Biomedical subjects

M J Kaufman

Publications and source records attributed to M J Kaufman.

At least 19 recordsLinked to original sources

PubMed2001

Test-retest reliability of DSC MRI CBV mapping in healthy volunteers.

Dynamic susceptibility contrast magnetic resonance imaging (DSC MRI) can be used to generate high resolution maps of cerebral blood volume (CBV). To determine the test-retest reliability, CBV was measured in eight volunteers on two occasions, separated by 4 weeks. The mean ratio (scan 2/scan 1) for 72 cortical regions of interest (ROIs) was 1.03, with a coefficient of variation of 14%. The correlation between the first and second scans was 0.73 (p < 0.0001; 95%). In five hand-drawn ROIs, the mean ratio was 1.08, with a coefficient of variation of 12%. The correlation between scans was 0.84 (p < 0.0001). The data presented here support the hypothesis that DSC MRI CBV mapping has acceptable test-retest reliability.

Adult↗

PubMed2001

Cocaine-induced cerebral vasoconstriction differs as a function of sex and menstrual cycle phase.

BACKGROUND: Chronic cocaine abusing women experience fewer cerebral perfusion defects and less neuronal injury than men with comparable drug use histories. This study assessed whether a basis for this discrepancy is a sex difference in cocaine's acute cerebrovascular effects. METHODS: The subjects in this study were 13 healthy and neurologically normal women, reporting occasional cocaine (mean 13, range 1-40 lifetime cocaine exposures). All subjects were administered cocaine (0.4 mg/kg) intravenously, during both the follicular (days 3-8) and luteal (days 18-24) menstrual cycle phases. Dynamic susceptibility contrast magnetic resonance imaging assessments of relative global cerebral blood volume (CBV) changes were conducted on both study days, 10 min after cocaine administration. RESULTS: Cocaine did not alter CBV in follicular phase women, but reduced luteal phase CBV by 10%, indicative of vasoconstriction (analysis of variance [ANOVA], F = 5.1, p <.05). Postcocaine CBV was lower in men administered the drug via an identical protocol relative to follicular phase women (ANOVA, F = 5.4, p <.04). Postcocaine CBV was also lower in the male referent group relative to luteal phase women, but this difference did not achieve statistical significance. No measurable sex or menstrual cycle phase differences in cocaine's cardiovascular effects were noted. CONCLUSIONS: These findings suggest both menstrual cycle phase and sex differences in cocaine's acute cerebrovascular effects, which may contribute to sex differences in the severity of brain dysfunction found in chronic cocaine abusers. These findings imply that gonadal steroids or the factors they modulate merit study as possible therapeutic agents for reducing cocaine-induced cerebrovascular disorders.

Adult↗

PubMed2001

Influence of baseline hematocrit and hemodilution on BOLD fMRI activation.

Current understanding of blood oxygenation level dependent (BOLD) fMRI physiology predicts a close relationship between BOLD signal and blood hematocrit level. However, neither this relationship nor its effect on BOLD percent activation (BPA) has been empirically examined in man. To that end, BPA in primary visual cortex in response to photic stimulation was determined in a group of 24 normal subjects. A positive linear relationship between BPA and hematocrit was seen, particularly in men. To evaluate the effect of change in hematocrit on BPA, 9 men were studied before and following isotonic saline hemodilution, resulting in an average 6% reduction in hematocrit and an 8-31% reduction in BPA. No significant change in the number of activated pixels was seen. A model of predicted BPA as a function of hematocrit and vessel size was developed, and results from this model closely mirrored the empiric data. These results suggest that hematocrit significantly influences the magnitude of BPA and that such baseline factors should be accounted for when comparing BOLD data across groups of subjects, particularly in the many instances in which hematocrit may vary systematically. Such instances include several disease states as well as studies involving sex differences, drug administration, stress and other factors. Finally, the robust agreement between predicted and empiric data serves to validate a semiquantitative approach to the analysis of BOLD fMRI data.

Brain↗

PubMed2001

Rate and equilibrium constants for the epimerization of the endothelin receptor antagonist J-104,132 in aqueous solution.

The degradation of [5S-[5alpha,6beta,7alpha(R*)]]-2-butyl-5-(1,3-benzodioxol-5-yl)-7-[(2-carboxypropyl)-4-methoxyphenyl]-6-dihydro-5H-cyclopenta[b]pyridine-6-carboxylic acid (J-104,132) was studied in aqueous solution as a function of temperature and pH. The degradation reaction does not proceed to completion; rather, a stable equilibrium is attained in which approximately 2% of the degradate is produced. Kinetic data for the formation of the degradate are analyzed using an integrated form of the rate law for a reversible first-order reaction, and the forward and reverse rate constants and overall equilibrium constants are presented. Isolation and spectroscopic structural determination indicate that the degradate is the C7 beta-epimer of the drug. A mechanism for the epimerization reaction involving a novel enamine-like intermediate is proposed and shown to be consistent with the kinetic data. The rate and equilibrium constants are used to predict the room temperature stability of an injectable formulation of J-104,132, and these predictions are compared to actual data from long-term stability studies. It is concluded that the preformulation kinetic studies provide essential data needed for optimum drug product development.

Endothelin Receptor Antagonists↗

PubMed2000

Proton magnetic resonance spectroscopy of human basal ganglia: response to cocaine administration.

BACKGROUND: Proton magnetic resonance spectroscopy was used to determine the effects of intravenous cocaine or placebo administration on human basal ganglia water and metabolite resonances. METHODS: Long echo time, proton magnetic resonance spectra of water and intracellular metabolites were continuously acquired from an 8-cm(3) voxel centered on the left caudate and putamen nuclei before, during, and after the intravenous administration of cocaine or a placebo in a double-blind manner. RESULTS: Cocaine, at both 0.2 and 0.4 mg/kg, did not alter the peak area for water. Cocaine at 0.2 mg/kg induced small and reversible increases in choline-containing compounds and N-acetylaspartate peak areas. Cocaine at 0.4 mg/kg induced larger and more sustained increases in choline-containing compounds and N-acetylaspartate peak areas. No changes in either water or metabolite resonances were noted following placebo administration. CONCLUSIONS: These increases in choline-containing compounds and N-acetylaspartate peak areas may reflect increases in metabolite T2 relaxation times secondary to osmotic stress and/or increased phospholipid signaling within the basal ganglia following cocaine administration. This is the first report of acute, drug-induced changes in the intensity of human brain proton magnetic resonance spectroscopy resonance areas.

Adult↗

PubMed2000

Illicit cocaine use patterns in intravenous-naive cocaine users following investigational intravenous cocaine administration.

This study evaluated whether cocaine use patterns changed following investigational intravenous cocaine administration to intravenous-naive cocaine users. Subjects were respondents to a follow-up survey who had participated in one to three intravenous double-blind cocaine (0.2 or 0.4 mg/kg) administration studies. The group included healthy men (n = 17) and women (n = 8) with histories of occasional cocaine use (lifetime self-reported use of 12+/-12 (mean +/- S.D.) exposures, primarily via nasal insufflation) who were recontacted an average of 39 weeks (range 7-107 weeks) after study participation. The recontacted group constituted 45% of the total eligible sample of 55 subjects. Baseline demographics for the recontacted and non-recontacted (n = 30) samples were similar, suggesting that the recontacted sample was representative of the group as a whole. Investigational cocaine exposure did not induce adverse health events in any subject. Self-reported cocaine use estimates obtained at follow-up were compared to baseline estimates obtained with identical questionnaires and were highly concordant (Spearman rank correlation p = 0.52 and 0.78, respectively; P < 0.02 and < 0.0002, respectively). This suggests that participants provided stable and reliable reports of cocaine use. No subject reported either illicit intravenous cocaine use or altered frequency of illicit cocaine use by the customary route after investigational intravenous cocaine exposure. These data suggest that illicit cocaine use frequencies and routes of administration are not altered following investigational intravenous cocaine administration to healthy, occasional cocaine users.

Adult↗

PubMed2000

Oxidation of HMG-CoA reductase inhibitors by tert-butoxyl and 1, 1-diphenyl-2-picrylhydrazyl radicals: model reactions for predicting oxidatively sensitive compounds during preformulation.

Hydrogen atom abstraction rate constants for the reaction of tert-butoxyl and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical with the HMG-CoA reductase inhibitors lovastatin, simvastatin, and statins I-IV were measured. This series of diene-containing drugs is known to be prone to oxidation. The tert-butoxyl radical was generated by the thermolysis of di-tert-butylperoxyoxalate at 40 degrees C. A competitive kinetic method was used to determine the relative rate of hydrogen atom abstraction by tert-butoxyl radical to beta-scission. The absolute rate constants were calculated using the experimentally determined product ratios of t-butanol to acetone and the known rate of beta-scission of tert-butoxyl radical. The rate constants for the reaction with DPPH radical were measured spectrophotometrically by monitoring the loss of DPPH radical as a function of substrate concentration. The rate constants correlate well with the structure of the molecules studied. These kinetic techniques allow for oxidatively sensitive compounds to be identified early in the drug development cycle. The tert-butoxyl radical, a strong hydrogen atom abstractor, is representative of the hydroxyl (. OH) and alkoxyl (. OR) radicals; in contrast the DPPH radical, a much weaker radical, is a good kinetic model for hydroperoxyl (. OOH) and peroxyl (. OOR) radicals. These kinetic methods can be used to quantitatively assess the lability of drug candidates towards reaction with oxygen-centered radicals at an early stage of development and facilitate the design of inhibiting strategies.

Bepridil↗

PubMed2000

Brain kinetics of paroxetine and fluoxetine on the third day of placebo substitution: a fluorine MRS study.

OBJECTIVE: This study tested whether a relationship exists between concentration and response following discontinuation of selective serotonin reuptake inhibitors. METHOD: Eight patients with remitted major depression who were taking 20 mg/day of either fluoxetine or paroxetine underwent placebo substitution for 3 days. Serum drug and brain fluorine levels were obtained before and after placebo substitution. RESULTS: With placebo substitution, a mean of 88% (SD=13%) of brain fluorine signal from fluoxetine (plus fluorinated metabolites) remained, compared with a mean of 38% (SD=17%) of the brain fluorine signal from paroxetine (plus fluorinated metabolites). Among patients taking paroxetine, adverse events during placebo substitution correlated highly with steady-state brain drug levels. CONCLUSIONS: The correlation of clinical effects with brain drug levels in the paroxetine group suggests that relationships between drug response and brain drug concentrations merit further investigation.

Adult↗

PubMed1999

Cocaine-induced erythrocytosis and increase in von Willebrand factor: evidence for drug-related blood doping and prothrombotic effects.

BACKGROUND: Mechanisms that mediate cocaine-induced cardiovascular events following vasoconstriction are incompletely understood. OBJECTIVE: To examine the effects of cocaine in moderate doses on hematologic and hemostatic parameters that influence blood viscosity and thrombotic potential. METHODS: Changes in hemoglobin concentration, hematocrit, and red blood cell counts were measured in human subjects who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for long-term cocaine abuse, before and sequentially after moderate intranasal and intravenous doses of cocaine. Hemostatic parameters, including von Willebrand factor, fibrinolytic activity, fibrinogen, plasminogen activator inhibitor antigen, and tissue-type plasminogen activator antigen, were sequentially measured after intravenous cocaine or saline placebo with cardiac troponin subunits T and I. RESULTS: Hemoglobin level (P= .002), hematocrit (P =.01), and red blood cell counts (P = .04) significantly increased from 4% to 6% over baseline from 10 to 30 minutes after intranasal (n = 14) and intravenous (n = 7) cocaine administration in doses of 0.9 mg/kg and 0.4 mg/kg, respectively, with no change in white blood cell or platelet counts. There was a significant increase (P =.03) in von Willebrand factor from 30 to 240 minutes, peaking at 40% over baseline following intravenous cocaine administration in a dose of 0.4 mg/kg (n = 12), with no change after 0.2 mg/kg (n = 3) or placebo (n = 6). Other hemostatic factors, creatinine, blood urea nitrogen, and cardiac troponin subunits T and I showed no changes. CONCLUSIONS: Cocaine induced a transient erythrocytosis that may increase blood viscosity while maintaining tissue oxygenation during vasoconstriction. An increase in von Willebrand factor without a compensatory change in endogenous fibrinolysis may trigger platelet adhesion, aggregation, and intravascular thrombosis.

Adult↗

PubMed1999

Cerebral phosphorus metabolite abnormalities in opiate-dependent polydrug abusers in methadone maintenance.

This study evaluated cerebral phosphorus metabolites in opiate-dependent polydrug abusers in methadone maintenance therapy (MMT) and determined whether metabolite profiles differed based on treatment duration. Phosphorus magnetic resonance spectroscopy (31P-MRS) data were acquired with the ISIS volume localization method from a 50-mm thick axial brain slice through the orbitofrontal and occipital cortices. Study subjects included 15 MMT subjects, seven having undergone treatment for an average of 39 +/- 23 weeks (mean +/- S.D.) and eight having undergone treatment for 137 +/- 53 weeks, as well as an age matched comparison group (n = 16). The methadone dose administered on the study day averaged 70.5 +/- 17.1 mg and was statistically equivalent in short- and long-term subgroups. MMT subjects (n = 15) differed from control subjects in percent phosphocreatine (%PCr) levels (-13%), and in both phosphomonoester (%PME, +13%) and phosphodiester (%PDE, +10%) levels, which likely reflect abnormalities in energy and phospholipid metabolism, respectively. There were no sex effects or group by sex interaction effects on these measures. In short-term MMT treatment subjects, abnormal %PCr (-18%), %PME (+20%) and %PDE (+17%) levels were found compared with control subjects. The only metabolite abnormality detected in long-term MMT subjects was decreased %PCr (-9%), in spite of continued illicit drug abuse. From these data, we conclude that polydrug abusers in MMT have 31P-MRS results consistent with abnormal brain metabolism and phospholipid balance. The nearly normal metabolite profile in long-term MMT subjects suggests that prolonged MMT may be associated with improved neurochemistry.

Adult↗

PubMed1999

Cocaine pharmacokinetics in men and in women during the follicular and luteal phases of the menstrual cycle.

Preclinical and clinical studies suggest that females may be less vulnerable to cocaine's toxic effects than males. The pharmacokinetics of intravenous cocaine (0.2 and 0.4 mg/kg) were measured in 12 men and 22 women with a history of cocaine abuse, matched with respect to age and body mass index (BMI). Women were studied during the follicular and the luteal phases of the menstrual cycle. There were no differences between men and women in pharmacokinetic measures [peak plasma cocaine levels (Cmax), elimination half-life (T 1/2 min), area under the curve (AUC)] or cardiovascular or subjective effects "high" measures. Heart rate increases were cocaine dose-related (p < .01-.02) and also did not differ between men and women. Cocaine's pharmacokinetic and pharmacodynamic effects were similar in men and women, and in women during the follicular and mid-luteal phases of the menstrual cycle.

Adult↗

PubMed1999

Selection of optimal hydrate/solvate forms of a fibrinogen receptor antagonist for solid dosage development.

The objective of this work was to compare the physicochemical properties of four crystalline forms of the fibrinogen receptor antagonist L-738,167 [2(S)-[p-toluenesulfonyl amino]-3-[[[5,6,7,8-tetrahydro-4-oxo-5-[2-(piperidin-4-yl)ethyl] -4-H-pyrazolo[1,5-a][1,4] diazepin-2-yl] carbonyl]amino]-propionic acid] to determine the best form for use in the development of oral dosage formulations. Four crystalline forms [form A (trihydrate), form B (pentahydrate), form C, and form D] were compared using x-ray powder diffractometry, thermal analysis, and moisture sorption studies. The trihydrate, form A, was demonstrated to hydrate upon exposure to relative humidity (RH) above 50% at room temperature (25 degrees C) with conversion to the pentahydrate. The pentahydrate, form B, converted to the trihydrate at room temperature when exposed to humidity levels below 25% RH. The crystalline pentahydrate was shown to be stable to dehydration upon storage at 30 degrees C/60% RH and 40 degrees C/75% RH for 3 months. The suspension of form A or form D in water resulted in conversion to form B, the stable hydrated form in an aqueous environment. Form C has a unique crystalline structure that is stable in an aqueous environment and not subject to hydration/dehydration with changes in relative humidity and thus may offer some advantages in pharmaceutical development.

Administration, Oral↗

PubMed1999

Investigation of the polymorphism of the angiotensin II antagonist agent MK-996.

The polymorphism of the angiotensin II antagonist agent MK-996 was studied, with particular emphasis on crystal form stability, solubility, and reproducible crystallization of the drug. X-ray powder diffraction patterns indicated differences in the crystal forms of early research and development lots. Solubility data for the different crystal forms in water at 25 degrees C are in agreement with the solution calorimetry data and indicated that crystalline form I is the thermodynamically stable polymorph of MK-996 under ambient conditions. In contrast to the other polymorphs, form I is reproducibly prepared on both the laboratory and production scale. This study examines methodology to determine the most suitable polymorph for development.

Angiotensin Receptor Antagonists↗

PubMed1998

Reduction in BOLD fMRI response to primary visual stimulation following alcohol ingestion.

The physiology of alcohol's effects on brain function is poorly understood. Emission tomographic imaging has revealed both acute and chronic alterations in resting cerebral hemodynamics and metabolism following alcohol ingestion. However, cerebral functional integrity under these conditions has received less attention. Functional magnetic resonance imaging (fMRI) offers a non-invasive method for assessing brain functional activation. In order to assess its utility for studying the effect of alcohol on brain function, we performed fMRI with photic stimulation before and after administration of either 0.7 mg/kg alcohol (N = 12) or placebo (N = 5), resulting in peak breath alcohol levels averaging 0.069 g/dl. We found that the amplitude of visual cortical activation in response to photic stimulation was significantly reduced by approximately 33% following alcohol administration (4.0 +/- 1.7% vs. 2.7 +/- 1.3%, P = 0.02), but not following placebo (4.2 +/- 1.5% vs. 4.1 +/- 1.4%, P = 0.7). The results also suggest that the baseline right hemispheric predominance of activation in response to photic stimulation may be reduced following alcohol, suggesting a greater effect on the right hemisphere, consistent with previous studies and alcohol's known effects on visuospatial processing. In addition, through the course of each activation session, there was a progressive reduction in response following alcohol. These data demonstrate that the cerebral effects of alcohol intoxication can be studied with fMRI, and that the effects on brain function of even moderate alcohol intoxication may be widespread, may be lateralized, and may include the visual system.

Adult↗

PubMed1998

Functional magnetic resonance imaging of alprazolam-induced changes in humans with familial alcoholism.

This study sought to identify whether subjects with a family history (FH + ) of alcoholism had changes in regional cerebral blood volume (rCBV) after an alprazolam challenge which distinguished them from subjects without a family history (FH -) of alcoholism using functional MRI (fMRI). Twelve FH + and eight FH - subjects were challenged with 1 mg of alprazolam or placebo in a double-blind crossover design. FMRI scans were obtained at baseline, 1 and 2 h after the challenge using the dynamic susceptibility contrast method with gadolinium. Mood scales, the Tufts Addiction Research Center Inventory-Morphine Benzedrine Group Scale and the drug liking scale, were administered every 30 min to assess drug effects. Global analysis of CBV showed a treatment by time decrease on alprazolam relative to placebo, but no effect by family history. The FH + group showed rCBV decreases at 1 h in the left caudate and left inferior prefrontal region, while the FH - group showed rCBV decreases at 2 h in the right inferior prefrontal region and anterior cingulate in response to alprazolam relative to placebo. FH + subjects reported more mood enhancement with alprazolam. This fMRI technique detected global and regional CBV changes induced by alprazolam. The location and rate of alprazolam-induced rCBV changes differed between FH + and FH - subjects. These changes may be related to the increased mood enhancement found in subjects genetically predisposed to alcoholism.

Adult↗

PubMed1998

Cocaine-induced cerebral vasoconstriction detected in humans with magnetic resonance angiography.

CONTEXT: Clinical observations and case reports suggest that there are important cerebrovascular complications of cocaine use, but no studies have documented a direct link. OBJECTIVE: To determine whether low-dose cocaine administration induces cerebral vasoconstriction in healthy cocaine users. DESIGN: Randomized controlled trial. SUBJECTS: Twenty-four healthy and neurologically normal men (mean age, 29 years) reporting median cocaine use of 8 lifetime exposures (range, 3 to >40). INTERVENTION: Double-blind intravenous administration of cocaine (0.4 or 0.2 mg/kg) or placebo, with cerebral magnetic resonance angiography performed at baseline and 20 minutes following infusion. MAIN OUTCOME MEASURE: Cocaine-induced angiographic change indicative of vasoconstriction, as independently and concordantly rated by 2 reviewers blind to treatment condition. RESULTS: Cocaine-induced cerebral vasoconstriction in a dose-related fashion (P=.03), with angiograms indicative of vasoconstriction found in 5 of 8 and 3 of 9 subjects receiving 0.4- and 0.2-mg/kg cocaine, respectively, compared with 1 of 7 subjects administered placebo. Outcome stratification by frequency of self-reported lifetime cocaine use (3-10 times, 11-40 times, or >40 times) revealed a statistically stronger dose-related effect (P<.001), suggesting that greater lifetime cocaine use was associated with a greater likelihood of vasoconstriction. CONCLUSIONS: Cocaine administration induced dose-related cerebral vasoconstriction on magnetic resonance angiograms. These changes occurred at low cocaine doses and in the absence of other risk factors, including polydrug abuse, hypertension, or cerebrovascular disease. Outcome stratification by prior cocaine use statistically strengthened the relationship between cocaine administration and vasoconstriction, suggesting that cocaine may have a cumulative residual effect in promoting cerebrovascular dysfunction.

Adult↗

PubMed1998

Altropane, a SPECT or PET imaging probe for dopamine neurons: II. Distribution to dopamine-rich regions of primate brain.

The dopamine transporter in brain, localized almost exclusively on dopamine neurons, is an effective window on dopamine neurons. SPECT or PET imaging of the transporter in brain requires selective imaging agents that display appropriate pharmacokinetic properties. We previously reported that [125I]altropane ([125I]IACFT,2beta-carbomethoxy-3beta-(4-fluorophenyl)-n-(1- iodoprop-1-en-3-yl)nortropane) bound with high affinity (Kd: 5.33 nM) to a single site on the dopamine transporter and was selective for dopamine over the serotonin transporter in homogenates of monkey striatum. To determine whether the selective binding of [125I]altropane is reflected in its brain distribution, the in vitro and ex vivo distribution of [125I]altropane in squirrel monkey (Saimiri sciureus) brain was determined by quantitative autoradiography of coronal brain sections. In vitro, [125I]altropane (2 nM) distribution was discrete and was detectable primarily in the dopamine-rich putamen, caudate nucleus, and nucleus accumbens. The resulting putamen:cerebellum ratio exceeded 120:1 (n = 3). The selective in vitro binding of [125I]altropane to the dopamine transporter, at concentrations approaching its Kd value (Kd: 5.33 nM, a single high affinity site), highlight its suitability for investigating the density of the dopamine transporter in various brain regions in vitro. Ex vivo autoradiography was conducted in monkeys to determine whether the brain distribution of [125I]altropane in vitro was predictive of its brain distribution pattern after intravenous administration. Thirty minutes after intravenous injection, highest levels of [125I]altropane (0.3 nmol/kg) were detected in the caudate-putamen and nucleus accumbens and lowest levels in the cerebellum and cortex. The putamen or caudate:cerebellum ratio was 7. SPECT imaging of the brain within 30 min of i.v. injection confirmed the rapid and selective accumulation of [123I]altropane to the striatum. The selective binding of altropane to the dopamine-rich striatum within 30 min of i.v. administration indicates that it is uniquely suited for SPECT or PET imaging of the dopamine transporter and associated dopamine neurons.

Animals↗

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↗