The neurotransmitter acetylcholine is an important modulator of cognitive functions including attention, learning, and memory. The actions of acetylcholine are mediated by five distinct muscarinic acetylcholine receptor subtypes (M 1 -M 5 ). The lack of drugs with a high degree of selectivity for these subtypes has impeded the determination of which subtypes mediate which components of cholinergic neurotransmission relevant to cognitive abilities. The present study examined the behavioral functions of the M 2 muscarinic receptor subtype by utilizing congenic C57BL/6 mice possessing a null-mutation in the M 2 muscarinic receptor gene (M 2 −/− mice). Comprehensive assessment of general health and neurological function found no major differences between M 2 −/− and wild-type (M 2 +/+ ) mice. In tests of learning and memory, M 2 −/− mice were impaired in the acquisition (trials to criterion), but not the retention (72 hr) of a passive avoidance task. In a novel open field, M 2 −/− mice were impaired in between-sessions, but not within-session habituation. In a holeboard test of spatial memory, M 2 −/− mice committed more errors in working memory than M 2 +/+ mice. Reference memory did not differ between the genotypes. M 2 −/− mice showed no impairments in either cued or contextual fear conditioning. These findings replicate and extend earlier findings in a hybrid strain and solidify the interpretation that the M 2 receptor plays a critical role in specific components of cognitive abilities.

Voriconazole is increasingly being used after HSCT. The hepatic cytochrome P450 isoenzyme 2C19 plays a significant role in voriconazole metabolism. As CYP2C19 exhibits significant genetic polymorphism, some patients metabolize voriconazole poorly resulting in increased plasma drug levels. However, the clinical significance of this is unknown. There is some evidence that toxicity rates are higher in patients with higher voriconazole levels (Boyd et al. Clin Infect Dis2004;39:1241–1244). In a preliminary study of 41 voriconazole levels in 25 patients, we had found that voriconazole levels correlated with aspartate aminotransferase (AST) and alkaline phosphatase (AP) levels (Trifilio et al. Bone Marrow Transplant2005;35:509–513). It was unclear if the abnormal liver function was the cause or the result of higher voriconazole levels. To further elucidate this relationship, we analyzed data on 171 steady-state plasma trough levels performed after at least 5 days of voriconazole therapy in 87 patients with hematologic malignancies. There were 1–5 levels per patient (median 2). Most patients had undergone allogeneic hematopoietic stem cell transplantation. Drug levels were monitored using HPLC (Pennick et al. Antimicrob Agents Chemother2003;47:2348–2350). Of the 201 samples assayed, 30 were below the detection limit of the assay (0.2 μg/mL), and were excluded. The daily voriconazole dose (divided into 2) was 200 mg (n=3), 400 mg (n=129), 500 mg (n=18), 600 mg (n=15), or 800 mg (n=6); corresponding to 2.0–13.3 mg/kg (median 5.3). The voriconazole levels were 0.2–12.5 μg/mL (median 1.7). The table shows the correlation between voriconazole levels, and weight, dose and biochemical parameters individually. However, in multivariate regression analysis, the parameters found to correlate significantly with voriconazole levels were ALT (P=0.0005), AST (P=0.003), and AP (P=0.027). The relationship with albumin was of borderline significance (P=0.062). Importantly, the daily dose of voriconazole in mg or in mg/kg was not predictive of drug levels. This larger data set confirms our previous observation that there is a significant relationship between elevated liver function tests and higher voriconazole levels. However, because of the relatively high frequency of abnormal liver function tests in such groups of patients, the cause-effect relationship still remains uncertain. These data suggest that pending further clarification, voriconazole levels may need to be monitored in patients with significantly abnormal liver function tests. Parameter Median (range) r P Dose (mg) 400 (200–800) 0.19 0.013 Weight (kg) 80 (39–135) 0.18 0.018 Dose (mg/kg) 5.3 (2.0–13.3) 0.23 0.002 ALT (IU/L) 25 (4–608) 0.10 0.25 AST (IU/L) 25 (6–524) 0.14 0.11 AP (IU/L) 95 (27–920) 0.27 0.002 Bilirubin (mg/dL) 1.1 (0.1–17.3) 0.01 0.89 Albumin (g/dL) 2.4 (0.8–3.9) 0.28 0.001 Creatinine (mg/dL) 1.1 (0.2–10.1) 0.01 0.92

Palonosteron is a long-acting serotonin antagonist active in chemotherapy-induced nausea and vomiting (N/V). High-dose melphalan (HDM) is highly emetogenic. Even with pre-HDM anti-emetic administration, patients require anti-emetics in the following few days. This retrospective analysis was undertaken to see if the serotonin antagonist used prior to HDM affected anti-emetic use in the first week after HDM. The treatment group comprised 20 myeloma patients who received 140–200 mg/m2 melphalan the day prior to autograft (day -1), and 0.25 mg palonosteron IV prior to HDM. The control group comprised 49 myeloma patients receiving HDM in a similar fashion with 24 mg ondasteron IV prior to HDM. The groups were otherwise comparable. In accordance with our standard policy, no anti-emetic administration was scheduled from the day of transplant (day 0) onwards, and anti-emetics were administered based on patient needs as assessed by the nursing staff, the clinical team on rounds, and patient symptoms/request. The agents administered for breakthrough symptoms were lorazepam (1 mg/dose), prochlorperazine (10 mg/dose), metoclopramide (10 mg/dose), ondansetron (8 mg/dose), and promethazine (12.5 mg/dose) singly or in combination. As the table below shows, starting 2 days after palonosetron administration, about half the patient complained of some nausea and 10–25% experienced emesis. Day Nausea Vomiting 0 10% 5% 1 50% 25% 2 60% 5% 3 50% 10% 4 60% 15% 5 35% 10% 6 40% 25% The palonosteron and ondansetron groups were compared based on the actual use of breakthrough anti-emetic medications starting the day after drug administration rather than symptoms to avoid bias. Day Any drug used for breakthrough Ondansetron used for breakthrough (0=HSCT) Palonosetron group Ondansetron group P Palonosetron group Ondansetron group P 0 30% 84% <0.0001 0% 41% <0.0001 1 50% 78% 0.024 5% 51% <0.0001 2 55% 86% 0.006 5% 59% <0.0001 3 55% 92% <0.0001 5% 59% <0.0001 4 70% 90% 0.042 20% 47% 0.056 5 65% 84% 0.16 15% 53% 0.006 6 75% 86% 0.29 20% 47% 0.056 As the table above shows, the need for breakthrough anti-emetic medications was significantly less in the palonosetron group than in the ondansetron group. Approximately 50% of patients in the ondansetron group needed ondansetron every day after the initial dose on day -1. The proportion of patients getting ondansetron in the palonosetron group was 5–20% - significantly lower for first 4 days. For the 7 days studied, the average daily cost for breakthrough medications in the palonosteron group per patient was $11.37 (range 0.90–24.49) compared to $56.21 (range 28.15–62.97) in the ondansetron group. The total average drug cost per patient (including the prophylactic drug) was $473.89 in the palonosteron group and $511.30 in the ondansetron group. We conclude that the use of palonosetron before HDM and autotransplantation, because of the long-acting nature of the drug, results in significantly better control of N/V than ondansteron. In addition to being better from the symptomatic perspective, the decreased requirement for other agents to treat breakthrough N/V after palonosetron - especially reduction in the use of ondansetron - results in an overall cost saving.