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The increases in aspartate aminotransferase occurred in the higher dose groups for each age group (0 order 20mg apcalis sx otc erectile dysfunction treatment after radical prostatectomy. A retrospective chart review of 113 children identified from a registry-type database examined children with erosive esophagitis who received a proton pump inhibitor for at least 1 264 year purchase apcalis sx american express erectile dysfunction shake ingredients. The majority (66%) was taking lansoprazole cheap apcalis sx 20 mg otc erectile dysfunction treatment san francisco, followed by omeprazole (22%), and few were taking pantoprazole, rabeprazole, or esomeprazole. Overall, 88% of the children had no adverse event while taking a proton pump inhibitor, with a range of 80% to 100% for specific proton pump inhibitors. The most frequent adverse events recorded in patients’ charts were constipation (4%) and diarrhea (5%). Serum gastrin level was elevated (>90 pg/mL) in 73% of children, with no statistically significant differences by specific proton pump inhibitor, dose, dosing frequency, or treatment duration. In a before-after study of omeprazole for esophageal reflux, 15 children were followed for a mean of 12 months. A short-term before-after study of pantoprazole reported elevated liver 211 enzymes in 1 of 18 children exposed for 28 days and 5 of 18 (28%) had hypergastrinemia. In a 2-week study of lansoprazole in children (mean age 11 years) only mild gastric adverse events 212 were reported. Two short-term trials compared lower dose and higher dose esomeprazole in children with gastroesophageal reflux disease. These trials made no comparison to placebo or other drugs. In 148 adolescents aged 12 to 17 years assigned 20 or 40 mg esomeprazole daily for 8 weeks, 15% experienced an adverse event considered related to esomeprazole; headache (8%), 266 abdominal pain (3%), nausea (2%), and diarrhea (2%). In 108 younger children, aged 1 to 11 years, who were assigned to 5 or 10 mg esomeprazole if weight < 20 Kg or 10 or 20 mg if weight > 20 Kg, 9% reported an adverse event considered related to esomeprazole; diarrhea (2. Serious adverse events thought to be related to esomeprazole were not reported in either study. Are there subgroups of patients based on demographics, other medications, or comorbidities for which a particular medication or preparation is more effective or associated with fewer adverse effects? Summary • Head-to-head comparison studies did not adequately describe or analyze subgroups for differences in effectiveness. However, 2 studies assessed adverse effects in subgroups of age, gender, and race and found no difference among groups. Only 1 of these studies was a head-to-head comparison, omeprazole compared with lansoprazole, but no difference was found between the drugs. Proton pump inhibitors Page 64 of 121 Final Report Update 5 Drug Effectiveness Review Project • While the effects of the proton pump inhibitors may differ by demographics, there was inadequate data to identify any of these differences. Analysis of the subgroup taking pantoprazole indicated no increased risk, while analysis of the other proton pump inhibitors (as a group) indicated a similar increase in risk. Detailed Assessment Age and sex In included head-to-head studies, the enrolled patients were middle aged, with mean ages 268 162 ranging from 43 to 70 years. The ethnicity of 4, 25, 75, 108, 268 participants was stated in only 5 trials. The majority of studies included mostly white populations. In those studies with greater variation subgroups were too small for meaningful analyses by racial or ethnic group. An open-label, single-center trial conducted in 320 patients over age 65 compared 4 269 proton pump inhibitors for healing and symptom resolution in erosive esophagitis. This was the only head-to-head trial conducted exclusively in elderly patients. Patients were randomized to omeprazole 20 mg, lansoprazole 30 mg, pantoprazole 40 mg, or rabeprazole 20 mg. After 8 weeks of treatment, the healing rate in the overall group was 85% (intention-to-treat). Healing rates in the pantoprazole (90%) and rabeprazole (89%) groups were significantly higher than the omeprazole group (75%; P=0. No difference was found between omeprazole and lansoprazole (75% and 85%; P=NS). Pantoprazole and rabeprazole were also superior to omeprazole and to lansoprazole for resolution of heartburn (rates 100% for pantoprazole and rabeprazole, 87% for omeprazole, and 82% for lansoprazole). The frequency of adverse events was low (4 patients; 1. There was 1 small, 12-month, placebo-controlled trial in which pantoprazole 20 mg was effective for maintenance treatment of gastroesophageal reflux disease in patients age 65 or 270 older. An age-based analysis of healing or prevention was not possible in most head-to-head trials, due to the small numbers of older patients. However, 2 trials did assess the impact of age, 5, 106 gender, and race on the incidence of adverse effects. There were no differences between proton pump inhibitors (omeprazole, rabeprazole, esomeprazole) on the basis of these 198 characteristics. The effect of age on eradication rate was also evaluated. This study found higher eradication rates among patients older than 50 years than patients younger than 50, but proton pump inhibitors were not compared. Proton pump inhibitors Page 65 of 121 Final Report Update 5 Drug Effectiveness Review Project In trials comparing a proton pump inhibitor with another drug, the same general statements can be made, but a few findings deserve comment. Studies looking at healing or prevention of nonsteroidal anti-inflammatory drug-induced ulcer included more women than men, with the proportion of women ranging from 62% to 67% and 64% to 83% in the respective types of study. This is most likely due to the greater prevalence among women of diseases requiring long-term nonsteroidal anti-inflammatory drug treatment. Genotype The proton pump inhibitors are all metabolized, largely by the CYP2C19 and CYP3A4 liver enzymes. Theses enzymes are estimated to be deficient in 3% of white and African Americans and 17% to 25% of Asians. The deficiency results in a significantly longer half-life of proton pump inhibitors, although clinically significant accumulation of these drugs has not been shown. While dose adjustments are not required, and adverse effect profiles of the drugs do not differ, 184, 271 there is some evidence that lower doses may be effective in these populations and that 176, 177, 187 rapid metabolizers may have a higher rate of failure to eradicate Helicobacter pylori 272 and to heal esophagitis. Subgroup analysis found no effect by race in 1 study of esomeprazole 4 and lansoprazole in healing of erosive esophagitis. A small study (N=80) found no statistically significant difference at 8 weeks in rate of ulcer healing between rabeprazole 10 mg daily and 108 omeprazole 20 mg daily among patients with differing CYP2C19 genotype. The few adverse events were not analyzed by genotype. A trial of omeprazole in Japanese patients with recurrent 273 esophagitis found no difference in efficacy or safety by genotype. Older patients also metabolize proton pump inhibitors more slowly, resulting in significantly higher drug levels and half-lifes. However, accumulation has not been shown, and dose adjustments are not recommended.

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Cytomegalovirus IgG antibody is associated with subclinical carotid artery disease among HIV-infected women effective apcalis sx 20 mg erectile dysfunction doctor new orleans. Cidofovir: a review of its use in cytomegalovirus retinitis in patients with AIDS purchase apcalis sx us impotence 18 year old. The search for new therapies for human cytomegalovirus infections order apcalis sx 20mg online impotence natural remedy. A role for CMV-specific CD4+CX3CR1+ T cells and CMV-induced T cell immunopathology in HIV-associated atherosclerosis. Incidence and prognosis of CMV disease in HIV-infected patients before and after introduction of combination antiretroviral therapy. Causes of visual acuity loss among patients with AIDS and cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Incidence of and risk factors for visual acuity loss among patients with AIDS and cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Long-lasting remission of cytomegalovirus retinitis without maintenance therapy in HIV-infected patients. Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy: recommendations of an international panel. Effect of cytomegalovirus-induced immune response, self antigen-induced immune response, and microbial translocation on chronic immune activation in successfully treated HIV type 1-infected patients: the ANRS CO3 Aquitaine Cohort. Opportunistic Infections (OIs) 351 Candidiasis Candidiasis is an infection with yeast-forming fungi. Of the 150 Candida species known to date, only approximately 20 cause disease. Although it was commonly assumed that azole resistance is a problem particularly with albicans strains, this has not been the case to date (Sanglard 2002). Candidiasis is an important indicator of immunodeficiency and should be seen as a reason to consider starting ART, even with good immune status. Esophageal candidiasis and even oral thrush often occur following other OIs. Fever, not a classic symptom of candidiasis, is a particular indication to be on the alert for. If immune status is good, it must be remembered that there are also other reasons for thrush – alcoholism and steroid treatment are only two of many possibilities. In addition to candidiasis of the oropharynx and esophagus, vaginitis is a frequent problem in women (also occurring in healthy individuals). Candidemia occurs only rarely in HIV+ patients, even with severe immunodeficiency. Signs and symptoms The oropharynx is usually affected, with taste disturbances and sometimes a burning sensation on the tongue. White, non-adherent plaques on the buccal mucosa, tonsillar ring and tongue confirm the diagnosis. Occasionally, there may be atrophic candidiasis, which presents only with an erythematous mucosa. Candida esophagitis usually occurs with oropharyngeal involvement, but in about one third of cases there is no oral thrush. It often presents with dysphagia (“drink- ing is ok, but food can’t go down”) and retrosternal pain. Some patients complain of nausea, although vomiting occurs only rarely. Diagnosis Diagnosis in the oropharynx can be made based on clinical appearance. Characterization by culture or even determination of drug sus- ceptibility (beware laboratory uncertainty! Oral candidiasis is not to be confused with oral hairy leukoplakia (OHL). In contrast to candidiasis, the whitish, hairy plaques of OHL, on the sides of the tongue, cannot be scraped off. OHL is not caused by fungi but by EBV, and is an important disease marker for HIV, even if it is harm- less and does not require treatment. Candida esophagitis can also initially be diagnosed clinically. Dysphagia, retrosternal pain and oral candidiasis make the diagnosis very probable. Empiric fluconazole therapy reduces costs (Wilcox 1996). Upper GI endoscopy is only required if com- plaints persist. To distinguish fluconazole-resistant esophageal candidiasis from herpes or CMV esophagitis, samples of lesions should always be taken. In contrast, determination of serum antibodies or antigen is always unnecessary. Treatment With relatively good immune status at first presentation, treatment with topical antimycotics such as nystatin, amphotericin B or miconazole can be attempted. This is more effective and prevents relapses for longer (Pons 1997). According to a recently published trial, shorter treat- ment duration with higher dosages may be an option. In this large randomized study, a single dose of 750 mg of fluconazole was safe, well tolerated, and as effective as the standard 14-day fluconazole therapy (Hamza 2008). If symptoms last for more than a week, a swab should be taken and the daily flu- conazole dose may be increased to 800 mg for the second attempt. Itraconazole should only be used if the second treatment attempt fails and non-albicans strains have been found. It will be effective in approximately two thirds of cases (Saag 1997). Although itraconazole suspension is as effective as fluconazole (Graybill 1998), we do not primarily use it as plasma levels are unreliable and there are problems due to numerous interactions. A new alternative are miconazole mucoadhesive tablets. These tablets adhere to the oral mucosa and provide sustained local release of miconazole over a period of several hours with just one daily application. Miconazole has recently been approved in Europe (Loramyc) and the USA (Oravig™) for the treatment of oropharyngeal candidiasis (Lalla 2011). In a large trial, miconazole was shown to be noninferior to treatment with clotrimazole 10 mg troches 5 times daily for 14 days in HIV+ patients (Vasquez 2010). Trials comparing miconazole with oral fluconazole are lacking.


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Sialic acid components of host cells form the primary site of influenza attachment buy apcalis sx mastercard erectile dysfunction treatment vacuum pump. Thus purchase apcalis sx with amex erectile dysfunction medication for sale, NA appears to cleave the host receptors to which influenza binds buy discount apcalis sx 20mg line no xplode impotence. This function seems to aid in releasing progeny viral particles from infected host cells. It may be that viruses lacking neuraminidase activity enter host cells and replicate, but get stuck on the surface of the cell by attachment to sialic acid (Palese and Compans 1976). First, surface mapping determines which amino acids occur in sites accessible to antibodies. Underwood (1982, 1984) raised a panel of 125 mouse IgG MAbs against HA. Underwood compared the reactivities of the MAb panel against different natural and laboratory sequence vari- ants of HA. Statistical methods identified which changed amino acids caused a reduction in antibody binding. The changed amino acids were located on the three-dimensional HA structure provided by Wilson et al. Almost the entire distal exposed surface of HA reacted with anti- body, suggesting that the exposed regions provide a nearly continuous surface of potential epitopes. There are some problems with inferring antibody pressure by map- ping surface antigenicity. Different natural and laboratory isolates of influenza may have multiple amino acid differences. This makes it dif- ficult to assign changed antibody binding either to single amino acid substitutions or to the role of the genetic background with variations at other sites. In addition, changed antibody binding at different sites may have different consequences for binding kinetics and viral fitness. Some of the following methods mitigate these limitations. Asecondapproach applies MAb to either cultured or in vivo influenza (Wiley et al. This experi- mental evolution favors escape variants that avoid neutralization. The locations of the escape variants map the potentially variable sites that can mutate to avoid recognition while preserving the ability to remain infectious. This antigenic map can be used to determine whether nat- urally varying amino acid sites likely changed under antibody pressure or by some other process. Often, the same amino acid substitution occurs in replicate lineages faced with the same MAb, suggesting that the particular substitution EXPERIMENTAL EVOLUTION: INFLUENZA 215 provides the best balance of escape from neutralization and preserva- tion of viral fitness. Sites that do not change under MAb pressure may either lack important contact with the antibody or may be constrained by function. These alternatives can be tested by site-directed mutagen- esis, which experimentally changes particular amino acids. Athirdexperimental technique simultaneously applies antibodies to twoormoresites (Yewdell et al. This mimics host reactions in which two or more immunodominant sites gen- erate neutralizing antibodies. The frequency of escape mutants to a sin- gle antibody is about 10−5,sosimultaneous escape against two distinct antibodies occurs at a vanishingly low frequency of 10−10. Itappears that host antibodies directed simultaneously to two or more sites can greatly reduce the chance of new escape mutants during the course of asingleinfection. Afourthexperimental method focuses on escape mutants from low- affinity, subneutralizing antibodies (Thomas et al. They used those mice to raise low-affinity MAbs against influenza X-31 (sub- type H3N2). In previous studies, high-affinity MAbs applied to influenza typically selected single amino acidchanges in one of the majorantigenic sites A– E(fig. By contrast, low-affinity MAbs selected escape mutants that had two amino acid substitutions, one in the conserved receptor-binding pocket and one in the highly antigenic regions next to the receptor- binding site. Clearance and protection probably derive from high-affinity IgA and IgG antibodies rather than low-affinity IgM. So results from low-affinity MAbs do not reflect the most common selective pressures on antigenic variation. This study does, however, call attention totheprocesses by which immunodominance develops within a host. The initial, naive an- tibody repertoire may span widely over the HA surface, including the receptor binding pocket. The stronger antigenic sites apparently out- compete weaker sites in attracting high-affinity antibodies. NA escape mutants have been studied less intensively than those for HA (Webster et al. Sialic acid occurs as the terminal residue attached to galactose on certain carbohydrate side chains. Two commonlinkagesbetween sialic acid and galactose occur in natural molecules, the α(2, 3) and α(2, 6) forms. Different amino acid residues in the HA receptor binding site affect the relative affinity of HA for α(2, 3) versus α(2, 6) linkage (Matrosovich et al. Isolates of influenza A from aquatic birds favor the α(2, 3) linkage. This matches the common α(2, 3) form on the intestinal tissues of those hosts. All fifteen HA subtypes in aquatic birds share a highly conserved receptor binding site (Webster et al. The binding site apparently evolved before the evolution of the different subtypes and has been retained during subsequent divergence. The human influenza A subtypes H1, H2, and H3 derived from avian ancestors (Webster et al. Each human subtype evolved from the matching subtype in aquatic birds, for example, human H1 from avian H1. In all three subtypes, the binding affinity of human lineages evolved to favor the α(2, 6) linkage (Paulson 1985; Rogers and D’Souza 1989; Connoretal. The evolutionary pathways differ for the human subtypes with regard to the amino acid substitutions and changes in binding that eventually led to preference for the α(2, 6) form. Human sub- types H2 and H3 have substitutions at positions 226 and 228 relative to avian ancestors.

This development process is characterized by funded and work across a broad array of projects that address basic an information-rich knowledge regime; risk is rapidly reduced cellular and molecular biological processes generic apcalis sx 20 mg erectile dysfunction medicine from dabur. The opposite applies to a novel cancer drug candidate order 20mg apcalis sx with visa erectile dysfunction obesity. If it fails buy apcalis sx with mastercard erectile dysfunction low testosterone treatment, it is likely to be because of lack of An example of these ideas in action is the Initiative in Systems efficacy discovered after completion of large, expensive, and Pharmacology at Harvard Medical School, directed by Marc time-consuming phase 2 or phase 3 studies. Although not primarily a drug discovery platform, the 312 American Society of Hematology Table 1. Solutions through collaboration: examples of PPPs ● Systems approaches to drug research; Organization Website ● Beyond high throughput screening—pharmacological interac- Innovative Medicines Initiative www. Kirschner recognizes that academia does not have a complete drug discovery Two examples of existing consortia are: the IMI One project, which tool kit but that “Science in general has gained a lot from being has assembled a 10 000-patient database on schizophrenia that forced to think about practical problems… We might learn some- includes genetic and imaging data, and the European Lead Factory. These capabilities are not commonly available to ogy to cancer drug discovery include efforts by Dar et al to refine academic investigators. The European Lead Factory will be a kinase targeting and those of Patel et al to develop systemic, collection of a half million compounds (sourced from public and multidisciplinary and computational methods to identify and match 20,21 private collections) placed in a high-throughput screening center. The facility will offer researchers in academia the opportunity to have their targets screened against its library to identify “hits” and Solutions through collaboration will then provide support that will enable a hit to be matured to a At a more applied level, several broad-based programs intended to product candidate. These product candidates may become drugs improve the process of drug discovery have recently been initiated and/or tools to validate disease targets. Among the most interesting are various public–private partnerships (PPPs). PPPs are intended to In the United States, there are also PPPs focused on creating catalyze significant interaction between pharmaceutical and biotech- collaboration across the same groups addressed by the IMI. In 2004, nology companies, academic institutions, science and regulatory the FDA launched that Critical Path Initiative (CPI), “critical path” agencies, patient advocacy groups, and occasionally other entities referring to key steps in drug development. CPI enunciates the interested in healthcare advances. The research agenda of a typical FDA’s strategy for “transforming the way FDA-regulated products PPP is directed at topics of common interest to all parties, usually 23 are developed, evaluated, and manufactured. The IMI is a PPP established to improve the process of discovery Funding to the scientific community to help address some of these and development of innovative medicines and thereby reinvigorate issues is provided by direct grants from the FDA and through a the biopharmaceutical industry in Europe. The IMI is guided by a nonprofit foundation, the CPI. Like the IMI, but on a smaller scale, strategic research agenda that is reviewed and updated over time. Consortia of corporate and nonprofit nongovernmental organizations (the same broad groups that the IMI entities apply for funding to conduct IMI-sponsored projects. The program is directed through the Foundation for the National Institutes of Health. One of the most advanced of Key research areas include: the resulting programs is the Biomarker Consortium (BC). Within these target areas, ● Rare diseases and stratified therapies; projects are funded that will: Hematology 2013 313 ● Facilitate the development and qualification of biomarkers; Some institutions are establishing their own venture funds to advance in-house discoveries. Partners Health Care, the parent ● Qualify biomarkers for diagnosing disease and predicting clinical organization of the Brigham and Women’s and Massachusetts response; General Hospitals, has been an early innovator in this area. With 30 million dollars in funding and professional staffing provided by ● Translate results to aid regulatory decision-making; and Partners, the fund is able to identify worthy discoveries, conduct due diligence, and partner with outside investors to create companies. The BC has established a simple process for investigators to submit a project concept for approval and funding. Applications are Academic centers, intent on maximizing the value of their reviewed on a rolling basis. Outsourcing various aspects of The Academic Drug Discovery Consortium (www. Individuals can join for free and be linked to a of fully integrated Chinese corporations that provide a compre- wealth of useful information. By working with these companies, a near Therapy Acceleration Program of the Leukemia & Lymphoma virtual enterprise can advance a new drug concept to the point of Society (www. Upfront payments, milestone have a high tolerance for risk, are willing to fund big “swing for the payments, and long-term royalty revenues will be increasingly fences” ideas, and can make decisions quickly. Efforts that risk-reduce assets will It is still too early to assess the impact of the PPP strategy, but these enhance their interest to corporate partners and increase their efforts are accelerating transformation of the drug discovery pro- intrinsic worth and, importantly, happy buyers will be repeat cess. Collaboration among commercial and nonprofit entities has customers. PPPs can catalyze the evolution of this new ecosystem. Conclusions Risk and failure will continue to be the norm for drug discovery. Getting the facts right Learning from failure is not a skill that is easily acquired. In the As I have noted already, the constant of failure is central to the rising academic world, we shun failure and failed results are rarely cost of pharmaceutical R&D. Wasting time and money on a bad published (except in the form of an occasional retraction). A topic of increasing interest and concern is the the pharmaceutical industry, a “fast to fail” mindset is seen as an common experience of published results that cannot be reproduced. To Scientists at Bayer reported that the company’s in-house experimen- suggest that success can be built from failure may be an extreme tal data do not match literature claims in 65% of target-validation view; however, it is likely that the rate of progress will improve if projects. Similarly, Amgen scientists report that they could not the new norm becomes an open discussion of failure rather than reproduce key results in reports of high interest to their oncology keeping failed results a secret. They have direct research, it is clearly a constant concern that the academic commu- access to patients, the definitive experimental system in drug nity must acknowledge and work to resolve. This institutional licensing offices want to make multiple lucrative deals is both an opportunity and a responsibility. Drug discovery is increasingly of interest to academic scientists. As industry tries to address the productivity gap and reduce the Several strategies have been initiated to provide an additional layer inefficiencies of its internal research efforts, opportunities are being of validation for ideas coming from nonprofit institutions. Elizabeth created for meaningful collaboration with academic partners. Iorns has started the Reproducibility Initiative, a consortium that allows scientists to submit studies to an independent advisory board for possible reproduction. If a project is selected, the scientist Disclosures provides funding and an independent laboratory conducts the Conflict-of-interest disclosure: The author is employed by Dyax Inc. Available from http:// Burt Adelman, Division of Hematology, Brigham and Women’s www. Hospital, Boston, MA 02115; Phone: 617-250-5587; Fax: 617-577- 14. The evolution of science-based business: innovating 9451; e-mail: burtadelman@gmail.