Flavonoids as DNA topoisomerase I poisons.

The therapeutic anticancer potential of flavonoids shown by recent research needs a greater understanding of these compounds. They are antioxidants and antimutagenic agents that can inhibit tumor promotion and transformation and can modify the activity of a large number of mammalian enzyme systems, such as human DNA-topoisomerases. Poisons of topoisomerases generate toxic DNA damage by stabilization of the covalent DNA-topoisomerase cleavage complex and some of them have therapeutic efficacy in human cancer. The present investigation has assayed ten flavonoids, isolated in our laboratory, as topoisomerase I poisons obtaining myricetin and myricetin-3-galactoside as two new topoiosomerase I poisons. These two flavonoids, and the plant extract from which they were isolated, were assayed for cytotoxic activity against three human cancer cell lines using the SRB assay. Taking into account our previous research, structural requisites implicated in the topoisomerase poisoning are discussed.

[Primary cardiac lymphoma: cytological diagnosis and treatment with response to polychemotherapy and hematopoietic precursor autotransplant. Presentation of a case a review of the literature]. / Linfoma cardiaco primario: diagnóstico citológico y tratamiento con respuesta a poliquimioterapia y a autotrasplante de precursores hematopoyéticos. Presentación de un caso y revisión de la literatura.

The primary cardiac lymphoma (PCL) is an extremely infrequent tumor suffered by immunocompetent patients with a difficult diagnosis and slow progress leading to a serious prognosis and few therapeutically possibilities. It's a primary-cardiac non-Hodgkin's lymphoma (NHL) in a patient of 46-year-old, immunocompetent, who started with a congestive heart failure and atrial flutter. Some examinations were carried out such as a transesophageal echocardiography (TEE), a computed tomography (TC) and a magnetic resonance imaging (MRI) and an intracardiac tumor placed in the interauricular septum was detected. The diagnosis was based on a pleural fluid cytological examination. It was decided to follow a chemotherapy treatment and the autologous peripheral blood stem cells transplantation was carried out. The patient remains in full remission thirty-six months after diagnosis and twenty-nine months after the autotransplant. Our clinical experience indicated that an early and accurate diagnosis combined with the appropriate and aggressive antilymphoma therapy can thus help in obtaining a long survival in patients with PCL.

A cytotoxic diarylheptanoid from Viscum cruciatum.

A diarylheptanoid, 1,7-di-(3',4'-dihydroxyphenyl)-4-hepten-3-one, hirsutanone, has been isolated from the methanolic extract of the aerial parts of Viscum cruciatum (Viscaceae) and characterized by spectroscopic methods and chemical transformations. This compound showed cytotoxic activity against melanoma (UACC-62), renal (TK-10) and breast (MCF-7) cancer cell lines.

Atherosclerotic aortic arch plaques in cryptogenic stroke: a microembolic signal monitoring study.

BACKGROUND AND PURPOSE: To find out the prevalence of relevant atherosclerotic plaques in the aortic arch and their potential role as a source of embolism in cryptogenic stroke. METHODS: We performed a transoesophageal echocardiography (TEE) on 49 patients with cryptogenic stroke from a total series of 212 non-selected patients with acute ischaemic stroke studied prospectively by cranial computed tomography (CT), colour-duplex and transcranial Doppler (TCD) sonography with micro-embolic signal (MES) monitoring. Cryptogenic stroke was diagnosed in those patients without carotid or intracranial stenosis > 50%, nor lacunar or cardio-embolic strokes. We defined relevant plaques as those > or = 4 mm thick located in the ascending aorta or proximal arch. RESULTS: Twenty-three patients (46.9%) had atherosclerotic aortic plaques (AAP): 3 in the ascending aorta (in 1 > or = 4 mm), 11 in the proximal aortic arch (in 4 > or = 4 mm) and 9 in the descending aorta (in 5 > or = 4 mm). Hence, 5 patients (10.2%) had relevant plaques. Aortic plaques were significantly related to older age (p < 0.001) and male gender (p = 0.042). A carotid artery stenosis < 50% was found in 39% of patients with AAP and in 8% of those without AAP (p = 0.009). MES were detected in 3 patients with plaques > or = 4 mm thick, but not in those without AAP or with AAP < 4 mm thick (p = 0.006). CONCLUSION: Although few patients with cryptogenic stroke had relevant plaques in our non-selected population, our results support the hypothesis that relevant aortic plaques have embolic potential.

Cytotoxic triterpenoids from Erica andevalensis.

The cytotoxic activity of two pentacyclic triterpenoids (ursolic acid and alpha-amyrine) isolated from the methanolic extract of the aerial parts from Erica andevalensis, whose structures have been established on the basis of spectroscopic and chemical evidence, has been assessed against three human cancer cell lines, TK-10 (renal adenocarcinoma), MCF-7 (breast adenocarcinoma) and UACC-62 (melanoma), recommended by NCI (National Cancer Institute) and we also evaluated the antimitotic effect in root meristematic cells of Allium cepa. Ursolic acid was found to possess the highest cytotoxic activity.

Cytotoxic compounds from Annonaceus species as DNA topoisomerase I poisons.

BACKGROUND: In the search for cytotoxic natural products as DNA topoisomerase poisons, we have assessed six annonaceus compounds (the acetogenins annonacin and rolliniastatin-1, the styryl-lactones etharversin and altholactone and the alkaloids thaligrisine and cepharanone-B) for cytotoxic activity against three human cancer cell lines and then we evaluated these compounds as DNA topoisomerase poisons. MATERIALS AND METHODS: The cytotoxicity parameters were determined following protocols established by the National Cancer Institute (NCI) using the SRB assay. In the topoisomerase assay, the supercoiled DNA produces open circle forms that are stabilised in the presence of DNA topoisomerase poisons and can be detected after a denaturation step by proteinase K-SDS. RESULTS: The six compounds showed cytotoxic activity, with cepharanone B being the most cytotoxic one, even more than the antineoplastic agent etoposide on two cancer cell lines, although it is the only one that does not act as a DNA topoisomerase poison. CONCLUSION: These results could justify the traditional use of the studied annonaceus species and topoisomerase-mediated DNA damage might be a possible mechanism by which five of these compounds exert their cytotoxicity.

Glucosylated isoflavones as DNA topoisomerase II poisons.

Since topoisomerase poisons allow the enzyme to cut and covalently bind to DNA but abort the subsequent rejoining of the molecule after relieving the torsional stress. To study their action we have made use of a supercoiled form of the pRYG plasmid that bears a specific topoisomerase recognition and binding region. The conversion of the supercoiled circular double-stranded DNA to the linear and open circle forms in the presence of a topoisomerase II poison and a denaturation step by proteinase K-SDS is indicative of the efficiency of our test agents to stabilize the cleavable complex. Using this system, three glucosylated isoflavones (6'-methoxy-pseudobaptigenin-7-O-beta-glucoside, genistin, and daidzin) isolated from cytotoxic chloroform and ethyl acetate extracts of Retama sphaerocarpa Boissier, were found to have the ability to stabilize the cleavage complex human DNA topoisomerase II.

Cardiovascular activity of a methanolic extract of Digitalis purpurea spp. heywoodii.

The paper deals with the effects of a glycosidal extract of Digitalis heywoodii, ssp. of Digitalis purpurea L., (Schrophulariaceae) grown in Badajoz (Spain), on isolated cardiac auricle of rabbits, urinary excretion of rats, as well as its emetic effect in pigeons. These effects using vehicle (propylene glycol-ethanol-water, 40:10:50) and digoxin as standards are presented. The extract at concentrations of 20 and 40 microg/ml produced an increase in the contraction force of auricles in a dose-dependent way. At doses of 15 and 30 mg/kg a slight diuretic and natriuretic effect was observed. The active dose range for emesis was 0.5-4 mg/kg and a decrease of the emesis time within 10 min of injection in dose-dependent manner was obtained. The pharmacological activity of the extract is related to gitoxin derivatives (digitalinum verum and strospeside), the most abundant compounds obtained from the leaves of Digitalis purpurea spp. heywoodii.

Cytotoxic activity of flavonoids and extracts from Retama sphaerocarpa Boissier.

Seven flavonoids isolated from chloroform, ethyl acetate and butanol extracts, obtained from the aerial parts of Retama sphaerocarpa, have been assessed for cytotoxic activity against three human cancer cell lines: TK-10 (renal adenocarcinoma), MCF-7 (breast adenocarcinoma) and UACC-62 (melanoma), using the SRB assay. All of them, extracts and flavonoids, were actives in, at least, one of the three cell lines at the recommended National Cancer Institute doses. They produce a dose-dependent inhibition of cell growth at concentrations in the 10(-6)-10(-4) M and 25-250 microg/ml range for the flavonoids and extracts respectively, being the flavonol rhamnazin the most cytotoxic.

Retamatrioside, a new flavonol triglycoside from Retama sphaerocarpa.

A new flavonol triglycoside, retamatrioside (1), has been isolated from the aerial parts of Retama sphaerocarpa. The structure of 1 has been determined as rhamnazin 3-O-beta-D-glucopyranosyl-(1-->5)-[beta-D-apiofuranosyl(1-->2)]-al pha -L-arabinofuranoside, using spectroscopic methods.

Two new flavonol glycosides as DNA topoisomerase I poisons.

Flavonoids are secondary plant metabolites whose anticancer properties are actually being studied from an epidemiological and pharmacological point of view. They are believed to be implicated in the lower risk of some forms of cancer observed in Asian countries, due to their capacity to control cell proliferation, to act on certain regulatory enzymes as protein kinases or topoisomerases. Based on these precedents, three flavonols isolated from a cytotoxic butanol extract from Retama sphaerocarpa Boissier have been assessed to study their topoisomerase I and II activity. Two new rhamnazin glycosides were found to have the ability to stabilize the cleavage complex human DNA topoisomerase I at concentrations in the 100-250 microM range, acting as topoisomersase I poisons.

The need to quantify right-to-left shunt in acute ischemic stroke: a case-control study.

BACKGROUND AND PURPOSE: Although right-to-left shunt (RLSh) has been reported to be significantly more frequent in young stroke patients with cryptogenic stroke, its relevance in a nonselected population of acute ischemic stroke is not well known. The aim of this study was to determine the importance of the RLSh magnitude as a risk factor for stroke in nonselected patients. METHODS: Two hundred eight patients hospitalized consecutively with transient ischemic attack or acute cerebral infarction and 100 healthy control subjects were studied. Transcranial Doppler ultrasonography (TCD) was performed in both middle cerebral arteries (MCAs) after intravenous application of agitated saline solution. The magnitude of RLSh was quantified by counting the number of signals in 1 MCA during a Valsalva maneuver. RLSh was classified as "no shunt," "small" (< 10 signals), and "large" (> 10 signals), with the latter including the "shower" (> 25 signals) and "curtain" (uncountable signals) patterns. Extensive investigations, including contrast transesophageal echocardiography, were carried out on patients diagnosed as suffering from stroke of an uncertain etiology. The importance of RLSh for stroke was assessed by logistic regression analysis. RESULTS: Contrast TCD detected a large RLSh in 40 (19.7%) patients and in 21 (21%) control subjects, all with cardiac RLSh characteristics. A large RLSh was present in 4.7% of atherothrombotic strokes, 10.5% of cardioembolic strokes, 15.4% of lacunar strokes, and 45.3% of cryptogenic strokes (P<0.001). Although the overall frequency of RLSh was not significantly different between patients and control subjects, the detection of curtain or shower patterns by contrast TCD was associated with a higher risk of stroke (odds ratio, 3.5; 95% confidence interval, 1.29 to 9.87), particularly with cryptogenic stroke (odds ratio, 12.4; 95% confidence interval, 4.08 to 38.09) after adjustment for concomitant vascular risk factors. CONCLUSIONS: It is essential to quantify RLSh by contrast TCD during the Valsalva maneuver given that only those with shower and curtain patterns are associated with a higher risk of ischemic stroke in a nonselected population.

Antiulcerogenicity of the flavonoid fraction from Erica andevalensis Cabezudo-Rivera.

Investigations were carried out to determine the antiulcerogenicity of the flavonoid fraction (ethyl acetate extract) of Erica andevalensis Cabezudo-Rivera on gastric ulceration induced by different experimental models. Oral treatment with the ethyl acetate extract and the major flavonoid (myricetin 3-O-D-galactoside) were found to be effective to prevent gastric ulceration induced by cold-restraint stress in rats. Statistically significant ulcer index values with respect to the control group were observed. Mucus content was not increased although it was accompanied by an increase in proteins and hexosamines. In pyloric-ligated animals flavonoids showed a significant reduction in the number and severity of the ulcers. Under the same conditions acidity did not decrease with the flavonoid extract and myricetin 3-O-D-galactoside significantly as compared to control. Gastric ulcers induced by oral administration of absolute ethanol were reduced by pretreatment with the flavonoid extract of doses from 125 to 250 mg/kg and the isolated flavonoid of 25 mg/kg p.o. However neither the flavonic extract nor the isolated flavonoid induced changes in the amount and glycoprotein content of gastric mucus.

[The use of transcranial Doppler ultrasonography with contrast medium for the diagnosis of left-to-right shunt in young adults with cerebral infarction]. / Utilidad del Doppler transcraneal con contraste para el diagnóstico de la communicación derecha-izquierda en el infarto cerebral de adultos jóvenes.

Paradoxical embolism by way of left-to-right shunt (LRSh) may be underestimated as a cause of stroke in young adults. We studied the prevalence of LRSh in 58 patients under 45 years of age. The sensitivity of transcranial Doppler ultrasound (TDU) with contrast medium and transthoracic echocardiography (TTE) with contrast for diagnosing LRSh, and the clinical and radiological signs of stroke are analyzed. TDU with contrast medium allowed shunt to be identified in 34.5%, whereas TTE identified 19%. The prevalence of LRSh was significantly higher in patients with cryptogenic stroke (p = 0.0043) and in patients without vascular risk factors (p = 0.0069). The group with shunt manifested less severe neurologic impairment both upon admission to the hospital and upon release. TDU with contrast medium is an excellent tool for diagnosing LRSh and a useful technique for studying cerebral infarction of uncertain origin.

Evaluation of plasminogen activators and plasminogen activator inhibitors in plasma and amniotic fluid in pregnancies complicated with intrauterine fetal growth retardation.

Several fibrinolytic parameters were determined in plasma and amniotic fluid from normotensive pregnancies complicated by intrauterine fetal growth retardation (IUGR) and severe preeclamptic (PE) patients with IUGR and compared with data from normal pregnancies. A significant decrease in plasminogen activator type 2 (PAI-2) and urokinase levels in plasma and amniotic fluid was observed in IUGR groups in comparison with normal pregnancy. No significant differences were observed between the control and IUGR groups in relation to the other fibrinolytic parameters, except for plasma PAI type 1 and tissue-type plasminogen activator levels, which were significantly increased in the PE group. A significant positive correlation was observed between birth weight and PAI-2 levels in both plasma and amniotic fluid, but the plasma PAI-2 levels showed a higher correlation. In conclusion, these results suggest that the PAI-2 level measured in plasma is a more adequate marker of placental function than the PAI-2 level measured in amniotic fluid.

On-line assessment of left ventricular function by automatic border detection echocardiography during rest and stress conditions.

A new echocardiographic system, automatic boundary detection (ABD) echocardiography, provides automatic on-line quantification of the left ventricular cavity area. To assess the potential of ABD echocardiography in measuring left ventricular dimensions and detect stress-induced changes in left ventricular function, we studied 25 patients. Thirteen were studied to compare left ventricular cavity areas and fractional area change by using 2DE and ABD echocardiography during routine studies in multiple views; 12 patients were studied during transesophageal atrial pacing by ABD-echocardiography in 4-chamber or short-axis views. End-diastolic and end-systolic left ventricular areas measured by ABD echocardiography were not significantly different from two-dimensional ones for all the echocardiographic views, except the apical 4-chamber view; fractional area change values obtained with ABD were slightly lower than 2DE ones, although not significantly. High correlation values were found between the 2 techniques for end-diastolic area (r = 0.94, SEE = 3.69 cm2), end-systolic area (r = 0.90, SEE = 4.49 cm2) and fractional area change (0.73, SEE = 9.7%); similar results were obtained for each single echocardiographic view. A decrease was found from rest to peak-pacing in end diastolic area (25.2 +/- 5.1 cm2 versus 21.1 +/- 4.3 cm2, p < 0.003), end systolic area (16.2 +/- 6.0 cm2 versus 14.8 +/- 5.3 cm2, p < 0.016) and fractional area change (38.5 +/- 12.7% versus 31.8 +/- 9.6%, p < 0.003) with a return to baseline values in post-pacing (26.3 +/- 4.3 cm2 and 17.0 +/- 5.4 cm2 and 37.3 +/- 11.3%, p < 0.003 versus peak-pacing, NS versus rest for each parameter).(ABSTRACT TRUNCATED AT 250 WORDS)

Recurrent pericarditis. Relief with colchicine.

Recurrence is one of the major complications of pericarditis. Treatment of recurrence is often difficult, and immunosuppressive drugs or surgery may be necessary. We conducted an open-label prospective study of nine patients (seven men and two women; age, 18-64 years; mean age, 41.7 +/- 13.7 years). Patients were treated with colchicine (1 mg/day) to prevent recurrences. All patients had suffered at least three relapses despite treatment with acetylsalicylic acid, indomethacin, prednisone, or a combination. Pericarditis was classified as idiopathic in five patients, postpericardiotomy in two, post-myocardial infarction in one, and associated with disseminated lupus erythematosus in one. For statistical analysis, we conducted a paired comparison design (Student's t test). All patients treated with colchicine responded favorably to therapy. Prednisone was discontinued in all patients after 2-6 weeks (mean, 26.33 +/- 10.9 days), and colchicine alone was continued. After a mean follow-up of 24.3 months (minimum, 10 months; maximum, 54 months), no recurrences were observed in any patient; there was a significant difference between the symptom-free periods before and after treatment with colchicine (p less than 0.002). Our study suggests that colchicine may be useful in avoiding recurrence of pericarditis, although these results need to be confirmed in a larger, double-blind study.