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A pilot double-blind, randomized, placebo-controlled trial of curcumin/bioperine for lung cancer chemoprevention in patients with chronic obstructive pulmonary disease

A pilot double-blind, randomized, placebo-controlled trial of curcumin/bioperine for lung cancer chemoprevention in patients with chronic obstructive pulmonary disease
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  PHARMACOKINETICS AND DISPOSITION  A pilot double-blind randomized placebo-controlled study of molsidomine 16 mg once-a-day in patients suffering  from stable angina pectoris: correlation between efficacy and over time plasma concentrations Received: 28 October 2002/ Accepted: 19 March 2003/Published online: 7 May 2003   Springer-Verlag 2003 Abstract  Objectives : A new once-a-day (o.a.d.) formu-lation of molsidomine (16 mg) was evaluated in pa-tients with stable angina pectoris. The aims were tocharacterize its pharmacokinetics after a single dose,to demonstrate its clinical efficacy and safety versusplacebo and to investigate correlations between phar-macokinetics and pharmacodynamics. Methods : Forty-two patients were recruited in a dou-ble-blind, crossover, randomized placebo-controlledtrial. The pharmacokinetics of molsidomine and SIN-1, its active metabolite, were determined at specifictime points (3, 6, 10, 14, 18, 22 and 24 h) after theadministration of a single dose of molsidomine 16 mgo.a.d. in all patients distributed into seven groups.Twenty-eight of these 42 patients showed a positivebaseline cycloergometric exercise test response duringthe run-in placebo period and were used to comparethe efficacy of molsidomine to placebo. Relationshipsbetween plasma concentration in molsidomine or SIN-1 and ischemic threshold were assessed in 16 of the 28patients with a positive exercise test at baseline. In-deed, the censored variable ischemia-limited toleranceto exercise could not be evaluated in those patientswho did not show exercise-induced ischemia anymoreunder molsidomine 16 mg o.a.d. Pharmacokinetic– pharmacodynamic relationships were evaluated usingregression models and correlation coefficients. Results : The highest average concentration in molsi-domine and SIN-1 occurred after 6 h, then a plateauof 15–20 ng/ml molsidomine and 0.8–3.0 ng/ml SIN-1was maintained for at least 8 h and the mean residualmolsidomine concentration 24 h post-drug intake wasaround 8 ng/ml, still in the effective range of 5–10 ng/ml.A significant increase in total workload (+52 W min, P =0.009), total exercise time (+32 s,  P =0.003) andtime to angina (+25 s,  P =0.016) was measured withmolsidomine 16 mg o.a.d. relative to placebo. Usinglinear regression, significant correlation coefficientswere determined between molsidomine plasma con-centrations (but not SIN-1) and exercise testimprovements (r=0.827,  P <0.001 for the totalworkload; r=0.772,  P <0.001 for the total exercisetime; and r=0.566,  P =0.028 for the time to 1 mmST-segment depression). Conclusion : The pharmacokinetics of molsidomine16 mg in patients with stable angina pectoris is com-patible with a o.a.d. dosage regimen. This o.a.d. for-mulation is effective and well-tolerated, providing a24-h therapeutic control of myocardial ischemia. Apositive and significant linear relationship betweenmolsidomine plasma concentration and the increase inexercise tolerance was observed. Keywords  Molsidomine  Æ  Stable angina pectorisExercise testing Eur J Clin Pharmacol (2003) 59: 227–232DOI 10.1007/s00228-003-0597-z Roger Messin  Æ  Tamas FenyvesiFabienne Carreer-Bruhwyler  Æ  Jacques CrommenPatrice Chiap  Æ  Philippe Hubert  Æ  Claude DuboisJean-Pierre Famaey  Æ  Joseph Ge ´czy R. Messin ( & )  Æ  C. Dubois  Æ  J.-P. Famaey  Æ  J. Ge ´czyTherabel Pharma S.A.,Rue Van Ophem 108,1180 Brussels, BelgiumE-mail: infos@research.therabel.comTel.: +32-2-3704638Fax: +32-2-3704688T. FenyvesiClinic of Internal Diseases III,Semmelweis Medical University,1125 Budapest, HungaryF. Carreer-BruhwylerSquarepoint-Pointcarre S.P.R.L.,Independent Statistical and Medical Writing Center,Rue Joseph Wauters 3,B-7190 Ecaussinnes, BelgiumJ. Crommen  Æ  P. Chiap  Æ  P. HubertDepartment of Analyticaland Pharmaceutical Chemistry,Institute of Pharmacy,University of Lie `ge, Sart-Tilman,4000 Lie `ge 1, Belgium  Introduction Molsidomine, a direct nitric oxide (NO) donor, is usedin the oral treatment of patients with stable anginapectoris. It dilates venous capacitance vessels; conse-quently, it decreases left ventricular filling pressure anddimensions, thus parietal tension, and so reduces myo-cardial oxygen consumption. Moreover, it increasesoxygen supply to the heart through dilating epicardialcoronary arteries, especially at the site of atheromatouslesions [1, 2, 3]. Molsidomine is a prodrug, enzymaticallyhydrolyzed and decarboxylyzed in the liver into its activemetabolite SIN-1, which is subsequently non-enzymati-cally transformed in the bloodstream into the activeintermediate SIN-1A [3]. The latter releases NO (iden-tical to the physiological endothelium-derived relaxingfactor, EDRF) [4, 5, 6] directly into smooth muscle cells,platelets and monocytes, where it activates solubleguanylyl cyclase, responsible for the synthesis of cyclic3 ¢ 5 ¢ -guanosine monophosphate (GMPc) from guanosinetriphosphate. This increase in GMPc is responsible forthe vasodilator, anti-aggregating and anti-adhesiveproperties of molsidomine [5, 6].Oral immediate-release tablets of 2 mg and 4 mg of molsidomine, to be taken three to four times per day,were recommended therapeutically in some Europeancountries from 1977. During the 1980s, 8-mg prolonged-release tablets, to be taken two times per day, were madeavailable in Germany and Belgium [7]. The efficacy andgood tolerability of these molsidomine formulations inthe treatment of patients suffering from stable anginapectoris have been demonstrated [8, 9, 10]. In 1992, thefirst attempt to develop a once-a-day formulation con-taining 24 mg molsidomine failed. Indeed, therapeuticlevels of molsidomine (greater than 5 ng/ml) were notmaintained over 24 h and a second absorption peak wasobserved 15 h after the oral administration [11]. Basedon the application of a controlled-release technology,named Geomatrix (Skyepharma) [12, 13], 16-mg once-a-day (o.a.d.) tablets of molsidomine have recently beendeveloped and registered in Belgium. Molsidomine16-mg o.a.d. tablets consist of a hydrophilic matrix core,containing the active ingredient, and two polymericcoatings applied on both bases of the core. These partialcoatings provide a modulation of the drug dissolutionprofile; they reduce the release rate from the device andshift the typical time-dependent release rate towardconstant drug release [12, 13].A correlation between efficacy and molsidomineplasma concentration has long been demonstrated bothin healthy volunteers and in patients suffering fromcoronary artery diseases (CADs) [3, 14], although it hasnever been possible to demonstrate the same correlationfor the active metabolite SIN-1. The minimum effectivemolsidomine plasma concentration was in a range of 5–10 ng/ml [3, 15].The first objective of the present study was to describethe pharmacokinetics of molsidomine 16 mg o.a.d. inpatients suffering from stable angina pectoris. The sec-ond objective was to assess the efficacy and safety of molsidomine 16 mg o.a.d. over placebo during a global24-h period, after a single-dose administration. The thirdobjective was to try to establish a correlation betweenexercise test (ET) capacity improvement and molsido-mine and/or SIN-1 plasma concentration to end up witha confirmed correlate of protection threshold. Materials and methods PatientsForty-two ambulatory patients, aged 49–73 years (61.5±7.5 years;mean±SD) were enrolled in the study. There were 27 males(64.3%) and 15 females (35.7%). All of them had a documentedhistory of positive ischemic response to the bicycle ergometer ET,i.e., at least 1-mm horizontal or down-sloping ST-segmentdepression below resting level, or 1-mm depression 0.08 s after theJ-point in case of up-sloping ST-segment. Coronary disease wasmoreover documented by a previous angiography or radionuclideexercise scintigraphy, possibly associated with an anamnesis of myocardial infarction, coronary by-pass (CABG) or angioplasty(PTCA) dating back to at least 6 months. Main exclusion criteriawere: unstable angina, history of myocardial infarction, CABG orPTCA inferior to 6 months, heart failure (NYHA II, III or IV),peripheral vascular disease, atrial fibrillation, severe hyper- orhypotension, hypertrophic obstructive or dilated cardiomyopathy,treatment with heparin or sildenafil, major renal or hepatic insuf-ficiency, anemia, hyper- or hypokalemia, significant elevation of cardiac enzymes, diabetes mellitus, any serious concomitant dis-order and history of psychological disorder, mental dysfunction,alcohol or drug abuse.MethodsPatients who were already receiving antianginal medication stop-ped taking it during a 5-day run-in period and for the duration of the study, with the exception of short-acting nitrates for relief of anginal pain. Patients who successfully completed the run-in periodwere submitted to a baseline maximal ET prior to randomization,according to a modified Redwood protocol, load increase being30 Watts every 3 min [16]. A computerized exercise system (GEMarquette Medical System, Milwaukee, WI, USA) was used.Maximum exercise was defined as the point at which exercise wasstopped because of limiting angina, severe breathlessness, fatigue,reach of theoretical maximum heart rate (i.e., 220 beats/min minusage), or safety concerns (ST segment depression >3 mm, fall insystolic blood pressure of >20 mmHg, severe arrhythmia or sig-nificant conduction disturbance).Patients were then included in a double-blind, balanced,crossover, placebo-controlled study design and were allocated totreatment with a single dose of oral molsidomine 16 mg o.a.d. orplacebo, according to a randomization schedule. A 2-day placebowashout period separated the acute administrations of placebo andmolsidomine. A flow diagram of the study design is shown inFig. 1. Total workload (sum of the power in Watts multiplied bytime in min at each work level), total exercise time, time to anginaand time to 1-mm ST-segment depression were calculated andcompared for ETs carried out under active treatment and placebo.Blood samples (10 ml) were taken for determination of molsi-domine and SIN-1. For ethical reasons, to avoid taking too muchblood, subjects were randomly assigned to seven groups, for whichthe intervals between drug administration and determination inplasma were 3, 6, 10, 14, 18, 22 and 24 h, respectively (Table 1).This study was conducted in strict agreement with GCP/ICHrecommendations and local ethics committees gave their approval.228  Power and statistical analysesIt was estimated that a sample size of at least 26 patients with apositive baseline ET would have 90% power to detect a differencein mean total exercise time of 30 s between placebo and molsido-mine 16 mg o.a.d., assuming a standard deviation of differences of about 45 s, using a paired  t -test with a 0.05 two-sided significancelevel. It was therefore decided to recruit a minimum of 39 patients(50% more) in order to be sure to have enough cases with a positivebaseline ET for this placebo-controlled study.An analysis of variance with the factors ‘treatment’, ‘period’and ‘sequence’ as classification criteria was used to evaluate thehypothesis of a possible carry-over effect. The number of patientsbeing borderline for the application of the central limit theorem,comparisons between placebo and molsidomine 16 mg o.a.d. weremade using Student’s paired  t -tests and Wilcoxon’s signed-ranktests simultaneously. The relationship between plasma concentra-tion of molsidomine and SIN-1 and the improvement in exercisetolerance after molsidomine compared with placebo were evaluatedusing linear regressions and Pearson’s correlation coefficients.Other regression models (logarithm, quadratic, cubic, exponentialand logistic) were also used to try to improve fitting. All statisticaltests were two sided with a significance fixed at 5%. The softwareused for all statistical computations was SPSS version 10.Plasma determination methodThe method used for the determination of molsidomine and SIN-1in plasma involved solid-phase extraction on disposable cartridgesthrough automatic sample handling, on-line enrichment of theextracts on a short column, elution of the analytes by the liquidchromatographic mobile phase (0.01 M phosphate buffer, pH 5.0,containing 1 mM 1-octanesulfonate) to the analytical column [17]and subsequent ultraviolet (UV) detection (301 nm and 311 nm).This method, validated according to the GLP (Good LaboratoryPractices) guidelines, was found specific, sensitive, accurate andprecise, with a lower limit of quantification of 2 ng/ml and a lowerlimit of detection of 0.7 ng/ml for both molsidomine and SIN-1.Calibration ranged from 2 ng/ml to 39 ng/ml and intra-assay var-iability from 4.6% to 4.8%. Results Blood sampling was performed from 3 h to 24 h afteradministration of a single tablet of molsidomine 16 mgo.a.d. in a total cohort of 42 patients. Figure 2 showsplasma concentrations of molsidomine and SIN-1 overtimeinthesevenindependentpatientgroups(asdescribedin Table 1). A mean plasma level of 31.1±14.4 ng/mlmolsidominewasobserved3 hpost-drugintake(ingroup1) and the highest average concentration, 34.4±16.4ng/ml, was measured 6 h after the administration (ingroup 2). Thereafter, concentrations decreased slowlyuntil 14 h post-drug intake (in group 4), from where aplateau at concentrations from 20.0±13.4 ng/ml to Table 1  Randomized distribution of patients with stable anginapectoris into seven groups according to time interval between oralintake of a single dose of molsidomine 16 mg once-a-day and bloodsampling and exercise testing.  N  1  total number of patients includedin the study and submitted to determination of molsidomine andSIN-1 in plasma,  N  2  total number of patients with a positivebaseline exercise test used to compare molsidomine to placebo,  n 1 distribution of the N 1  patients into the seven groups,  n 2  distributionof the N 2  patients into the seven groupsGroups N 1 =42 Time of drugintake(hours)Time of bloodsamplingand exercisetesting (hours)Time intervalbetweendrug intakeand bloodsamplingand exercisetesting (h)N 2 =28n 1 , n 2 1 3, 3 0800 1100 +32 3, 2 0800 1400 +63 5, 0 0800 1800 +104 8, 6 2000 1000 next day +145 7, 5 2000 1400 next day +186 8, 7 2000 1800 next day +227 8, 5 0800 0800 next day +24 Fig. 1  Flow chart of the study design.  Continuous line  groups 1–3, dashed line  groups 4–7,  visits 2 and 3  blood sampling formolsidomine and SIN-1 determination,  vertical continuous whitearrow  baseline exercise test,  vertical black arrow  exercise test forgroups 1–3,  vertical dashed white arrow  exercise test for groups 4–7.Drugs are taken on days +1 and +4229  14.3±6.7 ng/ml was maintained during an 8-h period.Finally, a residual mean plasma concentration of 8.0±8.7 ng/ml was still present 24 h after the single doseintake (in group 7) of molsidomine 16 mg o.a.d.For SIN-1, a mean plasma level of 6.8±6.4 ng/mlwas observed 3 h after the administration and thehighest average concentration, 9.3±10.7 ng/ml, wasmeasured 6 h post-drug intake. Thereafter, concentra-tions dropped rapidly (range of 0.8–3.0 ng/ml), valuesbeing sometimes below the quantification limit of 2ng/ml.Of the 42 patients enrolled in the study, 28 showing apositive ET at baseline were included in the according-to-protocol cohort used to compare exercise toleranceafter a single dose of molsidomine 16 mg o.a.d. orplacebo. They were 62.0±7.6 years old, and the mal-e:female sex ratio was 1.8—18 males (64.3%) and10 females (35.7%). They had a mean angina pectorishistory duration of 2.0±2.5 years. The carry-over effectwas non significant ( F  1,26 =0.04,  P >0.05; ANOVA). Astatistically significant increase in total workload(+52 W min,  P =0.009 paired  t -test,  P =0.009 Wilco-xon’s test), total exercise time (+32 s,  P =0.003 paired t -test,  P =0.006 Wilcoxon’s test) and time to angina(+25 s,  P =0.016 paired  t -test,  P =0.017 Wilcoxon’stest) was observed under molsidomine 16 mg o.a.d.relative to placebo. The increase in time to 1 mmST-segment depression (+7 s,  P =0.804 paired  t -test, P =0.484 Wilcoxon’s test) was non-significant (Table 2).The power was of course not sufficient to show astatistical difference at each time point due to the limitednumber of observations; however, the benefit of molsi-domine 16 mg o.a.d. remained measurable and at leastclinically significant even at trough (between 22 h and24 h post-dosing), with a mean increase of 28 W min inthe total workload and of 18 s in the total exercise timerelative to placebo. The overall incidence of adverseevents (AEs) was low: only two patients reported dizzi-ness and headache after molsidomine intake. These AEs,considered as possibly drug related, were mild, neededno corrective action from the investigator and resolvedspontaneously and completely.Relationships between plasma concentration inmolsidomine or SIN-1 and ischemic threshold set up byST-segment depression and/or angina were assessed in16 of the 28 patients with a positive ET at baseline.Indeed, the censored variable ischemia-limited toleranceto exercise could not be evaluated in those patients whodid not show exercise-induced ischemia anymore undermolsidomine 16 mg o.a.d. Strong linear relationshipsbetween efficacy and molsidomine plasma concentrationwere associated with significant positive correlationcoefficients for the total workload (r=0.827,  P <0.001Pearson’s test), total exercise time (r=0.772,  P <0.001Pearson’s test) and time to 1-mm ST-segment depression(r=0.566,  P =0.028). The correlation coefficient wasnon-significant for the time to angina, possibly due tothe fact that the number of observations was limited,time to angina being a censored variable. Figure 3 showsthe relationship between molsidomine plasma concen-tration and improvement in exercise tolerance expressedas the increase in total workload and total exercise time. Fig. 2  Over time, plasmaconcentration of molsidomineand SIN-1 after the oral intakeof a single dose of molsidomine16 mg once-a-day in 42 patientswith stable angina pectoris.Results were given asmeans+SD Table 2  Exercise tolerance after oral intake of a single dose of molsidomine 16 mg once-a-day compared with placebo in the 28 patientspresenting a positive baseline exercise test.  n  total number of patients,  SD  standard deviation,  P  probabilityExercise parameters  n  Placebo Molsidomine 16 mg once-a-day Paired  t -test Wilcoxon’s testMean (SD) Mean (SD)  P  value  P  valueTotal workload (W min) 28 539 (286) 591 (297) 0.009 0.009Total exercise time (s) 28 513 (167) 545 (162) 0.003 0.006Time to angina (s) 12 463 (137) 488 (151) 0.016 0.017Time to 1-mm ST-segmentdepression (s)26 444 (184) 451 (141) 0.804 0.484230  Linear regression equations were y=7.4 · ) 49.6 andy=3.9 · ) 21.2, respectively, for total workload and totalexercise time. According to these regression equations, amean molsidomine concentration of 8.0 ng/ml, as it wasdetected 24 h after a single drug administration, wouldstill induce an average improvement in total workloadand total exercise time of 10 W min and 10 s, respec-tively. Moreover, the minimum molsidomine plasmaconcentrations related to a clinically significantimprovement in ET would be equal to 13.5 ng/ml for anincrease in total workload of about 50 W min and13.1 ng/ml for an increase in total exercise time of about30 s.Non-significant association was found between SIN-1plasma concentrations and improvement in all the ETparameters (data not shown). The other regressionmodels using logarithmic, quadratic, cubic, exponential,or logistic approaches did not improve the fit betweenplasma concentrations and ET improvement. Discussion The pharmacokinetics of molsidomine 16 mg o.a.d.determined in the present study in patients sufferingfrom stable angina pectoris was closely related to thosepreviously observed in young and elderly healthy vol-unteers. This concordance between patients and healthyvolunteers also corroborates other research findings withthe immediate-release formulation of molsidomine [3].Molsidomine 16 mg o.a.d. provides plasma concen-trations over time well suited to the chronic treatment of angina pectoris. A high therapeutic plasma level wasindeed reached 3 h post-drug intake, the highest ave-rage concentration occurring 6 h post-administration.Thereafter, a slow decrease in concentration, followedby the maintenance of an 8-h plateau with therapeuticlevels between 14 ng/ml and 20 ng/ml, should guaranteeoptimal control of myocardial ischemia. Even at trough,i.e., 24 h post-drug intake, the mean residual plasmamolsidomine concentration was 8 ng/ml, which is withinthe range of 5–10 ng/ml, generally considered as stilltherapeutically active [3, 15].The results of this study provide evidence to supportthe clinical efficacy of molsidomine 16 mg o.a.d.: sig-nificant increase in total workload (+52 W min), totalexercise time (+32 s), and time to angina (+25 s)compared with placebo; only the increase in time to1-mm ST-segment depression (+7 s) was not significant.The ET improvement was still measurable and at leastclinically significant at trough (between 22 h and 24 hpost-administration) with a mean increase in totalworkload of 28 W min and in total exercise time of 18 s,which is totally compatible with the residual molsido-mine plasma concentration measured at the same timepoints (8–14 ng/ml).With the immediate-release formulation, a linearcorrelation was previously found between plasma con-centration and efficacy of molsidomine in nine patientswith CAD, ST-segment depression and workload beingused as measures of the pharmacological effects. Thesefindings were confirmed in ten other patients with CAD,in which a clear positive correlation between molsido-mine concentration and clinical effects was observedfollowing administration of molsidomine 4 mg orally orsublingually (subsidence of effort-induced ischemic ST-segment depression) [3]. The results of the present studyconfirm the existence of a significant correlation betweenplasma molsidomine concentration and clinical efficacy.According to linear regressions, the minimum molsido-mine plasma concentrations related to a clinically sig-nificant improvement in ET would be equal to 13.5ng/ml for an increase in total workload of about 50 Wmin and 13.1 ng/ml for an increase in total exercise time Fig. 3  Relationship betweenplasma molsidomine concen-tration and change in totalworkload (W min;  continuousline ,  black squares  and  crosses )and total exercise time (s;  da-shed line ,  white squares  and crosses ) after a single oraladministration of molsidomine16 mg once-a-day comparedwith placebo in patients withstable angina pectoris. Theregression line equations(y=bx+a) and the correlationcoefficients ( r ) were also added.Experimental points with thesame location around the tworegression lines were indicatedby crosses231
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