Abacavir pharmacokinetics during chronic therapy in HIV-1-infected adolescents and young adults.

The pharmacokinetics of abacavir and its metabolites were investigated in 30 human immunodeficiency virus (HIV)-infected adolescents and young adults 13-25 years of age, equally divided into two groups: <18 years of age and >or=18 years of age. All the subjects received the recommended adult dose of 300 mg twice daily. The area under the plasma concentration-time curve (AUC) and half-life of abacavir did not differ significantly between the age groups or by gender or race, and there were only modest associations of age with apparent abacavir clearance and with volume of distribution. There were no significant correlations of carboxylate or glucuronide metabolite levels with age or gender, although glucuronide AUC was higher in Hispanic subjects than in African-American subjects. Zidovudine and lamivudine concentration profiles were also similar in the two age groups. A novel aspect of the study included an assessment of intracellular carbovir, zidovudine, and lamivudine triphosphate levels, and these were found to be similar in the two age-based groups. Overall, these findings suggest that current recommendations relating to adult dosages are appropriate for adolescents and young adults.

Effects of flunarizine on neurological recovery and spinal cord blood flow in experimental spinal cord ischemia in rabbits.

BACKGROUND AND PURPOSE: The lipophilic calcium channel antagonist flunarizine has been demonstrated to be neuroprotective in several models of cerebral ischemia. Ischemic spinal cord injury may have a similar pathophysiology and hence may respond in a similar fashion. This study was designed to investigate the effects of pretreatment with flunarizine on systemic hemodynamics, spinal cord blood flow, and neurological recovery in a rabbit model of ischemic spinal cord injury. METHODS: New Zealand White rabbits were anesthetized with ketamine and xylazine and instrumented for systemic blood pressure monitoring and spinal cord blood flow measurements using the microsphere method. After pretreatment with flunarizine or vehicle, ischemic spinal cord injury was created selectively in the caudal regions of the spinal cord by cross-clamping the abdominal aorta for a period of 25 minutes. Spinal cord blood flow was measured before, during, and 15 minutes after cross-clamp removal. Animals were allowed to recover and were graded neurologically at 18 and 24 hours after ischemia. RESULTS: Flunarizine injection was associated with hypotension that was both transient and dose related. Animals pretreated with flunarizine 0.4 mg/kg had significantly improved neurological recovery scores at 18 hours after ischemia (P = .017) compared with vehicle controls. At 24 hours this effect was lessened (P = .095); however, 60% of flunarizine-treated animals retained their ability to hop, whereas all of the vehicle-treated animals were nonambulatory. CONCLUSIONS: Flunarizine has a protective effect on neurological recovery after experimental ischemic spinal cord injury. The therapeutic window is narrow, and dosing is limited by untoward hypotension. The mechanism of protection likely involves inhibition of pathological cytosolic calcium accumulation rather than a direct effect on vascular smooth muscle.

Somatostatin causes vasoconstriction, reduces blood flow and increases vascular permeability in the rat central nervous system.

Using radiolabeled microspheres, spinal cord blood flow was measured after spinal subarachnoid injections of 3.1- to 12.5-nmol doses of somatostatin through either indwelling i.t. catheters or acutely inserted intervertebral needles. With either injection technique, somatostatin caused significant dose-dependent reductions in thoracic and lumbosacral blood flow that could be partially blocked by a 5-min preinjection of the somatostatin receptor antagonist cyclo[7-aminoheptanoyl-Phe-D-Trp-Lys-Thr(Bzl)], which has previously been shown to block the hindlimb flaccidity produced by these doses of somatostatin in conscious rats. The duration of these blood flow changes were appreciably less in the rats injected through indwelling i.t. catheters. Somatostatin-induced reductions in spinal cord perfusion were accompanied by transient pressor responses, reduced cardiac output, 3-fold increases in spinal cord cerebrospinal fluid lactic acid concentrations and breakdown of the blood-spinal cord barrier, as reflected by significantly increased extravasation of [125I]bovine serum albumin. By 24 hr postinjection, a 12.5-nmol dose of somatostatin caused appreciable spinal cord cellular injury, as evidenced by significant elevations in cerebrospinal fluid concentrations of lactate dehydrogenase. After topical application to exposed pial vessels of the parietal cortex, comparable doses of somatostatin caused immediate intense dose-related arteriolar vasospasm and subsequent extravasation of the visible macromolecular tracer Evans blue dye. We conclude that somatostatin has significant vasoconstrictory effects on the blood vessels of the brain and spinal cord of the rat that must be recognized and appreciated when studying its neuropharmacological actions in vivo.

Effects of NMDA receptor antagonists following spinal ischemia in the rabbit.

Evidence has accumulated to implicate the excitatory amino acid neurotransmitters, glutamate and aspartate, in the pathophysiology of central nervous system (CNS) ischemic injury. It appears from both in vivo and in vitro experiments that they exert their excitotoxic effects in CNS ischemia by their actions at the N-methyl-D-aspartate (NMDA) receptor complex. In the present study, we examined the effects of MK-801 and ketamine, two noncompetitive NMDA receptor antagonists, in a model of spinal cord ischemia in conscious rabbits produced by occluding the infrarenal aorta for 25 min. Five minutes after reperfusion, animals were treated with either saline, ketamine, or MK-801. By 6 h postreperfusion, all treatment groups exhibited an initial recovery of hindlimb motor function, after which the saline- and ketamine-treated groups had a similar progressive deterioration in function over the next 48 h. However, the MK-801-treated rabbits continued to recover motor function such that neurological scores in these rabbits were significantly improved relative to those of the saline-treated animals at 48 h. Histopathological evaluation showed that MK-801-treated rabbits tended to have a lesser degree of central gray matter necrosis. These results indicate that MK-801 protected against the secondary deterioration associated with this model and strengthen the potential therapeutic use of NMDA receptor antagonists in the treatment of CNS ischemia.

A laboratory model for studying blast overpressure injury.

Blast injury remains an important source of trauma in both civilian and military settings. We have studied a recently developed blast wave generator to evaluate its effectiveness for laboratory study of blast injury. In order to determine the reliability of the device and the pathology of the lesions caused by the short duration (0.5-1.0 msec), and high intensity (60-375 psi) pressure wave, laboratory rats were exposed to the pressure waves generated by the machine. The animals were divided into three groups: the first exposed to midthoracic blasts, the second to abdominal blasts, and a group of controls exposed to a gentle stream of gas. Group I showed gross and microscopic evidence of lung blast injury of "rib imprint" hemorrhages, intra-alveolar hemorrhage, marked increase in lung weight, prolonged apnea, and bradycardia. Group II showed typical blunt abdominal trauma at the closest ranges, but characteristic submucosal hemorrhages up to 4.0 cm from the blast nozzle. In both groups, a protective effect was seen in heavier animals. The blast wave generator permits reproducible blast injury in the laboratory that is safer and faster than current methods. The lung and bowel lesions induced are grossly and microscopically similar to injuries of blast exposure seen in clinical patients.