Antinociceptive effects of a novel dual cyclooxygenase/5-lipoxygenase inhibitor (tepoxalin) and its primary (carboxylic acid) metabolite (RWJ 20142) in acute tests in mice and rats

Tepoxalin is a novel dual inhibitor of cyclooxygenase (CO) and lipoxygenase (LO) pathways of arachidonic acid metabolism with a relative lack of gastrointestinal side effects within its preclinical therapeutic dose range. The present study investigated the antinociceptive action of tepoxalin and its primary (carboxylic acid) metabolite (RWJ 20142) in several acute tests in mice and rats. Tepoxalin produced dose-related, non-opioid (i.e., naloxone-insensitive) antinociception in the mouse acetylcholine (ACh) induced abdominal irritant test (AIT) with an onset within 15 min and an exceptional duration (about 12 h). The oral ED₅₀ value at peak effect (30 min) was 0.3 mg/kg (0.8 μmol/kg), compared to 0.9, 38.0, and 164 mg/kg (2.5, 160.8, and 1, 085 μmol/kg), respectively, for indomethacin, zileuton, and acetaminophen. Tepoxalin was inactive via intracerebroventricular (i.c.v.) administration (up to 200μg) or (up to 100mg/kg [259 μg/kg] p.o. or s.c.) in the endothelin-1 (ET-1) AIT and mouse 48°C hot-plate tests. RWJ 20142 (a CO inhibitor), produced dose-related, non-opioid antinociception in the ACh test following oral (ED₅₀ = 0.3 mg/kg [0.8 μmol/kg] at 30 min) or i.c.v. administration (ED₅₀ = 3.3 μg [0.1 μmol] at 15 min) and was active p.o. in the phenyl-p -quinone (PpQ) (ED₅₀ = 0.2 mg/kg [0.6 μmol/kg] at 30 min) and ET-1 tests (ED₅₀ = 19.6 mg/kg [54.9 μmol/kg] at 30 min). It was the only compound active p.o. in the 48°C hot-plate test and was significantly more potent than tepoxalin in the rat air-induced AIT. Measurement of plasma levels suggests RWJ 20142 might be a major contributor to tepoxalin-induced antinociception. The inactivity of tepoxalin in the ET-1 test suggests a separate antinociceptive action of the parent compound. In summary, it appears that both tepoxalin and its primary metabolite contribute to tepoxalin-induced antinociception in rodents, possibly by different mechanisms or at different sites, i.e., peripheral vs. central. © 1995 Wiley-Liss, Inc.     

Skin nociceptive block with pramoxine delivery by subcutaneous injection in rats

Background

Pramoxine has been shown to produce spinal anesthesia, while cutaneous analgesia (peripheral) of pramoxine is not established. The experimental goal was to examine cutaneous antinociception produced by a local anesthetic (LA) pramoxine and compare this result with that of another well-known LA lidocaine.

Dopamine enhancement of dextrorphan-induced skin antinociception in response to needle pinpricks in rats

BackgroundDextrorphan with long-acting local anesthetic effects did not cause system toxicity as fast as bupivacaine, while catecholamines (i.e., epinephrine) with the vasoconstrictive characteristics enhanced the effects of local anesthetic drugs. The objective of the experiment was to examine the synergistic effect of local dopamine (a catecholamine) injection on cutaneous antinociception of dextrorphan.MethodsThe panniculus reflex in response to skin stimulation with a needle was used as the primary endpoint when dextrorphan (1.50, 2.61, 5.46, 10.20 and 20.40 μmol) alone, dopamine (16.20, 32.40, 51.60, 60.00 and 81.60 μmol) alone, or dopamine + dextrorphan (a ratio of ED₅₀ vs. ED₅₀) was injected subcutaneously on the rat's back. We used an isobolographic modelling approach to determine whether a synergistic effect would be observed.ResultsWe showed that dextrorphan, dopamine, or the mixture of dopamine and dextrorphan produced dose-related skin antinociception. The potency (ED₅₀, 50% effective dose) for cutaneous antinociception was dextrorphan [6.02 (5.93–6.14) μmol] greater than dopamine [48.91 (48.80–49.06) μmol] (p < 0.01). The duration of nociceptive inhibition induced by dopamine was longer than that induced by dextrorphan (p < 0.01) based on their equipotent doses (ED₂₅, ED₅₀, and ED₇₅). Enhancement and prolongation of skin antinociception occurred after co-administration of dopamine with dextrorphan.ConclusionsWhen compared to dopamine, dextrorphan was more potent and had a shorter duration of skin nociceptive block. Dopamine produced a synergistic effect on dextrorphan-mediated antinociception, and prolonged dextrorphan′s antinociceptive duration.     

Subcutaneous infiltration of doxylamine on cutaneous analgesia in rats

Background

We aimed to evaluate the effect of doxylamine, a first generation antihistamine, as a local analgesic agent by comparing its effect to bupivacaine.

A novel,orally effective hypoglycemic agent,SaRI 59–801, in laboratory animals

SaRl 59-801 (59-801) (α-[dimethylaminomethyl]-2-[3-ethyl-5-methyl-4-isoxazolyl]-1H-indole-3-methanol), is a novel, orally effective hypoglycemic compound which appears to act largely, if not entirely, by stimulation of insulin release. The compound is structurally unrelated to sulfonylurea derivatives. The 2-hr hypoglycemic ED₂₅ in fasting mice was 110 mg/kg; the plasma insulin levels were increased, with an ED₅₀ of 47 mg/kg. Significant hypoglycemic activity was observed 2 hr after oral administration of 59-801 to fasting rats (ED₂₅ = 86 mg/kg), while plasma insulin was elevated by 62% at 100 mg/kg. 59-801 caused an insignificant decrease in plasma lactic acid levels. The hyperglycemic response 30 min after an oral starch load was inhibited by 1-hr pretreatment with 59-801 (ED₅₀ = 37 mg/kg). No tolerance to the hypoglycemic effect was observed after 28 days of dosing in rats. In monkeys, the agent also produced hypoglycemia with a minimum effective dose of 10 mg/kg and an ED₂₅ of 33 mg/kg for a period of 6 hr after oral administration. In genetically diabetic (db⁺/db⁺) mice, 59-801 was more potent in producing hypoglycemia (ED₂₅ = 47 mg/kg) than their lean littermates (ED₂₅ = 131 mg/kg). In alloxan-diabetic rats or streptozotocin-diabetic mice, this agent was inactive at 200 mg/kg, but at 400 mg/kg, it caused reduction of blood glucose levels of 29–39 and 21%, respectively, possibly the result of stimulation of residual β-cell function. Thus far, stimulation of insulin release is the only mechanism found to explain the acute hypoglycemic activity of 59-801.     

Mexiletine has a local anesthetic effect on sciatic nerve blockade in rats

Mexiletine is an antiarrhythmic drug that has a Na⁺ channel blocking activity. The aim of the present study was to evaluate whether mexiletine had a local anesthetic effect as assessed by sciatic nerve blockade. Thus, the potency and duration of action of mexiletine on sciatic nerve blockade in terms of motor function and nociception were evaluated. Two local anesthetics, bupivacaine and lidocaine, were used as controls. Mexiletine produced a dose‐related local anesthetic effect on sciatic nerve blockade. The rank potency was bupivacaine >lidocaine >mexiletine (P<0.05 for each comparison). On an equi‐potent basis, the rank duration of action was bupivacaine>mexiletine>lidocaine (P<0.05 for each comparison). Co‐administration of mexiletine with bupivacaine produced an additive effect on sciatic nerve blockade. In conclusion, mexiletine had a local anesthetic effect on sciatic nerve blockades of motor function and nociception. Co‐administration of mexiletine with bupivacaine produced an additive effect on sciatic nerve blockade. Drug Dev. Res. 67:905–909, 2006. © 2007 Wiley‐Liss, Inc.     

The preclinical antipsychotic evaluation of HRP 913, a novel benzisoxazole derivative

HRP 913 {1-[3-(6-fluoro-1,2-benzisoxazole-3-yl)propyl]-4-(2-oxo-1-benzimidazolinyl)} piperidine demonstrated preclinical antipsychotic activity with features that may provide a clinical advantage over current therapy. It was effective in blocking amphetamine stereotypy in rats (ED₅₀ = 0.4 mg/kg, i.p.), amphetamine circling in SN-lesioned rats (ED₅₀ = 0.3 mg/kg, i.p.), apomorphine stereotypy in rats (ED₅₀ = 0.8 mg/kg, i.p.), but not apomorphine circling in SN-lesioned rats (up to 10 mg/kg, i.p.). It also blocked Sidman avoidance in rats (ED₅₀ = 0.17 mg/kg, i.p.) and monkeys (ED₅₀ = 0.2 mg/kg, p.o.) and blocked intracranial self-stimulation in rats (0.09 mg/kg, i.p.). A unique biphasic effect on catalepsy was found. Monkey EPS studies demonstrate a potential for EPS that is lower than some existing clinical standards. HRP 913 displaced ³H-spiroperidol from rat striatal sites (IC₅₀ = 6.0 × 10^?9 M) and inhibited WB-4101 binding (IC₅₀ = 2.6 × 10^?8 M) with only slight effect on QNB binding. HRP 913 does not appear to have marked α-blocking properties in vivo. HRP 913 is a potent dopamine antagonist and is predicted to have less side effects than current therapy.     

Nationwide linkage analysis in Scotland implicates age as the critical overall determinant of mortality in ulcerative colitis

Aliment Pharmacol Ther 31 , 1310–1321

Summary

Background Recent data associated higher mortality with medical rather than surgical intervention in patients with ulcerative colitis who require hospitalization. Aim To examine factors influencing UC‐related mortality in Scotland. Method Using the national record linkage database 1998–2000, 3‐year mortality was determined after four admission types: colectomy‐elective or emergency; no colectomy‐elective or emergency. Results Of 1078 patients, crude 3‐year mortality rates were: colectomy elective 5.6% (n = 177) and emergency 9.0% (100); no colectomy elective 9.8% (244) and emergency 16.0% (557). Using elective colectomy as reference, multivariate analysis [OR (95% CI)] showed that admission age >50 years [OR 5.46 (2.29–11.95)], male gender [OR 1.92 (1.23–3.02)], comorbidity [OR 2.2 (1.38–3.51)], length of stay >15 days [OR 2.04 (1.08–3.84)] and prior IBD admission [OR 1.66 (1.06–2.61)] were independently related to mortality. Age was the strongest determinant. No patient <30 years died. Mortality of patients aged <50 years [10/587 (1.7%)] was significantly lower than mortality of those aged 50–64 years [26/246 (10.6%)] (χ² = 32.91; P < 0.0000001) and >65 [96/245 (39.2%)] (χ² = 218.2; P < 0.0000001). For those patients aged more than 65 years, mortality in the four groups was 29.4%, 33.3%, 28.1% and 44.7%– all greater than expected in the Scottish population on assessment of standardized mortality ratios. Conclusion Hospital admission in UC patients >65 is associated with high mortality. Management strategies should consider this by treatment in specialist units, early investigation, focused medical treatment and earlier surgical referral.     

Comparison of the effects of calmidazolium, morphine and bupivacaine on N-methyl-d-aspartate- and septide-induced nociceptive behaviour

We have recently shown that spinal calmodulin inhibitors (W-7 and calmidazolium) dose-dependently inhibit the nociceptive reaction (biting, scratching, licking, BSL) evoked by intrathecal N-methyl-d-aspartate (NMDA) and septide, an agonist of the neurokinin (NK) NK₁ receptor. To compare this effect with that induced by standard analgesics, we now report a study of the effects of calmidazolium (14–420 nmol), bupivacaine (29–582 nmol) and morphine (26–260 nmol) when coadministered intrathecally with either NMDA (4 μg) or septide (0.5 μg). Calmidazolium had the highest potency for inhibiting septide-induced nociceptive behaviour, acting over a dose range of 34–130 nmol (dose eliciting a half-maximal response, ED₅₀, 67 nmol) lower than that of bupivacaine [ED₅₀ 234 (115–475) nmol]. Only the highest dose of morphine (260 nmol) inhibited septide-evoked BSL [ED₅₀=133 (69–255) nmol]. Higher doses of morphine could not be tested due to the appearance of an excitatory aversive reaction. Both calmidazolium [ED₅₀=232 (138–388) nmol] and bupivacaine [ED₅₀=123 (59–256) nmol] dose-dependently reduced NMDA-induced BSL reaching an almost maximal inhibition at the highest doses assayed (420 and 291 nmol, respectively). In contrast, morphine had less effect on NMDA-induced behaviour, inducing only a partial reduction of BSL even with the highest dose assayed (260 nmol). Overall, it can be concluded that the calmodulin inhibitor calmidazolium inhibits septide- and NMDA-evoked nociceptive behaviour with a potency and efficacy at least as high as those of morphine and bupivacaine. Received: 1 April 1998 / Accepted: 4 September 1998     

Anticonvulsant activity of (+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine (MK-801), a substance with potent anticonvulsant,central sympathomimetic,and apparent anxiolytic properties

MK-801 prevented tonic extensor seizures in the rat induced by bicuclline with the ED₅₀ being 23 μg/kg p.o. Clonazepam, phenobarbital, diazepam, phenytoin, γ-acetylenic GABA, sodium valproate, and trimethadione were all less potent. In mice, MK-801 was likewise the most potent (ED₅₀ = 0.35 mg/kg p.o.) compound in protecting against tonic seizures induced by electroshock. Clonazepam (ED₅₀ = 0.41 mg/kg p.o.) and MK-801 (ED₅₀ = 0.67 mg/kg p.o.) were by far more potent than any of the other anticonvulsants tested versus bicuculline-elicited seizures in mice. Besides being a potent anticonvulsant, MK-801 demonstrated selectivity, since much higher doses were required in mice to block clonic convulsions produced by pentylenetetrazol (ED₅₀ = 11 mg/kg p.o.) and tonic seizures caused by strychnine (ED₅₀ > 15 mg/kg p.o.) than were needed against electroshock or bicuculline. The anticonvulsant (electroshock) effect of MK-801 in mice was unaffected by pretreating the animals with various receptor antagonists (atropine, mecamylamine, chlorpheniramine, tripelennamine, cyproheptadine, cinanserin, methysergide, cimetidine, and propranolol). MK-801 was slightly, but significantly, antagonized by methergoline, naloxone, and theophylline, whereas haloperidol and especially α-adrenoceptor blockers (prazosin, HEAT, phenoxybenzamine) markedly reduced the anticonvulsant effect of MK-801. Haloperidol was selective for MK-801, not affecting the anticonvulsant actions of phenytoin or phenobarbital. Prazosin antagonized phenytoin and phenobarbital, but to a much lesser extent than it antagonized MK-801. MK-801 is an extremely potent and selective anticonvulsant acting at least partly via a catecholaminergic mechanism.     

Tricyclic Antidepressant Agents. II. Effect of Oral Administration on the Uptake of 3H-Noradrenaline and 14C-5-Hydroxytryptamine in Slices of the Midbrain-Hypothalamus Region of the Rat

Abstract: The inhibition of the simultaneous uptake of ³H-l-noradrenaline (NA) and ¹⁴C-5-hydroxytryptamine (5-HT) in slices of the midbrain-hypothalamus region of the rat brain after oral administration of desipramine, imipramine, nortriptyline, amitriptyline, chlordesipramine and chlorimipramine was determined. All compounds were more active in inhibiting the NA uptake than the 5-HT uptake. This difference was very marked for desipramine, imipramine, nortriptyline and chlordesipramine. Chlorimipramine was almost as active on the 5-HT uptake (ED₅₀ = 35 mg/kg orally) as on the NA uptake (ED₆₀ = 20 mg/kg orally) and amitriptyline had low activity on both uptake mechanisms (ED₅₀ > 50 mg/kg orally). Desipramine and imipramine were the most active compounds on the NA uptake (ED₅₀ = 8 mg/kg orally for both compounds) and the duration of the action was very long. The ED₅₀ values for nortriptyline and chlordesipramine in inhibiting the NA uptake were about 20 mg/kg orally for both compounds. The inhibition of the 5-HT uptake was less than 50% at 50 mg/kg orally for all compounds except for imipramine (ED₅₀ = 50 mg/kg orally) and for chlorimipramine. The role of the biotransformation for the inhibitory activities of imipramine, chlorimipramine and amitriptyline was investigated in animals pre-treated with SKF 525 A. The inhibitory potency of imipramine was increased by the same factor for both uptake mechanisms probably due to the large increase in the concentration of imipramine in the rat brain, which was demonstrated after the administration of ¹⁴C-imipramine. The inhibitory activity of chlorimipramine was somewhat more increased for the 5-HT uptake than for the NA uptake. The low activity of amitriptyline seems to be mainly due to poor resorption, since pretreatment of the animals with SKF 525 A only slightly increased the potency whereas intraperitoneal injection of amitriptyline had a rather marked effect on the NA uptake (ED₅₀ = 11 mg/kg intraperitoneally).     

Chlorpromazine as a discriminative stimulus in rats: Generalization to typical and atypical antipsychotics

The discriminative stimulus properties of the typical antipsychotic chlorpromazine were examined in a two‐lever drug discrimination procedure for food reward. Six of nine rats readily acquired the discrimination between 1.0 mg/kg chlorpromazine (i.p.) and vehicle in a mean of 29.7 training sessions. The chlorpromazine generalization curve was dose‐dependent and yielded an ED₅₀ of 0.305 mg/kg (95% confidence interval (CI) = 0.201–0.463 mg/kg). The chlorpromazine cue generalized to the atypical antipsychotics clozapine (ED₅₀ for the clozapine curve was 0.258 mg/kg [95% CI = 0.047–1.420 mg/kg]) and olanzapine (ED₅₀ for the olanzapine curve was 0.199 mg/kg [95% CI = 0.076–0.522 mg/kg]) and to the typical antipsychotic thioridazine (ED₅₀ for the thioridazine curve was 3.103 mg/kg [95% CI = 1.993–4.832 mg/kg]). Haloperidol (a typical antipsychotic) and raclopride (an atypical antipsychotic) did not substitute for chlorpromazine. It is clear from the present results that the discriminative stimulus properties of chlorpromazine share similarities both with the atypical antipsychotics clozapine and olanzapine and with the typical antipsychotic thioridazine. The extent to which the discriminative stimulus properties of antipsychotic drugs reflect or are predictive of their therapeutic effects in schizophrenic patients remains unclear. Drug Dev. Res. 48:38–44, 1999. © 1999 Wiley‐Liss, Inc.     

Physicochemical Modification of Lidocaine Uptake in Rat Lung Tissue

Abstract The uptake of lidocaine, methyllidocaine, bupivacaine, etidocaine was studied in rat lung slices at different pH-values. The accumulation of the quaternary analogue, methyllidocaine, was not changed in the pH interval 7.0-8.0. The uptake of the three other substances was about 3-4 times lower at pH 7.0 than at pH 8.0. The rank order of distribution at a fixed catiodbase ratio was bupivacaine>etidocaine>lidocaine. Interactions between lidocaine and other substances were studied in lung slices and in isolated perfused lungs. Bupivacaine and nortriptyline counteracted the accumulation of ¹⁴C-lidocaine in lung slices in a dose-dependent manner. Nortriptyline was more effective than bupivacaine. In isolated perfused lung, bolus injections of nortriptyline and lidocaine rapidly displaced ¹⁴C-lidocaine from the tissue. In this study we suggest that the base form of local anaesthetics accumulate in the lung tissue, while the cationic form binds to accessible binding sites in the cell membranes.     

Intratubular application of sodium azide inhibits loop of Henle reabsorption and tubuloglomerular feedback response in anesthetized rats

Sodium azide (NaN₃, AZ) is a potent inhibitor and uncoupler of oxidative phosphorylation as well as a nitrovasodilator after being converted to nitric oxide (NO). We studied the effect of intratubular application of AZ on loop of Henle reabsorption and tubuloglomerular feedback (TGF) employing renal micropuncture experiments in nephrons with superficial glomeruli of anesthetized Munich-Wistar-Frömter rats. During perfusion of Henle’s loop downstream from an obstructing wax block, AZ (3×10^–5 mol/l and 3×10^–4 mol/l) concentration-dependently increased early distal tubular flow rate and sodium and potassium ion concentration (V_ED, [Na⁺]_ED, [K⁺]_ED). In comparison, application of furosemide (10^–4 mol/l), the action of which is restricted to the water-impermeable thick ascending limb of Henle’s loop (TALH) and the macula densa, similarly increased [Na⁺]_ED and [K⁺]_ED, but did not affect V_ED. The effect of AZ on loop of Henle reabsorption appeared to be predominantly localized upstream to the TALH since (1) AZ significantly inhibited net fluid reabsorption (the latter being completely abolished at 3×10^–4 mol/l), (2) the effect of AZ on [Na⁺]_ED and [K⁺]_ED could be mimicked by perfusing the Henle’s loop at a flow rate that caused a comparable increase in V_ED (reflecting a comparable load to TALH), and (3) the effects of AZ and furosemide were additive. In spite of the increase in [Na⁺]_ED and [K⁺]_ED, intratubular application of AZ caused a concentration-dependent inhibition of TGF response, the latter being assessed as the fall in early proximal tubular stop flow pressure during perfusion of Henle’s loop at increasing flow rate. Like AZ and furosemide, the NO donor sodium nitroprusside (10^–4 mol/l) blunted the TGF response, but in contrast to furosemide or AZ, it caused a minor decrease in V_ED, without changing [Na⁺]_ED or [K⁺]_ED. The inhibitory effect of AZ on TGF was abolished by the NO scavenger carboxy PTIO. In summary, AZ inhibits both reabsorption in the water-permeable segment of Henle’s loop and the TGF response. The effect on reabsorption may be linked to metabolic inhibition rather than NO release, whereas the blunted TGF response appears to involve conversion to NO.     

Simultaneous measurement of bupivacaine, etidocaine, lidocaine, meperidine, mepivacaine, and methadone

A gas-liquid chromatographic method for the simultaneous measurement of bupivacaine, etidocaine, lidocaine, meperidine, mepivacaine, and methadone in serum is described. The drugs and the internal standard, prilocaine, are extracted from 1 ml of serum. The procedure involves a two-step extraction and injection of the extract into a gas chromatograph equipped with a 10-ft OV-11 glass column and a nitrogen-phosphorus detector. The temperature gradient program results in a run time of 16 min and retention times for meperidine, prilocaine (internal standard), lidocaine, etidocaine, mepivacaine, methadone, and bupivacaine of 3.8, 5.4, 6.0, 8.7, 11.0, 11.7, and 14.8 min, respectively. Standard curves for all drugs were linear over the 80 to 2,000-ng/ml range and recovery of all components averaged 97 +/- 2% with the lowest detection limit of 10 ng/ml for all drugs except meperidine and methadone, which were 20 ng/ml. The within-day coefficients of variation ranged from 12 to 8% at 500 ng/ml. The day-to-day coefficients of variation of the slope and intercept values ranged from 2 to 0% and 130 to 3%, respectively. Response factors of the nitrogen-specific collector varied with the drug analyzed and resulted in peak area variation at constant offset and attenuation of 30%. This method is intended and adequate for therapeutic monitoring of chronically treated pain patients who are being given various combinations of local anesthetic and/or narcotic agents.     

Benzodiazepine inhibition of [3H]flunitrazepam binding and caffeine-induced seizures in mice

The median inhibitory and anticonvulsant potencies of seven benzodiazepine (BDZ) agonists and one BDZ antagonist (Ro15-1788) were established by two tests: inhibition of [³H]flunitrazepam receptor binding and prevention of caffeine-induced seizures in mice. The effect of Ro15-1788 on the anticonvulsant potency of diazepam against caffeine-induced seizures was also investigated. The [³H]flunitrazepam receptor binding inhibitory potencies (IC₅₀s) of the BDZ agonists correlate well with their anticonvulsant potencies (ED₅₀s) against caffeine-induced seizures (r = 0.831; P > 0.01 and < 0.05). Ro15-1788 and clonazepam are the most potent inhibitors (IC₅₀s: 1.72 and 1.75 nM, respectively), but differ markedly in their ability to obtund caffeine-induced seizures (ED₅₀s: 43.2 and 0.226 mg/kg, respectively). Although both Ro15-1788 and diazepam are effective against caffeine-induced seizures, when used in combination Ro15-1788 antagonizes the anti-caffeine effect of diazepam. These data indicate that Ro15-1788 is a BDZ partial agonist with low efficacy as well as a potent antagonist.     

REGIONAL DISTRIBUTION OF 11C-LABELED LIDOCAINE,BUPIVACAINE, AND ROPIVACAINE IN THE HEART,LUNGS, AND SKELETAL MUSCLE OF PIGS STUDIED WITH POSITRON EMISSION TOMOGRAPHY

The regional myocardial uptake and kinetics of ¹¹C-lidocaine, ¹¹C-bupivacaine, and ¹¹C-ropivacaine were examined in the pig, utilizing positron emission tomography to determine whether disproportionate distribution exists among these agents. The three drugs were rapidly distributed to the myocardium and lung with mean peak radioactivities occurring between 0·35 and 0·48 min post-injection in myocardium and 0·35 and 0·65 min in lung. Radioactivities peaked later in skeletal muscle than in the myocardium and lung, occurring between 1·1 and 2·7 min post-end injection. Blood radioactivities for bupivacaine and ropivacaine were significantly higher than those of lidocaine, whereas myocardial, lung, and muscle uptakes for the three agents were not significantly different. Myocardium–blood partition coefficients were similar for bupivacaine and ropivacaine (0·55 and 0·49 respectively), while it was three times higher for lidocaine (1·4). A similar relationship existed for skeletal muscle– and lung–blood partition coefficients. Bupivacaine and ropivacaine t_1/2z in skeletal muscle were significantly longer than those of lidocaine. The results of this study indicate that the increased cardiotoxicity associated with bupivacaine does not appear to be related to disproportionate distribution in the myocardium when compared to lidocaine and ropivacaine. © 1997 by John Wiley & Sons, Ltd.     

The peripheral NK-1/NK-2 receptor antagonist MDL 105,172A inhibits tachykinin-mediated respiratory effects in guinea-pigs

1 Stimulation of sensory nerves causes release of tachykinins, including substance P (SP) and neurokinin A (NKA), which produce a variety of respiratory effects via NK-1 and NK-2 receptors, respectively. Hence, development of a compound which could potently and equivalently antagonize both receptors was pursued. 2 MDL 105,172A ((R)-1-[3-(3,4-dichlorophenyl)-1-(3,4,5-trimethoxybenzoyl)-3-pyrrolidinyl]-4-phenyl-piperidine-4-morpholinecarboxamide) exhibited high affinity for NK-1 (4.34 nm ) and NK-2 (2.05 nm ) receptors. In vitro, the compound antagonized SP (pA₂ = 8.36) or NKA (pA₂ = 8.61)-induced inositol phosphate accumulation in tachykinin monoreceptor cell lines. 3 In anaesthetized guinea-pigs, MDL 105,172A inhibited SP-induced plasma protein extravasation (ED₅₀ = 1 mg kg^?1, i.v.) and [β-Ala⁸]NKA 4–10-induced bronchoconstriction (ED₅₀ = 0.5 mg kg^?1, i.v.) indicating NK-1 and NK-2 antagonism, respectively. 4 Capsaicin was used to elicit respiratory effects in anaesthetized and conscious guinea-pigs; the latter were inhibited by MDL 105,172A following i.v. (ED₅₀ = 1 mg kg^?1) or oral (ED₅₀ = 20 mg kg^?1) adminstration. Hence, MDL 105,172A can inhibit pulmonary responses to tachykinins released endogenously in the airways. 5 At doses up to 200 mg kg^?1, p.o., MDL 105,172A failed to inhibit repetitive hind paw tapping induced by i.c.v. GR 73632, an NK-1 selective agonist, in gerbils, whereas CP-99,994 (0.87 mg kg^?1, s.c.) completely ablated the effect. These data suggest that MDL 105,172A does not penetrate the central nervous system (CNS) and its tachykinin antagonism is restricted to the periphery. 6 MDL 105,172A is a non-peptide, potent, equivalent antagonist of NK-1 and NK-2 receptors. Its ability to inhibit both exogenously administered as well as endogenously released tachykinins support its use in examining the role of sensory neuropeptides in diseases associated with neurogenic inflammation including asthma.     

Development of novel indole‐linked pyrazoles as anticonvulsant agents: A molecular hybridization approach

A series of 3‐{2‐[1‐acetyl‐5‐(substitutedphenyl)‐4,5‐dihydropyrazol‐3‐yl]hydrazinylidene}‐1,3‐dihydro‐2H‐indol‐2‐ones 24–43 was synthesized using an appropriate synthetic route and evaluated experimentally by the maximal electroshock test. These compounds were evaluated for antidepressant and antianxiety activities. The most active compound, 3‐{2‐[1‐acetyl‐5‐(4‐chlorophenyl)‐4,5‐dihydropyrazol‐3‐yl]hydrazinylidene}‐1,3‐dihydro‐2H‐indol‐2‐one 25 , exhibited an ED₅₀ of 13.19 mmol/kg, a TD₅₀ of 43.49 mmol/kg, and a high protective index of 3.29, compared with the standard drug diazepam. To get insights into the intermolecular interactions, molecular docking studies were performed at the active site of the GABA_A receptor and the MAO‐A enzyme. Molecular docking studies are also in agreement with the pharmacological evaluation with potent compounds, exhibiting docking scores of ?1.5180 and 0.7458 for the GABA_A receptor and MAO‐A, respectively. The 3D‐QSAR analysis was carried out by Vlife MDS engine 4.3.1, and a statistically reliable model with good predictive power (r² = 0.7523, q² = 0.3773) was achieved. The 3D‐QSAR plots gave insights into the structure–activity relationship of these compounds, which may aid in the design of potent benzopyrrole derivatives as anticonvulsant agents. So, our research can make a great impact on those medicinal chemists who work on the development of anticonvulsant agents.     

Intramuscular administration of lidocaine or bupivacaine alters the effect of midazolam from sedation to hypnosis in a dose-dependent manner

We examined the sedative/hypnotic interaction between the administration of intravenous (i.v.) midazolam and intramuscular (i.m.) lidocaine or bupivacaine. Women undergoing gynecological surgery (n = 150) were randomly assigned to 15 dose groups of 10 patients each. Fifty patients received one of five predetermined doses of midazolam for the calculation of its median effective dose (ED50). The remaining patients (n = 100) received i.v. midazolam 0.1 mg/kg following an i.m. injection of either bupivacaine, lidocaine, or saline (control). Three minutes after the i.v. dose, the loss of response to verbal command was evaluated. The ED50 of midazolam was 0.226 mg/kg (95% confidence interval [CI] 18-027; p = 0.03). Both bupivacaine and lidocaine enhanced the effect of midazolam in a dose-dependent fashion. The hypnotic ED50 for bupivacaine and lidocaine was 0.7 mg/kg (95% CI 0.5-1.0) and 3.32 mg/kg (95% CI 2.2-11.7), respectively. The slopes of the dose-response curves were significantly different (p < 0.01). Local anesthetics that are well within the range of clinical use for regional blocks or local infiltration can bring the effect of midazolam from the sedative into the hypnotic range.