Interaction pharmacokinetics of pegylated liposomal doxorubicin (Caelyx) on coadministration with paclitaxel or docetaxel

Purpose To investigate the pharmacokinetics of polyethylene glycol-coated liposomal doxorubicin (PLD, Caelyx) when given as a single agent and in combination with the taxanes paclitaxel or docetaxel in humans.Methods The plasma kinetics of PLD were studied in 19 cancer patients treated with PLD every 4 weeks combined with either paclitaxel (on a weekly basis in seven and as a single infusion in three patients) or docetaxel (weekly in seven and as a single infusion in two). Plasma concentrations of PLD were quantified in two sets of samples per patient to compare the same pharmacokinetic parameters in each subject when treated with single-agent PLD and again with the combination. Total doxorubicin concentrations in plasma were quantified by HPLC. Pharmacokinetics were evaluated by noncompartmental analysis and the data obtained were compared for differences by a matched-pairs nonparametric test.Results Coadministration of paclitaxel produced a median/mean 54/80% increase in PLD AUC_inf (95% confidence interval 23% to 136%, P=0.002). The observed increase was consistent among all subjects. PLD clearance was also decelerated in the presence of paclitaxel (P=0.013) while other pharmacokinetic parameters were affected modestly. A small increase in the AUC of PLD was observed in the docetaxel/PLD arm (mean increase 12%, P=0.039) while PLD clearance decreased marginally and other pharmacokinetic parameters remained unaffected. AUC extrapolated to infinity was below 8% in both arms.Conclusions This study showed the presence of a pharmacokinetic interaction that led to higher plasma concentrations of PLD when combined with paclitaxel and to a minor extent when combined with docetaxel. This pharmacokinetic information may be of value when planning combination therapies of PLD with taxanes.     

BM88 is an early marker of proliferating precursor cells that will differentiate into the neuronal lineage

Progression of progenitor cells towards neuronal differentiation is tightly linked with cell cycle control and the switch from proliferative to neuron-generating divisions. We have previously shown that the neuronal protein BM88 drives neuroblastoma cells towards exit from the cell cycle and differentiation into a neuronal phenotype in vitro. Here, we explored the role of BM88 during neuronal birth, cell cycle exit and the initiation of differentiation in vivo. By double- and triple-labelling with the S-phase marker BrdU or the late G2 and M-phase marker cyclin B1, antibodies to BM88 and markers of the neuronal or glial cell lineages, we demonstrate that in the rodent forebrain, BM88 is expressed in multipotential progenitor cells before terminal mitosis and in their neuronal progeny during the neurogenic interval, as well as in the adult. Further, we defined at E16 a cohort of proliferative progenitors that exit S phase in synchrony, and by following their fate for 24 h we show that BM88 is associated with the dynamics of neuron-generating divisions. Expression of BM88 was also evident in cycling cortical radial glial cells, which constitute the main neurogenic population in the cerebral cortex. In agreement, BM88 expression was markedly reduced and restricted to a smaller percentage of cells in the cerebral cortex of the Small eye mutant mice, which lack functional Pax6 and exhibit severe neurogenesis defects. Our data show an interesting correlation between BM88 expression and the progression of progenitor cells towards neuronal differentiation during the neurogenic interval.     

Treatment of relapsed/refractory multiple myeloma with thalidomide-based regimens: identification of prognostic factors

We evaluated the predictive value of several parameters, including the International Staging System (ISS) for myeloma, in patients with advanced disease treated with thalidomide-based regimens (TBR). We analyzed 119 patients, from 3 phase II studies. Patients with pretreatment beta2 microglobulin<3.5 mg/l and albumin 3.5 g/dl were scored ISS stage 1, patients with beta2 microglobulin<3.5 mg/l and albumin<3.5 g/dl or beta2 microglobulin 3.5-5.5 mg/l regardless of albumin levels were scored ISS stage 2, patients with beta2 microglobulin>5.5 mg/l ISS stage 3. ISS stage was 1, 2 and 3 in 45, 32 and 23% of patients respectively. Seventy-four patients (62%) achieved at least partial response. Median progression-free and overall survival were 8 months and 19.5 months respectively. ISS stage, serum LDH and performance status were independent predictive factors for survival. Based on these 3 variables a scoring system was developed with survival times of 38.1, 28.8 and 5.8 months for scores 0, 1 and 2 respectively. The ISS staging system was highly predictive for overall survival of patients with advanced myeloma treated with TBR. With the addition of performance status and serum LDH, a simple scoring system was developed which may help select patients likely to benefit from TBR.     

Impact of adenotonsillectomy on quality of life in children with obstructive sleep disorders

OBJECTIVES: To determine the impact of adenotonsillectomy on quality of life (QOL) in children with obstructive sleep disorders (OSDs) before and after surgery. DESIGN: Prospective, observational, before-and-after trial. SETTING: Seven tertiary pediatric otolaryngology practices. PATIENTS: Convenience sample of 101 children (mean age, 6.2 years) with adenotonsillar hypertrophy and OSD scheduled for adenotonsillectomy. INTERVENTION: Adenotonsillectomy was performed in children for OSDs. Quality of life was assessed using the Obstructive Sleep Disorders-6 survey, a validated instrument for detecting QOL change in children with OSDs. Surveys were completed at the initial office visit (visit 1), the day of surgery (visit 2), and at the postoperative office visit (visit 3). Physical characteristics were assessed using tonsillar and orocraniofacial scales (visit 1). Satisfaction with health care decisions was assessed using the Satisfaction With Decision and Satisfaction With Office Visit scales (visit 1). MAIN OUTCOME MEASURES: Short-term changes in QOL before (visits 1 and 2) and after (visits 2 and 3) surgery. RESULTS: Changes in QOL before surgery were trivial or small, and smaller than changes after surgery (mean change score, 0.18 vs 2.3; P<.001). Large, moderate, and small improvements in QOL were seen in 74.5%, 6.1%, and 7.1% of children, respectively. Sleep disturbance, caregiver concern, and physical suffering were the most improved domains, although significant changes also occurred for speech and swallowing problems, emotional disturbance, and activity limitations. Five percent of children had poorer QOL after surgery, but no predictive factors were identified. CONCLUSION: Adenotonsillectomy produces large improvements in at least short-term QOL in most children with OSDs.     

Gross chylous ascites in cirrhosis with massive portal vein thrombosis: diagnostic value of lymphoscintigraphy. A case report and review of the literature

Chylous ascites is an uncommon condition, which could be due to various causes. We report a case of gross chylous ascites in a patient with cirrhosis and portal vein thrombosis. It is confirmed that gross chylous ascites in a patient with cirrhosis and portal vein thrombosis heralds an ominous prognosis for the patient. Results also demonstrate that common therapeutic interventions confer minimal benefit to the patient, whose survival may be limited to a few months. The use of lymphoscintigraphy as a convenient method for diagnostic exploration of the chylous ascites is emphasized, as it does not lead to complications or adverse effects, and can be readily repeated as needed.     

Effects of single dose administration of ifosfamide on testes and semen characteristics in the rabbit

The effects on testes and semen characteristics were studied in the rabbit after a single dose administration of the chemotherapeutic agent ifosfamide. Sexually mature male rabbits received a single intravenous injection of either 0, 60, 90, 120, or 240mg/kg body weight ifosfamide. Two phases of experimentation were conducted, lasting 1 and 18 weeks, respectively, at the end of which half of the animals from each treatment group were euthanized. Reproductive organs weighing, as well as testicular qualitative and quantitative histological examinations were performed 1 and 18 weeks post-treatment, while semen quality and libido were evaluated on a weekly basis. A decrease in the paired testes weight (90, 120, and 240mg/kg groups) and the accessory sex glands weight (240mg/kg group) were noted 1 week post-treatment. Although no histopathologic lesions or significant changes in the quantitative histologic examination were observed, semen quality examination revealed transient oligospermia (60, 90, 120, and 240mg/kg groups), teratozoospermia (120 and 240mg/kg groups), and asthenozoospermia (240mg/kg group), which returned to normal by the 6th (60 and 90mg/kg groups), 7th (120mg/kg group), or 8th week after treatment (240mg/kg group). Libido remained normal. The results suggest that ifosfamide, at a single dose, causes transient and dose-dependent depression of spermatocytogenesis (240mg/kg), spermiogenesis (60, 90, and 120mg/kg), and sperm maturation in the epididymis (240mg/kg).     

Quantitative structure -- activity relationships (QSARs) of thrombin inhibitors: review,evaluation and comparative analysis

Thrombin has become an important target for designing antithrombotic drugs in the recent years. Thus, we have undertaken a QSAR analysis aimed at individuating the physicochemical properties governing the inhibitory activity of such compounds. The QSAR equations for ten series of derivatives have been calculated and discussed. The series studied are all those that we found in the literature suitable for a QSAR study. The equations we obtained show that the main physicochemical properties affecting the inhibitory activity are almost the same for all the series and can be individuated by the use of proper parameters. The conclusions of this analysis can be summarized as follows: a). hydrophobicity plays a critical role; b). steric factors are also significant but in some cases the collinearity between steric and hydrophobic parameters does not allow one to draw any final conclusion.     

Antimicrobial activity of essential oil and methanol extracts of Achillea sintenisii Hub. Mor. (Asteraceae)

The essential oil, obtained by Clevenger distillation, and water-soluble and water-insoluble parts of the methanol extracts of Achillea sintenisii Hub. Mor. were individually assayed for their antimicrobial activities against 12 bacteria and two yeasts, Candida albicans and C. krusei. No activity was exhibited by the water-soluble subfraction, whereas both the water-insoluble subfraction of the methanol extracts and the essential oil were found to be active against some test microorganisms studied. Since the essential oil possessed stronger activity than the other extracts tested, it was further fractionated and the fractions were evaluated for their antimicrobial activity, followed by GC-MS analysis, resulting in the identification of 32 compounds which constituted 90.2% of the total oil. The GC-MS analysis of the oil and its fractions revealed that the main components of the oil, e.g. camphor and eucalyptol, possessed appreciable activity against C. albicans and Clostridium perfringens. The fi ndings presented here also suggest that the other constituents of the oil, e.g. borneol and piperitone can also be taken into account for the activity observed.