Exposure to candesartan during the first trimester of pregnancy in type 1 diabetes: experience from the placebo-controlled DIabetic REtinopathy Candesartan Trials.

AIMS/HYPOTHESIS: The teratogenic consequences of angiotensin-converting enzyme inhibitors angiotensin receptor blockers (ARBs) during the second and third trimesters of pregnancy are well described. However, the consequences of exposure during the first trimester are unclear, especially in diabetes. We report the experience from DIRECT (DIabetic REtinopathy and Candesartan Trials), three placebo-controlled studies designed to examine the effects of an ARB, candesartan, on diabetic retinopathy. METHODS: Over 4 years or longer, 178 normotensive women with type 1 diabetes (86 randomised to candesartan, 32 mg once daily, and 92 assigned to placebo) became pregnant (total of 208 pregnancies). RESULTS: More than half of patients were exposed to candesartan or placebo prior to or in early pregnancy, but all discontinued it at an estimated 8 weeks from the last menstrual period. Full-term pregnancies (51 vs 50), premature deliveries (21 vs 27), spontaneous miscarriages (12 vs 15), elective terminations (15 vs 14) and other outcomes (1 vs 2) were similar in the candesartan and placebo groups. There were two stillbirths and two 'sick babies' in the candesartan group, and one stillbirth, eight 'sick babies' and one cardiac malformation in the placebo group. CONCLUSIONS/INTERPRETATION: The risk for fetal consequences of ARBs in type 1 diabetes may not be high if exposure is clearly limited to the first trimester. Long-term studies in fertile women can be conducted with ARBs during pregnancy, provided investigators diligently stop their administration upon planning or detection of pregnancy. TRIAL REGISTRATION: ClinicalTrials.gov DIRECT-Prevent 1 NCT00252733; DIRECT-Protect 1 NCT00252720; DIRECT-Protect 2 NCT00252694. FUNDING: The study was funded jointly by AstraZeneca and Takeda.

Retention processes on alpha 1-acid glycoprotein-bonded stationary phase.

Stereoselective separations of charged enantiomers on CHIRAL-AGP can be controlled by varying the pH and adding charged and uncharged additives to the mobile phase. The interaction with the selector, alpha 1-acid glycoprotein, was studied by monitoring the effects of the variables on retention and by indirect detection, in part using a simple multivariate design. The stereoselectivity is due to simultaneous retention processes involving ion-exchange and ion-pairing mechanisms. The predominant mode of interaction for different solutes was elucidated from variables that promote or counteract either of the processes. Considerable improvements in the stereoselectivity were achieved with chiral or achiral anionic and cationic additives that act in a synergistic or competitive mode.

Disopyramide in the maintenance of sinus rhythm after electroconversion of atrial fibrillation. A placebo-controlled one-year follow-up study.

In this multicentre study, 90 patients who left hospital in sinus rhythm after electroconversion of atrial fibrillation were randomized to double-blind treatment with either disopyramide (n = 44) or placebo (n = 46). The groups were comparable regarding age and sex distribution, duration of atrial fibrillation, heart volume and NYHA-classification. Life-table analysis was used to estimate the percentage of patients still in sinus rhythm and tolerating treatment at control visits after 1, 3, 6, 9 and 12 months. After 1 month there was already a significant difference (P less than 0.01) between the two groups (disopyramide 70%, placebo 39%), a difference that was still remaining after 12 months (disopyramide 54%, placebo 30%). Twenty-four patients, all relapsing to atrial fibrillation before six months on placebo, were converted to sinus rhythm once again. They were then treated with disopyramide in an open manner and after 12 months 37% were still in sinus rhythm. From the results of this study, disopyramide seems to be a useful drug in maintaining sinus rhythm after electroconversion of atrial fibrillation.

Characterization of drug purity by liquid chromatography.

Applications of liquid chromatography (LC) in the characterization of drug purity are reviewed. Examples are given of the development of methods for the separation of impurities in acids, amines and neutral drug substances. A variety of methods and techniques are discussed including normal-phase and reversed-phase LC, gradient elution, and multidimensional separation systems.

Two-phase titration of organic ammonium ions with lauryl sulphate and methyl yellow as indicator.

Conditions for determination of quaternary ammonium compounds and amines by two-phase titration have been calculated on the basis of extraction constants for the ion-pairs between the titrant (lauryl sulphate), the indicator (Methyl Yellow) and the sample. Methods for determination of extraction constants are presented. The precision and selectivity of the method are demonstrated by titrations of ammonium ions with different structures and degrees of substitution. The results are in agreement with the theoretical calculations.