Clopidogrel and proton pump inhibitor (PPI) interaction: separate intake and a non-omeprazole PPI the solution?

BACKGROUND: Dual therapy with aspirin and clopidogrel increases the risk of gastrointestinal bleeding. Therefore, co-therapy with a proton pump inhibitor (PPI) is recommended by most guidelines. However, there are warnings against combining PPIs with clopidogrel because of their interactions with cytochrome P450 isoenzyme 2C19 (CYP2C19). METHODS: The effects of the combined or separate intake of 20 mg of omeprazole and 75 mg of clopidogrel on the clopidogrel-induced inhibition of platelet aggregation were measured in four healthy subjects whose CYP2C19 exon sequences were determined. The effects of co-therapy with 10 mg of rabeprazole were also examined. RESULTS: Two subjects showed the wild-type CYP2C19 sequence. The concurrent intake of omeprazole had no effect on clopidogrel-induced platelet inhibition in these subjects. Two subjects were heterozygous for the *2 allele, with predicted reduced CYP2C19 activity. One of them was a clopidogrel non-responder. In the second heterozygous subject, omeprazole co-therapy reduced the clopidogrel anti-platelet effect when taken simultaneously or separately. However, the simultaneous intake of rabeprazole did not reduce the clopidogrel effect. CONCLUSION: The clopidogrel-PPI interaction does not seem to be a PPI class effect. Rabeprazole did not affect the clopidogrel effect in a subject with a clear omeprazole-clopidogrel interaction. The separate intake of PPI and clopidogrel may not be sufficient to prevent their interaction.

[Intrahepatic cholestasis in pregnancy. What to consider in jaundice and pruritus]. / Intrahepatische Schwangerschaftscholestase. Woran Sie bei Gelbsucht und Juckreiz denken sollten.

Intrahepatic cholestasis of pregnancy is a hepatopathy that occurs in the second or third trimester and accounts for 20% of cases of jaundice occurring in pregnancy. Both genetic and hormonal factors appear to play important roles in its development. The leading symptom is pruritus, and jaundice is common. Transaminases, serum bile acids and bilirubin are typically elevated, while gamma-GT is usually normal. For the differential diagnosis, in particular viral hepatitis, cholelithiasis, gestosis and acute fatty liver of pregnancy must be excluded. While the prognosis of intrahepatic cholestasis of pregnancy for the mother is good, the associated increased tendency for a premature birth represents a potential risk for the child. Early treatment with ursodeoxycholic acid appears to have a positive influence on both the mother's symptoms and the course of the pregnancy. Should the symptoms persist after delivery, consideration must be given to a chronic hepatopathy.

Procoagulant inflammatory responses of monocytes after direct balloon angioplasty in acute myocardial infarction.

This study sought to investigate monocyte procoagulant activity and Mac-1 expression after successful percutaneous transluminal coronary angioplasty (PTCA) in acute myocardial infarction (AMI). An increased leukocyte count is an important risk factor for subsequent adverse cardiac events in AMI. Cellular procoagulant responses may contribute to the risk of thrombotic events after AMI. In 20 patients with AMI serial venous blood samples were obtained before, 4, 8 hours, and daily after direct PTCA. Twenty patients with elective PTCA served as a control group. We measured leukocyte procoagulant activity with a 1-stage clotting assay, Mac-1 expression of monocytes by flow cytometry, concentrations of tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and IL-8 using immunoassays. Forty-eight hours after PTCA in patients with AMI, an increase in systemic IL-6 and C-reactive concentrations was found (p = 0.001, p = 0.008) associated with an increase in monocyte Mac-1 expression by 49 +/- 18% (p = 0.04) and followed by an increase in monocyte procoagulant activity by 140 +/- 63% 72 hours after PTCA (p = 0.01). None of these changes were detectable in the control group. No changes in the concentrations of the cytokines IL-1beta, tumor necrosis factor-alpha, or IL-8 were found. The present study demonstrates an increase in procoagulant activity along with an increase in Mac-1 expression on circulating monocytes after successful PTCA in AMI associated with an increase in systemic IL-6. These cellular procoagulant responses may limit the clinical benefit from timely reperfusion.

Effect of human recombinant interleukin-6 and interleukin-8 on monocyte procoagulant activity.

Interleukin (IL)-6 and IL-8 are important regulators of inflammatory responses in myocardial infarction. Induction of monocyte procoagulant activity (PCA) by these cytokines could present a mechanism that links inflammatory responses to thrombotic events. We therefore investigated the effect of IL-6 and IL-8 on monocyte tissue factor (TF) expression. Recombinant human IL-6 and IL-8 caused a time- and dose-dependent increase in PCA (recalcification time) of monocytic U937 cells and of mononuclear leukocytes. Using blocking anti-TF monoclonal antibodies and factor VII-deficient control plasma, this PCA was shown to be TF dependent. Compared with unstimulated cells, mononuclear cell PCA increased by 4.5-fold to 17 +/- 2 mU/5x10(5) cells after exposure to 100 ng/L IL-6 for 4 hours and by 6.6-fold to 27 +/- 4 mU/5x10(5) cells after exposure to IL-8 under the same conditions. Northern blot analysis showed an increase in TF mRNA after stimulation with IL-6 or IL-8 for 2 hours, and after 4 hours an increase in cellular TF protein content was found by immunoassay. Flow cytometry demonstrated that IL-6 and IL-8 induced an increase in TF surface expression on monocytes. Thus, IL-6 and IL-8 induce monocyte PCA by increasing mRNA, protein content, and surface expression of TF.