Oral lichen planus and neurogenic inflammation: new observations and therapeutic implications from four clinical cases.

Oral lichen planus (OLP) is a usually chronic and relapsing mucocutaneous disease with unknown etiology. Immunosuppressive treatment is sometimes unsatisfactory. We describe four cases of reticular OLP localized on the internal side of cheek, in the territory innervated by sensory free endings of the buccinator nerve, poorly responding to immunosuppressive treatment (topical/systemic corticosteroids, topical cyclosporin). Addition of prazepam 10 mg/day to standard therapy achieved significant improvement and clinical healing in 30-40 days. Because of the complex interplay between the nervous and immune systems, neuroinflammation, acting through conventional axon reflex and/or indirect reflex mechanism involving localized efferent vasodilatory parasympathetic fibers, could have an important pathogenic role in OLP. Such hypothesis could explain, at least partly, the spreading of lesions in OLP primarily triggered (and possibly sustained) by infections, irritants, or autoimmunity. Moreover, neuroinflammation could have a relevant role in OLP related to psychosomatic diseases, where the nervous component is the primary trigger and the main pathogen responsible for the lesions observed. Benzodiazepines modulate neuroinflammation through central, and, possibly, peripheral action. In OLP patients with mild/subclinical psychological conditions, low doses may effectively modulate neuroinflammatory pathways that are not always completely inhibited by immunosuppressive treatment and can contribute to the persistence of inflammation.

Contribution of neuroinflammation in burning mouth syndrome: indications from benzodiazepine use.

Characterized by burning and painful oral sensations in absence of clinically significant mucosal abnormalities, the burning mouth syndrome is, despite numerous researches made, basically idiopathic and, consequently, difficult to treat effectively. Therapy with tricyclic antidepressants and benzodiazepines has been proposed, although the exact pathomechanism is not clear. The objective of this study is to define the possible reasons for the efficacy of benzodiazepines in the treatment of the burning mouth syndrome. Starting from the report of eight cases successfully treated with prazepam, the present authors examined the clinical features and the evidence from literature that support the possibility of a role of neuroinflammation in the pathogenesis of the burning mouth syndrome. Available data suggest that the nervous system could be crucial in the pathogenesis of the syndrome (altered perception of pain, disturbance of neural transmission, increased excitability, negative involvement of trigeminal-vascular system), and the present authors' experience lets them suppose a role for neuroinflammation. This hypothesis could also explain the positive response to benzodiazepines in some patients. The important role of neuroinflammation in dermatologic and oral diseases has been only recently investigated and acknowledged. Further studies on the connection between neuroinflammation and burning mouth syndrome could open interesting perspectives in the understanding and management of this difficult clinical condition.

Induction of a mixed depressive episode during rTMS treatment in a patient with refractory major depression.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive experimental technique which has mostly been investigated in the treatment of mood disorders with possible efficacy in depression. Among its potential side effects, there have been some reports of rTMS-induced (hypo)mania in the literature but none for rTMS-induced mixed episodes. We report the case of a 39-year-old woman suffering from refractory chronic major depression who developed a depressive mixed episode associated with a mild serotonin syndrome during her second week of rTMS treatment. She was receiving a combination of antidepressants, the doses of which were kept unchanged during rTMS treatment. Mixed as well as manic episodes may be induced by transcranial magnetic stimulation, complications already observed with antidepressants and electroconvulsive therapy. Therefore, caution should be exercised among clinicians using this experimental procedure, particularly in the treatment of bipolar depressed patients.

[Comparative double-blind study of bromazepam versus prazepam in non-psychotic anxiety]. / Etude comparative en double insu du bromazépam versus prazépam dans l'anxiété non psychotique.

The efficacy of bromazepam and prazepam for the different components of anxiety: inhibition, asthenia and somatisation is evaluated in a multi-centric, comparative and randomised study, conducted as double blind and in parallel groups in 159 adult patients showing a manifest anxiety according to the F.D.A. criteria. After a 7 day wash-out period, the patients receive either bromazepam in a 12 mg/d dose or prazepam in a 40 mg/d dose, over 4 weeks (D0-D28), then in a decreasing dose from D28 to D43; follow-up is carried out using the anxious inhibition scale W.P.2, auto-questionnaire A.D.A., the Hamilton anxiety scale and the Tyrer questionnaire (benzodiazepine withdrawal symptoms questionnaire). Patients are evaluated seven times during the study: at day 7 for inclusion, day 0 for randomisation, then day 7 and day 14 for following visits, at day 28 for efficacy and tolerance evaluation, and at day 50 for utilisation and withdrawal evaluation. The major efficacy criteria are the evolution of inhibition, asthenia and somatisation as compounds of anxiety respectively evaluated by W.P.2 scale, asthenic partial score of autoquestionnaire A.D.A. and somatic partial score of Hamilton anxiety scale. The analysis of results don't show any significant difference between the two groups on the evolution of the components asthenia and inhibition. However the evolution of the somatic component clearly makes a significant difference in favour of bromazepam. There is also a significant difference in terms of global anxiolytic action efficacy, in favour of bromazepam.(ABSTRACT TRUNCATED AT 250 WORDS)

[Value of prazepam drops in the brief treatment of anxiety disorders]. / Intèrêt du prazépam gouttes dans le traitement bref des troubles anxieux.

In order to assess the clinical usefulness of benzodiazepine brief therapy with planned tapering, prazepam as drops was administered to 40 psychiatric outpatients suffering from generalized anxiety disorder. After a one-week placebo period, the patients received prazepam 40 mg daily (i.e., 10 drops in the morning, 10 drops at noon and 20 drops in the evening) during 3 weeks, with the possibility to adjust the doses after one week. The doses were then tapered at 4 mg/d (i.e., 1 drop in the morning, 1 drop at noon and 2 drops in the evening) until complete suppression of the treatment. The assessments, performed before the placebo period, at inclusion, after 1 and 3 weeks of active treatment, and after 1 and 2 weeks of tapering, included the Hamilton anxiety scale, the Lader tranquillizer withdrawal rating scale, and the collection of side effects; moreover, the patients completed daily a visual analogue scale. Results showed a very marked anxiolytic effect of prazepam with an already very significant decrease in the scores on the various scales after 1 week of treatment when the daily dose was significantly reduced. Three quarters of the patients were able to take part in the tapering of prazepam doses without exhibiting any reappearance of anxious symptomatology, rebound anxiety, or withdrawal symptoms. The tolerance of the treatment was rated as good or very good in 91.9% of the patients. This study demonstrates the possibility of a brief anxiolytic treatment followed by tapering in a majority of patients with generalized anxiety disorders. For this strategy, the availability of a drop form represents an obvious advantage.

[Prazepam drops versus 10 mg prazepam tablets in anxious patients in ambulatory care]. / Etude prazépam goutte versus prazépam comprimé 10 mg chez des patients anxieux traités en ambulatoire.

A multicentric study has been conducted with a new prazepam formulation (drop) which has been compared with 10 mg tablets. The aim of the study was to check the clinical equivalence of the two formulations. Nine generalists and 9 psychiatrists participated in this double blind study. One hundred fifty four patients with DSM III generalized anxiety criteria were included in this study and received prazepam at an average dosage of 20 mg per day. There were 11 drop outs: 6 in the tablet group and 5 in the drop group. The statistical analysis was done on 143 patients. Before treatment the two groups were equivalent. There was a very significant decrease (p less than 10(-4) in Hamilton anxiety scale scores, physician visual analogic scale and patient visual analogic scale with no difference between both groups. The vigilance, measured by the Mini-Folstein scale, was significantly increased (p less than 10(-4) in both groups. The tolerance was also similar: 14 patients in the tablet group and 10 in the drop one complained of asthenia and somnolence.

Comparison of sublingual and oral prazepam in normal subjects. II. Pharmacokinetic and pharmacodynamic data.

The pharmacokinetic profiles of oral and sublingual administrations of prazepam 20 mg to 5 normal volunteers were compared in order to explain the clinical observation that sublingual prazepam appears to exhibit sedative properties when compared to the same dose of oral prazepam. Blood samples for pharmacokinetic evaluation were collected just before drug intake and 7.5, 15, 22.5, 30, 45, 60, 90 min, 2, 3, 5, 6, 7, 8, 9, 10 and 24 h after drug intake. The study was performed in double-blind and crossover conditions. Serum levels of prazepam and its major metabolite N-desmethyl-diazepam were measured by HPLC. No prazepam was detected at a concentration higher than 20 ng/ml (limit of detection) whereas N-desmethyl-diazepam reached concentrations around 140 ng/ml. To correlate this observation with the clinical data, the affinity of prazepam and N-desmethyl-diazepam was compared measuring their ability to displace 50% of 3H-flunitrazepam bound to benzodiazepine receptors contained in synaptosomal preparation obtained from rat brain. N-desmethyl-diazepam was 17-fold more potent than prazepam. This data suggests that prazepam is a pro-drug which is transformed to the active compound N-desmethyl-diazepam and that the difference in clinical observation with both administrations could be correlated to N-desmethyl-diazepam concentration-time curves. Nevertheless, the comparison of the area under the N-desmethyl-diazepam serum concentration-time curves, the maximum concentrations, the times when the maximum concentrations were observed and the times needed to detect a significant level after oral and sublingual administration did not show statistical difference.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of sublingual and oral prazepam in normal subjects. I. Clinical data.

Five normal volunteers received at a 2-week interval a single dose of sublingual or oral prazepam in double-blind and cross-over conditions. All subjects completed a battery of 15 visual analogue scales before drug intake and 7.5, 15, 22.5, 30, 45, 60, 90 min, 2, 3, 5, 6, 7, 8, 9, 10 and 24 h following intake whereas a computerized assessment of vigilance (reaction time) was performed before intake, 15, 30, 60 min, 2, 3, 6, 8, 10 h following intake. Subjects rated themselves significantly more feeble, clumsy, lethargic, and incompetent following sublingual as compared to oral prazepam while a trend in the same direction was noted for the adjectives muzzy and mentally slow. In contrast, reaction time did not exhibit significantly different changes over time between the two forms. These results suggest a subjectively more rapid onset of activity following sublingual compared to oral prazepam.

Ranitidine versus ranitidine and prazepam in the short-term treatment of duodenal ulcer--a double-blind controlled trial.

Fifty out-patients with an active, endoscopically proven duodenal ulcer were entered a double-blind trial of ranitidine + prazepam or ranitidine + placebo. Two drop-outs occurred in the prazepam group and 1 in the placebo group. After 28 days of treatment, the ulcer had healed in 95.6% of the patients on ranitidine + prazepam and 75% of the patients on ranitidine + placebo (p = 0.03). Sleepiness was the most frequent side effect, reported by 8 subjects in the prazepam group and by 1 subject in the placebo group. It is concluded that prazepam can be usefully combined with ranitidine in the short-term treatment of duodenal ulcer.

Plasma concentrations and clinical effects after single oral doses of prazepam, clorazepate, and diazepam.

In a double-blind parallel-group pharmacokinetic and pharmacodynamic study, 31 healthy volunteers received single oral doses of prazepam (10 mg), clorazepate (7.5 mg), or diazepam (5 mg). Appearance in plasma of diazepam and of desmethyldiazepam was rapid after administration of diazepam and clorazepate, respectively, with peak plasma concentrations reached within an average of 1 hour. After oral prazepam, however, desmethyldiazepam appeared in blood slowly, with the highest mean concentration at 6 hours postdosage. Clinical self-ratings of fatigue and of "feeling spacey" were significantly different among groups, with changes over baseline being more marked with clorazepate and diazepam than with prazepam. Thus, differences in absorption rate of orally administered benzodiazepines can lead to differences in the intensity of single-dose effects, despite administration of doses that are equivalent in terms of long-term anxiolytic efficacy.

Duration of benzodiazepine clinical activity: lack of direct relationship with plasma half-life. A comparison of single vs divided dosage schedules of prazepam.

The anxiolytic activity and tolerance of two dosage schedules of prazepam, a long plasma half-life benzodiazepine, were compared under double-blind conditions in two groups of 10 inpatients each who met Research Diagnostic Criteria for Generalized Anxiety Disorder and presented chronic and severe symptomatology. Patients received prazepam 40 mg per day on one of two dosage schedules: divided dosage (DD) - 10 mg in the morning and at noon and 20 mg in the evening; or single dosage (SD) - 40 mg in the evening. The 3 weeks of therapy were preceded and followed by 1 week of wash-out for baseline and follow-up assessments, which were performed weekly with the Hamilton Anxiety Scale, Clinical Global Impression, rating of morning drowsiness and evening worsening of symptoms, and patient self-rating of anxiety by means of a visual analogue scale performed both in the morning and in the afternoon. The results showed a clear superiority of the DD over the SD schedule: better anxiolytic efficacy on the Hamilton Anxiety Scale (P less than 0.0005) and on both morning and afternoon visual analogue scales (P less than 0.01 and P less than 0.0002); less morning drowsiness (P less than 0.0001); and steadier anxiolytic effect during the daytime, as globally rated by the investigator (P less than 0.0001) or measured by morning-afternoon differences on the visual analogue scale (P less than 0.005). These results suggest that plasma pharmacokinetics alone may not be sufficient to predict the duration of benzodiazepine anxiolytic activity.

[Treatment of anxiety with prazepam, 40 mg. A controlled study versus lorazepam]. / Traitement de l'anxiété par le prazépam 40 mg. Une étude contrôlée contre le lorazépam.

Anxiolytic effects and tolerance of a four weeks treatment with prazepam (single dose of 40 mg in the evening) and with lorazepam (3 daily doses of 1.25 mg) are compared in a double blind study. Patients were treated by psychiatrists and were suffering from neurotic anxiety. Evaluation for therapeutic efficacy used a clinical global improvement scale and the Hamilton Anxiety Scale. Evaluation for side effects used the side effects symptoms check list. Anxiolytic effects of prazepam and lorazepam are not significantly different. Tolerance of the two treatments is comparable. The side effects are essentially an undesirable sedative action.

Clinical symptomatology and computer analyzed EEG before, during and after anxiolytic therapy of alcohol withdrawal patients.

In a double-blind study the clinical symptomatology and quantitatively analyzed EEG of 42 hospitalized chronic alcoholics (ICD 303) undergoing alcohol withdrawal were investigated before, during and after 3 weeks' treatment with 2 pharmacokinetically different benzodiazepines: the short-acting lopirazepam (a new pyridodiazepine) and the long-acting prazepam. At the end of weeks 1 and 3 the titrated optimal daily doses were 24 and 23 mg lopirazepam and 35 and 32 prazepam, respectively, thus confirming our earlier pharmaco-EEG predictions that on a mg to mg basis the former drug is slightly more CNS potent than the latter. Thereafter, the patient population was divided into 6 subgroups: 2 groups continuing on active medication, 2 groups receiving placebo, and 2 groups with no pharmacotherapy for 1 week. Clinical assessments included the CGI, the Hamilton Anxiety Score, the Zung Self-Rating Scale for Anxiety and Depression, the Zerssen Befindlichkeitsskala and the questionnaire for somatic findings and side effect and were carried out on days 0, 7, 21 and 28 as was a radioreceptor assay for benzodiazepines in plasma. Quantitative EEG investigations were carried out on days 0, 21 and 28 and included recordings before and 2 h after one single dose of 10 mg. Statistical analysis demonstrated a marked and highly significant decrease in psychopathology as well as good drug tolerance at the end of the first week of therapy and thereafter a slight continuation in improvement until the end of the 3rd week. There were, however, no statistically significant differences between the 2 active compounds, nor were there any statistically significant differences between the 6 subgroups in the 4th week. On the other hand, blood level investigations demonstrated that even after a 3-week treatment period, blood levels dropped down to a morning minimum 12 h after the last evening medication of the short-acting lopirazepam, while plasma levels of the long-acting prazepam remained high. This was also reflected in the spectral analyzed EEG, which showed, after one single dosage of both drugs, a typical anxiolytic profile which was more pronounced after lopirazepam than prazepam, while after the chronic administration (12 h after the evening medication) only prazepam showed an anxiolytic profile. The lopirazepam-treated patients exhibited on the one hand a lack of benzodiazepine-specific alterations, but showed on the other hand EEG changes possibly reflecting clinical improvement. The relevance of the findings will be discussed.

[Effect of prazepam on experimental hypertensive models].

Combined effects of prazepam and trichlormethiazide (TCM) which were given simultaneously were studied in renal hypertensive rats (1-kidney type) and DOCA hypertensive rats. In this study the blood pressure was measured by the plethysmographic method. Orally administered prazepam alone did not show any appreciable effect on the blood pressure, while TCM, even when administered alone, exhibited marked and long-lasting hypotensive effects of both hypertensive rats. In addition, the hypotensive effect of TCM was apparently potentiated by the concurrent use of prazepam. In the experiment where conscious and unconstricted spontaneous hypertensive rats (SHR) were used, the pressor response and tachycardia were observed when foot shock (acute stress) was loaded. This pressor response was the "all or none" type and a threshold existed. In contrast to the pressor response, the degree of tachycardia varied depending on the intensity of the stress. The similar responses were also observed in normotensive rats, although the degrees of the responses were significantly weaker than those in SHR. Prazepam given alone obviously suppressed the cardiovascular responses mentioned above. The present results suggest that prazepam is an useful drug for the treatment of hypertension.

Concentrations of N-descyclopropylmethylprazepam in whole-blood, plasma, and milk after administration of prazepam to humans.

After oral doses of 30 mg of prazepam to humans, N-descyclopropylmethylprazepam (desalkylprazepam, N-desmethyldiazepam) is the only major drug-related compound in plasma. Neither the parent drug, nor its major urinary metabolites were detected in plasma. The overall concentration-time profile of desalkylprazepam in the plasma of females was lower than, and significantly different (p less than 0.001) from that in the plasma of males. However, the mean peak desalkylprazepam concentrations in the plasma of females (265 ng ml-1 +/- 60 S.D.) were not significantly different (p greater than 0.05) from those in males (342 ng ml-1 +/- 60 S.D.). Concentrations declined in the plasma of either sex with similar half-lives (mean 60 h, range 37-93 h). Apparent plasma desalkylprazepam clearances were also similar (mean 60 h, range 37-93 h). Apparent plasma desalkylprazepam clearances were also similar (mean 1.09 l h-1), range 0.74-1.84 l h-1). At 12 h after the last of multiple doses of prazepam (60 mg d-1 for 3 days) to lactating women, mean plasma concentrations of desalkylprazepam were 823 ng ml-1 +/- 200 S.D. and declined with a mean half-life of about 60 h over the time-course studied. There was only slight uptake of desalkylprazepam into blood cells; plasma; whole blood concentration ratios were constant at about 1.6. Concentrations of desalkylprazepam in milk were low at about 10 per cent of the corresponding plasma levels (e.g. 86 ng ml-1 +/- 37 S.D. at 12 h). The data suggest that, expressed on a mg kg-1 basis, exposed neonates could receive about 4 per cent of the maternal dose of prazepam as desalkylprazepam.