M. Iomar. Alaska Pacific University.

What major contribution have advanced drug delivery systems made to anti-inflammatory drug therapy? Discuss the importance of the developing world as a market for advanced drug delivery systems pamelor 25mg low price. Systems are diversely referred to as “controlled release” discount 25 mg pamelor otc, “sustained release” purchase pamelor mastercard, “zero-order” discount 25 mg pamelor mastercard, “reservoir”, “monolithic”, “membrane-controlled”, “smart”, “stealth” etc. Unfortunately, these terms are not always used consistently and, in some cases, may even be used inaccurately. For clarity and consistency, some common terms used in this book are defined as follows: • Prolonged/sustained release: the delivery system prolongs therapeutic blood or tissue levels of the drug for an extended period of time. Conventional drug delivery systems are simple oral, topical or injection formulations. Also, rate-control and drug targeting are treated as two separate issues in this book and are dealt with in detail in Chapters 4 and 5 respectively. Although there are literally hundreds of commercial products based on controlling drug release rate from delivery systems, there are in fact only a small number of mechanisms by which drug release rate is controlled: • Diffusion-controlled release mechanisms • Dissolution-controlled release mechanisms 57 Figure 3. If the drug concentration gradient remains constant, for example where solid drug particles are present and constant dissolution maintains the concentration of the drug in solution, the rate of drug release does not vary with time and zero- order controlled release is attained (see Chapter 4 and Figure 4. Diffusion-controlled reservoir devices are used in a wide variety of routes including those shown in Table 3. Regardless of a drug’s physical state in the polymeric matrix, such devices do not usually provide zero-order drug release properties. This is because as the drug molecules at the surface of the device are released, those in the centre of the device have to migrate longer distances to be released, which takes a longer time. This increased diffusion time results in a decrease in the release rate from the device with time. Generally the rate of release is found to decrease in proportion to the square root of time (“M t1/2” kinetics; see Chapter 4 and Figure 4. However, the decrease in drug release rate can be compensated for by designing systems of special geometry, which provide an increasing surface area over time. Examples of diffusion-controlled matrix devices in drug delivery are shown in Table 3. After a certain period of time the polymeric membrane dissolves, thereby releasing the drug; • matrix devices: in which the drug is distributed throughout a polymeric matrix, which dissolves with time, thereby releasing the drug. Since the dissolution of polymeric materials is the key to this mechanism, the polymers used must be water- soluble and/or degradable in water. The choice of a particular polymer for a particular controlled release dosage form depends on various factors such as the dissolution mechanism, delivery period, delivery route, the drug etc. In general, synthetic water-soluble polymers tend to be widely used for oral-controlled release dosage forms. Biodegradable polymers tend to be used for injectable, or implantable, drug delivery systems. Once the coating polymer dissolves, the drug is available for dissolution and absorption. Drug cores can be coated with polymers of different coating thickness, so that drug release can be delayed for certain periods, for example 1, 3, 6 and 12 h after administration. By using a dosage form incorporating a spectrum of different coating thicknesses, the overall drug release from the dosage form (as a whole, rather than from the individual microparticles) can adjust to give zero-order drug release. Since the size of the matrix decreases as the dissolution process continues, the amount of drug released also decreases with time. The decrease in drug release can be compensated in part by constructing a non-linear concentration profile in the polymer matrix. This strategy is used in the oral dosage form, Adalat, where the core of the dissolution matrix contains more drug than the outer layer. Microparticulates made of proteins, in particular albumin, are also widely used in the preparation of injectable drug carriers. The movement of water results in an increase in pressure in the solution and the excess pressure is known as the osmotic pressure. Osmotic pressure can used to pump out a drug at a constant rate from the delivery system. Device and formulation parameters can be controlled so that drug release is zero- order. An important consideration is that osmotic-controlled devices require only osmotic pressure to be effective, thus such devices operate essentially independently of the environment. Hence, in vitro drug release rate is often consistent with the in vivo release profile. Also, for oral delivery, changes in pH or ionic strength in the gastrointestinal tract will not affect the drug release rate. In parenteral therapy, the subcutaneously implantable, osmotic mini-pumps developed by the Alza Corp. Osmotic mini-pumps, such as the Oros osmotic pump, are also available for controlled 60 release via the oral route (see Section 6. They allow physicians and patients to precisely control the infusion rate of a drug. Externally programmable pumps can facilitate: • zero-order controlled drug release; • intermittent drug release. Ideally, a pump should deliver the drug at the prescribed rate(s) for extended periods of time and thus should incorporate a wide range of delivery rates, ensure accurate, precise and stable delivery, contain reliable pump and electrical components and finally, provide a simple means to monitor pump status and performance. A pump should also be convenient for the patient and thus should ideally be reasonably small in size and inconspicuous, have a long reservoir life and be easy to program. The biocompatibility of the device surface is also an important issue for consideration. Other safety concerns include danger of over- dosage, drug leakage and pump blockage. For example, drug release may be controlled by the way in which pH or ionic strength affects the swellability of a polymeric delivery system. More sophisticated systems incorporate specific enzymes which causes changes in localized pH or increases in localized concentrations of specific substrates such as glucose. The change in pH caused by the biotransformation of the substrate by the enzyme thereby causes a change in permeability of a pH-sensitive polymeric system in response to the specific biomolecule. Such systems may be used to modulate the release of drug through a controlled feedback mechanism. Site-specific drug delivery is desirable in therapeutics, in order to improve: • drug safety, as toxic side-effects caused by drug action at non-target sites are minimized; • drug efficacy, as the drug is concentrated at the site of action rather than being dispersed throughout the body; 61 • patient compliance, as increased safety and efficacy should make therapy more acceptable and thus improve compliance. In its simplest form, drug targeting can be achieved by the local administration of the therapeutic compound; this strategy is feasible even with conventional dosage forms. For example, if the site for desired drug action is the skin, the medication may be applied in ointment, lotion, or cream form, directly on the desired site. Direct injection of an anti-inflammatory agent into a joint is another example of site-specific delivery which is achievable without having recourse to a highly specialized drug delivery and targeting system. Sophisticated drug targeting technology is also available, particularly for oral and parenteral delivery. However, technology is not yet advanced sufficiently for the design of “magic bullet” drug delivery systems, proposed by Paul Ehrlich at the turn of the 20th century (see Section 1. For oral delivery, systems are available to achieve site-specific delivery within the gastrointestinal tract; for example, targeting the drug to the small intestine, colon, or gut lymphatics. Drug delivery systems available for targeted oral delivery include those that use enteric coatings, prodrugs, osmotic pumps, colloidal carriers and hydrogels; these technologies are discussed in Chapter 6. Technologies for targeted drug delivery are most advanced for parenteral administration. Such technologies are concerned with delivering drugs to specific targets in the body and also to protect drugs from degradation and premature elimination. They include the use of: • soluble carriers, such as monoclonal antibodies, dextrans, soluble synthetic polymers; • particulate carriers, such as liposomes, micro- and nano-particles, microspheres; • target-specific recognition moieties, such as monoclonal antibodies, carbohydrates and lectins. These technologies, and the various anatomical, physiological and pathological issues that pertain to their use, are discussed in detail in Chapter 5. Recent advances in biological and chemical sciences have led to the development of various “Smart” technologies to ensure more effective drug delivery and targeting of drugs to specific sites within the body. The advantages and limitations of these systems are discussed in detail in Chapter 16.

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A before-after study of the system found no significant difference in the total inpatient costs among the groups before and after intervention order pamelor 25mg without a prescription. The authors stated that it took over 5 years to realize a net benefit and over 7 years to realize an operating budget benefit buy pamelor 25mg cheap. Based on total costs per admission cheap pamelor 25mg free shipping, no significant difference was seen in any of the U buy pamelor 25 mg fast delivery. Based on the data from 6 months before and 6 months after the intervention, a 47 redistribution of workload was found. The authors claim that if these effects were extrapolated to all medicine service admissions at that hospital, the projected savings in charges per year would be $3 million in 1993 U. In both studies, care recommendations were displayed electronically to either physicians, pharmacists, or both physicians and pharmacists, compared with no care recommendations. In the asthma and chronic obstructive lung disease study, the authors found no difference in total costs (i. It was noted that these savings coincided with only modest quality improvements in projected mortality rates and length of stay. The impact on total costs was markedly different in the two groups: €264,658 in the usual care group and €170,061 in the intervention group. When compared with a 6-month period where cost information was not displayed, it was concluded that no impact was found on overall drug costs to patients that could be related to the intervention. These alerts could have avoided health care resource utilization in a number of areas (e. The sentinel system was designed as a rule-based artificial intelligence engine combined with an automatic message generator that conveys clinical recommendations and supporting literature to treating physicians. Nine hundred and eight clinical recommendations were issued to the intervention group. Among those in both groups who triggered recommendations, there were 19 percent fewer hospital admissions in the intervention group compared with the control group (p < 0. However, it is important to note that this study was not intended as a formal cost-effectiveness analysis or cost savings analysis in that they did not directly measure costs at the patient or caregiver level, nor did they consider noneconomic costs or benefits. This study used data from two additional years to analyze the effect of the intervention on resource utilization. This evaluation showed that the intervention reduced the average total charges (i. Full economic evaluation studies measure the cost per successful patient outcome over time, whereas cost analyses measure only the costs of the alternatives examined. Cost analyses can provide useful information on ‘upfront’ costs compared with ‘downstream’ cost avoidance but an ideal economic evaluation would explicitly measure all direct health care costs (e. Additionally, the full enumeration of the total costs needs to be synthesized with the consequences or outcomes of the intervention (i. The effectiveness of any given system is dependent on the system’s design, implementation, the users of the system, and the setting into which the system is being introduced. Adoption of newer technologies needs to be based on formal evaluation of whether the additional health benefit (effectiveness) is worth the additional cost. However, given the uncertainty that surrounds the cost and outcomes data, and limited study designs available in the literature, it is difficult to reach any definitive conclusion as to whether the additional costs and benefits represent value for money. Studies that used monitoring approaches to identify and intervene with patients with actual problems (e. The effectiveness of monitoring interventions in ambulatory care is enhanced (or only effective) if patients are also sent reminders and decision support recommendations. This before-after study and its methods have been debated and its conclusions contested. See Appendix C, Evidence Table 16 for references to the included articles in each cell. Statistical 52 adjustment for differences in the intervention and control groups has not been conventionally advocated even though it is likely required for unbiased comparisons. The remaining studies were cohort, case control or observational; the majority were before- after studies or variants of this approach. Preintervention outcomes were compared with outcomes evaluated at two time periods of after implementation intervention. These comparisons sought to assess changes in care and the care processes associated with the interventions that were subsequently 482 introduced. In most of the before-after studies, no adjustment was done for differences in patient mix or cointerventions in the time periods with and without the intervention. Unless a systematic trend for changes in the patient population mix was shown, this problem may have minimal effect on the reported results. For these outcomes, the positive benefits in reductions of length of stay shown in nine of 15 studies that measured this outcome are likely overestimated. While the absence of a contemporaneous comparable control group is a problem with all before-after studies, the creation of control groups by comparing intervention patients to those that do not participate, or do not have a problem, to those that do is fundamentally far more likely to introduce major bias in the comparison (e. Volunteers in any study tend to have better outcomes than nonvolunteers, and selecting patients with problems compared with those that do not will ensure that at least both will regress to the mean—people with problems get better and those with no problems get worse, resulting in an overestimation of the effect of most interventions. Many of the observational studies suffered from selecting an outcome that was distantly or only marginally related to the intervention. Moreover, in a substantial proportion of negative studies, minimal adoption was evident. The clinicians failed to adjust therapy or treatment to match the recommendations, and thus it was not surprising to find that the interventions had no effect on outcomes. Finally, the rate of some outcomes such as readmission, mortality, and nosocomial infections were too low to detect clinically meaningful differences if they had existed. General Study Characteristics A total of 76 studies assessed improvements in clinical endpoints or reduction in adverse 15,16,18,401­ events (Appendix C, Evidence Table 9). Forty included the monitoring phase, only two evaluated clinical outcomes 15,581 581,630,693 associated with order communication, three studied drug administering and one each 15 695 looked at dispensing, reconciliation, and a cell phone-based diabetes management program 537 for educational purposes. It is also difficult to ascertain if a technology can affect clinical outcomes—drugs, surgeries, and other similar interventions are easier to tie to outcomes. Consequently, many systematic reviews have addressed the effects of these applications on clinical outcomes. One addresses onscreen point-of-care computer reminders on 715 outcomes of clinical importance. The review by Shojania and colleagues found some clinical improvements across studies with blood pressure (being reduced by a mean of 1. Numbers of participants in the trials are often small, studies are short term, and are often done by those who have developed and implemented systems. It is difficult, however, to separate out developer bias from system effectiveness as they are confounded. Because these studies evaluated clinical outcomes, all assessed patients and their caregivers. One study was done in a long-term care center, one was set in homes, and five 401-403,407,637 were set in hospitals. As seen in the systematic reviews, fewer articles address clinical outcomes than address process or other outcomes such as satisfaction and attitudes. Many of the studies that did evaluate clinical outcomes also did not find the expected improvements. Zanetti and colleagues studied prophylactic antibiotics in prolonged cardiac surgery. One study with asthma patients found improved lung function and airway 408 hyperresponsiveness. This is an important study and has garnered much discussion in the literature of its methods and findings with respect to the increase in mortality (2. The study by Han and colleagues evaluated dispensing; while 581,630,693 three studies addressed administering. One study was an integrated system in the Ohio State University Health System (James Cancer Center and three other tertiary care hospitals). They found a reduced length of stay for patients with heart disease (14 percent) and transplant patients (15 percent) but not for those with cardiothoracic surgery or 581 693 those in the cancer center. This provided the opportunity to use existing structured electronic information to assist clinicians in identifying patients who needed a change in their treatment plan.

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Group D streptococci (nonenterococci) streptococci Microbiology/Correlate clinical and laboratory data/ Microbiology/Evaluate laboratory data to make Bacteria/Streptococci/2 identifications/Bacteria/3 33 purchase discount pamelor on line. Te quellung test is used to identify which Answers to Questions 31–36 Streptococcus species? Both groups Microbiology/Apply knowledge of fundamental grow on bile esculin agar buy pamelor 25mg otc. Group A and B β-hemolytic streptococci methylene blue stain (microprecipitin reaction) C cheap 25 mg pamelor visa. Nongroup A or B β-hemolytic streptococci occurs between the carbohydrate of the capsule D buy cheap pamelor 25 mg on line. Binding Microbiology/Apply knowledge of fundamental of antibodies to the bacteria causes the capsule to biological characteristics/Streptococci/1 swell, identifying the organisms as S. The nongroup A, B, identifications/Bacteria/3 or D streptococci will not grow in 6. Staphylococcal cross-streak test Microbiology/Select methods/Reagents/Media/Bacteria/ Microbiology/Apply knowledge of fundamental Identification/1 biological characteristics/Streptococci/1 Answers to Questions 37–41 38. Many α-hemolytic streptococci recovered from a wound were found to be penicillin resistant. Two blood cultures on a newborn grew β-hemolytic streptococci with the following reactions: 41. Nystatin and amphotericin B are used to prevent growth of yeasts Which is the most likely identification? Nongroup A, nongroup B, nongroup D streptococci Microbiology/Evaluate laboratory data to make identifications/Bacteria/3 424 Chapter 7 | Microbiology 42. Variation in colony types seen with fresh isolates Answers to Questions 42–47 of Neisseria gonorrhoeae and sometimes with Neisseria meningitidis are the result of: 42. Multiple nutritional requirements sizes and appearances of gonococci are the result B. Colony size and coloration (or light reflection) are the basis of Kellogg’s scheme Microbiology/Apply knowledge of fundamental (types T1 through T5). Types T1 and T2 have pili biological characteristics/Neisseria/2 on the surface and T3, T4, and T5 do not. A Gram stain of a urethral discharge from a species form long filaments or long spindle-shaped man showing extracellular and intracellular cells when grown near a 10-unit penicillin disk. Neisseria lactamica flora contain gram-negative cocci and diplococci resembling gonococci and, therefore, no presumptive Microbiology/Evaluate laboratory data to make identification should be reported for N. A Oxacillin is the drug used to screen staphylococci Fructose = Neg for resistance to antibiotics having the β-lactam ring. Microbiology/Apply knowledge of fundamental biological characteristics/Gram-negative cocci/1 52. D The standard Kirby–Bauer method used for disk diffusion susceptibility testing recommended by 51. Tetracycline Microbiology/Apply knowledge of fundamental biological characteristics/Antibiotic susceptibility/1 426 Chapter 7 | Microbiology 53. Which one of the following organisms is a known Answers to Questions 53–54 producer of β-lactamase–producing strains, and should be tested (screened) by a commercial 53. C A test for β-lactamase production should be β-lactamase assay prior to susceptibility testing? An example is biological characteristics/Antibiotic susceptibility/2 heteroresistant mecA-positive S. This is referred to as being D-zone Microbiology/Apply knowledge of fundamental positive. Large gram-positive spore-forming rods growing Answers to Questions 1–2 on blood agar as large, raised, β-hemolytic colonies that spread and appear as frosted green-gray glass 1. Bacillus anthracis and Bacillus cereus can best be positive and produce acid from glucose. Lecithinase and catalase Microbiology/Select methods/Reagents/Media/Bacteria/ Identification/2 β Hemolysis Motility Oxidase Catalase Lecithinase Glucose B. Which is the specimen of choice for proof of food Answers to Questions 3–6 poisoning by Bacillus cereus? Penicillin (10-unit) susceptibility test performed in a biological safety hood, and personnel B. Which of the following tests should be performed appears on the Gram stain smear as gram-positive for initial differentiation of Listeria monocytogenes short, thin, diphtheroidal shapes, whereas from group B streptococci? Culture of a finger wound specimen from a meat streptococci packer produced short gram-positive bacilli on a blood agar plate with no hemolysis. Colonies Motility (wet prep) = Neg growing on blood agar are small and transparent, Motility (media) = Neg (bottle-brush growth in stab may be either smooth or rough, and are often culture) surrounded by a green tinge. Bacillus subtilis Microbiology/Evaluate laboratory data to make identifications/Bacteria/3 7. A non–spore-forming, slender gram-positive rod Answers to Questions 7–11 forming palisades and chains was recovered from a vaginal culture and grew well on tomato juice agar. D Corynebacterium species recovered from a throat Microbiology/Evaluate laboratory data to make culture are usually considered part of the normal identifications/Bacteria/2 throat flora. In this event, direct inoculation on Loeffler culture is considered a pathogen when it produces: serum medium or tellurite medium and the following A. A pseudomembrane of the oropharynx biochemical tests should be performed to confirm B. Gray-black colonies with a brown halo on Tinsdale’s agar Gelatin hydrolysis = Neg Catalase = + D. D A Gram stain smear from a vaginal secretion showing can be made using which of the following many squamous epithelial cells loaded with findings? A gram-positive branching filamentous organism Kinyoun stain and 1% sulfuric acid as the decolorizing recovered from a sputum specimen was found to agent. The other organisms listed are negative for be positive with a modified acid-fast stain method. Darkfield microscopy for direct identifications/Bacteria/2 visualization or indirect immunofluorescence using 11. Routine laboratory testing for Treponema fluorescein-conjugated antihuman globulin (the pallidum involves: fluorescent treponemal antibody-absorption test, A. Gram staining including chemiluminescence and point-of-care Microbiology/Select methods/Reagents/Media/ immunochromatography. Spirochetes often detected in the hematology Answers to Questions 12–17 laboratory, even before the physician suspects the infection, are: 12. D Lyme disease may result in acute arthritis and Microbiology/Apply knowledge of fundamental meningitis and is caused by B. This biological characteristics/Spirochetes/1 spirochete is carried by the deer tick belonging to the Ixodes genus (I. Which of the following organisms is the cause of North-central United States and I. A Serological analysis using immunofluorescence or Microbiology/Apply knowledge of fundamental an enzyme immunoassay is the method of choice biological characteristics/Spirochetes/1 for diagnosis of Lyme disease. Te diagnostic method most commonly used for be cultured directly from lesions, and darkfield the identification of Lyme disease is: microscopy can be used for detection of spirochetes A. Primary atypical pneumonia is caused by: from the upper and lower respiratory tracts onto A. Which organism typically produces “fried-egg” is grown on “M” agar containing arginine and colonies on agar within 1–5 days of culture from a phenol red. Treponema pallidum Colonies of Ureaplasma are small and golden brown on A7/A8 agar. Te manganous chloride–urea test is used for the utilizes manganous chloride (MnCl2) in the presence identification of which organism? Borrelia burgdorferi is observed under a dissecting microscope and is a Microbiology/Select methods/Reagents/Media/ rapid test for the identification of U. A gram-positive (gram-variable), beaded organism Answers to Questions 18–22 with delicate branching was recovered from the sputum of a 20-year-old patient with leukemia. D All of the listed organisms produce mycelium (aerial Te specimen produced orange, glabrous, waxy or substrate), causing them to appear branched colonies on Middlebrook’s agar that showed when Gram stained, but only the Nocardia spp. What is the most likely opportunistic pathogen, and cultures typically have a identification? A The “whiff” test is used for a presumptive diagnosis stained with Loeffler methylene blue stain showed of an infection with G.

Iontophoresis has been found to be both safe and effective in delivering the required doses locally buy cheap pamelor 25mg line, at the intended site of action 25 mg pamelor with visa. Excepting for lidocaine buy 25mg pamelor with amex, which has been tested in human volunteers buy generic pamelor 25 mg line, all the other drugs have been tested in rabbits. Retinotoxic effects associated with iontophoresis have been evaluated by slit lamp microscopy, indirect ophthalmoscopy, light and electron microscopy. Commonly reported toxic effects include slight retinal and choroidal burns and retinal pigment epithelial and choroidal necrosis, corneal epithelial edema, persistent corneal opacities and polymorphonuclear cell infiltration. Disadvantages of iontophoresis include side- effects such as itching, erythema and general irritation. Although many systems have been developed, very few have really tackled the overwhelming difficulty of delivering the medication to the eye. At the front of the eye, the efficient clearance mechanism and the nature of the precorneal and scleral barriers oppose retention of drug in periocular tissue. The penalty for prolonged delivery may be blurring of vision or the need to use an implant. Drug delivery to the back of the eye is fraught with difficulties and the poor penetration severely limits the treatment of sight-threatening diseases. Developments in the next century will have to focus on the need to provide prolonged release of disease modulators with less risk and easier access than the present generation of devices. Outline the structure and physiology of the cornea relevant to drug delivery and adsorption. List the various disperse systems which have been employed to enhance topical ocular drug delivery. Describe the use of liposomes, microparticulates and nanoparticulates in intraocular drug delivery. Outline the advantages and disadvantages of iontophoresis in ophthalmic drug delivery. However, drugs generally do not readily enter the brain from the circulating blood. Access to the brain is particularly difficult for the “new biotherapeutics” such as peptide, protein and nucleic-acid based biopharmaceuticals. The brain capillary endothelium comprises the lumenal and ablumenal membranes of capillaries, which are separated by approximately 300 run of endothelial cytoplasm (Figure 13. The structural differences between brain capillary endothelium and non-brain capillary endothelium are associated with the endothelial tight junctions. The non-brain capillaries have fenestrations (openings) between the endothelial cells through which solutes can move readily via passive diffusion. In brain capillaries, the endothelium has epithelial-like tight junctions which preclude movement via paracellular diffusion pathways. There is also minimal pinocytosis across brain capillary endothelim, which further limits transport of moieties from blood to brain. Extending from the sides of these cells are foot processes; or limbs, that spread out, and abutting one another, encapsulate the capillaries. There is a very close relationship between the endothelial cells and the astrocyte foot processes, they are separated by a distance of only 20 nm, or approximately the thickness of the basement membrane. The existence of the endothelial tight junctions means that passive diffusion between the cells is prohibited (paracellular route), so that passive diffusion is limited to the transcellular route. Lipid soluble drugs move across the lipid-rich 323 plasma membranes of the endothelial cells, down a concentration gradient according to Fick’s Law (see Section 1. The most common system is the one that mediates the transport of glucose, which provides the brain with virtually all its energy. Carrier-mediated mechanisms are also responsible for the absorption of two other energy sources: ketone bodies, which are derived from lipids, and lactic acid, a by-product of sugar metabolism. Carrier-mediated transport systems are also involved in the uptake of amino acids by the brain. The brain can manufacture its own small neutral and acidic amino acids; however, large neutral and basic amino acids are obtained from the bloodstream. When citrate, a tricarboxylic acid, chelates metals such as aluminum, the tetravalent citrate-aluminum complex leaves a free non-complexed monocarboxylic acid which is a substrate for the monocarboxylic acid or lactate carrier in the brain endothelium. This enzyme is localized in the astrocyte foot processes of the brain, with minimal localization in capillary endothelial cells. This astrocytic enzymatic barrier to adenosine movement into brain interstitial 324 fluid is an example of how the permeability barrier of the endothelium can work in tandem with the enzymatic barrier in astrocyte foot processes, to provide a multicomponent blood-brain barrier. In brief, a macromolecular drug combines with a membrane-bound receptor and is internalized into endocytic vesicles. Transcytosis is achieved if the endocytic vesicles containing the drug-receptor complexes can reach the basal membrane without fusion with lysosomes. This receptor is upregulated in development and downregulated in streptozotocin-induced diabetes mellitus. Physicochemical factors associated with the drug which facilitate this process have been discussed extensively in Chapter 1 (Section 1. However, this linear relationship is only applicable if the molecular weight of the molecule is under a threshold of 400–600 Da (Figure 13. Examples of decreased permeability due to high molecular weight include morphine-6-glucuronide (molecular weight=461 Da), somatostatin analog 201–995 (1,019 Da), vinblastine (814 Da), vincristine (825 Da), or cyclosporin (1,203 Da). Size exclusion is associated primarily with the molecular volume of the molecule and not strictly with the molecular weight (see Section 1. It is proposed that such an active efflux system is p- glycoprotein based (see Sections 1. For example, vinblastine, vincristine, and cyclosporin are all potential substrates for p-glycoprotein. Recent studies have shown that p-glycoprotein is located in the astrocyte membranes (and not in the brain capillary endothelium as previously accepted) and that it functions by reducing the volume of distribution of the drug in the brain. The unionized form of the drug is the lipophilic form which can cross membranes, whereas negligible transport occurs for the ionized form. In this process, the plasma” protein collides with the endothelial glycocalyx and this microcirculatory event triggers conformational changes in the plasma protein. These conformational changes may involve the drug binding site on the plasma protein, so that the drug undergoes enhanced dissociation from that binding site within the brain capillary. The enhanced dissociation of a drug from its binding site on plasma proteins in vivo in the brain capillaries has been demonstrated for a number of different drugs and ligands (Table 13. Strategies such as modifying the physciochemical properties of a drug to enhance uptake by specialized transport systems are described below. Following icv infusion, drug diffusion in the brain is limited by such factors as: • physical barriers such as synaptic regions protected by ensheathing glial processes; • catabolic enzymes; • high- and low-affinity uptake sites; • low diffusion coefficients of macromolecules. For example, within 30 minutes of administering cholecystokinin to the brain via icv infusion, the neuropeptide has reached the plasma and inhibits feeding via a peripheral rather than a central mechanism of action. The distribution of drug rapidly to the peripheral bloodstream following icv infusion has been demonstrated repeatedly for both large molecules, such as cytokines, and small molecules. These factors combine to limit drug delivery via icv to the surface of the brain, with minimal distribution of drug into brain parenchyma. This may be beneficial when target receptors are found on the surface, or for diseases confined to areas near the ventricle wall. The use of genetically engineered cells to secrete a drug is currently at a very preliminary stage of development. A wide variety of polymeric implants are available, with different rate-controlling mechanisms, degrees of biodegradability, shapes, sizes etc. The distribution of drug into the brain following the intracerebral implantation of a polymeric implant is also limited by diffusion, with a maximal penetration of drug into brain parenchyma of < 1 mm. Albumin is neurotoxic for astrocytes and normally exists at concentrations in brain interstitial fluid that are approximately 1,000-fold lower than the concentrations of albumin in the circulation. Newer strategies involving the use of drug delivery systems include the use of immunoliposomes to target vesicles to the brain, as discussed below (Section 13. One of the simplest methods of improving the uptake of a drug to the brain involves the conversion of the drug to a more lipophilic prodrug (see Section 1. If a drug possesses a molecular structure similar to that of a nutrient which is a substrate for carrier-mediated transport (Table 13. Due to the high structural specificity of the carriers, it is more advantageous to convert the drug into a structure similar to that of an endogenous nutrient, rather than conjugating the drug to the nutrient.

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