An 11-year-old girl with psychomotor regression.
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Brain↗
Biomedical subjects
J A Thompson
Publications and source records attributed to J A Thompson.
Inhibition by ketanserin of serotonin induced cerebral arteriolar constriction.
We studied the effects of serotonin on pial arterioles in anesthetized cats equipped with acutely implanted cranial window for the observation of the pial microcirculation. Serotonin topically applied caused cerebral arteriolar constriction. Ketanserin, a specific 5-HT2 inhibitor, completely blocked the vascular response of serotonin. Aggregated platelet supernatant was topically applied and caused generalized cerebral arteriolar constriction that could be blocked with ketanserin. We conclude that serotonin causes generalized cerebral arteriolar constriction that is due to the stimulation of 5-HT2 receptor. Aggregating platelets release serotonin, which mediates the vasoconstrictive action of the supernatant solution.
Animals↗
Carotid arterial elastic hyperplasia in a newborn.
Cerebrovascular insufficiency in infancy and childhood is well documented and has a diverse and often unknown etiology. Reported here is a polycythemic, microciphalic infant girl of 43 week's gestation with bilateral cerebral infarction occurring in the perinatal period. Infarction was the result of bilateral carotid artery stenosis produced by massive reduplication of the internal elastic lamina. Review of the literature failed to reveal any reports of similar arterial lesions. The angiographical picture was also unique. The etiology of this unusual defect is not known, but we believe the problem was congenital perhaps due to an intrauterine infectious process.
Carotid Arteries↗
Relationship between the metabolism of butylated hydroxytoluene (BHT) and lung tumor promotion in mice.
The widely used antioxidant butylated hydroxytoluene (BHT, 2,6-di-tert-butyl-4-methylphenol) produces acute pulmonary toxicity in mice, and also enhances the multiplicity of lung tumors in mice when chronically administered following a single dose of a carcinogen such as urethane. Evidence strongly indicates that the pulmonary effects of BHT are caused by one or more of its reactive metabolites, particularly the hydroperoxide or quinone methide products. The former, BHT-OOH (2,6-di-tert-butyl-4-hydroperoxy-4-methylcyclohexa-2,5-dienone+ ++), is later converted to free radicals by cytochrome P-450, and evidence implicating this pathway in BHT-OOH-induced cytotoxicity has been obtained using isolated rat hepatocytes. Pulmonary microsomes from mice effectively hydroxylate BHT to BHT-BuOH [6-tert-butyl-2-(hydroxy-tert-butyl)-4-methylphenol]; this metabolite was several-fold more effective than BHT as a lung tumor promoter, substantially more pneumotoxic than BHT in vivo, and more toxic to isolated rat hepatocytes and mouse bronchiolar Clara cells in vitro. These effects may be a result of oxidation of BHT-BuOH to the corresponding quinone methide, which is a highly electrophilic. The tumor promoting effects of BHT in mouse lung may be a result of selective cytotoxicity or altered signal transduction caused by radical-generating hydroperoxide and/or electrophilic quinone methide metabolites.
Animals↗
Studies on the N-demethylation and O-de-ethylation of ethylmorphine by hepatic microsomes from male rats.
On the basis of inhibition studies of the dealkylation of morphine and norcodeine, George and Tephly concluded that O-dealkylation and N-dealkylation are catalyzed by different enzymes. We have examined the microsomal dealkylation of 3-O-[1'-14Clethylmorphine by measuring HCHO colorimetrically and [1-14C]acetaldehyde radiometrically. We find that the KM for the O-de-ethylation is 57 muM, which is quite close to the KS(71 muM) for the type I binding of ethylmorphine in similar preparations. On the other hand, the KM for N-demethylation was 250 muM. Further, the N-demethylation was stoichiometric with the stimulation of both NADPH-cytochrome P-450 reductase and NADPH oxidase, whereas the sum of the N-demethylation and O-de-ethylation was significantly greater, suggesting that the O-de-ethylase activity does not involve stimulation of either of these two activities. Induction with phenobarbital increaesed N-demethylation 118% but did not affect O-de-ethylation. Finally, D2O inhibited the N-demethylase more than the O-de-ethylase.
Acetaldehyde↗
Echocardiographic profile of the transplanted human heart in clinically well recipients.
Thirty-four clinically well heart transplant recipients, aged 21 to 60 years, were selected for echocardiographic study at 12 +/- 2 months after transplantation. All had normal findings at stress thallium scintigraphy and at radionuclide left ventriculography, and no endomyocardial biopsy evidence of rejection was found within 36 hours of study. Multiple echocardiographic measurements were compared with those from two control groups. The first control group consisted of 15 normal subjects of similar ages as the donors, and the second group consisted of 15 normal subjects of similar ages as the recipients. Left ventricular mass (193 +/- 55 gm) was significantly increased in the transplant recipients compared with both control groups (p less than 0.001). Left ventricular volumes and ejection fractions of the transplanted heart, however, were normal. Right ventricular diastolic wall thickness (0.6 +/- 0.1 cm) and chamber area in both diastole (23.3 +/- 3 cm2) and systole (15.7 +/- 4 cm2) were significantly increased in the transplant patients (p less than 0.001), but fractional area change was similar to that of the normal group. Both left atrial area (26.9 +/- 4 cm2) and right atrial area (20.7 +/- 4 cm2) were significantly increased in the transplant recipients (p less than 0.001). One year after transplantation, clinically well recipients are characterized by increased left ventricular mass, but normal volumes and ejection fraction, increased right ventricular wall thickness and cavity size, but normal right ventricular systolic function, and markedly dilated atria.
Atrial Function↗
Oxidation of butylated hydroxytoluene to toxic metabolites. Factors influencing hydroxylation and quinone methide formation by hepatic and pulmonary microsomes.
The effects of inducing agents and inhibitors on the cytochrome P-450-catalyzed oxidations of butylated hydroxytoluene (BHT) to form three metabolites were investigated with liver and lung microsomes from rats and mice. These compounds, the quinone methide (QM) formed by two-electron oxidation of BHT, the hydroxy-tert-butyl analog of BHT (BHT-OH) resulting from aliphatic hydroxylation, and the hydroxy-quinone methide (QM-OH) derived from BHT-OH, have been implicated previously as intermediates or products involved in BHT bioactivation and toxicity. Although there was little or no increase in BHT metabolism in pulmonary microsomes from either species following phenobarbital (PB) administration, 6- to 37-fold enhancements occurred in the transformation of BHT to QM, and the conversion of BHT-OH to QM-OH with hepatic microsomes from both species. The first step in QM-OH formation, hydroxylation of BHT to BHT-OH, is a minor pathway with hepatic microsomes from treated or untreated rats, thereby explaining the lack of QM-OH formation from BHT by that species. The two-step oxidation of BHT to QM-OH, however, is a relatively important metabolic pathway with hepatic microsomes from PB-treated mice, due to an unusually large (111-fold) PB-induced increase in the tert-butyl hydroxylation step. These results demonstrate that pulmonary microsomes from mice, but not rats, have relatively high constitutive P-450 activity for the formation of QM-OH from BHT, supporting the proposal that this metabolite is involved in BHT-induced pneumotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Hypercholesterolemia in long-term survivors of heart transplantation: an early marker of accelerated coronary artery disease.
Coronary artery disease remains a significant long-term problem for survival after heart transplantation. Hyperlipidemia is a known risk factor for coronary artery disease in the general population, but the role of hyperlipidemia in cardiac allograft recipients has not been elucidated. To study this problem, we retrospectively reviewed 38 heart transplant recipients who survived more than 3 years after surgery and looked at age, development of diabetes, drug protocol, and development of hypercholesterolemia for a possible correlative or predictive value to the development of early coronary artery disease after heart transplantation. Eleven patients were identified as having coronary disease by the third year after transplantation. High-risk cholesterol values (in milligrams per deciliter) at 6 months after heart transplantation were defined as follows: for ages 10 to 20, 190; 20 to 30, 220; 30 to 40, 240; 40+, 260. We found a strong predictive value with high-risk lipid profiles (p less than 0.01) for the development of coronary artery disease by the third year. No significance was found for a low-risk value, the development of diabetes, or hypertension. All patients below the age of 20 years had coronary artery disease by the third year after transplantation. We conclude that a high-risk cholesterol value at 6 months after transplantation is a strong predictor for development of accelerated coronary artery disease and early graft failure. This has major implications for management of hyperlipidemia in the cardiac allograft recipient.
Adult↗
Metabolism of R-(+)-and S-(minus)-pentobarbital by hepatic microsomes from male rats.
Hepatic microsomes from male rats hydroxylate R-(+)- and (-)-[2-14-C]pentobarbital to the diasterioisomeric 3'-alcohols: metabolite I (1'RS, 3'SR)- and metabolite II (1'RS, 3'RS)-5-ethyl-5-(3'-hydroxy-1'methylbutyl) barbituric acids. The rate is linear up to 1.5 mg of microsomal protein per ml of incubation mixture and for up to 16 min. The metabolism of R-(+)-pentobarbital led to production of nearly equal quantities of metabolites I and II with a total hydroxylation of 1.08 nmol/min/mg of protein. On the other hand, the S-(-) pentobarbital gave 3- to 5-fold less of metabolite I than II and a total hydroxylation of 1.42 nmol/min/mg of protein. The KM values for formation of metabolite I were 381 muM from R-(+)- and 241 muM from the S-(-)-pentobarbital, while for metabolite II they were 115 muM from R-(+)- and 68 muM from S-(-)-pentobarbital. These data suggest that there are at least two enzymes catalyzing the hydroxylation of pentobarbital, one to give metabolite II and another or others to give metabolite I.
Animals↗
Hyperlipidemia after clinical heart transplantation.
Accelerated coronary atherosclerosis is a major cause of morbidity and death in the cardiac transplant recipient. Hypercholesterolemia has been implicated as a contributing risk factor. Because of this we reviewed lipoprotein profiles from transplant recipients from 1968 to 1986 in an attempt to identify the risk factors for the development of lipid disorders after transplantation. Patients were divided into three groups based on their immunosuppressive protocols. Group 1 consisted of 10 patients receiving azathioprine and prednisone. Group 2 consisted of 24 patients receiving cyclosporine and prednisone with or without azathioprine. Group 3 consisted of 18 patients receiving cyclosporine and azathioprine without prednisone. Total cholesterol levels at 1 year were highest in group 2 (266 mg/dl versus 236 mg/dl for group 1 [p = 0.16] and 223 mg/dl for group 3 [p = 0.005]). High-density lipoprotein cholesterol levels were lowest in group 3 (38 mg/dl versus 51 mg/dl for group 1 [p = 0.025] and 54 mg/dl for group 2 [p = 0.0001]). Subgroup analysis with multivariate and univariate analysis found that prednisone and preoperative coronary artery disease are the major contributors to the posttransplant lipid abnormalities.
Adult↗
Oxidative metabolism of butylated hydroxytoluene by hepatic and pulmonary microsomes from rats and mice.
Metabolism of the antioxidant butylated hydroxytoluene (BHT; 2,6-di-tert-butyl-4-methylphenol) has been studied with liver and lung microsomes from rats and mice. The structures of several previously reported metabolites were confirmed, the identities of four new metabolites were determined, pathways of oxidation were investigated, and quantitative data were obtained for several of the products. Two main metabolic processes occur, hydroxylation of alkyl substituents and oxidation of the aromatic pi electron system. The former leads to the 4-hydroxymethyl product (BHT-BzOH) and a primary alcohol resulting from hydroxylation of a t-butyl group (BHT-tBuOH). Additional metabolites were produced by oxidation of BHT-BzOH to the corresponding benzaldehyde and benzoic acid derivatives. Hydroxylation of BHT-tBuOH occurs at the benzylic methyl position, and the resulting diol is oxidized further to the hydroxybenzaldehyde derivative. Oxidation of the pi system leads to the quinol, 2,6-di-t-butyl-4-hydroxy-4-methyl-2,5-cyclohexadienone, the quinone, 2,6-di-t-butyl-4-benzoquinone, and the quinone methide, 2,6-di-t-butyl-4-methylene-2,5-cyclohexadienone. Derivatives of the quinol and quinone with a hydroxylated t-butyl group were also formed. Quantitative data demonstrate that BHT-BzOH is the principal metabolite in rat liver and lung microsomes. On the other hand, mice produce large amounts of both BHT-BzOH and BHT-tBuOH in these tissues. The metabolite profile was similar in rat liver and lung. Mouse lung, however, produced more quinone relative to other metabolites than mouse liver.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Are steroids essential for successful maintenance of immunosuppression in heart transplantation?
To determine the necessity for maintenance dosages of prednisone in the management of heart transplant patients, a retrospective study was made of 86 patients undergoing orthotopic heart transplantation and two patients having heart-lung transplantation from June 1985 through October 1986. Group 1 (n = 52) had maintenance immunosuppressive therapy that included cyclosporine, azathioprine, and prednisone. Group 2 (n = 36) received only cyclosporine and azathioprine with no maintenance dosage of steroids. Data were analyzed for frequency of rejections, infections, noninfectious complications, and mortality. The rate of rejection was 1.44 episodes per patient in group 1 and 1.58 episodes per patient in group 2. Twenty of 52 patients (38%) in group 1 had no rejection compared with 12 of 36 patients (33%) in group 2 (p = not significant [NS]). One or more infections occurred in 30 patients (58%) in group 1, whereas only 12 patients (33%) in group 2 had infections (p less than 0.05). Noninfectious complication rates were noted to be similar in both groups (27% versus 25%, p = not significant). There were five deaths in group 1: three from infections, one from rejection, and one from trauma. There were three deaths in group 2: two from infection and one from rejection. Although 14 patients in group 2 eventually were placed on low-dosage steroid maintenance, the remaining 22 patients (61%) never received maintenance dosages of steroids. We conclude that some patients can be successfully managed without maintenance dosages of steroids after heart transplantation. Such patients do not appear to have an increased risk of rejection and may have a reduced rate of infection.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Expectations and limitations of endomyocardial biopsy.
Endomyocardial biopsy represents an attempt at applying tissue examination to the diagnosis of primary myocardial disease. The right ventricular septum is biopsied from either the internal jugular or femoral venous approach. Left ventricular endomyocardial biopsy has not gained widespread acceptance in North America. A complication rate of 1-4% has been reported. Clinical indications for endomyocardial biopsy include acute cardiac allograft rejection, adriamycin cardiotoxicity and the differentiation of restrictive myopathy from constrictive pericardial disease. The biopsy of patients with idiopathic dilated congestive myopathy to find a treatable form of myocarditis remains controversial and principally a research tool. Only 5-25% of patients with dilated cardiomyopathy are found to have myocarditis and immunosuppressive therapy in these patients has yet to be proven beneficial.
Biopsy↗
Recombinant alpha-2 interferon in the treatment of hairy cell leukemia.
We treated 14 patients with hairy cell leukemia, 13 of whom had progressive disease, with recombinant alpha-2 interferon administered sc at 2 X 10(6) units/m2, three times per week. Thirteen patients were evaluable for response. All evaluable patients responded within 6-8 weeks. After a minimal treatment duration of 6 months and a maximal of 12 months, three patients have achieved complete response and ten have achieved partial response. With a median treatment duration of 10 months, the responding patients' hematologic parameters are continuing to improve, and no responding patients have relapsed. This outpatient self-administered regimen is well-tolerated, with mild fever, myalgias, and headache usually resolving within 2 months. Although the optimal regimen and the mechanism of action are unknown, recombinant alpha-2 interferon may be the treatment of choice for patients whose disease progresses after splenectomy or who are not surgical candidates.
Adult↗
Deuterium and tritium isotope effects on the microsomal N-demethylation of ethylmorphine.
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Animals↗
Influence of substrate configuration on chlorpheniramine N-demethylation by hepatic microsomes from rats, rabbits, and mice.
Measurements of formaldehyde formation in parallel incubations containing either (S)-(+)- or (R)-(-)-chlorpheniramine (CPA) and rat liver microsomes demonstrated that the active antihistamine, (S)-(+)-CPA, is N-demethylated about 35% faster than the inactive (R)-(-)-enantiomer. The KM values for the enantiomers were the same. Phenobarbital pretreatment increased Vmax values without affecting the stereoselectivity. N-Demethylation occurred at a several-fold faster rate with rabbit than with rat liver microsomes, but stereoselectivity was the same. N-Demethylation of CPA enantiomers were studied in microsomes prepared from each of four inbred strains of mice. These experiments demonstrated that stereoselectivity is species-dependent, as no significant differences in metabolism rates of CPA enantiomers could be detected with these microsomes. Pseudoracemic mixtures containing equal quantities of deuterated (S)-(+)-CPA and unlabeled (R)-(-)-CPA were incubated with microsomes from three species. Formation of the enantiomers of N-desmethyl- and N,N-didesmethyl-CPA (DMCPA and DDMCPA, respectively) were measured by GC/MS techniques. With microsomes from rats and mice, the ratio of (S)-DMCPA to (R)-DMCPA was essentially the same as that determined by measuring the formaldehyde formed in separate incubations of (S)-(+)- or (R)-(-)-CPA. Stereoselectivity with rabbit liver microsomes and pseudoracemic CPA was substantially higher than that determined in incubations with the separate enantiomers. The results suggest either that (S)-(+)-CPA inhibits the N-demethylation of (R)-(-)-CPA under these conditions, or that DMCPA undergoes further biotransformation by a route(s) which is stereoselective, favoring the (R)-enantiomer. Formation of DDMCPA could only be detected with rabbit microsomes and was found to occur with approximately the same stereoselectivity as that determined for the formation of DMCPA.
Animals↗
Glucuronidation of propranolol and 4'-hydroxypropranolol. Substrate specificity and stereoselectivity of rat liver microsomal glucuronyltransferases.
Liquid-chromatographic procedures were developed to assay the formation of diastereomeric glucuronides of propranolol (PG) and 4'-hydroxypropranolol (HPG) by rat liver microsomes, with identifications performed by GC/MS techniques. Propranolol was conjugated at a rate 10% of that determined for 4'-hydroxypropranolol. Glucuronyltransferase activity increased slightly (10-17%) in the presence of MgCl2. Inclusion of 0.04% Triton X-100 produced a 55% inhibition of PG formation, but increased HPG formation greater than 2-fold. Pretreatment of animals with phenobarbital resulted in a 4-fold increase in PG formation, but did not affect HPG formation unless MgCl2 was also present. Under these conditions, a 50-60% increase in HPG formation occurred. Pretreatment with 3-methylcholanthrene did not affect the formation of either glucuronide. (R)-(+)-Propranolol was glucuronidated 2-fold faster than the (S)-(-) enantiomer at substrate concentrations below 0.1 mM, and 1.3-fold faster at substrate concentrations above 2.0 mM. The estimated Vmax, 0.67 nmol/mg/min, was identical for both enantiomers. The dissociation constants were significantly different, however, being 0.57 mM for (R)-(+)-propranolol and 0.87 mM for (S)-(-)-propranolol. No stereoselectivity was observed in the formation of HPG when 4'-hydroxypropranolol was used as substrate, or when propranolol was incubated in the presence of an NADPH-generating system. Propranolol and 4'-hydroxypropranolol were used as substrate, or when propranolol was incubated in the presence of an NADPH-generating system. Propranolol and 4-hydroxypropranolol are apparently glucuronidated by different forms of rat liver glucuronyltransferase. Furthermore, propranolol glucuronidation occurs stereoselectively in vitro because of the different enzyme affinities for the enantiomers of the drug.
Animals↗
Glucuronidation of propranolol by dog liver microsomes. Effects of enantiomeric inhibition and detergent treatment on stereoselectivity.
The diastereomeric glucuronides of (R)- and (S)-propranolol [(R)-PG and (S)-PG] formed by incubating the racemic drug with dog liver microsomes were separated and quantitated chromatographically. Conjugation occurred stereoselectively with 3- to 4-fold more (S)-PG than (R)-PG produced. The values for the apparent Km were 1.0 and 1.7 mM, and those of the Vmax were 6.4 and 25 nmol/min/mg protein for (R)- and (S)-propranolol, respectively. Stereoselectivity was lower in parallel incubations conducted with the separate enantiomers than in incubates with the racemic substrate. The S enantiomer was found to be a noncompetitive inhibitor of (R)-PG formation, with a Ki of 1.8 mM. (S)-PG did not inhibit (R)-PG formation when added to incubates and (R)-propranolol did not inhibit the formation of (S)-PG. The presence of sodium cholate and Brij 35 stimulated glucuronidation by 60 and 120%, respectively, but did not affect the stereoselectivity even at concentrations high enough to inhibit conjugation. On the contrary, Triton X-100 and Emulgen 911 were inhibitory and produced a decrease in stereoselectivity; the magnitude of these effects increased with increasing detergent concentration.
Animals↗