Foods That Reduce Inflammation

Organic Health Protocol

This eBook from professional trainer and nutritionist Thomas DeLauer and Dr. Mike Brookins shows you all of the secrets to reducing inflammation all through your body. These body hacks are secrets to the way that your body works that you would never have thought of. You will learn the foods that you will need to avoid in order to have a really healthy life. You will learn to reset your body in 7 days or less just by eating organic, really healthy foods. Food affects they way that your body works so much more than people tend to believe. You will learn how to cut through all the nonsense that you will read on the internet and get right to the part that heals your inflammation and other health problems. Inflammation is only a symptom If you are not healthy and eating well, your whole body will suffer. We give you a way to reverse that! Read more here...

Organic Health Protocol Summary

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Author: Thomas DeLauer
Official Website: organichealthprotocol.com

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Highly Recommended

This is one of the best e-books I have read on this field. The writing style was simple and engaging. Content included was worth reading spending my precious time.

As a whole, this book contains everything you need to know about this subject. I would recommend it as a guide for beginners as well as experts and everyone in between.

Anti Inflammatory and Cytoprotective Mechanisms

The ability of protein C to inhibit thrombin generation could, in and of itself, reduce thrombin-mediated inflammatory effects resulting from decreased thrombin-receptor cleavage, and subsequently reduce platelet and endothelial cell activation (reviewed in 79 ). However, there is growing evidence that APC has direct anti-inflammatory properties (reviewed in 44,45,64-66,80 ), and modulatory effects on cellular functions. APC has been shown in supratherapeutic concentrations to inhibit the generation of cytokines such as tissue necrosis factor (TNF) and interleukin-1 (IL-1), to uncouple lipopolysaccharide (LPS) interactions with monocyte CD14, and has shown a selective inhibitory activity on the responses of human mononuclear phagocytes to LPS, interferon-y, or phorbol ester 80-85 . However, these reported effects of APC on cytokine secretion with supratherapeutic concentrations of APC have not been demonstrated in human studies 86-88 . APC may also modulate macrophage migration...

Antiinflammatory compounds

Brain inflammation and activation of microglia are early pathological events in AD, and epidemiological studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs cyclooxygenase (COX)-l and -2 inhibitors) may slow disease onset. Initial retrospective studies of patients with AD using indomethacin 42 showed a positive effect in reducing AD progress.54 However, prospective trials with NSAIDs, e.g., rofecoxib 43, celecoxib 44, and naproxen, failed to demonstrate efficacy in AD. Nonetheless, the COX-1 inhibitor, (R)-flurbiprofen 45, is in Phase III AD trials, despite limited benefit in a Phase II study. Nitroflurbiprofen (NCX-2216 46), an NO-donating flurbiprofen derivative, with reduced gastrointestinal side effects, is also in Phase II trials in AD. In preclinical studies, nitroflurbiprofen reduced lipopolysaccharide-induced microglial activation and decreased both the microglial activation and the amount of Ab deposits in the brains of transgenic mice with familial AD...

Antiinflammatory agents

Minocycline 87, a tetracycline antibiotic with anti-inflammatory activity, appears to have multiple effects on cell function, including inhibition of the mitochondrial permeability transition-mediated release of cytochrome c, an event key to the initiation of the apoptotic cascade. Additional activities of minocycline include inhibition of reactive microgliosis, caspase-1, caspase-3, and nitric oxide synthase transcriptional upregulation, and of p38 MAPK activation. It protects against motor neuron loss in a mouse ALS model (SOD-1 G93A) alone or in combination with creatine.87 The COX-2 inhibitor, celecoxib 44, preclinically slowed motor neuron deterioration in an organotypic model of motor neuron disease and improved survival up to 30 following oral administration in an ALS transgenic model.87 COX-2 is upregulated in both the transgenic SOD-1 G93A mouse model and in the CNS of ALS patients.86 COX-2 catalyzes the conversion of arachidonic acid to prostaglandin E2, a proinflammatory...

Anti Inflammatory Cytokines

Multiple mechanisms have been postulated to underly the therapeutic efficacy of IFN-b modulation of cytokine production toward anti-inflammatory cytokines inhibitory effects on proliferation of leukocytes and antigen presentation and inhibition of T cell migration across the blood-brain barrier by downregulating the expression of adhesion molecules, and inhibiting the activity of T cell matrix metalloproteinases.

Anti Inflammatory Strategies

Some of this cellular inflammatory response appears to continue for weeks and perhaps months, and may play a role in both secondary damage and repair processes.74 Considerable evidence exists to support the idea that much of this cellular inflammation can amplify the secondary injury process, and therefore should be inhibited via anti-inflammatory, immunosuppressive, or antiproliferative agents. With regard to the latter mechanistic possibility, a recent study in a rodent TBI model has shown that there is a considerable posttraumatic increase in cell cycle proteins, many of which have kinase activities.75 In the same study, the administration of the cell cycle inhibitor flavoperidol decreased posttraumatic elevations in neuronal and astrocyte cyclin D1 expression, reduced neuronal damage and astrocyte proliferation, and improved neurological recovery.

New oral antiinflammatory antioxidants

AGI-1067 (succinobucol 44, Figure 15), a metabolically stable derivative of probucol, where the introduction of a monosuccinate ester group alters its overall in vitro and in vivo pharmacology, is a new oral antioxidant being tested in atherosclerosis. AGI-1067, like probucol, is a potent extracellular antioxidant but has an enhanced intracellular uptake capability compared to probucol. AGI-1067 inhibited intracellular ROS production whereas probucol had no effect and also inhibited proinflammatory gene expression in stimulated endothelial cells, including the expression of several proteins associated with atherosclerosis VCAM-1 and MCP-1.93 In LPS-challenged mice, oral dosing with AGI-1067 reduced VCAM-1 and MCP-1 mRNA levels. In LDLr 7 mice, AGI-1067 reduced aortic atherosclerosis by 49 in the absence of a lipid-lowering effect.94 Like probucol, oral dosing with AGI-1067 inhibited restenosis in phase II trials, but an important antiatherosclerotic effect was observed in the...

Nonsteroidal Antiinflammatory Drugs

These drugs are so called because, like adrenocortical steroids (see below), they reduce inflammation, especially in joints, but also in other tissues. NSAIDs include aspirin (also present in many over-the-counter drugs), acetaminophen (also sold as Tylenol and present in many other combination drugs), celecoxib (sold as Celebrex), ibuprofen (sold under many names, including Advil, Nuprin, and Motrin), and rofecoxib (sold as Vioxx). These are probably the most widely used drugs on the market. NSAIDs are taken for arthritic pain and for headache, among many other indications. Avoiding these pain relievers is out of the question for most people. If you do find yourself in need of a pain reliever, do not take any of these drugs for more than a few days at a time.

Antiinflammatory Action

The anti-inflammatory effect of dapsone is not related to its antibacterial effect. Dermatoses that respond to dapsone are in general associated with the accumulation of large numbers of polymorphonuclear leukocytes, mainly neutrophils. After stimulation, neutrophils release the heme-containing enzyme myeloperoxidase, which converts nicotinamide adenine dinucleotide phosphate-dependent oxygen to toxic oxygen intermediates, such as hydrogen peroxide, superoxide anion, hydroxyl radical, hydroxyl ion, and peroxide anion. These intermediates seem to allow microbial killing and to contribute to ongoing tissue injury during inflammation. Dapsone has been shown to protect cells from neutrophil-mediated auto-oxidative tissue injury by converting myeloperoxidase to an inactive compound (compound II), thus suppressing the formation of toxic oxygen intermediates. Dapsone has also been shown to suppress neutrophil chemotactic migration and to interfere with 02 integrin-medi-ated adherence of...

Anti Inflammatory Approaches

Cellular levels of cyclic AMP (cAMP) regulate T cell activation and endothelial adhesion, the synthesis and release of pro-inflammatory cytokines (IFN-g, TNF-a, IL8, etc.) from macrophages and monocytes, and the generation of nitrous oxide and superoxide from neutrophils. PDE4A, PDE4B, and PDE4D are the predominant cAMP-hydrolyzing PDEs in most inflammatory cells, and their inhibition is associated with broad anti-inflammatory effects. The contribution of PDE7 activity to this process is now no longer considered significant.56 In the rat DSS model of colitis, the PDE4 inhibitors rolipram (9) (10mgkg_ 1, four times per day, intraperitoneally) and OPC-6535 Tetomilast (10) (1 mgkg _ 1, four times per day, orally) significantly reduce the extent of mucosal erosion, bleeding, and inflammation.57'58 There is tremendous structural diversity reported for PDE4 inhibitors,59 but, as a class, their therapeutic utility and clinical development had been historically dogged by dose-limiting nausea...

The Diagnosis of Kidney Failure

A striking difference between true prevalence and diagnosed disease was shown in diabetic kidney disease by a report from Atlanta. In 1994 the authors reviewed hospital charts of 260 people with diabetes aged 64 to 75. Only 63 percent of the sample had their urine analyzed during their admission. Of these, 31 percent had urine protein of 1+ or greater, indicating advanced kidney disease. Twenty-five percent of the people with diabetes had elevated serum creatinine, but abnormal kidney function was noted in the discharge summaries of only 8 percent. None of these patients' medical records indicated that they had received dietary instructions about protein restriction, education about avoiding unnecessary use of NSAID's nonsteroidal anti-inflammatory drugs, see Chapter 19 , or education about diabetic renal disease. (These are some of the treatments we'll be discussing later in the book). Angiotensin-converting enzyme-inhibitors (ACEIs) or angiotensin-receptor blockers were no more...

Macrophage activation and deactivation

The last point highlights an interesting feature of the control architecture of the macrophage transcriptional network. We have reviewed elsewhere the observation that many of the most LPS-inducible transcripts are actually not effectors of immunity, but feedback controllers that act at every level of the signalling pathway from the receptor to transcription, as well as repressors of the effectors (such as protease inhibitors and antiinflammatory cytokines) (Wells et al 2005). One might consider that this multilevel control exists to ensure robustness, but in fact mutation in any individual control leads to disordered or excessive macrophage activation. A prediction of the observation that the feedback control is itself inducible, and the system is sensitive to that feedback control, is that it will be relatively insensitive to inhibitors that act on the afferent pathways (Wells et al 2005).

Regulation Of Il10 Production

Adenosine has potent anti-inflammatory effects, and the activities of the immune-modulating drugs methotrexate and sulphasalazine have been related to adenosine release. In part, the anti-inflammatory activities of adenosine may be related to its ability to induce IL-10 production by monocytes (TNF-a or LPS-stimulated) (40). Methylprednisone increased the production of IL-10 by mouse peritoneal macrophages and, depending on the dose, differentially influenced the production of TNF-a and IL-10 in mouse endotoxemia At a low concentration, TNF-a, but not IL-10, production was inhibited, whereas at a high concentration, the production of both cytokines was decreased (41). In humans, hypercortisolemia markedly increases LPS-induced IL-10 production in vivo, but timing is important When hypercortisolemia preceded the endotoxin challenge by more than 6 hs, no effect was observed (42). Epinephrine importantly affects immune responses by reducing TNF-a and increasing IL-10 production by human...

Multiplicity and ligand selectivity

EPHX2 is found in high levels in the mouse cytosol, from which the enzyme was originally purified. The enzyme contains an imperfect peroxisome-targeting sequence at the C-terminus and so activity has also been detected in peroxisomes. Like EPHX1, EPHX2 is encoded by a single gene, but there is very little sequence similarity between the two enzymes. EPHX2 is a known hydrate range of aliphatic and extensively substituted, hindered arene oxides. However, current focus is on its physiological role, especially the metabolism of arachidonic, linoleic, and other fatty acid epoxides. These endogenous chemical mediators play an important role in blood pressure regulation and inflammation. It has been proposed that inhibitors of EPHX2 might be useful in the treatment of hypertension or as antiinflammatory agents and several potent and selective amide, carbamate, and urea-based inhibitors of EPHX2 have been developed.87

Ontogenic development

By UGT2B7.107 Morphine was found to undergo significant glucuronidation by the fetus liver. In vitro studies in hepatic microsomes obtained from fetuses (15-27 weeks) indicated that the glucuronidation rates were 10-20 of that observed in adult microsomes.108 In addition, the mean rate of morphine glucuronidation in fetal livers obtained after hysterectomy was twofold higher than that obtained from induced abortion livers, suggesting a possible regulatory mechanism for UGTactivity related to the birth process (Table 4).25 The glucuronidation of morphine in vivo has also been demonstrated in premature neonates as young as 24 weeks of gestation. Studies with other substrates which are mainly or partially glucuronidated by UGT2B7, such as naloxone, an opiate agonist, benzodiazepines, and nonsteroidal antiinflammatory drugs are all suggestive of a reduced glucuronidation ability in neonates compared to adults.109

Studies in MS and Other Conditions

Experimental studies indicate that the components of bee venom have biologic effects that could affect an inflammatory disease such as MS. Various mixtures of multiple venom proteins produced anti-inflammatory effects in one study. Other studies have shown that two specific components of venom, melittin and adolapin, also have anti-inflammatory properties. In contrast, other studies have shown that bee venom components actually cause an inflammatory response. Also, apamin, a chemical constituent of the venom, has some effects that could be beneficial for MS. Apamin inhibits the action of a component of the nerve cell known as the potassium channel. This is the same part of the nerve cell affected by the experimental drug 4AP (4-aminopyridine), which may be beneficial for MS-associated fatigue. However, it is not clear that bee venom therapy produces high enough levels of apamin in the central nervous system to significantly inhibit potassium channels. Further studies are needed in...

Treatment of Eczema

In exogenous irritant or allergic contact dermatitis the mainstay of treatment is to identify the precipitating agent and to avoid it if at all possible. Otherwise the same general principles apply to the treatment of all forms of eczema. If there is a possibility that the eczema may be infected, skin swabs should be submitted for bacterial culture and sensitivity and, if appropriate, an antibiotic such as flucloxacillin should be prescribed. For acute, particularly wet and weeping eczema, astringent solutions such as potassium permanganate (1 10,000) are indicated. The involved area, such as hands or feet, can be placed in a bowl of the solution or, alternatively, wet gauze swabs may be applied directly to the skin. The majority of patients with eczema have a chronic, dry scaling, rash. These patients should be advised to use emollients frequently. They should also avoid soap and use soap substitutes, such as emulsifying ointment or Diprobase, wherever possible. Emollient bath oil...

Hormonal versus nonhormonal

Pelvic pain associated with severe dysmenorrhea and or pain at the time of ovulation is likely due to endometriosis or adenomyosis. Women with endometriosis report premenstrual spotting, dyspareunia, dyschezia, poor relief of symptoms with nonsteroidal anti-inflammatory drugs, progressively worsening symptoms, inability to attend work or school during menses, and the presence of pelvic pain unrelated to menses more often than women with primary dysmenorrhea.

Primary Nursing Diagnosis

Other Medications Postoperatively, medications are prescribed to reduce Infection (gentamlcin or neomycin) and to reduce inflammation (dexamethasone), taking the form of eye drops. Acetaminophen is prescribed for mild discomfort tropicamide is prescribed to induce ciliary paralysis.

Figure 15 Structure of the cofactor undine5diphosphoaDglucuronic acid 39 UDPGA generic reactions of O and

An important pathway of O-glucuronidation is the formation of acyl-glucuronides (Figure 15a). Substrates are numerous nonsteroidal anti-inflammatory arylacetic and 2-arylpropionic acids (e.g., ketoprofen, 43 in Figure 16) and aliphatic acids (e.g., valproic acid, 44 in Figure 16). More recent drug classes such as statins and endothelin receptor antagonists may also yield acyl-glucuronides. Aromatic acids do not appear to be good substrates, but there are exceptions. The significance of acyl-glucuronides has long been underestimated. Indeed, these metabolites are quite reactive, rearranging to positional isomers and binding covalently to plasma and seemingly also tissue proteins.84,85 Thus, acyl-glucuronide formation cannot be viewed solely as a reaction of inactivation and detoxification.

APC Mechanisms of Action

The protein C pathway was traditionally described as an endothelial-based complex, including TM-thrombin-protein C-protein S that generates the natural anticoagulant APC 60 . Many review articles have been published on the protein C anticoagulation pathway and its role in hemostasis and thrombosis 44,45,61-66 . However, more recently described anti-inflammatory and antiapoptotic properties of APC suggest a role for APC as an endothelial cell or microvascular modulator, with properties in opposition to thrombin and proinflammatory cytokines 67-71 . In this section, we will review anticoagulant-antithrombotic mechanism of APC, but focus on more recent data describing its role as a modulator of endothelial and leukocyte function (Figure 4.5).

Interleukin1 and neurodegeneration

IL-1 is a monokine (macrophage cytokine) whose expression is regulated at multiple steps 49,50 . Following transcriptional activation and translation, generation of mature (active) IL-1 requires processing of proIL-1 by IL-1 converting enzyme (ICE caspase-1). Microglial expression of IL-1 is readily induced in vitro by a number of different stimuli, including HIV-1, hypoxia, P-amyloid, LPS, and cytokines (including IL-1 itself) 51-53 (and unpublished observations), as well as activation through the TLRs and scavenger receptors discussed above. IL-1 is unique in the sense that its own antagonist, IL-1 receptor antagonist (IL-1ra), is produced endoge-nously by macrophages. In the CNS, microglial cells express IL-1ra and recombinant IL-1ra is a potent and specific inhibitor of IL-1 action 54 . Microglial IL-1ra expression is subject to regulation by microbial components and cytokines. In general, proinflammatory cytokines that induce IL-1 also induce IL-1ra however, anti-inflammatory...

Chemical Background Properties

Salicylic acid (ortho-hydroxybenzoic acid) is a beta hydroxy acid agent (Fig. 6.1). It is a lipo-philic compound which removes intercellular lipids that are covalently linked to the cornified envelope surrounding cornified epithelioid cells 1 . Due to its antihyperplastic effects on the epidermis, multiple investigators have used salicylic acid as a peeling agent 2,3,4 . Recently, histologic assessments using salicylic acid peels in hairless mice reported loss of cornified cells followed by activation of epidermal basal cells and underlying fibroblasts. These findings suggest that salicylic acid peeling can alter the underlying dermal tissue without directly wounding the tissue or causing inflammation 5 . Salicylic acid has also been shown to have anti-inflammatory and antimicrobial properties. When used in combination with benzoic acid in Whitfield's ointment, it has fungicidal properties.

Summary And Concluding Remarks

The brain has a unique relationship with the immune system which is determined by the structural and physiological characteristics of the brain's vasculature. The restricted permeability seen as the BBB and the presence of a perivascular compartment in combination with the brain's small extracellular compartment constrain the functioning of the immune system in the brain. The immune system's surveillance function is compromised by the exclusion of antibody from the brain by the barrier, and although the role of activated T lymphocytes is unaffected, their passage through the tissue is normally restricted to the perivascular space. The extent of the drainage from the extracellular space in the brain into the lymphatic system is variable between species and between different brain regions. This, coupled with the partially suppressed activity of brain macrophages, which is probably partly due to the activity of the BBB, leads to a variability in the degree and the nature of the primary...

Mechanistic Observations from the Clinical Experience

Direct or indirect anti-inflammatory activity of drotrecogin alfa (activated) was less well demonstrated in clinical studies. Although a dose-dependent and statistically significant reduction in IL-6 levels was observed in the phase II study 46 , only a slightly more rapid reduction in IL-6 levels was observed in drotrecogin alfa (activated)-treated patients as compared with placebo-treated patients in the phase III study. Exploratory analyses of other measured cytokines (TNF-a, IL-p, IL-8, and IL-10) did not show statistical differences between treatment groups in the latter study 86 . Additionally, studies in healthy volunteers who were administered a single dose of endotoxin with or without the concomitant administration of drotrecogin alfa (activated) failed to demonstrate any direct effect of therapy on the observed cytokine profile 87,88 . Taken together, these data suggest that drotrecogin alfa (activated) has minimal to no effect on the early response cytokines that...

Drug interactions

Floxacin colchicine oral contraceptives diltiazem systemic corticosteroids eryth-romycin lovastatin glyburide metformin metronidazole nafcillin non-steroidal anti-inflammatory agents phenytoin pimozide potassium salts pravastatin protease inhibitors rifampin simvastatin verapamil vinca alkaloids

New Research Areas

Antiapoptotic agents (e.g., caspase inhibitors), anti-inflammatory agents (e.g., minocycline 87), bioenergetic enhancers antioxidants (e.g., creatine, coenzyme Q, lipoic acid, dicholoroacetate, cystamine), excitotoxic anatgonists (e.g., riluzole 88, remacemide 89), histone deacetylase inhibitors (sodium butyrate and suberoylanilide hydroxamic acid), and transcriptional inhibitors (e.g., mithramycin 90) have all been examined in the R6 2 mouse model of HD and have shown some benefit.84 Some of these agents have been advanced to clinical trials (Table 2). Aggregation inhibitors are also a target.85

Electronic Search for the Patent and Scientific Research Literature

Searching journal information continues to be the primary use of Sci-Finder for the medicinal chemist. One finds it especially useful for searching various topics, for instance, anti-inflammatory treatments. When performing structure reaction-based searches, many chemists also use Beilstein CrossFire in conjunction with SciFinder. The reaction information from these systems is often complementary, and it is quite useful to have both SciFinder and CrossFire in a medicinal chemistry group. However, companies with restricted budget may have to choose one or the other.

Therapeutic Vaccines and Toleragens

Glatiramer acetate is the first vaccine that has been used to treat an autoimmune disease - in this case RRMS32 it was approved by the US FDA in 1996. It is a mixture of many synthetic peptides - random polymers - that mimic the antigenic portion of MBP. It reduces the relapse rate in RRMS, impacts MRI markers of disease activity, is well tolerated, and does not appear to induce the formation of neutralizing antibodies. Several mechanisms of action have been proposed for glatiramer acetate, none of which reflect the theoretical mechanism proposed above for a prophylactic vaccine. Glatiramer acetate is a strong inducer of Th2 cells, and thus anti-inflammatory cytokine production one proposed mechanism is that it acts by inducing a Th1 to Th2 shift. In addition to glatiramer acetate, a vaccine for MG is in preclinical development.31

Electronic Search for Clinical and Preclinical Data

Pharma Projects predate the structure-based search tools available today. Twenty years ago, a person would look through three-ring binders of Pharma Projects pages, and now we can more thoroughly find what is needed in a fraction of the time. Access to these types of databases can greatly help the research team that is just beginning to approach a new field of interest. One can quickly find molecules relevant to his her topic of interest. For example, a quick search on anti-inflammatory brings back molecules that are in clinical trials as well as late-stage preclinical development with corresponding journal references. Combining the information related to these compounds in development with the more current molecular modifications can be quite useful for generating new ideas to help in discovery programs.

Biology and Atherosclerosis

Decrease in VCAM-1 expression (49), potentially consistent with some in vitro work and again indicative of possible issues with in vitro vs in vivo findings. Regardless, the decrease in atherosclerosis is fairly consistent and in keeping with early surrogate marker studies in humans. For example, the PPAR-y agonists in clinical use have been shown to lower levels of circulating MMP9 (50,51), replicating the responses seen in vitro with VSMCs (38) and macrophages (37). PPAR-y agonists also decrease circulating levels of C-reactive protein (CRP) and levels of CD40 ligand (CD40L), both suggestive of an antiinflammatory effect (50). Several PPAR-y agonists have been found to decrease carotid intimal-medial thickness, a parameter linked with cardiovascular risk (52,53). These studies have all bolstered ongoing clinical trials examining the impact of PPAR ligands on cardiovascular endpoints. Independent of these direct effects on atherosclerosis, it remains possible that PPAR-y agonists...

Peroxisome Proliferator Activated Receptora in Vascular Biology Inflammation and Atherosclerosis

A similar but distinct picture as to one described for PPAR-y has emerged for PPAR-a and its potential role in vascular responses. PPAR-a is also now known to be expressed throughout most vascular and inflammatory cells (56). PPAR-a activation has been shown to favorably alter a number of well-established pathways strongly implicated in atherosclerosis. PPAR-a ligands clearly limit the inflammatory cytokine induction of adhesion molecules (43,57). Importantly, this effect is absent when repeated in microvascular cells lacking PPAR-a (58). The salutary benefits of fish oil may derive in part from PPAR-a activation with certain fatty acids limiting adhesion molecule expression and leukocyte adhesion in vivo in wild-type but not PPAR-a-deficient mice (Fig. 1) (59). Interestingly, both omega-3 fatty acids and PPAR-a ligands can also limit expression of tissue factor, a protein found in macrophages and thought to be a major contributor to plaque thrombogenicity (60,61). PPAR-a has also...

Prepeeling Preparation

We do not discontinue use of any of the patient's medications including anticoagulants, aspirin or nonsteroidal anti-inflammatory drugs. Systemic isotretinoin (Acutane) is considered to be a contraindication to any external treatment of the skin. We feel that the minimal

Glucocorticoid Therapy

Pharmacodynamic therapy with glucocorticoids (A). In unphysio-logically high concentrations, cortisol or other glucocorticoids suppress all phases (exudation, proliferation, scar formation) of the inflammatory reaction, i.e., the organism's defensive measures against foreign or noxious matter. This effect is mediated by multiple components, all of which involve alterations in gene transcription (p. 64). Glucocorti-coids inhibit the expression of genes encoding for proinflammatory proteins (phospholipase-A2, cyclooxygenase 2, IL-2-receptor). The expression of these genes is stimulated by the transcription factor NFkb. Binding to the glucocorticoid receptor complex prevents translocation af NFkb to the nucleus. Conversely, glucocorticoids augment the expression of some anti-inflammatory proteins, e.g., lipocortin, which in turn inhibits phospholipase A2. Consequently, release of arachidonic acid is diminished, as is the formation of inflammatory mediators of the prostaglandin and...

Measures for Attenuating or Preventing Drug Induced Cushings Syndrome

A) Use of Cortisol derivatives with less (e.g., prednisolone) or negligible miner-alocorticoid activity (e.g., triamcinolone, dexamethasone). Glucocorticoid activity of these congeners is more pronounced. Glucorticoid, anti-inflammatory and feedback inhibitory (p. 250) actions on the hypophysis are correlated. An exclusively anti-inflammatory congener does not exist. The glucocorti-coid related Cushingoid symptoms cannot be avoided. The table lists relative activity (potency) with reference to cortisol, whose mineralo- and glucocor-ticoid activities are assigned a value of 1.0. All listed glucocorticoids are effective orally.

Glucocorticoids principal and adverse effects

For long-term medication, a just sufficient dose should be given. However, in attempting to lower the dose to the minimal effective level, it is necessary to take into account that administration of exogenous glucocorticoids will suppress production of endogenous cortisol due to activation of an inhibitory feedback mechanism. In this manner, a very low dose could be buffered, so that un-physiologically high glucocorticoid activity and the anti-inflammatory effect are both prevented.

Discharge And Home Healthcare Guidelines

Teach the patient and family the early and late clinical manifestations of bleeding. Outline measures to prevent bleeding episodes, such as use of a soft-bristled toothbrush or sponge sticks, avoidance of activities that are likely to result in trauma, and avoidance of nonsteroidal anti-inflammatory drugs.

Substrates of methyltransferases

Figure 10 also shows the main methylation reactions seen in drug metabolism. O-Methylations (Figure 10a) are common reactions of compounds containing a catechol moiety, with a usual regioselectivity for the meta position. The substrates can be xenobiotics and particularly drugs, l-DOPA being a classic example. More frequently, however, O-methylation occurs as a late event in the metabolism of aryl groups, after they have been oxidized to catechols (see Figure 8). This sequence was seen, for example, in the metabolism of the anti-inflammatory drug diclofenac, which in humans yielded 3'-hydroxy-4'-methoxy-diclofenac (23, Figure 11) as a major metabolite with a very long plasma half-life.44 The rates of O-methylation of about 50 substrates in recombinant human soluble COMT has been published and analyzed by partial least squares (PLS) QSAR and 3D-QSAR.45'46 The compounds examined were natural products. The results showed that increased acidity of the catechol group and a larger size of...

Background Information

Since the original discovery that a soluble factor transformed the phenotype of fibroblast cell lines (Letterio and Roberts, 1998), knowledge of the role of this growth factor, termed TGF-P, in development, growth regulation, neoplasia, inflammation, and host defense has spiraled. As a mediator of both pro- and antiinflammatory events, TGF-P's regulation, distribution and concentration often determine if the cellular response is beneficial or deleterious (McCartney-Francis et al., 1998 Wahl, 1994, 1999). Regulation of TGF-P occurs at multiple sites from the genes encoding the message to the secreted protein. The three mammalian iso-forms TGF-P1, -P2, and -P3 are encoded by individual genes however, their structures are highly conserved. This homology allows these molecules to bind to the same family of receptors, transducing signals with both functional diversity and overlap (Massague, 1998). Differential expression of these isoforms during embryogenesis, immune responses, and other...

Science Medicine and Leadership Win Out The Pendulum Swings in Carvedilols Favor

In addition, the other properties of carvedilol, namely its antioxidant actions, could also provide added benefit inasmuch as oxygen radicals were known to be potent activators of signaling pathways that have a short- and long-term negative impact on cardiac cell growth and survival. In particular, the emergence of apoptosis as a primary mechanism of cardiac cell death43 and remodeling in heart failure mediated in part by intracellular redox imbalance potentially expanded as we had successfully demonstrated in animal studies the potential benefits that this drug might have in heart failure beyond its adrenergic pharmacology. Thus, carvedilol could inhibit apoptotic cell death through modulation of expression of the Fas receptor, which is a cell surface receptor that activates a cell-death-signaling pathway.44-47 Additionally, carvedilol was also shown to possess antiproliferative actions on vascular smooth muscle cells and anti-inflammatory actions through its ability to inhibit...

Clustering of Autoantigens on Apoptotic Cells Insights from Phenotype Development in Neonatal Systemic Lupus

Several recent studies have demonstrated that although apoptotic cells are actively anti-inflammatory and tolerance inducing (Fadok et al. 1998, Gallucci et al. 1999, Huyn et al. 2002, Voll et al. 1997, Sauter et al. 2000), binding of antibodies to the cell surface abrogates these anti-inflammatory properties and renders apoptotic cells proinflammatory (Manfredi et al. 1998). Thus, apoptotic cells opsonized with autoantibodies that recognize antigens at the apoptotic cell surface are efficiently phagocytosed by macrophages, and their phagocytosis is accompanied by the secretion of tumor necrosis factor a. The presence of autoantibodies recognizing the apoptotic cell surface can therefore render normally quiet forms of apoptotic death occurring during development or homeostasis markedly proinflammatory. Buyon and colleagues recently demonstrated that in the developing conduction system of the heart, for example, apoptotic death of myocardial cells is associated with autoantigen...

Induction of a Specific Autoantibody Response Critical Component of Pathogenesis

Recent studies have demonstrated that apoptotic cells are a dominant toleragen for the immune system (Henson et al. 2001, Savill and Fadok 2000), with apoptosis occurring universally during development, homeostasis, and lymphocyte selection and actively inducing anti-inflammatory cytokine secretion on phagocytosis by macrophages (Hengartner 2000). Abnormalities in (a) the efficient, noninflammatory clearance of apoptotic cells or (b) the occurrence of unusual forms of apoptotic death that generate unique structures of autoantigens not generated during tolerizing apoptosis may render an individual susceptible to immunization with apoptotic cells. Examples of both mechanisms are dealt with in the following subsections.

Abnormal Clearance of Apoptotic Cells Renders Individuals Susceptible to Initiation of Systemic Autoimmunity

Apoptotic cell clearance is a complex process that actively inhibits the initiation of inflammation and immune responses, in part through the release of antiinflammatory cytokines (Henson et al. 2001, Savill and Fadok 2000). Clearance involves numerous components on both the phagocytic cell (including CD14, the PS receptor, CD36, and scavenger receptor class A) and the cell being engulfed (e.g., PS). Although numerous cell surface receptors on macrophages seem to be responsible for binding of the apoptotic cell, recent studies have demonstrated that ligation of the PS receptor by surface PS on the apoptotic cell is responsible for inducing the rapid and efficient uptake of the bound cell through stimulated macropinocytosis (Fadok et al. 2001, Hoffmann et al. 2001, Somersan et al. 2001). Recent studies have also implicated soluble components of the innate immune system in the efficient clearance of, and the induction of immune tolerance to, apoptotic material (Botto et al. 1998,...

Antipyretic Analgesics

Antipyretic Mechanism Action

Acetylsalicylic acid (ASA) exerts an antiinflammatory effect, in addition to its analgesic and antipyretic actions. These can be attributed to inhibition of cyclooxygenase (p. 196). ASA can be given in tablet form, as effervescent powder, or injected systemically as lysinate (analgesic or antipyretic single dose, 0.5-1.0 g). ASA undergoes rapid ester hydrolysis, first in the gut and subsequently in the blood. The effect outlasts the presence of ASA in plasma (ti 2 20 min), because cyclooxygenases are irreversibly inhibited due to covalent binding of the acetyl residue. Hence, the duration of the effect depends on the rate of enzyme resynthesis. Furthermore, salicylate may contribute to the effect. ASA irritates the gastric mucosa (direct acid effect and inhibition of cy-toprotective PG synthesis, p. 200) and can precipitate bronchoconstriction (aspirin asthma, pseudoallergy) due to inhibition of PGE2 synthesis and overproduction of leukotrienes. Because ASA inhibits platelet...

Clinical Trial Issues

Clinical trial designs often employ parallel placebo-controlled and randomized withdrawal types of experimental manipulations.14'35 The majority of these designs have been well validated using opioids however, the relative utility in assessing novel analgesics that target specific aspects of chronic pain (e.g., neuropathic allodynia) await further evaluation (e.g., non-NSAID (nonsteroidal anti-inflammatory drug) mediated analgesia in the third molar extraction model).

Summary And Conclusion

Since UVA- and UVB-induced skin damage is not solely dependent on ROS formation and their reaction with numerous skin biomolecules, topical (as well as systemic) antioxidant supplementation cannot be presumed to give complete photoprotection (196). Other ROS-independent processes, such as DNA dimer formation, will persist in causing skin damage, regardless of the effectiveness of the antioxidant(s) administered. Therefore, efficient sunscreens are indispensable in the effective prevention of skin photodamage. However, antioxidants, in combination with sunscreens (128) or anti-inflammatory agents (135), seem to be highly effective adjuncts increasing the safety and the efficacy of photopro-tective products.

Vascular Effects of Estrogens

NO synthesis by endothelial cells is of paramount importance for the regulation of vascular tone and blood flow and for control of the hemostatic process. Furthermore, endothelium-derived NO is a potent anti-inflammatory and antiatherogenic factor, being able to prevent endothelial cell dysfunction that has been proposed as an early manifestation of atherosclerosis (26,27).

Myrrh Commiphora myrrha Burseraceae

Myrrh is indigenous to Northeast Africa, particularly Somalia and Ethiopia, and is one of the oldest and most highly esteemed botanical drugs. The drug used is the gum resin (an exudate), which is excreted by the trees through the bark. In present-day Morocco, for example, it is used as a balsam and for nervous disorders, and it is applied in cleansing ceremonies such as ritual fumigations (Bellakhdar 1997). In vivo anti-inflammatory effects have been reported for its extract (Duwiejua et al. 1992).

St Johns wort Hypericum perforatum Hypericaceae

John's wort is a perennial which plays a primary role in modern evidence-based phytotherapy. The aerial parts of the plant have been used as an anti-inflammatory, healing application for wounds and as an antimelancholia remedy since the time of the ancient Greeks. In the Middle Ages many believed it to have magical powers to protect one from evil. Early Christian mystics named the plant after John the Baptist and it is traditionally collected on St. John's Day, June 24, and soaked in olive oil for several days in order to produce a red anointing oil to be used externally. This practice is still very common in many folk medicines of eastern and southern Europe, and some pharmacological evidence in support of the usage exists.

Ephedra Ma huang Ephedra sinica Ephedraceae

Ephedra sinica represents one of the oldest medicinal plants in China, where it is known by the name of ma huang. It is estimated that its use began 4,000 years ago, particularly in northern China and Mongolia. Ephedra was used in ethnomedicine as a stimulant, to increase perspiration, and as an anti-inflammatory. In the Chinese school of medicine, a preparation called mimahuang, containing roasted honey and chopped dried aerial parts of this species, is claimed to be an effective treatment for flu and respiratory tract inflammations. Ephedra, which contains ephedrine and similar alkaloids, has been used extensively in the ancient pharmacy as an antihistaminic in the treatment of asthma and as a natural decongestant. It has become a very popular ingredient in herbal combinations for allergies and hay fever. Since it is a central nervous system stimulant and increases the metabolism and increases body temperature, it has been used to control weight and to help prevent sleep, and by...

Overview of Absorption Distribution Metabolism and Excretion Correlations with Descriptors of Function

Despite the significant role of log P in ADME processes, it is worth noting that predictive equations that successfully correlate lipophilicity with ADME parameters are not as numerous as one would expect.84 This inherent difficulty can be explained considering that pharmacokinetic parameters result from a multiplicity of interactions with a variety of biological constituents that can be seen as fuzzy targets due to their fluctuating diversity. Moreover, a second difficulty is due to the heterogeneity of pharmacokinetic parameters, which, being obtained from complex biological systems, shows a decreased relatedness to molecular properties. These problems become apparent when examining correlations between lipophilicity and skin permeability for example, it was possible to derive parabolic equations with a significant predictive power when considering separately a homogeneous set of phenols and of nonsteroidal anti-inflammatory agents, but no correlation was obtained for the set of all...

Endometrial sampling

In-office sampling of the endometrial lining may be accomplished with a Novak or Kevorkian curet, the Pipelle endometrial-suction curet, or the Vabra aspirator. Before having an in-office biopsy, the patient should take a preoperative dose of a nonsteroidal anti-inflammatory drug (NSAID). With the patient in the lithotomy position, a speculum is inserted in the vaginal canal. The cervix should be cleansed with a small amount of an antiseptic solution. After 1 mL of a local anesthetic is infused into the anterior lip of the cervix, a tenaculum is placed. The paracervical block is then performed using 1 or 2 percent lidocaine (Xylocaine) without epineph-rine.

Psyllium Plantago spp Plataginaceae

The seeds, which have a seed coat particularly rich in mucilage, are used medicinally for treating constipation, dysentery, irritable-bowel syndrome, and a variety of skin conditions. Certain types of mucilage are well known to have beneficial effects, on the gastrointestinal tract including antidiar-rheal and anti-inflammatory effects. A number of species are used, including blond psyllium (Plantago ovata, Asia), black psyllium (P. afra, Asia), P. asiatica in Indochina, and great plantain (P. major, widespread throughout Asia).

Alkene oxide substrates

Drug Metabolism

Some drugs contain an unconjugated alkene group undergoing CYP-catalyzed epoxidation followed by EH-catalyzed hydration. Thus, the anti-inflammatory agent alclophenac contains an O-allyl group. Its epoxide (16, Figure 9) was found as a stable metabolite in the urine of mice and humans, and so was the diol, proving the involvement of the epoxide-diol pathway in the metabolism of this drug. The epoxide proved mutagenic, but only in the absence of a rat liver S-9 suspension (which contains EH).30 A few old barbiturates also contain an allylic group in the 5-position, e.g., allobarbital (17, Figure 9 R allyl), and secobarbital (17, Figure 9 R 1-methylbutyl). These compounds were substrates of the epoxide-diol pathway in rats and guinea pigs. The relative importance of this metabolic route was species dependent, but was also markedly influenced by the nature of the other C5-substituent.31

Lower Gastrointestinal Bleeding

Risk factors that may have contributed to the bleeding include and nonsteroidal anti-inflammatory drugs, anticoagulants, colonic diverticulitis, renal failure, coagulopathy, colonic polyps, and hemorrhoids. Patients may have a prior history of hemorrhoids, diverticulosis, inflammatory bowel disease, peptic ulcer, gastritis, cirrhosis, or esophageal varices.

UDPglucuronosyltransferases EC 24117

In a few cases, however, UGTs enhance the toxicity of their substrates. This is the case with some nonsteroidal anti-inflammatory drugs (NSAIDs). The resulting ester glucuronides can undergo acyl migration, i.e., the intramolecular transesterification from the C1 hydroxy group of the glucuronic acid to the C2 hydroxy group and further to the C3 and C4 hydroxy groups. This can lead to the formation of a free aldehyde group at C1, which can react with primary amino groups in proteins generating Schiff's bases. Amadori rearrangement can then lead to a stable protein adduct, which may give rise to allergic reactions, a well-known drug toxicity of some NSAIDs. Glucuronic acid conjugation can also result in enhanced genotoxicity. Aromatic amines, including important human carcinogens, are metabolized by CYPs (preferentially CYP1A2) to aromatic hydroxylamines. Glucuronidation of these leads to the formation of a (moderately good) leaving group, which after being cleaved off leaves behind a...

Scotch marigold Calendula officinalis Asteraceae

Scotch or pot marigold is used pharmaceutically, for example, to treat chilblains, chronic wounds (including ones which heal very slowly), and other inflammatory conditions of the skin. In some rural regions of Europe (e.g., Switzerland and the German Black Forest) the species is still widely used externally as a veterinary anti-inflammatory remedy. Normally the flower heads are mixed with lard or another animal fat, heated for a short period in order to extract the active lipophilic constituents, and the resulting product is stored for usage. The flower heads are also used to color butter and to thicken soups.

The atheroprotective effects of highdensity lipoprotein cholesterol

While excessive mmLDL plays an important proinflammatory role in atherosclerosis, HDL and its associated apoA-I exert a corresponding cardiovascular benefit through the RCT pathway and several other important protective mechanisms.16 HDL also has beneficial antioxidant and anti-inflammatory properties and improves endothelial dysfunction. HDL contains two antioxidant enzymes, paraoxonase and platelet-activating factor (PAF) acetylhydrolase (PAFAH), that not only inhibit the oxidation of LDL but also help degrade oxidized phospholipids within oxLDL. HDL and its associated apoA-I protect endothelial cells from damage induced by oxLDL. HDL also displays anti-inflammatory properties, since pretreatment of human endothelial cells with HDL inhibits the cytokine-induced expression of cell adhesion molecules. Alternatively, overall HDL functionality may be more important than absolute HDLc levels, since recent data indicate that HDL has both proinflammatory and anti-inflammatory properties....

Murine Models of Atherosclerosis

Both LDLr_ _ and apoE _ _ models have been further exploited by backcrossing with other knockouts or transgenic mice overexpressing specific proteins to create new transgenic models that have helped define many of the mechanistic components underlying this disease. As a result, the specific effects of both human proinflammatory, anti-inflammatory, oxidative, antioxidant, and redox-regulated proteins on the atherosclerotic process have been confirmed in animal studies.

Additional Contraindications

Special Concerns Use in children should be restricted to those unresponsive to or intolerant of other anti-inflammatory agents efficacy has not been determined in children less than 14 years of age. Geriatric clients are at greater risk of developing CNS side effects, especially confusion. To be used with caution in clients with history of epilepsy, psychiatric illness, or parkinsonism and in the elderly. Indomethacin should be used with extreme caution in the presence of existing, controlled infections.

Disorders of the Wrist and the Hand

Your doctor probably will recommend that you rest the affected hand and avoid the repetitive activity that is causing the problem. You also may need to wear a splint or a brace to immobilize your wrist while allowing you to continue using your hand. Nonsteroidal anti-inflammatory drugs such as aspirin or ibuprofen can relieve pain and inflammation. Injections with corticosteroids may be prescribed if pain persists. Surgery to relieve the pressure on the median nerve (a procedure called carpal tunnel release) is performed in severe cases that do not respond to other forms of treatment. To reduce pain and swelling, place an ice pack on the finger immediately after the injury occurs. See your doctor as soon as possible. He or she may X ray the finger to make sure it is not broken. The doctor probably will immobilize your finger with a splint for 2 to 3 months to help the joint heal properly. In some cases the doctor may insert a wire through the joint to hold the finger straight while...

Ketorolac tromethamine

Classification Nonsteroidal anti-inflammatory drug See also Nonsteroidal Antiinflammatory Drugs. Action Kinetics Possesses anti-inflammatory, analgesic, and antipyretic effects. Completely absorbed following IM use. Onset Within 30 min. Maximum effect 1-2 hr after IV or IM dosing. Duration 4-6 hr. Peak plasma levels 2.2-3.0 mcg mL 50 min after a dose of 30 mg. tv2, terminal 3.8-6.3 hr in young adults and 4.7-8.6 hr in geriatric clients. Over 99 is bound to plasma proteins. Metabolized in the liver with over 90 excreted in the urine and the remainder excreted in the feces.

Immunological Effects of Glatiramer Acetate in Multiple Sclerosis Patients 814421 Antibody response

GA binding to the relevant MHC leads to peripheral activation of the regulatory suppressor cells, which are activated by shared suppressive determinants between MBP and GA, to secrete Th2-suppressive cytokines. These GA-specific Th2 cross the blood-brain barrier. Local reactivation of these cells in the brain by MBP stimulates the release of anti-inflammatory cytokines which downregulate the autoaggressive response to MBP as well as to other myelin antigens (e.g., PLP and MOG), which are colocalized with MBP, due to bystander suppression (Figure 3). It is currently believed that Th2-regulatory Tcells play a major role in the mode of action of GA, and bystander suppression is a central element in it. In addition to the in situ release of anti-inflammatory cytokines, the GA-specific Th2 cells were also shown to release BDNF in the CNS, which may explain the neuroprotective effects recently attributed to GA.

Disorders of the Knee

Ligament injuries are first treated with RICE (see page 65). You also must use some form of support (such as crutches or a cane) to avoid putting weight on the injured knee joint. In some cases a splint or a brace is needed for long-term immobilization of the joint. Nonsteroidal anti-inflammatory drugs such as aspirin or ibuprofen will help relieve pain and reduce inflammation. Arthroscopy (see box) often is needed to repair the ligament. Your knee joint may be unstable after this injury and may be more susceptible to recurring ligament or cartilage tears. Your doctor may recommend working with a physical therapist or an athletic trainer on exercises that will stabilize the ligaments and tendons and strengthen the leg muscles.

Oral 5lipoxygenaseactivating protein inhibitors

An oral small molecule inhibitor of 5-lipoxygenase-activating protein (FLAP), DG-031, of unknown structure, is in clinical trials with CHD patients. FLAP inhibitors are anticipated to reduce proinflammatory leukotriene mediators such as the potent chemotactic agent, LTB4 (Figure 6). In a 4-week phase II trial in patients with a previous history of MI, DG-031 (250, 500, and 750 mg day 1 p.o.) at the highest dose reduced serum LTB4 (26 ) and MPO (12 ) levels as well as soluble intercellular adhesion molecule. As discussed previously, MPO and LTB4 are inflammatory markers associated with a higher risk of CHD. Plasma CRP levels were also reduced at the highest dose, but the response did not reach statistical significance. Accompanying these changes, LDLc levels increased slightly, by 8 with the highest dose.92 These results represent the first demonstration that two key biomarkers of inflammation were reduced following oral dosing with an anti-inflammatory agent in a CHD patient...

APC Mechanism and Sepsis

As discussed above, homeostasis is lost in sepsis, resulting in an uncontrolled cascade of coagulation, inflammation, and endothelial cell dysfunction. APC functions by reducing thrombin generation and, via cell signaling, may modulate anti-inflammatory and cyto-protective mechanisms. Considering the prominent role of microvascular coagulation in sepsis and the major role of protein C in normal hemostasis, a major mechanism for the benefit of rhAPC is likely to be its direct antithrombotic activity, which prevents microvas-cular thrombosis, vascular congestion, and resulting organ failure. However, several animal studies with other antithrombotic anticoagulants, while effective at inhibiting the DIC, did not reduce mortality 64,189,195 . Coupled with the failure of both tissue factor pathway inhibitor (TFPI) and antithrombin III (ATIII) in a large phase-III sepsis trial, it would appear that correcting the coagulation defect in sepsis, while probably necessary, may not be sufficient...

Topical Corticosteroids

Application of topical corticosteroids (CSs) is part of the standard external therapy in CLE. Alone or in combination with systemic anti-inflammatory agents, CSs are very effective in reducing the main symptoms of the skin lesions of LE, namely, redness and squamae. To be effective in LE, intermediate (e. g., triamcinolone acetonide) to potent or superpotent CS preparations (betamethasone dipropionate, halobetasol propionate, fluocinonide, and clobetasol propionate) have to be used to achieve significant amelioration of the skin lesions. Usually, potent CS preparations should not be used on the face since the well-known side effects (atrophy, telangiectasias, steroid dermatitis, and folliculitis) tend to be especially severe in facial skin. However, in view of the risk-benefit ratio, CLE represents an exception to that rule, since the facial skin lesions of LE are often exceedingly disfiguring so that the CS side effects are less troublesome. Twice-daily application for a few weeks...

Inhibitors of Tetrahydrofolate Synthesis

Trimoxazole

Although initially developed as an antirheumatic agent (p. 320), sulfasala-zine (salazosulfapyridine) is used mainly in the treatment of inflammatory bowel disease (ulcerative colitis and terminal ileitis or Crohn's disease). Gut bacteria split this compound into the sulfonamide sulfapyridine and mesala-mine (5-aminosalicylic acid). The latter is probably the anti-inflammatory agent (inhibition of synthesis of chemotactic signals for granulocytes, and of H2O2 formation in mucosa), but must be present on the gut mucosa in high concentrations. Coupling to the sulfon-amide prevents premature absorption in upper small bowel segments. The cleaved-off sulfonamide can be absorbed and may produce typical adverse effects (see above).

Experimental New Topical Therapeutic Agents

Since retinoids have been shown to possess anti-inflammatory and antiproliferative as well as regulatory capacity on keratinocyte differentiation, they are good candidates to be beneficial in LE. In fact, various topical and systemic retinoids have been reported to be effective in patients with subacute CLE (SCLE) and chronic CLE (Werth et al. 1997). However, systematic controlled studies are lacking here too.

Immunological Properties of Glatiramer Acetate

As Th2 3-type cells secreting anti-inflammatory cytokines such as interleukin (IL)-4, IL10, and transforming growth factor (TGFb), but not Th1 cytokines, in response to both GAand MBP. Other myelin antigens such as PLP, MOG and ab crystalline could not activate the GATs cells to secrete Th2 cytokines. Yet the disease induced by PLP and MOG can be suppressed by these Ts cells, probably due to a bystander suppression mechanism.53,54 More recently, it has been demonstrated that these GA-specific Th2 suppressor T cells which were induced in the periphery by either injection or oral treatment accumulate in the brain.55,56 The GA-specific cells accumulated in the CNS demonstrated in situ extensive expression of the anti-inflammatory cytokines IL10 and TGFband the brain-derived neurotrophic factor (BDNF), but not the inflammatory cytokine IFN-g. Furthermore, the GA-induced cells infiltrating the brain induced bystander expression of IL10 and TGFb by resident astrocytes and microglia.57 These...

The First Step The Discovery of Adrafinil

In the early 1970s, the Research Department of Laboratoire Louis Lafon, a small family-owned pharmaceutical company located in Maisons-Alfort, a suburb of Paris, had focused its research activities in three areas (1) cardiovascular (2) antispasmodics and (3) nonsteroidal anti-inflammatory drugs (NSAIDs) analgesics.

Hossam M Kandil and Raymond N DuBois 1 Introduction

Most epidemiological studies (1-7) support a protective role of aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) against colorectal cancer. People who (by their report) take aspirin regularly have about a 50 decrease in the incidence (3,4) and mortality (1,2) from colorectal cancer compared to those who reported no aspirin use. In addition, hospital-based case control studies suggest a protective effect of aspirin use on the development of large-bowel adenomas (5-7). On the other hand, the Physician's Health Study failed to detect any protective effect for aspirin against the subsequent development of colorectal cancer over 12 years of follow up, although this may be due to the short period of follow up (8,9).

NOC Thermoregulation

Teach parents that the main reason for treating a fever is discomfort two antipyretic drugs of choice Acetaminophen and nonsteroidal anti-inflammatory drugs such as Ibuprofen administer as ordered in the form (liquid, tablet) that is appropriate for the age of the child and illness severity.

Adiponectins direct vascular effects

As an anti-inflammatory agent, adiponectin may inhibit inflammatory mediators involved in atherosclerosis, particularly TNF-a. An in vivo study in mice demonstrated that administration of adiponectin decreased serum TNF-a levels (35). Although no significant correlation occurred between adiponectin and serum TNF-a receptors 1 (sTNFR1) and 2 (sTNFR2), which are markers of activation of the TNF-a system, a study in humans found lower sTNFR2 in the highest quartile of circulating adiponectin, suggesting a threshold effect instead of a dose-dependent relationship (78). A different study, however, found a significant negative correlation between plasma adiponectin and TNF-a mRNA expression (13). Besides inhibiting the production of TNF-a, adiponectin may impede TNF-a's involvement in atherosclerosis by reducing TNF-a-induced expression of endothelial cell adhesion molecules such as vascular cell adhesion molecule-1, SE-selectin, and intracellular adhesion molecule-1, that otherwise recruit...

Ocular pathologies in animals and available drugs4244

Ocular inflammation is one of the most common eye disorders in animals.45 The precise observation and interpretation of signs provides the basis for diagnosing the disease and its associated disorders, and for establishing their etiology (trauma, lid or lacrimal abnormalities, viral or bacterial infection, immune-related phenomena, corneal ulceration). Topical steroidal therapy in combination with non steroidal anti-inflammatory drugs, immunosuppressive agents such cyclosporine and azathiopr-ine, antimicrobial agents, mydriatic-cycloplegic agents (atropine) and additional specific therapies are frequently prescribed to treat conjunctivitis, keratitis and uveitis (Table l).46,47 Topically applied steroids are in most cases used in combination with an antimicrobial agent. The reason is probably that the concomitant administration of steroid can increase the efficacy of antibiotics.48 In addition, this association prevents a secondary infection that may occur after a corticosteroid...

Mechanisms of Renal Dysfunction

Inflammation is an important contributor to the renal injury and endothelial dysfunction observed in hypertension and obesity. Elevated circulating levels of IL6 and TNF-a are observed in obesity and metabolic syndrome patients. IL6 stimulates the central and the sympathetic nervous system, which may result in hypertension.30 IL6 induces increases in hepatic triglyceride secretion in rats. IL6 also stimulates the production of C-reactive protein in liver and plasma levels of this protein are a good predictor of vascular inflammation. Another cytokine linked to obesity is TNF-a. TNF-a is overexpressed in the adipose tissue of obese patients, as compared with tissues from lean individuals. A positive correlation has been found between serum TNF-a concentration and both systolic blood pressure and insulin resistance in subjects with a wide range of adiposity. TNF- a acutely raises serum triglyceride levels in vivo by stimulating very low-density lipoprotein (VLDL) production and hence it...

Dehydroepiandrosterone DHEA

Limited information is available about the effects of DHEA on immune system-related diseases such as MS. In the animal model of MS, DHEA appears to have an anti-inflammatory effect and to decrease the severity of the disease. However, in other studies, DHEA appears to activate T cells, immune cells that are already excessively active in MS. This effect raises a theoretical risk for DHEA use in MS. In another autoimmune disease, lupus, DHEA may be beneficial in the mouse model of the disease

Identification of p38 Mitogen Activated Protein Kinase as a Target for Inhibition of IL1 and TNF

Several structurally related pyridinyl imidazoles, which were originally designed to inhibit arachadonic acid metabolism (7), were found to inhibit IL-1 synthesis from lipopolysaccharide (LPS)-stimulated human monocytes and monocytic cell lines (see Fig. 1 for example structures). Further examination revealed that these compounds inhibited the production of both IL-1 isoforms, TNF, and IL-6 (8), and thus they were called cytokine suppressive antiinflammatory drugs (CSAID) (CSAID , SmithKline Beecham, King of Prussia, PA) to distinguish their mechanism from nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit eicosanoid production but have no effect on cytokine production. In contrast, the pyridinyl imidazoles did not show any

Clinical disorders of external potassium balance

Drugs that may cause hyperkalemia include nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, cyclosporine, and potassium-sparing diuretics. Hyperkalemia is especially common when these drugs are given to patients at risk for hyperkalemia (diabetics, renal failure, advanced age).

Drug Candidate Selection

The use of the skin as a route of delivery into the systemic circulation was neither commercially nor scientifically exploited until the 1950s, when ointments containing agents such as nitroglycerin and salicylates were developed. Angina could be controlled for several hours by applying an ointment containing 2 nitroglycerin (23). Similarly, topical salicylates could be absorbed through the skin into arthritic joints. More recently, nonsteroidal anti-inflammatory agents, such as ibuprofen and

Potential Future Extensions

Class I drug substances today are quite rare in pharmaceutical development, which limits the broad use of the BCS in the drug development. It has also been recognized that the present application represents a deliberately conservative approach, and proposals for extensions have been discussed since original publication of BCS.1,3 For example, in a recent paper it was suggested that the requirement of highest pH for the solubility measurements could be changed from 7.5 to 6.8 since the latter is more relevant for the pH in the upper GI tract.3 This revision would thus somewhat relax the requirements for basic drugs. It has also recently been suggested that for acidic drugs the boundaries for solubility are too restrictive (pH 1.0-7.5) and might be narrowed down to pH 5.0-7.4.115 Yazdanian et al. reported that, based on the current definition, 15 of 18 acidic nonsteroidal anti-inflammatory drugs (NSAIDs) were classified as class II compounds. If only a neutral pH was used, 15 of the...

Enzymes as Digestive Aids

Papain is a highly active plant protease obtained from the juice of the unripe fruit of the tropical plant Carica papaya Linn. It has a broad range of proteolytic activity and is less expensive to produce than microbial enzymes 162 . The proteolytic enzyme pepsin is derived from the zymogen pepsinogen, which is secreted by gastric mucosal cells, and it hydrolyzes dietary protein to shorter polypeptides and peptides. Pepsin used as a digestive aid is typically derived from the gastric mucosa of slaughterhouse animals 18 . Bromelain (EC 3.4.22.32) is a complex natural mixture of proteolytic enzymes derived from pineapple stems. Bromelain is used as a digestive aid to promote healthy digestion by assisting in the hydrolysis of dietary protein 160,163 . SODs play major roles in the protection of cells against ROS. As previously mentioned, CuZn-SOD has been marketed as a nutritional supplement with putative anti-inflammatory activity 127,164 .

Adjunctive Therapies For Neurodegenerative Disorders

Many diverse mechanisms, factors, and pathways are involved in neurodegenerative disorders, thus several different therapeutic methods have been developed to target a specific factor or a whole intricate pathway with the intent of ameliorating, preventing, or reversing neuronal cell damage. Inflammation and oxidative stress form a commonality between many neurode-generative diseases therefore most therapeutic modalities currently under investigation target MP activation to decrease the magnitude of the inflammatory responses (Fig. 19.4). The targets of these therapies include, but are not restricted to, enhancement of neurotrophic factors (brain-derived neurotrophic factor BDNF , glia cell-line derived neurotrophic factor GDNF , and nerve growth factor NGF ), up-regulation of anti-inflammatory cytokines (IL-4, IL-10, and TGF-P1), inhibition of enzymatic activities that encourage neurotoxicity (GSK-3P, g-secretase), Ca2+ and glutamate excitotoxicity blockers that inhibit NMDA receptor...

Thrombocytopenias Due to Increased Demand High Turnover

Etiology Thrombocytopenia

Drug-induced immunothrombocytopenia As in drug-induced agranulo-cytosis, the process starts with an antibody response to a drug, or its metabolites, and binding of the antibody complex to thrombocytes. Rapid thrombocyte degradation by macrophages follows (Table 29). The most common triggers are analgesic anti-inflammatory drugs and antibiotics.

Fields Of Expertise Within Toxicology

Among the drugs that can decrease immunological competence are anti-inflammatory steroids, cyclosporine, and tacrolimus. Certain of these compounds are used to prevent transplant rejection, but they simultaneously carry the risk of allowing infection to occur. The aplastic anemia caused by the bone marrow toxicity of benzene was described above. Lead and chlorinated aryl hydrocarbons such as hexachlorobenzene also can cause bone marrow suppression.

Current Treatment

Despite the introduction of anti-TNF-a antagonist therapies, such as Remicade infliximab for steroid refractory and fistulating CD, the treatment of IBD has not substantially changed in the last decades (Table 3). Front-line therapy in the management of patients with mild-to-moderate UC and CD, and as a maintenance therapy to prevent disease relapse in UC, are the 5-ASAs (e.g., mesalazine, sulfasalazine, and olsalazine). The 5-ASAs appear to exert their anti-inflammatory activity by inhibiting activation of NFkB. For disease in the distal bowel, multiple delayed and sustained release formulations, as well as prodrugs such as olsalazine, have been designed to release the majority of an oral dose directly in the distal ileum colon, thus preventing topical exposure in the proximal small intestine. For rectal disease, rectal foams are also administered. The most recently introduced prodrug, balsalazide (1), contains azo bonds that are cleaved by colonic bacterial azo-reductases and...

Ocular Surface Diseases

Allergic conjunctivitis and perennial conjunctivitis are fairly acute ocular surface disorders. However, vernal conjunctivitis, atopic keratonjunctivitis, and giant papillary conjunctivitis are chronic disorders.93 The hallmarks of allergic conjunctivitis are itching, redness, swelling, tearing, and temporary acute photophobia caused by various mast cell mediators released from mast cells when an allergen contacts the conjunctiva. The acute allergic conjunctivitis may develop into a chronic disease if left untreated, and this causes corneal and conjunctival remodeling and ulceration, sometimes accompanied by bacterial infection. Since mast-cell-derived histamine is the major culprit in allergic conjunctivitis, topical ocular antihistamines, such as emedastine, levocabastine, azelastine, and ketotifen, were considered the drugs of choice, often supplemented with vasconstrictors (e.g., oxymetazoline) and edema reducers (nonsteroidal anti-inflammatory agents and corticosteroids)....

ReEstablishing Mucosal Tolerance Probiotics Prebiotics Worms and Toll Like Receptor Modulators

As noted previously, the TLR system discriminates between many different microbial signatures and its role in controlling both normal gut immune homeostasis and pathogenesis is becoming dissected. Mucosal TLR4 expression is upregulated in UC patients and both the genetic epidemiology and the phenotype of the TLR4 _ _ mouse in response to DSS47 would suggest that TLR4 antagonists might be one approach to the treatment of IBD, which builds on the experience with probiotics. E5564 Eritoran (8)48 is a synthetic TLR4 antagonist currently in clinical assessment for sepsis, but an assessment either preclinically or clinically in IBD models is awaited. In contrast, CRX-526, a close structural homolog to E5564, prevents the development of colonic inflammation in both DSS-induced colitis and the Mdr1a _ models, as well as suppressing TNF-a release from monocytes in vitro and in vivo.49 Similarly, TLR9 agonists (unmethylated CpG DNA of bacteria and viruses, or immunostimulatory...

Behaviors and Medical History That May Lead to Kidney Failure

Nonprescription analgesic drugs, sometimes called nonsteroidal anti-inflammatory drugs (NSAIDs), sold singly or in combinations, have the potential to cause kidney failure, when taken long term. Examples are Advil, Aleve, Alka-Seltzer, aspirin, BC Powder, Ecotrin, Excedrin, ibuprofen, Motrin, Tylenol, Vanquish, and many others. Combination drugs seem to be especially dangerous. NSAIDs are probably the most widely used drugs in the United States, but no one knows for sure how many patients with chronic kidney failure got there because of these drugs. If you must take medication for chronic pain, don't take it for more than a few days at a time.

Other Diseases of the Retina

Diabetic retinopathy (DR) occurs in 27 of diabetics after 5-10 years of contracting diabetes and up to 90 have DR after more than 10 years of diabetes. DR essentially stems from retinal ischemia due to thickening of retinal capillary basement membranes when capillary pericytes start to die off. The ensuing ischemia causes the overexpression of VEGF, which in turn causes capillaries to leak and cause edema. VEGF also stimulates the growth of new blood vessels. This neovascularization could be perceived as a compensatory mechanism, but it is actually detrimental, since the new blood vessels disrupt retinal function. Deterioration of vision in DR is due to macular edema and proliferation of fibrovascular membranes that can lead to retinal detachment. Current treatments for DR are limited to laser photocoagulation of the leaky blood vessels, but this unfortunately destroys the underlying and surrounding retinal tissue. A much more specific approach is the use of photodynamic therapy,...

Poisoning with Nicotine Patches

The anti-inflammatory and analgesic effects of TD GTN was studied in 21 patients with mild to moderate leg varicose veins who underwent vein sclerotherapy in both legs (139). The vein in one leg was treated every 8 h with GTN and compared with a placebo ointment applied to the vein of the other leg. Inflammation signs were observed in all cases 15 min after first application. Intensity of inflammation signs were 26 in GTN-treated veins and 61.5 in placebo-treated veins. One hour later only 63 of cases in the GTN group, but all cases in the placebo group, showed signs of thrombophlebitis. All veins in the GTN group were free of signs of thrombophlebitis in fewer than 48 h, whereas, of the placebo group, 45 required more than 48 h.

Age Related Macular Degeneration

Perhaps the most significant hurdle for dry AMD clinical trials is that disease onset occurs late in life as a cumulative result of chronic damage to the RPE cells and their dependent photoreceptors. Most dry AMD patients are likely unaware of their disease until visual acuity begins to decline, at which point substantial morphological damage and dysfunction have occurred. It is thus unclear that intervening in a recognized AMD risk-increasing pathway (e.g., by administering an anti-inflammatory drug or by cessation of smoking) will work at this late stage. Since the RPE, photoreceptors, and Bruch's membrane target tissue are in the posterior segment of the eye, delivering an efficacious NCE concentration is usually ineffective using a topical eyedrop and instead requires locally invasive (e.g., intraocular injection) or systemic methods. On the positive side, since the most important disease risk factor is aging, a therapy that slows but does not arrest or reverse progression of dry...

Alzheimers disease

Based on the newer hypotheses of AD causality there are four active approaches to identifying new drugs to treat AD (1) preventing or reducing A 42 formation (2) reducing tau hyperphosphorylation (3) inhibiting neuronal apoptosis and (4) reducing brain inflammation. Progress in these initiatives has been slow. Inhibitors of the enzymes responsible for the formation of A 42 have been difficult to develop in the absence of true animal models of AD while a novel vaccine approach to aid in the clearance of A 42 encountered toxicity problems in clinical trials. Enzyme inhibitors to prevent tau hyperphosphorylation have also been difficult to identify given the multiple sites on tau amenable to phosphorylation and the diverse group of kinases that can act on these sites. Based on a positive retrospective analysis of the efficacy of the nonsteroidal anti-inflammatory drug (NSAID) indomethacin, reducing brain inflammation appeared to hold promise for AD treatment. However, prospective trials...

Early Years

I joined SK& Fin 1958 because it happened to be near where I was living at the time in London and its local organization, although small, appeared to me to be flexible and have potential for expansion I was also impressed by the people I would report to, namely David Jack (later to become Research Director at Allen & Hanburys and then Glaxo Research Laboratories) and Geoffrey Spickett (who eventually became Research Director at Laboratorios Almirall in Barcelona, Spain). The research, however, turned out to be unexciting. It was based upon testing compounds in animal models using very-low-throughput screening. We sought a novel antidepressant, or an analgesic, or anticon-vulsant, or anti-inflammatory drug. The chemical leads were either thrown up by the screens or they were reported compounds and we synthesized analogs. For example, we made partial structures of reserpine5 and tetrabenazine.6 We made some interesting indene isosteres of indoles7 and some 4-piperidones.8 These...

Conclusions

The availability of orally active inhibitors of ICE will no doubt advance anticy-tokine-based therapies for a variety of inflammatory and autoimmune diseases. Initially, ICE inhibition was thought to be highly specific, because it blocked the secretion of IL-1p. Inhibition of IL-1P also appeared to be safe in terms of host defense perturbations. With the discovery that processing of proIL-18 is also accomplished by ICE, there was no longer the advantage of specificity. In terms of host defense effects of ICE inhibitors, the role of IFN-y (as a product of IL-18 activity) must be considered, since a reduction in IFN-y is thought to be undesirable in terms of defense against tuberculosis and some other infectious diseases. On the other hand, inhibition of the Th1 response by ICE inhibitors (due to reduced IFN-y production) is a worthwhile strategy in many diseases. For example, graft versus host disease, organ rejection, type I diabetes, and other autoimmune diseases of the Th1 type. In...

Cold weather

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been variously reported to flare or improve psoriasis. Because of their extensive use, a decision should be made in each case based on history of disease activity relative to the indication for the NSAID. A psoriatic patient starting one of these agents should be warned to report flaring promptly.

Topical Steroids

Topical steroids have anti-inflammatory, immunosuppressive, antimitotic, and vaso-constrictive effects on the skin. Topical steroids are effective in reducing the inflammatory changes seen in psoriasis, but there is a risk of precipitating widespread erythroderma, particularly if potent preparations are used, or if topical steroids are suddenly withdrawn. For these reasons, topical steroids are usually avoided in the general treatment of psoriasis. However, weak topical steroids are useful in treating areas such as the scalp, face, and flexures, where other treatments such as tar, an-thralin, or calcipotriene are likely to cause irritation.

Cooh

The OAT proteins play a critical role in the excretion and detoxification of a wide variety of drugs, toxins, hormones, and neurotransmitter metabolites. Uremic toxins, which accumulate in the blood during chronic renal failure, inhibit renal transport, hepatic drug metabolism and serum protein binding. Several uremic toxins (indoxyl sulfate, indoleacetic acid, hippuric acid, etc.) are substrates or inhibitors of both rat and human OAT1 and OAT3 this could explain changes in the pharmacokinetics of other OAT substrates, including drugs.96 Several acidic metabolites of neurotransmitters are excreted into the CSF via OAT transporters, which is consistent with the presence of OATs in the choroid plexus. A number of common nonsteroidal anti-inflammatory drugs (NSAIDs), including acetyl salicylate and salicylate, acetaminophen, diclofenac, ibuprofen, ketoprofen, indomethacin, and naproxen, are substrates of one or more OAT isoforms, so that there can be significant interactions between...

Treatment of Acne

The aims of treatment are to reduce the bacterial population of the hair follicles to encourage the shedding of comedones to reduce the rate of sebum production and to reduce the degree of inflammation. Topical therapy is appropriate for mild-to-moderate acne, but more severe forms of acne, in which there is a risk of scarring, will require systemic therapy. Skin cleansers such as Phisomed or Hibiscrub are of some value. Benzoyl peroxide reduces comedone formation, as well as reducing the population of P. acnes, and may also have an anti-inflammatory effect. Benzoyl peroxide cream may be applied twice daily at an initial concentration of 2.5 and increased to 5 or 10 as tolerated. Benzoyl peroxide can have an irritant effect and may also bleach both hair and clothing.

Topical Antibiotics

Topical erythromycin, clindamycin, and tetracycline are all effective in acne (1417). These antibiotics reduce the population of P. acnes and Staph. epidermidis, and may have a separate anti-inflammatory action. The advantage of topical antibiotics is the reduction in the risk of potential systemic side effects, and this is particularly true with topical clindamycin. Topical tetracyclines may cause some yellow staining of clothing and fluoresce under ultraviolet radiation. It is also possible that they may exacerbate the problem of bacterial antibiotic resistance.

Crohns Disease

In patients with long-standing Crohn's disease and transmural fibrosis, mural stratification is lost so that the affected bowel wall typically has homogeneous attenuation on CT. Homogeneous attenuation of the thickened bowel wall in the presence of good intravascular contrast medium levels and thin-section scanning suggests irreversible fibrosis so that anti-inflammatory agents may not provide significant reduction in bowel wall thickness. If these segments become sufficiently narrow, surgery or stricturo-plasty will be necessary to relieve the patient's obstruction.

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