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.     

Plectin in the human central nervous system: predominant expression at pia/glia and endothelia/glia interfaces

Major problems with the treatment of osteomyelitis are associated with poor antibiotic distribution at the site of infection due to limited blood circulation to the skeletal tissue. Improved treatment procedures have been used in drug delivery systems that include bioceramics and natural and synthetic polymers. This work reports the development of anionic collagen:hydroxyapatite composite paste for sustained antibiotic release. Antibiotic release by the composite was characterized by two steps. In the first, 15.0+/-4.9% was released in the first 5 h (n = 53) by a normal Fick diffusion mechanism. In the second step, only 16.8+/-2.2% was released after 7 days. In conclusion, hydroxyapatite:anionic collagen composite can be an efficient support for sustained antibiotic release in the treatment of osteomyelitis because most of the antibiotic release may be associated with composite bioresorption, thus permitting antibiotic release throughout the healing process. Hydroxyapatite:anionic collagen paste showed good biocompatibility associated with bone tissue growth with material still being observed after 60 days from the time of implants.     

Bioerodible polymers for ocular drug delivery

Development of ophthalmic drug-delivery systems has always been challenging. The commonly used route for drug delivery to the anterior segment of the eye has been the conjunctival cul-de-sac. Because of drawbacks associated with this route, new approaches have been investigated for delivery of drugs to the eye by means of polymeric delivery systems. Development of controlled drug-release devices has been a major step forward in this respect. Bioerodible polymers have been at the forefront of such systems. They are very important because they eliminate the need for removing the implant after complete drug release. Bioerodible polymers have been divided into three classes based on their mechanism of hydrolysis: Type I--hydrolysis of crosslinked hydrogels; Type II--solubilization by ionization or hydrolysis of linear polymers; and Type III--biodegradation by backbone cleavage. Polymers from all three classes are discussed in detail in this review.     

FDA perspective on peptide formulation and stability issues

Traditionally, peptide drugs are prepared as sterile solutions and administered to patients by daily injection. However, this form of drug delivery causes pain and inconvenience to patients and thus has been poorly accepted. In addition to improving patient compliance, many novel delivery systems have been developed to address the need for prolonged, localized (targeted), or pulsatile drug action. Examples include, but are not limited to oral, nasal, or long-acting controlled release injectable dosage forms; a number of them have been approved by FDA recently. The unique characteristics and the relevant regulatory issues with respect to each type of delivery system are presented.     

Chitosan: a unique polysaccharide for drug delivery

The aim of this review is to give an insight into the many potential applications of chitosan as a pharmaceutical drug carrier. The first part of this review concerns the principal uses of chitosan as an excipient in oral formulations (particularly as a direct tableting agent) and as a vehicle for parenteral drug delivery devices. The use of chitosan to manufacture sustained-release systems deliverable by other routes (nasal, ophthalmic, transdermal, and implantable devices) is discussed in the second part.     

Transport of drugs across porous ion exchange membranes

Porous ion exchange membranes have potential applications for drug delivery systems. Permeability of these membranes can be controlled by environmental factors like pH and ionic strength but also the drug properties have an important role in the permeation process. In this paper the influence of the drug charge, lipophilicity and molecular weight on the diffusional drug flux is demonstrated. The membranes under study were poly(acrylic acid) (PAA) grafted porous poly(vinylidene fluoride) (PVDF) membranes which are cation selective due to the partial ionization of carboxyl groups in grafted PAA chains. At low pH the membrane pores are open and the drugs can diffuse through the membrane quite easily. However, at pH 7 the grafted chains partially block the pores and the diffusional flux of bigger drug molecules (Mw9400) decreases five orders of magnitude and also the flux of smaller molecules is clearly reduced. When the influence of the drug charge on the diffusion of the drugs across the membranes was studied, it turned out that the PAA-PVDF membranes facilitate the transport of cationic drugs and repel anionic ones. The presented mathematical model, based on Donnan drugs equilibrium and measured transport number data, predicted the observed trends reasonably well.     

Proton-dependent multidrug efflux systems

Multidrug efflux systems display the ability to transport a variety of structurally unrelated drugs from a cell and consequently are capable of conferring resistance to a diverse range of chemotherapeutic agents. This review examines multidrug efflux systems which use the proton motive force to drive drug transport. These proteins are likely to operate as multidrug/proton antiporters and have been identified in both prokaryotes and eukaryotes. Such proton-dependent multidrug efflux proteins belong to three distinct families or superfamilies of transport proteins: the major facilitator superfamily (MFS), the small multidrug resistance (SMR) family, and the resistance/ nodulation/cell division (RND) family. The MFS consists of symporters, antiporters, and uniporters with either 12 or 14 transmembrane-spanning segments (TMS), and we show that within the MFS, three separate families include various multidrug/proton antiport proteins. The SMR family consists of proteins with four TMS, and the multidrug efflux proteins within this family are the smallest known secondary transporters. The RND family consists of 12-TMS transport proteins and includes a number of multidrug efflux proteins with particularly broad substrate specificity. In gram-negative bacteria, some multidrug efflux systems require two auxiliary constituents, which might enable drug transport to occur across both membranes of the cell envelope. These auxiliary constituents belong to the membrane fusion protein and the outer membrane factor families, respectively. This review examines in detail each of the characterized proton-linked multidrug efflux systems. The molecular basis of the broad substrate specificity of these transporters is discussed. The surprisingly wide distribution of multidrug efflux systems and their multiplicity in single organisms, with Escherichia coli, for instance, possessing at least nine proton-dependent multidrug efflux systems with overlapping specificities, is examined. We also discuss whether the normal physiological role of the multidrug efflux systems is to protect the cell from toxic compounds or whether they fulfil primary functions unrelated to drug resistance and only efflux multiple drugs fortuitously or opportunistically.     

Development of drug delivery systems for macromolecular drugs

With a rapid progress in biotechnology, a variety of endogenous macromolecular substances have become a novel class of therapeutic agents. This review will focus on the development of delivery systems for macromolecular drugs. Current status and future perspectives in this research field are reviewed mainly based on the results obtained in our laboratory. First of all, we studied pharmacokinetic characteristics of macromolecules in relation to their physicochemical properties such as molecular weight and electric charge. Based on this information, we first developed macromolecular prodrugs as a delivery system for low molecular weight drugs. An antitumor antibiotic, mitomycin C (MMC) were covalently conjugated with dextran and various types of macromolecular prodrug of MMC were developed for tumor targeting. Secondly, delivery systems for protein drugs such as soybean trypsin inhibitor, uricase, and recombinant superoxide dismutase (SOD) were developed. In particular, successful targeting of SOD to the liver, kidney and blood circulation was achieved by chemical modification of the protein drug. Finally, we have been trying to develop delivery systems for nucleic acid drugs involving antisense oligonucleotides and plasmid DNA. Prior to the development of delivery systems, we found that the pharmacokinetics of the nucleic acid drugs are decided by their physicochemical properties as polyanions even if these materials contain genetic information. Several approaches were tested to control the in vivo behavior of the oligonucleotides and plasmid DNA based on the finding. Thus, we have established the strategy for rational design of delivery systems for various types of macromolecular drugs based on the pharmacokinetic considerations. This methodology can be a formidable tool for the development of clinically applicable macromolecular drugs.     

Controlled-release products for the control of the estrus cycle in cattle, sheep, goats, deer, pigs, and horses

This paper describes the estrus cycles of a number of livestock breeds and reviews the controlled-release drug delivery systems that are currently available for the purpose of controlled breeding. The bovine estrus cycle is reviewed in detail, and the estrus cycles of other species are described in a manner that highlights similarities and differences between species. Pertinent formulation and pharmacokinetic information about current drug delivery systems is presented and discussed, and recent advances in this area are also described.     

Application of capillary electrophoresis and related techniques to drug metabolism studies

The use of capillary electrophoresis (CE) for the separation of small organic molecules such as pharmaceutical agents and drug/xenobiotic metabolites has become increasingly popular. This has arisen, at least in part, from the complimentary mode of separation afforded by CE when compared to the more mature technique of HPLC. Other qualities of CE include relative ease of method of development, rapid analysis, and low solvent consumption. The recent introduction of a variety of detector systems (including UV diode array, laser-induced fluorescence, conductivity) and the demonstrated coupling of CE to MS have also aided acceptance of this technology. In the present report, we review the role of CE coupled to various detector systems including a mass spectrometer for the characterization of both in vitro and in vivo derived drug metabolite mixtures. Attributes of CE for this application are demonstrated by discussion of metabolism studies of the neuroleptic agent haloperidol. Various aspects of the development and use of CE and CE-MS for the characterization of haloperidol metabolites, including criteria for selection of parameters such as pH, ionic strength, extent of organic modification, and the use of nonaqueous capillary zone electrophoresis are discussed. We also consider potential limitations of CE and CE-MS for drug metabolism research and describe the introduction of membrane preconcentration-CE (mPC-CE) and mPC-CE-MS as a solution that overcomes the rather poor concentration limits of detection of CE methods without compromising the resolution of analytes or separation efficiency of this technique.     

Inhalation delivery systems with compliance and disease management capabilities

Non-compliance with prescribed medication is a major reason for poor therapeutic outcomes, leading to unnecessary contributions to healthcare costs. Poor technique in self-administration of inhalation therapy is a special type of non-compliance associated with this route of administration. However, pulmonary drug delivery has fundamental advantages for therapy of diseases of the respiratory tract because it is site-directed. The lung is also a promising portal for drug delivery into the systemic circulation. Incorporation of microprocessors into pulmonary drug delivery systems facilitates sophisticated compliance management of chronic diseases such as asthma and diabetes. Microprocessor-assisted systems afford control of patients' administration technique during the therapeutic inhalation event, thus leading to efficient and reproducible regional deposition of the inhaled drug or diagnostic agent. SmartMist is a hand-held asthma disease management device that aids patients to use optimally metered dose inhalers. It also measures pulmonary lung function and provides a long term downloadable electronic record of the therapeutic and diagnostic events. The AERx pulmonary delivery system utilizes similar microprocessor capabilities; however, it employs a novel means of generating aqueous aerosols from unit dose packages, thus providing a broad inhalation technology base for delivery of a wide variety of therapeutic and diagnostic agents into the respiratory tract, and via the lung into the systemic circulation.     

Chitosan and its use as a pharmaceutical excipient

Chitosan has been investigated as an excipient in the pharmaceutical industry, to be used in direct tablet compression, as a tablet disintegrant, for the production of controlled release solid dosage forms or for the improvement of drug dissolution. Chitosan has, compared to traditional excipients, been shown to have superior characteristics and especially flexibility in its use. Furthermore, chitosan has been used for production of controlled release implant systems for delivery of hormones over extended periods of time. Lately, the transmucosal absorption promoting characteristics of chitosan has been exploited especially for nasal and oral delivery of polar drugs to include peptides and proteins and for vaccine delivery. These properties, together with the very safe toxicity profile, makes chitosan an exciting and promising excipient for the pharmaceutical industry for present and future applications.     

Role of serological tests in the diagnosis of immune complex disease in infection of ventriculoatrial shunts for hydrocephalus

BACKGROUND: Transdermal drug delivery systems, a relatively recent development, are well accepted by physicians and patients because of reliability and ease of administration. The patch reservoirs, however, contain large quantities of drug, and the potential for considerable toxicity exists if they are used incorrectly. A case is presented of an apparent suicide attempt that involved the use of nicotine transdermal patches. METHODS: This case report involved a patient seen in the emergency department by one of the authors. Data were obtained from the patient's medical record while maintaining confidentiality. RESULTS: The drug overdose was a potentially serious one. The patient recovered fully after an uneventful hospital course. CONCLUSIONS: Transdermal drug delivery systems now deliver many drugs, several of which are quite potent. Intentional or unintentional misuse of the systems can result in toxicity. The physician and pharmacist should carefully instruct each patient in the appropriate use and handling of transdermal drug delivery systems.     

Danaparoid in the prevention of thromboembolic complications

OBJECTIVE: To review the therapies used to prevent postoperative thromboembolic complications with a focus on the role of danaparoid, a new low-molecular-weight glycosaminoglycan. DATA SOURCES: A MEDLINE search was performed to identify pertinent English-language literature including studies, abstracts, and review articles. Key search terms included danaparoid, heparinoid, lomoparin, heparin, prophylaxis, thrombosis, embolism, thromboembolism, and thromboembolic and postoperative complications. The manufacturer of danaparoid was contracted for additional information related to this compound. STUDY SELECTION AND DATA EXTRACTION: All identified articles were reviewed for possible inclusion in this review. Comparisons primarily focused on data obtained from prospective, randomized, controlled, blind clinical trials. Another important consideration was the use of venography to determine the presence of deep venous thrombosis. DATA SYNTHESIS: Various therapies are available for the prevention of postoperative thromboembolic complications. Effective pharmacologic treatments currently available include adjusted-dose heparin, warfarin, aspirin, dextran, and low-molecular-weight heparins (LMWHs). Until recently, warfarin was considered the drug of choice for thromboprophylaxis in high-risk patients, including patients undergoing orthopedic surgical procedures. Because of their comparable efficacy and greater ease of use, LMWHs are gaining favor over warfarin in this patient population. In well-designed clinical trials involving patients undergoing elective total hip replacement or fractured hip surgery, danaparoid has demonstrated greater efficacy than other active treatments, including warfarin, dextran, aspirin, and heparin plus dihydroergotamine. While studies comparing danaparoid with LMWHs have not yet been published, danaparoid may be more useful in patients with heparin-associated thrombocytopenia. CONCLUSIONS: Danaparoid is an antithrombotic agent with characteristics that distinguish it from heparin and LMWHs. Based on the efficacy and safety data reviewed, danaparoid should be considered one of the drugs of choice for the prevention of thromboembolic complications in patients undergoing orthopedic hip procedures and the drug of choice for the management of any patient with heparin-induced thrombocytopenia who requires anticoagulant therapy.     

Review article: issues in oral administration of locally acting glucocorticosteroids for treatment of inflammatory bowel disease

Inflammatory bowel diseases are treated in some cases by local administration of anti-inflammatory drugs. Local delivery of drugs in the colon following oral administration may lead to improved efficacy/side-effect profiles and may improve patient compliance. This review covers a number of issues important in the design of oral delivery systems of glucocorticosteroids for local therapy of colonic inflammation. The choice of specific glucocorticosteroids is based on the drug's physicochemical and pharmacological properties. The conditions under which an orally administered glucocorticosteroid (or other drug) must be delivered to treat ulcerative colitis are also discussed. These conditions include variations in local pH, transit throughout the gastrointestinal tract, the potential role of gut microflora, and drug dissolution in both the healthy and diseased large intestine. The effective delivery of topically-active glucocorticosteroids in ulcerative colitis and Crohn's colitis patients is complex, but if successful could improve their usefulness.     

Fluid-bed microencapsulation of ascorbic acid

Epidemiological studies suggest the prevalence of asthma is increasing, though some remain sceptical as to the magnitude or indeed the presence of an increase. However, despite improved diagnosis and the availability of the potent drugs now available there remains considerable respiratory morbidity associated with asthma. It is clear from a number of studies that failure to deliver drugs to the lungs when using inhaler devices is a factor contributing to this high level of morbidity. Failure of drug delivery may result from the prescribing of inappropriate devices, failure to use devices appropriately or failure to comply with a treatment regimen. For most of the currently available forms of asthma therapy there are significant advantages to be gained from administering them in aerosol form. The benefits to be derived from administering these drugs as an aerosol include a rapid onset of action for drugs such as beta-agonists and a low incidence of systemic effects from drugs such as beta-agonists and corticosteroids. Over the past 25 years our understanding of the nature of asthma has changed. Though this has been reflected in the emphasis on inhaled corticosteroid therapy in recent guidelines, it has not been reflected in the range of inhaler devices available. Manufacturers continue to place drugs such as corticosteroids in the same devices as short acting beta-agonists even though the requirements for these different drug classes are very different. It is likely that this contributes to suboptimal therapeutic responses with inhaled corticosteroids. However, the variability associated with current delivery systems is relatively small compared with the variability introduced by poor compliance. There is no work currently available to indicate how the use of cheap disposable devises which do not incorporate any form of positive feedback influence compliance with inhaled steroids. Optimising aerosolised drug delivery in childhood involves consideration of the class of drugs, the particular drug within a class but more importantly, the age and abilities of the child. Devices must be selected to suit a particular child's needs and abilities. Devices utilising tidal breathing are generally used such as spacing chambers or, less commonly these days, nebulisers. A screaming or struggling child, or failure to use a closely fitting mask, reduces drug delivery to the lungs enormously. Failure to respond to inhaled therapy in early childhood may be attributable to failure of drug delivery. Drug delivery in early childhood using current devices remains more an art than a science.     

Uptake and intracellular trafficking of asialoglycoprotein-polylysine-DNA complexes in isolated rat hepatocytes

Receptor-mediated gene delivery has been reported for a number of different receptor systems although the intracellular fate of such systems has not been systematically investigated. In this study, we have determined the fate of a commonly used asialoglycoprotein (ASGP)-dependent DNA delivery system in isolated rat hepatocytes. ASPG-polylysine (PLL296) was ionically complexed with pSV-CAT DNA at a molar ratio of 10:1. The resulting complex inhibited 125I-ASGP binding to rat hepatocytes but ASGP only partially inhibited the binding of complex. The ASGP-independent binding was due to the interaction of the PLL component of the complex with plasma membranes and could be minimised by replacing PLL296 with PLL19. Following internalisation, ASGP was cleaved from the complex and translocated to the lysosomes where it was degraded. The DNA, however, remained in an intracellular compartment that cosedimented with plasma membranes in Percoll density gradients. This study shows first that hepatocytes do not process DNA internalised as ASGP complexes in a manner similar to ASGP itself, and second that the differential sorting of the two cleaved molecules leads to a rapid intracellular compartmentalisation of the DNA. Controlled release from this compartment may be a means for prolonged gene expression in gene therapy protocols.