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M J Kaufman

Publications and source records attributed to M J Kaufman.

At least 37 records · Page 2Linked to original sources
PubMed1998

T1 effects in sequential dynamic susceptibility contrast experiments.

Residual effects of an initial bolus of gadolinium contrast agent have been previously demonstrated in sequential dynamic susceptibility contrast MR experiments. While these residual effects quickly reach a saturation steady state, their etiology is uncertain, and they can lead to spurious estimates of hemodynamic parameters in activation experiments. The possible influence of T1 effects is now investigated with experiments in which T1 weighting is varied as well as with serial regional T1 measurements. Little evidence for significant residual T1 effects is found, suggesting instead that susceptibility effects underlie these observations. An initial saturation dose of contrast agent minimizes this effect.

Adult↗
PubMed1998

Cocaine decreases relative cerebral blood volume in humans: a dynamic susceptibility contrast magnetic resonance imaging study.

Cocaine has substantial effects on cerebral hemodynamics which may partly underlie both its euphorigenic and toxic effects. Dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) was used to determine whether a dose-effect relationship could be detected between cocaine administration and cerebral blood volume reduction in human brain. Twenty-three healthy and neurologically normal adult males with a history of recreational cocaine use (3-40 lifetime exposures) participated. Subjects underwent DSC-MRI measurements of relative cerebral blood volume (rCBV) at baseline and 10 min after i.v. double-blind placebo or cocaine (0.2 or 0.4 mg/kg) administration. Placebo administration resulted in superimposable rCBV curves with post-placebo CBV averaging 104+/-4% (mean+/-SE) of baseline, indicating no CBV change. Both cocaine doses induced CBV decreases which were statistically equivalent and post-cocaine CBV averaged 77+/-4% of baseline (P < 0.002), when measured 10 min following drug administration. These data suggest that DSC-MRI can detect cocaine-induced CBV reductions indicative of vasoconstriction, and that it may be useful for evaluating treatments designed to reduce the cerebrovascular effects of cocaine.

Adult↗
PubMed1998

Meropenem exists in equilibrium with a carbon dioxide adduct in bicarbonate solution.

Evidence is provided for the existence of a second discrete chemical form of meropenem at clinically relevant concentrations prepared from the marketed formulation of the drug. Proton and carbon-13 NMR spectra in D2O, coupled with tandem mass spectroscopy (MS/MS) and cross polarization/magic angle spinning (CP-MAS) NMR experiments, allow structural assignment of the compound as a covalent carbon dioxide adduct of meropenem. This carbon dioxide adduct exists in equilibrium with the free drug in solution and can be observed in the solid state following lyophilization. The equilibrium constant of formation of the adduct (Keq = 20 +/- 8 M-1) was estimated in D2O at 25 degreesC.

Bicarbonates↗
PubMed1998

Cocaine administration induces human splenic constriction and altered hematologic parameters.

Cocaine is a potent vasoconstrictor that has been shown to alter hemoglobin, hematocrit, and red blood cell counts in both animals and humans. The present study evaluated whether cocaine administration induces splenic constriction in men and whether spleen-volume changes temporally correlate with altered hematologic parameters. Spleen volume was assessed at baseline and after cocaine administration (0.4 mg/kg) by using magnetic resonance imaging. A group of five healthy men, aged 31 +/- 2 (SE) yr and reporting occasional cocaine use (13 +/- 5 lifetime exposures), participated. Cocaine reduced spleen volume by 20 +/- 4% (P < 0.03) 10 min after drug administration. Spleen volume returned to normal (101 +/- 3% baseline) within 35 min after cocaine administration, indicating that the reduction is a transient phenomenon. In subjects administered cocaine from whom blood samples were obtained (n = 3), cocaine increased hemoglobin levels, hematocrit, and red blood cell count to 104.5 +/- 0.9, 105.6 +/- 1.2, and 106.5 +/- 1.0% of baseline levels, respectively (P < 0.03), but it did not alter white blood cell and platelet counts. Placebo administration (n = 5) did not alter hematologic parameters. These results suggest that cocaine induces splenic constriction in humans, and this may contribute to temporally concordant hematologic parameter changes. These events may help to preserve or increase tissue oxygenation in periods of high oxygen demand and/or increased vascular resistance.

Adult↗
PubMed1998

Functional magnetic resonance imaging of human brain activation during cue-induced cocaine craving.

OBJECTIVE: Functional magnetic resonance imaging (MRI) was used to test whether brain activation was detectable in regions previously associated with cocaine cue-induced craving. METHOD: Blood oxygenation level dependent (BOLD) functional activation was measured during presentation of audiovisual stimuli containing alternating intervals of drug-related and neutral scenes to six male subjects with a history of crack cocaine use and six male comparison subjects. RESULTS: Significant activation was detected in the anterior cingulate and left dorsolateral prefrontal cortex in the cocaine-using group. In addition, a correlation between self-reported levels of craving and activation in these regions was found. CONCLUSIONS: These results suggest that functional MRI may be a useful tool to study the neurobiological basis of cue-induced craving.

Adult↗
PubMed1998

Concurrent pharmacokinetic analysis of plasma cocaine and adrenocorticotropic hormone in men.

The purpose of this study was to determine the covariance between plasma cocaine and ACTH pharmacokinetics. Twelve healthy male occasional cocaine users participated in a double blind study. Intravenous cocaine (0.2 mg/kg) or placebo was infused over 1 min, and samples for cocaine, ACTH and cortisol analysis were collected at 2, 4, 8, 12, 16, 20, 30, 40, 60, 80, 120, 180, and 240 min. Peak cocaine plasma levels averaged 101.2 +/- 14.6 ng/mL. ACTH increases were significantly correlated (P < 0.0001) with increases in plasma cocaine levels (r = 0.67; r2 = 0.44). Pharmacokinetic analysis showed that the t(max) (observed time to maximum concentration) values for cocaine (6.0 +/- 1.4 min) and ACTH (7.3 +/- 1.2 min) were almost identical. The area under the curve was calculated using the trapezoidal rule. The area under the curve for plasma cocaine was 6463 +/- 1070 ng/min x mL, and the area under the curve for ACTH was 1873 +/- 188 pmol/min x L. The mean half-life for plasma cocaine was 46.7 +/- 4.0 min, and that for ACTH was 35.8 +/- 5.1 min. Cardiovascular and subjective effect measures were correlated with concurrent increases in plasma cocaine and ACTH levels.

Adrenocorticotropic Hormone↗
PubMed1997

Dynamic susceptibility contrast magnetic resonance imaging in neuropsychiatry: present utility and future promise.

Dynamic susceptibility contrast magnetic resonance imaging (DSC MRI) provides a noninvasive means to create high resolution maps of the regional distribution of cerebral blood volume (CBV). Most DSC MRI studies conducted to date have focused on the evaluation of patients with cerebral neoplasms, ischemia or infarction, and epilepsy. However, preliminary work suggests that DSC MRI may also provide clinically important information for the evaluation of patients with neuropsychiatric disorders, especially dementia and schizophrenia. Additionally, with appropriate modification, DSC MRI may be used to reliably evaluate the effects of pharmacological challenges on cerebral hemodynamics. As pharmacotherapy is an important component in the treatment of a range of psychiatric disorders, the dynamic assessment of changes in cerebral perfusion associated with drug administration may ultimately lead to the development of "brain function tests" for a wide range of disorders.

Brain↗
PubMed1996

Cyclic GMP inhibits phosphoinositide turnover in choroid plexus: evidence for interactions between second messengers concurrently triggered by 5-HT2C receptors.

The present study examined the effects of the nitric oxide generator sodium nitroprusside (SNP), a membrane-permeable cGMP analog (dibutyryl-cGMP) and low calcium buffer incubation on choroid plexus serotonin 5-HT2C receptor-mediated inositol monophosphate (IP) production. SNP (100 microM) substantially inhibited 10(-6)M serotonin-stimulated IP production (-46%, P < 0.02). Serotonin-stimulated IP production was increased in low calcium buffer (+280%, P < 0.01) in which serotonin-stimulated cGMP formation is attenuated. Addition of dibutyryl-cGMP (500 microM) inhibited IP formation in low calcium buffer. The present data are suggestive of an inhibitory effect of cGMP on IP formation in choroid plexus, and raise the intriguing possibility of interactions between second messenger systems concurrently activated by 5-HT2C receptors.

Animals↗
PubMed1996

Brain alcohol detectability increase with repeated administration in humans: a proton spectroscopy study.

Proton MRS was used to detect brain alcohol after repeated alcohol exposure in human subjects. MRS detectability measurements were made after administration of an alcoholic drink (0.6 g/kg alcohol) and after an identical drink administrated 6 h later. Between-drink differences in the methyl proton triplet resonance of ethyl alcohol were assessed at statistically equivalent and near-peak blood alcohol concentrations (reflecting brain alcohol concentrations) and statistically equivalent internal standard N-acetyl resonance areas after Drinks 1 and 2, respectively. Brain alcohol detectability was not altered in TE 30-ms spectra but was increased in all five subjects after Drink 2 by an average of 70% in TE 270-ms spectra (p < 0.01). This was accompanied by significant between-drink differences in subjective ratings of alcohol's effects, suggestive of induction of acute alcohol tolerance. These findings suggest increased brain alcohol detectability in TE 270-ms spectra after repeated alcohol exposure that may reflect acute alcohol tolerance.

Adult↗
PubMed1996

Abnormal cerebral metabolism in polydrug abusers during early withdrawal: a 31P MR spectroscopy study.

Phosphorus magnetic resonance spectroscopy (31P MRS) at 1.5 T was performed on nine polysubstance abusing men. All nine patients met DSM-III-R criteria for concurrent cocaine and heroin dependence, were neurologically normal, were negative for the human immunodeficiency virus, and had normal clinical brain MRI scans. Patients were scanned 2-7 days after admission to a drug treatment unit. Eleven age-matched control subjects also were studied. The ISIS localized phosphorus spectra were obtained from a 5-cm thick axial brain slice and a 100-cc white matter volume. In the brain slice, the phosphorus metabolite signal expressed as a percentage of total phosphorus signal was 15% higher for phosphomonoesters, 10% lower for nucleotide triphosphates (beta-NTP), and 7% lower for total nucleotide phosphates in polydrug abusers compared with those in controls. Phosphodiesters, inorganic phosphate, phosphocreatine, total phosphorus, pH, and free magnesium concentration were unchanged. None of these parameters correlated with the methadone dose or the number of days abstinence. Single photon emission computed tomographic imaging of a subgroup of the patients revealed abnormal cerebral perfusion in 80% of the patients scanned. These data suggest that cerebral high energy phosphate and phospholipid metabolite changes result from long term drug abuse and/or withdrawal and that these changes can be detected and studied by 31P MRS.

Adult↗
PubMed1996

Characterization of a solid state reaction product from a lyophilized formulation of a cyclic heptapeptide. A novel example of an excipient-induced oxidation.

PURPOSE: To elucidate the structure of a degradation product arising from a lyophilized formulation of a cyclic heptapeptide, and to provide a mechanism to account for its formation. METHODS: Preparative HPLC was used to isolate the degradate in quantities sufficient for structural studies. A structure assignment was made on the basis of the compounds spectroscopic properties (UV, MS, NMR) and the results of amino acid analysis. RESULTS: The degradate was identified as a benzaldehyde derivative arising from the oxidative deamination of an aminomethyl phenylalanine moiety. The extent of formation of this product is influenced by the amount of mannitol used as an excipient in the formulation. A mechanism is proposed whereby reducing sugar impurities in mannitol act as an oxidizing agent via the intermediacy of Schiff base adducts which subsequently undergo tautomerization and hydrolysis. CONCLUSIONS: Reducing sugar impurities in mannitol are responsible for the oxidative degradation of the peptide via a mechanism that involves Schiff base intermediates. This mechanism may be a potential route of degradation of other arylmethyl amines in mannitol-based formulations.

Benzaldehydes↗
PubMed1995

Sequential dynamic susceptibility contrast MR experiments in human brain: residual contrast agent effect, steady state, and hemodynamic perturbation.

The stability and reproducibility of the dynamic susceptibility contrast (DSC) MRI method for sequential relative cerebral blood volume (relCBV) measurements was evaluated to validate the method for use in quantitative studies of cerebral hemodynamics in humans. A spin echo echo planar imaging protocol was used in conjunction with multiple bolus injections of the susceptibility contrast agent gadoteridol (GD). The effects of variation in interbolus interval (10 min to 4 h), the number of injections (two to four), and the effect of the cerebral vasodilating agent acetazolamide (ACZ) were evaluated in 44 experiments performed with 22 normal subjects. Two fundamental observations were made. First, with multiple injections of GD, the change in MR signal over time was not consistent from first to subsequent boluses. A second bolus administered 10 min to 2 h after an initial bolus resulted in signal change of greater amplitude and duration, resulting in artifactually elevated estimates of relCBV, consistent with a residual effect of GD. Second, a relative steady state could be reached with serial injections of GD, such that the profile of subsequent boluses closely paralleled those of previous ones. This facilitates the reliable measurement of relCBV during activation, as demonstrated by use of ACZ.

Acetazolamide↗
PubMed1995

Serotonin 5-HT2C receptor stimulates cyclic GMP formation in choroid plexus.

The serotonin 5-HT2C receptor (formerly designated the 5-HT1C receptor) of the choroid plexus triggers phosphoinositide turnover. In the present study, we demonstrate that receptor activation also triggers the formation of cyclic GMP (cGMP). Application of 1 microM 5-HT to porcine choroid plexus tissue slices resulted in stimulation of cGMP formation to a maximum of five-fold basal level, with an EC50 of 11 nM. This response was not inhibited by muscarinic or beta-adrenergic receptor antagonists. Serotonin receptor antagonists inhibited cGMP formation with apparent Ki values of 1.3 (mianserin), 200 (ketanserin), and 5,500 (spiperone) nM, respectively. Neither serotonin-stimulated cGMP formation nor PI turnover was inhibited by pertussis toxin pretreatment. Preliminary biochemical studies suggested that serotonin-stimulated cGMP formation was calcium, phospholipase A2, and lipoxygenase dependent, as incubation in low calcium buffers or inclusion of the phospholipase A2 or lipoxygenase inhibitors p-bromophenacylbromide or BW 755c resulted in significant reduction of cGMP formation. The present results suggest that in addition to triggering phosphoinositide turnover, choroid plexus serotonin 5-HT2C receptors trigger cGMP formation in a calcium-sensitive manner.

Animals↗
PubMed1994

Cocaine accumulates in dopamine-rich regions of primate brain after i.v. administration: comparison with mazindol distribution.

Pharmacological and neurochemical evidence suggest that brain dopamine systems, and the dopamine transporter in particular, contribute significantly to the behavioral effects and reinforcing properties of cocaine. The first objective of this study was to determine whether the brain distribution of cocaine supports these conclusions. A high resolution neuroanatomical map of cocaine disposition in brain after i.v. administration was developed. [3H]Cocaine ([3H](-)-cocaine) was administered to squirrel monkeys (Saimiri sciureus) at a trace dose (0.001 mg/kg) and at doses at or above the threshold for producing behavioral effects (0.1 mg/kg, 0.3 mg/kg). After 15 min, ex vivo autoradiography revealed the highest accumulation of [3H]cocaine in dopamine-rich brain regions, including the caudate nucleus, putamen, and nucleus accumbens/olfactory tubercle. The norepinephrine-rich locus coeruleus, the hippocampus, and amygdala also accumulated large quantities of [3H]cocaine. Moderately high levels were found in the stria terminalis, medial septum, substantia nigra, and other regions. Lowest levels were found in the cerebellum. A high and positive correlation was established for the brain distribution of [3H]cocaine administered at trace or at behaviorally relevant doses (r: 0.94; P < 0.001). To determine whether radioactivity represented [3H]cocaine or its metabolic products, tissue extracts from brain regions with high levels of cocaine were subjected to thin layer chromatography using two solvent systems. In caudate-putamen, nucleus accumbens, cortex, and hippocampus, radioactivity comigrated with standard [3H]cocaine. In substantia nigra, less than 70% of the radioactivity comigrated with [3H]cocaine, suggesting that cocaine metabolites are generated more rapidly in the substantia nigra than in other brain regions. The second objective was to determine the brain distribution of mazindol, a potent norepinephrine and dopamine transport inhibitor with low abuse liability in humans. The disposition of intravenously administered [3H]mazindol in brain (0.001 mg/kg, 0.007 mg/kg) was surveyed by ex vivo autoradiography. In sharp contrast to [3H]cocaine distribution, the highest accumulation of [3H]mazindol was localized in the norepinephrine-rich pineal gland, discrete regions of the hypothalamus (paraventricular nucleus, supraoptic nucleus), and the locus coeruleus. Moderately high levels were detected in the caudate-putamen, nucleus accumbens, and other regions. The following conclusions were drawn: (1) Although dopamine-rich brain regions are principal targets of cocaine after i.v. administration to the nonhuman primate, other prominent targets of cocaine (locus coeruleus, hippocampus, and amygdala) may contribute to the acute and chronic effects of cocaine.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

In vivo proton magnetic resonance spectroscopy of alcohol in rhesus monkey brain.

Brain alcohol was measured in rhesus monkeys (Macaca mulatta) by proton magnetic resonance spectroscopy (MRS) following acute nasogastric alcohol administration (0.8 g/kg). Monkeys were anesthetized with ketamine and xylazine. A 1.5 T whole body imager and a 3-inch surface coil were used to acquire TE 30 and 270 ms spectra from a 7.5 cc voxel localized with a stimulated echo (STEAM) sequence. Venous blood samples were collected during spectral acquisitions for gas chromatographic determination of temporally concordant blood alcohol levels (BALs). Acute alcohol administration did not alter the resonance areas of N-acetylaspartate/N-acetyl containing compounds (NAA), choline containing compounds, or total creatine. The NAA resonance was used as an internal standard to calculate approximate brain alcohol concentrations, which averaged 27 +/- 3% and 27 +/- 8% of temporally concordant BALs (T2-corrected TE 30 and TE 270 ms spectra, respectively). In addition to reconfirming results from prior studies finding incomplete detection of brain alcohol with MRS, these results demonstrate the feasibility of measuring brain alcohol in anesthetized nonhuman primates to examine relationships between alcohol exposure history and MRS-visibility of brain alcohol.

Animals↗