Bioavailability, pharmacokinetics, and clinical effects of an oral preparation of etoposide

Bioavailability of an oral preparation of the antineoplastic drug etoposide (VP-16) was studied in 13 patients with advanced malignancies. An initial pilot study involving three patients suggested that approximately 50% of an orally administered dose was absorbed. Ten additional patients were randomized to receive either 100 mg/m2/day iv or 200 mg/m2/day orally. Three weeks later, the alternate dose schedule was administered. Plasma samples were assayed for VP-16 using a high-pressure liquid chromatography technique. Comparison of the area under concentration-time curves (C X t) revealed that 17%-72% (mean, 52%) of an orally administered dose was absorbed. Absorption was less than 40% for only one patient. For oral and iv preparations, mean peak plasma VP-16 concentrations were 9.6 and 13.0 micrograms/ml, mean alpha-half-lives were 0.96 and 0.82 hour, mean beta-half-lives were 7.2 and 6.8 hours, mean C X t values were 75.9 and 75.3 mg/L/hour, mean plasma clearances were 1.44 and 1.45 L/hour/m2, and mean extrapolated volumes of distribution were 15.2 and 16.9 L/m2, respectively. The half-life for oral absorption was 0.44 hour and peak plasma concentrations were noted 0.5-3 hours after oral drug administration. Granulocyte count nadirs tended to be lower in patients with high C X t values and low plasma clearance values. Granulocytopenia was dose-limiting. Gastrointestinal toxicity was extremely mild. We recommend doses of oral VP-16 of 800 mg/m2/course over 3-5 days for patients with a moderate amount of prior treatment. It is probable that previously untreated patients will tolerate a higher dose and that heavily pretreated patients will require a lower dose.     

Risk factors and outcome of ventilator associated tracheitis (VAT) in pediatric trauma patients

We sought to investigate the risk factors and outcome of Ventilator Associated Tracheitis (VAT) according to the Center for Disease Control (CDC) definition in pediatric trauma patients who were ventilated for ≥48 hr. In a retrospective cohort study, medical records of all pediatric trauma patients admitted to our Pediatric Intensive Care Unit (PICU) between April 2002 and April 2007 were reviewed. Medical records were reviewed for patients' demographics, Trauma Injury Severity Score (TISS), Glasgow Coma Scale (GCS), type of trauma, and other potential risk factors prior to the development of VAT (such as hyperglycemia, rate of re‐intubation and tracheotomy, presence of chest tubes and central lines, urinary tract infection, seizures, need for cardiopulmonary resuscitation, use of total parental nutrition, transfusion, use of H₂ blockers, steroids, and pressors/inotropes). Medical records were also reviewed for days of mechanical ventilation, PICU length of stay, and PICU mortality. During the study period, 217 trauma patients were admitted to the PICU, 113 patients met our inclusion criteria and 21.2% (24/113) developed VAT. On average patients with VAT (in comparison to patients without VAT), had a higher TISS score on admission [38.6 ± 16.9 vs. 24.2 ± 10.6; respectively (P < 0.01)], longer days of ventilation and PICU length of stay [11.5 ± 6.2 vs. 3.7 ± 2.3 days (P < 0.001) and 16.4 ± 8.3 vs. 5.4 ± 2.8 days (P < 0.001), respectively]. There was no difference in mortality between the two groups. In a logistic regression model adjusting for possible confounders, the TISS score (adjusted OR 7.53; CI: 2.01–28.14; P = 0.03 and use of pressors/inotropes (adjusted OR 4.64; CI: 1.28–16.86; P = 0.01) were the only independent risk factors associated with VAT. We conclude that the severity of illness and use of pressors/inotropes are associated with VAT in pediatric trauma patients. We also conclude that VAT is associated with an increase in days of mechanical ventilation and PICU length of stay in pediatric trauma patients. Pediatr Pulmonol. 2013; 48:176–181. © 2012 Wiley Periodicals, Inc.     

Isolation and Characterization of Lytic Pseudomonas aeruginosa Bacteriophages Isolated from Sewage Samples from Tunisia

Bacteriophages could be a useful adjunct to antibiotics for the treatment of multidrug-resistant Pseudomonas aeruginosa infections. In this study, lytic P. aeruginosa myoviruses PsCh, PsIn, Ps25, and Ps12on-D were isolated from Tunisian sewage samples. Phage Ps12on-D displayed an adsorption time of ~10 min, a short latency period (~10 min), and a large burst size (~115 PFU per infected cell) under standard growth conditions. All phages were active at broad temperature (4 °C to 50 °C) and pH (3.0 to 11.0) ranges and were able to lyse a wide variety of P. aeruginosa strains isolated from clinical and environmental samples worldwide. Illumina sequencing revealed double-stranded DNA genomes ranging from 87,887 and 92,710 bp with high sequence identity to Pseudomonas phage PAK_P1. All four phages based on sequence analysis were assigned to the Pakpunavirus genus. The presented characterization and preclinical assessment are part of an effort to establish phage therapy treatment as an alternative strategy for the management of multidrug-resistant P. aeruginosa infections in Tunisia.     

Early-onset breast cancer in a Lebanese family with Lynch syndrome due to MSH2 gene mutation

Background

There are still controversies about the integration of breast cancer as a part of the disease spectrum in Lynch syndrome.

Methods

A regular follow-up of a Lebanese pedigree with Lynch syndrome due to a point mutation of MSH2 gene at the splice donor site of intron 3 started in 1996.

Results

A 26-year-old pregnant woman, mutation carrier, developed an aggressive breast cancer, refractory to standard chemotherapy regimens. The microsatellite analysis of the tumor showed an unstable pattern for markers BAT25 and BAT26. The immunohistochemical staining was negative for MSH2 and MSH6 and normal for MLH1 and PMS6 enzymes.

Conclusion

The segregation of the mutation with the disease phenotype and these results suggest that MSH2 inactivation may be involved in the accelerated breast carcinogenesis and might be considered in the cancer screening program.     

Multicenter phase II study of brequinar sodium in patients with advanced gastrointestinal cancer

Summary Eighty-six patients with advanced colorectal, gastric or pancreatic carcinoma and no prior exposure to chemotherapy were treated with brequinar sodium. Brequinar was administered at a median weekly dose of 1200 mg/m² intravenously. The toxicity was moderate, with thirty patients (35%) experiencing grade 3 or 4 toxicity. Objective responses were observed in 1/32 evaluable colorectal and 2/29 evaluable gastric carcinoma patients. There were no objective responses in 17 evaluable pancreatic cancer patients. We conclude that, at this dose and schedule, brequinar does not have sufficient activity in these gastrointestinal malignancies to warrant further evaluation.     

Kidney transplantation after a severe form of pseudotumor cerebri

Pseudotumor cerebri is a syndrome characterized by intracranial hypertension (intracranial pressure >200 mmH₂O) and a normal ventricular system. The diagnosis should be made as early as possible to prevent impairment of vision. Several diseases have been reported in association with pseudotumor cerebri in pediatric patients, and have been occasionally also noted with chronic renal failure, heart and renal transplantation. We report a 7-year-old boy who complained of severe headaches and visual impairment 2 years after hemodialysis for renal hypoplasia. Pseudotumor cerebri was suspected and, despite treatment with corticosteroids, acetazolamide, and lumboperitoneal diversion, visual impairment worsened. Bilateral optic nerve sheath decompression (ONSD) was performed without success and the child completely lost his vision within 2 weeks. He was successfully transplanted 2 months later. Two years post transplantation, the blind child has a normal renal function and school performance. Pseudotumor cerebri must be rapidly suspected in a child with renal failure suffering from headaches and papilledema. Visual loss may progress rapidly and ONSD seems to be the best surgical treatment when medical treatment fails. In this patient renal transplantation was well tolerated, with no deterioration in the neurological status over 2 years of follow-up. Received December 30, 1997; received in revised form April 23, 1998; accepted June 15, 1998     

A comparison of epidural tramadol and epidural morphine for postoperative analgesia

The present study compared epidural tramadol with epidural morphine for postoperative analgesia in 20 patients undergoing major abdominal surgery. Intraoperatively, the patients were anaesthetized by a balanced technique of general anaesthesia combined with lumbar epidural lidocaine. In ten of the patients 100 mg tramadol diluted in 10 ml normal saline was also injected epidurally, while 4 mg epidural morphine was used in the other ten patients. In all patients, the visual analogue pain score, PaO₂, PaCO₂ and respiratory rate were monitored every hour for the first 24 hr postoperatively. In both the tramadol and morphine groups, the mean hourly pain scores ranged from 0.2 ± 0.6 to 1.4 ± 2.5 throughout the period of observations. However, the mean PaO₂ was decreased postoperatively in the epidural morphine group, while no change was observed in the epidural tramadol group. The maximal decrease of PaO₂ in the epidural morphine group was observed at the tenth hour postoperatively, when it decreased to 72.8 ± 10.3 mm Hg. This was not associated with any increase in PaCO₂ or a decrease of respiratory rate, suggesting that hypoxaemia rather than hypercarbia or decreased respiratory rate may be an earlier indicator of respiratory depression in patients breathing room air without oxygen supplementation. The absence of clinically relevant respiratory depression following epidural tramadol compared with epidural morphine may be attributed to the different mechanisms of their analgesic action. The results suggest that epidural tramadol can be used to provide prolonged postoperative analgesia without serious side effects.