Insomnia and sleep misperception.

Sleep misperception is often observed in insomnia individuals (INS). The extent of misperception varies between different types of INS. The following paper comprised sections which will be aimed at studying the sleep EEG and compares it to subjective reports of sleep in individuals suffering from either psychophysiological insomnia or paradoxical insomnia and good sleeper controls. The EEG can be studied without any intervention (thus using the raw data) via either PSG or fine quantitative EEG analyses (power spectral analysis [PSA]), identifying EEG patterns as in the case of cyclic alternating patterns (CAPs) or by decorticating the EEG while scoring the different transient or phasic events (K-Complexes or sleep spindles). One can also act on the on-going EEG by delivering stimuli so to study their impact on cortical measures as in the case of event-related potential studies (ERPs). From the paucity of studies available using these different techniques, a general conclusion can be reached: sleep misperception is not an easy phenomenon to quantify and its clinical value is not well recognized. Still, while none of the techniques or EEG measures defined in the paper is available and/or recommended to diagnose insomnia, ERPs might be the most indicated technique to study hyperarousal and sleep quality in different types of INS. More research shall also be dedicated to EEG patterns and transient phasic events as these EEG scoring techniques can offer a unique insight of sleep misperception.

Biphenyls as surrogates of the steroidal backbone. Part 1: synthesis and estrogen receptor affinity of an original series of polysubstituted biphenyls.

In the course of a programme aimed at discovering new ligands of the estrogen receptor, we explored a series of substituted biphenyls. Their synthesis and binding affinity are described.

Biphenyls as surrogates of the steroidal backbone. Part 2: discovery of a novel family of non-steroidal 5-alpha-reductase inhibitors.

A new family of non-steroidal 5-alpha-reductase inhibitors was designed by replacing the steroid skeleton of an inhibitor related to estrone by a biphenyl moiety. This hypothesis originated from the reported estrogenic activity of a few biphenyl compounds (see Part 1 of this paper; Lesuisse et al. Bioorg. Med. Chem. Lett. 2001, 11, 1709). Two compounds turned out to be potent type 2 5-alpha-reductase inhibitors with IC(50)'s of inhibition in the nanomolar range. These are to our knowledge amongst the most potent non-steroidal 5-alpha-reductase inhibitors described to date.

Molecular biology of Streptococcus pneumoniae: an everlasting challenge.

Streptococcus pneumoniae is a model for elucidating: 1) recombination steps of DNA, from its discovery to polarity of integration; 2) long-patch mismatch repair, short-patch repair triggered by A/G and exclusion of deletions; 3) resistance to beta-lactam antibiotics; and 4) factors of virulence. Several of these topics remain a challenge for future investigations.

Electrotransformation of Streptococcus pneumoniae: evidence for restriction of the DNA on entry.

Electrotransformation is a method generally used in biotechnology to introduce recombinant DNA into a wide range of bacteria. However the mechanism of DNA entry is poorly understood. We report that in Streptococcus pneumoniae, a naturally transformable species, electrotransformation efficiently introduces a plasmid replicon. DNA is strongly restricted by the restriction-modification systems DpnI and DpnII which degrade methylated and nonmethylated DNA respectively at GATC sequences. This suggests that in electrotransformation double-strand DNA penetrates into these bacteria without a single-strand step in contrast to natural transformation. Single-strand DNA by itself is able to electrotransform very weakly and linearized double-stranded plasmid DNA yields barely detectable levels of transformants.

Structure-activity relationships of a new family of steroidal aromatase inhibitors. 1. Synthesis and evaluation of a series of analogs related to 19-[(methylthio)methyl]androstenedione (RU54115).

During the course of a study aimed at the search for new potent aromatase inhibitors, several new androstenedione analogs were synthesized and evaluated. This study led to the discovery of 19-[(methylthio)methyl]androsta-4,9(11)-diene-3,17-dione (7; RU54115) already described by our laboratory. The object of the present series of papers is to disclose the result of the structure-activity relationship studies that gave rise to this compound. This first part deals mainly with the substitution in the 19-position of the steroid nucleus. Several parameters were varied, the length of the chain and its rigidity and branching, as well as the nature of the heteroatom itself and its substitution. The interaction of these new compounds with human placental aromatase in competition with the substrate androstenedione was studied by difference visible spectroscopy. The in vivo aromatase-inhibiting activities were evaluated by measuring the estradiol lowering after oral administration of the compounds to PMSG-primed female rats.

Genetic studies of cefotaxime resistance in Streptococcus pneumoniae: relationship to transformation deficiency.

A laboratory pneumococcal strain resistant to cefotaxime was studied by DNA-induced transformation in order to characterize its genetic structure. At least three independent genes were required to confer the highest level of resistance to this beta-lactam antibiotic. The accumulation of mutations in these three genes accounted for three levels of resistance. Mutation of the gene encoding penicillin-binding protein 2x was very likely responsible for the first step of resistance, which was a prerequisite for sequential increase in resistance. Additionally, strains highly resistant to cefotaxime were defective for natural transformation. Revertants of these strains were frequently observed. Such strains had recovered full transformability, suggesting a correlation between the inability to be transformed and a high level of resistance to cefotaxime. The possibility of electrotransforming these highly resistant strains suggests that natural transformation is probably blocked at the DNA-uptake level.

Low-response-rate conditioning history and fixed-interval responding in rats.

Bar presses by one group of rats were conditioned under a differential-reinforcement-of-low-rate reinforcement schedule immediately prior to conditioning under a fixed-interval schedule. In a second group of rats, bar presses were conditioned first under a differential-reinforcement-of-low-rate schedule and then under a fixed-ratio schedule prior to conditioning under a fixed-interval schedule. Low response rates occurred under the fixed-interval schedule only when it was immediately preceded by low-rate conditioning. Otherwise, fixed-interval responding was similar to responding under the fixed-ratio schedule. This finding suggests that responses of laboratory animals are sensitive to immediate history, and, unlike human responses, are relatively insensitive to a history of low-rate conditioning when it is followed by high-rate conditioning.

Determination of diclofenac sodium and related compounds in raw materials and formulations.

A liquid chromatographic method has been developed for determination of drug and related compounds in diclofenac sodium raw material, slow-release, and enteric coated tablets. The method specifies a 5 microns octadecylsilane bonded phase column, a mobile phase of tetrahydrofuran-acetonitrile-buffer, pH 5 (1 + 4 + 8.3), and detection at 229 nm. The method resolves 10 known related compounds with limits of quantitation of 0.2% or less. Seventeen drug raw material samples were evaluated. Total impurity levels ranged from 0.1 to 0.9%. The method has also been used for determination of drug content in raw materials and formulations. Mean assay levels in drug raw materials ranged between 98.3% and 101.8%.

The effects of a variety of instructions on human fixed-interval performance.

College students were instructed to press a button for points under a single reinforcement schedule or under a variety of reinforcement schedules. Instructions for a single schedule were either specific or minimal. Instructions on a variety of schedules involved specific instructions on eight different schedules of reinforcement. Subsequent to the varied training, responding under a fixed-interval schedule occurred at a low rate. Both the minimal and specific instruction training led to fixed-interval responding that was similar to the responding exhibited during training. These findings suggest that under certain conditions instructed behavior is sensitive to changes in contingencies.

[Diltiazem and digoxin interaction. Development of digoxin plasma levels and electrocardiographic parameters in healthy subjects]. / Interaction diltiazem-digoxine. Evolution de la digoxinémie et des paramètres électrocardiographiques chez le sujet sain.

In order to determine the interaction between diltiazem and digoxin, plasma digoxin concentrations and the principal ECG parameters (24 hour Holter monitoring) were measured in 10 healthy volunteers under basal conditions (P0), with 0.375 mg/day of digoxin (P1 = 17 days), during association with 240 mg/day of diltiazem (P2 = 17 days) and then again on digoxin alone (P3 = 10 days). The addition of diltiazem was associated with a 20.4% rise in plasma digoxin concentrations (0.59 ng/ml vs 0.49 ng.ml). There was no significant variation of plasma digoxin after withdrawal of diltiazem; in some cases it remained unchanged, in others it fell or continued to rise. During the administration of digoxin and diltiazem, the mean RR period and the duration of the maximal pauses increased (p less than 0.05); the RR interval also increased (p less than 0.01) but the mean QRS duration and the QTc interval did not change significantly with respect to their values on digoxin alone. After withdrawal of diltiazem, the PR interval was the only parameter to decrease significantly (p less than 0.05). These results suggest that patients receiving this drug association should be followed up carefully.

Speech perception through FM auditory trainers in noise and reverberation.

Speech perception through FM auditory trainers was explored in conditions of noise and reverberation. Special attention was paid to the mode of transmission and individual capabilities of various commercially-available units to handle speech in noise and reverberation. Results indicate an overwhelming advantage of FM transmission for maintaining speech intelligibility in noise and reverberation, irrespective of the instrument.

[Haemodynamic and metabolic effects of exercise test in diabetic patients with arteritis treated or not with nicergoline (author's transl)]. / Effets hémodynamiques et métaboliques de l'épreuve d'effort chez l'artéritique diabétique traité ou non par la nicergoline.

A randomised crossover study in eleven diabetic patients with arteritis compared the effects of nicergoline (2,5 mg i.v.) or placebo on haemodynamic and metabolic parameters after exercise tests. Haemodynamic modifications after effort following placebo administration were typical: raised systolic blood pressure, and increased heart rate and myocardial oxygen requirements (systolic BP x heart rate). Modifications after similar effort following nicergoline involved an increase in systolic B.P. only, heart rate and myocardial oxygen requirements remaining unchanged. Blood lactic acid levels after effort and treatment were significantly higher (p. less than 0.01) than after effort without treatment. Overall metabolic and haemodynamic results demonstrate an increase in effort tolerance in diabetic patients with arteritis after nicergoline, this having been previously observed in healthy subjects.

Haemodynamic effects of nicergoline in man at rest and during exercise.

1. The intravenous administration of nicergoline (5 mg) was followed by a rapid and sustained lowering of blood pressure; less rapid effects were bradycardia and an elevation of cardiac output. These delayed effects are consistent with an indirect action on the alpha-adrenoreceptors of the central nervous system. 2. Following the oral administration of nicergoline (30 mg), a partial reduction of exercise-induced lactacidaemia was demonstrated, which is consistent with the haemodynamic changes shown at rest.

[Hemodynamic effects of nicergolin in man at rest and during exertion (author's transl)]. / Hämodynamische Wirkungen von Nicergolin beim Menshcen in Ruhe und in Bewegung.

In 10 healthy subjects the injection of 10-methyl-1,6-diemthyl-ergoline-8 beta-methanol-(5-bromonicotinate (nicergoline, Sermion) (5 mg i.v.) caused a permanent decrease in blood pressure. This decrease in blood pressure is due to a rapidly occurring alpha-blocking effect and a secondary central alpha-stimulating effect which did not affect the postural regulating mechanisms of the arterial blood pressure in their function. The bradycardia and the elevation of the systolic volume and of the cardiac output are based on this central effect. After oral administration of 30 mg nicergoline the same modifications appeared but to a lesser extent. If nicergoline was administered in a dosage of 30 mg p.o. 1 h before bicyle exercise (100 W for 5 min), the cardiac output and blood flow in the lower extremities increased and the elevation of the systolic pressure was limited. However, the reactive tachycardia remained at the same level. The metabolic consequences of this administration resulted in an inhibited increase in the concentration of lactic acid in the blood, which is normally caused by this exertion. This favourable metabolic effect can be explained by 1. the initial bradycardia and the decrease in the total peripheral resistance whereby the oxygen consumption of the myocardium is reduced; 2. the peripheral vasodilation.

Biochemical and behavioural effects of hypoxic hypoxia in rats: study of the protection afforded by ergot alkaloids.

The conditioned avoidance response and the cerebral levels of dopamine and noradrenaline have been studied in control rats and in rats submitted to a hypobaric hypoxia. A protection against the effects of hypoxia was induced by both dihydroergocornine (20 microgram/kg) and dihydroergocryptine (100 microgram/kg), and the noradrenaline level did not decrease. This stabilization of cerebral noradrenaline level seems to be the main protection factor observed.

Action of cytidine diphosphocholine on functional and hemodynamic effects of cerebral ischemia in cats.

The depression of evoked cortical potentials caused by brief periods of cerebral ischemia is attenuated by prior intracarotid injection of cytidoline (2, 4 or 8 mg/kg). Studies performed in hypercapnic cats suggest that the protection afforded by cytidoline is of metabolic rather than hemodynamic origin. The participation of the central dopaminergic structures by the drug is suggested according to the previous data.