11 research outputs found
Particulate levodopa nose-to-brain delivery targets dopamine to the brain with no plasma exposure
Levodopa (L-DOPA) is an oral Parkinson's Disease drug that generates the active metabolite - dopamine (DA) in vivo. However, oral L-DOPA exhibits low oral bioavailability, limited brain uptake, peripheral DA-mediated side effects and its poor brain bioavailability can lead to long-term complications. Here we show that L-DOPA forms stable (for at least 5 months) 300 nm nanoparticles when encapsulated within N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ). A nano-in-microparticle GCPQ-L-DOPA formulation (D50 = 7.2 µm), prepared by spray-drying, was stable for one month when stored at room and refrigeration temperatures and was capable of producing the original GCPQ-L-DOPA nanoparticles upon aqueous reconstitution. Nasal administration of reconstituted GCPQ-L-DOPA nanoparticles to rats resulted in significantly higher DA levels in the brain (Cmax of 94 ng g-1 above baseline levels 2 h post-dosing) when compared to nasal administration of L-DOPA alone, with DA being undetectable in the brain with the latter. Furthermore, nasal GCPQ-L-DOPA resulted in higher levels of L-DOPA in the plasma (a 17-fold increase in the Cmax, when compared to L-DOPA alone) with DA undetectable in the plasma from both formulations. These data provide evidence of effective delivery of DA to the brain with the GCPQ-L-DOPA formulation
Structure–Activity Relationship Studies and Discovery of a Potent Transient Receptor Potential Vanilloid (TRPV1) Antagonist 4‑[3-Chloro-5-[(1<i>S</i>)‑1,2-dihydroxyethyl]-2-pyridyl]‑<i>N</i>‑[5-(trifluoromethyl)-2-pyridyl]-3,6-dihydro‑2<i>H</i>‑pyridine-1-carboxamide (V116517) as a Clinical Candidate for Pain Management
A series of novel tetrahydropyridinecarboxamide
TRPV1 antagonists
were prepared and evaluated in an effort to optimize properties of
previously described lead compounds from piperazinecarboxamide series.
The compounds were evaluated for their ability to block capsaicin
and acid-induced calcium influx in CHO cells expressing human TRPV1.
The most potent of these TRPV1 antagonists were further characterized
in pharmacokinetic, efficacy, and body temperature studies. On the
basis of its pharmacokinetic, in vivo efficacy, safety, and toxicological
properties, compound <b>37</b> was selected for further evaluation
in human clinical trials