Topical Anti-inflammatory Agents Research Articles

Effects of topical diclofenac and prednisolone eyedrops in laser in situ keratomileusis patients

Purpose To compare the effects of a topical nonsteroidal anti-inflammatory agent, diclofenac, and prednisolone acetate on wound healing, postoperative inflammation, and other clinical parameters in laser in situ keratomileusis (LASIK) patients. Setting Fundación VER, Córdoba, Argentina. Methods Laser in situ keratomileusis for myopia was performed simultaneously in both eyes of 16 patients by 1 surgeon. Patients were prospectively randomized to receive diclofenac eyedrops in the right eyes and prednisolone acetate eyedrops in the left. Postoperatively, the drops were administered topically every 2 hours the first day, every 6 hours the first week, every 8 hours the second week, and once a day the fourth week. Preoperatively and at each postoperative visit, evaluation of visual acuity, slitlamp biomicroscopy, corneal topography, and clinical scoring (0-III) of pain and photophobia were done; epithelial interface opacities were objectively evaluated. Follow-up was at 24, 48, and 72 hours, 1, 2, and 3 weeks, and 1, 2, 3, and 6 months. A paired t test was used for statistical analysis. Results Mean age of the 16 patients was 29.4 years ± 6.5 (SD). Preoperatively, mean spherical equivalent was −5.83 ± 3.61 diopters (D) in the right eyes and −6.96 ± 4.66 D in the left eyes. At 6 months postoperatively, it was −1.83 ± 1.87 D and −1.88 ± 2.13 D, respectively. In the first 24 hours, there were significant clinical symptoms in the diclofenac group. Conclusions Wound healing was stable, with no regression, in the diclofenac and prednisolone groups. Both anti-inflammatory agents worked well in LASIK patients.

Cystoid macular edema associated with latanoprost therapy in a case series of patients with glaucoma and ocular hypertension

Objective To identify coexisting ocular diagnoses in a case series of eyes that developed cystoid macular edema (CME) associated with latanoprost therapy. Design Retrospective observational case series. Participants Seven eyes of seven patients who developed CME possibly associated with latanoprost treatment were studied. Intervention When these patients, all of whom were treated with latanoprost in addition to other glaucoma medications, described blurred vision or eye irritation, ocular examination revealed CME, which was confirmed by fluorescein angiography. Latanoprost was discontinued, and in three cases topical corticosteroids and nonsteroidal anti-inflammatory agents were used to treat the CME. Main outcome measures Visual acuity and intraocular pressure were determined before latanoprost use began, during therapy, and after latanoprost use ceased. In these cases, resolution of CME was documented clinically after discontinuing latanoprost. Results Clinically significant CME developed after 1 to 11 months of latanoprost treatment, with an average decrease of 3 lines in Snellen visual acuity. Intraocular pressure decreased an average of 27.9% during treatment. Cystoid macular edema was confirmed in all cases by fluorescein angiography. In these seven patients, the following coexisting ocular conditions may have placed these eyes at risk for prostaglandin-mediated blood-retinal barrier vascular insufficiency: history of dipivefrin-associated CME, epiretinal membrane, complicated cataract surgery, history of macular edema associated with branch retinal vein occlusion, history of anterior uveitis, and diabetes mellitus. In all cases, the macular edema resolved following discontinuation of latanoprost, in some instances with concomitant use of steroidal and nonsteroidal anti-inflammatory agents. Conclusions In this case series of pseudophakic, aphakic, or phakic eyes, the temporal relationships between the use of latanoprost and developing CME, and the resolution of CME following cessation of the drug, suggest an association between latanoprost and CME. In all cases, coexisting ocular conditions associated with an altered blood-retinal barrier were present.

Is the face and neck pattern of atopic dermatitis in Japan a special variant?

Background: Adult atopic dermatitis (AD) with severe and refractory eruptions on the face, neck, and upper trunk, although quite rare in western countries, has increased in Japan. Objective: We have tried to clarify the possible causative factors for this particular type of AD, predominantly seen in Japan. Methods: Eighty-seven AD patients (37 men and 50 women) who had severe and refractory facial and neck lesions were patch tested with topical medicaments, cosmetics, and skin-management products. Results: Thirty-seven (42.5%) patients showed positive reactions to more than one of those products: 14 patients to shampoo, rinse, or soap; 11 to topical nonsteroidal anti-inflammatory agents (NSAIDs); 7 to cosmetics; and 6 to corticosteroids. Conclusion: We believe that topical NSAIDs, (which are often prescribed for the treatment of AD in Japan and rarely used for the treatment of eczamatous skin disorders in western countries), as well as common detergents, play important roles in the increased prevalence of AD patients with severe and refractory lesions on the face, neck, and upper trunk in Japan.

Topical amiloride accelerates healing and delays neovascularization in mechanically produced corneal ulcers in rabbits

The present investigation was undertaken to explore the ulcer healing and antiangiogenic efficacy of two dosage schedules of topically administered amiloride in mechanically produced corneal ulcers in rabbits and to compare its effect with the conventional topical antiinflammatory angiostatic agent flurbiprofen. The epithelium and superficial lamellae of the stroma of both eyes of each rabbit were cut through by a corneal trephine (8 mm diameter) up to a depth of 0.3 mm and removed after local anesthesia. The animals were randomly divided in groups of 4 rabbits each. In the eyes of 2 groups of animals, amiloride (4%) was instilled either q.i.d. or b.i.d.; in another, flurbiprofen (0.03%) was instilled twice daily whereas the saline-treated group served as control. The healing of ulcer was followed on a slit lamp regarding its size, depth, slough formation, infiltration and neovascularization on alternate days up to the 10th day with and without fluorescein staining. Healing of corneal ulcers was significantly accelerated by both dosage schedules of topical amiloride (4%) but more so following q.i.d. instillation. Topical flurbiprofen, on the other hand, delayed the healing process. Instillation of amiloride four times daily or flurbiprofen twice daily inhibited angiogenesis significantly. However, appearance of new vessels was completely prevented when amiloride (4%) was instilled twice daily. Thus topical amiloride (4%) may prove to be a cheap and better antineovascularization as well as ulcer healing agent with no apparent side effects. Inhibition of uPA by amiloride appears to be responsible for these effects.

A light at the end of the tunnel for psoriasis sufferers?

•Psoriasis is a common skin disorder, affecting 6.4 million US citizens—almost 2% of the total US population. In Europe, the estimated prevalence is even higher, at around 5%.•Psoriasis is characterized by the appearance of plaques of bright red lesions, covered by silver-grey scale. The affected skin can also be itchy and socially embarrassing for patients.•The severity of the condition changes with time, and there are frequent exacerbations and remissions.•Psoriasis is a multifactorial illness in which genetics, an unknown environmental trigger (possibly an infectious agent) and the immune system all play a role.•Current therapies aim to control the immune and inflammatory components of the disease, and range from topical anti-inflammatories to systemic immunosuppressants. However, none of these treatments is curative and most have problems: topical treatments are unpopular with patients because they take a long time to apply and many have a strong and unpleasant smell; systemic immunosuppressants can cause serious side effects.

Topical nonsteroidal anti-inflammatory agents in ophthalmology.

Nonsteroidal anti-inflammatory agents or NSAIDs are potent inhibitors of prostaglandin synthesis. As such, they have found many useful roles in ophthalmology. NSAIDs are approved by the FDA to prevent intraoperative miosis during cataract surgery, reduce postoperative inflammation following cataract surgery, and control symptoms of allergic conjunctivitis and pain following refractive surgery. In addition, they have been shown to be effective in preventing cystoid macular edema following cataract surgery or treating cystoid macular edema once it occurs.

The Calyculaglycosides: Dilophol-Type Diterpene Glycosides Exhibiting Antiinflammatory Activity from the Caribbean Gorgonian Eunicea sp.(1)(,)(2).

Three new diterpenoid hexose-glycosides, calyculaglycosides A-C (1-3) were isolated from the Caribbean gorgonian Eunicea sp. Calyculaglycosides A-C are rare diterpene glycosides possessing dilophol (4) aglycones related in biosynthetic origin to the elemene-type glycoside class of potent antiinflammatory agents known as fuscosides. The structures of the new compounds, which were assigned on the basis of spectral studies, were further corroborated by molecular modeling studies. Calyculaglycoside B (2) is an effective topical antiinflammatory agent stronger in potency than the industrial standard indomethacin. Calyculaglycoside B inhibits the synthesis of both prostaglandin PGE(2) and leukotriene LTB(4), suggesting it is a nonselective inhibitor of the 5-lipoxygenase and cyclooxygenase pathways. At concentrations of 10(-4)-10(-5)M, calyculaglycoside B produced LC(50)-level differential responses against a majority of the NCI ovarian cancer lines and several of the renal, prostate, and colon tumor lines.

Topical anti-inflammatory activity of dianemycin isolated fromStreptomyces sp. MT 2705-4

In order to develop new anti-inflammatory agents having different action mechanisms compared with nonsteroidal and steroidal anti-inflammatory drugs, the culture broths of various actinomycetes isolated from soil were screened using anin vivo mouse ear edma assay and one strain (Streptomyces sp. MT 2705-4: KCTC 8651P) was selected. Activity-guided purification led to the isolation of a polyether compound, dianemycin. Topically, dianemycin showed a potent anti-inflammatory activity in mouse ear edema induced by croton-oil or arachidonic acid. ED(50) value of dianemycin was found to be 0.8 mg/ear compared to 0.4 mg/ear of prednisolone in croton-oil ear edema. However, dianemycin did not show the inhibitory activity in UV-erythema and delayed hypersensitivity reaction. These results indicate that dianemycin is a potential topical anti-inflammatory agent.

FUSAFUNGINE REDUCES SYMPTOMS OF UPPER RESPIRATORY TRACT INFECTIONS (URTI) IN RUNNERS AFTER A 56KM RACE 1685

The effect of Fusifungine, a topical anti-inflammatory/anti-bacterial nasal/oral spray, on the incidence of symptoms of upper respiratory tract infections (URTI) in the 9 days following a 56km running event was studied. Male runners (n=96) with a 42km time of <3hrs. with no history of allergy, and with daily intakes of i) < 1000mg Vitamin C, ii) < 18mg Beta carotene, and iii) < 400 IU Vitamin E were recruited. Prior to the race, subjects were instructed on the proper use of the medication (4 sprays into each nostril and the throat 4 times daily) and then randomly allocated to either a group receiving Fusafungine (F:n=48) or a placebo (P:n=48) in a double blind manner. Subjects completed a daily logbook detailing symptoms[runny nose(RN), blocked nose (BN), all nasal symptoms (N=RN+BN), sore throat(ST), and all URT symptoms (URTS=RN+BN+ST), in the 2 days before the race, the first 3 days after, and the 4-9 days after the race. All the symptomatic subjects underwent medical evaluation. Throat swabs and viral gargles for culture were taken. No athlete with symptoms had a positive bacterial or viral culture. The incidence of symptoms (%) in the F and P group was as follows:Table There was a decreased incidence (%) in URTS in the F group(F=17%;P=40%:*:p<0.05) in the period Day 0-3 after the race, with a tendency for the nasal symptoms to be lower (F=9%; P=23%:+:p=0.08) in the same period. In summary, post-race URTS are not of infective origin (viral or bacterial) and their incidence can be reduced by a topical anti-inflammatory agent. Hence post-race URTS are likely the result of an inflammatory and not an infective process.

The emerging roles of topical non-steroidal anti-inflammatory agents in ophthalmology

The emerging roles of topical non-steroidal anti-inflammatory agents in ophthalmology

Measurement of croton oil induced rabbit ear swelling and evaluation of anti-inflammatory agents with a standard low pressure caliper.

Carbobenzoxy-phenylalanyl-methionine (CBZ-Phe-Met), a known inhibitor of the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP) in vitro, has not been evaluated as a topical anti-inflammatory agent in vivo. In order to measure the effect of CBZ-phe-met, one needs a repeat-able, quantitative, easily obtainable standard measurement of the edema formation. In this study, a caliper designed for measuring soft materials was used to evaluate the edema, induced by croton oil on rabbit ears, as well as the effects of CBZ-phe-met. The model used in this study was croton-induced inflammation on rabbit ears. A caliper for measuring soft materials (European standard DIN 863 part 3, manufactured by TESA Ltd., Renens, Switzerland) was used to evaluate the edema, which is part of the inflammatory effect. The action of CBZ-phe-met and two other anti-inflammatory agents; hydrocortisone and Na-ibuprofen, were compared. CBZ-phe-met 1-5% was found to reduce the edema on rabbit ears induced by croton oil by 15 to 93%. 5% CBZ-phe-met was found to be as effective as 5% Na-ibuprofen and 0.1% hydrocortisone. The caliper for soft materials was found to be suitable for measuring the edema induced by croton-oil, as well as the reducing edema due to anti-inflammatory treatment. It was also found that CBZ-phe-met is a potent topical anti-inflammatory agent in the croton-oil-induced inflammatory model. This may indicate a new approach in the treatment of inflammation.

Non-Phenolic Linear Diarylheptanoids fromCurcuma xanthorrhiza: A Novel Type of Topical Anti-Inflammatory Agents: Structure-Activity Relationship

The topical anti-inflammatory activity of three non-phenolic linear 1,7-diarylheptanoids, previously isolated from a Thai medicinal plant, Curcuma xanthorrhiza (Zingiberaceae) and four new semi-synthetic derivatives of the naturally occurring compounds were assessed in the murine model of ethyl phenylpropiolate-induced ear edema. The naturally occurring compound 1E,3E,1,7-diphenylheptadien-5-one (6) exerted the most potent anti-inflammatory activity, with an ID50 value of similar magnitude to that of the reference drug oxyphenbutazone (67 vs. 46 micrograms/ear, respectively). None of the semi-synthetic diarylheptanoids was more active than 6. The chemical structures and pharmacological data of the natural and semi-synthetic derivatives identified a distinct structure-activity relationship. The degree of unsaturation in positions 1 and 3, and the nature of the oxygenated functional group in position 5 of the C7-chain were found to play significant roles in determining the observed in vivo activity. Based on these findings, the non-phenolic linear 1,7-diarylheptanoids-are proposed to represent a novel class of topical anti-inflammatory agents.

The emerging roles of topical non-steroidal anti-inflammatory agents in ophthalmology.

The emerging roles of topical non-steroidal anti-inflammatory agents in ophthalmology.

Allergic and atopic diseases of the lid, conjunctiva, and cornea.

Ocular allergies are commonly encountered in clinical practice. The familiarity with the typical constellation of signs and symptoms, as well as the pathophysiology of these syndromes, is of utmost importance in diagnosing and treating these diseases. Several new therapeutic options have been tested in clinical settings in recent time. Lodoxamine tromethamine is a mast cell stabilizer at least as effective as cromolyn sodium, which is currently not available in the United States. Nedocromil sodium in addition to its mast cell stabilizing effect, has anti-inflammatory properties. Levocabastine hydrochloride is a very selective and potent H1 antihistamine. Ketorolac tromethamine is a topical nonsteroidal anti-inflammatory agent.

Effect of flurbiprofen on acetylcholine-induced pupillary contraction.

Preoperative treatment with topical nonsteroidal anti-inflammatory agents such as flurbiprofen (Ocufen) is used to maintain pupil dilation during cataract surgery. Flurbiprofen maintains pupil dilatation by inhibiting release of prostaglandins and other modulators of surgical miosis. Some reports suggest that these agents may reduce the miotic effect of intra-operative acetylcholine (Miochol). It is hard to explain this effect unless there is a pharmacological interaction between the two drugs. This study aimed to investigate the possibility of a direct interface by flurbiprofen with the action of acetylcholine on the pupil sphincter. Iris tissue of seven cadaver eyes were isolated and maintained in an organ bath containing Kreb's solution. Pupil contraction force induced by acetylcholine was measured in the presence and absence of flurbiprofen. Acetylcholine produced a mean pupillary contraction force of 52.4 x 10(-3) N. When it was added to the organ bath in the presence of flurbiprofen the mean contraction force was 50.5 x 10(-3) N (paired t-test P = 0.68). This study does not find any evidence to suggest that flurbiprofen reduces the pupil sphincter contraction that is induced by acetylcholine. It is likely that the apparent reduction in miosis is due to factors other than the mechanism of action of acetylcholine on the sphincter pupillae.

A specific enzyme immunoassay (EIA) with selective extraction for quantitation of a topical anti-inflammatory agent, SCH 40120, in human plasma

SCH 40120 is a potent anti-inflammatory agent under development for the topical treatment of dermal inflammatory and allergic disorders such as atopic dermatitis, contact dermatitis and psoriasis. We have previously described a sensitive enzyme immunoassay (EIA) for SCH 40120 in unextracted human plasma to support clinical studies. However, severe cross-reaction with unknown metabolites was observed during validation using samples from rats dosed with 14C-SCH 40120. Therefore, a selective extraction procedure was developed to remove the unknown plasma metabolites of SCH 40120 prior to EIA quantitation. The modified EIA using extracted plasma was cross-validated with an LC method using plasma samples from dosed subjects (human and rat), thereby confirming the specificity of the assay. The EIA can reliably quantitate SCH 40120 in plasma samples from 100 pg ml −1 to 10 ng ml −1 with good linearity, accuracy and precision, and is suitable for pharmacokinetic studies in man.

Medical Therapy of Ulcerative Proctitis and Proctosigmoiditis, Including Refractory Disease

Ulcerative proctosigmoiditis (also commonly referred to as distal ulcerative colitis) is defined as inflammation limited to the distal 30-50 cm of colonic mucosa, whereas ulcerative proctitis refers to disease confined to the rectum. The major recent breakthrough in the therapy of these conditions has been the advent of various topical anti-inflammatory agents. These agents directly contact the inflamed mucosa and have less systemic absorption than the oral medications. The first compounds used as rectal suspensions were corticosteroid enemas. Subsequently, sulfasalazine and 5-aminosalicylate (5-ASA) enemas were studied. Oral sulfasalazine and oral mesalamine also are being utilized, although there are very few studies assessing their efficacy specifically in disease limited to the distal colon. Immunomodulators have an increasingly important role in steroid dependent and steroid refractory distal colitis, situations in which physicians may be reluctant to send patients to surgery for disease that is so limited. This review discusses the various agents utilized in the therapy for conventional and refractory ulcerative proctitis and distal colitis. It will also outline our personal approach to treating patients with these conditions. Since there is very little data on Crohn's proctitis and proctosigmoiditis, we will not discuss these entities in our review.

Structure-function relations in the inhibition of murine contact hypersensitivity by amiloride.

Topical application of amiloride, a potent inhibitor of the Na+/H+ antiport, inhibits cutaneous inflammation induced by ultraviolet radiation or contact hypersensitivity in mice. Amiloride analogues with greater and lesser inhibition of the Na+/H+ exchange were tested to determine whether anti-inflammatory effects correlate with this activity. Structural analogues of amiloride without significant activity at the Na+/H+ antiport (pyrazine, pyrazinamide, and chloropyrazine) failed to inhibit contact hypersensitivity. N-amidino-3-amino-5-dimethyl amino-6-chloropyrazinecarboxamide (DMA) has a 23-fold greater affinity for the Na+/H+ antiport compared to amiloride, but failed to inhibit contact hypersensitivity in this assay. 3,5-diamino-6-chloropyrazine-amido-guanidine (DCG), which has only 7% of the affinity of amiloride for the antiport, suppressed contact hypersensitivity as well as amiloride. Experiments examining the ability of these agents to diffuse through mouse skin revealed amiloride to be superior to both DCG and DMA, which were approximately equal. DMA, with greater inhibition of the Na+/H+ antiport but lesser ability to inhibit contact hypersensitivity, inhibited protein synthesis and induced cell death more than amiloride or DCG. Amiloride and DCG hold promise as topical anti-inflammatory agents. Their anti-inflammatory properties do not correlate with affinity for the Na+/H+ antiport, ability to penetrate murine skin, or inhibition of protein synthesis.

Effects of topical antiinflammatory agents on Freund's adjuvant-induced skin lesions in rats.

Freund's adjuvant, when administered intradermally to rats, causes polyarthritis as well as inflammation of the skin, eye, gastrointestinal and genitourinary tracts. We assessed the effects of antiinflammatory drugs on ear skin lesions to determine if this might be a useful skin inflammation model. The hind paw of male Lewis rats was injected with Mycobacterium butyricum in paraffin oil. Lesions appeared between days 13 and 15 after adjuvant injection. Each ear exhibited on average 1 to 3 highly erythematous, elevated lesions, 2 to 3 mm in diameter. By histology, the lesions consisted of epidermal hyperplasia, with a prominent accumulation of inflammatory cells in the dermis. Ears were treated topically with glucocorticoids, cyclosporine and indomethacin on days 15 through 21 after adjuvant injection. By day 22, dexamethasone, fluocinolone acetonide, and cyclosporine caused near-complete clearing of lesions whereas indomethacin exacerbated the inflammation by causing increased numbers of skin lesions. These results show the potential usefulness of adjuvant-induced skin lesions in rats as a novel subchronic inflammation model.

The Degrees of UVB-Induced Erythema and Pigmentation Correlate Linearly and Are Reduced in a Parallel Manner by Topical Anti-Inflammatory Agents

To examine whether it is possible to evaluate the degree of ultraviolet B (UVB)-induced inflammation by measuring the degree of hyperpigmentation, we investigated the relationship between UVB-induced erythema and the subsequent pigmentation quantitatively. At 24 h and 7 d after irradiation with erythemogenic doses of UVB to the backs of 16 Japanese subjects, the degree of induced erythema (delta erythema index) and that of pigmentation (delta melanin index) were examined by an image analytic method using a videomicroscope interfaced with a computer. The relationship between two indices was linear in each subject, and the correlation coefficient was 0.83 when evaluated using whole data. The slope of the regression line for the delta melanin index against delta erythema index tended to become steeper as non-irradiated skin color became darker (r = 0.63), suggesting that more efficient melanogenesis takes place after the same level of inflammation in the subject with darker skin. Both erythema and hyperpigmentation were suppressed significantly and in a parallel manner by corticosteroids and indomethacin applied topically immediately after UVB irradiation. These results imply that the post-inflammatory hyperpigmentation correlates closely with the severity of the prior inflammation and that chemical mediators released in the inflammatory process have considerable influence on the melanogenesis. We conclude that the measurement of UVB-induced hyperpigmentation can be utilized for the assessment of topical anti-inflammatory agents, unless these have direct actions on the tyrosinase activity of melanocytes.