Treatment Of Inflammatory Conditions Research Articles

Oxidative stress and steroid resistance in asthma and COPD: pharmacological manipulation of HDAC-2 as a therapeutic strategy

Insensitivity to corticosteroid treatment in inflammatory conditions, such as asthma and chronic obstructive pulmonary disease, present considerable management problems and cost burdens to health services. Oxidative stress is a major component of chronic inflammation and can have a significant suppressive effect on corticosteroid efficacy. Recent advances in the understanding of both the mechanisms of corticosteroid action and corticosteroid insensitivity have provided hope for a therapeutic strategy of restoring corticosteroid sensitivity. Histone deacetylase 2 (HDAC-2) plays a pivotal role in corticosteroid action and is reduced in many cases of steroid insensitivity. Moreover, it has shown that oxidative stress can be responsible for this reduction in HDAC-2 activity. Two structurally different compounds; methyl-xanthine theophylline and polyphenol curcumin restore HDAC activity, thereby restoring corticosteroid function. Low, subbronchodilator doses of theophylline can also act as corticosteroid-sparing drugs in asthmatics. Although these compounds appear to restore corticosteroid function and may initially provide therapeutic potential, they lack specificity and the mechanism of their action is unknown. Once their mechanisms of action are established, it is likely that derivatives of these compounds may be used as a therapeutic strategy to restore corticosteroid insensitivity in the future.

The Pathogenesis, Epidemiology and Management of Glucocorticoid-Induced Osteoporosis

Oral glucocorticoids (GCs) are frequently used in the treatment of inflammatory conditions, such as rheumatoid arthritis or asthma. They have adverse skeletal effects, primarily through reductions in bone formation and osteocyte apoptosis. Several findings indicate that changes in the quality of bone may significantly contribute to the increased risk of fracture and that loss of BMD only partially explains the increased risk of fracture in oral GC users. Epidemiological studies have found that the increases in the risk of fracture in oral GC users are dose dependent and occur within three months of starting GC therapy. Daily doses of >2.5 mg prednisone equivalent have been associated with increases in the risk of fractures and randomised studies reported adverse skeletal effects with daily doses as low as 5 mg. After discontinuation of GC treatment, the risk of fracture may reduce towards baseline levels unless patients previously used high cumulative doses of oral GCs. Users of inhaled GCs have also an increased risk of fracture, especially at higher doses. But it is likely that this excess risk is related to the severity of the underlying respiratory disease, rather than to the inhaled GC therapy. It has been recommended that patients who start on oral GC therapy should receive calcium and vitamin D supplementation. Patients with a higher risk of fracture should also receive a bisphosphonate.

Cortisol Resistance in Conditions such as Asthma and the Involvement of 11β-HSD-2: A Hypothesis

The two types of corticosteroid hormones, the mineralocorticoids and glucocorticoids, act in a complementary manner and are functionally closely linked. Aldosterone and glucocorticoids express their functions through the glucocorticoid receptors (GRs; GRalpha and GRbeta) and the mineralocorticoid receptors (MRs). Commercially available steroidal drugs used in conditions such as asthma may act on both GR and MR receptors; although glucocorticoid-receptor agonists play a fundamental role in the treatment of inflammatory conditions, prolonged exposure may have adverse effects such as the development of resistance. Glucocorticoid resistance in such conditions has been observed to be accompanied by a downregulation of GRalpha, a twofold decrease in GR protein half-life, downregulation of GRalpha mRNA expression, and enhanced expression of GRbeta. Other suggestions for glucocorticoid resistance include alternative splicing of the GR gene with subsequent expression of the GRbeta protein isoform, defective regulation of gene transcription of the GR gene or GR mutations, defective DNA binding and transactivating domains of the GR. In addition, we would like to suggest that dysregulation of the MR enzyme 11beta-HSD-2 may be one of the causes of resistance. When expressed in cells with MRs, this enzyme's major role is to prevent permanent occupancy of MR by glucocorticoid hormones, allowing concentration-dependent binding of aldosterone to MR. However, deficiency of the 11beta-HSD isoforms (particularly 11beta-HSD-2) leads to the activation of MRs by glucocorticoids rather than the glucocorticoids interacting with its "normal" receptors, the GRs. We will substantiate on support for our hypothesis in the dysregulation of this enzyme, which is typically associated with significantly higher levels of circulating plasma cortisol and elevated levels of cholesterol, little or no response to systemic glucocorticoids, and problems associated with homeostasis primarily in the distal nephron and distal colon. These are some of the symptoms typically noted in cortisol resistance.

Gastrointestinal infections in immunocompromised hosts

Gastrointestinal infections in the immunocompromised host continue to have significant morbidity and mortality throughout the world. They all have similar exposures to viruses, bacteria and parasites and respond to these infections in a similar way. This review will summarize the latest reports on the epidemiology, diagnosis and treatment of known and emerging infections over the last 12 months.Highly active antiretroviral therapy has reduced esophageal opportunistic infections in HIV patients compared to patients who are not taking this therapy. Esophageal candidiasis responds to escalating doses of micafungin as effectively as fluconazole. HIV-infected patients with untreated Mycobacterium avium-complex diarrhea are associated with a wasting syndrome that disrupts the somatostatin axis. Polymerase chain reaction testing has improved diagnosis of microsporidial infections. Cytomegalovirus polymerase chain reaction of tissue may improve the diagnosis of cytomegalovirus disease of the gastrointestinal tract in organ-transplant recipients. The treatment of hypogammaglobulinemia in transplant recipients with recurrent cytomegalovirus gastrointestinal disease may resolve their symptoms. Community viruses are an emerging threat to transplant recipients and may affect drug levels. Lastly, anti-tumor necrosis factor alpha therapy in the treatment of inflammatory conditions may cause Listeria monocytogenes to disseminate.Immunocompromised hosts remain at risk for severe gastrointestinal and even disseminated infections. Management includes an early rapid diagnosis with rapid restoration of the immune system and appropriate anti-infective therapy. With the immunocompromised population rapidly increasing, prevention of these infections remains the greatest challenge.

Alkaline protease purified from Aspergillus oryzae prevents TNF‐a‐induced acute inflammation in the mouse small intestine

Enzyme replacement therapy is a growing clinical intervention primarily directed at correcting enzyme deficiencies, including the impaired production of digestive enzymes. We have asked whether microbial proteases have any potential therapeutic value in the treatment of inflammatory conditions whose pathogenesis involves peptide inflammatory mediators. The proteases of Aspergillus oryzae were selected due to their routine use in the processing foods. Pretreating mice with a partially purified mixture of A. oryzae proteases protected them against TNF-α-dependent lethality in an endotoxemia model. Pretreated mice showed decreased concentrations of detectable TNF-α, following challenge with bacterial endotoxin. Treating TNF- α with this protease preparation partially degraded the cytokine and blocked its ability to induce nitric oxide production by mouse myoblast cells in vitro. Three proteases were purified from this preparation by ion exchange chromatography and found by amino-terminal sequencing to be alkaline protease (AP), deuterolysin (DE) and 26 kDa protease. Purified AP inactivated mouse TNF-α. Treating TNF- α in vitro with AP, also destroyed its ability to induce activated caspase-3 in intestinal epithelial cells in vivo. Injecting with 1 μg AP by the i.p. route as much as 15 min prior to challenge with 5 ng TNF-α blocked the activation of intestinal caspase-3. These results suggest that A. oryzae AP has anti-inflammatory activity that may have therapeutic value in treating TNF-α-dependent inflammatory bowel diseases.

Anti-inflammatory therapy and cardiovascular risk: new insights

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been the predominant treatment for inflammatory conditions and chronic pain for nearly 40 years. However, when taken on a regular basis, anti-inflammatory agents are associated with a high risk of adverse events involving the upper gastrointestinal tract. It is estimated that approximately 1.1% of those taking NSAIDs develop significant gastrointestinal lesions (bleeding and gastric perforation), for which hospital recovery is necessary [1]. The inhibition of cyclooxygenase (COX) by NSAIDs produces both their therapeutic and their adverse events. The distinction between the enzymatic properties of COX-1 and COX-2 has led to the inception of selective COX-2 antiinflammatory agents (coxibs). The development and commercialization of these agents have led researchers to believe that problems with safety have been resolved, and that prolonged use of these new anti-inflammatory agents would allow easier control of many chronic pathologies, especially rheumatological disorders and arthritis. However, during their clinical development, an unexpectedly high incidence of cardiovascular events was observed. Clinical trial data first demonstrating increased cardiovascular risk with the use of these drugs came from the VIoxx Gastrointestinal Outcomes Research (VIGOR) trial that compared the gastrointestinal tolerability of rofecoxib (50 mg/day) with naproxen (1000 mg/day) in patients with rheumatoid arthritis [2]. The study demonstrated that rofecoxib was associated with a four-times greater risk of myocardial infarction than naproxen. This was attributed initially to a protective effect of naproxen [2], rather than to a specific effect of rofecoxib [3–6]. The problem became more evident in the Adenomatous Polyp PRevention On Vioxx (APPROVe) study carried out in patients with a history of colon adenomas [7]; this trial was interrupted when it was found that rofecoxib was associated with a two-fold higher risk of cardiovascular events than placebo (relative risk [RR] 1.92, confidence interval [CI] 1.19–3.11). In September 2004, Merck Sharpe & Dohme announced the voluntary worldwide withdrawal of Vioxx. Following publication of the APPROVe trial, other data from randomized, controlled clinical trials, as well as epidemiological data, became available. These studies suggested that increased cardiovascular risk is not a problem specific to rofecoxib, but is common to all analogous molecules. In the Adenoma Prevention with Celecoxib (APC) study, conducted in patients with adenomatous colorectal polyps, celecoxib (200 or 400 mg twice daily) was associated with a cardiovascular risk almost three-times higher than that of placebo (RR 2.8, CI 1.3–6.3) [8]. An increased cardiovascular risk, with respect to placebo, was also seen with valdecoxib (and its precursor parecoxib) in patients undergoing a coronary bypass [9,10]. It is likely that, in similar studies, without evidence of increased cardiovascular risk, this was actually due to insufficient statistical power (inadequate number, inclusion of a lowrisk population and low number of adverse events overall) more than intrinsic properties of that particular coxib!

Riboflavin in innate and acquired immune responses

Riboflavin, also known as vitamin B2, is a micronutrient with a key role in maintaining human health. It has also been shown to enhance host resistance to bacterial infections in mice. The aim of this study was to assess the role of vitamin B2 treatment in inflammatory conditions. Three models of inflammatory states were assessed. One of them encompasses neutrophil mediated but T cell/macrophage independent cutaneous inflammation. Another one is delayed type hypersensitivity reaction (DTH), a T cell/macrophage dependent but neutrophil independent inflammatory response. The third one is collagen- induced arthritis, having components from both of the above described reactions. Mice were treated with vitamin B2, administered by peritoneal injections, throughout the course of the experiments. The granulocyte dependent reaction to olive oil was significantly reduced in vitamin B2 treated mice. In contrast, DTH reactivity and collagen II arthritis were not affected by the treatment. Riboflavin administration affects neutrophil migration but does not alter acquired immune responsiveness.

EFFECT OF DIODE LASER IRRADIATION ON INTERLEUKIN-8 PRODUCTION BY HUMAN NEUTROPHILS

Low reactive-level laser therapy (LLLT) is a safe and easy therapeutic modality and now utilized in the treatment of inflammatory conditions. However, the clinical evidence base for such application remains sparse. This study was designed to examine the effects of LLLT on production of interleukin-8 (IL-8) by human neutrophils. Neutrophils, separated from blood drawn from 10 healthy volunteers, received laser irradiation (150 mW/cm2) for 30 or 60 sec at 60 min prior to or just before the stimulation with opsonized zymosan. These conditions had different effects on production of reactive oxygen species by neutrophils. After the incubation at 37 °C for 3 and 9 hours, the concentration of IL-8 was measured by ELISA. The concentration of IL-8 was higher when neutrophils were incubated longer. However, the levels of IL-8 production by irradiated neutrophils did not differ from those of unirradiated neutrophils even under the conditions whereby both the period of irradiation and the duration from irradiation to stimulation were different. IL-8 production by neutrophils may not play a role in the therapeutic effects of LLLT in inflammatory conditions.

Are All COX-2 Inhibitors Created Equal?

Prostaglandins (PGs) are biologically active lipids derived from the cyclooxygenase (COX)-mediated metabolism of arachidonic acid. They are constitutively produced in certain tissues (eg, brain, gut, and kidney), and their synthesis is increased at sites of inflammation. Prostanoids function as important mediators of inflammation and modulate a variety of physiological processes, including maintenance of gastric mucosal integrity, renal hemodynamic regulation, renin synthesis and release, and tubular reabsorption of salt and water.1 Cyclooxygenase, or PG synthase G2/H2, is the rate-limiting enzyme responsible for the initial conversion of arachidonic acid to PGG2 and subsequently to PGH2. PGH2 is then metabolized by tissue-specific isomerases to produce prostaglandins and thromboxanes. There are 2 distinct isoforms of cyclooxygenase, COX-1 and COX-2, which share 66% homology in amino acid sequence 2–4 but have different patterns of expression and regulation. COX-1, traditionally termed the “constitutive” enzyme, is widely distributed in tissues, and its level of activity is not dynamically regulated. COX-2, the glucocorticoid-sensitive “inducible” enzyme, is more restricted in its basal expression and is upregulated in response to inflammation, resulting in increased prostanoid production at the site of inflammation. NSAIDs, which block both isoforms COX-1 and COX-2, have been widely used in the treatment of inflammatory conditions. However, the adverse effects of NSAIDs, especially gastrointestinal toxicity, have limited their long-term use in clinical settings. The hypothesis that NSAID-induced gastrointestinal toxicity was related to the inhibition of gastric COX-1, whereas the anti-inflammatory properties caused by COX-2 inhibition5 led to the development of the new antiinflammatory agents, the coxibs, which were designed to inhibit COX-2 selectively. It was anticipated that these selective COX-2 inhibitors would be as effective as the nonselective NSAIDs in the treatment of inflammatory diseases but would be better-tolerated with fewer gastrointestinal side effects. Rofecoxib (Vioxx) and celecoxib (Celebrex) were the first COX-2–selective inhibitors to be marketed as effective antiinflammatory agents without serious gastrointestinal toxicity, based on the results of the VIoxx Gastrointestinal Outcomes Research (VIGOR) trial6 and the Celecoxib Long term Arthritis Safety Study (CLASS) trial, 7 respectively. The VIGOR trial reported that patients with rheumatoid arthritis receiving rofecoxib (50 mg daily) had fewer gastrointestinal events compared with those taking naproxen (500 mg twice daily) (2.1% versus 4.5%; P0.001), but there was similar efficacy between the drugs. However, the incidence of myocardial infarction was increased by a factor of 5 in the rofecoxib-treated group compared with the naproxen group. In the CLASS trial, celecoxib (400 mg twice daily) was compared with ibuprofen (800 mg thrice daily) or diclofenac (75 mg twice daily) in patients with osteoarthritis or rheumatoid arthritis. Celecoxib had a lower gastrointestinal side effect profile compared with other NSAIDs, and there was no difference in the incidence of cardiovascular events between celecoxib and NSAIDs regardless of aspirin use. Questions regarding the cardiovascular risk of the various coxibs remained, and on September 30, 2004 rofecoxib was withdrawn from the market based on the data from the Adenomatous Polyp PRevention On Vioxx (APPROVe) study. 8 This trial was prematurely discontinued after it was discovered that 3.5% of the patients treated with rofecoxib (25 mg once daily) had serious thromboembolic adverse events compared with 1.9% of patients in the placebo group (P0.001).8,9 The

Mast cells and mast cell mediators as targets of dietary supplements

To review the increasing amount of data that support or dispel the use of dietary supplements in the treatment of inflammatory conditions that involve mast cells, such as allergies, arthritis, and chronic pelvic pain syndrome. A search was conducted in MEDLINE for natural substances, dietary supplements, flavonoids, and proteoglycans for their in vitro or in vivo effects on allergic and inflammatory conditions. Studies were selected for inclusion because of the impact factor of the journal, the definitive nature of the findings, the soundness of the study design, and the expert opinion of the authors. Dietary supplements include a large group of products, such as vitamins, minerals, plant, or animal extracts, as well as herbal preparations that are often called medicinal herbs. Many of the available dietary supplements contain a multitude of ingredients, the source and/or purity of which is seldom disclosed; some of these may have biologic effects of their own or may interact with other supplements or drugs, often leading to adverse effects. The most well-documented evidence published to date is on the inhibitory action of natural compounds, especially flavonoids, on mast cells and allergic symptoms. Some flavonoids have weak inhibitory activity, whereas others may have no benefit or may be detrimental. Sulfated proteoglycans could provide synergistic action but require formulations with increased absorption. Combining the most active flavonoids with proteoglycans could be helpful in atopic and inflammatory conditions. However, a complete list of active ingredients and their source, purity, and exact concentration should be a requirement for nutraceuticals to standardize, compare, and promote their safe use.

Protease Inhibitors of the Sulfonamide Type: Anticancer, Antiinflammatory, and Antiviral Agents

AbstractFor Abstract see ChemInform Abstract in Full Text.

Antiinflammatory and antiulcer activities of Bambusa arundinacea

The extracts of Bambusa arundinacea have been used in Indian folk medicine to treat various inflammatory conditions. The plant has got antiulcer activity also. It is thought that these two properties in the same extract are very much useful in the treatment of inflammatory conditions. It is well known fact that the most of the available antiinflammatory drugs are ulcerogenic. The antiinflammatory effect of the methanol extract of the leaves of Bambusa arundinacea against carrageenin-induced as well as immunologically induced paw oedema and also its antiulcer activity in albino rats have been studied and found to be significant when compared to the standard drugs. The combination of methanol extract and phenylbutazone (Non-Steroidal Antiinflammatory Agent, NSAIA) has been studied and found to be the most potent antiinflammatory activity experimentally with least toxic (no ulcerogenic) activity. Thus, the combination of herbal product (methanol extract of Bambusa arundinacea) with modern medicine (NSAIAs) will produce the best antiinflammatory drug and will be useful for long-term treatment of chronic inflammatory conditions like rheumatoid arthritis with peptic ulcer, which are common.

Protease inhibitors of the sulfonamide type: anticancer, antiinflammatory, and antiviral agents.

The sulfonamides constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, anticarbonic anhydrase, diuretic, hypoglycemic, and antithyroid activity among others. A large number of structurally novel sulfonamide derivatives have ultimately been reported to show substantial protease inhibitory properties. Of particular interest are some metalloprotease inhibitors belonging to this class, which by inhibiting several matrix metalloproteases (MMPs) show interesting antitumor properties. Some of these compounds are currently being evaluated in clinical trials. The large number of sulfonamide MMP inhibitors ultimately reported also lead to the design of effective tumor necrosis factor-alpha converting enzyme (TACE) inhibitors, potentially useful in the treatment of inflammatory states of various types. Since both MMPs and TACE contribute synergistically to the pathophysiology of many diseases, such as arthritis, bacterial meningitis, tumor invasion; the dual inhibition of these enzymes emerged as an interesting target for the drug design of anticancer/antiinflammatory drugs, and many such sulfonamide derivatives were recently reported. Human neutrophyl elastase (HNE) inhibitors of the sulfonamide type may also be useful in the treatment of inflammatory conditions, such as emphysema, cystic fibrosis, chronic bronchitis, ischemia reperfusion injury, and acute respiratory distress syndrome. Inhibition of some cysteine proteases, such as several caspase and cathepsin isozymes, may lead to the development of pharmacological agents effective for the management of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, brain damage, and stroke. Another research line that progressed much in the last time regards different sulfonamides with remarkable antiviral activity. Some clinically used HIV protease inhibitors (such as amprenavir) possess sulfonamide moieties in their molecules, which are critical for the potency of these drugs, as shown by means of X-ray crystallography, whereas a very large number of other derivatives are constantly being synthesized and evaluated in order to obtain compounds with lower toxicity or augmented activity against viruses resistant to the such first generation drugs. Other viral proteases, such as those isolated from several types of herpes viruses may be inhibited by sulfonamide derivatives, leading thus to more effective classes of antiviral drugs.

Pyrrolidine dithiocarbamate is a potent antioxidant against hypochlorous acid-induced protein damage

The antioxidant potential of the dithiol compound pyrrolidine dithiocarbamate (PDTC) against protein damage induced by hypochlorous acid (HOCl) was investigated. The effects of PDTC were compared to those of reduced glutathione (GSH) and N-acetylcysteine (NAC). PDTC markedly and in a concentration-dependent manner inhibited HOCl-induced inactivation of α 1-antiproteinase, protein carbonyl formation on serum albumin and oxidation of human low-density lipoprotein. The direct scavenging of HOCl by PDTC was demonstrated by two quantitative methods, oxidation of ferrocyanide and chlorination of monochlorodimedon. In all assay systems, PDTC was two to three times more potent than GSH and NAC, while diethyldithiocarbamate was about as effective as PDTC. These data demonstrate that PDTC is a potent antioxidant against HOCl-induced protein oxidative damage, suggesting that PDTC might be useful in the prevention and treatment of inflammatory conditions.

HPTLC determination of diclofenac sodium from serum

Diclofenac sodium is one of the potent Non Steroidal Anti-Inflammatory Drugs (NSAID) used in the treatment of inflammatory conditions. The present work deals with the estimation of diclofenac sodium from serum by a novel High Performance Thin Layer Chromatographic (HPTLC) method developed in our laboratory. Standard diclofenac sodium was spotted on Silica Gel 60 F 254 precoated plates, which were developed using the mobile phase toluene:acetone:glacial acetic acid (80:30:1,v/v/v). Densitometric analysis of diclofenac sodium was carried out at 280 nm with diclofenac being detected at an R f of 0.58. The method was subsequently developed to estimate diclofenac sodium from serum. Diclofenac sodium was extracted with ethyl acetate from serum samples, spotted on Silica Gel 60 F 254 plates and the plates were developed using the above mentioned mobile phase. The method was validated for selectivity, extraction efficiency, sensitivity, accuracy, and intra and inter-day reproducibility studies. The extraction efficiency was found to range from 76 to 80%. The Limit of Detection (LOD) and Limit of Quantification (LOQ) of diclofenac sodium in serum were found to be 90 and 120 ng, respectively. The calibration curve of diclofenac sodium in serum was found to be linear in the range of 200–800 ng. The mean values (±S.D.) of correlation coefficient, slope and intercept were found to be 0.9876 (±0.0105), 0.0228 (±0.0036) and 6.15 (±1.4), respectively. The mean percentage coefficient of variation for accuracy, intra-day and inter-day analysis at 200–800 ng of diclofenac sodium were found to be 3.2, 6.35 and 8.025, respectively. The proposed method is a simple and sensitive method with good precision and reproducibility for the estimation of diclofenac sodium form serum samples.

Antiinflammatory activity of rotenoids from Clitoria fairchildiana.

Five structurally related rotenoids were isolated from the roots of Clitoria fairchildiana. The antiinflammatory activity was investigated using a capillary permeability assay. The protective effect was measured as the inhibition in vascular permeability produced by acetic acid in the peritoneal cavity. The results suggest that for maximum activity the maintenance of the B/C ring junction integrity is important. These findings support the traditional use of Clitoria species extracts in the treatment of inflammatory conditions.

Behandlung der oberflächlichen Thrombophlebitis

Superficial thrombophlebitis is a frequently occurring disease which, because of risk factors, affects women to a greater extent than men. The presence of deep venous thrombosis should be excluded by imaging procedures. Heparin or low-molecular weight heparins are indicated for treatment, if deep venous thrombosis is present or threatening. In the acute stage non-steroidal antiinflammatory drugs can be taken orally in order to alleviate pain and inflammation. In the case of concomitant chronic venous insufficiency, edema protective drugs (e. g. preparations containing horse chestnut extract and flavonoids) can support the therapy. For the treatment of inflammatory conditions in relatively short superficial vein segments without involvement of the deep venous system, a limitation to topical treatment is possible. In addition to compression therapy, the application of creams or gels containing heparin or heparinoids are the usual treatment approach. The use of topical products containing mucopolysaccharide polysulfate (MPS) has been proven to be beneficial. The problem of providing evidence of the efficacy of topical products in the therapy for superficial thrombophlebitis under the current strict demands of our regulatory authorities and of developing new products under these conditions is discussed.

The Role of Thalidomide in the Treatment of Rheumatic Disease

Thalidomide was first introduced in 1956 as a sedative hypnotic in Europe and Asia but was soon withdrawn from the market because of its association with severe birth defects. It has experienced a resurgence of interest in recent years as a treatment for inflammatory conditions. Since Jacob Sheskin's linkage of thalidomide with improvement of refractory inflammatory dermatoses, such as erythema nodosum leprosum in the 1960's, more recent work has centered on thalidomide's use in inflammatory rheumatologic conditions. There are varying levels of evidence supporting thalidomide's efficacy in Behcet's disease, refractory oral-genital ulcerations, cutaneous lupus erythematosus, RA, and sarcoidosis, although dosing, clinical response, and frequency of toxicity are variable. Thalidomide seems to have anti-inflammatory, immunomodulatory, and anti-angiogenic properties. It is not clear which of these mechanisms are chiefly responsible for the drug's clinical efficacy. Because of its potential for causing serious and less serious toxic effects, thalidomide should be reserved for the treatment of disease refractory to conventional therapy. In addition to its well known teratogenic potential, thalidomide-induced peripheral neuropathy, in some cases irreversible, has been documented in patients undergoing chronic therapy. Guidelines have been published, and a cooperative effort between the drug manufacturer, Celgene, and the US Food and Drug Administration has resulted in the establishment of a rigorous program governing both the dispensing of thalidomide and monitoring for side effects. Judicious patient selection and intense patient education remain the cornerstone of the safe use of thalidomide.

MDP(Lysyl)GDP, a Nontoxic Muramyl Dipeptide Derivative, Inhibits Cytokine Production by Activated Macrophages and Protects Mice from Phorbol Ester- and Oxazolone-Induced Inflammation

High levels of pro-inflammatory cytokines and nitric oxide are proposed to orchestrate pathophysiologic mechanism(s) associated with various inflammatory dermatoses. This study examines whether a water soluble 3-O-[N-acetylmuramyl-L-lysyl-D-iso]-2-di-on-glycine [MDP(Lysyl)GDP], a nontoxic and nonpyrogenic derivative of muramyl dipeptide (MDP), can inhibit the in vitro production of inflammatory mediators by lipopolysaccharide- or interferon-gamma-activated macrophages, and whether such an inhibitory effect can translate into in vivo protection of mice from irritant and allergic contact dermatitis. Thioglycollate-elicited peritoneal macrophages cultured in medium alone or in medium supplemented with MDP(Lysyl)GDP (1-100 microg per ml) expressed neither mRNA transcripts for inducible nitric oxide synthase, interleukin-1beta, and tumor necrosis factor-alpha, nor cytokine proteins and nitric oxide activity. Incubation of the cells with either lipopolysaccharide or interferon-gamma for 6 h resulted in a significant induction of inducible nitric oxide synthase, interleukin-1beta, and tumor necrosis factor-alpha mRNA, and the accumulation of high levels of monokines and nitrites in cultures by 24 h. Co-incubation of the macrophages with lipopolysaccharide or interferon-gamma and MDP(Lysyl)GDP (1-100 microg per ml) resulted in a concentration-dependent suppression of the steady-state mRNA transcripts for inducible nitric oxide synthase, tumor necrosis factor-alpha, and interleukin-1beta, induced by lipopolysaccharide, but not by interferon-gamma. In mouse models of phorbol ester- and oxazolone-induced ear inflammation, topical application of MDP(Lysyl)GDP significantly suppressed ear swelling in a dose-dependent manner. Likewise, oral treatment with MDP(Lysyl)GDP at days -3, -2, and -1 before elicitation with oxazolone also significantly inhibited ear inflammation. Taken together, our findings suggest that MDP(Lysyl)GDP has the potential to be a therapeutic application in the treatment of inflammatory conditions in which overproduction of pro-inflammatory mediators are implicated to play a pathogenic role.

Experimental evaluation of stem bark ofStryphnodendron adstringens (Mart.) Coville for antiinflammatory activity

The acetone soluble fraction from the crude extract of Stryphnodendron adstringens stem bark was evaluated in acute and chronic models of inflammation. It was found to cause significant inhibition of rat paw oedema induced by carrageenan and dextran; the exudate volume and migration of leukocyte number in the rat pleurisy test and also in the hind paw swelling in rats on Freund's adjuvant-induced arthritis. In addition, it significantly decreased the vascular permeability increase caused by intraperitoneal acetic acid in mice. These findings support the traditional use of S. adstringens bark extracts in the treatment of inflammatory conditions. © 1998 John Wiley & Sons, Ltd.