Osteonecrosis of the External Auditory Canal Associated With Oral Sorafenib Therapy: Sorafenib and Temporal Bone Osteonecrosis.

OBJECTIVE: To present the first case of osteonecrosis of the external auditory canal associated with sorafenib treatment. PATIENT: 58-year-old patient with right-sided otorrhea and otalgia was treated for otitis externa for 1 month without improvement. Otoscopic examination revealed a large defect in the inferior wall of the tympanic bone filled with skin debris and bony fragments. Previous medical history included treatment with sorafenib for metastatic renal cell cancer; he had never been exposed to radiotherapy. Computed tomography of the temporal bone showed a large right external auditory canal bony erosion with involvement of the tympanic bone and bony sequestra extending to the mastoid cells and temporomandibular joint. Histologic examination revealed necrotic bone and inflammatory changes with no signs of malignancy. A diagnosis of osteonecrosis of external auditory canal was made. INTERVENTION: Right subtotal petrosectomy with obliteration of surgical cavity with abdominal fat was performed. RESULTS: Final histological report revealed avascular necrosis of the bone with perivascular lymphocitic infiltration of the soft tissues. Diagnosis of medication-related external auditory canal osteonecrosis was confirmed. CONCLUSION: Medication-related osteonecrosis of the temporal bone is not a well-known entity among otolaryngologists and could therefore be misclassified as another diagnosis. In patients with othorrea and earache following sorafenib treatment, temporal bone osteonecrosis should be suspected.

Computational and Biological Comparisons of Plant Steroids as Modulators of Inflammation through Interacting with Glucocorticoid Receptor.

Despite the usefulness of glucocorticoids, they may cause hazardous side effects that limit their use. Searching for compounds that are as equally efficient as glucocorticoids, but with less side effects, the current study compared plant steroids, namely, glycyrrhetinic acid, guggulsterone, boswellic acid, withaferin A, and diosgenin with the classical glucocorticoid, fluticasone. This was approached both in silico using molecular docking against glucocorticoid receptor (GR) and in vivo in two different animal models. All tested compounds interacted with GR, but only boswellic acid and withaferin A showed docking results comparable to fluticasone, as well as similar in vivo anti-inflammatory effects, by significantly decreasing serum levels of interleukin-6 and tumor necrosis factor-α in cotton pellet-induced granuloma in rats. In addition, both compounds significantly decreased the percent of change in ear weight in croton oil-induced ear edema in mice and the granuloma weight in cotton pellet-induced granuloma in rats, to levels comparable to that of fluticasone. Both boswellic acid and withaferin A had no effect on adrenal index, but only withaferin A significantly increased the thymus index. In conclusion, boswellic acid may have comparable anti-inflammatory effects to fluticasone with fewer side effects.

Ginkgo biloba and Lycopene are Effective on Cisplatin Induced Ototoxicity?

OBJECTIVE: The purpose of this study was to examine the anti-ototoxic impact of Ginkgo biloba extract and lycopene on the model of cisplatin-induced ototoxicity in rats. MATERIALS AND METHODS: Thirty-two Wistar albino rats were examined with the distortion product otoacoustic emission (DPOAE) test (MADSEN Capella2 ; GN Otometrics, ICS Medical, Chicago USA), and they were randomly divided into four groups. Group 1 (n=8) was defined as the healthy control group. Cisplatin was given intraperitoneally as single dose of 12 mg/kg to group 2 (n=8), group 3 (n=8), and group 4 (n=8). Group 2 was determined as ototoxic control group. G. biloba extract (100 mg/kg) was given to group 3, and 20 mg/kg lycopene was given to group 4 with orogastric feeding tube daily for 10 days. DPOAE test was repeated on day 10 on all the groups. Finally, histopathological examination was performed. The study has been lead in agreement with the principles by the Institutional Animal Care and Use Committee Review Board at Kocaeli University Medical Center (KOÜ HADYEK- 1/9-14). The animals were treated in accordance with protocols approved by this committee. RESULTS: When DPOAE tests were compared, there was no significant difference in the four groups before the application (p > 0.05). At the end of day 10, in groups 2 to 4, statistically significant changes were observed (p < 0.05). According to the cisplatin group, a significant increase in the DP-grams on G. biloba and lycopene groups was observed (p < 00.5). Corti organ and spiral ganglion neurons of groups 1, 3, and 4 were observed to have weak expression. Strong reactions were determined in organum spirale and some spiral ganglions of the cisplatin group. The striae vascularis damage on group 2 was found to be more significant more compared with groups 3 and 4. CONCLUSION: There is a protective effect of G. biloba and lycopene on cisplatin-dependent ototoxic rat model.

Self-Nanoemulsifying Drug Delivery Systems Containing Plantago lanceolata-An Assessment of Their Antioxidant and Antiinflammatory Effects.

The most important components of Plantago lanceolata L. leaves are catalpol, aucubin, and acteoside (=verbascoside). These bioactive compounds possess different pharmacological effects: anti-inflammatory, antioxidant, antineoplastic, and hepatoprotective. The aim of this study was to protect Plantago lanceolata extract from hydrolysis and to improve its antioxidant effect using self-nano-emulsifying drug delivery systems (SNEDDS). Eight SNEDDS compositions were prepared, and their physical properties, in vitro cytotoxicity, and in vivo AST/ALT values were investigated. MTT cell viability assay was performed on Caco-2 cells. The well-diluted samples (200 to 1000-fold dilutions) proved to be non-cytotoxic. The acute administration of PL-SNEDDS compositions resulted in minor changes in hepatic markers (AST, ALT), except for compositions 4 and 8 due to their high Transcutol contents (80%). The non-toxic compositions showed a significant increase in free radical scavenger activity measured by the DPPH test compared to the blank SNEDDS. An indirect dissolution test was performed, based on the result of the DPPH antioxidant assay; the dissolution profiles of Plantago lancolata extract were statistically different from each SNEDDS. The anti-inflammatory effect of PL-SNEDDS compositions was confirmed by the ear inflammation test. For the complete examination period, all compositions decreased ear edema as compared to the positive (untreated) control. It can be concluded that PL-SNEDDS compositions could be used to deliver active natural compounds in a stable, efficient, and safe manner.

Evaluation of Biological Activity and Computer-Aided Design of New Soft Glucocorticoids.

Soft glucocorticoids are compounds that are biotransformed to inactive and non-toxic metabolites and have fewer side effects than traditional glucocorticoids. A new class of 17ß-carboxamide steroids has been recently introduced by our group. In this study, local anti-inflammatory activity of these derivatives was evaluated by use of the croton oil-induced ear edema test. Glucocorticoids with the highest maximal edema inhibition (MEI) were pointed out, and the systemic side effects of those with the lowest EC50 values were significantly lower in comparison to dexamethasone. A 3D-QSAR model was created and employed for the design of 27 compounds. By use of the sequential combination of ligand-based and structure-based virtual screening, three compounds were selected from the ChEMBL library and used as a starting point for the design of 15 derivatives. Molecular docking analysis of the designed derivatives with the highest predicted MEI and relative glucocorticoid receptor binding affinity (20, 22, 24-1, 25-1, 27, VS7, VS13, and VS14) confirmed the presence of interactions with the glucocorticoid receptor that are important for the activity.

Acral manifestations of contact dermatitis.

Contact dermatitis is a broad term that encompasses both nonimmunologic irritant contact dermatitis (ICD) and immunologically mediated allergic contact dermatitis (ACD). Both ICD and ACD can negatively affect a patient's quality of life and are a source of exorbitant medical and societal costs. Avoidance of inciting irritants and/or allergens and liberal use of emollients or humectants are the cornerstone of therapy. When an allergic cause is suspected, patch testing is highly encouraged. In this contribution, we highlight both the commonalities and differences of acral contact dermatitis as it relates to specific regions of the body. In addition, a review of the predisposing conditions, risk factors, and treatment options in the literature is presented to help with the care of these challenging patients.

The Incidence of Ototoxicity in Patients Using Iron Chelators.

OBJECTIVE: In this study, we aimed to detect the incidences of ototoxicity in patients with hemoglobinopathies taking deferoxamine (DFO), deferiprone, and deferasirox using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) scale to obtain more objective data. MATERIALS AND METHODS: Fifty-five transfusion-dependent patients were evaluated in this study. The NCI CTCAE scale was used to assess ototoxicity levels. The average ferritin and hemoglobin levels, the type of iron chelator, and the duration of therapy of all the patients were recorded. RESULTS: Ototoxicity was observed in 15 patients (31.9 %), all of whom were taking DFO. The median age was 19.5 (6-43) in patients without ototoxicity and 29 (16-50) in those with ototoxicity; this difference was statistically significant (p<0.05). The median ferritin and pre-tx Hb levels were 1391 ng/mL and 9.06 mg/dL, respectively, in patients with ototoxicity and 986.7 ng/mL and 9.24 mg/dL, respectively, in those without ototoxicity; these differences were not significant (p>0.05). Ototoxicity was not observed in the eight patients who used only deferasirox and deferiprone. CONCLUSION: The ototoxicity incidence with DFO at doses below 50 mg/kg/day was 27.3%. Deferiprone and deferasirox were not associated with ototoxic effects in patients taking these drugs.

Preventing amikacin related ototoxicity with N-acetylcysteine in patients undergoing peritoneal dialysis.

Amikacin is a frequently used antibiotic in the treatment of peritoneal dialysis (PD)-related peritonitis. Ototoxicity is a well-known complication of amikacin for which increased oxidative stress and free oxygen radicals are thought to be responsible. In this study, the effect of N-acetyl-cysteine (NAC) on cochlear function and oxidant situation in the amikacin related ototoxicity in PD-related peritonitis patients are investigated. Forty-six patients who had their first PD-related peritonitis attacks receiving empirical amikacin treatment were enrolled in the study. The patients were randomized into two groups; the first group (n = 23) as NAC receiving and the second group (n = 23) as a placebo receiving, control group. Otoacoustic emissions were measured before, 1 week after and 4 weeks after the treatment. Oxidative stress measurements were performed concurrently in order to evaluate the effectiveness of NAC. The results of screening with otoacoustic emission testing after amikacin treatment showed that cochlear function is protected especially in higher frequencies in NAC group when compared with the control group. Evaluation of the antioxidant status of the two groups showed no differences in the basal values, but at the first week there was an increase in the NAC group compared with the control group, and this increase became significant at the fourth week. NAC is found to be safe and effective in amikacin-related ototoxicity in patients with PD-related peritonitis. We suggest a close monitoring of the patients receiving amikacin containing treatment protocols and if amikacin is administrated supplementing the treatment with NAC.

Jellyfish model for ototoxicity.

OBJECTIVE: Pharmacologic ototoxicity is well described in the medical literature, yet efficient screening models are lacking. Aurelia aurita ephyrae, transparent jellyfish with identifiable hair cells, could be an effective model. Structural changes readily manifest behaviorally, and hair cells are easily stained and observed. We treated ephyrae with various gentamicin concentrations, evaluated its motility, and quantified its hair cell loss. STUDY DESIGN: Baseline pulsing per minute (P), swimming (S), and orientation (O) values were recorded from cultured ephyrae. Ephyrae were transferred into test tubes containing artificial seawater (ASW), gentamicin, or penicillin. P, S, and O were scored at 0, 24, and 48 hours. Ephyrae were formalin fixed, phalloidin stained, and imaged with confocal microscopy, and hair cells were then counted. RESULTS: P was impaired by gentamicin in a dose-dependent fashion, whereas ASW controls maintained baseline P, S, and O values. Impairment of S and O occurred with 3.5 mmol/L gentamicin at 24 hours. For six experiments each using 40 ephyrae, at 24 hours, average P was reduced from 75.2 in ASW to 28.8, 12.3, and 1.9 for 1, 2, and 3.5 mmol/L gentamicin, respectively (p < 0.05 for all cases). Hair cell loss at 24 and 48 hours was significant (32% and 48% reduction compared with control, p < 0.05) and correlated with motility deficits. Deficits from penicillin exposure were not statistically significant. CONCLUSION: The ephyra model demonstrated functional and histologic gentamicin-mediated impairments, showing promise as a screening tool for ototoxic agents. The changes in ephyra motility after gentamicin exposure correlated significantly with hair cell loss.

Cecropia pachystachya: a species with expressive in vivo topical anti-inflammatory and in vitro antioxidant effects.

Cecropia pachystachya is a species traditionally used in Brazil to treat inflammation. This work aims to evaluate the topical anti-inflammatory and antioxidant activities of the methanolic extract of C. pachystachya (CPM) and to perform its chemical fingerprint by HPLC-DAD. The topical anti-inflammatory activity was evaluated using the mouse models of acute ear inflammation induced by croton oil, arachidonic acid, capsaicin, EPP, phenol, and chronic inflammation induced by multiple application of croton oil. The in vitro antioxidant effect of CPM was investigated using DPPH, reducing power, ß -carotene bleaching, and TBARS assays. HPLC analysis was performed to quantify the antioxidant phenolics orientin, isoorientin, and chlorogenic acid previously identified in CPM. CPM exhibited significant anti-inflammatory effect in the acute models, in some cases comparable to the reference drugs. Histopathological analysis showed a moderate chronic skin anti-inflammatory effect with decrease in vasodilation, edema, cell infiltration, and epidermal hyperproliferation. It also showed strong in vitro antioxidant activity. The contents of orientin, isoorientin, and chlorogenic acid were 66.5 ± 1.8, 118.8 ± 0.7, and 5.4 ± 0.2 µg/mg extract, respectively. The topical anti-inflammatory activity of CPM could be based on its antioxidant properties, although other effects are probably involved, including COX inhibition and other mechanisms.

New phenylpropanoid and other compounds from Illicium lanceolatum with inhibitory activities against LPS-induced NO production in RAW 264.7 macrophages.

Illicium lanceolatum is a traditional Chinese medicine (TCM) for treating inflammatory diseases. Anti-inflammatory activities of I. lanceolatum stems and leaves were tested using ear edema models induced by dimethyl benzene in mice. Bioassay-guided fractionation of the ethanol extract of I. lanceolatum leaves and stems revealed that the ethyl acetate fraction exhibited inhibitory potency to dimethyl benzene-induced edema in the mouse ear. Phytochemical investigation on the active fraction led to the isolation of a new phenylpropanoid (1), together with fifteen known compounds. This is the first report of the isolation of 2-16 from I. lanceolatum. Of these compounds, compounds 1, 2 and 3 showed inhibitory activity on LPS-stimulated NO production in RAW 264.7 macrophages with IC50 values of 27.58, 26.59 and 34.35 µg/mL, respectively. I. lanceolatum stems and leaves can be exploited to alleviate inflammatory diseases, which makes the rare medicinal plant resources sustainable.

Ototoxicity of olive oil in a chinchilla animal model.

OBJECTIVES/HYPOTHESIS: Olive oil is often used by patients to soften ear wax or to relieve ear canal obstruction. It is also sold in drugstores as a cerumenolytic. To date, no study has assessed the safety of ototopical olive oil on hearing in the presence of tympanic membrane perforation. The present study aimed to assess the safety of ototopic olive oil on hearing in the presence of tympanic membrane perforation. STUDY DESIGN: Prospective, randomized, controlled trial in a chinchilla animal model. MATERIALS AND METHODS: Eleven chinchillas underwent bilateral myringotomy. In each animal, one ear was randomly assigned to receive olive oil (experimental ear), while the contralateral control ear received normal saline. Auditory brain response (ABR) test was performed at baseline and then 7, 14, and 30 days following the application. RESULTS: At 30 days follow-up, there was no significant change in auditory brain response thresholds at 8, 16, 20, or 25 kHz. Scanning electron microscope imaging showed no damage to the hair cells. CONCLUSION: Olive oil does not seem to cause hearing loss in chinchillas with perforated tympanic membranes. Future clinical studies are required.

Prevalence of ototoxicity in University of Benin Teaching Hospital, Benin city: a 5-year review.

BACKGROUND: Ototoxicity refers to damage of the cochlea and/or vestibular apparatus from exposure to chemical substances, resulting in hearing impairment and or disequilibrium. An earlier study carried out at University of Benin Teaching Hospital (UBTH) in 2000 implicated chloramphenicol as the commonest ototoxic drug, followed by antimalarials (Quinine). AIM: To identify the commonly implicated drugs in patients diagnosed with ototoxicity in Ear, Nose and Throat (ENT) Clinic of UBTH. MATERIALS AND METHODS: One-hundred and three patients' case notes, diagnosed as having ototoxicity, between June 2005 and July 2010 at the ENT Clinic of UBTH were reviewed. Seventy-nine cases met the criteria for diagnosis of ototoxicity in this study. RESULTS: Intravenous quinine (19.0%) was the commonest implicated drug, followed by oral chloroquine (6.3%), antihypertensive drugs (nifedipine, moduretics, artenolol [6.3%]), native herbal medicine (13.9%), chloramphenicol (1.3%), and unidentifiable drugs accounted for 53.2%. Most patients had severe to profound hearing loss at 4000 Hz and at 8000 Hz. Tinnitus was found in 84.8% of the patients. CONCLUSION: Quinine is still the commonest implicated ototoxic drug in this part of the country.

Anti-inflammatory effect of novel andrographolide derivatives through inhibition of NO and PGE2 production.

Andrographolide (1) is a major diterpene lactone exhibiting anti-inflammatory effects and is found in the plant Andrographis paniculata (Burm. f) Nees, which is widely used in Traditional Chinese Medicine. Synthesis of more effective drugs from andrographolide is very interesting and can prove to be highly useful. In this study, we investigated the anti-inflammatory effects of andrographolide and its derivatives (compounds 2-6) through dimethylbenzene-induced ear edema in mice. Substances under study were administrated intragastrically and the structure-activity relationship was analyzed. Results showed that compounds 5 and 6 significantly inhibited ear edema compared with compound 1 (p<0.05), indicating that the introduction of p-Chlorobenzylidene to C-15 of compound 2 enhances the anti-inflammatory effect. Moreover, compound 6 exhibited the strongest anti-inflammatory effect against ear edema in mice (79.4%; 1.35 mmol/kg, ig) and paw edema in rats (50.4%; 0.90 mmol/kg, ig). In addition, compound 6 significantly (p<0.05) inhibited granuloma formation and reduced the increase in vascular permeability induced by peritoneal injection of 0.6% acetic acid solution in mice. Findings indicate that compound 6 exerts its enhanced anti-inflammatory effects by decreasing serum iNOS activity, NO production, and PGE(2) production.

In vitro and in vivo models of drug ototoxicity: studying the mechanisms of a clinical problem.

INTRODUCTION: Drug ototoxicity represents one of the main preventable causes of deafness. Ototoxicity is a trait shared by aminoglycoside and macrolide antibiotics, antimalarial medications, loop diuretics, platinum-based chemotherapeutic agents, some NSAIDs and most recently described, acetaminophen when abused with narcotic medication. These medications are prescribed despite their side effects, which includes inner ear toxicity, because they are life-saving drugs or there is a lack of better treatment. AREAS COVERED: This review will discuss in vitro and in vivo models of ototoxicity highlighting recently published ototoxicity research. The reader will learn the strengths and limitations of different ototoxicity models and what molecular insights have been gained from their application. A better understanding of the cellular mechanisms of these ototoxins will help in the discovery of ways to prevent and treat hearing loss associated with ototoxic medications. EXPERT OPINION: There are benefits to both in vitro and in vivo models of ototoxicity. Research of a particular medication and its ototoxic mechanisms should draw from several models, enabling a better answer to the clinical question of prevention and treatment of inner ear drug toxicity.

Antinociceptive and anti-inflammatory activities of iridoid glycosides extract of Lamiophlomis rotata (Benth.) Kudo.

Lamiophlomis rotata (Benth.) Kudo is a perennial herb (Labiatae) used as the Tibetan traditional medicine with the effects of alleviating pain, detumescence, hemostasis, promoting blood circulation to remove blood stasis and reinforcing marrow. In this study, we investigated the antinociceptive and anti-inflammatory activities of iridoid glycosides extract of L. rotata (IGLR) in mice. Our results showed that the iridoid glycosides extract could decrease acetic-acid-induced writhings times and formalin-induced lickings times, inhibit carrageenan-induced hind paw edema and xylene-induced ear swelling, and suppress peritoneal capillary permeability and leukocyte infiltration also induced by acetic acid in mice. All of these results suggested that the iridoid glycosides extract possesses the significant antinociceptive and anti-inflammatory activities.

In vitro and in vivo anti-allergic effects of Arctium lappa L.

The discovery of drugs that can be used for the treatment of allergic disease is important in human health. Arctium lappa Linne (Compositae) (AL) has been used as a traditional medicine in Brazil and throughout Asia and is known to have an anti-inflammatory effect. In this study, the inhibitory effects of AL on degranulation and the release of mediators as well as on inhibition of cys-leukotriene biosynthesis by basophils were investigated. AL was selected out of 10,000 herbal extracts in a set-up for high throughput screening in which the degree of degranulation was monitored by the release of beta-hexosaminidase from rat basophil leukemia (RBL-2H3) cells. The AL extract significantly reduced degranulation and biosynthesis of cys-leukotrienes of human basophils in peripheral blood mono-nuclear cells (PBMCs) (50% inhibitory concentration [IC(50)] = 8.3 and 11.4 microg/ml, respectively). Viability and metabolic activity of the PBMCs were not affected. Although arctiin, the active component of AL that has been described in the literature, was not able to reduce degranulation in RBL-2H3 cells, a single high-performance liquid chromatography (HPLC) fraction from the AL extract inhibited beta-hexosaminidase release (IC(50) = 22.2 microg/ml). Topical administration of an aqueous extract of AL (5 mg/ear) on the ear of whey-sensitized mice 4 hrs before challenge with whey in the ear inhibited acute ear swelling by 50% in an in vivo cow's milk allergic model. The extract had no effect in this model when administered orally. In conclusion, the active component present in the active HPLC fraction of the AL extract was able to significantly reduce the release of inflammatory mediators through inhibition of degranulation and cys-leukotriene release in vitro. In addition, this active component was able to inhibit acute skin response in mice in vivo, indicating that AL is a very promising natural component for use in anti-allergic treatment.

Establishment of the model of white blood cell membrane chromatography and screening of antagonizing TLR4 receptor component from Atractylodes macrocephala Koidz.

A model of white blood cell membrane chromatography (WB-CMC) was established to screen active component from Atractylodes macrocephala Koidz. The component can antagonize Toll-like receptor 4 (TLR4) and inhibit inflammatory reaction. In the model of WB-CMC, cell membrane stationary phase (CMSP) was prepared by immobilizing the rabbit white blood cell membrane (WBCM) onto the surface of silica carrier and taxinol was used as a model molecule. The active component which can act on WBCM and its receptor (such as TLR4) as an effective target in A. macrocephala was determined by using a replacement experiment. The anti-inflammatory effects of the active component were tested by using pharmacological methods in vivo. The results indicated that the retention characteristics of atractylenolide I as active component was similar to that of taxinol in the model of WB-CMC. And so, atractylenolide I acted on the WBCM and TLR4 and its anti-inflammatory activity was related with antagonizing TLR4. Therefore, the interaction between the active component and WBCM and its receptor can be simulated by the model of WB-CMC in vitro. This model can be used to screen active components and to study effective characteristics for acting on definite targets.

Oral administration of the NADPH-oxidase inhibitor apocynin partially restores diminished cartilage proteoglycan synthesis and reduces inflammation in mice.

Apocynin, an inhibitor of NADPH-oxidase, is known to partially reverse the inflammation-mediated cartilage proteoglycan synthesis in chondrocytes. More recently, it was reported that apocynin prevents cyclooxygenase (COX)-2 expression in monocytes. The present study aimed to investigate whether these in vitro features of apocynin could be confirmed in vivo. In a mouse model of zymosan-induced acute arthritis apocynin was administered orally (0, 3.2, 16 and 80 microg/ml in the drinking water) and the effects on cartilage proteoglycan synthesis were monitored. In a mouse model of zymosan-induced inflammation of the ears apocynin was administered orally (14 mg/kg/day by gavage) and the effects on ear swelling and ex vivo produced prostaglandin E2 (PGE2) by lipopolysaccharide (LPS)-stimulated blood cells were measured. In this study, ibuprofen was used as a positive control (50 mg/kg/day by gavage) and animals received vehicle as a negative control. Apocynin dose-dependently reversed the inhibition of proteoglycan synthesis in articular cartilage of the arthritic joint. A statistically significant increase in proteoglycan synthesis was found at a dose of 80 microg/ml apocynin. Apocynin did not affect the proteoglycan synthesis of the control knee joints. Apocynin significantly decreased the zymosan-induced ear swelling at 1, 2 and 4 h (hours) after zymosan injection versus the vehicle treated group at 14 mg/kg/day. The ex vivo production of PGE2 by LPS-stimulated blood cells was significantly decreased after in vivo apocynin treatment. Ibuprofen decreased ear swelling at the same time-points as apocynin and inhibited the ex vivo produced PGE2. In conclusion, the present study confirmed two important features of apocynin in vivo: (1) oral administration of apocynin can partially reverse the inflammation-induced inhibition of cartilage proteoglycan synthesis, and (2) oral administration of apocynin has COX inhibitory effects similar to the non-steroidal anti-inflammatory drug (NSAID) ibuprofen. Therefore, apocynin might be of potential use during the treatment of chronic inflammatory joint diseases like osteoarthritis or rheumatoid arthritis.

Gaultherin, a natural salicylate derivative from Gaultheria yunnanensis: towards a better non-steroidal anti-inflammatory drug.

One of the major factors limiting the use of non-steroidal anti-inflammatory drugs is gastrointestinal toxicity. Gaultherin, 2-[(6-O-beta-D-Xylopyranosyl-beta-D-glucopyranosyl)oxy] benzoic acid methyl ester, a natural salicylate derivative extracted from Gaultheria yunnanensis, has been shown to have analgesic and anti-inflammatory effects and lack gastric ulcerogenic effect compared to aspirin in our primary study. The aim of this study was to investigate the mechanism of action of gaultherin, which may rely on its active metabolite, and the mechanism responsible for the non-ulcerogenic property. The results showed that gaultherin (200 mg/kg) significantly inhibited the abdominal contractions in the acetic acid-induced writhing test in mice. The anti-inflammatory effect of gaultherin was demonstrated in the croton oil-induced ear edema model in mice. The results showed that gaultherin and equimolar dose of aspirin produced comparable inhibitory effects. The study of the metabolism characters of gaultherin in mice and rats indicated that gaultherin could be metabolically converted to salicylate, which produced the pharmacological effects, and provided effective concentrations for an extended period. In vitro metabolism experiment showed that gaultherin was metabolized by beta-glycosidase produced by human intestinal bacteria and esterases in intestine, blood and liver successively to release salicylate finally. The study suggested gaultherin did not cause gastric ulcer for the reason that it released salicylate in intestine slowly, not in stomach and it left the cyclooxygenase-1 unaffected, which was the source of cytoprotective prostaglandins in gastric epithelium.