Biomedical subjects
Publications and source records attributed to M Monnier.
The therapeutic efficacy of benzydamine vaginal douche is compared with that of placebo in a randomized clinical study presently underway. A total number of 200 patients, grouped according to different types of vaginitis, will be included in the study. Preliminary results on 102 patients confirm the positive therapeutic effect of benzydamine.
A first study of DSIP (= synthetic delta sleep-inducing peptide) application to humans was carried out in six normal volunteers (four males and two females) under extensive psychophysiologic observations and measurements in a double-blind cross-over design. DSIP was applied as slow intravenous infusions at a dosage of 25 nmol/kg in the morning. The subjects immediately reported a feeling of sleep pressure, and sleep increased by 59% (median of total sleep time) within a 130-min interval after the treatment as compared with placebo. Delayed effects on subsequent night sleep were shorter sleep onset, reduced percentage of stage 1, and better sleep efficiency. Nevertheless, sophisticated behavioral and EEG analyses revealed no sedation in the classic pharmacologic way. The results suggest that DSIP in humans is also efficacious by sustaining natural sleep functions. The compound was well-tolerated and no psychologic, physiologic, or biochemical side effects were observed.
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A peptide which induces slow-wave EEG (sleep) after intraventricular infusion into the brain has been isolated from the extracorporeal dialysate of cerebral venous blood in rabbits submitted to hypnogenic electrical stimulation of the intralaminar thalamic area. It was shown by amino-acid analysis and sequence determination to be Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu and named "Delta Sleep-Inducing Peptide" (DSIP). This compound was synthesized as well as 5 possible metabolic products (1--8, 2--9, 2--8, 1--4 and 5--9), 2 nonapeptide analogues (with one and two amino-acids exchanged) and a related tripeptide (Trp-Ser-Glu). All 9 synthetic peptides were infused intraventricularly in rabbits (6 nmol/kg in 0.05 ml of CSF-like solution over 3.5 min) and tested under double-blind conditions. A total of 61 rabbits including controls were used. The EEG from the frontal neocortex and the limbic archicortex were subjected to direct fast-Fourier transformation and analyzed by an 1108 computer system. A highly specific delta and spindle EEG-enhancing effect of the synthetic DSIP could be demonstrated. The mean increase of EEG delta activity reached 35% in the neocortex and limbic cortex as compared to control animals receiving CSF-like solution or any of the other 8 peptides. The final chemical characterization of the synthetic DSIP revealed that only the pure alpha-aspartyl peptide is highly active in contrast to its beta-Asp isomer. A neurohumoral modulating and programming activity was suggested.
Electrical stimulation of the "somnogenic" thalamic area of Hess in chronic rabbit donors significantly increases the EEG delta activity against controls (41%; p less than or equal to 0.05). In recipient rabbits infused with cerebrospinal fluid (csf) from these donors, the delta increase against control rabbits (26%) suggests a sedative activity of the infused csf, able to counteract the waking tendency in chronic recipients.
The synthetic delta sleep inducing peptide (DSIP) passes the blood-brain barrier, since i.v. injection in free moving rabbits (30 nmoles/kg) significantly increases the cortical delta activity and decreases the motor activity during 5 h.
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A peptide that induces slow-wave (delta) and spindles electroencephalogram enhancement after intraventricular (brain) infusion has been isolated from rabbits and given the name delta-sleep-inducing peptide (DSIP). Amino acid seqeunce: Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu. This compound, five possible metabolic products (containing residues 1--8, 2--9, 2--8, 1--4, and 5--9), two nonapeptide analogues with two amino acids exchanged, and a related tripeptide (Trp-Ser-Glu) were synthesized. All nine synthetic peptides were infused intraventricularly in rabbits under double-blind conditions. A total of 58 rabbits including controls were evaluated. The electroencephalogram leads from the neocortex and the archicortex were directly fast-Fourier transformed and analyzed by a Univac 1108 computer system. Only the delta-sleep-inducing peptide (snythetic) showed significant and specific enhancement/induction of delta and spindle electroencephalogram patterns.
In hemodialysates of cerebral venous blood from rabbits kept asleep by electrical stimulation of the somnogenic intralaminar thalamus, a seasonal correlation was found between the histamine (H) concentration and the external daily temperature, with a minimum in winter and a maximum in summer. By contrast, in dialysates of rabbits aroused by electrical stimulation of the midtrain reticular formation, the H concentration reached in winter the same high level as in summer. During the winter, stimulation of the waking midbrain reticular system increased the H-level of the cerebral blood dialysate, whereas that of the somnogenic intralaminar thalamus did not enhance, sometimes even lowered, the H-concentration. This suggests that the mechanism of H release in blood might be associated with the midbrain activating reticular system and moderated by the intralaminar thalamus.
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1. In order to obtain information about production and activity of the "sleep factor delta", characterized as oligopeptide with MW approximately 860, the peptide concentration (in nM/g dry dialysate) and the EEG delta activity of the corresponding dialysate (delta percent and integral of delta increase) were determined for cerebral blood from the dural venous sinus, systemic blood from the femoral vein and cerebrospinal fluid (CSF) from sleeping and alert rabbit donors. 2. Before hypnogenic or walking stimulation all hemodialysates exhibit a basic peptide concentration (26 nM/g dry dialysate) and a corresponding basic delta activity (231 muV X sec delta integral within 6 sec). 3. The electric thalamic stimulation of donors, with parameters inducing orthodox delta-sleep, parallely increases the delta peptide concentration (160 nM/g) and its activity (543 muV X sec delta integral) in cerebral blood dialysate. 4. The cerebral blood plasma dialyzed in vitro after hypnogenic thalamic stimulation exhibits a still higher peptide concentration (197 nM/g) and delta activity (804 muV X sec), increased at will by using a steeper diffusion gradient in the dialyzer (possibility of extracting more peptide). 5. By contrast, the systemic femoral blood plasma, similarly dialyzed in vitro develops a weaker delta activity (646 muV X sec) than cerebral blood plasma, in spite of a higher peptide concentration (275 nM/g). This dissociation suggests an activity marked by concomittant waking factors added to the cerebral blood during passage through the hindlimbs musculature. 6. The fact that cerebral blood dialyzed in vivo in walking donors has no delta activity (-313 muV X sec) in spite of a minimal delta peptide concentration (10 nM/g) confirms the assumption that walking factors may mask the peptide activity. Additionally, it shows that they may also antagonize the peptide production. The sleep cycle seems to be regulated not only by neural, rapid acting antagonistic mechanisms, but also by humoral, slower acting antagonistic factors. 7. Cerebrospinal fluid withdrawn from sleeping donors induces insignificant changes in recipients, probably because of too small a peptide concentration in this fluid.
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