Short course of grass allergen peptides immunotherapy over 3 weeks reduces seasonal symptoms in allergic rhinoconjunctivitis with/without asthma: A randomized, multicenter, double-blind, placebo-controlled trial.

BACKGROUND: Immunotherapy with peptide hydrolysates from Lolium perenne (LPP) is an alternative treatment for seasonal allergic rhinitis with or without asthma. The aim of this study was to assess the clinical efficacy and safety of a cumulative dose of 170 µg LPP administered subcutaneously over 3 weeks. METHODS: In a randomized, double-blind, placebo-controlled trial, 554 adults with grass pollen rhinoconjunctivitis were randomized (1:2 ratio) to receive 8 subcutaneous injections of placebo or 170 µg LPP administered in increasing doses in 4 visits over 3 weeks. The primary outcome was the combined symptom and medication score (CSMS) measured over the peak pollen season. Reactivity to conjunctival provocation test (CPT) and quality of life (QOL) was assessed as secondary endpoints. RESULTS: The mean reduction in CSMS in the LPP vs placebo group was -15.5% (P = .041) during the peak period and -17.9% (P = .029) over the entire pollen season. LPP-treated group had a reduced reactivity to CPT (P < .001) and, during the pollen season, a lower rhinoconjunctivitis QOL global score (P = .005) compared with placebo group. Mostly mild and WAO grade 1 early systemic reaction (ESR) were observed ≤30 minutes in 10.5% of LPP-treated patients, whereas 3 patients with a medical history of asthma (<1%) experienced a serious ESR that resolved with rescue medication. CONCLUSION: Lolium perenne pollen peptides administered over 3 weeks before the grass pollen season significantly reduced seasonal symptoms and was generally safe and well-tolerated.

The treatment of severe or recurrent deep venous thrombosis. Beneficial effect of the co-administration of antiplatelet agents with or without rheological effects, and anticoagulants.

Deep venous thromboses can be divided into two groups according to their pathogenesis, anatomical features and differing responses to therapy. The first and most frequent consists of so-called simple venous thrombosis while the second group, which is less common, comprises severe or recurrent venous thrombosis characterised by a multifactorial pathogenesis, a mixed thrombus rich in platelets and by an incomplete response to both prophylactic and therapeutic treatment with anticoagulants (heparin or vitamin K antagonist). In a randomized, prospective blind study in patients with severe or recurrent venous thrombosis, which included 6 groups each of 100 patients, co-administration of anticoagulants with various types of antiplatelet agent, either with rheological effects (piracetam, buflomedil, pentoxifylline) or without them (dipyridamole), has shown a beneficial potentiating antithrombotic effect with those drugs possessing rheological effects and the absence of this effect with dipyridamole.

Relationship between alpha 2-adrenergic function and suicidal behavior in depressed patients.

The current main neurochemical theories of the biological correlates of suicidal behavior involve serotonergic and, to a lesser extent, dopaminergic systems. Few data are available about the possible implication of the noradrenergic function. In the present study, we assessed the growth hormone response to clonidine, a selective alpha 2-adrenergic agonist, in 15 DSM-III-R major depressive inpatients with a history of suicide attempts, compared with 15 age- and gender-matched major depressive inpatients without a history of suicidal behavior. Mean (+/- SD) growth hormone peak responses to clonidine were significantly lower in the group of suicide attempters than in the control group: 2.93 +/- 3.01 ng/ml vs. 8.28 +/- 8.15 ng/ml. Therefore, these results suggest that a blunted growth hormone response to clonidine could be a biological correlate of suicidal behavior.

Treatment of the Raynaud's phenomenon with piracetam.

Piracetam (Nootropil, CAS 7491-74-9) has been investigated in the treatment of primary and secondary Raynaud's phenomenon in three sequential and complementary studies. The first study in 20 patients with primary Raynaud's phenomenon, utilising clinical and ultrasound examination, capillaroscopy and laboratory tests established a daily dose of 8 g as most effective. The second study in 58 patients (47 primary, 11 secondary) confirmed the therapeutic efficacy of piracetam in both primary and secondary Raynaud's phenomenon. The third study, of crossover design, in 30 patients with severe Raynaud's syndrome, examined various agents given singly or in combination. The results not only confirmed the efficacy of piracetam but in addition allowed comparison of the efficacy of the principal therapeutic agents or regimens used in the treatment of Raynaud's syndrome and the formulation of a list of these therapies in decreasing order of efficacy, thus: piracetam 4 g/d + buflomedil 600 mg/d; piracetam 8 g/d; buflomedil 600 mg/d; piracetam 4 g/d + acetylsalicylic acid 100 mg/d; pentoxifylline 1200 mg/d; calcium antagonists; ketanserin 120 mg/d. The particular efficacy of 8 g piracetam daily in 3 divided doses at 8-hourly intervals can be attributed to its unique dual mode of action; inhibition of platelet function by inhibition of thromboxane A2 synthetase or antagonism of thromboxane A2 and increased formation of prostaglandin I2, together with a rheological effect involving reduction in blood and plasma viscosity through an increase in cell membrane deformability and a reduction of 30-40% in the plasma concentrations of fibrinogen and von Willebrand's factor. In addition, the administration of piracetam appears to be devoided of adverse effects.

Platelet anti-aggregant and rheological properties of piracetam. A pharmacodynamic study in normal subjects.

The random administration of four different single oral doses of piracetam (Nootropil, CAS 7491-74-9)--1.6 g, 3.2 g, 4.8 g and 9.6 g--at fixed intervals of 2 weeks to 5 healthy subjects has confirmed and explicited its platelet anti-aggregant and rheological properties after doses of 4.8 g and 9.6 g. The effect on platelet aggregation occurs through inhibition of thromboxane synthetase or anti-thromboxane A2 activity together with a reduction in the plasma level of von Willebrand's factor (F.VIIIR:vW). The rheological effect is related to the action of piracetam on cell membrane deformability (red cells, white cells and platelets) and to its simultaneous effect in reducing by 30-40% plasma levels of fibrinogen and von Willebrand's factor. In addition, it exerts a direct stimulant effect on prostacyclin synthesis in healthy endothelium. These effects are greatest between 1 and 4 h after dosage, and then diminish progressively to disappear between 8 and 12 h after administration. This explains the need to divide the total daily dose into 3 intakes at 8-hourly intervals. This study confirms the presence of four sites of action of piracetam: the vessel wall, platelets, plasma and cell membranes (RBC, WBC), which provide the basis for the potentially important antithrombotic activity of piracetam.

Oral contraceptives and the dexamethasone suppression test.

Among other confounding factors, the influence of the intake of estrogen-containing oral contraceptives on the dexamethasone suppression test (DST) results has never been specifically studied. Therefore, we performed 1 mg DSTs in 14 healthy women taking oral contraceptives and 14 age-matched women taking no oral contraceptives. Mean 0800h basal total cortisol was significantly higher among the women taking contraceptives than in the control group, whereas mean free cortisol did not significantly differ. At 1600h following DST, no significant difference existed between the two groups. Two subjects taking contraceptives and one control subject were considered DST nonsuppressors. These results confirm the powerful influence of oral contraceptives on basal total cortisol levels but suggest a lack of significant influence on DST results.

Dopaminergic function in panic disorder: comparison with major and minor depression.

Several lines of evidence suggest that dopamine might be involved in anxiety states. In this study, we assessed the growth hormone (GH) response to apomorphine (a dopaminergic agonist) 0.5 mg SC in nine drug-free inpatients meeting Research Diagnostic Criteria (RDC) for panic disorder who were age-matched and gender-matched with nine major depressive, and nine minor depressive inpatients. The three groups differed significantly in their mean GH peak response: 5.29 +/- 2.75 ng/ml in major depressives, 26.27 +/- 12.71 ng/ml in minor depressives, and 37.28 +/- 10.58 ng/ml in panics, with a significantly higher response in panic than in either minor or major depressive patients. These results support dopaminergic overactivity in panic disorder as compared with major and minor depression.

Apomorphine stimulation of vasopressin- and oxytocin-neurophysins. Evidence for increased oxytocinergic and decreased vasopressinergic function in schizophrenics.

Apomorphine challenge tests (0.5 mg SC) were performed in 14 normal male volunteers and in 9 male schizophrenic inpatients, drug-free for at least 2 wk. In the normal volunteers, apomorphine induced an increase of serum growth hormone (GH) (maximum at 40 min), of vasopressin-neurophysin (hNpI) (maximum at 20 min), and oxytocin-neurophysin (hNpII) (maximum at 20 min). The release of neurophysins was independent of digestive side effects. In the schizophrenics, the GH level and release pattern were similar to those in the controls. The basal level of hNpI was reduced (t0: 0.42 +/- 0.1 ng/ml in the schizophrenics and 0.66 +/- 0.05 ng/ml in the controls, p < 0.02). In contrast, the basal level of hNpII was increased (3.34 +/- 0.04 ng/ml in the schizophrenics to 0.92 +/- 0.21 ng/ml in the controls, p = 0.001). The response to apomorphine was blunted, with no significant release of hNpI or of hNpII. Although the hNpII data are consistent with an increased dopaminergic tone, the psychopathological meaning of the increased basal oxytocinergic and decreased vasopressinergic functions remains to be defined.

[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.

Interest of a loading dose of milnacipran in endogenous depressive inpatients. Comparison with the standard regimen and with fluvoxamine.

A multicenter controlled study was designed to test the hypothesis that a loading dose of an antidepressant could shorten the latency of its clinical efficacy. Three parallel groups of about 40 endogenous depressive inpatients received either a loading dose of milnacipran (300 mg daily for 2 weeks and 150 mg daily during the 2 following weeks), the standard regimen of milnacipran in severe depression (200 mg daily for 4 weeks), or fluvoxamine (200 mg daily for 4 weeks). The duration of the study was 4 weeks, with assessments at baseline and after 4, 9, 14, 21, and 28 days of therapy by means of Montgomery and Asberg depression scale (MADS), the Hamilton depression scale, the Clinical Global Impressions (CGI), and a checklist of symptoms and side-effects. Results showed very similar evolution in the 3 treatment groups. In addition, the level of side-effects did not exhibit significant differences among the treatment groups, except for excitement-nervousness and akathisia which were more frequently reported with fluvoxamine. These results do not support the usefulness of a loading dose of an antidepressant such as milnacipran. They demonstrate however that milnacipran can be given at a 300 mg daily dose from the very first day of treatment with an excellent tolerance.

Pilot study of PK 11195, a selective ligand for the peripheral-type benzodiazepine binding sites, in inpatients with anxious or depressive symptomatology.

PK 11195 is a selective ligand for the peripheral-type benzodiazepine binding sites which exhibits anti-conflict activity in animals. In a pilot open study, PK 11195 was administered to 10 psychiatric inpatients characterized by a rating of at least "moderate" for the item "felt loss of vitality" and a rating of at least "moderate" for the items "anxiety" and/or "inhibition of drive" from the psychopathological scale of the system developed by the Association for Methodology and Documentation in Psychiatry (AMDP). The duration of the study was two weeks, with an initial daily dose of 200 mg of PK 11195 which could be increased up to 400 mg. Patients were assessed weekly using the psychopathological and somatic AMDP scales and at days 0, 4, 7, and 14 using the Hamilton anxiety scale and a checklist of symptoms and side-effects. The results showed significant improvement in the AMDP factor scores related to somatic complaints, depression, anxiety, apathy-retardation, and psycho-organic symptoms. However, anxiolytic activity, confirmed on the Hamilton anxiety scale, remained moderate and reached maximum effect after one week. No side-effects, drowsiness in particular, were reported. This study therefore suggests a potential beneficial activity of PK 11195 on anxiety and inhibition, which merits further investigation in controlled studies.

Controlled comparison of the efficacy and safety of four doses of suriclone, diazepam, and placebo in generalized anxiety disorder.

The anxiolytic activity and tolerance of four doses of suriclone (0.1, 0.2, 0.3 and 0.4 mg tid), diazepam (5 mg tid), and placebo were compared in six parallel groups of 54-59 outpatients with generalized anxiety disorder (DSM III-R). After a 1-week placebo run-in period, the patients were treated for 4 weeks, with assessments at baseline and after 1, 2, and 4 weeks by the Hamilton anxiety scale and the Clinical Global Impressions. Results showed better improvement with active drugs as compared to placebo, without significant differences among the four different doses of suriclone and diazepam. The number of adverse events, particularly drowsiness, was significantly higher with diazepam than with suriclone, particularly 0.1 and 0.2 mg tid which did not differ from placebo. These results demonstrate that suriclone at daily doses ranging from 0.1 to 0.4 mg tid is an effective anxiolytic, better tolerated than diazepam.

The determination of megakaryocyte ploidy.

Methods which have been used to determine megakaryocyte ploidy in animals and humans are reviewed. Although the number of megakaryocyte nuclear units counted in bone marrow squashes is roughly proportional to ploidy, accurate determinations of DNA content require the use of microphotometry or flow cytometry. New techniques should make it possible to distinguish polyploidizing megakaryoblasts from promegakaryocytes and mature megakaryocytes which have arrested polyploidization. Only the latter should be included in histograms of the number of endoduplications, since only those have expressed their full polyploidization potential. Statistical techniques are available for analysis and comparison of both raw ploidy distributions or histograms of endoduplication numbers.

Cerebral glucose utilization during sleep-wake cycle in man determined by positron emission tomography and [18F]2-fluoro-2-deoxy-D-glucose method.

Using the [18F]fluorodeoxyglucose method and positron emission tomography, we studied cerebral glucose utilization during sleep and wakefulness in 11 young normal subjects. Each of them was studied at least thrice: during wakefulness, slow wave sleep (SWS) and rapid eye movement sleep (REMS), at 1 week intervals. Four stage 3-4 SWS and 4 REMS fulfilled the steady state conditions of the model. The control population consisted of 9 normal age-matched subjects studied twice during wakefulness at, at least, 1 week intervals. Under these conditions, the average difference between the first and the second cerebral glucose metabolic rates (CMRGlu was: -7.91 +/- 15.46%, which does not differ significantly from zero (P = 0.13). During SWS, a significant decrease in CMRGlu was observed as compared to wakefulness (mean difference: -43.80 +/- 14.10%, P less than 0.01). All brain regions were equally affected but thalamic nuclei had significantly lower glucose utilization than the average cortex. During REMS, the CMRGlu were as high as during wakefulness (mean difference: 4.30 +/- 7.40%, P = 0.35). The metabolic pattern during REMS appeared more heterogeneous than at wake. An activation of left temporal and occipital areas is suggested. It is hypothetized that energy requirements for maintaining membrane polarity are reduced during SWS because of a decreased rate of synaptic events. During REMS, cerebral glucose utilization is similar to that of wakefulness, presumably because of reactivated neurotransmission and increased need for ion gradients maintenance.

Pooling two controlled comparisons of milnacipran (F2207) and amitriptyline in endogenous inpatients. A new approach in dose ranging studies.

Milnacipran is a new potential antidepressant selected for its equipotent inhibition of noradrenaline and serotonin uptake and its lack of effect at any postsynaptic receptor. We recently compared milnacipran 100 and 50 mg/d and amitriptyline 150 mg/d in three parallel randomized groups of major depressive inpatients and found a statistically significant superiority of milnacipran 100 mg/d and amitriptyline over milnacipran 50 mg/d after 4 weeks of treatment. Later on we found similar improvement with milnacipran 200 mg and amitriptyline 150 mg but better tolerance with milnacipran. In order to compare the therapeutic activity of the three doses of milnacipran (50 mg/d, 100 mg/d, and 200 mg/d) we used the responses to amitriptyline as a reference against which to compare the 3 doses of the new drug using analysis of variance on the adjusted data. This approach reveals milnacipran 200 mg is more effective than milnacipran 50 and 100 mg and is the only dose which shows efficacy at least equivalent to that of amitriptyline 150 mg. The dose/efficacy relationship was linear.

Psychopathological correlates of dopaminergic disturbances in major depression.

In a recent report, we confirmed the role of dopamine in the pathophysiology of depression by demonstrating a blunted response of growth hormone (GH) to apomorphine, a selective dopaminergic agonist, in endogenous depressive patients. Few data are available on the possible psychopathological correlates of disturbances in the apomorphine test. In this study, we assessed the relationship between GH response to apomorphine and the Minnesota multiphasic personality inventory (MMPI) scales in a sample of 20 major depressive inpatients. The GH response (area under the curve) after apomorphine injection was positively correlated with the social introversion scale scores (r = 0.56, df = 19, p less than 0.01) and the anxiety scale scores (r = 0.45, df = 19, p = 0.04). These results suggest dopaminergic overactivity in anxious psychopathology rather than in depressive psychopathology. The relationship between the social introversion scale score and the apomorphine test is in agreement with the dopaminergic hypothesis of schizophrenic disorders.

Controlled comparison of two anxiolytic benzodiazepines, cloxazolam and bromazepam.

The clinical activity and the tolerance of cloxazolam (4 mg/day), a new anxiolytic benzodiazepine, was compared to bromazepam (12 mg/day) in two parallel groups of 427 and 410 psychiatric outpatients, respectively. The duration of the study was 4 weeks with clinical assessments at inclusion and after 2 and 4 weeks of therapy by the Hamilton anxiety scale and visual analogue scales. While the Hamilton anxiety scale did not exhibit significant differences between the two benzodiazepines, visual analogue scales showed significant superiority of cloxazolam over bromazepam on psychological anxiety, somatic anxiety, depressed mood, and sleep, with a lack of significant difference related to the sedative effect, but less muscle-relaxant effect with cloxazolam than with bromazepam. The better efficacy and tolerance of cloxazolam compared to bromazepam was confirmed by the global assessments using visual analogue scales; moreover, a significantly larger proportion of patients in the cloxazolam group wanted to continue the same treatment.

Controlled comparison of buspirone and oxazepam in generalized anxiety.

The anxiolytic activity, the tolerance, and the withdrawal symptoms of buspirone and oxazepam were compared in two groups of 14 and 12 outpatients, respectively, suffering from generalized anxiety in a double-blind study with random allocation of patients. The 6-week active period was preceded and followed by 1 and 2 weeks on placebo, respectively. Clinical assessments were performed before and after the predrug placebo period and every 2 weeks thereafter and included Hamilton anxiety and depression scales and AMDP anxiety subscale. The initial daily dose was 15 mg buspirone or 45 mg oxazepam in 3 intakes and the mean final daily doses were 22.2 and 55.8 mg, respectively. Results showed a slower anxiolytic activity of buspirone compared to oxazepam with less improvement after 2 weeks of treatment. The rebound anxiety following abrupt discontinuation of the drug and the level of side effects did not significantly differ between the two compounds.