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Web searchers signal their geographic intent by using place-names in search queries. They also indicate their flexibility about geographic specificity by reformulating their queries. By examining this data we can learn to understand web searcher flexibility with respect to geographic intent. We examine aggregated data of queries with locations, and locations identified from IP addresses, to identify overall distance preferences, as well as distance preferences by search topic. We also examine query rewriting: both deliberate query rewriting, conducted in web search sessions, and automated query rewriting, with manual relevance judgements of geo-modified queries. We find geo-specification in 12.7% of user query rewrites in search sessions, and show the breakdown into sub-classes such as same-city, same-state, same-country and different-country. We also measure the dependence between US-state-name and distance-of-modified-location-from-original-location, finding that Vermont web searchers modify their locations greater distances than California web searchers. We find that automatically-modified queries are perceived as much more relevant when the geographic component is unchanged. We look at the relationship between the non-location part of a query and the distance from the user. We see that people search for child day-care near their locations and maps far from where they are located. We also give distance profiles for the top topics which cooccur with place-names in queries, which could be used to set document priors based on document proximity and query topic.

ABSTRACT:The atypical antipsychotic drug clozapine (CLZ) is effective in a substantial number of patients who exhibit treatment-resistance to conventional agents. CYP1A2 is generally considered to be the major enzyme involved in the biotransformation of CLZ to its N-demethylated (norCLZ) and N-oxygenated (CLZ N-oxide) metabolites in liver, but several studies have also implicated CYP3A4. The present study assessed the interplay between these cytochrome P450s (P450s) in CLZ biotransformation in a panel of hepatic microsomal fractions from 14 individuals. The relative activity of P450s 1A2 and 3A4 in microsomes was found to be a major determinant of the relative susceptibility of norCLZ formation to inhibition by the P450-selective inhibitors fluvoxamine and ketoconazole. In contrast, the activity of CYP3A4 alone was correlated with the susceptibility of CLZ N-oxide formation to inhibition by these agents. These findings suggest that both P450s may be dominant CLZ oxidases in patients and that the relative activities of these enzymes may determine clearance pathways. In vivo assessment of CYP1A2 and CYP3A4 activities, perhaps by phenotyping approaches, could assist the optimization of CLZ dosage and minimize pharmacokinetic interactions with coadministered drugs.The atypical antipsychotic agent clozapine (CLZ) is effective in many patients who are resistant to treatment with conventional antipsychotic drugs, such as the phenothiazines and butyrophenones. However, its wider use is limited by interindividual variation in efficacy and toxicity. In vitro evidence suggests that the biotransformation of CLZ to its major metabolites N-desmethyl-CLZ (norCLZ) and CLZ N-oxide is catalyzed by hepatic cytochromes P450 (P450s) and flavin-containing monooxygenases (FMOs) (Pirmohamed et al., 1995). NorCLZ formation has been attributed to CYP1A2 and CYP3A4 (Pirmohamed et al., 1995;Linnet and Olesen, 1997) and CYP1A2 and CYP3A4, as well as the FMOs, catalyze CLZ N-oxygenation in vitro (Pirmohamed et al., 1995;Tugnait et al., 1997).There is wide interindividual variation in serum concentrations of CLZ and its active metabolite norCLZ, and the potential for pharmacokinetic drug-drug interactions in psychotic patients is high because of the likelihood of concurrent drug treatment. There have been numerous clinical reports that coadministration of alternate substrates and inhibitors of CYP1A2, such as the selective serotonin reuptake inhibitor fluvoxamine, fluoroquinolone antibacterials, and caffeine, inhibit CLZ clearance and mediate toxic interactions (Hiemke et al., 1994;Jerling et al., 1994). However, it has also been reported that drugs such as fluoxetine, paroxetine, and erythromycin, which inhibit CYP3A4 rather than CYP1A2, may also precipitate toxicity (Centorrino et al., 1996;Wetzel et al., 1998). The factors that determine individual susceptibility to CYP1A2 and CYP3A4 inhibition that leads to clinical toxicity are presently unclear.In a proportion of patients who receive CLZ therapeutic failure may occur because of rapid el...

Hepatic lipid infiltration (steatosis) is a complication of the metabolic syndrome and can progress to nonalcoholic steatohepatitis and severe liver injury. Microsomal cytochrome P450 (P450) drug oxidases are down-regulated in experimental steatosis. In this study we evaluated the separate and combined effects of lipid accumulation and P450 down-regulation on the microsomal oxidation of the antipsychotic agent clozapine (CLZ), the use of which is associated with an increased incidence of the metabolic syndrome. Several important drug oxidizing P450s were down-regulated, and the formation of Ndesmethyl-CLZ (norCLZ) and CLZ N-oxide was decreased in microsomal fractions from orotic acid-induced early steatotic rat liver. Inclusion of lipids extracted from steatotic, but not control, liver decreased the free concentration of CLZ in microsomes and suppressed norCLZ formation; CLZ N-oxidation was unchanged. Triglycerides increased in steatotic liver to 15-fold of control, whereas increases in the monounsaturated oleic acid to 10-fold of control and total polyunsaturated and saturated fatty acids to 4-and 5-fold of control also occurred. Addition of triglycerides containing esterified -6 and -3 fatty acids inhibited the microsomal formation of norCLZ but not that of CLZ N-oxide; triglycerides esterified with unsaturated and monounsaturated fatty acids were inactive. Thus, drug oxidation may be suppressed in steatosis by P450 down-regulation and the accumulation of polyunsaturated fatty esters. In contrast, the activity of the flavin-containing monooxygenase that mediates CLZ N-oxidation was unimpaired. Lipid deposition in livers of patients with the metabolic syndrome may necessitate dosage adjustments for toxic drugs, including CLZ.