Anti-inflammatory, antinociceptive effects and involvement of opioid receptors in the antinociceptive activity of Eugenia uniflora leaves obtained with water, ethanol, and propylene glycol mixture.

ETHNOPHARMACOLOGICAL RELEVANCE: Eugenia uniflora (Myrtaceae) is a species native to Brazil and has a traditional use in the treatment of inflammation. AIM OF THE STUDY: To evaluate the anti-inflammatory and antinociceptive effects, and the involvement of opioid receptors in the antinociceptive activity of extract and fractions from Eugenia uniflora leaves. MATERIALS AND METHODS: TLC and HPLC were used to characterize the spray-dried extract (SDE) and fractions. In the in vivo assays, Swiss (Mus musculus) mice were used. Carrageenan-induced hind-paw edema and carrageenan-induced peritonitis models were used to determine the anti-inflammatory effect of the extract (50, 100, or 200 mg/kg). Acetic acid-induced writhing, tail-flick, and formalin tests were used to determine the antinociceptive effect of the extract (50, 100, or 200 mg/kg). The aqueous (AqF) and ethyl acetate (EAF) fractions (6.25, 12.5, and 25 mg/kg) were then combined with naloxone to evaluate the involvement of opioid receptors in the antinociceptive activity. RESULTS: In this work, the TLC and HPLC analysis evidenced the enrichment of EAF, which higher concentration of gallic acid (5.29 ± 0.0004 %w/w), and ellagic acid (1.28 ± 0.0002 %w/w) and mainly myricitrin (8.64 ± 0.0002 %w/w). The extract decreased the number of total leukocytes and neutrophils in the peritoneal cavity (p < 0.05), at doses of 100 and 200 mg/kg and showed significant inhibition in the increase of paw edema volume (p < 0.05). The treatment per oral route (doses of 50, 100, and 200 mg/kg) significantly reduced the nociceptive response in acetic acid-induced abdominal writhing (p < 0.05). The effect of the extract on the tail-flick test showed a significant increase in latency time of animals treated at doses of 200 and 100 mg/kg (p < 0.05). The extract and ethyl acetate fraction reduced the nociceptive effect in both phases of formalin at all tested doses. The naloxone reversed the antinociceptive effect of EAF, suggesting that opioid receptors are involved in mediating the antinociceptive activity of EAF of E. uniflora in the formalin test. CONCLUSION: The current study demonstrates the anti-inflammatory and analgesic activities of water: ethanol: propylene glycol spray-dried extract from E. uniflora leaves using in vivo pharmacological models in mice. Our findings suggest that spray-dried extract and ethyl acetate fraction exhibit peripheral and central antinociceptive activity with the involvement of opioid receptors that may be related to the presence of flavonoids, mainly myricitrin.

Comparative study of cytotoxicity and genotoxicity of commercial Jeffamines® and polyethylenimine in CHO-K1 cells.

Jeffamines® are a family of polymers containing primary amine groups attached to the extremities of polyether backbone which can be used as biomaterials. They have been used in combination with polyethylenimine (PEI) to improve biocompatibility in drug and gene delivery systems. Despite these facts, very few studies have been done on cytotoxicity and genotoxicity of pure Jeffamines® or compared with PEI. The present study aimed to evaluate and compare the cytotoxic and genotoxic effects of Jeffamines® and PEI in CHO-K1 cells. Specifically, polypropylene oxide 2000 (PPO 2000, Jeffamine® D series), polyethylene oxide 1900 (PEO 1900, Jeffamine® ED series), branched 25 kDa PEI, and linear 20 kDa PEI were evaluated at different concentrations. Cell viability and proliferation were assessed by 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) and 5-bromo-2'-deoxyuridine (BrdU) assays, respectively. Genotoxicity was evaluated using single cell gel electrophoresis assay and the cytokinesis-blocked micronucleus assay. PPO 2000 was the most cytotoxic Jeffamine® , whereas PEO 1900 did not caused significant cell death at any tested concentration. Branched PEI was more cytotoxic than linear PEI (LPEI) and both were more cytotoxic than Jeffamines® . Only PPO 2000 induced DNA damage when evaluated in comet assay probably due to its cytotoxicity. PPO 2000, PEO 1900, and PEI did not increase the frequency of micronuclei when tested at sub-cytotoxic concentrations. This work provides new insights about biocompatibility of Jeffamines® and PEI and suggests the genotoxicological safety for further investigations of PEO 1900 in drug and gene delivery systems. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 742-750, 2018.

Evaluation of the lymphocyte trafficking drug FTY720 in vaginal tissues.

BACKGROUND: FTY720 is an immunomodulatory agent that reduces lymphocytes in peripheral tissues and circulation. Such agents may be effective as vaginal microbicides for HIV prevention. Systemic or vaginal application of FTY720 may reduce lymphocyte concentrations in genital tissues, reducing HIV target cell numbers. METHODS: Five female pigtail macaques received topical vaginal gel FTY720 (n = 2), intravenous (i.v.) FTY720 (n = 2), or placebo gel (n = 1) in this pilot study. Circulating and mucosal lymphocytes and genital mucosa, cytokines, and tissue histology were analyzed to document topical and i.v. FTY720 effects. RESULTS: Topical and i.v. FTY720 appeared to decrease the levels of cervicovaginal IL-8, IL-1ra, and genital inflammatory cells. Small sample size precluded statistical analysis. Topical administration had no overt adverse effects. CONCLUSIONS: This study introduces FTY720 as an immunomodulatory agent for the vaginal mucosa, compares topical effects to those of i.v. administration, and provides the basis for future studies involving FTY720 for HIV prevention.

The clinically-tested S1P receptor agonists, FTY720 and BAF312, demonstrate subtype-specific bradycardia (S1P1) and hypertension (S1P3) in rat.

Sphingosine-1-phospate (S1P) and S1P receptor agonists elicit mechanism-based effects on cardiovascular function in vivo. Indeed, FTY720 (non-selective S1P(X) receptor agonist) produces modest hypertension in patients (2-3 mmHg in 1-yr trial) as well as acute bradycardia independent of changes in blood pressure. However, the precise receptor subtypes responsible is controversial, likely dependent upon the cardiovascular response in question (e.g. bradycardia, hypertension), and perhaps even species-dependent since functional differences in rodent, rabbit, and human have been suggested. Thus, we characterized the S1P receptor subtype specificity for each compound in vitro and, in vivo, the cardiovascular effects of FTY720 and the more selective S1P1,5 agonist, BAF312, were tested during acute i.v. infusion in anesthetized rats and after oral administration for 10 days in telemetry-instrumented conscious rats. Acute i.v. infusion of FTY720 (0.1, 0.3, 1.0 mg/kg/20 min) or BAF312 (0.5, 1.5, 5.0 mg/kg/20 min) elicited acute bradycardia in anesthetized rats demonstrating an S1P1 mediated mechanism-of-action. However, while FTY720 (0.5, 1.5, 5.0 mg/kg/d) elicited dose-dependent hypertension after multiple days of oral administration in rat at clinically relevant plasma concentrations (24-hr mean blood pressure = 8.4, 12.8, 16.2 mmHg above baseline vs. 3 mmHg in vehicle controls), BAF312 (0.3, 3.0, 30.0 mg/kg/d) had no significant effect on blood pressure at any dose tested suggesting that hypertension produced by FTY720 is mediated S1P3 receptors. In summary, in vitro selectivity results in combination with studies performed in anesthetized and conscious rats administered two clinically tested S1P agonists, FTY720 or BAF312, suggest that S1P1 receptors mediate bradycardia while hypertension is mediated by S1P3 receptor activation.

Non-fragrance allergens in specific cosmetic products.

OBJECTIVES: Reports about the nature of the ingredients responsible for allergic contact dermatitis caused by specific cosmetic products are scarce. METHODS: Between January 2000 and December 2010, the specific cosmetic products having caused allergic contact dermatitis, as well as the individual allergenic cosmetic ingredients present in them, were recorded by use of a standardized form. RESULTS: Among 11 different categories of cosmetic product, skin care products, followed by hair care and body-cleansing products, were most often involved. The presence of the allergenic ingredient(s) in a specific cosmetic product was confirmed according to the ingredient label in 959 of 1448 records. Six hundred and twenty-one of 959 concerned non-fragrance components, preservatives being responsible for 58% of them. Reactions to formaldehyde and formaldehyde-releasers were most often correlated with body-cleansing products, particularly 2-bromo-2-nitropropane-1,3-diol and skin care products. They were followed by the methylchloroisothiazolinone/methylisothiazolinone mixture, most frequently found as allergens in hair care and intimate hygiene products, and facial cleansers (in the last category together with diazolidinyl urea). Octocrylene was by far the most frequent (photo)allergen in sun care products. CONCLUSIONS: This study provides information on the presence and frequency of allergens in specific causal cosmetic products.

Emergent and unusual allergens in cosmetics.

Allergic contact dermatitis from cosmetics is a common problem that is occasionally caused by new or rare allergens. When a patient has a positive patch test to a cosmetic product but to none of the common or commercially available allergens, it is important to further patch-test this patient to the ingredients of the product. Thorough testing with the breakdown of ingredients, usually obtained through cooperation with the manufacturer, often allows identification of the culprit allergen in the cosmetic product. In this article, we discuss emerging or rare allergens discovered by this method, including nail lacquer and lipstick allergens, copolymers, shellac, alkyl glucosides, glycols, protein derivatives, idebenone, and octocrylene.

Intralesional Ethibloc injections in primary aneurysmal bone cysts: an efficient and safe treatment.

OBJECTIVE: Ethibloc is a fibrogenic and thrombogenic agent recently proposed for the treatment of bone cysts. The purpose of this study is to report the results of direct Ethibloc injection in primary aneurysmal bone cyst (ABC) in children. DESIGN AND PATIENTS: Seventeen patients, aged from 2 to 18 years (mean 8 years), were treated with either a single injection (14 patients) or supplementary injections (3 patients) of Ethibloc. The histological diagnosis was assessed following surgical biopsy and was retrospectively reviewed. The mean follow-up was 5 years (range 18 months to 11 years). RESULTS: At 5 year follow-up, 14 of 17 patients demonstrated complete healing manifest by increased cortical and septal thickening. Surgical excision was required in three patients, in two of whom the ABC increased rapidly in size despite the injection, and in one of whom the healing was incomplete. We observed inflammatory reactions in 16 of 17 patients with local pain and fever. Three patients developed a small cutaneous fistula which resolved spontaneously in a few weeks. No major complications such as deep infection, pulmonary embolism, epiphyseal necrosis or malignant degeneration were observed. CONCLUSION: Percutaneous direct Ethibloc injection is a safe, efficient and noninvasive treatment for ABC. The authors highlight the frequent local reactions.

The Spanish toxic oil syndrome 20 years after its onset: a multidisciplinary review of scientific knowledge.

In 1981, in Spain, the ingestion of an oil fraudulently sold as olive oil caused an outbreak of a previously unrecorded condition, later known as toxic oil syndrome (TOS), clinically characterized by intense incapacitating myalgias, marked peripheral eosinophilia, and pulmonary infiltrates. Of the 20,000 persons affected, approximately 300 died shortly after the onset of the disease and a larger number developed chronic disease. For more than 15 years, a scientific committee supported by the World Health Organization's Regional Office for Europe and by the Institute of Health Carlos III in Madrid has guided investigation intended to identify the causal agent(s), to assess toxicity and mode of action, to establish the pathogenesis of the disease, and to detect late consequences. This report summarizes advances in research on this front. No late mortality excess has been detected. Among survivors, the prevalence of some chronic conditions (e.g., sclerodermia, neurologic changes) is high. Attempts to reproduce the condition in laboratory animals have been unsuccessful, and no condition similar to TOS has been reported in the scientific literature. Laboratory findings suggest an autoimmune mechanism for TOS, such as high levels of seric soluble interleukin-2 receptor. Epidemiologic studies integrated with chemical analyses of case-related oils have shown that the disease is strongly associated with the consumption of oils containing fatty acid esters of 3-(N-phenylamino)-1,2-propanediol (PAP). These chemicals have also been found in oils synthesized under conditions simulating those hypothesized to have occurred when the toxic oil was produced in 1981. Whether PAP esters are simply markers of toxicity of oils or have the capability to induce the disease remains to be elucidated.

Advances in the medical treatment of epilepsy.

Treatment options for epilepsy, especially using antiepileptic drugs, have increased substantially in the past five years. Since 1993, four novel antiepileptic drugs have been approved and marketed in the United States: felbamate, gabapentin, lamotrigine, and topiramate. Two others, tiagabine and vigabatrin, are likely to be approved in the near future. For many patients, these agents offer the realistic promise of improved seizure control, often with fewer adverse effects and less significant drug interactions compared with older agents. In addition, fosphenytoin, a water-soluble phenytoin prodrug with a number of advantages over intravenous phenytoin, has been released. There are new administration options for carbamazepine, diazepam, and valproic acid. For drug-resistant or -intolerant patients, there has been renewed interest in alternative therapies, especially the ketogenic diet. Taken together, these represent significant therapeutic advances that are benefiting patients with epilepsy. At the same time, improved understanding of the basic mechanisms of epileptogenesis, and of the cellular and molecular actions of available antiepileptic drugs, creates a framework for designing unique therapeutic strategies that are targeted at key sites of vulnerability involved in the development and maintenance of the epileptic state.

Vaginal lubricants for the infertile couple: effect on sperm activity.

OBJECTIVE: To determine the effects of natural vegetable oils and vaginal lubricants on sperm motion and viability. DESIGN: Four widely used vaginal lubricants (K-Y Jelly, Astroglide, Replens, and Touch) and two vegetable oil products that have been used as vaginal lubricants were purchased through local vendors. Sperm was obtained by masturbation without lubrication from normal, healthy donors. Lubricants were mixed with sperm from individual donors and the effects on sperm motility were determined at 1, 15, 30, and 60 minutes. SETTING: Southwestern Fertility Associates of The University of Texas Southwestern Medical Center at Dallas. MAIN OUTCOME MEASURES: Sperm motility was evaluated by manual motility counts and by computer-assisted semen analysis. Sperm viability was evaluated with Hoechst 33258 dye. The effects of the various lubricants were compared with those of a spermicidal agent, Gynol II (negative control) and Ham's F-10 (positive control). RESULTS: Commercial lubricants inhibited sperm motility by 60-100% after 60 minutes of incubation. Sperm exposed to Replens or Astroglide were nonmotile and nonviable after incubation for 60 minutes, similar to the control, nonoxynol-9 containing product Gynol II. Canola oil had no detrimental effects and was indistinguishable from Ham's F-10 in terms of sperm viability and motility. CONCLUSIONS: For couples with infertility, the use of vaginal lubricants during intercourse is not recommended. In cases where a lubricant is required, careful selection can maximize sperm motility and viability.

A comparison of the acute pathology induced by 3-phenylamino-1,2-propanediol (PAP) and its mono-oleoyl ester in rodents with the toxic oil syndrome in man.

Phenylamino-1,2 propanediol (PAP) and its mono-oleoyl ester have been identified in samples of the cooking oil thought to be responsible for the Toxic Oil Syndrome (TOS) which occurred in Spain in 1981. The acute toxicity of PAP and its mono-oleoyl ester have been examined in rats and mice, after daily administration for periods of up to 14 days to determine whether these compounds could produce any of the pathologies of TOS. Even at the highest dose, the 1-mono-oleoyl ester of 3-phenylamino-1,2 propanediol did not cause any toxicity in rats or mice when given intraperitoneally. 3-Phenylamino-1,2 propanediol, however, was toxic when administered to rats by this route. After 6-10 consecutive daily doses of PAP, at the highest dose administered (350 mg kg-1), all of the rats became unwell. Postmortem examination showed that the major pathology present was massive pulmonary thromboembolism. Further investigations of the toxicity of PAP after intravenous administration showed that it was not directly vasotoxic. The pulmonary thromboembolism seen with intraperitoneally administered PAP was due to the toxic effect of PAP on the mesenteric tissue and blood vessels, causing thrombosis which subsequently embolised the blood vessels in the lung. Intra-gastric administration of PAP caused no toxicity in rats. Comparatively, the pathology seen after intraperitoneal administration of PAP was not thought to be representative of the pathology of the toxic oil syndrome in man.

Contact dermatitis after transcutaneous electric analgesia.

Transcutaneous electric analgesia, based on the gate control theory, is used in stump pain, lumbar pain, traumatic pain following nerve damage and sciatic neuralgia. 3 patients using this method, showed contact dermatitis at the sites of contact of the electrodes. Patch tests were positive with the electrolyte gel, and in 2 cases, with propylene glycol. Transcutaneous electric analgesia may cause a certain number of side effects similar to those encountered with electrocardiography.

Dermatitis from transcutaneous electric nerve stimulation.

Transcutaneous electric nerve stimulation (TENS) is an effective treatment modality for chronic pain. Electrical impulses produced by a portable stimulator are transmitted by cable to electrodes which are attached to specific areas of the body by tape or adhesive. A conductive electrolyte jelly is utilized in order to make good electrical contact with the skin. Several dermatologic complications have been associated with the use of this technic, including allergic and irritant contact dermatitis and micropunctate burns caused by the improper use of poorly conductive lubricant jellies. A patient is reported herein who developed allergic contact dermatitis to propylene glycol in a conductive jelly (Neuromod TENS gel). In an attempt to continue therapy, the patient changed to a poorly conductive surgical lubricant jelly which caused irritation and micropunctate burns. Subsequently, electrodes not utilizing conductive jelly were applied, with excellent results.

Local reactions to i.v. diazepam in three different formulations.

Local venous reactions during and after i.v injections of three different formulations of diazepam were studied in 200 patients undergoing gastroscopy. Of the patients receiving diazepam in propylene glycol (Stesolid) 78% experienced pain on injection and 48% subsequently developed clinical evidence of thrombophlebitis. The figures for Stesolid MR (diazepam in Cremophor EL) were 38% and 9% respectively. A significant decrease was achieved (pain on injection 1%; clinical thrombophlebitis 4%) when using Diazemuls, a new formulation in which diazepam is dissolved in oil and emulsified in water. Since no difference in the therapeutic effect of the different formulations was observed, Diazemuls represents a clear advantage to Stesolid and Stesolid MR.