Analgesic effects of 5-alkyloxy-4-amino-2(5H)-furanones as cholecystokinin-2 antagonists

4-Amino-2(5H)-furanones were synthesized in high yields over two synthetic steps from readily available mucochloric acid. These 5-alkyloxy-4-amino-2(5H)-furanones were screened in a ([125]) I-CCK-8 radioligand receptor binding assay for CCK2 affinity and novel active ligands in the nanomolar range were identified. SAR was optimized leading to the cyclohexyl derivative 25 with an IC50 of 27 nM. Furanone 18 was obtained as a stable crystalline material with an IC50 of 85 nM, but had a higher CCK2 selectivity. It was subsequently tested in the isolated guinea pig ileum assay with sulfated CCK8 , and the CCK antagonizing properties of the ligand were confirmed. The CCK2 selective antagonist 18 was found to potentiate analgesia in the tail flick assay in mice, for the strong opiate morphine, the partial opiate agonist tramadol and the tricyclic antidepressant desimipramine

Potency of Netilmicin against Staphylococci Compared to Other Ophthalmic Antibiotics

Netilmicin is a potent and safe antibiotic with a very low incidence of resistance used as a topical ophthalmic medication in bacterial ocular infections. The aim of this study was to compare netilmicin’s Quotient of Inhibitions (QIs) and killing kinetics vs Staphylococci with other ophthalmic antimicrobials. Conjunctival and corneal QIs of netilmicin formulations, in single and multiple doses of administration, were compared with those of tobramycin, ofloxacin, levofloxacin and azithromycin preparations. The same analysis was performed in human tears, comparing netilmicin eye drops solution with tobramycin ofloxacin and levofloxacin. Furthermore, killing kinetics against Staphylococci (ATCC strains and ocular isolates) of the above-cited antibiotics, as well as chloramphenicol, were compared at different time points. QI results showed that in the conjunctiva, netilmicin, in both single and multiple doses of administration, is highly effective against all staphylococcal strains tested, while in the cornea it was particularly active against methicillin-resistant Staphylococci strains. Moreover, in human tears, netilmicin eye drops solution showed a more favourable QI against Staphylococci than tobramycin, ofloxacin and levofloxacin all in single-dose administration regimen. Killing kinetic results showed that netilmicin has a great bactericidal activity vs all the microbe strains tested as netilmicin showed to be almost the most active antibiotic. Results suggest that netilmicin has one of the most favourable killing kinetic and tissue inhibitory effects against Staphylococci than the principal ophthalmic antibiotics on the market

Cell-Mediated Assembly of Phototherapeutics

Light-activatable drugs offer the promise of controlled release with exquisite temporal and spatial resolution. However, light sensitive pro-drugs are typically converted to their active forms using short wavelengths, which display poor tissue penetrance. We report herein erythrocyte-mediated assembly of long wavelength-sensitive phototherapeutics. The activating wavelength of the constructs is readily pre-assigned by using fluorophores with the desired λex. Drug release from the erythrocyte carrier was confirmed by standard analytical tools and by the expected biological consequences of the liberated drugs in cell culture: methotrexate, binding to intracellular dihydrofolate reductase; colchicine, inhibition of microtubule polymerization; dexamethasone, induced nuclear migration of the glucocorticoid receptor

Attenuation of hyperalgesia in a rat model of neuropathic pain after intrathecal pre- or post-treatment with a neurokinin-1 antagonist

Although many studies have demonstrated a role for substance P in pain, there have been conflicting reports implicating the involvement of substance P in neuropathic pain models. In this study, the non-peptide neurokinin-1 (NK-1) receptor antagonist, L-732,138 was chronically administered by intrathecal (i.t.) injection to rats with mono-neuropathy produced by sciatic nerve constriction. Rats exhibited tactile allodynia and cold hyperalgesia over a 16-day testing period. L-732,138 (5-200 nmol) administered i.t. prior to and for 3 consecutive days post-surgery attenuated the mechanical allodynia and cold hyperalgesia on days 4 and 8 post-surgery. The effects of i.t. L-732,138 were also determined in rats with established nerve injury-induced neuropathy. The NK-1 receptor antagonist was injected for 4 consecutive days starting on day 8 post-sciatic nerve injury. Administration of L-732,138 (5-200 nmol) i.t. produced both anti-allodynic and anti-hyperalgesic effects on day 12, but the effect was not permanent, as nociceptive thresholds were similar to controls by day 16. These results demonstrate that substance P is involved both in the induction and the maintenance of neuropathic pain and provides justification for the development and administration of substance P antagonists for the management of clinical neuropathic pain