An explorative approach to understanding individual differences in driving performance and neurocognition in long-term benzodiazepine users.

OBJECTIVE: Previous research reported cognitive and psychomotor impairments in long-term users of benzodiazepine receptor agonists (BZRAs). This article explores the role of acute intoxication and clinical complaints. METHODS: Neurocognitive and on-road driving performance of 19 long-term (≥6 months) regular (≥twice weekly) BZRA users with estimated plasma concentrations, based on self-reported use, exceeding the therapeutic threshold (CBZRA +), and 31 long-term regular BZRA users below (CBZRA -), was compared to that of 76 controls. RESULTS: BZRA users performed worse on tasks of response speed, processing speed, and sustained attention. Age, but not CBZRA or self-reported clinical complaints, was a significant covariate. Road-tracking performance was explained by CBZRA only. The CBZRA  + group exhibited increased mean standard deviation of lateral position comparable to that at blood-alcohol concentrations of 0.5 g/L. CONCLUSIONS: Functional impairments in long-term BZRA users are not attributable to self-reported clinical complaints or estimated BZRA concentrations, except for road-tracking, which was impaired in CBZRA + users. Limitations to address are the lack of assessment of objective clinical complaints, acute task related stress, and actual BZRA plasma concentrations. In conclusion, the results confirm previous findings that demonstrate inferior performance across several psychomotor and neurocognitive domains in long-term BZRA users.

Discovery of Indoline-2-carboxamide Derivatives as a New Class of Brain-Penetrant Inhibitors of Trypanosoma brucei.

There is an urgent need for new, brain penetrant small molecules that target the central nervous system second stage of human African trypanosomiasis (HAT). We report that a series of novel indoline-2-carboxamides have been identified as inhibitors of Trypanosoma brucei from screening of a focused protease library against Trypanosoma brucei brucei in culture. We describe the optimization and characterization of this series. Potent antiproliferative activity was observed. The series demonstrated excellent pharmacokinetic properties, full cures in a stage 1 mouse model of HAT, and a partial cure in a stage 2 mouse model of HAT. Lack of tolerability prevented delivery of a fully curative regimen in the stage 2 mouse model and thus further progress of this series.

17 beta-estradiol stimulation of uterine blood flow in oophorectomized rabbits with complete inhibition of uterine ribonucleic acid synthesis.

The 17 beta-estradiol-induced increase of uterine blood flow (UBF) was studied in 7- to 8-month-old oophorectomized rabbits 6-39 days after operation. Baseline blood flows were determined with 141Ce-labeled microspheres and 2-h flows with 85Sr-labeled microspheres. Mean UBF in control groups ranged from 0.11-0.26 mi/min . g. Mean UBF 2 h after 17 beta-estradiol (10 microgram/kg BW) was 1.51 ml/min . g. Utilizing [3H]uridine (100 microCi/kg 15 min before the 2-h flow study), 3H incorporation into uterine RNA was 2-fold higher than background. Estradiol treatment produced a 4-fold increase in 3H incorporation into uterine RNA. Estradiol-treated animals, pretreated with actinomycin D (4 mg/kg), increased UBF to 1.09 ml/min . g 2 h after estradiol but failed to increase uterine RNA synthesis. 3H incorporation into uterine RNA in this group was suppressed to undetectable (background) levels. These findings indicate that a mechanism other than accelerated transcription, whether induced directly or by translocation of a cytosolic receptor, underlies the increased UBF after estradiol administration to oophorectomized rabbits.

Scintigraphic detection of osteomyelitis with Tc-99m MDP and Ga-67 citrate: concise communication.

Using both Tc-99m methylene diphosphonate and gallium-67 citrate, images of the lower extremities in New Zealand white rabbits were obtained on sequential days after inoculation of tibias with Staphylococcus aureus. Gallium-67 scintigraphy was positive earlier in the course of infection than Tc-99m MDP scintigraphy. In addition to 4-hr Ga-67 scintigrams, 24-hr and 48-hr scintigrams were obtained, contributing substantially to interpretation. However, 72-hr Ga-67 scintigrams contributed little additional information.

Predicting the cure of osteomyelitis under treatment: concise communication.

The right tibias of sixty-six rabbits were injected with a suspension of Staphylococcus aureus and sodium morrhuate. After four weeks, 43 rabbits developed osteomyelitis and were started on a course of antibiotics. During treatment a gallium-67 scintigram was obtained every two weeks, for up to 10 weeks. During the treatment weeks, 25 rabbits developed negative gallium-67 scintigrams and were killed. All 25 had negative bacteriologic cultures of the right tibia. At the end of 10 wk after start of treatment, the 18 rabbits with persistently positive scintigrams were killed. Eleven of these had positive bacteriologic cultures of the tibia, and seven were negative. The findings suggest that sequential gallium-67 scintigrams may be useful in predicting the cure of osteomyelitis during treatment.

The role of Tc-99m MDP and Ga-67 citrate in predicting the cure of osteomyelitis.

Twenty rabbits with chronic osteomyelitis of the tibia were treated for eight weeks and then scanned with Tc-99m MDP and Ga-67 citrate. All were sacrificed and bacteriologic cultures of the tibia were obtained. All rabbits had positive Tc-99m MDP scans at the end of treatment despite thirteen cures of osteomyelitis. Eight had negative gallium scans and negative cultures. Five of the twelve positive gallium scans had negative cultures, while seven had positive cultures. Tc-99m MDP alone is not sensitive enough to be useful in predicting the cure of osteomyelitis, and combining Tc-99m MDP and Ga-67 citrate scintigrams offers no additional information over the Ga-67 citrate scintigram alone in follow-up of osteomyelitis.