A validated LC-MS/MS assay for quantification of 24(S)-hydroxycholesterol in plasma and cerebrospinal fluid.

24(S)-hydroxycholesterol [24(S)-HC] is a cholesterol metabolite that is formed almost exclusively in the brain. The concentrations of 24(S)-HC in cerebrospinal fluid (CSF) and/or plasma might be a sensitive marker of altered cholesterol metabolism in the CNS. A highly sensitive 2D-LC-MS/MS assay was developed for the quantification of 24(S)-HC in human plasma and CSF. In the development of an assay for 24(S)-HC in CSF, significant nonspecific binding of 24(S)-HC was observed and resolved with the addition of 2.5% 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) into CSF samples. The sample preparation consists of liquid-liquid extraction with methyl-tert-butyl ether and derivatization with nicotinic acid. Good linearity was observed in a range from 1 to 200 ng/ml and from 0.025 to 5 ng/ml, for plasma and CSF, respectively. Acceptable precision and accuracy were obtained for concentrations over the calibration curve ranges. Stability of 24(S)-HC was reported under a variety of storage conditions. This method has been successfully applied to support a National Institutes of Health-sponsored clinical trial of HP-ß-CD in Niemann-Pick type C1 patients, in which 24(S)-HC is used as a pharmacodynamic biomarker.

Development and validation of sensitive LC-MS/MS assays for quantification of HP-ß-CD in human plasma and CSF.

2-Hydroxypropyl-ß-cyclodextrin (HP-ß-CD), a widely used excipient for drug formulation, has emerged as an investigational new drug for the treatment of Niemann-Pick type C1 (NPC1) disease, a neurodegenerative cholesterol storage disorder. Development of a sensitive quantitative LC-MS/MS assay to monitor the pharmacokinetics (PKs) of HP-ß-CD required for clinical trials has been challenging owing to the dispersity of the HP-ß-CD. To support a phase 1 clinical trial for ICV delivery of HP-ß-CD in NPC1 patients, novel methods for quantification of HP-ß-CD in human plasma and cerebrospinal fluid (CSF) using LC-MS/MS were developed and validated: a 2D-LC-in-source fragmentation-MS/MS (2D-LC-IF-MS/MS) assay and a reversed phase ultra performance LC-MS/MS (RP-UPLC-MS/MS) assay. In both assays, protein precipitation and "dilute and shoot" procedures were used to process plasma and CSF, respectively. The assays were fully validated and in close agreement, and allowed determination of PK parameters for HP-ß-CD. The LC-MS/MS methods are ∼100-fold more sensitive than the current HPLC assay, and were successfully employed to analyze HP-ß-CD in human plasma and CSF samples to support the phase 1 clinical trial of HP-ß-CD in NPC1 patients.

Putting evidence into practice: evidence-based interventions for the prevention and management of constipation in patients with cancer.

Constipation is a major source of distress for patients with cancer, significantly affecting quality of life. It can be secondary to disease sequelae, side effects of treatment, or preexisting conditions. It often is unrecognized, underassessed, and ineffectively managed. Nurses play a key role in the prevention and management of constipation and need evidence-based interventions. This article summarizes the existing research evidence for constipation interventions and identifies gaps. Many of the strategies have been evaluated in nononcology populations; researchers should evaluate their effectiveness in oncology populations.

Putting evidence into practice: prevention of infection.

The prevention of infection is an important outcome to measure in patients with cancer because infectious complications are a significant cause of morbidity and mortality. Nurses play a vital role in the prevention of infection in patients with cancer through nursing practice, research, and patient education. However, many common nursing interventions to prevent infection are based on tradition or expert opinion and have not been subjected to scientific examination. The 2005 Oncology Nursing Society Prevention of Infection Outcomes Intervention Project Team reviewed, critiqued, and summarized the research evidence for nursing interventions to prevent infections in patients with cancer. Pharmacologic and nonpharmacologic interventions were included because many advanced practice nurses prescribe medications. This article is an evidence-based review of nursing interventions to prevent infection in patients with cancer.

A constipation assessment scale for use in pediatric oncology.

Constipation is prevalent in pediatric oncology patients because of treatment with vinca alkaloids and/or narcotics and lifestyle changes secondary to disease process. Sequelae of constipation include anorexia, nausea, vomiting, abdominal pain, emergency department visits, and a decrease in quality of life. There are no reliable instruments to measure constipation in children. A pilot study (N = 21) evaluating the presence and severity of constipation and the reliability and validity of a modified version of the adult Constipation Assessment Scale (CAS) in children with cancer was conducted. Patients receiving weekly vinca alkaloids and/or narcotics = 2 times per day were recruited. Initial bowel function assessments included standardized nursing and nutrition assessments, history/physical review, and baseline CAS score repeated at 1 hour to assess test-retest reliability. Subsequent assessments included CAS administered 3 times per week and daily patient bowel diaries. Test-retest reliability was evident (r = .93; P = .000). Acceptable construct validity was indicated by a difference in mean CAS scores (t = 4.4, P <.001). Patients reported difficulty with CAS questions and response selections. Symptoms asked on CAS were often not viewed as a problem.