John R. Bend

Grapefruit‐felodipine interaction: Effect of unprocessed fruit and probable active ingredients

To determine whether unprocessed grapefruit can cause a drug interaction, whether the active ingredients are naturally occurring, and whether specific furanocoumarins or flavonoids are involved.

Erythromycin-felodipine interaction : Magnitude, mechanism, and comparison with grapefruit juice

To investigate a potentially marked effect by erythromycin on felodipine pharmacokinetics, to characterize the mechanism, and to compare the interaction with that between grapefruit juice and felodipine.

Bergamottin, lime juice, and red wine as inhibitors of cytochrome P450 3A4 activity: Comparison with grapefruit juice

Objectives: Our objective was to assess the importance of bergamottin in drug interactions through comparisons between grapefruit juice and lime juice and the potential for drug interactions with red wine.

Grapefruit juice-felodipine interaction : Effect of naringin and 6', 7'-dihydroxybergamottin in humans

To test whether naringin or 6′,7′‐dihydroxybergamottin is a major active substance in grape‐fruit juice‐felodipine interaction in humans.

Grapefruit juice—terfenadine single‐dose interaction: Magnitude, mechanism, and relevance

To investigate the single dose‐response effects of grapefruit juice on terfenadine disposition and electrocardiographic measurements.

Effects of acute sodium arsenite administration on the pulmonary chemical metabolizing enzymes, cytochrome P-450 monooxygenase, NAD(P)H: quinone acceptor oxidoreductase and glutathione S-transferase in guinea pig: Comparison with effects in liver and kidney

Tissue specific changes in the cytochrome P-450 (P-450) monooxygenase system were observed following a single subcutaneous dose of sodium arsenite (75 mumol/kg), a known inducer of stress proteins. P-450 monooxygenase activities were assayed with several isozyme selective substrates; 7-ethoxyresorufin, 7-pentoxyresorufin, 4-aminobiphenyl and erythromycin. Both tissue selective and isozyme selective changes in monooxygenase activity were noted. For example, the rate of 4-aminobiphenyl N-hydroxylation (ABH) was increased by arsenite administration in lung but not in liver. Arsenite inhibited 7-ethoxyresorufin O-deethylation (ERF) in all tissues of control animals, but to a lesser extent in lung. However, increases of ERF activity occurred after arsenite treatment in lung of beta-naphthoflavone (beta NF)-treated guinea pigs whereas arsenite decreased ERF activities in the kidney and liver of these animals. These complex effects on ERF activity may in part be modulated by induction of heme oxygenase, whose activity was increased 2.5-3.5-fold in these organs by arsenite. The highest heme oxygenase activity was found in kidney with lower activities being present in liver and lung, respectively. These data are consistent with the decreased P-450 content observed in kidney and liver microsomes of arsenite treated guinea pigs. On the other hand there was either no change or a slight increase (about 2-fold) in the pulmonary microsomal P-450 content of these animals. A complex pattern of induction for the non-heme, Ah locus associated enzyme, NAD(P)H:quinone acceptor oxidoreductase (QOR) was also observed. With menadione as substrate arsenite treatment increased QOR activity in all tissues studied. However, with dichlorophenolindophenol (DCPIP) as substrate a significant arsenite effect was observed only in the kidney. Significant differences between the QOR substrates were also observed in beta NF-treated guinea pigs and control animals. Our results are consistent with the presence of more than one form of QOR in the guinea pig. Arsenite treatment also caused an increase in glutathione S-transferase activity, with 2,4-dinitro-1-chlorobenzene (DNCB) as substrate, of guinea pig kidney but not liver or lung.

Defining a lowest observable adverse effect hair concentrations of mercury for neurodevelopmental effects of prenatal methylmercury exposure through maternal fish consumption: a systematic review.

Background: Methylmercury is an environmental pollutant that can cause irreversible effects on the development of children. Although there is no doubt that high exposure can cause neurodevelopmental deficits, the threshold that will adversely affect the developing fetus is not well defined. Our objective was to systematically review the evidence of neurodevelopmental risks of methylmercury to the unborn child from maternal fish consumption to define the lowest observable adverse effect hair concentration (LOAEHC). Methods: A systematic review was conducted of all original research reporting on the effects of methylmercury on the human fetus. A literature search was undertaken using SCOPUS, Medline-Ovid, PubMed, Google Scholar, and EMBASE. Papers were selected based on the following inclusion criteria: 1) child neurodevelopmental outcome; 2) comparison groups; and 3) methylmercury exposure through fish consumption. Results: Forty-eight publications met these inclusion criteria. Thirty articles reported on longitudinal studies and 18 were cross-sectional studies. Variations in study design precluded formal meta-analysis. Based on an evaluation of these studies, we defined the LOAEHC at 0.3 μg/g of maternal hair mercury. The longitudinal studies yielded a LOAEHC of 0.5 μg/g. Conclusion: In the clinical context, the majority of pregnant women consume mercury-containing fish in amounts that are lower than the LOAEHC defined in this study. However, the LOAEHC is in the same order of magnitude of mercury exposure that occurs in significant numbers of women. Hence, although it appears safe to suggest that eating the recommended types and amounts of fish poses no measurable risks for neurodevelopmental deficits, analysis of hair mercury content before pregnancy might be suggested because dietary modification can decrease body content and risk.

Patch testing for the diagnosis of anticonvulsant hypersensitivity syndrome: a systematic review.

Anticonvulsant hypersensitivity syndrome (AHS), also known by the other names drug rash (reaction) with eosinophilia and systemic symptoms (DRESS) and drug-induced hypersensitivity syndrome (DIHS), is a rare and potentially fatal reaction that occurs in susceptible patients after exposure to certain drugs, including aromatic anticonvulsants. Because of its ill-defined clinical picture and resemblance to other diseases, the diagnosis of AHS is often difficult and requires a safe and reliable diagnostic test. The skin patch test has been proven to be very useful for prediction and diagnosis of some types of hypersensitivity reactions such as delayed drug eruptions to β-lactam antibacterials. However, the diagnostic value of patch testing for AHS is yet to be determined and its negative predictive values (NPVs) and positive predictive values (PPVs) are still unknown.This systematic review attempts to evaluate the usefulness of patch tests in the diagnosis of AHS and to examine different technical aspects of patch testing that may contribute to its performance. We included studies in which aromatic anticonvulsant drugs are the likely causes of the hypersensitivity reaction.Analysis of original publications from 1950 to August 2008 and cited in PubMed, MEDLINE and EMBASE has revealed contradictory findings, possibly due mainly to the use of unstandardized methods. Numerous factors have been suggested to affect the final result of the test, including the following: type of drug tested; concentration of drug and vehicle used; timing of the test after exposure; and the clinical picture of the reaction. The PPV of the test in optimal conditions was as high as 80–90% depending on the drug tested. On the other hand, this value is around 10–20% in many other published studies.Although patch testing may be a useful diagnostic test for AHS, accurate determination of its sensitivity and specificity is yet to be achievable due to the lack of a gold standard test against which the performance of patch testing can be measured. Its PPV appears to be higher than its NPV, a matter that necessitates the use of other confirmatory tests in case of negative patch tests (e.g. careful systemic rechallenge). The benefit of testing appears to be maximal with certain drugs (i.e. carbamazepine and phenytoin) and for specific clinical manifestations (strong reactions). It should be performed 2–6 months after recovery from the date of the ADR for best results, with adequate vehicle control.

Red wine–cisapride interaction: Comparison with grapefruit juice

Our objective was to compare the interactions of red wine and grapefruit juice with cisapride.

Hair Mercury Levels of Women of Reproductive Age in Ontario, Canada: Implications to Fetal Safety and Fish Consumption

OBJECTIVE To study hair mercury concentrations among women of reproductive age in relation to fish intake in Ontario, Canada. STUDY DESIGN Three groups were studied: 22 women who had called the Motherisk Program for information on the reproductive safety of consuming fish during pregnancy, a group of Japanese residing in Toronto (n=23) consuming much larger amounts of fish, and a group of Canadian women of reproductive age (n=20) not seeking advice, were studied. Mercury concentrations in hair samples were measured using inductively coupled plasma mass spectrometry. Seafood consumption habits were recorded for each participant. Based on the types of fish consumed and consumption frequencies, the estimated monthly intake of mercury was calculated. Hair mercury concentrations were correlated to both the number of monthly seafood servings and the estimated ingested mercury dose. RESULTS There were significant correlations between fish servings and hair mercury (Spearman r=0.73, P<.0001) and between amounts of consumed mercury and hair mercury concentrations (Spearman r=0.81, P<.0001). Nearly two thirds of the Motherisk callers, all of the Japanese women, and 15% of the Canadian women of reproductive age had hair mercury above 0.3 microg/g, which was shown recently to be the lowest observable adverse effect level in a large systematic review of all perinatal studies. CONCLUSIONS Because of very wide variability, general recommendations for a safe number of fish servings may not be sufficient to protect the fetus. Analysis of hair mercury may be warranted before pregnancy in selected groups of women consuming more than 12 ounces of fish per week, as dietary modification can decrease body burden and ensure fetal safety.