New Class Of Anti-inflammatory Drugs Research Articles

Study of the anti-exudative activity of new 3-cyano-1,4- dihydropyridines, cyanotioacetamide derivatives, on the model of acute formalin edema

The inflammatory process accompanies most of the pathologies and requires pharmacological correction. In spite of significant achievements of scientists in the field of medicine and pharmacology, existing steroid and nonsteroidal antiinflammatory drugs have a number of undesirable reactions. To date, one of the most urgent directions is the search for new effective and safe drugs with anti-inflammatory activity. The aim of the study was to investigate the anti-exudative properties of new 3-cyano-1,4-dihydropyridines, cyanothioacetamide derivatives in the classical test of acute formalin edema. Material and methods. The study was conducted on 88 white rats weighing 210–250 g. The effectiveness of compounds was determined in a model of acute formalin edema, which was induced by subplantar injection of 0.1 ml of 2 % formalin solution into the right hind limb of the animals. The severity of exudation was evaluated oncometrically in comparison with reference drugs – ibuprofen, indomethacin, meloxicam and metamizole sodium. The studied substances were administered intragastrically at a dose of 5 mg/kg 1.5 hours before the induction of inflammation. Results. It was found that some compounds exhibit anti-exudative activity, more pronounced or similar to the activity of reference drugs. The laboratory sample with code mar-137 was the leading sample and outperformed the comparators; 24 hours after the modeling of edema, it exceeded ibuprofen (by 2.39 %), metamizole sodium (by 4.77 %) in anti-exudative efficacy and had an anti-inflammatory effect similar to the activity of indomethacin and meloxicam. Conclusions. Newly synthesized laboratory samples of 3-cyano-1,4-dihydropyridines, cyanothioacetamide derivatives, were found to exhibit pronounced anti-exudative activity and are of interest for further research as a new class of anti-inflammatory drugs.

P-173 - MP1032 - a novel anti-inflammatory drug- ameliorates the progression of autoimmune diseases

Inflammatory autoimmune diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), and psoriasis are a major health burden. A dysregulated redox system with excessive production of reactive oxygen species (ROS) is thought to play a central role in disease progression as these oxygen species facilitate the production of proinflammatory cytokines. MP1032 belongs to a new class of anti-inflammatory drugs that act as potent ROS scavengers. A unique feature of this compound class is that the scavenging activity is dynamically regulated by an intracellular feedback loop. Scavenging activity increases with increased inflammatory activation of innate immune cells and ceases at physiological, non-inflammatory activation states. Using ultra-weak photon emission imaging, ROS scavenging activity of MP1032 was demonstrated in mice directly at the site of inflammation. In adjuvant-induced RA, this effect was accompanied by markedly reduced serum levels of IL-6 and TNFα and reduced arthritic scores in MP1032-treated rats. MP1032 also ameliorated disease progression in models of MS. In a human Phase IIa trial, MP1032 demonstrated good clinical efficacy and safety in moderate psoriasis, highlighting the potential of redox-based therapies in chronic inflammatory and autoimmune diseases.

Anti-Oxidant and Anti-Inflammatory Activities of Different Varieties of Piper Leaf Extracts (Piper Betle L.)

Piper betle L. (locally known as Paan) is a widely distributed plant in the tropical and subtropical regions, its leaves being largely consumed as a masticator and mouth freshener. It is valued as a mild stimulant and also has its use in Ayurvedic medicine. The present study investigates on the free radical scavenging potential as well as total phenolic and aflavanoid contents of methanolic extract of 9 different varieties of Piper betle leaves (A,B,C,D,E,F,G,H&I). These extracts from diverse localities and varying on treatment, maturation at plucking etc. were used to evaluate antioxidant and antiinflammatory activities. The antioxidant potential of all 9 varieties of methanolic leaf extracts were evaluated by six methods: 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity, superoxide radical O2-scavenging activity by the riboflavin-light-nitroblue tetrazolium (NBT) system, Lipid peroxidation assay was done by a modified thiobarbituric acid reactive species (TBARS) assay and Nitric oxide (NO) scavenging activity . Total phenolic and total flavonoid content also determined by standard protocol. Anti-inflammatory effect of the extract evaluated on LPS induced RAW 264.7 cell line in dose dependent manner. RP-HPLC analyses of 9 varieties of methanolic crude extract, was done and picks were monitored at 254 nm. All of the nine extracts demonstrated highest antioxidant activities at concentration of 1 mg/ml. Among the nine varieties, five (C,E,F,G and I) demonstrated anti-inflammatory activity, one(H) is proinflammatory and three varieties of P.betle leaf (A,B and D) didn’t show significant antiinflammatory activity. the F variety was most effective at a concentration of 250 μg/ml to retained cell viability 99%, very close to control and positive control (Dexamethasone) but H variety of P.betle leaf extract showed proinflammatory activity and cell viability decreased by 29% than control. The results of the experiments suggest that selected variety of P.betle may be used as natural antioxidant as well as an alternative or supplementary herbal remedy for the treatment of inflammatory disease. Thus, the present study warrants further investigation involving components of P.betle for possible development of new class of anti-inflammatory drugs.

Anti-Interleukin-1 Therapy in the Management of Gout

Gout is the most common inflammatory arthritis in humans. Current treatment options to control the pain and inflammation of acute and chronic gout include nonsteroidal anti-inflammatory drugs, colchicine, and corticosteroids. However, patients are commonly unresponsive to, intolerant of, or have contraindications to current treatments. Interleukin-1 (IL-1), a proinflammatory cytokine, plays a major role in mediating gouty inflammation. This role of IL-1 has led investigators to explore a new class of anti-inflammatory drugs that inhibit IL-1 signal transduction. IL-1 inhibitors currently in trials for gout include anakinra, rilonacept, and canakinumab. Anakinra is an IL‑1 receptor antagonist that inhibits the activity of both IL‑1α and IL‑1β, rilonacept is a soluble decoy receptor and canakinumab is an anti‑IL‑1β monoclonal antibody. In case cohorts, anakinra was found to be efficacious in combating acute gout pain and inflammation, whereas rilonacept has been found to be efficacious for reducing the risk of recurrent attacks. Canakinumab has been shown to be efficacious in both reducing pain and inflammation in acute attacks, and for reducing the risk of recurrent attacks. All three IL-1 inhibitors are generally well tolerated. This article reviews the current IL-1 inhibitors and the results of trials in which they have been tested for the management of acute and chronic gouty inflammation.

Cysteine Cathepsins and the Skeleton

Cysteine cathepsins are lysosomal proteases with housekeeping as well as tissue-specific functions. One of their specialized functions includes the degradation of extracellular matrix proteins and the regulation of the immune response. In recent years, this protease family received increasing attention as drug targets for bone and cartilage-related diseases. Cathepsin K is identified as the major osteoclast protease with a potent and unique collagenase activity. The protease is responsible for the bulk of collagen degradation in bone remodeling and plays a significant role in the regulation of osteoclast activity. Major efforts in the pharmaceutical industry led to the development of highly potent and specific cathepsin K inhibitors for clinical trials in osteoporosis. Odanacatib, a nitrile-based non-lysosomotropic inhibitor is presently in phase III trials. The compound is well tolerated and showed efficacy regarding the increase of bone mineral density, and reduction of serum and urinary markers of bone resorption. Moreover, cathepsin inhibitors do less or not interfere with the bone formation process. Cathepsin K is also a drug target in arthritic diseases where it is likely involved in type II collagen and glycoprotein degradation. Cathepsin S, which lacks the collagenase activity, is involved in MHC class II antigen presentation in inflammatory and auto-immune related joint diseases and its inhibitors have the potential to represent a new class of anti-inflammatory drugs.

Sphingosine-1-Phosphate Modulates Vascular Permeability and Cell Recruitment in Acute Inflammation In Vivo

The sphingosine kinase (SPK)/sphingosine-1-phosphate (S1P) pathway recently has been associated with a variety of inflammatory-based diseases. The majority of these studies have been performed in vitro. Here, we have addressed the relevance of the SPK/S1P pathway in the acute inflammatory response in vivo by using different well known preclinical animal models. The study has been performed by operating a pharmacological modulation using 1) L-cycloserine and DL-threo-dihydrosphingosine (DTD), S1P synthesis inhibitors or 2) 2-undecyl-thiazolidine-4-carboxylic acid (BML-241) and N-(2,6-dichloro-4-pyridinyl)-2-[1,3-dimethyl-4-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-hydrazinecarboxamide (JTE-013), specific S1P(2) and S1P(3) receptor antagonists. After local injection of carrageenan in mouse paw S1P release significantly increases locally and decreases during the resolution phase. Expression of SPKs and S1P(2) and S1P(3) receptors is increased in inflamed tissues. Administration of L-cycloserine or DTD caused a significant anti-inflammatory effect. By using different animal models we have also demonstrated that the SPK/S1P pathway contributes to changes in vascular permeability and promotes cell recruitment. The S1P effect on cell recruitment results is receptor-mediated because both JTE-013 and BML-241 inhibited zymosan-induced cell chemotaxis without effect on vascular leakage. Conversely, changes in vascular permeability involve mainly SPK activity, because compound 48/80-induced vascular leakage was significantly inhibited by DTD. In conclusion, the SPK/S1P pathway is involved in acute inflammation and could represent a valuable therapeutic target for developing a new class of anti-inflammatory drugs.

Nonsteroidal Anti-Inflammatory Drugs: A Critical Review on Current Concepts Applied to Reduce Gastrointestinal Toxicity

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs worldwide. Nevertheless, their intake is frequently associated with gastrointestinal side effects, representing still an important medical and socio-economic problem. In recent years efforts focused on the development of highly selective COX-2 inhibitors with an improved gastric tolerability profile. However, severe cardiovascular adverse reactions challenged the initial enthusiasm in this new class of anti-inflammatory drugs. In addition, the market withdrawals of some coxibs led to a relative reluctance in prescribing COX-2 inhibitors in clinical practice. As a consequence, the interest for alternative approaches to reduce gastrointestinal side effects associated with NSAIDs has re-emerged. There are two main components of gastric damaging properties of NSAIDs: (1) the acute toxicity associated with the short-term intake of NSAIDs, which is principally caused by local irritation of the gastric mucosa (2) the chronic toxicity resulting mainly from systemic effects associated with prolonged administration of NSAIDs. Based on that background two different approaches were pursued in the search for GI sparing NSAIDs: a) modification of classical NSAIDs by associating them with phospholipids, cyclodextrins, or chemical moieties that release gastroprotective mediators and b) defining novel targets as well as developing new compounds like dual COX/5-LO or mPGES-1 inhibitors. This review provides the first comprehensive overview of all currently applied approaches taken to improve the risk-benefit ratio of NSAIDs focusing on the structure activity relationships and the respective mechanism of action underlying the individual approaches. The insight gained in this review is useful for further research activity in this field.

Cyclooxygenase-inhibiting nitric oxide donators for osteoarthritis

Nonsteroidal anti-inflammatory drugs (NSAIDs) remain the most commonly used medications for the treatment of the symptoms of many chronic inflammatory diseases, including osteoarthritis. Unfortunately, the toxicity of NSAIDs substantially limits their long-term use. Some newer NSAIDs, namely selective cyclooxygenase (COX)-2 inhibitors, exhibit greater gastrointestinal safety, and concomitant use of anti-secretory drugs can also reduce NSAID-induced gastropathy. However, NSAIDs also adversely affect the cardiovascular system. A new class of anti-inflammatory drugs, COX-inhibiting nitric oxide donators (CINODs), has been designed to exert similar anti-inflammatory effects as NSAIDs, but with an improved safety profile. CINODs release nitric oxide, providing protective effects in the gastrointestinal tract and attenuating the detrimental effects on blood pressure normally associated with NSAIDs. We provide an outline of the rationale for CINODs and their activity, in addition to an overview of the pre-clinical and clinical profile of the most advanced CINOD, naproxcinod.

Computer-Aided, Rational Design of a Potent and Selective Small Peptide Inhibitor of Cyclooxygenase 2 (COX2)

Cyclooxygenase (COX) is a key enzyme in the biosynthetic pathway leading to the formation of prostaglandins, which are the mediators of inflammation. This enzyme exists mainly in two isoforms, COX1 and COX2. Prostaglandins responsible for the inflammatory process could be sufficiently controlled with the conventional non-steroidal anti-inflammatory drugs (NSAIDs). These drugs, however, had adverse gastrointestinal side-effects and, therefore, drugs that selectively inhibit COX2, such as the coxibs, were developed. Recent reports on the harmful cardiovascular and renal side-effects of the conventional NSAIDs as well as the COX2 selective inhibitors valdecoxib and rofecoxib have once again led to the quest for a novel class of COX2 selective inhibitors. Keeping this in mind, we have used the available X-ray crystal structures of the complexes of COX' and COX2 with the known inhibitors to carry out a structure-based, rational, molecular modeling approach to design a small peptide inhibitor, which is both potent and selective for COX2. Docking studies using SYBYL 6.81 (Tripos, Inc.) and AutoDock 3.0, indicate that the designed peptides inhibit COX2 with potency in the nanomolar range. Furthermore, it is found to be a million-fold selective for COX2 as compared with COX1. Thus, the small peptide inhibitor is a suitable lead compound for the design of a new class of anti-inflammatory drugs.

Toward the development of chemoprevention agents. Part II: Chemo-enzymatic synthesis and anti-inflammatory activities of a new class of 5-amino-2-substitutedphenyl-1,3-dioxacycloalkanes

A new series of optically pure 5-amino-2-substitutedphenyl-1,3-dioxacycloalkanes were designed and synthesized via a chemo-enzymatic combined method to develop new chemoprevention agents. Twenty-four of newly synthesized compounds significantly inhibited xylene-induced rat ear edema and exhibited comparable or better anti-inflammatory activities than the reference drug aspirin. Treatment of these anti-inflammatory agents did not prolong the tail bleeding time in rat. In addition, 5-amino-2-substitutedphenyl-1,3-dioxacycloalkanes exhibited good membrane permeability based on in vitro Caco-2 cell monolayer permeability assay. Furthermore, some preliminary structure–activity relationships were further analyzed among these compounds. Taken together, 5-amino-2-substitutedphenyl-1,3-dioxacycloalkanes may represent a new class of anti-inflammatory drugs with safer pharmacological profile.

Modulation of angiogenesis by dithiolethione-modified NSAIDs and valproic acid.

Angiogenesis involves multiple signaling pathways that must be considered when developing agents to modulate pathological angiogenesis. Because both cyclooxygenase inhibitors and dithioles have demonstrated anti-angiogenic properties, we investigated the activities of a new class of anti-inflammatory drugs containing dithiolethione moieties (S-NSAIDs) and S-valproate. Anti-angiogenic activities of S-NSAIDS, S-valproate, and the respective parent compounds were assessed using umbilical vein endothelial cells, muscle and tumor tissue explant angiogenesis assays, and developmental angiogenesis in Fli:EGFP transgenic zebrafish embryos. Dithiolethione derivatives of diclofenac, valproate, and sulindac inhibited endothelial cell proliferation and induced Ser(78) phosphorylation of hsp27, a known molecular target of anti-angiogenic signaling. The parent drugs lacked this activity, but dithiolethiones were active at comparable concentrations. Although dithiolethiones can potentially release hydrogen sulphide, NaSH did not reproduce some activities of the S-NSAIDs, indicating that the dithioles regulate angiogenesis through mechanisms other than release of H(2)S. In contrast to the parent drugs, S-NSAIDs, S-valproate, NaSH, and dithiolethiones were potent inhibitors of angiogenic responses in muscle and HT29 tumor explants assessed by 3-dimensional collagen matrix assays. Dithiolethiones and valproic acid were also potent inhibitors of developmental angiogenesis in zebrafish embryos, but the S-NSAIDs, remarkably, lacked this activity. S-NSAIDs and S-valproate have potent anti-angiogenic activities mediated by their dithiole moieties. The novel properties of S-NSAIDs and S-valproate to inhibit pathological versus developmental angiogenesis suggest that these agents may have a role in cancer treatment.

The peptide analogue of MCP-1 65–76 sequence is an inhibitor of inflammationThis paper is one of a selection of papers published in this Special Issue, entitled The Cellular and Molecular Basis of Cardiovascular Dysfunction, Dhalla 70th Birthday Tribute.

Inflammation plays an important role in vessel wall remodeling that occurs in atherosclerosis and postangioplasty restenosis. Monocytic chemoattractant protein-1 (MCP-1) is one of the main attractors of monocytes and some lymphocyte subsets to the damaged vessel. The aims of the study were to confirm MCP-1 participation in the development of acute coronary syndromes, to produce the potential MCP-1 peptide antagonist, and to investigate its effects in vitro and in vivo in different animal models of inflammation. MCP-1 plasma concentration was measured by ELISA (enzyme-linked immunosorbent assay). Chemokine receptor expression by cells isolated from human atherosclerotic lesions was assessed by direct immunofluorescence and flow cytometry. MCP-1 sequence was analyzed with Peptide Companion software and peptides were synthesized using Fmoc strategy. The peptide resistance to degradation was checked by 1H-NMR spectroscopy. The peptide effect on MCP-1-stimulated cell migration was studied in Boyden chamber and in mouse air pouch model, and its influence on lipopolysaccharide (LPS)-induced inflammatory cell recruitment was investigated in models of subcutaneous inflammation in rats and nonhuman primates. We revealed nearly a 2-fold increase of MCP-1 plasma level in patients with unstable angina in comparison with patients with stable angina. The atherosclerotic plaque specimens obtained from patients with unstable angina contained a significant amount of chemokine receptor-expressing leukocytes. Peptide from MCP-1 C-terminal 65-76 sequence (peptide X) inhibited MCP-1-stimulated monocytic cell migration in vitro and in vivo. Peptide X labeled with 99mTc accumulated specifically at sites of inflammation in rats. Peptide X administrated i.m and i.v. suppressed monocyte and granulocyte recruitment induced by subcutaneous injection of LPS in the back of rats and non-human primates. Our data demonstrate that MCP-1-mediated chemotaxis could be responsible for atherosclerotic plaque "destabilization". Peptide X may represent a new class of anti-inflammatory drugs to be used in cardiology.

Is there a role for antileukotrienes in urticaria?

In vitro and in vivo clinical and experimental data have suggested that leukotrienes play a key role in inflammatory reactions of the skin. Antileukotriene drugs, i.e. leukotriene receptor antagonists and synthesis inhibitors, are a new class of anti-inflammatory drugs that have shown clinical efficacy in the management of asthma. We searched the MedLine database and carried out a manual search on journals specializing in allergy and dermatology for the use of antileukotriene drugs in urticaria. Montelukast might be effective in chronic urticaria associated with aspirin or food additive hypersensitivity or with autoreactivity to intradermal serum injection when taken with an antihistamine but not in moderate chronic idiopathic urticaria. Evidence for the effectiveness of zafirlukast and the 5-lipoxygenase inhibitor, zileuton, in chronic urticaria is mainly anecdotal. In addition, there is anecdotal evidence of effectiveness of antileukotrienes in primary cold urticaria, delayed pressure urticaria and dermographism. No evidence exists for other physical urticarias, including cholinergic, solar and aquagenic urticarias, vibratory angio-oedema, and exercise-induced anaphylaxis.

Monocyte Cyclooxygenase-2 Activity: A New Therapeutic Target for Atherosclerosis?

It is now widely accepted that atherosclerosis is a complex chronic inflammatory disorder of the arterial tree associated with several risk factors. From the initial phases of leukocyte recruitment to eventual rupture of vulnerable atherosclerotic plaques, a low-grade inflammation, also termed microinflammation, appears to play a key pathogenetic role. Experimental and clinical evidence suggests that cyclooxygenase-2 (COX-2), an enzyme which catalyzes the generation of prostaglandins from arachidonic acid, also contributes to lesion formation. COX-2 has been detected in macrophages, smooth muscle cells and endothelial cells in human atherosclerotic lesions. Several studies have also reported the presence of COX-2 in the shoulder region of atherosclerotic plaques, mainly colocalizing with macrophages and MMPs, enzymes that are involved in the destabilization of atherosclerotic plaques, leading to rupture and atherothrombotic syndromes (i.e. acute myocardial infarction). We have recently assessed monocyte COX-2 activity and the production of PGE(2) in a population of apparently healthy subjects free from clinically overt atherosclerosis. We found an association between increased PGE(2) and increasing number of cardiovascular risk factors and carotid intima-media thickness, a noninvasive surrogate marker of atherosclerosis, independently of traditional and non traditional cardiovascular risk factors. Our findings support the notion that the COX-2/PGE(2)axis may have a role in atherosclerosis, and this might be an attractive therapeutic target. COX-2 inhibitors, collectively called coxibs (celecoxib, rofecoxib, valdecoxib, lumiracoxib, etc), held a promise of improved treatment of arthritis without the gastrointestinal side effects associated with aspirin and other nonsteroidal anti-inflammatory drugs. However, clinical studies raise several clinically relevant questions as to their beneficial role in atherosclerosis prevention, because of increased thrombogenicity and cardiovascular risk. Only well designed large scale clinical trials can provide the answer as to the net effect of selective COX-2 inhibition on cardiovascular events before this new class of anti-inflammatory drugs can be incorporated into the armamentarium of atherosclerosis.

Combined Lipoxygenase/Cyclo-oxygenase Inhibition in the Elderly

One of the categories of drugs most frequently used by the elderly, and probably the most commonly self-prescribed class of drug in this age group, is NSAIDs. However, NSAIDs are one of the primary causes of adverse drug reactions and are notorious for their gastric toxicity. They also inhibit renal function and reduce the efficacy of diuretics and ACE inhibitors, drugs that are commonly used by elderly patients. Recent studies have shown that cyclo-oxygenase (COX)-2 is important in renal physiology. This means that selective COX-2 inhibitors, while undoubtedly safer than NSAIDs in terms of gastric toxicity, are not devoid of renal toxicity (in addition to their now clearly established adverse effects on coronary heart disease risk). Both the gastric and renal toxicities induced by traditional NSAIDs and selective COX-2 inhibitors seem to be related to inhibition of prostaglandin, but not leukotriene, synthesis. Maintaining the correct balance between prostaglandins and leukotrienes is essential for continuing good health, but both classes of mediators also play an important role in the pathogenesis of several diseases.Recently, a new class of anti-inflammatory drugs, the lipoxygenase (LOX)/COX inhibitors, has been developed as a means of simultaneously inhibiting the synthesis of prostaglandins, thromboxanes and leukotrienes. Inhibition of leukotriene synthesis increases anti-inflammatory efficacy, particularly in rheumatic diseases, while reducing the risk of gastric damage. The LOX/COX inhibitor licofelone, which is currently in phase III trials, is the first of this new class and in the most advanced stage of development. Preliminary data with this drug seem promising, but further well designed clinical trials of this agent in the elderly will be necessary before a final evaluation is possible.

Inhaled Corticosteroids versus Leukotriene Antagonists as First-Line Therapy for Asthma

Inhaled corticosteroids are the most effective anti-inflammatory drugs for asthma. Leukotriene receptor antagonists are a new class of anti-inflammatory drugs that have the advantage of oral administration and the potential for better compliance compared with inhaled corticosteroids. This article summarizes evidence from randomized controlled trials, comparing the efficacy and tolerability of inhaled corticosteroids with those of leukotriene receptor antagonists in patients with persistent asthma. The evidence derived from a systematic review of randomized controlled trials confirms that patients treated with inhaled corticosteroids of chlorofluorocarbon-propelled beclomethasone 400 mug/day or fluticasone propionate 200 mug/day have better asthma control than those treated with oral leukotriene receptor antagonists. More specifically, treatment with inhaled corticosteroids is associated with 65% fewer exacerbations requiring systemic corticosteroids, greater improvement in spirometry and symptoms, fewer night-time awakenings and less use of rescue beta(2)-adrenoceptor agonists. This review does not identify any difference in short-term safety between inhaled corticosteroids and leukotriene receptor antagonists. Although adverse effects typically associated with inhaled corticosteroids (such as growth suppression, osteopenia, and adrenal suppression) were not measured, preventing a fair comparison of the safety profile on long-term use.In conclusion, the scientific evidence does not support the substitution of leukotriene receptor antagonists for low doses of inhaled corticosteroids, which should remain first-line therapy for asthma control.

Pathophysiological role of leukotrienes in dermatological diseases: potential therapeutic implications.

In vitro and in vivo data have demonstrated that leukotrienes play a key role not only in allergic airway diseases but also in inflammatory reactions of the skin. Antileukotriene drugs, i.e. leukotriene receptor antagonists and synthesis inhibitors, are a new class of anti-inflammatory drugs that have shown clinical efficacy in the management of asthma, allergic rhinitis and inflammatory bowel disease. To address the question of the validity and applicability of published evidence of the use of antileukotriene drugs in dermatological diseases, we reviewed data concerning the pathophysiological effect of leukotrienes in the skin and in skin diseases, and the experience with antileukotriene treatment that has been published. In vivo and in vitro data suggest that antileukotriene treatment may have efficacy in atopic dermatitis, different types of urticaria or psoriasis and other skin diseases such as bullous skin diseases, collagenoses, Sjogren-Larsson syndrome or Kawasaki disease. Nevertheless, published evidence is very limited and before any conclusions can be drawn, additional basic research needs to be performed with regard to the role of different leukotrienes and leukotriene receptors in skin diseases. On the basis of these data, randomised and placebo-controlled clinical trials with leukotriene antagonists and synthesis inhibitors should be performed. Moreover, future studies investigating the additive benefit of antileukotriene drugs are warranted, e.g. in combination with antihistamines, corticosteroids or other anti-inflammatory drugs.

In vivo and in vitro treatment with the synthetic cannabinoid CP55,940 decreases the in vitro migration of macrophages in the rat: involvement of both CB1 and CB2 receptors

Cannabinoids have been shown to affect immune responses, acting on different populations of immune cells. In the present paper we analyze the ability of in vivo and in vitro treatment with the potent synthetic cannabinoid CP55,940 to interfere with an important function of rat peritoneal macrophages, i.e. spontaneous migration and formyl-metionyl-leucine-phenylalanine (fMLP)-induced chemotaxis, that were assessed by the use of a Boyden-modified microchemotaxis chamber. When added in vitro, CP55,940 induced a significant and dose-dependent inhibition of both spontaneous migration and fMLP-induced chemotaxis. Both the Cannabinoid Receptor 1 (CB1) and the Cannabinoid Receptor 2 (CB2) antagonists were able to block the CP55,940-induced inhibition of spontaneous migration, although the CB2 antagonist was more potent and only the CB2 antagonist was able to reverse the effect of CP55,940 on fMLP-induced chemotaxis. Similarly, in the in vivo experiments, 1 h after the acute subcutaneous administration of 0.4 mg/kg of CP55,940, both spontaneous motility and chemotaxis were reduced. The pretreatment with the CB2 antagonist, but not with the CB1 antagonist, was able to prevent this effect. Our data confirm that cannabinoids can affect some macrophage functions, mainly throughout CB2 receptors, and suggest that the development of specific CB2 ligands may lead to an interesting new class of anti-inflammatory drugs.

Antileukotriene Drugs in Childhood Asthma

Leukotriene antagonists are a new class of anti-inflammatory drugs which have shown clinical efficacy in the management of asthma. However, their role in paediatric asthma is still unclear. In essence, while there are theoretical reasons as to why leukotriene antagonists would be of use in the management of childhood asthma, there is little clinical data on their use in this patient group. Studies with leukotriene antagonists to date have been performed in children with chronic 'undertreated' asthma which, under current recommendations, should be treated with inhaled corticosteroids. Furthermore, the magnitude of effect of leukotriene antagonists on lung function (forced expiratory volume in one second of less than 5% better than placebo) and daily symptoms (0.23 puffs per day of B2 agonist less than placebo), while reaching statistical significance, is unlikely to be of clinical significance in children with chronic undertreated asthma. There is, however, good evidence for leukotriene antagonist use in exercise induced asthma in children. We conclude that although leukotriene antagonists may play an important role in the management of childhood asthma in the future, particularly as corticosteroid sparing agents and in exercise induced asthma, clinical data in paediatric asthma is poor.

Effects of COX-2 Inhibitors, a New Class of Anti-Inflammatory Drugs, on Kidney Function in Older Patients

Summaries for Patients4 July 2000Effects of COX-2 Inhibitors, a New Class of Anti-Inflammatory Drugs, on Kidney Function in Older PatientsSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-133-1-200007040-00023 SectionsAboutFull Text ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail What is the problem and what is known about it so far?Nonsteroidal anti-inflammatory drugs (NSAIDs) are useful in treating many painful conditions, including headaches and arthritis. Unfortunately, NSAIDs occasionally produce serious side effects, including stomach ulcers and kidney problems, particularly in older persons. A new type of NSAID, called cyclooxygenase-2 (COX-2) inhibitors, affects some important body processes less than do earlier NSAIDs (COX-1/COX-2 inhibitors). This suggests that COX-2 inhibitors (for example, rofecoxib) may cause fewer side effects in patients than COX-1/COX-2 inhibitors (for example, ibuprofen and indomethacin). However, some studies in animals suggest that COX-2 inhibitors also can cause ... Author, Article, and Disclosure InformationAffiliations: The summary below is from the full report titled “Effect of Cyclooxygenase-2 Inhibition on Renal Function in Elderly Persons Receiving a Low-Salt Diet. A Randomized, Controlled Trial.” It is in the 4 July 2000 issue of Annals of Internal Medicine (volume 133, pages 1-9). The authors are S.K. Swan, D.W. Rudy, K.C. Lasseter, C.F. Ryan, K.L. Buechel, L.J. Lambrecht, M.B. Pinto, S.C. Dilzer, O. Obrda, K.J. Sundblad, C.P. Gumbs, D.L. Ebel, H. Quan, P.J. Larson, J.I. Schwartz, T.A. Musliner, B.J. Gertz, D.C. Brater, and S.-L. Yao.Summaries for Patients are a service provided by Annals to help patients better understand the complicated and often mystifying language of modern medicine.Summaries for Patients are presented for informational purposes only. These summaries are not a substitute for advice from your own medical provider. If you have questions about this material, or need medical advice about your own health or situation, please contact your physician. The summaries may be reproduced for not-for-profit educational purposes only. Any other uses must be approved by the American College of Physicians-American Society of Internal Medicine. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoEffect of Cyclooxygenase-2 Inhibition on Renal Function in Elderly Persons Receiving a Low-Salt Diet Suzanne K. Swan , David W. Rudy , Kenneth C. Lasseter , Charles F. Ryan , Kristin L. Buechel , Laurence J. Lambrecht , Manuel B. Pinto , Stacy C. Dilzer , Olga Obrda , Kimberly J. Sundblad , Carol P. Gumbs , David L. Ebel , Hui Quan , Patrick J. Larson , Jules I. Schwartz , Thomas A. Musliner , Barry J. Gertz , D. Craig Brater , and Siu-Long Yao Metrics 4 July 2000Volume 133, Issue 1Page: 1KeywordsArthritisCyclooxygenase 2DietDrugsIbuprofenKidneysNSAIDsPatientsRenal failureSalts ePublished: 15 August 2000 Issue Published: 4 July 2000 Copyright & PermissionsCopyright © 2000 by American College of Physicians. All Rights Reserved.Loading ...