Search PubMed⌕ Search

Biomedical subjects

A Berson

Publications and source records attributed to A Berson.

At least 55 records · Page 3Linked to original sources
PubMed1994

Palladium 103 plaque radiotherapy for uveal melanoma. Clinical experience.

PURPOSE: To evaluate the effect of palladium 103(103Pd) ophthalmic plaque brachytherapy on patients with uveal melanoma. BACKGROUND: Radioactive 103Pd seeds have become available for plaque brachytherapy, and computer-aided simulations have compared the intraocular dose distribution of 103Pd versus iodine 125 (125I) plaques in patients with uveal melanoma. The use of the lower-energy radionuclide 103Pd increased the radiation to the tumors and decreases irradiation of most normal ocular structures. METHODS: The authors have begun a phase 1 clinical trial evaluating the effect of 103Pd ophthalmic plaque radiotherapy on intraocular tumors. Uveal melanoma was diagnosed, and the patients were found to be negative for metastatic disease. All patients were given one 103Pd radioactive plaque treatment, and six patients also were given adjuvant microwave hyperthermia. RESULTS: Palladium 103 ophthalmic plaque radiotherapy was used to treat 23 patients with uveal melanoma. Patients were followed for up to 27 months (mean, 13.5 months). One eye was enucleated for progressive tumor enlargement (4 months after treatment). One patient died (of metastatic melanoma). Eight patients have lost greater than two lines of visual acuity, one has gained more than two lines. Fifteen patients (65%) were within two lines or had better than their preoperative visual acuity. Relating to the effect of treatment on visual acuity, 15 (65%) tumors were located equal to or less than 2 mm from the fovea. CONCLUSION: Palladium 103 ophthalmic plaque radiotherapy was noted to control the growth of uveal melanomas. Compared with other forms of plaque radiotherapy at this follow-up interval, the authors have noted no new complications, no difference in local control, and/or changes in tumor response to treatment. More long-term follow-up will be required to demonstrate differences between 125I and 103Pd ophthalmic plaque brachytherapy.

Brachytherapy↗
PubMed1994

Possible role of HLA in hepatotoxicity. An exploratory study in 71 patients with drug-induced idiosyncratic hepatitis.

Possible associations between particular human leucocyte antigen molecules and immunoallergic hepatitis have been suggested previously (HLA-A11 in halothane hepatitis, HLA-DR6 and DR2 in nitrofurantoin hepatitis, HLA-B8 in clometacin hepatitis). In this study the HLA haplotype was determined in 71 patients with idiosyncratic hepatitis due to different drugs. The prevalence of HLA-A11 was twice as high in the 71 patients in the study (23%) as in controls (12%), but p-values were not significant when corrections were made for the large number of comparisons (n = 39). The prevalences of HLA-DR2, DR6, and B8 were similar in the 71 patients and in controls. When hepatitis due to particular drugs was considered, HLA-A11 was found to be present in six of 12 patients (50%) with hepatitis caused by tricyclic antidepressants, and three of four patients (75%) with diclofenac hepatitis, compared to 12% in controls. HLA-DR6 was present in four of five patients (80%) with chlorpromazine hepatitis, compared to 22% in controls. In conclusion, the HLA phenotype does not contribute significantly to idiosyncratic drug-induced hepatitis considered collectively. Possible associations between some HLA molecules and the hepatotoxicity of certain drugs require further confirmation.

Adolescent↗
PubMed1994

Toxicity of the antiandrogen flutamide in isolated rat hepatocytes.

The hepatotoxicity of flutamide, an antiandrogen that produces hepatitis in some human recipients, was studied in isolated rat hepatocytes. Flutamide (1 mM) led to the covalent binding of reactive electrophilic metabolites to male rat hepatocyte proteins. It decreased the reduced glutathione (GSH)/glutathione disulfide ratio and total protein thiols. This was associated with an early increase in phosphorylase a activity (a Ca(++)-dependent enzyme) and a decrease in cytoskeleton-associated protein thiols, the formation of plasma membrane blebs, the release of lactate dehydrogenase (LDH) and a loss of cell viability. Both covalent binding and LDH release were decreased by piperonyl butoxide (an inhibitor of cytochrome P450) and increased by dexamethasone pretreatment (which induces cytochrome P450 3A). The toxicity was increased by beta-naphthoflavone (which induces cytochrome P450 1A). Hepatocytes from female rats (which lack cytochrome P450 3A2) exhibited lower covalent binding and lower LDH release. The addition of cystine (a GSH precursor) increased hepatocellular GSH and decreased LDH release in male hepatocytes. The administration of a diet deficient in sulfur-containing amino acids had the opposite effects; it produced toxicity with 100 microM flutamide. Flutamide (50 microM) markedly inhibited respiration (mainly at the level of complex I) in isolated male rat liver mitochondria and flutamide (1 mM) decreased ATP levels in isolated male rat hepatocytes. It was concluded that flutamide is toxic to rat hepatocytes as a result of the cytochrome P450 (3A and also 1A)-mediated formation of electrophilic metabolites, whose damaging effects are further aggravated by the inhibitory effect of flutamide on mitochondrial respiration and ATP formation.

Adenosine Triphosphate↗
PubMed1994

Inhibition by nilutamide of the mitochondrial respiratory chain and ATP formation. Possible contribution to the adverse effects of this antiandrogen.

The effects of nilutamide on the mitochondrial respiratory chain were investigated in rats. In isolated mitochondria, nilutamide (100 microM) inhibited respiration that was supported by substrates feeding electrons into complex I of the respiratory chain but did not inhibit respiration that was supported by substrates donating electrons to complexes II, III or IV. Inhibition of complex I occurred without any lag time. In submitochondrial particles, nilutamide (100 microM) decreased both oxygen consumption mediated by NADH and the oxidation of NADH; addition of superoxide dismutase and catalase did not alleviate inhibition. There was no electron spin resonance evidence for detectable mitochondrial formation of the nilutamide nitro anion free radical by submitochondrial particles or for the formation of iron-nitrosyl complexes with mitochondrial Fe-S clusters in isolated hepatocytes. Severe inhibition of complex I by nilutamide (500 microM) led to upstream inhibition of fatty acid beta-oxidation. Nilutamide (100 microM) decreased the mitochondrial membrane potential and ATP formation in mitochondria energized by malate plus glutamate. In hepatocytes incubated without glucose, nilutamide (500 microM) led to an early (2 hr) drop in cellular ATP and early (4 hr) toxicity. With 5 mM glucose, however, ATP was not decreased and toxicity was mild at these early times. It was concluded that nilutamide itself inhibited the mitochondrial respiratory chain at the level of complex I and decreased ATP in hepatocytes incubated without glucose, which resulted in early toxicity. In the presence of glucose, ATP was not depleted at early times and delayed toxicity was probably the result of an oxidative stress (as previously reported).

Adenosine Triphosphate↗
PubMed1993

Evaluation of human blood lymphocytes as a model to study the effects of drugs on human mitochondria. Effects of low concentrations of amiodarone on fatty acid oxidation, ATP levels and cell survival.

Human lymphocytes were assessed as a cellular model for determining the effects of drugs on human mitochondria. Formation of total oxidized 14C-products was maximal with 1 mM [U-14C]palmitic acid, was linear for 90 min, linear with the number of lymphocytes, and decreased by 95% and 77% in the presence of 30 microM rotenone and 2 mM KCN. Seven drugs were tested which had previously been shown to inhibit beta-oxidation in animals; all decreased formation of total oxidized 14C-products by human lymphocytes, but with different IC50 values: 35 microM with amiodarone, 2.75 mM with tetracycline and amineptine, 3.75 mM with tianeptine, and more than 10 mM for valproic acid and the ibuprofen enantiomers. Formation of [14C]CO2 either increased or decreased, in relation to the various effects of these drugs on coupling, beta-oxidation, and the tricarboxylic acid cycle. There was a general trend for some relationship between inhibition of fatty acid oxidation and loss of cellular ATP. Those compounds, however, which uncoupled oxidative phosphorylation (2,4-dinitrophenol, amiodarone, ibuprofen) and/or inhibited the mitochondrial respiratory chain (amiodarone, rotenone, KCN) resulted in comparatively higher ATP depletion. Amiodarone, a drug which produces several effects (uncoupling, inhibition of beta-oxidation, of the tricarboxylic acid cycle and of the respiratory chain), caused a dramatic decrease in cellular ATP and cell viability at low concentrations (20-100 microM). Both these effects were prevented by the addition of 5 mM glucose, a substrate for anaerobic glycolysis. We conclude that human lymphocytes may be a useful model for assessing the effects of drugs on human mitochondrial function. IC50 values determined with this model may not necessarily apply, however, to other cells.

Adenosine Triphosphate↗
PubMed1993

Decreased mitochondrial oxidation of fatty acids in pregnant mice: possible relevance to development of acute fatty liver of pregnancy.

Severe impairment of the beta-oxidation of fatty acids, as a consequence of a single factor or a combination of different causes, leads to microvesicular steatosis of the liver. In an effort to understand the mechanism(s) leading to the development of acute fatty liver of pregnancy in some women, we determined the effects of pregnancy on the mitochondrial oxidation of fatty acids in mice. In vivo, the rate of oxidation of the whole fatty-acid chain length was determined by measuring the rate of exhalation of [14C]CO2 after intragastric administration of a tracer dose of [U-14C]palmitic acid. [14C]CO2 exhalation was not significantly decreased at 14 days of gestation, but it had declined by 40% at 18 days of gestation (i.e., 24 to 48 hr before delivery). The rate of first beta-oxidation cycle was assessed by measuring the rate of [14C]CO2 exhalation after administration of [1-14C]octanoic acid, [1-14C]butyric acid or [1-14C]palmitic acid. [14C]CO2 exhalation had declined by 60%, 46%, and 24% after administration of [1-14C]octanoic acid, [1-14C]butyric acid and [1-14C]palmitic acid, respectively, in 18-day-pregnant mice. Total hepatic lipids and triglycerides, expressed per gram of liver, remained unchanged in 18-day-pregnant mice. In vitro, the rate of mitochondrial beta-oxidation (expressed per milligram of protein) had decreased by 47% at 18 days' gestation with [U-14C]palmitic acid as substrate and by 33% with [1-14C]octanoic acid but remained unchanged with [1-14C]palmitic acid. The activity of the tricarboxylic acid cycle, assessed by the formation of [14C]CO2 from [1-14C]acetic acid, had decreased by 24%. We conclude that the mitochondrial oxidation of fatty acids decreased during late-term pregnancy in mice as a consequence of both decreased mitochondrial beta-oxidation of medium-chain fatty acids, and decreased activity of the tricarboxylic acid cycle. We suggest that this effect, in combination with other factors, may contribute to the development of fatty liver of pregnancy in some pregnant women.

Acyl-CoA Dehydrogenase↗
PubMed1993

Increased ethane exhalation, an in vivo index of lipid peroxidation, in alcohol-abusers.

Ethane exhalation was measured in 42 control subjects, 52 patients with various non-alcoholic liver diseases, and 89 alcohol abusers who had been admitted to hospital for alcohol withdrawal and assessment of liver disease (six with normal liver tests, 10 with steatosis with or without fibrosis, six with alcoholic hepatitis, 29 with cirrhosis, 34 with both cirrhosis and alcoholic hepatitis, and four with both cirrhosis and a hepatocellular carcinoma). Ethane exhalation was similar in control subjects and in patients with non-alcoholic liver diseases, but was five times higher in alcohol abusers. Ethane exhalation in alcohol abusers was significantly, but very weakly, correlated with the daily ethanol intake before hospital admission, and the histological score for steatosis, but not with the inflammation or alcoholic hepatitis scores. Ethane exhalation was inversely correlated with the duration of abstinence before the test. In nine alcoholic patients, the exhalation of ethane was measured repeatedly, and showed slow improvement during abstinence. Ethane exhalation was significantly but weakly correlated with the Pugh's score in patients with alcoholic cirrhosis. It is concluded that the mean ethane exhalation is increased in alcohol abusers. One of the possible mechanisms may be the presence of oxidizable fat in the liver. The weak correlation with the Pugh's score is consistent with the contribution of many other factors in the progression to severe liver disease.

Adult↗
PubMed1993

Metabolic activation of the nitroaromatic antiandrogen flutamide by rat and human cytochromes P-450, including forms belonging to the 3A and 1A subfamilies.

The in vitro metabolic activation of flutamide, a nitroaromatic antiandrogen which produces hepatitis in a few recipients, was first studied with male rat liver microsomes. There was no electron spin resonance evidence for the reduction of flutamide by reduced nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome P-450 reductase into a nitro anion free radical. In contrast, flutamide was oxidatively transformed by cytochrome P-450 into reactive metabolite(s) that covalently bound to microsomal proteins. Covalent binding required oxygen and NADPH, and was decreased by the nucleophile glutathione and by the cytochrome P-450 inhibitors SKF 525-A, piperonyl butoxide and troleandomycin (an inhibitor of the cytochrome P-450 3A subfamily). Covalent binding was increased markedly by pretreatment with dexamethasone (an inducer of the cytochrome P-450 3A subfamily) and moderately by pretreatment with beta-naphthoflavone (an inducer of the 1A family). Covalent binding was immunoinhibited markedly by anticytochrome P-450 3A immunoglobulin G and moderately by anticytochrome P-450 1A immunoglobulin G. Covalent binding was much lower with liver microsomes from female rats (not expressing P-450 3A2). Covalent binding of flutamide also occurred with human liver microsomes (where it was inhibited by troleandomycin), and with yeast microsomes expressing human liver cytochromes P-450 1A1, 1A2 or 3A4. We concluded that flutamide was oxidatively transformed into chemically reactive metabolite(s) by rat and human cytochromes P-450, including forms belonging to the 3A and 1A subfamilies.

Animals↗
PubMed1992

Generation of free radicals during the reductive metabolism of nilutamide by lung microsomes: possible role in the development of lung lesions in patients treated with this anti-androgen.

The pulmonary metabolism of nilutamide, a nitroaromatic anti-androgen drug leading to pulmonary lesions in a few recipients, has been investigated in rats. Incubation of nilutamide (1 mM) with rat lung microsomes and NADPH under anaerobic conditions led to the formation of the nitro anion free radical, as indicated by ESR spectroscopy. The steady state concentration of this radical was not decreased by CO or SKF 525-A (two inhibitors of cytochrome P450), but was decreased by NADP+ (10 mM) or p-chloromercuribenzoate (0.47 mM) (two inhibitors of NADPH-cytochrome P450 reductase activity). Anaerobic incubations of [3H]nilutamide (0.1 mM) with rat lung microsomes and a NADPH-generating system resulted in the in vivo covalent binding of [3H]nilutamide metabolites to microsomal proteins; covalent binding required NADPH; it was decreased in the presence of NADP+ (10 mM), or in the presence of the nucleophile glutathione (10 mM), but was unchanged in the presence of carbon monoxide. Under aerobic conditions, in contrast, the nitro anion free radical was reoxidized by oxygen, and its ESR signal was not detected. Covalent binding was essentially suppressed. Instead, there was consumption of NADPH and oxygen, and production of superoxide anion and hydogen peroxide. We conclude that nilutamide is reduced by rat lung microsomes NADPH-cytochrome P450 reductase into a nitro anion free radical. In anaerobiosis, the radical is reduced further to covalent binding species. In the presence of oxygen, in contrast, this nitro anion free radical undergoes redox cycling, with the generation of reactive oxygen species.

Androgen Antagonists↗
PubMed1992

Association of juxtapapillary diverticula with choledocholithiasis but not with cholecystolithiasis.

Juxtapapillary diverticula are often associated with biliary lithiasis. The aim of this study was to compare the prevalence of juxtapapillary diverticula in choledocholithiasis and in cholecystolithiasis without common bile duct stones. The results of 520 consecutive retrograde cholangiographies were retrospectively analysed. The prevalence of juxtapapillary diverticula was higher in patients with biliary lithiasis than in patients without: 26.0% vs 10.5% (p less than 0.001). However, juxtapapillary diverticula were more frequently encountered in patients with choledocholithiasis than in those with gallbladder lithiasis or previous cholecystectomy and a stone-free common bile duct: 40.0% vs 10.2% (p less than 0.001). There was no significant difference between the patients with cholecystolithiasis alone and those without biliary lithiasis. Among the patients with previous cholecystectomy or with gallbladder lithiasis, common bile duct stones were more frequently found in patients with juxtapapillary diverticula than in those without: 80.3% vs 40.6% (p less than 0.001). These data suggest that juxtapapillary diverticula are associated only with choledocholithiasis and not with gallbladder lithiasis.

Aged↗
PubMed1992

Human immunodeficiency virus type 1 envelope gene structure and diversity in vivo and after cocultivation in vitro.

Nested-primer polymerase chain reaction (PCR) has been applied to the molecular cloning of 4.6-kb half-genome fragments of human immunodeficiency virus type 1 (HIV-1) taken directly from the peripheral blood mononuclear cells (PBMC) of an individual with neurological symptoms of HIV-1 infection. In a similar manner, gp120-coding portions of the envelope gene were cloned after PBMC from the same blood sample were cocultivated with uninfected PBMC for 28 days. The complete 1.6-kb nucleotide sequence of the gp120 gene was determined from each of 35 clones examined. Two of 13 (15%) PBMC-derived gp120 genes and 3 of 22 (14%) coculture-derived gp120 genes were defective as a result of frameshifts and an in-frame stop codon(s). Mean diversity between individual gp120-coding sequences in PBMC was fivefold greater (3.24%) than after coculture (0.65%). A predominant sequence of "strain" was found after coculture that was distinct from the diverse viral genotypes detected in vivo and therefore was selectively amplified during in vitro propagation. Multiple distinct third variable (V3) regions encoding the principal neutralizing domain of the envelope protein were detected in PBMC-derived genes, suggesting the presence of immunologic diversity of HIV env genes in vivo not reflected in the cocultured virus sample. The large size of the HIV fragments generated in this study will permit analysis of the diversity of immunologic reactivity, gene function, and pathogenicity of HIV genomes present within infected individuals, including the functional significance of the loss of diversity that occurs upon coculture.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Mechanism for the hepatotoxicity of the antiandrogen, nilutamide. Evidence suggesting that redox cycling of this nitroaromatic drug leads to oxidative stress in isolated hepatocytes.

The nitroaromatic drug nilutamide has been shown previously to undergo redox cycling in aerobic rat liver microsomes, being reduced by NADPH-cytochrome P-450 reductase to a nitro anion-free radical which reacts with oxygen, to regenerate the parent drug, and form a superoxide anion dismuted to hydrogen peroxide. In the present study, the effects of nilutamide on isolated rat hepatocytes have been determined. After 6 and 8 hr of incubation with 0.5 mM nilutamide, lactate dehydrogenase was released in the incubation medium, and cell viability was decreased markedly. Consistent with a redox cycle producing reactive oxygen species, nilutamide increased nonmitochondrial (cyanide-resistant) oxygen consumption; the toxicity of nilutamide occurred sooner and was more extensive in the presence of sodium azide (an inhibitor of catalase). Consistent with an oxidative stress, the toxicity of nilutamide was associated with depletion of reduced glutathione, increased levels of glutathione disulfide, increased Ca(++)-dependent phosphorylase a activity, oxidation and accumulation of cytoskeleton-associated proteins and formation of blebs; toxicity was prevented by glutathione precursors, thiol reductants and/or antioxidants, such as L-cystine, L-cysteine, N-acetyl-L-cysteine, dithiothreitol, N,N'-diphenyl-p-phenylene-diamine and alpha-tocopherol. Feeding the animals with a diet supplemented with 2% L-cystine increased the initial glutathione stores of hepatocytes and prevented nilutamide toxicity. It is concluded that nilutamide is toxic to isolated rat hepatocytes, as a probable consequence of an oxidative stress due to the redox cycling of this nitroaromatic compound.

Animals↗
PubMed1991

Pharmacogenetics of human erythrocyte thiopurine methyltransferase activity in a French population.

1. A genetic polymorphism in human erythrocyte thiopurine methyltransferase activity (RBC TPMT) resulting in a trimodal phenotypic distribution has been demonstrated both in a North American population and in British children. 2. We studied whether such a polymorphism may be also present in a white French population by testing RBC TPMT activity in 303 randomly selected blood donors. 3. We found a large inter-individual variation in RBC TPMT activity which ranged from 2 to 40 nmol ml-1 packed RBC h-1, with a mean value of 15.4 +/- 7.0 nmol ml-1 packed RBC h-1. The enzyme activity was not significantly influenced by the sex and age of the subjects. 4. In our population sample, we found no subject with undetectable enzyme activity. However, the probit plot of the log RBC TPMT activity showed a highly significant change in slope at a TPMT activity of 7.5 nmol ml-1 packed RBC h-1. Thirty four subjects (11% of our population) had TPMT activities below 7.5 nmol ml-1 packed RBC h-1. 5. These data are consistent with the view that the genetic polymorphism of TPMT activity described in populations from North America and the United Kingdom is also present in a French population, with about 89% of subjects exhibiting a high activity and 11% an intermediate activity.

Adult↗
PubMed1991

Generation of free radicals during the reductive metabolism of the nitroaromatic compound, nilutamide.

Incubation of the antiandrogen nilutamide with rat liver microsomes and NADPH, under anaerobic conditions, led to the formation of the nitro anion free radical, as indicated by electron spin resonance spectroscopy. The steady-state concentration of the nitro anion free radical was not decreased by SKF 525-A, carbon monoxide or metyrapone (3 inhibitors of cytochrome P-450) but was decreased by NADP+ or p-chloromercuribenzoate (2 inhibitors of NADPH-cytochrome P-450 reductase). Under aerobic conditions, the nitro anion free radical was reoxidized by oxygen, and the electron spin resonance signal was not detected. This redox cycle was associated with NADPH oxidation, consumption of oxygen, and formation of superoxide anion, hydrogen peroxide and glutathione disulfide. Under anaerobic conditions, nilutamide was further reduced to chemically reactive metabolites. Anaerobic incubation of [3H]nilutamide (0.1 mM) with rat liver microsomes and a NADPH-generating system resulted in the in vitro covalent binding of [3H]nilutamide metabolites to microsomal proteins; covalent binding required NADPH; it was decreased in the presence of NADPH-cytochrome P-450 reductase inhibitors (methylene blue, 2'-adenosine monophosphate) or in the presence of the nucleophile glutathione, but was unaffected by cytochrome P-450 inhibitors (SKF 525-A, CO). Covalent binding was decreased markedly under aerobic conditions. We conclude that nilutamide is reduced by microsomal NADPH-cytochrome P-450 reductase into a nitro anion free radical. In the presence of oxygen, this nitro anion free radical undergoes redox cycling with oxygen, and forms reactive oxygen species. In anaerobiosis, it is reduced further to covalent binding species.

Androgen Antagonists↗
PubMed1991

Inhibition by salicylic acid of the activation and thus oxidation of long chain fatty acids. Possible role in the development of Reye's syndrome.

Administration of either aspirin or salicylic acid (3 mmol.kg-1 b.wt. i.p.) decreased by 50 and 65%, respectively, the in vivo oxidation of [U-14C]palmitic acid to [14C]CO2 in mice; after salicylic acid administration, exhalation of [14C]CO2 from [1-14C]palmitic acid, [1-14C]octanoic acid or [1-14C]butyric acid was decreased by 87, 33 and 38%, respectively. Inhibition lasted 9 hr. It was associated with markedly decreased blood glucose concentrations and increased plasma ketone bodies. Repeated administration of salicylic acid (2 mmol.kg-1 i.p. every 8 hr) tripled hepatic triglycerides and produced mild microvesicular steatosis of the liver at 22 hr in fasted mice. In vitro, salicylic acid (1.5 mM) had no or little effect on the formation of beta-oxidation products from [1-14C]octanoic or [1-14C]palmitoyl-L-carnitine, in the presence of ATP, carnitine (40 microM) and coenzyme A (40 microM), but decreased by 51% that from [1-14C]palmitic acid. In the latter system, increasing the concentrations of coenzyme A and carnitine to 200 microM suppressed the inhibitory effect of salicylic acid. Salicylic acid (1.5 mM) decreased by 80% the in vitro mitochondrial formation of palmitoyl-coenzyme A from [1-14C]palmitic acid and 10 microM coenzyme A; again, increasing the concentration of coenzyme A prevented inhibition. We conclude that salicylic acid decreases the mitochondrial activation and thus beta-oxidation of long chain fatty acids, presumably by sequestering extramitochondrial coenzyme A and possibly carnitine.

Adenosine Triphosphate↗