Untitled

Funder

Organizational Unit

Publications

Drug–lipid interaction evaluation : why a 19th century solution?

Publication . Ribeiro, Marta M. B.; Melo, Manuel N.; Serrano, Isa D.; Santos, Nuno C.; Castanho, Miguel A. R. B.

The affinity of a drug candidate for a biological membrane (its lipophilicity) is closely related to the pharmacologically crucial events of absorption, biodistribution, metabolization and excretion. The evolution of knowledge of biological membranes during the past two decades contrasts with the rudimentary parameter most commonly used to assess lipophilicity: Po/w, the octanol–water partition coefficient. Po/w is especially unrealistic when testing molecules that are polar or partially charged. By contrast, lipid vesicle-based methods determine the extent of the actual partition of a drug to a membrane Much more accurately, and have the additional advantage of enabling the choice of the lipid composition considered most suitable to answer a specific biological or pharmaceutical question. In addition, some of these methods are appropriate for high throughput screening, thus shifting determinations of membrane partition to a more preliminary stage of drug development. This stream lines research and development, by saving the time and money that would be spent on unpromising leads.

2010Journal article

Restricted access

Side-effects of analgesic kyotorphin derivatives : advantages over clinical opioid drugs

Publication . Ribeiro, Marta M. B.; Santos, Sónia Sá; Sousa, David S. C.; Oliveira, Margarida; Santos, Sara M.; Heras, Montserrat; Bardaji, Eduard; Tavares, Isaura; Castanho, Miguel A. R. B.

The adverse side-effects associated with opioid administration restrain their use as analgesic drugs and call for new solutions to treat pain. Two kyotorphin derivatives, kyotorphin-amide (KTP–NH2) and ibuprofen–KTP–NH2 (IbKTP–NH2) are promising alternatives to opioids: they trigger analgesia via an indirect opioid mechanism and are highly effective in several pain models following systemic delivery. In vivo side-effects of KTP–NH2 and IbKTP–NH2 are, however, unknown and were evaluated in the present study using male adult Wistar rats. For comparison purposes, morphine and tramadol, two clinically relevant opioids, were also studied. Results showed that KTP-derivatives do not cause constipation after systemic administration, in contrast to morphine. Also, no alterations were observed in blood pressure or in food and water intake, which were only affected by tramadol. A reduction in micturition was detected after KTP–NH2 or tramadol administrations. A moderate locomotion decline was detected after IbKTP–NH2-treatment. The side-effect profile of KTP–NH2 and IbKTP–NH2 support the existence of opioid-based mechanisms in their analgesic actions. The conjugation of a strong analgesic activity with the absence of the major side-effects associated to opioids highlights the potential of both KTP–NH2 and IbKTP–NH2 as advantageous alternatives over current opioids.

2013Journal article

Restricted access