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M J Kaufman

Publications and source records attributed to M J Kaufman.

53 records · Page 3Linked to original sources
PubMed1994

Comparison of the free radical-scavenging ability of captopril and ascorbic acid in an in-vitro model of lipid oxidation. Implications for reperfusion injury and ACE inhibitor therapy.

The free radical-scavenging activity of captopril and ascorbic acid was determined by assessing their ability to inhibit the peroxidation of linoleic acid in sodium dodecyl sulphate (SDS) micelles at 37 degrees C. The extent of peroxidation was monitored polarographically using an oxygen electrode to determine oxygen consumption rates. Ascorbic acid was observed to inhibit the peroxidation in a concentration-dependent fashion with an IC50 value of 17 microM. In contrast, the addition of captopril at concentrations up to 500 microM did not result in any detectable inhibition. Unlike ascorbic acid, no synergistic effect, as evidenced by the duration of inhibition, was observed with captopril/alpha-tocopherol mixtures. Measurements of the partitioning of captopril between SDS micelles and the aqueous phase show that 37% of the bulk captopril concentration is localized within the micellar phase; this indicates that phase separation of captopril from the lipid peroxyl radicals is not the cause of the observed lack of inhibitory activity.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1993

[3H]CFT ([3H]WIN 35,428) accumulation in dopamine regions of monkey brain: comparison of a mature and an aged monkey.

The distribution of a tracer dose of the dopamine transport probe [3H]CFT ([3H]WIN 35,428; 2.5 nmol/kg) in brain was examined 90 min following intravenous administration to a mature (8 years, approximately) and an aged (> 20 years) squirrel (Saimiri sciureus) monkey. Ex vivo autoradiography revealed [3H]CFT labeling predominantly in dopamine-rich regions. The high striatum:cerebellum ratio, 5.6, compares favorably with other markers for dopamine systems. Ligand accumulation in striatum was substantially lower in the aged monkey compared with the younger adult monkey. The present findings support the use of the cocaine congener CFT for monitoring the dopamine transporter on dopamine nerve terminals by PET (positron emission tomography) imaging.

Aging↗
PubMed1992

Distribution of cocaine recognition sites in monkey brain: II. Ex vivo autoradiography with [3H]CFT and [125I]RTI-55.

CFT [WIN 35,428, 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane] and its 4-iodinated analog RTI-55 have been proposed as imaging probes for cocaine recognition sites and for dopamine transporters. The central and peripheral distribution of radiolabeled forms of these compounds was studied 30 minutes after intravenous administration in squirrel monkey (Saimiri sciureus). Quantitative ex vivo autoradiography of brain tissue sections from animals receiving [3H]CFT (2.5 nmol/kg) revealed radioligand distribution primarily in dopamine-rich brain regions, and treatment with cocaine or mazindol substantially reduced [3H]CFT accumulation. The caudate nucleus, putamen, and nucleus accumbens/olfactory tubercle accumulated the highest levels of [3H]CFT, and within the caudate nucleus, medial-to-lateral and anterior-to-posterior gradients were observed. Low levels of [3H]CFT were found in the cortex, thalamus, hypothalamus, and background levels in white matter and in the cerebellum (striatal:cerebellar ratio > 3). The in vivo distribution of [3H]CFT closely paralleled its in vitro distribution (Synapse, 9:177-187). Although [125I]RTI-55 (0.2 nmol/kg) also distributed to dopamine-rich brain regions (striatal: cerebellar ratio of 3.6), high levels also were detected in cortex, thalamus, and in midbrain/brainstem structures. In the periphery, [125I]RTI-55 accumulation, measured as percent of administered dose, was higher than [3H]CFT in liver and lung, respectively. Of the radioactivity detected in soluble extracts of striatum, liver, and lung, greater than 90% comigrated with [3H]CFT or [125I]RTI-55 standards. The results support the hypothesis that dopamine-rich brain regions may be relevant to the effects of cocaine, and that both CFT and RTI-55 may be suitable imaging probes for these sites.

Animals↗
PubMed1991

Severe depletion of cocaine recognition sites associated with the dopamine transporter in Parkinson's-diseased striatum.

The cocaine congener [3H]CFT, also designated [3H]WIN 35,428 (2 beta-carbomethoxy-3 beta-(4-fluorophenyltropane), labels cocaine receptors associated with the dopamine transporter in primate striatum. Autoradiographic distribution of [3H]CFT binding (5 nM) in human postmortem control and Parkinson's-diseased striatal tissue sections was compared. In control tissue, high and comparable levels of [3H]CFT binding were observed in the putamen and caudate nucleus. At least 90-99% of total [3H]CFT bound was inhibited by (-)-cocaine (30 microM), suggesting that a high proportion of [3H]CFT is specifically bound. In Parkinson's-diseased tissue, binding sites for [3H]CFT were reduced by 80% in the caudate nucleus and 96% in the putamen. This pattern of depletion parallels the previously reported loss of dopamine in these brain regions (Kish, Shannak, and Hornykiewicz, New Engl. J. Med., 318:876-880, 1988). In the dorsal caudate nucleus of Parkinson's-diseased tissue, a lateral-to-medial gradient of [3H]CFT binding was observed, with the lateral caudate more severely depleted than the medial caudate. The marked decrease of [3H]CFT binding sites in Parkinson's diseased striatum supports the following conclusions: 1) the dopamine transporter is localized primarily on presynaptic nigrostriatal terminals; 2) in the caudate and putamen, cocaine recognition sites are associated primarily with the dopamine transporter; 3) the low level of nonspecific binding of [3H]CFT and the marked depletion of [3H]CFT-labeled sites suggest that radiolabeled derivatives of CFT or its congeners may be suitable imaging probes for presynaptic dopamine nerve terminals.

Aged↗
PubMed1991

Distribution of cocaine recognition sites in monkey brain: I. In vitro autoradiography with [3H]CFT.

The cocaine analog [3H]CFT ([3H]WIN 35,428) was used to map and characterize cocaine recognition sites in the squirrel monkey brain by quantitative autoradiography. Coronal tissue sections were incubated with 5 nM [3H]CFT to measure total binding or with [3H]CFT in the presence of 30 microM (-)-cocaine to measure nonspecific binding. High densities of [3H]CFT binding sites were present in dopamine-rich brain regions, including the caudate nucleus, putamen, nucleus accumbens, and olfactory tubercle. In each of these regions specific binding was greater than 90% of total binding. Several additional brain regions exhibited intermediate densities of [3H]CFT binding, including the substantia nigra, the zona incerta, the amygdala, and the hypothalamus. Low, though measurable levels of binding were observed in the bed nucleus of the stria terminalis, the ventral tegmental area, the medial preoptic area, the pineal, the hippocampus, and thalamic central nuclei. Near-background levels of binding were found in white matter, cortical regions, globus pallidus, and cerebellum. The pharmacological specificity of [3H]CFT binding in various brain regions was determined in competition studies using [3H]CFT and a range of concentrations of selected monoamine uptake inhibitors. In all brain regions examined, stereoselective inhibition of [3H]CFT binding was observed for the (-) over the (+) isomer of cocaine. For other drugs tested, competition experiments indicated a rank order of potency of GBR 12909 greater than or equal to CFT greater than bupropion, suggestive of binding of [3H]CFT to elements of the dopamine transport system. The results demonstrate that although densities of [3H]CFT binding sites are highest in the caudate nucleus, putamen, and nucleus accumbens/olfactory tubercle, significant levels of binding can be detected in other brain regions that may contribute to the behavioral and physiological effects of cocaine.

Animals↗
PubMed1991

Antagonism of oxytocin in rats and pregnant rhesus monkeys by the novel cyclic hexapeptides, L-366,682 and L-366,948.

Two cyclic hexapeptides unrelated in chemical structure to oxytocin (OT) were shown in vivo to be antagonists of the contractile action of OT on the uterus. In anesthetized rats challenged with OT (1 micrograms/kg) administered as an i.v. bolus, L-366,682 [cyclo-(L-Pro-D-Trp-L-Ile-D-pipecolic acid-L-pipecolic acid-D-His)] and L-366,948 (D-2-naphthyl-alanine in place of D-Trp) were equipotent with AD50 values of about 100 micrograms/kg i.v. At doses of L-366,682 or L-366,948 causing approximately 90 to 95% block (approximately the AD95 dose) of OT, the duration of action of the antagonists exceeded 145 min. Both compounds exhibited selectivity in the rat, as a dose of either at 300 micrograms/kg i.v. shifted the dose-response for OT-induced uterine contraction to the right by approximately 5-fold but did not affect the dose-response to prostaglandin F2 alpha. Furthermore, neither compound, at a dose of 3 mg/kg i.v., antagonized the action of arginine vasopressin acting at V-1 (pressor effect in pithed rats) or V-2 (antidiuretic) receptors. In conscious, freely moving, pregnant rhesus monkeys, L-366,948 or L-366,682 given i.v. or s.c. were effective antagonists of uterine contractions elicited by an infusion of OT. OT- or arginine vasopressin-like agonist activity was not observed in any of the in vivo models. It is concluded that L-366,682 and L-366,948 act in vivo as reasonably potent, long-acting and selective antagonists at OT receptors in the rat and rhesus uterus.

Animals↗
PubMed1990

Autoradiographic localization of cocaine binding sites by [3H]CFT ([3H]WIN 35,428) in the monkey brain.

The cocaine analog [3H]2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane ([3H]CFT or [3H]WIN 35,428 binds with high affinity and selectivity to cocaine receptors in the monkey caudate-putamen. [3H]CFT was used to map the regional distribution of cocaine binding sites in slide-mounted sections of monkey brains using autoradiographic techniques. Hemicoronal brain sections were incubated with [3H]CFT (3 nM) alone or in the presence of excess (-)-cocaine (30 microM) to mask the binding sites. High densities of [3H]CFT binding sites were detected in the caudate nucleus, putamen, and nucleus accumbens. In all three regions, binding was markedly reduced by coincubation with unlabeled (-)-cocaine, indicating low levels of nonspecific binding. Little or no binding was observed in the cortex, thalamus, globus pallidus, or white matter tracts at the levels studied. In order to characterize binding sites for [3H]CFT in tissue sections, competition experiments were conducted using a fixed concentration of [3H]CFT (3 nM) and a range of concentrations of (-)-cocaine, (+)-cocaine, CFT, Lu 19-005, GBR 12909, bupropion, and citalopram. The IC50 values for the drugs in tissue sections corresponded closely with their reported IC50 values in monkey caudate-putamen membranes (r = 0.99, p less than 0.001), suggesting that [3H]CFT binding is similar in the two preparations. These findings support the view that cocaine receptors labeled by [3H]CFT are localized predominantly in dopamine-rich brain regions implicated in the behavioral effects and abuse of cocaine.

Animals↗
PubMed1990

Applications of oxygen polarography to drug stability testing and formulation development: solution-phase oxidation of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors.

The kinetics of oxidation of the HMG-CoA reductase inhibitors lovastatin, simvastatin, L-157,012, and L-647,318 were studied in an aqueous surfactant solution. A thermally labile free radical initiator was used to attain measurable reaction rates at 40 degrees C and rate constants were determined by measuring oxygen consumption using an oxygen electrode. The stability of the drugs was found to increase in the order lovastatin = simvastatin less than L-157,012 less than L-647,318. The addition of butylated hydroxyanisole (BHA) was found to stabilize the drugs. For the oxidation of lovastatin, the effectiveness of antioxidants increased in the order propyl gallate less than BHA less than alpha-tocopherol. It is concluded that the stability of oxidizable drugs can be rapidly and conveniently assessed by the techniques described herein.

Antioxidants↗
PubMed1990

Serotonin induces constriction and relaxation of the guinea pig airway.

The response of guinea pig trachea to 5-hydroxytryptamine (serotonin; 5-HT) was investigated by studying tracheal strips suspended in organ chambers for isometric tension measurements. Serotonin concentrations of 0.1 to 10 microM produced concentration-dependent contractions, whereas at higher concentrations (10-300 microM) the agonist caused concentration-dependent relaxations. The 5-HT2 antagonist ketanserin shifted the bimodal 5-HT response-curve to the right (pA2 for ketanserin was 8.98). The 5-HT1A agonist, (+)-8-hydroxy-2-(di-N-propylamino)tetralin hydrobromide and 5-HT3 antagonist, ICS 205930 (3-tropanyl-indole-3-carboxylate) had no effect on the 5-HT-response curve. Incubation with atropine resulted in a depression of the maximal contractility and an increase in the EC50 without changing the bimodal nature of the concentration-response curve. Hexamethonium was able to block the atropine effect without significantly affecting the 5-HT concentration-response curve. Neither the constriction nor the relaxation was altered by propranolol, chlorpheniramine or capsaicin pretreatment. Histamine and carbachol preconstricted airways were also relaxed by 5-HT in a concentration-dependent fashion and this relaxation was antagonized by ketanserin (pKb for ketanserin in histamine preconstricted airways was 9.4). Epithelial denudation did not inhibit the 5-HT-induced relaxation. 5-HT stimulated inositol-monophosphate production which also exhibited a bimodal response and correlated well with the functional response. The above findings suggest that 5-HT causes both constriction and relaxation of the guinea pig airway, and that both responses are antagonized by a 5-HT2 receptor blocker. In addition, part of the constrictor response of 5-HT is mediated through a cholinergic preganglionic pathway. Finally, inositol-monophosphate production induced by 5-HT correlates with the functional response.

Acetylcholine↗
PubMed1987

Carbon monoxide exposure potentiates high-frequency auditory threshold shifts induced by noise.

Hypoxia has long been hypothesized to play a role in noise-induced hearing loss, and the disruption of auditory function by asphyxiation has been repeatedly demonstrated. Recent data, however, suggest that the cochlea is resistant to less extreme hypoxic events. The current report describes the combined effects of noise and hypoxia on a measure of auditory function, in an effort to clarify the role of hypoxia in hearing loss. Exposure to 1200 parts per million of carbon monoxide in air for 90 min preceding and 120 min concurrent with exposure to a broad-band noise at 110 dBA produced high-frequency threshold shifts of greater magnitude than those produced by exposure to noise alone. An equivalent carbon monoxide exposure in a 'quiet' environment did not produce any change in auditory detection thresholds. The potentiation of noise-induced threshold shifts by carbon monoxide provides additional support for the hypothesized role of metabolic exhaustion or bloodflow impairment in noise-induced hearing loss. It also suggests a possible interpretation of clinical findings of auditory impairment associated with carbon monoxide exposure.

Animals↗