Antiphlogistic Agents Research Articles

Differential inflammatory conditioning of the bone marrow by acute myeloid leukemia and its impact on progression

AbstractInflammation promotes solid tumor progression, but how regulatory mechanisms of inflammation may affect leukemia is less well studied. Using annexin A5 (ANXA5), a calcium-binding protein known for apoptosis, which we discovered to be differentially expressed in the bone marrow microenvironment (BMM) of mice with acute myeloid (AML) vs chronic myeloid leukemia, as a model system, we unravel here a circuit in which AML–derived tumor necrosis factor α (TNF-α) dose-dependently reduces ANXA5 in the BMM. This creates an inflammatory BMM via elevated levels of prostaglandin E2 (PGE2). Via binding to its EP4 receptor, PGE2 increases β-catenin and hypoxia-inducible factor 1α signaling in AML cells, thereby accelerating PGE2-sensitive AML. Human trephine biopsies may show lower ANXA5 expression and higher PGE2 expression in AML than other hematologic malignancies. Furthermore, syngeneic and xenogeneic transplantation models suggest a survival benefit after treatment with the inhibitor of prostaglandin-endoperoxide synthase 2 (cyclooxygenase 2 [COX2]), celecoxib, plus cytarabine in those AML types highly sensitive to PGE2 compared with cytarabine alone. Taken together, TNF-α/ANXA5/NF-κB/COX2/PGE2–mediated inflammation influences AML course in a highly differential and circular manner, and patients with AML with “inflammatory AML” may benefit from antiphlogistic agents as adjunct therapy.

Significant pharmacological activities of benzoquinazolines scaffold.

Benzoquinazolines, the essential constituents of numerous well-known heterocyclic systems, have occupied a prominent position and played a significant part in the synthesis of various pharmaceutical compounds. The wide range of pharmacological effects attributed to benzoquinazolines has been the subject of extensive study. These include their roles as anticancer, antimicrobial, anti-monoamine oxidase, anticonvulsant, antiviral, antinociceptive, antioxidant, antineoplastic, antituberculosis, antiplatelet, and antiphlogistic agents. This work provides an attempt at a literature review of the pharmacological activities of benzoquinazoline derivatives, including an up-to-date account of recent research findings, and suggests avenues for future exploration in the pursuit of more potent and specific analogues for a wide range of biological targets using this platform.

Effects of add-on Celecoxib treatment on patients with schizophrenia spectrum disorders and inflammatory cytokine profile trial (TargetFlame): study design and methodology of a multicentre randomized, placebo-controlled trial

Neuroinflammation has been proposed to impact symptomatology in patients with schizophrenia spectrum disorders. While previous studies have shown equivocal effects of treatments with add-on anti-inflammatory drugs such as Aspirin, N-acetylcysteine and Celecoxib, none have used a subset of prospectively recruited patients exhibiting an inflammatory profile. The aim of the study is to evaluate the efficacy and safety as well as the cost-effectiveness of a treatment with 400 mg Celecoxib added to an ongoing antipsychotic treatment in patients with schizophrenia spectrum disorders exhibiting an inflammatory profile. The “Add-on Celecoxib treatment in patients with schizophrenia spectrum disorders and inflammatory cytokine profile trial (TargetFlame)” is a multicentre randomized, placebo-controlled phase III investigator-initiated clinical trial with the following two arms: patients exhibiting an inflammatory profile receiving either add-on Celecoxib 400 mg/day or add-on placebo. A total of 199 patients will be assessed for eligibility by measuring blood levels of three pro-inflammatory cytokines, and 109 patients with an inflammatory profile, i.e. inflamed, will be randomized, treated for 8 weeks and followed-up for additional four months. The primary endpoint will be changes in symptom severity as assessed by total Positive and Negative Syndrome Scale (PANSS) score changes from baseline to week 8. Secondary endpoints include various other measures of psychopathology and safety. Additional health economic analyses will be performed. TargetFlame is the first study aimed at evaluating the efficacy, safety and cost-effectiveness of the antiphlogistic agent Celecoxib in a subset of patients with schizophrenia spectrum disorders exhibiting an inflammatory profile. With TargetFlame, we intended to investigate a novel precision medicine approach towards anti-inflammatory antipsychotic treatment augmentation using drug repurposing. Clinical trial registration:http://www.drks.de/DRKS00029044 and https://trialsearch.who.int/Trial2.aspx?TrialID=DRKS00029044

Bipolar affective disorder: A review of novel forms of therapy

Abstract Normothymic, antidepressant and antipsychotic pharmaceutics are, in accordance with international guidelines, employed both in the therapy and the prevention of bipolar disorder (BD). Long-term studies on the mechanisms of action of such medications, as well as on the pathogenetic background of BD, have led to the discovery of effective, albeit unconventional pharmacotherapeutic approaches. These methods have the potential to successfully treat mania and depression, as well as to counter affective episode relapse. Allopurinol - commonly used to treat gout, secondary hyperuricemia and Lesch-Nyhan syndrome, acts by inhibiting the synthesis of uric acid, levels of which are often increased in manic patients. Due to this, an evaluation of the potential effect of allopurinol on the reduction of mania symptoms seems to be reasonable. Additionally, the numerable research papers coming out of research regarding the role of purine neurotransmitters in mood alterations, indicate that adenosine agonists act analogously to dopamine antagonists. N-acetylcysteine (NAC), a supporting agent in the pharmacotherapy of depressive episodes in bipolar disorder, substantially accelerates mood stabilization in patients. In turn, memantine, known for its procognitive effect, not only has antimanic and normothymic properties, but also boosts the neuroprotective action of traditional lithium therapy. In view of the latest opinions, the subtle pro-inflammatory process is typical for the pathophysiology of bipolar disease. Acetylsalicylic acid (ASA) (a popular analgesic, antipyretic and antiphlogistic agent) may be useful in BD therapy. This is because that, via its effect upon cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), ASA modulates leukocyte recruitment in neuro-inflammation. Apart from the above-mentioned medications, this article introduces the results of recent investigations of ketamine, modafinil and tamoxifen, including their receptor mechanisms, as well as certain genetic aspects or elements of their pharmacodynamics, for use in BD therapy. We put forward that, possibly, more insightful cognition of these drugs will allow significant enrichment in the range of pharmacotherapy for BD in the near future.

Effect of the Achillea wilhelmsii extract intake upon blood lipid profile, haematologic and immunologic parameters in the rat

Achillea species are widely used in folk medicine as antispasmodic, choloretic, antiphlogistic, antifungal and antibacterial agents, but little is known about their effects on the immune system and blood lipid profile. In this study, effects of the Achillea wilhelmsii methanolic extracts (ME) upon the lipid, haematological parameters and immune system were examined. ME was given at dose 75 mg/kg/day for 30 days to Sprague–Dawley rats fed with high-fat diet. Haematology, flow cytometry, clinical, biochemical and histopathological examinations were performed in the sacrificed animals. Significant decreases in triglyceride and very low density lipoprotein cholesterol, and increases in CD4 expression in lymphocytes and monocytes were observed. Assessment of alanin aminotransferase, aspartat aminotransferase activities, histopathological examinations and proinflammatory cytokine levels (IL-1β, IL-6, IL-10, TNF-α) showed neither liver damage nor inflammation induction. Beside the improvements in lipid profile by ME treatment without any liver damage and inflammation, the increase of CD4 expression both on lymphocyte and monocyte populations need further investigation.

Electrospinning of multicomponent ultrathin fibrous nonwovens for semi‐occlusive wound dressings

This work describes the design and assembly of multifunctional and cost-efficient composite fiber nonwovens as semi-occlusive wound dressings using a simple electrospinning process to incorporate a variety of functional components into an ultrathin fiber. These components include non-hydrophilic poly(L-lactide) (PLLA) as fibrous backbone, hydrophilic poly(vinyl pyrrolidone)-iodine (PVP-I), TiO(2) nanoparticles, zinc chloride as antimicrobial, odor-controlling, and antiphlogistic agents, respectively. The process of synthesis starts with a multicomponent solution of PLLA, PVP, TiO(2) nanoparticles plus zinc chloride, in which TiO(2) nanoparticles are synthesized by in situ hydrolysis of TiO(2) precursors in a PVP solution for the sake of obtaining the particle-uniformly dispersive solution. Subsequent electrospinning generates the corresponding composite fibers. A further iodine vapor treatment to the composite fibers combines iodine with PVP to produce the PVP-I complexes. Experiments indicate that the assembled composite fibers (300-400 nm) possess the ointment-releasing characteristic and the phase-separate, core-sheath structures in which PVP-I residing in fiber surface layer becomes the sheath, and PLLA distributing inside the fiber acts as the core. Based on this design, the structural advantages combining active components endow the assembled composite nonwovens with a variety of functions, especially, the existence of PVP-I, endows the nonwoven with water absorbability, antimicrobial activity, adhesive ability, and transformable characteristic from hydrophilicity to non-hydrophilicity. The multifunctional, cost-efficient, and ointment-releasing characteristics make the multicomponent composite fibrous nonwovens potentially useful in applications such as initial stage of dressing of the cankerous or contaminated wounds.

Occurrence of a house-infesting Tropical rat mite ( Ornithonyssus bacoti) on murides and human beings

In Germany there is little information available about the distribution of the Tropical rat mite (Ornithonyssus bacoti) in rodents. A few case reports show that this haematophagous mite species may also cause dermatitis in man. All developmental stages are exclusively bloodfeeder. Three children (4, 11 and 15 years old) of a family and a 23-year-old medical student were attacked by the Tropical rat mite. Prior to the consultation of our institution, the patients' conditions had been diagnosed as allergic dermatitis of unclear origin and treated by several antiphlogistic agents, however without success. The conclusive diagnosis, Tropical rat mite dermatitis, was based on the identification of the arthropod Ornithonyssus bacoti in the flats of the patients (husbandry of gerbils, etc.). The diagnosis of a Rat mite dermatitis requires the detection of the parasite, which is more likely to be found in the environment of its host than on the hosts' skin itself.

Tropical Rat Mites as newly emerging disease pathogens in rodents and man

Different mite species, generally found on various animals, may temporarily also infest man and consequently, such arthropods may be responsible for pruritic skin reactions which are often misdiagnosed. Mite dermatitis caused by the Tropical Rat Mite Ornithonyssus bacoti occurs in several small mammals and rodents under tropical and temperate climatic conditions. This mite was identified in 1923 as a cause of human dermatitis in the United States. In Europe, the Tropical Rat Mite was first detected in the German seaport of Hamburg in 1931, a site indicating the mite was carried across the oceans along with infested ship rats, probably in the times of sailing vessels. According to various observations in Germany, O. bacoti appears in wild rodents more frequently than it seems. In most cases, symptoms of mites are recognized only when they attack humans, but the diagnosis of a rat mite dermatitis requires identification of the parasite, which however is more likely to be found in the environment of its host than on the hosts’ skin itself. Here, three different outbreaks from Bavaria are reported. As a clinical example is presented the case of a 23-year-old medical student and several other residents inhabiting a rat- and mice-infested house in Munich. The arthropods originally came from an Italian restaurant and surrounding facilities. Mites were found in large number in the students’ flat. The patient was suffering from severe itching and papular urticaria. He consulted a dermatology clinic complaining of a pruritic dermatitis for at least 2 weeks. Dermatitis was misdiagnosed as allergy, treatment with the antiphlogistic agent fluocinolonacetonid remained unsuccessful. Eradication of rodents and treatment of the rooms of the house with a pyrethroid were performed to prevent reinfestations. O. bacoti is a periodic hematophageous parasite and spends relatively short time on a host. Causal therapy by antiparasitic agents on human patients is not necessary. If indicated, treatment should be symptomatic.

Pharmaceutical Efficacy of Moxa (Artemisia asiatica)

Recently the study reported that a compound isolated from the tar of Artemisia asiatica, which is produced by burning moxa, was identical with authentic catechin (or called catechol) in infrared and proton NMR spectra. Catechin (1,2-dihydroxybenzene) has been known as an antioxidant and anti-inflammatory suppresive effects by the formation of TBA-reactive substances in the human skin. In this study the water extract of moxa was characterized which was obtained by steamed under a certain pressure cooker for 48 hours with several known anti-inflammatory drugs (antiphlogistic agent) as well as catechin. Furthermore, successful clinical experiments with moxa of various diseases or symptoms such as bronchitis, ashmatic patients, and dermatitis have been carried out. Subsequent experiment has been undertaken simultaneously. The moxa was treated and prepared as oral, mugwort-moxibustion pipe like cigarette (designated as SSook-GunHyang Cho). Everyone has been reported that the feeling relaxes tense caused either by stress or by other psychogenic factors as well as healing effects to asthmatic patients. The anti-inflammatory effect was found tobe caused by well known drugs for antiphlogistic agent, coumarin obtained from a plant of melilotus officinalis L. plus bromelain/bromelin (a protease obtained from the pineaple juice). Consequently, the reason of the wart cured by performing moxibustion on the focal lesion of a vulgar wart may be explained as benign tumor or letting a mixture of moxa-burnt ash penetrate into it rests in the synergic action of catechin contained in moxa-tar and minerals (about 5% of ash content of moxa) along with antiphlogistic agent.

Evaluations of Saponin Properties of HPLC Analysis of Platycodon grandiflorum A.DC.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Ineffective Elimination of Leishmania Major by Inflammatory (MRP 14-Positive) Subtype of Monocytic Cells

Myeloid-related protein (MRP) 14, an intracellular protein involved in calcium-dependent activation of myeloid cells, presents a differentiation marker for a subtype of macrophages. In experimental leishmaniasis, BALB/c mice succumb to visceral dissemination after infection with L. major, due to a Th2 cell response, while C57Bl/6 mice develop protective immunity associated with a Thl cell response. We have previously shown that resistance in C57Bl/6 mice was also associated with a significantly lower percentage of MRP14-positive cells in the infiltrate than in susceptible BALB/c mice. In C57Bl/6 mice, weekly injections of bone marrow (BM) cells enriched with MRP14-positive cells (dl of culture) did not reverse, but prolonged the course of infection, associated with increased local parasite spread. In BALB/c mice a single dose of an antiphlogistic agent (dexamethasone or lipoxygenase inhibitor) was associated with reduction of infiltrating MRP14-positive cells and also with a decrease of parasite loads in footpads, lymph nodes as well as spleens, and with delayed progression of disease. Double labeling experiments in vitro revealed that at least 43.1 % of MRP14-positive mononuclear cells in BM cultures (8h) had phagocytosed parasites after 4 h of co-incubation. Activation by IFN-γ (20 U/ml) for 24h and 48h did not significantly reduce parasite load in these cells. In contrast, 77.0% of F4/80-positive macrophages (6d of culture) were infected with L. major parasites and these cells responded to activation with IFN-γ (20 U/ml) with significant reduction of parasite load (25.3%). The protein MRP14 did not have an effect on parasite survival in vitro. Thus, the impaired capability of MRP14-positive cells to kill L. major upon stimulation may be one reason for the adverse course of infection observed with their increased appearance.

Effect of diclofenac on human osteoblasts and their stromal precursors in vitro in relation to arthroplasty

Results of animal experiments have demonstrated that the osseous integration of non-cemented prostheses can, at the very least temporarily, be impaired by the application of non-steroidal antiphlogistic agents (such as diclofenac). It is the objective of this study to examine whether there is a direct influence of diclofenac used in usual clinical dosages (3 times 50 mg daily) on bone cells and their progenitor cells which would explain the observed slow integration of the prostheses. To investigate this, cultivated human in vitro osteoblasts and stromal bone marrow cells were incubated with increasing doses of the medications. Our study focused on the effect of diclofenac application on proliferation and functional metabolism in both cell lines. The measurable maximal plasma concentration 2 h after the application of one tablet Voltaren 50 reached 1.6 micrograms/ml. This correlated with diclofenac concentrations between 1 and 10 ml found in our experiments. The detected values were correlated to the control group (0 microgram/ml diclofenac). The drug effect upon osteoblasts was higher than on progenitor cells. The proliferation of in vitro stromal bone marrow cells, compared to untreated cells, was found to be decreased. We observed a decrease to 82% at a diclofenac concentration of 1 microgram/ml, Osteoblasts exhibited a decrease to 97.5% at the same concentration. The DNA synthesis increased to 118% in stromal bone marrow cells, in osteoblasts to 144%. In contrast, we detected a neglectible decrease to 92% in the collagen synthesis of osteoblasts compared to untreated cells. The synthesis of osteocalcin by osteoblasts increased to 119%. The alkaline phosphatase activity was found to be decreased to 88% in stromal bone marrow cells and increased in osteoblasts to 111%. Temporary inhibiting effects on osseous integration in non-cemented prosthesis by diclofenac could be caused by a disturbance in the anabolic bone metabolism, exhibited by an increase of osteoblastic osteocalcin expression. Osteocalcin as a known negative regulator of the osteoneogenesis is most likely inhibiting the collagen matrix deposition.

In VivoSkin Penetration Studies of Chamomile Flavonoids

In vivo skin penetration studies of the Chamomile flavones apigenin, luteolin and apigenin 7-O-beta -glucoside were carried out with nine healthy, female volunteers. During seven h, the decline of flavonoid concn. in a satd. aq. alc. soln. filled in glass application chambers were repeatedly measured by spectrophotometry at fixed time periods. The max. fluxes were calcd. From the graph of the max. flux values as a function of time, it was concluded that the flavonoids are not only adsorbed at the skin surface, but also penetrate into deeper skin layers. This is important for their topical use as antiphlogistic agents.

Guidelines for Drug Treatment of Male Infertility

The prerequisite for rational therapy of male fertility disorders is an exact diagnosis. While the possibilities of influencing disturbances of spermiogenesis are limited, male adnexal diseases can be successfully treated in many cases. Drugs for the treatment of fertility disorders must be applied with this in mind, and empiric therapy is often performed in addition to causal treatment which, however, may be quite rationally determined. The therapeutic spectrum in andrology includes antibiotic and antiphlogistic agents, mast cell blockers, zinc, vitamins, and immunosuppressive drugs (corticosteroids). These agents are used for the treatment of inflammatory diseases of the testes and the accessory glands or for suppression of antispermatozoal antibodies. Hormonal disturbances are infrequently encountered by the andrologist, but they can be treated, with proven efficacy, with gonadotrophins, gonadotrophin-releasing hormone (GnRH) or androgens. In certain cases that are not hormonally related, the use of antiestrogens (clomifene, tamoxifen) as stimulating agents may be successful. Furthermore, tissue hormone releasing proteases (kallikrein) can be used both therapeutically (especially in motility disturbances that are not due to structural flagellar defects) and diagnostically (in order to distinguish between inflammatory and noninflammatory testicular damage). Anticholinergics and alpha-sympathomimetics are applied to ameliorate ejaculation or emission failure. In addition to a review of these treatment forms, the development of new concepts, e.g. angiotensin converting enzyme (ACE) inhibitors, is discussed.

ChemInform Abstract: (Benzo(4,5)cyclohepta(1,2‐b)thiophen‐4‐ylidene)acetic Acids: Novel Non‐ulcerogenic Antiinflammatory Agents.

AbstractIn order to find new antirheumatic and antiphlogistic agents some derivatives such as (IX) are prepared via the key intermediates (IV), which are formed by a new route.

鼻咽腔炎の処置後痛に対するスルガムの効果 消炎鎮痛剤薬効評価法への応用

鼻咽腔炎の処置後痛に対するスルガムの効果 消炎鎮痛剤薬効評価法への応用

非ステロイド系抗炎症剤（４８０１５６‐Ｓ）のプロプラノロール，ジアゼパム，ワーファリン，トルブタミド代謝に及ぼす影響

非ステロイド系抗炎症剤（４８０１５６‐Ｓ）のプロプラノロール，ジアゼパム，ワーファリン，トルブタミド代謝に及ぼす影響

A CASE OF DRUG-INDUCED ESOPHAGEAL ULCER

A case of esophageal ulceration caused by the antiphlogistic agent dicrophenac natrium was reported.A 77-year-old man suffered from a sensation of obstruction of the esophagus after taking a dicrophenac natrium tablet.Examination of the gastrointestinal tract 4 days later led to a suspicion of esophageal cancer.After 2 weeks, he came to this hospital because of the onset of hematemesis and tarry stools.An emergent esophagoscopy revealed multiple esophageal ulcers and a remnant of the drug in the upper portion of the intrathoracic esophagus.He was treated with antacids and a bland diet and improved rapidly.

Treatment of experimental lens-induced uveitis by dimethyl thiourea.

Dimethyl thiourea is a highly specific hydroxyl radical scavenger. The antiinflammatory potential of this hydroxyl radical scavenger was studied in Lewis rats sensitized with soluble lens protein. Intraperitoneal injection of dimethyl thiourea into the experimental animals at the onset of the disease resulted in marked reduction of intraocular inflammation, hemorrhage and edema, and eliminated the retinal and choroidal necrotizing vasculitis that was characteristic in untreated animals. These findings indicate that dimethyl thiourea may act as a potent antiphlogistic agent in the treatment of experimental lens-induced uveitis.

Synthesis of polymer bound antiphlogistic agents

AbstractDie kovalente Bindung der Antiphlogistika Mefenaminsäure, Flufenaminsäure und Indometacin an Eudragit® L 100 gelingt nach Derivatisierung mit einem N‐tritylgeschützten Aminoalkohol und anschließender Abspaltung der Schutzgruppe. Die Fixierung der derivatisierten Arzneistoffe erfolgt mittels Carbonyldiimidazol. Die quantitative Bestimmung der Arzneistoffe am Polymer wird UV‐spektroskopisch durchgeführt.