Philosophiae Doctor - PhD / The skin is the largest and most readily accessible organ of the body. The stratum corneum forms the outermost layer of the skin, which functions as a barrier to the external environment and regulates the passage of molecules across the skin. Drug delivery across the skin offers advantages over other routes of administration, bypassing the hepatic first pass metabolism, maintaining therapeutically effective drug levels, and improved patient compliance. Currently, there is a strong trend in the use of plant materials and extracts for medicinal purposes. Devil’s Claw (Harpagophytum procumbens) is a medicinal plant located in many regions throughout Southern and South Africa. It is used for its anti-inflammatory and analgesic properties with the harpagoside and harpagide components present reported to be responsible for these properties. Its activity has been reported to be as a result of the direct and indirect inhibition of Cyclooxygenase- 2 enzyme (COX-2). Efforts to improve the permeation of synthetic conventional compounds are constantly investigated, and great improvements of these formulations have led to very effective formulation of transdermal dosage forms such as anti-inflammatory drugs. The same should be possible for medicinal plants. Optimal permeation across the skin requires a drug to possess lipophilic as well as hydrophilic properties. Research suggests that a drug should have an aqueous solubility of more than 1 mg/ml and an octanol-water partition coefficient (log P) between 1 and 2 to optimally penetrate the skin (higher values indicating increased lipophilicity). Compounds not possessing these characteristics may be facilitated across the skin by the introduction of permeation enhancers in the formulation that include Azone® and sodium dodecyl sulphate xvi (SDS). The main aims of this study were to make an extract of Harpagophytum procumbens and to determine the direct COX-2 inhibition activity of this extract and further to formulate this extract into a pharmaceutical gel, with permeation enhancers that maintains its COX-2 enzyme inhibition qualities after transdermal penetration. The analytical techniques verified the existence of a harpagide and harpagoside components in the crude Harpagophytum procumbens extract and they were quantified in the extract at 3% and 1% respectively. COX-2 inhibition by the Harpagophytum procumbens extract was determined by a direct enzyme inhibition study and quantified by means of measuring the production of the product formed by the enzyme over a time interval in the presence of excess enzyme substrate. Crude Harpagophytum procumbens extract demonstrated a greater COX-2 enzyme inhibition than pure harpagide and harpagoside individually and combined. This indicated the existence of compounds in the extract contributing to this synergistic effect. This was reflected in the IC50 values indicating that the Harpagophytum procumbens crude extract had the lowest IC50 values concentration when compared to the harpagide and harpagoside. Octanol-PBS partition coefficient (log D) experiments were performed with various permeation enhancers and gels with varying combinations in order to determine the changing partitioning properties of harpagide and harpagoside. The octanol-PBS partition coefficient (log D) experiments indicated that harpagoside had a higher log D value than harpagide. The addition of permeation enhancers resulted in changes in the partition co-efficient of the marker compounds. The permeation enhancer, Azone®, resulted in the smallest reduction of Log D for harpagoside and the largest increase in Log D compared to other permeation enhancers tested for harpagide. xvii When the 2 marker compounds were formulated into different gel formulations (hydroxypropyl cellulose, Carbopol Ultrez 21® and Pluronic®), harpagide had the largest increase in Log D with the Carbopol Ultrez 21® gel. Harpagoside had the largest increase in the hydroxypropyl cellulose gel.Combinations of gel formulations with permeation enhancers were tested. The 2 best performing permeation enhancers in hydroxypropyl cellulose gel were SDS and Azone®. These compounds resulted in the largest increase in lipophilic partitioning for harpagide and harpagoside compound and higher values were achieved with SDS. Following the partition co-efficient determination, permeation studies with synthetic membranes were performed with the selected enhancer/gel formulations using Franz diffusional cells. The permeation (flux) across the hydrophobic synthetic membrane (Sil-Tec®) indicated flux of 27.1μg.cm-2.h-1 for harpagoside and 156.0 μg.cm-2.h-1 for harpagide in the hydroxypropyl cellulose gel. Incorporation of Azone® in the hydroxypropyl cellulose formulation resulted in an enhancement ratio (ER) of 14 for harpagoside. The hydroxypropyl cellulose gel with the permeation enhancers (Azone® and SDS) did not result in enhancement of permeation of the harpagide. Permeation of harpagoside and harpagide across the hydrophilic synthetic membrane (Tuffyrn®) yielded flux values of 537.1 μg.cm-2.h-1 and 101.1μg.cm-2.h-1 respectively in the Gel formulations. The Gel formulation containing Azone® and SDS, resulted in similar flux across this membrane compared to the formulation consisting of the Gel only, with the Azone® containing formulation resulting in lower flux for harpagide. Transdermal permeation was measured through excised female human abdominal skin using Franz diffusion cells. xviii Flux values for harpagoside and harpagide were 18.4 μg.cm-2.h-1 and 5.0 μg.cm-2.h-1 respectively when the crude extract was in the hydroxypropyl cellulose gel tested on human skin. Formulation of the crude extract in hydroxypropyl cellulose gel including Azone® and SDS permeation enhancers resulted in enhancement of 8 and 7 respectively for harpagide. Azone® increased the flux of harpagoside 14 times in the same hydroxypropyl cellulose gel formulation. The SDS had very little effect. The enhancement ratios achieved with the human skin was higher than that of the synthetic membranes. Post transdermal COX-2 inhibition activity studies were performed with the Azone® Gel formulation after it permeated across the human skin membrane to determine to what extent inhibitory activity of the crude extract was maintained. The crude drug retained its direct COX-2 inhibitory activity after permeation across the human skin with 77% inhibitory activity.

Made available in DSpace on 2016-08-17T18:39:50Z (GMT). No. of bitstreams: 1 6020.pdf: 1682477 bytes, checksum: 5dd37051fd1570e2897bd8af550c27c3 (MD5) Previous issue date: 2014-05-29 / Financiadora de Estudos e Projetos / Salmonellosis is an illness caused by bacteria of the genus Salmonella, a leading infectious disease worldwide. Due to the importance of this infection forward to eating habits, the search for a new compound that can contribute to current therapy against intestinal inflammation caused by Salmonellosis is of great value. The goal of this research was evaluate of this treatment effect with extract of Harpagophytum procumbens ( Hp ) in murine intestinal salmonellosis . In this research were realized counting of total cells and differential cell ( leukocytes, neutrophils and mononuclear cells) , dosages of cytokines (TNF- α , IL-12 , IL-10 and IL-4 ) and histopathological analysis of the liver and small intestine, at third and seventh day after the infection on animals treated with Hp and with animals didn t treated with. The animals were divided in: infected ( SE ) , infected and treated with Hp ( SE + HP ) and control group( C ). Balb / c mice ( female) were infected ( v.o ) with S. Enteritidis ATCC 13076 ( 1x108 UFC - 100 mL / animal) . The SE + HP group was treated with 150 mg / animal daily with Hp . The pathology of the liver and small intestine was prepared and stained with HE. Our results showed that there was an increase of leukocytes, specifically mononuclear cells analyzed in different compartments ( blood and CSF ), increased neutrophils in the blood in animals infected with SE on day 7 after infection. However, treatment with Hp was able to down modulate the recruitment of mononuclear cells on day 7 into the peritoneal cavity and negatively modulates the number of neutrophils in the same period. The levels of TNF-α showed a decrease on day 7 after treatment with Hp, suggesting a biological effect - down regulation - the inflammatory process in these animals . Furthermore, we also observed that animals treated with Hp infected with SE had a reduction in the number of neutrophils and mononuclear cells in the blood and decrease of IL -12. The production of IL-4 showed an increase in the + SE group HP suggesting that animals infected with S. Enteretidis and treated with H. procumbens appears to favor a microenvironment that directs the immune response profile of Th2 to Th1, whereas IL- 12 showed a decrease. IL- 10 has important regulatory effects on immunological and inflammatory responses mediated predominantly by macrophages. Our results show an increase of IL-10 in animals infected with SE, and this increase seems to be related to the severity of salmonellosis. Treatment with Hp stimulated inhibitory activity of IL - 10, favoring slight inhibition of the inflammatory process, on day 7 after infection. In the histopathological analysis of the liver observed that there was no difference between the groups, suggesting a local infection, since the blood culture was negative, carrying no systemic infection. In the small intestine was observed after 72 h in the SE group discrete wrinkle this epithelium, suggesting the invasion of S. Enteritidis, which was also observed hypertrophy of the wall of the villi and mild inflammatory infiltrate. In animals that received treatment with Hp hypertrophy was reduced with preservation of the villi of the intestinal architecture 7 days after infection. Thus, we suggest a possible role of Hp in modulating immune factors involved in the recruitment of inflammatory cells in the intestine of animals infected with SE, favoring discrete modulation of the inflammatory process in this model. / A Salmonelose é uma doença causada pela bactéria entérica do gênero Salmonella, uma das principais doenças infecciosas em todo o mundo. Devido à importância dessa infecção frente aos hábitos alimentares, a busca de um novo composto que possa contribuir com a terapia atual contra a inflamação intestinal causada pela Salmonelose é de grande valia. Assim, este estudo teve como objetivo avaliar os efeitos do tratamento com o extrato etanólico da Harpagophytum procumbens (Hp) na salmonelose intestinal murina. Neste estudo foram realizadas contagens das células totais e diferenciais (leucócitos, neutrófilos e células mononucleares), dosagem de citocinas (TNF-α, IL-12, IL-10 e IL-4) e analise histopatológica do fígado e intestino delgado ( 3º e 7º dia após a infecção) em animais tratados ou não com Hp. Os animais foram divididos em grupos: somente infectado (SE), infectado e tratado com Hp (SE+HP) e controle (C). Camundongos Balb/c (fêmeas) foram infectados (v.o.) com S. Enteritidis ATCC 13076 (1x108 UFC 100 μL/animal). O grupo SE+HP foi tratado com 150 μg/animal com Hp diariamente. O anatomopatológico do fígado e intestino delgado foi preparado e corado com HE. Nossos achados mostraram que, houve aumento de leucócitos, especificamente células mononucleares nos diferentes compartimentos analisados (sangue e LPC), aumento de neutrófilos no sangue nos animais infectados com SE no 7º dia após infecção. Entretanto, o tratamento com Hp foi capaz de modular negativamente o recrutamento de células mononucleares no 7º dia para a cavidade peritoneal e modulou negativamente o numero de neutrófilos no sangue no mesmo período. Os níveis de TNF-α apresentaram diminuição no 7º dia após tratamento com Hp, sugerindo um efeito biológico - down regulation - do processo inflamatório nesses animais. Além disso, observamos também que, animais tratados com Hp e infectados com SE tiveram redução no número de neutrófilos e células mononucleares no sangue e diminuição de IL-12. A produção de IL-4 apresentou aumento no grupo SE+HP sugerindo que animais infectados por S. Enteretidis e tratados com H. procumbens parece favorecer um microambiente que direcione o perfil da resposta imune de Th1 para Th2, visto que a IL-12 apresentou diminuição. A IL-10 tem efeitos regulatórios importantes sobre as respostas imunológicas e inflamatórias, sendo predominantemente mediada por macrófagos. Nossos resultados mostram aumento de IL-10 nos animais infectados com SE, e esse aumento parece estar relacionado com a gravidade da salmonelose. O tratamento com Hp estimulou atividade inibitória de IL-10, favorecendo discreta inibição do processo inflamatório, no 7º dia após a infecção. Nas analises histopatológicas do fígado observamos que, não houve diferença entre os grupos, sugerindo uma infecção local, visto que a hemocultura foi negativa, portando não houve infecção sistêmica. No intestino delgado observou após 72 h no grupo SE discreto enrugamento deste epitélio, o que sugere a invasão da S. Enteritidis, sendo observado também hipertrofia da parede das vilosidades e discreto infiltrado inflamatório. Nos animais que receberam tratamento com Hp houve uma redução da hipertrofia das vilosidades com preservação da arquitetura intestinal 7 dias após a infecção. Assim, sugerimos um possível papel da Hp em modular fatores imunológicos envolvidos no recrutamento de células inflamatórias no intestino de animais infectados com SE, favorecendo discreta modulação do processo inflamatório neste modelo.

OBJETIVO: O presente estudo avaliou o efeito dos extratos de H. procumbens e suas frações na atividade da COX-1 e COX-2 e produção de NO em ensaio de sangue total de voluntários sadios e pacientes com OA. MÉTODOS: A atividade da COX-1 foi determinada através da produção de TxB2 por plaquetas e da COX-2 pela produção de PGE2 por monócitos estimulados por LPS. A produção de NO2 -/NO3 - foi determinada por reação de Griess. Os ensaios in vitro foram realizados por incubação do extrato do extrato de H.procumbens e frações em sangue total. Os controles inibidores da atividade da COX-1 e COX-2 foram indometacina e etoricoxibe. A atividade enzimática das COXs e produção de NO foram avaliadas antes e após o tratamento com garra-dodiabo em pacientes com OA de coluna lombar. RESULTADOS: O tratamento com garra-do-diabo foi eficaz clinicamente e aumentou a atividade da COX-1 e COX-2 basal sem LPS. O extrato bruto do H. procumbens não alterou a atividade das COX. Entretanto, o harpagosideo inibiu a atividade da COX-1, COX-2 e a produção de NO. CONCLUSÃO: A garra-do-diabo mostrou-se eficaz no tratamento de pacientes com OA de coluna lombar. O harpagosideo deve ser alvo estudos específicos. / OBJECTIVE: The present study evaluated the effect of H. procumbens extracts and its fractions on COX-1 and COX-2 activity and NO production in whole blood assays of volunteers and OA patients. METHODS: The COX-1 and COX-2 activity was quantified as platelet TXB2 production in blood clotting and as PGE2 production in heparinized LPS-stimulated whole blood, respectively. Total NO2 -/NO3 - was determined by Griess reaction. In vitro assays were performed through incubation of the extract and fractions with whole blood from volunteers. Controls of the inhibition of COX-1 and COX-2 activity were indomethacin and etoricoxib. Before and after treating OA lumbar spine patients with devil\'s claw the COX-1 and COX-2 activity and NO production were evaluated in their whole blood. RESULTS: The treatment promoted clinical improvement and increase in the activity of COX-1 and basal COX-2, without LPS. The crude extract did not affect the activity of both enzymes. However, harpagoside inhibited COX-1 and COX-2 activity and NO production. CONCLUSION: Devil\'s claw promoted clinical improvement of OA patients and harpagoside must be focus of specific studies.

OBJETIVO: O presente estudo avaliou o efeito dos extratos de H. procumbens e suas frações na atividade da COX-1 e COX-2 e produção de NO em ensaio de sangue total de voluntários sadios e pacientes com OA. MÉTODOS: A atividade da COX-1 foi determinada através da produção de TxB2 por plaquetas e da COX-2 pela produção de PGE2 por monócitos estimulados por LPS. A produção de NO2 -/NO3 - foi determinada por reação de Griess. Os ensaios in vitro foram realizados por incubação do extrato do extrato de H.procumbens e frações em sangue total. Os controles inibidores da atividade da COX-1 e COX-2 foram indometacina e etoricoxibe. A atividade enzimática das COXs e produção de NO foram avaliadas antes e após o tratamento com garra-dodiabo em pacientes com OA de coluna lombar. RESULTADOS: O tratamento com garra-do-diabo foi eficaz clinicamente e aumentou a atividade da COX-1 e COX-2 basal sem LPS. O extrato bruto do H. procumbens não alterou a atividade das COX. Entretanto, o harpagosideo inibiu a atividade da COX-1, COX-2 e a produção de NO. CONCLUSÃO: A garra-do-diabo mostrou-se eficaz no tratamento de pacientes com OA de coluna lombar. O harpagosideo deve ser alvo estudos específicos. / OBJECTIVE: The present study evaluated the effect of H. procumbens extracts and its fractions on COX-1 and COX-2 activity and NO production in whole blood assays of volunteers and OA patients. METHODS: The COX-1 and COX-2 activity was quantified as platelet TXB2 production in blood clotting and as PGE2 production in heparinized LPS-stimulated whole blood, respectively. Total NO2 -/NO3 - was determined by Griess reaction. In vitro assays were performed through incubation of the extract and fractions with whole blood from volunteers. Controls of the inhibition of COX-1 and COX-2 activity were indomethacin and etoricoxib. Before and after treating OA lumbar spine patients with devil\'s claw the COX-1 and COX-2 activity and NO production were evaluated in their whole blood. RESULTS: The treatment promoted clinical improvement and increase in the activity of COX-1 and basal COX-2, without LPS. The crude extract did not affect the activity of both enzymes. However, harpagoside inhibited COX-1 and COX-2 activity and NO production. CONCLUSION: Devil\'s claw promoted clinical improvement of OA patients and harpagoside must be focus of specific studies.

Le cancer est une maladie multifactorielle dont la première étape est souvent une mutation. Il est envisageable de prévenir l'apparition de cette maladie en limitant l'apparition de mutations. Le benzo(a)pyrène et le 1-nitropyrène sont deux mutagènes et cancérogènes très répandus dans notre environnement. Ces deux composés entrainent une réponse inflammatoire chez l'homme qui à son tour induit un stress oxydant aboutissant à des mutations. L'objectif de cette étude est de rechercher l'activité antimutagène de sept plantes médicinales et de deux molécules naturelles anti-inflammatoires, avec un intérêt plus développé pour l'Harpagophytum procumbens (HP) et son principal iridoïde : l'harpagoside. Elle consiste également à vérifier si l'activité anti-inflammatoire peut être reliée à une activité antimutagène. L'activité antimutagène a été étudiée au niveau des mutations chromosomiques à l'aide du test des micronoyaux sur lymphocytes humains, et au niveau des mutations ponctuelles à l'aide du test d'Ames. Tous les extraits HP, à l'exception de l'extrait méthanolique, possèdent une activité antimutagène importante dans le test des micronoyaux, mais aucun dans le test d'Ames. Pour les six autres plantes anti-inflammatoires, plus de la moitié des extraits possèdent une activité antimutagène. Nous avons montré que l'activité antioxydante n'est pas ou peu impliquée dans l'activité antimutagène. Il est probable que d'autres mécanismes d'action soient impliqués tels que l'inhibition de l'inflammation (NF-ĸB). C'est la première fois que ce type d'études est réalisé sur des plantes possédant une activité anti-inflammatoire et plus particulièrement sur l' Harpagophytum procumbens. / Cancer is a multifactorial disease in which the first step is often a mutation in the genome. It is then possible to prevent the onset of the disease by limiting the occurrence of mutations. Benzo (a) pyrene (BaP) and 1-nitropyrene (1-NPY) are two widespread mutagens and carcinogens in our environment. These two compounds produce an inflammatory response in humans which in turn induces oxidative stress leading to gene mutations. The objective of this study was to investigate the antimutagenic activity of seven medicinal plants and two natural anti-inflammatory molecules, especially in Harpagophytum procumbens (HP) with its major iridoid: harpagoside. However, also to check whether the anti-inflammatory activity may be related to antimutagenic activity. The antimutagenic activity was investigated with chromosomal mutations using the in vitro cytokinesis-block micronucleus assay in primary cultures of human lymphocytes, and at the point mutations using the Ames test. All HP extracts, except for the methanol extract, showed a significant anti-mutagenic activity in the micronucleus test. No antimutagenic activity could be detected by the Ames assay. For the six other anti-inflammatory plants, more than half of the extracts possessed an antimutagenic activity. We have shown that the antioxidant property was not responsible for the antimutagenic activity. Thus, it is likely that other mechanisms of action are involved, such as anti-adduct mechanism, inhibition of metabolism or inhibition of inflammation (NF-ĸB). This is the first report of antimutagenic properties of anti-inflammatory plants and more particularly of the Harpagophytum procumbens.

Made available in DSpace on 2016-06-02T19:02:45Z (GMT). No. of bitstreams: 1 6626.pdf: 3445812 bytes, checksum: 7cade950ece338c3975f5a311fc17e38 (MD5) Previous issue date: 2014-08-08 / Universidade Federal de Minas Gerais / Mansonic schistosomiasis is a disease that infected more than 240 million people worldwide, it is caused by Schistosoma mansoni. It is the second only to malaria in public health importance. The only drug currently effective against S. mansoni is Praziquantel (PQZ), however, has been reported strains of S. mansoni with loss of sensitivity. Such reports reinforce the need to develop new safer treatment against S. mansoni. The natural compounds are important to develop new drugs. Mentha piperita L. also known as peppermint, studies reported the treatment as antiparasitic diseases (for example giardiasis). In ours laboratory showed a decrease of inflammatory process of schistosomiasis in a murine model after treatment with ethanolic extract of M. piperita. However don´t know nothing about action of this plant against adult worms of S. mansoni. Harpagophytum procumbens is a plant that has origins in Africa, studies showed promising results antibacterial and against rheumatism diseases, but has no studies against schistosomiasis. In this study we evaluated effect of ethanolic extract of H. procumbens and ethanolic extract of Mentha piperita L. and its fractions against Schistosoma mansoni, its observed for optical microscopic and change in protein expression, after in vitro assay. It was observed that all extract and its fraction caused the motor activity reduction and separation of couple worms. Exceptions of hydroalcoholic fraction of M. piperita, S. mansoni adult worms were death after treatment. We observed that ethanolic extract of H. procumbens showed more promising results when compared with M. piperita. And we observed that ethyl acetate shoed more promising result than ethanolic extract of M. piperita and its other fractions.In this work was observed change in protein expression in 2D gel electrophoresis after all ethanolic extractions and fractions treatment. The proteins in gel electrophoresis have been identified by mass spectrometry. The mass spectrometry assay showed important proteins for S. mansoni homeostasis and possible therapeutic target, for example actin, enolasis, fructose-biphosphate aldolase, and others important proteins. These results indicate that these plants may be anthelmintic activity against S. mansoni. However, it has need for more studies to complete undesiring of these extract against S. mansoni. / A esquistossomose mansônica, doença que afeta mais de 240 milhões de pessoas no mundo é causada por um trematódeo, o Schistosoma mansoni. Entre as doenças tropicais, ocupa o segundo lugar em mortalidade no mundo, perdendo apenas para a malária. A presença de cepas com perda de sensibilidade ao tratamento com o farmaco comercial disponível (Praziquantel) sugere a necessidade de desenvolvimento de novos fármacos para o tratamento desta doença. O uso de compostos naturais é uma área de grande interesse no desenvolvimento de novos farmacos. A Mentha piperita L. conhecida popularmente como hortelã pimenta, tem seus efeitos terapêuticos comprovados no tratamento de algumas parasitoses (como giardíase). Estudos recentes em nosso laboratório demonstraram diminuição do processo inflamatório no modelo murino da esquistossomose, quando os animais foram tratados com extrato da M. piperita. No entanto, nada se sabe sobre a ação da M. piperita no parasito. E a planta, nativa da África, Harpagophytum procumbens apresenta eficácia contra bactérias e doenças reumáticas, mas nada foi descrito contra a esquistossomose. Dessa forma, propomos a avaliação do efeito do extrato etanólico e suas diferentes partições da Mentha piperita e o extrato etanólico da Harpagophyrum procumbens em vermes adultos de S. mansoni, observando efeito por microscopia óptica e a ocorrência de alterações no perfil da expressão proteica, após o tratamento in vitro. As analises por microscopia revelou que, todos os extratos testados induziram separação dos casais e redução da atividade motora. E exceção foi observada com a partição hidroalcoólica da M. piperita, onde todos os vermes adultos de S. mansoni estavam mortos, após exposição. O extrato da H. procumbens provocou mortes dos vermes adultos, com menor concentração, comparado ao extrato da M. piperita. E entre os extratos com a M. piperita foi observado que, a partição com o acetato de etila apresentou resultados mais promissores no controle dos parasitas. Na análise proteômica, todos os tratamentos revelaram spots diferentes em géis de eletroforese bidimensionais após analises por software. Posteriormente, as proteínas presentes nos spots foram reveladas, e utilizando a espectrometria de massas identificadas proteínas que se apresentam como importantes para homeostase celular do S. mansoni e podem ser consideradas como possíveis alvos para vacinas, como actina, enolase, Frutose-bifosfato aldolase, entre outras. Nossos resultados sugerem que, estas plantas podem apresentar efeito antihelmintico contra S. mansoni. Por tanto é preciso mais estudos para melhores entendimentos dos efeitos dos extratos destas plantas nesse modelo.

Made available in DSpace on 2016-08-17T18:39:45Z (GMT). No. of bitstreams: 1 4791.pdf: 1129656 bytes, checksum: 3d25d8e4c71842592c3397b419db0ca8 (MD5) Previous issue date: 2012-02-29 / The Syndrome of Visceral Larva Migrans (VLMS) is a parasitic disease caused by Toxocara canis, one of the most common helminthes in dogs. In the definitive hosts are present in different morphological forms, embryonated eggs, adult males and females. However, in unusual hosts (humans and rodents), present only in stage infective larvae (L3) and do not complete their life cycle. The infection in man occurs by ingestion of embryonated eggs which release in the small intestine infective larvae (L3), which cross the intestinal mucosa and the lymphatic vessels reach the circulation port reaching the lungs and liver. Larvae can still cross the gut wall actively start a process of erratic migration through different host tissues. The main characteristics of this disease in the chronic phase are eosinofilias blood and tissue and high levels of serum IgE. The immune response of host larvae occurs during tissue migration, where the larvae release antigenic products of excretion-secretion (TES) that protect against host reactions. The TES have a fraction of the allergen responsible for stimulating production and release of eosinophils. In this context, the search for new therapeutic tools that promote less damage to individuals affected by increased systemic eosinophil becomes important. In this study, we evaluated the modulatory activity and anti-inflammatory eosinophilia Harpagophytum procumbens against using the model of experimental infection with T. VLMS kennels. Our results showed that the extract of Harpagophytum procumbens has anti-inflammatory effects in reducing eosinophil infiltration in the blood and washed from the peritoneal and bronchoalveolar at different periods analyzed. The antiinflammatory may be due to the ability of the extract Harpagophytum procumbens decrease the production of factors that favor the proliferation and activation of eosinophils (IL-5, IL-4 and IL-13) during 18, established as the peak of eosinophilia. Furthermore, our treatment decreases the expression adhesion molecules, CD11b, CD11c peak of eosinophilia during infection by T. kennels. The CD40 molecule expression by eosinophils seems to favor the survival of leukocytes, however, would require further investigations that contributed to the understanding of the mechanisms by which the extract of H. procumbens can interfere with the migration of eosinophils into the inflammatory site in this model, since this event is characterized as being complex order. / A Síndrome da Larva Migrans Visceral (SLMV) é uma parasitose, causada pelo Toxocara canis, um dos helmintos mais freqüente em cães. Nos hospedeiros definitivos, se apresentam em diferentes formas morfológicas, ovos embrionados, adultos machos e fêmeas. Entretanto, nos hospedeiros não habituais (ex.: homem e roedores), apresentam-se apenas no estádio de larvas infectantes (L3) e não completam seu ciclo biológico. A infecção no homem ocorre pela ingestão acidental de ovos larvados, que no intestino delgado liberam as larvas infectantes (L3), as quais atravessam a mucosa intestinal e pela via linfática atingem a circulação porta e o fígado chegando aos pulmões. As larvas podem ainda atravessar ativamente a parede do intestino, iniciar um processo de migração errática através dos diferentes tecidos do hospedeiro. As principais características dessa doença na fase crônica são as eosinofilias sanguínea e tecidual e altos níveis de IgE sérica. A resposta imunológica do hospedeiro as larvas, ocorre durante a migração tecidual, onde as larvas liberam produtos antigênicos de secreção-excreção (TES) que as protegem contra a reação do hospedeiro. Os TES apresentam uma fração alergênica responsável pela estimulação da produção e liberação de eosinófilos. Neste contexto, a busca por novas ferramentas terapêuticas que promovam menos danos aos indivíduos acometidos pelo aumento sistêmico dos eosinófilos torna-se importante. Assim, neste estudo, avaliamos a atividade modulatória e anti-inflamatória da Harpagophytum procumbens contra eosinofilia utilizando o modelo de infecção experimental com T. canis SLMV. Nossos resultados demonstraram que o extrato da Harpagophytum procumbens possui efeitos anti-inflamatório diminuindo no infiltrado eosinofílico no sangue e lavados da peritoneal e broncoalveolar, nos diferentes períodos analisados. O efeito anti-inflamtório pode ser decorrente da capacidade do extrato de Harpagophytum procumbens diminuir a produção de fatores que favorecem a proliferação e ativação de eosinófilos (IL-5, IL-4 e IL-13) no período 18°, estabelecido como o pico da eosinofilia. Além disso, nosso tratamento diminui a expressão das moléculas de adesão CD11b, CD11c no pico da eosinofilia durante a infecção por T. canis. A expressão da molécula CD40 por eosinófilos parece favorecer a sobrevida deste leucócito, todavia, serão necessárias outras investigações que contribuíam para o entendimento dos mecanismos pelos quais o extrato de H. procumbens pode interferir na migração dos eosinófilos para o sitio inflamatório neste modelo, uma vez que este evento é caracterizado como sendo ordem complexa e multifatorial.

Durch eine optimierte Anwendungsbeobachtung (AWB) sollte die Dokumentation der therapeutischen Anwendung eines Phytopharmakons vervollständigt werden. Ausgewählt wurde ein wässriger Extrakt aus der südafrikanischen Teufelskralle im Anwendungsgebiet der Therapie degenerativer Erkrankungen des Bewegungsapparates (Gon- und Coxarthrose). Wie eine Darstellung der Klinik zeigte, lag bis dahin keine Studie für diese Anwendung des Extraktes vor. Die Therapie erfolgte über 12 Wochen, die Wirksamkeit wurde bewertet primär mit dem Western-Ontario-McMaster-Universities-Osteoarthritis-Index (WOMAC) und der VAS-Schmerzskala. Die Ergebnisse dieser AWB belegen erstmalig die Wirksamkeit bei degenerativen rheumatischen Erkrankungen. Mit einer Verbesserung des WOMAC-Scores um 22,9 % im gesamten Kollektiv und um 24,1 % bei Patienten mit stärkeren Beschwerden dürfen die Ergebnisse als klinisch relevant erachtet werden. Besonders stark war die Wirkung im Subscore zur Steifigkeit (Verbesserung um mehr als 30 % im stärker betroffenen Kollektiv und in der Gesamtgruppe um 22,2 %). Durch den verwendeten Erfassungsparameter Arhuser Rückenschmerzindex war ein Vergleich mit den Ergebnissen früherer Studien mit dem gleichen Extrakt möglich. Die Verbesserung in annähernd vergleichbarer Größenordnung zeigte, dass die Ergebnisse der AWB valide sind. Für den WOMAC-Gesamtscore wurden in Studien mit nicht-steroidalen Antirheumatika Verbesserungen um 25 - 40 % berichtet; der Subscore zur Steifigkeit verbesserte sich um 20 - 50 % in den Verum- und bis zu 20 % in den Placebo-Gruppen. Die Wirkstärke der Teufelskralle ist im Vergleich zu den Wirkstärken synthetischer Arzneistoffe daher beachtlich. Die Teufelskralle kann als alleinige medikamentöse Maßnahme eingesetzt werden. Mittels einer verbesserten Qualität in Planung, Durchführung und Auswertung sowie Berichterstattung von Anwendungsbeobachtung kann ein wichtiger Beitrag für den therapeutischen Stellenwert von Phytopharmaka geleistet werden.