Alkaline cooking (nixtamalisation) and the reduction in the in vivo toxicity of fumonisin-contaminated corn in a rat feeding bioassay.

Nixtamalisation is a widely used food processing method in which whole kernel corn is cooked and steeped in alkaline water. It reduces the amount of fumonisin B1 (FB1) that can be detected after cooking. However, the fate of FB1 during nixtamalisation is not fully understood and potentially toxic reaction products, including matrix-associated "masked" FB1 forms that are not detected by routine analytical methods might remain in nixtamalised corn. To assess how nixtamalisation of whole kernel corn affects fumonisin toxicity, male rats were fed diets containing low, mid or high levels of uncooked (LU, MU, HU) or alkaline cooked (LC, MC, HC) FB1-contaminated corn for 3 weeks. The control diet contained uncontaminated corn only. Apoptotic kidney lesions of the type caused by FB1 were not found in the LC or MC groups. Lesions in the group fed HC were minimal and less severe than those found in the rats fed LU, MU or HU. Furthermore, significantly increased sphinganine and sphingosine concentrations indicative of FB1 exposure were found in the kidneys of the rats given LU, MU or HU. Concentrations were also elevated, but to a lesser extent, in rats fed HC, whereas sphinganine and sphingosine concentrations in rats given LC or MC did not differ from the control group. FB1 concentrations in the LC (0.08 mg kg(-1)), MC (0.13 mg kg(-1)) and HC (0.37 mg kg(-1)) diets were markedly reduced compared with their LU (1.8 mg kg(-1)), MU (3.5 mg kg(-1)) and HU (4.2 mg kg(-1)) counterparts as determined by HPLC (n = 1 analysis/diet). Taken together, the findings show that nixtamalisation is an effective cooking method for reducing the potential toxicity of FB1 contaminated corn.

Suicide attempts in a prospective cohort of patients with schizophrenia treated with sertindole or risperidone.

The incidence of suicide attempts (fatal and non-fatal) was analysed in a prospective cohort of patients with schizophrenia randomly assigned to sertindole (4905 patients) or risperidone (4904 patients) in a parallel-group open-label study with blinded classification of outcomes (the sertindole cohort prospective study--SCoP). The total exposure was 6978 and 7975 patient-years in the sertindole and risperidone groups, respectively. Suicide mortality in the study was low (0.21 and 0.28 per 100 patients per year with sertindole and risperidone, respectively). The majority (84%) of suicide attempts occurred within the first year of treatment. Cox's proportional hazards model analysis of the time to the first suicide attempt, reported by treating psychiatrists and blindly reviewed by an independent expert group according to the Columbia Classification Algorithm of Suicide Assessment (both defining suicide attempts by association of suicidal act and intent to die), showed a lower risk of suicide attempt for sertindole-treated patients than for risperidone-treated patients. The effect was statistically significant with both evaluation methods during the first year of randomized treatment (hazard ratios [95% CI]: 0.5 [0.31-0.82], p=0.006; and 0.57 [0.35-0.92], p=0.02, respectively). With classification by an independent safety committee using a broader definition including all incidences of intentional self-harm, also those without clear suicidal intent, the results were not significant. A history of previous suicide attempts was significantly associated with attempted suicides in both treatment groups.

When patients report diseases that prescribers seem unaware of: discordance between patient and physician reporting of risk-related previous history in NSAID users from the CADEUS study.

Prescribers are often unaware of possibly dangerous previous medical histories (PMHs) of their patients. Data from a study of nonsteroidal anti-inflammatory drug (NSAID) users served to identify factors associated with this lack of awareness. In this study, we analyzed the factors that may have led prescribers to report the absence of some PMHs that the patients reported as being present. Of 26,618 patients prescribed an NSAID, 469 (1.7%) reported a PMH of unstable angina, 648 (2.4%) reported heart failure, 2,244 (8.4%) reported gastric or duodenal ulcer, 489 (1.8%) reported upper gastrointestinal tract bleeding (UGIB), 5,343 (20.0%) reported gastroesophageal reflux disease (GERD), and 7,832 (29.4%) reported dyspepsia. Between 64 (GERD) and 92% (UGIB) of these patient-reported PMHs were absent in the corresponding prescribers' reports. This discordance was associated with the following factors: patients of younger age, female patients, less frequent patient-prescriber contact, prescription of NSAID by a specialist, no recent specialist consultation, hospitalization or surgery related to the PMH, and no dispensation of proton-pump inhibitors (PPIs) for digestive disorder-related PMHs. The study showed that a substantial proportion of prescribers seemed unaware of the presence of risk-related PMHs that the patient reported when asked.

Safety of sertindole versus risperidone in schizophrenia: principal results of the sertindole cohort prospective study (SCoP).

OBJECTIVE: To explore whether sertindole increases all-cause mortality or cardiac events requiring hospitalization, compared with risperidone. METHOD: Multinational randomized, open-label, parallel-group study, with blinded classification of outcomes, in 9858 patients with schizophrenia. RESULTS: After 14147 person-years, there was no effect of treatment on overall mortality (sertindole 64, risperidone 61 deaths, Hazard Ratio (HR) = 1.12 (90% CI: 0.83, 1.50)) or cardiac events requiring hospitalization [sertindole 10, risperidone 6, HR = 1.73 (95% CI: 0.63, 4.78)]: Of these, four were considered arrhythmia-related (three sertindole, one risperidone). Cardiac mortality was higher with sertindole (Independent Safety Committee (ISC): 31 vs. 12, HR=2.84 (95% CI: 1.45, 5.55), P = 0.0022; Investigators 17 vs. 8, HR=2.13 (95% CI: 0.91, 4.98), P = 0.081). There was no significant difference in completed suicide, but fewer sertindole recipients attempted suicide (ISC: 68 vs. 78, HR=0.93 (95% CI: 0.66, 1.29), P = 0.65; Investigators: 43 vs. 65, HR=0.67 (95% CI: 0.45, 0.99), P = 0.044). CONCLUSION: Sertindole did not increase all-cause mortality, but cardiac mortality was higher and suicide attempts may be lower with sertindole.

Is reporting rate a good predictor of risks associated with drugs?

AIMS: Uncertainty as to relative under-reporting plagues the comparisons of spontaneous reporting rates as a tool for decision-making in pharmacovigilance. However, it is generally accepted that under-reporting should be reasonably similar for similar drugs sharing the same indication, country and period of marketing. To test this, we compared the adverse drug reaction reporting rates to the French regional pharmacovigilance centres for six pairs of identical drug marketed at the same time by different companies under different brand names (co-marketing). METHODS: All reaction reports were related to sales, to compute reporting rate; within each pair, the reporting rate ratio and its confidence interval were calculated. RESULTS: The rate ratios were all between 0.76 and 1.33. Two of them were significantly different from 1 (1.28; 95% C.I. [1.01; 1.60] and 1.33; 95% C.I. [1.06; 1.74]). CONCLUSIONS: These small differences in reporting rates would not warrant regulatory action and support the usual assumption of similar reporting for similar drugs.

Influence of divalent cations on nucleotide exchange and ATPase activity of chloroplast coupling factor 1.

The ATPase activity of the catalytic part of ATP synthases is inhibited by free Mg2+, even though MgATP is the substrate. Here we show that the inhibition of the MgATPase activity of chloroplast coupling factor 1 deficient in its epsilon subunit (CF1-epsilon) by Mg2+ is complex. The hydrolysis of MgATP by CF1-epsilon that contains tightly bound ADP, but no bound Mg2+, is initially rapid and decreases within about 1 min to a steady-state rate. The bound MgADP content of CF1-epsilon was varied. The initial fast phase of MgATP hydrolysis is eliminated when the molar ratio of MgADP to CF1-epsilon approaches 2. Loosely bound Mg2+ also affects the initial kinetics of the enzyme that contains bound MgADP. At molar ratios of bound MgADP to enzyme in excess of 1, the initial ATPase activity was low and reached the steady state after about 30 s. Free Mg2+ in the assay mix also inhibited steady-state ATP hydrolysis by all forms of the enzyme. The results are consistent with a model in which two Mg2+ bind cooperatively, probably to the dissociable nucleotide-binding sites on CF1-epsilon. Thus, four different nucleotide-binding sites may be involved in the inhibition of the MgATPase activity of CF1-epsilon. Three of these sites are potentially catalytic, and the fourth may be regulatory. The exchange of bound trinitrophenyl-ADP induced by the addition of MgATP or CaATP was found to be fast enough for the site to be involved in catalysis.

Maternal serum Down syndrome screening: free beta-protein is a more effective marker than human chorionic gonadotropin.

The use of quantitative human chorionic gonadotropin measurement in obstetrics has a long and successful history. Prior studies on the utility of human chorionic gonadotropin in Down syndrome screening have utilized assays that measure the intact human chorionic gonadotropin molecule. This study targeted a distinct marker, the human chorionic gonadotropin free beta-protein, which is present in second-trimester maternal serum at much lower concentrations than is intact human chorionic gonadotropin. Our study of 29 cases of trisomy 21 and 450 control samples shows 80% detection efficiency with maternal serum alpha-fetoprotein, the free beta-protein, and maternal age in pregnancies under 17 weeks' gestation. We conclude that the combination of maternal serum alpha-fetoprotein and the human chorionic gonadotropin free beta-protein will be useful in the prenatal detection of trisomy 21.

Nifedipine in chronic bronchial asthma: a randomized double-blind crossover trial against placebo.

Calcium-channel blockers such as verapamil and nifedipine have been shown to inhibit exercise-induced asthma as well as acutely induced bronchoconstriction, but little is known of their chronic effects, if any, on bronchial asthma. Nifedipine, 60 mg/day for 3 weeks, was compared to placebo in a double-blind randomized crossover study, as an addition to the usual treatment of 11 patients with severe chronic bronchial asthma. Nifedipine decreased the weekly duration of the attacks (102 +/- 34 vs 193 +/- 49 min, p less than 0.05), the number of betamimetic puffs inhaled per week (13 +/- 3 vs 18 +/- 4, p less than 0.05), and the duration of intercritical dyspnoea (7.9 +/- 3.9 vs 15.9 +/- 2.3 h, p less than 0.05) without significantly changing the number of asthma attacks (4.8 +/- 1.2 vs 4.7 +/- 1.7, NS). Nifedipine did not significantly change basal respiratory function, nor did it change heart rate or blood pressure. Side effects were noted in 5 patients taking nifedipine, leading to a decrease in the dosage to 30 mg per day in 3, and in one patient taking placebo. In this study nifedipine had essentially subjective effects, but these warrant a longer-term study of nifedipine or other calcium antagonists in the treatment of bronchial asthma.

Ability of calcium bis acetyl homotaurine, a GABA agonist, to prevent relapse in weaned alcoholics.

After they had been weaned off alcohol in hospital 85 severe alcoholics (above 200 g alcohol/day) were included in a double-blind study of calcium bis acetyl homotaurine (Ca AOTA, 25 mg/kg/day), a new gamma-aminobutyric acid agonist, versus placebo. Patients were treated as outpatients during the 3-month study. The only other treatment that patients received was meprobamate, 800 to 1200 mg/day, in the first month. The criterion for success was abstinence at 3 months (with normal gamma-glutamyl transpeptidase being one of the criteria). Of the 70 patients who completed the study, 33 received Ca AOTA and 37 placebo. 20 patients on Ca AOTA did not relapse, compared with 12 on placebo (p less than 0.02 by X2 test). Side-effects were noted by 7 patients on Ca AOTA and 2 on placebo. The results suggest that Ca AOTA may be useful in helping severe alcoholics who have been weaned off alcohol not to relapse.

Some haemodynamic effects of nicergoline, a new alpha-blocking agent, in the closed-chest anaesthetized dog as compared with nitroprusside and nitroglycerin.

Considering the recent rediscovery of the use of alpha-blocking agents in the treatment of hypertension and heart failure, we have studied the haemodynamic effects of 10-methyl-1,6-dimethyl-ergoline-8 beta-methanol-(5-bromonicotinate (nicergoline, Sermion), a new alpha-blocking ergot derivative, on the closed-chest anesthetized dog. For comparative reasons, the effects of nitroglycerin and nitroprusside were studied on the same model. The doses were adjusted to give an identical decrease in blood pressure after 30 min infusion (nearly 30%). Nicergoline did not change the heart rate, decreased total and femoral arterial resistance, did not change the cardiac output or the femoral flow, as opposed to nitroglycerin which decreased the cardiac output and systolic volume, causing a reflex tachycardia and femoral constriction, confirming its predominantly venous effect. Nitroprusside did not cause tachycardia, and the femoral resistances were increased, though less so than with nitroglycerin. Both nitroglycerin and nitroprusside apparently had no direct effect on myocardial performance, whilst nicergoline seemed to increase the myocardial compliance (by a decrease of the sympathetic tone). This drug merits further attention in that it is readily soluble and can easily be administered i.v., for treatment of acute heart failure, for example.