Asthma Holistic Treatments

Asthma Free Forever

With Asthma Free Forever, asthma sufferers worldwide will learn how they can cure asthma easily, naturally, and permanently in Asthma Free Forever. This guide was written by Jerry Ericson, an alternative medical practitioner and former asthma sufferer. This downloadable eBook format of the program is all about suggesting you right kind of lifestyle and strategies towards keeping the symptoms of asthma at bay and initializing the complete treatment to get you back to the normal life. Devised by inputting his self tested asthma recovery solutions, Mr. Ericson has got it right as there are many positive feedbacks are coming across all the corners enough to advocate the use and relief by this digital product. Conventional medicine offers no real solution to the seventeen million Americans suffering from this disease. But in this remarkable book, Jerry Ericson, shares his natural alternative that can help asthma sufferers worldwide break the bonds of asthma forever in only minutes a day! Continue reading...

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Pharmacotherapy Of Asthma

In the U.S., asthma accounts for 1-3 of all office visits, 500,000 hospital admissions per year, more pediatric hospital admissions than any other single illness, and 5000 deaths annually. The pharmacotherapy of asthma employs drugs aimed at reducing airway inflammation (i.e., antiinflammatory agents) and drugs aimed more directly at decreasing bronchospasm (i.e., bron-chodilators). To these ends, six classes of therapeutic agents are presently indicated for asthma treatment b adrenergic receptor agonists, glucocorticoids, leukotriene inhibitors, chromones, methylxanthines, and inhibitors of immunoglobulin E (IgE).

Asthmaas An Inflammatory Illness

Asthma is associated with inflammation of the airway wall. Increased numbers of various types of inflammatory cells, most notably eosinophils but also basophils, mast cells, macrophages, and certain types of lymphocytes, can be found in airway wall biopsies and in bronchoalveolar lavage fluid from asthmatic patients. Inflammatory mediators and various cytokines also are increased in the airways of asthmatic subjects compared with healthy control subjects. How bronchial inflammation contributes to the asthmatic condition remains poorly understood. Even asthmatics with normal baseline lung function and no recent exacerbations of their asthma have increased numbers of inflammatory cells in their airways. Conversely, many individuals allergic to inhaled allergens have evidence of lower airway inflammation but suffer only from the symptoms of allergic rhinitis. Many individuals with asthma are atopic and have clearly defined allergen exposures that are partially or substantially...

Mechanism Of Glucocorticoid Action In Asthma

Glucocorticoids do not directly relax airway smooth muscle and thus have little effect on acute bronchoconstriction. Their anti-inflammatory effects in asthma include modulation of cytokine and chemokine production inhibition of eicosanoid synthesis marked inhibition of accumulation of basophils, eosinophils, and other leukocytes in lung tissue and decreased vascular permeability. Because of their profound and generalized anti-inflammatory actions, glucocorticoids are the most effective drugs used in the treatment of asthma. INHALED GLUCOCORTICOIDS A major advance in asthma therapy was the development of inhaled glucocorticoids that targeted the drug directly to the relevant site of inflammation. These formulations greatly enhance the therapeutic index of the drugs, substantially diminishing the number and degree of side effects without sacrificing clinical utility. There are five glucocor-ticoids available in the U.S. for inhalation therapy beclomethasone dipropionate (beclovent,...

Concurrent Use ofInhaled Long Acting b2Adrenoceptor Agonists and Topical Antiinflammatory Glucocorticoids in Asthma

The reason why chronic asthma should be treated by concurrent inhalation of a b2-agonist, such as salmeterol, and a topical anti-inflammatory steroid is that their inhibitory actions on the inflammatory cells involved are complementary and their therapeutic effects are synergistic. The cellular basis for this approach is summarized in Table 11. The effects of b2-agonists on these cells have already been outlined in Section II. The complexity of the actions of glucocorticoids on them is well summarized in Taylor and Shaw's review (59). Table 11 Complementary Actions of b2-Adrenoceptor Stimulants and Antiinflammatory Steroids on Cells Involved in the Pathology of Asthma Comparative effects of treatment with beclomethasone dipropionate (200 mg) bid plus salmeterol (50 mg bid) or beclomethasone dipropionate (500 g bid) in asthmatic patients stabilized on beclomethasone dipropionate (200 g bid). (From Ref. 59.) Comparative effects of treatment with beclomethasone dipropionate (200 mg) bid...

Treatment of asthma with antileukotrienes

The suggestions from bronchoprovocation studies that cysteinyl leukotrienes mediate essential components of asthma have indeed been corroborated when the effects of anti-leukotrienes have been assessed in the treatment of asthma. The CysLTr antagonists montelukast, pranlukast and zafirlukast are registered for treatment of asthma in Europe, the US and many countries around the world, whereas the 5-lipoxygenase inhibitor zileuton is approved for use in the US alone. The effects which have been consistently observed in treatment trials are summarized in Table 9-1. It is beyond the scope of this chapter to dwell on the clinical use of anti-leukotrienes, suffice to say that anti-leukotrienes may be used alone as first-line therapy or as an adjunct to other asthma medications to obtain improved control of asthma. Reduced use of bronchodilators Fewer asthma symptoms (day and night) Fewer asthma exacerbations When anti-leukotrienes are administered to asthmatics with baseline asthma symptoms...

Antiinflammatory and antiasthmatic effects of PGE2

It appears very likely that E-prostaglandins are the mediators of the tachyphylaxis to repeated challenge with exercise, LTD4 or histamine, but it remains to be demonstrated that these responses are associated with in vivo release of PGE2 in humans. In further support of the hypothesis that E-prostaglandins mediate the tachyphylaxis, pre-treatment of asthmatics with PGEi, in doses which do not cause bronchodilation, reduced airway responsiveness to both histamine and methacholine 352 . Furthermore, inhaled PGE2 also protects from allergen-induced bronchoconstriction 306 and exercise-induced bronchoconstriction 353 , Inhalation of PGE2 has also been shown to inhibit aspirin-induced bronchoconstriction 354,355 , The findings with PGE2 in bronchoprovocation studies may be explained by the well-known ability of PGE2 to inhibit the activation of inflammatory cells 66 , The effect is, at least in vitro, due to EP2 receptor-mediated elevations of intracellular cAMP (see Section 1.6.2), which...

Factors Affecting Asthma

Several factors are affecting asthma including environmental and individual factors. There is seasonal variability in asthma in autumn, it is increased, while in summer, it is minimum in the United States (Silverman et al., 2003). The reasons for these variations include increased exposure to allergens such as pollen, house dust mites, and mould spores among younger generation and in adults it may be increased influenza or other respiratory tract infections (Riccioni et al., 2001). Moreover, cigarette smoke is one of the most common asthmatic reasons. Both indoor and outdoor air pollutants may also increase asthma. Inhalation of toxic vapors from industrial fumes, bleach sulfur, or smoke from fire or tobacco may also affect asthma ( Just et al., 2002). Several individual factors may also influence the variability of asthma. Poor inhaler technique for both metered-dose and dry powder inhalers is often observed in asthma patients and may be the cause for an increased risk of death....

Brief Mechanism About Asthma

FceRI is located on the surfaces of basophils and mast cells, which act as effector cells in IgE-mediated immune responses (Kinet, 1990). FceRI is composed of four subunits one p-chain, one a-chain, and two disulfide-linked g-chains. Most of the a-chain extends into the extracellular region, where it binds directly and with high-affinity to the Fc portion of IgE antibodies thus, the a-chain is the most important component of the FceRI molecule (Hakimi et al., 1990). The cross-linking of FceRI with allergen-IgE complexes causes the release of inflammatory mediators such as histamine, leukotrienes, and prostaglandins from activated basophils and mast cells, which contributes to the allergic responses in asthma, atopic dermatitis, allergic rhinitis, and food allergies (Drombrowicz et al., 1993 Gauchat et al, 1993 Metzer, 1991 Yanagihara et al., 1997). The progression of airway inflammations involves several types of cells such as CD4+, Th2 cells, eosinophils, and mast cells (Wills-Karp,...

Macroalgae As Potential Antiasthmatic Agents

Algae extracts and compounds are well known for variety of biological activities including antiasthmatic activity. In addition, some algal species are used in Asian menus from long time. In a study, Kim et al. (2008) have shown that extract from E. cava suppresses the cytokine signaling in an animal model. The treatment of animals with E. cava extracts significantly reduced the concentration of Th2 (IL-4 and IL-5) cytokine in the airway. Hence, in their studies, they have proved that E. cava extract reduced the airway inflammation and hyperresponsiveness via inhibition of SOCS-3 protein expression. Shim et al. (2009) have also shown that extracts from E. cava inhibited the expression of FceRI in human basophilic KU812F cells. Moreover, active compounds that are responsible for some specific activity have been isolated from E. cava. Compounds isolated from E. cava including phloroglucinol, dieckol, 6,6'-bieckol, and 2,4 9-trihydroxydibenzo-1,4-dioxin were assessed by histamine release...

Microalgae As Potential Antiasthmatic Agents

It has been used as potential source to treat various diseases in Chinese medicine and has been suggested that it can be used to treat a variety of diseases including inflammation, night blindness, digestion, and burns (Qui et al., 2002). Depending on the variety of usages of this important microalga, Park et al. (2008) have shown that the lipid extract from N. commune var. sphaeroids represses the expression of several genes involved in the proinflammatory responses to inflammatory stimuli. Fatty acid mixture significantly reduced RNA abundance of TNF-a and COX-2. Further, DNA binding activity was also evaluated as NF-kB is the major regulator of proinflammatory gene expression and revealed that DNA binding activity of NF-kB significantly reduced by the treatment with N. commune lipid extract. Evaluation of dialyzed Chlorella pyrenoidosa extract (DCPE) on mast cell mediator release in vitro and overalbumin-induced airway inflammation in vivo revealed that in vitro treatment of mouse...

The G Protein Coupled Receptor Associated with Asthma

The GPCR associated with asthma, GPRA (or GPR154), located on chromosome 7p13, was identified from linkage studies of asthma in a Finnish population and five other Western European populations (138-140). GPRA was identified as a candidate gene in the pathogenesis of asthma and other diseases mediated by immunoglobulin E (IgE). Like other GPCRs, GPRA may act as a receptor for unidentified ligands and is therefore a potential drug target. GPRA along with its two main isoforms GPRA-A and GPRA-B and its ligands define a distinct signaling pathway that is dysregulated in asthma (141). GPRA-B is more highly expressed in the bronchial epithelia and smooth muscle of asthmatics compared with healthy individuals suggesting that the GPRA-B receptor is a promising reagent against which to screen asthma drugs (141).

Asthma GPCR Pharmacogenomics

Studies of GPCRs in asthma can be differentiated on the basis of whether they measure the contribution of candidate genes to atopy, bronchial hyperreactivity (BHR), drug response nonresponse, or another phenotype. The contribution of selected GPCR variants to the risk for developing asthma or altered drug response is reviewed. The evidence suggests that the involvement of P2-adrenergic receptor (ADRB2) variants in the development of asthma and adrenergic drug pharmacogenetics (160). Although the P2-adrenergic receptor Arg16Gly variant (p.R16G) is associated with reduced lung function (158) and familial nocturnal asthma (12,161), it is also commonly resistant to some P2-adrenergic receptor agonists (162). This may result from receptor loss from the cell surface during defective downregulation. Not surprisingly, in the event that drug response phenotypes and disease phenotypes result from the same genetic variants, clinical management can become very difficult. The P2-adrenergic...

Adrenergic Receptor Agonists The Development Of Antiasthma Drugs

Hydrogenation Reaction Mechanism

Bronchial asthma is characterized by breathlessness and bronchial constriction. It may affect as many as 5 of the population. A number of asthma attacks are initiated by the inhalation of an allergen. This induces an inflammatory response in the lungs and a constriction of the bronchial muscle. Treatment involves reducing the response to the allergen, alleviating the inflammatory response and reducing the bronchial constriction using a bronchodilating agent. Agonists of -ad-renergic receptors bring about a relaxation of the bronchial muscle but they can also produce an increase in the force and rate of contraction of cardiac muscle. Examination of a series of isoprenaline analogues led to a division of the -receptors into the 1 (cardiac) and 2 (bronchial) muscle sub-types. Interaction with the 2-receptor led to a relaxation of the bronchial muscle. In particular, the t-butyl analogue 3.37 of isoprenaline was considerably more potent on bronchial tissue than on cardiac tissue, i.e. it...

Inhaled Corticosteroids For Asthma And Allergic Rhinitis

The National Asthma Education and Prevention Program has provided recent recommendations on the treatment of asthma, including a strong recommendation for the first-line use of inhaled corticosteroids for severe and moderate persistent asthma in all age groups. The corticosteroids currently used in inhaled formulations are all relatively potent topical corticos-teroids that have the advantage of rapid deactivation inactiva-tion for the portion of the dose that is swallowed. The development of GCs that are efficiently inactivated metabolically when swallowed has greatly reduced the systemic side effects associated with the use of steroids in asthma treatment. The older corticosteroids that are used orally (e.g., methylpred-nisolone, prednisolone, and prednisone) have much greater systemic side effects, and their use should be limited, if possible. Although systemic side effects are reduced, they are not completely eliminated. The side effects can vary with the steroid used and the...

Pediatric patient with accidental theophylline overdose

A 3-year, 10-month female child with a two-year history of asthma developed tachynea, respiratory difficulty and fever. She was accidentally given 750mg of theophylline, an amount 10 times in excess of that prescribed. She became restless, developed tachycardia, and vomited coffee-ground material positive for occult blood. Her serum theophylline level was 67 g ml 1 h and 45 min after being given the drug. She was transferred to the intensive care unit. The hospital immediately referred the patient to me for possible treatment with ACAC hemoperfusion. It was decided to carry out the procedure immediately because 1) The theophylline level varied from 67 to 74 g ml and 40 g ml being considered a potentially lethal dose (2) It is known that if the level is not lowered quickly, the child would suffer irreversible brain damage as in an earlier case when the child was referred to us too late and (3) Available dialysis systems at that time were not effective in removing theophylline. A 3 h...

Characteristics Of Asthma

The most important functional abnormality in asthma is increased resistance to airflow. This is the basis of most striking clinical manifestation of asthma, including breathlessness and wheezing. The mechanisms of increased airflow resistance include (1) decreased physical dimensions of the airways as a consequence of bronchoconstriction, (2) luminal narrowing due to airway wall edema, and (3) luminal obstruction resulting from hypersecretion of mucus (McFadden, 1998). Those changes induced by the various inflammatory mediators released by mast cells as part of hypersensitivity reactions are reversible. Another functional abnormality in asthma is a heightened responsiveness of the airways to stimuli that might normally be expected to provoke airway narrowing. Inflammation of the airway is the peculiar pathological abnormality in asthma (Hegele and Hogg, 1996). Inflammatory responses are associated with the accumulation of numerous cells including lymphocytes, macrophages, and plasma...


The prevalence of asthma has been increasing worldwide despite aggressive efforts to treat and prevent it.22 Asthma is a chronic disease affecting millions around the world. In the United States alone there are approximately 15 million patients with asthma. The airways of a person with asthma are Use of magnesium therapy in asthma was first described in 1936 by two Uruguayan physicians.25 Despite this, it is not a standard recommendation of the National Heart, Lung and Blood Institute (NHLBI) guidelines26 for diagnosis and management of asthma because of conflicting reports regarding its efficacy. The mechanism by which magnesium works in asthma is still unclear but it is likely that it is related to relaxation of bronchial smooth muscle cells.27,28 It has been demonstrated that when magnesium is administered to animals, relaxation of bronchial smooth muscle cells ensues.29 Magnesium seems to inhibit the release of histamine from mast cells which recruits inflammatory mediators.30...


Theophylline and related drugs are often prescribed as modified-release formulations and toxicity can therefore be delayed. They cause vomiting (which may be severe and intractable), agitation, restlessness, dilated pupils, sinus tachycardia, and hyperglycaemia. More serious effects are haematemesis, convulsions, and supraven-tricular and ventricular arrhythmias. Severe hypokal-aemia may develop rapidly. Repeated doses of activated charcoal can be used to eliminate theophylline even if more than 1 hour has elapsed after ingestion and especially if a modified-release preparation has been taken (see also under Active Elimination Techniques, p. 33). Ondansetron (section 4.6) may be effective for severe vomiting that is resistant to other antiemetics unlicensed indication . Hypokalaemia is corrected by intravenous infusion of potassium chloride and may be so severe as to require 60mmol hour (high doses require ECG monitoring). Convulsions should be controlled by intravenous administration...

Arrestin Receptor Interface

Selective reduction of arrestin interactions with a particular GPCR would slow down its desensitization and internalization, thereby enhancing and prolonging G protein-mediated signaling. This kind of intervention has therapeutic potential in conditions usually treated with GPCR agonists (e.g., asthma) and agonist precursors (e.g., Parkinson's disease) because it counteracts the very process that severely

Confounding by indication

Bias arises in observational studies when patients with the worst prognosis are allocated preferentially to a particular treatment. These patients are likely to be systematically different from those not treated or treated with something else (paracetamol rather than nonsteroidal anti-inflammatory drugs (NSAID) in asthma, for instance).

Identifying effective drug treatments

The prescribing notes in the BNF provide an overview of the drug management of common conditions and facilitate rapid appraisal of treatment options (e.g. hypertension, p. 104). For ease of use, information on the management of certain conditions has been tabulated (e.g. acute asthma, p. 173). Information is also provided on the prevention of disease (e.g. malaria prophylaxis for travellers, p. 404). Cardiovascular risk prediction charts for the primary prevention of cardiovascular disease can be found in the glossy pages at the back of the BNF.

G proteincoupled receptors gpcrs

Dhanak et al.15 at SmithKline Beecham Pharmaceuticals reported the optimization of N-acytaled dipeptides as CCR3 antagonists. CCR3 is a chemokine receptor involved in inflammatory diseases such as asthma. The CCR3 chemokine is activated by proteins such as eotaxin, eotaxin-2, and MCP-4.

Solubility of Polymorphic Substances

Several indirect methods have been proposed to determine the solubility of metastable polymorphs. Milosovish (1964) deduced the relative solubilities of metastable and stable polymorphs based on the measurement of intrinsic dissolution rates. Ghosh and Grant (1995) proposed an extrapolation technique to determine the solubility of a crystalline solid that undergoes a phase change upon contact with a solvent medium. Brittain (1996) used the time evolution of light scattering from aqueous suspensions of anhydrous theophylline as a means to evaluated its solubility, and also to study its phase transformation into its monohydrate solvatomorph.

Prescribing for patients who are pregnant or breastfeeding

Provide guidance on the drug treatment of common conditions that can occur during pregnancy and breastfeeding (e.g. asthma, p. 170). Information about the use of specific drugs during pregnancy and breast-feeding can be found in their drug monographs under Pregnancy and Breast-feeding (e.g. fluconazole, p. 374). However, if a class of drugs (e.g. tetracyclines, p. 346) share the same recommendations for use during pregnancy or breast-feeding, this advice is amalgamated in the prescribing notes under Pregnancy and Breastfeeding while any advice that is unique to a particular drug in that class is included in its individual drug monograph.

Selecting a suitable preparation

Where a drug has several preparations, those of a similar type may be grouped together under a heading (e.g. 'Modified-release' for theophylline preparations, p. 181). Where there is good evidence to show that the preparations for a particular drug are not interchangeable, this is stated in a Note either in the Dose section of the monograph or by the group of preparations affected. When the dose of a drug varies according to different formulations of that drug, the right dose should be prescribed for the preparation selected. In the case of compound preparations, the prescribing information of all constituents should be taken into account for prescribing.

Coping with heterogeneity

For example, the medical health care system in Iceland has provided a very large database on subject medical and genealogical information, which has provided researchers with not only medical history information, but also detailed family history. This latter information, not often available, dramatically increases the specificity of the findings and helps to reduce heterogeneity. The identification of a locus involved in asthma (Hakonarson et al. 2002) was, for example, based on such approach. Sometimes however, alleles have a clearly defined functional impact that over-shadows ethnic heterogeneity. A good example of this is seen for the drug metabolizing enzyme TPMT (thiopurine methyltransferase). Deficient patients carry one of three alleles (G238C, G460A and A719G). These have different frequencies according to their ethnic origins but with the same impact, namley to increase the risk of developing haematopoietic toxicity when subjects with these...

Precautions Toxicity and Contraindications

Major contraindications to the use of the muscarinic agonists are asthma, hyperthyroidism, coronary insufficiency, and acid-peptic disease. Their bronchoconstrictor action is liable to precipitate an asthma attack hyperthyroid patients may develop atrial fibrillation. Hypotension induced by these agents can severely reduce coronary blood flow, especially if it is already compromised. Other possible undesirable effects of the cholinergic agents are flushing, sweating, abdominal cramps, belching, a sensation of tightness in the urinary bladder, difficulty in visual accommodation, headache, and salivation.

Therapeutic Uses Of Muscarinic Receptor Antagonists

Systemic administration of belladonna alkaloids or their derivatives for bronchial asthma or COPD carries the disadvantage of reducing bronchial secretions and inspissation of the residual secretions. This viscid material is difficult to remove from the respiratory tree, and its presence can dangerously obstruct airflow and predispose to infection. By contrast, ipratropium and tiotropium, administered by inhalation, do not produce adverse effects on mucociliary clearance, and can be used safely in the treatment of airway disease (see Chapter 27).

Other Routes Of Administration

The final major method of administration, inhalation, is rapid and it is not restricted to compounds that are volatile. Indeed, a number of nonvolatile compounds such as steroids that are used in the treatment of asthma are given by inhalation as aerosols. The advantage of inhalation in the treatment of asthma is the directness of action.

Adrenergic Receptor Agonists

B Adrenergic receptor agonists play a major role only in the treatment of bronchoconstriction in patients with asthma (reversible airway obstruction) or chronic obstructive pulmonary disease (COPD). Minor uses include management of preterm labor, treatment of complete heart block in shock, and short-term treatment of cardiac decompensation after surgery or in patients with congestive heart failure or myocardial infarction. The chronotropic effect of b agonists is useful in the emergency treatment of arrhythmias such as torsades de pointes, bradycardia, or heart block (see Chapter 34).

Antagonism of adenosine receptors

The antagonism of adenosine receptors by caffeine is currently the most widely accepted mechanism of its action. The elucidation of this mechanism stemmed from a discovery by Sattin and Rall,11 who noticed that theophylline often reduced the accumulation of cAMP in cerebral slices rather than increasing it, as would be expected from a phosphodiesterase inhibitor. Furthermore, it was noted that adenosine itself produces effects opposite to those of caffeine, and it was later determined that methylxanthines act as competitive antagonists at adenosine receptors at concentrations well within the therapeutic range (less than 100 g, which can be attained by drinking 1 to 3 cups of coffee).

Discussion Of Health Effects By Route Of Exposure

Although methods have been established to derive these levels (Barnes et al. 1988 EPA 1989a), uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an example, acute inhalation MRLs may not be protective for health effects that are delayed in development or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic bronchitis. As these kinds of health effects data become available and methods to assess levels of significant human exposure improve, these MRLs will be revised.

Clinical trials with other DTbased fusion protein toxin constructs

There is an increasing number of novel diphtheria-based fusion protein toxins being reported in the literature. Several of those with potential therapeutic applications are listed in Table 2.1. Although the majority of these constructs were designed for the treatment of malignant disease, the diphtheria-based fusion protein toxin constructs can be applied to the treatment of a diverse group of diseases. Selective targeting of mast cells might prove beneficial in the treatment of asthma, whereas the selective targeting of adipocytes might prove effective in treating obesity. Nonetheless, three of the fusion protein constructs listed in Table 2.1 - DAB388GM-CSF, DAB389IL3, and DAB389EGF - have been rigorously tested as potential therapeutics for the treatment of malignant disease and are described in the following sections.

Receptor Engineering Is Required for GPCR Structure Determination

Route very similar to the one developed by Kobilka and coworkers for the p2-adrenergic receptor by using a T4 lysozyme (T4L) fusion protein (Jaakola et al., 2008 Rosenbaum et al., 2007). As for the b2-adrenergic receptor, this approach proved to be successful. Most of the flexible and potentially disordered third cytosolic intracellular loop of the A2A AR (Leu209-Ala221) was replaced with the very stable and easily crystallized lysozyme protein from T4 bacteriophage, increasing the available surface area potential for crystal contacts (Fig. 1A). The receptor was further stabilized by deletion of the larger part of the very flexible C-terminus (Ala317-Ser412), and a histidine purification epitope (6X-His tag) was added. This C-terminal truncation removed the predicted disordered regions and improved the likelihood of crystal formation. During purification this construct (A2A-T4L-DC), the presence of a high concentration of sodium chloride, cholesterol, and a receptor-saturating...

Devices for Therapeutic Aerosol Generation

Which system is the most suitable for a particular drug or therapy is determined by both the physicochemical properties of the drug as well as by patient condition in relation to the chosen therapy. Asthma and COPD treatment using drugs such as 2-agonists or corticosteroids is carried out with MDIs and DPIs. For children, nebulizers seem to be preferred, but MDIs with spacers can also be used. For antibiotic (e.g. tobramycin or colistin) therapy in cystic fibrosis patients nebulizers still seem the device of choice. Probably the patient population in this case is too small to make the development of DPIs or MDIs containing antibiotic drugs economically feasible. When peptide or protein delivery is considered, newer and more advanced systems such as the 'AERx system' or dry powder generators such as the 'Inhale Therapeutic System (Innova )' have been developed 40,41 .

Adverse Effects And Precautions

PULMONARY FUNCTION A major adverse effect of b receptor antagonists is the bronch-constriction resulting from blockade of b2 receptors in bronchial smooth muscle. b Blockers may cause a life-threatening increase in airway resistance in patients with bronchospastic disease. b1-selective antagonists or those with intrinsic sympathomimetic activity at b2 adrenergic receptors may be somewhat less Likely to induce bronchospasm however, the selectivity of current b1 blockers is modest, and these drugs should be avoided if possible in patients with asthma.

Neurotransmitter modulation

Neurotransmitters, including norepinephrine, dopamine, serotonin, acetylcholine, glutamate, and GABA.716 Release inhibition is mediated by activation of presynaptic adenosine receptors. As antagonists of adenosine at both high-affinity (A1) and low-affinity (A2) receptors, caffeine and other methylxanthines have demonstrated the ability to increase the release and functional turn-over of these neurotransmitters by blocking activation of these receptors. In further support for the action of methylxanthines at adenosine receptors, chronic administration of caffeine or theophylline by various routes increased the number of adenosine receptors in mouse brain.17-19 However, the affinity of the receptors for adenosine is mostly unchanged by chronic administration of caffeine.1719 Some studies have shown an increased sensitivity to adenosine in cerebral slices, although an increase in receptor density does not always correspond to a functional change observed in the animal.20

Inspiratory Pressure and Relevant Flow Parameters

However, pulmonary obstructions usually restrict the expiratory performance rather than the inhalation manoeuvre (e.g. 102,103 ). Therefore, maximal in-spiratory pressure (MIP) values of asthmatic and COPD patients can be of the same order of magnitude as that of healthy subjects 104 . Only severe COPD patients may not be able to generate MIPs higher than 1.5-2.0 kPa. The effect of airflow resistance and clinical condition on the generated pressure drop across an external airflow resistance is summarized in Figure 3.5 (data derived from reference 104 ).The data show that in vitro testing of dry powder inhalers at only 4 kPa, as prescribed by various guidelines, is inadequate for the prediction of their performance in practice. Attained flow parameters during inhalation can either be calculated (Eq. 3.1) from recorded pressure drop curves or measured directly, using the equipment described in Section 3.9.1. Various studies report peak inspiratory flow rate...

Side effects and their management

Overall, NSAIDs have a good safety record but, due to the enormous quantities prescribed, they account for a large proportion of serious adverse drug events. In 1985, from all reported adverse drug reactions, NSAIDs accounted for 25 percent in men and 30 percent in women. The elderly account for approximately 40 percent of NSAID prescriptions and are at greater risk of side effects.19 In a recent retrospective study conducted by Gallelli et al.,20 NSAIDs were found to be responsible for 55.2 percent of the episodes of adverse drug reactions overall. Diclofenac and aspirin were the drugs most frequently involved, while the skin was the system most susceptible to NSAID-induced adverse drug reactions (43 percent). Withdrawal of NSAID therapy resulted in resolution of side effects in 86 percent of episodes. NSAID side effects may present with a life-threatening event. As well as the elderly, those at higher risk include patients who are hypovolemic, immunocompromised or taking...

Respiratory complications

NSAIDs may aggravate asthma and reversible airway disease.54 Up to 10-20 percent of the general asthmatic population has hypersensitivity to aspirin and there is as much as 98 percent cross-reactivity with NSAIDs in those patients, but only 7 percent with paracetamol.55 This may cause severe exacerbation of asthma and naso-ocular reactions. Approximately half of this group is steroid dependent.56 This risk is highlighted in publications such as the British National Formulary.57 Other respiratory risk factors include nasal polyps and rhinitis.58 The NSAIDs are therefore relatively contraindicated in this group of patients. It is now clear that the specific COX-2 inhibitors do not cross-react with aspirin and are safe in patients with aspirin-sensitive airways and chronic obstructive pulmonary disease (COPD). The safety of COX-2 inhibitors in asthma and COPD does not imply that other hypersensitivity reactions do not occur.59

Final Conclusions and Perspectives

With regard to delivery to the lung, local therapies for asthma or COPD have an established position. New developments will focus on inhalation devices and formulations that allow a more reproducible and easy generation of the aerosol cloud and a less critical inhalation procedure. Generally, improved deposition of the drug in the airways is desirable to improve dosing accuracy and decrease side-effects. Together with the introduction of new drug substances technical improvements can still significantly improve the therapy of pulmonary diseases. For example, a major improvement in the treatment of cystic fibrosis can be achieved in the coming 5 years due to the development of new inhalation therapies for antibiotic drugs. Currently, the pulmonary use of about 10 antibiotic drugs has been reported but only two (tobramycin and colistin) have found a place in regular prophylactic use and therapy. Moreover, these drugs are still administered by quite inefficient nebulizers that provide...

Chemistry And Formulation

DOSAGE AND CLINICAL USE Ketamine (ketalar, others) has unique properties that make it useful for anesthetizing patients at risk for hypotension and bronchospasm and for certain pediatric procedures. However, significant side effects Limit its routine use. Ketamine rapidly produces a hypnotic state quite distinct from that of other anesthetics. Patients have profound analgesia, unresponsiveness to commands, and amnesia, but may have their eyes open, move their limbs invol-untariiy, and breathe spontaneously, a cataleptic state that has been termed dissociative anesthesia.

Pharmacodynamic Variation

A recent survey of receptor pharmacogenetics based on the PubMed database turned up an abundance of information on a number of nuclear and cell surface receptors.50 Among the most prevalent of the nuclear receptors for the most recent 5-year period for which data were available (1999-2003) were polymorphic receptors for glucocorticoids, mineralocorticoids, androgens, estrogens, retinoic acid, vitamin D, and arylhydrocarbon hydroylases, and among cell surface receptors were polymorphic receptors for ion channels, sulfonylurea, che-mokines (CCR5, CCR2), angiotensin II Type 1, and receptors implicated in asthma (p2-adrenergic, the high-affinity receptor for IgE, FcsRI-p) and the Toll (TLR4) receptor implicated in endotoxic shock. A similar search for developmental changes among these receptors for infants and children failed to yield any citations for years 1996-2006. However, the search did identify citations on the developmental pharmacodynamics of the GABA receptor complex,...

Gastrooesophageal reflux disease

Gastro-oesophageal reflux disease (including non-erosive gastro-oesophageal reflux and erosive oesophagitis) is associated with heartburn, acid regurgitation, and sometimes, difficulty in swallowing (dysphagia) oesophageal inflammation (oesophagitis), ulceration, and stricture formation may occur and there is an association with asthma.

Biological functions of 15lipoxygenases

The major 15-LOX products, 15-H(P)ETE and 13-H(P)ODE, exhibit interesting biological activities which have been reviewed recently 175). 13-HPODE and 15-HPETE are regulators of various enzymes of the arachidonic acid cascade (5-LOX and cyclooxygenase-1) activation and inactivation of these enzymes have been described. At the cellular level, 15-HETE and 13-HODE have been implicated in cell proliferation, cell adhesion and metastasis. Exogenous 15-HETE induces contraction of human bronchial smooth muscle cells at submicromolar concentrations, but this effect appears to be restricted to in vitro conditions since inhaled 15-HETE did not exhibit any effect on airway caliber in either normal or asthmatic individuals. In contrast, pre-inhalation of 15-HETE did significantly increase the early allergic response 175 , There are several reports suggesting a role of 15-LOX metabolites in hormone synthesis, in diabetes mellitus and in the male and female reproductive system 175J.

Insomnia Accompanying Other Medical Illnesses

For long-term insomnia owing to other medical illnesses, adequate treatment of the underlying disorder, such as congestive heart failure, asthma, or COPD, may resolve the insomnia. Adequate pain management in conditions of chronic pain, including terminal cancer pain, will treat both the pain and the insomnia and may make hypnotics unnecessary. Many patients simply manage their sleep poorly. Adequate attention to sleep hygiene, including reduced caffeine intake, avoidance of alcohol, adequate exercise, and regular sleep and wake times, often will reduce the insomnia.

Introduction A Objectives ofthe Chapter

This chapter gives a brief account of how selectively acting b-adrenoceptor agonists and glucocorticoid steroids were developed in Glaxo-Allenburys Laboratories for use by inhalation in asthma and of their therapeutic use. It is written in tribute to the colleagues and clinical investigators whose efforts have transformed the treatment of asthma during the past 30 years and in the hope that it may lead to better understanding and use of these drugs. The views expressed are, however, personal and may not accord with those of former colleagues or with current medical opinion.

The Therapeutic Problem

Asthma is characterized by variable obstruction of the airways that is a consequence of inflammation in the lungs. There are two distinct causes of airways obstruction. The most obvious is contraction of bronchial muscle, which responds rapidly to epinephrine and other b-adrenergic bronchodilators. The most dangerous is physical occlusion of the airways caused by osmotic swelling and other derangements of bronchial mucosal structure and function. It is not relieved by bronchodilators and is reliably prevented or reversed only by cortisol and other glucocorticoid steroids. Bronchodilators are effective in less severe asthma because bronchoconstriction is the dominant cause of airway obstruction at this stage. As asthma worsens, Causes of airway obstruction in asthma, effects of epinephrine and cortisol on them, and relationship between the severity of asthma and the bronchodilating effect of inhaled b-adrenergic bronchodilators. however, they become progressively less effective...

Chiropractic And Manual Therapies

Chiropractic literally means hand work'' or manual therapy.'' It can be classified as a comprehensive system of medicine or as an individual therapy in the mechanical-manipulative category. How one classifies chiropractic depends on how broadly one defines its scope. There is the school that sees chiropractic as a complete system of medicine applicable to a wide range of ailments from musculoskeletal pain to asthma and diabetes. On the other side, many chiropractors profess a narrower scope that primarily addresses neuromusculoskeletal symptoms.

Ahlquists Classification of Adrenoceptors andIsoprenaline

Modern drug research on asthma remedies began in 1948 when Ahlquist (7) subdivided adrenoceptors in a- and b-types on the basis of the relative activities of a few close analogs of epinephrine in a range of pharmacological tests. His evidence for the new classification is summarized in Table 2. Both Table 1 Cellular Origins of the Principal Spasmogenic Mediators in Asthma Spasmogen Mast cell Basophil Eosinophil Because of its selectivity for b-receptors isoprenaline steadily replaced epinephrine as an inhaled bronchodilator during the 1950s. Therapeutic doses of the drug induce prompt intense bronchodilation, which lasts for about 1-1.5 hr and is accompanied by obvious cardiac stimulation. Its parenteral use is precluded by its intense inotropic and chronotropic actions on the heart. A longer-acting, more selectively acting bronchodilator was needed to replace isoprenaline, and around 1960, different approaches were made to the problem in the laboratories of Winthrop in the United...

Lands Classification ofbAdrenoceptors and Selective b2Adrenergic Bronchodilatation

The important finding for asthma research was that the desired bronchodilating action is mediated by b2-receptors and unwanted cardiac stimulation by b1-receptors, so that they were separable. The new classification also gave an accurate forecast of the main side effects found with systemic use of b2-agonists, namely tremor of skeletal muscles and hypokalemia, which are caused by accelerated repolarization and hyperpolarization of the muscle cells, and tachycardia, which is secondary to dilatation of arteries in skeletal muscle beds. The practical outcome of Lands' work was isoetharine, the first b2-selective agonist to be used to treat asthma. Its bronchodilating action after

Drug Interactions

It remains to be established whether the increased incidence of rash in patients receiving concurrent allopurinol and ampicillin should be ascribed to allopurinol or to hyperuricemia. Hyper-sensitivity reactions have been reported in patients with compromised renal function, especially those who are receiving a combination of allopurinol and a thiazide diuretic. The concomitant administration of allopurinol and theophylline leads to increased accumulation of an active metabolite of theophylline, 1-methylxanthine the concentration of theophylline in plasma also may be increased (see Chapter 27).

Systemic Glucocorticoids

Systemic glucocorticoids are used for acute asthma exacerbations and chronic severe asthma. Substantial doses of glucocorticoids (e.g., 40 60 mg prednisone or equivalent daily for 5 days 1 2 mg kg day for children) often are used to treat acute exacerbations of asthma. Although an additional week at somewhat reduced dosage may be required, the steroids can be withdrawn once control of the symptoms by other medications has been restored any suppression of adrenal function dissipates within 1 2 weeks. More protracted bouts of severe asthma may require longer treatment and slower tapering of the dose to avoid exacerbating asthma symptoms and suppressing pituitary adrenal function. Previously, alternate-day therapy with oral prednisone was employed commonly in persistent asthma. Now, most patients with asthma are better treated with inhaled glucocorticoids.

Drug InteractionsP450 Metabolism

The inhibitory action of SSRIs may give rise to multiple drug-drug interactions with other medications these interactions when the drugs are coadministered may lead to no effect, intoxication, or even improving a drug's therapeutic response via a rise in its plasma concentration. Generally, SSRIs that inhibit the CYP 450 systems will impair metabolism of other medications (P450 enzyme substrates), thus prolonging their elimination half-life and increasing their blood level. For example, the SSRI inhibition of cytochrome P450 activity may lead to elevated levels of concurrently administered TCAs which are metabolized by CYP 2D6 and 3A4 isoenzymes (62). This may lead to side effects, but it may also permit clinicians to use a low-dose TCA to augment or potentiate the SSRI. Citalopram does not alter TCA levels (62). On the other hand, fluvoxamine inhibits the CYP 1A2 isoenzyme and can produce toxic levels of medications that are usually metabolized by this isoenzyme, namely tacrine,...

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Pected ways, but the rapid recovery with formoterol was suprising because it is known to be long-acting after inhalation by asthmatic patients, another result that requires explanation. Details of the mechanism of action of salmeterol and other b-agonists are dealt with later. salmeterol inhibits histamine-induced bronchoconstriction for much longer than salbutamol. More importantly, 50- or 100-mg single inhaled doses of the drug induce near-maximal bronchodilatation in asthmatic patients, which is greatest after 1-2 hr and still marked after 12 hr, without causing side effects other than tremor with the higher dose (24). Furthermore, when inhalations are repeated at 12-hr intervals, effective bronchodilatation is maintained both night and day after prolonged use of the drug. These results and those obtained in early clinical pharmacological and trial studies fostered hope that salmeterol would prove to have a useful anti-inflammatory action in patients, different from and perhaps...

Mechanism Of Action

Cromolyn and nedocromil inhibit mediator release from bronchial mast cells reverse the increased functional activation in leukocytes obtained from the blood of asthmatic patients suppress the activating effects of chemotactic peptides on human neutrophils, eosinophils, and monocytes inhibit parasympathetic and cough reflexes and inhibit leukocyte trafficking in asthmatic airways. PHARMACOKINETICS For asthma, cromolyn is given by inhalation using either solutions (delivered by aerosol spray or nebulizer) or, in some countries but not in the U.S., powdered drug (mixed with lactose and delivered by a special turboinhaler). The pharmacological effects result from the topical deposition of the drug in the lung, since only -1 of an oral dose of cromolyn is absorbed. Once absorbed, the drug is excreted unchanged in the urine and bile in about equal proportions. Peak concentrations in plasma occur within 15 minutes of inhalation, and excretion begins after some delay such that the biological...

Apnea Of Preterm Infants

In premature infants, episodes of prolonged apnea lasting 15 seconds and accompanied by bradycardia pose the threat of recurrent hypoxemia and neurologic damage. Although they often are associated with serious systemic illness, in many instances no specific cause is found. Methylxanthines have undergone numerous clinical trials for the treatment of apnea of undetermined origin. The oral or intravenous administration of methylxanthines can eliminate episodes of apnea that last 20 seconds and markedly reduces the number of episodes of shorter duration. Satisfactory responses may occur with plasma concentrations of theophylline of 4-8 mg mL, but concentrations of nearly 13 mg mL are required more frequently. Still higher concentrations may produce a more regular pattern of respiration without further reduction in the frequency of episodes of apnea and bradycardia, and these usually are associated with a definite tachycardia. Therapeutic concentrations are achieved with loading doses of 5...

Crystalline Pharmaceuticals

The majority of APIs will be encountered, at least in some stage in the production of medicinal products, in the solid state, and typically in the form of polycrystalline powders. As already stated, the size, shape, structure, and properties of the individual crystallites comprising the powder have significant influence over the properties of the final dosage form and therefore characterization, and control of solid-state forms is an important aspect of drug development (9-11). Solid-state form is not only of relevance to APIs many excipients, including lactose (12), mannitol (13), and calcium hydrogen phosphate, for example, are also crystalline materials and can display a variety of crystalline forms, which if uncontrolled, may impact upon the performance of the final product. Excipients can also influence the physical stability of APIs during processing. For example, hydroxypropylmethylcellulose has been shown to inhibit the anhydrous-to-hydrate transformation of ciprofloxacin (14)...

Coupling between cerebral blood flow and metabolism

Agents to which man is frequently exposed, and as shown in Figure 3.5, caffeine has the property to induce cerebral hypoperfusion accompanied by a simultaneous increase in glucose utilization15-1952 in other words, caffeine resets the level of coupling between cerebral blood flow and energy metabolism. Methylxanthines thus seem to modify the regulating mechanism between cerebral blood flow and cerebral metabolism. Although this mechanism is not yet fully understood, adenosine, with which methylxanthines compete, is known to be one of the modulators of the regulation of the relationship of blood flow to metabolism in the central nervous system.5 6 62 Indeed, theo-bromine, a weaker adenosine antagonist than caffeine or theophylline, has only minor effects on cerebral blood flow and metabolism, while propento-phylline, an adenosine uptake blocker, induces the reverse effect, i.e., an increase in cerebral blood flow and a decrease in glucose utilization. Thus, several xanthine derivatives...

Beclomethasone Dipropionate

Fate of inhaled steroids in the body. For a clinically useful selective effect in asthma, the steroid must (1) have a persistent action in the lungs, and (2) be poorly absorbed from the gut, and or (3) be substantially inactivated by firstpass Fate of inhaled steroids in the body. For a clinically useful selective effect in asthma, the steroid must (1) have a persistent action in the lungs, and (2) be poorly absorbed from the gut, and or (3) be substantially inactivated by firstpass Daily doses of inhaled BDP up to 1 mg proved to be effective in chronic asthma without causing significant systemic glucocorticoid actions. The greater doses used to control more severe asthma do, however, cause modest, but significant suppression of hypophysial-pituitary-adrenal function and perhaps a degree of osteoporosis after prolonged use (43). This is why a more selectively acting topical steroid was sought and found in fluticasone propionate, and also why the effectiveness of concurrent treatment...

Fluticasone Propionate

In clinical trials it proved to be twice as active, on a weight basis, as BDP in asthmatic patients and to have less effect on HPA function (45). The exceptional anti-inflammatory activity of fluticasone propionate is a consequence of its persistent binding to the glucocorticoid receptor protein (46). Fluticasone propionate (Flixotide) inhaler was marketed in 1994. It may have a special place for treating severe asthma.

Recent Concern About Inhaled b2Adrenoceptor Agonists

Inhaled b2-agonists have been problematic for a long time. During the 1960s and the 1970s there were epidemics of unexpected deaths, especially of young asthmatics, associated with their use Pearce and coworkers have provided a detailed analysis of these events (47). The main reason for these deaths is now accepted by most to be inadequate use of glucocorticoids to control the life-threatening physical occlusion of the airways that occurs as asthma worsens. As explained above, rational treatment of chronic asthma requires the concurrent use of glucocorticoids, to contain the inflammatory process, and inhaled b2-adrenergic bronchodilators, to relieve acute bronchospasm and to reduce bronchial tone. More recent concern is that regular multiple daily inhalations of b2-agonists may cause asthma to worsen and thus be one of the causes of the gradual increase in mortality reported by Jackson and co-workers (48). The most damning indictment of this use of b2-agonists was that of Sears and...

Early Clinical Trials ofSalmeterol

Salmeterol has performed to best expectations in clinical use. The key results of a large early trial* (53,54) are summarized in Figures 10 and 11. Evening and especially morning respiratory performance were obviously better with salmeterol than with salbutamol. That nocturnal asthma attacks were virtually abolished by salmeterol treatment was particularly gratifying since this was one of the starting objectives of the project. More importantly, however, no evidence was found of tolerance to the actions of either b2-agonist if anything, the incidence of exacerbations of disease fell during the 12 months' treatment with salmeterol. Salmeterol and salbutamol behaved similarly in all the other early clinical studies* (55-57). These results, and Comparison of the effects of treatment with inhaled salmeterol or salbutamol in mild to moderate asthma for 12 weeks. Comparison of the effects of treatment with inhaled salmeterol or salbutamol in mild to moderate asthma for 12 weeks. Effects of...

Therapeutic Applications of CpG Oligonucleotides

As a result of the activation of both innate and adaptive immunity, CpG ODNs can be applied in the therapy of cancer, infectious diseases, and asthma and or allergy, but also as highly effective adjuvants in vaccination.50 The therapeutic approaches in cancer and antiviral therapy involve both mono-therapy and combination therapies. TLR9 agonists are attractive drug candidates capable of triggering T helper cell 1 (Th1)-type immune responses (e.g. secretion of Th1-promoting chemokines and cytokines).14,51 It is known that the Th2-type cytokines IL-4, IL-5, IL-6, IL-10 and IL-13 play a central role in the pathogenesis of allergic diseases, including asthma. While the Th2-type cytokines are secreted by activated CD4+ T-cells, the Th1-type cytokines IL-2 and IFN-g are produced by Th1 cells (Figure 6.3). Th1 and Th2 cells interact in a counter-regulatory fashion, since the Th2-type cytokines Il-4 and IL-10 promote Th2 development and inhibit Th1 cell and cytokine production. In contrast,...

Identify and Remove Precipitating Factors

Factors that commonly precipitate cardiac arrhythmias include hypoxia, electrolyte disturbances (especially hypokalemia), myocardial ischemia, and certain drugs (Table 34-1). For example, theophylline can cause multifocal atrial tachycardia, while torsades de pointes can arise not only during therapy with action potential prolonging antiarrhythmics but also with other drugs, including erythromycin (see Chapter 46) pentamidine (see Chapter 40) and some antipsychotics, notably thioridazine (see Chapter 18).

Antiarrhythmic Drugs

Adverse Effects A major advantage of adenosine therapy is that adverse effects are short-lived because the drug is transported into cells and deaminated so rapidly. Transient asystole is common but usually lasts less than 5 seconds and is in fact the therapeutic goal. Most patients feel a sense of chest fullness and dyspnea when therapeutic doses (6-12 mg) of adenosine are administered. Rarely, an adenosine bolus can precipitate bronchospasm or atrial fibrillation. Clinical Pharmacokinetics Adenosine is eliminated with a t1 2 of seconds by carrier-mediated uptake in most cell types and subsequent metabolism by adenosine deaminase. Adenosine probably is the only antiarrhythmic drug whose efficacy requires a rapid bolus dose, preferably through a large central intravenous line slow administration permits elimination of the drug prior to its arrival at the heart. The effects of adenosine are potentiated in patients receiving dipyridamole, an adenosine-uptake inhibitor, and in patients...

Conclusions and Future Research Considerations

In summary, GluRs have a wide and unique distribution in peripheral tissues. These receptors are pharmacologically similar to their counterparts in the CNS, although the possibility that there are subtle distinctions such as glycosylation cannot be ignored (Gonoi et al., 1994). The presence of the GluRs in peripheral tissues may provide explanations for the autonomic disturbances (GI, salivation, cardiovascular, vomiting) that have been reported in human intoxications and in animals dosed with potent excitotoxins such as domoic acid (Thompson et al., 1983 Iverson et al., 1990 Perl et al., 1990 Teitlebaum et al., 1990 Tryphonas et al., 1990 Peng et al., 1994 Truelove et al., 1996). Since the EAA excitotoxic-ity is intimately associated with the GluRs, the toxic effects may be more generalized than initially assumed, particularly in the light that GluRs are widely present in peripheral tissues which are not protected by a blood barrier (Price et al., 1981 Bruni et al., 1991)....

Drugs for arrhythmias

Adenosine is usually the treatment of choice for terminating paroxysmal supraventricular tachycardia. As it has a very short duration of action (half-life only about 8 to 10 seconds, but prolonged in those taking dipyrid-amole), most side-effects are short lived. Unlike verap-amil, adenosine can be used after a beta-blocker. Verap-amil may be preferable to adenosine in asthma. Dronedarone is a multi-channel blocking anti-arrhythmic drug it is licensed for use in clinically stable patients with previous or current non-permanent atrial fibrillation, to prevent recurrence or to lower the ventricular rate.

Helena Viita and Seppo YlHerttuala

Lipoxygenases are intracellular enzymes that oxidize either free or esteri-fied polyunsaturated fatty acids. Their metabolites are lipid peroxides that can react with other biological compounds and alter the cellular redox state. Many of the physiological roles of lipoxygenases are still unknown, but 5-lipoxygenase is involved in leukotriene metabolism, 12-lipoxygenase in the angiotensin pathway, and 15-lipoxygenase in reticulocyte maturation. A common finding characterizing lipoxygenases is their involvement in the regulation of gene expression of transcription factors, cytokines, protoonco-genes, and growth factors. Acting as secondary messengers in various signal transduction pathways, lipoxygenases have been linked to many pathological conditions, such as asthma, inflammation, immune response, and atherosclerosis. This chapter reviews literature about the effects of lipoxygenases on the regulation of gene expression in mammalian cells.

Chemokine Receptors in Allergic Lung Disease

This chapter is an attempt to integrate recent studies concerning the role of chemokine receptors in the initiation, development, and maintenance of allergic lung diseases collectively referred to as asthma. The pathogenesis of asthma involves the coordinated trafficking of inflammatory cells to the lungs and draining lymph nodes, as well as the activation of these inflammatory cells. Chemokine receptors and their ligands play a prominent role in directing the inflammation associated with allergic lung disease. T lymphocyte-mediated immune responses can be broadly categorized as being type 1 or type 2, based on the cell types present and the associated cytokines produced. Allergic lung disease is a predominately type 2-mediated disease. The chemokine receptors CCR4, CCR6, and CCR8 serve to promote the recruitment of type 2 T (T helper 2 Th2) cells, whereas CXCR3 antagonizes type 2 and promotes type 1 T (T helper 1 Th1) cells. The pathophysiologic manifestations of asthma, including...

Therapeutic Applications

7.5.1 Asthma With a prevalence of 5-10 and an annual increment of some 10 , asthma is one of the most common diseases in developed countries. It is an inflammatory disease of the conducting airways characterized by bronchial oedema, bronchial hyper-responsiveness and reversible airway obstruction. In mild-to-moderate disease, standard therapies, such as short-acting beta-agonists and topical or systemic corticosteroids, are very effective. However, in severe asthma, affecting only 5-10 of the asthma population, but accounting for up to half of the total treatment costs, inflammation and clinical symptoms are under poor control as a result morbidity and mortality are highest among these patients. Thus far, three transcription factors have been addressed as possible drug targets in asthma, i.e. AP-1, NF-kB and Stat-1. Corresponding decoy ODNs have been tested in the same standard model of allergic airway inflammation, i.e. in ovalbumin-sensitized mice, where they were administered once...

Physiological Roles of Lipoxygenases

All LOs are intracellular enzymes involved in the regulated metabolism of AA (Fig. 1), which is a common constituent of cell membrane phospholipids. In response to various external stimuli, free AA is released from the membranes by the action of phospholipases. The released AA is consequently metabolized via the cyclooxygenase (CO) or the LO pathway (Sigal, 1991). The best known physiological role of 5-LO is the production of leukotrienes (LT) (A4, B4, C4, D4, and E4), which have been indicated in immune reactions, hypersensitivity, inflammation, and asthma (Samuelsson et al., 1987). 5-LO activating protein (FLAP) is also essential for leukotriene synthesis (Mancini etal., 1993).

Betaadrenoceptor blocking drugs

Beta-blockers can precipitate bronchospasm and should therefore usually be avoided in patients with a history of asthma. When there is no suitable alternative, it may be necessary for a patient with well-controlled asthma, or chronic obstructive pulmonary disease (without significant reversible airways obstruction), to receive treatment with a beta-blocker for a co-existing condition (e.g. heart failure or following myocardial infarction). In this situation, a cardioselective beta-blocker should be selected and initiated at a low dose by a specialist the patient should be closely monitored for adverse effects. Atenolol, bisoprolol, metoprolol, nebivolol, and (to a lesser extent) acebutolol, have less effect on the beta2 (bronchial) receptors and are, therefore, relatively car-

Formation of eicosanoids in allergic inflammation

It was described early on that antigen challenge was an effective cause of the release of SRS from perfused animal lungs 15 . Brocklehurst 17 demonstrated allergen-induced liberation of SRS from lung tissue of asthmatics and introduced the name SRS-A (slow-reacting substance of anaphylaxis). In the years before the discovery of the leukotrienes, SRS-A was primarily considered as a prominent mediator of allergy and immediate hypersensitivity 18 . Following the structural identification of SRS-A as being composed of the cysteinyl leukotrienes LTC4, LTD4 and LTE4 19 ,

Diseases Associated with Selenium Deficiency

17.2.1 Asthma A symptom of asthma is lung inflammation, which has been associated with the generation of hydrogen peroxide as a by-product of increased metabolic activ-ity.32 Hydrogen peroxide activates a nuclear transcription factor for inflammatory cytokines, NF-kB.32,33 GPx appears to have a role in the regulation of NF-kB activity. Comparison of selenium-deficient and selenium-supplemented cells showed upregulation and inhibition of NF-kB, respectively. Whether these results are purely due to removal of hydrogen peroxide by GPx remains unclear.17 Studies have found evidence of a relationship between dietary selenium intake and asthma, and subjects supplemented with dietary sodium selenite showed decrease in asthma symptoms.26 Recent research by Kim and co-workers established that GPx levels increased and the activity of NF-kB was reduced in allergen-sensitized mice treated with sodium selenite. Additionally, selenium-pretreated mice were less affected by exposure to the allergen.32

Cysteinyl leukotrienes as mediators of allergeninduced airway obstruction and bronchial hyperresponsiveness

From the first reports demonstrating that prostaglandins were formed in the lungs and had biological activity on bronchi and blood vessels 173 , the hypothesis emerged that these compounds contributed to asthmatic airway obstruction. However, the results that have since accumulated make it likely that COX products are of minor im

Physiology and disease relevance

Compounds interacting with several of the adrenoceptors have proven to be important drugs, the primary examples being nonselective -adrenoceptor antagonists for hypertension and heart failure, -adrenoceptor agonists for asthma and a1 -adrenoceptor antagonists for benign prostatic hyperplasia and hypertension (Ruffolo etal. 1995).

Or CysLTi receptor antagonists on allergeninduced airway obstruction

It was indeed the first compound to enter the final stages of clinical development, which means that most published studies of the effects of anti-leukotrienes in asthmatics have been conducted with this particular compound 195 , Furthermore, the CysLTj receptor antagonists montelukast and zafirlukast have been registered for treatment of asthma in many parts of the world and pranlukast has been registered in Japan (see Section 12.5). The compounds are administered orally and have been found to cause significant (25-1000 fold) shifts in the dose-response relation for inhaled LTD4 in normal subjects or asthmatics 196-199 . After the structural elucidation of SRS-A, it was possible to obtain in vitro evidence that cysteinyl leukotrienes mediated a major part of the Schultz-Dale contraction to allergen in human bronchi 42 , When more specific pharmacological tools became available, it was possible to demonstrate that cysteinyl leukotrienes indeed mediated major...

Allergeninduced bronchial hyperresponsiveness

Been attributed to the resulting allergic inflammation 216 and irritation of sensory nerves 217J. Structural changes in airways of asthmatics 218 may also increase airway responsiveness. The role of cysteinyl leukotrienes in bronchial hyper-responsiveness is less well established. In asthmatics, inhalation of LTD4 or LTE4 has been reported to produce increased airway responsiveness to histamine 221,222 . In one of the studies 221 , there was a more than threefold increase in histamine reactivity at 7 h following bronchoprovocation with LTE4 and there was still a significant increase in histamine responsiveness 4 days after the inhalation of LTE4. However, one study failed to detect increased histamine responsiveness following inhalation of LTD4 223 , Recently, increased infiltration of eosinophils into the airway mucosa of asthmatics was observed following inhalation of LTE4 185 and inhalation of LTD4 increased the number of eosinophils in induced sputum samples from asthmatics 224 ,...

Discovery Of New Medicines

Currently when a pharmaceutical company considers the development of new medicines, it focuses in certain therapeutic areas only. It is still considered very difficult for even the biggest companies to be active in all therapeutic areas. Then within the therapeutic area, the company will select a disease target. Therefore if it is decided to concentrate on respiratory medicine, a target disease might be asthma or cystic fibrosis or chronic bronchitis. A company will consider many factors before embarking on a particular search for a new medicine. For example, the company will look at diseases which are common but for which there are no, or only unsatisfactory, treatments available. The company will consider their internal expertise, they will consider the commercial return, the competitor activity in this therapeutic area, the current therapies available, the epidemiology of the disease, the cost of the research program etc., before starting. Once the target disease has been selected...

Of airway obstruction induced by other factors

The mechanisms that initiate airway obstruction following exercise, inhalation of dry cold air or bronchoprovocation with adenosine 236 , sulfur dioxide 237 or platelet-activating factor (PAF) 238,239 are clearly different from those that trigger the early phase of allergen-induced bronchoconstriction. Nevertheless, for all of these trigger factors, it appears as if the contributions of different eicosanoid mediators to the primary bronchoconstrictor response are closely similar or identical to the mechanisms described for allergen-induced airway obstruction (Fig. 9-5). Accordingly, cysteinyl leukotrienes mediate significant parts of the airway obstruction evoked by these different challenges, whereas COX products do not. This suggests that different trigger factors converge on one and the same effector mechanism, resulting in release of leukotrienes. Such a common feature may be due to activation of one and the same cell type, e.g. the mast cell, but may also be explained if...

Control of cAMP Levels Is Implicated in Normal and Diseased TCell Function

Into the airways during asthma (Walker et al. 2003). The activities of both PKA and PDE4 therefore seem to be important for regulation of TCR-induced signaling and T-cell function. We propose a novel role for TCR and CD28 co-stimulation in down-modulation of TCR-induced cAMP-mediated inhibitory signals through the recruitment of -arrestin and PDE4 to lipid rafts and thus allowing a full T-cell response to occur. Interestingly, the cAMP inhibitory pathway has also been shown to be implicated in several immune diseases. T cells from HIV-infected patients have elevated levels of cAMP and hyperactivation of PKA. Targeting of the cAMP-PKA type-I pathway by selective antagonists reverses T-cell dysfunction in HIV T cells ex vivo (Aandahl et al. 1998, 1999), and targeting cyclooxygenase 2 to reduce PGE2 production lowers cAMP and increases T-cell function in vivo (Johansson et al. 2004 Kvale et al. 2006). A similar mechanism contributes to the T-cell dysfunction in a subset of patients with...

Prodrugs for transdermal delivery

Other examples of prodrug applications for transdermal delivery include using a-(acyloxy) alkyl derivatives to change the physicochem-ical properties of the parent drug (e.g., nitrofurantoin, benzylpenicillin, and theophylline derivatives),97 derivatization of the drug with a pro-moiety that can enhance permeation by covalently conjugating the drug with fatty acids (e.g., propranolol hydrochloride),98 and novel duplex prodrugs that increase the transdermal drug delivery rate via a permeability increase as a result of the bioconversion-induced steepening

Intolerance to aspirin and other NSAIDs

Subjects with asthma and aspirin intolerance may develop severe bronchoconstric-tion upon accidental ingestion of an NSAID. The reaction develops largely (although not identical to) as the early airway response following allergen provocation. However, in contrast to the allergen-induced reactions, there is no evidence that the NSAID intolerance is associated with dual responses. For example, bronchoprovocations with inhaled lysine-aspirin produce bronchoconstriction in aspirin-intolerant asthmatics without systemic symptoms and late reactions 264-266 . Challenge with aspirin in aspirin-intolerant asthmatics is associated with increased urinary excretion of LTE4 190,192,267,268 and the PGD2 metabolite 9

Genetic Polymorphisms Predicting Drug Response

One example is the relationship between polymorphisms in the B2-adrenergic gene and response to B agonists aimed at reversing acute bronchospasm in asthma. Even though the SNPs identified in the B2-adrenergic receptor gene have demonstrated functional consequences in vitro and in vivo, their relationship with bronchodilatory response to B agonists remains uncertain. A multitude of reasons could account for the conflicting results including that a haplotype, or combination of SNPs, rather than an individual variant is associated with clinical response. In a recent trial 13 SNPs in the gene were organized into 12 haplotypes estimated using phylogenetic analysis. Some of these haplotypes but not individual SNPs were found to be associated with bronchodilatory response to albuterol in a sample of Caucasians 46 . The association of genetic variants with dose response is complex. Multiple SNPs within a haplotype may have a biological effect through interactions involving transcription,...

Release of COX products

In man, synthesis of PGD2 is almost exclusively confined to the mast cell 26 . This presumably explains why increased levels of PGD2 have been demonstrated in the airways following allergen challenge 337 . Interestingly, the urinary excretion of the PGD2 metabolite 9a, 11P-PGF2 has recently been found to be elevated after bronchoprovocation with allergen 192 , Measurement of this metabolite in urine provides a sensitive, non-invasive marker of mast cell activation in vivo during both the early and late asthmatic responses 189 ,

The Fc2 3PE40 chimeric protein a possible treatment for allergy responses

About 20 of the world population suffers from various allergic diseases such as asthma, allergic rhinitis, food allergies, atopic dermatitis and anaphylaxis. The alarming increase in the prevalence of these diseases over the past decade has led to a clear need for more effective therapeutic strategies.

Influence of inhibition of COX products on allergeninduced bronchoconstriction

There is thus good evidence that TP receptor activation produces bronchoconstriction in asthmatics and that the two most potent endogenous TP agonists, TXA2 and PGD2, are formed in increased amounts during allergen-induced bronchoconstriction. The first pharmacological studies indeed seemed to support the idea that COX products were significant mediators of the response to allergen. For example, pre-treatment with indomethacin was reported to inhibit the late response in 10 out of 11 subjects studied 338 , without having a major effect on the early response. More recent studies 336,339 , however, have not confirmed these observations on either allergen-induced early or late responses. These results rather suggest that COX products are unimportant mediators in causing these asthmatic responses. Even more compelling evidence against a role for TP receptors or thromboxane in allergen-induced airway obstruction has been produced in studies using either a potent TP antagonist 340 or a...

COX products in airway hyperresponsiveness

Evidence has been obtained in both animal models of airway hyper-responsiveness 339,342,343 and in human subjects with asthma that COX products are involved in the airway hyper-responsiveness that develops after inhalation of stimuli such as allergens. There is, however, little convincing evidence that COX products are important in causing the ongoing, persisting airway hyper-responsiveness that is characteristic of asthma. to other agents both through direct spasmogenic effects and through local modulation of neurotransmission. On the other hand, it is difficult to know which endogenous compound is the most important activator of this receptor in vivo. Most often, TXA2 has been implicated in the pathogenesis of airway hyper-responsiveness in asthmatic subjects 232 , This assumption is supported by TXA2 being the most potent endogenous TP agonist and by experimental findings in models of airway hyper-responsiveness in dogs 109,344-346 and primates 347 . There are also implications for...

Drug Design for Airway Epithelial P2Y2 Receptors A Specificity and Safety

A major consideration in determination of optimal P2Y2 receptor-directed molecules derived from adenine and uridine is selectivity. As described earlier, the P2 receptor family is expanding with at least seven P2X and two P2Y receptors at which ATP is a potent agonist (Table 1). The presence and role in the lung of each receptor are not known. Thus, the administration of ATP to diseased airways potentially could result in unpredictable events via P2X and or P2Y1 receptors. Rapid conversion of ATP into adenosine on the airway surfaces also should be taken into consideration. Adenosine, via A2-adenosine receptors, may be a physiological regulator of ion transport in normal individuals but is ineffective in CF (52). Moreover, adenosine is known to induce bronchoconstriction in individuals with asthma and, therefore, any protocol designed to treat diseased airways with nucleotides should avoid the potential formation or accumulation of adenosine. Acute adenosine formation should be...

Existing Remedies And Disadvantagesfailures

Since the identification of asthma, many remedies have been implemented for curing it. However, most methods have failed to control this problem successfully they are able to control the symptoms up to some extent. Presently, a number of treatments are used to control asthma. Glucocorticoids are effective for the treatment of allergic inflammation in asthma and result in reduced airway hyperresponsiveness which is thought to be due to reduced inflammation (Djukanovic et al., 1992). Moreover, it has been reported that long-term use of corticosteroids does not eliminate the airway hyperresponsiveness (Van Essen-Zandvliet et al., 1992). Therefore, this suggests that there are limitations to the use of these remedies in airway remodeling changes. However, there are some evidences that inhaled corticosteroids may stop or reverse the structural changes in airway (Hoshino, 2004). Another drug used for the treatment of asthma is p-agonists. In many instances, it is used together with...

Cigarette Smoking and Pulmonary Antioxidants

Several studies have reported an increase in gluatathione in ELF of smokers (Linden et al., 1989 Morrison et al., 1994). This may be as a consequence of increased cell turnover due to chronic airways inflammation. Ascorbate may also be somewhat increased in ELF from smokers (Bui et al., 1992), while a-tocopherol is decreased (Pacht et al., 1986). Results relating to antioxidant enzymes in macrophages from human lungs have been variable, with both increased activity of SOD and catalase (McCusker and Hoidal, 1990) and decreased activity (Kondo et al., 1994) having been reported.

Pharmacology and pharmaceutics

Drug interactions Alfa interferons may affect the oxidative metabolic process by reducing the activity of hepatic micro-somal cytochrome enzymes in the P450 group. Although the clinical relevance is still unclear, this suppression should be taken into account when prescribing concomitant therapy with drugs metabolized in this manner. Roferon-A has been reported to reduce the clearance of theophylline. Caution should also be exercised when administering Roferon-A in combination with other potentially myelosuppressive agents. The neurotoxic, hematotoxic, or cardiotoxic effects of previously or concurrently administered drugs may be increased by interferons. Interactions could occur following concurrent administration of centrally acting drugs. Use of Roferon-A in

Recombinant Human InterferonaA

In another study, the same authors (20) studied the effect of IFN-aA (single intramuscular dose) on theophylline clearance in five patients with stable chronic active hepatitis B and four healthy subjects. Like antipyrine, theophyl-line clearance was reduced and varied from 31 to 81 in eight of nine patients. In one patient, no change in theophylline clearance was observed.

Evidence from Human Studies

Experimental animal models have been informative to understand the mechanism of fibrosis and appear to replicate some patterns observed in human disease. Data from human subjects relating to chemokines and chemokine receptor expression in fibrosis correlates with that from animal studies. Human lung epithelial cells from patients with idiopathic pulmonary fibrosis strongly express CCL2 mRNA and its protein product, CCL2, in contrast with those cells from healthy patients (98). Schmidt et al. correlate observations from human and animal studies within the same study and show that both models support a role for fibrocytes in pulmonary fibrosis in the context of bronchial asthma (33). In patients with allergen-induced asthma, endobronchial biopsies (that were performed after antigen challenge) show airway fibrosis is associated with the presence of fibrocytes (33). Similar to murine fibroblasts, human fibro-cytes isolated from human peripheral blood express CD45, collagen I, and CXCR4...

Antioxidant Therapy and Respiratory Disease

Glutathione cannot be administered orally, due to lack of bioavailability. However, oral or intravenous administration of -acetylcysteine (NAC) is an effective means of increasing glutathione in plasma, red blood cells and ELF (Bridgeman et al., 1994), and observational studies suggest a possible beneficial effect in adult respiratory distress syndrome (Bernard, 1990). Administration of ascorbate or a-tocopherol by the oral route effectively increases antioxidant concentrations in many body fluids, but no data are available with regard to effects on lung lining fluids. Perhaps of more relevance to public health, recent evidence has shown that a switch to a diet rich in fruit and vegetables will result in a significant increase in plasma levels of ascorbate and carotenoids. However, further studies are required to show whether this type of intervention will translate into improved respiratory function in subjects with asthma or other respiratory disease.

Clinical pharmacology The interferons

Drug Interactions According to the product label, interactions between Intron A and other drugs have not been fully evaluated. Caution should be exercised when administering Intron A therapy in combination with other potentially myelo-suppressive agents such as zidovudine. Concomitant use of alfa interferon and theophylline decreases theophylline clearance, resulting in a 100 increase in serum theophylline levels.

Pegylated Interferona2a

Peg-IFN-a2a is a covalent conjugate of recombinant IFN-a2a. Treatment with peg-IFN-a2a once weekly for four weeks in healthy subjects resulted in inhibition of P450 1A2 and a 25 increase in theophylline area under the curve (AUC). On the basis of the study, it was suggested that theophylline serum levels should be monitored and appropriate dose adjustments considered for patients given both theophylline and peg-IFN-a2b (package insert). There was, however, no effect of peg-IFN-a2b on the pharmacokinetics of drugs that are metabolized by CYP2C9, CYP2C19, CYP2D6, or CYP3A4.

Ligand Subtype Selectivity in GPCR Models

Promiscuous ligand binding among GPCR subtypes is a frequent obstacle to the design of safe and effective drugs 88 . This issue is particularly critical for clinically relevant GPCR families (including the adrenergic, adenosine, and dopamine receptors), where several functionally distinct receptor subtypes share a conserved endogenous ligand. For example, the p1AR, p2AR, and p3AR receptors are all activated by the endogenous ligand norepinephrine. p-blocker medications that target the p1AR receptor mediate a desirable anti-hypertensive effect and are frequently used in the treatment of high blood pressure. However, cross-reactivity of these compounds with the p2AR receptor results in airway constriction and asthma-like symptoms. Thus, small molecule antagonists with improved p1AR versus p2AR specificity are desired. Optimization of specificity is challenging due to high levels of sequence conservation within the core ligand binding pocket residues. This limits the efficacy of...

A aApplication ofLigand BasedDesign to Adenosine Receptor Antagonists

Shown in which a large Y-shaped area of negative molecular electrostatic potential (at a level of -5 kcal mol) is apparent, resulting from the aromatic system of the 6 5 fused heterocycle. This area extends from the ring system at three points, designated NEG1, NEG2, NEG3. NEG1 and NEG2 have various molecular determinants, whereas NEG3 is invariably caused by a nitrogen lone pair. There are also two areas of positive molecular electrostatic potential (at +5 kcal mol). Three other areas (dashed lines) can be identified, amenable to further (hydrophobic) substitution. All this information was used to design and synthesize a novel class of adenosine receptor antagonists, the imidazoquinolinamines (10). The core structure complies with the steric and electronic pattern in Figure 5, and it allows for further substitution. In Table 1 affinities for the rat adenosine A1 and A2A receptor are gathered for a selected number of derivatives. The unsubstituted compound (R1 R2 H) had moderate...

Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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