2009 - 08

Br J Pharmacol. 2009 Jul 23. [Epub ahead of print]

Antinociceptive effects of NCX-701 (nitro-paracetamol) in neuropathic rats: enhancement of antinociception by co-administration with gabapentin.

Curros-Criado MM, Herrero JF. Departamento de Fisiología, Campus Universitario, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.

Background and purpose: Neuropathic pain is characterized by a poor response to classic analgesics. In the present study, we have assessed the antinociceptive activity of NCX-701 (nitro-paracetamol) in neuropathic rats, after systemic and intrathecal (i.t.) administration. In addition, we analysed the possible benefit of the combination of NCX-701 and gabapentin, a well-known potent analgesic, in the treatment of neuropathic pain Experimental approach: The antinociceptive effects of i.v. and i.t. NCX-701 and paracetamol were studied in spinal cord neuronal responses from neuropathic adult male Wistar rats, using the recording of single motor units technique. The effect of i.v. and i.t. NCX-701 in combination with i.v. gabapentin was studied by isobolographic analysis. Key results: The experiments showed that NCX-701, but not paracetamol, dose-dependently reduced the nociceptive responses evoked by noxious mechanical and electrical stimulation, after i.v. (ID(50) 542 +/- 5 micromol.kg(-1) for noxious mechanical stimulation) or i.t. (ID(50) 932 +/- 16 nmol.kg(-1)) administration. The combined administration of i.v. or i.t. NCX-701 and i.v. gabapentin induced a more intense antinociceptive effect than any of the two drugs given alone. The isobolographic analysis showed a synergistic effect. Conclusions and implications: NCX-701 is an effective antinociceptive compound in situations of neuropathy-induced sensitization, with an action mainly located in the spinal cord. The combination of NCX-701 and gabapentin induces a synergistic enhancement of the depression of nociceptive responses evoked by natural noxious stimulation. The use of NCX-701 alone or in combination with gabapentin might open up new and promising perspectives in the treatment of neuropathic pain.

J Neurochem. 2009 Aug 21. [Epub ahead of print]

NO-flurbiprofen reduces amyloid beta, is neuroprotective in cell culture, and enhances cognition in response to cholinergic blockade.

Abdul-Hay SO, Luo J, Ashghodom RT, Thatcher GR. Dept. of Medicinal Chemistry & Pharmacognosy, College of Pharmacy University of Illinois at Chicago, Chicago, IL, 60612.

The nonsteroidal anti-inflamatory drug (NSAID) flurbiprofen is a selective amyloid lowering agent (SALA) which has been studied clinically in Alzheimer's disease. HCT-1026 is an ester prodrug of flurbiprofen incorporating a nitrate carrier moiety that in vivo provides NO bioactivity and an improved safety profile. In vitro, HCT-1026 retained the COX inhibitory and NSAID activity of flurbiprofen, but at concentrations at which levels of Abeta(1-42) were lowered by flurbiprofen, Abeta(1-42) levels were elevated 200% by HCT-1026. Conversely, at lower concentrations, HCT-1026 behaved as a SALA with greater potency than flurbiprofen. The difference in concentration responses between flurbiprofen and HCT-1026 in vitro suggests different cellular targets; and in no case did a combination of nitrate drug with flurbiprofen provide similar actions. In vivo, HCT-1026 was observed to reverse cognitive deficits induced by scopolamine in two behavioral assays; activity that was also shown by a classical nitrate drug, but not by flurbiprofen. The ability to restore aversive memory and spatial working and reference memory after cholinergic blockade has been demonstrated by other agents that stimulate NO/cGMP signaling. These observations add positively to the preclinical profile of HCT-1026 and NO chimeras in Alzheimer's disease.

2009 - 03

Georgian Med News. 2009 Feb;(167):7-16.

In vitro effects of a novel class of nitric oxide donating compounds on isolated human urinary bladder

Kedia GT, Neumayer E, Scheller F, Kuczyk MA, Uckert S. Hannover Medical School, Department of Urology and Uro-Oncology, Hannover,Germany. Nitric oxide (NO) has been identified an important neurotransmitter involved in the control of the human urinary tract. It has been suggested that NO is one of the factors keeping the bladder relaxed during the filling phase. This function might be mediated by the NO-induced elevation of intracellular cyclic GMP. Prostaglandins (PG) are known to exert contractile effects on the bladder smooth musculature, especially in pathological conditions. The aim of the present study was to examine the effects of a new class of NO donor drugs, combining both anti-phlogistic and NO-donating activity (NCX 2111 and HCT 1026), on the contraction induced by PG or electrical field stimulation (EFS) of isolated human detrusor. Effects were compared to those of sodium nitroprusside (SNP), forskolin, tolterodine, and oxybutynin. Using the organ bath technique, drug effects on the contraction induced by PG ((F2 alpha)) or EFS of isolated human detrusor smooth muscle were investigated. Detrusor strips were also exposed to increasing concentrations of the compounds (0.1 microM - 10 microM) and the accumulation of cyclic GMP and cyclic AMP was determined by means of radioimmunoassays. The tension induced by PG was dose-dependently reversed by the drugs. The rank order of efficacy was: forskolin > SNP > NCX 2111 > HCT 1026. R(max) values ranged from 57% (forskolin) to 24% (HCT 1026). Compounds also dose-dependently reduced the amplitudes of contraction induced by EFS (tolterodine > oxybutynin > NNP = forskolin > HCT 1026 > 2111). The effects of forskolin, HCT 1026, NCX 2111 and SNP were paralleled by an increase in cyclic AMP or cyclic GMP. Our results provide evidence that the NO-cGMP pathway is not of utmost significance in the control of human detrusor smooth muscle. In vitro, the combination of NO-donating with anti-phlogistic activity does not seem to be of functional advantage with regard to the facilitation of detrusor relaxation.