Buffered Versus Non-Buffered Lidocaine With Epinephrine for Mandibular Nerve Block: Clinical Outcomes

Outcomes for peak blood levels were assessed for buffered 2% lidocaine with 1:100,000 epinephrine compared with non-buffered 2% lidocaine with 1:100,000 epinephrine. In this institutional review board-approved prospective, randomized, double-blinded, crossover trial, the clinical impact of buffered 2% lidocaine with 1:100,000 epinephrine (Anutra Medical, Research Triangle Park, Cary, NC) was compared with the non-buffered drug. Venous blood samples for lidocaine were obtained 30 minutes after a mandibular nerve block with 80 mg of the buffered or unbuffered drug. Two weeks later, the same subjects were tested with the alternate drug combinations. Subjects also reported on pain on injection with a 10-point Likert-type scale and time to lower lip numbness. The explanatory variable was the drug formulation. Outcome variables were subjects' peak blood lidocaine levels, subjective responses to pain on injection, and time to lower lip numbness. Serum lidocaine levels were analyzed with liquid chromatography-mass spectrometry. Statistical analyses were performed using Proc TTEST (SAS 9.3; SAS Institute, Cary, NC), with the crossover option for a 2-period crossover design, to analyze the normally distributed outcome for pain. For non-normally distributed outcomes of blood lidocaine levels and time to lower lip numbness, an assessment of treatment difference was performed using Wilcoxon rank-sum tests with Proc NPAR1WAY (SAS 9.3). Statistical significance was set at a P value less than .05 for all outcomes. Forty-eight percent of subjects were women, half were Caucasian, 22% were African American, and 13% were Asian. Median age was 21 years (interquartile range [IQR], 20-22 yr), and median body weight was 147 lb (IQR, 130-170 lb). Median blood levels (44 blood samples) at 30 minutes were 1.19 μg/L per kilogram of body weight. Mean blood level differences of lidocaine for each patient were significantly lower after nerve block with the buffered drug compared with the non-buffered agent (P < .01). Mean score for pain on injection for nerve block (n = 46 scores) was 3.3 (standard deviation, 0.9). Seventy-eight percent of subjects reported lower or the same pain scores with the buffered drug; 61% of subjects reported a shorter time to lower lip numbness with the buffered drug. Buffering 2% lidocaine with epinephrine can produce clinical outcomes favorable for subjects and clinicians without clinically detrimental peak blood lidocaine levels

Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation

Aerobic glycolysis supports proliferation through unresolved mechanisms. We have previously shown that aerobic glycolysis is required for the regulated proliferation of cerebellar granule neuron progenitors (CGNP) and for the growth of CGNP-derived medulloblastoma. Blocking the initiation of glycolysis via deletion of hexokinase-2 (Hk2) disrupts CGNP proliferation and restricts medulloblastoma growth. Here, we assessed whether disrupting pyruvate kinase-M (Pkm), an enzyme that acts in the terminal steps of glycolysis, would alter CGNP metabolism, proliferation, and tumorigenesis. We observed a dichotomous pattern of PKM expression, in which postmitotic neurons throughout the brain expressed the constitutively active PKM1 isoform, while neural progenitors and medulloblastomas exclusively expressed the less active PKM2. Isoform-specific Pkm2 deletion in CGNPs blocked all Pkm expression. Pkm2-deleted CGNPs showed reduced lactate production and increased SHH-driven proliferation.13C-flux analysis showed that Pkm2 deletion reduced the flow of glucose carbons into lactate and glutamate without markedly increasing glucose-to-ribose flux. Pkm2 deletion accelerated tumor formation in medulloblastoma- prone ND2:SmoA1 mice, indicating the disrupting PKM releases CGNPs from a tumor-suppressive effect. These findings show that distal and proximal disruptions of glycolysis have opposite effects on proliferation, and that efforts to block the oncogenic effect of aerobic glycolysis must target reactions upstream of PKM