Anthracenedione Antineoplastic Agent Effects on Drug Metabolism in Vitro and in Vivo: Relationship between Structure and Mechanism of Inhibition

Anthracenedione Antineoplastic Agent Effects on Drug Metabolismin Vitro and in Vivo:Relationship between Structure and Mechanismof Inhibition. KHARASCH, E. D., WENDEL, N. K., AND NOVAK, R.F. (1987). Fundam. Appl Toxicol. 9, 18–25. Two anthracenedioneantineoplastic agents, mitoxantrone and the nonhydroxylatedanalog, ametantrone, were found to inhibit hepatic microsomalcytochrome P-450-dependent drug metabolism in vitro and in vivo.Ethoxycoumarin deethylase activity of phenobarbital-inducedrabbit hepatic microsomes was inhibited 56 and 100% at 0.1 and0.5 mM mitoxantrone, respectively, whereas activity was inhibited38 and 88% at 0.1 and 0.5 mM ametantrone, respectively. Bothmitoxantrone and ametantrone were noncompetitive inhibitorsof ethoxycoumarin metabolism. Aryl hydrocarbon hydroxylase activityof hepatic microsomes was diminished 41 and 56% by 1 and 3 mMmitoxantrone, respectively; identical concentrations of ametantroneinhibited metabolism by 20 and 31%, respectively. In contrastto the inhibitory influence of both agents on monooxygenaseactivity, a differential effect on NADPH oxidation was observed.In the presence of benzo[]-pyrene, mitoxantrone enhanced microsomalNADPH oxidation by 21%, whereas ametantrone produced a 22% decreasein cofactor oxidation relative to the control rate. The anthracenedionesalso inhibited hepatic cytochrome P-450-dependent monooxygenaseactivity in vivo, as evidenced by altered hexobarbital sleeptimes of mice. Mitoxantrone (20 and 40 mg/kg) prolonged sleeptime by 59 and 68%, respectively; ametantrone (50 mg/kg) produceda 56% enhancement. These results demonstrate that both mitoxantroneand ametantrone inhibit drug metabolism in vitro and in vivo.     

Immunohistochemical and ultrastructural analysis of a mammary cystic hypersecretory carcinoma

Cystic hypersecretory carcinoma (CHC) is a rare variant of intraductal carcinoma. A CHC in a 50-year-old woman was excised and processed for light and electron microscopy and immunohistochemistry. The tumor had a marked cystic appearance. The walls of the cysts consisted of epithelial and myoepithelial cells and a well-developed basement membrane. The epithelial cells contained well-developed rough-surfaced endoplasmatic reticulum and Golgi apparatus. Secretory granules were not detected, with the exception of a few mucus-producing cells. The secretion was predominantly homogenous, reminiscent of thyroid colloid, and demonstrated distinct PAS positivity. The cells displayed a strong labeling with epithelial membrane antigen (EMA) and EMA-positive structures were observed within the intraluminal secretion, too. Some of these were stained by alcian blue. In addition, the colloid-like material was admixed with mucus showing a filamentous internal structure and lipid droplets resulting in some heterogenity of the secretion. Intraductal micropapillary proliferation in some of the cysts and adjacent nondistended ducts was a further defining feature of the tumor. Steroid hormone receptor and Ki-67 proliferation marker immuno his Tochemistry showed scattered positivity among the tumor cells. These results are in agreement with previous observations and further clarify the nature of this low-grade in situ cancer.     

Developmental Toxicity of N-Methylformamide Administered by Gavage to CD Rats and New Zealand White Rabbits

N-Methylformamide (NMF) is a metabolite of dimethylformamide(DMF), a solvent with wide applications in the chemical industry.The potential developmental toxicity of NMF was evaluated inCD rats and New Zealand white rabbits. Pregnant rats and rabbitswere dosed once daily by gavage on Gestation Days 6–15and 6–18, respectively. Doses for rats were 0, 1, 5, 10,or 75 mg/kg; doses for rabbits were 0, 5, 10, or 50 mg/kg. Cesareansections were performed on rats and rabbits on Gestation Days20 and 29, respectively. No treatment-related maternal deathsor clinical signs occurred in either species. Body weight gainand food consumption were depressed in rats given 75 mg/kg andrabbits given 50 mg/kg. Fetal viability was reduced at 75 mg/kgin rats and at 50 mg/kg in rabbits. In rats, a significant increasein the incidence of malformations including cephalocele andstern-oschisis was observed in fetuses from the 75 mg/kg group.In addition, a developmental delay was indicated by reductionof fetal weight and by a significant increase in the occurrenceof incomplete ossification of various skeletal structures. Inthe rabbit, fetal body weight was reduced at 50 mg/kg. Malformationsobserved at 50 mg/kg included gastroschisis, cephalocele, domedhead, flexed paw, and skull and sternum anomalies. The lowest-observed-adverse-effectlevels for maternal and developmental toxicity in the rat andrabbit were 75 and 50 mg/kg, respectively. The no-observed-adverse-effectlevel for maternal and developmental toxicity in the rat andrabbit was 10 mg/kg.     

Use of the Implantable Loop Recorder in Evaluation of Patients with Unexplained Syncope

Syncope is a complex symptom with multiple potential etiologies that can be difficult to establish. The major obstacles to diagnosis are the periodic and unpredictable nature of events and the high spontaneous remission rate. Short-term ECG monitoring often is unproductive when initial noninvasive testing is negative due to the low probability of recurrence during the brief monitoring period. Implantable loop recorders extend the ability to monitor cardiac patients, enhancing the diagnostic yield to as high as 85% in difficult to diagnose syncope. Several recent studies suggest that prolonged monitoring with an implantable loop recorder has a role in patients with syncope and conduction disturbances, negative tilt testing, and unexplained seizures, and may be superior to conventional testing with tilt and electrophysiologic studies. (J Cardiovasc Electrophysiol, Vol. 14, pp. S70-S73, September 2003, Suppl.)     

Protective effect of flavonoids against red blood cell hemolysis by free radicals

BACKGROUND:

Flavonoids are polyphenolic substances with antioxidant properties, and they are found in different vegetables and fruits. Epidemiological studies have shown that the consumption of flavonoids reduces the prevalence of cardiovascular diseases. The use of synthetic antioxidants, however, has been limited because of their toxicity. Therefore, medical researchers have intensified their quest to find natural antioxidants.

OBJECTIVES:

To investigate the effect of several pure flavonoids, such as kaempferol, quercetin, morin and rutin, on red blood cell hemolysis and evaluate their -SH capacity as an indicator of membrane protection.

METHODS:

The rate of hemolysis and cell membrane -SH capacity were determined by spectrophotometry. Red blood cell peroxidation was induced using 2,2′-azo-bis-(2-amidinopropane) dihydrochloride. The effect of each flavonoid on hemolysis was examined at three concentrations (0.5 μg/mL, 5 μg/mL and 10 μg/mL), however, only the greatest concentration (10 μg/mL) of each flavonoid was used to study the effect on -SH groups.

RESULTS:

In all cases, the antioxidant activity was dose-dependent. Rutin showed the highest inhibitory effect on hemolysis among flavonoids (42.5%). The protective effect of kaempferol, rutin and morin against -SH group oxidation measured 7.7%, 23.3% and 26.4%, respectively.

CONCLUSIONS:

Results showed that flavonoids and flavonoid-containing plants can be used as natural antioxidants for the treatment and prevention of disease conditions, the pathogenesis of which is mediated by lipid peroxidation.     

PATTERN OF T-CELL RECEPTOR DELTA GENE REARRANGEMENT BY SOUTHERN BLOTTING AND POLYMERASE CHAIN REACTION TECHNIQUE IN HONG KONG CHINESE PATIENTS WITH NON-T-CELL HEMATOLOGICAL MALIGNANCIES

It has been recognized that clonal T-cell receptor delta (TCRδ) gene rearrangement is present in both T- and B-cell malignancies. The highly sensitive polymerase chain reaction (PCR) technique may be applicable to cases of leukemia and lymphoma of non-T-cell origin for detection of minimal residual disease (MRD). A PCR technique was used in this study to investigate the pattern of clonal TCRδ gene rearrangement in Hong Kong Chinese patients with non-T-cell hematological malignancies. Seventy-three patients with the diagnosis of acute leukemia and non-Hodgkin's lymphoma of non-T-cell origin were included in this study. There were 20 patients with common ALL (cALL), seven precursal B-cell ALL (PreB-ALL), 23 acute myeloid leukemia (AML), and 23 non-Hodgkin's lymphoma of B-lineage (B-NHL). Clonal rearrangement was detectable by Southern analysis using a Jδ1 probe in 41 per cent of ALL of B-lineage but in none of the B-NHL or AML. The samples were also studied further by monoclonal PCR amplification for TCRδ gene rearrangement. Three different sets of primers were employed to detect clonal rearrangement of the TCRδ gene. The Vδ1(D)Jδ1 recombination typically seen in T-cell malignancies were not seen in any of the of the non-T-cell malignancies. The Vδ2(D)Dδ3 recombination was found exclusively in ALL of B-lineage and was seen in 73 per cent of the Southern positive cases. Although clonal TCRδ gene rearrangement was undetectable by Southern analysis in our AML cases, 26 per cent had a Vδ2(D)Jδ1 recombination found by the PCR technique. Sensitivity of the PCR technique was determined by serial mixing and was up to 5–10 leukemic cells per 10⁴ nucleated cells. It was apparent from this study that it was feasible to detect clonal TCRδ gene rearrangement by the PCR technique in a proportion of the cases of non-T-cell hematological malignancies. The PCR technique can be applied to detect residual leukemic cells in marrow of patients in an apparent morphological complete remission. The value of this application requires further clinical evaluation and correlation.     

INITIAL DEVELOPMENT OF A NEW CULTURE-SPECIFIC SCREEN FOR EMOTIONAL DISTRESS IN OLDERCARIBBEAN PEOPLE

Previous research and our own observations suggested that older Caribbean people might use terms for emotional distress that differed from those found in standard screening instruments. Using a combination of qualitative approaches derived from the ‘new cross-cultural psychiatry’, we have developed a new 13-item culture-specific screen containing items which both overlap and differ from those found in, for example, the Geriatric Depression Scale. Further research is in progress to test the validity of this screen in a large community sample.     

Outcome of major cardiac injuries at a Canadian trauma center

Background  

Canadian trauma units have relatively little experience with major cardiac trauma (disruption of a cardiac chamber) so injury outcome may not be comparable to that reported from other countries. We compared our outcomes to those of other centers.