Antioxidant therapy: current status and future prospects

Reactive oxygen species (ROS) are widely believed to cause or aggravate several human pathologies such as neurodegenerative diseases, cancer, stroke and many other ailments. Antioxidants are assumed to counteract the harmful effects of ROS and therefore prevent or treat oxidative stress-related diseases. In this report, recent human studies exploring the efficiency of antioxidants in prevention and treatment of various diseases are reviewed. Few antioxidants including edaravone (for ischemic stroke in Japan), Nacetylcysteine (for acetaminophen toxicity), alfa-lipoic acid (for diabetic neuropathy) and some flavonoids (polyphenolic compounds present in dietary plants), such as micronized purified flavonoid fraction (diosmin and hesperidin) and oxerutins (for chronic venous insufficiency) as well as baicalein and catechins (for osteoarthritis) have found accepted clinical use. However, despite much enthusiasm in the 1980s and 1990s, many well-known agents such as antioxidant vitamins and also more recently developed compounds such as nitrones have not successfully passed the scrutiny of clinical trials for prevention and treatment of various diseases. This has given rise to a pessimistic view of antioxidant therapy, however, the evidence from human epidemiological studies about the beneficial effects of dietary antioxidants and preclinical in vitro and animal data are compelling. We have probably wasted too much time on agents like antioxidant vitamins instead of focusing on more disease specific, target-directed, highly bioavailable antioxidants. We here discuss possible reasons for the lack of success in some clinical trials and seek to provide some suggestions to be considered if antioxidant therapy is to succeed as an effective therapeutic strategy.     

Tuberculosis vaccines: current status and future prospects

There is an urgent need to develop more effective tuberculosis vaccines as chemotherapy and Bacille Calmette-Guérin (BCG) have failed to control the current epidemic. BCG does have some protective effect in childhood, so using a second vaccine to boost BCG would be the most ethical and logistically feasible strategy. The cost of tuberculosis efficacy trials will be high and return on investment into the development of a tuberculosis vaccine will be low. Incentives such as orphan drug status could encourage industrial interest. As more vaccines enter into early clinical trials, there is an urgent need for the identification of correlates of protection to aid decisions about which vaccines should go forward into efficacy testing. Research efforts that focus on reducing the cost and risk of conducting clinical trials will be of direct benefit to tuberculosis vaccine development.     

Low-frequency sonophoresis: current status and future prospects

Application of ultrasound enhances skin permeability to drugs, a phenomenon referred to as sonophoresis. Significant strides have been made in sonophoresis research in recent years, especially under low-frequency conditions (20 kHz相似文献   

Treatment of multidrug-resistant and extensively drug-resistant tuberculosis: current status and future prospects

Drug resistance in Mycobacterium tuberculosis arises from the man-made selection of mutants that result from spontaneous chromosomal alterations. Preventing the development of drug-resistant TB through a good control program based on directly observed treatment, short-course, is of paramount importance. Established multidrug-resistant (MDR)-TB requires alternative specific chemotherapy, comprising drugs with higher cost and greater toxicity delivered on a programmatic basis. The development of new anti-TB drugs would help to prevent and treat MDR-TB. Notably, moxifloxacin and gatifloxacin are being tested for shortening treatment in Phase III trials, while three novel compounds, TMC-207, OPC-67683 and PA-824 are in Phase II studies for both drug-susceptible and drug-resistant disease. The roles of surgery and immunotherapy in the management of MDR-TB require further evaluation. The recent emergence of extensively drug-resistant TB poses a serious challenge to the global control of TB. In order to combat extensively drug-resistant TB, strengthening of directly observed treatment, short-course and drug-resistance programs, alongside other strategies, including the development of newer diagnostics and drugs, is mandatory.     

Treatment of multidrug-resistant and extensively drug-resistant tuberculosis: current status and future prospects

Drug resistance in Mycobacterium tuberculosis arises from the man-made selection of mutants that result from spontaneous chromosomal alterations. Preventing the development of drug-resistant TB through a good control program based on directly observed treatment, short-course, is of paramount importance. Established multidrug-resistant (MDR)-TB requires alternative specific chemotherapy, comprising drugs with higher cost and greater toxicity delivered on a programmatic basis. The development of new anti-TB drugs would help to prevent and treat MDR-TB. Notably, moxifloxacin and gatifloxacin are being tested for shortening treatment in Phase III trials, while three novel compounds, TMC-207, OPC-67683 and PA-824 are in Phase II studies for both drug-susceptible and drug-resistant disease. The roles of surgery and immunotherapy in the management of MDR-TB require further evaluation. The recent emergence of extensively drug-resistant TB poses a serious challenge to the global control of TB. In order to combat extensively drug-resistant TB, strengthening of directly observed treatment, short-course and drug-resistance programs, alongside other strategies, including the development of newer diagnostics and drugs, is mandatory.     

Direct thrombin inhibitors: current status and future prospects

Thrombin is a pivotal enzyme in the coagulation cascade and in the pathogenesis of thrombosis, which can lead to the occurrence of a number of coronary syndromes. Thrombin inhibition, by either recombinant or synthetic inhibitors, has now been recognised as a possible mechanism by which to modulate thrombosis; a cause of considerable mortality and morbidity, particularly in the western world. This approach represents a departure from established antithrombotic therapy, the mainstay therapies for which are aspirin, heparin or warfarin. There is now a body of clinical evidence with recombinant peptide or protein based thrombin inhibitors, and, to a lesser extent, synthetic agents, which give useful insights into the potential therapeutic impact of direct thrombin inhibitors. As well as defining the key clinical parameters where these drugs can be beneficial, clinical studies have also highlighted specific areas which need to be addressed by newer compounds in this class. A number of examples of low molecular weight and potentially orally available compounds are now in early clinical development; they may serve to answer many of the questions raised by Phase III trials with compounds based on hirudin.     

Prostate cancer chemoprevention: current status and future prospects

Chemoprevention is a strategy that aims to reduce the incidence and burden of cancer through the development of agents to prevent, reverse or delay the carcinogenic process. Prostate cancer is a suitable target for prevention because it has a high incidence and prevalence, as well as a long latency and disease-related mortality, and furthermore it is a disease in which lifestyle and environmental factors may play critical roles. The development of chemoprevention strategies against prostate cancer will have a huge impact, both medically and economically. Large-scale clinical trials suggest that some agents such as selenium, lycopene, soy, green tea, vitamins D and E, anti-inflammatory and inhibitors of 5alpha-reductase are effective in preventing prostate cancer. Although each agent has the potential to affect the natural history of the disease, it is important to develop strategies to strategically proceed for the design and selection of test agents in order to demonstrate clinical benefit with the minimum of adverse effects. Appropriate selection of agent(s), disease stage, trial design and endpoints is critical in selecting the most promising regimens to accomplish these goals. This review highlights the present status of prostate cancer chemoprevention and discusses future prospects for chemopreventive strategies that are safe and clinically beneficial.     

Direct thrombin inhibitors: current status and future prospects

Thrombin is a pivotal enzyme in the coagulation cascade and in the pathogenesis of thrombosis, which can lead to the occurrence of a number of coronary syndromes. Thrombin inhibition, by either recombinant or synthetic inhibitors, has now been recognised as a possible mechanism by which to modulate thrombosis; a cause of considerable mortality and morbidity, particularly in the western world. This approach represents a departure from established antithrombotic therapy, the mainstay therapies for which are aspirin, heparin or warfarin. There is now a body of clinical evidence with recombinant peptide or protein based thrombin inhibitors, and, to a lesser extent, synthetic agents, which give useful insights into the potential therapeutic impact of direct thrombin inhibitors. As well as defining the key clinical parameters where these drugs can be beneficial, clinical studies have also highlighted specific areas which need to be addressed by newer compounds in this class. A number of examples of low molecular weight and potentially orally available compounds are now in early clinical development; they may serve to answer many of the questions raised by Phase III trials with compounds based on hirudin.     

Topical antibiotic therapy: current status and future prospects

As we enter a new decade, topical antibiotics are the subject of much renewed interest and are being used on a wider scale than ever before. The reasons for using topical rather than oral therapy for a variety of dermatoses include the reduced risk of systemic side effects, the avoidance of resistance selection in the gut microflora, the higher achievable concentration of antibiotic at the site of action and the overall usage of less drug. Somewhat surprisingly, treatment costs are not reduced by the use of topical therapy. The number of antibiotics licensed for topical use has increased in recent years and now includes representatives of the tetracycline, macrolide, lincosamide, aminoglycoside and peptide families of antibiotics in addition to fusidic acid, chloramphenicol and pseudomonic acid. Opinions regarding the clinical efficacy of topical antibiotics are conflicting, and for most indications alternative oral therapies are available. Topical antibiotics are the drugs of choice for the elimination of nasal carriage of Staphylococcus aureus and for the therapy of eye and external ear infections. They are also effective in the treatment of impetigo and other superficial pyodermas and in the management of localised infected eczema. Topical preparations of erythromycin, clindamycin and tetracycline are widely prescribed for the therapy of acne and are of clinical benefit in mild--moderate cases. However, they are no more effective against inflamed lesions than benzoyl peroxide and are less effective against non-inflamed lesions. They are not as effective as oral tetracycline in moderate to severe acne and should not be considered as a therapy for severe acne, for which 13-cis-retinoic acid is the drug of choice. It is well known that many antibiotics, when used topically, especially for prolonged periods, select for antibiotic-resistant staphylococci at the skin surface. Tetracyclines, erythromycin and clindamycin also select for resistant staphylococci on the surface of intact skin when delivered by the oral route. The contribution of topical antibiotic usage to the current high level of antibiotic resistance in coagulase-negative staphylococci, which are increasingly implicated in infections of compromised hosts, has not been quantified, although it is known that cutaneous staphylococci possess a large pool of transferable resistance genes.(ABSTRACT TRUNCATED AT 400 WORDS)     

The treatment of tuberculosis: current status and future prospects

Although a vaccine and effective chemotherapy against tuberculosis (TB) have been available for more than half a century, TB was declared a global emergency in 1993. Current chemotherapeutic regimens are being undermined by lack of resources for proper implementation and control, and the emergence of multi-drug resistant strains of Mycobacterium tuberculosis. Several new chemotherapeutic agents are under development, mainly derived from existing anti-TB drugs or broad-spectrum antibiotics. New experimental agents include immunomodulants and drugs directed against novel cellular targets.     

Antistaphylococcal vaccines and immunoglobulins: current status and future prospects

Staphylococci are among the most frequently encountered pathogens in both the inpatient and the outpatient setting. Management of infections caused by these organisms is complicated by the increasingly common resistance of staphylococcal pathogens to commonly used antibacterials. As a consequence, novel approaches to prevention and treatment are urgently required. Such approaches include the development of vaccines and immunoglobulin preparations targeted at virulence factors expressed in vivo by staphylococci. This article reviews the biopharmaceutical progress made to date in this field and suggests approaches to further progress.     

Diagnosis of malignant melanoma with radiolabeled monoclonal antibodies: current status

Since the advent of the technique for preparation of monoclonal antibodies in 1975, these agents have been used in a variety of experimental procedures, including investigations into the structure of the human genome. The increasing availability of these highly specific antibodies has also spawned the development of kits for in vitro diagnosis of a number of diseases, and now radiolabeled monoclonal antibodies are undergoing clinical trials to assist in vivo diagnosis of several different cancers. We report our results in four representative cases comparing the efficacy of 111Indium-labeled antimelanoma, type 96.5, monoclonal antibodies against standard diagnostic imaging techniques at accurately diagnosing metastatic malignant melanoma lesions. In some cases the monoclonal antibody studies provided unequivocal evidence of the existence of metastases. In other cases no localization occurred, and we suggest plausible reasons for this failure and modifications of imaging technique to improve the performance. Overall, we believe monoclonal antibodies represent a promising new clinical aid in disease diagnosis which may ultimately permit direct targeting of therapeutic agents.     

Phytochemical based nanomedicines against cancer: current status and future prospects

Cancer continues to be one in all the leading reasons for death worldwide. The mean cancer survival through standard therapeutic strategies has not been significantly improved over the past few decades. Hence, alternate remedies are needed to treat this terrible disease. Recently, natural compounds present in the plants, i.e. phytochemicals have been widely exploited for their anticancer potential. Phytochemicals may exhibit their anticancer activity through targeting different cancer cell signalling pathways, promoting cell cycle arrest and apoptosis, regulating antioxidant status and detoxification. Despite their excellent anticancer activity, the phytochemicals are limited by their low aqueous solubility, poor bioavailability, and poor penetration into cells, hepatic disposition, narrow therapeutic index and rapid uptake by normal tissues. Therefore, to address these challenges, the scientific community has shifted its significant interests towards nanocarriers-based delivery of phytochemicals due to their ability to enhance aqueous solubility, and bioavailability, specific tumour cell/tissue targeting, improved cellular uptake, reducing doses of phytochemicals and achieving steady-state therapeutic levels of the phytochemicals over an extended period of time. Additional advantages include excellent blood stability, multifunctional design of nanocarriers and improvement in anticancer activities. This review aims to summarise recent progress in phytochemical based nanomedicines for effective treatment of cancer.     

Telomerase as an anti-cancer target: current status and future prospects

As is common with a newly discovered cancer-associated gene/protein, there is a lag between the elucidation of its cellular and molecular biology and appropriate therapeutic intervention. Telomerase represents an interesting and promising anticancer drug target but poses a particular drug discovery challenge. It is unclear at present what is the optimum means of targeting this complex ribonucleoprotein and associated telomeric DNA and binding proteins: various strategies are actively being explored. Some recent data (e.g. 2-5A antisense against telomeric RNA, targeting TRF2, introduction of dominant-negative hTERT into cells) has raised doubts over the previously presumption of a requirement for prolonged enzyme inhibition with gradual telomere erosion, especially in tumour cells with relatively short telomeres. Highly potent and selective in vivo inhibitors are required to validate the target and address these critical issues.     

Inhalational therapy for pulmonary arterial hypertension: current status and future prospects

This review summarizes the pathophysiology and current therapeutic and drug delivery strategies for pulmonary arterial hypertension (PAH), a rare but devastating disorder of the pulmonary circulation affecting 50,000 to 100,000 persons in the United States. Chief clinical features of PAH include increased mean pulmonary arterial pressure (>25 mm Hg) and right ventricular and smooth muscle hypertrophy. A wide variety of agents have been studied for use as anti-PAH drugs, including prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors, to name a few. However, a major shortcoming of anti-PAH medications is their short half-lives, requiring them to be administered via parenteral routes, which lead to undesirable side effects, including systemic vasodilation. Inhalational delivery of anti-PAH drugs provides an attractive alternative to conventional routes, with ease of administration and minimal systemic vasodilation. Recently, the U.S. Food and Drug Administration approved inhalable iloprost (Ventavis?), a prostacyclin analogue, for PAH treatment. Other drugs being studied for their potential in inhalable PAH therapy include PGE1, treprostinil, vasoactive intestinal peptide, and fasudil. Controlled-release inhalable delivery systems for anti-PAH medications have also been proposed to facilitate long-term and selective vasodilation of pulmonary arteries. Extensive studies are warranted to develop safe and effective drug delivery systems that will provide a better quality of life to patients.