Drug discovery for polycystic kidney disease

In polycystic kidney disease (PKD), a most common human genetic diseases, fluid-filled cysts displace normal renal tubules and cause end-stage renal failure. PKD is a serious and costly disorder. There is no available therapy that prevents or slows down the cystogenesis and cyst expansion in PKD. Numerous efforts have been made to find drug targets and the candidate drugs to treat PKD. Recent studies have defined the mechanisms underlying PKD and new therapies directed toward them. In this review article, we summarize the pathogenesis of PKD, possible drug targets, available PKD models for screening and evaluating new drugs as well as candidate drugs that are being developed.     

Pharmacotherapeutic approach to prevent or treat chronic allograft nephropathy

In the current paper we will review the evidence that drug therapy may be of value to prevent or treat chronic allograft nephropathy. We will review the immunosuppressive therapy and non-immune therapies in use to treat risk factors associated with chronic allograft nephropathy and evaluate their efficacy with respect to long term outcome as well as their effect on markers of long-term survival. In the last part of this review, we will indicate possible benefits of new approaches being explored but most of these data are obtained in in vitro test systems and rodent models.     

Progress in structure-based drug design against influenza A virus

Introduction: The 2009-H1N1 influenza pandemic has prompted new global efforts to develop new drugs and drug design techniques to combat influenza viruses. While there have been a number of attempts to provide drugs to treat influenza, drug resistance has been a major problem with only four drugs currently approved by the FDA for its treatment. Areas covered: In this review, the drug-resistant problem of influenza A viruses is discussed and summarized. The article also introduces the experimental and computational structures of drug targeting proteins, neuraminidases, and of the M2 proton channel. Furthermore, the article illustrates the latest drug candidates and techniques of computer-aided drug design with examples of their application, including virtual in silico screening and scoring, AutoDock and evolutionary technique AutoGrow. Expert opinion: Structure-based drug design is the inventive process for finding new drugs based on the structural knowledge of the biological target. Computer-aided drug design strategies and techniques will make drug discovery more effective and economical. It is anticipated that the recent advances in structure-based drug design techniques will greatly help scientists to develop more powerful and specific drugs to fight the next generation of influenza viruses.     

Current and future antifungal therapy: new targets for antifungal therapy

Invasive fungal infections will continue to cause major complications in immunocompromized patients. At the moment, the expansion of antifungal drug research has occurred because there is a critical need for new antifungal agents to treat these life-threatening invasive fungal infections. The overview of the development of antifungal therapy which is provided here demonstrates the increased interest in this very special area of infectious diseases. Although we now have some newer and less toxic antifungal agents that are currently available for clinical use, their clinical efficacy in some invasive fungal infections, such as aspergillosis and fusariosis, is not very good. Intense efforts in antifungal drug discovery are urgently needed to develop more promising and effective antifungal agents for use in the clinical arena.     

Conventional and gene therapy strategies for the treatment of brain tumors

There are several types of primary tumors of the central nervous system (CNS), and almost half of them are gliomas. In particular, glioblastoma multiforme (GBM) is very aggressive and infiltrates into the CNS parenchyma. Despite intense clinical efforts, the prognosis of patients with this type of tumors remains very poor, and has not improved in decades, with a median survival of approximately one year after diagnosis. Current treatments include surgical resection, radiotherapy and chemotherapy. However, our knowledge regarding the genetic basis, as well as the molecular signaling pathways involved in the origin and progression of the tumors has increased significantly in the last few years, thus allowing the generation of new chemotherapeutic agents that are used together with sophisticated surgical and radiation techniques. Nevertheless, new approaches are necessary to develop effective treatments for these tumors. One of these novel strategies is gene therapy which is particularly well suited to treat gliomas. In this review we will discuss current therapeutic approaches, as well as critically analyzing gene therapy methods, the use of diverse viral and non-viral vectors, different genes and strategies to treat gliomas, from experimental models to clinical applications.     

Pharmacokinetic characterization of extracorporeal therapy

The efficiency of extracorporeal therapy with immobilized enzymes (reactive devices) and hemoperfusion cartridges (nonreactive devices) is evaluated in terms of a new pharmacokinetic parameter, the bioefficacy. A detailed analysis is provided in the former case, and it is shown how the bioefficacy can be calculated from a combined pharmacokinetic and reactor analysis. The theory is presented for evaluating bioefficacy in terms of linear pharmacokinetic models that view the reactor or other extracorporeal appliance as an artificial organ. Examples are drawn from recent work on methotrexate rescue with immobilized carboxypeptidase G₁ and from literature data on the use of hemoperfusion to treat drug overdose to illustrate the calculations.This work was supported by a grant No. CA 28037 from the National Institute of Health and by a grant from the Donors of the Petroleum Research Fund, administered by the American Chemical Society.     

Kidney protective potential of lactoferrin: pharmacological insights and therapeutic advances

Kidney disease is becoming a global public health issue. Acute kidney injury (AKI) and chronic kidney disease (CKD) have serious adverse health outcomes. However, there is no effective therapy to treat these diseases. Lactoferrin (LF), a multi-functional glycoprotein, is protective against various pathophysiological conditions in various disease models. LF shows protective effects against AKI and CKD. LF reduces markers related to inflammation, oxidative stress, apoptosis, and kidney fibrosis, and induces autophagy and mitochondrial biogenesis in the kidney. Although there are no clinical trials of LF to treat kidney disease, several clinical trials and studies on LF-based drug development are ongoing. In this review, we discussed the possible kidney protective mechanisms of LF, as well as the pharmacological and therapeutic advances. The evidence suggests that LF may become a potent pharmacological agent to treat kidney diseases.     

Challenges and hopes for Alzheimer’s disease

Recent drug development efforts targeting Alzheimer’s disease (AD) have failed to produce effective disease-modifying agents for many reasons, including the substantial presymptomatic neuronal damage that is caused by the accumulation of the amyloid β (Aβ) peptide and tau protein abnormalities, deleterious adverse effects of drug candidates, and inadequate design of clinical trials. New molecular targets, biomarkers, and diagnostic techniques, as well as alternative nonpharmacological approaches, are sorely needed to detect and treat early pathological events. This article analyzes the successes and debacles of pharmaceutical endeavors to date, and highlights new technologies that may lead to the more effective diagnosis and treatment of the pathologies that underlie AD. The use of focused ultrasound, deep brain stimulation, stem cell therapy, and gene therapy, in parallel with pharmaceuticals and judicious lifestyle adjustments, holds promise for the deceleration, prevention, or cure of AD and other neurodegenerative disorders.     

Progress in structure-based drug design against influenza A virus

Introduction: The 2009-H1N1 influenza pandemic has prompted new global efforts to develop new drugs and drug design techniques to combat influenza viruses. While there have been a number of attempts to provide drugs to treat influenza, drug resistance has been a major problem with only four drugs currently approved by the FDA for its treatment.

Areas covered: In this review, the drug-resistant problem of influenza A viruses is discussed and summarized. The article also introduces the experimental and computational structures of drug targeting proteins, neuraminidases, and of the M2 proton channel. Furthermore, the article illustrates the latest drug candidates and techniques of computer-aided drug design with examples of their application, including virtual in silico screening and scoring, AutoDock and evolutionary technique AutoGrow.

Expert opinion: Structure-based drug design is the inventive process for finding new drugs based on the structural knowledge of the biological target. Computer-aided drug design strategies and techniques will make drug discovery more effective and economical. It is anticipated that the recent advances in structure-based drug design techniques will greatly help scientists to develop more powerful and specific drugs to fight the next generation of influenza viruses.     

Surface antigens/receptors for targeted cancer treatment: the GnRH receptor/binding site for targeted adenocarcinoma therapy

Colon, breast and lung adenocarcinomas - three of the major malignancies occurring in humans, together with ovarian, endometrial, kidney and liver adenocarcinomas, account for more then 50% of cancer-related death. As the number of cancer-related deaths has not decreased in recent years, major efforts are being made to find new and more specific drugs for cancer treatment. One of the approaches developed in recent years for targeted cancer therapy is the construction and use of chimeric proteins. Chimeric cytotoxins are a class of targeted molecules designed to recognize and specifically destroy cells over-expressing specific receptors. These molecules, designed and constructed by gene fusion techniques, comprise both the cell-targeting and the cell-killing moieties. Our laboratory has developed a number of chimeric proteins based on an analog of Gonadotropin Releasing Hormone (GnRH) as their targeting moiety. These chimeras recognize a GnRH-binding site that, we found, was over-expressed on a surprisingly wide variety of cancers, all confined to the adenocarcinoma type. A GnRH analog was fused to a large number of killing moieties, including bacterial or human pro-apoptotic proteins. All GnRH-based chimeric proteins selectively killed adenocarcinoma cells both in vitro and in vivo. Utilizing GnRH-based chimeric proteins for targeted therapy could open up new vistas in the fight against adenocarcinomas in humans. This review summarizes the latest developments in the area of targeted cancer therapy via specific antigens/receptors, as well as our latest findings in targeting GnRH-binding sites using GnRH-based chimeric proteins for specific and targeted adenocarcinoma therapy in humans.     

Trends in Drug Targeting for Cancer Treatment

Various drug delivery and targeting systems and approaches are currently utilized for cancer chemotherapy. Many drugs being developed through biotechnology are also in various stages of clinical trials. The most common approaches with drug delivery and targeting systems have been those using stealth liposomes or microspheres. Recent efforts have been made to use stealth nanoparticles for cancer drug delivery. In the next few years, it is expected that several liposomal products will be on the market. Another approach that has been utilized for some time has been the use of antibody-directed drugs or toxins. Several immunotoxins are currently in phase III trials, and efforts are being made to potentiate their activity with different potentiators. In an effort to understand the intricacies of tumor morphology and the limitations of drug targeting, various mathematical models have been proposed that help in designing appropriate delivery systems for successful tumor targeting. This review considers a number of drug targeting systems, especially microparticulate and colloidal systems, for cancer therapy.     

Anthracyclines as effective anticancer drugs

Anthracyclines have received significant attention due to their effectiveness and extensive use as anticancer agents. At present, the clinical use of these drugs is offset by drug resistance in tumours and cardiotoxicity. Therefore, a relentless search for the ‘better anthracycline’ has been ongoing since the inception of these drugs > 30 years ago. This review focuses on the most recent pharmacology and medicinal chemistry developments on the design and use of anthracyclines. Based on their crystal structures as well as molecular modelling, a more detailed mechanism of topoisomerase poisoning by these new anthracyclines has emerged. Chemical modifications of anthracyclines have been found to possibly change the target selectivity among various topoisomerases and, thus, vary their anticancer activity. Additionally, recent sugar modifications of anthracyclines have also been found to overcome P-glycoprotein-mediated drug resistance in cancer therapy. The continued improvement of anthracycline clinical applications so far and the clinical trials of the ‘third generation’ of anthracyclines (such as sabarubicin) are also discussed. To finally find the ‘better’ anthracycline, further areas of research still need to be explored such as: the elucidation of the topoisomerase and P-glycoprotein crystal structures, molecular modelling based on crystal structure in order to design the next generation of better anthracycline drugs, the continued modifications of the anthracycline sugar moieties, and the further improvement of anthracycline drug delivery methods.     

Has molecular and cellular imaging enhanced drug discovery and drug development?

A great many efforts have been made to accelerate the drug discovery and development process, which is extremely time and money consuming. Recently developed molecular imaging has many significant advantages over conventional methods for examining molecular pathways and obtaining pharmacokinetic, pharmacodynamic and mechanistic information. This review briefly summarizes various molecular and cellular imaging techniques and discusses several important applications of molecular and cellular imaging in drug discovery and development, which include: (i) measurement of pharmacodynamic endpoints by imaging metabolism and proliferation, imaging angiogenic parameters, and imaging a particular pathway or downstream target; (ii) evaluation of pharmacokinetics; and (iii) imaging therapeutic gene expression with relevance to gene therapy. Molecular imaging is becoming more widely used as a non-invasive tool for drug discovery and drug screening. Further refinements in imaging techniques, optimization of imaging probes and collaborative efforts will be needed to fully realise the vast potential of molecular imaging techniques in discovering and developing new drugs.     

Deciphering calcineurin inhibitor nephrotoxicity: a pharmacological approach

The calcineurin inhibitors ciclosporin and tacrolimus are used to prevent acute rejection of solid organs after transplantation. Their use can lead to chronic renal damage characterized by progressive and irreversible deterioration of renal function associated with interstitial fibrosis, tubular atrophy, arteriolar hyalinosis and glomerulosclerosis. Many approaches to better understand the mechanisms of this toxicity are in use. The aim of these approaches is to find biomarkers of early kidney injury and potential therapeutic targets. Despite these efforts, the biological processes leading to calcineurin inhibitor nephrotoxicity remain poorly understood. Furthermore, the diagnosis of chronic renal damage remains inaccurate without definitive diagnostic tools, no effective prevention exists and a therapy to treat the damage has yet to be developed. In this article, theories of pharmacodynamics, pharmacokinetics, therapeutic drug monitoring and pharmacogenetics are synthesized in ways that may improve the understanding of mechanisms leading to calcineurin inhibitor toxicity. The importance of global approaches such as toxicogenomics is emphasized to characterize early cellular responses implicated in calcineurin inhibitor nephrotoxicity.     

Sonophoresis: recent advancements and future trends

Objectives Use of ultrasound in therapeutics and drug delivery has gained importance in recent years, evident by the increase in patents filed and new commercial devices launched. The present review discusses new advancements in sonophoretic drug delivery in the last two decades, and highlights important challenges still to be met to make this technology of more use in the alleviation of diseases. Key findings Phonophoretic research often suffers from poor calibration in terms of the amount of ultrasound energy emitted, and therefore current research must focus on safety of exposure to ultrasound and miniaturization of devices in order to make this technology a commercial reality. More research is needed to identify the role of various parameters influencing sonophoresis so that the process can be optimized. Establishment of long‐term safety issues, broadening the range of drugs that can be delivered through this system, and reduction in the cost of delivery are issues still to be addressed. Summary Sonophoresis (phonophoresis) has been shown to increase skin permeability to various low and high molecular weight drugs, including insulin and heparin. However, its therapeutic value is still being evaluated. Some obstacles in transdermal sonophoresis can be overcome by combination with other physical and chemical enhancement techniques. This review describes recent advancements in equipment and devices for phonophoresis, new formulations tried in sonophoresis, synergistic effects with techniques such as chemical enhancers, iontophoresis and electroporation, as well as the growing use of ultrasound in areas such as cancer therapy, cardiovascular disorders, temporary modification of the blood‐brain barrier for delivery of imaging and therapeutic agents, hormone replacement therapy, sports medicine, gene therapy and nanotechnology. This review also lists patents pertaining to the formulations and techniques used in sonophoretic drug delivery.     

Gene therapy for kidney disease

Gene therapy has distinct potential to treat disease at the most fundamental level. However, the ability to pursue gene therapy for renal disease has been limited by the availability of an adequate system for gene delivery to the kidney and for regulation of transgene expression. Presently, there are several limitations to overcome before clinical use of viral vector systems for targeting kidney can be considered. Non-viral vectors such as haemagglutinating virus of Japan (HVJ)-liposome mediated gene transfer and cationic liposome are promising but need to be improved. Given that the systemic delivery of the functional protein can serve as therapy for the renal diseases, skeletal muscle targeting gene therapy might be an alternative strategy for the treatment of renal disease. Gene therapy to the transplant kidney may potentially improve the graft outcome by reducing acute and chronic rejection. We review emerging strategies of gene transfer with reference to the kidney and discuss the potential application of gene therapy to renal diseases.     

Public Health Department Response to Mercury Poisoning: The Importance of Biomarkers and Risks and Benefits Analysis for Chelation Therapy

Chelation therapy is often used to treat mercury poisoning. Public health personnel are often asked about mercury toxicity and its treatment. This paper provides a public health department response to use of a mercury-containing cosmetic in Minnesota, a perspective on two unpublished cases of chelation treatment for postulated mercury toxicity, and comments on the use of a nonsystemic treatment for removal of mercury following the Iraqi seed coat poisoning incident. Physicians should evaluate sources of exposure, biomarkers, and risks and benefits before recommending chelation therapy for their patients. Potential risks to chelation therapy and its little understood subtle or latent effects are areas of public health concern.     

Gene therapy for kidney disease

Gene therapy has distinct potential to treat disease at the most fundamental level. However, the ability to pursue gene therapy for renal disease has been limited by the availability of an adequate system for gene delivery to the kidney and for regulation of transgene expression. Presently, there are several limitations to overcome before clinical use of viral vector systems for targeting kidney can be considered. Non-viral vectors such as haemagglutinating virus of Japan (HVJ)-liposome mediated gene transfer and cationic liposome are promising but need to be improved. Given that the systemic delivery of the functional protein can serve as therapy for the renal diseases, skeletal muscle targeting gene therapy might be an alternative strategy for the treatment of renal disease. Gene therapy to the transplant kidney may potentially improve the graft outcome by reducing acute and chronic rejection. We review emerging strategies of gene transfer with reference to the kidney and discuss the potential application of gene therapy to renal diseases.     

Carbapenem-hydrolyzing gram-negative bacteria: current options for treatment and review of drugs in development

Multidrug resistant gram-negative bacteria are an increasing therapeutic challenge. The beta-lactamases are a group of enzymes that confer resistance to the beta-lactam antibiotics. The carbapenems have been in wide use to treat beta-lactamase producing, multidrug resistant gram-negative bacterial infections. However, the emergence of carbapenemases, enzymes capable of hydrolyzing the carbapenems, has limited our therapeutic options. In the recent years, there has been some development in the discovery of new agents such as boronic acid derivatives, ME1071 and Ca-EDTA that may enhance the activity of existing antibiotics, CTC-96 which reverses antibiotic resistance and polymyxin derivatives with decreased renal toxicity. While global efforts towards new drug development should continue, appropriate use of currently available antibiotics is equally important. In this review, we will discuss the general characteristics of carbapenemases, recent patents with drugs under development and current treatment options.     

Resistant TB: Newer Drugs and Community Approach

Drug resistance in tuberculosis (TB) is a serious problem compromising both the treatment and control programs. Poor usage of the available anti TB drugs has led to progressive drug resistance-multi drug resistance (MDR), extensively drug-resistance (XDR) and even total drug resistance (TDR). While drug sensitive TB is completely curable, MDR-TB is difficult to treat, XDR and TDR are often fatal. Non availability of new drugs to treat drug resistant cases further complicates the problem. The Global Alliance for Tuberculosis Drug Developments, a non-profit organization with the World Health Organization (WHO) as a partner was formed in February 2000 for the development of new drugs. In the last decade this venture has resulted in several promising new antituberculosis drugs like TMC207 (diaryquinoline), PA-824 (nitroimidazo-oxazine), OPC-67683 (nitroimidazo-oxazole) and SQ 109 (diamine compound). Drug resistance in TB is a man made problem. Therefore, while global efforts towards new drug development must continue it is equally important to have a well defined community approach to prevent the emergence of drug resistance to the existing and newer drugs. The present review article discusses some recent drug patents for the treatment of tuberculosis and the appropriate community approach to prevent and treat drug resistant TB.