Thesis (M.S.)--University of Michigan, 1993.

Made available in DSpace on 2016-08-17T18:39:50Z (GMT). No. of bitstreams: 1 6068.pdf: 11514210 bytes, checksum: 8c9214a7a0368fd3be3320eb3e04318d (MD5) Previous issue date: 2013-08-13 / The non steroidal anti-inflammatory drugs have been known for over 100 years and has been widely used by mankind. However cause adverse effects, since gastrointestinal complications to cardiac diseases many of these symptoms related to its nonspecific action in biological systems. Thus, the proposal of a drug delivery system for loading these drugs to the site of inflammation, could reduce these unwanted effects in the body due to the limitation of more targeted effects beyond its site of action.In this study, the graphene and graphite plates were used as carriers, since studies demonstrate the usefulness of other conformational structures of carbon as drug carriers for the treatment of cancer, for example. Two models were studied for the plates by softwares of molecular docking: template sandwich, which comprises two carbon plates, with ligant between them, and the model surfing with one carbon plate comprising the ligant. The compounds were obtained from data banks, such as CSD, PDB and SD, the plates were obtained by molecular modeling. The analysis of intermolecular interactions, essential knowledge for understanding the structures obtained was done using molecular imaging with high resolution. The experimental results showed that the in silico model sandwich was the most favorable for this system, providing stability and protection for the ligand that this does not become detached from the plates during the path taken in the body to the desired location. / Os anti-inflamatórios não esteroidais são conhecidos há mais de 100 anos e vem sendo amplamente utilizados pela humanidade. No entanto, causam efeitos adversos, desde problemas gastrointestinais até complicações cardíacas, muitos desses sintomas relacionados com sua ação inespecífica nos sistemas biológicos. Dessa forma, a proposta de um sistema de drug delivery para o carreamento desses fármacos até o local da inflamação, poderia reduzir esses efeitos indesejados no organismo devido a limitação de alvos mais específicos além do seu local de ação. No presente estudo, foram utilizadas placas de grafeno e grafite como carreadores, uma vez que estudos demonstram a utilidade de outras estruturas conformacionais do carbono como carreadores de fármaco para o tratamento de câncer, por exemplo. Foram estudados dois modelos para as placas por meio de software de docking molecular: modelo sandwich, o qual engloba duas placas de carbono, com os ligantes entre elas, e o modelo surf, com uma placa de carbono comportando o ligante. Os compostos estudados foram obtidos dos bancos de dados como CSD, SD e PDB e as placas foram obtidas por modelagem molecular. A análise das interações intermoleculares, conhecimento essencial para o entendimento das estruturas obtidas, foi feita utilizando visualização molecular de alta resolução. Os resultados dos experimentos in silico mostraram que o modelo sandwich foi o mais favorável para esse sistema, posto que confere estabilidade e proteção ao ligante para que este não se desprenda das placas durante o caminho percorrido pelo organismo até o local desejado.

Trata-se de estudo comparativo para avaliar a atividade dos medicamentos nimesulida, Arnica TM, Arnica 6CH comparados com H2O no tratamento da Doença Periodontal experimental induzida por ligadura em ratos. Esta doença se caracteriza por processo inflamatório que pode evoluir até ao ligamento periodontal e tecido ósseo provocando perda óssea. Mediadores produzidos pelo hospedeiro e substâncias do biofilme são responsáveis pelos danos que podem levar até a perda do elemento dentário. O objetivo deste trabalho foi desenvolver estudo exploratório descritivo para analisar, aprofundar e comparar os efeitos das medicações citadas, investigando possíveis inovações no tratamento da doença periodontal. A metodologia consistiu em: 1) colocação, sob anestesia, da ligadura no primeiro molar inferior esquerdo. 2) administração diária por gavagem de H2O (controle) (1&#x3BC;l/g), nimesulida (1&#x3BC;l/g, de uma suspensão com 5mg/ml), Arnica TM (8&#x3BC;l/300g) ou Arnica 6CH (3,21&#x3BC;l/300g) durante 14, 21 e 28 dias a quatro grupos de ratos Wistar (n=30/ grupo); 3) eutanásia e coleta de material para análises histológica, da perda óssea e RT-PCR (alvos: TNF-&#x3B1;, COX-2, IL-6, OPG e RANKL); 4) análise estatística paramétrica realizada por ANOVA a um ou dois critérios, seguida do teste de Tukey, ou por análise não paramétrica por Kruskal-Wallis, seguido do método de Dunns, nível de significância de 5%. Quanto à perda óssea, não houve diferença estatística entre os grupos e nenhum dos tratamentos foi capaz de contê-la. Os escores para o infiltrado inflamatório não mostraram diferença significativa entre os grupos nos períodos estudados. Quanto ao escore geral, que envolve intensidade do infiltrado inflamatório, migração do epitélio juncional, integridade do cemento e da crista óssea alveolar, não houve diferença significativa entre os grupos nos períodos. Na expressão do RNAm para as citocinas vimos para o TNF-&#x3B1; não haver diferença significativa entre os grupos, quando se analisou isoladamente os períodos de 14 e 28 dias. No entanto, no período de 21 dias, houve redução significativa no grupo nimesulida comparado ao grupo Arnica 6CH (&#x2217;p<0,05). Para a COX-2, não houve diferença significativa quanto à expressão do RNAm entre os grupos, analisando isoladamente cada período de estudo, sendo nítida a redução desta expressão no grupo Arnica 6CH em todos os períodos; para a IL-6, OPG e RANKL não houve diferença significativa quanto à expressão do RNAm entre os grupos nos períodos estudados. No entanto, no grupo Arnica 6CH nota-se tendência nítida para o aumento da expressão do RNAm para OPG, ao longo do tempo. Comparando com o grupo H2O a ação de cada medicamento quanto à expressão do RNAm para todas as citocinas, considerando o conjunto dos 3 períodos, vê-se redução significativa para a expressão de RNAm para COX-2 e RANKL após o tratamento com Arnica 6CH (&#x2217;p<0,05). O mesmo pode ser visto para a nimesulida quando se estuda a expressão do RNAm para RANKL (&#x2217;p<0,05). No estudo ficaram destacados os efeitos biológicos da Arnica 6CH sobre a leitura e transcrição do DNA, notadamente sobre genes relacionados à perda óssea, o que vislumbra a possibilidade de sua utilização terapêutica. / This is a comparative study to evaluate the activity of nimesulide medicines, Arnica TM, Arnica 6CH compared with H2O in the treatment of experimental periodontal disease induced by ligation in rats. This disease is characterized by an inflammatory process that may progress to the periodontal ligament and bone tissue leading to bone loss. Mediators produced by the host and biofilm substances are responsible for the damage that can lead to tooth loss. The aim of this exploratory and descriptive study was to analyze, deepen and compare the effects of the mentioned medications, investigating possible innovations in the treatment of periodontal disease. The methodology consisted of: 1) placing under anesthesia ligature in the first lower left molar. 2) daily administration by gavage H2O (control) (1&#x3BC;l/g), nimesulide (1&#x3BC;l/g, a suspension of 5 mg / ml), Arnica TM (8&#x3BC;l/300g) or Arnica 6CH (3,21&#x3BC;l/300g) for 14, 21 and 28 days to four groups of Wistar rats (n = 30 / group); 3) euthanasia and collection of material for histological, bone loss and RTPCRanalysis (targets: TNF-&#x3B1;, COX-2, IL-6, OPG and RANKL); 4) parametric statistical analysis performed by ANOVA to one or two criteria, followed by Tukey test, or nonparametric analysis by Kruskal-Wallis, followed by Dunns method, 5% significance level. Regarding the bone loss, there was no statistical difference between the groups and none of the treatments was able to contain it. The scores for the inflammatory infiltrate showed no significant difference between the groups in the study periods. Regarding the general score, which involves intensity of the inflammatory infiltrate, migration of the junctional epithelium integrity of the cement and the alveolar bone crest, there was no significant difference between groups in the periods. At the mRNA expression for the cytokines we saw for TNF-&#x3B1; no significant difference between groups when analyzed separately periods of 14 and 28 days. However, in the 21day period, there was significant reduction in nimesulide group compared to the Arnica 6CH group (&#x2217; p <0.05). For COX-2, there was no significant difference in mRNA expression between the groups, separately analyzing each study period, being sharper reduction of this expression in Arnica 6CH group in all periods; for IL-6, OPG and RANKL no significant difference in mRNA expression between the groups in the study periods. However, it is noted in the Arnica 6CH group a clear tendency to increase of the mRNA expression for OPG over time. Comparing with H2O group action of each medicine on the mRNA expression for all cytokines, considering the set of three periods, we see a significant reduction in mRNA expression for COX-2 and RANKL after treatment with Arnica 6CH (&#x2217; p <0.05). The same can be seen for nimesulide when studying the mRNA expression for RANKL (&#x2217; p <0.05). In the study were highlighted the biological effects of Arnica 6CH about reading and transcription of the DNA, notedly about genes related to bone loss, which envisions the possibility of its therapeutic use.

Accumulating evidence suggests that anti-inflammatory agents and antioxidants have neuroprotective properties and may be beneficial in the treatment of neurodegenerative disorders. In the present study, the possible neuroprotective properties of tolmetin, sulindac and turmeric were investigated. The antioxidant effects of tolmetin and sulindac were determined by inducing free radical generation with quinolinic acid (QA), cyanide or iron (II) in rat brain homogenates or primary hippocampal neurons. Tolmetin and sulindac significantly reduce lipid peroxidation and scavenge the superoxide anion. Metal binding studies were conducted to determine whether metal chelation is a possible mechanism through which these agents reduce QA and iron (II)-induced lipid peroxidation. UV/VIS, infrared spectroscopy as well as electrochemical studies show that both agents bind to iron (II) and/or iron (III). Histological examination of the hippocampus showed that pre-treatment of animals with tolmetin or sulindac offers protection against intrahippocampal injections of QA. These agents also attenuate QA-induced apoptosis and reduce the loss of neurons in the hippocampus. The co-incubation of primary hippocampal neurons with the NSAIDS also enhanced cell viability which is significantly reduced by QA. Behavioural studies using a water maze showed that the treatment of animals after QA-induced neurotoxicity reduces QA-induced spatial memory loss. Tolmetin and sulindac also reduced glutathione depletion and protein oxidation in rat hippocampus. Both NSAIDS inhibit liver tryptophan 2,3-dioxygenase activity in vitro and in vivo and subsequently increased hippocampal serotonin levels. However, both NSAIDS also reduce dopamine levels in rat striatum. Tolmetin but not sulindac increased the synthesis of melatonin by the pineal gland. The active components of turmeric known as the curcuminoids were separated using preparative thin layer chromatography (TLC). The purity was confirmed by TLC, NMR and mass spectrometry. The environmental toxin lead, induces lipid peroxidation and reduces primary hippocampal neuronal viability. The co-incubation of the neurons with the curcuminoids significantly reduces lead-induced lipid peroxidation and enhances neuronal cell viability in the presence of lead. Lead-induced spatial memory deficit is also attenuated with curcumin, demethoxycurcumin but not bisdemethoxycurcumin. The curcuminoids also reduce lead-induced hippocampal glutathione depletion and protein oxidation. Metal binding studies show that the curcuminoids bind to lead and is another possible mechanism through which the curcuminoids reduce lead-induced neurotoxicity. The findings of this study indicate a possible role of tolmetin, sulindac and turmeric in neurodegenerative disorders such as Alzheimer’s disease. However, tolmetin and sulindac reduce dopamine levels.

in Hradec Králové Student: Johana Urbanová Supervisor: PharmDr. Jana Mandíková, Ph.D. = 38.02 μM), lowest indometacin μM

Non-steroidal anti-inflammatory drugs (NSAID) are a class of medications used in the treatment of pain, inflammation, and illness. These medications are common, affordable, and easy to access. For these reasons, NSAIDs are commonly used by athletes of all backgrounds for treating injuries and as ergogenic aids. However, despite these behaviors, NSAIDs have well-documented side effects and the efficacious nature of these medications has been brought into question. Despite this, many athletes continue to use these medications frequently and indiscriminately. It is not known why athletes use these medications in light of their questionable effectiveness and cited adverse effects. Therefore, this study was designed to (1) further investigate the prevalence of NSAID use in collegiate-level athletes, (2) investigate attitudes and behaviors toward the use of NSAIDs cross-tabulated by sport, gender, and competition level, and (3) investigate athletes' general knowledge of NSAIDs. Subjects for this study included 79 student-athletes (44 male; 25 female) attending Portland State University (PSU). The majority of the athletes started taking NSAIDs before high school (72% of the males and 64% of the females). Thirty-three percent of males and 32% of females reported that they had been taking NSAIDs within the past week. High in-season use of NSAIDs was reported by 52% of the male athletes and 48% of the female athletes, whereas off-season use was reported by 21% and 12% of the males and females, respectively. Cited reasons for NSAID use both in-season and off-season were relief of pain due to injury, prevention, recovery, soreness, and tightness. In total, 83% of males and 76% of females reported obtaining NSAIDs primarily through means other than health-care professionals. With regard to dosage, athletes reported taking NSAIDs based on product directions, instructions of an athletic trainer or perceived pain levels. An overwhelming majority of athletes (83% male; 76% female) were not aware of any side-effects from taking NSAIDs In summary, this study revealed a pattern of high NSAID use in athletes competing in-season compared to a high prevalence of low NSAID use in athletes off-season. It also revealed a high prevalence of non-prescription NSAID use. Additionally, there was a high prevalence of self-purchasing of NSAIDs, combined with self-medication and a long history of NSAID use. This study also revealed a general lack of knowledge about NSAIDs.

Inhibition of cyclooxygenase (COX)-2 increases cardiovascular deaths. Identifying a biomarker of COX-2 is desirable but difficult, since COX-1 and COX-2 ordinarily catalyze formation of an identical product, prostaglandin H2. When acetylated by aspirin, however, COX-2 (but not COX-1) can form 15(R)-HETE, which is metabolized to aspirin-triggered lipoxin (ATL), 15-epi-lipoxin A4. Here we have used COX-1- and COX-2-knockout mice to establish whether plasma ATL could be used as a biomarker of vascular COX-2 in vivo. Vascular COX-2 was low but increased by LPS (10 mg/kg; i.p). Aspirin (10 mg/kg; i.v.) inhibited COX-1, measured as blood thromboxane and COX-2, measured as lung PGE2. Aspirin also increased the levels of ATL in the lungs of LPS-treated wild-type C57Bl6 mice (vehicle: 25.5±9.3 ng/ml; 100 mg/kg: 112.0±7.4 ng/ml; P<0.05). Despite this, ATL was unchanged in plasma after LPS and aspirin. This was true in wild-type as well as COX-1−/− and COX-2−/− mice. Thus, in mice in which COX-2 has been induced by LPS treatment, aspirin triggers detectable 15-epi-lipoxin A4 in lung tissue, but not in plasma. This important study is the first to demonstrate that while ATL can be measured in tissue, plasma ATL is not a biomarker of vascular COX-2 expression.—Kirkby, N. S., Chan, M. V., Lundberg, M. H., Massey, K. A., Edmands, W. M. B., MacKenzie, L. S., Holmes, E., Nicolaou, A., Warner, T. D., Mitchell, J. A. Aspirin-triggered 15-epi-lipoxin A4 predicts cyclooxygenase-2 in the lungs of LPS-treated mice but not in the circulation: implications for a clinical test.

Dissertation submitted in partial compliance with the requirements for a Masters Degree in Technology: Chiropractic, Durban University of Technology, 2009. / Headaches are one of the most common clinical conditions in medicine, and 80% of these are tension-type headaches (TTH). TTH has a greater socioeconomic impact than any other type of headache due to its prevalence. Within the TTH category, episodic TTH are more prevalent than chronic TTH. The mainstay in the treatment of TTH are simple analgesics and NSAIDs. Unless contraindicated, NSAIDs are often the most effective treatment for ETTH. However patients suffering with TTH tend to relate their headaches to increased muscle stiffness in the neck and shoulders and thus the non-pharmacological treatment of ETTH could be directed at the associated musculoskeletal components of ETTH. It is therefore proposed that the Kinesio Taping® Method may have an effect in the treatment of the muscular component of ETTH. Method: This study was a prospective randomised clinical trial with two intervention groups (n=16) aimed at determining the relative effectiveness of a NSAID and the Kinesio Taping® Method in the treatment of ETTHs. The patients were treated at 5 consultations over a 3 week period. Feedback was obtained using the: NRS – 101, the CMCC Neck Disability Index and a Headache Diary. Results: The Headache Diary showed a reduction in the presence and number, mean duration and pain intensity of ETTH in both groups. These treatment effects were sustained after the cessation of treatment with the exception of mean pain intensity in the Kinesio Taping® Method group. The mean NRS score decreased in both groups but at a slightly faster rate in the Kinesio Taping® Method group. The CMCC showed an improvement in the functional ability of the patients in both groups. Conclusion: There seems to be no significant difference in the relative effectiveness of the treatment modalities. We can thus state that the overall short-term reduction in symptomatology supports the use of NSAIDs or Kinesio Taping® Method in the treatment of ETTH.

Dissertation submitted in partial compliance with the requirements for the Masters Degree in Technology: Chiropractic, Durban University of Technology, 2010. / The 1 year overall prevalence of Episodic Tension-Type Headache (ETTH) is 38.3%; with lifetime prevalence at 46% for TTH. Little literature exists to support the effectiveness of spinal manipulation in the treatment of ETTH. Therefore aim of this study was to determine the relative effectiveness of cervical spine manipulation and a Nonsteroidal Anti-inflammatory drug (NSAID) (Ibuprofen®) in the treatment of ETTH. Method: This study was a prospective randomised clinical trial with two intervention groups (N=32, n1=16 and n2=16). The allocation of participants to the two groups was completed by means of simple randomization. Group one were treated using cervical spine manipulation. Group two were treated using Ibuprofen. Subjective measurements included the Numerical Rating Scale 101 Questionnaire (NRS-101), Short Form McGill Pain Questionnaire (SF-MPQ), CMCC Neck Disability Index (CMCC) and Headache Diary. A p value <0.05 was considered as statistically significant. Results: The subjective measurements of the NRS-101, SF-MPQ and CMCC showed a significant time effect in both treatment groups. Several of the subjective Headaches Diary outcomes followed this trend with significant time effect in both groups. There was a significant treatment effect for the NRS-101. Several subject outcomes from the Headache Diary showed a significant treatment effect in favour of manipulation, namely frequency and duration of headaches. Conclusion: The findings in this study have shown that cervical spine manipulation is more effective than Ibuprofen® for the treatment of ETTH in terms of several subjective outcomes namely: pain intensity (NRS-101), and the frequency and the duration of headache per day.

Prostanoids are oxygenated derivatives of arachidonic acid with a wide range of physiological effects in vertebrates including modulation of inflammation and innate immune responses. Nonsteroidal anti-inflammatory drugs (NSAIDs) act through inhibition of cyclooxygenase (COX) conversion of arachidonic acid to prostanoids. In order to better understand the potential of environmental NSAIDS for interruption of normal levels COX products in fishes, we developed an LC/MS/MS-based approach for tissue analysis of 7 prostanoids. Initial studies examining muscle, gut and gill demonstrated that prostaglandin E2 (PGE2) was the most abundant of the measured prostanoids in all tissues and that gill tissue had the highest and most consistent concentrations of PGE2. After short-term 48-h laboratory exposures to concentrations of 5, 25, 50 and 100 ppb ibuprofen, 50.0ppb and 100.0 ppb exposure concentrations resulted in significant reduction of gill tissue PGE2 concentration by approximately 30% and 80% respectively. The lower exposures did not result in significant reductions when compared to unexposed controls. Measured tissue concentrations of ibuprofen indicated that this NSAID had little potential for bioaccumulation (BCF 1.3) and the IC50 of ibuprofen for inhibition of PGE2 production in gill tissue was calculated to be 0.4 µM. Short-term laboratory exposure to ibuprofen did not result in significant alteration of concentrations of PGE2 at environmentally relevant concentrations.