Scintigraphic detection of infection and inflammation: new developments with special emphasis on receptor interaction

Various conventional radiopharmaceuticals are currently available for scintigraphic imaging of infection and inflammation. Although a wide variety of infectious and inflammatory foci can be detected with these agents, several disadvantages limit their application. These limitations have stimulated the search for new radiopharmaceuticals. In the past decade a new class of radiopharmaceuticals has emerged: radiolabelled receptor-specific small proteins and peptides. These proteins and peptides are naturally occurring inflammatory mediators which specifically bind to receptors abundantly present in the area of inflammation. In addition, owing to their small size, they rapidly clear from all non-target tissues. This paper provides an overview of these newly developed agents, focussing on imaging characteristics and in vivo uptake mechanisms.     

Oral treatment options for onychomycosis

The author discusses the new oral antifungal agents for the treatment of onychomycosis. The history, mechanisms of action, efficacies, dosing, safety profiles, and costs of itraconazole, terbinafine, and fluconazole are reviewed. The author emphasizes that use of these effective antifungals represents an important paradigm shift for podiatric physicians away from the palliative therapy of nail debridement to a potentially curative treatment.     

The roles of the human major histocompatibility complex and human papillomavirus infection in cervical intraepithelial neoplasia and cervical cancer

Germ theory and pure culture methods have provided invaluable information concerning the role of bacteria in diseases resulting from a single organism which bypasses a host's defenses. However, they do not provide sufficient information concerning the synergisms which allow the members of biofilm communities to proliferate more effectively as communities rather than as individuals. The mechanisms of these synergies are potential targets for antimicrobial agents as well as potential mechanisms of resistance to antimicrobial agents. Understanding community-level phenomena in oral biology requires the culture, identification, and classification of functional plaque communities as well as new methods of identifying and quantifying communal relationships. Cultured biofilm communities also provide ideal models of bacterial self-organization in which information related to adaptive strategies arises not only through the recombination of genes within genomes, but also through the recombination of organisms within communities.     

Antifungal resistance trends towards the year 2000. Implications for therapy and new approaches

Medical advances have led to increased numbers of immunocompromised patients living longer. Coinciding with this increase in the immunocompromised patient population is an increase in the number of clinically significant fungal infections. Unfortunately, widespread use of the limited numbers of antifungal agents to treat these infections has led to the development of drug resistance. Thus, in an attempt to sort out the mechanisms of resistance for each of the systemically useful antifungal agents, a comprehensive review of the literature has been carried out. The most common mechanisms for the development of resistance involve changes in the enzymatic pathways which serve as the drug targets. For instance, changes in enzymes responsible for the biosynthesis of ergosterol, the target of azole activity, lead to azole resistance. Another common mechanism used by fungi to avoid drug toxicity includes reduced intracellular accumulation of the drug through both decreased permeability and energy-dependent efflux pumps. Using our current understanding of the mechanisms of drug resistance as a template, several strategies to overcome resistance have been identified. These include improvement of host immune function, the use of adjuvant surgery, the development of new drug delivery systems for currently available drugs and the development of new classes of antifungal agents. Also, clinical trials to establish appropriate drug doses and duration of therapy are needed, as well as the benefits of antifungal prophylaxis explored and the use of combination therapies entertained. The war against drug resistant fungi has been identified as we approach the year 2000. With careful and cogent investigations, we do have the tools to fight back against these opportunists. Of all the strategies reviewed, however, in our opinion, the development of new antifungal drugs is likely to have the most significant future impact on our management of drug resistance in fungal infections.     

A therapeutic taxonomy of treatments for erectile dysfunction: an evolutionary imperative

AIM OF THE STUDY: A functional classification of treatments for erectile dysfunction is important but none exists at present. Advances in the understanding of the mechanisms of drug action and of the mechanisms of penile erection suggest that there is now a rational basis for a therapeutic classification, with the expectation that a logical diagnostic classification will follow. METHODS: The currently available treatments for erectile function and the known relevant basic science were reviewed and assessed. From this, and analysis of classification systems in other fields, a classification was proposed and evaluated with respect to existing treatments. RESULTS: The treatments for erectile dysfunction were classified into five major classes by their mode of action: (I) Central Initiators, (II) Peripheral Initiators, (III) Central Conditioners, (IV) Peripheral Conditioners and (V) Other. Drugs in these classes are further subdivided by the routes of administration and the mechanisms of specificity. CONCLUSIONS: It is possible to analyze all known treatments using this classification. The principles of this scheme should be sufficiently clear as to enable knowledgeable specialists to arrive at similar conclusions about a drug. The classification proposed is general enough such that most new drugs should fall within a class. However, it should be modified if necessary, if new therapeutic agents can not be appropriately classified. It is our conclusion that with such endeavours the specialty itself and national regulatory bodies will find it easier to define and control how to apply new drugs, how to evaluate new drugs, and how to establish reasonable equivalences among agents and in whom these drugs and devices should be used.     

Rapid overdrive pacing of refractory tachyarrhythmias in patients after open-heart surgery

The efficacy of rapid ventricular pacemaker overdrive in the treatment of supraventricular and ventricular tachyarrhythmias is presented as a new approach to the management of these rhythm disorders inpatients after cardiac surgery. This mode of therapy is exemplified in the control of heart rate and return of normal sinus rhythm in patients with both types of tachyarrhythmias refractory to conventional antiarrhythmic agents. In addition, the pathogenesis and mechanisms of pacemaker overdrive in termination these rhythm disturbances are delineated.     

Radiolabelled human immunoglobulins

Radiolabelled human immunoglobulins have been available for 5 years. Within that time there have been many publications on the use of these agents labelled with both technetium-99m (99Tcm) and indium-111 (111In). The results of these data appear contradictory and only now do we understand both some of the mechanisms of radiolabelled immunoglobulins and some of their limitations. While 111In-polyclonal immunoglobulin seems to have a wide range of clinical applications in infection and inflammation, the more readily available 99Tcm-labelled product is best suited to the localization of peripheral bone and joint disease. The ease of producing these agents from commercially available immunoglobulins will ensure continued interest and research into these new tracers.     

New drugs of 1997

OBJECTIVE: To provide information regarding the most important properties of the new therapeutic agents marketed in 1997. DATA SOURCES: Published studies, drug information reference sources, and product labeling. DATA SYNTHESIS: A record-setting number of 45 new therapeutic agents were marketed in 1997. The indications and information on dosage and administration for each new agent are reviewed, as are the most important pharmacokinetic properties, adverse events, drug interactions, and other precautions. Practical considerations for the use of the new agents are also discussed. Where possible, the properties of the new drugs are compared with those of older drugs marketed for the same indications. CONCLUSION: A number of the new therapeutic agents marketed in 1997 have important advantages over older medications. An understanding of the properties of these agents is important for the pharmacist to effectively counsel patients about their use and to serve as a valuable source of information for other health professionals regarding these drugs.     

Recent advances in chemoprevention of cancer

Chemoprevention is the use of pharmacologic or natural agents that inhibit the development of invasive cancer either by blocking the DNA damage that initiates carcinogenesis or by arresting or reversing the progression of premalignant cells in which such damage has already occurred. Recent advances in our understanding of the mechanisms of carcinogenesis have led to the synthesis of new drugs that can inhibit tumor development in experimental animals by selective action on specific molecular targets, such as the estrogen, androgen, and retinoid receptors or inducible cyclooxygenase. Several of these agents (including tamoxifen, 13-cis-retinoic acid, retinyl palmitate, and an acyclic retinoid) are clinically effective in preventing the development of cancer, particularly in patients who are at high risk for developing second primary tumors after surgical removal of the initial tumor.     

Clinical applications of transpulmonary contrast echocardiography

BACKGROUND: The recent development of new fluorocarbon-based echocardiographic contrast agents that are capable of opacification of the left-sided cardiac chambers after intravenous injection is a major new advance in diagnostic cardiac imaging. METHODS AND RESULTS: This is a review article focusing on these novel contrast agents, new echocardiographic imaging techniques to optimize their efficacy, and their clinical applications. Specific clinical applications of these agents are (1) enhancement of endocardial border definition to improve assessment of regional and global left ventricular function, (2) myocardial perfusion imaging by intravenous contrast echocardiography, (3) augmentation of spectral and color flow Doppler images, and (4) tissue-specific targeting of microbubbles for delivery of therapeutic agents. CONCLUSIONS: New intravenous contrast agents offer the possibility to assess myocardial perfusion echocardiographically. It is also possible to use these agents for delivery of therapeutic agents, including gene therapy.     

低碱环境铜硫分离研究进展

介绍了铜硫分离过程的理论研究进展．归纳和概括了对黄铜矿有较强选择性的传统捕收剂，详细阐述低碱环境中能够实现铜硫分离的捕收剂研究进展，对比了新型捕收剂与传统药剂的分子结构，并分析和推断其作用机理．阐述了在低碱环境中实现铜硫有效分离的抑制剂研究进展．最后对铜硫分离今后的发展进行一些展望．     

Cell biological markers of drug resistance in ovarian carcinoma

The aim of the study is to review the mechanisms of resistance to four classes of drugs that are widely used in ovarian carcinoma: platinum (cisplatin/carboplatin) compounds, classical alkylating agents (cyclophosphamide/melphalan), natural drugs (doxorubicin), and "new drugs" (taxol and taxotere). Both platinum and classical alkylating agents mediate their cytotoxicity by the formation of drug-DNA adducts, resulting in DNA damage. Therefore, drug resistance mechanisms are (in part) comparable. In ovarian carcinoma cell lines increased repair of DNA damage and increased detoxification by binding of drugs to glutathione, possibly catalyzed by glutathione S-transferases, have been identified as the most prominent resistance mechanisms to these drugs. Studies on the role of DNA repair mechanisms and glutathione in human ovarian carcinoma are hampered by the complexity of enzyme systems involved in DNA repair and intratumor heterogeneity for glutathione. Resistance to doxorubicin appears to be mediated by enhanced efflux from the cell by increased expression of membrane glycoproteins acting as a drug efflux pump, such as P-glycoprotein. Resistance to doxorubicin can also be due to quantitative and/or qualitative changes in the nuclear target of doxorubicin, topisomerase (Topo) II. Finally, resistance to taxol may be mediated by enhanced expression of P-glycoprotein, while presumed other mechanisms such as alterations in tubulin structure, the cellular "target" of taxol, and changes in polymerization of tubulin are still largely unresolved. Several ways to modulate the reviewed resistance mechanisms are also described. In conclusion, this review shows that many cell biological factors may be involved in drug resistance. The relevance of the identification of most of these factors in ovarian carcinoma patients however remains to be established.     

Depressive symptoms associated with gonadotropin-releasing hormone agonists

The gonadotropin-releasing hormone (GnRH) agonists are a relatively new class of drugs that are potentially effective in treating disorders that are aggravated either by estrogen or testosterone. GnRH agonists are effective in the treatment of endometriosis, as well as other disorders, such as advanced prostrate cancer, precocious puberty and uterine leiomyomata. While the GnRH agonists reduce the extent of the endometrial lesions and the occurrence of pelvic pain associated with endometriosis, these agents are associated with physical and psychiatric side effects. The adverse effects of these agents are consistent with the physiological effects of ovarian suppression, such as vasomotor instability, vaginal dryness, and headaches. Preliminary results of a prospective, double-blind placebo-controlled study and an open label trial indicates that depressive mood symptoms increase in women treated with GnRH agonist therapy for endometriosis. Additional evidence suggest that sertraline effectively manages depressive mood symptoms associated with GnRH agonist therapy. The reason for the decline in mood on GnRH agonists is postulated to be associated with the decline in estrogen levels. Effective treatment strategies for depressive mood symptoms in women on GnRH agonists therapy may offer insight into the mechanisms of action of estrogen on mood.     

Amino acid variation in the GyrA subunit of bacteria potentially associated with natural resistance to fluoroquinolone antibiotics

In studies of genetic diversity in natural microbial populations, we have analyzed nucleotide sequences in the quinolone resistance-determining region of the bacterial gyrA gene in ciprofloxacin-resistant and nonselected soil bacteria obtained from the environment. It is apparent that this sequence is highly variable, and resistance to fluoroquinolone antibiotics occurring in environmental populations of bacteria is due at least in part to natural sequence variation in this domain. We suggest that the development of new antimicrobial agents, including completely synthetic antimicrobials such as the fluoroquinolones, should incorporate the analysis of resistance mechanisms among microbes in natural environments; these studies could predict potential mechanisms of resistance to be encountered in subsequent clinical use of the agents and would guide chemical modification designed to evade resistance development.     

Antiseptics and disinfectants: activity, action, and resistance

Antiseptics and disinfectants are extensively used in hospitals and other health care settings for a variety of topical and hard-surface applications. A wide variety of active chemical agents (biocides) are found in these products, many of which have been used for hundreds of years, including alcohols, phenols, iodine, and chlorine. Most of these active agents demonstrate broad-spectrum antimicrobial activity; however, little is known about the mode of action of these agents in comparison to antibiotics. This review considers what is known about the mode of action and spectrum of activity of antiseptics and disinfectants. The widespread use of these products has prompted some speculation on the development of microbial resistance, in particular whether antibiotic resistance is induced by antiseptics or disinfectants. Known mechanisms of microbial resistance (both intrinsic and acquired) to biocides are reviewed, with emphasis on the clinical implications of these reports.     

Antimicrobial resistance: implications for the clinician

Antimicrobial resistance has become an issue of global proportion, and this dilemma has greatly affected the intensive care unit (ICU) setting. Increased antimicrobial use and other selective pressures have created an environment in the ICU that is a testing ground for survival of microorganisms. By various mechanisms, gram-positive cocci and gram-negative bacilli are becoming more resistant to our current armamentarium of antimicrobials. Strategies to improve the current situation of reduced microbial susceptibility include the following: continued and specific surveillance in ICUs, antimicrobial protocols, continued isolation precautions and appropriate handwashing, increased education at all levels, increased use of immunotherapies, better use of our current antimicrobial agents, and increased research in finding new and innovative antimicrobial agents while curtailing the marketing ploys that promote excessive and inappropriate use of these valuable medications.     

Angiographic methods to assess human coronary angiogenesis

It is unclear how agents designed to promote angiogenesis in the human heart affect the arteriographic appearance of the collateral circulation. Possible changes in collateral vessels include new collateral vessels arising from epicardial arteries, new branches emanating from existing collateral vessels, wider or longer collateral vessels, and higher dye transit rates that result in improved recipient vessel filling. Given the multiple mechanisms by which these new agents may improve myocardial perfusion, a rigorous, systematic, and comprehensive analysis of coronary arteriograms is required to discern the true mechanism of benefit. The method of analysis must account for potential changes in collateral blood flow, number, branching pattern, and length as well as changes in recipient vessel filling. The ability to detect differences between intricate networks of vessels in an angiographic study is dependent on maintaining consistency in cinefilming as well as the core laboratory methods between time points. In this report, we describe the methodology our angiographic core laboratory has found to be most effective to evaluate these very complex angiograms and attempt to capture all the possible modalities of angiogenesis.     

Long-term changes of ionotropic glutamate and GABA receptors after unilateral permanent focal cerebral ischemia in the mouse brain

The mechanisms by which chemotherapeutic agents kill neoplastic cells have been controversial. Recently, however, accumulated evidence has suggested that these agents exert their cytotoxic effects mainly by inducing apoptosis in tumor cells. This article reviews the findings of recent studies on the mechanisms by which chemotherapeutic agents induce apoptosis and their implications in cancer chemotherapy.