Biomedical subjects
E Morel
Publications and source records attributed to E Morel.
Notice of retraction.
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Repeated treatment with alpidem, a new anxiolytic, does not induce tolerance or physical dependence.
Alpidem is a new anxiolytic of imidazopyridine structure which has a high affinity for the omega 1 (BZ1) modulatory site of the GABAA receptor. The present study investigated whether tolerance and physical dependence develop after repeated treatment with alpidem, as is observed with benzodiazepines. Mice were given alpidem (100 mg/kg, p.o.) or diazepam (5 mg/kg, p.o.) twice daily for 10 consecutive days. Tolerance was assessed by measuring antagonism of pentylenetetrazole- and isoniazid-induced convulsions and bicuculline-provoked mortality, following repeated drug treatment. Decreases in the latency to isoniazid-induced convulsions and in the minimal convulsant dose of pentylenetetrazole were taken as an index of physical dependence and were evaluated at different times (3, 6, 14, 42, 67, 96 hr) after drug withdrawal or after flumazenil administration. In addition, changes in sensitivity to the convulsant effect of a beta-carboline (beta-CCM) were measured. Repeated treatment with diazepam produced tolerance to its anticonvulsant activities as indicated by shifts of the dose-response curves by a factor of 3-5. After discontinuation of diazepam treatment, spontaneous withdrawal occurred within 24 hr and lasted 67 hr as indicated by decreases in the threshold for convulsions induced by isoniazid and pentylenetetrazole. Flumazenil-induced withdrawal was observed in both isoniazid and pentylenetetrazole-induced convulsion models. Hypersensitivity of mice to the convulsant effect of beta-CCM also occurred. In contrast, repeated treatment with alpidem did not produce tolerance to its anticonvulsant effects and neither spontaneous nor flumazenil-induced withdrawal was observed in the pentylenetetrazole and isoniazid models. Moreover, withdrawal of alpidem did not induce any change in the convulsant activity of beta-CCM. These differences between alpidem and diazepam may be related to the low level of receptor occupancy during repeated treatment with alpidem because of its selectivity for omega 1 (BZ1) sites and to its moderate intrinsic activity.
Autoimmune diseases, IgA deficiency, and intravenous immunoglobulin treatment.
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Combined effects of a thymic peptide, thymopoietin and myasthenic patient sera in rat myotube culture.
We investigated in a rat myotube assay the combined effect of 26 myasthenic (MG) patient sera and a thymic peptide, thymopoietin (Tpo) which had previously been shown to bind Torpedo and human AChR and to compete with alpha-bungarotoxin (alpha-Bgt) binding. Cultures were first exposed to Tpo alone for 3 h (0.3, 7.5, 15 nM), then MG sera (5% final dilution) were added for an additional 18 h. Reduction in the amount of 125I-alpha-Bgt binding sites in the presence of various concentrations of Tpo were similar with control sera and in all the patients with low or undetectable anti-AChR Ab (11 cases). In cultures exposed to Tpo and sera with high anti-AChR Ab titre (15 cases), Tpo and anti-AChR Ab have an additive capacity to reduce the number of alpha-Bgt binding sites. The results are compatible with the hypothesis that anti-AChR Ab and Tpo could impair neuromuscular transmission by complementary mechanisms.
Follow-up of soluble interleukin-2 receptor levels after thymectomy in patients with myasthenia gravis.
Soluble interleukin-2 receptor (sIL-2R) levels were followed up after thymectomy by a quantitative immunoradiometric assay in 59 patients with myasthenia gravis (MG). Increased levels of sIL-2R were found in 30.5% of the patients before thymectomy. Serum levels were significantly higher in severely affected patients. Sequential sampling after thymectomy indicated a significant and progressive decline of sIL-2R levels within 2 years after surgery, which was well associated with clinical improvement or remission. The sIL-2R purified from sera of patients with MG had a molecular mass of 45 kDa as the normal sIL-2R. The decline after thymectomy of sIL-2R titers suggests a possible role of the thymus in the occurrence of sIL-2R in the periphery. Soluble IL-2R levels may represent a marker of disease severity in MG, which might be useful in the follow-up of individual patients.
Activity of litoxetine and other serotonin uptake inhibitors in the tail suspension test in mice.
Compounds known to selectively inhibit the neuronal reuptake of serotonin are clinically effective antidepressants. However, in a number of the behavioral models used for detecting and analysing antidepressant action these drugs are inactive. The forced swimming test is not consistently sensitive to these drugs but it has recently been reported that a variation of this procedure, the tail suspension test in mice, is sensitive. The present study showed that five compounds previously shown to be selective serotonin uptake inhibitors--fluoxetine, zimeldine, paroxetine, indalpine, and litoxetine--produced dose-related decreases in immobility in the tail suspension test typical of the effects shown by other antidepressants. In separate experiments, fluoxetine, zimeldine, and indalpine decreased locomotor activity at doses similar to those that decreased immobility. In contrast, paroxetine and litoxetine had no effect on locomotion at the dose ranges active in the tail suspension test. These results confirm the sensitivity of the tail suspension test and indicate that serotonin uptake inhibitors probably decrease immobility and reduce locomotor activity through different mechanisms.
A simple method for the quantitative evaluation of neuromuscular blockade in mice.
The purpose of this study was to develop a simple and noninvasive method for the quantitative evaluation of neuromuscular blockade in mice. The sciatic nerve in anesthetized animals (etomidate, 50 mg/kg or mephenesin, 250 mg/kg) was stimulated using transcutaneous electrodes; repetitive supramaximal stimulations (3 Hz during 3.3 sec) were applied each minute until recovery or death occurred. Evoked action potentials of the gastrocnemius muscle were recorded. The effect of each pharmacological agent was expressed as the ratio (S5/S1) of the area of the fifth response (S5) to the first one (S1). The performance of the method was tested using neuromuscular blocking agents such as alcuronium, suxamethonium, or alpha-bungarotoxin. It was concluded that the method exhibits the required statistical performances (sensitivity, repeatability, and specificity) to be recommended for in vivo investigation of neuromuscular impairment.
The frequency of selective IgA deficiency in myasthenia gravis.
The frequency of selective IgA deficiency is unknown in myasthenia gravis. We screened a series of 333 consecutive adult myasthenic patients for selective IgA deficiency and found only one patient with a selective IgA deficiency, which is not significantly different from the normal population. Organ-specific autoimmune diseases may differ from systemic autoimmune diseases concerning their frequency of association with selective IgA deficiency.
Lack of tolerance and physical dependence upon repeated treatment with the novel hypnotic zolpidem.
Zolpidem is a new, short-acting hypnotic of imidazopyridine structure which binds selectively to a subpopulation of receptors involved in the action of benzodiazepines [omega 1 (BZ1) sites of the gamma-aminobutyric acidA receptors]. The present study investigated whether tolerance and physical dependence develop after repeated treatment with zolpidem as is observed with benzodiazepines. Mice were given zolpidem or the benzodiazepine midazolam (2 x 30 mg/kg, p.o.) for 10 consecutive days. Tolerance to central depressant effects (evaluated by recording spontaneous locomotor activity) and to anticonvulsant effects (measured against pentylenetetrazole-, electroshock- and isoniazid-induced convulsions) was assessed 42 hr after the last administration. A decrease in the latency to isoniazid-induced convulsions was taken as an index of physical dependence and was evaluated 3, 6, 14, 24, 42 and 67 hr after the end of chronic drug treatment. Repeated treatment with midazolam produced tolerance to its sedative and anticonvulsant activities as indicated by shifts of the dose-response curves by a factor of 3 to 5. Fourteen hr after discontinuation of treatment, spontaneous withdrawal was observed and lasted 3 days. When flumazenil was given 3 or 6 hr after the final midazolam injection, precipitated withdrawal was observed. In contrast, after repeated treatment with zolpidem, there was no change in its ability to produce sedative and anticonvulsant effects. Moreover, neither spontaneous nor flumazenil-induced precipitated withdrawal was observed in zolpidem-treated mice.
Intravenous gamma-globulin in myasthenia gravis: interaction with anti-acetylcholine receptor autoantibodies.
Clinical improvement has been observed in myasthenia gravis patients treated by intravenous immunoglobulin (IVIg). In order to investigate the mechanism of action of these IVIg, we looked for an in vitro interaction between IVIg and the anti-acetylcholine receptor autoantibodies. Significant inhibition by IVIg of anti-acetylcholine receptor autoantibody activity from 30 MG sera was observed and binding of anti-acetylcholine receptor autoantibodies on IVIg was found for four of five myasthenia gravis sera. These observations suggest that IVIg contains Ig directly binding to and inhibiting pathogenic autoantibodies.
Autoantibodies in D-penicillamine-induced myasthenia gravis: a comparison with idiopathic myasthenia and rheumatoid arthritis.
The distribution of autoantibodies was studied in patients with rheumatoid arthritis (RA) treated by D-penicillamine and who developed myasthenia gravis (MG). The anti-human acetylcholine receptor (AChR) antibodies were specifically associated with clinical symptoms of MG without any difference in the pattern of specificities in idiopathic (id-MG) or in induced MG (DPen-MG). Conversely, anti-nuclear antibodies were elevated in DPen-MG sera compared to id-MG sera (P less than 0.001) but were also compared to patients with RA treated by D-penicillamine (or thiopronine) and who did not develop MG. Anti-denatured DNA antibodies were enhanced in sera from treated patients, whether they had presented or not a MG disease. Anti-histone antibodies were associated with RA. These observations suggest that the immunological imbalance in RA patients, can be increased by a drug treatment which may trigger the appearance of a second autoimmune disease such as MG, where anti-AChR antibodies are associated with anti-nuclear antibodies.
Sesquiterpene quinones as immunomodulating agents.
The influence of sesquiterpene quinones and of a sesquiterpene hydroquinone, isolated from the sponge Smenospongia sp. on normal and tumour cells, was investigated. Most showed cytotoxic effects on L1210 leukemia cells. However, their activity on normal cells, such as murine spleen lymphocytes and human peripheral lymphocytes, revealed different behaviours: some of them inhibited, while other enhanced mitogen-stimulated lymphocyte proliferation. These biological studies revealed products modulating immune responses.
Animal models of anxiety and the development of novel anxiolytic drugs.
1. The behavioural effects of classical anxiolytics such as barbiturates and benzodiazepines have been well characterised. However, recent research has been aimed at the development of novel anxiolytics without problems of sedation, muscle relaxation, amnesia and dependence. 2. A number of novel omega (benzodiazepine) receptor ligands with anxiolytic properties have been described including alpidem, bretazenil, suriclone and abecarnil. Although these compounds share some behavioural effects with older anxiolytic drugs, such as increasing punished drinking, they also show many differences. Their novel profiles may be related to low intrinsic activity or to selectivity for omega receptor subtypes. 3. The possibility that novel anxiolytics may be found among compounds active at serotonin receptors remains a strong hypothesis. Compounds, which, like buspirone, are active at 5HT1A receptors may be anxiolytic as may be antagonists at 5HT2 and 5HT3 receptors. All these compounds have behavioural effects which differ from those of benzodiazepines. 4. In order more effectively to screen for and develop novel anxiolytics it will be necessary to refine behavioural models in the light of feedback from the clinic.
Anti-acetylcholine receptor antibodies in neonatal myasthenia gravis: heterogeneity and pathogenic significance.
Precipitating, blocking and modulating anti-AChR antibodies and their capacity to recognize embryo or adult muscle were investigated in parallel in maternal and neonatal sera of fifty-two newborns and their myasthenic mothers. Twenty-four babies presented neonatal myasthenia gravis (NMG) with a common expression in twenty cases and foetal involvement in four cases. Occurrence of NMG was clearly related to levels of maternal precipitating, decamethonium blocking (DC blocking) and modulating antibodies (respectively P less than 0.001, P less than 0.02, P less than 0.01, Mann-Whitney test), these three parameters being interrelated. The only significant difference between mothers with severely affected babies and others with mild NMG newborns concerned DC blocking antibodies. Transfer fraction of DC blocking antibodies was significantly higher in NMG than in asymptomatic babies. Our data suggest that (1) the amount of anti-AChR antibodies, whatever the tested category, is involved in the pathogeny of NMG in a more direct manner than in adult MG where the correlation with their levels is poor, and (2) among antibodies, those with blocking effects could be preponderant for triggering NMG and be involved in the severity of the disease in the child.
[Diagnostic and therapeutic problems of aorto-enteric fistulas caused by aortic prostheses. 5 surgical cases of which 4 were successful].
The clinical characteristics, surgical treatment and therapeutic results, were surveyed in 5 cases of aorto-enteric fistulas observed in 650 abdominal aortic reconstructive operations in ten years. The fistula concerned the duodenum in two cases, the jejunum in one and the ileum in two cases. Two patients were treated by removal of the prosthesis and an axillofemoral bypass, one by an axillofemoral shunt only and the two others by repair of the graft. One patient died a few days after the operation, another eighteen months later. The prognosis of aorto-enteric fistulas after aortic reconstructive surgery is often bleak. It should be improved by an early diagnosis, supported by anamnestic history and an upper endoscopy. An aggressive surgery, whose modalities are discussed, gives maximum chances of success.
Differences in pharmacological profiles of a new generation of benzodiazepine and non-benzodiazepine hypnotics.
The hypnotics, quazepam (a benzodiazepine), brotizolam (a thienotriazolodiazepine), zopiclone (a cyclopyrrolone) and zolpidem (an imidazopyridine) have a common ability to bind to the benzodiazepine recognition site (omega receptor) within the GABAA receptor. For this reason we compared their pharmacological profiles in mice. All compounds shared anticonvulsant and central depressant effects. However, the sedative activity of zolpidem appeared at much lower doses than did the anticonvulsant and myorelaxant effects but the opposite was observed with the other hypnotics. In contrast to brotizolam, quazepam and zopiclone, zolpidem did not increase food intake in mice placed in a novel environment, indicating that this drug lacks disinhibitory activity. Moreover the efficacy of zolpidem at the GABAA receptor, as indicated by its activity against convulsions induced by the GABA synthesis inhibitor, isoniazid, was much greater than that of other hypnotics. These results suggest that the hypnoselective properties observed with zolpidem might be related to a high selectivity for the omega 1 recognition site of the GABAA receptor coupled with a very high intrinsic activity.
Pharmacological and behavioral profile of alpidem as an anxiolytic.
Pharmacological and behavioral studies in mice and rats have shown that the imidazopyridine alpidem possesses anxiolytic activity with a profile which is substantially different from that of benzodiazepines. Thus, in mice, alpidem inhibited marble-burying behavior and enhanced feeding under stressful conditions, as did benzodiazepines; in contrast to these drugs, however, alpidem was inactive against shock-induced fighting and shock-suppressed exploration. In rats, alpidem exerted anticonflict activity in the punished drinking test, but failed to antagonize punishment-induced inhibition of operant behavior. Moreover, in rats trained to discriminate chlordiazepoxide from saline, alpidem did not produce a benzodiazepine-like interoceptive stimulus. Alpidem also produced anticonvulsant effects in a variety of tests sensitive to benzodiazepines. However, the order of potencies against convulsions induced by different convulsive agents was different from that of the benzodiazepines. Alpidem decreased motor performance in the rotarod test and only produced a deficit in muscle strength at doses which were more than 20 times higher than the doses active in anxiolytic tests. Moreover, alpidem did not interfere with the acquisition of conditioned fear, except at very high doses, indicating a weak potential to impair memory. The effects of alpidem were antagonized by flumazenil, indicating that central omega receptors are involved in the action of this drug. The weak sedative effects of alpidem may be attributed to its low intrinsic activity, as demonstrated by its low efficacy in increasing latency to isoniazid-induced convulsions.