Targeting glucose consumption and autophagy in myeloma with the novel nucleoside analogue 8-aminoadenosine.

Multiple myeloma, an incurable plasma cell malignancy, is characterized by altered cellular metabolism and resistance to apoptosis. Recent connections between glucose metabolism and resistance to apoptosis provide a compelling rationale for targeting metabolic changes in cancer. In this study, we have examined the ability of the purine analogue 8-aminoadenosine to acutely reduce glucose consumption by regulating localization and expression of key glucose transporters. Myeloma cells counteracted the metabolic stress by activating autophagy. Co-treatment with inhibitors of autophagy results in marked enhancement of cell death. Glucose consumption by drug-resistant myeloma cells was unaffected by 8-aminoadenosine, and accordingly, no activation of autophagy was observed. However, these cells can be sensitized to 8-aminoadenosine under glucose-limiting conditions. The prosurvival autophagic response of myeloma to nutrient deprivation or to nucleoside analogue treatment has not been described previously. This study establishes the potential of metabolic targeting as a broader means to kill and sensitize myeloma and identifies a compound that can achieve this goal.

A comparison of epinephrine concentrations in local anesthetic solutions using a "wash" versus measured technique.

INTRODUCTION: Anesthesiologists often prepare epinephrine-containing local anesthetic solutions. We compared epinephrine concentrations of solutions prepared using the "wash" technique with solutions prepared using the measured technique (using an insulin syringe), and compared epinephrine concentrations among anesthesiologists. METHODS: Five anesthesiologists prepared syringes for spinal and epidural anesthesia using both techniques. Epinephrine concentrations were measured using high-performance liquid chromatography. RESULTS: Measured technique concentrations were higher than those of the wash technique for the spinal but not epidural solutions. CONCLUSIONS: Concentrations of all measured spinal solutions were higher than the target concentrations, as were concentrations of three of five measured epidural solutions. There were significant differences among anesthesiologists.

Gastric emptying of water in obese pregnant women at term.

BACKGROUND: Healthy nonpregnant and pregnant patients may ingest clear liquids until 2 h before induction of anesthesia without adversely affecting gastric volume. In this study, we compared gastric emptying in obese, term, nonlaboring pregnant women (prepregnancy body mass index >35 kg/m2) after the ingestion of 50 and 300 mL of water. METHODS: Gastric emptying was assessed in 10 obese, term pregnant volunteers using both serial gastric ultrasound examinations and acetaminophen absorption in a crossover study design. After an overnight fast, volunteers ingested 1.5 g acetaminophen and 50 or 300 mL water (randomly assigned) on two occasions separated by at least 2 days. Serial gastric antrum cross-sectional areas were determined using gastric ultrasound imaging and the half-time to gastric emptying (T([1/2])) was calculated. Areas under the plasma acetaminophen concentration versus time curve (AUC), peak concentrations (C(max)), and time to peak concentration (t(max)) for 50 mL and 300 mL ingestions were compared. RESULTS: Mean prepregnancy body mass index was 41 +/- 9 kg/m(2). Gastric emptying T([1/2]) was not different after ingestion of 300 mL water compared with 50 mL (23 +/- 11 min vs 32 +/- 15 min). There were no differences between acetaminophen AUCs at 60, 90, or 120 min, C(max) or t(max) after ingestion of 300 mL compared with 50 mL of water. CONCLUSIONS: Gastric emptying in obese, nonlaboring term pregnant women is not delayed after ingestion of 300 mL compared with 50 mL of water. Gastric antral volume after ingestion of 300 mL of water is similar to the baseline fasting level at 60 min.

Pharmacokinetics of midazolam, propofol, and fentanyl transfer to human breast milk.

BACKGROUND AND OBJECTIVES: Lactating women undergoing operations requiring general anesthesia are advised to pump and discard their milk for 24 hours after the procedure. Data on anesthetic drug transfer into breast milk are limited. This study determined the pharmacokinetics of midazolam, propofol, and fentanyl transfer into milk to provide caregivers with data regarding the safety of breast milk after administration of these drugs. METHODS: Five lactating women participated in this study after providing institutionally approved written informed consent. Patients underwent premedication with midazolam before induction of anesthesia with propofol and fentanyl. Anesthesia was maintained with a potent volatile anesthetic. Milk and blood were collected before drug administration. Milk was collected 5, 7, 9, 11, and 24 hours after drug administration. Venous blood was collected at intervals up to 7 hours. Plasma and milk midazolam, propofol, and fentanyl concentrations were measured by HPLC with tandem mass spectrometric or fluorescence detection. The pharmacokinetics of drug transfer into milk was modeled with plasma pharmacokinetics. RESULTS: Plasma midazolam, propofol, and fentanyl pharmacokinetics were consistent with reports of others. In 24 hours of milk collection, averages of 0.005% (range, 0.002%-0.013%) of the maternal midazolam dose, 0.027% (0.004%-0.082%) of the propofol dose, and 0.033% (0.006%-0.073%) of the fentanyl dose were collected in milk, representing averages of 0.009%, 0.025%, and 0.039% of the respective elimination clearances. CONCLUSION: The amount of midazolam, propofol, and fentanyl excreted into milk within 24 hours of induction of anesthesia provides insufficient justification for interrupting breast-feeding.