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.     

Current status of intraperitoneal therapy for ovarian cancer

Recent attention has focused on evaluating those clinical situations in which intraperitoneal drug delivery may be an appropriate treatment option for patients with ovarian cancer. When employed as a second-line strategy, approximately 20% to 30% of patients with small-volume residual disease (microscopic, largest tumor mass < or = 0.5 to 1 cm in maximum diameter) at initiation of treatment are expected to achieve a surgically documented complete response with a variety of organoplatinum-based intraperitoneal regimens. However, responses are rarely observed in such patients who have failed to demonstrate tumor sensitivity to systemically delivered organoplatinum drugs, despite the presence of small-volume residual disease. Investigators at several centers are currently exploring a possible role for regional drug delivery in the initial management of selected patients (ie, small-volume disease) with ovarian cancer. A recently reported trial of intraperitoneal taxol suggests this may be an ideal drug for regional therapy of ovarian cancer due to a major pharmacokinetic advantage associated with this route of drug delivery.     

The potential of liposomes in oral drug delivery

Oral liposome drug delivery has been the subject of much cynicism. Results have been quite variable and, for the most part, have not been predicated on specific objectives that would lead to success. Prerequisites are stability in the gastrointestinal environment and binding to specific sites. Transport via paracellular and transcellular routes from normal epithelial tissue or Peyer's patches leads to different outcomes of drug delivery and immunization, respectively. Polymerized, microencapsulated, and polymer-coated liposomes have all increased the potential of oral liposomes. Using targeted liposomes and a greater understanding of their cellular processing will ultimately lead to effective therapies from oral liposomes.     

Augmentation of transdermal drug penetration

Transdermal drug delivery is an alternative to conventional routes of administration. It is limited due to the low permeability of the skin. Iontophoresis (application of low intensity current) and electroporation (application of high voltage pulses) increase drug delivery by several orders of magnitude. The mechanisms and the parameters controlling drug transport as well as safety issues have been studied. New therapeutic applications for the delivery of drugs, peptides and nucleic acids, have been developed.     

Diminished kidney function and nephrocalcinosis in rats fed a magnesium-deficient diet

Microcapsules have been used as drug delivery systems in the pharmaceutical field for sustained or controlled release of drug, and for artificial cells and organs. Biodegradable polymers, especially polylactic acid, have been widely used in this field. In this study, an attempt was made to develop a new method to prepare polylactic acid microcapsules for drug delivery. The biodegradable polylactic acid microcapsules were made by the phase separation process: two types of polylactic acid, poly[(D,L)lactic acid] and poly[(L)lactic acid] were combined as the membrane material. Because of the difference of the crystal properties of the two polymers, the aggregation which happens frequently in the phase separation process was prevented. As a model drug, Ciprofloxacin was encapsulated in the polylactic acid microcapsules.     

Review article: factors influencing antibiotic transfer across the gastric mucosa

The delivery of antimicrobial drugs to Helicobacter pylori within the stomach is poorly understood. The gastric environment represents a unique pharmacokinetic compartment, into which drug can be delivered directly following oral administration, or indirectly following intestinal absorption and transfer from the blood into the stomach across the gastric mucosa. Several methods have been used to study drug disposition across the gastric mucosa, including endoscopic biopsy studies, nasogastric intubation studies and animal models. Direct, or topical, delivery is limited by luminal drug degradation, drug formulation and the permeability of the mucus layer. Indirect, or systemic, delivery is limited by factors affecting the concentration gradient across the gastric mucosa and the permeability of the mucosa. These factors include intragastric pH, plasma protein binding, drug lipophilicity, the presence of active transport mechanisms, drugs that damage the gastric mucosa and inflammation secondary to H. pylori infection. Little is known about the last of these, and further research in this area should help in the rational approach to development of treatments against H. pylori.     

Distribution of drugs following controlled delivery to the brain interstitium

Intracranial controlled release polymers have been used for drug delivery to the brain, bypassing the blood brain barrier (BBB). By understanding the rates and patterns of transport in the local tissues, it is possible to design delivery systems that provide the optimal spatial and temporal pattern of chemotherapy within the intracranial space. This paper reviews the kinetics of drug release from polymeric controlled release implants, and describes the fate of drug molecules following release into the brain interstitium. Potential improvements in drug delivery based on the understanding of the mechanisms of drug release, transport and elimination are discussed.     

Theoretical models for drug delivery to solid tumors

The effectiveness of anti-cancer drug therapies is often limited by the difficulty of achieving drug delivery throughout solid tumors. Mathematical models permit an analysis of the factors leading to inadequate drug delivery to tumors and can suggest strategies for improving delivery. An overview is given of key factors that influence drug delivery and the extent to which they have been incorporated into existing theoretical models. These factors include spatial gradients of drug concentration and other variables within tumors and other parts of the body, and the relative magnitudes of the time scales involved in drug transport, tumor cell kinetics, and host toxicity. Models for both systemic and regional delivery methods are considered, including intravenous, intraarterial, intraperitoneal, intrathecal, and intratumoral delivery. Strategies for improving delivery are discussed, including use of two-step therapies, hyperthermia, liposome encapsulation, and magnetic targeting. Until now, modeling has mainly developed in separate subfields of tumor growth and cell kill kinetics, compartmental modeling of the body, spatially distributed models for single tissues, radiation dose calculations, tumor oxygenation, tumor blood flow, and cellular pharmacokinetics. In the future, models that integrate these subfields should be developed.     

Colonic drug targeting

Specific targeting of drugs to the colon is recognized to have several therapeutic advantages. Drugs which are destroyed by the stomach acid and/or metabolized by pancreatic enzymes are slightly affected in the colon, and sustained colonic release of drugs can be useful in the treatment of nocturnal asthma, angina and arthritis. Treatment of colonic diseases such as ulcerative colitis, colorectal cancer and Crohn's disease is more effective with direct delivery of drugs to the affected area. Likewise, colonic delivery of vermicides and colonic diagnostic agents require smaller doses. This article is aimed at providing insight into the design considerations and evaluation of colonic drug delivery systems. For this purpose, the anatomy and physiology of the lower gastrointestinal tract are surveyed. Furthermore, the biopharmaceutical aspects are considered in relation to drug absorption in the colon and hence various approaches to colon-specific drug delivery are discussed.     

High and low density water and resting, active and transformed cells

Melanoma is prone to spread to the brain and is the third most common source of intracranial metastasis. Patients usually present with signs and symptoms of increased intracranial pressure, a new focal neurologic deficit, or seizures. Contrasted magnetic resonance imaging (MRI) is the single most valuable imaging modality. Surgical therapy is the appropriate choice for single lesions that are accessible, especially if they are causing significant mass effect or are located in the posterior fossa. Patients with several intracranial metastases who undergo resection of all lesions may have a similar prognosis to those with single resected lesion. Stereotactic radiosurgery appears to provide good local control of small lesions. External beam radiotherapy may provide some benefit to patients, and is often used in conjunction with surgery or stereotactic radiosurgery. To date, chemotherapy has been limited because of chemo-resistance and drug delivery issues. Future directions for treatment may include local sustained delivery of either chemotherapy or immunoregulatory molecules.     

Controlled drug delivery by biodegradable poly(ester) devices: different preparative approaches

There has been extensive research on drug delivery by biodegradable polymeric devices since bioresorbable surgical sutures entered the market two decades ago. Among the different classes of biodegradable polymers, the thermoplastic aliphatic poly(esters) such as poly(lactide) (PLA), poly(glycolide) (PGA), and especially the copolymer of lactide and glycolide referred to as poly(lactide-co-glycolide) (PLGA) have generated tremendous interest because of their excellent biocompatibility, biodegradability, and mechanical strength. They are easy to formulate into various devices for carrying a variety of drug classes such as vaccines, peptides, proteins, and micromolecules. Most importantly, they have been approved by the United States Food and Drug Administration (FDA) for drug delivery. This review presents different preparation techniques of various drug-loaded PLGA devices, with special emphasis on preparing microparticles. Certain issues about other related biodegradable polyesters are discussed.     

Chronotherapeutics for cardiovascular disease

Chronotherapeutics, or delivery of a medication in concentrations that vary according to physiological need at different times during the dosage period, is a relatively new practice in clinical medicine. Epidemiological studies document that the incidence of many cardiovascular diseases, including myocardial infarction and stroke, varies predictably in time over 24 hours (the circadian period). Advanced diagnostic technologies using ambulatory monitoring of the blood pressure and electrocardiogram have also demonstrated that there is marked variability in the level of pressure in hypertensive patients and the degree of myocardial ischaemia in patients with coronary disease. These diagnostic techniques also allow us to study the effects of varying the timing of administration or delivery of a concentration of a drug on end-points such as changes in blood pressure, heart rate or intensity of angina. The first chronotherapeutic agent for hypertension and angina pectoris, controlled onset, extended release (COER-24) verapamil, has recently been developed and registered in the US, Brazil, Canada and Mexico. The theoretical advantage of this formulation is that delivery of the active drug, verapamil, has been tailored to the typical circadian rhythm of blood pressure and heart rate in patients with hypertension and angina to better cover the early morning hours when cardiovascular need appears to be the greatest. An outcome study (CONVINCE) that evaluates primary prevention of cardiovascular events with this chronotherapy versus standard of care therapy is under way in several countries in North and South America and Europe.     

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.     

Novel approaches for oral delivery of macromolecules

Traditional forms of administrations of nonabsorbable drugs and peptides often rely on their parenteral injection, since the intestinal epithelium is poorly permeable to these therapeutical agents. A number of innovative drug delivery approaches have been recently developed, including the drug entrapment within small vesicles or their passage through the intestinal paracellular pathway. Zonula occludens toxin, a recently discovered protein elaborated by Vibrio cholerae, provided tools to gain more insights on the pathophysiology of the regulation of intestinal permeability through the paracellular pathway and to develop alternative approaches for the oral delivery of drugs and macromolecules normally not absorbed through the intestine.     

E. coli endotoxin affinity at the nicotinic2 receptor: receptor theory revisited, ilumina nostros occulae

Response rates following systemic chemotherapy for hepatic tumours are disappointing. The drugs used have a narrow therapeutic ratio, which limit the scope for dose escalation of these potentially toxic agents. Therefore, alternative delivery methods that optimise the efficacy of currently available cytotoxic agents have been explored. Several novel approaches have attempted to 'target' treatment so that it reaches the tumour whilst minimising systemic exposure. There is some evidence to suggest that certain agents, including monoclonal antibodies and liposomes, selectively lodge in tumours following intravenous administration. Alternatively, the route of administration may be modified to enhance targeting of the administered drug. Delivery via the hepatic arterial, portal venous, and peritoneal routes as well as drug delivery via direct implantation may provide certain pharmacokinetic advantages. Infusion rates may be adjusted to optimise the pharmacokinetic profile. Chemoembolisation with microspheres, microcapsules or macromolecules might enhance targeting further. Variations in particle characteristics or by modifying hepatic arterial blood flow with vasoactive substances may be used to further refine this technique. The ultimate 'magic bullet', which allows total delivery of treatment to malignant cells whilst eliminating exposure of healthy tissues to these toxic agents, has not been developed as yet. However, currently available techniques allow considerable dose escalation that, whilst not providing a significant survival advantage, certainly improves response rates.     

Reinforcing effects of stimulants in humans: Sensitivity of progressive-ratio schedules.

Drug self-administration methodologies have been developed for use in humans to model naturalistic stimulant drug-taking behaviors. These methodologies use a number of schedules of reinforcement, including progressive-ratio schedules. As the name implies, in a progressive-ratio schedule, the response requirement for each subsequent delivery of drug increases, and the primary outcome variable is often the break point (i.e., the last ratio completed to receive a drug delivery). These schedules have been used in a number of human laboratory studies evaluating the reinforcing effects of stimulants. The results of these studies have demonstrated that progressive-ratio schedules are sensitive to manipulation of a pharmacological variable, dose, and to nonpharmacological variables contributing to stimulant drug effects. In addition, findings with progressive-ratio schedules are largely concordant with clinical findings, suggesting that drug self-administration under these schedules has predictive validity in terms of drug abuse and dependence. Future research is necessary, however, to understand better how pharmacological factors like route of administration, onset of effects, and pretreatment influence the reinforcing effects of stimulants under progressive-ratio schedules. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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.     

Neonatal androgen and estrogen treatments masculinize the size of motoneurons in the rat spinal nucleus of the bulbocavernosus

Electrically-assisted transdermal delivery (EATDD) is the facilitated transport of compounds across the skin using an electromotive force. It has been extensively explored as a potential means for delivering peptides and other hydrophilic, acid-labile or orally unstable products of biotechnology. The predominant mechanism for delivery is iontophoresis, although electroosmosis and electroporation have also been investigated. The focus of this review is to put these different mechanisms in perspective and relate them to the drug and skin model system being investigated.     

Drug delivery system for infectious diseases

Various types of antimicrobial agents have been evolved to inhibit growth of or to kill different microorganisms. In recent years, encapsulation of antimicrobial agents in lipid formulations has been a popular practice in research work related to drug delivery system, although most of the studies are based primary on animal models. The recent developments of lipid formulations of anti-infectious drug (antibiotics, antifungals, and antiviral agents) with longer half-life opens new therapeutic avenues in treating infections. The passive targeting of liposomes to the sites of infection is of great value with respect to clinical application. Liposome entrapment can exchange their pharmacokinetics and, hence reduce their toxicity.