A meta-analysis of the association between pre-eclampsia and childhood-onset Type 1 diabetes mellitus.

AIMS: To review and synthesize the evidence for an increased risk of childhood Type 1 diabetes mellitus in children born to mothers diagnosed with pre-eclampsia during pregnancy. METHODS: A comprehensive search of the published literature was performed in MEDLINE, Web of Science and EMBASE limited to studies published before August 2010. Crude odds ratios and 95% confidence intervals were calculated from the data reported in each study. Meta-analysis techniques were then used to derive a combined odds ratio and investigate heterogeneity. Sensitivity analyses were conducted by study design, ascertainment of pre-eclampsia and study quality. RESULTS: Data were available from 16 studies including 8315 children with Type 1 diabetes. Overall, there was little evidence of an increase in the risk of Type 1 diabetes in children born to mothers who had pre-eclampsia during pregnancy (OR = 1.10, 95% CI 0.96-1.27; P = 0.17). This association did not vary much between studies (I(2) = 28%, P for heterogeneity =0.14). The association was similar in three cohort studies (OR = 1.05, 95% CI 0.77-1.44; P = 0.75) and in seven studies with a low risk of bias (OR = 1.13, 95% CI 0.91-1.40; P = 0.27), but was more marked in 13 studies which ascertained pre-eclampsia from obstetrical records or birth registry data (OR = 1.18, 95% CI 1.03-1.36; P = 0.02). CONCLUSIONS: This analysis demonstrates little evidence of any substantial increase in childhood Type 1 diabetes risk after pregnancy complicated by pre-eclampsia.

Proton pump inhibitors reduce the bioavailability of dietary vitamin C.

BACKGROUND: The gastric juice concentration of vitamin C is reduced in subjects with elevated intragastric pH. This is probably because of the fact that the vitamin is unstable at non-acidic pH and undergoes irreversible denaturation. AIM: To determine whether elevation of intragastric pH reduces the bioavailability of dietary vitamin C. METHODS: Plasma vitamin C was measured before and after a course of omeprazole 40 mg/day for 4 weeks in 14 Helicobacter pylori positive and 15 H. pylori negative subjects. Dietary intake of vitamin C was measured and intragastric pH monitored. RESULTS: Compared with the H. pylori negative subjects, H. pylori positive subjects had a lower mean daily vitamin C intake (141.7 mg vs. 41.5 mg, P < 0.01) and also lower plasma vitamin C concentration (25.1 microg/mL vs. 17.4 microg/mL, P < 0.0001). After 28 days of 40 mg/day of omeprazole the mean plasma vitamin C level had fallen by 12.3% (P = 0.04). This fall affected both the H. pylori positive and negative subjects. CONCLUSIONS: We have shown that a short course of omeprazole will cause a reduction in the plasma vitamin C level of healthy volunteers. This decrease in plasma vitamin C is independent of dietary intake of the vitamin and indicates reduced bioavailability. The clinical significance of this is unclear but any adverse effects will be most apparent in H. pylori infected subjects who have a low pre-treatment vitamin C status.

Effect of fluconazole on the disposition of phenytoin.

In a randomized, placebo-controlled, parallel study, phenytoin was given in the presence and absence of fluconazole. Twenty healthy male subjects received phenytoin, 200 mg orally, on study days 1 to 3 and 18 to 20 and 250 mg intravenously on study days 4 and 21. Ten subjects received fluconazole, 200 mg orally, and 10 received placebo daily on study days 8 to 21. Serial blood samples were collected during a 24-hour period after the intravenous phenytoin dose. Fluconazole trough concentrations were determined on days 14, 18, and 21. Serum phenytoin area under the concentration-time curve from 0 to 24 hours increased 75% and minimum plasma drug concentration increased 128% after administration of fluconazole, 200 mg/day, for 14 days. These values were significantly greater than the 5% increase in area under the concentration-time curve from 0 to 24 hours and 11.6% increase in minimum plasma drug concentration in the placebo group. Fluconazole trough concentrations remained unchanged during the coadministration of phenytoin. The increased phenytoin concentrations in the presence of fluconazole suggest that fluconazole inhibits phenytoin metabolism. Serum concentration monitoring with a reduction in phenytoin dosage is clinically warranted in patients receiving phenytoin and concomitant fluconazole therapy.

The effects of an antacid or cimetidine on the serum concentrations of azithromycin.

The effects of an antacid and of cimetidine on the serum concentrations of azithromycin were examined in volunteers. Ten subjects were given 500 mg azithromycin alone and immediately after being given 30 mL Maalox (Rorer, Fort Washington, PA) in a crossover design. There were no statistically significant differences in Tmax or AUC0-48 after administration of azithromycin alone or with antacid, but mean values of Cmax were reduced by 24% (P = .015). Thus, although Cmax was decreased, the extent of absorption of azithromycin was not affected by coadministration with an antacid. Two groups of six volunteers were given 500 mg azithromycin on day 1. On day 8, one group was given 800 mg cimetidine 2 hours before a dose of azithromycin; the remaining group received placebo before azithromycin. There were no differences in the pharmacokinetic parameters produced by administration with cimetidine or placebo, relative to those on day 1. Thus, cimetidine administered 2 hours before a dose of azithromycin had no apparent effect on the serum concentrations of azithromycin.

Induction of fluconazole metabolism by rifampin: in vivo study in humans.

The effects of rifampin on the pharmacokinetics of fluconazole were analyzed in an open-label, placebo-controlled, parallel study. Sixteen healthy male volunteers, randomized into two groups, received 200 mg of oral fluconazole on days 1 and 22. On days 8 through 27, group I received oral rifampin, 600 mg/d, and group II received placebo. Fluconazole in serum was analyzed by HPLC. On days 1 and 22, respectively, the AUC (micrograms.hr/mL) (mean +/- SD) was 160.5 +/- 19.5 and 124 +/- 22.2 in group I, 152 +/- 25 and 152.8 +/- 33.9 in group II; the Kel (hr-1) was .0211 +/- .0030 and .0264 +/- .0040 in group I, .0219 +/- .0036 and .0216 +/- .0053 in group II. Cmax and Tmax did not change significantly in either group. Urinary 6 beta-hydroxycortisol/cortisol increased from 3.47 +/- 1.04 to 15.2 +/- 5.07 in group I, but was unchanged (3.54 +/- 1.33-4.26 +/- 2.36) in group II on days 1 and 22, respectively. The findings in this study indicate that rifampin induces the metabolism of fluconazole.

Sertraline does not alter steady-state concentrations or renal clearance of lithium in healthy volunteers.

An open-label, placebo-controlled study was conducted to determine the effects of sertraline on the steady-state levels and renal clearance of lithium in 20 healthy volunteers. Subjects received 600 mg of lithium twice daily for 9 days. On the evening of day 8, subjects received orally either placebo or 100 mg of sertraline; these were administered twice, 8 hours apart, beginning 2 hours after the evening dose of lithium. In a comparison of day 8 with day 9 (before administration of the morning doses of lithium), sertraline was associated with only a 0.01 mEq/L (1.4%) decrease in steady-state levels and a 0.11 L/hour (6.9%) increase in the renal clearance of lithium. Neither change was statistically significant relative to placebo. Four subjects were excluded from analysis because of protocol violations or laboratory abnormalities unrelated to sertraline. Seven subjects who received lithium plus sertraline experienced side effects, mainly tremors, possibly related to treatment, whereas none of those administered lithium plus placebo experienced side effects. No sertraline-related laboratory abnormalities were observed.