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Continuous monitoring of cerebral hemodynamic reserve in acute brain injury: relationship to changes in brain swelling.

A new concept of cerebral hemodynamic and metabolic physiology, cerebral hemodynamic reserve (CHR), was evaluated in 20 comatose adults with acute traumatic brain swelling who were undergoing continuous monitoring of the arteriojugular difference in oxyhemoglobin saturation, along with cerebral perfusion pressure and expired PCO2. The CHR was measured as the ratio of relative (percent) changes in cerebral oxygen extraction to relative changes in cerebral perfusion pressure during spontaneous increases in intracranial pressure. In patients with initially severe brain swelling, the CHR was more frequently abnormal (compromised) on the first day, and tended to improve on the second day. In patients with initially moderate brain swelling, the CHR was more frequently normal (preserved) on the first day, but tended to become compromised on the second day if the brain swelling exacerbated. It is concluded that cerebral hemodynamic reserve abnormalities very closely associate with signs of increased intracranial "tightness" on computed tomographic scans of the head. Cerebral hemodynamic reserve could therefore become an important guide in the functional evaluation and management of acute brain swelling (focusing on cerebral oxygenation and perfusion pressure) in a variety of predominantly diffuse acute intracranial disorders.

Adult↗

Interleukin-1beta messenger ribonucleic acid and protein levels after fluid-percussion brain injury in rats: importance of injury severity and brain temperature.

OBJECTIVE: Posttraumatic temperature manipulations have been reported to significantly influence the inflammatory response to traumatic brain injury (TBI). The purpose of this study was to determine the temporal and regional profiles of messenger ribonucleic acid (mRNA) expression and protein levels for the proinflammatory cytokine interleukin-1beta (IL-1beta), after moderate or severe TBI. The effects of posttraumatic hypothermia (33 degrees C) or hyperthermia (39.5 degrees C) on these consequences of TBI were then determined. METHODS: Male Sprague-Dawley rats underwent fluid-percussion brain injury. In the first phase of the study, rats were killed 15 minutes or 1, 3, or 24 hours after moderate TBI (1.8-2.2 atmospheres), for reverse transcription-polymerase chain reaction analysis. Other groups of rats were killed 1, 3, 24, or 72 hours after moderate or severe TBI (2.4-2.7 atmospheres), for protein analysis. In the second phase, rats underwent moderate fluid-percussion brain injury, followed immediately by 3 hours of posttraumatic normothermia (37 degrees C), hyperthermia (39.5 degrees C), or hypothermia (33 degrees C), and were then killed, for analyses of protein levels and mRNA expression. Brain samples, including cerebral cortex, hippocampus, thalamus, and cerebellum, were dissected and stored at -80 degrees C until analyzed. RESULTS: The findings indicated that mRNA levels were increased (P < 0.05) as early as 1 hour after TBI and remained elevated up to 3 hours after moderate TBI. Although both moderate and severe TBI induced increased levels of IL-1beta (P < 0.05), increased protein levels were also noted in remote brain structures after severe TBI. Posttraumatic hypothermia attenuated IL-1beta protein levels, compared with normothermia (P < 0.05), although the levels remained elevated in comparison with sham values. In contrast, hyperthermia had no significant effect on IL-1beta levels, compared with normothermic values. Posttraumatic temperature manipulations had no significant effect on IL-1beta mRNA levels. CONCLUSION: Injury severity determines the degree of IL-1beta protein level elevation after TBI. The effects of posttraumatic hypothermia on IL-1beta protein levels (an important mediator of neurodegeneration after TBI) may partly explain the established effects of posttraumatic temperature manipulations on inflammatory processes after TBI.

Animals↗

The brain erythropoietin system and its potential for therapeutic exploitation in brain disease.

The discovery of the broad neuroprotective potential of erythropoietin (EPO), an endogenous hematopoietic growth factor, has opened new therapeutic avenues in the treatment of brain diseases. EPO expression in the brain is induced by hypoxia. Practically all brain cells are capable of production and release of EPO and expression of its receptor. EPO exerts multifaceted protective effects on brain cells. It protects neuronal cells from noxious stimuli such as hypoxia, excess glutamate, serum deprivation or kainic acid exposure in vitro by targeting a variety of mechanisms and involves neuronal, glial and endothelial cell functions. In rodent models of ischemic stroke, EPO reduces infarct volume and improves functional outcome, but beneficial effects have also been observed in animal models of subarachnoid hemorrhage, intracerebral hemorrhage, traumatic brain injury, and spinal cord injury. EPO has a convenient therapeutic window upon ischemic stroke and favorable pharmacokinetics. Results from first therapeutic trials in humans are promising, but will need to be validated in larger trials. The safety profile and effectiveness of EPO in a wide variety of neurologic disease models make EPO a candidate compound for a potential first-line therapeutic for neurologic emergencies.

Animals↗

Focal brain damage enhances experimental allergic encephalomyelitis in brain and spinal cord.

The immunological basis of multiple sclerosis (MS) is well recognized but the factors inducing MS lesions are unclear. In this study, we test the hypothesis that focal brain injury, inflicted during the pre-clinical stages of experimental allergic encephalomyelitis (EAE), will enhance the severity of immunological damage in the cerebral hemispheres and spinal cord. Acute EAE was induced in 30 Lewis rats by the injection of guinea pig spinal cord homogenate in complete Freund's adjuvant. A cryolesion to the surface of the left cerebral hemisphere was induced at 3 days (n = 6) or 8 days (n = 10) postinoculation (p.i.) and animals were killed at 15 days p.i. Control animals were EAE only (n = 9), cryolesion only (n = 4), EAE and sham cryolesion (n = 5) and normal animals (n = 3). Brain and spinal cord were stained by immunocytochemistry using W3/13 (T-lymphocytes) OX6 (MHC Class II) and GFAP (astrocytes) antibodies. The results showed a 2-fold increase in the number of EAE lesions in the brain with significant and widespread increase of MHC Class II antigen expression by microglia, in the cryolesion EAE 8 days p.i. when compared with EAE only animals. The pattern of enhancement suggests that it is due to (i) local spread of tissue or serum factors from the cryolesion; (ii) neural factors affecting remote regions of the CNS; (iii) stimulation of the immune system which may occur due to products of brain injury draining to regional cervical lymph nodes. Investigation of the mechanisms involved may prove fruitful in establishing factors which initiate, aggravate or ameliorate brain damage in multiple sclerosis.

Animals↗

Facilitation of drug entry into brain by osmotic opening of the blood-brain barrier.

1. After osmotic opening, the blood-brain barrier (BBB) has been shown to reclose more rapidly to large than to small neutral, water-soluble molecules. Quantitative analysis of these data supports the creation of interendothelial pores with radii of about 200 A through which such molecules pass by both restricted diffusion and bulk flow (with solute drag) from blood to brain. 2. The major reduction in BBB permeability from 6 to 35 min following osmotic opening seems to be due to a reduction in bulk flow by a factor of about 10, rather than marked decreases in pore densities or effective pore size. On this basis, quantitative predictions of brain uptake of neutral, water soluble substances are made for various times after osmotic opening of the BBB, as a function of molecular size. 3. Implications of these results are discussed for enhancement of uptake of drugs, including enzymes and certain anti-cancer agents, by the brain. 4. The idea of a 'therapeutic window' as the period of time, following reversible osmotic opening, during which the permeability of the BBB is enhanced significantly for a particular compound, is introduced. Since the BBB is normally highly impermeable to plasma proteins, the effect of BBB opening on the uptake of highly protein-bound drugs is discussed briefly. 5. The effect of molecular charge on the passage of molecules through interendothelial pores into the brain is also discussed.

Animals↗

Kinetics of regional blood-brain barrier transport and brain phosphorylation of glucose and 2-deoxyglucose the barbiturate-anesthetized rat.

Recent studies indicate the lumped constant (LC), which defines the relative rates of brain utilization of glucose and 2-deoxyglucose (2-DG), doubles to values greater than 1.0 under conditions of hypoglycemia. Since changes in the LC should be predictable given the kinetic parameters of blood-brain barrier (BBB) transport and brain phosphorylation of glucose and 2-DG, the present studies were designed to measure the necessary kinetic parameters. The carotid injection technique ws used to determine cerebral blood flow and the Km, Vmax, and KD of glucose and 2-DG transport through the BBB in seven brain regions in rats anesthetized with 50 mg/kg i.lp. pentobarbital. Regional glucose transport through the BBB was characterized by an average Km = 6.3 mM, average Vmax = 0.53 mumol min-1g-1, and average KD = 0.022 ml min-1g-1.l The nonsaturable route of transport of glucose represented on the average 40% of the total glucose influx into brain regions at an arterial glucose concentration of 10 mM. In addition, the rate constants of phosphorylation of glucose and 2-DG were measured for each region. Substitutions of the measured kinetic parameters for sugar transport and phosphorylation into equations defining the LC confirm the observation that the LC would be expected to vary under extreme conditions such as hypoglycemia and to exceed values of 1.0 under these conditions.

Anesthesia↗

Measurement of solute transport across the blood-brain barrier in the perfused guinea pig brain: method and application to N-methyl-alpha-aminoisobutyric acid.

A technique for the vascular perfusion of the guinea pig head in vivo, suitable for measurements of blood-to-brain transport under controlled conditions of arterial inflow, has been developed. With a perfusion pressure ranging between 13 and 18 kPa and PCO2 in the arterial inflow of 5 and 5.5 kPa, cerebral blood flow, measured with [14C]butanol, was about 1 ml min-1 g-1 in the cerebral cortex, hippocampus, and caudate-putamen of the ipsilateral hemisphere; in the cerebellum and pontine white matter it was considerably less, and much higher perfusion pressures were required to establish equal blood flow throughout the whole brain. Regional water content, Na+/K+ ratio, ATP, energy charge potential, and lactate content of the ipsilateral side of perfused and nonperfused brain were not significantly different after 10 min perfusion. The D-[3H]mannitol space did not exceed 1% after 30 min of perfusion, indicating the integrity of the barrier. Over this period, EEG, ECG, and respiratory waveform remained normal. When [14C]N-methyl-alpha-aminoisobutyric acid (MeAIB), and D-[3H]mannitol were perfused together over periods extending to 30 min progressive uptakes of both solutes by the parietal cortex could be measured, and the unidirectional transfer constants estimated from multiple time-uptake data. The Kin for MeAIB (0.75 X 10(-3) ml min-1 g-1) was some three times that for mannitol. It is concluded that the technique provides a stable, well-controlled environment in the cerebral microvasculature of the ipsilateral perfused brain hemisphere suitable for examining the transport of slowly penetrating solutes into the brain.

Aminoisobutyric Acids↗

Phenylalanine transport across the blood-brain barrier as studied with the in situ brain perfusion technique.

Unidirectional L-phenylalanine transport into six brain regions of pentobarbital-anesthetized rats was studied using the in situ brain perfusion technique. This technique allows both accurate measurements of cerebrovascular amino acid transport and complete control of perfusate amino acid composition. L-Phenylalanine influx into the brain was sodium independent and could be described by a model with a saturable and a nonsaturable component. Best-fit values for the kinetic constants in the parietal cortex equaled 6.9 X 10(-4) mumol/s/g for Vmax, 0.011 mumol/ml for Km, and 1.8 X 10(-4) ml/s/g for KD during perfusion with fluid that did not contain competing amino acids. D-Phenylalanine competitively inhibited L-phenylalanine transport with a Ki approximately 10-fold greater than the Km for L-phenylalanine. There were no significant regional differences in Km, KD, or Ki, whereas Vmax was significantly greater in the cortical lobes than in the other brain regions. L-Phenylalanine influx during plasma perfusion was only 30% of that predicted in the absence of competing amino acids. Competitive inhibition increased the apparent Km during plasma perfusion by approximately 20-fold, to 0.21 mumol/ml. These data provide accurate new estimates of the kinetic constants that describe L-phenylalanine transport across the blood-brain barrier. In addition, they indicate that the cerebrovascular transfer site affinity (1/Km) for L-phenylalanine is three- to 12-fold greater than previously estimated in either awake or anesthetized animals.

Amino Acids↗

Kinetic analysis of leucine-enkephalin cellular uptake at the luminal side of the blood-brain barrier of an in situ perfused guinea-pig brain.

The uptake of enkephalin-(5-L-leucine) (Leu-enkephalin) at the luminal side of the blood-brain barrier was measured by means of an in situ vascular brain perfusion technique in the anaesthetized guinea pig. This method allows measurements of cerebrovascular peptide uptake over periods of up to 20 min, and excludes the solute under study from the general circulation and systemic metabolic influences. A capillary unidirectional transfer constant, Kin, for [tyrosyl-3,5-3H]Leu-enkephalin was estimated graphically from the multiple-time brain uptake data in the presence of different concentrations of unlabelled peptide, and dose-dependent self-inhibition was demonstrated. Analysis of unidirectional influx of blood-borne Leu-enkephalin into the brain revealed Michaelis-Menten saturation kinetics in the parietal cortex, caudate nucleus, and hippocampus, with Vmax between 0.14 and 0.16 nmol min-1 g-1 and Km ranging from 34 to 41 microM, for the saturable component, whereas the estimated diffusion constant, Kd, was not significantly different from zero. Entry of [3H]Leu-enkephalin was not inhibited in the presence of either a 5 mM concentration of unlabelled L-tyrosine, tyrosylglycine, and tyrosylglycylglycine, or aminopeptidase inhibitor, bestatin (0.5 mM), suggesting that the saturable mechanism of the tracer at the luminal side of the blood-brain barrier does not involve uptake of the peptide's N-terminal amino acid and/or its tyrosine-containing fragments.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Acid lability of metabolites of 2-deoxyglucose in rat brain: implications for estimates of kinetic parameters of deoxyglucose phosphorylation and transport between blood and brain.

The steady-state brain/plasma distribution ratios of [14C]deoxyglucose ([14C]DG) for hypoglycemic rats previously determined by measurement of DG concentrations in neutralized acid extracts of freeze-blown brain and plasma exceeded those predicted by simulations of kinetics of the DG model. Overestimation of the true size of the precursor pool of [14C]DG for transport and phosphorylation could arise from sequestration of [14C]DG within brain compartments and/or instability of metabolites of [14C]DG and regeneration of free [14C]DG during the experimental period or extraction procedure. In the present study, the concentrations of [14C]DG and glucose were compared in samples of rat brain and plasma extracted in parallel with perchloric acid or 65% ethanol containing phosphate-buffered saline. The concentrations of both hexoses in acid extracts of brain were higher than those in ethanol, whereas hexose contents of plasma were not dependent on the extraction procedure. The magnitude of overestimation of DG content (about 1.2-to fourfold) varied with glucose level and was highest in extracts isolated from hypoglycemic rats; contamination of the [14C]DG fraction with 14C-labeled nonacidic metabolites also contributed to this overestimation. Glucose concentrations in acid extracts of brain exceeded those of the ethanol extracts by less than 40% for normal and hypoglycemic rats.

Acids↗

Specific brain protein changes correlated with behaviourally effective brain transplants.

The objective of this study was to identify cellular proteins that are associated with foetal brain transplants effective in reinstating memory function in adult rats with brain lesions. Quantitative memory deficits can be created in rats by lesioning the cholinergic projection system, using ibotenic acid. Previous work suggested that injection of cell suspensions prepared from presumptive cholinergic cells of foetal basal forebrain into adult brain, after such lesions, are most effective in restoring cognitive function. It was not clear, however, whether it was the cholinergic nature of the transplants that was critical for their success or whether other factors were involved. In this study, the proteins present in transplanted tissues and control brains were analysed by two-dimensional polyacrylamide gel electrophoresis to identify markers for the cells that were specifically correlated with restoration of cognitive function. On each gel, the relative optical densities of the same 33 selected proteins were measured on an interactive computerised image analyser. The amount of each protein was compared between treatment groups and correlated with four behavioural measurements. Seven of the proteins analysed had levels of expression that were either related to transplantation or correlated with behavioural performance. The proteins of interest were divided into the following three groups: (1) transplant-related proteins, (2) cholinergic transplant-specific proteins, and (3) behaviour-related proteins. Notable among the proteins of interest was one of the cholinergic transplant-specific proteins that was positively correlated with three of the four behavioural measurements and was also the only protein among those analysed that was significantly correlated with choline acetyltransferase (ChAT) levels. This has been identified, by immunoblotting, as glial fibrillary acidic protein, an astrocytic cell marker. These results suggest, therefore, that at least two cell types, astrocytes and ChAT(+)-staining cells, play an important role in the successful recovery of cognitive function. This study also identified possible protein markers for cognitive performance. The level of expression of two of the proteins analysed was not affected by lesioning or transplantation, but was significantly correlated with behaviour. One of these proteins, whose amounts correlated negatively with behavioural measurements, has been identified as neurone-specific enolase, a brain-specific neuronal cell marker.

Animals↗

Local blood-brain barrier in the newborn rabbit: postnatal changes in alpha-aminoisobutyric acid transfer within medulla, cortex, and selected brain areas.

Postnatal changes in local permeability of the blood-brain barrier to an inert neutral amino acid (alpha-[14C]-aminoisobutyric acid) were investigated in 25 rabbits. The local transfer constant (K) for this tracer was measured with quantitative autoradiographic techniques at postnatal ages of 1, 3, 8, and 17 days, and adult. In adults, the amino acid penetrated the blood-brain barrier poorly in most regions examined (K less than 1 microliter.g-1.min-1) except within and in proximity to structures with a relatively leaky blood-brain barrier such as area postrema and choroid plexus. The rate of tracer entry into "impermeable" regions was seven- to 10-fold greater in 1-day-old rabbits than adults and not dependent on active transport. In young animals, there was a pronounced regional variation in K with the lowest values occurring in white matter and the highest in gray matter such as cerebral cortex, posterior thalamus, and hippocampus. During postnatal development, K decreased (p less than 0.01) with most regions having values near those of adults by 17 days of age. The results indicate that the blood-brain barrier of the newborn rabbit is relatively leaky to a small hydrophilic nonelectrolyte with a distribution that is heterogeneous regionally. Irrespective of age, such blood-borne substances can accumulate in certain brain areas considered to have impermeable vessels (e.g., nucleus tractus solitarii).

Aging↗

Rapid brain uptake of manganese(II) across the blood-brain barrier.

54Mn2+ uptake into brain and choroid plexus from the circulation was studied using the in situ rat brain perfusion technique. Initial uptake from blood was linear with time (30 s to 6 min) and extrapolated to zero with an average transfer coefficient of approximately 6 x 10(-5) ml/s/g for brain and approximately 7 x 10(-3) ml/s/g for choroid plexus. Influx from physiologic saline was three- to fourfold more rapid and exceeded that predicted for passive diffusion by more than one order of magnitude. The lower uptake rate from blood could be explained by plasma protein binding as the free fraction of 54Mn2+ in rat plasma was < or = 30%. Purified albumin, transferrin, and alpha 2-macroglobulin were each found to bind 54Mn2+ significantly and to restrict brain 54Mn2+ influx. The results demonstrate that 54Mn2+ is readily taken up into the CNS, most likely as the free ion, and that transport is critically affected by plasma protein binding. The results support the hypothesis that Mn2+ transport across the blood-brain barrier is facilitated by either an active or a passive mechanism.

Animals↗

The membrane-associated progesterone-binding protein 25-Dx is expressed in brain regions involved in water homeostasis and is up-regulated after traumatic brain injury.

After traumatic brain injury, progesterone has important neuroprotective effects in the nervous system. There is better functional outcome and less oedema formation in pseudopregnant rat females (high levels of endogenous progesterone) than in males. In addition to intracellular progesterone receptors, membrane binding sites of the hormone such as 25-Dx may also be involved in neuroprotection. In the present study we investigated the distribution of the membrane-associated progesterone-binding protein 25-Dx in rat brain. Immunohistochemical analysis showed that 25-Dx is particularly abundant in the hypothalamic area, circumventricular organs, and ependymal cells of the lateral walls of the third and lateral ventricles. A strong signal was also detected in the meninges. Double immunofluorescence immunolabelling and confocal microscopy showed that 25-Dx is co-expressed with vasopressin in neurones of the paraventricular, supraoptic and retrochiasmatic nuclei. Levels of 25-Dx expression were higher in pseudopregnant females than in males. After traumatic brain injury, 25-Dx expression was up-regulated in neurones and induced in astrocytes, which play an important role in regulating water and ion homeostasis. The expression of 25-Dx in structures involved in CSF production (choroid plexus) and in osmoregulation (circumventricular organs, hypothalamus and meninges), and its up-regulation after brain damage, point to a novel and potentially important role of this progesterone-binding protein in the maintenance of water homeostasis after traumatic brain injury.

Animals↗

REMOVAL OF INTERFERING NUCLEOTIDES FROM BRAIN EXTRACTS CONTAINING SUBSTANCE P. EFFECT OF DRUGS ON BRAIN CONCENTRATIONS OF SUBSTANCE P.

Several methods for removing interfering nucleotides, adenosine-5'-monophosphate and adenosine 5'-triphosphate from brain extracts have been studied. An enzymic method, using adenylic acid deaminase, has been found suitable. This deaminates adenosine monophosphate to 5'-inosinic acid, an inactive compound which does not influence the estimations of substance P. Owing to the adenosine triphosphatase content of the enzyme extract, adenosine triphosphate was also inactivated. For the estimation of adenosine monophosphate-deaminase activity, a simple colorimetric method is described which measures the ammonia liberated from adenosine monophosphate. Substance P in mouse brain extracts was estimated after treatment of the animals with various drugs, and after the enzymic removal of interfering nucleotides from the brain extracts. The drugs had no effect on the substance P content of mouse brain. The effect of drugs on the contractions of the guinea-pig ileum induced by substance P was also investigated, and the effect of drugs on the estimations of substance P in brain extracts is discussed.

Adenine Nucleotides↗

Localizing brain stem lesions with brain stem auditory evoked potentials.

Based on a survey of brain stem auditory evoked potentials (BAEPs) in animals and humans with localized brain stem lesions compared to the recognizability of BAEP components in normal materials, it was concluded that BAEP examination might localize lesions to a high or low level and diffusely within the brain stem. In 155 patients with multiple sclerosis, vascular disorders or other lesions from a neurological department, the involvement of the brain stem was clinically estimated to be negative, situated at a high or low level or diffuse. Correlation between location of the lesions assessed by clinical versus BAEP examination showed correspondence between negative and diffusely abnormal findings, but not with regard to levels within the brain stem. CT-scanning similarly failed to localize lesions to various levels. This was probably due to poorly circumscribed or widespread lesions. The main value of BAEP in neurological patients was to establish clinically silent lesions, especially in patients with multiple sclerosis and only spinal signs.

Animals↗

Developmental changes in blood-brain barrier potassium permeability in the rat: relation to brain growth.

1. The potassium permeability of the blood-brain barrier (BBB) was determined in anaesthetized rats aged between 21 days gestation and adult using 86Rb+ as a marker for potassium. 2. The brain influx rate constant for 86Rb+ was high in fetal cortex at 21 days gestation (42.5 +/- 4.3 microliters g-1 min-1) but had decreased markedly by just after birth (12.2 +/- 0.6 microliters g-1 min-1). There was a further, gradual, postnatal decline to 7.0 +/- 0.3 microliters g-1 min-1 by 50 days after birth. 3. Developmental changes in passive BBB permeability were examined over the same age range using 14[C]urea. These studies showed similar developmental changes in influx rate to those found for 86Rb+. Specifically, a marked perinatal decline followed by a more gradual postnatal fall. Thus, the changes in potassium permeability probably reflect a decrease in the BBB paracellular leak during development. 4. The changes in BBB permeability coincide with changes in the rate of brain growth and the associated rate of brain potassium accumulation. As the potassium permeability properties of the adult BBB would provide insufficient potassium influx to meet the requirement associated with fetal brain growth, it is suggested that need for potassium may be the reason for the greater BBB permeability early in development.

Animals↗

Evaluation of the blood-brain barrier transport, population pharmacokinetics, and brain distribution of benztropine analogs and cocaine using in vitro and in vivo techniques.

The N-substituted 3alpha-[bis(4'-fluorophenyl)methoxy]tropanes (AHN 2-003, AHN 1-055, AHN 2-005, and JHW 007) bind with high affinity to the dopamine transporter and inhibit dopamine uptake more potently than cocaine, but they demonstrate behavioral profiles in animal models of psychostimulant abuse that are unlike that of cocaine. The objective of this study was to characterize the in vitro permeability, brain distribution, and pharmacokinetics of the benztropine (BZT) analogs. Transport studies of cocaine and the BZT analogs (10-4 M) were conducted across bovine brain microvessel endothelial cells. Male Sprague-Dawley rats (approximately 300 g) were administered BZT analogs (10 mg/kg) or cocaine (5 mg/kg) via the tail vein. Blood and brain samples were collected over 36 h and assayed using UV-high-performance liquid chromatography. Transport of both AHN 1-055 (2.15 x 10-4 cm/s) and JHW 007 (2.83 x 10-4 cm/s) was higher (p < 0.05) than that of cocaine (1.63 x 10-4 cm/s). The volume of distribution (12.3-30.5 l/kg) of the analogs was significantly higher than cocaine (0.9 l/kg). The BZT analogs displayed a > or =8-fold higher elimination half-life (4.12-16.49 h) compared with cocaine (0.49 h). The brain-to-plasma partition coefficients were at least two-fold higher for the BZTs versus cocaine, except for AHN 2-003. The BZT analogs are highly permeable across the blood-brain barrier and possess a pharmacokinetic profile different from that of cocaine. These characteristics, in addition to their distinctive behavioral profiles, suggest that the BZT analogs may be promising candidates for the treatment of cocaine abuse.

Animals↗