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By J. Ismael. Louisiana State University at Baton Rouge. 2018.

It is appropriate to consider gastrointestinal structure in relation to gastrointestinal function discount 40 mg nexium visa. The function of the digestive system is to break down complex molecules discount nexium 20 mg free shipping, derived from ingested food, into simple ones for absorption into the blood or the lymph. This process occurs in five main phases, within defined regions of the gastrointestinal system: • ingestion (mouth); • fragmentation (mouth and stomach); • digestion (stomach and small intestine); • absorption (small and large intestine); • elimination of waste products (large intestine). There has recently been considerable interest in this site for the systemic delivery of drug moieties. The possibility of transmucosal delivery via the mucous membranes of the oral cavity is discussed in Chapter 7. The stomach The stomach is a sack that serves as a reservoir for food, where fragmentation is completed and digestion initiated. Digestion is the process by which food is progressively broken down by enzymes into molecules small enough to be absorbed; for example, ingested proteins are initially broken down into polypeptides, then further degraded into oligopeptides and finally into di- and tri-peptides and amino acids, which can be absorbed. Although the stomach does not contribute as much as the small intestine to the extent of drug 133 Figure 6. The small intestine The small intestine, comprising the duodenum, jejunum and ileum, is the principal site for the absorption of digestive products from the gastrointestinal tract. The first 25 cm of the small intestine is the duodenum, the main functions of which are to neutralize gastric acid and pepsin and to initiate further digestive processes. Digestive enzymes from the pancreas (which include trypsin, chymotrypsin, amylase and lipases) together with bile from the liver, enter the duodenum via the common bile duct at the ampulla of Vater (or hepatopancreatic ampulla). Bile contains excretory products of liver metabolism, some of which act as emulsifying agents necessary for fat digestion. The next segment of the small intestine, the jejunum, is where the major part of food absorption occurs. In addition to the great length of the small intestine, the available surface area is further enhanced by the presence of (Figure 6. The large intestine has two main functions: • to absorb water and electrolytes; • to store and eliminate fecal matter. The submucosa This is a layer of loose connective tissue that supports the epithelium and also contains blood vessels, lymphatics and nerves. The muscularis propria This consists of both an inner circular layer and an outer longitudinal layer of smooth muscle and is responsible for peristaltic contraction. The serosa This is an outer layer of connective tissue containing the major vessels and nerves. Four main types of mucosa can be identified, which can be classified according to their main function: • Protective: this is found in the oral cavity, pharynx, esophagus and anal canal. The surface epithelium is stratified squamous and may be keratinized (see Section 1. The mucosa consists of long, closely packed, tubular glands which, depending on the stomach region, secrete mucus, the hormone gastrin and the gastric juices. The intestinal villi are lined by a simple, columnar epithelium which is continuous with that of the crypts. The cells of this epithelium are of two main types: (i) the intestinal absorptive cells (enterocytes), which are tall columnar cells with basally located nuclei; (ii) the mucus-secreting goblet cells, which are scattered among the enterocytes. The mucosa is arranged into closely packed straight glands consisting of cells specialized for water absorption and also mucussecreting goblet cells, which lubricate the passage of feces. Segmentation, tonic contraction, and peristalsis are the three major types of motility patterns observed in the gut. Gastrointestinal, Hepatobiliary, and Nutritional Physiology, Lippincott-Raven, Philadelphia, pp. The Peyer’s patches are found particularly in the distal ileum of the intestinal tract. The epithelium covering the Peyer’s patches comprises specialized antigen-presenting epithelial cells, called M-cells (modified epithelial cells). The uptake and translocation of antigen by the M-cells of Peyer’s patches can be exploited for oral drug and vaccine delivery, as described below (Section 6. It propels intestinal contents, mixes them with digestive juices, and prepares unabsorbed particles for excretion. Gastric motility has been shown to be inhibited by D-glucose in the intestinal fluid. The length of time a drug moiety is in contact with the absorbing tissue will obviously influence the extent of drug absorption. Intestinal motility moves materials in the stomach or small intestine distally towards the large intestine and it has been estimated that in some cases residence of a drug moiety in the small intestine can be in the order of minutes, thereby severely limiting the effective contact time. Following the ingestion of food, the gastric pH rises transiently to 4–5 or higher, but this provokes further acid secretion.

The role of these two groups of antigens in the immune response observed during the infection is discussed discount 20mg nexium. In the alimentary tract of the insect vector cheap 40 mg nexium with mastercard, the parasite exists ex- Leishmaniasis are parasitic diseases, caused by protozoan tracellularly as a flagellated motile form, the promastigote. The disease has a wide range and phagocyted by resident macrophages within which the of clinical manifestations that depend not only on the infect- parasite differentiates into the nonmotile amastigote form ing Leishmania species but also on the immune status of the and multiplies. The most extensively studied leishmanial disease is dendritic cells may also harbour parasites [4]. These cells are responsible for the microbicidal cosal membranes giving origin to the mucocutaneous form and antigen-presenting functions however they serve as a of the disease. The existence of inbred mice, ceral one that, if untreated, gives rise to a high mortality rate. HeJ) has helped to elucidate the pro- and hypergamaglobulinemia and is caused by members of tective or nonprotective role of cytokine and T-helper cell the L. This will ultimately lead to the ac- tivation of parasite-infected macrophages that, through the The secreted proteins have distinct functions during Leish- induction of effector molecules as nitrogen and oxygen re- mania infection. First, they play a role in the establishment active species, will kill the intracellular parasites [5]. In con- of the infection [12] in conjunction with important elements trast, failure to control the infection has been associated with existent in the saliva of the sandfly vector [13, 14]. Given the ancient evolutionary di- by interfering with the macrophagic microbicidal functions, vergence in Leishmania species, it is not surprising that the cytokine production, antigen presentation, and effector cells control of the different Leishmania driven diseases is related activation. This is achieved by repression of gene expression, to different immunological properties. This gression, in visceral leishmaniasis its importance has been macrophagic anergy enables the continuous multiplication ruled out [7]. The importance of some of these tibodies can also have a function in restricting the infection molecules in the establishment of the infection is well doc- when the parasite is exposed to the extracellular milieu [9]. However, until now, no effective vaccine resent the first challenge following entrance into the blood- against human leishmaniasis is available for clinical use [3]. Procyclic promastigotes are highly susceptible to Leishmania parasites inside their hosts do not behave complement action, unlike the metacyclic that can avoid inertly. Rather, the virulence related to their pathology seems complement mediated lysis [17]. This remarkable difference to be linked to an induced lack of immune response control. The importance of the secreted versus sion [24–26], and inhibition of phagosome-derived superox- nonsecreted antigens ide [27]. Nine of them were already described as excreted/secreted proteins in Leishmania or other species, 11 corresponded to known proteins but not characterized as secreted and the other 13 were completely new and unchar- acterized proteins [51]. This shows how little is known about the Leishmania secretome since only a few proteins are exten- sively characterized [52–56]. Chang et al suggest that these secreted/excreted proteins were evolutionarily selected becoming immunolog- ically “silent” [60]. The first steps of infection, while the parasite is still exposed to binding of gp63 to fibronectin receptors favours the parasite the extracellular environment. Furthermore, gp63 is an we present three distinct proteins: a cytosolic tryparedoxin endopeptidase with the potential to degrade immunoglobu- peroxidase of L. The nia silent information regulator 2 (Sir2) [52], and a try- optimal proteolitic activity of gp63 is at pH 4 that may indi- cate some active proteolitic function in the amastigote stage paredoxin of L. Despite this, gp63 expression is downregulated in nia secreted proteins (Figure 1)[52], that show distinct im- amastigotes [36]. More- is maintained during the Leishmania infection and decreases over, gp63 mutation in L. So the importance of gp63 in when tested in vitro or in vivo using the Balb/c model, this the course of the infection remains elusive. Another interesting group of proteins are the cys- Sir2 immunization results in a decreased infectivity in the teine proteases. This could be partially due to the to be associated with disease progression [42]. The tease activity can be found at the parasite surface or inside immunization leads to a significant decrease of the spleen 4 Journal of Biomedicine and Biotechnology Weeks after L. However, it is incapable by itself of resolving the in- fection, as seen six weeks after infection, where there is no (a) significant difference between the immunized infected group Liver and the infected control group (Figure 3). Certain secreted 6 proteins seem to function as immunomodulatory compo- ∗ nents, acting as host immune evasive proteins. The mice were sacrificed after 2 and 6 weeks of infection and the parasite load in the spleen and liver determined by the organ involved in macrophagic disruption [16, 58, 68, 69]. The data represent means and stan- gest that amastigote secreted proteins will be more immuno- dard deviations for three mice and are representative of two inde- genic and can have interesting immunomodulatory proper- pendent experiments. Statistical analysis was performed using Stu- ties since they have not been under the selective pressure as dent t-test.

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There are many exemplary manufacturers in de- veloping countries that observe international best practices buy nexium 20 mg low price. There are also many that do not purchase 20 mg nexium visa, but they operate anyway, either because the regulatory authority is unaware of the problem, or because regulators are under pres- sure to ignore it in the name of promoting industry. Quality control is a part of good manufacturing practices sometimes neglected in developing countries. The majority of the pharmaceutical industry in the poorest countries only formulates and re- Copyright © National Academy of Sciences. Confrming the quality control measures used by suppliers, who are often in other countries, is particularly diffcult for these frms. Formulation companies have about a 6-month lag between placing an order for an active ingredient and selling a fnished drug (Bumpas and Betsch, 2009). This delay can be even longer for frms in landlocked countries or places where customs clearance and transportation from the port of entry are slow or unpredictable (McCabe, 2009). It takes substan- tial working capital to cover costs during those lags (Bumpas and Betsch, 2009). The market for active ingredients has been especially volatile in recent years because of increas- ing costs of raw materials and growing environmental regulation in India and China (Bumpas and Betsch, 2009). Price volatility further complicates business for smaller frms, who tend to deal with less consistent (therefore cheaper) suppliers who are more vulnerable to market shocks. Although proper quality-control measures require purchasing only from suppliers who observe good manufacturing practices, supplier quality is often ne- glected because of logistical and fnancial obstacles. And, because the cost of active ingredients is by far the largest fraction of overall cost, a small reduction in active ingredient can vastly increase the proft margin. Good quality comes at a price, either from equipment costs, better ingredients, or the higher process cost of quality assurance. Microbial con- tamination is more of a threat in countries with poor water quality; much equipment cannot run on erratic power supplies (Anderson, 2010). Some small-scale pharmaceutical companies make few fnished formu- lations, but others make a wide range of products. Small frms are not gen- erally able to dedicate equipment to specifc products; equipment cleaning and cleaning validation become especially important. When equipment used for multiple products is not properly cleaned, and the cleaning not validated prior to changing the product line, the drugs produced can become con- taminated. Quality-control assays generally test for the presence of the known ingredients, not the wide Copyright © National Academy of Sciences. Of the 46 countries in sub-Saharan Africa, about 80 percent have local pharmaceutical industries, but only South Africa produces active ingredients (Bumpas and Betsch, 2009). South Africa alone accounts for 70 percent of the region’s medicines production (Bumpas and Betsch, 2009). The frms that make fnal formulations in developing countries buy excipients and active ingredient from chemical suppliers abroad, mostly from China and India. China supplies about 43 percent of the world’s active ingredients for anti-infective medicines and exports 77 percent of the active ingredient made in the country, a $4. India exports 75 percent of the $2 billion worth of active ingredients it pro- duces (Bumpas and Betsch, 2009). There is signifcant expense necessary for pharmaceutical companies to follow good manufacturing practices. In India, for example, large pharma- ceutical companies supply medicines and vaccines of the highest quality to every country in the world, but thousands of small manufacturers struggle to implement quality-assurance and quality-control procedures (Kaplan and Laing, 2005). A World Bank study found that one-tenth of Indian regis- tered pharmacies report substandard medicines, most of them coming from small- and medium-sized producers (Kaplan and Laing, 2005). Because the registered pharmacy is the most strictly regulated medicines outlet in India, the proportion of substandard medicines sold in the informal market is presumably much higher. In a survey of antibiotic quality in Indonesia, investigators found 89 percent of samples of one local company’s cotrimoxazole were substandard (Hadi et al. Critics of local manufacture have cited these problems as reasons against pharmaceutical manufacturing in low- and middle-income coun- tries (Ahmed, 2012; Bate, 2008). Domestic manufacture of medicines is an important part of health and industrial policy in many countries. Governments are understandably eager to ensure a safe drug supply for their population. In theory, locally made products could be cheaper because of lower shipping costs incorporated into the fnal price (Kaplan et al. Manufacturing medicines also gives people jobs and facilitates technology transfer (Wilson et al. Companies that start out packaging only fnished drugs will slowly develop the trained workforce needed for more complicated secondary and primary manufacturing. Initial capital investments and infrastructure problems stand between quality medicines and many small- and medium-sized medicine manufactur- ers. There are companies in developing countries that want to meet inter- national quality standards and buy from reliable suppliers, but they fail to do so for reasons beyond their control. Governments alone cannot supply the technical depth or money to fx these problems (Wilson et al.

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Changes in pharmacodynamic response to fentanyl in neonates during continuous infusion cheap 20mg nexium visa. Issues of pharmacology in pediatric cardiac extracorpor- eal membrane oxygenation with special reference to analgesia and sedation buy 40mg nexium with mastercard. Opioid withdrawal in neonates after continu- ous infusions of morphine or fentanyl during extracorporeal membrane oxygena- tion. Effects of extracorporeal membrane oxygenation on morphine pharmacokinetics in infants. Plasma fentanyl levels in infants under- going extracorporeal membrane oxygenation. Plasma concentrations of midazolam in neonates receiving extracorporeal membrane oxygenation. Pharmacokinetics of midazolam in neonates undergoing extracorporeal membrane oxygenation. Phenobarbital dosing and pharmacokinetics in a neonate receiving extracorporeal membrane oxygenation. Wessel Pathophysiology of Pulmonary Hypertension Elevated pulmonary arterial pressure arises from three well-characterized vascular changes: vasoconstriction, thrombus formation, or proliferation of smooth muscle and/or endothelial cells in the pulmonary vessels. Recent advances in molecular biology have allowed for the identification of several key mediators of vascular function in the pulmonary vasculature. This, in turn, has enabled development of specific pharmacological therapies for the disease. Arachidonic acid metabolites, such as prostacyclin and thromboxane A2, are active in the pulmonary vessels, associated with vasodilation and vaso- constriction, respectively. In addition, prostacyclin is a platelet inhibitor and is capable of inhibiting endothelial cell proliferation, whereas thromboxane A2 is a platelet activator. Endothelin-1 is a vasoconstrictor that causes smooth- muscle proliferation in pulmonary vessels. With great consistency, patients with pulmo- nary hypertension have been found to have altered homeostatic balances of these factors, tending toward prothrombotic, vasoconstrictive physiology. These clinical findings suggest that acquired alterations in normal vascular physiology contribute to the onset of pulmonary hypertension. Other conditions that contribute to chronic changes in the pulmonary vasculature include hypoxemia and small vessel thrombosis. Thrombotic events in the micro- vasculature contribute to hypoxia and also release acute mediators that contribute to vasoconstriction. Pharmacological Treatment 227 medial hypertrophy, smooth muscle extension into nonmuscular arteries, and intimal cell proliferation from smooth muscle thickening. Progressive changes include intimal fibrosis, and eventual thinning of the media with dilation of the vessels (Grade 3 and 4). Eventually, medial fibrosis and necro- tizing arteritis (Grade 5 and 6) changes arise in the pulmonary vessels. Longstanding expo- sures to high flow and pressure in the pulmonary circulation are associated with gradual reduction in endothelial function. Imbalances between vasodilators/vasoconstrictors, platelet activation/inhibition, and endothelial and smooth muscle cell proliferation/inhibition conspire to cause chronic pathological changes in pulmonary vessels and worsening clinical symptoms (Figure 10-1). Importantly, these contributing factors to the pathophysiol- ogy of pulmonary hypertension also serve as emerging targets for treatment. Strategies that reverse these underlying contributors to pulmonary hyperten- sion seem able to improve clinical function in patients. Histori- cally, the incidence of true postoperative pulmonary hypertensive crises in patients who were judged preoperatively to be at risk for these events was high, probably greater than 50%. Vasodilators by class Drug class Advantages Disadvantages Nitrates Easily titratable, rapid onset and 1. Little effect on pulmonary myocardial remodeling circulation Calcium channel blockers Orally active, best defined role 1. Intravenous forms produce systemic increase cardiac output, some hypotension pulmonary selectivity, titrat- 2. Aerosolized delivery systems not well established, with frequent administration required Endothelin receptor Effective for disease states with 1. Minimal experience in critically ill pulmonary specificity patients on mechanical ventilation 3. Intravenous forms more suitable for postoperative setting but not yet approved for use in humans βagonists Increases cardiac output, titratable 1. Hypotension at high doses for pressures, acts synergistically refractory pulmonary hypertension with catecholamines, not 3. Slightly long duration of action arrhythmogenic (1–3 h) Phosphodiesterase Orally active, act synergistically 1. Longer-acting oral forms under agent pulmonary vasodilator, development may have additive effects with 4. Complex delivery compared with shunt, no myocardial depres- oral medication sion, may have benefit from 4. Pharmacological Treatment 231 markedly reduce the incidence of postoperative pulmonary hypertension and mortality associated with this condition.

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