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.

Effects of lysine clonixinate on cyclooxygenase I and II in rat lung and stomach preparations.

Lysine clonixinate (LC) is a drug of antiinflammatory antipyretic and analgesic activity that produces minor digestive side-effects. This fact induced us to think that LC is possibly a weak COX-1 inhibitor. In order to investigate our hypothesis we inhibited cyclooxygenase activity with LC or indomethacin (INDO) in rat lung and stomach obtained from rats treated with lipopolysacharide (LPS) and control rats. Rat lung preparations incubated with 14C-arachidonic acid synthesise mainly PGE2. LC at 2.5 and 4.1 x 10(-5) M does not modify the basal production of PGE2 (probably COX-1) but at 6.8 x 10(-5) M significantly inhibited PGE2 production (approximately 48.5% inhibition, P<0.001). On the other hand, INDO at 10(-6) inhibited the basal production of PGE2 by around 73%. In LPS-treated rats, the production of PGE2 was significantly higher than in the lungs of control rats, probably due to the induction of COX-2. The addition of LC at 2.7 and 4.1 x 10(-5) M recovered the control values of PGE2 inhibiting, probably only from COX-2 activity. LC at higher concentrations (6.8 x 10(-5) M) and INDO 10(-6) M inhibited PGE2 formed by COX-2 and also partly by COX-1 activity.

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.

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.

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.

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.

Efficacy and tolerance of lysine clonixinate versus paracetamol/codeine following inguinal hernioplasty.

In this study lysine clonixinate, a nonsteroidal antiinflammatory agent with selective inhibition of cyclooxygenase-2 and 5-lipooxygenase in in vitro and in vivo pharmacodynamic studies, was evaluated in a prospective, randomized, double-blind, double-dummy clinical study versus paracetamol/codeine, in 151 patients with pain following inguinal hernioplasty. Patients were treated with one 125 mg tablet of lysine clonixinate or paracetamol/codeine (500 mg + 30 mg) administered at fixed doses every 4 h during 2 days. Controls were carried out 1, 2 and 4 h after the first intake of day 1 and day 2. Each control included assessment of pain at rest, when coughing, sitting and upon moderate pressure. Both treatment groups (lysine clonixinate, 77 patients and paracetamol/codeine, 74 patients) were comparable in terms of demographic and baseline pain intensities. Spontaneous pain was reduced significantly in both treatment groups from the 1st-h control. The following values were recorded in the lysine clonixinate group during day 1: baseline: 6.86 +/- 1.24; 1st h: 4.49 +/- 1.77; 2nd h: 2.96 +/- 1.74; 4th h: 2.23 +/- 1.51. The following values for the same group during day 2 were: predose: 1.70 +/- 1.64; 1st h: 1.16 +/- 1.17; 2nd h: 0.78 +/- 1.06; 4th h: 0.63 +/- 1.05. The paracetamol/codeine group revealed the following values: day 1: baseline: 6.72 +/- 1.22; 1st h: 4.57 +/- 1.72; 2nd h: 2.97 +/- 1.68; 4th h: 2.47 +/- 1.68 and day 2: predose: 2.02 +/- 1.57; 1st h: 1.32 +/- 1.23; 2nd h: 0.82 +/- 0.99; 4th h: 0.66 +/- 0.89. Reduction of pain induced by coughing, sitting and pressure showed similar behavior patterns. No significant differences between both treatment groups were encountered in terms of analgesic efficacy. Incidence of adverse effects was significantly higher in the paracetamol/codeine group (X2: p < 0.05): 11 out of 74 patients; three patients had to discontinue treatment. In the lysine clonixinate group four out of 77 patients showed side effects but these did not require treatment discontinuation.

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.

Lysine clonixinate in minor dental surgery: double-blind randomized parallel study versus paracetamol.

Lysine clonixinate (LC), an effective and well tolerated non-morphinic analgesic whose mechanism of action is basically due to the inhibition of cyclo-oxygenase, was assessed with a double-blind randomized dummy design versus paracetamol (P) on 200 patients suffering from pain after minor dental surgery. Patients received according to their needs 1 or 2 tablets of 125 mg lysine clonixinate or 500 mg paracetamol every 8 h during 48 h or until pain relief. Both groups, each composed of 100 patients, were comparable in terms of demographic conditions (t test), initial symptoms (chi-square test), characteristics of the extracted dental pieces, surgical complications and wound treatment (chi-square test). Pain intensity scores and daily average intake of tablets (3.4/day) documented in the patients' diary revealed no statistically significant differences between the two treatments (chi-square test). It was found that spontaneous pain measured using a visual analogue scale (VAS) decreased significantly in both treatment groups at the 24-h control examination. The following values were observed in the LC group: baseline 4.38 +/- 1.7; 24-h * 1.20 +/- 1.4; 48-h * 0.36 +/- 1.2. In the P group the values were: baseline 4.28 +/- 1.6; 24-h * 1.11 +/- 1.4; 48-h * 0.30 +/- 0.7 (*p < 0.05). Other variables like facial swelling and night pain, evaluated on a score from 0 to 4 and symptom presence or absence respectively, showed a similar response.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effect of lysine clonixinate and indomethacin on lipoxygenase and cyclooxygenase activity in colon isolated from cancer patients]. / Efecto del clonixinato de lisina y la indometacina sobre la actividad de la lipooxigenasa y la ciclooxigenasa de colon aislado de pacientes con neoplasias.

The non-steroidal anti-inflammatory drugs (NSAIDS) induced ulcerations in the gastrointestinal tract are possibly associated with the reduction in prostaglandin (PGs) synthesis due to the inhibition of cyclooxygenase. On the other hand, it has been shown that 5-lipooxygenase products (5-LO) are ulcerogenic agents. In some cases, the utilization of NSAIDS stimulates 5-LO pathway to an excess of arachidonic acid because of cyclooxygenase inhibition. In these cases, the damage produced by NSAIDS is greater, since not only the cytoprotective PGs decrease but also the products of 5-LO are increased. The object of the present paper was to study the effects of lysine clonixinate (LC) and indomethacin (INDO) on PGs and 5-HETE synthesis. The concentrations used of LC (4 and 6 micrograms/ml) and INDO (0.035 micrograms/ml and 0.35 micrograms/ml) correspond to the plasmatic values reached with oral therapeutic doses for both drugs. The results show that in no case did LC reduce the production of PGE2. On the contrary INDO inhibited significantly the synthesis of PGe2. It is interesting to mention that LC 4 and 6 micrograms/ml inhibited drastically the production of 5-HETE. Only with the higher concentration of INDO did we observe a similar effect. These results may indicate an inhibitory action on 5-LO, the first enzyme in the metabolic pathway of arachidonic acid in the production of HETEs and LTS. We conclude that LC in therapeutic doses has a mechanism of action different from the classical NSAIDS. The data obtained in this study could explain the low incidence in gastrointestinal lesions with LC.

[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).

[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.

[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.

[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.

Lysine clonixinate vs. paracetamol/codeine in postepisiotomy pain.

This study was conducted to compare the analgesic action of Lysine Clonixinate (LC) vs Paracetamol/Codeine association (PC) in the treatment of postepisiotomy pain in primiparae women: 131 primiparous patients with moderate-to-severe postepisiotomy pain were enrolled in a double blind dummy design study and randomly allocated to either treatment with fixed doses of LC 125 mg or Paracetamol 500 mg+Codeine 30 mg 6 qh during 24 hours. Intensity of spontaneous pain and pain on walking was assessed according to a visual analog scale (VAS) and patient's assessment before receiving treatment and after 1, 2, 6 and 24 hours. Intensity of spontaneous pain was reduced in 24 hours from 4.28 +/- 2.11 to 1.73 +/- 1.46 (P < 0.0001) in the LC group and from 4.78 +/- 2.08 to 1.90 +/- 1.72 in the PC-treated group (p < 0.0001); with no significant differences between treatments. 54% of the patients treated with LC and 55% of those receiving PC showed onset of analgesic action 30 minutes following dose administration. Patient's final global assessment revealed that 95% of LC-treated patients and 96% of the PC group showed total or partial pain relief during the first treatment day. No sleep disturbances were seen during the night in 75% of patients. Only one patient receiving LC showed nausea not requiring treatment discontinuation. It is concluded that both treatments are equally effective to relieve moderate-to-severe postepisiotomy pain.

Lysine clonixinate in the treatment of primary dysmenorrhea.

The efficacy and tolerance of Lysine Clonixinate (LC), a NSAID with prostaglandin synthesis inhibiting mechanism was studied in 24 patients with primary dysmenorrhea according to a double-blind randomized crossover Placebo (P) controlled design with patients serving as their own controls. Treatment consisted in administering 1 tablet of LC or P q6h as from onset of menstrual pain during 5 days and 6 menstrual cycles. Patients were controlled monthly as from the 5th day of the cycle, rating changes in pain intensity according to a 4-point scale, presence of pain during pre-, post- and menstrual periods; possible intracycle changes, amount of bleeding, tolerance and related total and general signs and symptoms. Intensity of baseline menstrual pain amounted to 2.9. Menstrual, intramenstrual and postmenstrual pains were observed in 19 out of 24, 24/24 and only 2 out of the 24 patients, respectively. Concomitant symptoms consisted in headache (12), mastalgia (14) and discomfort (12). Results were obtained by averaging the data from the treatment periods with each drug. Menstrual pain was reduced from 2.9 +/- 0.7 to 1.9 +/- 0.7 with P administration and to 0.66 +/- 0.4 with the administration of LC, a highly significant difference between treatments (p < 0.0001). Premenstrual pain was reduced nonsignificantly from 0.79% to 0.58% with P administration and significantly to 0.29% with administration of LC (p < 0.001). Intramenstrual pain affecting all patients at baseline was reduced significantly by 9% with P and also significantly by 50% with LC (p < 0.001). No differences were encountered in concomitant symptoms during P treatment periods while the incidence was significantly reduced with LC (p < 0.0001). No changes in cycle duration or amount of bleeding were observed between treatments. No adverse events were reported.