Anti-echinococcal activity of menthol and a novel prodrug, menthol-pentanol, against Echinococcus multilocularis.

Alveolar echinococcosis is one of the most dangerous parasitic zoonoses. This disease, widely distributed in the northern hemisphere, is caused by the metacestode stage of the tapeworm Echinococcus multilocularis. All surgical and non-surgical patients should perform chemotherapy with benzimidazoles, mainly with albendazole. However, the efficacy of albendazole is variable due to its deficient pharmacokinetic properties. Therefore, the need to find new therapeutic alternatives for the treatment of alveolar echinococcosis is evident. Menthol is a natural compound of low toxicity, used in industries such as cosmetics and gastronomy and generally recognized as safe by the Food and Drug Administration. In addition, menthol has important pharmacological effects and is effective against a wide variety of organisms. The development of prodrugs allows improving the pharmacokinetic properties of the parental drug. To improve lipophilicity and therefore the bioavailability of menthol, a novel prodrug called menthol-pentanol was developed by masking the functional polar group of menthol by linking n-pentanol by a carbonate bond. The aim of the current work was to evaluate the in vitro and in vivo efficacy of menthol and menthol-pentanol against E. multilocularis. Menthol-pentanol had a greater protoscolicidal effect than menthol. In addition, the prodrug demonstrated a similar clinical efficacy to albendazole. The increase in lipophilicity of the prodrug with respect to menthol was reflected in an increase in its antiparasitic activity against E. multilocularis. Thus, menthol-pentanol appears as a promising candidate for further evaluation as a potential alternative for the treatment of alveolar echinococcosis.

Modulations of microbehaviour by associative memory strength in Drosophila larvae.

Finding food is a vital skill and a constant task for any animal, and associative learning of food-predicting cues gives an advantage in this daily struggle. The strength of the associations between cues and food depends on a number of parameters, such as the salience of the cue, the strength of the food reward and the number of joint cue-food experiences. We investigate what impact the strength of an associative odour-sugar memory has on the microbehaviour of Drosophila melanogaster larvae. We find that larvae form stronger memories with increasing concentrations of sugar or odour, and that these stronger memories manifest themselves in stronger modulations of two aspects of larval microbehaviour, the rate and the direction of lateral reorientation manoeuvres (so-called head casts). These two modulations of larval behaviour are found to be correlated to each other in every experiment performed, which is in line with a model that assumes that both modulations are controlled by a common motor output. Given that the Drosophila larva is a genetically tractable model organism that is well suited to the study of simple circuits at the single-cell level, these analyses can guide future research into the neuronal circuits underlying the translation of associative memories of different strength into behaviour, and may help to understand how these processes are organised in more complex systems.

Protective effect of potassium 2-(l-hydroxypentyl)-benzoate on hippocampal neurons, synapses and dystrophic axons in APP/PS1 mice.

RATIONALE: As the hub of memory and space, hippocampus is very sensitive to a wide variety of injuries and is one of the earliest brain structures to develop neurodegenerative changes in AD. Previous research has showed a protective effect of potassium 2-(l-hydroxypentyl)-benzoate (PHPB) on cognitive deficits in animal models of AD. However, it is unclear whether this protective effect is associated with hippocampal alterations. OBJECTIVES: The present study was conducted to evaluate the protective effect of PHPB on hippocampal neurodegenerative changes in middle-aged APP/PS1 mice. METHODS: Ten-month-old male APP/PS1 transgenic mice and age-matched wild-type mice were randomly divided into three groups. PHPB-treated APP/PS1 group received 30 mg/kg PHPB by oral gavage once daily for 12 weeks. Wild-type group and APP/PS1 group received the same volume of water alone. Twelve weeks later, mice (13-month-old) were tested for in vivo 1H-MRS examination and then sacrificed for subsequent biochemical and pathological examinations using transmission electron microscopy, Golgi staining, immunohistochemistry, and western blotting. RESULTS: We found that PHPB treatment significantly improved the micromorphology of hippocampal neurons and subcellular organelles, ameliorated synapse loss and presynaptic axonal dystrophy, increased hippocampal dendritic spine density and dendritic complexity, enhanced the expression of hippocampal synapse-associated proteins, and improved hippocampal metabolism in middle-aged APP/PS1 mice. CONCLUSIONS: Our study showed for the first time the protective effect of PHPB on hippocampal neurons, synapses, and dystrophic axons in APP/PS1 mice, which to some extent revealed the possible mechanism for its ability to improve cognition in animal models of AD.

Animal Derived Thiol Induced Work Exacerbated Asthma: A Brief Case Report of a Unique Workplace Hazard.

A 33 year old female healthcare worker with a history of cough variant asthma presented with 2 weeks of dyspnea and cough that she believed to be due to recurring exposure to skunk spray in her work environment. The employee was working in a temporary structure outside the primary hospital campus. During the preceding 2 weeks, at least one striped skunk was observed multiple times by staff members to be crawling under the structure. The employee's symptoms were not initially considered serious by her supervisors who felt that the appreciable "skunk smell" was merely a nuisance odor. Repeated pre- and postexposure spirometry noted a 350 mL and 11% reduction in forced expiratory volume at one second (FEV1). A review of organic chemistry literature found that 2 thiols, also known as mercaptans, produced in striped skunk spray are structurally related to 1-butanethiol, a chemical workplace hazard and known respiratory irritant with established occupational exposure limits. The observation of the chemical similarities between these skunk-derived thiols and workplace thiols was the key factor in getting the employee temporarily removed from a hazardous, albeit unique, working environment.

Comparison of Occlusive and Open Application in a Psoriasis Plaque Test Design, Exemplarily Using Investigations of Mapracorat 0.1% Ointment versus Vehicle and Reference Drugs.

BACKGROUND/AIMS: Psoriasis plaque tests (PPTs) are important tools in the early phases of antipsoriatic drug development. Two distinct PPT design variants (open vs. occluded drug application) are commonly used, but no previous work has aimed to directly compare and contrast their performance. METHODS: We compared the antipsoriatic efficacy of mapracorat 0.1% ointment and reference drugs reported in 2 separate studies, representing open and occluded PPT designs. The drug effect size was measured by sonography (mean change in echo-poor band thickness), chromametry, and standardized clinical assessment. RESULTS: Antipsoriatic effects were detectable for the study drugs in both occluded and open PPTs. Differences between the potency of antipsoriatic drugs and vehicle were observable. The total antipsoriatic effect size appeared to be higher in the occluded PPT than the open PPT, despite the shorter treatment duration (2 vs. 4 weeks). Effect dynamics over time revealed greater differences between some study drugs in the open PPT compared to the occluded PPT. CONCLUSION: Taking the higher technical challenges for the open PPT into account, we recommend the occluded PPT as a standard screening setting in early drug development. In special cases, considering certain drug aspects or study objectives that would require procedural adaptations, an open PPT could be the better-suited design. Finally, both PPT models show clear advantages: classification as phase I studies, small number of psoriatic subjects, relatively short study duration, excellent discrimination between compounds and concentrations, parallel measurement of treatment response, and go/no go decisions very early in clinical development.

The selective glucocorticoid receptor agonist mapracorat displays a favourable safety-efficacy ratio for the topical treatment of inflammatory skin diseases in dogs.

BACKGROUND: Mapracorat is a nonsteroidal Selective Glucocorticoid Receptor Agonist (SEGRA) that is presumed to have a better therapeutic index compared to classical glucocorticoids. OBJECTIVES: To compare the efficacy and safety of mapracorat with classical glucocorticoids used for the treatment of allergic skin diseases in dogs. ANIMALS: Six laboratory beagles. METHODS: The effect of mapracorat on lipopolysaccharide-induced TNFα secretion from canine peripheral blood derived mononuclear cells (PBMC) was tested. In vivo, mapracorat was compared to triamcinolone acetonide using a skin inflammation model. Skin fold thickness was determined after daily administration of mapracorat and triamcinolone acetonide over 14 days. RESULTS: Mapracorat concentration dependently inhibited TNFα secretion from activated canine PBMC with a half maximal inhibitory concentration (IC50 ) value of approximately 0.2 nmol/L. Intradermal injection of compound 48/80 (50 µg in 50 µL saline) resulted in a clear wheal and flare reaction over the 60 min observation period. Topical pre-treatment with mapracorat (0.1%) and triamcinolone acetonide (0.015%) led to significant reduction in the wheal and flare responses compared to vehicle (acetone) treated areas. However, once daily topical administration of triamcinolone acetonide significantly reduced skin fold thickness from day 8 to 14, whereas no such reduction was observed for mapracorat. CONCLUSION: These results demonstrate that mapracorat has comparable anti-inflammatory efficacy to classical steroidal glucocorticoids under these experimental settings and maintenance of skin fold thickness indicates a better safety profile compared to triamcinolone acetonide at equipotent concentrations. This profile further suggests that SEGRAs show promise in the management of inflammatory and pruritic skin diseases in dogs.

Field evaluation of the bacterial volatile derivative 3-pentanol in priming for induced resistance in pepper.

Plants are defended from attack by emission of volatile organic compounds (VOCs) that can act directly against pathogens and herbivores or indirectly by recruiting natural enemies of herbivores. However, microbial VOC have been less investigated as potential triggers of plant systemic defense responses against pathogens in the field. Bacillus amyloliquefaciens strain IN937a, a plant growth-promoting rhizobacterium that colonizes plant tissues, stimulates induced systemic resistance (ISR) via its emission of VOCs. We investigated the ISR capacity of VOCs and derivatives collected from strain IN937a against bacterial spot disease caused by Xanthomonas axonopodis pv. vesicatoria in pepper. Of 15 bacterial VOCs and their derivatives, 3-pentanol, which is a C8 amyl alcohol reported to be a component of sex pheromones in insects, was selected for further investigation. Pathogens were infiltrated into pepper leaves 10, 20, 30, and 40 days after treatment and transplantation to the field. Disease severity was assessed 7 days after transplantation. Treatment with 3-pentanol significantly reduced disease severity caused by X. axonopodis and naturally occurring Cucumber mosaic virus in field trials over 2 years. We used quantitative real-time polymerase chain analysis to examine Pathogenesis-Related genes associated with salicylic acid (SA), jasmonic acid (JA), and ethylene defense signaling. The expression of Capsicum annuum Pathogenesis-Related protein 1 (CaPR1), CaPR2, and Ca protease inhibitor2 (CaPIN2) increased in field-grown pepper plants treated with 3-pentanol. Taken together, our results show that 3-pentanol triggers induced resistance by priming SA and JA signaling in pepper under field conditions.

Mapracorat, a selective glucocorticoid receptor agonist, causes apoptosis of eosinophils infiltrating the conjunctiva in late-phase experimental ocular allergy.

BACKGROUND: Mapracorat, a novel nonsteroidal selective glucocorticoid receptor agonist, has been proposed for the topical treatment of inflammatory disorders as it binds with high affinity and selectivity to the human glucocorticoid receptor and displays a potent anti-inflammatory activity, but seems to be less effective in transactivation of a number of genes, resulting in a lower potential for side effects. Contrary to classical glucocorticoids, mapracorat displays a reduced ability to increase intraocular pressure and in inducing myocilin, a protein linked to intraocular pressure elevation. Allergic conjunctivitis is the most common form of ocular allergy and can be divided into an early phase, developing immediately after allergen exposure and driven primarily by mast cell degranulation, and a late phase, developing from 6-10 hours after the antigen challenge, and characterized by conjunctival infiltration of eosinophils and other immune cells as well as by the production of cytokines and chemokines. METHODS: In this study, mapracorat was administered into the conjunctival sac of ovalbumin (OVA)-sensitized guinea pigs 2 hours after the induction of allergic conjunctivitis, with the aim of investigating its activity in reducing clinical signs of the late-phase ocular reaction and to determine its mechanism of anti-allergic effects with respect to apoptosis of conjunctival eosinophils and expression of the chemokines C-C motif ligand 5 (CCL5), C-C motif ligand 11 (CCL11), and interleukin-8 (IL-8) and the proinflammatory cytokines interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α). RESULTS: Mapracorat, administered into the conjunctival sac of OVA-sensitized guinea pigs 2 hours after allergen exposure, was effective in reducing clinical signs, eosinophil infiltration, and eosinophil peroxidase activity in the guinea pig conjunctiva; furthermore, it reduced conjunctival mRNA levels and protein expression of both CCL5 and CCL11. Mapracorat was more effective than dexamethasone in increasing, in conjunctival sections of OVA-treated guinea pigs, apoptotic eosinophils. CONCLUSION: Mapracorat displays anti-allergic properties in controlling the late phase of ocular allergic conjunctivitis and is a promising candidate for the topical treatment of allergic eye disorders.

A cause for concern: male couples' sexual agreements and their use of substances with sex.

Substance use is strongly associated with HIV risk among gay men. Many gay couples establish sexual agreements. However, little is known about gay couples' use of substances with sex, and whether substance use is associated with couples' agreements. The present study assessed whether gay couples' use of substances with sex was associated with their establishment of, type of, and adherence to, a sexual agreement. Dyadic data from 275 HIV-negative US gay couples were collected online in a nation-wide, cross-sectional study, and analyzed at the couple-level. Findings revealed that couples with an established agreement, and a recently broken agreement, were more likely to have used amyl nitrates and marijuana with sex within their relationship. This same trend was also noted, but for alcohol use with sex outside of couples' relationships. Further research is urgently needed to examine the fluidity of HIV-negative gay male couples' sexual agreements and substance use with sex.

In-vitro evaluation of chronic alcohol effects on expression of drug-metabolizing and drug-transporting proteins.

OBJECTIVES: In alcoholics without alcoholic liver disease, boosted drug elimination has been reported. However, mechanistic explanations for this phenomenon remain uncertain. In particular, data on the potential role of drug transporters are sparse. METHODS: Using a well-established in-vitro model for induction of human drug-metabolizing and drug-transporting proteins, we evaluated the potency of ethanol and the major fermentation side-product isopentanol to alter expression and function of these proteins by quantitative real-time polymerase chain reaction, Western blotting and flow cytometry. P-glycoprotein (Pgp)-inhibiting properties of ethanol and isopentanol were investigated via calcein extrusion assay. KEY FINDINGS: Ethanol and isopentanol significantly changed expression levels of drug-metabolizing and drug-transporting proteins that normalized within 2 weeks upon withdrawal. Cytochrome P-450 2C19 and Pgp were most strongly induced. Ethanol-induced Pgp at the messenger RNA (mRNA) (twofold to eightfold) and protein level (twofold), but not at the functional level. Both compounds did not inhibit Pgp. CONCLUSIONS: Ethanol is demonstrated to increase mRNA and protein expression of human drug transporters such as Pgp in vitro. Withdrawal of ethanol exposure causes return to non-induced conditions within weeks. Functional consequences of increased Pgp expression in alcoholics need to be evaluated by clinical trials applying selective Pgp substrates such as digoxin.

Repeated administration of tribromoethanol in C57BL/6NHsd mice.

We evaluated the effect of repeated intraperitoneal administration of tribromoethanol on various parameters in C57BL/6NHsd mice. Mice (n = 68) were randomly assigned to 1 of 7 groups to receive tribromoethanol (500 mg/kg IP) on day 0 or days 0 and 8; vehicle (tert-amyl alcohol in sterile water) only on day 0 or days 0 and 8; sterile water injection on day 0 or days 0 and 8; or no treatment. A single dose of tribromoethanol failed to produce loss of pedal reflex and had no effect on median food and water consumption but altered median body weight on days 1 through 4 when compared with that in mice that received vehicle only or no treatment. Median body weight did not differ between mice that received a single dose of tribromoethanol and those that received an injection of water. Among mice given 2 doses of tribromoethanol, induction time, anesthetic duration, and recovery time varied widely. Repeated administration of tribromoethanol had no effect on median food and water consumption or body weight compared with those in controls. Median liver weight was significantly greater in mice that received 2 doses compared with a single dose of tribromoethanol. Median liver weight did not differ between untreated mice and those that received tribromoethanol. No significant organ or tissue pathology was observed in any study animal. Although tribromoethanol did not produce morbidity, mortality, or pathologic changes in treated animals, we urge caution in use of tribromoethanol in C57BL/6NHsd mice due to its variable anesthetic effectiveness.

Vitiliginous lesions induced by amyl nitrite exposure.

Chemical (or contact) leukoderma is a condition induced by local cutaneous exposure to chemicals or medicaments that are toxic to melanocytes and/or koebnerize preexisting vitiligo vulgaris. Chemicals known to induce leukoderma include phenol/catechol derivatives (eg, hydroquinone), sulfhydryls, contact sensitizing agents (eg, squaric acid dibutylester), and more recently imiquimod, among others. We report the case of a 37-year-old black man with human immunodeficiency virus who developed chemical leukoderma in the nasal and perioral areas within 4 weeks of spilling liquid amyl nitrite, which he had been inhaling as a recreational drug, on his lower face. The depigmented regions were treated with a biweekly regimen of 308-nm excimer laser treatment for a total of 78 sessions. More than 90% cutaneous repigmentation was achieved. Amyl nitrite-induced vitiliginous lesions are rare. We also discuss potential mechanisms of hypopigmentation from chemical agents and therapeutic options for chemical leukoderma.

Two forms of learning following training to a single odorant in Caenorhabditis elegans AWC neurons.

The nematode Caenorhabditis elegans can adapt to both the AWC-sensed odorants benzaldehyde (Bnz) and isoamyl alcohol (IsoA) and can reciprocally cross-adapt. Yet we reveal that these four adaptation scenarios actually represent two distinct forms of learning: nonassociative habituation and associative learning by pairing with a starvation unconditioned stimulus. Training to the single odorant IsoA leads to both associative and nonassociative memory traces, which can be preferentially accessed by either a Bnz or IsoA retrieval stimulus, respectively. This represents the first demonstration in which the form of learning displayed after training to a single stimulus is a function of the retrieval stimulus used. Furthermore, these two forms of learning can be genetically double dissociated despite both forms occurring within the AWC primary sensory neuron. We find that associative learning requires the cGMP-dependent kinase egl-4 and insulin signaling, which acts downstream of egl-4. In contrast, nonassociative learning requires neither of these genes, but does require the TRPV channel osm-9, which is dispensable for associative learning. In addition, we find that the arrestin arr-1 is promiscuous between associative and nonassociative learning in mediating the adaptive response to the IsoA retrieval stimulus, suggesting that distinct forms of memory may nonetheless use common downstream effectors.

A conditioned aversion study of sucrose and SC45647 taste in TRPM5 knockout mice.

Previously, published studies have reported mixed results regarding the role of the TRPM5 cation channel in signaling sweet taste by taste sensory cells. Some studies have reported a complete loss of sweet taste preference in TRPM5 knockout (KO) mice, whereas others have reported only a partial loss of sweet taste preference. This study reports the results of conditioned aversion studies designed to motivate wild-type (WT) and KO mice to respond to sweet substances. In conditioned taste aversion experiments, WT mice showed nearly complete LiCl-induced response suppression to sucrose and SC45647. In contrast, TRPM5 KO mice showed a much smaller conditioned aversion to either sweet substance, suggesting a compromised, but not absent, ability to detect sweet taste. A subsequent conditioned flavor aversion experiment was conducted to determine if TRPM5 KO mice were impaired in their ability to learn a conditioned aversion. In this experiment, KO and WT mice were conditioned to a mixture of SC45647 and amyl acetate (an odor cue). Although WT mice avoided both components of the stimulus mixture, they avoided SC45647 more than the odor cue. The KO mice also avoided both stimuli, but they avoided the odor component more than SC45647, suggesting that while the KO mice are capable of learning an aversion, to them the odor cue was more salient than the taste cue. Collectively, these findings suggest the TRPM5 KO mice have some residual ability to detect SC45647 and sucrose, and, like bitter, there may be a TRPM5-independent transduction pathway for detecting these substances.

Fragrance material review on 2-methyl-5-phenylpentanol.

A toxicologic and dermatologic review of 2-methyl-5-phenylpentanol when used as a fragrance ingredient is presented. 2-Methyl-5-phenylpentanol is a member of the fragrance structural group aryl alkyl alcohols and is a primary alcohol. The AAAs are a structurally diverse class of fragrance ingredients that includes primary, secondary, and tertiary alkyl alcohols covalently bonded to an aryl (Ar) group, which may be either a substituted or unsubstituted benzene ring. The common structural element for the AAA fragrance ingredients is an alcohol group -C-(R1)(R2)OH and generically the AAA fragrances can be represented as an Ar-C-(R1)(R2)OH or Ar-Alkyl-C-(R1)(R2)OH group. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 2-methyl-5-phenylpentanol were evaluated then summarized and includes physical properties, acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, repeated dose, and genotoxicity data. A safety assessment of the entire aryl alkyl alcohols will be published simultaneously with this document; please refer to Belsito et al. (2012) for an overall assessment of the safe use of this material and all other branched chain saturated alcohols in fragrances.

Eosinophil as a cellular target of the ocular anti-allergic action of mapracorat, a novel selective glucocorticoid receptor agonist.

PURPOSE: Glucocorticoids can either suppress gene transcription (transrepression) or activate it (transactivation). This latter process may contribute to certain side effects caused by these agents. Mapracorat (also known as BOL-303242-X or ZK 245186) is a novel selective glucocorticoid receptor agonist that maintains a beneficial anti-inflammatory activity but seems to be less effective in transactivation, resulting in a lower potential for side effects; it has been proposed for the topical treatment of inflammatory skin disorders. This study assessed the anti-allergic activity of mapracorat at the ocular level and whether eosinophils and mast cells are targets of its action. METHODS: With in vitro studies apoptosis was evaluated in human eosinophils by flow cytometry and western blot of caspase-3 fragments. Eosinophil migration toward platelet-activating factor was evaluated by transwell assays. Interleukin (IL)-6, IL-8, tumor necrosis factor-α (TNF-α), and the chemokine (C-C motif) ligand 5 (CCL5)/regulated upon activation normal T cell expressed, and presumably secreted (RANTES) were measured using a high-throughput multiplex luminex technology. Annexin I and the chemochine receptor C-X-C chemokine receptor 4 (CXCR4) were detected by flow cytometry. With in vivo studies, allergic conjunctivitis was induced in guinea pigs sensitized to ovalbumin by an ocular allergen challenge and evaluated by a clinical score. Conjunctival eosinophils were determined by microscopy or eosinophil peroxidase assay. RESULTS: In cultured human eosinophils, mapracorat showed the same potency as dexamethasone but displayed higher efficacy in increasing spontaneous apoptosis and in counteracting cytokine-sustained eosinophil survival. These effects were prevented by the glucocorticoid receptor antagonist mifepristone. Mapracorat inhibited eosinophil migration and IL-8 release from eosinophils or the release of IL-6, IL-8, CCL5/RANTES, and TNF-α from a human mast cell line with equal potency as dexamethasone, whereas it was clearly less potent than this glucocorticoid in inducing annexin I and CXCR4 expression on the human eosinophil surface; this was taken as a possible sign of glucocorticoid-dependent transactivation. In the guinea pig, mapracorat or dexamethasone eye drops induced an analogous reduction in clinical symptoms of allergic conjunctivitis and conjunctival eosinophil accumulation. CONCLUSIONS: Mapracorat appears to be a promising candidate for the topical treatment of allergic eye disorders. It maintains an anti-allergic profile similar to that of dexamethasone but seems to have fewer transactivation effects in comparison to this classical glucocorticoid. Some of its cellular targets may contribute to eosinophil apoptosis and/or to preventing their recruitment and activation and to inhibiting the release of cytokines and chemokines.

In vivo ocular efficacy profile of mapracorat, a novel selective glucocorticoid receptor agonist, in rabbit models of ocular disease.

PURPOSE: To compare the efficacy of mapracorat (formerly ZK-245186, and subsequently BOL-303242-X), a novel selective glucocorticoid receptor agonist (SEGRA), with that of dexamethasone (DEX) in rabbit models of ocular disease. The effects of topical BOL-303242-X and DEX on intraocular pressure (IOP) and body weight changes were also evaluated. METHODS: Dry eye was induced by atropine sulfate administration and was treated with saline, BOL-303242-X (0.1%-1.0%), DEX (0.1%), Restasis 0.05% (Allergan, Inc., Irvine, CA), or Refresh Endura (Allergan, Inc.) three times per day for 7 to 8 days. For paracentesis studies, vehicle, BOL-303242-X (0.1%, 0.5%, and 1.0%), or DEX (0.1%) were repeatedly administered topically 3 hours before paracentesis and continued for 90 minutes afterward. For IOP and body weight measurements, right eyes of rabbits were topically treated with vehicle, BOL-303242-X (1.0% or 0.1%), or DEX (0.1%) four times per day for 6 weeks. RESULTS: In the dry eye model, BOL-303242-X and DEX were fully efficacious, maintaining tear volume and tear breakup time (TBUT) at baseline levels. Although Restasis improved tear volume compared with vehicle, no changes were observed in TBUT. In the paracentesis study, BOL-303242-X and DEX improved ocular inflammation. BOL-303242-X reduced protein and PGE(2) levels. Finally, BOL-303242-X showed no effects on integrated IOP or body weight, whereas DEX significantly increased integrated IOP and prevented the increase of body weight observed in the vehicle-treated animals. CONCLUSIONS: BOL-303242-X shows full anti-inflammatory efficacy (similar to DEX) in experimental models of dry eye and postoperative inflammation while demonstrating reduced effects in IOP and body weight. These data indicate that mapracorat, a SEGRA, shows efficacy similar to that of traditional steroids while exhibiting an improved side effect profile in IOP and muscle wasting.