Znaczenie glikoproteiny PCSK9 w farmakoterapii hipercholesterolemii rodzinnej

It has been shown that subtilisin-like proprotein convertase expression seems to be strongly correlatedwith low-density lipoprotein (LDL)-receptors decreased on the cells surface. Consequently , it contri -butes to increase of coronary incidents risks. Currently, the protein inhibition is therefore one of the mostpromising therapeutic strategy which can be used in the treatment of familiar hypercholesterolemia. Apartfrom small-molecule lead compounds, the high-affinity protein binding ligands are some of monoclonalantibodies. The preliminary studies suggest that SAR236553/REGN726, J16 and mAb1 reduce significantlyLDL cholesterol and can be used in the combination with statins. Moreover , in case of patients takinghydroxy-methylglutaryl coenzyme A inhibitors, the administration of AMG145 is not related with a highrisk of some adverse drug reactions (especially myopathy).Wykazano, że nadmierna ekspresja konwertazy proproteinowej jest silnie skorelowana ze zmniejszonągęstością receptorów lipoprotein o niskiej gęstości (LDL) na powierzchni komórek, a tym samym przyczyniasię do wzrostu ryzyka wystąpienia incydentów wieńcowych. Inhibicja białka jest więc obiecującąstrategią terapeutyczną między w terapii innymi hipercholesterolemii rodzinnej. Oprócz związków drobnocząsteczkowychduże powinowactwo do białka wykazują liczne przeciwciała monoklonalne. Wstępnewyniki badań sugerują, że SAR236553/REGN726, J16 i mAb1 nie tylko istotnie zmniejszają stężenie cholesterolufrakcji LDL, ale można je również wykorzystać w leczeniu skojarzonym ze statynami. Co więcej,zastosowanie niektórych z nich (AMG145) pozwala na znaczne obniżenie ryzyka wystąpienia miopatiiu chorych przyjmujących wcześniej inhibitory reduktazy 3-hydroksy-3-metyloglutarylo-koenzymu A

Efficacy-based perspective to overcome reduced opioid analgesia of advanced painful diabetic neuropathy in rats

Reduction of the opioid analgesia in diabetic neuropathic pain (DNP) results from mu-opioid receptor (MOR) reserve reduction. Herein, we examined the antinociceptive and antiallodynic actions of a novel opioid agonist 14-O-methymorphine-6-O-sulfate (14-O-MeM6SU), fentanyl and morphine in rats with streptozocin-evoked DNP of 9-12 weeks following their systemic administration. The antinociceptive dose-response curve of morphine but not of 14-O-MeM6SU or fentanyl showed a significant right-shift in diabetic compared to non-diabetic rats. Only 14-O-MeM6SU produced antiallodynic effects in doses matching antinociceptive doses obtained in non-diabetic rats. Co-administered naloxone methiodide (NAL-M), a peripherally acting opioid receptor antagonist failed to alter the antiallodynic effect of test compounds, indicating the contribution of central opioid receptors. Reduction in spinal MOR binding sites and loss in MOR immunoreactivity of nerve terminals in the spinal cord and dorsal root ganglia in diabetic rats were observed. G-protein coupling assay revealed low efficacy character for morphine and high efficacy character for 14-O-MeM6SU or fentanyl at spinal or supraspinal levels (E-max values). Furthermore, at the spinal level only 14-O-MeM6SU showed equal efficacy in G-protein activation in tissues of diabetic- and non-diabetic animals. Altogether, the reduction of spinal opioid receptors concomitant with reduced analgesic effect of morphine may be circumvented by using high efficacy opioids, which provide superior analgesia over morphine. In conclusion, the reduction in the analgesic action of opioids in DNP might be a consequence of MOR reduction, particularly in the spinal cord. Therefore, developing opioids of high efficacy might provide analgesia exceeding that of currently available opioids