Recent trends in drug delivery systems: liposomal drug delivery system--preparation and characterisation

The strong relation between increased left ventricular mass and cardiovascular events makes accurate measurement of left ventricular mass a high priority, especially in patients with hypertension. M-mode echocardiography is used most widely to measure left ventricular mass because of its wide availability, moderate expense, anatomic and prognostic validation and lack of radiation or claustrophobia; however, this technique is expertise-dependent and may give erroneous results in distorted ventricles. Two-dimensional and especially three-dimensional echocardiography increase the precision with which left ventricular mass is measured but they are more time-consuming and difficult to perform on a large scale. Magnetic resonance imaging provides highly accurate left ventricular mass measurements and permits tissue imaging but its use is limited by expensive, fixed facilities and claustrophobia. Cine computed X-ray tomography also measures left ventricular mass accurately and permits perfusion assessment with contrast injection but it involves radiation and the use of fixed facilities of limited availability. Understanding the strengths and limitations of available techniques can facilitate selection of the most appropriate method to measure left ventricular mass in a particular setting.     

Swelling of and drug release from monoglyceride-based drug delivery systems

Sudden sensorineural hearing loss (SNHL) is a well-recognized phenomenon that is attributed to a variety of etiologies. Sudden SNHL after cardiopulmonary bypass surgery has been well reported and is thought to be due to microemboli. However, a review of the English literature revealed only 15 cases of SNHL after general anesthesia for nonotologic surgery. Several etiologies for this loss have been suggested, but no proven pathogenesis is yet available. This report adds to the literature three additional cases of sudden SNHL after general anesthesia for nonotologic surgery. The literature is reviewed and proposed mechanisms of injury are discussed.     

Recent developments of collagen-based materials for medical applications and drug delivery systems

In this review, an attempt was made to summarize some of the recent developments in the application of collagen as a biomaterial and in drug delivery systems. The main applications covered include: collagen for burn/wound cover dressings; osteogenic and bone filling materials; antithrombogenic surfaces; and immobilization of therapeutic enzymes. Recently, collagen used as a carrier for drug delivery has attracted many researchers throughout the world. The use of collagen for various drug delivery systems has also been reviewed in this article. Collagen-based drug delivery systems include: injectable microspheres based on gelatin (degraded form of collagen); implantable collagen-synthetic polymer hydrogels; interpenetrating networks of collagen; and synthetic polymers collagen membranes for ophthalmic delivery. Recent efforts to use collagen-liposomal composites for controlled drug delivery, as well as collagen as controlling membranes for transdermal delivery, were also reviewed. In this review, the main emphasis was on the work done in our laboratory.     

Testing of drug delivery systems for use in the treatment of narcotic addiction

The evaluation of the drug release characteristic of four naltrexone delivery systems has been carried out together with the development of analytical techniques and an investigation of the metabolic profile of naltrexone. Pharmacologic evaluation of the four delivery systems in the mouse indicated significant analgesic antagonism for a period of from 16-22 days. Further evaluation of one of these systems by measurement of the rate of excretion of radioactivity after administration of radiolabelled naltrexone in the delivery system confirmed that significant release occurs for a time period of about 15 days. Electron capture gas-liquid chromatographic assays for naltrexone and naloxone in plasma or urine have been developed that yield linear calibration curves and are sensitive to one ng/ml. Studies on naltrexone disposition indicate that (a) binding to plasma proteins in several species varies from 20-26 per cent, (b) distribution of drug from blood is extremely rapid and extensive, (c) beta-naltrexol is a major metabolite of naltrexone in man, monkey and guinea pig among six species studied, whereas alpha-naltrexol is a minor metabolite in the monkey and guinea pig only, and (d) metabolic reduction of naltrexone occurs in the 100,000 x g supernatant of guinea pig liver. Pharmacokinetic studies of naltrexone in the dog and monkey indicate that the drug is rapidly distributed and eliminated, has a very large apparent volume of distribution and a total body clearance greater than the rate of liver blood flow.     

Biologically erodable microspheres as potential oral drug delivery systems

Biologically adhesive delivery systems offer important advantages over conventional drug delivery systems. Here we show that engineered polymer microspheres made of biologically erodable polymers, which display strong adhesive interactions with gastrointestinal mucus and cellular linings, can traverse both the mucosal absorptive epithelium and the follicle-associated epithelium covering the lymphoid tissue of Peyer's patches. The polymers maintain contact with intestinal epithelium for extended periods of time and actually penetrate it, through and between cells. Thus, once loaded with compounds of pharmacological interest, the microspheres could be developed as delivery systems to transfer biologically active molecules to the circulation. We show that these microspheres increase the absorption of three model substances of widely different molecular size: dicumarol, insulin and plasmid DNA.     

Development of drugs to overcome drug resistance--basic approaches

P-glycoprotein plays a key role in the mechanisms of multidrug resistance in experimental tumors as well as in clinical tumors both in acquired and intrinsic-type resistance. Thus the therapeutic approaches targeting P-glycoprotein would provide benefits in eradication of drug-resistant tumor cells, although some potential problems concerning side effects still remain to be studied. Practical approaches to overcoming multidrug resistance by targeting the P-glycoprotein would be (1) to use antibodies against P-glycoprotein; and (2) to use agents, including calcium channel blocker-related agents and membrane-modifying agents, that interact with P-glycoprotein. These therapeutic approaches will be discussed in the symposium.     

Importance of chronopharmacokinetics in design and evaluation of transdermal drug delivery systems

BACKGROUND: Sodium-potassium-adenosinetriphosphatase (Na,K-ATPase) is the primary membrane enzyme responsible for the reabsorption of sodium ions in the kidney. It is known that in the nephron the major subunit isoforms of Na,K-ATPase are alpha 1 and beta 1. Previous reports on the presence of alpha 2 and alpha 3 isoforms in the kidney were mixed and controversial. METHODS: Techniques of ultrathin cryosectioning and immunoelectron microscopy were used to study the distribution of alpha subunit isoforms (alpha 1, alpha 2, alpha 3) and beta subunit (beta 1 isoform) of Na,K-ATPase in renal tubular cells. Western blot analysis was used to show the presence of the alpha 3 isoform in the extract of kidney mitochondria. RESULTS: We were able to confirm the previous finding that the alpha 1 isoform and the beta 1 isoform were the preponderant isoforms of the alpha and beta subunits of Na,K-ATPase in the basolateral membrane. In addition, we unexpectedly found the presence of the alpha 3 isoform in the mitochondria of rat renal tubular cells. The alpha 2 and alpha 3 isoforms were not observed in either the apical or basolateral membrane. CONCLUSIONS: Both immunoelectron microscopy and Western blot analysis of the rat kidney mitochondria confirm the presence of the alpha 3 isoform of Na,K-ATPase in the rat kidney mitochondria. The function of this enzyme in the mitochondria is not clear at this time.     

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.     

A novel method for efficient drug delivery

Local delivery of anti-thrombotic and anti-restenotic drugs is desired to achieve high concentrations of agents which may be rapidly degraded systemically or which exhibit very short half-lives in vivo. In this article, the operating characteristics of a novel local drug delivery method are described and its effectiveness demonstrated computationally and experimentally. Computational models used a finite volume method to determine the concentration field. Optical dye density measurements of Evans blue in saline were performed in an in vitro steady flow system. Modeling parameters were kept in the physiologic range. Experimental flow visualization studies demonstrated high concentrations of infusate near the vessel wall. Computational studies predicted high, clinically significant drug concentrations along the wall downstream of the infusion device. When the radial infusion velocity is large (infusion flow rate, Qinf>0.5% of the main flow rate, Q), the wall concentration of the infused drug remains high, e.g., levels are greater than 80% of the infusate concentration 5 cm downstream of the infusion device. At lower infusion rates (Qinf<0.001Q), the drug concentration at the wall decreases exponentially with axial distance to less than 25% of the infusate concentration 5 cm downstream of the infusion device, although therapeutic drug levels are still readily maintained. The near wall drug concentration is a function of flow conditions, infusion rate, and the drug diffusivity. Good agreement was obtained between computational and experimental concentration measurements. Flow simulation and experimental results indicate that the technique can effectively sustain high local drug concentrations for inhibition of thrombosis and vascular lesion formation.     

Large porous particles for pulmonary drug delivery

A new type of inhalation aerosol, characterized by particles of small mass density and large size, permitted the highly efficient delivery of inhaled therapeutics into the systemic circulation. Particles with mass densities less than 0.4 gram per cubic centimeter and mean diameters exceeding 5 micrometers were inspired deep into the lungs and escaped the lungs' natural clearance mechanisms until the inhaled particles delivered their therapeutic payload. Inhalation of large porous insulin particles resulted in elevated systemic levels of insulin and suppressed systemic glucose levels for 96 hours, whereas small nonporous insulin particles had this effect for only 4 hours. High systemic bioavailability of testosterone was also achieved by inhalation delivery of porous particles with a mean diameter (20 micrometers) approximately 10 times that of conventional inhaled therapeutic particles.     

Novel delivery systems for coagulation proteins

Interferon-alpha (IFN-alpha) is an important molecule in the antiviral response, but cells from HIV-1-infected individuals show a reduced ability to secrete IFN-alpha. We investigated an association between an imbalance of type 1/type2 cytokines and the production of IFN-alpha in HIV-1 infection. We used whole blood culture to study the cytokine production profile, interferon-gamma (IFN-gamma) and interleukin-4 (IL-4), in response to HIV-1 antigens and to study the Sendai Virus and HSV-1-induced-production of IFN-alpha in seven HIV-1-infected patients. An impaired synthesis of IFN-alpha was obtained in patients with a predominant IL-4 production (IL-4 > IFN-gamma), and we found a positive correlation between the ex vivo production of IFN-alpha and the IFN-gamma/IL-4 ratio but not with the HIV RNA copy number in plasma. We investigated the role of T-cell-derived cytokines in the in vitro production of IFN-alpha by PBMC from eight healthy donors, activated with Sendai Virus or HSV-1. Whereas type 2 cytokines (IL-4, IL-13) inhibited virus-induced IFN-alpha synthesis, on the contrary, type 1 cytokines (IL-2, IFN-gamma) enhanced it. A disarray in the T-cell-derived cytokine response may play a role in the defect of IFN-alpha production in HIV-1-infected individuals. Further investigations are needed to explore this hypothesis.     

Novel systems for controlled delivery of macromolecules

Gene therapy promises new treatments for human disease by alterations in the DNA content of tissues. Methods for efficient and stable introduction of genes into target cells in the body are critically important in this effort. Researchers and physicians now have many years of experience with synthetic polymers for controlled drug delivery; many of these polymers can also be used to deliver macromolecules at controlled rates to tissues. This article reviews the use of polymers in controlled protein delivery and suggests ways that polymer delivery systems may be useful in the delivery of gene transfer agents.     

Intra-hepatic arterial drug delivery

BACKGROUND AND AIM: The recent introduction of new measurement technology (using ion specific electrodes) makes intraoperative evaluation of blood ionized magnesium (Mg2+, or iMg)--the bioactive fraction of circulation magnesium--possible. The goals of this study were: (1) to examine the longitudinal pattern(s) of change in blood iMg during cardiopulmonary bypass (CPB); and (2) to determine the relationship of iMg to Ca2+ (iCa), K, pH, Na, and hematocrit (Hct) during CPB. METHODS: Blood was collected serially before, during, and after CPB on 30 patients undergoing elective coronary artery bypass graft procedures and the iMg was measured with an AVL Scientific Corp., model 988-4 instrument. RESULTS: Overall, 73% of iMg results were abnormally low, 50% during CPB. Some cases had both hypo- and hyperionized magnesemic episodes. There were low iCa during CPB in 97% of cases. Using Spearman's rank order correlations and p < 0.05, iMg and K were directly correlated before, during, and after bypass, suggesting their parallel movement between tissue and blood. iMg and iCa were directly correlated before, and inversely correlated after, CPB, but unassociated during bypass. iMg and Na were inversely correlated after bypass in all cases. iMg was inversely correlated to pH and positively correlated to Hct during CPB only, and only in patients with concurrent association of iMg and iCa. CONCLUSIONS: Blood iMg depletion occurs frequently in CPB patients. iMg changes are not readily predictable. The association of intraoperative iMg depletion with postsurgical atrial fibrillation--reported to have a hypomagnesemic connection- should be investigated.     

In vivo target-specific delivery of macromolecular agents with MR-guided focused ultrasound

Pelvic cartilage of chick embryo was used to demonstrate that presence of boron in culture medium decreases synthesis of proteoglycans, collagen and total proteins but on the other hand increases the release of these macromolecules. However, when glucose concentration in culture medium is brought to 22mM, the synthesis decrease is no longer observed, whereas release increase persists. Proteins released into the culture medium included heat shock proteins (70 hsp) and tumor necrosis factor alpha (TNF alpha). The amount of phosphorylated proteins was enhanced in presence of boron while endoprotease activity in cartilage and in culture medium was significantly augmented. The in vitro effects of boric acid may explain its in vivo effect on wound healing.