RTOG 0518: randomized phase III trial to evaluate zoledronic acid for prevention of osteoporosis and associated fractures in prostate cancer patients.

BACKGROUND: RTOG 0518 evaluated the potential benefit of zoledronic acid therapy in preventing bone fractures for patients with high grade and/or locally advanced, non-metastatic prostate adenocarcinoma receiving luteinizing hormone-releasing hormone (LHRH) agonist and radiotherapy (RT). METHODS: Eligible patients with T-scores of the hip (<-1.0, but >-2.5 vs >-1.0) and negative bone scans were prospectively randomized to either zoledronic acid, 4 mg, concurrently with the start of RT and then every six months for a total of 6 infusions (Arm 1) or observation (Arm 2). Vitamin D and calcium supplements were given to all patients. Secondary objectives included quality of life (QOL) and bone mineral density (BMD) changes over a period of three years. RESULTS: Of 109 patients accrued before early closure, 96 were eligible. Median follow-up was 36.3 months for Arm 1 and 34.8 months for Arm 2. Only two patients experienced a bone fracture (one in each arm) resulting in no difference in freedom from any bone fracture (P=0.95), nor in QOL. BMD percent changes from baseline to 36 months were statistically improved with the use of zoledronic acid compared to observation for the lumbar spine (6% vs -5%, P<0.0001), left total hip (1% vs -8%, P=0.0002), and left femoral neck (3% vs -8%, P=0.0007). CONCLUSIONS: For patients with advanced, non-metastatic prostate cancer receiving LHRH agonist and RT, the use of zoledronic acid was associated with statistically improved BMD percent changes. The small number of accrued patients resulted in decreased statistical power to detect any differences in the incidence of bone fractures or QOL.

Effect of 4-aminopyridine in acute spinal cord injury.

BACKGROUND: The demyelination process has been proven to be an important factor contributing to long-term sensory and motor impairments after spinal cord injury (SCI). The loss of myelin promotes exposure of K+ channels in internodal region of the damaged myelinated axons leading to K+ efflux into the neurons with subsequent blockage of action potentials. The potassium channel blocker 4-aminopyridine (4-AP) has been effective in restoring some sensory and motor impairment in incomplete SCI patients. The effect of this compound given immediately after an acute injury is not known. The objective of this study was to determine if blockage of K+ ions efflux immediately after an acute SCI would improve neuronal conduction in this model of injury. METHODS: Cortical somatosensory evoked potentials (SSEPs) were recorded before and after a weight-induced compression injury of 120 grams, and were monitored up to 5 hours postinjury. A randomized treatment was initiated with administration of either vehicle or 4-AP. All 4-AP treatments were given as intravenous bolus injections of 1.0, 0.5, and 0.3 mg/kg at 1, 2, and 3 hours after the trauma. RESULTS: The SSEPs were abolished immediately after the injury in all control and treated animals. Both groups showed spontaneous recovery of the SSEPs at the rate of 44.5% for the 4-AP treated and nontreated groups at the second hour postinjury. This recovery rate remained the same for both groups at the end of the experiments. CONCLUSIONS: Based on the recovery of the SSEPs, our data indicate that early administration of 4-AP lacks any beneficial effect on axonal function during acute stage of spinal cord injury.

Tolerance, cross-tolerance and withdrawal in rats made dependent on diazepam.

Rats were trained to discriminate pentylenetetrazole (PTZ; 20 mg/kg) from midazolam (MDZ; 1 mg/kg) and from saline using a three-lever food-reinforced choice task. Using a cumulative dosing procedure, PTZ substituted for PTZ, and MDZ, chlordiazepoxide and diazepam (DZP) substituted for MDZ, in a dose-dependent manner. The animals were then treated with chronic DZP (20 mg/kg/8 hr for 7 days); 24 hr after the last dose of this regimen, the dose-effect curve of DZP was redetermined. The ED50 for the discrimination of DZP increased 4.8-fold after chronic DZP. In a second group of subjects trained on this discrimination and treated with DZP (20 mg/kg/8 hr for 7 days), the ED50 for the discrimination of MDZ was increased 2.2-fold. After 14 days of recovery, the MDZ dose-effect curve shifted back to the left and was not significantly different from the ED50 value obtained before chronic DZP treatment. When the benzodiazepine antagonist flumazenil was tested in a cumulative manner (1.0-32.0 mg/kg), the animals selected the saline lever. Analogous to the previous chronic dosing regimen, DZP (20 mg/kg/8 hr/7 days) was then administered, and a combination of three tests were then given at 1, 2, 4, 7, 10 and 14 days after the last DZP treatment. On each of these days, a saline test was given first; it was followed by a DZP (2.5 mg/kg) test; which was then followed by a flumazenil (32.0 mg/kg) test. On the 1st day of testing, tolerance was seen to DZP and precipitated withdrawal (PTZ lever selection) was seen with flumazenil.(ABSTRACT TRUNCATED AT 250 WORDS)