Pharmacokinetic study of gemcitabine, given as prolonged infusion at fixed dose rate, in combination with cisplatin in patients with advanced non-small-cell lung cancer.

International audienc

Ebola: translational science considerations

We are currently in the midst of the most aggressive and fulminating outbreak of Ebola-related disease, commonly referred to as “Ebola”, ever recorded. In less than a year, the Ebola virus (EBOV, Zaire ebolavirus species) has infected over 10,000 people, indiscriminately of gender or age, with a fatality rate of about 50%. Whereas at its onset this Ebola outbreak was limited to three countries in West Africa (Guinea, where it was first reported in late March 2014, Liberia, where it has been most rampant in its capital city, Monrovia and other metropolitan cities, and Sierra Leone), cases were later reported in Nigeria, Mali and Senegal, as well as in Western Europe (i.e., Madrid, Spain) and the US (i.e., Dallas, Texas; New York City) by late October 2014. World and US health agencies declared that the current Ebola virus disease (EVD) outbreak has a strong likelihood of growing exponentially across the world before an effective vaccine, treatment or cure can be developed, tested, validated and distributed widely. In the meantime, the spread of the disease may rapidly evolve from an epidemics to a full-blown pandemic. The scientific and healthcare communities actively research and define an emerging kaleidoscope of knowledge about critical translational research parameters, including the virology of EBOV, the molecular biomarkers of the pathological manifestations of EVD, putative central nervous system involvement in EVD, and the cellular immune surveillance to EBOV, patient-centered anthropological and societal parameters of EVD, as well as translational effectiveness about novel putative patient-targeted vaccine and pharmaceutical interventions, which hold strong promise, if not hope, to curb this and future Ebola outbreaks. This work reviews and discusses the principal known facts about EBOV and EVD, and certain among the most interesting ongoing or future avenues of research in the field, including vaccination programs for the wild animal vectors of the virus and the disease from global translational science perspective

Concentration of moxifloxacin in plasma and tonsillar tissue after multiple administration in adult patients.

OBJECTIVES: The antibacterial spectrum of moxifloxacin includes all the major respiratory pathogens, and its pharmacokinetics demonstrate high peak concentrations in plasma as well as at respiratory sites. Nevertheless, tonsillar tissue concentrations have never been investigated. In this study we determined the moxifloxacin concentrations in plasma and tonsillar tissue after the administration of three doses of moxifloxacin 400 mg to adult patients with chronic or recurrent tonsillitis undergoing tonsillectomy. METHODS: This was an uncontrolled, open-label, randomized, parallel group study including 35 patients assigned randomly to five groups of 7 patients each, depending on the time between the last dose of moxifloxacin and plasma and tissue sampling. Moxifloxacin was given orally once daily for 3 days; its concentrations were measured using a validated HPLC assay and fluorescence detection. Each sample was analysed twice and the mean value obtained used for the statistical analysis. Pharmacokinetic data were analysed by presenting descriptive statistics of moxifloxacin concentrations in plasma and tonsillar tissue. RESULTS: C(max) occurred at 3 h in tonsillar tissue (mean 8.96 mg/L) and in plasma (mean 3.20 mg/L), the tissue/plasma concentration ratios (mean values) being constantly >2, ranging between 2.37 (after 2 h) and 2.93 (after 24 h), which indicates a prolonged maintenance of moxifloxacin concentration in tonsillar tissue compared with plasma. Variability among patients was present at 6 h, with the tonsillar tissue/plasma concentration ratio ranging between 0.8 and 3.4. CONCLUSIONS: Moxifloxacin achieves a good penetration in tonsillar tissue, which compares favourably with that reported for other fluoroquinolones. The moxifloxacin concentrations we observed exceed the MICs for the usual respiratory tract pathogen

Concentration of moxifloxacin in plasma and tonsillar tissue after multiple administration in adult patients.

OBJECTIVES: The antibacterial spectrum of moxifloxacin includes all the major respiratory pathogens, and its pharmacokinetics demonstrate high peak concentrations in plasma as well as at respiratory sites. Nevertheless, tonsillar tissue concentrations have never been investigated. In this study we determined the moxifloxacin concentrations in plasma and tonsillar tissue after the administration of three doses of moxifloxacin 400 mg to adult patients with chronic or recurrent tonsillitis undergoing tonsillectomy. METHODS: This was an uncontrolled, open-label, randomized, parallel group study including 35 patients assigned randomly to five groups of 7 patients each, depending on the time between the last dose of moxifloxacin and plasma and tissue sampling. Moxifloxacin was given orally once daily for 3 days; its concentrations were measured using a validated HPLC assay and fluorescence detection. Each sample was analysed twice and the mean value obtained used for the statistical analysis. Pharmacokinetic data were analysed by presenting descriptive statistics of moxifloxacin concentrations in plasma and tonsillar tissue. RESULTS: C(max) occurred at 3 h in tonsillar tissue (mean 8.96 mg/L) and in plasma (mean 3.20 mg/L), the tissue/plasma concentration ratios (mean values) being constantly >2, ranging between 2.37 (after 2 h) and 2.93 (after 24 h), which indicates a prolonged maintenance of moxifloxacin concentration in tonsillar tissue compared with plasma. Variability among patients was present at 6 h, with the tonsillar tissue/plasma concentration ratio ranging between 0.8 and 3.4. CONCLUSIONS: Moxifloxacin achieves a good penetration in tonsillar tissue, which compares favourably with that reported for other fluoroquinolones. The moxifloxacin concentrations we observed exceed the MICs for the usual respiratory tract pathogens

Posaconazole oral suspension primary prophylaxis in acute leukemia and allogeneic stem cell transplant patients: can it be used without measurement of plasma concentration?

Posaconazole oral suspension (PCZ-susp) can display a variable degree of inter and intra-individual absorption. However, there is no agreement on the need of plasma-posaconazole-concentration (PPC) monitoring as a routine practice in patients receiving PCZ-susp. In this prospective, multicenter study we evaluated the variability of PPCs in hematologic patients receiving PCZ-susp prophylaxis with the aim to define conditions at different risk of subtherapeutic PPCs. Overall, 103 acute leukemia (AL) patients submitted to intensive chemotherapy (115 courses) and 46 allogeneic stem cell transplant (allo-SCT) recipients (47 courses) receiving PCZ-susp prophylaxis were considered. The adequacy of PPC pattern after the steady state (≥day 7 of treatment) in courses with two or more PPC measurements was defined as follows: inadequate pattern: PPC < 0.5 mcg/ml at least once; borderline pattern: PPC always ≥0.5mcg/ml but < 0.7 mcg/ml at least once; adequate pattern: PPC always ≥0.7 mcg/ml. The PPC pattern was evaluable in 83 and 37 AL and allo-SCT patients, respectively. It was adequate, borderline and inadequate in 63.9%, 14.5%, and 21.7% of courses, respectively, in AL, and in 62.2%, 10.8%, and 27.0% of courses, respectively, in allo-SCT. In both groups, an inadequate PPC pattern was associated with the development of diarrhea. In absence of diarrhea, the probability of an inadequate PPC pattern was 11.9% in AL and 17.2% in allo-SCT patients. PCZ-susp might be used without stringent need of PPC monitoring in patients without diarrhea

Voriconazole treatment in adults and children with hematological diseases: Can it be used without measurement of plasma concentration?

Indication and timing of trough plasma-voriconazole (VCZ)-concentration (t-PVC) measurement during VCZ treatment is a debated issue. Patterns of t-PVC were prospectively evaluated in pediatric (50 courses) and adult (95 courses) hematologic patients. Efficacy patterns were defined: adequate, t-PVC always ≥1 mcg/ml; borderline, at least one t-PVC measurement <1 mcg/ml but median value of the measurements ≥1 mcg/ml; inadequate, median value of the measurements <1 mcg/ml. Toxicity patterns were defined: favorable, t-PVC always ≤5 mcg/ml; borderline, one or more t-PVC measurements >5 mcg/ml but median value of the measurements ≤5 mcg/ml; unfavorable, median value of the measurements >5 mcg/ml. In children and adults the mean t-PVCs were higher during intravenous treatments. The t-PVC efficacy pattern was adequate, borderline and inadequate in 48%, 12%, and 40% of courses, respectively, in children, and in 66.3%, 16.8%, and 16.8% of courses, respectively, in adults. Adequate efficacy pattern was more frequent in children with body weight above the median (≥25 kg) (OR 4.8; P = .011) and in adults with active hematological disease receiving intravenous therapy (OR 3.93; P = .006). Favorable toxicity pattern was more frequent in children receiving VCZ daily dosage below the median (<14 mg/kg) (OR 4.18; P = .027) and in adults with body weight below the median (<68 kg) (OR 0.22; P = .004). T-PVC measurement is generally needed, however, a non t-PVC guided approach may be considered in heavier adults receiving intravenous VCZ. The risk of supratherapeutic levels does not seem an absolute indication for t-PVC monitoring