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Equimolar Dose (equimolar + dose)

Distribution by Scientific Domains

Medical Sciences	53%
Life Sciences	33%
Chemistry	13%

Distribution within Medical Sciences

Pharmacology & Pharmaceutical Medicine	24%

Selected Abstracts

Proliferation of glial cells in vivo induced in the neural lobe of the rat pituitary by lithium

CELL PROLIFERATION, Issue 4 2000
S. Levine
Lithium salts are widely used for treatment of psychiatric illness. Lithium also affects cell proliferation. During investigation of the effect of lithium chloride on the central nervous system (CNS) of nephrectomized rats, we noted numerous mitotic figures in the neural lobe of the pituitary. Morphologic criteria established that the mitotic cells were astrocytes, the supporting glial cells of the CNS, also known as pituicytes. Equimolar doses of chlorides of chemically related cations (sodium, potassium, rubidium) had no such effect. [source]

The role of peripheral Na+ channels in triggering the central excitatory effects of intravenous cocaine

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2006
P. Leon Brown
Abstract While alterations in dopamine (DA) uptake appear to be a critical mechanism underlying locomotor and reinforcing effects of cocaine (COC), many centrally mediated physiological and affective effects of this drug are resistant to DA receptor blockade and are expressed more quickly following an intravenous (i.v.) injection than expected based on the dynamics of drug concentration in the brain. Because COC is also a potent local anesthetic, its rapid action on Na+ channels may be responsible for triggering these effects. We monitored temperatures in the nucleus accumbens, temporal muscle and skin together with conventional locomotion during a single i.v. injection of COC (1 mg/kg), procaine (PRO, 5 mg/kg; equipotential anesthetic dose), a short-acting local anesthetic drug that, like COC, interacts with Na+ channels, and cocaine methiodide (COC-MET, 1.31 mg/kg, equimolar dose), a quaternary COC derivative that is unable to cross the blood,brain barrier. In this way, we explored not only the importance of Na+ channels in general, but also the importance of central vs. peripheral Na+ channels specifically. COC induced locomotor activation, temperature increase in the brain and muscle, and a biphasic temperature fluctuation in skin. Though PRO did not induce locomotor activation, it mimicked, to a greater degree, the temperature effects of COC. Therefore, Na+ channels appear to be a key substrate for COC-induced temperature fluctuations in the brain and periphery. Similar to PRO, COC-MET had minimal effects on locomotion, but mimicked COC in its ability to increase brain and muscle temperature, and induce transient skin hypothermia. It appears therefore that COC's interaction with peripherally located Na+ channels triggers its central excitatory effects manifested by brain temperature increase, thereby playing a major role in drug sensing and possibly contributing to COC reinforcement. [source]

CDP-choline increases plasma ACTH and potentiates the stimulated release of GH, TSH and LH: the cholinergic involvement

FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 5 2004
Sinan Cavun
Abstract In the present study, we investigated the effect of intracerebroventricular (i.c.v.) administration of cytidine-5,-diphosphate (CDP) choline on plasma adrenocorticotropin (ACTH), serum growth hormone (GH), thyroid stimulating hormone (TSH), follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels in conscious rats. The involvement of cholinergic mechanisms in these effects was also determined. In basal conditions, CDP-choline (0.5, 1.0 and 2.0 ,mol, i.c.v.) increased plasma ACTH levels dose- and time-dependently, but it did not affect the TSH, GH, FSH and LH levels. In stimulated conditions, i.c.v. administration of CDP-choline (1 ,mol, i.c.v.) produced an increase in clonidine-stimulated GH, thyrotyropin-releasing hormone (TRH)-stimulated TSH, LH-releasing hormone (LHRH)-stimulated LH, but not FSH levels. Injection of equimolar dose of choline (1 ,mol, i.c.v.) produced similar effects on hormone levels, but cytidine (1 ,mol, i.c.v.) failed to alter plasma levels of these hormones. Pretreatment with hemicholinium-3, a neuronal high affinity choline uptake inhibitor, (20 ,g, i.c.v.) completely blocked the observed hormone responses to CDP-choline. The increase in plasma ACTH levels induced by CDP-choline (1 ,mol, i.c.v.) was abolished by pretreatment with mecamylamine, a nicotinic receptor antagonist, (50 ,g, i.c.v.) but not atropine, a muscarinic receptor antagonist, (10 ,g, i.c.v.). The increase in stimulated levels of serum TSH by CDP-choline (1 ,mol, i.c.v.) was blocked by atropine but not by mecamylamine pretreatment. However, CDP-choline induced increases in serum GH and LH levels were greatly attenuated by both atropine and mecamylamine pretreatments. The results show that CDP-choline can increase plasma ACTH and produce additional increases in serum levels of TSH, GH and LH stimulated by TRH, clonidine and LHRH, respectively. The activation of central cholinergic system, mainly through the presynaptic mechanisms, was involved in these effects. Central nicotinic receptors solely mediated the increase in plasma ACTH levels while the activation of central muscarinic receptors was involved in the increase in TSH levels. Both muscarinic and nicotinic receptor activations, separately, mediated the increases in serum GH and LH levels after CDP-choline. [source]

Distinct effects of methamphetamine and cocaine on preprodynorphin messenger RNA in rat striatal patch and matrix

JOURNAL OF NEUROCHEMISTRY, Issue 1 2003
David H. Adams
Abstract We and others previously reported that equimolar doses of methamphetamine and cocaine differentially increase preprodynorphin mRNA in striatum: methamphetamine causes a patchy increase, whereas cocaine produces a more homogenous one. The current study directly examined whether this effect reflects differential induction in the patch,matrix division of striatum, as identified by µ opioid receptor immunohistochemistry. In addition, we determined whether doses of cocaine (30 mg/kg) and methamphetamine (2 mg/kg) that produced equivalent increases in extracellular dopamine differentially affected preprodynorphin mRNA expression in striatum of male, Sprague,Dawley rats. In both experiments, methamphetamine and cocaine differentially affected preprodynorphin mRNA in striatum after 3 h. The high, equimolar dose of methamphetamine selectively increased preprodynorphin mRNA in the patch division of rostral striatum, whereas cocaine increased preprodynorphin mRNA throughout patch and matrix divisions of striatum. In contrast, a dose of methamphetamine (2.0 mg/kg) that caused an increase in extracellular dopamine similar to that produced by 30 mg/kg cocaine did not significantly affect preprodynorphin mRNA in any region of striatum. These data provide further evidence that cocaine and amphetamines exert distinct effects on the patch,matrix division of striatum and suggest further that the post-synaptic consequences of elevated extracellular dopamine produced by methamphetamine and cocaine are distinct. [source]

Targeted Cytotoxic Analogue of Luteinizing Hormone-Releasing Hormone (LH-RH) Only Transiently Decreases the Gene Expression of Pituitary Receptors for LH-RH

JOURNAL OF NEUROENDOCRINOLOGY, Issue 1 2002
M. Kovacs
Abstract A cytotoxic analogue of LH-RH, AN-207, consisting of 2-pyrrolinodoxorubicin (AN-201) linked to carrier [D-Lys6]LH-RH, was developed for targeted therapy of cancers expressing LH-RH-receptors. To determine its possible side-effects on the pituitary gland, we investigated the gene expression of pituitary LH-RH-receptors and LH secretion in ovariectomized female and normal male rats after treatment with the maximum tolerated dose of AN-207. The effect of AN-207 on the gene expression of the pituitary GH-RH-receptors and GH secretion was also assessed in male rats. Five hours after a single i.v. injection of AN-207 at 175 nmol/kg, there was a 39,51% decrease in mRNA expression for the pituitary LH-RH-receptors in male and female rats. The carrier, at an equimolar dose, caused a similar reduction (37,39%), whereas the cytotoxic radical AN-201, at an equitoxic dose (110 nmol/kg), produced only a 12,24% decrease (NS) in the mRNA expression of LH-RH-receptors. AN-207 and the carrier analogue induced a comparable 90,100-fold increase in serum LH concentrations in male rats, and the same 12-fold elevation in OVX rats at 5 h. Seven days after treatment with AN-207, the mRNA levels for the LH-RH receptors and the serum LH concentration were back to normal in both sexes. AN-207, the carrier, and AN-201 had no significant effect on the expression of mRNA for GH-RH-receptors in the pituitary. In vitro, a continuous perfusion of pituitary cells with 10 nM AN-207 did not affect the hormone-releasing function of the targeted LH cells or the nontargeted GH cells. Our results demonstrate that cytotoxic LH-RH analogue AN-207, at the maximum tolerated dose causes only a transient decrease in the gene expression of the pituitary LH-RH receptors, and the levels of mRNA for LH-RH receptor fully recover within 7 days. Moreover, the carrier hormone moiety, and not the cytotoxic radical in AN-207 is responsible for this transient suppression. Our findings suggest that the therapy with cytotoxic LH-RH analogues will not inflict permanent damage to pituitary function. [source]

Application of pharmacokinetic,pharmacodynamic modeling to predict the kinetic and dynamic effects of anti-methotrexate antibodies in mice

JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 8 2003
Evelyn D. Lobo
Abstract We have shown that intravenous (iv) administration of anti-methotrexate (MTX) antibodies (AMAb) reduces the systemic exposure of intraperitoneal (ip) MTX therapy, and we have proposed that AMAb effects on MTX systemic exposure would allow a reduction in MTX-induced systemic toxicity (i.e., producing a desirable antagonistic effect). However, many literature reports have shown that anti-toxin antibodies occasionally demonstrate unexpected agonist-like activity, increasing the extent of toxicity induced by their ligand. In this report, we have utilized a pharmacokinetic,pharmacodynamic (PKPD) model to predict the potential of AMAb to increase or decrease the magnitude of MTX-induced body weight loss in mice. Simulations predicted that both anti-MTX immunoglobulin G (AMI) and anti-MTX Fab fragments (AMF) would lead to increases or decreases in MTX toxicity, with effects dependent on the dosing protocol used. Based on the computer simulations, two protocols were selected for in vivo evaluation of predicted agonistic or antagonistic effects. Murine monoclonal AMI and AMF were produced, purified, and characterized. Agonistic effects were tested after 24-h infusion of ip MTX (10 mg/kg) and iv administration of an equimolar dose of AMI. Antagonistic effects were tested after 72-h infusion of ip MTX (5 mg/kg) and iv infusion of an equimolar dose of AMF. Consistent with model predictions of agonist-like activity, the 24-h AMI protocol led to significantly increased animal mortality (all animals died, p,<,0.005) and mean nadir weight loss (p,<,0.005). Also consistent with the predictions of the PKPD model, the 72-h AMF protocol significantly decreased animal mortality and mean nadir body weight loss (p,<,0.01). Thus, these studies demonstrate that agonistic and antagonistic effects of anti-toxin antibodies may be predicted through the use of an integrated PKPD model. © 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:1665,1676, 2003 [source]

Efficacy and safety of conversion of mycophenolate mofetil to enteric-coated mycophenolate sodium in Mexican renal transplant children

PEDIATRIC TRANSPLANTATION, Issue 6 2010
H. Reyes
Reyes H, Hernández AM, Valverde S, Cataneo A, Mendoza A, Barrera I, Ortíz L, García-Roca P, Lopéz-Martínez B, Castañeda-Hernández G, Medeiros M. Efficacy and safety of conversion of mycophenolate mofetil to enteric-coated mycophenolate sodium in Mexican renal transplant children. Pediatr Transplantation 2010: 14:746,752. © 2010 John Wiley & Sons A/S. Abstract:, The aim of the study was to evaluate the efficacy and safety of the conversion of MMF to EC-MPS in pediatric renal transplant recipients. We included 12 patients with stable graft function who were receiving MMF treatment. In the first visit, a complete medical examination was performed, which included a GSRS, a nine-point pharmacokinetic profile, samples for renal, liver and hematological tests and evaluation of IMPDH2 gene expression. The patients were transferred to an equimolar dose of EC-MPS. Two wk later, a clinical evaluation and blood collection, as in the first visit were performed. There was no change in serum creatinine, leukocyte count, serum albumin, or transaminase levels, but we found a statistically significant reduction of hemoglobin after conversion (13.2 ± 1.6 g/dL with MMF vs. 12.5 ± 1.3 g/dL when receiving EC-MPS). The GSRS total mean score was 16 ± 12 with MMF vs. 8 ± 5 with EC-MPA (p < 0.05). There was no statistically significant difference between formulations in the gene expression of IMPDH 2, in the AUC0-12h or in Cmax. However, peak concentration occurred later with EC-MPS. [source]

Pharmacological and pharmacokinetic evaluation of celecoxib prodrugs in rats

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7 2002
Rao N.V.S. Mamidi
Abstract This study demonstrates the utility of an in vitro , in vivo correlative approach in the selection and optimization of a prodrug candidate of celecoxib (CBX), a COX2 inhibitor. As an initial screening step, a comparative single oral dose pharmacokinetic study was conducted in rats for CBX and its three aliphatic acyl water-soluble prodrugs viz., CBX-acetyl (CBX-AC), CBX-propionyl (CBX-PR) and CBX-butyryl (CBX-BU) at high equimolar dose, 100 mg/kg. Only CBX-BU and CBX-PR converted rapidly to CBX and yielded approximately five-fold greater systemic exposure of CBX than CBX alone or CBX-AC. Rank order of systemic exposure of prodrugs in its intact form was CBX-AC >CBX-PR >CBX-BU. Further in vitro hydrolysis studies of CBX prodrugs in intestinal mucosal suspensions and liver homogenates indicated that CBX-BU is rapidly and completely converted to CBX, whereas CBX-PR and CBX-AC require longer incubation period for complete conversion to CBX. There was a very good correlation of the in vitro and in vivo data supporting CBX-BU as the prodrug of choice. Further in vitro pharmacological studies showed that COX2 selective inhibition is improved for CBX-BU as compared to CBX-AC and CBX-PR. Dose proportionality in pharmacokinetic studies of CBX-BU and CBX at equimolar oral doses confirmed that relative oral bioavailability of CBX was improved following CBX-BU administration and there was linearity in pharmacokinetics of CBX over a wide dose range (10,100 mg/kg), whereas CBX in its conventional form showed poor bioavailability and lack of dose linearity in pharmacokinetics. The oral bioavailability of CBX from CBX-BU was dose independent and was in the range 78,96%. At a 50% reduced molar dose, CBX-BU showed an equivalent efficacy to that of CBX in the in vivo carrageenan model. Based on the study, water-soluble CBX-BU prodrug can be considered for clinical development in view of its potential advantages.Copyright © 2002 John Wiley & Sons, Ltd. [source]

Genotoxicity of acrylamide and its metabolite glycidamide administered in drinking water to male and female Big Blue mice,

ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 1 2006
Mugimane G. Manjanatha
Abstract The recent discovery of acrylamide (AA), a probable human carcinogen, in a variety of fried and baked starchy foods has drawn attention to its genotoxicity and carcinogenicity. Evidence suggests that glycidamide (GA), the epoxide metabolite of AA, is responsible for the genotoxic effects of AA. To investigate the in vivo genotoxicity of AA, groups of male and female Big Blue (BB) mice were administered 0, 100, or 500 mg/l of AA or equimolar doses of GA, in drinking water, for 3,4 weeks. Micronucleated reticulocytes (MN-RETs) were assessed in peripheral blood within 24 hr of the last treatment, and lymphocyte Hprt and liver cII mutagenesis assays were conducted 21 days following the last treatment. Further, the types of cII mutations induced by AA and GA in the liver were determined by sequence analysis. The frequency of MN-RETs was increased 1.7,3.3-fold in males treated with the high doses of AA and GA (P , 0.05; control frequency = 0.28%). Both doses of AA and GA produced increased lymphocyte Hprt mutant frequencies (MFs), with the high doses producing responses 16,25-fold higher than that of the respective control (P , 0.01; control MFs = 1.5 ± 0.3 × 10,6 and 2.2 ± 0.5 × 10,6 in females and males, respectively). Also, the high doses of AA and GA produced significant 2,2.5-fold increases in liver cII MFs (P , 0.05; control MFs = 26.5 ± 3.1 × 10,6 and 28.4 ± 4.5 × 10,6). Molecular analysis of the mutants indicated that AA and GA produced similar mutation spectra and that these spectra were significantly different from that of control mutants (P , 0.001). The predominant types of mutations in the liver cII gene from AA- and GA-treated mice were G:C,T:A transversions and ,1/+1 frameshifts in a homopolymeric run of Gs. The results indicate that both AA and GA are genotoxic in mice. The MFs and types of mutations induced by AA and GA in the liver are consistent with AA exerting its genotoxicity in BB mice via metabolism to GA. Environ. Mol. Mutagen., 2006. Published 2005 Wiley-Liss, Inc. [source]

The influence of curcumin and manganese complex of curcumin on cadmium-induced oxidative damage and trace elements status in tissues of mice

JOURNAL OF APPLIED TOXICOLOGY, Issue 3 2006
Vladislav Eybl
Abstract Curcumin (diferuoyl methane) from turmeric is a well-known biologically active compound. It has been shown to ameliorate oxidative stress and it is considered to be a potent cancer chemopreventive agent. In our previous study the antioxidative effects of curcumin in cadmium exposed animals were demonstrated. Also manganese exerts protective effects in experimental cadmium intoxication. The present study examined the ability of the manganese complex of curcumin (Mn-curcumin) and curcumin to protect against oxidative damage and changes in trace element status in cadmium-intoxicated male mice. Curcumin or Mn-curcumin were administered at equimolar doses (0.14 mmol/kg b.w.) for 3 days, by gastric gavages, dispersed in methylcellulose. One hour after the last dose of antioxidants, cadmium chloride (33 µmol/kg) was administered subcutaneously. Both curcumin and Mn-curcumin prevented the increase of hepatic lipid peroxidation , expressed as MDA level, induced by cadmium intoxication and attenuated the Cd-induced decrease of hepatic GSH level. No change in hepatic glutathione peroxidase or catalase activities was found in Cd-exposed mice. A decreased GSH-Px activity was measured in curcumin and Mn-curcumin alone treated mice. Neither curcumin nor Mn-curcumin treatment influenced cadmium distribution in the tissues and did not correct the changes in the balance of essential elements caused by Cd-treatment. The treatment with Mn-curcumin increased the Fe and Mn content in the kidneys of both control and Cd-treated mice and Fe and Cu content in the brain of control mice. In conclusion, regarding the antioxidative action, introducing manganese into the curcumin molecule does not potentiate the studied effects of curcumin. Copyright © 2005 John Wiley & Sons, Ltd. [source]

Distinct effects of methamphetamine and cocaine on preprodynorphin messenger RNA in rat striatal patch and matrix

Pharmacokinetics, biodistribution, and antitumor efficacy of a human glandular kallikrein 2 (hK2)-activated thapsigargin prodrug

THE PROSTATE, Issue 4 2006
Samuel Janssen
Abstract BACKGROUND Prostate cancer cells secrete unique proteases such as prostate-specific antigen (PSA) and human glandular kallikrein 2 (hK2) that represent targets for the activation of prodrugs as systemic treatment of metastatic prostate cancer. Previously, a combinatorial peptide library was screened to identify a highly active peptide substrate for hK2. The peptide was coupled to an analog of the potent cytotoxin thapsigargin, L12ADT, to generate an hK2-activated prodrug that was efficiently hydrolyzed by purified hK2, stable to hydrolysis in human and mouse plasma in vitro and selectively toxic to hK2 producing prostate cancer cells in vitro. METHODS In the current study, toxicology, pharmacokinetics, prodrug biodistribution, and antitumor efficacy studies were performed to evaluate the hK2-activated prodrug in vivo. RESULTS The single intravenous maximally tolerated dose of prodrug was 6 mg/kg (i.e., 3.67 µmole/kg) which produced peak serum concentration of ,36 µM and had a half-life of ,40 min. In addition, over a 24 hr period <0.5% of free L12ADT analog was observed in plasma. The prodrug demonstrated significant antitumor effect in vivo while it was being administered, but prolonged intravenous administration was not possible due to local toxicity to tail veins. Subcutaneous administration of equimolar doses produced lower plasma AUC compared to intravenous dosing but equivalent intratumoral levels of prodrug following multiple doses. CONCLUSIONS The hK2-activated prodrug was stable in vivo. The prodrug, however, was rapidly cleared and difficult to administer over prolonged dosing interval. Additional studies are underway to assess antitumor efficacy with prolonged administration of higher subcutaneous doses of prodrug. Second-generation hK2-activated thapsigargin prodrugs with increased half-lives and improved formulations are also under development. © 2005 Wiley-Liss, Inc. [source]

Pharmacokinetic and Pharmacodynamic Comparison of Enteric-Coated Mycophenolate Sodium and Mycophenolate Mofetil in Maintenance Renal Transplant Patients

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2007
K. Budde
The aim of this single-center crossover substudy was to assess pharmacokinetics and pharmacodynamics [inosine 5,-monophosphate dehydrogenase (IMPDH) activity] of enteric-coated mycophenolate sodium (EC-MPS) and mycophenolate mofetil (MMF) at steady-state conditions. Stable maintenance renal transplant patients on 1 g MMF b.i.d. participating in a double-blind, multicenter study, were randomized to receive EC-MPS (720 mg b.i.d.) or continue receiving MMF (1000 mg b.i.d.) for 12 months. Thereafter, all patients (n = 18) received 720 mg EC-MPS b.i.d. Area under the plasma mycophenolic acid (MPA) concentration,time curve with EC-MPS (57.4 ± 15.0 ,g h/mL) fulfilled bioequivalence criteria (geometric mean 0.98 (90% CI: 0.87,1.11) compared to MMF (58.4 ± 14.1 ,g h/mL). Consistent with the delayed release characteristics of EC-MPS, peak MPA concentration (geometric mean 0.89; 90% CI: 0.70,1.13) occurred approximately 0.5 h later (p < 0.05) and predose MPA levels (geometric mean 2.10; 90% CI: 1.51,2.91) were higher and more variable, not fulfilling bioequivalence criteria. IMPDH activity inversely followed MPA concentrations and was inhibited to a similar degree (approximately 85%) by both formulations. The calculated value for 50% IMPDH inhibition was identical for both drugs. In conclusion, equimolar doses of EC-MPS and MMF produce equivalent MPA exposure, while the delayed release formulation of EC-MPS exhibits more variable predose levels and Tmax. Overall, IMPDH activity reflected MPA pharmacokinetics. [source]

Effect of norethisterone and its A-ring reduced metabolites on the acrosome reaction in porcine spermatozoa

ANDROLOGIA, Issue 5 2002
G. Martinez
Summary. The synthetic progestin, norethisterone (NET), has been reported as a contragestational postcoital agent in humans, rodents and rabbits. The effect and molecular mechanisms of NET and its A-ring reduced metabolites, 5,-NET and 3,5,-NET, on the acrosome reaction (AR) are unknown. The aim of this study was to assess the effect of these compounds on an in vitro progesterone-induced AR in porcine spermatozoa. The spermatozoa were obtained from semen ejaculated by proven fertile adult pigs. Seminal plasma removed and incubated under capacitating conditions was performed in TALP-Hepes medium for 4 h. Progesterone (P4) and three different progestins: norethisterone (NET), 5,-norethisterone (5,-NET) and 3,5,-NET were then added at equimolar doses, and the spermatozoa were incubated for 15 min. Double-staining with PSA-FITC and Hoechst-33258 assessed the AR and sperm viability. Both P4 and NET induced the AR, while 5,-NET not only did not induce this process, but was able to block the effect of P4 on the spermatozoa. 3,5,-NET was not able to inhibit P4 action. These results suggest that NET and its A-ring reduced metabolites act in different ways on the progesterone-induced AR in porcine spermatozoa. [source]

A nitric oxide (NO)-releasing derivative of gabapentin, NCX 8001, alleviates neuropathic pain-like behavior after spinal cord and peripheral nerve injury

BRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2004
Wei-Ping Wu
Nitric oxide (NO) participates, at least in part, to the establishment and maintenance of pain after nerve injury. Therefore, drugs that target the NO/cGMP signaling pathway are of interest for the treatment of human neuropathic pain. Various compounds endowed with NO-releasing properties modulate the expression and function of inducible nitric oxide synthase (iNOS), the key enzyme responsible for sustained NO production under pathological conditions including neuropathic pain. With this background, we synthesized a new chemical entity, [1-(aminomethyl)cyclohexane acetic acid 3-(nitroxymethyl)phenyl ester] NCX8001, which has a NO-releasing moiety bound to gabapentin, a drug currently used for the clinical management of neuropathic pain. We examined the pharmacological profile of this drug with respect to its NO-releasing properties in vitro as well as to its efficacy in treating neuropathic pain conditions (allodynia) consequent to experimental sciatic nerve or spinal cord injuries. NCX8001 (1,30 ,M) released physiologically relevant concentrations of NO as it induced a concentration-dependent activation of soluble guanylyl cyclase (EC50=5.6 ,M) and produced consistent vasorelaxant effects in noradrenaline-precontracted rabbit aortic rings (IC50=1.4 ,M). NCX8001, but not gabapentin, counteracted in a concentration-dependent fashion lipopolysaccharide-induced overexpression and function of iNOS in RAW264.7 macrophages cell line. Furthermore, NCX8001 also inhibited the release of tumor necrosis factor alpha (TNF,) from stimulated RAW264.7 cells. NCX8001 (28,280 ,mol kg,1, i.p.) reduced the allodynic responses of spinal cord injured rats in a dose-dependent fashion while lacking sedative or motor effects. In contrast, gabapentin (170,580 ,mol kg,1, i.p.) resulted less effective and elicited marked side effects. NCX8001 alleviated the allodynia-like responses of rats to innocuous mechanical or cold stimulation following lesion of the sciatic nerve. This effect was not shared by equimolar doses of gabapentin. Potentially due to the slow releasing kinetics of NO, NCX8001 alleviated pain-like behaviors in two rat models of neuropathic pain in a fashion that is superior to its parent counterpart gabapentin. This new gabapentin derivative, whose mechanism deserves to be explored further, offers new hopes to the treatment of human neuropathic pain. British Journal of Pharmacology (2004) 141, 65,74. doi:10.1038/sj.bjp.0705596 [source]