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Biomedical subjects

A Marzo

Publications and source records attributed to A Marzo.

At least 19 recordsLinked to original sources
PubMed2001

Organ-specific regulation of the CD8 T cell response to Listeria monocytogenes infection.

The intestinal mucosal CD8 T cell response to infection with Listeria monocytogenes was measured using MHC class I tetramers and was compared with the response in peripheral blood, secondary lymphoid tissue, and liver. To assess the vaccination potential of Listeria and to analyze responses in C57BL/6 mouse strains, a recombinant Listeria expressing OVA (rLM-ova) was generated. The response peaked at 9 days postinfection with a much larger fraction of the intestinal mucosa and liver CD8 T cell pool OVA specific, as compared with the spleen. However, these differences were not linked to bacterial titers in each site. The higher responses in lamina propria and liver resulted in a larger CD8 memory population in these tissues. Furthermore, the level of memory induced was dependent on infectious dose and inversely correlated with the magnitude of the recall response after oral challenge. Recall responses in the tissues were most robust in the lamina propria and liver, and reactivated Ag-specific T cells produced IFN-gamma. Infection of CD40- or MHC class II-deficient mice induced poor CD8 T cell responses in the intestinal mucosa, but only partially reduced responses in the spleen and liver. Overall, the results point to novel pathways of tissue-specific regulation of primary and memory antimicrobial CD8 T cell responses.

Administration, Oral↗
PubMed2001

Absorption of calcium administered alone or in fixed combination with vitamin D to healthy volunteers.

Calcium supplementation is widely used in deficiency status and as an adjuvant in the treatment of osteoporosis. As usual with endogenous substances, the calcium absorption, distribution and elimination processes are strictly controlled by homeostatic equilibria. Free calcium ion is the most representative active fraction of the circulating ion. Ion excretion is controlled by a saturable tubular reabsorption process which leads to a renal threshold. Cumulative urinary excretion of calcium is the end-point of absorption, distribution and elimination processes, and is thus a good indicator of bioavailability. In order to increase the oral bioavailability of calcium, the ion is administered in association with vitamin D, which is known to enhance intestinal calcium absorption. The aim of this study was to evaluate the absorption of calcium administered alone and in fixed combination with cholecalciferol (vitamin D3, CAS 67-97-0). In accordance with the study protocol, calcium carbonate (CAS 471-34-1; 1500 mg = 600 mg as calcium ion) was administered as such (reference) and associated with cholecalciferol (400 IU) (test) for four days (2 doses/day) to 18 healthy male volunteers in a sequential pattern, namely reference followed by test. Urinary excretion of total calcium, and serum concentration of free and total calcium, 25-OH-vitamin D3 and parathyroid hormone were carefully analysed the day before (baseline) and on the 4th day of dosing, with validated methods. The effect of cholecalciferol in promoting calcium absorption was clearly observed from urinary excretion of total calcium, which with the test treatment showed a 16.6% increase in excretion (p = 0.025) compared with the reference treatment. The mean excretion values on the 4th day, expressed in mg, were 238.85 and 204.83 with test and reference respectively. Moreover, the results demonstrated an increased serum concentration of both free and total calcium after dosing with test and reference by comparison with the baseline situation. The area under the serum concentration-time curve of total calcium increased from day -1 to day 4 from 550.98 to 575.90 mg l-1 h with test and from 543.03 to 568.16 mg l-1 h with reference. Similarly, ionised calcium increased on day 4 with both the treatments. Parathyroid hormone showed the expected typical decreasing behaviour after dosing with the test and reference drugs. The results of this study suggest that calcium carbonate is absorbed through the intestine when administered either alone or in association with cholecalciferol. Cholecalciferol, however, showed the typical expected activity in promoting calcium absorption, which was evident from the cumulative urinary excretion of the ion. To the authors' knowledge, this study is the first published paper demonstrating the absorption and pharmacodynamic effect of short-term administration of vitamin D associated with calcium at the doses recommended for supplementation in a fixed-combination pharmaceutical product.

Adolescent↗
PubMed2000

Assay of zofenopril and its active metabolite zofenoprilat by liquid chromatography coupled with tandem mass spectrometry.

Zofenopril is a pro-drug designed to undergo metabolic hydrolysis yielding the active free sulfhydryl compound zofenoprilat, which is an angiotensin converting enzyme (ACE) inhibitor, endowed also with a marked cardioprotective activity. A simple, highly sensitive specific LC-MS-MS method was developed for the determination of zofenopril and zofenoprilat in human plasma. In order to prevent oxidative degradation of zofenoprilat and its internal standard, their free sulfhydryl groups were protected by treatment with N-ethylmaleimide (NEM), which produced the succinimide derivatives. The compounds and their corresponding fluorine derivatives, used as internal standards, were extracted from plasma with toluene. The reconstituted dried extracts were chromatographed and then monitored by a triple-stage-quadrupole instrument operating in the negative ion spray ionization mode. The method was validated over the concentration range of 1-300 ng/ml for zofenopril and 2-600 ng/ml for zofenoprilat. Inter- and intra-assay precision and accuracy of both zofenopril and zofenoprilat were better than 10%. The limit of quantitation was 1 ng/ml with zofenopril and 2 ng/ml with zofenoprilat. Extraction recovery proved to be on average 84.8% with zofenopril and 70.1% with zofenoprilat. Similar recoveries were shown by the above two internal standards. The method was applied to measure plasma concentrations of zofenopril and zofenoprilat in 18 healthy volunteers treated orally with zofenopril calcium salt at the dose of 60 mg.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

Bioequivalence of endogenous substances facing homeostatic equilibria: an example with potassium.

Oral administration of endogenous substances in most cases results in negligible net increases in baseline plasma concentrations, associated with high variability. This poses the problem of their bioequivalence. Using the data obtained from a bioequivalence investigation of potassium aspartate (test vs reference formulation), the authors demonstrate the inconsistency of bioequivalence based on plasma concentrations and standard methods. Potassium aspartate was given orally at a dose of 15.8 mmoles to 12 healthy volunteers as test and reference values according to a two-period, two-formulation, two-sequence design. The individual net values of the area under the curve of plasma concentration (AUC) and cumulative urinary excretion (CUE), both obtained with the test formulation as post-dose minus baseline, were multiplied by 2, 3, 4, 5 and 6 and added to the baseline in order to simulate the administration of increasing single doses of the test, assuming dose-linear kinetics. Data generated with the test formulation were compared with original data of the reference according to 90% confidence intervals. With AUC, bioequivalence of test and reference formulations was demonstrated with 1 : 1, 2 : 1 and 3 : 1 test to reference dose ratios. With CUE only the 1 : 1 dose ratio comparison produced bioequivalence. The authors conclude that bioequivalence of endogenous substances conducted with standard procedures in most cases is a useless exercise. With potassium and more generally with drugs cleared via urine, urinary excretion would reflect the extent of absorption more faithfully than AUC.

Adult↗
PubMed2000

Pharmacokinetics of diclofenac after oral administration of its potassium salt in sachet and tablet formulations.

This paper reports the results of a pharmacokinetic study involving 24 healthy volunteers and designed to characterise the rate and extent of diclofenac absorption after the administration of a single dose of diclofenac (CAS 15307-86-5) potassium salt 50 mg in sachet (Voltfast) and tablet (Cataflam) formulations. Timed plasma concentrations of diclofenac during a 12-h-period after dosing were measured by means of HPLC with UV detection at 275 nm and a quantification limit of 10 ng/ml; the method was fully validated for pharmacokinetic purposes. These plasma concentrations were used to calculate Cmax, tmax, trapezoidal AUC0-t and AUC0-infinity and t1/2 by means of noncompartmental analysis. Cmax and tmax are the parameters expressing the rate of absorption, whereas the AUCs reflect the extent of absorption. The rate of absorption with the sachets proved to be very fast, reaching peak values at 10 min in seven subjects and at 15 min in the remaining subjects: mean time was 13.68 min, with concentrations at 5 min being 38% of Cmax. The average time to peak concentration with the tablets was 53.10 min. The extent of absorption of the sachets and tablets was similar, with AUC0-infinity values of respectively 1362 and 1214 ng.ml-1.h, and a 90% confidence interval 1.05-1.20. The highly soluble potassium salt of diclofenac was rapidly absorbed, especially in its sachet formulation, and thus appears to be an invaluable analgesic agent that is particularly useful for quick pain relief.

Administration, Oral↗
PubMed2000

Bioequivalence of inhaled formoterol fumarate assessed from pharmacodynamic, safety and urinary pharmacokinetic data.

This paper deals with a crossover trial on healthy volunteers performed to obtain combined pharmacodynamic, safety and pharmacokinetic data in order to assess the bioequivalence of formoterol fumarate (CAS 43229-80-7) delivered by mono-dose dry powder inhalers, as test and reference. The trial was carried out on 24 Caucasian healthy male and female volunteers treated with 12 micrograms formoterol fumarate bihydrate capsules for inhalation route. Pharmacodynamics was evaluated through a challenge test with methacholine on the forced expiratory volume in 1 s (FEV1). Safety was achieved from glucose and potassium serum levels assayed on timed samples over a 12-h period cost-dosing and from blood pressure, heart rate and ECG recording. Pharmacokinetics was obtained from urinary excretion of formoterol, assessed by a highly sensitive analytical method (LC-MS-MS). Pharmacodynamic, safety and pharmacokinetic results evidenced the bioequivalence of the two formulations investigated. This investigation is an interesting approach how to assess bioequivalence when the classical approach based on the similarity of plasma concentrations can not be applied.

Administration, Inhalation↗
PubMed2000

Amlodipine bioequivalence achieved with a very sensitive liquid chromatography tandem mass spectrometric bioassay.

Amlodipine (CAS 88150-42-9) is a 1,4-dihydropyridine derivative, one of the most widely used drugs for the management of essential hypertension. In developing manidipine (CAS 120092-68-4), a new antihypertensive drug, amlodipine was selected as the reference comparator drug in a Phase III double blind clinical trial. However, manidipine is formulated in hard gelatin capsules, whereas amlodipine is presented as a tablet. In order to respect the double blind design of the study, it was necessary to insert the amlodipine tablet into hard gelatin capsules matching those of the new test product. This called for an amlodipine bioequivalence study on two halves of one tablet inserted into a capsule (test formulation) and two halves of one tablet ingested as such (reference formulation). The bioequivalence trial was carried out on 18 healthy volunteers (9 males and 9 females). Subjects were administered a single 10 mg dose of test and reference products according to a two-treatment, two-period, two-sequence crossover design, with a wash-out period of three weeks. Plasma concentrations of the parent compound were monitored over a period of 6 days, considering the long half-life of amlodipine. The drug was quantified with a very sensitive, robust bioassay, which was set up and validated in our laboratory. Peak concentration and area under the curve of plasma concentrations were log-transformed and analyzed to obtain 90% confidence intervals which proved to be 0.94-1.06, and thus within the acceptable bioequivalence range of 0.80-1.25. Time to peak, analyzed according to a non-parametric test, did not show any statistically significant difference between the test and reference. Both the test and reference products showed a similar and very good safety profile. The conclusion is that one amlodipine tablet broken into two halves and administered as such (reference formulation) is bioequivalent with one amlodipine tablet broken into two halves and encapsulated (test formulation).

Adult↗
PubMed2000

Comparative bioavailability of two formulations containing atenolol and chlortalidone associated in a 4:1 fixed combination.

Atenolol (CAS 29122-68-7) and chlortalidone (CAS 77-36-1) are marketed associated in a 4:1 strength ratio (100/25 and 50/12.5 mg) for the treatment of hypertension. According to EU guidelines, the bioequivalence of one dosage strength can also cover additional strengths when the pharmacokinetics of a given drug is linearly related with the dose. The kinetics of atenolol is linearly correlated with the dose and chlortalidone has linear kinetics with doses < or = 100 mg. Thus this trial carried out on the 100/25 mg strength also covers the 50/12.5 mg strength. The trial was carried out on 18 healthy volunteers (9 males and 9 females) according to a single dose, two-period, two-treatment, two-sequence study design with washout. Timed atenolol plasma concentrations and chlortalidone blood concentrations were used to assess primary pharmacokinetic parameters Cmax, tmax and AUC extrapolated to infinity by a non-compartmental model. The bioavailability of the two formulations was compared through the 90% confidence intervals (C.I.) of Cmax and AUC in accordance with operating guidelines. C.I. of chlortalidone were fully comprised in the 0.80-1.25 range. In the case of atenolol, which displayed a higher data dispersion, C.I. were comprised in the enlarged 0.70-1.43 range. Time to peak, tmax, did not show any statistically significant difference between the test and reference product with respect to both analytes. Pharmacodynamic measurements of the decrease in systolic blood pressure led to fully overlapping results with test and reference. The authors conclude that the test formulation should be considered bioequivalent with the reference with chlortalidone and in the borderline of bioequivalence with atenolol. As no safety problems were involved and pharmacodynamics led to overlapping results as between test and reference, the bioequivalence conclusion could be extended also to atenolol.

Adrenergic beta-Antagonists↗
PubMed1999

Highly sensitive bioassay of lidocaine in human plasma by high-performance liquid chromatography-tandem mass spectrometry.

A very sensitive HPLC-tandem mass spectrometric (LC-MS-MS) method for assaying lidocaine in human plasma was set up and fully validated. Lidocaine and an internal standard (bupivacaine) were extracted from 1 ml of alkalinized plasma with tert.-butylmethyl ether, back-extracted to a H3PO4 acidified solution and injected into a C18 column. Acetonitrile-26 mmol/l ammonium acetate, pH 4.5 (70:30, v/v) was the mobile phase at a flow-rate of 1 ml/min. The effluent was detected by PE Sciex API 365 LC-MS-MS system in positive ion mode. Ionisation was performed using an atmospheric pressure chemical ionization ion source operating at 400 degrees C. The multi reaction monitoring transition 235-->86 was monitored. Linearity was ascertained in the 0.2-30 ng/ml range with a limit of quantitation of 0.2 ng/ml. Intra- and inter-assay precision and accuracy were < or =3.8%. The high sensitivity and specificity achieved by the method allowed concentrations of lidocaine to be measured in plasma of healthy subjects topically treated with lidocaine (5% ointment) on normal skin over a 32-h period after dosing.

Administration, Topical↗
PubMed1999

Bioequivalence of levothyroxine tablets administered to a target population in steady state.

Two parallel trials were carried out with levothyroxine sodium salt in 50 and 100 microg strengths, respectively, giving 100 microg day-1(50x2 microg day-1 or 100x1 microg day-1) in both trials in a repeated dose regimen. Twenty patients suffering from primary hypothyroidism under treatment with 100 microg day-1 of thyroxine sodium salt were enrolled in each trial. They were clinically and chemically euthyroid. Each trial lasted 114 days, with 57 days being devoted to the first treatment (test or reference) and 57 days to the other (reference or test), according to a two-period, two-sequence, two-formulation design in a steady state without wash-out. The test formulation was prepared with a technological improvement and is being produced to replace that at present on the market. Serum concentrations of free and total levothyroxine, and free and total levotriiodothyronine were assayed repeatedly during the treatment and in timed samples after the last dose of each formulation, using radioimmunoassays. Cmax and AUCss,tau were considered to be target parameters for bioequivalence which was assessed through 90% confidence intervals in the 0.80-1.25 range, as required by EU and US FDA operating guidelines. The results have shown that of these hormones, the free and total parent compound thyroxine is that which most clearly showed a peak after dosing, whereas its metabolite, free and total triiodothyronine, fluctuated around pre-dose concentrations. Bioequivalence was fully assessed with Cmax and AUCss,tau, with all four hormones tested and at both strengths administered. The two test formulations in 50 and 100 microg are thus bioequivalent with the two reference preparations. Tolerability was very good in all cases.

Adult↗
PubMed1999

Open questions on bioequivalence: some problems and some solutions.

This paper focuses on some specific situations where bioequivalence requires careful attention and tailored protocols in order to overcome intrinsic difficulties either marginally covered or fully neglected by operating guidelines. Some problems congregate with serious difficulties, namely high variability, very poorly absorbed drugs and endogenous substances with their own baseline. With endogenous substances, the dilemma faced is whether to subtract baseline from post-dose values in assessing bioequivalence. Either approach has intrinsic problems and is somewhat puzzling. In an attempt to resolve other existing problems, the most appropriate approach should be selected on a case-by-case basis, ensuring that the adopted procedure does not conflict with operating guidelines and scientific literature on the matter. Problematic cases include the management of trials with a predominant active metabolite, the absence of a reliable analytical bioassay, the availability of various strengths of the same drug on the market, a wide acceptability titre range, the management of studies on topical drugs that are devoid of systemic activity, the management of drugs that cannot be given for ethical reasons to healthy subjects or that may cause adverse events, especially when a steady state design is required. The parallel group study design appears to be more appropriate than the cross-over or the individual bioequivalence design in assessing drugs with a long half-life. Some pharmacokinetic and statistical analysis-related issues are also discussed such as the sequence/period interaction sometimes encountered in these trials, which, in the absence of the carry-over effect, does not bias the bioequivalence results and the need to process data with non-compartmental pharmacokinetic analysis.

Biopharmaceutics↗
PubMed1999

Experimental, extrapolated and truncated areas under the concentration-time curve in bioequivalence trials.

OBJECTIVE: The extrapolated area under the concentration-time curve (AUC0-infinity) for any drug is considered by operating guidelines as the primary parameter related to the extent of absorption in single-dose bioavailability and bioequivalence trials. Not more than 20% should be added to the experimental AUC (AUC0-t) in the extrapolating procedure. However, in certain specific cases, it is problematic and, in other cases, impossible to respect the above requirement. It was intended to demonstrate that truncated AUC or AUC0-t would be used in bioequivalence trials when the AUC cannot be extrapolated. METHODS: AUC0-t and truncated AUC were compared at various time intervals with AUC0-infinity in a series of 19 single-dose bioequivalence trials covering 15 different drugs, each carried out on 12-24 healthy volunteers. Point estimators and 90% confidence intervals in the 0.80-1.25 and 0.70-1.43 ranges were statistically processed using log-transformed parameters. RESULTS: In all the trials considered, overlapping point estimators and 90% confidence intervals were invariably obtained, regardless of the AUC used. CONCLUSION: The use of AUC0-t or truncated AUC may be considered an ancillary procedure in bioequivalence trials when AUC cannot be extrapolated. This occurs with most extended-release formulations, endogenous substances, and poorly absorbed drugs. It also occurs in trials with one or more poor metabolisers, with drugs possessing very long elimination half-lives, and with bioassays having problems of sensitivity that preclude sufficiently precise plasma concentration measurement over the required sampling period.

Anticarcinogenic Agents↗
PubMed1999

Pharmacokinetics and pharmacodynamics of zofenopril in healthy volunteers.

This study was carried out to investigate the pharmacokinetics of zofenopril (CAS 81938-43-4) and zofenoprilat, the behaviour of the angiotensin converting enzyme (ACE) (pharmacodynamics) following the administration of zofenopril calcium at the single oral dose of 60 mg in eighteen healthy volunteers. This open label, one-way study was carried out in a single centre on 18 healthy volunteers. The volunteers received an oral single 60 mg dose of zofenopril calcium following an overnight fast. The tablet was swallowed with 250 ml of water. Fasting continued for additional 4 h after dosing and no other liquid intake was allowed from 1 h before to 2 h after administration. Plasma concentrations of zofenopril and its active metabolite zofenoprilat as well as serum ACE activity were measured before drug intake (baseline) and on timed samples over a 36 h period after dosing by LC-MS-MS, a highly sensitive, validated method for active moiety concentrations. Peak plasma concentration was reached on average at 1.19 h with zofenopril and at 1.36 h with zofenoprilat. Concentrations then decreased reaching values under or close to the limit of quantitation (1 ng.ml-1 for zofenopril, 2 ng.ml-1 for zofenoprilat) from 8 to 16 h after dosing. Complete inhibition of ACE was seen at the first blood sampling time (1 h) and lasted on average up to 9.44 h. ACE activity then slowly reactivated, but enzyme inhibition continued and was estimated to be 74% and 56% at 24 and 36 h following drug administration, respectively. From these data a complete or almost complete enzyme inhibition is expected with zofenopril given in repeated dose regimen.

Adult↗
PubMed1998

Chromatography as an analytical tool for selected antibiotic classes: a reappraisal addressed to pharmacokinetic applications.

The first antibiotic discovered, penicillin, appeared on the market just after the Second World War. Intensive research in subsequent years led to the discovery and development of cephalosporins, aminoglycosides, tetracyclines and rifamycin. The chemotherapeutic quinolones and the more recently discovered fluoroquinolones have added promising new therapeutic weapons to fight the microbial challenge. The major role pharmacokinetics has played in developing these compounds should be highlighted. Plasma concentration-time profiles and the therapeutic activity evoked by these compounds allow the therapeutic window, doses and dose turnovers to be appropriately defined as well as possible dose adjustment to be made in renal failure. The pharmacokinetics of antimicrobial agents were initially explored by using microbiological methods, but these lack specificity. The HPLC technique with UV, fluorometric, electrochemical and, in some cases, mass spectrometry detection has satisfactory solved the problem of antimicrobial agent assay for pharmacokinetic, bioavailability and bioequivalence purposes alike. Indeed, in these studies, plasma concentrations of the given analyte must be followed up for a period > or = 3 times the half-life, which calls for specific sensitive assays. In the review, the authors have described the analytical methods employed in the pharmacokinetics of antibiotics, including some chemotherapeutic agents which are used in medical practice as alternatives to antibiotics. The pharmacokinetic characteristics of each class of drugs are also briefly described, and some historical and chemical notes on the various classes are given.

Animals↗
PubMed1998

Acceptable and unacceptable procedures in bioavailability and bioequivalence trials.

Both the US FDA and EU guidelines recommend fundamental procedures for bioavailability and bioequivalence studies. The use of unacceptable procedures in conducting these studies can in fact complicate drug development at NDA or ANDA levels. The most common unacceptable procedures are as follows: the use of compartmental analysis in calculating Cmax, tmax and AUC, which must be evaluated with the non-compartmental approach in pivotal studies; the need to use only homogeneous concentrations in pharmacokinetic analysis, and to avoid using the sum of various individual concentrations, e.g. parent drug plus metabolite(s); the need to consider plasma clearance in evaluating absolute bioavailability with dose-dependent kinetics; the need to use the simultaneous fitting procedure when drugs and metabolite(s) are considered; the unacceptable procedure of either disregarding some experimental data or adding simulated data in pharmacokinetic and statistical analysis; and the use of the additive model rather than the multiplicative procedure in assessing bioequivalence with Cmax and AUC. This paper describes in detail acceptable and unacceptable procedures in bioavailability and bioequivalence studies, covering operating guidelines and principles of pharmacokinetics. (c) 1998 The Italian Pharmacological Society.

Biological Availability↗
PubMed1998

[What model for pharmacokinetic analysis of tissue distribution and bioequivalence?].

Pharmacokinetic analysis of experimental data is usually carried out through two different approaches: non compartmental model or standard compartmental models. Benefits and restrictions of these two approaches are here discussed, with attention to the studies of clinical pharmacokinetics and, particularly, to those of bioavailability and bioequivalence. In fact, different opinions about the most appropriate model to be used with these studies were encountered. Besides, the paper deals with European and American guidelines, data from a check of the literature published during 1995 on two international journals of clinical pharmacology and results of non-compartmental and non-linear fitting analyses on plasma concentrations obtained with an oral administration of a delayed dosage form in humans.

Area Under Curve↗
PubMed1998

Bioavailability, food effect and tolerability of S-naproxen betainate sodium salt monohydrate in steady state.

S-Naproxen betainate sodium salt monohydrate (naproxen-beta Na, CAS 104124-26-7, Aprenin) in 550 mg capsules (corresponding to 327 mg of naproxen) was administered to 24 healthy volunteers (12 males and 12 females) b.i.d. to steady state in order to check its bioavailability, food interaction and tolerability. Plasma concentrations of naproxen were measured by a well validated HPLC method with fluorimetric detection as a morning pre-dose on days 1 to 6 and in timed samples in three different situations, as follows: a) after the morning dose on day 7 in a fasting status, b) after the evening dose and dinner on day 7 and c) after the morning dose of day 8, taken after a high-fat content breakfast. Pharmacokinetic parameters were evaluated from plasma concentrations by non-compartmental analysis to describe the above three situations. The steady state was reached early, namely by the second day of treatment. The extent of absorption did not differ in the three situations tested, whereas the rate of absorption was fastest in fasting conditions, lowest with the evening dose and intermediate after the high-fat content breakfast. The slow absorption rate of the evening dose was attributed to a circadian rhythm and should allow therapeutically active levels early in the morning, when arthritis pain is particularly tedious. In the three situations explored Cmax, Cmin and AUC were associated with CV % values ranging from 11.7 to 17.2%, which are very low and rare in pharmacokinetic trials. This low variability should allow an accurate estimate of the therapeutic effect expected. Tolerability was checked by objective and subjective symptoms, including vital signs, blood/urine biochemical parameters and occult blood in stools, and proved to be very good. From the comparison of these data with those previously published by other authors who have administered 500 mg of naproxen b.i.d., pre-dose concentrations in a steady state proved to be similar, despite the different doses administered, whereas Cmax and AUC obtained in this study were marginally lower. The kind of food interaction was the same as previously described in literature with naproxen.

Adolescent↗