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Whole-rock geochemical data on basaltic to rhyolitic samples from 12 late Pleistocene-Holocene centers are used to constrain the role of continental crust in the genesis of melts formed beneath the anomalously wide arc in Ecuador. Primitive and relatively homogeneous isotopic compositions observed across the arc imply that Ecuador lavas were produced largely within the subduction zone and not by extensive melting of crustal rocks similar to those upon-which the volcanoes were built. Mixing calculations limit the quantity of assimilated crust to less than approximately 10%. Cross-arc geochemical variation (e.g., in 143Nd/144Nd, Ba/Nb, La/Yb) indicates that assimilation of crustal rock is most active in the center-arc area, around the Inter-Andean Graben, at distances from 330-360 km from the trench. Characteristically 'adakitic' features (low Y, Yb, high La/Yb), which are observed in virtually all andesites and dacites in Ecuador as well as throughout the central and southern Andes, appear to be strongly influenced by crystal fractionation (e.g., as indicated by compatible element behavior for Y) and are most clearly developed in lavas that, based on isotopic compositions, have assimilated the most crust. A subset of andesites, which display an unusual combination of high Sr (>900 ppm) and non-radiogenic isotopes (eNd>4.1, D7/4Pb

Primitive high-alumina olivine tholeiites have been documented from a wide area of Cenozoic volcanism in the northwestern United States. Several new localities extend the geographic range of these rocks to the Cascade Range of northern Oregon, the Picture Gorge region of north-central Oregon, and the Powder River volcanic field of northeastern Oregon. These new sites also extend the age range over which these primitive magmas were generated in the northwestern United States to between 16 Ma and the present. All of the high-alumina olivine tholeiites are of remarkably uniform chemical and mineralogical composition and are similar to primitive ocean-ridge and island-arc tholeiites. The wide distribution in time and space of this magma type and uniform primitive composition suggest that a relatively homogeneous oceanic mantle source underlies much of the northwestern United States. Basalts from the different volcanic provinces exhibit varied evolutionary trends away from this parental composition, reflecting the distinct magmatic processes involved in each province. Trace element and rare earth element abundances in the primitive high-alumina olivine tholeiite lavas record the involvement of crustal material in their genesis. It is argued that this chemical signature was acquired by assimilation of crustal material by a primitive magma such as mid-ocean ridge basalt (MORB) en route to the surface.

Grapefruit juice produces mechanism-based inhibition of intestinal drug metabolism when consumed in normal quantities. This can produce clinically important increases in oral drug bioavailability when coadministered with substrates of cytochrome P450 3A4 (CYP3A4) that undergo high presystemic metabolism. Furanocoumarins such as bergamottin and 6′,7′-dihydroxybergamottin have been identified as probable active constituents. Grapefruit juice may also inhibit intestinal P-glycoprotein-mediated efflux transport of drugs such as cyclosporine to increase its oral bioavailability. However, grapefruit juice does not enhance the absorption of digoxin, a prototypical P-glycoprotein substrate, likely because it has high inherent oral bioavailability. Grapefruit and other fruit juices have recently been shown to be potent in vitro inhibitors of a number of organic anion-transporting polypeptides (OATPs). These juices were also found to decrease the absorption of the nonmetabolized OATP substrate, fexofenadine. Taken together, the data support inhibition of intestinal uptake transporters by fruit juices to decrease drug bioavailability. This would represent a new mechanism for food–drug interactions. These findings with grapefruit and other fruit juices continue to enhance our understanding of the complex nature of food–drug interactions, and their possible influence on the clinical effects of medications. [ABSTRACT FROM AUTHOR]

Drug interactions occur when the efficacy or toxicity of a medication is changed by administration of another substance. Pharmacokinetic interactions often occur as a result of a change in drug metabolism. Cytochrome P450 (CYP) 3A4 oxidises a broad spectrum of drugs by a number of metabolic processes. The location of CYP3A4 in the small bowel and liver permits an effect on both presystemic and systemic drug disposition. Some interactions with CYP3A4 inhibitors may also involve inhibition of P-glycoprotein. Clinically important CYP3A4 inhibitors include itraconazole, ketoconazole, clarithromycin, erythromycin, nefazodone, ritonavir and grapefruit juice. Torsades de pointes, a life-threatening ventricular arrhythmia associated with QT prolongation, can occur when these inhibitors are coadministered with terfenadine, astemizole, cisapride or pimozide. Rhabdomyolysis has been associated with the coadministration of some 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (‘statins’) and CYP3A4 inhibitors. Symptomatic hypotension may occur when CYP3A4 inhibitors are given with some dihydropyridine calcium antagonists, as well with the phosphodiesterase inhibitor sildenafil. Excessive sedation can result from concomitant administration of benzodiazepine (midazolam, triazolam, alprazolam or diazepam) or nonbenzodiazepine (zopiclone and buspirone) hypnosedatives with CYP3A4 inhibitors. Ataxia can occur with carbamazepine, and ergotism with ergotamine, following the addition of a CYP3A4 inhibitor. Beneficial drug interactions can occur. Administration of a CYP3A4 inhibitor with cyclosporin may allow reduction of the dosage and cost of the immunosuppressant. Certain HIV protease inhibitors, e.g. saquinavir, have low oral bioavailability that can be profoundly increased by the addition of ritonavir. The clinical importance of any drug interaction depends on factors that are drug-, patient- and administration-related. Generally, a doubling or more in plasma drug concentration has the potential for enhanced adverse or beneficial drug response. Less pronounced pharmacokinetic interactions may still be clinically important for drugs with a steep concentration-response relationship or narrow therapeutic index. In most cases, the extent of drug interaction varies markedly among individuals; this is likely to be dependent on interindividual differences in CYP3A4 tissue content, pre-existing medical conditions and, possibly, age. Interactions may occur under single dose conditions or only at steady state. The pharmacodynamic consequences may or may not closely follow pharmacokinetic changes. Drug interactions may be most apparent when patients are stabilised on the affected drug and the CYP3A4 inhibitor is then added to the regimen. Temporal relationships between the administration of the drug and CYP3A4 inhibitor may be important in determining the extent of the interaction. [ABSTRACT FROM AUTHOR]