Cadmium therapeutic agents

Pollution of the environment with toxic metals has increased dramatically since the beginning of the industrial revolution. Cadmium is of particular concern because it accumulates in the human body with a half-life exceeding 10 years and has been linked with a number of health problems including renal tubular dysfunction, pulmonary emphysema, significant kidney damage, and possibly osteoporosis. Moreover, in 1993 the International Agency for Research on Cancer (IARC) classified cadmium and compounds containing cadmium as human carcinogens. The field of cadmium intoxication therapy has seen increases in interest due to its poignant toxicity in both humans and animals. Preliminary attempts to combat acute cadmium poisoning included the use of the chelating agents ethylenediaminetetraacetic acid (EDTA) and British anti-Lewisite (BAL). This review will focus on the chemistry, biology, and effectiveness of cadmium intoxication therapy to date. The toxicokinetics of cadmium mammals will be discussed briefly to understand the extent and severity of overexposure. An overview of cadmium chelation therapy will be given with an emphasis on the measurable effectiveness of each and significant structure activity relationships. Cadmium intoxication therapy will be reviewed by their indicated routes of action: direct (chelation and antagonism), indirect (induction), and symptom alleviation. The methods by which cadmium therapeutics are evaluated (in vivo, in vitro) are to be discussed. An evaluation of the clinical potential for promising therapeutics will be given.     

治疗药物监测

<正>治疗药物监测(therapeutic drug monitoring, TDM)是近代临床药物治疗学重大进展之一。目前 TDM已发展成为专门的学科,有关治疗药物监测的杂志、专著和论文逐年增多。国际治疗药物监测和临床毒理学会每两年都要召开一次国际会议,2005 年4月将在美国召开第9届大会。药物监测的范围     

Protein phosphatase inhibition: structure based design. Towards new therapeutic agents

Cellular signalling processes are governed by a delicate balance of phosphatase and kinase activity. Over the past few years there has been considerable effort directed toward the development of kinase based therapeutic agents, whilst phosphatase based therapeutics have lagged. Herein we address key issues relating to selected therapeutic targets: malignancy, diabetes, immunosuppression, cystic fibrosis, asthma and cardiovascular disease. As part of ongoing studies we examine the recent developments in understanding the key interactions between the okadaic acid class of compounds and the serine/threonine protein phosphatases 1, 2A and 2B. Crystal structure and molecular modelling guided inhibitor development is also a key focus of this article.     

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.     

New therapeutic agents for hypertension

1 Over the last 40 years a range of therapeutic strategies has been introduced for the long term treatment of hypertension.
2 Although safe effective agents are available a significant number of patients are unable or unwilling to take these drugs as long term treatment.
3 Both insufficient efficacy and adverse effects justify the search for new antihypertensive strategies.
4 Recent developments include orally active angiotensin (AT₁) receptor antagonists (ARA) which appear to offer the benefits of prevention of angiotensin II effects without the adverse effects of bradykinin potentiation, such as cough, which limit the usefulness of angiotensin converting enzyme (ACE) inhibitors.
5 Imidazoline receptor agonists offer the potential of centrally active antihypertensives without the adverse effects of sedation and dry mouth. Further clinical experience is necessary to confirm whether the clinical efficacy and good tolerability are confirmed with long term use.
6 Both ARA and imidazoline preferring substances offer the bonus of a desirable haemodynamic profile in patients with heart failure and may open new therapeutic avenues in the management of cardiac failure.     

Nucleic acids as therapeutic agents

Therapeutic nucleic acids (TNAs) and its precursors are applied to treat several pathologies and infections. TNA-based therapy has different rationales and mechanisms and can be classified into three main groups: 1) Therapeutic nucleotides and nucleosides; 2) Therapeutic oligonucleotides; and 3) Therapeutic polynucleotides. This review will focus in those TNAs that have reached clinical trials with anticancer and antiviral protocols, the two most common applications of TNAs. Although therapeutic nucleotides and nucleosides that interfere with nucleic acid metabolism and DNA polymerization have been successfully used as anticancer and antiviral drugs, they often produce toxic secondary effects related to dosage and continuous use. The use of oligonucleotides such as ribozyme and antisense oligodeoxynucleotides (AS-ODNs) showed promise as therapeutic moieties but faced several issues such as nuclease sensitivity, off-target effects and efficient delivery. Nevertheless, immunostimulatory oligodeoxynucleotides and AS-ODNs represent the most successful group of therapeutic oligonucleotides in the clinic. A newer group of therapeutic oligonucleotides, the aptamers, is rapidly advancing towards early detection and treatment alternatives the have reached the commercial interest. Despite the very high in vitro efficiency of small interfering RNAs (siRNAs) they present issues with intracellular target accessibility, specificity and delivery. DNA vaccines showed great promise, but they resulted in very poor responses in the clinic and further development is uncertain. Despite their many issues, the exquisite specificity and versatility of therapeutic oligonucleotides attracts a great deal of research and resources that will certainly convert them in the TNA of choice for treating cancer and viral diseases in the near future.     

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.     

Thrombospondins as anti-angiogenic therapeutic agents

Thrombospondin-1 (TSP-1) was one of the first endogenous inhibitors of angiogenesis to be discovered. This large multimodular protein of around 600 kDa inhibits endothelial cell proliferation, migration and morphogenic organization into capillary tubes. TSP-2 shares homology with TSP-1 in primary sequence, structural organization and angiostatic properties. TSP-1-null and TSP-2-null mice display increased tissue vascularity and enhanced sensitivity to carcinogenesis. Conversely, overexpression of TSP-1 or TSP-2 in cancer cells results in reduced tumor vascularization and tumor growth. In this review, we focus on the preclinical data obtained in experimental anti-tumorigenic assays using either TSP-1, TSP-2 or shorter peptides derived from the type 1 repeats of these molecules. In contrast with the full length thrombospondin molecules, which present a poor bioavailability and are highly susceptible to proteolytic degradation, TSP-derived angiostatic peptides appear as potent and promising therapeutic agents in anti-angiogenic therapy.     

The therapeutic monitoring of antimicrobial agents

AIMS: To review the basis and optimal use of therapeutic drug monitoring of antimicrobial agents. METHODS: Antimicrobial agents for which a reasonable case exists for therapeutic drug monitoring were reviewed under the following headings: pharmacokinetics, why monitor, therapeutic range, individualisation of therapy, sampling times, methods of analysis, interpretative problems and cost-effectiveness of monitoring. RESULTS: There is a strong historical case for monitoring aminoglycosides. The recent move to once-daily dosing means that criteria for therapeutic drug monitoring need to be redefined. Vancomycin has been monitored routinely but many questions remain about the most appropriate approach to this. A case can be made for monitoring teicoplanin, flucytosine and itraconazole in certain circumstances. CONCLUSIONS: The approach to monitoring aminoglycosides needs to be redefined in the light of once-daily dosing. It is premature to suggest that less stringent monitoring is necessary as toxicity remains a problem with these drugs. The ideal method of monitoring vancomycin remains to be defined although a reasonable case exists for measuring trough concentrations, mainly to ensure efficacy. Teicoplanin is monitored occasionally to ensure efficacy while flucytosine is monitored occasionally to avoid high concentrations associated with toxicity. Itraconazole has various pharmacokinetic problems and monitoring has been suggested to ensure that adequate concentrations are achieved.     

The therapeutic monitoring of antimicrobial agents

Aims  To review the basis and optimal use of therapeutic drug monitoring of antimicrobial agents.
Methods  Antimicrobial agents for which a reasonable case exists for therapeutic drug monitoring are reviewed under the following headings: pharmacokinetics, why monitor, therapeutic range, individualization of therapy, sampling times, methods of analysis, interpretative problems and cost-effectiveness of monitoring.
Results  There is a strong historical case for monitoring aminoglycosides. The recent move to once-daily dosing means that criteria for therapeutic drug monitoring need to be redefined. Vancomycin has been monitored routinely but many questions remain about the most appropriate approach to this. A case can be made for monitoring teicoplanin, flucytosine and itraconazole in certain circumstances.
Conclusions  The approach to monitoring aminoglycosides is being redefined in the light of once daily dosing. It may be that less stringent monitoring is required in some circumstances but toxicity, especially ototoxicity, remains a problem with these drugs. Monitoring to avoid high AUCs (areas under the concentration-time curve) is recommended. The ideal method for monitoring vancomycin remains to be defined although a reasonable case exists for measuring trough concentrations, mainly to ensure efficacy. Teicoplanin is sometimes monitored to ensure efficacy while flucytosine may be monitored to avoid high concentrations associated with toxicity. Itraconazole has various pharmacokinetic problems and monitoring has been suggested to ensure that adequate concentrations are achieved.     

Vaccines and therapeutic agents for tularemia

Tularemia is not particularly prevalent in North America under normal circumstances; however, recent concerns about bioterrorism have brought Francisella tularensis, the causative agent of tularemia, into the limelight. Although certain antibiotics can successfully treat tularemia, therapy must begin shortly after exposure to ensure a positive outcome. The only vaccine developed to date is a live attenuated strain of F. tularensis subspecies holarctica. Unfortunately, it has been plagued by regulatory issues. In the past few years, considerable research effort and funding have been committed for developing an effective treatment or vaccine for tularemia and, as a result, a small number of patents have been published that describe the development of potential therapeutics and new live attenuated or subunit vaccines against tularemia.     

Recent patents therapeutic agents for cancer

Cancer is one of the most dreaded diseases with a complex pathogenesis, which threats human life greatly. Multidisciplinary scientific investigations are making best efforts to combat this disease and put to the identification of novel anticancer agents. Patent anticancer agents registered in China are therefore increasing dramatically during the past ten years, which will be reviewed briefly in this article. platinum complexes anthracycline analogs (including doxorubicin derivatives) quinoline analogs podophyllotoxins analogs taxane analogs camptothecin (CPT) analogs.     

Novel antiepileptic and anticonvulsive therapeutic agents

Epilepsy is a broad-reaching central nervous system condition and the underlying pathology suggests a number of pharmacological pathways that can be targeted for drug therapy. These include ion channel modulation, historically the most investigated therapeutic approach, as well as regulation of excitatory and inhibitory neurotransmission. A broad range of drugs that act at each of these targets has been marketed, and promising new drug candidates are being developed constantly. In addition, new drug candidates with novel mechanisms of action are beginning to emerge. This review covers patent literature with the indication for epilepsy between January 2001 and March 2002, and includes brief overviews and backgrounds on currently used anti-epileptic and anticonvulsive drugs.