Intracellular ATP depletion inhibits swelling-induced -[H]aspartate release from primary astrocyte cultures

Volume expansion-sensing outward rectifier (VSOR) anion channel, also referred to as volume-sensitive organic osmolyte-anion channel (VSOAC), appears to be responsible for cell swelling-induced amino acid release in a variety of cells. One prominent feature of the VSOR/VSOAC is that non-hydrolyzed intracellular ATP binding to the channel or an accessory protein is required for its activation. In this study, the effect of intracellular ATP depletion on the swelling-induced release of -[³H]aspartate from rat primary astrocyte cultures due to exposure to either high K⁺ or hypotonic media was studied. When the cells were pretreated for 10 min with a combination of the metabolic inhibitors 2-deoxyglucose and rotenone, 100 mM K⁺ media- or hypotonic media-induced -[³H]aspartate release was completely suppressed. Added separately, each inhibitor showed only partial or no inhibition of -[³H]aspartate release, which correlated with its relative effectiveness in decreasing intracellular ATP levels. These data are consistent with the view that during high [K⁺]_o or hypotonic media-induced swelling of primary astrocyte cultures an ATP-dependent swelling-activated VSOAC channel is responsible for -[³H]aspartate release and close to normal ATP is required for full channel activation.     

Smoking and Carboxyhemoglobin in the St. Louis Metropolitan Population

The most important source of carbon monoxide (CO) exposure is smoking. If a person smokes and inhales, the carboxyhemoglobin (COHb) level in his blood is due primarily to smoking, and other sources of CO exposure are relatively unimportant. The COHb data for smokers are analyzed by type of smoking, sex, and whether or not the subject has an industrial occupation. Data indicate that men and women who smoke at the same rate reach the same equilibrium level of COHb, but women achieve lower COHb levels after ceasing smoking for the day. Restriction or elimination of cigarette smoking makes the most sense for protecting the atherosclerotic population from chronic CO exposure.     

Clinical evaluation of oral mexiletine therapy in the treatment of ventricular arrhythmias

The effect of oral mexiletine therapy on ventricular arrhythmias was evaluated in 58 patients in whom conventional drugs had been unsuccessful. Mean daily dose of mexiletine was 652 mg (range 250 to 1,500) and mean duration of therapy was 14.4 months (range 0.1 to 34.4). Mexiletine was associated with a decrease of 52% in total premature ventricular complexes in 24 hours compared with control (6,841 +/- 1,053 [SEM] versus 3,248 +/- 734, p less than 0.005) and 19 patients (36.5%) had a greater than 83% decrease in ventricular ectopic rhythm. The drug was discontinued in 6 of these 19 patients because 5 of them (26%) experienced side effects after a mean period of 29.6 weeks (range 0.83 to 63.2) and sudden death occurred in 1 patient (5%); this indicates effective suppression of ventricular ectopic rhythm without significant side effects in 13 (25%) of 52 patients during long-term therapy. Adjustment of drug dosage to achieve therapeutic blood levels resulted in an efficacy on ventricular ectopic rhythm similar to that obtained with the maximal tolerated dose. There was no correlation between drug dose and therapeutic effectiveness. Mexiletine was associated with a 48% decrease in episodes of ventricular tachycardia (345.5 versus 179.3/24 h) and 5 of 10 patients with a history of cardiac arrest remained free of symptomatic ventricular tachyarrhythmias for 14.8 months (range 3.7 to 24.3).(ABSTRACT TRUNCATED AT 250 WORDS)     

Bevacizumab and Temozolomide Plus Radiation Regimen for Glioblastoma Multiforme

The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: OncRxSvc@comcast.net; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: ten.retrahc@ruofddaw. Regimen name: Bevacizumab and temozolomide plus radiationOrigin of name: The regimen is named for the 3 components comprising the regimen; bevacizumab, temozolomide, and radiation.     

Hemostatic plug formation in normal and von Willebrand pigs: the effect of the administration of cryoprecipitate and a monoclonal antibody to Willebrand factor

Hemostatic plug (HP) formation was investigated in the ear bleeding time incision in normal and von Willebrand pigs. HP volume was calculated by integrating the areas of serial sections. In normal pigs (n = 11), platelets immediately formed a layer on the surface of the cut channel. Platelet aggregates formed at the ends of transected vessels and gradually enlarged. Finally, all transected vessels were occluded by HP and bleeding stopped. In contrast, large HPs were formed in the incision in von Willebrand's disease (vWD) pigs (n = 4); these HPs did not cover the ends of the transected vessels, which continued to bleed, allowing the formation of large hemostatically ineffective platelet aggregates in the incision. Canals traversed these HPs, and bleeding from the open vessels may have continued through them. After infusion of cryoprecipitate into a vWD pig, the bleeding time shortened, and the morphological findings of the HPs were similar to those of normal pigs. In normal pigs (n = 3) infused with an anti- Willebrand factor monoclonal antibody, which prolonged the bleeding time, a large HP formed in the incision, similar to that observed in the vWD pig. The volume of the normal and vWD HPs increased with time. These in vivo findings suggest that Willebrand factor is involved in the localization of the HP to the damaged vessel and may also play a role in platelet-platelet interaction. A computerized morphometric technique was used for measuring the volume of the hemostatic plugs and the distance of sequential points on the perimeter of the HP from the center of selected bleeding vessels.