The control of prescription drug advertising: a controversial issue.
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Advertising↗
Biomedical subjects
P Jaillon
Publications and source records attributed to P Jaillon.
Simultaneous determination of the five HIV-protease inhibitors: amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir in human plasma by solid-phase extraction and column liquid chromatography.
A sensitive and selective liquid chromatographic assay has been developed for the determination of the five protease inhibitors currently approved by the Food and Drug Administration (FDA) (amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir) in a single run. Pretreatment of a 1-mL plasma sample spiked with internal standard was made by a solid-phase extraction procedure using a polymeric reversed-phase sorbent. Liquid chromatography was performed using a narrowbore C18 reversed-phase column and gradient elution. A double ultraviolet detection at 265 nm (amprenavir) and at 210 nm (indinavir, nelfinavir, ritonavir, saquinavir and internal standard) was used. Calibration curves were linear in the range 25-10000 ng/mL and the assay has been validated over the range 25-5000 ng/mL. Average accuracy at four concentrations was in the range of 100.5-104.2% and 96.9-100.5% for within-day and between-day, respectively. The coefficients of variation were less than 10%. Mean absolute recoveries varied from 85.4% (ritonavir) to 98.8% (saquinavir). No metabolite of the protease inhibitors was found to coelute with the drugs of interest or with the internal standard. At this time, among the tested drugs, especially all the presently licensed nucleoside and nonnucleoside reverse transcriptase inhibitors that can be used in combination with the protease inhibitors, none was found to interfere with the assay. This method is now in use in the authors' laboratory for the therapeutic monitoring of the HIV-protease inhibitors.
Carbamates↗
Pharmacokinetic and pharmacodynamic drug interactions between digoxin and macrogol 4000, a laxative polymer, in healthy volunteers.
AIMS: The aim of this study was to examine the bioequivalence between a single oral dose of digoxin administered alone and with a coadministration of macrogol 4000 (a laxative polymer) in 18 healthy volunteers. METHODS: This was an open, randomised, two-way cross-over study, with a single dose oral administration of 0.5 mg digoxin administered alone or in combination with macrogol 4000, 20 g day-1 during 8 days. Pharmacokinetics of digoxin, heart rate and PR ECG interval at rest were assessed. RESULTS: Macrogol 4000 coadministration was associated with a 30% decrease of digoxin AUC and a 40% decrease in its Cmax (P<0.05). Digoxin tmax and t1/2,z were not significantly altered. Heart rate and PR interval did not differ during the two therapeutic sequences, digoxin alone and digoxin in combination. CONCLUSIONS: Macrogol 4000 coadministration interacts with single-dose digoxin pharmacokinetics. This is most likely due to a reduction of the intestinal absorption of digoxin. However, there was no consequence of this interaction on heart rate and AV conduction.
Adult↗
Electrophysiological effects of cetirizine, astemizole and D-sotalol in a canine model of long QT syndrome.
Observations of torsades de pointes during therapy with terfenadine and astemizole has raised concern about the cardiac safety of non-sedating H1-antagonist agents. We compared cetirizine, another compound of that class, to D-sotalol and to astemizole in a model of acquired long QT syndrome. Open-chest surgery was performed in adult beagle dogs anaesthetized with halothane and thiopental. Bradycardia was produced with beta-adrenergic blockade and sinus node crush. Four left ventricular intramyocardial unipolar monophasic action potentials (MAP) were recorded during atrial pacing at basic cycle lengths (BCL) 400-1500 msec, before and during three successive 1-h drug infusions (0.14, 0.45 and 1.4 mg/kg/h for astemizole and cetirizine and 1.1, 2.2 and 4.5 mg/kg/h for D-sotalol). Dose- and bradycardia-dependent prolongations of MAP duration (MAPD) were produced by D-sotalol (P < 0.001) and astemizole (P < 0.001) but not by cetirizine. At BCL 1500 ms, the three infusions of astemizole prolonged endocardial MAPD from 323 +/- 8 msec (mean +/- SE) at baseline to 343 +/- 10, 379 +/- 13 and 468 +/- 26 msec, respectively (n = 9). Sotalol prolonged that MAPD from 339 +/- 6 msec to 377 +/- 7, 444 +/- 15 and 485 +/- 24 msec (n = 7). In contrast, cetirizine did not prolong MAPD: 341 +/- 8 msec at baseline Vs 330 +/- 8, 324 +/- 9 and 323 +/- 11 msec (n = 9). Drug-induced increase in transmural dispersion reached +79 +/- 19 msec after astemizole, +59 +/- 21 msec after D-sotalol and only +7 +/- 11 msec after cetirizine. Runs of ventricular tachycardias and torsades de pointes occurred during dose three of astemizole (5/9 dogs) and D-sotalol (4/7 dogs) but never during cetirizine. In the present model, astemizole and D-sotalol but not cetirizine prolonged MAPD and transmural dispersions of repolarization and produced torsades de pointes. These results suggest that the halothane-anaesthetized bradycardic dog could be a valuable model to discriminate drugs for their class III effects and proarrhythmic potencies.
Action Potentials↗
Determination of acyclovir in plasma by solid-phase extraction and column liquid chromatography.
After oral administration, valacyclovir, the L-valyl ester of acyclovir, converts to the antiherpes virus drug, acyclovir. The bioavailability of acyclovir after valacyclovir administration is between 3- to 4.5-fold higher than that achieved after oral acyclovir administration. Therefore, despite the drug's short terminal half-life (3 hours), acyclovir plasma concentrations obtained after oral administration of the prodrug offer a more convenient dosage regimen in patients with herpes zoster than that required after acyclovir administration. Acyclovir is also used for viral infection prophylaxis in patients with hematologic disorders and in those who have undergone solid organ transplantation. We have described a simple and selective liquid chromatographic method for the determination of acyclovir in plasma using a new polymeric reversed-phase sorbent for solid-phase extraction. A mean acyclovir absolute recovery of 90% was found after elution of the drug from the cartridge with the mobile phase. This procedure allowed us to measure 62.5 ng/mL of acyclovir with an acceptable precision using a plasma volume of 250 microL, and no drug was found to interfere with the assay. This method is suitable for the therapeutic monitoring of acyclovir in patients who have been given a wide variety of coadministered drugs.
Acyclovir↗
Improved sensitivity of digoxin assay by modification of the EMIT 2000 method.
A modified EMIT 2000 digoxin assay was developed on the Cobas Mira plus analyzer for the determination of very low plasma concentrations of the drug. The major modifications were a higher plasma volume withdrawn during the analysis step and calibration curves constructed in the range 0-2 ng/ml using calibrators made up with biological matrix. Assays were controlled with an internal, four-level quality control (targets: 0.15; 0.60; 1.70; 2.70 ng/mL). The within-day and day-to-day mean observed values +/- SD (n = 10) of these quality controls were 0.14 +/- 0.02 and 0.15 +/- 0.02 ng/mL; 0.57 +/- 0.01 and 0.64 +/- 0.03 ng/mL; 1.55 +/- 0.06 and 1.62 +/- 0.04 ng/mL, 2.82 +/- 0.09 and 2.82 +/- 0.12 ng/mL, respectively. The detection and the quantification limits were 0.02 and 0.08 ng/mL, respectively. No significant difference was observed between digoxin plasma concentrations measured by the original and the modified EMIT 2000 digoxin assay in 25 plasma specimens, ranging from 0.4 to 3.0 ng/mL, from patients receiving the drug. This modified digoxin EMIT 2000 assay was subsequently used to study digoxin pharmacokinetics after each of 18 healthy volunteers was administered a single 0.5 mg oral dose. The pharmacokinetic parameters found in this study were in accordance with the literature in healthy subjects, using radioimmunoassay (RIA) for digoxin plasma concentration determinations. In conclusion, the lower limit of quantification of this modified EMIT 2000 digoxin assay is similar to that of RIA and can serve as a valuable screen for digoxin pharmacokinetic interactions studies.
Cardiotonic Agents↗
Determination of indinavir in plasma by solid-phase extraction and column liquid chromatography.
Indinavir is a specific and potent HIV protease inhibitor. A new column liquid chromatographic method for the determination of this drug is described. This assay was developed for the clinical monitoring of trough concentrations in AIDS patients, using a 1-mL plasma sample volume. Determination of indinavir was made by a rapid solid-phase extraction procedure with the new polymeric Oasis HLB sorbent followed by a reversed-phase liquid chromatography and a UV detection at 210 nm. A weighted least squares linear regression (weighting factor = 1/y where y = peak height ratio) was used to calculate the equation relating the peak-height ratio of the drug and the internal standard to the concentration of indinavir in the range 10-800 ng/mL (0.014-1.124 microM). At the lower limit of quantification (10 ng/mL), the mean accuracy was 102 +/- 7% and 104 +/- 11% for within- and between-day analysis, respectively. The limit of detection, based on a signal-to-noise ratio of 2:1, was 4 ng/mL (0.006 microM). Compounds of interest were eluted from the extraction cartridges with 300 microL of mobile phase, and mean absolute recoveries of indinavir and internal standard were 66.4% and 80.3%, respectively. No metabolite of indinavir was found to co-elute with the drug or its internal standard. Among the tested drugs, especially nucleoside analogues and the other protease inhibitors used in clinical care, none was found to interfere with the assay at this time. This simple and selective method is suitable for therapeutic indinavir monitoring.
Anti-HIV Agents↗
Effects of cigarette smoking on short-term variability of blood pressure in smoking and non smoking healthy volunteers.
The present trial was planned to study the effects of smoking on short-term variability of blood pressure and on haemodynamic parameters after an overnight cessation and after one day of repeated smoking in healthy cigarette smoking volunteers, compared to a control group of non-smokers who were not asked to smoke. 40 healthy male volunteers, 20 smokers and 20 non-smokers, participated in an open study with two period of measurements over a single day (morning and afternoon). Blood pressure and heart rate were measured using standard and finger recordings over 6 min before and 10 min after smoking one cigarette (in smokers only). During the two periods, smokers were asked to smoke 4 cm of a cigarette containing 1 mg of nicotine in 2 min, and a blood sample was taken for a plasma nicotine assay. In the smoking group, smoking the first cigarette of the day caused a significant increase of systolic blood pressure (+7%), diastolic blood pressure (+10%) and heart rate (+25%). The blood pressure variability in the frequency range of the Mayer waves (66-129 mHz) was increased after an overnight cessation of smoking in the smoking group in comparison to the non-smokers, and decreased significantly after the first cigarette of the day (7.1 +/- 4.0 to 3.2 +/- 1.8 mmHg2; P < 0.01). The changes observed in the afternoon after continuous smoking were significantly less important (3.8 +/- 1.9 to 3.2 +/- 1.9 mmHg2; NS). In the non-smoking group, the different parameters remained stable between the different measurements. These results suggest that an overnight cessation of smoking in smoking subjects is associated with a increase in sympathetic activity to the vascular system in the morning, which is released by smoking the first cigarette. This effect of smoking is reduced in the afternoon after a continuous nicotinic impregnation.
Adult↗
Mibefradil, a potent CYP3A inhibitor, does not alter pravastatin pharmacokinetics.
Dramatic drug-drug interactions have been observed between several HMG-CoA reductase inhibitors and cytochrome P450 3A (CYP3A) inhibitors. The aim of the present study was to investigate the effects of mibefradil, a potent CYP3A inhibitor, on pravastatin pharmacokinetics. 12 healthy volunteers were included in this open-label one-period study. Pravastatin pharmacokinetics (following a single oral dose of 40 mg) was studied in the absence of mibefradil (day 1) and after repeated doses (100 mg/day) of mibefradil (day 8). Pravastatin pharmacokinetics after repeated doses of 40 mg/day was also studied in association with repeated doses (100 mg/day) of mibefradil (day 16). Pravastatin area under the plasma concentration vs. time curve (AUC0-infinity) and Cmax in the absence of mibefradil on day 1 (170 [117 to 395] ng h/mL and 91 [72 to 200] ng/mL respectively, geometric mean [95% confidence intervals]) were not significantly altered in the presence of mibefradil on day 8 (224 [174 to 381] ng h/mL and 124 [72 to 200] ng/mL) and on day 16 (200 [137 to 555] ng h/mL and 91 [74 to 184] ng/mL). Tmax of pravastatin in the absence of mibefradil (0.9 +/- 0.1 h, arithmetic mean +/- SD) was slightly delayed in the presence of mibefradil on day 8 and 16 (1.1 +/- 0.3 and 1.2 +/- 0.3 h respectively, p < 0.01 for both comparisons). The results of the present study confirm the lack of pharmacokinetic interactions between mibefradil and pravastatin and indicate that pravastatin may be safely prescribed in the presence of potent CYP3A inhibitors.
Adult↗
Cytochrome P-450 3A4 and 2C8 are involved in zopiclone metabolism.
Zopiclone is a widely prescribed, nonbenzodiazepine hypnotic that is extensively metabolized by the liver in humans. The aim of the present study was to identify the human cytochrome P-450 (CYP) isoforms involved in zopiclone metabolism in vitro. Zopiclone metabolism was studied with different human liver microsomes and a panel of heterologously expressed human CYPs (CYP1A2, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, and 3A4). In human liver microsomes, zopiclone was metabolized into N-desmethyl-zopiclone (ND-Z) and N-oxide-zopiclone (NO-Z) with the following K(m) and V(m) of 78 +/- 5 and 84 +/- 19 microM, 45 +/- 1 and 54 +/- 5 pmol/min/mg for ND-Z and NO-Z generation, respectively. Ketoconazole (CYP3A inhibitor) inhibited approximately 40% of the generation of both metabolites, sulfaphenazole (CYP2C inhibitor) inhibited the formation of ND-Z, whereas alpha-naphtoflavone (CYP1A), quinidine (CYP2D6), and chlorzoxazone (CYP2E1) did not affect zopiclone metabolism. The generation of ND-Z and NO-Z were highly correlated to testosterone 6beta-hydroxylation (CYP3A activity, r = 0.95 and 0.92, respectively; p =.0001), and ND-Z was highly correlated to CYP2C8 activity (paclitaxel 6alpha-hydroxylase; r = 0.76, p =.004). Recombinant CYP2C8 had the highest enzymatic activity toward zopiclone metabolism into both its metabolites, followed by CYP2C9 and 3A4. CYP3A4 is the major enzyme involved in zopiclone metabolism in vitro, and CYP2C8 contributes significantly to ND-Z formation.
Azabicyclo Compounds↗
[Drug-induced hepatic diseases].
The contribution of drugs to hepatic disorders, long viewed as insignificant, is now widely recognized. Advances have been made over the last few years in our understanding of the mechanisms underlying drug-induced hepatic injury. Conversion of drugs to toxic or reactive metabolites has been demonstrated. Drugs can induce the full range of hepatic disorders, and the diagnostic approach is the same as for the other causes of liver disease. The evaluation of the hepatotoxicity of drugs requires use of available classification schemes for assigning causal relationships with drugs. Over 1000 drugs have been incriminated in the occurrence of hepatic lesions. Hepatox is a computerized database that has become vital to the storage of new information. Part of the contents of the Hepatox database is presented in this article.
Chemical and Drug Induced Liver Injury↗
[Drug-induced liver injury. Twelfth updated edition of the bibliographic database of liver injuries and related drugs].
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Chemical and Drug Induced Liver Injury↗
Pharmacokinetic-pharmacodynamic modeling of the effects of ivabradine, a direct sinus node inhibitor, on heart rate in healthy volunteers.
OBJECTIVE: Ivabradine (S-16257) is a new bradycardic agent with a direct effect on the sinus node. Its N-dealkylated metabolite, S-18982, has shown a bradycardic activity in animals. The aim of this trial was to study the correlation between drug bradycardic activity and plasma levels of the parent compound and its metabolite in healthy volunteers. METHODS: Eighteen healthy volunteers participated in three successive study periods: an oral double-blind period with two parallel groups of doses (10 or 20 mg, single and repeated); a 10 mg intravenous bolus open period; and a final control period. The effects of ivabradine on heart rate were studied at rest and during bicycle exercise tests (at 85% of maximum workload) during 24-hour postdosing, and ivabradine and S-18982 plasma levels were determined simultaneously. RESULTS: The maximal reductions of exercise heart rate were 11% +/- 4% (10 mg) and 18% +/- 6% (20 mg) after single oral doses (p < 0.05) and 18% +/- 4% (10 mg) and 27% +/- 6% (20 mg) after repeated doses (p < 0.01). Maximum heart rate reduction after the intravenous bolus was 19% +/- 4%. After oral administrations an indirect relationship between the bradycardic effect and the plasma concentrations of the two compounds was found. A pharmacokinetic/pharmacodynamic population analysis done with the NONMEM computer program showed that S-18982 contributes in part to the overall activity of ivabradine: modeling suggested that the metabolite is responsible for the initial bradycardic effect, whereas the parent compound is responsible for the duration of action. CONCLUSION: This study shows that ivabradine exerts a dose-dependent bradycardic effect and that its N-dealkylated metabolite contributes to this bradycardic effect.
Adult↗
Use of heterologously expressed human cytochrome P450 1A2 to predict tacrine-fluvoxamine drug interaction in man.
The aim of the present study was to evaluate the use of recombinant human cytochrome P-450 1A2 (rH-CYP1A2) in studies performed in vitro in order to predict metabolic drug-drug interactions occurring in man. In vitro metabolism of tacrine (a CYP1A2 probe) in the presence and absence of fluvoxamine, a CYP1A2 inhibitor, was investigated in human liver mircrosomes and with different rH-CYP. Vmax, Km and Ki determined with human liver microsomes were compared with those observed using rH-CYP1A2, assuming that 1 mg of liver microsomes contains, on average, 69 pmol of CYP1A2. The extent of tacrine metabolism inhibition procured by fluvoxamine with rH-CYP1A2, was compared with previous results observed in man. The Vax and Km for 1-hydroxytacrine formation rates obtained with rH-CYP1A2 were in good agreement with those observed in human liver microsomes (175+/-9 versus 140+/-60 pmol/min/mg for Vmax and 14+/-2 versus 16+/-2 microM for Km, respectively. The Ki of fluvoxamine on 1-hydroxytacrine formation rate observed with rH-CYP1A2 was similar to that observed with human liver microsome (0.35+/-0.05 versus 0.20+/-0.20 microM, respectively). Using the Km, Vmax and Ki determined with rH-CYP1A2, we calculated that fluvoxamine produced an inhibition of 1-, 2- and 4-hydroxytacrine formation rate of 91, 87 and 88%, respectively, in the range of tacrine and fluvoxamine concentrations observed in man. These percentages of inhibition calculated in vitro were in agreement with the percentage of fluvoxamine-dependent decrease in tacrine apparent oral clearance previously observed in man (83+/-13%). We conclude that human CYP1A2 expressed in yeast is a powerful tool to predict and to quantify drug-drug interactions in man.
Antidepressive Agents, Second-Generation↗
[Drug-induced hepatotoxicity. Eleventh update of the bibliographic database on liver injuries and responsible drugs].
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Chemical and Drug Induced Liver Injury↗
Prognostic value of bisoprolol-induced hemodynamic effects in heart failure during the Cardiac Insufficiency BIsoprolol Study (CIBIS).
BACKGROUND: To further evaluate the mechanism of beta-blocker-induced benefits in heart failure, the relationships between bisoprolol-induced hemodynamic effects and survival were studied during the Cardiac Insufficiency BIsoprolol Study (CIBIS). METHODS AND RESULTS: In 557 patients studied, bisoprolol significantly reduced heart rate (-16.3+/-15.3 versus -1.6+/-13.4 bpm, respectively; P<.001) compared with placebo at 2 months after inclusion in the study. Heart rate change over time had the highest predictive value for survival (P<.01). Left ventricular fractional shortening (LVFS) significantly increased in the bisoprolol group compared with the placebo group 5 months after inclusion (+0.04+/-0.06 versus -0.001+/-0.05, respectively; P<.001; n=160). LVFS change over time was also significantly correlated with further survival (P<.02 by Cox analysis). Using a nonparametric approach, we demonstrated a significant interaction between study treatment group and LVFS over time. Patients who demonstrated improvement of LVFS over time (82% and 51% of patients in the bisoprolol and the placebo groups, respectively; P<.02) were at lower risk, but the hazard did not further decrease with a further increase of fractional shortening, and there was no significant difference between study treatment groups. Finally, it could be demonstrated that each of the three factors (heart rate change over time, LVFS change over time, and bisoprolol treatment) made a specific contribution to mortality rate. CONCLUSIONS: Preservation of left ventricular function appears to play a key role in the bisoprolol-induced beneficial effects on prognosis in heart failure. Short-term beta-blocker-induced cardiac effects could provide a means to identify those patients who will experience improved survival over the long term.
Adrenergic beta-Antagonists↗
Influence of the CYP1A2 inhibitor fluvoxamine on tacrine pharmacokinetics in humans.
OBJECTIVE: Tacrine is extensively metabolized by cytochrome P4501A2 (CYP1A2). Fluvoxamine, a potent CYP1A2 inhibitor, may be coadministered with tacrine. The aim of this study was to examine the influence of fluvoxamine administration on the disposition kinetics of single-dose tacrine administration. METHODS: Thirteen healthy volunteers participated in this double-blind, randomized crossover study, which compared the effects of fluvoxamine (100 mg/day during 6 days) and placebo on the pharmacokinetics of a single oral dose of tacrine (40 mg). RESULTS: Fluvoxamine caused a significant increase in tacrine area under the plasma concentration versus time curve (AUC): arythmetic mean, 27 (95% confidence interval [CI], 19 to 38) ng.hr/ml versus 224 (95% CI, 166 to 302) ng. hr/ml. Fluvoxamine caused a decrease in the apparent oral clearance of tacrine from 1683 +/- 802 to 200 +/- 106 L/hr (mean +/- SD), which was explained by a decrease in its nonrenal clearance. Five subjects had gastrointestinal side effects during fluvoxamine administration. Fluvoxamine administration was associated with significant increases in the plasma AUC values of three monohydroxylated tacrine metabolites and in the total urinary recovery measurements of tacrine and its metabolites (9.1% +/- 4.6% versus 24.0% +/- 2.6% of recovery). These results may be attributable to fluvoxamine-dependent inhibition of CYP1A/, which is responsible of the biotransformation of tacrine into its monohydroxylated metabolites and further into dihydroxylated and reactive metabolites. CONCLUSION: Fluvoxamine inhibits the metabolism of tacrine. CYP1A2 may be the target of this inhibition. Fluvoxamine may modulate the hepatotoxicity of tacrine, depending on the relative contribution of tacrine and its reactive metabolites to this toxicity.
Adult↗
Repeatability of spectral components of short-term blood pressure and heart rate variability during acute sympathetic activation in healthy young male subjects.
1. Changes in the low-frequency (LF) components of blood pressure and heart rate variability and in the ratio of LF to high-frequency (HF) components of heart rate variability (LF/HF ratio) are used to assess acute changes in sympathetic control of blood pressure or heart rate and in sympathovagal balance that occur in response to physiological or pharmacological stimuli. Before these spectral indexes can be used to assess the effects of drug therapy or other clinical interventions on reflex sympathetic activity, their repeatability must be evaluated. 2. Intra-observer repeatability was studied by analysing changes in the LF components (expressed as absolute or normalized units) of cardiovascular variability and in the LF/HF ratio during sympathetic activation induced by nitroglycerin infusion (n = 10 subjects) or 60 degrees head-up tilt (n = 13 subjects) repeated on two occasions, 2 days and 1 week apart respectively, in healthy young male volunteers. Repeatability was estimated as recommended by Bland and Altman. 3. Bland and Altman's plots of the repeatability of changes in the LF components and LF/HF ratio showed that measurements were sufficiently repeatable to be used over periods of time of up to 1 week in clinical studies. 4. The sample-size tables derived from our results show that expression of spectral components as normalized units, and use of a cross-over design, minimize the number of subjects to be included in clinical studies conducted using similar designs and LF component changes as endpoints.
Adult↗