By H. Gamal. Indiana University Northwest.

Iontophoresis has a long history and the earliest documented use dates back to 1740 purchase 12.5mg hyzaar free shipping blood pressure medication problems. The versatility of the technique has made it a useful investigative tool for local drug delivery in several areas of medicine cheap hyzaar 50 mg with mastercard blood pressure vertigo, including dermatology, dentistry, ophthalmology, otolaryngology and for systemic delivery of proteins and peptides. The attractiveness of the method lies in the non-invasive nature and the suitability for transferring high molecular weight, charged ions. The advantage in local drug delivery lies in reducing the risk of side-effects and provides an important alternative to parenteral administration. In ophthalmology, both trans-scleral and transcorneal drug delivery has been studied. Drugs investigated include fluorescein, tobramycin, gentamicin, ticarcillin, cefazolin, dexamethasone and ketoconazole. Iontophoresis has been found to be both safe and effective in delivering the required doses locally, at the intended site of action. Excepting for lidocaine, which has been tested in human volunteers, 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.

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Clinicians may want to consider target- voxamine discount 50mg hyzaar overnight delivery atrial fibrillation guidelines, paroxetine buy cheap hyzaar 50 mg line heart attack age, and sertraline had similar efficacy ing family accommodation in order to improve treatment but better tolerability [711,713,714,716-718,720,724]. It has been hypothesized that the symmetry/ ing and depression symptoms while bibliotherapy alone hoarding symptom dimension may be mediated by the was associated with very limited improvements [691]. These findings suggest that if pharma- ally better tolerated [711,713,714,716-718,720,724]. Considering the tolerability concerns of aty- treatment of non-responders to previous treatment with pical antipsychotics, these data reinforce that this augmen- the alternate antidepressant [733]. Another option to be associated with greater benefit compared with oral which may be useful as an adjunctive therapy in those therapy alone [743,744]. In the placebo-controlled trial, post-hoc analysis nificantly improved compulsions but not obsessions suggested that phenelzine may be beneficial in patients [796]. Additional open-label data support the use of with symmetry or other atypical obsessions [738]. These agents are recommended as third-line options, Third-line adjunctive therapies: The agents discussed and may be useful in refractory patients after first- and below are recommended as third-line adjunctive options, second-line monotherapies and adjuncts have been since some data are available to suggest they may be unsuccessful. These agents may Adjunctive strategies have generally been studied in be useful for some patients, but more data are needed. A meta-analysis demonstrated that including olanzapine (Level 1, conflicting) [760,762,763], response rates with adjunctive medication were twice amisulpride (Level 3) [770], and ziprasidone (Level 4) those of placebo, however these were still quite low [767]. Open-label data also suggest that adjunctive preg- obsessions, but less so for compulsions, however it was abalin may be useful (Level 3) [801,802]. Unfortunately, because these preparations Long-term therapy has been evaluated in relapse preven- are poorly standardized and have substantial variation in tion and naturalistic follow-up studies. A therapies may be useful for some patients; however, meta-analysis of six relapse prevention studies included more data are needed. It is characterized by paroxetine [722], sertraline [819], and high-dose fluoxetine the presence of obsessions (persistent, intrusive [820] have demonstrated reductions in relapse rates. Open trials have macotherapy appears to be superior to pharmacotherapy Katzman et al. Third-line agents, ing actual or threatened death, serious injury, or sexual adjunctive therapies, as well as biological and alternative violation [26]. It is characterized by intrusive and distres- therapies may be useful when patients fail to respond to sing memories or dreams, dissociative reactions, and sub- optimal treatment trials of first- and second-line therapies stantial psychological or physiological distress related to used alone and in combination. Onset is generally in the mid to of “traumatic event,” and there are now four symptom late 20s [2], and the prevalence is about twice as high clusters rather than three with the “avoidance” and “numb- among women versus men [849,851]. Psychotherapy individual debriefings only; there is insufficient evidence has demonstrated significant efficacy, although a meta- to comment on the utility of group debriefings. Imaginal gated, in part because they can be administered remotely appears to be as effective as in vivo exposure [69,916]. When used as an adjunct to lished through the internet, which improved the treatment exposure therapy, cognitive restructuring may improve process [936]. In this regard, ment effects of exposure therapy [953,954], and may in Bradley et al. Addition- that benefits are maintained at six- to 18-month assess- ally, numerous studies fail to report whether patients ments after treatment [923,955-958]. Conflicting results may be related to the types of and are summarized in Tables 29 and 30. Debriefing of all trauma victims is not Maintenance pharmacological treatment recommended, rather, screening and treating appropriate Long-term therapy has been evaluated in relapse- individuals is preferred. In general, there is little evidence prevention and naturalistic follow-up studies. Benefits are maintained during placebo over approximately six months (odds ratio for long-term follow-up of up to one to 10 years after treat- relapse was 0. Therefore, augmentation with second- or third-line agents may be Biological and alternative therapies important early in treatment. In general, these therapies may be useful for some Patients who do not respond to multiple courses of ther- patients; however, more data are needed. Third-line agents, ments were maintained at two to three months after treat- adjunctive therapies, as well as biological and alternative ment [1078,1079]. Anxiety disorders small trials; and in a small case series, patients with during the perinatal period are increasingly gaining Katzman et al. Although further investigation is that is gaining increasingly more research attention.

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In addition purchase hyzaar 50mg with amex blood pressure chart images, the buccal delivery of insulin in rabbits has been shown to be increased from approximately 3–5% by co-administration of edetate (least effective) purchase 12.5mg hyzaar with amex blood pressure normal heart rate high, sodium dextransulfate, sodium methoxysalicylate, sodium deoxycholate, sodium lauryl sulfate, sodium taurocholate and Brij 35 (most effective); with Brij 35 increasing the bioavailability of insulin to 12% by this route. A smooth surface and good flexibility are prerequisites to prevent mechanical irritation or local discomfort. Adequate evaluation of patient acceptability and compliance of buccal patches should include a clinical examination to observe local tolerance, and the incidence and degree of irritation. Trials should also involve the use of questionnaires, in order to determine a subject assessment of such factors as: • overall comfort; • sensation (taste, movement, swelling); • pain (during wear, on removal); • whether the patch interferes with normal activities (talking, eating, drinking, sleeping). The pill-sized patch uses a new bioadhesive which sticks to the gum, the cheek or the lip without causing irritation and is designed to deliver drugs for short and extended periods (up to 24 h). Cydot technology accommodates both uni-directional and multidirectional release, and both reservoir- and matrix-type systems are possible. However, when administered orally, melatonin shows low and variable bioavailability, presumably due to the extensive first-pass metabolism and/or variable absorption. Its low molecular weight (Mw=232 Da) and the fact that it is largely non-ionized at salivary pH make this drug a suitable candidate for transmucosal delivery. Gingival delivery of melatonin has been investigated using Cydot technology, using a uni-directional, matrix-type patch (Figure 7. Various pharmacokinetic evaluations in humans, including those illustrated in Figure 7. In contrast, transdermal delivery of melatonin results in a significant delay in systemic melatonin levels and a gradual decline in drug delivery after patch removal, possibly due to deposition of melatonin in the skin (Figure 7. Moreover, plasma levels tend to be lower after transdermal delivery and inter-subject variability to be higher. Pharmacokinetic evaluations comparing transmucosal, oral-controlled release and transdermal delivery of melatonin clearly demonstrated that the transmucosal route is the best dosage form to mimic endogenous secretion of this drug (Figure 7. Acceptability and compliance studies have shown that the patch is accepted favorably by patients. They are recommended for use in the post-operative prevention of thromboembolic disorders and are conventionally administered via the subcutaneous route. To maximize transmucosal absorption, the active was incorporated in a Cydot uni-directional reservoir system. Use of a reservoir system allows a high degree of drug loading and also permits absorption enhancers to be included with the drug in the central reservoir compartment. Studies have demonstrated that the patches: • possess prolonged adhesion properties; • are of low irritancy; • have bioavailabilites ranging from 50% to 75%. The TheraTech buccal delivery system comprises a bilayer tablet, with an adhesive layer on one side, and an active layer on the other side, which lies in contact with the cheek mucosa. However, the route is associated with many advantages for drug delivery and there is clearly considerable ongoing research in this area. In the past decade, new and highly sophisticated formulations have been developed; drug delivery using the new types of retentive systems for buccal absorption is a particularly promising area. Some success has also been attained in the transbuccal delivery of peptides and proteins. Thus it can be expected that a more exponential growth phase will develop in the coming years. Name 3 differences between the buccal mucosa and the mucosa of the gastrointestinal tract. What advantages does the buccal route offer for the systemic delivery of peptides? What is the main structural difference between the gingival and the cheek epithelium? Rank the permeability of the gastrointestinal mucosa, the skin and the buccal mucosa in the order lowest to highest. Evolution has provided the mammalian organism with an external covering, the principal function of which is to act as a barrier, specifically to the loss of tissue water. Think about it: the concentration of water inside the human body is 190 on the order of 50 M, while that in the atmosphere is clearly very much less. Thus, there is a strong driving force for water to be lost from the body and, to prevent desiccation, an efficient barrier at the interface is therefore required. The skin, and more specifically skin’s outermost layer, the stratum corneum, provides this shield. Of course, in so doing, the skin also presents a formidable resistance to the absorption, either deliberate or accidental, of chemicals which contact the external surface.