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.

Differing effects of antiinsulin serum and antiinsulin receptor serum on 123I-insulin metabolism in rats.

Anesthetized rats were treated with saline, antiinsulin receptor serum, or antiinsulin serum, and the biodistribution of high pressure liquid chromatography-purified 123I-Tyr A14-insulin was studied by scintillation scanning. Time activity curves over organs of interest were calibrated by sacrificing the rats at the end of the experiment and directly determining the radioactivity in the blood, liver, and kidneys. Saline-treated rats exhibited normal insulin biodistribution. The highest concentration of 123I-insulin was found in the liver, and reached 30% of total injected dose between 3 and 5 min after injection. After this peak, activity rapidly decreased with a t1/2 of 6 min. Activity of 123I-insulin in kidney showed a more gradual rise and fall and was approximately 15% of injected dose at its maximum. In rats treated with antiinsulin antiserum, insulin biodistribution was markedly altered. Peak liver activity increased with increasing antibody concentration with up to 90% of injected dose appearing in the liver. In addition, there was no clearance of the liver 123I-insulin over 30 min. Autoradiographic studies demonstrated that in contrast to the normal rats in which radioactivity was associated with hepatocytes, in rats passively immunized with anti-insulin serum, 125I-insulin was associated primarily with the Kuppfer cells. In contrast, antibodies to the insulin receptor markedly inhibited 123I-insulin uptake by the liver. Kidney activity increased, reflecting the amount of free 123I-insulin that reached this organ. This is similar to the pattern observed when insulin receptors are saturated with a high concentration of unlabeled insulin. Thus, both insulin antibodies and anti-receptor antibodies alter the distribution of insulin, but with very different patterns. The use of 123I-insulin and scintillation scanning allows one to study specific alterations in insulin distribution in animal models of insulin-resistant states, and should also be useful in human disease states.

Scintigraphic distribution of complexes of antiinsulin antibodies and 123I-insulin. In vivo studies in rats.

Clearance of immune complexes made of antiinsulin antibodies and 123I-insulin was studied with scintillation scanning in anesthetized rats. Complexes made with purified guinea pig antiinsulin IgG2 (cytophilic isotype) were rapidly cleared by the liver whereas those made with IgG1 remained in the plasma, as did 123I-labeled IgG1 or IgG2 of control animals. Hepatic clearance of insulin-antiinsulin IgG complexes was not inhibited by either an excess of insulin or decomplementation, thereby ruling out interaction with insulin and C3b receptors. Insulin and guinea pig antiinsulin serum or its purified IgG isotypes formed large aggregates exceeding 5 IgG. Antiinsulin antibodies of diabetics, mostly IgG1 and IgG3 (cytophilic isotypes), formed complexes that either remained in plasma (small aggregates) or were cleared by the liver (large aggregates). In conclusion, clearance of insulin-antiinsulin IgG complexes is probably mediated by Fc gamma receptors on macrophages and requires cytophilic subclass composition and formation of large IgG aggregates.

Dose-response relationship between plasma oxytocin and cortisol and adrenocorticotropin concentrations during oxytocin infusion in normal men.

We previously demonstrated that acute injection of a pharmacological dose of oxytocin (2 IU) in humans decreased the concentrations of ACTH and cortisol, a neuroendocrine action opposite that of vasopressin. In the present work the effect of continuous infusion of lower doses of oxytocin was tested. Plasma oxytocin was also measured using an oxytocin RIA to study the dose-response relation. Infusion of oxytocin (8 mIU/min for 30 min) resulted in a plasma oxytocin level of 9.9 +/- 1.4 (+/- SD) muIU/ml and induced a decrease in the plasma concentration of ACTH in three of four normal subjects. Infusion of oxytocin at the rate of 16 mIU/ml for 30 min resulted in plasma oxytocin level of 17.7 +/- 1.6 muIU/ml and decreases in plasma ACTH and cortisol concentrations in all six subjects tested. Increasing the oxytocin dose from 32 to 64 and 128 mIU/min for three additional 30-min periods induced more pronounced decreases in plasma ACTH and cortisol. In each subject, there was a highly significant inverse relationship between plasma oxytocin, and ACTH and cortisol (r = -0.85 to -0.99). During saline infusion, a significant inverse relationship with a 10-min lag period between plasma oxytocin and ACTH (r = -0.55) was found in only one of six subjects. These data demonstrate that infusion of exogenous oxytocin leading to plasma levels approximately 10 times higher than normal induced consistent decreases in corticotropic function. Because the oxytocin concentration in portal blood is approximately 300 times higher than that in peripheral blood, it is likely that the inhibitory action of oxytocin on ACTH secretion is of physiological significance.

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.

Diagnostic performance of basal free cortisol/18-hydroxy-11-deoxycorticosterone (18-OH-DOC) ratio in endogenous depression: comparison with the dexamethasone suppression test.

We assessed the 8:00 AM ratio of free cortisol/18-hydroxy-11-deoxycorticosterone (18-OH-DOC) in 56 endogenous depressive inpatients and in 22 normal volunteers. A ratio higher than 40 was associated with a diagnostic sensitivity for endogenous depression of 75%, a specificity of 95.5%, and a diagnostic confidence of 97.7%. These diagnostic results were at least equivalent to the Dexamethasone Suppression Test (DST) using a cortisol cut-off limit of 5 micrograms/dl. This may thus represent a simpler procedure than the DST in the diagnostic analysis of endogenous depression.

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.

Release of human neurophysin I during insulin-induced hypoglycemia in depressed patients is abolished after recovery with clomipramine treatment.

Release of human neurophysin I (hNp I) and neurophysin II (hNp II) during insulin-induced hypoglycemia was studied in 10 unipolar depressed women before and after 4-5 weeks of standard antidepressant drug treatment with daily intravenous infusions of clomipramine. Before treatment, a significant increase of hNp I but not of hNp II serum levels in response to hypoglycemia was observed. At retest during clomipramine administration, a marked clinical amelioration occurred in all patients as determined with the Hamilton Rating Scale for Depression; the hNp I response to insulin was abolished, but no effect on hNp II concentration could be demonstrated. No correlation was found between the degree of the depression score decrease and the amplitude of the inhibition of hNp I release or serum levels of clomipramine or its metabolite, desmethylclomipramine. The meaning of this difference in reactivity of the neurohypophyseal system in the course of depressive illness, based on the pharmacological and biochemical profiles of clomipramine action, is discussed.

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.

Initial study of methylclonazepam in generalized anxiety disorder. Evidence for greater power in the cross-over design.

The anxiolytic activity of methylclonazepam was compared to lorazepam and placebo in a double-blind, randomized cross-over study, using a latin square design, in 18 inpatients meeting Research Diagnostic Criteria for Generalized Anxiety Disorders. Patients presented at least 1 year of symptomatology and had a minimum score of 20 on the Hamilton Anxiety Scale, despite chronic anxiolytic pharmacotherapy. Daily dosage was flexible, from three to six tablets of methylclonazepam 1 mg, lorazepam 2.5 mg, or placebo. Clinical evaluation included Hamilton Anxiety Scale, Clinical Global Impression (CGI), a side-effects checklist, completed every 2 days, and the global preference of the patient for one of the treatment periods. Results showed a highly significant superiority of both benzodiazepines over placebo on the Hamilton Scale (P less than 0.000001) and CGI (P less than 0.001), and also a significant superiority of methylclonazepam over lorazepam on the Hamilton Scale (P less than 0.01), CGI-1 (P less than 0.01), and in the number of patient preferences (14 versus 1; P less than 0.001), with no significant differences in side-effects or related to position in the trial. These results support the value of the cross-over design in chronic and severe anxious inpatients for the demonstration of differences in efficacy between anxiolytic pharmacotherapies.

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.

Prediction of cortisol response to dexamethasone from age and basal cortisol in normal volunteers: a negative study.

The dexamethasone suppression test (1 mg at 23 h and 4 P.M. blood collection) was performed in 22 normal subjects. In contrast to a previous study using 0.5 mg dexamethasone and a 8-9 A.M. post-dexamethasone blood sample, age and basal cortisol level did not significantly predict postdexamethasone cortisol levels.

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.

Controlled comparison of two doses of milnacipran (F 2207) and amitriptyline in major depressive inpatients.

A multicenter study compared the antidepressant efficacy and the tolerance of two doses of milnacipran (50 mg and 100 mg/day) and amitriptyline (150 mg/day) in three parallel groups of 45 major depressive inpatients defined by Research Diagnostic Criteria. After a wash-out period of 4-7 days on placebo with lorazepam and/or nitrazepam if necessary, patients were randomly assigned to a daily dose of milnacipran 50 mg, milnacipran 100 mg or amitriptyline 150 mg reached on the 5th day and then stable over a 4-week period, with weekly assessments by means of the Montgomery and Asberg depression scale, the Hamilton depression scale, the Clinical Global Impressions (CGI) and the Target Emergent Signs and Symptoms. Results showed significant superiority of both milnacipran 100 mg/day and amitriptyline over milnacipran 50 mg/day at the end of the treatment period. However, amitriptyline induced a nonsignificant trend toward more rapid improvement after 2 weeks of treatment, mainly based on items related to insomnia, supporting more sedative properties of amitriptyline as compared to milnacipran. Anticholinergic side-effects were significantly lower with milnacipran than with amitriptyline, explaining why milnacipran 100 mg exhibited at the end of the treatment period, a nonsignificantly better efficacy index on the CGI. Moreover, in contrast to milnacipran, amitriptyline was responsible for a significant decrease in blood pressure and a significant weight gain.

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.

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.

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.

Evaluation of the sedative properties of PK 8165 (pipequaline), a benzodiazepine partial agonist, in normal subjects.

The sedative properties of two doses (50 and 150 mg) of a benzodiazepine partial agonist, PK 8165 (pipequaline), were compared to diazepam 10 mg and placebo in 12 normal volunteers. The assessment, performed before drug intake and 2 and 5 hours after drug intake, included a battery of visual analogue scales and standardized computerized tests (labyrinths, series of digits, colour test, and Zazzo test). Results showed that, at low dose, PK 8165 is not only devoid of any sedative effect but presents psychostimulating properties. In contrast, diazepam 2 hours after intake and PK 8165 150 mg, 5 hours after drug intake induced a significant decrease in performance compared to placebo. This study suggests that small doses of PK 8165 merits further development as an anxiolytic/psychostimulating drug devoid of sedative properties.

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.

A correlation study of contingent negative variation, reaction time, and EEG power spectrum in control and psychopathological populations.

Contingent negative variation (CNV), reaction time (RT), and EEG power spectrum were measured in a group of 27 neurotics and 26 controls subjects, male and female, aged 18 to 38. CNV was recorded with a 1 sec interstimulus interval and averaged over 48 trials. Two spectral analyses of the EEG were performed, the first during the 1 sec period preceding S1 (spontaneous EEG), the second during the S1-S2 interval (activated EEG). For each group of subjects, we calculated the correlations between four measures of CNV amplitude, RT duration, and the relative powers of the delta, theta, alpha and beta activities during spontaneous and activated EEG. In neurotic subjects there was an absence of correlation between the pre- and post-imperative segments of the CNV, and between early CNV amplitude and per cent alpha power. Both groups shared in common strong correlations relating CNV amplitude and RT length, on the one hand, and the different components of the EEG spectrum, on the other hand, Principal component analysis applied to the pooled data revealed different factors for CNV and EEG parameters, suggesting independence of the neurophysiological mechanisms implied in the two phenomena.