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Biomedical subjects

J Bergman

Publications and source records attributed to J Bergman.

At least 127 records · Page 7Linked to original sources
PubMed1993

Insulin resistance is localized to skeletal but not heart muscle in type 1 diabetes.

To determine the tissue localization of insulin resistance in type 1 diabetic patients, whole body and regional glucose uptake rates were determined under euglycemic hyperinsulinemic conditions. Leg, arm, and heart glucose uptake rates were measured using positron emission tomography-derived 2-deoxy-2-[18F]-fluoro-D-glucose kinetics and the three-compartment model described by Sokoloff et al. (L. Sokoloff, M. Reivich, C. Kennedy, M.C. DesRosiers, C.S. Patlak, K.D. Pettigrew, O. Sakurada, and M. Shinohara. J. Neurochem. 28: 897-916, 1977) in eight type 1 diabetic patients and eight matched normal subjects. Whole body glucose uptake was quantitated by the euglycemic insulin clamp technique. Whole body glucose uptake was approximately 31% lower in the diabetic patients (P < 0.01) than in the normal subjects, thus confirming the presence of whole body insulin resistance. The rate of glucose uptake was approximately 45% lower in leg muscle when measured in the femoral region (55 +/- 7 vs. 102 +/- 13 mumol.kg muscle-1.min-1, diabetic patients vs. normal subjects, P < 0.05) and approximately 27% lower in the arm muscles (66 +/- 4 vs. 90 +/- 13 mumol.kg muscle-1.min-1, respectively, P < 0.05), whereas no difference was observed in heart glucose uptake [789 +/- 80 vs. 763 +/- 58 mumol.kg muscle-1.min-1 not significant (NS)]. Whole body glucose uptake correlated with glucose uptake in femoral (r = 0.93, P < 0.005) and arm muscles (r = 0.66, P < 0.05) but not with glucose uptake in the heart (r = 0.04, NS). We conclude that insulin resistance in type 1 diabetic patients is localized to skeletal muscle, whereas heart glucose uptake is unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Dopamine D1 receptor involvement in the discriminative-stimulus effects of SKF 81297 in squirrel monkeys.

The discriminative-stimulus effects of the selective dopamine D1 agonist 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benzazepine (SKF 81297) were investigated in squirrel monkeys trained to discriminate i.v. injections of SKF 81297 from saline in a two-lever drug-discrimination procedure. SKF 81297 produced dose-related increases in responding on the SKF 81297-associated lever with full substitution occurring at the training dose in all monkeys. Pretreatment with the selective D1 antagonist(-)-trans-6-7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N- methyl-5H- benzo(d)naphtho-(2,1-b)azepine 2-(SCH 39166) and the D1 partial agonist 7,8-dihydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benzazepine (SKF 75670) produced rightward shifts of the dose-effect curve for the discriminative-stimulus effects of SKF 81297, indicative of surmountable antagonism. Pretreatment with the selective D2 antagonist eticlopride, however, did not systematically alter the discriminative-stimulus effects of SKF 81297. Stereoselectivity was evident in the discriminative-stimulus effects of the enantiomers of the structurally related D1 agonist 3-allyl-6-bromo-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benz azepin e (6-Br-APB), with the R-, but not the S-enantiomer, producing dose-related increases in responding on the SKF 81297-associated lever and full substitution in all monkeys. Another selective D1 agonist 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-3-allyl-[1H]-3- benzazepine (SKF 82958) and the nonselective D1/D2 agonists (-)apomorphine and (-)4,6,6a,7,8,12b-hexahydro-7 methyl-indolo[4,3-ab]phenanthridine (CY 208-243), also engendered dose-related increases in SKF 81297-appropriate responding with full substitution occurring in one-half of the monkeys studied. The D2 agonists, (+)-4-propyl-9-hydroxynaphthoxazine and quinpirole, engendered dose-related increases in SKF 81297-appropriate responding but did not substitute fully in any monkey studied. Other dopaminergic drugs, including the D1 partial agonists SKF 75670 and R(+)-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-[1H]-3- benzazepine (R-SKF 38393), and the indirect dopamine agonists, cocaine, d-amphetamine and 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine (GBR 12909), did not substitute fully for SKF 81297 in any monkey studied. These results suggest that agonist actions at the D1 subtype of dopamine receptor are prominently involved in the discriminative-stimulus effects of SKF 81297.

Animals↗
PubMed1993

Modification of the behavioral effects of the selective dopamine D2 agonist (+)-4-propyl-9-hydroxynaphthoxazine by dopamine antagonists in monkeys.

The present studies were conducted to evaluate the modification of the behavioral effects of the selective D2 agonist (+)-4-propyl-9-hydroxynaphthoxazine [(+)-PHNO] by dopamine receptor blockade. In squirrel monkeys responding under a fixed-ratio schedule of stimulus-shock termination, the effects of (+)-PHNO were determined alone and in combination with the selective D2 antagonist eticlopride, the selective D1 antagonist (-)-trans-6,7,7a,8,9,13b- hexahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo(d)naphtho-(2,1)azepine (SCH 39166), the nonselective D1/D2 antagonist cis-flupentixol or the atypical neuroleptic clozapine. When administered alone, (+)-PHNO produced dose-dependent decreases in rates of responding. Pretreatment with eticlopride and cis-flupentixol resulted in dose-dependent right-ward shifts of the (+)-PHNO dose-effect curve, indicative of surmountable antagonism. Pretreatment with SCH 39166 and clozapine failed to antagonize the effects of (+)-PHNO and resulted in a downward shift of the (+)-PHNO dose-effect curve. Other experiments were conducted to determine the duration of either catalepsy-associated behavior or repetitive scratching produced by (+)-PHNO alone and in combination with selected dopamine receptor blockers. Low doses of (+)-PHNO (0.001-0.003 mg/kg) increased the duration of catalepsy-associated behavior, whereas higher doses (0.003-0.01 mg/kg) restored the duration of catalepsy-associated behavior to control values and produced increases in the duration of repetitive scratching.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

The value of quantitative analysis of glucose utilization in detection of myocardial viability by PET.

To study whether absolute quantitation of regional myocardial glucose utilization (rMGU) enhances detection of myocardial viability, 70 nondiabetic patients with prior myocardial infarction and angiographically confirmed coronary artery disease were studied with [18F]FDG PET after oral glucose loading. Forty-eight patients were also revascularized and underwent echocardiography after revascularization to detect wall motion recovery. The rMGU was calculated in eight myocardial segments in each patient and the results were compared to normalized (relative) [18F]FDG uptake values. In normal segments (n = 225), rMGU was 56 +/- 18 mumole/min/100 g (mean +/- s.d.) and relative [18F]FDG uptake 97% +/- 12%. The interindividual variation of rMGU in normal myocardium was greater than the intraindividual variation (s.d. 31% versus 11%). The respective values for relative [18F]FDG uptake were 9% and 10%. Both rMGU and [18F]FDG uptake were significantly reduced in segments with scarring observed visually during bypass surgery (29 +/- 19 mumole/min/100 g and 45% +/- 22%, n = 26). The rMGU and [18F]FDG uptake were higher in segments that recovered after revascularization (53 +/- 17 mumole/min/100/g and 110% +/- 21%, n = 27) than in those that did not (37 +/- 20 mumole/min/100 g and 65% +/- 24%, n = 63). However, due to larger variability of rMGU values, normalized [18F]FDG uptake was superior to rMGU in separating normal and scar segments as well as in predicting wall motion recovery. We conclude that rMGU variability is notable and is caused mainly by variations between patients. Interindividual variation is reduced by normalization, which results in more accurate assessment of myocardial viability. Thus, static imaging and semiquantitative analysis are sufficient for the clinical assessment of myocardial viability.

Coronary Angiography↗
PubMed1993

Interactions of indolo[3,2-b]carbazoles and related polycyclic aromatic hydrocarbons with specific binding sites for 2,3,7,8-tetrachlorodibenzo-p-dioxin in rat liver.

In the present study we have investigated the capacity of various compounds sterically related to indolo[3,2-b]carbazole to inhibit specific 2,3,7,8-tetrachloro[1,6-3H]dibenzo-p-dioxin binding in rat liver cytosol, as analyzed by electrofocusing in polyacrylamide gels. When the two nitrogen atoms of indolo[3,2-b]carbazole (IC50 = 3.6 nM) were replaced with sulfur atoms, the affinity for the specific binding sites (IC50 = 3.3 nM) was similar to that of the parent compound, whereas the affinity decreased when the two nitrogen atoms were replaced with oxygen atoms (IC50 = 29 nM). Substitution with methyl groups at positions 5 and 11 (on the nitrogens) of indolo[3,2-b]carbazole resulted in increased affinity (IC50 = 1.2 nM), compared with that of the parent compound, whereas dimethylation at the 4,10- or 2,8-positions decreased the affinity (IC50 = 19 nM and IC50 > 150 nM, respectively). Substitution at positions 5 and 11 of indolo[3,2-b]carbazole with substituents larger than methyl, as in 5,11-diethylindolo[3,2-b]carbazole (IC50 = 8.9 nM), diacetylindolo[3,2-b]carbazole (IC50 = 11.2 nM), 5,11-dibutylindolo[3,2-b]carbazole (IC50 > 150 nM), and 5,11-di(N,N-dimethylaminoethyl)indolo[3,2-b]carbazole (IC50 > 1500 nM), also decreased the affinity. Introduction of oxygen in, or hydroxylation of, the middle ring of indolo[3,2-b]carbazole, giving indolo[3,2-b]carbazole-6,12-quinone (IC50 > 150 nM) or 6,12-dihydroxyindolo[3,2-b]carbazole (IC50 > 1500 nM), respectively, also lowered the affinity. We calculated the Gibbs free energy of solvation of the analogue isoquino[3,4-b]phenanthridine (IC50 = 137 nM), relative to that of dibenz[a,h]anthracene (IC50 = 2.5 nM), in water to be -6 kcal/mol by free energy perturbation, which indicates that the most important explanation for the observed difference in binding affinity is the smaller difference in relative free energy of binding at the binding sites, compared with the Gibbs free energy of solvation of the two compounds.

Animals↗
PubMed1993

Comparison of fluorine-18-fluorodeoxyglucose and carbon-11-methionine in head and neck cancer.

The positron emission tomography (PET) tracer 2-18F-fluoro-2-deoxy-D-glucose (FDG) is the most widely used tracer in oncology. PET tracer. Another radiotracer, L-methyl-11C-Methionine (11C-methionine), also has been used successfully for PET imaging of brain and lung tumors, non-Hodgkin's lymphoma, breast cancer and head and neck cancer. This study compared FDG and 11C-methionine as tumor-detecting agents in head and neck cancer. Prior to cancer therapy, fourteen patients underwent a PET study with FDG and one with 11C-methionine. Nineteen of 21 malignant lesions that could be evaluated were visible with both tracers. Tracer uptake was measured as standardized uptake values (SUV) and Ki values according to Patlak et al. The mean SUV in FDG studies was 7.7 +/- 4.2 and in 11C-methionine studies 7.7 +/- 2.5, whereas the Ki values in 11C-methionine studies (mean, 0.128 +/- 0.068 min-1) were always higher than in FDG studies (mean, 0.036 +/- 0.023 min-1). A good correlation was found between the SUVs (r = 0.79, p < 0.0001) and the Ki values (r = 0.82, p < 0.001) between the two tracers. Both FDG and 11C-methionine are effective in PET imaging of head and neck cancer, and the uptake rates of the tracers seem to be closely related.

Adult↗
PubMed1993

Influence of the blood glucose concentration on FDG uptake in cancer--a PET study.

Radiolabeled [11F]-2-fluoro-2-deoxy-D-glucose (FDG) is a glucose analogue widely used to study tumor metabolism by means of positron emission tomography (PET). Little is known about the effect of hyperglycemia on FDG uptake and PET imaging of tumors. Five patients with head and neck cancer underwent two PET studies prior to cancer therapy, first in the fasting state and then 2-5 days later after oral glucose loading. FDG uptake was measured with standardized uptake values (SUV) and Ki values according to Patlak et al. The fasting SUVs ranged from 4.1 to 10.9 and Kis from 0.021 min-1 to 0.067 min-1, whereas after loading both the SUVs (range 2.2-5.9, p < 0.02) and Ki values (range 0.006-0.042 min-1, p < 0.05) decreased significantly, and the quality of the PET images became markedly poorer. The FDG metabolic rate (Ki x P-Gluc) remained similar in different plasma glucose concentrations in tumors, but increased clearly in muscles after loading. Therefore, patients entering PET-FDG studies should fast and their blood glucose concentration needs to be taken into account when evaluating FDG accumulation.

Aged↗
PubMed1992

Stereoselective behavioral effects of Lu 19-005 in monkeys: relation to binding at cocaine recognition sites.

The effects of the monoamine uptake inhibitor Lu 19-005 ((+/-)-trans-3-(3,4-dichlorophenyl)-N-methyl-1-indanamine) and its (+) and (-) enantiomers, Lu 20-042 and Lu 20-043, were compared with those of cocaine and the selective dopamine uptake inhibitor GBR 12909 (1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine) in behavioral and radioligand binding experiments. Behavioral experiments were conducted in groups of squirrel monkeys trained under fixed-interval schedules of reinforcement in which responding was maintained either by presentation of food or by termination of a visual stimulus associated with mild electric shock. Radioligand binding studies were conducted using [3H]CFT and [3H]GBR 12935 to label elements of the dopamine uptake system in caudate-putamen membranes of cynomolgus monkeys. All drugs produced dose-related increases in response rate under the fixed-interval schedules. Lu 19-005, Lu 20-042, and Lu 20-043 had relatively slow onsets (approximately 2 h) and relatively long durations of action, with effects persisting for two or more days following administration. Stereoselectivity was evident in the behavioral effects of the enantiomers of Lu 19-005, with Lu 20-042 being approximately 14 times more potent than Lu 20-043. In radioligand binding experiments, Lu 19-005 and its enantiomers were potent inhibitors of specifically bound [3H]CFT and [3H]GBR 12935. As in behavioral experiments, Lu 20-042 was more potent than Lu 20-043. The degree of stereoselectivity, however, varied with the temperature of the assay medium.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Angioedema associated with lisinopril.

Angioedema has been reported to occur in association with all angiotensin-converting enzyme inhibitors used in the United States. We reviewed nine cases of angioedema associated with lisinopril use seen in the emergency department at our hospital among 1,970 patients that had been prescribed lisinopril from March 1989 to May 1990. Cases were considered as probably (six cases) or possibly (three cases) drug related, depending on the temporal relationship of the initiation of therapy and the onset of angioedema. All of the cases had edema of the lips, buccal mucosa, and or face. None presented with laryngeal edema or stridor. The angioedema resolved within 1 to 2 days with diphenhydramine treatment and discontinuation of lisinopril. Our data suggest that the incidence of angioedema associated with lisinopril is greater than that associated with captopril or enalapril.

Adult↗
PubMed1992

Glucose-free fatty acid cycle operates in human heart and skeletal muscle in vivo.

Positron emission tomography permits noninvasive measurement of regional glucose uptake in vivo in humans. We employed this technique to determine the effect of FFA on glucose uptake in leg, arm, and heart muscles. Six normal men were studied twice under euglycemic hyperinsulinemic (serum insulin approximately 500 pmol/liter) conditions, once during elevation of serum FFA by infusions of heparin and Intralipid (serum FFA 2.0 +/- 0.4 mmol/liter), and once during infusion of saline (serum FFA 0.1 +/- 0.01 mmol/liter). Regional glucose uptake rates were measured using positron emission tomography-derived 18F-fluoro-2-deoxy-D-glucose kinetics and the three-compartment model described by Sokoloff (Sokoloff, L., M. Reivich, C. Kennedy, M. C. Des Rosiers, C. S. Patlak, K. D. Pettigrew, O. Sakurada, and M. Shinohara. 1977. J. Neurochem. 28: 897-916). Elevation of plasma FFA decreased whole body glucose uptake by 31 +/- 2% (1,960 +/- 130 vs. 2,860 +/- 250 mumol/min, P less than 0.01, FFA vs. saline study). This decrease was due to inhibition of glucose uptake in the heart by 30 +/- 8% (150 +/- 33 vs. 200 +/- 28 mumol/min, P less than 0.02), and in skeletal muscles; both when measured in femoral (1,594 +/- 261 vs. 2,272 +/- 328 mumol/min, 25 +/- 13%) and arm muscles (1,617 +/- 411 to 2,305 +/- 517 mumol/min, P less than 0.02, 31 +/- 6%). Whole body glucose uptake correlated with glucose uptake in femoral (r = 0.75, P less than 0.005), and arm muscles (r = 0.69, P less than 0.05) but not with glucose uptake in the heart (r = 0.04, NS). These data demonstrate that the glucose-FFA cycle operates in vivo in both heart and skeletal muscles in humans.

Adult↗
PubMed1992

[18F]-6-fluorodopa PET scanning in Parkinson's disease after selective COMT inhibition with nitecapone (OR-462).

PET studies were performed to investigate the effects of a new cathechol-O-methyltransferase (COMT) inhibitor, nitecapone (OR-462 [3-(3,4-dihydroxy-5-nitrobenzylidene)- 2,4-pentadione]), on the accumulation of dopamine in the striatum and whether it is able to improve [18F]6-fluorodopa imaging of the brain. Altogether, three patients with Parkinson's disease (PD) and three normal volunteers were examined, first without nitecapone and then with an oral dose of 100 mg of nitecapone 1 hour before the IV injection of 3 mCi of [18F]6-fluorodopa. High-pressure liquid chromatography analysis of arterial plasma samples showed a significant reduction in the metabolic conversion rate from [18F]6-fluorodopa to [18F]3-O-methylfluorodopa after the administration of nitecapone. PET studies showed that nitecapone significantly (p less than 0.05) increased the [18F]6-fluorodopa accumulation in the striatum both in PD patients and normal controls; the magnitude of this increase was 20.0 +/- 5.5% (mean +/- SEM). The ratio of radioactivity in the striatum and arterial plasma was increased 39.0 +/- 5.0% (mean +/- SEM) after the administration of nitecapone. Consequently, the quality of PET images after OR-462 was better, which has implications for future [18F]6-fluorodopa studies. In addition, COMT inhibition may have clinical advantages by improving levodopa treatment in PD.

Adult↗
PubMed1992

Modulation of the discriminative stimulus effects of cocaine by mu and kappa opioids.

The effects of cocaine alone and after pretreatment with selective mu and kappa opioids were determined in squirrel monkeys trained to discriminate i.m. injections of cocaine from vehicle in a two-lever discrimination procedure. Lever pressing was maintained under a fixed ratio schedule of food presentation. When administered alone, cocaine engendered dose-related increases in the proportion of cocaine-appropriate responding with an average ED50 of 0.19 mg/kg. Pretreatment with the mu agonists morphine (0.3 and 1.0 mg/kg), levorphanol (0.03 and 0.1 mg/kg) and methadone (0.1 and 0.3 mg/kg), as well as the mu partial agonist buprenorphine (3.0 and 5.6 micrograms/kg), potentiated the discriminative stimulus effects of cocaine such that the cocaine dose-effect functions were shifted to the left and the average ED50 for cocaine was reduced maximally by about one order of magnitude. None of the mu agonists consistently substituted for cocaine when administered alone, indicating that the observed interactions were not simply the result of additive discriminative stimulus effects. A similar potentiation by mu agonists was observed for the effects of cocaine on fixed ratio response rate. In contrast to the mu agonists, pretreatment with the kappa agonists N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yll-4- benzofuranacetamide (CI 977; 3.0 and 5.6 micrograms/kg) and benzeneacetamide methane sulfonate (U 50,488; 0.3 and 1.0 mg/kg) attenuated the discriminative stimulus effects of cocaine in most monkeys, resulting in a modest (2- to 3-fold) increase in the average ED50 for cocaine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

1H-NMR studies of the interaction between a self-complementary deoxyoligonucleotide duplex and indolo[2,3-b]quinoxaline derivatives active against herpes virus.

1H NMR has been used to study the interactions of ellipticine and the ellipticine analogues 2-3-dimethyl-6-(2-dimethylaminoethyl)6H-indolo-[2,3-b]quinoxaline and 6-(2-dimethylaminoethyl)6H-indolo-[2,3-b]quinoxaline with the self-complementary decadeoxyribonucleotide d(CGCGATCGCG)2. The Watson-Crick H-bonded imino proton resonances were studied. The drugs were shown to bind to the duplex by intercalation involving slow exchange kinetics for the imino proton resonances on the NMR time scale (500 MHz). Ellipticine and the 2,3-dimethyl analogue were found not to show strong base preferences, while the other analogue was found to have a preferred primary binding site between the A.T base pairs with a probable minor secondary binding site between the A.T and adjacent G.C base pairs. The new drug-shifted imino proton resonances were assigned through saturation transfer experiments. The base-specific interactions were accompanied by drug-induced non-uniform broadening of the resonances (due to intermediate chemical exchange kinetics), in the spectral region of the non-exchangeable aromatic and sugar H1' proton resonances of the oligonucleotide at 25 degrees C.

Antiviral Agents↗
PubMed1991

Self-administration of the high-affinity cocaine analog 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane.

Self-administration of the high-affinity cocaine analog 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane (CFT) and cocaine were compared in squirrel monkeys responding under a second-order schedule of IV drug injection. Both CFT and cocaine maintained self-administration in all subjects. As the dose of either drug was increased, the rate of responding first increased and then decreased. Although the two drugs had qualitatively similar effects, CFT was approximately six times more potent than cocaine. This potency relation corresponds closely with the potency relations reported for CFT and cocaine in studies of dopamine uptake inhibition and binding at cocaine recognition sites. The results are consistent with the view that the reinforcing effects of cocaine-like drugs are mediated at cocaine recognition sites associated with the dopamine uptake system, and suggest that radioligand probes based on CFT may be suitable markers for these sites.

Animals↗