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Integrated delivery systems focus on service delivery after capitation efforts stall. Integrated delivery systems are going through changes that are focusing the provider organizations more on delivering care than managing risk, says Dean C. Coddington, one of the leading researchers into capitated organizations and a senior consultant with McManis Consulting in Denver.
The diuretic amiloride has been reported to inhibit both Na+-H+ antiport and the urokinase-type plasminogen activator. As a consequence of these inhibitions, neovascularization may also be inhibited. We hypothesized that if amiloride could be effectively delivered in a site-specific manner, a system might be developed that could inhibit localized angiogenesis. In order to evaluate this possibility we conducted a study that compared two different controlled-release systems into which amiloride had been incorporated. The effectiveness of amiloride release from each delivery system was determined by quantitating angiogenic patterns in a chick chorioallantoic membrane (CAM) system using a fractal analysis software program. The two delivery systems compared were sucrose acetate isobutyrate (SAIB) and calcium alginate. Initial HPLC laboratory tests confirmed that amiloride could be released from both SAIB and calcium alginate in vitro in a sustained manner for 72 h. The CAM studies confirmed that neither SAIB nor calcium alginate alone promoted or inhibited angiogenesis when compared to nontreated controls. The release of amiloride from each delivery vehicle resulted in a significant (P < 0.05) inhibition of angiogenesis following both 24 and 48 h of release compared to controls. There was no difference in inhibition of angiogenesis, however, when comparing SAIB + amiloride treated CAMs with calcium alginate + amiloride treated CAMs. These data suggest that both SAIB and calcium alginate may be useful delivery vehicles for the localized application of amiloride to control angiogenesis. Such a system could potentially control tumor angiogenesis without systemic effects.
In the present paper a new methodological setup to objectify the parameters adhesiveness and adhesive strengths of Transdermal Delivery Systems is presented. The setup includes 6 steps: Evaluation of skin type, application of the patch by a pneumatic device, evaluation of detached area of the patch by planimetric means, assessment of the adhesive strength by a patch removal unit, evaluation of reddening of the skin, and examination for water uptake of the skin layers by high resolution ultrasound. Each step is described individually. Further problems arising from studies performed with this methodological setup concerning possible adhesive-drug interactions as well as uncorrelated drug behavior to nondetached area of the patch with regard to the pharmacokinetic profile are discussed.
The history of pharmaceuticals has reflected a concern with the development of new chemical entities. Only recently has the importance of dosage form design been recognized as a vital component of effective therapy. Not only has the time and expense involved in the research of the new molecules escalated dramatically, but it has been discovered that many of these products might be improved through incorporation in rate-controlled dosage forms. Conventional formulations have provided vehicles with which to introduce agents into the body. New therapeutic systems offer great versatility since they permit localized treatment of specific tissues, sophisticated methods of animal experimentation, and controlled-release methods for systemic delivery. These new dosage forms are diverse, precise, and adaptable in many therapeutic situations. A membrane-controlled gastro-intestinal therapeutic (GIT) system resembling a conventional tablet in external appearance has recently been developed. This system is designed for the constant, controlled release over a period of 10 to 12 hours of drug in solution and uses osmotic activity as the source of energy. The GIT system, as used for 'Osmosin' (sodium indomethacin trihydrate), differs from conventional sustained-release and other controlled-release dosage forms in that the rate of release is not dependent upon pH to release the medication and is designed, therefore, to overcome the problems associated with unpredictable release patterns.
Chemical delivery systems (CDSs) based on the redox conversion of a lipophilic dihydropyridine to an ionic, lipid-insoluble pyridinium salt have been developed to improve the access of therapeutic agents to the central nervous system. A dihydropyridinium-type CDS or a redox analog of the drug is sufficiently lipophilic to enter the brain by passive transport, then undergoes an enzymatic oxidation to an ionic pyridinium compound, which promotes retention in the CNS. At the same time, peripheral elimination of the entity is accelerated due to facile conversion of the CDS in the body. This review discusses chemical, physicochemical, biochemical, and biological aspects in relation to the principles and practical implementation of the redox brain-targeting approach to various classes of drugs. Representative examples to the brain-enhanced delivery of neurotransmitters, steroids, anticonvulsants, antibiotics, antiviral, anticancer and antidementia agents, and neuropeptides and their analogs are presented in detail. In vivo and in vitro studies and preliminary clinical data of several novel derivatives have been promising, which could lead to a practical use of the redox CDSs after proper pharmaceutical development. The investigations accentuate the need for considering physicochemical, metabolic, and pharmacokinetic properties in designing of carrier systems that are able to target drugs into the central nervous system.
The improvement of non-viral-based gene delivery systems is of prime importance for the future of gene and antisense therapies. We have previously described a peptide-based gene delivery system, MPG, derived from the fusion peptide domain of HIV-1 gp41 protein and the nuclear localisation sequence (NLS) of SV40 large T antigen. MPG forms stable non-covalent complexes with nucleic acids and improves their delivery. In the present work, we have investigated the mechanism through which MPG promotes gene delivery. We demonstrate that cell entry is independent of the endosomal pathway and that the NLS of MPG is involved in both electrostatic interactions with DNA and nuclear targeting. MPG/DNA particles interact with the nuclear import machinery, however, a mutation which affects the NLS of MPG disrupts these interactions and prevents nuclear delivery of DNA. Nevertheless, we show that this mutation yields a variant of MPG which is a powerful tool for delivery of siRNA into mammalian cells, enabling rapid release of the siRNA into the cytoplasm and promoting robust down-regulation of target mRNA. Taken together, these results support the potential of MPG-like peptides for therapeutic applications and suggest that specific variations in the sequence may yield carriers with distinct targeting features.
We demonstrate transport across, intracellular accumulation and bioreductive activation of a conformationally constrained, anticancer drug delivery system (the CH(3)-TDDS) using Caco-2 cell monolayers (CCMs) as an in vitro model of the human intestinal mucosa. Reverse-phase High Performance Liquid Chromatography (HPLC) coupled with UV detection was used to detect CH(3)-TDDS, the bioreduction product (lactone) and the released drug (melphalan methyl ester; MME). Upon incubation of the CH(3)-TDDS with the apical (AP) surface of 21-day-old CCM, we observed rapid decrease in the AP concentration of the CH(3)-TDDS (60%/hr) as a result of cellular uptake. Rapid intracellular accumulation of the CH(3)-TDDS was followed by bioreductive activation to deplete the cellular levels of CH(3)-TDDS. The drug part (MME) and lactone, as well as CH(3)-TDDS, were detected in the basolateral (BL) chamber. Intracellular Caco-2 levels of TDDS and lactone were also detectable. Bioreductive activation of the CH(3)-TDDS was additionally confirmed by formation of lactone after incubation of the CH(3)-TDDS in the presence of freshly prepared Caco-2 cell homogenates. During transport studies of melphalan or MME alone (as control), the intact drug was not detected in the intracellular compartment or in the BL chamber. These observations demonstrate that CH(3)-TDDS has potential for improving intestinal delivery of MME. TDDS could be useful in facilitating oral absorption of MME as well as the oral delivery of other agents.
Nasal route of drug delivery is commonly known for treatment of local ailments like-cold, cough, rhinitis etc. Recently, efforts have been made to deliver various drugs, specially peptides and proteins, through nasal route for systemic use; utilizing the principles and concepts of rate controlled drug delivery and various polymers and absorption promoters. Considering the large number of problems associated with oral, parenteral, rectal and other routes of drug administration and gradual increase in interest of pharmaceutical scientists towards exploring the possibilities of intranasal delivery of various drugs, this article aims at giving an insight into nasal cavity, consideration of factors affecting and strategies to improve drug absorption through nasal route, pharmaceutical dosage forms and delivery systems with examples of some peptides for intra nasal delivery, its advantages and limitations.
Integrated delivery systems that promote learning and flexibility will be better prepared to face the challenges imposed by a complex and competitive environment. The integration of learning into these systems requires a shared vision, facilitative leadership, and highly functioning communication channels within an organic structure. Strategies that promote positive attitudes toward change are necessary for learning as is the provision of resources, training, incentives, and rewards that support learning, and feedback on how new administrative and clinical practices advance the mission and goals of the system.
Development of a Sustained-Release Biodegradable Polymer Delivery System for Site-Specific Delivery of Oligonucleotides: Characterization of P(LA-GA) Copolymer Microspheres In Vitro Antisense oligodeoxynucleotides (ODNs) can selectively inhibit individual gene expression provided they gain access to and remain stable at the target site for a sufficient period of time. Biodegradable sustained-release delivery systems may facilitate site-specific delivery and also prevent degradation of ODNs by nucleases whilst delivering the nucleic acid in a controlled manner to the desired site of action. In this study, we have characterized biodegradable poly (lactide-co-glycolide) (P(LA-GA)) 50:50 microspheres for the potential delivery of antisense oligonucleotides in vivo. Phosphodiester (PO) oligonucleotides complementary to either c-myc proto-oncogene or the tat gene in HIV-RNA were adequately incorporated within P(LA-GA) microspheres with entrapment efficiencies up to 60% depending on particles size. In vitro release profiles of antisense nucleic acids from 10-20 microm size microspheres over 56 days in physiological buffer were triphasic. Profiles were characterised by an initial burst effect during the first 48 hours (phase 1) of release followed by a more sustained release (phase 2) with an additional increased release (phase 3) being observed after 25 days which corresponded with bulk degradation of the copolymer matrix. The release profiles were influenced by microsphere size, copolymer molecular weight, ODN loading, ODN length and by the pH of release medium used. The serum stability of PO ODNs was significantly improved when entrapped within P(LA-GA) microspheres and the hybridization capability, as assessed by duplex melting (Tm) measurements, of released ODN was not impaired by the double-emulsion microsphere fabrication procedure used. Thus, P(LA-GA) microspheres appear to be promising candidates for improving site-specific delivery profiles for ODNs and are worthy of further evaluation in vivo.
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.
The development and implementation of the information systems necessary to support an effective and efficient continuum of care and to measure the quality and cost of that care present complex information systems integration challenges. The article discusses the integration challenges and concludes with a review of strategies that an integrated delivery system can adopt to begin to address them.
The delivery of exogenous genes into the brain is becoming an increasingly important strategy for answering questions about the molecular mechanisms of brain function. Answers to these questions may be applied to many of the disorders that affect the brain. For example, a detailed understanding of the mechanisms that modulate long-term changes in neurotransmitter release will almost certainly lead to new approaches to diseases such as the epilepsies, in which neurotransmitter release is altered. Knowledge of the molecular means by which neurotransmitters shape neuronal development and cause neurodegeneration, or how trophic factors regulate neuronal health, will lead to insights into how defects in these pathways cause specific diseases. To answer these questions, we have developed a defective herpes simplex virus (HSV) system for the delivery of exogenous genes into the brain. This system directs precise spatial and temporal expression of recombinant genes in the brain. We discuss its utility in comparison to other methods of gene transfer into the brain for answering basic questions about the molecular basis for neuronal physiology and for gene therapy.
Many drug delivery systems have been developed to provide sustained release of proteins in vivo. However, the ability to predict and control the rate of release from delivery systems is still a challenge. Toward this goal, we screened a random drug-binding peptide library (12 amino acids) to identify peptides of varying (i.e. low, moderate, and high) affinity for a model polysaccharide drug (heparin). Peptide domains of varying affinity for heparin identified from the library were synthesized using standard solid phase chemistry. A mathematical model of drug release from a biomaterial scaffold containing drug-binding peptide domains identified from the library was developed. This model describes the binding kinetics of drugs to the peptides, the diffusion of free drug, and the kinetics of enzymatic matrix degradation. The effect of the ratio of binding sites to drug, the effect of varying the binding kinetics and the rate of enzymatic matrix degradation on the rate of drug release was examined. The in vitro release of the model drug from scaffold containing the peptide drug-binding domains was measured. The ability of this system to deliver and modulate the biological activity of protein drugs was also assessed using nerve growth factor (NGF) in a chick dorsal root ganglia (DRG) neurite extension model. These studies demonstrate that our rational approach to drug delivery system design can be used to control drug release from tissue-engineered scaffolds and may be useful for promoting tissue regeneration in vivo.
Membrane permeation-controlled transdermal drug delivery systems were prepared using the natural polymer, chitosan. An adhesive sealing technique was used to construct the devices. Propranolol hydrochloride was selected as the model drug for the present study. Chitosan membranes with different permeability to propranolol hydrochloride obtained by controlled cross-linking with glutaraldehyde were used to regulate the drug release in the devices. Chitosan gel was used as the drug reservoir. The ability of these devices to deliver the drug while supported on rabbit pinna skin was tested by conducting in vitro studies in modified Franz diffusion cells. The drug release profiles showed that the drug delivery is completely controlled by the devices. The rate of drug release was found to be dependent on the type of membrane used.
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The objective of this study was to test the three novel ester derivatives of phenylephrone (isovaleryl, phenylacetyl, and pivalyl esters) as potential site-specific chemical delivery systems. The mydriatic effect and ocular distribution/metabolism of these compounds were studied by topical application to the eyes of normal rabbits. It was assumed that a reduction-hydrolysis sequence could produce the active phenylephrine in the iris-ciliary body tissues. All the derivatives showed a more pronounced mydriatic effect than that of phenylephrine, whereas phenylephrone was completely devoid of any mydriatic activity. Phenylacetyl ester was the most potent drug, with short duration of action, and showed maximum activity in the presence of 0.01% benzalkonium chloride without causing any visible irritation to the rabbit eye. Administration of the novel compounds to the eyes of the rabbits showed no traces of phenylephrine in the systemic circulation, contrary to topical administration of phenylephrine. Phenylephrone was detected in different compartments of the eye, whereas phenylephrine was present only in the iris-ciliary body tissues following administration of phenylacetyl ester. The conversion of phenylephrone esters to the active drug, phenylephrine, and thus their subsequent activity was dependent on the physicochemical characteristics of the drugs. The results suggest the potential use of phenylacetyl ester as a potent short-term mydriatic agent without systemic side effects.
Local delivery of cancer chemotherapeutics enables sustained drug levels at the site of action thereby reducing systemic side effects. A novel insertable polymeric drug delivery system for cervical cancer treatment is presented. Cisplatin, the first line of therapy employed for cervical cancers, was incorporated in a poly(ethylene-co-vinyl acetate) (EVAc) device that is similar to those currently used for vaginal contraceptive delivery. Cisplatin crystals were uniformly dispersed in the polymeric system without undergoing significant dissolution in the polymer matrix. Cisplatin dissolution from the devices was biphasic, consistent with a matrix-type controlled-release system with an initial rapid release phase followed by a slower, near linear release phase. Depending on the drug loading in the polymeric devices, the near-linear release phase varied in rate according to both empirical, linear curve-fitting (0.38+/-0.15 microg/day to 46.9+/-10.0 microg/day) and mechanistic, diffusion analysis based upon diffusion through a porous structure (D(app) from 1.3+/-0.5 x 10(-9) cm2/s to 5.8+/-0.3 x 10(-12) cm2/s). The devices were tested for in vitro activity and found to be effective against both HPV positive and HPV negative cervical cancer cell lines. Preliminary studies indicate that this delivery system would be a good candidate for investigation as a choice of treatment in cervical cancers.