Quantification of fatal helium exposure following self-administration.

Helium is nontoxic at standard conditions, plays no biological role, and is found in trace amounts in human blood. Helium can be dangerous if inhaled to excess, since it is a simple tissue hypoxia and so displaces the oxygen needed for normal respiration. This report presents a fatal case of a middle-aged male victim who died from self-administered helium exposure. For the first time, the quantification of the helium levels in gastric and lung air and in blood samples was achieved using gas chromatography-mass spectrometry after airtight sampling. The results of the toxicological investigation showed that death was caused directly by helium exposure. However, based on the pathomorphological changes detected during the forensic autopsy, we suppose that the fatal outcome was the result of the lack of oxygen after inhalation.

Screening for childhood lead poisoning in the industrial region of Fez, Morocco.

The study objectives were to estimate lead poisoning prevalence among children living next to an industrial area, to compare it to that in a control population, and to establish clinical and biological follow-up of the poisoned children. This is a descriptive cross-sectional study including 150 children (exposed and unexposed) performed between January 2012 and April 2013. It was meant to determine blood lead levels (BLLs) in children considered to be an exposed population (EP N 90), living in the industrial area Ain Nokb Fez compared with BLLs of children of other areas belonging to the same city supposed to be unexposed [UP (N = 60)]. A sociodemographic questionnaire was obtained, and a blood lead analysis was performed. Clinical and biological follow-up has been performed of poisoned children. The sample consisted of 90 EP children with an average age of 6.82 ± 3.32 years and male-to-female sex ratio (SR) of 1.5 and 60 UP children with an average age of 6.45 ± 3.29 years and an SR of 1.2. Among the 150 children recruited, the average of BLLs was 58.21 ± 36 µg/L (18-202.3 µg/L). The average of BLLs in EP children (71 ± 40 µg/L) was statistically greater (p < 0.0001) than that registered in UP children (38 ± 13 µg/L). All poisoned children belonged to the EP group at a prevalence of 21.1 %. The clinical and biological examinations of poisoned children showed a few perturbations such as anemia, hypocalcaemia, and deficiencies in magnesium and iron. No renal disease or objective neurological disorders were observed. In the follow-up of the children with BLL ≥100 µg/L (19 cases). BLL monitoring showed a significant decrease in average of blood concentration ranging from 136.75 ± 32.59 to 104.58 ± 32.73 µg/L (p < 0.0001) and in lead poisoning prevalence (p < 0.001), which decreased to 7.8 % from 21.1. Our study showed a high prevalence of lead poisoning (21.1 %) in EP children. The relocation of the industrial site associated with corrective and preventive measures has contributed to a decrease of exposure and lead poisoning prevalence in the aforementioned population.

Triketone toxicity: a report on two cases of sulcotrione poisoning.

INTRODUCTION: Sulcotrione is a herbicidal agent belonging to the family of triketones. Sulcotrione herbicides are used for weed control in maize and flax crops. To date, no cases of human poisoning had been reported in the literature linked to different herbicidal agents in the triketone family. We report here on two cases of the voluntary ingestion of this substance in the form of the branded product Mikado(TM), which were recorded by the Angers Poison Centre. CASE REPORT: Both cases of voluntary ingestion constituted attempted suicide, and involved two men aged 30 and 37 years. Their symptoms linked to sulcotrione were limited to vomiting, despite elevated plasma concentrations of sulcotrione. In one case, hypertyrosinemia has been demonstrated. The outcome was favourable in both patients and at follow up, no ocular disorders were observed. In the second case, hypotension and transient renal failure could be linked to the concomitant ingestion of chlorophenoxy herbicides. DISCUSSION: In animal toxicity studies, sulcotrione inhibit 4-hydro-phenylpyruvate dioxygenase leading to hypertyrosinemia and corneal opacities. In both cases, no ocular disorders were observed despite hypertyrosinemia in one case. These case reports were consistent with the animal toxicology findings concerning triketones, and particularly their relative safety in mammals following acute poisoning. However it seems prudent to monitor plasma tyrosine concentrations and to screen prospectively for corneal deposits if further acute intoxication events occur.

[Peganum harmala L. poisoning and pregnancy: two cases in Morocco]. / Intoxication au Peganum harmala L. et grossesse : deux observations marocaines.

Peganum harmala L. (wild or Syrian rue) is commonly used as an emmenagogue and abortifacient in traditional medicine in the Middle East and North Africa including Morocco. The purpose of this report is to describe two cases of Peganum harmala L. poisoning in pregnant women. Both cases were treated successfully with good maternal-fetal outcome good for mother and child.

Pharmacokinetic analysis of pralidoxime after its intramuscular injection alone or in combination with atropine-avizafone in healthy volunteers.

BACKGROUND AND PURPOSE: Treatment of organophosphate poisoning with pralidoxime needs to be improved. Here we have studied the pharmacokinetics of pralidoxime after its intramuscular injection alone or in combination with avizafone and atropine using an auto-injector device. EXPERIMENTAL APPROACH: The study was conducted in an open, randomized, single-dose, two-way, cross-over design. At each period, each subject received either intramuscular injections of pralidoxime (700 mg), or two injections of the combination: pralidoxime (350 mg), atropine (2 mg), avizafone (20 mg). Pralidoxime concentrations were quantified using a validated LC/MS-MS method. Two approaches were used to analyse these data: (i) a non-compartmental approach; and (ii) a compartmental modelling approach. KEY RESULTS: The injection of pralidoxime combination with atropine and avizafone provided a higher pralidoxime maximal concentration than that obtained after the injection of pralidoxime alone (out of bioequivalence range), while pralidoxime AUC values were equivalent. Pralidoxime concentrations reached their maximal value earlier after the injection of the combination. According to Akaike and to goodness of fit criteria, the best model describing the pharmacokinetics of pralidoxime was a two-compartment with a zero-order absorption model. When avizafone and atropine were injected with pralidoxime, the best model describing pralidoxime pharmacokinetics becomes a two-compartment with a first-order absorption model. CONCLUSIONS AND IMPLICATIONS: The two approaches, non-compartmental and compartmental, showed that the administration of avizafone and atropine with pralidoxime results in a faster absorption into the general circulation and higher maximal concentrations, compared with the administration of pralidoxime alone.

Feasibility of, and critical paths for mycophenolate mofetil Bayesian dose adjustment: pharmacological re-appraisal of a concentration-controlled versus fixed-dose trial in renal transplant recipients.

The aim of this study was to analyze retrospectively and critically the different steps of the individual dose adjustment procedure employed in the concentration-controlled (CC) versus fixed-dose trial Apomygre, which showed that mycophenolate mofetil (MMF) dose adjustment using a limited sampling strategy significantly reduced the risk of treatment failures and acute rejection in renal transplants at one year posttransplantation. The number of AUCs performed during the study and circumstances of collection, time of blood sampling, Bayesian mycophenolic acid (MPA) area-under-the-curve (AUC) estimation procedures and physicians' compliance with MMF dose recommendations were retrospectively analyzed. 92% of AUCs scheduled over the study were actually performed. Sampling times were very well respected. Bayesian estimation of MPA exposure was done by the pharmacologists locally in accordance with the protocol instructions and the AUC estimates obtained were virtually all confirmed a posteriori. On the other hand, a second AUC estimated by multiple linear regression could only be provided for 84% of the profiles and showed a large overestimation with respect to Bayesian estimates for AUC values between 10 and 55mgh/L. In the CC arm, a very good physicians' compliance was observed (85%) and application of the dose recommendations led to higher values of AUCs (42.1+/-14.6mgh/L versus 36.7+/-16.3mgh/L, p=0.0035) and to more AUCs in the target range (69% versus 56%, p=0.0343) than when dose recommendations were not applied. By analyzing in detail the feasibility criteria of MMF Bayesian dose adjustment, this study highlighted the requirements for successful extrapolation of the Apomygre trial results to routine practice: (i) respect of the PK sampling time-windows; (ii) use of relevant tools for accurate drug exposure estimation and dose adjustment calculation; and (iii) good compliance of the physicians with regard to the recommended doses.

Bioavailability of diazepam after intramuscular injection of its water-soluble prodrug alone or with atropine-pralidoxime in healthy volunteers.

BACKGROUND AND PURPOSE: The aim of this study was to assess the relative bioavailability of diazepam after administration of diazepam itself or as a water-soluble prodrug, avizafone, in humans. EXPERIMENTAL APPROACH: The study was conducted in an open, randomized, single-dose, three-way, cross-over design. Each subject received intramuscular injections of avizafone (20 mg), diazepam (11.3 mg) or avizafone (20 mg) combined with atropine (2 mg) and pralidoxime (350 mg) using a bi-compartmental auto-injector (AIBC). Plasma concentrations of diazepam were quantified using a validated LC/MS-MS assay, and were analysed by both a non-compartmental approach and by compartmental modelling. KEY RESULTS: The maximum concentration (C(max)) of diazepam after avizafone injection was higher than that obtained after injection of diazepam itself (231 vs. 148 ng.mL(-1)), while area under the curve (AUC) values were equal. Diazepam concentrations reached their maximal value faster after injection of avizafone. Injection of avizafone with atropine-pralidoxime (AIBC) had no effect on diazepam C(max) and AUC, but the time to C(max) was increased, relative to avizafone injected alone. According to the Akaike criterion, the pharmacokinetics of diazepam after injection as a prodrug was best described as a two-compartment with zero-order absorption model. When atropine and pralidoxime were injected with avizafone, the best pharmacokinetic model was a two-compartment with a first-order absorption model. CONCLUSION AND IMPLICATIONS: Diazepam had a faster entry to the general circulation and achieved higher C(max) after injection of prodrug than after the parent drug. Administration of avizafone in combination with atropine and pralidoxime by AIBC had no significant effect on diazepam AUC and C(max).

[Benzodiazepine poisoning in a neonate: clinical and toxicokinetic evaluation following enterodialysis with activated charcoal]. / Intoxication par les benzodiazépines chez un nouveau-né: évaluation clinique et toxicocinétique de l'entérodizlyse par le charbon activé.

CASE REPORT: A pregnant woman who was a regular user of anxiolytics was admitted to the maternity ward at 38 weeks and 4 days amenorrhea after a massive overdose of clorazepate dipotassium, a benzodiazepine. The exact quantity ingested was undetermined. The infant, born at 39 weeks, presented no spontaneous breathing and tracheal intubation was necessary in the delivery room. The neonatal blood concentrations of the clorazepate metabolites were very high at delivery (26 mg/l nordiazepam and 3.5 mg/l oxazepam) and showed little change over the next 5 days (16 mg/l nordiazepam and 2.1 mg/l oxazepam, with an apparent half-life of 168 h for nordiazepam and 160 h for oxazepam). By day 6, the infant was still dependent on ventilator support and enterodialysis was begun with repeated doses of activated charcoal (1 g/kg every 6 h by gastric tube). Treatment was continued for 5 days and a spectacular diminution in the serum concentrations of the two metabolites was noted on day 11: 1.5 mg/l nordiazepam and less than 0.1 mg/l oxazepam. The nordiazepam and oxazepam half-lifes were reduced to 42 h and 30 h respectively. The concomitant clinical improvement authorized the weaning from ventilation on day 12. CONCLUSION: This is the first report of the use of enterodialysis to treat severe benzodiazepine poisoning in a neonate. Depuration of the toxin was accelerated and the duration of intensive care was shortened thanks to this technique.

[Chemical submission]. / Soumission chimique.

INTRODUCTION: The clinical submission syndrome is well known by the general population, but too frequently ignored by physicians. OBSERVATION: A 23 year-old woman was drugged by a third person wishing to sexually abuse of her. The diagnosis was proved biologically after the judicial enquiry. COMMENTS: The diagnosis of clinical submission is difficult to make because of the frequent delays in emergency consultations and the difficulties in biological assays, since the doses of drugs administered are often very low and infra-therapeutic. Over a period of one year, we evoked the diagnosis four times and it was confirmed only once. It sometimes leads to diagnostic peregrinations. Close cooperation between the physicians and the police is required so that a judicial enquiry can be rapidly set-up.

Fatal acute poisoning by bentazon.

A case of fatal suicidal bentazon poisoning is presented along with a description of the different analytical methods involved. A 56-year-old farmer was examined by the family doctor 1 h after voluntarily ingesting 500 mL of FIGHTER (bentazon, 480 g/L water). He presented a Glasgow score of 15, polypnea, diarrhea, and vomiting. During transport by ambulance to the hospital, he tossed, sweated, and suddenly presented breathing difficulty followed by heart failure. Tracheal intubation was impossible (H1.5) despite use of different diameter cannulas because of extreme general muscle rigidity. All attempts at resuscitation failed, and the patient died within 2 h postingestion. Blood and urine samples were taken just before death. General basic and neutral drug screening by high-performance liquid chromatography-diode-array detection and gas chromatography-nitrogen-phosphorus detection showed no strychnine or other drugs or toxics except for citalopram (< 0.1 mg/L) and bentazon, but this weak acidic molecule (pKa3.3) was badly extracted in alkaline conditions. Plasma and urine levels, measured after acidic extraction, protein precipitation, or simple dilution, were 1500 and 1000 mg/L, respectively. Bentazon (M.W. 240) was confirmed by its basic mass spectrum (ESI-, m/z 239, 197, 175, 132) or by that of methylated derivative (El+, m/z 254, 212, 175). An hydroxylated metabolite (ESI-, m/z 255, 213, 191, 148; El+, m/z 284, 242, 163) and the N1-glucuronide conjugate of bentazon (ESI-, m/z 415, 239) were also detected in urine. (Quantitation ions are underlined.) This first case of bentazon poisoning with available analytical data revealed the high toxicity of this compound after large dose ingestion with early and heavy symptoms such as muscle rigidity probably related to muscular toxicity. Comparison with another nonfatal case and with toxicological data on animals is discussed.

Determination of LSD and its metabolites in human biological fluids by high-performance liquid chromatography with electrospray tandem mass spectrometry.

A liquid chromatographic procedure with electrospray ionization tandem mass spectrometric detection has been developed and validated for LSD and iso-LSD determination. A one-step liquid-liquid extraction on 1 ml blood or urine was used. The lower limit for quantitative determination was 0.02 microg/l for LSD and iso-LSD. The analytical procedure has been applied in two positive cases (case 1: LSD=0.31 microg/l, iso-LSD=0.27 microg/l in plasma and LSD=1.30 microg/l, iso-LSD=0.82 microg/l in urine; case 2: LSD=0.24 microg/l, iso-LSD=0.6 microg/l in urine). LSD metabolism was investigated using MS-MS neutral loss monitoring for the screening of potential metabolites. The main metabolite was 2-oxo-3-hydroxy-LSD (O-H-LSD) present in urine at the concentrations of 2.5 microg/l and 6.6 microg/l, respectively, for case 1 and 2, and was not present in plasma. Nor-LSD was also found in urine at 0.15 and 0.01 microg/l levels. Nor-iso-LSD, lysergic acid ethylamide (LAE), trioxylated-LSD, lysergic acid ethyl-2-hydroxyethylamide (LEO) and 13 and 14-hydroxy-LSD and their glucuronide conjugates were detected in urine using specific MS-MS transitions.

Acute metobromuron poisoning with severe associated methemoglobinemia. Identification of four metabolites in plasma and urine by LC-DAD, LC-ESI-MS, and LC-ESI-MS-MS.

A case of self poisoning with metobromuron, a urea derivative used as a herbicide, is reported. Severe methemoglobinemia observed at the admission (80%) disappeared only at day 11, and hemolysis appeared at day 4 and decreased slowly to day 12. Metobromuron was analyzed by liquid chromatography with diode-array detection. Initial plasma concentration and elimination half-life were 4.9 mg/L and 5 h, respectively. Several metabolites were also detected, and four of those were identified by liquid chromatography-electrospray mass spectrometry. Normetobromuron, bromophenylurea, and bromoacetanilide were detected in plasma, but only N-methyl bromophenylurea was detected in urine. Bromoacetanilide probably results from acetylation of the intermediate bromoaniline. Methemoglobinemia could result from metabolization of metobromuron to bromoaniline and bromoacetanilide.

Determination of opiates and cocaine and its metabolites in biological fluids by high-performance liquid chromatography with electrospray tandem mass spectrometry.

A rapid, sensitive, and specific method for the determination of opiates and cocaine and metabolites in urine, plasma, and blood was established. A one-step extraction followed by liquid chromatography-electrospray ionization tandem mass spectrometry operating in multiple reaction monitoring mode was used. Two chromatographic runs were performed, each in less than 6 min. The lower limit for accurate quantitative determination was 5 microg/L for cocaine and metabolites and 10 microg/L for opiates. Linearity was obtained from 10 to 1000 microg/L. Intraday (n = 6) and interday (n = 6) precisions and recoveries (n = 6) were determined at 10 or 25, 100, and 1000 microg/L concentrations. Precisions with a coefficient of variation less than 15% were obtained. Recoveries between 85 and 115% were determined.

Determination of monomethylarsonic acid and dimethylarsinic acid in urine by liquid chromatography-tandem mass spectrometry.

A method for the simultaneous measurement of monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in human urine using liquid chromatography-tandem mass spectrometry with electrospray ionization (LC-ES-MS-MS) was developed. The multiple reaction monitoring mode (MRM) was used for quantitation. The protonated molecule ions (m/z 141.0 for MMA and m/z 139.0 for DMA) were selected as precursor ions, and the same fragment ion AsO+ (m/z 91.1) was monitored as the product ion. A two-step liquid-liquid extraction of MMA and DMA from urine provided recoveries of 92-100%. The coefficients of variation were lower than 7% for the within-day precision and lower than 11% for the between-day precision. The limit of quantitation was 25 microg/L as As for the two analytes. The assay was linear over the range of 25-800 microg/L.

Ethylene glycol poisoning in a child treated with 4-methylpyrazole.

OBJECTIVE: The alcohol dehydrogenase inhibitor 4-methylpyrazole (4-MP) is a new antidote of ethylene glycol (EG) intoxication. The purpose of the present case report was to demonstrate 4-MP efficiency in EG poisoning in a 4-year-old child. METHOD AND RESULTS: 4-MP Treatment was performed 7 hours after EG ingestion. Plasma EG and 4-MP concentrations were measured 2 hours after each infusion of 4-MP. Plasma 4-MP concentrations were in the range of the values reported to block EG metabolism. The efficiency of 4-MP treatment was confirmed by the rapid correction of metabolic acidosis without alkalization and by the increase in EG half-life. No adverse effect of 4-MP was observed. CONCLUSION: This child ingested a potentially lethal dose of EG despite a high concentration of bittering agent in antifreeze. EG poisoning was treated efficiently by 4-MP without recourse to hemodialysis.

Determination of unbound platinum after oxaliplatin administration: comparison of currently available methods and influence of various parameters.

Variations in plasma protein binding may have profound effects on both disposition and activity of drugs, especially for those which are tightly bound to proteins, such as anticancer platinum derivatives. Methods of separation of the non-protein-bound fraction and some technical parameters may influence the results. We have compared ultrafiltration and ultracentrifugation, as well as the effect of potentially interfering factors, upon the determination of the plasma unbound platinum fraction after oxaliplatin administration to cancer patients. Ultrafiltration and ultracentrifugation provided very closely correlated results, so that either technique can be used. The ultrafiltration cut-off (3000-30,000 Da) devices, the type of tube for blood sampling and the type of anticoagulant (none, lithium heparinate or EDTA) did not influence the results markedly. In contrast, results were greatly influenced by freezing: erratic results were obtained on thawed plasmas when compared with those on fresh serum or plasma. Consequences may be important in usual practice, since many pharmacokinetic studies are carried out in multicentric trials with plasma processing centralized in one reference laboratory. The methods for the determination of protein-drug binding should be standardized and guidelines elaborated where optimal conditions for each type of binding assay are given.

Study of haemostasis in depressive patients treated with fluoxetine.

The object of this study was to investigate a possible pharmacological effect of fluoxetine on haemostatic function, with special attention on primary haemostasis, in order to explain haemorrhagic complications reported in some treated, depressed patients. The haemostatic function of depressive patients, who required fluoxetine therapy, was studied before and after 1 month of treatment with fluoxetine 20 or 40 mg daily. Exclusion criteria were: pregnancy, initial abnormal haemostatic function, history of coagulation abnormalities, treatment with drugs that interfere with haemostasis, and recent fluoxetine therapy. The following tests were performed: prothrombin time, partial thromboplastin time, thrombin time, plasma fibrinogen, platelet counts, bleeding time, platelet aggregation induced by ADP, epinephrine, ristocetin, collagen, arachidonic acid, and plasma determination of fluoxetine and norfluoxetine levels. Statistical analysis was performed by Wilcoxon paired sample, one-tailed test (alpha=0.05). Among 18 patients included, only eight completed the trial. The single statistically significant difference was a decreased velocity in platelet aggregation induced by epinephrine without increased bleeding time. The results failed to demonstrate any compromised haemostatic function after 20 mg daily fluoxetine therapy in patients with initial haemostatic function. However, the results suggest possible effects of fluoxetine on platelet adrenoreceptors.

Rapid and sensitive high-performance liquid chromatographic analysis of halogenopyrimidines in plasma.

Recent studies have stressed the need for individual adjustment of 5-fluorouracil (5-FU) dosage. Most of the techniques previously reported are not well adapted to routine application. We describe a sensitive, selective and simple HPLC technique under isocratic conditions for the quantitation of 5-FU and other halogenopyrimidines. The proportion of reagents and internal standard were optimised to allow the use of minitubes, particularly adapted to large series of plasma assays. High extraction yield, 75% for 5-FU and 90% for 5-bromouracil and 5-chlorouracil, was obtained using 1.2 ml isopropanol-ethyl acetate (15:85, v/v) following precipitation of plasma proteins with 300 mg ammonium sulfate. The mobile phase was 0.01 M phosphate buffer (pH 3.0). Uracil and 5-fluorouracil were fully resolved with Spherisorb ODS2 column. The limits of quantitation and detection in human plasma were 6 ng ml(-1) and 3 ng ml(-1), respectively, for all compounds studied. The total analysis time required for each run was 25 min. Final results could be given within 90 min of blood sampling. At least 50 plasma samples could be analysed per day. This method has been successfully used for monitoring 5-FU-based treatments.

High-performance liquid chromatographic determination of 4-methylpyrazole in plasma and in dialysate.

A rapid method for the determination of 4-methylpyrazole (4-MP) levels in plasma and in dialysate by isocratic reversed-phase high-performance liquid chromatography with UV detection is described. The internal standard was the 3-methylpyrazole (3-MP). Plasma sample preparation consisted of a protein precipitation. Dialysate samples were injected without preparation. The method was linear up to 30 mg l(-1) in plasma and up to 5 mg l(-1) in dialysate. The within-day precisions (C.V.) were less than 4% in plasma and were less than 2% in dialysate. The day-to-day precisions (C.V.) were less than 7% in plasma and were less than 3% in dialysate. This method is easy to perform and has practical interest for clinicians who need to monitor in emergency 4-MP levels in ethylene glycol and methanol poisonings.

Cumulative pharmacokinetic study of oxaliplatin, administered every three weeks, combined with 5-fluorouracil in colorectal cancer patients.

The cumulative pharmacokinetic pattern of oxaliplatin, a new diamminecyclohexane platinum derivative, was studied in patients with metastatic colorectal cancer. Oxaliplatin was administered by i. v. infusion (130 mg/m2) over 2 h every 3 weeks, and 5-fluorouracil and leucovorin were administered weekly. A very sensitive method, inductively coupled plasma-mass spectrometry, allowed for the determination of total plasma and ultracentrifugable (UC) and RBC platinum levels on day 1, at 0, 2, and 5 h, and on days 8, 15, and 22. Sixteen patients underwent three or more courses, and six of them underwent six or more courses. The platinum concentration curves were quite similar from one course to another, with a high peak value 2 h after administration (day 1, Cmax = 3201 +/- 609 microgram/liter) and a rapid decrease (day 8, 443 +/- 99 microgram/liter). Cmax of both total and UC platinum levels in plasma remained unchanged throughout the treatment. The mean total platinum half-life in plasma was 9 days. We found residual levels of total platinum on day 22 (161 +/- 45 microgram/liter), but we observed no significant accumulation for the four first cycles (P = 0.57). In contrast, platinum accumulated significantly in RBCs after three courses (+91% at day 22 of the third cycle versus day 22 of the first cycle, P = 0.000018), and its half-life there was equivalent to that of RBCs. The patterns of UC and total platinum concentration curves were very similar and correlated significantly (P < 10(-6)) at all sampling times. The mean UC:total platinum ratio was 15% at day 1 and 5% at days 8, 15, and 22 in the 3-week treatment course. Unlike cisplatin, which rapidly accumulates in plasma as both free and bound platinum, oxaliplatin does not accumulate in plasma, but it does accumulate in RBCs, after repeated cycles at the currently recommended dose (130 mg/m2) and schedule of administration (every 3 weeks).