Recovery of Cognitive and Behavioural Function During Long-term Inpatient Rehabilitation in Patients with Moderate-To-Severe Traumatic Brain Injury: Evaluation of a Retrospective Case Series.

OBJECTIVE: To elucidate the characteristics of recovery progression during long-term rehabilitation after moderate-to-severe traumatic brain injury. METHODS: Longitudinal changes in consciousness, swallowing disorders, activities of daily living, and psychological and behavioural status were studied in 7 patients with moderateto-severe traumatic brain injury, using scores of the National Agency for Automotive Safety & Victim's Aid (NASVA score), Glasgow Coma Scale (GCS), Dysphagia Severity Scale (DSS), Eating Status Scale (ESS), Functional Independence Measure (FIM), Cognitive-related Behavioural Assessment (CBA), and Neuropsychiatric Inventory (NPI). Scores were collected every month until discharge (median 359 days after injury), or until the study end date for those patients who remained hospitalized (432 days). RESULTS: Patients were qualitatively classified into those who improved well in the early phase, in terms of consciousness, swallowing, and activities of daily living, and those with less or delayed improvement. Psychological and behavioural difficulties appeared to remain less improved than the other functions for longer periods in many patients. Statistical comparisons that included all 7 patients revealed a significant improvement in NASVA score, GCS, DSS, and ESS, but not in FIM, CBA, and NPI at discharge/at the last measurement compared with scores at admission. CONCLUSION: Swallowing function is more responsive to long-term rehabilitation in patients with moderate-to-severe traumatic brain injury, while neuropsychiatric and behavioural difficulties tend to persist for longer periods.

An Electroencephalography Bioassay for Preclinical Testing of Analgesic Efficacy.

We present a multimodal method combining quantitative electroencephalography (EEG), behavior and pharmacology for pre-clinical screening of analgesic efficacy in vivo. The method consists of an objective and non-invasive approach for realtime assessment of spontaneous nociceptive states based on EEG recordings of theta power over primary somatosensory cortex in awake rats. Three drugs were chosen: (1) pregabalin, a CNS-acting calcium channel inhibitor; (2) EMA 401, a PNS-acting angiotensin II type 2 receptor inhibitor; and (3) minocycline, a CNS-acting glial inhibitor. Optimal doses were determined based on pharmacokinetic studies and/or published data. The effects of these drugs at single or multiple doses were tested on the attenuation of theta power and paw withdrawal latency (PWL) in a rat model of neuropathic pain. We report mostly parallel trends in the reversal of theta power and PWL in response to administration of pregabalin and EMA 401, but not minocycline. We also note divergent trends at non-optimal doses and following prolonged drug administration, suggesting that EEG theta power can be used to detect false positive and false negative outcomes of the withdrawal reflex behavior, and yielding novel insights into the analgesic effects of these drugs on spontaneous nociceptive states in rats.

Osteosarcoma in Sprague-Dawley rats after long-term treatment with teriparatide (human parathyroid hormone (1-34)).

Teriparatide, a therapeutic agent for osteoporosis, has been reported to increase the incidences of bone neoplasms such as osteosarcoma when administered subcutaneously to Fischer 344 (F344) rats for a long term, but its non-carcinogenic dose level following 2-year daily administration has not been established. Here we report detailed studies on the carcinogenicity of teriparatide following long-term administration. When teriparatide was administered subcutaneously to male and female Sprague-Dawley (SD) rats daily for 2 years, the incidence of osteosarcoma was increased at 13.6 µg/kg/day. The non-carcinogenic dose level was 4.5 µg/kg/day for both males and females. The development of osteosarcoma in SD rats depends on the dose level of, and treatment duration with, teriparatide. Responses of the bones to teriparatide were similar between F344 and SD rats in many aspects. These results suggested that the carcinogenic potential of teriparatide in SD rats is essentially the same as in F344 rats.

The role of the liver and kidneys in the pharmacokinetics of subcutaneously administered teriparatide acetate in rats.

Teriparatide acetate, a synthetic polypeptide fragment consisting of human parathyroid hormone residues 1-34 [hPTH(1-34)], is a bone anabolic agent used to treat osteoporosis. The present study was conducted to characterise the pharmacokinetics of teriparatide acetate in rats after subcutaneous administration. Teriparatide was rapidly absorbed into the circulation and eliminated immediately. No intact teriparatide was detected in the urine. To elucidate the mechanism of teriparatide metabolism, we performed in vivo and in vitro studies using the radiolabelled bioactive analogue, [(125)I]-[Nle(8,18),Tyr(34)]-hPTH(1-34). After subcutaneous administration, the concentration of analogue metabolites increased in the plasma time-dependently. The concentration in the kidneys was more than 3-fold the concentration in the liver. In vitro analyses suggested that kidney radioactivity was associated with degraded bioactive analogue. In model rats, renal failure, but not hepatic failure, affected the pharmacokinetics of teriparatide acetate, which accounted for the decrease in the clearance of teriparatide. In conclusion, our results suggest that after subcutaneous administration of teriparatide acetate, teriparatide is rapidly absorbed and distributed to the liver or kidneys, where it is immediately degraded. The kidneys play a particularly important role in the distribution and metabolism of teriparatide, but not its excretion.