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! More here...

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Brain Functional Proinflammatory Stimulatory and Antiinflammatory Inhibitory Cytokine Balance

Data continue to accumulate that cytokine positive and negative feedback systems and a balance between stimulatory and inhibitory cytokines may be pivotal for an appropriate modulation of cellular responses in the brain. An unopposed proinflammatory cytokine response cascade could aggravate the magnitude of neurological and neu-ropsychiatric manifestations and may influence wasting and cachexia 36 . This relevant concept that focuses on the temporal profile of proinflam-matory and anti-inflammatory cytokines and their relationship balance during a pathophysio-logical process or disease condition is applicable to all systems. The notion of proinflammatory anti-inflammatory cytokine balance (e.g. IL-1p IL-1 receptor antagonist) could be extended to a model of pro-catabolic pro-anabolic cytokine balance based on new accumulating evidence. For instance, IL-1 p and TNF-a act as pro-catabolic and IL-15 as pro-anabolic cytokines. IL-15 in fact inhibits skeletal muscle wasting in...

Nonsteroidal antiinflammatory drugs

A recent case-control study found a protective effect of self-reported use of nonsteroidal anti-inflammatory drugs (NSAIDs) against glioblastoma 45 . A previous cohort study of low-dose aspirin users had found a significantly increased risk of brain cancer 46 . This does not contradict the hypothesis that NSAIDs could protect against glioma, however, as the excess was entirely in the 1st year of follow-up and could well have been an artifact resulting from use of aspirin to relieve symptoms of an as yet undiagnosed tumor, and for follow-up in excess of 5 years there was in fact a nonsig-nificantly reduced risk similar to that observed in the case-control study.

Anticytokine and Antiinflammatory Agents

Both progestagens and the polyunsaturated fatty acid EPA 139 have anti-cytokine properties and have been discussed above. EPA is also an anti-inflammatory agent. Non-steroidal antiinflammatory drugs (NSAIDs) have been studied alone and in combination with other drugs and there are data to support a role for them in the management of cachexia 140-143 . An NSAID and progestagen combination has activity in patients with advanced gastrointestinal cancer with effects on weight and quality of life and the combination deserves further study 144 . Selective cyclo-oxygenase-2 (COX-2) inhibitors may also modulate cachexia with an improved side-effect profile over traditional NSAIDs but they require further investigation 145-147 . While there is experimental evidence in tumour-bearing animals that NSAIDs may beneficially affect skeletal muscle mass 148 , it is also important to note that the interaction between inflammation and muscle repair is incompletely understood 149 and there are...

Other Antiinflammatory Agents

One of the most promising studies to look at anti-inflammatory agents was a landmark trial from Lundholm et al. 27 . In a placebo-controlled trial, these investigators found that indomethacin resulted in an improvement in survival in advanced cancer patients with the anorexia weight loss syndrome. Since then, other studies have suggested that non-steroidal anti-inflammatory agents may play a role in treating this syndrome 28 . Although direct antineoplastic effects may be at work in achieving these benefits, the implication that the cancer anorexia weight loss syndrome is mediated by inflammation suggests that these agents might also be directly treating this syndrome. Further confirmatory clinical studies and further mechanistic studies with these agents in this setting are indicated.

Nonsteroidal antiinflammatory drugs NSAIDs

Drugs that reduce inflammation without the use of cortisone or other steroids nonwaived - complex tests that require skill to perform and interpret and are therefore regulated nuclease - an enzyme that participates in the hydrolysis of nucleic acids obesity - body mass index > 30 kg m2 obstructive - causing blockage oligoclonal - showing small discrete bands in cere-brospinal fluid electrophoresis indicating local production of immunoglobulin G (IgG) oliguria - decreased urine output, < 400 mL of urine

The Molecular Basis for the Action of Nonsteroidal Antiinflammatory Drugs

Prostaglandins are potent mediators of inflammation. The first and committed step in the production of prostaglandins from arachidonic acid is the bis-oxygenation of arachindonate to prostaglandin PGG2. This is followed by reduction to PGH2 in a peroxidase reaction. Both these reactions are catalyzed by prostaglandin endoperoxide synthase, also known as PGH2 syn-thase or cyclooxygenase, thus abbreviated COX. This enzyme is inhibited by the family of drugs known as nonsteroidal anti-inflammatory drugs, or NSAIDs. Aspirin, ibuprofen, flurbiprofen, and acetaminophen (trade name Tylenol ) are all NSAIDs.


Autonomic Instability

The discovery of triflocin sulted from a study of derivatives of ic acid for possible anti-inflammatory activity. Compounds incorporating a nicotinic moiety unexpectedly exhibited diuretic flocin is structurally a novel and diuretic agent, capable of promoting the excretion of as much as 30 of the sodium chloride filtered at the glomerulus. It was effective in the rat, rabbit, guinea pig, dog , and monkey. Triflocin is characterized by After oral administration, MK 447 is rapidly absorbed from the gastrointestinal tract. It has a plasma half-life in rats and dogs of 1 and 7.5 h, respectively. In humans, the halflife is 4-8 h (281). The compound undergoes extensive metabolism in rats, dogs, and humans. The major metabolite identified in rat and dog urine is the 0-sulfate conjugate (282). In humans, 17 of the activity of radiolabeled MK 447 is ascribed to the 0-sulfate conjugate. The major metabolite in human urine was tentatively identified as the N-glucuronide. It...

Chief Complaint And History Of Present Illness

The patient is a 55-year-old man with a longstanding history of ulcerative colitis. His acute episodes have been treated with highdose steroids. Recently, he has developed severe right knee weight-bearing discomfort. He also has pain at rest and at night. The joint pain is confined to his right knee only. He denies generalized malaise, fever, or erythema of the knee joint. Antiinflammatory medications and corticosteroid injections have not helped. He is unable to walk without the use of a cane.

Classic Clinical Problem Solving

For example, a patient who complains of upper abdominal pain and has a history of nonsteroidal antiinflammatory drug (NSAID) use may have peptic ulcer disease another patient who has abdominal pain, fatty food intolerance, and abdominal bloating may have cholelithiasis. Yet another individual with a 1-day history of periumbilical pain that now localizes to the right lower quadrant may have acute appendicitis.

Physiological Effects Of Heme Oxygenase And Carbon Monoxide

Anti-Inflammatory Effects of CO The studies of Otterbein et al. in this laboratory showed that the anti-inflammatory properties of CO are mediated by p38 MAPK and its upstream MAPK kinase (MKK3) (20). CO inhibited the expression of lipopolysaccharide (LPS)-induced pro-inflammatory cytokines in RAW 264.7 macrophages, including tumor necrosis factor (TNF)-a, interleukin (IL)-10, and macrophage inflammatory protein-1a, while simultaneously increasing expression of the anti-inflammatory cytokine IL-10. Similar observations were made in a mouse model of lung inflammation. Using mice genetically deficient for MKK3, the upstream kinase of p38 MAPK, Otterbein et al. demonstrated the critical role of the p38 MAPK pathway in the anti-inflammatory effect of CO in vivo. In this model, the inhibitory effect of CO on TNF-a production did not require cGMP or NO production, or depend on the ERK1 2 or JNK MAPK pathways (20). Sethi et al. demonstrated the inhibition of TNFa-induc-ible ERK1 2...

Physicochemical Basis of Pain Intervention

Pain management can be approached by intervening at various points of the nociceptive pathway. Transduction is the conversion of the peripheral stimulus at the nociceptor into an electrical signal (35). Agents that have been shown to work at the periphery include nonsteroidal anti-inflammatory agents and capsaicin. Transmission is the afferent ascendance of the electrical signal from the periphery to the neuraxis. Local anesthetics temporarily block transmission. Modulation (i.e., inhibition or facilitation) occurs at the level of the interneurons and supraspinal pathways (36). Opioids, tricyclic antidepressants (TCAs), and GABA agonists are some of the agents effective in manipulating suppression of perceived pain (37).

Hiv Coinfection Accelerates Natural History Of Hcv Disease

Alters the response of immune cells to HCV when CD3+ CD30+ cells are infected with both HIV and HCV, their cytokine production is skewed toward an anti-inflammatory TH2 response, rather than the protective TH1 response seen when cells are infected with HCV alone (11). HCV can also escape from immunologic control through mutation of its hypervariable region, which is a major target of cell-mediated and humoral immune mechanisms (12) thus, heterogeneity of this region, as seen to a greater degree in HIV-infected patients, may permit increased viral replication (13). Although there is not a direct correlation between the plasma titers of HCV RNA and disease course, co-infected patients harbor greater amounts of HCV than immunocompetent patients, both in their plasma (14,15) and in their liver (16).

Individual risk factors

Another example of drug-drug interaction occurs when non-steroidal anti-inflammatory drugs are given to patients receiving anti-hypertensive drugs 127 . Due to the action of the NSAID to inhibit prostaglandin synthesis, the loss of endogenous induced vasodilatation causes the blood pressure to become uncontrolled often necessitating increasing the current anti-hypertensive drug dosage or prescribing additional anti-hypertensive drugs 128 . Recently, Mehta et al. 129 have called attention to the increased mortality and permanent residual renal impairment in ARF patients who are treated with diuretics. Once again we are reminded that empirical treatment, for which pathophysiologic rationale can be developed, must be evaluated in a controlled clinical trial before being universal accepted as standard therapy. So not only is it important to understand the patients diseases, but also a complete list of all medications that the patient takes on a regular basis including those purchased over...

Interactions During Distribution

For a displacement interaction to become clinically important, a second mechanism usually operates sodium valproate can cause phenytoin toxicity because it both displaces phenytoin from its binding site on plasma albumin and inhibits its metabolism. Similarly aspirin and probenecid (and possibly other nonsteroidal anti-inflammatory drugs) displace the folic acid antagonist methotrexate from its protein-binding site and reduce its rate of active secretion by the renal tubules the result is serious methotrexate toxicity.

Cancer Immunoediting

The recognition of tumor cells and how the unmanipulated immune system can be activated in a developing tumor, even though tumor-specific antigens may be expressed as distinct recognition molecules on the surface of tumor cells, have been controversial topics in the oncology field. As a hypothesis of the so-called danger theory, discussed in detail in Chapter 3, it was considered that cellular transformation did not provide sufficient proinflammatory signals to activate the immune system in response to a developing tumor. In the absence of such signals, there is often no immune response, and tolerance may develop. However, studies have indicated that danger signals, such as buildup of uric acid, presence of potential toll-like receptor ligands (e.g., heat shock proteins), the occurrence of a ligand transfer molecule in the signaling cascade induced by CpG DNA, and the presence of extracellular matrix (ECM) derivatives, may induce proinflam-matory responses that activate innate immune...

Pain Intervention 101 Techniques

Nonsteroidal Anti-Inflammatory Drugs Limited anti-inflammatory effect From ref. 153. GI, gastrointestinal NSAID, nonsteroidal anti-inflammatory drug im, intramuscular po, per os (by mouth) iv, intravenous. From ref. 153. GI, gastrointestinal NSAID, nonsteroidal anti-inflammatory drug im, intramuscular po, per os (by mouth) iv, intravenous.

Regulation Of Proinflammatory Signaling Pathways By Parp

In addition to its effect on transcription factor activation, PARP inhibition attenuates IL-1P-mediated iNOS expression in rodent pancreatic beta islet cells and in activated macrophases.62-65 Similar anti-inflammatory effects have been noted in vitro in murine macrophages and in vivo in rats. PARP inhibition has been shown, for example, to suppress endotoxin-induced expression of TNF-a, IL-6, iNOS, and cyclooxygenase-252 and to elevate the expression of the anti-inflammatory cytokine IL-10.52 These effects are associated with the near total blockade of endotoxin-medi-ated induction of MAP kinase activity.52 Since MAP kinase plays a major role in the pleiotropic transduction of intracellular inflammatory cascades, the anti-inflammatory effects of PARP inhibition may be accounted for at this level of gene regulation. One may also expect that PARP-dependent regulation of NF-kB activation66,67 has a pleio-tropic effect on the expression of proinflammatory genes, given the broad role that...

Neuropsychology Of Aged Rodents

Adams et al. 42 investigated the association between levels of the NR1 subunit of N-methyl-D-aspartate (NMDA) receptors and performance in the Morris water maze task. Although neither global nor region-specific differences in hippocampal NR1 levels were observed, there was a selective association between individual behavioral performance and NR1 immunofluorescence levels in the CA3 region, suggesting that NMDA abundance in the CA3 region is critical for spatial learning over the lifespan. More recently, Clayton and colleagues 43 used antisense oligonucleotides to knock down the NR2B subunit expression in the hippocampus, suggesting a key role for reduced NR2B expression in aged-related cognitive deficits in older animals. Another way to examine NMDA subunit involvement in learning and memory is by pharmacological manipulation. Suldinac is a nonsteroidal anti-inflammatory drug (NSAID) that is a nonselective cyclooxygenase (COX) inhibitor. Chronic administration of suldinac, but not its...

Treatment Of Dependence

Severe pain in an opioid addict presents a special problem. High-efficacy opioid may be ineffective (tolerance) or overdose may result low-efficacy opioids will not only be ineffective but may induce withdrawal symptoms, especially if they have some antagonist effect, e.g. pentazocine. This leaves as drugs of choice nonsteroidal anti-inflammatory drugs (NSAIDs), e.g. indometacin, and nefopam (which is neither opioid nor NSAID).

Toll Like Receptor

The TLR-4 intracellular and transmembrane domains interact with a number of adaptor proteins extensive mutagenesis experiments have been performed on the cytoplasmic region of TLR-4 to identify specific regions of the protein required for these interactions (168). The Toll-like receptors contain three conserved sequences in their cytoplasmic regions, termed 'boxes' (173). In macrophages, two structural surfaces of the TLR-4 cytoplasmic domain were required for downstream activation of the pro-inflammatory IL-12 p40 and antiinflammatory IL-10 promoters, as well as for downstream activation of minimal promoters dependent on individual transcription factors (168). The same regions were required for activation of all promoters tested, suggesting that the signaling pathways diverge downstream of the adaptors (168). One of the major cellular adaptor protein identified for TLR-4 signaling is myeloid differentiation factor

Inflammatory pathway in atherosclerosis biological basis of biomarkers in prediction and prognostication in

Recognition of the role of inflammation as a master regulator of atherogenesis has provided a fresh intellectual construct for understanding this disease. This new scientific foundation for understanding atherogenis also furnishes insights into novel therapeutic targets that may assist its mitigation. While inflammation biology currently furnishes new insights into the mechanism of benefit of existing therapeutics, the promise of targeted anti-inflammatory interventions to prevent or treat atherosclerosis will require much greater time and effort. Yet, one type of practical application of inflammation biology promises favorable outcome in terms of more prompt clinical applicability. Biomarkers of inflammation may soon merit inclusion in clinical application, the topic of many contributions to this volume.

Effects of Ectodomain Shedding

The ectodomain can be a soluble competitor of the membrane-bound receptor for its ligand. This mechanism has been demonstrated for growth factors and cytokine receptors and for adhesion molecules. The ectodomains of syndecans and fibroblast growth factor receptor (FGFR) bind fibroblast growth factor (FGF) and inhibit FGF activity by diminishing the availability for the membrane-associated receptor (184, 185). The soluble platelet derived growth factor receptor (PDGFR) competes with cell-associated PDGFR for ligand binding and is antagonist of PDGF stimulated effects on full length PDGFR expressing cells (186, 187). The c-kit receptor ectodomain retains the ability to bind to the ligand and blocks c-kit induced proliferation of M-07e myeloid cells (188). The mechanism of competition for ligand binding between the soluble and the transmembrane receptor was also described for interleukin-1 receptor II (IL-1RII). The soluble E-selectin fragment has an anti-inflammatory function because it...

The inflammatory response

Example, then peptides such as substance P, and neurokinins A and B, are produced by the C fibres (the axon effect) which then stimulate the nociceptive signal to the centre (Rang and Bevan 1994). The sympathetic nerves release noradrenaline, acetylcholine and adenosine, adding to the effect. Thus is achieved the perception and continuation of the feeling of pain from the sprain. An important part of this process is played by arachidonic acid, which, under the influence of the cyclo-oxygenases 1 and 2, produces prostaglandins which are an important part of the inflammatory process too. Certain drugs interfere with the action of the cyclo-oxygenases (the non-steroidal anti-inflammatory drugs, NSAIDs), which we shall consider in Chapter 7.

Aspirin and Other Antiplatelet Agents

The ability of antiplatelet therapy to prevent future cardiovascular events appears to vary by hsCRP level. In the Physicians' Health Study, a large primary prevention trial, the reduction in risk of future MI associated with assignment to aspirin (325 mg on alternate days) was 56 (p 0.02) among participants with baseline hsCRP levels in the highest quartile and declined with hsCRP levels such that a reduction of only 14 (p 0.80) was observed among those in the lowest quartile, suggesting that aspirin may prevent ischemic events through anti-inflammatory as well as antiplatelet effects (39). Similarly, observational data indicate that the beneficial effects of clopidogrel and abciximab may be greatest in patients with elevated CRP levels prior to percutaneous coronary interventions (111-113). On the other hand, ticlopidine was associated with a significant risk reduction in subsequent cardiovascular events among ischemic stroke patients with admission hsCRP levels in the bottom two...

Tubulointerstitial nephritides

The drugs that are most frequently responsible for tubulointerstitial nephritis are antibiotics, especially P-lactams, and non-steroidal anti-inflammatory drugs. Hypersensitivity reactions directed against the drug or its metabolites are usually found 43 . One study reported an association between tubulointerstitial nephritis and minimal change disease in 18 cases out of 27 patients with non-steroidal anti-inflammatory drugs-induced tubulointerstitial nephritis 51 .

Minimum Clinical Priority Dietary Program

Increased intake of anti-inflammatory fatty acids (oleic acid and n-3 fatty acids) and decreased intake of pro-inflammatory fatty acids (n-6 fatty acids). The best way is to exclusively use olive oil and canola oil for cooking and salad dressing and canola oil-based margarine instead of butter and polyunsaturated oils and margarines. Patients should also systematically reject convenience food prepared with fats rich in saturated, polyunsaturated, and trans fatty acids.

Radionuclide Approaches

Patients with symptomatic MACE often have many lesions that meet the histologic criteria for vulnerable plaque. The stimuli leading to rupture of the culprit lesion also act on the remaining lesions, contributing to the high incidence of recurrent events that often occur during recovery. Managing patients with MACE must address both the acute event (usually with a percutaneous intervention) and reduce the likelihood of another event during convalescence. To reduce the possibility of another event, aggressive pharmacologic therapies are advocated to reduce inflammation and stabilize the remaining vulnerable lesions. An alternative approach may be the immediate stabilization of these vulnerable non-culprit lesions using a percutaneous catheter-based intervention applied at the time of the emergency percutaneous intervention therapy for the patient's acute coronary event. A major challenge to this therapeutic approach is identifying and localizing these lesions with certainty. Since many...

Prediction ofClinical Recurrence After Percutaneous Coronary Intervention

The concept of clinical recurrence is of particular interest when considering patients undergoing percutaneous coronary intervention (PCI), whether for management of ACS or in patients undergoing elective PCI. In the current era of continued frequent use of bare-metal stents in some regions of the world, clinical restenosis after PCI in patients with ACS is expected in approx 20 of patients. Evidence provided by some studies suggests that the recurrence of clinical events after PCI is confined to patients with high CRP levels (21-24). In these studies, the risk of death or MI following PCI in patients with low CRP levels (< 3-5 mg L) was very low (< 1 ) (21-24). This observation may have important consequences for follow-up and treatment of patients with ACS managed with contemporary early invasive therapy. Versaci et al. (25) have showed that by targeting potent anti-inflammatory therapy (high-dose prednisone) to those patients with effort-induced stable angina pectoris and high...

Ten Aspects To Consider for Future Research into Brain Mechanisms Involved in Wasting and Cachexia

A pivotal area of research will continue to be on the cytokine balance characterisation and on how cytokines interact sequentially and in parallel during wasting and cachexia. The concepts of proinflammatory anti-inflammatory and pro-catabolic pro-anabolic cytokine balance remain a key area to define contributory mechanisms in wasting and cachexia.

MPO as a Marker for Oxidative Stress

(NO), thereby reducing NO bioavailability and impairing its vasodilatory and antiinflammatory functions (53,54). Two recent studies have also revealed that MPO is strongly associated with adverse outcome in patients with ACS (55,56). Particularly in individuals with low troponin levels, MPO identified patients at increased risk for early cardiovascular events that occur within days after the onset of symptoms (Fig. 11) (55). This suggests

Interleukin10 as a Marker ofInflammatory Balance

Inflammatory balance may also play an important role in patients with ACS (57,58). Interleukin (IL)-10 is secreted by activated monocytes macrophages and lymphocytes (59). It has multifaceted anti-inflammatory properties including inhibition of the proto-typic proinflammatory transcription factor nuclear factor-kB leading to suppressed cytokine production (60), inhibition of matrix-degrading metalloproteinases (61), reduction of tissue factor expression (62), inhibition of apoptosis of macrophages and monocytes following infection (63,64), and promotion of the phenotypic switch of lymphocytes into the Th2 phenotype (65). These inflammatory mechanisms have been shown to play a pivotal role for atherosclerotic lesion development and progression, suggesting a potential regulatory role of IL-10. Indeed, numerous recent experimental studies have shown that either systemic or local IL-10 gene transfer not only attenuates atherogenesis (59,66,67) but also affects processes associated with...

Innate Immune Mechanisms

C. pneumoniae is generally transmitted from person to person via the respiratory route,(1'2) where mechanical barriers and innate immune mechanisms comprise the first defense systems of the host. Epithelial cells lining the trachea and nasopharynx are the first cellular barriers against inhaled pathogens. Infection of airway epithelial cells can trigger a preliminary cascade of pro-and antiinflammatory immune reactions (secretion of IL-8, prostaglandin and expression of the epithelial adhesion molecule-1) that initiate drifting of polymorphonuclear neutrophils (PMN) and acute inflammation.(3-7) Accordingly, experimental C. pneumoniae pneumonia in mice begins with local infiltration of PMN in the early stages and mononuclear cells in the later stages of the infection.(8'9) The onset of acquired antigen-specific immune responses depends on the speed of microbial dissemination from the initial site to local lymph nodes.(10)

Toxicogenomics Experimental Design

Another major advantage of toxicogenomics is that just knowing the genes and pathways affected by a hepatotoxic compound frequently increases understanding of relevant toxic mechanisms. PPARa agonists, which are peroxisome proliferators and nongenotoxic carcinogens in rodent liver, provide a good example of a class of toxicants amenable to investigation through transcriptional profiling. These compounds exert their pharmacological effects by activating a transcription factor, and most of their toxicities appear to reflect exaggerated pharmacology for example, the more efficacious in activating PPARa, the more likely a compound is to induce tumors 55 . Many enzyme inductions by peroxisome proliferators, particularly those enzymes involved in P-oxidation of fatty acids, were characterized long before PPARa was identified as the transcription factor responsible. Data obtained using microarrays are largely confirmatory of such historic data, but additional relationships with other genes...

Answers To Case 24 Low Back Pain

Next step Encourage continuation of usual activity, avoiding twisting motions or heavy lifting. Use nonsteroidal antiinflammatory drugs (NSAIDs) on a scheduled basis you can also recommend muscle relaxants, although these drugs may cause sleepiness. Massage might be helpful. Follow-up in 4 weeks. Long-term advice includes weight loss and back-strengthening exercises.

Mechanisms Of Analgesia

Plainly, a drug that prevents the synthesis of prostaglandins is likely to be effective in relieving pain due to inflammation of any kind, and this is indeed how aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) act. This discovery was made in 1971, aspirin having been extensively

T and B Cell Activation and Costimulation

Antigen-dependent and costimulatory signals, CD4 T and CD8 T cells undergo clonal expansion and differentiate into effector helper and cytolytic T cells, respectively. Activated CD4 T effector cells produce either pro-inflammatory cytokines (Th1), or anti-inflammatory cytokines (Th2).

Atherosclerotic Cardiovascular Disease

Cachexia, by virtue of MICS, may predispose CKD patients to atherosclerotic cardiovascular disease 24, 49, 51 . Dialysis patients with coronary heart disease often have hypoalbuminaemia and elevated levels of acute-phase reactants 24 . Moreover, progression of carotid atherosclerosis during dialysis may be related to IL-6 levels 137 . It should be noted that the cascade of inflammatory factors leading to an acute-phase reaction is counter-regulated by various anti-inflammatory cytokines, such as IL-10. Recently, Girndt et al., in a study of 300 haemodialysis patients 138 , showed that the -1082A allele, which is associated with low production of IL-10, is associated with an increased risk of cardiovascular events. Inflammatory processes may promote proliferation and infiltration of inflammatory cells into the tunica intima of small arteries, including the coronary arteries these processes lead to atherosclerosis and stenosis of blood vessels and consequent coronary and other vascular...

Conclusions and Future Steps

(CHF) and geriatric populations have risk-factor reversal as well 192 . Hence, a better understanding of the role of chronic cachexia in CKD patients may help improve clinical management of not only these patients but also CHF, geriatric, and other vulnerable populations. According to an epidemiological study of over 55 000 haemodialysis patients, if an intervention could increase serum albumin above 3.8 g dl and by doing so improve survival in dialysis patients, almost one-third of all deaths among these patients could be hypo-thetically prevented or delayed. Since approximately 60 000 patients out of over 300 000 haemodialysis patients in the USA die every year, a hypoalbuminaemia-correcting intervention might theoretically prevent 15 000-20 000 deaths every year 25 . If this is correct, there is a great need to develop effective nutritional and or anti-inflammatory interventions and to carry out randomised, prospective, controlled clinical trials to demonstrate the benefits of such...

Strategies for Genetic Manipulation of the Myocardium

A wide selection of therapeutic strategies, vectors, and delivery methods are available for genetic manipulation of the myocardium with variable degrees of efficiency (6,1719). The most common gene therapy strategy for the myocardium involves the exogenous delivery and expression of genes whose endogenous activity may either be defective or attenuated as a result of a mutation or a pathological process. Such gain-of-function gene transfer strategies have been widely used with a variety of therapeutic genes, including proangiogenic and survival factors (21,22), antioxiadant enzymes (22), and antiinflammatory cytokines (23). On the other hand, strategies have also been devised for inhibition of genes that may be involved in the development of heart disease. Acute inhibition of transcription and translation can be achieved by treatment with short single-stranded antisense oligdeoxynucleotides, ribozymes, and more recently, using RNA interference technology (12,18,24-26). Inhibition of...

For Cellbased Interventive Therapies

Chronic neuropathic pain following damage to the peripheral or CNS has been difficult to treat clinically (14). As an illustration of the severity of pain following spinal cord injury (SCI), patients often report pain, rather than immobility, as the major deterrent to good quality of life (15). Pharmacological pain management is based on nonopioid and opioid analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase 2 (COX-2) inhibitors (16), calcium channel blockers (17), capsaicin (18), nicotine receptor agonists (19), and opioids (20) (e.g., morphine and its derivatives). Adjunct drugs, such as antidepressants and anticonvulsants, often accompany more antinociceptive agents in certain types of pain, like diabetic neuropathy (21). Gabapentin, an anticonvulsant, has become the most common medication for SCI pain (22), probably owing to its calcium channel-blocking functions (23). Combination of medications, such as NSAIDs with opioids, seems to be more...

Inflammatory Bowel Diseases

Has been a major focus of research, as IBD is characterized by a hyper-reactive immune system, underlined by a heavy influx of T cells, B cells, monocytes, and neutrophils into the intestinal mucosa. On the simplest level, an imbalance between pro- and anti-inflammatory mediators leads to chronic inflammation in the gastrointestinal tract of patients with IBD. Specific cytokines important for the induction of mucosal immunity and regulation of the mucosal immune responses include the pro-inflammatory mediators IL-1, IL-6, IL-12 and TNF-a, produced by monocytes and macrophages. In addition, the CD4+ T cells infiltrating the lamina propria (LP) of IBD patients display an altered cytokine profile as compared withhealthyindividuals. LP-derived CD4+ Tcellsfrom CD patients produce increased levels of IFN-y and IL-2, whereas LP-derived CD4+ T cells from UC patients produce increased levels of IL-4 and IL-5 (Farrell et al. 2001). These observations suggest that that the immune responses are...

Gene Therapy for Protection From Ischemia and Reperfusion Injury

The inhibition of proinflammatory genes involved in the pathogenesis of I R injury offers another option for cardioprotection. Morishita et al. (28) showed that pretreatment with a decoy oligonucleotide capable of inhibiting the transactivating activity of the proinflammatory transcription factor NFkB reduces MI after coronary artery ligation in rats. Similarly, intravenous administration of antisense oligonucleotide against angio-tensin converting enzyme mRNA (97) or angiotensin AT receptor (94) significantly reduces myocardial dysfunction and injury following ischemia and reperfusion. Although the rapid in vivo degradation of oligonucleotides would preclude their use in long-term myocardial protection, they may be useful in treatment of acute myocardial ischemia and cardiac transplantation (98) by providing a tool for inhibiting of prooxidant, proinflammatory and immunomodulatory genes activated by ischemia and reperfusion. For example, treatment with antisense oligonucleotide...

Nutritional Support

Catecholamines and cytokines, which are elevated in heart failure, are stimuli for free-radical production. Therefore, antioxidants and free radical scavengers, such as vitamins C and E, are therapeutic options in cardiac cachexia. This was proven by a study showing that muscle wasting in mice was prevented by an antioxidant 92 . Additionally, it was shown that antioxidants suppress the production of free radicals in leucocytes 93 . The presence of elevated levels of markers of oxidative stress in heart-failure patients correlates with functional class, reduced exercise tolerance, lower antioxidant levels, and worse prognosis, including cachexia 94, 95 . These patients also tend to have micronutrient deficiency through, e.g. urinary losses or therapy with diuretics. Deficiencies of specific micronutrients, such as selenium, copper, calcium, zinc, or thiamine, can also cause heart failure 96 . Thus, it is important to keep CHF patients on a diet with sufficient calories and with...

Pseudoallergic Reactions

Pseudoallergie effects mimicking type I reactions (above) are called anaphylactoid and they occur with aspirin and other nonsteroidal anti-inflammatory drugs (indirect action as above) (see also Pulmonary reactions, above) corticotrophin (direct histamine release) i.v. anaesthetics and a variety of other drugs i.v. (morphine, tubocurarine, dextran, radiographic contrast media) and inhaled (cromoglicate). Severe cases are treated as for true allergic anaphylactic shock (above) from which, at the time, they are not distinguishable.

Pretreatment Evaluation And Education

In addition, use of other medication is discussed, particularly the use of Tylenol and nonsteroidal anti-inflammatory drugs (NSAIDs). Tylenol is preferred as the drug of choice for the flu-like symptoms associated with IFN, and for the headaches, but many patients are worried about the use of Tylenol and need to be informed that up to 3 g d has little liver toxicity. Patients are advised that, before they start any new therapy, they should inform their caregiver that they have chronic liver disease. Many patients are interested in the use of vitamin preparations and herbal remedies, which are discussed in Chapter 13. The authors do, however, recommend that patients should avoid iron-containing multivitamins and high doses of vitamin A. Antioxidant therapy, such as milk thistle (Silymarin) and vitamin E, are almost ubiquitously used by patients with CHC. The vitamin E is the preferred antioxidant, at a dose of 800 U d. Many patients will not stop their herbal remedies, even...

Marine Invertebrates of the Andaman and Nicobar Islands

About 50 species of marine sponges occur in these Islands and only a few of them have been investigated. Even their classification is in a confused state. Several bioactive metabolites of considerable interest have been isolated from Agelas species182 183 found in the Andaman and Nicobar Islands. A. nata the only species reported to occur remains to be investigated. Four species of Cliona, C. ensifera, C. lobata, C. mucronata and C. quadrata occur in the Andaman Islands. However, none of these appear to have been investigated. Two species of genus Craniella, C. cranium and C. dactyloides that are found in the Islands have remained uninvestigated. Phyllospongia foliascens Pallas which occurs in the Islands has furnished foliaspongin,184 an antiinflammatory bishomosesterpene. An antiallergic and antiinflammatory glycolipid has been isolated from P. foliascens.185 Chemical investigation of Petrosia testudiana is expected to furnish compounds of biological interest. Two species of genus...

Late Vein Graft Failure

Coronary artery bypass grafting (CABG) is a procedure that successfully alleviates angina pectoris and increases life expectancy in patients with coronary artery disease. However, the vein graft undergoes adaptive responses to transplantation into the arterial circulation, with early thrombus formation occurring in 10 of grafts, and patency dropping to 50 at 10 yr postprocedure. Vein graft failure is associated with progressive intimal thickening, atheroma development, and neointima formation (96), with associated affects on morbidity and mortality after CABG. Drug treatments (typically antiplatelet agents) can slow and reduce this process, but can be associated with hemor-rhagic events. However, vein grafting is particularly amenable to gene transfer, as the vein graft itself is isolated and able to undergo genetic modification during the surgical procedure. This concept was demonstrated clearly in a clinical trial in which vein grafts transduced during the procedure with vectors...

Diagnosis and Management of MICS and Wasting Syndrome in CKD

Protein-energy malnutrition and inflammation lead to wasting syndrome and cachexia and are powerful predictors of death risk for CKD patients thus, if they are treatable, it is possible that nutritional and anti-inflammatory interventions will improve poor outcome in the CKD population. Experience with nutritional support of sick or malnourished individuals who do not have CKD may provide some insight into the independent role of protein-energy malnutrition on clinical outcome in dialysis patients. Ample evidence suggests that maintaining an adequate nutritional intake in patients with a number of acute or chronic catabolic illnesses improves their nutritional status irrespective of its aetiology 165,166 . In some of these studies, such improvement was associated with reduced morbidity and mortality and improved quality of life 167 . However, evidence as to whether nutritional treatment improves morbidity and mortality in dialysis patients is quite limited. There are no large-scale,...

Pharmacokinetic Properties Some

(317) and (2) blockade of GABA receptors, which can cause convulsions (318). A study on proconvulsant effects of quinolones in a strain cf DBA 2 mice susceptible to sound-induced seizures showed an incidence in the order pe-floxacin > enoxacin > rufloxacin > norfloxacin > cinoxacin > ciprofloxacin > nalidixic acid (319). Another study based on the induction cf fatal convulsions by a combination of nonsteroidal anti-inflammatory drugs and quinolones gave the following order of potency when fenbufen was the anti-inflammatory agent enoxacin > lomefloxacin > norfloxacin, with ofloxacin and ciprofloxacin causing no deaths (320).

Concluding Discussion

Receptors and their endogenous agonists in disease states. Given the known pharmacological properties of cannabis and cannabinoid receptor agonists and the distribution pattern of cannabinoid receptors, initial experiments should perhaps focus on the role of the endogenous cannabinoid system in disorders of cognition, memory, affect, motor control and immune function. The therapeutic potential of cannabinoid receptor ligands as anti-inflammatory agents and analgesics and in the control of glaucoma, bronchial asthma, epilepsy and or gastrointestinal motility disorders also merits attention (Hollister, 1986). Another important goal is to establish more fully the part played by cannabinoid receptors in tolerance. A summary of current information about the pathophysiology of cannabinoid receptors and about their role in the production of cannabinoid tolerance can be found elsewhere (Pertwee, 1997).

Treatment Strategies to Prevent Resistance to Estrogen Deprivation

A number of pathways stimulate the activity of the aromatase enzyme including prostaglan-dins IL6 and TNFa. Potentially this could cause resistance to aromatase inhibitors by increasing the substrate. Thus, there remains interest in attempting to reduce aromatase activity by inhibitors of prostaglandin synthesis via COX-2. Potentially TNFa and IL6 production by macrophages and adipocytes could be reversed by calorie restriction (as could several other pathways including NFKB and leptin). In this regard, it is of interest that a recent study examining gene expression profiles in subcutaneous abdominal fat in obese premenopausal women showed upregu-lation of multiple anti-inflammatory genes and downregulation of pro-inflammatory genes after a 1-month 800-calorie diet (Clement et al. 2004). We have recently reported that loss of 5 or more of body weight (and maintaining the loss) reduces premenopausal breast cancer by 40 and postmenopausal disease by 25 (Harvie et al. 2005). The...

Prevention of Elevated Troponin Levels After PCI

The use of other classes of drugs has also been examined in relation to the incidence of post-PCI troponin elevation. Intravenous nitroglycerine started immediately after PCI and continued for 12 h was shown to be superior to placebo in reducing the frequency of troponin I elevation > 0.1 pg L at 12 h post-PCI (5 vs 19 p 0.036) (42). This finding may be related to the improved coronary blood flow and myocardial perfusion that occur with iv nitroglycerine. Interventions that induce ischemic preconditioning, such as nico-randil, may also reduce the frequency of minor myocardial damage during PCI (43). A randomized, placebo-controlled trial of atorvastatin (40 mg d) started 7 d prior to PCI demonstrated a marked reduction in troponin I elevation (20 vs 48 p 0.0004) in the first 24 h after PCI (27). Given the effect of atorvastatin on reducing CRP levels and the association of CRP with elevated troponin post-PCI (26), it has been postulated that atorvastatin prevents periprocedural...

Lifespan Of Galactocele

Fibrocystic changes, the most common of the benign breast conditions, are described as multiple, irregular, lumpiness of the breast. It is not a disease per se but rather an exaggerated response to ovarian hormones. Fibrocystic changes are very common in premenopausal women but are rare following menopause. The clinical presentation is cyclic, painful, engorged breasts, more pronounced just before menstruation, and occasionally associated with serous or green breast discharge. Fibrocystic changes usually can be differentiated from the three-dimensional dominant mass suggestive of cancer, but occasionally FNA or core-needle biopsy must be performed to establish the diagnosis. Treatment includes decreasing caffeine ingestion and adding nonsteroidal antiinflammatory drugs, a tight-fitting bra, oral contraceptives, or oral progestin therapy. With severe cases, danazol (a weak antiestrogen and androgenic compound) or even mastectomy is considered.

CD137 Ligand Activities on Monocytes and Macrophages

The signal through CD137 ligand activates monocytes and the CD137 lig-and signal alone is sufficient for activation. When CD137 ligand is crosslinked by recombinant CD137 protein or an anti-CD137 ligand antibody, it induces adherence of monocytes within a few hours. The adherent monocytes change their shape over the course of a week and adopt the three basic macrophage morphologies, which are round, elongated, and branched cells (Langstein and Schwarz, 1999). Concomitantly with adherence the CD137 ligand signaling induces the expression of proinflammatory cytokines (TNF, IL-6, IL-8, IL-12) and activation markers (ICAM-1), and it inhibits expression of anti-inflammatory cytokines (IL-10) and differentiation markers (FcyRIII), (Laderach et al., 2003 Langstein et al., 1998).

Atherosclerosis And Antiinfective Therapy

A similar dose of clarithromycin starting 2 weeks after the third inoculation and continued for 6 weeks thereafter (delayed treatment). To test for a possible antiinflammatory effect of clarithromycin, two other groups of uninfected rabbits (12 animals in each) were fed 0.5 cholesterol-enriched chow, and one of these groups was treated with clarithromycin at 30 mg kg day for 6 weeks. Of 23 untreated infected rabbits, 8 developed early lesions of atherosclerosis, whereas 2 of the 24 early-treated (group II) had similar changes (P 0.036 75 efficacy ). However, in the delayed-treatment group, (group III) 3 of 24 rabbits developed early lesions of atherosclerosis, thus demonstrating 62.5 reduction compared with the untreated controls (P 0.07 trend to statistical significance ). C.pneumoniae antigen was detected in 8 of 23 group I (untreated) rabbits versus 1 of the 24 group II rabbits and 4 of 24 animals in group III (P 0.009 and 0.138, respectively) . All of the untreated,...

New Horizons in Chemoprevention

Chemopreventive drugs for an average risk population must be proven efficacious and safe. Data accumulating in recent years have suggested that aspirin, nonsteroidal anti-inflammatory drugs and possibly also selective COX-II inhibitors, all have a potential to reduce colorectal cancer and colorectal adenomas in average and high-risk populations (Thun et al. 2002 Hull 2005). Such data came from association case-control and cohort studies (Poynter et al. 2005 Chan et al. 2005 Sansbury et al. 2005 Slattery et al. 2004b), and from randomized controlled studies (RCTs) (Baron et al. 2003 Sandler et al. 2003 Benam-ouzig et al. 2003 Phillips et al. 2002) (Table 1) and were supported by laboratory studies (Charames and Bapat 2006 Din et al. 2004 Boon et al. 2004 Reddy et al. 2005). Two randomized trials have not demonstrated a preventive effect of these drugs against CRC (Cook et al. 2005 Gann et al. 1993). Issues of safety and therapeutic indexes have recently come up as barriers to the use...

Supragingival Irrigation

Subgingival Irrigation

Oral irrigators lor daily home use by patients work by directing a high-pressure, steady or pulsating stream of water through .i nozzle to the tooth surfaces (see also Chapter 44). Most commonly, a device with a built-in pump generates the pressure ilig. 40-24, A), but other devices attach to the water faucet. Oral irrigators clean nonadherent bacteria and debris from the oral cavity more effectively than toothbrushes and mouthrinses. I hey are particularly helpful for removing debris from inaccessible areas around orthodontic appliances and fixed prostheses. When used as adjuncts to loothbrushing, these devices can have a beneficial effect on periodontal health by retarding the accumulation of plaque and calculus80'100,125 and by reducing inflammation and pen ket depth.'*125

Strategies To Fight Cachexia Based on Cytokines and Transcriptional Factors

The appearance of the cachectic syndrome is dependent not only on the production of the above-mentioned cytokines, known as catabolic pro-inflammatory cytokines, but also on so-called anti-inflammatory cytokines (Fig. 1), such as IL-4 and IL-10. Mori et al. 60 demonstrated that administration of IL-12 to mice bearing colon-26 carcinoma alleviated the body weight loss and other abnormalities associated with cachexia, such as adipose tissue wasting and hypoglycaemia. The anti-cachectic properties were obtained at low doses of IL-12, insufficient to inhibit tumour growth. The effects of IL-12 seem to be dependent on an important decrease of IL-6, a cytokine responsible for cachexia associated with this tumour model. A similar action was described for INF-a. Administration of this cytokine promoted a decrease in IL-6 mRNA expression in the tumour and in serum IL-6 levels, resulting in the amelioration of cachexia in a murine model of malignant mesothelioma. IL-15 has been reported to be...

Infections Transmitted Through the Respiratory Route

Respiratory tract infections are common, usually mild, and self-limiting, although they may require symptomatic treatment with paracetamol or a nonsteroidal antiinflammatory. These include the common cold (80 rhi-noviruses and 20 coronaviruses), adenoviruses, influenza, parainfluenza, and, during the summer and early autumn, enteroviruses. Special attention should be given to detainees with asthma or the who are immunocompromised, because infection in these people may be more serious particularly if the lower respiratory tract is involved.

Inflammation In Alzheimer Dementia

There is now substantial epidemiological evidence of the involvement of inflammation in Alzheimer's dementia. There are now about 20 reports on the incidence of Alzheimer's dementia in populations with a long antiinflammatory drug consumption history. Nearly all of these studies showed a lower AD incidence with a decrease of 50 or a delay in onset of 5-7 yr, and, in one prospective study, the relative risk fell with increasing duration of drug use (16). Clinical trials with indomethacin or propentofylline, another agent with antiinflammatory properties, showed both a significant cognitive improvement (17,18), whereas one study on diclofenac and one recent study on hydroxychloroquine did not demonstrate a positive effect on the progression of the disorder (19,20). Alzheimer's dementia shows an apolipoprotein E (ApoE) genotype susceptibility with ApoE4 as a risk factor. Interestingly, ApoE4 seems essential

Markers of inflammation

The anti-inflammatory effects of statins are still unclear experimental evidence posits statin-mediated reduction in macrophage activation, antiproliferative effects on smooth muscle cells, improvements in endothelial function and vasomo-tion, and antithrombotic effects 34,35 . At 5-year follow-up of stable post-MI patients randomized in the Cholesterol and Recurrent Events trial, mean hsCRP levels decreased by 37.8 in those randomized to pravastatin therapy, whereas levels increased in the placebo patients 36 . This reduction in hsCRP was independent of the magnitude of changes in lipid levels. Furthermore, patients randomized to pravastatin therapy had a twofold reduction in risk for recurrent MI or fatal coronary event in the elevated hsCRP group compared with the group that did not have elevated hsCRP, even though baseline lipid levels were identical in both groups 15 .

Byung Zun Ahn and Dai Eun Sok Contents

11.4.2 Anti-Inflammatory and Antiallergic Bupleurum species are naturally occurring small shrubs widely distributed in East Asia and the Mediterranean area. This plant has been traditionally used in folk medicine (Lin, 1990 Tang and Eisenbrand, 1992) as anti-inflammatory, antitussive, and antipyretic drugs, and in the treatment of liver disease. In particular, the roots of Bupleurum species are listed in the Chinese and Japanese Pharmacopoeias. The crude saponin from this plant possesses a hemolytic activity, and is known to show various activities such as anti-inflammatory, inhibitory effects on chronic hepatitis, immu-nostimulating effects, and others, in in vitro bioassays. Recently, as part of the research for bioactive saponins in the root of Bupleurum species, a series of triterpene saponins, such as saikosaponins-a, -b, -c, and -d, and their corresponding prosaikogenins and saikogenins have been isolated, and there have been a number of reports on pharmacological actions of...

Adverse Effects Of Herbal Therapy

Herbal remedies may be toxic for other reasons. For example, toxic substances, i.e., heavy metals, or substitutes such as nonsteroidal anti-inflammatory medications, may contaminate herbal products and cause adverse events. An additional area of concern is the interactions between herbal remedies and medications. Chinese herbal drugs have been found to increase the activity of coumarin other plants high in vitamin K reduce the drug's effectiveness (33). A recent letter to the editor (34) stated that eight patients taking St. John's Wort developed breakthrough bleeding, despite being on oral contraceptives. Because of its efficacy in treatment of mild depression, St. John's Wort has been suggested as a possible addition to IFN regimens, because IFN treatment is associated with the development ofdepression. This has raised concerns that St. John's Wort therapy may result in unwanted pregnancy. This is of concern to hepatologists, because patients on IFN therapy are mandated to utilize...

Chemokines And Cervical Cancer

The JE gene, a rodent homolog of human MCP-1, was initially isolated as an immediate-early gene, which can be stimulated at the level of initiation of transcription by the platelet-derived growth factor (75). Analyzing its transcriptional regulation in greater detail, it became clear that JE (MCP-1) expression can not only be induced by particular cytokines such as TNF-a (13,76), TGF-P (77), or IFN-y (76), but is also negatively controlled by antiinflammatory acting glucocorticoids (78) or even by hormones such as estrogen (79).

Neuroinflammatory Imaging

Visualizing neuro-inflammation in Alzheimer's dementia is of interest, first for clarifying the pathophysiology, second for selecting patient subgroups that are more eligible for antiin-flammatory treatment, and finally for monitoring patients during trials with these antiinflammatory agents. Here we review and discuss current neuro-inflammatory imaging modalities, both structural and functional. Structural imaging aims to describe in detail the spatial relationship of neurodegenerative and inflammatory consequences like mass effects, edema, vascular congestion, thrombosis, petechial hemorrhages, secondary demyelinization, gliosis, and finally neuronal destruction, necrosis, or atrophy, as well as visualizing other (nonspecific) structural changes.

The Large Intestine Rectum and Anus

Genetic models have been used with some success to examine visceral pain. For example, the Wistar Kyoto rat (a high-anxiety strain) exhibits significantly more colonic hypersensitivity than other strains, including the commonly used Sprague Dawley rat strain (50). Specific transgenic models have been produced with intestinal inflammation, results that have been used to propose the pathophysiology of inflammatory bowel disease (IBD). Such genetic models include the knockout of genes such as that for the anti-inflammatory cytokine interleu-kin-10, which results in increased cytokine production by TH1 lymphocytes and chronic enterocolitis with some IBD-like symptoms (51).

Ongoing Clinical Antiinfective Trials

Finally, another large randomized trial, entitled PROVE-IT, is also underway. In this study, > 3,000 patients presenting with acute coronary syndrome are randomized in a 2 x 2 factorial fashion to one of two statins, pravastatin or atorvastatin, in different relative doses, and then to an intermittent course of gat-ifloxacin or placebo. The primary endpoint is major cardiovascular clinical endpoints after at least 18 months' follow-up. The study has combined the evaluation of two different statins, each with very different lipid-lowering potencies but potentially similar antiinflammatory effects with the testing of a quinolone with potential bactericidal antimicrobial activity. This study will potentially answer a number of questions regarding the importance of inflammation and infection in the pathogenesis of acute coronary syndromes in relationship to lipid-related risk. It is the first major clinical trial testing an agent other than azithromycin.

Administration of Melatonin in Cancer Associated Cachexia

Standard supportive care included nonsteroidal anti inflammatory drugs and opioid drugs for pain palliation. Steroids (dexamethasone or methylprednisolone) were administered in case of dyspnoea or hypotension (i.e. lung infiltration). Melatonin was administered per os daily in the evening, at 20 mg day. The dose was chosen empirically, based on the previous studies available at the time.

Inflammatory Mediators

Evidence from many laboratories and studies suggests that aging-related increases in inflammatory processes contribute to the development of neural deficits (e.g., 167-170 ). This hypothesis is based on evidence that (1) basal levels of many pro-inflammatory cytokines increase in older brains and (2) those cytokines affect the function, and even the survival, of neurons, glia, and progenitor cells. Although not yet established, it is reasonable to suspect that aging-related activation of microglia suppresses neurogenesis (and thereby cognitive function), because neurogenesis is profoundly affected by changes in the neurogenic microenvironment that are mediated by reactive microglia and inflammatory cytokines. Inducing an inflammatory response by infusion of the bacterial toxin lipopolysaccharide (LPS) virtually eliminates neurogenesis in the adult brain, with the extent of reduction in individuals well correlated with the number of activated microglia 171 . Neurogenesis is restored in...

Protein Engineering And Sitedirected Mutagenesis

A recent success story in new target identification and validation is seen in the introduction of two new nonsteroidal antiinflammatory drugs (NSAIDs),Vioxx and Celebrex, by Merck Frosst and Monsanto-Pfizer, respectively. Until recently, the onset of inflammation and pain has been linked to one cyclooxy-genase enzyme, COX. Clinically useful NSAIDs such as aspirin, diclofenac, and ibu-profen exhibit their anti-inflammatory and antipyretic activity by inhibiting COX. A prolonged use of most NSAIDs results in gastrointestinal (GI) toxicity (46), which may be debilitating enough to require hospitalization in many patients. Recent progresses in the understanding of the biology of COX, championed by elegant biochemical and recombinant DNA studies, revealed that it exists in two iso-forms constitutive COX-1 and inducible COX-2 (Fig. 4.2). COX-1 is always expressed and mediates the synthesis of prostaglandins that regulate normal cell functions, whereas COX-2 is active only at the onset of...

Crystalloid Solutions

Hypertonic saline solutions have not yet been incorporated into perioperative fluid management, although there are many promising studies addressing the volume effects and anti-inflammatory properties during surgical procedures (Christ et al., 1997 Junger et al., 1997 Kreimeier et al., 1997). Saline solutions with sodium concentrations ranging from 1.5 per cent to 30 per cent have been used in a variety of circumstances. In general, hypertonic crystalloid solutions cause greater plasma volume expansion than do similar volumes of isotonic solutions, but in the pre-hospital and military settings (Committee on Fluid Resuscitation for Combat Casualties, 1999) they have been introduced, and they are commonly used in several countries other than the US (Wade et al., 1997a, 1997b). Perhaps their best theoretical application is in the resuscitation of trauma patients who have both severe systemic hemorrhage and traumatic brain injury (Vassar et al., 1991, 1993). Nevertheless, a recent...

Cinnamon And Mydriasis

Despite extensive research, certain aspects of ulcer disease are not clearly elucidated. Because of the multiple processes that control acid and pepsin secretion and defense and repair cf gastroduodenal mucosa, it is more likely that causes of ulceration differ among individuals (Section 3.5). Two other factors have been acknowledged as risk factors in the pathophysiology of peptic ulcers nonsteroidal anti-inflammatory drugs (NSAIDs) and Heli-cobacter pylori infection (47-50). NSAIDs induce a significant number of gastric and duodenal ulcers, possibly because of inhibition of prostaglandin synthesis with consequent loss of protective effects. H. pylori has been recognized as a risk factor in the ulcerative process, similar to acid and pepsin. Duodenal ulcer is typified by H. pylori infection and duodenitis i and possibly impaired duodenal bicarbonate

Screening Models and Activity

Excellent accounts of various models are published6,25 for screening antibacterial, antifungal, antileishmanial, anthelmintic, antitapeworm, antimalarial, antiviral, antiinflammatory, analgesic, antiallergic, antiarhythmic, hypolipidaemic, hypoglycemic, antihypertensive, diuretic adaptogenic, immunomodulatory, hepatoprotective, choleretic, anticholesteric, CNS, activities and toxicity. 3.6 Antiinflammatory Activity A large number of tests have been developed to evaluate potential antiinflammatory compounds in vitro,25 but no single test is satisfactory.

Main Chemical Constituents Of Italian Bupleurum

Triterpene glycosides of the oleanane series (the so-called saikosaponins, from the Japanese name Saiko, the common name of Bupleurum spp. used in Kampo medicine) are considered the major bioactive components of Bupleurum crude drug, mainly used for its anti-inflammatory and

Clinical Use Of Agents

Dal anti-inflammatory agent e.g., aspirin (ASA) or ibuprofen for mild to moderate pain. If the pain persists or increases, then treatment progresses to the second tier, where a narcotic analgesic is added to the regimen. Frequently, this is accomplished by use of a combination product such as ASA plus codeine that combines an opioid with a nonnarcotic analgesic. The third tier is reached when the pain escalates from moderate to severe. At this level the opioid may be used as a single agent, given that opioids do not have a ceiling to their analgesic effect as do the nonnarcotic analgesics such as ASA and APAP (20). Adjuvant drugs, such as tricyclic antidepressants or an-ticonvulsants, may be added to opioid therapy as a means to enhance the efficacy of opioids for pain relief (17, 21).

Myeloma cast nephropathy

Myeloma cast nephropathy (MCN) is the most common form of myeloma renal disease and frequently progresses to chronic renal failure. It is often precipitated by dehydration, hypercalcemia, and use of diuretics or nons-teroidal anti-inflammatory drugs, all causing a reduction in glomerular filtration. Renal failure is reversible in about 50 of patients.8-10,46 The physical basis for light-chain nephrotoxicity has not been elucidated. The initial finding that the isoelectric point of light chain was the determinant for its nephrotoxicity has not been con-firmed.45 47 Nevertheless, coprecipitation of light chain and Tamm-Horsfall protein in distal tubules leads to obstructing cast formation, tubular atrophy, disruption of the basement membrane, interstitial inflammation and fibrosis and eventually nephrosclerosis, all features characteristic of myeloma kidney.4648

Bioactivity of Marine Organisms

Alcoholic extracts of 50 Indian marine algae collected from the coasts of Goa, Maharashtra, Tamilnadu, Gujarat, Lakshadweep, Orissa and the Andaman and Nicobar Islands during pre-monsoon and post-monsoon periods have been tested for a wide range of biological activities. Of these, two extracts exhibited antiamoebic and antiviral activity each three of them had antiimplantation activity, nine had hypoglycaemic activity while hypotensive activity was associated with 11 extracts, 14 extracts were found to be diuretic and one of them had antiinflammatory activity. Further, ten of these extracts exhibited two types of activities, while a combination of 3 and 4 types of activities was observed in one extract each.66 majusculla6 which causes swimmers itch. Of the compounds isolated from this species lyngbyotoxin and bromoaplysiatoxin are highly toxic. Alcoholic extracts of Ulva faciata and Ulva lactua from the Gujarat coast exhibited antiviral and antiimplantation activities, respectively....

Analgesics And How They Work

NSAIDs (non-steroidal anti-inflammatory drugs) such as aspirin, ibuprofen and indomethacin, have anti-inflammatory activity inhibiting the formation of prostaglandins from arachidonic acid via the cyclo-oxygenase pathway. Their main site of action is in the periphery at the site of tissue damage but there may also be an effect within the spinal cord. Paracetamol is a para-aminophenol derivative with analgesic and antipyretic activity but no anti-inflammatory activity, with the spinal cord as its site of probable action. Opioid analgesics such as morphine and pethidine act on specific receptors on the descending pathways to inhibit pain. The main mode of action is by pre and post-synaptic inhibition thereby preventing transmission of neural signals to the brain.

COX2 Selective Inhibitors Celecoxib Rofecoxib and Valdecoxib

Notwithstanding their potential interest also in the treatment of cancer cachexia, some questions have arisen on the clinical use of these agents because of their toxicity and particularly cardiovascular risks. For this reason, rofecoxib has been withdrawn by the manufacturer. Another drug in this class, valdecoxib, has shown an increased risk for cardiovascular events in patients after heart surgery. As regards celecoxib, in December 2004 the National Cancer Institute stopped celecoxib (Celebrex) administration in an ongoing clinical trial investigating a new use of the drug to prevent colon polyps because of an increased risk of cardiovascular events in patients taking Celebrex versus those taking a placebo. Patients in the clinical trial taking 400 mg of Celebrex twice daily had a 3.4 times greater risk of cardiovascular events compared to placebo. For patients in the trial taking 200 mg of Celebrex twice daily, the risk was 2.5 times greater. The average duration of treatment in...

Anabolic Androgenic Steroids and Other Anabolic Steroids

Anabolic steroids are analogues of testosterone that can increase lean body mass 107, 108 and increase weight and activity in hypogonadal males 109, 110 . Although a proportion of cancer patients may be hypogonadal 111 , the role of these drugs and how they should be combined with other modalities (e.g. physical therapy, nutrition and anti-inflammatory anti-catabolic therapies) in cancer cachexia is currently unclear. As with other anabolic agents there has been some concern that tumour growth may be promoted. There has also been wariness of potential toxicity. Once again, present data can lend support to opposing points of view. In two contemporary studies, oxandrolone was reported to improve weight, lean body mass, performance status and

Clinical Assessment of Patients with Established Heart Failure

Treatment of HF causative factors (hypertension, coronary artery disease, atrial fibrillation, and valvular heart disease) and correction of precipitating causes (non-compliance with drugs, use of non-steroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors, nasal decongestants, infections, pulmonary emboli, dietary indiscretion, inactivity, hyperthyroidism).

PPARs as Fatty Acid and Drug Binding Receptors

For the first 5 years of the characterization of PPARs it was still unclear whether they were activated by direct binding of the various peroxisome proliferators, or whether the different compounds provoked the production of an endogenous li-gand. It was not until 1995 that the group of Steven Kliewer at Glaxo Wellcome demonstrated that the insulin-sensitizing drug rosiglitazone bound directly to and activated PPARy 41 . This group utilized radiolabeled rosglitazone to determine a binding affinity of 50 nM to the ligand binding domain of PPARy that had been expressed in E. coli and purified. This was the first finding of a compound that was of a high enough affinity for PPARs to demonstrate specific binding using a radioligand. The same group then demonstrated that a natural prostanoid fatty acid 15-deoxy A12,14PGJ2 could displace rosiglitazone and was an agonist of PPARy 42 . This was the first direct demonstration that a fatty acid could bind to PPARs. They then used the same...

Mechanism Of Gastric Mucosal Toxicity

Aspirin and the other NSAIDs exert their antiinflammatory effect through inhibition of the enzyme cyclo-oxygenase (COX) (see Chapter 15). This enzyme is present in two isoforms. COX-1 is involved in the formation of prostaglandins, which protect the gastric mucosa, while COX-2 is induced in response to inflammatory stimuli and is involved in the formation of cell-damaging cytokines. Most NSAIDs inhibit both isoforms so the beneficial anti-inflammatory effect is offset by the potential for gastric mucosal injury by depletion of prostaglandins. The latter leads to deleterious effects including reduction of mucosal blood flow and a reduced capacity to secrete protective mucus and bicarbonate ion. Aspirin is particularly potent in this respect, perhaps due to the fact that it inhibits COX irreversibly, unlike the other NSAIDs where inhibition is reversible and concentration dependent. Gastrointestinal bleeding can complicate use of low-dose aspirin.

Treatment Of Nsaidinduced Peptic Ulcers

Withdrawal of NSAIDs and acid suppression with standard doses of antisecretory drugs will allow prompt resolution of these ulcers, which should not recur unless the drugs are resumed. Many patients are prescribed NSAIDs inappropriately when their symptoms could be controlled by paracetamol or by local treatment. Topical NSAID creams applied over an affected joint may be helpful, but peptic ulcers can complicate therapy with NSAIDs administered as rectal suppositories. Prodrugs such as sulindac, which are metabolised to form antiinflammatory derivatives, can also produce ulcers.

Prevention Of Nsaidinduced Peptic Ulcers

Selective inhibition of COX-2 has the objective of preserving anti-inflammatory activity whilst avoiding gastric mucosal toxicity. Rofecoxib, celecoxib and meloxicam vary in their selectivity for COX-2. The incidence of peptic ulcers and their complications with rofecoxib is similar to that seen when proton pump inhibitors are co-administered with nonselective NSAIDs. The adverse effect profile of these drugs remains fully to be evaluated.

The Use of Outcome Measures The Current Status

Recently, there has been considerable interest in the potential therapeutic value of eicosapentaenoic acid (EPA), an omega n-3 polyunsaturated fatty acid with anti-inflammatory anti-catabolic properties, for the treatment of cancer cachexia. A series of clinical studies has been conducted to assess the efficacy of EPA, and this body of litera

Steroid Receptor Superfamily

The steroid receptor superfamily comprises the glucocorticoid (GR), progesterone (PR), mineralocorticoid (MR), androgen (AR), thyroid hormone (TR),and vitamin D3 (VDR) receptors (60). These receptors bind to steroid hormones and are translocated to the nucleus where they bind to hormone responsive elements on DNApromotor regions to alter gene expression. While steroids are very effective anti-inflammatory agents, they have a multiplicity of serious side effects that limit their full use.

Corroborative Results From Genetic And Pharmacological Inactivation Of Parp

Death during ischemia and validated targeting PARP for neuroprotection. In one rodent model of MPTP-induced Parkinson's disease, dopamine neurons in the substantia nigra in PARP-- mice could survive MPTP toxicity while most of those neurons in the wild-type littermates were degenerated.109 Indeed, PARP inhibitors offered effective neuroprotection in MPTP-treated mice.110 In other rodent models of traumatic brain injuries, PARP inhibition significantly ameliorated neural damage and PARP gene deletion offered significant functional benefit in motor skills and learning.811 PARP activation mediated ischemia-reperfusion injury was also found in other organs, e.g., in heart and muscle, suggesting a general role for PARP in free radical-elicited necrotic cell death.111112 PARP-- mice or hearts prepared from them were spared of myocardium and preserved myocardial functions after being subject to ischemia.113-115 Although the in vitro cardioprotective effects of PARP inactivation could largely...

NonGPCRLinked Cytokine Receptors

Cytokines are polypeptide mediators and are involved in the inflammatory immune response (86).There are three cytokine families hematopoietin, which includes IL-2-IL7, L-9-13 IL-15-IL-17 IL-19,1L-21, IL-22, GMCSF, GCSF, EPO, LIF, OSM, and CNTF, with primary signal transduction through the Jak STAT pathway tumor necrosis factor, comprising the receptors, TNFRSFl-18 that signal through NFkB, TRAF and caspases and the interleukin 1 TIR family that includes IL-1RI and IL-1RII, IL-lRrp2, and IL1RAPL. TIGGR-1,ST2, IL-18, and Toll 1-9 also signal through NFkB and TRAF. Some of these cyto-kine receptors mediate inflammatory responses, whereas others are anti-inflammatory, making this a highly complex as well as multimembered family (87).

Crosstalk with Inflammatory Signaling

One of the most exciting aspects of PPAR biology is their potential to modulate inflammatory processes. This is also, however, the area that it is almost impossible to interpret from the current literature. This is due to the existence of many discordant studies and the use of rather poorly selective compounds (or the poor use of reasonably selective compounds). It has been proposed that PPARy mediates the anti-inflammatory actions of the m-3fish oils such as eicosapentaenoic acid (EPA) 84 , however the pharmacology of the thiazolidinedione drugs in vitro and in vivo has been contradictory and does not completely support this hypothesis 58, 85-87 . Of course there is a very good precedent for the ability of nuclear receptors to have anti-inflammatory activity the glucocorticoid receptor (GR) is the archetypal anti-inflammatory mediator and there are many parallels between the proposed anti-inflammatory mechanisms for PPAR and those of GR. Both have been shown to mediate the repression...

Amplification of Visceral Afferent Signals

It is commonly observed that patients with chronic abdominal pain can have prior episodes of frequent or recurrent pain events or procedures that later become generalized to a chronic and persistent symptom presentation. Patients with IBS undergo more abdominal and gynecological operations for painful conditions than control groups (16). Although the surgeries have been attributed to increased health-care seeking and illness behaviors, an alternative explanation is that the surgical insult triggered the painful functional GI disorder and manifested clinically in patients physiologically and psychologically predisposed. Symptoms suggestive of IBS arise de novo in about 10 of women undergoing hysterectomy (17), and preoperative treatment with local or regional anesthesia or nonsteroidal anti-inflammatory medications reduces the severity of postoperative pain (14). These observations suggest that

Clinical Role for Troponin Testing in Sepsis

At present, data supporting any clinical application of troponin for prognostic assessment in SIRSs are limited, and, more important, no specific therapeutic strategies that might modify the risk of patients with SIRS have been identified. Application of aggressive antithrombotic, antiplatelet, and invasive therapies effective for patients presenting with ACS and elevated troponin are not supported by clinical data in this setting and may expose patients with sepsis to additional, unacceptable risks. Specific anti-inflammatory therapies such as antibodies to TNF-a have shown promising preliminary results. Research providing additional insight into the pathogenesis of troponin elevation in sepsis may also further clarify the mechanisms underlying myocardial dysfunction and guide the development of new approaches to the treatment of this highly morbid syndrome (33).

Mechanism Of Action

Glucocorticoids diffuse into the cell but access to the receptor may be prevented, for example in kidney, by the enzyme 11-beta hydroxysteroid dehydrogenase, which converts active Cortisol into inactive cortisone. When activated, the receptors translocate to the nucleus where they can upregu-late gene transcription by dimerising on specific DNA response elements and recruiting co-activator proteins, but can also oppose other transcription factor function, for example NFkB and AP-1, by protein-protein interaction. The anti-inflammatory actions of glucocorticoids are mediated mainly by this latter mechanism, suggesting that one day drugs may be found which have the beneficial

Analysis And Confirmation Of Urinary Drugs And Metabolytes By Cems

Tural information of compounds, and to use the MS as a CE detector (70,71). Currently there are few published articles discussing CE-MS monitoring of drugs in urine. The best examples are CE-MS determination of urinary N-l-hydroxyethylflurazepam (the major metabolite of flurazepam) (72), halo-peridol (48), anti-inflammatory drugs (ibuprofen, flurbiprofen) and their metabolites (73), paracetamol and metabolites (24,25,74), nonopioid analgesics (24), methadone (30,36), and methylphenidate (75). In addition, the feasibility of using MS as the detector for the enantiomers of terbutaline spiked into a urine blank has been demonstrated (76). In this instance the use of the chiral selector (heptakis (2,6-di-0-methyl)-p-cyclodextrin) in addition to the use of MS gave the selectively needed to verify the chiral composition in complex matrices.

Molecular Mechanisms in Angioprevention

This can be expanded to include the vast majority of the numerous potential cancer chemopre-vention agents that have been studied by different laboratories these have been shown interfere with pathways leading to NF-kB activation, and to repress AKT activation (Aggarwal and Shisho-dia 2004 Dorai and Aggarwal 2004 Pfeffer et al. 2005 Tosetti et al. 2002). The exceptions to this are the compounds devoid of antioxidant activity, such as the retinoid 4HPR (Ferrari et al. 2005) and possibly the steroid analogs. We have shown that repression of the NF-kB and Akt pathways produces downregulation of downstream elements such as p21, p53, and survivin (Dell'Eva et al., unpublished data), that in turn correlate with reduced endothelial cell activation, proliferation, migration, and even survival. Taken together, these data show that the AKT-NF-kB pathway lies at the core of angiogenesis as a common target for the angioprevention molecules. Given the central role of NF-kB in regulating...

Angiogenesis Inflammation and Angioprevention

Interestingly, neutrophils have been found to be a target for the angiogenesis inhibitor angio-statin (Benelli et al. 2002). We would extend this to suggest that inhibitors of angiogenesis will inhibit inflammation, and that anti-inflammatory agents will also repress angiogenesis. This has in part been suggested for classic COX inhibitors such as aspirin of specific COX2 inhibitors (Albini and Noonan 2005 Brown and DuBois 2005). These inflammation inhibitors have been shown to be effective in prevention of colon cancer (Brown and DuBois 2005), where the antiangio-genic activity has been postulated to play a role.

Actions of Adiponectin

Protective action of adiponectin in the initiation and progression of atherosclerosis through anti-inflammatory and antiatherogenic effects. NO, nitric oxide. (Reprinted from ref. 128 with permission from Elsevier, Copyright 2005.) Fig. 4. Protective action of adiponectin in the initiation and progression of atherosclerosis through anti-inflammatory and antiatherogenic effects. NO, nitric oxide. (Reprinted from ref. 128 with permission from Elsevier, Copyright 2005.)

Implications for Therapy

An intense effort is under way to identify therapies directed at the inflammation underlying plaque instability in patients with ACS. Laboratory and clinical studies have revealed anti-inflammatory effects of established treatments aimed at other contributors to athero-thrombosis (e.g., aspirin, statins, angiotensin-converting enzyme inhibitors and clopidogrel) (43). The evidence for anti-inflammatory actions of statins continues to grow and supports intensive statin therapy as being particularly important for patients with evidence of inflammation (44). In addition, clopidogrel decreases the expression of CD40L and may have a greater impact on reducing ischemic events after percutaneous coronary intervention in patients with elevated markers of inflammation (45). Agonists of the protein peroxisome proliferator activated receptor-a (PPAR-a), such as fibric acid derivatives, can reduce the expression of adhesion molecules on vascular endothelial cells, inhibit T-lym-phocyte function,...

Visceral Pain Therapy Current And Future

The current treatment of visceral pain associated, for instance, with functional bowel disorders (FBDs) such as functional dyspepsia and irritable bowel syndrome (IBS) is unsatisfactory. Therapeutic advances are badly needed in view of the high prevalence of chronic or recurrent visceral pain and its socioeconomic burden as outlined in Chapters I 1 and I 2. This gap in the pharmacologic management of visceral pain reflects the incomplete understanding of the underlying mechanisms, which lags behind the knowledge of somatic pain mechanisms. In addition, the utility of nonsteroidal anti-inflammatory drugs and opiates, which are the mainstay in somatic pain management, is limited by their severe adverse effects on gastrointestinal (GI) mucosal homeostasis and motility, respectively. Although progress in the use of opioid and nonopioid drugs for the treatment of abdominal pain is being made (see Chapters III 18 and III 19), there is clearly a need to identify new targets for visceral pain...

Toxicity Of Other Analgesics

Salicylates are a group of organic acids used as painkillers (analgesics) and fever-reducing drugs (antipyretics) and to control inflammation and platelet function. They are called nonsteroidal anti-inflammatory drugs (NSAIDs). An important example is acetylsalicylic acid (ASA). Also known as aspirin, ASA has a broad-range t1 of 2 to 20 hours depending on the amount taken. Small amounts of salicylate are excreted unchanged in urine while the majority is metabolized in the liver to organic acids before elimination. For treatment of severe inflammatory disease, the typical therapeutic level of salicylates is 150 to 300 g mL.

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