Premarketing surveillance of ibuprofen suppositories in febrile children

In many countries, ibuprofen is available only in oral formulations. The authors aimed to investigate parental satisfaction and possible adverse reactions among children receiving newly marketed ibuprofen suppositories, prior to their arrival at the pharmaceutical points of distribution. Children needing antipyretic medication were recruited from 11 pediatric wards and clinics in Israel. Each patient received ibuprofen suppositories (5-10 mg/kg/dose) after completing a data collection form. After 3 to 7 days of treatment, information regarding parent satisfaction, possible adverse reactions, and concomitant use of drugs was obtained. Overall, 490 children completed the study. Parents' satisfaction was high (4.5 ± 0.47 on a scale of 1-5), and 92.2% reported that they would use the medication in the future. Adverse reactions were reported in 8 patients (1.63%, 95% confidence interval = 1.77-3.25), the most common being diarrhea. Rectal administration of ibuprofen suppositories is well tolerated and overall satisfaction and the repeated expected use were high.     

Hepcidin in acute iron toxicity

Background

Hepcidin regulates extracellular iron concentration by inhibiting iron release from macrophages and preventing iron absorption in the intestine. Our objective was to evaluate the expression of hepcidin in the liver in acute iron poisoning in a rat model.

Methods

Male Wistar rats were assigned to group 1, who received 750 mg/kg elemental iron (LD₅₀) by gavage, and group 2 (control), who received distilled water. Iron concentrations and liver transaminases were measured in the serum. Hepcidin messenger RNA levels were measured in the liver.

Results

Mean serum iron levels, aspartate aminotransferase, alanine aminotransferase, and uric acid were significantly higher in group 1 compared to group 2 (P < .0001, P = .01, P < .0001, and P = 0.0001, respectively). Hepcidin messenger RNA levels in the liver were significantly higher in the study group (P = .005).

Conclusions

In acute iron intoxication, hepcidin expression in the liver significantly increased. Further studies are needed to determine whether hepcidin levels correlate with the severity of the intoxication.     

Metamizol (dipyrone,optalgin) in pregnancy,is it safe? A prospective comparative study

AIM: To assess the teratogenic effect of metamizol when used during the first trimester of pregnancy. METHODS: One hundred and eight women who used metamizol during the first trimester of pregnancy were recruited from 4 teratogen information centers in Israel (3) and in Italy (1). The study group was paired for age, smoking habits and alcohol consumption with a comparative group exposed to acetaminophen. RESULTS: Maternal demographics and history, birth weight, gestational age at delivery, rate of live births, spontaneous abortions and fetal distress were comparable in both groups. The rate of major malformations in the metamizol group (3%) did not differ significantly from the rate in the comparative group (2%) (P = 0.57, relative risk = 1.55, 95% confidence interval 0.26-9.05). CONCLUSIONS: Our data may suggest that exposure to metamizol during the first trimester of pregnancy is probably not associated with a significantly increased risk for malformations or spontaneous abortions.     

Oral N-acetylcysteine has a deleterious effect in acute iron intoxication in rats

Acute iron intoxication is associated with depletion of reduced glutathione in hepatocytes and changes in the glutathione system enzymes. We hypothesized that treatment with N-acetylcysteine (NAC), a glutathione reducing agent and an antioxidant, would reduce mortality in acute iron intoxication. We used a rat model to test this hypothesis. Male rats were assigned to 4 groups. Group 1 received 400 mg/kg elemental iron by oral gavage, group 2 received the same dose of iron followed by NAC, group 3 received NAC only, whereas group 4 received distilled water. Iron and liver transaminases in the blood, and glutathione system enzymes in the liver and erythrocytes were measured. Mortality in group 2 was significantly higher after 2, 6, and 24 hours compared with group 1 (P < .001). No deaths were observed in groups 3 and 4. Serum iron levels were significantly higher in group 2 rats compared to group 1 rats (P < .001). Hepatic and erythrocyte glutathione system enzymes were significantly lower among rats in group 2 compared to rats in group 1. The administration of NAC probably increased the absorption of iron through the gastrointestinal tract, causing higher serum iron levels with significant hepatic damage. These results indicate that in a rat model of acute iron intoxication, orally administered NAC may increase mortality.     

Disruption of Conscious Access in Psychosis Is Associated with Altered Structural Brain Connectivity

According to global neuronal workspace (GNW) theory, conscious access relies on long-distance cerebral connectivity to allow a global neuronal ignition coding for conscious content. In patients with schizophrenia and bipolar disorder, both alterations in cerebral connectivity and an increased threshold for conscious perception have been reported. The implications of abnormal structural connectivity for disrupted conscious access and the relationship between these two deficits and psychopathology remain unclear. The aim of this study was to determine the extent to which structural connectivity is correlated with consciousness threshold, particularly in psychosis. We used a visual masking paradigm to measure consciousness threshold, and diffusion MRI tractography to assess structural connectivity in 97 humans of either sex with varying degrees of psychosis: healthy control subjects (n = 46), schizophrenia patients (n = 25), and bipolar disorder patients with (n = 17) and without (n = 9) a history of psychosis. Patients with psychosis (schizophrenia and bipolar disorder with psychotic features) had an elevated masking threshold compared with control subjects and bipolar disorder patients without psychotic features. Masking threshold correlated negatively with the mean general fractional anisotropy of white matter tracts exclusively within the GNW network (inferior frontal-occipital fasciculus, cingulum, and corpus callosum). Mediation analysis demonstrated that alterations in long-distance connectivity were associated with an increased masking threshold, which in turn was linked to psychotic symptoms. Our findings support the hypothesis that long-distance structural connectivity within the GNW plays a crucial role in conscious access, and that conscious access may mediate the association between impaired structural connectivity and psychosis.     

A locking mechanism preventing radical damage in the absence of substrate, as revealed by the x-ray structure of lysine 5,6-aminomutase

Lysine 5,6-aminomutase is an adenosylcobalamin and pyridoxal-5'-phosphate-dependent enzyme that catalyzes a 1,2 rearrangement of the terminal amino group of dl-lysine and of l-beta-lysine. We have solved the x-ray structure of a substrate-free form of lysine-5,6-aminomutase from Clostridium sticklandii. In this structure, a Rossmann domain covalently binds pyridoxal-5'-phosphate by means of lysine 144 and positions it into the putative active site of a neighboring triosephosphate isomerase barrel domain, while simultaneously positioning the other cofactor, adenosylcobalamin, approximately 25 A from the active site. In this mode of pyridoxal-5'-phosphate binding, the cofactor acts as an anchor, tethering the separate polypeptide chain of the Rossmann domain to the triosephosphate isomerase barrel domain. Upon substrate binding and transaldimination of the lysine-144 linkage, the Rossmann domain would be free to rotate and bring adenosylcobalamin, pyridoxal-5'-phosphate, and substrate into proximity. Thus, the structure embodies a locking mechanism to keep the adenosylcobalamin out of the active site and prevent radical generation in the absence of substrate.     

Early and late effects of low-dose aspirin on renal function in elderly patients

Background

Although low-dose aspirin is used by many elderly patients, monitoring of renal function is currently not recommended. We recently reported transient retention of uric acid and creatinine caused by aspirin in doses of 75 to 325 mg/d. We therefore evaluated the renal effects of aspirin (100 mg/d), including post-treatment effects.

Methods

We studied 83 stable geriatric patients in long-term care (aged 56 to 98 years) who were treated with low-dose aspirin (100 mg/d) for 2 weeks and 40 control patients. Other medications and diet were kept constant. Biochemical monitoring including blood samples and 24-hour urinary collections for creatinine and uric acid at baseline and weekly for a total of 5 weeks.

Results

After 2 weeks on aspirin, urinary excretion of creatinine decreased in 60 (72%) and excretion of uric acid decreased in 54 (65%) of the 83 patients, and their mean clearances decreased; during the same period, serum blood urea nitrogen, creatinine, and uric acid levels increased (P <0.05 for all). Deterioration from baseline levels was significantly greater (and more prevalent) in the aspirin-treated group than in the 40 control patients (P = 0.001 to 0.09). After withdrawal of aspirin these parameters improved. However, 3 weeks after stopping aspirin, 48% (35 of the 73 in whom this measurement was available) had a persistent decline in creatinine clearance from baseline, as compared with only 8% (3/36) controls (P <0.001).

Conclusion

Short-term low-dose aspirin treatment may affect renal function in elderly patients. These effects persist 3 weeks after cessation of the drug in some of these patients.