Temozolomide-induced severe myelosuppression: analysis of clinically associated polymorphisms in two patients.

Genotyping of putative determinants of temozolomide (TMZ)-induced life-threatening bone marrow suppression was performed in two patients with glioma treated with adjuvant TMZ and radiation therapy. DNA was extracted from the patients' mononuclear cells and genotyping of O-methylguanine-DNA-methyltransferase (MGMT), multidrug resistance (MDR1; also known as ABCB1), NQO1, and GSTP1 genes and analysis for the epigenetic silencing of specific MGMT gene promoters were carried out to evaluate the possible genetic determinants of increased risk of severe TMZ-induced myelosuppression. Although both patients were heterozygous for all ABCB1 single nucleotide polymorphisms and for rs12917 and rs1803965 in the MGMT gene, patient 1 was heterozygous for rs1695 in GSTP1 and rs2308327 in the MGMT gene. This patient also exhibited GG genotype for the MGMT single nucleotide polymorphisms, rs2308321, which is noteworthy for its 0.7% frequency globally. Epigenetic silencing of MGMT gene was not detected in either patient. Two single nucleotide polymorphisms identified in patient 1 (missense I143V and K178R polymorphisms; rs2308321 and rs2308327, respectively) have recently been shown to correlate with an increased risk of severe TMZ-induced myelosuppression. The polymorphisms identified in patient 2 have not been associated with an increased risk of severe TMZ-induced myelosuppression. Genotyping analyses of larger patient populations administered TMZ are required to validate the genetic determinants of severe TMZ-induced myelosuppression.

The Effect of Prerequisite Pharmacodynamics Course Timing on Student Performance in Pharmacotherapy Courses.

Objective. To evaluate the impact that decreasing the time from 12 to three months between prerequisite pharmacodynamics courses and their corresponding pharmacotherapy courses had on overall student performance in the pharmacotherapy courses measured by course examination scores. Methods. Two cohorts of second-professional year (P2) and third professional year (P3) classes, respectively, following different curriculum plans, simultaneously took two pharmacotherapy courses (infectious disease and neoplastic disease). Admission data (age, gender, prior bachelor's degree status, grade point average (GPA), Pharmacy College Admission Test (PCAT) score, and interview score) were collected to establish baseline characteristics between the two cohorts. Examination scores in the corresponding prerequisite pharmacodynamics and pharmacotherapy courses were also collected. The variable was the difference in time each cohort experienced between the prerequisite pharmacodynamics courses and the subsequent pharmacotherapy courses. Results. No difference was found in baseline admission characteristics between the two cohorts, except for increased average age, which favored the P2 cohort. In the infectious disease pharmacotherapy course, the P3 cohort performed better than the P2 cohort as measured by average examination scores. In the neoplastic disease pharmacotherapy course, the P3 cohort also achieved significant higher average examination scores than the P2 cohort. The P3 cohort achieved higher overall scores than the P2 cohort in both courses despite a longer interval between the applicable pharmacodynamic and pharmacotherapy courses (12 months vs 3 months, respectively). Conclusion. Shortening the time interval from 12 months to three months between prerequisite and requisite courses did not result in improved, or even equivalent, academic performance relative to the P2 cohort that had only a 3-month interval between courses. Placing like content closer together, as the only intervention, is not enough to ensure improved student performance measured by examination scores in corresponding requisite courses.

Clinical applications of colony-stimulating factors: a historical perspective.

The development of the therapeutic roles of filgrastim and sargramostim over the past decade is reviewed. Filgrastim, a recombinant granulocyte colony-stimulating factor (G-CSF), and sargramostim, a recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF), have been available in the United States for over a decade to treat various types of neutropenia. In addition, data are available to support their use in a variety of clinical settings. Because of the high cost of these agents, clinical guidelines for their appropriate use have been developed. With respect to the comparability of filgrastim and sargramostim, the American Society of Clinical Oncology recommends that additional data be generated since current data are insufficient to adequately address this question in each clinical setting. A limited number of randomized, comparative trials have directly compared filgrastim with sargramostim. Outcomes data from these trials are reviewed. Further, there is evidence to suggest that, at least for GM-CSF, tolerability is dependent on the degree of protein glycosylation. A nonglycosylated protein, molgramostim, available in Europe appears to be associated with greater toxicity in clinical trials, although randomized comparative trials are lacking. The therapeutic equivalence of CSFs requires further study. While data show that the efficacy and tolerability of CSFs are similar in certain settings, there has been no definitive, randomized, large-scale clinical trial conducted to address this issue. Pharmacists should continue to evaluate clinical data to determine not only which CSF to use but also when a CSF should be used.

The conversion challenge: from intrathecal to oral morphine.

Numerous articles have described the methodologies used and outcomes achieved with the intrathecal (IT) administration of morphine for pain. However, only one case report has been published that describes converting a patient's IT morphine to an oral regimen. This case report describes the experience of converting a patient's IT morphine to oral morphine and discusses the scarcity of published data to validate suggested equianalgesic intraspinal morphine recommendations. The calculated equianalgesic oral to IT ratio in this case was 12:1. This is substantially lower than the 300:1 ratio published by Krames and the 90:1 ratio employed by a commercially available software program for calculating equianalgesic opioid doses. We recommend caution when applying existing guidelines for conversion of morphine from an IT to an oral regimen.

Evaluation of methadone absorption after topical administration to hospice patients.

CONTEXT: Increased use of methadone (MTD) applied topically as an extemporaneously compounded gel was documented on routine review of medication profiles of hospice patients. A literature search did not identify any published clinical studies assessing the systemic absorption or clinical efficacy of MTD administered topically to intact skin for systemic pain. OBJECTIVES: To compare serum MTD levels achieved after topical and oral administration to hospice patients. METHODS: To assess the absorption of MTD administered topically, two steady-state serum levels were determined in 10 patients administered MTD topically (10-45 mg/day as powder dissolved in ethoxydiglycol added to the calculated volume of pluronic lecithin organogel [PLO]), five patients administered MTD orally (PO) (15-40 mg/day), and one subject administered placebo topically. RESULTS: MTD levels from the subject administered placebo were <10 ng/mL. Eighteen of 20 serum MTD concentrations from nine patients administered topical MTD were identical to those in the placebo control. Only one of 10 patients administered topical MTD achieved measurable serum MTD levels. This patient was on the highest topical dose administered (45 mg/day) and achieved a mean serum concentration of 25.8 ng/mL (18-35 ng/mL). All MTD serum concentrations from patients administered oral MTD exceeded the lower limit of the reference range (10 ng/mL). The range of concentrations in the oral group ranged from 62 to 393 ng/mL (mean=150.9 ng/mL). CONCLUSION: The topical application of an MTD-PLO gel in doses <45 mg/day did not result in trough MTD serum concentrations associated with analgesia. An observer placebo response may explain the perceived benefit of MTD applied topically as a PLO gel in doses <45 mg/day. The evaluation of systemic absorption of MTD-PLO gel in doses >45 mg/day is warranted.

A hospice-based advanced pharmacy experience.

OBJECTIVE: To evaluate a hospice-based advanced pharmacy practice experience (APPE). DESIGN: Two years of data gathered from student evaluation forms and reflective journals were analyzed. ASSESSMENT: Students completed reflective journals and expressed a high level of satisfaction with the hospice-based learning experience. They gained a better understanding of end-of-life care provided by a hospice and the pharmacist's role in optimizing supportive care for patients receiving hospice care. CONCLUSION: Hospice-based APPEs can provide a rich interdisciplinary learning environment for pharmacy students interested in developing knowledge, attitudes, and skills to effectively manage the pharmacotherapy of patients receiving end-of-life care.