Correlation of hair cortisol and interleukin 6 with structural change in the active progression of keratoconus.

PURPOSE: To evaluate interleukin (IL) and hair cortisol concentrations (HCCs) in progressive keratoconus (KC) and compare them with KC-stable eyes and healthy control, and to determine the correlation of these inflammatory mediators and HCCs and their relationship with structural damage represented by increased corneal curvature. SETTING: University of Sao Paulo, Brazil. DESIGN: Prospective observational comparative study. METHODS: 133 eyes of 74 patients were included. The concentrations of tear cytokines: IL1B, IL6, IL8, IL10, IL12p70, and tumor necrosis factor α were obtained by capillary flow and measured using a flow cytometer. HCCs were determined from the most proximal hair segment as an index of cumulative secretion and measured by liquid chromatography mass spectrometry. RESULTS: 133 eyes of 74 patients. Only IL6 was increased in progressive KC tears compared with stable KC (6.59 ± 3.25 pg/mL vs 4.72 ± 1.91 pg/mL; P < .0001) with a positive correlation between IL6 and maximum keratometry (Kmax) (P < .0001). Progressive KC exhibited significantly higher HCC than stable KC (0.624 ± 0.160 ng/mg vs 0.368 ± 0.0647 ng/mg; P < .0001) and healthy controls (0.624 ± 0.160 ng/mg vs 0.351 ± 0.0896 ng/mg; P < .0001). There was a significant correlation between HCC and Kmax (P < .0001). CONCLUSIONS: KC eyes that are progressing have a higher concentration of IL6 and long-term cortisol than patients with stable forms of KC; second, there is a significant correlation between this increase in IL6 and cortisol with corneal structural damage. Finally, there is a meaningful relationship between this interleukin and the previous few months' cortisol levels.

Acute toxicity, antinociceptive, and anti-inflammatory activities of the orally administered crotamine in mice.

Crotamine is a polypeptide toxin isolated from rattlesnake venom. Although several studies have been developed identifying many biological effects of isolated crotamine, none of them evaluated its acute toxicity, antinociceptive, and anti-inflammatory activities through oral administration. All in vivo experiments from this study were performed in mice. The up-and-down procedure and hippocratic screening were carried out to evaluate possible pharmacological and toxic effects. Antinociceptive and anti-inflammatory activities of this toxin were evaluated using acetic acid-induced abdominal writhing, formalin-induced pain assays, croton oil-induced ear edema, and carrageenan-induced pleurisy. Crotamine did not cause lethality or signs of intoxication up to the maximum dose tested (10.88 mg/kg). The number of contortions was reduced significantly by 34, 57, and 74% at the oral doses of 0.08, 0.16, and 0.32 mg/kg, respectively. At the dose of 0.16 mg/kg, crotamine decreases pain time-reactivity at neurogenic phase by 45% and at inflammatory phase by 60%. Also, crotamine elicited antiedematogenic activity through the attenuation of the croton oil-induced ear edema by 77%. In the carrageenan-induced pleurisy, the leukocyte, neutrophil, and mononuclear cell migration to the lesion site were reduced by 52%, 46%, and 59%, respectively. Altogether, crotamine demonstrated in vivo antinociceptive and anti-inflammatory effect through acute oral administration, generating an anti-migratory mechanism of action at non-toxic doses.

Food-Effect on (-) - Hydroxycitric Acid Absorption After Oral Administration of Garcinia cambogia Extract Formulation: a Phase I, Randomized, Cross-Over Study.

Garcinia cambogia extract (GCE)/(-) - hydroxycitric acid (HCA) has been identified as a potential antiobesity agent. However, controversial clinical trial results have been published on its biological effect and poor pharmacokinetic (PK) information increases its dubious efficacy. The aim of this study was to determine the main PK parameters of GCE/HCA in healthy women, and to evaluate food effects on HCA absorption. Healthy women ages 21-41 years with body mass index (BMI; kg/m2) 20.29-25.82 participated in a phase I, open-label, randomized, single-dose, cross-over study. In the fasted- and fed-conditions subjects received 1500/750 mg of GCE/HCA under 8 h of fasting. In the fed-period was given a high calorie breakfast (~600 calories) after dosing. Plasma HCA concentrations were substantially reduced in fed-state. Peak plasma concentration (Cmax) and area under the curve of time-concentration (AUC0-10h) were 3-fold and 2-fold lower (p < 0.001, 0.01) in fed-condition, respectively. Higher volume of distribution (Vd/F) and clearance (Cl/F) were achieved in fed state, probably due to the lower fraction (F) of HCA absorbed induced by food effect. Large inter-individual variations were observed for the main pharmacokinetics parameters in both periods. These findings suggest that HCA might suffer an active absorption uptake and intense adsorption on food.

LQFM184: A Novel Wide Ultraviolet Radiation Range Absorber Compound.

The use of sunscreen has become an indispensable daily routine since UV radiation is a critical environmental stress factors for human skin. This study focused on the design, synthesis, thermal/chemical stability and efficacy/safety evaluations of a new heterocyclic derivative, namely LQFM184, as a photoprotective agent. The compound showed stability when submitted under oxidative and high-temperature conditions. It also revealed an absorption at 260-340 nm (UVA/UVB), with a main band at 298 nm and a shoulder close to 334 nm. LQFM184 showed capacity to interact with other existing UV filters, promoting an increase in the sun protection factor. In relation to acute toxicity, its estimated LD50 was >300-2000 mg kg-1 , probably with a low potential of inducing acute oral systemic toxicity hazard. In addition, our data showed that this compound did not have eye irritation, skin sensitization or phototoxicity potentials. Taken together, these findings make LQFM184 a promising ingredient to be used, alone or in association with other UV filters, in cosmetic products such as sunscreens with a broad spectrum of protection.

Salvindolin elicits opioid system-mediated antinociceptive and antidepressant-like activities.

BACKGROUND: Salvinorin A is known as a highly selective kappa opioid receptor agonist with antinociceptive but mostly pro-depressive effects. AIMS: In this article, we present its new semisynthetic analog with preferential mu opioid affinity, and promising antinociceptive, as well as antidepressant-like activities. METHODS: Competitive binding studies were performed for salvindolin with kappa opioid and mu opioid. The mouse model of nociception (acetic-acid-induced writhing, formalin, and hot plate tests), depression (forced swim and tail suspension tests), and the open field test, were used to evaluate antinociceptive, antidepressant-like, and locomotion effects, respectively, of salvindolin. We built a 3-D molecular model of the kappa opioid receptor, using a mu opioid X-ray crystal structure as a template, and docked salvindolin into the two proteins. RESULTS/OUTCOMES: Salvindolin showed affinity towards kappa opioid and mu opioid receptors but with 100-fold mu opioid preference. Tests of salvindolin in mice revealed good oral bioavailability, antinociceptive, and antidepressive-like effects, without locomotor incoordination. Docking of salvindolin showed strong interactions with the mu opioid receptor which matched well with experimental binding data. Salvindolin-induced behavioral changes in the hot plate and forced swim tests were attenuated by naloxone (nonselective opioid receptor antagonist) and/or naloxonazine (selective mu opioid receptor antagonist) but not by nor-binaltorphimine (selective kappa opioid receptor antagonist). In addition, WAY100635 (a selective serotonin 1A receptor antagonist) blocked the antidepressant-like effect of salvindolin. CONCLUSIONS/INTERPRETATION: By simple chemical modification, we were able to modulate the pharmacological profile of salvinorin A, a highly selective kappa opioid receptor agonist, to salvindolin, a ligand with preferential mu opioid receptor affinity and activity on the serotonin 1A receptor. With its significant antinociceptive and antidepressive-like activities, salvindolin has the potential to be an analgesic and/or antidepressant drug candidate.

Evaluation of the chemical composition and variability of the volatile oils from Trembleya parviflora leaves

Abstract Trembleya parviflora (D. Don) Cogn., Melastomataceae, also known as "quaresmeira-branca", is a subshrub that is commonly used to treat verminosis, scabies, dermatoses, rheumatism, vaginal infections, ulcerations and wounds. The aim of this work was to perform a morphological study of T. parviflora, evaluate the composition and chemical variability of the volatile oils from the leaves, perform phytochemical screening of the powder from the leaves and to define parameters for quality control of the plant material. Macroscopic characterization of T. parviflora was carried out by naked eye in Serra dos Pireneus, Pirenópolis, Goiás for 12 months. Volatile oils were subjected to hydrodistillation with Clevenger apparatus and analyzed by gas chromatography-mass spectrometry. Phytochemical screening and ash and volatile compound content determination were performed by conventional techniques. T. parviflora has simple, oppositely crossed and petiolate leaves. The inflorescence of this plant is a cyme. The presence of coumarins, steroids, triterpenes, flavonoids and tannins was observed. The total ash content was 4.05 ± 0.02%; the insoluble ash content was 0.10 ± 0.03%; and the volatile compound content was 9.53 ± 0.02%. The major compounds present in the volatile oils were α-terpineol (2.7-16.5%), α-pinene (0.6-25.4%), β-pinene (2.7-23.1%), sabinene (1.2-14.1%), acetoxyeudesman-4-α-ol (0.6-6.3%) and 2,4a-8,8-tetramethyldecahydrocyclopropanaphtalene (2.4-24.4). Two clusters were identified: Cluster I represented the period with low levels of rainfall, and Cluster II represented the period with high levels of rainfall. This study provides data that can be applied for the quality control of powdered leaves and is the first description of the chemical composition and variability of the volatile oils from the leaves of T. parviflora.

Molecular docking and pharmacological/toxicological assessment of a new compound designed from celecoxib and paracetamol by molecular hybridization.

Nonsteroidal anti-inflammatory drugs are commonly used worldwide; however, they have several adverse effects, evidencing the need for the development of new, more effective and safe anti-inflammatory and analgesic drugs. This research aimed to design, synthesize and carry out a pharmacological/toxicological investigation of LQFM-102, which was designed from celecoxib and paracetamol by molecular hybridization. To evaluate the analgesic effect of this compound, we performed formalin-induced pain, hot plate and tail flick tests. The anti-inflammatory effect of LQFM-102 was evaluated in carrageenan-induced paw oedema and pleurisy tests. The biochemical markers indicative of toxicity-AST, ALT, GSH, urea and creatinine-as well as the index of gastric lesion after prolonged administration of LQFM-102 were also analyzed. In addition, the interaction of LQFM-102 with COX enzymes was evaluated by molecular docking. In all experimental protocols, celecoxib or paracetamol was used as a positive control at equimolar doses to LQFM-102. LQFM-102 reduced the pain induced by formalin in both phases of the test. However, this compound did not increase the latency to thermal stimuli in the hot plate and tail flick tests, suggesting an involvement of peripheral mechanisms in this effect. Furthermore, LQFM-102 reduced paw oedema, the number of polymorphonuclear cells, myeloperoxidase activity and TNF-α and IL-1ß levels. Another interesting finding was the absence of alterations in the markers of hepatic and renal toxicity or lesions of gastric mucosa. In molecular docking simulations, LQFM-102 interacted with the key residues for activity and potency of cyclooxygenase enzymes, suggesting an inhibition of the activity of these enzymes.

Identification of terpenes and phytosterols in Dipteryx alata (baru) oil seeds obtained through pressing

ABSTRACTThe oil from seeds of Dipteryx alata Vogel, Fabaceae, popularly known as baru, was extracted by hydraulic and continuous screw pressing. A total of eleven chemical constituents obtained by hydraulic pressing, including steroids, mono and sesquiterpenes and tocopherol derivatives were identified by gas chromatography–tandem mass spectrometry (GC–MS). Compounds limonene, β-elemene, γ-elemene, α-caryophyllene, β-caryophyllene, campesterol, stigmasterol, β-sitosterol and cycloartenol are being described for the first time in the baru oil.

Individualizing oral busulfan dose after using a test dose in patients undergoing hematopoietic stem cell transplantation: pharmacokinetic characterization.

BACKGROUND: Busulfan is an alkylating agent used for conditioning patients undergoing hematopoietic stem cell transplantation with a narrow therapeutic range and highly variable pharmacokinetics. High concentrations induce toxicity, especially hepatic veno-occlusive disease, also referred to as sinusoidal obstruction syndrome. This study aimed to assess busulfan pharmacokinetic variability in pretransplant conditioning regimens using an analytical method validated by high-performance liquid chromatography coupled to diode array detector (HPLC/PDA). METHODS: Eight patients who used the test dose (TD) of 1 mg/kg busulfan 10 days before conditioning were included, and 10 serial blood samples were collected to determine: the elimination half-life (t1/2), total area under the curve (AUCT), total clearance (Cl(T)/F), and plasma concentration at steady state (C(ss)), using a monocompartmental model and first-order kinetics. The instrumental conditions were: HPLC/PDA Shimadzu, column ACE C18 (150 mm × 4 mm); methanol/water/acetonitrile (65:20:15) eluent flow rate of 1 mL/min; 1,6-bis-(methanesulfonyloxy)-hexane; UV λ = 276 nm; analysis time 17 minutes; and derivatization with sodium diethylcarbamate. The dose was adjusted, and 4 blood samples per day were collected at days 2, 3, and 4 of treatment for new plasma determinations. RESULTS: Four patients needed higher doses; the mean dose administered was 1.02 ± 0.19 mg/kg. Mean results at TD: t1/2 = 2.88 ± 0.5 hours; Cl(T)/F = 0.18 ± 0.03 L · h(-1) · kg(-1); AUC(T) = 5461.00 ± 961.15 ng · mL(-1) · h(-1); and C(ss) = 911.3 ± 159.8 ng/mL. Mean results of samples collected during conditioning: t1/2 = 3.21 ± 0.9 hours; Cl(T)/F = 0.13 ± 0.02 L · h(-1) · kg(-1); AUC(T) = 7571 ± 1705 ng · mL(-1) · h(-1); and C(ss) = 1262.0 ± 284.3 ng/mL. CONCLUSIONS: High variability in the assessed pharmacokinetic parameters was observed, with a 38% variation in C(ss) between TD and conditioning regimen; Cl(T)/F decreased by 30%, suggesting drug accumulation after multiple-dose regimen. Although being lower than reported in the literature, this variation may be associated with toxicity of the proposed treatment, justifying patient monitoring and enhancing validity of previous pharmacokinetic evaluation using TD regimen.

Antinociceptive and antiinflammatory activities of grandisin extracted from Virola surinamensis.

The antinociceptive and antiinflammatory properties of the neolignan, grandisin, isolated from Virola surinamensis (Myristicaceae) were investigated. Grandisin (GRA) is present in several plant species from Brazil used in popular medicine for the treatment of disorders such as colic, inflammation, rheumatism, dyspepsia and liver dysfunction. These studies demonstrated that GRA is able to inhibit the acetic acid-induced writhing in mice dose-dependently, and that this effect is not caused by motor incoordination or sedation due to depressant effect in the CNS. Through the formalin test the antiinflammatory activity of GRA was characterized, this substance reduced the time licking the paw by 60.5% (only in the second phase (inflammatory pain). This activity was also verified by the oil-induced ear oedema test, where GRA 10.0 mg/kg reduced the oedema by 36.4%. The results suggest that GRA has antinociceptive effects arising from antiinflammatory activity.

Avaliação da toxicidade aguda e subaguda, em ratos, do extrato etanólico das folhas e do látex de Synadenium umbellatum Pax / Acute and subacute toxicity studies of the latex and of the ethanolic extract of the leaves of Synadenium umbellatum Pax in rats

O uso de plantas medicinais tem sido muito significativo nos últimos anos, sendo incentivado pela Organização Mundial de Saúde (OMS). Synadenium umbellatum Pax, Euphorbiacea (vulgo cola-nota, cancerola, milagrosa) tem o látex usado empiricamente como antitumoral e antiinflamatório. Por existir espécies tóxicas nesta família e visando à segurança no uso de extratos vegetais, tal estudo avaliou a toxicidade pré-clínica do látex e do extrato etanólico das folhas (EEF) de S. umbellatum, por via oral, em ratas Wistar. O estudo seguiu diretrizes do Guideline 423 (toxicidade aguda) e Guideline 407 (toxicidade subaguda) da OECD (Organisation for Economic Cooperation and Development). Na toxicidade aguda do látex e do EEF, não se observou letalidade nem alterações fisiológicas e comportamentais das ratas na dose de 2000 mg/kg, sendo praticamente atóxico. Porém, na análise histopatológica, o látex ocasionou congestão e infiltrado leucocitário nos rins, fígado e pulmões, efeitos não observados com o EEF. Na toxicidade subaguda, doses de 50, 100 e 200 mg/kg de EEF não produziram alterações dose-dependentes significativas nos parâmetros laboratoriais e fisiológicos, nem alterações macroscópicas e histopatológicas nos órgãos das ratas. Contudo, o uso crônico da planta S. umbellatum merece mais estudos.

The use of medicinal plants has been being very significant in the last years, being the use encouraged by WHO. Synadenium umbellatum Pax, Euphorbiacea (popularly known as cola-note, cancerola, miraculous) has the latex used empirically as anti-cancerous and anti-inflammatory. For there being toxic species in this family and aiming at the safety in the use of vegetable extracts, such study evaluated the pre-clinical toxicity of the latex and of the ethanolic extract of the leaves (EEL) of S. umbellatum, administrated by oral route, in Wistar female rats. The study followed OECD's Guidelines for test of acute toxicity (Guideline 423) and for subacute toxicity (Guideline 407). In the acute toxicity of latex and EEL, behavioral and physiological alterations were not observed neither animal's death in the dose level of 2,000 mg/kg. However, the latex caused congestion and leukocytes infiltration of the kidneys, liver and lungs, effects not observed with EEL. In the subacute toxicity, dose levels of 50, 100 and 200 mg/kg of EEL did not produced significant dose-dependent alterations in the lab results and no physiologic, macroscopic and hystopathological alterations. EEL of S. umbellatum is practically poisonless in acute exposure; already the latex can cause hystological damages. The chronic use of S. umbellatum needs more specific studies.

Revisão crítica do uso de testes rápidos imunológicos para verificar o consumo de substâncias psicoativas / Critical review of immunological on-site drug-testing devices

In the last years, numerous on-site drug-testing devices have become avaiable world-wide. These tests are based on antigen-antibody reactions and their main feature is the fast results obtained by color visualization. With the increased popularity of on-site drug testing, matters of performance (sensitivity, specificity) and applicability of these tests have been raised by specialists. In the present paper, fundamentals and efficiency of on-site drug-testing devices are reviewed. The indications and limitations of these devices are also discussed...

Análise e avaliação crítica da incidência de fármacos anorexígenos sintéticos em produtos naturais para o emagrecimento em Goiânia-GO / Analysis and critical evaluation of incidence of synthetic anorexic drugs

A perda de peso, visando reduzir problemas decorrentes da obsidade ou, simplesmente, para "manter a forma" é objetivo estético extremamente desejado. Visando ajustamento a padrões estéticos, obesos e pessoas com leve excesso de peso, buscam métodos miraculosos e, pensando que produtos naturais não tem contra-indicação, abusam do uso de fitoterápicos. Suspeitando-se da comercialização indevida de fitoterápicos emegrecedores contendo anorexígenos sintéticos na composição, foram investigadas 40 amostras de fitoterápicos. Constataram-se, quanto à comercialização, falhas nas informações exigidas pela legislação sanitária e do consumidor, erros no acondicionamento e indicação sem fundamentação científica. Analisada a presença de fármacos sintéticos, 23 por cento dos produtos naturais mencionavam fármacos sintéticos na bula e 18 por cento apresentaram fármacos sintéticos (dietilpropiona, fempreporex, fluoxetina, benzocaína) não descritos na bula após cromatografia em camada delgada comparativa. Tais falhas trazem riscos permanentes à saúde da população como dependência física e psíquica, com o agravo do usuário não saber do problema. Assim, a dispensação de fototerápicos deve ser melhor monitorada pela fiscalização sanitária