Therabel (Belgium)

Although the advantages of the TN-C – Protective Multiple Earthing (PME) scheme are well known, with the PEN conductor being locally earthed at multiple locations along its path and the PEN voltage profile being consequently kept further close to zero, the quantification of those advantages are lacking in the literature. The actual impact of the amount of PME earthing points and the distribution of their earth resistance value in a typical Belgian LV distribution grid and their relevance in problematic cases such as single-phase short circuits, load unbalance (with or without neutral rupture) and EM travelling waves has been assessed via dedicated simulations. The conclusions are that although PME earthing points can have a significant impact in the worst-case scenarios of such problematic situations, they have a negligible impact in most cases and it should not be assumed that the presence of PME earthing points along a LV feeder actually keeps the PEN voltage close to zero.

Stratigraphic analysis of cored and geophysically logged boreholes in the Kasterlee-Geel-Retie-Mol-Dessel area of the Belgian Campine has established the presence of two lithostratigraphic units between the classical Diest and Mol Formations, geometrically related to the type Kasterlee Sand occurring west of the Kasterlee village and the study area. A lower ‘clayey Kasterlee’ unit, equivalent to the lithology occurring at the top of the Beerzel and Heist-op-den-Berg hills, systematically occurs to the east of the Kasterlee village. An overlying unit has a pale colour making it lithostratigraphically comparable to Mol Sand although its fine grain size, traces of glauconite and geometrical position have traditionally led stratigraphers to consider it as a lateral variety of the type Kasterlee Sand; it has been named the ‘lower Mol’ or ‘Kasterlee-sensu-Gulinck’ unit in this study. In the present analysis, the greenish glauconitic Kasterlee Sand in its hilly stratotype area evolves eastwards into the lower ‘clayey Kasterlee’ unit and possibly also into an overlying ‘lower Mol’ or ‘Kasterlee-sensu-Gulinck’ unit, although it is equally possible that the latter unit has an erosive contact and therefore is stratigraphically slightly younger than the type Kasterlee Sand west of the Kasterlee village. A lateral extension of this detailed stratigraphic succession into the faulted zone of east Limburg is proposed.

A new once-a-day (o.a.d.) formulation of molsidomine (16 mg) was evaluated in patients with stable angina pectoris. The aims were to characterize its pharmacokinetics after a single dose, to demonstrate its clinical efficacy and safety versus placebo and to investigate correlations between pharmacokinetics and pharmacodynamics. Forty-two patients were recruited in a double-blind, crossover, randomized placebo-controlled trial. The pharmacokinetics of molsidomine and SIN-1, its active metabolite, were determined at specific time points (3, 6, 10, 14, 18, 22 and 24 h) after the administration of a single dose of molsidomine 16 mg o.a.d. in all patients distributed into seven groups. Twenty-eight of these 42 patients showed a positive baseline cycloergometric exercise test response during the run-in placebo period and were used to compare the efficacy of molsidomine to placebo. Relationships between plasma concentration in molsidomine or SIN-1 and ischemic threshold were assessed in 16 of the 28 patients with a positive exercise test at baseline. Indeed, the censored variable ischemia-limited tolerance to exercise could not be evaluated in those patients who did not show exercise-induced ischemia anymore under molsidomine 16 mg o.a.d. Pharmacokinetic-pharmacodynamic relationships were evaluated using regression models and correlation coefficients. The highest average concentration in molsidomine and SIN-1 occurred after 6 h, then a plateau of 15-20 ng/ml molsidomine and 0.8-3.0 ng/ml SIN-1 was maintained for at least 8 h and the mean residual molsidomine concentration 24 h post-drug intake was around 8 ng/ml, still in the effective range of 5-10 ng/ml. A significant increase in total workload (+52 W min, P=0.009), total exercise time (+32 s, P=0.003) and time to angina (+25 s, P=0.016) was measured with molsidomine 16 mg o.a.d. relative to placebo. Using linear regression, significant correlation coefficients were determined between molsidomine plasma concentrations (but not SIN-1) and exercise test improvements (r=0.827, P<0.001 for the total workload; r=0.772, P<0.001 for the total exercise time; and r=0.566, P=0.028 for the time to 1 mm ST-segment depression). The pharmacokinetics of molsidomine 16 mg in patients with stable angina pectoris is compatible with a o.a.d. dosage regimen. This o.a.d. formulation is effective and well-tolerated, providing a 24-h therapeutic control of myocardial ischemia. A positive and significant linear relationship between molsidomine plasma concentration and the increase in exercise tolerance was observed.

Abstract Pirlindole is an antidepressant drug. It acts principally as reversible inhibitor of monoamine oxidase‐A (RIMA) and appears relatively potent in comparison with reference drugs. Pirlindole possesses stereogenic center but is generally used as racemate. In this work, the first preparative resolution of its enantiomeric couple is described. Whereas selective crystallization of salts of chiral acid failed, two asymmetric synthetic pathways were also examined; however, without success. Finally separation and isolation of enantiomers of pirlindole was completed by using the derivatization method coupled with preparative HPLC. Optical purity of each isomer was determined by chiral HPLC. The specific rotation of each antipode was also determined.

The efficacy and safety of pirlindole (300 mg/day), a new reversible inhibitor of monoamine oxidase A, have been evaluated in a multicentre placebo-controlled double-blind randomized trial in 103 in-patients suffering from unipolar major depression (DSM-III-R 296.2, 296.3) over a 42-day period after a run-in placebo period of 6 days. Pirlindole produced a significantly greater decrease than placebo in the Hamilton depression score (from day 28), the Hamilton anxiety score (from day 28) and the Montgomery-Asberg depression score (on day 42). On day 42, the Hamilton depression score was < or = 7, > or = 8 and < or = 15, or > or = 16 in 21%, 45% and 34%, respectively, in the placebo group compared to 72%, 24% and 3.4%, respectively, in the pirlindole group (P < 0.001). The differences between the two groups in terms of tolerance and safety were not statistically significant.

Dibenzoazepine derivatives have represented and still represent today an interesting and exciting field of investigation in medicinal chemistry. A slight modification of the tricyclic structure leads to a profound alteration of the activity profile. Indeed, clothiapine is a neuroleptic drug with strong pro­pensity to induce extrapyramidal side effects (EPS) while clozapine possesses an atypical neuroleptic profile and produces only minimal EPS. The action mechanisms of clozapine have not been completely elucidated. Although clozapine represents a great advance in the treatment of psychiatric disorders, the induction of dramatic toxic effects has stimulated the search for an alternative to clozapine. This challenge is currently the focus of the most active efforts in contemporary neuropharmacology. This review attempts to describe the development of atypical neuroleptic drugs through the diarylazepine series, a promising and modulable class of compounds.