Montelukast

Michael J. Lipinski, MD

• Resident in Medicine, Department of Medicine, University of Virginia,
• Charlottesville, VA, USA

The effector cell then releases the contents of these granules onto the target cell asthma symptoms emphysema generic montelukast 5 mg fast delivery. The target cell may be damaged by the perforins or enzymatic contents of the cytolytic granules asthma 1930s discount 10 mg montelukast visa. Once it has degranulated define asthma triggers buy montelukast 4 mg cheap, the effector cell can release the dying target and move on to kill other target cells asthma 5 month old cheap montelukast 4 mg fast delivery. In response, the macrophages release various mediators, including reactive oxygen species and proteases, which act to kill the infected cell. Finally, it is clear that many of the soluble factors critical to the innate immune system are also primary effectors in the acquired immune system, including reactive oxygen species, granzyme, perforin, cytokines, and interferons, again demonstrating the interplay among the various arms of the immune system. Again, it is important to emphasize that whereas inflammation is a natural reaction to repair tissue damage or attack foreign invaders, the process often results in destruction of adjacent cells and/or tissues. In addition, recent studies have suggested that inflammation exacerbates idiosyncratic reactions to drugs and other chemicals (reviewed in Ganey et al. Major cellular contributors to an inflammatory response are macrophages, neutrophils, and T cells. Neutrophils are often the first, and most numerous, responders to sites of insult. Macrophages also induce apoptosis of cells in the insult area through the release of nitric oxide and other reactive oxygen species, resulting in disruption of extracellular structures that compromise tissue structure and function (reviewed in Duffield, 2003). Both neutrophils and macrophages are phagocytic cells and can contribute to clearing of apoptotic cells. Schematic diagram of chemical interaction leading to hypersensitivity reactions or autoimmunity. Depending on the differentiation signals that the T cell receives, it may secrete cytokines that either mediate direct cell killing (Th1) or recruit other cells (Th2), such as B cells, to aid in resolution of the insult. Although many soluble factors that contribute to inflammation were mentioned above, there are several others that warrant discussion as well. As previously mentioned, reactive oxygen species are released from both macrophages and neutrophils to compromise membrane integrity and interact with several macromolecules in the insulted cells. A plethora of cytokines and chemokines also contribute to the inflammatory process, not only by acting as chemotactic factors, but also by dictating differentiation processes of T cells. Many of these pro-inflammatory cytokines also induce acute phase proteins, such as C-reactive protein. C-reactive protein binds to several ligands, including phosphatidlycholine on the membranes of cells, Fc receptors, and C1q (part of the complement C1 complex), which activates the classical complement cascade (reviewed in Marnell et al. Furthermore, complement fragments, such as C3a and C5a, act as chemotactic factors to recruit other phagocytic cells to sites of insult (reviewed in Roozendaal and Carroll, 2006). Finally, prostaglandins and other eicosinoids possess various proinflammatory actions, including T-cell proliferation (thromboxane A2), Th1/Th2 polarization (prostaglandin E2), and increase vascular permeability (prostacyclin I2) (reviewed in Hata and Breyer, 2004). In addition, prostaglandins contribute to hyperalgesia and it is for this reason that cyclooxygenase-2, which converts arachidonic acid to other bioactive prostaglandins, is an attractive therapeutic target to reduce inflammation and pain (see section "Immunomodulation by Xenobiotics, Anti-Inflammatory Agents"). Immune-Mediated Disease As stated earlier, the purpose of the immune system is to preserve the integrity of the individual from disease states, whether infectious, parasitic, or cancerous, through both cellular and humoral mechanisms. In so doing, the ability to distinguish self from nonself plays a predominant role. These disease states fall into two categories (1) hypersensitivity, or allergy, and (2) autoimmunity. Figure 12-10 is a schematic delineating the possible cascade of effects that can occur when a chemical produces an immune-mediated disease. Hypersensitivity reactions result from the immune system responding in an exaggerated or inappropriate manner. These reactions have been subdivided by Coombs and Gell (1975) into four types, which represent four different mechanisms leading to tissue damage. Hypersensitivity Classification of Hypersensitivity Reactions One characteristic common to all four types of hypersensitivity reactions is the necessity of prior exposure leading to sensitization in order to elicit a reaction upon subsequent challenge. Figure 12-11 illustrates the mechanisms of hypersensitivity reactions as classified by Coombs and Gell. Although not completely understood, regulation of immunoglobulin production is dependent in part on the characteristics of the antigen, the genetics of the individual, and environmental factors. The mechanisms of antibody production in hypersensitivity reactions are identical to those described earlier in the chapter. Sensitization occurs as the result of exposure to appropriate antigens through the respiratory tract, dermally, or by exposure through the gastrointestinal tract.

The molecule is chiral due to restricted rotation asthma disease montelukast 10 mg order with amex, and can thus exist as two atropisomers which do not easily racemize (Figure 5 asthmatic bronchitis 40 generic montelukast 4 mg buy on line. Only the (-)-isomer is pharmacologically active as a contraceptive asthma kids symptoms proven 4 mg montelukast, whereas most of the toxic symptoms appear to be associated with the (+)-isomer asthma symptoms in 3 month old order montelukast 5 mg without a prescription, which also displays antitumour and antiviral activities. Racemic (±)-gossypol (but neither of the enantiomers) complexes with acetic acid, so that suitable treatment of cotton seed extracts actually separates the racemate from the excess of (+)-isomer. Other plants in the Gossypieae tribe of the Malvaceae also produce gossypol, with the barks of Thespia populnea (3. The trichothecenes are a group of fungal toxins found typically in infected grain foodstuffs. Their name comes from the fungal genus Trichothecium, but most of the known structures are derived from cultures of Fusarium species. A particularly prominent trichothecene contaminant is deoxynivalenol (vomitoxin), which is produced from the less substituted trichothecene isotrichodermol by a sequence of oxygenation reactions (Figure 5. The trichothecenes have their origins in nerolidyl diphosphate, and ring closure of the bisabolyl cation derived from it generates a new carbocation with a five-membered ring (Figure 5. At this stage, a series of one hydride and two methyl migrations occur to give a cation, which loses a proton to produce the specific trichothecene precursor trichodiene. These migrations are fully backed up by experimental data, and although not immediately predictable, can be rationalized satisfactorily by consideration of the cation suitably bound to the enzyme surface as shown in Figure 5. The sequence is initiated by a 1,4-hydride shift which is spatially allowed by the relative proximity of the centres. Two electrophilic addition leads to five-membered ring and secondary cation 1,2-methyl shifts then follow, and it is important to note that each migrating group attacks the opposite side of the centre from which the previous group is departing, i. Accordingly, a concerted sequence of migrations is feasible, such a process being seen more vividly in the formation of triterpenoids and steroids (see page 216). Loss of a proton and generation of a double bond terminates the process giving trichodiene. Two of the hydroxylations are at activated allylic positions; hydroxylation on the five-membered ring will therefore occur before the epoxidation. Ether formation, involving perhaps protonation, loss of water and generation of an allylic cation, completes the pathway to the basic trichothecene structure as in isotrichodermol. Finally, it is worth noting how many of the sesquiterpene derivatives described above are found in plants belonging to the daisy family, the Compositae/Asteraceae. Whilst sesquiterpenes are by no means restricted to this family, the Compositae/Asteraceae undoubtedly provides a very rich source. About 150 different structures have been identified, with some of these being isolated from plants of the genus Baccharis (Compositae/Asteraceae), where a symbiotic plant­fungus relationship may account for their production. The double bond and the epoxide group in the basic trichothecene skeleton are essential for toxicity, and the number of oxygen substituents and ester functions also contribute. Macrocyclic ester functions as seen in verrucarin A tend to produce the most toxic examples. Although these compounds are more toxic when injected, oral toxicity is relatively high, and lethal amounts can easily be consumed because of the nature of the host plants. They are sufficiently toxic to warrant routine analysis of foodstuffs such as wheat and flour, and also flour-derived products. It is relevant to note that when mammals ingest these compounds, a degree of de-epoxidation can occur, ascribed to gut microflora, thus providing some detoxification by removing a structural feature necessary for toxicity. As their main mechanism of action, these compounds inhibit protein biosynthesis by binding to the ribosome and inhibiting peptidyl transferase activity (see page 407). This had become badly contaminated with Fusarium sporotrichioides and hence T-2 toxin. Many trichothecene derivatives have been tested as potential anticancer agents but have proved too toxic for clinical use. Available evidence suggests that geranylgeranyl diphosphate is involved in forming the ester linkage, and the three reduction steps necessary to form the phytol ester occur after attachment to the chlorophyll molecule. The phytyl group of phylloquinone is introduced by alkylation of dihydroxynaphthoic acid with phytyl diphosphate and a similar phytylation of homogentisic acid features in the formation of the E group vitamins (tocopherols).

Chronic iron toxicity from iron overload in adults is a relatively common problem chronic asthma definition generic 5 mg montelukast fast delivery. There are three basic ways in which excessive amounts of iron can accumulate in the body asthmatic bronchitis is it contagious best montelukast 5 mg. The first is hereditary hemochromatosis due to abnormal absorption of iron from the intestinal tract asthma symptoms only during a cold buy cheap montelukast 4 mg online. Hereditary hemochromatosis is an autosomal recessive disorder attributed to mutation in the hemochromatosis gene asthma treatment review buy montelukast 5 mg otc. About 90% of patients are homozygous for C282Y mutation, while a few patients are heterozygotes for C282Y with a second mutation for H63D. The second possible cause of iron overload is excess intake via the diet or from oral iron preparations. The third circumstance in which iron overload can occur is repeated blood transfusions for some form of refractory anemia and is referred to as transfusional siderosis. The body iron content can increase 20­40 g, up to 10 times higher than normal levels. Hemochromatosis refers to excessive deposition of iron that causes organ damage, often resulting in fibrosis. Inhalation of iron oxide fumes or dust by workers in hematic mines (mainly Fe2 O3), steel workers, and welders may produce siderosis (nonfibrotic), and in some cases silicosis (fibrotic) in the lung, with increases in total body iron (Doherty et al. Liver iron overload from hereditary hemochromatosis is associated with a high risk for hepatocellular carcinoma, as well as with other malignancies (Papanikolaou and Pantopoulos, 2005). It is suspected that iron may act as a catalyst to produce free radical damage resulting in artherosclerosis and ischemic heart disease (Alpert, 2004). This iron hypothesis is controversial, but it is clear that mortality from cardiovascular disease is correlated with liver iron overload (Yuan and Li, 2003). Treatment Desferrioxamine is the chelator of choice for the treatment of acute iron intoxication and chronic iron overload. Iron chelators have also been proposed for the treatment of cancers with iron overload (Buss et al. Paints that were pigmented with manganese dioxide can be traced back to ancient times. The pure element was isolated in 1774 and named after the Latin magnes, meaning "magnet. Manganese metalloenzymes include arginase, glutamine synthetase, phosphoenolpyruvate decarboxylase, and manganese superoxide dismutase (Aschner and Aschner, 2005). Manganese exists in many valences but the divalent cation is by far the predominant species within cells. Occupational exposures to high concentrations of manganese can occur in a number of settings, including manganese dioxide mines and smelters. The industrial use of manganese has expanded in recent years as a ferroalloy in the iron industry and as a component of alloys used in welding (Crossgrove and Zheng, 2004). Environmental exposures are often associated with manganesebased organometallic pesticides, maneb and mancozeb. The name originates from the Greek word for a district in Thessaly called Magnesia. Magnesium is a nutritionally essential metal that plays a key role in a wide range of important fundamental cellular reactions (Shils, 1996). Magnesium citrate, oxide, sulfate, hydroxide, and carbonate are widely taken as antacids or cathartics. Magnesium hydroxide, or milk of magnesia, is one of the universal antidotes for poisoning. Parenteral administration of magnesium sulfate has been used in the treatment of seizures associated with eclampsia of pregnancy and acute nephritis. Calcium and magnesium are competitive with respect to absorption, and excess calcium will partially inhibit magnesium absorption. Magnesium is excreted into the digestive tract by the bile and in pancreatic and intestinal juices. Approximately 60­65% of the total body magnesium is in the bone, 27% in muscle, 6­7% in other organs, and only 1% is in extracellular fluid. Of the magnesium filtered by the glomeruli about 95% is reabsorbed, an important factor in maintaining homeostasis. In the glycolytic cycle, there are seven key enzymes that require divalent magnesium.

Evidence for such "endocrine disruptions" by environmental xenoestrogens appears to be overall stronger for wildlife than for humans asthma treatment videos montelukast 10 mg sale, likely due to instances of elevated exposures that are less prone to confounding factors than is typically the case for human exposures asthma symptoms 8 weeks 5 mg montelukast with mastercard. Also asthma stepwise approach generic montelukast 10 mg line, egg-laying vertebrates provide a unique biomarker of estrogen exposure that has contributed to ecotoxicological studies in this area definition von asthma bronchiale montelukast 5 mg overnight delivery. Vitellogenin (Vtg) is a protein that is normally produced by the liver of females and transported via the bloodstream to the ovary where, as a key component of yolk, it provides nourishment to the developing embryo. Interestingly, males of egglaying vertebrate species contain the molecular machinery to produce Vtg, but production and circulating levels are normally very low, due to low titers of estrogen. However, exposures of males to estrogen and xenoestrogens upregulate Vtg production, which can be readily measured in blood samples. Consequently, elevated Vtg in males of these species is a useful biomarker of estrogenic chemical exposures (Sumpter and Jobling, 1995; see Biomarker discussion below). While the bulk of research related to estrogenic compounds in natural systems have focused on fish, this approach has merit for other egg-laying vertebrates (Lorenzen et al. Briefly, they play key roles for transforming many lipophilic chemicals, including numerous common organic contaminants, into more water soluble, and hence excretable, products. However, this biotransformation activity can result in production of highly reactive products that are more toxic than their parent compounds, i. In some cases, this can be interpreted as an adaptive response-the organism is reacting to exposure to a lipophilic xenobiotic in order to enhance its elimination. However, as noted above, biotransformation can also lead to enhanced toxicity of some substrates. Genomics and Ecotoxicogenomics Recent advances in gene sequencing and associated techniques for investigating mechanism underlying gene expression have revolutionized molecular biology. These advances are rapidly permeating many areas of biological research, including toxicology and environmental science. Underlying these advances are very large projects to sequence the entire genomes of various species, such as the highly publicized Human Genome Project that was completed in 2003 (Little, 2005). Other species that have been completely or largely sequenced include the mouse, rat, cow, dog, chimpanzee, chicken, zebrafish (Danio rerio), puffer fish (Fugu rubripes), medaka (Oryzias latipes), fruit fly (Drosophila melanogaster), a sea urchin (Strongylocentrotus purpuratus), a soil nematode (Caenorhabditis elegans), a yeast (Saccharomyces cerevisiae), and rice (Oryza sativa), and the number of species sequenced is anticipated to expand rapidly (see The study of changes in gene expression arising from chemical exposures is a key component of "toxicogenomics" (Schmidt, 2002). Microarrays for genomes or genome components of interest (such as genes associated with stress responses, carcinogenesis, and development) are commercially available for many species, and rapidly expanding. This has led to the development of the field of "bioinformatics" that includes the application of sophisticated statistical and computing approaches for revealing biologically meaningful patterns of gene expression such as relationships to cellular signaling pathways. Omics have spread into the science and applications of ecotoxicology, collectively termed ecotoxicogenomics. As is the case for human health-oriented toxicogenomics, ecotoxicogenomics has great potential for elucidating impacts of chemicals of ecological concern and ultimately for playing an important role in ecological risk assessments and regulatory ecotoxicology (Snape et al. Specific areas to which this emerging field can contribute include prioritization of chemicals investigated in ecological risk assessments, identification of modes of action of pollutants, identification of particularly sensitive species, and effect prediction at higher levels of organization. As in other areas of ecotoxicology, a major complexity faced is the vast array of species of potential concern. However, as mentioned earlier, the number of ecologically relevant species for which this information is becoming available is expanding rapidly, and is likely to accelerate as tools are refined. Moreover, as information grows, genomic approaches hold great promise for identifying appropriate surrogate species for laboratory studies used in basic ecotoxicological research and in support of regulatory ecotoxicology (Benson and Di Giulio, 2006). Protein Damage the study of chemical effects on proteins, particularly enzymes, has a long history in toxicology. This sensitivity has been exploited widely as a biomarker for lead exposure in humans and wildlife. In wildlife, concerns for lead exposure have included ingestion by birds of spent lead shot used in hunting (Kendall et al. This reduction of O2 to H2 O requires four electrons that are sequentially added; this process is tightly coupled so that the one, two, and three electron intermediates are released at low amounts (less than 0. Oxidative stress has been defined as "a disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage" (Sies and Cadenas, 1985)-i.

These centers became valuable resources for information about product ingredients asthma prevention purchase montelukast 5 mg without prescription, potential toxicity asthma journal articles generic 4 mg montelukast fast delivery, and recommendations for the treatment of poisoned patients asthma symptoms clip art order montelukast 10 mg fast delivery. Poison control centers proliferated over the next two decades and peaked at 661 centers in 1978 (Scherz and Robertson asthma symptoms 5 year old montelukast 10 mg amex, 1978). Most of these centers served small areas; each state had a least one poison center; several states had more than 20 poison centers active at the same time; and there was little standardization throughout the specialty. Staffing of a poison control center usually consists of a medical director (medical toxicologist), administrator or managing director, specialists in poison information, and educators for poison prevention programs. The medical toxicologist, managing director, and specialists in poison information are health care professionals who are credentialed by their respective boards. The American Board of Medical Subspecialties offers a subspecialty certificate in medical toxicology to physicians who successfully complete the certifying examination. The public health services provided by poison control centers have been well documented. These services include direct information to patients with recommendations for needed treatment, critical diagnostic and treatment information for health care professionals, education for health care personnel and poison prevention activities through public education. An often cited example of the economic benefit from access to a poison control center comes from a one year forced closure of the Louisiana State Poison Center. It was estimated that the increased costs to the state for emergency medical services was $1. Studies have shown that for each dollar spent to operate a poison control center a saving of approximately $3­6. Recently, the Institute of Medicine commissioned an in-depth study of poison prevention and control services in the United States. Most clinical toxicologists agree that a methodically executed, stepwise approach to the treatment of the poisoned patient is recommended for optimal care (Goldfrank, 2006; Ellenhorn, 1997). In that setting, the following general steps represent important elements of the initial clinical encounter for a poisoned patient: 1. Stabilization of the patient Clinical evaluation (history, physical, laboratory, radiology) Prevention of further toxin absorption Enhancement of toxin elimination Administration of antidote Supportive care and clinical follow-up Clinical Stabilization the first priority in the treatment of the poisoned patient is clinical stabilization. Assessment of the vital signs and the effectiveness of respiration and circulation are the primary objectives of this initial encounter. Early in the course of some poisonings there is a varying range of severity of demonstrated toxic effects by patients poisoned with even lethal dosages of toxins. Some chemicals, such as a benzodiazepine can cause pronounced clinical effects early such as sedation but can have a comparatively mild clinical course; while other chemicals, such as camphor, show little clinical effects initially but can produce a fatal outcome. Control of chemical-induced seizures can be an important component of the initial stabilization of the poisoned patient. The degree of initial clinical stabilization required for a poisoned patient therefore is highly variable. The clinical procedures available to stabilize a critically ill poisoned patient include the initial and ongoing assessment and, if indicated, support of ventilation, circulation, and oxygenation. A detailed description of the various clinical methods available to treat abnormalities in these parameters is beyond the scope of this chapter. The reader is referred to textbooks of emergency medicine and critical care medicine for further information on this subject. Once the poisoned patient is clinically stabilized, the remainder of the assessment and treatment steps can proceed. In critically ill patients, sometimes treatment interventions must be initiated before a patient is truly stable. Clinical History in the Poisoned Patient the primary goal of taking a medical history in poisoned patients is to determine, whenever possible, what substance the poisoned patient has been exposed to and to determine the extent and time of exposure. Unfortunately, in contrast to most specialties of medicine, the clinical history available during the initial clinical encounter in the treatment of poisoned patients is sometimes not helpful because it may be either unreliable or unobtainable. In the setting of a suicide attempt, the patient often is not willing to provide a history or may give incorrect information to increase the possibility of success of their attempt to bring harm to themselves. For these reasons, additional sources for the clinical history are often incorporated to aid the clinical team in determining what substances the patient has been exposed to . In estimating the exposure level to the poison, generally one should maximize the possible dose received. That is, one should assume that the entire prescription bottle contents were ingested, that the entire bottle of liquid was consumed or that the highest possible concentration of airborne contaminant was present for a patient poisoned by inhalation unless definite evidence exists to the contrary.

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