of both P-glycoprotein and altered topoisomerase II, limitations on drug distribution to and transport into tumours, low extravascular pH in tumours and the cardiotoxic side-effects of quinonoid chromophores. These considerations provide a set of constraints on physicochemical properties which must be considered in future design. However, within these constraints, there are useful future avenues for the development of DNA-intercalators as anti-cancer drugs. These include: (i) the production of improved topoisomerase inhibitors (by consideration of drug/protein as well as drug/DNA interactions); (ii) the development of reductively-activated chromophores as hypoxia-selective agents; and (iii) the use of DNA-intercalators of known DNA binding orientation as 'carriers' for the delivery of other reactive functionality specifically (sequence-, regio- and site-specifically) to DNA.     

Using cDNA microarray to assess Parkinson's disease models and the effects of neuroprotective drugs

The remarkable progress made by molecular biology and molecular genetics during the past decade, and the advent of the novel tools of genomics and proteomics, are expected to reveal differential expression profiles of thousands of genes and proteins involved in the degeneration of dopamine-containing cells in Parkinson's disease and allow more focused treatments according to individual genotypes. Of particular interest is the application of microarrays in drug discovery and design to identify 'fingerprints' as potential candidate targets for drug intervention. The major microarray findings relevant to Parkinson's disease and its neurotoxin-induced animal and cell models will be discussed, with particular reference to the neuroprotective therapeutic potential that could arise from the development of drugs 'a la carte'.     

Emerging neuroprotective drugs for the treatment of acute ischaemic stroke

Introduction: Neuroprotection aims to restrict the ischaemic damage following stroke by preventing salvageable neurons from dying. Despite successes in experimental stroke studies, neuroprotective strategies have failed in clinical trials so far. Nevertheless, promising neuroprotective drugs are currently being investigated in clinical trials.

Areas covered: This review provides an overview of the existing treatment of acute ischaemic stroke, discusses current research goals and puts special emphasis on emerging neuroprotective drugs. The authors systematically searched the database Clinicaltrials.gov for ongoing Phase II and Phase III clinical trials of neuroprotective drugs for acute ischaemic stroke. Mechanisms of action of these candidate neuroprotectants and the results of preceding preclinical studies and clinical pilot trials are described.

Expert opinion: In order to facilitate a successful translation from bench to bedside, future experimental studies should follow rigorous quality standards. Recent concepts to overcome the translation roadblock include the implementation of multicentre preclinical Phase III studies, the use of stroke models in non-human primates and the introduction of a preclinical trial registration.     

脑卒中神经保护剂的治疗现状和未来

神经保护剂通过阻断缺血级联反应阻止神经细胞死亡,已成为近30年人类探索缺血性卒中早期治疗的一个重要途径,并在大量临床前研究中得以证实,然而其临床试验结局却是令人失望的。本文旨在总结脑卒中神经保护剂的治疗现状,分析其未能成功用于临床的可能原因,并探讨未来研究对策。     

Immunophilin ligands decrease release of pro-inflammatory cytokines (IL-1beta, TNF-alpha and IL-2 in rat astrocyte cultures exposed to simulated ischemia in vitro

The aim of present study was to evaluate the effects of immunophilin ligands (cyclosporin A, FK506 and rapamycin) on the simulated ischemia-induced release of pro-inflammatory cytokines (IL-1beta, TNF-alpha and IL-2) in rat primary astrocyte cell cultures. Astrocytes were exposed to cyclosporin A (CsA) (0.25, 0.5, 1, 10, 20 and 50 microM), FK506 (1, 10, 100, 1000 nM) and rapamycin (10, 100, 500 and 1000 nM). In vitro simulated ischemia significantly increased secretion of IL-1beta, TNF-alpha and IL-2 by astrocyte cultures deprived of microglia (by shaking and incubating with L-leucine methyl ester). CsA (at concentrations of 10-50 microM), FK506 (at all used concentrations) and rapamycin (in dose-dependent manner) significantly attenuated IL-1beta release after 24 h exposure to ischemic conditions. Immunophilin ligands at all used concentrations significantly decreased TNF-alpha levels in culture media after 24 h exposure to ischemia. Moreover, significant decrease in IL-2 secretion at 0.25, 0.5, 1 and 50 microM CsA and FK506 at concentrations of 100 and 1000 nM were observed. The results suggest that immunophilin ligands may regulate glial activity during ischemia by affecting the release of pro-inflammatory cytokines.