[Hemolytic uremic syndrome as a complication of gemcitabine treatment: report of six cases and review of the literature]. / Syndrome hémolytique et urémique secondaire à la gemcitabine: à propos de six observations et revue de la littérature.

UNLABELLED: Hemolytic uremic syndrome is a rare condition during gemcitabine therapy. METHODS: We report six new cases of hemolytic uremic syndrome related to gemcitabine, three issued from a retrospective study of 136 consecutive patients treated with gemcitabine for which a systematic screening of this side effect has been performed and 29 cases with clinical data available identified in the literature in order to better characterised frequency and clinical presentation of this side effect. RESULTS: In our series, frequency of HUS is 2.2% and is higher than this previously reported (0.015%) or estimated with the data of clinical trials analysed (0.072 %). For 35 cases with clinical data available, the patients were always treated for a local advanced and/or metastatic disease. For our cases and for literature cases, at the time of diagnosis of hemolytic uremic syndrome, mean number of doses received (mean+/-standard deviation. Minimum/maximum)) (personal cases: 26.5+/-6.6. 16/36, literature cases: 21+/-11. 8/54), cumulative dose received (g/m2) (personal cases : 24.5+/-6.3. 16/31.6, literature cases: 21.7+/-12.4. 2.4/54) and duration of treatment (months) (personal cases: 8.2+/-1.9. 5.6/11, literature cases: 8.5+/-4.0. 3/18) are very closed and high individual variations observed for these factors are not consistent with a time and/or dose dependant toxicity. New-onset hypertension or exacerbation of underlying hypertension is the most common clinical manifestation, with mild anemia; thrombocytopenia is inconstant. The degree of severity of renal failure is highly variable. The existence of subacute clinical form with progressive worsening of the symptoms and biological form at the time of diagnosis suggest the interest of a systematic clinical and biological screening of this side effect, before each injection of gemcitabine. Early prognosis is linked to the evolution of hemolytic uremic syndrome and after hemolytic uremic syndrome healing, cancer progression. Treatment include gemcitabine discontinuation, antihypertensive drugs and if necessary fresh frozen plasma. CONCLUSIONS: Systematic clinical and biological screening of hemolytic uremic syndrome during gemcitabine therapy should allow to better know this complication, to recognize and treat it earlier with a potential positive impact for patients.

Transitory increased blood pressure after upper airway surgery for snoring and sleep apnea correlates with the apnea-hypopnea respiratory disturbance index.

A transitory increase in blood pressure (BP) is observed following upper airway surgery for obstructive sleep apnea syndrome but the mechanisms implicated are not yet well understood. The objective of the present study was to evaluate changes in BP and heart rate (HR) and putative factors after uvulopalatopharyngoplasty and septoplasty in normotensive snorers. Patients (N = 10) were instrumented for 24-h ambulatory BP monitoring, nocturnal respiratory monitoring and urinary catecholamine level evaluation one day before surgery and on the day of surgery. The influence of postsurgery pain was prevented by analgesic therapy as confirmed using a visual analog scale of pain. Compared with preoperative values, there was a significant (P < 0.05) increase in nighttime but not daytime systolic BP (119 5 vs 107 3 mmHg), diastolic BP (72 4 vs 67 2 mmHg), HR (67 4 vs 57 2 bpm), respiratory disturbance index (RDI) characterized by apnea-hypopnea (30 10 vs 13 4 events/h of sleep) and norepinephrine levels (22.0 4.7 vs 11.0 1.3 g l-1 12 h-1) after surgery. A positive correlation was found between individual variations of BP and individual variations of RDI (r = 0.81, P < 0.01) but not between BP or RDI and catecholamines. The visual analog scale of pain showed similar stress levels on the day before and after surgery (6.0 0.8 vs 5.0 0.9 cm, respectively). These data strongly suggest that the cardiovascular changes observed in patients who underwent uvulopalatopharyngoplasty and septoplasty were due to the increased postoperative RDI.

Transitory increased blood pressure after upper airway surgery for snoring and sleep apnea correlates with the apnea-hypopnea respiratory disturbance index

A transitory increase in blood pressure (BP) is observed following upper airway surgery for obstructive sleep apnea syndrome but the mechanisms implicated are not yet well understood. The objective of the present study was to evaluate changes in BP and heart rate (HR) and putative factors after uvulopalatopharyngoplasty and septoplasty in normotensive snorers. Patients (N = 10) were instrumented for 24-h ambulatory BP monitoring, nocturnal respiratory monitoring and urinary catecholamine level evaluation one day before surgery and on the day of surgery. The influence of postsurgery pain was prevented by analgesic therapy as confirmed using a visual analog scale of pain. Compared with preoperative values, there was a significant (P < 0.05) increase in nighttime but not daytime systolic BP (119 ± 5 vs 107 ± 3 mmHg), diastolic BP (72 ± 4 vs 67 ± 2 mmHg), HR (67 ± 4 vs 57 ± 2 bpm), respiratory disturbance index (RDI) characterized by apnea-hypopnea (30 ± 10 vs 13 ± 4 events/h of sleep) and norepinephrine levels (22.0 ± 4.7 vs 11.0 ± 1.3 æg l-1 12 h-1) after surgery. A positive correlation was found between individual variations of BP and individual variations of RDI (r = 0.81, P < 0.01) but not between BP or RDI and catecholamines. The visual analog scale of pain showed similar stress levels on the day before and after surgery (6.0 ± 0.8 vs 5.0 ± 0.9 cm, respectively). These data strongly suggest that the cardiovascular changes observed in patients who underwent uvulopalatopharyngoplasty and septoplasty were due to the increased postoperative RDI.

Variability of cytochrome P450 1A2 activity over time in young and elderly healthy volunteers.

AIMS: To assess the age-associated changes over time of plasma paraxanthine/caffeine (PAX/CAF) ratios used as a probe for CYP1A2 activity. METHODS: Intraindividual and interindividual variabilities in PAX/CAF ratio were compared by phenotyping with caffeine, 16 young and 16 elderly healthy subjects on five occasions. RESULTS: PAX/CAF ratio variability was comparable regardless of age (intraindividual CV: 17.6 +/- 6% and 16.2 +/- 5.9%, interindividual CV: 48.1 +/- 2.9% and 42.7 +/- 3.6% in young and elderly, respectively). The PAX/CAF ratio was lower in elderly than in young subjects (95% CI for the difference: 0.004, 0.32) but the difference was not significant in nonsmokers compared separately. CONCLUSIONS: The variability over time of the PAX/CAF ratio is not influenced by age.

Is diclofenac a valuable CYP2C9 probe in humans?

INTRODUCTION: Besides the low therapeutic index drug tolbutamide, there is no validated in vivo probe to assess the genetically determined CYP2C9 activity in humans. The in vitro CYP2C9-specific substrate diclofenac might be a valuable, well-tolerated probe candidate. In order to validate diclofenac as an in vivo CYP2C9 probe, we planned to show that urinary 4'-hydroxydiclofenac/diclofenac metabolic ratio (MR) would correlate to the apparent partial metabolic clearance of diclofenac into 4'-hydroxydiclofenac (Clmet). PATIENTS AND METHODS: Eighteen healthy volunteers received a single oral dose of 50 mg diclofenac in its enteric-coated form. Blood and urinary pharmacokinetics of diclofenac were studied over 48 h. Identification of the CYP2C9 alleles (CYP2C9*1, CYP2C9*2, and CYP2C9*3) was performed with genomic DNA sequencing. RESULTS: We observed a dramatic inter-individual variability in the delay of diclofenac intestinal absorption since its first detectable blood concentration ranged from 0.5 h to more than 12 h after drug intake. The Clmet of diclofenac could not be determined in two subjects who started to absorb the drug after 12 h. No correlation could be observed between Clmet of diclofenac and the different MRs calculated at 0-4 h, 0-8 h, 0-12 h, 0-24 h and 0-48 h urinary collections. The Clmet of diclofenac in heterozygous subjects tended to be lower than among wild-type homozygous subjects, but this difference did not reach statistical significance due to an insufficient number of subjects studied. CONCLUSION: Diclofenac, in its enteric-coated form, is not a useful in vivo CYP2C9 probe probably because of its highly variable intestinal absorption rate. However, since we found a lower metabolic clearance of diclofenac in heterozygous CYP2C9 subjects, as observed with other CYP2C9 substrates, diclofenac, in another galenic form, might be a potential probe to quantify CYP2C9 activity in humans.

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.

Assessment of CYP2D6 and CYP2C19 activity in vivo in humans: a cocktail study with dextromethorphan and chloroguanide alone and in combination.

OBJECTIVES: Dextromethorphan and chloroguanide (INN, proguanil) are used as prototypic phenotyping substrates of polymorphically expressed CYP2D6 and CYP2C19 in humans. We determined whether the dextromethorphan/dextrorphan and chloroguanide/cycloguanil metabolic ratios, obtained after administration of the parent drugs either alone or in combination, are equivalent. METHODS: Thirty-six healthy male volunteers received single oral doses of 80 mg dextromethorphan and 200 mg chloroguanide during a three-period, randomized crossover study. Plasma and urine were collected to calculate metabolic ratios and analyze the disposition kinetics of the probe drugs. RESULTS: All subjects were extensive metabolizers for both CYP2D6 and CYP2C19. Chloroguanide kinetics and urinary metabolic ratio were not altered after dextromethorphan administration. Dextromethorphan urinary metabolic ratio increased from -2.52 +/- 0.67 to -2.03 +/- 0.58 (P < .001) in the presence of chloroguanide. This was caused by an increase of dextromethorphan without a significant change of dextrorphan in both urine and plasma. Inhibition of CYP3A-dependent biotransformation of dextromethorphan to methoxymorphinan did not appear to be responsible for this change because the log(dextromethorphan/methoxymorphinan) urinary ratio, an index of CYP3A activity, did not significantly change during chloroguanide coadministration. The chloroguanide and dextromethorphan metabolic ratio determined from urine collection correlated with the corresponding metabolic ratio determined from plasma obtained 3 hours after oral administration. CONCLUSION: When CYP2D6 and CYP2C19 activity are assessed, dextromethorphan and chloroguanide cannot be associated in a cocktail because chloroguanide increases the dextromethorphan metabolic ratio. CYP2D6 and CYP2C19 activity can be determined from a blood sample drawn 3 hours after oral administration of dextromethorphan and chloroguanide, respectively.

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.

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.

[Prevention of aspergillosis with itraconazole in neutropenic patients: importance of drug monitoring]. / Prophylaxie de l'aspergillose par l'itraconazole chez les patients neutropéniques: valeur des dosages plasmatiques.

Itraconazole is being used increasingly as prophylaxis of systemic aspergillosis in patients with immunodepression. Therapeutic itraconazole monitoring by plasma concentrations measurement is justified by its dose-dependent pharmacokinetics, drug interactions, and frequent bioavailability modifications observed in immunocompromised patients. A first study was carried out in 16 patients with haematological malignancies, given chemotherapy plus itraconazole 400-800 mg/day in a single dose as prophylactic treatment. Therapeutic through drug plasma concentration (Cmin > or = 250 ng/ml of itraconazole, or > or = 750 ng/ml of itraconazole plus hydroxyitraconazole) was not reached in 5/16 patients. Moreover results emphasised the wide inter and intra-individual variability of the steady-state plasma concentrations. In another study we used a multiple dose regimen (100-200 mg x 3/day), instead of a single dose regimen. An adequate Cmin value was found in 34/36 patients. In conclusion, the wide inter and intra-individual variability of itraconazole pharmacokinetics necessitate regularly to measure the drug plasma concentrations in patients with life-threatening fungal infections.

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.

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.

Effects of chronic treatment by amiodarone on transmural heterogeneity of canine ventricular repolarization in vivo: interactions with acute sotalol.

OBJECTIVE: The present study was designed to examine the effects of chronic amiodarone on the different ventricular cell subtypes in situ and to evaluate its interactions with sotalol. METHODS: Three groups of dogs were studied. Group I (n = 8) received no treatment. Group II (n = 7) and group III (n = 8) received, respectively, 100 and 200 mg amiodarone orally twice a day for 6 weeks to 8 months. In vivo studies were performed under halothane anesthesia 14 h after the last administration of amiodarone. Three leads ECG, femoral blood pressure and left ventricular intramural monophasic action potentials (MAP) were continuously recorded. Bradycardia was obtained by clamping the sinus node and beta-blockade and the heart was driven by atrial pacing. Three weeks before the in vivo experiments, the cellular electrophysiologic properties of right ventricular tissues obtained by cardiac biopsy in six treated and six control dogs were studied with standard microelectrodes. RESULTS: Amiodarone produced a dose-dependent decrease in plasma levels of triiodothyronine (T3; 5.9 +/- 0.4 pM in control dogs, 3.1 +/- 0.2 pM in group III, P < 0.001) without affecting thyroxine (T4). Under anesthesia, the QT interval was 14% larger in group III compared to group I at a paced cycle length (PCL) of 1500 ms (P < 0.05). This is consistent with the 10% increase in endocardial MAP duration in group III at the same PCL (P < 0.05). There was no significant increase in transmural dispersion of MAP duration. In group I, sotalol induced a significant reverse use-dependent increase in MAP duration. This effect was reduced in group II and completely suppressed in group III. Amiodarone prevented the sotalol-induced increase in transmural dispersion of ventricular repolarization which was 69 +/- 12 ms in untreated dogs, 41 +/- 8 ms in group II (P < 0.05) and 34 +/- 8 ms (P < 0.05) in group III at PCL = 1500 ms. Amiodarone also prevented the sotalol-induced ventricular tachyarrhythmias. In vitro, the action potential duration was longer in amiodarone-treated dogs that in control ones (208 +/- 5 ms versus 188 +/- 9 ms at PCL = 1000 ms, P < 0.05). The sotalol-induced prolongation of repolarization was reduced in amiodarone-treated dogs. CONCLUSION: Chronic treatment of dogs with amiodarone induced a moderate prolongation of the QT interval and MAP duration without affecting transmural dispersion of repolarization and inhibited the effects of acute sotalol, including the prolongation of repolarization, the increase in transmural dispersion of repolarization and the induction of arrhythmias.

[Recent aspects of monitoring the dosage of aminoglycosides and vancomycin]. / Quelques aspects récents du suivi posologique des aminosides et de la vancomycine.

The narrow range of therapeutic serum concentrations of aminoglycosides and vancomycin and the great variations in their pharmacokinetics from one person to another makes it important to monitor patients at risk that are treated with them. The technique of customizing dosages based on the population pharmacokinetics enables an effective treatment to be rapidly established from a few measurements of serum concentrations. Aminoglycosides may be given as single daily doses because of their concentration-dependent activity. The high peak concentration produces an enhanced, prolonged bactericidal activity, while a low residual concentration reduces the risk of toxicity. The effect of vancomycin is time-dependent. Giving it by continuous i.v. infusion maximizes the time during which the serum antibiotic concentration is effective but non-toxic. Monitoring serum concentrations can help reduce health care costs. But medical training in pharmacokinetics is needed for the optimal use of these therapeutic tools.

Combination of sotalol and quinidine in a canine model of torsades de pointes: no increase in the QT-related proarrhythmic action of sotalol.

INTRODUCTION: Clinical treatment with a combination of Class IA and III antiarrhythmic drugs is not recommended, as they both favor bradycardia-dependent proarrhythmic events such as torsades de pointes (TdP). However, this theoretical additive effect on ventricular repolarization has never been demonstrated and could be questioned as other Class I drugs, such as mexiletine, a Class IB drug, limit the number of sotalol-induced TdP in dogs with AV block, suggesting the possibility of an antagonistic action of Class I properties against Class III effects. METHODS AND RESULTS: We compared the electrophysiologic and proarrhythmic effects of sotalol (Class III) alone and combined with quinidine (Class IA) in a canine model of acquired long QT syndrome. Seven hypokalemic (K+: 3 +/- 0.1 mEq/L) dogs with chronic AV block had a demand pacemaker implanted and set at a rate of 25 beats/min. They were submitted to two (sotalol-alone and sotalol-plus-quinidine) experiments 48 hours apart using a randomized cross-over protocol. They were pretreated with quinidine (10 mg/kg + 1.8 mg/kg per hour) or saline infused throughout the experiment, and given sotalol (4.5 mg/kg + 1.5 mg/kg per hour) for 2 hours, 30 minutes after the beginning of the pretreatment infusion during both experiments. Ventricular and atrial cycle lengths were similarly increased by sotalol after quinidine or saline. The sotalol-induced prolongation of the QT interval was significantly shorter in quinidine-pretreated dogs (24 +/- 7 msec after quinidine vs 40 +/- 8 msec after saline). Fewer dogs developed TdP: significantly during the first hour of infusion (1/7 sotalol-plus-quinidine vs 6/7 sotalol-alone dogs, P < 0.05) but nonsignificantly during the second hour (3/7 vs 6/7). CONCLUSION: In this model, the sotalol-plus-quinidine combination is at least no more arrhythmogenic than either of the drugs given alone.

Optimisation of itraconazole therapy using target drug concentrations.

Itraconazole is a new triazole compound with a broad spectrum of activity against a number of fungal pathogens, including Aspergillus species. The drug is being used increasingly as prophylaxis in patients with immunodepression. Itraconazole is highly lipophilic and only ionised at low pH. The absolute availability of capsules in healthy volunteers under fasting conditions is about 55% and is increased after a meal. Itraconazole is 99.8% bound to human plasma proteins and its apparent volume of distribution is about 11 L/kg. The drug is extensively metabolised by the liver. Among the metabolites, hydroxy-itraconazole is of particular interest because its antifungal activity measured in vitro is similar to that of the parent drug and its plasma concentration is 2 to 3 times higher than that of itraconazole. Mean total itraconazole blood clearance determined in healthy volunteers following a single intravenous infusion was 39.6 L/h. After a single oral dose, the terminal elimination half-life of itraconazole is about 24 hours. The drug exhibits a dose-dependent pharmacokinetic behaviour. Renal failure does not affect the pharmacokinetic properties of itraconazole; however, little is known about the effects of hepatic insufficiency. In immunocompromised patients the absorption of itraconazole is affected by gastrointestinal disorders caused by diseases and cytotoxic chemotherapy. The pharmacokinetics of itraconazole may be significantly altered when the drug is coadministered with certain other agents. Itraconazole is a potent inhibitor of cytochrome P450 (CYP) 3A4 and, thus, can also considerably change the pharmacokinetics of other drugs. Such changes may have clinically relevant consequences. Itraconazole appears to be well tolerated. Gastrointestinal disturbances and dizziness are the most frequently reported adverse effects. Clinical studies in patients with haemotological malignancies suggest that plasma concentrations [measured by high performance liquid chromatography (HPLC)] > or = 250 micrograms/L itraconazole, or 750 to 1000 micrograms/L for itraconazole plus hydroxy-itraconazole, are required for effective prophylactic antifungal activity. It seems that a curative effect may be enhanced by ensuring that itraconazole plasma concentrations exceed 500 micrograms/L. The marked intra- and inter-patient variability in the pharmacokinetics of the drug, and the fact that it is impossible to predict steady-state plasma concentrations from the initial dosage are major factors obscuring any clear relationship between dose and plasma concentrations and clinical efficacy. Thus, in patients with life-threatening fungal infections treated with itraconazole drug, plasma concentrations should be regularly monitored to ensure sufficient drug exposure for antifungal activity.

Plasma itraconazole concentrations in patients with neutropenia: advantages of a divided daily dosage regimen.

A group of 36 patients in the hematology department of Saint-Antoine Hospital, Paris, France, was on chemotherapy. The patients were also given antiacid drugs to prevent gastrointestinal toxicity and itraconazole as prophylaxis against aspergillosis. The antifungal drug was given as 100-mg capsules three times a day shortly after meals. The plasma itraconazole and hydroxyitraconazole concentrations were measured by high-performance liquid chromatography at steady state. Of 36 patients, 29 (81%) had adequate plasma itraconazole concentrations (> or = 250 ng/ml) after 8 +/- 2 days. The 7 patients with low plasma itraconazole concentrations were given 200 mg three times a day. Of the 36 patients, 34 (94%) had effective plasma concentrations within 2 weeks of the beginning of treatment. The two remaining patients were lost to follow-up. The proposed itraconazole regimen provides effective prophylaxis against aspergillosis and represents a substantial economic advantage over a single daily dose of 400 to 600 mg. The marked intrapatient and interpatient variations in plasma itraconazole indicate the need for regular therapeutic drug monitoring to ensure effective plasma itraconazole concentrations in all neutropenic patients.

Cauda equina syndrome with pagetic vertebral fusion. Clinical recovery under calcium-vitamin D supplementation plus clodronate after apparent failure of pamidronate and acquired resistance to etidronate.

A patient with an osteolytic L2-L3 pagetic block and pagetic lesions of L1 and the sacrum seen only as increased radionuclide activity became resistant to etidronate after the fifth course (5 mg/kg/d six months per year) and developed severe cauda equina syndrome (reduction in walking distance to 30 m and sphincter dysfunction) due primarily to vertebral hypertrophy. Five months after a ten-day course of intravenous pamidronate (22.5 mg/d), the clinical symptoms were unchanged, although the alkaline phosphatase level was down 50%. Oral clodronate (1,600 mg/day for six months per year) in combination with calcium and vitamin D supplementation dramatically improved the walking distance and sphincter disorders. Resolution of the neurological manifestations was complete after the second clodronate course. At last follow-up nine months after the fourth clodronate course, there was no evidence of a relapse and the alkaline phosphatase level was normal. The time course of events in this patient does not allow to affirm that pamidronate was ineffective and suggests that calcium and vitamin D supplementation improved mineralization of the pagetic block and enhanced the effect of bisphosphonate therapy.

Pharmacokinetics of beta-adrenoceptor blockers in obese and normal volunteers.

AIMS: Obesity can modify the pharmacokinetics of lipophilic drugs. As beta-adrenoceptor blockers (BB) are often prescribed for obese patients suffering from hypertension or coronary heart disease, this study compares the pharmacokinetics of lipophilic beta-adrenoceptor blockers in obese and control subjects. METHODS: Nine obese (157 +/- 24% of ideal body weight (IBW) mean +/- s.d.) and nine non-obese healthy volunteers (98 +/- 10% IBW), aged 32 +/- 9 years, were included in the study. Subjects were randomly given a single i.v. infusion of one of the following racemic beta-adrenoceptor blockers, whose doses (expressed as base per kg of IBW) were: propranolol (0.108 mg), labetalol (0.99 mg) and nebivolol (0.073 mg). The plasma concentrations of unchanged drugs were measured by h.p.l.c. The ionisation constants and lipophilicity parameters of beta-adrenoceptor blockers were assessed. RESULTS: The pharmacokinetic data for the three drugs were qualitatively similar. There was a trend towards a greater total distribution volume (Vss) in obese patients than in controls. However, Vss expressed per kg body weight was slightly smaller in obese patients. The relationship between Vss and lipophilicity of five beta-adrenoceptor was studied by combining the current results with those previously obtained with a moderately lipophilic drug (bisoprolol) and a hydrophilic one (sotalol). The Vss of the five drugs was positively and well-correlated (r2 = 0.90; P < 0.01) with their distribution coefficient at pH 7.4 (log D7.4), but not with their partition coefficients. The linear regression coefficients for lean and obese subjects were very similar. CONCLUSIONS: Lipophilic beta-adrenoceptor blockers seem to diffuse less into adipose than into lean tissues. All electrical forms of the drugs (i.e. cations, neutral forms, or zwitterions) present at physiological pH contribute to their tissue distribution, in both obese and lean subjects. Their tissue distribution in obese patients could be restricted by the sum of hydrophobic forces and hydrogen bonds they elicit with macromolecules in lean tissues.