Transporter hypothesis in pharmacoresistant epilepsies. Is it at the central or peripheral level?

The multidrug-resistance (MDR) phenotype is typically observed in patients with refractory epilepsy (RE) whose seizures are not controlled despite receiving several combinations of more than two antiseizure medications (ASMs) directed against different ion channels or neurotransmitter receptors. Since the use of bromide in 1860, more than 20 ASMs have been developed; however, historically ~30% of cases of RE with MDR phenotype remains unchanged. Irrespective of metabolic biotransformation, the biodistribution of ASMs and their metabolites depends on the functional expression of some ATP-binding cassette transporters (ABC-t) in different organs, such as the blood-brain barrier (BBB), bowel, liver, and kidney, among others. ABC-t, such as P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP-1), and breast cancer-resistance protein (BCRP), are mainly expressed in excretory organs and play a critical role in the pharmacokinetics (PK) of all drugs. The transporter hypothesis can explain pharmacoresistance to a broad spectrum of ASMs, even when administered simultaneously. Since ABC-t expression can be induced by hypoxia, inflammation, or seizures, a high frequency of uncontrolled seizures increases the risk of RE. These stimuli can induce ABC-t expression in excretory organs and in previously non-expressing (electrically responsive) cells, such as neurons or cardiomyocytes. In this regard, an alternative mechanism to the classical pumping function of P-gp indicates that P-gp activity can also produce a significant reduction in resting membrane potential (ΔΨ0 = -60 to -10 mV). P-gp expression in neurons and cardiomyocytes can produce membrane depolarization and participate in epileptogenesis, heart failure, and sudden unexpected death in epilepsy. On this basis, ABC-t play a peripheral role in controlling the PK of ASMs and their access to the brain and act at a central level, favoring neuronal depolarization by mechanisms independent of ion channels or neurotransmitters that current ASMs cannot control.

Estudo do mecanismo de resistência a compostos derivados da classe das tiossemicarbazonas em tripanosomatídeos, com ênfase na glicoproteína-P e na nitrorredutase do tipo I / Study class of compounds derived from the resistance mechanism of thiosemicarbazones in trypanosomatids, with emphasis on P-glycoprotein and type I nitroreductase

Os tratamentos disponíveis para a doença de Chagas e as leishmanioses não são eficientes e apresentam alta toxicidade. Diversos estudos mostram que há possibilidade de indução de resistência de Trypanosoma cruzi ao Benznidazol (BZ) o que pode interferir na eficácia do tratamento. O mesmo tem sido relatado com relação aos fármacos utilizados para o tratamento das leishmanioses, embora não exista um mecanismo de ação definido para a resistência a drogas nestes protozoários. Neste trabalho foram focalizados dois potenciais mecanismos: 1) atividade da glicoproteína-P (Pgp), uma proteína de membrana que atua como uma bomba de efluxo dependente de energia e associada ao fenótipo de resistência a múltiplas drogas (MDR); 2) a enzima nitrorredutase presente em T. cruzi (TcNTR), reponsável pela redução de nitroderivados, como BZ, para obter o efeito tripanocida. Na busca de novos compostos seletivos contra T. cruzi e Leishmania amazonensis, nosso grupo vem estudando derivados da classe das tiossemicarbazonas. Em estudos prévios foi observado que o derivado 4-N-(2-metoxi-estiril)-tiossemicarbazona (2-MEOTIO) foi o composto mais efetivo sobre diferentes formas de T. cruzi, enquanto 4-N-(4’-hidroxi-3’-metoxi-estiril)-tiossemicarbazona (3-MEOTIO) se mostrou o mais eficiente contra L. amazonensisO mecanismo de resistência a estes compostos foi avaliado, e nossos resultados mostram a participação da Pgp na resistência a 2-MEOTIO e BZ em T. cruzi, e a 3-MEOTIO em L. amazonensis...

The available drugs for the treatment of Chagas disease and leishmaniasisare not efficient and cause toxic side effects. Several studies show the possibilityof drug resistance induction to Benznidazol (BZ) in Trypanosoma cruzi, whichmay interfere with the treatment efficacy. The same has been observed regardingcompounds used to treat leishmaniasis, although more studies on drug resistancemechanism are needed. In the present study we focused on two potential drugresistance mechanisms: 1) P-glycoprotein (Pgp) activity, a membrane proteinwhich acts as an efflux pump energy-dependent and is associated with themultidrug resistance fenotype (MDR); 2) the enzyme nitroreductase (TcNTR)found in T. cruzi, which is responsible for the reduction of nitroheterocyclicderivatives, such as Bz and Nifurtimox, generating metabolites with trypanocidalactivity. In the search for new selective drugs for the treatment of Chagas diseaseand leishmaniasis, our group has been studying compounds from the class of thethiosemicarbazones. Previous studies showed that the 4-N-(2-methoxy-styryl)-thiosemicarbazone (2-MEOTIO) was the most efficient compound on differentforms of T. cruzi, whereas 4-N-(4’-hidroxy-3’-methoxy styryl)-thiosemicarbazone(3-MEOTIO) was the most active on Leishmania amazonensis. Here weevaluated the drug resistance mechanism to both thiosemicarbazone derivatives,as well as, to BZ which was used as reference drug for T. cruzi. Our results showthe participation of Pgp in the resistance to both 2-MEOTIO and BZ in T. cruzi, aswell as in the resistance in L. amazonensis to the compound 3-MEOTIO.Interestingly, in T. cruzi the participation of Pgp is related to its localization notonly in the plasma membrane but also in the mithocondrion...

Interference with P-glycoprotein improves ivermectin activity against adult resistant nematodes in sheep.

The in vivo co-administration of ivermectin (IVM) with P-glycoprotein (P-gp) modulator agents has been shown to enhance its systemic availability. However, there is no sufficient evidence on the impact that this type of drug-drug interaction may have on the in vivo efficacy against resistant nematodes in ruminant species. The current work reports on the effects of loperamide (LPM), a P-gp modulating agent, on both IVM kinetic behaviour and anthelmintic activity in infected lambs. Eighteen (18) lambs naturally infected with IVM-resistant gastrointestinal nematodes were allocated into three (3) experimental groups. Group A remained as untreated control. Animals in Groups B and C received IVM (200mug/kg, subcutaneously) either alone or co-administered with LPM (0.2 mg/kg, twice every 12h), respectively. Individual faecal samples were collected from experimental animals at days -1 and 14 post-treatment to perform the faecal eggs count reduction test (FECRT). Blood samples were collected between 0 and 14 days post-treatment and IVM plasma concentrations were determined by HPLC. Additionally, at day 14 post-treatment, lambs from all experimental groups were sacrificed and adult gastrointestinal nematode counts were performed. FECRT values increased from 78.6 (IVM alone) to 96% (IVM+LPM). Haemonchus contortus was highly resistant to IVM. The IVM alone treatment was completely ineffective (0% efficacy) against adult H. contortus. This efficacy value increased up to 72.5% in the presence of LPM. The efficacy against Trichostrongylus colubriformis increased from 77.9% (IVM alone) to 96.3% (IVM+LPM). The described favorable tendency towards improved anthelmintic efficacy was in agreement with the enhanced IVM plasma availability (P<0.05) and prolonged elimination half-life (P<0.05) induced by LPM in infected lambs. A LPM-induced P-gp modulation increases IVM systemic exposure in the host but also it may reduce P-gp efflux transport over-expressed in target resistant nematodes.

Ciclosporina A e seus análogos como reversores da resistência a múltiplas drogas em células tumorais / Cyclosporin A and analogues as multidrug resistance modulating agents in tumour cell

A resistência a múltiplas drogas (MDR) é um dos principais obstáculos no tratamento quimioterápico de pacientes com câncer. O processo de resistência é multifatorial, mas o mecanismo mais bem caracterizado é a superexpressão da glicoproteína P (Pgp), uma proteína de membrana plasmática que funciona como uma bomba de efluxo levando a uma diminuição da concentração intracelular do quimioterápico. A circunvenção da resistência pode ser obtida utilizando-se agentes reversores capazes de inibir a atividade funcional da Pgp e de outras bombas de efluxorelacionadas. Nesta revisão, discutimos o uso do imunossupressor Ciclosporina A (CSA) e de seus análogos como agentes reversores da MDR. Aspectos como sua combinação com ciclofilinas, sua capacidade de inibir a atividade funcional da Pgp e seu uso clínico, especialmente em leucemias, são discutidos baseados tanto na literatura quanto em resultados dos próprios autores.

[Pharmacological biomodulation in cancer]. / Biomodulación farmacológica en cáncer.

The discovery of the P-glycoprotein as a mediator of multidrug resistance (MDR) represents one of the most important research accomplishments in antineoplastic pharmacology during the last decade. Demonstration of Pgp in epithelial tissues, untreated and chemotherapeutically pretreated human malignancies, and identification of various agents capable of reversing in vitro resistance has generated enthusiasm for clinical studies throughout the world. This review discusses recent developments of experimental and clinical investigations of MDR reversing agents in cancer.

Resistencia a drogas mediada por la glicoproteína P / P-glycoprotein-mediated resistance to drug

A pesar de los logros alcanzados en la quimioterapia de las enfermedades malignas, la resistencia a citotóxicos constituye un gran obstáculo para la curación de los pacientes. Se han identificado varios genes, proteínas y vías metabólicas implicados en este fenómeno. Hasta el momento el más estudiado es el gen mdr 1 y su producto, la glicoproteína p, que actúa como una bomba extractora dependiente de energía; se ha demostrado en tejidos normales vinculados con funciones secretoras o de barrera, así como en neoplasias humanas, donde provoca un fenotipo de resistencia simultánea a múltiples drogas. El aumento en la expresión del gen mdr 1, se señala como un factor pronóstico adverso en leucemias, linformas y algunos tumores sólidos. La importancia clínica de este hecho ha llevado a múltiples estrategias para evitar o revertir los efectos de la resistencia a las drogas antineoplásicas(AU)