The research presented in this thesis addressed knowledge gaps for three medicinal plant taxa, Souroubea spp. (Marcgraviaceae) and Platanus (Platanaceae) as well as Echinacea spp. (Asteraceae). The primary pharmacological mechanism of Souroubea sympetala and Platanus occidentalis were well established, with pentacyclic triterpenes identified as major active principles. My results indicate that major triterpenoids, and crude plant extracts, selectively inhibited monoacyglycerol lipase (MAGL) activity but not fatty acid amide hydrolase (FAAH) activity. These data suggest a possible secondary anxiolytic mechanism of action through the endocannabinoid system (ECS). My study of herb-drug interactions of Souroubea and Plantanus products showed some potential risk when combined with a classic benzodiazepine class drug, diazepam, and I proposed a mechanism through in vitro CYP450 enzyme inhibition. The pharmacokinetic study revealed the difficulty of detecting betulinic acid in animal blood. To support the development a commercial botanical composed of these medicinal plants, an extraction method and a highly sensitive and selectivity HPLC-APCI-MS based quantification method was successfully developed and validated. Part II of this thesis focused on the impact of phytochemical variation and hepatic metabolism on the ECS activity of Echinacea spp. and explored the potential for new applications of Echinacea spp. as a natural health product. My research indicated that considerable variability in the content of phenolic and alkylamide (AKA) compounds reflected similar variability in in vitro bioactivity at ECS-related pharmacological targets. Following biochemometric analysis, several phenolic compounds and AKAs in Echinacea spp. were found to be significant independent variables determining FAAH inhibition and CB receptor activation. Hepatic metabolism was also found to affect the FAAH inhibition of AKA, as increased FAAH inhibitory effects were observed after CYP450-mediated metabolism of both individual AKAs and crude extracts of E angustifolia and E. purpurea, suggesting a “pro-drug” mechanism. Dose dependent activities were observed with oral administration of both E angustifolia and E. purpurea root extract in rat paw model of inflammation and pain. Further tests indicated these activities can be partially blocked by co-administration of CB1 and CB2 receptor antagonists AM251 and AM630, respectively. This evidence suggests activity for peripheral pain was at least partially mediated through the ECS.

Herbal medicines are widely used in our community. A survey of Australian consumers indicated that 60% had used complementary and/or alternative medicines in the past year with the majority not informing their doctor that they were using herbal medicines. Little is known about the potentially serious consequences of interactions between herbal and conventional medicines. Warfarin has an important role in treating people with heart disease, yet it has a narrow therapeutic range, is highly bound to plasma proteins, and is metabolised by cytochrome P450. This creates the potential for life-threatening interactions with other drugs and foods leading to excessive bleeding. Hence, warfarin is one of the most frequently investigated drugs for interaction studies. Early clinical reports suggest that there exists the potential for an interaction between warfarin and four herbal medicines: St John�s wort, ginseng, ginkgo and ginger. However, these herb-drug combinations have never been conclusively studied. The two clinical studies conducted as part of this research had an identical study design. Twenty-four healthy male subjects were recruited into the two separate studies. This was an open label, three-way crossover randomised study in twelve healthy male subjects, who received a single 25 mg dose of warfarin alone or after 14 days pre-treatment with St John�s wort, or 7 days pre-treatment with ginseng. Dosing with St John�s wort or ginseng was continued for 7 days after administration of the warfarin dose in study I or who received a single 25 mg dose of warfarin alone or after 7 days pre-treatment with recommended doses of ginkgo or ginger from single ingredient products of known quality. Dosing with ginkgo or ginger was continued for 7 days after administration of the warfarin dose in study II. Platelet aggregation, international normalised ratio (INR) of prothrombin time, warfarin enantiomer protein binding, warfarin enantiomer concentrations in plasma and S-7-hydroxywarfarin concentration in urine were measured in both studies. Statistical comparisons were made using ANOVA and 95% confidence interval (CI) for mean value and 90% CI for geometric mean ratio value are reported. n study I, the mean (95% CI) apparent clearance of S-warfarin after warfarin alone or with St John�s wort or ginseng were, respectively, 198 (174 � 223) ml/h, 269 (241 � 297) ml/h and 220 (201 � 238) ml/h. The respective apparent clearances of R-warfarin were 110 (94 � 126) ml/h, 142 (123 � 161) ml/h and 119 (106 � 131) ml/h. The mean ratio of apparent clearance for S-warfarin was 1.29 (1.16-1.46) and for R-warfarin was 1.23 (1.11-1.37) when St John�s wort was co-administered. The mean ratio of AUC0-168 of INR was 0.79 (0.70 - 0.95) when St John�s wort was co-administered. The urinary excretion ratio of S-7-hydroxywarfarin after administration of warfarin alone was 0.04 (0.03 � 0.06) mg/h and there was no significant difference following treatment with either St John�s wort 0.03 (0.02 � 0.04) mg/h or ginseng 0.03 (0.02 � 0.04) mg/h. The ratio of geometric means for S-7-hydroxywarfarin UER was 0.82 (0.61-1.12) for St John�s wort, and 0.68 (0.50-0.91) for ginseng. St John�s wort and ginseng did not affect the apparent volumes of distribution or protein binding of warfarin enantiomers. In study II, the mean (95% CI) apparent clearance of S-warfarin after warfarin alone, with ginkgo or ginger were 189 (167 � 210) ml/h, 200 (173 � 227) ml/h and 201 (171 � 231) ml/h, respectively. The respective apparent clearances of R-warfarin were 127 (106 � 149) ml/h, 126 (111 � 141) ml/h and 131 (106 � 156) ml/h. The mean ratio of apparent clearance for S-warfarin was 1.05 (0.98 -1.12) and for R-warfarin was 1.00 (0.93 -1.08) when co-administered with ginkgo. The mean ratio of AUC0-168 of INR was 0.93 (0.81 -1.05) when co-administered with ginkgo. The mean ratio of apparent clearance for S-warfarin was 1.05 (0.97 -1.13) and for R-warfarin was 1.02 (0.95 -1.10) when co-administered with ginger. The mean ratio of AUC0-168 of INR was 1.01 (0.93 -1.15) when co-administered with ginger. The urinary excretion ratio (UER) of S-7-hydroxywarfarin after administration of warfarin alone was 0.04 (0.03 � 0.05) mg/h and there was no significant difference following treatment with either ginkgo 0.04 (0.03 � 0.04) mg/h or ginger 0.03 (0.02 � 0.04) mg/h. The ratio of geometric means for S-7-hydroxywarfarin UER was 1.07 (0.69-1.67) for ginkgo, and 1.00 (0.64-1.56) for ginger. Ginkgo and ginger did not affect the apparent volumes of distribution or protein binding of either S-warfarin or R-warfarin. In conclusion, St John�s wort significantly induced the apparent clearance of both S-warfarin and R-warfarin, which in turn resulted in a significant reduction in the pharmacological effect of rac-warfarin. Ginseng, ginkgo and ginger at recommended doses affect neither clotting status, nor the pharmacokinetics or pharmacodynamics of either S-warfarin or R-warfarin in healthy subjects.

Herbal medicines are widely used in our community. A survey of Australian consumers indicated that 60% had used complementary and/or alternative medicines in the past year with the majority not informing their doctor that they were using herbal medicines. Little is known about the potentially serious consequences of interactions between herbal and conventional medicines. Warfarin has an important role in treating people with heart disease, yet it has a narrow therapeutic range, is highly bound to plasma proteins, and is metabolised by cytochrome P450. This creates the potential for life-threatening interactions with other drugs and foods leading to excessive bleeding. Hence, warfarin is one of the most frequently investigated drugs for interaction studies. Early clinical reports suggest that there exists the potential for an interaction between warfarin and four herbal medicines: St John�s wort, ginseng, ginkgo and ginger. However, these herb-drug combinations have never been conclusively studied. The two clinical studies conducted as part of this research had an identical study design. Twenty-four healthy male subjects were recruited into the two separate studies. This was an open label, three-way crossover randomised study in twelve healthy male subjects, who received a single 25 mg dose of warfarin alone or after 14 days pre-treatment with St John�s wort, or 7 days pre-treatment with ginseng. Dosing with St John�s wort or ginseng was continued for 7 days after administration of the warfarin dose in study I or who received a single 25 mg dose of warfarin alone or after 7 days pre-treatment with recommended doses of ginkgo or ginger from single ingredient products of known quality. Dosing with ginkgo or ginger was continued for 7 days after administration of the warfarin dose in study II. Platelet aggregation, international normalised ratio (INR) of prothrombin time, warfarin enantiomer protein binding, warfarin enantiomer concentrations in plasma and S-7-hydroxywarfarin concentration in urine were measured in both studies. Statistical comparisons were made using ANOVA and 95% confidence interval (CI) for mean value and 90% CI for geometric mean ratio value are reported. n study I, the mean (95% CI) apparent clearance of S-warfarin after warfarin alone or with St John�s wort or ginseng were, respectively, 198 (174 � 223) ml/h, 269 (241 � 297) ml/h and 220 (201 � 238) ml/h. The respective apparent clearances of R-warfarin were 110 (94 � 126) ml/h, 142 (123 � 161) ml/h and 119 (106 � 131) ml/h. The mean ratio of apparent clearance for S-warfarin was 1.29 (1.16-1.46) and for R-warfarin was 1.23 (1.11-1.37) when St John�s wort was co-administered. The mean ratio of AUC0-168 of INR was 0.79 (0.70 - 0.95) when St John�s wort was co-administered. The urinary excretion ratio of S-7-hydroxywarfarin after administration of warfarin alone was 0.04 (0.03 � 0.06) mg/h and there was no significant difference following treatment with either St John�s wort 0.03 (0.02 � 0.04) mg/h or ginseng 0.03 (0.02 � 0.04) mg/h. The ratio of geometric means for S-7-hydroxywarfarin UER was 0.82 (0.61-1.12) for St John�s wort, and 0.68 (0.50-0.91) for ginseng. St John�s wort and ginseng did not affect the apparent volumes of distribution or protein binding of warfarin enantiomers. In study II, the mean (95% CI) apparent clearance of S-warfarin after warfarin alone, with ginkgo or ginger were 189 (167 � 210) ml/h, 200 (173 � 227) ml/h and 201 (171 � 231) ml/h, respectively. The respective apparent clearances of R-warfarin were 127 (106 � 149) ml/h, 126 (111 � 141) ml/h and 131 (106 � 156) ml/h. The mean ratio of apparent clearance for S-warfarin was 1.05 (0.98 -1.12) and for R-warfarin was 1.00 (0.93 -1.08) when co-administered with ginkgo. The mean ratio of AUC0-168 of INR was 0.93 (0.81 -1.05) when co-administered with ginkgo. The mean ratio of apparent clearance for S-warfarin was 1.05 (0.97 -1.13) and for R-warfarin was 1.02 (0.95 -1.10) when co-administered with ginger. The mean ratio of AUC0-168 of INR was 1.01 (0.93 -1.15) when co-administered with ginger. The urinary excretion ratio (UER) of S-7-hydroxywarfarin after administration of warfarin alone was 0.04 (0.03 � 0.05) mg/h and there was no significant difference following treatment with either ginkgo 0.04 (0.03 � 0.04) mg/h or ginger 0.03 (0.02 � 0.04) mg/h. The ratio of geometric means for S-7-hydroxywarfarin UER was 1.07 (0.69-1.67) for ginkgo, and 1.00 (0.64-1.56) for ginger. Ginkgo and ginger did not affect the apparent volumes of distribution or protein binding of either S-warfarin or R-warfarin. In conclusion, St John�s wort significantly induced the apparent clearance of both S-warfarin and R-warfarin, which in turn resulted in a significant reduction in the pharmacological effect of rac-warfarin. Ginseng, ginkgo and ginger at recommended doses affect neither clotting status, nor the pharmacokinetics or pharmacodynamics of either S-warfarin or R-warfarin in healthy subjects.

Thesis (PhD)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: Introduction Earlier studies have shown the popularity of herbal products among people as traditional, complementary or alternative medication. One of the major clinical risks in the concomitant administration of herbal products and prescription medicine is pharmacokinetic herb-drug interaction (HDI). This is brought about by the ability of phytochemicals to inhibit or induce the activity of metabolic enzymes and transport proteins. The aim of this study was to investigate the potential of the crude extracts of popular medicinal herbs used in South Africa to inhibit major cytochrome P450 (CYP) enzymes and transport proteins through in vitro assessment. Methods Medicinal herbs were obtained from traditional medical practitioners and 15 were selected for this study. The selected herbal products were extracted and incubated with human liver microsomes to monitor the following reactions as markers for the metabolic activities of the respective CYP: phenacetin O-deethylation (CYP1A2), diclofenac 4‟-hydroxylation (CYP2C9), S-mephenytoin 4‟- hydroxylation (CYP2C19) and testosterone 6β-hydroxylation (CYP3A4). In addition, the influence of Lessertia frutescens (formerly Sutherlandia frutescens) and Hypoxis hemerocallidea was investigated on more isozymes: coumarin 7-hydroxylation (CYP2A6), bupropion hydroxylation (CYP2B6), paclitaxel 6α-hydroxylation (CYP2C8), bufuralol 1‟-hydroxylation (CYP2D6), chlorzoxazone 6- hydroxylation (CYP2E1) and midazolam 1‟-hydroxylation (CYP3A4/5). The generation of the CYPspecific substrates/metabolites were monitored and quantified with the aid of LC-MS/MS. The metabolic clearance of midazolam using cryopreserved hepatocytes was monitored in the presence of Lessertia frutescens and Hypoxis hemerocallidea. The potential of both to inhibit human ATP-binding cassette (ABC) transporter activity was assessed using recombinant MDCKII and LLC-PK1 cells overexpressing human breast cancer resistant protein (BCRP) and human P-glycoprotein (P-gp), respectively. Similarly, the potential for interactions with human organic anion transporting polypeptide (OATP1B1 and OATP1B3) was assessed using recombinant HEK293 cells over-expressing OATP1B1 and OATP1B3, respectively. Results Bowiea volubilis, Kedrostis Africana, Chenopodium album, Lessertia frutescens (methanolic extract), Hypoxis hemerocallidea, Spirostachys africana and Lessertia frutescens (aqueous extract), in ascending order of potency demonstrated strong inhibition of CYP1A2 activity (IC50 = 1-100 g/mL). Similarly, Emex australis, Alepidea amatymbica, Pachycarpus concolor, Lessertia frutescens, Capparis sepiaria, Kedrostis africana and Pentanisia prunelloides inhibited CYP2C9 with IC50 less than 100 g/mL. The following demonstrated strong inhibition of CYP2C19 with IC50 values less than 100 g/mL: Acacia karroo, Capparis sepiaria, Chenopodium album, Pachycarpus concolor, Ranunculus multifidus, Lessertia frutescens and Zantedeschia aethiopica. CYP3A4 was inhibited by Lessertia frutescens, Hypoxis hemerocallidea, Spirostachys Africana, Bowiea volubilis, Zantedeschia aethiopica, Chenopodium album, Kedrostis Africana, Acacia karroo, Emex australis, Pachycarpus concolor, Ranunculus multifidus, Capparis sepiaria and Pentanisia prunelloides. Time-dependent (irreversible) inhibition of CYP3A4/5 (KI = 296 μg/mL, kinact = 0.063 min-1) and delay in the production of midazolam metabolites in the human hepatocytes, leading to a 40% decreased midazolam upscaled in vivo clearance, was observed with Lessertia frutescens. Further, Lessertia frutescence inhibited the activity of P-gp (IC50 = 324.8 μg/mL), OATP1B1 (IC50 = 10.4 μg/mL) and OATP1B3 (IC50 = 6.6 μg/mL). Hypoxis hemerocallidea inhibited the activity of OATP1B1 (IC50 = 118.7 μg/mL) and OATP1B3 (IC50 = 290.1 μg/mL) with no potent inhibitory effects on P-gp. None of the two inhibited the activity of BCRP within the tested concentrations. Conclusion The result indicates the potential for HDI between the selected medicinal herbs and the substrates of the enzymes investigated in this study, if sufficient in vivo concentrations are achieved. / AFRIKAANSE OPSOMMING: Inleiding Vroeëre studies het aangedui dat die gebruik van plantaardige produkte as tradisionele, aanvullende en alternatiewe medikasie baie gewild is. Een van die grootste kliniese risiko‟s geassosieer met die gelyktydige gebruik van plantaardige produkte met voorskrifmedikasie is farmakokinetiese kruiegeneesmiddel interaksies (HDI). Hierdie interaksies word veroorsaak deur die vermoë van plantchemikalieë om die aktiwiteit van metaboliese ensieme en transportproteïene te inhibeer of te induseer. Die doel van hierdie studie is om ondersoek in te stel na die moontlikheid van onsuiwer ekstrakte van gewilde Suid-Afrikaanse medisinale kruie om die belangrikste sitochroom P450 (CYP)- ensieme en transportproteïene te inhibeer. Hierdie ondersoek sal plaasvind deur middel van in vitrostudies. Metodes Medisinale kruie is verkry vanaf tradisionele genesers, waaruit ʼn totaal van 15 kruie geselekteer is vir gebruik tydens hierdie studie. Die geselekteerde kruie is geëkstraheer en met menslike lewermikrosome geïnkubeer om die volgende reaksies as merkers vir die metaboliese aktiwiteit van die onderskeie CYP-ensieme te moniteer: fenasetien-O-deëtilasie (CYP1A2), diklofenak-4‟- hidroksilasie (CYP2C9), S-mefenitoïen-4‟-hidroksilasie (CYP2C19) en testosteroon-6β-hidroksilasie (CYP3A4). Afgesien van die voorafgaande, is ook die invloed van Lessertia frutescens en Hypoxis hemerocallidea op verskeie ander iso-ensieme ondersoek. Hierdie iso-ensieme is soos volg: koumarien-7-hidroksilasie (CYP2A6), bupropioonhidroksilasie (CYP2B6), paklitaksiel-6α-hidroksilasie (CYP2C8), bufuralol-1‟-hidroksilasie (CYP2D6), chloorsoksasoon-6-hidroksilasie (CYP2E1) en midasolaam-1‟- hidroksilasie (CYP3A4/5). Die produksie van CYP-spesifieke substrate/metaboliete is gemoniteer en deur middel van LC-MS/MS-analises gekwantifiseer. Die metaboliese opruiming van midasolaam deur middel van krio-gepreserveerde hepatosiete is gemoniteer in die teenwoordigheid van Lessertia frutescens en Hypoxis hemerocallidea. Die moontlikheid van beide om menslike ATPbindingskasset (ABC)-transporteerderaktiwiteit te inhibeer is bepaal deur die gebruik van rekombinante MDCKII- en LLC-PK1-selle wat onderskeidelik menslike borskanker-weerstandige proteïen (BCRP) en menslike P-glikoproteïen (P-gp) potensieel. Op ʼn soortgelyke wyse is die moontlikheid vir interaksies met menslike organiese anion-transportpolipeptiede (OATP1B1 en OATP1B3) bepaal deur rekombinante HEK293-selle te gebruik wat onderskeidelik OATP1B1 en OATP1B3 potensieel. Resultate Bowiea volubilis, Kedrostis Africana, Chenopodium album, Lessertia frutescens (metanol-ekstrak), Hypoxis hemerocallidea, Spirostachys africana en Lessertia frutescens (water-ekstrak), in toenemende potensie, het sterk inhibisie van CYP1A2-aktiwiteit (IC50 = 1-100 g/mL) getoon. In ooreenstemming met die voorafgaande resultate het Emex australis, Alepidea amatymbica, Pachycarpus concolor, Lessertia frutescens, Capparis sepiaria, Kedrostis africana en Pentanisia prunelloides CYP2C9 met IC50–waardes van minder as 100 g/mL geïnhibeer. Die volgende het sterk inhibisie van CYP2C19 met IC50-waardes van minder as 100 g/mL getoon: Acacia karroo, Capparis sepiaria, Chenopodium album, Pachycarpus concolor, Ranunculus multifidus, Lessertia frutescens en Zantedeschia aethiopica. CYP3A4 is deur Lessertia frutescens, Hypoxis hemerocallidea, Spirostachys Africana, Bowiea volubilis, Zantedeschia aethiopica, Chenopodium album, Kedrostis Africana, Acacia karroo, Emex australis, Pachycarpus concolor, Ranunculus multifidus, Capparis sepiaria en Pentanisia prunelloides geïnhibeer. Tydafhanklike (onomkeerbare) inhibisie van CYP3A4/5 (KI = 296 μg/mL, kinact = 0.063 min-1) en vertraging in die produksie van midasolaammetaboliete in menslike hepatosiete wat aanleiding gee tot ʼn 40% afname in midasolaam bepaal in vivo opruiming, is waargeneem met Lessertia frutescens. Lessertia frutescens het ook die aktiwiteit van P-gp (IC50 = 324.8 μg/mL), OATP1B1 (IC50 = 10.4 μg/mL) en OATP1B3 (IC50 = 6.6 μg/mL) geïnhibeer. Hypoxis hemerocallidea het die aktiwiteit van OATP1B1 (IC50 = 118.7 μg/mL) en OATP1B3 (IC50 = 290.1 μg/mL) geïnhibeer met geen betekenisvolle effekte op P-gp nie. Geen een van die twee het die aktiwiteit van BCRP geïnhibeer binne die konsentrasies waarin getoets is nie. Gevolgtrekking Die resultate van hierdie studie dui aan dat wanneer voldoende in vivo-konsentrasies bereik word, die moontlikheid vir kruie-geneesmiddel interaksies tussen die geselekteerde medisinale kruie en ensiemsubstrate ʼn werklikheid word.

Bakgrund: I Sverige har naturläkemedel huvudsakligen använts på patienters eget initiativ och utan kontakt med vårdgivare. Många tror att naturmedel inte är mediciner utan säkra och naturliga i tillägg till en hälsosam diet. Precis som konventionella läkemedel kan naturmedel ge upphov till både biverkningar och interaktioner. Det finns få rapporterade biverkningar av godkända naturläkemedel och växtbaserade läkemedel. Syfte: Syftet med studien är att undersöka användandet av naturmedel som egenvård, hur vårdgivare och patienter kommunicerar om naturmedel som egenvård samt kunskapen om naturmedel hos vårdpersonal. Metod: Litteraturstudie baserad på kvantitativa studier. Resultat: Resultatet i denna studie visar på ett varierat användande av naturmedel. Det som framkommer är att det är mer kvinnor och framförallt högutbildade personer som använder det i högre utsträckning. Det är få som väljer att diskutera sin användning av naturmedel med läkare eller annan vårdpersonal. Vårdpersonal frågar å sin sida heller inte om patienter använder sig av naturmedel. Slutsats: Vårdpersonal skattar sin kunskap om naturmedel som låg eller obetydlig men att många ville lära sig mer om naturmedel. För att undvika biverkningar och interaktioner bör användandet av naturmedel uppmärksammas inom vården. / Background: Natural remedies have mostly been used on the initiative of the patient without contact with healthcare staff in Sweden. Many people believe that natural remedies are a safe and natural supplement to healthy living and not a medicine. Just like ordinary drugs, natural remedies can cause side effect and interactions with other medicines. There are few reported adverse effects of herbal medicine and traditional medicine. Aim: The aim of this study was to examine the use of natural remedies as a selfcare treatment, to study the communication between healthcare staff and patients and to study the knowledge of natural remedies among healthcare staff. Method: The study is in form of a literature review based on quantitative studies. Results: The result indicates a range of uses of natural remedies. It is predominantly women and especially highly educated people who use natural remedies. Only a few choose to discuss their use of natural remedies with their doctor or healthcare staff. Healthcare staff do not tend to ask the patients about their use of natural remedies. Conclusion: Healthcare staff rate their knowledge about natural remedies as being low or insignificant, but many would like to learn more about them to avoid adverse effect or interactions, the use of natural remedies needs to be highlighted within the health service.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Treatment with neuroleptic drugs has been associated to side effects like tardive diskynesia and hepatic damage. In spite of the several reports of hepatotoxicity after neuroleptic administration, few data are available in the literature about these effects and the precise mechanisms by which neuroleptics induce hepatotoxicity remain unclear. In the same way, there are few studies about the effects of neuroleptics on kidney. In this way, the first aim of the present work was to assess the effects of chronic exposure to fluphenazine in liver and kidney of rats, as well as the protective effect of diphenyl diselenide on the fluphenazine-induced damage (article 1). Long-term treatment with fluphenazine caused an increase in lipid peroxidation levels in liver and kidney homogenates, a decrease in hepatic SOD activity, and an increase in hepatic CAT activity. Diphenyl diselenide was able to protect liver and kidney from lipid peroxidation, ameliorate SOD activity in liver, and prevent the increase in hepatic CAT activity. Diphenyl diselenide treatment did not affect δ-ALA-D activity, but fluphenazine and/or in combination with diphenyl diselenide showed an inhibitory effect on δ-ALA-D activity in liver and kidney. The second objective of this study was to determine whether the treatment with haloperidol (HP), valerian or both in association impairs liver or kidney functions (article 2). Valerian did not affect oxidative stress parameters in the liver or kidney of rats. HP only increased glutathione (GSH) depletion in liver, but not in kidney. However, when HP was associated with valerian, an increase in lipid peroxidation levels and reactive species production was observed in the hepatic tissue. HP and valerian when administered independently did not affect the activity of hepatic and renal δ-ALA-D, however, these drugs administered concomitantly provoked an inhibition of hepatic δ-ALA-D activity. Serum aspartate aminotransferase (AST) activity was not altered by any treatment. However, serum alanine aminotransferase (ALT) activity was higher in the HP group and HP plus valerian group. Taken together, these results indicate the relationship between the treatment with flufenazine and the oxidative stress, and also point to the protective role of diphenyl diselenide on the oxidative damage induced by fluphenazine in liver. Our data also suggest adverse interactions between haloperidol and valerian treatments causing hepatic damage related to oxidative stress. / O tratamento com drogas neurolépticas tem sido associado a efeitos colaterais como a discinesia tardia (DT) e o dano hepático. Apesar dos inúmeros casos de hepatotoxicidade após a administração de neurolépticos, são escassos os dados na literatura a respeito desses efeitos e o mecanismo exato pelo qual neurolépticos induzem hepatotoxicidade permanece incerto. Da mesma forma, existem poucos estudos relatando os efeitos dos neurolépticos sobre o rim. Dessa forma, o primeiro objetivo deste trabalho foi avaliar os efeitos da exposição crônica à flufenazina em fígado e rim de ratos bem como o efeito protetor do disseleneto de difenila sobre o dano induzido por flufenazina (artigo 1). O tratamento prolongado com flufenazina causou um aumento na peroxidação lipídica no fígado e no rim, uma diminuição na atividade da SOD hepática, e um aumento na atividade da CAT hepática. O disseleneto de difenila foi capaz de proteger o fígado e o rim da peroxidação lipídica, melhorou a atividade da SOD no fígado, e preveniu o aumento na atividade da CAT no fígado. O tratamento com disseleneto de difenila não afetou a atividade da δ-ALA-D, mas a flufenazina e/ou em combinação com disseleneto de difenila demonstrou ter efeito inibitório sobre a atividade da δ-ALA-D no fígado e no rim. O segundo objetivo deste estudo foi determinar se o tratamento com haloperidol (HP), valeriana ou a associação de ambas as drogas pode alterar as funções hepáticas e renais (artigo 2). A valeriana não afetou nenhum parâmetro de estresse oxidativo no fígado e no rim dos ratos. O HP apenas aumentou a depleção de glutationa (GSH) no fígado, mas não no rim. Entretanto, quando o HP foi associado com a valeriana, um aumento na peroxidação lipídica e produção de espécies reativas foram observados no tecido hepático. HP e valeriana quando administrados independentemente não afetaram a atividade da δ-ALA-D hepática e renal, contudo, quando estas drogas foram administradas concomitantemente provocaram uma inibição da atividade da δ-ALA-D hepática. A atividade da aspartato aminotransferase (AST) do soro não foi alterada por nenhum dos tratamentos. No entanto, a atividade da alanina aminotransferase (ALT) do soro estava aumentada nos grupos tratados com HP e HP mais flufenazina. Juntos estes resultados indicam uma relação entre o tratamento com flufenazina e o estresse oxidativo, e também apontam para o papel protetor do disseleneto de difenila no dano oxidativo induzido por flufenazina no fígado. Nossos dados também sugerem interações adversas no tratamento com haloperidol e valeriana, ocasionando dano hepático associado ao estresse oxidativo.