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The effect of selected methoxy flavonoids on the in vitro efflux transport of rhodamine 123 using rat jejunum / Stanley Anthony DoddDodd, Stanley Anthony January 2005 (has links)
Many orally administered drugs must overcome several barriers before
reaching their target site. The first major obstacle to cross is the intestinal epithelium.
Although lipophilic compounds may readily diffuse across the apical plasma membrane,
their subsequent passage across the basolateral membrane and into blood is by no
means guaranteed. Efflux proteins located at the apical membrane, which include P-glycoprotein
(P-gp, MDR1) and Multidrug Resistance-associated Protein (MRP2), may
drive compounds from inside the cell back into the intestinal lumen, preventing their
absorption into the blood. Intestinal P-gp is localised to the villus tip enterocytes, i.e. the
main site of absorption for orally administered compounds and in close proximity to the
lumen. P-gp is therefore ideally positioned to limit the absorption of compounds by
driving efflux back into the lumen. Drugs may also be modified by intracellular phase I
and phase II metabolizing enzymes. This process may not only render the drug
ineffective, but it may also produce metabolites that are themselves substrates for P-gp
and/or MRP2. Drugs that reach the blood are then passed to the liver, where they are
subjected to further metabolism and biliary excretion, often by a similar system of ATP binding
cassette (ABC) transporters and enzymes to that present in the intestine. Thus
a synergistic relationship exists between intestinal drug metabolizing enzymes and
apical efflux transporters, a partnership that proves to be a critical determinant of oral
bioavailability. Aim: The aim of this study was to investigate the effect of selected
methoxy flavonoids (3-methoxyflavone, 5-methoxyflavone, 6-methoxyflavone and 7-
methoxyflavone) on the mean ratio of Rhodamine123 (Rho 123) transport across rat
intestine (jejunum) and to investigate structure activity relationships (SAR) of the
selected flavonoids with reference to inhibition of P-gp. Methods: 3-Methoxyflavone, 5-
methoxyflavone, 6-methoxyflavone and 7-methoxyflavone were evaluated at a
concentration of 10μM and 20μM as modulators of Rho 123 transport across rat
jejunum. The Sweetana-Grass diffusion cells were used to determine the transport of
Rho 123. Each modulator was studied bidirectionally with two cells measuring transport
in the apical to basolateral direction (AP/BL) and two cells measuring transport in the
basolateral to apical direction (BUAP). The rate of transport was expressed as the
apparent permeability coefficient (Papp)and the extent of active transport was expressed
by calculating the ratio of BUAP to AP/BL. Each modulators Papp ratio was then
compared with that of the control. Results: 3-Methoxyflavone decreased the Papp
ratio from 3.34 (control) to 1.66 (10μM) and 1.33 (20μM) and showed statistical
significant differences. 7-Methoxyflavone decreased the Papp ratio to 1.94 (10μM) and
1.55 (20μM) but only showed a statistical significant difference at 10μM. 5-
Methoxyflavone decreased the Papp ratio to 2.41 (10μM) and 1.71 (20μM) and 6-
methoxyflavone decreased the Papp to 3.03 (10μM) and 2.49 (20μM). Both 5- and 6-
methoxyflavone showed no statistical significant differences from the control. The
structure activity relationships with reference to P-gp inhibition clearly indicated that the
C3 and C7 positioning of the methoxy-group on the A ring played a major role in the
inhibition of Rho 123 transport. Conclusion: All the selected modulators showed
inhibition of Rho 123 transport across the jejunum. This should affect the bioavailability
of the substrates of P-gp and other active transporters. In summary, this study describe
the inhibitory interaction of selected flavonoids with P-gp. Structure activity relationships
were identified describing the inhibitory potency of the flavonoids based on methoxy
groups positioning. The inhibitory potency results were 3-methoxyflavone > 7-
methoxyflavone > 5-methoxyflavone> 6-methoxyflavone / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2005.
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The effect of selected hydroxy flavonoids on the in vitro efflux transport of rhodamine 123 using rat jejunum / S. van HuyssteenVan Huyssteen, Stephanie January 2005 (has links)
Background: Multidrug resistance (MDR) is resistance of cancer cells to multiple
classes of chemotherapeutic drugs that can be structurally unrelated. MDR involves
altered membrane transport that results in a lower cell concentration of cytotoxic drugs
which plays an important role during cancer treatment. P-glycoprotein (Pgp) is localised
at the apical surface of epithelial cell in the intestine and it functions as a biological
barrier by extruding toxic substances and xenobiotics out of cells (Lin, 2003:54). The
ATP-binding-cassette superfamily is a rapidly growing group of membrane transport
proteins and are involved in diverse physiological processes which include antigen
presentation, drug efflux from cancer cells, bacterial nutrient uptake and cystic fibrosis
(Germann, 1996:928; Kerr, 2002:47). A number of drugs have been identified which are
able to reverse the effects of Pgp, multidrug resistance protein (MRPI) and their
associated proteins on multidrug resistance. The first MDR modulators discovered and
studied during clinical trials were associated with definite pharmacological actions, but
the doses required to overcome MDR were associated with the occurrence of
unacceptable side effects. As a consequence, more attention has been given to the
development of modulators with proper potency, selectivity and pharmacokinetic
characteristics that it can be used at a lower dose. Several novel MDR reversing agents
(also known as chemosensitisers) are currently undergoing clinical evaluation for the
treatment of resistant tumours (Teodori et al., 2002:385). Aim: The aim of this study was
to investigate the effect of selected flavonoids (morin, galangin, kaempferol and
quercetin) at two different concentrations (10 μM and 20 μM) on the transport of a known
Pgp substrate, Rhodamine 123 (Rho 123) across rat intestine (jejunum) and to
investigate structure activity relationships (SAR) of the selected flavonoids with
reference to the inhibition of Pgp. Methods: Morin, galangin, kaempferol and quercetin
were evaluated as potential modulators of Rho 123 transport, each at a concentration of
10 μM and 20 μM across rat jejunum using Sweetana-Grass diffusion cells. This study
was done bidirectionally, with two cells measuring transport in the apical to basolateral
direction (AP-BL) and two cells measuring transport in the basolateral to apical direction
(BL-AP). The rate of transport was expressed as the apparent permeability coefficient
(Pap,) and the extent of active transport was expressed by calculating the ratio of BL-AP
to AP-BL. Results: The BL-AP to AP-BL ratio calculated for Rho 123 with no
modulators added was 3.29. Morin decreased the BL-AP to AP-BL ratio to 1.88 at a
concentration of 10 μM and to 1.49 at a concentration of 20 μM. Galangin decreased
the BL-AP to AP-BL ratio to 1.60 at a concentration of 20 μM. These two flavonoids
showed statistically significant results and inhibition of active transport were clearly
demonstrated. However, the other flavonoids inhibited active transport of Rho 123 but
according to statistical analysis, the results were not significantly different. The two
different concentrations (10 μM and 20 μM) indicated that galangin, kaempferol and
quercetin showed practically significant differences according to the effect sizes. Morin,
however, did not show any practically significant differences at the different
concentrations. Regarding .the SAR, it was shown by Boumendjel and co-workers
(2002:512) that the presence of a 5-hydroxyl group and a 3-hydroxyl group as well as
the C2-C3 double bond are required for high potency binding to the nucleotide binding
domain (NBD) of Pgp. All the flavonoids tested had the above-mentioned
characteristics. Conclusion: All the selected flavonoids showed inhibition of active
transport of Rho 123 and should have an effect on the bioavailability of the substrates of
Pgp and other active transporters. This study described the inhibitory interaction of
selected flavonoids on Pgp activity. Practical significant differences between the same
modulator at different concentrations were also observed. Structure activity
relationships were identified describing the inhibitory potency of the flavonoids based on
hydroxyl group positioning / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2005.
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Marcacao do iomazenil com 123/131 iodo para uso como neurotracador em medicina nuclearPETRONI, MARIANE F. 09 October 2014 (has links)
Made available in DSpace on 2014-10-09T12:46:45Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T13:58:33Z (GMT). No. of bitstreams: 1
08366.pdf: 2503408 bytes, checksum: 7a96383a00a09101cb3350bf14e5b149 (MD5) / Dissertacao (Mestrado) / IPEN/D / Instituto de Pesquisas Energeticas e Nucleares - IPEN/CNEN-SP
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Marcação do peptídeo intestinal vasoativo (VIP) e do fragmento VIP10-28 com radioiodo por método direto. Estudo comparativo da cinética de biodistribuição e da afinidade por células de tumor neuroendócrinoCOLTURATO, MARIA T. 09 October 2014 (has links)
Made available in DSpace on 2014-10-09T12:50:55Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T13:58:25Z (GMT). No. of bitstreams: 1
11107.pdf: 5050996 bytes, checksum: 5619119599cfe5e14f17122301eaafa7 (MD5) / Tese (Doutoramento) / IPEN/T / Instituto de Pesquisas Energeticas e Nucleares - IPEN/CNEN-SP
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Estudo de parâmetros relevantes na irradiação de sup(124)Xe, visando a otimização na obtenção de sup(123)I ultra puro no ciclotron cyclone-30 IPEN-CNEN/SPSUMIYA, LUIZ C. do A. 09 October 2014 (has links)
Made available in DSpace on 2014-10-09T12:52:20Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T14:00:49Z (GMT). No. of bitstreams: 0 / Tese (Doutoramento) / IPEN/T / Instituto de Pesquisas Energeticas e Nucleares - IPEN/CNEN-SP
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Marcação do peptídeo intestinal vasoativo (VIP) e do fragmento VIP10-28 com radioiodo por método direto. Estudo comparativo da cinética de biodistribuição e da afinidade por células de tumor neuroendócrinoCOLTURATO, MARIA T. 09 October 2014 (has links)
Made available in DSpace on 2014-10-09T12:50:55Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T13:58:25Z (GMT). No. of bitstreams: 1
11107.pdf: 5050996 bytes, checksum: 5619119599cfe5e14f17122301eaafa7 (MD5) / Tese (Doutoramento) / IPEN/T / Instituto de Pesquisas Energeticas e Nucleares - IPEN/CNEN-SP
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Marcacao do iomazenil com 123/131 iodo para uso como neurotracador em medicina nuclearPETRONI, MARIANE F. 09 October 2014 (has links)
Made available in DSpace on 2014-10-09T12:46:45Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T13:58:33Z (GMT). No. of bitstreams: 1
08366.pdf: 2503408 bytes, checksum: 7a96383a00a09101cb3350bf14e5b149 (MD5) / Dissertacao (Mestrado) / IPEN/D / Instituto de Pesquisas Energeticas e Nucleares - IPEN/CNEN-SP
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Estudo de parâmetros relevantes na irradiação de sup(124)Xe, visando a otimização na obtenção de sup(123)I ultra puro no ciclotron cyclone-30 IPEN-CNEN/SPSUMIYA, LUIZ C. do A. 09 October 2014 (has links)
Made available in DSpace on 2014-10-09T12:52:20Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T14:00:49Z (GMT). No. of bitstreams: 0 / O desenvolvimento da Medicina Nuclear, aliado à evolução dos equipamentos de diagnóstico e terapia, necessita, cada vez mais, da disponibilidade comercial de radioisótopos. Nesse contexto, o IPEN tem buscado atender e abastecer o mercado nacional. Um dos investimentos nesta área foi a aquisição de um ciclotron de 30 MeV, modelo Cyclone-30, que permitiu a produção dos radioisótopos tais como, o 18F, 67Ga, 201Tl e o 123I, sendo este último o foco do presente trabalho. Através de dados de produções rotineiras de 123I via irradiação com prótons em alvo gasoso de Xenônio com enriquecimento superior a 99,8% em 124Xe, foi realizado um estudo para identificar os fatores relevantes que influenciam diretamente o rendimento de obtenção de 123I com altíssimo grau de pureza. Embora a metodologia seja bem conhecida, quando se trata de produção comercial há uma escassez de dados sobre os parâmetros operacionais utilizados. Os parâmetros avaliados foram: pressão do gás 124Xe, intensidade de corrente de feixe de prótons, tempo de irradiação, temperatura de operação do sistema durante a irradiação, tempo de espera para formação de 123I, tempo de aquecimento do porta-alvo para recuperação do 123I formado, temperatura de aquecimento da solução de lavagem e influência do revestimento interno da câmara de irradiação com Ni. Com os resultados obtidos, foi possível alterar as condições operacionais nas produções rotineiras, conduzindo a um aumento de eficiência do processo em torno de 30%. / Tese (Doutoramento) / IPEN/T / Instituto de Pesquisas Energeticas e Nucleares - IPEN/CNEN-SP
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Missa solemnis. Beethoven in seinem WerkSchmidt-Görg, Joseph 14 January 2020 (has links)
No description available.
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Zu den Satzschlüssen der Missa solemnisGeorgiades, Thrasybulos G. 14 January 2020 (has links)
No description available.
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