New natural sesquiterpenes as modulators of daunomycin resistance in a multidrug-resistant Leishmania tropica line.

The effects produced by nine dihydro-beta-agarofuran sesquiterpenes isolated from Crossopetalum tonduzii (1-8) and Maytenus macrocarpa (9) (Celastraceae) on the reversion of the resistant phenotype on a multidrug-resistant Leishmania line and their binding to recombinant C-terminal nucleotide-binding domain of Leishmania P-glycoprotein-like transporter were studied. The structures of the new compounds (1-5) were elucidated by spectroscopic methods, including (1)H-(13)C heteronuclear correlation (HMQC), long-range correlation spectra with inversal detection (HMBC), ROESY experiments, and chemical correlations. The absolute configuration of one of them (1) was determined by CD studies. The structure-activity relationship is discussed.     

The formation of DNA interstrand cross-links by a novel bis-[Pt2Cl4(diminazene aceturate)2]Cl4.4H2O complex inhibits the B to Z transition

We present data demonstrating that the cytotoxic compound [Pt2Cl4(diminazene aceturate)2]Cl4.4H2O (Pt-berenil) circumvents cisplatin resistance in ovarian carcinoma cells. The analysis of the interaction of Pt-berenil with linear and supercoiled DNA indicates that this compound induces the formation of a large number of covalent interstrand cross-links on DNA and that this number is significantly higher than that produced by cis-diamminedichloroplatinum(II) (cis-DDP). Renaturation experiments, interstrand cross-link assays, and electron microscopy indicate that the kinetics of DNA interstrand cross-link formation caused by Pt-berenil binding is faster than that caused by cis-DDP at similar levels of platinum bound to DNA. Furthermore, the number of DNA interstrand cross-links in Pt-berenil-DNA complexes is influenced by supercoiling. Circular dichroism experiments show that Pt-berenil strongly inhibits the B-DNA-to-Z-DNA transition of poly(dG-m5 dC). poly(dG-m5dC) at salt concentrations (3 mM MgCl2) at which the native methylated polynucleotide readily adopts the Z-DNA conformation, which suggests that the induction of interstrand cross-links by Pt-berenil inhibits the Z-DNA transition. On the basis of these results, we propose that bis(platinum) compounds with structure similar to Pt-berenil may act as blockers of DNA conformational changes and may also display activity in cisplatin-resistant cells.     

Drug-induced parkinsonism in a movement disorders unit: A four-year survey

To establish the frequency of drug-induced parkinsonism (DIP) and the drugs responsible for this side-effect we reviewed the database of our Movement Disorders Unit during the first 4 years of its use. The diagnostic criteria for DIP included: (1) the presence of two or more cardinal symptoms of parkinsonism, (2) an absence of parkinsonian symptoms before the exposure to the offending drug, (3) a disappearance or significant improvement in parkinsonism after withdrawal of the offending drug, (4) no better explanation for the parkinsonism. One-hundred and five patients fulfilled the diagnostic criteria for DIP (16.3% of total patients referred and 33.8% of patients with parkinsonian syndromes). Drug-induced parkinsonism was related to 1, 2, 3, 4, 5 and 7 drugs in 62, 30, 9, 1, 2 and 1 patients, respectively. The most frequently offending drugs were: calcium-channel blockers (61 cases), antipsychotic drugs (29 cases), thiethylperazine (18 cases), clebopride (14 cases), and sulpiride (10 cases). When compared with idiopathic Parkinson's disease patients, DIP patients were predominantly female and showed an older age at the onset of parkinsonian signs. Parkinsonian signs only disappeared completely in 41 patients (39.0%). In conclusion: (1) DIP was a frequent cause of parkinsonism in our Movement Disorder Unit, (2) calcium-channel blockers, and/or orthopramides and substituted benzamides were a frequent cause of DIP in our series, (3) old age and the female gender were frequent among DIP patients, (4) DIP is not always reversible.     

The evolution of breast cancer mortality and morbidity in Spain (1977–1988)

A study of breast cancer mortality and cancer morbidity has been carried out in Spain recently for the period 1977–1988, covering the population of the 17 Autonomous Communities and 50 provinces of the country. Data was obtained from INE, Instituto Nacional de Estadistica (National Institute of Statistics), with age standardization using the indirect method. The different Autonomous Communities and provinces were compared in order to establish possible significant differences. The crude mean mortality rate was 21 cases per 100,000 inhabitants/year; Las Palmas, Gerona, Barcelona, the Balearic Islands, Navarra and Zaragoza have the highest mortality rates, with a proportional increment of 54% in that period. The crude national mean morbidity rate for the considered period was 64.0 cases per 100,000 inhabitants, and the proportional increment 180%. According to provincial figures, Alava had the highest fitted mean morbidity rate, 135 cases per 100,000 inhabitants, whilst the highest fitted mean rate was Las Palmas (28 cases/100,000 inhabitants), and the highest proportional increment was the rate for the province of Huesca (169%). When using the ANOVA test on the mean rate of the period, for mortality as well as morbidity, we observed significant differences among provinces and among Autonomous Communities (p 0.05).     

Absorption/metabolism of sulforaphane and quercetin, and regulation of phase II enzymes, in human jejunum in vivo.

For the first time the human intestinal effective permeability, estimated from the luminal disappearance and intestinal metabolism of phytochemicals, sulforaphane and quercetin-3,4'-glucoside, as well as the simultaneous changes in gene expression in vivo in enterocytes, has been studied in the human jejunum in vivo (Loc-I-Gut). Both compounds as components of an onion and broccoli extract could readily permeate the enterocytes in the perfused jejunal segment. At the physiologically relevant, dietary concentration tested, the average effective jejunal permeability (Peff) and percentage absorbed (+/- S.D.) were 18.7 +/- 12.6 x 10-4 cm/s and 74 +/- 29% for sulforaphane and 8.9 +/- 7.1 x 10-4 cm/s and 60 +/- 31% for quercetin-3,4'-diglucoside, respectively. Furthermore, a proportion of each compound was conjugated and excreted back into the lumen as sulforaphane-glutathione and quercetin-3'-glucuronide. The capacity of the isolated segment to deconjugate quercetin from quercetin-3,4'-diglucoside during the perfusion was much higher than the beta-glucosidase activity of the preperfusion jejunal contents, indicating that the majority (79-100%) of the beta-glucosidase capacity derives from the enterocytes in situ. Simultaneously, we determined short-term changes in gene expression in exfoliated enterocytes, which showed 2.0 +/- 0.4-fold induction of glutathione transferase A1 (GSTA1) mRNA (p < 0.002) and 2.4 +/- 1.2-fold induction of UDP-glucuronosyl transferase 1A1 (UGT1A1) mRNA (p < 0.02). The changes in gene expression were also seen in differentiated Caco-2 cells, where sulforaphane was responsible for induction of GSTA1 and quercetin for induction of UGT1A1. These results show that food components have the potential to modify drug metabolism in the human enterocyte in vivo very rapidly.