[Chronic postoperative pain after general anesthesia with or without a single-dose preincisional paravertebral nerve block in radical breast cancer surgery]. / Comparación entre anestesia general con o sin bloqueo paravertebral preincisional con dosis única y dolor crónico postquirúrgico, en cirugía radical de cáncer de mama.

BACKGROUND AND OBJECTIVE: Over 50% of patients still experience pain a year after mastectomy with or without lymphadenectomy. We aimed to determine the association between anesthetic technique, acute postoperative pain intensity, and the development of chronic postoperative pain. PATIENTS AND METHODS: Forty patients were randomly assigned to receive general anesthesia with or without a paravertebral nerve block for modified radical mastectomy. Postoperative pain was assessed on a visual analog scale at 60 minutes and 24 hours; the patients were also asked to respond to a telephone questionnaire on chronic pain 4 to 5 months later. RESULTS: No significant differences in acute pain were observed. Twenty-nine responded to the telephone questionnaire. Only 1 patient in the paravertebral block group reported chronic neuropathic pain and none had phantom breast pain. Only 1 patient (6.7%) in the paravertebral block group reported chronic neuropathic pain and none had phantom breast pain. In the group that received general anesthesia alone, 1 patient reported phantom breast pain and 6 patients had neuropathic pain, associated with phantom breast pain in 2 cases (incidence of chronic pain 50%; P = .01, Fischer exact test; relative risk, 7.5, 95% confidence interval, 1.0-53.5). The incidences of myofascial pain (neck muscle tightness) were similar in the 2 groups. CONCLUSIONS: Four to 5 months after mastectomy, fewer cases of chronic pain developed in the group operated under general anesthesia with a preincisional paravertebral block than in the group that received only general anesthesia, with postoperative morphine chloride for analgesia.

[Acute opiate tolerance and postoperative hyperalgesia after a brief infusion of remifentanil managed with multimodal analgesia]. / Tolerancia aguda a opioides e hiperalgesia postoperatoria tras breve infusión de remifentanilo controlados con analgesia multimodal.

Postoperative analgesia may be complicated by the occurrence of acute opiate tolerance and hyperalgesia. We present the case of a patient who underwent gynecological surgery that was complicated by intense pain in the immediate postoperative period. The pain was attributed to the development of acute opiate tolerance caused by the brief infusion of a high dose of remifentanil. The opiate tolerance was complicated by tactile hyperalgesia at the site of the surgical wound. Pain management with the usual dose of nonsteroidal anti-inflammatory drugs associated with a high dose of morphine (50 mg administered in less than 2 hours) produced no analgesic or adverse effects. The pain was finally brought under control by epidural perfusion of ropivacaine and fentanyl and subsequently maintained with multimodal analgesia.

Effects of cyclooxygenase inhibitor pretreatment on nitric oxide production, nNOS and iNOS expression in rat cerebellum.

1. The therapeutic effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is thought to be due mainly to its inhibition of cyclooxygenase (COX) enzymes, but there is a growing body of research that now demonstrates a variety of NSAIDs effects on cellular signal transduction pathways other than those involving prostaglandins. 2. Nitric oxide (NO) as a free radical and an agent that gives rise to highly toxic oxidants (peroxynitrile, nitric dioxide, nitron ion), becomes a cause of neuronal damage and death in some brain lesions such as Parkinson and Alzheimer disease, and Huntington's chorea. 3. In the present study, the in vivo effect of three NSAIDs (lysine clonixinate (LC), indomethacine (INDO) and meloxicam (MELO)) on NO production and nitric oxide synthase expression in rat cerebellar slices was analysed. Rats were treated with (a) saline, (b) lipopolysaccharide (LPS) (5 mg kg(-1), i.p.), (c) saline in combination with different doses of NSAIDs and (d) LPS in combination with different doses of NSAIDs and then killed 6 h after treatment. 4. NO synthesis, evaluated by Bred and Snyder technique, was increased by LPS. This augmentation was inhibited by coadministration of the three NSAIDs assayed. None of the NSAIDs tested was able to modify control NO synthesis. 5. Expression of iNOS and neural NOS (nNOS) was detected by Western blotting in control and LPS-treated rats. LC and INDO, but not MELO, were able to inhibit the expression of these enzymes. 6. Therefore, reduction of iNOS and nNOS levels in cerebellum may explain, in part, the anti-inflammatory effect of these NSAIDs and may also have importance in the prevention of NO-mediated neuronal injury.

The effect of Enalapril on PGI(2) and NO levels in hypertensive patients.

The effects of the angiotensin-converting enzyme inhibitors (ACEIs), may be partially mediated by the kinins' paracrine influence. Their actions may be exerted through nitric oxide and prostacyclin (PGI(2)) synthesis stimulation. The aim of our study was to determine whether the antihypertensive effect of Enalapril correlated with the increment in the plasmatic levels of NO and PGI(2) in essential moderate hypertensive patients. Normalization of blood pressure was observed in 20 patients, four on the 28th day, 15 on the 42th day and one on the 56th day. Enalapril-respondent subjects showed increased nitrate/nitrite levels on the 14th day (30% increment), on the 28th day (64%), on the 42th day (93.5%) and on the 56th day (96.2%) compared with basal levels, but they did not modify the circulating 6-keto PGF(1 alpha) levels. Four non-respondent patients showed a diminution in nitrate/nitrite and 6-keto PGF(1 alpha) circulating levels along the treatment. We conclude that the administration of 5-30 mg of Enalapril increases circulating NO metabolites in respondent-essential hypertensive subjects. The lack of responsiveness to the treatment may be related to the presence of risk factors such as those linked to an increase of oxidative stress. Finally, we consider that the evaluation of circulating NO may represent a predictive of the response to Enalapril in essential hypertensive patients.

[Effect of nonsteroidal antiinflammatory drugs on colonic lipoxygenase and cyclooxygenase activities from patients with colonic neoplasia]. / Acción de los antiinflamatorios no esteroideos sobre la actividad lipooxigenasa y ciclooxigenasa colónica de pacientes con neoplasia de colon.

Lysine clonixinate (LC) is a nonsteroidal anti-inflammatory drug (NSAID) with good gastrointestinal tolerance. Treatment with LC at levels equivalent to those found in plasma following therapeutic doses resulted in significant inhibition of both cyclooxygenase 2 (COX-2) and production of 5 hydroxy-eicosatetraeonic acid (5-HETE) and slightly affected levels of cyclooxygenase 1 (COX-1) in in vitro studies carried out on human tissues. This study deals with the in vivo effect of the drug on human colon segments. Experiment 1: Five patients about to undergo hemicholectomy due to colon neoplasia were treated preoperatively with a continuous infusion of LC, to achieve a steady-state concentration between 4 and 6 mg/ml. Human colon segments from the five patients and from another five control patients receiving no treatment with [14C]-arachidonic acid were incubated. Human colon segments treated with LC showed significant inhibition of PGE2, the only prostaglandin (PG) synthesised by the tissue, as well as of 5-HETE. Experiment 2: Fifteen patients received an i.v. bolus of LC 100 mg (n1 = 5); LC 200 mg (n2 = 5) or indomethacin (INDO) 50 mg (n3 = 5). Both doses of LC showed greater inhibition of PGE2 synthesis than the INDO bolus. Both NSAIDs studied proved to have different effects on the production of 5-HETE; while treatment with LC elicited significant inhibition, levels with INDO remained unchanged. Western blotting analysis showed expression of both COX isoforms in colon segments, COX-2 levels being 20% higher. Both types of in vivo studies conducted continuous infusion and i.v. bolus, revealed that LC exerted significant inhibition of basal synthesis of PGE2 and 5-HETE.

Antispasmodic/analgesic associations in primary dysmenorrhea double-blind crossover placebo-controlled clinical trial.

We studied 125 patients with primary dysmenorrhea in a prospective randomized double-blind crossover study. After an admission pretreatment period without medication, the patients completed three consecutive randomized treatment phases with lysine clonixinate 125 mg plus propinox 10 mg or paracetamol 500 mg plus hyoscine N-butylbromide 10 mg or placebo, according to a fixed-dose schedule of 1 tablet every 6 h, 3 days before onset of menses and for 5 days thereafter. Changes in menstrual pain intensity and duration, amount of bleeding measured according to the number of daily pads used and concomitant symptoms were assessed on the fifth day of each cycle. Every night, the patients recorded the average intensity of menstrual pain during the first 4 days of menstruation in a diary The follow-up visit carried out at day 5 showed significant reduction in pain intensity with both active treatments vs. the other two phases: baseline: 2.72 +/- 0.61; placebo: 1.85 +/- 0.87; lysine clonixinate plus propinox 1.36 +/- 0.81, and paracetamol plus hyosine N-butylbromide: 1.45 +/- 0.87. The patients' diaries showed increasingly lower pain intensities starting from day 1 with the three treatments. Active treatments revealed significantly higher analgesic efficacy from the outset compared with baseline and placebo; however, only the lysine clonixinate plus propinox combination reached a statistically significant difference by days 3 and 4. No changes in duration or intensity of menstrual bleeding or in the incidence of adverse effects were observed during the four study periods.

[Effects of lysine clonixinate on platelet function. Comparison with other non-steroidal anti-inflammatory agents]. / Acción del clonixinato de lisina sobre la función plaquetaria. Comparación con otras drogas antiinflamatorias no esteroideas.

One of the mechanisms of action of non steroid antiinflammatory drugs (NSAIDs) consists of inhibition of prostaglandin synthesis. This explains many of the pharmacological effects and adverse events observed in medical practice. Administration of NSAIDs to patients with hemostatic disorders or perioperative conditions entails the risk of bleeding due to inhibition of platelet function. This study deals with platelet changes induced by lysine clonixinate vs diclofenac, ibuprofen and aspirin in classical tests such as platelet count, platelet factor 3 (PF3) activity and platelet aggregation with various inductors and more recent procedures such as P-selectin measurement by flow cytometry. Unlike control drugs, lysine clonixinate did not induce changes in platelet count or function when administered to healthy volunteers at the commonly used therapeutic doses.

In vivo and in vitro effects of lysine clonixinate on nitric oxide synthase in LPS-treated and untreated rat lung preparations.

Recent studies have shown that some nonsteroidal antiinflammatory drugs (NSAIDS) inhibited the inducible NO synthase (iNOS) without direct effect on the catalytic activity of this enzyme. This study was conducted to investigate the in vitro and in vivo effects of lysine clonixinate (LC) and indomethacin (INDO) on NOS activity in rat lung preparation. LC is a drug with antiinflammatory, antipyretic, and analgesic action. In the in vitro experiments, rats were injected with saline or lipopolysaccharide (LPS) and killed 6 h after treatment. Lung preparations were incubated with LC at 2.3 x 10(-5) M or 3.8 x 10(-5) M. The minimum concentration did not modify NOS activity in control or LPS-treated rats but the maximum dose inhibited increased NO production induced by LPS. Furthermore, INDO at 10(-6) M had no effect on enzymatic activity in control or LPS-treated rats. In the in vivo experiments, 40 mg/kg of LC were injected ip. Such a dose did not affect basal production of NO. When LC and LPS were injected simultaneously 6 h before sacrifice, a significant decrease in LPS-induced NOS activity was observed. INDO 10 mg/kg injected in control animals had no effect on NOS activity and did not block LPS induced stimulation of NO production when injected simultaneously. Finally, when LC (40 mg/kg) was injected 3 h after LPS, the enzymatic activity remained unchanged. Expression of iNOS was detected by Western blotting in rats treated with LPS plus 4, 10, 20, and 40 mg/kg of LC. The lowest dose was the only one showing no effect on LPS-induced increase of iNOS. In short, LC is a NSAID with inhibitory action on the expression of LPS-induced NOS, effect that was not seen with INDO in our experimental conditions.

Acción del clonixinato de lisina sobre la función plaquetaria. Comparación con otras drogas antiinflamatorias no esteroideas. / [Effects of lysine clonixinate on platelet function. Comparison with other non-steroidal anti-inflammatory agents]

One of the mechanisms of action of non steroid antiinflammatory drugs (NSAIDs) consists of inhibition of prostaglandin synthesis. This explains many of the pharmacological effects and adverse events observed in medical practice. Administration of NSAIDs to patients with hemostatic disorders or perioperative conditions entails the risk of bleeding due to inhibition of platelet function. This study deals with platelet changes induced by lysine clonixinate vs diclofenac, ibuprofen and aspirin in classical tests such as platelet count, platelet factor 3 (PF3) activity and platelet aggregation with various inductors and more recent procedures such as P-selectin measurement by flow cytometry. Unlike control drugs, lysine clonixinate did not induce changes in platelet count or function when administered to healthy volunteers at the commonly used therapeutic doses.

Acción de los antiinflamatorios no esteroideos sobre la actividad lipooxigenasa y ciclooxigenasa colónica de pacientes con neoplasia de colon. / [Effect of nonsteroidal antiinflammatory drugs on colonic lipoxygenase and cyclooxygenase activities from patients with colonic neoplasia]

Lysine clonixinate (LC) is a nonsteroidal anti-inflammatory drug (NSAID) with good gastrointestinal tolerance. Treatment with LC at levels equivalent to those found in plasma following therapeutic doses resulted in significant inhibition of both cyclooxygenase 2 (COX-2) and production of 5 hydroxy-eicosatetraeonic acid (5-HETE) and slightly affected levels of cyclooxygenase 1 (COX-1) in in vitro studies carried out on human tissues. This study deals with the in vivo effect of the drug on human colon segments. Experiment 1: Five patients about to undergo hemicholectomy due to colon neoplasia were treated preoperatively with a continuous infusion of LC, to achieve a steady-state concentration between 4 and 6 mg/ml. Human colon segments from the five patients and from another five control patients receiving no treatment with [14C]-arachidonic acid were incubated. Human colon segments treated with LC showed significant inhibition of PGE2, the only prostaglandin (PG) synthesised by the tissue, as well as of 5-HETE. Experiment 2: Fifteen patients received an i.v. bolus of LC 100 mg (n1 = 5); LC 200 mg (n2 = 5) or indomethacin (INDO) 50 mg (n3 = 5). Both doses of LC showed greater inhibition of PGE2 synthesis than the INDO bolus. Both NSAIDs studied proved to have different effects on the production of 5-HETE; while treatment with LC elicited significant inhibition, levels with INDO remained unchanged. Western blotting analysis showed expression of both COX isoforms in colon segments, COX-2 levels being 20

higher. Both types of in vivo studies conducted continuous infusion and i.v. bolus, revealed that LC exerted significant inhibition of basal synthesis of PGE2 and 5-HETE.

Propinox in intestinal colic: multicenter randomized prospective double-blind study of three doses of propinox vs. placebo in acute intestinal colic pain.

The aim of this double-blind study was to assess the efficacy and tolerability of propinox administered i.v. and to establish a dose-response relationship according to three dose levels (10 mg, 20 mg and 30 mg), vs. placebo in patients with moderate-to-severe acute intestinal colic pain. Four hundred patients (100 per treatment group) were included and allocated to the following treatment groups: propinox 10 mg, 20 mg, 30 mg and placebo. All treatments induced significant and progressive pain reduction as from the 20 min evaluation of 20.3% in the placebo group, 45% in the group treated with propinox 10 mg; 52% in the group receiving propinox 20 mg and 56% in the propinox 30 mg group. Statistical comparison showed differences between placebo and the three active doses as well as between propinox 10 mg and the 20 mg and 30 mg doses. The 20 min evaluation revealed that 40% of patients receiving placebo had to be excluded from the study due to lack of efficacy; the percentage of which was significantly higher compared with those observed with the three doses of propinox ranging between 10% and 13%. The 120 min evaluation revealed that 47.7% of patients treated with propinox 10 mg were free from pain vs. 68.8% and 73.5% of those receiving 20 mg and 30 mg, respectively. These percentages were considerably higher than the 15% found with placebo. Statistical analysis revealed significant differences between the 10 mg vs. the 20 mg and 30 mg groups with not differences between the latter doses. No differences in blood pressure or heart rate were found among treatments. The incidence of mouth dryness was significantly more frequent with the 20 mg and 30 mg doses of propinox than with the placebo or the 10 mg dose.

[Differential action of non-steroidal antiinflammatory drugs on human gallbladder cyclooxygenase and lipoxygenase]. / Acción diferencial de los antiinflamatorios no esteroideos sobre la ciclooxigenasa y lipooxigenasa de vesícula biliar humana.

Lysine clonixinate (LC) is a non-steroidal antiinflammatory agent (NSAID) with only few adverse effects. This characteristic has prompted us to suggest that its administration, at levels equivalent to those found in human plasma following therapeutic doses, slightly inhibits cyclooxygenase I (COX I). Three experiments were performed. Experiment 1: to study the in vitro effect of LC at concentrations of 4 and 6 micrograms/ml, comparable with those found in plasma following an oral therapeutic dose of 125 mg. Gallbladder tissue segments were incubated with 0.25 microCi of 14C-arachidonic acid and the production of prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2 alpha) and 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) was measured. LC did not affect basal production of any of the 3 prostaglandins (PGs) but at 6 micrograms/ml slightly reduced the levels of 5-hidroxyeicosatetraenoic acid (5-HETE). Experiment 2: LC was administered preoperatively to 6 patients by continuous perfusion, to achieve a steady-state concentration between 4 and 6 micrograms/ml. Gallbladder segments from the 6 treated and another 6 control patients were incubated in 14C-arachidonic acid. Gallbladder segments treated with LC did not show a decreased production of any of the three PGs whereas 5-HETE released to the medium was significantly lower. Experiment 3: 18 patients received an i.v. bolus of LC 100 mg (n1 = 6) or LC 200 mg (n2 = 6) or indomethacin (INDO) 50 mg (n3 = 6). Unlike the administration of INDO bolus, LC in the above doses did not inhibit PG synthesis. Both NSAIDs showed different effects when the production of 5-HETE synthesis was assessed. Treatment with INDO did not alter the production of 5-HETE while LC elicited significant inhibition. The three studies conducted, namely in vitro and in vivo continuous perfusion and i.v. bolus, revealed that LC had no effect on prostaglandin synthesis while reducing significantly the levels of 5-HETE.

Acción diferencial de los antiinflamatorios no esteroideos sobre la ciclooxigenasa y lipooxigenasa de vesícula biliar humana. / [Differential action of non-steroidal antiinflammatory drugs on human gallbladder cyclooxygenase and lipoxygenase]

Lysine clonixinate (LC) is a non-steroidal antiinflammatory agent (NSAID) with only few adverse effects. This characteristic has prompted us to suggest that its administration, at levels equivalent to those found in human plasma following therapeutic doses, slightly inhibits cyclooxygenase I (COX I). Three experiments were performed. Experiment 1: to study the in vitro effect of LC at concentrations of 4 and 6 micrograms/ml, comparable with those found in plasma following an oral therapeutic dose of 125 mg. Gallbladder tissue segments were incubated with 0.25 microCi of 14C-arachidonic acid and the production of prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2 alpha) and 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) was measured. LC did not affect basal production of any of the 3 prostaglandins (PGs) but at 6 micrograms/ml slightly reduced the levels of 5-hidroxyeicosatetraenoic acid (5-HETE). Experiment 2: LC was administered preoperatively to 6 patients by continuous perfusion, to achieve a steady-state concentration between 4 and 6 micrograms/ml. Gallbladder segments from the 6 treated and another 6 control patients were incubated in 14C-arachidonic acid. Gallbladder segments treated with LC did not show a decreased production of any of the three PGs whereas 5-HETE released to the medium was significantly lower. Experiment 3: 18 patients received an i.v. bolus of LC 100 mg (n1 = 6) or LC 200 mg (n2 = 6) or indomethacin (INDO) 50 mg (n3 = 6). Unlike the administration of INDO bolus, LC in the above doses did not inhibit PG synthesis. Both NSAIDs showed different effects when the production of 5-HETE synthesis was assessed. Treatment with INDO did not alter the production of 5-HETE while LC elicited significant inhibition. The three studies conducted, namely in vitro and in vivo continuous perfusion and i.v. bolus, revealed that LC had no effect on prostaglandin synthesis while reducing significantly the levels of 5-HETE.

Propinox in biliary colic: a multicenter, randomized, prospective and parallel double-blind study of three doses of propinox versus placebo in acute biliary colic pain.

The aim of this study was to assess the efficacy and tolerance of propinox administered i.v., and establish a dose-response relation according to three dose levels (10, 20 and 30 mg), vs. placebo in patients with moderate to severe acute biliary pain. Three hundred and fifty patients were included: 85 received placebo treatment, 81 were treated with propinox 10 mg, 91 with propinox 20 mg and 93 received propinox 30 mg. Spontaneous pain intensity was assessed according to a visual analog and a verbal scale before treatment and 20, 60 and 120 min after. All treatments induced significant and progressive pain reduction at all controls, but patients treated with 20 and 30 mg of propinox showed significantly lower pain intensity after 120 min compared to the placebo group. The last control revealed that 28% of patients receiving placebo had no pain while 60% of patients treated with propinox 30 mg reported absence of pain with a statistically significant difference (p < 0.001). All treatments were very well tolerated and there were no dropouts due to adverse events. Mouth dryness was the adverse effect occurring with a significantly higher frequency than that observed with placebo although it was only seen in patients treated with 20 mg and 30 mg active doses. The results of this study showed that propinox was an effective drug in the treatment of moderate to severe colic pain of biliary origin. Concerning efficacy and side effects, a clear dose-response relation was observed; the 20 mg and 30 mg doses being significantly superior to placebo.

[Menstrual prostaglandin and dysmenorrhea: modulation by non-steroidal antiinflammatory drugs]. / Prostaglandinas menstruales y dismenorrea su modulación por antiinflamatorios no esteroideos.

The analgesic efficacy and tolerance of lysine clonixinate (LC) as well as LC-induced changes in menstrual prostaglandin levels were studied according to a prospective double-blind randomized crossover design, controlled with ibuprofen (I) and placebo (P). Treatment consisted in 4 consecutive phases: in the first phase, patients refrained from taking medication and during the remaining three phases, they received double-blind fixed doses of 1 tablet of lysine clonixinate 125 mg, I 400 mg or P, q.6 h. at random, three days before onset of menses and during 8 days thereafter. Controls were carried out at each menstrual cycle, assessing pain according to a scale from 0 to 4, onset of premenstrual and intramenstrual symptoms, relief of pain and occurrence of side-effects. During menstruation, patients recorded their assessments of pain in a diary and collected the whole menstrual bleeding during the first three days. The intensity of menstrual pain remained unchanged in controls upon admission (3.16) and during the phase with no treatment (3.04), but was significantly reduced with P (2.4), LC (1.79) and I (1.54). Significantly lower pain intensities compared with placebo were seen with active treatment phases. Forty-two percent of patients treated with P reported premenstrual pain which was significantly reduced to 17% with LC and to 12.5% with I. Active treatment phases revealed 21% of asymptomatic patients during premenstrual and menstrual periods and 71% (LC) and 75% (I) of cases with partial relief of pain. Patients' diaries showed significant pain reductions with LC and I, during the 1st and 2nd days compared with P; such differences were gradually reduced to nil by the 4th day. Levels of menstrual PGs changed according to pain intensity reductions from baseline (P: 29%, (NS); LC: 58% and I: 61%; both were statistically significant, p < 0.01).

Comparison of the isolated human and guinea pig gallbladder strip models in the assessment of antispasmodic drugs.

The objective of this study was to compare the antispasmodic activities of atropine, verapamil, (-)scopolamine n-butyl bromide and propinox in the isolated human and guinea pig gallbladder strip models. Concentration-response curves for each of the agents were obtained in both models following administration of carbachol. Atropine was the only drug to show marked activity in the guinea pig gallbladder model (ED50 = 2.75 x 10(-7) M); the remaining drugs elicited less inhibition of a similar order of magnitude (ED50 = 1.65 x 10(-5), 4.18 x 10(-6) and 2.71 x 10(-5) M for verapamil, [-]scopolamine n-butyl bromide and propinox, respectively). In contrast, results obtained from the human gallbladder strip model revealed differences among the drugs (ED50 = 5.03 x 10(-8), 1.34 x 10(-6), 6.63 x 10(-6) and 5.45 x 10(-5) M for atropine, propinox, verapamil and [-]scopolamine n-butyl bromide, respectively). Based on these results, propinox showed a relative potency in the human gallbladder that was 20.22-fold higher than that in the guinea pig model followed by atropine (5.47-fold) and verapamil (2.49-fold), whereas (-)scopolamine n-butyl bromide was 0.07 times more potent in the guinea pig model. Regression analysis of ED50 values showed a lack of correlation between the two models (r = 0.44). Considering interspecies variations, further studies in human tissues are needed to evaluate the efficacy of antispasmodic drugs.

Antispasmodic action of propinox on the isolated human gallbladder: possible mechanism of action.

Propinox is an antispasmodic drug frequently used in the treatment of disorders of the gastrointestinal tract, the uterus and the gallbladder, but little is known about its relaxing activity in gallbladder tissue. The main objective of this study was to determine the antispasmodic activity of propinox, compared to other antispasmodics, in the gallbladder and to assess its binding affinity to receptor sites which may be involved in its mechanism of action. Antispasmodic activity of propinox, (-) scopolamine-n-butyl bromide, atropine and verapamil was determined in human gallbladders to reduce the risk of interspecies variability. Inhibitory activities (ED50) of carbachol-induced contraction were: atropine 5.03 x 10(-8) M > propinox 1.25 x 10(-7) M > verapamil 6.63 x 10(-6) M > (-) scopolamine-n-butyl bromide 5.4 x 10(-5) M. pD'2 for propinox was 6.94, indicating non competitive inhibition of carbachol action. Radioligand binding studies were performed to determine if the antispasmodic action of the drug involved binding to muscarinic receptors or calciumantagonist sites. The inhibition constant (Ki) of propinox for muscarinic receptors of guinea pig ileum smooth muscle, which contains a mixed M2-M3 receptor population, was 1.6 x 10(-6) M. Ki for brain muscarinic receptors (M1) was 1.0 x 10(-4) M, for cardiac receptors (M2) 1.2 x 10(-6) M and from salivary gland receptors (M3) 1.5 x 10(-6) M. For binding to the dihidropiridine calcium antagonist binding sites, Ki were: 4.9 x 10(-5) M for propinox and 2.2 x 10(-7) M for verapamil. For the phenylalkylamine binding sites Ki were: 5.0 x 10(-6) M for propinox and 3.5 x 10(-8) M for verapamil. For the benzothiacepine binding sites, Ki for propinox was 5.2 x 10(-6) M. The following may be concluded: 1.--The antispasmodic activity of propinox in isolated human gallbladder was comparatively less potent than that of atropine and more potent than those of verapamil and (-) scopolamine-n-butyl bromide. 2.--Propinox showed binding to muscarinic and calcium receptors that can be related to its antispasmodic activity; suggesting that the drug is an antispasmodic with anticholinergic and musculotropic activity. 3.--The dual mechanism of action, anticholinergic and calcium-blocking, would induce synergism of pharmacodynamic effects and minimize adverse events of pure antimuscarinic drugs or calcium antagonists.

Ex vivo effects of lysine clonixinate on cyclooxygenases in rat lung and stomach preparations.

Lysine clonixinate (LC) is an anti-inflammatory, anti-pyretic and analgesic drug with minor digestive side effects, which might suggest a weak COX-1 inhibitor. The aim of this study focused on ex vivo effects of LC 40 mg/kg ip and indomethacin (INDO) 10 mg/kg ip in lung and stomach preparations of control rats and LPS-treated rats (5 mg/kg ip). The non-steroidal antiinflammatory drugs were administered concomitantly, following three hours and before one, two or three hours of LPS treatment. Tissues were weighed and incubated in 2 ml of Kress Ringer Bicarbonate buffer containing glucose (11 mM) under an atmosphere of 95% oxygen and 5% CO(2). Approximately 200 mg of tissue were used for each determination; 0.25 microCi of (14)C-arachidonic acid was added to each tube and the tissues were incubated for 60 min. Prostanoids were extracted from the incubation medium and separated by TLC. Results were expressed as a percentage of the total radioactivity of the plates (% of cpm on plate/100 mg ww). It was found that LC animals that were not given LPS did not modify the synthesis of PGE(2); in lung and stomach tissues showing that did not inhibit COX-1 activity. However, LC inhibited clearly the synthesis of PGE(2) in both preparations obtained from LPS-treated animals. The inhibition was shown when the rats were treated concomitantly, 3 h after or 1 or 2 h before the injection of LPS.