The objective of this research was to examine the effects of plant sterols and glucomannan on lipid profiles, plasma plant sterol levels and glycemic control in mildly hypercholesterolemic subjects. Thirteen type 2 diabetic and sixteen non-diabetic individuals participated in a randomized crossover trial consisting of 4 phases, of 21 days each. During the study period, subjects were supplemented with plant sterols and/or glucomannan. Overall reductions of total cholesterol and low-density lipoprotein (LDL) cholesterol concentrations were greater after consumption of plant sterols and glucomannan compared to plant sterol or glucomannan supplementation alone. Plasma lathosterol levels, indicators of cholesterol biosynthesis, were decreased after combination treatment. The results suggest that a combination of glucomannan and plant sterols substantially improve plasma lipids by reducing cholesterol absorption and synthesis simultaneously. Supplementation of plant sterols and glucomannan can thus be used as an effective treatment for management of circulating cholesterol levels and prevention of cardiovascular disease.

Type 1 diabetes (T1D) is a metabolic disorder characterized by destruction of the pancreatic beta-islet cells leading to complete loss of insulin production. Gliclazide is used in Type 2 diabetes (T2D) to stimulate insulin production but it also has beneficial extrapancreatic effects which make it potentially useful in T1D. In fact, some T2D patients continue to use gliclazide even after their diabetes progresses to T1D since it provides better glycemic control than insulin alone. About 30% of a gliclazide dose undergoes enterohepatic recirculation which may contribute to the observed high interindividual variability in its pharmacokinetics. This may limit its efficacy in T1D especially since diabetes can disturb the gut microbiota and give rise to changes in bile composition and enterohepatic recirculation. Improving the absorption of gliclazide through the use of bile acids and probiotics may reduce this variability and improve the efficacy of gliclazide in T1D. The aim of this thesis was to investigate the interaction between the semisynthetic bile acid, 12-monoketocholic acid (MKC) and gliclazide in terms of pharmacokinetics and hypoglycemic effects in a rat model of T1D with and without probiotic pretreatment. A parallel ex vivo (Ussing chamber) study was carried out to investigate the mechanism of the interaction. Sensitive LC-MS and HPLC methods (Chapter 2) were developed to determine the concentrations of gliclazide and MKC in Ringer's solution and rat serum. Diabetes was induced in male Wistar rats by intravenous (i.v.) alloxan (30 mg/kg). Rats with blood glucose concentration > 18 mmol/l and serum insulin concentration < 0.04 [mu]g/l, 2-3 days after alloxan injection were considered diabetic. A total of 280 male Wistar rats (Chapter 3) were randomly allocated into 28 groups (n=10) of which 14 were made diabetic. Then 7 groups of healthy and 7 groups of diabetic rats were gavaged with probiotics (10⁸ CFU/mg, 75 mg/kg) every 12 hours for three days after which single doses of gliclazide (20 mg/kg), MKC (4 mg/kg) or the combination were administered either by tail vein injection (i.v.) or by gavage. The other 14 groups (7 healthy and 7 diabetic) were gavaged with saline every 12 hours for three days and then treated in the same way. Blood samples were collected from the tail vein for 10 hours after the dose and analyzed for blood glucose, serum gliclazide & serum MKC concentrations. Serum concentration-time curves for gliclazide and MKC were used to determine pharmacokinetic parameters. In the parallel ex vivo study (Chapter 4), 88 rats were randomly divided into 22 groups (n=4 rats per group, 8 chambers per rat), of which 11 groups were made diabetic. Of the 22 groups, 8 groups (4 healthy and 4 diabetic) were pretreated with probiotics as described above to study their influence on gliclazide and MKC flux, 8 groups (4 healthy and 4 diabetic) were used to investigate the interaction between gliclazide and MKC during transport, and 6 groups (3 healthy and 3 diabetic) were used to study the influence of selective inhibitors of the drug transporters Mrp2, Mrp3 and Mdr1 on gliclazide flux. 10 cm piece of the ileum was removed from each rat, the underlying muscle layer and connective tissue removed and the epithelial sheets mounted into Ussing chambers. Gliclazide, MKC or a combination were added to either the mucosal or serosal side and samples collected from both sides for 3 h to determine mucosal-to-serosal absorptive flux (Jss[MtoS]) and serosal-to-mucosal secretory flux (Jss[StoM]) of gliclazide and MKC as appropriate. In diabetic rats, gliclazide alone had no effect on blood glucose levels (Ch3, exp2) whereas MKC reduced it from 23 � 3 to 18 � 3 mmol/l (Ch3, exp3) and the combination of gliclazide and MKC reduced it even further from 24 � 4 to 16 � 3 mmol/l (Ch3, exp4). In diabetic rats, probiotic treatment reduced blood glucose by 2-fold (Ch3, exp1) and enhanced the hypoglycemic effect of the combination of gliclazide and MKC (blood glucose decreased from 24 � 3 to 10 � 2 mmol/l). The bioavailability of gliclazide was higher in healthy rats (53.2 � 6.2%) than in diabetic rats (39.9 � 6.0%) (Ch3, exp2). In healthy rats, MKC enhanced gliclazide bioavailability (82.7 � 8.2%) but in diabetic rats MKC had no effect on gliclazide bioavailability (Ch3, exp4). In healthy rats, probiotic pretreatment significantly reduced gliclazide and MKC bioavailabilities (p<0.01) while in diabetic rats, probiotic pretreatment significantly increased the low bioavailability of gliclazide to a level similar to that in healthy rats (Ch3, exp2 & 3). MKC showed clear evidence of enterohepatic recycling and probiotics delayed and reduced its systemic absorption (Ch3, exp3). In ileal tissues from healthy rats, Ussing chamber studies showed gliclazide is most likely a substrate of Mrp2 and Mrp3 (Ch4, exp5) and MKC significantly reduced gliclazide Jss[MtoS] probably through Mrp3 inhibition (Ch4, exp1). In ileal tissue from diabetic rats, MKC had no effect on gliclazide Jss[MtoS] and Jss[StoM] (Ch4, exp2) and none of the inhibitors had any effect of gliclazide flux (Ch4, exp6). This suggests that these transporters are dysfunctional in this model of T1D. Probiotics and MKC have hypoglycemic effects that appear to be enhanced by gliclazide and all appear to interact at the level of ileal drug transporters. The combination of probiotic treatment, gliclazide and MKC exerted the greatest hypoglycemic effect in T1D rats. Accordingly, the application of this combination may have potential in improving the treatment of T1D.

Type 1 diabetes (T1D) is a metabolic disorder characterized by destruction of the pancreatic beta-islet cells leading to complete loss of insulin production. Gliclazide is used in Type 2 diabetes (T2D) to stimulate insulin production but it also has beneficial extrapancreatic effects which make it potentially useful in T1D. In fact, some T2D patients continue to use gliclazide even after their diabetes progresses to T1D since it provides better glycemic control than insulin alone. About 30% of a gliclazide dose undergoes enterohepatic recirculation which may contribute to the observed high interindividual variability in its pharmacokinetics. This may limit its efficacy in T1D especially since diabetes can disturb the gut microbiota and give rise to changes in bile composition and enterohepatic recirculation. Improving the absorption of gliclazide through the use of bile acids and probiotics may reduce this variability and improve the efficacy of gliclazide in T1D. The aim of this thesis was to investigate the interaction between the semisynthetic bile acid, 12-monoketocholic acid (MKC) and gliclazide in terms of pharmacokinetics and hypoglycemic effects in a rat model of T1D with and without probiotic pretreatment. A parallel ex vivo (Ussing chamber) study was carried out to investigate the mechanism of the interaction. Sensitive LC-MS and HPLC methods (Chapter 2) were developed to determine the concentrations of gliclazide and MKC in Ringer's solution and rat serum. Diabetes was induced in male Wistar rats by intravenous (i.v.) alloxan (30 mg/kg). Rats with blood glucose concentration > 18 mmol/l and serum insulin concentration < 0.04 [mu]g/l, 2-3 days after alloxan injection were considered diabetic. A total of 280 male Wistar rats (Chapter 3) were randomly allocated into 28 groups (n=10) of which 14 were made diabetic. Then 7 groups of healthy and 7 groups of diabetic rats were gavaged with probiotics (10⁸ CFU/mg, 75 mg/kg) every 12 hours for three days after which single doses of gliclazide (20 mg/kg), MKC (4 mg/kg) or the combination were administered either by tail vein injection (i.v.) or by gavage. The other 14 groups (7 healthy and 7 diabetic) were gavaged with saline every 12 hours for three days and then treated in the same way. Blood samples were collected from the tail vein for 10 hours after the dose and analyzed for blood glucose, serum gliclazide & serum MKC concentrations. Serum concentration-time curves for gliclazide and MKC were used to determine pharmacokinetic parameters. In the parallel ex vivo study (Chapter 4), 88 rats were randomly divided into 22 groups (n=4 rats per group, 8 chambers per rat), of which 11 groups were made diabetic. Of the 22 groups, 8 groups (4 healthy and 4 diabetic) were pretreated with probiotics as described above to study their influence on gliclazide and MKC flux, 8 groups (4 healthy and 4 diabetic) were used to investigate the interaction between gliclazide and MKC during transport, and 6 groups (3 healthy and 3 diabetic) were used to study the influence of selective inhibitors of the drug transporters Mrp2, Mrp3 and Mdr1 on gliclazide flux. 10 cm piece of the ileum was removed from each rat, the underlying muscle layer and connective tissue removed and the epithelial sheets mounted into Ussing chambers. Gliclazide, MKC or a combination were added to either the mucosal or serosal side and samples collected from both sides for 3 h to determine mucosal-to-serosal absorptive flux (Jss[MtoS]) and serosal-to-mucosal secretory flux (Jss[StoM]) of gliclazide and MKC as appropriate. In diabetic rats, gliclazide alone had no effect on blood glucose levels (Ch3, exp2) whereas MKC reduced it from 23 � 3 to 18 � 3 mmol/l (Ch3, exp3) and the combination of gliclazide and MKC reduced it even further from 24 � 4 to 16 � 3 mmol/l (Ch3, exp4). In diabetic rats, probiotic treatment reduced blood glucose by 2-fold (Ch3, exp1) and enhanced the hypoglycemic effect of the combination of gliclazide and MKC (blood glucose decreased from 24 � 3 to 10 � 2 mmol/l). The bioavailability of gliclazide was higher in healthy rats (53.2 � 6.2%) than in diabetic rats (39.9 � 6.0%) (Ch3, exp2). In healthy rats, MKC enhanced gliclazide bioavailability (82.7 � 8.2%) but in diabetic rats MKC had no effect on gliclazide bioavailability (Ch3, exp4). In healthy rats, probiotic pretreatment significantly reduced gliclazide and MKC bioavailabilities (p<0.01) while in diabetic rats, probiotic pretreatment significantly increased the low bioavailability of gliclazide to a level similar to that in healthy rats (Ch3, exp2 & 3). MKC showed clear evidence of enterohepatic recycling and probiotics delayed and reduced its systemic absorption (Ch3, exp3). In ileal tissues from healthy rats, Ussing chamber studies showed gliclazide is most likely a substrate of Mrp2 and Mrp3 (Ch4, exp5) and MKC significantly reduced gliclazide Jss[MtoS] probably through Mrp3 inhibition (Ch4, exp1). In ileal tissue from diabetic rats, MKC had no effect on gliclazide Jss[MtoS] and Jss[StoM] (Ch4, exp2) and none of the inhibitors had any effect of gliclazide flux (Ch4, exp6). This suggests that these transporters are dysfunctional in this model of T1D. Probiotics and MKC have hypoglycemic effects that appear to be enhanced by gliclazide and all appear to interact at the level of ileal drug transporters. The combination of probiotic treatment, gliclazide and MKC exerted the greatest hypoglycemic effect in T1D rats. Accordingly, the application of this combination may have potential in improving the treatment of T1D.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

Thesis (M.Sc. (Pharmacology))--Mahidol University, 1984.

Thesis (Ph.D.)--University of Alberta, 2009. / A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Epidemiology, Department of Public Health Sciences. Title from pdf file main screen (viewed on October 11, 2009). Includes bibliographical references.

CoordenaÃÃo de AperfeiÃoamento de NÃvel Superior / O nÃo cumprimento do regime medicamentoso, por parte dos usuÃrios com Diabetes Mellitus tipo 2 (DM 2), à um dos principais problemas encontrados para a manuntenÃÃo do equilÃbrio glicÃmico e, consenquentemente, prevenÃÃo das complicaÃÃes micro e macrovasculares do DM 2. O estÃgio desse problema e a melhor forma para detectÃ-lo ainda nÃo estÃo definidos em Fortaleza-CE e em outras partes do paÃs. Dessa maneira, objetivou-se avaliar o cumprimento da terapia farmacolÃgica de usuÃrios com DM 2 aos antidiabÃticos oriais na rede bÃsica de Fortaleza-CE e validar dois mÃtodos indiretos utilizados para medir o cumprimento do tratamento medicamentosos: o teste de Batalla e o teste adaptado de Morisky, Green e Levine e Delgado e Lima (MGLDL). Trata-se de um estudo tranversal e de uma validaÃÃo de critÃrio. Foram investigados 437 usuÃrios com DM 2, de ambos os sexo, na faixa etÃria de 18-92 anos de idade, de 12 Unidades BÃsicas de SaÃde da FamÃlia (UBASF), duas unidades de cada uma das seis regiÃes do municÃpio, durante os meses de marÃo a junho de 2009. Nas UBASF foi utilizado um formulÃrio para coleta das informaÃÃes sociodemogrÃficas, clÃnicas e medicamentosas. AlÃm disso, foi entregue a cada pesquisado uma embalagem plÃstica para armazenagem dos antidiabÃticos orais prescritos. No domicÃlio dos sujeitos foram aplicados o Teste de Batalla, o MLGDL e a contagem dos comprimidos armazenados na embalagem plÃstica disponibilizada. Na determinaÃÃo do cumprimento do tratamento farmacolÃgico a contagem de comprimidos foi considerado o mÃtodo padrÃo ouro. Os dados sofreram tripla digitaÃÃo e foram armazenados no software SPSS. Na anÃlise dos dados foram calculados estatÃstica descritiva, coficientes de validaÃÃo, correlaÃÃo de Spearman e o Alpha de Cronbach. Houve uma maior participaÃÃo feminina (70,3%), daqueles com idade entre 18-59 anos (41,1%) e dos casados (55,8%). A classe econÃmica e escolaridade predominates foram a D (47,8%) e o primÃrio incompleto (38,9%). A prevalÃncia de nÃo cumprimento ao tratamento com antidiabÃticos orais foi de 74,6; 86,3 e 71,2, segundo os mÃtodos de Batalla, MGLDL e contagem de comprimidos, respectivamente. Em relaÃÃo ao padrÃo ouro, o teste MGLDL (66,3%) apresentou uma associaÃÃo maior de casos de nÃo cumprimento ao regime medicamentoso do que Batalla (p=0,000). Todos os coeficientes de validade do mÃtodo de MGLDL foram maiores que o de Batalla. O teste MGLDL apresentou uma melhor correlaÃÃo com a contagem de comprimidos (p<0,001) e exatidÃo do que o de Batalla (0,646>0,561). Portanto, o teste MGLDL demonstrou ser mais qualificado na detecÃÃo de usuÃrios com DM 2 nÃo cumpridores da terapÃutica medicamentosa a partir de antidiabÃticos orais. à pertinente que o enfermeiro da atenÃÃo bÃsica possa conhecer esse mÃtodo, a fim de identificar usuÃrios com DM 2 nÃo cumpridores e orientÃ-los na perspectiva de melhorar sua adesÃo à terapÃutica medicamentosa.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A trans-desidrocrotonina (t-DCTN) Ã o principal composto diterpenÃide presente no extrato da casca do caule de Croton cajucara (Euphorbiaceae). Este diterpeno possui um amplo espectro de atividades farmacolÃgicas que inclui antiinflamatÃria, antinociceptiva, e efeitos hipoglicemiante e hipolipidÃmico. SubstÃncias com esse perfil farmacolÃgico sÃo comumente associadas a efeitos deletÃrios sobre o fÃgado. Tendo em vista que estudos in vitro e in vivo mostraram uma hepatotoxicidade da t-DCTN, o presente estudo objetivou analisar em maior profundidade o seu potencial em causar dano hepÃtico e, entÃo, buscar estratÃgias farmacolÃgicas para mitigar tal toxicidade. Desta forma, os experimentos iniciais foram direcionados para observaÃÃo do dano hepÃtico em camundongos que receberam, por gavagem, uma Ãnica (aguda) ou repetidas administraÃÃes de t-DCTN, em doses que variam de 10 a 300 mg/kg. A segunda sÃrie de experiÃncias foi projetada para avaliar os efeitos do (i) prÃ-condicionamento com a menor dose de t-DCTN (10 mg/kg) ou etanol (1 g/kg), e do (ii) prÃ-tratamento com Vitamina E ou N-acetilcisteÃna (NAC) no dano hepÃtico associado a altas doses de t-DCTN em camundongos. Um possÃvel envolvimento de NO tambÃm foi verificado no efeito prÃ-condicionante de t-DCTN e/ou Etanol. t-DCTN em doses mais altas (100 e 300 mg/kg, v.o.) causou dano hepÃtico severo, comprovado por aumentos significativos (p <0,001) nos nÃveis sÃricos de ALT e AST e por alteraÃÃes histopatolÃgicas, quando administrada isolada ou repetidamente. Em contraste, as doses de 10 e 30 mg/kg nÃo promoveram alteraÃÃes significantes, sugerindo que a toxicidade da t-DCTN Ã dose dependente. O prÃ-condicionamento farmacolÃgico com t-DCTN (10 mg/kg, v.o.) e Etanol (1 g/kg, v.o.) atenuaram significativamente (p <0,001) a hepatotoxicidade associada a alta dose (100 mg/kg) de t-DCTN, como comprovado pela reduÃÃo na atividade das transaminases sÃricas, como tambÃm nas lesÃes hepÃticas. A suplementaÃÃo em camundongos com L-arginina, um substrato para geraÃÃo de NO, preveniu parcialmente o efeito hepatotÃxico da t-DCTN, possivelmente devido a um aumento na microcirculaÃÃo hepÃtica. Adicionalmente, o prÃ-tratamento com Vitamina E, mas nÃo com NAC, reduziu efetivamente os efeitos hepatotÃxicos de t-DCTN, comprovado pela diminuiÃÃo dos nÃveis sÃricos de ALT e AST, de TBARS hepÃtico e das alteraÃÃes histolÃgicas. Isto sugere que Vitamina E protege contra o aumento da peroxidaÃÃo lipÃdica hepÃtica promovido por alta dose de t-DCTN. Paradoxalmente, comparada a outros hepatotoxicantes relatados na literatura, a t-DCTN aumenta os nÃveis de glutationa hepÃtica que pode ser uma conseqÃÃncia do estresse oxidativo prolongado. Em conjunto, estes resultados confirmam as observaÃÃes anteriores sobre o potencial hepatotÃxico da t-DCTN e sugerem que um aumento no estresse oxidativo e na peroxidaÃÃo lipÃdica das membranas dos hepatÃcitos contribui para o dano hepÃtico desse diterpeno. A suplementaÃÃo com Vitamina E, um antioxidante lipossolÃvel, ou o prÃ-condicionamento com doses menores de t-DCTN ou etanol poderiam ser profilaticamente Ãtil para superar os efeitos hepatotÃxicos de t-DCTN / The trans-dehydrocrotonin (t-DCTN) is a major diterpenoid compound present in bark extracts of Croton cajucara (Euphorbiaceae) stem. This diterpene possesses a wide spectrum of pharmacological activity that include anti-inflammatory, antinociceptive, hypoglycemic and antihyperlipidemic effects. Deleterious effects on liver are not uncommon with substances having this pharmacological profile. Keeping in view the reported hepatotoxicity of t-DCTN in vitro and in vivo, the present study was carried out to analyse in greater depth its potential to cause hepatic damage and then to seek pharmacological strategies to mitigate such a toxicity. Accordingly, our initial experiments were aimed to observe the hepatic damage in mice that received the single (acute) or repeated administrations of t-DCTN by oral gavage, at doses ranging from 10 to 300 mg/kg. The second series of experiments were designed to evaluate the effects of (i) pre-conditioning with a smaller dose t-DCTN or ethanol, and (ii) pre-treatments with Vitamin E or NAC on high-dose -associated hepatic injury in mice. A possible involvement of NO was also verified on the pre-conditioning effects of t-DCTN and or Ethanol. t-DCTN at higher doses (100 e 300 mg/kg, v.o.) caused severe hepatic damage as evidenced by significant (p<0,001) increases in the serum levels of ALT and AST and histopathological alterations, whether administered singly or repeatedly. In contrast, at the doses of 10 e 30 mg/kg, there were no significant alterations suggesting that the toxicity is a dose-related one. Pharmacological pre-conditioning with t-DCTN (10 mg/kg, p.o.) e Ethanol (1 g/kg, p.o.) significantly (p<0,001) attenuated the high-dose t-DCTN (100 mg/kg) -associated hepatotoxicity, as evidenced by reductions in serum enzyme activities as well as the hepatic lesions. In mice supplemented with L-arginine, the substrate for NO generation only partially prevented the hepatotoxic effect of t-DCTN most possibly due to an improved hepatic microcirculation. Additionally, pre-treatment with Vitamin E but not the NAC effectively reduced hepatotoxic effect of t-DCTN, evidenced by diminished serum levels of ALT, AST and hepatic TBARS and histological alterations. This suggests that Vitamine E protects against the increased hepatic lipid peroxidation promoted by high-dose t-DCTN. Paradoxically, compared to other hepatotoxicants reported in literature, t-DCTN enhanced the hepatic glutathione levels, which may be a consequence of prolonged oxidative stress. Taken together, these results confirm the earlier observations on the hepatotoxic potential of t-DCTN and suggest that an increased oxidative stress and lipid peroxidation of hepatocyte membranes contributes to hepatic damage. Supplementation with liposoluble antioxidant Vitamina E, or prÃ-conditioning with smaller doses of t-DCTN or ethanol might be useful prophylactically to overcome hepatotoxic effects of t-DCTN

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-04-04T11:43:58Z No. of bitstreams: 1 daniellemariadeoliveiraaragao.pdf: 2211938 bytes, checksum: f8c23516b09f7a351827796c4800d319 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-04-04T11:50:39Z (GMT) No. of bitstreams: 1 daniellemariadeoliveiraaragao.pdf: 2211938 bytes, checksum: f8c23516b09f7a351827796c4800d319 (MD5) / Made available in DSpace on 2017-04-04T11:50:39Z (GMT). No. of bitstreams: 1 daniellemariadeoliveiraaragao.pdf: 2211938 bytes, checksum: f8c23516b09f7a351827796c4800d319 (MD5) Previous issue date: 2009-03-27 / Diabetes mellitus é uma síndrome que afeta mais de 180 milhões de pessoas no mundo e é provável que esse número chegue a mais que o dobro desse valor em 2030. A principal característica clínica do diabetes é a hiperglicemia. Vários trabalhos mostram que a hiperglicemia é crítica para o desenvolvimento de complicações nos diabéticos e que estes efeitos são associados ao estresse oxidativo. Neste contexto, o presente estudo investigou o efeito hipoglicemiante do extrato metanólico das folhas de C. pachystachya (400 mg/ml) em ratos normais e diabéticos induzidos com aloxano durante um período de 42 dias. O extrato apresentou uma acentuada redução dos níveis de glicemia de ratos diabéticos após 12 horas de sua administração. Este efeito não foi observado para ratos normais. Parâmetros bioquímicos foram determinados após 42 dias do tratamento e não foram observadas alterações significativas. Também foi realizado o estudo histológico do fígado e rim e não houve alterações nestes órgãos. Esse extrato apresentou igualmente relevante atividade antioxidante (DPPH e redução do poder). A triagem fitoquímica preliminar revelou a presença de fenóis, flavonóides, cumarinas, taninos, esteróides, antraquinonas e alcalóides. Ácido clorogênico também foi identificado no extrato. As conclusões revelam que C. pachystachya possui uma potente atividade antioxidante e hipoglicemiantes. Não foram observados efeitos adversos durante o período estudado indicando que a espécie vegetal é promissora para o tratamento da diabetes. / Diabetes mellitus is a syndrome that affects more than 180 million of people around the world and the number is likely to more than double by 2030. The prime clinical characteristic of diabetes is the hyperglycemia. Several works show that hyperglycemia is critical on diabetic complication development and that these effects are associated to oxidative stress. In this regard, this study investigate the hypoglycemic effect of the methanolic extract of leaves of C. pachystachya (400 mg/ml) in normal, glucose loading and alloxan-induced diabetic rats during a period of 42 days. The extract presented a pronounced decrease on the blood glucose levels of diabetic rats in 12 hours after extract administration. This effect was not observed for normal rats. Biochemical parameters were determined after 42 days treatment and no significant changes were observed. The histological study of the liver and kidney was also performed and no alterations were observed in these organs. This extract also presented relevant antioxidant activity (DPPH and reduction power). A preliminary phytochemical screening revealed the presence of phenols, flavonoids, coumarins, tannins, steroids, anthraquinones and alkaloids. Chlorogenic acid was also identified in the extract. The findings show that C. pachystachya possesses a powerful hypoglycemic and antioxidant activity. No adverse effects were observed during the studied period indicating that is promising plant species for handling of diabetes.

In part 1 of this thesis, the antidiabetic activity of a series of novel oxovanadium(IV) complexes was investigated. A range of bidentate N,O-donor ligands, which partially mimic naturally occurring bioligands, were prepared and reacted with the vanadyl ion to form the corresponding bis-coordinated complexes. Initially, 2-(2ˊ-hydroxyphenyl)-1R-imidazoline (where R = H, ethyl and ethanol) ligands were prepared. The aqueous pH-metric chemical speciation was investigated using glass electrode potentiometry which allowed for the determination of protonation and stability constants of the ligands and complexes, respectively. The species distribution diagrams generated from this information gave an indication of how the complexes might behave across the broad pH range experienced in the digestive and circulatory systems. This information was used to create an improved 2nd generation of ligands that were constructed by combining the imidazole and carboxylic acid functionalities. These corresponding bis[(imidazolyl)carboxylato]-oxovanadium(IV) complexes displayed a broader pH-metric stability. Both sets of complexes improved glucose uptake and reduced coagulation in vitro. In part 2 of this thesis, a range of homogeneous and heterogeneous oxovanadium(IV) catalysts were prepared. Firstly, Merrifield beads were functionalized with ligands from Part 1 and then reacted with vanadyl sulfate to afford the corresponding heterogeneous catalysts. These displayed promising catalytic activity for the peroxide facilitated oxidation of thioanisole, styrene and ethylbenzene as well as the oxidative bromination of phenol red. Smaller imidazole-containing beads with higher surface areas than the Merrifield beads were prepared by suspension polymerization. These beads similarly demonstrated excellent catalytic activity for the oxidation of thioanisole and were highly recyclable. In attempt to increase the exposed catalytic surface area, while retaining the ease of separation achieved in the before mentioned systems, micron to nano sized electrospun fibers containing coordinating ligands were fabricated. The corresponding oxovanadium(IV) functionalized fibers were applied to the oxidation of thioanisole using a continuous flow system. The flexible and porous nature of the fiber mats was well suited to this approach. After optimization of the reactant flow rate and catalyst amount, near quantitative (> 99%) oxidation was achieved for an extended period. In addition, leaching of vanadium was mitigated by modification of the attached ligand or polymer material.