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Attending a movie alone and sitting in the middle (95) Attending a movie alone and sitting in the back row by the door (92) Going to the movies with Doug and having him sit in a row behind me (88) Going to the movies with Doug and sitting in the middle (75) Going to the movies and sitting with Doug in the last row by the door (71) Imagining going to the movie and getting stuck in a crowd (70) Going into the theater lobby for a while (69) Buying a ticket by myself (68) Walking up to the ticket window and asking for times of shows (65) Figure 18-1: Walking by the theater while imagining buying a ticket (60) Rosie’s staircase Driving past the theater (48) of fear cheap 20 mg arava with visa. Imagining going to the movie (28) 276 Part V: Helping Others with Anxiety Doug plays a role in most of Rosie’s tasks generic arava 10mg with visa. He reads the script out loud to Rosie while she closes her eyes and tries to picture the experiences order arava 20mg free shipping. She rates her level of anxiety, and during the first few steps, he stays with her until her anxiety goes down. Not only does he accompany her to the movies, but he also celebrates her successes and encourages her when she starts to falter. It takes attending a number of movies with Doug before she agrees to the final tasks of going by herself. In fact, they begin enjoying their nights at the movies and find that they both love talking about their experiences afterwards over coffee and dessert. Although Rosie balks at going to the theater by herself, her comfort level has increased over the last few months. Rosie and Doug drive to the theater together on her last two items, but he chooses a movie playing on a different screen. Rosie’s fear of the movies had not yet reached the level of severely interfer- ing with her life. Had Rosie not dealt with her fear in this early stage, it would likely have spread from fear of movies to fear of other crowded places. Most people with fears, obsessions, or compulsions need to develop a plan with the help of a therapist. However, the example of Rosie and Doug can serve as an illustration of how a simple plan can be carried out without a therapist. Teaming Up against Anxiety One way you can help your partner overcome anxiety is to collaborate on ways to decrease stress in both your lives. With a little ingenuity, you can explore a variety of solutions that are likely to feel good to you even if you per- sonally don’t suffer from anxiety at all. For example: ✓ Take a stress management class at a local center for adult continuing education. Many of the ideas make life more fun and interesting in addition to reducing stress. It’s a great way to reduce stress, but even if you don’t have much stress, strolling under the sky together is a wonderful time to talk and is great for your health. Chapter 18: When a Family Member or Friend Suffers from Anxiety 277 ✓ Take a yoga, Pilates, or tai chi class together. Again, even if you don’t have anxiety, these classes are terrific for balance, muscle strength, flex- ibility, and overall health. You may choose to attend a church, a synagogue, or a mosque, or scope out a less traditional method of com- muning with a higher power, such as immersing yourselves in nature. Thinking about things bigger than yourselves or the mundane events of the world provides a peaceful perspective. Many people feel that such work enhances the mean- ing and purpose of their lives. And if you don’t have the time for a long vacation, go away for an occasional evening at a local hotel. Getting away from texting, telephones, e-mails, doorbells, and other endless tasks and demands, even for a night, can help rejuvenate both of you. Accepting Anxiety with Love It may seem rather counterintuitive, but accepting your loved one’s battle with anxiety is one of the most useful attitudes that you can take. In other words, whenever you discuss your loved one’s anxiety or engage in any effort to help, you need to appreciate and love all your partner’s strengths and weaknesses. If perfect people even existed, we can only imagine that they would be quite boring. Besides, studies show that people who try to be perfect more often become depressed, anxious, and distressed. You need to accept and embrace both the possibility of productive change as well as the chance that your partner may remain stuck. Accepting your partner is especially important when your efforts to help ✓ Result in an argument ✓ Seem ineffective 278 Part V: Helping Others with Anxiety ✓ Aren’t well-received by your partner ✓ Seem merely to increase your partner’s anxiety even after multiple expo- sure trials What does acceptance do? Acceptance allows you and your loved one to join together and grow closer, because acceptance avoids putting pressure on the one you care about. This message frees your loved one to ✓ Take risks ✓ Make mistakes ✓ Feel vulnerable ✓ Feel loved Change requires risk-taking, vulnerability, and mistakes. When people feel that they can safely goof up, look silly, cry, or fail miserably, they can take those risks. Giving up anxiety and fear takes tremendous courage in order to face the risks involved. Letting go of your need to see your partner change helps bol- ster the courage needed. When you take on the role of a helper, it doesn’t mean that your worth is at stake. Chapter 19 Recognizing Anxiety in Kids In This Chapter ▶ Seeing what’s making kids so scared ▶ Knowing when to worry about your kids’ anxiety ▶ Recognizing the usual anxieties of childhood ▶ Looking at the most common anxiety disorders among kids any adults can recall childhood as being a time of freedom, explora- Mtion, and fun. Not too many years ago, kids rode bikes in the street and played outside until dark. Now, anxious parents wait with their children at bus stops until they’re safely loaded. In this chapter, you discover the dif- ference between normal and problematic anxiety in kids. We explain that some childhood fears are completely normal, while others require interven- tion. If you’re concerned about a particular child, we urge you to seek professional diagno- sis and treatment. Numerous studies confirm this alarming development, but one in particular is a shocker. Psychologist Jean Twenge compared symptoms 280 Part V: Helping Others with Anxiety of anxiety in today’s kids with symptoms in seriously disturbed kids receiv- ing hospital treatment in 1957. She reported in the Journal of Personality and Social Psychology (December 2000) that boys and girls today report a greater number of anxiety symptoms than psychiatric inpatient children in 1957. The statistics are bad enough in their own right, but when you consider the fact that anxiety disor- ders often precede the development of depression later on, it raises concerns that the consequences of childhood anxiety could worsen in the years to come. Of course, we all know the complexities and tensions of the world today — longer work hours, rapidly developing technologies, violence on television, and even terrorism. We also suspect that certain types of parenting hold par- tial responsibility, as we discuss in Chapter 20. For the moment, what you as a parent need to know is how to distinguish the normal anxieties of childhood from abnormal suffering. Realize that the vast majority of kids feel anxious at various times to one degree or another. After all, one of the primary tasks of childhood is to figure out how to overcome the fears that life creates for everyone. Successful resolution of those fears usually results in good emotional adjustment. You just need to know whether your children’s fears represent normal development or a more sinister frame of mind that requires help. Look at Table 19-1 to get an idea of the anxiety that you can expect your children to experience at one time or another during their youth. Anxiety Problem When Anxiety Is When Anxiety Should Go Normal Away Fear of separation Common between If this continues with no from mother, father, or the ages of 6 months improvement after 36 to 48 caregiver and 24 months. Chapter 19: Recognizing Anxiety in Kids 281 Anxiety Problem When Anxiety Is When Anxiety Should Go Normal Away Fear of unfamiliar Common from age 2 If this continues without peers until around 3 years showing signs of reduc- old. Fear of animals, dark- Common between If these fears don’t start to ness, and imaginary ages 2 and 6 years. School phobia Mild to moderate This should decline and school or day-care cause no more than minimal phobia is common problems after age 6. A brief from ages 3 to 6; it reemergence at middle can briefly reappear school is okay, but it should when moving from quell quickly. Fear of evaluation by This fear almost It should gradually reduce others defines adolescence. But Most teens worry it’s not uncommon for it to a fair amount about last through the late teens.

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Moreover buy generic arava 20mg on line, adverse reactions arava 10mg without prescription, such as urinary tract infections buy discount arava 10mg, alterations in vaginal flora and occurrence of toxic shock syndrome, have been associated with their use. In contrast the silicone-based device described above has been reported to be stable, non-irritating and non-toxic. A vaginal sponge has also been recently developed comprising a soft poly(urethane) sponge impregnated with a gel containing 1% benzalkonium chloride, 0. The sponge therefore combines the actions of: • a physical barrier that blocks the cervix; • a material that absorbs the ejaculate; • a spermicide; • an antiviral agent. Antiviral liposomal preparations Intramuscular injection of α interferon was shown to be fairly efficacious in the treatment of genital warts; however, this route was associated with a number of side-effects including fever, myalgia, headache, nausea and fatigue. A liposomal preparation of α interferon for topical vaginal delivery has been developed, which offers the advantage of treating latent human papillomavirus infections as well as visible genital warts. The liposomal preparation can be self-administered intravaginally, without the need for multiple painful local, or im, injections. In the vagina, mucosal immune responses are initiated by the uptake of antigens from the vaginal surfaces (Figure 11. Whereas the gastrointestinal tract has identifiable aggregates of lymphoid tissue within the epithelium known as the Peyer’s patches (see Section 6. Antigen-specific effector lymphocytes (B cells and T cells) migrate through the lymphatics and exit via the thoracic duct into the bloodstream. The primed B and T cells home to various mucosal sites including the genital mucosa, where they undergo maturation and secretion. A vaginal vaccine has been developed for the treatment of recurrent urinary tract infections. The multi- strain vaccine, composed of 10 heat-killed bacterial uropathogenic strains, has been shown to be efficacious against cystitis in non-human primates when administered by the vaginal route. Bladder infections were significantly reduced and both systemic and local immune responses were generated. It was determined that vaginal immunization resulted in two different types of immune responses in mice: high and low. High responders to the immunizations had been immunized in the diestrous phase of the cycle. As explained above, the vaginal epithelium is thin and porous during this phase, which facilitates vaccine uptake. Similarly, rectal immunization induced high levels of specific IgA and IgG in rectal secretions, but not in female genital tract secretions. Thus, generation of optimal immune responses to sexually transmitted organisms in both the rectal and the genital mucosa of women may require local immunization at both of these sites. Association of an antigen with an appropriate microparticulate carrier may enhance antigen uptake by vaginal antigen-presenting cells. The effect was further enhanced when the penetration enhancer lysophosphatidylcholine was used. Hyaluronan ester microspheres Hyaluronan is a naturally occurring mucopolysaccharide, consisting of repeating disaccharide units of D- glucuronic acid and N-acetyl-D-glucosamine. By esterification of the carboxyl groups of the glucuronic acid residue with alcohols, modified biopolymers can be produced which are biocompatible, mucoadhesive and biodegradable. The degradation rate can be controlled by the degree of esterification and by the type of alcohol substituent. Experiments using radio-labeled microspheres have shown that after vaginal administration the microspheres are dispersed along the length of the vagina for prolonged periods, thereby demonstrating their potential as a long-acting intravaginal delivery system. Suppocire, a mixture of semi-synthetic polyethylene triglycerides, melts at 35–37 °C. After administration of the pessary, the formulation forms a fine emulsion on contact with the aqueous environment of the vagina, thus encouraging the dispersion of microspheres throughout the vaginal cavity. It has been proposed that the bioadhesive microspheres may induce transient widening of intercellular junctions when applied nasally, or added to Caco-2 cell monolayers. It is thought that drug microspheres take up water from the cells, causing the cells to dehydrate and “shrink”, thereby inducing the transient widening of the intercellular junctions and increased drug transport. Work in this field has concentrated on the use of poly(lactide-co-glycolide) microparticles, which have the advantages of being biocompatible, biodegradable and well tolerated in humans. Promising results have also been obtained with the use of biodegradable starch microspheres in conjunction with the absorption enhancer lysophosphatidylcholine. However, in general, only low levels of antibodies have been induced by intravaginal immunizations and the antibodies generated have been predominantly localized in the genital tract, even in the presence of potent antigen delivery systems. Such formulations are prone to leakage, which can result in: • low efficacy, due to limited contact time with the absorbing surface; • poor compliance. Bioadhesive polymers can be used to prolong the contact of a drug with a mucosal surface, without inducing adverse local effects on the epithelium. Other beneficial effects conferred by the use of bioadhesive polymers include: • increasing the local drug concentration at the site of adhesion/absorption; • protecting the drug from dilution and possible degradation by vaginal secretions; • prolonging the contact time of the dosage form near the absorbing surface. Thus such polymers have attracted considerable interest as a means of improving drug delivery at mucosal sites, including the vagina. Reference has already been made to the promising results obtained using bioadhesive hyaluronane ester microspheres for vaginal drug delivery. Other bioadhesive polymers under investigation include: Polycarbophil Polycarbophil, a poly(acrylic acid) lightly cross-linked with divinyl glycol, can remain on vaginal tissue for extended periods and has demonstrated many potential clinical applications: 296 Dry vagina: the bioadhesive gel can hydrate vaginal tissue for 3–4 days after a single application. Tissue hydration is caused by an increased blood flow, thus increasing transudation of vaginal fluid though the intercellular channels of the vaginal epithelium. Clinical assessment of local tissue pH in postmenopausal women shows a reduction in pH from about 7 to 4 and maintenance of this acidic pH for about 3–4 days. This acidic pH is an unfavorable environment for pathogens, thereby protecting against bacterial vaginosis. Spermicide-antiviral: the polymer appears to be an effective delivery system for the spermicidal/antiviral agent nonoxynol-9. By its ability to adhere to vaginal tissue while retaining nonoxynol-9 in its gel structure, it is an excellent extended effect spermicide. In contrast, the bioadhesive gel containing nonoxynol-9 attaches to lymphocytes and maintains sufficient contact time to allow the nonoxynol-9 surfactant to disrupt the cell wall, thus eliminating the lymphocyte and killing the virus within. Progesterone delivery: as described above, estrogen replacement therapy increases the risk of endometrial cancer when used alone. This risk can be eliminated by treatment with a progestational agent for up to 14 days a month. The vaginal delivery of a polycarbophil gel loaded with progesterone has been shown to allow the extended vaginal delivery of the drug for 2–3 days from a single dose and protect the endometrium against cancer. Low serum levels of progesterone were detected after vaginal delivery, which corresponds to fewer side-effects. A commercial progesterone-loaded polycarbophil gel preparation for intravaginal delivery, Crinone, has recently been launched. Smart hydrogel Smart hydrogel preparations, comprising poly(acrylic acid) and a poloxamer (see Section 16. The temperature- dependent gelling of the system helps to prevent leak-back and provides sustained release properties. Smart hydrogel preparations containing estradiol have shown similar bioavailability to a commercial vaginal cream and suppository, even though the gel contained only 20% of the relative estradiol dose. However, the low and erratic bioavailability of biopharmaceuticals via this route necessitates the use of absorption enhancers. Until safe, non-toxic absorption enhancers can be found, the route is of limited potential. A further major limitation of this route is the lack of reproducibility resulting from cyclic changes in the reproductive system. Finally, no matter what degree of optimization can be achieved via this route, it can only ever benefit approximately 50% of the population! Mucosal penetration enhancers for facilitation of peptide and protein drug absorption. Give examples of the classes of the pharmaceutical agents which are presently marketed as topical formulations for vaginal administration.

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It has been a stimulating period for molecular biology cheap arava 20mg amex, with a raft of innovative technologies providing the basis for profound advances in our appreciation of the inner workings of cells cheap arava 10mg online, tissues and buy arava 10mg visa, increasingly, whole organisms. A heady mixture of scientific opportunism and commercial exploitation has led us to the point where virtually all the genes in the human genome are now known. However, as unfair as it may seem, this genetic heritage is not yet available to all scientists. A small number of companies still hold the keys to the majority of these genes, 364 and, with recent developments, it looks as though the same may prove true for the framework sequence of the entire genome. Potentially more frustrating for the academic scientist, the patenting of such information may lock away the fruit of genomics for decades to come. From this it has proved possible to survey the majority of the genes expressed in a particular cell or tissue. The broad applicability of such techniques not only to tissues but also to established cell lines and model cell systems is illustrated in Figure 15. The latter effort is still under way in companies as well as in public institutions. The economies of scale provided by industrial-scale sequencing have hastened progress to the point where at least two companies now have the majority of expressed human genes in their freezers. This has certainly had the effect of restricting access to key therapeutic genes, but on the other hand subscribers to these proprietary databases have early access to information which would not otherwise be available. At the moment, the main beneficiaries of this commercial effort are pharmaceutical and biotech companies who see such access as conferring a significant competitive advantage on their research and development activities. Although there are as yet no methodologies for real-time gene expression observations, the attempt by companies such as Incyte and Affymetrix to place whole genomes on silicon chips, together with the advent of continuous flow hybridization approaches, promises a much greater depth to temporal analysis of complex biological processes than hitherto possible, bringing with it new opportunities for defining appropriate therapeutic intervention points in complex biological cascades. This information can now be complemented by hybridization array approaches, in which the expression of defined subsets of genes (or indeed the expression of entire genomes) can be carefully monitored at high volume across specific time courses and dose regimens, providing a degree of accuracy and reproducibility in determining the level of gene expression which sequencing alone cannot achieve. Together, sequencing and arraying techniques can be used to provide information on both the biology of disease and the behavior of compounds as they impact a biological system. The scientific basis of hybridization arraying as a technique for the determination of gene expression levels is shown in Figures 15. A full description of these hybridization arraying approaches has been published and is also available on the Web (see Table 15. Access to comprehensive sequence databases and the bioinformatics tools to analyze them plays a central role in these gene expression monitoring approaches, illustrating their “reach-through” impact in genomics in general. A further technique which holds considerable promise for evaluating individual gene expression at the histological or cellular level is in situ hybridization. This provides a cellular level of resolution to gene expression analysis which complements that of microarray analyses. All the above techniques have major potential applications in drug delivery, from defining new members of key transporter and receptor gene families and their expression, to providing experimental systems for evaluating the efficacy of new delivery systems. Similar databases will undoubtedly emerge from mammalian systems as mammalian cell genome closure and proteomics advance. Systematic approaches to biological function are encompassed within the broad area of “functional genomics”. For most of this century, our knowledge of cell biology has been primarily descriptive, reproducible in vitro work dating only from the 1960s. From the ability to induce neuronal cell differentiation to the observation of cellular apoptosis, cell culture is now offering radically new insights into the way in which genetic programs are executed at a functional level. The advent of genomic biology places cell structure and structural biology in a new context. Processes fundamental to cell biology, such as protein translocation and apoptosis, can now be seen as variations on an evolutionarily conserved theme. For drug discovery and delivery, this growing knowledge of cell biology is extremely useful. Not only has an intimate appreciation of cellular processes behind disease revealed new therapeutic targets, the inner workings of the cell have now become accessible to exploitation. The development of cell-based screening technologies, ranging from yeast-based screening to reporter gene assays, underlies the increasing trend towards directly harnessing cell biology to drug discovery. Cell-based systems are biology’s way of dividing the expressed genome into functional units. In drug discovery, a focus on specific cell systems, such as T-cells and fibroblasts for assembly of human immunodeficiency virus or herpes simplex virus particles and endothelial cells for demonstrating adhesion- dependent processes, often provides convenient primary drug screening systems. Other single cell systems, such as yeast, and even entire organisms, such as Caenorhabditis elegans, have themselves been positioned as cell-based screening systems, capable of relatively high-throughput screening using appropriate reporters, or even visual analysis. The value of such systems for functional genomics and genetic engineering has been greatly enhanced by access to genome sequences of both organisms, and they may provide new and sensitive ways of examining the potential of new delivery mechanisms. Proteomics may therefore be more useful than genomics for identifying therapeutic targets within the cell. Until recently the development of proteomics was limited by the availability of technology to reproducibly separate protein components from the cellular pool and to specifically identify the protein sequence of small amounts of protein products. The development of 2 D polyacrylamide gels which separate proteins according to molecular weight in one dimension and charge in the other direction has provided a high- resolution quantitative method for separation of low levels of expressed proteins. Tissue extracts are pooled and initial protein purification undertaken using ion-exchange and affinity chromatography. The resultant protein fractions are further separated by reverse-phase high performance liquid chromatography. The bands are identified using standard techniques such as silver or fluorescent dyes and the expression profile may be used to compare expression of proteins in normal and diseased tissue or to examine changes in expression under stress conditions or following drug administration. In this way proteins associated with different diseased or stress conditions can be identified and the changes in protein expressions, for example, due to drug metabolism may be identified. The specific proteins may be identified by in situ digestion and analysis by mass spectrometry. Recent developments in this technology have resulted in the technique being accepted as the primary tool for high- throughput, high-sensitivity protein analysis. The identification of the mass of individual peptide fragments allows the analyst to search genomic and protein sequence databases in order to find genes and/or proteins which would be expected to give the same fragmentation patterns. A highly matched database sequence will provide the full sequence and identify the protein. Although reliable, this technique may lead to false positive results in some cases. To overcome this problem many proteomic companies are now adopting the technique of tandem mass spectrometry to unambiguously identify protein sequences. This technique subjects proteins to successive routines of fragmentation and mass analysis in order to provide the actual amino acid sequence. Mode of drug action 372 By probing drug treated cells for expression of genes and proteins it may be possible to more precisely identify the specific mode of action of a drug of known therapeutic value, for example natural herbal remedies, thereby offering opportunities to develop new drugs for such therapeutic conditions. Toxicology The monitoring of expression of certain genes and proteins in, for example, hepatic cells offers a means of detecting upregulation of metabolic enzymes such as P450 isoenzymes. Similarly, such profiling may also provide opportunities to identify the mechanisms of drug toxicity of therapeutic agents in order to design new drugs to overcome these problems. Clinical applications These technologies will also allow the screening of patients for particular diseases or metabolic polymorphisms, which may dictate whether a patient is a rapid or slow metabolizer of certain drugs. Such response markers will allow more stringent selection criteria to be applied to clinical trials selection and could also be used to more specifically adjust a drug dosing regimen to a particular patient’s metabolic profile. Such diagnostic screens allow more effective patient treatment and the development of therapeutic agents specifically designed for the treatment of specific patient subpopulations. In the future these screening techniques will allow us to more readily identify upregulated enzymes in diseased tissues which will facilitate the development of prodrug-based technologies for the site-specific chemical delivery of drugs to these diseased cells. The identification of surface-expressed disease-specific ligands will allow targeting of polymeric and microparticulate drug delivery systems to these particular diseased cells through the use of molecular entities specifically targeted against these ligands. It is clear that genomics and proteomics are complementary in that genomics has an important role in providing data for elucidating amino acid sequences identified through proteomics, and proteomics provides a means of identifying those genes which have functional importance. The identification of future therapeutic targets will be driven by cross-fertilization between these two disciplines through bioinformatics. A perfect prodrug is a molecule which has no intrinsic pharmacological activity until it is converted enzymatically to a new molecular form which displays pharmacological activity. In principle, prodrug activation simply mirrors activation processes which are used widely in biological systems to regulate important enzymatic cascades. A particularly widespread example in biology is pro- protease activation, in which a small “extension” peptide can be used to restrain or “mask” inherent proteolytic activities which, if they occurred in inappropriate tissue locations, would pose a major problem.

D. Arakos. Wright Institute.

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